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REVIEW

C URRENT
OPINION Setting positive end-expiratory pressure: role in
diaphragm-protective ventilation
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Myrte Wennen a, Wout Claassen b and Leo Heunks a,c

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Purpose of review
With mechanical ventilation, positive end-expiratory pressure (PEEP) is applied to improve oxygenation and
lung homogeneity. However, PEEP setting has been hypothesized to contribute to critical illness associated
diaphragm dysfunction via several mechanisms. Here, we discuss the impact of PEEP on diaphragm
function, activity and geometry.
Recent findings
PEEP affects diaphragm geometry: it induces a caudal movement of the diaphragm dome and shortening
of the zone of apposition. This results in reduced diaphragm neuromechanical efficiency. After
prolonged PEEP application, the zone of apposition adapts by reducing muscle fiber length, so-called
longitudinal muscle atrophy. When PEEP is withdrawn, for instance during a spontaneous breathing trial,
the shortened diaphragm muscle fibers may over-stretch which may lead to (additional) diaphragm
myotrauma. Furthermore, PEEP may either increase or decrease respiratory drive and resulting
respiratory effort, probably depending on lung recruitability. Finally, the level of PEEP can also influence
diaphragm activity in the expiratory phase, which may be an additional mechanism for diaphragm
myotrauma.
Summary
Setting PEEP could play an important role in both lung and diaphragm protective ventilation. Both high and
low PEEP levels could potentially introduce or exacerbate diaphragm myotrauma. Today, the impact of
PEEP setting on diaphragm structure and function is in its infancy, and clinical implications are largely
unknown.
Keywords
diaphragm dysfunction, diaphragm protective ventilation, mechanical ventilation, positive end-expiratory pr-
essure

INTRODUCTION MECHANISMS OF CRITICAL ILLNESS

In patients with acute hypoxemic failure on inva-
sive mechanical ventilation, positive end-expira-
tory pressure (PEEP) is applied to improve
oxygenation and lung homogeneity. However,
PEEP has effects beyond the lung, of which the
hemodynamic consequences are best known and
are taken into account in clinical practice.
Recently, several studies have evaluated the impact
of PEEP on the respiratory pump, especially the
diaphragm. Shortly, these effects can be attributed
to modulation of the respiratory drive and changes
in position and shape of the diaphragm due to
(excessive) PEEP. In this review, after a brief over-
view of the pathophysiology of critical illness asso-
ciated diaphragm weakness, we will discuss in more
detail the impact of setting PEEP on diaphragm
function, activity and its geometry in patients on
mechanical ventilation.
ASSOCIATED DIAPHRAGM DYSFUNCTION
Respiratory muscle weakness frequently develops in
critically ill patients and is associated with adverse
effects including difficult ventilator weaning [1].
Mechanical ventilation plays an important role in
the pathophysiology of diaphragm weakness in crit-
ically ill patients [1]. It may affect respiratory muscle
a
Department of Intensive Care, Erasmus Medical Center, Rotterdam,
b
Department of Physiology, Amsterdam UMC, location VUmc, Amster-
dam and cDepartment of intensive care medicine, Radboud University
Medical Center, Nijmegen, The Netherlands
Correspondence to Leo Heunks, Radboud University Medical Center,
Nijmegen 6525 GA, The Netherlands.
E-mail: leo.heunks@radboudumc.nl
Curr Opin Crit Care 2023, 30:000–000
DOI:10.1097/MCC.0000000000001126

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KEY POINTS

Positive end-expiratory pressure (PEEP) decreases the
neuromechanical efficiency of the diaphragm.

