CHEST Postgraduate Education Corner

CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

Severe Hypoxemic Respiratory Failure

Part 2—Nonventilatory Strategies

Suhail Raoof, MD, FCCP; Keith Goulet, MD; Adebayo Esan, MD;
Dean R. Hess, PhD, RRT, FCCP; and Curtis N. Sessler, MD, FCCP

ARDS is characterized by hypoxemic respiratory failure, which can be refractory and life-
threatening. Modifications to traditional mechanical ventilation and nontraditional modes of ventila-
tion are discussed in Part 1 of this two-part series. In this second article, we examine nonventilatory
strategies that can influence oxygenation, with particular emphasis on their role in rescue from
severe hypoxemia. A literature search was conducted and a narrative review written to summarize
the use of adjunctive, nonventilatory interventions intended to improve oxygenation in ARDS.
Several adjunctive interventions have been demonstrated to rapidly ameliorate severe hypox-
emia in many patients with severe ARDS and therefore may be suitable as rescue therapy for
hypoxemia that is refractory to prior optimization of mechanical ventilation. These include neu-
romuscular blockade, inhaled vasoactive agents, prone positioning, and extracorporeal life sup-
port. Although these interventions have been linked to physiologic improvement, including relief
from severe hypoxemia, and some are associated with outcome benefits, such as shorter duration
of mechanical ventilation, demonstration of survival benefit has been rare in clinical trials. Fur-
thermore, some of these nonventilatory interventions carry additional risks andⲐor high cost;
thus, when used as rescue therapy for hypoxemia, it is important that they be demonstrated
to yield clinically significant improvement in gas exchange, which should be periodically reas-
sessed. Additionally, various management strategies can produce a more gradual improvement
in oxygenation in ARDS, such as conservative fluid management, intravenous corticosteroids, and
nutritional modification. Although improvement in oxygenation has been reported with such
strategies, demonstration of additional beneficial outcomes, such as reduced duration of mechanical
ventilation or ICU length of stay, or improved survival in randomized controlled trials, as well
as consideration of potential adverse effects should guide decisions on their use. Various non-
ventilatory interventions can positively impact oxygenation as well as outcomes of ARDS. These
interventions may be considered for use, particularly for cases of refractory severe hypoxemia, with
proper appreciation of potential costs and adverse effects. CHEST 2010; 137(6):1437–1448

Abbreviations: ALI 5 acute lung injury; ECLS 5 extracorporeal life support; EPA 5 eicosapentaenoic acid;
GLA 5 g-linoleic acid; iNO 5 inhaled nitric oxide; LOS 5 length of stay; NMBA 5 neuromuscular blocking agent;
PAP 5 pulmonary arterial pressure; RCT 5 randomized controlled trial

Hypoxemia is a core feature of ARDS and, more

broadly, acute lung injury (ALI). Management
of the underlying cause(s) of ARDS and provision
of supportive care, including mechanical ventilation,
are the key components of patient care. Many aspects
Manuscript received October 9, 2009; revision accepted January
21, 2010.
Affiliations: From the Division of Pulmonary and Critical
Care Medicine (Drs Raoof and Esan), New York Methodist
Hospital, Brooklyn, NY; the Department of Pulmonary and
Critical Care Medicine (Dr Goulet) and the Department of
Internal Medicine (Dr Sessler), Virginia Commonwealth University;
and Respiratory Care Services (Dr Hess), Massachusetts General
Hospital, Boston, MA.
of management are directed toward hastening the
recovery from hypoxemic respiratory failure, as well
as avoidance of further exacerbating lung injury or
gas exchange abnormalities. Such salutary interventions
may lead to improved oxygenation andⲐor better lung
mechanics. In some cases, these physiologic gains
Correspondence to: Suhail Raoof, MD, FCCP, Division of Pulmo-
nary and Critical Care Medicine, New York Methodist Hospital,
506 Sixth St, Brooklyn, NY 11215; e-mail: sur9016@nyp.org
© 2010 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians ( www.chestpubs.orgⲐ
siteⲐmiscⲐreprints.xhtml).
DOI: 10.1378Ⲑchest.09-2416

