Respiratory failure

The major function of the lung is to get oxygen into the body and carbon dioxide out.

nability to transfer oxygen and/or carbon dioxide between the atmosphere and the blood

Definitions
 acute respiratory failure occurs when:  pulmonary system is no longer able to meet the metabolic demands of the body  hypoxaemic respiratory failure:

PaO2 ≤ 50 mm Hg when breathing room air

 hypercapnic respiratory failure:  PaCO2 ≥ 50 mm Hg.

Oxygen in
 Depends on
 

PAO2

Diffusing capacity  Perfusion  Ventilation-perfusion matching

Carbon dioxide out
 Largely dependent on alveolar ventilation  Anatomical deadspace constant but

physiological deadspace depends on ventilation-perfusion matching •Respiratory rate •Tidal volume •Ventilation-perfusion matching

inadequate blood oxygenation or CO2 removal
A syndrome rather than a disease

Respiratory Failure

PaO 2 < 60 mmHg or PaC O2 > 50 mmH g

Hypoxemic
PaO 2 < 5 5~6 0 mmHg or Sa wit h FiO 2 > = 6 0%

Hypercapnic
O2 < 90 % PaCO 2 > 4 5~5 0 mmHg

This two types of respiratory failure always coexist Ac ute: develops in minutes to hours, pH < 7.30 Chro nic: develops over several days or longer

Tr ansfe r o f o xygen o f inh aled air into t he blood and of wast e c ar bon diox ide of blo od int o t he lungs

Vent ilatio n

Gas Exchang e

Hypercapnic respiratory failure

Hypoxemic respiratory failure

Ventilation
CNS Efferents PNS Respiratory Muscles Chest Wall Airways

CNS Afferents/ Intergration

Dysfunction of any component of the ventilation system may result in ventilat ory fai lur e

Alveoli

Chemoreceptors

PaO2 PaCO2

Alveolar Ventilation

Minute Ventilation

Control of Ventilation
Mechanical stimuli, Chemical stimuli, Higher CNS input Medulla
Dorsal respiratory group Ventral respiratory group Ventral and Lateral columns of the spinal cord Switching between the inspiratory and expiratory phase

Pneumotaxic center
Dorsolateral pons Nucleus parabrachialis medialis

Phrenic n.  diaphragm Intercostal n.  intercostal m.

rhythm, rate, depth of breathing

Chemical Stimuli
 Peripheral chemoreceptors

Carotid bodies, Aortic bodies  Stimulus: PaO2, Acidemia (pH), PaCO2

 Central chemoreceptors

Near the ventrolateral surface of the medulla  Stimulus: H+ of brain ECF (pH), PaCO2

Chemical Stimuli
 Hypoxia  peripheral receptors  Hypercapnea  central receptors (80%)

 For the same pH change, the ventilatory

response to respiratory acidosis is greater than metabolic acidosis:

CO2 (gas) readily crosses the BBB, but H+ and HCO3- (ion) cross the BBB more slowly.

Respiratory Muscles
 Inspiration: active

Diaphragm:

phrenic n. (C3-5) T (their own level)

Intercostal muscles:

Accessory muscles

 Expiration: passive

Abdominal muscles: (active expiration)

Lower T and L level T (their own level)

Intercostal muscles:

O2 demand CO2 production Dead space

Respiratory drive Motor neuron/nerve function Muscle strength Respiratory mechanics

Ve nti lator y De man d

Ve nti lat or y S up ply

Ventilatory Demand > Ventilatory Supply  Ve nti lator y F ai lur e

Low I nsp ire d Oxy ge nAlv eolar Hy po ventil atio nSh un t V-Q misma tch Diffusion im pairment

Hypoxe mic R espiratory Fa
Resp onse we ll t o oxy gen t herapy

ilure

Hypoxic Respiratory Failure
1. Low inspired oxygen  High altitudes 2. Hypoventilation  Conditions described in hypercapnic respiratory failure  Oxygen therapy improve hypoxemia but may worsen the hypoventilation

Hypoxic Respiratory Failure
3. Shunt (right-to-left shunt)
 Normal shunting: (2~3% of C.O.)  Some of the bronchial arterial blood  Some of the coronary venous blood  Abnormal shunting:

Congenital defects in the heart or vessels

ASD, VSD, Pulmonary AVM Pneumonia, Cardiogenic or Non-cardiogenic pulmonary edema