Long term application of PEEP may lead to
diaphragm remodeling.
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PEEP can modulate respiratory drive and concomitant
breathing effort, which is important in diaphragm- and
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lung-protective ventilation.
function through different pathways. Ventilator
over-assist may lead to disuse atrophy of the
diaphragm. Atrophy is characterized by a loss of
contractile proteins that may result in muscle
weakness [2]. Activation of the ubiquitin-protea-
some pathway results in upregulated proteolysis
and loss of contractile protein [3]. In mechanically
ventilated animal models, apoptotic processes
were also found to contribute to diaphragm
atrophy [3– 5]. On the other hand, insufficient
unloading of the diaphragm during mechanical
ventilation (ventilator under-assist), has been pro-
posed to result in muscle injury and inflammation,
so-called load-induced myotrauma [6]. Although
load-induced myotrauma has been demonstrated
in nonrespiratory muscles, little evidence is cur-
rently available for diaphragm weakness due to
high loading in ICU patients. Finally, certain types
of patient-ventilator asynchrony may contribute to
diaphragm myotrauma due to the occurrence of
injurious eccentric (lengthening) contractions [7].
In an animal model of acute respiratory distress
syndrome (ARDS), reverse triggering caused eccen-
tric contractions of the diaphragm with concom-
&
itant diaphragm myotrauma [8 ]. This has been
discussed in more detail in a recent narrative
review [9]. In this paper we will specifically focus
on the effects of PEEP on diaphragm structure and
function.
SETTING PEEP IN CLINICAL PRACTICE
In routine practice, clinicians typically titrate PEEP,
based on gas exchange and/or pulmonary mechan-
ics (respiratory compliance, driving pressure) [10].
Several randomized studies that assessed the impact
of a higher versus lower PEEP strategy failed to
identify a strategy that is universally associated with
better outcome [11–13]. We refer to a narrative
review [14] and a recent network meta-analysis
[15]. These studies did however not take into
account the effects of PEEP on the diaphragm,
which is the focus of the current paper.
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THE EFFECT OF PEEP ON RESPIRATORY
DRIVE AND EFFORT
The respiratory drive is defined as the neural output
of the respiratory centers in the brain stem, and
respiratory effort is defined as the mechanical out-
put of the respiratory muscle pump [15]. High drive
usually results in high effort, but in some cases, for
example in patients with respiratory muscle weak-
ness or pulmonary hyperinflation, a high drive may
fail to increase respiratory effort [16].
Respiratory drive cannot be quantified directly at
the bed side as it would require measurement of
electrical activity of the respiratory centers in the
brain stem. However, electrical activity of the dia-
phragm is an accepted surrogate of respiratory drive
[17]. P0.1, the decrease in airway pressure during the
first 100 ms of inspiration, is another surrogate
measure of respiratory drive that can be measured
at the bed side [18].
The state-of-the-art technique to quantify respi-
ratory effort requires an esophageal balloon to meas-
ure the inspiratory muscular pressure [19,20].
However, this technique is invasive, requires sub-
stantial expertise, and is not yet routinely available
on all ICU ventilators. A noninvasive surrogate
measure for respiratory effort is the drop in airway
pressure during an expiratory hold, the so-called
&
occlusion pressure (Pocc) [21 ,22]. Safe ranges for Pocc
&
have been proposed [21 ,23], although this requires
further validation.
High respiratory effort has been proposed to
result in lung injury in mechanically ventilated
patients, so-called patient self-inflicted lung injury
[24]. Moreover, both low respiratory effort and high
effort have been linked to diaphragm weakness in
ICU patients [25]. As respiratory effort plays and
important role in lung and diaphragm protective
mechanical ventilation, monitoring respiratory
effort may be of clinical benefit.
Ventilator settings have been shown to affect
respiratory drive and effort in critically ill patients
[15]. PEEP has been shown to increase or decrease
respiratory drive and effort in ventilated critically ill
patients, possibly depending on specific patient
characteristics. The effects of PEEP on respiratory
drive and effort appear rather complex. In patients
with auto-PEEP on assisted mode of ventilation,
increasing extrinsic PEEP resulted in a decrease of
electrical activity of the diaphragm at onset of inspi-
ration, indicating decreased respiratory drive [26].
In a heterogeneous cohort of invasively ventilated
patients, decreasing PEEP increased respiratory
drive, as assessed by diaphragm electrical activity
[27]. An increase in PEEP was also associated with a
decrease in respiratory drive, assessed by the drop in
P0.1 in a recent large observational study [28]. To
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Setting positive end-expiratory pressure: role in diaphragm-protective ventilation Wennen et al.
summarize, these studies suggest that an increase in
PEEP is generally associated with a decrease in
