The

n e w e ng l a n d j o u r na l

of

m e dic i n e

edi t or i a l

PEEP Guided by Esophageal Pressure Any Added Value?

Gordon R. Bernard, M.D.
Treatment of the acute respiratory distress syndrome (ARDS) with positive end-expiratory pressure (PEEP) was introduced more than 40 years
ago.1,2 Few practitioners question the effects of
PEEP on hemoglobin saturation, but the optimal
dose titration is controversial. Usually PEEP is simply adjusted to a suitable increase in oxygenation
efficiency (i.e., the ratio of the partial pressure of
arterial oxygen [PaO2] to the fraction of inspired
oxygen [FiO2]) or according to an algorithm such
as the Acute Respiratory Distress Syndrome Network (ARDSNet) protocol.3 Because PEEP can impair cardiac output, some clinicians advocate titration to maximal oxygen delivery, a method that
requires measurement of cardiac output. More
complex techniques such as titration with the use
of the pressurevolume relationship in the respiratory system have been reported.4
In this issue of the Journal, Talmor and colleagues5 describe a randomized trial of a mechanical-ventilation strategy in which PEEP was adjusted according to end-expiratory transpulmonary
pressures (ClinicalTrials.gov number, NCT00127491).
Transpulmonary pressure was measured as the
difference between the airway opening pressure
and the pleural pressure; pleural pressure was estimated from esophageal pressure. A small catheter with a balloon covering the holes at its end
was used to measure pneumatic pressure in the
esophagus. PEEP was then adjusted to produce an
estimated transpulmonary pressure at end expiration of 0 to 10 cm of water, according to
PaO2:FiO2. Originally designed to enroll 200 subjects, the trial was stopped by the safety board
after only 61 subjects were enrolled. Termination
was based on an a priori stopping rule requiring
a difference in PaO2:FiO2 between groups that was
of a critical significance level (P<0.02).
2166

Adjusting PEEP on the basis of transpulmonary pressure is a reasonable physiological premise, since this pressure is derived by calculating
the difference between airway pressure and the
highly variable pleural pressure. Pleural pressure
can be unpredictable in cases of critical illness due
to pleural effusion, elevated abdominal pressure,
and variations in the elastance of the chest wall.
For example, a large pleural effusion may raise
pleural pressure, thereby reducing transpulmonary
pressure at any given PEEP. However, accurate
measurements of pleural pressure in the intensive care unit (ICU) are rarely possible. Because of
this drawback, pleural pressure can be estimated
only from esophageal pressure. The methods and
limitations of estimating esophageal pressure have
been published previously.6,7 In brief, many assumptions must be made in order to accept that
pressure in the esophagus dynamically and accurately reflects pleural pressure. For instance, we
must assume that the balloon pressure reflects the
esophageal pressure, that the transmural pressure
in the esophagus is 0 cm of water, that the esophagus is not compressed by intrathoracic structures
such as the heart, that the pressures in the peri
esophageal area are the same as the pleural pressure, and that pleural pressure is relatively uniform
throughout the thorax.
In fully one third of the patients in the study
by Talmor et al., the balloon placement was inadequate, according to monitoring pressure recordings, and alternative placement techniques were
used; this requirement calls into question the consistency of positioning and thus the reliability and
reproducibility of the measurements. In addition,
a correction factor of 5 cm of water was subtracted from the esophageal pressure in an attempt to
compensate for the known artifacts of mediasti-

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editorial

Table 1. Patients with Discrete Changes in PEEP from Baseline to Day 1 (First Therapeutic Day) in the Study by Talmor
et al. and in the ARDSNet ALVEOLI Trial.*
Change in PEEP

Talmor et al.
Esophageal-Pressure
Guided Group
(N=30)

ALVEOLI Trial

ConventionalTreatment Group
(N=31)

Higher PEEP
(N=276)

Lower PEEP
(N=273)

percent of study population

1 to 6 cm of water

10

39

33

0 to 5 cm of water

30

58

40

58

6 to 10 cm of water

40

52

11 to 15 cm of water

13

16 to 20 cm of water

* Data are from Brower et al.3 and Talmor et al.5 ALVEOLI denotes Assessment of Low Tidal Volume and Elevated EndExpiratory Volume to Obviate Lung Injury, ARDSNet Acute Respiratory Distress Syndrome Network, and PEEP positive end-expiratory pressure.
An additional 5% of subjects had PEEP adjusted downward by more than 6 cm of water.

