REVIEW

CURRENT
OPINION Diaphragm function in acute respiratory failure and
the potential role of phrenic nerve stimulation
Peter M. Reardon, Jenna Wong, Aisling Fitzpatrick and Ewan C. Goligher

Purpose of review
The aim of this review was to describe the risk factors for developing diaphragm dysfunction, discuss the
monitoring techniques for diaphragm activity and function, and introduce potential strategies to incorporate
diaphragm protection into conventional lung-protective mechanical ventilation strategies.
Recent findings
It is increasingly apparent that an approach that addresses diaphragm-protective ventilations goals is
needed to optimize ventilator management and improve patient outcomes. Ventilator-induced diaphragm
dysfunction (VIDD) is common and is associated with increased ICU length of stay, prolonged weaning and
increased mortality. Over-assistance, under-assistance and patient-ventilator dyssynchrony may have
important downstream clinical consequences related to VIDD. Numerous monitoring techniques are
available to assess diaphragm function, including respiratory system pressures, oesophageal manometry,
diaphragm ultrasound and electromyography. Novel techniques including phrenic nerve stimulation may
facilitate the achievement of lung and diaphragm-protective goals for mechanical ventilation.
Summary
Diaphragm protection is an important consideration in optimizing ventilator management in patients with
acute respiratory failure. The delicate balance between lung and diaphragm-protective goals is
challenging. Phrenic nerve stimulation may be uniquely situated to achieve and balance these two
commonly conflicting goals.
Keywords
acute respiratory failure, diaphragm dysfunction, phrenic nerve stimulation

INTRODUCTION addition to disuse atrophy, injury can occur via

Lung-protective ventilation is of paramount impor-
tance in managing patients with acute hypoxemic
respiratory failure. Low tidal volumes achieved with
deep sedation, passive modes of ventilation and
neuromuscular blockade (NMB) facilitate the pro-
excessive effort [6,9,10], and from eccentric contrac-
tions in the context of ventilator dyssynchrony [11].
Moreover, many patients arrive in the ICU with
established diaphragm dysfunction; this is also inde-
pendently associated with morbidity and mortality
&

tection of alveolar units from excessive stress and [12,13 ].

strain, and decrease mortality in patients with acute
respiratory distress syndrome (ARDS) [1]. Yet,
mounting evidence highlights the important down-
stream costs of diaphragm inactivity resulting from
this approach. A landmark study by Levine et al. [2]
demonstrated greater than 50% decrease in cross-
sectional area of the diaphragm in just 18–69 h of
mechanical ventilation among brain dead donors.
Multiple studies have since supported this finding
that diaphragm weakness is highly prevalent in ICU
patients [3–6] and is associated with an increased
ICU length-of-stay, prolonged mechanical ventila-
tion and increased mortality [5–8].
However, protecting the diaphragm during
mechanical ventilation is a complex problem. In
This clinical review will describe the risk factors
for development of diaphragm dysfunction, discuss
the monitoring techniques for both diaphragm
activity (effort) and function (strength), and then
introduce strategies to integrate diaphragm protec-
tion into a lung-protective ventilation approach.
Interdepartmental Division of Critical Care Medicine, University of Tor-
onto, Toronto, Ontario, Canada
Correspondence to Ewan C. Goligher, MD, PhD, Toronto General
Hospital, 585 University Ave, Peter Munk Building, 11th Floor, Room
192, Toronto, ON M5G 2N2, Canada.
E-mail: ewan.goligher@utoronto.ca
Curr Opin Crit Care 2021, 27:282–289
DOI:10.1097/MCC.0000000000000828

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 Diaphragm function in acute respiratory failure Reardon et al.

KEY POINTS
 Diaphragm dysfunction in common in the ICU and
associated with increased ICU length of stay,
prolonged weaning and increased mortality.
 There are numerous methods available for monitoring
diaphragm activity and function.
 Achieving diaphragm-protective goals while
maintaining lung protection may optimize
patient outcomes.
 Phrenic nerve stimulation may facilitate achieving lung
and diaphragm-protective targets.

Phrenic nerve stimulation may be uniquely situated

to achieve and balance these two frequently
competing goals.