Lung atelectasis or consolidation

 Resistant to O2 supply when shunt fraction of CO > 30%  Hypercapnia develops when shunt fraction > 60%

Hypoxic Respiratory Failure
4. Ventilation-Perfusion Mismatch
 Vascular obstruction

Pulmonary embolism Pneumonia, Pulmonary edema

 Air-space consolidation

Hypoxic Respiratory Failure
5. Diffusion Impairment
 Interstitial lung disease

Pulmonary fibrosis, Connective tissue disease, Interstitial pneumonia, interstitial pulmonary edema

 ARDS. RDS  Obstructive lung disease

Emphysema, Asthma

↓FIO2

Ventilation without perfusion (deadspace ventilation) Diffusion abnormality

Hypoventilation

Normal Perfusion without ventilation (shunting)

Hypercapnic Respiratory Failure
Increase carbon dioxide production
 Fever, sepsis, seizure, obesity, anxiety  Increase work of breath (Asthma, COPD)  high carbohydrate diet with underlying lung

disease (high RQ)

Hypercapnic Respiratory Failure
Decreased minute ventilation
 CNS disorders  stroke, brain tumor, spinal cord lesions, drug overdose  Peripheral nerve disease  Guillain-Barre syndrome, botulism, myasthenia gravis  Muscle disorders  muscular dystrophy, respiratory muscles fatigue  Chest wall abnormalities  scoliosis, kyphosis, obesity  Metabolic abnormalities  myxedema, hypokalemia  Airway obstruction  Upper airway obstruction, Asthma, COPD

Hypercapnic Respiratory Failure
Increase dead space
 Airway obstruction

Upper airway obstruction  Asthma, COPD  Foreign body aspiration (check-valve)

 ARDS, Pulmonary embolism  Chest wall disorder

Brainstem Airway Spinal cord Nerve root

Lung Pleura

Nerve

Chest wall

Neuromuscular junction Respiratory muscle

Sites at which disease may cause ventilatory disturbance

Respiratory Failure Symptoms
 Respiratory compensation  Sympathetic stimulation  Tissue hypoxia  Haemoglobin desaturation

•Often nonspecific (and unrecognized) •Dyspnea •Cynosis

Dyspnea
 Short of breath  Abnormally uncomfortable awareness of

breathing
subjectively  Increased work of breath

Cynosis
 Cyanosis is a blue coloration of the skin and

mucous membranes due to the presence of deoxygenated hemoglobin in blood vessels near the skin surface.  It occurs when the oxygen saturation of arterial blood falls below 85-90% (>5 g/dl deoxyhemoglobin).

Asthma
Definition
 Chronic inflammatory disorder

of bronchi characterized by episodic, reversible bronchospasm resulting from an exaggerated bronchoconstrictor response to various stimuli

Asthma

Etiology
 Allergens  Occupational  Fumes, smoke,

chemical  Viruses  Genetic factors  Prematurity  Lack breast feeding  Smoking

sprays  Diurnal variation  Exercise, cold air  Fog  Emotion  Allergens, anaphylaxis  Viruses  Drugs - NSAID, Beta

Types of asthma
 Extrinsic (Allergic/Immune)

Atopic - IgE  Occupational – IgG

 Intrinsic (Non immune)

Aspirin induced  Infections induced

Mechanisms of asthma
Risk Factors (for development of asthma)

Airway Hyperresponsiveness Risk Factors (for exacerbation)

Airflow Limitation

Symptoms

Mechanisms of asthma
 Edema  Excesive mucus  Bronchospasm  Obstructed

bronchiole

Factors in inflammatory process
 MEDIATORS  HISTAMINE  LEUCOCYTE C F  PROSTAGLANDINS  LEUKOTRIENES  PAF  KININS  CELL TYPES  MAST CELLS  MACROPHAGES  EOSINOPHILS  T LYMPHOCYTES

Mast cell in asthma

Mast cell in asthma

Eosinophils in asthma

EOSINOPHIL RECRUITMENT IN ASTHMA
IL-5 IL-4 Th2 cell Survival IL-3, IL-5, GM-CSF

Adhesion VCAM-1 VLA4 Chemotaxis Eotaxin, RANTES, MCP-4

Activation Bone marrow Airway vessel CCR3 Basic proteins Mediators AIRWAY HYPERRESPONSIVENESS

