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Recruitment Maneuvers and PEEP Titration

Dean R Hess PhD RRT FAARC

Introduction
Physiologic Concepts
Stress and Strain
Potential for Recruitment
Stress, Strain, and Stress Raisers in the Context of Recruitment
Maneuvers and PEEP
Recruitment Maneuvers
Types of Recruitment Maneuvers
The Evidence
Summary and Recommendations: Recruitment Maneuvers
PEEP Titration
Gas Exchange
Compliance
Pressure-Volume Curve
Stress Index
Esophageal Manometry
Lung Volume
Imaging
How Long to Wait Between Changes in PEEP
Higher Versus Lower PEEP: The Evidence
Summary and Recommendation: PEEP
Summary

The injurious effects of alveolar overdistention are well accepted, and there is little debate
regarding the importance of pressure and volume limitation during mechanical ventilation. The
role of recruitment maneuvers is more controversial. Alveolar recruitment is desirable if it can
be achieved, but the potential for recruitment is variable among patients with ARDS. A step-
wise recruitment maneuver, similar to an incremental PEEP titration, is favored over sustained
inflation recruitment maneuvers. Many approaches to PEEP titration have been proposed, and
the best method to choose the most appropriate level for an individual patient is unclear. A
PEEP level should be selected that balances alveolar recruitment against overdistention. The
easiest approach to select PEEP might be according to the severity of the disease: 510 cm H2O
PEEP in mild ARDS, 10 15 cm H2O PEEP in moderate ARDS, and 1520 cm H2O PEEP in
severe ARDS. Recruitment maneuvers and PEEP should be used within the context of lung
protection and not just as a means of improving oxygenation. Key words: ARDS; mechanical
ventilation; PEEP; recruitment maneuver. [Respir Care 2015;60(11):1688 1704. 2015 Daedalus
Enterprises]

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Introduction recruitment maneuvers and lower versus higher PEEP are


more controversial. The purpose of this narrative review is
The respiratory mechanics of the lungs of patients with to summarize the available literature related to this subject.
ARDS are characterized by their heterogeneity. Some al- Although this is not a systematic review or practice guide-
veoli are relatively normal, some are collapsed, some are line, the intent is to provide a balanced review of the
fluid-filled, and some are consolidated (Fig. 1). This has subject.
given rise to the concept of a baby lung,1 suggesting that
only a fraction of the lung is functional in ARDS. During Physiologic Concepts
positive-pressure ventilation, alveoli that are spared from
the disease process are subject to overdistention (volu- Stress and Strain
trauma). Alveoli that are collapsed are subject to repetitive
opening and closing (opening during inspiration and col- Stress is a force applied to an area, such as pressure
lapse during expiration [atelectrauma]).2 The mechanisms, applied to the alveolus (transalveolar pressure). Strain is
however, for the de-recruitment of dependent alveoli are the physical deformation, or change in shape, of an alve-
controversial. Hubmayr3 has argued that the dependent olus, caused by stress. Stress and strain can be described
lung may be de-recruited because it is filled with fluid, not by the relationship,13
because it is collapsed.
The injurious effects of alveolar overdistention have PL (stress) specific lung elastance
been well accepted since publication of the seminal ARDS
Network study in 2000,4 showing that ventilation at a tar- V/functional residual capacity (strain),
get tidal volume (VT) of 6 mL/kg of predicted body weight,
similar to and often called ideal body weight, results in an where PL is the trans-alveolar pressure, and V is the
important reduction in mortality, compared with a VT of change in lung volume above resting functional residual
12 mL/kg predicted body weight. The ARDS Network capacity with the addition of PEEP and VT. Specific lung
study led to the widespread recommendation of ventilation elastance (compliance per lung volume) is constant at
with 6 mL/kg predicted body weight and a plateau pres- 13.5 cm H2O. A harmful threshold of strain is 2. Thus,
sure (Pplat) 30 cm H2O. Subsequent studies have con- the harmful threshold of stress (PL) is 27 cm H2O, and
firmed a survival benefit for low VT ventilation.5,6 Some lower values (eg, 20 cm H2O) are preferred.
studies have reported regional overdistention even with A stress raiser is the result of inhomogeneity within the
Pplat 30 cm H2O, suggesting that there might not be a lungs where regions of collapse border regions of venti-
safe Pplat.7,8 Thus, the lungs should be ventilated with Pplat lation.13 Consider 2 adjacent alveoli fully expanded at a PL
as low as possible. Moreover, there is evidence supporting of 30 cm H2O. If one of the 2 regions collapses, the ap-
the use of a VT of 6 mL/kg predicted body weight in all plied force concentrates in the other, thereby increasing its
mechanically ventilated patients and suggesting that large strain and stress. Mead et al14 calculated the result if the
VT might contribute to the development of ARDS.9 The volume ratio of the 2 regions goes from 10:10 (ie, both
use of conventional ventilation in patients with ARDS has regions distended) to 10:1 (one region distended and the
been reviewed elsewhere.10-12 other collapsed). Because the area is V/0.66, a volume
Although volume and pressure limitation has become ratio of 10:1 is equal to an area ratio of (10/1)/0.66, or
well accepted as a lung-protective strategy, the roles of 4.57, thereby increasing the stress of the open unit to
137 cm H2O. The stress of the open regions therefore
increases from 30 cm H2O to 137 cm H2O.
Dr Hess is affiliated with Massachusetts General Hospital, Harvard Med-
ical School, and Northeastern University, Boston, Massachusetts. Potential for Recruitment
Dr Hess has disclosed relationships with Philips Respironics, Bayer,
McGraw-Hill, Jones and Bartlett, UpToDate, and the American Board of The benefit of recruitment maneuvers and PEEP might
Internal Medicine. be related to the potential for alveolar recruitment in the
lungs of patients with ARDS. Gattinoni et al15 tested the
Dr Hess presented a version of this paper at the 30th New Horizons
Symposium at the AARC Congress 2014, held December 10, 2014, in potential for recruitment in 68 subjects with ARDS using
Las Vegas, Nevada. computed tomography (CT) of the lungs during breath-
holds at airway pressures of 5, 15, and 45 cm H2O. They
Correspondence: Dean R Hess PhD RRT FAARC, Respiratory Care defined the percentage of potentially recruitable lung as
Services, Ellison 401, Massachusetts General Hospital, 55 Fruit Street,
Boston, MA 02114. E-mail: dhess@mgh.harvard.edu the proportion of lung tissue in which aeration was re-
stored at airway pressures between 5 and 45 cm H2O.
DOI: 10.4187/respcare.04409 They found that the potential for recruitment varied widely.