RESPIRATORY PHYSIOLOGY

Anatomy of the diaphragm and course of the

phrenic nerves
The diaphragm is a dome-shaped muscle, which
separates the abdominal and thoracic cavities. The
anatomical components include the anterior costal
diaphragm attaching to the lower ribs and xiphoid
process, the crural diaphragm posteriorly, which
attaches to the first three lumbar vertebrae and
admits the aorta and oesophagus, and the central
tendon, which is a strong, noncontractile aponeu-
rosis admitting the inferior vena cava [14,15]. Inner-
vation from the phrenic nerves originates in the
neck from the third to fifth cervical nerve roots
bilaterally. The phrenic nerves descend caudally
and pass on either side of the heart before dividing
into four branches that innervate the diaphragm
from the abdominal side.
A sound understanding of diaphragmatic anat-
omy is critical in order to appropriately interpret its
biomechanics and function and to appreciate the
basis for monitoring and therapeutic intervention.
The costal diaphragm can be visualized by ultra-
sound at the zone of apposition of the chest wall
(Fig. 1). The dome of the diaphragm can be visual-
ized by ultrasound subcostally. The crural dia-
phragm with intervening oesophagus offers
potential for both manometry and electromyogra-
phy (EMG) with nasogastric catheters. Finally, the
course of the phrenic nerve offers many potential
targets for electrical stimulation whether more
cephalad (i.e. implantable neck electrodes) or more
caudad via transvenous stimulation or implantable
electrodes.
FIGURE 1. Diaphragm anatomy and potential targets for
therapeutic monitoring. Nasogastric tube is in situ with
oesophageal balloon and gastric balloons for monitoring
transdiaphragmatic pressure. Ultrasound probes also
depicted with linear transducer at the zone of apposition,
and a lower frequency probe (i.e. phased array or
curvilinear) transducer subcostally.
Respiratory system pressures
During diaphragmatic contraction, the dome
descends, exerting a piston-like action that generates
negative pleural pressure and draws air into the lungs.
The transdiaphragmatic pressure gradient, Pdi, can be
measured as the difference between gastric pressure,
Pga, and oesophageal pressure, Pes, (Pdi ¼ Pga – Pes).
The Pes can also be used to estimate pleural pressure
given the juxtaposition of the oesophagus and the
pleura. The transpulmonary pressure, PL, is then
calculated as the difference between airway pressure
(Paw) and Pes (PL ¼ Paw – Pes). Respiratory system
pressures are depicted in Fig. 2.
FACTORS AFFECTING DIAPHRAGM
MUSCLE FUNCTION IN ACUTE
RESPIRATORY FAILURE
Ventilator-induced diaphragm dysfunction
The ventilator is a double-edged sword when it
comes to unloading the diaphragm. Certainly,

