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ADVANCES IN RESPIRATORY AND CRITICAL CARE MEDICINE
RESPIRATORY DISORDERS
IN NEUROMUSCULAR DISEASE
MANAGEMENT AND PRACTICE PRINCIPLES
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ADVANCES IN RESPIRATORY
AND CRITICAL CARE MEDICINE
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ADVANCES IN RESPIRATORY AND CRITICAL CARE MEDICINE
RESPIRATORY DISORDERS
IN NEUROMUSCULAR DISEASE
MANAGEMENT AND PRACTICE PRINCIPLES
GIUSEPPE FIORENTINO
AND
ANTONIO ESQUINAS
EDITORS

Copyright © 2021 by Nova Science Publishers, Inc.
DOI: https://doi.org/10.52305/BJYU4836
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Library of Congress Cataloging-in-Publication Data

Names: Fiorentino, Giuseppe (Editor with Nova Science Publishers), editor.
| Esquinas, Antonio M., editor.
Title: Respiratory disorders in neuromuscular disease : management and
practice principles / Giuseppe Fiorentino, MD, UOC Fisiopatologia and
Respiratory Rehabilitation AO Dei Colli, Naples, Italy, Antonio
Esquinas, MD, Intensive Care Unit; Hospital Morales Meseguer, Murcia,
Spain, editors.
Description: New York : Nova Science Publishers, [2021] | Series: Advances
in respiratory and critical care medicine | Includes bibliographical
references and index. |
Identifiers: LCCN 2021050703 (print) | LCCN 2021050704 (ebook) | ISBN
9781536198904 (hardcover) | ISBN 9781685072704 (adobe pdf)
Subjects: LCSH: Respiratory organs--Diseases. | Neuromuscular diseases.
Classification: LCC RC731 .R4687 2021 (print) | LCC RC731 (ebook) | DDC
616.2--dc23/eng/20211102
LC record available at https://lccn.loc.gov/2021050703
LC ebook record available at https://lccn.loc.gov/2021050704
Published by Nova Science Publishers, Inc. † New York

CONTENTS
Preface ix
Introduction Overview of Neuromuscular Disorders (NMDs)
Affecting Respiratory Function 1
Giuseppe Fiorentino, Anna Annunziata and Antonio Esquinas
Section 1 Physiology Neuromuscular Disorders 23
Chapter 1 Respiratory Phenotypes of Pediatric Patients 25
Adele Corcione, Melissa Borrelli and Francesca Santamaria
Chapter 2 Respiratory Muscle Strength 47
Aditi S. Shah and Jeremy D. Road
Chapter 3 Cough Function Abnormalities 63
Mariano Mollica, Martino Flora, Elena Sciarrillo
and Salvatore Musella
Chapter 4 Diurnal Pulmonary Function Testing
in Neuromuscular Disorders 71
Francesca Simioli, Maria Martino and Sara Gioia
Section 2 Methodology/Non Invasive Ventilation 81
Chapter 5 Sleep Disorders in Neuromuscular Diseases 83
Michalis Agrafiotis and Paschalis Steiropoulos
Chapter 6 Initiation of Non-Invasive Ventilation
in Children with Neuromuscular Disease 95
Sherri Lynne Katz
Chapter 7 Initiation of NIV in Adults 109
Eugenio Sabato and Emanuela Profilo
Chapter 8 Modes of Ventilation 117
Asier Bengoechea Calafell and Salvador Díaz Lobato

vi Contents
Chapter 9 Interface, Mouthpiece, Nasal Face/Alternative Interface 131

Anna Annunziata, Maurizia Lanza,
Antonio Esquinas and Giuseppe Fiorentino
Chapter 10 Negative Mechanical Ventilation 147
U. Vincenzi
Chapter 11 Intermittent Abdominal Mechanical Ventilation 161
Paola Pierucci, Valentina Di Lecce and Onofrio Resta
Chapter 12 MPV and Other Emergent Therapies 169
Anna Annunziata, Ediva Myriam Borriello
and Giuseppe Fiorentino
Chapter 13 Noninvasive Ventilation 177
Nanette C. Joyce
Chapter 14 Continuous Noninvasive Ventilator Support 187
Fabrizio Rao, Marino Iatomasi and Lucia Greco
Chapter 15 Risk of Unsuccessful Non-Invasive Ventilation
in Neuromuscular Patients 203
Paola Pierucci, Andrea Portacci and Carla Santomasi
Section3 Monitoring 229
Chapter 16 Monitoring and Synchrony Ventilator Patients 231
Mariano Alberto Pennisi and Paolo De Santis
Section 4 Airways and Clearance 245
Chapter 17 Laryngeal Response Patterns during NIV
and Mechanically Assisted Cough 247
Tiina M. Andersen and Maria Vollsæter
Chapter 18 Tracheostomy Timing and Choice of Cannula 259
Piero Ceriana and Cinzia Lastoria
Chapter 19 Cough Management 271
Alexander Müller
Section 5 Methodology/ Invasive Ventilation 285
Chapter 20 Invasive Ventilation 287
David Orlikowski
Chapter 21 Weaning from Mechanical Ventilation and Extubation 301
Piero Ceriana and Cinzia Lastoria
Chapter 22 Ventilatory Dependent Patient’s Unweanable Conditions 311
A. Marotta, R. Maffucci and G. Cioffi

Contents vii
Section 6 Perioperative Respiratory Management 319

Chapter 23 Perioperative Respiratory Management
of Pediatric Patients with NMD 321
Domenico Faticato
Chapter 24 Anesthetic Considerations for Neuromuscular Diseases 331
A. Corcione, L. Bucci and C. Esposito
Chapter 25 Management of Acute Respiratory Failure in Pregnancy 345
Antonietta Coppola, Giuseppe Fiorentino
and Antonio Esquinas
Chapter 26 Cardiac Manifestations of Neuromuscular Disease 359
Gerardo Nigro, V. Russo, A. Rago and A. A. Papa
Chapter 27 Therapy of Scoliosis in Neuromuscular Pathology 377
Valerio Pipola, Konstantinos Martikos,
Emanuela Asunins and Alessandro Gasbarrini
Section 7 Diagnosis Approach in Neuromuscular Disorders 389
Chapter 28 Imaging Techniques in NMD 391
Tullio Valente and Roberta Lieto
Chapter 29 Sonography in the Evaluation of the Disease 407
Salvatore Guarino, Christina Anne Jelly and Tullio Valente
Chapter 30 Vocal Cord Dysphonia and Sialorrhea 423
Raffaele Dubbioso and Rafael Soler
Chapter 31 Screening and Evaluation Tools
of Dysphagia in Neuromuscular Disorders 443
Maria Rosaria Valentino, Gerardo Langella
and Valentina Di Spirito
Chapter 32 Aspiration Treatment and Decisional Algorithm 453
Maurizia Lanza
Chapter 33 Infections in Neuromuscolar Disease Patients:
A Point in the Right Direction 463
Novella Carannante, Eugenio Piscitelli
Chapter 34 Nutritional Support in Neuromuscular Diseases 471
D. Tammaro, M. Rispoli and A. Corcione
Section 8 Pulmonary Rehabilitation 483
Chapter 35 Respiratory Muscle Training in Children
and Adults with Neuromuscular Diseases 485
Paolo Buonpensiero and Emilia Privitera

viii Contents
Chapter 36 Prevention of Pulmonary Morbidity 495

Barbara Garabelli and Emilia Privitera
Section 9 Home Mechanical Ventilation 511
Chapter 37 Discharge Planning from Hospital
to Home Mechanical Ventilation 513
Salvador Díaz Lobato, Asier Bengoechea Calafell
and Johanny Vargas
Chapter 38 Home Mechanical Ventilation 523
Giorgio Emanuele Polistina,
Pasquale Imitazione and Vittoria Graziani
Section 10 Outcome 531
Chapter 39 Cause and Outcome of Acute
Neuromuscular Respiratory Failure 533
Saint-Clair Bernardes Neto and Antonio Sarmento
Section 11 Health Care and Ethical Aspects 541
Chapter 40 The Caregiver Formation 543
Fabrizio Rao and Alice Pirola
Chapter 41 The Role of Non Invasive Ventilation in Quality
of Life in Neuromuscular Diseases 557
E. Volpato, F. Pagnini and P. Banfi
Chapter 42 Telemonitoring 567
Giancarlo Garuti, Jacopo Garuti and Alessia Zanoli
Chapter 43 Palliative Care 579
Salvador Díaz Lobato, Sagrario Mayoralas
and Johanny Vargas
Chapter 44 End-of-Life Care 593
Francesca Trojsi, Giulia D’Alvano and Gioacchino Tedeschi
Chapter 45 Ethical and Medico-Legal Aspects 603
Nicoletta Carmine, Spinelli Sara and Cauteruccio Rosa
Editors’ Contact Information 611
Index 613

PREFACE
Over the years, the life expectancy of patients with neuromuscular disease has
improved thanks to new knowledge and technological innovations. This new book is
entirely dedicated to the knowledge of the complex and unique profile of patients
suffering from neuromuscular pathology. Many key points are discussed by
specialists dedicated to neuromuscular patient care.
Respiratory support is often indispensable to sustain the patient’s life. Non-
invasive ventilation (NIV) has taken on an increasingly important role in the care of
patients with chronic respiratory failure secondary to neuromuscular disease. The
NIV approach and complementary techniques are described. The management of
airways and clearance of secretions are important aspects which are dealt with in a
dedicated session, and a new theme – laryngeal response pattern during NIV and
cough assist techniques – is also addressed.
The timing of the tracheostomy and choice of cannula are decisive in the
management of the neuromuscular patient, thus the use of invasive mechanical
ventilation. Topics of interest also include perioperative respiratory management,
weaning from mechanical ventilation and extubation.
The use of imaging techniques, such as videofluoroscopy of swallowing and
sonography can support the clinician in the diagnosis of complications. Today, even
pulmonary rehabilitation is an integral and indispensable part of patient care.
The text – developed with the contribution of experts dedicated to the daily care
of patients with neuromuscular disorders – is an ambitious project which aims to
provide an extensive discussion of the topic and support for those who already work
with this type of patient, as well as for those who are starting to engage in this type of
patient care.
Chapter 1 - Most neuromuscular diseases (NMDs) have a genetic basis and are
characterized by overt presentation in childhood. These include disorders affecting
the anterior horn cell, the peripheral nerve, the neuromuscular junction, the muscle
and also metabolic myopathies associated to congenital defects in glycogen, lipid, or
mitochondria metabolism. Weakness of the respiratory muscles associated to the act
of breathing is a clinical hallmark of NMDs, and results in the development of short-
or long-term sequelae. Although NMDs are heterogeneous, many lead to progressive

x Giuseppe Fiorentino and Antonio Esquinas
impairment of the function of the respiratory system including upper airway tone,
cough and secretion clearance and chest wall support. Respiratory symptoms and
signs which may also occur very early and are often severely disabling or
significantly impact on the disease course and the final outcome. Studies that assess
the potential to improve quality of life and reduce hospitalizations and frequency of
lower respiratory tract infections will help clinicians to decide which techniques are
best suited for use in children. As children with NMDs survive longer, coordinated
programs for transitioning these patients to adult care must be developed to enhance
their quality of life. This chapter examines issues related to the different respiratory
phenotypes of the congenital NMD at different pediatric ages, and summarizes the
work-up that physicians should plan to investigate the associated respiratory
disease.
Chapter 2 - Respiratory muscle impairment can occur in a wide range of
neuromuscular conditions ranging from disorders of the spinal cord, neuromuscular
junction, upper and lower motor neurons and of the muscle. Assessment of
respiratory muscle strength informs us about severity of muscle weakness,
progression of disease, prognosis and helps guide management of neuromuscular
patients. In particular, it helps identify patients that are at risk of hypoventilation and
respiratory complications due to poor respiratory reserve allowing for an initiation of
appropriate support strategies such as non-invasive ventilation. Respiratory muscle
weakness can be identified based on physical exam features, imaging and
objectively through various volitional and non-volitional measurements. Imaging
modalities such as chest fluoroscopy, diaphragm ultrasound and volitional tests of
respiratory muscle strength such as supine and sitting spirometry, mouth and nasal
pressure measurements are more commonly utilized in clinical practice. Non-
volitional tests such as phrenic nerve stimulation and cervical magnetic stimulation
provide valuable objective information about diaphragm function but are primarily a
research tool due to various reasons that are discussed in this chapter. This chapter
will provide insight into various tests that can be utilized to measure respiratory
muscle strength including their performance, advantages and limitations and clinical
application.
Chapter 3 - Cough, a vital respiratory reflex, is considered as the most common
experienced respiratory symptom which ensures airways to be cleared from mucus,
secretions, and foreign bodies. For cough reflex to occur, several structures, such as
receptors, neuronal pathways, muscles, are harmoniously recruited. Failure of cough
reflex does have dramatic consequences. In subjects affected by neuromuscular
diseases, onset of cough reflex abnormalities emerges as a crucial turning point. As
airways are no more successfully cleared, subjects become prone to developed lung
infections, chronic pneumonia, and, lastly, respiratory failure. In this scenario, a
prompt detection of cough reflex abnormalities is of strategic importance. This
chapter gives an insight into the physiology of cough reflex; moreover, it discusses
the clinical implications of cough reflex abnormalities in patients affected by
neuromuscular diseases and how they may be clinically and functionally assessed in
these subjects.

Preface xi
Chapter 4 - Respiratory complications are common in subjects affected by

neuromuscular diseases (NMD). Muscle weakness can lead to ineffective cough.
Furthermore the ventilatory pump dysfunction eventually causes respiratory
failure. Objective pulmonary function testing is crucial at the time of diagnosis and
throughout the disease progression. Primary tools are: dynamic and static lung
volumes assessment, respiratory muscle strength measurement, peak cough flow
and diurnal blood gas analysis.
Chapter 5 - Sleep is a state of increased physiologic vulnerability associated with
impairments in gas exchange and blunted ventilatory control. These changes are
particularly prominent during the rapid eye movement (REM) sleep. Involvement of
respiratory muscles in patients with neuromuscular diseases (NMDs) initially
manifests in the form of sleep-disordered breathing events including “pseudocentral”
hypopneas, sleep hypoventilation, obstructive and central apneas/hypopneas and
periodic breathing. These changes are compensated by the recruitment of accessory
inspiratory and expiratory muscles and with the reduction or abolishment of REM
sleep. The implementation of noninvasive ventilatory support during sleep can
improve quality of sleep, quality of life and survival, and can additionally alter sleep
respiratory physiology by inducing glottic closure, changes in ventilatory drive and
various asynchronies. Non-respiratory sleep problems are also frequently reported in
patients with NMDs.
Chapter 6 - The advent of non-invasive ventilation (NIV) has changed the
prognosis and outcomes of children with neuromuscular disease dramatically, as
respiratory failure has traditionally been the main cause of morbidity and mortality in
this population. NIV has had one of the single greatest impacts on longevity for
children with neuromuscular conditions, compared to other existing therapies. It
improves gas exchange, reduces hospitalization rates for respiratory infections and
improves quality of life for children with neuromuscular disease.
Chapter 7 - Neuromuscular diseases (NMDs) patients are characterized by an
increased risk of lung complications and, throughout the natural history of the
disease, they present chronic respiratory failure (CRF); CRF is the most common
cause of morbidity and mortality in patients with rapidly progressive NMDs, such as
Amyotrophic Lateral Syndrome (ALS). For this reason, an increasing number of
patients are successfully subjected to non-invasive ventilation (NIV). NIV has
become a fundamental therapeutic strategy for the symptomatic treatment of ALS,
leading to a marked improvement in survival, quality of life, and cognitive
performances. It’s generally accepted that NIV should be initiated in advanced
stages of the disease when the clinical symptoms of CRF are evident. However,
recent studies have shown that initiating NIV at an early stage of the disease could
bring greater benefits by highlighting that ventilatory treatment should be an election
and not an urgent choice. In this context, a wide variety of diagnostic measures, like
Forced Vital Capacity (FVC), Nasal Inspiratory Pressure (SNIP), Maximum
Inspiration (MIP) and Expiratory Pressure (MEP), and analysis of arterial blood gas
should be evaluated to improve the early diagnosis of respiratory decline and to
intervene promptly. This chapter is meant to provide an overview of the most recent

xii Giuseppe Fiorentino and Antonio Esquinas
developments and insights about indication criteria and initiation of NIV in adult
NMDs patients, focusing on ALS patients.
Chapter 8 - Respiratory muscle weakness is the main contributor to respiratory
imbalance in patients with neuromuscular diseases (NMDs). In the advanced stages
of the disease, patients develop a chronic respiratory failure due to muscle
weakness, which is the principal cause of death among these patients. Respiratory
muscle weakness ultimately causes alveolar hypoventilation, initially nocturnal, and
later daytime respiratory failure.
Chapter 9 - In the last decades many new interfaces have been developed and
interfaces such as mouthpiece and armor have been further implemented thanks to
the evolution of software. These advances have allowed the clinician today to have a
wide choice, such as to be able to optimize the treatment for each individual patient
and pathological condition. For those who approach non-invasive mechanical
ventilation it is necessary to be clear about all the possible interfaces and
complications related to their use.
Chapter 10 - Negative pressure ventilation (NPV) has its origin in the first device
created by P. Drinker and A. Shaw in the 1930s and was the main mode of
ventilation until the 1950s. We would like to mention the principles of ventilatory
mechanics involved in extra-thoracic negative ventilation and the non-invasive and
intermittent characteristics of NPV which have ensured the treatment, even for years,
of patients with severe chronic respiratory insufficiency. Today it is used, albeit not as
a first choice, in the treatment of neuromuscular diseases, kyphoscoliotic alterations
of the spine, respiratory insufficiency in adults and children and, experimentally, also
in ARDS. The main advantages of NPV are non-invasiveness, compliance with
physiological ventilation, reduction of inspiratory intra-thoracic pressures with the
absence of barotrauma, the possibility of suspending and resuming, several times a
day, even intensive ventilation. The disadvantages are often related to the
characteristics of the patient (e.g., severe obesity, claustrophobia, recent surgery on
the abdomen and chest, presence of tracheostomy, obstructions of the upper
airways) or of the ventilator (size and weight of the ventilators, need of assistance in
case of the iron lung).
Chapter 11 - Non-invasive ventilatory support (NVS), has become the focus of
respiratory failure treatment, especially in chronic restrictive chest diseases. It is
based on applying a pressure difference across the lung. This is possible either using
positive pressure ventilators so that high air pressures is transferred directly to the
airways, or by using negative pressure ventilators. In the latter case the pressure is
applied outside the body (i.e., to the chest, to the abdomen or the whole body) and
indirectly transferred to the pleural space. In patients with ventilatory pump failure
due to progressive diseases noninvasive positive pressure ventilation (NPPV) via
continuous positive airway pressure (CPAP) or bi-level positive airway pressure (Bi-
Level, NIV), is widely applied in the treatment of nocturnal and sometimes diurnal
respiratory failure and it is also used for continuous noninvasive ventilatory support
(CNVS). In the context of CNVS, another niche role is played by the body ventilators.
They include negative pressure ventilators, such iron lungs, poncho, pneumo-suits,

Preface xiii
pneumo-wraps, and intermittent abdominal pressure ventilators (IAPV). The latter

one (IAPV) consists of an air-sack inside a corset inflated by a ventilator. The sack
compresses the abdomen to raise the diaphragm and to increase tidal volumes. It
represents a practical and comfortable alternative to daytime support with the patient
in a sitting position. Several applications in clinical practice have been studied over
time, confirming its usefulness as ventilatory support. This chapter will focus on
describing in more details this alternative ventilation technique.
Chapter 12 - Several conditions may also be responsible for the failure of NIV,
including claustrophobia, mask-induced skin lesions and rhinitis, non-tolerance of
pressure on the face. Other daytime NIV procedures should be considered in highly
ventilator-dependent patients in addition to mask ventilation. Mouthpiece ventilation
(MPV) is a type of non invasive ventilation delivered via a mouthpiece. MPV is used
for the first time on ventilator-dependent polio patient. MPV, as we know it today, is
used from many years, and there are already evidence in literature documenting
effectiveness of treatment and increased compliance by the patient. Despite this,
there is little knowledge and practicality of the use of non invasive mechanical
ventilation with mouthpiece.
Chapter 13 - Normal breathing depends on the intact function of the ventilator
pump, which consists of the central respiratory control centers, the bony rib cage,
and the muscles of breathing. In progressive neuromuscular diseases (NMDs), the
ventilator pump is often impaired due to characteristic muscle weakness with
contracture, stiffening the chest wall and increasing the work of breathing.
Respiratory failure, and, ultimately, death due to extra-parenchymal restrictive lung
disease with failure of the ventilator pump is a leading cause of mortality in patients
with NMDs.
Chapter 14 - In asymptomatic neuromuscular patients the primary cause of
hypoventilation seems to be an imbalance between a reduced muscular force and
the elastic load imposed on the respiratory system that therefore causes a
respiratory drive mechanical modification necessary to reduce dyspnoea symptoms
that involve the RSB onset that eventually causes a PaCO2 increase. Nocturnal
hypercapnia, frequently associated with respiratory sleeping disorders and daily
normocapnia possibly associated to daily symptoms such as morning cephalalgy and
hypersomnia in spontaneous breathing patients: these symptoms, associated to the
nocturnal exams, establish the beginning of nocturnal NIV in election. Consider daily
NIV when paCO2 > 45 mm Hg, despite optimization of nocturne NIV or daily
dyspnoea symptoms persist; evaluate different interfaces to prevent skin lesions;
evaluate different ventilation systems like MPV, IACP; pay attention to warning signs
to switch to invasive ventilation.
Chapter 15 - Non-invasive mechanical ventilation has been shown to be a
fundamental tool for the treatment of the respiratory failure in neuromuscular
diseases (NMDs) patients, both in acute and chronic settings. However, the
complications related to NIV failure are within important causes of death in NMDs
patients. Its use in the acute setting allows to improve gas exchange and the
ventilatory dynamic, reduces dyspnoea and respiratory load, avoiding intubation in

xiv Giuseppe Fiorentino and Antonio Esquinas
many cases. As for the chronic setting, non-invasive ventilation is helpful in order to
postpone tracheostomy and endotracheal intubation; moreover, it allows to improve
not only gas exchange and symptoms, but survival and quality of life and sleep.
However, many conditions can lead to a loss of NIV effectiveness and to NIV failure.
Identifying this conditions is necessary in order to ensure the best use and results of
NIV. This chapter focus on this topic with reference not just to the reasons and timing
of NIV failure, but also to the predictive factors of such failure describing possible
consequences and therapeutic alternatives both in the acute and chronic setting.
Chapter 16 - Clinical parameters monitoring is fundamental during noninvasive
ventilation (NIV) in neuromuscolar diseases (NMD) patients. The most relevant items
of clinical monitoring are the compliance with the interface, the assessment of
swallowing and gastrointestinal function, the evaluation of cough efficacy and
the consciousness-sensorium evaluation and delirium condition
identification. Assessment of the interface and NIV compliance is one of the most
important steps in NIV clinical monitoring. During NIV reduced tolerance to the
interface is associated with higher incidence of NIV failure and endotracheal
intubation.
Chapter 17 - Respiratory management of people with neurological disorders has
improved significantly during the two last decades. This positive development has
occurred for a range of reasons, primarily due to increased interest and knowledge
within the medical community, accompanied by technological advances. A better
understanding of the pathogenesis of chronic respiratory failure and the role played
by weak cough have been important. Nevertheless, especially patients with
Amyotrophic Lateral Sclerosis (ALS) and bulbar dysfunction are still been challenging
to treat successfully. More recently, understanding of laryngeal response patters
during respiratory treatment options, as Mechanical Insufflation-Exsufflation (MI-E)
and Non-Invasive Ventilation (NIV) indicates that treatment failure may be due to
disturbed laryngeal responses during the respiratory treatment. The larynx is located
in the throat and it is the gateway to the lungs. In respiratory therapy, the larynx is
recognized as an account holder of airflow limitation and turbulence to the lungs. The
larynx can sense both gas, liquids and solids, it is a highly active organ functioning
as a valve to the airways with major functions to control airflow during respiration, to
protect the lungs from aspiration and it plays a key role in phonation and in cough.
Symptoms of laryngeal dysfunction may mimic respiratory disease, as shortness of
breath and abnormal airway sounds. Laryngeal dysfunction leads to a risk of
pulmonary aspiration and pneumonia. The purpose of this chapter is to describe the
laryngeal function during breathing and response patterns to MI-E and NIV.
Chapter 18 - The work of breathing is the summation of elastic and resistive
work; in addition to different patient factors, the breathing apparatus, such as the
ventilator, circuit, and endotracheal or tracheostomy tube, can contribute to increase
resistive work. Tracheostomy tube type can change resistance to air flow during
inspiration and expiration, which may have important repercussions for airflow
dynamics and work of breathing in patients receiving artificial ventilation or during the
weaning procedure.

Preface xv
Chapter 19 - Background: Impaired cough function is one of the main reasons for
morbidity and mortality in patients with neuromuscular diseases (NMDs). Cough
augmentation techniques aim at compensating for ineffective cough. Purpose: To
investigate current evidence-based practice on the evaluation and management of
impaired cough function in patients with NMDs. Methods: Databases (PubMed,
CINAHL, JAMA Network, PEDro) were used to find recent publications on cough
augmentation techniques in NMDs. Literature findings were critically analysed and
summarised. Results: Regular measurement of cough function parameters including
peak cough flow, vital capacity, insufflation capacity, maximum expiratory pressure
and bulbar function is necessary to identify the relevant components of cough
impairment. The choice of cough augmentation techniques must be based on a
case-by-case analysis and no overall valid assumptions can be made of which cough
augmentation technique to use. Conclusions: Further research investigating the long-
term benefits and possible adverse effects of certain cough augmentation techniques
is needed. Special considerations need to be put on home-care setting and the
application of certain techniques by non-professionals.
Chapter 20 - Neuromuscular diseases represent a group of pathologies
characterized by a progressive muscular weakness that can involve respiratory
muscle. Home Ventilation is usually proposed for occurrence of alveolar
hypoventilation during nighttime and first non-invasively. Some diseases as
Duchenne Muscular dystrophy will evolve to full ventilator dependency conducting to
full time ventilation non-invasively or invasively. In other situations invasive
ventilation is proposed after acute respiratory failure. Invasive ventilation through a
tracheostomy tube was the first technique that allowed long term ventilation, survival
and discharge of NMD patients. Whatever the situation invasive ventilation require
adequate choice in term of type of ventilation, ventilator choice and interface in order
to preserve security, autonomy, speech and nutritional aspects in this population.
Chapter 21 - Approximately 40 per cent of patients admitted to the intensive care
unit (ICU) for acute respiratory failure (ARF) require mechanical ventilation, in the
majority of cases for pneumonia, congestive heart failure, sepsis, trauma,
postoperative ARF and acute respiratory distress syndrome (ARDS). With the
exception of a limited percentage of patients treated with non-invasive mechanical
ventilation (NIMV), the vast majority receive translaryngeal intubation and invasive
mechanical ventilation (IMV). Mechanical ventilation works as a bridge to maintain
adequate gas exchange until the restoration of the native respiratory system function.
Therefore, when the underlying cause of ARF starts to improve, liberation from
mechanical ventilation and removal of endotracheal tube become the main objectives
to achieve. The term “weaning” implies the transition from full artificial respiratory
assistance to unsupported spontaneous breathing through the native airways.
Chapter 22 - The pathologic processes involving the motor unit are the most
common cause of prolonged ventilator failure. There are three respiratory muscle
groups that progressively weaken in Neuromuscular Diseases (NMDs): the
inspiratory group, the expiratory group and the bulbar-innervated muscles. The latter
group protects the airways and permits the glossopharyngeal breathing (GPB) and

xvi Giuseppe Fiorentino and Antonio Esquinas
active lung volume recruitment (LVR). Neuromuscular disorders may affect ventilator
function through the involvement of the proximal muscle groups, including the
respiratory muscles. These may be involved selectively or as a part of a systemic
process. Conventional mechanical ventilation (MV) weaning is the process of
transition to spontaneous ventilation.
Chapter 23 - Pediatric patients affected by neuromuscular diseases who undergo
surgical procedures share the same respiratory failure risks regardless of their
underlying disease. These risks are added to those related to the specific disease.
Moreover, such patients usually face longer hospitalization and higher risk of in-
hospital morbidity. The muscular contractility impairment, whose clinical features vary
according to the localization of the primary lesion and which can be accompanied by
a bulbar dysfunction, causes a state of respiratory failure due to reduced ventilation
and impaired airway clearance mechanisms and to frequent inhalation episodes,
which determine a chronic inflammation of the airway epithelium. The possible
occurrence of perioperative complications demands a multidisciplinary integrated
management during the whole perioperative period, as well as a team of experienced
professionals, specific protocols for the most critical patients and the availability of
ventilation assistance devices.
Chapter 24 - Patients affected by pre-existing neuromuscular disorders who
experience scheduled or emergency surgery are known to be at risk for several
postoperative complications related, in most cases, to drugs administered
intraoperatively during the anesthesia period. Therefore a careful preoperative
assessment is paramount, aiming to reduce morbidity and also adverse outcome. In
particular, one of the major and feared risk is a postoperative respiratory failure
condition, with concomitant need for a long-term ventilation period; it appears a
preferred option, nowadays, that this scenario should be reviewed with the patient
and the relatives. The use of quantitative neuromuscular monitoring should be
strongly recommended whenever newer nondepolarizing neuromuscular blocking
agents (NBA) are administered, with pharmacological reversal disposable in the
anesthesiologist’s tool box. For this reason, as an example, several case series and
reports have been recently published suggesting that agent like sugammadex, as a
rapid reversal of NBA such as rocuronium, can be safely used in patients with
neuromuscular disease (NMD). Patients with NMDs are at high risk of intra-operative
and post-operative complications; in this view, a proactive, multidisciplinary approach
should be planned before, during and after any surgical procedure, requiring general
or regional anesthesia or even sedation. However, surgery in this patient population
should be performed in a well equipped institution having expertise in NMDs full
management.
Chapter 25 - Pulmonary physiological and anatomic changes during pregnancy
affect the overall management and predispose patients to complications during
respiratory illness. Patients with neuromuscular disease and severe respiratory
impairment, specifically when vital capacity (VC) is below 60% of predictions, are
often discouraged from becoming pregnant due to potential respiratory complications
and the possibility of the need for invasive ventilation and/or tracheostomy. During

Preface xvii
labour, pulmonary function can be decreased. The management of women in

pregnancy requires awareness of the inspiratory and expiratory muscle aids that can
be used to maintain alveolar ventilation and airway secretion clearance throughout
gestation, labour and delivery.
Chapter 26 - Neuromuscular diseases are a group of complex multisystem
disorders that commonly and prominently affect striated muscle. Cardiac involvement
in neuromuscular diseases namely conduction disorders, ventricular arrhythmias and
cardiomyopathy with its impact on prognosis, is often dissociated with the peripheral
myopathy. Therefore, close surveillance is mandatory in the affected patients. In this
context, preventive therapy has been recently recommended in the most common
neuromuscular diseases. This chapter focuses on the heart involvement of the
muscular dystrophies exhibiting prominent cardiac manifestations, including Myotonic
dystrophy type 1, Duchenne (DMD), Becker (BMD), Emery-Dreifuss (EDMD) and
Facio-Scapulo-Humeral muscular dystrophies.
Chapter 27 - Neuromuscular scoliosis are coronal plane deformities of the spine
that develop in patients with abnormalities of the myoneural pathways. The disorders
which cause this type of deformity comprise a group of diseases characterized by a
breakdown in the normal neural integrated pathway that includes brain, spinal cord,
peripheral nerves, neuromuscular junction and muscles. Patients affected by these
diseases usually have poor head control, lack of neck and trunk balance and
discoordination. Despite the wide spectrum of conditions that can lead to the
development of Neuromuscular Scoliosis, the final functional path to be altered is the
muscle unit, which manifest its dysfunction through decreased motion (flaccidity),
increased motion (spasticity) or out of sequence motion (dyskinetic). Scoliosis
associated with neuromuscular disorders can be classified, according to Scoliosis
Research Society, in two large groups: Neuropathic and Myopathic. Neuropathic
diseases can be classified according to the level of the lesion in upper motor neuron
and lower motor neuron disease.
Chapter 28 - Dysphagia is often underestimated in neuromuscular disorders
(NMD). It can be prominent in dystrophies, inflammatory myopathy, mitochondrial
myopathy, myasthenia, motor neuron diseases, and peripheral neuropathy. Certain
NM conditions leading to dysphagia such as amyotrophic lateral sclerosis can be
fatal, and bulbar presentation may be the predominant feature, requiring a diligent
workup and intervention to prevent unwanted complications such as aspiration
pneumonia. A prompt assessment of the swallowing function is crucial to organize
proper interventions and prevent complications in NMD patients. The video-
fluoroscopic swallowing study (VFSS) is considered the gold standard not only for a
diagnostic purpose, but also for planning the rehabilitation therapy and type of
nutrition, and for the results of the therapy evaluation. The spectrum of aspiration-
induced lung diseases (AILD) imaging patterns must be known by both the
radiologist and the clinician and managed in a multidisciplinary team.
Chapter 29 - Neuromuscular disorders affecting respiratory function typically
compromise the contraction of the diaphragm. Ultrasound (US) is a very reliable
exam in assessing diaphragmatic function in the clinic or at the bedside. There are

xviii Giuseppe Fiorentino and Antonio Esquinas
two approaches to assess the diaphragmatic function: the first evaluates the
diaphragm dome motion, while the second evaluates the diaphragm thickening
during inspiration at zone of apposition (ZOA). Moreover, US can also be routinely
used in patients with neuromuscular diseases to diagnosis, characterization and
monitor pleuropulmonary complications, such as lung consolidation and pleural
effusion, that may contribute to respiratory failure. In addition, US can be used to
guide needle position during diagnostic and therapeutic thoracentesis or chest tube
placement and then evaluate success of therapeutic manipulations.
Chapter 30 - Neuromuscular diseases are a heterogeneous group of diseases
affecting to different degree the peripheral nervous system, ranging from the second
motor neuron to the muscle. Weakness in the facial and oral muscles that control the
use of the tongue, lips, soft palate, cheeks, and diaphragm results in problems with
speech quality (dysarthria) and voice quality (dysphonia). Analogously, impairment of
oral muscles as well as pharyngeal and oesophageal muscles can lead to swallowing
problems (dysphagia). The reduction of oral clearance mostly due to dysphagia
or medical conditions that cause saliva overproduction are two main
mechanisms of excess saliva in the mouth beyond the lip margin, causing the so-
called sialorrhea. The approach to dysphonia and sialorrhea should be
multidisciplinary and begins with an appropriate clinical assessment, speech therapy,
respiratory and dysphagia physiotherapy, and the use of anticholinergic drugs and
botulinum toxin injection.
Chapter 31 - Dysphagia, is one of the most critical problems in patients with
neuromuscular diseases. The lack of standardized assessment procedure to detect
earlier dysphagia in these patients, makes it harder prevention and gets worse
quality of life. Various examinations have been developed and used to evaluate
accurately the swallowing function and different tools used to study dysphagia for
each NMDs. We can distinguish tools used in instrumental and non instrumental
examinations.
Chapter 32 - The neuromuscular disease (NMD) often leads to difficulty
swallowing (dysphagia) and managing secretions (salivation and/or excessive mucus
thick). The prevalence of dysphagia in people with muscle diseases is difficult to
determine and is not known precisely. Eating problems often develop insidiously and
people can compensate for abnormal swallowing when it is measured objectively.
We know that dysphagia can be diagnosed based on a symptom, clinical sign,
radiological sign, or as a cause of nutritional or respiratory problems. Dysphagia in
chronic muscle disease is mainly caused by muscle weakness. The weakness of the
tongue, face and jaw or abnormal architecture of the mouth can affect the ability to
properly prepare a bolus and retrieve bolus particles. Normal swallowing is usually
divided into three phases: oral, pharyngeal and oesophageal. When food is prepared
from the lips, tongue and teeth to form a bolus projected backwards from the tongue,
we are in the oral phase. At this stage, the protection of the airway is obtained by
closing the larynx. The larynx and forward-resulting upward movement provides
additional protection to the airways, but especially opens the upper oesophageal
sphincter. A fall in pressure in the upper oesophageal sphincter moves the bolus

Preface xix
from the base of the tongue to the lower pharynx and upper oesophagus. A wave of
peristalsis initiated by contact of the base of the tongue and pharynx free from
residual bolus.In addition, in the base of the tongue and the posterior pharyngeal wall
free the pharynx of bolus residues; this constitutes the transition from the pharyngeal
phase to the oesophageal phase. Usually, laryngeal penetration occurs with the
passage of the laryngeal vestibule but not beyond the vocal cords. Simultaneously,
suction is typically defined as the passage of the bolus beyond the vocal cords.
Palatal weakness may predispose to nasal regurgitation. The weakness of the
suprahyoid muscles leads to an alteration of the upper oesophageal sphincter, which
in turn leads to altered bolus transit, accumulation of the bolus in the pharynx and an
increased risk of aspiration into the larynx. Muscle weakness can also affect
laryngeal function, affecting laryngeal closure and coughing. Because of this muscle
weakness of the airway defence mechanisms and the impaired cough reflex that
goes with it, it predisposes to respiratory complications. Despite the obvious
importance of maintaining adequate nutritional intake in people with muscle
diseases, the evidence for optimal management of this problem are extremely scarce
and largely anecdotal. The main treatment options available are food handling, safe
swallowing techniques, surgery and enteral feeding.
Chapter 33 - Neuromuscular disorders comprise a diverse group of inherited and
acquired disease. The consequences of progressive muscle weakness include
impaired cough and secretion clearance, restrictive lung disease, dysphagia and
aspiration, recurrent respiratory infections, airway obstruction and sleep disordered
breathing, and leading to alveolar hypoventilation and respiratory failure is a frequent
cause of death. Infections with related acute respiratory failure is the common reason
for hospitalizations, and chronic respiratory failure is a frequent cause of death. A
coordinated multidisciplinary care has led to improved survival outcome in recent
decades.
Chapter 34 - Patients with neuromuscular disease are often at risk of
malnutrition. This is due to frequent dysphagia, motorimpairment, breathing
difficulties and mood disorders. Malnutrition contributes to the loss of lean mass and
consequently to hypotonia and worsening of muscle performance as well as
contributing to micronutrient deficiency disorders. A correct diagnosis of malnutrition
is the basis of an adequate nutritional support plan. The study of physical indices,
such as body mass index and weight loss, with laboratory parameters (pre-albumin,
transferrin and retinol binding protein) as well as an adequate assessment of
nutritional needs allows to set up an adequate support plan. The oral route is always
to be preferred; if not available, the enteral route via gastrostomy or jejunostomy is
the gold standard. Parenteral nutrition in association or exclusive will be used if the
enteral route is impractical or insufficient. Several mixtures are commercially
available for both enteral and parenteral administration. Administration must be
tailored on the specific needs of every single individual patient in accordance with
international guidelines (ESPEN, ASPEN). A careful monitoring of the parameters
used for the diagnosis of malnutrition and a safe management of the devices is
essential to manage the patient with chronic nutritional support.

xx Giuseppe Fiorentino and Antonio Esquinas
Chapter 35 - Respiratory muscle weakness and dysfunction are

pathophysiological elements commonly observed in patients with neuromuscular
diseases (NMD). Although in varying degrees and with different topographical
anatomical distribution (in relation to the different observable diseases) this element
is responsible for 90% of respiratory insufficiency and deaths of our
patients. Respiratory muscle weakness expresses itself in a restrictive pulmonary
pattern complicated by recurrent pneumonia and atelectasis, which further affect the
prognosis, quality of life and the usage of the resources needed for
care [1]. Respiratory muscle training it’s a therapeutic component, part of respiratory
rehabilitation programs (PR) since many years. Historically with a precise rationale
based on pathophysiological findings in COPD patients and healthy volunteers. Also,
the mean to improve muscle force and endurance via specific resistive training
programs mainly for inspiratory muscles, in neuromuscular diseases, has been
evaluated in some studies and clinical trials. In COPD studies, the body of evidence
in favour of RMT cannot suggest its generalized use. In NMD studies, with similar
low and very low grade of evidence studies, the risk of inducing muscle damage and
ipoventilation is still more concerning when using the IMT. This chapter explores the
technical and methodological specifications of RMT in the neuromuscular patient, as
well as the evidence produced by the scientific community, up to date.
Chapter 36 - Pulmonary morbidity is common in neuromuscular diseases
(NMDs), unfortunately often from the first years of life. It represents one of the main
causes of respiratory failure, reduced quality of life, mortality. Since the 1950s, the
spread of mechanical cough assistance techniques, alongside non-invasive
ventilation, has made it possible to improve the clearance of bronchial secretions and
reduce the morbidity of these patients. In neuromuscular diseases, although mainly
characterized by ineffectiveness of cough caused by muscle failure, respiratory tract
infections, when recurrent, can cause damage to the deep lung, some of
those issues may be as atelectasis, fibrosis, dystrophy of the lung tissue,
bronchiectasis. For this reason, in the perspective of personalized medicine, it is
important to examine the specific situation of the individual and to consider the
possible effectiveness of mechanical devices that improve the clearance of the deep
lung. In this chapter we will talk about the usefulness of operative protocols in the
management of respiratory infections, but also of techniques not routinely used in the
bronchial management of neuromuscular diseases. Which have shown a clear
efficacy in reducing pulmonary morbidity when the only cough assistance techniques
are not enough, improving the quality of life of patients.
Chapter 37 - When we evaluate the possibility of referring a neuromuscular
patient to home, it is necessary to verify that a series of requirements are met to
ensure that it is feasible to manage the patient at home. We need to consider not
only human factors, but also technological factors, factors related to the medical
team and legal, social and economic factors. There is no single way to organize the
care plan a patient needs at home. This will depend not only on the patient’s clinical
situation, but also on the existing financing model, the culture of the organization, the
existence of structured home care and hospitalization programs, the patient’s

Preface xxi
economic resources, the collaboration between primary care and hospital care, or
the existence of consolidated home respiratory care providers in the sector. The
patient must have the opportunity to express his/her experiences and feelings, to
explain his/her concerns and doubts and to decide for him/herself if he/she wants to
continue in a hospital institution (acute hospital, chronic hospital, weaning or other
facilities) or to take an important step and return home. We must not forget that the
involvement of the family in the care process is essential and therefore their consent
is required.
Chapter 38 - In the last decades, the use of home mechanical ventilation (HMV)
has steadily increased worldwide, with varying prevalence in different countries. HMV
is a treatment of choice for chronic respiratory failure with alveolar hypoventilation
and important common themes such as airway clearance and the process of
transition to home care. Recent home ventilators are pressure-targeted and have
sophisticated modes, alarms, and graphics, thereby facilitating the ventilator settings’
optimization. However, home ventilators have different settings for each algorithm as
tidal volume estimation and leak compensation, and even there are several different
circuit configurations. A basic understanding of HMV is of paramount importance to
healthcare workers taking care of patients with HMV. When choosing a home
ventilator, they should consider many indicators as health status and prognosis of the
primary disease, patient’s daily performance status, time (hour/day) needed for
ventilator support, family support, and financial costs. In this chapter we describe the
indications for HMV and the factors that influence successful delivery.
Chapter 39 - Some neuromuscular diseases have an acute or subacute onset of
respiratory failure, but it can be unrecognized because of different presentations.
Health care professionals must be able to identify predictor signs of acute respiratory
failure for neuromuscular patients and predictors for several outcomes. Usually, three
main components contribute to respiratory failure in this population: inspiratory
muscle weakness, which decreases pressure and volume with possible fatigue and
reduced total lung capacity, vital capacity, and tidal volume; expiratory muscle
dysfunction, with impaired cough efficiency and difficult clearance of secretions; and
bulbar muscle weakness that leads to upper airway obstruction and swallowing
dysfunction. Some general, subjective, or objective signs indicate probable acute
respiratory failure and should be searched by professionals to establish early
treatment. Once it is installed, predictors for different outcomes such as endotracheal
intubation, prolonged mechanical ventilation, functional decline, and death must be
monitored since they are associated to worse outcomes. Most predictors are related
to rapid progression of general and respiratory weakness, bulbar dysfunction, and
dysautonomia. Early detection of predictors can lead to adequate treatment
measures for better outcomes.
Chapter 40 - The last decades saw important advancements in both the
neurological medical field and that of applied technology: as a result, both the life
expectancy and the quality of life of neuromuscular patients has registered significant
improvements. At the same time, with the diffusion of cost-efficiency policies, the
tendency to cut on the duration of hospitalizations has also been registered. This

xxii Giuseppe Fiorentino and Antonio Esquinas
encouraged the further development and specialization of the caregiver figure, which,
at lower costs, could provide that long-term care needed for those patients suffering
from a neuromuscular condition. However, as the role and importance of this figure
progresses, so do its job requirements and, consequently, the need for a specific
formation. As the task expected from a caregiver may vary widely according to the
condition and needs of the patients, a general guideline for his/her training is
currently not available. However, many centres worldwide designed local programs
to match the requirements specific to their patients. This is also true for the
respiratory management of neuromuscular patients discharged home. In the
following chapter, we will therefore review the main points that both literature and
clinical experience evidenced as necessary topics in the caregiver formation, from
daily regular maintenance to emergency management, as well as the modalities for
their assessment. Lastly, attention will be drawn on caregivers’ wellbeing, which
could significantly affect their work performance, by outlining the common causes of
burden development and the possible ways to prevent or counteract it.
Chapter 41 - In patients with neuromuscular diseases (NMDs), respiratory
conditions represent a relevant threat which can progressively impacts on their
quality of life. Non Invasive Ventilation (NIV) has been shown to significantly improve
respiratory parameters and to extend survival in patients affected by different NMDs.
Although once therapy is undertaken, an improvement is generally detected, its
impact on both psychological factors and quality of life is frequently mentioned and
less studied. Nevertheless, underestimating the quality of life of NMDs patients can
influence both the kind of therapies and the ways through which they are offered. An
accurate assessment of quality of life and the involved psychological factors should
be undertaken routinely before offering patients the option to undertake NIV and
during follow ups.
Chapter 42 - Telemedicine is involved in a variety of fields. While interest for
health care has only become evident recently, the sudden rise in health care costs is
forcing medical practitioners to seek practical, cost effective solutions. Information
Technology (IT) and, in particular, the latest methods for remote surveillance via
teleassistance interventions seem to be promising. Chronic diseases have become
an increasingly bigger issue for public healthcare. Neuromuscular diseases (NMDs)
are chronic conditions that present with progressive muscle atrophy leading to
difficulties for walking, swallowing, and eventually, breathing and clearing the
airways. Chronic respiratory insufficiency in NMDs develops insidiously and at very
variable rates. The specific characteristics of it displayed by these patients require
planning and may benefit by telemedicine solutions. However there is still little
information regarding the advantages of this technology for this patient population.
Chapter 43 - Palliative care (PC) has become an essential component of the
treatment of neuromuscular patients, although the most published literature has been
focused in ALS patients. They have been described some barriers for an appropriate
utilization of PC in neuromuscular patients: Physicians have less experience with PC
in noncancer patients; they associate PC with death and dying, or are afraid to
diminish patients’ hope by introducing PC and patients associate PC with end-of-life

Preface xxiii
care. It is very important that patient and family members be involved in making
decisions about the disease. This should be done when the patient’s functional
status is still good and always after receiving adequate information about the
different therapeutic alternatives. It is also very important to avoid making decisions
in the course of an acute situation in the emergency department or in the intensive
care unit. The PC approach have to be defined from a holistic point of view taking
into account a series of therapeutic measures, such as pharmacological treatment,
oxygen therapy, mechanical ventilation, respiratory physiotherapy, nutritional
assessment, communication and emotional and spiritual support. We must learn to
communicate the prognosis of the disease. All patients have the right to know the
details about the disease they suffer from, but not everyone wants to know about it,
and this should also be respected. Even if they want to know everything about the
disease, patients always prefer the delicate truth, so one must act with tact and
sensitivity. It is important to make them understand that all is not lost and that they
are not alone in this hard process, that they will be accompanied not only by their
family but also by the medical team.
Chapter 44 - Management of the end-of-life phase represents a crucial part of the
care of lethal neuromuscular diseases (NMDs), aiming to improve quality of life of
both the patients and caregivers and to perform appropriate palliation of stressful
physical, psychosocial, and existential suffering. Some NMDs produce progressive
atrophy and weakness of limb, trunk, bulbar and respiratory muscles, resulting
inexorably progressive. Discussing on the end-of-life issues is an integral part of the
palliative approach, incorporated into the care plan for the patient and caregiver from
the time of diagnosis of these fatal illnesses. Specific triggers for initiation of end-of-
life discussions can be usefully anchored to defined points in the disease trajectory.
Health-care professionals may inform patients and caregivers about the alternative
scenarios relating to the development of life-threatening crises in a controlled
environment, thereby limiting unplanned or unwanted interventions or procedures.
Among NMDs, we overviewed recent literature on end-stage management in Spinal
Muscular Atrophy (SMA) type I and II and Duchenne Muscular Dystrophy (DMD),
both affecting childhood, and ALS, affecting adulthood. With regard to patients
affected by SMA I and II, the therapeutic opportunities have been enriched by the
introduction of Nusinersen, an antisense oligonucleotide able to increase the
production of fully functional survival motor neuron (SMN) protein, modifying SMA
natural history and the approach and the timing of discussions on end-of-life care in
this disease. With regard to DMD, in addition to respiratory dysfunction,
cardiomyopathy has been revealed an increasing cause of morbidity and mortality,
thereby needing intervention to ameliorate symptoms, such as the use of intra-
cardiac device (ICD) or resynchronizing devices with defibrillator (CRT-D). Finally, in
case of ALS, acknowledged as the neurodegenerative disease of the adulthood with
the worst prognosis, symptoms management, and nutritional and respiratory support
are the main targets of end-of-life care. This chapter is intended to overview current
evidence regarding end-of-life care in fatal NMDs of childhood and adulthood,

xxiv Giuseppe Fiorentino and Antonio Esquinas
focusing on crucial aspects of end-stage management and on the psychosocial

effects of these illnesses on the patients and their families.
Chapter 45 - Neuromuscular diseases often affect young people, depriving them
of autonomy and the possibility of social interaction. Several studies have clearly
shown that NIV treatment can prolong survival of NMD patients who accept and
tolerate NIV compared to those who do not accept, tolerate or use it. When
respiratory function get worse, despite the use of full-time NIV and cough assist
combination or bulbar muscular impairment is too advanced and the patient is unable
to protect the airways tracheostomy and invasive mechanical ventilation (IMV) should
be considered in ALS and other NMD. Dialogue and discussion regarding treatment
and care is ongoing from the initial planning of NIV until death and special emphasis
must be placed on the patient’s autonomy and the particular dilemmas involved.
There is no universally accepted strategy in the management of NMD patients,
because in this highly disabling pathologies, the line between survival and life is very
blurred. As is often the case in our medical profession, there is no unique solution.
For this reason, the care pathway in this kind of patient must be shared and planned
with patients and care-givers, illustrating step by step therapeutic option and life
expectancies.

Introduction
OVERVIEW OF NEUROMUSCULAR DISORDERS

(NMDS) AFFECTING RESPIRATORY FUNCTION
Giuseppe Fiorentino1,, MD, Anna Annunziata1, MD

and Antonio Esquinas2, MD
1
UOC Fisiopatologia and Respiratory Rehabilitation AO Dei Colli, Naples, Italy
2
Intensive Care Unit; Hospital Morales Meseguer, Murcia, Spain
ABSTRACT
Neuromuscular disorders (NMDs) are hereditary or acquired, slowly or

rapidly progressive disease that affects the central nervous system, the
peripheral nerves, the neuromuscular junction and the muscles. This group of
disorders varies markedly in aetiology, prognosis, progression, therapy, clinical
course and respiratory involvement.
All NMDs present a common impairment of ventilatory function caused by
compromised airway patency and protective reflexes and/or reduced respiratory
pump efficiency. The ventilation alteration in NMDs differs on the specific
disorder, such as disease that affects one level (e.g., unique diaphragm
paralysis) or diverse levels (e.g., multiple sclerosis). The gravity of deficiency
may be marginal and resolve with time and proper treatment (e.g., Guillain–Barré
syndrome) or is characterized by constant evolution to subsequent respiratory
death (e.g., amyotrophic lateral sclerosis).
ABBREVIATIONS
AIDP Acute inflammatory demyelinating polyneuropathy

ALS Amyotrophic lateral sclerosis

Corresponding Author’s E-mail: giuseppefiorentino1@gmail.com.

2 Giuseppe Fiorentino, Anna Annunziata and Antonio Esquinas
CCAH Central alveolar hypoventilation

CIDP Chronic inflammatory demyelinating polyneuropathy
NMDs Neuromuscular disorders
CIP Critical Illness Polyneuropathy
CMT Charcot – Marie – Tooth
CNS Central nervous system
EPP Endplate potential
FEV1 Forced expiratory volume in the 1st second
FVC Forced vital capacity
GBS Guillain–Barre syndrome
HMERF Ereditary myopathy associated with early respiratory failure
LEMS Lambert-Eaton myasthenic syndrome
MG Myasthenia Gravis
MS Multiple sclerosis
NAMs Necrotizing autoimmune myopathies
NMJ Neuromuscular junction
PCF Peak Cough Flow
PD Parkinson’s disease
PPS Post-poliomyelitis syndrome
SMA Spinal muscular atrophy
SNIP sniff nasal inspiratory pressure
SAP Stroke-associated pneumonia
SCI Diseases of the Spinal Cord
SIRS Systemic inflammatory response syndrome
UPPER MOTONEURON LESIONS/PYRAMIDAL INSUFFICIENCY
Upper motor neuron lesions are the consequence of pathology in the cerebral
cortex, brainstem, or spinal cord. They are marked by increased muscle tone with
spasticity, hyperreflexia, and the persistence or reappearance of primitive reflexes as
deep breaths ("sighs") and cough despite having the very low vital capacity PCFs.
Injuries in the cortex or subcortical areas often are related to alteration of speech or
other cortical functions. Lesions in the brainstem frequently alter ipsilateral cranial
nerve function and contralateral hemiplegia. Anomalies in the spinal cord classically
produce consensual weakness because of the proximity of the descending tracts.
The lower motor neuron resides in the anterior horn of the central grey matter of the
spinal cord. Dysfunction of the lower motor neuron leads to weakness and atrophy of
the muscle it innervates and fasciculations, cramps, and decreases deep tendon
reflexes. Although they can be focal, the lower motor neuron diseases are usually
more diffuse conditions and often involve motor neurons innervating respiratory
muscles, giving rise to respiratory difficulties.

Overview of Neuromuscular Disorders (NMDs) … 3
Stroke
Hemispheric lesions can also affect breathing. In hemiplegia following a stroke,

chest wall and diaphragm movements on the cortical injury’s contralateral side can
be decreased, resulting in restrictive physiology. The classic disturbance of
automatic but not intentional breathing is congenital central alveolar hypoventilation
(CCAH). A variability of other irregular breathing patterns is also related to CNS
disease, including Cheyne- Stokes respiration and ataxic breathing. This breathing
pattern may result from augmented receptiveness to carbon dioxide due to the
interruption of normal cortical inhibition. Injury to the brainstem’s automated
respiratory centres leads to central sleep apnea when the patient falls asleep and
loses voluntary respiration. CNS tumor or infection can affect the outcome in
hyperventilation.
Numerous stroke patients have compromised swallowing mechanisms, leading
to oral content aspiration during sleep, which theoretically may be related to
abnormal dopamine transmission. Stroke-associated pneumonia (SAP) has been
implicated in the morbidity and mortality after acute ischemic stroke. SAP is defined
as early when it occurs in the first 72 h of admittance to the hospital. Another
classification divides SAP into acute (within a month of stroke) and chronic (later than
a month). Impaired consciousness and dysphagia are significant risk factors for
aspiration [1].
Multiple sclerosis is characterized by intermittent demyelination in regions of the
central nervous system, indicated clinically by “relapsing-remitting” pattern. There are
clearly defined symptomatic attacks lasting 24 hours or more, followed by complete
or almost complete improvement.
Different respiratory impairment patterns can occur, including respiratory muscle
weakness as diaphragmatic paralysis, bulbar dysfunction, obstructive sleep apnea,
and respiratory control dysfunction.
The respiratory centre’s involvement in the medulla or cervical spinal cord can
cause loss of automatic respiratory control, and central apnea can cause automatic
breathing failure, apneustic or neurogenic pulmonary oedema.
There is an association between the degree of pulmonary dysfunction and the
phase of neurological disability, but no correlation has been found between
pulmonary dysfunction and the disease’s duration. The progress of bulbar and
respiratory muscle lack result in atelectasis, aspiration, pneumonia and subsequent
acute or chronic ventilatory failure. Wheelchair-using patients, especially those with
debilitated upper extremities, often have a severely limited respiratory function.
In the progressive stages of MS respiratory deficiency can happen in the early
course of the disease or during acute attacks, resultant in respiratory insufficiency
has also been described. Rarely dyspnea is present in MS patient until severe
disability and impaired respiratory muscle strength for the restricted motor activities
and greater expiratory than inspiratory muscle dysfunction. Clinical evidence that
may help predict respiratory muscle deficiency are unproductive cough and
incapacity to clear secretion, inadequate to count on a single exhalation and upper

extremity contribution. Acute respiratory failure rarely appears in this disease. Still, it
can happen in the central spinal cord’s severe demyelination: muscle training
improvement expiratory muscle strength, vital capacity, and residual volume.
Breathing rehabilitation with positive expiratory pressure is frequently suggested to
patients with progressive neurological deficits and may help patients with mild to
moderate MS stages [2].
Diseases of the Spinal Cord (SCI)
SCI is due to tumour, vascular accident, transverse myelitis, syringomyelia,

traumatic injury caused by motor vehicle accidents, falls, sports accidents and
gunshot wounds. Some other causes include.
It severely compromises respiratory function due to paralysis and respiratory
muscles’ impairment.
Respiratory complications such as atelectasis, pneumonia and respiratory failure
are common, and a primary cause of both short and long-term morbidity and
mortality. After acute SCI, several pathophysiologic changes can affect the
respiratory system and predispose to respiratory problems, cough inefficiency
(expiratory muscle weakness), ciliary dysfunction, mucous hypersecretion
(diminishing of the peripheral autonomous nervous system), glottis dysfunction or
gastric hypomotility increase the probability of aspiration and loss of consciousness
increasing the risk of aspiration.
The degree of respiratory deficiency is contingent on the level and extent of the
spinal cord injury. Firstly, the vital capacity, maximum inspiratory pressure, and
maximum expiratory pressure are reduced. In the initial period, chest wall flaccidity is
substituted with spasticity. There is an enhancement in the vital capacity as the more
rigid chest wall resists collapse. In SCI patients, the practice of abdominal binders
and/or the supine position can increase diaphragm function, increasing vital capacity.
In contrast, lung function (FEV1 and PEF) changes, pulmonary infections and airway
problems are the main reasons for life-threatening respiratory failure.
Injuries at or above C3 to C5 comprise the phrenic nerves with partial or
complete bilateral hemi-diaphragmatic paralysis. For damages at C3 and above,
ventilatory support is usually required. Intercostal muscle paralysis below the lesion
level limits the normal external expansion of the middle and upper rib cage,
compromising inspiration supplementary. Paralysis of the abdominal and additional
expiratory muscles can reduce expiration. Injuries below C5 hardly outcome in need
for continuous ventilator support. Cervical or thoracic spinal cord injury can affect the
ability to cough and clear secretions.
High-level quadriplegics may be incapable of producing sufficient tidal volumes,
and the associated hypoventilation and atelectasis can cause product hypoxemia.
Low-level cervical quadriplegics with integral phrenic nerves can contract their
diaphragms, but my failure to use the expiratory muscles. United inspiratory and
expiratory weakness can prevent them from efficiently coughing and clearing

secretions and put them at high risk for pneumonia. Sleep apnea is more common in
SCI. Possible causes comprise more time sleeping in the supine position,
hypertrophy of neck muscles increasing the risk of obstruction, the use of sedating
anti-spasticity medications, or an as yet undefined central neural effect of SCI. The
asleep study should be contemplated when nocturnal hypoventilation symptoms
such as morning headache, daytime hypersomnolence, or unexplained nocturnal
awakenings are existing or when daytime hypercarbia (PaCO2 > 45 mm Hg),
inexplicable core pulmonary, or FVC less than 50% predicted are present. SCI often
requires for long-term ventilation.
Early surgical stabilization, careful weaning from mechanical ventilation,
meticulous search and treatment of infections, aggressive posturing and mobilization
and support of impaired mechanical functions by physiotherapy, muscle training,
noninvasive respiratory support, and some cases electrophoretic pacing increase
survival and independency of quadriplegic patients.
Various respiratory muscle training improve respiratory function for people with
cervical SCI. For patients with spinal cord injury who necessitate chronic ventilator
support, a tracheostomy is an option. However, several practical noninvasive
approaches are available, including mouth-piece and mask ventilation. Patients with
severe disease can be candidates for phrenic nerve pacemakers [3].
Parkinson’s Disease
Extrapyramidal disorders such as Parkinson’s disease can distress voluntary

breathing. Parkinson’s disease results in disordered coordination and activation of
upper airway and chest wall muscles, resulting in functional glottis obstruction and/or
ineffective synchronization of repetitive respiratory tasks. In this disease pneumonia
being the most common cause of death. Physiological evidence of upper airway
obstruction may be present if there is an abnormal flow-volume loop contour showing
regular or irregular flow oscillations. Parkinson’s patients have observed a rounding
off of the middle expiratory flow-volume curve peak and a lowered peak expiratory
flow rate.
Levodopa is considered the standard gold therapy for Parkinson’s disease (PD)
with an improved FVC and PEF, but no changes in FEV (1) and FEV(1)/FVC. Sleep
disorders with central and obstructive sleep apnea are common in patients with
Parkinson.
Poliomyelitis is a young children infection that starts with fever and upper
respiratory symptoms and asymmetric flaccid paralysis with signs of meningeal
irritation that can comprise the skeletal, respiratory, and bulbar-innervated
musculature. The respiratory motor nuclei can be directly convoluted with
diaphragmatic and accessory respiratory muscle consequential dysfunction.
Respiratory muscle paralysis is the most devastating manifestations and is preceded
by a period of fever and mild illness. Lower cranial nerve nuclei can provide product
upper airway obstruction, with phenomena of secretions, and aspiration. The

medullary respiratory center also can be affected, resultant in irregular respiration

and apnea. The central respiratory centres can be frankly affected by irregular
respirations. Many patients require aggressive ventilator and hemodynamic support
during the acute phases of their illness [4].
Some patients gave a history of poliomyelitis report late-onset decline in
functional capacity. These late symptoms are indicated as post-poliomyelitis
syndrome (PPS). The syndrome is characterized by unique and increased muscle
weakness, fatigue, muscle pain, joint pain, muscle cramps, cold intolerance, and lung
problems. The average time to onset from the initial infection time is 35 years. The
cause of PPS is unknown. PPS results on the respiratory function with restrictive
disease produced by weakness of respiratory muscles and chest wall deformities,
obstructive and central sleep apnea and hypercarbia respiratory failure. The real
incidence of respiratory system involvement in postpolio syndrome is unknown. Risk
factors for restrictive disease later in life include a requirement for mechanical
ventilation at the time of acute polio onset. Sleep-disordered breathing is common.
Diaphragm paralysis or liability can be caused by motor nerve and muscle problems
and may be either unilateral or bilateral. Although most patients show substantial
muscle healing over time, they gradually reduce ventilatory assistance later in life
with the senescent ageing and dropping out of overworked anterior motor neurons
with ageing. Some patients continue to need long-term nocturnal ventilatory support;
others are weaned but require support because of a late deterioration in ventilatory
function.
Amyotrophic Lateral Sclerosis (ALS)
ALS is a disease that can interest upper and lower motor neurons. The condition
has a peak incidence in the seventh and eighth decades of life and affects men more
than women. The disease usually begins asymmetrically in either a leg, arm, or
pharyngeal muscles. It tends to progress regionally (e.g., affecting one leg, then the
other, and moving from there to the arms or pharynx). On examination, both lower
motor neuron (weakness, atrophy, fasciculations) and upper motor neuron
dysfunction (weakness, spasticity, increased reflexes, positive Babinski signs) are
present. Sensation, extraocular muscles, and bowel and bladder function should be
standard. Early participation of pharyngeal muscles imparts a poorer prognosis
related to impaired nutrition and increased risk of aspiration, although advanced age
is an even more critical adverse prognostic factor. As the diaphragm becomes
involved, respiratory function declines and FVC and sniff nasal inspiratory pressure
(SNIP) is a reliable predictor of prognosis, though other parameters may be better.
The respiratory muscle tests have been used to define the prognosis and choose
when to start ventilatory support in predominantly bulbar disease. Respiratory failure
tends to occur early, and the use of NIV can reduce mortality. The prognosis for
these patients appears similar to that of other ALS patients.

The American Academy of Neurology guidelines recommends treatment with

noninvasive mechanical ventilation once the FVC is below 50 per cent of predicted.
Noninvasive positive pressure ventilation may improve quality of life and prolong
survival in a patient with ALS [5].
Additionally, to respiratory dysfunction, sleep-disordered breathing is common
and noninvasive nocturnal ventilation can be highly adequate. The advanced age at
diagnosis and airway mucus increase represents poor prognosis for ALS patients
treated with NIV. In contrast, airway intubation may be required because of bulbar
dysfunction further impairing cough and the inability to clear secretions. Also,
tracheostomy and invasive mechanical ventilation can prolong survival.
Anterior Horn Cell Disorders
Spinal muscular atrophy (SMA) is a genetic autosomal-recessive degenerative

disorder that has an onset in infancy. It happens in some forms, with SMA types 1–4
going from most to least severe muscle impairment. Intercostal muscles are more
expressively affected. The diaphragm is relatively spared, resulting in the chest wall’s
paradoxical movement during inspiration with inward movement of the ribcage and
outward sign of the abdominal wall. Still, NIV is useful in many of these patients and
may buy time for medical therapies to take effect or even undergo development.
SMA 1 or Werdnig-Hoffman disease exhibits in the first 6 months of life. Infants
with this disease lack head control and are nearly always unable to sit and walk.
There is severe hypotonia, generalized weakness, and lean muscle mass. These
patients have paradoxical inward rib cage retraction with each inspiration, the
diaphragm being relatively spared. During the earliest year of life, the chest wall is
particularly compliant, resulting in distortion of the chest wall and developing the
chest with pectus excavatum in SMA 1. There is respiratory failure beginning with
anatomical changes that lead to recurrent respiratory infections, advanced
respiratory failure firstly at night but later during the day, and ultimately complete
respiratory failure [6].
The benefits of NIV for children with SMA 1 involve the possible for ventilatory
support without surgical intervention, improvement of the chest wall deformity, and
enhancement in lung development and potentially lung function. NIV is not always
gold therapy. Tracheostomy ventilation and palliative care options need to be
examined with a caregiver, especially for those with SMA 1. They progress pectus
excavatum and severe restriction of the lungs and chest wall. Unless sustained by
respiratory muscle assistances, more than 90% of patients die by 2 years of age.
In SMA type 2, swallowing difficulties or choking with feeds becomes evident in
the preschool years, disposing them to frequent pneumonia and chronic suppurative
lung disease. These patients can sit but not walk. About half of these patients
develop paradoxical breathing and necessitate nocturnal NIV for sleep-disordered
breathing.

Kugelberg-Welander disease is the SMA (type 3), and patients can seem natural
in infancy. The gradual weakness is proximal in presentation, principally comprising
shoulder girdle muscles. In the adult-onset form, SMA type 4, patients can walk for
some time. An X-linked adult-onset type 5 SMA (which affects only men), or Kennedy
disease, is correlated with gynecomastia, temporal atrophy, and endocrine disorders
hypospermia. Typically, invasive ventilation is not required chronically for SMA type
2, 3, or 4 [7].
Brachial Plexitis
Also identified as neuralgic amyotrophy or Parsonage-Turner syndrome, brachial

plexitis is an idiopathic, presumably inflammatory, process affecting unilateral
brachial plexus function that usually presents as a monomeric mononeuropathy
multiplex. Less often, it offers as a hereditary neuralgic amyotrophy. The course
begins with the acute onset of severe pain in the scapular and shoulder region on
one side, which abates over several weeks and is replaced by progressive
weakness, atrophy, and sensory loss in the arm and shoulder. The phrenic nerve
may be involved, and unilateral diaphragmatic paralysis is not uncommon. Given the
length of the phrenic nerve and a decreased reinnervation chance, the diaphragm’s
involvement worsens the overall prognosis. It may permanently lose function,
vasculitis, or diabetes mellitus and as part of the multifocal motor neuropathy
syndrome.
Multifocal motor neuropathy is an autoimmune motor neuropathy preferentially
involving the distal upper limbs. These patients present at high risk of developing
respiratory failure and should undergo routine evaluation for respiratory muscle
weakness.
Peripheral Neuropathies
Polyneuropathy refers to a diffuse dysfunction of peripheral nerves, usually in

asymmetric, distal-greater- than-proximal, distribution. Polyneuropathy can occur
acutely or develop more gradually and can be divided into demyelinating or axonal
neuropathies depending on the distribution of pathological involvement.
Polyneuropathies can also be subdivided into hereditary and acquired causes. The
most commonly encountered acute neuropathy that impairs the respiratory system is
Guillain–Barre syndrome (GBS).
It presents over days as an ascending motor disturbance, often preceded by a
poorly localized but progressive sensory disorder. GBS affects the respiratory system
by causing weakness of the upper airway muscles, inspiratory and expiratory
muscles, and secondary problems such as pneumonia or pulmonary embolism. Daily
bedside evaluation of respiratory function and arterial blood gases is essential for

correct evaluations concerning the need for mechanical ventilatory support, which is
required in 20% of affected children [8]. Acute respiratory failure can be avoided
using NIV when bulbar-innervated muscle function is sufficient to prevent continuous
aspiration of saliva or oxyhemoglobin desaturation. Half of the patients present
respiratory insufficiency. Patients usually become too weak to ambulate, and a
significant proportion requires ventilatory assistance for anywhere from a few days to
several months. Significant autonomic disturbance affects 25% of patients with acute
inflammatory demyelinating polyneuropathy (AIDP), including sudden arrhythmias,
blood pressure instability, constipation, and bladder retention severe enough to
necessitate intubation and mechanical ventilation. With fast progressive disease, the
intensive care unit is contemplated as the best monitoring setting. Absolute
indications for intubation comprise impaired consciousness, respiratory or cardiac
arrest, shock, arrhythmias, blood-gas alterations, or bulbar dysfunction with
confirmed aspiration. In patients with high risk for aspiration because of bulbar
muscle involvement, noninvasive ventilation is generally not a practical option. After
the initial worsening, the natural course of the disease is gradual recovery over
weeks to months. Despite medical treatment, GBS often rests a severe illness; 3-
10% of patients die, and 20% are still incapable of walking after 6 months. Within 12
months, 80% of patients with AIDP are functionally average.
Critical illness polyneuropathy is part of a spectrum of diseases that include
dysfunction of neuromuscular transmission and critical illness myopathy, elements of
which may be present in any given patient. Patients with the entity share respiratory
failure, multiorgan failure, impaired nutrition, infection, and medications, including
steroids and neuromuscular blocking agents. The condition is suspected when a
patient fails to wean from mechanical ventilation and is discovered to have limb
weakness. Treatment is supportive, including steroid withdrawal, physical therapy,
nutritional support, and resolution of the underlying medical conditions that
precipitated the acute illness.
Acute intermittent porphyria, hereditary coproporphyrin, and variegate porphyria
are all inherited as autosomal dominant traits and neuropathic involvement. Most
patients have abdominal pain, often with antecedent gastrointestinal symptoms and
fever suggestive of a viral illness. Acute motor weakness and areflexia progressing
over a few days, often leading to respiratory failure, can make the differentiation from
GBS difficult. Treatment is supportive, including avoiding the many medications that
can precipitate or worsen porphyria and use intravenous hematin. Unfortunately, the
prognosis is guarded.
Respiratory failure is present in other peripheral neuropathies. Lyme disease can
present with a syndrome equal to Guillain-Barré syndrome. Acute intermittent
porphyria can produce a neuropathy severe enough to outcome in respiratory failure.
Post-diphtheritic neuropathy, toxic neuropathies (thallium, phosphate, and lead)
avitaminosis, paralytic shellfish (saxitoxin) poisoning, and the polyneuropathies
related with systemic lupus erythematosus and polyarteritis nodosa also can produce
ventilatory failure.

Chronic polyneuropathies are much more common than acute ones but,
conversely, are less frequently associated with respiratory compromise. Chronic
inflammatory demyelinating polyneuropathy (CIDP) is a sensorimotor
polyneuropathy, similar to AIDP in many ways except for its prolonged course of
repeated remissions and relapses. Occasionally, it is severe enough to compromise
respiration, leading to progressive weakness, sensory loss, ataxia, and pain, with
subsequent debilitation and disability.
Other Neuropathies Which Can Cause Acute Respiratory Impairment
Respiratory muscle weakness culminating in acute respiratory insufficiency or

failure has been described in Charcot – Marie – Tooth (CMT) 1A, CMT 4J, chronic
inflammatory demyelinating polyneuropathy, multifocal motor neuropathy,
transthyretin-associated amyloidosis, sarcoidosis, and Sjogren’s syndrome. Another
chronic neuropathy, occasionally affecting pulmonary function, is hereditary sensory-
motor neuropathy (HSMN), also known as Charcot-Marie- Tooth disease (CMT). Two
forms of CMT have been recognized. CMT is characterized by onset in the first or
second decade. With hammertoes atrophied calves (stork legs), distal sensory loss,
and muscle atrophy and weakness progressing from distal to proximal, affecting legs
and then hands. The neuropathy can progress to involve diaphragm and other
respiratory muscle function, but this is rare, and life expectancy is not substantially
affected otherwise. However, a variant of CMT, type 2C, predisposes to respiratory
involvement. Possible respiratory complications include vocal cord paralysis early in
life, laryngeal weakness leading to inspiratory stridor, and intercostal muscle and
diaphragm weakness progressing to respiratory compromise. Many other processes
cause chronic polyneuropathies, but they are too numerous to discuss individually.
The most common causes of polyneuropathy are diabetes mellitus and alcoholism,
but these rarely involve respiratory nerves. Other causes of chronic polyneuropathy
that may infrequently impair respiratory muscle function include vasculitis,
amyloidosis (hereditary and primary), gammopathies, paraneoplastic syndromes,
sarcoidosis, and toxins.
DISORDERS OF PERIPHERAL NERVES
Diaphragm Paralysis
Unilateral or bilateral diaphragm paralysis subsequent phrenic nerve damage can

result from cardiac surgery, trauma, mediastinal tumours, infections of the pleural
space and forceful manipulation of the neck. Phrenic neuropathies are an important
cause of dyspnoea, orthopnoea, and hypercapnia respiratory failure. In numerous
patients, the reason for phrenic nerve impairment remains uncertain (idiopathic

phrenic neuropathy). Some authors consider this condition a variant of brachial

neuritis, but others suggest that it is idiopathic. Phrenic nerve involvement may be
unilateral or bilateral, and pain is more common in unilateral. Both forms are
associated with trigger factors in up to 50% of cases, but respiratory insufficiency is
generally only apparent in bilateral phrenic neuropathy. A significant proportion of
patients have selective phrenic nerve involvement suggesting a systemic process
that affects the phrenic nerve, either unilaterally or bilaterally, with occasional
spillover to the neighboring brachial plexus other nerve branches (e.g., recurrent
laryngeal nerve). A specific immunological mechanism might cause this form of
phrenic neuropathy. Although spontaneous improvement is uncommon and phrenic
neuropathy does not respond to steroids or immunosuppression; thus, the condition
generally necessitates prolonged NIV. However, it is important to recognize that
phrenic neuropathy may occur following surgery due to local or generalized
inflammation of the micro vessels in the nerve and subsequent ischemic injury.
Interscalene block is associated with diaphragm paralysis because of phrenic
nerve damage. The injury mechanism is uncertain and may relate to local anesthetic
effects, the development of adhesions around the nerve, or a steroid-responsive
microvasculitis.
Isolated phrenic neuropathy has been associated with a variety of causes
summarized below: Infections (Herpes zoster virus, HIV, Borrelia, Echinococcosis,
Diphtheria, West Nile, Dengue), Physical causes (manipulation), drug (Amiodarone,
Chemotherapy) Iatrogenic (Malpositioning of a chest tube thoracic surgery).
Diaphragm paralysis may also be seen with various motoneuron diseases,
myelopathies, neuropathies and myopathies, and COPD and other diseases that
produce lung hyperinflation [9].
Bilateral Diaphragm Paralysis
The usual causes are diffuse muscle diseases or motor neuron disease such as
ALS. In bilateral diaphragm paralysis orthopnea, dyspnea with exertion is
characterized by severe restrictive ventilatory impairment. TLC, FRC and static
pulmonary compliance, maximal inspiratory pressure is also markedly reduced.
Disability can be quite noticeable. Phrenic nerve pacing is not applicable in most
diaphragm paralysis cases because it requires intact phrenic nerves and normal
diaphragmatic motor function [9].
Critical Illness Polyneuropathy (CIP)
CIP and myopathy (CIM) are significant complications of severe acute illness and
its management. CIP/CIM protracts weaning from mechanical ventilation and
physical rehabilitation since both limb and respiratory muscles can be affected.

The significant risk factors for critical illness polyneuropathy include sepsis and
systemic inflammatory response syndrome (SIRS), treatment with steroids or
neuromuscular blocking agents, and hyperglycemia. Other factors that are thought to
contribute to this disorder include total parenteral nutrition, aminoglycoside use,
catecholamines, hyperosmolality, female gender, longer duration of multiorgan
failure, greater illness severity, and renal failure.
The patients typically exhibit varying musculoskeletal weakness, ranging from
mild weakness to near-total paralysis with diminished deep tendon reflexes.
Unfortunately, a physical examination is unreliable as the sole means of diagnosis
and electromyography with nerve conduction studies (EMG/NCS) must confirm the
diagnosis.
A patient who develops CIP tends to require a longer mechanical ventilation
period, and more extended hospital stays with a protracted rehabilitation period.
There is evidence of persistent neuropathy on EMG/NCS as long as 5 years after
discharge from the intensive care unit. Because no specific therapy for CIP happens,
treatment is purely helpful and comprises rehabilitation, nutritional integration, and
medical complications.
DISORDER OF THE NEUROMUSCULAR JUNCTION
Once the motor nerves enter the muscle, they divide into multiple terminal
branches. These terminal axons each innervate one muscle fibre at the motor
endplate or, more accurately, the neuromuscular junction (NMJ). The primary
purpose of the NMJ is the neuromuscular transmission, utilizing the neurotransmitter
acetylcholine. Acetylcholine is contained in the terminal axon within synaptic vesicles
that are situated at active zones. When an action potential traverses the motor axon
to its terminus, voltage-gated calcium channels on the presynaptic membrane are
opened, causing the release of the synaptic vesicles’ contents. The released
acetylcholine passively diffuses across the synaptic cleft where a significant
proportion is catabolized by acetylcholinesterase. The remainder binds with
acetylcholine receptors arranged in large numbers on the aperture’s postsynaptic
(muscle) side. Once activated by acetylcholine, the receptors open a sodium-
potassium channel causing depolarization of the local muscle membrane. When this
endplate potential (EPP) reaches a threshold, an action potential is generated and
propagated along the muscle membrane, causing muscle fibre contraction. Several
diseases affect NMT, but only three are associated with significant pulmonary
morbidity.

Myasthenia Gravis (MG)
MG is the most common autoimmune defect of NMT with a postsynaptic defect

of neuromuscular transmission as the standard feature. It is caused by polyclonal
autoantibodies directed against the postsynaptic acetylcholine receptors. MG can
also happen as a paraneoplastic syndrome in relationship with thymoma. The most
severe manifestation is termed a myasthenic crisis with respiratory failure that may
develop with alarming speed. There may be few or no warning signs before the
respiratory arrest. It refers to impending or actual respiratory failure. However, it can
also refer to the acute inability to swallow, with respiratory failure following shortly
after that because of airway secretion retention. Dysphagia and aspiration are
common in MG.
Respiratory difficulties are correlated to feeding problems causing aspiration
pneumonia, upper airway obstruction owing to the inability to handle oropharyngeal
secretions or respiratory muscle weakness [10].
Augmented secretions from cholinergic drugs used to treat MG may make cough
insufficiency and secretion management more difficult.
Isolated diaphragmatic paralysis can occur in myasthenia gravis without phrenic
nerve damage. Such diaphragmatic weakness may present postoperatively and be
falsely attributed to nerve damage during surgery. It is essential to recognize that
postoperative isolated diaphragmatic paralysis can be myasthenic in origin and may
respond to immunosuppressive therapy.
Authors from a single specialized neuromuscular unit have suggested that
myasthenic crisis can be treated with NIV support. Yet, it is typically unsuccessful in
patients with GBS and can be dangerous in these cases. NIV mast is strictly
observed for the rapidly evolving myasthenic crisis with disastrous consequences.
The use of NIV for the myasthenic crisis should be reserved for use only by the most
experienced. Also, repeated clinical assessment and arterial blood gas
measurements for the first 6–8 hours are usually necessary to judge the
effectiveness of NIV and the need for invasive ventilation. If there is any uncertainty,
these patients should be routinely intubated, mechanically ventilated, and treated
conventionally. Some patients may require ventilatory support during this period.
Lambert-Eaton myasthenic syndrome (LEMS) LEMS is a myasthenic syndrome
related to small cell lung cancer (3% of cases) that can distress the respiratory
muscles in a mode similar to that of myasthenia gravis. Typical clinical features are
fatigue, proximal more significant than the distal weakness of limbs, areflexia,
dysautonomia, occasional respiratory compromise, and intact sensation and
oculomotor movement. Although respiratory involvement is often a late outcome,
frank respiratory failure can be present, and this disorder should be contemplated in
individuals with unexplained neuromuscular weakness [10].

Botulism
Botulism is produced by a toxin of the Clostridium botulinum (A-F toxin) from

contaminated, improperly canned foods. In the infant, respiratory failure results from
respiratory muscle weakness and paralysis, causing hypoventilation; bulbar palsy
and upper airway muscle weakness, aspiration pneumonia or upper airway
obstruction; and inability to clear secretions in pneumonia atelectasis. Endotracheal
intubation is performed as soon as depression of the gag reflex is noted. In older
children, the beginning of neurologic symptoms follows a characteristic pattern of
diplopia, blurred vision, ptosis, dry mouth, dysphagia, dysarthria, reduced gag reflex,
and decreased corneal reflex followed by flaccid descending paralysis that
progresses to affect the respiratory muscles and involvement of the upper airway,
diaphragm and intercostal muscles often lead to the requirement for intubation and
mechanical ventilation. Respiratory muscle aids are usually required, and pneumonia
is a common complication and a significant cause of death.
Management necessitates intensive care with mechanical ventilation and
administration of antitoxin. Deferral in conduct may allow paralysis progression,
prolonged hospitalization and deaths of long-term mechanical ventilation and
intensive care unit care.
CONGENITAL MYOPATHIES
The congenital myopathies are a diverse group of disorders, often differentiated

based on pathological findings on muscle biopsy and usually presenting in the
neonatal period. In general, earlier presentation indicates more severe and rapid
disease, and many of these disorders are fatal. However, the clinical course is
variable, and patients with the same pathological findings may present during
childhood or later in life. Later presentations are usually accompanied by milder
symptoms and static or slowly progressive weakness. The congenital myopathies
with severe infantile-onset are characterized by weakness, hypotonia, deficient motor
development, skeletal abnormalities, and respiratory compromise, usually leading to
an early death.
Duchenne Muscular Dystrophies
DMD is a progressive myopathic disorder caused by mutations of the dystrophin

gene on chromosome Xp21. DMD usually presents by age 5 years with impaired
ambulation and proximal weakness of the pelvic girdle muscles. Symptoms typically
are present in early childhood with an exaggerated lumbar lordosis. If not arrested by
spinal immobilization surgery or external bracing, scoliosis causes progressive
restriction of pulmonary expansion, and in combination with the cardiac dysfunction,

further compromises respiratory muscle function. Chest wall muscle weakness and
contractures, spinal deformity, and vertebra-costal ankylosis also occur. Death is
predictable, usually by the second decade’s conclusion, due to heart failure or
pulmonary causes [11].
Loss of lung function developments linearly after the beginning of wheelchair
use; increasing hypoxemic dips are observed during the night in subsequent teenage
years, and respiratory failure happens between 18 and 20 years of age. A restrictive
syndrome secondary to muscle weakness typifies the pulmonary compromise in
DMD patients. If adequately managed with respiratory muscle aids, these patients
habitually die before age 30. In DMD, the decline in pulmonary function parallels the
evolution of the disease. An FVC of less than 1 L is a predictor of poor outcome, with
a 5-year survival rate of only 8% if mechanical ventilation is not used. When daytime
hypercapnia develops in DMD patients, life expectation without NIV is approximately
9 to 10 months. Patients with DMD finally require 24-hour use of noninvasive
inspiratory muscle aids. Managing of a patient with DMD is mainly supportive.
Several factors contribute to improved DMD survival as pharmacological
interventions (including corticosteroids and idebenone) significantly reduce
spirometric parameters, scoliosis, NIV, and cough assist devices tracheostomy.
Maintaining cough and adequate airway clearance is extremely important in
preventing atelectasis and pneumonia in this patient population [12]. Respiratory
tract infections are a severe complication of DMD patients and must be treated
aggressively with physiotherapy, postural drainage, assisted cough techniques and
apposite antibiotics. Care must be centre in specialized units with multidisciplinary
support, including physiotherapy, occupational therapy, speech therapy, specialist
nursing, and general medical help, particularly in gastrointestinal and cardiovascular
care.
A genetic defect of dystrophin also causes Becker muscular dystrophy (BMD),
but the deletion or duplication maintains the gene’s reading frame, allowing the
protein to be produced. The severity of the disease correlates with how much of the
dystrophin molecule is available. Loss of the central rod domain is much better
tolerated than the loss of either the carboxy or amine terminal anchors. The clinical
progression of BMD is more variable than DMD. In general, important clinical
milestones are delayed by 10 years. As such, scoliosis and pulmonary compromise
are slower to progress and allow for more effective management. Cardiac disease is
less common with BMD, but progressive cardiomyopathy may be more severe than
the skeletal myopathy in exceptional cases. Treatment of both Duchenne and Becker
muscular dystrophies is palliative for the most part and directed against scoliosis,
contractures, and functional disabilities [13]. Prednisone has been shown to slow
disease progression, at a dose of 0.75 mg/kg/day, Noninvasive ventilation is useful
for disease management.

Myotonic muscular dystrophy is a multisystem disease inherited as an autosomal

dominant trait, caused by a triplet repeat expansion (CAG) on chromosome 19q21.
There are two significant classifications including DM1, formerly known as Steinert’s
disease, and DM2, a milder disease form. DM diverges from other muscular
dystrophies with multisystem effects, comprising cardiac conduction abnormalities,
insulin resistance, cataracts, and infertility [14]. DM1 presents at birth through
adulthood in its milder form and DM2 only in adult-onset. Respiratory muscle
weakness is usual in DM1, resulting in restrictive pulmonary evidence and alveolar
hypoventilation. Diaphragm weakness is typical in DM and gives to hypoventilation.
Oropharyngeal muscle weakness can cause product dysphagia, chronic aspiration
risk, sleep-disordered breathing with a prominent central apnea component and
nocturnal hypoxemia. Severe oropharyngeal muscle weakness may develop chronic
upper airway airflow restriction or aspiration.
In DM, sudden death is correlated with a significant risk factor for cardiac
arrhythmia and nocturnal hypoxemia secondary to sleep-disordered breathing.
Although NIV has been associated with improved survival, there are limitations in
using this therapy for DM patients. The characteristic facial muscle weakness in this
kind of patient often limits the ability to apply positive-pressure mask ventilation
successfully. Cognitive impairment also has been correlated with a critical restriction
in the patient’s compliance with the nightly use of positive-pressure mask ventilation.
A tracheotomy may be implied to improved respiration support. Patient with myotonic
dystrophy is particularly susceptible to development to respiratory failure during
general anaesthesia and sedative use [15].
Facioscapulohumeral Dystrophy (FSH)
FSH is autosomal dominant dystrophy that primarily affects muscles of the face
and proximal portion of the upper extremities. Clinically, the hyper and hypokalemic
periodic paralysis can be differentiated by myotonia in hyperkalemic periodic
paralysis. Despite the frightening rapidity of onset and four-limb involvement,
respiration is uncommonly compromised. Treatment of hypokalemic sporadic
paralysis attacks includes oral or parenteral potassium, with prophylaxis revolving
around avoidance of precipitating factors, diuretics, and carbonic anhydrase
inhibitors. Respiratory muscle weakness is moderately not uncommon in FSH. In a
patient with FSH, the FVC is significantly reduced, although facial weakness
complicates spirometric assessment [16].
In facioscapulohumeral and oculopharyngeal muscular dystrophy, respiratory
muscle weakness is uncommon, until the development of severe functional
impairment, when deficiency affects the intercostal diaphragm is generally
associated with severe scoliosis. However, selective diaphragm weakness may
occur, and early intervention with NIV can improve survival and quality of life.

Limb-Girdle Dystrophy (LGD)
LGD typically do not present the early contribution of respiratory muscles. The
condition usually presents in the 2nd or 3rd decade of life. Several case reports have
documented chronic hypercapnia development in patients with LGD who have
severe diaphragm weakness of bilateral diaphragm paralysis. Respiratory muscle
involvement has been described, and patients with LGMD2I are at particular risk of
respiratory muscle weakness. Still, there is no absolute correlation between skeletal
muscle weakness and selective involvement of the diaphragm. There is a significant
risk of developing respiratory muscle weakness following anaesthesia.
Mitochondrial Myopathy (MM)
Metabolic myopathies are inborn errors of metabolism that affect muscle, and
usually present as recurrent rhabdomyolysis or exercise-induced myalgias. Several
genetic metabolic myopathies can affect the respiratory muscles, including glycogen
storage and lipid metabolism disorders. Pompe disease (or type II glycogenosis) is a
disorder that involves respiratory muscles. This enzyme’s deficiency leads to
accumulation of glycogen within cardiac and skeletal muscle lysosomes, resulting in
myopathy. Complete enzyme deficiency effects in cardiorespiratory failure and death,
usually in the first year of life. There may be a restrictive ventilatory limitation with
respiratory muscle involvement and respiratory failure in severe cases. The disease
is slowly progressive, and respiratory failure is the leading cause of death,
sometimes after several decades. Treatment is mostly supportive, but inspiratory
muscle training may improve respiratory function, at least temporarily.
These are multisystem disorders, and several syndromes have been described,
including progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome,
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
(MELAS), myoclonus epilepsy with ragged red fibres (MERRF), mitochondrial neuro-
gastrointestinal encephalopathy (MNGIE), and neuropathy, ataxia, and retinitis
pigmentosa (NARP). The onset of these disorders is usually in childhood or young
adulthood, with progressive skeletal, smooth and cardiac myopathy, cerebral and
cerebellar dysfunction, peripheral neuropathy, and ocular disease. Respiratory
muscles are involved, but not out of proportion to other muscles. All disorders are
described with hypoventilation and depressed responses to hypoxia and hypercapnia
and an unsolved respiratory failure [17].
Inflammatory Myopathy
Inflammatory myopathies include rhabdomyolysis, electrolyte disturbances,

dermatomyositis, polymyositis systemic lupus erythematosus, and endocrine

myopathies (hyper- hypothyroidism, hyperadrenocorticism), high dose exogenous

corticosteroids, and inclusion body myositis are systemic inflammatory diseases of
unknown aetiology that produce intense skeletal muscle weakness. Respiratory
muscle weakness in MM may be underdiagnosed.
Dermatomyositis is the usual manifestation in children, and both occur in adults,
most commonly in the fifth and sixth decades. An associated malignancy is more
familiar with dermatomyositis than polymyositis, especially in patients over 40 years.
The clinical hallmarks of polymyositis/dermatomyositis include myalgia and stiffness,
proximal greater than distal weakness, elevated creatine phosphokinase levels,
features of a destructive myopathy on electromyography, and inflammation and
myonecrosis on muscle biopsy. Cardiac abnormalities are frequent, including
electrocardiogram changes, atrial arrhythmias, progressive heart block requiring a
pacemaker insertion, congestive heart failure, dilated cardiomyopathy, and
pericarditis. Pulmonary complications are also common, including restriction due to
chest wall and diaphragm weakness; interstitial lung disease occurs in 10% of
patients and is significantly associated with the Jo-1 antibody syndrome; and, rarely,
pulmonary hypertension.
In patients with systemic lupus erythematosus, diaphragm dysfunction and
respiratory muscle weakness with small lung volumes occur without apparent
involvement of the peripheral skeletal muscle. This syndrome has been titled "the
shrinking lung syndrome." Reduced lung volumes do not seem to be due to
parenchymal lung disease or phrenic neuropathy, but instead of a myopathic process
affecting diaphragm strength. It is estimated that approximately 25 per cent of SLE
patients have diaphragm weakness, even in the absence of a generalized myopathy.
Myopathy due to drugs or toxins is common and may at times become severe
enough to impair respiration. The syndrome most likely to be seen by a
pulmonologist is necrotizing myopathy, causing rhabdomyolysis, severe weakness,
pain, and swelling. Secondary complications include respiratory failure, renal failure,
hyperkalemia, and compartment syndromes. Among the more commonly
encountered entities that can cause myonecrosis are the cholesterol-lowering
agents, particularly the HMG-CoA reductase inhibitors, alcohol, and steroids.
Treatment is supportive, with cessation and avoidance of the inciting substance. (18)
Finally, although steroid-induced myopathy was first explained almost 30 years
ago, the increase of severe respiratory muscle weakness and protracted respiratory
failure subsequent high dose steroids, usually in asthmatic patients in ICU, has
received renewed interest.
Other Myopathies
Inclusion-Body Myopathy (IBM)

IBM is an adult-onset myopathy correlated with respiratory failure. SDB with
nocturnal respiratory dysfunction is usual in IBM and does not appear to correspond
with the degree of limb weakness [19].

Titinopathy and Myofibrillar Myopathy

Hereditary myopathy associated with early respiratory failure (HMERF) is an
adult-onset autosomal-dominant myopathy. Respiratory muscle weakness is present
in patients who are still ambulant also in other MFM subtypes.
Necrotizing Autoimmune Myopathies (NAMs)

NAMs are acute myopathies associated with a specific histological pattern of
necrosis and simultaneous muscle fibre regeneration but little or no inflammation.
Respiratory muscle weakness is significantly related to the presence of anti-signal
recognition protein antibodies, and maybe paraneoplastic, or related to the acute
myopathy that occurs in patients on statins. Toxic necrotizing myopathy occurs
because of drug ingestion, alcohol, medication, is often associated with
rhabdomyolysis, and can also lead to acute respiratory failure, but – unlike
necrotizing autoimmune myopathy – ventilatory impairment resolves with
discontinuation of the precipitating medication. Ventilatory failure associated with
respiratory muscle weakness is also recognized in inflammatory myopathies,
including body myositis, radiation myopathy, viral myositis, acute alcoholic
rhabdomyolysis, and myopathy secondary hypophosphatasemia, and diaphragm
myopathies associated with sarcoidosis and amyloidosis.
CONCLUSION
A great many neuromuscular diseases affect respiratory function by weakening,

singly or in combination, the muscles of inspiration (particularly the diaphragm),
expiration (impairing cough), and bulbar function (disrupting cough and swallowing).
A wide range of progressive neuromuscular disorders leads to dysfunction of the
respiratory muscles, respiratory failure, pneumonia, and death. The diseases’
morbidity and mortality are related to the age of onset, rapidity of progression, and
diffuseness of neuromuscular involvement. Vigilant evaluation and management of
respiratory problems can increase both the quality and length of life.
No conflict of interest.
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SECTION 1.
PHYSIOLOGY NEUROMUSCULAR DISORDERS

In: Respiratory Disorders in Neuromuscular Disease ISBN: 978-1-53619-890-4
Editors: G. Fiorentino and A. Esquinas © 2021 Nova Science Publishers, Inc.
Chapter 1
RESPIRATORY PHENOTYPES
OF PEDIATRIC PATIENTS
Adele Corcione, Melissa Borrelli

and Francesca Santamaria*
Departments of Translational Medical Sciences,
Federico II University, Naples, Italy
ABSTRACT
Most neuromuscular diseases (NMDs) have a genetic basis and are

characterized by overt presentation in childhood. These include disorders
affecting the anterior horn cell, the peripheral nerve, the neuromuscular junction,
the muscle and also metabolic myopathies associated to congenital defects in
glycogen, lipid, or mitochondria metabolism. Weakness of the respiratory
muscles associated to the act of breathing is a clinical hallmark of NMDs, and
results in the development of short- or long-term sequelae. Although NMDs are
heterogeneous, many lead to progressive impairment of the function of the
respiratory system including upper airway tone, cough and secretion clearance
and chest wall support. Respiratory symptoms and signs which may also occur
very early and are often severely disabling or significantly impact on the disease
course and the final outcome. Studies that assess the potential to improve quality
of life and reduce hospitalizations and frequency of lower respiratory tract
infections will help clinicians to decide which techniques are best suited for use in
children. As children with NMDs survive longer, coordinated programs for
transitioning these patients to adult care must be developed to enhance their
quality of life. This chapter examines issues related to the different respiratory
phenotypes of the congenital NMD at different pediatric ages, and summarizes
the work-up that physicians should plan to investigate the associated respiratory
disease.
* Corresponding Author’s E-mail: santamar@unina.it.

26 Adele Corcione, Melissa Borrelli and Francesca Santamaria
Keywords: respiratory phenotype, respiratory failure, recurrent pneumonia,

ventilatory support, pulmonary function
INTRODUCTION
The term pediatric neuromuscular diseases (NMD) encompasses several

disorders with onset in childhood. Overall, the pediatric conditions share the common
feature of predominant affection of the neuromuscular unit including motor neuron,
peripheral nerve, neuromuscular junction, or muscle fiber [1]. Although children or
adolescents may be affected by some acquired, mostly inflammatory, and treatable
diseases (notably, the Guillain–Barré syndrome and chronic inflammatory
polyneuropathy), most conditions reported in the pediatric age are hereditary and are
associated to a de novo or an inherited pathogenic variant in a single gene [2]. Only
NMD with a genetic basis will be herein discussed. These include disorders affecting
the anterior horn cell (e.g., spinal muscular atrophy), peripheral nerve (e.g., Charcot–
Marie–Tooth disease), the neuromuscular junction (e.g., congenital myasthenic
syndrome), and the muscle (muscular dystrophies, congenital myopathies and
myotonic dystrophy). In addition to these, pediatric NMD also include the metabolic
myopathies, namely a group of muscle disorders associated to congenital defects in
glycogen, lipid, or mitochondria metabolism. Among these, the glycogen
abnormalities-associated respiratory involvement may affect either newborns and
infants or older children, while the lipid metabolism or mitochondria defects are
reported primarily in adults.
Overall, most NMDs show prevalence rates between 1 and 10 per 100,000
individuals, hence are considered rare disorders, except for some of them, for
instance the Charcot-Marie-Tooth disease that has a prevalence >10/100,000 [3].
The common denominator of pediatric NMD is the weakness of the respiratory
muscles which are responsible for the act of breathing and result in the development
of short- or long-term sequelae. The clinical course pf most NMDs is indeed
dominated by respiratory symptoms and signs which may also occur very early and
are often severely disabling or significantly impact on the disease course, patients’
and family quality of life and the final outcome.
We herein will present the pathophysiology of the respiratory complications of
NMD and provide a description of the major congenital NMDs that can occur in
children or adolescents. Finally, we will discuss presently the different respiratory
phenotypes of the congenital NMDs at different pediatric ages, and summarize the
work-up that physicians should plan to investigate the associated respiratory
disease.

Respiratory Phenotypes of Pediatric Patients 27
PATHOPHYSIOLOGY OF THE RESPIRATORY COMPLICATIONS OF NMD
The likelihood that a child with NMD develops respiratory complications is

extremely variable and depends on several factors, including the underlying
condition-specific clinical and genetic characteristics, as well as the patient’s age.
The most important effect of NMD on the respiratory system is a limited capacity
to breathe that tends to progressively worsen with ageing [4]. In affected patients,
breathing is restricted because of weakened or paralyzed upper and lower airways
muscles. At rest, the diaphragm and the accessory muscles are the principal
muscles used for inspiration, while the expiratory muscles, initially passive, are
activated during the final part of expiration. Any decrease in the activity of the
expiratory muscles leads to augmented residual volume (RV) and reduced vital
capacity (VC). Main clinical consequences are impaired gas exchange and
hypoventilation, which may be later complicated by sleep disordered breathing (SDB)
and obstructive sleep apnea syndrome (OSAS), especially when VC falls to less than
60% predicted [4]. In the typical sleep-associated supine position, the functional
residual capacity (FRC) tends to further decrease because of the inward movements
of the abdominal content and, finally, also the tonic activity of several muscles
involved in the respiratory cycle progressively decreases. These events are
responsible, at least in part, for the development of paradoxical rib cage movements
during inspiration, which appears more pronounced in the rapid-eye movement
(REM) sleep phase. Indeed, nocturnal hypoventilation and impaired gas exchanges
with hypoxemia and hypercapnia are the typical signs of chronic respiratory failure
occurring in most congenital NMD, especially those progressively deteriorating. Both
upper and lower airways, including the lungs, are intrinsically normal in NMD, but get
secondarily involved because of the limited excursions of the thoracic cage. Early, or
sometimes delayed complications are due to inability to cough or swallow effectively
with chronic aspiration into the airways, which can be worsened by impaired
pulmonary defense mechanisms with pneumonia and segmental-to-lobar atelectasis
also due to abnormal mucus production and clearance. Pulmonary vascular
abnormalities have not been reported as complications in pediatric NMD, except for
one anecdotal report of moderate pulmonary arterial hypertension in an adolescent
with a mitochondria myopathy. Eventually, most if not all children with NMD develop
a restrictive disease with the typical pattern at spirometry. In addition to reduced
respiratory muscle strength, the lung function derangement is worsened by the
progressive development of vertebral scoliosis and reduced chest wall and lung
compliance. All these events explain the progression to respiratory failure and the
ultimate dramatic outcome occurring in the majority of infants, children or
adolescents with congenital NMD.

MAJOR CONGENITAL NMDS OCCURRING IN PEDIATRIC PATIENTS
NMD Affecting the Anterior Horn Cells
Spinal Muscular Atrophy

The term spinal muscular atrophy (SMA) refers to a genetically heterogeneous
group of lower motor neuron diseases that are classified into clinical groups on the
basis of age of onset and maximum motor function achieved.
SMA Linked to SMN1 Gene

This frequent autosomal recessive disease has an incidence of 1/5000–10 000
births and a frequency of heterozygous carriers of 1/35–60 in the general population
[5]. It is caused by biallelic pathogenic variants in the SMN1 gene on chromosome
5q13.2. 5q13. Although 3 distinct clinical forms are classically reported (SMA I, also
named Werdnig–Hoffman disease; SMA II; and SMA III, also known as Kugelberg–
Welander syndrome), a considerable overlap exists between the subtypes. Thus, a
clinical continuum between the earliest forms, which may be overt at birth or even in
utero as fetal distress and severe arthrogryposis (SMA 0), and the latest forms
described in adulthood (SMA IV), has been reported.
SMA-1, which is responsible for most of the cases with the “floppy infant”
syndrome, is an extremely common anterior horn cell disorder of children. Usually,
infants are easily recognized because of their clinical presentation with severe
generalized hypotonia associated with a typical “alert facies” and/or failure to develop
early motor milestones between ages 1 to 3 months. The muscle stretch reflexes are
typically absent, and in most cases fasciculations of tongue may be observe. A
prenatal subtype with overt manifestations yet at birth has been reported as SMA 0
[6]. Infants with prenatal SMA and SMA-1 have impaired head control, with weak cry
and cough. Intercostal muscle weakness is responsible for paradoxical inward rib
cage movement at each inspiration, while the diaphragm is relatively spared. Most
cases with prenatal SMA and SMA1 require the neonatal intensive care unit
monitoring. Chest x-rays show a reduced intrathoracic volume and a bell-shaped
thorax. Infants present also with early swallowing disorders and aspiration
phenomena, and are at risk of respiratory failure due to recurrent airways infections.
There are few studies about SDB in SMA 1 and they predominantly report marked
thoraco-abdominal asynchrony with only mild signs of sleep disordered breathing.
SDB often precedes manifest diurnal respiratory failure by years, and causes sleep
disturbance, restless sleep, nocturnal hypoxemia and CO2 retention, inducing
autonomic nervous system dysfunction and neurobehavioral daytime symptoms. The
few data published, as well as the limited clinical experience, indicate that children
with SMA type 1 may develop respiratory distress with pulmonary aspiration that, at
least initially, is not related to SDB. The decision of ventilatory support is based on
the need of treating dyspnea and improving the thoraco-abdominal asynchrony,
which occur during sleep because of reduced muscle tone and hypoxaemia [7].

Patients with SMA1 were unable to sit without support and never start walking. The
prognosis is poor, with 95% of infant dying for respiratory failure by the age of 18
months without intensive respiratory intervention. Current clinical management of
SMA primarily includes aggressive treatment of respiratory infections and early
ventilatory support. The effect on respiratory complaints of the new agent Nusinersen
given via intrathecal injection to modify the splicing of exon 7 appears promising [8].
In children with SMA-2, muscle weakness usually occurs after the first 6 months of
age and has a relatively slow course. The ability to sit is present when the child is
placed in a setting position, while inability to start walking is very common. Low
muscle tone is generally present. School-age children with SMA 2 can have SDB
during REM sleep as first sign of respiratory failure. With adequate respiratory
management tailored to respiratory involvement, such as noninvasive ventilation,
mechanical in-exsufflation and the prevention of respiratory infections, a good quality
of life and lifespan into adulthood is expected for most SMA-2 patients. Children with
SMA-3 usually present with proximal limb weakness after the age of 10 months. Legs
are more severely affected than arms. Patients are able to walk at least 25 meters,
but frequently fall or present with trouble walking up and down stairs at age 2 to 3
years. Respiratory involvement is usually minimal in SMA-3, even if a small and slow
decline of pulmonary function can be observed in the natural history of the disease. A
normal lifespan is expected.
Other, NON-SMN1 Linked SMAs

These rare conditions, including SMA with respiratory distress (SMARD), are
characterized by wide clinical and genetic heterogeneity. Age at onset ranges from
birth to 6 months. The gene identified as causing SMARD type 1 (immunoglobulin l-
binding protein 2 [IGHMBP2]) has not been related to all cases of SMARD. SMARD
type 1 has an autosomal recessive mode of inheritance due to mutations in the
IGHMBP2 gene on chromosome 11q13, which codes for a protein involved in mRNA
processing machinery. Major clinical features of SMARD include peripheral
hypotonia with distal weakness, hemidiaphragmatic palsy, and absent deep tendon
reflexes. Clinically, it looks like the severe infantile SMN-linked SMA, with severe
respiratory distress reported as early finding usually after a symptom-free interval of
several weeks in the post-partum period. The clinical picture is characterized by
initial respiratory insufficiency due to diaphragmatic palsy and often followed by
distally pronounced weakness and wasting, which is in contrast to SMA type I, where
weakness is predominantly present in the proximal muscles. The prognosis is usually
poor, with early death unless mechanical ventilation is provided. The disease can be
easily mistaken for infantile SMA.
NMDs Affecting the Peripheral Nerve
The genetic neuropathies are a heterogeneous group of diseases including those

in which neuropathy is the sole manifestation of the disorder (Charcot–Marie–Tooth

disease, CMT) and those in which the neuropathy is part of a more generalized
neurologic or multisystem disorder (e.g., familial amyloid polyneuropathy,
neuropathies associated with mitochondrial diseases, or with hereditary ataxias, or
porphyrias). The term CMT, also reported as hereditary motor and sensory
neuropathy or peroneal muscular atrophy, includes a heterogeneous group of
conditions associated with demyelinating distal muscle weakness and atrophy with
accompanying sensory loss, decreased deep tendon reflexes, and reduced nerve
conduction velocities [9]. CMT represents the most common type of hereditary
neuropathy as a whole, with an incidence of approximately 1 in 3300. Inheritance can
be autosomal recessive, autosomal dominant, or X-linked. Salient features include
peripheral hypotonia with distal weakness (feet, ankles, legs and hands), atrophy,
sensory loss, and decreased deep tendon reflexes. Symptoms of CMT usually
appear between the age of 5 and 15 years, although they may not develop until
middle age or even later. CMT is a slowly progressive condition, this meaning that
the symptoms slowly get worse and most subtypes do not have a reduced lifespan.
While the majority of affected individuals have the classical presentation described
above, cases with very severe neuropathy may present yet in infancy with a clinical
phenotypic appearance similar to SMA I and profound weakness [10]. Respiratory
involvement may occur early and infants may be so ill to require ventilatory support
[11]. Indeed, any floppy infant presenting with a “frog leg” posture and tongue
fasciculations most likely has SMA I. Conversely, electromyography (EMG) findings
with very slow motor conduction velocities, dispersed low-amplitude compound
muscle action potentials, and absent sensory nerve action potentials indicate that an
acquired demyelinating polyneuropathy, and not an abnormality primarily at the
motor neuron level is present [12]. This group of genetic neuropathies also includes
the Dejerine-Sottas syndrome and the Congenital Hypomyelinating Neuropathy,
which are characterized by generalized hypotonia in infancy (the “floppy infant”) and
also early, respiratory disturbances associated with feeding difficulties. In these form
of very severe disease neuropathy can lead to sleep disturbances. Both disorders
might represent the severe end of the same disease, i.e., the CMT1, and share the
same underlying genetic defect.
NMD Affecting the Neuromuscular Junction
The disorders of the neuromuscular junction (NMJ) include a wide range of

human diseases with only a proportion of these occurring in infancy. The
autoimmune maternal-associated myastenia gravis is the most easily recognized and
probably the most common entity reported in childhood. This relatively short-lived
disorder typically occurs at birth in 15% to 20% of infants whose mothers have
myasthenia gravis.

Congenital Myasthenic Syndromes (CMS)

They are a number of relatively rare congenital conditions caused by mutations in
approximately 30 genes that form and/or regulate the neuromuscular junction with a
primary pathophysiologic site of difficulty varying between the presynaptic NMJ, the
synapse, and the postsynaptic NMJ [13]. Although CMS are the less common
myasthenic disorders (estimated prevalence 1–9 per million), they indeed show a
wide clinical and pathologic diversity. Age at onset ranges from birth or shortly after
birth to early childhood, or rarely later childhood. Symptoms occurring in the neonatal
presentation can include feeding difficulties, poor suck, weak cry, eye ptosis, and
facial weakness. An endplate deficiency of choline acetyltransferase is a CMS that
predisposes the infant to an acute-onset disorder. Typically, infants have recurrent
episodic apnea and cyanosis with high risk of respiratory failure. In contrast, it is
unusual for other CMS forms to have such an acute presentation and they may be
particularly difficult to diagnose in neonates in whom nonspecific features such as
poor suck or cry, generalized hypotonia, or arthrogryposis may be the only overt
clinical features [14]. Older children may present with increased fatigability and have
difficulty running or climbing the stairs. Ptosis or intermittent extraocular muscle
weakness may be present as well. Diagnosis of myasthenia relies on the typical
EMG findings and on negative anti-acetylcholine receptor testing.
NMD Affecting the Muscle
The disorders of the muscle include the group of the muscular dystrophies, the
congenital myopathies and the myotonic dystrophy.
Muscular Dystrophies (MD)

The Muscular Dystrophies (MD) are a clinically and genetically heterogeneous
group of extremity muscles disease presenting with muscular weakness and raised
serum creatine kinase (CK) levels [15]. Recent literature distinguishes several
categories of MD such as the dystrophinopathies [Duchenne muscular dystrophy
(DMD caused by the X-linked recessive out-of-frame mutations of the dystrophin
gene and deficiency of the protein dystrophin) and Becker MD (caused by dystrophin
gene mutation with expression of mutant forms of dystrophin], the limb girdle
muscular dystrophies, the Emery-Dreifuss muscular dystrophies, and the congenital
muscular dystrophies [1, 14, 19].
The Duchenne Muscular Dystrophy (DMD) is the most common and severe form
of MD, with an estimated prevalence of 1:5000 boys [16]. DMD presents at 2-4 years
of age, with symptoms such as abnormal gait, frequent falls, and difficulty climbing
steps due to proximal muscles weakness. In the early phases of the disease,
pulmonary function may be normal and the onset of progressively increasing
respiratory problems coincides with the loss of ambulation. Patients with DMD also
have a lung function restrictive pattern due to muscle weakness and contractures,

spinal deformity, vertebra-costal joint ankylosis and frequent obesity. Monitoring of

pulmonary function is critical because FVC will eventually declines silently (in the
absence of dyspnea). In most patients, FVC increases with growth until loss of
ambulation develops, at which point FVC will sequentially peak, plateau, and then
deteriorate over time [17]. The first sign of chronic respiratory failure in DMD is
nocturnal hypoventilation, which can be further increased by the development of
SDB, yet in the first decade of life. The diagnosis is suspected by delayed muscle
function, speech delay and elevated serum CK concentration and then confirmed by
molecular genetic testing. Death is most often related to respiratory insufficiency. The
use of ventilator support with early and aggressive management of respiratory
infections, has been reported to prolong life. Systemic steroids are currently the only
drugs that can be successfully administered also to children or adolescents with
DMD to sustain muscle strength and function even though the rationale for their use
is not completely clear and the risk of side effects should not be underestimated. Use
of steroids can prolong the period of ambulation and preserve pulmonary function in
individuals with DMD [18]. However, weight gain is a common side effect and as a
result, OSAS is the most common form of SDB among steroid- treated patients,
affecting patients as young as those aged 12 years. To prevent or minimize
respiratory illnesses, individuals should receive routine immunization with the
influenza and pneumococcal vaccine.
In the Becker muscular dystrophy (BMD) the distribution of muscle weakness is
similar to DMD, but the disease onset may be delayed to the late first decade, or the
second decade, or also later to age 30 or 40 years (mild BMD). Some patients may
present initially in the late second or third decade with signs of cardiomyopathy with
clinically normal strength or mild strength loss. Respiratory involvement occurs in a
subset of patients and ventilator dependency is required in only severe patients.
The Facio Scapulo Humeral Muscular Dystrophy (FSHD) is an autosomal
dominant disorder linked to the chromosome 4q35 locus, with abnormalities in the
D4Z4 DNA fragment, with predominant involvement of facial and shoulder girdle
musculature, often asymmetrically. Prevalence estimate is of 1 to 5/100,000.
Presentation ranges from early to later life, but typically occurs before age 20.
Initially, 85% of patients show predominant involvement of the facial and shoulder
girdle musculature with facial weakness commonly being the initial manifestation.
Severe infantile onset type is associated with sensorineural deafness. Severe
respiratory weakness does occur, but less than 5% of cases will require ventilator
assistance and life expectancy is often normal. Serum CK concentrations are normal
or mildly elevated.
The Limb girdle muscular dystrophy (LGMD) is caused by a number of distinct
genetic mutations, with either autosomal dominant (LGMD1) or autosomal recessive
inheritance (LGMD2) and a progressive pattern of greater proximal than distal
muscular weakness. Lower extremities tend to be more affected than upper
extremities. In patients with autosomal recessive inheritance (LGMD2) generally
symptoms associated with muscle weakness occur earlier than in those with
autosomal dominant inheritance (LGMD1). Respiratory involvement in LGMD1 is

characterized by mild restrictive lung disease. In LGMD2, the distribution and pattern
of weakness tends to be similar to DMD, however, the rate of progression tends to
be slower than in DMD. In LGMD2 respiratory involvement is variable, with FVC
ranging from normal to severely reduced.
The term Emery Dreifuss Muscular Dystrophy (EMD) refers to a group of MD
associated with abnormalities of the protein emerin characterized by weakness,
contractures, and cardiac conduction abnormalities, which includes the types 1 and
2. In type 1 EMD the age of presentation ranges from the neonatal period with
hypotonia to the third decade of life, however patients usually present in the teenage
years. Progressive cardiac disease is almost invariably present with onset after the
early second decade. Some cases with EMD1 can have nocturnal hypoventilation as
a result of restrictive expansion of the chest in association with the rigid spine, and
partly because of the involvement of the diaphragm. In type 2 EMD, patients with
missense mutations show symptoms due to scapuloperoneal muscle weakness at a
mean age of 2.4 years. Respiratory insufficiency is common in early childhood and
may precede the loss of ambulation.
The term Congenital Muscular Dystrophies (CMDs) classically defines a group of
disease characterized by an early onset of muscle weakness with histologic evidence
of dystrophy, with an overall prevalence of 0.99 per 100,000 for all age groups, of
which 80% are reported in childhood. CMDs include severe and often early fatal
disorders as well as relatively mild conditions which are compatible with survival into
adult life [14, 20]. Clinical features include hypotonia, muscle weakness at birth or in
the early childhood and congenital contractures. The CMD include the following
conditions:
 The Merosin-Deficient CMD (MDC1A, Laminin- α2 Related CMD): this is an

autosomal recessive disorder, caused by LAMA2 mutations, that encodes
laminin-α2, the most important extracellular interaction partner of the α-
dystroglycan complex, which is also located in the extracellular matrix. The
latter is a constituent of the dystrophin-associated glycoprotein complex,
which links dystrophin to the extracellular matrix. Phenotypes of mutations in
this gene can be classified by the amount of merosin in muscle or skin
biopsy. Complete absence of this protein leads to a severe CMD with
congenital or early onset during the first months of life, characterized by
marked muscular hypotonia and weakness, involvement of the facial
muscles, and sometimes presence of distal contractures that may resemble
arthrogryposis. Facial weakness and jaw contractures disrupt normal feeding,
resulting in failure to thrive and need of early nutritional support. Motor
milestones are delayed and ambulation is rarely achieved. By mid-teenage
years respiratory muscle weakness results in recurrent chest infections and
respiratory insufficiency requiring nocturnal non-invasive ventilation.
 The LMNA-Related Congenital Muscular Dystrophy: Mutations in LMNA
encoding the nuclear intermediate filament laminin A/C (a protein which is an
intermediate filament located at the inner nuclear membrane) are most

commonly associated with the Emery–Dreifuss muscular dystrophy (with its

characteristic phenotype of scapulohumeral–peroneal muscular weakness,
cardiomyopathy, and multiple contractures). However, the phenotypic
spectrum of LMNA mutations encompasses a variety of unique entities,
including the early onset muscular dystrophy (termed LMNA-CMD),
characterized by a predominantly congenital or early infantile onset of severe
muscular weakness. Primarily of axial and neck muscles, involvement of the
extremities that is more proximal in the upper limbs and distal in the lower
limbs, early lumbar hyperlordosis, and multiple contractures. The
characteristic and often severe weakness of axial and neck muscles is
denoted by the term “dropped head syndrome”. Free sitting is commonly
achieved, except in the most severe cases, but ambulation can be variable.
Respiratory compromise is common in early childhood and may precede loss
of ambulation.
 The Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy
Spectrum: this disorder is caused by mutations in COL6A1, COL6A2,
COL6A3 that encode for the three α-chains of Collagen VI, a major
component of the extracellular matrix, which associates with the basal
lamina. Mutations in the same genes also cause the milder phenotype of the
Bethlem myopathy. Inheritance for these entities is either autosomal
recessive or autosomal dominant. Both phenotypes show not only the
genetic but also clinical overlap and therefore a continuum between both
entities is assumed. The distinct phenotype of Ulrich CMD is characterized by
congenital generalized muscular weakness and typical hypermobility of distal
joints in association with proximal joint contractures. Affected children show
significant delay in motor development, although ambulation may be
achieved in milder forms. The natural course often shows progression of
contractures, muscle weakness, and scoliosis with concomitant deterioration
of lung function. Inadequate ability to thrive commonly requires gastrostomy.
Respiratory insufficiency may start early but is fully manifested by the early
teens who need nocturnal respiratory support. Cognitive development is
normal. In the allelic milder phenotype of Bethlem myopathy, symptoms
typically start in late adolescence, but cases presenting in the neonatal
period have been reported. The clinical course may be slowly progressive. A
range of transitional severity between the Ullrich and the Bethlem types is
referred to as intermediate phenotype. These patients ambulate beyond the
early teenage years, are unable to run and may show a pattern of
progressive respiratory failure.
 The Rigid spine with muscular dystrophy is caused by mutations in a gene
encoding selenoprotein N (SEPN1), which maps to 1p35- 36. There are
many similarities to Emery– Dreifuss syndrome, but symptoms and signs
occur early. The most common clinical findings include axial hypotonia and
weakness, often in the first year of life, usually in a child with otherwise
normal motor milestones and no significant contractures. Ambulation is

usually maintained into adulthood unless a severe progressive scoliosis

develops. The overall muscle mass is reduced, especially in the medial
aspects of the thighs. The most prominent clinical feature is spinal rigidity
and scoliosis due to contractures of the spine extensor muscles, which may
develop between 3 and 12 years. There is often a significant clinical
discrepancy between the functional abilities of affected individuals, who are
able to walk, and the compromise of respiratory function. Low vital capacity is
due to stiffness of the rib cage and tends to decrease progressively. This is
almost invariably aggravated by the diaphragmatic weakness which leads to
progressive respiratory failure. Many patients require ventilator assistance as
early as in the first decade of life. Early ventilator support instigation allows to
preserve an active life with good quality and reasonable muscle function over
many years or possibly decades.
 The α-Dystroglycan Related Dystrophies: the largest group of the congenital
muscular dystrophies, are disorders of glycosylation of α-dystroglycan. α-
Dystroglycan is a sarcolemmal membrane protein that mediates interactions
of the cytoskeletal matrix and muscle extracellular matrix. The complexity of
symptoms and the partially profound clinical overlap of phenotypes of the
different genes has led to a new nomenclature which includes the “congenital
muscular dystrophy-dystroglycanopathy with brain and eye anomalies” (type
A or MDDGA) and the “congenital muscular dystrophy-dystroglycanopathy
with or without mental retardation” (type B or MDDGB) and “limb-girdle
muscular dystrophy-dystroglycanopathy” (type C). Among the major
disorders, including also the Fukuyama congenital muscular dystrophy and
the muscle eye brain disease, the Walker-Warburg Syndrome delineates the
most severe phenotype within the continuum of α-dystroglycan related
dystrophies and is characterized by muscular dystrophy in combination with
ocular and cerebral malformations. Prognosis is poor with only little
psychomotor development and most children dying during their first year of
life because of respiratory failure aggravated by recurrent aspiration
pneumonia.
Congenital Myopathies
The Congenital Myopathies are a group of heterogenous disorders, including the
Central Core Myopathy, the Nemaline myopathy, the Centronuclear myopathy (non
X-linked), the Severe X-Linked Centronuclear (Myotubular) Myopathy, and the
Congenital Fiber-Type Size Disproportion. Patients generally present with congenital
hypotonia, muscle weakness, delayed motor milestones and feeding difficulties.
Weakness is most often generalized or more pronounced in the proximal muscles
and frequently involves facial muscles. External ophthalmoparesis, and ptosis are
common features. In contrast to congenital muscular dystrophy, weakness in patients
with congenital myopathies is less progressive, the CK levels are often normal or
only mildly elevated, and no neurological involvement occurs. In patients with
congenital myopathies symptoms generally start in the first year, but a wide spectrum

of severity is reported, including later-onset phenotypes. Prenatal onset is common

and results in decreased fetal movements and polyhydramnios. As a result, affected
infants can be born with arthrogryposis and facial dysmorphisms. There is also wide
heterogeneity even among the affected members from the same family, in terms of
progression, age at onset, and presence of other complications such as
cardiomyopathy and respiratory impairment. Clinical phenotypes are largely
overlapping across the different disorders, making clinical diagnosis virtually
impossible. A specific diagnosis of each entity is made based on the specific
histologic and electron microscopic changes found on muscle biopsy. Molecular
genetic studies are increasingly being used to confirm the subtypes diagnosis.
In the group of congenital myophaties, the respiratory involvement, typically
aggravated by early feeding difficulties in infancy, is commonly reported in patients
affected by the core myopathy, especially the Multiminicore disease and the
Nemaline myopathy. In the latter, patients with the severe or intermediate type show
reduced diaphragmatic motility and may become dependent of the ventilator support
by age 11 years. Among the centronuclear myopathies, males with the X-linked form
show a generalized muscle weakness yet at birth or in early infancy that requires
invasive ventilation and often die prematurely because of severe respiratory failure
[20].
Myotonic Dystrophies
Among the Myotonic Dystrophies, the myotonic dystrophy type 1 (DM1) and 2
(DM2) represent two entities that may show an overlap in the clinical features. The
myotonic muscular dystrophy type I (DM1) is an autosomal dominant multisystem
MD caused by an expansion of the cytosine-thymine-guanine (CTG) trinucleotide in
the nontranslating region of the dystrophia myotonica protein kinase gene. It is
classified into 3 subtypes and has a combined incidence of approximately 1 in
20.000 [14]. The phenotype and the age of onset, from prenatal period to adulthood,
are related to the size of the CTG expansion. The disorder affects skeletal muscle,
smooth muscle, myocardium, brain, and ocular structures. Myotonia, which is a state
of delayed relaxation or sustained contraction of skeletal muscle, is easily identified
in school-aged children, adolescents, and adults with DM1. The Congenital myotonic
dystrophy (cDM) is considered primarily when an affected mother delivers a floppy
infant born presenting with feeding difficulties and early respiratory failure that
requires soon after birth intubation and ventilation. Respiratory failure causes a high
rate of mortality, owing to diaphragmatic and intercostal muscle involvement,
pulmonary immaturity, aspiration pneumonia, and⁄or cerebral disturbances.
Prematurity, polyhydramnios and fetal hydrops with pleural effusions and pulmonary
hypoplasia can increase respiratory complaints. Severe respiratory difficulties with
need of ventilator support are reported in 50% of cases and are responsible for
neonatal death in approximately 30% of these. If ventilator support is prescribed
beyond the first month of life, the prognosis is poor, with the risk of sudden death in
survivors, even without apparent respiratory exacerbation. However, those who
survive generally show improvement in hypotonia. Facial weakness may remain

stable or become more significant, causing speech delay and the risk of aspiration
remains high. Electrocardiograms are crucial for evaluation of syncope and
palpitations, and annual screening should occur for potential asymptomatic cardiac
conduction defects. Mental retardation of varying severity occurs in approximately
half of affected children. In the Childhood Onset Myotonic Dystrophy symptoms
present between age 1 and 10 years. Weakness of the respiratory and swallowing
muscle renders patients prone to repeated aspiration pneumonias and recurrent
airways infections. SDB and OSAS are often reported. However, a true restrictive
syndrome is commonly reported only in adults and chronic respiratory failure is rare
before late adulthood. In the Myotonic muscular dystrophy type II (DM2) respiratory
disturbances are rarely described in the pediatric age.
Figure 1. A 1-year old boy with acid maltase deficiency (Pompe disease). Chest X-ray
film shows multiple airspace consolidations in the right lower lobe, and diffuse
reticulonodular infiltrates.
Metabolic Myopathies
The metabolic myopathies are a group of muscle disorders resulting from failed
energy production related to defects in glycogen, lipid, or mitochondrial metabolism,
which may result in dysfunction of muscle or other energy dependent tissues, or
both. Most patients with metabolic myopathies have dynamic rather than static
findings, and therefore usually complain of exercise intolerance, muscle pain, and
cramps with exercise rather than fixed weakness. Nevertheless, some patients may
develop progressive muscular weakness, which is usually proximal, mimicking an
inflammatory myopathy or limb girdle muscular dystrophy. Older children and adults
with these disorders present primarily with exercise intolerance, weakness, and
myoglobinuria. Newborns and infants may present with severe multisystem

disorders, but the respiratory system appears to be involved only in the group of
glycogen metabolism abnormalities [21].
Disorders of Glycogen Metabolism
The Acid maltase deficiency (AMD, Pompe disease) results from mutations in the
alpha-1,4-glucosidase (GAA) gene which has been mapped to the long arm of
chromosome 17 (17q25.2–q25.3). More than 350 different mutations have been
described, and the genotype–phenotype relationship is a subject of active
investigation. It is associated with an absence or reduction of functional GAA which
results in extensive glycogen accumulation in skeletal muscles, visceral organs and
the central nervous system (CNS). The disease occurs in approximately 1 per 40,000
births, and based on appearance of symptoms, patients are typically classified as
having either the early (infantile) or late-onset (juvenile/adult) disease. These
classifications, however, actually represent a continuum that relates to the extent of
residual enzyme deficiency. The infantile form, caused by less than 1% activity of the
enzyme, presents in the neonatal period and, when untreated, leads to death from
cardiorespiratory failure or respiratory infection by 1 year of age (Figure 1). The
juvenile- and adult-onset forms present with progressive skeletal muscle dysfunction
and less severe cardiac involvement. Enzyme activity can range from 1 to 40% and
generally correlates with age at onset and disease severity. Myopathy is present in
all affected individuals eventually, with progressive muscle weakness in the trunk,
lower limbs, and diaphragm. Severe cardiomyopathy from glycogen accumulation in
cardiac muscle causes thickening of the ventricles and interventricular septum. It is
present only in the infantile form, generally occurring before 6 months of age. Most
die of cardiorespiratory failure before 2 years of age. Infants have profound
hypotonia with head lag, failure to thrive owing to feeding difficulties, and respiratory
difficulties. In the childhood variety of AMD, patients usually present with delayed
gross-motor development and progressive limb-girdle weakness. Respiratory muscle
weakness is always present, and leads to respiratory failure and death in the second
or third decade. Older children with AMD usually do not have cardiac involvement.
More than half of infants have also macroglossia and ⁄or moderate hepatomegaly
because of the glycogen accumulation, with consequent development of SDB and
OSAS, which represent a substantial problem. The respiratory muscle pathology and
dysfunction are prominent features of Pompe disease and contribute to respiratory
impairments as the disease progresses. Glycogen accumulates also in the CNS. A
neural mechanism can be considered to underlie the respiratory symptoms and it
explains enzyme replacement therapy delays symptom progression, even though
many patients eventually require ventilatory assistance, especially during sleep. This
would be explained because the recombinant protein used in the treatment of the
disease does not cross the blood-brain-barrier.

The Phosphorylase Deficiency (Glycogenosis Type V, McArdle’s Disease) is

characterized by a cluster of clinical features including exercise intolerance due to
muscle pain and cramps during exercise; stiffness shortly afterwards associated with
rhabdomyolysis and myoglobinuria; and the dark urine which may be the main
reason for seeking medical advice. Typically, the syndrome presents in the first two
decades of life, however, a heterogeneous clinical spectrum of the syndrome is now
recognized. It can occur in infancy with progressive weakness, hypotonia, respiratory
distress and insufficiency yet at or shortly after birth that may lead to premature
death and therefore must be considered in the differential diagnosis of the “floppy
baby” syndrome. When the onset is delayed until adult life, the clinical findings can
often be atypical, e.g., pain and tenderness in the masticatory muscles when eating,
or symmetrical, slowly progressive, limb weakness and muscle wasting which may
remain focal. Furthermore, asymptomatic McArdle’s disease associated with high
serum CK levels only and the absence of myophosphorylase has been recently
described. However, no correlation has been found between a specific mutation and
a clinical phenotype.
Disorders of Lipid Metabolism

In two disorders of lipid metabolism, namely the carnitine palmitoyltransferase 2
(CPT II) deficiency and the VLCAD deficiency, the abnormalities are usually induced
by prolonged exercise and the associated rhabdomyolysis and to prolonged fasting.
The impact of these disorders on the respiratory pathology is unclear and the
reported cases are only adults.
Mitochondrial Defects (MD)

These are a heterogeneous group of genetic diseases caused by dysfunction of
the mitochondrial respiratory chain or metabolism. Mitochondrial myopathies are
frequently multisystem disorders and those presenting in early childhood are usually
progressive and cause early death. Approximately 45% of the pediatric patients with
MD first present with a neuromuscular problem [13, 14]. However, the characteristics
and degree of neuromuscular impairment are poorly defined. There are two
conditions in which skeletal muscle is selectively affected which may cause
respiratory failure in childhood. Mutations in the thymidine kinase 2 gene (TK2)
cause a mitochondrial DNA depletion syndrome with manifest clinical variability.
Some mutations may cause a rapidly progressive myopathy with respiratory failure in
infancy. An unusual and benign cytochrome C oxidase deficiency myopathy is also
described. These infants have marked hypotonia and weakness with feeding and
respiratory difficulties (which may require mechanical ventilation) yet in the first days
or weeks of life with many of the features of other progressive mitochondrial
disorders. The condition is associated with spontaneous improvement, which occurs
between 5 and 20 months of age, with most children making a full recovery by 2 or 3
years of age.

Infants with deficiency of cytochrome C oxidase (COX) due to SCO2 mutations

observed so far usually demonstrated early cardiomyopathy, encephalopathy and
lactic acidosis. The main clinical manifestations are progressive muscular hypotonia,
hypertrophic cardiomyopathy, and encephalopathy. The disease typically presents
during the neonatal period with SMA-like phenotype, and the majority of the patients
die in the first year of life. Cardiopulmonary failure is the most common cause of
death.
Figure 2. Respiratory polygraphy of a 10-year old girl with mitochondrial disorder due SCO2
gene mutations. The cardiorespiratory monitoring used sensors to detect airflow
(nasal air pressure transducer), respiratory effort (inductance plethysmography) and blood
oxygen (pulse oximetry). This monitoring showed: central apnea characterized by fall
in amplitude of the nasal pressure >90% and absent inspiratory effort; obstructive hypopnea
with airflow reduction >30% and out of phase (paradoxical) motion of the thorax
and abdomen excursions; and oxygen desaturation >3%.

Table 1. Different respiratory phenotypes of congenital neuromuscular disorders at different pediatric age
Age Condition Inability to Recurrent airway infections Sleep disordered Progression of respiratory disease
cough/swallow breathing Acute Slow Rapid
Newborns SMA0 and SMA1 Marked Common Possible Common Common
SMARD1 Marked Common Unknown Common Common
Congenital myasthenic syndromes Possible during Possible (if severe and Unknown Possible during
myasthenic crisis persistent weakness) myasthenic crisis
Congenital myotonic dystrophy Common Common Possible Common
Nemaline myopathy Common Common Unknown Common
Centronuclear myopathies Common Common Possible Common
Glycogenosis Type V Common Common Unknown Common
Mitochondrial disease Common Common Common Common Common
(SMA-like) phenotype
Infants Charcot–Marie–Tooth disease (severe Common Common Possible Common
early onset form)
Congenital- hypomyelinating neuropathy Common Common Possible Common
Dejerine–Sottas syndrome Common Common Possible Common
Pompe disease Common Common Common Common
(early onset/infant form)
Preschool- SMA2 Possible Possible Possible
school age Rigid spine with muscular dystrophy Possible Uncommon Possible Common
children
Childhood-onset Myotonic Dystrophy Common Common Possible Possible
Facioscapulohumeralmuscular dystrophy Possible Possible Possible Possible
Mitochondrial disease Possible Possible Possible Possible
Adolescents SMA3 Rare Possible Possible
Duchenne Muscular Dystrophy Common Common Common Common
Becker muscular dystrophy Rare Possible Possible Variable
Limb-girdle muscular dystrophy Common Common Possible Common
Ullrich Congenital Muscular Dystrophy Possible Rare Possible Common

Myotonic dystrophy type 1 Common Common Common Common
Nemaline myopathy Possible Possible Possible Uncommon
Pompe disease Common Common Common Often precipitated by Common
(late-onset/juvenile-adult form) pulmonary infections
Sleep pathology may be an underreported complication of primary mitochondrial

diseases. The likely underlying mechanism is cellular energy failure causing both
central neurological and peripheral neuromuscular degenerative changes that
commonly present as central sleep apnea and poor ventilatory response to
hypercapnia (Figure 2).
Table 1 summarizes the respiratory phenotypes of congenital NMD. A proposal
of clinical and diagnostic work-up in children and adolescents with NMD and
respiratory involvement is shown in Table 2.
Table 2. Assessment of pediatric patients with neuromuscular disorders

and respiratory manifestations
Medical history
 Progression of muscle weakness, degree of ambulation and muscle fatigability

 Strength of voice and cough
 Drooling, coughing or choking with foods, difficulties with chewing or in clearing secretions
 Respiratory infections and their management
 Disturbed sleep, morning headache, morning anorexia or nausea, daytime sleepiness, fatigue
and poor concentration (symptoms of nocturnal hypoventilation)
 Snoring, breathing effort and arousal (symptoms of obstructive sleep apnea syndrome)
 Headache, nausea, dyspnea, tachycardia, sweating, peripheral vasoconstriction or
vasodilation, fatigue and anxiety (symptoms of daytime hypoventilation)
Clinical examination
 Vital signs, body weight, height or ulna length/arms span

 Growth and nutritional status
 Posture, seating and the development of kyphosis and scoliosis
Investigations
 Pulmonary function tests

 Spirometry
 Tests of respiratory muscle strength:
1. Noninvasive tests: MIP and MEP; Sniff nasal inspiratory pressure; Cough peak flow;
Crying mouth pressure
2. Invasive tests: Breathing pattern with Pes and Pgas measurement; Pes and Pdi
measurement during maximal sniff; Pgas measurement during a maximal cough; crying
Pdi
 Measurement of daytime arterial blood gases
 Overnight sleep monitoring: pulse oximetry; capnography; respiratory polygraphy/
polysomnography
 Swallowing/aspiration studies (video fluoroscopy swallow study; fiberoptic endoscopic
evaluation of swallowing; airways endoscopy with bronchoalveolar lavage)
Abbreviations: Maximum inspiratory pressure, MIP; Maximal expiratory pressure, MEP; esophageal
pressure, Pes; gastric pressure, Pgas; Transdiaphragmatic pressure, Pdi

CONCLUSION
The NMDs include a large variety of disorders, which may affect the upper motor
neurons, lower motor neurons, peripheral nerves, the neuromuscular junction. Most
NMD share a common trait, i.e., the impairment of the respiratory system which is
caused by either compromised airway patency, secondary to both secretion
clearance difficulty and the airway collapsibility, and reduced respiratory pump
efficiency, mainly due to respiratory muscle weakness. Moreover, chest wall
compliance may further decrease as a result of the vertebral scoliosis and the
thoracic cage stiffening. Finally, frequent aspirations and recurrent airway infections
significantly contribute to further reduce the lung compliance. In the past, respiratory
insufficiency was the major cause of morbidity and mortality in patients with NMD
until modern and aggressive respiratory care became available. Early recognition of
respiratory impairment with pulmonary function test (such as spirometry and tests of
respiratory muscle strength) is crucial and a multidisciplinary approach should be
adopted in order to provide the best optimal treatment. Noninvasive positive pressure
ventilation, volume recruitment strategies and assisted cough techniques are
currently the standard of care in pediatric NMD as they improve symptoms, sleep,
quality of life and survival and offer significant advantages over other invasive
procedure of ventilation.
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Chapter 2
RESPIRATORY MUSCLE STRENGTH
Aditi S. Shah1,2 and Jeremy D. Road1,2,

1
Division of Respiratory Medicine, University of British Columbia,
Vancouver, Canada
2
Department of Medicine, University of British Columbia,
Vancouver General Hospital, Vancouver, Canada
ABSTRACT
Respiratory muscle impairment can occur in a wide range of neuromuscular

conditions ranging from disorders of the spinal cord, neuromuscular junction,
upper and lower motor neurons and of the muscle. Assessment of respiratory
muscle strength informs us about severity of muscle weakness, progression of
disease, prognosis and helps guide management of neuromuscular patients. In
particular, it helps identify patients that are at risk of hypoventilation and
respiratory complications due to poor respiratory reserve allowing for an initiation
of appropriate support strategies such as non-invasive ventilation.
Respiratory muscle weakness can be identified based on physical exam
features, imaging and objectively through various volitional and non-volitional
measurements. Imaging modalities such as chest fluoroscopy, diaphragm
ultrasound and volitional tests of respiratory muscle strength such as supine and
sitting spirometry, mouth and nasal pressure measurements are more commonly
utilized in clinical practice. Non-volitional tests such as phrenic nerve stimulation
and cervical magnetic stimulation provide valuable objective information about
diaphragm function but are primarily a research tool due to various reasons that
are discussed in this chapter.
This chapter will provide insight into various tests that can be utilized to
measure respiratory muscle strength including their performance, advantages
and limitations and clinical application.

Corresponding Author’s E-mail: jeremy.road@vch.ca.

48 Aditi S. Shah and Jeremy D. Road
Keywords: control of breathing, ventilation, respiratory muscle anatomy, function,

assessment tools
ABBREVIATIONS

COPD chronic obstructive pulmonary disease
DMD Duchenne muscular dystrophy
FRC functional residual capacity
MEP maximum expiratory pressure
MIP maximal inspiratory pressure
NIV non-invasive ventilation
Pab abdominal pressure
PCFR Peak cough flow rate
Pdi transdiaphragmatic pressure
PEFR Peak expiratory flow rate
Pes esophageal pressure
Pmouth mouth pressure
PNS phrenic nerve stimulation
Ppl Pleural pressure
RMS respiratory muscle strength
RV residual volume
SNIP sniff nasal inspiratory pressure
TLC total lung capacity
VC vital capacity
INTRODUCTION
Effective ventilation is determined by organization of three key elements

including the central pattern generator and the, efferent and afferent limbs of the
respiratory neural network. Inspiratory and expiratory neurons located within the
pons and medulla form the central pattern generator and are responsible for
respiratory rhythmicity and the central control of breathing. There is a feedback
system that consists of mechano and chemoreceptors which can influence the
central pattern generator. The respiratory muscles form the end point of the efferent
pathway which consists of bulbospinal neurons from the brainstem and then the
peripheral nerves arising from the anterior horn cells of the spinal cord. Activation of
respiratory muscles leads to muscle shortening which by virtue of their mechanical
attachments to the chest wall increases the volume of thoracic cavity and generates
a pressure difference between the thoracic cavity and the atmosphere that drives
ventilation. These actions are dependent on adequate respiratory muscle strength

Respiratory Muscle Strength 49
(RMS) and hence the function of the ventilatory pump. Respiratory muscle weakness
can occur in a large number of disorders, both acute and chronic, including
neuromuscular diseases, obstructive airway disease such as chronic obstructive
pulmonary disease, congestive heart failure, post mechanical ventilation and
metabolic syndromes. Dysfunction of the ventilatory pump can result in alveolar
hypoventilation, hypercapnic ventilatory failure and in some cases lead to death [1].
Assessment of respiratory muscle function provides useful information that aides
in understanding the etiology of dyspnea, severity of the disorder, progression of
disease and optimal timing of interventions such as initiation of non-invasive
ventilation [1]. Measures of respiratory muscle strength are particularly important in
assessment of patients with various neuromuscular disorders. Some measures such
as MIP have been shown as predictors of survival as well as daytime and nocturnal
gas-exchange abnormalities in patients with ALS [2]. In addition, respiratory muscle
strength enables an earlier detection of muscle weakness than vital capacity, as it is
reduced earlier than vital capacity (see Figure 1). This is because the respiratory
muscles have a much larger capacity than required to fully inflate the lungs so that
respiratory muscle strength can be reduced without any reduction in Vital Capacity.
Figure 1 also shows that actual patients tend to have a greater reduction in VC than
expected. This is believed to be related to reduced compliance of the respiratory
system that can occur in those with longstanding neuromuscular disorders [3].
Ventilatory muscle assessment is not restricted to respiratory medicine as it is
utilized in diagnostics and formulating treatment in various other specialities such as
critical care, sleep medicine, speech therapy, rehabilitation and sports medicine.
Figure 1. The solid line denotes a theoretical relationship of inspiratory muscle strength and
vital capacity, assuming normal mechanics of respiratory system. Dashed line represents
relationship between vital capacity and inspiratory muscle strength in patients with varying
severity of respiratory muscle weakness [3]. Adapted by permission from BMJ Publishing
Group Limited. [Analysis of lung volume restriction in patients with respiratory muscle
weakness, De Troyer A, Borenstein S, Cordier R, 35, 603-610, 1980].

The purpose of this review is to present current techniques of evaluating

respiratory muscle strength, interpretation of the test results and an overview of their
clinical application.
ANATOMY AND PHYSIOLOGY OF THE RESPIRATORY MUSCLES
The respiratory muscles can be broadly classified into two muscle groups the
inspiratory and the expiratory muscles. The diaphragm, parasternal and scalene
muscles are considered the primary muscles of inspiration [3]. The abdominal
muscles (rectus abdominis, internal oblique, external oblique and transverses
abdominis) and the internal intercostal muscles of the rib cage form the expiratory
muscles and during quiet breathing they are inactive but, for example, during the
hyperpnea of exercise they become important in hastening expiration Although they
are predominantly expiratory muscles to a small degree they can assist inspiration by
increasing outward chest wall recoil by compressing the lung volumes below FRC as
can occur with exercise. In addition, expiratory muscles constitute the efferent
pathway of the cough reflex, which is an important function in those with
neuromuscular disorders [1].
The accessory muscles of inspiration are comprised of the external intercostals,
sternocleidomastoid, trapezii, latissimus dorsi, platysma and pectoralis major and
minor. They are part of the inspiratory muscle group but are not active during quite
breathing. This muscle group assists inspiration, when ventilatory demand is
increased such as during exercise or when other inspiratory muscles are unable to
meet the physiologic demand. The muscles of upper airway also constitute an
important role in ensuring ventilation as they maintain upper airway patency [1]. The
functional capacity and contractile properties of the respiratory muscles is largely a
function of their resting length which is a determined by the elastic recoil of the lungs
plus the effect of gravity on thorax and abdomen4 .When measuring RMS we are
measuring the combined contraction of all of the inspiratory muscles during the MIP
maneuver and all of the expiratory muscles during the MEP maneuver.
The diaphragm is considered the major inspiratory muscle and is estimated to
account for 70% of the tidal volume during quiet breathing. It is a dome-shaped
musculotendinous structure that separates the thorax from the abdominal cavity and
has three anatomic attachment sites including a costal, a lumbar and a sternal
portion. From an anatomic and functional perspective, it has two main components;
the crural and the costal muscles. Both of these muscles have distinct functions, i.e.,
the crural region provides stability and displaces the abdomen during its contraction
and the costal forms the insertional component of the diaphragm and contributes to
thoracic volume change by cranial displacement of the rib cage [5, 6].