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 contribute to more rapid recovery from respiratory
failure, resulting in shorter duration of mechanical
ventilation and reduced ICU andⲐor hospital length
of stay (LOS). The decision of whether to implement
any intervention for a particular patient should be
based on assessment of benefit, strength of the evi-
dence supporting the therapy, potential risks, and
other barriers to use.
In some cases, hypoxemia can be profound and
life threatening, being of such a severe reduction as
to present a threat to cellular function, and is often
refractory to conventional management. Such cases
are not uncommon. For example, 26% of patients with
ALI who enrolled in trial comparing two ventilatory
strategies failed to achieve oxygen saturation . 88%
or Pao2 . 55 mm Hg on Fio2 ⱖ 0.8 during the first
7 days.1 In a similar study, 7% of patients experienced
refractory hypoxemia, defined as Pao2 , 60 mm Hg
lasting at least 1 h while breathing Fio2 1.0.2 Ninety
percent of these patients died, often despite use of
rescue therapies.2 The clinician is faced with a diffi-
cult situation, and various interventions that have a
high likelihood of improving oxygenation to a clini-
cally significant degree form the basis for rescue
therapy. In this paper, we review nonventilatory
interventions that can acutely improve oxygenation.
We also review interventions that have been demon-
strated to influence oxygenation in a more gradual
fashion during the care of a critically ill mechanically
ventilated patient.
Nonventilatory Interventions Associated
With the Potential for Rapid Improvement
of Hypoxemia
Neuromuscular Blocking Agents
From 25% to 55% of patients with ALI enrolled in
contemporary multicenter randomized controlled
trials (RCTs) received neuromuscular blocking agents
(NMBAs),1-4 a prevalence that increases further
with use of nonconventional modes of ventilation,
such as high-frequency oscillatory ventilation.5 The
most common reason for using an NMBA is to pro-
mote patient-ventilator synchrony and improve oxy-
genation.6 Data that directly examine the impact of
NMBAs on oxygenation using an RCT design in the
era of lung-protective ventilation are, to our knowl-
edge, limited to two studies by one group of inves-
tigators.7,8 They studied patients with Pao2ⲐFio2
ratio , 150 mm Hg who were receiving low tidal vol-
ume ventilation and were deeply sedated to eliminate
spontaneous breathing. Administration of an NMBA
for 48 h resulted in sustained improvements in oxy-
genation, with average increases in Pao2ⲐFio2 of
25% to 75% on day 1 and 50% to 140% by day 5, sig-
nificantly higher than the control patients who were
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receiving sedation alone. Interestingly, these remark-
able improvements in oxygenation occurred despite
the absence of patient-ventilator asynchrony at base-
line. Although possible explanations for better oxy-
genation include improved chest wall compliance
and reduced oxygen consumption, the investigators
also reported lower concentrations of pulmonary and
systemic proinflammatory cytokines and postulated
that NMBAs may blunt the pulmonary inflammation
associated with ARDS in some fashion.8 Enthusiasm
for use of NMBAs must be tempered by the recog-
nized risks for prolonged weakness from myopathy,
particularly when concomitantly administered with
systemic corticosteroids. There is evidence that pro-
longed weakness is more common with aminosteroid
agents, although it is seen with all classes of NMBA.6,9
Administration of an NMBA can result in improve-
ment in severe hypoxemia. However, given the risk
for myopathy, particularly if corticosteroids are used
concomitantly, we recommend demonstrating clini-
cally significant improvement in oxygenation with a
single dose prior to committing to continuous infu-
sion of NMBAs. Periodic retesting for the necessity
of continued therapy and using the train-of-four
monitoring while on this class of medications is
recommended.
Inhaled Nitric Oxide and Vasoactive Therapy
Inhaled Nitric Oxide: By using an inhaled vasodi-
lator, such as inhaled nitric oxide (iNO), selective
vasodilation of the pulmonary blood vessels in ventilated
lung units may occur, often resulting in improved
ventilation-perfusion mismatch, better oxygenation,
and lower pulmonary arterial pressure (PAP).10 In a
study by Rossaint et al10 of patients with ARDS, iNO
redistributed pulmonary blood flow away from non-
ventilated lung zones to ventilated lung regions,
thus decreasing intrapulmonary shunting and
thereby improving arterial oxygenation, while
selectively reducing PAP without causing systemic
vasodilation.
In RCTs11-15 that examined the effect of iNO in
adults with ARDS, iNO was associated with a tran-
sient improvement in oxygenation. However, no sur-
vival benefit or reduction in ventilator-free days has
been observed. In a systemic review of five RCTs that
enrolled 535 patients (approximately 80% adults)
with acute hypoxemic respiratory failure, oxygenation
was significantly improved, but no statistically signifi-
cant effect on mortality was demonstrated.16 Sokol