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Table 1. Methods to Achieve Alveolar Recruitment

Treatment of underlying disease process: removal of airway


obstruction, diuresis, treatment of infection
Sustained inflation followed by decremental PEEP
Stepwise recruitment (incremental PEEP)
Airway pressure release ventilation
High frequency oscillatory ventilation
Sigh
Prone positioning

Stress, Strain, and Stress Raisers in the Context of


Recruitment Maneuvers and PEEP

The potential benefit or harm of recruitment maneuvers


and PEEP can be illustrated physiologically through con-
sideration of stress, strain, and stress raisers. In the setting
of low potential for recruitment, an increase in alveolar
pressure results in overdistention of already open alveoli,
and this is magnified due to the effect of stress raisers. In
this setting, VT should be reduced to as low as tolerated to
decrease Pplat and minimize the effect of stress raisers.
Fig. 1. A: Schematic representation of the heterogeneity of the With low potential for alveolar recruitment, lower PEEP
lungs of patients with ARDS. Normal alveoli are subject to injury should be set. On the other hand, when there is a greater
due to overdistention, whereas collapsed alveoli are subject to potential for recruitment, the addition of higher levels of
injury due to cyclic opening and closing throughout the respiratory PEEP results in alveolar stability and better homogeneity
cycle. B: Chest CT of a patient with ARDS. Note that the collapse
and consolidation are primarily in the dependent lung zones. The
within the lungs. Because the volume is distributed to a
nondependent regions appear relatively normal. larger number of alveoli, strain (and subsequently stress) is
reduced. The greater number of open alveoli also reduces
the effect of stress raisers. It thus follows that attempts at
Subjects with a higher percentage of potentially recruitable alveolar recruitment and higher PEEP might result in ben-
lung had a lower PaO2/FIO2, lower compliance, and a higher efit or harm.
dead-space fraction. A PaO2/FIO2 150 at a PEEP of
5 cm H2O and a decrease in dead space (ie, decrease in Recruitment Maneuvers
PaCO2) or an increase in compliance when PEEP was in-
The application of low VT ventilation limits injury from
creased from 5 to 15 cm H2O identified subjects with a
alveolar overdistention. However, it does not address in-
greater potential for recruitment and thus might inform the
jury from repetitive alveolar opening and closing. A re-
use of recruitment maneuvers or higher levels of PEEP.
cruitment maneuver (Table 1) is a sustained increase in
Perhaps the most important finding from this study was
airway pressure with the goal to open collapsed alveoli,
that the lungs of some subjects with ARDS are highly after which sufficient PEEP is applied to keep the lungs
recruitable, whereas others may have a low potential for open.18 The goals of a recruitment maneuver are to serve
recruitment. as part of a lung protection strategy and to improve oxy-
The level of PEEP might affect PaO2/FIO2 and thus genation. It should be appreciated that alveolar recruitment
mask ARDS severity.16 Chiumello et al17 used whole- can be achieved without a recruitment maneuver per se.
lung CT to assess lung recruitability at the level of For example, removal of a mucous plug will promote re-
PEEP selected clinically (11 3 cm H2O), at 5 cm H2O, cruitment of the distal lung, and a change in patient posi-
and at 15 cm H2O. Only when ARDS severity was tion might promote recruitment of previously collapsed
classified at 5 cm H2O PEEP did lung recruitability alveoli. Although recruitment maneuvers have been in
increase with severity; lung recruitability was greatest vogue among some clinicians, the advice of Hubmayr3
with severe ARDS (PaO2/FIO2 100) and least with mild should be remembered: Maximizing oxygen tension
ARDS (PaO2/FIO2 200). The authors concluded that the through the use of aggressive recruitment may be gratify-
Berlin definition assessed at 5 cm H2O allows evalua- ing in the short-term, but at this point, who can say that it
tion of lung recruitability. prevents lung injury and promotes alveolar repair?