These two regions receive motor innervation by separate branches of the phrenic
nerve that arise from spinal roots of C3 to C5. During inspiration, downward motion
of the diaphragm reduces pleural pressure and increases abdominal pressure. The
increase in abdominal pressure leads to expansion of the lower rib cage through the
appositional component of diaphragm contraction which transmits the positive intra-
abdominal pressure to the lower rib cage. The parasternal intercostal and scalene
muscles stabilize the rig cage and are active during quiet breathing. Tetraplegic
patients who have complete paralysis of all inspiratory muscles, except the
diaphragm, show a paradoxical pattern of chest wall movement due to the negative
intra thoracic pressure produced by the diaphragm’s contraction which is unopposed
by the parasternal intercostal muscles. The result is a caudal and inward force on the
upper rib cage and outward directed force on the lower rib cage which leads to
paradoxical inward motion of the upper rib cage [6].
The respiratory muscles are striated, skeletal muscles. Their microscopic
striations reflect the contractile units, the sarcomeres, that produce force. These
contractile units produce muscle contraction by an ATP dependent process which
involves interaction between the thick and thin filaments. The filaments slide over
each other by the process of cross bridge cycling. The maximum force occurs at the
optimal length where the optimal overlap of these filaments occurs. In most muscles
the natural resting length is also the optimal length. Accordingly, RMS is lung volume
dependent. As lung volume increases RMS ie MIP decreases due to shortening of
muscle length, so for example with dynamic hyperinflation or acute asthma the
potential for RMS generation decreases. The diaphragm also loses force due to
reduction in its mechanical advantage because as lung volume increases the
appositional component decreases as does the insertional component. Breathing
around FRC clearly has its advantages from a muscle perspective.
The respiratory muscles, as other skeletal muscles, can lose strength due to
fatigue or injury. The respiratory muscles are required to contract phasically
throughout our lives but fortunately the majority of muscle fibers in respiratory
muscles are composed of slow twitch fatigue resistant fibers. During quiet breathing
these fibers are activated by small motoneurons with lower stimulation thresholds
and it is only with increased respiratory drive that the larger motoneurons become
activated and fast twitch fatigable motor units are active. In this case muscle fatigue
may well develop. Muscle injury may also occur with hyperpnea and can lead to loss
of force. In those with Duchene’s muscular dystrophy vigorous muscle contraction
easily leads to muscle injury and inflammation due to the absence of the cytoskeletal
structural protein dystrophin. This injury and subsequent inflammation lead to a
further loss of muscle strength. Histological examination of diaphragms from those
without neuromuscular disorders exposed to prolonged loaded breathing also shows
evidence of injury [7]. How much muscle fatigue and muscle injury contributes to loss
of RMS in those with chronic neuromuscular disorders remains an area in need of
more research.

ASSESSMENT OF RESPIRATORY MUSCLE STRENGTH
The process of performing respiratory muscle strength assessment includes a

thorough history and physical examination, imaging, blood gas analysis, lung
function assessment and in some cases neurodiagnostic testing. Assessment of
respiratory muscle function should be prompted in a variety of situations. First,
establishing etiology of dyspnea, for instance in determining the etiology of extra
parenchymal restrictive lung function disorders. Secondly, investigating involvement
of ventilatory muscles in patients with neuromuscular disease and lastly, follow-up in
patients with known ventilatory muscle weakness to allow for timely introduction of
supportive modalities such as cough assist or non-invasive ventilation.
History and Physical Examination
History and physical examination can draw initial suspicion of respiratory muscle
weakness. Respiratory muscles weakness can dominate clinical manifestations in
various pathologic conditions such as obstructive airway diseases, chest wall
deformities, primary neurologic and neuromuscular disorders and metabolic diseases
[8]. Ventilatory muscle dysfunction manifests clinically in each of the conditions in its
unique way. For instance, in many of the neuromuscular diseases, generalized
ventilatory muscle weakness including bulbar dysfunction (e.g., Amyotrophic lateral
sclerosis) can predispose to ineffective cough, aspiration and increase risk of
pneumonia and ventilatory failure. Cough inefficiency may be suspected if patient
describes inability to expectorate secretions or if they report frequent respiratory
infections [1]. Patients with diaphragm weakness or paralysis may report orthopnea.
Attention to symptoms indicative of sleep disordered breathing such as daytime
somnolence, lethargy, morning headaches, confusion or fatigue may alert the
clinician to investigate further into an underlying restrictive or neuromuscular disorder
leading to hypoventilation [8]. Patients who are able to maintain physical activity may
report dyspnea.
Diagnosis of chest wall deformity such as those related to the congenital
myopathies i.e., kyphoscoliosis can be made by examining the chest wall. Reduced
rib cage expansion may be appreciated at the bedside along with generalized muscle
atrophy and weakness of all muscle groups. When diaphragmatic weakness or
paralysis is suspected paradoxical abdominal wall movement with the patient supine
is diagnostic.

Imaging
Radiographs
Radiographic techniques primarily play a role in evaluating diaphragm position
and motion. Position of the hemidiaphragm domes at total lung capacity can provide
useful information about diaphragm function. In close to 90% of the healthy
individuals, the plane of the right diaphragmatic dome tends to be higher than the left
by half an interspace. However with unilateral paralysis we may observe elevation,
and sometimes to a large degree, of the paralyzed dome [9].
Diagnosis of unilateral diaphragm paralysis is therefore often suggested by plain
radiograph and can be confirmed with the fluoroscopic sniff test. Excursion of
diaphragm can be accessed via video fluoroscopy. In this study, inspiratory and
expiratory radiographs are obtained during quiet tidal breathing with the patient in an
erect position. Paradoxical cranial motion (due to increase in abdominal pressure
and decrease in pleural pressure) during tidal inspiration of the paralyzed dome and
descent of normal hemidiaphragm can be detected via this technique .A sniff
maneuver and visualization of diaphragm movement by fluoroscopy will amplify this
paradoxical motion and unilateral hemi diaphragmatic paralysis can be readily
recognized [9].
Ultrasound
Ultrasound can be used to image the diaphragm and to monitor its displacement
during respiratory maneuvers. This technique allows visualization of the diaphragm
without subjecting the patient to radiation risk associated with fluoroscopy. The
diaphragm appears as a bright echogenic arc, with estimates of normal thickness
ranging from 1.7-3.3 mm during relaxation at FRC. Ultrasound can be used to assess
thickness of the zone of apposition at different lung volumes, tidal breathing and
static inspiratory efforts. In absence of diaphragm pathology, we would observe
diaphragm thickening with increasing lung volumes, the so-called thickening fraction.
Chronic unilateral diaphragm paralysis can be recognized as a hemidiaphragm that
fails to thicken with inspiration which can be done by placing the transducer at the
xyphoid process; permitting visualization of both the hemidiaphragms [10].
Ultrasound is a relatively simple assessment tool that can be utilized to evaluate
diaphragm involvement in neuropathy, myopathies in the ICU, post cardiothoracic
surgery and to track progress with pulmonary rehabilitation [9]. Diaphragm thickness
and thickening fraction can reflect RMS as the cross-sectional area of muscle is
linearly related to the force production.

Volumetric Imaging
Other radiologic modalities such as CT-scan and MRI scan are limited by
expense, radiation exposure with CT scan and prolonged study acquisition times with
the latter. In theory, both of these volumetric imaging techniques can be used to
conduct more detailed assessment of shape of the diaphragm, the ribs, chest wall
configuration and intra-parenchymal disease [9].
OBJECTIVE MEASUREMENTS OF RESPIRATORY MUSCLE STRENGTH
Volitional Tests of Respiratory Muscle Strength
Static and Dynamic Lung Function

The pattern of abnormality that is characteristic on lung function tests with
respiratory muscle weakness is a low vital capacity, reduced total lung capacity and
preserved diffusion capacity. Preservation of diffusion capacity in context of a
restrictive pattern helps differentiate intraparenchymal disorders from extrapulmonary
pathologies such as ventilatory muscle weakness from other various conditions. In
patients with chronic respiratory muscle weakness, reduction in vital capacity occurs
as a result of both loss of RMS and decreased compliance of chest wall and lungs.
Residual volume can be increased, particularly in patients with expiratory muscle
weakness. This leads to a pattern of increased RV/TLC, which is not a result of
airway obstruction. Vital capacity is less sensitive than MIP in detecting mild
respiratory muscle weakness for reasons mentioned previously [11].
Supine and sitting spirometry is a particularly useful assessment tool to evaluate
diaphragm weakness. In normal subjects, due an effect of gravity, a 5-10% postural
fall in vital capacity can be observed in the supine position. In patients with severe
isolated or disproportionate bilateral diaphragm weakness, this fall can exceed 25%
[12]. This is a simple test to perform and provides valuable information to the
clinician. Hypoventilation in those with neuromuscular disease usually occurs initially
at night with nocturnal hypercapnia. The supine VC correlates well with the
development of first REM related hypercapnia, then nocturnal hypercapnia and
ultimately diurnal hypercapnia [13]. The correlation between supine VC and
hypercapnia is not surprising given the knowledge that, during sleep, ventilation is
particularly dependent on the diaphragm especially during REM sleep. Thus, the
results of sitting and supine VC, which provides evidence of impaired diaphragm
function, is a strong predictor of hypoventilation
Maximum flow-volume loops also provide valuable information about upper
airway muscles. For instance, a saw-tooth appearance can be seen in patients with
weak upper airway muscles. Therefore, visual inspection of the flow-volume loop in
an appropriate clinical context can suggest upper airway muscle weakness [1, 11].
Flow volume loops in those with advanced respiratory muscle weakness may show

loss of peak expiratory flow rate and a shallow inspiratory limb. The loss of peak flow
can signal weakness of the expiratory muscles as, of course, can a reduction in
MEP. Peak cough flow rate (PCFR) has evolved as a useful field test to evaluate an
important function of the expiratory muscles; the cough. There are no published
normal values. PCFRs are generally higher than PEFRs and an artificial cough
measured this way is less than a spontaneous cough; however, PCFRs less than
270 L/min are associated with clinically important reductions in airway clearance2
and can point to the need for techniques to assist with the cough.
Pressure Measurement
Transdiaphragmatic Pressure
Transdiaphragmatic pressure (Pdi) measurement is considered the “gold
standard” diagnostic test for diagnosing bilateral diaphragmatic paralysis. However, it
is not routinely measured in Lung Function Labs and involves the placement of intra
esophageal and intra gastric pressure transducers. Pdi is specific for diaphragm
contraction and in the research, lab can give true maximum values for diaphragm
strength. Chest radiography and fluoroscopic sniff testing are not useful for the
diagnosis of bilateral diaphragmatic weakness/paralysis, since there is no normal
hemidiaphragm for comparison. The MIP measures global muscle weakness and is
not specific for diaphragm function, although reduced MIP with preserved MEP does
suggest diaphragmatic weakness Transdiaphragmatic pressure (Pdi) is the
difference between pleural (Ppl) and abdominal pressure (Pab), which in clinical
practice is equated to difference between esophageal (Pes) and gastric pressure
(Pga) (Pdi = Pga – Pes). Pes and Pga are measured by passing a pair of thin
balloon-tipped catheters through the nose, and placed in esophagus and stomach
after application of topical anesthetic to the upper airway. Position is confirmed by
asking the patient to do sniff maneuvers while monitoring pressure deflection.
Esophageal and gastric pressures serve as surrogate measurements of pleural and
abdominal pressure respectively. In principle, the diaphragm is the only muscle that
upon contraction simultaneously lowers esophageal pressure and increases gastric
pressure, thereby increasing transdiaphragmatic pressure. Therefore, in theory if
inspiration occurs by mechanism other than diaphragm contraction, changes will be
transmitted uniformly across the diaphragm and there will be no change in Pdi. This
is a result of passive motion of diaphragm that produces negative change in both Pes
and Pga. Lack of ability to generate transdiaphragmatic pressure during a maximal
maneuver confirms diaphragmatic paralysis [1, 9, 11].
Mouth and Nasal Pressure Measurements

Both nasal and mouth pressures are easy to measure, albeit with a few caveats.
First, mouth pressure provides an estimation of change in alveolar pressure and also
Pes, with an assumption of little pressure loss across lungs and airways. It also
makes an assumption of skeletal muscles being under isometric conditions with
muscle at its optimal length. The muscles do shorten even when the airway is

occluded and hence the contraction is not isometric. The test can also be effected by
conditions such as severe airway or parenchymal disease or if there is glottic
closure, all of which may prevent adequate equilibration. Additionally, the force-
length relationship is altered due to hyperinflation induced muscle shortening in
patients with severe airway disease. These patients are able to generate less
maximum inspiratory pressure, which is a reflection of shortened inspiratory muscle
fiber length and reduced mechanical advantage rather than inherent muscle
weakness. Secondly, it is important to place the results of these tests into clinical
context, as results can often be compounded due to poor technique or underlying
pathological conditions such as bulbar dysfunction that can impede ability to perform
the maneuvers. Third, these pressure measurements provide a global assessment of
inspiratory and expiratory respiratory muscle strength, therefore does not allow
clinician to differentiate between weakness of different muscle groups. However,
specific patterns as mentioned can alert the clinician to an underlying pathology such
as low MIP and normal MEP which suggests isolated diaphragm weakness. Lastly,
there is considerable between and within-individual variation in muscle strength
measures compared to static lung volume measurements such as vital capacity.
Maximum Inspiratory and Expiratory Pressure

With the above caveats pressure measured as maximum inspiratory pressure
(MIP) or maximum expiratory pressure (MEP) is reflective of respiratory muscle
strength plus the passive elastic recoil of lung and chest wall. A standardized
approach to measuring MIP and MEP is well described in American Thoracic Society
guidelines (Figure 2) [9]. MIP is measured at RV (residual volume) and MEP close to
total lung capacity (TLC) to optimize muscle lengths and to offer mechanical
advantage. Both MIP and MEP maneuvers require that the pressure is sustained for
1 second and warrant repeating to determine the maximum values. Normal values
differ according to age and sex, but normal values are established in large series [1,
9, 11]. There are also reports that provide LLN for MIP and MEP which helps with the
interpretation of results [14]. Values less than MIP -80cmH2O usually excludes
clinically important inspiratory muscle weakness. Factors that may impact the
accuracy of measurements should be taken into consideration such as patient effort,
technique and underlying comorbidities, in particular, airway disease.
Nasal Pressure
Sniff Nasal Inspiratory Pressure (SNIP) as detected by sniff test gives a
reasonable estimate of inspiratory muscle strength. In healthy subjects, pressures
measured at the mouth, nasopharynx and one nostril are closely related to
esophageal pressure during sniffs [11]. This test is conducted by subjects performing
a maximal sniff through one un-occluded nostril. The pressure in the obstructed
nostril reflects pressure in the nasopharynx which provides an estimation of alveolar
pressure. Similar to mouth pressure measurements, this technique also assumes
normal lung physiology and so requires careful interpretation in patients with severe
airway or parenchymal disorders. In COPD, nasal sniff pressure can underestimate

esophageal pressure during sniff as transmission of the pressure response from

esophagus to mouth and nose is dampened in COPD. SNIP however can be a
helpful adjunctive test to MIP in deciding whether further investigations should be
pursued for a low MIP and in patients with bulbar weakness such as in ALS [9, 11].
Furthermore there are also predicted values available for this test with LLN to aid
with interpretation [15].
Figure 2. Technique for measuring maximal static respiratory pressure [9].

Reprinted with permission of the American Thoracic Society.
Copyright © 2021 American Thoracic Society. All rights reserved.
Cite: American Thoracic Society/European Respiratory, Society/2002/ATS/ERS Statement on
respiratory muscle testing/Am J Respir Crit Care Med/166/518-624.
The American Journal of Respiratory and Critical Care Medicine is an official journal of the
American Thoracic Society.
Non-Volitional Tests of Respiratory Muscle Strength
Phrenic Nerve Stimulation

The diaphragm is innervated exclusively by the phrenic nerve so that phrenic
nerve stimulation provides direct assessment of diaphragm function, independent of
other inspiratory muscles. Additionally, it also eliminates the influence of the central
nervous system ie incomplete effort. Phrenic nerve stimulation (PNS) provides
valuable information about diaphragm function such as objective estimate of maximal
voluntary pressure produced by the diaphragm, utilizing twitch interpolation. In this

way if the twitch pressure signal is occluded or absent during a contraction the
contraction is deemed maximal.Phrenic nerve stimulation in the EMG lab is also
useful in evaluating the continuity of the phrenic nerve.
In response to PNS at relaxed FRC, transdiaphragmatic pressure rises and then
decreases to baseline. Pes and mouth pressure decrease and rise as a result of
diaphragmatic contraction that generates negative intra-pleural pressure and as a
result of caudal displacement increases abdominal pressure. The amplitude of the
twitch is dependent on few factors including diaphragm strength and chest and
abdominal wall compliance [9, 11]. Pes can be assessed with Pmouth in patients
with respiratory muscle weakness, provided that there are no confounding variables
that may interfere with adequate transmission of pressure from the alveoli to the
mouth. For this reason, this test is less useful in COPD patients, who have slower
equilibration of Pes and Pmouth [9, 11].
Phrenic nerve can be stimulated externally in a non-invasive manner by
transcutaneous electrical PNS or by magnetic stimulation. The effects of phrenic
nerve stimulation can be studied both electro physiologically and mechanically.
Methodology of this study is described in detail in the American thoracic society
guidelines for respiratory muscle strength9. In brief, transcutaneous PNS is
performed at FRC. Depolarization of the phrenic nerve is induced by an externally
applied electrical field at the level of the cricoid cartilage, beneath the posterior
border of the sternocleidomastoid muscle where the nerve is usually situated. The
placement of electrode site is standardized with one electrode placed at the motor
point and recording electrode at the diaphragm’s tendon site [15]. Intensity of electric
stimulation is increased gradually, while monitoring EMG output to achieve maximal
stimulation. There are few drawbacks to this technique. First, is the difficulty
identifying the location of the phrenic nerve, particularly in obese or older subjects
and in order to achieve supramaximal stimulation precise placement of electrode is
essential. To achieve this, repeated stimulation may be required, which can be
uncomfortable. Secondly, electric currents may be attenuated by barriers such as
skin and bone. For aforementioned reasons, this is largely a research tool [9, 11].
Pulsed magnetic fields similarly can be utilized to study diaphragm function.
Cervical magnetic stimulation (CMS) elicits bilateral diaphragm contraction through
stimulation of the cervical roots. This technique is able to generate greater
transdiaphragmatic pressure than electrical stimulation, which is thought to be due to
simultaneous activation of neck and upper rib cage muscles by the magnetic field. In
that regard, it is also considered one of the drawbacks of CMS. Coactivation of
muscles innervated by brachial plexus, reduces its specificity for the diaphragm
appreciated with electrical stimulation. In comparison to electric field stimulation
technique, it has an advantage of being less painful, signals are not dampened by
structural elements, and it has better sensitivity in patients with moderate
diaphragmatic weakness. However, similarly to electric field stimulation technique
CMS also is affected by twitch potentiation and it is largely a research tool [9, 11].
These tests have particular relevance when results of volitional tests are questioned.

Overall, PNS can play an important part of inspiratory muscle function

assessment and quantifying diaphragmatic weakness, particularly when other
studies are equivocal. It can assist in diagnosis of various neuropathies through
assessment of conduction times which can be prolonged or absent e.g., definitive in
hemi diaphragm paralysis and it can be utilized to measure mechanical function of
the diaphragm [16]. However, the use of these techniques requires clinicians be
mindful of confounding variables that may hinder validity of findings such as influence
of lung volumes, failure to achieve supramaximal stimulation, hypertrophy of neck
muscles, twitch potentiation and influence of patient demographic factors [9].
Abdominal Muscle Stimulation

Abdominal muscles are major contributors to expiration and have mechanical
linkage to diaphragm and rib cage. Abdominal muscles can be stimulated by direct
electrical stimulation. Clinically this tool can help increase cough efficiency in patients
with cervical cord injury. However, electrical stimulation can be quite painful, making
it challenging to achieve supramaximal contraction of all muscle groups in synchrony.
CLINICAL APPLICATION OF RESPIRATORY MUSCLE

STRENGTH ASSESSMENT TOOLS
Sleep Disordered Breathing in Neuromuscular Patients
Sleep related hypoventilation, particularly during REM sleep can occur in various
neuromuscular disorders. This is related to multifactorial mechanism, including
diaphragmatic weakness and hypotonia of upper airway muscles. Also, during sleep
respiratory central drive decreases [8]. Polysomnography is the gold standard for
sleep disordered breathing assessment; however, its application can be limited due
to functional disabilities in neuromuscular patients and furthermore, acid-base
derangements may not occur until late in the disease course. Vital Capacity
particularly the supine VC, as mentioned, has been shown to correlate with nocturnal
hypoventilation and to sleep disordered breathing. A threshold of <50% has been
identified as that which increases the risk of respiratory complications and alveolar
hypoventilation that initially develops at night [13]. Identification of sleep disordered
breathing, specifically sleep apnea or hypopnea, also has important treatment
implications in this patient population as both assistance with inspiration and
treatment of central or obstructive events are required [13].
Prognostication
Where respiratory weakness is identified by mainly volitional tests of RMS the VC

and frequently including the supine VC becomes part of the routine assessment of

patients with respiratory muscle weakness secondary to a neurologic disorder. The

VC is a widely used measure to assess progression of respiratory muscle weakness.
The rate of decline in vital capacity has been shown to predict survival in ALS and
DMD patients [2].
CONCLUSION
In conclusion, various techniques are available to assess respiratory muscle

strength. In clinical practice, non-invasive assessment tools have made it possible to
quantify respiratory muscle dysfunction including volitional studies such as MIP,
MEP, sniff test and non-volitional tests including electrical and cervical magnetic
stimulation. These tools form an important part of clinical evaluation that assist in
evaluating the etiology of dyspnea. Measurement of respiratory muscle strength
provides useful prognostic information and can help making treatment decisions.
Key Messages
1. Respiratory muscle strength measurement is useful for determining

neuromuscular etiology of patient reported symptoms.
2. There are two main groups of muscles that assist in ventilation and form the
ventilatory pump the inspiratory, expiratory muscles. Respiratory muscle
strength assessment tools provide valuable information about the function of
these muscle groups.
3. Respiratory muscle strength can be assessed on basis of physical exam
findings, imaging such as radiography, ultrasonography of the diaphragm,
volitional and non-volitional tests.
4. Non-volitional tests such as phrenic nerve stimulation and cervical magnetic
stimulation are primarily utilized as research tools but can help when volition
is questioned.
5. Respiratory muscle strength assessment provides valuable information about
progression of disease, severity of illness and initiation of non-invasive
ventilation among other support strategies in patients that are at higher risk of
respiratory complications and hypoventilation. These tests are more sensitive
for the early detection of weakness of the ventilatory pump but the VC
including the supine VC is more specific for the need for ventilatory support in
those with progressive neuromuscular disorders.

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(1985). 2016 Aug 1;121(2):391-400.
[7] Scott A, Wang X, Road JD, et al. Increased injury and intramuscular collagen of
the diaphragm in COPD: autopsy observations. Eur Respir J. 2006
Jan;27(1):51-9.
[8] Laghi F, Tobin MJ. Disorders of the respiratory muscles. Am J Respir Crit Care
Med. 2003 Jul 1;168(1):10-48.
[9] American Thoracic Society/European Respiratory S. ATS/ERS Statement on
respiratory muscle testing. Am J Respir Crit Care Med. 2002 Aug
15;166(4):518-624.
[10] Roussos C., Vassilakopoulos T. (1995). The Thorax, - Part B. Boca Raton:
CRC Press, Chapter 44, Ultrasonography of the Diaphragm; p. 1295-1311.
Available from: https://doi-org.ezproxy.library.ubc.ca/10.1201/9781420000665.
[11] Polkey MI, Green M, Moxham J. Measurement of respiratory muscle strength.
Thorax. 1995 Nov;50(11):1131-5.
[12] Fromageot C, Lofaso F, Annane D, et al. Supine fall in lung volumes in the
assessment of diaphragmatic weakness in neuromuscular disorders. Arch Phys
Med Rehabil. 2001 Jan;82(1):123-8.
[13] Ragette R, Mellies U, Schwake C, et al. Patterns and predictors of sleep
disordered breathing in primary myopathies. Thorax. 2002 Aug;57(8):724-8.
[14] Evans JA, Whitelaw WA. The assessment of maximal respiratory mouth
pressures in adults. Respir Care. 2009 Oct;54(10):1348-59.

[15] Uldry C, Fitting JW. Maximal values of sniff nasal inspiratory pressure in healthy
subjects. Thorax. 1995 Apr;50(4):371-5.
[16] Roussos C., Vassilakopoulos T. (1995). The Thorax, - Part B. Boca Raton:
CRC Press, Chapter 35, Electrical Assessment of Respiratory Muscles; p.
1029-1048. Available from: https://doi-org.ezproxy.library.ubc.ca/10.1201/
9781420000665.

Chapter 3
COUGH FUNCTION ABNORMALITIES
Mariano Mollica, MD, Martino Flora, MD,

Elena Sciarrillo and Salvatore Musella
UOC Fisiopatologia e Riabilitazione Respiratoria AO dei Colli, Naples, Italy
ABSTRACT
Cough, a vital respiratory reflex, is considered as the most common

experienced respiratory symptom which ensures airways to be cleared from
mucus, secretions, and foreign bodies. For cough reflex to occur, several
structures, such as receptors, neuronal pathways, muscles, are harmoniously
recruited. Failure of cough reflex does have dramatic consequences. In subjects
affected by neuromuscular diseases, onset of cough reflex abnormalities
emerges as a crucial turning point. As airways are no more successfully cleared,
subjects become prone to developed lung infections, chronic pneumonia, and,
lastly, respiratory failure. In this scenario, a prompt detection of cough reflex
abnormalities is of strategic importance. This chapter gives an insight into the
physiology of cough reflex; moreover, it discusses the clinical implications of
cough reflex abnormalities in patients affected by neuromuscular diseases and
how they may be clinically and functionally assessed in these subjects.
ABBREVIATIONS
Cough Pga Gastric Pressure during cough manoeuvre

CVA Cough Volume Acceleration
MEP Maximal Expiratory Pressure
MIC Maximum Insufflation Capacity
MIP Maximal Inspiratory Pressure

Corresponding Author’s E-mail: mollicamariano@gmail.com.

64 Mariano Mollica, Martino Flora, Elena Sciarrillo and Salvatore Musella
NMDs Neuromuscular diseases

PCF Peak Cough Flow
PEF Peak Respiratory Flow
RAR Rapidly Adapting Receptors
INTRODUCTION
Cough is the most common experienced respiratory symptom and represents an

essential respiratory manoeuvre which ensures removal of secretions, mucus, and
other foreign particulates from airways. If an excessive cough often hints a
respiratory disease, absence of cough is incompatible with life. Interestingly, cough
reflex can be faithfully and voluntarily reproduced even in the absence of either
chemical or mechanical stimulus.
In patients affected by neuromuscular diseases (NMDs), cough represents a
bothering symptom and at the same time a life-saving reflex. Unfortunately, in these
subjects, cough reflex as well as voluntary cough are impaired and become
completely inefficient with time.
As mechanism of cough reflex fails, airway clearance becomes no more assured
exposing subjects to risk of chronic lung infection, respiratory failure and, lastly,
death.
Management of cough abnormalities in subject affected by NMDs is
consequently of paramount importance.
PHYSIOLOGY OF COUGH
Stimulation of receptors innervated by vagus nerve and its branches is the

starting point for cough reflex to occur. Several structures are reached by vagus
nerve; these include the bronchi, the proximal tracheobronchial tree, larynx,
oropharynx as well as the external auditory meatus and the tympanic membrane.
Mechanically, cough reflex consists of three phases: inspiratory, compressive, and
expiratory phase (Broaddus et al. 2016). A deep inspiration through an opened glottis
represents the crucial step of the inspiratory phase. A variable amount of air is
inhaled, ranging from few hundreds of millimetres up to 50% of vital capacity
(Broaddus et al. 2016). Different muscles are recruited in this phase. The main are
diaphragm and external intercostal muscles. Others are the accessory inspiratory
muscles, such as sternocleidomastoid, trapezius, levator scapulae, pectoralis major,
scalenus anterior and medius (Hadjikoutis, Wiles, and Eccles 1999). At this point, the
respiratory muscles are stretched and elongated. The greater the volume of inhaled
air, the greater is the lengthening reached by respiratory muscles. As result of this
eruptive stretching, the expiratory length-tension relationship is optimised. Moreover,
a stronger elastic recoil of the lung will facilitate the following expiratory phase.

Cough Function Abnormalities 65
However, there is not a minimum critical volume required; an efficient cough can be
achieved also with a small volume of inhaled air (McCool 2006).
A successful closure of glottis marks the transition from the first to second phase.
In this phase, the time frame during which the glottis remains closed is estimated to
be about 200 ms. Due to the closed glottis, the activated expiratory muscles contract
without remarkably changing their length, in the so-called isometric contraction; thus,
intrathoracic pressure rises quickly, reaching a potential value of 300 mmHg (McCool
2006). In a similar fashion, intra-abdominal pressure increases, explaining the
deleterious effects of an uncontrolled and pathological cough on abdominal
ecosystem. Due to this harmonious rise of both intra-pulmonary and intra-abdominal
pressure, diaphragm remains in a low position. Here, the lateral cricoarytenoids and
the transverse arytenoid, innervated by the recurrent laryngeal nerve, emerge as the
main muscles recruited (Hadjikoutis, Wiles, and Eccles 1999).
As glottis opens, the expiratory phase explosively begins. In addition to
abdominal muscles, other muscles involved are serratus posterior inferior, latissimus
dorsi as well as the quadratus lumborum. Moreover, diaphragm abruptly rises
(Hadjikoutis, Wiles, and Eccles 1999). In this phase, respiratory flow rates have been
reported to reach values as great as 12 L/s. Intriguingly, calibre of bronchi decreases
in this phase. In this way, airflow linear velocity increases and inhaled substances
are less prone to reach the distal airways.
Cough receptors are recognized to be divided into two main categories: the C
fibre receptors with non-myelinated afferent fibres and the rapidly-adapting
pulmonary stretch receptors (RARs) (Hadjikoutis, Wiles, and Eccles 1999). Whilst
larynx and trachea are more sensitive to the presence of external materials, such as
accidentally ingested food or fluid, bronchi receptors are more chemosensitive. In
this site, mucus itself would stimulate cough reflex to promote airway clearance.
Obviously, if cough reflex results impaired, mucus may accumulate into bronchi
leading to development of pulmonary infections.
Upper brainstem and pons correspond to the centre of cough reflex (Polverino et
al. 2012). Whether the cough neural pathways overlap the normal respiratory ones is
still under investigation. What instead it seems clear is that higher centres to the
brainstem play an important role. They are not only the source of the ‘voluntary’
pathway of the cough; they also are able to inhibit the downstream ‘reflex’ pathway of
the cough (Hadjikoutis, Wiles, and Eccles 1999).
CLINICAL AND FUNCTIONAL ASSESSMENT OF COUGH
Anamnesis does undoubtedly represent a straightforward and an essential step

in the diagnostic algorithm. Firstly, it emerges as crucial for comprehending when
cough abnormalities appear in the lifespan of patient affected by NMDs. Secondsly,
clinical history should provide a complete examination of symptoms other than
cough, such as altered speech or swallowing, postural control or balance problems,

impaired eye movement and muscular weakness. Thirdly, it must be investigated

whether patients consider their cough reflex as adequate, satisfactory, and
manageable or not. Finally, observing how symptoms change through time and
identifying potential ‘changing factors’ would be beneficial.
With respect to cough, physical examination may vary according to the phase of
disease. If it results normal in some circumstances, in others may be completely
abnormal. Chest movement may appear decreased. Moreover, examinators may
notice related chest abnormalities, which may interfere with a satisfactory cough
manoeuvre. An impaired cough might lead to mucus collection deeply in the airways.
This might be mirrored by abnormal sounds intercepted during auscultation.
Functionally, examinators have available some tests to assess cough reflex.
Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) refer
to non-invasive tests which stand as straightforward tools in the evaluation of
respectively inspiratory and expiratory muscle strength. Tests are performed as
follows: after an expiration to residual volume level, a forceful inspiration must be
performed (in the case of MIP) or an efficient expiration after a full inspiration to total
lung capacity (in the case of MEP) with an open glottis against an occluded
mouthpiece (Stefanutti et al. 2000). It may be useful to consider not only the MIP;
considering the Maximum Insufflation Capacity (MIC), the greatest amount of air held
by the patient with a closed glottis, would be beneficial as well. Sine qua non to
accomplish the manoeuvre is the efficient closure of glottis. A bulbar dysfunction may
interfere with the efficiency of glottis closure, prompting to a pathological decrease of
MIC. 1000 mL is the minimum volume of inhaled air required to perform an efficient
cough and avoid mucous accumulation (Servera, Sancho, and Zafra 2003).
Assessing the maximum air flow obtained during a cough manoeuvre results in
the peak cough flow (PCF). In simple terms, it represents a peak respiratory flow
(PEF) during cough. It is graduated in liters/minutes and it can be either assisted or
unassisted. Normal values range from to 3.60 to 8.40 L/min (Chatwin et al. 2018). A
value of 2.70 L/m represents the threshold beneath which cough may be not
adequate and airways clearance not satisfactory. At this point, patient should be
trained in assisted techniques (Servera, Sancho, and Zafra 2003). Diminished PCFs
have been reported in patients with a MIC less than 1500 mL. Moreover, a PCF less
than 2.7 L/s with a MIC greater than 1 L may suggest a significant bulbar dysfunction
leading to a hypopharyngeal collapse or a fixed upper airway obstruction.
Cough volume acceleration (CVA) is another measurable cough flow variable
which is derived by dividing PCF by the peak expiratory flow rise time, which is the
time necessary to reach the peak expiratory flow rate. It has been reported a
threshold of 28.9 L/sec2 beneath which cough may be ineffective. Similarly, CVA has
been reported to correlate with the risk of aspiration in patients affected by NMDs
(Voulgaris et al. 2019).
Based on the assumption that a satisfactory peak flow during cough correlates
with a proper abdominal muscle strength, measurement of Gastric Pressure during
cough manoeuvre (Cough Pga) may be useful tool in cough function assessment.
Values of Cough Pga should be greater than 175 cm H2O for men and 100 cm H2O

for women to be considered as normal. On the other side, Cough Pga values which
do not reach 50 cm H2O are related to failure to generate cough spikes. However, it
must be considered the potential technical issues during this procedure, especially in
patients with NMDs (Servera, Sancho, and Zafra 2003).
Any progression of disease, whichever the method employed to detect it, must
be promptly observed to arrange an efficient strategy to face the challenge.
COUGH REFLEX IN NEUROMUSCOLAR DISEASES
Onset of cough impairment represents a turning point in the clinical history of

patients affected by NMDs.
Contrary to expectation, cough reflex seems to be initially enhanced in NMDs. It
has been indeed reported that in patients with abnormal swallowing, cough threshold
is prone to be lower (Smith and Wiles 1998). A decrease in descending inhibition due
to a loss of corticobulbar pyramidal fibres may in part justify this phenomenon.
However, recurrent aspiration and the consequent inflammation may lead to a cough
reflex desensitization with time (Hadjikoutis, Wiles, and Eccles 1999).
In NMDs patients, diaphragm function deteriorates later compared to expiratory
muscles. It has been reported that MEP declines before MIP in children with NMDs,
with a difference of 6 years (Schramm 2000).
A decrease of diaphragmatic stiffness or a denervation of the expiratory muscle
may lead to a reduction of expiratory pressure and the effectiveness of cough results
diminished. With time, an inspiratory impairment develops as well and the inspiratory
capacity drops. In this scenario, incapacity to obtain an optimal length-tension
relationship of respiratory muscles jeopardizes an efficient clearance of distal airways
which are far to be reached by the airflow. As a consequence, risk of pneumonia
results considerably increased.
Besides the cough reflex inefficiency, patients with NMDs often show an impaired
voluntarily cough (Hadjikoutis, Wiles, and Eccles 1999). In addition to these muscular
changes, skeletal abnormalities, which often coexist, worsen the severity of
restrictive pulmonary disease. A reduction of vital capacity is indeed the functional
hallmark of these conditions.
Patients with NMDs often develop a type II respiratory failure which is
characterized by an accumulation of carbon dioxide; hypercapnia seems to impact
on cough reflex by compromising both respiration and swallowing (Nishino et al.
1998).
The respiratory muscle weakness combined to restrictive ventilatory defect
hinder the inspiratory phase of cough manoeuvre. To this, impaired deglutition is
added leading to an increased risk of aspiration and pneumonia. Concurrently,
recurrent pulmonary infection sequalae, e.g., peripheral atelectasis, aggravate the
restrictive disorder, fostering the vicious circle. Main cough reflex abnormalities are
summarized in Figure 1.

Figure 1. Cough abnormalities in MSDs.
REFERENCES
Broaddus, V. Courtney, Robert J. Mason, Joel D. Ernst, Jr. Talmadge E. King,

Stephen C. Lazarus, John F. Murray, Jay A. Nadel, Arthur S. Slutsky, and
Michael B. Gotway. 2016. Murray and Nadel’s Textbook of Respiratory Medicine.
Murray and Nadel’s Textbook of Respiratory Medicine. https://doi.org/10.1016/
c2011-1-08123-7.
Chatwin, Michelle, Michel Toussaint, Miguel R. Gonçalves, Nicole Sheers, Uwe
Mellies, Jesus Gonzales-Bermejo, Jesus Sancho, et al. 2018. “Airway Clearance
Techniques in Neuromuscular Disorders: A State of the Art Review.” Respiratory
Medicine 136 (March): 98-110. https://doi.org/10.1016/j.rmed.2018.01.012.
Hadjikoutis, S., C. M. Wiles, and R. Eccles. 1999. “Cough in Motor Neuron Disease:
A Review of Mechanisms.” QJM: An International Journal of Medicine 92 (9):
487-94. https://doi.org/10.1093/qjmed/92.9.487.
McCool, F. Dennis. 2006. “Global Physiology and Pathophysiology of Cough: ACCP
Evidence-Based Clinical Practice Guidelines.” Chest. https://doi.org/10.1378/
chest.129.1_suppl.48S.
Nishino, T., R. Hasegawa, T. Ide, and S. Isono. 1998. “Hypercapnia Enhances the
Development of Coughing during Continuous Infusion of Water into the Pharynx.”
American Journal of Respiratory and Critical Care Medicine 157 (3 Pt 1): 815-21.
https://doi.org/10.1164/ajrccm.157.3.9707158.
Polverino, Mario, Francesca Polverino, Marco Fasolino, Filippo Andò, Antonio Alfieri,
and Francesco De Blasio. 2012. “Anatomy and Neuro-Pathophysiology of the
Cough Reflex Arc.” Multidisciplinary Respiratory Medicine 7 (1): 5. https://doi.org/
10.1186/2049-6958-7-5.

Schramm, C. M. 2000. “Current Concepts of Respiratory Complications of

Neuromuscular Disease in Children.” Current Opinion in Pediatrics 12 (3): 203-7.
https://doi.org/10.1097/00008480-200006000-00004.
Servera, E., J. Sancho, and M. J. Zafra. 2003. “Cough and neuromuscular diseases.
Noninvasive airway secretion management.” Archivos de bronconeumologia
[Bronconeumology Archives] 39 (9): 418-27. https://doi.org/10.1016/s0300-2896
(03)75418-0.
Smith, P. E. M., and C. M. Wiles. 1998. “Cough Responsiveness in Neurogenic
Dysphagia.” Journal of Neurology, Neurosurgery & Psychiatry 64 (3): 385 LP-
388. https://doi.org/10.1136/jnnp.64.3.385.
Stefanutti, D., M. R. Benoist, P. Scheinmann, M. Chaussain, and J. W. Fitting. 2000.
“Usefulness of Sniff Nasal Pressure in Patients with Neuromuscular or Skeletal
Disorders.” American Journal of Respiratory and Critical Care Medicine 162 (4 Pt
1): 1507-11. https://doi.org/10.1164/ajrccm.162.4.9910034.
Voulgaris, Athanasios, Maria Antoniadou, Michalis Agrafiotis, and Paschalis
Steiropoulos. 2019. “Respiratory Involvement in Patients with Neuromuscular
Diseases: A Narrative Review.” Pulmonary Medicine 2019: 2734054. https://doi.
org/10.1155/2019/2734054.

Chapter 4
DIURNAL PULMONARY FUNCTION TESTING

IN NEUROMUSCULAR DISORDERS
Francesca Simioli*, MD, Maria Martino, MD

and Sara Gioia, MD
Department of Respiratory Pathophysiology and Rehabilitation,
Monaldi Hospital – A.O. Dei Colli, Naples, Italy
ABSTRACT
Respiratory complications are common in subjects affected by

neuromuscular diseases (NMD). Muscle weakness can lead to ineffective cough.
Furthermore the ventilatory pump dysfunction eventually causes respiratory
failure.
Objective pulmonary function testing is crucial at the time of diagnosis and
throughout the disease progression. Primary tools are: dynamic and static lung
volumes assessment, respiratory muscle strength measurement, peak cough
flow and diurnal blood gas analysis.
Keywords: ventilatory pump, lung volumes, ineffective cough, forced vital capacity,
peak cough flow
INTRODUCTION
Respiratory complications are common and contribute to increased morbidity and

mortality in subjects affected by neuromuscular diseases (NMD) [1]. Expiratory
muscle weakness can lead to ineffective cough. Retained secretions predispose to
*
Corresponding Author’s E-mail: francesimioli@gmail.com.

72 Francesca Simioli, Maria Martino and Sara Gioia
recurrent respiratory tract infections and lung atelectasis. Besides the inspiratory
muscles contribute most to ventilation. Its weakness can lead to a rapid shallow
breathing, increased work of breathing. Bulbar muscles (facial, oropharyngeal and
laryngeal muscles) as well preserve a sufficient airflow especially during sleep, but
also guarantee speaking, swallowing and airway patency.
The ventilatory pump impairment results in decreased lung compliance,
increased airway resistance and increased work of breathing, potentially causing
hypoventilation, first in supine position, and subsequently progressing to diurnal
respiratory failure [2].
The clinical evaluation alone is a poor predictor of respiratory complications and
survival in NMD. Therefore objective pulmonary function testing (PFT) is pivotal at
the time of diagnosis and throughout the disease progression. Serial measurements
of PFT provide a simple way to follow up NMD subjects and to help decision-making
regarding medical and surgical interventions.
Figure 1. Spirometer with pneumotachograph.
PULMONARY FUNCTION TESTING
Spirometry
Spirometry is a fundamental component of routine pulmonary function testing.

The flow-volume and the volume-time curves consist of measuring the inhalation and
exhalation volumes of air via a spirometer (Figure 1). Data is typically reported in
absolute measured litres and percent of predicted values on the basis of reference
ranges accounting age, gender and height. An American Thoracic Society and
European Respiratory Society consensus has developed spirometry reference

Diurnal Pulmonary Function Testing in Neuromuscular Disorders 73
values for a wide range of ethnicities and ages (3–95 years) [3]. However dynamic
volumes measurement requires a good compliance and ability.
Cognitive and physical limitations in some NMD individuals may interfere with the
acceptability and reliability of the test. Although spirometry is usually performed via a
mouthpiece, a flanged mouthpiece or a face mask can be considered for subjects
with NMD who may be unable to adequately maintain a lip seal around a
conventional mouthpiece (Figure 2). Likewise the standing height may be
unattainable in some patients (e.g., significant scoliosis or contractures) and
therefore surrogate measures such as arm span or ulna length can be used.
a.
b.
Figure 2. Conventional mouthpiece and face mask.
Forced vital capacity (FVC) and forced expiratory volume during the first second
(FEV₁) are particularly relevant in individuals with NMD.

They are often reduced compared to healthy controls (< 80%) because they are
determined by inspiratory and expiratory muscle performance and indirectly
influenced by chest wall and lung compliance. Since FEV₁ and FVC are
proportionally reduced, the FEV₁/FVC ratio is generally in the normal range or even
increased (0.80-1.00). The overall findings are consistent with a restrictive ventilatory
pattern, as reported in Table 1.
Due to reduced volumes, the flow-volume curve appears to be smaller than
expected (Figure 3).
FVC has a diagnostic and prognostic value. In presence of disordered breathing
symptoms associated with FVC < 1L or < 50% of predicted value, the use of
mechanical ventilation is strongly recommended [4].
Table 1. Restrictive pattern of pulmonary function testing (PFT) in NMD
Test Result
FEV1 ↓
FEV1/FVC ↔/↑
FVC or VC ↓
TLC ↓
RV ↑
FRC ↔
MIP ↓
MEP ↓
PCF ↓
FEV1, forcefully exhaled volume of air in the first second; FVC, forced vital capacity; VC, vital capacity;
TLC, total lung capacity; RV, residual volume; FRC, functional residual capacity; MIP, maximal
inspiratory pressure; MEP, maximal expiratory pressure; PCF, peak cough flow.
Table 2. Respiratory complications based on pulmonary

function testing in NMD
Test Respiratory complication

FVC < 50%/ < 1 L Hypoventilation/
VC decrease > 25% to supine position Respiratory failure
MIP < 40 cmH₂O
Diurnal pCO₂ > 45 mmHg
PCF < 160 L/min Ineffective cough
PCF < 270 L/min and respiratory infections
MEP < 60 cmH₂O
FVC, forced vital capacity; VC, vital capacity; MIP, maximal inspiratory pressure; MEP, maximal
expiratory pressure; PCF, peak cough flow; pCO2, partial carbon dioxide.

Figure 3. Restrictive pattern on flow-volume curve.
When a forced manoeuvre is impossible and FVC is not obtained, the vital
capacity (VC) is considered an acceptable surrogate. It is recorded during a slow
manoeuvre, and corresponds with the maximum amount of air exhaled after a
maximum inhalation. VC is a helpful tool to determine diaphragmatic performance, in
fact a diaphragm weakness is characterized by a decrease of 25% or more in VC
values from sitting to supine position. In addition lung function is associated with
nocturnal hypercapnia, with a VC < 680 mL being very sensitive to predict daytime
hypercapnia [5].
Lung Volumes
Total and fractional lung volumes can be specifically measured by standardized

techniques such as body plethysmography, gas dilution or washout. Similarly to
spirometry lung volumes are usually attainable by 6 years of age. Measured values
are compared to predicted values based on age, gender and height. Total lung
capacity (TLC) is the total air in both lungs. In NMD TLC is usually reduced (< 80%)
because it is determined by the strength of chest muscles as well as by the lung’s
inward recoil. A restrictive ventilatory pattern is defined by a reduction of TLC
associated with a normal FEV₁/FVC ratio. The severity of restriction can be ranked
on the basis of TLC, as mild (> 65%), moderate (50-65%) and severe (< 50%). TLC
is the sum of VC and residual volume (RV), which is the volume of air that remains in
lungs after a maximal expiration. While TLC and VC are harmoniously reduced, RV

is often elevated as a result of expiratory muscle weakness that makes impossible to

completely deflate the lungs. As a result the RV/TLC ratio is typically increased (>
130%) thus differentiating restrictive pattern in NMD compared to parenchymal
restrictive diseases. RV may be one of the only abnormal findings at diagnosis of
NMD and precede other abnormalities.
Respiratory Muscle Strength Testing (MIP, MEP and SNIP)
Assessment of the respiratory muscle strength is recommended in patients with

NMD in association with the other lung function tests such as spirometry and lung
volumes for a global diurnal pulmonary evaluation.
Maximal inspiratory (MIP) and expiratory pressures (MEP) are measured at
mouth, these tests are volitional and require full subject cooperation. MIP is usually
measured forcefully inspiring from residual volume (RV) and MEP conversely
expiring from total lung capacity (TLC). The maximum value of three manoeuvres is
recorded; each value should vary by less than 10% to be acceptable [6]. Normal
reference values of MIP in adults are 100-140 cmH2O for males and 70-110 cmH2O
for females.
MIP is strongly related to exertional dyspnoea [7] and is useful as a screening
instrument to identify patients with respiratory muscle weakness [8]. Normal values
range is between 200-250 cmH2O for males and 130-170 cmH2O for females.
Maximal sniff nasal inspiratory pressure (SNIP) consists of measuring the nasal
pressure in an occluded nostril whilst the patient sniffs, quickly and deeply, through
the contralateral unobstructed nostril, inspiring from FRC.
The pressure in the obstructed nostril is superimposable to the pressure present
in the nasopharynx and consequently in pulmonary alveoli. Values in healthy adults
are of 104 ± 26 cmH2O in males and 93 ± 23 cmH2O in females. This test has been
shown to be easier to perform than and well correlated with MIP in patients with NMD
[9].
Peak Cough Flow
The cough reflex is a defense mechanism developed over the course of evolution
to protect the airways from inhaling harmful substances and to eliminate potential
pathogens.
In the NMD patients the weakness of the respiratory muscle with, in some cases,
the bulbar dysfunction, results in an impaired cough reflex. This failing lead to
stagnation of secretions which can act as pabulum for bacteria with chronic
infections, persistent inflammatory response and lung damage [10]. Furthermore the
formation of mucous plug with subsequent bronchial obstructions causes
microactelectasis [11].

The peak cough flow is assessed using a handheld peak flow meter (Figure 4).
The patient inspires to TLC and then forcibly coughs, while wearing nose clips, into
the device via a mouthpiece or a mask. Normal PCF values for adults are greater
than 400 L/min, whereas PCF values of 270 L/min or less have been shown to
increase the risk of pulmonary complications in adults with NMD. There are
recommendations that suggest using cough augmentation devices, such as lung
volume recruitment (LVR) bag or the mechanical in-exsufflation (MIE) machine to
improve peak cough flow in adults with NMD when the PCF become < 270 L/min
[12]. PCF ≤ 160 L/min is associated with higher percentage of weaning/extubation
failure in NMD patient [13].
Figure 4. Peak flow meter.
Mechanical in-exsufflation, by applying a positive pressure followed by a rapid

shift to negative pressure, wipes out secretions in the respiratory tract as a natural
cough. Lung volume recruitment consists of a self-inflating resuscitation bag attached
to a one-way valve. Improving PCFs is obtained by the compression of the LVR bag
in coordination with the patient’s sequential inhalations resulting in hyperinflations of
the lungs [14].
Diurnal Blood Gas Analysis
Blood gas analysis provides a complete evaluation of oxygenation, alveolar

ventilation and acid-base balance. Relevant findings compatible with sustained
alveolar hypoventilation and respiratory failure are: increased partial pressure of
carbon dioxide (pCO₂ > 45 mmHg), a bicarbonate accumulation (HCO₃⁻ > 29
mmol/L) or decreased partial pressure of oxygen dioxide (pO₂ < 60 mmHg). An acidic
pH is likely observed in acute respiratory conditions.
Acute respiratory failure in NMD is often triggered by respiratory infections, and is
itself an important indication for non invasive ventilation. A non invasive approach
prevents endotracheal intubation avoiding mortality during these episodes.

Gas exchange is crucial in NMD assessment and follow up in fact respiratory

failure is related to disease progression and lower survival.
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Respir. Care. 2017 Jun;62(6): 826-848. doi: 10.4187/respcare.05250. PMID:
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17189.93. PMID: 16244522.

SECTION 2.
METHODOLOGY/NON INVASIVE VENTILATION

Chapter 5
SLEEP DISORDERS IN NEUROMUSCULAR DISEASES
Michalis Agrafiotis1,, MD
and Paschalis Steiropoulos2, MD, PhD
1
Department of Pulmonary Medicine,
“Georgios Papanikolaou” General Hospital of Thessaloniki, Exohi, Greece
2
Department of Pneumonology, Medical School,
Democritus University of Thrace, Alexandroupolis, Greece
ABSTRACT
Sleep is a state of increased physiologic vulnerability associated with

impairments in gas exchange and blunted ventilatory control. These changes are
particularly prominent during the rapid eye movement (REM) sleep. Involvement
of respiratory muscles in patients with neuromuscular diseases (NMDs) initially
manifests in the form of sleep-disordered breathing events including
“pseudocentral” hypopneas, sleep hypoventilation, obstructive and central
apneas/hypopneas and periodic breathing. These changes are compensated by
the recruitment of accessory inspiratory and expiratory muscles and with the
reduction or abolishment of REM sleep. The implementation of noninvasive
ventilatory support during sleep can improve quality of sleep, quality of life and
survival, and can additionally alter sleep respiratory physiology by inducing glottic
closure, changes in ventilatory drive and various asynchronies. Non-respiratory
sleep problems are also frequently reported in patients with NMDs.
ABBREVIATIONS
ALS amyotrophic lateral sclerosis

CMT Charcot-Marie-Tooth

Corresponding Author’s E-mail: m.agrafiotis@gmail.com.

84 Michalis Agrafiotis and Paschalis Steiropoulos

EEG electroencephalography
EMG electromyography
FRC functional residual capacity
IVC inspiratory vital capacity
MV minute ventilation
NIV noninvasive ventilation
NMDs neuromuscular diseases
NREM non-rapid eye movement
OSA obstructive sleep apnea
PLMD periodic limb movement disorder
RDI respiratory disturbance index
REM rapid eye movement
RLS restless leg syndrome
SDB sleep-disordered breathing
tcPCO2 transcutaneous PCO2
VC vital capacity.
INTRODUCTION
The term neuromuscular diseases (NMDs) refers to a diverse group of diseases

that may affect the upper motor neuron, the lower motor neuron, the peripheral
nerves, the neuromuscular junction and the muscles. When the function of the
respiratory muscles is impaired, sleep-disordered breathing (SDB) is observed,
before the occurrence of daytime ventilatory failure. Respiratory complications, such
as infections, atelectasis and aspiration, represent a major cause of morbidity and
mortality in patients with NMDs. In addition, involvement of the cardiac muscle, which
is very common in patients with muscular dystrophies, may lead to left heart disease
and manifestations of heart failure [1]. However, recent advances in the respiratory
care have significantly improved the survival and quality of life of patients with NMDs.
Among the most prominent respiratory interventions in the management of these
patients is the introduction of ventilatory support in the early phases of symptomatic
sleep hypoventilation, especially in the form on noninvasive ventilation (NIV) [2]. On
the other hand, NIV application in NMDs has been associated with several untoward
respiratory events that may affect sleep quality and gas exchange [3]. It should be
added that several non-respiratory sleep disorders, i.e., insomnia, restless leg
syndrome (RLS) and periodic limb movement disorder (PLMD), are commonly
reported in patients with NMDs. The purpose of this chapter is to provide an overview
of the sleep problems observed in patients with NMDs, with emphasis on their
respiratory aspect and to discuss their association with the disease pathophysiology
and the implementation of ventilatory support.

Sleep Disorders in Neuromuscular Diseases 85
NORMAL SLEEP RESPIRATORY PHYSIOLOGY
Normal adult sleep is divided into: non-rapid eye movement (NREM) sleep and
rapid eye movement (REM) sleep. These alternate during sleep, with NREM
occupying 75-80% of the total sleep time. Overall, normal adult sleep is
characterized by a programmed transition from wakefulness to NREM sleep at first,
followed later by REM sleep. Normal sleep architecture includes 3-5 alternating
NREM/REM sleep cycles, repeated every 90-110 minutes. In contrast to
wakefulness, NREM sleep state is characterized by a synchronized
electroencephalographic (EEG) pattern and mildly reduced skeletal muscle tone.
Slow rolling eye movements may appear at the transition from wakefulness to sleep,
but then are abolished. During REM sleep, EEG reveals a desynchronized pattern,
while skeletal muscle tonic activity is further reduced. This persistent
hypotonic/atonic state is interrupted by short phasic bursts of REMs associated with
several other phasic events, including muscle bursts, blood pressure swings,
irregularities in breathing rhythm and vivid dreaming [4]. While the tone of intercostal
muscles is reduced during NREM sleep and even more during REM sleep, the tone
of the diaphragm is only reduced slightly during NREM sleep and remains
unchanged during REM sleep. The phasic (respiratory) intercostal muscle activity is
high during NREM sleep, leading to an increased ribcage contribution to ventilation,
but then virtually ceases during REM sleep, while the phasic activity of the
diaphragm and the oculomotor muscles is maintained. Therefore, during REM sleep,
ventilation becomes totally dependent on diaphragmatic mechanical efficiency [5, 6].
However, during phasic REM bursts, clusters of short interruptions (40-80
milliseconds) of diaphragmatic activity are commonly registered [4]. Overall, NREM
sleep is associated with increased intercostal electromyographic (EMG) activity,
while REM sleep with increased diaphragmatic EMG activity. In addition, both the
tonic and the phasic activity of upper airway muscles (e.g., genioglossus) decrease
with sleep, especially during its REM state [7].
Gas exchange and ventilatory control are significantly altered during sleep. Body
metabolism is reduced, leading to a decrease in oxygen consumption and carbon
dioxide production, while the wakefulness stimulus is withdrawn and breathing
control is transferred to chemical stimuli [8]. Functional residual capacity (FRC) also
decreases, as a result of the supine position and intercostal muscle hypotonia/atonia,
leading to a higher ventilation/perfusion mismatch [5]. Upper airway resistance
increases during sleep (NREM<REM) due to upper airway muscle hypotonia and to
the lower resting lung volume; posterior displacement of the tongue and soft palate in
the supine position may also contribute to this effect [9]. Importantly, the upper
airway muscle reflexes, which are responsible for dilating the upper airway lumen
during inspiration, are attenuated during sleep [10]. In addition, both hypoxic and
hypercapnic ventilatory response are blunted significantly during NREM sleep and
even further during REM sleep [11, 12]. Minute ventilation (MV) is also reduced as
compared to wakefulness. Overall, MV decreases by 6-7% during NREM sleep and

by 16% during REM sleep; again, the effect of REM sleep on ventilation is more
pronounced during its phasic stage [13]. MV reduction is mainly associated with a
decrease in tidal volume by 6-16% during NREM sleep and by 25% during REM
sleep, while respiratory rate increases slightly during NREM sleep, but it can become
irregular during the phasic stage of REM sleep [14, 15]. There are several factors
contributing to MV reduction including reduced metabolism, withdrawal of the
wakefulness stimulus, reduced chemosensitivity and increased upper airway
resistance. Overall, these changes result in an increase in PCO2 by 2-8 mmHg and a
drop in PO2 by 3-10 mmHg, while oxygen saturation (SpO2) is reduced by 2% [16].
SLEEP-DISORDERED BREATHING IN PATIENTS

WITH NEUROMUSCULAR DISEASES
Symptoms and Signs
Respiratory muscle involvement in patients with NMDs may manifest with

breathlessness and symptoms suggestive of SDB. Orthopnea, i.e., breathlessness
when lying supine, is one of the most characteristic manifestation of diaphragmatic
weakness. Symptoms suggestive of SDB include unrefreshing sleep, daytime
sleepiness, morning headache and mood disorders. Patients also commonly report
weak cough and recurrent respiratory tract infections. Difficulties in phonation,
impaired swallowing, weight loss and frequent aspirations indicate involvement of
upper airway muscles. Common signs include tachypnea, abdominal paradox and
use of accessory respiratory muscles. Signs of left heart failure, e.g., ankle swelling,
lung crackles, jugular distention should be sought in patients with concurrent
cardiomyopathies [17, 18].
Types of Sleep-Disordered Breathing Events in Patients

with Neuromuscular Diseases
SDB events in patients with NMDs can be classified into those associated with
the disease pathophysiology and those associated with the implementation of
noninvasive ventilation during sleep. The former can be further classified into primary
pathologic events and compensatory mechanisms (Table 1).
Sleep-Disordered Breathing Events Associated with Disease

Pathophysiology
Primary pathologic events in patients with NMDs and SDB include
“pseudocentral” or “diaphragmatic hypopneas,” sleep hypoventilation, obstructive
and central sleep apneas/hypopneas and periodic breathing.

Table 1. Types of sleep-disordered breathing events in patients

with neuromuscular diseases
Primary sleep-disordered Compensatory Events associated with

breathing events mechanisms sleep ventilatory support
Sleep hypoxemia Recruitment of accessory Glottic closure
inspiratory muscles
Sleep hypoventilation Recruitment of abdominal Changes in ventilatory drive
muscles
“Pseudocentral”/”diaphragmatic” Reduction or abolishment Autotriggering
hypopneas of REM sleep
Obstructive apneas/hypopneas Ineffective triggering
Central apneas/hypopneas Prolonged insufflation
Periodic breathing
“Pseudocentral” or “diaphragmatic” hypopneas appear during the phasic stage of

REM sleep. According to some authors, “pseudocentral” hypopneas are the most
common cause of SDB in patients with NMDs, representing an early warning sign of
respiratory muscle involvement and are commonly associated with diaphragmatic
dysfunction [19–21]. These events are attributed to the almost complete cessation of
the intercostal muscle activity during REM bursts, which causes a total shift in the
work of breathing to the weakened diaphragm. As a result, inspiratory airflow is
reduced leading to a drop in SpO2 and thus a hypopnea is registered. The SpO2
signal reveals a saw-tooth pattern of desaturation dips corresponding to REM bursts,
while chest wall excursion is disproportionally reduced relative to abdominal
excursion [22]. In a polysomnographic study of 8 patients with various NMDs and a
mean vital capacity (VC) of 57%, “pseudocentral” hypopneas were present in all
patients who achieved at least 1 epoch of REM sleep (6/8) and were associated with
reduced intercostal muscle activity and more severe desaturation as compared to
NREM sleep [21]. In a study of 42 patients with primary myopathies, “REM
hypoventilation” was defined as a nocturnal transcutaneous PCO2 (tcPCO2) > 50
mmHg for >50% of REM sleep time and “continuous sleep hypoventilation” as a
tcPCO2 > 50 mmHg for both REM sleep and >50% of NREM sleep time. SDB was
diagnosed based on a respiratory disturbance index (RDI) >5 events/hour of total
sleep time or >10 events/hours of REM sleep time. This study showed that “REM
hypopneas” were the earliest and most prevalent polysomnographic finding in
patients with primary myopathies, while an inspiratory VC (IVC) <60% had a
sensitivity of 91% and specificity of 89% in predicting the onset of SDB. As IVC
decreased, polysomnographic findings progressed from “REM hypopneas” to “REM
hypopneas” plus “REM hypoventilation,” to “continuous sleep hypoventilation” and
finally to daytime hypoventilation. However, as restriction worsened, “REM
hypopneas” became rarer and less well defined and were subsequently replaced by
prolonged phases of sleep hypoventilation, while RDI was high only in the early
phases of restriction [20]. Likewise, “REM hypopneas” with or without hypoventilation
were also the earliest and most common finding in group of 27 patients with acid

maltase deficiency, while “continuous sleep hypoventilation” was associated with

lower IVC values [19]. It should be noted that “pseudocentral” events can be easily
misclassified as “central” or “obstructive,” unless more sensitive methods for
registering respiratory efforts (e.g., EMG, esophageal pressure monitoring, pulse
transit time) are employed.
Sleep hypoventilation is the most prominent manifestation of SDB in patients with
NMDs. Hypoventilation occurs as the result of the imbalance between the increased
respiratory load (due to upper airway resistance, microatelectases, thoracic wall
contractures and scoliosis) and the impaired ability of the weakened respiratory
muscles to generate force. Sleep hypoventilation is diagnosed when PCO2 (arterial,
end-tidal or transcutaneous) increases to a value higher than that expected during
sleep and its prevalence may vary according to the definition used. Ogna et al.
retrospectively analyzed nocturnal tcPCO2 data from a population of 232 adult
patients with various NMDs. In patients with daytime normocapnia the prevalence of
sleep hypoventilation was 2% based on a mean tcPCO2>50 mmHg; 4% based on a
tcPCO2 > 55 mmHg for >10 minutes and; 28% when hypoventilation was defined as
a peak tcPCO2 ≥ 49 mmHg [23]. Nevertheless, an overnight peak nocturnal tcPCO2 ≥
49 mmHg has been associated with a higher risk for NIV in patients with NMDs
[2, 24]. In patients with severe diaphragmatic involvement, episodes of sleep
hypoventilation are usually accompanied by severe and sustained decreases in
SpO2, yielding a “sagging” profile in the overnight oximetry signal [1]. On the other
hand, when diaphragmatic function is spared (e.g., type 2 spinal muscular atrophy),
sleep hypoxemia is usually mild and PCO2 values are marginally increased [25].
Although several definitions of sleep hypoventilation according to oximetry recordings
have also been proposed [1], the use of oximetric cut-off points appears to be a less
sensitive method for detecting sleep hypoventilation in patients with NMDs [26].
Sleep hypoventilation appears initially during REM sleep, which is the most
vulnerable sleep state, and then gradually progresses into NREM sleep and finally to
wakefulness. In the study by Ragette et al, an IVC < 60% predicted the onset of SDB
with a sensitivity of 91% and a specificity of 89%; an IVC < 40% predicted continuous
sleep hypoventilation with a sensitivity of 94% and a specificity of 79% and; an
IVC < 25% predicted diurnal hypoventilation with a sensitivity of 92% and a
specificity of 93% [20]. On the other hand, based on retrospective data from 131
patients with amyotrophic lateral sclerosis (ALS), sleep hypoventilation was present
in half of those who did not report dyspnea and had a VC > 75% [27].
Patients with NMDs share the same risk factors for obstructive sleep apnea
(OSA) with the general population (obesity, male gender, etc.). In addition, other
factors such as macroglossia (e.g., in patients with muscular dystrophies) [28] and
reduced lung volumes [29] may increase susceptibility to upper airway collapse.
However, other pathophysiologic features directly related to the NMD per se may
also predispose to OSA. These include upper airway muscle hypotonia, pharyngeal
neuropathy and bulbar dysfunction. Upper airway muscle hypotonia is a common
finding in various myopathies and may account for the fact that OSA is observed in
20% of patients with muscular dystrophies and acid maltase deficiency [30]. OSA

follows a distinctive bimodal pattern in patients with muscular dystrophies and acid
maltase deficiency with obstructive events prevailing in the early disease stages,
while hypoventilation becomes the predominant finding in more advanced disease.
Thus, in a retrospective study of polysomnographic findings of 34 patients with
Duchenne muscular dystrophy (DMD), OSA prevailed within the first decade of life
(median age 8 years), while hypoventilation was the main finding in the second
decade (median age 13 years) [31]. This pattern of distribution however may simply
reflect progressive weakening of respiratory muscles and inability to generate the
negative pressure required for upper airway collapse [30]. Pharyngeal neuropathy
may account for the higher incidence of OSA in patients with type I hereditary motor
sensor neuropathy (Charcot-Marie-Tooth disease, CMT) as opposed to normal
controls (38 vs. 5%, respectively) while the severity of OSA in patients with CMT is
positively correlated with the severity of neurologic disability [32, 33]. Bulbar
dysfunction is quite common in patients with ALS, spinal muscular atrophy, post-polio
and Gullain- Barre syndrome and may predispose to the development of OSA,
although the evidence is equivocal and probably true obstructive events are rare [1,
30]. Factors that may account for this finding include accelerated weight loss and
tongue atrophy in patients with advanced bulbar disease as well as inability of the
respiratory muscles to generate negative force in advanced disease stages [30].
Overall, obstructive events in patients with NMDs are associated with snoring,
inspiratory flow limitation, thoracoabdominal paradox and are usually terminated by
arousals [34]. However, the presence of thoracoabdominal paradox per se may
simply indicate respiratory muscle weakness without the co-existence of a true upper
airway obstruction. Its absence, however, does not exclude upper airway obstruction
in patients with advanced disease and weakened respiratory muscles. Thus, in the
first case, “pseudocentral”/ “diaphragmatic” events can be classified as obstructive,
while in the latter case, obstructive events can be registered as central [30].
Obstructive events are usually associated with sleep hypoxemia and a saw-tooth
pattern in oximetry and are usually observed during both sleep states, although they
are worse during REM sleep and in the supine position [22]. When REM-related
events predominate, they most likely represent “pseudocentral” hypopneas rather
than true obstructive events.
Central sleep apnea and Cheyne-Stokes breathing are associated with the
presence of cardiomyopathies in patients with muscular dystrophies [35]. Other types
of periodic breathing in some patients with NMDs (e.g., in spinal cord injury or type 1
myotonic dystrophy) are attributed to diaphragmatic weakness [36, 37]. Brainstem
abnormalities may also account for central events in patients with ALS [38] or
myotonic dystrophy [39]. As a rule, central events are uncommon during REM sleep
and arousals occur several breaths after their termination, while the oscillation in the
oximetry signal yields a square-like symmetric pattern [40]. However, while Cheyne-
Stokes breathing has a cycle time that exceeds 40 seconds, other types of periodic
breathing have shorter cycles [34].
Possible compensatory mechanisms include the reduction or complete
abolishment of REM sleep in patients with advanced diaphragmatic dysfunction and

the recruitment of accessory muscles. The former protects against the occurrence of
SDB events during the most vulnerable sleep period [41]. During NREM sleep the
ventilatory function can be supported by recruitment of the genioglossus, intercostal
and sternocleidomastoid muscles, while the contraction of the abdominal muscles
pushes the diaphragm cranially to assist its passive descent during inspiration
[21, 42]. Likewise, the recruitment of the accessory respiratory muscles during both
phasic and tonic REM sleep may offer protection against hypoventilation [41, 43].
Sleep-Disordered Breathing Events Associated

with Noninvasive Ventilation
The implementation of nocturnal NIV improves gas exchange, quality of sleep,
quality of life and survival in patients with NMDs. However, NIV is commonly
associated with several undesirable events. These events include glottic closure and
changes in ventilatory drive leading to periodic breathing and central apneas. In
addition, various types of asynchronies and air leaks might influence the
effectiveness of ventilatory support and the quality of sleep.
Central apneas and/or periodic breathing are caused when PCO2 is reduced
below the hypocapnic apneic threshold and are usually associated with high
pressure support levels or auto-triggering [44, 45]. Glottic closure is a protective
reflex commonly activated at low PCO2 values and is commonly associated with
central apneas [46, 47]. Ineffective triggering is a frequently described asynchrony in
mechanically ventilated patients and is usually associated with hyperinflation due to
higher pressure support and respiratory rate and to a lesser extend with respiratory
muscle weakness [44]. Autotriggering is most commonly associated with a high
inspiratory trigger sensitivity combined with the presence of air leaks, water
condensation or the cardiobalistic artifact [22]. Air leaks are very common in
noninvasively ventilated patients and can lead to prolonged insufflation, persistent
hypercapnia and compromised sleep quality [48, 49]. In a study of 18 chronically
mechanically ventilated patients with NMDs, asynchronies were more common
during NREM than REM sleep and were correlated with a high incidence of air leaks.
Autotriggering was the most common respiratory event, followed by ineffective
triggering and prolonged insufflation, while the presence of asynchronies was
commonly associated with arousals and sleep disruption [48].
NON-RESPIRATORY SLEEP DISORDERS IN PATIENTS

WITH NEUROMUSCULAR DISEASES
RLS and PLMD are more frequent in patients with ALS and myotonic
dystrophies, as compared to the general population [50, 51] and they represent
common causes of sleep disruption and impaired sleep quality. REM sleep without
atonia, commonly associated with the recruitment of accessory respiratory muscles,
has also been reported in patients with ALS and myotonic dystrophies [52, 53]. Some

patients with myotonic dystrophies may also manifest a narcolepsy-like state

associated with lower orexin levels in the cerebrospinal fluid and presenting clinically
with central hypersomnolence [54]. Body pain, muscle cramps, difficulties in handling
secretions and saliva, depression and drugs may also cause insomnia and affect
sleep quality in patients with NMDs.
CONCLUSION
SDB is one of the earliest and most prominent manifestations of respiratory

muscle involvement in patients with NMDs. While sleep hypoventilation is the
hallmark of SDB events in patients with NMDs, “pseudocentral” hypopneas,
obstructive and central apneas/hypopneas and periodic breathing are also quite
common findings. The implementation of NIV during sleep can induce various
respiratory events as glottic closure, changes in ventilatory drive and asynchronies.
Moreover, non-respiratory sleep disorders are not uncommon.
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Neurodegener Dis 2013;2013:692026.

Chapter 6
INITIATION OF NON-INVASIVE VENTILATION

IN CHILDREN WITH NEUROMUSCULAR DISEASE
Sherri Lynne Katz

Division of Respiratory Medicine, Department of Pediatrics,
Children’s Hospital of Eastern Ontario/University of Ottawa,
Ottawa, Ontario, Canada
ABSTRACT
The advent of non-invasive ventilation (NIV) has changed the prognosis and
outcomes of children with neuromuscular disease dramatically, as respiratory
failure has traditionally been the main cause of morbidity and mortality in this
population. NIV has had one of the single greatest impacts on longevity for
children with neuromuscular conditions, compared to other existing therapies. It
improves gas exchange, reduces hospitalization rates for respiratory infections
and improves quality of life for children with neuromuscular disease.
INTRODUCTION
NIV is usually initiated when sleep disordered breathing, often the first
manifestation of respiratory compromise, is recognized. In some instances, it may be
initiated because of recurrent respiratory infections and/or atelectasis. Unfortunately,
recognition of isolated nocturnal respiratory dysfunction is challenging and in some
cases NIV may be initiated only when daytime symptoms and/or respiratory failure
are evident; this represents a missed opportunity to intervene with a therapy that can
greatly improve quality of life in this population.

Corresponding Author’s E-mail: skatz@cheo.on.ca.

96 Sherri Lynne Katz
NIV is most often initiated and titrated in the context of an overnight sleep study,
or polysomnogram. Individualized selection of interfaces and titration of NIV settings
are required. Longitudinal follow-up is needed to ensure adequate respiratory
support is maintained with growth and disease progression. In this chapter,
identification of the need for NIV, practical aspects of initiation and titration, as well
as benefits and complications of NIV will be addressed.
IDENTIFYING THE NEED FOR NIV
Development of weakness of respiratory muscles often parallels that of skeletal

muscle weakness in childhood neuromuscular conditions. As tidal volume decreases
during sleep, respiratory dysfunction often manifests first as sleep disordered
breathing. If the diaphragm and intercostal muscles are weak, hypoventilation,
particularly during REM sleep, often ensues (Sawnani 2019b). While the timing of
onset of sleep-disordered breathing may vary in different neuromuscular diseases
and may have individual variability as well, the prevalence of sleep-disordered
breathing is high, estimated at 25 to 40% in cross-sectional screening studies, with
gas exchange abnormalities and disturbed sleep architecture present in more than
80% of individuals when evaluated (Katz 2009).
Nocturnal hypoventilation in children is defined by the American Academy of
Sleep Medicine as a minimum of 25% of sleep time with carbon dioxide level greater
than 50 mmHg (Berry et al. 2012). In a Care Considerations Guideline for individuals
with Duchenne Muscular Dystrophy, elevation of carbon dioxide during sleep to a
value above 50 mmHg for more than 2% of sleep time, an increase in carbon dioxide
level of more than 10 mmHg above baseline during sleep, an oxygen saturation
below 88% for 2% or more of sleep time or a duration of at least 5 minutes, and/or an
apnea hypopnea index of greater that 5 events/hour all constitute indications for
initiation of NIV (Bushby et al. 2010). Additionally, more subtle signs of respiratory
compromise including paradoxical respiration, tachypnea and sleep fragmentation
may be early signs of impending nocturnal respiratory compromise (Sawnani 2019b).
Diaphragm weakness may result in hypopnea events that are neither secondary to
upper airway obstruction nor impaired central respiratory drive. Intercostal muscle
atonia, resulting in greater loss of chest excursion as compared to abdominal
obstruction, may give the appearance of pseudo-obstruction on polysomnogram. If
upper airway hypotonia is also present, obstructive sleep apnea may co-exist, or
even precede the presence of hypoventilation. For example, in children with
Duchenne Muscular Dystrophy, a bimodal distribution of sleep disordered breathing
has been observed, with obstructive sleep apnea appearing the first decade of life
and nocturnal hypoventilation occurring in the second decade. Early development of
obstructive sleep apnea has also been noted in children with Duchenne Muscular
Dystrophy who receive oral steroids, which leads to central distribution of adiposity,
promoting upper airway obstruction. The development of scoliosis may also

Initiation of Non-Invasive Ventilation in Children … 97
contribute to the development of sleep-disordered breathing by further restricting the

chest wall and promoting hypoventilation.
The greatest challenge for clinicians lies in the identification of the onset of sleep
disordered breathing to guide optimal timing for initiation of NIV. Although a study in
individuals with Duchenne Muscular Dystrophy did not find benefit in the prophylactic
use of NIV, it has been shown that in the presence of nocturnal hypoventilation, the
use of NIV improves quality of life (Ward et al. 2005). Further, children with nocturnal
hypoventilation are likely to develop progressive symptoms and/or daytime
hypercapnia within 2 years, if not treated with NIV (Ward et al. 2005). Yet, most
individuals with neuromuscular hypoventilation remain asymptomatic despite its
presence, likely because of the insidious nature of the onset of symptoms. As a
result, symptoms are often recognized in hindsight after hypoventilation has been
corrected. Morning headaches, anorexia/poor growth, daytime fatigue or
hyperactivity, daytime neurobehavioral impairment, nocturnal sleep disruption and
fear of going to sleep should prompt clinicians to investigate for the presence of
nocturnal respiratory dysfunction (Hull et al. 2012). Daytime pulmonary function tests
have limited sensitivity and specificity in the identification of sleep disordered
breathing and may not be able to be performed by young children, those with
cognitive delay and/or bulbar weakness (Katz 2009). Due the limitations in
recognition of symptoms or other daytime indicators of sleep disordered breathing in
children with neuromuscular disease, maintenance of a high degree of clinical
suspicion is required and proactive evaluation for its presence is needed. The
American Academy of Sleep Medicine guidelines recommend polysomnography to
evaluate for the presence of nocturnal respiratory dysfunction in the presence of
sleep-related symptoms in individuals with neuromuscular disease where there is no
alternative clinical explanation(Kushida et al. 2005). The American Centres for
Disease Control and British Thoracic Society also recommend that nocturnal
respiratory evaluation be pursued in the presence of forced vital capacity less than
50-60% predicted and/or in children who are non-ambulant, have symptoms of sleep
disordered breathing, have evidence of diaphragm weakness and/or rigid spine
(Bushby et al. 2010, Hull et al. 2012). Previous guidelines have also recommended
evaluation for sleep disordered breathing prior to surgeries, in order to help guide
postoperative management, which may include use of NIV.
Nocturnal respiratory evaluations are most useful in identifying the need for
nocturnal support with NIV. Polysomnography, the most comprehensive of
evaluations, is the gold standard for nocturnal respiratory evaluation and
identification of nocturnal hypoventilation. It provides the most comprehensive
assessment of nocturnal respiratory function and pattern. It has the added advantage
of the ability to initiate, titrate and evaluate success of NIV treatment all in the same
study, if required. Overnight oximetry, capnography and polygraphy have also been
used to screen for nocturnal hypoventilation (Katz 2009) and may be particularly
useful in resource limited settings and/or when polysomnography is unavailable, for
example during pandemics. NIV may be initiated in an intensive care unit,

polysomnography laboratory or in some cases in an ambulatory setting, depending

on local resource availability.
INTERFACES AND VENTILATION MODES
For children with neuromuscular weakness and evidence of nocturnal

hypoventilation, NIV is administered as bi-level nocturnal respiratory support,
consisting of a set inspiratory positive airway pressure, an expiratory positive airway
pressure and a back-up respiratory rate, via a mask interface. The positive
inspiratory pressure assists in achieving inspiration deep enough to reach an
appropriate tidal volume, whereas the expiratory positive airway pressure maintains
airway patency (Sawnani 2019b). Bi-level respiratory support is preferred even if
sleep disordered breathing manifests initially as obstructive sleep apnea because of
the inevitable development of nocturnal hypoventilation with increasing muscle
weakness over time in children with progressive neuromuscular disease. A back up
rate can also be set to ensure delivery of a minimum number of breaths per minute.
In cases of advanced muscle weakness or in young children whose respiratory
efforts may not trigger the ventilator, the backup rate may be set to approximate the
child’s physiologic respiratory rate to allow their respiratory muscles to rest during
sleep (Sawnani 2019a).
PEDIATRIC INTERFACES
NIV is administered through a mask interface (Table 1). Nasal masks or nasal
pillows are most common, with several commercially available models for children of
different sizes. In some specialized centres, masks may be customized with the aid
of 3D printers. Oronasal or full face masks may be considered if there is a sizable air
leak, for example due to mouth-breathing. Masks are secured with a headgear,
typically with adjustable straps.
There is limited evidence comparing the efficacy of different masks in children;
the choice of interface should be individualized to provide optimal safety, seal and
comfort (Castro-Codesal, Olmstead, and MacLean 2019). Nasal interfaces are
preferred over oronasal or full face masks(Hull et al. 2012, Amin, Al-Saleh, and
Narang 2016, Castro-Codesal, Olmstead, and MacLean 2019), as they minimize the
risk of aspiration if a child were to vomit while wearing NIV. As some of the air
delivered with NIV will be swallowed into the stomach, distension of the stomach
could occur, inducing vomiting. With a nasal interface, the mouth is not obstructed,
lessening the risk of aspiration with vomiting. Suctioning, communication and use of
pacifiers can also be simultaneously achieved with nasal interfaces in place (Castro-
Codesal, Olmstead, and MacLean 2019). In young babies, pacifiers may be used

specifically to overcome mouth leaks when nasal interfaces are used (Mortamet et al.
2017).
Table 1. Relative Advantages and Disadvantages of Interfaces and Ventilator

Modes in Children with Neuromuscular Disease
Advantages Disadvantages
Interface
Nasal mask/ pillows  Minimizes aspiration risk  Leak from mouth
 Can simultaneously suction, talk and use
pacifier
Oronasal/full face mask  Avoids mouth leak  Risk of aspiration if vomiting
and cannot remove mask
Ventilator Mode
Pressure Targeted  Lightweight
 Less expensive
 Better leak compensation than volume-
cycled ventilators
Spontaneous  Not appropriate: child triggers
all breaths, this mode does not
minimize work of breathing nor
does it guarantee a minimum
respiratory rate
Spontaneous/timed  Child can trigger breaths- more  Spontaneous breaths above
comfortable if they often generate set respiratory rate do not
sufficient respiratory effort receive pressure support
 Set minimum number of breaths with
fixed inspiratory time delivered = assures
ventilation in young children or those with
weakness that cannot trigger ventilator to
initiate inspiration
Pressure Control  Provides pressure support for each
breath to achieve tidal volume and has
fixed inspiratory time = better support for
those with greater muscle weakness
Volume Assured  Adapts pressure delivered to achieve  Algorithms may be slow to
Pressure Support tidal volume = better for those with respond to a needed change in
variable needs in different sleep stages respiratory support, particularly
in young children
Volume Targeted  Can be used to provide breath stacking  More cumbersome and
and/or daytime mouthpiece ventilation expensive than pressure
targeted ventilation
Aspiration risk is highest amongst children who could not recognize that they
were nauseated and/or lack the dexterity to remove the mask interface themselves.
In instances where an oronasal mask is required to achieve adequate ventilation, if
the child would not be able to remove the mask themselves in the above
circumstances, it is often necessary to have an awake caregiver at the bedside or a
call system, in order to mitigate the aspiration risk. Chin straps may also be used to
minimize leak of air from the mouth but are subject to the same limitations as
oronasal masks with respect to aspiration risk. Full face masks resembling scuba

diving gear and helmets with gas inflow and outflow have also been used for NIV
provision.
Regardless of the interface used, ensuring a good seal on the child’s face is
critical for delivery of the set positive pressure and for avoidance of discomfort or
complications. The minimum skin pressure compatible with effective ventilation
should be utilized to avoid pressure sores or skin breakdown. A second interface is
sometimes needed to alternate if the skin is sensitive. Additionally, frequent cleaning
of the mask may help to minimize skin irritation and protective skin dressings may be
used if skin breakdown occurs.
The use of heated humidity in the NIV circuit reduces nasal dryness, prevents
thickening of secretions and improves comfort (Castro-Codesal, Olmstead, and
MacLean 2019). It is also important to ensure that the exhalation ports on the mask
interface are not blocked, as the single limb NIV circuits designed for home use
require the use of vented masks and/or an intentional leak in the circuit, in order to
allow for exhalation and clearance of carbon dioxide.
Finally, gradual desensitization to the NIV interface may be required for some
children. Practice during the daytime without pressure first for short periods may be
helpful for adapting to the mask and its introduction and may be a useful strategy to
enhance tolerance. The use of a ramp to initiate NIV at low pressure with a gradual
increase to the prescribed pressure over several minutes may also be helpful for NIV
acclimatization (Castro-Codesal, Olmstead, and MacLean 2019).
VENTILATOR MODES
Although both volume and pressure ventilation can be used to provide NIV,
pressure modes are more commonly employed. There are different ventilation
modes that could be considered, depending on the needs of the child (Table 1).
Pressure-Targeted Ventilation
Pressure-targeted ventilation is most commonly used for NIV in children with

neuromuscular disease (Hull et al. 2012). These machines tend to be less expensive
and less heavy than volume-targeted ventilators. They also have the advantage of
adjusting well for unintentional leaks around masks.
Spontaneous Mode
With this mode of ventilation, a set inspiratory and expiratory pressure is
delivered with each breath sensed by the machine. The child must trigger each
breath and no back up rate is set (Amin, Al-Saleh, and Narang 2016). This mode
should not be used for children with neuromuscular disease, as it does not optimally
minimize work of breathing, the child’s respiratory efforts may not reliably trigger the

ventilation to cycle between inspiration or expiration, nor will it guarantee a minimum

respiratory rate per minute (Hull et al. 2012).
Spontaneous/Timed Mode Ventilation

Spontaneous/timed mode ventilation is most commonly used to support children
with neuromuscular disease requiring NIV. In this mode, an inspiratory positive
airway pressure (IPAP), expiratory positive airway pressure (EPAP), inspiratory time
and back-up respiratory rate are set. The child can spontaneously trigger breaths.
The ventilator will support a set number of mandatory breaths per minute to the set
inspiratory pressure. The ventilator does not provide pressure support for additional
patient-initiated breaths above the set rate. Inspiratory pressure is delivered when
the ventilator senses a change in airflow with the child’s inspiratory effort. Pressure
delivered by the ventilator is reduced to the EPAP when the circuit flow rate
decreases with the onset of the child’s exhalation. The inspiratory time can be fixed,
to ensure appropriate cycling between inspiration and expiration. If the machine
senses a decrease in the child’s respiratory rate below the set back-up rate, an
additional number of breaths are delivered by the ventilator per minute to ensure the
minimum number of breaths/minute set are achieved.
This mode of ventilation is most suitable for those with neuromuscular weakness
who have intact respiratory drive and often generate sufficient respiratory effort to
trigger the ventilator but who do not achieve adequate tidal volumes consistently.
Young children, as well as older children with low tidal volumes, benefit from this
mode of ventilation as the sensitivity of the inspiratory and expiratory triggers may
not be sufficient to recognize their respiratory efforts, but a minimum number of
breaths will be delivered with a fixed inspiratory time.
Pressure Control Mode

Pressure control mode may be used when individuals have a greater degree of
muscle weakness and require support for each breath in order to achieve tidal
volume. In this mode, similar to spontaneous-timed mode, inspiratory time can be
fixed. The key difference is that pressure support and a fixed inspiratory time are
provided for both mandatory and patient-triggered breaths, to ensure peak inspiratory
pressure is achieved with each inspiration. A back-up respiratory rate may also be
set. This mode provides a greater degree of rest for respiratory muscles as each
breath is supported by the ventilator.
Volume Assured Pressure Support
In this mode of ventilation, a targeted tidal volume is set and a variable pressure
support is delivered by the ventilator in order to achieve it. Inspiratory time can be
variable in some devices. A back-up respiratory rate can be set. This mode of
ventilation can be helpful in older children whose respiratory support needs may vary

between sleep stages. For example, an individual with predominantly REM-related

sleep disordered breathing due to diaphragmatic weakness or upper airway
obstruction may benefit from this type of ventilation. Volume assured pressure
support may not be successful, however, in some young children or those with weak
respiratory effort, in whom changes in pressure delivered by the machine in response
to a reduction in tidal volume may be slow to occur as the algorithms are not
designed for children with body weight less than 30 kilograms.
Volume Targeted Ventilation
Volume-targeted ventilators deliver pressure to achieve a set tidal volume. They

are less frequently used for home NIV as pressure-targeted ventilators are lighter,
less expensive and provide better compensation for leaks. As compared to volume
averaged devices (VAPS), true volume-cycled ventilators have the advantage of
being able to be used to provide breath-stacking to assist with lung volume
recruitment and airway clearance (Hull et al. 2012).
INITIAL VENTILATOR SETTINGS
Ventilator settings should be individualized and determined through observation

in a monitored setting by an individual with expertise in NIV titration. This ideally
occurs in the setting of a polysomnography laboratory but may also be achieved with
oximetry and capnography (end-tidal or transcutaneous carbon dioxide) monitoring.
For children with relatively normal chest compliance, starting pressures of IPAP
of 8 cm water and EPAP of 4 cm water may be used (Hull et al. 2012), with titration
to achieve stable gas exchange, as well as adequate chest excursion and tidal
volume. A minimum pressure support of 4 cm water should be maintained to avoid
carbon dioxide rebreathing that could occur if airflow was low during exhalation and
exhaled gas was not well-cleared through the expiratory ports in the circuit (Chatwin
et al. 2015). Higher PIP and PEEP may be needed if the lungs or chest wall are less
compliant. In children with spinal muscular atrophy, higher pressure spans have
been used to assist in minimizing chest wall deformity. In children less than 12 years
old, a maximum IPAP of 20 cm water pressure is recommended. A maximum IPAP
of 30 cm water is recommended for children 12 years and older (Berry et al. 2010). A
back-up respiratory rate can be matched to the child’s expected respiratory rate in
order to ensure that all breaths are supported in spontaneous timed mode, which will
allow rest of the respiratory muscles during sleep, in children who are very weak or
do not trigger the ventilator.
Inspiratory time increases with age and decreasing respiratory rate. It should
similarly be individually titrated. A minimum inspiratory to expiratory time ratio of 1:2

should be maintained. Children with stiffer lungs and/or chest walls will require longer
inspiratory times to overcome resistance.
The rise time determines how quickly pressure is increased to IPAP. This should
be titrated for comfort, but a shorter rise time will result in greater unloading of the
respiratory muscles and require less work from the child to achieve IPAP.
The ventilator’s trigger sensitivity should be set so that spontaneously initiated
breaths are detected, and the machine will begin to deliver pressure in response to
an increase in air flow. If trigger sensitivity is too low, the ventilator will not detect
spontaneously triggered breaths and will deliver ventilator breaths out of sync with
the child’s respiratory efforts.
When the ventilator senses decreased air flow, it cycles to expiration and
reduces its pressure to EPAP. If the ventilator does not detect the end of inspiratory
effort, it continues to provide pressure at IPAP, resulting in the child experiencing a
greater resistance to exhalation. This could cause air trapping and/or dysynchrony.
The cycle sensitivity should therefore be titrated as part of the ventilator settings.
ALARMS AND MONITORING
The need for and type of ventilator alarms should be individualized to the clinical
situation. Alarms may be set to indicate loss of power, disconnection, low battery
charge, high or low pressure, flow or volume, or the presence of apnea.
Children and families must have a clear understanding of the benefits and risks
associated with NIV (Edwards et al. 2020). Families and community caregivers need
to be able to manage the child’s care, including NIV needs, in a home environment.
Appropriate monitoring needs to be in place and should be individualized. This may
include alarms on the ventilator, saturation monitoring and/or observation by trained
caregivers. Consideration may be given to the need for a second ventilator in the
home, in case of equipment failure, for children who have a high dependency on NIV.
Benefits of NIV in Childhood Neuromuscular Disease
The use of NIV in children with neuromuscular disease has been shown to confer
multiple health benefits (Table 2). Nocturnal gas exchange can be normalized, with
improvement in oxygen saturation and resolution of hypercapnia. Sleep architecture
is also improved with fewer arousals. Improvements in gas exchange can be
sustained for several years with NIV (Mellies et al. 2003).
In addition to improvements in nocturnal respiratory function, NIV has also been
shown to improve daytime pulmonary function by slowing the decline in vital capacity
(Hull et al. 2012). It may also prevent development of pectus excavatum, a chest wall
deformity, by providing passive range of motion stretch of intercostal and
costovertebral joints and lung inflation (Hull et al. 2012).

Table 2. Benefits and Complications of NIV in Children

with Neuromuscular Disease
Benefits Complications
↑ longevity Skin irritation/breakdown
↑ quality of life Midface flattening
↓ hospitalizations for respiratory infections Aspiration of gastric contents
↓ pulmonary function decline Aspiration of oral secretions
↑ gas exchange Nasal dryness/congestion
↓ chest wall deformity Eye irritation
The use of nocturnal NIV has been demonstrated to reduce frequency of

hospitalizations for respiratory infections and to improve quality of life. In a
randomized trial, children with neuromuscular disease and nocturnal hypoventilation
had improvements in general health scores (SF-36) with NIV treatment at 18 months,
compared to an untreated control group (Ward et al. 2005).
Finally, NIV improves longevity for children with neuromuscular disease. With the
introduction of nocturnal NIV therapy, the mean age of death for boys with Duchenne
Muscular Dystrophy increased from 17.7 years to 27.9 years. Similarly, increased
survival to adulthood has been shown in a large retrospective study of children
receiving NIV (Chatwin et al. 2015).
NIV Complications
Attention should be paid to the possibility of developing complications related to

NIV use (Table 1). The most common complication is skin breakdown, which can be
avoided with careful attention to mask fit to avoid pressure points, the use of
protective skin dressings when needed and use of alternate interfaces to allow rest
and healing when necessary (Castro-Codesal, Olmstead, and MacLean 2019). Nasal
congestion or dryness can be reduced with increased humidity in the circuit, nasal
lubricants and/or nasal steroids (Amin, Al-Saleh, and Narang 2016). Eye irritation
due to air leaking from the interface can be managed by ensuring a good seal of the
mask on the face. In growing children, particularly when NIV is initiated at a young
age, longitudinal monitoring is needed to watch for potential development of midface
flattening due to pressure from the mask causing underdevelopment of the maxilla
and malocclusion of teeth. There are isolated reports of pneumothorax and
gastric/bowel necrosis in individuals with DMD using NIV (Chatwin et al. 2015).
Finally, aspiration risk needs to be considered, both due to the risk of aerophagia
with NIV causing abdominal distention and the risk of aspiration/asphyxiation if
vomiting occurs, particularly in children wearing full-face masks who cannot promptly
remove the interface themselves (Castro-Codesal, Olmstead, and MacLean 2019).

Relative Contraindications to NIV
While the majority of children with neuromuscular disease benefit from NIV, there
are a few relative contraindications. These mostly relate to bulbar dysfunction with
inability to manage secretions that significantly increase aspiration risk. Children with
uncontrolled gastroesophageal reflux also have an increased aspiration risk with NIV
but can be successful with treatment of reflux. A competent caregiver is required for
NIV to be successful for a child in a home environment. Children with the need for
ventilatory support for more than 16 hours a day may be considered for daytime
mouthpiece ventilation to supplement nocturnal NIV, invasive ventilation via
tracheostomy or palliation, dependent on the clinical situation and family preferences.
Monitoring NIV in Children
NIV therapy requires frequent evaluation and titration over time, particularly in
children who are growing and in those with changes in respiratory muscle strength.
Polysomnography remains the gold standard for evaluation of NIV settings, but other
tools are available that can assist with longitudinal monitoring (Katz 2009). Oximetry
and capnography can be used as screening tools to identify gas exchange
abnormalities. Ambulatory polysomnography has yet to be fully validated in the
pediatric population, particularly in children with neuromuscular disease. NIV
machines store information on ventilation over time within their memories, which can
be downloaded for review. Information on mask leak, tidal volume and respiratory
events can be accessed and may provide longer-term data that can provide insights
into what has happened over time. Careful attention and evaluation over time is
needed to ensure that NIV provides the optimal respiratory support for children with
neuromuscular disease.
Long-Term Goals of NIV
For children with neuromuscular disease, the primary goals of NIV are to
increase longevity and quality of life. NIV also improves nocturnal (and sometimes
daytime) gas exchange, alleviates symptoms of sleep disordered breathing and
decreases work of breathing. NIV also decreases frequency of hospital admissions
for neuromuscular weakness, in addition to promoting weight gain. Ultimately, NIV is
a critical tool for management of respiratory impairment secondary to neuromuscular
disease. As a new era of management of neuromuscular disease is beginning with
disease-modifying therapies being developed and implemented, respiratory support
with NIV will be critical to ensuring that children are able to maintain lung health to
benefit from new treatments.

REFERENCES
Amin, R., S. Al-Saleh, and I. Narang. 2016. “Domiciliary noninvasive positive airway
pressure therapy in children.” Pediatr Pulmonol 51 (4):335-348.
Berry, R. B., R. Budhiraja, D. J. Gottlieb, D. Gozal, C. Iber, V. K. Kapur, C. L.
Marcus, R. Mehra, S. Parthasarathy, S. F. Quan, S. Redline, K. P. Strohl, S. L.
Davidson Ward, M. M. Tangredi, and Medicine American Academy of Sleep.
2012. “Rules for scoring respiratory events in sleep: update of the 2007 AASM
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doi.org/10.5664/jcsm.2172.
Berry, R. B., A. Chediak, L. K. Brown, J. Finder, D. Gozal, C. Iber, C. A. Kushida, T.
Morgenthaler, J. A. Rowley, and S. L. Davidson-Ward. 2010. “Best clinical
practices for the sleep center adjustment of noninvasive positive pressure
ventilation (NPPV) in stable chronic alveolar hypoventilation syndromes.” J Clin
Sleep Med 6 (5):491-509.
Bushby, K., R. Finkel, D. J. Birnkrant, L. E. Case, P. R. Clemens, L. Cripe, A. Kaul,
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Frederic Shapiro, Jean Tomezsko, Carolyn Constantin, and D. M. D. Care
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Gordon, I. Hughes, R. McCulloch, R. R. Russell, and A. Simonds. 2012. “British
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Katz, S. L. 2009. “Assessment of sleep-disordered breathing in pediatric
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Jr., L. Friedman, M. Hirshkowitz, S. Kapen, M. Kramer, T. Lee-Chiong, D. L.
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Sleep 28 (4):499-521. doi: 10.1093/sleep/28.4.499.
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Ward, S., M. Chatwin, S. Heather, and A. K. Simonds. 2005. “Randomised controlled
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Thorax 60 (12):1019-1024. doi: 10.1136/thx.2004.037424.

Chapter 7
INITIATION OF NIV IN ADULTS
Eugenio Sabato*, MD and Emanuela Profilo, PhD

Department of Pneumology, “A. Perrino” Hospital, Brindisi, Italy
ABSTRACT
Neuromuscular diseases (NMDs) patients are characterized by an increased

risk of lung complications and, throughout the natural history of the disease, they
present chronic respiratory failure (CRF); CRF is the most common cause of
morbidity and mortality in patients with rapidly progressive NMDs, such as
Amyotrophic Lateral Syndrome (ALS). For this reason, an increasing number of
patients are successfully subjected to non-invasive ventilation (NIV).
NIV has become a fundamental therapeutic strategy for the symptomatic
treatment of ALS, leading to a marked improvement in survival, quality of life, and
cognitive performances. It’s generally accepted that NIV should be initiated in
advanced stages of the disease when the clinical symptoms of CRF are evident.
However, recent studies have shown that initiating NIV at an early stage of the
disease could bring greater benefits by highlighting that ventilatory treatment
should be an election and not an urgent choice. In this context, a wide variety of
diagnostic measures, like Forced Vital Capacity (FVC), Nasal Inspiratory
Pressure (SNIP), Maximum Inspiration (MIP) and Expiratory Pressure (MEP),
and analysis of arterial blood gas should be evaluated to improve the early
diagnosis of respiratory decline and to intervene promptly.
This chapter is meant to provide an overview of the most recent
developments and insights about indication criteria and initiation of NIV in adult
NMDs patients, focusing on ALS patients.
Keywords: ventilation, non-invasive ventilation, neuromuscular diseases, chronic

respiratory failure, respiratory muscle weakness
*
Corresponding Author’s E-mail: sabatoeugenio@gmail.com.

110 Eugenio Sabato and Emanuela Profilo
PURPOSE OF REVIEW
Over the past few years, the utilization of NIV in ALS patients has been greatly
increased. In these patients, NIV determines both an increase in survival and a
reduction in hospitalizations, avoids patient intubation, and determines a better
quality of life [1].
The optimal timing for NIV initiation and for obtaining the maximum benefit has
not yet been determined. It’s generally accepted that NIV should be applied in the
presence of clear clinical symptoms of CRF. However, recent studies have evaluated
whether initiating NIV at an early stage of the disease could maximize the resulting
benefits on the rate of decline in lung function.
The purpose of this chapter is precisely to evaluate and compare the various
studies focused on NIV initiation in adult patients with NMDs, in particular patients
with ALS.
RECENT FINDINGS
Older documents [2, 3] suggested starting NIV in NMDs patients with diurnal
hypoventilation symptoms who had hypercapnia or nocturnal desaturations (SpO2 <
88% for more than 5 minutes consecutively).
In the most progressive NMDs, such as ALS, NIV was recommended in the case
of nocturnal hypoventilation or orthopnea with MIP < 60% of the theoretical value or
FVC < 50% of the predicted value. Nocturnal hypoventilation is a common feature of
disorders affecting the diaphragm function or central respiratory drive mechanisms.
The resulting change in gas exchange is initially limited to REM sleep, but over time
the buffering of the raised carbon dioxide produces a secondary depression of the
respiratory drive that will further reduce ventilation not only during sleep but also
during wakefulness. Qualifying symptoms of nocturnal hypoventilation are daytime
hypersomnolence, morning headaches, fatigue, nightmares, and enuresis.
A further study [4] suggested that at least 1 of the following criteria must be met
to start NIV: chronic diurnal hypercapnia (PaCO2 ≥ 45 mmHg), nocturnal hypercapnia
(PaCO2 ≥ 50 mmHg), daytime normocapnia with a rise in trans-cutaneous CO2
(TcCO2) of ≥ 10 mmHg during the night, a rapid and significant reduction in FVC.
Authors had underlined that, at least in ALS, early NIV initiation, before the onset
of diurnal hypercapnia, can significantly improve the symptoms of the pathology and
the quality of life.
In 1999 the first evidence-based guidelines for the clinical care of ALS patients of
the American Academy of Neurology (AAN) were published. [5] Their revision [6] and
the European Federation of Neurological Societies (EFNS) 2005 [7] and 2011 [8]
recommend, in ALS patients, a multidisciplinary approach and symptoms
management including the NIV initiation to maintain quality of life. EFNS indications
for NIV initiation are shown below in Figure 1.

Initiation of NIV in Adults 111
Figure 1. EFNS recommendations for the timing of NIV initiation [8].
The National Institute for Health and Clinical Excellence UK (NICE) had
published guidelines on the use of NIV in ALS patients [9].
In particular, NICE guidelines [9] recommend that a healthcare professional, with
adequate training and competence, should perform respiratory function tests every 2-
3 months and, in case of desaturation, arterial blood gases analysis. In the case of
sleep-related respiratory symptoms, night oximetry, or a sleep study was
recommended. NICE indication criteria for NIV initiation were reported in Table 1:
Table 1. NICE indication criteria for NIV initiation [9]
FVC (%) SNIP/MIP (cmH2O)

 < 50 of predicted value  ≤ 40
 < 80 of theoretical value with  ≤ 65 for men or ≤ 55 for women, with
symptoms or signs of respiratory symptoms or signs of respiratory
impairment impairment
 Repeated regular tests show a rate of
change of > 10 cmH2O over 3 months
The first Canadian Thoracic Society (CTS) guideline for NIV was published in
2011 and included a section with recommendations for using NIV in ALS patients
[10]. In 2018 there was an update of these guidelines that addressed issues such as
respiratory muscle testing, benefits of NIV, the timing of initiation and the modalities,

settings and place of initiation [11]. Rimmer et al., [11] supported the
recommendations listed in Figure 2.
Figure 2. CTS recommendations for the timing of NIV initiation [11].
The most recent guidelines [8, 9, 11] recommend considering FVC as a crucial
parameter for starting NIV and in particular have suggested initiating NIV when FVC
is < 80% of the expected value in the presence of symptoms of respiratory failures,
such as dyspnoea, tachypnea, orthopnea, disturbed sleep, morning headache, use
of auxiliary respiratory muscles at rest, paradoxical respiration, daytime fatigue,
excessive daytime sleepiness (Epworth Sleepiness Score > 9) and/or a rate of
reduction of SNIP or MIP greater than 10 cm H2O over 3 months. SNIP < 40 cmH2O
and MIP < 60 mmH2O are also used as an indication to start NIV in patients with
ALS.
However, the use of absolute values, although useful, can be limited. The
deterioration of pulmonary functions over 3 months should be taken into account and
supplemented with the presence of symptoms to make a complete assessment of
respiratory impairment in these patients.
Recent findings stated that to detect early respiratory decline, sensitive
diagnostic tools were represented by nighttime trans-cutaneous capnometry or
polygraphy [12]. These studies had revealed that many patients, even with normal
FVC, suffered from sleep disturbances related to recurrent oxygen desaturation and
hypercapnia.
In this context, sleep apnea studies in ALS patients play a fundamental role.
These results imply that respiratory diagnostics should also be performed in
asymptomatic patients and that NIV should be started earlier, i.e., as soon as
respiratory symptoms appear. In this regard, randomized controlled trials are needed
[13].
The study by Khamankar et al., [14] proposed an "optimized" NIV protocol (start
NIV when FVC% ≥ 80, use NIV > 8 hours/day, daily use of cough assistance). In
these conditions, it was seen that the survival median was 30.8 months, which was
double that expected by the "standard" NIV protocol (start NIV when FVC% < 50, use
> 4 hours/day, no cough assistance).

SUMMARY
The researchers sought to define the optimal NIV initiation time in adult NMDs
patients to maximize the resulting benefits.
Regular monitoring of lung function and symptoms is essential to assess the
timing of interventions such as the start of NIV.
Sleep monitoring, before the start of NIV, is also useful in determining early
initiation times.
In ALS patients, a delay in initiating NIV treatment depends primarily on poor
surveillance of lung function; the main difficulties are related to patient’s mobilization
as well as technical difficulties to perform respiratory tests. A standardized method to
study, follow, and screen respiratory function is needed to avoid the difficulty to
decide when to start NIV. In the retrospective study on the French registry, authors
had analyzed the importance of guidelines use for NIV treatment in ALS patients
[15]. Georges and colleagues described a less frequent indication to NIV for daytime
hypercapnia while a larger number of patients had breathing-related sleep disorders,
suggesting a trend to earlier initiation of NIV.
However, at the same time, there is the potential problem of the lack of
compliance and adherence to NIV by asymptomatic patients which should be the
subject of further studies.
MAIN SUMMARY RESULTS
Below is a table (Table 2) that compares the recommendations of the EFNS,

CTS and NICE guidelines and recent developments in the field of NIV initiation in
ALS patients:
Key Messages
 The great benefits associated with NIV use in ALS have supported the
anticipation of the timing for starting NIV.
 The NIV introduction in early stages of symptomatic sleep hypoventilation, as
well as various other advances in respiratory care have contributed
significantly to the improvement of survival and the quality of life of ALS
patients.
 Many studies recommend starting NIV in patients with symptoms of nocturnal
hypoventilation, as well as abnormal results of oximetry or capnometry.
 Guidelines recommend regular monitoring (every 2-3 months) to track the
decline in respiratory muscle function.

Table 2. Indication of NIV in ALS patients [13]
EFNS CTS NICE Recent Developments

-Clinical - Orthopnea -FVC< 50% -Consider NIV in
symptoms/signs or or patients with FVC
or - daytime arterial or -FVC< 80% + < 80% and in
-FVC< 80% capillary pCO2> 45 orthopnea asymptomatic patients
or mmHg or -Use of capnometry,
-SNIP< 40 cm H2O or or -SNIP/MIP < 40 polygraphy to detect
-significant nocturnal - sleep disordered cmH2O early sleep disturbance:
desaturation breathing or nocturnal hypercapnia
or or -SNIP/MIP ≤ 65 nocturnal desaturation
-daytime pCO2> 45 - FVC< 50%, cmH2O (men), ≤ sleep apnea
mmHg FVC sitting or 55 cm H2O
supine < 80% + (women) +
symptoms orthopnea
or or
-SNIP/MIP <40 -SNIP/MIP −10
cmH2O cm H2O over 3
or months
- SNIP/MIP ≤65
cmH2O (men), ≤55
cm H2O (women) +
symptoms
REFERENCES
[1] Bourke, S. C., M. Tomlinson, T. L. Williams, R. E. Bullock, P. J. Shaw, and G. J.

Gibson. “Effects of Non-Invasive Ventilation on Survival and Quality of Life in
Patients with Amyotrophic Lateral Sclerosis: a Randomised Controlled Trial.”
The Lancet Neurology 5, no. 2 (2006): 140–47. https://doi.org/10. 1016/s1474-
4422(05)70326-4.
[2] “Clinical Indications for Noninvasive Positive Pressure Ventilation in Chronic
Respiratory Failure Due to Restrictive Lung Disease, COPD, and Nocturnal
Hypoventilation—A Consensus Conference Report.” Chest 116, no. 2 (1999):
521–34. https://doi.org/10.1378/chest.116.2.521.
[3] Finder, J. D., D. Birnkrant, J. Carl, H. J. Farber, D. Gozal, S. T. Iannaccone, T.
Kovesi, et al. “Respiratory Care of the Patient with Duchenne Muscular
Dystrophy.” American Journal of Respiratory and Critical Care Medicine 170,
no. 4 (2004): 456–65. https://doi.org/10.1164/rccm.200307-885st.
[4] Shneerson, J. M., and A. K. Simonds. “Noninvasive Ventilation for Chest Wall
and Neuromuscular Disorders.” European Respiratory Journal 20, no. 2 (2002):
480–87. https://doi.org/10.1183/09031936.02.00404002.
[5] Miller, R. G., J. A. Rosenberg, D. F. Gelinas, H. Mitsumoto, D. Newman, R.
Sufit, G.D. Borasio, et al. “Practice Parameter: The Care of the Patient with

Amyotrophic Lateral Sclerosis (An Evidence-Based Review).” Muscle & Nerve

22, no. 8 (1999): 1104–18. https://doi.org/10.1002/(sici)1097-4598(199908)
22:83.0.co;2-2.
[6] Miller, R. G., C. E. Jackson, E. J. Kasarskis, J. D. England, D. Forshew, W.
Johnston, S. Kalra, et al. “Practice Parameter Update: The Care of the Patient
with Amyotrophic Lateral Sclerosis: Drug, Nutritional, and Respiratory
Therapies (an Evidence-Based Review): Report of the Quality Standards
Subcommittee of the American Academy of Neurology.” Neurology 73, no. 15
(2009): 1218–26. https://doi.org/10.1212/wnl.0b013e3181bc0141.
[7] Andersen, P. M., G. D. Borasio, R. Dengler, O. Hardiman, K. Kollewe, P. N.
Leigh, P.-F. Pradat, V. Silani, and B. Tomik. “EFNS Task Force on
Management of Amyotrophic Lateral Sclerosis: Guidelines for Diagnosing and
Clinical Care of Patients and Relatives. An Evidence-Based Review with Good
Practice Points.” European Journal of Neurology 12, no. 12 (2005): 921–38.
https://doi.org/10.1111/j.1468-1331.2005.01351.x.
[8] Andersen, P. M., S. Abrahams, G. D. Borasio, M. D. Carvalho, A. Chio, P. Van
Damme, O. Hardiman, et al. “EFNS Guidelines on the Clinical Management of
Amyotrophic Lateral Sclerosis (MALS) - Revised Report of an EFNS Task
Force.” European Journal of Neurology 19, no. 3 (2011): 360–75.
https://doi.org/10.1111/j.1468-1331.2011.03501.x.
[9] “Motor Neurone Disease: Assessment and Management: Guidance.” NICE.
National Clinical Guideline Centre (UK). February 2016. https://www.
nice.org.uk/guidance/ng42. NICE Guideline, No. 42.
[10] Mckim, D. A., J. Road, M. Avendano, S. Abdool, F. Côté, N. Duguid, J. Fraser,
et al. “Home Mechanical Ventilation: A Canadian Thoracic Society Clinical
Practice Guideline.” Canadian Respiratory Journal 18, no. 4 (2011): 197–215.
https://doi.org/10.1155/2011/139769.
[11] Rimmer, K. P., M. Kaminska, M. Nonoyama, E. Giannouli, F. Maltais, D. L.
Morrison, C. O’Connell, B. J. Petrof, and D. A. Mckim. “Home Mechanical
Ventilation for Patients with Amyotrophic Lateral Sclerosis: A Canadian
Thoracic Society Clinical Practice Guideline.” Canadian Journal of Respiratory,
Critical Care, and Sleep Medicine 3, no. 1 (2019): 9–27.
https://doi.org/10.1080/24745332.2018.1559644.
[12] Boentert, M., C. Glatz, C. Helmle, A. Okegwo, and P. Young. “Prevalence of
Sleep Apnoea and Capnographic Detection of Nocturnal Hypoventilation in
Amyotrophic Lateral Sclerosis.” Journal of Neurology, Neurosurgery &
Psychiatry 89, no. 4 (2017): 418–24. https://doi.org/10.1136/jnnp-2017-316515.
[13] Dorst, J., and A. C. Ludolph. “Non-Invasive Ventilation in Amyotrophic Lateral
Sclerosis.” Therapeutic Advances in Neurological Disorders 12 (2019):
175628641985704. https://doi.org/10.1177/1756286419857040.

[14] Khamankar, N., G. Coan, B. Weaver, and C. S. Mitchell. “Associative Increases

in Amyotrophic Lateral Sclerosis Survival Duration With Non-Invasive
Ventilation Initiation and Usage Protocols.” Frontiers in Neurology 9:578 (2018).
https://doi.org/10.3389/fneur.2018.00578.
[15] Georges, M., J. L. Golmard, C. Llontop, A. Shoukri, F. Salachas, T. Similowski,
C. Morelot-Panzini, and J. Gonzalez-Bermejo. “Initiation of Non-Invasive
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Chapter 8
MODES OF VENTILATION
Asier Bengoechea Calafell* and Salvador Díaz Lobato

Emergency Medicine and Pulmonologist in Hospital de La Ribera,
Valencia, Spain
ABSTRACT
Respiratory muscle weakness is the main contributor to respiratory

imbalance in patients with neuromuscular diseases (NMDs). In the advanced
stages of the disease, patients develop a chronic respiratory failure due to
muscle weakness, which is the principal cause of death among these patients.
Respiratory muscle weakness ultimately causes alveolar hypoventilation, initially
nocturnal, and later daytime respiratory failure.
INTRODUCTION
The signs and symptoms of early respiratory muscle weakness are discrete,
namely: dyspnoea on effort, orthopnea, insomnia, frequent nocturnal awakenings,
morning headache, loss of appetite, excessive daytime sleepiness, depression,
anxiety, and marked fatigue [1-2].
The management of respiratory failure in neuromuscular diseases requires the
use of non-invasive ventilation (NIV) to assist the respiratory muscles, in order to
correct the alveolar hypoventilation and ameliorate gas exchange1. NIV slows down
the decline of forced vital capacity, thereby improving the patient’s quality of life,
physical activity and hemodynamics, normalization of blood gases, slight
improvement in other physiological measures, and maximal mouth pressures and
increases survival. NIV support should be offered to all patients who present with
*
Corresponding Author’s E-mail: a_bengoetxea@hotmail.com.

118 Asier Bengoechea Calafell and Salvador Díaz Lobato
early signs of ventilatory failure, as it is probably the most effective among treatments
in prolonging life in neuromuscular patients [2].
Before explaining the different ventilatory modes, it is of vital importance to
understand the pathophisiology of NMDs.
Pathophisiology of Respiratory Failure in Neuromuscular Diseases
Alveolar hypoventilation, defined as inappropriately low alveolar ventilation for

the patient´s level of carbon dioxide production, is the primary mechanism
responsible for respiratory failure in NMDs2 (Table 1). The rise in the partial pressure
of carbon dioxide in the alveoli, that accompanies hypoventilation, causes a
decrease in the partial pressure of oxygen. This means that hypoventilation can
cause hipoxaemia, even when the lung parenchyma is normal. When NMDs cause
pulmonary complications that impair gas exchange and, thus, increase alveolar-to-
arterial oxygen gradient (A-aDO2) [3], hypoxaemia can be out of proportion to the
degree of alveolar hypoventilation. In patients with increased A-aDO2 the magnitude
of neuromuscular disorder causing hypercapnia can be less than in patients with
NMDs and normal gas exchange4. When gas exchange is impaired, or when the
pattern of breathing is rapid and shallow, alveolar hypoventilation can occur despite
normal or increased total minute ventilation.
Alveolar Hypoventilation
In patients with NMDs, alveolar hypoventilation can result from decreased
respiratory drive, increased mechanical load, diminished respiratory muscle
performance, and impaired cardiovascular performance.
Decreased Respiratory Drive

Structural lesions of the central nervous system can contribute to, or cause,
alveolar hypoventilation and hypercapnic respiratory failure. These lesions can be
the result of trauma, infections, post-polio syndrome, paraneoplasic syndromes and
cerebrovascular accidents4.
When present severe hypercapnia depresses the central nervous system and
decreases respiratory motor output [2]. A vicious cycle can arise, whereby
hypercapnia causes depressed drive leading to more hypercapnia. Hypercapnia can
decrease diaphragmatic contractility, although not consistently. Acidosis may be
more important than hypercapnia in causing respiratory muscle impairment (mortality
is more closely related to acidosis than to hypercapnia) [4]. Even this last possibility
is uncertain because diaphragmatic contractility was not affected by acidosis in one
study.

Modes of Ventilation 119
Table 1. Mechanisms involved in respiratory failure in neuromuscular diseases
VT: Tidal volume.
Increased Mechanical Load

In patients with NMDs, upper airway obstruction and reduced chest wall and lung
compliances can limit the ability of the respiratory muscles to generate and sustain
adequate alveolar ventilation.
Upper Airway Obstruction

Parkinson´s disease, amyotrophic lateral sclerosis (ALS) and botulism are some
of the NMDs that can cause vocal cord dysfunction and frank vocal cord paralysis [3].
Presence of vocal cord dysfunction or paralysis can predispose the patient to upper
airway obstruction and, thus, contribute to ventilatory failure and death.

Impaired Chest Wall and Lung Mechanics

Severe weakness of the inspiratory muscle produces a restrictive pattern with
decreases in vital capacity, total lung capacity and functional residual capacity. When
respiratory muscle strength is less than 50 per cent of predicted, the loss in vital
capacity is greater than expected [4]. The decrease is secondary to decreases in
compliance of the chest wall and lungs.
Decrease in lung compliance can result from inflammatory and fibrotic changes
of the lung parenchyma. The last two processes can be triggered by recurrent
aspiration of gastric contents and impaired cough.
Disminished Respiratory Muscle Performance

Respiratory muscle weakness frequently goes undetected in patients with NMDs
until ventilatory failure is precipitated by aspiration pneumonia or cor pulmonale.
Diagnosis is delayed because limb muscle weakness prevents patients from
exceeding their limited ventilatory capacity. In specific cases such as multiple
sclerosis or ALS, the lack of dyspnoea may reflect the difficulty in communicating
symptoms because of cognitive impairment [3-4]. In patients with NMDs, respiratory
muscle weakness may be present at birth, arise later in the course of the disease or
be acquired.
In clinical practice it may be impossible to identify the specific cause of
diaphragmatic weakness/paralysis. It is likely that many of these cases of idiopathic
diaphragm weakness/paralysis are secondary to neuralgic amyotrophy. Neuralgic
amyotrophy is an inflammatory condition of unknown aetiology that is usually limited
to the brachial plexus [4]. One to five per cent of patients affected by neuralgic
amyotrophy develop unilateral or bilateral diaphargamtic paralysis. Dyspnoea occurs
after a prodromal flu-like episode, followed by acute severe neck and shoulder pain
with or without arm weakness. The first episode of dyspnoea may also be
precipitated by surgery. More than 90 per cent of patients recover upper limb function
within 3 years after the onset of weakness or paralysis4. Recovery of diaphragmatic
function is slower and less complete. Similar to limb muscles, diaphragmatic
paralysis can recur after complete recovery. No specific therapy is available for
patients with neuralgic amyotrophy.
Patients with respiratory muscle weakness take rapid shallow breaths, possibly
as a result of afferent signals in weakened respiratory muscles, intrapulmonary
receptors, or both. PaCO2 may be reduced early in the disease, but hypercapnia is
likely when respiratory muscle strength falls to 25 per cent of predicted [2]. Reduction
in strength, however, does not consistenly predict alveolar hypoventilation, because
factors, such as elastic load and breathing pattern also contribute. Abnormalities in
resporatory muscle preformance and in alveolar ventilation may initially be evident
only during exercise or sleep. When inspiratory strength and vital capacity are 50 per
cent of predicted, hypoventilation can occur with minor upper respiratory tract
infections.
Orthopnoea that develops within seconds of lying down is often reported as a
classic symptom of bilateral diaphragmatic paralysis and, less often, unilateral

diaphragmatic paralysis. This contrasts with the more gradual onset of orthopnoea
occurs when maximal transdiaphragmatic pressure is less than 30 cm H2O4.
The increased hydrostatic pressure surrounding an individual immersed in water
decreases the chest wall compliance and, as a result of movement of blood into the
thorax, in decreases lung compliance [2]. These unfavourable changes in lung
mechanics cause a rise in the elastic load on the respiratory muscles. Not
surprisingly, when immersed in water, patients with severe diaphragmatic weakness
or with diaphragmatic paralysis often complain of dyspnoea and experience greater
increases in respiratory drive than healthy subjects.
Patients with bilateral paralysis often complain of dyspnoea when bending or
lifting, activities that require expiratory muscle requirement4. These symptoms may
arise because the paralysed diaphragm cannot prevent the rise in intrathoracic
pressure caused by expiratory muscle recruitment. The variability of symptoms, loss
of lung volume, and inspiratory strength among reports is probably related to the
coexistence of weakness of other inspiratory and expiratory muscles in some
patients but not in others. In contrast to the orthopnoea in patients with
diaphragmatic paralysis, patients with quadriplegia can report playpnoea (dyspnoea
when sitting and relieved in the supine position). In the supine position the area of
apposition of the diaphragm with respect to the abdominal wall and its resting length
are increased. These two factors enhance the force generation capacity of muscle.
Irrespective of the primary pathology, patients with NMDs commonly develop
abnormalities during sleep: frequent arousals, increased stage 1 sleep, decreased
rapid eye movement (REM) sleep, hypoventilation, and hypoxaemia. Patients with
diaphragmatic paralysis are at particular risk of developing hypoventilation during
REM sleep (when the diaphragm is almost the only active muscle) [2]. To dicrease
the likelihood, the central nervous system can adopt two strategies: phasic
recruitment of inspiratory muscles other than the diaphragm during REM sleep, or
suppression of REM sleep. The failure of some patients to develop these adaptative
strategies may explain discrepancies among reports on oxygenation during sleep in
patients with isolated diaphragmatic paralysis.
Sleep-disordered breathing usually precedes, and probably contributes to,
daytime ventilatory failure. Patients commonly report symptoms of nocturnal
hypoventilation and sleep disruption (insomnia, morning headache, daytime
somnolence, decreased intellectual performance) [2]. Sleep-disordered breathing
usually develops when vital capacity in the supine position is < 60 per cent of the
predicted value or maximal inspiratory pressure is less negative than -34 cm H2O.
The degree of abnormality parallels the extent of respiratory weakness. Hypopnoeas
and apnoeas in NMDs can be central, pseudo-central (inspiratory effort too weak to
be identified on polysomnography) or obstructive. The central events result from
involvement of the central nervous system4. Obstructive events tipically result from
weakness of the upper airway musculature. Hypoventilation and daytime
hypercapnia may be aggravated by resetting of chemoreceptors during sleep, which
is reversible with chronic nocturnal ventilation.

Hypopnoeas predominate in the early stage of a NMD. As the respiratory muscle

weakness progresses, clear short-lasting hypopnoeas tend to be replaced by more
prolonged episodes of hypoventilation that are not captured by the apnoea-
hypopnoea score1. Accordingly, apnoea-hypopnoea scores can underestimate the
effect of nocturnal hypoventilation on quality of life or functional status. Sleep
disruption in patients with NMDs may also result from an inability to change position
during sleep, muscle twitches, and leg jerks.
Impaired Cardiovascular Performance

NMDs caused by genetic abnormalities such as myotonic dystrophy, Duchenne
muscular dystrophy, type II glycogenesis and mitochondrial síndromes can cause
myocardial dysfunction 2. Myocardial dysfunction can cause respiratory muscle
weakness, According to investigations conducted in laboratory animals and in
patients with heart failure (without NMDs), respiratory muscle weakness associated
with heart failure can result from several mechanisms.
As with respiratory muscle strength, endurance too is reduced in heart failure.
Two factors may contribute to the decreased endurance: Decreased circulatory
supply of energy substrates and increased work of breathing caused by decreased
static lung compliance (when pulmonary congestion or pleural effusions are present)
[2].
Impaired Gas Exchange

Ventilation/perfusion inequalities and less often increased intrapulmonary shunt
can complicate the clinical course of NMDs [4]. The mechanisms for such
impairments in gas exchange include development of diffuse microatelectasis,
ineffective cough with retention of secretions/bronchopneumonia and heart failure.
Diffuse Microatelectasis
In the past investigators considered the presence of diffuse microatelectasis a
common occurence in patients with NMDs. Purported mechanisms for the
development of microatelectasis include infrequent, and small, sighs and rapid and
shallow breathing, the real impact of diffuse microatelectasis in NMDs has been put
into question [4]. On high-resolution computed tomograhpy diffuse microatelectasis
was found in only two of 14 patients with NMDs who had a 30 per cent decrease in
lung compliance.
Ineffective Cough/Bronchopneumonia
Ineffective cough is a common cause of retention of secretions and
bronchopneumonia in patients with NMDs2. Ineffective cough can result from
inspiratory muscle weakness, expiratory muscle weakness and/or bulbar muscle
impairment. Inspiratory muscle weakness decreases the effectiveness of cough
because the inhaled volume preceding the expulsive phase of cough is smaller.
Smaller inhaled volumen limits the increase in length (and thus in force output) of the
expiratory muscles during the expulsive phase of cough [4]. Expiratory muscle

weakness decreases the efectiveness of cough because of impairment in cough-

induced dynamic airway compression, leading to a reduction in the velocity airflow.
Dysfunction of the bulbar muscles can impair cough through involuntary closure of
the vocal cords during rapid exhalation3. Moreover, bulbar muscle dysfunction
predisposes to aspiration of secretions and foreign material into the airway. Bulbar
muscle impairment can occur in several NMDs.
Decreased Cardiac Function

In patients with NMDs and decreased cardiac function, impaired gas exchange
can result from pulmonary congestion/alveolar flooding and pleural effusions. The
combination of impaired gas exchange and decreased mixed venous oxygen
content, caused by increased oxygen extraction in the peripheral circulation of
patients with heart failure, can contribute to worsening of hypoxaemia [4].
MECHANISMS OF ACTION IN NIV
The mechanisms by which NIV produces beneficial effects are not fully
understood, although the following factors have been proposed to explain them: a)
respiratory muscle rest; b) improved central respiratory response CO2 c) changes in
pulmonary mechanics; and d) improved sleep architecture [5].
The first mechanism assumes that inspiratory muscles are in a state of “chronic”
fatigue. Intermittent nocturnal ventilation allows muscles to rest and recover, with a
consequent improvement in inspiratory muscle function, ventilation and arterial blood
gases during the day. Although some authors have shown that muscles rest during
NIV, others have nevertheless observed increased inspiratory muscle effort in
patients whose alveolar hypoventilation has been corrected by NIV [6].
The second mechanism of action postulates that nocturnal NIV prevents
hypoventilation during sleep, resetting central response to CO2 and improving
ventilation and gas exchange during the day.
NIV has also been said to improve pulmonary function by recruiting atelectasic
zones, increasing pulmonary distensibility and improving ventilation- perfusion ratios.
None of these mechanisms has been shown to be uniquely responsible for
improving respiratory insufficiency during the day, and therefore part of the
improvement has been attributed to the beneficial effects of NIV on sleep
architecture and fragmentation. Disordered sleep associated with central and
mechanical respiratory dysfunction aggravates changes in arterial blood gases,
particularly during rapid eye movement (REM) sleep [5]. Moreover, the symptoms
most commonly reported by these patients are daytime sleepiness, fatigue, morning
headache, cognitive dysfunctions and dyspnea, mainly related to sleep fragmentation
secondary to apneas. NIV largely corrects these problems, such that this mechanism
of action would also be implicated in producing treatment benefits [6]. Results from
the few studies evaluating the effect of withdrawing NIV from patients in whom the

treatment has corrected hypoventilation support this hypothesis. Thus, one week
after withdrawal of NIV, nocturnal hypoventilation became aggravated and symptoms
recurred, in the absence of lung function changes. Similarly, some studies showed
that suspending NIV for 15 days produced no changes in arterial blood gases,
spirometry, lung volumes or maximal respiratory pressures measured during the day,
even though there was severe deterioration in gas exchange during REM sleep a
long with polysomnographic changes [5].
CLINICAL AND FUNCTIONAL EFFECTS OF NIV
Many studies enrolled patients with both neuromuscular diseases and thoracic
restriction, and most reported beneficial effects on both clinical and functional
variables. Among the clinical gains were decreased daytime sleepiness, increased
ability to perform activities of daily living, greater sense of well-being, a reduction in
the number of hospitalizations and prolonged survival [7]. The main functional
benefits were improved or corrected diurnal hypoxemia and hypercapnia,
improvement in nocturnal hypoventilation, and in come cases increases in maximal
respiratory pressures [8].
NIV has become a cornerstone in the management of patients with chronic
respiratory failure resulting from neuromuscular disease. Indeed, NIV lowers daytime
carbon dioxide partial pressure in arterial blood (PaCO2), raises daytime oxygen
partial pressure in arterial blood (PaO2), and eliminates morning headache and
sleepiness [6].
Volume-limited ventilation remains a standard ventilatory mode for home NIV in
patients with neuromuscular diseases [9] (Table 2). In this modality the ventilator
delivers a fixed volume during a given time and will generate whatever pressure is
necessary to achieve this, regardless of the patient contribution to ventilation.
Pressure in the airways (Paw) is not constant and results from the interaction
between ventilator settings, compliance and resistance of the respiratory system and
spontaneous inspiratory effort [10]. It should be emphasised that any additional
inspiratory effort will not lead to changes in delivered volumes or flows but only result
in a decrease in Paw. As each breath is delivered with the same predetermined flow-
time profile and as the area under the flow-time curve defines the volume, the
advantage of this modality is the strict delivery, in the absence of leaks, of the preset
volume, whatever the values of compliance (C) and resistance (R). A major
disadvantage of VTV is precisely that delivery of this fixed ventilatory assistance
does not allow account to be taken of patients' varying requirements. Another
inconvenience is that, if there is a leak, there will be no increase in flow rate to
compensate for it and the generated pressure will be lower, so that the effectively
delivered volume will be reduced in proportion [7].

Table 2. Comparison of volume and pressure ventilatory modes in patients

with neuromuscular diseases
Volume ventilation Pressure ventilation

More complicated to use Simple to use
Constant tidal volume Varible tidal volume
Breath-stacking possible Breath-stacking not posible
No leak compensation Leak compensation
Can be used without PEEP PEEP (EPAP) always present
Rebreathing minimized Rebreathing possible
PEEP: Positive end-expiratory pressure.
EPAP: Expiratory positive airway pressure.
The most used ventilatory modes in patients with NMDs are the following:
Assited/Controlled Ventilation
This mode operates as an assist one but also allows selecting a back-up
respiratory rate (RR). If the patient's spontaneous frequency is lower than the preset
ventilator back-up RR, the system moves to control mode. Therefore, this mode
allows the patient to trigger the ventilator but also grants a minimum back-up rate. In
this mode the clinician must select the same settings as in assist mode but also add
a back-up rate [8].
Pressure-Support Ventilation
Pressure-support ventilation (PSV) is pressure-limited ventilation activated by the

patient’s inspiratory effort. Once activated, the ventilator sends into the circuit a flow
of gas that is sufficient to meet the patient inspiratory demand so that the pressure
rapidly reaches the set level [7]. A pressure plateau is then achieved and maintained
until the inspiratory flow decreases below a predetermined value and, consequently,
exhalation occurs. Thus, during PSV, tidal volume (VT) and inspiratory time are
influenced by the patient’s respiratory effort. This results in greater patient comfort.
Currently, PSV is widely used for NIV [8]. However, the appropriateness of PSV for
patients with neuromuscular disease remains a matter of debate.
Assist Pressure-Controlled Ventilation
Another pressure limited ventilatory mode is assist pressure-controlled ventilation

(APCV). Despite the fact that APCV is a pressure-limited ventilatory mode, it could

be considered as an intermediate mode, with a flow pattern similar to PSV but a

respiratory cycling pattern similar to assisted-controlles ventilation (ACV) [7].
A limitation of pressure ventilation is that it cannot guarantee a tidal volume
delivered to the patient. Volume targeting is a feature available in some ventilators
that could allow this limitation to be overcome [8]. This hybrid modality combines
features of pressure and volume ventilation. The ventilator estimates the delivered
tidal volume and adjusts its parameters to ensure a predetermined target tidal
volume. Some ventilators adjust a target volume within each cycle (each breath
starts as a pressure-limited breath and if the set tidal volume is not reached, the
breath converts to a flow-cycled modality by prolonging the inspiratory time), but
most of them progressively adjust the pressure level during several cycles to provide
a tidal volume as close as possible to the target volume set by the clinician [6].
DISCUSSION
There are several studies that showed that PSV, APCV, and ACV produced a
similar improvement in pattern of breathing and alveolar ventilation and induced a
comparable reduction in inspiratory effort in patients with chronic neuromuscular
disease requiring NIV [8].
In patients with respiratory failure secondary to neuromuscular disease, home
NIV is usually used at night because of the risk of hypoventilation related to rapid eye
movement sleep. During sleep, leakage may occur around the mask or through the
mouth, resulting in a reduction in the effectiveness of NIV. Daytime and nocturnal
NIV are similar in reversing hypoventilation.
ACV and APCV produced similar improvements in minute ventilation and
respiratory muscle unloading. In theory, when ACV and APCV are adjusted to obtain
a similar VT, the main difference between the two modes lies in the flow pattern.
Indeed, the flow pattern is constant during ACV and decelerates during APCV [9].
Several studies have suggested that the flow pattern may be of importance in
reducing respiratory muscle work during ACV.
In patients with neuromuscular disease, high output and rapid shallow breaths
characterize the spontaneous pattern of breathing. When ventilated, these patients
tend to reduce their respiratory rate substantially. Studies showed that the vast
majority of patients with NMDs had no triggering during ACV and APCV [8].
Interestingly, despite absence of triggering, all patients maintained an effort that was
synchronized with the ventilator. Thus, absence of triggering may not indicate
absence of effort in this population.
When compared to ACV, PSV produced a similar decrease in inspiratory effort
despite a significantly higher rate of cycle triggering [7]. This may be attributable to
the good sensitivity of the inspiratory trigger used.
The objective of mechanical ventilation is to improve alveolar ventilation without
increasing respiratory effort, but it is unclear whether an additional objective would be

to decrease the respiratory effort [2]. Maintaining a reasonable level of inspiratory

activity may be desirable. Indeed, the inspiratory training may improve respiratory
muscle function in patients with neuromuscular disease. This three modes are
beneficial in order to decrease the respiratory effort and improve the PaCO2 levels in
patients with NMDs.
ACV, APCV, and PSV have similar effects on alveolar ventilation and respiratory
muscle unloading despite differences in inspiratory flow pattern and triggered cycle
percentage. PSV and APCV are as appropriate as ACV for patients with chronic
neuromuscular disease requiring NIV.
TRIGGER
Modern ventilator triggers are very sensitive to patient effort, so auto-triggering

can be problematic. Auto-triggering can occur because of leaks, which is less of a
problem with a bi-level ventilator. Failure to trigger is usually due to muscle
weakness, intrinsic PEEP, or a high level of support [9]. Central apnea was found to
be more prevalent with PSV in normal subjects using a nasal mask, in intubated
patients, and in patients being evaluated in an out-patient sleep laboratory. For these
reasons, a back-up rate is recommended during NIV, particularly with nocturnal
applications.
RISE TIME
Rise time (pressurization rate) is the amount of time required to reach the
pressure target at the onset of inhalation with PSV and ACV. With a slow rise time it
takes longer to reach the pressure target, and with a fast rise time the pressure
target is reached sooner [8]. The rise time during NIV can be adjusted on some
ventilators. A faster rise time has been shown to better unload the respiratory
muscles of patients with COPD, but this may be accompanied by substantial air
leaks and poor tolerance. In patients with neuromuscular disease, a slower rise time
is often better tolerated. Rise time should be set to maximize patient comfort.
CYCLE
The term “cycle” refers to the change-over from the inspiratory phase to the
expiratory phase. During PSV, the inspiratory phase terminates when flow falls to a
predetermined fraction of peak inspiratory flow. PSV, applied in the presence of an
inspiratory leak, can be accompanied by variations in the duration of the inspiratory
phase and the development of intrinsic PEEP [9]. Several approaches can be taken
to address this issue. First, mask leak should be minimized. Second, some

ventilators allow setting the maximum inspiratory time, which is useful in the
presence of leaks.Third, on some ventilators the flow cycle criteria can be adjusted to
mitigate issues with leaks.
RAMP
Ramp is a feature available on many bi-level ventilators. Ramp causes the

pressure to increase gradually, from a low level to the prescribed level. This may be
useful in patients with obstructive sleep apnea (OSA) who require a high level of
continuous positive airway pressure, to improve tolerance of the pressure and mask
when first applied [10]. In patients with neuromuscular disease who require
ventilatory assistance, the use of ramp is undesirable because it can delay the onset
of effective therapy. In patients who are having difficulty acclimating to the mask and
pressure, however, ramp may help the patient adjust to the therapy.
REFERENCES
[1] Shneerson J M, Simonds A K. Non-invasive ventilation for chest wall and

neuromuscular disorders. European Respiratory Journal. 2002; 20:480-487.
DOI: 10.1183/09031936. 02.00404002.
[2] Simonds A K. Chronic NIV in hereditary neuromuscular disorders, ERS
Practical Handbook of Noninvasive ventilation, In: Paolo Palange, Anita K,
Simonds, editors. ERS Book. 2015. pp. 163-175. DOI: 10.1183/
9781849840415-hba02.
[3] Pinto S et al. Predicting respiratory insufficiency in ALS. Clinical
Neurophysiology. 2009; 120(5):941-946. Epub 2009 Apr 1.
[4] Lo Mauro A, Aliverti A. Physiology of respiratory disturbances in muscular
dystrophies. Breathe. 2016;12(4):318-327. DOI: 10.1183/20734735.012716.
[5] Ambrosino N, Carpenè N, Gherardi M. Chronic respiratory care for
neuromuscular diseases in adults. European Respiratory Journal. Aug
2009;34(2):444-451. DOI: 10.1183/09031936.00182208.
[6] Lisboa C, Díaz O, Fadic R. Noninvasive mechanical ventilation in patients with
neuromuscular diseases and in patients with chest restriction. Archivos de
Bronconeumología. 2003; 39:314-320 Vol. 39 Num. 7.
[7] Hutchinson D, Whyte K. Neuromuscular diseases and respiratory failure.
Practical neurology. 2008;8:229-237. DOI: 10.1136/pn.2008.152611.
[8] Hill N S. Neuromuscular disease in respiratory and critical care medicine.
Respiratory Care. 2006;51(9):1065-1071.

[9] Janssens J P. Indications in long term NIV in chronic respiratory failure-ERS

Course NIV, Hanover, 2017. Available from: http://www.erseducation.org/
events/courses/noninvasive-ventilation-basic-concepts,-hanover-2017.aspx
[Accessed: March 01, 2018].
[10] Nice Guideline-Motor neurone disease: Assessment and management, 2016.
Available from: https://www.nice.org.uk/guidance/ng42 [Accessed: February
28, 2018.

Chapter 9
INTERFACE, MOUTHPIECE, NASAL

FACE/ALTERNATIVE INTERFACE
Anna Annunziata1,*, Maurizia Lanza1, Antonio Esquinas2

and Giuseppe Fiorentino1
1
Unit of Respiratory Physiopathology, Monaldi Hospital, Naples, Italy
2
Intensive Care Unit; Hospital Morales Meseguer. Murcia, Spain
ABSTRACT
In the last decades many new interfaces have been developed and
interfaces such as mouthpiece and armor have been further implemented thanks
to the evolution of software. These advances have allowed the clinician today to
have a wide choice, such as to be able to optimize the treatment for each
individual patient and pathological condition. For those who approach non-
invasive mechanical ventilation it is necessary to be clear about all the possible
interfaces and complications related to their use.
Keywords: nasal mask, oral mask, total face mask, helmet, mouthpiece
ABBREVIATIONS
ALS amyotrophic Lateral Sclerosis

ARF acute respiratory failure
BDP bilateral diaphragmatic paralysis
COPD chronic obstructive pulmonary disease
CPAP continuous positive airway pressure
* Corresponding Author’s E-mail: anna.annunziata@gmail.com.

132 Anna Annunziata, Maurizia Lanza, Antonio Esquinas et al.
DMD duchenne muscular dystrophy

EPAP expiratory positive airway pressure
IAPV intermittent abdominal compression ventilation
MPV mouthpiece ventilation
NIV non invasive ventilation
INTRODUCTION
Success of non-invasive ventilation (NIV) depend often from alternatively

external devices acknowledged as interfaces. Various types of interfaces can be
used during NIV therapy - mouthpiece, nasal mask, face mask, helmet mask. Patient
comfort and enhanced compliance are critical factors in determining the NIV
outcome. The impact of the device itself on the skin and the skin breakdown in this
context is now recognized to be another clinically significant adverse effect of NIV [1].
Nasal bridge pressure ulcers linked to the use of NIV masks happen in 5-20% cases
[2]. The role of therapeutic devices in the development of hospital-acquired pressure
ulcers has been increasingly recognized over recent years. The development of
pressure lesions can appear in prejudice to NIV and decide possibly treatment
failure. So, the choice of interface for each patient is crucial.
INTERFACES
Types of Interfaces
A different kinds of interfaces can be used during NIV treatment in the acute
context. Deciding the fitting interface for patients, including ARF requires thinking of
patient preferences and tolerance, and discovering the exact size and fit is crucial to
successful ventilation. Although interfaces are created from a variety of materials, the
most usually used material is silicone, although gel masks are prepared from some
producers as well. The benefit of gel masks is that they accommodate to the
silhouettes of the face. The availability of different types of interfaces makes the
choice of appropriate interface for patients with ARF a significant challenge. Non-
invasive support in the use of negative ventilation, CPAP, bi-level positive airway
pressure, or other pressure- and volume-limited ventilatory modes is applied in
patients with ARF. Unrelatedly of mode, however, a well-fit interface is necessary for
all forms of NIV.
Nasal Mask
This mask covers the nose only are preferable for long-term ventilation but have
also been used for acute hypercapnic and hypoxemic respiratory failure. Preliminary

Interface, Mouthpiece, Nasal Face/Alternative Interface 133
studies with normal adults suggested that nasal ventilation is of limited effectiveness
when nasal resistance exceeds 5 cm H2O (Figure 1A).
Oro-Nasal Mask
Oro-Nasal Mask (also related to as a full-face mask). This mask incorporates the
nose and mouth and rests on the mandible, the surfaces of the nose and mouth
(Figure 1B).
Oral Mask
This mask fits inside the mouth connecting the teeth and lips and has a tongue
controller to inhibit the tongue from blocking the airway passage. This type is not
usual in practice (Figure 1C).
Mouthpiece
Flexed mouthpiece fixed near to the mouth by a flexible support arm are most
useful for air supply. Many patients used simple mouthpiece NIV since 1953. The
Bennett Lipseal is made for to fixes the mouthpiece in the mouth during the sleep
and closures the lips to avoid insufflated air from leaking out of the mouth. Patients
described mouthpiece to be easy to use, and simple to usage during activities of
daily living such as eating and speaking. Custom-molded bite-plates have also been
made for mouthpiece NIV with and without retaining straps. Bach also described the
usage of daytime mouthpiece NIV in combination with lip covering custom-molded
orthodontic bite plates for mouthpiece NIV use overnight. More recently, mouthpiece
NIV was described to be as effective as a full-face mask NIV in decreasing
inspiratory effort for treating ARF. Mouthpieces for daytime use may produce
salivation and long-term use can cause orthodontic malformations after a long use.
(Figure 1D)
Nasal Pillow Mask

This mask fixes on the perimeter of the noses. This type of mask is regularly
designated for persons who find nasal or oro-nasal masks painful or involvement skin
breakdown on the nasal bridge. Nasal pillows like nasal slings, have less dead space
than masks, are less likely to make claustrophobia, and permit the patient to wear
glasses. Nasal pillows are used principally in stable patients with sleep-disordered
breathing (Figure 1E).
Total Face Mask

This mask coverings the full face and is used mainly in patients with ARF
(Figure 1F).
Helmet
The helmet is a transparent shade that covers the complete head and face of the
patient and has a rubber collar neck tape. It is used as an alternative for the oro-

nasal mask in patients with acute hypoxemic respiratory failure or acute cardiogenic
pulmonary oedema in some states. It was acquired to improve tolerability and
decrease difficulties in patients with ARF on NIV [3]. It is not generally used in
patients with acute hypercapnic respiratory failure (Figure 1G).
IAPV
Intermittent Abdominal Pressure Ventilation consists of an elastic inflatable
bladder incorporated within a corset surrounding the abdomen. With bladder inflation
by a ventilator, the abdominal content and diaphragm move upward, assisting
expiration. With bladder deflation, inspiration occurs passively. IAPV facilitates
diaphragmatic motion and may be particularly useful in patients with bilateral
diaphragmatic weakness or paralysis. (Figure 1H).
Cuirass
The chest cuirass (a rigid case) and wrap-type structure (nylon poncho) are
enclosures that allow application of negative pressure to the thorax. The
effectiveness in producing tidal volume is correlated to the grade of body surface
area that is exposed to negative pressure, it is larger with the iron lung type than with
cuirass or poncho type of negative pressure ventilators. (Figure 1I).
Figure 1. Different interfaces. A: nasal mask, B: oro-nasal mask, C: oral mask D: mouthpiece,
E:nasal pillows, F: full face mask, G: helmet, H: IAPV, I: Cuirass.

