REVIEW

URRENT
C
OPINION

Ventilator-induced diaphragmatic dysfunction: what

have we learned?
Basil J. Petrof a and Sabah N. Hussain a,b

Purpose of review
The purpose of the review is to summarize and discuss recent research regarding the role of mechanical
ventilation in producing weakness and atrophy of the diaphragm in critically ill patients, an entity termed
ventilator-induced diaphragmatic dysfunction (VIDD).
Recent findings
Severe weakness of the diaphragm is frequent in mechanically ventilated patients, in whom it contributes to
poor outcomes including increased mortality. Significant progress has been made in identifying the
molecular mechanisms responsible for VIDD in animal models, and there is accumulating evidence for
occurrence of the same cellular processes in the diaphragms of human patients undergoing prolonged
mechanical ventilation.
Summary
Recent research is pointing the way to novel pharmacologic therapies as well as nonpharmacologic
methods for preventing VIDD. The next major challenge in the field will be to move these findings from the
bench to the bedside in critically ill patients.
Keywords
critical illness myopathy, diaphragm disuse, ICU-acquired weakness, mechanical ventilation, weaning failure

INTRODUCTION
Diaphragmatic weakness is highly prevalent in the
ICU patient population [13]. This has been postulated to be a major cause of failure to successfully
wean patients from mechanical ventilation. In
addition, two independent studies recently reported
substantially increased mortality in ICU patients
with reduced diaphragmatic strength [4,5], giving
added impetus to the importance of addressing this
frequent problem. Limb muscle weakness is also
common in the ICU and associated with long-term
disability in those individuals who manage to survive critical illness [6]. Although multiple factors
undoubtedly contribute to the development of diaphragm and limb muscle weakness in the ICU, a
fundamental question which has arisen in recent
years is whether mechanical ventilation itself plays
an important role in this process. The purpose of this
review is to summarize and provide perspective on
recently published research in this area.

DOES MECHANICAL VENTILATION IMPAIR

DIAPHRAGMATIC FUNCTION?
Ventilator-induced diaphragmatic dysfunction
(VIDD) as originally defined [7] refers to a loss of

diaphragmatic force-generating capacity specifically

related to the use of mechanical ventilation. In
other words, the weakness cannot be readily
explained by other factors such as sepsis, drugs,
metabolic derangements, and so forth. Unfortunately, in critically ill patients undergoing longterm mechanical ventilation, many of these confounding factors are almost invariably present.
Therefore, the most direct proof for the existence
of VIDD is derived from studies performed in animal
models. The evidence for VIDD in humans is by
necessity more correlative and circumstantial in
nature, but nonetheless compelling and consistent
with the animal data.

Meakins Christie Laboratories, and Translational Research in Respiratory Diseases Program, McGill University Health Centre and Research
Institute and bDepartment of Critical Care, McGill University Health
Centre, Montreal, Quebec, Canada
Correspondence to Basil J. Petrof, MD, Meakins-Christie Laboratories,
1001 Decarie Boulevard, Montreal, QC H4A 3J1, Canada. Tel: +514
934 1934; ext 76172; fax: +514 398 7483;
e-mail: basil.petrof@mcgill.ca
Curr Opin Crit Care 2016, 22:6772
DOI:10.1097/MCC.0000000000000272

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Respiratory system

KEY POINTS

preparations, together with impaired calcium sensitivity that was partially reversed with a troponin
protein activator [13 ,14 ]. The above elegant
studies indicate that the diaphragm is weak in many
ICU patients who are undergoing mechanical ventilation, and also suggest that magnetic stimulation of
the phrenic nerves likely provides a reasonably good
index of what is occurring at the diaphragm muscle
level. However, the specific etiologic role of mechanical ventilation in producing diaphragmatic
weakness cannot be clearly determined from these
investigations because of the confounding effects of
critical illness.
In comparison to other ICU patients, brain-dead
organ donors are generally free of many (but certainly not all) confounding factors, such as multiple
organ failure and sepsis. Therefore, a few groups
have studied diaphragm biopsies from such patients
after delivering controlled mechanical ventilation
(i.e., without spontaneous breathing efforts) for
variable periods before organ procurement. These
studies have been remarkably concordant with
animal models of VIDD in demonstrating ultrastructural injury and atrophy of diaphragmatic
fibers [11,15], which are significantly correlated
with mechanical ventilation duration [11]. Other
features of VIDD animal models reproduced in this
human model include increased oxidative stress,
activation of major proteolytic pathways, and
mitochondrial dysfunction [1519]. An important
internal control in these studies is the demonstration that nonrespiratory muscles showed little
alteration in these parameters relative to the major
changes observed in the diaphragm. With respect to
muscle contractility, one study found no changes in
the force generated by permeabilized diaphragm
fibers from brain-dead organ donor patients after
an average mechanical ventilation period of 26 h
[20]. However, another recent study with a longer
(49 h) average period of mechanical ventilation
reported decreased active as well as passive force
production by isolated diaphragm myofibrils [21].
&&

