REVIEW

CURRENT
OPINION Diaphragm protection: what should we target?
Tom Schepens a and Jose Dianti b,c

Purpose of review
Diaphragm weakness can impact survival and increases comorbidities in ventilated patients. Mechanical
ventilation is linked to diaphragm dysfunction through several mechanisms of injury, referred to as
myotrauma. By monitoring diaphragm activity and titrating ventilator settings, the critical care clinician can
have a direct impact on diaphragm injury.
Recent findings
Both the absence of diaphragm activity and excessive inspiratory effort can result in diaphragm muscle
weakness, and recent evidence demonstrates that a moderate level of diaphragm activity during mechanical
ventilation improves ICU outcome. This supports the hypothesis that by avoiding ventilator overassistance
and underassistance, the clinician can implement a diaphragm-protective ventilation strategy. Furthermore,
eccentric diaphragm contractions and end-expiratory shortening could impact diaphragm strength as well.
This review describes these potential targets for diaphragm protective ventilation.
Summary
A ventilator strategy that results in appropriate levels of diaphragm activity has the potential to be
diaphragm-protective and improve clinical outcome. Monitoring respiratory effort during mechanical
ventilation is becoming increasingly important.
Keywords
diaphragm, mechanical ventilation, myotrauma, weakness

INTRODUCTION diaphragm pacing to prevent atrophy in a setting

The diaphragm is vulnerable to injury during
mechanical ventilation, and diaphragm weakness
is common among ventilated patients [1]. It impacts
patients’ outcome by prolonging ventilator depen-
dence and predisposes to nosocomial complications
&
and death [2 ]. Several factors that are often simul-
taneously present in critically ill patients are at the
basis of this problem [3]. Mechanical ventilation by
itself is related to diaphragm weakness through
multiple mechanisms, which are referred to as
&&
diaphragmatic myotrauma [4 ]. These include
both excessive and insufficient diaphragm activity,
eccentric diaphragm contractions, and excessive
end-expiratory shortening. Interestingly, these
mechanisms could potentially be targeted by spe-
cific ventilation strategies and fine-tuning of inspi-
ratory effort, mitigating the occurrence or severity of
diaphragmatic myotrauma. Further research will
need to evaluate how both diaphragm and lung-
protective targets can be merged into a single venti-
&
lation strategy [5 ]. This review summarizes the
evidence that created the basis for determining
diaphragm protective targets, with a focus on
determining the levels of appropriate inspiratory
effort. We furthermore evaluate the potential of
where spontaneous breathing activity is not feasible.
CRITICAL ILLNESS ASSOCIATED
DIAPHRAGM WEAKNESS
Diaphragm weakness in ventilated patients in the
ICU has multiple causes. Several factors that are
related to critical illness and ICU stay are often
simultaneously present and can result in critical
illness associated with diaphragm weakness. Among
these, sepsis and mechanical ventilation have the
largest impact. The precise mechanisms by which
these entities are linked to diaphragm dysfunction
are detailed in a recent review [3]. Of specific interest
a
Department of Critical Care Medicine, Antwerp University Hospital,
Antwerp, Belgium, bInterdepartmental Division of Critical Care Medicine,
University of Toronto, Toronto, Canada and cDepartment of Medicine,
Adult Intensive Care Unit, Hospital Italiano de Buenos Aires, Buenos
Aires, Argentina
Correspondence to Tom Schepens, Department of Critical Care Medi-
cine, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem,
Belgium. Tel: +32 3 821 36 35; e-mail: tom.schepens@uza.be
Curr Opin Crit Care 2020, 26:35–40
DOI:10.1097/MCC.0000000000000683

