REVIEW

C URRENT
OPINION Hemodynamic effects of positive end-expiratory
pressure
Adrien Joseph a,
, Matthieu Petit a,b,
and Antoine Vieillard-Baron a,b

Purpose of review
Positive end-expiratory pressure (PEEP) is required in the Berlin definition of acute respiratory distress
syndrome and is a cornerstone of its treatment. Application of PEEP increases airway pressure and modifies
pleural and transpulmonary pressures according to respiratory mechanics, resulting in blood volume
alteration into the pulmonary circulation. This can in turn affect right ventricular preload, afterload and
function. At the opposite, PEEP may improve left ventricular function, providing no deleterious effect occurs
on the right ventricle.
Recent findings
This review examines the impact of PEEP on cardiac function with regards to heart-lung interactions, and
describes its consequences on organs perfusion and function, including the kidney, gut, liver and the brain.
PEEP in itself is not beneficious nor detrimental on end-organ hemodynamics, but its hemodynamic effects
vary according to both respiratory mechanics and association with other hemodynamic variables such as
central venous or mean arterial pressure. There are parallels in the means of preventing deleterious impact
of PEEP on the lungs, heart, kidney, liver and central nervous system.
Summary
The quest for optimal PEEP settings has been a prominent goal in ARDS research for the last decades.
Intensive care physician must maintain a high degree of vigilance towards hemodynamic effects of PEEP on
cardiac function and end-organs circulation.
Keywords
acute kidney injury, acute respiratory distress syndrome, hemodynamics, positive end-expiratory pressure,
right ventricle

INTRODUCTION In the past 50 years, tremendous progress were

The acute respiratory distress syndrome (ARDS) has made in understanding the epidemiology and
been first described in 1967 in a case series of 12 pathophysiology of ARDS [5]. Undoubtedly, no
patients with new onset hypoxemia refractory to other intensive care syndrome has been as exten-
supplemental oxygen, bilateral infiltrates on chest sively studied, especially concerning the ventila-
radiograph, and reduced respiratory system compli- tory strategy.
ance [1]. Since then, several definitions have been
proposed: in 1994 with the American-European
consensus conference on ARDS [2] and in 2012
a
leading to the so-called Berlin definition [3]. This Medical Intensive Care Unit, Ambroise Par
e Hospital, Assistance
includes respiratory failure within 1 week of a Publique-H^ opitaux de Paris, Boulogne-Billancourt and bInserm, CESP,
Paris-Saclay University, Universit
e de Versailles Saint-Quentin-en-Yve-
known insult or new and/or worsening respiratory lines, Villejuif, France
symptoms, not fully explained by cardiac dysfunc-
Correspondence to Antoine Vieillard-Baron, Pr, Medical Intensive Care
tion or volume overload, bilateral opacities on chest Unit, Ambroise Par
e Hospital, Assistance Publique-H^
opitaux de Paris, 9
X-ray or computed tomography and hypoxemia Av. Charles de Gaulle, Boulogne-Billancourt 92100, France.
defined as paO2/FiO2 less than 300 mmHg on at least Tel: +33149095605; fax: +33 1 49 09 58 92;
a PEEP of 5 cmH2O. This definition has been e-mail: [email protected]


updated after the COVID-19 pandemic to include Adrien Joseph and Matthieu Petit contributed equally to this study.
patients treated with high-flow-nasal oxygen and a Curr Opin Crit Care 2024, 30:10–19
SpO2/FiO2 less than 315 [4]. DOI:10.1097/MCC.0000000000001124

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 Effects of positive end-expiratory pressure Joseph et al.

(low driving pressure). What was remarkable in their

KEY POINTS study is that right ventricular failure was progres-
sively observed in the former condition while not in
 Application of PEEP modifies pleural and
the later [12].
transpulmonary pressures, hence affecting pulmonary
circulation and cardiac function. This review will first examine the impact of PEEP
on cardiac function with regards to heart-lung inter-
 Excessive PEEP may alter organs perfusion and actions, and second will describe its consequences
function, including the kidney, gut, liver and brain. on organ perfusion and function, including the
 The balance between alveolar recruitment and kidney, gut, liver and the brain.
overinflation induced by PEEP mainly mediates the
deleterious impact of PEEP on organ perfusion and
function. It is predictable with difficulty and must be IMPACT OF POSITIVE END-EXPIRATORY
then reassessed frequently. PRESSURE ON CARDIAC FUNCTION