 Diaphragmatic weakness is common in mechanically

ventilated patients and associated with adverse
outcomes.
 Controlled mechanical ventilation is a cause of
diaphragmatic atrophy and weakness in animal
models, and current data suggest a similar
phenomenon in humans
 Mitochondrial dysfunction appears to play a central
role in VIDD.
 Therapeutic avenues under investigation include various
methods to augment diaphragmatic activity during
mechanical ventilation, drugs targeting mitochondrial
dysfunction, modulators of muscle proteolysis, and
myofilament calcium sensitizers.

In animal models, multiple studies have shown

that mechanical ventilation leads to a fairly stereotypical series of events in the diaphragm which are
characteristic of VIDD. This includes early signs of
oxidative stress and decreased force-generating
capacity that cannot initially be explained by fiber
atrophy, which is then followed by the development
of diaphragm atrophy leading to even greater
muscle weakness [8]. The onset of force loss after
initiating mechanical ventilation is rapid (612 h in
rodents) with a similarly swift recovery after resumption of normal spontaneous breathing in rats [9,10].
The magnitude of mechanical ventilation-induced
alterations in the diaphragm generally correlates
well with the duration of mechanical ventilation,
whereas nonrespiratory muscles remain largely
unaffected within the first 2448 h of mechanical
ventilation. In previously healthy animals without
baseline diaphragmatic dysfunction, this pattern is
quite robustly reproduced across different species.
In some human studies [3,11] but not others
[4,5], the duration of mechanical ventilation has
been significantly correlated with the severity of
diaphragmatic force loss over time. Ultrasound
imaging also showed a progressive loss of diaphragm
thickness (averaging 6% per day) during mechanical
ventilation [12]. The lack of correlation with mechanical ventilation duration in certain studies may
be explained by the heterogeneous nature of the
underlying critical illness and particularly by the
presence of sepsis, which appears to cause a very
early onset of diaphragmatic weakness irrespective
of mechanical ventilation [4]. In other investigations of ICU patients receiving mechanical ventilation, significantly impaired contractile function
was documented in permeabilized diaphragm fiber
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&&

PATHOPHYSIOLOGIC MECHANISMS
Various manifestations of VIDD have been closely
linked to oxidative stress in the diaphragm, and
when antioxidants are administered to animals at
the onset of mechanical ventilation the development of VIDD is largely prevented [22,23]. Transcription factors of the FOXO (forkhead box O) and
signal transducer and activator of transcription
(STAT) families are upregulated and act as important
mediators of VIDD [1618,24]. Two recent studies
reported that pharmacological blockade of STAT3
phosphorylation in the diaphragm via continuous
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Ventilator-induced diaphragmatic dysfunction Petrof and Hussain

intravenous infusion of Janus kinase (JAK) inhibitors during 18 h of mechanical ventilation in rats
prevented signs of mitochondrial dysfunction, oxidative stress, force loss, and proteolysis [25 ,26 ]. A
particularly intriguing finding is that phosphorylated STAT3 appears to translocate into the mitochondria during mechanical ventilation [25 ],
indicating a possible direct effect in promoting
mitochondrial dysfunction [26 ,27]. Other signaling molecules such as nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kB) [28]
and different proteolysis pathways (e.g., calpains,
caspases, and ubiquitin-proteasome) contribute to
VIDD to variable degrees and are activated by
oxidative stress [24,29].
Importantly, data from both animal [19,30,31]
and human studies [18,19] strongly suggest that the
predominant source of oxidative stress in the diaphragm during mechanical ventilation is excess
mitochondrial reactive oxygen species (ROS) production. What remains much less clear, however, is
why this occurs. In other words, what specific mechanisms triggered by mechanical ventilation are
responsible for the rapid development of mitochondria-derived oxidative stress? In an excellent review,
Powers et al. [32] outlined a number of mechanisms
which could account for increased mitochondrial
ROS production by inactive skeletal muscles, including the potential toxic effects of fatty acids on
mitochondria [33] and disruption of the normal
mitochondrial fission/fusion balance [34].
There is recent evidence supporting several of
these mechanisms in VIDD. Picard et al. [19]
reported mitochondrial DNA damage and increased
intramyocellular lipid accumulation in the diaphragms of brain-dead organ donor patients undergoing mechanical ventilation, and additionally
demonstrated that induction of hyperlipidemia
during mechanical ventilation in mice worsened
oxidative stress in the diaphragm. An analogous
situation has been described in cancer cachexia,
where exaggerated free-fatty acid release from adipose tissue leads to pathological fat uptake by
skeletal muscle and associated proteolysis [35,36].
Another recent study demonstrated a rapid onset of
mitochondrial fission-fragmentation and activation
of the profission dynamin-related protein-1 in the
diaphragm within 6 h of initiating mechanical
ventilation in mice [37]. Interestingly, mitochondrial fragmentation preferentially involved the
more abundant intermyofibrillar mitochondria that
are most closely linked to contractile function [37],
suggesting at least one possible explanation for the
very rapid loss of diaphragmatic force observed with
VIDD. A study in rats reported reduced blood flow
associated with decreased microvascular pO2 in the
&&