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Cardiopulmonary monitoring
FIGURE 2. Respiratory system pressures. Palv, alveolar
pressure; Paw, airway pressure; Pcw, chest wall elastic recoil
pressure; Pdi, transdiaphragmatic pressure (Pes – Pga); Pes,
oesophageal pressure; Pga, gastric pressure; PL,
transpulmonary pressure; Pmus, respiratory muscle pressure.
inactivity with complete passive ventilation leads to
expedient and substantial diaphragm atrophy from
excessive unloading [2,3,16]. On the contrary,
under-assistance from the ventilator can also cause
diaphragm myotrauma [6,17]. Goligher et al. [6]
examined the end-expiratory thickness of the dia-
phragm, Tdi, and thickening fraction, TFdi, daily in
mechanically ventilated patients over the course of
their ICU stay. The Tdi decreased by more than 10%
in 41% of patients, and this atrophy was associated
with increased duration of mechanical ventilation
and ICU length of stay. Decreased Tdi correlated
with decreased diaphragmatic effort as monitored
by TFdi. Conversely, increased Tdi was seen in 24% of
patients, and these patients were at higher risk of
prolonged mechanical ventilation. Increased Tdi
was related to excessive spontaneous effort, suggest-
ing that increases in Tdi may represent inflamma-
tion and oedema from injury to the diaphragm.
Synchronous ventilation also appears to be
important for preserving diaphragm function. It
has long been observed in exercise physiology that
eccentric contractions (e.g. contractions of a muscle
during lengthening) are particularly injurious to
skeletal muscle tissue [18,19]. The diaphragm is
no exception [11,17]. During mechanical ventila-
tion, this action is recreated when diaphragm
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contraction occurs during the ventilator’s expira-
tory phase (i.e. reverse triggering).
Finally, selecting the optimal positive end-expi-
ratory pressure (PEEP) may also play an import role.
PEEP is an important tool to optimize oxygenation
and avoid de-recruitment in ARDS. However, consid-
ering the domed shape of the diaphragm, increased
PEEP and end-expiratory lung volume will shorten
diaphragm muscle fibres and confer a mechanical
disadvantage in the length-tension relationship of
the muscle during contraction [20,21]. This may also
lead to sarcomere dropout (‘longitudinal atrophy’),
and further disadvantage the diaphragm biomechan-
ically when PEEP is subsequently lowered and the
diaphragm is lengthened once again [22].
Disease-related and comorbid factors
Critical illness with respiratory failure creates the
perfect storm for deterioration of muscle function in
general, but the diaphragm appears to be particu-
larly susceptible. Common contributing factors
include malnutrition, electrolyte deficiencies, pro-
longed immobility and hyperglycaemia [23,24].
Sepsis is also known to exacerbate VIDD [25] and
can reduce diaphragm strength by as much as 80%
in the first 24 h [26,27]. Meticulous attention must
be paid to improve all potentially modifiable factors
in order to optimize diaphragm function.
Preexisting diaphragm dysfunction
Many patients have preexisting diaphragm dysfunc-
tion at the time of admission to the ICU. Demoule
et al. [12] measured magnetic phrenic nerve twitch
airway pressure in 85 ICU patients at the time of
admission. Compared with control individuals, 64%
of patients had diaphragm weakness (defined as less
then fifth percentile of Ptr,stim in the control popu-
lation). Patients with diaphragm dysfunction were
more likely to be older, septic or to have higher
&
illness severity. Another study by Sklar et al. [13 ]
examined diaphragm muscle mass at baseline based
on Tdi on ultrasound in mechanically ventilated
patients. Low baseline Tdi was associated with com-
plications of mechanical ventilation, prolonged
weaning and increased risk of death during hospital
admission. Taken together, these studies reinforce
the clinical relevance of diaphragm dysfunction to
patient outcomes in the ICU.
MONITORING DIAPHRAGM ACTIVITY AND
FUNCTION
There are numerous ways to assess and monitor
diaphragm activity and function in the critical care
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 Diaphragm function in acute respiratory failure Reardon et al.

Table 1. Monitoring tools to evaluate diaphragm activity and function

Suggested target for dia-

Parameter Description Advantages Disadvantages phragm protection

Ultrasound Thickening fraction of Noninvasive and widely Imprecise measurements TFdi 15–30%31
TFdi the diaphragm available. Can be used to
measure activity and
function (e.g. maximal TFdi).
EXdi Diaphragmatic Noninvasive and widely Technical limitations. Must N/A (cannot be used to
excursion available. be done during monitor respiratory effort
unassisted breaths only during mechanical
ventilation)
Electromyography Electrical activity of the Continuous data output. Requires specialized Patient-specific depending
EAdi diaphragm Minimally invasive. Strong equipment. on the neuromuscular
correlation with PL and Pdi No reference ranges efficiency index. Can
available. target values based on
Pocc, DPdi or DPes
Respiratory system Oesophageal pressure Continuous data output. Requires specialized DPes 3–10 cmH2O31
pressures Minimally invasive. Allows equipment for placement
Pes for estimation of PL to and monitoring.
facilitate lung protection.
Pocc The negative inspiratory Readily available on most Estimation only. Not as DPocc 8–15 cmH2O
pressure generated ventilators. Noninvasive. accurate as direct (Predicted Pmus
during a tidal Can estimate Pmus and PL measurement. 5–10 cmH2O)
inspiratory effort with without an oesophageal Predicted DPL,
the airway occluded manometer. dyn < 15–20 cmH2O2