Anatomical and physiological considerations

Positive end-expiratory pressure (PEEP) is Intrathoracic cardiopulmonary vascular system con-
required in the Berlin definition of ARDS [3], while tains about 17% of the vascular volume, 9% being in
its presence to define ARDS was recently extensively the pulmonary circulation responsible to generate
&&
debated [6 ]. The quest for optimal PEEP settings the left ventricular preload and stroke volume (SV)
has been a prominent goal in ARDS research for the [13]. Then, every phenomenon that affects the
last decades [7]. Indeed, application of PEEP leads to amount of blood into the pulmonary circulation
beneficial but also detrimental effects, mostly directly alters SV and hemodynamics.
hemodynamic, and the benefit/risk balance is diffi- Cardiac cavities (in the absence of pericardial
cult to address as related to its level, the generated effusion) and some great vessels such as superior
driving pressure and the severity of lung injury. vena cava or pulmonary arteries are directly submit-
In the recent ESICM guidelines, experts were unable ted to pleural pressure (Ppl) while pulmonary capil-
to make a recommendation for or against the rou- laries are submitted to transpulmonary pressure
&&
tine application of ‘high’ versus ‘low’ PEEP [6 ]. (TPP), which is the distending pressure of the lungs.
While the beneficial effects of PEEP have been The pericardium is an acutely inextensible envelope
described since the original description of ARDS [8], around the heart, which means that every change in
adverse effects are indeed numerous, among them one ventricular volume will affect the other through
circulatory failure is key as associated with a poor the interventricular septum, a phenomenon called
prognosis [9]. In a randomized controlled trial, ventricular interdependence [14].
the ART investigators reported that a (very) high Tidal ventilation and application of PEEP
PEEP strategy, along with recruitment maneuvers, increase airway pressures (Paw) and then modify
increased mortality compared to a lower PEEP strat- Ppl and TPP, according to respiratory mechanics,
egy [10]. Interestingly, 1 h after randomization, resulting in blood volume alteration into the pul-
34.8% of patients in the high PEEP group required monary circulation [15]. This is mainly mediated by
commencement or increase of vasopressors or hypo- changes in right ventricular preload, afterload and
tension compared to 28% in the low PEEP group function. At the opposite, through its action on the
[10], and this increase did not seem to be temporally left ventricle, PEEP may improve left ventricular
associated with recruitment maneuvers. This poten- function and SV in certain type of patients, provid-
tial effect of PEEP on hemodynamics is especially of ing no deleterious effect occurs on the right side.
importance as many patients treated for ARDS have
already a circulatory impairment. In a systematic
review and meta-analysis on the impact of PEEP on Effect of positive end-expiratory pressure on
outcome, more than 65% of patients with ARDS the right ventricle
required vasopressors during their ICU stay [11]. According to Guyton physiology, the systemic
PEEP is often proposed to maintain or restore venous return (Qvr) can be written as follows:
oxygenation, and to prevent cyclic alveolar collapse Qrv ¼ (Pms-Pra)/Rvr where Pms is the mean systemic
and ventilator induced lung injury. If so, it could filling pressure, Pra is the right atrial pressure and
protect the heart and the hemodynamics. Katira Rvr the resistance to venous return. In most cases,
et al. [12] nicely re-emphasized that a moderate tidal application of PEEP decreases the systemic venous
volume with zero PEEP (high driving pressure) return but does not always decrease right ventricular
induced acute lung injury in animals compared preload, especially in patients ventilated for ARDS.
to the same tidal volume but application of PEEP Briefly, it depends on respiratory mechanisms and

