Opinion Editorial

coverage and Sustainable Development Goals, including
infectious diseases control and access to essential medicines.
To avoid a backslide with serious ramifications for popula-
tions worldwide, the US and other wealthy nations must
remain engaged and invested in efforts to strengthen health
systems in low- and middle-income countries.
Certainly, COVID-19 is a worst-case scenario, one that
would strain any health system. But there were quality short-
comings long before COVID-19. Crucially, as the health care
community begins to recover after the pandemic, quality must
remain a central focus. Now is the time to examine US and
global systems through a fresh lens. With the right planning,
the COVID-19 recovery efforts could provide the impetus
needed to reinvigorate the quality movement and build a sys-
tem that consistently delivers safe, effective, and affordable
care to everyone who needs it.
On the threshold of an uncertain future, and one in
which the health care system will be forever changed, 3
Viewpoints in this issue of JAMA and related to the 20th an-
niversary of the IOM reports examine urgent areas of focus
for the care quality movement. The Viewpoint by Corrigan
and Clancy8 looks holistically at system performance in the
context of the pandemic and according to the 6-element
quality checklist set forth in the 2001 report. In their
Viewpoint, Singh and Carayon9 look beyond the hospital
setting, where most quality improvement efforts have
focused to date, to the opportunities for ambulatory care
and digital health. Acknowledging the interconnectedness
of global societies, the Viewpoint by Leatherman and
Berwick10 provides an important agenda for accelerating
progress in care quality and safety globally in the quest for
universal health coverage.
The next 20 years of the quality movement will be defined
by the priorities established today. As infectious diseases, cli-
mate change, health inequity, and information warfare re-
shape society more quickly than ever imagined, there is an
opportunity—and an imperative—to design a system of care that
learns, adapts, and holds quality and equity at the center.

ARTICLE INFORMATION
Author Affiliations: National Academy of
Medicine, Washington, DC (Dzau); Department of
Internal Medicine, Dell Medical School, University of
Texas, Austin (Shine).
Corresponding Author: Victor J. Dzau, MD,
National Academy of Medicine, 500 Fifth St NW,
Washington, DC 20001 (vdzau@nas.edu).
Conflict of Interest Disclosures: Dr Dzau is
president of the National Academy of Medicine
(previously the Institute of Medicine [IOM]).
Dr Shine is a former president of the IOM
(1992-2002).
2. Gray BH, Gusmano MK, Collins SR. AHCPR and
the changing politics of health services research.
Health Aff (Millwood). 2003;22(suppl web
exclusives):W3-283-307. doi:10.1377/hlthaff.W3.283
3. President Clinton: taking new steps to ensure
patient safety. The White House. Published 1999.
Accessed November 5, 2020. https://
clintonwhitehouse4.archives.gov/textonly/WH/
Work/120799.html
4. Advancing patient safety. Agency for Healthcare
Research and Quality. Published 2018. Accessed
November 5, 2020. https://www.ahrq.gov/patient-
safety/resources/advancing.html
5. Institute of Medicine. Crossing the Quality
7. AHRQ National Scorecard on hospital-acquired
conditions: updated baseline rates and preliminary
results 2014-2017. Agency for Healthcare Research
and Quality. Published 2019. Accessed November 5,
2020. https://www.ahrq.gov/sites/default/files/
wysiwyg/professionals/quality-patient-safety/pfp/
hacreport-2019.pdf
8. Corrigan JM, Clancy CM. Assessing progress in
health care quality through the lens of COVID-19.
JAMA. Published December 22, 2020. doi:10.1001/
jama.2020.17392
9. Singh H, Carayon P. A roadmap to advance
patient safety in ambulatory care. JAMA. Published
December 22, 2020. doi:10.1001/jama.2020.18551

REFERENCES
1. Institute of Medicine. To Err Is Human: Building a
Safer Health System. National Academies Press;
2000.
Chasm: A New Health System for the 21st Century. 10. Leatherman S, Berwick DM. Accelerating global
National Academies Press; 2001. improvements in health care quality. JAMA. Published
December 22, 2020. doi:10.1001/jama.2020.17628
6. Millennium Development Goals (MDGs). World
Health Organization. Published 2018. Accessed
November 5, 2020. https://www.who.int/news-
room/fact-sheets

Searching for the Optimal PEEP in Patients Without ARDS

High, Low, or in Between?
Sarina K. Sahetya, MD, MHS; Ewan C. Goligher, MD, PhD; Arthur S. Slutsky, MD