respiratory drive.
However, Morais et al. investigated the effects of
changing PEEP on both respiratory drive and effort
in patients with ARDS (N ¼ 11, PaO2/FiO2 range: 79–
265 mmHg) [28]. In that study, the response of
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respiratory drive to increased PEEP levels was vari-
able: increasing PEEP from 5 cmH2O to 15 cmH2O
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decreased respiratory drive in 3/6 patients and
increased respiratory drive in 3/6 patients. Respira-
tory effort, as assessed with esophageal pressure
swings, decreased in all patients when PEEP level
was increased [29]. Thus, it appears that in some
patients, changing PEEP, results in an uncoupling of
drive and effort.
It can be hypothesized that the response of
respiratory drive to increasing PEEP depends on lung
recruitability [15]. Although respiratory drive is
mainly determined by the PaCO2 (and therewith
pH) levels of the cerebrospinal fluid and blood,
other mechanisms also play a role. Stretch and
irritant receptors in the lungs and respiratory pump
as well as cortical and emotional processes can also
provide feedback to the respiratory centers in the
brainstem [15]. Pulmonary C-fibers and irritant
receptors may be activated by consolidations or
atelectasis [15,30]. In case of high recruitability,
increasing PEEP could decrease the activity of these
receptors and thereby decrease respiratory drive. On
the other hand, when increasing PEEP does not
reduce consolidations, increasing of PEEP will not
affect activity of these irritant and stretch receptors,
but will mainly increase end expiratory lung vol-
ume, and thereby affect diaphragm geometry and
contractile strength.
In general, a decrease in respiratory drive will
translate to a decrease in respiratory effort (Fig. 1).
Morais et al. indeed found a decrease of respiratory
effort at high PEEP, as mentioned before [29], as
mentioned before. Additionally, in COVID-19-
patients on helmet continuous airway pressure ven-
tilation, respiratory effort – quantified with dia-
phragmatic pressure swings – decreased with
increasing PEEP levels [31]. Lastly, in healthy vol-
unteers receiving noninvasive ventilation, an
increase in PEEP also resulted in a decrease of res-
piratory effort [32]. When considering diaphragm-
protective ventilation, the resulting respiratory
effort is crucial: in the case of (very) low breathing
effort patients may be at risk for disuse atrophy [33],
but high effort might induce injury to both lungs
and diaphragm [9]. In clinical practice, it is relevant
to monitor breathing effort when changing PEEP
when a patient is on an assisted ventilator mode. As
mentioned, respiratory effort can be assessed by
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measuring Pocc, or if available by measuring the
swings in pleural pressure estimated by an esoph-
&
ageal balloon [21 ].
DECREASED NEUROMECHANICAL
EFFICIENCY OF THE DIAPHRAGM AS AN
ACUTE EFFECT OF POSITIVE END-
EXPIRATORY PRESSURE
Application of PEEP causes an increase in end-expir-
atory lung volume, leading to changes in thorax
geometry. In a recent study in healthy volunteers,
diaphragm geometry was evaluated using magnetic
resonance imaging [32]. The application of PEEP
displaced the diaphragm caudally, shortening its
zones of apposition due to increased end-expiratory
lung volume (see Fig. 2). Furthermore, neurome-
chanical efficiency of the diaphragm (i.e., dia-
phragm pressure normalized to its electrical
activity) decreased with increasing PEEP levels
(Figs. 1 and 3) [32]. The following mechanism
may explain these findings. The muscle fibers
in the zone of apposition shorten when higher
PEEP levels increase lung volume. This causes a
sub-optimal overlap between the myosin and the
actin filaments (the contractile proteins) within the
muscle fibers. As force generation is dependent on
adequate overlap between these filaments, the neu-
romechanical efficiency of the diaphragm decreases
(Fig. 3, T1). Thus, an acute increase in PEEP could
decrease force generating capacity of the diaphragm
due to suboptimal position of muscle fibers on the
length tension curve (Fig. 3, T1). This results in a
markedly decreased effort if the drive remains con-
stant (Fig. 1).
Indeed, in a recent observational study in
ICU patients assessing the diaphragm using
ultrasound, an increase in PEEP level reduced the
thickening fraction. Assuming that thickening
fraction correlates with respiratory effort, this sug-
gests that increasing PEEP decreases the contractile
efficiency of the diaphragm in ICU patients. This
could be due to the effect of PEEP on diaphragm
geometry [34].
DIAPHRAGM REMODELING AFTER
PROLONGED POSITIVE END-EXPIRATORY
PRESSURE
It has been demonstrated in animal models that
with prolonged application of PEEP, the diaphragm
muscle fibers in the zone of apposition adapt to its
changed geometry by absorbing sarcomeres (con-
tractile units) to restore optimal length for force
production (Fig. 3, T2) [23]. The loss of sarcomeres
in series has been termed ‘longitudinal atrophy’.
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FIGURE 1. Graphical abstract describing the possible effects of PEEP on the diaphragm. PEEP, positive end-expiratory
pressure.