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Respiratory system

volemia. Augmentation of PEEP inducing a drop in and Brochard [29], that determines the effect of
right ventricular preload means that the right ven- PEEP on right ventricular function. PEEP can result
tricle acts on the steep part of the Frank-Starling in alveolar recruitment and when the Yin (recruit-
curve (preload dependent part). In this situation, ment) is predominant, increase in PEEP may even
Ppl is usually more affected than TPP by PEEP decrease right ventricular afterload and improve
and hypovolemia is frequently present [16]. Qvr right ventricular function and hemodynamics. In
decreases either because Pra is simply increased by this situation, PEEP also frequently decreases
transmission of Ppl or because Rvr is increased due hypoxic pulmonary vasoconstriction. Figure 1 sum-
to an ‘adaptive’ phenomenon through barorecep- marizes different situations where PEEP may unload
tors on the chest [17] or due to collapse of the or overload the right ventricle. It depends on the
&
superior vena cava [18]. Lai et al. [19 ] recently level of PEEP, the severity of the baby-lung and its
reported in 66 patients ventilated with a high PEEP potential restoration (how decreased and normal-
(66% of them for an ARDS) that PEEP reduction ized is FRC), and the transpulmonary pressure gen-
(12 to 7 cmH2O) only induced an increase in cardiac erated by PEEP.
output when patients were fluid-responsive (then
the right ventricle working on the steep part of the
Frank-Starling curve). Effect of positive end-expiratory pressure on
However, augmentation of PEEP may also the left ventricle
decrease Qvr as a consequence of an increase in On one side, it is expected that PEEP improves left
right ventricular preload. In this case, Pra is ventricular function and SV by decreasing left ven-
increased because PEEP induces an increase in right tricular afterload. By increasing ITP, PEEP increases
ventricular afterload with an obstruction of the right the pressure around all the structure in the thorax,
ventricular ejection [20] leading to dilatation of more than the one in the abdominal cavity, relative
the right heart. When lung compliance is severely to atmospheric pressure creating a pressure gradient
impaired [21] and pulmonary hyperinflation occurs between the left ventricle (LV) and the aorta and the
[22], airway pressure is less transmitted to pleural rest of systemic circulation, working at the atmos-
pressure and TPP is more affected by augmentation phere pressure. Thus, increased ITP decrease the
of PEEP, a situation much more frequently observed transmural left ventricular pressure and the force
in patients ventilated for an ARDS. Such patients necessary to eject blood into the circulation [30,31].
are especially sensitive to this effect as ARDS is In the other side, left ventricular diastolic function
also a disease of the pulmonary circulation [23] can be altered by augmentation of PEEP [32]. This
and is associated with pulmonary hypertension occurs when right ventricle (RV) is overloaded by
[24]. When PEEP is increased, expected beneficial PEEP as discussed above. In this case, augmentation
changes are the recruitment of nonventilated areas in right ventricular size and pressure shifts the inter-
with a distribution of gas in the dependent region of ventricular septum towards the left ventricle,
the lung (mostly the posterior parts in supine posi- impairing its filling [33].
tion). However, when gas is more distributed in the
nondependent areas (mostly the anterior parts in
supine position), hyperinflation occurs in this area CONSEQUENCES ON ORGAN PERFUSION
with compression of pulmonary capillaries by TPP AND FUNCTION
and finally an increase in right ventricular afterload During the last decades, seminal studies have high-
with hemodynamic compromise. Valta et al. [25] lighted the complexity of the interorgan cross talk
reported that at PEEP 12 cmH2O, the percentage of between the lungs, kidney and heart [34,35]. In this
lung recruitment only regarded 25% of the delta in sense, PEEP participate in this cross talk through its
functional residual capacity (FRC) induced by PEEP. hemodynamic, inflammatory and neurohormonal
We found similar results [26]. Using the pulmonary effects.
artery catheter, Jardin et al. [27] reported in ARDS In the following sections, we will describe the
the adverse effect of PEEP on right ventricular after- effects of PEEP on the kidney, gut, liver and cerebral
load and function at end-expiration during a PEEP circulation, emphasizing the clinical impact of PEEP
trial from 0 to 15 cmH2O. They found a progressive settings in the context of multiorgan failure (Fig. 2).
increase in right ventricular afterload with a pro- As discussed above, the impact of PEEP depends on
gressive decrease in right ventricular SV [27]. More its respective effects on the lungs and then as a
recently, we reported similar results using critical consequence on cardiac function and organ conges-
care echocardiography [28]. To summarize, this is tion being part of the definition of right ventricular
the balance between recruitment and hyperinfla- failure [36]. However, impact of PEEP is at least
tion, the Yin and the Yang discussed by Rouby unpredictable and should be regularly monitored.

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 Effects of positive end-expiratory pressure Joseph et al.