Positive pressure ventilation is lifesaving for patients with
acute respiratory failure and has been the cornerstone
of care for critically ill patients since the polio epidemic in
the 1950s. Increasing end-expiratory pressure in venti-
lated patients, termed posi-
Related article page 2509
tive end-expiratory pressure
(PEEP), was noted to be ben-
eficial for acute pulmonary edema as early as the 1930s by
Barach et al.1 However, it was not widely used until 1967,
when Ashbaugh and colleagues2 “discovered” acute respira-
tory distress syndrome (ARDS) and demonstrated that PEEP
improved arterial oxygenation in some patients with ARDS.
For decades, the major goal of PEEP was to improve oxygen-
ation or oxygen delivery,3 but over the past few decades, this
goal has shifted to minimizing ventilator-induced lung injury,
an approach that includes limiting tidal volumes and inspira-
tory pressures while providing sufficient PEEP to minimize
lung collapse.4
From a physiological perspective, PEEP may be beneficial
by maintaining lung units (alveoli and small airways) open
that would otherwise collapse at end expiration, thus
improving gas exchange. By keeping additional lung units
open, PEEP can reduce injurious shear forces due to cyclic
opening and closing of these units during ventilation, and

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allow distribution of tidal volumes over a larger and more
homogeneously inflated lung surface, thereby reducing
dynamic stress and strain. During spontaneous breathing,
maintaining lung recruitment with PEEP may also decrease
respiratory effort and eccentric diaphragm loading.
However, higher PEEP levels can have detrimental conse-
quences by leading to increased inspiratory pressures and
overdistention of the lung along with increased lung stress
and strain, and therefore, more ventilator-induced lung
injury. Higher intrathoracic pressures with PEEP can also
impair hemodynamics by reducing venous return and
increasing pulmonary vascular resistance. The net benefit or
harm from PEEP therefore depends on this balance of alveo-
lar recruitment to overdistension and should be particularly
beneficial in disease states with substantial alveolar collapse,
such as ARDS.
These trade-offs in using PEEP have been studied for de-
cades in patients with ARDS, with 5 large randomized clinical
trials of higher vs lower PEEP providing somewhat variable
findings.5-9 A meta-analysis demonstrated that patients with
moderate or severe ARDS—but not mild ARDS—benefited from
a higher PEEP ventilation strategy.10
Much less attention has been paid to the use of PEEP in
patients without ARDS and who have relatively healthy
lungs. These studies have largely focused on patients at
increased risk of atelectasis, eg, patients receiving anesthesia
for operative procedures. The optimum PEEP level in
patients without ARDS would be expected to be lower and
the risk-benefit ratio higher because they have relatively less
lung collapse than patients with ARDS and require less pres-
sure to open the collapsed lung. In 2 randomized trials evalu-
ating patients undergoing open abdominal surgery (n = 900)
and obese patients undergoing surgery (n = 1976), there were
no differences in postoperative pulmonary complications
between an intraoperative ventilation strategy using ultra-
low PEEP (<5 cm H2O) and use of a PEEP of 12 cm H2O plus
recruitment maneuvers, which included incremental
increases in tidal volume and/or PEEP that were repeated
intermittently. 11,12 In nonsurgical patients with a risk of
ARDS, Pepe and colleagues13 also found no difference in sub-
sequent development of ARDS using a PEEP of 0 cm H2O vs
a PEEP of 8 cm H2O.
In this issue of JAMA, the RELAx Collaborative Group add
to this literature by reporting results of a large, randomized
clinical trial of higher vs lower PEEP in 980 ventilated
patients.14 The study, conducted in 8 Dutch intensive care units,
enrolled patients without ARDS who were expected to be in-
tubated for more than 24 hours. Participants were random-
ized to receive either a lower PEEP strategy, in which PEEP was
titrated close to 0 with a maximum of 5 cm H2O (n = 476), or a
higher PEEP strategy of 8 cm H2O (n = 493). Fraction of in-
spired oxygen was titrated to a maximum of 0.6 before PEEP
could be increased to maintain adequate oxygenation. Most
patients enrolled were nonsurgical patients (79%); the 2 main
reasons for intubation were respiratory failure (30%) and car-
diac arrest (27%).
The primary outcome was the number of ventilator-free
days at day 28. The investigators used a noninferiority trial
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Editorial Opinion
design, with the noninferiority margin set at −10%, roughly
equivalent to 1.6 ventilator-free days or 12 hours of ventila-
tion, on the reasonable assumption that this difference was
not clinically meaningful. They found that the lower PEEP
strategy met criteria for noninferiority with a median of 18
ventilator-free days compared with 17 days in the higher
PEEP strategy (mean ratio, 1.04; 95% CI, 0.95-⬁; P = .007 for
noninferiority). A superiority analysis also suggested no sta-
tistically significant difference between groups (P = .22).
What are the clinical implications of this trial? Although
this investigation is a large, randomized, multicenter clini-
cal trial and was rigorously conducted, there are a few chal-
lenges in interpreting the results. First, as the authors
acknowledge, neither strategy they chose represents stan-
dard care. The investigators chose 8 cm H2O, rather than 5
cm H2O, as their control strategy based on evidence that
“usual care” PEEP has drifted higher over time.15 However,
based on other large observational studies, it appears that
clinicians largely use PEEP levels less than 8 cm H2O for this
patient population.16
Second, heterogeneity of treatment effect is a widely docu-
mented challenge to interpreting clinical trials of lower vs
higher PEEP in patients with ARDS.17,18 This challenge may be
even more pronounced in this trial of diverse non-ARDS pa-
tients. Although there were no statistically significant differ-
ences in outcomes by the evaluated subgroups, there was sug-
gestion of possible differences in treatment effect according
to the reason for intubation (P = .08 for interaction). Thus, it
is possible that the lower PEEP strategy may not be noninfe-
rior in all patient populations, especially those intubated for
respiratory failure.
Third, the trial was based on a noninferiority design.
Noninferiority designs are usually used to evaluate new
interventions that have some compelling advantage in terms
of lower toxicity, cost, or effort (such as mode or frequency of
administration).19 The novel intervention is typically com-
pared with an “active control” or known effective treatment
because there would be little benefit in demonstrating that
the new intervention is not inferior to an unproven therapy.
For example, in a novel drug trial, a lower dose may have less
toxicity and also lower efficacy, so demonstrating noninferi-
ority may be clinically relevant. In the intensive care unit,
lower PEEP is achieved by turning a knob on the ventilator
and is not less expensive or less logistically challenging
than providing higher PEEP. Moreover, lower PEEP may
have its own adverse effects (eg, atelectasis, hypoxemia) and
may have less, equivalent, or greater efficacy than a higher
PEEP strategy. In this study, the rates of severe hypoxemia
(20.6% vs 17.6%) and the need for rescue therapy (19.7% vs
14.6%) were numerically higher (but not statistically signifi-
cantly different in adjusted analysis) in the lower PEEP
group, suggesting the possibility that lower PEEP may have
been inferior for some patients. For an average patient with-
out ARDS, however, the results suggest that clinicians should
feel as comfortable choosing a lower PEEP as they do choos-
ing a higher PEEP.
Ultimately, clinicians will need to decide what the results
of this study mean for the care of patients receiving mechanical
(Reprinted) JAMA December 22/29, 2020 Volume 324, Number 24 2491
 Opinion Editorial