et al16 concluded that iNO may be useful as a rescue
treatment to improve oxygenation for a short period
of time (24-96 h) in acute hypoxemic respiratory
failure. In a systematic review and metaanalysis of
1,237 patients with ALI or ARDS from 12 trials, iNO was
Postgraduate Education Corner
 associated with modest improvements in oxygenation
on day one, no effect on mean PAP, and no effect on
survival or duration of mechanical ventilation.17 Influ-
enced by the single largest study,13 a significantly
increased risk of developing renal dysfunction was
noted in patients randomized to iNO in this metaanal-
ysis.17 Although iNO may result in systemic methe-
moglobinemia or in generation of inhaled nitrogen
dioxide, dose-ranging studies demonstrate that these
effects are rare when , 80 ppm of iNO are used.13
Despite the lack of evidence that iNO improves
important outcomes, it is used as rescue therapy for
refractory hypoxemia. In an RCT that investigated
ventilatory strategies for ARDS, about 20% of patients
received iNO.1 The acquisition cost of iNO in the
United States is very high, generally assessed on an
hourly basis—a cost that is not offset by third-party
reimbursement or in cost savings from fewer days on
the ventilator. Because improvement in oxygenation
can be dramatic in the setting of life-threatening hyp-
oxemia, its use can be supported in this setting on a
trial basis, after optimization of mechanical ventila-
tion. Clinically significant improvement in oxygena-
tion following initiation of iNO should be demon-
strated within the first hour of therapy to justify
continued use. Dose-ranging studies suggest that
peak oxygenation benefit typically occurs with iNO
dose ⱕ 20 ppm.18
IV Phenylephrine: Phenylephrine is a nonselective
a-receptor agonist, which produces both pulmonary
and systemic vasoconstriction. In a study19 of 12 patients
with Pao2ⲐFio2 ⱕ 180 mm Hg, six of 12 patients (50%)
showed a ⱖ 10 mm Hg improvement in Pao2 when
given IV phenylephrine. When iNO alone was given
to this same group of patients, it resulted in similar
improvement in 11 of 12 patients (92%). When phenyl-
ephrine was combined with iNO, this improvement was
further accentuated in the phenylephrine responders
as compared with the phenylephrine nonresponders.
More work is needed before IV phenylephrine can
be endorsed as adjunctive therapy with or without
iNO for refractory hypoxemia.
Inhaled Prostacyclins: Prostacyclins are natu-
rally occurring prostanoids that are endogenously pro-
duced as metabolites of arachidonic acid in the vascu-
lar endothelium.20 Inhalation of prostacyclins produces
selective pulmonary vasodilation, which might improve
oxygenation in some patients. However, the vast
majority of the relevant research in adults is from stu-
dies that address pulmonary hypertension andⲐor right
heart failure, rather than ARDS. Although high-level
evidence is lacking to support its use, aerosolized
prostacyclin offers a lower-cost alternative to iNO as
a pulmonary vasodilator.21,22 Aerosolized epopros-
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tenol has been demonstrated to be an effective alter-
native to iNO as a pulmonary vasodilator in the acute
care setting.21-23 Aerosol delivery systems for epopros-
tenol include various pneumatic and ultrasonic
nebulizers.22-29 Because of its short half-life, epopros-
tenol is continuously inhaled at 10 to 50 ngⲐkgⲐmin.
Iloprost is the first inhaled prostaglandin to be
approved by the US Food and Drug Administration
for the treatment of pulmonary arterial hypertension.
Iloprost is a stable prostaglandin with a half-life of 20
to 30 min and duration of effect of up to 120 min.30,31
A breath-actuated nebulizer system is the approved
device for iloprost administration, but this device
cannot be used during mechanical ventilation. A
delivery system for iloprost in critically ill patients has
been described, but this awaits clinical confirma-
tion.32 Inhaled treprostinil and iloprost have been
shown to produce comparable decreases in pulmo-
nary vascular resistance, but inhaled treprostinil has
not been evaluated in critically ill patients.33 In an
uncontrolled study of 15 patients with ARDS, aero-
solized alprostadil was associated with significant
increases in Pao2ⲐFio2, averaging 55 mm Hg and
84 mm Hg at 4 h and 24 h, respectively.34 Aerosolized
alprostadil improved oxygenation in infants with hyp-
oxic respiratory failure as well.35 It should be pointed
out that the dose of inhaled prostacyclin, delivered
through various nebulizer systems, may vary consid-
erably. Many different factors may affect the delivery
of this medication, most notable of which is the neb-
ulizer. The type of nebulizer used may also affect the
tidal volume delivered. Continuous nebulization of
prostacyclin may result in occlusion of the expiratory
filters and malfunction of the expiratory valves. In
summary, there are currently few data to support the
use of inhaled pulmonary vasodilators as alternatives
to iNO for severe refractory hypoxemia in ARDS,
although this approach is increasingly used because
of the high cost of iNO. Further research is needed in
this area.
Avoidance of Systemic Vasodilators