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Respiratory system

the diaphragm, more than the effects of mechanical

KEY POINTS
 Several mechanisms link mechanical ventilation with
diaphragm weakness, including excessive and
insufficient respiratory support, eccentric diaphragm
contractions, and end-expiratory muscle shortening.
 A ventilation strategy resulting in appropriate levels of
diaphragm activity has the potential to be diaphragm-
protective and improve clinical outcome.
 Monitoring diaphragm activity and patient–ventilator
dyssynchrony during mechanical ventilation have
become more important for critical care clinicians.
for this manuscript are the mechanisms of myo-
trauma, as these can be addressed by specific venti-
lation targets. These different pathways linking
mechanical ventilation to diaphragm myotrauma
&&
were recently outlined [4 ], and Fig. 1 summarizes
these mechanisms along with the different pro-
posed targets for diaphragm protection.
AVOIDING INACTIVITY
The mechanism of diaphragm myotrauma that has
arguably been best documented is the effect of
excessive respiratory support. The unloading of
ventilation itself, results in disuse atrophy and weak-
ness. This is called overassistance myotrauma and
affects about 50% of patients receiving mechanical
ventilation [6]. Consequently, maintaining dia-
phragm activity during mechanical ventilation
has been a subject of interest in several studies as
this has the potential to mitigate this type of myo-
trauma. Several studies have shown that muscle
proteolysis and weakness can be attenuated by pro-
viding assisted mechanical ventilation instead of
controlled mechanical ventilation [7,8]. In an ani-
mal model, diaphragm atrophy and weakness could
be prevented with adaptive support ventilation [9]
and intermittent spontaneous breathing was better
than controlled ventilation, but worse than contin-
uous spontaneous ventilation, in preserving dia-
phragm force in mechanically ventilated rats [10].
One of the first articles to support this hypothe-
&
sis in patients in the ICU was by Goligher et al. [2 ].
In this study, the authors measured the thickening
fraction as a parameter of diaphragm activity and
demonstrated that the level of activity was directly
related to the percentage of change in diaphragm
thickness from baseline. Patients that had a thick-
ening fraction that corresponded to diaphragm
activity of healthy patients (thickening fraction
15–30%) had the fastest liberation from mechanical

Inappropriately
titrated mechanical
ventilation

Eccentric Insu cient Excessive End-expiratory

contractions unloading unloading muscle shortening

Load-induced
Atrophy
injury

Avoid dyssynchrony Preserve low-normal amount of diaphragm activity PEEP titration

Potential targets for

diaphragm-protective
ventilation

FIGURE 1. Summary of potential mechanisms linking mechanical ventilation to diaphragm dysfunction and proposed targets
for a diaphragm protective mechanical ventilation strategy. Dotted lines indicate limited experimental evidence. PEEP, Positive
end-expiratory pressure.