DIFFERENT INTERFACES IN THE ACUTE SETTING
In ARF, NIV effectiveness is more prominent than patient comfort, yet

appropriate mask fitting and care are necessary to improve patient tolerance and,
subsequently, to develop NIV outcome. Because there is no extensively ideal NIV
interface, determining an interface requires a thorough evaluation of patient
characteristics, ventilatory modes, and respiratory failure type. NIV can be used
through a closed dual-limb circuit, an open single-limb circuit, or a closed single-tube
circuit with a breath valve. A dual-limb circuit is formed by one tube for inhalation and
another for exhalation, and a built-in exhalation port or filter for CO2 elimination.
Therefore, a non-vented mask is used to support the closed circuit. On the other
hand, a vented mask should be used in open single-limb circuits. If a non-vented
mask is utilized (open single-limb circuit), an additional exhalation valve in the circuit
must be combined to allow CO2 removal. Clinicians and respiratory therapists must
be conscious of this life-threatening difference between ventilators because the use
of a non-vented mask in an open single-tube system without an exhalation port in the
system can be tragic. It is worth considering that the interface itself acts as a dead
space, which probably may improve the risk of CO2 rebreathing and retention,
especially in hypercapnic respiratory failure. The dead space is correlated to the
internal volume of the interface. Nevertheless, an in vivo study revealed that the
internal volume of the masks had no manifest short-term dead-space consequence
on gas exchange, minute ventilation, or patient work [4]. Additionally, the different
study that used computational fluid dynamics to describe pressure, flow, and gas
composition during ventilation with the various interfaces showed that the adequate
dead space is not correlated to the inside gas volume of the interface, which
specifies that the internal volume is not a restrictive factor for the interface efficacy
during NIV [5]. This recommends that the interfaces may be interchangeable in
clinical practice with the difference of the helmet.
The decision of just interface is determined by the contour of the patient’s profile,
mouth, and nose, breathing pattern, choice and the experience of the medical staff.
Two randomized controlled trials that confronted the oro-nasal mask with the nasal
mask in subjects with ARF recorded no evidence that one type of interface is
consistently more reliable than another in terms of clinical efficacy [6]. A recent study
randomly selected 48 subjects with ARF into groups using an oronasal mask or a
total face mask and observed responses for 24 h. At six hours, the use of a full-face
mask was significantly more effective in reducing PaCO2 [7]. However, there was no
difference between the two masks once subjects received the acute phase.
Recognition and comfort were similar in both groups [7] to increase comfort and
reduce interface complexities of NIV in patients with ARF, the helmet was
industrialized, which has the advantage of avoiding skin contact and hence improving
patient tolerance independent of face morphology. The helmet has some intrinsic
benefits as it allows patients to drink, communicate, and expectorate freely.
Furthermore, it allows for the clearance of secretions and interaction with caregivers

without removing the NIV interface. Studies have revealed that the patient tolerance
scale in the helmet group is significantly more effective than with face masks [8].
The possible use of alternative interfaces such as mouthpiece and IAPV must
foresee experience with these interfaces and the possible possibility of combining or
alternating them to avoid the onset of decubitus, requires careful choice of the
candidate patient and close monitoring
MPV
Several conditions may also be responsible for the failure of NIV, including
claustrophobia, mask-induced skin lesions and rhinitis, non-tolerance of pressure on
the face. Other daytime NIV procedures should be considered in highly ventilator-
dependent patients in addition to mask ventilation. Mouthpiece ventilation (MPV) is a
type of non-invasive ventilation delivered via a mouthpiece. MPV is used for the first
time on ventilator-dependent polio patient. MPV, as we know it today, is used from
many years, and there is already evidence in literature documenting the efficiency of
management and improved compliance by the patient. Notwithstanding this, there is
little data and sensibleness of the use of non-invasive mechanical ventilation with
mouthpiece. Due to a recent evolution since 2013, mouthpiece ventilation modes are
being introduced to commercially available portable ventilators, increasing the
interest for this ancient modern interface [9]. For all clinicians working with
mechanical ventilation, it is advantageous to have many treatment options available
to sew the best suit for each patient.
Mouthpiece ventilation used a single-limb non-vented circuit ventilator in
pressure-controlled or, more often, in the volume-controlled mode for permitting air
stacking. The patient can catch mouthpiece ventilation, breaths inactively, using the
set backup frequency on the ventilator, or he/she can actively trigger the breath,
maintaining a part or all of the delivered volume. It is possible to use a simple single-
tube circuit or a circuit with a valve. The valve is preferable for patients who cannot
disconnect to exhale outside the circuit. Patients with the valve can stay connected
for a long time in a row. The clinician should evaluate the patient’s ability to
synchronize with the mouthpiece held in the mouth and to exhale outside the
mouthpiece or not. Depending on the capacity to move the neck, the patient can
constantly retain the mouthpiece between his/her lips or disconnect it for a variable
time. The patient can self-sufficiently disconnect from the mouthpiece to speak, eat,
cough or call a family member. It presents no risk of skin breakdown, conjunctivitis,
absence of claustrophobia and lower probability of gastric distension. It is safer by
permitting the use of glossopharyngeal breathing in the event of sudden ventilator
failure or accidental disconnection from the ventilator [10]. Despite these obvious
benefits, this modality is not frequently used. The same problem has been detected
with a traditional interface in pediatric patients. Nose clips or nasal pledges can be
used to avoid air leak through the nares for patients using lip covering interfaces for
mouthpiece NIV especially during sleep [11]. During the night, most patients use a

mask because a mouthpiece needs cooperation and is uncomfortable. Air may also
be swallowed and produce gastric enlargement. Mouthpiece and nasal NIV are open
systems of ventilator support, the low-pressure alarms of ventilators not having
mouthpiece NIV modes can often be sound. Back pressure from a 15 mm angled
mouthpiece is sufficient to inhibit a low-pressure alarm set at 2 cmH2O. The patient
starts the inhalation by placing the mouth on the mouthpiece and making a slight
negative pressure in the circuit by swallowing or gasping. Mouthpieces are very
advantageous in adjunct daytime ventilation for patients suffering from
neuromuscular diseases who cannot maintain adequate diurnal arterial blood gases
without frequent recurrent periods of support [12]. Still, the risk of the use of MPV is
that the patient may accidentally under ventilate themselves because of the common
disconnection from mouthpiece [13]. The period of disconnection is probably the
major limitation of this approach to NIV. The authors recognised that the periods of
disconnection were connected with > 5 mmHg paCO2 increases, and > 2% spO2
decreases but no clinical complication happened before or after the monitoring
period. Few patients accepted protracted disconnections without developing
hypercapnia [13]. The most common type of asynchrony was an ineffective effort,
also suggesting a need for improved trigger sensitivity. The recently introduced MPV
software that allows insufflation to be triggered only by the positioning of the patient’s
lips appears to be an option for the patient with severe muscle weakness. Moreover,
the software of many new ventilators is adding the mouthpiece mode. EPAP cannot
be maintained for patients who use open NIV system, and is indeed rarely, if ever,
necessary for these patients. Apnea alarms, when existing, should be fixed at the
maximum threshold to avoid avoidable start and discomfort. The usual ventilator
mode used is assisted volume- and pressure-controlled with no EPAP, low-pressure
alarm set to apnea minimum and maximum duration. The specificities of MPV, such
as the intermittent disconnection of the patient and the presence of continuous leaks,
may thus represent a challenge for turbine-based home ventilators. There is a great
variance in the capacity of the different life-support ventilators to deal with the rapidly
changing respiratory load features that characterize MPV, which can be further
accentuated according to the choice of ventilator settings. It is always indispensable
to prudently observer the patient during the adaption phase since MPV needs true
collaboration from the patient, and not all ventilators ensure rapid adjustment to the
patient’s respiratory acts [13]. However, due to its specific features and
inconveniencies (air leaks, etc.), MPV must be used by professional hands and well-
monitored. The use of MPV is likely limited to a few centres, for the longest time
required to adapt and monitor the patient. In summary, the mouthpiece is a
preferable and comfortable alternative to NIV, but more active participation is needed
compared to the use of traditional masks.

Data in literature confirmed the useful of MPV. Bedard and McKim recently
studied utilization of daytime mouthpiece ventilation in an ALS population using 24-h
NIV. Results demonstrate the effectiveness of mouthpiece ventilation as well as the
importance of preserved bulbar function and ability to produce an acceptable peak
cough flow with lung-volume recruitment for survival. Mouthpiece ventilation is
infrequently used in patients with ALS requiring continuous ventilatory support [12]
With adequate bulbar muscle function, mouthpiece ventilation was shown to be an
effective alternative to tracheostomy [12]. The use of mouthpiece ventilation,
combined with other interfaces, leads to an improvement in QoL and adherence to
NIV. The patient who uses ventilation even during the night can alter an interface for
sleeping and using MPV during the day; also, patients with skin lesions can benefit
from using MPV.
Duchenne Dystrophy
The custom of mouthpiece ventilation in patients with DMD is documented in the

literature. McKim discuss that twenty-four hours NIV should be considered a safe
alternative for patients with DMD because its use may obviate the need for
tracheostomy in patients with chronic respiratory failure demanding more than
nocturnal ventilation alone [13]. The authors examine the impact of diurnal
mouthpiece intermittent positive pressure ventilation and conclude that daytime
mouthpiece ventilation is safe, prolongs survival and stabilizes vital capacity in
Duchenne muscular dystrophy patients. As time passes, patients with DMD develop
constant hypoventilation and need respiratory support 24 h a day; then, mouthpiece
can be very valued, principally in patients who use the NIV many hours a day and
showing skin lesions, gastric distension or eye irritation, sometimes alternating nasal
and full-face masks. It is useful also to promote adherence to NIV.
Other Neuromuscular Disease
Bach and others have described a sizeable number of patients with

neuromuscular diseases achieved long beyond the point of respiratory failure with 24
h NIV. Even patients before ventilated 24 h per day via a tracheostomy have been
adapted to non-invasive mechanical ventilation with MPV [14]. Bach also describes
non-invasive acute and long-term management of quadriplegia due to high spinal
cord lesions. This includes full-setting, continuous ventilatory support by non-invasive
intermittent positive pressure ventilation to support inspiratory muscles and
mechanically assisted coughing to support inspiratory and expiratory muscles.

Bilateral diaphragmatic paralysis (BDP) is associated with dyspnoea that

worsens when the patient is recumbent, increased work of breathing and exercise
intolerance. With BDP progression, there is increasing ventilatory failure with
hypoxaemia and hypercapnia, which may further worsen due to atelectasis and
ventilation–perfusion mismatch. There are reports showing that MPV is a clinically
beneficial treatment to improve exercise tolerance and exercise-induced dyspnoea in
patients with BDP [15]. MPV can be useful for weaning from orotracheal tube or
tracheostomy.
There are inadequate data on the usage of MPV in patient with Steinert
dystrophy. Some authors described that it can be useful for Steinert patients (Figure
1) who previously rejected the application of NIV for tightness, claustrophobia and
reduced compliance interface [16].
COPD
The benefits of non-invasive mechanical ventilation (NIMV) as first line therapy in
patients with exacerbations of COPD and hypercapnic respiratory failure are widely
established. NIMV avoids intubation and is successful (>85%) especially in case of
mild to moderate acidosis with the aim to prevent further deterioration and need for
intubation [17].
Recent ERS/ATS guidelines on management of non-invasive ventilation in acute
respiratory failure (ARF), in fact, commend that there is no lower limit of Ph below
which a trial of NIMV is inappropriate in hypercapnic COPD exacerbation; however,
its failure is directly related to severity of acidosis [18] so a close monitoring is
necessary, and unsuccess can often occur for poor tolerance to NIMV, mostly
depending to fit and shape of the interface used [19]. In approximately the large
majority of cases, non-invasive positive pressure ventilation in ICU is administered
through face or nasal masks, with some common disadvantages, such as air leaks,
discomfort, pain, anxiety, secretions, skin lesions until to pressure necrosis,
claustrophobia, asynchrony between the patient and the ventilator, inability to eat,
drink, speak or cough. Regrettably, all these adverse effects not infrequently lead to
discontinuation of ventilation.
Intermittent Abdominal Compression Ventilation (IAPV)

Intermittent abdominal compression ventilation (IAPV) is it consists of a corset
with an elastic inflatable bladder that fits over the abdomen. The bladder is attached
by a hose to a ventilator that give up to 2.5 liter of air to the bladder and, whereby, to
the abdominal wall. This raises the diaphragm to cause expiration below the
functional residual capacity. Bach in 1990 described the use of intermittent
abdominal pressure ventilator, in ventilator-dependent traumatic quadriplegic
patients, spinal cord injury; non-Duchenne myopathy; Duchenne muscular dystrophy;
myelopathy, polymyositis, Friedreich’s ataxia, also employed for long-term
respiratory support. Intact mental status and bulbar musculature, and absence of
obstructive lung disease, patients with traumatic high-level spinal cord injury are
candidates to benefit from these techniques. New models avoid clothing taking on

the corset buckles and are more comfortable [20]. They are now lightweight, suitable,
easy to done and fit and employ Velcro for fastening. The following IAPV parameters
can be set: Pressure inside the bladder, Inspiratory time (real inspiratory time when
the diaphragm moves down), frequency (respiratory rate), and Rise Time (time to
inflate the bladder). The IAPV works well when a patient is in sitting position at an
angle of 30° or greater and is optimal at 75°. IAPV is described in patient with a post-
ischemic cervical myelopathy with success. IAPV can be used in patients who
require NIV many hours a day [21]. Patients with gastric distension may benefit from
the abdominal compression exerted by the device during the exhalation phase. Also,
IAPV should be considered for patients with chronic disease who need to start NIV; it
is helpful to promote a positive approach to NIV.
NEGATIVE INTERFACE
Negative pressure ventilation (NPV) has played a crucial role in the history of
ventilatory support for patients with respiratory failure in preventing endotracheal
intubation in patients with acute exacerbation of COPD or neuromuscular disease.
Jacket ventilators provided an inner framework of metal or plastic which was covered
with a hermetic jacket with closures around the neck, arms, and thighs. The air in the
jacket was alternatingly exiled, providing the ventilator action. Patients often desired
assistance to put on and seal these jackets but they were proper for home use.
Cuirass negative pressure ventilators were principally advantageous in children with
neuromuscular disorders. Children had their own cuirass built from a plaster
prototypical of the thorax and abdomen. This is important when there was a severe
thoracic scoliosis. The cuirass is a plastic model of the front and sides of the trunk,
the edges were padded with air tight material and the cuirass attached to the patient
with a back strap [22]. Pressure lesions with cuirasses were usual and new cuirasses
were necessary as the patient grew. Cuirass ventilators were easy to wear and
suitable for home use with a variety of negative pressure pumps which provided a
preset negative pressure within the cuirass.
NPV preserve physiological functions, such as speech, cough, swallowing and
feeding and its major advantage is the prevention of endotracheal intubation and its
related problems. The limitations are the lack of upper airway protection, particularly
in comatose and/or neurological patients may end in aspiration, given the described
consequence of NPV on the lower esophageal sphincter. Upper airway obstruction
may occur or be amplified in unconscious patients, in patients with neurological
disorders with bulbar dysfunction and in those with sleep apnea syndrome. This can
be escaped by the use of nasal CPAP, although in this situation, it may be more
applicable to change to NPPV. Most of the descriptions of side-effects of NPV
originated from stable, chronically-ventilated patients: poor compliance, upper airway
obstruction and musculoskeletal pain. NPV has been associated with the possibility
of rib fractures and pneumothorax. NPV can be efficaciously used in patients in

whom excessive airway secretion or difficulty in wearing a mask avoid the application
of NPPV. The iron lung is cumbersome and needs a large amount of space rather
than problems associated with NPV. The effectiveness of NPV depends on strict
supervision by well-trained nurses and physiotherapists with significant skill with
NPV. The major problems correlated to the support of patients with NPV by an iron
lung are the transfer from the bed to inside the chamber of the tank ventilator; and
the access to patients for nursing practices during mechanical ventilation.
PROBLEMS RELATED TO THE INTERFACE
Interface Type and Upper Airway Obstruction
It is vital to know the physiological effects of positive airway pressure applied

through various interfaces on upper airway dynamics. To explain the consequences
of different interfaces on upper airway patency, we need to review the difference
between nose breathing and mouth breathing briefly. When breathing happens
through the mouth, there is an improvement in upper airway resistance and an
augmented propensity to acquire upper airway obstruction. Moreover, open-mouth
breathing while awake decreases the retropalatal and retroglossal cross-sectional
area and reduces the positive pharyngeal critical closing pressure during sleep. The
oro-nasal mask applies pressure through the mouth and nose simultaneously, which
may lead to a collapse of the airway. It is proposed that oro-nasal complimentary
airway pressure therapy applies equal positive pressure in both nasopharyngeal and
oropharyngeal compartments, which reduces the pressure gradient and allows
gravity to displace the tongue and soft palate backward, resulting in airway
obstruction [23]. The therapist needs to understand that the diversity in the efficacy of
positive airway pressure applied via nasal and oro-nasal masks may determine the
efficiency of NIV therapy, particularly in patients with hypercapnic obesity
hypoventilation syndrome. Therefore, oro-nasal masks or face masks are favored in
the acute settings; however, once the patient is stable, shifting to a nasal mask if
accepted, is suggested (Figure 2).
AIR LEAKS
Air leaks are prevalent during NIV. There are two varieties of air leaks: intentional
and unintentional leaks. Intentional leaks are intentionally produced during NIV when
a one-limb circuit without an expiratory valve is present. An intentional leak is
designed to bypass breathing again having holes in the mask or circuit to allow for a
leak proportional to their size and set inspiratory pressure or typical inspiratory flow.
Air leaks they depend on the sealing features of the interfaces; leakage is
proportionally more prominent with a smaller face mask than with a larger mask or

helmet [24] Large air leaks are detrimental to the success of NIV, as leaks decrease
FiO2 arterial oxygen saturation and improve in the automatic activation of the
ventilator, thereby improving patient-ventilator asynchrony, which increases the risk
of NIV failure. Additionally, air leaks can cause dry mouth and throat, conjunctivitis,
or sleep disturbances [23]. In general, nasal masks tend to have more air leaks than
face masks. Besides, the use of an oral-nasal mask reduces changes in relative
humidity related to leaks from the mouth. Air leakage is negligible when a suitable
interface for the NIV is chosen and installed [25]. Tight-fitting of the interface can
partly enhance the air outflow and patient asynchronous ventilator; yet, it should be
done with caution as it raises the risk of facial skin discomfort and ulceration [25].
Also, it is essential to know that masks have different levels of loss. Therefore, each
time activating sensitivity, pressure level and rebreathing must be reduced when
switching to a mask with a different degree of leakage.
NASAL OR ORAL DRYNESS AND NASAL CONGESTION
Nasal or oral dryness and nasal congestion are typical during NIV. These side
effects can be correlated to air leaks and the interface utilized. Previous studies have
explained that during NIV, nasal or oral dryness and nasal congestion influence 10–
20% and 20–50% of subjects, particularly when a nasal mask is applied [26].
Progressive nasal mucosal dryness releases inflammation mediators that increase
nasal congestion and hence nasal obstruction, which in chance decreases tidal
volume and patient comfort. Strategies to reduction airway dryness and congestion
during NIV mainly focus on reducing air leak [27].
DECUBITUS
With extensive use of NIV, nasal skin lesions such as erythema and ulcers may
develop at the site of mask contact. Nasal erythema or ulcers consider for a
significant portion of interface developments during NIV, reported to occur in 5–30%
of patients and to increase to 50% of patients after a few hours; skin lesions may
happen in almost 100% of patients after 48 h of NIV with a mask [27]. Although the
nasal bridge is the most delicate area, skin lesions can also appear on other facial
areas, in particular over the zygomatic bone. There are many types of skin lesions,
ranging from slight redness over the nasal bridge to open ulcers. The evolution of
skin abrasions or necrosis is an influential factor that limits the tolerance and
continuance of NIV. There is also evidence of decubitus during negative ventilation
(Figure 3).

Figure 2. Oronasal mask pressure on month.
Figure 3. Decubitus from positive and negative ventilation.
CONCLUSION
The decision of the proper interface is crucial for the success of NIV therapy.
Most interfaces are presented with a fitting measure to help choose the exact size to
improve tolerance and bypass complications. Settling the interface too tightly
minimizes patient tolerance and raises the risk of facial skin breakdown;
consequently, if the headgear is fixed, it should be reasonable to permit 2 fingers
beneath it. If the patient not tolerates the interface or if a significant leak is identified,
a distinct interface should be utilized to avoid NIV failure. Although, when a different
interface is used, trigger sensitivity, pressurization level, and compatibility with the
circuitry must be verified. Once the patient’s health is stable, a nasal mask can be
tried because it is less claustrophobic and is correlated with a lower risk for skin
problems. Knowledge of the risk factors associated with pressure ulcer development
is the key to the success of prevention strategies. The risk of developing pressure

ulcers should be assessed in patients in all care settings within the first 6 h after
patient admission. Routine assessment of the skin (check every 3–4 h) and
possibility of pressure ulcers, regular pressure support, and skin-protective tactics
should be involved in the routine use of NIV to decrease discomfort and the
occurrence of soft tissue injury. Rotation or alteration of the interface and the
interruption of usage duration of NIV may help to prevent face lesions.
Key Messages
1. The decision of the proper interface is crucial for the success of NIV therapy
2. Non-optimal interface can produce several leaks and can produce a patient’s
intolerance.
3. We can think also a negative or positive abdominal ventilation if the patient is
intolerant.
4. To avoid decubitus, we can use an interface alternation
5. when a different interface is used, trigger sensitivity, pressurization level, and
compatibility with the circuitry must be verified
REFERENCES
[1] Rochwerg, B; Brochard, L; Elliott, MW; Hess, D; Hill, NS; Nava, S; et al. Official
ERS/ATS clinical practice guidelines: non-invasive ventilation for acute
respiratory failure. Eur Respir J., 2017, 50.
[2] Yamaguti, WP; Moderno, EV; Yamashita, SY; Gomes, TG; Maida, AL; Kondo,
CS; et al. Treatment-related risk factors for development of skin breakdown in
subjects with acute respiratory failure undergoing non-invasive ventilation or
CPAP. Respir Care., 2014, 59(10), 1530-6.
[3] Munckton, K; Ho, KM; Dobb, GJ; Das-Gupta, M; Webb, SA. The pressure
effects of facemasks during non-invasive ventilation: a volunteer study.
Anaesthesia., 2007, 62(11), 1126–31.
[4] Schettino, GP; Chatmongkolchart, S; Hess, DR; Kacmarek, RM. Position of
exhalation port and mask design affect CO2 rebreathing during noninvasive
positive pressure ventilation. Crit Care Med, 2003, 31(8), 2178-82.
[5] Fodil, R; Lellouche, F; Mancebo, J; Sbirlea-Apiou, G; Isabey, D; Brochard, L; et
al. Comparison of patient-ventilator interfaces based on their computerized
effective dead space. Intensive Care Med, 2011, 37(2), 257-62
[6] Sadeghi, S; Fakharian, A; Nasri, P; Kiani, A. comparison of comfort and
effectiveness of total face mask and oronasal mask in noninvasive positive
pressure ventilation in patients with acute respiratory failure: a clinical trial. Can
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[7] Liu, Q; Gao, Y; Chen, R; Cheng, Z. Noninvasive ventilation with helmet versus
control strategy in patients with acute respiratory failure: a systematic review
and meta-analysis of controlled studies. Crit Care, 2016, 20, 265.
[8] BaHammam, AS; Singh, T; George, S; Acosta, KL; Barataman, K; Gacuan, DE.
Choosing the right interface for positive airway pressure therapy in patients with
obstructive sleep apnea. Sleep Breath, 2017, 10.1007/s11325-11017-11490-
11329.
[9] Pinto, T; Chatwin, M; Banfi, P; Winck, JC; Nicolini, A. Mouthpiece ventilation
and complementary techniques in patients with neuromuscular disease: A brief
clinical review and update. Chron Respir Dis., 2017, 14(2), 187-193.
doi:10.1177/1479972316674411.
[10] Garuti, G; Nicolini, A; Grecchi, B; Lusuardi, M; Winck, JC; Bach, JR. Open
circuit mouthpiece ventilation: Concise clinical review. Rev Port Pneumol.,
2014, 20(4), 211-218. doi:10.1016/j.rppneu.2014.03.004.
[11] Giuseppe Fiorentino; Antonio M Esquinas. Home ventilator performances with
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2018 Apr, 12(4), 1765-1766; doi: 10.1111/crj.12676. Epub 2017 Aug 6.
[12] Bédard, ME; Douglas, A McKim, DA; Daytime Mouthpiece for Continuous
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Respir Care., 2016, 61, 1341-1348.
[13] Bach, JR; Alba, AS; Saporito, LR. Intermittent positive pressure ventilation via
the mouth as an alternative to tracheostomy for 257 ventilator users. Chest,
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[14] McKim, DA; Griller, N; LeBlanc, C; Woolnough, A; King, J; et al. Twenty-four-
hour non-invasive ventilation in Duchenne muscular dystrophy: a safe
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20734735.005817.
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[17] Rochwerg, B; Brochard, L; Elliott, M; Nava, S; et al. Official ERS/ATS Clinical
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2017, 50, 1602426.
[18] Confalonieri, M; Garuti, G; Cattaruzza, MS; Osborn, JF; Antonelli, M; et al. A
chart of failure risk for non invasive ventilation in patients with COPD
exacerbations. ERJ, 2005, 25(2), 348-355.
[19] Nava, S; Navalesi, P; Gregoretti, C. Interfaces and humidification for non
invasive ventilation. Resp Care, 2009, 54(1), 71-84.
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non-invasive ventilatory support. Chest., 1991, 99(3), 630-636. doi:10.1378/
chest.99.3.630.

[21] Banfi, PI; Volpato, E; Bach, JR. Efficacy of new intermittent abdominal pressure
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0169-4.
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oronasal versus nasal mask ventilation in the treatment of acute respiratory
failure. Crit Care Med, 2003, 31(2), 468-73.
[23] Sadeghi, S; Fakharian, A; Nasri, P; Kiani, A. comparison of comfort and
effectiveness of total face mask and oronasal mask in noninvasive positive
pressure ventilation in patients with acute respiratory failure: a clinical trial. Can
Respir J, 2017, 2017, 2048032.
[24] Liu, Q; Gao, Y; Chen, R; Cheng, Z. Noninvasive ventilation with helmet versus
control strategy in patients with acute respiratory failure: a systematic review
and meta-analysis of controlled studies. Crit Care, 2016, 20, 265.
[25] Schettino, GP; Chatmongkolchart, S; Hess, DR; Kacmarek, RM. Position of
exhalation port and mask design affect CO2 rebreathing during noninvasive
positive pressure ventilation. Crit Care Med, 2003, 31(8), 2178-82.
[26] Fodil, R; Lellouche, F; Mancebo, J; Sbirlea-Apiou, G; Isabey, D; Brochard, L; et
al. Comparison of patient-ventilator interfaces based on their computerized
effective dead space. Intensive Care Med, 2011, 37(2), 257-62.
[27] Carron, M; Freo, U; BaHammam, AS; Dellweg, D; Guarracino, F; Cosentin, R;
et al. Complications of non-invasive ventilation techniques: a comprehensive
qualitative review of randomized trials. Br J Anaesth, 2013, 110(6), 896-914.

Chapter 10
NEGATIVE MECHANICAL VENTILATION
U. Vincenzi*, MD
ABSTRACT
Negative pressure ventilation (NPV) has its origin in the first device created
by P. Drinker and A. Shaw in the 1930s and was the main mode of ventilation
until the 1950s. We would like to mention the principles of ventilatory mechanics
involved in extra-thoracic negative ventilation and the non-invasive and
intermittent characteristics of NPV which have ensured the treatment, even for
years, of patients with severe chronic respiratory insufficiency. Today it is used,
albeit not as a first choice, in the treatment of neuromuscular diseases,
kyphoscoliotic alterations of the spine, respiratory insufficiency in adults and
children and, experimentally, also in ARDS.
The main advantages of NPV are non-invasiveness, compliance with
physiological ventilation, reduction of inspiratory intra-thoracic pressures with the
absence of barotrauma, the possibility of suspending and resuming, several
times a day, even intensive ventilation. The disadvantages are often related to
the characteristics of the patient (e.g., severe obesity, claustrophobia, recent
surgery on the abdomen and chest, presence of tracheostomy, obstructions of
the upper airways) or of the ventilator (size and weight of the ventilators, need of
assistance in case of the iron lung).
BACKGROUND
The idea of applying negative pressure on the human body dates back to 2
centuries ago, but the first scientist who tried to build a machine that contained the
entire human body on which to apply it was Alfred F. Jones, from Lexington State of
Kentucky, who presented its “Depurator” (Patent No. 44,198) on September 13,
*
Corresponding Author’s E-mail: uvincenzi@gmail.com.

148 U. Vincenzi
1864. This machine, which worked with a manually- operated pump, created a
negative pressure that acted, with the exclusion of the head, on the entire body of the
patient, positioned seated inside a wooden container.
In the following years there were other attempts to apply negative pressure on
the human body, but it was only in 1928 that the first real lung ventilator came to
light. It was driven by an electric motor and consisted of a cylindrical metal box in
which the entire body of the patient, with the exclusion of the head, was placed
supine. The inventors, Philip Drinker and Louis Agassiz Shaw, relying on studies of
human physiology, aimed to improve the gaseous exchanges of the patients by
subjecting them to mechanical ventilation determined by cyclical variations of
external negative pressure.
The ventilator, called "iron-lung" due to its metal structure, was immediately
successful all over the world, so much so that NPV was the main mode of ventilation
in patients suffering from acute respiratory failure until the 1950s.
In the 90s, negative pressure ventilation, initially operating exclusively in
"controlled" mode, was also enhanced by the "assisted" mode. This took place
through the use of thermistors, positioned near the upper airways and with "trigger"
functions, which allowed coordination between the machine and the patient.
In the following years, with the advent of positive pressure ventilation and with
the succession of increasingly smaller and easier to transport equipment, negative
mechanical ventilation became a secondary therapeutic choice.
However, in many centers, negative mechanical ventilation was used as the
preferred noninvasive ventilation mode for many years. This went on up to and
beyond the first decade of the current century. The choice was based not only on its
effectiveness, but also on the possibility of treating patients suffering from respiratory
failure for even prolonged periods, without incurring infectious complications of the
airways. This method was also indicated as a non-invasive ventilatory modality in
those patients suffering from severe respiratory acidosis or severe cerebral
impairment dictated by hypercapnia and/or hypoxia in which positive pressure
ventilation in mask and/or helmet did not guarantee therapeutic success or in
situations in which patients were excluded from non-invasive positive pressure
ventilation (e.g., patients with facial deformities, with skin lesions from bedsores, with
claustrophobia, with excess bronchial secretions and with the need for frequent
broncho-aspirations).
External negative pressure ventilators are so defined since they produce,
cyclically, a sub-atmospheric pressure inside a rigid container that holds, with the
exclusion of the head, the entire human body (iron-lung), the abdominal thoracic
trunk (poncho) or only the chest (cuirass) [1].
If we start from a moment of static equilibrium between the intra-thoracic forces,
for example at the level of Residual Functional Capacity (RFC), by applying an
external negative pressure to a patient in supine position, we will have a lifting of the
thoracic cage and of the abdominal wall and, of consequently, even a lowering of the
diaphragm. All this leads to a reduction of the pleural pressure (Ppl) and, therefore,
of the alveolar pressure (PA). The difference in pressure between the negative

Negative Mechanical Ventilation 149
pressure present at the alveolar level (PA) and the one present in the upper airways
(Pawo), equal to the external environment, will determine the force to perform an
inspiratory act. The measurement of a pressure differential between the upper
airways and the alveoli is indicated as Transairway Pressure (Pta = Pawo - PA),
while the difference between the alveolar pressure and the pleural pressure is
indicated as Transpulmonary Pressure (PL = PA - Ppl). Both indicate the force
required to perform a complete inspiratory act.
The mechanism consisting in lowering the pressure at the level of the alveoli
compared to the external environment is exactly what happens in physiological
muscular respiration, therefore it can be said that negative external mechanical
ventilation respects the normal physiology of human ventilation.
Using, instead, a ventilator that uses positive pressure, either invasively or non-
invasively applied to the airways, the first thing we notice is an increase in the
pressure in the upper airways (Pawo), while the pressure in the alveolar level
remains at the atmospheric level. The pressure difference existing between the
upper airways and the alveoli will cause a flow of air towards the lung structures at a
lower pressure that will terminate only when a predetermined pressure level is
reached. When this is achieved, there will be a pressure balance between the upper
airways and the alveoli and the inspiratory air flow will be annulled. However, in the
case of positive pressure ventilation, since the pressures introduced into the airways
are higher than those initially present, it can be observed that, during both the
inspiratory phase and the expiratory phase, the pressures inside the chest will be
always positive. This type of ventilation, therefore, will go against the rules of normal
physiological breathing.
VENTILATION MECHANICS
To carry out a normal respiratory act, the muscles must produce sufficient force,
or pressure, necessary to overcome the resistances that are present inside the
chest. These resistances consist of:
1. elastic resistances of the thoraco-pulmonary system,

2. resistances related to the generation of a flow in the airways,
3. inertial resistances.
Therefore, the pressure necessary to mobilize the entire respiratory system (Prs)
must overcome the sum of the elastic pressure (Pel), the resistive pressure (Pres)
and the inertial pressure (Pin).
Prs = Pel + Pres + Pin (1)

150 U. Vincenzi
The elastic pressure (Pel) increases with an increase in lung volume, the
pressure necessary to overcome the flow-resistance (Pres) increases with the flow
itself, the inertial pressure (Pin), which is generally negligible, increases with the
acceleration of the thoracic movement, that is with the variation of the air flow in the
unit of time.
An elastic system, such as the respiratory system, can also be expressed in
terms of Elastance (E) or Compliance (C), which is its reciprocal (E = 1/C).
The Elastance of the entire thoraco-pulmonary system (Ers), which is also
affected by the lung filling volume, is the sum of the Elastance relating to the lungs
and airways (EL) and the Elastance relating to the entire chest wall (Ecw) according
to the formula:
Ers = EL + Ecw (2)
Elastic pressure (Pel), needed to increase lung volume, is equal to Elastance

(Ers) multiplied by the volume change (V):
Pel = Ers ⋅ ΔV (3)
The resistive pressure (Pres), that is the pressure which is dispersed when the
gaseous flows go through the airways, is directly proportional to the resistances
present in the airways and to the amount of the generated air flow:
Pres = Raw ⋅ V ' (4)
At this point, starting from formula (1), we can rewrite it as follows:
Prs = (Ers ⋅ ΔV) + (Raw ⋅ V ’) + Pin (5)
This formula, also called the Equation of Motion of the Respiratory System,
demonstrates that, in order to perform an inspiratory act, it is necessary to take into
account elastic and dynamic forces, volumes and air flows and inertial aspects
present inside the chest.
If we separate the total Elastance of the thoraco-pulmonary system (Ers) into its
two components, (EL and Ecw), we can rewrite the above number (5) into:
Prs = (EL + Ecw) ⋅ ΔV + (Raw ⋅ V ’) + Pin (6)
This last formula makes us understand how the total pressure (Prs), necessary to
mobilize the entire thoraco-pulmonary system, must simultaneously mobilize both the
lungs with its internal airways and the entire rib cage. Therefore, an analysis of the
aforementioned thoracic structures is important as it is important to observe the
individual variations of Elastance (E) and Resistance (Raw) in order to intervene with
the ventilation methods and with the most appropriate equipment.

What generates an inspiratory or expiratory flow is the transairway pressure

(PTA) i.e., the difference between the alveolar pressure and the airway pressure in
contact with the outside (PTA = PA - Pawo). This pressure, of course, changes sign
depending on whether it is an inhalation or an exhalation.
Therefore, to expand the entire thoraco-pulmonary system and generate an
inspiratory act, it is necessary a force (PTA) that determines a pressure difference
between the external airways (Pawo) and the alveoli (PA) or an equivalent force, the
Transpulmonary Pressure (PL), which creates a pressure difference between the
alveolar pressure (PA) and the pleural pressure (Ppl).
To obtain this inspiratory act one can intervene in two distinct and opposite ways:
1. Increase the pressure in the upper airways and push air from the outside into
the inside of the chest (Positive Pressure Ventilation or PPMV).
2. Reduce the pressure at the level of the alveoli and suck air from the external
environment towards the alveoli (Negative Pressure Ventilation or NPV).
The exhalation begins with the suspension of the mechanical activity of the
ventilator and, generally, it is a passive act linked to the strength of the elastic return
of the thoraco-pulmonary system.
Some forces present in the thorax are shown in Figure 1.
Figure 1.
By measuring these pressures, present inside the chest during an entire

ventilatory cycle, we can see how these forces change depending on whether it is a

152 U. Vincenzi
healthy subject, who uses his own muscles (H), a subject in positive mechanical
ventilation (P) or a subject in negative mechanical ventilation (N) (Table 1).
Table 1.
End of Inspiration End of Expiration

Expiration Inspiration
H P N H P N H P N H P N
PTA = PA - Pawo 0 0 0 -5 -5 -5 0 0 0 2 2 2
Pawo 0 0 0 0 10 0 0 10 0 0 4 0
PA = PL + Ppl 0 0 0 -5 5 -5 0 10 0 2 6 2
PL = PA - Ppl 5 5 5 7 7 7 10 10 10 8 8 8
Ppl = PA - PL -5 -5 -5 -12 -2 -12 -10 0 -10 -6 -2 -6
Pcw -5 -5 -5 -2 -2 -2 0 0 0 -2 -2 -2
Pmusc 0 0 0 -10 0 0 -10 0 0 0 0 0
Pneg 0 0 0 0 0 -10 0 0 -10 0 0 -6
Prs = PL +Pcw 0 0 0 5 5 5 10 10 10 6 6 6
Pbs 0 0 0 0 0 -10 0 0 -10 0 0 -6
By evaluating the entity of transairway pressure (PTA) or transpulmonary

pressure (PL), measured in subjects H, P and N, we will notice that these pressures
have always the same value and the same sign. Therefore, this indicates that, by
applying the same amount of force, an equal breath is generated both in the normal
subject and in the subject in positive or negative external mechanical ventilation.
What changes, however, is that in muscular breathing (H) and in negative
pressure ventilation (N) the pressure in the airways (Pawo) and in the alveoli (PA) is
always low, while in positive pressure ventilation (P) it is always high, except at the
end of the exhalation.
The differences between positive pressure ventilation and negative pressure
ventilation, from the point of view of ventilatory mechanics, can therefore be
summarized as explained and shown above.
MACHINES FOR NON-INVASIVE EXTRA-THORACIC

NEGATIVE VENTILATION
In selected patients, negative pressure ventilators may offer advantages

compared to ventilators that require an artificial airway. It has been observed that,
even used intermittently, they can stabilize or reverse the trend towards hypercapnia
in patients with chronic, slowly progressive respiratory failure, due to neuromuscular
diseases, kyphoscoliosis and COPD. The effectiveness is due not only to the forced
ventilation imposed by the ventilator, but also to an inversion of chronic respiratory
muscle fatigue following rest.

Depending on the size and some technical characteristics, the machines that
create an NPV are: the “iron-lung,” the so-called “poncho” and the “cuirass” as may
be seen from Figure 2.
Figure 2. The machines that create an NPV are: A) Iron-lung, B) Poncho, C) Cuirass.
Iron Lung
Its name, "iron lung," derives from the first ventilator designed by Philip Drinker
and Louis Agassiz Shaw which consisted of a machine made entirely of metal. This
was equipped with a cylinder-shaped caisson in which, with the exception of the
head, the entire body of the patient to be treated was positioned. In more recent
times, lighter materials (fiberglass, aluminum, polycarbonate and various plastics)
have replaced a large part of the metal structure of the caisson in order to facilitate
maneuverability and transport. In some models (Porta-Lung), the ventilator motor is
separated from the cylinder container which can also have various dimensions.
On inspiration, the iron-lung creates a negative pressure inside the chest, which
results in a lifting of the chest and abdomen and, therefore, a lowering of the
diaphragm of the patient lying in supine position. The lifting of the chest and the
lowering of the diaphragm result in a volumetric increase inside the chest or an inlet
of air from the outside. Exhalation is based on the elastic return of the thoraco-
pulmonary system or, if so desired, with the delivery of an adjustable positive
pressure. Inside the caisson the pressure variations are provided by high-power
turbines controlled by a digital electronic control unit. The machine can operate in
both "assisted" and "controlled" mode (at one time, only in controlled mode). It has

154 U. Vincenzi
several portholes that allow access to the inside of the caisson and make it possible
to intervene on the patient's body, to position probes, to monitor situations, to
position catheters and to take blood samples. It can be tilted both longitudinally and
transversely and can be heated to improve comfort. Lastly, it is equipped with
alarms, which can also be activated by the patient himself in case of need.
Since the head is positioned outside the caisson, it is possible to perform
aspirations of the nasal and oral-pharyngeal cavities as well as fibrobronchoscopic
investigations, all the while, the patient can talk, eat, drink, sneeze, cough and
expectorate and devices can be applied to the face to enrich oxygen intake.
Poncho
To create an effective negative extra-thoracic pressure, this machine, also called

"wrap" or "pneumo-wrap," uses a turbine engine and some accessories such as a
metal net, a supporting plane and an airtight suit, closed at the neck, wrists and
ankles by stripes. The suit (in the shape of a "poncho" and hence its name) is worn
by the patient and, to create an air space between the suit and the patient's body, the
metal net is inserted in the front and the supporting plane, which acts as the base of
the metal net, is placed in the rear. The nets and suits are of different sizes in order
to fit best the body of the patient to be treated.
In the space created between the suit, often made of Goretex, and the patient's
body surface, the pressures, necessary for ventilation, are modulated by the
ventilator.
This machine, in addition to operating in a "controlled" mode, can also work in an
"assisted" mode by means of sensors positioned at the level of the upper airways.
Cuirass
With the cuirass, the turbine machine or something similar is used, but instead of
the accessories utilized by the "pneumo wrap," cuirass or shells of transparent plastic
material are positioned on the patient's chest and held by fabric straps that go
around the back of the chest. The principle of operation is the same as the
"poncho’s" with the advantage of having greater availability of sizes and shapes of
the shells that can even accommodate babies. Some of them are even made to
specs to perfectly fit the patient's body.
To limit possible damages caused by the sharp edges of the shell and to prevent
air leaks in the support points, the edges are covered with an elastic and soft
material. The operation is to create pressure variations between the cuirass and the
patient's chest.
Similarly to the "poncho," the cuirass can operate in both "controlled" and
"assisted" modes. To avoid large air leaks and provide adequate ventilation, it must

adjust to the size of the chest. Air leaks dissipate negative pressure and limit its
effectiveness. Compared to the iron-lung, the cuirass applies negative pressure on a
lower surface, but, compared to the Poncho, it can also assist the patient during
exhalation by providing an adjustable positive pressure.
Extra-Toracic Negative Mechanical Ventilation Mode
Extra-thoracic Negative Pressure Ventilators (hence the name of the ventilation

mode: NPV) act on the space created between the machine and the patient's trunk.
In the case of the iron-long, the variations in pressure act on the whole body, while in
the case of the Poncho or the cuirass they work on inferior surfaces. In inspiration,
they create sub-atmospheric pressures, in expiration, they can vary the degree of
depression, annul it or provide positive pressure. In the latter case, the machines that
can produce it are the iron-lug and the cuirass.
The modes of extra-thoracic negative ventilation are 4: 1) Intermittent negative
pressure ventilation (NPV). 2) Negative and positive pressure ventilation (also
referred to as NPV). 3) Continuous Negative Pressure Ventilation (CNPV). 4)
Ventilation at two levels of negative pressure (NPV-NEEP).
Intermittent Negative Pressure Ventilation (NPV)

The negative pressure created by the machine, administered to the patient in a
cyclic manner, determines an inspiratory act. The volume inspired by this act is a
consequence of the force set on the ventilator by the operating doctor, while the
beginning and duration of the inspiratory act can be determined by the patient
himself (as long as he is awake and cooperating) through sensors positioned near
the nose or mouth. The exhalation, which begins at the end of the delivery of
negative pressure, is a passive movement due to the thoraco-pulmonary elastic
forces with return to the FRC position.
Negative and Positive Pressure Ventilation (NPV)

This mode, exclusive only for ventilators acting extra-thoracically, includes
ventilatory assistance in both the inspiratory and expiratory phases which alternate
cyclically. In expiration, the force of the ventilator, preset by the operator, is added to
the patient's elastic return.
Extra-Thoracic Continuous Negative Pressure Ventilation (CNPV)

In reality, this is not a true ventilatory mode because, like CPAP, the machine
does not produce true ventilator cycles, but constantly applies negative extra-thoracic
pressure. The continuous negative pressure brings the chest to a higher resting level
of the FRC, reducing muscle strain, while leaving the patient full freedom of control
over their breathing. All this facilitates the inspiratory act.

156 U. Vincenzi
Ventilation at Two Levels of Negative Pressure (NPV-NEEP)

Similarly to what happens with PS + PEEP in positive pressure ventilation, this
ventilatory mode cycles the inspiratory act between two levels of extra-thoracic
negative pressure. Therefore, at the end of expiration, a Negative End Expiratory
Pressure (NEEP) remains in the ventilator which keeps the patient's chest and
airways slightly expanded, favoring the subsequent inspiratory act and counteracting
intrinsic PEEP (PEEPi).
APPLICATIONS OF NPV IN VARIOUS PATHOLOGIES
Non-invasive extra-thoracic negative ventilation has been used successfully all

over the world. Some centers have had a very large number of patients treated with
NPV. Among these, there is A. Corrado [2] and collaborators who treated, in 16 yrs
of experience, 2564 patients with acute-on-chronic respiratory failure (ACRF)
including: 2116 patients with COPD and 604 with restrictive thoracopulmonary
disease (RTD) with mortality of 10% and 8.9% respectively. Even in the field of
pediatrics there have been a large number of recent cases in the use of NPV [3]
demonstrating the validity and diffusion of this ventilatory method.
Neuromuscular Disorders
Non-invasive extra-thoracic NPV proved to be an excellent mode of ventilation in

patients suffering from neuromuscular diseases since, due to their marked muscle
weakness, it was difficult for them to counteract the ventilatory action imposed by the
machine. Therefore, even in the early periods of NPV application, when the
ventilatory modality was exclusively of the "controlled" type, few ventilatory
asynchronies were found. After the 90s of the last century, with the possibility of
being able to ventilate even in "assisted" mode, further improvements were achieved
in this ventilatory treatment.
A large number of neuromuscular patients were treated with this method and, it
can be said with certainty, that NPV was the treatment of choice until the 1950s for
patients suffering from poliomyelitis. Many of these patients, however, after the acute
phase, found themselves dependent on the ventilator due to severe muscle
weakness resulting from the disease. In this case, NPV, the only non-invasive
ventilation modality until then, was particularly indicated in helping these patients.
The application of NPV in neuromuscular patients also occurred in the following
years [4].

In the 1950s, NPV was also the only ventilatory treatment modality for use in
chronic modality. Given the considerable number of patients affected by poliomyelitis
who had overcome the acute period of the disease, but who still needed ventilatory
support to survive, a care model to be used even at home, of intermittent non-
invasive mechanical ventilation was devised. In the case of patients with still residual
respiratory capacity, NPV was generally applied at night and, in some cases, at
home, while in the case of patients whose respiratory capacity was significantly
reduced, NPV was also administered during the day and, often, in the hospital. In the
following years, the marketing of lighter and smaller ventilators, including the cuirass,
spread the home use of NPV.
The survival of patients treated at home has reached levels of several decades
[5]. There is the case of an Italian woman (R.B.), suffering from quadriplegia resulting
from polio, who lived, in an iron-lung, 29 years.
Some authors (Libby Bm. [6] and Braun Sr. [7]) have demonstrated the
usefulness of negative pressure ventilators in neuromuscular patients to avoid
endotracheal intubation and facilitate the weaning process from IMV.
The greatest difficulties in the application of NPV were found in the severe
alterations of the rib cage with marked curvatures of the vertebral column. These did
not allow the correct supine position and easily created decubitus in the contact
points of the column on the support plane. To bypass this last problem, special
supporting cushions and containers have been customized to fit the patient's body.
Extra-Thoracic Ventilation in Adults with Respiratory Failure
Numerous scientific publications of the 80s and 90s, some of them full of
hundreds of cases treated [2, 8], have amply demonstrated the effectiveness of NPV
in subjects suffering from acute respiratory failure (ARF) resulting in exacerbated
COPD with clear improvement of blood gases.
The use of iron-lung, as A. Corrado [9] demonstrated, was also successfully
extended to the treatment of patients in hypercapnic coma, thus expanding the
possibility of non-invasive ventilatory techniques.
NPV was also directly compared to noninvasive positive pressure ventilation
(NPPV) [10]. The patients were matched in 53 couples, with a correspondence of
98.4% based on the clinical and pathophysiological characteristics and it was
examined whether there were differences, in the results and in the complications,
related to the different ventilatory treatments used. Duration of mechanical ventilation
(29.6 ± 28.6 vs 62.3 ± 35.7h) and hospital stay (10.4 ± 4.3 vs 15 ± 5.2) were
significantly lower in the NPV group than in the NPPV group (p = 0.001 and p =
0.001). Cases of treatment ineffectiveness were similar and not significant between
the two groups and both techniques have been shown to be effective in avoiding
endo-tracheal intubation and death in COPD patients.

158 U. Vincenzi
Negative ventilation was also used in the ARDS. K. Raymondos [11], in 6

patients with ARDS and intubated, compared the application of continuous external
negative pressure ventilation (CNPV) with continuous positive pressure ventilation
(CPPV) and found better oxygenation (PaO2/FiO2 = 345 mmHg vs 256 mmHg, P <
0.05) and less lung injury compared to continuous positive pressure ventilation with
significant reduction in airway pressure, both during inspiration and during expiration.
Extra-Thoracic Ventilation in Rehabilitation
Recently, Hung-Yu Huang [12] has studied the effects and costs of long-term (5
years) NPV therapy on 129 COPD patients. It is possible to claim that pulmonary
rehabilitation associated with negative pressure ventilation lowers the decline in lung
function, hospitalizations and medical costs in COPD.
Extra-Thoracic Ventilation in Children and Infants
There have also been successes with NPV in the field of pediatrics. MP Samuels
and DP Southall [13] highlighted the beneficial effects of NPV on 88 infants and
young children with respiratory failure from various causes, in which the need for
intubation and its negative consequences was reduced, and in addition it favored an
early extubation.
ADVANTAGES AND DISADVANTAGES OF NEGATIVE

EXTRA-THORACIC MECHANICAL VENTILATION
NPV is a non-invasive method that can be used intermittently and, therefore, also
in chronic and prolonged treatments. It can be used to treat patients with different
degrees of ARF, from hypercapnic coma to minor degrees, up to respiratory
rehabilitation. NPV guarantees physiological ventilation avoiding the problems
associated with excessively high pressures in the airways, as it can happen with
positive pressure ventilation. With NPV, intubation is avoided, and with it, all related
complications, in particular lung infections. The airways are in close communication
with the external environment, so the patient can speak, swallow, blow his nose and
cough.
NPV is not recommended for claustrophobic patients, for those who have
undergone recent chest or abdomen surgery, for those who are very obese (due to
their body size) and for those with tracheostomy tubes (possible obstruction of the
cannula).

The disadvantages include the need for assistance for patients treated with iron-
lung, the possibility of obstruction of the upper airways and ineffective
ventilation [14].
In recent years, the reduction of the ventilators in their size and weight, which are
considered negative aspects, has favored their spread.
REFERENCES
[1] Levine S, Henson D. Negative pressure ventilation. In: Tobin MJ (a cura di).
Principles and practice of mechanical ventilation. New York: McGraw-Hill; 1994.
pp. 393-411.
[2] Corrado A, Gorini M, De Paola E, Bruscoli G, Tozzi D, Augustynen A, Nutini S,
Ginanni R. Iron lung treatment of acute on chronic respiratory failure: 16 yrs of
experience. Monaldi Arch Chest Dis. 1994 Dec;49(6):552-5.
[3] Hassinger A. B., Breuer R. K., Nutty K., Ma C-X, Al Ibrahim O. S. Negative-
Pressure Ventilation in Pediatric Acute Respiratory Failure. Respir Care
2017;62(12):1540–1549.
[4] Braun S. R., Sufit R. L., Giovannoni R. et Al. Intermittent negative pressure
ventilation in the treatment of respiratory failure in progressive neuromuscular
disease Neurology December 01, 1987; 37 (12).
[5] Ralph C., Frates R. C. Jr., Jefferson L. S. et Al. Home Negative Pressure
Ventilation: Report of 20 Years of Experience in Patients with Neuromuscular
Disease. Arch Phys Med Rehabil. 1985.
[6] Libby Bm, Briscoe Wa, Boyce B, Smith Jp. Acute respiratory failure in scoliosis
or Kyphosis. Am J Med 1982;73:532-38.
[7] Braun Sr, Sufit Rl, Giovannoni R, O’connor M, Peters H. Intermittent negative
pressure ventilation in the treatment of respiratory failure in progressive
neuromuscular disease. Neurology 1987;37:1874-1875.
[8] Gunella G. Treatment of acute on chronic respiratory failure with iron lung:
results in a series of 560 cases. Ann Med Physique 1980;2:317-327.
[9] Antonio Corrado, Eduardo De Paola, Massimo Gorini, Andrea Messori,
Giovanni Bruscoli, Sandra Nutini, Donatella Tozzi, Roberta Ginanni. Intermittent
negative pressure ventilation in the treatment of hypoxic hypercapnic coma in
chronic respiratory insufficiency Thorax 1996;51:1077-1082.
[10] Corrado A, Ginanni R, Villella G. Negative pressure ventilation (NPV) by iron
lung versus conventional mechanical ventilation (CMV) in the treatment of
acute respiratory failure (ARF) in COPD patients: a prospective randomised
controlled study. Eur Respir J 2001;18:suppl. 33,185s.
[11] Raymondos K, Molitoris U, Capewell M, Sander B., Dieck T., Ahrens J.,
Weilbach C., Kniysch W., Corrado A. Negative versus positive pressure
ventilation in intubated patients with acute respiratory distress syndrome Critical
Care. 2012 Dec 12;16 (2):R37.

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[12] Hung-Yu Huang, Pai-Chien Chou, Wen-Ching Joa, Li-Fei Chen, Te-Fang
Sheng, Horng-Chyuan Lin, Lan-Yan Yang, Yu-Bin Pan, Fu-Tsai Chung, Chun-
Hua Wang, Han-Pin Kuo Pulmonary rehabilitation coupled with negative
pressure ventilation decreases decline in lung function, hospitalizations, and
medical cost in COPD. A 5-year study. Medicine (2016) 95:41.
[13] Samuels MP, Southall DP Negative extrathoracic pressure in treatment of
respiratory failure in infants and young children Br Med J 1989 Nov
18;299:1253-7.
[14] Levy RD, Cosio MG, Gibbons L, et al. Induction of sleep apnoea with negative
pressure ventilation in patients with chronic obstructive lung disease. Thorax
1992;47:612–5.

Chapter 11
INTERMITTENT ABDOMINAL
MECHANICAL VENTILATION
Paola Pierucci, MD, Valentina Di Lecce, MD

and Onofrio Resta, MD
Cardio Thoracic department, Respiratory ad Sleep medicine Unit,
Bari Policlinic. “Aldo Moro” University School of medicine, Bari, Italy
ABSTRACT
Non-invasive ventilatory support (NVS), has become the focus of respiratory

failure treatment, especially in chronic restrictive chest diseases. It is based on
applying a pressure difference across the lung. This is possible either using
positive pressure ventilators so that high air pressures is transferred directly to
the airways, or by using negative pressure ventilators. In the latter case the
pressure is applied outside the body (i.e., to the chest, to the abdomen or the
whole body) and indirectly transferred to the pleural space.
In patients with ventilatory pump failure due to progressive diseases
noninvasive positive pressure ventilation (NPPV) via continuous positive airway
pressure (CPAP) or bi-level positive airway pressure (Bi-Level, NIV), is widely
applied in the treatment of nocturnal and sometimes diurnal respiratory failure
and it is also used for continuous noninvasive ventilatory support (CNVS). In the
context of CNVS, another niche role is played by the body ventilators. They
include negative pressure ventilators, such iron lungs, poncho, pneumo-suits,
pneumo-wraps, and intermittent abdominal pressure ventilators (IAPV).
The latter one (IAPV) consists of an air-sack inside a corset inflated by a
ventilator. The sack compresses the abdomen to raise the diaphragm and to
increase tidal volumes. It represents a practical and comfortable alternative to
daytime support with the patient in a sitting position. Several applications in
clinical practice have been studied over time, confirming its usefulness as

Corresponding Author’s E-mail: paola.pierucci@policlinico.ba.it.

162 Paola Pierucci, Valentina Di Lecce and Onofrio Resta
ventilatory support. This chapter will focus on describing in more details this
alternative ventilation technique.
INTRODUCTION
In the paste decades the use of noninvasive ventilation (NIV) and noninvasive
ventilatory support in patients with neuromuscular disorders (NMD) has gradually
increased changing the landscape of current treatment for their acute and chronic
respiratory failure [1]. However when the need of respiratory support overcome the
limits of the night only, patients with NMD need to be supported also during daytime.
In this chapter the use of intermittent abdominal mechanical ventilation will be
evaluated in detail underlying its historic background, potential benefits, mechanism
of action and clinical application.
ADVANCES OVER THE YEARS
Over the past few decades, increasing attention has been focused on
noninvasive ventilatory support (NVS) and its role in reducing the need of invasive
ventilation (IV) use. Indeed, the use of IV via tracheostomy or endotracheal
intubation is vital in the emergency treatment of acute respiratory failure (ARF),
however, it may be burdened with complications that increase mortality risk and
cause limitations to patients’ daily life, especially when used over a long term. NVS
relies on devices that work by applying a pressure difference across the lung,
allowing to assist inspiratory and expiratory muscles in preserving alveolar ventilation
and improving cough flows. This difference can be generated by negative pressure
ventilators applied outside the body that indirectly transfer the pressure applied to the
pleural space, or by positive pressure ventilators, which directly applied a high air
pressure into the airways [1].
Nowadays, noninvasive positive pressure ventilation (NPPV) has gradually
become the cornerstone in the treatment of patients with respiratory failure.
Nocturnal continuous positive airway pressure (CPAP) and bi-level positive airway
pressure via noninvasive ventilation (Bi-Level NIV) have a recognize effectiveness in
the treatment of respiratory failure due to lung disease and ventilatory pump failure
[2-7]. Although the standardized guidelines indicate non-invasive ventilation (NIV)
nocturnal initiation, in patients with ventilatory pump failure due to progressive
restrictive diseases (i.e., neuromuscular disorders), the appearance or persistence of
diurnal hypercapnia or dyspnea causes to progress NIV use from nocturnal use only
to daytime hours, thus leading to continuous noninvasive ventilatory support (CNVS).
The latter one consists of higher positive pressures support through mechanical
ventilation use via a facial interface (nasal, oro-nasal, mouthpiece etc.) and, as a
consequence, it allows improving gas exchanges, muscle fatigue related symptoms,

Intermittent Abdominal Mechanical Ventilation 163
quality of life, and reducing the need of switch to IV via tracheostomy [8]. Side effects
include airway and mouth dryness, which can leads to atelectasis, and skin
breakdowns, especially if interface is not correctly chosen and adapted to the specific
patients’ face characteristics, and/or if a rotational strategies of different interfaces is
not performed during prolonged daily use [9, 10]. Mouthpiece and nasal interfaces
are the main interafaces preferred for the daytime NIV, allowing to speak, eat and to
reduce claustrophobia and intolerance. Oral and full-face interface are more used for
sleep, reducing air leaks and requiring less patient collaboration [8].
In the same context of CNVS, another role is played by body ventilators. They
include negative pressure ventilators, such iron lungs, pancho, pneumosuits and
pneumowraps, and intermittent abdominal pressure ventilators (IAPV).
Negative pressure ventilators (NPV) have historically played a key role in the
treatment of respiratory failure. They work applying negative (sub-atmospheric)
pressure to the chest wall during inspiration, causing chest expansion and reduction
the pleural and alveolar pressure; this pressure gradient allows air to move from the
airways to the alveoli. On the other hand, the exhalation occurs passively when the
pressure around the chest wall increases and becomes atmospheric or greater. Over
time, more advanced models of tank ventilators have been developed and used in
treatment of chronic and acute respiratory failure. These have been tested on patient
with chronic obstructive pulmonary disease (COPD), neuromuscular disorders
(especially during the poliomelytis epidemics in 1930s and 1940s) and pediatric
diseases [11]. However, with the spread of NPPV, the role of NPV has been revised.
Despite its proven efficacy especially in patients with chronic respiratory insufficiency
due to neuromuscular disorders or chest wall diseases [12], its use in clinical practice
was limited by its side effects (upper airway obstruction, poor compliance, back
pain), contraindications (claustrophobia, obesity, sleep apnea syndrome, severe
kyphoscoliosis) and the difficulty of using it in respiratory intensive care units (RICUs)
or intensive care units (ICUs), related to the devises’ volume and the need of
experienced professionals in their use [13].
In this context, the intermittent abdominal pressure ventilator (IAPV) was
developed in 1940s and widely used for daytime ventilatory support until 1970s when
the use of tracheostomy via IV prevailed over NVS. Currently, its use is spreading
again. Its mechanism of action and its applications in clinical practice will be explored
in the following sections.
IAPV MECHANISM OF ACTION
In normal conditions, the contraction of the diaphragm and the activity of the
intercostal muscles increase the total air volume of the thoracic cavity, this allowing
the lungs to expand. In case of diaphragmatic weakness, the external pressure
applied to the abdominal wall via an inflatable bag inside the belt allows the upward
displacement of the diaphragm and the air exhalation from residual volume. Then,

gravity allow the diaphragm to return to its resting position allowing air to be inhaled
through the airways [14].
The IAPV functions reproducing the physiological respiratory mechanics. It
consists of a corset applied to the patient’s abdomen in a sitting position (an angle of
30 degrees or greater is required for correct functioning). Inside the corset, there is
an inflatable and deflatable bladder. When it is inflated it allows the lifting of the
diaphragm and therefore an assisted exhalation; when deflated, it guarantees the
diaphragm returning to the initial position and therefore a passive inspiration. The
corset is connected to a positive pressure ventilator on which the inflation pressure of
the bladder (Pbelt), the inspiratory time (Tinsp), the respiratory rate (frequency) and
the time to reach the Pbelt (Rise time) are set [8].
Although it can also be used during sleep if the patient maintains a sitting
position, the IAPV represents a practical and comfortable alternative to other daytime
ventilation supports. It encounters several advantages in case of continuous NVS
needed. First of all, by eliminating the need of facial ventilation interfaces, it reduces
the side effects associated with their use (i.e., skin breakdowns, airway and mouth
dryness, eye irritation). The abdominal compression generates expiratory and cough
flows and it increases tidal volume and as a consequence speech duration and
volume, facilitating social interactions. It can also reduce dyspnea and help to
manage the tracheobronchial secretions. Considering that swallowing involves a
phase of exhalation, followed by glottis closure, swallowing and then exhalation, the
increase in tidal volumes and the consequent reduction of tachypnea allowed by the
IAPV, can also facilitate eating. Moreover, it is simple to wear, even on a wheelchair,
and also beneath patient’s clothing, which makes it more tolerable by the patient [8,
14].
Among the disadvantages, there is the possibility of regurgitation after meals and
the impossibility to use during bathing. Since its effectiveness depends on the
surface of the abdomen on which it is applied, it is necessary to maintain the sitting
position or at least an angle of 30 ° and it can be less effective in the presence of
obesity or severe kyphoscoliosis. A careful follow up is necessary because its
effectiveness can decrease over time [8].
CLINICAL APPLICATIONS
Several clinical applications of IAPV have been described over time. In 1938,
McSweeney reported the use of the “Bragg-Paul pulsator” in 34 patients affected by
post-diphteric respiratory paralysis; of these, 26 cases were treated successfully,
eight died of causes other than respiratory failure [15].
Following a technical improvement, from 1946 the IAPV was introduced as a
non-invasive ventilatory support, not only during the day but also at night. In 1989,
Yang and colleagues described its use in three patients with chronic respiratory
failure due to syringomyelia, poliomyelitis and Friedreich’s ataxia. In these patients,

diurnal and nocturnal use of IAPV as ventilatory support improved and maintained
their daily functions, allowing the respiratory muscles to rest during the night and
ensuring the maintenance of the necessary tidal volume during sleep [16].
In 1991, Bach and colleagues reported data on IAPV use in 54 patients with
paralytic/restrictive respiratory insufficiency requiring 24-hour ventilatory support. Of
these, 48 patients used IAPV only for daytime support, one patients only for
nocturnal support, and five for continuous support. After 12.3 ± 9.5 years of use,
IAPV became ineffective for 12 patients, necessitating the shift to daytime
intermittent positive pressure ventilation (IPPV) via facial interfaces. The results of
this study confirmed the IAPV effectiveness as a method of long-term daytime non-
invasive ventilation, especially in combination with other types of ventilatory support,
reducing the risk of resorting to tracheostomy [17].
Despite these results, with the spread of invasive mechanical ventilation, IAPV
use has significantly reduced in the mid 70ies. Lately, with the return of non-invasive
mechanical ventilation as the first choice of treatment for chronic respiratory failure,
starting in the early 2000s, IAPV was again used as an alternative to Bi-level NIV in
patients with neuromuscular disorders or other causes of respiratory muscle
dysfunction.
Figure 1. Patient with LOPD wearing IAPV.

In 2019, Banfi and colleagues described the case of a 51 year-old male affected
by chronic ventilatory insufficiency caused by post-ischemic cervical myelopathy,
dependent on NVS sleep since 2003. Due to the development of diurnal
hypercapnia, he was placed on daytime mechanical ventilation via mouthpiece, to
which he was intolerant. Therefore, he was introduced to the use of the IAPV. After 3
months of its constant use for at least 8 hours a day, the patient showed stable
respiratory gas exchanges, absence of daytime symptoms even during spontaneous
breathing, and a net improvement in quality of life [18].
The role of IAPV as daytime ventilatory support in a patient with hypoventilation
caused by late onset Pompe disease (LOPD) was recently reported for the first time
by Pierucci and colleagues. This 22-year-old male university student began nocturnal
CPAP for obstructive sleep apnoea and then, due to hypercapnia, he was placed in
nocturnal Bi-level NIV. After 1 month, despite the good compliance and the
improvement of ventilation parameters, he showed persistence of daytime
symptoms. The introduction of daytime ventilation via mouthpiece or nasal mask was
proposed, but the patient refused due to university or social commitments. Then, he
was trained to IAPV use in combination to nocturnal Bi-level NIV (Figure 1). After 3
months of its use he reported improvement in both diurnal symptoms and quality of
life. The increase in nocturnal ventilation parameters made it possible to completely
correct residual hypercapnia. The results of this study confirmed the validity of IAPV
as an alternative to NIV in daytime ventilatory support also in patients affected by
LOPD [19-20].
Although the use of IAPV has been mainly evaluated as an alternative method of
NVS, De Mattia and colleagues reported its use in a patient with amyotrophic lateral
sclerosis (ALS) undergoing IV via tracheostomy. Diurnal IAPV was associated to IV
and to the use of a speaking valve to facilitating speaking. In this case, the use of
IAPV allowed to improve speech but also respiratory gas exchanges and secretions
management, with good patient compliance [21].
CONCLUSION
In conclusion, in this era characterized by a growing attention on NVS use and

reduced approach to IV use, the reported experiences on the IAPV use confirm its
effectiveness as an alternative option of daytime support, especially when other type
of nocturnal ventilation choices are already in use. Furthermore, the possibility to use
it even in patients with tracheotomy further extends the range of its application.
Careful follow up is always required, especially during long-term use, considering
that muscle functions continue to decline in progressive neuro-muscular diseases,
causing IAPV to reduce its effectiveness over time. Further studies will be required to
confirm the preliminary findings already present in the literature.

REFERENCES
[1] Bach J. R. Noninvasive Respiratory Management of Patients With

Neuromuscular Disease. Ann. Rehabil. Med. 2017;41(4):519-538.
[2] Carlucci A., Richard J. C., Wysocki M., Lepage E., Brochard L. SRLF
collaborative group on mechanical ventilation. Noninvasive versus conventional
mechanical ventilation. An epidemiologic survey. Am. J. Respir. Crit. Care Med.
2001;163:874–80.
[3] Mas A., Masip J. Noninvasive ventilation in acute respiratory failure. Int. J.
Chron. Obstruct. Pulmon. Dis. 2014;9:837–52. https://doi.org/10.2147/COPD.
S42664 eCollection 2014.
[4] Ward S., Chatwin M., Heather S., Simonds A. K. Randomised controlled trial of
non-invasive ventilation (NIV). Thorax. 2005;60:1019–24
[5] Crimi C., Pierucci P., Carlucci A., Cortegiani A., Gregoretti C. Long –term
ventilation in neuromuscular patients: review of concerns, beliefs, and ethical
dilemmas. Respiration. 2019;97(3):185–96.
[6] Perrin C., Rolland F., Berthier F., Duval Y., Jullien V. Noninvasive ventilation for
acute respiratory failure in a pulmonary department. Rev. Mal. Respir. 2015;
32(9):895–902.
[7] Bello G., De Pascale G., Antonelli M. Noninvasive ventilation. Clin. Chest Med.
2016;37(4):711–21.
[8] Banfi P., Pierucci P., Volpato E., Nicolini A., Lax A., Robert Dominique, Bach J.
Daytime noninvasive ventilatory support for patients with ventilatory pump
failure: a narrative review. Multidiscip. Respir. Med. 2019 Nov 30;14:38.
[9] Wood K. E., Flaten A. L., Backes W. J. Inspissated secretions: a life-threatening
complication of prolonged noninvasive ventilation. Respir. Care. 2000;45(5):
491–3.
[10] Nava S., Navalesi P., Gregoretti C. Interfaces and humidification for
noninvasive mechanical ventilation. Respir. Care. 2009;54(1):71–84.
[11] Corrado A., Gorini M., Vilella G., De Paola E. Negative pressure ventilation in
the treatment of acute respiratory failure: an old noninvasive technique
reconsidered. Eur. Respir. J., 1996, 9, 1531–1544.
[12] Levine S., Henson D. Negative pressure ventilation. In: Tobin M. J., ed.
Principles and Practice of Mechanical Ventilation. New York, McGraw-Hill,
1994; pp. 393–411.
[13] Corrado A., Gorini M. Negative-pressure ventilation: is there still a role? Eur.
Respir. J 2002; 20: 187–197.
[14] Bach J. R., Radbourne M., Potpally N., Chiou M. A Mechanical Intermittent
Abdominal Pressure Ventilator. Am. J. Phys. Med. Rehabil. 2019;98:e144–
e146.
[15] McSweeney C. J. The Bragg-Paul Pulsator in treatment of respiratory paralysis.
Br. Moo J. 1938;1:1206–7.

[16] Yang G-FW, Alba A., Lee M., Khan A.: Pneumobelt for sleep in ventilator user:
clinical experience. Arch. Phys. Med. Rehabil. 70:707-711, 1989.
[17] Bach J. R., Alba A. S. Intermittent abdominal pressure ventilator in a regimen of
noninvasive ventilatory support. Chest. 1991 Mar;99(3):630-6.
[18] Banfi P. I., Volpato E., Bach J. R. Efficacy of new intermittent abdominal
pressure ventilator for post-ischemic cervical myelopathy ventilator
insufficiency. Multidisciplinary Respiratory Medicine (2019) 14:4.
[19] Pierucci P., J. R. Bach, V. Di Lecce, P. Banfi, G. E. Carpagnano, O. Resta
Pulmonology 2020 Aug 30;S2531-0437(20)30184-7. doi: 10.1016/j.pulmoe.
2020.08.003. Online ahead of print. Daytime non-invasive ventilatory support
via intermittent abdominal pressure for a patient with Pompe disease.
[20] P.Pierucci, V.Di Lecce, P.Banfi, GE Carpagnano, JR Bach American Journal of
Physical Medicine & Rehabilitation May 28, 2021 - Volume Publish Ahead of
Print PMID: 34091472 DOI: 10.1097/PHM.0000000000001804 The Intermittent
Abdominal Pressure Ventilator as an alternative modality of noninvasive
ventilatory support: a narrative review
[21] De Mattia E., Iatomasi M., Garabelli B., Lunetta C., Sansone V. A., Rao F. Use
of the Intermittent Abdominal Pressure Ventilation to guarantee speech in a
tracheostomized Amyotrophic Lateral Sclerosis patient. Rev. Port. Pneumol.
(2006). Jul-Aug 2017;23(4):236-239.

Chapter 12
MPV AND OTHER EMERGENT THERAPIES
Anna Annunziata*, Ediva Myriam Borriello

Department of Critic Area, Unit of Respiratory Disease,
Monaldi Hospital, Naples, Italy
ABSTRACT
Several conditions may also be responsible for the failure of NIV, including
claustrophobia, mask-induced skin lesions and rhinitis, non-tolerance of pressure
on the face. Other daytime NIV procedures should be considered in highly
ventilator-dependent patients in addition to mask ventilation. Mouthpiece
ventilation (MPV) is a type of non invasive ventilation delivered via a mouthpiece.
MPV is used for the first time on ventilator-dependent polio patient. MPV, as we
know it today, is used from many years, and there are already evidence in
literature documenting effectiveness of treatment and increased compliance by
the patient. Despite this, there is little knowledge and practicality of the use of
non invasive mechanical ventilation with mouthpiece.
ABBREVIATIONS
ALS amyotrophic lateral sclerosis
BDP bilateral diaphragmatic paralysis
EPAP expiratory positive airway pressure
IAPV intermittent abdominal compression ventilation
MPV mouthpiece ventilation
NIV non invasive mechanical ventilation
*
Corresponding Author’s E-mail: anna.annunziata@gmail.com.

170 Anna Annunziata, Ediva Myriam Borriello and Giuseppe Fiorentino
INTRODUCTION
Due to a recent evolution since 2013, mouthpiece ventilation modes are being
introduced to commercially available portable ventilators, increasing the interest for
this ancient modern interface [1]. For all clinicians working with mechanical
ventilation it is very useful to have many treatment options available to sew the best
suit for each patient.
MPV VENTILATION
Mouthpiece ventilation is used with single-limb non-vented circuit ventilators in
pressure-controlled or, more frequently, in volume-controlled mode for allowing air
stacking. The patient can get mouthpiece ventilation, breaths passively, using the set
backup frequency on the ventilator, or he/she can actively trigger the breath,
retaining a part or all of the delivered volume. It is possible to use a simple single-
tube circuit or a circuit with a valve. The valve is preferable for patients who cannot
disconnect to exhale outside the circuit. Patients with the valve can stay connected
for a long time in a row. The clinician should evaluate the patient's ability to
synchronize with the mouthpiece held in the mouth and to exhale outside the
mouthpiece or not. As a matter of fact, depending on the ability to move the neck, the
patient can continuously keep the mouthpiece between his/her lips or leave it for a
variable time. The patient can independently disconnect from the mouthpiece to
speak, eat, cough or call a family member. It is clear that it present no risk of skin
breakdown, conjunctivitis, absence of claustrophobia and lower probability of gastric
distension. It is safer by permitting use of glossopharyngeal breathing in the event of
sudden ventilator failure or accidental disconnection from the ventilator [2]. Despite
these obvious advantages, this modality is not commonly used. Mouthpieces for
daytime use may elicit salivation and more rarely vomiting [3] and long-term use can
cause orthodontic deformities after 20 years use. However the same problem has
been detected with traditional interface in pediatric patients. Nasal pledges or nose
clips can be used to avoid air leak through the nares for patients using lip covering
interfaces for mouthpiece NIV during sleep [3, 4]. During the night while sleeping,
most patients use a mask because a mouthpiece requires collaboration and is
uncomfortable. However, although rarely, air may also be swallowed and cause
gastric distension. Mouthpiece and nasal NIV are open systems of ventilator support,
the low pressure alarms of ventilators not having mouthpiece NIV modes can often
be sound. Back pressure from a 15mm angled mouthpiece is sufficient to prevent a
low-pressure alarm set at 2cmH2O. Carlucci et al. recently studied how to set
different type of ventilator when using the mouthpiece [4]. They found that an
appropriate alarm setting and combination of tidal volume and inspiratory time would
allow the majority of the tested ventilators to be used for mouthpiece ventilation
without alarm activation [4].

MPV and Other Emergent Therapies 171
The patient triggers the breath by placing the mouth on the mouthpiece and
creating a small negative pressure in the circuit by sipping or inhaling. Mouthpieces
are very useful in adjunct daytime ventilation for patients suffering from
neuromuscular diseases who do not have the ability to maintain acceptable diurnal
arterial blood gases without frequent intermittent periods of assistance [5]. Khirani et
al., report their study of ventilators for mouthpiece ventilation in patients with
neuromuscular disease, and confirm the useful of this interface. The authors find
subjects are satisfied with mouthpiece ventilation [6] Nardi et al., also describes that
patients were satisfied with MPV and preferred the mouthpiece to the nasal mask,
this aspect can favour adherence to NIV but the risk of the use of MPV is that the
patient may unknowingly under ventilate themselves because of the frequent
disconnection from mouthpiece [7]. The time of disconnection is probably the major
limit of this approach to NIV. The authors documented that the periods of
disconnection were associated with > 5mmHg paCO2 increases and > 2% spO2
decreases but no clinical complication occurred before or after the monitoring period.
Few patients tolerated prolonged disconnections without developing hypercapnia [7].
The most common type of asynchrony was ineffective effort, also suggesting a need
for improved trigger sensitivity. The recently introduced MPV software that allows
insufflation to be triggered only by the positioning of the patient's lips appears to be
an option for the patient with severe muscle weakness [5]. Moreover, the software of
many new ventilators are adding the mouthpiece mode. EPAP cannot be maintained
for patients who use open NIV system, and is indeed rarely, if ever, necessary for
these patients. Apnea alarms, when present, should be set at the highest threshold
to avoid unnecessary activation and discomfort. The most common ventilator mode
used is assisted volume- and pressure-controlled with no EPAP, low-pressure alarm
set to apnea minimum and maximum duration [8]. The specificities of MPV, such as
the intermittent disconnection of the patient and the presence of continuous leaks,
may thus represent a challenge for turbine-based home ventilators. There is a large
differences in the capacity of the different life-support ventilators to deal with the
rapidly changing respiratory load features that characterize MPV, which can be
further accentuated according to the choice of ventilator settings. It is always
necessary to carefully monitor the patient during the adaption phase since MPV
requires true collaboration from the patient, and not all ventilators ensure rapid
adaption to the patient's respiratory acts [8]. However, due to its specific features and
disadvantages (air leaks, etc.), MPV must be managed by expert hands and well-
monitored. The use of MPV is likely limited to a few centres, for the longest time
required to adapt and monitor the patient. In summary, the mouthpiece is a
preferable and comfortable alternative to NIV, but a more active participation is
needed compared to the use of traditional masks.

IN WHAT DISEASES?
Data in literature confirmed the useful of MPV. Bédard and McKim recently
studied utilization of daytime mouthpiece ventilation in an ALS population using 24-h
NIV. Results confirm the effectiveness of mouthpiece ventilation as well as the
importance of preserved bulbar function and ability to generate an adequate peak
cough flow with lung-volume recruitment for survival. The authors point out that
despite its effectiveness and convenience, mouthpiece ventilation is rarely used in
individuals with ALS needing continuous ventilatory support [9] Full-time NIV using
different interfaces has been previously reported, including in ALS. Bach et al.
reported NIV via the mouth in 257 subjects with neuromuscular diseases (5 with
ALS), of whom 144 used 24-h NIV (2 with ALS). With adequate bulbar muscle
function, mouthpiece ventilation was shown to be an effective alternative to
tracheostomy [10]. In patients showing poor NIV tolerance with oronasal and nasal
masks, mouthpiece ventilation should always be considered. In patients using NIV
many hours a day or in the case of skin lesions, eye irritation, or gastric distention,
mouthpiece ventilation should be also considered. The use of mouthpiece ventilation
combined with other interfaces leads to an improvement in quality of life and
adherence to NIV. The patient who uses ventilation even during the night can alter
an interface for sleeping and using MPV during the day; also patients with skin
lesions can benefit from using MPV.
Duchenne Muscular Distrophy
The use of mouthpiece ventilation in patients with Duchenne muscular dystrophy

is documented in literature. McKim et al. argue that twenty-four hours NIV should be
considered a safe alternative for patients with DMD because its use may obviate the
need for tracheostomy in patients with chronic respiratory failure requiring more than
nocturnal ventilation alone [11].
The authors examine the impact of diurnal mouthpiece intermittent positive
pressure ventilation and conclude that daytime mouthpiece ventilation is safe,
prolongs survival and stabilises vital capacity in Duchenne muscular dystrophy
patients. As time passes, patients with DMD develop a constant hypoventilation and
need respiratory support 24h a day; then, mouthpiece can be very valuable,
particularly in patients who use the NIV many hours a day and presenting skin
lesions, gastric distension or eye irritation, sometimes alternating nasal and full face
masks. It is useful also to promote adherence to NIV.

Myotonic Dystrophy
There are limited data on the use of MPV in patient with Steinert dystrophy.
Some authors described that it can be useful for Steinert patients (figure 1) who
previously rejected the application of NIV for tightness, claustrophobia and poor
compliance interface. The use of MPV has allowed us to treat patients who had
previously refused nasal, oral or oro-nasal interface [12].
Figure 1. Weaning from tracheostomy with the help of MPV in spinal muscular atrophy.
Other Neuromuscular Disease
Bach and others have reported a large number of patients with neuromuscular
diseases managed long beyond the point of respiratory failure with 24h NIV. Even
patients previously ventilated 24h per day via a tracheostomy have been converted
to non invasive mechanical ventilation with MPV [13]. Bach also describes non
invasive acute and long-term management of quadriplegia due to high spinal cord
lesions. This includes full-setting, continuous ventilatory support by non invasive
intermittent positive pressure ventilation to support inspiratory muscles and
mechanically assisted coughing to support inspiratory and expiratory muscles [13].
Bilateral diaphragmatic paralysis (BDP) is associated with dyspnoea that
worsens when the patient is recumbent, increased work of breathing and exercise
intolerance. With BDP progression, there is increasing ventilatory failure with
hypoxaemia and hypercapnia, which may further worsen due to atelectasis and
ventilation–perfusion mismatch. There are reports showing that MPV is a clinically
beneficial treatment to improve exercise tolerance and exercise-induced dyspnoea in
patients with BDP [14]. MPV can be useful for weaning from orotracheal tube or
tracheostomy (figure 1).

Intermittent Abdominal Compression Ventilation (IAPV)
IAPV consists of a corset with an elastic inflatable bladder that fits over the
abdomen. The bladder is attached by a hose to a ventilator that give up to 2.5 liter of
air to the bladder and, whereby, to the abdominal wall. This raises the diaphragm to
cause expiration below the functional residual capacity. Bach in 1990 described the
use of intermittent abdominal pressure ventilator, in ventilator-dependent traumatic
quadriplegic patients, spinal cord injury; non-Duchenne myopathy; Duchenne
muscular dystrophy; myelopathy, polymyositis, Friedreich’s ataxia, also employed for
long-term respiratory support. It was concluded that, in general, because of their
youth, intact mental status and bulbar musculature, and absence of obstructive lung
disease, patients with traumatic high level spinal cord injury are candidates to benefit
from these techniques. New models avoid clothing taking on the corset buckles and
are more comfortable. They are now lightweight, suitable, easy to done and fit and
employ velcro for fastening [15]. The following IAPV parameters can be set:
Pressure inside the bladder, Tinsp (real inspiratory time when the diaphragm moves
down), frequency (respiratory rate), and Rise Time (time to inflate the bladder). The
IAPV only works efficiently when a patient is in sitting position at an angle of 30° or
greater and is optimal at 75°. IAPV is described in patient with a post-ischemic
cervical myelopathy with success. IAPV can be used in patients who require NIV
many hours a day. Patients with gastric distension may benefit from the abdominal
compression exerted by the device during the exhalation phase. Also IAPV should be
considered for patients with chronic disease who need to start NIV; it is helpful to
promote a positive approach to NIV.
CONCLUSION
The mouthpiece should always be considered for patients with neuromuscular

disease that has to start NIV; it is useful to promote a positive approach and rapid
acceptance of the new condition. The mouthpiece ventilation should be considered
for patients poorly tolerant to NIV and particularly in patients who use the NIV many
hours a day and presenting skin lesion, gastric distension or eye irritation, sometimes
alternating with the nasal or full face mask; it is used also in weaning from
tracheostomy tube. Mouthpiece ventilation must be always considered as a possible
option. The clinician needs to know in deep details the patient’s ventilator to properly
set the parameters. The existence of a dedicated mode simplifies the setting but in
fact, the interface can be used with most of the ventilators. The use of MPV, alone or
combined with other interfaces improves the quality of neuromuscular patient’s life
and promotes greater adherence to mechanical ventilation.

Key Messages
1 MPV must be always considered as a possible options alone or combined

with other interfaces
2 The use of MPV improve the quality of neuromuscular patient’s life and
promote adherence to mechanical ventilation
3 MPV should be considered for patients poorly tolerant to NIV and particularly
in patients who use NIV many hours a day and presenting skin lesion, gastric
distension or eye irritation
4 MPV is useful also in weaning from tracheostomy tube
5 MPV and IAPV are preferable and comfortable alternative to NIV, but a more
active participation is needed compared to the use of traditional masks
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and complementary techniques in patients with neuromuscular disease: A brief
clinical review and update. Chron. Respir. Dis., 2017; 14(2):187 - 193.
doi:10.1177/1479972316674411.
[2] Fiorentino, G., Annunziata, A., Gaeta, A. M., Lanza, M., Esquinas, A.
Continuous noninvasive ventilation for respiratory failure in patients with
amyotrophic lateral sclerosis: Current perspectives. Degener. Neurol.
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[3] Garuti, G., Nicolini, A., Grecchi, B., Lusuardi, M., Winck, J. C., Bach, J. R. Open
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2014; 20(4):211 - 218. doi:10.1016/j.rppneu.2014.03.004.
[4] Carlucci, A., Mattei, A., Rossi, V., Paracchini, Raineri, S. M., Gregoretti, C.
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Respir. Care, 2016; 61: 462 - 467.
[5] Ogna, A., Prigent, H., Falaize, L., Leroux, K., Santos, D., Vaugier, I., Orlikowski,
D., Lofaso, F. Bench evaluation of commercially available and newly developed
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894. doi: 10.1111/crj.12601. Epub 2017 Jan. 9. PMID: 28026119.
[6] Khirani, S., Ramirez, A., Delord, V., Leroux, K., Lofaso, F., Hautot, S. et al.
Evaluation of ventilators for mouthpiece ventilation in neuromuscular disease.
Respir. Care, 2014; 59: 1329 - 37.
[7] Nardi, J., Leroux, K., Orlikowski, D., Prigent, H., Lofaso, F. Home monitoring of
daytime mouthpiece ventilation effectiveness in patients with neuromuscular
disease. Chron. Respir. Dis., 2016; 13: 67 - 74.

[8] Fiorentino, Giuseppe, Esquinas, Antonio M. Home ventilator performances with

mouthpiece ventilation: Does resistance change effectiveness? Clin. Respir. J.,
2018 Apr.; 12(4):1765 - 1766, doi: 10.1111/crj.12676. Epub 2017 Aug. 6.
[9] Bédard, M. E., Douglas A., McKim, D. A. Daytime Mouthpiece for Continuous
Noninvasive Ventilation in Individuals with Amyotrophic Lateral Sclerosis.
Respir. Care, 2016; 61: 1341 - 1348.
[10] Bach, J. R., Alba, A. S., Saporito, L. R. Intermittent positive pressure ventilation
via the mouth as an alternative to tracheostomy for 257 ventilator users. Chest,
1993; 103: 174 - 182.
[11] McKim, D. A., Griller, N., LeBlanc, C., Woolnough, A., King, J. et al. Twenty-
four hour noninvasive ventilation in Duchenne muscular dystrophy: A safe
alternative to tracheostomy. Can. Respir. J., 2013; 20: 5 - 9.
[12] Annunziata, A., Fiorentino, G., Esquinas, A. Effect on lung function of
mounthpiece ventilation in Steinert disease. A case report. Acta Myol., 2017;
36(1):33 - 35.
[13] Bach, J. R., Alba, A. S. Intermittent abdominal pressure ventilator in a regimen
of noninvasive ventilatory support. Chest, 1991; 99(3):630 - 636. doi:10.1378/
chest.99.3.630.
[14] Koopman, M., Vanfleteren, L. E. G. W., Steijns, S., Wouters, E. F. M.,
Sprooten, R. Increased exercise tolerance using daytime mouthpiece
ventilation for patients with diaphragm paralysis. Breathe, (Sheff). 2017;
13(3):225 - 229. doi:10.1183/20734735.005817.
[15] Banfi, P. I., Volpato, E. and Bach, J. R. Efficacy of new intermittent abdominal
pressure ventilator for post-ischemic cervical myelopathy ventilatory
insufficiency. Multidiscip. Respir. Med., 14, 4 (2019). https://doi.org/10.1186/
s40248-019-0169-4.

Chapter 13
NONINVASIVE VENTILATION
Nanette C. Joyce
Clinical Physical Medicine and Rehabilitation,
Department of Physical Medicine and Rehabilitation,
University of California, Davis School of Medicine, CA, USA
ABSTRACT
Normal breathing depends on the intact function of the ventilator pump,

which consists of the central respiratory control centers, the bony rib cage, and
the muscles of breathing. In progressive neuromuscular diseases (NMDs), the
ventilator pump is often impaired due to characteristic muscle weakness with
contracture, stiffening the chest wall and increasing the work of breathing.
Respiratory failure, and, ultimately, death due to extra-parenchymal restrictive
lung disease with failure of the ventilator pump is a leading cause of mortality in
patients with NMDs.
INTRODUCTION
Breathing is an active, primarily involuntary process requiring work. Inspiration

occurs as the diaphragm and external intercostal muscles contract and expand the
thorax, causing the intrapulmonary pressure to decrease and pull air into the lungs.
After air exchange, quiet exhalation occurs passively from the recoil of the rib cage
and lung tissues, which increases intrapulmonary pressure, reversing airflow and
expelling CO2 laden air from the lungs. Normal breathing depends on the intact
function of the ventilator pump, which consists of the central respiratory control
centers, the bony rib cage, and the muscles of breathing. In progressive

Corresponding Author’s E-mail: ncjoyce@ucdavis.edu.

178 Nanette C. Joyce
neuromuscular diseases (NMDs), the ventilator pump is often impaired due to

characteristic muscle weakness with contracture, stiffening the chest wall and
increasing the work of breathing. There is a predictable pattern of progressive
respiratory compromise in NMDs:
 Early disease: Normal or near normal unassisted gas exchange.

 Mid-stage disease: Adequate daytime gas exchange with nocturnal
hypoventilation.
 Late disease: Chronic and/or acute respiratory failure requiring full-time
assisted ventilatory support.
Respiratory failure, and, ultimately, death due to extra-parenchymal restrictive

lung disease with failure of the ventilator pump is a leading cause of mortality in
patients with NMDs [1, 2]. Appropriate screening with timely intervention using
augmentative respiratory devices, such as non-invasive positive pressure ventilation
(NIV), can prevent complications and prolong life in those with compromised
respiratory system due to NMD [2–4].
WORK OF BREATHING AND NONINVASIVE VENTILATION
The work of breathing depends on both the elastic and viscous forces of the
chest wall and lung. With normal breathing less than 5% of total resting O2 is
consumed. In extra-parenchymal restrictive lung disease associated with NMD, the
work of breathing increases as the chest wall becomes increasingly rigid. Respiratory
failure results from several factors related to the increased work of breathing,
including:
 Respiratory muscle weakness and fatigue

 Alteration in respiratory system mechanics
 Impairment of the central control of respiration
Respiratory muscle weakness occurs because of abnormal neural input or

intrinsic muscle disease, as in amyotrophic lateral sclerosis and spinal muscular
atrophy or the muscular dystrophies, respectively. Weakness of the muscles of
inspiration (the diaphragm, intercostals, and accessory muscles) result in inadequate
thorax expansion with low volume inspirations. Resultant microatelectasis leads to
ventilation/perfusion mismatch and consequent hypoxemia. Compensatory
tachypnea, with smaller tidal volumes and inadequate passive exhalation,
exacerbates atelectasis and increases CO2 retention [4]. As muscle weakness and
fatigue progress hypoventilation and eventual hypercarbic respiratory failure occur.
Non-invasive positive pressure ventilation by augmenting the inspiratory effort,
achieving normal tidal volumes, and reducing the work of breathing slows the

Noninvasive Ventilation 179
progression of restrictive lung disease, supports more normal respiratory function,

and prolongs life in NMD patients.
BENEFITS OF NONINVASIVE VENTILATION
Benefits ascribed to the use of assisted ventilation in patients with NMD are
numerous and include reduced PaCO2 and increased PaO2, decreased symptoms of
respiratory failure, improved daytime fatigue, improved quality of life, and reduced
morbidity and mortality. Nocturnal ventilation has become a widely accepted clinical
practice, providing ventilatory assistance for patients while sleeping, and allowing
them to breathe on their own during the day [5-9].
During periods of mechanical ventilation, there is a significant reduction in
diaphragm and accessory muscle electromyographic activity [10-11]. This likely
signifies a decrease in the work of breathing and a reduction of oxygen consumed by
the respiratory muscles. It has been suggested that nighttime ventilation rests
fatigued respiratory muscles, allowing improved daytime function [12]. In one study,
daytime inspiratory muscle endurance was noted to increase 3 months after initiation
of nighttime ventilation [13].
There also appears to be a reversing of the adverse effects of chronic NMD on
respiratory system mechanics [14]. Improvements in lung and chest wall compliance,
increases in resting lung volumes, and a decrease in the work of breathing have
been reported [8, 15] in patients with NMD after NIV [12, 14].
In addition to improvement in arterial blood gases, other measures of physiologic
function have been shown to improve with intermittent ventilation. Hoeppner and
colleagues showed increases in vital capacity, reduction in erythrocytosis, and
improvement in right-sided heart failure following nighttime ventilation, with changes
maintained during a mean follow-up period of 3.4 years [14].
ASSESSING NEED FOR NONINVASIVE VENTILATION
The aim of respiratory care in NMD is to allow timely prevention and

management of respiratory complications. Pulmonary assessment should be
performed frequently enough to provide early identification for need of non-invasive
ventilation. Symptoms and signs of nocturnal hypoventilation include complaints of
air hunger, snoring, choking, orthopnea, cyanosis, restlessness, insomnia, daytime
hypersomnolence, morning headaches, drowsiness, fatigue, depression, and
impaired cognition.16 Patient’s reporting these symptoms should be evaluated for
sleep disordered breathing and the possible need for NIV.
Respiratory screening with spirometry is recommended every 3-6 months, or at
every appointment, depending on the aggressiveness of decline from the underlying
NMD (ALS every 3 months, DMD every 6 months, etc.). Spirometry can be reliably

performed in children between the ages of 4-6 years. For infants and children who
are not able to perform spirometry, polysomnography or a nocturnal pulse oximetry
study should be performed to assess respiratory function. Documented
hypoventilation with Sp02 equal to or less than 88% on nocturnal pulse oximetry for 5
minutes or more provides reason to initiate NIV. No single screening test of
respiratory muscle strength can accurately predict the development of nocturnal
hypoventilation in NMDs. Multiple modalities testing has been shown to be the most
effective strategy (see table) [17-18]. Maximal inspiratory pressure (MIP), maximal
expiratory pressure (MEP), and forced vital capacity (FVC) have been used as
measures of respiratory strength. Testing in the supine position eliminates the effects
of gravity and may be a better marker of diaphragmatic strength. Several studies
have identified sniff nasal inspiratory pressure (SNIP) as a consistent measure with
good prognostic value [19-20]. In the setting of Duchenne muscular dystrophy
(DMD), FVC values have no ability to predict nocturnal elevation in end-tidal CO2
[21]. Instead, a forced expiratory volume in 1 second (FEV1) of less than 40%
predicted, a PaCO2 45 mm Hg or greater, and a base excess greater than 4 mmol/L
are factors that indicate the development of sleep disordered breathing and should
lead to the initiation of NIV [17].
Table 1.
Key indicators for initiating NIV

FVC 50% predicted or below Supine or seated
FEV1 40% predicted or below Supine or seated
MIP -60 cmH20 Supine or seated
SNIP - 40cmH20 Supine or seated
Base excess 4 mmol/L or more
PaCO2 45mmHg or more
Nocturnal pulse oximetry SpO2 less than 88% for 5
minutes or more
Polysomnography Sleep disordered breathing
[17, 22].
NONINVASIVE VENTILATION BASICS
Noninvasive ventilation was first used in the 1950s to allow polio patients time
out of the iron lung. Use of NIV is now a standard of care intervention for many
NMDs. NIV is strongly supported and has been used with excellent results in a wide
range of patients [17, 22, 23-25]. Those who require only nocturnal ventilatory
support may be particularly suitable candidates for this form of therapy, however,
successful progression to 24-hour use is becoming commonplace in those requiring
daytime ventilation who are uninterested in tracheostomy and mechanical ventilation
[26].

The most common NIV device used is a bilevel positive airway pressure device
(BiPAP). A BiPAP has two pressure settings that control the positive airflow pressure
from the machine during inspiration and expiration. The inspiratory positive airway
pressure (IPAP) setting provides the pressure of airflow to augment inspiration. The
expiratory positive airway pressure (EPAP) is set to maintain airway patency during
exhalation. One of the goals in treating restrictive lung disease of NMD is to reach a
widespan pressure support (10cmH20 or greater). Pressure support (PS) is
calculated as the pressure difference between the IPAP and EPAP. A lower EPAP
(4-6cmH20) allows the patient with a rigid chest wall and reduced chest recoil to
adequately exhale over the EPAP. CO2 retention may occur with an EPAP setting
that is too high. The gold standard is to perform polysomnography to determine
appropriate settings.
Airflow is provided from the machine through a tube to a mask interface that is
worn by the patient. There are many mask interfaces including nasal masks, nasal
pillow masks, full face masks, mouth piece masks and total face masks. Finding a
comfortable mask interface can be a challenge and if not actively sought can
interfere with successful transition to use of the BiPAP. Patient comfort and fit, to
reduce unintentional leak (air that leaks out from around the mask interface), should
be the primary considerations for mask choice.
Standard BiPAP devices provide static IPAP and EPAP support. Newer devices
provide self-adjusting pressures. They offer volume assured pressures (VAPS) and
adjust to changes in a patients’ respiratory flow to maintain alveolar ventilation
(Respironics, average VAPS- AVAPS and Resmed, intelligent VAPS – iVAPS). A
study assessing iVAPS showed this technology to be more comfortable for patients
than standard BiPAP, making the transition to use more successful [27-29].
VAP machines require settings that include an IPAP minimum and maximum,
EPAP, a tidal volume (Vt) and a back-up respiratory rate. Tidal volumes are weight-
based, and can be safely set between 6ml/kg in early disease to 10ml/kg in late
disease, when patients begin to experience shortness of breath while using their
device. Some have auto-titrating EPAP to help achieve upper airway patency in
patients with hypotonic upper airways (Respironics AVAPS-AE) [30].
There are three commonly used modes: Spontaneous, Spontaneous timed (ST),
and Pressure control (PC). Standard BiPAP uses spontaneous mode, where the
inspiratory flow is triggered and sustained throughout an inspiratory effort. No back-
up respiratory rate is provided and is best used in patients with unaltering normal
respiratory rates. ST mode is paired with VAP therapy. In this mode, a back-up
respiratory rate is required and if not met by spontaneous breathing, will provide a
machine delivered breath. The machine triggered breath in ST mode has a
programmed inspiratory time (Ti) but the spontaneous breath does not. PC mode
also provides spontaneously triggered and machine triggered breaths, however, the
programmed Ti is applied to both the spontaneous and machine triggered breaths.
This equalizes Ti between spontaneous and machine triggered breaths, preventing
shallow breathing [31]. The choice between VAPS-ST and PC mode should be
determined by patient tolerance and evidence of successful treatment of

hypoventilation. Additional settings can be used to maximize patient comfort and

improve compliance by addressing synchrony between the patient’s respirations and
machine delivered breaths. They include:
 Ramp – A comfort setting that starts the BiPAP at a lower IPAP setting when
turned on and gradually increases to goal IPAP over a specified amount of
time.
 Trigger sensitivity – A setting that determines the amount of inspiratory flow
required to trigger IPAP.
 Rise time – The amount of time taken to reach IPAP within an inspiration.
Unintentional leak around the mask interface is problematic. When leak occurs,
the BiPAP increases airflow to ensure it reaches the target IPAP. Patients report this
as a negative experience due to the large volume of air being delivered. Leak may
cause oxyhemoglobin desaturation, elevation of arterial CO2, and associated
symptoms. In this situation, the use of a chin strap or full oral-facial mask interface
may be appropriate [32].
It has been suggested that the use of noninvasive positive pressure devices be
avoided in patients with coexisting severe lung disease when secretions may be a
problem; who are obtunded or uncooperative; when poor oropharyngeal muscle
strength is present and secretions cannot be handled effectively; who have
uncontrolled seizure disorders; with orthopedic conditions that interfere with
placement of the devices; an in acute respiratory failure associated with Guillain-
Barre Syndrome [33]. These represent relative instead of absolute contraindications,
and experienced practitioners and motivated patients may still be able to use NIV,
even in these situations.
ENSURING ADEQUATE VENTILATION OVERTIME
Initiating NIV should begin a cycle of determining adequate BiPAP settings,

ongoing assessment of respiratory function with spirometry, interrogation of the
bilevel device with downloads of stored parameters of patient use, and re-evaluation
of the adequacy of settings. Due to the progressive nature of NMD, patients
eventually fail to be supported by their initial and subsequent BiPAP settings. The
necessary rate of assessment and adjustment is determined by the underlying
disease process and can be patient specific. In slowly progressive NMD a
polysomnograph yearly may be adequate to manage NIV. In ALS, however, using
polysomnography is not practical and in-home nocturnal pulse oximetry testing after
changes are made to settings, provides a more nibble strategy for assessing and
adjusting NIV due to progressive hypoventilation.
Inevitably, many patients with NMD-related restrictive lung disease will require
increasing respiratory support. As the patient begins to experience shortness of

breath during the daytime they are better served by a battery-operated volume-
cycled ventilator that allows for continued access to the community. The newer
ventilators offer similar, if not the same, bilevel settings as a BiPAP and can be
carried in a backpack on the patient’s wheelchair.
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[15] Szeinberg A, Tabachnik E, Rashed N, et al. Cough capacity in patients
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[18] Lechtzin N, Scott Y, Busse A, et al. Early use of non-invasive ventilation
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when to use and when to avoid. Curr. Opin. Crit. Care. 2016 Apr;22(2):94-99.

Chapter 14
CONTINUOUS NONINVASIVE VENTILATOR SUPPORT
Fabrizio Rao1,2,, Marino Iatomasi3 and Lucia Greco1

1
NeMO Clinical Centre, Milano, Italy
2
NeMO Clinical Centre, Arenzano, Genova, Italy
3
Fisiocare Sagl, Lugano, Switzerland
ABSTRACT
In asymptomatic neuromuscular patients the primary cause of

hypoventilation seems to be an imbalance between a reduced muscular force
and the elastic load imposed on the respiratory system that therefore causes a
respiratory drive mechanical modification necessary to reduce dyspnoea
symptoms that involve the RSB onset that eventually causes a PaCO2 increase.
Nocturnal hypercapnia, frequently associated with respiratory sleeping disorders
and daily normocapnia possibly associated to daily symptoms such as morning
cephalalgy and hypersomnia in spontaneous breathing patients: these
symptoms, associated to the nocturnal exams, establish the beginning of
nocturnal NIV in election.
Consider daily NIV when paCO2 > 45 mm Hg, despite optimization of
nocturne NIV or daily dyspnoea symptoms persist; evaluate different interfaces to
prevent skin lesions; evaluate different ventilation sistems like MPV, IACP; pay
attention to warning signs to switch to invasive ventilation.
Keywords: long-term non invasive ventilation, neuromuscular disease, respiratory

failure, mouthpiece ventilation

Corresponding Author’s E-mail: fabrizio.rao@centrocliniconemo.it.

188 Fabrizio Rao, Marino Latomasi and Lucia Greco
INTRODUCTION
Historical Background
Since the ‘60s the medical institution tried to propose to patients with alveolar
hypoventilation effective methods to bring ventilation back to a normal range and
also tried to promote a greater long-term survival.
At first, especially with post poliomyelitis syndromes, they used the so-called
“iron lung,” an instrument that applied a negative pressure directly on the patient’s
chest to facilitate the chest’s expansion and thus the daily and nocturnal
hypoventilation correction.
Together with the “iron lung,” in 1957 the first portable ventilator was put on the
market and the introduction of this instrument enabled the management at home of
patients mechanically ventilated with a tracheostomy [1].
In 1985 Fischer observed that among 146 patients affected by poliomyelitis or by
restrictive lung disease due to kyphoscoliosis, 75% requested ventilator assistance
and among these 52% had a tracheostomy [2].
During the ‘70s and especially during the ‘80s a ventilator method close to what
we use now started to be developed: positive ventilator methods with the use of oral
masks, especially with DMD patients at late stages of the disease.
Indeed during those years, a portion of the population started to have the
possibility to access continuous positive pressure ventilation, both daily and
nocturnal, with home ventilators, and thus they experienced life expectancy
extension [3].
J. Bach took the next step in 1986 by managing to make progresses with
instruments and experiences very different from today: he ventilated 5 patients who
already had a positive pressure home ventilator but he substituted their oral masks
with nasal ones that up to then had only been used for CPAP.
This breakthrough, that opened the doors to the current respiratory failure
management, occurred because these 5 patients, that up to then had been ventilated
twenty-four hours a day with a non invasive oral mask, needed dental care [1].
Following this turning point there was an increase in the use and experience with
this non invasive positive pressure ventilation that was indeed refined.
Currently, we face an increase of information on ventilation instructions and
recommendations on settings together with the increase of different types of
applications that are possible thanks to the constant ventilator and masks’
technological refinement and the growth of available clinical models.
Important is an historical note on two techniques that nowadays may be used for
the care of patients affected by daily respiratory failure: the pneumobelt and the
mouthpiece ventilation (MPV).
The pneumobelt, a rubber bladder that is inflated and deflated by a positive
pressure ventilator, was used and documented for the first time in 1959 [4], even
though since then it rarely has been used or studied.

Continuous Noninvasive Ventilator Support 189
As for the MPV, this is a technique that has been used for quite some time now
and that has been more studied and used compared to the pneumobelt.
During the last years this technique was subjected to a technological
development thanks to the progress of specific software that facilitate its settings and
thus the patient’s adjustment, simplifying its use.
Pathophysiology
Neuromuscular diseases are characterized, with differential prognosis, by

common clinical aspects such as muscular weakness that can show different
progressions and can affect the inspiratory, expiratory and/or pharyngolaryngeal
muscles.
As the disease progresses patients affected by neuromuscular diseases are
more predisposed to recurrent acute respiratory events, usually caused by inhalation
episodes that determine recurrent infections and lower respiratory tract ateletactis
that can residue causing a significant implication of the lung-chest system
compliance [7].
The neuromuscular patient’s hypoventilation paradigm, following a chronological
order, has been known for some time now:
 Nocturnal hypercapnia, frequently associated with respiratory sleeping

disorders and daily normocapnia possibly associated to daily symptoms such
as morning cephalalgy and hypersomnia in spontaneous breathing patients:
these symptoms, associated to the nocturnal exams, establish the beginning
of nocturnal NIV in election [5].
 Nocturnal and daily hypercapnia in non-ventilated patients: in DMD patients
this condition, if not treated, induces a median survival of 9,7 months [6].
There are three important elements that seem to promote alveolar

hypoventilation and thus an accumulation of CO2 in blood beyond 45 mmHg:
 Imbalance between generated muscular force and lung-chest elastic load;

 Reaching the muscular fatigue threshold;
 Alteration of the respiratory drive functioning [7].
These three elements seem to interact causing a modification in the

neuromuscular patient’s respiratory pattern.
Among a group of asymptomatic patients affected by different types of
neuromuscular diseases Misuri and colleagues [8] demonstrated that the
physiological index that has the major direct correlation with the PaCO2 variations is
Eldyn (%Ppl).

Moreover, in this study group, a Ti and Vt reduction was observed as well as an

RSBI index increase while Ve remained normal. Vt, Ti and Ppl showed to be
inversely proportional to PaCO2.
In conclusion, the authors demonstrated how in asymptomatic neuromuscular
patients the primary cause of hypoventilation seems to be an imbalance between a
reduced muscular force and the elastic load imposed on the respiratory system that
therefore causes a respiratory drive mechanical modification necessary to reduce
dyspnoea symptoms that involve the RSB onset that eventually causes a PaCO2
increase.
Toussaint and colleagues in 2008 [9] confirmed Misuri’s data on the mechanism
of progressive onset of alveolar hypoventilation in asymptomatic neuromuscular
patients, but in addition they studied a group of patients more compromised and thus
showing daily hypercapnia.
Among the group of daily hypercapnic patients the respiratory pattern resulting
from RR and RSBI showed to be identical to the one of nocturnal hypercapnic
patients, demonstrating how once this mechanism sets on it does not modify
anymore.
Comparing the group of nocturnal hypercapnic patients with the group of daily
hypercapnic patients Toussaint study showed how the mechanics between the two
groups is similar and how the mostly predictive parameter for daily hypercapnia
onset is the VC < 680 mL reduction with ROC = 0,97 [CI 95% 0,90-0,99].
In conclusion, in more severe patients the parameter that best causes and
predicts the daily hypercapnia onset is the VC time reduction, caused by the
progressive muscle weakness, and not the drive alteration and the respiratory
pattern modification that by then already seems to be altered.
In paediatric neuromuscular patients there is instead a substantial difference in
mechanisms that cause hyoventilation.
In adult patients the elastic load increase is due to the VC progressive reduction
and thus to micro- ateletactis with consequent CI reduction and rib cage stiffening
that causes chest wall compliance (Ccw) decrease.
Differently, in paediatric patients, between 3 months and 4 years of age, there is
at least twice an increase of Ccw in comparison to healthy patients.
The Ccw increase, considering the same muscular strength of an adult, produces
a rib cage deformation during Vt with a consequent diaphragmatic mechanical
inefficacy increase and thus a WOB growth with consequent alveolar hypoventilation
onset [10, 11].
Moreover, in neuromuscular paediatric patients aged between 6 and 18 at least a
four-time TTImus increase compared to normal values of daily hypercapnic patients
has been demonstrated, healthy controls TTImus = 0,1+-0,06 vs neuromuscular
patients with daily respiratory failure TTImus = 0,44+-0,36 (TTImus = tension time
index inspiratory muscles, similar to TTIdi but measured not invasively trough the
equation Pi/Pimax*Ti/Ttot where Pi = 5*P0,1*Ti, it describes the muscular fatigue
threshold).

The authors have also verified that P0.1, the index representing the central drive
efficacy, has a significant difference between those who are developing a nocturnal
hypoventilation and healthy controls, difference that doesn’t seem to be significant
when comparing patients with nocturnal hypoventilation and those who have
developed daily respiratory failure [12].
Therefore, also in this study, the drive seems to be altered only during the first
respiratory failure stages while it stabilizes in later stages of the disease.
The TTImus increase in paediatric neuromuscular patients with daily respiratory
failure, associated with a significant reduction in vital capacity and in maximal
inspiratory pressure, demonstrates how with the disease progression the muscular
weakness, thus the lung volume reduction, the elastic load increase, and the
closeness to the muscular fatigue threshold of inspiratory muscles, causes daily
hypoventilation [12-13].
A particular group among neuromuscular diseases is represented by Myotonic
Dystrophies.
In 2015 Foussel and colleagues demonstrated a CO2 answer reduction in the
central drive in DM1 patients, a causal relationship among lung volume reduction,
hypercapnia, and hypoxemia in DM1 patients and in the same cohort the absence of
correlations among respiratory drive answer, lung volume and PaCO2.
Starting from there the authors assumed that in this specific type of
neuromuscular disorder, the respiratory drive alteration is responsible for both the
progressive muscular weakness and the daily hypoventilation onset, independently
from the muscular weakness and lung restriction severity.
It is not possible to establish a unidirectional causal link between daily
hypercapnia and reduction in the central drive answer, confirming the complexity in
these patients’ respiratory ventilation regulation mechanisms [14].
Long-Term Continuous NIV and Survival
Throughout the years non-invasive ventilation has demonstrated to be effective

in prolonging neuromuscular patients’ survival and thus in modifying the natural
history of those diseases in which progressive respiratory failure is the main death
cause [6, 16, 17, 18, 19].
Daily ventilation, by reducing the muscles’ load during ventilation, seems to
reduce daily hypoventilation, probably causing a better prognosis in the long-term.
Toussaint and colleagues [15] showed how in patients already using nocturnal
NIV, who developed daily dyspnoea and a daily pattern modification in terms of RR
increase, VC decrease and normal VE, a two-hour daily NIV use significantly
reduced, at the end of the day, the perceived dyspnoea and the fatigue threshold
measured through TT0,1 (=TTdi non-invasive surrogate) and the Tlim increase and
thus the inspiratory muscular endurance.
Noteworthy in this study is that, differently from parameters that describe
respiratory patterns, Pi max measured in the morning was the same as the one

measured in the evening, confirming its role as the main factor involved in daily
hypoventilation and confirming that what is mainly taken care by daily NIV is not
muscular force but its expression in time, that is respiratory muscular endurance.
The diseases in which survival extensions through continuous NIV use are
mainly studied are DMD, SMA and ALS.
A second important outcome in the evaluation of continuous NIV use efficacy on
long periods is the tracheostomy positioning timing in relation to the disease’s natural
history.
It must be underlined that survival or tracheostomy positioning timing are not
correlated only to NIV’s efficacy but may also be influenced by other factors. In case
of the tracheostomy positioning there are important cultural and health policy factors:
in Japan for example, differently from the United States of America, there is a high
percentage of tracheostomy positioning, also thanks to the economic and social
possibilities that the country offers; as for survival, when considering DMD patients, it
has been seen that the cardiology therapy optimization is one of the positive factors
for its extension.
A further important factor in optimizing respiratory management is the cough
assist treatment: Bach J.’s retrospective studies showed how the outcome
improvement is associated with a cohort of patients that not only is continuously
ventilated but, if in presence of an ineffective cough, has an optimization of the
secretions management through the use of manual and mechanical techniques and
through the use of a management model guided by an oximeter evaluation for an
early obstruction recognition [17].
In the 2016 Cochrane Review [16], on the basis of only the two available RCTs
by Bourke 2006 and Jackson 2001, Radunovic and colleagues concluded that NIV
use in ALS patients extends survival with an average of 48 days in comparison to
patients who do not use it.
This data seems even more significant if the patients with a major bulbar
involvement are excluded from the analysis, for which survival extends with an
average of 205 days in comparison to patients who receive standard care.
The group of patients with a severe bulbar involvement treated with NIV seems
not to have advantages in survival terms; despite this the indications are to treat
these patients with NIV because there is a quality of life improvement and a
respiratory disturbances reduction during sleep.
As for ALS patients, it must be noted how another factor that positively influences
survival is nutritional support and thus a percutaneous gastrostomy-positioning
proposal.
In case of DMD patients it has been demonstrated that NIV significantly improves
survival.
The1994 experimental prospective study by Vianello and colleagues [6] showed
that at 24 months the control group of DMD patients non-ventilated were all dead,
contrarily to those in the NIV group.
The 2011 retrospective observational study by Bach J. and Martinez D. [17],
conducted without a control group because it had been established that it is unethical

to not propose NIV to DMD patients, demonstrated instead that a cohort of 120
ventilated DMD patients reaches a median of 30,1 +- 6,1 years of age with
continuous NIV and with continuous 24-hours a day NIV use of 7,4+-6,1 years.
Moreover, in this retrospective population, 14 patients seem to have died
consequently to respiratory complications, 22 consequently to cardiology
complications and 17 consequently to other causes: this demonstrates how death
risk for respiratory complications in ventilated patients is reduced.
This data is confirmed by another prospective study conducted by Toussaint and
colleagues in 2006 [18] in which a population of 42 DMD subjects was followed
during time and underwent nocturnal and daily ventilation through MPV when daily
hypercapnia showed, despite the nocturnal NIV optimization.
In this study, that lasted 7 years, the population reached an average age of
32,5 +- 4,4 and 50% of patients survived throughout the study.
It must be highlighted how average survival in DMD patients before NIV
introduction was around the third decade of life.
Another category of patients that benefits from a progressive increase in NIV use
is SMA type 1.
This data is confirmed by Oskui and colleagues that in 2007 [19] conducted an
observational study on SMA1 patients that showed how the factors that are linked to
a longer survival are a NIV use > 16 h/day, the use of a cough assistant device and
the PEG positioning.
These three factors reduce death risk up to 70%, improving survival that shows
to be equal to an average of 7,5 months in patients that follow the disease’s natural
history with no therapeutic intervention and equal to an average of 24 months in
patients that use NIV, cough assistant devices and undergo PEG positioning.
Therefore, 2018 SMA guidelines [20] add among the pro-active non-sitter
respiratory recommendations, apart from manual and mechanical unblocking
techniques, the NIV adaptation in all asymptomatic patients that must be provided
with at least two types of masks to alternate in order to normalize gas exchanges,
reduce breathing work and prevent skin decubitus injuries.
INDICATIONS AND METHODS OF USE
Criteria to Start Daily NIV (Table 1)
There can be an indication for daily NIV with a progressive hour increase in case
of chronic patients and progressive deterioration following the natural history’s
respiratory functioning but there may also be a daily NIV indication with a sudden
hour increase, or a full-time introduction, in cases of acute patients that rapidly
worsen from a respiratory point of view.
Currently there are no certain and shared criteria on the neuromuscular diseases’
guidelines to establish the right timing to start daily ventilation in chronic cases [21],

even though a 2007 study by Toussaint and colleagues [9] on a population of DMD
patients showed that a VC < 680 mL, a MIP < 22 cmH2O and a Vt/VC > 33% predict
daily hypercapnia.
As for chronic patients, 2012 EFNS (European Federation of Neurological
Societies) guidelines for ALS patients [22] establish the indications for nocturnal NIV
but do not specify anything on daily NIV.
Also the 2009 American Academy of Neurology’ guidelines [23] are very detailed
when explaining the criteria necessary to start nocturnal NIV and report its efficacy
on survival but however they do not specify criteria on daily NIV, its use and methods
to verify its efficacy or optimization.
Concerning DMD patients, the latest 2018 Care Considerations [24] remind us
that often patients start using NIV during daytime on their own but they however add
criteria for the beginning of daily NIV, other than those for nocturnal NIV, that are
quite precise:
 If despite nocturnal NIV use, daily SpO2 < 95%

 If despite nocturnal NIV use, daily PaCO2 > 45 mmHg
 If despite nocturnal NIV use, daily dyspnoea symptoms persist
Table 1.
Criteria for daily NIV:

 Acute/subacute patient 1. Acute respiratory event:
o Pneumonia
o Hypercapnic/Hypoxemic ARF (Bach 1987)
o EPA
2. Minor surgery procedures:
o PEG/RIG
o RMN
o Minor cardiac surgery
3. Post-extubation after acute event and/or major surgery
 Chronic patient 1. Criteria to predict daily hypercapnia:
o VC < 680 mL
o MIP < 22 cmH2O
o Vt/VC > 33%
2. AAN/EFNS criteria for ALS:
o No criteria concerning daily NIV are currently
mentioned
3. 2018 Care Considerations 2018 criteria for DMD patients:
o Patient’s independent decision due to a perceived
dyspnea
o Daily SpO2 < 95% despite nocturnal NIV
o Daily PaCO2 > 45 mmHg despite nocturnal NIV
o Perceived daily dyspnea despite nocturnal NIV
These indications are based mainly on Bach and Toussaint’s studies previously
mentioned.

In addition, this document gives precise indications on the necessary instruments

to maintain a safe 24-hour NIV, thus the use of a nasal mask or of a MPV, indications
on the different types of bi-level or pressure-volume ventilators, it recommends the
use of an ambu balloon and of a back-up electric current source and the possible
presence of a nurse during the night hours.
Regarding those patients who show a rapid respiratory deterioration not due to
the disease’s natural progression and thus need immediately a continuous NIV, the
causes and therefore the indications may be:
 Acute respiratory event in a ventilated/non-ventilated patient such as

pneumonia
 Necessity to support the patient during minor diagnostic or interventional
surgery such as PEG/RIG positioning that may cause a respiratory
depression due to the to use of hypno-inducing or morphine agents
 Necessities to support patients that are extubated after an acute event or that
undergo major surgery from a respiratory point of view.
In these cases the daily NIV introduction doesn’t necessarily mean that it will be
used also after the acute event is solved, it twill therefore be necessary to monitor
the patient’s progress to evaluate the eventuality of a ventilator support reduction in
terms of hours or its termination if the patient was not ventilated previously to the
acute event.
Not by chance the DMD Care Considerations [24] advise the anaesthetist to
evaluate patients pre-surgery but especially they advice a NIV training previously to
the surgery and its use after for those who show a FVC < 50% and they advice
against the use of oxygen during post-surgery stages in absence of non invasive
ventilation.
The patients’ respiratory functioning evaluation, the classification within his/her
clinical history and the evaluation of the patient’s clinical circumstances determine
the choice of using daily ventilation, what type of instruments to use and what type of
monitoring to evaluate efficacy in time.
Necessary Instruments and Settings
Through the use of daily ventilation we want to achieve the following goals:
 Ventilation normalization and thus maintenance of PaCO2, PaO2 and pH

normality ranges
 A reduction in perceived daily dyspnoea
 Possibility to phone without perceiving dyspnoea or without increasing the
voice tone
 Possibility to orally feed without perceiving dyspnoea

To achieve these goals there are a set of instruments that must be available and
that must be managed correctly:
Ventilator
The definition of ventilator-dependent patient changes from country to country,
mainly it is defined as who uses NIV more than 16 or 20 hours a day. For those who
are ventilator-dependent it is suggested to use two pressure-volume ventilators with
internal batteries and alarms.
The presence of an internal battery allows the patient to be independent while
moving in and out of the house.
The alarm setting, mainly for disconnection and for VE or Vt reduction, is
necessary to guarantee the patient’s safety while on a continuous ventilation at
home.
The possibility to set more than one ventilator program, with in addition different
configurations in terms of ventilating modalities and circuits, allows to specifically
ventilate patients according to their daily needs such as speaking, sleeping, doing
air-stacking exercises, coughing.
The majority of these ventilators have also the possibility to set a ventilation
program specific for MPV that results easier to use for the clinician.
Finally by now all ventilators are equipped with a memory card to download
clinical and adherence data [25].
Ventilation Modality and Circuit

It has been demonstrated how a unique ventilation modality does not exist,
pressure vs volume or assisted vs pressure support, higher in terms of alveolar
ventilation improvement, muscular fatigue or survival reduction.
The pressure-controlled ventilation’s benefit is the loss compensation and a
higher perceived comfort that results especially useful during the night.
The volume-controlled ventilation’s benefit is the possibility to do air stacking and
to better compensate the possible presence of obstructions or apnoea.
It has also been demonstrated how there is no support efficacy ventilation
difference between a simple circuit and one with a valve.
To summarise what concerns nocturnal ventilation, the optimal choice seems to
be the use of a simple circuit with a ventilated mask, in light of the demonstrated
efficacy and in light of the larger range of this type of mask choice in comparison to
the non-ventilated masks.
Also, with regard to the daily ventilation there is freedom of choice on the
ventilation modalities and using a simple circuit with a ventilated mask seems
efficient and convenient [25, 26].
Interfaces (Figure 1)
There are many different models on the market, mainly ventilated types. This big
variety allows an interface rotation that prevents decubitus injuries in patients using
NIV many hours a day or even all day long.

Different types of masks can solve different problems: oro-nasal or facial masks
optimize ventilation in extremely fatigued patients during an acute event or in patients
who use a nasal mask and have strong air losses, while nasal masks allow patients
who use NIV 24 hours-a-day and have a preserved bulbar function to talk while using
NIV in a clear and intelligible way.
Figure 1. Interfaces.
Daily NIV with a nasal mask in patients who have preserved bulbar functioning
allows, other than to rotate and prevent decubitus injuries, to have a ventilator
support in those patients who perceived dyspnoea while eating [25, 26, 27, 28].
Alternative Daily Ventilation Systems

MPV system (Figure 2): specific kits produced and composed by a circuit, fittings,
angled mouthpiece and pipe holder are on the market.
Modern pressure-volume ventilators allow a specific ventilation program for MPV
with some benefits compared to the past: the possibility to use a simple circuit, the
possibility to set PEEP = 0 cmH2O and the alarm optimization that intervenes only in
case of the patient’s actual disconnection.
MPV ventilation requires the patient’s collaboration and ad adequate bulbar
functioning and it allows the reduction of decubitus injuries as well as the opportunity
to speak and eat comfortably [25, 26, 27, 28].
Pneumobelt system: it is composed by a valve circuit, an elastic bladder and a
corset that maintains position.
The benefit of a system not having face supports is that it allows a ventilation
care very similar to physiological ventilation through a negative pressure inspiration.
The elastic bladder on the patient’s abdomen allows the viscera and diaphragm
descent, generating negative pressure.
The ventilator inflates and deflates the bladder: when the ventilator, during the
inspiratory phase, inflates the bladder, there is an external pressure on the viscera
that causes the expiratory phase; when the ventilator is instead in the expiratory
phase the bladder is deflated and the patient passively breaths consequently to the
diaphragm fall down.
Generally an assisted pressometric modality is used or alternatively one
controlled by relatively high pressures (i.e., between 30 and 50 H2O), based on the
patient’s weight and with a time cycling in which the inspiratory time set is actually
the patient’s expiratory time (reversed cycle).

Figure 2. MPV.
This technique is applicable and effective with a sitting or a semi-sitting patient

and is instead difficult to apply in patients with a big abdominal muscular mass or
with patients who have a deviated spine.
Its use has been ideated exclusively for daily hours; the patient’s adaptation to
this technique is difficult because it requires passive ventilation and expertise.
Monitoring
There are many indications regarding nocturnal NIV efficacy’s monitoring while
concerning daily NIV there are less.
The effectiveness criteria mainly used for nocturnal NIV are the following:
maintenance during daily NIV of Vt = 6-8 mL/Kg, oxygen saturation >95%,
TpCO2 < 45 mmHg.
The recommended follow-up, and thus NIV efficacy’s long-term monitoring in
ventilator-dependent patients, is every three months [25, 26, 28].
From the memory card’s download you can verify the main ventilation
parameters such as adherence and therefore you can verify an eventual increase of
ventilation hours or a non-adherence to therapeutic indications, the presence of
excessive and unintentional air loss both during daily and nocturnal NIV or the
average Vt.
Tele-Monitoring
In the past years tele-monitoring methods have been developed: the possibility to
download remotely clinical data obtained by the ventilator and/or by the oximeter or
by other monitoring instruments.
The first step in monitoring is the ventilator’s memory card download during the
patient’s follow-up visit.
There is a higher complexity and technological level that allows the ventilator that
may be integrated with an oximeter registration system to send in real time the
registered signals.

The main ventilator producers have created software platforms that allow not
only remote monitoring but also the parameters’ monitoring with a real time
verification of the patient’s ventilation pattern [25, 26, 28].
The Caregiver’s Home Management

Before the discharge of a ventilator-dependent patient the caregiver must
undergo training in order to be able to manage both daily routine and respiratory
acute events.
To achieve this goal the caregiver must be provided with written or multimedia
educational material regarding ventilation home management.
It is also necessary to give to the patient a resuscitator ambu bag in case of a
technological adverse event or in case of respiratory acute events [25, 26, 28].
TWENTY-FOUR HOUR VENTILATION LIMITS

AND TRANSITION TO INVASIVE VENTILATION
It has been demonstrated that among the main neuromuscular diseases NIV
extends survival but can also have limits therefore it is necessary to discuss with the
patient the possibility of a transition to invasive ventilation.
ALS guidelines [23] suggest an invasive ventilation proposal when NIV doesn’t
guarantee anymore a SpO2>90%, a PaCO2<50 mmhg or the secretions’
management.
In ALS patients it has actually been demonstrated that bulbar involvement and
disease’s rate of progression are the main aspects in limiting NIV and unblocking
techniques’ efficacy and thus negatively influencing survival [29, 30].
In this category of patients it seems that those who mostly choose to transit to
invasive ventilation are young men with children.
The category of ALS patients that instead seems to be less inclined to transit to
invasive ventilation is the one composed by NIV long survival women with bulbar
involvement [28, 30].
Regarding DMD patients, the guidelines establish that these are the following
criteria for an invasive ventilation transition: the patient’s choice, impossibility to
further maintain NIV, three failed extubations during an acute event despite an
optimal NIV use and an optimal unblocking technique management or
ineffectiveness in preventing secretions’ aspiration or saliva because of weak bulbar
muscles [24].
Key Messages
1. Consider daily NIV when paCO2 > 45 mm Hg, despite optimization of

nocturne NIV or daily dyspnoea symptoms persist.

2. Evaluate different interfaces to prevent skin lesions

3. Evaluate different ventilation systems like MPV, IACP
4. Pay attention to warning signs to swicth to invasive ventilation
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Chapter 15
RISK OF UNSUCCESSFUL NON-INVASIVE

VENTILATION IN NEUROMUSCULAR PATIENTS
Paola Pierucci*, MD, Andrea Portacci, MD

and Carla Santomasi, MD
Cardio Thoracic department, Respiratory ad Sleep medicine Unit, Bari Policlinic.
“Aldo Moro” University School of medicine, Bari, Italy
ABSTRACT
Non-invasive mechanical ventilation has been shown to be a fundamental

tool for the treatment of the respiratory failure in neuromuscular diseases (NMDs)
patients, both in acute and chronic settings. However, the complications related
to NIV failure are within important causes of death in NMDs patients. Its use in
the acute setting allows to improve gas exchange and the ventilatory dynamic,
reduces dyspnoea and respiratory load, avoiding intubation in many cases. As
for the chronic setting, non-invasive ventilation is helpful in order to postpone
tracheostomy and endotracheal intubation; moreover, it allows to improve not
only gas exchange and symptoms, but survival and quality of life and sleep.
However, many conditions can lead to a loss of NIV effectiveness and to NIV
failure. Identifying this conditions is necessary in order to ensure the best use
and results of NIV. This chapter focus on this topic with reference not just to the
reasons and timing of NIV failure, but also to the predictive factors of such failure
describing possible consequences and therapeutic alternatives both in the acute
and chronic setting.
*
Corresponding Author’s E-mail: paola.pierucci@policlinico.ba.it.

204 Paola Pierucci, Andrea Portacci and Carla Santomasi
NIV FAILURE IN THE ACUTE SETTING
Introduction
Nowadays, non-invasive mechanical ventilation (NIV) is widely used for the

management of acute and chronic respiratory failure in patients affected by restrictive
chest diseases (RCD). However, there is not yet unanimous scientific consensus
about its indication of use. In regards to NIV use in neuro-muscular diseases
(NMDs), its failure is of fundamental importance for the catastrophic consequences
which can lead it to. In this chapter the failure of NIV in patients affected by NMDs
will be addressed in details, with particular reference to the timing and reasons both
in the acute and in the chronic setting.
Indeed, the use of NIV in the patient with NMDs has the purpose of improving
respiratory gas exchanges, ventilatory mechanics and dynamics, reducing the
sensation of dyspnoea and respiratory load. In the event of an acute respiratory
failure (ARF) among the most important indications for its use there is the acute
respiratory acidosis, tachypnoea, acute dyspnoea, respiratory infections and the FVC
reduction below 1 litre or 50% of the predicted value or 30% depending on different
NMDs diseases [2, 3, 4]. While the correct timing of onset of NIV is fundamental for
improving the prognosis of patients with NMDs, on the other hand it is equally
important to identify the characteristics of those patients who have a higher
probability of NIV failure. This approach may allow clinician to avoid time waste and
to consider an early endo-tracheal intubation (ETI) and invasive mechanical
ventilation (IMV) use.
Definition
The failure of NIV is usually defined as its inability to resolve an episode of ARF
needing to resort to ETI. There are many pathophysiological factors that may
contribute to NIV failure in patients with NMDs, defining a complex clinical scenario
that often requires the strict interaction between various figures: specialists
physicians, nurses, respiratory dedicated physiotherapists, care givers, and home
care providers.
Timing
The failure of NIV may occur across different timing as many different causes
may contribute to its development. Nava and colleagues defined three different
moments for the onset of NIV failure: immediate failure (up to the first hour of NIV
trial), early failure (from 1 h to 48 h) and late failure (after 48 h). This distinction has
important clinical implications, since every moment is characterized by different

Risk of Unsuccessful Non-Invasive Ventilation in Neuromuscular Patients 205
pathophysiological features and, consequently, by different clinical and therapeutical

actions strategies [5].
 Immediate failure: it occurs within the first minutes of NIV trial and can the
result of inability to remove excessive secretions, NIV intolerance, altered
mental status or patient-ventilator asynchrony. Up to 15% of NIV trials end
with an immediate failure.
 Early failure: this period covers from the first hour to 48 h of NIV. About 65%
of NIV failures take place during the first 48 hours. Reasons for early NIV
failure are multiple: inability to improve gas exchange, respiratory rate
(RR)>25 breaths/min, higher severity scores, presence of multiorgan failure
or sepsis.
 Late failure: 15% of NIV failures occurs after 48h of ventilation. Possible risk
factors are related to delay in the NIV start, the lack of experience of the
medical staff, decrease of NIV compliance, sleep disturbances, poor clinical
status or progression of the acute disease.[5]
Reasons for Failure
 Inability to correct ABG parameters: Several studies used blood gas

parameters (pH, PaCO2, P/F ratio) as predictors for NIV failure. An
interesting comparison study between patients diagnosed with COPD vs
patients with ARF secondary to other diseases (including patients with
NMDs), highlighted how the inability to correct hypercapnia during a 1 hour
NIV trial is considered as risk factor for NIV failure [6]. This aspect can have
multiple explanations: incorrect ventilatory parameter setting, poor
experience of healthcare professionals in managing patients with NMDs,
poor secretion management, insufficient functional muscle reserve to ensure
adequate ventilation/minute with the same in-expiratory pressures.
 Correct choice of Interface: The choice of the correct interface in hypercapnic
ARF secondary to NMDs remains a crucial point in the management of such
patients and one of the main risk factors for NIV failure. Currently various
options of ventilatory interfaces are available (i.e., nasal, oronasal, full face,
total face, nasal pillows, helmet, mouthpiece etc.), each one with peculiar
characteristics and with specific methods of use [7]. Although there is no
univocal scientific evidence on which is the best interface to be used in the
acute setting for patients with ARF [8, 9], it is possible to identify strategies
for the best management of NIV masks, in order to reduce the risk of NIV
failure [10]. In patients with ARF, the main symptom is represented by
dyspnoea and respiratory fatigue, with consequent compensation via mouth-
breathing; therefore, in these cases, although alternative options may be
considered, it would be preferable to start NIV trial with an oronasal, full-face

mask, or a total-face mask [7, 8, 11] or, if available, with the helmet [12].
Alternatively, if the patient is intolerant or claustrophobic, a good alternative
to consider could be the nasal mask with a chinstrap, in order to minimizing
oral leaks or mouthpiece [13, 14]. However, it is important to remember that
nasal mask do not allow to achieve very high pressure delivered for
discomfort related problems. The choice of the most correct type of interface
must consider the anatomy of the patient’s face, the level of patients’ comfort
in wearing it and during ventilation and the patient’s breathing pattern [6].
 Mask pressure ulcers: ulcers formation is a major issue related to NIV use
and a crucial factor promoting NIV failure [15]. Ulcers and skin lesions can be
avoided using some conservative strategies and matching the proper type of
mask according to patient’s face features. When choosing interfaces, the
clinician must pay close attention not only to the face anatomy of the patient,
but also to patient’s comfort preferences, in order to achieve the best NIV
compliance [6]. In addition, skin lesions formation may be related to other risk
factors such as dehydration, steroid therapies, vascular diseases, diabetes,
malnutrition, presence of other prior skin lesions or previous skin diseases.
They may act as predisposing factors, increasing the risk of mask intolerance
[6]. This problem may be avoided or improved via the use of skin protections;
for instance, hydrocolloid, foam or gel sheets which can be easily shaped
according to mask’s design. They are essential to prevent skin lesions in NIV
trials, as they create a soft cushion layer between the patient’s skin and the
mask, allowing a more uniform distribution of the mask points of pressure on
patient’s face [16].
 Interface rotation: it is a strategy for the prevention of face pressure ulcers
which consists of mask switching during prolonged period of NIV to avoid
using the same type of interface. This technique guaranties a periodic
change of the pressure points on patient’s face, increasing relief and,
consequently, NIV compliance [17]. The use of alternative different masks
can be achieved only with a close cooperation between the specialist
physician, the nurse and the physiotherapist whom after the correct mask
choice manage masks change during the hospitalization.
 Air leaks: Leak management as a central role for achieving adequate tidal
volumes and effective intra-alveolar pressure during NIV. While on the one
hand it is necessary to ensure that the mask is as close as possible to the
patient’s face, on the other hand it must be taken into account that excessive
pressure may lead to the formation of facial ulcers and a consequent lower
NIV tolerance. This problem can be solved by obtaining a fair compromise
between interface adherence and acceptable leaks, considering the
possibility of leaks compensation guaranteed by the ventilator [18]; it will also
be possible to adopt strategies that envisage an increase of the pressure
support (PS) values or of the target volume even with greater air leaks, as
long as the relationship between adequate tidal volume and patient comfort is
preserved [19]. Air leak management is also fundamental for the avoidance

of excessive noises and eye irritation; the former interferes mainly during
nocturnal ventilation causing sudden awakenings and ineffective sleep, the
latter can cause conjunctivitis and eye dryness [20]. In this regard, a proper
mask refitting can correct the problem and improve NIV tolerance; eye
dryness can also be solved with the use of artificial tears [7].
 Patient-machine asynchrony: the achievement of a proper interaction
between patient and ventilator is essential for a correct use of the NIV.
Therefore, minimizing asynchronies is one of the target to be reached by
clinicians who really want to tailor a correct ventilation to their patient. The
presence of asynchronies during a NIV trial has been related to the increase
of mortality rate, a longer hospitalization (especially in ICU) and an increased
rate of tracheostomy [21]. A worst patient-ventilator interaction leads to an
improper support for patient’s ventilatory needs, increasing NIV discomfort
and reducing NIV compliance. About the correction of asynchronies, the
clinician has to take into account the pathophysiological mechanism of the
ARF, choosing carefully ventilatory parameters (PS, inspiratory time, triggers,
raise time) and correcting air leaks (to avoid auto-triggers). Modern
ventilators have specific NIV algorithms which have shown to be more
performing in a non-invasive setting, ensuring better air leaks compensation
and ameliorated patient-ventilator synchrony compared to other types of ICU
ventilators [22]. In addition to this, some studies confirmed an important role
of neurally adjusted ventilatory assist (NAVA) in achieving a better patient-
ventilator synchrony and compliance; the use of this ventilatory mode has
shown good reliability in patient with ARF, reducing asynchronies with the
use of face mask or helmet compared to standard pressure support modes
[23, 24]. However, to our knowledge, no specific studies about management
of patients with ARF due to NMDs with NAVA have been made.
 Sedation: patients with ARF often show mental alterations such as anxiety,
agitation, delirium and other psychotic disruptions [25]. Moreover, it is well
known that patients with NMDs suffer from depression with a frequent high
level of anxiety and stress [26]. All these factors can negatively contribute to
NIV adaptation leading to NIV failure; therefore sedation is sometimes
necessary to achieve a better NIV compliance. Despite all these reasons,
sedation is unfrequently used in acute settings during NIV trials. One
possible explanation can be found in the lack of experience using sedative
drugs and the potential worsening the ARF in patients with NMD; moreover,
clinicians often fear hemodynamic and neurological side effects of these
drugs, avoiding their use or limiting it to the minimum [27]. Another reason
could be the absence of a standardized protocol in the scientific literature,
leading to an uneven use of sedatives in terms of type, posology and
methods of administration [27]. Among the large amount of sedative drugs
available, Midazolam, Remifentanil and Dexmedetomidine are frequently
chosen to treat acute mental alterations during NIV.

o Midazolam: is one of the most used drug among benzodiazepines. It is

administered usually intravenous or intramuscular, with a half-life ranging
from 1,5 to 2,5 hours. Most of his anxiolytic, relaxing and sedative effects
are related to the interaction with GABA receptors. Regarding its side
effects, the most common are hemodynamic (hypotension, tachycardia),
respiratory (drive suppression with respiratory depression) and
neurological (anterograde amnesia, confusion, paradoxical aggression).
Moreover, a special mention is for vomiting, a class side effect of
benzodiazepines, which can cause inhalation during NIV. For all these
reason, Midazolam has to be used very carefully, especially in elderly
patients, with hepatic or renal impairment, starting with a low dose of
0,01-0,05 mg/kg and titrating it according to clinical response. If
respiratory depression occurs, the use of the antidote flumazenil can be
considered [28].
o Remifentanil: is an opioid with µ-selectivity; it induces a rapid onset
sedation with a half-life time of 8-10 min. The Remifentanil titration is
achieved starting with a dose of 0,05-0,1 mcg/Kg/min, using a Target
Controlled Infusion (TCI), which ensures a controlled administration of
this drug and a careful titration with progressive increases of the [29].
Even if Remifentanil does not require an adjustment of the dose in
patients with hepatic or renal failure, it can cause hypotension,
bradycardia, muscle stiffness and respiratory depression [30, 31].
Moreover, there are no studies about the use of this drug for a period
longer than three days in NIV sedation, so the use of Remifentanil for a
longer trial is not recommended. J.M. Constantin and colleagues have
shown how Remifentanil can be used in ICU settings to reach a better
NIV compliance [32]. In addition to this, the use of Remifentanil has been
studied during fiber-optic bronchoscopy (FOB) which sometimes of vital
importance to drain abundant secretion which may failure via the simple
use of local anaesthesia alone. FOB is an essential tool for secretions
management in acute settings, even during NIV and the use of
Remifentanil could guarantee a proper sedation for both purposes [33].
 Dexmedetomidine: is an α-receptor agonist used in ICU for its sedative and
analgesic properties. It has a half-life time of 2-3h with a stable steady state
concentration in patients with normal liver function. The starting dose of 1
mcg/Kg guarantees the onset of sedation in about 5-15 min, with a following
infusion rate of 0,2-0,7 mcg/Kg/hr [34]. Dexmedetomidine has minimal
depressive effect on respiratory drive, although can cause hypotension and
bradycardia, especially with the IV loading dose. In addition to this,
Dexmedetomidine can also lead to a reduction of oropharyngeal muscle tone
with consequent obstruction, so attention must be paid in case of
desaturation or hypoventilation [34]. In a randomized, prospective trial,
Senoglu and colleagues found that Dexmedetomidine has no relevant
differences compared to Midazolam for sedation in ICU ventilated patients

[35]. Furthermore, in another randomised, double blind pilot study, Devlin and
colleagues demonstrated that the administration of Dexmedetomidine,
compared with the intermittent use of Midazolam and Fentanyl, lead to a
reduction of delirium episodes and an higher NIV compliance in patients with
ARF, although the occurrence of more episodes of deep sedation [36].
Finally, Dexmetomidine has a potential use also during invasive procedures
such as FOB, with good level of light sedation, analgesia and safety
compared to Midazolam [37].Humidification: it is essential to use NIV with the
adequate humidification, in order to easily manage secretions clearance and
to achieve a better NIV tolerance, especially in patients with NMDs [14].
Despite that, the use of NIV with heat and moisture exchanger (HME) filters
or heated humidifiers (HH) in acute settings is still a matter of discussion.
Physiological studies shows that the use of HH instead of HME can cause a
reduction of the work of breathing, a better CO2 clearance and an
improvement of alveolar ventilation. Furthermore, HH seems to be useful to
reduce oral/nose dryness and to prevent bronchial hyper-reactivity caused by
ventilator dry gases [38, 39]. This features lead to a better NIV compliance
and acceptance by the patient, affecting positively on NIV success rate [40].
In the absence of important air leaks, HME and HH generates similar
amounts of humidity, while it has been demonstrated that, in presence of
more consistent air-leaks, there is a significative decrease of humidification
using HME filters [41, 14]. In contrast with these findings, Lellouche and
colleagues, in their real life trial, reported no differences in the intubation rate
due to NIV failure using HME or HH, without an improvement of CO2
elimination or mucosal dryness [41]. In summary, although the use of
humidification is highly recommended in patients with NMDs and ARF, there
are some concerns about which device is preferable to use and more studies
are needed to solve this problem.
 Sleep quality: one study focused on sleep alterations as a risk factor for NIV
failure; reduced REM sleep time and circadian sleep-cycle alterations are
associate to delirium occurrence and late NIV failure [42]. However, this
study was not focus on patients with NMDs; nevertheless, EEG
abnormalities, poor sleep quality and nocturnal obstructive events are
frequently found in NMDs and could be considered potential risk factors for
NIV failure, also in acute settings [43, 44].
 Secretions clearance: accumulation of respiratory secretions has a key role
in ARF secondary to NMDs and can lead to early NIV failure [45]. Despite
that, few data are available about the role of secretion clearance during a NIV
trial. FOB has been evaluated as a safe and potentially useful tool to remove
excessive secretions in ICUs. Its use allows clinicians not only to manage
mucus removal but also to obtain microbiological samples, which can be
useful to guide the antibiotic therapy in case of Ventilator Associated
Pneumonia (VAP). FOB has been evaluated in patients with hypoxemic ARF
requiring NIV resulting safe and feasible, with a lower rate of ETI after this

procedure [46]. Nevertheless is frequently required adjustment of ventilatory

parameters during FOB to provide the correct respiratory support to this kind
of patients [46]. Regarding non-invasive techniques, high-frequency chest
wall oscillation (HFCWO) and cough assistance with mechanical in-
exsufflation (MI-E) have been used in hyper secretive patients, allowing
better ventilation of dorsal regions of lungs [47]. HFCWO uses small tidal
volumes (up to 300 ml) at high frequencies, increasing secretions’ drainage
from distal to proximal airways and their subsequent removal by an aspiration
probe. HFCWO mechanisms of action have not been completely understood
but it seems to improve muco-ciliary clearance, expiratory flow and
viscoelastic properties of bronchial mucus. One of the main advantages of
HFCWO is the possibility to use it during NIV and regardless patient
collaboration, since this technique is independent from the ability of the
patient to generate an effective cough reflex [48]. MI-E devices apply a
positive inspiratory pressure followed by a rapid shift to a negative expiratory
pressure. The shift from one phase to the other can be made manually by the
physician or automatically. MI-E can be applied via oronasal mask or via
tracheostomy/endotracheal tube [49]. The use of MI-E in the acute setting
prevents late onset ventilatory failure related to ineffective secretions
clearance and reduces the need of FOB [50]. In patient with restrictive
pulmonary diseases undergoing extubation, a protocol using NIV and MI-E
has been proposed for un-weanable patients, avoiding tracheotomy and its
complications [51]. A similar result was reached in ALS non-bulbar patients;
the combination of continuous non-invasive ventilatory support (CNVS) and
MI-E prolonged intubation/tracheotomy avoidance up to 9 years or until the
onset of bulbar impairment [52]. MI-E can also positively affect breathing
pattern, reducing respiratory rate and rapid and shallow breathing. This effect
was shown in patients with Duchene Muscular Dystrophy (DMD) and
Amyotrophic Lateral Sclerosis (ALS) can be explained not only with the
augmented secretions clearance but also with the increase of stretch
receptor activation. It is hypothesized that the positive pressure applied
during a cycle of MI-E can elicits the Hering-Breuer inflation reflex, causing a
rapid decrease of RR [53].
NIV FAILURE IN THE CHRONIC SETTING
Introduction
Non-invasive ventilation (NIV) represents a fundamental tool that allows to

prolong survival, to improve symptoms, quality life and sleep of neuromuscular
patients also in the chronic setting [54, 55]. However, even in chronic setting it may
be burdened by the possibility of failure. Thus, it would negatively impact on the

clinical course of the disease. Therefore, this second part of the chapter will focus on
the major reasons that could lead to a failure of home chronic NIV in patients
affected by NMDs.
Timing for NIV Initiation
Despite the presence of guidelines, a lot of patients do not start NIV at the
suggested time within the disease course thus causing drop out from NIV treatment
and failure [56, 57, 58, 59]. Indeed, NIV should be applied early in the natural history
of NMDs and the previous recommendations [60, 61] to start NIV in case of
dyspnoea, respiratory muscle weakness symptoms, exacerbations or increased
pCO2 could be insufficient, because symptoms are insidious and pCO2 typically
rises belatedly in the natural history of NMDs when respiratory muscle impairment is
already established and advanced [54, 62]. Many studies have already demonstrated
that the anticipation of NIV onset can prolong survival and improve the quality life of
these patients [63, 64]. In fact, the most recent literature suggest that NIV should be
started earlier in case of symptoms of nocturnal hypoventilation and/or evidence of
nocturnal hypoventilation/significant nocturnal desaturation on overnight oximetry;
initial reduction of forced vital capacity predicted value (e.g., <80%), reduction of
maximum inspiratory pressure (e.g., MIP < 60 cmH20) or reduction of sniff nasal
pressure (e.g., SNIP < 40 cmH20). The reduction in three months of pulmonary
function tests (PFT), especially the decrease of more than 10 cmH20 of SNIP/MIP),
with respiratory weakness symptoms detection can represent another criteria [65,
66]. Great importance should be given to the timing of follow up for the respiratory
function tests in these fragile patients. Indeed for instance a 4 monthly visit should be
scheduled [65]. Furthermore, the maintenance of the same order of lung function
testing (LFT) should be provided to patients as respiratory muscle weakness may
occur in these patients during its performance disease related [67]. In regards to
LFT, a very important parameter for NIV initiation is represented by the reduction of
the forced vital capacity (FVC) compared to the theoretical value, because it appears
earlier in the course of the disease [54, 55, 63, 68]. A value of VC less than 50%
predicted was commonly used as an indication for NIV. However, more recently for
ALS disease patients it has been recommended to anticipate the NIV application to
FVC values ≤ 80% even in the absence of respiratory muscle weakness as yet. [54,
62, 64, 69]. Nocturnal hypoventilation (NH) anticipates daytime hypercapnia onset in
NM asymptomatic patients and it often represents the first sign of respiratory
impairment. Therefore, if left untreated may lead to faster disease deterioration, rapid
onset of hypercapnia and daytime symptoms. [54, 70, 71, 72].
To avoid a possible NIV failure it is important to identify the optimum moment for
NIV starting. Monitoring of different respiratory parameters pCO2, FVC, MIP, SNIP,
nocturnal SaO2, PFT, together with the assessment via LFT and respiratory muscle
testing over time of symptoms and signs of respiratory impairment (i.e., dyspnea,
tachypnea, orthopnea, disturbed sleep, morning headache, use of auxiliary

respiratory muscles at rest, paradoxical respiration, daytime fatigue, excessive

daytime sleepiness) allowing to identify the best timing to start and it ensures the
lower drop out and failure of NIV treatment.
The Choice of Interface
As already extensively discussed in the first part of the chapter, the wrong choice
of the interface may represent a vital problem during non-invasive ventilation in these
patients. Discomfort and unintentional leaks are the main causes of mask-related
NIV failure also in the chronic setting. It is, therefore, essential to remember that the
choice of a correct interface should be addressed addressing many factors (clinician
bias, costs, nasal problems, breathing pattern, capacity of maintain mouth seal,
patient’s physiognomy and preferences including psychological aspects) and
different strategies should be tried until the best fitting mask for patient is found [73].
Moreover, since has been demonstrated that the use of mouthpiece in NMD patients
who need to start NIV favours a better acceptance and compliance to NIV, the
mouthpiece should be always considered at a new start and in patients intolerant to
other interfaces [74].
Ventilator Setting
Different ventilation modes are often used in the settings of NIV for NM patients,
although some more frequently than others: pressure assisted ventilation (PSV),
pressure-controlled ventilation (PCV), spontaneous/time mode (S/T), volume
controlled ventilation, average volume-assured pressure support mode (AVAPS),
volume-targeted pressure-controlled ventilation (VTPCV) etc. [55, 73]. Currently
there is no consensus on the best ventilator setting and, since NMD are many,
different from each other and some very rare, the application of a default setting that
can fit all could result in the failure of NIV [75]. Indeed, the choice of a wrong setting
could be responsible for patient-ventilator asynchrony, poor comfort, persistence of
obstructive respiratory events with consequent NIV failure. To avoid this, it is very
important to set modes and parameters individualizing and tailoring them according
to the patients’ comfort and the underlying pathology. Examples of possible incorrect
setting are shown below with their results on NIV use.
 The Triggers: the inspiratory and the expiratory one. The wrong trigger
setting could be responsible for higher patients’ effort and for patient-
ventilator asynchrony. It is therefore important to set a trigger that can
minimize the patient’s effort allowing the patients to be best supported by the
machine during breathing, avoiding the onset of auto-triggering events when
too sensible[73].