T cell in asthma

Neural mechanisms
PARASYMPATHETIC AFFERENT SENSORY HISTAMINE KININS EFFERENT BRONCHOCONSTRICTOR MUCUS SECRETION

PATHOPHYSIOLOGY OF ASTHMA
Allergen
Macrophage Th2 cell Eosinophil Epithelial shedding Nerve activation
Subepithelial fibrosis

Mast cell Neutrophil

Mucus plug

Plasma leak Oedema Mucus Vasodilatation hypersecretion New vessels hyperplasia

Sensory nerve activation Cholinergic reflex

Bronchoconstriction Hypertrophy/hyperplasia

COPD
Definition
 COPD is a disease state characterised by

airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.  Includes  Emphysema  Chronic bronchitis

Risk factors for COPD

Endogenous factors

Genes (e.g. alpha1-antitrypsin deficiency) Hyperresponsiveness Lung growth Tobacco smoke Occupational dusts and chemicals Infections Socioeconomic status

Exogenous factors

Chronic bronchitis
 Persistent cough

with sputum production for at least 3 months in ≥ consecutive years

Chronic bronchitis
• Mucosa of the lower respiratory passages

becomes severely inflamed

• Mucus production increases • Pooled mucus impairs ventilation and gas

exchange

• Risk of lung infection increases • Pneumonia is common • Hypoxia and cyanosis occur early

Chronic bronchitis
 Hypersecretion of mucus in large airways  Submucosal gland hypertrophy  Increase in goblet cells in small airways  Excessive mucus → airway obstruction  Cigarette smoke predisposes to infection

Emphysema
 Emphysema is

defined by destruction of airways distal to the terminal bronchiole.

Emphysema
• Alveoli enlarge as adjacent chambers break

through

• Chronic inflammation promotes lung fibrosis • Airways collapse during expiration • Patients use a large amount of energy to

exhale

• Overinflation of the lungs leads to a

permanently expanded barrel chest

• Cyanosis appears late in the disease

CELLULAR MECHANISMS OF COPD
Cigarette smoke

CD8 lymphocyte
+

?

Alveolar macrophage
MCP-1

Neutrophil chemotactic factors Cytokines (IL-8) Mediators (LTB4)4)) Neutrophil

PROTEASE INHIBITORS

-

PROTEASES

Neutrophil elastase Cathepsins Matrix metalloproteinases

Alveolar wall destruction (Emphysema)

Mucus hypersecretion (Chronic bronchitis)

PROTEASE-ANTIPROTEASE IMBALANCE IN COPD

α 1-Antitrypsin SLPI Neutrophil elastase Cathepsins MMP-1 Granzymes Perforins

Alpha1-Antitrypsin Deficiency
 Enzyme prevents loss of lungs’

elastic fibers  Deficiency – Pan-lobular emphysema  Homozygous – PiZZ – 15-30% of normal AAT levels (PiMM) Earlier development of COPD
  

Airflow obstruction in early 40s Accelerated by 10 to 15 years occurs in 1:5000

 Heterozygous – PiMZ – 50-80% -

smokers  Z allele – 3-5% population

MUCUS HYPERSECRETION IN COPD

Epithelium

Mucus

• Acetylcholine • Tachykinins • Proteinases
Sensory nerve

Goblet cell hyperplasia Cholinergic ACh nerve N E

SP

Mucus gland hyperplasia Cytokines ROS

• Cytokines (TNF-α ) • Oxidants • Growth factors • ↑ MUC genes
MUC5a, MUC8

neutrophil elastase

INFLAMMATION
Neutrophils

OVERLAP BETWEEN COPD AND ASTHMA
COPD
Neutrophils No AHR No steroid response
~10%

ASTHMA
Eosinophils AHR Steroid response

“Wheezy bronchitis”

Asthma and COPD
Inflammation
CELLS

ASTHMA
Mast cells Eosinophils CD4 T cells macrophages LTD4,histamineIL­ 4,IL­5,  ROS + All airways Little fibrosis Ep shedding +++

COPD
Neutrophils CD8 T cells Macrophages++ LTB4’ IL­8, TNFa, ROS+++ Periph airways Lung destruction Fibrosis + Sq metaplasia ±

MEDIATORS

EFFECTS

Response steroids

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