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ventilation and preserved their diaphragm thickness
during the course of mechanical ventilation.
Neuromuscular blockers appear to increase
the effect of overassistance myotrauma apart from
their effect of inducing inactivity [11] and should
probably be avoided from a diaphragm-protective
perspective.
Duty cycles and pacing
The diaphragm is a highly active muscle with a high
duty cycle compared with other muscles, contracting
about 25–30% of the time [12]. This high level of
activity in a physiological setting could partly explain
why the diaphragm is so rapidly vulnerable to injury,
already showing signs of mitochondrial dysfunction
6–12 h after the onset of mechanical ventilation.
It is unclear how much activity is needed to
preserve muscle function. Diaphragm activity can
be maintained during mechanical ventilation by
either preserving respiratory effort by the patient,
or by pacing the phrenic nerve at the cervical level or
in the diaphragm. Several studies have evaluated the
effect of diaphragm pacing during mechanical ven-
tilation on diaphragm function, most of them in
animal models (Table 1). Interestingly, in these
studies, the duty cycles (i.e., the time the diaphragm
spent in contraction versus in relaxation) are fre-
quently much shorter than those observed in a
physiological setting, ranging between 0.9 and
15% (versus the 25–30% seen in healthy patients).
Pacing can either be synchronous [18] or given
at random moments during the respiratory cycle
[13]. Of importance is that diaphragm activity was
always confirmed either by electromyography or by
visual inspection of the diaphragm. In human stud-
ies, brief periods (duty cycle of 1.7%) of confirmed
activity during mechanical ventilation seem to be
sufficient to protect the muscle against mitochon-
drial dysfunction [13]. Similarly, Ahn et al. [14]
showed that 1 min of 0.5 Hz stimulation every
30 min (duty cycle of 1.7%) during cardiothoracic
Table 1. Duty cycles of diaphragm activity used in different studies and its result on diaphragm structure or function
Duty cycle (%)
Healthy adults 25–30
Pacing studies 1.7
1.7
4.2
5.6
0.9
15
A duty cycle defines the time the diaphragm spends in contraction versus in relaxation, for example, a contraction during 1 s/min is a duty cycle of 1.66%.
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Diaphragm protection: what should we target? Schepens and Dianti
surgery preserved diaphragm force. This amount of
pacing furthermore decreased biomarker levels of oxi-
dative stress and upregulated autophagy [19]. Others
have suggested much longer episodes of pacing (up to
17–19 h/day) to further improve or preserve muscle
function [20]. In animal models, phrenic nerve or
diaphragm pacing has shown to be able to preserve
structural muscle integrity [15] and force [16] during
mechanical ventilation when compared with inactive
muscles. In a study by Reynolds et al. [18], transvenous
phrenic nerve pacing resulted in decreased diaphragm
atrophy. These patients received a synchronous
pacing stimulus every other breath, resulting in an
average transdiaphragmatic pressure (Pdi) swing of
8.0  4.2 cmH2O or a mean esophageal pressure (Pes)
swing of minus 5.7  3.6 cmH2O during inspiration,
similar to what is normally seen during tidal breath-
ing. Transvenous pacing is currently being evaluated
for its potential to assist in ventilator weaning of weak
&
patients [21 ].
Important to note is that these studies were
performed in noncritically ill patients, often with
small cohorts, and usually in a setting without other
risk factors for diaphragm weakness. Furthermore,
some of these studies have evaluated mitochondrial
function and oxidative stress as outcome parame-
ters. However, mitochondrial morphology and
function, as well as markers of oxidative stress,
appear to be normal in the diaphragm of ICU
patients [22]. As a result, it is difficult to translate
the observed amount of duty cycles to what should
minimally be targeted in clinical practice. Neverthe-
less, these studies seem to suggest that in some
settings, diaphragm activity levels lower than nor-
mal could be sufficient to avoid dysfunction.
Ventilator modes
Choosing a specific ventilator mode by itself will not
guarantee diaphragm activity. Assisted modes of ven-
tilation have shown to be protective against over-
assist myotrauma only when diaphragm activity is
Effect on diaphragm muscle structure or function Reference
[12]
Improved diaphragm muscle fiber mitochondrial function [13]
Resulted in a 30% increase in diaphragm fiber force [14]
Prevented the presence of structural abnormalities in the muscle fibers [15]
Prevented gene expression changes and preserved function [16]
Prevented atrophy [17]
Prevented atrophy [18]
www.co-criticalcare.com 37
Respiratory system
present. Furthermore, in a secondary analysis of a
& &&
cohort study [2 ], Goligher et al. [4 ] demonstrated
that the effect of a ventilator mode (controlled versus
assisted) on diaphragm dysfunction was mediated by
the amount of associated diaphragm activity. For this
reason, diaphragmatic activity should be monitored