Longitudinal atrophy is characterized by a decrease
in muscle length in contrast to the well known
cross-sectional atrophy that is characterized by thin-
ning of the muscle [35]. This length adaptation is
hypothesized to contribute to weaning failure
through the following mechanism. During a spon-
taneous breathing trial, PEEP is acutely withdrawn.
Therefore, end-expiratory lung volume is reduced,
and the shortened (longitudinal atrophied) dia-
phragm stretches. This may lead to inadequate over-
lap between the myosin and actin filaments, causing
impaired force generation (Fig. 3, T3).
Longitudinal atrophy may not be the only dia-
phragm adaptation that is induced by long term PEEP
application. In a study in long-term mechanically
ventilated rabbits, PEEP was shown to cause collagen

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FIGURE 2. Magnetic resonance image in healthy volunteer with PEEP applied using noninvasive ventilation at 2 (left) and 15
(right) cmH2O. This illustrates the caudal movement of the dome (dashed line) and decrease in length of the zone of
apposition (ZOA, solid line) due to an increase of PEEP. The ZOA is marked with an oil filled tube alongside the rib cage,
which can be seen as the white circles at the caudal insertion of the ZOA (data also reported in [32]). PEEP, positive end-
expiratory pressure.

&
deposition and fibrosis in the diaphragm [36 ]. In ICU
patients, today no data is available on PEEP induced
diaphragm remodeling or longitudinal atrophy.
DIAPHRAGM BLOOD FLOW
A recent study in animals showed that application of
PEEP was associated with impaired diaphragm blood
flow, and the effects were more pronounced at
higher PEEP levels [37]. This effect can be attributed
to an (further) increase in intrathoracic pressure and
a concomitant compression of thoracic vasculature,
in combination with absent diaphragm activity.
Diminished blood flow can potentially contribute
to the development of diaphragm dysfunction dur-
ing mechanical ventilation due to impaired oxygen
delivery and removal of waste products.
THE DIAPHRAGM AS A BRAKE: ROLE OF
POSITIVE END-EXPIRATORY PRESSURE
The diaphragm is the main muscle for generation of
inspiratory flow. However, more recently, it has been
recognized that the diaphragm may be active during
expiration as well [38]. It is proposed that diaphragm
activation during the expiratory phase decreases
expiratory flow rate and consequently limits develop-
ment of atelectasis. Consequently, the diaphragm is
active while its muscle fibers lengthen, resulting in
lengthening activations (eccentric contractions). It
has been suggested that these lengthening activa-
tions could be both harmful and beneficial for the
diaphragm structure [39]. Lengthening activations
can increase the strain on the muscle fibers, especially
compared to concentric contractions, which may
induce myotrauma but also potentially prevent
muscle (cross-sectional) atrophy.
Pellegrini et al. [40] demonstrated electrical activ-
ity of the diaphragm during expiration in pigs with
ARDS. Expiratory diaphragm activity increased when
reducing PEEP in this experimental model, which may
signify a protective reflex of the diaphragm. Reducing
expiratory activity with sedation and paralysis
increased atelectasis, confirming the hypothesis that
the diaphragm is recruited during expiration to limit
atelectasis and tidal lung derecruitment. In line with
these observations, in young children, the electrical
activity of the diaphragm was increased at zero PEEP
during expiration [38]. The activity is thought to
decrease the velocity of the diaphragm moving cra-
nially during expiration, and this supports the
hypothesis that the ‘braking’ of the diaphragm keeps
the lungs open to prevent atelectasis. Therefore, low
PEEP could increase the level of eccentric contractions
in the diaphragm. These mechanisms have not yet
been studied in vivo, which is an important next step.

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FIGURE 3. Description of acute and subacute effects of PEEP on the diaphragm. From T0 to T1, PEEP is introduced, which
increases the end-expiratory lung volume and therewith displaces the diaphragm caudally. This results in shortened muscle
fibers. As an acute effect, the neuromechanical efficiency decreases, resulting in an uncoupling of respiratory drive and effort.
After prolonged application of PEEP (T2), sarcomeres are absorbed to recover the length-tension relationship of the muscle
(36). Hypothetically, this could give rise to additional diaphragm weakness after weaning (T3), because there is sub-optimal
overlap of muscle filaments due to stretch on the diaphragm after withdrawal of PEEP. PEEP, positive end-expiratory pressure.