&&

&&

&&

diaphragm after 6 h of mechanical ventilation [38],

which could potentially serve as an additional
stimulus for mitochondrial fission [39].
The presence of mitochondrial damage and
increased mitochondrial fission may also help to
explain why autophagy is upregulated in the human
diaphragm during mechanical ventilation [17].
Autophagy is a lysosomally mediated proteolytic
process which plays a critical role in eliminating
dysfunctional cellular constituents. This includes
removal of damaged or fragmented mitochondria
in what is termed mitophagy [34]. Pharmacological
stimulation of autophagy was recently shown to be
associated with prevention of diaphragmatic
weakness during the early phase of VIDD [40 ].
Therefore, autophagy appears to be a beneficial
adaptive response which initially helps to mitigate
force loss in the diaphragm during mechanical
ventilation, possibly through removal of damaged
mitochondria responsible for excessive ROS
generation. Whether autophagy activation is
beneficial or harmful in the later stages of VIDD
when diaphragm muscle atrophy is a prominent
feature has not been determined. However, a recent
study of ICU patients randomized to early versus
late parenteral nutrition found that the latter
group showed evidence for increased autophagy
and this was associated with greater muscle strength
[41].
&

INTERACTING FACTORS
Sepsis is one of the most common diagnoses in ICU
patients undergoing mechanical ventilation, and is
an important cause of diaphragmatic weakness in its
own right [4,5]. Recent evidence suggests that the
adverse effects of sepsis and mechanical ventilation
on diaphragmatic function may potentiate one
another. In comparing muscle volumes (by computed tomography scan) of mechanically ventilated
patients with and without sepsis, Jung et al. [42 ]
observed greater diaphragm atrophy in the septic
group while no differences were found in two nonrespiratory muscles from the same patients. In
addition, Maes et al. [43] studied the effects of
mechanical ventilation on the diaphragm in rats
with prior lipopolysaccharide-induced sepsis (12 h
earlier), and showed that several aspects of VIDD
were exacerbated by coexistent sepsis. Interestingly,
mice deficient in Toll-like receptor 4 (the lipopolysaccharide receptor) had a lower degree of IL-6
induction in the diaphragm during mechanical
ventilation even in the absence of sepsis [44],
suggesting that Toll-like receptor 4 activation could
be a shared pathway for both sepsis-induced
diaphragmatic dysfunction and VIDD. Indeed,

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69

Respiratory system

Mitochondria-targeted
antioxidants

Potential aggravating
factors

Sepsis
Fatty acid oversupply
Aging
Drugs

JAK-STAT3 inhibitors

Mechanical
ventilation

Diaphragm muscle
activation
(assist modes of MV,

Mitochondrial
reactive oxygen
species (ROS)
generation

training, phrenic
stimulation)

Mitochondrial
fission

Lysosomal degradation of
dysfunctional mitochondria
Apoptosis

Energy deficiency

Nonlysosomal proteolysis
(proteasome, calpains,
caspases)

Stimulators of
autophagy and mitophagy

Inhibitors of
proteolysis pathways

FIGURE 1. Outline of key cellular mechanisms implicated in VIDD. Mitochondrial dysfunction plays a central role in VIDD,
and several potential therapies for VIDD are aimed at diminishing mitochondrial reactive oxygen species production and/or
mitigating its downstream consequences. See text for further explanations. VIDD, ventilator-induced diaphragmatic dysfunction.