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Types of Recruitment Maneuvers mon, but serious complications were infrequent. They rec-
ommended that, given their uncertain benefit and the po-
A sustained inflation is the recruitment maneuver that tential for complications with repeated application, the
has probably been used most commonly. A common ap- routine use of sustained inflation recruitment maneuvers is
proach has been to set the ventilator to CPAP mode and not justified.
increase the pressure to 30 40 cm H2O for 30 40 s while The optimal duration of a sustained inflation recruit-
monitoring the patient for signs of adverse effects, such as ment maneuver in subjects with ARDS was evaluated by
hemodynamic compromise. More aggressive techniques Arnal et al,23 who applied a 40-cm H2O sustained inflation
add pressure-controlled breaths during the PEEP increase for 30 s in 50 subjects within the first 24 h of meeting
(eg, pressure control of 10 20 cm H2O with a breathing ARDS criteria. They found that most of the recruitment
frequency of 10 breaths/min and an inspiration-expiration occurs during the first 10 s of the maneuver, but hemody-
ratio of 1:1.)18 There was much enthusiasm for the use of namic impairment was significant after 10 s of initiation.
recruitment maneuvers after the report by Amato et al19 of An approach that has been advocated is application of a
a survival benefit associated with an open lung strategy. recruitment maneuver followed by a decremental PEEP
The ARDS Network investigated the use of recruitment titration (open lung approach).24 With this approach, a
maneuvers.20 In 69 subjects, they applied recruitment ma- recruitment maneuver is applied, after which the PEEP is
neuvers (CPAP of 35 45 cm H2O for 30 s), compared set at a high level (eg, 20 25 cm H2O). PEEP is then
with sham recruitment maneuvers (no change in ventilator decreased in 2-cm H2O decrements, and the compliance is
settings). The responses to recruitment maneuvers were measured at each step to determine best compliance. Oth-
highly variable. In 10 instances, SpO2 increased by 59% ers have used arterial oxygenation25-27 or dead space28
during the first 10 min, but in 14 instances, SpO2 decreased rather than compliance to identify best PEEP during the
by 1 4% after initiating the recruitment maneuver and did decremental PEEP titration. After using either compliance
not return to baseline SpO2 within 10 min. After 6 h, re-
or oxygenation to identify the pressure at which recruit-
spiratory system compliance increased significantly more
ment is not maintained, the recruitment maneuver is then
after sham recruitment maneuvers. Hypotension and de-
repeated, after which PEEP is set 2 cm H2O greater than
saturation were more prevalent with the application of
the level identified as best compliance.
recruitment maneuvers than sham. Due to these results, the
In a provocative editorial, Marini29 suggests that there
routine use of recruitment maneuvers was not continued in
are good reasons to retire the sustained inflation recruit-
the ARDS Network studies.
ment maneuver from clinical practice. In its place, he sug-
Meade et al21 conducted a prospective multi-center phys-
gests that stepwise approaches are perhaps more effective
iologic study of sustained inflation recruitment maneuvers
than abrupt applications of the same peak pressure. More-
in 28 consecutive subjects with a PaO2/FIO2 250. A re-
cruitment maneuver was applied at 35 cm H2O for 20 s. If over, the graded rise of pressure is better tolerated from a
the initial response was unclear, a second recruitment ma- hemodynamic standpoint. In his words, clinicians are well
neuver at a pressure of 40 cm H2O and then a third at advised to relegate this once useful clinical tool to the
45 cm H2O or for longer periods (30 s and then 40 s) was growing archive of historically instructive but now obso-
applied. There was no net effect on oxygenation or pul- lete methodologies.
monary mechanics following the first or subsequent re- An example of a stepwise recruitment maneuver is shown
cruitment maneuvers. Augmenting the inflation pressure in Figure 2. This approach utilizes an incremental PEEP
or duration had no significant effect. For the 122 recruit- titration and balances recruitment against overdistention.
ment maneuvers applied, 5 subjects developed ventilator PEEP is increased in increments of 25 cm H2O with a
asynchrony, 3 appeared uncomfortable, 2 experienced tran- fixed VT of 6 mL/kg ideal body weight using volume
sient hypotension, and 4 developed barotrauma that re- control ventilation. Driving pressure (Pplat PEEP), com-
quired intervention. These results do not support the use of pliance, SpO2, and blood pressure are monitored at each
recruitment maneuvers in addition to usual care for ARDS. step. PEEP is increased if there is evidence of recruitment:
A secondary analysis was performed by Fan et al22 of decreased driving pressure, Pplat 30 cm H2O, or increased
data from a randomized controlled trial of an open lung SpO2. PEEP (or perhaps VT) is decreased to the previous
ventilation strategy that included sustained inflation re- step if there are indications of overdistention: increased
cruitment maneuvers. Desaturation and hypotension from driving pressure, Pplat 30 cm H2O, hypotension, or de-
recruitment maneuvers occurred in 22% of all subjects, but creased SpO2. Each step is 35 min unless there is an
new air leak through an existing chest tube was uncom- adverse effect (hypotension, desaturation) that prompts a
mon (5%). The number of recruitment maneuvers was decrease in PEEP to the previous step. An alternative ap-
associated with increased risk. The authors concluded that proach uses a fixed level of pressure control as the PEEP
complications related to recruitment maneuvers were com- is increased; evidence is lacking that one approach is bet-

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strated with HFOV. In one randomized clinical trial, Young