P0.1 The negative pressure
generated during the
first 100 ms of an
inspiratory effort
against an occluded
airway
Pdi Transdiaphragmatic
pressure, or gradient
between gastric and
oesophageal
pressure
Readily available on most
ventilators. Noninvasive.
High P0.1 with a
concomitantly low Pocc is
suggestive of diaphragm
weakness.
Continuous data. Minimally
invasive. Directly measures
diaphragm activity and
function.
Relatively unaffected by 1.0–3.5 cmH2O37
diaphragm weakness.
Monitors respiratory
drive and is correlated to
respiratory effort.
Requires specialized DPdi 5–10 cmH2O31
equipment, that is
manometer with both
gastric and oesophageal
balloons

EAdi, electrical activity of the diaphragm; EXdi, caudal excursion of the diaphragm; P0.1, airway occlusion pressure during first 100 ms; Pdi, transdiaphragmatic
pressure; Pes, oesophageal pressure; Pmus, respiratory muscle pressure; Pocc, expiratory occlusion pressure; TFdi, thickening fraction of the diaphragm.

setting (Table 1). Although measures of activity Diaphragm ultrasound

assess the presence and magnitude of spontaneous
efforts, functional metrics assess muscle strength
and performance. The latter measurements necessi-
tate maximum volitional efforts (e.g. maximal inspi-
ratory pressure) or a standardized muscle stimulus
(e.g. magnetic twitch stimulation) to differentiate
weakness from incomplete muscle activation (i.e.
due to sedation or delirium). There are a few differ-
ent ways to encourage maximal contraction. The
gold standard is supramaximal magnetic twitch
stimulation of the phrenic nerve [12]. Alternatively,
if the patient is able to perform a sniff nasal inspira-
tory pressure, this has been shown to be a close
approximation of maximal diaphragm contraction
[28]. Finally, a Marini manoeuvre, or 20-s airway
occlusion with a one-way valve, can be used to
generate approximately maximum efforts [29].
At the zone of apposition, end-expiratory Tdi and
TFdi during contraction can be measured (Fig. 3)
[30]. Tdi as a single static measurement is useful to
assess diaphragm muscle mass at baseline and over
time [6]. Measurement of TFdi provides a noninva-
sive surrogate measure of inspiratory effort that
allows the bedside clinician to gauge over versus
under-assistance with the ventilator. Observa-
tional data suggest that the optimal range of effort
for TFdi is probably 15– 30% [31]. Furthermore,
maximal TFdi can offer insight into diaphragm
function with a cutoff of less than 20% defining
weakness [32]. We generally suggest that maximal
TFdi can be measured immediately after releasing
the airway occlusion following a Marini manoeu-
vre to generate large volitional inspiratory efforts;
during the airway occlusion, the diaphragm is

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Cardiopulmonary monitoring

FIGURE 3. Diaphragm ultrasound image captured at the zone of apposition with a linear transducer. The B-mode image is
above for reference. M-mode is shown below, which captures the diaphragm through tidal breathing.

unable to shorten and hence maximal TFdi will
appear artificially low.
The diaphragm can also be visualized subcos-
tally with ultrasound, and the excursion, EXdi, mea-
sured. However, given positive pressure ventilation
will also generate diaphragm excursion, this mea-
surement must be obtained during unassisted
breaths only. Notably, in the presence of severe
diaphragm weakness, accessory muscle activation
may elevate the diaphragm during inspiration from
accessory muscle use, giving rise to the sonographic
correlate of abdominal paradox. In this context,
cross-sectional imaging of diaphragm thickness
may reveal a decrease in Tdi during inspiration
(i.e. TFdi<0%).
adjusted ventilatory assist, NAVA, is a mode of
ventilation that uses EAdi and delivers assistance
from the ventilator in proportion to the intensity
of the signal [33]. The peak EAdi signal during a
normal breath and maximal breath can be
recorded, and the EAdi and transdiaphragmatic
and transpulmonary pressures demonstrate good
correlation. However, the neuromuscular effi-
ciency index, or the amount of pressure generated
per unit of EAdi, is variable between patients and
within patients over time [34]. Thus, there is a
paucity of evidence to define reference values for
weakness or for optimal diaphragm activity during
mechanical ventilation using EAdi. Normalizing
EAdi based on airway occlusion pressure offers a
promising approach [35].