sepsis triggers many of the same pathophysiologic

mechanisms in skeletal muscle which underlie
VIDD [45].
Drugs are also likely candidates for interaction
with VIDD, with the most frequently studied agents
being neuromuscular blockers and corticosteroids.
However, their impact with respect to VIDD is seemingly quite complex and divergent findings have
been reported depending upon variations in dosage
and other experimental conditions including mode
of mechanical ventilation [4648].
Hypercapnia, on the other hand, is more clearly
protective against VIDD. In this regard, piglets
ventilated with increased dead space to achieve moderate hypercapnic acidosis (pCO2 5570 mmHg)
showed preserved diaphragmatic force production
after 72 h of mechanical ventilation [49]. A similar
level of hypercapnia induced by adding inspired CO2
also attenuated several aspects of VIDD in rats [50].
The cellular mechanisms underlying the improvements associated with hypercapnia are yet to be
elucidated but likely involve anti-inflammatory
and/or antioxidant effects. VIDD does not appear
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to be correlated with ventilator-induced lung injury

[5153].

CONCLUSION
The development of VIDD is closely related to the
extent to which diaphragmatic effort is abolished by
mechanical ventilation. Hence, the use of mechanical ventilation modes which entail partial diaphragm muscle activation such as assist-control
[54], adaptive servo-ventilation [55], or the use of
short periods of intermittent spontaneous breathing
[56], can substantially prevent VIDD. On the other
hand, use of negative pressure ventilation or
positive end-expiratory pressure does not appear
to either mitigate or hasten the development of
VIDD [51,57]. However, it is important to emphasize
that all of these studies have been performed in
healthy animals and hence normal diaphragms
prior to the initiation of mechanical ventilation.
Given recent evidence that a majority of patients
may already have severe diaphragmatic weakness on
admission to the ICU [4], there is a need to repeat
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Ventilator-induced diaphragmatic dysfunction Petrof and Hussain

these experiments in models which better reflect the

comorbidities found in ICU patients.
Recent investigations have begun to explore
phrenic nerve stimulation as a means of increasing
diaphragmatic activity during mechanical ventilation. Transvenous unilateral phrenic nerve stimulation has been shown to be safe in the treatment of
central sleep apnea [58]. Another option is intermittent magnetic stimulation of the phrenic nerves,
which is painless and noninvasive [59]. In rats,
bilateral phrenic nerve stimulation preserved diaphragmatic force production after 18 h of mechanical ventilation [60]. A pilot study of unilateral
phrenic nerve stimulation in sheep showed reduced
atrophy and muscle fiber injury in the stimulated
hemidiaphragm after 72 h of mechanical ventilation [61]. Martin et al. [62 ] performed unilateral
phrenic nerve stimulation in patients undergoing
mechanical ventilation during cardiothoracic
surgery and reported increased mitochondrial (State
III) respiration rates in the stimulated hemidiaphragm. Further work is needed to determine whether
phrenic nerve stimulation is effective and feasible as
a strategy for preventing VIDD in ICU patients.
Another promising approach may be to augment the diaphragms intrinsic ability to resist VIDD
before initiating mechanical ventilation. Whole
body endurance exercise (1 h per day for 10 days)
offered significant protection against VIDD in rats,
possibly because of an upregulation of antioxidant
enzymes and heat shock proteins in the diaphragm
[63]. In human studies to date, there is no information available regarding the baseline level of
diaphragmatic strength or endurance which was
present prior to the initiation of mechanical ventilation. It may be possible to increase the baseline
diaphragmatic reserve of certain patients who are
at risk for VIDD, such as those anticipated to require
more than 24 h of mechanical ventilation following
surgery. Preoperative inspiratory muscle training
has been reported to reduce postoperative pulmonary complications [64], and its potential to prevent
or delay the onset of VIDD deserves further investigation.
Finally, we are now beginning to gain a better
understanding of the pathophysiologic mechanisms driving VIDD at the cellular and molecular
levels (see Fig. 1). These insights are pointing the
way to new therapeutic approaches such as the
use of mitochondria-targeted antioxidants [31],
JAK-STAT inhibitors [25 ,26 ], different modulators of proteolysis pathways including autophagy [40 ,41] and myofilament calcium sensitizers [13 ]. Future work should be directed at translating these findings to the bedside in critically
ill patients.
&

&&

&

&&

&&

Acknowledgements
None.
Financial support and sponsorship
This work was supported by the Canadian Institutes of
Health Research (CIHR), Fonds de recherche du Quebec
Sante (FRQS), the McGill University Health CentreResearch Institute.
Conflicts of interest
There are no conflicts of interest. B.P. is on the speakers
bureau for Genzyme, Inc.

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Volume 22  Number 1  February 2016

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