et al35 found no significant difference between conven-
tional ventilation and HFOV. Ferguson et al36 randomly
assigned adults with new-onset, moderate to severe ARDS
to HFOV or to a control strategy targeting lung recruit-
ment with the use of low VT and high PEEP. The study
was stopped early with an in-hospital mortality of 47% in
the HFOV group, compared with 35% in the control group
(relative risk of death with HFOV 1.33, 95% CI 1.09
1.64). These studies bring into question whether HFOV is
a viable approach in adults with ARDS.37
A sigh function was available on ventilators in the 1970s
and 1980s. But interest in the use of sigh diminished, and
this feature was removed from many ventilators. Interest
in the use of sigh has reemerged, particularly in patients
ventilated with pressure support. Periodic sighs can be
provided using modes such as the PCV mode (called
biphasic positive airway pressure in Europe) of the Drager
ventilator or the BiLevel mode of the Puritan-Bennett 840
or 980 ventilators. Several studies have evaluated the ef-
fect of sighs.38-42 In the most recent of these, Mauri et al42
examined the effect of adding a sigh to pressure-support
ventilation in 20 critically ill subjects with a PaO2/FIO2
300. They used biphasic positive airway pressure at
35 cm H2O for 3 4 s at rates of 2 sighs/min, 1 sigh/min,
and 1 sigh/2 min. The pressure support level was
Fig. 2. A: Schematic representation of a stepwise recruitment ma- 8 2 cm H2O, PEEP was 8 2 cm H2O, and FIO2 was
neuver. B: An example of a stepwise recruitment maneuver in a
patient with severe ARDS due to H1N1 infection. When PEEP is
0.5 0.1. Global and regional end-expiratory lung vol-
increased to 25 cm H2O, there is an improvement in SpO2, but the ume were estimated using electrical impedance tomogra-
Pplat is unacceptably high. The PEEP and tidal volume are de- phy. With sigh, PaO2 improved (from 85 mm Hg to
creased so that the Pplat and driving pressure are acceptable. The 108 mm Hg on average). Sigh-induced alveolar recruit-
PEEP was increased every 25 min. ment of previously collapsed regions occurred both in de-
pendent and nondependent lung zones, suggesting that it
ter than the other, and the choice is determined by indi- might result in more homogeneous distribution of tidal
vidual bias. ventilation. A limitation of this study is that the authors
Several ventilator modes are used to promote alveolar only evaluated the effects of sigh; whether similar results
recruitment. Airway pressure release ventilation allows pa- would have occurred with an increase in PEEP is un-
tients to breathe spontaneously while receiving high air- known.
way pressure with an intermittent pressure release. The Prone positioning promotes recruitment of non-aerated
high pressure is used for alveolar recruitment. By promot- alveoli, which results in improved oxygenation and makes
ing spontaneous breathing, it might improve alveolar re- the lung more homogeneous.43-45 Prone position may re-
cruitment to the dorsal caudal regions of the lungs.30 Al- duce lung stress and strain in severe ARDS. Thus, prone
though arterial oxygenation might be better with airway positioning might be considered a recruitment maneuver.46
pressure release ventilation, evidence is lacking to support One randomized controlled trial47 and several meta-anal-
improved outcomes.31-33 Given that the trans-alveolar dis- yses report a survival benefit for prone position,48,49 par-
tending pressures are probably high during spontaneous ticularly in severe ARDS.43
breathing with airway pressure release ventilation, the po-
tential for lung injury is of concern.34 The Evidence
High frequency oscillatory ventilation (HFOV) has also
been used to increase airway pressure and promote alve- Despite the clinical and academic interest in recruitment
olar recruitment. It was hoped that the delivery of a small maneuvers, most of the studies have been physiologic as-
VT and a high mean airway pressure with HFOV would sessments, and there have been few outcome studies. In
improve alveolar recruitment with less risk of overdisten- the open lung approach of Amato et al,19 recruitment ma-
tion. A survival benefit, however, has not been demon- neuvers were a CPAP of 35 40 cm H2O applied for 40 s.

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Although this study included recruitment maneuvers as Table 2. Methods for Setting PEEP in Patients With ARDS
part of a lung-protective ventilation strategy that resulted
Gas exchange
in better patient outcomes, the contribution of recruitment
Compliance
maneuvers to the other interventions is unclear. Villar et al50
Pressure-volume curve
conducted a study similar to that of Amato et al19, except Stress index
that they did not use recruitment maneuvers as used in the Esophageal manometry
Amato et al19 study. Interestingly, they found that a me- Lung volume
chanical ventilation strategy with higher PEEP and lower Imaging
VT had a beneficial impact on outcome in patients with
severe ARDS, this without the use of a recruitment ma-
neuver per se.
Meade et al51 compared a low-VT ventilation strategy 2. Alveolar recruitment is desirable if it can be achieved
with an open-lung approach, which combined low VT, safely, but there is variable potential for recruitment
recruitment maneuvers, and high PEEP. Unlike in the pa- among patients with ARDS.
per by Amato et al,19 the open lung approach resulted in no 3. A stepwise recruitment maneuver is preferred over sus-
significant difference in hospital mortality compared with tained inflation.
a low-VT ventilation strategy, although it did improve sec- 4. Complications of recruitment such as hypotension and
ondary end points related to hypoxemia and the use of desaturation are common but temporary; complications
rescue therapies. Hodgson et al52 conducted a randomized such as barotrauma appear to be rare.
controlled trial comparing an open lung strategy with a 5. If a recruitment maneuver is effective, sufficient PEEP
stepwise recruitment maneuver with a PEEP strategy us- is necessary to maintain the recruitment.
ing the ARDS Network PEEP/FIO2 table.4 There were only 6. Evidence is not sufficient to recommend the routine use
10 subjects in each group, however, which makes difficult of recruitment maneuvers as standard practice.
any meaningful interpretation.
Suzumura et al53 conducted a meta-analysis to assess PEEP Titration
the effects of recruitment maneuvers on clinical outcomes
in subjects with ARDS. Their review identified 10 ran- In the first clinical description of ARDS, Ashbaugh et
domized controlled trials of 1,594 subjects. For the out- al54 reported their use of PEEP in 5 subjects as a thera-
come of in-hospital mortality, the meta-analysis found a peutic trial of apparent value. Soon thereafter, Downs
risk ratio of 0.84 (95% CI 0.74 0.95). However, the qual- et al55 reported their experience with incremental PEEP
ity of evidence was considered low because recruitment titration on PaO2, suggesting that PEEP should be increased
maneuvers were usually conducted together with other ven- to obtain optimal PaO2 without hemodynamic compromise.
tilatory interventions, making it difficult to isolate the ef- This led to the recommendation of Kirby et al56 to use very
fect of the recruitment maneuvers per se. There were no high levels of PEEP to effect the greatest reduction in
differences in the rates of barotrauma or the need for res- shunt fraction. These super high levels of PEEP (as high as
cue therapies. There was no effect of recruitment maneu- 44 mm Hg [60 cm H2O]) most assuredly resulted in over-
vers in terms of duration of mechanical ventilation, ICU distention of some parts of the lungs.
stay, and hospital stay. When considering only studies Setting PEEP appropriately is now recognized as an
with a low risk of bias, there was no significant effect of important aspect of a lung-protective ventilation strategy
recruitment maneuvers on mortality (risk ratio 0.90, 95% CI and not just a strategy to improve oxygenation. Setting
0.78 1.04). Perhaps the greatest issue with this meta-anal- PEEP levels 5 cm H2O may be harmful in the acute
ysis is the considerable heterogeneity in how individual phase of ARDS.57 Setting PEEP appropriately is a balance
studies were conducted, such as the specific method used between maintaining alveolar recruitment and avoiding al-
to perform the recruitment maneuver and the method used veolar overdistention. There are several methods that have
to set PEEP after the recruitment maneuver. The authors been proposed for PEEP titration in an individual patient
correctly conclude that, although recruitment maneuvers with ARDS (Table 2). Although non-respiratory adverse
may decrease the mortality of patients with ARDS, the effects of PEEP are important (eg, hemodynamic, renal,
currently available evidence is not definitive. neurologic), this review will focus on respiratory effects.