 The rise time: is the time required by the machine to reach the maximal
inspiratory pressure set in the pressure modes. It should be modified
according to the patient’s comfort since too slow or too fast could be
responsible of patients’ discomfort [73].
 Elevated PEEP (positive end-expiratory pressure): Typically NM patients
have normal lungs parenchyma, therefore they do not require elevated PEEP
to compensate an intrinsic one, typical of obstructive disease patients, unless
a concomitant parenchymal disease occurs. The PEEP setting should be
therefore only considered in patients with concomitant sleep-obstructive
breathing disorders or obstructive lung diseases. Indeed, high levels of PEEP
may be responsible for patient’s intolerance, increased leaks, ineffective
efforts, central apnea and glottis closure. [55, 76, 77]
 Pressure support: To achieve adequate correction of the alveolar
hypoventilation the right level of pressure support must be set up. According
to the NIV initiation protocols, low levels of IPAP are used to start and then
they are gradually increased once the patient is adapted in order to
completely correct the present symptoms. Some patients, however, do not
tolerate the ideal PS levels and the IPAP is kept low in order to ensure
minimum ventilation with a greater risk of worsening respiratory failure [78].
Patient-Ventilator Asynchrony
The synchrony between patient’s breathing and the ventilator is crucial during
NIV. Asynchrony between patient and ventilator (PVA) is a mismatch between the
patient and the breathing pattern delivered by the ventilator. PVA are frequent events
in NIV and their presence is often associated with NIV failure, poor tolerance and
muscle damage [79]. The most common PVA are those related to triggering
(ineffective effort, auto-triggering, and double triggering), to cycling (premature or
delayed) and to flow (insufficient or excessive) [79, 80].
These events may be due patient’s related issues, ventilator’s related issues, or
both.
Patient Related Issues
1) Impaired respiratory drive: if the respiratory drive is reduced the ventilator

may not be able to respond to the weaker effort (ineffective efforts); if the
drive is increased the inspiration could be longer than the preset ventilator
inhalation time, causing the patient to breathe further (double triggering);
2) Altered respiratory mechanic: prolonged inspiratory time or weakness of the
respiratory muscles could lead to double triggering and ineffective efforts
respectively while a restrictive respiratory mechanic can lead to premature
cycling;

3) Pathological conditions: concomitant presence of sleep obstructive

respiratory events or patient’s anxiety, agitation and fear [80].
Ventilator Related Issues
1) Malfunctions or excessive sensitivity;

2) Unintentional leaks;
3) Condensation in the ventilator circuit;
4) Incorrect parameters setting;
5) Wrong Interfaces [80].
In regards to the unintentional leaks, they are the most important cause of PVA.
Indeed, leaks can interfere with patient-ventilator interaction in different phases of the
respiratory cycle. During the inspiratory phase they may primarily affect the trigger
causing auto-triggering; on the other hand, during the expiratory phase, they may
affect the cycling causing delayed cycling. The interfaces themselves, regardless of
the amount of leaks, may be responsible for patient ventilator asynchrony; in fact,
several studies have shown that patient-ventilator synchrony may vary depending on
the interface used. [81, 82, 83].
Therefore, in the presence of PVA the presence of leaks should be firstly
checked, then, in the absence of them or when they are small and correctly
compensate by the ventilator, the responsible mechanism of PVA should be
investigated and solved [84].
Residual Sleep Respiratory Events
During the night, residual sleep related respiratory events such as obstructive
apnoea /hypopnea (AH), central apnoea/hypopnea or patient-ventilator asynchrony
(PVA) may be responsible of NIV failure. They may compromise treatment efficacy,
comfort, sleep quality and adherence to NIV [85]. These events could be patient
related as the NMD progresses, ventilator related or from patient-ventilator
interaction.
First of all is important to analyze the events that arise from patients himself.
Sleep obstructive respiratory events in NM patients are usually due to facial and
airways muscles weakness, atrophy of the tongue with fasciculations and abnormal
corticobulbar reflexes, which can also be associated with high BMI in the initial
stages of ALS disease and macroglossia [62, 86].
Obstructive apnoea or hypopnea events can persist in case of unintentional leaks
and in case of insufficient positive pressure support which is not able to maintain the
patency of the upper airways. In some patients the use of a nasal mask can also lead
to worsening of apnoea and desaturation due to the the posterior movement of the
tongue which is displaced by the passage of air from the mouth [81]. The persistence
of obstructive events is correlated with PVA, poor prognosis and reduced survival

[87]. Central respiratory events, especially hypopneas, may also occur in these
patients and are the result of central neural instability in the control of breathing and
dysfunction of the upper motor neuron predominant at the bulbar level. [62, 63, 86,
88].
The NIV treatment itself could be responsible of some events which may
compromise NIV efficacy. For instance, NIV setting may leads to hyperventilation,
central apnoea or hypopnea as a result respiratory drive suppression. Similarly too
high support may induce glottic closure. [76]. Respiratory drive could also be
suppressed by the thoracic afferents feedbacks NIV induced.
It is important to underline that a good synchronism between patient and the
ventilator during the day does not necessarily reflects exactly what happens during
the night. Therefore, an adequate daytime setting may result in night-time PVA [77,
89]. This is usually related to the changes in the facial muscles weakness that occur
during sleep which can contribute to the onset of obstructive events or mask-leaks.
For this reason PVA must always be investigated during day and night. [85, 87, 90]
Therefore, if hypoventilation persists after leaks correction, respiratory
polysomnography with continuous CO2 monitoring (if not available overnight pulse
oximetry with continuous Co2 monitoring) is recommended to be performed to
identify the responsible mechanism during nocturnal NIV [61, 76].
Adherence to Non-Invasive Ventilation
NIV outcome is closely related to therapy adherence, especially in cases of

prolonged treatment. To avoid a NIV failure, at least in the initial stages, NIV must be
performed for an adequate number of hours. In addition to interface-related
discomfort, PVA and residual nocturnal events, various other socio-cultural,
behavioral, psychological and family factors can strongly influence adherence to
therapy. Sometimes, also the absence of symptoms at beginning of NIV may not
encourage the patient to use NIV correctly [91, 92].
Socioeconomic and cultural conditions influence the choice to start NIV, but also
the prosecution of a correct therapy. The different national health system can make
the difference especially in the case of families with a poor socioeconomic level. In
Italy, NIV and home support are provided free of charge and this favours the use of
ventilation regardless of the patient’s socio-economic context [81].
The diagnosis of a disease with very poor and short prognosis which rely on the
use of a ventilatory support for survival may lead to different behavioral and
important psychological consequences. Fear and embarrassment often affect the
patients’ behavior of those who refuse to use NIV and to carry ventilator out from the
house [91, 92]. The presence of anxiety and depression has been demonstrated in a
non-negligible percentage of patients affected by NMDs and specific
pharmacological and psychological support.
It is often required to allow greater compliance with NIV use. In this regards,
particular attention should be paid to the use of sedative and opioid drugs which

when used without caution and in a non-palliative context may worsen respiratory
impairment, sleep structure and daytime sleepiness [62, 91, 93].
A solid family and caregiver support have been proved to be a fundamental
factor for the NIV continuation because not only represents a practical help for the
patient in the management of it, but it is also a motivation and a purpose to move
forward [81, 91, 92]. However, NIV management responsibility together with the
progressive loss of independence and need of care of NMD patients can lead to a
worsening in the quality of life of family members and caregivers who are at high risk
of burnout [65].
The guidelines recommend that a good relationship should be established
between the doctor, the patient and the family. The need to initiate NIV should be
discussed extensively upstream with the patient and family member and care giver to
facilitate subsequent adherence; it further recommend that any psychological
consequences on the patient and his family should be identified and treated in time.
A multidisciplinary approach in the management of NIV in NM patients must
therefore always be considered. [65, 70].
Management of Secretion and Airflow Humidification
NIV capability of releasing volumes and pressures to achieve an adequate

ventilation is possible only if airways are clean and free from mucus and debris. NMD
patients, due to the weakness of the inspiratory, expiratory and glottis muscles, loose
the effective cough function and tend to accumulate secretions. The presence of
secretions during NIV results in reduced ventilation, lower ventilation/perfusion ratio
with the consequent risk of atelectasis and shunts, neutralizing the effectiveness of
NIV [54, 94]. As previously mentioned in the acute setting, the management of
respiratory secretions has a priority importance and allows to increase the NIV
effectiveness [65]. The combined use of secretion management techniques and non-
invasive mechanical ventilation have been shown to be effective in increasing the
survival of these patients [95].
Cough function can be assessed by performing PCF (the highest peak flow
obtained after performing a deep inspiration and forced cough maneuver), MIC (the
maximum volume of air that can be held in the lungs at glottides closed after
retaining several volumes of air following a deep inspiration), MEP (maximum
expiratory pressure) [54]. Values of PCF <270 l/min and MEP < 45 cmH20 suggest
the presence of ineffective cough and airway clearance techniques should be used
[54, 61, 94].
The first line of treatment involves manual assisted cough techniques. These
include an assisted inspiration through different modalities (glossopharyngeal
breathing, air stacking, application of positive pressure with self-inflating bag and
mask, positive pressures released by ventilator) and a forced expiration obtained by
pressing on the upper portion of the abdomen or the chest wall simultaneously with
the subject’s expiratory effort. In case cough remains ineffective, a mechanical

insufflator-exsufflator device, which provides cough assistance throughout the

respiratory cycle releasing a positive pressure in inspiration and a negative pressure
in expiration, must be considered. [61, 70, 96].
In physiological conditions the inspired air is heated and humidified by the upper
airways mucosa in order to allow optimal temperature of gas at the alveolar surface
and to avoid damage to the lung tissue. The humidification of the inspired air also
allows the fluidification of the airways secretions. The NIV use may cause the loss of
normal humidification and of the heating systems of the upper airways, due to high
inspiratory flow, high inspiratory oxygen fraction and air leaks from the mask. Dry air
inhalation results in nasal and throat dryness and alterations of the nasal mucosa
with local vasoconstriction which, especially in those patient who uses nasal mask
with mouth leaks, can increase nasal resistances [97, 98]. These factors strongly
contribute to reducing the patient’s tolerance to NIV. The absence of humidification in
these NM ventilated patients, predisposed also to retention of secretions, causes dry
and thickened secretions that tend to accumulate forming mucus plugs leading to
increased airway resistances, atelectasis, impaired gas exchange and respiratory
infections. All this factors create a vicious cycle that would nullify the NIV
effectiveness. The association with NIV and humidification systems allows to improve
patient comfort and obtain fluid secretions easier to expel [14, 99].
There is no clear indication which of the two humidification systems should be
preferred, the heated humidifier (HH) and passive humidification system through a
heat and moisture exchanger (HME).The choice depends on several factors like the
patient’s interface and the ventilator. Active humidification is more effective and does
not introduce additional dead space into the circuit, however it requires electricity and
is more bulky. The second, on the other hand, is less bulky however it increases
dead space and CO2 retention, increases airway resistance in case of excessive
secretions and could be ineffective if associated with excessive unintentional leaks
from the mask. A possible compromise could be the use of the passive system
during the day and the active one at night [73, 99].
Follow-Up
In order to try to avoid all these potential reasons for NIV failure, a close follow-
up is essential. It allows to check the correct use of ventilation and cough assist
devices by the patient and his caregiver, the state of the disease, adherence to
therapy, the presence of complications, the correct ventilator functionality and the
appropriateness of the ventilator parameters which should be periodically evaluated
[55, 70]. Furthermore, each patient should have an emergency number that they can
call at any time regarding NIV related problems [100].
In this context, it is important to underline that an increasing crucial role has been
played by telemedicine and tele-monitoring in recent years. These systems allow to
evaluate the NM patients remotely and several studies have shown their
effectiveness in preventing hospitalizations, urgent calls and in reducing healthcare

costs [55, 101]. Furthermore, studies conducted on NM patients have demonstrated

the patients’ ability to use these systems and their satisfaction [102]. Many ventilators
have the possibility to record different parameters, leaks, which can be periodically
re-evaluated. This allows the prescriber to evaluate the ventilation trend over a
period and make specific changes, if necessary. Other ventilators are also equipped
with a modem, which allows the direct access of the operator to the ventilator
remotely with the possibility to modify the parameters and to evaluate the response.
All these new technological systems represent a valid method for optimizing the
management of NIV at home and avoiding the NIV failure [73, 103].
CONCLUSION
In patients with NMDs respiratory failure may have an acute or chronic onset
leading to the use of NIV. Therefore the Failure of NIV may occur in a variety of
different situations. The most important reasons for its failure in the acute setting may
be summarize as following: Inability to correct ABG parameters, incorrect choice of
Interface, mask pressure ulcers, patient-machine asynchrony and incorrect
secretions clearance. On the other hand, reasons for NIV failure in the chronic
setting may be: the wrong choice of the interface, non-adequate ventilatory
parameters, the presence of PVA, residual sleep respiratory events, the poor
adherence to the therapy, the incorrect management of tracheobronchial secretions
and humidification. A close and constant follow-up of patients affected by NMDs
using NIV reduces the possibility of encountering these risks. Furthermore, the
emerging role of telemedicine and telemonitoring may enhances the possibility of
close follow up of these fragile patient to further avoid the onset of NIV failure.
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SECTION 3. MONITORING

Chapter 16
MONITORING AND SYNCHRONY

VENTILATOR PATIENTS
Mariano Alberto Pennisi* and Paolo De Santis

UOSD Trauma E Schock, Policlinico Gemelli Roma, Italy
ABSTRACT
Clinical parameters monitoring is fundamental during noninvasive ventilation

(NIV) in neuromuscolar diseases (NMD) patients.
The most relevant items of clinical monitoring are the compliance with the
interface, the assessment of swallowing and gastrointestinal function, the
evaluation of cough efficacy and the consciousness-sensorium evaluation and
delirium condition identification.
Assessment of the interface and NIV compliance is one of the most important
steps in NIV clinical monitoring. During NIV reduced tolerance to the interface is
associated with higher incidence of NIV failure and endotracheal intubation.
CLINICAL MONITORING
In NMD patients muscle weakness in the oropharyngeal area reduces ability to

close the mouth carrying difficulties in managing leaks; it also can cause NIV failure
in absence of a careful choice of the interface typology [1].
In relation to the different typology of interfaces, tolerance was poorest for the
mouthpiece followed by the nasal and oronasal masks [2].
Integrity of the mechanisms of airway protection is mandatory during NIV. In
NMD patients bulbar involvement exposes to the risk of recurrent aspiration. The
potential risk of inhalation can be assessed by a swallowing evaluation performed at
the bedside.
*
Correspondent Author’s E-mail: marianoalberto.pennisi@policlinicogemelli.it.

232 Mariano Alberto Pennisi and Paolo De Santis
NMD patients have a markedly disturbed gastrointestinal motor function and

abdominal distension is not infrequent during NIV. Gastroparesis and chronic
constipation can lead to life threatening gastric and small bowel dilatation. Monitoring
of gastric and/or intestinal distension in these patients is mandatory to avoid the risk
of complications during NIV [3].
Gastric distension induced by insufflation during NIV can cause diaphragm
displacement and consequently reduction of the respiratory system compliance with
necessity of higher pressure during ventilation. Choose of the correct interface in
terms of size and typology and reduction of ventilatory pressure are crucial to reduce
the gastric distension risk. Gastric drainage positioning must be considered in
selected cases.
Cough is impaired in NMD and therefore cough assisting is an important part of
the management of this condition. Monitoring of cough ability is a focal point in NMD
patients management.
An effective cough requires:
 adequate deep inspiration

 closure of the glottis
 contraction of the expiratory muscles to increase intrathoracic pressure
 abrupt opening of the glottis at the start of the expiratory phase to produce a
rapid, forceful flow of air from the lung.
In neuromuscolar diseases many factors are involved in cough impairment:
 inspiratory muscles weakness leading to a reduction of inspiratory volume

 expiratory muscles weakness reducing cough pressure
 bulbar weakness impairing the glottis closure.
Ineffective airway clearance is associated to the risk of atelectasis, respiratory

infections and consequently, hypoxemia. Use of cough support strategies can
prevent these complications.
Peak cough flow (PCF), vital capacity and maximal inspiratory and expiratory
pressures have been used to identify patients necessitating cough support strategies
and should be routinarly measured in NMD patients.
PCF measurement is the most important clinical parameter in terms of deciding
when cough support strategies must be started.
Measurement of PCF through the peak flow meter or through pneumotachograph
is a very simple system to evaluate maximum cough strength and predict secretion
clearance efficacy [4].
Adults require a peak expiratory cough flow of 160 L/min for an effective cough.
When routinely measured assisted PCFs are < 270 L/min, it has been reported that
PCF drops to values <160 L/min during chest infections and the risk of pneumonia
and respiratory failure increases greatly [5, 6].

Monitoring and Synchrony Ventilator Patients 233
Consciousness-sensorium evaluation during NIV is possible using score like the

Glasgow Coma Score (GCS) and the Kelly–Matthay score.
Abnormalities in sleep pattern are a common problem during mechanical
ventilation in NMD patients. Sleep quality can influence the risk of delirium.
Precocious identification of delirium is important because this condition is associated
with an elevated risk of NIV failure [7].
The use of validated instruments for delirium condition identification can be
helpful [8].
MONITORING OF GAS EXCHANGE
Pulse oximetry has become standard practice in monitoring oxygenation.

Measures to remove secretions should therefore be taken when SaO2 < 95%, or a 2–
3% drop in the patient’s individual best value occurs [9].
SaO2< 90% under optimal ventilation and after correct application of secretion
removal strategies indicates the need for additional oxygen supply.
In comparison to patients with lung disease, alveolar hypoventilation in
neuromuscolar patients is rarely accompanied with ventilation-perfusion alteration;
for this reason PaO2 values are relatively higher and it remains on the flat portion of
the oxyhaemoglobin dissociation curve. As a consequence, small decreases in PaO2
during alveolar hypoventilation are poorly reflected by changes in SpO2. This
explains why pulse oximetry in NMD patients is less sensitive for detecting alveolar
hypoventilation than in patients with lung disease. Adam Ogna and coll. [10] in a
study on 234 NMD patients underline the discordance between SpO2 recordings and
other methods to assess nocturnal hypoventilation in NMD patients.
Nardi and coll. [11] in a study on 58 NMD mechanically ventilated patients
demonstrated that nocturnal pulse oximetry used to assess the efficiency of MV was
not sufficient to exclude alveolar hypoventilation. About one third of the patients had
alveolar hypoventilation manifesting as high transcutaneous CO2 pressure (PTcCO2)
values without substantial oxygen desaturation. On the other hand, oxygen
desaturation without nocturnal hypercapnia was rare. Among the 34 patients with
normal PTcCO2 values only one patient had abnormal SpO2 values.
Respiratory polygraphy is generally used to detect nocturnal hypoventilation;
oxycapnography may also be used.
Blood gas analysis (day and night) or continuous overnight transcutaneous
measurement of CO2 (PTcCO2) are mandatory in monitoring ventilated patients.
Transcutaneous CO2 monitors are increasingly being employed. Current monitors, in
fact, are more accurate, easier to use than older devices. The PTcCO2 monitoring
can reduce number of arterial puncture. Compared to arterial PaCO2 measurements,
transcutaneous CO2 monitoring showed high agreement. PTcCO2 monitoring is a
useful trigger for arterial blood gas analysis. A synchronous blood gas analysis may
be advisable in cases of higher PTcCO2 values (⩾60 mmHg) [12].

For adults patients, nocturnal hypoventilation during sleep is defined as an

increase in the arterial PTcCO2 to a value > 55 mmHg for > 10 minutes, or a greater
than or equal to 10 mmHg increase in the arterial PTcCO2 relative to the awake
supine value, to a value exceeding 50 mmHg for 10 minutes or more [13, 14].
During NIV PTcCO2 monitoring is more reliable than end tidal CO2 for
noninvasive evaluation of PaCO2 level.
In a prospective observational cohort study in 25 spontaneously breathing
patients comparing PTcCO2 and EtCO2, Lermuzeaux M. and coll. [15] demonstrated
that transcutaneous partial pressure of carbon dioxide and PaCO2 were well
correlated (R = 0.97), whereas the correlation between EtCO2 and PaCO2 was poor
(R = 0.62).
Despite the interest of noninvasive strategies in the blood gas evaluation arterial
blood gas analysis (ABG) remains the gold standard for monitoring during NIV also in
NMD patients.
ABG gives also information about pH and offers the possibility of assessing
additional parameters such as haemoglobin and electrolytes. Blood samples are
normally taken via single arterial puncture. Subcutaneous anaesthetic infiltration
before arterial puncture may significantly reduce pain associated with arterial
puncture. Arterialised earlobe blood gas analysis compares very well with arterial
sampling and is sufficiently accurate to be reliably substitute for arterial sampling in
routine clinical practice [16].
Precocious identification of nocturnal hypoventilation is essential in the
management of NMD patients because, if not treated with NIV, this condition evolves
within 2 years into symptomatic daytime hypercapnia [17].
To prevent the deterioration of the respiratory function and the progression
toward daytime hypercapnia, home NIV in NMD patients is predominantly applied
during sleep time.
Nocturnal hypoventilation it is an accepted indication for initiation of non-invasive
ventilation, even if it is an under diagnosed condition. The most appropriate strategy
to identify sleep hypoventilation is not yet clearly defined. In clinical practice it is
indirectly assessed using nocturnal pulse oximetry and morning arterial blood gases.
TIDAL VOLUME
Monitoring of expiratory tidal volume (VTE) is crucial during NIV as this

parameter reflects the patient’s alveolar ventilation.
Expiratory tidal volume is directly measured by a proximal flow sensor on the
expiratory line in a double-limb circuit system. In vented circuits VTE is estimated
during a constant leak; however, these devices may perform less well when the
amount of leak varies. Estimation of leaks performed by ventilator software is less
precise when the leak increases. Non vented single limb circuit only provide
inspiratory tidal volume and cannot measure VTE.

The desirable VTE is usually calculated on the basis of ideal body weight and for
neuromuscular and restrictive chest wall disorders is 6 mL·kg−1.
AIR LEAKS
During NIV unintentional leaks are a common problem as a consequence of the

non-hermetic nature of the system. Leakage may be minimal when the patient is
awake, but during sleep leak can increase as a result of decreased muscle tone.
Intermittent obstruction of the upper airway is commonly observed during sleep in
NMD patients due to increased upper airways collapsibility and can cause an
increase in leaks.
Air leaks can be recognized by a fall in the pressure signal. A fall in positive
pressure (inspiratory and expiratory) indicates major unintentional leaks (ie, inability
of the ventilator to maintain the preset pressure in the ventilator circuit). The amount
of the leaks and the performance of the ventilator to compensate will determine the
entity of the pressure signal fall. This sign has a strong positive predictive value for
leaks, but a fall in the pressure signal in some cycles may also indicate a major
increase in patient effort.
Others signs are:
 amputation of the expiratory flow signal

 two-sloped aspect of the inspiratory flow curve with an initial rapid increase
followed by a slower increase in flow until cycling occurs
 increased inspiratory time in the case of flow cycling ventilatory modality
 decrease in belt signals
Air leaks may respond to the regulation of chin strap tension, change of the
interface, better mask adjustment, reduction of pressure assistant levels.
Crescimanno G. and coll. [18] in a study on eighteen NMD patients during
domiciliary ventilation investigated the relationships between patient ventilator
asynchronies and air leaks, sleep stages, and arousals or awakenings recorded
during polysomnography. In this study patient ventilator asynchronies had a low rate
of occurrence, but with an increase during home polysomnographies in comparison
to the hospital. The increase of patient ventilator asynchronies was correlated to an
increase in air leaks during home ventilation probably related to the attitude of the
patients to rearrange their mask to maximize comfort.
Leaks were not measured in the same way by all ventilator software.
Contal O e coll. [19] conducted a bench study comparing different home bilevel
ventilators to assess the reliability in leaks and Vt measurement provided by the
different home bilevel ventilators by comparing results with objective assessment on
a bench test. About leaks measurement one device estimated leaks only PEEP
results are thus misleading and cannot be compared with those of other devices;

furthermore, some devices subtract from their estimation of leaks the intentional
leaks expected for a given type of mask at a given pressure setting while others
report the sum of intentional and unintentional leaks. Caution needs to be used when
applying an oronasal mask because this could paradoxically worsen the upper
airway resistance. Performing nasal endoscopy during CPAP delivered by oronasal
mask is possible to document posterior displacement of the tongue causing
obstruction of the oropharyngeal airway [20]. The shift from oronasal to the nasal
interface may solve the problem. Nasal masks, in fact, producing a differential
pressure gradient between the nasopharynx and oropharynx, pushes the soft palate
and the tongue away from the posterior pharyngeal wall causing pneumatic splinting
of the airways [21].
ASYNCHRONIES
Clinicians generally try to provide assisted/supported ventilation instead of fully

controlled ventilation in NMD patient. Modes of partial ventilatory assistance, where a
patient’s breathing effort drives the ventilator, offer many clinical advantages:
 reduced need for sedation

 reduced risk of respiratory muscle atrophy
 improved oxygenation
 less haemodynamic impairment.
During NIV, the patient-ventilator interaction is an important clinical challenge. A

good interaction between patient effort and ventilator assistance is necessary to
avoid asynchronies-related problems. Asynchrony is present when a mismatch
between the neural (patient) and mechanically (ventilator) assisted breaths is present
and/or when flow delivered by mechanical ventilator is inadequate to match the
patient’s ventilatory flow request despite a matched inspiratory time.
There is an high prevalence of asynchrony in non-invasively ventilated patients.
Vignaux et al. [22] in a prospective multicenter observation on 60 patients (55%
hypercapnic) found an asynchrony index (defined as the total number of
asynchronies divided by the number of breaths) >10% in 43% of patients during NIV.
In this study level of pressure support and the magnitude of leaks were independent
predictive factors of severe asynchronies. Many studies demonstrated adverse
effects of asynchronies during mechanical ventilation.
Thille and coll. [23] in a study on 62 patients requiring mechanical ventilation for
more than 24 h demonstrated that one-fourth of patients exhibit a high incidence of
asynchrony (asinchrony index >10%) during assisted ventilation. Such a high
incidence is associated with a prolonged duration of mechanical ventilation. In this
study ineffective triggering occurence is more common during ventilation using
elevated ventilatory support levels.

Blanch L e coll. [24] conducted a prospective, observational study of 50 patients

admitted to intensive care unit equipped with a software detecting the asynchronies
and computing the asynchrony index (AI) for each hour. When authors compared
patients with AI > 10 vs AI ≤ 10%, they found similar reintubation and tracheostomy
rates but higher ICU and hospital mortality and a trend toward longer duration of MV
in patients with an AI > 10%.
Asynchronies during mechanical ventilation can affect hemodynamics. Variations
in intrathoracic pressure during mechanical ventilation impact on ventricular preload
and afterload, thereby affecting cardiac output. Hemodynamic effects are different in
relationship to the asynchrony typology: ineffective efforts can decrease intrathoracic
pressure, but double cycling can increase it.
Dedicated NIV ventilators allow better patient-ventilator synchrony than ICU
ventilators developed to function with a leak-free closed circuit. New ICU ventilators
are equipped with NIV algorithms (“NIV modes”) aiming to ameliorate
patients/ventilator synchrony with a reduction of the impact of leaks on the ventilator
performance. The NIV algorithm improves, at least slightly and with a wide variation
among ventilators, triggering and/or cycling off synchronization [25].
Patient-ventilator asynchrony are common in patients during long-term
domiciliary ventilation and are related to major problems like:
 patient discomfort and dyspnea

 nocturnal sleep disruption leaking to arousals
 ultrastructural injury of the respiratory muscles
Patient–ventilator asynchrony cannot be recognized by clinical inspection or

evaluating awake patient comfort and differently to hypoventilation and other
respiratory disorders during sleep, frequently is not associated with significant
changes in PTcCO2 or oxygen saturation [26].
Accurate assessment of patient-ventilator interactions requires measurements of
esophageal pressure and/or respiratory muscle electromyogram. Visual inspection of
airway pressure, volume and flow waveforms has been shown to correlate well with
esophageal-balloon readings, but is not without error [27, 28].
Nocturnal non-invasive ventilation in neuromuscular disease has been proposed
with the aims of normalizing nocturnal ventilation, improving sleep quality, avoiding
progression to daytime hypercapnia, and improving survival. But nocturnal ventilator
support itself may disturb sleep if air leaks or patient–ventilator asynchronies occurs.
Patients who require home NIV during sleep normally have the ventilation settings
adjusted empirically during daytime wakefulness. In stable patients with
neuromuscular disorders, the settings of NIV chosen on an empirical basis while the
patient is awake do not predict ventilator synchrony while asleep. Monitoring of
breathing during sleep, either with a cardio-respiratory polygraphy or a
polysomnography, is essential to identify patient ventilator asynchronies.
Fanfulla e coll. [29] tested in a randomly way in nine patients affected by chronic
respiratory failure or nocturnal hypoventilation due to neuromuscular disorder, two

different ventilatory setting modality: the usual, based on simple clinical parameters
and the physiological tailored to the patient's respiratory mechanics. In this study
noninvasive pressure support ventilation is effective in improving daytime ABG
parameters and in unloading inspiratory muscles independently of whether it is set
on the basis of clinical parameters or on the patient's respiratory mechanics.
However the physiological setting modality is associated with better sleep
architecture, improvement in night-time gas exchange and a reduction in ineffective
efforts.
INEFFECTIVE EFFORT
Ineffective efforts (also known as ineffective triggering, untriggered breaths, or

trigger asynchrony) are among the most common types of patient–ventilator
asynchrony during mechanical ventilation in patients with neuromuscular diseases.
The patient’s inspiratory effort fails to trigger the ventilator. Ineffective efforts may
result from:
 respiratory muscle weakness due to neuromuscolar disease

 dynamic hyperinflation
 uncorrected trigger threshold setting.
Traditionally ineffective efforts are associated to the obstructive lung disease due
to the threshold load imposed by the autoPEEP.
Nevertheless hyperinflation may be related to an incorrect ventilator setting
during mechanical ventilation. In pressure support ventilation the end of the
ventilator’s inflation cycle is not always synchronized with the end of the patient’s
inspiratory effort and, consequently, ventilator cycle extends into neural expiration
reducing the time available for expiratory flow. In this setting passive functional
residual capacity (FRC) is not reached due to the reduction of the expiratory phase
duration and dynamic hyperinflation can occur or worsen.
Dynamic hyperinflation makes difficult for the patient to trigger the ventilator
making the occurrence of ineffective breathing more likely. Fanfulla et al. [30] found
that the patients with recurrent ineffective breathing during sleep were those with the
highest level of inspiratory assistance and high respiratory rate, two conditions that
are commonly associated with dynamic hyperinflation.
Nevertheless the impact of the mechanic characteristics of the respiratory system
are not so relevant. Carlucci A and coll. [31] conducted a study on 69 stable patients
with chronic respiratory failure ready to be discharged with a home non-invasive
ventilatory program. Thirty percent of patients showed an asynchrony index >10%,
most of asynchronies are ineffective efforts (detected in 20% of patients).
Occurrence of asynchrony is not correlated to any variable of respiratory mechanics
recorded during spontaneous breathing and does not differ between patients with

obstructive or restrictive disease. In this study patients with a high incidence of

asynchronies has also a poorer tolerance of NIV.
During nocturnal NIV in NMD patients ineffective efforts occur predominantly in
the NREM sleep phase and are associated with increased arousals [18].
Ciorba C. and coll. [32] conducted an observational study to assess the
performance of ineffective efforts detection based on pressure and flow signals,
using esophageal pressure monitoring as the reference standard. Ineffective efforts
was detected as a decrease in airway pressure coinciding with a notch in the flow
curve, not resulting in inspiratory trigger activation. With the invasive method,
ineffective efforts was detected as a swing in esophageal pressure with no
inspiratory trigger activation.
Authors concluded that a careful inspection of the flow-time and pressure-time
tracings available on most ventilators is useful for ineffective efforts identification.
This method is easy to use, and requires no additional parameters than those
routinely recorded. Ineffective efforts can be detected as a decrease in airway
pressure (Paw) with a simultaneous drop in expiratory flow during expiration. In this
study in detecting ineffective efforts airway flow and pressure signals analysis had
good sensitivity and specificity as compared to the reference standard.
Nevertheless different conditions may mistaken for ineffective efforts using flow
and pressure curves detection like:
 cardiac contractions affecting both airway pressure and flow signals

 premature cycling of the ventilator
 upper airways obstruction during expiration
 delayed triggering of the ventilator
Adding to the pressure and volume curves examination pulse oximeter

plethysmography and /or electrocardiographic recordings may be helpful to identify
cardiac contractions affecting airway pressure and flow curves simulating ineffective
efforts.
Breathing pattern during wakefulness does not predict ventilatory asynchrony
while asleep. Fanfulla and coll. [29] demonstrated that during nocturnal ventilation
“usual” ventilator settings may be associated with poor synchrony, despite obtaining
improvement in gas-exchange, compared to unsupported breathing.
AUTOTRIGGERING
Autotrigger is also a common asynchrony in neuromuscular diseases as

documented in a study on asynchronies and sleep disruption in neuromuscular
patients [18]. Air leaks, water condensation, cardiac oscillations are the more
common causes of autotrigger during noninvasive ventilation. Auto-triggering occurs
more often with low respiratory drive and breathing frequency and when dynamic

hyperinflation is absent. Such factors allow zero flow for some time during expiration
before the next inspiration, making the system vulnerable to triggering from changes
of airway pressure not induced by patient inspiratory effort. Nevertheless, circuit
leaks may cause autotriggering even in patients with dynamic hyperinflation.
Autotriggering causes unwanted respiratory rate increases, hypocapnia,
hyperinflation, muscle deconditioning and patient discomfort. The absence of the
initial pressure drop below end-expiratory pressure at the beginnig of inspiratory
assistance is suggestive of autotriggering. With flow triggering systems, however, the
pressure drop before the mechanical breath may be minimal, making the signal less
clear. Triggering occurring synchronously with cardiogenic oscillations also suggests
autotriggered breaths. With pressure regulated ventilatory mode (PCV and PSV)
considerable variation in peak inspiratory flow or in the duration of mechanical
inspiration may be associated with autotriggered cycles. In fact, differently from
triggered breaths, during autotrigger episode the airway flow is product only by the
ventilator pushing and not by the association between patient muscles and ventilator
Strategies to prevent and correct auto-triggering are based on
 Minimize leaks
 Remove condensation from the circuit
 Make the trigger threshold less sensitive
During nocturnal noninvasive ventilation in NMD patients autotrigger occurs

mostly in NREM sleep and is usually associated with increased arousals [18].
CYCLING ASYNCHRONY
Other types of asynchrony are that have been reported as less common than
triggering asynchrony affecting approximately 5% of breaths in patients receiving
long-term home mechanical ventilation (HMV) [33].
Cycling asynchrony are distincted in:
 late cycling (mechanical inspiratory time > neural inspiratory time), the patient

may wish to exhale and the ventilator inappropriately continues to deliver an
inspiratory breath
 premature cycling (mechanical inspiratory time<neural inspiratory time) the
patient may wish to breathe in for an extended period of time and the
ventilator inappropriately cycles into expiration early
Prolonged insufflation due to late cycling is frequently associated with leaks

during pressure ventilation with flow cycled modality and may be more common with
volume guarantee ventilation. Is more common in NREM sleep but usually is not
associated with desaturations or arousals [13]. Strategies aiming to reduce leaks

(reduction of the pressure support levels, change of the interface) can correct late
cycling.
PATIENT VENTILATORY ASYNCHRONY AND SLEEP ALTERATION
Despite improvements in the delivery of ventilation, the incidence of patient

ventilatory asynchrony during domiciliary NIV remain high [33, 34]
Fanfulla and Coll [29] demonstrated in NMD patients receiving NIV an
association between the number of ineffective efforts observed and the time spent
overnight in REM sleep, suggesting that ineffective effort asynchrony may reduce
REM sleep. Whether patient ventilatory asynchrony is a marker or is the driver of
underlying sleep alterations is yet to be fully delucided. During sleep, the apneic
threshold for PaCO2 increases. Excessive ventilation inducing a reduction of the
PaCO2 level below this threshold cause central apneas that negatively influence
sleep especially in the absence of backup ventilation. Avoiding excessive levels of
assistance, especially during sleep, is very important to prevent sleep fragmentation
[35, 36]. IN NMD patients with chronic alveolar hypoventilation noninvasive positive
pressure titration with polysomnography is recommended to determine an effective
level of nocturnal ventilatory support. Neurological disfunction leading to pharyngeal
hypotonia, bulbar disfunction and structural anatomic alteration (macroglossia) can
cause in NMD patients obstructive sleep hypopnea/apnea. Increase the EPAP levels
in the case of obstructive apneas and increase of the IPAP levels for obstructive
hypopneas can help to correct these anomalies. Diaphragm and respiratory muscle
involvement in NMD patients often limits the identification of the precise etiology of
sleep-related breathing disorders leading to obstructive apneas misclassification as
central due to the inability of weak respiratory muscles to expand the chest or
abdomen in the presence of airways obstruction. Instability to control breathing in
relationship to diaphragm weakness and Cheyne- Stokes breathing in association
with cardiomyopathy are common cause of the sleep disturbance in NMD patients.
Monitoring of the mask pressure, flow rate, thoracic and abdominal movements,
and SpO2 are essential as a minimal prerequisite for tracing analysis. Other optional
signal monitoring are useful for a more detailed patient evaluation:
 monitoring of respiratory efforts using diaphragmatic electromyogram

 esophageal pressure
 pulse transit time
 supra-sternal notch pressure.
PtcCO2 monitoring provides information about alveolar ventilation but related to

the long time for PtcCO2 tracing modification give a little contribution for the analysis
of short respiratory events.

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SECTION 4. AIRWAYS AND CLEARANCE

Chapter 17
LARYNGEAL RESPONSE PATTERNS DURING NIV

AND MECHANICALLY ASSISTED COUGH
Tiina M. Andersen1,2,3,, PhD and Maria Vollsæter1,4,5, PhD

1
Norwegian Advisory Unit on Home Mechanical Ventilation,
Thoracic Department, Bergen, Norway
2
Department of Physiotherapy Haukeland University Hospital,
Bergen, Norway
3
The Faculty of Health and Social Sciences,
Western Norway University of Applied Sciences,
Bergen, Norway
4
Department of Pediatrics, Haukeland University Hospital,
Bergen, Norway
5
The Faculty of Medicine, Department of Clinical Science,
University of Bergen, Bergen, Norway
ABSTRACT
Respiratory management of people with neurological disorders has improved
significantly during the two last decades. This positive development has occurred
for a range of reasons, primarily due to increased interest and knowledge within
the medical community, accompanied by technological advances. A better
understanding of the pathogenesis of chronic respiratory failure and the role
played by weak cough have been important. Nevertheless, especially patients
with Amyotrophic Lateral Sclerosis (ALS) and bulbar dysfunction are still been
challenging to treat successfully. More recently, understanding of laryngeal
response patters during respiratory treatment options, as Mechanical Insufflation-
Exsufflation (MI-E) and Non-Invasive Ventilation (NIV) indicates that treatment
failure may be due to disturbed laryngeal responses during the respiratory
treatment [1-5]. The larynx is located in the throat and it is the gateway to the

Corresponding Author’s E-mail: tiina.andersen@helse-bergen.no.

248 Tiina M. Andersen and Maria Vollsæter
lungs. In respiratory therapy, the larynx is recognized as an account holder of

airflow limitation and turbulence to the lungs [6]. The larynx can sense both gas,
liquids and solids, it is a highly active organ functioning as a valve to the airways
with major functions to control airflow during respiration, to protect the lungs from
aspiration and it plays a key role in phonation and in cough [7]. Symptoms of
laryngeal dysfunction may mimic respiratory disease, as shortness of breath and
abnormal airway sounds. Laryngeal dysfunction leads to a risk of pulmonary
aspiration and pneumonia. The purpose of this chapter is to describe the
laryngeal function during breathing and response patterns to MI-E and NIV.
Keywords: mechanical insufflation–exsufflation, mechanically assisted cough, non-

invasive ventilation, larynx, laryngoscopy
LARYNGEAL ANATOMY AND FUNCTION
The larynx is divided to the levels of the hypopharynx, supraglottis, glottis and
subglottis. The larynx functions as a valve to the airways with three major functions:
1) to control airflow during respiration, 2) to protect the lungs from aspiration and 3)
to play a key role in phonation and in cough. Abduction of the glottis is fundamental
for free airflow in and out of the lungs during respiration with the least possible
resistance [7]. During normal quiet breathing, the glottis widens during inspiration
and narrows during expiration. This widening occurs ahead of the onset of
inspiration, whereas the narrowing begins before the onset of expiration [8]. Both
forced inspiration and expiration are associated with increased activation of the
intrinsic laryngeal muscles [7]. The laryngeal inlet is situated at the inferior part of the
pharynx (hypopharynx), and the larynx extends from the tip of the epiglottis, through
the true vocal folds to beneath the border of the cricoid cartilage. The larynx consists
of rigid cartilage skeletons, ligaments and muscles for adduction and abduction. The
intricate skeleton of hyaline and nine elastic cartilages are connected to each other
by joints and elastic ligaments. The aryepiglottic folds connect the epiglottis and
arytenoid cartilage on either side of the midline. Within the mucous membrane, there
are two tubercles (corniculate and cuneiforme tubercles) formed by the two cartilages
of the corresponding name. See Figure 1 for illustration. The laryngeal muscles can
be described as either intrinsic or extrinsic, and are under voluntary as well as
involuntary (reflex) control. The larynx is innervated by the internal branch of the
superior laryngeal nerve and the recurrent laryngeal nerves; both branches of the
vagus nerve [7].
The laryngeal extrinsic muscles can be referred to as strap muscles. They control
the position of the larynx in the neck and are particularly important in swallowing,
which involves elevating and depressing the larynx in the longitudinal axis. The small
intrinsic laryngeal muscles move the laryngeal structures in relation to each other.
They are essential in breathing, speech, cough and swallowing, where they interact
in complex manners. The larynx has several small intrinsic adductor muscles, but
only one abductor muscle; musculus cricoarytenoideus posterior (the PCA muscle).

Laryngeal Response Patterns during NIV… 249
Figure 1. Side view of the laryngeal levels and structures.
It operates in a coordinated and phasic relationship with the diaphragm, meaning

that diaphragmatic vagal stimulation is coupled with increased activity of the PCA
muscle, leading to laryngeal abduction and thereby opening of the laryngeal inlet
immediately before diaphragmatic contraction [8].
COUGH AT THE LARYNGEAL LEVEL
The cough job is the expulsion, during which the central airways are cleared from
secretions. Movements at the laryngeal level are crucial for this; a cough requires
intrinsic laryngeal muscle contractions and consists of three distinct phases:

1) An initial abduction to allow airflow into the lungs.

2) A closing phase (0.2 seconds) to allow build-up of intrathoracic pressure.
3) A secondary abduction of the true vocal folds to allow high expiratory airflow.
The expiratory phase of cough can also present with a varying number of
sequential glottic closures and openings [9].
During the closing phase, tight adduction of the true vocal folds, together with the
activity of the aryepiglottic muscles lead to closure of the inlet of larynx by bringing
the aryepiglottic folds tight together. This enables the larynx to withstand the high
pressures that can be generated in the thorax, e.g., during cough. This closure is
further aided by squeezing of the pharyngeal walls, collectively creating a
supraglottic sphincter [9]. Figure 2 demonstrates an open and closed glottis as
viewed through a laryngoscope.
Opening and closure of the glottis require complex and concerted intrinsic
laryngeal muscle contractions, involving similarly complex neural interactions that are
only partially understood. Volitional cough is mediated through corticobulbar
pathways, whereas reflex cough is mediated (afferent) through the vagal nerve.
Stimulation of extremely sensitive receptors in the supraglottic larynx induce complex
adductor reflexes that, for example, prevent foreign bodies from entering the airways
[8].
BULBAR INNERVATED MUSCLE WEAKNESS
Laryngeal muscles, as well as muscles of the jaw, face, soft palate, pharynx and
the tongue, are innervated by neurons located in the so-called bulbar region of the
brain stem.
Figure 2. Top view of the larynx; open and closed glottis.

Bulbar innervated muscle dysfunction appears in several neurological conditions,

leading to so-called bulbar symptoms. Weakness of pharyngeal muscles, spasticity
or lack of coordination of laryngeal or lingual muscles impair both, speech,
swallowing and coughing [10].
Thus, bulbar muscle dysfunction is often associated with ineffective non-invasive
respiratory management. Respiratory treatment of ALS patients with bulbar
symptoms is particularly challenging.
Clinically, bulbar involvement in ALS is primarily characterized by either spasticity
or flaccid paresis and atrophy. This depends on the extent of upper versus lower
motor neuron involvement, the former usually labeled pseudobulbar palsy and the
latter progressive bulbar palsy, or a combination.
ALS mainly involving the upper motor neurons leads to pseudobulbar palsy,
clinically characterized by spasticity of the bulbar innervated muscles, emotional
lability (e.g., pathological laughing and crying) and an enhanced masseter reflex (jaw
jerk reflex).
ALS mainly involving the lower motor neurons leads to progressive bulbar palsy,
clinically characterized by flaccid paresis and muscular atrophy, and fasciculation of
the tongue (i.e., small, local, involuntary muscle contraction and relaxation) and/or
tongue fibrillations (rapid, irregular, and unsynchronized contraction of muscle fibers).
Pharyngeal and laryngeal complications lead to increased risk of aspiration, and
eventually a need for the patient being fed bypassing the mouth, via a percutaneous
endoscopic gastrostomy tube [10].
EVALUATION OF THE LARYNGEAL RESPONSES

DURING RESPIRATORY THERAPY
Laryngeal evaluation is not routinely indicated to monitor and follow-up patients

using NIV and MI-E. However, evaluation of the upper airways and larynx may be
considered in patients with bulbar dysfunction or residual obstructive events
associated with poorer prognosis [1, 2, 5].
Transnasal fiberoptic laryngoscopy (TLF) (Figure 3) is a feasible and well-
tolerated method to describe and characterize laryngeal movements throughout an
MI-E protocol. Findings can easily be video-recorded, and thus scrutinized and
interpreted outside the immediate examination context. TFL does not require
sedation, and skilled hands can perform it with little discomfort and at no risk. TFL is
"the gold standard" to visualize abnormal laryngeal movements.
Regular decongestant nasal spray may be used to facilitate the introduction of
the laryngoscope. The flexible laryngoscope is lubricated with local anesthetic gel
and led through an oronasal mask, via the nose and nasopharynx until a good view
of the larynx is obtained. A modified oronasal facemask serves to fasten the
laryngoscope and to allow TFL video recordings to be obtained simultaneously with
the MI-E or NIV procedures [1, 2, 11].

Figure 3. A laryngoscope passing through a modified MI-E interface with the laryngoscope
supported and adjusted manually. Examination visualized on the screen: two continuously
running video recordings: the endoscopic video from the TFL (on right) and an external video
camera to the control panel of the MI-E device (on left), documenting the phases of
insufflation and exsufflation from the device manometer. Situation arranged.
LARYNGEAL RESPONSES TO NON-INVASIVE VENTILATION
In Health
With laryngoscopic evaluation of awake healthy subjects (n = 7), Jounieaux et al.

revealed that positive pressure ventilation tended to cause progressive glottic
narrowing, increasing the inspiratory resistance and thereby progressively reducing
the fraction of air delivered to the lungs [12]. This was further aggravated during
stable sleep, and even more during deep sleep stages [13].
Parreira et al. monitored laryngeal behaviour with TFL in awake healthy subjects
(n = 6) during nasal bi-level NIV in pressure controlled mode with three different
levels of Inspiratory Positive Airways Pressures (IPAP): 10, 15 and 20 cmH2O),
combined with 5 cmH2O of Expiratory Positive Airway Pressure (EPAP). They
compared their findings to previous observations using volumetric ventilator [14]. A
significant narrowing of the true vocal folds was observed in all subjects, and
increasing the IPAP did not always lead to increase of effective lung ventilation. The
study advocated that the use of a bi-level positive-pressure ventilator in controlled
mode is less predictable and less stable compared to volumetric ventilators [15]. In a
another study from the same group using bi-level NIV in spontaneous mode in
healthy subjects (n = 10), the researchers found laryngeal responses did not seem to

play clear role to ventilation efficacy in the spontaneous mode, and that the efficacy
of positive pressure ventilation was better with IPAP of 20 cmH2O compared to 10
and 15 cmH2O [16]. The explanation discussed was the physiological glottic
widening in spontaneously initiated inspiration [8].
In Patients
In a case description back from 1991, Delguste et al. reported complete upper
airway obstruction in association with NIV-induced hypocapnia in three of four
examined patients with long-term NIV. The authors suggested that the use of positive
pressure devices to extreme hyperventilation may increase upper airway resistance,
further proceeding to complete closure [14].
A recent study examined laryngeal responses in COPD patients (n = 8) using
NIV during acute exacerbation. The researchers found that using different ventilatory
modes with high pressures did not cause laryngeal obstruction, but increased
respiratory volume. The researchers therefore speculated whether the possible
protective and normal reflex responses at high pressures did not occur in COPD
patients.
The main explanation raised was the chronic CO2 exposure (by tobacco
smoking) altering the receptors’ response to chemical stimuli. This may be the
reason for tolerability to high-pressure NIV effectiveness in COPD patients [17].
Georges et al. [4] inspected the larynx with TFL during NIV in patients with ALS
(n = 11), to increase the understanding of potentially counterproductive laryngeal
response patterns. They observed immediate obstruction of the upper airway at all
levels from the tongue to the true vocal folds. A study by Sayas Catalàn et al. [3]
used TFL with NIV titration in patients with long-term NIV (n = 13) in the case of
obstructive events during treatment. The researches postulated that this approach of
NIV setting titration during visualization of the laryngeal structures leads to fewer
obstructive events in subjects with upper-airway obstruction. The researches also
reported a variation of laryngeal responses during NIV: retroflex movement of the
epiglottis, backward movement of the tongue base and hypopharyngeal constriction.
They concluded that dynamic TFL during NIV helped to identify anatomic and
functional mechanisms underlying upper airway obstruction. Hence, a systematic
evaluation using this technique guided physicians to choose the most appropriate
strategy to improve the quality of ventilation.
The results of these studies support the theory that afferent (i.e., pressure and
flow receptors) activation in the larynx play an important role in modulating upper
airway muscle activity during ventilation, thus, influencing motor patterns with impact
on laryngeal adduction. Stimulation of extremely sensitive supraglottic receptors
normally induces complex adductor reflexes that prevent foreign bodies from
entering the airways [8]. In fact, stimulation with positive air pressures has been used
by otolaryngologists to provoke laryngeal reflex activities leading to both laryngeal
closure and swallowing. It is also suggested that in absence of spontaneus

inspiratory muscle activity, the glottic aperture represents the main factor regulating
ventilation during NIV [12].
LARYNGEAL RESPONSES TO MECHANICALLY ASSISTED COUGH
In Health
Andersen et al. studied both healthy young medical students (n = 20) [11] and
healthy adults age- and gender matched (n = 20) to ALS patients with dynamic TFL
during MI-E intervention with a range of treatment pressures from ±20cmH2O to
±50cmH2O [1]. Healthy persons adequately managed to coordinate glottic closure
during MI-E manoeuvres when instructed to cough. An initial abduction of the vocal
folds was observed both during the insufflation and exsufflation phases, similar to
normal cough. When instructed simply to exhale during exsufflation, the glottis stays
open in the majority. However, subsequent to an initial abduction during exsufflation
and cough, various obstructive laryngeal movements were observed in some
subjects, such as narrowing of the true vocal folds, retroflexion of the epiglottis,
hypopharyngeal constriction and backward movement of the base of the tongue [11].
Thereby, the researches advocated that MI-E may not be thought of as a device that
simply "fills up" and "empties" the lungs of air, suggesting that therapists should use
an individualized approach when using MI-E treatment, both as regards pressure and
time settings and instructions to patients [11].
In Patients
The first study describing laryngeal response patterns to MI-E was the study of
Sancho et al., who examined three patients with ALS at baseline and during
application of mechanical exsufflation with a computerized tomography (CT)
scanning of their upper airways (hypopharynx and oropharynx). They found that
failure to increase peak cough flow to an adequate level was associated with a
dynamic collapse of the upper airway during exsufflation. Although they did not
examine directly the laryngeal level of the upper airways, they used their findings to
suggest that coordinated movements of the glottis and intact bulbar function are
necessary elements for effective use of non-invasive MI-E [18].
Thereafter, the group of Andersen et al. have examined the larynx systematically
in ALS patients (n = 20), using TFL during ongoing MI-E with the clinical range of
treatment pressures (±20, ±30, ±40 and ±50cmH2O) [1]. They included dynamic TFL
during the whole MI-E cycles [1, 2]. Their first cross-sectional study revealed
inspiratory adduction of supraglottic structures during insufflation in patients with
bulbar ALS, the opposite of the inspiratory abduction observed in non-bulbar patients
and in healthy controls. This might explain treatment failures in bulbar ALS patients,

as the compromised size of the laryngeal inlet obstructs the inspiratory airflow from
the MI-E, resulting in poor filling of the lungs during the first phase of cough. Patients
with ALS and no bulbar symptoms were not always able to coordinate their laryngeal
cough movements during MI-E cycles.
Generally, in ALS patients the larynx moved downwards during applied
insufflation and upwards (cranially) during exsufflation. In all ALS patients (with or
without bulbar symptoms), initial abduction of true vocal folds was followed by
subsequent adduction during insufflation and exsufflation. Hypopharyngeal
constriction during exsufflation was observed in all subjects (both ALS and healthy),
most prominently in patients with ALS and bulbar symptoms [1].
Andersen et al. also examined ALS patients (n = 13) with the same methods in a
longitudinal manner, following them for up to five years during disease progression.
With disease progression, supraglottic inspiratory adduction appeared in spinal onset
ALS patients before the evolvement of other bulbar signs and symptoms. The
highest treatment pressures were those most counterproductive. Generally, cough
during MI-E altered with disease progression, and became slower, less expulsive
and desynchronized. MI-E treatment may be complicated by swallowing, which
seemed to be associated with retroflex movement of epiglottis. Individually modified
MI-E settings were assessed with TFL (n = 6) as ALS patients met for their
scheduled and consecutive outpatient assessments. Customized use of MI-E,
applying lower insufflation pressures and flows together with patient triggered
insufflations, were observed to provide less laryngeal adduction, both at the
supraglottic and glottic level, with more appropriate laryngeal responses to
insufflation at least in some (possibly all) cough cycles. This prolonged the time for
which the treatment was perceived efficient by patients. The use of one cough cycle
at the time, allowing for a ‘pause’ prior to the next insufflation, and instructions to
actively inhale prior to insufflation, was observed to induce better cough
synchronization, particularly in cases of a retroflex epiglottis or spasticity at the
laryngeal level.
The researchers concluded that individually customized settings seemed to
promote more optimal laryngeal response patterns to MI-E and to prolong the
patency of the larynx during mechanically assisted cough, and thus facilitated
prolonged successful use of this technique [2].
The results from these studies suggest that the application of high positive
pressure is the principle challenge also in MI-E therapy, especially when bulbar
dysfunction is present. Conceivably, the observed adduction prevents lung
insufflation and leads to inadequate filling of the lungs; a situation that will
compromise attempts to assist the expiratory phase of cough through exsufflation,
and thus lead to inefficient MI-E. However, the larynx is a highly complex organ that
integrates a number of vital functions and similarly, ALS is a complex disease
involving several mechanisms. Thus, inefficient MI-E in these patients is likely to be
multifactorial and also to vary between patients.

Since ALS affects motor neurons in the brain and spinal cord, both afferent and
efferent innervation may play a part in the adverse laryngeal response patterns
during MI-E in these patients.
CLINICAL IMPLICATIONS
There is still scarce data about laryngeal response patterns to NIV and MI-E.
Nevertheless, published studies and clinical observations with TFL have provided a
better understanding, and support the hypothesis that preserved laryngeal function is
crucial to the effectiveness of NIV and MI-E treatment. Therapeutic positive
pressures may provoke disadvantageous laryngeal responses, especially in patients
with disturbed motor control. This should be tested in larger studies.
Considering the challenges with NIV and MI-E treatment of bulbar ALS patients,
previous applied therapy may in fact have failed the patients, due to erroneously
applied settings.
A better understanding of laryngeal response patterns under different modes and
settings of NIV and MI-E will thus help to obtain better compliance, more effective
tidal volumes and thereby higher success rates in patients. The knowledge so far
suggest that clinical use of MI-E and NIV in ALS should be individualized and
respiratory therapists and doctors may need to alter their clinical management of
challenging patients. Individually adjusted settings, carefully applied as patients
deteriorate, may prevent adduction of laryngeal structures during insufflation, and
thus prolong the period of successful non-invasive use of MI-E and possibly also
NIV. One should be aware that in the “start-up titration” of both MI-E and NIV, high
inspiratory pressures may generate airway closure, thus pressures should be gently
titrated upwards. If problems are encountered, TFL can be a valuable tool.
TFL examination during MI-E and NIV may have limitations, which can affect the
validity of the findings. During MI-E manoeuvres, the larynx tend to move upwards
during the MI-E cycle, requiring adjustments of the position of the laryngoscope. In
some subjects, anatomical characteristics could preclude visual access, such as a
high standing epiglottis. In some cases, airway secretions lead to poor-quality
recordings. Pre-treatment aiming to clear secretions should be considered,
particularly with disease progression. Further, adduction of the aryepiglottic folds
obscures the view of the true vocal folds, and therefore the glottic level is not always
successfully visualized. To compensate for these challenges and to produce
adequate recordings, repetition of the MI-E cycles may be needed, which should lead
to adequate quality recordings in at least one MI-E cycle per intervention in almost all
sessions. We hold that direct clinical visualization of the larynx using TFL provides a
good overview of laryngeal responses to MI-E in patients who are difficult to treat.

Key Messages
 Video-recorded flexible transnasal laryngoscopy is a feasible method to

characterize laryngeal responses throughout an MI-E and NIV interventions
in patients whose laryngeal responses to treatment are suspected to
complicate the respiratory treatment.
 Therapeutic positive pressures seem to provoke the disadvantageous
laryngeal responses, especially in patients with disturbed motor control.
 Laryngeal adduction during positive pressure treatment may preclude air
filling of the lungs, causing discomfort and affecting the respiratory treatment
efficacy.
 Individually tailored treatment can improve - and may possible extend - the
use of NIV and MI-E in ALS.
 Video-recorded flexible transnasal laryngoscopy can be a valuable tool
during these processes.
REFERENCES
[1] Andersen, T. et al. Laryngeal response patterns influence the efficacy of

mechanical assisted cough in amyotrophic lateral sclerosis. Thorax, 2017.
72(3): p. 221 - 229.
[2] Andersen, T. M. et al. Laryngeal Responses to Mechanically Assisted Cough in
Progressing Amyotrophic Lateral Sclerosis. Respir. Care, 2018. 63(5): p. 538 -
549.
[3] Sayas Catalan, J. et al. Videolaryngoscopy With Noninvasive Ventilation in
Subjects With Upper-Airway Obstruction. Respir. Care, 2017. 62(2): p. 222 -
230.
[4] Georges, M. et al. Reduced survival in patients with ALS with upper airway
obstructive events on non-invasive ventilation. J. Neurol. Neurosurg.
Psychiatry, 2016. 87(10): p. 1045 - 50.
[5] Conde, B. et al. Upper Airway Video Endoscopy: Assessment of the response
to positive pressure ventilation and mechanical in-exsufflation. Pulmonology,
2019. 25(5): p. 299 - 304.
[6] Ferris, B. G. Jr., Mead, J. and Opie, L. H. Partitioning of Respiratory Flow
Resistance in Man. J. Appl. Physiol., 1964. 19: p. 653 - 8.
[7] Pierce, R. J. and Worsnop, C. J. Upper airway function and dysfunction in
respiration. Clin. Exp. Pharmacol. Physiol., 1999. 26(1): p. 1 - 10.
[8] Brancatisano, T. P., Dodd, D. S. and Engel, L. A. Respiratory activity of
posterior cricoarytenoid muscle and vocal cords in humans. J. Appl. Physiol.
Respir. Environ. Exerc. Physiol., 1984. 57(4): p. 1143 - 9.
[9] Britton, D. et al. Endoscopic assessment of vocal fold movements during cough.
Ann. Otol. Rhinol. Laryngol., 2012. 121(1): p. 21 - 7.

[10] Woodson, G. Management of neurologic disorders of the larynx. Ann. Otol.

Rhinol. Laryngol., 2008. 117(5): p. 317 - 26.
[11] Andersen, T. et al. Laryngeal response patterns to mechanical insufflation-
exsufflation in healthy subjects. Am. J. Phys. Med. Rehabil., 2013. 92(10): p.
920 - 9.
[12] Jounieaux, V. et al. Effects of nasal positive-pressure hyperventilation on the
glottis in normal awake subjects. J. Appl. Physiol. (1985), 1995. 79(1):
p. 176 - 85.
[13] Jounieaux, V. et al. Effects of nasal positive-pressure hyperventilation on the
glottis in normal sleeping subjects. J. Appl. Physiol. (1985), 1995. 79(1):
p. 186 - 93.
[14] Delguste, P., Aubert-Tulkens, G. and Rodenstein, D. O. Upper airway
obstruction during nasal intermittent positive-pressure hyperventilation in sleep.
Lancet, 1991. 338(8778): p. 1295 - 7.
[15] Parreira, V. F. et al. Nasal two-level positive-pressure ventilation in normal
subjects. Effects of the glottis and ventilation. Am. J. Respir. Crit. Care Med.,
1996. 153(5): p. 1616 - 23.
[16] Parreira, V. F. et al. Glottic aperture and effective minute ventilation during
nasal two-level positive pressure ventilation in spontaneous mode. Am. J.
Respir. Crit. Care Med., 1996. 154(6 Pt 1): p. 1857 - 63.
[17] Oppersma, E. et al. Glottic patency during noninvasive ventilation in patients
with chronic obstructive pulmonary disease. Respir. Physiol. Neurobiol., 2019.
259: p. 53 - 57.
[18] Sancho, J. et al. Efficacy of mechanical insufflation-exsufflation in medically
stable patients with amyotrophic lateral sclerosis. Chest, 2004. 125(4):
p. 1400 - 5.

Chapter 18
TRACHEOSTOMY TIMING AND CHOICE OF CANNULA
Piero Ceriana* and Cinzia Lastoria

Pneumologia Riabilitativa e Terapia Sub-Intensiva Respiratoria,
ICS Maugeri IRCCS, Pavia, Italy
ABSTRACT
The work of breathing is the summation of elastic and resistive work; in

addition to different patient factors, the breathing apparatus, such as the
ventilator, circuit, and endotracheal or tracheostomy tube, can contribute to
increase resistive work. Tracheostomy tube type can change resistance to air
flow during inspiration and expiration, which may have important repercussions
for airflow dynamics and work of breathing in patients receiving artificial
ventilation or during the weaning procedure.
Keywords: intubation, tracheostomy, mechanical ventilation, cannula, anticipate

directives
INTRODUCTION
Invasive mechanical ventilation (IMV) through translaryngeal intubation

represents the mainstay of acute respiratory failure treatment, regardless of its origin,
when non-invasive ventilation is contraindicated or fails [1, 2]. Almost 30% of patients
undergoing this procedure cannot be easily weaned from mechanical ventilation and
require maintenance of IMV and translaryngeal tube for a longer period [3]. However,
prolonged translaryngeal intubation can increase the risk of ventilator-associated
pneumonia [4], laryngeal injury [5] and sinusitis [6]. Based on these issues, it is
*
Corresponding Author’s E-mail: piero.ceriana@icsmaugeri.it.

260 Piero Ceriana and Cinzia Lastoria
common practice to convert the interface for IMV from translaryngeal tube into
tracheostomy cannula in those patients who require prolonged mechanical
ventilation. Besides the reduction of translaryngeal tube-related complications,
tracheostomy carries other potential advantages like less need for sedation, better
airway hygiene, improved patient’s comfort including ability to communicate,
decreased airway resistance and easier patient’s discharge from ICU [7].
General and most common indications for tracheostomy [8] are:
- Relief of upper airways obstruction

- Inability to protect the lower airways
- Failure to wean from IMV
- Need for prolonged IMV
The first indication refers to any cause of upper airway obstruction, as it was in
the 19th century for diphtheria or, later, for laryngeal cancer. Now these cases are
rather uncommon so that it becomes more often an indication for tracheostomy
maintenance rather than for tracheostomy performance, i.e., in cases of failed
decannulation due to post-intubation laryngeal stenosis or vocal cord paralysis.
The second indication is typical of patients with severely impaired
consciousness, secondary to head trauma, neurosurgical operations or vascular
accidents where the protective reflexes of upper airways are impaired or absent.
Under this definition it is often included the indication to place and maintain
tracheostomy for the inability to manage copious secretions: we think that with the
availability of modern cough-assist devices this indication should be limited to very
selected and difficult cases.
Third and fourth indications apparently seem rather similar, but, while the former
refers to cases of failed weaning in those patients in which tracheostomy must still be
considered a temporary measure and a bridge to the restoration of the previous
respiratory autonomy, the latter can be viewed as a permanent procedure for those
patients in which this restoration cannot be expected based on the nature of the
underlying disease.
INDICATIONS TO TRACHEOSTOMY IN NEUROMUSCULAR PATIENTS
Based on the previous considerations, it could be easy to conclude that, in a

patient suffering from a neuromuscular disease, tracheostomy is generally performed
in presence of the second and/or the fourth indications.
Amyotrophic lateral sclerosis (ALS) is taken as the stereotype of a
neuromuscular disease characterized by development of respiratory failure requiring
noninvasive mechanical ventilation (NIV) and cough assist device. At some point of
the disease course, however, NIV can become inadequate to maintain adequate gas
exchange even if applied round-the-clock and the patient can become intolerant due

Tracheostomy Timing and Choice of Cannula 261
to possible facial skin pressure lesions, inability to discontinue NIV for eating,
drinking and speaking without the risk of desaturation and severe dyspnoea. Up to
few years ago, the need to apply NIV round-the-clock together with uncontrollable
airway secretions were considered absolute indications for tracheostomy in the
neuromuscular patient [9]. Nowadays the use of cough assist devices [10] together
with the improved strategies to apply NIV round-the-clock [11] enable the
management of many neuromuscular patients without tracheostomy for a longer
period of time. There is, on the other hand, an almost general agreement on the
indication for tracheostomy for bulbar phenotypes of ALS, where glottis
incompetence makes difficult, if not impossible, the correct application of NIV and
mechanical in-exsufflation [12]. Hence, in case of persistence of symptomatic
respiratory failure despite NIV and oxygen desaturation refractory to the combined
support of inspiratory and expiratory aids, tracheostomy must be viewed as the only
mean enabling airway and gas exchange control.
However, there is no doubt that tracheostomy in a neuromuscular patient is not
only a clinical problem but also a social and ethical one. First of all, it must be taken
into account that the progression of the disease up to the total impairment of motor
function at the spinal and bulbar level makes the patient totally dependent on artificial
machines to support respiration and feeding, and not every patient accepts this kind
of locked-in existence. Then, it must be considered the subsequent heavy burden of
care at home or in a long-term facility and the possible risk of complications during
long-term tracheostomy management [13]. Therefore, the possibility to express
anticipate directives to avoid extraordinary lifesaving measures, makes tracheostomy
in neuromuscular patients a complex matter, so that the decision to perfom
tracheostomy should be the result of a shared decision between the patient and the
caring team. Hence, tracheostomy must not be proposed to the patient as a
mandatory choice, but as a treatment option alternative to prolonging non-invasive
aids with sedation as an add-on in the terminal phases. Therefore, this issue should
be discussed between patient, caring team and relatives during the course of the
disease, as part of a multidisciplinary approach including psychological support and
counselling, in those cases where the natural course of the disease, especially in
presence of bulbar muscle involvement, makes the use of non-invasive respiratory
aids, sooner or later, ineffective. In this context, the use of NIV prolongs survival and
gives more time to discuss the issue of anticipate directives and living will [14].
TIMING OF TRACHEOTOMY
The optimal time window for tracheostomy represents a highly controversial

point. Supporters of early tracheostomy (< 10 days) advocate lower risk of
pneumonia and shorter intensive care unit (ICU) length of stay. Clinicians in favour of
late tracheostomy (> 10 days) think that a significant group of patients can be
weaned in this time frame, and many tracheostomies can be avoided [15]. However,

this issue finds its main reason of debate for patients undergoing protracted invasive
mechanical ventilation and showing difficult weaning for causes of respiratory failure
different from neuromuscular disease (i.e., de novo respiratory failure). Actually,
based on the previous assumptions, the issue of proper tracheostomy timing in
neuromuscular disease, refers to the time point, during the course of the disease,
when non-invasive inspiratory and expiratory aids can no longer maintain adequate
oxygen saturation, airway clearance and carbon dioxide washout. When the patient
has given consent to tracheostomy, this should be performed as an elective
procedure before clinical deterioration, since the course of the disease is such that
the failure of respiratory function progresses in an unpredictable way, and sometimes
urgent invasive mechanical ventilation cannot be avoided in order to treat acute
respiratory failure. The “real life,” however, is far different: a significant percentage of
patients, in fact, develop acute respiratory failure before a decision about anticipate
directives, including invasive ventilation, has been taken [16]. Therefore, upon the
occurrence of acute respiratory failure, patients generally receive translaryngeal
intubation in the hospital casualty department; then, they are transferred in the ICU.
During the following course of ICU stay, these patients can in theory be extubated
and switched to non-invasive aids [17], but this approach is generally applied in very
selected expert centres and is not routine in most ICU [18]. In most cases, in fact,
conversion of translaryngeal intubation to tracheostomy is the only alternative to
extubation and terminal sedation, should the patient ask for invasive treatment
withdrawal [19] and avoidance of invasive treatment.
TRACHEOSTOMY TECHNIQUE
Tracheostomy can be performed surgically (ST) or with dilatational percutaneous

technique (PDT). Both techniques appear to be safe with a low complication rate;
PDT seems to be superior to ST with respect to wound infection and unfavourable
scarring [20]. On the other hand, ST has the advantage to be feasible almost in all
patients, while PDT must be done with caution in case of previous surgery, abnormal
anatomy, coagulation disorders and difficult patient’s airway [21]. However, it must
be taken into account the advantage that PDT can be performed at the bedside in
the ICU without the need to move the patient to the operating theatre. Surgical
tracheostomy starts with a horizontal incision, ligation of superficial vessels and
transection or lateral displacement of the thyroid isthmus away from the incision. The
second or third tracheal ring is identified and cut about 1.5–2 cm below the cricoid
membrane. The stoma is made through the anterior tracheal wall by means of an
incision that can be horizontal, vertical or cruciate, although most surgeons seem to
prefer the horizontal incision. Percutaneous tracheostomy can be performed with
different techniques: Ciaglia’s original technique and subsequent modifications with
single or multiple dilators, Griggs, Fantoni, Blue Dolphin etc. [22]. Independently of
the technique used, the main difference between PDT and ST is that with PDT the

tracheal wall is not cut, since there is only dissociation and dilation of fibers. This
should assure more attention to tissue integrity and should favour a faster stoma
closure after decannulation [23]. Based on these technical peculiarities, a common
opinion is to prefer PDT for “temporary tracheostomy,” i.e., for those cases in which
there is the real chance to wean the patient from both mechanical ventilation and
tracheostomy, while choosing ST for “permanent tracheostomy,” including patients
with ALS and other progressive neuromuscular diseases where the option of
weaning is not feasible. On a theoretical basis, the tracheal openings done during ST
are generally wider than those created with PDT, and this should facilitate the
replacement of cannula during routine scheduled changes and reduce the risk of
creating a false route with insertion of cannula in the paratracheal spaces. However,
it must be said that these concepts are part of common and real-life experience
shared between clinicians involved in the care of tracheostomized patients and they
are not fully supported by evidence based-medicine and published papers.
Therefore, in summary, the choice of tracheostomy technique, in the “real world” is
far for being guided by these directions and is more influenced by local hospital
settings, wards organization and availability of staff expertise. The great majority of
tracheostomy are performed percutaneously and only a minority are ST with a
percentage, respectively, of 89% VS 11% in Italy [24] and 72% VS 28% overall in the
world [25].
CHOICE OF CANNULA
The tracheostomy cannula available inside the commercial sets for PDT is used
as a temporary one, but, when the patient must be prepared for domiciliary long-term
treatment, a proper cannula tailored according to the patients need must be chosen
and positioned. Plastic (PVC) and silicone tubes are currently available in a huge
variety of models, size and design, and they can fit almost any kind of patient and
any individual need and peculiarity. The choice of the cannula in a neuromuscular
patient depends on several factors:
- need for IMV

- ability to protect the lower airways
- specific anatomical problems (neck size and length, deformities)
- presence of tracheal or glottic stenosis.
The ideal tracheostomy tube should meet all the above requirements, should
facilitate proper speech and swallowing function (when still preserved) and should
minimize complications. One of the first features to consider is the size: this should
be proportional to the size of the native airway, in order to achieve a proper airway
seal without the need to overinflate the cuff (Figure 1). Tubes are identified by three
measurements: inner diameter (ID), outer diameter (OD) and length, they can be

angled or curved and can be available in standard size as well as with the proximal
or the distal segment longer, in order to adjust to different anatomical variants [26].
Some tubes have a suction port just above the cuff, in order to aspirate subglottic
secretions; others are made of silicone and reinforced by an inner spiral wire, so that
they never kink or collapse: they are especially helpful for tracheal stenosis,
tracheomalacia and thoracic deformities. In different types of cannula the presence of
an adjustable flange allows the clinician to easily advance or withdraw it up to the
desired length. Special features to be considered when choosing the kind of cannula
for the neuromuscular patient include fenestration, presence of inner cannula and
cuff type and management.
Fenestration
Fenestrated tubes are similar to non-fenestrated ones, but have an opening in

the posterior convex part above the cuff, which can be single or multiple. The
requirement is the correct adaptation to the patient’s anatomy, so that the
fenestration is properly placed in the middle of the tracheal lumen. During expiration,
air passes through the fenestration and crosses the glottis, thus facilitating
phonation. Our suggestion is to leave the fenestration open only temporarily; in fact,
if the fenestration is left open permanently, the posterior tracheal wall can be drawn
inwards by suction, leading to adherence and granulation inside the cannula with
problems during airway suctioning and serious risks during cannula replacement.
This risk is greater for single rather than for multiple fenestration.
Inner Cannula
The presence of an inner cannula, in the so-called dual-cannula tubes, prevents

the deposition of thickened secretions into the internal lumen, thus maintaining its full
patency and postponing the time of replacement: the reusable inner cannula is
removed and cleaned while the new one is positioned. The presence of an inner
cannula reduces the true ID and this can have an influence on the inspiratory
resistive load [27] and the imposed work of breathing. Fenestrated cannulas have a
disposal inner cannula available with and without fenestration: only when the
fenestrated inner cannula is in place, the opening is complete and effective The
advantages of the inner cannula in long-term domiciliary management include longer
duration with less need to anticipate replacement and, above all, the possibility to
relieve a sudden mucus plug obstruction by simply pulling out the inner cannula (13)
without replacing in emergency the main cannula in cases when the plug cannot be
suctioned.

Figure 1. The ratio between tracheostomy cannula cuter diameter and tracheal lumen
diameter should allow enough airflow through the upper airways (courtesy of Marta Lazzeri).
Cuff Type and Management
Tracheostomy tubes may or may not have an inflatable cuff, which is designed to
seal the residual natural airspace between the cannula and the tracheal wall. The
maintenance of a closed system is desirable for those patients who cannot protect
their lower airways from spillage of nose and mouth secretions, in order to prevent
respiratory tract infections, but it is mainly indicated during invasive mechanical
ventilation to avoid leaks and to achieve easier control and manipulation of gas
exchange. This is not mandatory in neuromuscular patients, since ‘open’ ventilation
using cuffless tubes can be effectively performed in patients with preserved glottic
function and adequate pulmonary compliance [28]. When patients can no longer use
non-invasive inspiratory and expiratory aids and accept the progression to
tracheostomy, the use of a cuffless tube can represent an intermediate step before
the use of a cuffed one, until his/her glottis function is preserved, with a positive
impact on phonation and survival [29].
The cuff should be inflated with air, except in special cases when normal saline
must be used, up to a pressure not higher than the tracheal capillary perfusion
pressure, to avoid mucosal ischaemia. It is generally agreed that a maximum intra-
cuff pressure of 25 mm Hg (or 35 cm H2O) is acceptable. Monitoring cuff pressure
with only manual appreciation of the pilot balloon tension can be misleading,
therefore the manoeuvre should be done with a manometer, every time that the cuff
is inflated or deflated or when the cannula is repositioned or replaced. If the cannula
has been chosen of the right size for the patient, a volume not greater than 10 ml
should be sufficient to seal the peri-cannular space; in case of persistent air leaks
despite adequate insufflation of the cuff or of the need to use a greater volume of air,
it must be considered that the cannula is undersized with respect to the tracheal

diameter, or that there is a leak in the cuff. Besides, this is also the case when the
tracheal wall has been dilated and deformed by a tracheal tube cuff maintained
overinflated for many days.
Cuffs are available in three different kinds:
a) Tight-to-shaft cuffs, when deflated, perfectly adhere to the tube surface

(Figure 2). Some of them, including the cuff, are silicone-made and
permeable to gas, so that they must be filled with sterile water instead of air.
The advantage of these tubes is the easier insertion through the stoma, and
the easier passage of air when the cuff is deflated.
b) High-volume low-pressure cuffs are most commonly used for the specific
design that reduces the risk of tracheal damage. Compared with tight-to-shaft
tubes, the cuff, when deflated, forms protruding wrinkles and folds (figure 2).
c) Foam-cuffed tubes have a large cuff made of polyurethane foam lined on the
outer surface by a sheath of silicone. Before insertion, the cuff is evacuated,
then it is allowed to re-expand without manual syringe inflation: the pilot
conduit remains open to the atmosphere, so that the intra-cuff pressure
equals ambient pressure. This cannula is specifically designed to avoid
mucosal ischaemia and to minimize tracheal injury, but, despite this sound
rationale, it has not gained widespread use.
Figure 2. Left side: cuffed tracheostomy cannula with standard high-volume low-pressure cuff.
right side: tracheostomy cannula with TTS cuff (tight-to-shaft). in both cases the cuff is
deflated but only the tts cuff maintains full adherence to the shaft without protrusion of
creases.

Practical recommendations – The most important requirement is that the cannula

has been chosen of the right size and length according to the patient’s anatomy.
Then, two important requirements are the dual cannula and the cuff type. The first
one, in fact, prevents encrustation in the main cannula, thus postponing its
replacement and reducing the risk of stenosis and occlusion from mucus plugs.
However, the care giver must be adequately trained to do this regularly and with
constancy, whatever the place where the patient is cared for (home or nursing home
or long term facility). With respect to the cuff type, we recommend the use of a tight-
to shaft cuffed cannula; this offers the dual advantage of a cuffed cannula when
sealing the airway is needed, but when the cuff is deflated it behaves like a cuffless
tube, allowing the entire peri-cannular space available for passage of air during open
ventilation with a phonation quality generally better than that offered by a fenestrated
cannula.
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[10] Auger C., Hernando V., Galmiche H.: Use of mechanical insufflation-
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Daytime noninvasive ventilatory support for patients with ventilatory pump
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Chapter 19
COUGH MANAGEMENT
Alexander Müller*
Institute for Physical and Rehabilitation Medicine
Cardiorespiratory Therapy Team, Clinic Floridsdorf, Vienna, Austria
ABSTRACT
Background
Impaired cough function is one of the main reasons for morbidity and
mortality in patients with neuromuscular diseases (NMDs). Cough augmentation
techniques aim at compensating for ineffective cough.
Purpose
To investigate current evidence-based practice on the evaluation and

management of impaired cough function in patients with NMDs.
Methods
Databases (PubMed, CINAHL, JAMA Network, PEDro) were used to find

recent publications on cough augmentation techniques in NMDs. Literature
findings were critically analysed and summarised.
Results
Regular measurement of cough function parameters including peak cough

flow, vital capacity, insufflation capacity, maximum expiratory pressure and
bulbar function is necessary to identify the relevant components of cough
*
Corresponding Author’s E-mail: alexander.mueller3@gesundheitsverbund.at.

272 Alexander Müller
impairment. The choice of cough augmentation techniques must be based on a

case-by-case analysis and no overall valid assumptions can be made of which
cough augmentation technique to use.
Conclusions
Further research investigating the long-term benefits and possible adverse

effects of certain cough augmentation techniques is needed. Special
considerations need to be put on home-care setting and the application of certain
techniques by non-professionals.
Keywords: cough effectiveness, cough evaluation, cough management, cough

augmentation, assisted cough
INTRODUCTION
Cough is an essential defense mechanism of the respiratory system to remove

foreign particles from the upper respiratory tract. These particles are captured in
bronchial secretions and moved to the central airways via the mucociliary escalator.
The physiological cough manoeuvre consists of three components: A deep
inspiration with thoracic expansion, glottic closure with an increase in intrathoracic
pressure, followed by glottic opening and abdominal muscle contraction to create
maximum expiratory airflow resulting in the expectoration of mucus through shear
forces.
Although neuromuscular diseases (NMDs) vary in their pathophysiology and
phenotypes, some similarities exist regarding cough function impairment. Patients
with NMDs often present with reduced lung function parameters, such as a reduced
vital capacity (VC) and reduced peak cough flow (PCF) [1]. The reasons for these
impairments are the progressive decline in inspiratory and expiratory muscle strength
accompanied by structural changes of the thorax and a reduction in thoracic
compliance and elasticity. In addition, bulbar palsy with insufficient glottic closure
may occur in some NMD patients, leading to the inability to generate high
intrathoracic pressure and inadequate coordination of the cough manoeuvre. All
these factors contribute to a significant reduction in cough effectiveness in patients
with NMDs. The possible consequences of insufficient cough are the retention of
bronchial secretions, recurring atelectasis and frequent infections of the respiratory
tract. Respiratory complications are the most common cause of hospitalisation,
morbidity and mortality in patients with NMDs and lead to a significant impairment in
health-related quality of life [2].
The pathophysiological mechanisms of ineffective cough in patients with NMDs
were discussed in detail previously (see chapter 6). This chapter aims at providing an
insight to the evaluation and therapeutic management of impaired cough function in
NMDs based on recent literature findings.

Cough Management 273
EVALUATION OF COUGH FUNCTION
A relevant aspect in the treatment of patients with NMDs is the evaluation of the
risk for respiratory complications, which includes the evaluation of cough function in
regular intervals.
The early detection of the risk factors associated with respiratory deterioration
helps in slowing down the decline in lung function, maintaining quality of life and
reducing the requirement of medical interventions. Specific objective and measurable
parameters are associated with impaired cough function. These measurements in
combination with the patient’s medical history and the clinical assessment are the
basis of decision-making when thinking about the initiation or adaptation of cough
augmentation techniques. Table 1 gives an overview of relevant measurements to
identify cough impairment in NMD patients and guide clinical decision-making
regarding cough augmentation techniques. The presented parameters will be further
discussed in the following sections.
Table 1. Parameters to identify cough impairment in patients with NMDs

and guide therapeutic clinical reasoning
Baseline Measurements
PCF <270l/min consider cough augmentation techniques
<160l/min definite need for cough augmentation techniques
VC <60% predicted consider assisted inspiration techniques
MEP <40cmH2O consider assisted expiration techniques
PEF measure to monitor glottic function in patients with suspected bulbar palsy
Additional Measurements
IC measure regularly to optimise cough augmentation techniques
PCFass
Peak Cough Flow (PCF)
The most commonly described parameter used to evaluate cough effectiveness

is PCF. The patient is asked to perform a deep inspiration followed by a forced cough
manoeuvre into a measuring device. PCF measurements can provide a generalised
impression about cough effectiveness, but it is not possible to draw conclusions
about which of the components of the cough manoeuvre are impaired based on PCF
measurement alone. Healthy adults usually reach PCF values greater than 360l/min.
A PCF of 160l/min is commonly described as the threshold value for cough
effectiveness, whereby a PCF of lower than 160l/min indicates an insufficient cough
with a reduced ability of clearing secretions from the upper respiratory tract. PCF
values below 270l/min are considered to be sufficient for effective mucus
expectoration, but patients with a PCF ranging between 160l/min and 270l/min are
likely to drop below the threshold of 160l/min in case of an acute respiratory infection,

thus leading to cough impairment, mucus retention and further respiratory

deterioration [3].
The PCF values described above have been frequently cited since their first
publication by Bach and Saporito in 1996. Despite their common usage in
publications and clinical practice, some critical reflection on these parameters is
necessary:
First, it is key to mention, that these PCF threshold values have barely been
revalidated by other studies after their first publication in 1996. This is of importance,
as the cut-off values defined by Bach and Saporito were originally used to predict
extubation outcome in critically ill NMD patients only, but since then were widely
applied to various populations without re-evaluating their validity. It has to be
questioned whether the same cut-off values can be applied to varying populations.
Another factor that requires consideration when interpreting PCF values is the
mode and procedure of measurement. PCF can be measured by using several
different devices such as portable peak flow meters, which are widely used in
asthmatic patients, as well as with portable spirometers or pneumotachographs. The
accuracy of some of these devices has been doubted in recent publications. Chatwin
and colleagues recommend measuring PCF by using a calibrated
pneumotachograph as these devices have proven to be the most accurate ones [4].
This approach is supported by a 2015 study on the accuracy of PCF measuring tools
by Kulnik and colleagues. The authors found out, that measuring PCF with a peak
flow meter or a spirometer might lead to significantly inaccurate results when
compared to pneumotachograph measurements as the defined gold standard.
Especially in PCF values below 270l/min, the portable devices measured significantly
lower values and based on the previously described threshold values the differences
were clinically relevant [5]. These findings indicate that portable PCF measuring tools
need to be used with caution. Peak flow meters and portable spirometers may be
cost-effective and easy to use, but due to their inaccuracy, they alone cannot be
validly used for the diagnosis of impaired cough function and further tests will be
necessary to identify cough insufficiency. Using peak flow meters in NMDs in the
same way as they are used for peak flow diaries in asthma patients might be a
helpful tool to monitor PCF trends when the patient is not hospitalised, as the
application of peak flow meters can be easily learnt by patients or caregivers and
does not require profound medical knowledge.
Independent from the type of measuring device, air leakage has to be avoided
when measuring PCF to receive accurate results. As patients with NMDs may not be
able to form a tight lip seal due to progressed facial muscle palsy, PCF measurement
with a tight-fitting oronasal mask is therefor currently recommended [4].
As mentioned previously, increasing intrathoracic pressure by closure of the
glottis is an essential component of the physiological cough mechanism. In patients
with bulbar palsy, which is commonly observed in amyotrophic lateral sclerosis
(ALS), glottic closure might not be possible due to vocal fold paralysis. This effect is
of importance when measuring PCF. Aside from PCF, peak expiratory flow (PEF)
can be measured in the same way. Instead of coughing, the patient is thereby asked

to perform a forced expiration manoeuvre with open glottis. In healthy individuals,

PCF is usually slightly greater than PEF. The approximation of PCF and PEF values
can therefore indicate progressive glottic closure insufficiency due to bulbar palsy [2].
This is relevant, as glottic function influences the choice of cough augmentation
techniques and thereby influences therapeutic approaches and clinical reasoning.
After initiation of a cough augmentation technique, it is useful not only to
measure unassisted PCF, but also assisted PCF (PCFass), defined as PCF while
performing the chosen technique. This can provide information about the efficacy of
the technique and the possible need for adaptations. PCFass measurement should
be performed when patients visit the hospital for regular check-ups.
Vital Capacity (VC) / Insufflation Capacity (IC)
Beside measurements of PCF, the evaluation of dynamic supported and

unsupported lung volumes in regular intervals is useful. Recent literature findings
have shown that cough effectiveness is highly associated with the amount of inspired
air prior to coughing.
Deep inspiration up to 80% of vital capacity (VC) signifies the first phase of the
cough manoeuvre. VC is often reduced in patients with NMDs, caused by the
progressive reduction in inspiratory muscle strength (diaphragm and external
intercostal muscles), as well as by the ongoing decline in thoracic compliance [6]. VC
is usually measured via spirometry and can provide useful information about
diaphragmatic function and inspiratory muscle weakness when performed in both,
upright and supine position. A reduction in VC of more than 20% in supine position
indicates impaired diaphragm strength. This drop in VC is more striking in supine as
abdominal organs oppose an additional load towards the already weakened
diaphragm [7]. This is of clinical relevance, as progressive diaphragmatic muscle
weakness with reduced VC may result in the need for additional support to increase
inspiratory lung volume and thereby improve PCF.
Insufflation Capacity (IC) is the maximum assisted inspiratory lung volume. In
contrast to VC, which is generated by the patient’s own effort without further
assistance, IC represents the volume generated with external positive pressure
support. IC is therefore usually greater than VC and can be used to guide the
initiation and evaluate the effects of cough augmentation techniques [4]. Various
approaches exist to support inspiration in patients with NMDs including intermittent
positive pressure breathing (IPPB), breath stacking (also known as air stacking) with
a manual resuscitation bag or by using volume-cycled mechanical ventilation as well
as single-breath manual hyperinflation with a resuscitation bag. IC can be subdivided
into maximum insufflation capacity (MIC) and lung insufflation capacity (LIC). LIC
signifies the maximum assisted lung volume without the patient holding his/her
breath at the end of inspiration, whereby MIC measures the maximum lung volume
the patient can hold in his/her lungs when holding his/her breath and closing the
glottis. LIC and MIC can both be measured with portable spirometers on expiration

after assisted inspiration. The method of assisted inspiration is thereby dependent on

the patient’s ability to cooperate and to hold his/her breath.
As in many other lung function parameters, VC, LIC and MIC are strongly
dependent on the patient’s age, height and sex but primarily on disease progression.
It is therefore not possible to define standardised cut-off values for these parameters
regarding cough effectiveness. Regular measurements can give an impression on
the trend and development of respiratory compromise in NMD patients to guide
possibly necessary adaptations to cough augmentation therapy.
Maximum Expiratory Pressure (MEP)
Beside PCF, VC and IC, maximum expiratory pressure (MEP) is a valid and
sensitive predictor of cough effectiveness. MEP strongly relates to expiratory muscle
insufficiency caused by abdominal muscle weakness. Transverse and oblique
abdominal muscles are needed to generate cough flow by forced contraction during
glottis opening. A MEP of 40cmH2O is commonly described as the threshold value
for expiratory muscle strength with regards to cough impairment [8]. In patients with a
MEP lower than 40cmH2O, assisted coughing techniques such as manually assisted
cough (MAC) or mechanical insufflation-exsufflation (MI-E) might be needed to
compensate for expiratory muscle weakness.
Some authors have proposed measuring maximum inspiratory pressure (MIP) to
evaluate cough effectiveness and MIP can be measured as part of routine lung
function measurements. Nevertheless, measurements of VC and IC have shown to
be more relevant than MIP as they indirectly refer to diaphragm strength but the
amount of inspired lung volume seems to be of higher importance than the negative
pressure, which can be generated by the diaphragm.
COUGH AUGMENTATION TECHNIQUES
If an impairment in cough function was identified in a patient with NMDs based

on the evaluation strategies described above, several techniques exist to support the
patient’s cough manoeuvre. The choice of the most suitable approach is dependent
on the patient’s individual degree of impairment. Based on the assessment and
measurements it is key to identify the affected components of the cough mechanism
leading to the reduction in cough effectiveness in order to find appropriate techniques
to compensate for these affected components. An overview over common cough
augmentation techniques is presented in table 2. The techniques used for cough
augmentation have barely changed over the last years. However, some new findings
on the efficacy and safety of some techniques will be discussed in the next sections.

Table 2. Overview of commonly used cough augmentation techniques
Assisted Inspiration
intermittent positive pressure breathing (IPPB)
breath stacking (air stacking)
assisted single-breath insufflation
glossopharyngeal breathing (GPB)
mechanical insufflation (MI)
Assisted Expiration
manually assisted cough (MAC)
mechanical exsufflation (ME)
Assisted Inspiration and Expiration
manually assisted cough with assisted inspiration
mechanical insufflation-exsufflation (MI-E)
Assisted Inspiration
If progressive muscle weakness in NMDs affects the inspiratory muscles (mainly

the diaphragm), a reduction in vital capacity is likely to occur. This leads to an
inability to increase inspiratory volume and intrathoracic pressure in order to cough
efficiently. Externally assisted inspiration helps in raising intrathoracic pressure. In
addition, increased thoracic expansion through assisted inspiration leads to a better
useof the lungs‘elastic forces, thus augmenting expiratory airflow through elastic
recoil while coughing. Another positive effect of assisted inspiration to maximum IC is
the recruitment of collapsed or poorly ventilated lung areas to prevent the occurrence
of atelectasis. Recent publications have concluded that assisted inspiration may be
equally as important as assisted expiration in patients with weak cough [4]. In many
cases, supporting deep inspiration to reach IC can increase PCF effectively without
any further need of assisted expiration.
Various techniques exist to support deep inspiration. IPPB, GPB, breath stacking
(or air stacking) with a manual resuscitation bag or by using volume-cycled
mechanical ventilation as well as single-breath manual hyperinflation with a
resuscitation bag are commonly described in the literature. The choice of the
technique used is thereby dependent on the patient’s ability to cooperate, glottic
function and the personal preference and comfort of the patient. A frequently
discussed issue regarding assisted inspiration techniques is the optimal applied
pressure and volume to successfully improve cough flow while at the same time
avoid any risk of lung tissue damage due to barotrauma. Mellies and Goebel have
tried to investigate the optimal IC to maximise PCF. This study showed that the most
effective increase in PCF was not reached after maximum IC, but at about 80-90% of
maximum IC [6]. In addition, the optimum positive pressure used to assist inspiration
prior to coughing was significantly lower than the commonly cited 40cmH2O with a
mean pressure of 27cmH2O. The authors concluded that deep but submaximal
insufflation with a longer inspiratory rise time of about three seconds results in the
most effective increase in PCF and the lower pressures used to reach the

submaximal insufflation contributes to a reduction in the risk for barotrauma while at

the same time improving patients’ comfort during therapy. The techniques used in
this study were two variations of IPPB, but the results might be helpful in guiding
clinical practice also in other assisted inspiration manoeuvres.
Assisted inspiration is an important and effective approach to augment PCF and
for itself can often be helpful in improving cough function in NMD patients.
Nevertheless, when expiratory muscle weakness progresses it might be necessary to
additionally support the patient’s expiration to sufficiently increase PCF.
Manually Assisted Cough (MAC)
Manually assisted cough (MAC) is the most basic method of assisted expiration
in patients with NMDs and ineffective cough. It is usually performed by a therapist or
caregiver and consists of manually applied central or lateral abdominal thrust and/or
abdominal or thoracic compression to compensate for abdominal muscle weakness.
It is thereby not dependent on any device. MAC can be used as a technique on its
own or in combination with the assisted inspiration techniques described above. The
aim of MAC is to abruptly increase intraabdominal pressure in order to increase
expiratory airflow due to a strong cephalad movement of the diaphragm.
Studies on MAC report on differing results with some showing positive effects on
PCF and others resulting in no or clinically not relevant increases in expiratory airflow
[2]. However, recent publications mostly agree that combining MAC with assisted
inspiration techniques such as breath stacking, is more effective than MAC alone.
The combination of MAC with mechanical insufflation-exsufflation (MI-E) is also
possible and might be an option in patients with very low baseline PCF and severe
forms of cough impairment [9].
The use of MAC may be limited by some factors. In patients with severe NMD-
related kyphoscoliosis, MAC may be difficult to apply due to the altered structural
constitution of the thorax. In addition, MAC requires a good coordination between the
therapist/caregiver and the patient and some patients might find the applied manual
pressure uncomfortable [2].
Another aspect regarding MAC that has barely been investigated is its
applicability in the outpatient setting. Almost all papers on MAC investigate its effect
on PCF when health-care professionals carry out the technique. To reduce the risk of
respiratory complications requiring hospital treatment in NMD patients it is key to
provide them with effective cough augmentation techniques that they or their families
and caregivers can carry out at home. Kan and colleagues have investigated the
effects of MAC performed by non-professionals in a recently published study. The
authors found out that MAC was ineffective in augmenting PCF to a relevant extent
not only when performed by non-professionals, but also when carried out by
therapists [10]. Two major conclusions can be drawn from this publication. First, it is
necessary to instruct MAC to caregivers and families several times and re-evaluate
the execution of the technique. In Kan’s study, instructions were only given once.

Second, in this study MAC was performed without prior assisted inspiration, which
again indicates that the inspiratory component of cough augmentation might be
equally as important as the expiratory component. It has to be taken into account that
performing an assisted inspiration technique prior to MAC requires further knowledge
and training for families/caregivers and might therefore not be the best option for
long-term treatment at home.
MAC has shown to be an effective treatment for impaired cough function when
combined with assisted inspiration but its efficiency when performed alone and its
use in the outpatient setting have to be questioned. An alternative cough
augmentation technique that might be easier to apply for non-professionals is
mechanical insufflation-exsufflation.
Mechanical Insufflation-Exsufflation (MI-E)
Mechanical insufflation-exsufflation (MI-E), commonly known as cough assist,

consists of a mechanically assisted deep inspiration, followed by a mechanically
supported forced expiration or cough manoeuvre. PCF augmentation is achieved by
using positive (insufflation) and negative (exsufflation) pressures to compensate for
both, inspiratory and expiratory muscle weakness. The lungs are thereby inflated to
optimal IC before air and secretions are removed from the lungs due to the
suctioning effect resulting from the negative pressure during the exsufflation phase.
MI-E can be applied via oronasal mask or by using a tracheostomy or endotracheal
tube connector and can be prescribed in the clinical, as well as in the home-care
setting.
The use of MI-E has become more and more common during the last years and
it is frequently prescribed in patients with NMDs as a regular out-of-hospital
treatment to prevent respiratory infections. MI-E is recommended for patients with
severely impaired cough function and low baseline PCF who fail in increasing PCF
with other approaches [4]. Lacombe and colleagues have compared MI-E with
assisted inspiration followed by MAC and showed that MI-E+MAC and MI-E alone
were less effective than IPPB+MAC in increasing PCF [9]. The authors concluded
that IPPB+MAC is easier to use and more beneficial than MI-E in NMD patients. This
statement again leads to the question, how the results would have looked like if non-
professionals, for example the patient’s relatives, carried out the techniques. It has to
be considered that performing an assisted inspiration technique followed by MAC
requires good coordination and practice and may be challenging for non-
professionals. MI-E might be a good choice for home-care as the machines are
usually easy to handle after initial setup in the hospital. In a 2015 survey among
Australian NMD patients who used MI-E at home, more than 90% of the patients
reported on a subjective benefit from the device and would recommend it to other
NMD patients [11]. Patients who did not use MI-E also faced a higher risk of
hospitalisation (RR = 1.76, 95%CI 1.1-2.84). The survey’s results show that home

use of MI-E might be highly beneficial for NMD patients, although only 37 patients
participated in this study.
Beside the discrepancy between inpatient and home-care setting, which also
affects other cough augmentation techniques, some other questions regarding MI-E
have not been clearly answered by now. Despite its common usage, evidence on the
effects and possible risks of MI-E is still low. In a systematic review including 12
publications on safety and benefits of MI-E, Auger and colleagues showed that
evidence on long-term outcomes of MI-E is still lacking and recent publications have
not conducted follow-up measurements on mortality, hospitalisation rates and
respiratory decline over longer periods [12]. This lack of robust data stays in contrast
with the common usage of MI-E and its recommendation in current guidelines.
The two main concerns that arose in the past regarding the safety of MI-Ewere
the suspected risk for barotrauma due to high insufflation pressures and the limited
use of MI-E in patients with bulbar palsy, due to dynamic airway narrowing.
There is currently no clear consensus on positive pressure limits to avoid
barotrauma due to the insufficient evidence about long-term effects as mentioned
above. In most publications, pressure settings of -40cmH2O to +40cmH2O have been
regarded as safe, whereby some studies also used higher pressures (up to
+70cmH2O) and didn’t report any adverse events [4]. Despite the lack of information
on peak pressure settings, some recommendations can be made to avoid the risk for
barotrauma. First, as mentioned in the section about assisted inspiration, maximum
IC may not result in the highest increase in PCF. In the previously presented study
by Mellies and Goebel, submaximal insufflation did bring the most benefit [6].
Although the authors used IPPB for insufflation assisted inspiration, applying the
findings to insufflation via MI-E seems logical. It might therefore be worth to measure
maximum IC before MI-E setup and choose inspiratory pressures to reach sufficient
but submaximal IC. This approach is also consistent with the recommendations by
Chatwin and colleagues not to use standardised settings for each patient, but
gradually increase pressures based on the PCF achieved and the patient’s individual
perception and comfort [4].
Previous publications discussed the use of MI-E in patients with bulbar palsy and
non-invasive respiratory management. Some authors concluded that its use in this
cohort of patients was either ineffective or even dangerous due to hypopharyngeal
narrowing. Andersen et al. investigated the effects of MI-E in 20 ALS patients with
bulbar palsy and 20 healthy controls using varying pressure settings while performing
laryngoscopy [13]. The authors found out, that laryngeal constriction on exsufflation
can be observed in the ALS as well as in the healthy control group, but participants
with bulbar palsy showed laryngeal adduction also during insufflation. The authors
concluded that protective laryngeal reflexes are triggered during insufflation and lead
to the observed constriction, which might limit efficacy of MI-E. Instead of seeing
bulbar symptoms as a contraindication for MI-E, Andersen and colleagues suggest to
adapt the settings by using patient-triggered MI-E modes with a longer inspiratory
time of three seconds, lower inspiratory flow and lower inspiratory pressure to avoid
the risk of treatment failure.

Another limitation of MI-E is its difficult use in patients who are not able to
coordinate their cough manoeuvre with the machine’s settings, e.g., young children
or patients with cognitive impairment, but patient-triggered MI-E modes may help in
coping with this problem. In addition, patients with active airway bleeding, nausea or
pneumothorax are not suitable for MI-E. The concern of developing pneumothorax
due to MI-E has been raised but there is no evidence for an increased risk of this
complication based on recent findings [12].
CONCLUSION
Summarising the findings on cough management, some conclusions can be

drawn for research and clinical practice:
A lot is known about the physiological cough mechanism and its pathological
alterations in patients with neuromuscular diseases. Various techniques for cough
augmentation exist and the choice of the right approach remains challenging.
Regular evaluation of cough function and measurements of objective parameters is
the foundation for clinical decision-making and no overall valid recommendations can
be made on which cough augmentation technique to use. Solutions have to be found
on a case-by-case basis and clinical evaluation as well as close cooperation with the
patient and his/her family and caregivers is key in finding effective and sustainable
approaches.
Further research on cough augmentation in NMDs needs to focus on two main
aspects: Investigating long-term effects and long-term outcomes of different
therapeutic techniques and examining the efficacy and feasibility of these techniques
when performed by non-professionals in the home-care setting. These two topics
seem to be relevant as avoiding hospitalisations and deterioration as well as
maintaining quality of life for patients at home is one of the main goals of medical
management in patients with these mostly incurable diseases. It is therefore
necessary to provide them with techniques that are effective, easy to apply and as
comfortable as possible.
Key Messages
 Evaluate cough function by measuring PCF, PCFass, PEF, VC, IC and MEP
in addition to the patient’s history and clinical examination at every hospital
visit to early detect cough insufficiency and initiate or adapt cough
augmentation techniques.
 The choice of cough augmentation techniques is based on case-by-case
decisions and dependent on the impaired cough components and the
patient’s preference.

 Assisted inspiration alone can be sufficient to increase PCF in patients with

maintained expiratory muscle strength.
 Assisted expiration (MAC or ME) without assisted inspiration appears to be
ineffective based on recent publications.
 In patients with severe cough impairment, assisted inspiration and expiration
(assisted inspiration + MAC, MI-E, MI-E + MAC) is needed.
 When choosing a cough augmentation technique for a patient, always
consider home-care management and feasibility of the technique.
 MI-E pressure settings need to be increased gradually and individually
targeted for each patient.
 MI-E in patients with bulbar dysfunction is possible but requires certain
adaptations regarding pressure and flow settings.
REFERENCES
[1] Bach, John R. 2017. “Noninvasive Respiratory Management of Patients with

Neuromuscular Disease.” Annals of Rehabilitation Medicine. https://doi.org/
10.5535/arm.2017.41.4.519.
[2] Boitano, Louis J. 2006. “Management of Airway Clearance in Neuromuscular
Disease.” In Respiratory Care.
[3] Bach, John R., and Lou R. Saporito. 1996. “Criteria for Extubation and
Tracheostomy Tube Removal for Patients withVentilatory Failure: A Different
Approach to Weaning.” Chest. https://doi.org/10.1378/chest.110.6.1566.
[4] Chatwin, Michelle, Michel Toussaint, Miguel R. Gonçalves, Nicole Sheers, Uwe
Mellies, Jesus Gonzales-Bermejo, Jesus Sancho, et al. 2018. “Airway
Clearance Techniques in Neuromuscular Disorders: A State of the Art Review.”
Respiratory Medicine. https://doi.org/10.1016/j.rmed.2018.01.012.
[5] Kulnik, Stefan Tino, Victoria MacBean, Surinder Singh Birring, John Moxham,
Gerrard Francis Rafferty, and LalitKalra. 2015. “Accuracy of Portable Devices
in Measuring Peak Cough Flow.” Physiological Measurement. https://doi.org/
10.1088/0967-3334/36/2/243.
[6] Mellies, Uwe, and Christof Goebel. 2014. “Optimum Insufflation Capacity and
Peak Cough Flow in Neuromuscular Disorders.” Annals of the American
Thoracic Society. https://doi.org/10.1513/AnnalsATS.201406-264OC.
[7] Benditt, Joshua O. 2019. “Respiratory Care of Patients with Neuromuscular
Disease.” Respiratory Care. https://doi.org/10.4187/respcare.06827.
[8] Sferrazza, Papa, Giuseppe F., Giulia M. Pellegrino, Hameeda Shaikh, Agata
Lax, Luca Lorini, and Massimo Corbo. 2018. “Respiratory Muscle Testing in
Amyotrophic Lateral Sclerosis: A Practical Approach.” Minerva Medica.
https://doi.org/10.23736/S0026-4806.18.05920-7.
[9] Lacombe, Matthieu, Lorena Del AmoCastrillo, AurélienBoré, David Chapeau,
Eric Horvat, Isabelle Vaugier, Michelle Lejaille, David Orlikowski, Hélène

Prigent, and FrédéricLofaso. 2014. “Comparison of Three Cough-Augmentation

Techniques in Neuromuscular Patients: Mechanical Insufflation Combined with
Manually Assisted Cough, Insufflation-Exsufflation Alone and Insufflation-
Exsufflation Combined with Manually Assisted Cough.” Respiration. https://doi.
org/10.1159/000364911.
[10] Kan, Amelia F., Jane M. Butler, Meghan Hutchence, Kristi Jones, John Widger,
and Michael A. Doumit. 2018. “Teaching Manually Assisted Cough to
Caregivers of Children with Neuromuscular Disease.” Respiratory Care.
https://doi.org/10.4187/respcare.06213.
[11] Mahede, Trinity, Geoff Davis, April Rutkay, Sarah Baxendale, Wenxing Sun,
Hugh J.S. Dawkins, Caron Molster, and Caroline E. Graham. 2015. “Use of
Mechanical Airway Clearance Devices in the Home by People with
Neuromuscular Disorders: Effects on Health Service Use and Lifestyle
Benefits.” Orphanat Journal of Rare Diseases. https://doi.org/10.1186/s13023-
015-0267-0
[12] Auger, Catherine, Vanessa Hernando, and Hubert Galmiche. 2017. “Use of
Mechanical Insufflation-Exsufflation Devices for Airway Clearance in Subjects
with Neuromuscular Disease.” Respiratory Care. https://doi.org/10.
4187/respcare.04877.
[13] Andersen, Tiina, Astrid Sandnes, Anne Kristine Brekka, Magnus Hilland,
HegeClemm, Ove Fondenes, Ole BjørnTysnes, et al. 2017. “Laryngeal
Response Patterns Influence the Efficacy of Mechanical Assisted Cough in
Amyotrophic Lateral Sclerosis.” Thorax. https://doi.org/10.1136/thoraxjnl-2015-
207555.

SECTION 5. METHODOLOGY/INVASIVE VENTILATION

Chapter 20
INVASIVE VENTILATION
David Orlikowski*
Intensive Care Unit, Home Ventilation Department,
Neuromuscular Disease Center Paris, North, East
Raymond Poincaré Hospital, Paris Saclay University hospital,
Versailles Saint Quentin University
ABSTRACT
Neuromuscular diseases represent a group of pathologies characterized by a

progressive muscular weakness that can involve respiratory muscle.
Home Ventilation is usually proposed for occurrence of alveolar
hypoventilation during nighttime and first non-invasively. Some diseases as
Duchenne Muscular dystrophy will evolve to full ventilator dependency
conducting to full time ventilation non-invasively or invasively. In other situations
invasive ventilation is proposed after acute respiratory failure.
Invasive ventilation through a tracheostomy tube was the first technique that
allowed long term ventilation, survival and discharge of NMD patients
Whatever the situation invasive ventilation require adequate choice in term of
type of ventilation, ventilator choice and interface in order to preserve security,
autonomy, speech and nutritional aspects in this population.
Keywords: invasive ventilation, tracheostomy tube, home ventilation, critical care
INTRODUCTION
Neuromuscular diseases represent a group of more than 120 different

pathologies. Their main common feature is the motor unit impairment that can
*
Corresponding Author’s E-mail: david.orlikowski@aphp.fr.

288 David Orlikowski
concern muscle, neuromuscular junction, nerves and second motor neurons. Only
one part of the motor unit is usually involved and the most important group
represented is myopathies. Association can occur and sometimes different motor unit
component could be concerned together (peripheral nerve and muscle in DM1 or
Mitochondrial myopathies by example) as nervous central system could be involved
(respiratory command in DM1) or other organs like heart like Duchenne Muscular
Dystrophy or some limb girdle muscular dystrophies or congenital muscular
dystrophies.
Their clinical presentation, evolution and prognosis could also be different within
disease and within patients.
The severity and prognosis of these diseases are closely linked to the severity of
the respiratory impairment conducting to respiratory muscle weakness, cough
impairment, sometimes swallowing and/or glottis dysfunction. Natural histories
maybe different but the result is occurrence of alveolar hypoventilation and indication
of mechanical ventilation. In France it is estimated by the French High authority of
Health that more than 20 000 patients are concerned [1]. Invasive ventilation is
usually realized through a tracheostomy tube to permit full time ventilation both
daytime and night time 24h a day.
For chronic patients it was the first technique that was proposed for long term
ventilation in NMD patients [2] permitting to improve life expectancy for these
patients [3].
Despite introduction of full-time noninvasive ventilation techniques as mouthpiece
ventilation and existing debate concerning its safety and economic burden [4],
Invasive ventilation remains appropriate for more severe and ventilator dependent
patients.
The rate of invasively ventilated patients varies widely between countries.
Common in Scandinavian countries and France but rare in United Kingdom and
USA. In European countries it was evaluated at 13% and 18% in Canada [5 and 6].
HISTORY OF INVASIVE VENTILATION IN NMD
Invasive ventilation is a technique derived from anesthesia delivered through an

intubation or a tracheostomy tube. It is the first technique that was used for long term
mechanical ventilation, first for days or weeks in the acute setting and became the
gold standard for caring patients with acute respiratory failure but also in the long
term for patients remaining dependent of the ventilator after one episode of ARF or
due to respiratory or neurological disease.
Its introduction followed the poliomyelitis pandemic of the 1950-60’s and
development of mechanical ventilation. The usage of iron lung was limited by a
mortality rate over 80%.

Invasive Ventilation 289
Because severe upper airways obstructions during negative pressure phase of

ventilation can occur tracheostomy was proposed to be associated with negative
pressure ventilation. This rate was not reversed by tracheostomy usage [17].
Ibsen during the polio epidemics in Denmark and Sweden in the early 50’s
introduced manual intermittent pressure ventilation (a technique derived from
anesthesia) that as permitted to ventilate invasively (with help of more than 1000
medical students and nurses) and during weeks severe poliomyelitis patients until
they recover or be placed under mechanical ventilation. Survival improved
dramatically dropping mortality from 87% to 26% and this demonstration of invasive
techniques and positive pressure ventilation was accompanied with the development
of mechanical positive pressure ventilators. Interestingly this technique was
previously used with mechanical ventilator 1948 by Albert Bower with 17% mortality
rate [18].
The first machines use for IPPV were primarily anesthetic ventilators as
Pulmoflator, Mørch-1 respirator but were rapidly followed by introduction of dedicated
commercial device as Engström 150 developed in 1954 in Sweden which
inaugurated the mechanical ventilation Era [18 and 19].
In Europe a new medical specialty merged “Intensive care” and this period saw
the birth of several ICU on the model of dedicated poliomyelitis unit first developed
as in France in Parisian Claude Bernard Hospital by Pr Mollaret.
Quality, knowledge and management of care increase gradually over time
transforming acute disease in chronic disease and questioning for discharge and
long-term facilities.
Development of the first lightweight respirators making it possible, for the first
time, to consider the return home of patients. By example he “Radcliffe”, of English
origin, was powered by an electric motor and a weight to compress the air blown into
the lungs. However, adapting these techniques to patients’ homes still posed
problems of monitoring, oxygen supply, autonomy, and even congestion.
Subsequently, many technical advances were made, introduction of positive
expiratory pressure (PEP) and barometric ventilation modes. The introduction of
electronics has made it possible to improve the performance of fans, better cycling,
therefore better tolerance, but also better monitoring through the use of alarms. The
addition of batteries also allowed greater mobility and greater autonomy for the
patient, as for the first time with the EOLE © (SAIME company, Savigny le Temple,
France) [19], thus making it possible to embark the ventilator on a wheelchair and
thus giving the patient the possibility of leaving his home.
First used to discharge post-poliomyelitis patients and after vaccination
implementation these techniques were progressively proposed to neurological
disease acute or chronic with respiratory failure.

INDICATIONS OF INVASIVE VENTILATION
Two methods of long-term/home ventilation can be distinguished: invasive

ventilation (IV), refers to methods requiring tracheostomy, and non-invasive
ventilation (NIV) grouping all ventilation methods using upper airways interfaces [7,
8, 9, 10].
Table 1. Principal progressive neuromuscular disease

with respiratory failure and respiratory management
Diagnosis Characteristics of respiratory Management

failure
Duchenne muscular Severe and progressive occurring NIV first nightime and full time (mouthpiece)
dystrophy after loss of ambulation IV could be required for full time ventilation
Becker Muscular Dystrophy Rare usually associated with loss NIV principally, IV rarely required
of ambulation
Limb girdle myopathy 2C Severe and progressive like DMD NIV first nightime and full time (mouthpiece)
and D (α and γ IV could be required for full time ventilation
sarcoglycanopathy)
Limb girdle myopathy 2I (α Severe and progressive like DMD NIV first nightime and full time (mouthpiece)
dystroglycanopathy) IV could be required for full time ventilation
Myotonic dystrophy type 1 Frequent and complex (Myotonia, NIV
respiratory command, sleep IV sometimes required usually after ARF
disturbance)
Emery Dreyfuss muscular Severe and progressive like DMD NIV first nightime and full time (mouthpiece)
dystrophy IV could be required for full time ventilation
Limb girdle myopathy 2B Rare NIV, IV rarely required
(Dysferlin),
Desmin related myopathy Progressive and severe NIV first nightime and full time (mouthpiece)
IV could be required for full time ventilation
Facio-scapulo-humeral Uncommon usually associated to NIV first
myopathy loss of ambulation IV sometimes used for more severe form
Pompe disease Common could be dissociated of NIV first
limb weakness Full time NIV or IV could be required
Ullrich congenital muscular Severe usually occurring during NIV first
dystrophy childhood could be dissociated of Full time NIV or IV could be required
limb weakness
SEPN1 congenital muscular Severe usually occurring during NIV first
dystrophy childhood or later could be Full time NIV or IV could be required
dissociated of limb weakness
Hereditary myopathy with Rare disease severe respiratory NIV first
early respiratory failure impairment Full time NIV or IV could be required
(Titin)
SMA Frequent for type 1 and 2 NIV first
Uncommon for type 3 and 4 IV (except type 1a) usually required during
childhood
Congenital myasthenic Variable within subtypes, DOK7 NIV first
syndrome frequent and severe Full time NIV or IV could be required
Mitochondrial myopathies Variable within subtypes NIV first
Full time NIV or IV could be required

Long-term ventilation can be initiated either as part of patient planned follow-up

or during an episode of acute respiratory failure. Such episodes may reveal the
disease or occur due to lack of follow-up [11]. Planned initiation of HMV usually
begins by noninvasive ventilation carried out according to consensus criteria, which
are defined by the existence of clinical signs suggestive of hypercapnia associated
with alveolar hypoventilation (PaCO2 >= 45 mmHg), nocturnal desaturation (SaO2
<= 88% for five consecutive minutes) or restrictive lung disease (vital capacity below
60% of predicted) [12, 13, 14].
The evolution of motor impairment and/or weakness of the respiratory muscles
will be accompanied by increasing dependence on the ventilator. This is particularly
observed in the case of progressive muscular dystrophies such as DMD [15]. The
discussion will therefore be to increase the duration of ventilation by combining night
ventilation, daytime ventilation up to 24-hour ventilation in order to reverse alveolar
hypoventilation.
An important issue is the indication for a tracheostomy. In clinical practice, the
most important factors to indicate tracheostomy is progression of disease and
respiratory weakness and thus inefficacy of noninvasive techniques rather than
events related to cough and bulbar weakness with aspiration despite adequate
cough assistance [16]. Also, when patient requires daytime ventilation or is ventilator
dependent, the tracheostomy is not yet proposed as a first choice but must still be
considered as an option for full time ventilation and for relieve upper airway
obstruction and facilitated of tracheobronchial toileting [7]. Tracheostomy may be
necessary transiently, to remove a patient from intensive care or to facilitate
ventilatory weaning in the event of an acute pathology, but the problem is especially
important in chronic evolutive pathologies where it will most often be permanent. In
practice, the most important decision factors are the progression of the disease, the
weakness of the respiratory muscles and the ineffectiveness of non-invasive
ventilation techniques more than the existence of crowding or bulbar disorders [20].
The decision to have a tracheostomy will involve considerations including the risk
of complications, the means available (in terms of cost, technical and human aids),
quality of life, aesthetic considerations and the wishes of the patient.
This technique was one of the first used for long-term ventilation and has long
been the gold standard for ventilation in neuromuscular diseases [20 and 21]. It is
still used in many countries for ventilation in proportions ranging from 10 to 80% of
patients [5]. There are great cultural and social differences vis-à-vis this technique
and in the way of treating patients with tracheostomies. In Europe, France and the
Scandinavian countries in particular, care networks are organized, and resources are
allocated to allow the maintenance and care at home of highly dependent patients,
including those with tracheostomies and ventilated 24 hours a day. Conversely, in
Anglo-Saxon countries there are no such management systems [22] for
tracheostomized patients, which could explain in particular that in the United States,
non-invasive mechanical ventilation techniques are preferred, including for the most
dependent patients [23].

Indications have changed over time and those proposed by the American
College of Chest Physicians [24], and recently by the American Thoracic Society [25
and 26] and DMD care considerations group include: the need for daytime
ventilation, ventilator dependence, the existence of a bulbar involvement with
frequent inhalations despite effective cough assistance. Tracheostomy is no longer
considered the first line for 24-hour ventilation but remains a therapeutic technique.
These recommendations emphasize the patient’s choices and the importance of
educating both the patient and those around him.
Table 2. Guidelines for invasive ventilation
 ACCP consensus 1998 Indications for invasive  Uncontrollable airway secretions despite use of
ventilation noninvasive expiratory techniques; or
 Impaired swallowing leading to chronic aspiration
and repeated pneumonias
 Persistent symptomatic respiratory insuffisiency
and fails to tolerate or improve with NIV.
 Ventilatory support >20h00 per 24h
 Choice of patients
 ATS 2004 Duchenne muscular dystrophy  Consider daytime ventilation if PaCO2> 50 mmHg
guidelines SaO2<92%
 Consider tracheostomy when contraindications or
patient aversion to NIV or when NIV is not
feasible due to severe bulbar dysfunction.
 Education +++
 DMD Care considerations working Group (2010)  Indications of tracheostomy include :
 Patients and clinician preference
 Patient cannot successfully use non-invasive
ventilation
 Inability to support fulltime non-invasive ventilation
by the medical structure
 Threes failures to achieve extubation during ICU
stay
 Failure of non-invasive methods of cough
assistance to prevent aspiration of secretions
Some authors have proposed using non-invasive methods, such as mouthparts

or pipettes, for the continuous ventilation of neuromuscular patients. These
techniques, combined with cough assistance techniques, are offered as an
alternative to tracheostomy [27]. Recently Toussaint et al. have shown that
continuous ventilation in patients with DMD from Boulogne allowed a life expectancy
of up to 31 years [28]. However, these methods should be applied by experienced
centers because they are particularly time consuming for caregivers, particularly
during episodes of acute respiratory decompensations [29].
These methods have been used to wean neuromuscular patients from
tracheostomy and place them (or put them back on non-invasive ventilation). In a
study of 257 patients requiring mechanical ventilation, Bach et al. were able to

decanulate and place (or replace) 67 patients under non-invasive ventilation, while
52 patients underwent tracheostomy at the same time. However, these methods
appeared to be less effective in the subgroup of patients with myopathy and mortality
was 2 times lower in patients with tracheostomy (10.5%) than in patients receiving
non-invasive techniques (22.5%) [27]. These observations are consistent with the
results reported by Raphaël et al. which suggested that patients with DMD may have
prolonged survival compared to ventilated patients with non-invasive ventilation [30].
These results must be qualified by the fact that the patients were not systematically
educated in the techniques of assisted coughing and that the existence of cardiac
involvement was not reported [30]. Recently Soudon et al. compared 2 series of
patients with continuously ventilated DMD, one group was ventilated by
tracheostomy and the other exclusively by non-invasive techniques. Despite a longer
duration of disease and greater respiratory involvement in the group of tracheostomy
patients, mortality and causes of death were identical regardless of the type of
interface used, invasive or not [31].
Many advantages are associated with tracheostomy ventilation: better ventilation
efficiency, better interface connection to the ventilator circuit, direct access to
tracheal secretions and reduced work of breathing when disconnecting the ventilator
and breathing free (reducing dead space and work of breathing) [32]. It is obvious
that the connection is of better quality than a mouthpiece or a pipette, the aspirations
and the change of cannula are possible in the event of obstruction by secretions and
the caregivers as well as the entourage of the patient can be easily educated [33].
However, there are many complications usually associated with a tracheostomy,
such as difficulty speaking and swallowing. Mechanical complications such as plugs
or tracheal lesions (sometimes fatal when they lead to cataclysmic bleeding) are also
attributed to the tracheostomy as well as reduced quality of life [34].
There is no study that has compared the effectiveness of invasive and non-
invasive ventilation, but Gonzalez et al. [35] demonstrated that despite more
advanced respiratory involvement for the same level of leakage, ventilation was more
effective in tracheostomy patients compared to non-invasive ventilated patients. In a
population of patients ventilated for sequelae of polio, sleep appeared to be of better
quality in patients with tracheostomies despite the same efficiency of mechanical
ventilation [35 and 36]. Recently we demonstrated in sever DMD that despite
adequate daytime ventilation IV could be associated to nocturnal hypoventilation due
to leaks during sleep [37].
MANAGEMENT OF INVASIVE VENTILATION
Mode of Ventilation
The choice of the ventilatory mode between pressure modes (pressure controlled
or pressure support) and volumetric mode has no incidence in correction of alveolar

hypoventilation ventilation and decrease of respiratory effort indices in

neuromuscular patients [32].
Volume targeted modes deliver a preset inspiratory flow until the targeted volume
is reached, sometimes with variation of peak inspiratory pressure to achieve. These
modes are able to compensate for changes in resistance and compliance by varying
inspiratory pressure. They cannot fully compensate for the presence of airway leaks
with the risk of underventilation in patients invasively ventilated with uncuffed tubes.
Pressure targeted modes deliver a preset inspiratory pressure but inspiratory
flow and volume may vary considerably, depending on compliance, resistance and
leaks [24]. These modes are able to compensate for leaks by varying inspiratory flow
(Table 3).
The assist control mode with a backup rate set to allow triggering is usually
preferred to control alveolar hypoventilation. [24], notably because of available
alarms in case of mucus plugging or cannula obstruction. Standard tidal volumes (8
to 12 ml/kg) or adequate inspiratory pressures to provide these volumes are usually
recommended for settings. If needed additional oxygen could be provided in order to
maintain a PaO2 at least 65-70 mmHg.
Table 3. Characteristics of pressure and volume modes
Volume Pressure
Advantages  Known insufflated volume  Better patient-ventilator
 Guaranteed volume whatever interaction
the resistance  (partial) compensation for leaks
 Extensive alarm possibilities  Lower cost (BiPap)
 High pressure alarms
(obstruction)
 Possibility of practicing "air
stacking"
Disadvantages  No compensation for leaks  Variability of tidal volumes
 Risk of patient/ventilator  Need for PEEP for BiPaP only
asynchronism  Limited possibilities of
 Risk of high insufflation obstruction alarm
pressures and barotrauma (if  Risk of hypoventilation in case
high resistance and / or reduced of apnea (S mode)
compliance)  Dry mucous membranes if high
 More frequent digestive flow
insufflation  No possibility of air stacking
Choice of Ventilator
The choice of ventilator must take in account the different possibilities and
specificities of ventilation for a type of patients, the autonomy of batteries, alarms and
monitoring, the mobility and usability for patients and care givers. Actual portable
ventilators are adapted for home ventilation and management of severe and fully

ventilator dependent patients. These patients require a life support device with
batteries, alarms (disconnection and obstruction) and monitoring possibilities.
Circuits must be choose in accordance to mode of ventilation i.e., vented or not
vented, type of ventilator, kind of monitoring required, humidification and mobility
constraints. Ideally, circuit needed for Life support are double limb or single limb with
expiratory valve. Some life support ventilators use vented circuit with ACV mode.
For monitoring, the minimal required is VT, respiratory rate and pressures. Actual
life support device have extended capabilities of inspiratory and expiratory pressures,
VT, minute ventilation and leaks. Expiratory Vt, more representative of alveolar
ventilation is usually measurable only in a configuration with double limb circuit.
Volume measurement may vary widely within ventilators.
Alarms are crucial especially in case of disconnection, obstruction, major leaks
and machine dysfunction. They must be set in order to be not too much sensitive (to
avoid unjustified alerts) but sufficiently secure. In our experience for ventilator
dependent and tracheostomized patients we deactivated alarms and keep only
disconnection and high pressure alarms. For tracheostomized patients ventilated in
pressure mode, it is not possible to set a high pressure alarm. Thus only low VT or
low minute ventilation alarms without drop in pressure could be identified as an
obstruction.
Humidification is mandatory for tracheostomized patients because of
humidification shunt from upper airways. It is critical for ventilation with uncuffed tube
and high amount of leaks. It is particularly critical for ventilation with vented circuit
due to high flow in trachea and high amount of leaks.
Humidification system are not usable during mobility or be put on a wheelchair
and could be only during bedtime. Moisture exchanger filters could be used during
mobility but with variable results.
To permit sufficient power autonomy is crucial for these patients for security
reason and autonomy. Duration of battery efficiency depends of minute ventilation
and flow generated by ventilator turbine, could be very variable between ventilators.
A ventilator with sufficient charge life battery (6-8 h at least) must be preferred with
the possibility of supplemental external batteries [38].
Plan for Patients
A discharge plan as a risk assessment must be proposed to patients and families

according to the use of invasive ventilation and type of ventilators [24 and 39]. In a
study on 150 tracheostomized patients defective equipment or ventilator failure were
present in 39% of cases essentially due to improper usage by caregivers [40] In a
more recent study on a total of 1200 home ventilated patients, one quarter of home
visit was for ventilator problems mainly misinterpreted by patients [41].
Ideally such discharge plan after implementation of invasive ventilation should
contain 3 components as assessment, education and training. Assessment of
resources both human in terms of caregivers and healthcare professionals (nurses,

respiratory therapist, etc. …) but also in terms of material and device available in
patient’s place. A dedicated company usually provide ventilators, circuit, connector,
humidifier, suctioning unit and catheter, tracheostomy tubes and supplies and a
manual resuscitator that is mandatory for patients without respiratory autonomy.
This company will be responsible of technical management of ventilator,
management of technical emergencies and failure and material supplies. For daily
ventilation time over 16 h per day a second ventilator is usually recommended.
Training and learning for caregivers and family in order to feel comfortable with
medical tasks as suctioning and tracheostomy care and for technical skills as
ventilator knowledge [24].
Tracheostomy Management
ACCP guidelines has recommended in 1998 to choose tracheostomy tubes in

order to assure optimal speech and swallowing as well as to minimize complications
[24].
Tracheostomy can worsen swallowing in neuromuscular patients; Soudon et al.
reported that there were more swallowing disorders in patients with DMD and
tracheostomies [31]. Paradoxically, non-invasively ventilated patients were more
often gastrostomized and lost more weight than with invasive ventilation. As we have
seen previously, swallowing may be impaired in neuromuscular patients which may
be responsible for a lack of synchronization with breathing and worsen the risk of
inhalation. As we specified in chapter 2.c.vi, we demonstrated on the one hand that
in NM patients with tracheotomies swallowing was shorter and less fragmented
under mechanical ventilation than on spontaneous ventilation [42], and other than in
a population of DMD patients for whom the indication for tracheostomy was raised,
the joint effect of tracheostomy and mechanical ventilation improved swallowing
performance [42]. To better appreciate the effect of tracheostomy on the interaction
between breathing and swallowing, we compared in 7 Duchenne muscular
dystrophy, this interaction before and after tracheostomy. We were thus able to
demonstrate that in this population, for whom the indication for tracheostomy is
posed by a dependence on mechanical ventilation and poor tolerance of non-
invasive ventilation that the tracheostomy associated with ventilation improved the
swallowing parameters [43].
Speech is sometimes impaired and is usually only possible in tracheostomy
patients during the inspiratory phase of mechanical ventilation, if there is sufficient
leakage around the tracheostomy cannula. The lack of leakage around the cannula
during exhalation explains the inability to speak and the fragmentation of speech,
punctuated by the frequency of the ventilator. Several methods can be used to
improve speech in a patient with a tracheostomy. First it is essential to deflate the
cuff or use cannulas without cuff [44], which allows the use of unidirectional
phonation valves in spontaneous breathing [45] or a Passy-Muir valve during
ventilation [46]. Another method to improve ventilated speech is to add positive

expiratory pressure (PEP) and/or increase inspiratory time to allow speech

throughout the respiratory cycle [47].
CONCLUSION
Invasive ventilation is not actually the first choice for long term and full time
ventilation in most dependent neuromuscular patients and is now proposed in
patients without efficacy or tolerance of noninvasive approaches.
A careful management of mode ventilation, settings, and choice of ventilators
dedicated materials and supplies, interfaces and training of caregivers is necessary
to optimize patient’s respiratory care.
Despite several complications and limitations, this technique is still used in many
countries permitting to maintain quality of ventilation and quality of life.
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Chapter 21
WEANING FROM MECHANICAL

VENTILATION AND EXTUBATION
Piero Ceriana* and Cinzia Lastoria

Pneumologia Riabilitativa e Terapia Sub-Intensiva Respiratoria,
ICS Maugeri IRCCS – Pavia, Pavia, Italy
ABSTRACT
Approximately 40 per cent of patients admitted to the intensive care unit
(ICU) for acute respiratory failure (ARF) require mechanical ventilation [1], in the
majority of cases for pneumonia, congestive heart failure, sepsis, trauma,
postoperative ARF and acute respiratory distress syndrome (ARDS) [2]. With the
exception of a limited percentage of patients treated with non-invasive
mechanical ventilation (NIMV) [3], the vast majority receive translaryngeal
intubation and invasive mechanical ventilation (IMV). Mechanical ventilation
works as a bridge to maintain adequate gas exchange until the restoration of the
native respiratory system function. Therefore, when the underlying cause of ARF
starts to improve, liberation from mechanical ventilation and removal of
endotracheal tube become the main objectives to achieve. The term “weaning”
implies the transition from full artificial respiratory assistance to unsupported
spontaneous breathing through the native airways.
PHASES OF WEANING
Treatment of ARF with both mechanical ventilation and medical therapy specific
for the underlying cause represents the first step for any patient undergoing artificial
respiratory assistance. Then, the process of weaning starts with the perception that
the baseline cause of ARF is improving and the suspicion that liberation from artificial
*
Corresponding Author’s E-mail: piero.ceriana@icsmaugeri.it.

ventilation could be successful [4]. During the following step, clinicians starts daily
evaluations in order to verify the reliability of previous suspicions and to plan
attempts of spontaneous breathing. Once patients have met the requirements for
starting the spontaneous breathing trial (SBT), this is carried out according to current
protocols [5]. When the patient does not fulfill the criteria for a successfull SBT,
ventilatory assistance is resumed until the next attempt, while if he/she passes the
SBT, mechanical ventilation can be discontinued. The process of weaning is
completed with the removal of the endotracheal tube, a decision based on the criteria
of preservation of upper airway patency and adequate cough mechanism [6].
WEANING FAILURE AND FAILED EXTUBATION
The need to reintubate and resume IMV within 48 hours after extubation or the
inability to pass the SBT represent the criteria commonly accepted to define weaning
failure in the acute care setting [7]. The SBT is considered failed in presence of
objective parameters like tachypnoea, tachycardia, hypertension, arrhythmia,
hypoxemia, acidosis, diaphoresis and/or subjective symptoms like distress, agitation,
perception of increased respiratory effort and impending fatigue [8]. Baseline
mechanism underlying weaning failure is the inability of the respiratory pump to
support the respiratory load, but the causes can find their origin in different systems:
respiratory, cardiovascular, neuromuscular, metabolic and psychological, in some
cases isolated, but often acting in synergy [4]. Failure of one or more of these
systems can also be the cause of almost 60% of cases of extubation failure, while in
about 30% of cases the cause must be found in the upper airways (obstruction,
aspiration, excessive secretions) [9]. Failed extubation carries a significant risk of
increased morbidity and mortality, especially when it is secondary to respiratory or
cardiovascular failure or encephalopathy rather than to an upper ayrway problem and
when there is a longer time interval from extubation to reintubation [9].
CRITICAL WEANING ISSUES
Assessment of Readyness to Wean
Unnecessary prolongation of mechanical ventilation in patients potentially

capable to breath spontaneously must be avoided, not only for the increased risk of
complications connected to invasive ventilation (infections and airway trauma) [10]
but also for the reduction of health care cost [11]. Therefore, it is strongly
recommended to apply protocols of daily screening in order to assess the readiness
to wean. In presence of all, or at least great part, of clinical criteria and objective
measures [12] indicating that the patient is ready to start a SBT, this must be done

Weaning from Mechanical Ventilation and Extubation 303
without postponement. This strategy has demonstrated a possible reduction of

unnecessary days of mechanical ventilation and a shorter duration of weaning [13].
How to Perform the SBT
The SBT has the aim to reproduce the conditions of unsupported breathing, in
order to verify the ability of the patient to breathe without artificial ventilatory aid.
Different techniques have been used to apply the SBT in practice and none of them
has demonstrated significant superiority in terms of increased weaning rate, duration
of hospital stay and morbidity or mortality. However, since the transition from artificial
ventilation to unsupported breathing implies an increased respiratory effort, the
various techniques used for the SBT may have a different impact on the patients,
expecially the ones with a limited ventilatory reserve [14]. Among the various
physiological indicators used, there are direct measurement of the work of breathing
or of the pressure-time product of the respiratory muscles [15, 16] or some
surrogates like the diaphragm electrical activity, the airway occlusion pressure in the
first 100 milliseconds (P0.1) and the rapid-shallow breathing index (ratio between
respiratory rate and tidal volume) [17-19]. Spontaneous breathing trials can be
carried out without any support, when the T-tube technique is employed, or with
some form of inspiratory and expiratory aid [20]. In these cases low pressure support
(5-7 cmH20) with or without positive end-expiratory pressure or simple CPAP can be
used. When the SBT is performed with the patient connected to the ventilator, an
aliquot of the support is due to counterbalance the respiratory circuit resistance. An
alternative SBT technique is the automatic tube compensation (ATC), which applies
an algorythm to support the extra load of the artificial airway [21]. A recent meta-
analysis [22] on this topic concluded that low pressure support reduces the work of
breathing during SBT, while T-tube or zero in-exp pressure on the ventilator best
mimic the post-extubation physiologic condition. Based on these issues, recent
guidelines suggest to conduct the SBT with pressure support (5-8 cmH2O) in
patients on IMV for >24 hours for any form of ARF [23]. None recommendation is
given with respect to the tube cuff during SBT, should it be maintained inflated or
deflated; possible advantages of a deflated tube cuff could be the reduced work of
breathing [24] and the cuff leak test for the early detection of patients at risk of post-
extubation stridor [25]. Recent guidelines [23] suggest that the performance of the
cuff leak test may reduce the risk of extubation failure in patients considered at
increased risk of post-extubation stridor and upper airway obstruction. In case the
patient fails the cuff leak test but is anyway considered ready for extubation, it is
recomended the administratuion of systemic steroids at least four hours before
extubation [23].

Management of Difficult Weaning
Among all patients treated with IMV for ARF, approximately 80% can be easily
liberated from mechanical ventilation within 24 hours, while the remaining 20%
require more days of mechanical ventilation and a well structured weaning process
[26]. This is based on the medical treatment of the undelying conditions responsible
for the disrupted load-force ratio but also on a ventilatory strategy able to generate a
gradual transition from full artificial support to respiratory autonomy. Among the
different techniques used, the most relevant are daily trials of T-tube of increased
duration and gradual reduction of pressure support ventilation, while intermittent
mandatory ventilation (SIMV) with a gradual reduction of back-up rate does not offer
any advantage over the others [27, 28]. Automatic modes of ventilation have been
devised in the past years in order to quickly adapt to the changing ventilatory
demand and respiratory mechanics of the patient. These “smart” ventilatory modes
should perform, in a closed loop way, those fast adaptations to the ventilator setting
needed to speed up the weaning process. Adaptive support ventilation (ASV) and a
knowledge-based expert system commercially available under the brand name
“Smartcare®” have been used so far, albeit without a widespread clinical experience
[29, 30].
In a selected population of patients, mainly those affected by chronic obstructive
pulmonary disease (COPD), NIMV can be used as a weaning tool. In practice,
patients initially treated with IMV for hypercapnic respiratory failure, can be
subsequently extubated and converted to NIMV in a phase when they are not yet
ready to be weaned from the ventilator, in order to shorten the IMV duration with an
advantage in terms of reduced mortality, rate of pneumonia and shortened hospital
stay [31]. Another category of patients for which NIMV can find a role in weaning is
represented by those at high risk of extubation failure. Actually, despite the correct
application of any step during the weaning process, there are some patients, i.e.,
those with hypercapnia, congestive heart failure, COPD and other relevant
comorbidities, which have an increased rate of post-extubation failure [32]. Current
guidelines recommend the early application of NIMV to this group of patients after
extubation for the prevention of development of ARF relapse and extubation failure
[23, 31].
Emerging Weaning Issues
IMV generally requires some form of sedation, in order to facilitate tolerance of

artificial airways and adaptation to the mechanical ventilatory pattern. Continuous
sedation, however, can prolong the duration of mechanical ventilation and impede
the weaning process [33]. The emerging tendency to use sedation protocols aimed to
alternate nocturnal sedation with diurnal awakenings can reduce the duration of
mechanical ventilation and of ICU stay. Current guidelines recommend the use of

protocols attempting to minimize sedation in patients acutely ventilated for more than
24 hours [23]. The second emerging issue is the early mobilization of patients in the
intensive care unit; it is known that exercise and physical therapy interventions in
critically ill patients can improve outcomes like less days spent in bed and easier gain
of functional independence [34, 35]. Now there is also evidence that early
mobilization can also have a positive impact on the duration of mechanical ventilation
and of ICU stay [36]. Therefore, the current guidlines recommend the application of
rehabilitation protocols focused on early mobilization of patients on mechanical
ventilation for more than 24 hours [23].
The Role of Tracheotomy in Weaning
Conversion of the translaryngeal tube into tracheostomy implies the potential

advantage of a reduced resistive work of breathing. This has been demonstrated in a
group of difficult-to-wean patients [37] in which, after tracheostomy, there was a
lower ventilatory demand, respiratory drive, work of breathing and intrinsic positive
end-expiratory pressure. Other advantages of tracheostomy include easier secretions
clearance, better patient comfort and oral care, easier and more secure airway
fastening, less need for sedation, enhanced ability to communicate, greater mobility
and the possibility to discharge the patient from the ICU. The process of weaning from
prolonged mechanical ventilation is complex and multifactorial, so that the link between
tracheostomy and weaning cannot be neither linear nor consequential. It is likely,
however, that, for a subset of patients, tracheostomy could play a crucial role in the
weaning process [38].
Use of High-Flow Nasal Cannula (HFNC)
After extubation, patients can experience a ventilatory pattern with reduced tidal
volumes and functional residual capacity, alveolar de-recruitment, tendency to
atelectasis and hypoxaemia. Compared to conventional oxygen therapy, HFNC can
supply a mixture of heated and humidified inspired gas at adjustable oxygen fraction
and at a very high flow. Besides, HFNC can generate a positive end-expiratory
pressure, can decrease respiratory rate, work of breathing and improve dyspnea and
oxygenation [39]. There is some evidence that the use of HFNC, compared to
conventional oxygen therapy, can decrease the rate of post-extubation respiratory
failure [40].