during assisted ventilation modes as well.
Some studies have evaluated the effect of propor-
tional assist modes on diaphragm function [23]. Di
Mussi et al. [24] randomized a cohort of patients into
either a proportional assist mode (NAVA) or pressure
support ventilation after a period of controlled ven-
tilation. In the NAVA group, their neuroventilatory
efficiency (NVE, which quantifies the mL of tidal
volume generated per microvolt of electric activity)
increased. In the pressure support group, the NVE
stayed the same over the course of the assisted venti-
lation period, presumably secondary to a lack of
recovery from the injury that the muscle sustained
during the period of controlled ventilation. This may
be explained by the fact that even though these
patients were ventilated in an assisted ventilation
mode, the amount of diaphragm activity was lower
than normal as defined by the pressure–time product
of the diaphragm (PTPdi). The patients in the pressure
support group were overassisted, with an inactive
diaphragm during approximately half of the com-
bined delivered inspiratory flow times. Similar to the
observations in the study by Di Mussi et al. [24], an
inspiratory assist can decrease the respiratory drive to
such an extent that in conventional support modes,
patients frequently relax their diaphragm immedi-
&&
ately after triggering [25 ]. This effectively decreases
the duty cycle of the diaphragm muscle. This phe-
nomenon is not possible during proportional modes
of ventilation, as a sustained or adequate inspiratory
effort is required to achieve sufficient minute venti-
lation. Some studies have defined the time that a
diaphragm is active as time spent in assisted modes
and time spent in controlled modes with a respiratory
&
rate higher than the set rate [26 ]. Using this defini-
tion, the less time that the patient spent in ‘non-
active’ time, the less diaphragm myofiber damage
&
was present on biopsies [26 ]. However, there is no
guarantee that the diaphragm was sufficiently active
in these modes, or that the amount of activity was not
excessive, so a specific amount of activity to mini-
mize myotrauma cannot be extrapolated from that
study. These observations further support the need
for diaphragm monitoring to facilitate diaphragm-
protective mechanical ventilation.
AVOIDING INSUFFICIENT UNLOADING
The diaphragm is susceptible to injury resulting
from excessive muscle loading, resulting in
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prolonged loss of muscle force, structural injury,
and muscle-tissue inflammation [27,28].
Even when the time that an increased load is
applied on the diaphragm is short, it can be poten-
tially harmful. Diaphragm muscle damage has been
demonstrated after just 90 min of inspiratory resis-
tive loading [27]. These effects have been demon-
strated in healthy diaphragms, and may even be
more pronounced in the diaphragm of patients in
the ICU, as both chronic obstructive pulmonary
disease [29] and sepsis renders the myocytes suscep-
tible to injury [27]. Mechanical ventilation has
proven to be able to reduce sarcolemmal injury
and preserve force-generating capacity by poten-
tially reducing the (excessive) mechanical stress in
a sepsis model in rats when they were ventilated for
4 h [30]. However, when rats were ventilated for 12 h
after the onset of sepsis, mechanical ventilation
seemed to increase the amount of contractile dysfunc-
tion, compared with spontaneous breathing [31].
Recent evidence has shown that increased dia-
phragm activity during mechanical ventilation is
associated with an increase in diaphragm thickness
&
[2 ]. This increase in thickness may represent tissue
edema and thus load-induced injury, as it predicted
prolonged ventilator dependence and decreased
strength in this cohort. Of note, the amount of
diaphragm activity needed to result in the increase
in thickness exceeded normal breathing activity.
From this perspective, avoiding excessive dia-
phragm activity to protect the diaphragm from
load-induced injury seems a prudent strategy.
Precise cutoff values that define safe ranges for
inspiratory effort are not available. Safe thresholds
of diaphragm activity to avoid underassistance and
thus load-induced injury, especially in the setting of
sepsis, are absent. Furthermore, these limits are
likely to vary per person depending on diaphragm
strength. Nevertheless, common parameters that are
used to define underassistance are available and are
provided in Table 2. These are frequently based on
cutoff values predicting successful spontaneous
breathing trials, and could potentially be a guide
to define underassistance.
AVOIDING DYSSYNCHRONY
Patient-ventilator dyssynchrony has been proposed
as one of the mechanisms linking mechanical ven-
tilation to diaphragm weakness. Diaphragm con-
tractions during lengthening (eccentric loading)
[36] lead to muscle weakness [37]. Eccentric con-
tractions can occur as a result of different patient–
ventilator interactions and forms of dyssynchrony,
leading to activation of the diaphragm during the
ventilators’ expiratory phase. These include reverse
Volume 26  Number 1  February 2020