Bene al Peep Detrimental Peep

(a) right ventricle afterload right ventricle afterload (b) Recruitment Overdistension
Clin
Pulmonary vascular resistance

Upper in tion point

Lung volume
TLC

Intra- Extra-
alveolar alveolar Lower in tion point
RV PEEPi
resistance resistance
FRC

Lung volume Transpulmonary pressure

FIGURE 1. Differential hemodynamic effects of beneficial and detrimental positive end-expiratory pressure (PEEP).
(a) Relationship between lung volume and pulmonary vascular resistance. As lung volume increases toward total lung capacity
(TLC) or decreases toward residual volume (RV), pulmonary vascular resistance increases and impacts right ventricular
afterload. Pulmonary vascular resistance increases with hyperinflation because of increased intraalveolar pulmonary arteries
resistance, whereas it increases with lung collapse because of increased extraalveolar pulmonary arteries resistance. (b)
Pressure volume curve showing the effects of PEEP, which becomes detrimental in the overdistension (right-hand) zone. Clin,
compliance of the intermediate, linear segment of the pressure volume slope; FRC, functional residual capacity; Peepi, intrinsic
PEEP; TPP, transpulmonary pressure.

FIGURE 2. Impact of positive end-expiratory pressure on cardiac function and end-organs circulation Dotted lines represent
associations with uncertain clinical significance.
Intrathoracic pressures refer to pleural and transpulmonary pressures. AKI,
acute kidney injury; LV, left ventricle; RV, right ventricle.

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Respiratory system

Impact of positive end-expiratory pressure antidiuretic hormone are stimulated after applica-
on renal hemodynamics and risk of acute tion of PEEP [62]. Interestingly, in kidney transplant
kidney injury recipients, renal denervation does not seem to
Acute kidney injury (AKI) affects more than half of mitigate the effect of PEEP, suggesting that this
ICU patients and deeply impact prognosis [37]. On effect is perfusion pressure-dependent rather than
the one hand, AKI patients are twice as likely to hormone-induced [63].
require invasive mechanical ventilation [35–38], Apart from renal congestion, injurious mechan-
but on the other hand, patients under mechanical ical ventilation with high tidal volume and low PEEP
ventilation also face a threefold increase in the risk has been shown to induce systemic inflammation in
of kidney injury [39,40]. the context of ARDS, with the release of IL-1B, IL-6,
Acute respiratory failure in itself is associated IL-8 TNF-alpha, MCP-1 and VEGF, leading to epi-
with an increased risk of developing AKI [41,42], and thelial cell apoptosis [64,65]. On the contrary, lung
in addition, application of mechanical ventilation protective ventilation with PEEP based on the pres-
has long been suspected to participate in worsening sure-volume curve is associated with lower concen-
renal function [30,43], prompting authors to coin the trations of inflammatory markers in plasma and
term ventilator-induced kidney injury [25]. The mecha- bronchoalveolar lavage [66,67], even though these
nisms by which mechanical ventilation contributes findings have not been replicated in the ALVEOLI
to AKI are multifactorial and implicate the release of trial [68]. Interestingly, preclinical data and dosage
inflammatory mediators as a result of biotrauma from patients’ serum suggest that the Fas-Fas ligand
[42,44–48], decrease in renal blood flow secondary system, implicated in the regulation of cell death