nal weight and balloon air volume on the observed pressures. However, the exact correction
factor for this artifact is highly variable among
even normal subjects, let alone the critically ill,
and presents another potential source of error in
using this estimate of pleural pressure.6 It is also
noteworthy that at least one subject could not be
sedated sufficiently for balloon placement, and in
another subject, obtaining readable tracings required extra sedation (see the data for Patient 3 in
the Supplementary Appendix, available with the
full text of the article by Talmor et al. at www.
nejm.org), which may increase morbidity in this
population.8
On the basis of their previous work,6 the authors could be fairly certain that using esophageal pressure to adjust PEEP would result in an
increase in PEEP for most patients and would result in increased oxygenation efficiency. In this
regard, the study was nicely designed and reasonably powered for the primary end point of increased PaO2:FiO2. The use of PaO2:FiO2 as the
outcome measure in this trial, since it is a derived variable, creates additional issues in interpreting the results. The investigators modified the
ARDSNet protocol for the adjustment of PEEP and
FiO2 to allow a range for PaO2 of 55 to 120 mm Hg,
as compared with the standard 55 to 80 mm Hg.
Table 2 in the article by Talmor et al.5 shows that
this range was relaxed even more in practice, since
the mean (+SD) PaO2 was 124+44 mm Hg in the
esophageal-pressureguided group at 72 hours
(the time of the primary end point). Hence, it is

likely that more than half the patients in the

esophageal-pressureguided group had a PaO2
above the range stipulated by the protocol. This
was not the case in the conventional-treatment
group, in which the mean PaO2 was only 101
mm Hg. Aside from issues related to protocol
compliance, this difference in PaO2 at the critical time of assessment for the primary outcome
can create a profound artifact on PaO2:FiO2.9
Therefore, it is unfortunate that the stopping rules
were constructed around a noisy oxygenation end
point instead of other outcomes. As the authors
point out, the intriguing question of effects on
important clinical outcomes such as long-term
mortality, ventilator-free days, and length of stay
in the ICU remain unanswered.
A discrepancy between oxygenation and clinical improvement in the end point has been observed previously. The only large trial to show a
lowering of mortality rates in association with a
particular method of ventilation also found that
the group with improved oxygenation (the group
with higher tidal volume) had higher mortality
rates.3 Thus, in my opinion, it is no longer acceptable to use oxygenation as a surrogate for
improved clinical outcome. The ARDSNet Assessment of Low Tidal Volume and Elevated
End-Expiratory Volume to Obviate Lung Injury
(ALVEOLI) trial compared higher PEEP with lower PEEP with the use of a standard protocol.10 It
and other studies showed that higher PEEP produced remarkable improvements in oxygenation
yet no improvement in the rate of survival.11,12

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editorial

Table 2. Changes in PEEP and PaO2:FiO2 from Baseline to Day 3 in the Study by Talmor et al. and in the ARDSNet
LVEOLI Trial.*
A
Variable

Talmor et al.

ALVEOLI Trial

Esophageal-Pressure
Guided Group
(N=30)

ConventionalTreatment Group
(N=31)

Higher PEEP
(N=276)

Lower PEEP
(N=273)

Baseline

135

133

104

94

Day 3

176

104

135

94

Baseline

14756

14557

15167

16577

Day 3

280126

19171

20676

16969

PEEP (cm of water)

PaO2:FiO2

* Data are from Brower et al.3 and Talmor et al.5 ALVEOLI denotes Assessment of Low Tidal Volume and Elevated EndExpiratory Volume to Obviate Lung Injury, ARDSNet Acute Respiratory Distress Syndrome Network, FiO2 the fraction
of inspired oxygen, PaO2 the partial pressure of arterial oxygen, and PEEP positive end-expiratory pressure.

Interestingly, the cohorts in the ALVEOLI trial and the current study were fairly similar, but
without direct measurements of pleural pressure,
we cannot know for sure the transpulmonary
pressures of the patients in either study. Tables
1 and 2 show PEEP and PaO2:FiO2 data comparing
the trial by Talmor et al. with the ALVEOLI trial.
The amount of PEEP in the first 24 hours (Table 1)
and at 72 hours (Table 2) was greater in the study
by Talmor et al. The increase in PaO2:FiO2 was
also proportionately greater, suggesting that improvements in oxygenation in the study by Talmor
et al. were reflective of generically higher PEEP,
rather than a unique response to the PEEP titration method. Although the study by Talmor et al.
is not sufficient to recommend a change in current practice, it has shown acceptable safety, and
in the absence of a practical standard for pleural
pressure, it seems reasonable to conduct further
studies of this technique to assess feasibility and
clinical benefit.
Supported in part by the National Heart, Lung, and Blood
Institute ARDS Clinical Trials Network contracts (NO1-HR 46054
through 46064).
Dr. Bernard reports receiving consulting fees from AstraZeneca
and Novo Nordisk, having equity ownership in Cumberland
Pharmaceuticals, and receiving grant support from Takeda and
Novo Nordisk. No potential conflict of interest relevant to this
article was reported.
This article (10.1056/NEJMe0806637) was published at www.
nejm.org on November 11, 2008.
From the Department of Medicine, Vanderbilt University School
of Medicine, Nashville.

2168

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Copyright 2008 Massachusetts Medical Society.

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