Summary and Recommendations: Recruitment Gas Exchange


Maneuvers
Oxygenation is a commonly used target when selecting
1. Evidence is lacking that the use of recruitment maneu- PEEP for a patient with ARDS. However, this physiologic
vers improves patient outcomes. target should be viewed with some caution. Goligher et al58

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conducted a secondary analysis of the Lung Open Venti- level to individual lung mechanics and because they are
lation study51 and the ExPress63 study to examine the re- based on expert opinion rather than empiric evidence.
lationship between the initial response to changes in PEEP They are, however, very easy to apply at the bedside
after randomization and mortality. An increase in PaO2/FIO2 and have the face validity of having been used in all of
when PEEP was increased was associated with reduced the ARDS Network studies. One of the tables is more
mortality (OR 0.80, 95% CI 0.72 0.89) for an increase of aggressive in the approach to PEEP than the other. Given
25 in PaO2/FIO2, particularly in subjects with a PaO2/FIO2 that the lungs of patients with more severe ARDS are
150. A decrease in PaO2/FIO2 after an increase in PEEP likely to be more recruitable and given evidence for
was associated with an increase in mortality (Fig. 3). The better outcomes with higher PEEP in moderate and se-
PaO2/FIO2 response after decreased or unchanged PEEP was vere ARDS, it would be reasonable to use the lower
not associated with mortality. These results suggest that PEEP table strategy for mild ARDS (less potential for
improved oxygenation after an increase in PEEP might be recruitment) and the higher PEEP table strategy for mod-
associated with a lower risk of death. Thus, the oxygen- erate and severe ARDS (greater potential for recruit-
ation response to PEEP might be used to predict whether ment).12 Intellivent is a ventilator mode that incorpo-
an individual patient will benefit from a higher versus a rates the ARDS Network tables into the ventilator
lower PEEP setting. software.60-62
Combinations of PEEP and FIO2 to maintain a tar- PEEP/FIO2 tables were also used in the Lung Open
geted SpO2 (88 95%) or PaO2 (55 80 mm Hg) have been Ventilation study,51 very similar to those used by the
used in the ARDS Network studies (Fig. 4).59 These ARDS Network. In 51 subjects, Chiumello et al17 com-
tables are criticized because they do not target the PEEP pared the use of this table against 3 other approaches for
setting PEEP: compliance,63 stress index,64 and esoph-
ageal manometry.65 Lung recruitability was assessed by
whole-lung CT scans taken in static conditions at 5 and
45 cm H2O during an end-expiratory and end-inspira-
tory pause. Only the Lung Open Ventilation study table
resulted in PEEP levels related to lung recruitability,
with a progressive increase from mild to moderate and
severe ARDS (Fig. 5). This provides physiologic sup-
port for the use of a PEEP/FIO2 table, such as those used
by the ARDS Network or the Lung Open Ventilation
study.
The appropriate level of PEEP should correspond to the
lowest dead-space fraction (VD/VT), as has been reported
many years ago by Suter et al66 and more recently by
Fengnei et al28 Because end-tidal PCO2 (PETCO2) is deter-
mined, in part, by VD/VT, there has been interest in the use
of capnography to assess best PEEP. In an experimental
model of ARDS, Murray et al67 reported that best PEEP
was associated with the smallest difference between PaO2
and PETCO2. Subsequent clinical studies,68,69 however, have
had mixed results, and thus PETCO2 is not commonly used
Fig. 3. The relationship between oxygenation response and mor- to determine best PEEP.
tality depends on whether the PEEP was increased. Changes in Mainstream capnography measures CO2 excretion.
oxygenation after increased PEEP are strongly associated with Theoretically, an increase in PEEP that causes overdis-
adjusted mortality, whereas changes in oxygenation with de-
creased or unchanged PEEP are not associated with adjusted
tention will disrupt the steady-state balance between
mortality. Shaded zones represent 95% confidence intervals. From CO2 production and CO2 excretion.70 This is due to the
Reference 58, with permission.

Fig. 4. Tables used to set combinations of FIO2 and PEEP in the ARDS Network study. Data from Reference 59.

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respiratory failure; because some subjects were reported