WEANING FROM PROLONGED MECHANICAL VENTILATION
Prolonged mechanical ventilation (PMV) is defined the need of ≥6 hours/day of

invasive ventilation for more than 21 consecutive days [41]. The 72-hour criteria used
in the acute care setting for successful weaning is not applied also to patients
undergoing PMV, where a period of at least 7 days without the need of respiratory
support is considered appropriate for considering the patient liberated from IMV [41].
Almost 3% of all patients admitted to ICU and treated with IMV [26] fails repeated
weaning attempts and requires protracted artificial ventilation. These patients are
generally converted to tracheostomy and sent to specialized weaning centres [42]
where a percentage ranging from 35 to 60% of them can successfully be weaned
from mechanical ventilation [43]. The approach of care in these specialized long
term- facilities is based on treatment of the underlying problems responsible for
prolonged ventilation, physiotherapy [44] and holistic care including nutrition, sleep
and psychological problems. Cases poorly responsive to all these treatments and
considered unweanable after repeated attempts, must be prepared for domiciliary
ventilation with proper care-giver training.
Figure 1. The use of high flow nasal cannula (HFNC) during weaning from PMV.
As already demonstrated for the acute care setting, there is some evidence that
NIMV could represent a weaning tool also for weaning from PMV [45]. Actually, in
patients still needing ventilator support but with a preserved partial respiratory
autonomy, the use of NIMV, applied while maintaining the tracheostomy cannula
capped, can be part of a combined process of conversion from IMV to NIMV and
decannulation.

With respect to the growing use of HFNC, there are some reports suggesting a
possible facilitating effect also during weaning from PMV [46] (Figure 1). However, a
physiologic study in tracheotomised patients at risk of weaning failure, showed lack
of improvement in ventilatory drive, respiratory rate, work of breathing and gas
exchange with HFNC compared to conventional oxygen therapy [47], indicating that
all the physiologic effects of HFNC observed when applied through the nose, cannot
be replicated when applied through the tracheostomy cannula.
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American thoracic society/American college of chest physicians clinical practice
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weaning failure. Ann Intensive Care 2019; 9(1):4.

Chapter 22
VENTILATORY DEPENDENT PATIENT’S

UNWEANABLE CONDITIONS
A. Marotta, MD, R. Maffucci, MD and G. Cioffi, MD

Monaldi Hospital - A. O. Dei Colli, Naples, Italy
ABSTRACT
The pathologic processes involving the motor unit are the most common
cause of prolonged ventilator failure. There are three respiratory muscle groups
that progressively weaken in Neuromuscular Diseases (NMDs): the inspiratory
group, the expiratory group and the bulbar-innervated muscles. The latter group
protects the airways and permits the glossopharyngeal breathing (GPB) and
active lung volume recruitment (LVR). Neuromuscular disorders may affect
ventilator function through the involvement of the proximal muscle groups,
including the respiratory muscles. These may be involved selectively or as a part
of a systemic process. Conventional mechanical ventilation (MV) weaning is the
process of transition to spontaneous ventilation.
Keywords: neuromuscular diseases, weaning, NIV, assisted coughing
INTRODUCTION
In Neuromuscular Diseases, weaning is generally difficult due to the respiratory

muscle weakness, especially when the diaphragm is involved. NMDs are the most
important cause of prolonged ventilator dependency due to the neuromuscular
ventilator insufficiency, therefore, complete weaning is generally impossible. The

Corresponding Author’s E-mail: austen.anto@gmail.com.

312 A. Marotta, R. Maffucci and G. Cioffi
part-time Non Invasive Ventilation (NIV) is a good compromise to achieve partial

autonomy and normal eating during ventilator-free time.
Weaning a patient with an NMD is challenging and in the case when it is not
possible to perform the daily NIV, the only alternative is the tracheotomy and long -
term invasive ventilation. Some studies demonstrate that NIV can be successfully
applied in a subgroup of NMD patients with specific characteristics.
VENTILATORY DEPENDENT
Non-invasive management of the NMD patient is always preferred rather than the
tracheostomy for several reasons such as safety, comfort, swallowing and in general
for the acceptance by the patient itself [1]. It is also demonstrated that the non-
invasive approach has a significantly longer survival rate than the tracheostomy
mechanical ventilation, by reducing the typical complications as ventilator
dependence, ineffective cough and more frequent pneumonia and hospitalizations
[2].
For all the above reasons it is preferred to resort to tracheostomy the least
possible in neuromuscular patients, in addition to the fact that weaning is very difficult
and, in some cases, impossible. Tracheostomy should only be used in patients who
cannot maintain an SpO2 in ambient air greater than or equal to 95% despite the use
of mechanical assisted coughing and non-invasive ventilation.
Generally, it’s preferable to do the tracheostomy in patients with severe mental
impairment and in those treated by Center with sub-optimal expertise in non-invasive
ventilation and mechanical assisted coughing [3].
The 2010 Consensus for tracheotomy recommendations doesn’t appropriately
support the use of noninvasive management. Conversely, promoting the equipping
and training of the healthcare personnel involved in the care of these patients is
fundamental to improve the patient’s quality of life and reduce costs associated with
invasive ventilation.
Successful weaning is defined as the ability to maintain spontaneous ventilation
without the need for reintubation and invasive mechanical ventilation for 48 hours
after the extubation. Meanwhile, for NMD patients it may be also defined as the
absence of a need for tracheostomy and mechanical ventilation for 5 days after the
extubation. The Weaning process, evaluated with spontaneous breathing test (SBT),
can be conducted in protocols such as T piece, CPAP or Pressure Support
Ventilation. Table 1 shows some criteria of readiness for weaning trial in NMD
patients.
T piece consists in the administration of only supplemental oxygen through a
T-shaped tube connected to an endotracheal tube.

Ventilatory Dependent Patient’s Unweanable Conditions 313
Table 1. Criteria of readiness for weaning trial
1. Subjective assessment
Adequate cough
No neuromuscular blocking agents
Absence of excessive trachea-bronchial secretion
Reversal of the underlying cause for respiratory failure
No continuous sedation infusion or adequate mentation on sedation.
2. Objective measuremets
Stable cardiovascular status
Heart rate ≤140 beat/minute
No active myocardial ischemia
Adequate hemoglobin level (≥8 g/dl)
Systolic blood pressure 90-160 mmHg
Afebrile (36°C < temperature <38°C)
No or minimal vasopressor or inotrope (<5 µg/kg/minute dopamine or dobutamine).
3. Adequate oxygenation
Tidal volume >5 mL/kg
Vital capacity >10 mL/kg
Proper inspiratory effort
Respiratory rate ≤35/minute
PaO2 ≥ 60 and PaCO2 ≤ 60 mmHg
Positive end expiratory pressure ≤8 cmH2O
No significant respiratory acidosis (pH ≥ 7.30)
Maximal inspiratory pressure (MIP) ≤ -20– -25 cmH2O
O2 saturation >90% on FIO2 ≤ 0.4 (or PaO2/FIO2 ≥ 200)
Rapid Shallow Breathing Index (respiratory Frequency/Tidal Volume) <10.
 Continuous positive airway pressure (CPAP): the weaning protocol involves

using a continuous pressure, equal to the positive end-expiratory pressure
level used previously.
 Pressure support: the use of progressive lower levels of inspiratory pressure
support until it reaches 5-8 cmH2O [4]. For some authors, NMD patients are
often inadequately treated with ventilation because doctors are scared by the
barotrauma as seen for the Acute Respiratory Distress Syndrome (ARDS)
patients. Bach suggests that the “light” approach with low volumes such as
5-7 ml/kg can’t be used in the NMDs because of the stiffness of the thoracic
wall and lungs, but he claims that an aggressive program of LVR is
necessary at high insufflation pressures. This happens because the lung
volumes increase the intrapulmonary pressures, due to insufflated volumes,
increasing not linearly but exponentially [5].
There is no current evidence suggesting that one of these approaches is better

than the others, however it’s suggested that the T-piece technique may be used if
there are unsatisfactory results with the other approaches or when the PEEP
removal could result into a patent lung or cardiac dysfunction [6]. Having a well-

defined protocol for SBT is also demonstrated to lead to a total shorter duration of
the mechanical ventilation without extra side effects.
The SBT should last between 30 to 120 minutes to evaluate correctly the
tolerance of the test and the early appearance of respiratory muscle fatigue. Another
important factor to be properly assessed for successful weaning is the optimization of
sedation therapy. Excessive sedation can result in poor performance in SBT and
prolong the duration of the mechanical ventilation. Anyhow, these trials are not
always necessary prerequisites for successful extubation to continuous MV.
The Internation Consensus Conference in 2005 defined three categories of
weaning outcome: a) simple if it is successful at first attempt; b) difficult if it requires
up to three trials or <7 days to reach SBT and c) prolonged if 7 or more days are
needed to reach SBT. Table 2 shows criteria of successful spontaneous breathing
trial.
There are some useful parameters, which could help in predicting whether a
weaning attempt will be successful or not. These parameters are not recommended
by the international consensus conference in 2005, but can facilitate the detection of
signs indicating that the patient is not yet ready for extubation, such as:
 Reduced heart rate variability;

 Impaired mental status;
 Poor quality of sleep;
 Patient inability to manage respiratory tract secretions;
 Muscle weakness assessed with handgrip strenght test;
 Acquired diaphragmatic dysfunction defined as a difference equal or greater
than 30% of the diaphragm thickness at the end of inspiration and expiration
measured with ultrasonography (US);
 High plasma level of oxidative stress markers as malondialdehyde and
ascorbic acid [7].
Weaning can be considered unsuccessful when there are at least two of these
criteria: respiratory acidosis (pH < 7.35; PaCO2 > 45 mm Hg); SpO2 < 90% or
PaO2 < 60 mm Hg with FiO2 > 50%; i > 35 rpm; decreased level of consciousness,
restlessness or excessive sweating; or signs suggesting respiratory muscle fatigue,
such as the use of accessory muscles or paradoxical movement of the abdomen [8].
The chances of extubation greatly decrease if pCO2 is >35-40 mmHg, pO2 in ambient
air is <95% and if airway secretions aren’t correctly swiped out neither using
mechanical insufflation-exsufflation.
If SBT is unsuccessful it is sensible to: a) search removable underlying causes of
respiratory failure, b) replace the respiratory support in use with another more
comfortable and well synchronized with the patient’s breathing acts to not cause
fatigue; c) try again the SBT every 24 hours.

Table 2. Criteria of successful spontaneous breathing trials
Respiratory rate <35 breaths/minute

Good tolerance to spontaneous breathing trials
Heart rate <140/minute or heart rate variability of >20%
Arterial oxygen saturation >90% or PaO2 > 60 mmHg on FiO2 < 0.4
80<Systolic blood pressure <180 mmHg or <20% changes from baseline
No signs of increased work of breathing or distress*
*
Accessory muscle us, paradoxical or asynchronous rib cage – abdominal movements, intercostal
retractions, nasal flaring, profuse diaphoresis, agitation.
It is recommended to avoid the extubation failure as this factor is independently

associated with prolonged hospitalization, increased use of tracheotomy and higher
mortality [9].
In the case of intubated patients in which ventilator weaning or spontaneous
breathing trial fails the only option is tracheotomy.
There are no guidelines for extubating unweanable patients with NMD due to the
exclusion of these kind of patients from the extubation studies. NMD patients with a
VC of 200 mL or more can be weaned with a self-conducted method that consists in
reducing NIV time from continuous to partial, by taking gradually fewer intermittent
positive pressure ventilation via mouthpiece (self-weaning). Using this type of
interface for ventilation improves comfort, speech, oral intake and maintains
pulmonary compliance by taking advantage of the air stacking effect. Furthermore, it
reduces the compression skin lesions and makes it easier to assist manually the
cough reflex [10]. In all these cases, nocturnal ventilation via nasal/oronasal mask
must be continued.
These NMD patients can also have ineffective cough peak flows (CPFs), that
leads to extubation failure due to the inability to excrete effectively airway secretions
[11]. PCF ≤ 160 L/min is associated with higher percentage of weaning/extubation
failure in NMD patient [12]. Unmeasurable CPFs indicates an incomplete closure of
the glottis that causes saliva aspiration and consequently increases the risk of
pulmonary complications.
For these reasons, the early application of assisted coughing in association with
NIV can improve extubation outcome reducing the need of reintubation, the use of
tracheostomy and the duration of ICU stay [13].
Assisted coughing can be conducted with two different techniques:
 manually assisted coughing: insufflation, provided by ventilator that expand

lungs with “air stacking” effect, followed by an abdominal push in support of
the patient cough effort;
 mechanical assisted cough: mechanical insufflation-exufflation is used when
there is a severe stiffness of the chest wall or when the patient can’t close
properly the glottis and therefore is unable to correctly perform “air stacking.”
A mechanical device alternating positive and negative pressures (between
+40 and -40 cmH2O when used oronasal interfaces or mouthpiece,

60-70 cmH2O when used transaryngeal tube) facilitates the expulsion of the
bronchial secretions.
Assisted coughing continues until there are no more mucus present in the
bronchial tree and secretion-related desaturation end. This treatment is required
every 30 minutes for 36 hours following extubation or decannulation: therefore, it can
be useful to train the caregiver in ordere to help with this demanding procedure.
The aim of the extubation in this group of “unweanable” NMD patients is to
reduce mortality and long-term pneumonia [14], improving quality of life [15] with the
maximization of ventilator-free breathing to make it easier to return home.
The crucial step is to provide timely inspiratory and expiratory aids, which allows
the virtual elimination of extubation failure in patient with neuromuscular weakness.
Unfortunately, there is a subgroup of patients with advanced nonverbal bulbar ALS,
usually characterized by a relevant swallowing impairment and dysphagia, that
cannot benefit of this weaning method due to the high risk of inhalation of
oropharyngeal secretions.
In conclusion, unweanable intubated patients with NMD who satisfy very specific
criteria can be successfully extubated to full NIV and MAC with an improvement in
their quality of life, which was already put to the test by the disease.
REFERENCES
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SECTION 6.
PERIOPERATIVE RESPIRATORY MANAGEMENT

Chapter 23
PERIOPERATIVE RESPIRATORY MANAGEMENT

OF PEDIATRIC PATIENTS WITH NMD
Domenico Faticato, MD
Anesthesiology and Hyperbaric Medicine Unit,
A.O.R.N. Santobono Pausilipon, Naples, Italy
ABSTRACT
Pediatric patients affected by neuromuscular diseases who undergo surgical

procedures share the same respiratory failure risks regardless of their underlying
disease. These risks are added to those related to the specific disease.
Moreover, such patients usually face longer hospitalization and higher risk of in-
hospital morbidity [1].
The muscular contractility impairment, whose clinical features vary according
to the localization of the primary lesion and which can be accompanied by a
bulbar dysfunction, causes a state of respiratory failure due to reduced ventilation
and impaired airway clearance mechanisms and to frequent inhalation episodes,
which determine a chronic inflammation of the airway epithelium [2, 3].
The possible occurrence of perioperative complications demands a
multidisciplinary integrated management during the whole perioperative period,
as well as a team of experienced professionals, specific protocols for the most
critical patients and the availability of ventilation assistance devices.
PREOPERATIVE MANAGEMENT
During the preparation phase prior to surgical operations, evaluations of the

respiratory function, the cardiac function and the nutritional state are required.

Corresponding Author’s E-mail: mfaticato@hotmail.it.

322 Domenico Faticato
Respiratory Evaluation
It is advised to carry out an anamnestic evaluation of the development of the

respiratory disease and to collect information about changes in the voice intensity,
cough, sialorrhoea, expectoration and chewing difficulties, macroglossia, spinal
deformity, frequency and intensity of respiratory infections. Sleeping disorders, which
can cause non-specific symptoms such as headache and morning nausea, daytime
sleepiness, and concentration difficulty, may be related to nocturnal hypoventilation,
to the presence of OSA, or both. In case of nocturnal pulse oximetry never under
93%, a clinically remarkable hypoventilation is considered unlikely; such pulse
oximetry can represent an acceptable screening in asymptomatic patients [4].
Performing arterial blood gas analysis allows to evaluate the pCO2. A daytime
hypercapnia indicates hypoventilation in state of wakefulness, while an isolated
serum bicarbonate increase suggests nocturnal hypoventilation [5-7]. By means of
an ABG test it is also possible to measure the A-a gradient to evaluate the alveolar-
capillar integrity and the causes of hypoxemia related to chronic inhalation or to the
presence of atelectases.
In cooperative patients, but rarely before the age of 6 years, it is possible to
perform a pulmonary function test [8].
Children affected by NMDs have decreased lung compliance as a result of micro-
atelectases [9, 10] and of a reduced compliance of the thoracic wall due to a
progressive fibrosis of muscle cells as well as skeletal deformities [11-13]. Tests
show a restrictive pattern, characterized by reduced Vital Capacity (VC), Total Lung
Capacity (TLC) and Functional Residual Capacity (FRC), while the FEV1/FVC ratio is
relatively unvaried.
The use of the evaluation of Vital Capacity (VC) in DMD to stratify the risk of
pulmonary complications may be extended to other NMDs [14-18]. CV values are
shown to be strongly related to the susceptibility to infections, to sleeping disorders
and to daytime hypercapnia occurrence. VC values < 60% indicate an increase in the
risk of pulmonary complications, while values under 30% strongly predict
hypoventilation and hypercapnia in state of wakefulness [19] and high post-operative
risk [20].
In SMA, predictive indexes are less clear [21]. The Peak Cough Flows (PCF), the
Maximal Inspiratory Pressure (MIP) and the Maximal Expiratory Pressure (MEP) can
be used to evaluate the grade of impairment of the inspiratory and expiratory
muscles [22]. A PCF > 270 l/m seems sufficient to ensure an efficient airway
clearance [23-25].
In myotonic dystrophy, the impairment of respiratory muscles can cause a
chronic hypercapnia predicting respiratory complications as well [26].
In NMD patients at risk of hypoventilation, a pre-operative NIV may be
considered, which can increase the possibility of successful post-operative NIV [27,
28]. The same applies for patients with ineffective cough [29, 30] history of recurring
pneumonia and low MEP (<60 cm H2O).

Perioperative Respiratory Management … 323
Here too, a pre-operative training with an assisted-cough mechanical device is

advised [31].
Cardiovascular Evaluation
NMDs are associated with cardiovascular functions which often initially occur
with rather blurred clinical signs and non-specific symptoms, such as asthenia,
weight loss, vomit and sleeping disorders.
DMD is associated with dilated cardiomyopathy in over 80% of the patients over
18 years old and with arrhythmia [32]. In myotonic dystrophy, cardiovascular
disorders represent 20% of the causes of death [33]. Several heart abnormalities are
associated with metabolic diseases [34, 35], while conduction disturbances are
present in CMT [36]. In Type 1 SMA, ECG abnormalities are often detected, and the
presence of respiratory problems may involve associated cardiac dysfunctions [37].
The American Academy of Pediatrics has released some recommendations
about the monitoring of cardiovascular diseases in Duchenne and Becker Dystrophy,
which may also be applied to other NMDs [38].
ECG and pre-operative echocardiography at rest do not necessarily prove
sufficient to evaluate the perioperative risk. In particular, if the echo at rest detects
alterations, it is advisable to perform a stress echo with dobutamine, while alterations
in the rhythm may suggest resorting to a Holter ECG [39].
Moreover, in patients with more severe cardiac dysfunctions, an anti-coagulant
therapy is advised to avoid thromboembolic complications.
In any case, optimization of the nutritional state is suggested.
Nutritional Evaluation
Malnutrition is often present in NMD patients due to eating difficulties connected

to dysfunctions in the related musculature [40, 41]. A further cause of low weight is
the high energy consumption brought about by the increase in the respiratory labour
connected to chronic respiratory insufficiency [42, 43, 20]. Malnutrition also affects
the muscular strength and increases the risk of pulmonary complications. Moreover,
it increases the risk of developing decubitus ulcers.
The presence of signs of malnutrition in these patients suggests the
implementation of NIV and that a gastrostomy be taken into consideration [44, 20].
Evaluation of the Consent
Taking in account the major risks associated with surgery in these patients, the
possibility of performing surgical procedures is to be evaluated with the child’s

parents after a careful analysis of costs and benefits. The possibility of a prolonged
post-operative mechanic ventilation and of a tracheostomy – along with the
complications connected to it – will be evaluated. In any case, a choice must be
made by taking in consideration the comfort and the quality of life that can be
assured to the child [66].
INTRAOPERATIVE MANAGEMENT
It is advisable for this kind of patients to be treated in a centre provided with a

PICU and an expert team of anaesthesiologists-resuscitators and of respiratory
therapists [28].
Any procedure requiring sedation is to be performed while monitoring the vital
parameters, SpO2 and EtCO2 or transcutaneous CO2 [45, 46]. The ventilation and
airway management difficulties must be evaluated as well, since they may be
connected to macroglossia, neck stiffness or difficulty positioning the patient on the
operating table due to the skeletal malformations [47]. During induction or
awakening, patients with chronic respiratory failure may need O2 and ventilator
support; also, with regard to pre-operative evaluations, it is possible to plan
extubation switching directly to NIV [48].
POST-OPERATIVE MANAGEMENT
Respiratory Management
NMD patients are particularly susceptible to side effects of general anaesthesia

and surgery and show an increased probability of hypercapnia due to their ventilation
deficiency [49].
In high-risk children showing a VC <60% in pre-operative evaluation, ineffective
cough, history of failed extubations or already using NIV at home (usually for
nocturnal hypoventilation), protocols of extubation must be applied which provide for
the application of NIV immediately after extubation and airway clearance techniques
[50-52]. The NIV is often more effective if used immediately after extubation, since in
several cases a late application entails a progressive muscular failure, retention of
secretions and a need for reintubation [53].
In the post-operative period, oxygen supplementation needs to be carefully
provided, since a high percentage of O2 contributes to further suppress the
respiratory drive by exacerbating hypercapnia, and it is important to ensure an
appropriate supporting ventilation.
The potential increase in the oxygen demand is to be carefully evaluated since it
might be due to the presence of atelectases or aspiration episodes. The mucociliary
clearance transports 10 - 100ml of liquids a day into the trachea [54]. The coughing

mechanism aimed at expectorating secretions requires a deep inspiration amounting

to about 95% of the Total Lung Capacity, the closure of the glottis with preserved
bulbar functions, and an effective contraction of the respiratory, intercostal, and
abdominal muscles, which generate a rapid expiratory flow [55, 56]. Patients with
pre-operative evidence of ineffective cough (a standard spirometry resulting in a low
peak flow, decreased MIP and MEP) [57, 58] need an assisted cough device to be
associated with respiratory physiotherapy [59].
Patients with a history of respiratory failure will probably need to be extubated
switching directly to a NIV regime. The use of a non-invasive ventilation can shorten
intubation time or reduce the need of tracheostomy in any situation requiring
sedoanalgesia, which implies the use of drugs that alter the respiratory dynamics and
an effective cough [60].
Pain Management
An appropriate level of sedoanalgesia is fundamental in post-operative

management [20]. In NMD patients, an appropriate pain management may require
the use of drugs which may cause respiratory depression and thus prolong the time
of assistance time and ventilation support [61, 62]. For this reason, it is always
advisable to resort to techniques of local or regional anaesthesia when possible.
These forms of anaesthesia ensure a full control of pain and allow a more superficial
sedation plan with fewer effects over spontaneous ventilation [63].
Cardiovascular Management
The management of intra- and post-operative fluidotherapy needs careful

evaluation: the fluid-shift connected with the surgical procedure and a careless
management of liquids may increase the possibility of heart failure in patients with
myocardic dysfunction [38].
Nutritional Management
NMD patients are often faced with bowel functional problems [64], which may be
increased by immobility and the use of opiate analgesics during the post-operative
period. The poor nutritional intake can affect the respiratory dynamics and is
therefore necessary to grant a correct calorie intake, through the use of enteral and
parenteral nutrition, if necessary [65]. The use of prokinetic agents and gastric
decompression through nasogastric intubation is advised to avoid gastric distension
and a subsequent diaphragm rigidity, as well as a further deterioration of the
respiratory dynamics.

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Chapter 24
ANESTHETIC CONSIDERATIONS
FOR NEUROMUSCULAR DISEASES
A. Corcione1,, MD, L. Bucci2, MD and C. Esposito1, MD

1
Department of Critical Care Area, Monaldi Hospital,
Ospedali dei Colli, Naples, Italy
2
Anesthesia and Intensive Care Unit, AORN Sant’Anna e San Sebastiano,
Caserta, Italy
ABSTRACT
Patients affected by pre-existing neuromuscular disorders who experience

scheduled or emergency surgery are known to be at risk for several
postoperative complications related, in most cases, to drugs administered
intraoperatively during the anesthesia period. Therefore a careful preoperative
assessment is paramount, aiming to reduce morbidity and also adverse outcome.
In particular, one of the major and feared risk is a postoperative respiratory
failure condition, with concomitant need for a long-term ventilation period; it
appears a preferred option, nowadays, that this scenario should be reviewed with
the patient and the relatives. The use of quantitative neuromuscular monitoring
should be strongly recommended whenever newer nondepolarizing
neuromuscular blocking agents (NBA) are administered, with pharmacological
reversal disposable in the anesthesiologist’s tool box. For this reason, as an
example, several case series and reports have been recently published
suggesting that agent like sugammadex, as a rapid reversal of NBA such as
rocuronium, can be safely used in patients with neuromuscular disease (NMD).
Patients with NMDs are at high risk of intra-operative and post-operative
complications; in this view, a proactive, multidisciplinary approach should be
planned before, during and after any surgical procedure, requiring general or
regional anesthesia or even sedation. However, surgery in this patient population

Corresponding Author’s E-mail: Antonio.corcione@ospedalideicolli.it.

332 A. Corcione, L. Bucci and C. Esposito
should be performed in a well equipped institution having expertise in NMDs full

management.
Keywords: neuromuscular disorders; anesthesia; neuromuscular blocking agents;

reversal; neuromuscular monitoring
PURPOSE OF REVIEW
Anesthesiologists as key consultants in taking care of surgical patients, both in

emergency and scheduled scenarios, are very challenged when facing with
neuromuscular diseases (NMDs). For these reasons, all anesthesiologists must have
an extensive knowledge of neuromuscular junction physiology, as well as the
anesthetic medications they use in daily practice, with their effects on neuromuscular
transmission and muscle function [1, 2]. In this view, a careful assessment and
management of patients with these underlying disorders is required to reduce
postoperative complications, especially a respiratory failure condition.
In this chapter we aim to review: a) the assessment and anesthesiological
management of patients with NMDs undergoing general anesthesia (when feasible),
loco-regional procedures or during sedation; b) the main implications of anesthetic
drugs and inhaled agents administered during the anesthesia period; c) the
postoperative phase in protected areas such as Recovery Room and/or PACU (Post
Anesthesia Care Unit), aiming to the surveillance, monitoring and even the treatment
of these patients, referring to the weaning from mechanical ventilation, the extubation
time and the alternative with non-invasive respiratory support techniques. Literature
addressing these topics is limited by the small number of patients and randomized
trials are very few. In this chapter we often refer to recommendations derived from
the Consensus Conference between SIAARTI (Società Italiana Anestesia Analgesia
Rianimazione e Terapia Intensiva) and AIM (Associazione Italiana Miologia)
published in Minerva Anestesiologica in 2013, in which the Authors reviewed the
literature, expressing the strength of recommendations and quality evidence adopting
a GRADE approach [3, 4].
RECENT FINDINGS
Patients with neuromuscular diseases are very challenging for the

anesthesiologists during the anesthesia period and are at greater risk for
perioperative complications, including a respiratory failure and pulmonary aspiration,
as well as cardiovascular dysfunction. These patients require special attention and
precautions, with a comprehensive, multidisciplinary and shared approach based on
communication between several specialists and consultants: Primary care
Physicians, Neurologists, Pneumologists, Physiatrists, Surgeons and

Anesthetic Considerations for Neuromuscular Diseases 333
Anesthesiologists. Therefore, the work-up program based on a preoperative global

evaluation and optimization of comorbidities appear fundamental for the common
goal and the final result [5].
According to Racca et al, in order to plan a safer anesthetic strategy,
neuromuscular diseases are divided into four main categories [3]:
1) Motor neuron disorders (e.g., spinal muscle atrophy and amiotrophic lateral
sclerosis)
2) Pathologies of the peripheral nerves (e.g., Guillain-Barrè syndrome)
3) Neuromuscular junction disorders (e.g., myasthenia gravis)
4) Myopathies (e.g., progressive muscular dystrophies, congenital
myopathies, congenital dystrophies, metabolic myopathies,
channelopathies)
PREOPERATIVE
Pre-anesthesia evaluation should include both the assessment of the
neuromuscular disease and the associated neurological issues (e.g., developmental
delay and cognitive dysfunction) as well as patient’s current treatment. Moreover,
these patients may also have involvement of other organs/systems, particularly heart
diseases (e.g., cardiomyopathies, cardiac conduction abnormalities and autonomic
dysfunction), lung diseases (e.g., respiratory failure and chronic pulmonary
aspiration) and gastrointestinal tract abnormalities. All patients with a neuromuscular
disease type must be considered at high risk for acute rhabdomyolysis, malignant
hyperthermia and hyperkalaemia secondary to denervation (Grade 1C). Focusing on
these comorbidities is mandatory to avoid perioperative complications aiming to
improve the final outcome. It is very important to discuss with the patient and with the
family the risk / benefit ratio of the proposed surgical procedure (Grade 1C).
In scheduled surgery, a recent evaluation of the respiratory function is highly
recommended even in non-symptomatic patients, aimed to assess the risk of
respiratory complications and the need of specific peri- and post-operative monitoring
and management (Grade 1C). In addition to an accurate medical history and physical
examination, a chest X-ray, an evaluation of sleep-disordered breathing, the
measurements of respiratory function and cough effectiveness, an arterial blood gas
both with serum electrolytes Na, K, Cl, Ca, Mg, creatine kinase (CK) and myoglobin
levels should be included [6, 7]. Evaluation of respiratory function and cough
effectiveness includes measurement of FVC, maximum inspiratory pressure,
maximum expiratory pressure (MEP), peak cough flow (PCF), diurnal pulse oximetry
(SpO2). SpO2 less than 95% in room air has been established as a clinically
significant abnormality, requiring carbon dioxide (PCO2) level measurement. All
neuromuscular disease patients with a limited respiratory reserve and/or cough
deficiency should be trained in the use of non-invasive ventilation and/or manual or
mechanical cough assistance techniques: a) during the pre-operative period; b)

during the intra-operative period, if the anesthesia is performed with locoregional

anesthesia or sedation; c) always in the postoperative period (Grade 1C). When
respiratory function measurements are altered, a non-invasive ventilation (NIV)
support and manual or mechanically assisted cough techniques appear to be
indicated. Therefore, planning and coordination with the hospital respiratory
therapists is crucial. In particular, mechanical insufflators-exsufflator (MI-E) can
increase coughing, promote deep lung inflation, and treat or prevent atelectasis [8,
9], being careful with possible complications and/or contra-indications such as
pneumothorax, emphysema, endocranial hyperthension and severe cardiac
dysfunction.
About cardiological assessment, several NMDs are associated with cardiac
dysfunctions (cardiomyopathies and/or rhythm abnormalities-disturbances): Guillain-
Barrè syndrome, myotonic dystrophies, glycogen storage diseases type II, lipid
storage myopathies. However, clinical manifestations of heart failure are often
unrecognized until very late, due to musculoskeletal limitations. All patients with
NMDs undergoing anesthesia or sedation with a cardio-circulatory system
involvement must be careful evaluated about cardiac function, in order to optimize
the cardiological therapy (Grade 1C). They should include baseline EKG, an Holter
EKG in case of known frequent arrythmias, echocardiography with a specific cardiac
function evaluation (as an example in case of surgeon’s need for a Trendelemburg
position during laparoscopic surgery). All these patients showing cardiac
dysfunctions have limited reserve to increase cardiac output in response to stress.
Moreover, they are at high risk for perioperative cardiac side effects due to negative
inotropic effect of volatile and i.v. anesthetic agents, the positive pressure ventilation,
hypoxemia and acute anemia. Inhaled anesthetics may also induce arrhythmia due
to sensitization of the heart to catecholamines [10]. Finally, NMDs patients with
respiratory involvement leading to nocturnal hypoxemia may be affected by
pulmonary hypertension with a right ventricle involvement. In all patients with
neuromuscular disease with major cardiac involvement intra- and post-operative
monitoring should at least include an invasive blood pressure measurement (Grade
2C) and if indicated, whenever possible and feasible, a cardiac output monitoring.
During the pre-operative anesthetic evaluation, a particular attention must also
be given to a difficult airways management. Often, these patients suffering from
neuromuscular disorders may have a reduced oral opening, macroglossia and/or a
limited mobility of the cervical spine. In these cases, intubation must be performed
taking into account the guidelines for difficult airway management described in adults
and children (Grade 1C) [11].
A planned strategy shared with the Operative Room Team is required, which
focus on maintaining adequate level of oxygenation as the main patient's need; the
target is to ensure "continuous peri-procedural oxygenation", regardless of the
techniques and the device used to obtain it. In the event of a planned difficult airway
management, the first fundamental decision concerns the choice to abolish or not the
patient's spontaneous breathing, in order to minimize the risk and the possibility of
sudden "rescue" maneuvers need. Therefore, the use of awake intubation

techniques should be considered. Evaluation of airways management, even with its

limitations, must always be performed in every setting, in all patients and in all
procedures that require sedation, locoregional or general anesthesia; the awareness
of managing a difficult airway guides the choice of strategy and decreases the risk of
unexpected CICO (Can’t Intubate Can’t Oxygenate) versus conscious FONA (Front
Of Neck Airway: i.e., cricothyrotomia) critical scenarios [12]. It is also evident that the
evaluation phase carried out in the clinical context of the scheduled surgery presents
differences with respect to the urgent-emergency setting or the critical patient in an
intensive care environment, where the "time" factor appears to be fundamental for
maintaining the oxygenation itself. During the apnoic phase, especially in the case of
patients at high risk of desaturation, the continuous administration of O2 is
recommended, by applying the so-called NO DESAT (Nasal Oxygen During Efforts
Securing a Tube) techniques. However it is possible to consider the adoption of low-
flow nasal cannulas, the high-flow cannulas (THRIVE- AIVO2) which improve
oxygenation while ensuring a minimum clearance of CO2 or even a CPAP technique.
In order to facilitate glottic vision and mask ventilation, high risk patients’ induction
must always be performed in the so-called "ramped position."
Other issues include to consider nutritional status which should be optimized
prior to surgery. In fact, in case of malnutrition, the surgical wounds scaring could be
delayed and difficult, while the malnutrition itself can further compromise the
effectiveness of breathing and coughing (Grade 2C). For patients chronically taking
steroid therapy the need for glucocorticoid administration should be carefully
considered during the intra-operative period to prevent acute adrenal gland failure.
Patients with mitochondrial myopathies may present increased blood lactate levels
during periods of stress. For this reason during the pre-operative fast they would be
treated with isotonic solutions containing glucose (for example a physiological NaCl
0.9% with 5% glucose) intravenously, in order to keep blood sugar within normal
values (Grade 1C).
INTRAOPERATIVE
Whenever possible, in all patients with neuromuscular disease, loco-regional

anesthesia should be preferred to general anesthesia (Grade 1C), even in the case
of patients with peripheral nerves pathologies (Grade 2C). Regional or local
anaesthetic techniques can be employed in patients with cardiac and/or respiratory
involvement [5, 6]. However, in patients with autonomic dysfunction, a potential
sympathetic block resulting from regional anaesthesia requires careful control of
blood pressure. In patients in whom volatile anaesthetics and regional techniques are
not indicated, an i.v. anesthetic such as propofol togheter with short-phase opioids
are recommended; over the last 10 years they have replaced neurolept analgesia. In
patients suffering from neuromuscular pathology it could be difficult to ensure
adequate venous access. Cannulation of a peripheral vein can be facilitated by

ultrasound approach. Also, in case of need for central venous access, the
ultrasound-guided central venous cannulation technique is considered of choice,
through a peripheral vein in the arm or through a central vein (Grade 1C). If venous
access is difficult to find, some Authors consider it safe to administer for short
periods an inhalation anesthesia also in patients with myopathy. However, the
participants in the Turin Consensus Conference [3] recommend the use of
intramuscular ketamine for this circumstance (Grade 2C).
In all patients with neuromuscular disease for which the use of halogenated
inhalation anesthetics should be avoided, a general anesthesia should be performed
with intravenous drugs (Total Intra Venous Anesthesia-TIVA; Target Controlled
Infusion-TCI) (Grade 1C: see Table 1). Monitoring anesthesia depth of these patients
during the TIVA-TCI approach by applying systems such Bispectral Index Monitor
(BIS ) or Sed-line may prevent both the risk of awareness, while reducing drugs’
overdose.
The use of halogenated inhaled anesthetics is allowed for patients suffering from
motor neuron pathologies or peripheral nerves diseases, while for these patients it is
absolutely to avoid the use of succinylcholine (Grade 1C). It is well known that the
use of succinylcholine, an historical depolarizing neuromuscular blocking drug, is
nowadays of very limited use and moreover it should be avoided in several
conditions: muscular dystrophies, motor neuron diseases and intrinsic muscle
disease, aiming to avoid the possible risk of malignant hyperthermia,
rhabdomyolysis, hyperkalemia and cardiac arrest. It is allowed the use of
halogenated inhalation anesthetics and succinylcholine for patients with
neuromuscular joint pathologies (Grade 1C). It is absolutely necessary to avoid the
use of halogenated inhalation anesthetics and succinylcholine in patients with
myopathies of any type (Grade 1C). Moreover, these patients may also be sensitive
to sedative-hypnotics and opioids agents, to be used carefully and judiciously [3, 5].
During the anesthesia period, is mandatory to avoid the risk of malignant
hyperthermia (MH) in certain neuromuscular diseases, avoiding triggering agents
such as succinylcholine and certain inhaled anesthetics. A predisposition exists to
malignant hyperthermia (MH), that results in a hypermetabolic cascade after
exposure to inhaled anesthetics and succinylcholine. The clinical picture of MH is
characterized by hyperthermia, rhabdomyolysis, lactic acidosis, disseminated
intravascular coagulopathy and fatal arrhythmias. A high index of suspicion, a rapid
diagnosis and the early administration of dantrolene have reduced significantly the
morbidity and mortality of this dangerous and potentially letal intra-operative
complication [3].

Table 1. Overview of anesthetic choices in neuromuscular diseases
Neuromuscular disease Regional Volatile Succinylcholi NDMR Opioids Other issues

anesthesia anesth ne
Spinal muscular atrophy YES YES NO  dose dec-reased; M 
Amyotrophic lateral YES YES NO  dose decreased; M  Dysautonomia
sclerosis
Myastenia gravis YES YES   dose decreased; M  Sugammadex
should be
considered
Lambert-Eaton syndrome YES YES   dose decreased; M
Guillain-Barrè syndrome YES YES NO  dose decreased; M  Dysautonomia
Duchenne and Backer YES NO NO  dose decreased; M  Avoid AChE
neuromuscular Dystrophy Sugammadex
should be
considered
Miotonic dystrophy YES controversial NO  dose decreased; M  Avoid AChE
Sugammadex
should be
considered
Congenital Myopathy YES NO NO  dose decreased; M 
Congenital muscular YES controversial NO  dose decreased; M 
dystrophies

Table 1. (Continued)
Neuromuscular disease Regional Volatile Succinylcholi NDMR Opioids Other issues

anesthesia anesth ne
Mitochondrial myopathy YES YES NO  dose decreased; M  Avoid prolonged
use of propofol.
Prevent lactic
acidosis, avoiding
hypoglycemia,
hypoxia,
hypotension
Glycogenoses YES NO NO  dose decreased; M 
YES: may be used or should be performed;
NO: contraindicated. M: muscle relaxation monitor must be used.
 dose should be decreased; AChE: anticholinesterase drugs; NDMR: non-depolarizing muscle relaxants. Modified from Racca et al., [3].

Rhabdomyolysis represents an uncommon but potentially fatal event,

characterized by muscle necrosis with release into systemic circulation of
intracellular muscle constituents (i.e., myoglobin, potassium and creatine kinase).
This complication is more frequent in obese patients (male, BMI > 50 kg/m2), with
associated diabetes and peripheral vascular disease. It can be acute, resulting in
hyperkalaemic cardiac arrest or subacute, presenting as dark urine output or cardiac
arrest in the post-anaesthesia care unit.
These patients may have adverse response to neuromuscular blocking agents
(NBA) and the reversal drugs (e.g., neostigmine). These drugs should be used with
caution and guided by modern neuromuscular monitoring systems, like TOF (Train of
Four) watch and TOF cuff [13, 14]. Drugs that increase neuromuscular block should
also be avoided or their doses limited if possible: corticosteroids, antibiotics such as
aminoglycosides and vancomycin, ester-type local anesthetics, calcium channel
blockers are all examples of how certain drugs can amplify effects of NBA. In all
patients suffering from neuromuscular disease, use of neuromuscular blocking
agents can lead to prolonged neuromuscular blockage; at the end of anesthesia
period, the effect of muscle relaxant drugs should be antagonized (Grade 2C).
Nowadays, the use of sugammadex as a specific reversal for steroid myorelaxant
agents may eliminate the risk of post-operative residual muscle paralysis also in
these patients with neuromuscular disease. All conditions in patients with myasthenia
gravis which can increase the duration of neuromuscular block should be avoided
(especially hypothermia, hypokalaemia, hypophosphatemia and the use of certain
drugs such as benzodiazepines, phenytoin, anticholinesterases, aminoglycosides,
fluoroquinolones, beta-blockers, calcium channel blockers, steroids, iodized contrast
medium, etc.) (Grade 1C).
POSTOPERATIVE
The post-operative phase focus on the surveillance and monitoring of these

patients in adequate protected areas such Recovery Room and/or PACU (Post
Anesthesia Care Unit), in particular for those who have one or more of the following
pre-assessed conditions: 1) a severe cardiac impairment, 2) a limited respiratory
reserve, 3) a significant cough deficiency, 4) a known swallowing impaired, 5) an
intraoperative neuromuscular blockers administration, with incomplete recovery from
TOF monitoring 6) use of intravenous opioids, if indicate and if permitted, in the post-
operative period for pain control (Grade 1C).
Pain Control Management
Adequate post-operative pain control is essential to prevent hypoventilation for

analgesic purposes especially after thoracic surgery, upper abdominal surgery or

spinal surgery (Grade 1C). A protocolized, multimodal approach for pain control is
nowadays strongly suggested, looking at opioid sparing in order to minimize
secundary effects, in particular on respiratory function. If necessary, is useful to
choice a short-acting molecule such as remifentanil; an analgesia approach via
epidural catheters with local anesthetic and/or a short acting opioid may be used
when appropriate. This goal is best accomplished with preemptive analgesia strategy
and using a multimodal approach. Oral clonidine administered preoperatively has
been shown to reduce the requirement for postoperative analgesics; i.v.
paracetamol, administered alone or in combination with nonsteroidal anti-
inflammatory drugs (e.g., ketorolac), has been shown to reduce the amount of
opiates delivered [15]. A neuropathic deep pain is very frequent in Guillain-Barrè
syndrome; in this case the use of gabapentin must be considered. In those patients
not responding to treatment with gabapentin, a remifentanil infusion may provide a
better analgesia. A recent alternative that has been suggested is represented by
dexmedetomidine, a modern alpha-2 adrenergic receptor agonist [16].
Finally, wound infiltration using local anesthetic solutions and ultrasound-guided
techniques with continuous infusion via peripheral nerve block catheters should be
considered, when appropriate, as a safer alternative (Grade 1C) [3].
Postoperative Nausea and Vomiting (PONV)
PONV risk is based on patient characteristics: female sex, history of motion

sickness (car, ship, plane, etc.), or previous history of PONV, non-smoking habits, or
planned postoperative opioid therapy. The antiemetic combination strategy and a
multimodal prevention approach seem to be effective in preventing PONV.
Among approved drugs in the 2014 Consensus Guidelines for the Management
of Postoperative Nausea and Vomiting by Gan et al. are: (1) 5-HT3 receptor
antagonists; (2) corticosteroid: methylprednisolone; (4) butyrophenone: haloperidol
and (5) anti-histamine. Adequate hydration is another simple strategy to reduce
emesis.
Respiratory Management
Postoperative management should be assessed by preoperative respiratory

function tests both with the type of surgery performed. Patients with normal cough
clearance and relatively preserved muscle function appear not at increased risk for
postoperative complications. On the other hand, patients with decreased respiratory
muscle strength require close monitoring and adequate respiratory management.
The application of a protocol based on the combination of NIV with MI-E
(assisted cough machine) after extubation for high-risk NMDs patients, may provide
a clinically important advantage, being the anesthesiologists and/or intensivists

prepared for the need of reintubation or even tracheotomy, aiming for shortening
their ICU stay (Grade 1C).
After extubation, a rapid NIV trial should be considered for patients with baseline
value of FVC < 50% of predicted, and should be strongly considered for those with
FVC < 30% of predicted. Assisted cough is obviously also recommended for patients
already using MI-E and NIV preoperatively. However, a shared plan and daily
coordination with the hospital respiratory therapists is fundamental. Oxygen must be
applied with caution in NMDs patients because it can correct hypoxemia without
treating the underlying cause such as hypercapnia, mucus plugging and atelectasis.
To facilitate appropriate oxygen use, CO2 levels should be monitored (Grade 2C) [3].
CONCLUSION
Patients with NMDs are at high risk of intra-operative and post-operative

complications. An intensive, proactive, multidisciplinary approach should be planned
before, during and after any surgical procedure requiring general, regional
anesthesia or sedation. Loco-regional technique approach, nowadays ultrasound
guided, should be preferred to general anesthesia (Grade 1C), even in case of
patients with pathologies of peripheral nerves (Grade 2C), employed also in patients
with cardiac and/or respiratory involvement. However, surgery in this patient
population should be performed in a fully equipped centre with extensive experience
in NMDs management.
Key Messages
 In daily practice the preoperative anesthesiological examination include a

fundamental focus of NMDs associated organ involvement, i.e., in particular
cardiac and respiratory dysfunction
 Regional anesthesia vs. general anesthesia should be preferred whenever
possible, including patients with preexisting peripheral nervous system
disorders. When a general anesthesia is performed, a TIVA-TCI strategy
should be preferred with short-acting drugs
 -Adequate intra and post-operative monitoring (e.g., cardiac, anesthesia
depth); moreover, a quantitative neuromuscular monitoring should be
strongly considered whenever nondepolarizing neuromuscular blocking
agents are administered
 Awareness of intraoperative triggering of malignant hyperthermia,
hyperkalemia, rhabdomyolysis, fatal arrythmias and cardiac arrest appear
fundamental during the anesthesia time
 Case series and reports recently published suggest that sugammadex can be
safely used as a reversal of aminosteroid relaxant agent; the risk of residual

neuromuscular block appears eliminated when this agent is administered

intraoperatively.
REFERENCES
[1] Hirsch N P. Neuromuscular junction in health and disease. Br. J. Anaesth.

2007; 99:132 – 138.
[2] Drissen J J. Neuromuscular and mitochondrial disorders: what is relevant to the
anaesthesiologist? Curr. Opin. Anesthesiol. 2008; 21: 350 – 355.
[3] Racca F, Mongini T, Wolfler A, et al. Recommendations for anesthesia and
perioperative management of patients with neuromuscular disorders. Minerva
Anesthesiol. 2013; 79:419 – 433.
[4] Guyatt G H, Oxman A D, Vist G E, Kunz R, Falck-Ytter Y, Alonso-Coello P et
al. GRADE: an emerging consensus on rating quality of evidence and strength
of recommendations. BMJ 2008;336:924-6.
[5] Katz J A, Murphy G S: Anesthetic consideration for neuromuscular diseases
Curr. Opin. Anesthesiol. 2017, 30:435–44.0
[6] Birnkrant D J, Panitch H B, Benditt J O, Boitano L J, Carter E R, Cwik V A et al.
American College of Chest Physicians consensus statement on the respiratory
and related management of patients with Duchenne muscular dystrophy
undergoing anesthesia or sedation. Chest 2007;132:1977- 86.
[7] Wang C H, Bonnemann C G, Rutkowski A, Sejersen T, Bellini J, Battista V et
al. Consensus statement on standard of care for congenital muscular
dystrophies. J. Child Neurol. 2010;25:1559-81.
[8] Tzeng A C, Bach J R. Prevention of pulmonary morbidity for patients with
neuromuscular disease. Chest 2000;118:1390-6.
[9] Vianello A, Arcaro G, Braccioni F, Gallan F, Marchi M R, Chizio S et al.
Prevention of extubation failure in high- risk patients with neuromuscular
disease. J. Crit. Care 2011;26:517-24.
[10] Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anaesthesia in
neuromuscular disorders. Neuromuscul. Disord. 2005;15:195-206.
[11] Frova G, Sorbello M Algorithms for difficult airway management: a review.
Minerva Anestesiologica 2009; 75: 201- 9.
[12] Sorbello M, Frova G When the end is really the end? The extubation in the
difficult airway patient. Minerva Anestesiologica 2013. Feb; 79(2): 194-9.
[13] Gratarola A. et al. Miorisoluzione, monitoraggio neuromuscolare ed
antagonismo. www.siaarti.it/pages/formazione-e-risorse/linee-guida.aspx.
[Miorisoluzione, neuromuscolare monitoring of antagonism]
[14] De Boer H et al. Reversal of neuromuscular blockade with sugammadex in
patients with myasthenia gravis. Eur. J. Anaesthesiol. 2014;31:708-721.

[15] Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol

and selective and non-selective non-steroidal anti-inflammatory drugs for the
reduction in morphine-related side-effects after major surgery: a systematic
review. Br. J. Anaesth. 2011;106:2927.
[16] Romagnoli S et al. Light sedation with dexmedetomidine: a practical approach
for the intensivist in different ICU patients. Minerva Anestesiologica 2018
giugno; 84(6): 731-746.

Chapter 25
MANAGEMENT OF ACUTE RESPIRATORY

FAILURE IN PREGNANCY
Antonietta Coppola1,, Giuseppe Fiorentino1, MD

and Antonio Esquinas2, MD
1
UOC Fisiopatologia e Riabilitazione Respiratoria AO Ospedali dei Colli,
Naples, Italy
2
Intensive Care Unit, Hospital Morales Meseguer, Murcia, Spain
ABSTRACT
Pulmonary physiological and anatomic changes during pregnancy affect the

overall management and predispose patients to complications during respiratory
illness. Patients with neuromuscular disease and severe respiratory impairment,
specifically when vital capacity (VC) is below 60% of predictions, are often
discouraged from becoming pregnant due to potential respiratory complications
and the possibility of the need for invasive ventilation and/or tracheostomy.
During labour, pulmonary function can be decreased. The management of
women in pregnancy requires awareness of the inspiratory and expiratory muscle
aids that can be used to maintain alveolar ventilation and airway secretion
clearance throughout gestation, labour and delivery.
Keywords: acute respiratory failure, pregnancy, NIV

Corresponding Author’s E-mail: antonietta.coppola84@gmail.com.

346 Antonietta Coppola, Giuseppe Fiorentino and Antonio Esquinas
ABBREVIATIONS
AFE Amniotic fluid embolism

ARF Acute respiratory failure
FRC Functional residual capacity
ICU Intensive care unit
NIV Noninvasive ventilation
NMD Neuromuscolar disease
PE Pulmonary oedema
PEEP Positive end expiratory pressure
V/Q Ventilation/perfusion
VC Vital capacity
INTRODUCTION
The respiratory tract undergoes significant anatomical and physiological changes

during pregnancy, which increase maternal susceptibility to respiratory failure. Acute
respiratory failure (ARF) occurs in less than 0.1% of pregnancies (Chen et al., 2003);
however, it is one of the most common reasons for obstetric admissions to the
intensive care unit (ICU) and carries high mortality for both mother and fetus
(Christiansen and Collins, 2006). The application of noninvasive ventilation (NIV) in
ARF treatment continues to expand as its benefits are increasingly recognised. NIV
is often avoided in pregnancy due to the theoretical risk of aspiration.
PHYSIOLOGIC RESPIRATORY CHANGES IN PREGNANCY
During pregnancy, anatomical and physiological respiratory changes occur. The

increase in oestrogen production increases upper airway resistance due to
hyperaemia with oedema. These modifications influence obstructive sleep apnoea,
especially in patients with bulbar dysfunction, which may increase upper airway
instability, with an increased risk of obstructive apnoeas during progesterone rise
(Bonica, 1974).
Anatomical changes consist of displacement of the diaphragm upwards by up 4
cm. Despite this, the potential loss of lung volume is offset by the widening of the
anteroposterior and transverse thoracic diameters and increased subcostal angle
from 60 to 130 to accommodate an enlarging uterus (Bonica, 1974).
Physiological changes are various. Usually, functional residual capacity (FRC)
decreases by 10–25% by term. The VC does not change, and total lung capacity
minimally decreases. Measurements of airflow (FEV1) and lung compliance are not
altered during pregnancy, but chest wall and complete respiratory compliance are
reduced in the third trimester. Minute ventilation progressively increases during

Management of Acute Respiratory Failure in Pregnancy 347
pregnancy, beginning in the first trimester and reaching 20–40% above baseline by
term. The increase in progesterone level stimulates the respiratory centre in the brain
to increase respiratory depth, but not rate (hyperpnoea, not tachypnoea), producing
an increase of tidal volume with very little change in respiratory rate (Bonica, 1974).
In late pregnancy, blood gases exhibit respiratory alkalosis due
tohyperventilation, with a PaCO2 of 28–32 mmHg, and plasma bicarbonate of 18–21
mEq/L for renal compensation. There is a decrease in oxygen reserve because
oxygen consumption increases (beginning in the first trimester and reaching 20–33%
by the third trimester) and FRC is reduced. The combination of increased oxygen
consumption and reduced FRC explain why pregnant patients develop hypoxia
rapidly in response to hypoventilation or apnoea (Elkus and Popovich, 1992).
Fetal oxygenation is determined by placental function and uterine oxygen
delivery, which depends on maternal oxygen content and uterine blood flow. Uterine
blood flow is decreased by alkalosis, catecholamines, hypotension and contractions.
CAUSES OF RESPIRATORY FAILURE IN PREGNANCY
Respiratory failure in pregnancy occurs in fewer than 0.1% of pregnancies, and it

is one of the most common indications for obstetric admissions into the ICU. ARF
may be caused by several pregnancy-specific complications and other conditions,
some of which may be exacerbated by pregnancy. Principal causes can be
pregnancy-specific, aggravated by pregnancies and also due to non-specific
conditions (Chen et al., 2003; Elkus and Popovich, 1992).
PREGNANCY-SPECIFIC
Pulmonary Oedema
The constellation of changes seen in pregnancy predisposes the gravida to the

development of hydrostatic pulmonary oedema (PE), which affects 0.08–1.5% of
women during pregnancy and in the postpartum (Lapinsky, 2015).
Preeclampsia/eclampsia are major obstetric causes of acute PE, with 0.6–5% of
patients with preeclampsia/eclampsia developing acute PE (Lapinsky, 2015). There
could be standard or low left ventricular preload, or increased afterload with normal
or low cardiac output. The systolic and diastolic function may also be impaired.
Women with pre-existing heart disease are at risk of cardiac decompensation. In
particular, women affected by cyanotic disease, left heart valvular stenotic lesions or
systolic dysfunction are at most risk. In patients with stenotic mitral valves, the
physiologic rise in cardiac output and heart rate during pregnancy increase the
gradient across the valves. A reduction of systemic vascular resistance improves
mitral and aortic regurgitation and the intracardiac shunt, but worsened the effect of

uncorrected tetralogy of Fallot and Eisenberg’s syndrome. Significant is peripartum

cardiomyopathy, which is a rare, often dilated, cardiomyopathy with systolic
dysfunction present in late pregnancy or, more commonly, the early postpartum
period. This condition present as congestive heart failure and is associated with a
risk of pulmonary and systemic embolisation. Iatrogenic pulmonary oedema can be
treated with tocolytic therapy using beta-2 agonists. In recent years, the use of
tocolysis has decreased (Abenhaim et al., 2008; Lapinsky, 2015).
Amniotic Fluid Embolism
Amniotic fluid embolism (AFE) is one of the most important complications of

pregnancy in which amniotic fluid, fetal cells, hair, or other debris enters the maternal
pulmonary circulation, causing cardiovascular collapse (Lapinsky, 2015; Collop and
Sahn, 1993). Its etiology remains largely unknown, but it may occur in healthy
women during labour, cesarean section, abnormal vaginal delivery and also during
the second trimester of pregnancy. It may also occur 48 hours post-delivery, during
an abortion, after abdominal trauma, and during amnio-infusion (Lapinsky, 2015).
The condition is characterised by the development of hypoxaemia and severe
dyspnoea, followed by seizure and cardiovascular collapse or arrest. Moreover,
those who survive the initial event may develop disseminated intravascular
coagulation and acute respiratory syndrome (ARDS). Acute pulmonary hypertension
development is observed, followed by dysfunction of the left ventricle with radiologic
bilateral pulmonary infiltrates. Management is supportive since there is no specific
treatment for amniotic fluid embolism and consists of therapy for disseminated
intravascular coagulation and left ventricular and respiratory failure. The prognosis
after AFE is very poor, and most women do not survive. Most survivors of this
embolism have neurologic deficits. The infant survival rate is 70% and the neurologic
status of the infant is directly related to the time lapsed between maternal arrest and
delivery (Abenhaim et al., 2008; Collop and Sahn, 1993).
AGGRAVATED BY PREGNANCY
Gastric Aspiration
Pregnant women have a higher risk of aspiration due to increased gastric

pressure, delayed gastric emptying, and decreased esophageal sphincter tone
(Rodrigues and Neiderman, 1992). The labouring patient is exposed to additional
risks for aspiration, including sedation, analgesia, increased intra-abdominal
pressure related to contractions, pushing efforts and recumbent position. Women
undergoing emergent cesarean section under general anaesthesia are particularly at

risk for aspiration. Aspiration of gastric contents can lead to aspiration pneumonia,
acute bronchospasm, and ARDS. Strategies to avoid aspiration include the use of
regional anaesthesia, minimising gastric contents by limiting or avoiding food intake
during labour, and administering H2 blockers to decrease gastric content acidity
(Lapinsky, 2015).
Pulmonary Thromboembolic Disease
Thrombosis risk is increased during pregnancy due to a hypercoagulability state

with an increase in coagulation factors, such as V, VIII, X and Von Willebrand factor,
and a deficit in protein S level and venous stasis due to the uterine compression of
the inferior vein cava and iliac veins as pregnancy progresses. The peak incidence of
thromboembolism is in the postpartum period, especially after cesarean section.
Diagnosis includes a careful history and physical examination with recognition of
specific risk factors such as obesity, advanced maternal age, family or personal
history of thromboembolic events and prolonged immobility. In addition, signs and
symptoms of dyspnoea, chest pain, and tachycardia should be recognised. Ifthe
patient history suggests pulmonary embolism, a confirmatory ventilation/perfusion
(V/Q) scan or computed tomographic (CT) pulmonary angiography should be
performed. Anticoagulation therapy with low molecular weight heparin is safe in
pregnancy. It should be used on a weight-adjusted dosing regimen for six weeks
postpartum for a minimum duration of six weeks (Abenhaim et al., 2008; Collop and
Sahn, 1993).
Asthma
Asthma is the most common chronic medical disease to be reported in

pregnancy, and its prevalence has increased in recent years. Maternal asthma is
associated with a major risk of adverse perinatal outcomes, and changes in the
disease course maybe unpredictable during pregnancy. Asthma exacerbations are a
significant medical problem during pregnancy with up to 45% of women requiring
medical support, and resulting in poor outcomes, such as low birth weight and
preterm delivery,in mothers and babies. The goals of effective asthma management
in pregnancy are to maintain the best possible asthma control and prevent
exacerbations (Murphy, 2015). A highvolume of literature demonstrates the lack of
teratogenicity of drugs used in the pharmacotherapy of asthma in pregnancy. Short-
acting beta agonists have been shown to have acceptable safety profiles for the
fetus. Simultaneously, non-selective beta-agonists, such as epinephrine, carry a risk
of uterine vasoconstriction and should be avoided during pregnancy. Systemic
corticosteroids are used in severe asthma, and halogenate corticosteroids, such as
prednisolone and prednisone, do not cross the placenta (Schatz, 1997). Severe

asthma exacerbations seem to be expected during the second trimester of

pregnancy. Initial management of the pregnant patient suffering from acute life-
threatening bronchospasm consists of administering supplemental oxygen,
intravenous fluids, intravenous steroids and beta-agonist therapy to alleviate
bronchospasm and airway inflammation. Combining the oedematous airway seen in
pregnancy with bronchial over-responsiveness seen in an asthmatic patient can
make this patient very difficult to intubate and ventilate. Intubation should be
considered early (Murphy, 2015).
NON-SPECIFIC CONDITIONS
Pulmonary Infection
The pathogenesis, signs and symptoms, and diagnostic procedures for

pneumonia are similar for pregnant and nonpregnant women. Incidence does not
appear to be higher than in the general population. Bacterial pneumonia has a similar
microbiological spectrum in comparison to the usual community-acquired
pneumonia. Viral pneumonia is most commonly due to influenza and varicella. One-
third of women with respiratory failure in pregnancy have had pneumonia in the
course of their pregnancy (Rodrigues and Neiderman, 1992). Prevention of disease,
including influenza vaccinations for women during pregnancy and early diagnosis
and treatment of infection with antibiotics or antivirals, are critical to avoiding
complications, including ARDS and respiratory failure.
Acute Respiratory Distress Syndrome
ARDS is a rare occurrence in the pregnant patient with an estimated incidence of

16–70 per 100,000 pregnancies (Mabie, Barton and Sibai, 1992)]. Most of the
published information on pregnancy-related ARDS comes from case reports or small
series in which pregnancy-related ARDS was attributed to pyelonephritis, tocolytic
use, sepsis, placental abruption, disseminated intravascular coagulopathy,
chorioamnionitis, sickle cell disease, or preeclampsia-eclampsia (Mabie, Baron and
Sibai, 1992). There are few differences in the management of a pregnant patient with
ARDS compared to one who is not pregnant. Survival from ARDS seems to be as
good as or better than in the general population.
Restrictive Lung Disease
Few data existson restrictive lung disease in pregnancy. Interstitial lung disease
(ILD) is not very common in patients of childbearing age, except for

lymphangioleiomyomatosis and systemic lupus erythematosus. Chest wall disease,

such as kyphoscoliosis or neuromuscular weakness, require increased ventilation
during pregnancy; thus exposing an increased risk for respiratory failure.
Neuromuscular Disease
Patients with severe respiratory muscle impairment are often advised against
becoming pregnant for fear of respiratory complications and the need for
tracheostomy and invasive mechanical ventilation (Yim et al., 2003). A growing fetus
can impair diaphragm excursion and cough function and increase oxygen
consumption and ventilation requirement. Complications of pregnancy and the need
for analgesics and anaesthesia during labour and delivery can also cause ventilatory
failure.
In pregnancy, the increase in diaphragm lengthening and curvature may facilitate
the weak, flattened, and shortened diaphragms of patients with both diaphragm and
abdominal muscle weakness. Likewise, the weakened and shortened intercostal
muscles of patients with neuromusculoskeletal conditions may be at a mechanical
advantage when the transverse lower thoracic diameter increases. The average
woman loses 30% of VC during the last trimester of an uncomplicated pregnancy. It
would be anticipated that women with neuromuscular diseases would also lose VC.
In the literature, there are few data about the management of respiratory failure by
neuromuscular illness in pregnancy. Some reports show that NIV could be used
during pregnancy to decrease ventilatory insufficiency symptoms and maintain
adequate alveolar ventilation while permitting natural, full-term completion. Thus,
ventilatory insufficiency, and even total respiratory muscle failure, can be
compensated by the use of NIV (Yim et al., 2003). However, other reports of women
with restrictive pulmonary syndromes have had successful pregnancies without
ventilatory support.
Labour
In neuromuscular disease, ventilatory failure can be precipitated during labour

because of ventilatory requirements, cardiac output, and venous return increase due
to muscular activity. During the expulsive phase, maximal isometric diaphragmatic
contractions are sustained for approximately 15 seconds with a reduction in
perfusion of the diaphragm during these contractions, which can precipitatemuscle
fatigue and lead to ventilatory failure. Patients with a spinal deformity can have
cephalopelvic disproportion, making a cesarean section necessary.

However, it is technically more challenging to carry out a cesarean section on

those patients with severe spinal curves due to anteflexion of the uterus in the
abdominal cavity. The result is that the lower uterine segment is inaccessible.
Sedation and analgesia using during labour or cesarean section can precipitate a
hypercapnic respiratory failure in these patients due to depression of the respiratory
centre (Lapinsky, 2015; Yim et al., 2003).
Postpartum
During the postpartum period, pain induced by labour or a cesarean section

produces a diminution in coughing effort intensity, which results in a decrease in
cough capacity. This event can be fatal in those patients with expiratory muscle
weakness as it increases the risk of atelectasis or superinfection due to retained
secretions. In this phase, sedatives and analgesics must be used carefully due to the
respiratory centre’s risk of depression resulting in ventilator failure. A decrease in
cough capacity and effectiveness, resulting in atelectasis, has been reported after
using spinal and epidural anaesthesia for a cesarean section in a normal pregnant
woman (Yim et al., 2003).This risk increases the neuromuscular muscle weakness of
underlying disease.
Management of Pregnancy in Neuromuscular

and Chest Wall Disease
Although there are reports of women with restrictive pulmonary syndromes

secondary to neuromuscular and chest wall diseases who have had successful
pregnancies without ventilatory support (and one case in which pregnancy was
supported by intermittent positive pressure ventilation delivered via an indwelling
tracheostomy tube), in many cases, the deliveries were induced once respiratory
symptoms developed. In none of the cases were symptoms relieved or pregnancy
extended by noninvasive ventilatory support (Lapinsky et al., 2014). However, full-
term gestation is possible, even for women without functional respiratory muscles.
Such patients need to be made aware of the inspiratory and expiratory muscle aids
that can be used to maintain alveolar ventilation and airway secretion clearance
throughout gestation, labour and delivery. These aids should be introduced at the
first signs of alveolar hypoventilation or ineffective cough capacity. The three goals of
optimal respiratory management for patients with neuromuscular diseases are to
maintain alveolar ventilation as normal as possible around the clock, expand the
lungs to sustain pulmonary compliance, and maximise airway secretions when
necessary (Yim et al, 2003; Lapinsky et al., 2014).

Monitoring during Pregnancy
Women with neuromuscular diseases should be closely examined before

becoming pregnant to determine their baseline situation and respiratory muscle
function. Spirometry is carried out to measure vital capacity and maximal and
expiratory pressures (Pmax) at the mouth, nocturnal pulse oximetry and arterial
blood is performed when the patient is awake. With the aid of these procedures and
evaluation of the patient’s symptoms, the indication for inspiratory muscles aids can
be assessed. Cough capacity must also be carefully assessed. During a cough effort,
the initial high flows in the expulsive phase are essential for mucus clearance (thus,
peak cough flow [PCF] measurement), which is mainly dependent on the intensity of
the cough and has been explicitly proposed for evaluation of cough effectiveness.
Measurement of PCF is readily available for neuromuscular patients: it does not
need sophisticated equipment, is easy and quick to determine, and does not cause
the patient to suffer (Bach, 2003).
Moreover, when values are still not significantly decreased, PCF can be
measured using a portable device to measure peak expiratory flows in asthmatic
patients. Assisted PCF generated with manually and mechanically coughing
techniques must be measured to assess the efficacy of expiratory muscle aids.
When vital capacity is lower than 1.5 L, measurement of maximum insufflation
capacity must be performed. This parametreis the maximum volume of air that can
be held with a closed glottis and then expelled (Al-Ansari et al., 2007), which can be
obtained by blowing air via an inflatable bag or a volumetric ventilator, coordinating
insufflations with glottic closure to avoid air leaks. Patients with bulbar dysfunction
preventing effective glottic closure cannot achieve this. Attaining a much higher MIC
than vital capacity has proved to be a fundamental condition for successfully
maintained, noninvasive management in the medium term. Consequently, MIC is a
better prognostic factor than vital ability in NMD. Moreover, patients with a MIC < 1.5
L have diminished spontaneous and assisted PCFs, which increases morbidity and
mortality. It is necessary to reach a minimum MIC of l L for manually assisted
coughing to achieve flows that avoid mucous accumulation. During pregnancy,
patients should be closely monitored and symptoms of hypoventilation
(breathlessness, orthopnoea, morning headache, and tiredness), oxyhaemoglobin
saturation (SpO2), PaCO2 (non-invasively with transcutaneous or end-tidal CO2 or
invasively with arterial blood gasometer), and PCF should be regularly measured.
Respiratory Muscle Aids
Inspiratory and expiratory muscle aids are manual or mechanical devices that
assist inspiratory or expiratory muscle function by applying forces to the intermittent
pressure changes of the airway. The aim of these aids is to help or replace
respiratory muscle function; these aidsdo not require training or invasion of the

airway (noninvasive) to maintain adequate alveolar ventilation and remove

respiratory secretions. Inspiratory muscles are assisted in maintaining alveolar
ventilation with noninvasive mechanical ventilation, and manual- or mechanical-
assisted coughing techniques are applied to the expiratory muscles.
VENTILATORY MANAGEMENT
Noninvasive Ventilation
NIV provides mechanical ventilation without accessing the airway. Devices that
offer intermittent positive pressure ventilation are more effective and comfortable
than other alternatives, such as negative pressure body ventilation (iron lung, chest
shell-style ventilators, and wrap-style ventilators) and intermittent abdominal
pressure ventilation. The NIV technique is applied through an interface and delivered
by pressure- or volume-cycled ventilators. This technique is considered when
hypoventilation symptoms (such as fatigue, dyspnoea, morning headache, and
tiredness) are present together with specific physiologic criteria. These criteria should
even be looser in the pregnant patient since fetal oxygenation and ventilation are
closely related to maternal oxygenation and ventilation. Initially, NIV is used during
sleep, when hypoventilation signs are more apparent, but as the NMD progresses,
the number of hours of use should increase. Nowadays, around-the-clock NIV can be
used if different interfaces are alternated (Lapinsky et al. 2014).
An interface passes pressurised air from the ventilator to the patient’s upper
airway. Selection of the correct maskdepending on the area of the patient’s face to
which it be applied during wakefulness, including nasal masks, oronasal masks, and
mouthpieces, is crucial for NIV interface success. Nasal masks are tolerated better
than oronasal masks, with less dead space, but can produce more significant air
leaks through the mouth. Nasal pillows are a type of nasal mask consisting of soft,
cone-shaped rubber pledges inserted into each nostril and connected to the
ventilator instead of nasal masks, with possible leakyplastic tubing assembly.
Oronasal masks used through the mouth are excessive, and may compromise the
efficacy of ventilation. However, oronasal interfaces result in greater claustrophobia
and may interfere with coughing. Nasal prongs/lip seal interfaces provide support
with minimal skin pressure and are increasingly popular. Mouthpiece ventilation is an
alternative interface and is associated with improved cough, speech and pulmonary
compliance. Nasal or oronasal masks are usually used during sleep (Lapinsky et al,
2014).
NIV is often avoided in pregnancy due to the theoretical risk of aspiration and
gastric distension due to the inhaled oxygen and air going to the stomach as a result
of high pressure and flow rates of the gases used (Lapinsky, 2014).

Routinely, gastric distension is rarely a complication of NIV, especially when the

peak inspiratory pressure does not exceed 25 cmH2O. One of the most interesting
aspects of NIV is its usage as an alternative to invasive ventilation, avoiding all the
risks, complications and side effects of endotracheal intubation. However, current
literature concerning the safety and efficacy of NIV for the management of respiratory
failure in pregnancy are few and based on weak evidence. Only a few case reports
and small case series have been published in which this modality has been used in
the parturient, most of the time successfully. In a case series, Bach et al. (2003)
described the successful use of NIV in four full-term pregnant women. Three women
had chronic NIV-dependent respiratory failure due to poliomyelitis and one female
developed respiratory failure due to severe kyphoscoliosis. Using NIV, all four
females delivered healthy, full-term babies (Bach, 2003). Al-Ansari et al. (2007)
described four pregnant patients with sickle cell disease who presented with ARDS.
They were successfully supported with NIV, and endotracheal intubation was
avoided. None of the patients experienced episodes of aspiration. Some reports
have demonstrated perioperative use of NIV in combination with spinal anaesthesia
for a parturient patient with respiratory failure requiring emergency cesarean delivery
(Erdogan et al., 2010). A recent reportdescribed the use of NIV and
dexmedetomidine for sedation in a pregnant woman with hypoxaemic respiratory
failure from severe aspiration pneumonia (Duan, Lee and Bittner, 2012).
In conclusion, NIV should be considered a safe option for the treatment of ARF in
a carefully selected group of parturient patients with ARF. The ideal candidate should
meet at least the following criteria: adequate respiratory drive, ability to control one’s
airway, ability to tolerate a tight-fighting mask, haemodynamic stability, and low risk
for aspiration.
Invasive Mechanical Ventilation
Prolonged mechanical ventilation of pregnant patients in the ICU is uncommon,

and few data are available to guide management. Hyperventilation and alkalosis
should be avoided due to the risk for uterine vasoconstriction. Chest wall compliance
is reduced by an enlarging uterus, and the usual pressure limits may not be
appropriated. The choice of an initial ventilatory rate, tidal volume, oxygen
percentage, and need for PEEP should be balanced against the potential induction of
barotrauma. Oxygenation should ensure adequate fetal oxygenation and a maternal
oxygenation goal of PaO2of 70 mmHg is suggested (Lapinsky, Posadas-Calleja,and
McCullagh, 2009). Hypocapnia can cause fetal harm by reducing placental perfusion.
The effect of hypercapnia is less clear, but maternal hypercapnia can produce fetal
respiratory acidosis. Permissive hypercapnia has not yet been evaluated in
pregnancy.

REFERENCES
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implicated in the outcome of pregnancies complicated by acute respiratory
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year retrospective study and overall review of maternal pathophysiology. Am. J.
Foren. Med. Path., 27(1), pp. 11-19.
[3] Bonica, J. (1974). Maternal respiratory changes during pregnancy and
parturition. Clin. Anesth., 10(2), pp. 1-19.
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risk factors of amniotic fluid embolisms: A population-based study on 3 million
births in the United States. Am. J. Obstet. Gynecol., 199(1), pp. 49e1-8.
[6] Lapinsky, S. (2015). Acute respiratory failure in pregnancy. Obstet. Med., 8(3),
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[7] Collop, N.,and Sahn, S. (1993). Critical illness in pregnancy. An analysis of 20
patients admitted to a medical intensive care unit. Chest., 103(5), pp. 1548-
1552.
[8] Murphy, V. (2015). Managing asthma in pregnancy. Breathe (Sheff)., 11(4), pp.
258-267.
[9] Schatz, M. (1997). The safety of asthma and allergy medication during
pregnancy. J. Allergy Clin. Immunol.,100(3), pp. 301-306.
[10] Rodrigues, J., and Neiderman, M. (1992). Pneumonia complicating pregnancy.
Clin Chest Med., 13(4), pp. 679-691.
[11] Mabie, W., Barton, J.,and Sibai, B. (1992). Adult respiratory distress syndrome
in pregnancy. Am. J. Obstet. Gynecol., 167(4 Pt 1), pp. 950-957.
[12] Yim, R., Kirschner, K., Murphy, E., Parson, J., and Winslow, C. (2003).
Successful pregnancy in a patient with spinal muscular atrophy and severe
kyphoscoliosis. Am. J. Phys. Med. Rehabil., 82(3), pp. 222-225.
[13] Lapinsky, S., Tram, C., Mehta, S., and Maxwell, C. (2014). Restrictive lung
disease in pregnancy. Chest, 145(2), pp. 394-398.
[14] Bach, J.(2003). Successful pregnancies for ventilator users. Am. J. Phys. Med.
Rehabil., 82(3), pp. 226-229. doi: 10.1097/01.PHM.0000053395.41165.73.
PMID: 12595775.
[15] Al-Ansari, M., Hameed, A., Al-jawder, S., and Saeed, H. (2007). Use of
noninvasive positive pressure ventilation during pregnancy: case series. Ann.
Thorac. Med., 2(1), pp. 23-25.
[16] Erdogan, G., Okyay, D.,Yurtlu, S., Hanci, V., Ayoglu, H., Koksal, B., and Turan,
I. (2010). Noninvasive mechanical ventilation with spinal anesthesia for
cesarean delivery. Int. J. Obstet. Anesth., 19(4), pp. 438-440.

[17] Duan, M., Lee, J., and Bittner, E. (2012). Dexmedetomidine for sedation in the
parturient with respiratory failure requiring noninvasive ventilation. Respir Care.,
57(11), pp. 1967-1969.
[18] Lapinsky, S., Posadas-Calleja, J., and McCullagh, I. (2009). Clinical review:
Ventilatory strategies for obstetric, brain-injured and obese patients. Crit. Care.,
13(2), p. 206. doi: 10.1186/cc7146.

Chapter 26
CARDIAC MANIFESTATIONS
OF NEUROMUSCULAR DISEASE
Gerardo Nigro, MD, PhD, V. Russo, MD,

A. Rago, MD and A. A. Papa, MD
Department of Cardiothoracic and Respiratory Sciences,
University of Campania “L. Vanvitelli,” Monaldi Hospital, Naples, Italy
ABSTRACT
Neuromuscular diseases are a group of complex multisystem disorders that

commonly and prominently affect striated muscle. Cardiac involvement in
neuromuscular diseases namely conduction disorders, ventricular arrhythmias
and cardiomyopathy with its impact on prognosis, is often dissociated with the
peripheral myopathy. Therefore, close surveillance is mandatory in the affected
patients. In this context, preventive therapy has been recently recommended in
the most common neuromuscular diseases. This chapter focuses on the heart
involvement of the muscular dystrophies exhibiting prominent cardiac
manifestations, including Myotonic dystrophy type 1, Duchenne (DMD), Becker
(BMD), Emery-Dreifuss (EDMD) and Facio-Scapulo-Humeral muscular
dystrophies.
Keywords: Myotonic dystrophy type 1, Dystrophinopathies, Duchenne Muscular

Dystrophy, Becker Muscular Dystrophy, Emery-Dreifuss muscular dystrophies,
arrhythmias; sudden death, left ventricle systolic dysfunction, heart failure

Corresponding Author’s E-mail: gerardo.nigro@unicampania.it.

360 Gerardo Nigro, V. Russo, A. Rago and A. A. Papa
INTRODUCTION
Neuromuscular diseases often affect the heart, and in many cases

cardiovascular disease limits life expectancy in these patients. Many neuromuscular
diseases (NMD) have been associated with myocardial impairment, atrial/ventricular
arrhythmias and/or sudden cardiac death (SCD). In each disease, recognition and
treatment of cardiac involvement can prolong and improve the quality of life. The
spectrum of cardiovascular manifestations of NMDs range from asymptomatic
incidental findings to life-threatening conditions. This chapter focuses on the cardiac
manifestations of muscular dystrophies exhibiting prominent heart involvement,
including Myotonic dystrophy type 1 or Steinert disease, Duchenne (DMD), Becker
(BMD) and Emery-Dreifuss (EDMD) muscular dystrophies and Facio-Scapulo-
Humeral-dystrophy (FSHD). The cardiovascular presentation and management of
patients with a NMD is dependent on the specific type of disease (Table 1).
Table 1. Cardiovascular manifestations of the muscular dystrophies
Neuromuscular DCM Conduction Ventricular Atrial

disease disorders arrhythmias arrhythmias
Steinert Disease Rare +++ ++ ++
DMD +++ + + +
BMD +++ + ++ +
EDMD A/C ++ +++ +++ ++
EDMD X-linked + +++ + Rare
FSHD Rare Rare Rare +
Abbreviations: BMD, Becker muscular dystrophy; DCM, dilated cardiomyopathy; DMD,Duchenne muscular
dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; FSHD, Facio-Scapulo-Humeral-dystrophy.
As is shown in Table 1 cardiac involvement is an almost constant feature in a

great part of these diseases, as both primary myocardial involvement and secondary
involvement due to respiratory insufficiency, pulmonary hypertension or reduced
mobility. Usually the myocardial disease manifesting as cardiomyopathy and
congestive heart failure is characteristic of dystrophinopathies (DMD/BMD) and some
rare types of sarcoglycanopathies. Conversely, abnormalities in the conduction
system causing heart blocks, arrhythmias and sudden cardiac death are more
commonly seen in Myotonic Dystrophy type 1 (DM1), Emery-Dreifuss muscular
dystrophies (EDMD), and less frequently in Facio-Scapulo-Humeral-dystrophy
(FSHD).
MYOTONIC DYSTROPHY TYPE 1
Myotonic dystrophy type 1 (DM1), also called Steinert’s disease, is the most
common muscular dystrophy in adult life with an incidence of 1 in 8000 births and a
worldwide prevalence from 2.1 to 14.3:100.000 inhabitants [1-3]. DM1 is a clinically

Cardiac Manifestations of Neuromuscular Disease 361
and genetically heterogeneous disorder resulting from an amplified CTG trinucleotide

repeat (> 50) in the 3prime untranslated region of the dystrophia myotonica protein
kinase gene (DMPK gene) on chromosome 19q13.3 [4]. The CTG repeat size
correlates with the severity of DM1 phenotype, but there is a considerable variability
and overlap between phenotypes: in general, normal individuals have 5 to 37
repeats, mildly affected persons have 50 to 150 repeats, patients with classic DM1
have 100 to 1,000 repeats, and those with congenital onset can have more than
2,000 repeats [5-7] There are overall positive associations between CTG repeat size
and cardiac involvement and between the degree of neuromuscular and cardiac
involvement [8-9]. Based on the age at onset, DM1 can be divided into three
subtypes: congenital, childhood onset and adult-onset. Congenital DM1 is the most
severe and earliest occurring form of myotonic dystrophy that presents potentially
life-threatening issues at birth. In the classical form, the muscular symptomatology
becomes evident between the second and the fourth decade of life, showing a slow
progression over time [10]. Besides muscle involvement, the affected patients may
manifest abnormalities of other organs and systems, including eye (cataract),
endocrine system (diabetes, thyroid dysfunction, hypogonadism), central nervous
system (cognitive impairment, mental retardation, attention disorders),
gastrointestinal system (dysphagia, constipation, gallbladder stones, pseudo-
obstruction), respiratory apparatus (respiratory failure) and heart [11].
Cardiac Involvement and Sudden Death in DM1
Cardiac involvement, often preceding that of the skeletal muscle, occurs in 80%
of DM1 patients and represents the second most common cause of death, after
respiratory causes [12]. Endomyocardial biopsies performed on patients with DM1
have shown specific changes, such as perivascular interstitial fibrosis, fatty
infiltration, hypertrophy of myocardiocites and focal myocarditis [12]. The localization
of DMPK in the heart muscle at the level of intercalated discs combined with the
observation that DMPK reduction in animal models compromises the conduction at
both the level of the atrioventricular node and the His-Purkinje system [6]. This
suggests the impairment of intercellular impulse propagation as a possible
mechanism of disease. Mathieu et al. [11], during a 10 year follow-up study on 367
DM1 patients, reported a mortality 7.3 times higher than in an age-matched control
population, with a mean age for death of 53 years; furthermore they showed a
positive correlation between age of onset of DM1 and age of death. In their series,
respiratory failure and cardiovascular disease were the most prevalent causes of
death, accounting for about 40% and 30% of fatalities, respectively. Cardiac mortality
usually occurred as a result of unexpected sudden cardiac death or of progressive
left ventricular dysfunction, ischaemic heart disease, pulmonary embolism [13].

Sudden Cardiac Death
DM1 patients have a three-fold higher risk of sudden cardiac death (SCD) than
age-matched healthy controls [14]. The risk of SCD in an unselected DM1-population
was 0.56% per follow-up year [14]. Sudden cardiac death accounts for up to 33% of
all deaths in DM-1. The hypothesis that cardiac arrhythmias may represent the most
prevalent cause of sudden death in DM1 patients is supported by the absence of
other causes of sudden death at necropsy studies. The evidence of the progressive
degeneration of the conduction system in DM1 patients may explain the role of
bradyarrhythmias as the most prevalent mechanism of sudden death (SD). However,
the reports of sudden death in DM1 patients with pacemakers and spontaneous or
inducible ventricular tachycardia (VT) suggests that the ventricular arrhythmias,
increasingly recognised in DM1 population, might represent a possible mechanism of
SD [15].
Conduction Defects
Conduction defects are the most prevalent cardiac abnormalities in DM1

patients. Any section of the conducting system can be affected, but the His-Purkinje
system is primarily involved. It was reported that first degree atrioventricular block
(AVB) in 28,2%, second degree AVB in 2,1%, QRS duration > 120 ms occurred in
19.9% of DM1 population. First degree AVB was found to be associated with
increased risk of atrial fibrillation, PM-implantation and allcause mortality, and
therefore challenges the perception that first degree AVB has a benign prognosis
[16]. Left bundle branch block (LBBB) and right bundle branch block (RBBB) had a
prevalence of 5.7% and 4.4%, respectively [14]. There is a general consensus on the
unpredictable progression of minor conduction defects to more severe forms. The
main clinical concern is the development of complete heart block and its role in
sudden death. The prevalence of third degree atrioventricular block was 0,3%.
Correct QT interval was prolonged (>440 ms) in 22% of DM1 patients [16]. DM1
patients with conserved systolic and diastolic function presented increased maximum
P wave duration and P-wave dispersion values [17], two electrocardiographic
parameters considered to reflect the discontinuous and inhomogeneous propagation
of sinus impulses and the prolongation of atrial conduction time.
Clarke et al. [8] showed that larger CTG expansions predict a higher rate of QRS
broadening and a trend towards a higher incidence of cardiac events. Those
experiencing cardiac events during follow-up had a significantly higher rate of PR
interval progression. The HV interval was increased in about 50% of unselected DM1
patients. A small study has suggested that prolongation of the HV interval (> 70 ms)
in invasive electrophysiological study (EPS) is predictive of complete AV block [18].
In a large retrospective, single centre registry of 486 genetically confirmed DM1
patients with conduction disease (PR interval >200 ms and/or QRS duration >100

ms), the EPS guided (HV interval > 70 ms) pacemaker implantation did not show
significant difference in overall mortality over a median follow-up of 7.4 years. When
adjusted for baseline characteristics, there was borderline significance in overall
survival in favour of the invasive strategy, largely due to a significant reduction in
adjusted survival from sudden cardiac death [19].
Tachyarrhythmias
Paroxysmal supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter,

atrial tachycardia) are a common finding on 12 lead ECG or 24 hour Holter
monitoring, often asymptomatic, with a prevalence up to 25% in DM1 patients [14].
Atrial tachycardias are observed in up to 7.3% of patients, both as unsustained and
sustained forms.
The mean prevalence of atrial fibrillation (AF) among patients affected by DM1 is
11%, with a median age of 43.08 years at presentation [20, 21]. Considering that the
prevalence of AF in the general population younger than 49 years is 0.12%–0.16%,
the prevalence of AF in DM1 patients seems to be about 70 times higher.
Furthermore, papers including a large number of DM1 patients who underwent
PM/ICD or external loop recorder (ELR) monitoring implantation [22, 23] report an
higher prevalence ranging from 19 to 32%. The prevalence of AF could be higher in
DM1 patients who have underwent PM/ICD/ELR implantation because AF episodes,
often asymptomatic, could be remain undetected during the conventional follow-up
(periodic ECG/24h Holter monitoring). Furthermore, DM1 patients who underwent
PM implantation are often affected by severe conduction defects [24]. Therefore, the
higher prevalence of AF in PM/ICD carriers could be expression of a greater
sensitivity of the detection modality and a more advanced disease of the conduction
system. Atrial fibrillation is associated with an higher overall mortality in DM1 patients
[22, 25]. In particular, according to Groh et al. [25] AF was the only variable
associated to both sudden cardiac (HR: 9.34, CI 3.8-22.9, p<0.001) and non-cardiac
death (HR: 6.49 CI 2.64-15.6 p<0.001).
Ventricular premature beats are the most prevalent arrhythmia (14.6%) [26, 27].
Non sustained ventricular tachycardia may also occur in patients with DM1 with a
prevalence about 4% [26]. The possible mechanisms leading to VT may be a re-
entry around areas of fibro-fatty degeneration of the myocardium [26] or an increased
dispersion of myocardial repolarization [28].
Myocardial Impairment and Heart Failure
The prevalence of left ventricular systolic dysfunction (LVSD: Ejection fraction<

50%) among patients affected by DM1 is 13.8%, with a median age of 46.65 years at
presentation [29]. Considering that the prevalence of LVSD in the general 50-year

population is 3% [30], the prevalence of LVSD in DM1 patients seems to be about

4.5 times higher.
Symptomatic heart failure (HF) was also more prevalent in DM1 patients than in
the general population, despite their limited level of physical activity. Paunic et al.
[31] and Bhakta et al. [32] reported a clinical HF prevalence respectively of 5.6% and
5.7%, far greater than the 1-2% of the adult population in developed countries.
Various mechanisms may explain the high prevalence of LVSD/HF in DM1 patients.
The progressive myocardial fibrosis, a common histological characteristic of various
muscular dystrophies, has been reported with a prevalence of up to 40% in DM1,
according to cardiovascular magnetic resonance studies, and it represents the
substrate for the development of cardiomyopathy [33]. An essential role may be
played by conduction defects, which seem to be strongly associated with a reduced
systolic function of the LV [34], and which can cause mechanical impairment. In the
study of Paunic et al. [31] systolic dysfunction was present in 22.2% of patients with
LBBB and only 3.9% of those without LBBB (P<0.05). This showed a possible role of
LBBB in determining the early onset of LVSD and symptomatic HF, probably due to
electromechanical delay caused by both intra- and inter-ventricular asynchrony, that
leads to uncoordinated myocardial contraction.
Implantable Cardiac Electrical Devices
Several studies have associated electrocardiographic baseline abnormalities with

a risk of sudden death [15], leading to pacemaker (PMK) implantation in 4.1% to 11%
of patients and the use of an cardioverter defibrillator (ICD) in 1.1% to 5.3% to
prevent a fatal event, especially when a Holter monitoring is used [26, 35]. The
probability of receiving a PMK or ICD was 1.0 and 0.2% per follow-up year,
respectively [26]. Development of criteria for PMK and ICD implantation is
challenging because of the small size and heterogeneity of published cohort studies
and the confounding effect of progressive neuromuscular disease on survival. Groh
et al. [25] found that DM1 patients – even when asymptomatic – presenting with
prolonged PR intervals (≥ 240 milliseconds), wide QRS complex (≥ 120
milliseconds), or atrial tachyarrhythmias were at higher risk of SCD when compared
to those with normal ECGs. They also showed that SCD was more common in
patients with advanced age and a higher muscle impairment score, indicating more
severe disease. Also the male gender was reported as a SCD risk factor [35].
Because the risk of SCD most often appears to be associated to paroxysmal
complete AV block, it has become common practice to implant a prophylactic
permanent pacemaker in DM1 patients when they have ECG abnormalities
suggestive of advance conduction system disease even if they are asymptomatic.
Laurent et al. [19] reported a very low incidence of sudden death in DM1 patients
receiving a prophylactic pacemaker in the presence of a prolonged HV interval (>70
msec) and ECG abnormalities according to Groh criteria [25]. In a large retrospective
single-center registry, Wahbi et al. [26] demonstrated that systematic EPS and

prophylactic permanent pacing for HV intervals greater than 70 ms in DM1 patients

with an abnormal resting ECG were associated with a higher rate of 9-year survival
than a noninvasive strategy. The reports of sudden death in patients with
pacemakers and spontaneous or EPS inducible VT suggest that ventricular
arrhythmias might explain some cases [36, 37]. In the largest registry published to
date, 406 DM1 were followed for 9.5 years [37]. Forty-six patients received
pacemakers for conduction abnormalities and 21 patients received ICDs primarily for
LV dysfunction. During follow-up, 76.5% of patients had sudden death due to
ventricular tachyarrhythmias. In the pacemaker group 7 patients had sudden cardiac
death. Bhatk el al. concluded that the risk of VT/VF and sudden death suggests that
ICDs rather than pacemakers should be considered for these patients.
Cardiac Resynchronization Therapy in DM1 Patients
Heart failure is rare in DM1 patients and often occurs late in the course of the
disease. However, subclinical mild myocardial dysfunction may be detected [33].
Symptoms of heart failure are infrequent because of the limited level of activity of
these patients and their difficulties in reporting symptoms caused by mental
retardation. The progressive deterioration of the left ventricular function, the
progression of AV conduction disturbances and the occurrence of ventricular
tachyarrhythmia pose the question whether a biventricular ICD should be the
management of choice if a pacemaker is indicated [15]. Kilic et al. [38] described the
first case of beneficial cardiac resynchronization in one DM1 patient with heart
failure, complete LBBB and ventricular asynchrony, who was not subjected to an
intracardiac defibrillator implantation, because no serious life threatening ventricular
arrhythmias were induced at the EPS. Russo et al. (described two cases of DM1
patients with early onset heart failure, overt ventricular dyssynchrony, complete
LBBB, and EPS inducible ventricular tachycardia that underwent ICD-CRT
implantation [34, 39]. Cardiac resynchronization therapy may improve the “electrical”
left ventricular dysfunction, induce reverse remodelling and relief in symptoms of
heart failure, although the improvement in ejection fraction does not seem to reduce
the arrhythmic risk in DM1 patients. The early deterioration of the left ventricular
function related to left bundle branch dyssynchrony and the occurrence of ventricular
tachyarrhythmia pose the question whether a biventricular ICD should be the first
choice management in DM1 patients with early onset “electrical” heart failure and
complete LBBB.
DYSTROPHINOPATHIES
Dystrophinopathies are X-linked muscular dystrophies caused by mutations in

the dystrophin gene, located at Xp21, that encodes for the sarcolemmal protein

dystrophin virtually present in all tissues, but most abundant in skeletal muscle cells
and heart [40-42]. Cardiomyopathy associated with dystrophinopathies (Duchenne
muscular Dystrophy and Becker muscular dystrophy) is an increasing recognized
manifestation of these neuromuscular disorders and contributes significantly to their
morbidity and mortality. Dystrophinopathic cardiomyopathy is the result of the
dystrophin protein deficiency at the myocardium level, parallel to the deficiency
occurring at the skeletal muscle level. Cardiomyopathy begins as a “presymptomatic”
stage in the first decade of life and evolves in stepwise manner toward pictures of
overt cardiomyopathy. Nearly complete replacement of the myocardium by fibrous
and fatty connective tissue results in irreversible cardiac failure, characterized by a
further reduction of ejection fraction (EF <35%) and frequent episodes of acute
congestive heart failure (CHF). Despite correct pharmacological treatment, this
condition is irreversible because of the extensive loss of myocites and the picture of
a severe dilated cardiomyopathy with intractable heart failure is typical of Becker and
Duchenne cardiomyopathy.
Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD, OMIM 310200) is the most common

muscle disorder in infancy, affecting 1 in 3.500 male newborns [43]. It is the most
severe form of dystrophinopathy, caused by the complete absence of the dystrophin
protein at both skeletal and cardiac muscle level. Cardiomyopathy in patients with
DMD is typically asymptomatic in childhood and during the early teens, with only a
small subset of patients progressing to endstage heart failure before the age of 18
years. The disease progresses over time with a variable onset of ventricular
dysfunction [44-47]. Distinct dystrophin mutations have been correlated to an
increased incidence of cardiomyopathy, and possible response to the treatment [48].
Despite the significant advances in the pharmacological treatment [44, 49], dilated
cardiomyopathy and heart failure remain the main cause of morbidity and mortality in
DMD after respiratory failure.
Becker Muscular Dystrophy
Becker muscular dystrophy (BMD, OMIM 300376) is a milder X-linked

dystrophinopathy affecting 1 in 18.450 males [43]. Symptoms typically begin between
ages 3 and 21, with a mean age of onset of 11 years old. The disease is caused by
mutations - usually “in frame” - able to produce a certain amount of dystrophin [50].
BMD, unlike Duchenne-type muscular dystrophy, is characterized by a slow
progression of muscle weakness so that in many patients the independent activity is
maintained until adulthood.

Patients with BMD seem to pay a better muscle phenotype with a higher
occurrence of heart involvement and dilated cardiomyopathy, that represents the
major cause of morbidity and mortality [51-53]. As for DMD, genotype-phenotype
correlation exist and some dystrophin mutations have been correlated to an
increased incidence of severe cardiomyopathy.
Dystrophinopathic Cardiomyopathy: Stages and Evolution
The above mentioned clinical presentations are characterized by variable

degrees of cardiac involvement. Cardiac death usually occurs from ventricular
dysfunction and dilated cardiomyopathy, that represents the end stage of
dystrophinopathic cardiomyopathy (DCM) [54, 55]. DCM is constantly progressive
and evolves in a stage-wise manner, passing from a presymptomatic condition to
dilated cardiomyopathy through a number of pathophysiologically distinct stages [56,
57]. In brief, the presymptomatic stage is followed by a stage in which the myocardial
fibrosis is limited to few foci (spotty or focal fibrosis), often with consequent regional
heterogeneity of repolarization that can favor the onset of arrhythmias. Over time, the
foci of myocardial fibrosis merge in a picture of diffuse fibrosis, prelude of the stage
of dilated cardiomyopathy (Figure 1, 2).
Figure 1. Apical view of the left ventricle in a young man affected by Becker muscular
dystrophy. A marked left ventricular dilatation can be noted (end diastolic diameter = 72 mm).

Figure 2. M-mode scan of the left ventricle derived from two-dimensional parasternal long axis
view in a 18 years old man affected by Duchenne Muscular Dystrophy. A marked left
ventricular dilatation can be noted. The interventricular septum is hypokinetic and motion of
the left ventricular posterior wall is virtually absent.
In this stage the clinical examination shows signs of decreased cardiac output,
distention of jugular veins and hepatomegaly. The ECG may show signs of fibrosis
and various degrees of conduction defects. Echo reveals dilated cardiac chambers,
reduced ejection fraction (<45%), reduced shortening fraction, and diffuse dyskinesia
of the ventricular walls. Dilated cardiomyopathy is frequently observed in patients
preserving an autonomous ambulation for prolonged periods. Dilated
cardiomyopathy in turn evolves toward the stage of heart failure. The first episodes of
HF are usually responsive to pharmacological treatment; subsequently, HF evolves
to the stage of intractable HF not amenable to adequate drug treatment. Therefore
heart failure remains an important contributor to mortality in these patients for which
heart transplantation remains the ultimate intervention to preserve life. There is no
specific treatment for DCM. Corticosteroids and angiotensin receptor blockers have
been used to treat skeletal muscle disease and may delay the progression the
associated cardiomyopathy [58]. Treatment of cardiovascular disease typically
involves the treatment of the cardiomyopathy, including standard pharmacotherapy
that includes angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II
receptor blockers (ARBs), beta blockers and diuretics for congestion. The addition of
aldosterone antagonists may provide benefit if used early.

EMERY-DREIFUSS MUSCULAR DYSTROPHY
Emery-Dreifuss muscular dystrophy (EDMD) is a group of hereditary muscular

dystrophy syndrome caused by deficiency of genes encoding nuclear envelope
proteins. In contrast to the Duchenne and Becker varieties of muscular dystrophy,
locomotor abnormalities are mild and progress slowly. Patients having EDMD show
the triad of muscle dystrophy, joint contracture, and cardiac disease. In almost all
patients, cardiac involvement is prevalent and is the most severe aspect of EDMD
[59]. Among the affected families, different inheritance patterns have been observed.
Are described 7 variants of EDMD, the most common forms are EDMD1 and
EDMD2. Emery Dreifuss muscular dystrophy 1 (EDMD1) is an uncommon X linked
recessive muscular dystrophy which encodes the nuclear membrane protein emerin.
Similarly, another inheritance type of EDMD is autosomal dominant (AD-EDMD). For
autosomal dominant EDMD (EDMD2), mutation in LMNA is the most common cause.
LMNA encodes lamins A and C, both of which are components of nuclear envelope
and located in the lamina. Mutations in lamins have been identified in up to 6% of
patients with dilated cardiomyopathy and 33% of those patients presenting with
cardiac conduction defects [60, 61]. Data suggest that the combined prevalence of
the X-linked and autosomal dominant forms of Emery–Dreifuss muscular dystrophy
is 0.1–0.4 cases per 100.000 [62].
Cardiac Involvement in EDMD
Cardiac involvement is estimated to occur in more than 90% of patients with this
condition, manifesting as a variety of conduction defects and variable dilated
cardiomyopathy [63]. In both form of EDMD, conduction disturbances are the
predominant cardiac involvement. The initial cardiac finding is often accidental
identification of a prolonged PR interval and reduced amplitude of P wave in the
ECG. Furthermore, various degrees of heart block may occur. In EDMD, electrical
silence of atrium is typically observed, which is noticed by the P wave’s absence and
the junctional or ventricular escape rhythm in the surface ECG. Longitudinal studies
related to EDMD suggested that atrial fibrillation and flutter, which can occur at
various stages of EDMD, are the most frequent cardiac incidents [63]. In the
presence of either atrial standstill or atrial fibrillation/flutter, there is risk of cerebral
thromboembolism because of emboli of cardiac origin. Note that a stroke can be the
first clinical manifestation of EDMD in young adults and can be disabling. Therefore,
for antithromboembolic prophylaxis, administration of anticoagulants is probably
required in EDMD patients affected by atrial fibrillation/flutter or standstill [63]. In
EDMD 1, less commonly, dilated cardiomyopathy and ventricular arrhythmias have
been described. Conversely, in patients with lamin A and C mutations, early onset of
dilated cardiomyopathy is a more prominent feature, and conduction disease with
ventricular arrhythmias are commonly described. Patients carrying mutation in LMNA

gene (EDMD 2) had an unexpected high risk of premature sudden death. This risk
was not related to heart failure and seems to have been caused by lathy ventricular
tachyarrhythmia because it cannot be prevented by pacemaker therapy. It is unclear
which clinical factors predicted the increased risk of sudden death. In a European
cohort study, nonsustained ventricular tachycardia, left ventricular ejection fraction of
< 45%, male sex, and non-missense mutations were identified to be risk factors for
malignant ventricular arrhythmias [64, 65]. To decrease the risk of potentially life-
threatening bradycardia, when symptomatic bradycardia or conduction disease is
identified, it is essential to implant a cardiac pacemaker. However, a pacemaker
does not eliminate the risk of sudden death, particularly in those carrying LMNA
mutation. Considering the high risk of malignant ventricular arrhythmia, ICD may be
considered when AD-EDMD patients require pacemakers [59].
FACIO-SCAPULO-HUMERAL-DYSTROPHY
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent

inherited neuromuscular disorders, having significant intra- and interfamilial variability
in disease presentation, progression and age of onset, with most individuals
becoming symptomatic in their second decade. Patients with childhood onset have a
more severe clinical presentation. Juvenile or adult onset male patients are more
severely affected than females. Subjects with FSHD generally do not suffer from
significant cardiac symptoms. Studies reported to date indicate that heart alterations
unrelated to cardiomyopathy are possible in FSHD, especially in patients older than
45 years. However in the last years some articles appeared showing that a few
percentage of FSHD patients may present atrial involvement with episodes of atrial
fibrillation/flutter [66, 67]. The protocol adopted in these patients includes a
cardiological examination, an ECG and an echocardiogram to be performed once at
year; more frequently checks, every six month or more, are recommended in the
case of arrhythmias [68].
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Chapter 27
THERAPY OF SCOLIOSIS
IN NEUROMUSCULAR PATHOLOGY
Valerio Pipola, Konstantinos Martikos,

Emanuela Asunins and Alessandro Gasbarrini*
Department of Spine Surgery,
IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
ABSTRACT
Neuromuscular scoliosis are coronal plane deformities of the spine that

develop in patients with abnormalities of the myoneural pathways. The disorders
which cause this type of deformity comprise a group of diseases characterized by
a breakdown in the normal neural integrated pathway that includes brain, spinal
cord, peripheral nerves, neuromuscular junction and muscles [1]. Patients
affected by these diseases usually have poor head control, lack of neck and
trunk balance and discoordination. Despite the wide spectrum of conditions that
can lead to the development of Neuromuscular Scoliosis, the final functional path
to be altered is the muscle unit, which manifest its disfunction through decreased
motion (flaccidity), increased motion (spasticity) or out of sequence motion
(dyskinetic). Scoliosis associated with neuromuscular disorders can be classified,
according to Scoliosis Research Society [2], in two large groups: Neuropathic
and Myopathic. Neuropathic diseases can be classified according to the level of
the lesion in upper motor neuron and lower motor neuron disease.
*
Corresponding Author’s E-mail: alessandro.gasbarrini@ior.it.

378 Valerio Pipola, Konstantinos Martikos, Emanuela Asunins et al.
NEUROMUSCULAR SCOLIOSIS CLASSIFICATION
Primary Neuropathies
 Upper motor neuron

 Cerebral palsy
 Spinocerebellar degeneration
 Friedreich ataxia
 Roussy - Levy disease
 Spinocerebellar ataxia
 Syringomyelia
 Spinal cord tumor
 Spinal cord trauma
Lower Motor Neuron
 Polyomyelitis
 Other viral myelitis
 Traumatic
 Charcot-Marie-Tooth disease
 Spinal muscular atrophy
 Werdnig-Hoffman disease (SMA type 1)
 Kulberg-Welander disease (SMA type 2)
 Dysautonomia
 Riley-Day syndrome
 Combined upper and lower pathologies
 Amyotrophic lateral sclerosis
 Myelomeningocele
 Tethered cord
Primary Myopathies
 Muscular dystrophy
 Duchenne muscular dystrophy
 Limb-girdle dystrophy
 Facioscapulohumeral dystrophy
 Arthrogryposis
 Congenital hypotonia
 Myotonic dystrophy

Therapy of Scoliosis in Neuromuscular Pathology 379
The incidence of scoliosis varies according to the underlying neuromuscular

disease:
 Cerebral palsy (2 limbs involved): 25%;

 Myelodysplasia (lower lumbar): 60%;
 Spinal muscle atrophy: 67%;
 Friedreich ataxia: 80%;
 Duchenne muscular dystrophy: 90%;
 Myelodysplasia (thoracic level): 100%;
 Traumatic paralysis (< 10 years): 100%.
Although the long-term use of glucocorticoid has been shown to be effective in

reducing the need of surgery to treat scoliosis [3].
ETIOPATHOGENESIS
Neuromuscular Scoliosis present as long C-shaped curves collapsing into

scoliosis, kyphosis or hyperlordosis often including the sacrum as part of the curve.
Kyphosis is due to the compromise in the muscular function that represents the
dynamic support for vertebral column stability. The lack in spine stability support is
associated with a postural curve that compromise head and neck positioning which
worsens in the growing spine. In fact, according to the Heuter Volkmann law, small
curves can produce asymmetric force on vertebral body end plates leading to the
establishment of vicious circle that determines the progressive worsening of
deformity. The end plates on the concave side of the curve, whether it be in the
sagittal or coronal plane, are subject to increased compression causing decreased
growth. On the convex side, instead, an increased growth can be observed due to a
decreased loading. Given these factors, the earlier a curve’s onset, the greater is the
potential for increased severity and progression of deformity over time. Osteopenia
and weakness in the bone structure induced by disuse and anti-seizure medication
can lead to osteomalacia that worsens bone quality and promotes the development
of deformity. The interaction between biomechanical and biological factors is at the
basis of scoliosis onset in neuromuscular disease [4].
PHYSICAL EXAMINATION
Clinical assessment includes, first of all, the evaluation of the presence of hyper-
or hypotonia and joint stiffness [5]. Asymmetric hip stiffness may represent the prime
symptom with a classic rightward or leftward drift aspect that causes an imbalance in
sitting position and an asymmetric pressure on the ischia with scabbed areas of
hyper-pressure. The imbalance in sitting position can be compensated with the trunk

imbalance by the upper limbs. When the upper limbs compensation becomes
impossible, the help from another person to maintain upright trunk is required.
Inspection may reveal rib prominence (rib hump), shoulder asymmetry, trunk
imbalance and “wind-swept” hip deformity that describes and abduction and external
rotation of one hip with the opposite hip in adduction and internal rotation. It may
occur in association with hip dislocation.
The presence of abnormal reflexes, including abnormal reflexes such as the
Beevor and the Babinski sign, and hyperreflexia suggest upper motor lesions.
Instead, hyporeflexia supports lower motor injuries.
Manual elongation in seated posture is useful to assess clinical reducibility of
trunk collapse.
Neuromuscular scoliosis are characterized by the development of Pelvic
Obliquity. It can result from an asymmetric retraction of muscles connecting trunk
and pelvis, also called Pelvic Obliquity of “upper origin.” Instead, when hip posture
asymmetry usually predominating in one hip causes retraction in adduction, flexion
and internal rotation, the resulting Pelvic Obliquity is defined to be of “lower origin.”
This retraction indices pelvic malpositioning in sitting and lying posture that
accentuates scoliosis [1]. In some case, Pelvic Obliquity is induced by both
mechanisms.
Pelvic Obliquity reducibility should be assessed with positioned in ventral
decubitus and lying at the end of the table with lower limbs in flexion. The ability to
level the pelvis by asymmetric traction on the elevated and contracted hip implies a
Pelvic Obliquity of “lower origin,” instead, the obliquity persistence despite the
asymmetrical traction is indicative of a Pelvic Obliquity of “upper origin.”
Of a paramount importance is the evaluation of patient walking ability which
should not be limited to the distinction between “walking” or “not walking” but must
assess the overall evaluation of patient’s autonomy in the activity of daily living. This
element is important to establish the timing of surgery since arthrodesis can lead to a
further reduction in independence, surgery can be postponed in case of worsening of
neuromuscular disease or complete loss of autonomy.
MEDICAL CONSIDERATIONS
Respiratory complications occur due to weakness in intrinsic and accessory

muscles of respiration. Thoracic deformities decrease the volume of the thorax
causing a decreasing in forced vital capacity and a restrictive lung disease. Deformity
affects the bellows mechanism formed by the rib cage, thoracic spine and diaphragm
configuring the Thoracic Insufficiency Syndrome (TIS) that leads to alveolar
hyperventilation, carbon dioxide retention, pulmonary hypertension and right-sided
heart failure. Diminished pulmonary function is associated to an increased risk of
pneumonia. Patients with neuromuscular disease show an increased prevalence of
sleep disorders breathing.

Cardiomyopathy is a well-known comorbidity in patients with neuromuscular

disease, especially in those with myopathies. Gastrointestinal reflux, chronic
constipation, bladder dysfunction and endocrine aberrancies are also common.
Gastroesophageal reflex exposes to the risk for aspiration in the perioperative period.
Chronic constipation, prevalent in wheelchair-bound patients, can predispose to
postoperative paralytic ileus and can accentuate the pulmonary compromise.
Nutritional impairments and feeding difficulties may exist and can require nonoral
means of nutrition. Severe spasticity increases caloric consumption which may be
not adequately met by oral nutrition. Poor nutrition predisposes to skin breakdown
and poor healing.
RADIOGRAPHIC ASSESSMENT
Standing Posteroanterior and lateral radiographs of the thoracolumbar spine

provide the best information of spinal imbalance in ambulatory patients. Radiographs
with patient in a wheelchair can be obtained in non-ambulatory patients. Bending
views in supine position are needed to evaluate deformity stiffening. AP radiographs
under asymmetric traction applied to a single lower limb are useful to assess Pelvic
Obliquity reducibility whose correction is demonstrated by the alignment of the line
through the foot of the two sacroiliac interlines with respect to the shoulder line [6]
(Figure 1). MRI is essential in case of suspicion of medullary pathology, to detect a
syringomyelic cavity that may induce a pre- or postoperative neurologic impairment,
above all when medullary function is still present. Pre-operative CT scan may help
evaluate the anatomy of the pelvis which is often hypoplastic in neuromuscular
patients. There is also evidence in the literature that greater pelvic obliquity is
associated to more accentuated transverse-plane asymmetry of the pelvis, which
represents an important notion for adequate surgical planning [7].
CONSERVATIVE TREATMENT
Bracing should be considered as a bridging treatment with the goal to allow the
growth while achieving the greatest possible deformity correction and preserving
respiratory function. The brace should be designed in order to correct the spinal
collapse caused by the muscle weakness and to correct the deformity to the extent
possible without putting an excessive pressure on the fragile ribcage.

Figure 1. Radiographic assessment of Pelvic Obliquity that is evaluated as the angle

subtended by a line drawn between the most proximal points of the iliac crests and the
horizontal line.
SURGICAL TREATMENT
Surgical treatment of neuromuscular scoliosis may be considered when the

primary curve shows a progressive trend, exceeding 50 Cobb. In skeletally
immature patients, if deformity does not show an extremely severe and rapid
progression, it is preferable to delay surgery until late adolescent or early adult age in
order to allow for adequate cardiopulmonary function. Given the need for extensive
surgery, that implies fusion of the thoracolumbar spine that must be frequently
extended to the pelvis, the risk of cardiopulmonary complications is significantly
higher in early pediatric age than in late skeletal maturity stage.
The objective of surgical treatment in neuromuscular spinal deformities is to
obtain a balanced spine in the frontal and sagittal plane in order to allow for better life
quality in terms of pain, daily health care and pulmonary impairment. If not treated
surgically, severe neuromuscular deformities, inevitably progress towards severe
pulmonary restriction syndrome, that thanks to surgery may be prevented or even
improved. On the other hand, surgery for severe neuromuscular scoliosis should be
performed ideally in experienced spinal surgery centers because surgical and
anesthesiologic experience in treating such rare pathologies may significantly reduce
intra- and perioperative risks [8]. Prior to surgery patients should be thoroughly
studied both from the skeletal and general health point of view and a multi-specialist
evaluation is mandatory in order to adapt patients to the upcoming treatment.
Patients families should also be informed of the severity of the pathology and the

need for surgery, highlighting increased risks of complications both intraoperative

and post-operative such as need for prolonged post-operatory intubation and
assisted ventilation, prolonged hospitalization, need for transfer to secondary health
care centers, wound infection, need for revision surgeries and even higher mortality
rate compared to idiopathic deformities that are not associated to other underlying
pathologies. These risks are proportional to the severity of the deformity and to the
compromise of patient’s general health conditions.
Therefore, an adequate preoperative evaluation is mandatory. Given the possible
pulmonary complications, authors have conducted studies on strategies for
improving respiratory function. Khirani et al. [9] placed 13 neuromuscular patients
with planned spinal surgery in a respiratory training program based on non-invasive
positive pressure ventilation and mechanical insufflation-exsufflation for 30 minutes
per day for at least 1 to 4 weeks before surgery. No post-operative pulmonary
complications were observed, demonstrating the need for respiratory optimization
prior to surgery. Identifying risk factors for infections is also important. Patients with
cerebral palsy were 6.4 times as likely to have post-operatory infection if they had a
history of gastroesophageal reflux [10].
Regarding surgical procedure, nowadays, neuromuscular deformities are usually
treated with a single stage posterior instrumented fusion. The advent of solid
multilevel spinal constructs provides adequate purchase to the spinal column
allowing for satisfactory deformity correction and balanced spine. Modern spinal
instrumentations and perfection or spinal osteotomies (mainly posterior column
osteotomies in these patients) have drastically reduced the need for anterior or
combined surgical approach, therefore reducing significantly surgical stress and
complication rate.
One of the most frequent dilemmas in patients with neuromuscular scoliosis is
whether to extend fusion to the pelvis. Pelvic fixation is highly recommended in cases
of severe pelvic obliquity exceeding 15. The risk of not extending instrumentation to
the pelvis is progression of the residual lumbar-sacral deformity, worsening of the
pelvic obliquity, development of abnormal hyperlordosis of the lumbar-sacral junction
(L4-S1), leading to the need for revision surgery that can be much more complex
than initial surgery in terms of instrumentation, correction, blood loss. This is the
main reason why pelvic fixation should be considered the landmark in the surgical
planning of neuromuscular deformities. Nevertheless, in the presence of certain
conditions, fusion could be limited to distal lumbar levels, mainly L4, with the main
objective of allowing movement at the lumbar sacral junction that could be valuable
patients that present active movements. Factors that could help avoid pelvic fixation
are less severe pelvic obliquity (inferior to 15) associated to a relatively proximal
apex of the main scoliotic curve (possibly proximal to L1) patients able to stand or
ambulate.
Technically, pelvic fixation can be obtained with a variety of methods. In the past,
the most efficient pelvic fixation method in neuromuscular deformities were the Unit
Rods. More recently, iliac screws have been introduced, with placement at the ileum
either with a starting point directly at the iliac crest either with a more medial starting

point at the posterior inferior iliac spine. The most recent technique is represented by
the S2-sacral-alar (S2SA) screws that have multiple advantages such as the
possibility for placement of large diameter iliac bolts, no need for connectors as
screw heads are aligned with the rest of the instrumentation, superior stability as the
screw passes through the sacral-iliac joint therefore penetrating multiple cortical
bone layers, less risk of prominence and decubitus as screw heads are situated
beneath the muscle layers and less need for muscle dissection when compared to
iliac crest screws [11] (Figure 2).
The main objective of the surgical procedure is to provide e balanced spine in the
frontal and sagittal plane, therefore there is not an absolute need for high density
constructs. A high density of anchor points should be present mainly at the apex of
the main curve but is not mandatory at the proximal thoracic levels. Thoracic
kyphosis should be abundantly included in the fused area reaching the apical
thoracic levels (generally T2 or T3) but it should not be corrected excessively in order
to avoid proximal junctional kyphosis.
Post-operative infection represents one of the main concerns in surgery for
neuromuscular scoliosis. Best practice indicates abundant wound irrigation during
surgical procedure and use of peri-operatory intravenous cefazoline and
perioperative intravenous prophylaxis for Gram-negative bacilli [12]. Infection risk has
been associated to more neurologically impaired patients.
The use of growth friendly techniques in early onset neuromuscular deformities
has been described by various authors [13-15]. Both growing rods (either with distal
purchase at the lumbar spine or to the pelvis) and VEPTR-like devices have been
described. The results with growth friendly devices have been described as
satisfactory in terms of correction and lung function, nevertheless with relatively high
infection rates that may exceed 40%. The advent of magnetically controlled growing
rods that reduce the need for lengthening surgery, may reduce the incidence of
infection [16].
a b
Figure 2. Pelvic fixation. Traditional (black arrow) and S2-sacral-alar (white arrow) iliac screw
fixation (a). Iliac screw fixation with a starting point at posterior inferior iliac spine (b).

a b
Figure 3. Female, 19 years old. Cerebral Palsy. Sitting pre- and post-operative antero-
posterior XRay.
Intraoperative neuromonitoring with somatosensory and motor evoked potentials

is contradictory in patients with neuromuscular deformities. Hammet et al. [17, 18]
evaluated a 7-year history of intraoperative neuromonitoring in 66 neuromuscular
patients, finding reliable baseline somatosensory evoked potentials readings in 88%
of patients, only 2 patients developed post-operatory neurological deficits, both of
whom had no intraoperative neuromonitoring events.
CONCLUSION
Neuromuscular Scoliosis represent a broad, heterogeneous nosological category

in which the specificity of each case is essentially defined by the repercussion of the
underlying neurologic or muscular pathology require a multidisciplinary management
given the complexity multi-organ involvement. Conservative management should be
considered a bridging treatment until surgical correction whose time must be chosen
in relation to the evolution of the curve, skeletal maturity and patient independence in
the activity of daily living.

a b
Figure 4. Male, 20 years old. Duchenne Muscular Dystrophy. Sitting pre- and post-operative
antero-posterior XRay.
REFERENCES
[1] Vialle R, Thèvenin-Lemoine C, Mary P. Neuromuscular scoliosis. Orthop.

Traumatol. Surg. Res. 2013 Feb;99(1 Suppl.):S124-39.
[2] Newton PO. Neuromuscular scoliosis. Available at etext.srs.org/book/.
Accessed April 8, 2012.
[3] Connolly A, Han Jo K, Bridwell K. Corticosteroids can reduce the severity of
scoliosis in Duchenne Muscular Dystrophy. J. Bone Joint Surg. Am. 2013 Jun.
19;95(12):e86.
[4] Vialle R, Delecourt C, Morin C. Surgical treatment of scoliosis with pelvic
obliquity in cerebral palsy: the influence of intraoperative traction. Spine
2006;31:1461-6.
[5] Cottalorda J. Neuropédiatrie à l’usage de l’Orthopédiste. Conférences
d’Enseignement de la SOFCOT [Neuropediatrics for use by the orthopedic
surgeon. SOFCOT Teaching Conferences]. Paris: Elsevier ed; 2010, p-231-50.
[6] Zahi R, Vialle R, Abelin K et al. Spinopelvic fixation with iliosacral screws in
neuromuscular spinal deformities: results in a prospective cohort of 62 patients.
Childs Nerv. Syst. 2010;26:81-6.

[7] Ko PS, Jamesson PG II, Chang TL, et al. Transverse-plane pelvic asymmetry in
patients with cerebral palsy and scoliosis. J. Pediatr. Orthop. 2011;31:277-283.
[8] Sponseller PD, Jain A, Shah SA, et al. Deep wound infections after spinal
fusion in children with cerebral palsy: a prospective cohort study. Spine (Phila.
PA 1976). 2013;38:2023-2027.
[9] Khirani S, Bersanini C, Aubertin G, et al. Non-invasive positive pressure
ventilation to facilitate the post-operative respiratory outcome of spinal surgery
in neuromuscular children. Eur. Spine J. 2014;23(suppl. 4):S406-S411.
[10] Vitale MG, Riedel MD, Glotzbecker MP, et al. Building consensus: development
of a Best Practice Guideline (BPG) for surgical site infection (SSI) prevention in
high-risk pediatric spine surgery. J. Pediatr. Orthop. 2013;33:471-478.
[11] Lee MC, Jarvis C, Solomito MJ, Thomson JD. Comparison of S2-Alar and
traditional iliac screw pelvic fixation for pediatric neuromuscular deformity.
Spine J. 2018 Apr;18(4):648-654.
[12] Mackenzie WGS, Matsumoto H, Williams BA, et al. Surgical site infection
following spinal instrumentation for scoliosis: a multicenter analysis of rates, risk
factors, and pathogens. J. Bone Joint Surg. Am. 2013;95:800-806.
[13] White KK, Song KM, Frost N, et al. VEPTR growing rods for early-onset
neuromuscular scoliosis: feasible and effective. Clin. Orthop. Relat. Res.
2011;469:1335-1341.
[14] Chandran S, McCarthy J, Noonan K, et al. Early treatment of scoliosis with
growing rods in children with severe spinal muscular atrophy: a preliminary
report. J. Pediatr. Orthop. 2011;31:450-454.
[15] McElroy MJ, Sponseller PD, Dattilo JR, et al. Growing rods for the treatment of
scoliosis in children with cerebral palsy: a critical assessment. Spine (Phila. PA
1976). 2012;37:e1504-e1510.
[16] Yoon WW, Sedra F, Shah S, et al. Improvement of pulmonary function in
children with early-onset scoliosis using magnetic growth rods. Spine (Phila. PA
1976). 2014;39:1196-1202.
[17] Hammett TC, Boreham B, Quraishi NA, et al. Intraoperative spinal cord
monitoring during the surgical correction of scoliosis due to cerebral palsy and
other neuromuscular disorders. Eur. Spine J. 2013; 22(suppl. 1):S38-S41.
[18] Hammett T, Harris A, Boreham B, et al. Surgical correction of scoliosis in Rett
syndrome: cord monitoring and complications. Eur. Spine J. 2014;23(suppl.
1):S72-S75.

SECTION 7. DIAGNOSIS APPROACH
IN NEUROMUSCULAR DISORDERS

Chapter 28
IMAGING TECHNIQUES IN NMD
Tullio Valente, MD and Roberta Lieto†, MD

Radiology, Azienda Ospedali dei Colli, Monaldi Hospital, Naples, Italy
ABSTRACT
Dysphagia is often underestimated in neuromuscular disorders (NMD). It can

be prominent in dystrophies, inflammatory myopathy, mitochondrial myopathy,
myasthenia, motor neuron diseases, and peripheral neuropathy. Certain NM
conditions leading to dysphagia such as amyotrophic lateral sclerosis can be
fatal, and bulbar presentation may be the predominant feature, requiring a
diligent workup and intervention to prevent unwanted complications such as
aspiration pneumonia. A prompt assessment of the swallowing function is crucial
to organize proper interventions and prevent complications in NMD patients. The
video-fluoroscopic swallowing study (VFSS) is considered the gold standard not
only for a diagnostic purpose, but also for planning the rehabilitation therapy and
type of nutrition, and for the results of the therapy evaluation. The spectrum of
aspiration-induced lung diseases (AILD) imaging patterns must be known by both
the radiologist and the clinician and managed in a multidisciplinary team.
INTRODUCTION
Key facts:
 Dysphagia and aspiration syndromes are strongly related

 Dysphagia and aspiration may be silent, particularly in NMD patients
 A swallowing objective test is mandatory in NMD patients.

Corresponding Author’s E-mail: tullio.valente@gmail.com.
†
Corresponding Author’s E-mail: roblieto@gmail.com.

392 Tullio Valente and Roberta Lieto
Dysphagia is an increasing problem with age (presbyphagia), one of the most

critical problems in patients with long-term, progressive congenital or acquired NMD
(Table 1), and can occur relatively early in the course of the disease. Reports of the
prevalence of dysphagia range from 25% to 80% in Myotonic Dystrophy type 1
(DM1) patients, and it is higher than 80% in advanced Amyotrophic Lateral Sclerosis
(ALS) patients regardless of the onset modality (Andrenelli E. et al., 2018).
Dysphagia leads to severe consequences, such as malnutrition, dehydration,
aspiration pneumonia or airway obstruction. Aspiration is defined as, “the inhalation
of oropharyngeal or gastric contents into the laryngeal or lower respiratory tract”
(Marik P. E., 2001). A prompt assessment of the swallowing function is crucial to
organize proper interventions and prevent complications in NMD patients.
Dysphagic patients are three times, and those with confirmed aspiration eleven
times, more likely to develop aspiration pneumonia (Marik P. E., 2001).
Macroaspiration can cause a wide spectrum of airways/lung diseases with various
clinical presentations, and can be overt or silent and its content can be variable (for
example oropharyngeal or gastric).
Dysphagia is of great interest to radiologists because the dynamic radiological
examination of swallowing, the video-fluoroscopic swallowing study (VFSS), is
considered the gold standard not only for a diagnostic purpose (helps to identify the
causes of aspiration, often treatable), but also for planning the rehabilitation therapy
and type of nutrition, and for the results of the therapy evaluation (Eisenhuber E. et
al., 2002; Matsuo K. et al., 2008, Jaffer N. M. et al., 2015).
Table 1. Main selected causes of dysphagia

in some congenital or acquired NMD
Neurologic disorder Structural Lesions Psychiatric Connective Iatrogenic

and stroke congenital or acquired Disorder tissue Causes
diseases
Cerebral infarction Thyromegaly Psychogenic Polymyositis Surgical
dysphagia resection
Brain-stem infarction Cervical hypertosis Muscular Radiation
Dystrophy fibrosis
Intracranial Congenital web Medications
hemorrhage
Parkinson’s disease Zenker’s diverticulum
Multiple sclerosis Ingestion of caustic
material
Motor neuron disease Neoplasm
Poliomyelitis Cleft lip and palate
Myasthenia gravis Cervical osteophytes
Dementias

Imaging Techniques in NMD 393
Since 1988 the fiberoptic endoscopic evaluation of swallowing (FEES) has

appeared alongside VFSS and has become increasingly employed (Bastian R. W.,
1993). Due to availability, expertise needed, patient compliance and the evolution of
the swallowing disorder, sometimes rapidly progressive, it is not possible to perform
instrumental examination on every patient with suspected dysphagia, so it is not
considered part of a standard protocol for neuromuscular patients in many clinical
services (Knuijt S. et al., 2014). A better understanding of the swallowing problems
associated with these disorders may help in guiding treatment, choosing technical
aids, modifying the consistency of foods, swallowing rehabilitation, and nutritional
support by the nonoral route. It is important to evaluate the respiratory function in
NMDs leading to dysphagia, because many of these disorders disrupting deglutition
may interfere with either diaphragmatic or intercostal muscle function.
Anatomic/Physiological Background and VFSS Technique
Eating, swallowing and breathing are tightly functionally coordinated systems.

Swallowing is a complex physiologic act consisting of simultaneous and sequential
contractions of oro-facial, pharyngeal, laryngeal, and esophageal muscles to propel
ingested materials through the upper aero-digestive tract with simultaneous
protection of the airways. It involves approximately 50 paired muscles and virtually all
levels of the central nervous system (cerebral cortex, brainstem swallowing center,
motoneurons, and sensory receptors in the oropharynx, larynx and esophagus by
cranial nerves V, VII, IX, X, XII).
Schematically, in normal swallowing it is possible to distinguish:
 an oral preparatory phase: the bolus is manipulated by lingual motion, mixed

with saliva and masticated, sized, shaped, and if necessary, and also tasted
or savored. All the actions of this phase are conscious and voluntary, the
swallow reflex is absent and the airway remains open for the usual purpose
of respiration.
 an oral propulsive phase: the tongue starts to squeeze the bolus between the
soft palate and itself. A groove or channel becomes evident in the tongue and
its pressure conveys the food bolus posteriorly into the back of the mouth. As
the bolus passes the posterior faucial pillars, the involuntary swallow reflex
occurs (Page et al., 2006);
 a pharyngeal phase: five main physiologic events can be distinguished:
o naso-pharyngeal seal;
o elevation and anterior displacement of the larynx and hyoid bone;
o laryngeal closure;
o bolus compression and propulsion;
o cricopharyngeal opening.

 an esophageal phase: a normal primary peristalsis as an aboral contraction

wave that progressively obliterates the esophageal lumen is appreciable
(Figure 1).
Figure 1. LL and AP views of a normal VFSS examination in a 58 year-old ALS woman.
Pathophysiological Mechanisms of Dysphagia in NMD Patients
Two main pathophysiological mechanisms operate in the NMD patients

dysphagia:
1. the triggering of the swallowing reflex for the voluntarily initiated swallows is
delayed, disordered and eventually absent;
2. the cricopharyngeal sphincter muscle of the pharyngo-esophageal segment
became hyper-reflexic and hypertonic.
Delayed bolus transit, palatal weakness predisposing to nasal regurgitation,

decreased laryngeal elevation, and bolus residue after swallowing are other
mechanisms that determine swallow impairment and aspiration. For example,
dysphagia in ALS (present in more than 50% of patients) is mainly caused by
degeneration of the motor nuclei of the glossopharyngeal, vagus and hypoglossal
cranial nerves of the brain stem and the progressive degeneration of the excitatory

and inhibitory corticobulbar pyramidal fibres (Ertekin C. et al., 2001). The weakness
and the impaired coordination of facial, oral and pharyngeal muscles compromise all
the phases of swallowing (Fattori et al., 2006). As a result, regardless of the
predominance of bulbar or spinal symptoms, the laryngeal protective system and the
bolus transport system of deglutition lost their co-ordination during voluntarily initiated
oropharyngeal swallowing (Ertekin C. et al., 2001).
Pathological VFSS Findings in NMD Patients
Lateral (LL) and Anteroposterior (AP) Direct Neck Radiograph

Ideally all patients should be examined in both lateral and frontal (AP) positions.
In the real life the examination starts and ends only in latero-lateral (LL) projection
with the bedside or wheelchair NMD patient, and should always begin with the
assessment without contrast medium.
Laryngeal thyroid, cricoid and most of the arytenoid are hyaline cartilages that
undergo enchondral ossification over aging both in males and in females and may
cause VFSS misdiagnosis (Figure 2).
Figure 2. Diagram of laryngeal structures and calcified physiological structures projecting over
upper aerodigestive tract causing confusion and misdiagnosis in VFSS evaluation. A) Lateral
diagram of larynx. Dashed line. Projection of the cricoid (C) arch. E. epiglottis. V. Vallecula. T.
Thyroid cartilage. Arrowheads (false vocal cords) and large arrowhead (true vocal cords) point
on slit-like ventricle. B) Illustration of laryngeal cartilages that can calcify. 1. Thyroid cartilage.
2. Calcification of superior cornua of thyroid cartilage. 3. Inferior cornua of thyroid cartilage. 4.
Cricoid cartilage. 5. Arytenoid cartilage. 6. Calcification of triticeous cartilage. C) LL close-view
without oral contrast medium. T. Trachea. H. Hyoid bone projects over the region of vallecula.
* Calcification of posterior aspect of thyroid cartilage. White arrow. Calcification of anterior
margin of thyroid cartilage. X. Calcification of posterior aspect of cricoid cartilage lamina. Y.
Calcification of narrow anterior cricoid arch. o. Oropharynx. S. Soft palate. Black line.
Retropharyngeal space. Black curved form. Pre-vertebral space ossification/calcification (e.g.,
C5-C6 osteophytes). White curved arrow. Calcification of superior margin of cricoid cartilage.
Frequency of thyroid ossification is more than cricoid in both sexes.

Figure 3. Multiple VFSS signs of decompensation in a patient with advanced ALS. A) Bolus of
liquid consistency. 1. Posterior premature leakage from the mouth. 2. 2bis. Overflow of
retained bolus into the vallecula and piriform sinuses. 3. Large immediate tracheal aspiration.
4. Large osteophytes extending down the anterior cervical spine from C2. B) Bolus of solid
(cookie fragments) consistency. 1. Overflow of retained bolus into the vallecula. 2. Aspiration
of a big cookie fragment in gastrografin paste.
VFSS on LL Projection in NMD Patients

Latero-lateral projection best allows documentation of the contrast medium
passage in the laryngeal vestibule (penetration) and/or in the trachea (aspiration).
Small and then gradually increasing amounts of contrast medium of different texture
are administered. This allows the radiologist to identify the food textures responsible
for aspiration (Figure 3). In more severe neurological deficits the contrast agent
(barium, gastrografin) can be administered through a syringe connected to a tube
placed in the oral cavity.
ASPIRATION-INDUCED LUNG DISEASES (AILD) IN NMD
Key facts:
 96% of ALS patients die from respiratory failure, and 90% of deaths occur in
conjunction of pneumonia
 Aspiration complicates many genetic or metabolic disorders associated with
significant neurologic compromise particularly in children (e.g., familial
dysautonomia or Riley-Day syndrome).
Aspiration represents a broad spectrum of diseases, with patterns of

tracheobronchial tree and lung injury that overlap, both pathologically and
radiographically, finally leading to respiratory distress (Maroum E. M. et al., 1999;
Prather A. D. et al., 2014; Hu X. et al., 2015; Scheeren B. et al., 2016).

Table 2. Spectrum of Aspiration-induced lung diseases (AILD)

and patterns in NMD patients
Acute-Subacute Subacute-Chronic
Tracheobronchial foreign body* Diffuse aspiration bronchiolitis (DAB)*
Aspiration pneumonia (infectious origin) Bronchiectasis
Aspiration pneumonitis (chemical origin) Organizing pneumonia (OP)
Mendelson’s syndrome Chronic interstitial lung disease (chronic-ILD)
Near drowning Chronic exogenous lipoid pneumonia
Abscess formation
ARDS
These patterns are determined by the aspirated content and volume, the
chronicity, as well as by host defenses (Table 2). In NMD patients usually inability to
ventilate (diaphragm weakness and chest wall stiffness), reduced airflow velocity
restricts secretion clearance and decreased coughing limit airway clearance. On the
past few years the importance of cough augmentation and airway clearance has
been increasingly recognized. Moreover, daytime and nighttime sialorrhea (bulbar
symptom in >20% of ALS patients) with poor lip seal and posterior spillage into
pharynx causes aspiration of saliva. Evaluation for AILD usually entails visualization
of the airways with laryngoscopy or bronchoscopy and pulmonary function testing.
Aspiration-induced parenchymal diseases, such as aspiration pneumonitis, aspiration
pneumonia, and exogenous lipoid pneumonia, are generally diagnosed by clinical
and radiologic findings.
Aspiration Pneumonia (with or without Abscess Formation)

(AILD-Parenchymal Lung Manifestation)
Because of its low pH, gastric contents are sterile under normal conditions. Thus,
aspiration is required but not sufficient for the formation of aspiration pneumonia that
refers to an infectious process secondary to aspiration of colonized oropharyngeal
secretions (The Japanese Respiratory Society, 2004; Shigemitsu H. et al., 2007). It
usually results in localized segmental or lobar airspace consolidations in dependent
portions of lung, with or without an associated parapneumonic effusion. In supine
patients, the material is most commonly aspirated into the right middle lobe, into the
posterior segments of the upper lobes or into the superior and posterior basal
segments of the lower lobes. This primarily happens because of the larger caliber
and more vertical course of the right main bronchus compared with the left (Marom
E. M. et al., 1999; Franquet T. et al., 2000). These secretions or food debris-filled
airways cause airspace opacities that can become more confluent and appear as
consolidation, with patent airways within these regions appearing as air
bronchograms (Figure 4).

Figure 4. Imaging findings in aspiration pneumonia. A) Admission CXR in a 15 year-old man

with Duchenne muscular dystrophy (DMD) in acute respiratory failure with endotracheal tube
shows an ill-defined opacity over middle lobe. B) On the third day, fever appears and the CXR
shows bilateral middle and lower lobes opacities. C) Bedside US shows right lower lobe
consolidation and pleural effusion. D) On the fourth day a coronal reconstruction HRCT image
confirms bilateral alveolar consolidations containing the air bronchogram sign.
Figure 5. Aspirated material filling the airways. CT coned views show aspirated food A) into
the tracheal lumen (arrow), B) in the main left bronchus lumen (arrow) in the axial image and
C) coronal reconstruction (arrow). D) Axial CT image shows distal atelectasis in the left lower
lobe and multiple tiny centrilobular nodules in both lungs. E) After VFSS study a CXR shows
preferential aspiration of the contrast media in the left lower lobe (arrows).

Heterogeneous opacities on CXR and thin-slice CT usually represent small areas

of atelectasis caused by distal airway obstruction by aspirated material (Komiya K. et
al., 2013). Aspirated material can also be seen filling the airways, which is an
important clue to the diagnosis (Figure 5). In normal individuals (not in NMD patients)
resolution is commonly observed within 24-48 hours as mucociliary action and
coughing clear the airways, and persistent opacities for more than 4-5 days suggest
superimposed infection. In addition, depending on the bacterial contents of the
aspirate, abscess formation, cavitation, or empyema may result. The differential
diagnosis (DD) includes other causes of segmental or lobar consolidation, such as
community-acquired pneumonia, pulmonary contusion or hemorrhage, or pulmonary
infarct (Komiya K. et al., 2013).
Aspiration Pneumonitis and Mendelson Syndrome

Aspiration pneumonitis is caused by the acute inhalation of a large volume of

acidic gastric contents, resulting in chemical lung injury. A cascade of inflammatory
response follows this initial injury and includes recruitment of inflammatory cells and
release of various inflammatory mediators. This disorder is known as Mendelson
syndrome when the acute aspiration is massive and when aspirated contents have a
pH of <2.5 (Landay M. J., 1999). First described in association with obstetric
anesthesia, it is now known to occur in patients with markedly decreased levels of
consciousness from multiple causes (drug overdose, following head trauma,
seizures). Recurrent small-volume aspirations of refluxed gastric contents during
sleep appear to result in chronic and less severe forms of lung injury, such as diffuse
aspiration bronchiolitis or chronic exogenous lipoid pneumonia (when oil-based
substances [e.g., mineral oil laxative] are aspirated). On imaging, the severity of the
resulting lung injury depends on the pH and volume of the aspirate, including airway
thickening with ground-glass opacities and nodules in a centrilobular and
peribronchovascular distribution. Because of dispersion of the aspirate by coughing,
the distribution can be diffuse, bilateral, and symmetric. The DD of diffuse aspiration
pneumonitis includes aspiration pneumonia, community-acquired pneumonia,
cardiogenic or noncardiogenic pulmonary edema, pulmonary hemorrhage, and acute
hypersensitivity pneumonitis (Prather A. D. et al., 2014).
Bronchiectasis (AILD-Airway Manifestation)
Bronchiectasis, defined by irreversibly widened bronchi due to damage to the

bronchial walls, usually arises from some combination of bronchial obstruction and
infection (Trinick R. E. et al., 2015). Bronchiectasis is a well-known sequela of

chronic pulmonary aspiration that can result in significant respiratory morbidity and
death (Lee A. S. et al., 2018).
Diffuse Aspiration Bronchiolitis (DAB)

(AILD-Airway Manifestation)
Bronchiolitis refers to a broad spectrum of disorders characterized by

inflammation and fibrosis of the bronchioles (internal diameter of ≤2 mm). DAB
describes the resultant inflammation of bronchioles secondary to aspiration. There is
a high association of DAB with oropharyngeal dysphagia, bedridden status,
dementia, and neurological disorders. Its onset is often insidious, making it difficult to
establish a direct association with food intake. On imaging, DAB resembles diffuse
panbronchiolitis, typically manifesting as unilateral or bilateral tree-in-bud nodularity,
centrilobular nodules, and poorly marginated acinar areas of increased attenuation
(Rossi S. E. et al., 2005) (Figure 6). Segmental and subsegmental air trapping can
be seen in expiratory imaging. In contrast to asthma, imaging findings are often
concentrated in the lower lobes or dependent aspects of the lungs. Associated
imaging findings include an esophageal mass, hiatal hernia, or air-fluid level in the
esophagus. DD for this pattern is broad and includes other causes of small airway
disease, such as infectious bronchiolitis, diffuse panbronchiolitis, cystic fibrosis,
allergic bronchopulmonary aspergillosis, and collagen vascular disorders (Rossi S. E.
et al., 2005).
Figure 6. A 68 year-old male with Parkinson’s disease and home-nursing care. CXR and
HRCT images show bilateral centrilobular and tree-in-bud nodular pattern and subsegmental
pleural-based lower lobes consolidations HRCT pattern is fully consistent with diffuse
aspiration bronchiolitis (DAB) diagnosis.

Tracheobronchial Foreign Body (AILD-Airway Manifestation)
Big-sized foreign body aspiration may result in obstruction of the central airway
and sudden death from asphyxiation. In a small-sized inhaled and retained foreign
body, most patients present with a nonresolving cough, sometimes associated with
exertional dyspnea, chest pain, or hemoptysis. Imaging findings can include
postobstructive atelectasis or rarely hyperinflation, air trapping, recurrent pneumonia,
bronchial wall thickening, and bronchiectasis; complications are distal abscess
formation and parenchymal necrosis (Figure 7). Chest CT scanning often provides
additional diagnostic information including demonstration of an intrabronchial mass,
which may be mistaken for an endobronchial malignancy (Kim M. et al., 2008).
Expiratory images may show air trapping in the affected segment (or lobe). When
bronchial obstruction is chronic, consolidative opacities from postobstructive
pneumonia may be demonstrated along with bronchiectasis. On high-resolution
computed tomography (HRCT) of the chest, lentil aspiration pneumonia manifests as
centrilobular nodules, some with a tree-in-bud configuration (Marom E. M. et al.,
1998). Pill aspiration represents a unique type of foreign body aspiration because
some pills such as potassium and iron preparations may dissolve in the airways,
causing intense bronchial inflammation and stenosis (Mehta A. C. et al., 2014). DD
for this pattern is similar to that described for aspiration bronchiolitis. An additional
concern in adults is that aspiration of undigested food can have similar imaging
characteristics to an endobronchial neoplasm, and can be associated with
lymphadenopathy and lobar collapse when chronic.
Figure 7. CT of aspirated endobronchial foreign body (chicken bone). A 67 year-old man with
5-years Parkinson disease who was admitted at emergent department with acute cough,
shortness of breath, and hemoptysis after a meal. A) Coronal oblique MDCT reconstruction
showed an opaque foreign body in the left lower bronchus. B) After two months of COVID-19
lockdown the patient repeated the CT which showed a more distal, segmental, 1.5 cm long
foreign body site and a near complete lobar collapse.

Near-Drowning
In near-drowning, defined as severe asphyxia caused by submersion in water but

not resulting in death, chemical and organic contaminants in the aspirated water are
thought to cause adult respiratory distress syndrome. Radiographic findings are often
presented as scattered ground-glass opacities that progress to patchy airspace
consolidation over the next several days. Mild cases may present as perihilar
ground-glass opacity, progressing to coalescent opacities in severe cases. Ground-
glass opacities and consolidation likely represent pulmonary edema and adult
respiratory distress syndrome, largely secondary to fluid entering the alveoli from the
blood or disruption of the surfactant production.
Chronic Exogenous Lipoid Pneumonia

Figure 8. Imaging of chronic exogenous lipoid pneumonia. A 64 year-old ALS woman with a
history of longstanding ingestion of animal oil (Squalene) and a retained SVC lead. A) CXR
shows a mild middle lobe airspace opacity (red circle). B) CT shows a middle lobe low density
consolidation indicating the presence of lipid deposition. C) CT (parenchymal window) axial
image confirms middle lobe consolidation well appreciated on D) coronal reconstruction
image.

The aspiration of oily material, whether mineral, vegetable, or animal, commonly

mineral oil, which leads to exogenous lipoid pneumonia. The severity of the reaction
depends largely on the amount of free fatty acid in the aspirate. The lung
parenchyma in these cases may show fibrosis, as well as a histiocytic reaction
involving the accumulation of lipid-laden macrophages. Radiographically, the
distribution is predominantly basilar and paramediastinal. Early in the disease
course, centrilobular or panlobular ground-glass opacities are identified, which
progress to volume loss and interlobular septal thickening. When present, airspace
consolidation or mass-like opacities with attenuation values of ≤10 HU are diagnostic
of this condition and can be seen in either the acute or chronic setting (Figure 8).
Ground-glass opacities associated with interlobular septal thickening in a “crazy
paving” pattern have also been described (Maroum E. M., et al., 1999). The DD of
focal consolidation or mass-like opacity can include carcinoma and acute bacterial
pneumonia or OP. The differential for a “crazy paving” pattern is broad and includes
alveolar proteinosis, pneumocystis pneumonia, and diffuse alveolar damage or
hemorrhage.
Chronic Interstitial Lung Disease (Chronic-ILD) and Organizing

Pneumonia (AILD-Parenchymal Lung Manifestations)
Chronic aspiration may be asymptomatic or present nonspecifically with

symptoms such as chronic cough or dyspnea. GERD with repeated reflux of gastric
contents into the superior esophagus and pharynx also likely contributes to chronic
microaspiration.
Secondary aspiration organizing pneumonia (OP) pattern is often basilar
predominant and peripheral or bronchovascular in distribution. A suggestive imaging
finding of OP is the reverse halo sign, also called the atoll sign or fairy ring sign.
Another pattern that may be related to chronic aspiration is a usual interstitial
pneumonia (UIP) pattern of pulmonary fibrosis (Cardasis J. J. et al., 2014).
MULTIDISCIPLINARY TEAM
Dysphagia affects most patients with NMD and each patient with dysphagia is
different owing to the underlying neurological impairment. Aspiration can cause a
wide spectrum of pulmonary diseases (AILD), is often silent/occult and undetected
clinically, has the potential for dire consequences. Etiologic diagnosis is possible by
VFSS and by knowledge of the chest imaging patterns, and the radiologist plays an
important role in suggesting the diagnosis when proved by VFSS. A multidisciplinary
management is needed, including neurologist, respiratory physician, intensivist, ENT
specialist, nutritionist, speech patologist, and last but not least radiologist.