to hypercapnia [49–52], hemodynamic and neuro- and immune tolerance, is involved in renal tubular
hormonal processes [35] related to elevation of intra- epithelial cell apoptosis, highlighting a therapeutic
thoracic pressure and renal toxicity of concomitant potential for blockade of this pathway in ARDS-
medication (e.g. inhaled nitric oxide [53,54]). induced kidney and multiorgan dysfunction [65].
From a mechanistic point of view and as To sum up, the effects of PEEP on kidney hemo-
described above, application of PEEP may increase dynamics and function are not straightforward. an
Pra. As Pra, also referred to as central venous pressure interplay between effect of PEEP on lung mechanics,
(CVP), acts as the outflow pressure of renal blood cardiac function, CVP and fluid status more likely
flow, elevated CVP results in increased renal venous influence the risk of AKI during mechanical venti-
pressure, also called renal congestion. Renal venous lation [59,69]. Whether a given ventilation strategy
hypertension reverberates on increased efferent would potentially protect the kidney without sacri-
pressures, increased intraglomerular hydrostatic ficing the support of the respiratory system deserves
pressure, and reduced net filtration pressure, ulti- further investigations.
mately leading to glomerular capillaries collapse
[55]. Venous congestion, rather than impairment
of cardiac output, is considered to be the main driver Impact of positive end-expiratory pressure
for kidney injury during decompensated heart fail- on gastrointestinal and liver circulation
ure [56], while the key actor in patients with shock is Similar to AKI, the deleterious effects of inadequate
probably the mean perfusion pressure (mean arterial PEEP levels on pulmonary mechanics can translate
pressure minus CVP) [57]. Similarly, CVP has been into increased venous pressure that reverberates on
consistently associated with an increased risk of AKI gastrointestinal and liver hemodynamics. Since the
in ICU patients [58]. More specifically, in patients splanchnic perfusion is particularly sensitive and a
undergoing mechanical ventilation, a recent study small reduction in perfusion can compromise its
found a synergistic detrimental effect of CVP and barrier function, decreased mesenteric and portal
PEEP levels on worsening kidney function [59]. blood flows have been suspected to precipitate the
Additionally, PEEP-induced right ventricular dys- progression to multiorgan dysfunction in patients
function can result in elevated abdominal pressure, with ARDS [70,71].
which can also alter kidney function [60,61]. In another model than ARDS, for example
Reduced left ventricular preload and cardiac output decompensated advanced heart failure, Nikolaou
as adverse effects of alveolar overdistension can et al. [72] suggested that congestion induces bile
jeopardize renal blood flow [34], even though this duct congestion and then increase of alkaline phos-
mechanism probably contributes less to PEEP- phatase, while liver ischemia induces centrolobular
induced renal dysfunction [56]. cell necrosis and then rather augmentation of trans-
PEEP-induced neuro-hormonal alterations can aminases. Early liver dysfunction, as reflected by
also cause fluid retention. The sympathetic nervous increased serum bilirubin levels in the initial phase
system, renin angiotensin aldosterone system and of ARDS, is seen in approximately 15–20% of