to be breathing an FIO2 of 0.21, presumably some did
not have ARDS. They made a number of physiologic
measurements as they conducted an incremental PEEP
titration from 0 to the level at which there was a marked
decrease in cardiac output. VT was set at 1315 mL/kg
(the authors do not indicate whether this was ideal body
weight or actual body weight). They found that the
PEEP corresponding to maximum oxygen delivery cor-
responded to the lowest VD/VT and the highest compli-
ance. The best PEEP varied from 0 to 15 cm H2O among
subjects.
Pintado et al71 evaluated the effect of setting PEEP at
the highest compliance on oxygenation, multiple-organ dys-
function, and survival in subjects with ARDS. VT was set
at 6 8 mL/kg ideal body weight, and Pplat was maintained
30 cm H2O. Subjects were randomized to PEEP titration
using the low PEEP/FIO2 table of the ARDS Network or
compliance-guided PEEP. For the compliance group, PEEP
was increased in steps of 2 cm H2O, beginning at 5 cm H2O
and without an upper limit. PEEP was adjusted once daily
in the morning. Subjects in the compliance-guided group
had a lower 28-d mortality (20.6% vs 38.9%), although
this did not reach statistical significance due to the small
sample size (n 70). Multiple-organ dysfunction-free days
(median 6 vs 20.5 d, respiratory failure-free days (median
7.5 vs 14.5 d), and hemodynamic failure-free days (me-
dian 16 vs 22 d) at 28 d were significantly lower in sub-
jects with a compliance-guided setting of PEEP. In a
physiologic study, Fengmei et al28 reported that, using
an open lung approach and decremental PEEP titration,
best PEEP was similar for highest compliance and low-
est VD/VT.
The randomized controlled trial by Mercat et al63
compared a low PEEP strategy of 59 cm H2O (n 382)
Fig. 5. Relationship between the average PEEP and end-expira- with a PEEP strategy set to reach a Pplat of 28 30 cm H2O
tory transpulmonary pressure levels selected with the 4 bedside (n 385). The maximum Pplat strategy is essentially a
methods and lung recruitment. From Reference 17, with permission. best compliance, or lowest driving pressure, strategy
because a higher PEEP for the same Pplat means that
Pplat PEEP must be lower. Although 28-d mortality
effects of overdistention on dead space and on venous was not different between groups, the Pplat group did
return. Thus, there should be a temporary decrease in have better lung function and a shorter duration of me-
CO2 excretion until a new steady state is reached. This chanical ventilation.
physiologic effect of PEEP has not been well studied, A recent analysis of data from 9 randomized controlled
and thus the use of CO2 excretion during PEEP titration trials (N 3,562 subjects with ARDS) evaluated the re-
is not commonly used. lationships between driving pressure (Pplat PEEP) and
mortality.72 Driving pressure is the denominator of the
Compliance compliance equation: compliance VT/(Pplat PEEP).
The results of this post hoc analysis suggest an increased
A common approach used to determine optimum PEEP risk in mortality for driving pressure 15 cm H2O. This
is based on incremental or decremental PEEP titration has implications for PEEP titration. If an increase in
and selecting the level of PEEP with the highest com- PEEP results in overdistention, driving pressure will
pliance. Suter et al66 first described this in 1975. They increase with a potential increased risk of mortality.
conducted a physiologic study of 15 subjects in acute On the other hand, if an increase in PEEP results in

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Fig. 6. Lung CT images were obtained while tracing the curve in static conditions. Note that recruitment only starts when airway
pressure is higher than the lower inflection point (LIP) of the inspiratory limb and continues up to the maximum pressure reached, even
above the upper inflection point (UIP). There is, however, no de-recruitment when airway pressure decreases from this level to the
expiratory point of maximum curvature (PMC). With pressures below this point, de-recruitment starts and continues along the rest of
the expiratory limb of the curve. From Reference 73, with permission.

recruitment and improved compliance, the driving issues preclude routine use. Correct P-V curve measure-
pressure will decrease, which might afford a survival ment requires sedation and often paralysis. It is often
benefit. difficult to identify the inflection points, and precise
identification may require mathematical curve fitting.76
Pressure-Volume Curve Esophageal pressure measurement is needed to separate
lung from chest wall effects.77 Although the inflation
The pressure-volume (P-V) curve displays the rela- limb of the P-V curve is most commonly measured, the
tionship between volume and pressure as the lungs are deflation limb may be more useful. Because the P-V
inflated and deflated (Fig. 6).74 It can be measured with curve treats the lungs as a single compartment and be-
a supersyringe, constant slow inflation (10 L/min), or cause the lungs of patients with ARDS are heteroge-
measurement of Pplat at various inflation volumes.75 Cor- neous, recruitment has been shown to occur along the
rect interpretation of the P-V curve during non-constant entire inflation P-V curve.73 The shape of the P-V curve
flow ventilation (eg, pressure-controlled ventilation), might not be related to recruitment and might be ex-
during spontaneous breathing, and with high inspiratory plained by other mechanisms, such as inflation of an
flows is problematic. Some ventilators measure the P-V edematous lung.3
curve with a constant slow inflation, and some are able One approach to setting PEEP is to perform a recruit-
to measure both inflation and deflation curves. ment maneuver followed by a decremental PEEP titra-
Amato et al19 popularized an approach for setting tion.78 The intent is to shift ventilation from the inflation
PEEP based upon the P-V curve and identification of limb to the deflation limb of the P-V curve. This results in
lower and upper inflection points. The lower inflection a greater lung volume for the same applied PEEP. Al-
point is thought to represent the pressure at which a though this is theoretically attractive, whether it affects
large number of alveoli are recruited, and Amato et al19 important patient outcomes is unclear. Performing P-V
recommended that PEEP be set 2 cm H2O above this curves and measuring lung volume corresponding to dif-
pressure. An upper inflection point on the P-V curve ferent PEEP levels can assess PEEP-induced lung recruit-
might indicate overdistention, or, alternatively, it might ment. Lung recruitment at a given airway pressure is the
represent the end of recruitment. difference in lung volume between P-V curves starting
Despite prior enthusiasm for the use of P-V curves to at different end-expiratory lung volumes corresponding to
set the ventilator in patients with ARDS, a number of different levels of PEEP.73

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Fig. 7. Top: Stress index (SI) in a patient early in the course of ARDS. In this case, the stress index improved as PEEP was increased.
Bottom: Stress index in a patient late in the course of ARDS. In this case, the SI improved as PEEP was decreased. Pplat plateau pressure.
From References 10 and 79.