Diaphragm electromyography
Electrical activity of the diaphragm, EAdi, can be
monitored through surface or needle EMG, but
the most useful method in the ICU settings is with
oesophageal recordings of the crural diaphragm
EMG via a specialized nasogastric tube. Neurally
Respiratory system pressures
There are many different ways to assess activity and
function of the diaphragm using respiratory system
pressures. The precision of the measurement will
depend on the equipment available and whether an

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 Diaphragm function in acute respiratory failure Reardon et al.
indicator of activity or function is desired. As a
foundation, all ventilated patients can have an air-
way occlusion pressure measured. Laveneziana et al.
[28] demonstrated at least 80 cmH2O excludes weak-
ness during maximal inspiratory effort or sniff,
while Demoule et al. [12] showed that a twitch
airway pressure less than 11 cmH2O is diagnostic
for diaphragm weakness.
Alternatively, for monitoring diaphragm activ-
ity, P0.1, or the pressure generated during the first
100 ms of an inspiratory effort against an occluded
airway, offers a reliable measurement for respiratory
&
drive [36,37 ]. Threshold pressures of 1.0 cmH2O or
less and more than 3.5 cmH2O have been suggested
to detect insufficient or excessive respiratory effort,
respectively [38]. P0.1 is relatively unaffected by
diaphragm function; hence, a high P0.1 with a con-
comitantly low respiratory effort (i.e. estimated by
Pocc) is suggestive of diaphragm weakness.
The Pocc is a similar airway occlusion manoeuvre
that enables a direct estimate of pressure generated
by respiratory muscle. It is defined as the negative
inspiratory pressure generated during a tidal inspi-
ratory effort with the airway occluded: respiratory
muscle effort (Pmus) is approximately two-third of
Pocc measurement. To avoid artificially increasing
patient respiratory effort, Pocc should be measured
during a randomly applied airway occlusion at infre-
quent intervals. It also allows for a noninvasive
estimation of transpulmonary pressure [39]. There-
fore, Pocc can be used to allow for spontaneous
breathing and diaphragm work, while also avoiding
potentially injurious transpulmonary pressures. A
target dynamic transpulmonary driving pressure
of less than 15 cmH2O is suggested for lung protec-
tion [40].
As mentioned above, an oesophageal catheter
allows for an estimation of pleural pressure (Fig. 1).
The pressure-time integral of the negative oesopha-
geal pressure generated during spontaneous respira-
tion, the pressure-time product (PTP) of Pes, is
indicative of respiratory effort [41]. PTPdi measured
with Pdi can measure diaphragm work more specifi-
cally. To assess muscle function, Pes and Pdi can also
be measured during a magnetic twitch, sniffing or a
Marini manoeuvre, which all have different cut-offs
for defining weakness (e.g. twitch Pdi < 18 cmH2O,
and sniff or Marini 80 cmH2O excluding weakness)
[24,28,42].
THE LUNG AND DIAPHRAGM PROTECTION
PARADOX
Although lung protection is an immediate priority
in patients with acute hypoxemic respiratory failure,
the negative effects associated with VIDD also
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necessitate that attention be paid to diaphragm-
protective goals. However, these objectives often
conflict as vigorous negative inspiratory force can
cause damaging increases in transpulmonary pres-
sures and tidal volumes beyond well tolerated limits,
leading to patient self-inflicted lung injury [43–45].
Yoshida et al. [46] demonstrated that the safety of
spontaneous breathing may be related to the degree
of acute lung injury, with benefit occurring among
those on the milder end of the spectrum, and more
risk extending to patients who have more severe
underlying acute respiratory failure. Certainly, prior
studies have shown that NMB infusions to eliminate
spontaneous breathing in patients with moderate to
severe ARDS can decrease inflammation and
improve patient outcome [47,48]. Therefore, there
are competing priorities between preserving spon-
taneous breathing to prevent VIDD, while maintain-
ing spontaneous breathing at safe levels to prevent
