REVIEW

CURRENT
OPINION Mechanical ventilation of the healthy lungs:
lessons learned from recent trials
Fabienne D. Simonis a, Nicole P. Juffermans b,c, and Marcus J. Schultz a,b,d,e

Purpose of review
Although there is clear evidence for benefit of protective ventilation settings [including low tidal volume and
higher positive end-expiratory pressure (PEEP)] in patients with acute respiratory distress syndrome (ARDS),
it is less clear what the optimal mechanical ventilation settings are for patients with healthy lungs.
Recent findings
Use of low tidal volume during operative ventilation decreases postoperative pulmonary complications
(PPC). In the critically ill patients with healthy lungs, use of low tidal volume is as effective as intermediate
tidal volume. Use of higher PEEP during operative ventilation does not decrease PPCs, whereas
hypotension occurred more often compared with use of lower PEEP. In the critically ill patients with healthy
lungs, there are conflicting data regarding the use of a higher PEEP, which may depend on recruitability of
lung parts. There are limited data suggesting that higher driving pressures because of higher PEEP
contribute to PPCs. Lastly, use of hyperoxia does not consistently decrease postoperative infections,
whereas it seems to increase PPCs compared with conservative oxygen strategies.
Summary
In patients with healthy lungs, data indicate that low tidal volume but not higher PEEP is beneficial.
Thereby, ventilation strategies differ from those in ARDS patients.
Keywords
driving pressure, healthy lungs, mechanical ventilation, oxygen target, positive end-expiratory pressure,
tidal volume

INTRODUCTION exchange, such as undergoing an operative proce-

Recognition of ‘ventilator-induced lung injury
(VILI)’ and the broad acceptation of ‘lung-protec-
tive’ ventilation strategies in ICUs worldwide has led
to wide adoption of a strategy using low tidal vol-
umes and higher levels of positive end-expiratory
pressure (PEEP) in patients with the acute respira-
tory distress syndrome (ARDS). More recently, a
high driving pressure level (DP, which is the differ-
ence between PEEP and plateau pressure in volume-
controlled ventilation, or between PEEP and maxi-
mum airway pressure in pressure-controlled venti-
lation) has been identified as a contributor to lung
injury in ARDS, although it is currently not known
whether ventilation strategies aiming at a lower
driving pressure improves outcome.
In contrast, patients with healthy lungs often
receive ventilator settings known to cause VILI [1].
However, it is increasingly recognized that mechani-
cal ventilation is potentially injurious in all recipi-
ents. Of note, most recipients of mechanical
ventilation are patients with healthy lungs, requiring
ventilation for other purposes than compromised gas
dure. Indeed, injury inflicted by the ventilator can
occur within a short period of time [2,3]. Studies in
surgical patients suggest that intraoperative ventila-
tion with higher tidal volumes is associated with an
increased risk for postoperative pulmonary compli-
cations (PPC), including ARDS, which occurs in up to
8% of patients [3]. These complications are associated
with an increased duration of ventilation and hospi-
tal stay [2,3].
Operative patients are most often ventilated in a
controlled mode, whereas many patients on
mechanical ventilation in the intensive care, who
a
Department of Intensive Care, bLaboratory of Experimental Intensive
Care and Anesthesiology (LEICA), Amsterdam University Medical Cen-
ter, cOLVG Hospital, Amsterdam, The Netherlands, dMahidol University,
Bangkok, Thailand and eUniversity of Oxford, Oxford, UK
Correspondence to Nicole P. Juffermans, MD, PhD, Amsterdam UMC
Location AMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
E-mail: n.p.juffermans@amsterdamumc.nl
Curr Opin Crit Care 2021, 27:55–59
DOI:10.1097/MCC.0000000000000787