AUTO-POSITIVE END-EXPIRATORY diaphragm described in this review can apply to

PRESSURE
Auto-PEEP, or intrinsic PEEP, is the pressure at the
end of expiration on top of the set (extrinsic) PEEP
level. It arises from increased airway resistance,
which is common in obstructive airway diseases
[41]. The effects of high PEEP levels on the
cases of (high) auto-PEEP as well, because auto-PEEP
increases end-expiratory lung volume. In addition,
auto-PEEP can introduce patient-ventilator asyn-
chronies due to the impact on the timing of inspi-
ration and expiration [42,43]. In turn, patient-
ventilator asynchronies could have an adverse effect

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Setting positive end-expiratory pressure: role in diaphragm-protective ventilation Wennen et al.
on the diaphragm. In a recent study in a rabbit ARDS
model, reverse triggering and breath stacking
&
resulted in both diaphragm and lung injury [8 ].
However, no indications of diaphragm myotrauma
caused by patient-ventilator asynchronies were
found in another study in pigs with ARDS [44]. A
possible explanation is the effort of the diaphragm
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associated with these asynchronies.
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SHOULD WE TAKE THE RESPIRATORY
PUMP INTO ACCOUNT WHEN SETTING
POSITIVE END-EXPIRATORY PRESSURE?
As outlined above, setting PEEP may affect dia-
phragm structure, activity, and geometry. These
data provide new insight into the pathophysiology
of diaphragm weakness in ventilate critically ill
patients. However, it remains to be investigated if
modifications in the diaphragm due to PEEP setting
affect patient outcome, especially weaning dura-
tion. Today, in clinical practice, PEEP is titrated to
improve oxygenation and lung homogeneity, facil-
itating lung protective ventilation [45]. Given avail-
able evidence, the priority of PEEP titration should
be focused on the lung. However, clinicians may
take into account the effects of PEEP on the dia-
phragm. Firstly, the decrease in neuromechanical
efficiency of the diaphragm due to high PEEP favors
setting the PEEP as low as possible while preventing
lung collapse. It should be noted that decreased
neuromechanical efficiency of the diaphragm,
requires higher respiratory drive for the same
mechanical output. It has been demonstrated that
high respiratory drive is associated with sensations
of dyspnea [46]. Lower PEEP will minimize the
decrease in neuromechanical efficiency (Figs. 1
and 3), because of a more optimal force-length
relationship of the diaphragm (see also ‘Decreased
neuromechanical efficiency of the diaphragm as an acute
effect of PEEP’). Secondly, adapting PEEP settings can
modulate respiratory drive and resulting effort
(Fig. 1), which is an important factor for preserving
diaphragm function in the phase of supported
mechanical ventilation and, as mentioned, dyspnea
sensation [46]. It is difficult to predict whether
respiratory drive will increase or decrease in
response to a change in PEEP, but this can be
assessed bed-side using P0.1, or by measuring elec-
trical activity of the diaphragm. Ultimately, the
resulting breathing effort is most important in dia-
phragm protective ventilation, which can be modu-
lated with PEEP (Fig. 1). Respiratory effort can be
monitored bed-side by measuring the inspiratory
& 12. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-
occlusion pressure [21 ]. Of course, a modulation
of respiratory drive and effort is also important for
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lung-protective ventilation, which is well described
in a review by Spinelli and colleagues [17].
CONCLUSION
To conclude, setting PEEP could play an important
role in both lung and diaphragm protective ventila-
tion. Both high and low PEEP levels could potentially
introduce or exacerbate diaphragm myotrauma (see
Fig. 1). It is therefore relevant to consider the effects of
setting PEEP on the diaphragm in a clinical setting,
especially in patients at risk for diaphragm myo-
trauma.
Acknowledgements
None.
Financial support and sponsorship
This work was supported by a grant from ZonMw
(#09120011910004).
Conflicts of interest
L. Heunks has received honoraria and a research grant
from Liberate Medical. The remaining authors have no
conflicts of interest.
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Volume 30
Number 00
Month 2023