lung injury. The best method to achieve balance
between the two is not yet known.
THE POTENTIAL ROLE OF PHRENIC NERVE
STIMULATION FOR LUNG AND
DIAPHRAGM PROTECTION
Phrenic nerve stimulation (PNS) may be uniquely
situated to achieve both lung and diaphragm-pro-
tective ventilation. Previous animal studies have
demonstrated that PNS during mechanical ventila-
tion can mitigate VIDD [49–51]. A study by Rey-
nolds et al. [52] examined the use of temporary
transvenous PNS, the LIVE catheter from Lungpacer
Medical Inc (Vancouver, British Columbia, Canada)
in a porcine model. In a three-arm randomized trial
in a porcine model, they compared Tdi and myofiber
cross-length in mechanically ventilated animals
without pacing to a group of mechanically venti-
lated animals who underwent pacing. The third arm
was a control group that was neither ventilated nor
paced. They found that although both Tdi and sar-
comere length were significantly reduced in the
ventilated-not paced group after 60 h of ventilation,
the ventilated-paced group had similar measure-
ments to the control group.
In humans, the use of temporary PNS to prevent
VIDD is less well studied, but the existing literature
is promising. Ahn et al. studied unilateral PNS dur-
ing cardiac surgery and found that muscle trains
every thirty minutes lead to a 30% increase in dia-
phragm fibre contractile force when compared with
the contralateral side, which was used as a control
[53]. PNS titrated to maintain diaphragm activity
within lung protective targets may prove to be an
optimal strategy in patients with acute respiratory
failure.
www.co-criticalcare.com 287
Cardiopulmonary monitoring
OTHER NOVEL STRATEGIES FOR LUNG
AND DIAPHRAGM PROTECTIVE
VENTILATION
Partial neuromuscular blockade
Partial NMB has been proposed to manage high
respiratory drive in patients with ARDS in whom
deep sedation is inadequate. The absence of complete
NMB would allow for some diaphragm activity
while simultaneously preserving lung protective
goals. A study of 10 patients with acute lung injury
and tidal volumes greater than 8 ml/kg under deep
sedation demonstrated that partial NMB with
rocuronium infusion allowed for a decrease in tidal
volumes (9.3 to 5.6 ml/kg, P < 0.0001) and transpul-
monary pressure (26.7–10.7 cmH2O, P < 0.0001),
while still maintaining EAdi [54].
Extracorporeal carbon dioxide removal
Hypercapnea is a potent stimulus for respiratory
drive. ECCO2R has been proposed as another strat-
egy to decrease spontaneous respiratory drive by
decreasing the ventilatory demands [55]. Mauri
et al. [56] demonstrated reduced P0.1 pressures with
higher levels of ECCO2R in patients with ARDS
when measured during pressure support ventilation
and NAVA. Transpulmonary pressure also decreased
in a linear fashion relative to the level of ECCO2R
support delivered. Another study demonstrated
decreased EAdi with increasing sweep gas flow dur-
ing extracorporeal membrane oxygenation [57]. In
patients in whom clinicians deem spontaneous
breathing to be unsafe, this may be one strategy
to implement prior to NMB to allow for lung and
diaphragm protection.
CONCLUSION
Diaphragm dysfunction is common in the ICU and
represents a hidden cost of lung-protective ventila-
tion. If overlooked, the downstream consequences
such as difficult weaning, increased duration of ICU
stay, and mortality can cause great difficulty. Moni-
toring diaphragm activity and function can inform
bedside clinical decision-making and novel techni-
ques such as phrenic nerve stimulation may enable
delivery of lung and diaphragm-protective ventila-
tion in patients with acute respiratory failure.
Acknowledgements
P.M.R. and E.C.G. proposed and structured the article
and wrote the first draft. All authors participated in
writing, editing, revising its content and agree to be
responsible for its contents.
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Financial support and sponsorship
None.
Conflicts of interest
E.C.G. is supported by an Early Career Investigator
award from the Canadian Institutes of Health Research.
He reports receiving personal fees from Getinge, and
research support in the form of equipment from Getinge
and Timpel.
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