Table 2. Available parameters to evaluate ventilator under
and overassist
Threshold value
Parameter Underassist Overassist
P0.1 >3.5 cmH2O 1.6 cmH2O
WOB >0.9 J/l <0.3 J/l
PTPes >200 cmH2O s/min <50 cmH2O s/min
TTI >0.15 <0.03
Ultrasound TF > 30% TF < 10%
P0.1, Airway occlusion pressure; PTPes, esophageal pressure–time product;
TF, thickening fraction; TTI, tension–time index; WOB, work of breathing.
triggering, ineffective triggering and premature
&
cycling-off [38 ,39]. Many of these dyssynchonies
can only be detected when respiratory activity is
monitored. Another form of eccentric activity
occurs when the diaphragm ‘brakes’ during the
expiratory phase, in an effort to increase end-expi-
ratory lung volume [40]. Even though this effect
may be beneficial for the lungs, it could lead to
diaphragm myotrauma. Eccentric contractions can
also occur when the diaphragm is pulled upward
(and thus lengthened) as a result of forceful acces-
sory muscle activity [41]. These forms of dyssyn-
chrony and patient–ventilator interactions all lead
to eccentric contractions. This form of myotrauma
could explain why proportional assist modes and
decreased asynchrony indexes may result in
improved NVE [24]. Even though these mechanisms
of load-induced diaphragm injury seem plausible,
the precise effect of dyssynchrony and eccentric
activity on diaphragm function needs to be further
clarified.
LONGITUDINAL ATROPHY AND THE
EFFECT OF POSITIVE END-EXPIRATORY
PRESSURE
Recent evidence has suggested that apart from the
typically observed cross-sectional atrophy, the dia-
phragm can also sustain longitudinal atrophy. In
this type of injury, called expiratory myotrauma, the
sarcomeres realign as a result of applied positive
end-expiratory pressure (PEEP) and the resulting
change in end-expiratory muscle fiber length. This
results in a decrease of sarcomeres along the length
&
of the muscle fibers [42 ]. Furthermore, when PEEP
is reduced again, the length–tension relationship
changes again, possibly affecting muscle function at
that time [43]. This mechanism of longitudinal
atrophy is at the moment not yet fully understood
and has limited experimental evidence in its sup-
port. Its clinical impact remains uncertain to date.
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Diaphragm protection: what should we target? Schepens and Dianti
EXPIRATORY MUSCLE ACTIVITY
In addition to the interaction between the diaphragm
and the ventilator, the expiratory muscles should not
be neglected. Expiratory muscles are recruited during
Reference
increased loads on the respiratory system, relieving
[32] the diaphragm from some of the work of breathing.
[33] Furthermore, abdominal muscle activity can push
[34]
the diaphragm upwards, placing the diaphragm in
an advantageous length–tension mechanical posi-
[35]
tion [44]. Expiratory muscle weakness during
[2 ]
&
mechanical ventilation has been documented exten-
sively, but the association between expiratory and
inspiratory respiratory muscle function and activity
&
in the ICU has yet to be explored [45 ].
CONCLUSION
Diaphragm weakness is common in ventilated
patients, prolongs ventilator dependence and
increases mortality. Mechanical ventilation by itself
is related to diaphragm weakness through multiple
mechanisms, referred to as myotrauma. Balancing
inspiratory effort during mechanical ventilation, so
that is neither absent nor excessive, seems to lessen
the amount of injury and has the potential to
improve outcome. Targeting a specific ventilator
mode is only protective if it results in adequate
diaphragm activity. Patient–ventilator dyssyn-
chrony potentially has an impact on diaphragm
function as well, and proportional assist modes
could be of interest if they are able to reduce dyssyn-
chrony. Monitoring respiratory effort during
mechanical ventilation has become an important
element in a lung and diaphragm-protective venti-
lation concept.
Acknowledgements
None.
Financial support and sponsorship
T.S. has received support from the European Respiratory
Society, Fellowship STRF October 2018.
Conflicts of interest
There are no conflicts of interest.
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&& of outstanding interest
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This manuscript nicely details our current knowledge about the expiratory muscles
in the ICU, and how expiratory muscle dysfunction can impact outcome.
Volume 26  Number 1  February 2020