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 Effects of positive end-expiratory pressure Joseph et al.

patients and is strongly associated with the 90-day recruitment/overdistention can modulate arterial
mortality rate [73,74]. Although lung-liver interac- inflow. Then, increased intrathoracic and jugular
tions have been extensively studied, mostly with pressures impedes cerebral venous return. Greater
respect to the regulation of inflammation and repair inflow or less blood outflow will ultimately lead to
mechanisms [75], sound data on the impact of ven- raised ICP once the capacity to displace cerebrospinal
tilator parameters on the development of gastroin- fluid is exceeded. Lastly, in cases where PEEP levels
testinal and liver failure are currently lacking. impair cardiac output, lower cerebral perfusion pres-
Experimental models from the 1980 to 1990s showed sure beyond cerebral autoregulatory mechanisms
an inverse relation between PEEP levels and splanch- will thereby decrease ICP. In case of impaired cerebral
nic blood flow, mainly driven by a reduction in autoregulation, a linear relationship exists between
cardiac output, while splanchnic oxygen consump- mean arterial pressure and cerebral perfusion pres-
tion is usually maintained by compensatory increase sure and any impact of PEEP on cardiac output will
in oxygen extraction [76,77]. On the other hand, translate into changes in cerebral perfusion pressure,
increased rates of epithelial cell apoptosis were also potentially compromising brain perfusion.
noted in the small intestine villi in animals subject to Unsurprisingly, application of moderate levels
injurious mechanical ventilation with high tidal vol- of PEEP in patients undergoing extracranial surgery
umes (15–17 ml/kg) and low PEEP (0–3 cmH2O) [65]. (uninjured brains) does not seem to affect ICP
In humans, several small studies did not show [88,89]. On the contrary, raising PEEP levels will
any alteration in gastric mucosal perfusion [78] or translate into increased ICP in neurosurgical inten-
splanchnic blood flow using continuous infusion of sive care patients, not always clinically relevant and
indocyanine green dye [79] in response to PEEP not systematically followed by decreased cerebral
increase, but due to the lack of recent data with perfusion pressure [90–94]. In a recent monocentric
contemporary ventilatory management of ARDS, it study, PEEP increments increased ICP in 58% and
is difficult to draw conclusions about the clinical brain tissue oxygenation (PbtO2) in 21% of patients,
significance of these findings, and the role of PEEP but these changes were largely unpredictable and no
in gastrointestinal and liver failure in ARDS patients correlation was found between DPEEP and DPbtO2
or DICP [95 ].
&
remains to be determined.
The Venous Excess Ultrasound Grading System Rather than initial compliance of the respiratory
(VExUS) score, a four-step ultrasound protocol eval- system, alveolar recruitment and changes in respi-
uating the inferior vena cava, renal vein, but also the ratory compliance after application of PEEP is asso-
hepatic and portal vein by Doppler, has been pro- ciated with changes in ICP, highlighting the
posed as a means to measure venous congestion importance of optimal PEEP titration and integra-
[80]. It correlates with Pra [81] and can predict acute tion of respiratory mechanics in the prediction of
renal injury after cardiopulmonary bypass [82]; the hemodynamic effects of PEEP on distant organs
&
however, its clinical significance in the context of [91,95 ,96,97]. Some authors proposed PICGap, rep-
ventilation and PEEP-induced venous congestion resenting the gap between baseline intracranial and
and liver injury remains to be evaluated. CVP, as a potential predictor of ICP responsiveness
Outside the context of ARDS, application of to PEEP adjustments [98]. This comes back to the
different levels of PEEP during liver transplantation idea that PEEP by itself is not beneficious nor detri-
does not seem to affect liver hemodynamics and mental on end-organ hemodynamics, but its effects
function, despite increased CVP [83–85]. depends on respiratory mechanics and association
with other hemodynamic variables such as CVP [59].
Based on these considerations, applying a lung
Impact of positive end-expiratory pressure protective ventilation strategy in brain-injured
on cerebral circulation patients with ARDS should not be discouraged,
Mechanical ventilation is a mainstay in the manage- and optimal PEEP level should be determined using
ment of patients with neurological failure. Further- conventional respiratory and hemodynamic param-
&
more, acute lung injury is the most common eters as well as monitoring of ICP [93,99,100 ].
extracranial complication in patients with acute Therefore, a ventilation strategy taking account
brain injury, affecting as much as 35% of patients of the cerebral consequences of PEEP (and other
[86]. Although the impact of paCO2 on intracranial respiratory parameters) has a most prominent place
pressure (ICP) is well documented and accounted in neurosurgical patients with prior or at risk of
for, the impact of ventilator settings and PEEP on intracranial hypertension. Otherwise, the cerebral
cerebral hemodynamics is less appreciated [87]. consequences of PEEP in the context of ARDS with-
PEEP can affect ICP through distinct mecha- out neurological failure is less likely to be clinically
nisms. First, modifications in paCO2 related to lung significant.

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Respiratory system

HEMODYNAMIC IMPACT OF POSITIVE elevated ICP or chronic liver disease. Moreover,

END-EXPIRATORY PRESSURE IN impact on brain, gut and liver function are seldom
RANDOMIZED CONTROLLED TRIALS reported. However, higher PEEP levels combined
The most reliable evidence of the impact of PEEP on with lung recruitment maneuvers seem to be associ-
cardiac output and end-organs function is expected ated with a harmful cardiovascular impact [2,3],
to come from randomized controlled trials which, whereas PEEP titration based on respiratory mechan-
throughout the history of ARDS, strived to deter- ics seems to be associated with increases in cardiac
mine the best PEEP settings [7]. This is summarized output and hemodynamic stability [101–103].
in Table 1.
Interpretation of these results are made difficult
by concurrent interventions on tidal volumes, ven- CONCLUSION
tilator strategies and recruitment maneuvers, as well Ideal PEEP settings should aim to a balance between
as exclusion of patients with acute brain injury/ its capability to re-open the collapsed lung and the

Table 1. Impact of positive end-expiratory pressure on cardiac, kidney, gut, liver and central nervous system circulations in
the main randomized controlled trials with different PEEP settings
Effect on blood Effect on kidney Effect on gut and liver Effect on central
PEEP settings pressure/cardiac output function functions nervous system