Stress Index stress index approach. Plasma concentrations of inflam-


matory mediators were significantly lower during the stress
The stress index79 is based on the shape of the pressure- index approach. The results of this study suggest that, at
time curve during constant flow volume control ventila- least in these subjects, the ARDS Network low PEEP/FIO2
tion (Fig. 7). A linear increase in pressure (stress index 1) table can contribute to overdistention.
suggests alveolar recruitment without overdistention. A In 30 subjects with ARDS, Huang et al80 randomly
decrease in compliance as the lungs are inflated (upward set PEEP according to stress index, oxygenation, com-
concavity, stress index 1) suggests overdistention, and pliance, or P-V curve. VT was set at 6 mL/kg, and all
the recommendation is to decrease PEEP, VT, or both. subjects were paralyzed. PEEP determined by stress in-
An increase in compliance as the lungs are inflated dex (15.1 1.8 cm H2O) was similar to that determined
(downward concavity, stress index 1) suggests tidal by oxygenation (14.5 2.9 cm H2O) but higher than that
recruitment and the potential for additional recruitment, titrated by compliance (11.3 2.5 cm H2O) and P-V
and the recommendation is to increase PEEP. The stress curve (12.9 1.6 cm H2O).
index can be determined by curve fitting and is incor- In a physiologic study, Terragni et al7 examined the
porated into the software of one commercially available accuracy of Pplat and stress index to identify injurious ven-
ventilator. tilation in subjects with ARDS. Using CT to identify over-
In 15 subjects with ARDS, Grasso et al64 randomly distention, they found that injurious ventilation was asso-
applied PEEP using the ARDS Network low PEEP/FIO2 ciated with a Pplat 25 cm H2O and a stress index of
table or stress index. VT was 6 mL/kg in all subjects. In all 1.05. It is interesting to note that PEEP, on average, was
subjects, the stress index demonstrated alveolar hyperin- higher in the setting of overdistention, although VT values
flation with the ARDS Network strategy. Thus, PEEP was were similar. The authors also found that bronchoalveolar
lower with the stress index approach than with the ARDS lavage concentrations of inflammatory mediators were
Network approach. Compliance was also better with the higher in subjects with overdistention.

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Fig. 8. Esophageal pressure, with airway pressure, can be used to determine end-inspiratory and end-expiratory transpulmonary pressure.
In this example, PEEP is set so that the end-expiratory transpulmonary pressure is zero. See text for details. PIP peak inspiratory
pressure; Pplat plateau pressure. From Reference 79.

Esophageal Manometry Lung Volume

Chest wall compliance may be reduced in patients with The end-expiratory lung volume (EELV) can be mea-
ARDS. This can result in an increase in pleural pressure, sured during mechanical ventilation using helium dilu-
and if pleural pressure is high relative to alveolar pressure, tion or nitrogen washout techniques.83-85 A modified
there is a potential for alveolar collapse.81 Thus, it may be nitrogen washout technique is available on one com-
desirable to set PEEP greater than end-expiratory pleural
mercially available ventilator. If EELV is measured on
pressure. The use of an esophageal balloon to estimate
0 PEEP and then again after PEEP is added, it is pos-
pleural pressure has been advocated to allow a more pre-
sible to calculate strain, an important determinant of
cise setting of PEEP (Fig. 8). In a study by Talmor et al,65
lung injury. This would seem attractive during PEEP
61 subjects with ARDS were randomly assigned to PEEP
adjusted according to measurements of esophageal pres- titration. A PEEP-induced increase in EELV, however,
sure or according to the ARDS Network low PEEP table. might be the result of recruitment, or it might be due to
The strategy using esophageal pressure resulted in signif- overdistention of already open alveoli. Thus, EELV by
icantly greater oxygenation and compliance. A multi-cen- itself may not be useful to assess PEEP response. The
ter study is under way to determine whether this use of value of EELV to assess PEEP response might be im-
esophageal pressure to set PEEP improves patient out- proved if it is combined with measurement of compli-
comes (ClinicalTrials.gov registration NCT01681225). Re- ance.86,87 Compliance can be used to estimate the in-
gardless of whether esophageal manometry proves useful crease in EELV if no recruitment occurs. For example,
for routine setting of PEEP, it might be beneficial in se- if the compliance is 30 mL/cm H2O, one can predict an
lected patients, such as those with morbid obesity or ab- increase in EELV of 150 mL if PEEP is increased from
dominal hypertension.82 5 cm H2O to 10 cm H2O. In this example, if EELV

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Fig. 9. Recruitment maneuver ultrasound evaluation. A: Consolidated parenchymal area in a patient with ARDS. B: The hyperreflectant air
aspect reaching the pulmonary consolidation and the progressive reduction of its compactness. C: Recruitment. Consolidation is dimen-
sionally reduced and partly replaced by normal air parenchyma, full of B lines, an expression of interstitial thickening. From Reference 97.

increases by 150 mL, the additional volume can be EIT is a noninvasive, radiation-free monitoring tool that
attributed to recruited volume. allows real-time imaging of ventilation. Electrical imped-
ance tomography uses high frequency and low amplitude
Imaging electrical currents, typically through 16 or 32 electrodes
around the thorax, to obtain images of a cross section of
Imaging techniques hold promise for setting PEEP be- the lungs.98 Electrical impedance tomography has the po-
cause, unlike evaluations of mechanics, they allow assess- tential for bedside use to estimate regional alveolar col-
ment of heterogeneity within the lungs.88-91 CT imaging lapse and overdistention.98-103 To date, experience with
has long been the accepted standard for assessments of electrical impedance tomography in North America is lim-
alveolar recruitment and overdistention. Digital chest ra- ited.
diography done at the bedside with PEEP of 5 and Lung ultrasound and electrical impedance tomography
15 cm H2O might also be useful to detect recruited lung show promise as technologies to allow application of me-
volume.92 chanical ventilation. Ultrasound technology is widely avail-
Ultrasound uses an emission frequency of 57 MHz for able in the ICU. Respiratory therapists should develop the
visualization of the lung. The probe should have a small skills to use lung ultrasound to assess real-time lung aer-
convex tip that can be easily placed on intercostal spaces ation and the response to changes in ventilator settings.
to allow an acoustic window on the parenchyma. The ul- Electrical impedance tomography is not yet widely avail-
trasound pattern corresponds to the degree of lung aera- able, but this is also a technology in which respiratory
tion.88,93-96 This allows the potential for the use of ultra- therapists can gain expertise.
sound to monitor the response to recruitment maneuvers
and PEEP titration (Fig. 9).97 In 40 subjects with ARDS,
How Long to Wait Between Changes in PEEP
Bouhemad et94 al compared P-V curves and ultrasound at
PEEP of 0 and 15 cm H2O. A significant correlation was
found between PEEP-induced lung recruitment assessed A practical question at the bedside is how much time is
by P-V curves and ultrasound reaeration score, suggesting necessary to assess a change in PEEP. If too little time is
that PEEP-induced lung recruitment can be adequately es- allowed, the effect of the change in PEEP will not be fully
timated with bedside ultrasound. A limitation of lung ul- realized. On the other hand, if too much time is allowed,
trasound is that it cannot detect overdistention, and thus it more time will be necessary for the full PEEP titration, and
should be combined with other assessments, such compli- the patient will be potentially subjected to injurious ven-
ance. tilation due to inappropriate PEEP.