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10.1513/AnnalsATS.201310-360OC.

Chapter 29
SONOGRAPHY IN THE EVALUATION OF THE DISEASE
Salvatore Guarino1,, MD, Christina Anne Jelly2, MD

and Tullio Valente1, MD
1
Department of Radiology, Monaldi Hospital, Naples, Italy
2
Department of Anesthesia and Critical Care,
Vanderbilt University Medical Center, Nashville, TN, USA
ABSTRACT
Neuromuscular disorders affecting respiratory function typically compromise

the contraction of the diaphragm. Ultrasound (US) is a very reliable exam in
assessing diaphragmatic function in the clinic or at the bedside. There are two
approaches to assess the diaphragmatic function: the first evaluates the
diaphragm dome motion, while the second evaluates the diaphragm thickening
during inspiration at zone of apposition (ZOA).
Moreover, US can also be routinely used in patients with neuromuscular
diseases to diagnosis, characterization and monitor pleuropulmonary
complications, such as lung consolidation and pleural effusion, that may
contribute to respiratory failure.
In addition, US can be used to guide needle position during diagnostic and
therapeutic thoracentesis or chest tube placement and then evaluate success of
therapeutic manipulations.
Keywords: ultrasound, diaphragm dome motion, diaphragm thickening, lung

consolidation, pleural effusion

Corresponding Author’s E-mail: sag1981@libero.it.

408 Salvatore Guarino, Christina Anne Jelly and Tullio Valente
ANATOMY AND PHYSIOLOGY OF THE DIAPHRAGM
Neuromuscular disorders affecting respiratory function typically compromise the

contraction of the diaphragm, the main respiratory muscle, accounting for
approximately 70% of the inspired air volume during regular breathing [1, 2].
The diaphragm is a dome-shaped musculotendinous structure, separating the
chest from the abdomen [3]. It consists of a muscular component and a central
tendon, covered by pleura on the thoracic surface and peritoneum on the abdominal
surface [3]. The muscular component is divided into costal and crural diaphragm [3].
The costal diaphragm originates anteriorly from the sternum and laterally from the
lower 6 ribs [3]. The crural diaphragm is formed by right and left crus, originating from
the upper 3 lumbar vertebrae and from medial and lateral arcuate ligaments [3]. The
muscular component inserts on the central tendon, that generally is V-shaped and
has variable size among individuals, ranging from less than 10% to more than 35%
of the diaphragm [3]. The muscular component is thicker than the central tendon.
Functionally two regions have to be considered (Figure 1): 1) an upper dome-
shaped musculotendinous portion, that forms the floor of the thoracic cavity; 2) a
lower muscular region in contact with the lower rib cage, known as zone of
apposition (ZOA) [3]. ZOA is the major contractile portion, where most diaphragmatic
motion occurs [3].
Figure 1. Computed Tomography MPR reconstruction on coronal plane and schematic

drawing showing diaphragm dome (pink arrow) and zone of apposition (dotted blue line).
The diaphragm has several openings, named caval, esophageal and aortic
hiatus, which allow the passage of the great vessels, thoracic duct and esophagus
between chest and abdomen. The foramen of Morgagni is an anterior parasternal
opening, through which superior epigastric vessels pass.
The phrenic nerves innervate the diaphragm and both divide into 3-5 trunks,
innervating anterolateral, posteromedial, sternal and crural diaphragmatic regions [3].
Their branches then run within the diaphragm muscle halfway between the pleural

Sonography in the Evaluation of the Disease 409
and the peritoneal layers [3]. A small accessory phrenic nerve may be present in
20% to 80% of individuals [3].
As mentioned above, the diaphragm is the main muscle of inspiration and during
its contraction it moves caudally, increasing intrabdominal pressure and reducing
intrapleural pressure. The reduction of intrapleural pressure decreases the
intraalveolar pressure, favouring the passage of air from atmosphere into the alveoli
[3]. The diaphragmatic contraction causes the lower rib cage to move outwards
(inflationary movement), due to increased intraabdominal pressure in the ZOA and to
insertional force of the diaphragm on the lower rib cage [3].
CAUSES OF DIAPHRAGM DYSFUNCTION
Diaphragmatic dysfunction (weakness or paralysis) can involve either one or both

hemidiaphragms and can be caused by a multitude of disorders affecting nervous
system, neuromuscular junction and muscle [3].
The disorders of nervous system can involve:
 central nervous system (brain and/or spinal cord), such as cerebrovascular

accidents, demyelinating diseases, Arnold-Chiari malformation, spinal cord
injuries, syringomyelia and spinal cord atrophy;
 motor neurons, such as amyotrophic lateral sclerosis, poliomyelitis and
paraneoplastic motor neuropathies;
 peripheral nervous system, such as Guillain-Barrè syndrome, chronic
inflammatory demyelinating polyneuropathy, neuralgic amyotrophy
(Parsonage-Turner syndrome), critical illness polyneuropathy and phrenic
nerve injury (trauma, compression by mediastinal or cervical masses,
schwannomas of phrenic nerve and following surgery) [3].
The disorders of neuromuscular junction include myasthenia gravis, Lambert-

Eaton syndrome and botulism [3].
Muscular disorders associated with diaphragmatic weakness or paralysis include:
 Duchenne, limb girdle and Becker muscular dystrophy;

 chronic inflammatory myopathies, such as dermatomyositis, polymyositis and
inclusion body myositis;
 metabolic myopathies;
 infectious myositis;
 critical illness polymyopathy and ventilator-induced diaphragm dysfunction in
patients undergoing mechanical ventilation [3].

ULTRASOUND ASSESSMENT OF DIAPHRAGMATIC FUNCTION
The suspicion of unilateral or bilateral diaphragmatic paralysis is often suggested

by elevation of one or both hemidiaphragms on chest radiograph [3]. However, poor
inspiratory effort, obesity or atelectasis can also be associated with elevation of one
or both hemidiaphragms on chest radiograph, while diaphragmatic eventration,
pleural effusion, lobar atelectasis or a sub phrenic abscess can simulate the
radiographic appearance of an elevated hemidiaphragm [3].
Transthoracic diaphragm ultrasound (US) is non-invasive, non-ionizing, low cost
and readily available imaging technique, that allows to evaluate accurately the
function of both hemidiaphragms in the clinic or at the bedside [3].
There are two approaches to assess the diaphragmatic function. The first
approach evaluates the diaphragm dome motion, while the second approach
assesses the diaphragm muscle thickening during inspiration at ZOA [4]. In both
approaches, the supine position of the patient is preferred, as it offers ease of use in
critically sick patients, less overall variability, less side to side variability and greater
reproducibility [5].
Diaphragm Dome Motion
The diaphragm dome motion, due to contraction of the costal diaphragm and
displacement of the central tendon, is assessed placing a low-frequency (3.5-5 MHz)
convex probe below the anterior costal margin between the mid-clavicular line and
the anterior axillary line for the right side and between the anterior and mid-axillary
lines for the left side, using liver or spleen as acoustic windows respectively [3–7].
The probe is then tilted in the cranial direction, so that the ultrasound beam reaches
the posterior part of the diaphragm perpendicularly [4, 5, 7].
The right hemi-diaphragm is better visualized than the left because there is no
gastric air and the liver provides a better acoustic window compared to the limited
spleen window [4, 8].
The diaphragmatic dome excursion can be easily measured with US using B-
mode or M-mode views [4] during quiet respiration, deep breathing and voluntary
sniff manoeuvres [1, 7].
In B-mode view, the diaphragm dome is identified as a crescent-like single thick
hyperechoic structure moving with breath [1, 4–6]. Because the air reflects all
ultrasound waves transmitted toward it, the image of the diaphragm dome is
generated by the reflection of ultrasounds at the interface between diaphragm and
lung and not the diaphragm muscle itself [3].
A normally diaphragm dome moves toward the probe during inspiration [3]. It
should be noted that the motion of the diaphragm dome is not uniform, because the
middle and posterior regions show greater caudal motion than of the anterior region
[4].

Conversely, a paralyzed hemidiaphragm will not move or will move cranially

rather than toward the probe [3]. This paradoxical cranial movement of the paralyzed
hemidiaphragm is exaggerated by performing a vigorous sniff [9]. However, the
hemi-diaphragmatic paradoxical motion is a reliable finding only for unilateral
diaphragm paralysis [3]. Indeed, a bilateral diaphragm paralysis cannot be confirmed
by assessing diaphragm dome motion because in this condition a caudal movement
of the diaphragm can be observed during inspiration due to compensatory activation
of external intercostal and abdominal muscles, thereby reducing sub-diaphragmatic
pressure and attracting the passive diaphragm [3].
Moreover, the diaphragmatic dome excursion during quiet breathing, deep
respiration and sniff manoeuvres should also be assessed in M-mode view [1, 7, 10,
11]. The movement of diaphragm dome toward the probe during inspiration induces
a positive deflection on a time-based plot in M-mode [5]. However, a negative
excursion during inspiration suggests paradoxical diaphragmatic movement
associated with diaphragmatic paralysis and use of accessory muscles [6, 12].
Diaphragmatic motion is quantified mainly by calculating the amplitude of
diaphragmatic excursion (cm) [10]. The values of diaphragmatic excursion in healthy
individuals were reported to be 18 ± 3, 70 ± 11 and 29 ± 6 mm for men and 16 ± 3,
57 ± 10, and 26 ± 5 mm for women during quiet, deep breathing and sniff test,
respectively [11].
Values of diaphragmatic excursion < 10, 47 and 18 mm for men and < 9, 37 and
16 mm for women during quiet, deep breathing and sniff test respectively were
considered pathological [11]. Other less used parameters are the speed of
diaphragmatic contraction (cm/s), the inspiratory time (s) and the duration of the
cycle (s) [13].
Diaphragm Muscle Thickening during Inspiration
A normal diaphragm shortens and thickens with contraction during inspiration.

Diaphragm paralysis is characterized by absence of diaphragm thickening during
inspiration on US [3]. The optimal area for US assessment of diaphragm thickening is
ZOA, placing a high-frequency (> 10 MHz) linear probe in the eighth to ninth
intercostal space on the mid-axillary line [6] and in the coronal plane [3, 4]. It is
important to specify the intercostal space where the diaphragm thickness is
evaluated, because it is variable: the more inferior portions of the diaphragm are
thicker than more superior portions [10]. The optimal US depth to view ZOA usually
ranges between 3 and 6 cm depending on the thickness of the rib cage [4].
The result is a B-mode US image with high spatial resolution [3, 4], where ZOA
appears as a hypoechoic linear structure delimited by two parallel hyperechoic
layers, corresponding to the pleura and peritoneum [4]. Often inside the diaphragm
there is a third hyperechoic line, representing a neurovascular bundle [4].
Diaphragm contraction is assessed by measuring the following parameters in B-
mode:

 diaphragm thickness (tdi) at relaxed end-expiration and at end-inspiration [4].

Normal diaphragm thickness at end-expiration is generally 2.0-3.5 mm [4],
while the thickness of a paralyzed diaphragm is 1.3-1.9 mm [10]. A
diaphragm thickness < 2 mm at the end-expiration has been proposed as
cut-off to define paralyzed diaphragm [14, 15]. In healthy subjects the normal
diaphragm thickness at ZOA increases to 4.5 ± 0.9 mm when they breath
holding at total lung capacity (TLC) [16]. A minimal difference in
hemidiaphragm thickness between the two sides has been reported in
healthy subjects [1].
 percentage of diaphragm thickening with inspiration (Dtdi%) or thickening
fraction (TF), that ranges between 20% and 100% [4]. Dtdi% or TF <20% are
consistent with diaphragmatic paralysis [12].
The major advantage of this technique is the evaluation of the diaphragm during
its activation [4]. However, it is more difficult compared with imaging the dome and
requires more operator skill [4].
CLINICAL APPLICATIONS OF DIAPHRAGM ULTRASOUND
Diaphragm function is inevitably impaired in neuromuscular disorders affecting

respiratory function. In such diseases diaphragm US is a very useful tool, because it
allows real-time assessment of diaphragmatic contraction, detecting any weakness
or paralysis [7].
Diaphragm weakness on US is characterized by:
 less than normal excursion in M-Mode on deep breathing with or without

paradoxical movement on sniff manoeuvres [13, 17];
 normal or thinned hemidiaphragm with decreased thickening during deep
inspiration in B-Mode.
Diaphragm paralysis on US is characterized by:
 absent excursion in M-Mode with quiet breathing and deep breathing (Figure
2 A-B);
 absence of movement or paradoxical movement either with normal breathing
or with manoeuvres [10, 13];
 typically, thinned hemidiaphragm with no thickening during deep inspiration
on B-mode (Figure 2 C-D).

Figure 2. A-B) Bilateral diaphragm US (subcostal window) showing absent movement of both
hemidiaphragms at B and M mode in paediatric patient with chronic and progressive dyspnea.
C-D) Right hemidiaphragm thickness of critically patient in ICU with difficult weaning from
mechanical ventilation evaluated with B mode US at ZOA (right intercostal window). In this
patient the diaphragm thickness at end-expiration and end-inspiration was 1.8 and 2.2 mm
respectively, suggesting diaphragmatic paralysis.
As already mentioned above, they are considered pathological:
 a diaphragm thickness at ZOA < 2 mm at the end of expiration [14, 15];

 a Dtdi% or TF < 20% [12];
 values of diaphragmatic excursion < 10, 47 and 18 mm for men and < 9, 37
and 16 mm for women during quiet, deep breathing and sniff test,
respectively [11].
Diaphragm weakness and paralysis must be distinguished from eventration, that

refers to a condition characterized by localized diaphragm atrophy or replacement of
a part of the diaphragm with fibroelastic tissue [3]. The most common location is the
anteromedial portion of the right hemidiaphragm [3]. The suspicion of eventration is
often suggested by a localized area of diaphragm elevation on chest radiograph,
often best appreciated on the lateral radiograph [3]. If the eventration involves an
extensive area, the entire hemidiaphragm may appear elevated [3]. Eventration can

be distinguished from unilateral paralysis by diaphragm US, revealing a normal

diaphragm thickening in the ZOA [3].
US can also be used as guidance for positioning the needle in electromyography,
increasing its accuracy and reducing the risk of complications, such as
pneumothorax [1].
Moreover, diaphragm US is routinely used in mechanically ventilated patients in
intensive care unit (ICU) to a) monitor diaphragmatic function, b) diagnose
diaphragmatic dysfunction [7], known as ventilator-induced diaphragmatic
dysfunction (VIDD), induced by muscle disuse leading to atrophy and contractile
dysfunction [18, 19], and c) predict extubation success or failure [6, 13, 20]. In this
regard, a diaphragmatic excursion > 25 mm and a diaphragm thickening fraction >
30-36% during spontaneous breathing trial have been reported to predict extubation
success in mechanically ventilated patients [21, 22].
ULTRASOUND DIAGNOSIS AND MONITORING

OF PLEUROPULMONARY COMPLICATIONS
Chest US can also be routinely used in patients with neuromuscular diseases to

diagnosis and monitor pleuropulmonary complications, such as respiratory infection,
aspiration pneumonia and pleural effusion, that may contribute to respiratory failure.
Alternatively, chronic respiratory failure due to weakness of the respiratory muscles
may also present acutely in presence of an acute illness.
In many cases the progressive muscle weakness causes low upper airway tone,
ineffective airway clearance, dysphagia and poor swallow coordination in addition to
insufficiency of inspiratory muscles. Low upper airway tone may induce upper airway
obstruction and obstructive sleep apnea, while the ineffective airway clearance
predisposes to recurrent respiratory infections [23]. Moreover, dysphagia and poor
swallow coordination can lead to chronic pulmonary aspiration, inducing aspiration
pneumonia, atelectasis, bronchiectasis and fibrosis [23]. Pleural effusion may
accompany lung consolidation or be secondary to dilated cardiomyopathy, induced
by Duchenne and Becker muscular dystrophy or autoimmune chronic inflammatory
myopathies, such as dermatomyositis and polymyositis [24].
Lung and pleural US exam is performed using either low-frequency (3.5-5 MHz)
convex probe and high-frequency (> 10 MHz) linear probe [25]. The patient may be
in a sitting or supine position; the patient may rarely be asked to stand during the
exam to evaluate cost-phrenic recess [25]. However, patients with respiratory failure
should receive oxygen during US exam to relieve their symptoms and reduce the risk
of motion-related artefacts caused by labored breathing [25].
In sitting patient, longitudinal scans are performed placing the probe on the mid-
scapular line to evaluate the lung base [26].
In supine patient, various scanning planes may be used. The anterior chest wall
is usually investigated using intercostal, longitudinal, supra- and para-sternal, sub-

xiphoid and supraclavicular scans [25]. The posterior wall, on the other hand, is
explored using: - intercostal and transversal scans, obtained placing the probe on the
posterior axillary line at the lung base, middle point and apex; - longitudinal scans,
placing the probe on the posterior axillary line to identify the liver on the right side
and the spleen on the left side; - paravertebral scans [25, 26].
Furthermore, additional abdominal acoustic windows (liver on the right side and
spleen on the left side) may be used to improve the evaluation of basal pleura [25].
Lung US is an excellent tool for diagnosing inflammatory processes, such as
pneumonia, involving the peripheral regions of the lung [25, 27]. Pneumonia can only
be detected by US if there is no air between the probe and the lesion; even a thin
layer of air can seriously impair the detection of solid lesions, regardless of their size
[25].
Figure 3. US scans showing typical findings of lung consolidation and pleural effusion. A)
Lung consolidation (white arrows) and air bronchogram (yellow arrowheads. B) Lung
consolidation (white arrow), fluid bronchogram (yellow arrowheads) and shred sign (yellow
arrows). C) Lung consolidation (white arrow) and anechoic pleural exudate (yellow
arrowheads). D) fibrin strands or septa (yellow arrowheads) inside the pleural effusion
suggesting empyema. E) coexistence of hypoechoic (white arrowheads) and hyperechoic
(yellow arrowheads) areas, due to the formation of clot mixed with blood, within the pleural
effusion suggesting hemothorax. F) liver metastasis (yellow arrowhead) suggesting neoplastic
pleural effusion (white arrow).Lung US is also useful in the follow-up of a patient with
pulmonary consolidation, since it allows to monitor evolution after therapy without X-ray
exposure [25].
An inflammatory process can show the US findings of interstitial syndrome or

pulmonary consolidation.
Interstitial syndrome is characterized by confluent B-lines, corresponding to
vertical hyperechoic reverberations arising from the pleural line, generated by fluid
interlobular septal thickening.

Subpleural pulmonary consolidation appears as a hypoechoic lesion, showing an

echo-texture similar to liver (“lung hepatization”) (Figure 3 A-C) [25, 27, 28]. Within
the consolidated lung, dynamic hyperechoic foci (representing “air bronchogram”)
(Figure 3 A) and, less frequently, hypoechoic tubular lines (corresponding to “fluid
bronchogram”) (Figure 3 B) and foci (correlating to foci of necrosis) may be visible
[25, 27, 28]. The distal margin of a consolidated area often appears irregular and
serrated (“shred sign”) (Figure 3 B) [27, 28].
Inflammatory processes of the lung are frequently associated with pleural
effusion. However, in addition to pneumonia, the pleural effusion can also be
secondary to dilated cardiomyopathy, induced by Duchenne and Becker muscular
dystrophy or autoimmune chronic inflammatory myopathies, such as
dermatomyositis and polymyositis [24].
Chest US is a very reliable exam in detecting, quantifying and characterizing
pleural effusion, which consist of a fluid collection between the visceral and parietal
pleura. US has consistently been shown to recognize small amount of pleural
effusion (less then 10 ml) and predict its volume with an accuracy greater than chest
radiography (CXR) and equivalent to chest computed tomography (CT) [25, 26]. The
other great advantage of US compared to CXR and CT is the possibility of being
performed frequently at the bedside without X-ray exposure [26].
Various methods have been proposed to estimate pleural effusion volume and
there is no established best method [26]. The method proposed by Balik et al. is to
measure in supine position at the lung base the maximal interpleural distance (mm)
between the visceral pleura that covers the base of the lung and the parietal pleura
that covers the diaphragm at end-expiration and to multiply that distance (mm) by a
factor of 20 to give an estimate of the volume (ml) of the effusion [29]. An alternative
method proposed by Usta et al. measures in the sitting position in spontaneously
breathing patients the maximal distance (mm) between the mid-height of the
diaphragm and the visceral pleural and multiplied this value by a factor of 16 to
estimate volume (ml) [30]. However, variations in patient size, changes in patient
position and factor that affect diaphragmatic excursion, such as abdominal
hypertension or diaphragmatic paralysis, may influence the volumetric assessment,
leading to errors in estimating pleural effusion volume [26]. Therefore, such
measures of pleural effusion volume should not be considered alone in making
determinations to drain pleural effusions, but should be considered along with patient
clinical factors [26].
In addition to assess pleural effusion volume, chest US is used to characterize
effusion and differentiate a simple from a complex effusion, which is not possible with
CXR.
Analysis of the internal echogenicity, homogeneity and changes in pleural
thickness are the primary US characteristics used to define the nature of pleural
effusions [25, 26]. Based on internal echogenicity, several types of pleural effusion
may be distinguished on US:

 anechoic;
 homogeneously hyperechoic;
 hyperechoic complex non-septate;
 hyperechoic complex septate [25, 31].
Effusion is defined as anechoic when it is echo-free, as homogeneously

hyperechoic when it has evenly distributed corpuscular characters, as hyperechoic
complex non-septate when hyperechoic floating material is inside the effusion and as
hyperechoic complex septate when hyperechoic floating fibrin strands or septa are
found inside the effusions [25, 26, 31].
The internal echogenicity, homogeneity or not of a pleural effusion, as well as
pleural thickness may direct the diagnosis towards a transudate, exudate, empyema,
hemothorax or neoplastic effusion.
Anechoic effusion could be either a transudate or an exudate, but bilateral
anechoic effusions and normal pleural thickness are most suggestive of transudate
[31]. The exudates, although they may also be anechoic and homogeneous (Figure 3
C), are more apt to have areas of heterogeneity or septa, as well as be associated to
pleural thickening and lung changes [31].
Empyema, hemothorax and malignant effusion are often hyperechoic and
associated to changes in pleural thickness, but the presence of septa is a common
finding in the empyema (Figure 3 D), as well as the coexistence of areas of hypo-
and hyper-echogenicity due to the formation of clot mixed with blood is highly
suggestive of hemothorax (Figure 3 E), whereas irregular pleural thickness is most
commonly associated with neoplastic effusions [31] (Figure 3 F).
However, in all these cases, the diagnosis needs to be confirmed by exploratory
thoracentesis and eventually biopsy [25].
The lung parenchyma adjacent to the pleural effusion may be well aerated,
consolidated or atelectatic [25].
In addition to assess and monitor pleural effusion volume and characteristics,
chest US can be used to guide needle position during diagnostic and therapeutic
thoracentesis or chest tube placement and then evaluate success of therapeutic
manipulations [25, 26].
LIMITATIONS OF DIAPHRAGM AND CHEST ULTRASOUND
Although chest US is an evolving technique for assessing the diaphragmatic

function and pleuropulmonary complications in neuromuscular disorders and
mechanically ventilated patients, there are several limitations to its use, namely:
 US image acquisition and analysis is operator dependent and requires

training [5];

 unsatisfactory visualization of the left hemi-diaphragm, due to the

interposition of gastric air and to the limited spleen window [4, 8, 10];
 the degree of shortening of the diaphragm during contraction is strongly
influenced by the level of diaphragm motor outflow, which in mechanically
ventilated patients varies greatly as a function of the degree of sedation [5];
 lung consolidations not contacting the pleural surface may be missed due to
the reflection of US waves at the pleural interface [27, 28];
 subpleural lung consolidations on US does not always indicate pneumonia,
because they can also be caused by solid pulmonary masses and pulmonary
infarction [27];
 when patients with large pleural effusions are examined in the sitting position,
sometimes it is possible to detect paradoxical diaphragmatic motion,
suggesting a false paralysis [10]. This finding has been reported to revert to
normal motion when the exam is performed with the patient in the supine
position, therefore representing the favoured position [10]. Paradoxical
movements of an unparalyzed diaphragm have also been reported in
negative pressure pneumothorax, lung fibrosis, atelectasis and sub-phrenic
abscess [10];
 the acoustic shade caused by a dense rib, which an inattentive observer may
confuse with an anechoic tumor mass.
FUTURE DIRECTIONS
The use of diaphragm US has spurred work in using US of the intercostal muscle
to assess success in weaning from mechanical ventilation. Dres et al. assessed
readiness to wean from mechanical ventilation by using parasternal intercostal
muscle US and found that parasternal intercostal muscle thickening fraction can
predict difficulty in weaning patients from mechanical ventilation with good
interobserver reproducibility [32].
Shear wave sonoelastography, evaluating soft tissue stiffness, has also been
used to assess diaphragmatic function and found to have good inter-operative
reproducibility and reliability in critically ill patients [33].
Additional applications of diaphragm US include using diaphragmatic excursion
as a marker of lung recruitment in critically ill patients. Dorsal diaphragmatic
excursion using M-mode US was affected by incremental PEEP titration towards a
positive transpulmonary pressure and may be a potential target for bedside
assessment of lung recruitment [34].
Diaphragm US may also be used to stratify risk in patients prior to ICU
admission. Patients prior to cardiac surgery had preoperative assessment of
diaphragmatic excursion. Patients with low preoperative maximal thickening fraction
during inspiration were more likely to develop pneumonia or require prolonged

mechanical ventilation. Those with pulmonary complications also had prolonged ICU
and hospital length of stays [35].
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Chapter 30
VOCAL CORD DYSPHONIA AND SIALORRHEA
Raffaele Dubbioso1, PhD, MD and Rafael Soler2,, MD

1
Department of Neurosciences, Reproductive Sciences and Odontostomatology
University of Naples Federico II, Napoli, Italy
2
Department of Neurology University Hospital. Melilla, Spain
ABSTRACT
Neuromuscular diseases are a heterogeneous group of diseases affecting to

different degree the peripheral nervous system, ranging from the second motor
neuron to the muscle. Weakness in the facial and oral muscles that control the
use of the tongue, lips, soft palate, cheeks, and diaphragm results in problems
with speech quality (dysarthria) and voice quality (dysphonia). Analogously,
impairment of oral muscles as well as pharyngeal and oesophageal muscles can
lead to swallowing problems (dysphagia). The reduction of oral clearance mostly
due to dysphagia or medical conditions that cause saliva overproduction are two
main mechanisms of excess saliva in the mouth beyond the lip margin, causing
the so-called sialorrhea.
The approach to dysphonia and sialorrhea should be multidisciplinary and
begins with an appropriate clinical assessment, speech therapy, respiratory and
dysphagia physiotherapy, and the use of anticholinergic drugs and botulinum
toxin injection.
Keywords: Dysphonia, Sialorrhea, Botulinum Toxin, Surgery, Local Radiotherapy
VOCAL CORD DYSPHONIA

Dysphonia (impaired voice production) is a very common complaint affecting
nearly one-third of the population at some point in its life. The term dysphonia is often

Corresponding Author’s E-mail: rafael_soler_gonzalez@yahoo.es.

424 Raffaele Dubbioso and Rafael Soler
used interchangeably with hoarseness; however, this terminology is imprecise, as

hoarseness is a symptom of altered voice quality reported by patients, while
dysphonia characterizes impaired voice production as recognized by a clinician [1].
Acute and chronic conditions, which result in abnormal vibrations of the vocal
folds, can cause dysphonia. These causes can range from vocal abuse and misuse
to systemic diseases. Among acute conditions, clinicians should consider viral,
bacterial, fungal infection of the throat and/or larynx, foreign body in larynx, trachea,
or oesophagus and neck or laryngeal trauma.
Chronic causes of dysphonia can be divided into five basic categories:
neurologic, systemic disease/medication (e.g., diabetes, Sjögren’s syndrome,
hypothyroidism, sarcoidosis, amyloidosis, acromegaly, alcohol, certain medications
used for hypertension, schizophrenia, osteoporosis), inflammatory conditions
(chronic tobacco use, infective laryngitis, chemical laryngitis, reflux, allergic rhinitis,
chronic rhinitis), neoplastic/structural (laryngeal cancer, lung cancer or metastasis to
the lung, thyroid cancer, vocal cord dysplasia, cysts, polyps, nodules and carcinoma)
and functional disorders with no corresponding physiological abnormalities of the
larynx (psychogenic such as dissociation disorder and vocal abuse).
Neurologic disorders may affect voice and speech production in several ways.
Central injury may affect initiation, coordination, and quality of voice and speech.
Direct effects on the larynx can affect glottic closure patterns and efficiency along
with laryngeal muscle tone. Denervation of muscles involved in the support
mechanism of the voice, such as the diaphragm or chest wall musculature, affects
voice strength and quality. Dysfunction of oropharyngeal musculature may affect
resonance. A palatal paralysis result in a more hypernasal voice. Impairment of
cranial nerve V, VII, or XII function can affect articulation. Findings on general
neurologic and laryngeal examination depend on which nerves are involved and
where the disorder affects the neuromuscular pathway.
As for neuromuscular diseases, dysphonia could be sometimes the presenting
symptom. The knowledge and awareness of the neuromuscular diseases, the signs
and symptoms that could impair the voice and swallowing, and performing a detailed
neurological examination are essential to diagnose neurological diseases long before
they are more widespread and obvious.
In this chapter we will focus on neuromuscular conditions causing dysphonia
(Table 1), with a particular interest for spasmodic dysphonia.
Motor Neuron Diseases
Motor neuron diseases may result from degeneration of upper motor neurons,
lower motor neurons, or both. When both upper and lower motor neurons are
involved, the diagnosis of amyotrophic lateral sclerosis (ALS) is made. ALS is fatal,
usually from respiratory failure, but the clinical course is variable. Other examples of
upper motor neuron disease processes include primary lateral sclerosis and
pseudobulbar palsy. Primary lateral sclerosis typically involves destruction of upper

Vocal Cord Dysphonia and Sialorrhea 425
motor neurons only. The diagnosis is typically made after 2 years of predominantly
upper motor neuron involvement. Pseudobulbar palsy results from interruption of
bilateral corticospinal tract axons from other disease processes, such as stroke,
multiple sclerosis, or tumour, as opposed to destruction of the neuronal cell body
itself. Patients who have pseudobulbar palsy often have inappropriate emotional
outbursts. A pseudobulbar palsy affect is often seen in patients who have ALS.
Lower motor neuron diseases include ALS, progressive bulbar palsy, spinal muscle
atrophy and Spinal-bulbar muscular atrophy (Kennedy’s disease). Progressive bulbar
palsy is essentially ALS affecting only the cranial nerves. Spinal muscle atrophy is an
autosomal-recessive disorder that involve degeneration of the anterior horn cells of
the spinal cord. Although some forms present in adulthood, many presents in
younger patients or new-born. Physical findings differ between upper and lower
motor neuron processes.
Upper motor neuron findings include spasticity of musculature and hyperreflexia.
Spasticity of laryngeal musculature often results in a strained voice that might be
misconstrued as spasmodic dysphonia. Patients may suffer from intermittent
laryngospasm. Spasticity of oral musculature results in strained, effortful dysarthria.
Myoclonus may occur. Extremity involvement may be noted. A positive Babinski
reflex is a classic finding of upper motor neuron disease.
Lower motor neuron processes result in flaccid paralysis, muscle atrophy, and
fasciculations. Patients may develop weak, breathy voices, bowing of the vocal folds,
and poor cough. Palatal involvement may lead to nasal regurgitation and hypernasal
speech. Pharyngeal musculature involvement leads to oropharyngeal dysphagia.
Tongue and facial muscle involvement lead to slurred speech and oral dysphagia.
With poor oral motor function, pharyngeal squeeze, and glottic incompetence, these
patients are often at significant risk for aspiration.
Disease of the Neuromuscular Junction
Myasthenia gravis is an autoimmune disease characterized by muscle weakness

exacerbated by repetitive use and improved with rest. Although ocular involvement is
most common, laryngeal myasthenia may present independently or in conjunction
with other muscles. Laryngeal finding is best appreciated with fibre-optic laryngeal
examinations. Vocal fold fatigability with repetitive phonatory tasks is characteristic.
Fluctuating movement asymmetry may be observed (one side appears to move more
briskly and then appears more sluggish in comparison with the contralateral side).
Patients may also suffer from dysphagia and dysarthria. Antibodies against post-
synaptic acetylcholine receptor and less frequently against Musk receptor can be
detected. Involvement of the pharyngeal muscles in Lambert-Eaton syndrome has
been described, but it is less common than in myasthenia gravis.

Diseases of the Peripheral Nerves
Acquired and hereditary neuropathies can present with vocal cord paralysis.
Specifically, patients with acquired acute immune-mediated polyneuropathy such as
Guillain-Barré Syndrome and its variants can display vocal cord impairment usually
together with other bulbar symptoms (e.g., diplopia, dysphagia). Analogously, vocal
cord palsy has been described as the initial presentation of chronic inflammatory
demyelinating polyradiculoneuropathy. Hereditary neuropathies, such as Charcot-
Marie-Tooth type 2 due to mutations in GDAP1 and some forms of Hereditary Motor
Neuropathies (HMN) are characterized by vocal cord palsy, that may represents an
hallmark that helps the clinician for differential diagnosis.
Peripheral nerve injury, specifically to the vagus nerve or the recurrent (RLN) or
superior laryngeal nerve (SLN) branches, typically presents with absent or sluggish
vocal fold movement. Proximal vagal injuries may also present with palatal and
pharyngeal paralysis. Clinically, unilateral RLN paralysis typically presents as a
breathy voice. Dysphonia and aspiration may occur. Classically, paralysis of the SLN
results in loss of a patient’s upper register. Normally, the cricothyroid muscle
contracts briskly in falsetto or modal phonation to increase tension in the vocal fold.
The inability to increase vocal tension results in poor vocal performance, especially
at higher pitches. The clinical manifestations specific to SLN paralysis are likely more
troublesome for singers and professional speakers. Moreover, the internal division of
the SLN carries afferent fibres from the larynx to the central nervous system. This
afferent input likely plays a role in vocal control and modulation.
More subtle paresis of the SLN or RLN may cause numerous voice complaints,
including vocal fatigue, hoarseness, impairment of volume, loss of upper range, loss
of projection, and breathiness. Vocal fatigue may be caused by the additional effort
required to raise vocal pitch and project, and by hyper functional compensatory
gestures.
Other symptoms may occur with injury to the vagus or the laryngeal nerve
branches. Hypoesthesia of the supraglottic larynx suggests injury to the internal
division of the superior laryngeal nerve and may cause intermittent choking
symptoms. Hypoesthesia in addition to pharyngeal dysfunction can place the patient
at significant risk for aspiration.
Neuralgia or paraesthesia of the laryngeal nerves may also manifest as or
contribute to chronic cough, globus, or laryngeal pain syndromes. Dysphagia often
occurs with vocal fold paralysis and paresis. Patients may aspirate, particularly if
there is significant pharyngeal involvement. Injury to the SLN may result in dysphagia
by several mechanisms. Injury to the internal division results in loss of afferent input
to the swallowing center in the brainstem. In addition, recent evidence has suggested
that the external division of the SLN may supply innervation to the cricopharyngeus.
Denervation may result in cricopharyngeal dysfunction and subsequent dysphagia.
Laryngeal findings usually depend on which nerves are involved and the severity
of injury. A vocal fold paralysis results in absent motion on the affected side. Vocal
fold paresis may be more subtle. Vocal fold lag, or sluggishness, is the most

common sign. This lag may only become apparent with repetitive tasks that cause
the patient to fatigue. Asymmetry in motion should raise suspicion of a paresis but
does not always indicate which nerves are involved. Supraglottic hyperfunction is
often present in patients who have paresis and may make the examination more
difficult to interpret. Efforts to try to relax or ‘‘unload’’ the hyperfunction may help in
determining which muscles are affected. Asymmetry may be present in patients who
have muscle tension dysphonia without paresis.
Vocal fold tone is variable after injury to the recurrent laryngeal nerve and
depends on the degree of reinnervation. Reinnervation prevents muscle atrophy.
Spontaneous reinnervation may occur after nerve transection. The source of the
reinnervation is not known, but may include regenerating fibres from the transected
RLN, the SLN, cervical autonomic nerves, and nerve branches innervating
pharyngeal constrictors.
The clinical course after 4 months is determined by the degree of reinnervation
and synkinesis. Although reinnervation after a complete RLN transection prevents
muscle wasting, typically it does not restore useful movement to the vocal fold
because of synkinesis. Synkinesis results from nonselective reinnervation of
adductor and abductor muscles. As a result, muscles that perform opposing
functions contract simultaneously, resulting in immobility or hypomobility of the vocal
fold. The clinical picture depends on the proportion of adductor and abductor fibres
reinnervated and the ability of the contralateral vocal fold to compensate by crossing
the midline of the glottis.
Myopathy
Myopathies may be inherited or result from metabolic or inflammatory processes.

Among hereditary myopathies, mitochondrial myopathy can cause an early-onset
vocal fold atrophy. In some types of muscular dystrophy, weakness in the facial and
oral muscles that control the use of the tongue, lips, soft palate, cheeks, and
diaphragm results in problems with speech quality (dysarthria) and voice quality
(dysphonia). For instance, oculopharyngeal muscular dystrophy (OPMD) is a rare
genetic muscle disorder with onset during adulthood most often between 40 and 60
years of age. OPMD is characterized by slowly progressive muscle disease
(myopathy) affecting the muscles of the upper eyelids and the throat. Affected
individuals may develop drooping of the eyelids (ptosis), trouble moving their eyes
(ophthalmoplegia) and/or difficulty swallowing (dysphagia), limb muscles may
become involved including those of the upper legs and arms (proximal limb
weakness). Additional symptoms may eventually occur including weakness and
degeneration (atrophy) of the tongue, weakness, and atrophy of the proximal
muscles of the arms, limitation of upward gaze, difficulty speaking (dysphonia), and
weakness of additional facial muscles. Analogously, myotonic dystrophy type 1,
patients might have difficulties in speech fluency and articulation due to weakness in
the oral and facial muscles. Autoimmune inflammatory myopathy is a heterogeneous

group of disorders characterized by muscle inflammation or myositis, including

dermatomyositis, polymyositis, and myositis overlap syndrome (including
antisynthetase syndrome), which are the most common types, as well as inclusion
body myositis (IBM) and immune-mediated necrotizing myopathy. Larynx is an
important site of myositis activity and muscular voice disorders (dysphonia) represent
one of the most important complications together with dysphagia in inflammatory
myopathies.
Isolated laryngeal myopathy is rarely reported, although chronic steroid inhaler
use has been insinuated as a cause. Laryngeal findings include loss of muscle tone
and hypomobility. These findings are similar to those that may be seen with motor
neuropathy. Some have suggested that myopathy is underdiagnosed as a laryngeal
disorder, because we tend to think more about nerve injuries when we see weak,
flaccid vocal folds.
Extrapyramidal Diseases
Diseases of the extrapyramidal system include Parkinson’s disease, spasmodic

dysphonia, and laryngeal tremor. More than 70% of patients who have Parkinson’s
disease have voice and speech manifestations. Patients who have Parkinson’s
disease often have soft, breathy, monotonal voices. Laryngeal tremor is common.
Patients often perceive their voice as normal. Affect is often flat (‘‘masked’’). In
addition, patients who have Parkinson’s disease may have significant dysarthria and
dysphagia. Characteristic laryngeal signs include vocal fold bowing, glottic
insufficiency, and slow vibration. The glottic insufficiency and poor breath support
attributable to debilitation and chest wall rigidity result in a soft, breathy voice quality.
Vocal fold paralysis should raise suspicion of a Parkinson plus syndrome, such
as progressive supranuclear palsy, Multiple system atrophy. These diseases are
usually more rapidly progressing and less responsive to medication. In addition,
patients who have Multiple system atrophy are at risk for bilateral vocal fold paralysis
and airway obstruction.
Spasmodic Dysphonia (SD)
Spasmodic dysphonia (SD) or laryngeal dystonia encompasses several

overlapping clinical phenotypes characterized by abnormal activity of the muscles of
the larynx. The most common subtypes are adductor or abductor spasmodic
dysphonia, whereas less common subtypes include laryngeal breathing dystonia
(also known as dystonic respiratory stridor) and singer’s dystonia.
SD is a task-specific dystonia in which spasms typically occur during speaking
but abate with singing, shouting, crying, or whispering. In SD, spasms of laryngeal
muscles cause intermittent voice breaks. SD presents two main phenotypes based

on the abnormal deviation of vocal cords in adduction or in abduction as result of

excessive contraction of laryngeal muscles. Adductor SD affects 90% of cases and is
caused by excess activity of vocal fold adductors, with intermittent hyperadduction
leading to an intermittently strained and strangled voice. Spasms tend to occur with
vowels, particularly during glottal stops between vowels. Abductor SD is less
common and is caused by excess activity of the abductor muscles, with excessive
opening of the vocal folds and prolonged breathy voice breaks. Spasms are most
prominent with voiceless consonants (p, t, k, h, s, f) before vowels. Rarely, adductor
SD and abductor SD occur together. SD may be difficult to differentiate from vocal
tremor, which is characterized by more regular oscillations of multiple laryngeal
muscles However SD patients can present apparently regular voice breaks that may
resemble the rhythmic oscillations of tremor. SD is also readily confused with another
disorder, muscle tension dysphonia (MTD), which is characterized by an excessive
tension of the (para)- laryngeal musculature, caused by a diverse number of
etiological factors and leading to a strained voice. In MTD the stained voice does not
usually vary with different part of the speech and isolated MTD can be reversed with
voice therapy. However, many SD patients may present features of MTD, and the
exact relation between the two diseases remains unclear. MTD may not be a
manifestation of dystonia but, rather, a behavioural compensation for voice
weakness or instability.
Aetiology and Pathogenesis
The cause of spasmodic dysphonia is unknown. Because the voice can sound
normal or near normal at times, spasmodic dysphonia was once thought to be
psychogenic, or originating in a person's mind, rather than from a physical cause. In
rare cases, psychogenic forms of spasmodic dysphonia do exist; however, in most
instances, the muscle spasms are caused by abnormalities in the central nervous
system.
The neuroanatomical basis for SD also remains an open question. Any model for
pathogenesis should account for difficulties with speaking while sparing closely
related tasks of singing, whispering, shouting, and crying. Positron emission
tomography (PET) studies have revealed both increases and decreases in blood flow
to several regions of the cerebral cortex in adductor SD. Studies involving functional
Magnetic Resonance Imaging during symptomatic and asymptomatic tasks also
have pointed to abnormal activation of the cerebral cortex, especially within the
primary somatosensory cortex, and cerebellum, whereas diffusion tensor imaging
has revealed white matter defects in or near the basal ganglia, cerebellum, and
thalamus. A voxel-based morphometry (VBM) study revealed changes in cerebral
cortex and cerebellum. In some cases, spasmodic dysphonia may run in families. It
may be a particularly prominent or isolated manifestation of mutations more
commonly associated with generalized dystonia, especially the THAP1 gene.
Recently, mutations in the gene encoding tubulin beta 4A (TUBB4A) have emerged

as a potential cause in some families in which generalized dystonia includes

prominent laryngeal and lingual dystonia. The “whispering dysphonia” in these
patients is atypical for sporadic SD and may reflect a compensatory adaptation to
laryngeal spasms. These families emphasize the importance of phenotypic subtypes
within LD. There also is strong epidemiological evidence for nongenetic
contributions. Many patients report developing LD after an upper respiratory
infection, laryngeal trauma, exposure to a neuroleptic, or periods of high stress.
Diagnosis
The assessment and diagnosis of a dysphonic voice is completed by a

multidisciplinary team, such as an otolaryngologist, Speech-Language Pathologist
and Neurologist involving the use of both objective and subjective measures to
evaluate the quality of the voice as well as the condition of the vocal fold tissue and
vibration patterns.
Auditory-Perceptual Measures
Auditory-perceptual measures are the most used tool by clinicians to evaluate
the voice quality due to its quick and non-invasive nature. Additionally, these
measures have been proven to be reliable in a clinical setting. Ratings are used to
evaluate the quality of a patient's voice for a variety of voice features, including
overall severity, roughness, breathiness, strain, loudness, and pitch. These
evaluations are done during spontaneous speech, sentence or passage reading or
sustained vowel productions. The GRBAS (Grade, Roughness, Breathiness,
Asthenia, Strain) and the CAPE-V (Consensus Auditory Perceptual Evaluation—
Voice) are two formal voice rating scales commonly used for this purpose. Lastly, the
Voice Handicap Index (VHI) is a questionnaire assessing the functional, emotional,
and psychosocial consequences of voice disorders.
Vocal Fold Imaging

Vocal fold imaging techniques are used by clinicians to examine the vocal folds
and allows them to detect vocal pathology and assess the quality of the vocal fold
vibrations. Laryngeal stroboscopy is the primary clinical tool used for this purpose.
Laryngeal stroboscopy uses a synchronized flashing light passed through either a
rigid or flexible laryngoscope to provide an image of the vocal fold motion; the image
is created by averaging over several vibratory cycles and is thus not provided in real-
time As this technique relies on periodic vocal fold vibration, it cannot be used in
patients with moderate to severe dysphonia. High speed digital imaging of the vocal
folds (videokymography), another imaging technique, is not subject to the same
limitations as laryngeal stroboscopy. A rigid endoscope is used to take images at a
rate of 8000 frames per second, and the image is displayed in real time. As well, this

technique allows imaging of aperiodic vibration and can thus be used with patients
presenting with all severities of dysphonia.
Acoustic Measures
Acoustic measures can be used to provide objective measures of vocal function.
Signal processing algorithms are applied to voice recordings made during sustained
phonation or during spontaneous speech. The acoustic parameters which can then
be examined include fundamental frequency, signal amplitude, jitter, shimmer, and
noise-to-harmonic ratios. However, due to limitations imposed by the algorithms
employed, these measures cannot be used with patients who exhibit severe
dysphonia.
Voice spectrograph gives further information on sound alteration, since it
produces a visual representation of a given set of sounds in the parameters of time,
frequency, and amplitude.
Aerodynamic Measures
Aerodynamic measures of voice include measures of air volume, air flow and sub
glottal air pressure. The normal aerodynamic parameters of voice vary considerably
among individuals, which leads to a large overlapping range of values between
dysphonic and non-dysphonic patients. This limits the use of these measures as a
diagnostic tool. Nonetheless, they are useful when used in adjunct with other voice
assessment measures, or as a tool for monitoring therapeutic effects over time.
Therapy
An effective treatment for spasmodic dysphonia is botulinum toxin (BoNT)

injection. The toxin acts by blocking acetylcholine release at the thyro-arytenoid
muscle. Although the use of botulinum toxin injections is considered relatively safe,
patients' responses to treatment differ in the initial stages; some have reported
experiencing swallowing problems and breathy voice quality as a side-effect to the
injections.
The literature in BoNT treatment of SD is marked by a notable scarcity of
controlled trials [2]. Despite the lack of clinical trial data, BoNT injections are
regarded by many as first-line treatment for SD primarily due to the degree of benefit
noted in open-label studies and lack of alternative treatment approaches. One
randomized, double-blind, parallel group study consisted of only 13 patients with
adductor spasmodic dysphonia who received saline or BoNT injections. Those in the
treatment group had significantly greater subjective and objective improvements in
dystonia. Adverse effects in the treatment group included excessive breathiness in
two patients and mild bleeding in one patient. Other data regarding BoNT treatment
of laryngeal dystonia primarily come from case series, including a 1300 patient
longitudinal case series over 24 years. Within this cohort, 82% of patients had

adductor (ADSD) and 17% had abductor spasmodic dysphonia (ABSD). Treatment
approaches were variable, including both unilateral and bilateral injections and
variation in timing, frequency, and dosing of BoNT. Overall, the ADSD patients
experienced an average duration of benefit of 15.1 weeks with most frequent side
effects of breathy voice (25%) and transient coughing when drinking fluids (10%).
The ABSD group experienced an average 10.5 weeks of benefit with most common
side effects of mild transient dysphagia of solids (6%) and mild exertional wheezing
(2%). Despite many years of clinical experience documented in open-label series,
well-designed trials are still needed to get a higher level of evidence for BoNT
treatment of laryngeal dystonia, particularly in less common presentations such as
ABSD.
The American Academy of Neurology (AAN) task force gathered in 2008
identified only one single class I study for adductor spasmodic dysphonia, leading to
a level B recommendation of BoNT in its treatment. It concluded there was
insufficient evidence to evaluate the use of BoNT in abductor spasmodic dysphonia
leading to a level U designation for this condition. The subsequent European
Federation of the Neurological Societies guidelines in 2011 confirmed that BoNT-A is
probably effective for adductor-type laryngeal dystonia, but there is insufficient
evidence to support efficacy in abductor-type laryngeal dystonia and in muscular
tension dysphonia. A recent longitudinal study further supported the efficacy of
recurrent BoNT-A injection with electromyographic guidance in drug-naïve patients
with adductor type SD [3].
Several different surgical approaches also are offered to patients with SD,
including myectomy targeting the thyroarytenoids, thyroplasty to alter the
cartilaginous structure of the larynx, or denervation-reinnervation procedures that cut
branches of the recurrent laryngeal nerve to the thyroarytenoid muscles and suture
the stump to the ansa cervicalis [2]. However, there are no controlled trials
addressing the safety and efficacy for these procedures.
SIALORREA
Sialorrhea, also known as drooling, is a debilitating symptom which occurs when

there is excess saliva in the mouth beyond the lip margin. Drooling is common in
normally developed babies but subsides between the ages 15 to 36 months with
establishment of salivary continence. Pathologic sialorrhea can be an isolated
phenomenon due to hypersalivation or occur in conjunction with several neurologic
disorders, characterized by reduced oral clearance mostly due to dysphagia, such as
amyotrophic lateral sclerosis (ALS), cerebral palsy (CP), Parkinson’s disease (PD),
or as a side effect of medications. In children, the most common cause of sialorrhea
is CP, which persists in 10%–38% of these individuals. In adults, PD is the most
common cause with 70%–80% of PD patients demonstrating sialorrhea. In 30%–
80% of schizophrenic patients, hypersalivation occurs when taking clozapine.

Within the neurological diseases, sialorrhea has been widely studied in patients
suffering from central nervous system diseases, generally neurodegenerative,
particularly in Parkinson's disease, where most therapeutic efforts have been
devoted.
Sialorrhea is a really disabling symptom, regardless of whether the origin is
central or peripheral. It is not only a problem in social interaction but also a significant
reduction in the patient's quality of life.
The clinical examination of the swallow is an essential part of the neurological
examination, being important in patients suffering from neuromuscular pathologies. It
will depend on the type of disease, as well as its severity and will inform us on the
evolution and clinical course [4].
Acting on dysphagia will be decisive, since it will allow us to reduce severe
complications, such as aspiration pneumonia and respiratory failure.
Swallowing is a complex process and needs the integrity of numerous functional
systems. It involves efficient coordination of several structures including the oral
cavity, pharynx, larynx, and oesophagus. These structures coordinate to form three
phases; an oral phase which is under voluntary control, followed by the pharyngeal
and oesophageal phases which are under involuntary control.
In addition, the oral phase, can be also divided into two subphases: the
preparatory oral phase and the oral transport phase. The pharyngeal phase is
characterized by four main components: deglutition, pharyngeal elevation, glottal
closure, and relaxation of the cricopharyngeal sphincter.
The neurological control of these phases is also multimodal since it requires the
integrity of cortical, subcortical and infratentorial structures, among which the medulla
oblongata occupies a preeminent position. Swallowing is a complex process,
involving exteroceptive, interoceptive, affective and cognitive differences.
Neurological control involves various centres: reticular formation, solitary tract
nucleus and the ambiguous nucleus. The latter centre exercises the function of
coordination, regulating the start of swallowing and synchronizing the different
phases. The efferent part would be represented by the lower cranial pairs (IX, X and
XII), together with the V and VII cranial pair [6].
The upper cortical control of swallowing is represented by several interconnected
brain areas: insula, premotor area, sensory-motor cortex, and cerebellum. A healthy
swallow requires not only the strength and coordination of the bulbar muscles but
also the correct functioning of the sensory, oesophageal, respiratory, and central
structures.
Salivary secretion, instead, is regulated via a reflex arch which has various
influences. The afferent branch consists of chemoreceptors in taste buds and
mechanoreceptors in the periodontal ligament. Afferent innervations of cranial nerves
V, VII, IX and X also play a role by carrying impulses to salivary nuclei in the medulla
oblongata. Efferent influences are mainly parasympathetic via cranial nerve VII which
control the submandibular, sublingual, and other minor glands, and CN IX which
influences the parotid gland.

Specifically, the secretory control of the salivary glands is mostly

parasympathetic. Innervation of the parotid gland is from the salivary nucleus via the
glossopharyngeal nerve, the tympanic plexus in the middle ear, the otic ganglion,
and the auriculotemporal nerve. The submandibular and sublingual glands receive
fibres carried by the facial nerve and chorda tympani, which originate in the superior
salivatory nucleus.
Numerous neuromuscular pathologies are accompanied by dysphagia, due to a
failure of the muscle, the nerve component, the neuromuscular junction, or the motor
neuron. This dysfunction will produce a disorder of swallowing and, therefore, of the
management of salivary secretions causing sialorrhea.
The daily secretion of saliva is around half a litre, on average. Unconsciously, we
swallow saliva, almost continuously, every 1, 2 or 3 minutes, depending on the
patient. In the unstimulated state, 70% of saliva is secreted by submandibular and
sublingual glands. Conversely, in the stimulated state the parotids glands provide
most of the saliva. The flow of saliva is five times greater in the stimulated state than
in the resting state. An example of an exogenous source causing stimulation is
chewing. The weakness of the bulbar and respiratory muscles, which are usually
involved in neuromuscular diseases, impairs to swallow saliva properly, causing
sialorrhea. Far beyond an aesthetic or social problem, sialorrhea represents a severe
medical problem. Furthermore, the dysphagia itself, in addition to pulmonary
complications (aspiration pneumonia, respiratory failure), usually generates
malnutrition and dehydration, as the patient is unable to feed and hydrate himself or
herself correctly, which leads to a situation of very significant medical fragility [4].
Sialorrhea is common in some neuromuscular diseases associated to severe
dysphagia. For instance, among the motor neuron diseases (MND), patients with
amyotrophic lateral sclerosis, especially its bulbar variant, patients with spinal
muscular atrophy and Spinal-bulbar muscular atrophy (Kennedy’s disease) often
complaint of sialorrhea. Degeneration of bulbar neurons in motor neuron diseases
causes weakness in orofacial and lingual muscles which can result in difficulties in
clearing oral secretions, leading to perioral ulcerations and risk of aspiration
pneumonia. The latter of these is the most harmful complication of MND and has
been associated with increased rates of hospitalization and reduced duration of
survival. Non-invasive ventilation (NIV) can prolong survival in patients with
amyotrophic lateral sclerosis (ALS), particularly in patients with spinal-onset ALS.
However, bulbar impairment and the presence of secretions in the airways can
reduce patients’ tolerance to NIV. In addition, NIV in the presence of sialorrhea, can
be ineffective or even produce severe complications, such as aspiration pneumonia
[7].
On the contrary, sialorrhea is less frequent in people with motor neuron diseases
secondary to infectious diseases, such as poliomyelitis. Muscular diseases,
especially those with bulbar muscle involvement, can cause sialorrhea. For instance,
muscular dystrophies, such as myotonic dystrophy, metabolic, mitochondrial, and
inflammatory myopathies. Analogously diseases affecting the neuromuscular
junction, such as myasthenia gravis and less frequently Eaton-Lambert syndrome,

should be considered as alterative cause of sialorrhea. Lastly, neuropathies affecting

the facial or the hypoglossal nerve should not be neglected in patients with
sialorrhea. In table 2 are listed the most common causes of sialorrhea.
A correct exploration of the dysphagia, as we have mentioned, is essential for the
correct approach to sialorrhea. Oral and pharyngeal phases are affected in
neuromuscular pathology, while the oesophageal phase is usually due to other types
of diseases (table 2).
Sialorrhea, in neuromuscular diseases, usually appears when the disease is
highly evolved and, therefore, dysphagia has made its appearance, both being of a
progressive nature. The first manifestations of dysphagia usually translate into
alterations in swallowing safety, in the form of coughing, throat clearing, voice
changes and desaturation during swallowing. Importantly, between 15 and 20% of
patients, bronchopulmonary aspirations can be silent, which implies the need for
early diagnosis of dysphagia [6].
Patients often adopt certain swallowing tricks, such as fractionated swallowing,
forced Valsalva manoeuvres or the adoption of specific swallowing positions.
Unlike diseases of the central nervous system, in which dysphagia initially
predominates with liquids, in neuromuscular pathologies, this predominance does not
exist.
Diagnosis
When we explore dysphagia, we start with the oral phase, reviewing problems in
the preparation and handling of the oral bolus, as well as in its containment and
propulsion.
In the pharyngeal phase, we must carefully explore the hyolaryngeal mobility, the
ascent of the larynx, the glottal closure and the capacity for laryngeal propulsion, until
the bolus reaches the upper oesophageal sphincter. The oesophageal phase, as we
have previously explained, would be outside the scope of the neurological
exploration.
At a second stage, it would be necessary to perform a volume-viscosity swallow
test (V-MECV), with oximeter control. This exploration is carried out by applying pins
of different textures to the patient, evaluating the safety, by detecting the alarm
symptoms already mentioned (coughing, throat clearing, etc.). In addition to clinical
assessment, different imaging techniques can be used, such as video-endoscopy
and video-fluoroscopy (technique of choice), which allow to visualize the entire
swallowing process and to determine the safety and efficacy of the deglutition
process. Finally, these techniques can be complemented by nuclear medicine
techniques, using radioisotope marking.

Therapy
The treatment of sialorrhea is multidisciplinary and presents several different

approaches [8].
The first line of treatment involves the use of anticholinergic drugs, used since
ancient times. The positive aspects of the use of anticholinergic drugs should be
noted, the broad experience in the use of these drugs and the convenience of their
application, in the form of oral tablets, sublingual presentations or transcutaneous
patches [9].
These drugs, with a muscarinic action, are used within a full spectrum of
indications; among their side effects, precisely because of the muscarinic
hyperfunction, they can produce dryness of the mouth and mucous membranes, due
to the decrease in saliva production. This secondary effect, however, in sialorrhea,
can be an essential benefit, by decreasing salivary production.
The five most used active ingredients are hyoscine (oral or transdermal),
amitriptyline (oral), atropine (sublingual or transdermal), oral propantheline and oral
glycopyrronium. Sometimes more than one anticholinergic can be combined
simultaneously. In general, the effectiveness of anticholinergics is around 40-60%,
with atropine in solution and hyoscine patches being the most used active
ingredients [9].
Unfortunately, the side effects of anticholinergic drugs limit their pharmacological
use, mainly in elderly patients. In fact, in addition to dry mucous membranes,
confusion, drowsiness, walking disorders and urinary retention are frequent causes
of treatment discontinuation.
Treatment with local radiotherapy is also a therapeutic option to be considered
[10].
Radiation therapy has proven to be an effective and long-lasting treatment for
sialorrhea, acting both functionally and structurally on the salivary glands.
In a recent review [8], the effectiveness and tolerance of this technique has been
evaluated in a significant number of patients, from several different studies.
Treatment with external beam radiation therapy (EBRT) was shown to be effective in
81% of patients, the most frequent therapeutic target being the lower two-thirds of
the parotid gland. Short-term toxicity was relatively high (40%), although in the long
term it was significant in only 12% of patients.
The treatment of sialorrhea with botulinum toxin, initially considered as a third
line, has been gaining ground, due to its high effectiveness, accessibility and scarcity
of side effects, when applied by expert hands [9].
Botulinum toxin works by blocking the release of acetylcholine in the peripheral
cholinergic nerve endings, in order to cleave SNAP-25, a protein necessary for the
adequate fixation and release of acetylcholine from the vesicles located in the nerve
endings. After injection, the toxin initially binds rapidly and with high affinity to specific
receptors on the cell surface. The toxin then passes through the plasma membrane
via receptor-mediated endocytosis and is released into the cytosol.

This last step is coupled with a progressive inhibition of acetylcholine release;

clinical signs are evident within 2-3 days, with a peak effect 5-6 weeks after injection.
Recovery after injection usually occurs within 12 weeks of injection as the nerve
endings branch out and connect back to the terminal plates. As for the salivary
glands, this cholinergic blockade produces a significant decrease in salivary
production, due to the involvement of the sympathetic nerve endings.
It can be performed with or without ultrasound control, due to the low anatomical
variability of the major salivary glands.
There are several commercial brands of botulinum toxin: Dysport®, which
diffuses 2-3 cm beyond its point of application, and therefore, is used mainly in large
skeletal muscles, Xeomin®, of lesser antigenicity, but similar diffusion to the previous
one, Neurobloc®, botulinum toxin type B, less used, and it is indicated mainly in
cervical dystonia and Botox®. The latter, due to its lower diffusion (around or less
than 2 cm) is mainly used in children, craniofacial dystonia, and chronic migraine
and, in general, when the target is small. Due to its lower diffusion to the injection
site, it tends to produce fewer side effects than the previous brands and is used, for
sialorrhea, with increasing frequency, even though there is wide clinical variability
and that the type of botulinum toxin used depends fundamentally on the experience
and personal preferences of the doctor who injects the toxin [9].
In the case of Botox®, to prevent the appearance of neutralizing antibodies, it is
necessary to apply the lowest possible effective doses and to respect at least 12
weeks between applications. One of the advantages, and at the same time
disadvantages, of the botulinum toxin is that its effect is reversible, so that, between
2 and 6 months, depending on the patient, its effect disappears, due to a local
reinnervation effect, which fights the cholinergic blockage, which forces the patient to
be injected periodically, to maintain the desired effect. However, in patients with long-
lasting botulinum toxin injections, a specific, irreversible effect is achieved, by
permanent partial chemical denervation, which is usually used to increase the
intervals of application, or to reduce the doses applied, which translates into greater
patient comfort and a lesser possibility of loss of effectiveness, due to the
appearance of neutralizing antibodies [11].
The points of application can be obtained through ultrasound control, or by
anatomical references. In the case of the parotid gland, as it is superficial and
extensive, it is relatively easy to locate, applying toxin at two key points: the first
point, one centimetre in front and below the tragus, and the second, lower, behind
the masseter, in front of the mastoid, following the mandibular branch. However,
ultrasound control is becoming more and more important, allowing the number of
injection points to be increased. In the case of the submaxillary glands, since the
application of botulinum toxin by anatomical reference is more complicated, injection
under ultrasound control is mandatory.
The doses of toxin applied are highly variable. For Botox®, they range from 7.5
to 50 units per parotid and 5-15 units for the submaxillary glands. Average doses of
Dysport® per parotid are around 60 units, while for Neurobloc® are 3000 units.

The side effects, when expert hands apply the toxin, are infrequent and not very
relevant, being the excessive mucous dryness and dysphagia, by diffusion to the
masseter, the most annoying, although they are always transitory.
The authors of this chapter generally opt for Botox®. Its lower diffusion allows the
injection to be more selective and, therefore, a lower diffusion to other anatomical
structures. Generally, a 30G type needle is used, which is painless for the patient,
and we systematically use ultrasound to control the application. However, it is true
that, in patients with parotid glands in a normal anatomical situation, application by
anatomical reference is safe and effective.
Other procedures, such as injection of ethanol or other toxic substances that
irreversibly depress the production of toxin, are in disuse.
Surgical procedures are usually one of the last options, reserved for very severe
cases, where all the previously mentioned therapies have failed. However, a recent
study [12] has shown them to be useful and safe, albeit in an adolescent population
and with central nervous system pathology.
Ligation of the submandibular duct is a surgical procedure that is even more
effective than botulinum toxin since it acts directly on the efferent duct and not on the
production. On the contrary, the fact that it is irreversible and has more side effects,
including serious events, makes it a last choice option.
Both partial or total surgical removal of the parotid and submaxillary glands are
entirely out of use, due to the possibility of severe adverse events, in addition to the
possible injury of nervous or vascular structures.
Finally, the adjuvant role of dysphagia rehabilitation should not be overlooked [6].
This therapy is not only useful for the dysphagia itself and the optimization of the
respiratory musculature but, secondarily, it can improve sialorrhea, although partially.
The strengthening of the orolingual and pharyngeal muscles, the exercises for the
control of the alimentary bolus and the swallowing reflexes favour and improve
swallowing, partially reducing sialorrhea. They also serve to protect the airway,
promote laryngeal closure, and facilitate the passage of the bolus [6]. Overall, these
techniques should complement any treatment for sialorrhea in neuromuscular
diseases.

Table 1. Neuromuscular disorders causing dysphonia.
Site of Lesion Neurologic Diseases Vocal/ Swallowing Symptoms Laryngeal Findings

Upper Motor Neuron (bilateral) Amyotrophic lateral sclerosis, Primary Strained voice, breathy voice, Spastic vocal fold paresis/ paralysis
lateral sclerosis, Pseudobulbar palsy laryngospasm, breathing, dysarthria
incoordination, altered prosody
Lower Motor Neuron Amyotrophic lateral sclerosis, Spinal Weak, breathy voice, hypernasal Flaccid vocal paresis/ paralysis, glottic
muscle atrophy speech, flaccid dysarthria, nasal insufficiency
Spinal-bulbar muscular atrophy regurgitation, oropharyngeal dysphagia,
altered prosody?
Extrapyramidal Parkinson’s Disease, Atypical Tremor, laryngeal dystonia, weak, Vocal fold bowing, tremor, dystonia,
Parkinsonism, Spasmodic dysphonia, breathy voice, monotone, dysphagia dysdiadochokinesia
laryngeal tremor
Peripheral Nerve Hereditary neuropathies (CMT-HMN), Weak, breathy voice, hypernasal Paresis/paralysis
immune-mediated neuropathies (GBS, speech, dysphagia, aspirations, pitch
CIDP), Vagal nerve, SLN, RLN injury. abnormalities
Myopathy Inflammatory myopathies, muscular Weak, breathy voice Paresis, flaccidity
dystrophies, isolated laryngeal myopathy
Neuromuscular Junction Disorder Myasthenia Gravis Weak, breathy voice, dysarthria, Fluctuating paresis/ paralysis
dysphagia, vocal fatigue, altered
resonance, hypernasal speech

Table 2 Causes of Sialorrhea
EXCESSIVE PRODUCTION
Conditions that can cause saliva overproduction include:
Pellagra (niacin or Vitamin B3 deficiency)
Gastroesophageal reflux disease
Gastroparesis (main symptoms are nausea, vomiting, and reflux)
Pregnancy
Excessive starch intake
Anxiety
Pancreatitis
Liver disease
Serotonin syndrome
Mouth ulcers
Oral infections
Sjögren syndrome
Medications that can cause overproduction of saliva include
aripiprazole, clozapine, pilocarpine, ketamine, potassium chlorate, risperidone, pyridostigmine
Substances that can cause hypersalivation include
mercury, copper, organophosphates (insecticide), arsenic, nicotine, thallium
DECREASED CLEARANCE
Neurologic
Cranial neuropathy (bilateral facial nerve palsy, hypoglossal nerve palsy)
Stroke
Parkinson’s Disease
Atypical Parkinsonism (Progressive Supranuclear Palsy, Multisystemic Atrophy)
Myasthenia Gravis and Eaton-Lambert disease
Motor Neuron Diseases (Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis, Spinal
Muscular Atrophy, Spinal-bulbar muscular atrophy)

Inflammatory myopathy (Polymyositis, Inclusion body myositis), Mitochondrial Myopathy
Muscular Dystrophy (Duchenne muscular dystrophy, Becker muscular dystrophy, Myotonic
Dystrophy, Oculo-pharyngeal muscular dystrophy)
DECREASED CLEARANCE
Cranial nerve palsies (Facial, hypoglossal nerves)
Acquired brain injury
Neurodevelopmental disorders (Cerebral palsy, Rett’s Syndrome, Down’s Syndrome, Intellectual
disability, Autistic spectrum disorders, Tic disorders)
Infections
Tonsillitis, retropharyngeal and peritonsillar abscesses, epiglottitis and mumps
Structural of the jaw
Fracture or dislocation
Radiation therapy

REFERENCES
[1] Stachler RJ, Francis DO, Schwartz SR, Damask CC, Digoy GP, Krouse HJ,
McCoy SJ, Ouellette DR, Patel RR, Reavis CCW, Smith LJ, Smith M, Strode
SW, Woo P, Nnacheta LC. (2018). Clinical Practice Guideline: Hoarseness
(Dysphonia) (Update). Otolaryngol Head Neck Surg, 158 (1_suppl):S1-S42.
[2] Ludlow CL. (2009). Treatment for spasmodic dysphonia: limitations of current
approaches. Curr Opin Otolaryngol Head Neck Surg, 17(3):160-5.
[3] Esposito M, Dubbioso R, Apisa P, Allocca R, Santoro L, Cesari U. (2015).
Spasmodic dysphonia follow-up with videolaryngoscopy and voice
spectrography during treatment with botulinum toxin. Neurol Sci, 36(9):1679-
82.
[4] Britton D, Karam C, Schindler JS. (2018). Swallowing and secretion
management in neuromuscular disease. Clin Chest Med, 39: 449-457.
[5] Engel AG, Franzini-Armstrong CF. (2004). Myology. New York. McGraw-Hill.
Third edition.
[6] Ibarra JI, Cutillas R, Fernández C. (2017). Rehabilitación en las enfermedades
neuromusculares. In: Manual de Enfermedades Neuromusculares. Gutiérrez-
Rivas, E, Editor. 541-550. Madrid. Ergon. [Rehabilitation in neuromuscular
diseases. In: Manual of Neuromuscular Diseases]
[7] Sahni AS, Wolfe L. (2018). Respiratory Care in Neuromuscular Diseases.
Respiratory Care, 63 (5): 601-608.
[8] McGeachan AJ, Hobson EV, Al-Chalabi A, Stephenson J, Chandran S,
Crawley F, Dick D, Donaghy C, Ellis CM, Gorrie G, Hanemann CO, Harrower
T, Jung A, Malaspina A, Morrison KE, Orrell RW, Talbot K, Turner MR,
Williams TL, Young CA, Shaw PJ, McDermott CJ. (2017). A multicentre
evaluation of oropharyngeal secretion management practices in amyotrophic
lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener, 18(1-2):1-9.
[9] Garuti G. Mandrioli J, Esquinas AM. (2016). Radiotherapy treatment of the
salivary glands, sialorrhea, and noninvasive mechanical ventilation in
amyotrophic lateral sclerosis: what are we doing? Journal of Neurology,
263(3):583-4.
[10] Hawkey N, Zaorsky N, Galloway T. (2016). The Role of Radiation Therapy in
the Management of Sialorrhea: A Systematic Review. Laryngoscope, 126 (1):
80-85.
[11] Glaser DA, Naumann K. (2009). Botulinum neurotoxin in the management of
Hyperhidrosis and other hypersecretory disorders. In Botulin Toxin.
Therapeutic clinical practice and science, edited by Jankovic J. 303-323.
Philadelphia. Saunders Elsevier.
[12] Bekkers S, Delsing CP, Kok SE, Van Hulst K, Erasmus CE, Scheffer A, Van
den Hoogen F. (2019). Randomized Controlled Trial Comparing Botulinumvs
Surgery for Drooling in Neurodisabilities. Neurology, 92(11): e1195-e1204.

Chapter 31
SCREENING AND EVALUATION TOOLS

OF DYSPHAGIA IN NEUROMUSCULAR DISORDERS
Maria Rosaria Valentino, MD Gerardo Langella, MD

and Valentina Di Spirito, MD
Monaldi Hospital – A.O. Dei Colli, Naples, Italy
ABSTRACT
Dysphagia, is one of the most critical problems in patients with

neuromuscular diseases. The lack of standardized assessment procedure to
detect earlier dysphagia in these patients, makes it harder prevention and gets
worse quality of life.
Various examinations have been developed and used to evaluate accurately
the swallowing function and different tools used to study dysphagia for each
NMDs. We can distinguish tools used in instrumental and non instrumental
examinations.
Keywords: dysphagia, instrumental examinations, non instrumental examinations,

amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD)
INTRODUCTION
Neuromuscular diseases (NMD) are a group of disorders that can modify the
swallowing pattern and that are characterized by impairment of the motor component
and by a change of the cell body of superior or inferior motor neurons, or both.

Corresponding Author’s E-mail: rosyvalentinodoc@gmail.com.

444 Maria Rosaria Valentino, Gerardo Langella and Valentina Di Spirito
Dysphagia, is one of the most critical problems in patients with neuromuscular

diseases (NMDs). It may vary with the natural course of the disease and either be
present from the early stages of the disease progression or appear with time in end-
stage patients.
Impaired swallowing can be related to increased morbidity and mortality, due to
severe complications, such as malnutrition, dehydration, aspiration pneumonia, and
other pulmonary sequelae [1].
The lack of standardized assessment procedure to detect earlier dysphagia in
these patients, makes it harder prevention and gets worse quality of life.
Actually, different assessment strategies are utilized in adult patients with NMDs
depending on the center, the country and the usual practices [2].
International guidelines concerning patients with NMDs only mentioned that
patients with a clinical history of swallowing difficulties or recurrent chest infections
should have a specialist assessment by a speech and language therapist (SLT) if the
swallow is thought to be unsafe [3].
Several studies have clearly shown that early signs related to dysphagia, such as
‘wet voice’, silent aspiration, or loss of weight, are often discreet and unclear and
dysphagia detection should contribute to earlier management, and possible
prevention, of comorbidities, and prolong survival of NMD patients. For this
evaluation, it also appears important to quantify the severity and progression of
dysphagia. An ideal swallowing assessment tool should offer quantitative measures
and be indicated for patients with NMDs with symptoms or underlying conditions
potentially associated with dysphagia to eliminate or minimize the complications of
dysphagia [1].
Various examinations have been developed and used to evaluate accurately the
swallowing function and different tools used to study dysphagia for each NMDs.
We will focus on techniques used in amyotrophic lateral sclerosis (ALS) and
Duchenne muscular dystrophy (DMD). In other NMDs, such as myotonic dystrophy
type 1 (DM1), inclusion body myositis (IBM), myasthenia gravis (MG), spinal
muscular atrophy (SMA), polymyositis/dermatomyositis (PM/DM), Friedreich’s ataxia
(FA) and spinal and bulbar muscular atrophy (SBMA), actually further studies are
needed and no firm conclusion can be made because of insufficient data and
heterogeneity of NMDs.
We can distinguish tools used to study dysphagia in instrumental and non
instrumental examinations. In the following paragraphs, we focus on the differences
between these techniques and their use in NMDs.
INSTRUMENTAL EXAMINATIONS
Videofluoroscopic swallowing study (VFSS) and fiberoptic endoscopic evaluation

of swallowing (FEES) are considered standard criteria for the evaluation of
swallowing problems in adult patients with non-NMD disorders [4].

Screening and Evaluation Tools of Dysphagia in Neuromuscular Disorders 445
Manometry, Surface electromyography (sEMG), electrophysiologically

submental/suprahyoid activity (SHEMG) and laryngeal-pharyngeal movements
(LPMs), maximum tongue pressure, Real-time magnetic resonance imaging (RT-
MRI) are also used.
The Videofluoroscopic swallowing study (VFSS), also reported as the modified
barium swallowing examination, is the most recommended test to evaluate
dysphagia, as it shows the real situation during swallowing, or as reference to
compare the other techniques [4].
In ALS, two generic scales are used for VFSS analysis, the dysphagia outcome
severity scale (DOSS) and the penetration aspiration score (PAS) [5].
Evaluation of swallowing kinematics seems to be one of the major advantages of
VFSS. It was observed that in patients with ALS, the oral phase seem the most affect
and pharyngeal contraction correlates with PAS and may play a role in penetration or
aspiration even in patients without bulbar symptoms. However, it has been
demonstred that aspiration or penetration is not common in those patients in the first
stages of the disease. When compared with FEES and manometry findings, VFSS
shows a significantly greater sensitivity (92%), to highlight swallowing impairment,
especially when silent in ALS and SMA patients.
In contrast, in many studies most of the nondysphagic patients also showed
radiological swallowing abnormalities indicating a low specificity.
In DMD patients, VFSS abnormalities seems to be related with advanced age,
except for impaired oral holding. VFSS is a better indicator for the oral phase of
swallowing and the pooling of contrast fluid in the valleculae than the ‘dysphagia
questionnaire’, a standard set of questions related to the frequency of 10 symptoms
of upper gastrointestinal dysfunction.
In MG, the abnormal laryngeal elevation observed during VFSS seems to be
significantly correlate with aspiration and may lead to predicting aspiration and
pneumonia [6].
However, across the different studies evaluating VFSS, a great variety of
methodological settings is observed in terms of thickness, viscosity and volume of
contrast fluids used.
There is a great heterogeneity in the VFSS procedures and analysis used,
depending on the procedure and bolus consistency used to assess swallowing in
adult patients.
There are considerable changes in physiology observed depending of the bolus
consistency (volume, viscosity, solid or fluid), size, method of ingestion (e.g., cup,
straw) and chemosensory input (taste, smell, sensory receptors) in the normal
swallow.Those properties need to be considered by the clinician during dysphagia
assessments when considering what is normal from what is pathological [7].
Classically, patients with solid food dysphagia are more likely to have disorders
of esophageal phase, whereas those with difficulty with liquids are more likely to
have oropharyngeal dysphagia. However, in NMD patients, this dichotomy may be
artificial because it is well known that those with oropharyngeal dysphagia can have

dysphagia for liquids and solids in the different phases of swallowing, specific
patterns of dysphagia depending on the underlying disease [8].
For example, DMD patients may have difficulties with chewing and
oropharyngeal transport of solid foods, as well as pharyngeal residue without
aspiration is more common and is likely due to muscle weakness.
In ALS, difficulties may likely be inability to hold bolus, reduced mastication,
residue in the oral cavity and delayed swallow reflex.
Moreover, all patients with NMDs may also have difficulty with management of
excessive thick mucus, which may contribute to breathing discomfort.
The use of bolus with different properties seems also extremely helpful in the
assessment of patients with NMDs in order to assess the further therapeutic and
dietetic management. Atually, there is not a standardization specifically for the
different NMDs.
Manometry is especially use in patients with ALS and SMA. It showes that an
abnormal upper esophageal sphincter (UES) opening and hypotonia of the proximal
pharynx is the most sensitive physiological signs of dysphagia (80%).
With this techinuque it is highlighted that patients present a greater number of
incomplete UES openings and a significantly extended ‘intra-bolus’ pharyngeal
pressure. As demonstrated in VFSS, dysphagia appeared to be linked to the
presence of a defective oropharyngeal phase of swallowing. The specificity of
pharyngo-esophageal manometry is weak (20%) [9].
Fiberoptic endoscopic evaluation of swallowing (FEES examination) is not
sensitive in highlighting swallowing alterations both in dysphagic and in
nondysphagic patients (53%) but has a good specificity to rule out other organic
causes of dysphagia (85%). During the exam, the participant remain seated while the
device is introduce into the more pervious nasal fossa without the use of a topical
anesthetic in order to avoid changes in local sensitivity. The nasal, pharyngeal and
laryngeal cavities are evaluated by observing the vocal folds during the sound
emission of the vowel /i/. Laryngeal sensitivity is tested by touching the bilateral
aryepiglottic folds and the arythenoid folds with the distal tip of the nasofibroscope.
Foods of standardized consistencies, i.e., pureed, thickened liquid and liquid, is used
in the videoendoscopic study of swallowing. Since 2015, the terminology used levels
2, 1 and 0, respectively, based on the International Dysphagia Diet Stardartization
Initiative (IDDSI) [10]. Posterior oral spillage, pharyngeal residues and
laryngotracheal penetration and/or aspiration is recorded for data collection.
Surface electromyography (sEMG)is usedto assess swallowing and dysphagia in
patients with DMD, ALS, DM1, PM/DM and MG. Someone use the dysphagia limit
(DL) to compare the peak duration and relative timing of muscle activity during
swallowing of four muscle groups (orbicularis oris, masseter, submental, and
infrahyoid muscles) in ALS, DM1, PM/DM and MG patients [11].
DL is a quantitative and noninvasive method for the assessment of swallowing
impairment. It represents the volume at which two or more swallows become
necessary to swallow the whole bolus. Values for DL are compared with the clinical
degrees of dysphagia, graded from 1 (no clinical signs and symptoms of dysphagia)

to 4 (obvious clinical signs and symptoms of dysphagia, including aspiration).

Patients with clinical dysphagia has abnormal DL.Also, DL can be useful to assess
the effect of treatment as well as changes of dysphagia over time.
During swallowing is demonstrated a relative activity of the orbicularis oris,
masseter, infrahyoid, and submental muscles. So can be useful test peak activity of
this muscle group. Thus, a distinction between a preserved and disordered
swallowing function in patients with DMD could be made.
Patients with DMD have usually to use a greater maximal muscle activity to
swallow [masseter orbicularis oris, submental], indicating muscle weakness [12].
Electrophysiologicallysubmental/suprahyoid activity (SHEMG) and laryngeal-
pharyngeal movements (LPMs) provide valuable information on physiological and
pathophysiological characteristics of human swallowing. In patients with dysphagic
ALS, is usually detected reduction of SHEMG and LPM.
Moreover, a decrease in swallowing reproducibility could be a preclinical sign of
dysphagia and, beyond a certain threshold, a pathological hallmark of oropharyngeal
dysphagia. Interestingly, SHEMG seem to be the only electrophysiological parameter
correlated with the disease duration and could be an expression of the progressive
degeneration of the motor neurons occurring in the course of the disease [13].
Overall, it was assessed the validity of maximum tongue pressure (MTP) in ALS
and SBMA patients. [18-19] Both used a digital tongue pressure manometer
equipped with a balloon probe (JMS Co. Ltd., Hiroshima, Japan) and asked the
participants to compress the balloon upward onto their palates for 7 seconds, three
times at 1-minute intervals, using the maximum voluntary effort of the tongue. The
maximum value of these three measurements was considered as the MTP for each
patient. Was evaluated the relationship between MTP and the characteristics of
swallowing disorders in patients with ALS. MTP was significantly lower in the patients
with ALS with reduced tongue function or with pharyngeal residue than in the
patients with normal characteristics. Bolus formation and oral and pharyngeal transit
time observed in VFSS were significantly prolonged among those with reduced MTP.
In SBMA, were described a decrease in patients within 3 years from the onset of
the disease compared with healthy controls. In comparison with VFSS, the values of
tongue pressure in the patients with laryngeal penetration were significantly smaller
than those of the patients without.
Real-time magnetic resonance imaging (RT-MRI) allowed precise time
measurements and identification of the respective tissue morphology.
Bolus retention in the pharyngeal tract is believed to be the most sensitive
indicator of functional deficits in swallowing and was reliably identified by all three
modalities (FEES, VF, RT-MRI).
Finally, some studies identified the cough volume acceleration (CVA), peak
expiratory flow rate (PEFR) and peak expiratory flow rise time (PEFRT) as significant
predictors of penetration/aspiration status in ALS patients.
Following these studies, ALS patients with a CVA less than 45.3 l/s2 were 5.6
times more likely to penetrate/aspirate. A PEFR lower than 4.0 l and a PEFRT
greater than 80 ms increased 3.6 and 3.2 times the risk of penetration/aspiration,

respectively.62 Those cutoffs for CVA, PEFR and PEFRT had sensitivities of 91.3%,
82.6%, and 73.9% respectively and, specificities of 82.2%, 73.9%, and 78.3% for
identifying ALS penetrator/aspirators.
Instrumental examinations (VFSS and FEES) showed good validity and should
be used for diagnosis or when aspiration status is unclear from noninvasive
approaches. VFSS also presents an important role in the follow up of aspiration
occurrence and the evaluation of the improvements related to the treatment, and
maybe the reduction of symptoms. On the other side, FEES can provide real-time
visual feedback during swallowing therapy contrary to VFSS. FEES may be helpful to
test many therapeutic interventions and many strategies without a time limit when the
patient’s intake and quality of life depend on a diet upgrade. FEES allows the
assessment of a meal in a functional, real-life situation. Fatigue increases can also
be checked as the meal progresses, but also if positioning, rate of intake, and
method of feeding impact the safety. Moreover, the study of Andersen and
colleagues has shown the interest of FEES in the assessment of the laryngeal
responses during treatment with mechanical insufflation-exsufflation.
Several details need to be highlighted about instrumental examinations.
First, the fatigability, an important factor in patients with NMDs with muscle
weakness. Tools only give a snapshot and do not consider factors such as fatigability
or ventilatory support needed.
Secondly, some assessments are invasive and can cause discomfort to the
patient (e.g., manometry and FEES), and potentially involves exposure to radiation
(e.g., in VFSS).
Finally, examinations that include large volumes of liquids may put the patient at
risk of aspiration and choking.
In addition, VFSS, MRI or FEES are often not possible in daily routine or in out-
of-hospital settings such as physiotherapist and SLT practices due to the required
expertise, the patient compliance, and the evolution of the swallowing disorder which
can be sometimes rapidly progressive. In regular follow-up assessments, even if the
specific equipment needed may be considerate expensive, 2 the cost burden is often
distributed among departments (radiology, gastroenterology, or otolaryngology).
NON INSTRUMENTAL EXAMINATIONS
Noninstrumental examinations, done subjectively or by self-administration, can

be interesting alternatives for screening, follow up or complementation of
instrumental evaluations in the diagnosis. These may be useful, in particular, in the
assessment of the fluctuating nature of the motor and emotional symptoms in NMDs
and their impact on quality of life [15].

The eating assessment tool 10 (EAT-10), a 10-question selfadministered,

symptom-specific dysphagia outcome tool to score patients with ALS.
The total EAT-10 score is calculated with scores ranging from 0 (no impairment)
to 40 (severe impairment) and demonstrated good discriminant ability to accurately
identify ALS penetrator/ aspirators (PAS ⩾ 3) with a cutoff score of 3.
It demonstrated excellent accuracy at identifying aspirators (PAS ⩾ 6) utilizing a
cutoff score of 8.
On average, EAT-10 scores were five times higher in ALS aspirators than in
those patients who demonstrated safe swallowing.
The neuromuscular disease swallowing status scale (NdSSS), an 8-stage scale
for dysphagia in patients with progressive NMD, is correlated with PAS significantly
in patients with ALS but not in DMD patients.
Another examination, the volume-viscosity swallow test (V-VST) showed a high
sensitivity and specificity (93% and 80%, respectively) for screening and diagnosing
oropharyngeal dysphagia in patients with ALS. The V-VST involved administering
increasing fluid volumes of different textures/thicknesses and the assessment of
efficiency and safety of swallowing.
In DMD patients, the Sydney swallow questionnaire (SSQ),19 a self-administered
questionnaire based on 17 questions using visual analogue scales, detected
dysphagia with good sensitivity and specificity (78 and 83%, respectively) at a cutoff
score of 234 (total maximum score = 1700).
The 3-ounce water swallow test (3SwT), validated previously in other patient
groups (e.g., stroke, head and neck surgery, Parkinson’s disease, dementia), 58, 64,
65 was compared with VFSS and a 25-item form (one of them is ‘history of cough’),
identifying dysphagia. The 3Swt showed a higher specificity than clinical signs (86
versus 30%) but a lower sensitivity (52%) compared with VFSS in patients with
NMD.47 The association of ‘history of cough’ (coughing episode reported by the
patient) with the 3SwT gives an increase in both positive and negative predictive
values (84 and 76%, respectively).
From a clinical point of view, following the definition outlined previously, we can
consider that noninstrumental examinations (SSQ, V-VST, EAT-10 and 3SwT),
voluntary cough airflow (VCA) and sEMG represent ideal screening or follow-up tools
with high sensitivity and specificity and are quick, cost-effective, and easy to
interpret. Moreover, they give accurate cutoff scores and are more effective to detect
early swallowing problems or risk factors. Validated self-reported questionnaires
have been increasingly used in clinical research as well as clinical practice to capture
the individual’s perspective regarding their disease symptoms. When identified by the
screening tool, the patient should be referred for diagnosis of swallowing disorders,
conducted from clinical evaluation and supplemented, when necessary [15].

Table 1. Tools used to study dysphagia in each NMD
Underlying diseases Tools

ALS VFSS, sEMG (DL),FEES, V-VST, Man., VCA, 3SwT, NdSSS,
MTP,EAT-10
DMD VFSS, SSQ, sEMG, NdSSS
DM1 FEES, sEMG (DL), 3Sw
MG sEMG (DL), VFSS
IBM Standard Questionnaire, RT-MRI
SMA VFSS, Man., FEES
PM/DM sEMG (DL)
FA 3SwT
SBMA MTP M
3SwT, 3-ounce water swallow test; ALS, amyotrophic lateral sclerosis; DL, dysphagia limit; DM1,
myotonic dystrophy type 1; DMD, Duchene muscular dystrophy; EAT-10, eating assessment tool;
FA, Friedreich’s ataxia; FEES, fiberoptic endoscopic evaluation of swallowing; IBM, inclusion body
myositis; Man., pharyngo-esophageal manometry; MG, myasthenia gravis; MTP, maximum tongue
pressure; NdSSS, neuromuscular disease swallowing status scale; NMD, neuromuscular disease;
PM/DM, polymyositis/dermatomyositis; RT-MRI, real-time magnetic resonance imaging; SBMA,
spinal and bulbar muscular atrophy; sEMG, surface electromyography; SMA, spinal muscular
atrophy; SSQ, Sydney Swallow Questionnaire; VCA, voluntary cough airflow; VFSS,
videofluoroscopic swallow study; V-VST, volume-viscosity swallow test.
CONCLUSION
Further studies are needed to standardize assessment procedures (tools,

settings and chronology) according to the evolution and the specificities of each adult
patient with an NMD.
There is no universally accepted strategy in the management of NMD patients
but it would be relevant to adapt tools to the timing of occurrence and evolution of the
disease and to recognize specific clinical profiles for the different disease and guide
the detection of swallowing disorders. Diagnosis aims to determine presence of
dysphagia, its severity and changes that it may cause, and the rehabilitation plan.
With new treatments (like noninvasive ventilation), life expectancy of patients
with NMDs continues to increase. It will be more and more important in the future to
deal with associated complications such as swallowing impairments.
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[2] Britton D, Karam C and Schindler JS. Swallowing and Secretion Management
in Neuromuscular Disease. Clin. Chest. Med. 2018; 39: 449–457.
[3] Willig TN, Paulus J, Lacau Saint Guily J, et al. Swallowing problems in
neuromuscular disorders. Arch. Phys. Med. Rehabil. 1994; 75: 1175–1181.
[4] Peng J. Imaging features of advanceaged dysphagia patients and risk factors
for swallowing. Chin. J. Geriatr. Heart Brain Vessel Dis. 2015;17:53–54.
[5] O’Neil KH, Purdy M, Falk J. The dysphagia outcome and severity scale., et al.
Dysphagia 1999; 14: 139–145.
[6] Higo R, Nito T and Tayama N. Videofluoroscopic assessment of swallowing
function in patients with myasthenia gravis. J. Neurol. Sci. 2005; 231: 45–48.
[7] Cichero JAY and Murdoch BE. Chichester. Dysphagia: foundation, theory and
practice., England; New York: Wiley, 2006. 74.
[8] Logemann JA. The dysphagia diagnostic procedure as a treatment efficacy
trial. Clin. Commun. Disord. 1993; 3: 1–10.
[9] Groher ME and Crary MA. Dysphagia: clinical management in adults and
children.Maryland Heights, Mo.: Mosby Elsevier, 2010.
[10] Jani MP and Gore GB. Swallowing characteristics in Amyotrophic Lateral
Sclerosis. Neurorehabilitation 2016; 39: 27.
[11] Briani C, Marcon M, Ermani M, et al. Radiological evidence of subclinical
dysphagia in motor neuron disease. J. Neurol. 1998; 245: 211–216.
[12] National dysphagia diet: standardization for optimal care. ADA: American
Dietetic Association. Chicago: ADA; 2002.
[13] Cosentino G, Alfonsi E, Mainardi L, et al. The importance of the reproducibility
of oropharyngeal swallowing in amyotrophic lateral sclerosis. An
electrophysiological study. Clin. Neurophysiol. 2017; 128: 792–798.
[14] Archer SK, Garrod R, Hart N, et al. Dysphagia in Duchenne muscular
dystrophy assessed objectively by surface electromyography. Dysphagia 2013;
28: 188–198.
[15] Manor Y, Giladi N, Cohen A, et al. Validation of a swallowing disturbance
questionnaire for detecting dysphagia in patients with Parkinson’s disease.
Mov. Disord. 2007; 22: 1917–1921.

Chapter 32
ASPIRATION TREATMENT
AND DECISIONAL ALGORITHM
Maurizia Lanza*, MD
Unit of Respiratory Physiopathology, Monaldi Hospital, Naples, Italy
ABSTRACT
The neuromuscular disease (NMD) often leads to difficulty swallowing

(dysphagia) and managing secretions (salivation and/or excessive mucus thick).
The prevalence of dysphagia in people with muscle diseases is difficult to
determine and is not known precisely. Eating problems often develop insidiously
and people can compensate for abnormal swallowing when it is measured
objectively. We know that dysphagia can be diagnosed based on a symptom,
clinical sign, radiological sign, or as a cause of nutritional or respiratory problems.
Dysphagia in chronic muscle disease is mainly caused by muscle weakness. The
weakness of the tongue, face and jaw or abnormal architecture of the mouth can
affect the ability to properly prepare a bolus and retrieve bolus particles. Normal
swallowing is usually divided into three phases: oral, pharyngeal and
oesophageal. When food is prepared from the lips, tongue and teeth to form a
bolus projected backwards from the tongue, we are in the oral phase. At this
stage, the protection of the airway is obtained by closing the larynx. The larynx
and forward-resulting upward movement provides additional protection to the
airways, but especially opens the upper oesophageal sphincter. A fall in pressure
in the upper oesophageal sphincter moves the bolus from the base of the tongue
to the lower pharynx and upper oesophagus. A wave of peristalsis initiated by
contact of the base of the tongue and pharynx free from residual bolus.In
addition, in the base of the tongue and the posterior pharyngeal wall free the
pharynx of bolus residues; this constitutes the transition from the pharyngeal
phase to the oesophageal phase. Usually, laryngeal penetration occurs with the
passage of the laryngeal vestibule but not beyond the vocal cords.
Simultaneously, suction is typically defined as the passage of the bolus beyond
*
Corresponding Author’s E-mail: maurizia.lanza85@gmail.com.

454 Maurizia Lanza
the vocal cords. Palatal weakness may predispose to nasal regurgitation. The
weakness of the suprahyoid muscles leads to an alteration of the upper
oesophageal sphincter, which in turn leads to altered bolus transit, accumulation
of the bolus in the pharynx and an increased risk of aspiration into the larynx.
Muscle weakness can also affect laryngeal function, affecting laryngeal closure
and coughing. Because of this muscle weakness of the airway defence
mechanisms and the impaired cough reflex that goes with it, it predisposes to
respiratory complications. Despite the obvious importance of maintaining
adequate nutritional intake in people with muscle diseases, the evidence for
optimal management of this problem are extremely scarce and largely anecdotal.
The main treatment options available are food handling, safe swallowing
techniques, surgery and enteral feeding.
Keywords: neuromuscular disease, dysphagia, sialorrhea, amyotrophic lateral

sclerosis, dystrophy
ABBREVIATIONS
NMD Neuromuscular disease

UES Upper oesophageal sphincter
OPMD Oculopharyngeal muscular dystrophy
IBM Inclusion body myositis
FEES Fibreoptic endoscopic evaluation of swallowing
MBSS Modified barium swallow
OVERVIEW OF DYSPHAGIA ASSOCIATED

WITH NEUROMUSCULAR DISEASE
Specific patterns of dysphagia associated with NMD reflect the underlying

disease. Therefore, these patterns vary depending on several factors, including the
disorder’s characteristics, severity, natural course or stage of progression, and the
options for intervention. For example, dysphagia in some NMDs, such as Duchenne
muscular dystrophy, progresses relatively slowly, while others, such as amyotrophic
lateral sclerosis (ALS), often progress rapidly [1]. Dysphagia in myasthenic patients
tends to fluctuate. It is typically reversible with proper treatment of the disease [2].
Also, the pattern of impairments related to swallowing reflects the neuromuscular
weakness pattern. For example, reduced speed, aspiration (even silent aspiration),
coughing and choking, upper oesophageal sphincter hypertonicity (UES), and
laryngospasm in individuals with ALS are related to the combination of spastic and
flaccid weakness associated with ALS [3].

Aspiration Treatment and Decisional Algorithm 455
However, in Duchenne muscular dystrophy, a model with oropharyngeal difficulty

chewing and transporting solid food and pharyngeal residue without aspiration is
common. This is likely due to the flaccid weakness of the jaw, tongue and pharyngeal
muscles [4]. The weakness of the respiratory muscles associated with NMD leads to
restrictive lung disease and reduced coughing ability, contributing to the risk of
dysphagia, aspiration pneumonia and other pulmonary complications. It can also
disrupt breathing and swallowing. When these respiratory impairments are combined
with bulbar damage, the impact on swallowing and on lung defences can be
synergistic, even lethal [5]. The ability to cough requires active coordination of the
respiratory muscles and intrinsic laryngeal muscles. The impaired bulbar and
respiratory muscles can utilise compensatory strategies for ineffective cough when
the protective defence is needed against cough to protect the lungs from aspiration.
Excessive saliva or drooling frequently occurs with dysphagia and manifests as
difficulty in swallowing and eliminating normal secretions, rather than an increase in
salivary flow. The increase in salivary flow is challenging to treat, even
pharmacologically. Simultaneously, there is a reduction in the frequency of automatic
saliva swallowing in patients with dysphagia. Also, individuals with dysphagia due to
NMD may have difficulty with the management of too much thick mucus, which can
contribute to respiratory distress [6].
In conditions such as oculopharyngeal muscular dystrophy (OPMD), dysphagia is
part of a complex of symptoms, to a certain extent, in all those who are suffering from
the condition. OPMD is a late-onset autosomal dominant or autosomal recessive
inherited disease related to expanded GCG repeats in the PABPN1 gene and with
rimmed vacuoles in muscle biopsy; the muscles of voluntary swallowing, including
those used for speech, are affected in this condition [7], and in rare cases, there is
evidence of involvement of the peripheral nervous system. Oropharyngeal dysphagia
is a common feature of MD type I, the most prevalent inherited neuromuscular
disorder; MD type I is associated with expanded CTG repeats in the DMPK gene.
Oropharyngeal dysphagia is less common in type II MD, associated with mutations in
the CCTG ZNF9 repeat sequence in the gene. The presentation of oropharyngeal
dysphagia in MD has been attributed to myopathic weakness in control and bolus
formation, muscle myotonia with warming, as well as possible involvement of the
central nervous system in the reflections of delayed swallowing [8].
Other chronic muscle diseases that cannot be treated and are often associated
with dysphagia include the inclusion body myositis (IBM), advanced Duchenne
muscular dystrophy (DMD) and some types of metabolic myopathy. The congenital
myopathies are less commonly associated with difficulty swallowing. The cause of
dysphagia in DMD has been attributed to oral muscle weakness and changes in
facial and dental morphology [9]. A combination of reduced muscle function and
reduced cricopharyngeal sphincter opening has been implicated in cases of
dysphagia in IBM [10]. Table 1 outlines the literature describing the prevalence of
dysphagia in selected NMDs.

456 Maurizia Lanza
Table 1. Prevalence of dysphagia in selected neuromuscular disease
Examples Prevalence
Inclusion body myositis 65% to 80%
Duchenne muscular dystrophy Unknown; 30% report dysphagia >95% based on
(muscle level) MBSS findings; greater with advancing age
Myasthenia gravis 30% as an early symptom
(neuromuscular junction (up to two-thirds of individuals with myasthenia
disease) gravis)
Amyotrophic lateral sclerosis 95%-98% bulbar onset; 35%-73% spinal onset
(motor neuron disease)
Abbreviations: CNS, central nervous system; MBSS, modified barium swallow study.
PATIENT EVALUATION OVERVIEW
The assessment and clinical intervention of swallowing are indicated for

individuals with symptoms and/or underlying conditions potentially associated with
dysphagia to eliminate or minimise dysphagia complications. For individuals who are
asymptomatic, but at risk of dysphagia, validated dysphagia screening tools can
identify the need for an evaluation of swallowing. However, it is necessary to further
the development of swallowing screening tools for NMD populations. In the United
States, speech therapists evaluate oral and pharyngeal swallowing problems in
adults. Gastroenterologists assess the problems of the oesophageal phase. A clinical
examination of swallowing, supplemented by a speech therapist, includes three
components [11]: (1) obtain information through medical records, interviews with the
individual and family or health workers, (2) examination of the oral mechanism,
including bulbar cranial nerve function, muscle strength and coordination, and
observation of intraoral tissues and teeth and (3) observations during swallowing of
food or liquids, depending on the patient’s tolerance. The clinical examination of
swallowing provides information about the underlying neuromuscular function that
leads to dysphagia symptoms, the potential benefit and timing for further instrumental
studies, the prognosis for improvement in swallowing function, and the potential to
benefit from surgery. For individuals with progressive NMD, it is useful to periodic
reassessment to monitor the progression of dysphagia and update the
recommendations. A specific limitation of clinical swallowing examination is the
inability to definitively determine the presence of aspiration and other aspects of
pharyngeal swallowing [12]. However, some observations from the clinical
examination of swallowing may be associated with an increased risk of aspiration,
such as impaired lingual mobility [13] and a reduced frequency of spontaneous
swallowing (6). Besides, dysphagia experts can have an informed sense of potential
swallowing disorders based on what is known about related dysphagia models with
regard to the underlying condition. Some patients may experience significant
dysphagia without suction. For example, the obstruction of the pharyngeal or
oesophageal phase to the bolus flow can lead to regurgitation without suction;

however, the residue of the pharyngeal or oesophageal phase can increase the risk
of aspiration of the residue after the ingestion. This type of post-delayed swallowing
suction can pass unnoticed by instrumental studies, such as the study of the
modified barium swallow (MBSS). The risk of developing aspiration pneumonia is not
determined solely by the presence or absence of aspiration. The clinical examination
of swallowing may reveal factors associated with a higher risk of pneumonia,
including impairment of basic lung defences, such as compromised protective
reflexes, cough capacity, mucociliary clearance and/or immunological defences [14].
Since the risk of pneumonia is multifactorial, aspiration is only one of many important
factors in determining tolerance for safe oral intake. Instrumental evaluation, such as
dynamic imaging of the swallowing mechanism by MBSS or fibre-optic endoscopic
evaluation of swallowing (FEES), or dynamic evaluation of swallowing related
through pressure manometry, can provide additional objective information on aspects
of swallowing function. Current guidelines regarding when to recommend diagnostic
imaging of dysphagia are largely based on expert opinion documented with a
guideline from the American Speech-Language-Hearing Association (15) and
continue to be debated. Imaging is needed when clinical examination is inconsistent
or inadequate. Below are the advantages and limitations of MBSS over FEES,
respectively:
MBSS provides assessment of the following:
 Dynamic swallowing biomechanics across all phases of swallowing: oral,

pharyngeal and oesophageal
 Airway protection before, during and after swallowing
 Oropharyngeal residue, as well as underlying patterns and contributing
factors to residue and aspiration
 Adequacy of upper oesophageal sphincter opening
 Submucosal structural abnormalities, for example, osteophytes
 Effectiveness of postural adjustments, manoeuvres, texture modification and
other intervention strategies on swallowing safety and efficiency
FEES provides assessment of the following:
 Hypopharynx and anatomy of the laryngeal surface, including the adequacy

of glottic closure
 Abnormalities of the mucosa
 Pooled saliva or secretions
 Laryngeal sensation
 Adequacy of velopharyngeal closure
 Transportable system
 No adverse complications with repeated examinations or longer (no radiation
exposure)

458 Maurizia Lanza
 It can be used as a means of therapeutic biofeedback
Limitations of MBSS:
 Constraints on study time and repeated examinations to minimise radiation

exposure
 Unnatural food (contrast agent, i.e., barium) and environment
 Unable to view accumulated saliva or secretions
Limitations of FESS:
 The oral and oesophageal phases are not displayed

 Displaying limited opening of the upper oesophageal sphincter
 Biodynamics swallowing can not be observed
However, other considerations include the availability of tools and skills needed
for assessment, which may differ between institutions and locations, and the
individual’s ability to participate adequately with various forms of assessment. For
example, many rural clinics, as well as urban nursing facilities, do not have access to
MBSS or providers capable of performing FEES. A variety of factors can also
preclude the ability to participate in instrumental evaluation, such as the need for
intensive monitoring in the ICU, mobility problems, and behavioural or cognitive
problems that affect the ability to cooperate with instrumental evaluation. Finally, it
can be difficult to determine the optimal timing of instrumental evaluation for
individuals with progressive NMD because dysphagia continues to progress and
changes after the assessment.
THE INTERVENTION FOR DYSPHAGIA ASSOCIATED

WITH NEUROMUSCULAR DISEASE
A primary purpose of dysphagia treatment is to reduce the risk of aspiration

pneumonia and other complications of dysphagia. The goals vary according to the
specific biomechanical aspects of dysphagia of an individual, the natural course of
the underlying disease and the individual’s preferences. In developing intervention
plans for each patient, doctors assess the results of clinical research trials, which are
often limited in scope and applicability to patients with a unique set of comorbidities,
along with pathophysiological reasoning, clinical experience, consideration of patient
preferences and available family and resources. Generally, the first step is to change
the consistency of food and liquids and add appropriate dietary supplements [16].
The drug treatment options for dysphagia in individuals with NMD fall into three
categories: (1) interventions for neurological disease, (2) management of symptoms

and (3) management of contributing factors, such as reflux. Since dysphagia occurs
as a result of disease, surgery to improve the underlying condition can also lead to
an improvement in swallowing. An example of this type of improvement is in
myasthenia gravis, an autoimmune disease that causes global weakness that often
leads to dysphagia. Swallowing typically improves after the control of the disease
with drugs such as pyridostigmine and/or immunosuppression [17]. In conditions
such as ALS, for which there are very few medical or pharmaceutical options for
slowing progression, there are limited options for slowing the progression of the
underlying dysphagia. For patients struggling with sialorrhea and/or excessive thick
mucus, pharmacologic management may aid the balance between the extremes of
dryness or excessive secretions. As an adjunct to behavioural management
techniques and/or the use of a suction machine, oral or transdermal medications may
offer relief. For sialorrhea, medications with drying side effects are used, such as
amitriptyline (Elavil), scopolamine (transdermal hyoscine), atropine and/or
glycopyrrolate (Robinul). For the control of excessive thick mucus, medications to
thin out saliva (e.g., guaifenesin) without additional drying are helpful. Botulinum
toxin injections (Botox, Myobloc, etc.) are sometimes used to temporarily relieve a
variety of dysphagia symptoms, including inadequate relaxation of the UES [18] and
severe drooling. Injections of botulinum to the parotid glands can be useful for the
most severe cases of sialorrhea. However, some researchers have reported concern
that the injection of botulinum toxin may spread and further weaken the muscles
required for swallowing. Irradiation of the salivary glands is sometimes also
considered in severe cases, usually when the abovementioned management
techniques are ineffective [19].
Non-drug treatments fall into two categories: (1) behavioural management and
maintenance strategies that offer an immediate counteractive effect of the
neurological condition on swallowing and (2) rehabilitation interventions that seek to
improve or restore swallowing function. The best intervention plans include both
components. Behavioural management approaches include a variety of
compensatory strategies, such as diet modification, sensory stimulation, position or
posture adjustments, swallowing manoeuvres, saliva management, respiratory
support, cough assistance and nutritional management. Specific recommended
strategies depend on the underlying impairments contributing to dysphagia. For
example, thickening agents in water may be suggested for individuals aspirating thin
fluids due to spastic weakness and slow laryngeal closing. Another example is the
strategy of an ipsilateral head turn, which can reduce pharyngeal residues in
individuals with unilateral pharyngeal and/or laryngeal weakness [20]. Additionally,
manual cough assisting strategies and/or use of mechanical insufflation and
exsufflation will help the key lung defence of effective coughing in individuals with
weakened abdominal muscles. Prevention strategies also fall under this heading. For
example, optimal oral hygiene (including regular mechanical cleaning of the teeth,
tongue and palate) has been linked to a reduced risk of pneumonia. Positional
strategies and/or the use of aspiration can be used to facilitate oral hygiene when
there is concern about aspiration. Rehabilitation interventions for dysphagia include

460 Maurizia Lanza
exercises to improve the strength, ability, or biomechanical support needed for

swallowing. In accordance with the principles of specificity of neural and muscular
plasticity and ‘use it or lose it’, swallowing is the best exercise for swallowing [21].
The complete cessation of swallowing can weaken the necessary musculature due to
disuse. If not, it is worth keeping an individual swallowing safely, even if limited. For
the principle of transference, exercises aimed at strengthening the underlying
musculature beyond the normal use level can benefit the function of swallowing and
the functional reserve needed for the resistance to swallowing. The recommended
exercises are very important [22]. The three main active interventions used in the
treatment of dysphagia are (1) cricopharyngealmiotomy (CPM) (surgical division of
the cricopharyngeal muscle), (2) botulinum toxin injection of the cricopharyngeal
muscle, and (3) oesophageal dilation of the upper oesophageal sphincter.
Videofluoroscopy often shows that the cricopharyngeal muscle is apparently
hypertrophied or in spasm, making it a popular target for interventional therapy.
Muscle myotomy has gained popularity as a treatment for a series of swallowing
disorders. However, the evidence of benefit is based on retrospective reports of a
small number of people with a variety of disorders, evaluated inconsistently before
and after the procedure and followed only for a short period of time. More recently,
botulinum toxin has been injected directly into the cricopharyngeal muscle to
temporarily weaken the muscle [23]. Finally, a study reports that balloon dilation of
the upper oesophageal sphincter may be helpful in some muscle diseases,
particularly OPMD, with modest improvement in dysphagia in over 50% of people
with moderate to severe symptoms [24]. Enteral feeding may be considered for a
number of reasons: to try to prevent recurrent aspiration, to supplement or replace
oral intake, or to aid in the administration of drugs and fluids. The preferred method is
the insertion of a percutaneous endoscopic gastrostomy tube (PEG) because it is
more aesthetically acceptable and may be more effective in reducing suction than a
nasogastric tube [25].
CONCLUSION
NMDs frequently appear with dysphagia and sialorrhea. Because dysphagia is a

symptom of the underlying condition, the characteristics of swallowing saliva or
management impairments vary with the ordinary development of the underlying
NMD. Treatment options depend on the underlying characteristics of the individual’s
dysphagia and the underlying causal condition and may include behavioural,
pharmacologic, and/or surgical interventions. Dysphagia intervention aims to reduce
the risk of dysphagia-related medical complications, to increase participation in life
activities involving the intake of food, and to improve quality of life.

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[14] Happel KI, Bagby GJ, Nelson S. Defense of the host and bacterial pneumonia.
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[16] Low J, Wyles C, Wilkinson T, Sainsbury R. The effect of compliance on clinical

outcomes for patients with dysphagia on videofluoroscopy. Dysphagia
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[17] Shoesmith C, Nicolle MW. Myasthenia gravis (MG). In: Jones H, Rosenbek J,
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[18] Restivo DA, Marchese-Ragona R, Patti F, et al. Botulinum toxin improves
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[22] Burkhead LM, Sapienza CM, Rosenbek JC. Strength-training exercise in
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Chapter 33
INFECTIONS IN NEUROMUSCOLAR DISEASE

PATIENTS: A POINT IN THE RIGHT DIRECTION
Novella Carannante1,, MD, Eugenio Piscitelli2,†, , MD

and Giuseppe Fiorentino3,‡, MD
1
Emergency Infectious Disease, Cotugno Hospital, AO Ospedali dei Colli,
Naples, Italy
2
Intensive Care Unit and ECMO, Monaldi Hospital, AO Ospedali dei Colli,
Naples, Italy
3
UOC Fisiopatologia e Riabilitazione Respiratoria, Monaldi Hospital,
AO Ospedali dei Colli, Naples, Italy
ABSTRACT
Neuromuscular disorders comprise a diverse group of inherited and acquired

disease. The consequences of progressive muscle weakness include impaired
cough and secretion clearance, restrictive lung disease, dysphagia and
aspiration, recurrent respiratory infections, airway obstruction and sleep
disordered breathing, and leading to alveolar hypoventilation and respiratory
failure is a frequent cause of death.
Infections with related acute respiratory failure is the common reason for
hospitalizations, and chronic respiratory failure is a frequent cause of death. A
coordinated multidisciplinary care has led to improved survival outcome in recent
decades.

Corresponding Author’s E-mail: Carannantenovella@gmail.com.
†
Corresponding Author’s E-mail: Eugenio.piscitelli@libero.it.
‡ Corresponding Author’s E-mail: giuseppefiorentino1@gmail.com.

464 Novella Carannante, Eugenio Piscitelli and Giuseppe Fiorentino
PNEUMONIA AND PNEUMONIA IN NMD
Community Infection pneumonia: diagnosed at the time of admission or within

the first 48 hours in a patient without assistance contacts.
From an epidemiological point of view, Streptococcus pneumoniae is still the
most relevant pathogen, followed by significant infections caused by H. influenzae
and Moraxella catharralis.
A multiplicity of infectious agents, of a viral and bacterial nature, circulates in the
human population and causes, with particular epidemiological relevance,
manifestations of respiratory infection in the period between October and April,
although, in other seasonal periods, respiratory forms mostly caused by so-called
atypical respiratory pathogens (such as Mycoplasma pneumoniae, Chlamydia
pneumoniae and Legionella spp.) which probably also exert a predisposing function
for a second bacterial infection, occupying - in a hypothetical top ten of the
aetiologies - the positions of immediate reinforcement. About 10% of hospitalized
CAPs require hospitalization in intensive care units (ICU), especially for forms
sustained mainly by S. pneumoniae and Legionella spp.
Similar considerations deserve viral infections that are sustained by a large
number of agents: influenza A and B virus, respiratory syncytial virus (RSV),
Rhinovirus (HRV), coronavirus (hCoV), metapneumovirus (hMPV), parainfluenza
virus (hPIV), adenovirus (ADV), measles virus.
Healthcare-related infection: nosocomial, onset 48 hours after hospitalization;
non-nosocomial, onset within 48 h of hospitalization in patients with previous care
contacts such as 1) nursing or home IV therapy, wound care, hemodilaysis, IV
chemotherapy in the last 30 days; 2) hospitalization in the previous 90 days; 3)
residence in a nursing home or long-term care.
The pattern of etiological agents is much broader and moreover is represented
by resident species in the nosocomial environment, therefore with complex
resistance profiles.
Pseudomonas aeruginosa and methicillin-resistant S. aureus are the most
represented microorganisms, followed by Enterobacteriaceae and other non-
fermenting Gram negative such as A. baumannii and P. aeruginosa. Episodes of
pneumonia caused by multidrug-resistant microorganisms (MDRs) - including
enterobacteria (primarily Klebsiella pneumoniae) carbapenemase-producing (KPC) -
are increasingly frequent in long-term care and in hospitals.
Also not to be overlooked is the risk of nosocomial pneumonia related to
exogenous colonization, by environmental pathogens, mainly contaminating the
water systems, which are inhaled after aerosolization of the water. Legionella spp
represents the archetype of this category of pathogens, but others (such as P.
aeruginosa, Aspergillus spp and fast-growing mycobacteria) have non-secondary
roles. The mode of transmission in cases is linked to aspiration maneuvers, use of
bronchoscopes, contamination of nebulizers, humidifiers and ventilation circuits.

Infections in Neuromuscolar Disease Patients 465
Pulmonary complications are the leading cause of death, with most respiratory
deaths attributed to pneumonia. Hypoxemia is common and results from both
hypoventilation and microatelectasis.
In Patients with neuromuscular disease, over 90% of pneumonias are triggered
by upper respiratory tract infections. Chest infections pose a serious treatment to
vulnerable patients with muscle weakness and a poor cough [1].
Pneumonia is the major complication in these patients for pathophysiological
reasons of inefficient respiratory mechanics as well as lack of mucociliary clearance
capacity that is theoretically preserved, but ciliary function could be impaired by
chronic aspiration and mucopurulent bronchitis.
Overtime, individuals may become colonized with opportunistic pathogens such
as Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus. In
some case irreversible lung damage can occur with the development of
bronchiectasis and pulmonary fibrosis [2].
MICROBIOLOGY
The etiology of pneumonia can be multifactorial but essentially arises from

compromised lung and chest wall function, which produce obstructive and restrictive
lung disease.
The first point is to understand when to treat the patient by distinguishing when
he is colonized from when he is in an acute infection; clinical evaluation usually
involves measurement of temperature, tracheobronchial secretion volume, culture
and purulence assessment of tracheobronchial secretions, evalution for chest
radiograph resolution, white blood cell count, arterial oxygen tension / inspiratory
oxygen fraction (PaO2/FiO2) [3].
The most frequent pathogens remain in patients with NMD are MRSA,
Pseudomonas aeruginosa and MDR pathogens. Prolonged antibiotic treatment is
unlikely to prevent this secondary pneumonia but may select for more multidrug-
resistant (MDR) pathogens. Anaerobes are the etiology in only 0.2% to 0.3% of all
patients.
The microbiology of pneumonia after macroaspiration has changed over the last
60 years from anaerobic infection to one of aerobic and nosocomial bacteria [4].
Microaspiration has long been known to be the dominant pathophysiologic
mechanism behind CAP. Supporting evidence includes the finding that most
common CAP causing microorganisms colonize the oropharynx or nasopharynx in
non hospitalized patients. The distinct microbiology of HAP stems from
microaspiration occurring after hospitalized patients become colonized with the
virulent organisms found in intensive care unit and hospital environments [4].

DIAGNOSIS
Microbiological samples were collected from respiratory tract, sputum, pleural

fluid, endotracheal aspirate, or bronchoalveolar lavage, and blood within 24 hours of
hospitalization.
Biomarkers determinations may include C-reactive protein (PCR), procalcitonin
(PCT), copeptin and ADM.
A very important role is now played by the latest generation molecular tests for
the rapid diagnosis of upper and lower respiratory tract infections. In particular
Biofire respiratory panel RP2. 1 plus for the upper respiratory tract and BioFire
Pneumonia Plus (Pneumoplus) for lower respiratory tract. The RP2. 1 plus allows is
a nasopharyngeal swab collected on viral transport, sample volume 300 microL
which collects all respiratory viruses including SarsCov2 as well as atypical
pathogens responsible for pneumonia (Bordetella, Chlamidia, Mycoplasma).
The Pneumo plus panel, on the other hand, which involves a sample of about
200microL of sputum and BAL, includes bacteria, viruses, atypical bacteria and
antibiotic resistance genes; this last point is very important for those patients who
undergo multiple antibiotic therapies over time [5].
For infections due to Fungi, blood cultures are always important, even these
tested with BioFire film array panels that allow the identification of a broad spectrum
of yeasts, not least Candida auris, as well as antimicrobial resistance genes on the
blood. Sputum culture and research mannan, galactomannan and betaDglucan
markers of fungi on blood for further help of diagnosis.
TREATMENT
Numerous trails in the field of hospital pneumonia suggest using a 7-8 day
course of antibiotic therapy in patients with VAP without immunodeficiency, cystic
fibrosis, empyema, lung abscess, cavitation or necrosin pneumonia and with a good
clinical response to therapy. Patients with neuromuscular disease can be included in
these types of patients where the higher percentage of infection is determined by
forms also aspiration pneumonia as they are continuously subjected to aspirations
and difficulty in swallowing.
Community-Acquired Pneumonia
Community-acquired pneumonia have etiologies prevalent with S. Pneumoniae,

atypicals and mycoplasma, in particular Haemophilus, Moraxella and in 30% cases
to virus Influenza, Parainfluenza, RSV, and in the last year 2020 SarsCoV2 [6].
Oropharyngeal aspiration is an important etiologic factor leading to pneumonia in
the elderly and patients with neuromuscular. These disorders are associated with

dysphagia and an impaired cough reflex with the increased likelihood of

oropharyngeal aspiration. Aspiration pneumonia is difficult to distinguish from other
pneumonia syndromes.
More than 90% of hospitalized patients have risk factors for aspiration but some
study do not support the routine use of antianaerobic antibiotic coverage [7].
Primary regimen therapy for CAP is Amoxicillin 1 gr p.o. tid or Doxyciclina 100mg
po bid; if patient have co-morbidity Amox-Clav 875 mg/125 mg po bid for 7 days plus
Azitromicin 500 mg po 1 in day for 5 days or Levofloxacin 750 mg po die for 5 days.
If local rates of antibiotic resistant is very important for therapeutic choice. In patients
admitted to hospital where are included S. aureus and Legionella primary therapy
with Ceftriaxone 1-2 gr ev/24 h or Ceftarolina 600 mg ev/12 h plus Azitromicin 500
mg die or Levofloxacin 500 mg for 5 dies. For severe CAP use betalactam plus
macrolide. Sputum and blood culture recommended for in patients. Covarage for
MRSA and Pseudomonas aeruginosa is raccomanded for patient with
neuromuscular disease. Time treatment for CAP is 5-7 days [8].
Important to discontinue antibiotics with normalization of procalcitonin to 0.1-0.2
mcg/mL.
Patient with Hospital Acquired Pneumonia have a range of MDR and Gram
negative [9] therapy is indicated with Cefepime 2 gr ev/12 h or Pip-Taz 4.5/6 h,
alternative regimen is Meropenem 1 gr ev/8 h. Add Vancomicin or Linezolid if unit or
Hospital have prevalence of MRSA > 10-20%. For suspected pseudomonas or
highrisk mortality use Ciprofloxacin 400 mg every 8 h or Tobramicin 5 mg/kg ev 24 H
or Amikacina 15 mg/kg 24 h (aminoglycoside are not indicated in patients with
neuromuscular plaque damage). Aztreonam is other possibility and consider Colistin
if carbapenem resistant Gram negative is suspected. Every therapy are selected with
specific therapy after culture results (sputum, blood, pleural fluid, etc.).
Aspiration Community Acquired Pneumonia (ACAP)
Aspiration community acquired pneumonia (ACAP) is frequent in NM patient;

Dysphagia, lack of cough reflex, esophogeal motility disorders typically from
neurologic disease is considered are the most important risk factor for aspiration
pneumonia.
Etiologies anaerobes and viridans streptococci group are predominant. Primary
therapy regimen is with Amp/sulb 3 gr ev/6 h or Ceftriaxone 1 gr in 24 h plus
Metronidazolo 500 mg ev every 6 hours [9]. Infections associated with anaerobes do
not evidence pathogenic role [10] and Gram Negative bacteria were more prevalent
in patients with severe ACAP, with higher prevalence of Pseudomonas aeruginosa
and Enterobacteriaceae (Other GNB). Oral cavity is considered the principal source
of pathogens responsible for aspiration pneumonia. Microbiology data from patients
with other comorbid conditions suggested that P. aeruginosa, K pneumoniae and E.
Coli were frequently isolated from oral samples. For the right therapeutic choice it is

essential to always keep in mind the local epidemiology of antimicrobic resistance

which varies according to geographic areas.
Finally antibiotic administration can also adversely affect respiratory muscle
function; so many studies have valuted that penicillin type drugs rarely are
associated with the development of a myopathy; so is very important that the choice
of targeted antibiotic therapy which, on the one hand, must eradicate infections, on
the other, must not cause damage to the muscles or neuromuscular plaque.
CAP or HAP in patient with NM disease

Assess risk for MDR pathogens and mortality if patients
(Regular function cough, Dysphagia o impaired cough in NMD?)

YES NO
High MDR pathogen risk: Low MDR pathogen risk

Antibiotic monotherapy:
A: with septic shock risk  Ertapenem, ceftriaxone, cefotaxime
dual Gram negative antibiotics Levofloxacin, Moxifloxacin
Pseudomonas coverage+- MRSA therapy
B: no septic shock 
single Gram negative agent + MRSA therapy
Figure 1. ([12] reference to European HAP/VAP guideline 2017).
Virus Interstizial Pneumonia
Virus interstizial pneumonia suspected consider etiologies to Influenza

Adenovirus MERS/SARS SarsCov2, hantavirus, metapneumovirus, parainfluenza
virus, RSV.
Oseltamivir and Zanamivir indicated in influenza virus, no known efficacious
drugs for adenovirus, hanta, meta parainfluenza, coronavirus o RSV.
Pulmunary Fungai Infection
Pulmonary IFIs that occur mostly as pulmonary nodules see aspergillosis the
most frequent cause. Interstitial pneumonia is caused by Pneumocystis.
Histoplasmosis and aspergillosis can also be presented as ground glass pictures.
The first therapeutic choice is represented by echinocandins, especially if the
patient is unstable or has already taken azoles. For aspergillosis the drug of choice is
voriconazole. Alternative to voriconazole is Amphotericin B [11].

Other Infections
In any case, the surveillance of infections must also be carried out in other sites
of possible infection such as bacteremia, sepsis, urinary tract infections, catheter
infections; therefore, adequate source control with culture tests such as blood
cultures, urinoculture, nasal swabs and catheter culture tests is essential.
An antimicrobial stewardship program is fundamental in the therapeutic choice of
antibiotics to prevent antimicrobial resistance according to local microbiological
epidemiology; combination therapy was associated with a significantly lower risk of
death compared with monotherapy.
PREVENTION
Dietary interventions have been studied in patients with dysphagia secondary to

neurodegenerative disease. A number of small studies have reviewed pharmacologic
intervention to protect the airway via the cough reflex.
Vaccinations play an important role in disease management for prevention: the
23-valent pneumococcal vaccine, Haemophiles vaccine, annual influenza vaccine
and respiratory syncytial virus antibody prophylaxis for infants are all recommended.
Diagnostic tests play a vital role in healthcare: they help to further improve
antimicrobial stewardship by optimizing the use of antibiotics a therapy more in
vulnerable patients.
REFERENCES
[1] Umakant Amabalalsa Khatwa et al. Pulmonary Manifestations of

Neuromuscolar Disease. Review Article. Indian J. Pediatr. September 2015.
82(9):841-851.
[2] Smith, P. E. M. et al. Pratical problems in the respiratory care of patients with
muscular dystrophy. N. Engl. J. Med. 1987; 316:1197-1205.
[3] L. Campogiani et al. Evidence supporting recommendations from international
guidelines on treatment, diagnosis, and prevention of HAP and VAP in adults.
European Journal of Clinical Microbiology & Infectiuos Disease (2020) 39:483-
491.
[4] David M. Di Bardino et al. Aspiration pneumonia: a review of modern trends. J.
Crit. Care 2015 Feb; 30 (1): 40-8.
[5] David M. Di Bardino, et al. Aspiration pneumonia: A review of modern trends.
Journal of Critical Care 30 (2015) 40-48.
[6] Blake, W. Buchan et al. Pratical compararison of the Biofire Film array
Pneumonia Panel to routine diagnostic methods and potential impact on

antimicrobial stewardship in adult hospitalized patients with lower respiratory

tract infections. Journal of Clinical Microbiology July 2020 Volum 58, Issue 7.
[7] IDSA/ATS Guideline for CAP in adults: Am. J. Crit. Care Med. 2019, 200.
[8] Corral et al. Chest 2021, 159 (1): 58-72.
[9] NEJM 370-543, 2014 and J. Respir. Crit. Care Med. 200:45, 2019.
[10] Judith Marin-Corral et al. Aspiration Risk Factors, Microbiology, and Empiric
Antibiotics for Patients Hospitalized with Community-Acquired Pneumonia.
Chest 2020, 2 October.
[11] C. Tascini, B. Viaggi. L’Uso dei Farmaci antifungini nel paziente critic [The use
of the antifungal Pharmacy in the critical peacekeeper]. Ed. 2017.
[12] International ERS/ESICM/ESCMID/ALAT guidelines for the management of
hospital-acquired pneumonia and ventilator-associated pneumonia. 2017.

Chapter 34
NUTRITIONAL SUPPORT IN
NEUROMUSCULAR DISEASES
D. Tammaro1,*, M. Rispoli1 and A. Corcione2

1
Critical Care Department, AO “Ospedali Dei Colli” – Monaldi Hospital, Naples
2
Chief of Critical Care Department,
AO “Ospedali Dei Colli” – Monaldi Hospital, Naples
ABSTRACT
Patients with neuromuscular disease are often at risk of malnutrition. This is

due to frequent dysphagia, motorimpairment, breathing difficulties and mood
disorders. Malnutrition contributes to the loss of lean mass and consequently to
hypotonia and worsening of muscle performance as well as contributing to
micronutrient deficiency disorders. A correct diagnosis of malnutrition is the basis
of an adequate nutritional support plan. The study of physical indices, such as
body mass index and weight loss, with laboratory parameters (pre-albumin,
transferrin and retinol binding protein) as well as an adequate assessment of
nutritional needs allows to set up an adequate support plan. The oral route is
always to be preferred; if not available, the enteral route via gastrostomy or
jejunostomy is the gold standard. Parenteral nutrition in association or exclusive
will be used if the enteral route is impractical or insufficient. Several mixtures are
commercially available for both enteral and parenteral administration.
Administration must be tailored on the specific needs of every single individual
patient in accordance with international guidelines (ESPEN, ASPEN). A careful
monitoring of the parameters used for the diagnosis of malnutrition and a safe
management of the devices is essential to manage the patient with chronic
nutritional support.
* Corresponding Author’s E-mail: dariotammaro@libero.it.

472 D.Tammaro, M.Rispoli and A.Corcione
INTRODUCTION
Neuromuscular diseases (NMDs) constitute a large group of congenital or

acquired pathologies.
They comprise several subgroups which include:
 dystrophic forms (Duchenne muscular dystrophy, Becker muscular

dystrophy, facio-scapulo-humeral dystrophy, Emery-Dreifuss muscular
dystrophy, oculo-pharyngeal dystrophy, girdle dystrophy including LGMD2A,
LGMD1C and LGMD2B, etc.) metabolic myopathies (glycogenosis, lipidosis,
mitochondrial myopathies)
 congenital myopathies (central core myopathy, centronuclear myopathy,
nemaline myopathy, etc.)
 myotonic forms: myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2
(DM2-PROMM), muscle channelopathies
 inflammatory forms (myositis including dermatomyositis, polymyositis,
inclusion body myositis)
 myasthenic forms (myasthenia gravis)
 neuropathies
 motor neuron diseases (amyotrophic lateral sclerosis, etc.) and others [1]
Regardless of the etiology, the dominant and common element of all

neuromuscular disorders is hypotonia causing muscle weakness with consequent
fatigue and reduced mobility.
Patient’s quality of life is often further worsened by the coexistence of cardiac,
respiratory, infectious and orthopedic disorders.
Nutritional problems are often present in NMD and worsen with age. In
congenital pathologies, considering the growth of the child, deleterious effects due to
overeating may occur on glucose metabolism, mobility and cardiorespiratory
functions.
At the same time, undernutrition causes worsening of muscle tone getting worse
motor and ventilatory functionality, both in the child and in the adult patient.
Hypotonia worsens intestinal motility, with the risk of severe constipation and
consequent gastrointestinal dysfunctions and complications. Chewing and
swallowing difficulties constitute the basis for the risk of aspiration of food material
with a high risk of respiratory infectious diseases. The risk of early osteoporosis
linked to hypomobility should not be overlooked [2]
Adequate nutritional support contributes to reduce the risk of the just described
complications and improve the quality of life of patients.

Nutritional Support in Neuromuscular Diseases 473
MALNUTRITION
Malnutrition is a functional, structural and developmental alteration of the

organism that follows an improper relationship between intake and use of nutrients,
such as to impact on patient’s quality of life and increase the risk of morbidity and
mortality. Malnutrition therefore includes both conditions in which there is an
excessive supply of nutrients compared to needs and, more frequently, an
insufficient intake or excessive consumption of the same.
In the ESPEN (European Society of Parenteral and Enteral Nutrition) consensus
conference in 2015, malnutrition is defined as the presence of a body mass index
(BMI) of less than 18.5 kg/m2 of body surface area or weight reduction associated
with a reduction in lean mass [3]
For ASPEN (American Society of Parenteral and Enteral Nutrition), malnutrition
is defined by the presence of at least two of the following criteria:
 reduced calorie intake

 weight loss
 loss of muscle mass
 loss of subcutaneous fat
 fluid accumulation
 reduction of hand grip strength
To the general diagnosis of malnutrition, the evaluation of the specific type of

malnutrition should be addedand, in this regard,, the malnutritions classification
provides:
 inflammatory diseas (acute traumatic and non traumatic pathologies, chronic

pathologies such as cancer)
 Not inflammatory diseases (neuromuscular diseases, neurological diseases
such as Parkinson’s and Alzheimer’s, eating disorders, chronic intestinal
syndromes)
 Socio-economic factors [11]
The second group includes neuromuscular pathologies. In these cases, the

mechanisms underlying malnutrition are not inflammatory but mainly linked to the
alteration of the ability to proper eat, as occurs for example in the case of dysphagia.
In the neuromuscular patient, malnutrition is the result of a deficit, especially chronic,
of both calories and proteins that form the picture of the so-called protein-calorie
malnutrition (PCM). It involves a reduction in lean mass with a consequent further
deficit in muscle tone and strength.
Nutritional support is not only intended to avoid malnutrition and its
complications, but also to modify the pathogenetic mechanisms of diseases and their

treatment, as it seems that there are close relationships between nutrient metabolism
and pathologies [12]
The first step in establishing the need for nutritional support is to assess the
presence of calorie protein malnutrition. It is therefore advisable to know the tools for
an adequate nutritional assessment of the patient
NUTRITIONAL ASSESSMENT
For a correct nutritional assessment and to identify the metabolic consequences

of malnutrition, anamnestic data, clinical evaluations, anthropometric measurements
and biochemical parameters are commonly used.
A thorough physiological and pathological history and a careful objective
examination are essential for a correct nutritional evaluation.
The main parameter used to assess the extent of malnutrition is the loss of body
weight. Unintentional weight loss in the last 6 months of> 10% compared to usual
weight, or greater than 5% in a month is considered significant. In the absence of the
usual weight, a body weight 20% lower than the ideal one can be considered
indicative of malnutrition.
In addition to body weight and the criteria already indicated by ESPEN and
ASPEN, SINPE (Italian Society for Parenteral and Enteral Nutrition) suggests
considering other clinical parameters that can be used to diagnose and quantify
PCM.
The creatinine/height index estimates lean mass as urinary creatinine is the final
product of creatine metabolism present mainly in muscle tissue. It is calculated with
the following formula: [24-hour creatininuria/ideal urinary creatinine (evaluated
according to height and sex according to the reference tables) x 100]. Some plasma
proteins also correlate with the nutritional status and severity of the underlying
disease: albumin; transferrin which, with its short half-life (8 days) and its relatively
small body pool, faithfully reflects the loss and recovery of protein assets; prealbumin
which, with the half-life of 2-3 days, can help monitor the response to nutritional
treatment; the retinol-binding protein
BMI values <18.5 kg/m2 are now considered PCM indicator, BMI values of 14-15
kg/m2 are associated with increased mortality, values> 25 kg/m2 indicate overweight
and those> 30 kg/m2 obesity.
In clinical practice, different evaluation protocols can be adopted. An initial
nutritional screening should normally be done within 48 hours of admission to identify
patients who are malnourished or at risk of becoming malnourished and to determine
if a more in-depth nutritional assessment is needed. The most frequently used
indicators can be obtained quickly and easily; they are specific, reproducible and
highly cost-effective: basic pathology; weight changes; food income; any loss of
nutrients; level of independent physical activity; clinical judgment based on physical
examination with evidence of loss of skeletal muscle mass (in particular of the

temporal, deltoid, triceps and quadriceps and interosseous muscles of the hand) and
subcutaneous fat, possible presence of cachexia, edema, glossitis, stomatitis,
impaired cicatrization, etc.
To integrate anamnestic data, signs and symphtoms of the patients in order to
provide an evaluation score of the nutritional status, some standardized associations
of indices have been developed such as the SGA (Subjective Global Assessment) or
the MNA (Mini Nutritional Assessment) for elderly subjects. The SGS includes the
collection of anamnestic data (weight loss, food intake, gastrointestinal symptoms,
diagnosis, functional capacity) and an objective examination of muscle mass, fat
mass and the presence of edema. Despite the limitations of the SGA (difficult
screening investigations in the case of limited resources and lack of objective indices
of the state of nutrition) it is a valid tool through which the indication can be made to
the NA in the hospital setting. The MNA provides for anamnestic type findings
(appetite, weight loss, type of diagnosis, motor activity, neuropsychiatric problems)
associated with the calculation of the body mass index, possibly completed by an
assessment of functional autonomy, drug intake, presence of bedsores, skin ulcers,
the relief of the circumference of the arm and calf.
More complex techniques such as indirect calorimetry and body composition
analysis are another important nutritional assessment and monitoring tool [4]
NUTRITIONAL SUPPORT PLANNING
Having established the presence of malnutrition or the risk of it occurring, it is

necessary:
 Identify nutritional needs

 Define the route of administration of the nutrients
 Choose nutritional blends
 Monitor the parameters chosen for the diagnosis of malnutrition
Nutritional Requirements
The caloric requirement is the sum of the basal energy expenditure (BEE) and
the share of energy for the subject’s physical activity.
The BEE can be calculated through indirect calorimetry. If this tool is not
available, the BEE estimate can be made through the Harris Benedict equation and
its corrective measures. Overall, it is estimated that patients benefit from daily caloric
intake of 20 - 35 per kg of current weight.
Tolerance to caloric intake is limited by the ability to metabolize caloric
substrates, carbohydrates (4-5 mg/kg/min corresponding to approximately 5.76-7.2
g/kg/day) and lipids (2.5 g/kg/day) [5]

The protein requirement can be estimated by means of the nitrogen balance (N)
that is the difference between nitrogen introduced and lost.
In clinical practice, the protein requirement of adults, in the absence of organ
failure, (with normal renal and hepatic function) varies between 0.8 and 2 g/kg/day
(nitrogen requirement 0.13-0.35 g/kg/day), and reduces in the elderly.
The water requirement is influenced by the degree of physical activity and food
intake as well as by pathological states.
The adult water requirement in the absence of pathological losses and organ
failure (with normal renal, cardio-respiratory and hepatic function) varies between 30
and 40 mL/kg/day, or between 1 and 1.5 mL/Kcal administered. In the elderly, the
water intake must be reduced to 25 mL/kg/day
Micronutrients (vitamins and trace elements) and mineral salts must always be
adequately supplied to the patient, especially in the case of artificial nutritional
support, respecting the parameters provided by the Nutrient Reference Intake Levels
(LARN) and the World Health Organization (WHO).
Routes of Administration of Artificial Nutrition
Nutritional support can be provided enterally or parenterally.

The enteral route is always to be preferred for several reasons:
 Maintenance of the functional anatomical integrity of the intestinal mucosa

 Better use of nutrient substrates
 Easier and safer administration
 Lower cost
The oral route, if available safely, is the most physiological one. There are
different products to provide adequate nutritional support to the patients able to
swallow. Even in the case of dysphagic patient it is possible to use some dedicated
preparations, within certain safety margins [13]
In doubtful cases it is advisable to proceed early with the evaluation of
dysphagia. For this purpouse, the use of the Smithard method is recommended, and
can be used at the patient’s bed assessesing level of consciousness, motility of the
palate, choking reflex, laryngeal function and voluntary cough;
Swallowing is evaluated by initially drinking 10 mL of water three consecutive
times, in normal cases 50 mL of water are then used. The test must be repeated
every day for a week. In neurological and neuromuscular pathologies, the swallowing
function and the entire process of buccal bolus formation can be progressively
altered and the intake of a meal can last up to an hour. The management of
nutritional support in subjects with dysphagia requires a multidisciplinary approach
(neurologists, nutritionists, dieticians, speech therapists, nurses) to evaluate the
indication for enteral nutrition and, if possible, oral nutrition. Furthermore the

rehabilitation process and the method (consistency and frequency of meals) of

feeding muste be assessed. In general, soft, hydrated, non-particulate foods are
preferred, which reduce the possibility of aspiration into the airways. It is necessary
to initiate NA when, despite adequate dietary phoniatric measures, the nutritional
status tends to deteriorate [14]
If the oral route is not usable, it is possible to provide nutritional support through
nasogastric or nasodijunal tubes. However, considering the nutritional support is
allowed for maximum of 30 days, the solution is the positioning of a gastrostomy or
jejunostomy tube.
Gastrostomy (PEG) can be performed endoscopically, radiologically or surgically.
PEG allows the administration of nutrients in a controlled manner by means of
specific peristaltic pumps; if it is not possible to perform gastrostomy due to
functional or structural alterations of the stomach, it is possible to perform
jejunostomy (PEJ). Also in this case it is possible to practice it by radiological or
surgical way. The probe is placed in the upper part of the jejunum for 15 - 20 cm and
anchored to the skin. In this case are used, tubes with a diameter smaller compared
to those used for PEG. Also through this route it is possible to use nutritional
preparations that can be administered through special peristaltic pumps [6].
The enteral route is rarely not practicable, especially in the chronic
neuromuscular patient. However, in the following cases, nutritional support must be
provided parenterally:
 Chronic intestinal obstruction or subocclusion of mechanical origin

 Severe intestinal ischemia
 High flow jejunal or ileal fistulas (output> 400 mL/day)
 Severe alteration of intestinal function secondary to enteropathies
orinsufficiency of the absorbent surface, such as not to allow the
maintenanceof an adequate nutritional status
It is also possible to combine enteral and parenteral nutrition if the first is unable
to entirely support patient’s nutritional needs.
Parenteral nutrition is applicable through the provision of stable venous access.
In recent years, the use of peripherally inserted central venous accesses (PICC)
has become widespread. These devices are placed in a sterile environment, with
ultrasound guidance, in a peripheral vein (preferably basilica vein; second choice,
brachial or cephalic vein) and guided until reaching the atrio-caval junction. The
alternative to PICC for nutritional purposes, is represented by venous catheters
positioned in the internal jugular vein up to the atriocaval joint and tunneled under the
skin in order to reduce the risk of infections and ensure stability of the venous access
[7].
Parenteral nutrition is practiced through volumetric pumps that allow the precise
administration of nutritional mixtures.

Nutritional Mixtures
The use of fresh or preserved food in PEG or PEJ should not be recommended
due to the risks of:
 Bacterial contamination during preparation

 Enzymatic alteration of the components for cell lysis of fresh food
 Oxidations caused by the air incorporated in the mixing processes
(smoothies, homogenized)
 Obstruction from the tube due to poor fluidity and homogeneity of the final
mixture
There are various nutritional blends on the market to be administered through

gastrostomy and jejunostomy probes.
These NE formulations come in liquid or powder form. The calorie content of
diets is on average 1 Kcal/mL, with wide fluctuations for special blends. In fact, there
are mixtures with contents higher than 1.5 Kcal/ml or with less than 1 Kcal/ml.
The macronutrients present in these mixtures are distributed as follows:
 Glucides: the caloric intake is on average between 40 and 60%. However,

specific blends are available containing much less carbohydrates.
Carbohydrates are supplied in the form of starches (e.g., from corn, barley),
maltodextrins (hydrolysis of starches), disaccharides (lactose, sucrose) or
monosaccharides (fructose).
 Proteins: the caloric intake is on average between 16 and 20% of total
calories. Specific blends require lower contributions (5-6%). The supplies are
provided as lactalbumin or casein (whole or partially hydrolysed proteins) and
free amino acids. Blends are available in which the protein content derives
from soy (for patients with intolerances to milk proteins)
 Lipids: the caloric intake is between 30 and 40%, with some diets having
extreme values (9% and 55%). They are present as vegetable oils (corn,
sunflower, soy, coconut, rapeseed, olive seeds) and medium chain fatty
acids
 Vitamins and mineral salts: their composition is indicated by the LARN and
the WHO guidelines). For formulas indicated for special pathologies, different
contributions may be provided
 Fibers: when present, the indigestible molecules of these diets are made up
of insoluble polymers (lignins, cellulose, hemicelluloses), or soluble (pectins,
gums, mucilages), the latter chemically referable to glucomannans, inulin,
fructooligosaccharides.
 Water: some diets appear as powders to be restored with water; others are
mixtures in aqueous solution with free water varying between 85% (norm-
calorie) and 60% (high-calorie).