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Respiratory system
KEY POINTS
! Use of low tidal volume leads to relatively few
pulmonary complications without causing other adverse
events in patients with healthy lungs requiring operative
ventilation or ventilation in the ICU.
! Use of higher PEEP does not improve outcome of
surgical and critically ill patients with healthy lungs.
! Targeting lower driving pressure appears a
reasonable approach.
! Use of hyperoxia should be avoided in surgical and
critically ill patients with healthy lungs.
are not deeply sedated, such as neurologic patients,
are more likely to receive pressure support. However,
strong spontaneous effort may also contribute to
lung injury [4].
In this review, we discuss the available evi-
dence for benefit of protective ventilation strate-
gies in patients with healthy lungs. We aimed to
categorize the evidence in perioperative and criti-
cally ill patients.
LOW TIDAL VOLUMES
Low tidal volume in the operating room
For many years, anesthesiologists believed that high
tidal volumes would recruit collapsed lung parts at
the end of expiration and thereby improve oxygen-
ation, preventing the need for high fractions of
oxygen. In line with this, in a substantial proportion
of patients, intraoperative ventilation is not applied
in a lung-protective manner [5].
However, in four randomized controlled trials
(RCT) on intraoperative ventilation, it was shown
that tidal volume reduction decreases the incidence
of PPCs and improves outcome [2,6–8]. This is
relevant, as there is a strong association between
the development of PPC and worse outcome in
surgery patients [5]. Three of these trials showed
that tidal volume reduction prevented PPCs in nor-
mal ‘two-lung’ ventilation; in an Italian single-cen-
ter trial in patients undergoing open abdominal
surgery, a tidal volume reduction from 9 to 7 ml/
kg predicted body weight (PBW) prevented postop-
erative pulmonary dysfunction [8]. A French multi-
center RCT including patients undergoing major
abdominal surgery [2] and a Chinese single-center
RCT in patients undergoing spinal surgery [6] both
showed a decrease in the incidence of PPCs in
patients ventilated with a tidal volume of 6 ml/kg
PBW opposed to 12 ml/kg PBW.
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
There is also evidence for an optimal tidal vol-
ume in a one-lung ventilation setting. In a French
RCT in patients undergoing lung resection, tidal
volume reduction (10–5 ml/kg PBW) decreased
development of PPC from 22.2 to 13.4%. Of note,
this trial was stopped prematurely because of a low
inclusion rate, which does not allow firm conclu-
sions [7].
Most of the abovementioned results are summa-
rized in a Cochrane review, showing that lower tidal
volumes (<10 ml/kg PBW) decrease the need for
postoperative ventilatory support and development
of pneumonia [9].
Opposed to these findings, a recent Australian
single-center RCT in surgery patients compared low
tidal volume to intermediate tidal volume (6 versus
10 ml/kg PBW), whereas all patients received a PEEP
level of 5 cmH2O and were ventilated in a volume-
controlled mode [10]. In this trial, the use of low
tidal volume did not significantly reduce the devel-
opment of PPC compared with conventional
tidal volume.
Low tidal volume in the intensive care unit
In recent years, investigations on lung-protective
ventilation in critically ill patients without ARDS
have appeared. Two RCTs, a North-American single-
center RCT [11] and a Dutch multicenter RCT [1],
showed that a low tidal volume strategy of 6 ml/kg
PBW compared with 10–12 ml/kg PBW reduced the
incidence of pulmonary complications and ARDS
and shortened the duration of ventilation. These
results were confirmed in several metaanalyses
[12,13] and a large observational trial showed that
low tidal volume was more commonly used world-
wide in the years following [14]. However, whether
the results found in these RCTs where actually
caused by harm from very high tidal volumes, and
not from benefit of low tidal volume was not clear.
Also, concerns about the use of low tidal volumes
remained, including the presumed higher need for
sedation and patient–ventilator asynchrony due to
the necessary higher respiratory rate. This triggered
the ‘PReVENT’ study [15 ], which compared venti-
&&
lation with a low tidal volume to ventilation with an
intermediate tidal volume (4–6 versus 8–10 ml/kg
PBW), using a pragmatic protocol with a preference
to switch to pressure support ventilation when pos-
sible, while accepting the tidal volume range to be
less controllable. There was no difference in any
outcome parameter. It was concluded that in criti-
cally ill patients with healthy lungs who are quickly
weaned, ventilation with a low tidal volume was as
effective as ventilation with an intermediate tidal
volume [15 ]. Although one could argue that a
&&
Volume 27 ! Number 1 ! February 2021