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Chiumello et al104,105 conducted a physiologic study to


address this question. When PEEP was decreased, PaO2
and the other oxygenation-related variables significantly
decreased within 5 min and remained unmodified in the
following 55 min. When PEEP was increased, the PaO2
continuously rose, and equilibrium was not reached by
60 min. When PEEP was decreased, compliance was un-
changed at 5 min but decreased over the next 55 min. In
the individual patients, the change of oxygenation-related
variables and compliance at 5 min could predict the changes
recorded after 60 min. Thus, when doing a PEEP titration,
changes in oxygenation and respiratory mechanics after
5 min might be used to judge the direction of change
(improving or worsening), but the full effect might take
60 min.
Fig. 10. Potential effects of an increase in PEEP. If the potential for
Higher Versus Lower PEEP: The Evidence recruitment is low, an increase in PEEP results in a large increase
in plateau pressure (Pplat) (increased driving pressure) to an unsafe
There have been 6 clinical trials that assessed the level. In this case, the potential harm from overdistention probably
outweighs any benefit resulting from increased alveolar recruit-
use of lower versus higher PEEP in subjects with
ment. If the potential for recruitment is high, an increase in PEEP
ARDS.19,50,51,59,63,65 In 2 studies, there was a significant results in little increase in Pplat. In this case, the potential benefit of
mortality reduction in the group who received higher PEEP, increased PEEP probably outweighs the harm due to the small
but a higher PEEP was combined with a lower VT, and increase in Pplat. From Reference 10.
therefore it is unknown whether the mortality benefit is
attributable to higher PEEP.19,50 The ARDS Network and
the Lung Open Ventilation study compared PEEP/FIO2 200). Patients with moderate and severe ARDS likely
tables directing higher or lower PEEP,51,59 and the have more potential for recruitment than patients with
ExPress study63 compared lower PEEP versus a PEEP mild ARDS.
strategy based on compliance. Each of these 3 studies was
negative for the primary outcome of mortality. There are
several potential reasons why these 3 trials were negative: Summary and Recommendations: PEEP
(1) perhaps a higher level of PEEP is not effective; (2)
perhaps the methods used to set PEEP were not the correct 1. PEEP should be selected as a balance between alveolar
approaches; (3) perhaps higher PEEP is not effective in recruitment and overdistention.
unselected patients with ARDS but might be effective in 2. PEEP of 5 cm H2O is probably harmful early in the
patients with a higher potential for recruitment (Fig. 10); course of ARDS.
(4) perhaps these studies were underpowered to show a 3. Randomized controlled trials have failed to show a sur-
difference in outcome.10 vival benefit for the use of higher versus lower levels of
The meta-analysis by Briel et al106 provides some in- PEEP.
sight. Using individual subject data from 3 trials, the mor- 4. Post hoc analysis of randomized controlled trials and a
tality was 32.9% for subjects assigned to treatment with strong physiologic rationale support lower levels of
higher PEEP and 35.2% for subjects assigned to lower PEEP for mild ARDS and higher levels of PEEP for
PEEP (adjusted relative risk 0.94, 95% CI 0.86 1.04). moderate and severe ARDS: 510 cm H2O in mild
However, treatment effects varied, depending on the ARDS, 10 15 cm H2O in moderate ARDS, and 15
severity of ARDS. In subjects with moderate and severe 20 cm H2O in severe ARDS.107
ARDS, the mortality was 34.1% in the higher-PEEP 5. Evidence is not currently available to suggest that one
group and 39.1% in the lower-PEEP group (adjusted approach to setting PEEP leads to better outcomes than
relative risk 0.90, 95% CI 0.811.00). In subjects with other approaches.
mild ARDS, the mortality was 27.2% in the higher- 6. In many hospitals, the PEEP/FIO2 tables of the ARDS
PEEP group and 19.4% in the lower-PEEP group (ad- Network or best compliance can be used for PEEP
justed relative risk 1.37, 95% CI 0.98 1.92). This anal- selection; advanced methods, such as stress index,
ysis suggests that treatment with lower PEEP should esophageal manometry, ultrasound, and electrical im-
be used with mild ARDS, and higher PEEP should pedance tomography, can be used in hospitals with the
be used with moderate and severe ARDS (PaO2/FIO2 necessary equipment and expertise.

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Summary 15. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM,


Quintel M, et al. Lung recruitment in patients with the acute respi-
ratory distress syndrome. N Engl J Med 2006;354(17):1775-1786.
Alveolar recruitment is desirable if it can be achieved 16. Villar J, Perez-Mendez L, Lopez J, Belda J, Blanco J, Saralegui I,
safely. If a recruitment maneuver is considered, the poten- et al. An early PEEP/FIO2 trial identifies different degrees of lung
tial beneficial effects must be weighed against the poten- injury in patients with acute respiratory distress syndrome. Am J
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17. Chiumello D, Cressoni M, Carlesso E, Caspani ML, Marino A,
cruitment against overdistention. Rather than a best PEEP
Gallazzi E, et al. Bedside selection of positive end-expiratory pres-
approach, Gattinoni107 suggests that we should think of a sure in mild, moderate, and severe acute respiratory distress syn-
better PEEP approach as a reasonable compromise among drome. Crit Care Med 2014;42(2):252-264.
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Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on
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