Some mixtures are enriched with products which, although present in small
quantities in foods, at high dosage can have therapeutic actions (e.g., arginine,
glutamine, nucleotides).
It should not be overlooked that there are nutritional supplements that can be
administered orally. In this case, the products also have aromas that improve their
palatability
In the context of parenteral nutrition, the mixtures consist of Water, glucose,
lipids (fatty acids and triglycerides), amino acids. Among the lipid constituents in
recent years, omega 3 fatty acids have been given great importance for their
documented anti-inflammatory role. Vitamins and trace elements are added to the
preconstituted bags; the electrolytes can be already present or added secondarily.
There are pre-made bags on the market defined as binary (if containing amino acids
and glucose) or ternary (if they have the 3 macronutrients). There is also the
possibility of galenic preparations usingparenteral bags in a sterile environment if the
patient needs a specific distribution of micro and macronutrients not satisfied by the
mixtures on the market [8] [9].
Monitoring Artificial Nutrition
Artificial nutrition, both enteral and parenteral, can be associated with infectious,
mechanical and metabolic complications.Infectious complications may be due to
contamination of the mixtures (especially parenteral) or of the devices.
Mechanical complications refer to the dislocation of the probes or their
alteration.In this case, the correct management of the devices prevents these
problems.
The alterations in the acid-base and electrolyte balance during NA are generally
due more to the patient’s underlying disease than to nutritional treatment.
However, it should be remembered that amino acid solutions for intravenous use
are often buffered with acetates which can alkalize the patient.
The hypertriglyceridemia that can accompany the intravenous infusion of lipids, if
left untreated, can induce the development of pancreatitis or changes in lung
function.
Among the serious complications, even fatal, which can be prevented with
careful monitoring, it is essential to remember Refeeding Syndrome (RS) which can
occur in the initial stages of re-feeding with enteral or parenteral carbohydrates, in
patients chronically in a semi-fast state. These patients are used to using ketone
bodies and fatty acids. The reintroduction of carbohydrates results in the release of
insulin which reactivates the processes of glycogenosynthesis, lipogenesis and
protein synthesis. These processes require large amounts of phosphates and
magnesium which are already reduced in the undernourished patient. The further
decrease of these trace elements determines severe alterations of cellular functions.
The alarm parameters of RS are hypophosphatemia, hypokalemia and
hypomagnesemia, in addition to water retention due to the antinatriuretic effect of the

increase in insulin, or to dehydration due to osmotic diuresis induced by the

administration of glucose. In the most severe cases, hypophosphatemia is
associated with haematological, respiratory, cardiac and neuromuscular alterations
[10]
Another problem is represented by Overfeeding Syndrome (OS), frequently
encountered in the past decades during PN with high doses of glucose even in
previously normonnourished patients. It can be accompanied by excessive
production of CO2, and can lead to a worsening of respiratory functions. OS does not
develop if nutritional intakes are kept within the recommended ranges and if the
patient’s needs are periodically re-evaluated with careful monitoring.
In all patients, even non-diabetic or glucose intolerant, blood glucose must be
monitored as hyperglycemia (> 200 mg/dL) can also be present in 7% of cases in
which the caloric intake is correctly administered (5 mg/kg/min), and the development
of non-ketotic hyperosmolar coma can be prevented. Obviously, in the diabetic
patient in NA, glycemic control is also essential to reduce infectious complications.
During long-term PN, hepatobiliary and bone metabolism complications of
multifactorial origin may develop which can be detected early and treated if sought
with periodic targeted monitoring. In the course of NE, the most fearful and frequent
complications are gastroesophageal reflux, pulmonary aspiration and diarrhea. Such
complications can be prevented and successfully treated if monitoring is adequate.
The nutritional evaluation performed before the start of nutritional therapy, as well as
the calculation of needs, must be periodically repeted. The same parameters used
for nutritional evaluation are used for monitoring and evaluating the effectiveness of
nutritionaltherapy: indirect calorimetry, nitrogen balance, body weight,
anthropometry, SGA or MNA, bioimpedance analysis, plasma proteins, functional
evaluation, and clinical examination. For the short-term monitoring of the efficacy or
adequacy of nutritional support, prealbumin and retinol-binding protein (RPB) have
proved useful. At the beginning of the nutritional treatment it is good to monitor until
stabilization:
 daily: electrolytes, blood sugar and magnesium

 2-3 three times a week: Blood Urea Nitrogen (BUN), creatinine, calcium,
phosphorus, prealbumin, transaminases, triglycerides
 Once a week: transferrin
 10-15 days: Total protein and albumin
When the patient is metabolically stable, the frequency of monitoring depends

on the patient’s clinical situation. Medium to long term treatment in a metabolically
stable patient may allow for monthly or more spaced monitoring

REFERENCES
[1] Jaydeep, M; et al. “The Epidemiology of Neuromuscular Diseases” Neurol Clin,

2016 Nov, 34(4), 999-1021.
[2] Salera, S; et al. “Nutritional Challenges in Duchenne Muscular
Dystrophy.Nutrients., 2017 Jun, 10, 9(6), 594.
[3] Kondrup, J; et al. “ESPEN Guidelines for Nutrition screening 2002” Clinical
Nutrition, (2003), 22(4), 415–421.
[4] Sornwichate Rattanachaiwong, Singer, P “Indirect calorimetry as point of care
testing” Clin Nutr, 2019 Dec, 38(6), 2531-2544.
[5] SINPE Guidelines, 2002.
[6] Ao, P; et al. “Comparison of complication rates, types, and average tube
patency between jejunostomy tubes and percutaneous gastrostomy tubes in a
regional home enteral nutrition support program” Nutr Clin Pract., 2015 Jun,
30(3), 393-7.
[7] Debra, S; et al. “American Society for Parenteral and Enteral Nutrition
Guidelines for the Selection and Care of Central Venous Access Devices for
Adult Home Parenteral Nutrition Administration” Journal of Parenteral and
Enteral Nutrition, Volume 43, Number 1, January 2019, 15–31.
[8] Boullata, JI; et al. “A.S.P.E.N. clinical guidelines: parenteralnutrition ordering,
order review, compounding, labeling, and dispensing” JPEN J Parenter Enteral
Nutr., 2014 Mar-Apr, 38(3), 334-77.
[9] Reber, E; et al. “Pharmaceutical Aspects of Artificial Nutrition” J Clin Med., 2019
Nov, 8(11), 2017.
[10] da Silva, JSV; et al. “ASPEN Consensus Recommendations for
RefeedingSyndrome” Nutr Clin Pract., 2020 Apr, 35(2), 178-195.
[11] Cederholm, T; et al. “ESPEN guidelines on definitions and terminology of
clinical nutrition” Clin Nutr., 2017 Feb, 36(1), 49-64.
[12] Di Renzo, L; et al. “Role of Personalized Nutrition in Chronic-Degenerative
Diseases Nutrients, 2019, Jul 24, 11(8), 1707.
[13] Jeejeebhoy, KN. “Enteral nutrition versus parenteral nutrition: the risks and
benefits” Nat Clin Pract Gastroenterol Hepatol, 2007 May, 4(5), 260-5.
[14] Laura, Wj Baijens; et al., “European Society for Swallowing Disorders -
European Union Geriatric Medicine Society white paper: oropharyngeal
dysphagia as a geriatric syndrome” Clin Interv Aging, 2016, Oct 7, 11, 1403-
1428

SECTION 8. PULMONARY REHABILITATION

Chapter 35
RESPIRATORY MUSCLE TRAINING IN CHILDREN

AND ADULTS WITH NEUROMUSCULAR DISEASES
Paolo Buonpensiero1, and Emilia Privitera2

1
University of Neaples Federico II Departement of Pediatrics, Italy
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
2
Health Professions Department Unit, Milan, Italy
ABSTRACT
Respiratory muscle weakness and dysfunction are pathophysiological

elements commonly observed in patients with neuromuscular diseases (NMD).
Although in varying degrees and with different topographical anatomical
distribution (in relation to the different observable diseases) this element is
responsible for 90% of respiratory insufficiency and deaths of our patients.
Respiratory muscle weakness expresses itself in a restrictive pulmonary
pattern complicated by recurrent pneumonia and atelectasis, which further affect
the prognosis, quality of life and the usage of the resources needed for care [1].
Respiratory muscle training it’s a therapeutic component, part of respiratory
rehabilitation programs (PR) since many years. Historically with a precise
rationale based on pathophysiological findings in COPD patients and healthy
volunteers. Also, the mean to improve muscle force and endurance via specific
resistive training programs mainly for inspiratory muscles, in neuromuscular
diseases, has been evaluated in some studies and clinical trials.
In COPD studies, the body of evidence in favour of RMT cannot suggest its
generalized use. In NMD studies, with similar low and very low grade of evidence
studies, the risk of inducing muscle damage and ipoventilation is still more
concerning when using the IMT.
This chapter explores the technical and methodological specifications of
RMT in the neuromuscular patient, as well as the evidence produced by the
scientific community, up to date.

Corresponding Author’s E-mail: pbuonpensiero@gmail.com.

486 Paolo Buonpensiero and Emilia Privitera
Keywords: neuromuscular disease (NMD), respiratory muscle training (RMT),

respiratory muscle (RM), pulmonary rehabilitation programs (PR), muscle force
(MF)
INTRODUCTION
In chronic obstructive pulmonary disease (COPD) chronic inflammation

represents an important factor of disease manifestations that involves peripheral and
respiratory muscles, causing in association with well-known biomechanical
responses to dynamic hyperinflation and the resulting intrinsic positive end expiratory
pressure (PEEPi), inspiratory muscle shortening with biomechanical disadvantage
and a secondary “functional weakness” [2].
Dynamic hyperinflation is therefore responsible for an augmented workload of the
diaphragm, with predisposition to fatigue, expressing itself with dyspnea and reduced
tolerance to exercise. The rationale for inspiratory muscle training is therefore related
to the primary goal of reducing exertional dyspnea and improving exercise capacity
in these patients.
Expiratory muscles weakness in COPD its mainly attributable to other factors
such as a generalized myopathy with reduced oxidative enzymes activity. [3] Many
non-pharmacological approaches to major symptoms related to COPD and well
represented in pulmonary rehabilitation programs (PR) are of proven benefits while
other, as respiratory muscle training, are still controversial [4].
Many observations and one meta-analysis supported the positive effects of the
inspiratory muscle training (IMT) on young healthy subjects [5]. Furthermore, a
substantial body of evidence highlighted the role of different type of RMT in
increasing strength, thus causing a meaningful reduction of breathlessness and an
increase of physical exercise ability in COPD patients [6]. However, some features of
the physio pathological rationale supporting the generalized use of the IMT in COPD
patients is until now subject of debate and the effective clinical relevance cannot be
extrapolated from the existing literature, because of relevant methodological bias [7].
Neuromuscular diseases include heterogenous neurological disease affecting the
cortex, brainstem and neuromuscular junction motor nerves [1]. Pathologies affecting
the cortex, brainstem, spinal cord, motor nerves, neuromuscular junction and
muscles, can all lead to dysfunction of the respiratory system.
Muscle weakness, respiratory muscle weakness and dysfunction, represent a
common element albeit in different forms with varying severity patterns, age at onset
and prognosis with a specific natural history. Respiratory muscle weakness can vary,
with acute onset happening in many forms. NMDs that cause respiratory muscle
weakness include muscular dystrophies, such as Becker muscular dystrophy (BMD),
Duchenne muscular dystrophy (DMD), limb-girdle, Emery-Dreifuss and facio scapula
humeral muscular dystrophy, myotonic dystrophy, metabolic and congenital
myopathies, inflammatory myopathies, myasthenia gravis, neuropathies (hereditary

Respiratory Muscle Training in Children and Adults… 487
and acquired), amyotrophic lateral sclerosis (ALS), poliomyelitis and spinal muscular
atrophy [8]. Complications such as recurrent pneumonia and atelectasis are
sustained by severe functional complication, with a restrictive pattern, decreased
chest expansion, poor alveolar ventilation, ineffective clearance and progression to
respiratory insufficiency, failure, and premature death.
RESPIRATORY MUSCLE TRAINING
Assessment of respiratory muscle strength is extremely useful for detecting

weakness and the related consequences that are detected on patients. This is
necessary to set up a commensurate training program for the respiratory muscles. A
low inspiratory or expiratory muscle strength without clinical context has relatively
poorly defined clinical consequences and the range of normality in healthy subjects is
very large.
Measurement of respiratory muscle strength is not restricted to patients with lung
diseases and should also be carried out in neuromuscular, systemic, and cardiologic
conditions. In addition, in the follow-up of patients treated with drugs that may induce
myopathy, the assessment of respiratory muscle function is advised.
In the large majority of cases, the assessment of maximal inspiratory pressures
gives sufficient information. In rare cases, measurements of pressures in the
abdomen or esophagus may be needed. In a limited number of laboratories, other
invasive assessment methods for respiratory muscles are used, such as magnetic or
electrical stimulation of the phrenic nerve, with uncoordinated subjects or incapable
of executing voluntary maneuvers [9].
Clinical signs of respiratory muscle weakness should be sought after with a
clinical examination, searching for any pathognomonic symptom (abdominal or
thoracic paradox, use of accessory muscles, asymmetry of chest expansion,
orthopnea ...) [10] In presence of a respiratory muscle deficit, spirometry is not
specific. However, a difference of vital capacity greater than or equal to 20% of the
measurement in the supine position, compared to the standard sitting position, is
indicative of respiratory muscle weakness [11].
The Peak Cough Expiratory Flow reached during the cough maneuver
expresses, if different from normal values, the consequence of the muscle deficit on
the ability to cough. The reduced value of maximal voluntary ventilation (MMV) can
highlight at first the weakness of the respiratory muscles, although this is also a
measure non-specific. Maximum inspiratory pressure (MIP), maximum expiratory
pressure (MEP) and the Sniff Nasal Pressure Test (SNIP) are voluntary non invasive
tests, normal values (shown in table 1) exclude a possible muscle weakness. To
check the effectiveness and in order to set up a workout for respiratory muscles, MIP
and MEP are useful outcome measures.

Table 1. Modified ATS/ERS Statement on respiratory in muscle testing Am. J.

Resp. Crit. Care Med. 2002; 166:518-624
Normal values
Male Female
MIP (Cm H2O) 200-250 130-70
MEP (Cm H2O) 100-140 70-110
Although maximal in- and expiratory muscle strength gives important information
on respiratory muscle function, the respiratory muscles (especially the inspiratory
muscles) should be able to cope with endurance tasks. Measurements of respiratory
muscle endurance, therefore, give further insights in the function of the respiratory
pump.
Figure 1. Micro RPM (MIP, MEP), Peak expiratory flowmeter (PEF or PCEF).
In the authors’ opinion, measurements of inspiratory muscle endurance are

particularly helpful when inspiratory muscle weakness is important. The respiratory
muscle endurance is generally assessed using the Maximal sustainable voluntary
ventilation. The maximal sustainable voluntary ventilation (MSVV) is measured or
estimated from protocols with incremental ventilation [12].
The achieved sustainable ventilation is then reported as a fraction of the actually
measured 12–15 s maximum voluntary ventilation (MVV), and/or as a fraction of the
predicted MVV. MSVV should be 60–80% of the 12 second MVV. This test can be
considered as a test of in- and expiratory muscles, but it is relatively sensitive to
changes in airway obstruction, and needs careful control and adjustment of CO2
tension in arterial blood, by adding or removing dead space or CO2 to the inspired
air.
The three most common modes of respiratory muscle training are based [13]:
 On breathing against a resistive load which consists of an inhalation or deep

exhalation through a resistance of variable diameter, where, for a given air
flow, the smaller is the diameter the greater is the load reached. It is essential

that the patient’s ventilatory pattern and inspiratory flow are constantly
monitored, allowing to quantify training. This real-time control requires the
use of expensive and complex equipment.
 Breathing against a threshold pressure. This mode involves execution with
instruments that allow the passage of airflow only when the patient is able to
overcome a predetermined resistance, represented by a pressure that can be
inspiratory or expiratory. The instrument used for training the inspiratory
muscles, economical and portable, called the threshold IMT (Inspiratory
Muscle Training) consists of a valve that opens allowing the passage into the
airways only when the patient generates a predetermined negative
inspiratory pressure, while the exhalation is hindered. The expiratory
musculature can be trained through another Threshold PEP (Expiratory
Muscle Training) device. For both modalities, monitoring the subject’s
breathing is not necessary.
 Isocapnic hyperpnea the method involves performing voluntary hyperpnea
maneuvers, which consist of fast and deep breaths without incurring
hyperventilation hypocapnia and without altering the physiological oxygen /
carbon dioxide ratio. In respiratory muscle training it is impossible to train
strength and endurance selectively, there are protocols whose modality
involves greater strength training and protocols that involve greater use of
resistance with the common feature of having to be reviewed cyclically every
4 weeks.
Figure 2. RMT devices Strenght and Endurance training (Treshold IMT, Powerbreathe).
But what can we expect, what results does this training achieve in terms of
fighting weakness of the respiratory muscles and in the neuromuscular patient? What
are the effects when compared with standard treatment, is there an increase in MIP
and MEP? Which patients can benefit from it and for how long? In the next

paragraph the scientific literature will be explored to answer these questions and find
evidence of effectiveness to support this practice.
Table 2. FITT Strength, Endurance
Type Timing Frequency Intensity Modality

Strength 6-8 week 3-7 22-60%MIP 10-15 inspiratory efforts
sessions/week 10-60% MEP of 2 min; max 30 reps
Endurance 6-8 week 3-7 30% MIP 1-2 min of work x 10 reps
sessions/week 30 min
EVIDENCE
Try to answer to relevant clinical questioning using primary outcomes, such as

The number of pulmonary exacerbations, health status or lifespan it’s not realistic
due to the complexity of the questions and the specific characteristics of the studies
until now produced. Furthermore, the studies produced until now clearly show that is
not possible to generalize the results obtained to the multiple categories of patients.
The weaknesses of the studies produced so far, in relation to the use of
inspiratory muscle threshold (IMT) in neuromuscular patients have recently been
reiterated. Since 2014 many systematic reviews have agreed on the limited evidence
of IMT to produce statistically significant modification of strength. The efficacy of IMT
in people with Amyotrophic Lateral Sclerosis (ALS) has been reviewed in 2014. The
authors found four studies: two RCTs one pre experimental study and one. With a
historical control group. They concluded that IMT has limited evidence in inducing
positive effects on strengthening inspiratory muscles in these patients [14].
A different observation was published in 2016 in another systematic review and
meta-analysis, including people with neurodegenerative disorders (Multiple Sclerosis
and ALS).
The review included nine papers (194 patients) and RMT produced a significant
increase of MIP (23.50cmH2O; 95% CI: 7.82 to 39.19), MEP (12.03cm H2O; 95% CI:
5.50 to 18.57) and FEV1 (0.27L; 95% CI: 0.12 to 0.42) compared to the control group
but did not differ in FVC (0.48L; 95% CI: -0.15 to 1.10) and distance in 6MWT
(17.95m; 95% CI: -4.54 to 40.44).
The reviewed papers covered training protocols that were carried out for 8 weeks
up to 3 months, at a frequency of 7 days/week with 2 daily sessions, consisting of 3
sets of 15 repetitions or 10 minutes at an intensity of 30 to 40 or 60% of the subject’s
maximum pressure. The utilization of three sets has a duration of a few minutes and
we considered it equivalent to a 10minute training [15]. Studies about the effects of
RMT in NMD focused mainly on DMD, SMA, LGMD and BMD. Studies from the past
few years on IMT in NMD focused mainly on DMD, SMA, LGMD and BMD. In people
with DMD, RMT can lead to improvement of muscle strength, when compared to no

training (in the medium term) [16]. The regular and generalized use of RMT in DMD
patients remains controversial but some studies show promising results, especially in
the early stage of the disease with no severe impairment of functional status [16].
Improvements of inspiratory muscle endurance in people with DMD seems to be
related to a dose-dependent effect of the inspiratory training itself (with a specific
individualized low-intensity inspiratory resistive training during one year of
intervention) [17]. Using Pimax as guideline for intensity to train with a total exercise
time ranging from 10 to 30 minutes and a frequency from one to thrice a day,
produced significant changes both in strength and endurance [18]. The concept of
“fine tuning” with a dose-response concept of the training stimulus must be
considered in conjunction of a general safety concept that locate a threshold of VC a
muscle strength not below the 50% of the predicted values risk of hypoventilation
[19].
Adult patients with progressive multiple dystrophy and SMA, increased VC and
maximal voluntary ventilation and not after a four week IMT programme [20].
A delay in the onset of respiratory complications, with improvement of RM
strength after a six week of IMT programme, has been reported by an observational
study in children and adolescents with DMD, Limbe gird muscular dystrophy and one
patient with facio scapular muscular dystrophy.
Some studies reported RM strength improvements, observing statistically
significative changes between intervention and control group of Pimax [21, 22, 23].
In one study that included children and adolescent in the range ages 7-17 years,
was implemented a six months intervention with IMT at intensity of minimum 30% of
Pimax twice a day with a threshold device.
CONCLUSION
The clinical characteristics of NMD depend on where the lesion occurs, and
these lesions can be found anywhere between the anterior horn cells of the spinal
cord and the skeletal muscle. Subjects with NMD may present with muscle
weakness, loss of spontaneous movement, involuntary muscle activity and muscle
atrophy. Generally, children are affected by hereditary NMD, which cause physical
disability, usually through progressive skeletal muscle weakness, and in some
conditions, this includes respiratory muscle weakness (diaphragm and accessory
muscles of respiration). Both inspiratory and expiratory muscles are needed to
produce a cough strong enough to maintain upper airway patency.
The deterioration of respiratory muscle function in these diseases, in addition to
the effects on lung function, reduces functional capacity, limits activities of daily living
and limits quality of life. Furthermore, it precipitates the onset of respiratory failure,
and contributes significantly to morbidity and mortality.
RMT could be considered a possible adjunctive therapy for people with
suspected or confirmed respiratory muscle weakness [24].

RMT may improve lung capacity and respiratory muscle strength in some NMDs.
In ALS there may not be any clinically meaningful effect of RMT on physical
functioning or quality of life and it is uncertain whether it causes adverse effects and
may result in some improvements in lung function for people with amyotrophic lateral
sclerosis and Duchenne muscular dystrophy.
To authors’current knowledge, no articles reported the number of unscheduled
hospitalisations for sudden infection or worsening of chronic respiratory failure, for
RMT. Therefore, authors believe that is important to find appropriate evidence of
safety and efficacy for its usage. The evaluation of respiratory muscles is of
paramount importance, in relation to the level of functionality of the patient and his
clinical history. This, especially to understand the development of potential
complications in NMDs subjects with verified respiratory muscle weaknesses, which
may hinder the recovery processes or even put the patient’s life at risk. These
complications should be tackled with properly targeted evidence-based interventions,
so that timing of care is proper and beneficial. This means considering first-choice
interventions such as the usage of NIV, in-exsufflator, or others, well-known for their
effectiveness and the scientific evidence in their support. Therefore, the usage of
RMT should only be considered as an adjunct, for selected clinical situations, with
precise casuistries. Particular attention should be given to FITT components
(Frequency, Intensity, Time and Type of exercise). However, the choice of specific
parameters for each component of the FITT should always be subordinated to type
and phase of the disease, together with clinical evaluation and reasoning. This to
promote accurate, safe, and properly timed interventions, to the specific patient, that
can response appropriately.
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Echenne, Bernard & Préfaut, Christian & Ramonatxo, Michele. (2002). Dose-
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Chapter 36
PREVENTION OF PULMONARY MORBIDITY
Barbara Garabelli1 and Emilia Privitera2,

1
Pulmonary Unit, Centro Clinico Nemo c/o ASST Grande Ospedale
metropolitano, Niguarda, Milan, Italy
2
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
Health Professions Department Unit, Milan, Italy
ABSTRACT
Pulmonary morbidity is common in neuromuscular diseases (NMDs),

unfortunately often from the first years of life.
It represents one of the main causes of respiratory failure, reduced quality of
life, mortality.
Since the 1950s, the spread of mechanical cough assistance techniques,
alongside non-invasive ventilation, has made it possible to improve the clearance
of bronchial secretions and reduce the morbidity of these patients.
In neuromuscular diseases, although mainly characterized by ineffectiveness
of cough caused by muscle failure, respiratory tract infections, when recurrent,
can cause damage to the deep lung, some of those issues may be as
atelectasis, fibrosis, dystrophy of the lung tissue, bronchiectasis.
For this reason, in the perspective of personalized medicine, it is important to
examine the specific situation of the individual and to consider the possible
effectiveness of mechanical devices that improve the clearance of the deep lung.
In this chapter we will talk about the usefulness of operative protocols in the
management of respiratory infections, but also of techniques not routinely used in
the bronchial management of neuromuscular diseases. Which have shown a
clear efficacy in reducing pulmonary morbidity when the only cough assistance
techniques are not enough, improving the quality of life of patients.

Corresponding Author’s E-mail: emilia.privitera@policlinico.mi.it.

496 Barbara Garabelli and Emilia Privitera
Keywords: pulmonary morbidity, peripheral airway clearance techniques (ACT’s),

neuromuscular disease
INTRODUCTION
Patients with NMDs can experience little to profound limitation of both ventilation
and cough, with different rates of pulmonary morbidity and mortality.
Recurrent respiratory tract infections (RTI’s), together with severe bulbar
dysfunction, are the main causes of morbidity and mortality in patients with
NMDs [1].
A recent “state of the art” review on airway clearance techniques (ACT’s) divided
ACT’s into “proximal” (cough augmentation) and “peripheral” (sputum mobilization))
[2].
In Chapter 23 we have already discussed about cough augmentation techniques.
In the current chapter we will give a complete view of peripheral ACT’s
techniques effective in NMDs to prevent pulmonary morbidity.
A PROTOCOL TO MANAGE RESPIRATORY TRACT INFECTIONS
A study dated 1997 showed that in a sample of different NMDs upper respiratory
tract infections (URTI) caused a reduction in respiratory muscle strength: VC, MIP,
MEP and SpO2 abruptly decreased, while End tidal PCO2 augmented.
It took a mean of 21 days to regain baseline values in respiratory parameters [3].
In some cases, RTI involve the deep lung, causing little airway obstruction,
multiple atelectasis, ventilation/perfusion (V/Q) mismatch and oxygen desaturation.
In the distant 2000 Tzeng and Bach published an article [1] which presented an
oximetry feedback protocol proposed for the management of chest infections in
NMDs and compared it to the standard treatment used in those times.
They studied 2 different groups of patient: group 1 consisted of by patient that
were not previously in charge to their center, were managed conventionally, and
attended their hospital after an episode of respiratory failure. After acceding the
hospital, they had access to the protocol and started being managed as group 2.
Group 2 comprised of by patient already in charge of the hospital and already
managed with the oximetry feedback protocol, started since when their PCF
decreased to <270 l/min.
Conventional treatment described by the authors included routine monitoring of
pulmonary function tests and symptoms of sleep disordered breathing.
A low- range bilevel positive pressure ventilation was prescribed if the patient
showed nocturnal ventilatory disorders.

Prevention of Pulmonary Morbidity 497
Respiratory muscle aids were not used during RTI.

During a RTI, physical examination, images of the thorax, arterial blood gas
analysis, oxygen was delivered arbitrarily, without considering the risk of
hypercapnia, to maintain a saturation >95%.
Conventional chest physiotherapy consisted in chest percussion, postural
drainage, use of bronchodilators and deep airway suctioning.
When the patient desaturated, supplemental oxygen was used to correct
desaturation. When intubated, the weaning from the tube was performed without
using non invasive ventilation to correct hypercapnia, and if the patient was
unweanable, a tracheostomy was then performed.
The authors presented a different way to routinely ensure and maintain the
patient’s respiratory well-being. The protocol provided regular monitoring of VC, MIC,
Sao2, and Petco2. Air-stacking was taught when VC was inferior to 2 liters, and
oximetry feedback was introduced when the patient started to have weak cough
(PCF < 270 l/min). A portable volume-cycling ventilator with a nasal mask was used
to correct hypoventilation.
During chest infections continuous NIV use and cough assistance were provided
and if the patient conditions became unstable hospitalization was provided.
Supplemental oxygen was delivered only in intubated patients.
MI-E was used as needed, even continuously, to maintain SpO2 > 95%, using
mouth suctioning, if necessary, after the MI-E. No deep airway suction was provided.
If intubated, patient were extubated only when saturation was normal at room air,
receiving continuous non invasive ventilation as needed to avoid hypercapnia.
The authors demonstrated that non-protocol patients tended to have repeated
episodes of respiratory failure until being introduced to the protocol.
The protocol permitted to avoid on average 1 episode of respiratory tract
infection and 1 hospitalization per patient per year.
They calculated that maximum time without hospitalization due to the protocol
was 31.5 years in non-ventilator users, 13,8 years for part time ventilator users and
16,8 years for full time ventilator users.
From those years the knowledge on correct management of pulmonary
assessment, cough assistance manual and mechanical techniques, non-invasive
ventilation modes and RTI interventions have changed the prognosis of NMDs and
improved their quality of life.
Nevertheless, respiratory management of critical NM patients sometimes cannot
be pigeonholed into a single protocol, and alternative respiratory physiotherapy
approaches may be helpful in restoring the patient’s respiratory well-being.
In the next chapter we will focus on the principles of chest physiotherapy and
different peripheral airway clearance techniques useful in case of deep lung mucus
engagement which find space of use in neuromuscular diseases.

PRINCIPLES OF CHEST PHYSIOTHERAPY
Multiple techniques of chest physiotherapy could be useful to loosen secretion

and augment sputum mobilization, while seeking an improvement in peripheral
ventilation.
Peripheral ACTs act from the 12th generation of bronchial tree and above.
Generally, the aim of chest physiotherapy while working on the deep lung is to
open atelectasis, restore alveolar ventilation by emptying the alveoli of inflammatory
contents, improve local ventilation and ventilation/perfusion ratio (V/Q) in every
pulmonary section, maintain bronchial airways prone to collapse open, mobilize
secretions to central airways and toward the mouth and restore normal oxygen
saturation.
To reach these aims it is necessary to produce adequate volume in every single
pulmonary section and create adequate inspiratory/expiratory flow bias.
Therefore, during chest physiotherapy, the peak expiratory flow (PEF) must
exceed the inspiratory flow (PIF) by at least 10 percentage points (PIF: PEF = 1: 1.1).
Besides, the flow must be between 30-60 l / min, depending on the rheological
characteristics of the mucus.
The mucus undergoes the physical stresses due to the variations in flows and
pressures inside the lung: in vitro studies have shown that the passage of air above
the mucus layer is able to develop shear forces which, exceeding the surface tension
of the fluid, are able to drag the bronchial secretions in the same direction of the flow.
Increasing the speed of expiratory flows is therefore the main strategy for
mobilizing bronchial secretions in the airways.
The transport speed is functionally related to the diameter of the airways and the
thickness of the mucous layer. Transport in small caliber airways or heavily cluttered
from secretions requires smaller expiratory flows than in larger the ones caliber
airways or these with the same dimensions but with less mucus encumbrance.
In healthy lung and normal muscle strength, the difference in transverse diameter
between inspiration and expiration, even at tidal volume, is sufficient to ensure that
the PEF is higher than the PIF, just enough to promote cephalad airflow bias.
The alveolar driving pressure and the resistances of the bronchial tree ensure a
gradual pressure drop: the EPP is reached at the level of the bronchi and the
dynamic narrowing that is observed at the level of the peripheral airways does not
reach the collapse point, but it favors the local increase of the linear speed of the air
(Venturi effect) and the interaction with the mucus.
In case of severe obstruction or loss of elasticity of the lung, the resistance
increases, and the expiratory pressure drop occurs much earlier in the peripheral
airways not supported by cartilage.
If forced expiratory maneuvers are performed, especially if started at low lung
volumes, the airways can collapse, trapping a portion of air upstream of the point of
equal pressure (EPP).

The modulation of the expiratory flow is therefore the most important strategy
useful to counteract the collapse of the airways.
The generation of flows depends on the volume of air present in the airways: a
large starting volume allows to generate very high flows if expelled in a short time by
cough, but it can also be used for a slow and prolonged exhalation, maximizing the
effect of the interaction time between air and mucus.
This mechanism of interaction between air and mucus can be effective from the
first up to the 10-16th bronchial generation (the variability is due to the irregular
distribution of the bronchial tree).
The optimal interaction zone is located in the central airways (3-4 generation)
where higher velocities and turbulent flows can be generated.
Going towards the periphery, in the middle passages, the flow becomes linear
and decreases in the single airways, due to the distribution on an increasingly wider
bronchial section. Where the exchange area begins, with the terminal bronchioles
and alveolar chambers, the diffusion of oxygen is faster than the residual air flow
itself, still present in the alveolar canals, which disappears completely inside the
alveoli (Brownian motions of the molecules). It is therefore unthinkable that the
strategy of modulation of flows can act with the same purpose of air-mucus
interaction even in the periphery of the lung.
The deep lung, as well as being the seat of the main respiratory functions and
the one in which, normally, there are the least resistance, represents the reservoir of
air that is used to generate the expiratory flows that move secretions into the "small"
conduction area.
Two structural elements of the deep lung define the rationale for each
intervention aimed at volume recruitment: alveolar interdependence and collateral
airways.
Any variation in one point affects the immediate surrounding areas and the entire
structure.
In the presence of obstruction, even partial, the inspired air reaches the alveoli
upstream of this, much more slowly. The air-filling constant of these high resistance
areas is much higher than normal and, if the principal airway is completely blocked,
air needs more time to reach them through the collateral airways.
In this case, strategies that allow to increase the inspiratory time and modulate
the expiratory flow will be the most suitable [4].
Neuromuscular patients need to support or replace cough when it becomes
ineffective. If hypoventilation can be managed with the use of mechanical ventilation,
the generation of cough-like expiratory flows must be achieved by means of manual
or mechanical insufflation of air followed by sudden compression of the abdomen
and/or chest, even associated with mechanical exsufflation, to rapidly expel the air
previously inhaled.
The intervention of respiratory physiotherapy cannot be standardized: each
action must be guided by the patient’s individual response, his thoraco-pulmonary
system and the clinical conditions of the moment. Furthermore, although the main

problem is cough, the possibility of involvement of the peripheral airways should not
be overlooked.
In some secondary neuromuscular diseases, we must also keep in mind that the
incidence increases with increasing age, as in ALS.
Therefore, it is not unlikely to find situations in which not only the respiratory
muscles are compromised, but the lung develops the typical alterations of aging,
such as emphysema and the reduction of parenchymal elasticity.
Furthermore, patients with COPD are frequent, as it is also a disease whose
incidence increases with age.
PERIPHERAL AIRWAY CLEARANCE TECHNIQUES
A recent state of the art review lists these different techniques as acting on the
deep lung: manual techniques (MT), high frequency chest wall oscillation (HFCWO)
and compression (HFCWC), intrapulmonary percussive ventilation (IPV) and chest
wall strapping (CWS) [2].
Some other positive experiences are to be considered with the expiratory flow
acceleration produced through the EFA technology (expiratory flow accelerator) used
in SMA type 1 patients [5].
The use of peripheral airway clearance techniques (pACTs) is possible in infants,
children and adults, even in the presence of a tracheostomy and/or bulbar failure or
intellectual impairment.
Most of pACTs are to be performed in combination with mechanical ventilation, if
the technology used does not increase lung volume itself, or the VC of the patient is
too much little to conclude chest physiotherapy without an inspiratory aid.
Manual Techniques
Manual Techniques (MT) consist of chest percussion and vibration, generally

using hands and fingers. MT are classically performed during the expiration,
accompanying with the entire palm of the hand the desufflation of the chest and
applying extra-thoracic vibrations until the end of the desufflation. MT are particularly
suitable in little patients (infants and children or little-size adult) because of the
efficacy in transmitting the vibration through the pulmonary tree. The compression
and oscillation applied to the chest are believed to improve secretion clearance
through the increase in peak expiratory flow. Secretion are then expelled, when
arrived in the large airways via suction or cough [6, 7]. Even if lacking scientific
evidence for these techniques is lacking, MTs are widely used in clinical practice.
Figure 1 shows the correct hand placement on the thorax of a new-born patient
to use manual vibration during exhalation.

Figure 1. Correct hand placement for Manual vibration of the thorax.
HFCWO and HFCWC
High frequency chest wall oscillation (HFCWO) and compression (HFCWC)

cause air to move inside and outside the lungs at high velocity, at frequencies similar
to the resonant frequency of the lung, between 5 and 20 Hz [8].
In HFCWC an external air pulse generator relates to a double circuit to a jacket.
The air generator delivers intermittent positive pressure into the jacket, causing the
jacket to rapidly inflate and deflate, percussing the thorax at different frequencies.
This movement produces a transient/oscillatory increase in airflow, vibrating the
secretions from the peripheral airways toward the mouth enhancing airway
clearance.
Pulse frequency is adjustable from 5 to 25 Hz and the pressure in the jacket can
range from 28 mmHg at 5 Hz to 39 mmHg at 25 Hz [9].
HFCWC is generally much more effective in NMD if the patient uses mechanical
ventilation to correct hypoventilation and increase local regional ventilation.
It can be used either with in non-invasive or invasive ventilation ed subjects, to
augment airway clearance. Initial settings start at 5 Hz up to 10–15 Hz.
It is necessary to remember that this technique is effective to collect secretion
from the lower airways to the more central ones but does not substitute for cough.
Considering this, patient treated with HFCWC frequently need to cough
mechanically assisted receive during or after the treatment, to complete the
expulsion of secretions from the upper airways [10].
Published data suggest the tolerability and safety in NMDs [11, 12]. Some
authors promote the use of HFCWC in patients with scoliosis in whom conventional

chest physiotherapy is not possible [12]. Others showed a reduction in medical costs
along the inpatient courses in case of pneumonia [13]. Therefore, published
experiences and experiences from clinical practice suggest that this technology could
be useful in hypersecretory NMDs or affected by pneumonia. Manufacturer’s
guidelines suggest the use of HFCWC in patient > 3 years old.
The airway vibration favors fluid-liquid interaction enhancing the cephalad
movement of secretions. This makes bronchial unblocking sessions more effective,
limiting the patient’s muscle exhaustion.
Another issue to keep in mind is the characteristic of bronchial secretion and the
ability of the patient to control upper airways and collaborate with cough.
If the secretions are too liquid, with little elasticity and viscosity, the use of
HFCWC could create problems in the upper management of secretions that are
mobilized towards the mouth. The mobilization of large volumes of bronchial
secretions may not be the best strategy, because the rheological characteristics of
the mucus would not facilitate their removal from the central airways, putting the
patient at risk of complete obstruction of the main bronchi and deep desaturations.
Figure 2 shows a typical HFCWC device.
HFCWO, on the other hand, uses negative pressure to produce the vibration of
the cuirass. As the ventilator delivers negative pressure the transverse diameter of
the thorax increases and the air comes into the lungs. When the negative pressure
ceases the patient expires. HFCWO can deliver high frequency intermittent negative
pressure during spontaneous breathing or mechanical ventilation. The Hayek
oscillator can deliver either negative or positive pressure, ranging from -70 to + 70
mmHg.
Positive pressure is usually used to compress the chest and produce a forced
expiration. Airway pressure during expiration can be positive, atmospheric or
negative, causing ventilation to occur above, at, or under the functional residual
capacity of the patient.
Adjustable variables in the Hayek oscillator include frequency (8 to 999
oscillation/min), I/E ratio (6:1 to 1:6) and inspiratory pressure (-70 to + 70 mmHg).
Figure 2. HFCWC components.

Figure 3. Hayek Oscillator components.
Clinical practice suggest 2 sets of cycles: several minutes at high frequencies

(usually 600/720 cycle/min) at an I/E ratio of 1:1, followed by several minutes at
60/90 cycle/min frequency and 5:1 I/E ratio [9].
In the case of HFCWO, there is no limitation in the age of use, so young children
can be treated with this technology. In a case report of a child with SMA type 1
treated with HFCWO the authors suggested that the device was safe and that the
increase in spontaneous breathing time was attributed to improved secretion
clearance [14].
Figure 3 shows an Hayek Oscillator components.
The duration of the treatment with HFCWC and HFCWO goes from a minimum of
5 min to 15-30 min length, stopping whenever the patient needs to cough. These
times, however, derive only from clinical practice experiences. Clinical trials
describing the most effective timing in the treatment of neuromuscular patients have
not yet been published [2].
In order to choose the most effective and tolerated pressure transmitted in the
cuirass or jacket, and the most effective oscillation frequency, it is possible to use a
pneumotachograph to visualize PIF and PEF and makes sure that PEF is higher than
PIF during the treatment, to promote transport of secretions towards the main
bronchi.
As previously mentioned, the use of HFCWO and HFCWO does not occur
regularly in the neuromuscular patient, as cough assist techniques are usually
sufficient to ensure adequate clearance of the airways. In case of complicated
respiratory infections, pneumonia, bronchiectasis or hyper secretiveness, the
addition of HFCWC and HFCWO can be used to improve deep lung clearance,
resolve atelectasis, improve regional ventilation and speed up the recovery process
from respiratory infection.
INTRAPULMONARY PERCUSSIVE VENTILATION (IPV)
IPV is a kind of intermittent positive pressure ventilation delivered via a

pneumatic device. Boluses of air are delivered at frequencies of 100–300 cycles per
minute at peak pressures ranging from 10 to 40 cm H2O.

The technology can be used while the patient is spontaneously breathing or

during mechanical ventilation (face masks, tracheostomy). High-frequency bursts of
air are superimposed on top of the patient’s own respiration.
The intrapulmonary percussion permits to expand the lungs, vibrate and enlarge
the airways. IPV potentially delivers air to the distal lung units, beyond accumulated
secretions, improving homogeneity of ventilation in very different patient populations,
including NMD patients [15].
The parameters that can be titrated in order to increase PEEP, percussion or
ventilation are frequency of air pulse, I/E time, PEEP, operational pressure.
Parameters of IPV should be set to obtain the highest peaks of pressure, high
frequency, and short inspiration times.
Increasing frequency increases positive end-expiratory pressure (PEEP) and
percussion by enhancing the peak of pressure but decreases the provided tidal
volume. Increasing inspiratory/expiratory (I/E) time ratio increases PEEP and
decreases percussion (I.E., with I/E ratios of 2:1). Maximal percussion is reached by
increasing operational pressure and with a I/E ratio of 1:1. Increasing pressure
increases also PEEP and ventilation.
Lower frequencies and higher pressures are required when patients need
assisted ventilation, to avoid oxygen desaturation and maintain correct CO2 levels.
Lower pressures and higher frequencies should be set for infants and children.
Higher expiratory than inspiratory flows are always produced by IPV, favoring
cephalad secretion mobilization.
Therapeutic sessions could range from 9 to 15 min or longer. Usually a
progression in the frequency of bursts is used, to move secretions from pulmonary
periphery (high frequencies, high PEEP, lower ventilation) to central airways (low
frequencies, low PEEP, higher ventilation).
Some limits of this technology, however, are to be listed: it’s a very expensive
technology and some training is needed to learn how to modify settings during the
treatment in order to reach the best results. Besides, IPV may hyperventilate patients
when there is no control of arterial carbon dioxide during titration, in children.
Therefore, transcutaneous CO2 monitoring or end-tidal CO2 measurements could be
useful tools to prevent hypocapnia during the treatment.
IPV is especially useful in patients with NMDs and acute respiratory failure. IPV
can also improve persistent pulmonary consolidation and appeared to be safe and
effective in case of non-responders to conventional chest physiotherapy [16].
In a comparison study conducted on pediatric tracheostomized patients, IPV was
associated with a significant decline in hospitalizations, decreased in respiratory tract
infections, antibiotic, bronchodilator, and steroid use. The authors suggested that IPV
could be more effective and beneficial in providing airway clearance in some fragile
pediatric populations [17].
Oscillatory techniques such intrapulmonary percussive ventilation should be
considered in children who have difficulty mobilising secretions or who have
persistent atelectasis despite use of other airway clearance technique [18].
Figure 4 shows different IPV devices available for hospital and home use.

Figure 4. IPV devices for hospital and home treatment.
Chest Wall Strapping
Chest wall strapping (CWS) permits to lower the functional residual capacity of
the patient without the use of expiratory muscles. The strapping of the thorax causes
an improvement in airway conductance and reduction in airway resistance. Even
lung elastic recoil is improved. A small airways dilatation appears bronchial dilation is
greater the closer the patient approaches to breathing at residual volume (RV + 0,5
liters) [19]. CWS enhances forced expiratory airflows. Eberlein et al. found that
maximal expiratory airflows for the same absolute lung volumes were consistently
and substantially increased, ranging 147–188% of the flow rates in the control
condition (spontaneous breathing at FRC) [20].
The principles of CWS can be overlapped to those of Autogenic Drainage,
facilitating mucus transport [2].
Some limitation about the use of this technique in neuromuscular diseases are to
be considered: breathing at low lung volumes causes a reduction in tidal volume, that
could be reduced by the 25%. Dyspnea could occur in very weak patients, so
mechanical ventilation in recommended to avoid its onset.
Despite the lack of evidence comparing deflation by CWS to breathing at a low
lung volume (as in Autogenic Drainage) to improve airway secretion clearance,
physiological principles and experience in clinical practice suggest that this very
cheap technique could be a tool to increase maximal expiratory flows and improve
airway clearance in the middle bronchial branches, when mechanical respiratory
devices are lacking.
Figure 5 shows a classical strapping of the thorax, reproduced with permission
from Sybrecht GW et al., J Appl Physiol 1975.

Figure 5. Chest Wall Strapping.
Expiratory Flow Acceleration
A very interesting new technology is approaching the world of neuromuscular

disease with interesting issues in patient who cannot tolerate high pressure treatment
or cannot control their upper airways or simply want treat the status of mucus
encumbrance with a very tolerable technique.
The Expiratory Flow Acceleration produced by the device Free Aspire (Medical
Products Research Srl, Italy) accelerate patient’s expiratory flow through a special
connector which takes advantage of the Venturi Effect.
The technique is performed with a face mask or mouthpiece applied to the
connector that produces the Venturi effect. An adjustable flow generated by an
external compressor allows to accelerate the patient’s natural expiratory flow,
exploiting the interaction between the speeds of the two fluids.
The acceleration in the respiratory flow occurs only during expiration (while
inspiration remains unchanged) and is proportional to the airflow on spontaneous
breathing, respecting the natural rhythm of the patient and without the need of active
collaboration.
The expiratory flow accelerated by the technique guarantee a PIF/PEF ratio < 1.
The secretions are dragged more rapidly towards the central airways by the
augmented gas-fluid interaction. No negative pressure is generated in the airways,
canceling the risk of their collapse.
For that reason, the EFA technology could be very suitable in patients with
augmented collapsibility of the airways, proximal or peripheral.
Producers recommend a minimum of 10 consecutive minutes treatment to a
maximum of 30 minutes treatment, respecting patient tolerability and muscular
waste. Aspiration of the upper airways is possible whenever the patient needs to be
suctioned, stopping the therapy for a few moments. Effective cough is not requested
to use this technology.

Figure 6. Free Aspire device for EFA.
The EFA technology was successfully used with a 3-year-old SMA type 1 little
girl and permitted to resolve a right pneumonia in a few days, with a normal x-ray
image at discharge. The child performed the treatment 3 times a day for 20 minutes
duration, without oxygen desaturation and improving lung objectivity [5].
Another Italian study conducted on cerebral palsy showed that in a patient
population characterized by little collaboration the EFA permitted to reduce the
number of pneumological visits, use of antibiotics and the length of hospital stays
[21]. Figure 6 shows the EFA device and its components.
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Management of bronchial secretions with Free Aspire in children with cerebral
palsy: Impact on clinical outcomes and healthcare resources. Italian Journal of
Pediatrics BioMed Central Ltd.; 2016; 42.

SECTION 9. HOME MECHANICAL VENTILATION

Chapter 37
DISCHARGE PLANNING FROM HOSPITAL

TO HOME MECHANICAL VENTILATION
Salvador Díaz Lobato1,*, MD, PhD,

Asier Bengoechea Calafell2, MD and Johanny Vargas3, MD
1
Medical Director Nippon Gases Healthcare, Spain
2
Hospital de la Ribera. Valencia, Spain
3
Medical Dept. Nippon Gases Healthcare, Spain
ABSTRACT
When we evaluate the possibility of referring a neuromuscular patient to

home, it is necessary to verify that a series of requirements are met to ensure
that it is feasible to manage the patient at home. We need to consider not only
human factors, but also technological factors, factors related to the medical team
and legal, social and economic factors. There is no single way to organize the
care plan a patient needs at home. This will depend not only on the patient’s
clinical situation, but also on the existing financing model, the culture of the
organization, the existence of structured home care and hospitalization
programs, the patient’s economic resources, the collaboration between primary
care and hospital care, or the existence of consolidated home respiratory care
providers in the sector. The patient must have the opportunity to express his/her
experiences and feelings, to explain his/her concerns and doubts and to decide
for him/herself if he/she wants to continue in a hospital institution (acute hospital,
chronic hospital, weaning or other facilities) or to take an important step and
return home. We must not forget that the involvement of the family in the care
process is essential and therefore their consent is required.
Keywords: discharge plan, neuromuscular disease, home respiratory care,

mechanical ventilation
*
Corresponding Author’s E-mail: sdiazlobato@gmail.com.

514 Salvador Díaz Lobato, Asier Bengoechea Calafell and Johanny Vargas
When we evaluate the possibility of referring a neuromuscular patient to home, it

is necessary to verify that a series of requirements are met to ensure that it is
feasible to manage the patient at home. Some requirements are related to human
factors, patient and medical equipment; other requirements are technological,
adequacy of circuits and of course, we have to take into account economic
requirements. Let us comment on the most important aspects.
1. Factors related to the patient:

- The patient must be stable, without presenting acute unresolved
problems. We cannot propose the home referral of a neuromuscular
patient who does not meet minimum criteria for clinical stability. The
persistence of bronchospasm, signs of heart failure, high oxygenation
requirements, pulmonary Rx infiltrates, fever, significant dyspnea or
abundant secretions, would be aspects that we should control before
thinking about continuing the patient’s care at home.
- In the case of the more ventilodependent patients, they should express
his/her desire to continue care at home. If the patient expresses doubts,
concerns, uncertainties, insecurity.... if he is not fully convinced that he
wants to go home, that he can go home and that he will feel better at
home, in a much less hostile environment than the hospital, the
possibilities of claudication, failure and return to the hospital will be very
high.
- The patient and caregivers must be involved and motivated. In relation to
the previous section, this is a fundamental requirement to guarantee the
patient’s maintenance at home. During the stay in the hospital critical
care unit, it is necessary to delegate functions to caregivers and family
members, until they feel safe in their actions, which will increase their
involvement. The involvement in the care in the hospital environment, will
translate into greater motivation to feel integrated into the care team and
part of the process of care.
- It is essential to identify the figure of the main caregiver. Many times this
figure will be assumed by a direct family member of the patient and it will
be necessary to give him/her our full attention and care as if he/she were
also a patient, since the success of the home care plan will depend on
the primary caregiver remaining motivated and involved.
- Before referring home a neuromuscular patient, it is necessary to verify
that the home environment allows the patient to remain at home. We
must take into account the habitability conditions of the home, if it has
electricity, if it is a small apartment where the main elements (ventilator,
aspiration devices, oxygen...) or accessories (lift, mobility, wheelchair....)
will not be able to be located. We will check again and again that these
factors prevent us from referring a patient to his home, which is otherwise
stable and without other problems for his transfer. In some cases, we are
going to need high energy consumption by having several machines

Discharge Planning from Hospital to Home Mechanical Ventilation 515
plugged into the power grid simultaneously. It is necessary to verify that

the home can assume this consumption of electricity without jeopardizing
the safety of the same.
- Likewise, it is necessary to check that the house is accessible. It is
necessary to think about the possibility of potential transfers of the
patient, emergency situations, mobilization of the patient...). In a patient
who lives on a 4th floor without an elevator, with narrow stairs, it is
probably not advisable to refer him/her to the home.
2. Factors related to the medical team:
- It is necessary to talk openly and continuously with the patient and family
members. The decision to continue care at the patient’s home should not
come as a surprise to the family. This possibility should be worked on
during the stay in the critical care unit, for as long as is necessary to
ensure that the patient and family are prepared for it. A task of education
and training of the patient and his or her family should be carried out, with
special emphasis on the main problems that may arise. It is necessary to
transmit to the caregivers feelings of security in their actions and to feel
that they are trained to face the possible problems, because they know
and master the possible solutions that can be applied.
- The medical team must ensure clinical stability in a safe home
environment. Define actions, protocols, circuits of action... The patient
must know what to do at all times, in the face of any unforeseen event
that may arise.
- It is necessary to ensure continuity of care at home. It is not enough to
move the patient from the hospital to his home and get rid of him. It is
essential to maintain contact and information between the home and the
hospital professionals.
- As a consequence of the above, it is necessary to verify that medical
follow-up at home is possible and to articulate the coordination of all the
professionals who are going to be involved in the care of the patient.
When different professionals are visiting the patient’s home, it is
advisable to have there a sheet of evolutionary comments where to write
what we have done, what is pending, therapeutic changes made or
incidents presented.
- It is considered essential to establish a treatment plan upon discharge.
What measures should the patient take into account from the therapeutic
point of view, medication controls (for example, if he/she takes
acenocumarol, who and how is going to monitor the INR), dose, rescue
medication... and fundamentally, to establish an action plan in case of
exacerbations, what to take in case certain symptoms are presented (for
example, if it starts with more expectoration, the color of the sputum
changes, the secretions are greenish... to begin to take antibiotics, to
define which, dose, duration...).

- Define circuits of urgent, preferential and scheduled attention. Once the

patient is at home, he must know perfectly what to do in case of crisis
and need of urgent attention. Who to consult, where to call, define the
hours of urgent care according to the resources available, for example,
until 8 pm you can call the hospital, but after that time you must call the
out-of-hospital emergency services. It is also necessary to define how the
programmed revisions will be done, if the patient will go to the hospital or
if a medical team will go to his home.
- It is highly recommended to provide psychosocial support to the patient,
family and caregivers.
- The literature is full of tips or advice that we should take into account
when moving a patient from the hospital to their home. Among the most
important we could highlight two:
o Avoiding weekend transfers.
o Provide all the information in writing, leaving a copy of these
documents at home, so that they can be consulted at any time by
professionals who can go to the patient’s home.
3. Availability of appropriate technological resources at home:
It is essential to have a ventilator appropriate for the patient’s pathology and that
meets the appropriate requirements to ensure effective ventilation. The international
recommendations establish different categories of ventilators, specifying the
characteristics that must be provided by ventilators authorized to treat patients with
more than 20 hours a day. Among them, it is worth mentioning that they should have
batteries and the capacity to estimate or measure the exhaled tidal volume.
In the case of patients with ventilodependence, some basic principles must be
observed:
 The patient must have two ventilators at home in order to be able to change
the ventilator in the event of a breakdown or electrical failure. The ventilators
must be the same and must be kept in perfect working order. The
recommendation is to alternate between the two ventilators (for example, by
changing them every week) to ensure that they are working correctly.
 Ventilators should have effective alarms to prevent serious or fatal episodes
(disconnection, low pressure or low volume, high pressure alarm). Alarms
should be audible throughout the home.
 It is essential to have an auxiliary battery for the ventilator, if there is absolute
dependence on ventilation (life support or 24 h), to act in case of power
failure and to provide a greater degree of autonomy and mobility to the
patient.
 In patients who travel in vehicles, it is recommended that they have an
adapter for connection to the cigarette lighter socket.

 Tracheostomized patients should have an ambú at home in order to solve

asphyctic problems or obstruction of the cannula.
The patient should have at home the appropriate consumables necessary for the
proper functioning of the ventilators and other devices. The patient should never be
in the situation where a fundamental connection piece is missing (for example, a
tracheostomy tube,...) and should never resort to homemade, such as joining pieces
with tape. Things it is necessary to have at home:
 In the case of non-invasive ventilation: non-invasive interfaces, ideally of

various models, to be able to rotate and relieve pressure points on the
patient’s face. In patients with many hours of ventilation per day, the use of a
pipette or ventilation with a mouthpiece is recommended on demand. It is
necessary to ensure that the ventilator used incorporates this mode of
ventilation. In these ventilators different programs can be selected, where
conventional ventilation can be programmed in one of them and pipette
ventilation (ventilatory mode to be chosen: MPV, “Mouth piece Ventilation”) in
another program.
 In the case of patients with tracheostomy ventilation, they should have
appropriate tracheostomy cannulas at home. The medical team will select the
type of cannulas that the patient will use, fenestrated or non-fenestrated, with
balloon or without balloon.
 It is important to have the appropriate tubing for the type of ventilation that
the patient is going to perform, especially with regard to the management of
expiration:
o The ventilation can be leakage, in this case it should have simple pipes,
but always identifying where the leakage port is. This can be located in
the mask or in the tube, and if not, it will be necessary to insert an
additional leakage port in the circuit. There are different additional leak
pieces on the market that perform this function.
o Ventilation can be carried out with an active valve. In this case, it is
necessary to have these valves, which can be basically of two types, with
a return cable that commands the valve or with two return cables, one for
the valve and another for the pressure sensor. It is important that the
ventilator is qualified to work with the active valve that we are going to
use, and it is very important to select the type of ventilation that we are
going to carry out on the ventilator, leak or with active valve, so that it
works correctly.
o A third way to carry out ventilation is with a double branch circuit, an
inspiratory and an expiratory one. Obviously, the ventilator used must be
appropriate for working with a dual circuit.

 In patients with tracheostomy ventilation, humidification is mandatory, and

the recommended type of humidifier, HME or active humidifier must be
selected. The patient must have sufficient spare material available at home to
ensure continuity of treatment.
 It should be considered whether the patient needs a secretion aspiration
device with an aspiration pressure regulation device at home. In this case, it
is necessary to have a sufficient number of aspiration probes at home.
 Patients who require it should have a cough assistant, such as the cough
assits, with the appropriate consumables for use.
 Others:
o Ensure adequate consumables for feeding the patient, whether natural or
gastrostomy.
o Ensure devices that allow the patient’s mobility (lift, wheelchair adapted
to the respirator, articulated bed, ...).
o In the event that the patient requires treatment with aerosolized
medication, we must provide the appropriate equipment according to our
recommendations. In the market we have available flow, ultrasonic and
mesh nebulizers, and there are also devices that can be attached to the
ventilator tubing, such as the Aerogen system. We can also use a
specific spacer for mechanical ventilation, such as the Aerochamber, or
T-pieces where we can directly administer the medication. In the case of
tracheostomized patients, we will assess the need for adapters to the
tracheostomy tube.
Given the amount of equipment, devices and consumables that ECC patients will
need at home, it is necessary to coordinate who will be in charge of their
maintenance and supply of materials. It may be the hospital itself that is responsible
for this task, but the usual model in Europe and other countries is the outsourcing of
this service through home respiratory care providers. These companies are in charge
of providing the necessary material, its maintenance and replacement. They have a
“call center” that attends to the calls of the patients and manages the priority of the
actions, and they have a technical service available at home for maintenance of
equipment, revisions, breakdowns, replacement of equipment, ... In Spain, for
example, these companies are selected by the health administration through public
tenders.
One last aspect to take into consideration when we are considering the referral of
a patient to a neuromuscular patient at home, is the economic one. Who is going to
pay all this? Who is going to take care of the cost of keeping the patient at home?
Who is going to take over the work of the home respiratory tcare provider or who and
how is one of these companies hired? The financing of the home program is
fundamental.
Who is responsible for the costs? Depending on the existing health system,
funding may be provided by:

 Public health system.

 Private insurance.
 Other financial entities.
 Charity systems.
 The patient himself.
What program coverage ensures this funding? We can find the paying agent to
finance:
1. A total coverage, in which they are included:

 Technology resources, respirators, consumables....
 Human resources, in variable numbers, nursing, doctors,
physiotherapists...
 The medication that the patient should receive.
 Other costs: transfers, economic aid to subsidize the consumption of
electricity...
2. A partial coverage, in which not everything is included, being able to be
financed:
 Only the technological resources.
 Part-time human resources.
 Full time human resources (24 hours).
ORGANIZATION OF THE PLAN OF CARE
There is no single way to organize the care plan a patient needs at home. This
will depend not only on the patient’s clinical situation, but also on the existing
financing model, the culture of the organization, the existence of structured home
care and hospitalization programs, the patient’s economic resources, the
collaboration between primary care and hospital care, or the existence of
consolidated home respiratory care providers in the sector.
When the time comes to consider that a neuromuscular patient meets the
appropriate criteria to go home, a series of aspects must be taken into consideration.
1. The patient must be informed of the different options available where he can
continue his care, taking into consideration that his home can be an
alternative.
2. The decision cannot be taken unilaterally by the hospital team, nor can it take
the patient and his/her family by surprise.
3. It must be explained to him/her that we guarantee his/her clinical stability in a
safe environment, and that we evaluate together with him/her and his/her
family the viability of the care plan.

4. The patient must have the opportunity to express his/her experiences and
feelings, to explain his/her concerns and doubts and to decide for him/herself
if he/she wants to continue in a hospital institution (acute hospital, chronic
hospital, weaning or other facilities) or to take an important step and return
home.
5. It is important to have a lot of common sense and not to force situations,
since this would only lead to failure in keeping the patient at home.
6. We must not forget that the involvement of the family in the care process is
essential and therefore their consent is required.
Table 1. Criteria required to assess the referral

of a neuromuscular patient to home
1. By the patient:
- Stable patient, with no unresolved acute problems.
- Patient’s desire to continue care at home.
- Patient and caregivers involved and motivated.
- Identify the figure of the main caregiver.
- The home environment allows the patient to stay at home (living conditions, electricity,
...).
- Accessibility of the home (considering possible transfers, emergencies, mobilization of
the patient, ...).
2. By the medical team:
- To guarantee clinical stability in a safe environment at home.
- Ensure continuity of care at home.
- Check that medical follow-up at home is possible.
- Establish treatment plan at discharge.
- Define circuits of urgent, preferential and programmed care.
- Existence of psychosocial support for patient, family and caregivers.
- Tips:
- Avoid weekend transfers.
- Provide written information.
3. Availability of appropriate technological resources at home:
- Respirator appropriate to the pathology. In case of ventilodependence:
o Two respirators to prevent electrical failure.
o Effective alarms to prevent serious or fatal episodes (disconnection, low pressure or
low volume, high pressure alarm). Alarms should be audible throughout the home.
o Auxiliary battery for the respirator, if there is absolute dependence on ventilation
(life support or 24 h), to act in case of power failure and to provide a greater degree
of autonomy and mobility to the patient.
o Connection for cigarette lighter socket in vehicles.
o Ambu.
- Adequate fungibles:
o Non-invasive interfaces. Pipette.
o Tracheostomy cannulas. Fenestrated, non-fenestrated, with balloon, without
balloon.
o Tubing.

o Expiratory/leak valves.
- Active humidifier.
- Secretion aspirator with suction pressure regulation device. Suction probes.
- Cough assistant.
- Others:
o Food (gastrostomy, ...)
o Mobility (crane, wheelchair adapted to the respirator, articulated bed, ...).
o High flow or ultrasonic spray with tracheostomy adaptation system.
4. Technical service available at home for equipment maintenance, revisions, breakdowns,
equipment replacement, ...
5. Economic aspects: financing the home program.
- Who is responsible for the costs:
o Public health system.
o Private insurance
o Other financial entities.
o Charity systems.
o The patient himself.
- Program coverage:
o Total coverage:
 Technological resources.
 Human resources.
 Medication.
Others.
o Partial coverage:
 Only technological resources.
 Part-time human resources.
 Full time human resources (24 hours).
REFERENCES
Ambrosino N, Vitacca M. The patient needing prolonged mechanical ventilation: a

narrative review. Multidiscip Respir Med. 2018 Feb 26;13:6.
Crimi C, Pierucci P, Carlucci A, Gregoretti C. Long-term ventilation in neuromuscular
patients: review of concerns, beliefs, and ethical dilemmas. Respiration
2019;97:185-196.
Dale CM, King J, Nonoyama M, Carbone S, McKim D, Road J, Rose L. Transitions to
home mechanical ventilation. The experience of Canadian ventilator-assisted
adults and their family caregivers. Ann Am Thorac Soc 2018;15:357–364.
Egea C, Chiner E, Díaz Lobato S, González-Mangado N, Capelastegui A, de Lucas
P. Ventilación mecánica a domicilio. Monografías de Arch Bronconeumol 2015;
2(5):178-201. [Mechanical ventilation at home. Arch Bronconeumol Monographs]
Navalesi P, Frigerio P, Patzlaff A, Häußermann S, Henseke P, Kubitschek M.
Prolonged weaning: from the intensive care unit to home. Rev Port Pneumol.
2014 Sep-Oct;20(5):264-72.

Szubski CR, Tellez A, Klika AK, Xu M, Kattan MW, Guzman JA, Barsoum WK.
Predicting discharge to a long-term acute care hospital after admission to an
intensive care unit. Am J Crit Care. 2014 Jul;23(4):e46-53.
Wilson ME, Rhudy LM, Ballinger BA, Tescher AN, Pickering BW, Gajic O. Factors
that contribute to physician variability in decisions to limit life support in the ICU:
a qualitative study. Intensive Care Med. 2013;39:1009–18.

Chapter 38
HOME MECHANICAL VENTILATION
Giorgio Emanuele Polistina1,, Pasquale Imitazione1,†

and Vittoria Graziani1
1
Department of Pathophysiology and Respiratory Rehabilitation
and Subintensive Respiratory Unit, Monaldi Hospital, Naples, Italy
ABSTRACT
In the last decades, the use of home mechanical ventilation (HMV) has
steadily increased worldwide, with varying prevalence in different countries.
HMV is a treatment of choice for chronic respiratory failure with alveolar
hypoventilation and important common themes such as airway clearance and the
process of transition to home care.
Recent home ventilators are pressure-targeted and have sophisticated
modes, alarms, and graphics, thereby facilitating the ventilator settings’
optimization.
However, home ventilators have different settings for each algorithm as tidal
volume estimation and leak compensation, and even there are several different
circuit configurations.
A basic understanding of HMV is of paramount importance to healthcare
workers taking care of patients with HMV.
When choosing a home ventilator, they should consider many indicators as
health status and prognosis of the primary disease, patient’s daily performance
status, time (hour/day) needed for ventilator support, family support, and financial
costs.
In this chapter we describe the indications for HMV and the factors that
influence successful delivery.
Keywords: Home mechanical ventilation, non-invasive ventilation, neuromuscular

disease, quality-of-life, respiratory failure

Corresponding Author’s E-mail: giorgiopolistina@gmail.com.
†
Corresponding Author’s E-mail: pasquale.imitazione@gmail.com.

524 Giorgio Emanuele Polistina, Pasquale Imitazione and Vittoria Graziani
INTRODUCTION
Across populations, prevalence and indications for home mechanical ventilation

(HMV) are highly variable; however, in the past two decades, HMV showed a
significant increase worldwide for several reasons.
EUROVENT survey reported a prevalence of HMV in 2005 of 6.6 per 100,000
patients (range, 0.1 – 17.0 per 100,000 patients), with neuromuscular and
lung/airway diseases being the most common diagnosis [1].
Chronic ventilatory insufficiency is the main indication for HMV.
Furthermore, as the population ages, the need for ongoing mechanical ventilation
in the home or long-term care facilities is likely to increase due to several reasons:
 improved survival following acute respiratory failure episodes as a direct

result of advanced treatment options in Intensive Care.
 development of compact, portable ventilators, as well as non-invasive (mask
ventilation) modes of ventilation; more comfortable commercial mask
interfaces
 a further shift from clinical care to home care
 the successful development of telemedicine
Considering the rising prevalence of HMV and the increasing number and
complexity of available HMV devices [2], a basic understanding of the fundamentals
of HMV is of paramount importance to physicians and nurses involved in pulmonary
and critical care medicine.
This chapter describes the indications for HMV and the factors that influence
successful delivery, including equipment.
A guide on this topic is needed to inform best practices, provide a basis to
identify gaps in care, and provide direction for future research.
The combination of non-invasive ventilation and cough-assist devices has
reduced tracheostomy ventilation indications in neuromuscular patients has also
prolonged survival.
NON-INVASIVE VENTILATION (NIV) OR MASK VENTILATION
Ventilatory support is capable of reliably providing volume and pressure for

adequate ventilation, but this can only be assured if the airways remain clear of
mucus and debris. During long-term invasive tracheostomy ventilation, airway
clearance (usually by suctioning) is routine. In neuromuscular disease (NMD)
patients, recognizing this principle is equally important – even before the need for
ventilatory support – and is critical in addressing the issues of worsening respiratory
mechanics and the inability to cough effectively.

Home Mechanical Ventilation 525
CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP)
Continuous positive airway pressure (CPAP) is a setting to delivering PEEP

during both inspiration and expiration but also maintains the set pressure throughout
the respiratory cycle [3].
The application of CPAP maintains PEEP, can decrease atelectasis, increases
the surface area of the alveolus, improves V/Q matching, and hence, improves
oxygenation.
INDICATION
Neuromuscular disorders may share common features of the reduced

neuromuscular weakness of upper airway dilators, diaphragmatic strength, or
cardiomyopathy that contribute to the development of sleep-disordered breathing.
Survival and quality-of-life benefits of nocturnal non-invasive ventilation
demonstrated that sleep-disordered breathing is a strong contributor to the morbidity
of neuromuscular diseases.
Hypopneas/hypoventilation is the most common sleep-disordered breathing in
neuromuscular disease, with a characteristic dips sawtooth pattern of desaturation
occurring during phasic REM sleep, representing an early warning of respiratory
muscle involvement. As the neuromuscular disease progresses, hypoventilation
develops initially in REM sleep with decreased intercostal EMG activity, then in
NREM sleep [4].
Definition of nocturnal hypoventilation for adults during sleep is an increase in the
arterial PaCO2 to a value greater than or equal to 55mm Hg for greater than or equal
to 10 minutes, or a greater than or equal to 10–mm Hg increase in the arterial
PaCO2 relative to the awake supine value, to a value exceeding 50mm Hg for 10
minutes or more.
For children, hypoventilation is scored when more than 25% of the sleep time is
spent with an arterial PaCO2 greater than 50mm Hg [5].
Risk factors of obstructive sleep apnea in neuromuscular diseases are generally
similar to those of the general population (including obesity, male sex, or
adenotonsillar enlargement in children), and desaturation events are predominantly
due to hypoventilation from reduced inspiratory muscle activity in association with
phasic REM sleep rather than obstructive events [4]. Nevertheless, pathophysiologic
features of some neuromuscular diseases may predispose to obstructive events,
including factors that impair the compensatory neuromuscular response (such as
pharyngeal hypotonia or neuropathy, or bulbar dysfunction) and, to a lesser extent,
anatomic and structural changes (such as macroglossia and reduced lung volumes).
Central sleep disturbance in neuromuscular disorders is due either to Cheyne
Stokes breathing could be associated with cardiomyopathy, as can be seen in some
dystrophies, or to instability in control of breathing due to diaphragm weakness, as

has been proposed in myotonic dystrophy, spinal cord injury, or the post-polio
syndrome.
TELEMONITORING
Home telemonitoring has generated great interest due to the increasing ability to
access data remotely from the ventilator.
The latest generation systems [6] have constant analytical and decision-making
support in which monitoring centers are physician-led and staffed by specialist
nurses and have full authority to effect therapy changes 24 hours per day, seven
days per week.
A pilot study [7] showed reduced hospital admissions in patients who complied
with the telemonitoring protocol and were increased slightly in those who did not. In
this study, vital observations combined with ventilator data were reviewed weekly
and as required by the hospital team.
BILEVEL POSITIVE AIRWAY PRESSURE
Biphasic modes of ventilation is a different setting mode with pressure-controlled,

intermittent mandatory ventilation with unrestricted spontaneous breathing.
This ventilation method could increase patient comfort and synchrony with the
ventilator.
Two levels of pressure could also be settled: the inspiratory pressure limit (P
high) and the positive end-expiratory pressure (PEEP) low (P low). Tidal volume (VT)
is represented by the difference between the two levels and can be adjusted to
deliver as requested [8].
INDICATION
The key indication for HMV with biphasic modes of ventilation is chronic
respiratory failure arising from alveolar hypoventilation. On common congenital
neuromuscular causes of respiratory failure include primary muscular dystrophies
(e.g., myotonic dystrophy, Duchenne muscular dystrophy, and Becker muscular
dystrophy) and diseases of the motor neurons such as spinal muscular atrophy. Of
the acquired NMDs, the most prominent requiring HMV are amyotrophic lateral
sclerosis (ALS), spinal cord injury, and chronic inflammatory demyelinating
neuropathies.
An important prognostic indicator is age at initiation of HMV; patients requiring
non-invasive ventilation (NIV) before 17 years showed a worse prognosis than those
starting NIV at an older age [9]. NIV should be initiated on the evidence of nocturnal

hypoventilation, although earlier initiation may be considered in the presence of

significant respiratory compromise.
ALS is an increasingly common indication for the initiation of HMV. It is
characterized by progressive degeneration of both upper and lower motor neurons
and presents initially with predominant bulbar or limb weakness. NIV should be
started on the evidence of symptomatic sleep-disordered breathing, daytime
hypercapnia, or orthopnea, with an associated reduction in forced vital capacity to
less than 80% of predicted or a sniff nasal inspiratory pressure of less than 60cm
H2O.
Only one randomized controlled trial has evaluated the survival benefit of NIV in
patients with ALS. Median survival was 219 days in the NIV group compared with
171 days in the control group, with the greatest advantage seen in patients without
bulbar involvement [10].
NIV intolerance is known to be associated with bulbar-onset ALS. However, NIV
should be started with careful titration of ventilation pressures, where IPAP should be
started low and titrated gently.
Cough-assistance maneuvers are an important adjunct to home NIV in
neuromuscular disease. Mechanical insufflation-exsufflation devices in adjunct with
respiratory and breath stacking therapy with an “Ambu” bag for lung volume
recruitment may augment cough and should be used in neuromuscular disorders and
ALS.
Indeed, both inspiratory and expiratory muscle strength deteriorates in parallel in
most conditions such as myopathies and muscular dystrophies, affecting respiratory
muscles, with the exception of spinal muscular atrophy (SMA).
However, in the face of severe laryngeal problems such as laryngospasm and
nocturnal choking, inability to control arterial blood gas tensions with NIV, or
recurrent aspiration, tracheotomy ventilation is a necessary consideration. Locked-in
syndrome is a potential consequence of ventilation via tracheotomy, but respiratory
complications are one of the fatal complications of many patients with ALS.
Duchenne muscular dystrophy (DMD) was one of the first to receive home NIV,
and outcomes of them represent one of the greatest success stories with HMV.
Literature showed considerable improvements in survival with NIV with a
reduction of pulmonary morbidity if associated cough assistance [11].
Time to start NIV could be a prognostic factor; worse prognosis is related to
those requiring NIV before the age of 17 years than those starting NIV at an older
age. Guidelines suggest that NIV should be introduced immediately on the evidence
of nocturnal hypoventilation to reduce uncontrolled respiratory decompensation [12].
Although in DMD, preemptive use of NIV did not alter loss of vital capacity or impact
on survival, earlier use has been advocated in infants with severe respiratory
limitation caused by SMA types 1 and 2.
A combination of cough assistance, home NIV, and gastrostomy feeding to
manage respiratory symptoms may increase life expectancy, reduce hospital
admissions, facilitate care at home.

Non-invasive modes are the treatment of choice in SMA type 2, although NIV
may have been used for a more palliative approach than therapeutic.
DIFFERENT NON-INVASIVE TECHNIQUES
In acute respiratory failure, mechanical ventilation almost always relies on

positive pressure ventilation. The mechanical ventilators are set to detect the rapid
decrease in airway pressure that occurs at the early phase of inspiration and set to
release the gas (usually enriched in oxygen) into the upper airway and the lung.
The delivery of gas by the mechanical ventilator is regulated either by fixing the
volume of gas to be injected (volume control mode) or by fixing a pressure or flow to
be achieved in the airway within a predetermined time (pressure control mode).
Invasive mechanical ventilation commonly uses the volume control mode with
tidal volume and respiratory rate titrated to normalize arterial CO2 tension and
titration of the inspired fraction of oxygen to achieve an arterial oxygen saturation of
more than 90%.
Non-invasive ventilation commonly uses the pressure control mode. Over the last
decade, non-invasive mechanical ventilation (NIV) has become routine practice
worldwide in the management of acute respiratory failure of various origins [13].
Invasive or non-invasive positive pressure ventilation is expected to compensate
for respiratory muscle weakness and to allow appropriate recruitment of lung alveoli
to restore normal minute ventilation.
In addition, by maintaining a positive pressure, mechanical ventilation prevents
the upper airway from collapsing. Subsequently, positive pressure ventilation
improves the clearance of CO2 from arterial blood and reverses lungs atelectasis
and normalizes ventilation/perfusion mismatch.
Type of ventilation:
Negative pressure includes different types of body enclosures:
 body wraps (nylon or plastic jackets that surround the chest and abdomen),
 body tanks (iron lungs),
 chest shells (rigid domes that fit over the chest and abdomen), and
 abdominal pneumobelts (inflatable rubber bladders held firmly against the
abdomen by nylon corsets).
ETHICAL APPROACH
A critical aspect that should not be overlooked is the patient’s quality of life in
long-term ventilation.
Several studies evaluated this condition; Valko et al. demonstrated that the effect
of home mechanical ventilation on quality of life in chronic respiratory failure patients

was indifferent due to ventilation interface but was dependent on the initial diagnosis
and some baseline characteristics, i.e., acute initiation, oxygen supplementation
need, and baseline quality of life [14]. Huttmann et al. reported that the most
important areas of displeasure were communication, mobility, social contacts, and
care dependency. Importantly, one-third of patients would have preferred to die
rather than receive invasive HMV.
This raises ethical concerns about the practice of long-term mechanical
ventilation following unsuccessful weaning. Therefore, to avoid unethical
prolongation of life, long-term outpatient care and prolonged weaning care should
move closer together in order to improve individual decision-making processes that
incorporate patients’ beliefs, circumstances, and expectations [15].
REFERENCES
[1] Lloyd-Owen, S. J., Donaldson, G. C., Ambrosino, N., Escarabill, J., Farre, R.,
Fauroux, B. et al. Patterns of home mechanical ventilation use in Europe:
Results from the Eurovent survey. Eur. Respir. J., 2005; 25:1025 - 31.
[2] Kacmarek, R. M., Malhotra, A. Equipment required for home care ventilation.
In: Tobin, M. J., editor. Principles and practice of mechanical ventilation. 2nd ed.
New York: McGraw Hill; 2006. p. 97 - 127.
[3] Gupta, S., Donn, S. M. Continuous positive airway pressure: Physiology and
comparison of devices. Semin. Fetal. Neonatal Med., 2016 Jun.; 21(3):204 -
11.
[4] White, J. E., Drinnan, M. J., Smithson, A. J., Griffiths, C. J., Gibson, G. J.
Respiratory muscle activity and oxygenation during sleep in patients with
muscle weakness. Eur. Respir. J., 1995; 8:807 - 814.
[5] Berry, R. B., Brook, R., Gamaldo, C. E., Harding, S. M., Marcus, C. L., Vaughn,
B. V.; American Academy of Sleep Medicine. The AASM manual for the
scoring of sleep and associated events: Rules, terminology and technical
specifications. Darien, IL: American Academy of Sleep Medicine; 2014.
[6] Koehler, F., Anker, S. D. Noninvasive home telemonitoring: The Trans-
European Network-Home-Care management system. J. Am. Coll. Cardiol.,
2006; 48:850 - 851.
[7] Bertini, S., Picariello, M., Gorini, M., Renda, T., Augustynen, A., Villella, G.,
Misuri, G., Maluccio, N. M., Ginanni, R., Tozzi, D. et al. Telemonitoring in
chronic ventilatory failure: A new model of survellaince, a pilot study. Monaldi
Arch Chest Dis., 2012; 77:57 - 66.
[8] Gallagher, J. J. (2018). Alternative modes of mechanical ventilation. AACN
Advanced Critical Care, 29(4), 396 - 404.
[9] Chatwin, M., Tan, H. L., Bush, A., Rosenthal, M., Simonds, A. K. Long term
non-invasive ventilation in children: Impact on survival and transition to adult
care. PLoS One, 2015; 10:e0125839.

[10] Bourke, S. C., Tomlinson, M., Williams, T. L., Bullock, R. E., Shaw, P. J.,
Gibson, G. J. Effects of non-invasive ventilation on survival and quality of life in
patients with amyotrophic lateral sclerosis: A randomised controlled trial.
Lancet Neurol., 2006; 5:140 - 7.
patients with Duchenne muscular dystrophy. Chest, 1997; 112:1024 - 1028.
[12] Hull, J., Aniapravan, R., Chan, E., Chatwin, M., Forton, J., Gallagher, J.,
Gibson, N., Gordon, J., Hughes, I., McCulloch, R. et al. British Thoracic Society
guideline for respiratory management of children with neuromuscular
weakness. Thorax, 2012; 67:i1 - i40.
[13] Esteban, A., Ferguson, N. D., Meade, M. O., Frutos-Vivar, F., Apezteguia, C.,
Brochard, L. et al. VENTILA Group. Evolution of mechanical ventilation in
response to clinical research. American Journal of Respiratory and Critical
Care Medicine, 2008; 177(2):170 - 7.
[14] Valko, L., Baglyas, S., Gyarmathy, V. A. et al. Home mechanical ventilation:
Quality of life patterns after six months of treatment. BMC Pulm. Med., 20, 221
(2020).
[15] Huttmann, S. E., Magnet, F. S., Karagiannidis, C. et al. Quality of life and life
satisfaction are severely impaired in patients with long-term invasive ventilation
following ICU treatment and unsuccessful weaning. Ann. Intensive Care, 8, 38
(2018).

SECTION 10. OUTCOME

Chapter 39
CAUSE AND OUTCOME

OF ACUTE NEUROMUSCULAR RESPIRATORY FAILURE
Saint-Clair Bernardes Neto1,, MD

and Antonio Sarmento2, PhD
1
Catholic University of Brasília, Brasília/DF, Brazil
Department of Physical Therapy of Estácio Fatern,
Federal University of Rio Grande do Norte (UFRN),
SOMA Capacitações, Natal/RN, Brazil
2
Federal University of Rio Grande do Norte (UFRN),
Probatus Academic Services, Natal/RN, Brazil
ABSTRACT
Some neuromuscular diseases have an acute or subacute onset of

respiratory failure, but it can be unrecognized because of different presentations.
Health care professionals must be able to identify predictor signs of acute
respiratory failure for neuromuscular patients and predictors for several
outcomes. Usually, three main components contribute to respiratory failure in this
population: inspiratory muscle weakness, which decreases pressure and volume
with possible fatigue and reduced total lung capacity, vital capacity, and tidal
volume; expiratory muscle dysfunction, with impaired cough efficiency and
difficult clearance of secretions; and bulbar muscle weakness that leads to upper
airway obstruction and swallowing dysfunction.
Some general, subjective, or objective signs indicate probable acute
respiratory failure and should be searched by professionals to establish early
treatment. Once it is installed, predictors for different outcomes such as
endotracheal intubation, prolonged mechanical ventilation, functional decline,
and death must be monitored since they are associated to worse outcomes. Most
predictors are related to rapid progression of general and respiratory weakness,

Corresponding Author’s E-mail: netosam@gmail.com.

534 Saint-Clair Bernardes Neto and Antonio Sarmento
bulbar dysfunction, and dysautonomia. Early detection of predictors can lead to

adequate treatment measures for better outcomes.
Keywords: neuromuscular disease, respiratory failure, outcome, acute respiratory

failure
INTRODUCTION
Various neuromuscular diseases (NMD) can cause respiratory muscle weakness

and respiratory failure. The latter refers to the inability of the respiratory system to
provide proper oxygenation and carbon dioxide elimination and occurs slowly in
patients with chronic, progressive neuromuscular diseases; however, some
neuromuscular diseases have an acute or subacute onset, thus presenting with
acute respiratory failure and premature death [6].
Respiratory complications and failure will eventually develop in most NMD
patients. Unlike in patients with respiratory diseases, respiratory failure in NMD can
be initially unrecognized because frank abnormalities on auscultation or severe
cyanosis are not always present. On the one hand, certain signs such as paradoxical
abdominal movement, use of accessory respiratory muscles, or dyspnea may
facilitate diagnosis of acute respiratory failure, but on the other hand, it is challenging
since clinical examination is often limited by the patients’ inability to communicate
and cooperate with examination during an ongoing clinical event [12]. Therefore,
health care professionals must anticipate respiratory failure onset in patients with
acute and chronic neuromuscular disorders.
CAUSES OF ACUTE NEUROMUSCULAR RESPIRATORY FAILURE
Although respiratory failure can precede respiratory muscle weakness in some

NMD diseases [1, 14], three main components that may contribute to respiratory
failure and the need for mechanical ventilation in these patients are inspiratory
muscle weakness, expiratory muscle weakness, and upper airway compromise [4].
Respiratory muscle weakness is the inability to generate adequate levels of
pressure and volume in the respiratory cycle. Its diagnosis is frequently undetected
until ventilatory failure is precipitated by aspiration or respiratory tract infection in
NMD, probably because daily activity of these patients is often reduced, thus limiting
ventilatory demands. When weakness is combined with reduced lung and chest wall
compliance, the work of breathing increases and predisposes respiratory muscles to
fatigue. Although respiratory failure does not usually occur until respiratory muscle
strength has fallen to ~25-30% of normal, the onset of respiratory failure can be
subtle to the point that most patients are not aware of the respiratory muscle strength
loss [5, 7, 8].

Cause and Outcome of Acute Neuromuscular Respiratory Failure 535
Inspiratory muscle weakness can lead to inadequate ribcage expansion and

consequently reduced total lung capacity, vital capacity, and tidal volume, resulting in
basal microatelectasis and ventilation-perfusion mismatch. Reduced inspiratory
volume also influences cough peak flow (CPF) and predisposes the patient to
recurrent aspiration and pneumonia, while upper airway hypotonia leads to increased
airflow resistance, contributing to increased work of breathing and further acute
respiratory failure. Subacute muscle weakness (mainly resulted from the diaphragm)
develops hypopnoea, oxygen desaturation, and hypercarbia for the first time during
REM sleep, and, in some cases, rapid and shallow breathing is adopted to reduce
dyspnea and the elastic work within each breath [3, 4].
Cough efficiency is also reduced when expiratory muscle dysfunction is present,
impairing clearance of secretions. In rapidly progressing NMDs, acute respiratory
failure due to lung secretion accumulation can be the earliest symptom. Reduced
expiratory muscle strength diminishes both the intra-airway gas compression and
explosive expiratory force for cough during the opening of the glottis; therefore,
increasing the risk of retained secretions, frequent aspiration, and pneumonia and
leading to acute respiratory failure and death. Moreover, other features also affect
the expiratory cough phase and airway resistance during expiration, such as
stiffened chest wall, properly expiratory muscle stretch to their optimal point of
contraction, limited passive elastic recoil of the lungs during expiration, and
diminished cross-sectional diameter of the airways that are not fully dilated because
the lung is not fully inflated [2, 8, 11].
Bulbar muscle weakness, when severe, can cause upper airway obstruction,
swallowing dysfunction, and impaired airway protection, leading to recurrent
episodes of aspiration and pneumonia [11]. Facial, oropharyngeal, and laryngeal
muscle weakness, together with dysfunction of the lips and tongue, may also result in
mechanical upper airway obstruction and bacteria from the oral cavity entering the
lower airways, particularly in the supine position [10].
OUTCOMES OF ACUTE NEUROMUSCULAR RESPIRATORY FAILURE
Acute respiratory failure in NMD may lead patients to several negative outcomes,
and these outcomes can be minimized with early recognition and appropriate
treatment. The main outcomes related to this condition are the need for intubation
and mechanical ventilation (MV), increased length of stay in both the ICU and the
hospital, functional decline at and after discharge, and death [9, 15].
The early diagnosis of acute neuromuscular respiratory failure in the ICU is not
an easy procedure for health care professionals, and signs of impending respiratory
failure must be considered (Figure 1) [6, 10, 15]. These signs may be general
(increasing weakness, dysphagia, or at rest dyspnea, especially), subjective (rapid
shallow breathing, tachycardia, weak cough, accessory muscle use, single-breath
count, and cough after swallowing), and objective (MIP > -30 cmH2O, MEP < 40

cmH2O, and VC < 15 ml/kg or < 1 L). Based on these signs, the decision to intubate
should be early rather than later to avoid emergency intubation [10, 13].
Decreased CPF, which stands for the highest flow presented after a deep breath
and forced cough, also indicates a higher risk for acute respiratory failure [17].
Most predictors for MV requirement are described for Guillain-Barré syndrome
patients, but they can be generalized for other NMD. The most common predictors
are: rapid weakness progression due to the disease, dysautonomia, and bulbar
dysfunction [10, 13, 15]. Other predictors have also been reported, such as time from
onset to admission of <7 days, inability to cough, inability to stand, inability to lift
elbows or head, liver-enzyme increases, and VC < 60% of predicted, especially if
they are present together [16].
Another strategy used to avoid emergency intubation in Guillain-Barré syndrome
is the “20/30/40 rule” which postulates that patients presenting forced vital capacity
<20 ml/kg, MIP > - 30 cmH2O, and MEP < 40 cmH2O should be intubated [10, 13].
Up to 50% of Guillain-Barré syndrome and up to 25% of myasthenia gravis
patients require MV, and the time spent on ventilatory support is relatively high,
mainly for Guillain-Barré condition. NMD is an independent cause of prolonged MV
[13]. For those with myasthenia gravis, pre-intubation HCO3 > 30 mEq/L, peak VC
on days 1-6 after intubation <25 ml/kg, and age >50 years can predict prolonged
ventilation, progressively depending on the number of factors presented [10].
Figure 1. Signs of impending respiratory failure. MIP: Maximal inspiratory pressure; MEP:
Maximal expiratory pressure; VC: Vital capacity; CPF: Cough peak flow.

Noninvasive ventilation is described in some guidelines as a strategy to avoid

intubation in patients with acute respiratory failure and reduce negative outcomes
related do MV. But in NMD patients, especially those with bulbar impairment, there is
not enough evidence supporting this treatment over invasive MV. In addition, NIV
failure is associated with rapid deterioration of respiratory function, leading to
emergency intubation [9].
Some data report that patients with Guillain-Barré syndrome evolve with
significant improvement in functional changes, showing independent walking
afterward. But patients who present associated respiratory muscle weakness or
require MV for a long time have functional limitations up to 1 year after discharge
from the ICU [10]. When all NMD diseases are considered, disability is severe and
present in more than half of the patients with acute respiratory failure at discharge
[6].
Mortality is not a very high and prevalent outcome in the ICU for NMD patients,
but is increased for the ones that develop complications, such as prolonged MV,
ventilator-associated pneumonia, and prolonged ICU length of stay. Thus, early
diagnosis of acute neuromuscular respiratory failure is crucial to minimize
complications and, consequently, outcomes, such as increased mortality [10, 13].
Figure 2. Outcome predictors in acute neuromuscular respiratory failure.

Outcomes can also be measured by the Rankin or the modified Rankin score.
Usually, scores >3 can indicate poor outcomes. Using this score, Serrano e
Robinstein found that patients with older age, higher ICU length of stay, diabetes or
pneumonia, and cardiopulmonary diseases develop worse outcomes, even after one
year of discharge [6].
Health care professionals should constantly and thoroughly monitor NMD
patients for signs of acute respiratory failure and all possible predictors of outcomes
(Figure 2), search for the best therapeutic strategies as soon as possible, and,
consequently, positive outcomes.
REFERENCES
[1] Al-Shaikh B., Kinnear W., Higenbottam T. W., Smith H. S., Shneerson J. M.,
and Wilkinson I. Motor neurone disease presenting as respiratory failure. Br
Med J (Clin Res Ed) 292: 1325-1326, 1986.
[2] Ambrosino N., Confalonieri M., Crescimanno G., Vianello A., and Vitacca M.
The role of respiratory management of Pompe disease. Respiratory medicine
107: 1124-1132, 2013.
[3] Benditt J. O. The neuromuscular respiratory system: physiology,
pathophysiology, and a respiratory care approach to patients. Respiratory care
51: 829-837; discussion 837-829, 2006.
[4] Benditt J. O., and Boitano L. J. Pulmonary issues in patients with chronic
neuromuscular disease. American journal of respiratory and critical care
medicine 187: 1046-1055, 2013.
[5] Buyse B., Demedts M., Meekers J., Vandegaer L., Rochette F., and Kerkhofs L.
Respiratory dysfunction in multiple sclerosis: a prospective analysis of 60
patients. The European respiratory journal 10: 139-145, 1997.
[6] Cabrera Serrano M., and Rabinstein A. A. Causes and outcomes of acute
neuromuscular respiratory failure. Archives of neurology 67: 1089-1094, 2010.
[7] Hutchinson D., and Whyte K. Neuromuscular disease and respiratory failure.
Practical neurology 8: 229-237, 2008.
[8] Lo Mauro A., and Aliverti A. Physiology of respiratory disturbances in muscular
dystrophies. Breathe 12: 318-327, 2016.
[9] Luo F., Annane D., Orlikowski D., He L., Yang M., Zhou M., and Liu G. J.
Invasive versus non-invasive ventilation for acute respiratory failure in
neuromuscular disease and chest wall disorders. The Cochrane database of
systematic reviews 12: CD008380, 2017.
[10] Mehta S. Neuromuscular disease causing acute respiratory failure. Respiratory
care 51: 1016-1021; discussion 1021-1013, 2006.
[11] Perrin C., Unterborn J. N., Ambrosio C. D., and Hill N. S. Pulmonary
complications of chronic neuromuscular diseases and their management.
Muscle & nerve 29: 5-27, 2004.

[12] Rabinstein A. A. Update on respiratory management of critically ill neurologic

patients. Current neurology and neuroscience reports 5: 476-482, 2005.
[13] Racca F., Vianello A., Mongini T., Ruggeri P., Versaci A., Vita G. L., and Vita G.
Practical approach to respiratory emergencies in neurological diseases. 41:
497-508, 2020.
[14] Rosenow E. C., and Engel A. G. Acid maltase deficiency in adults presenting as
respiratory failure. The American journal of medicine 64: 485-491, 1978.
[15] Schoser B., Fong E., Geberhiwot T., Hughes D., Kissel J. T., Madathil S. C.,
Orlikowski D., Polkey M. I., Roberts M., Tiddens H. A., and Young P. Maximum
inspiratory pressure as a clinically meaningful trial endpoint for neuromuscular
diseases: a comprehensive review of the literature. Orphanet Journal of Rare
Diseases 12: 52, 2017.
[16] Sharshar T., Chevret S., Bourdain F., Raphael J. C., and French Cooperative
Group on Plasma Exchange in Guillain-Barre S. Early predictors of mechanical
ventilation in Guillain-Barre syndrome. Critical care medicine 31: 278-283,
2003.
[17] Voulgaris A., Antoniadou M., Agrafiotis M., and Steiropoulos P. Respiratory
Involvement in Patients with Neuromuscular Diseases: A Narrative Review.
Pulm Med 2019: 2734054, 2019.

SECTION 11. HEALTH CARE AND ETHICAL ASPECTS

Chapter 40
THE CAREGIVER FORMATION
Fabrizio Rao1,2,* and Alice Pirola1

1
NeMO Clinical Centre, Milano, Italy
2
NeMO Clinical Centre, Arenzano (Genova), Italy
ABSTRACT
The last decades saw important advancements in both the neurological

medical field and that of applied technology: as a result, both the life expectancy
and the quality of life of neuromuscular patients has registered significant
improvements. At the same time, with the diffusion of cost-efficiency policies, the
tendency to cut on the duration of hospitalizations has also been registered. This
encouraged the further development and specialization of the caregiver figure,
which, at lower costs, could provide that long-term care needed for those patients
suffering from a neuromuscular condition. However, as the role and importance
of this figure progresses, so do its job requirements and, consequently, the need
for a specific formation. As the task expected from a caregiver may vary widely
according to the condition and needs of the patients, a general guideline for
his/her training is currently not available. However, many centres worldwide
designed local programs to match the requirements specific to their patients. This
is also true for the respiratory management of neuromuscular patients
discharged home. In the following chapter, we will therefore review the main
points that both literature and clinical experience evidenced as necessary topics
in the caregiver formation, from daily regular maintenance to emergency
management, as well as the modalities for their assessment. Lastly, attention will
be drawn on caregivers’ wellbeing, which could significantly affect their work
performance, by outlining the common causes of burden development and the
possible ways to prevent or counteract it.
Keywords: caregiver, education, neuromuscular, ventilation
*
Corresponding Author’s E-mail: fabrizio.rao@centrocliniconemo.it.

544 Fabrizio Rao and Alice Pirola
INTRODUCTION
Despite positive pressure mechanical ventilators being available for more than a
century by now, it is in the last decades that the theoretical and technical progresses
in this field allowed to increase, on one side, the typology of patients eligible for an
efficient long term ventilation and, on the other side, the number of those who can be
kept on non-invasive ventilation (NIV), thus forgoing or delaying the invasive option
(IMV) [1, 2].
However, despite the subsequent increase in the number of ventilated patients,
particularly the neuromuscular (NMD) ones, little attention has been paid to the
impact of these interventions on these patients’ caregivers. This is especially true
when we consider the subjects who received a tracheostomy and are on IMV, with
even less attention directed at determining the best possible interventions to optimize
their respiratory management once back at home, while maintaining an adequate, if
not improved, quality of life (QoL) for both patient and caregiver [1].
Additionally, when considering the current most common policies in terms of
health assistance, both at local and international level, cost-efficiency seems a
shared, recurrent theme. For this reason, the perspective of reducing, if not avoiding,
prolonged hospitalisations by implementing a program of advanced domiciliary
management of these patients is convenient not only economically-wise, but also for
the wellness of the patient, who will benefit from the return to a familiar setting.
This being said, it should be remembered NMD subjects invasively ventilated and
often those on continuous (or almost) NIV, still remain a fragile, heterogeneous
category, prone to comorbidities, strongly dependent on specific assistive devices
and, as such, predisposed to adverse events in domestic settings [2, 3].
Considering these premises, the fact that, most of the times, the patient’s
relatives are expected to cover the caregiver role and the frequent lack of a solid
support from the healthcare discharging centre, it should not come as a surprise the
fact that the overall burden on this figure is another important issue that needs to be
addressed with timely, appropriate interventions.
In this chapter, we will therefore try to explain the role of the main caregiver
figure, in both adult and paediatric settings, what the current requisites are in terms
of an up-to-date and effective respiratory management and how to assess them.
Lastly, we will address the issue of this figure’s physical and, most of all,
psychological burden, examining eventual prevention and/or coping strategies
currently available in the literature.
THE CAREGIVER FIGURE: DEFINITION AND ROLE
Up to the most recent years, the caregiver has been seen either as a “secondary
patient,” in need of protection and guidance in the execution of his/her daily tasks, or
as an “implementer of care,” more convenient than a nurse in terms of availability

The Caregiver Formation 545
and costs, but also at high risk of harming the assisted if inadequately formed.
Nowadays, as previously anticipated, all the progresses in the field of respiratory
care, together with the pressure to contain the costs in healthcare, brought many
health centers to increasingly rely on this figure in the domiciliary setting, the facto
making it a part of the team [2].
The tasks the caregiver of a NMD ventilated patient is expected to carry out are
manifold and not limited to those learnt from the different specialists at the clinic
(personal and respiratory hygiene, launching enteral nutrition, stretching, mobilization
and so on, depending on the patient’s needs). In fact, he/she is often in charge,
though informally, of ensuring a smooth passage of information between the patient,
the family and all the different implementers of care involved. It is also not
uncommon, for this very figure, to assist any eventual new home healthcare
personnel that may lack the practical experience in a specific area or simply may not
know the individual needs and preferences of their new patient, yet. Lastly, a study
carried out on ALS patients and caregivers evidenced how even a short, but well-
tailored education program, carried out before the onset of respiratory failure, could
help both to choose the preferred ventilatory support option for the future, without this
knowledge affecting, often even improving, their well-being and anxiety [4].
However, no comparable “upgrade” in caregiver’s support, in terms of both
education and psychological guidance, followed up this rise in responsibilities,
negatively affecting their quality of life. Particularly, some works already recognised
and stressed the caregivers’ need to be able, after a proper training, to recognise
and manage the first moments of any eventual emergency/out-of-the-ordinary
situation, including (but not limited to) the respiratory ones. Yet, upon discharge from
the clinic, only the 48% of IMV patients’ caregivers would report to feel satisfactorily
prepared for their upcoming job and only 5% to have received a specific training in
emergency management [1, 2, 5].
Similarly, the last decades also saw an increment in the number of paediatric
NMD patients on long-term ventilation, both invasive and not. While this allowed
prolonging their life expectancy and generally spending most of it at home, with all
the psychosocial and developmental benefits coming from it, it demanded a major
increase in the competencies required to their main caregivers, these generally being
the patient’s parents or guardians. So far, the literature evidenced only a partial
validity of the available educational programs directed specifically to the carers of
these children [6]. However, the clinical status of these patients is very often severe,
furtherly complicated by associated comorbidities: it is therefore essential to include
these caregivers’ in an appropriate, specifically tailored educational program that will
allow them to deal with both daily-life, routine situations and eventual emergencies
that may occur during the homestay.

CAREGIVER AND PATIENT FORMATION: A STATE OF THE ART
The majority of NMDs will face, along the course of their disease, a variable
amount of respiratory muscle weakening: this will vary in severity and progression
rate depending on the condition, but if unaddressed will negatively affect both
patient’s survival and quality of life. A proactive approach has therefore been
promoted in the last decades, particularly in those severe conditions where
respiratory failure is among the leading causes of morbidity and mortality (ALS, SMA,
and DMD, only to cite a few). This approach should assess the patient’s ventilatory
capacity as well as his/her ability to get rid of secretions and/or foreign bodies from
the airways by the means of an efficient cough. In case any deficit is detected, the
centre of reference should provide the subject with adequate support, through the
most appropriate respiratory assistive devices, while ensuring both patient and
eventual caregiver are trained in their usage, to ensure an optimal continuity of care
once discharged.
Broadly speaking, the respiratory management of an NMD subject may be
carried out either invasively or not, according to both the patient’s condition severity
and the level of expertise of the center in charge of his/her management. Regardless
the modality, adequate formation and support of the relatives and carers will be
fundamental if the patient, once initiated to the respiratory devices, will continue
his/her life at home. It is also not so uncommon that these very primary carers
(usually one or more members of the family) will have to provide some patient-
specific training to eventual auxiliary personnel, for example, the basic functions of
every respiratory device and how to use it properly [7]. Given this pivotal role, the
education of the primary caregiver should be considered a core component of the
management of all cases of home ventilation and several specialised centers in the
world have therefore compiled ad hoc protocols aiming at standardizing the
education of the caregivers who will take care of their patients. However, it must be
noted that most of the times these protocols, often in the form of “packages” of
knowledge, theoretical and practical, laid out by various specialised contributors,
have only local value and therefore their quality may very well be variable.
Nevertheless, some common themes can be individuated, and are described
here below, evidencing any eventual difference between NIV and IMV management.
Why
The primary aim of these protocols should be to empower the future caregivers
with a “package” of basic, yet essential, knowledge and practical skills for the correct
management of their client [8]. Such thorough education, in fact, seems to contribute
to lessen not only the emotional burden of both patient and caregiver, but also an
eventual financial one, coming from non-planned hospitalisations: some of the most
common sources of respiratory problems that, if not managed adequately, could lead

to unplanned hospitalizations, can be actually be dealt with from home. It is the case
of fatigue, insufficient ventilation from several causes, increased “unmanageable”
secretions, cannula mucus plugging, accidental de-cannulation and difficulties
interpreting and acting upon the ventilator’s alarms [1, 6, 9, 10].
Where
Usually, a major part of this educational process will be provided at the

specialised center, while the patient is being introduced to NIV or IMV, post
tracheostomy placement. However, it is fundamental to ensure this type of support
throughout the course of patient’s life: whenever a change in the respiratory
management of the subject occurs (for example, the ventilator model, the modality of
ventilation are modified, a new caregiver is hired, etc.) or one or more of the
respiratory specialists deems it necessary, a “refresh” or update session should be
provided. It is also not uncommon that some centers, in agreement with their
personnel or selected home care providers, offer this type of service directly at the
patient’s domicile.
When
Ideally, the educational protocol should be planned and implemented, for both
patient and the eventual caregiver, as soon as the decision to undergo NIV or IMV
has been made. Clearly IMV initiation is more complex, both physically and mentally
for patient and caregiver and, as in the case of tracheostomies performed in
emergency settings, it is not always possible to plan and implement such protocols
beforehand.
As regards the supposed duration of an initial educational program, there is not a
clear consensus throughout the current literature: some evidence suggests 2 weeks
as the maximum duration [1], while other report the training program can be started
even 24 hours after the tracheostomica cannula placement [11].
What
Generally, respiratory therapists and/or specialised nurses, coordinated by an

appointed medical figure of reference, will deal with the caregiver’s education on all
the aspects of ventilatory management, from the devices in use to the tracheostomy
correct daily care. This tutoring phase can include few theoretical frontal lectures, in
order to clarify the aims and objectives of the different aspects of home mechanical
ventilation and the relative respiratory management. As we will see later on, the
modalities can vary, but it is important that, by the end of these lectures, the

caregivers/patients are left with some kind of supportive material, often in the guise
of a paper booklet, summarising the concepts just exposed. However, the “hands on”
sessions at the bedside of the patient should be the real fulcrum of the whole
educational program: as it will be explained later on, during these practical parts the
caregiver will go from closely observing the specialist carrying out all those steps
required for a correct respiratory management to perform them him/herself with
crescent independence.
Although no shared guidelines are currently available on the contents an optimal
training programme for caregivers of ventilated NMD patients should include [8, 11],
some main, basic concepts and skills can be individuated. These concepts and
abilities, which acquisition should be a paramount requirement before patient
discharge, have been summarised here below in six broader areas of competence.
Rationale for Ventilatory Support

The caregiver will need to demonstrate his/her knowledge of the anatomical and
physiological bases of the human respiratory system, in order to understand the
clinical rationale, which led to either NIV or IMV initiation. Additionally, a brief
explanation of the expected course of the patient’s condition, possibly adjusted
according to any eventual, specific precipitator factors, will help the caregiver to
better understand what the present and future requirements, expected from him/her,
will be.
The Ventilator
Together with the rationale for mechanical support, the caregiver will need to
know the minimal daily duration of NIV or IMV currently prescribed to the patient, as
well as the importance of a consistent compliance in its use, in order to better
support and motivate the patient in case of need. Furtherly, from the practical point of
view, the caregiver will need to demonstrate to be accustomed to the use and
maintenance of the ventilator, as well as those of any other respiratory device
assigned to the patient. This should include knowing the appropriate cleaning
procedure, when to change the consumables and who to contact in case of technical
issues.
Ventilatory Parameters Surveillance

The caregiver will need to be able to know and demonstrate how to monitor the
main vital signs connected to ventilation, specifically the heart and respiratory rates,
as well as the oxy-haemoglobinic saturation. In addition, he/she must be able to carry
out the appropriate interventions in case these parameters may indicate the need for
it. These interventions may include selecting another pre-set program on the
ventilator, modify the humidification levels, carry out one or more mechanical in-
exsufflator cycles to get rid of obstructions along the airways, check the circuits
and/or the tracheostomic cannula for patency, as well as the tracheostomic cuff or
the mask for eventual air leaks. Particularly, in case of air leaks from the mask, the
caregiver will need to be able to reposition it correctly and, in case of pressure sores,

take appropriate counteracting measures (colloidal pads, switch masks, use

mouthpiece ventilation when available,…). Once again, the monitoring tools for the
life parameters may vary from one patient to the other, according to devices
assigned; therefore, each caregiver’s education will have to be specifically tailored on
the machines in possession of his/her patient.
Alarms and Devices Technical Malfunctioning

The caregiver will need to be formed to recognise those ventilator alarms that
may signal a technical malfunctioning and know who to contact depending on the
issue evidenced.
Airway Patency and Secretion Removal

The caregiver will need to know in theory, but most importantly in practice, what
measure to adopt to keep the patency of the airways, whether on NIV or IMV. These
measures will include techniques to bring the secretions closer to the higher airways,
those helping with the production of an effective cough and, if necessary the use of
suctioning devices. Additionally, a correct management of the humidification systems
in use and the daily cleaning of the tracheostomic cannula will help with preventing
the accumulation of secretions as well as the formation of potentially fatal mucous
plugs.
Relatively to cough assistance techniques, the caregiver will need to be
knowledgeable of the rationale behind their use and of the minimum frequency of
daily application recommended for the patient. Above all, similarly to the ventilator,
he will need to demonstrate, in practice, his/her ability to use the instrument assigned
to his client, as well as to carry out the tool’s necessary cleaning and maintenance.
Lastly, as regards secretions suctioning, to avoid further infections and injuries to
the mucous membrane, it is of primary importance that the caregiver learns and
practices the correct method of aspiration (generally, the so-called “clean technique”)
in autonomy and safety.
Emergency Management
Generally, the most common causes of respiratory complications/emergencies
and subsequent hospitalizations in the NMD population are infections not responsive
to traditional treatments, food aspirations (often with consequent ab ingestis
pneumonia). Additionally, as regards IMV patients, the development of granulomas
and fistulas along the airways, thus affecting the quality of ventilation and accidental
decannulation, without the ability to reinsert the cannula from the caregiver, are
additional common causes of respiratory emergency [1, 6, 9]. The caregiver should
be trained to be able to recognize and manage such complications/emergencies
once the patient has returned home. Unfortunately, if on a theoretical level the
preparation of flowcharts and action tables can provide a guide on what to do in
every moment of these situations, this set of skills still remains the most difficult to
learn, train and evaluate through a hospitalization [9, 12], constituting one of the main
causes of re-hospitalization. Although it may not always be possible to completely

avoid their onset, their prevention should be a fundamental part of the caregiver
formation, including the development of an appropriate awareness of the importance
of personal hygiene (both carer’s and patient’s), device cleanliness and regular anti-
flu vaccines [8].
Although each of these “skills” can be exercised separately during the patient’s
stay in the facility, operators should allow, if not encourage, caregivers to implement
these skills learned in a more comprehensive way, through practical sessions in
which they look after their future client for the entire day.
How
The educational path of the caregiver of a NMD chronically ventilated patient can
be divided into different moments.
During the initial phase, once the decision of discharge the patient home has
been made and the future caregiver(s) identified, the therapist (or nurse in charge),
having collected the necessary information on the patient from the other members of
the multidisciplinary team, can begin to outline the discharge program, including the
training on respiratory management. For this reason, the designed trainer will agree
with both patient and caregiver the dates of the theoretical and practical sessions.
During the theoretical sessions, which should precede the practical ones, the
caregiver will receive basic education on respiratory physiology, invasive and non-
invasive mechanical ventilation (including its rationale), modalities and aims of
monitoring vital parameters, as well as recognition and management of emergencies.
To facilitate learning, the therapist/nurse can make use of various supports, such as
multimedia presentations, anatomical models, demonstrative use of devices and
consumables. Of course a similar approach can be applied to other areas of patient
care (for example nutrition), according to each case’s specific needs.
This first phase will be followed by the demonstrative and practical part. In this,
with increasing independence, but always in a protected, supervised environment,
the caregiver will be able to practice the respiratory management of his future client.
This will include the daily hygiene of the stoma and cannula when present, the
removal and aspiration of secretions with the assigned devices, the management of
the ventilator, monitoring instruments and any oxygen and/or inhalation therapy as
well as the use of the resuscitation bag in case of failure/malfunctioning of the
ventilator or emergency.
At the end of this phase, before finalizing the patient’s home discharge, the
caregiver will preferentially undergo one or more assessment sessions, in which the
health personnel in charge will have the task of evaluating the skills learned.
However, the caregiver’s education should, ideally, be considered a continuous
process, which does not end with a successful patient’s discharge home, instead
continues throughout the course of his/her condition, evolving accordingly to its
specific requirements.

The teaching method deserves a separate discussion. The age of the “pupils” is,
in fact, an important factor to take into consideration when outlining the training
program.
The andragogical theory of learning, suggests each phase of the training should
be timed and planned in accordance with the learner and his/her commitments or
needs, such as working hours or family, and that the training approach should be
“problem-centered,” focused on the acquisition of notions and skills aimed at tackling
practical issues [8, 11, 13].
Another key concept is the personalization of the topics covered: to optimize the
caregiver’s learning, it is preferable that the different sessions focus on practical
aspects that the individual learner, after a self-assessment process guided by the
therapist/nurse, has recognized as important. It is therefore of fundamental
importance that those in charge of training highlight, from the very first sessions, the
implications and practical value of each topic on the program.
Lastly, the style of teaching should be kept into consideration: ideally, the
preferences of the individual caregiver on this aspect should be investigated and,
when possible, implemented [8].
However, to optimize the available resources, it is not uncommon for the
theoretical sessions to be held for multiple caregivers at the time, normally sharing a
close discharge date. In these cases, a multimodal approach, including printed
material (written in clear accessible language), multimedia presentations with
images, diagrams and videos, anatomical models and exposure of medical material
in actual use, is commonly suggested [8, 11].
EVALUATING THE CAREGIVER FORMATION
Following the practical phase at the patient’s bed, of variable duration depending
on the centre, the patient’s condition, as well as the skills of the caregiver, an
evaluation of the skills acquired is carried out before patient’s discharge.
As already anticipated, despite the heterogeneity characterizing the chronically
ventilated NMD population, as well as the absence of globally recognized guidelines
for the training of the caregivers in the management of ventilatory aspects, it is
essential for this educational path to include, both in theory and practice, those six
macro areas previously illustrated.
Additionally, to assess all of these required areas of expertise, each centre has
historically opted for one or more modalities, including written quizzes, self-
assessment questionnaires, and bedside practical tests.
Nevertheless, during hospitalization, most of the caregivers in training will not
have the opportunity to assist, let alone practice, on a real emergency: at the time of
discharge, therefore, this specific part will remain, at the very least, uncertain [9].
A possible solution may come from the latest developments in medical training,
with the introduction of hyper-realistic simulators also for the practice and evaluation

of the skills acquired by caregivers, particularly, but not exclusively, in the context of
emergency management.
FUTURE PERSPECTIVES: HIGH FIDELITY SIMULATION TRAINING
Various specialized centers around the world have tried to standardize, at least
locally, their caregiver training interventions; however, additional difficulties appear
whenever attempting to objectively evaluate the preparation of these figures upon
patient’s discharge. Often, this is due to the fact that during the hospital stay, given
the protected environment, the patient may never be in an emergency situation:
consequently, the caregiver could find himself faced with this unprecedented
scenario, up to that moment faced exclusively on a theoretical level, only once he
has arrived home. This is confirmed by the high rate of readmissions in the first 30
days of discharge [7].
To address this issue, specifically, but not exclusively, in the case of IMV,
protocols have been developed that involve the use of high fidelity simulation
training, capable of reproducing the most diverse management scenarios, from the
most common to overt respiratory emergency. This offers designated caregivers the
opportunity to practice recognizing the signs of respiratory complications and acting
accordingly.
These simulators, in the form of hyper-realistic mannequins, accessorised with a
monitor to allow the “detection” of vital parameters, have already been used
successfully for years in the training of medical personnel of various levels (doctors,
paramedics, nurses, etc.).
At each training session, the designed operator can simulate a wide range of
respiratory noises, both physiological and pathological, a state of cyanosis in the lips
and alter vital parameters. Additionally, what makes these tools truly interactive is the
fact that all these variables can be modified consequently to interventions previously
carried out on them. Lastly, the presence of a tracheostomy opening on the
mannequin makes it possible to learn to place and use real consumables
(tracheostomy tubes with fixing systems, suction tubes, ventilation circuits ...). In a
study recently conducted on caregivers of IMV paediatric patients, the association of
these tools with traditional training methods proved to allow for greater effectiveness
of the training program in three of the most common emergencies at home:
desaturation, obstruction of the tracheal tube and accidental decannulation [7]. This
type of training on a hyper-realistic simulator has allowed to introduce caregivers to
the management of emergency and stressful situations while still being in the
protected environment of the health centre. The same work also highlighted how
such a training program contributed to increasing the level of confidence and
preparation (perceived and effective) of the caregivers, while evidencing their
remaining gaps/uncertainties, thus allowing, when necessary, to specifically review
some specific areas [7].

Despite the increased costs in terms of material, human resources and time that
such a training program would require compared to traditional methods, its potential
for a much widespread application remains undeniable. Future studies will need to
weigh its possible added value in terms of training efficacy for both naïve caregivers
and those already trained, but in need of a refreshment against those more practical
aspects.
THE CAREGIVER’S BURDEN
Lastly, when addressing the caregivers’ education, attention should also be paid
to their quality of life, specifically to the assessment and quantification of their
psychophysical burden. In this section we will try to outline the main components of
this condition, as well as some of the principal counteracting interventions; for more
detailed information, we suggest to start consulting the bibliography provided.
Caregiver’s burden concerns his/her feelings towards the physical, psychological,
social and economic losses he/she may suffer or is currently suffering as a
consequence of taking care of his/her clients. Together with depression and anxiety,
caregiver’s burden is a sign of psychological distress, which tends to vary as the
patient’s disease progresses (from either the physical, cognitive or the behavioural
point of view), the amount of care required increases, patient’s residual autonomy
decreases. Taken to the extreme, carer’s burden can cause a situation of overt
burnout, characterised by emotional and/or physical exhaustion [14]. Other modifiers
can be the socioeconomic status (both of the caregiver and the patient’s family, who
may or may not opt for dividing the workload among multiple carers), the caregiver’s
prior health status, age and social support [15]. From the respiratory point of view,
while ventilator introduction proved to ameliorate a patient’s quality of life, the same
cannot always be said about that of caregiver. This seems to apply equally in the
case of NIV and IMV, especially when NIV guidance from the discharge centre has
been suboptimal [10]. Furthermore, as a work on ALS population suggested,
patient’s behavioural changes, together with caregiver’s overall stress level may
have a comparable, if not greater, influence on their burden than any other patient-
related variable, included physical function [16]. Lastly, given a great number of
primary caregivers of NMDs belongs to the same patient’s family, further precipitator
factors may include the perceived loss of intimacy, the occurrence of major strains on
the familiar relationship, as well as reduced social and personal time [15].
Several self-report questionnaires are available to assess the presence and
severity of caregiver’s burden, together with the correlate symptoms of depression
and anxiety. Particularly, the Caregiver Burden Inventory (CBI) evaluates the burden
in five different areas (time-dependent, developmental, physical, social and
emotional aspects of burden) [17]. However, recent works pointed out how the
assessment of a concept so heterogeneous as burden may still be too vague to allow
for clear diagnoses [14].

As for the modalities of addressing this aspect, three main coping strategies have
been identified in the literature: emotion-oriented, task-oriented and avoidance-
oriented. Among these, the task-oriented one proved the only effective one for
caregivers of a NMD population, provided reasonable goals could be chosen [17].
Additionally, formal and informal supports may be provided to address carer’s
situation: the first is provided by professionals and public services and mainly offers
informational and instrumental support through, for example, nursing home care,
medical and social-working assistance). The second is the support coming from the
caregiver’s and/or patient’s informal relationships, such as relatives, friends and
neighbours: usually they provide emotional support, which several works found to be
particularly effective in relieving caregiver’s burden, acting more directly on the
psychological aspects of the condition than those previous two [18].
However, given the mentioned multifaceted nature of burden, further efforts will
be needed to better define and consequently address this debilitating condition. In
the meanwhile, this aspect should be kept into consideration throughout the whole
course of caregiver education, to help raise awareness both among these subjects
as well as patient’s families.
CONCLUSION
The last decades’ developments in both the medical and technical fields
contributed to extend the life expectancy of even those NMD patients with the more
severe respiratory involvement. However, this has led to a parallel increase in the
population on chronic ventilation, the management of which has consequently
affected the local national health budgets. In order to contain this increase in
healthcare costs, without the already fragile NMD population paying the price for it, a
policy encouraging an earlier discharge to home management of these subjects has
been widely adopted. This was possible thanks to parallel innovations in the field of
home ventilators, but also, if not most importantly, to the diffusion and progressive
specialization of the personal home assistant, the caregivers.
Although that cannot be called a novel figure, it is true that over the years it has
undergone such an evolution leading to the acquisition of new skills and
responsibilities, previously exclusively intended for medical and health personnel.
Consequently, several centers have been developing specific training programs to
ensure patients a safe transition from hospital to home, avoiding all those problems
deriving from recurrent re-hospitalizations. On the other hand, such programs also
allow protecting the caregiver himself from excessive physical and emotional
burdens, as well as from episodes of burnout that could follow.
Future ameliorative works in this direction should not disregard the latest
evidence from the literature, as well as the updates in the field of the most commonly
prescribed devices.

On the other hand, further focus will still be needed on the training and
assessment methods of all those skills necessary for emergency management,
which, despite their importance, are, to date, the main area of a caregiver’s
weaknesses and insecurities. Lastly, research will need to also try to improve the
understanding of the factors influencing the caregiver burden so that to implement
better practical measures to support the caregiver.
REFERENCES
[1] Nakarada-Kordic, I., Patterson, N., Wrapson, J. & Reay, S. D. A Systematic

Review of Patient and Caregiver Experiences with a Tracheostomy. Patient -
Patient-Centered Outcomes Res. 11, 175–191 (2018).
[2] Schaepe, C. & Ewers, M. “I see myself as part of the team” – family caregivers’
contribution to safety in advanced home care. BMC Nurs. 17, 40 (2018).
[3] Blais, R. et al. Assessing adverse events among home care clients in three
Canadian provinces using chart review. BMJ Qual. Saf. 22, 989–97 (2013).
[4] McKim, D. A. et al. Formal ventilation patient education for ALS predicts real-life
choices. Amyotroph. Lateral Scler. 13, 59–65 (2012).
[5] McCormick, M. E. et al. Life after Tracheostomy. Otolaryngol. Neck Surg. 153,
914–920 (2015).
[6] Gaudreau, P. A. et al. Preventing Complications of Pediatric Tracheostomy
Through Standardized Wound Care and Parent Education. JAMA Otolaryngol.
Neck Surg. 142, 966 (2016).
[7] Prickett, K., Deshpande, A., Paschal, H., Simon, D. & Hebbar, K. B. Simulation-
based education to improve emergency management skills in caregivers of
tracheostomy patients. Int. J. Pediatr. Otorhinolaryngol. 120, 157–161 (2019).
[8] Joseph, R. A. Tracheostomy in Infants: Parent Education for Home Care.
Neonatal Netw. 30, 231–242 (2011).
[9] Kun, S. S., Davidson-Ward, S. L., Hulse, L. M. & Keens, T. G. How much do
primary care givers know about tracheostomy and home ventilator emergency
care? Pediatr. Pulmonol. 45, n/a-n/a (2010).
[10] Kim, C. H. & Kim, M. S. Ventilator use, respiratory problems, and caregiver
well-being in Korean patients with amyotrophic lateral sclerosis receiving home-
based care. J. Neurosci. Nurs. 46, E25–E32 (2014).
[11] Tearl, D. K. & Hertzog, J. H. Home discharge of technology-dependent children:
evaluation of a respiratory-therapist driven family education program. Respir.
Care 52, 171–6 (2007).
[12] Tofil, N. M. et al. Ventilator Caregiver Education Through the Use of High-
Fidelity Pediatric Simulators. Clin. Pediatr. (Phila). 52, 1038–1043 (2013).
[13] Knowles, M. Adult Learning Processes: Pedagogy and Andragogy. Relig. Educ.
72, 202–211 (1977).

[14] Gérain, P. & Zech, E. Informal Caregiver burnout? Development of a theoretical

framework to understand the impact of caregiving. Front. Psychol. 10, 1748
(2019).
[15] Galvin, M. et al. Caregiving in ALS - A mixed methods approach to the study of
Burden. BMC Palliat. Care 15, 81 (2016).
[16] Lillo, P., Mioshi, E. & Hodges, J. R. Caregiver burden in amyotrophic lateral
sclerosis is more dependent on patients’ behavioral changes than physical
disability: A comparative study. BMC Neurol. 12, (2012).
[17] Siciliano, M. et al. Coping strategies and psychological distress in caregivers of
patients with Amyotrophic Lateral Sclerosis (ALS). Amyotroph. Lateral Scler.
Front. Degener. 18, 367–377 (2017).
[18] Shiba, K., Kondo, N. & Kondo, K. Informal and formal social support and
caregiver burden: The AGES caregiver survey. J. Epidemiol. 26, 622–628
(2016).

Chapter 41
THE ROLE OF NON INVASIVE VENTILATION

IN QUALITY OF LIFE IN NEUROMUSCULAR DISEASES
E. Volpato1,2, PhD, F. Pagnini2,3, PhD and P. Banfi1,, MD

1
IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
2
Department of Psychology, Università Cattolica del Sacro Cuore, Milan, Italy
3
Department of Psychology, Harvard University, Cambridge, MA, USA
ABSTRACT
In patients with neuromuscular diseases (NMDs), respiratory conditions

represent a relevant threat which can progressively impacts on their quality of
life. Non Invasive Ventilation (NIV) has been shown to significantly improve
respiratory parameters and to extend survival in patients affected by different
NMDs. Although once therapy is undertaken, an improvement is generally
detected, its impact on both psychological factors and quality of life is frequently
mentioned and less studied. Nevertheless, underestimating the quality of life of
NMDs patients can influence both the kind of therapies and the ways through
which they are offered. An accurate assessment of quality of life and the involved
psychological factors should be undertaken routinely before offering patients the
option to undertake NIV and during follow ups.
Keywords: neuromuscular diseases (NMD), non invasive ventilation (NIV), quality of

life (QoL), health related quality of life (HRQoL)

Corresponding Author’s E-mail: pabanfi@dongnocchi.it.

558 E. Volpato, F. Pagnini and P. Banfi
ABBREVIATIONS
ALS Amyotrophic Lateral Sclerosis

DMD Duchenne Muscular Dystrophy
FSHD Facioscapulo-Humeral Muscular Dystrophy
HMSN Hereditary Motor and Sensory Neuropathy
HRQoL Health Related Quality of Life
LGD Limb-Girdle Muscular Dystrophies
MD Myotonic Dystrophy
MND Motor Neuron Disorders
NIV Non Invasive Ventilation
NMD Neuromuscular diseases
QoL Quality of Life
SAQLI Sleep Apnea Quality of Life Index
SMA Spinal Muscular Atrophy
WHO World Health Organization
INTRODUCTION
A Definition of Neuromuscular Disease
Neuromuscular diseases (NMD) represent a disparate group of rare diseases

involving different components of the nervous system such as muscles, the spinal
cord, peripheral nerves and junctions. The definition includes a vast and
heterogeneous group of pathologies affecting different motor units: the I and II motor
neurons (the first neuron placed in the cerebral cortex and the second motor neuron
in the brainstem and spinal cord), the nerve fiber (motor and/or sensory), the
neuromuscular plate and the muscle fiber (Bos, Kuks, and Wynia 2015).
NMDs can occur both in childhood and adulthood. At every level, there are
genetically determined and acquired pathologies. The impairment of these structures
determines deficits in strength and/or sensitivity, that can vary in size, location and
course over time in relation to the type of pathology. An involvement of the cardiac
and respiratory muscles can be present, leading to respiratory failure and death from
diaphragmatic paralysis and/or bulbar muscle dysfunction.
Due to the anatomical localization of the impairment, four categories can be
identified (Robinson, M. T., & Estupinan 2019):
 Motor Neuron Disorders (MND) such as Amyotrophic Lateral Sclerosis (ALS)

and Spinal Muscular Atrophy (SMA) which may involve motor neurons in the
spinal cord, and ultimately weaken the muscles;

The Role of Non Invasive Ventilation in Quality of Life … 559
 Motor Nerve Root Disorders and peripheral neuropathies such as Hereditary

Motor and Sensory Neuropathy (HMSN), and Guillain Barré Syndrome, that
not only affect motor but also sensory nerves;
 Neuromuscular Transmission Disorders in which the neuromuscular junction
may also be directly involved in disease such as myasthenia gravis;
 Muscle Disorders such as Duchenne Muscular Dystrophy (DMD), Becker
Muscular Dystrophy (BMD), Myotonic Dystrophy (MD), Facioscapulo-
Humeral Muscular Dystrophy (FSHD) and Limb-Girdle Muscular Dystrophies
(LGD) etc.
What is Quality of Life?
The general concept of quality of life was initially considered a useful adjunct to
traditional concepts of health and functional status. The World Health Organization
(WHO) defines Quality of Life (QoL) as the way individuals perceive themselves
about their goals and suggests that it can be affected by physical and psychological
health, independence and relationships with both others and the environment (World
Health Organization 1995). A number of terms have been used interchangeably,
including functional status, health status, quality of life, subjective wellbeing and
health-related quality of life. While the health status typically involves also the
individual’s subjective experience of his/her physical and psychological health, the
functional status refers to the ability to perform independently the activities on a daily
basis. Subjective well-being, on the other hand, was defined as an assessment that
people make about their life, the events that happen to them and the circumstances
in which they live (Diener 2006). Finally, Testa and Simonson define Health Related
Quality of Life (HRQoL) as “physical, psychological and social domains of health,
seen as distinct areas that are influenced by a person’s experiences, beliefs,
expectations and perceptions” (Testa and Simonson 1996, p. 835). In conclusion, the
idiosyncratic feature of QoL is the consideration of judgments, expectations, values
and preferences of the patience (Gill and Feinstein 1994) in NMD as well as in other
chronic diseases (Pozzar, M., Volpato, E., Valota, C., Pagnini, F., & Banfi 2020;
Volpato et al., 2018).
EXPLORING QUALITY OF LIFE IN NEUROMUSCULAR DISEASES
A Brief Analysis of Quality of Life in Neuromuscular Diseases
Symptoms of the disease affect the quality of life (QoL) of NMD patients, but they
are not the only ones. It is important to take into account other aspects that, in
addition to the symptoms, can affect the patient’s QoL such as psychosocial,
spiritual, existential factors, coping strategies and support network (Pagnini et al.,

2017). First of all, hope and hopelessness play a relevant role in the framework of a
progressive disease: indeed, people with psychological vulnerabilities may develop a
tremendous sense of hopelessness when confronted with the prospect of imminent
death from a severe illness. Furthermore, the evidence suggests that the
development of a state of hopelessness could influence the course of the disease
itself (Ingre et al., 2015). Emotional distress does not depend solely on the physical
damage that is experienced but on the way in which the mind processes the
experience. Secondly, although NMD people may appear more depressed than
anxious, the progressive loss of control of one’s body, immobility and increasing
dependence on others generates severe anxiety, especially during the early stages
of the disease. Thirdly, the impaired body function such as decreased physical
abilities and muscle power were found to be indicative factors to employment:
therefore, most NMD people strive to stay employed without disclosing their illness or
progression of their illness until it becomes noticeable. Finally, it is relevant to note
that the quality of the care received and the patients’ perception of their social
network of support people are predictive factors of the affective state of patients and
their quality of life.
The Link between Quality of Life and Non Invasive Ventilation
In NMDs, the aim of respiratory management is represented by three functions:

ventilatory support, which assists the respiratory functions and stabilizes gas
exchanges; cough augmentation, which improves the cough flows and clears
secretions; lung volume recruitment, which avoids functional decline. Ventilatory
support can be provided by Non Invasive Ventilation (NIV) or invasively, via
tracheostomy (Voulgaris et al., 2019). As the respiratory muscle progresses,
nocturnal ventilation becomes insufficient to control daytime respiratory failure,
leading to the need of daytime NIV, which can be delivered adopting the same
interface used during the night or a mouthpiece ventilation. The main advantage of
mouthpiece is represented by the possibility to speak, swallow and avoid the
fastidious skin breakdown, favouring the social contacts.
Despite a lot of concerns regarding the if and when of NIV, it is generally
recommended in order to prolong survival, improve respiratory functions and QoL
and its impact is ostensibly considered more “patient-focused.” Nevertheless, a
substantial proportion of people affected by NMDs tend to reject or be disengaged by
NIV. Recent studies demonstrated that the main reasons for decline or withdrawn
from NIV, are represented by the discomfort of the mask and the sense of loss of
control, resulting in crisis of anxiety, claustrophobia or panic attacks. The average
time of NIV’s adaptation is significantly influenced by both the presence of sialorrhea,
the respiratory status and behavioural and cognitive impairment (Russo et al., 2020).
Some patients see in NIV a threat to self’s preservation, especially in terms of loss of
autonomy, dignity and quality of life. Finally, other patients associate negative views
about NIV’s usage and the experiences with health care systems (Ando et al., 2015).

The news that the respiratory functions might be compromised by NMD leads to
emotional responses per se, because it represents the idea that there is an additional
area of the body encountering decline. Respiratory impairment could be seen as
incongruent with illness expectations as well as a source of anxiety, shock and/or
disappointment. Since any news about the decline naturally evokes negative
emotions and the need of restore confidence to the future, patients tend to afford
greater attention than ever to respiratory symptoms, sometimes even modifying
behaviour to avoid strain on it. In addition, every patient conceptualises each
respiratory change within the wider framework of NMD: generally, patients are not
apprehensive about the current respiratory status, but the future illness’ possible
development. Indeed, there are patients who are unable to recognise the respiratory
changes or perhaps don’t wish to recognise them.
These findings suggest the relevance of paying attention to the psychological
dimensions involved in the decision-making process regarding the uptake of NIV as
well as the need of a multidisciplinary evaluation before suggesting it.
The Controversial Sides of Measuring Quality of Life

in Neuromuscular Diseases
Literature report QoL of NMD people as conflicting. Some studies show a

reduced QoL, while others find no significant differences if compared with other
chronic illnesses. However, it is possible that the findings are impacted by the way in
which QoL was measured.
Some problems related to measures are due to the fact that HRQoL is more
narrowly defined than overall quality of life. It is largely seen from a medical
perspective and, therefore, it does not usually include non-medical concepts, such as
family, support systems, friends, and the complex environment, unless these areas
are directly influenced by the patient’s health status. HRQoL theoretically differs from
global QoL because it seeks to address those aspects of self-perceived well-being
that are related or influenced by the presence of the disease or clinical treatment.
However, this distinction between QoL and HRQoL is often blurred and changes in
scores are often believed to be related to changes in disease status. HRQoL
measures are more likely to be used in clinical trials to evaluate changes in the
patient’s perspective in relation to any effect of the treatment they are currently
undergoing. However, it is necessary to pay attention:
1. Whether the measure is considered to be as global QoL or a HRQoL

measure therefore if is disease-specific or generic;
2. Which aspects of life (e.g., psychological well-being, social activity) are
referred to and which are not;
3. To which population and context the measure is intended;
4. Ease of administration and interpretation;

5. Who performs the assessment (for example, whether or not self-

administered);
6. How the results are intended to be used (for example, whether to improve the
patient’s quality of life).
An advantage of using a disease-specific HRQOL measure over generic

measures is that disease-specific assessments include only elements that are
relevant to a given disease and/or treatment and exclude elements that are not. The
specificity of a QoL scale for a disease allows for optimal psychometric properties
and avoids creating an additional burden for patients and caregiver caused by long
scales containing unnecessary items. Moreover, it avoids the inclusion of elements
that run the risk of being seen by patients as unnecessarily intrusive.
There are HRQoL scales that explore other areas of the neuromuscular disease
itself, such as possible respiratory or heart disease complications.
It is relevant to note that, while Bourke et al., found an improvement in sleep-
related quality of life in all patients, failed to demonstrate a life-prolonging effect in
patients with pronounced bulbar involvement (Bourke et al., 2006). Although it is
unanimously accepted that NIV is more complicated in bulbar patients due to other
aggravating factors (sialorrhea, vocal cord dysfunction), more recent studies have
shown that bulbar patients may also have a prolonged survival, while obviating the
importance of QoL (Berlowitz et al., 2016). Numerous studies have also shown that
the quality of life in patients with ALS, even advanced, can be high (Abramson 1996).
To further support this, QoL, depression, hopelessness, and psychological well-being
of patients with ALS who were on ventilatory therapy were not significantly different
from those who did not receive mechanical ventilation (McDonald, Hillel, and
Wiedenfeld 1996; Kaub-Wittemer et al., 2003). Similarly, in DMD, QoL was
independent by the degree of respiratory disability and impairment. These findings
are important, as the underestimation of quality of life by health professionals and
caregivers can occur if quality of life is based on judgments of the severity of physical
disability. If not recognized, the result could be an inaccurate estimate of QoL and an
undesirable impact on care decisions (Gibson 2001). Gholamreza Zamani studied
QoL in 85 unventilated vs. 136 healthy Iranian DMDs (8-18 years), from the
perspective of children, adolescents and their parents using KIDSCREEN-27. This
questionnaire essentially evaluates physical activity and health, mood and feelings in
general, family, free time, friends, school and learning. The study showed that, from
the point of view of children and adolescents, the QoL was similar in boys with DMD
to that in healthy controls, with the exception of the “physical activity and health” and
“friends” subclasses (Zamani et al., 2016). In their review, Wei et al., found that the
HRQoL scores of boys with DMD appears to be significantly lower than that those of
their healthy peers, particularly in the physical sphere. Within the DMD sample, boys
who are in a more severe phase of the disease consistently reported a poorer
“physical” HRQOL than boys who are in a less severe phase of the disease; this
difference, however, was not so consistent with the quality of life in the psychosocial
sphere. Similarly, while the physical domains of HRQoL tools correlated well with

clinical measurements of physical disability, the psychosocial domains did not. The
study of QoL in spinal muscular atrophy is even more complex due to the different
phenotypes of the disease. A systematic review highlights that evolving standards of
care will lead to increased interest in methods used to measure quality of life in
infants and children in all types of SMA. Generic tools currently used may not
adequately highlight changes in quality of life in SMA, especially given the age group
affected by the disease.
GENERAL DISCUSSION
What’s Still Missing?
In NMDs, the literature of QoL is complex and challenging for many reasons,
including the large number of neuromuscular diseases being studied, the
heterogeneous QoL measures in use, the inaccurate understanding of what it really
constitutes the construct of quality of life and the dynamic and constantly evolving
nature of everything that then contributes to it. Further studies are needed to answer
to the controversies previously illustrated as well as to improve the multidisciplinary
approach and its application since the adaptation to NIV. The impact of NIV or other
assisted ventilation devices is poorly explored on both pediatric and adult samples.
Future studies should deeply consider HRQoL across childhood and adolescence as
well as the parenting stress. Similarly, more specific and standardised measures are
needed to enhance understanding of how interventions impact and maintain
wellbeing over time in adult patients and their caregivers. Finally, while from a clinical
point of view, the successful implementation and adaptation to NIV requires an
appropriate choice of the ventilator setting, together with a comfortable interface and
a constant close monitoring; from a psychological standpoint, significant efforts are
needed to achieve the proper transition to the usage of a new device.
Nevertheless, studying the quality of life as much as possible is essential for
understanding patients with neuromuscular disorders. Providentially, significant
progress has been made in quality of life research for neuromuscular diseases in
recent decades, in part due to the use of specific quality of life measures validated
for the disease in question.
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Bos, I., Jan B. M. Kuks, and Klaske Wynia. 2015. “Development and Testing
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70326-4.
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Being.” Journal of Happiness Studies. https://doi.org/10.1007/s10902-006-9000-
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Pozzar, M., Volpato, E., Valota, C., Pagnini, F., & Banfi, P. I. 2020. “How People with
Chronic Obstructive Pulmonary Disease Perceive Their Illness: A Qualitative
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Neuropalliative Care, Springer, 101-15.
Russo, M., Carmen Bonanno, Claudia Profazio, Stefania La Foresta, Cristina
Faraone, Andrea Lizio, Gian Luca Vita, et al., 2020. “Which Are the Factors
Influencing NIV Adaptation and Tolerance in ALS Patients?” Neurological
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0277-9536(95)00112-K.
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2016. “The Quality of Life in Boys with Duchenne Muscular Dystrophy.”
Neuromuscular Disorders. https://doi.org/10.1016/j.nmd.2016.05.004.

Chapter 42
TELEMONITORING
Giancarlo Garuti1,, Jacopo Garuti2 and Alessia Zanoli3

1
Pulmonology Unit, Santa Maria Bianca Hospital, Mirandola MO, Italy
2
School of Medicine, University of Modena and Reggio Emilia, Modena MO, Italy
3
School of Medicine, Humanitas University, Milan, Italy
ABSTRACT
Telemedicine is involved in a variety of fields. While interest for health care

has only become evident recently, the sudden rise in health care costs is forcing
medical practitioners to seek practical, cost effective solutions. Information
Technology (IT) and, in particular, the latest methods for remote surveillance via
teleassistance interventions seem to be promising. Chronic diseases have
become an increasingly bigger issue for public healthcare. Neuromuscular
diseases (NMDs) are chronic conditions that present with progressive muscle
atrophy leading to difficulties for walking, swallowing, and eventually, breathing
and clearing the airways. Chronic respiratory insufficiency in NMDs develops
insidiously and at very variable rates. The specific characteristics of it displayed
by these patients require planning and may benefit by telemedicine solutions.
However there is still little information regarding the advantages of this
technology for this patient population.
INTRODUCTION
Background
In Europe, in 2023, on average 14% of Ground Domestic Product (GDP) will be

spent on Health Care. Reasons for increasing cost have been attributed to a

Corresponding Author’s E-mail: g.garuti@ausl.mo.it.

568 Giancarlo Garuti, Jacopo Garuti and Alessia Zanoli
progressively aging population, patients’ requests for possibly extraneous

interventions and lifestyles. European health is forced to deal with the demand of
new increasingly expensive medications and other interventions on one hand and
with patients’ requests on the other hand. Despite it is nowadays more and more
frequently meant to be a way to meet healthcare professionals through
videoconference platforms, telemedicine itself represents all kinds of remote medical
assistance lacking a face to face contact with a health care practitioner [1]. It occurs
either in real time as if it was a synchronous communication via phone or
videoconference, or asynchronously (store and forward) by receiving and storing
medical interviews to be viewed at a later time.
Health data remote collection is performed by an increasing number of devices
for both consumers and professionals, such as applications aimed to the filling in of
patients data to be used for live interpretation or asynchronous revision.
Telemedicine, indeed, represents an innovative way to break down the barriers
of distance and time while decreasing costs. There are now over 2000 studies over
the last 40 years exclusively concerning the benefits of telemedicine. In the U.S.
treatment of the chronically ill represents almost four-fifths of health care
expenditures. A study carried out by two American clinics compared the telemedicine
program “Health Buddy” with a control group of patients and noted a significant
decrease in cost of 13% ($312-543) per patient. An accurate study, performed on
Behalf of Leadership Partners Heal Health Care in 2007, took into account different
specific applications of telemedicine and defined both individual costs and nationwide
financial benefits in the following:
 Connection between emergency services and reduction of transport costs

(estimated savings equal to 537 millions dollars per year);
 Decrement of patients’ transportation from Penitentiary facilities to first aid
departments and medical surgeries, and decrease of hospitalisation costs
(estimated savings equal almost to 210 millions dollars per year);
 Reduction of transfers from Nursing homes to emergency departments and
medical surgeries avoiding transport costs (estimated savings equal to 327
millions of dollars per year) and visits/hospitalisations (savings equal to 479
millions of dollars per year).
The Veterans Health Administration has introduced a telemedicine program for

long-term coordinated management of veterans with chronic conditions who are
treated in residential institutions. Despite an increase in the number of veteran
patients, estimated from 2,000 to 31,570 (1,500% growth) between 2003 and 2007,
the introduction of telemedicine resulted in a reduction of 25% in recovery
(hospitalization) durations, a reduction of 19% in hospital admissions, and dramatic
cost reductions with an increase in quality of care [2].

Telemonitoring 569
In the monitoring and self-management of diabetic patients, telemedicine

provided a reduction in the risk of related disabilities. According to the Indian Service
Health, an innovative use of IT and telemedicine promotes programs aimed at the
improvement of disease management and health care equality in a society with
strong economic disparities. A meta-analytic study led by Pennsylvania Politic Health
Department took into consideration 29 research articles published between 2001 and
2007 [3] and underlined the positive effects of telemedicine for some categories of
diseases including:
 cardiovascular diseases;
 psychiatric diseases (telepsychiatry) with psychiatric interview via
teleconference;
 paediatric diseases.
In Europe, thanks to Europe Commission incentives, many countries have

started to introduce and evaluate the feasibility of telemedicine services.
Economic Considerations
Below some advantages concerning telemedicine applications which have

positive outcomes on the economic aspect of the processes involved in healthcare:
 New possibilities of interventions that may improve care without increasing

healthcare expenses;
 Diminution of overall costs of interventions (despite the growth of healthcare
service costs caused by ageing population, increase of chronic disease,
patients’ requests regarding additional care acquisition, and lifestyles);
 Better employment of current resources by enhancing cooperation and
communication among the different professional roles involved;
 Shifting of costs currently inherent in some sanitary activities to a new ambit
involving in a combined way technologies (medical devices, computer, etc.)
and telecommunications. The increased chance to communicate offers the
possibility to rapidly get information and exchange experiences among
colleagues, less displacement of doctors and patients, less use of paper
material and manual transfer of information;
 Integration among different health services, contributing both to focus
attention on clinical aspects and decentralization of care to the home setting;
 Increasing the number of patients who can be treated, a very important point
since there may be an inadequate number of health care professionals in
certain medical domains;

 Offering qualitatively and quantitatively improved health services;

 Increasing physician knowledge, both concerning capacities and transversal
skills.
Critical Issues
Besides the countless advantages, the critical issues arising from the
applications of telemedicine should always be kept in mind, in order to prevent,
reduce and solve them. In particular:
 Excessive addiction to technology could expose patients to several risk

related to ethical and medical-legal issues;
 To define the responsibility of the practictioner who performs the examination
and requests the consultation to whom reports the data from remote;
 Excessive use of teleassistance could influence the safety and the quality of
traditional medical action because of possible increased risk of misdiagnosis
or failure to diagnose complicating conditions that are not apparent on
computer screens;
 Excessive use of technology could drive to depersonalisation and removal of
responsibility, being at the same time dangerous due to the unreliability of the
collected data;
 Issues related to the necessity to standardise physical and logical interfaces
in order to allow the exchange of information through a net;
 Evanescence of doctor-patient relationship, therefore creating a distance
between doctors and patients’ personal problems, reducing knowledge of
psychological factors that may be important, rather than only biological
considerations,
Furthermore, the numerous and complex technical aspects can induce errors:
 Excess of integrated and involved equipment;

 Errors in the installation or in the implementation of devices (collocated in
distant locations);
 Ineffective maintenance of equipment;
 Erroneous employments of devices and equipment, including wrong data
transmission and/or evaluation.
Finally, it is necessary to remember that most countries are still deficient in

specific laws and regulations, orders or related protocols.

Telemonitoring 571
THE TELEMONITORING IN THE CONTEXT

OF NEUROMUSCULAR PATIENTS
General Considerations
The NMDs include diseases of the central and peripheral nervous system and
skeletal muscles, the majority of which progress at varying rates but ultimately result
in ventilatory failure. The home care of patients with NMD consists of
multidisciplinary interventions to prevent or reduce the number of hospitalisations, to
delay respiratory failure, and to more appropriately dispense health resources (e.g.,
abuse of antibiotic therapy). A program of domiciliary respiratory management of
NMDs is focused on three big themes:
1. To monitor gas exchange;

2. To manage airway secretions;
3. To prevent hospitalisation.
A series of periodic domiciliary telemedicine controls can be executed to check:
1. The patient’s global clinical state and medical conditions;

2. The appearance of any side effects to the treatments undertaken;
3. Compliance to treatment;
4. The presence of an adequate level of assistance from relatives or caregivers;
5. The efficacy of the therapy such as by nocturnal SpO2 monitoring of assisted
ventilation.
Hospital follow-ups are necessary only for a complete revaluation including

general, functional, neurologic and respiratory conditions measuring the same
parameters at the moment of prescription.
Because of deficient cough flows, patients with NMDs who develop upper
respiratory tract infections have a high risk of developing pneumonia. Optimal
domiciliary monitoring and management can help to avoid emergency room visits
and hospitalizations and management by physicians not specialised in taking care of
such patients.
A solution to combine the information collected from both sides, at home and
from hospital, could be via telematics, having as result a higher control of the patient,
an increased chance of preventive intervention avoiding hospitalisations and an
increase in the feeling of safety of the patient itself and its family.
The utilisation of IT, in fact, could bring benefit to the patient by facilitating
instantaneous communication with the physician specialist who will evaluate whether
to propose a domiciliary or hospital intervention according to the values showed by
the monitoring.