reduction in tidal volume is therefore not needed in
patients with healthy lungs, it is necessary to realize
that ARDS is easily missed. In addition, sicker
patients who cannot be weaned as quickly from
controlled to spontaneous ventilation may also ben-
efit from low tidal volumes. Another argument to
use low tidal volume in patients with healthy lungs
is the potential protection of low tidal volume
against decreased cardiac output [16 ]. Lastly, dis-
&
advantages of ventilation with low tidal volume
were not noted in the PREVENT trial [15 ].
&&
HIGHER POSITIVE END-EXPIRATORY
PRESSURE LEVELS
Higher positive end-expiratory pressure in
the operating room
Three RCTs have suggested benefit of a higher level
of PEEP in patients undergoing general anesthesia
for surgery [2,6,8]. However, all of them actually
studied the effects of bundles of protective ventilator
settings, combining low tidal volumes with a higher
level of PEEP, which makes it difficult to discern the
effect of a (higher) level of PEEP from that of a low
tidal volume. An international multicenter RCT of
intraoperative ventilation in (nonobese) patients
undergoing major abdominal surgery compared a
lower level of PEEP (<2 cmH2O) with higher levels of
PEEP (12 cmH2O including recruitment maneuvers),
whereas all patients received low tidal volume ven-
tilation (8 ml/kg PBW) [17]. This trial showed no
impact of the PEEP level on the occurrence of PPCs,
whereas higher PEEP levels led to negative events
such as hypotension, requiring increased fluid resus-
citation and use of vasopressors [17]. An individual
patient data metaanalysis using data from the four
abovementioned RCTs did not find an association
between improved outcome and the use of higher
levels of PEEP [18].
It is thought that obese patients may particu-
larly benefit from higher PEEP levels. Therefore, a
similar trial with differential PEEP levels and appli-
cation of tidal volume of 7 ml/kg PBW was con-
ducted in obese patients (PROBESE) under general
anesthesia. However, also in obese patients, higher
level of PEEP (12 cmH2O including recruitment
maneuvers) was not better than a lower level of
PEEP (4 cmH2O) with respect to the development
of PPCs [19 ].
&&
These results suggest that regardless of body
composition, high levels of PEEP should not be
applied in patients with healthy lungs during intra-
operative ventilation, as no benefit of high PEEP
levels is shown, while there potential harmful side-
effects.
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Mechanical ventilation of the healthy lungs Simonis et al.
Higher positive end-expiratory pressure in
the intensive care unit
Four RCTs suggest benefit from higher levels of PEEP
in critically ill patients who do not have ARDS [20–
23]. A study found benefit of a strategy using higher
levels of PEEP (11–30 versus 3–10 cmH2O) with
respect to 28-day survival rates [20]. Three other
studies found that patients receiving PEEP levels
between 5 and 8 cmH2O less often progressed to
ARDS compared with ZEEP (0 cmH2O) [21–23]
and had a lower incidence of ventilator-associated
pneumonia compared with patients ventilated with
higher levels of PEEP [21]. However, a meta-analysis
did not find any benefit for patients receiving higher
levels of PEEP [24]. Notably, there was substantial
heterogeneity of the included studies and their
quality was often low.
In observational studies in ICU patients, the
effect of PEEP seems opposite; higher PEEP is benefi-
cial in ARDS patients, but not in patients without
ARDS. This effect can be extrapolated to most
patients; when there is more recruitable lung tissue
(more sick lungs or ARDS), PEEP may be beneficial by
recruiting collapsed lung parts and thereby decreas-
ing the driving pressure. In patients with ‘healthy’
lungs, in who the lung is mostly open, PEEP could
cause overdistension of nondependent lung tissue,
thereby increasing DP and compromising the hemo-
dynamic system, which could lead to harm.
LOWER DRIVING PRESSURE
In ARDS patients, tidal volume normalized to respi-
ratory system compliance (termed driving pressure,
DP) may be a better predictor of outcome than tidal
volume expressed in ml/kg PBW. DP can be influ-
enced by changes in tidal volume (lowering tidal
volume will decrease the DP), and changes in PEEP
(raising PEEP will decrease the DP if it results in lung
recruitment, or increase the DP if it results in over-
distension).
Lower driving pressure in the operating room
In an individual patient data meta-analysis of clinical
trials of intraoperative ventilation, a rise in DP was
strongly associated with development of PPCs [odds
ratio (OR) for one unit increase of DP, 1.16; 95%
confidence interval (CI) 1.13–1.19] [25]. In the addi-
tional mediator analysis, DP was the only significant
mediator of the effects of protective ventilation on
development of postoperative pulmonary complica-
tions. In the two randomized clinical trials in this
metaanalysis, that compared intraoperative low with
high PEEP during low tidal volume ventilation, an
increase in PEEP that resulted in an increase in DP
www.co-criticalcare.com 57
Respiratory system
was associated with more postoperative pulmonary
complications (OR 3.11, 95% CI 1.39–6.96). A strat-
egy of titrating PEEP against Crs or DP was recently