Amato, NEJM. 1998 9.3  0.5 versus 13.2 NA RRT: 5 (21%) versus 7 One death from diffuse NA
[112]  0.4 cmH20 (with (24%) patients, P > 0.10 gastrointestinal bleeding
protective ventilation in the protective
strategy) ventilation group
ARDS Net, NEJM. 8.6  3.6 versus 9.4 Days without circulatory Days without renal failure NA NA
2000 [67]  3.6 cmH2O (with failure: 19  10 versus 20  11 versus 18  11
lower tidal volumes) 17  11 days, days, P ¼ 0.005
P ¼ 0.004
Ranieri, JAMA. 2000 6.5  1.7 versus 14.8 Cardiovascular failure: 8 AKI: 19 (86%) versus 4 5 (23%) versus 1 (5%) liver Neurological failure: 4
[113]  2.7 cmH2O (36%) versus 3 (14%) (18%), P ¼ 0.04 dysfunction (18%) versus 0 (0%)
Brower, NEJM. 2004 8.3  3.2 versus 13.2 No significant differences NA
(ALVEOLI) [68]  3.5 cmH2O in the number of days
without circulatory,
hepatic, or renal failure
Villar, CCM. 2006 9.0  2.7 versus 14.1 Cardiovascular failure: 28 18 (40%) versus 21 (42%) Liver failure 8 (17.8%) 8 (18%) versus 5 (10%)
[102]  2.8 cmH2O (PEEP (62%) versus 9 (18%), versus 4 (8%)
above the lower P < 0.001 Cardiac Gastrointestinal failure
inflection point of the index 4.7  1.4 versus 8 (17.8%) versus 8
pressure volume curve 5.8  1.5 l/min/m2, (16%)
of the respiratory P < 0.05
system)
Manzano, CCM. 0.12  0.7 versus 5.78 NA RRT: 3 (5%) versus 1 (2%) NA NA
2008 [114]  1.0 cmH2O
Mercat, JAMA. 2008 7.1  1.8 versus 14.6 Cardiovascular failure--free Renal-failure free days: NA NA
(EXPRESS) [103]  3.2 cmH2O days: 21 (4--26) versus 27.5 (8.0--28.0) versus
23 (10--26) days, 28.0 (11.0--28.0) days,
P ¼ 0.09 P ¼ 0.23
Talmor, NEJM. 2008 10  4 versus 17 Shock-free days: 17 (0-- NA NA NA
[109]  6 cmH2O (guided by 21) versus 14 (0--21)
esophageal pressure) days, P ¼ 0.47
Meade, JAMA. 2008 10.1  3.0 versus 15.6 Days of vasopressor: 5 (2-- RRT: 85 (19%) versus 71 NA NA
(LOVS) [106]  3.9 cmH2O 9) versus 4 (2--8) days (17%)
Pintado, ERJ. 2013 10  3 versus 12 Hemodynamic failure-free Renal-failure-free days at Hepatic-failure-free days at NA
[104]  2 cmH2O days at day 28: 16 (0-- 28 days: 28 (0--28) 28 days 28 (0--28)
(compliance-guided) 23.75) versus 22 (0-- versus 28 (0--28), versus 28 (0--28)
25) days, P ¼ 0.04 P ¼ 0.39 P ¼ 0.08
Kacmarek, CCM. 11.6  2.5 versus 15.8 Cardiac failure as the NA NA NA
2016 [105]  3.8 cmH2O primary cause of death
1 (3%) versus 1 (4%)
Multiple organ failure
as the primary cause of
death 10 (33%) versus
4 (16%)
Cavalcanti, JAMA. 12.0  0.6 versus 16.2 Hypotension 144 (28%) NA NA NA
2017 (ART) [10]  0.7 cmH2O (þ lung versus 174 (35%),
recruitment maneuver) P ¼ 0.03
Hodgson, AJRCCM. 11.7  3.0 versus 16.1 Severe hypotension 12 NA NA NA
2019 (PHARLAP)  3.6 cmH2O (with (21%) versus 20 (35%),
[101] staircase recruitment P ¼ 0.12
maneuver)
Beitler, JAMA. 2019 16  4 versus 17 NA RRT: 21 (21%) versus 32 NA NA
[111]  6 cmH2O (guided by (33%), P ¼ 0.056
esophageal pressure)

Effects related to PEEP (reported as low versus high PEEP) are difficult to analyze, as modification in PEEP is usually integrated in a more global ventilator strategy.

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 Effects of positive end-expiratory pressure Joseph et al.

7. Sahetya SK, Goligher EC, Brower RG. Fifty years of research in ARDS.
risk of overdistension in already open alveoli. In this Setting positive end-expiratory pressure in acute respiratory distress syn-
narrative review, we describe the pathophysiologi- drome. Am J Respir Crit Care Med 2017; 195:1429–1438.
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