Hospital discharge is a key point in the treatment of such patients. The continuity
of care and home case manager’s role are crucial. It is known that NMD patients
require huge support from the health system. In particular, Amyotrophic Lateral
Sclerosis (ALS) necessitates dramatic physical, time, and economic commitment
from families to assist activities of daily living, for medical and respiratory failure,
management of any tracheotomy and mechanical ventilation, travel needs, instability,
doctors’ visits and hospitalizations.
Improving NMPs’ life’s quality is also to guarantee some kind of follow-up and the
necessity of a rigorous continuity in assistance.
It seems rational that the most serious patients request a more frequent follow-
up. Thus, matters such as the supervision of domestic devices, as well as the
planning of outpatient and home visits for a constant education and training can
improve quality of life of such patients and their caregivers’ security. This could be
very difficult for NMPs with a high grade of physical disability, and transferring them
to a dedicated medical centre could be quite complicated. To date, there are not
clear proves or agreements on the best way to take care of domiciliary NMPs: all the
available programs are not necessarily complementary to the level of load,
dependence or gravity of the disease.
Symptoms correlated to chronic diseases can cause high levels of disabilities in
people affected by rare diseases, and can worsen life’s quality related to one’s
health: Twork et al. [4] reported that a sample of 1,518 patients affected by Miastenia
Gravis (MG) showed lower level of HRQoL than a healthy group. Leonardi et al. [5]
underlined that HRQoL of patients affected by MG was inversely proportional to the
severity of the disease. A similar reduction of HRQoL has been observed in other
studies regarding other kinds of NMDs: ALS, facial-scapular-humeral muscular
dystrophy (FSHD) and other dystrophies.
In the last years several solutions have been proposed for domiciliary monitoring
via telematics of NMPs with secondary chronic respiratory disease. The design of
more up to date electronic medical tools and the possibility to dispose of more
practical, solid and simple devices for non invasive ventilation (NIV) are now more
readily available for these patients in their domestic environment. In the frame of
respiratory medicine, a huge potential exists for such technology in order to provide a
better assistance to people affected by chronic pulmonary diseases. NMDs are the
main Health management challenge from a respiratory point of view, because
models based only on purely medical management are not sustainable in these critic
patients and very often are not compliant.
The concept of teleassistance or telemonitoring, thus the utilisation of new
technologies to provide health services, could be considered an alternative and
innovative way to improve disabled people’s quality of life, and to make truly
multidisciplinary these patients’ management [6]. Teleassistance has been used in
the ambit of numerous diseases, including cancer, diabetes, post-traumatic stress
disturb, obesity, chronic respiratory insufficiency, cystic fibrosis, chronic pain and
ictus. Most of these studies consider teleassistance useful and beneficial. Few
studies examined the application of new technologies to improve the health of people

Telemonitoring 573
with rare diseases. These studies conclude that teleassistance is an important and
useful tool to improve quality of life of children and adolescents affected by
Duchenne muscular dystrophy, and of their parents as well. Furthermore, Vitacca et
al. [8] have conducted a study regarding teleassistance in ALS patients and their
caregivers, concluding that the applied programme could be useful for the follow-up
of ALS patients and the improvement of their quality of life. Similarly, the study of
Boeschoten et al. [9] pointed out that online applied therapy to resolution of problems
is practicable and reduces depressive symptoms in multiple sclerosis patients. In
fact, quality of life related to health could be influenced by the lack of a social network
or daily issues in front of a disease, such as mobility limitations or the difficulty this
population can face in finding other NMPs nearby: such gaps can be reduced with
videoconference. This tool is an available way to keep in touch with patients with rare
diseases who live in rural zones and might not have easy access to psychosocial
assistance services. Rural life and the elevated geographic dispersion rate of this
population can complicate the creation of social nets among peers. Studies on this
topic conclude that telemedicine or teleassistance are suitable methods to assist
people with rare neurodegenerative disease in rural environments [7] or
geographically isolated populations [10]. Furthermore, these authors underline that
psychotherapy via videoconference “is a valid alternative to face to face therapy.”
The satisfaction deriving from teleassistance has been evaluated in some studies as
the measurement of approval of this new tool of intervention [11], for example,
authors have conducted a revision of 32 studies on the use of videoconference and
have concluded that teleconsult is an acceptable connecting way in different
circumstances.
Doorenbos et al. [12] found out that online support groups are a precious method
to put in contact people who face similar experiences. Other studies have showed
that satisfaction of participants in interactive teleconsults in real-time exceeded 98%.
Telemedicine in the Long-Term Disease Monitoring
For many patients, the ability to interact with a doctor from remote, reducing
travel’s costs and time, and the potential reduction of salary loss, overcome
medium’s limits, in particular for patients who require frequent evaluations. For those
bearing a severe disability and special transport requirements, the journey to reach a
doctor in order to be visited can be uncomfortable, expensive, laborious, exhausting
and even dangerous for the patient and the caregivers too. It is estimated that
caregivers spend an average of 11 hour per day to take care of an ALS individual,
living a physical and emotive burden that worsens with the progression of the
disease: for this reason, telemedicine can improve the doctor-patient/caregiver
relationship, reducing the fatigue of the long and laborious patient’s preparation to a
clinic visit. Hospitals which employ telemedicine have been proved to be safe and
effective. Different forms of telemedicine have been tested in the treatment of ALS
patients: for example, the utilisation of live teleconferences with the rehabilitation

centre may be happily welcomed by small groups of patients and their caregivers, as
it happens in North Europe countries. In Cleveland VA Hospital, ALS patients have
been evaluated remotely around patients’ residential area and multidisciplinary
assistance has been provided according to patients and caregivers needs. In almost
7 years a total of 32 patients have been evaluated and compared to 36 patients
visited in clinic; no differences have been found between the groups concerning the
quality of recommended solutions. Although many articles are in favour of
telemedicine there is not evidence that this new technology can improve survival or
reduce the disease progression.
The most commonly used method in ALS is live videoconference among the
sanitary team, the caregiver and the patient, at patient’s home or in a local sanitary
facility. Limitations of such methods include the necessity for the patient to go in a
presentation site, the necessity to gather the entire team at the moment of the
meeting and rely on real time video which can be disturbed by connection issues or
other factors.
A recent study conducted by Massachusetts General Hospital and Boston
Healthcare System [13] aimed to evaluate the costs of televisit in ALS patients both
from patient and institutional’s perspective. Costs are aligned according to the the
patient/caregiver and the doctor’s perceptions on the medical usefulness of the visit.
Results are impressive: in the basic case, from the patient’s point of view, clinical
visits cost $1,116 while televisits $89 ($119 after MU update). From the institutional
point of view, clinical visits cost $799 and televisits $354 ($472 after MU update).
Adjusted costs savings are $997 (patient) and $327 (institute) for each televisit.
Telemedicine in the Monitoring and Setting of Mechanical Ventilation
Positive pressure non invasive ventilation (NIV) has become the standard
management of respiratory compromises in NMPs, increasing quality of life and
reducing the probability to resort to tracheostomy. Survival rate and quality of life
seem to be correlated to the early prescription of NIV, before the diurnal signs of
respiratory insufficiency are evident, with a forced vital capacity (FVC) <50% of the
expected value, or the individuation of early signs of the forthcoming night respiratory
collapse.
NIV requests a dynamic process of adaptation: patients with severe bulbar
weakness and relevant scialorrhea have the highest rate of poor compliance. In fact,
adaptation to NIV is a complex issue and certainly, the improvement of tolerance and
the continuity of its use can be reached only via the personalised setting of the
device, on which numerous factors depends, such as pulmonary mechanics,
pressures and ventilation modes adopted, inspiratory and expiratory triggers, backup
respiratory frequency, effective gas correction in bloodstream. NIV compliance in
ALS has been evaluated only in terms of number of hours of use per day, which is a
very limited data: nevertheless, most authors reported a longer survival in patients
who resort to NIV for more than 4 hours per day. Recent technological progresses

Telemonitoring 575
have made possible a more deepened inspection of pertinent sets, beyond the
analysis of number of hours/day utilisation. Via telemedicine it is possible to evaluate
supplied pressure, respiratory volumes, percentage of utilisation of a predetermined
target pressure, respiratory rate, peak flow, number of apnoea, losses percentage
and oxygen saturation: lately also pH, PaCO2 and PaO2 can be monitored online
non-invasively. Via remote connection it is also possible to perform controls and
online corrections in order to improve patient’s comfort, tolerance and compliance.
Nevertheless, these new technologies are of recent application in NMPs. Pinto and
collaborators [14] describe their experience as a significant progress in the
management of domiciliary NIV: they have used a system commonly connected to a
wireless network able to monitor ventilatory parameters, such as pressure and
inspiratory volume and used pulsossimetry as clinical parameter. Furthermore, they
were also able to modify ventilator’s settings in wireless mode from hospital’s lab,
without the need to visit the patients. Pre-set limits have been set on NIV protocol on
individual basis for each patient, and modem connection reported variations from the
predetermined limits. Appropriate modification in ventilator’s settings have been
transmitted in wireless mode to the patient’s ventilator. The interactive ability of this
system, the wireless modem, is a key characteristic. Such strategy has reduced both
non-planned hospital visits and, above all, the number of emergency admissions,
with demonstrable improvement in quality of life [14]. Also adaptation phase to NIV
has been simplified by the ability to modify ventilator’s settings in relation to
information received from ventilator’s modem. No effects concerning survival have
been registered. In the latter study, however, the stress experienced by patients and
caregivers has not been evaluated because there was not face to face meeting with
sanitary personal. An American evaluation on the cost of domiciliary ventilation in
ALS has suggested an annual cost of $153,252 [15]: it has been concluded that
domiciliary telemonitoring of NIV in ALS is a cheap intervention. It is required a
significant economic effort by the hospital to acquire all the appropriate technology.
However, a long-term saving on annual costs has been estimated around €700 for
each patient [15]. Since positive pressure ventilation (both invasive through
tracheotomy, both non invasive) has become more and more used in NMPs with type
2 respiratory insufficiency, it is now a practical, efficient and safe procedure also
thanks to technical progresses in domiciliary version. NIV success at home requests
a careful monitoring, implying need of domicile visits of qualified personal, regular
visits to hospital and availability of an emergency backup service. Emergencies
concern mainly respiratory passages’ obstruction by mucus or infections, rather than
technical breakdowns; such events can be foreseen and reduced through
telemedicine.
Telemedicine in Rehabilitative Context
The use of telerehabilitation in the model of healthcare supplying has been

successfully tested in patients with various diseases. When patients are not able to

access to specialized centres, telemonitoring allows the healthcare team to interact

with patients and their family in the domestic environment. Furthermore, such activity
has the potential to involve local and community services with specialised centres in
the decisional process. In a recent study, the impact of domicile telemonitored
rehabilitation has been measured on ALS patients: [16] patients and caregivers
considered telemonitoring a user-friendly system and compliance was excellent. The
constant monitoring of O2 saturation and heart rate during exercise showed that a
domiciliary programme of exercises is clinically safe when planned around anaerobic
threshold (VT1), limiting in this way overtraining leading to possible fatigue and
dyspnoea. Patients with signs of overtraining have been contacted promptly and
recommended to maintain the physical effort as predefined; this would be impossible
without this type of monitoring. Another study conducted on a heterogeneous group
of NMPs aimed to evaluate the advantages of telemonitoring system on the
management of secretions [17]: in 24 months 241 interventions have been executed
by respiratory therapists on 11 patients. During the first 12 months 4 episodes of
hospitalisation occurred, none in the following 12 months. During the year before the
project 7 cases of hospitalisation and one single case of admission to ER occurred.
Authors conclude that combination of telemonitoring and respiratory physiotherapy at
home is feasible in the long-term for NMPs. Even if we are positive about the
advantages of rehabilitation telemonitoring in NMDs, some restrictions should be
mentioned before a wider application, such as underestimation of fatiguing, data
protection, data accessibility, financial investments and the great amount of time
spent by the medical staff.
CONCLUSION
There are challenges and diffidence to overcome to make a change in the

current system of monitoring of chronic patients and in particular of NMPs:
1. Firstly, the incapacity to perform the traditional meeting face to face beside
the patient’s bed with a deepened physical exam seems to be an obstacle for
most traditional healthcare professionals. In our opinion, this is due more to a
misunderstanding on telemedicine’s role and its benefits rather than a real
system failure.
2. Secondly, the lack of awareness of these options and their utility among
patients, sanitary management and politicians has led to delays in the
adoption of these tools. In the US there is substantially more consolidated
evidence for what concerns the efficacy of costs and the improvement of
quality that telemedicine brings to the sanitary system.
Appropriate telemedicine technologies could be used in an environment with

limited resources using internal/open source solutions. This requires the analysis of

Telemonitoring 577
available resources from an experienced team in the field of telemedicine and with a
strong background in the application and personalisation of technology.
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Cost effectiveness of a telerehabilitation program to support chronically ill and
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and life circumstances in German myasthenia gravis patients. Life Outcomes
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Functioning and disability in adults with myotonic dystrophy type 1. Disabil.
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[7] Ferrer-Roca, O., Garcia-Nogales, A., Pelaez, C., The impact of telemedicine on
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[10] Backhaus, A., Agha, Z., Maglione, M. L., Repp, A., Ross, B., Zuest, D., Thorp,
S. R. (2012). Videoconferencing psychotherapy: A systematic review.
Psychological Services 9: 111-131.
[11] Mair, F., Whitten, P. (2000). Systematic review of studies of patient satisfaction
with telemedicine. BJM 320: 1517-1520.
[12] Doorenbos, A. Z., Eaton, L. H., Haozous, E., Towle, C., Revels, L., Buchwald,
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American Indian and Alaska native communities. Clinical Journal of Oncology

Nursing 14: 765-770.
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Carvalho, M. (2010). Home telemonitoring of non-invasive ventilation decreases
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[15] Almeida, J. P., Pinto, A., Pinto, S., Ohana, B., De Carvalho, M. (2012)
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home-based exercise program in amyotrophic lateral sclerosis: a feasibility
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Lusuardi, M. (2013) Pulmonary rehabilitation at home guided by telemonitoring
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2012 Jul. 23.

Chapter 43
PALLIATIVE CARE
Salvador Díaz Lobato*, MD, PhD,

Sagrario Mayoralas, MD, PhD and Johanny Vargas, MD
1
Medical Director Nippon Gases Healthcare, Spain
2
Hospital Quirón Salud San José, Madrid, Spain
3
Medical Dept. Nippon Gases Healthcare, Spain
ABSTRACT
Palliative care (PC) has become an essential component of the treatment of

neuromuscular patients, although the most published literature has been focused
in ALS patients. They have been described some barriers for an appropriate
utilization of PC in neuromuscular patients: Physicians have less experience with
PC in noncancer patients; they associate PC with death and dying, or are afraid
to diminish patients’ hope by introducing PC and patients associate PC with end-
of-life care. It is very important that patient and family members be involved in
making decisions about the disease. This should be done when the patient’s
functional status is still good and always after receiving adequate information
about the different therapeutic alternatives. It is also very important to avoid
making decisions in the course of an acute situation in the emergency
department or in the intensive care unit. The PC approach have to be defined
from a holistic point of view taking into account a series of therapeutic measures,
such as pharmacological treatment, oxygen therapy, mechanical ventilation,
respiratory physiotherapy, nutritional assessment, communication and emotional
and spiritual support. We must learn to communicate the prognosis of the
disease. All patients have the right to know the details about the disease they
suffer from, but not everyone wants to know about it, and this should also be
respected. Even if they want to know everything about the disease, patients
always prefer the delicate truth, so one must act with tact and sensitivity. It is
important to make them understand that all is not lost and that they are not alone
*
Corresponding Author’s E-mail: sdiazlobato@gmail.com.

580 Salvador Díaz Lobato, Sagrario Mayoralas and Johanny Vargas
in this hard process, that they will be accompanied not only by their family but
also by the medical team.
Keywords: neuromuscular disease, palliative care, home respiratory care, ALS,

mechanical ventilation
INTRODUCTION
Palliative care (PC) is an approach that improves the quality of life of patients
and their families facing the problem associated with life-threatening illness, through
the prevention and relief of suffering by means of early identification and impeccable
assessment and treatment of pain and other problems, physical, psychosocial and
spiritual. If palliative care is mentioned in relation to neuromuscular disease
amyotrophic lateral sclerosis (ALS) immediately comes to mind due to the fact that
most published literature related to PC is focused in these patients. Palliative care
seems to be underutilized in other neuromuscular disorders.
They have been described some barriers for an appropriate utilization of PC in
neuromuscular patients. Probably, PC specialists are reluctant to take other patients
than those suffering from cancer on board due to limited capacity and lack of
disease-specific knowledge. It is also possible that pphysicians might not always see
a role for palliative care in their (complex) patients, and associate PC with death and
dying, or are afraid to diminish patients’ hope by introducing PC. Finally, patients
themselves might be reluctant to accept a referral, for reasons such as the
association of PC with end-of-life care.
The fact is that PC has become an essential component of the treatment of
neuromuscular patients. The growing development of PC teams has allowed the care
of these patients from the beginning, not only in the initial stages of the disease
attending to diagnostic and therapeutic aspects, but also in the advanced stages of
the disease, when the most important thing is the approach of the patient as a
human being, with full rights to maintain dignity until the end of the disease and to die
without suffering. Symptoms control, emotional support, communication ability or the
importance of caring for the caregiver are the essence of PC, showing themselves to
be essential in the care of these patients.
In patients with neuromuscular diseases we know the evolution of the disease
precisely and the establishment of the terminal phase is closely linked to the natural
history of the disease. Thus, the onset of respiratory failure can be predicted
according to different parameters that vary according to the speed of progression of
the underlying disease. In moderately progressive neuromuscular diseases, such as
Duchenne’s disease, age is the determining factor in the onset of respiratory failure,
but treatment with NIV can result in a significant improvement in quality of life and
survival for many years. However, in rapidly progressive diseases such as
amyotrophic lateral sclerosis (ALS), the presence of respiratory symptoms is directly
related to a dramatic decrease in lung function. This drop is more or less abrupt in

Palliative Care 581
individual patients and is not predictable. The inexorable progression of the disease
towards respiratory failure has been able to be modified thanks to the incorporation
into our habitual practice of ventilatory support and nutritional intake techniques. Far
from staying in the hospital waiting for the final outcome, away from their family
environment, it is now possible to keep the ALS patient at home, helping them to
achieve the highest possible quality of life and independence, which is the primary
objective of PC.
From a technological point of view, we have no problems providing the patient
with ventilatory or nutritional support at home, whether by non-invasive methods or
by the use of tracheostomy and gastrostomy. Where we really find difficulties is when
it comes to having social resources that allow a patient with high care dependency
and high technological complexity to be kept at home, without overloading the family.
If nutritional needs are met, respiratory care is adequately provided and infections
are treated conveniently, people affected by ALS can survive and participate in a
meaningful life for years.
In the case of patients in whom home mechanical ventilation is not indicated or is
rejected by the patient, it is necessary to have an alternative palliative care plan.
Health professional, patient and its family must define the limits of the emergency
services and the hospital. Planning therapeutic attitudes and medical guidance,
patients can live with the feeling that they are treated, and not abandoned to their
fate, something very common in daily practice.
ALS is a clear example of how important is that patient and family members be
involved in making decisions about the disease. This should be done when the
patient’s functional status is still good and always after receiving adequate
information about the different therapeutic alternatives. It is very important to avoid
making decisions in the course of an acute situation in the emergency department or
in the intensive care unit. Patients with ALS can therefore benefit from home
mechanical ventilation (HMV) and thus increase survival by about 3-5 years, if not
more, if adequate minimum care and means are taken into account. HMV places a
heavy burden on the patient and especially on family members. Its use should be
proposed initially and used when indicated and desired. Under HMV the quality of life
of patients can be satisfactory but death is not avoidable and there will come a time
when a decision will have to be made whether or not to continue with therapy and
other measures will be needed to alleviate the last moments of the illness. These
patients also require comprehensive management to control other symptoms and
improve comfort. A recently published study has shown that patients with ALS may
have many unmet holistic care needs identifying as key areas that require particular
focus would be expressed in terms of service development include neuromuscular
respiratory physiotherapy and psychological services for patients.

END-STAGE MANAGEMENT
There are no clear guidelines for action in relation to the management of patients
in this situation, although all the documents that review this matter emphasise the
fact that the fundamental objective of treatment must be to restore and maintain
health, as long as these therapies do not imply more prejudice than benefits. The
existence of different symptoms in each patient makes it essential, before starting
any treatment, to make a global assessment of the patient, trying to determine not
only his physical situation but also his emotional state, since ignorance of
psychological factors can make us fail to control physical symptoms.
In order to set priorities, it will be necessary to determine the impact that the
symptom has on the patient both from the psychological point of view, since the
psychological state of the patient acts by modulating the intensity with which he or
she perceives the symptom, and from the functional point of view, that is, the
consequences that the symptom has on the patient’s activity and daily life. Once the
priorities have been established and the treatment plan has been decided, it is
advisable to explain to the patient in a way that he or she can understand, the cause
of his or her discomfort, the purpose of the treatment to be initiated, the possible side
effects and the time it may take to obtain an improvement.
In the final stages of disease, a series of therapeutic measures should be
considered, such as pharmacological treatment and oxygen therapy, non-invasive
ventilation, rehabilitation, nutritional assessment, communication and emotional and
spiritual support.
Pharmacological Treatment
This should include both treatment of respiratory symptoms and of other general
symptoms that occur in these phases of the disease. The main aspects to bear in
mind are:
1. Dyspnoea. This is probably the most important symptom and the one that
most incapacitates the patient. The usual treatments with beta-2 agonists,
anticholinergics or corticoids are not usually effective in neuromuscular
patients In those patients in whom dyspnea is intolerable and progressive,
we must consider it a terminal symptom. In these cases the use of
benzodiazepines and opiods may be recommended. Although these drugs
have only proved to be useful in small and heterogeneous groups of patients,
they are the most widely used at present. Most authors recommend the use
of opioids. Oral morphine is the most widely used presentation (2-5 mg/4h or
10-20mg/12h if delayed release preparations are used), although
subcutaneous, intravenous or sublingual administration are also valid. The
nebulized route has been described as a potential alternative in very

Palliative Care 583
advanced disease as a substitute for systemic treatment due to its lower

number of side effects. Some authors recommend the use of
benzodiazepines as an alternative, especially in patients with a high level of
anxiety associated with dyspnea. Often the most uncomfortable symptom for
the patient is insomnia related to the presence of orthopnea.
2. Coughing and handling of secretions. Management of secretions can
become a major problem in neuromuscular patients, so assisted cough
techniques are recommended. Manual techniques, the use of complex
equipment such as Cough Assist®, or a combination of both strategies, can
be essential tools for the proper control of secretions. In tracheostomized
patients, secretion aspiration is an effective alternative.
3. Anxiety, depression and fear of death. Most of the time the treatment of these
symptoms is relegated to the background, assuming that this is what is
expected in this situation. There is not enough scientific evidence to support
pharmacological treatment of anxiety in these circumstances, although we do
have information about the efficacy of treatment of depression with
antidepressants and various psychological interventions.
4. Digestive disorders. In patients with advanced neuromuscular diseases there
is a high incidence of swallowing disorders. Their management should
involve the selection of the most appropriate diet and the correct position of
the head during meals. It is important to take special care in tracheostomized
patients, securing the cannula, sometimes requiring a gastrostomy. In this
case, percutaneous endoscopic and the use of radiological equipment allows
us to ensure that the patient is fed through procedures that are minimally
invasive and generally well tolerated. Prevention of constipation with mild
laxatives is very important, especially when using opiates. Finally, special
attention must be paid to the care of the mouth, particularly adequate control
of sialorrhea, avoiding dry mucous membranes and monitoring the
appearance of ulcers. Injections of botulinum toxin into the parotid gland (and
another salivar glands) may be an effective and simple treatment for
excessive disabling drooling of saliva in selected patients.
5. Postural care, seeking ergonomic positions that avoid bedsores.
Oxygen Therapy and Mechanical Ventilation
Oxygen administration has been considered as an alternative to relief dyspnoea

in some subgroups of patients like COPD patients, but this is not the case of
neuromuscular patients in whom mechanical ventilation has proven to be clearly
superior. HMV is another therapeutic alternative to consider when seeking relief from
respiratory patient dyspnoea. Its efficacy in the treatment of ventilatory failure in
patients with restrictive ventilatory impairment, as is the case of neuromuscular
patients, has been clearly demonstrated. In these patients HMV improves dyspnoea,
prolongs survival and improves quality of life. Initially its use is nocturnal, although

we can reach patterns of use of 24 hours a day as the disease progresses. The
combination of different interfaces (nasal mask, facial mask and mouth pieces),
together with the use of assisted coughing techniques, can maintain good ventilation
in these patients delaying and even preventing, the performance of the
tracheostomy. In the most dramatic case of ALS patients, NIV has been shown to
prolong survival and improve quality of life, so that its use at the end of the disease
and its potential removal is left to the patient and family members to decide, as we
have already mentioned.
Pulmonary Physiotherapy
Existing evidence, though in its preliminary stages, advocates the role of

physiotherapists and rehabilitation in palliative care. Early referral to palliative care
rehabilitation has been linked to higher-functioning patients, therefore appropriate
referral to palliative care physiotherapy is critical for optimal and patient-centred care.
Despite potential benefits of palliative care physiotherapy, evidence suggests a
lack of palliative care patients receiving physiotherapy treatment. As a result, to the
detriment of patients and the NHS (National Health Service UK), specialist palliative
care teams may be failing to deliver patient-centred care, in failing to refer. Research
suggests the reluctance of referral, by other allied health professions, due to the
misconceived perception of inappropriateness of terminally ill patients to
rehabilitation. With palliation, physiotherapy treatment aims to maintain quality of life
while alleviating stress from symptoms in particular, pain, and effects from treatment.
Palliative care physiotherapy has been found to positively influence QoL and
perceived wellbeing in a range of palliative care populations, including
neuromuscular diseases.
The main objetives of physiotherapy from a palliative care point of view are:
 Pain relief – TENS, heat, massage, lymphedema treatment and acupuncture

are common forms of pain relief. Pain relief is often employed where
rehabilitation is not appropriate.
 Passive movements – These are often used in bed bound patients.
 Physical exercise – This may have a positive effect on depression and is
currently emerging as a major aspect of the treatment of patients in palliative
care.
 Soft tissue massage and/or therapeutic massage is used to relieve muscle
tension can often aid in easing the symptoms of anxiety.
 Secretions drainage: manual and mechanical aids to cough.
There are no specific rehabilitation programmes for patients in an advanced

stage. It seems logical to think that it should be aimed at patients who do not can
perform the basic activities of daily life and have great difficulty in wandering around

Palliative Care 585
their homes. There are many questions about what programmes are suitable in the
terminal phases of the disease. It seems clear that the objectives should be aimed at
the deconditioning of skeletal muscles in relation to immobility (sedentariness) and
nutritional deficit. It is important that the patient maintains his autonomy in the most
basic activities and that bed rest can be avoided. To do this, the patient should be
encouraged to dress and wash daily, even if he/she does not plan to leave the
house, to go for short walks in the home and to avoid prolonged sitting. In this way
we will manage to maintain a minimum physical form. It seems reasonable to think
that in the situation in which the patient finds himself, programmes that involve going
out home are not valid, and it is necessary to establish programmes of domestic
care. Adapting the exercises to the patient’s daily life at home, these authors have
shown a reduction in the sensation of dyspnoea and an improvement in the quality of
life.
Nutritional Assessment
There is little evidence on the benefits of a nutritional intervention in patients with

chronic respiratory failure in advanced stages. However, basic dietary
recommendations consisting of a balanced intake of small amounts of food five or six
times a day should be established. Moderate consumption of alcohol with meals is
not contraindicated, although it is preferable to avoid it at dinner. The cause of weight
loss is multifactorial.
Communication Support
Many patients with neuromuscular disorder, mainly ALS patients, experience a

motor speech disorder, such as dysarthria, as the disease progresses. At some
point, 80 to 95% of people with ALS are unable to meet their daily communication
needs using natural speech. Unfortunately, once intelligibility begins to decrease,
speech performance often deteriorates so rapidly that there is little time to implement
an appropriate augmentative and alternative communication (AAC) intervention;
therefore, appropriate timing of referral for this assessment and intervention
continues to be a most important clinical decision-making issue. Alternative
communication acceptance and use have increased considerably during the past
decade. Many people use it until within a few weeks of their deaths.
Because of the pathophysiology and the degenerative nature of ALS, speech
treatment strategies that are designed to increase strength or mobility of the oral
musculature are not recommended. People with ALS, or those close to them, often
request oral exercises to improve strength and mobility for speech and swallowing,
as strengthening exercises seem intuitive to them as way to increase performance.
However, such exercise programs should be discouraged, and those with ALS

should be informed that the speaking that they do each day provides a sufficient
amount of speech mechanism activity and exercise.
Speech intervention should focus on learning to conserve energy for priority
speaking tasks and to rest often to reduce fatigue instead of increasing effort and use
with speech exercises. ALS speakers should learn to avoid adverse
speaking/listening situations by muting the television, inviting people to speak with
them in a quiet place rather than in a crowded room, and using voice amplification
when speaking in noisy environments to reduce the effort required. As speech
becomes difficult to understand, many ALS speakers supplement their speech by
identifying the first letter of each word on an alphabet board (alphabet
supplementation) or by identifying the topic on a communication board (topic
supplementation).
In the last years, we have assisted to a revolution in the development of
technology associated to improvement of communication. For persons with ALS who
experience speech impairment or loss, there are a number of AAC approaches
available, often described in three broad categories:
 Unaided AAC can include gestures, signs, and/or facial expressions.

 Aided low-technology (low-tech) systems include letter-or picture boards as
well as devices with a limited number of voice output messages (usually
digital) that can be accessed by selecting a picture or word.
 High-technology (high-tech) options are mainly computer- based systems
that allow individuals to communicate and to control their environments
through multiple access methods despite profound motor impairments. In
recent years, the greatest advances in the high-tech arena have been made
in reliable eye-tracking control of computer-based systems for
communication and other technology applications, such as for environmental
control, e-mail…
COMMUNICATION AND EMOTIONAL SUPPORT
Accompanying and supporting a person who is facing his own death is always a
demanding, exhausting and stressful task, but it is one of the most important things
one human being can do for another. Communication is the process that allows
people to exchange information about themselves and their environment. It is a basic
human need and is part of therapy, sometimes the only therapeutic element. It
increases patient participation and satisfaction, improves compliance with therapy
and gives the doctor-patient interaction a therapeutic nature. However, it requires
more thought and planning than a pharmacological prescription, so it is unfortunately
still administered in subtherapeutic doses. Death and the process of dying evoke
psychological reactions in caregivers, so establishing open communication with the
terminally ill patient is difficult for professionals, who tend to avoid communication

Palliative Care 587
with the patient and family. The objectives of communication in the terminal phase
are shown in Table 1.
Bad news is all news that alters the person’s expectations for the future. It does
not have to refer to the diagnosis of diseases with immediate vital risk, nor to the fact
of death itself. Only communicating the diagnosis of a neuromuscular disease to the
patient (let´s think in an ALS diagnosis) can be just as shocking, since everything
that happens from that moment can condition their life in a significant way. The
communication of the diagnosis is crucial in ALS, and is the start of PC. If the
communication is poor this may lead to dissatisfaction and the relationship between
the patient and caregivers and the treating physician is compromised. The
communication of bad news provokes a mixture of reactions in the patient that will
depend on the usual way the patient faces serious problems according to his/her
previous personality and lifestyle. When bad news are communicated the message
must be firm, but at the same time with a delicate balance between prudence and
hope. Communication is very important in PC and it should be provided by a
multidisciplinary team including at least a physician (neurologist, rehabilitation
physician or palliative care specialist), a nurse, social worker and
psychologist/counsellor. Moreover, since the disease follows a progressive course,
preferences of the patients may change accordingly and therefore, assessment of
physical symptoms and psychosocial issues should be regularly reviewed.
Table 1. General objectives of communication in the terminal phase
 Collect basic information for diagnosis and treatment

 Make you feel cared for and accompanied
 Assess your reaction to the illness, your fears and anxieties
 Knowing your previous experiences with the disease
 Provide effective symptom relief and improve self-esteem
 Help you to advance in your process of adaptation to the disease
 Provide you with truthful, sensitive and progressive information according to your needs so
that you can plan your future and resolve your outstanding issues
 Make it easier for you to participate in your process
 Help you keep your hope
 Knowing what can increase your well-being
 Help you overcome the taboo of death
 To know whether or not you have the final will:
 Living will
 Previous guidelines
 Detect the needs of the family and open doors or improve the relationship with their loved
ones
We must learn to communicate the prognosis of the disease. All patients have
the right to know the details about the disease they suffer from, but not everyone
wants to know about it, and this should also be respected. Even if they want to know
everything about the disease, patients always prefer the delicate truth, so one must

act with tact and sensitivity. It is important to make them understand that all is not
lost and that they are not alone in this hard process, that they will be accompanied
not only by their family but also by the medical team.
Information is valuable for those who want it, so 75% of informed patients share
their concerns about the disease and its consequences with their families, while only
25% of uninformed patients do the same. In the case of Duchenne, a recently
published qualitative study revealed that none of them could recall that any of their
medical professionals had discussed end of life and most men assumed that the
clinicians had been too anxious to bring this up. There was a clear need to be given
proactive messages and cues that this topic could be raised. They also voiced the
desire to know more about the possible causes of death and the management of end
of life in terms of support and pain control. The Duchenne patients expressed their
wish to discuss the last stages of life and the options of hastened death. The study
also showed that wills or formal written information about their wishes about place of
death, funeral arrangements, were not present and that was a concern to most of the
patients. Conspicuously, effective emotional and psychological support seemed to be
absent but not only the healthcare professionals but also parents feel a shared
reluctance to offer opportunities for end-of-life-care conversations.
Communication should always consider the possible positive aspects of the
evolution of the situation, as these produce a better understanding and assumption
of the disease. The credibility of the professional rests on the way he/she speaks. He
will be more persuasive when he does so clearly, without hesitation, emphasising
those concepts that he considers most relevant, by means of the necessary pauses
that allow the interlocutor to assimilate the information, and even participate in it in a
dialogical manner.
Some people are very clear about what medical care they would like to receive if
they were very ill and were to die. For this reason it is always essential to ask the
family members if the patient at any time expressed “how would like to die” and how
to guide decisions about their health in the event of becoming incapacitated,
protecting their autonomy until the end. These advances directives are of two types:
1) Vital will: instructions related to the maintenance, withdrawal or establishment of
life support measures (cardio-pulmonary resuscitation, hydration, nutrition,
mechanical ventilation), and 2) Permanent legal powers for health care or
appointment of representatives, through which decisions concerning your medical
treatment are delegated to a person who will make decisions in the case of future
mental incapacity. Preferences may change over time as the illness progresses and
should therefore be checked regularly.
THE FAMILY
In PC the patient and the family are one therapeutic unit because what happens
to one affects the other. Warrier et al. have shown us that the life of the person with

Palliative Care 589
ALS and their spouse is never the same after the diagnosis and that the palliative
approach in the management of this disease has to take into account the
experiences and needs of carergivers since care happens at home.
Good communication with the family reduces the patient’s feelings of isolation
and favours a more adaptive family dynamic. Their pace, limits and content should
almost always be different from those offered to the patient. The terminal stage is a
very hard phase for all families, who react to these circumstances with an emotional
ambivalence, because although they want the end for both physical and
psychological relief, the loss they suffer is not easy to bear because it is not only
physical but also economic and social.
The family provides important care and help to most patients, but they often
underestimate the patient’s capacity to make decisions. Most people when asked
about a probable future illness would like to know the seriousness, however when it
comes to informing their loved ones, many would prefer this not to be done. Thus,
although we seem capable of facing our death, for our relatives we prefer protective
silence, arguing in our defence the fear of a possible total collapse. A study by an
American Presidential Commission came to the tentative conclusion that informing
patients is no more dangerous to their health than withholding information, especially
when this is done with discretion and sensitivity.
Different cultures face death and bad news in different ways. In our culture the
family is an essential agent and usually claims total autonomy for itself. Sometimes
this automomy leads to paternalistic treatment of the sick person, trying to condition
doctor-patient communication so that the information given to them is what they
consider necessary. At the present time and according to the current law regulating
about patient autonomy, rights and obligations, the holder of the right to information
is the patient, although if the patient authorises it, the persons linked to him or her
may be informed. It is understandable, however, that the family is afraid of the
consequences of the information, if once given they must bear it alone. For this
reason, efforts will be made from the outset to establish a dialogue with them to
improve the understanding of the patient’s reactions and to talk about their feelings
and concerns.
It is important to identify the main caregiver and assess how the situation is
affecting them, whether they are overburdened, what help is available, whether there
are signs of internal conflicts and if these reach the patient. It is necessary to work
with them so that they can come to terms with the idea of death. It is important to
highlight the effort that the family is making and the value of their presence in the
final phase both for the patient and for themselves.
In our environment most of the carergivers are direct relatives, a fact that will
probably change in the future due to cultural changes and changes in the
demographic structure of our society. These caregivers have a higher prevalence of
physical and psychological morbidity and therefore sometimes behave like hidden
patients. The task of caring often entails the appearance of a wide variety of physical,
psychic and social-family problems that constitute a real syndrome that needs to be
known, diagnosed early and prevented. An even higher incidence of depressive

symptoms has been observed in the primary carers of patients with neuromuscular
diseases than in the patients themselves, and these symptoms are related to the
social support received and to communication problems. There are general
recommendations for the prevention of caregiver syndrome (Table 2). These include
informing the caregiver regularly, being accessible in times of need, providing
indications on the care regime as clearly as possible, encouraging respite time
(scheduled admissions) and providing information on Associations and Community
Support Networks.
Table 2. Prevention of Carergiver’s Syndrome
 Regular information to the caregiver

 Accessibility for the caregiver in times of need
 Clearest possible indications on the care regime
 Encourage the taking of respite times (scheduled admissions)
 Providing information on Associations and Community Support Networks
Decisions at the End of Life (The Good Death)
In a medicalized culture, there is a permanent risk of the “medicalization of

death,” understood in the pejorative sense of pursuing unrealistic goals that involve
putting deteriorating technology before the human person. The “medicalization” or
technological intervention of life and death implies in many situations that death is
assumed to be a failure for both professionals and families. This can result, in
situations where there is no possibility of recovery, the patient is being trapped in
their bodies and suffering slow agonies.
Life is not an absolute good and there is no obligation to use some therapies
when its use can best be described as a prolongation of the agony. There comes a
time, different for every patient, when technology-based efforts can interfere with the
most important personal values. Decisions at the end of life needs not be taboo, we
need to inform ourselves in detail, analyze, contemplate and design the possible
options, the most humanitarian ones, and focus the debate on quality of life not
quantity of life. True respect for life begins when the needs and requests of patients
are heard. Almost all hospitals and clinics have intensive care units, but very few
operate palliative care units for non-oncology patients. This is because palliative
medicine is bringing about a change in the decision-making scheme, the doctor
provides his scientific knowledge and experience without displaying paternalistic
attitudes and it is the patient and the family who decide.
Any intervention must take into account the balance between the ethical
principles of Beneficence (do good) and Nonmaleficence (do not harm). There must
be a balance between the expected benefit from the application of life-prolonging
techniques and the burden or suffering they imply. Decisions must also consider the
principle of autonomy, according to which the refusal of the patient to receive life-

Palliative Care 591
prolonging treatment must always be respected. Ideally, medical decisions at the end
of life should be taken jointly by the patient, the family and the medical team. They
should be based on the patient’s objectives, the prognosis of the disease and the
judgement of the medical team. However, in the majority of studies we find that
communication at this point is not correct. According to Wegner et al. patients
consider themselves capable of making decisions but not always of discussing them
with the medical team. This is often related to fear and anxiety on both sides. Golin et
al. al report that less than 40% of patients with a clear decision on what to do before
they are admitted to hospital tell this their doctors. It is therefore necessary to create
an open channel of communication to deal with these issues and thus facilitate the
decision-making process for all parties. Helping to achieve a “good death” is the
clinical goal at this time. To this end, five points have been established that
determine the quality of the final phase of life: 1. clear decision making to achieve a
sense of control; 2. appropriate management of pain and other uncomfortable
symptoms; 3. avoid prolonging the process of dying; 4. alleviate the patient’s
burdens; and, 5. promote and consolidate relationships with loved ones.
Another important factor to consider is the ideal place to die. Most patients, if
asked in advance, prefer the home to the hospital. We do not have information on
the most suitable place to die. Death at home is usually associated with a lower risk
of medical aggression for the patient and also with a greater possibility of saying
goodbye to this world in the same environment in which one has lived. At home
everything is more humane and more rewarding, but going home or staying home is
a hard and liberating experience. It should be an option and never an obligation,
since sometimes the patient and the family need institutional support to control the
symptoms and share the workloads and emotional pressure that this moment entails.
The best way to offer PC is to establish specific care programmes involving
various levels of care (primary care, acute hospitals and social health care hospitals)
with the participation of different professionals (doctors, nurses, social workers and
psychologists, among others). These programmes are known as integral or shared
care systems and are the future in the management of patients with chronic
respiratory pathologies. Unfortunately there is still much to be achieved and it will be
the effort of all professionals that will allow these patients to be cared for so that the
final phase of their illness is not a path of despair, anguish, suffering and loneliness.
REFERENCES
[1] De Visser M, Oliver DJ. Palliative care in neuromuscular diseases. Current

Opinion Neurol 2017;30(6):686-91.
[2] Oliver DJ, Borasio GD, Caraceni A, et al. A consensus review on the
development of palliative care for patients with chronic and progressive
neurological disease. Eur J Neurol 2016; 23:30-38.

[3] Aoun SM, Breen LJ, Oliver D, et al. Family carers’ experiences of receiving the
news of a diagnosis of Motor Neurone Disease: a national survey. J Neurol Sci
2017; 372:144-151.
[4] Abbott D, Prescott H, Forbes K, et al. Men with Duchenne muscular dystrophy
and end of life planning. Neuromusc Disord 2017; 27:38-44.
[5] Hiscock A, Kuhn I, Barclay S. Advance care discussions with young people
affected by life-limiting neuromuscular diseases: a systematic literature review
and narrative synthesis. Neuromuscul Disord 2017; 27:115-119.
[6] Mc Veigh C, Donaghy C, Mc Laughlin B, Dick A, Kaur K, Mc Conville J, Watson
M. Palliative care for patients with motor neurone disease and their bereaved
carers: a qualitative study. BMC Palliat Care 2019;18(1):39.
[7] Chang RS, Wong YK. Prognostic indicators of neuromuscular disorders for
palliative care referral. Ann Palliat Med 2018;7(3):335-8.
[8] Carter GT, Joyce NC, Abresch AL, Smith AE, VandeKeift GK. Using palliative
care in progressive neuromuscular disease to maximize quality of life. Phys
Med Rehabil Clin N Am 2012;23(4):903-9.
[9] Warrier MG, Sadasivan A, Polavarapu K, Kumar VP, Mahajan NP, Reddy CPC,
Vengalil S, Nashi S, Nalini A, Thomas PT. Lived Experience of Spouses of
Persons with Motor Neuron Disease: Preliminary Findings through
Interpretative Phenomenological Analysis. Indian J Palliat Care. 2020;26(1):60-
65.
[10] Wenger NS, Phillips RS, Teno JM, et al. Physician understanding of patient
resuscitation preferences: insights and clinical implications. J Am Geriatr Soc
2000; 48: S44–51.
[11] Golin CE, Wenger NS, Liu H, et al. A prospective study of patient-physician
communication about resuscitation. J Am Geriatr Soc 2000; 48: S52–60.

Chapter 44
END-OF-LIFE CARE
Francesca Trojsi*, Giulia D’Alvano

and Gioacchino Tedeschi
Department of Advanced Medical and Surgical Sciences,
Università degli Studi della Campania “Luigi Vanvitelli,” Naples, Italy
ABSTRACT
Management of the end-of-life phase represents a crucial part of the care of

lethal neuromuscular diseases (NMDs), aiming to improve quality of life of both
the patients and caregivers and to perform appropriate palliation of stressful
physical, psychosocial, and existential suffering. Some NMDs produce
progressive atrophy and weakness of limb, trunk, bulbar and respiratory muscles,
resulting inexorably progressive. Discussing on the end-of-life issues is an
integral part of the palliative approach, incorporated into the care plan for the
patient and caregiver from the time of diagnosis of these fatal illnesses. Specific
triggers for initiation of end-of-life discussions can be usefully anchored to
defined points in the disease trajectory. Health-care professionals may inform
patients and caregivers about the alternative scenarios relating to the
development of life-threatening crises in a controlled environment, thereby
limiting unplanned or unwanted interventions or procedures. Among NMDs, we
overviewed recent literature on end-stage management in Spinal Muscular
Atrophy (SMA) type I and II and Duchenne Muscular Dystrophy (DMD), both
affecting childhood, and ALS, affecting adulthood. With regard to patients
affected by SMA I and II, the therapeutic opportunities have been enriched by the
introduction of Nusinersen, an antisense oligonucleotide able to increase the
production of fully functional survival motor neuron (SMN) protein, modifying
SMA natural history and the approach and the timing of discussions on end-of-
life care in this disease. With regard to DMD, in addition to respiratory
dysfunction, cardiomyopathy has been revealed an increasing cause of morbidity
and mortality, thereby needing intervention to ameliorate symptoms, such as the
*
Corresponding Author’s E-mail: francesca.trojsi@unicampania.it.

594 Francesca Trojsi, Giulia D’Alvano and Gioacchino Tedeschi
use of intra-cardiac device (ICD) or resynchronizing devices with defibrillator

(CRT-D). Finally, in case of ALS, acknowledged as the neurodegenerative
disease of the adulthood with the worst prognosis, symptoms management, and
nutritional and respiratory support are the main targets of end-of-life care. This
chapter is intended to overview current evidence regarding end-of-life care in
fatal NMDs of childhood and adulthood, focusing on crucial aspects of end-stage
management and on the psychosocial effects of these illnesses on the patients
and their families.
Keywords: end-of-life care, Spinal Muscular Atrophy, Duchenne Muscular

Dystrophy, Amyotrophic Lateral Sclerosis, tracheostomy, gastrostomy,
cardiomyopathy
INTRODUCTION
Among neuromuscular diseases (NMDs), some severely disabling disorders are

fatal leading to respiratory failure and death. In these cases, therapies can only
alleviate symptoms, without modifying the prognosis of patients. As a consequence,
managing of end-stages symptoms represents a crucial part of the care of
progressive NMDs, thereby aiming to improve quality of life of both the patient and
caregiver and, when feasible, to perform appropriate palliation of stressful physical,
psychosocial, and existential suffering [1, 2]. Particularly, early and open discussion
of end-of-life issues with patients and families allows time for reflection and planning,
and can obviate the introduction of unwanted interventions or procedures, provide
reassurance, and alleviate fear [1, 2]. In this regard, consensus guidelines for
integration of palliative care for progressive non-cancerous neurological diseases
have been produced by the European Academy of Neurology [3] and by the
European Federation of Neurological Societies [4], especially related to management
of end-of-life care of amyotrophic lateral sclerosis (ALS) patients. According to these
guidelines, a palliative approach should be incorporated into the care plan for the
patient and caregiver from the time of diagnosis, with the aim of improving the quality
of life of patients and families by relieving symptoms, providing emotional,
psychological, and spiritual support, removing obstacles to a peaceful death, and
supporting the family in bereavement (Figure 1) [5]. Although these topics have to be
considered crucial for a correct management of severely disabling NMDs, few
studies have investigated optimum management strategies for NMDs patients at the
end stages.
The first step of end-of-life care is discussing about the approach to this phase
with the patient and her/his family. Since it is source of great anxiety for both the
patients and the healthcare providers (i.e., many physicians and health-care
providers find this process difficult and stressful, depending on their own experience,
philosophy, and ability to communicate), discussions and decision making about end-
of-life are often delayed [1] or triggered in a crisis situation by the occurrence of life-
threatening complications. To note, limits to introduce these discussions are related

End-of-Life Care 595
to the fact that medical school curricula provided limited training in palliative care,
focusing more widely on knowledge accumulation and less on the psychosocial and
existential effects of disease on the patients and their families [6]. From the point of
view of health-care professionals, the emotional burden associated with breaking bad
news and needed to provide professional care in terminal illnesses may produce
increased risk of burnout and fatigue [7, 8]. Therefore, psychological support should
be provided to health-care professionals who care for patients with terminal
neurological illness [2]. Moreover, frameworks for understanding and addressing
moral distress could be incorporated into a wider palliative care training program
during the early stages of physicians careers in order to better prepare health-care
professionals to manage end-stage illnesses [2].
Discussing on the end-of-life issues allows the patient (and/or her/his caregivers)
to exercise autonomy regarding preferred end-stage management strategies, giving
advanced care directives. Moreover, it prepares and support patients and their
beloved, giving dignity to death [9]. The intervention should be multidisciplinary and
person-centered [2]. Of note, end-of-life discussions should be led by experienced
health-care professionals who are appropriately trained in communicating bad news,
and who are also in a position to judge the degree of distress generated, and the
point at which further discussion should be deferred [2].
Figure 1. Factors influencing quality of life (QoL) in patient-centered medical care of ALS.
Derived from Lulè et al. [5] distributed under the terms of the Creative Commons Attribution
License (CC BY).
With regard to the timing of end-of-life discussions, advance care planning can
lead to unplanned crisis intervention, including full invasive mechanical ventilation.
By contrast, when the patient or family member has not required information in
advance, specific triggers for initiation of end-of-life discussions can be usefully

anchored to defined points in the disease trajectory. This strategy may offer the
opportunity to discuss the alternative scenarios relating to the development of life-
threatening crises in a controlled environment [2]. In particular, for more rapidly
progressive NMDs, such as ALS, the introduction of gastrostomy and non-invasive
ventilation (NIV) may represent useful “anchor points” for formal initiation of end-of-
life discussions. Importantly, in case of ALS, executive and behavioural impairment
are recognized as an integral part of ALS (i.e., ALS with behavioural impairment
[ALSbi], with cognitive impairment [ALSci], and with both [ALSbci]) [10] and up to
13% of patients with ALS fulfill the Neary critera for frontotemporal dementia [10]: this
condition, assessed by using validated screening protocols, raises inevitable
questions around capacity for decision making in some patients with ALS because
the autonomy of those with dementia is irreversibly compromised. Similarly to other
disorders characterized by degenerative cognitive impairment, the appointment of
surrogate decision makers should be encouraged in patients with early evidence of
cognitive decline [11].
This chapter is intended to give more insights regarding end-of-life care in fatal
NMDs of childhood and adulthood, focusing on crucial aspects of end-stage
management of NMDs and on the psychosocial effects of the illnesses on the
patients and their families. Among the most disabling NMDs, we addressed end-of-
life issues in Spinal Muscular Atrophy I and II (SMA I and SMA II) and Duchenne
Muscular Dystrophy (DMD), both affecting childhood, and ALS, mainly affecting
adulthood. For these NMDs, the most common complication, representing the major
cause of death, is respiratory failure, although other complications include
cardiomyopathy, cardiac arrest, coronary disease, asphyxia, and pulmonary
embolism [2]. Moreover, indicators of the end-of-life phase are rapid physical decline,
infection in combination or not with cognitive impairment, and risk of aspiration [12].
SPINAL MUSCULAR ATROPHY (SMA)
SMA is a rare, autosomal-recessive disorder characterized by selective loss of

brainstem and spinal motor neurons, causing progressive atrophy and weakness of
limb, trunk, bulbar and respiratory muscles [13]. SMA is classified into five subtypes
according to age of symptoms onset (from in utero to adulthood) and achieved motor
milestones (from reduced or absent movements in SMA 0 to very mild adult-onset
phenotypes in SMA IV) [13]. Type I presents by definition during the first 6 months of
life, and death usually occurs within the first 2 years of life if there is no aggressive
respiratory support. Type II presents slightly later, at 6-18 months, and shortens life
expectancy. SMA is caused by homozygous deletions or loss-of-function mutations
in the survival motor neuron 1 (SMN1) gene, responsible for transcribing the majority
of functional full-length survival motor neuron (SMN) protein. The main difference
between SMN1 and its paralogue, SMN2, is a C > T substitution in exon 7 that
results in a truncated nonfunctional protein due to lack of exon 7 in the majority of

SMN2 transcripts. Recently, Nusinersen (Biogen inc., Cambridge, Massachusetts,

US), an antisense oligonucleotide administered intrathecally and able to modify the
pre-mRNA splicing of SMN2, increasing the production of fully functional SMN
protein, has been shown effective in improving motor function in phase III
randomized controlled trials in infants with SMA I and in children with later onset
SMA aged 2-12 years, modifying SMA natural history [14, 15]. This substantial
modification of SMA clinical course could significantly modify the approach and the
timing of discussions on end-of-life care in this NMD.
The main clinical requirements during end-of-life phase in SMA I and II are
respiratory and nutritional support, including tracheostomy and percutaneous
endoscopic gastrostomy (PEG) [16]. In addition, some patients need pain
management and postural care [16]. Symptoms management can require higher
dose of drugs such as morphine and/or benzodiazepines. In addition, enteral
nutrition can be needed to guarantee satiety and prevent thirst and fatigue. Of note,
end-of-life care in SMA I and II does not finish with patients’ death: psychological and
spiritual support for parents is a crucial part of it, since death may occur during
childhood [16, 17]. Parents are the main actors involved in choices about end-of-life.
Thus, support during end-of-life and after death is fundamental to face and overcome
this dramatic event [16, 17].
DUCHENNE MUSCULAR DYSTROPHY (DMD)
Similarly to SMA I and II, DMD is a disease that affects children and adolescents.
It is a lethal hereditary disorder caused by inherited or spontaneous mutations of the
dystrophin gene located in the X chromosome that results in absent or insufficient
functional dystrophin. As for others NMDs, the main causes of death are respiratory
failure and ab ingestis pneumonia. However, the improvement in respiratory care
over the last few years has made cardiomyopathy an increasing cause of morbidity
and mortality in DMD patients [18].
Respiratory impairment manifests during adolescence and requires ventilation
support. While during the first stages of respiratory dysfunction negative pressure
devices offer the best results, as the disease progresses positive pressure ventilation
is required (for more details, see chapters 3, 10-19). Patients frequently refuse
tracheostomy, but it is necessary during crises or in patients who lack a functional
cough or who have recurrent aspiration [19].
Cardiomyopathy can contribute to the development of hypoventilation and
orthopnoea and reduce benefits from long-term ventilation. When cardiomyopathy
becomes drug resistant, the only curative therapy is heart transplantation. However,
it is generally not performed due to the scarcity of donors and to the fact that
myopathy will limit the potential benefits. Therefore, the only approach to ameliorate
symptoms and quality of life is the use of intra-cardiac device (ICD) or
resynchronizing devices with defibrillator (CRT-D). The implantation of an ICD is

planned in cases of non-sustained ventricular tachycardia unresponsive to drug

treatment, while a CRT-D system is preferred in presence of a drug-resistant heart
failure associated to a left branch bundle block [20]. Finally, Left Assisted Ventricular
Devices (LAVD) are used in more advanced stages [18].
AMYOTROPHIC LATERAL SCLEROSIS (ALS)
ALS is a degenerative NMD of the adulthood involving motor neurons and

causing the paralysis of all voluntary muscles [21]. Although disease progression is
variable, based on the phenotype, it is a fatal and life-limiting illness, remaining the
neurodegenerative disease of the adulthood presenting the worst prognosis. Also in
this case, symptoms management, and nutritional and respiratory support are the
main targets of end-of-life care.
Respiratory system is affected at different levels. Since death is ultimately
caused by the paralysis of the respiratory muscles, several studies investigated
respiratory function during the course of the disease to predict and ultimately prolong
survival in ALS patients. Forced Vital Capacity (FVC) is generally used as a
measurement of respiratory function, mostly at diagnosis. However, FVC is
performed through a forced and fast exhalation; its value could thus be biased by
many factors in ALS patients, such as concomitant obstructive diseases or the
paralysis of facial muscles. Slow vital capacity (SVC) consists of a slow exhalation
after a maximal inspiration. Since theoretically it does not present the same limits as
FVC, it could provide a more accurate estimate of the respiratory function in ALS
patients. Despite being as volitional as FVC, SVC is less influenced by facial paresis
and executive dysfunction, frequently associated in patients with bulbar signs [22].
The non-invasive ventilation (NIV) with bilevel intermittent positive pressure
ventilator improves respiratory function and quality of life. The associated problems
for NIV are nasal bridge soreness, abdominal bloating, claustrophobia, anxiety, and
excessive salivation. Assisted cough device, suction machine, and mucolytic drugs
can help to alleviate respiratory symptoms, especially in case of acute episodes [2,
23]. To ameliorate mucus clearance, mechanical insufflation-exsufflation (MIE)
devices have been developed. The most widely used machines have a facemask or
mouthpiece interface that provides rapid positive pressure followed by negative
pressure to mimic a cough. Treatment regimens are usually three to five “coughs”
done in rapid succession several times per day. Initial settings can start at +20/-20
cmH2O and titrated up to +40/-40 cmH2O based on level of comfort [23].
When NIV is not tolerated any more or become ineffective, invasive mechanical
ventilation trough tracheostomy may be introduced. If the patient refuses
tracheostomy, respiratory symptoms will be alleviated with supportive symptomatic
care. Patients and their families should be aware that tracheostomy does not stop
the progression of the disease or change the outcome [23]. Tracheostomy alters
phonation and the presence of a tracheostomy tube alters swallowing. Supportive

symptomatic care of dyspnoea, despite the use of the NIV, is based on morphine,
starting at 2.5-5 mg every 4 hours, increased in dose and frequency as needed [1].
Oral secretion management includes anticholinergic drugs (such as scopolamine,
amitriptyline, atropine, and glycopyrrolate) as first-line therapies. If the response is
minimal, a different anticholinergic agent should be selected, while combinations of
agents rarely provide significant clinical improvement and only increase the potential
side effects (confusion, drowsiness, and urinary retention). Botulinum toxin injection
into the submandibular and/or parotid gland is a second line option. Unfortunately,
responses vary between patients and there are a few data regarding dosing or
frequency of administration. The most prominent side effect is paralyzing surrounding
musculature and worsening bulbar function. As a third line therapy, irradiation to the
salivary glands is descripted as an option, although there are few data regarding
optimal dosing and duration of this therapy [23].
Differently from respiratory supportive care, benefits from gastrostomy insertion
are less documented. It is generally considered as a quality-of-life measure, which
reduces the risk of rapid weight loss and avoids dehydration [1, 2]. PEG tube or
equivalent device is preferably inserted prior to significant respiratory functional
decline (before FVC is ≤ 50%). However, small studies suggest that the procedure
can be safely considered in patients whose respiratory status has further declined
when performed by an experienced team. Newer techniques under radiographic
guidance can use local anaesthetic alone and may be beneficial for patients with
depressed respiratory function [23, 24] (Figure 2).
Figure 2. (A) Percutaneous radiological gastrostomy tube insertion; (B) A schematic

description of the percutaneous radiological gastrostomy procedure. Derived from Hermush et
al. [24] distributed under the terms of the Creative Commons Attribution License (CC BY).

In addition to dyspnoea, weakness and fatigue, common symptoms during the

last months of life in ALS patients include insomnia, anxiety, pain, depressed mood
and confusion. Anxiety and restlessness can be treated with benzodiazepines (e.g.,
lorazepam 0.5-2 mg every 4 hours as needed), while opiates and anxiolytics doses
should be increased if they are not providing satisfactory control [1].
With regard to the terminal phase management, most patients prefer to die at
home. However, palliative end-of-life care is often done in hospital settings.
Differences exist across countries as to where people with ALS die, indicative of
different health-care system structures and priorities. For example, in Italy, 85% of
patients with ALS died at home, compared with 64% in North America, 55% in
Germany, 52% in the UK, and 36% in France [2]. Alternative places of death include
hospitals and nursing homes, while the availability of specialist palliative care teams
increases the likelihood of dying in a hospice [2].
CONCLUSION
Health-care professionals need to be trained on palliative medicine in addition to

curative medicine in order to perform effective end-of-life care in case of fatal
illnesses. In particular, initiation of end-of-life discussions should be triggered at
pivotal points in inexorably progressive NMDs, thereby avoiding unplanned crisis
intervention. Early identification of impaired cognitive and behavioural impairment in
ALS patients, using validated screening methods, may significantly influence the
timing and modality of end-of-life discussions. Finally, psychological support should
be provided to patients, caregivers/parents and health-care professionals who care
for patients with terminal neuromuscular illnesses. In fact, improving wellbeing of
family caregivers and health-care professionals may even result in a better disease
management of end-stage NMDs, reducing the risk of burnout and fatigue.
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[1] Rudnicki S, McVey AL, Jackson CE, Dimachkie MM, Barohn RJ. Symptom
management and end of life care. Neurol. Clin. 2015; 33: 889-908.
[2] Connolly S, Galvin M, Hardiman O. End-of-life management in patients with
amyotrophic lateral sclerosis. Lancet Neurol. 2015; 14: 435-442.
[3] Oliver D, Borasio GD, Voltz R, et al. The development of a consensus paper on
palliative care in neurology: the implications for ALS care. Amyotroph Lateral
Scler Frontotemporal Degener. 2014; 15: 117-118.
[4] EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral
Sclerosis; Andersen PM, Abrahams S, Borasio GD, de Carvalho M, Chiò A,
Van Damme P, et al. EFNS guidelines on the clinical management of

amyotrophic lateral sclerosis (MALS): revised report of an EFNS task force.

Eur. J. Neurol. 2012; 19: 360-375.
[5] Lulé D, Kübler A, Ludolph AC. Ethical principles in patient-centered medical
care to support quality of life in amyotrophic lateral sclerosis. Front. Neurol.
2019; 10: 259.
[6] Vail L, Sandhu H, Fisher J, Cooke H, Dale J, Barnett M. Hospital consultants
breaking bad news with simulated patients: an analysis of communication using
the Roter Interaction Analysis System. Patient Educ. Couns. 2011; 83: 185-194.
[7] Brown R, Dunn S, Byrnes K, Morris R, Heinrich P, Shaw J. Doctors’ stress
responses and poor communication performance in simulated bad-news
consultations. Acad. Med. 2009; 84: 1595-1602.
[8] Gama G, Barbosa F, Vieira M. Personal determinants of nurses’ burnout in end
of life care. Eur. J. Oncol. Nurs. 2014; 18: 527-33.
[9] Cheng HWB, Chan OMI, Chan CHR, Chan WH, Fung KS, Wong KY. End-of-life
characteristics and palliative care provision for patients with motor neuron
disease. Am. J. Hosp. Palliat. Care. 2018; 35: 847-851.
[10] Strong MJ, Abrahams S, Goldstein LH, Woolley S, Mclaughlin P, Snowden J, et
al. Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD):
revised diagnostic criteria. Amyotroph. Lateral Scler. Frontotemporal. Degener.
2017; 18: 153-174.
[11] van der Steen JT, van Soest-Poortvliet MC, Hallie-Heierman M, Onwuteaka-
Philipsen BD, Deliens L, de Boer ME, et al. Factors associated with initiation of
advance care planning in dementia: a systematic review. J. Alzheimers Dis.
2014; 40: 743-757.
[12] Hussain J, Adams D, Allgar V, Campbell C. Triggers in advanced neurological
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Palliat. Care. 2014; 4: 30-37.
[13] Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, et al. Diagnosis
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2018; 28: 103-115.
[14] Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al.
Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N.
Engl. J. Med. 2017; 377: 1723-1732.
[15] Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, et al.
Nusinersen versus sham control in later-onset spinal muscular atrophy. N. Engl.
J. Med. 2018; 378: 625-635.
[16] Di Pede C, Agosto C, De Tommasi V, De Gregorio A, Benini F. Symptom
management and psychological support for families are the cornerstones of
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Pædiatrica 2017; 107:140-144.
[17] Lövgren M, Sejersen T and Kreicbergs U. Parents’ Experiences and Wishes at
End of Life in Children with Spinal Muscular Atrophy Types I and II. J. Pediatr.
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[18] Shih JA, Folch A, Wong BL. Duchenne Muscular Dystrophy: the Heart of the
Matter. Curr. Heart Fail. Rep. 2020; 17: 57-66.
[19] Hilton T, Orr RD, Perkin RM, Ashwal S. End of life care in Duchenne muscular
dystrophy. Pediatr. Neurol. 1993; 9: 165-177.
[20] Palladino A, Papa AA, Morra S, Russo V, Ergoli M, Rago A, et al. Are there real
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[22] Calvo A, Vasta R, Moglia C, Matteoni E, Canosa A, Mattei A, et al. Prognostic
role of slow vital capacity in amyotrophic lateral sclerosis. J. Neurol. 2020; 267:
1615-1621.
[23] Niedermeyer S, Murn M, Choi PJ. Respiratory failure in amyotrophic lateral
sclerosis. Chest. 2019; 155: 401-408.
[24] Hermush V, Berner Y, Katz Y, Kunin Y, Krasniansky I, Schwartz Y, et al.
Gastrostomy tube placement by radiological methods for older patients
requiring enteral nutrition: not to be forgotten. Front. Med. (Lausanne). 2018; 5:
274.

Chapter 45
ETHICAL AND MEDICO-LEGAL ASPECTS
Nicoletta Carmin, MD, Spinelli Sara, MD

and Cauteruccio Rosa, MD
UOC Fisiopatologia and Respiratory Rehabilitation,
AO Dei Colli, Naples, Italy
ABSTRACT
Neuromuscular diseases often affect young people, depriving them of

autonomy and the possibility of social interaction. Several studies have clearly
shown that NIV treatment can prolong survival of NMD patients who accept and
tolerate NIV compared to those who do not accept, tolerate or use it. When
respiratory function get worse, despite the use of full-time NIV and cough assist
combination or bulbar muscular impairment is too advanced and the patient is
unable to protect the airways tracheostomy and invasive mechanical ventilation
(IMV) should be considered in ALS and other NMD. Dialogue and discussion
regarding treatment and care is ongoing from the initial planning of NIV until
death and special emphasis must be placed on the patient’s autonomy and the
particular dilemmas involved. There is no universally accepted strategy in the
management of NMD patients, because in this highly disabling pathologies, the
line between survival and life is very blurred. As is often the case in our medical
profession, there is no unique solution. For this reason, the care pathway in this
kind of patient must be shared and planned with patients and care-givers,
illustrating step by step therapeutic option and life expectancies.

Corresponding Author’s E-mail: carminenicoletta1983@gmail.com.

604 Nicoletta Carmine, Spinelli Sara and Cauteruccio Rosa
ABBREVIATIONS
ALS Amyotrophic Lateral Sclerosis

HRQOL Health-Related Quality of Life Questionnaire
IMV Invasive mechanical ventilation
NIV mechanical noninvasive ventilation
NMD neuromuscular disorders,
INTRODUCTION
Neuromuscular diseases often affect young people, depriving them of autonomy

and the possibility of social interaction. In recent years, various therapeutic strategies
have been improved to treat these diseases, increasing these patients' life
expectancy. When we talk about highly disabling pathologies, the quality of life must
always be considered in addition to Survival.
Currently, patients with neuromuscular disorders (NMD), accounting for around
10 – 51% of the overall indications for home mechanical noninvasive ventilation
(NIV).
Several studies have clearly shown that NIV treatment can prolong Survival of
NMD patients who accept and tolerate NIV compared to those who do not accept,
tolerate or use it [1].
Regarding patients' quality of life, this can be assessed using the Health-Related
Quality of Life Questionnaire (HRQOL). Contemporary interpretations of HRQOL are
based on the World Health Organization's definition of health as a state of complete
physical mental, and social well-being and not merely the absence of disease. In
broad terms, HRQOL may be conceived as the ratio of an individual's actual status
over expected status. HRQOL studies cast a broader net to include the bother
associated with particular dysfunctions, any impact on normal functions or social
roles, and a composite of other psychosocial domains [2].
NIV PROLONGS SURVIVAL, BUT IMPROVES

THE QUALITY OF LIFE TOO?
HRQOL may improve at a different rate in NMD patients on long-term NIV.

Indeed, patients without Amyotrophic Lateral Sclerosis (ALS), such as Duchenne
Muscular Dystrophy (DMD), showed a more evident HRQOL improvement after 6
months from NIV initiation to the ALS group in whom only a few of the considered
domains have ameliorated. Also, despite various strategies adopted for optimizing
patient comfort and prolonging NIV use, almost 30% of ALS patients can be
intolerant to NIV utilization after only 1 month cause several motivations as [1]:

Ethical and Medico-Legal Aspects 605
 anxiety,
 emotional lability from pseudobulbar palsy,
 claustrophobia,
 nasal bridge soreness,
 excessive salivation.
 presence of cognitive impairment
 severe bulbar dysfunction
On the other hand, R. A. Lyall et al. prospectively measured Quality of Life (QL)
in a cohort of patients with ALS with symptomatic hypoventilation treated with NIV
and a control group of patients with ALS without evidence of hypoventilation. QL was
measured using the Short Form 36 (SF-36) questionnaire. When completed, the SF-
36 questionnaire provides scores for eight QL domains. Four are functional status
measures:
 Physical Functioning
 Role Physical
 Role Emotional
 Social Functioning
Three are measures of well-being:
 Bodily Pain
 Vitality,
 Mental Health
and the last "General Health" is a measure of overall health. Final scores went
from 0 to 100%, higher scores indicating a more positive QL status.
Using the SF-36 questionnaire, R.A Lyall et al. have shown that the QL of
patients with ALS with sleep-disordered breathing improved significantly with NIV, as
measured by the "Vitality" domain. This improvement was maintained despite
increasing generalized disability and progressive respiratory muscle weakness.
Patients on NIV completed questionnaires to within 3 months of the death, and in the
majority, the final scores were higher than baseline scores. Improved QL scores
were recorded at 15 months after ventilation in the most extended surviving
members of the cohort. In the SF-36 domains that reflect well-being, patients with
ALS on NIV had scores as high as an average age- and sex-matched population. As
expected in disease-causing generalized muscle weakness, scores in domains
reflecting overall functional status were low. Still, comparison with a group of patients
with ALS not requiring ventilation shows that noninvasive ventilation did not cause
reduced QL scores [3].
In another work of Bourke et al. the quality of life of patients has measured using
three questionnaires:

 Short Form 36 questionnaire (previously illustrated)

 Sleep apnoea quality of life index (SAQLI): Includes 4+1 categories, daily
functioning, social interactions, emotional functioning, symptoms and
negative quality of life impact of treatment side-effects
 Chronic Respiratory Disease Questionnaire (CRQ): includes 4 categories,
dyspnea, fatigue, emotional function, mastery
They reported that the quality-of-life benefits exceeded Survival's improvement,

with the most significant enhancements in domains assessing problems related to
sleep. Progress in the similar quality of life has been documented in non-randomized
studies, notably the SF36 energy vitality, mental health, and emotional role domains,
all domains of the CRQ, especially fatigue and mastery SAQLI social isolation and
symptoms domain and summary score. The SF36 general health perception domain
and SAQLI daily functioning and emotional function domains improved in all patients
and the subgroup with better bulbar function. Furthermore, the better bulbar function
was associated with improvements in the SF36 social function domain and physical
component summary.
In those with normal or only moderately impaired bulbar function, the
improvement in median Survival (205 days) was considerable, and much more
significant, for example, than the benefit from riluzole (2 – 3 months). Patients with
severe bulbar impairment had no survival benefit with NIV. The quality of life
improved in CRQ dyspnoea and SAQLI daily functioning, social isolation, and
symptoms. In this, work Bourke et al. did not examine if patients with poor bulbar
function allocated NIV failed to benefit in terms of Survival because NIV does not
improve Survival in this subgroup or because they were intolerant. However, NIV use
did not correlate with Survival in this subgroup, suggesting the former was more
likely. Patients with severely impaired bulbar function treated with NIV had a more
significant mean improvement in several quality-of-life domains than controls [4].
TRACHEOTOMY IS THE BEST SOLUTION FOR PROGRESSION

OF DISEASE… AND THE PATIENT?
When a respiratory function worsens, despite full-time NIV and cough assist
combination, or bulbar muscular impairment is too advanced. The patient is unable to
protect the airways (peak cough flow, PCF, < 160lt/min), tracheostomy and invasive
mechanical ventilation (IMV) should be considered in ALS and other NMD.
In these patients, HRQOL is often worse than before tracheotomy, and in some
studies, > 50% of patients declared they did not want to be tracheotomized before
the procedure [1].
In a Japanese long-term retrospective study, the authors analyzed the long-term
use of NIV in a group of patients with ALS and their transition to IMV.
They found that significant factors related to IMV avoidance were:

 female gender,
 NIV use longer than 6 months,
 bulbar onset,
 absence of spouse/partner
When physicians evaluate tracheotomy option, they have to consider that ALS
patients during NIV show a decreased pain threshold leading to avoidance of further
invasive procedures, increased social restrictions, and raised psychological barriers
against the transition from NIV to IMV [1]. So "timeliness" of the intervention or the
ability to switch to alternative solutions (like a daytime mouthpiece option) becomes
decisive.
WHEN TO SAY "STOP?"
Facing end-of-life discussion is difficult, especially in young patients. In one

study, older interviewed DMD patients emphasized that it is essential to face end-of-
life issues "within a positive frame of reference, focusing first, on living with DMD and
having a good life with it and then, as a natural part of it, about death and dying."
These patients underlined the importance to die at home, surrounded by family and
not in the hospital. This emphasizes the need for home care-based palliative care
training to deal with NIV-dependent patients [5].
One study reported that the last days of life for ALS patients who did not choose
IMV are usually characterized by dyspnea, pain, and fatigue. More than one-third of
patients decide to continue NIV to relieve symptoms until the last 24 h rather than
oxygen alone [6, 7].
When planning care and treatment, the patient's autonomy should be respected,
especially about advance directives for end-of-life care [8].
Many studies emphasize the need to establish advance directives for end-of-life
care [9-11]. The terminal phase of the disease should be discussed before the
patient experiences dyspnea symptoms to prevent unwarranted fears of "choking to
death" [12, 13].
Dialogue and discussion regarding treatment and care are ongoing from the
initial planning of NIV until death, and particular emphasis must be placed on the
patient's autonomy and the specific dilemmas involved. The need for careful planning
and discussion must be emphasized to make decisions promptly due to careful
consideration and not hurriedly in an emergency. As Silvers and colleagues found as
long ago as 1991, ALS patients change their minds and decisions regarding life-
sustaining therapy can vary during the disease. As Sander Dreyer P et al. found in
their study, periodic reevaluation with the patients must be encouraged about
advance directives for end-of-life care.

Discontinuation of mechanical ventilation in these circumstances is expected to

result in the rapid onset of hypoxia. This implies a likelihood of dyspnea and anxiety if
it is not accompanied by deep sedation.
Dreyer and al. concluded that the termination of ventilatory treatment requires the
induction of deep sedation [8].
CONCLUSION
There is no universally accepted strategy in managing NMD patients, because, in

this highly disabling pathology, the line between Survival and life is very blurred. As
is often the case in our medical profession, there is no unique solution. For this
reason, the care pathway in this kind of patient must be shared and planned with
patients and care-givers, illustrating the step by step therapeutic options and life
expectancies.
REFERENCES
[1] Crimi, C., Pierucci, P., Carlucci, A., Cortegiani, A., Gregoretti, C. Long-Term
Ventilation in Neuromuscular Patients: Review of Concerns, Beliefs, and
Ethical Dilemmas. Respiration, 2019; 97(3):185 - 196.
[2] Hobson, E. V., McDermott, C. J. Supportive and symptomatic management of
amyotrophic lateral sclerosis. Nat. Rev. Neurol., 2016 Sep.; 12(9):526 - 38. doi:
10.1038/nrneurol.2016.111. Epub 2016 Aug. 12. PMID: 27514291.
[3] Lyall, R. A., Donaldson, N., Fleming, T., Wood, C., Newsom-Davis, I., Polkey,
M. I., Leigh, P. N., Moxham, J. A prospective study of quality of life in ALS
patients treated with noninvasive ventilation. Neurology, 2001 Jul. 10;
57(1):153 - 6. doi: 10.1212/wnl.57.1.153. PMID: 11445650.
[4] Bourke, Stephen C., Tomlinson, Mark, Williams, Tim L., Bullock, Robert E.,
Shaw, Pamela J., Gibson, G. John. Effects of noninvasive ventilation on
Survival and Quality of life in patients with amyotrophic lateral sclerosis: A
randomized controlled trial. Lancet Neurol., 2006; 5: 140 - 47.
[5] Abbott, D., Prescott, H., Forbes, K., Fraser, J., Majumdar, A. Men with
Duchenne muscular dystrophy and end of life planning. Neuromuscul. Disord.,
2017 Jan.; 27(1): 38 - 44.
[6] Veronese, S., Valle, A., Chiò, A., Calvo, A., Oliver, D. The last months of life of
people with amyotrophic lateral sclerosis in invasive mechanical ventilation: A
qualitative study. Amyotroph. Lateral Scler. Frontotemporal Degener, 2014
Dec.; 15(7-8): 499 - 504.
[7] Kettemann, D., Funke, A., Maier, A., Rosseau, S., Meyer, R., Spittel, S. et al.
Clinical characteristics and course of dying in patients with amyotrophic lateral

sclerosis withdrawing from long-term ventilation. Amyotroph. Lateral Scler.

Frontotemporal Degener, 2017 Feb.; 18(1 - 2): 53 - 9.
[8] Dreyer, P. S., Fielding, M., Charlotte Sønderskov Klitnæs, C. S. and Kirkegard
Lorenzen, Charlotte. Withdrawal of Invasive Home Mechanical Ventilation in
Patients with Advanced Amyotrophic Lateral Sclerosis: Ten Years of Danish
Experience. Journal of Palliative Medicine, Volume 15, Number 2, 2012 Mary
Ann Liebert, Inc. DOI: 10.1089pmm.2011.0133.
[9] Borasio, G. D., Miller, R. G. Clinical characteristics and management of ALS.
Semin. Neurol., 2001; 21:155 - 166.
[10] Ganzini, L., Johnston, W. S., Silveira, M. J. The final month of life in patients
with ALS. Neurology, 2002; 59:428 - 431.
[11] Goy, E. R., Carter, J., Ganzin, I. L. Neurologic disease at the end of life: Care-
giver descriptions of Parkinson disease and amyotrophic lateral sclerosis. J.
Palliat. Med., 2008; 11:548 - 554.
[12] Albert, S. M., Whitaker, A., Rabkin, J. G., del Bene, M., Tider, T., O'Sullivan, I.
et al. Medical and supportive care among people with ALS in the months
before death or tracheostomy. Pain Symptom Manage, 2009; 38:546 - 553.
[13] Neudert, C., Oliver, D., Wasner, M., Borasio, G. D. The course of the terminal
phase in patients with amyotrophic lateral sclerosis. J. Neurol., 2001; 248:612 -
616.

EDITORS’ CONTACT INFORMATION
Giuseppe Fiorentino, MD
UOC Fisiopatologia and Respiratory Rehabilitation AO Dei Colli,
Naples, Italy
giuseppefiorentino1@gmail.com
Antonio Esquinas, MD
Intensive Care Unit; Hospital Morales Meseguer, Murcia, Spain
antmesquinas@gmail.com

INDEX
149, 150, 151, 152, 156, 158, 161, 162, 163,

A
164, 210, 214, 216, 217, 236, 241, 248, 249,
250, 253, 254, 260, 263, 265, 272, 301, 304,
acid maltase deficiency (AMD), 37, 38, 88, 92,
311, 334, 335, 392, 393, 397, 398, 399, 401,
539
434, 453, 477, 489, 498, 499, 500, 501, 502,
acute respiratory distress syndrome, xv, 159,
503, 504, 505, 506, 508, 509, 524, 535, 546,
301
548, 549, 567, 603, 606
acute respiratory failure, vii, xv, xix, xxi, 4, 9, 19,
alveoli, 58, 76, 118, 149, 151, 152, 163, 402,
77, 131, 139, 144, 145, 146, 148, 157, 159,
409, 498, 499, 528
162, 163, 167, 178, 182, 183, 204, 218, 219,
amyotrophic lateral sclerosis, xvii, 1, 20, 83, 88,
220, 221, 242, 243, 259, 262, 287, 288, 291,
93, 94, 119, 166, 169, 175, 178, 183, 184,
301, 309, 310, 345, 346, 356, 398, 463, 504,
201, 202, 220, 223, 224, 226, 244, 257, 258,
524, 528, 533, 534, 535, 536, 537, 538
268, 269, 274, 316, 327, 391, 404, 409, 424,
adduction, 248, 250, 253, 254, 255, 256, 257,
432, 434, 442, 443, 444, 450, 451, 454, 461,
280, 380, 429
462, 472, 487, 492, 493, 526, 530, 555, 556,
adjunctive therapy, 491
577, 578, 580, 594, 600, 601, 602, 608, 609
adolescents, 26, 27, 32, 36, 42, 91, 107, 326,
anatomy, 48, 206, 262, 264, 267, 381, 420, 457
491, 562, 573, 597
anemia, 334
adult respiratory distress syndrome, 402
anesthesia, xvi, 288, 289, 327, 331, 332, 333,
adulthood, xxiii, 16, 17, 28, 29, 35, 36, 104, 366,
334, 335, 336, 337, 338, 339, 341, 342, 356,
425, 427, 558, 593, 596, 598
399, 407
adults, xii, 18, 19, 26, 36, 37, 39, 61, 76, 77, 78,
antibiotic, 209, 465, 466, 467, 468, 504, 571
92, 128, 133, 147, 234, 254, 273, 308, 309,
anticholinergic, xviii, 423, 436, 599
310, 328, 334, 372, 401, 405, 432, 451, 456,
anticholinergic drugs, xviii, 423, 436, 599
469, 470, 476, 494, 500, 508, 521, 525, 539,
anticipate directives, 259, 261, 262
577
anxiety, 42, 117, 139, 207, 214, 215, 545, 553,
age, 6, 7, 14, 15, 19, 20, 26, 27, 28, 29, 30, 31,
560, 583, 584, 591, 594, 598, 600, 605, 608
32, 33, 36, 38, 39, 41, 56, 72, 75, 89, 92,
apnea, xi, 3, 5, 6, 16, 31, 40, 83, 87, 90, 91, 94,
102, 104, 190, 193, 254, 276, 322, 349, 350,
96, 103, 123, 127, 137, 171, 213, 241, 294
361, 362, 363, 364, 366, 370, 371, 382, 392,
apneas/hypopneas, xi, 83, 87, 91
427, 445, 456, 472, 486, 500, 503, 526, 527,
appropriate technology, 575
536, 538, 551, 553, 563, 580,596, 605
arrhythmias, xvii, 9, 18, 336, 359, 360, 362,
ageing population, 569
365, 367, 369, 370, 371, 375
airway inflammation, 350, 405
airways, ix, x, xii, xiv, xv, xviii, xxii, xxiv, 27, 28,
37, 42, 55, 63, 64, 65, 66, 67, 76, 124, 148,

614 Index
arterial blood gas, xi, 8, 13, 42, 109, 111, 123, autonomy, xv, xxiv, 260, 287, 289, 294, 295,
137, 171, 179, 233, 234, 322, 333, 353, 497, 296, 304, 306, 312, 380, 475, 516, 520, 549,
527 553, 560, 585, 588, 589, 590, 595, 596, 603,
aspiration, vii, xiv, xvii, xix, 3, 4, 5, 6, 9, 13, 14, 604, 607
16, 27, 28, 35, 36, 42, 52, 66, 67, 84, 98, 99, autosomal dominant, 9, 16, 30, 32, 34, 36, 369,
104, 105, 120, 123, 140, 199, 210, 231, 248, 455
251, 291, 292, 302, 315, 324, 332, 333, 346, autosomal recessive, 28, 29, 30, 32, 33, 34, 455
348, 354, 355, 381, 391, 392, 394, 396, 397, autotriggering, 87, 90, 239, 240
398, 399, 400, 401, 403, 404, 405, 414, 425, avoidance, 16, 18, 100, 206, 210, 262, 554,
426, 433, 434, 444, 445, 446, 447, 448, 453, 606, 607
454, 455, 456, 457, 458, 459, 461, 462, 463, awareness, xvii, 335, 336, 345, 424, 550, 554,
464, 465, 466, 467, 469, 470, 472, 477, 480, 576
506, 514, 518, 527, 534, 535, 549, 550, 583,
596, 597
aspiration pneumonia, xvii, 13, 14, 35, 36, 120,
B
349, 355, 391, 392, 397, 398, 399, 401, 404,
bacteria, 76, 465, 466, 467, 535
405, 414, 433, 434, 444, 455, 457, 458, 466,
bacterial infection, 464
467, 469
barium, 396, 404, 445, 454, 456, 457, 458
aspiration pneumonitis, 397, 399, 404
barotrauma, xii, 147, 277, 280, 294, 313, 355
aspiration-induced lung diseases (AILD), xvii,
Becker muscular dystrophy, 15, 32, 41, 290,
391, 396, 397, 399, 400, 401, 402, 403
328, 359, 360, 366, 367, 374, 409, 414, 416,
assisted cough, 15, 43, 216, 257, 272, 276,
440, 472, 486, 526, 559
283, 293, 311, 312, 315, 316, 325, 340, 341,
benefits, xi, xv, 7, 96, 103, 109, 110, 111, 113,
354, 583, 584, 598
123, 124, 135, 136, 139, 193, 197, 272, 280,
assisted coughing, 276, 293, 311, 312, 315,
310, 324, 346, 481, 486, 525, 545, 568, 576,
316, 354, 584
582, 585, 597, 599, 602, 606
assisted inspiration, 216, 273, 276, 277, 278,
beta-2 agonist, 348, 582
279, 280, 282
Bethlem myopathy Spectrum, 34
assisted mechanical ventilation, 243
bilateral, 4, 6, 10, 11, 17, 54, 55, 58, 120, 121,
asthma, 274, 349, 356, 400
131, 134, 169, 348, 398, 399, 400, 410, 411,
asymmetry, 380, 381, 387, 425, 487
417, 425, 428, 432, 439, 440, 446
asymptomatic, xiii, 37, 39, 97, 112, 113, 114,
blood, xi, 9, 38, 40, 52, 71, 85, 117, 121, 124,
187, 189, 190, 193, 211, 322, 360, 363, 364,
154, 157, 189, 205, 233, 234, 243, 313, 315,
366, 403, 429, 456
334, 335, 347, 353, 383, 402, 415, 417, 429,
atelectasis, xx, 3, 4, 14, 15, 27, 67, 72, 84, 95,
466, 467, 469, 480, 488, 528
139, 163, 173, 178, 216, 217, 232, 272, 277,
blood cultures, 466, 469
305, 334, 341, 352, 398, 399, 401, 410, 414,
blood flow, 347, 429
418, 485, 487, 495, 496, 498, 503, 504, 525,
blood gas analysis, xi, 52, 71, 233, 234, 243
528
blood pressure, 9, 85, 313, 315, 334, 335
atrial fibrillation, 362, 363, 369, 370, 371, 374
body composition, 328, 475
atrial flutter, 363
body mass index, xix, 471, 473, 475
atrioventricular block, 362, 371, 374
body weight, 42, 102, 235, 474, 480
atrioventricular node, 361
bone, 58, 142, 202, 218, 379, 393, 395, 401,
atrophy, xxiii, 2, 6, 7, 8, 20, 26, 28, 30, 43, 44,
480
88, 89, 102, 173, 178, 201, 214, 251, 327,
botulinum toxin (BoNT), xviii, 423, 431, 432,
328, 337, 356, 378, 387, 409, 413, 414, 420,
436, 437, 438, 442, 459, 460, 462, 583, 599
425, 427, 428, 434, 439, 440, 444, 450, 487,
botulism, 119, 409
508, 526, 527, 563, 593, 596, 601
bowel, 6, 104, 232, 325
autoimmune disease, 425, 459
brachial plexus, 8, 11, 58, 120
autonomic nervous system, 28
bradycardia, 208, 370

Index 615
brain, xvii, 35, 36, 38, 221, 250, 256, 347, 357, cardiovascular disease, 323, 360, 361, 368,
377, 394, 409, 433, 441, 462 374, 569
brain damage, 462 cardiovascular disorders, 323
brainstem, 2, 3, 48, 65, 393, 426, 486, 558, 596 cardiovascular function, 323
breakdown, xvii, 100, 104, 132, 133, 136, 143, central apneas, 87, 90, 94, 241
144, 170, 377, 381, 516, 560 central nervous system, 1, 3, 38, 57, 118, 121,
breathlessness, 86, 353, 486 361, 393, 409, 426, 429, 433, 435, 438, 455,
bronchial airways, 498 456
bronchial tree, 316, 498, 499 central sleep apnea, 3, 6, 42, 86, 89, 93, 94
bronchiectasis, xx, 78, 329, 397, 399, 401, 414, cerebral cortex, 2, 393, 429, 558
465, 495, 503 cerebral palsy, 378, 379, 383, 385, 386, 387,
bronchioles, 400, 499 432, 441, 507, 508, 509
bronchiolitis, 397, 399, 400, 401 Charcot-Marie-Tooth disease, 26, 89, 93, 328,
bronchitis, 465 378
bronchodilator, 504 chemical, 64, 85, 253, 397, 399, 402, 424, 437
bronchopneumonia, 122 childhood, ix, xxiii, 14, 17, 25, 26, 30, 31, 33,
bronchoscopy, 208, 221, 222, 397 34, 38, 39, 96, 184, 290, 328, 361, 366, 370,
bronchospasm, 349, 350, 514 558, 563, 593, 596, 597
bronchus, 397, 398, 401 children, x, xi, xii, 5, 7, 9, 14, 18, 20, 25, 26, 27,
bulbar dysfunction, xiv, xvi, xxi, 3, 7, 9, 52, 56, 28, 31, 32, 34, 35, 36, 37, 38, 39, 41, 42, 67,
66, 76, 88, 105, 140, 247, 251, 255, 282, 78, 95, 96, 97, 98, 99, 100, 101, 102, 103,
292, 321, 346, 353, 496, 525, 534, 536, 605 104, 105, 106, 107, 140, 147, 158, 160, 180,
burnout, 216, 553, 554, 556, 595, 600, 601 199, 281, 324, 326, 329, 334, 387, 396, 405,
420, 432, 437, 451, 491, 493, 494, 500, 503,
504, 508, 509, 525, 529, 530, 545, 555, 562,
C 573, 597, 601
chromosome, 14, 16, 28, 29, 32, 38, 361
calcium channel blocker, 339
chronic diseases, 559, 572
caloric intake, 475, 478, 480
chronic exogenous lipoid pneumonia, 397, 399,
calorie, 325, 473, 474, 478
402
candidates, 5, 139, 174, 180
chronic illness, 561
cannula, vi, ix, 158, 259, 260, 263, 264, 265,
chronic inflammatory polyneuropathy, 26
266, 267, 269, 293, 294, 296, 305, 306, 307,
chronic interstitial lung disease, 397, 403
310, 517, 547, 548, 549, 550, 583
chronic obstructive pulmonary disease, 48, 49,
carbohydrates, 475, 478, 479
92, 131, 163, 219, 258, 304, 486, 492
carbon dioxide, 3, 67, 74, 77, 85, 93, 96, 100,
chronic respiratory failure, ix, xi, xii, xiv, xix, xxi,
102, 110, 118, 124, 234, 242, 262, 333, 380,
27, 32, 37, 109, 114, 117, 124, 129, 138,
489, 504, 534
156, 159, 162, 164, 165, 172, 183, 184, 204,
carbonic anhydrase inhibitors, 16
225, 227, 228, 237, 238, 242, 247, 298, 324,
carcinoma, 403, 424
328, 414, 463, 492, 493, 523, 526, 528, 585
cardiac arrest, 9, 336, 339, 341, 596
claustrophobia, xii, xiii, 133, 136, 139, 147, 148,
cardiac arrhythmia, 16, 362
163, 169, 170, 173, 354, 560, 598, 605
cardiac involvement, 38, 293, 334, 360, 361,
clinical application, x, 47, 50, 162, 164, 420
367, 369, 370, 371, 375
clinical assessment, xviii, 13, 273, 423, 435
cardiac muscle, 38, 84, 366
clinical diagnosis, 36
cardiac output, 237, 334, 347, 351, 368
clinical examination, 281, 368, 433, 456, 480,
cardiac pacemaker, 370
487, 534
cardiac surgery, 10, 194, 418, 421
clinical judgment, 474
cardiomyopathy, xvii, xxiii, 15, 18, 32, 34, 36,
clinical presentation, 28, 288, 367, 370, 392
38, 40, 241, 323, 328, 348, 359, 360, 364,
clinical symptoms, xi, 109, 110, 371
366, 367, 368, 369, 370, 373, 374, 381, 414,
clinical trials, xx, 485, 561
416, 420, 525, 593, 594, 596, 597, 602

616 Index
close relationships, 474 cough augmentation techniques, xv, 271, 272,

closure, xi, xix, 56, 65, 66, 83, 87, 90, 91, 94, 273, 275, 276, 277, 278, 280, 281, 496
123, 164, 213, 215, 232, 250, 253, 254, 256, cough effectiveness, 272, 273, 275, 276, 333,
263, 272, 274, 315, 325, 353, 393, 424, 433, 353
435, 438, 454, 457 cough evaluation, 272
cognitive dysfunction, 123, 333 cough function, v, xv, 63, 66, 216, 271, 272,
cognitive impairment, 120, 281, 361, 560, 596, 273, 274, 276, 278, 279, 281, 351
605 cough management, vi, 271, 272, 281
cognitive performance, xi, 109 cough reflex, x, xix, 50, 63, 64, 65, 66, 67, 76,
collaboration, xxi, 137, 163, 170, 197, 210, 506, 210, 315, 454, 467, 469
507, 513, 519 coughing, xix, 4, 42, 138, 173, 184, 196, 227,
communication, xxiii, 98, 158, 332, 568, 569, 251, 274, 275, 276, 277, 293, 311, 312, 315,
571, 579, 580, 582, 585, 586, 587, 589, 590, 316, 324, 334, 335, 352, 353, 354, 397, 399,
591, 592, 601 432, 435, 449, 454, 459, 584
community, xiv, xx, 103, 183, 247, 298, 350, critical care, 49, 57, 68, 69, 114, 115, 128, 159,
372, 399, 467, 485, 576 221, 222, 226, 267, 287, 307, 331, 407, 421,
compensation, xxi, 99, 102, 125, 196, 205, 206, 469, 471, 514, 515, 524, 529, 530, 538, 539
207, 220, 294, 303, 308, 347, 380, 429, 523 culture, xx, 465, 466, 467, 469, 513, 519, 589,
compression, 77, 123, 132, 139, 164, 169, 174, 590
278, 315, 349, 379, 393, 409, 499, 500, 501, cystic fibrosis, 78, 328, 466, 572
535
conduction, xvii, 12, 16, 30, 33, 37, 59, 323,
333, 359, 360, 361, 362, 363, 364, 365, 368,
D
369, 371, 372, 499
daily care, ix, 547
conference, 268, 298, 299, 310, 314, 473
daily living, 124, 133, 380, 385, 491, 572
congenital hypomyelinating neuropathy, 30
deaths, xx, 14, 356, 362, 396, 465, 485, 585
congenital muscular dystrophies, 31, 33, 35,
defects, ix, 25, 26, 37, 362, 363, 364, 368, 369,
223, 288, 337, 342
372, 429
congenital myasthenic syndrome, 20, 26, 31,
defibrillator, xxiii, 364, 365, 373, 594, 597
41, 44, 290
deficiency, xix, 1, 3, 4, 16, 17, 31, 37, 38, 39,
congenital myopathies, 14, 26, 31, 35, 43, 52,
88, 92, 324, 333, 339, 366, 369, 440, 471,
223, 333, 455, 472, 486
539
congenital myopathies and myotonic dystrophy,
deficit, 349, 473, 487, 546, 585
26
dehydration, 206, 392, 434, 444, 480, 599
congestive heart failure, xv, 18, 49, 301, 304,
depression, 14, 91, 110, 117, 155, 179, 195,
348, 360, 366
207, 208, 215, 325, 352, 553, 562, 583, 584
consciousness, xiv, 3, 9, 231, 260, 314, 399,
depressive symptoms, 573, 577, 590
476
depth, 336, 341, 347, 411, 474
control group, 104, 192, 280, 490, 491, 527,
dermatomyositis, 17, 18, 409, 414, 416, 428,
568, 605
444, 450, 472
control of breathing, 48, 215, 226, 525
detection, x, xxi, 49, 60, 63, 211, 239, 273, 303,
coordination, 5, 77, 148, 251, 272, 278, 279,
314, 363, 415, 444, 450, 534, 552
334, 341, 395, 414, 424, 433, 455, 456, 515
diabetes, 8, 10, 206, 339, 361, 424, 538, 572
correlation, 3, 17, 39, 54, 189, 201, 234, 367,
diabetic patients, 569
371
diagnostic criteria, 601
cost, xxi, xxii, 160, 274, 291, 294, 302, 308,
diaphoresis, 302, 315
310, 410, 414, 448, 449, 474, 476, 518, 543,
diaphragm dome motion, xviii, 407, 410, 411
544, 567, 568, 574, 575, 578
diaphragm thickening, xviii, 53, 407, 411, 412,
cough augmentation, xv, 77, 271, 272, 273,
414
275, 276, 277, 278, 279, 280, 281, 282, 329,
diaphragmatic hypopneas, 86
397, 496, 560
differential diagnosis, 39, 399, 405, 426

Index 617
diffuse aspiration bronchiolitis (DAB), 397, 399, dystrophy, xv, xx, 15, 16, 17, 31, 32, 33, 34, 35,
400 36, 41, 45, 48, 51, 84, 89, 93, 94, 96, 122,
diffusion, xxi, 54, 156, 429, 437, 438, 499, 543, 132, 138, 139, 169, 173, 176, 180, 183, 184,
554 200, 201, 202, 210, 223, 242, 287, 290, 296,
dilated cardiomyopathy, 18, 323, 360, 366, 367, 299, 322, 323, 327, 328, 329, 330, 337, 360,
369, 373, 374, 414, 416 366, 367, 369, 370, 371, 372, 373,374, 375,
directives, 259, 261, 262, 588, 595, 607 378, 392, 404, 409, 414, 416, 427, 434, 440,
disability, 3, 10, 89, 441, 491, 537, 556, 562, 450, 454, 461, 469, 472, 486, 491, 494, 495,
572, 573, 577, 605 526, 558, 559, 572
discharge plan, viii, 295, 513
discomfort, 100, 137, 139, 142, 144, 171, 206,
207, 213, 215, 237, 240, 251, 257, 446, 448,
E
560, 582
education, 292, 295, 515, 543, 545, 546, 547,
disease progression, xi, 15, 71, 72, 78, 96, 191,
549, 550, 553, 554, 555, 572
255, 256, 276, 372, 444, 574, 598
educational process, 547
disorder, 1, 7, 8, 12, 13, 14, 17, 28, 29, 30, 31,
educational programs, 545
32, 33, 34, 36, 40, 49, 52, 60, 67, 84, 93, 94,
electromyography, 12, 18, 30, 84, 244, 414,
118, 191, 237, 361, 366, 392, 393, 399, 424,
445, 446, 450, 451
425, 427, 428, 429, 434, 448, 454, 455, 585,
emergency, xvi, xxii, xxiii, 162, 217, 264, 331,
596, 597, 601
332, 335, 355, 515, 516, 536, 537, 543, 545,
disorders of lipid metabolism, 39
547, 549, 550, 551, 552, 555, 568, 571, 575,
disorders of the neuromuscular junction, 30
579, 581, 607
dispersion, 362, 363, 371, 399, 573
emergency management, xxii, 543, 545, 552,
displacement, 50, 53, 58, 85, 163, 232, 236,
555
262, 346, 393, 410, 419, 569
Emery-Dreifuss muscular dystrophies, 31, 359,
distress, 5, 13, 28, 29, 39, 302, 315, 396, 455,
360
560, 595
empyema, 399, 415, 417, 466
distribution, xx, 8, 32, 33, 89, 96, 206, 399, 403,
encephalopathy, 17, 40, 302
479, 485, 499
end-of-life care, xxiii, 579, 580, 593, 594, 596,
drainage, 15, 210, 232, 497, 584
597, 598, 600, 601, 607
drooling, 42, 432, 442, 455, 459, 583
endotracheal intubation, xiv, xxi, 77, 79, 140,
drug treatment, 368, 458, 459, 598
157, 162, 203, 231, 309, 355, 533
drugs, xvi, xviii, 13, 18, 32, 91, 207, 215, 325,
endurance, xx, 122, 179, 191, 192, 201, 485,
331, 332, 336, 338, 339, 340, 341, 349, 423,
488, 489, 491, 493
436, 459, 460, 468, 487, 582, 597, 598, 599
energy, 37, 122, 183, 323, 475, 514, 586, 606
dysarthria, xviii, 14, 423, 425, 427, 428, 439,
epiglottis, 248, 253, 254, 255, 256, 395
585
esophagus, 55, 57, 393, 400, 403, 408, 487
dysphagia, vii, xvii, xviii, xix, 3, 13, 14, 16, 69,
evolution, xii, 1, 15, 76, 131, 136, 142, 170, 288,
202, 316, 361, 391, 392, 393, 394, 400, 403,
291, 373, 374, 385, 393, 415, 433, 448, 450,
404, 414, 423, 425, 426, 427, 428, 432, 433,
554, 580, 588
434, 435, 438, 439, 443, 444, 445, 446, 447,
examinations, xviii, 425, 443, 444, 448, 449,
449, 450, 451, 453, 454, 455, 456, 458, 459,
457, 458
460, 461, 462, 463, 467, 469, 471, 473, 476,
exercise, 17, 37, 39, 50, 120, 139, 145, 173,
481, 535
176, 305, 460, 462, 486, 491, 492, 576, 578,
dysphonia, vii, xviii, 423, 424, 426, 427, 429,
584, 585, 595
430, 431, 432, 439, 442
expertise, xvi, 102, 198, 263, 312, 332, 393,
dyspnea, 3, 11, 28, 32, 42, 49, 52, 60, 78, 88,
448, 546, 551
123, 162, 164, 194, 211, 237, 305, 401, 403,
exposure, 54, 253, 336, 415, 416, 430, 448,
413, 486, 514, 534, 535, 582, 606, 607, 608
457, 458, 551
dystonia, 428, 429, 431, 432, 437, 439
external beam radiation therapy, 436
dystrophinopathies, 31, 359, 360, 365, 374

618 Index
eye movement, xi, 27, 66, 83, 84, 85, 92, 121, glottic closure, xi, 56, 83, 87, 90, 91, 94, 215,
123 250, 254, 272, 274, 353, 424, 457
glottis, 4, 5, 64, 65, 66, 94, 164, 213, 216, 232,
248, 250, 254, 258, 261, 264, 265, 274, 275,
F 276, 288, 315, 325, 353, 427, 535
glycogen, ix, 17, 25, 26, 37, 38, 328, 334
facial expression, 586
gravity, 1, 50, 54, 141, 164, 180, 572
facial muscles, 33, 35, 215, 427, 598
growth, 32, 96, 97, 188, 190, 379, 381, 384,
facio scapulo humeral muscular dystrophy, 32
387, 472, 568, 569
facioscapulohumeral, 16, 375
guidelines, xix, 7, 20, 56, 58, 97, 110, 111, 112,
families, xxiv, 103, 215, 278, 295, 369, 382,
113, 139, 144, 162, 193, 194, 199, 201, 211,
429, 554, 572, 580, 588, 589, 590, 594, 595,
216, 218, 219, 223, 224, 225, 268, 280, 292,
596, 598, 601
296, 303, 304, 309, 315, 329, 334, 432, 444,
family members, xxiii, 216, 514, 515, 579, 581,
457, 469, 470, 471, 478, 481, 502, 537, 548,
584, 588
551, 582, 587, 594, 600
feelings, xxi, 513, 515, 520, 553, 562, 589
H
fi
head trauma, 260, 399
fiberoptic endoscopic evaluation of swallowing
headache, 5, 42, 86, 112, 117, 121, 123, 124,
(FEES), 393, 444, 445, 446, 447, 448, 450,
211, 322, 353, 354
454, 457, 458
health care, xxii, 302, 382, 534, 535, 560, 567,
568, 569, 588, 591
F health care costs, xxii, 567
health care professionals, 534, 535, 569
fibers, 51, 251, 263, 420 health care system, 560
fibrosis, xx, 322, 361, 364, 367, 368, 372, 392, health condition, 383
400, 414, 418, 465, 495 health related quality of life (HRQoL), 557, 558,
financial, xxi, 519, 521, 523, 546, 568, 576 559, 561, 562, 563, 572
fluid, 65, 217, 325, 346, 348, 402, 415, 416, health services, 569, 570, 572
421, 445, 449, 466, 467, 473, 498, 502, 506 health status, xxi, 490, 523, 553, 559, 561
food, xviii, 65, 349, 393, 396, 397, 398, 400, heart block, 18, 360, 362, 369
401, 445, 453, 455, 456, 458, 460, 472, 474, heart disease, 84, 333, 347, 374, 375, 562
475, 476, 478, 549, 585 heart failure, xv, 15, 18, 49, 84, 86, 122, 123,
force, xiii, xx, 20, 51, 53, 56, 88, 89, 121, 122, 179, 301, 304, 325, 328, 334, 348, 359, 360,
149, 151, 152, 155, 187, 189, 190, 192, 201, 363, 364, 365, 366, 368, 370, 372, 373, 374,
218, 224, 304, 379, 409, 432, 485, 486, 520, 380, 493, 514, 598
535, 601 heart rate, 314, 315, 347, 576
forced vital capacity, xi, 2, 71, 73, 74, 97, 109, heart transplantation, 368, 597
117, 180, 211, 380, 527, 536, 574, 598 height, 42, 72, 75, 276, 416, 474
formation, xxii, 76, 206, 397, 399, 401, 415, helmet, 131, 132, 133, 134, 135, 142, 145, 146,
417, 433, 447, 455, 476, 543, 546, 549, 550 148, 205, 207, 219, 220
hereditary neuropathies, 426, 439
heterogeneity, 29, 36, 364, 367, 417, 444, 445,
G
551
history, xi, xxiii, 6, 29, 42, 43, 52, 65, 67, 109,
gastrostomy, xix, 34, 192, 323, 327, 328, 329,
140, 191, 192, 193, 195, 201, 211, 281, 322,
471, 477, 478, 481, 518, 521, 527, 581, 583,
324, 325, 340, 349, 371, 383, 385, 402, 444,
594, 596, 599, 602
449, 474, 486, 492, 580, 593, 597
genetic neuropathies, 29
hoarseness, 424, 426, 442

Index 619
holistic care, 306, 581 234, 273, 275, 291, 424, 526, 527, 529, 547,
home mechanical ventilation, viii, xxi, 61, 115, 548, 593, 595, 600, 601, 604
227, 240, 244, 247, 268, 297, 298, 511, 513, insertion, 18, 263, 266, 460, 599
521, 523, 524, 528, 529, 530, 547, 581, 609 insomnia, 84, 91, 117, 121, 179, 583, 600
home respiratory care, xxi, 513, 518, 519, 580 instrumental examinations, 443, 444, 448
home ventilation, xv, 235, 268, 287, 290, 294, intensive care unit, xv, xxiii, 9, 12, 14, 28, 97,
299, 546 163, 237, 242, 261, 267, 268, 269, 297, 299,
hospitalization, xi, xvi, xx, 14, 95, 206, 207, 315, 301, 305, 308, 309, 310, 330, 346, 356, 414,
317, 321, 383, 434, 464, 466, 497, 513, 519, 420, 464, 465, 521, 522, 579, 581, 590
549, 551, 568 interface, xiv, xv, 98, 99, 100, 104, 132, 135,
human body, 147, 148 136, 138, 139, 142, 143, 144, 145, 162, 170,
human resources, 519, 521, 553 172, 173, 174, 181, 182, 196, 205, 206, 212,
hyperinflation, 11, 51, 56, 90, 183, 238, 240, 214, 215, 217, 218, 219, 226, 231, 232, 235,
275, 277, 401, 486 236, 241, 252, 260, 287, 293, 315, 354, 410,
hyperkalemia, 18, 336, 341 418, 529, 560, 563, 598
hypertrophy, 5, 59, 361, 374, 461 intermittent abdominal compression ventilation
hyperventilation, 3, 215, 253, 258, 380, 489 (IAPV), xiii, 132, 134, 136, 139, 161, 163,
hypoxemia, 4, 16, 27, 28, 87, 88, 89, 124, 178, 164, 165, 166, 169, 174, 175
191, 232, 302, 322, 334, 341 interstitial lung disease, 18, 397
hypoxia, 17, 148, 338, 347, 608 interstitial pneumonia, 403
intervention, xvii, xxiii, 16, 29, 178, 180, 193,
254, 256, 368, 391, 454, 456, 457, 458, 459,
I 460, 469, 491, 499, 571, 573, 575, 577, 585,
586, 590, 593, 595, 600, 607
improvements, xxi, 103, 104, 126, 156, 184,
intra-cardiac device (ICD), xxiii, 363, 364, 365,
241, 297, 431, 448, 491, 492, 527, 543, 606
370, 372, 594, 597
incidence, xiv, 6, 28, 30, 36, 89, 90, 231, 236,
intubation, xiii, xiv, xv, xxi, 7, 9, 14, 36, 77, 79,
239, 241, 293, 308, 349, 350, 360, 362, 364,
110, 139, 140, 157, 158, 162, 185, 203, 204,
366, 367, 373, 374, 379, 384, 462, 500, 583,
209, 210, 231, 259, 260, 262, 267, 288, 301,
589
309, 325, 334, 350, 355, 383, 533, 535, 536,
independence, 216, 305, 380, 385, 548, 550,
537
559, 581
iron, xii, 134, 141, 147, 148, 153, 155, 157, 159,
induction, 324, 335, 355, 608
161, 163, 180, 188, 288, 354, 401, 528
ineffective cough, xi, xv, 52, 71, 74, 122, 192,
issues, x, xx, xxiii, 25, 67, 111, 128, 213, 214,
216, 271, 272, 278, 312, 315, 322, 324, 325,
259, 303, 333, 335, 337, 338, 361, 374, 492,
327, 352, 455, 508
495, 506, 524, 538, 548, 551, 570, 573, 574,
ineffective triggering, 87, 90, 236, 238
587, 591, 593, 594, 595, 596, 607
infants, 26, 27, 28, 30, 31, 36, 37, 38, 39, 44,
106, 158, 160, 180, 328, 469, 500, 504, 527,
563, 597 L
infection, 3, 5, 6, 9, 38, 64, 67, 273, 327, 350,
383, 384, 387, 399, 414, 464, 465, 466, 469, laparoscopic surgery, 334
492, 497, 503, 534, 596 laryngeal cancer, 260, 424
inflammation, xvi, 11, 18, 19, 51, 67, 142, 321, laryngeal dystonia, 428, 431, 432, 439
400, 401, 428, 486 laryngoscope, 250, 251, 252, 256, 430
inflammatory cells, 399 laryngoscopy, 248, 251, 257, 280, 397
inflammatory disease, 18, 473 laryngospasm, 425, 439, 454, 527
inflammatory mediators, 399 larynx, xiv, xviii, 64, 65, 247, 248, 250, 251,
inflation, 103, 134, 164, 210, 238, 266, 334 253, 254, 255, 256, 258, 329, 393, 395, 424,
influenza, 32, 350, 464, 468, 469 426, 428, 432, 433, 435, 453
initiation, x, xii, xxiii, 47, 49, 60, 96, 97, 109, lateral sclerosis, 1, 48, 52, 260, 333, 337, 378,
110, 111, 112, 113, 162, 179, 180, 211, 213, 424, 434, 439, 454, 456, 601, 602

620 Index
left ventricle, 348, 359, 367, 368 333, 349, 356, 423, 434, 456, 459, 460, 502,
left ventricle systolic dysfunction, 359 513, 514, 515, 516, 517, 520, 543, 547, 551,
lesions, xiii, 2, 3, 118, 132, 136, 138, 139, 140, 552, 554, 561, 567, 568, 569, 570, 571, 572,
142, 144, 148, 169, 172, 173, 187, 200, 206, 574, 576, 580, 581, 588, 591, 595, 601, 603,
261, 293, 315, 347, 380, 415, 491 608
life expectancy, ix, xxi, 10, 32, 184, 188, 288, medical assistance, 568
292, 297, 360, 450, 527, 543, 545, 554, 596, medical care, 588, 595, 601
604 medical history, 273, 333
life quality, 382 medication, 19, 356, 379, 424, 428, 515, 518,
light, 148, 196, 209, 313, 430 519
limb girdle muscular dystrophy, 32, 37 medicine, xx, 49, 128, 161, 200, 203, 222, 263,
limb weakness, 9, 18, 29, 39, 290, 427, 527 435, 495, 524, 538, 539, 572, 590, 600
liquids, xiv, 248, 324, 325, 435, 445, 448, 456, Mendelson syndrome, 399
458 merosin-deficient CMD, 33
LMNA-related congenital muscular dystrophy, meta-analysis, 145, 146, 219, 268, 303, 309,
33 310, 486, 490, 493, 577
local radiotherapy, 423, 436 metabolic myopathies, ix, 17, 25, 26, 37, 45,
long-term non invasive ventilation, 187 333, 409, 472
lower esophageal sphincter, 140 metabolism, ix, 17, 25, 26, 37, 39, 85, 472, 474,
lower respiratory tract infection, x, 25, 466, 470 480
lung abscess, 466 mitochondrial defects (MD), 1, 31, 33, 36, 39,
lung cancer, 13, 424 63, 71, 83, 109, 147, 161, 203, 219, 222,
lung consolidation, xviii, 407, 414, 415, 418 311, 321, 331, 345, 359, 387, 391, 407, 423,
lung disease, xvii, 7, 18, 162, 182, 233, 328, 443, 453, 455, 463, 513, 533, 557, 558, 559,
333, 350, 356, 391, 392, 397, 404, 405, 487 579, 603, 611
lung function, 4, 7, 15, 20, 27, 31, 34, 52, 54, moisture, 209, 217, 221
75, 76, 110, 113, 124, 145, 158, 160, 176, molecular weight, 349
201, 211, 224, 273, 276, 384, 479, 491, 492, mood disorder, xix, 86, 471
580 morbidity, xi, xv, xvi, xx, xxiii, 3, 4, 12, 19, 43,
lung volumes, xi, 18, 50, 53, 59, 61, 71, 75, 76, 71, 79, 84, 95, 109, 179, 242, 271, 272, 299,
88, 124, 179, 275, 313, 498, 505, 509, 525 302, 303, 321, 327, 331, 336, 342, 353, 366,
367, 400, 444, 467, 473, 491, 495, 496, 507,
525, 527, 530, 546, 589, 593, 597
M mortality, xi, xiii, xv, xx, xxiii, 3, 4, 6, 19, 36, 43,
71, 77, 84, 95, 109, 118, 156, 162, 177, 178,
macroglossia, 38, 88, 214, 241, 322, 324, 334,
179, 207, 237, 242, 243, 267, 271, 272, 280,
525
288, 289, 293, 302, 303, 304, 315, 316, 328,
magnetic resonance, 364, 372, 445, 447, 450
336, 346, 353, 361, 362, 363, 366, 367, 368,
magnetic resonance imaging, 445, 447, 450
371, 372, 374, 383, 444, 467, 473, 474, 491,
malignant hyperthermia, 333, 336, 341
495, 496, 537, 546, 593, 597
malnutrition, xix, 206, 323, 330, 335, 392, 434,
motor control, 256, 257
444, 471, 473, 474, 475
motor neuron disease, xvii, 2, 11, 28, 201, 326,
manually assisted cough, 276, 277, 278, 283,
336, 377, 391, 424, 425, 434, 451, 456, 472,
315, 353
601
mechanical insufflation–exsufflation, 248
motor neurons, x, 2, 6, 43, 47, 251, 256, 288,
mechanical ventilator, 9, 236, 289, 304, 317,
409, 424, 443, 447, 526, 527, 558, 596, 598
528, 544
mouthpiece, vi, xii, xiii, 66, 73, 77, 99, 105, 131,
mechanically assisted cough, vi, 138, 173, 184,
132, 133, 134, 136, 138, 145, 162, 166, 169,
227, 247, 248, 254, 255, 257, 334
170, 171, 172, 174, 175, 176, 187, 188, 197,
medical, xiv, xviii, xx, xxi, xxii, xxiii, xxiv, 7, 9,
201, 205, 212, 219, 225, 231, 288, 290, 293,
12, 15, 39, 72, 135, 158, 160, 188, 205, 247,
315, 354, 506, 517, 549, 560, 598, 607
254, 273, 274, 281, 289, 292, 296, 301, 304,

Index 621
mouthpiece ventilation, xiii, 99, 105, 132, 136, necrosis, 19, 104, 139, 142, 339, 401, 416
138, 145, 169, 170, 171, 172, 174, 175, 176, negative consequences, 158
187, 188, 219, 225, 288, 354, 549, 560 nerve, ix, x, 5, 6, 8, 10, 11, 12, 13, 25, 26, 30,
mucosa, 217, 457, 476 47, 48, 51, 57, 58, 60, 64, 65, 248, 250, 288,
mucous membrane, 248, 294, 436, 549, 583 340, 409, 426, 427, 428, 432, 433, 434, 436,
mucus, x, xviii, 7, 27, 63, 64, 65, 66, 209, 216, 437, 439, 441, 487, 538, 558
217, 264, 267, 272, 273, 294, 316, 341, 353, neurodegenerative disorders, 490
446, 453, 455, 459, 497, 498, 499, 502, 505, neurologic symptom, 14
506, 524, 547, 575, 598 neurological disability, 3
muscle atrophy, xxii, 10, 52, 236, 333, 379, 425, neurological disease, 288, 289, 424, 433, 458,
427, 439, 491, 567 473, 486, 539, 591, 594
muscle biopsy, 14, 18, 36, 455 neuromuscular blocking agents, xvi, 9, 12, 313,
muscle contraction, 51, 249, 250, 251, 272 331, 332, 339, 341
muscle force (MF), xx, 300, 371, 485, 486 neuromuscular disorders, v, vii, ix, xvi, xvii, xix,
muscle mass, 7, 35, 473, 475 1, 2, 19, 23, 41, 42, 43, 44, 49, 50, 51, 52,
muscle performance, xix, 74, 118, 120, 471 59, 60, 61, 68, 71, 94, 107, 114, 128, 140,
muscle relaxant, 338, 339 156, 162, 163, 165, 200, 201, 223, 225, 227,
muscle spasms, 429 237, 242, 282, 283, 299, 311, 326, 329, 331,
muscle strain, 155 332, 334, 342, 366, 370, 377, 387, 389, 391,
muscle strength, x, xi, 3, 27, 32, 42, 43, 47, 48, 407, 408, 412, 417, 419, 439, 443, 451, 463,
49, 50, 51, 52, 56, 58, 60, 61, 66, 71, 76, 472, 493, 507, 525, 527, 534, 563, 565, 580,
105, 120, 122, 180, 182, 272, 275, 276, 282, 592, 604
340, 456, 487, 488, 490, 492, 496, 498, 527, neuromuscular monitoring, xvi, 331, 332, 339,
534, 535 341
muscular mass, 198 neurons, 43, 48, 250, 424, 434
musculoskeletal, 12, 140, 298, 334 neuropathy, 8, 9, 10, 11, 12, 17, 18, 29, 41, 53,
mutations, 14, 29, 31, 33, 34, 38, 39, 40, 365, 88, 428, 440, 525
366, 369, 373, 374, 426, 429, 455, 596, 597 nodules, 398, 399, 400, 401, 424, 468
myasthenia gravis, 13, 30, 327, 333, 339, 342, non instrumental examinations, xviii, 443, 444,
409, 425, 434, 444, 450, 451, 459, 472, 486, 448
536, 559, 577 non-rapid eye movement (NREM), 84, 85, 87,
myasthenic syndrome, 2, 13, 26, 41, 44, 290 88, 90, 92, 239, 240, 525
myopathy, xvii, 2, 9, 11, 15, 17, 18, 19, 27, 34, normal swallowing, xviii, 393, 453
35, 36, 37, 38, 39, 41, 45, 139, 174, 290, nurses, 141, 204, 289, 295, 476, 524, 526, 547,
293, 336, 337, 338, 359, 391, 420, 427, 428, 552, 591, 601
439, 440, 455, 468, 472, 486, 487, 597 nursing, 15, 141, 267, 400, 458, 464, 519, 554,
myositis, 18, 19, 21, 409, 428, 440, 444, 450, 600
454, 455, 456, 461, 472 nursing care, 400
myotonic dystrophy type 1, xvii, 20, 36, 41, 93, nursing home, 267, 464, 554, 600
290, 359, 360, 371, 372, 373, 427, 444, 450, nutrients, 473, 474, 475, 477
472, 577 nutrition, xvii, xix, 6, 9, 306, 325, 381, 391, 392,
471, 475, 476, 477, 479, 481, 545, 550, 588,
597, 602
N
nutritional assessment, xxiii, 474, 475, 579, 582
nutritional screening, 474
nasal mask, 98, 99, 127, 131, 132, 133, 134,
nutritional status, 42, 335, 474, 475, 477
135, 139, 141, 142, 143, 146, 166, 171, 172,
181, 195, 197, 206, 214, 217, 236, 243, 354,
497, 584 O
nasogastric tube, 460
nasopharynx, 56, 76, 236, 251, 465 obesity, xii, 32, 88, 92, 141, 147, 163, 164, 244,
near-drowning, 402 349, 410, 474, 525, 572

622 Index
obstructive and centra, xi, 6, 83, 86, 91 pain management, 325, 597
obstructive and central sleep palate, xviii, 85, 141, 236, 250, 392, 393, 395,
apneas/hypopneas and periodic breathing, 423, 427, 459, 476
86 palliative care, viii, xxii, 7, 579, 580, 581, 584,
obstructive lung disease, 139, 160, 174, 213, 587, 590, 591, 592, 594, 595, 600, 601, 607
238 palliative medicine, 564, 590, 600, 609
obstructive sleep apnea (OSA), 3, 5, 27, 42, 84, paralysis, 1, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 16,
88, 96, 98, 128, 145, 322, 414, 525 17, 51, 52, 53, 55, 59, 94, 119, 120, 121,
oculopharyngeal muscular dystrophy, 16, 427, 131, 134, 139, 145, 164, 167, 169, 173, 176,
454, 455, 461, 462 260, 274, 298, 339, 379, 409, 410, 411, 412,
oedema, 3, 134, 346, 347 413, 416, 418, 424, 425, 426, 428, 439, 558,
oesophageal, xviii, 423, 433, 435, 453, 454, 598
456, 457, 458, 460 parents, 324, 545, 562, 573, 588, 597, 600
optimization, xiii, xxi, 187, 192, 193, 194, 197, parotid, 433, 434, 436, 437, 438, 459, 583, 599
199, 314, 323, 333, 383, 438, 523 parotid gland, 433, 434, 436, 437, 438, 459,
oral cavity, 396, 433, 446, 535 583, 599
oral mask, 131, 133, 134, 188 pathogenesis, xiv, 21, 44, 247, 350, 429
oral preparatory, 393 pathology, ix, 2, 38, 39, 42, 53, 56, 110, 121,
oral preparatory phase, 393 212, 291, 335, 381, 382, 385, 430, 435, 438,
oral propulsive, 393 474, 516, 520, 558, 608
oral propulsive phase, 393 pathophysiological, xx, 157, 204, 205, 207, 272,
organ, xiv, 201, 248, 255, 341, 385, 476 374, 394, 447, 458, 465, 485
organize, xvii, xx, 391, 392, 513, 519 pathophysiology, 26, 84, 86, 272, 356, 538, 585
organizing pneumonia, 397, 403 pathway, xvii, xxiv, 48, 50, 65, 377, 424, 603,
orthopnea, 11, 52, 86, 110, 112, 114, 117, 179, 608
211, 487, 527, 583 peak cough flow, xi, xv, 2, 48, 55, 64, 66, 71,
oscillation, 89, 210, 222, 500, 501, 502, 503, 74, 76, 77, 138, 172, 232, 254, 271, 272,
508 273, 282, 322, 333, 353, 606
outcome, viii, x, xvi, xix, 3, 4, 9, 13, 15, 25, 26, peak expiratory flow rate, 5, 55, 66, 447
27, 44, 132, 135, 192, 215, 274, 300, 307, percutaneous endoscopic gastrostomy (PEG),
308, 309, 310, 314, 315, 331, 333, 356, 387, 193, 194, 195, 251, 460, 462, 477, 478, 597,
445, 449, 451, 461, 463, 487, 531, 533, 534, 599
537, 577, 581, 598 perfusion, 85, 122, 123, 139, 173, 178, 216,
outpatient, 255, 278, 279, 529, 572 233, 265, 346, 349, 351, 355, 496, 498, 528,
overlap, 28, 34, 35, 36, 51, 65, 361, 396, 428 535
oxygen, xxiii, 40, 77, 85, 96, 103, 112, 118, 123, periodic breathing, xi, 83, 86, 87, 89, 90, 91,
124, 142, 154, 179, 195, 198, 217, 233, 237, 244
261, 262, 289, 294, 305, 307, 308, 310, 312, periodic limb movement disorder, 84
315, 317, 324, 341, 347, 350, 351, 354, 355, peripheral airway clearance techniques (ACT’s),
414, 465, 489, 496, 497, 498, 499, 504, 507, 496, 497, 500
514, 528, 529, 535, 550, 575, 579, 582, 607 peripheral nerve injury, 426
oxygen consumption, 85, 308, 347, 351 peripheral nervous system, xviii, 341, 409, 423,
oxyhemoglobin, 9, 182 455, 571
pH, 77, 195, 205, 234, 313, 314, 397, 399, 575
pharmacological treatment, xxiii, 366, 368, 579,
P 582, 583
pharynx, xix, 6, 248, 250, 397, 403, 433, 446,
pacemaker, 18, 363, 364, 365, 370, 374
453
paediatric patients, 190, 552
phenotype, 26, 34, 35, 36, 38, 39, 40, 41, 361,
pain, 6, 8, 9, 10, 11, 18, 37, 39, 91, 120, 139,
367, 598
140, 234, 325, 339, 349, 352, 382, 401, 426,
572, 580, 584, 588, 591, 597, 600, 607

Index 623
phenotypes, x, 25, 26, 34, 35, 36, 41, 42, 261,

Q
272, 361, 373, 428, 563, 596
phosphorylase deficiency (glycogenosis type V,
quality of life (QoL), x, xi, xiv, xviii, xx, xxi, xxii,
McArdle’s disease), 39, 41
xxiii, 7, 16, 25, 26, 29, 43, 83, 84, 90, 95, 97,
physical activity, 52, 117, 328, 364, 474, 475,
104, 105, 109, 110, 113, 117, 122, 138, 163,
476, 562
166, 172, 179, 192, 203, 216, 220, 272, 273,
physical exercise, 486
281, 291, 293, 297, 298, 312, 316, 317, 324,
physical therapy, 9, 305
360, 433, 443, 444, 448, 460, 472, 473, 485,
physicians, x, 25, 26, 204, 253, 308, 327, 524,
491, 492, 495, 497, 528, 530, 543, 544, 545,
571, 594, 607
546, 553, 557, 558, 559, 560, 561, 562, 563,
physiology, x, xi, 3, 20, 56, 63, 83, 148, 149,
572, 574, 575, 577, 580, 581, 583, 584, 585,
332, 356, 445, 461, 509, 538, 550
590, 592, 593, 594, 595, 597, 598, 601, 604,
pleural effusion, xviii, 36, 122, 123, 398, 407,
605, 606, 608
410, 414, 415, 416, 417, 418, 420, 421
questionnaire, 430, 445, 449, 451, 562, 605,
pneumonia, x, xiv, xv, xx, 2, 3, 4, 5, 7, 8, 14, 15,
606
19, 26, 27, 52, 63, 67, 195, 232, 248, 259,
261, 267, 301, 304, 312, 316, 317, 322, 350,
380, 396, 397, 399, 401, 402, 403, 405, 415, R
416, 418, 434, 445, 457, 459, 461, 462, 464,
465, 466, 467, 468, 469, 470, 485, 487, 502, radiation, 19, 53, 54, 436, 448, 457, 458
503, 507, 535, 537, 538, 549, 571, 597 rapid eye movement (REM), xi, 27, 29, 54, 59,
pneumonitis, 397, 399, 404 83, 84, 85, 87, 88, 89, 90, 92, 94, 96, 102,
pneumothorax, 104, 140, 281, 334, 414, 418 110, 121, 123, 126, 209, 241, 525, 535
polio, xiii, 6, 89, 118, 136, 157, 169, 180, 289, rapid eye movement sleep, 126
293, 526 recognition, 19, 43, 95, 97, 192, 349, 360, 535,
Pompe disease, 17, 37, 38, 41, 166, 168, 224, 550
290, 538 recommendations, iv, 20, 77, 111, 112, 113,
post-polio, 2, 6, 89, 118, 289, 526 188, 193, 211, 221, 267, 280, 281, 292, 312,
post-polio and Gullain- Barre syndrome, 89 323, 332, 456, 469, 516, 518, 585, 590
pregnancy, vii, xvi, 345, 346, 347, 348, 349, recurrent pneumonia, xx, 26, 401, 485, 487
350, 351, 352, 353, 354, 355, 356, 440 reduced lung function, 272
prevention, xviii, 29, 140, 143, 179, 206, 304, rehabilitation, xvii, xx, 4, 11, 12, 49, 158, 160,
340, 387, 443, 444, 469, 544, 550, 580, 590 305, 391, 392, 393, 438, 450, 459, 462, 477,
primary caregivers, 553 485, 573, 576, 578, 582, 584, 587, 601
principles, xii, 147, 460, 462, 497, 505, 516, rehabilitation program, xx, 485, 584
590, 601 relatives, xvi, 261, 279, 331, 544, 546, 554, 571,
prophylactic, 97, 364, 371, 372, 374 589
prophylaxis, 16, 369, 384, 469 resistance, xiv, 72, 85, 88, 91, 92, 103, 124,
pulmonary diseases, 210, 403, 420, 572 133, 141, 145, 150, 176, 217, 227, 236, 248,
pulmonary edema, 399, 402 252, 253, 259, 260, 294, 303, 346, 347, 460,
pulmonary embolism, 8, 349, 361, 596 464, 466, 468, 469, 488, 489, 498, 499, 505,
pulmonary function, v, xi, xvii, 10, 15, 26, 29, 535
31, 42, 43, 71, 72, 74, 93, 97, 103, 104, 112, resources, xx, 291, 295, 458, 475, 485, 509,
123, 211, 322, 345, 380, 387, 397, 496 516, 519, 520, 521, 551, 569, 571, 576
pulmonary function test, xi, 43, 71, 72, 74, 97, respiration, xiv, 3, 6, 10, 16, 18, 67, 96, 112,
211, 322, 397, 496 149, 178, 200, 212, 248, 257, 261, 380, 393,
pulmonary hypertension, 18, 334, 348, 360, 380 410, 411, 491, 504
pulmonary morbidity, viii, xx, 12, 79, 242, 299, respirator, 289, 309, 518, 520, 521
327, 342, 495, 496, 507, 527, 530 respiratory acidosis, 148, 204, 313, 314, 355
pulmonary rehabilitation programs (PR), 486 respiratory arrest, 13
respiratory disorders, 237

624 Index
respiratory distress syndrome, 356, 402 352, 397, 433, 434, 442, 463, 465, 498, 500,
respiratory dysfunction, xxiii, 7, 18, 95, 96, 97, 501, 502, 503, 504, 505, 518, 535, 583, 599
123, 341, 593, 597 sensitivity, xxiii, 58, 87, 88, 90, 97, 101, 103,
respiratory muscle anatomy, 48 126, 137, 142, 143, 144, 171, 182, 214, 239,
respiratory muscle training (RMT), vii, xx, 5, 363, 445, 446, 449, 558, 579, 588, 589
485, 486, 487, 488, 489, 490, 491, 492, 494 severe asthma, 349
respiratory muscle weakness, x, xii, xx, 3, 8, 10, shortness of breath, xiv, 181, 183, 248, 401
13, 14, 16, 17, 18, 19, 20, 33, 38, 43, 47, 49, sialorrhea, vii, xviii, 397, 423, 432, 433, 434,
52, 54, 58, 60, 61, 67, 76, 89, 90, 109, 117, 435, 436, 437, 438, 440, 442, 454, 459, 460,
120, 122, 178, 200, 211, 224, 238, 288, 311, 560, 562, 583
326, 485, 486, 487, 491, 492, 528, 534, 537, side effects, 32, 142, 163, 164, 207, 208, 314,
605 324, 334, 355, 432, 436, 437, 438, 459, 571,
respiratory phenotype, v, x, 25, 26, 41, 42 582, 583, 599
respiratory problems, xviii, 4, 19, 31, 323, 453, signs, x, xiii, xxi, 5, 6, 13, 25, 26, 27, 28, 32, 34,
546, 555 42, 86, 96, 111, 114, 117, 118, 179, 187,
respiratory rate, 86, 90, 98, 99, 101, 102, 125, 200, 211, 235, 255, 291, 314, 315, 323, 349,
126, 140, 164, 174, 181, 205, 210, 238, 240, 350, 352, 354, 368, 396, 424, 428, 437, 444,
295, 303, 305, 307, 347, 528, 548, 575 446, 449, 475, 487, 514, 533, 534, 535, 538,
respiratory syncytial virus, 464, 469 548, 552, 574, 576, 586, 589,598
respiratory therapist, 135, 256, 296, 334, 341, skeletal muscle, 17, 18, 36, 38, 39, 51, 55, 85,
547, 576 96, 361, 366, 368, 437, 474, 491, 571, 585
response, ix, xiv, 2, 12, 42, 57, 58, 76, 85, 92, skin, xiii, 33, 58, 100, 104, 132, 133, 135, 136,
102, 103, 123, 201, 208, 218, 247, 253, 254, 138, 139, 142, 143, 144, 148, 163, 164, 169,
255, 256, 257, 258, 334, 339, 347, 366, 399, 170, 172, 174, 175, 187, 193, 200, 206, 261,
466, 474, 491, 492, 499, 525, 530, 599 315, 354, 381, 475, 477, 560
restless leg syndrome (RLS), 84, 90 sleep apnea, 59, 89, 94, 96, 112, 114, 140, 163
restrictive lung disease, xiii, xix, 33, 177, 178, sleep disorders, 84, 91, 113, 380
179, 181, 182, 188, 291, 298, 350, 380, 455, sleep disturbance, 28, 30, 112, 114, 142, 205,
463, 465 241, 290, 525
resynchronizing devices with defibrillator (CRT- sleep fragmentation, 96, 123, 241
D), xxiii, 594, 597 sleep hypoventilation, xi, 83, 84, 86, 87, 88, 91,
reversal, xvi, 183, 184, 313, 331, 332, 339, 341, 113, 184, 234, 326
342 sleep medicine, 49
rhabdomyolysis, 17, 18, 19, 39, 333, 336, 341 sleep stage, 99, 102, 235, 252
rhinitis, xiii, 136, 169, 424 sleep-disordered breathing, xi, 6, 7, 16, 83, 84,
rhythm, 85, 323, 334, 369, 506 86, 87, 90, 92, 93, 96, 97, 106, 121, 133,
rigid spine with muscular dystrophy, 34, 41 333, 525, 527, 605
spasmodic dysphonia, 424, 425, 428, 429, 431,
432, 439, 442
S sphincter, xviii, 250, 348, 394, 433, 435, 446,
453, 454, 455, 457, 458, 460, 462
safety, 98, 196, 209, 276, 280, 288, 312, 349,
spinal cord, x, xvii, 2, 3, 4, 5, 47, 48, 89, 138,
355, 356, 432, 435, 448, 449, 457, 476, 491,
139, 173, 174, 222, 256, 377, 387, 409, 425,
492, 501, 515, 549, 555, 570, 571
486, 491, 526, 558
saliva, xviii, 9, 91, 199, 315, 393, 397, 423, 432,
spinal cord injury, 4, 5, 89, 139, 174, 222, 526
434, 436, 440, 455, 457, 458, 459, 460, 462,
spinal fusion, 387
583
spinal muscular atrophy, xxiii, 2, 7, 20, 26, 28,
scoliosis, xvii, 14, 15, 16, 27, 34, 35, 42, 43, 73,
44, 88, 89, 102, 173, 178, 201, 327, 328,
88, 96, 140, 159, 329, 377, 379, 380, 382,
337, 356, 378, 387, 434, 444, 450, 487, 508,
383, 384, 386, 387, 501
526, 527, 558, 563, 593, 594, 596, 601
secretion, x, xvii, xix, 3, 13, 25, 43, 69, 141,
spinal muscular atrophy I and II, xxiii, 593, 597
205, 208, 209, 216, 232, 233, 313, 316, 345,

Index 625
spinal symptoms, 395 369, 371, 378, 382, 387, 396, 397, 399, 409,
spinal-bulbar muscular atrophy, 425, 434, 439, 415, 424, 425, 428, 434, 440, 481, 526, 527,
440 536, 537, 589
spine, xii, xvii, 33, 34, 41, 97, 147, 198, 334, syringomyelia, 4, 164, 409
377, 379, 380, 381, 382, 383, 384, 387, 396 systemic lupus erythematosus, 9, 17, 18, 351
steroid inhaler, 428
steroids, 9, 11, 12, 18, 32, 96, 104, 303, 339,
350
T
stimulation, x, 47, 48, 51, 57, 58, 59, 60, 249,
tachycardia, 42, 208, 302, 349, 363, 372, 535
253, 434, 459, 487
tachypnea, 86, 96, 112, 164, 178, 211
stress, 207, 323, 334, 335, 383, 430, 553, 563,
technological advances, xiv, 247
572, 575, 584, 601
technological progress, 574
stress response, 601
tendon, 2, 12, 29, 30, 58, 408, 410
structure, 50, 134, 148, 153, 216, 292, 379,
tension, 64, 67, 190, 235, 265, 426, 427, 429,
408, 410, 411, 432, 499
432, 465, 488, 528, 584
sudden death, 16, 36, 359, 361, 362, 364, 370,
terminal illness, 595
371, 372, 375, 401
terminally ill, 584, 586
surgery, xii, xvi, xix, 10, 11, 13, 14, 53, 120,
testing, 31, 52, 55, 57, 61, 78, 111, 180, 182,
147, 158, 194, 195, 262, 268, 323, 324, 326,
211, 308, 481, 488, 493
328, 329, 331, 333, 334, 335, 339, 340, 341,
therapeutic approaches, 275
343, 377, 379, 380, 382, 383, 384, 387, 409,
therapeutic change, 515
418, 421, 423, 442, 449, 454, 456, 459
therapeutic effects, 431
surgical intervention, 7, 72, 460
therapeutic interventions, 448
surgical removal, 438
therapist, 141, 278, 444, 456, 550, 551, 555
surgical technique, 268
therapy, xiv, xvii, xviii, xxii, xxiii, 1, 5, 7, 12, 13,
surveillance, xvii, xxii, 113, 332, 339, 359, 469,
15, 16, 38, 49, 95, 104, 105, 106, 120, 128,
567
132, 139, 141, 143, 144, 145, 158, 180, 181,
survival, xi, xiv, xv, xix, xxii, xxiii, xxiv, 5, 7, 15,
192, 209, 215, 217, 218, 248, 255, 256, 276,
16, 33, 43, 49, 60, 72, 78, 83, 84, 90, 104,
278, 301, 305, 307, 309, 310, 314, 317, 323,
106, 109, 110, 112, 113, 117, 124, 138, 157,
334, 335, 340, 348, 349, 350, 359, 365, 370,
172, 184, 188, 189, 191, 192, 193, 194, 196,
373, 374, 391, 392, 415, 423, 429, 436, 438,
199, 201, 202, 203, 210, 211, 214, 215, 216,
441, 448, 460, 464, 466, 467, 468, 469, 480,
226, 237, 257, 261, 265, 269, 287, 293, 298,
506, 526, 527, 550, 557, 562, 571, 573, 579,
312, 348, 363, 364, 372, 373, 434, 444, 463,
581, 582, 586, 597, 599, 607
524, 527, 529, 530, 546, 557, 560, 562, 574,
thoracoabdominal paradox, 89
580, 581, 583, 593, 596, 598, 603, 606
thorax, 28, 40, 50, 121, 134, 140, 151, 177,
survival rate, 15, 312, 348
178, 250, 272, 278, 380, 497, 500, 501, 502,
survivors, 36, 348
505
swallowing, ix, xiv, xvii, xviii, xxi, xxii, 3, 7, 19,
tissue, xx, 144, 217, 263, 277, 392, 413, 418,
28, 37, 42, 65, 67, 72, 86, 137, 140, 164,
430, 447, 474, 495, 584
202, 231, 248, 251, 253, 255, 263, 288, 292,
tobacco smoking, 253
293, 296, 300, 312, 316, 339, 391, 392, 393,
topical anesthetic, 55, 446
394, 404, 405, 423, 424, 426, 427, 431, 433,
total face mask, 131, 133, 135, 144, 146, 181
434, 435, 438, 439, 442, 443, 444, 445, 446,
toxin, xviii, 14, 423, 431, 436, 437, 438, 442,
447, 448, 449, 450, 451, 453, 454, 455, 456,
459, 460, 462, 583, 599
457, 458, 459, 460, 461, 466, 472, 476, 481,
trachea, 65, 295, 313, 324, 396, 424
533, 535, 567, 583, 585, 598
tracheal tube, 266, 552
symptomatic treatment, xi, 109
tracheobronchial foreign body, 397, 401
syndrome, 1, 2, 6, 8, 9, 10, 12, 13, 15, 17, 18,
tracheostomy, vi, ix, xii, xiv, xv, xvi, xxiv, 5, 7,
26, 27, 28, 30, 34, 37, 39, 41, 42, 84, 89, 94,
15, 105, 138, 139, 145, 147, 158, 162, 163,
118, 140, 141, 163, 333, 334, 337, 340, 348,
165, 166, 172, 173, 174, 175, 176, 180, 183,

626 Index
185, 188, 192, 203, 207, 210, 237, 242, 259, ventricle, 395
260, 261, 262, 263, 265, 266, 268, 269, 279, ventricular arrhythmias, xvii, 359, 360, 362, 365,
282, 287, 288, 289, 290, 291, 292, 293, 296, 369, 375
299, 300, 305, 306, 307, 310, 312, 315, 316, ventricular tachycardia, 362, 363, 365, 370, 598
324, 325, 345, 351, 352, 497, 500, 504, 509, vibration, 428, 430, 500, 501, 502, 508
517, 518, 520, 521, 524, 544, 547, 552, 555, video-fluoroscopic swallowing study (VFSS),
560, 574, 581, 584, 594, 597, 598, 603, 606, xvii, 391, 392, 393, 394, 395, 396, 398, 403,
609 444, 445, 446, 447, 448, 449, 450
tracheostomy tube, xiv, xv, 158, 174, 175, 242, viscoelastic properties, 210
259, 263, 265, 269, 282, 287, 288, 296, 352, viscosity, 435, 445, 449, 450, 502
517, 518, 552, 598 vomiting, 98, 99, 104, 170, 208, 440
transmission, 3, 9, 12, 13, 57, 58, 332, 464, 570
trauma, xv, 10, 118, 301, 302, 348, 378, 409,
424, 430
W
water, 90, 102, 121, 239, 266, 402, 449, 450,

U 459, 464, 476, 478, 479
weaning, vi, ix, xiv, xv, xvi, xxi, 5, 11, 77, 139,
Ullrich congenital muscular dystrophy, 34, 41, 157, 173, 174, 175, 222, 242, 259, 260, 262,
290 263, 267, 282, 291, 301, 302, 303, 304, 305,
ultrasonography, 60, 314, 419 306, 307, 308, 309, 310, 311, 312, 313, 314,
ultrasound, x, xvii, 47, 53, 329, 336, 340, 341, 315, 316, 332, 413, 418, 420, 421, 497, 513,
407, 410, 412, 414, 417, 419, 420, 421, 437, 520, 521, 529, 530
438, 477 weight changes, 474
upper airways, xii, 147, 148, 149, 151, 154, 159, weight gain, 32, 105
181, 214, 217, 235, 239, 251, 254, 260, 265, weight loss, xix, 86, 89, 323, 471, 473, 474,
289, 290, 295, 302, 501, 502, 506 475, 585, 599
upper respiratory infection, 430 weight reduction, 473
upper respiratory tract, 120, 272, 273, 465, 466, well-being, 124, 497, 545, 555, 559, 561, 587,
496, 571 604, 605
wound infection, 262, 383, 387
V
Y
vagus nerve, 64, 248, 426
valve, xiv, 77, 135, 136, 141, 166, 170, 196, young adults, 93, 329, 369
197, 248, 295, 296, 300, 489, 517 young people, xxiv, 592, 603, 604
ventilatory pump, xi, xii, 49, 60, 71, 72, 161,
162, 167, 268
ventilatory support, xi, xii, xiii, 4, 6, 7, 9, 13, 26,
α
28, 30, 60, 83, 84, 87, 90, 105, 138, 140,
α-dystroglycan related dystrophies, 35
145, 157, 161, 162, 163, 164, 165, 166, 167,
168, 172, 173, 176, 178, 180, 183, 185, 201,
210, 215, 223, 236, 241, 268, 292, 299, 351,
352, 448, 524, 536, 545, 548, 560, 581


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MANAGEMENT AND PRACTICE PRINCIPLES

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Additional books and e-books in this series can be found

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MANAGEMENT AND PRACTICE PRINCIPLES

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NOTICE TO THE READER

Library of Congress Cataloging-in-Publication Data

Published by Nova Science Publishers, Inc. † New York

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Chapter 9 Interface, Mouthpiece, Nasal Face/Alternative Interface 131

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Section 6 Perioperative Respiratory Management 319

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Chapter 36 Prevention of Pulmonary Morbidity 495

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Chapter 4 - Respiratory complications are common in subjects affected by

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pneumo-wraps, and intermittent abdominal pressure ventilators (IAPV). The latter

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labour, pulmonary function can be decreased. The management of women in

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Chapter 35 - Respiratory muscle weakness and dysfunction are

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focusing on crucial aspects of end-stage management and on the psychosocial

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OVERVIEW OF NEUROMUSCULAR DISORDERS

Giuseppe Fiorentino1,, MD, Anna Annunziata1, MD

Neuromuscular disorders (NMDs) are hereditary or acquired, slowly or

AIDP Acute inflammatory demyelinating polyneuropathy

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CCAH Central alveolar hypoventilation

UPPER MOTONEURON LESIONS/PYRAMIDAL INSUFFICIENCY

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Hemispheric lesions can also affect breathing. In hemiplegia following a stroke,

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Diseases of the Spinal Cord (SCI)

SCI is due to tumour, vascular accident, transverse myelitis, syringomyelia,

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Extrapyramidal disorders such as Parkinson’s disease can distress voluntary

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medullary respiratory center also can be affected, resultant in irregular respiration

Amyotrophic Lateral Sclerosis (ALS)

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The American Academy of Neurology guidelines recommends treatment with

Anterior Horn Cell Disorders

Spinal muscular atrophy (SMA) is a genetic autosomal-recessive degenerative

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Also identified as neuralgic amyotrophy or Parsonage-Turner syndrome, brachial