tested in two randomized clinical trials, with mod-
erate success, one in patients undergoing abdomi-
nal surgery [26] and one in patients undergoing
thoracic surgery [27]. Of note, the first trial was
not powered to test a difference in occurrence of
postoperative pulmonary complications, and the
second trial was small, and thereby probably under-
powered to draw firm conclusions.
Lower driving pressure in the intensive care
A retrospective analysis of a cohort of ventilated
patients without ARDS failed to show an association
of DP and hospital mortality (OR 1.01, 95% CI 0.97–
1.05). Of note, however, in hypoxemic patients with-
out ARDS [lower arterial oxygen partial pressure
(PaO2)/FiO2 < 300], DP was associated with hospital
mortality (OR ¼ 1.08, 95% CI ¼ 1.04–1.11). Another
retrospective study of a cohort of ventilated ICU
patients confirmed an association of DP (OR 1.1, CI
1.06–1.14) and tidal volume (OR 1.17, CI 1.04–1.31)
with mortality, and only showed an association of
tidal volume with mortality (OR 1.18 per 1 ml/kg
PBW increase in tidal volume, CI 1.04 to 1.35) [28].
These results collectively suggest that it may
seem reasonable to target a low DP in hypoxemic
patients without ARDS.
OPTIMAL OXYGEN TARGET
Oxygen targets in the operating room
Ensuring sufficient oxygenation during operative
ventilation is essential. Thereby, oxygen is adminis-
tered liberally in the operating room. In a prospec-
tive study in nearly 10 000 patients from 29
countries requiring operative ventilation, the
majority of patients are ventilated with FiO2 higher
than 0.4. Although a high FiO2 during induction of
anesthesia is widely accepted to ensure safe intuba-
tion, the optimal FiO2 during surgery is more highly
debated. Excessive oxygenation can have deleteri-
ous effects, because of occurrence of reactive oxygen
species. In addition, high oxygen concentrations
increase vascular resistance and decrease cardiac
output, even when applied for a short while [29].
Yet, supraphysiological oxygen levels may reduce
the incidence of surgical-site infections (SSI). A
Cochrane metaanalysis on the effects of a high
intraoperative FiO2 showed disparate results [30];
low-quality evidence suggested a reduction in the
incidence of SSIs, whereas moderate-quality evi-
dence suggested an increased risk of PPCs in patients
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receiving high versus low FiO2, with a trend toward
increased mortality. After this metaanalysis, a large
observational study appeared [31], suggesting that
higher FiO2 was associated with an increased inci-
dence of PPCs and increased mortality. Interest-
ingly, the incidence of SSIs was not reduced with
higher FiO2 in this study. Together, evidence so
far does not seem to underline the use of higher
FiO2.
Oxygen targets in critically ill patients
Also in critically ill patients, oxygen is applied
liberally, also in patients with normal gas exchange.
Cardiac arrest patients very often receive high FiO2
levels, despite having a supranormal (>13.3 kPa)
oxygenation [32]. Several RCTs have compared
the impact of higher and PaO2 on outcome. A
single-center Italian trial showed that a higher
PaO2 target resulted in a remarkable increase in
mortality [33]. These results were not confirmed
in a large RCT in 1000 patients, which found no
difference between conventional or conservative
oxygen targets [34 ]. An explanation for these dis-
&&
parate results may be that oxygenation levels were
higher in the single-center study compared with the
ICU-randomized trial comparing two approaches to
oxygen therapy (ROX) trial, suggesting that severe
hyperoxia may be detrimental. Of note, these stud-
ies were done in the general ICU population and do
not provide an answer to the specific question of
optimal oxygen target in patients with healthy
lungs. A registry trial comprising 40 000 patients
comparing conservative and liberal oxygenation
targets is planned (mega-ROX trial), of which sub
analyses will perhaps contribute to the generation of
specific recommendations.
CONCLUSION
The impact of ventilation settings on outcome of
patients with healthy lungs partially differs from the
impact observed in ARDS patients. Contrary to
beliefs, use of low tidal volume decreases postopera-
tive pulmonary complications. In the critically ill,
use of low tidal volume is as effective as intermediate
tidal volume. Therefore, we recommend standard
use of low tidal volume in patients with healthy
lungs. Conversely, no benefit was observed for
higher PEEP during operative ventilation, whereas
hypotension occurred more often. Also in critically
ill patients with healthy lungs, evidence for benefit
of a higher PEEP setting is not convincing. We
suggest the general use of lower PEEP in patients
with healthy lungs, with the exception of those
patients who display recruitable lung regions during
Volume 27 ! Number 1 ! February 2021

a PEEP trial. In line with the PEEP data in the
operating room, a low driving pressure should
probably be targeted in patients receiving operative
ventilation. Lastly, we feel that the use of hyperoxia
in general should be avoided.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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