ventilation. A PEEP of 0 to 5 cm H2O is noninferior to a PEEP
of 8 cm H2O with respect to ventilator-free days. However,
given the concern about possible increased rates of hypox-
emia and need for rescue strategies in the lower PEEP group,
an intermediate option of 5 to 8 cm H2O that is consistent
with the current PEEP management for many non-ARDS
patients is likely reasonable and may be safer than a very low
PEEP strategy.15
Future trials of PEEP should be designed using strate-
gies that individualize PEEP according to a specific patient’s
physiology rather than focusing simply on dose. For
example, comparing high and low insulin doses is less infor-
mative than comparing tight vs liberal glucose goals in
patients with diabetes. In the context of PEEP, the potential
benefit of PEEP is almost certainly proportional to the
degree of recruitable atelectasis. However, no trial to date
has attempted to assess PEEP responsiveness in specific
patients prior to randomization. Thus, it is possible, and
perhaps even likely, that the beneficial effect of higher
PEEP for some patients with recruitable lung tissue is nulli-
fied by the detrimental effects of overdistension and hemo-
dynamic compromise in others. These trials should be con-
ducted using an enriched population of patients with the
highest probability of benefit rather than simply using high
vs low PEEP applied uniformly to all patients who require
mechanical ventilation.

ARTICLE INFORMATION
Author Affiliations: Division of Pulmonary and
Critical Care, Department of Medicine, Johns
Hopkins School of Medicine, Baltimore, Maryland
(Sahetya); Interdepartmental Division of Critical
Care Medicine, University of Toronto, Toronto,
Ontario, Canada (Goligher, Slutsky); Division of
Respirology, Department of Medicine, University
Health Network, Toronto, Ontario, Canada
(Goligher); Toronto General Hospital Research
Institute, Toronto, Ontario, Canada (Goligher);
Keenan Research Center, Li Ka Shing Knowledge,
St Michael’s Hospital, Unity Health Toronto,
Toronto, Ontario, Canada (Slutsky).
Corresponding Author: Arthur S. Slutsky, MD,
Keenan Research Center, Li Ka Shing Knowledge,
St Michael’s Hospital, 30 Bond St, Toronto, Ontario
M5R 3T5, Canada (arthur.slutsky@unityhealth.to).
Published Online: December 9, 2020.
doi:10.1001/jama.2020.23067
Conflict of Interest Disclosures: Dr Goligher
reported receipt of research equipment from
Timpel Research and personal fees from Getinge.
Dr Slutsky reported receipt of personal fees for
consulting from Krypton, Baxter, and Novalung/
Xenios. No other disclosures were reported.
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