Systemically administered vasodilators can pro-
duce hypoxemia for a number of reasons, including
altered distribution of pulmonary blood flow due to
(1) increases in cardiac output, (2) impairment of
hypoxic vasoconstriction as a direct drug effect or as a
result of higher mixed venous Po2, (3) changes in
intracardiac pressure or PAP leading to redistribution
of pulmonary blood flow, and (4) direct action on
pulmonary vascular tone.36 Nitroprusside,37 hydra-
lazine,38,39 nitroglycerine,40,41 nifedipine,42-44 dopamine,
dobutamine,45 and other vasodilators can produce
this effect. Additionally, dopamine can depress the
CHEST / 137 / 6 / JUNE, 2010 1439
 hypercapnic ventilatory response,46-48 potentially exac-
erbating hypoxemia as a result of hypoventilation.
Pulmonary vasodilation does not uniformly cause
worsening oxygenation. The effect of the vasodilator
prostacyclin was tested in patients who had ARDS
and pulmonary hypertension.49 Infusion of prosta-
cyclin reduced PAP and increased cardiac output
but significantly worsened intrapulmonary shunt.
Overall, Pao2 was unchanged, believed to be due to
increased mixed venous Po2 balancing the effects of
increased shunt. Prostaglandin E1 is a vasodilator
that additionally has potent inhibitory effects on neu-
trophil adhesion. In a multicenter placebo-controlled
RCT of patients with ARDS, liposomal prostaglandin
E1 resulted in more rapid improvement in Pao2Ⲑ
Fio2 and shorter duration of mechanical ventilation
compared with placebo, but had more adverse events,
including systemic hypotension; no survival benefit
was demonstrated.50
Bronchodilators, such as intravenous aminophyl-
line and inhaled albuterol and isoproterenol, possess
inotropic and vasodilator properties that can increase
perfusion of poorly ventilated lung units, potentially
worsening hypoxemia.51,52 The preliminary results of
a recently completed multicenter placebo-controlled
RCT found nebulized albuterol to be ineffective in
ALI, with no impact on ventilator-free days or 60-day
mortality.53 In summary, numerous widely used vaso-
dilator medications can exacerbate hypoxemia—a
consideration in the management of patients with
hypoxemic respiratory failure.
Almitrine
Almitrine bismesylate is a selective pulmonary
vasoconstrictor that promotes hypoxic vasoconstric-
tion when administered intravenously and has been
demonstrated to improve oxygenation, particularly in
combination with iNO.54 In studies of patients with
ARDS and sepsis who are responding to iNO, a dose-
dependent increase in Pao2ⲐFio2 ratio was demon-
strated with addition of almitrine.54,55 In these studies,
the nonselective vasoconstrictor, norepinephrine,
had no significant effect on oxygenation, although
both almitrine and norepinephrine increased PAP.
Available in Europe, but not the United States, almi-
trine was used infrequently as rescue therapy for
refractory hypoxemia in a large European ARDS
RCT.1
Prone Position
Placing a patient in the prone position is an adjunc-
tive strategy that has been used to improve oxygena-
tion in patients with severe ARDS, particularly those
with refractory hypoxemia. A number of case series56-60
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have demonstrated the improvement in oxygenation.
However, physiologic benefit has not translated into a
documented survival benefit.
In a review,61 oxygenation was reported to improve
by various mechanisms, which include alveolar
recruitment,62 redistribution of ventilation toward
the dorsal regions resulting in enhanced ventilationⲐ
perfusion matching,63 and the elimination of com-
pression of the lungs by the heart.64 Another mecha-
nism that has been reported for prone positioning is a
decrease in shunt, as a result of better perfusion of
previously atelectatic lung regions that are recruited.60
Both the redistribution of ventilation toward the dor-
sal lung regions and the decrease in shunt perfusion
are believed to occur as a result of the redistribution
of the gravitational forces and the reduction in the
pleural pressure gradient in these regions.60,65,66 Irre-
spective of the mechanisms postulated, the extent of
response or improvement in these patients has been
varied, ranging from approximately 61% to 92% in
some case series.56-60,67 Three groups of patients have
been described by Chatte et al59: (1) patients who do
not respond to prone positioning (ie, nonresponders,
22%), (2) patients whose oxygenation improved when
prone but was not maintained when returned to the
supine position (31%), and (3) patients whose oxy-
genation improvement persists when returned to
the supine position (41%).
There are four RCTs68-71 in which adults with ALI
or ARDS were randomized to conventional ventila-
tion or to mechanical ventilation with prone posi-
tioning (Table 1). As a limitation of the three earlier
trials, patients were ventilated with larger tidal
volumes than those recommended by the ARDS
Network.72 Nevertheless, the majority of patients
undergoing prone positioning experienced an
improvement in their oxygenation. Although none of
these trials demonstrated a survival benefit, pro-
longed periods of prone ventilation were demon-
strated to be both feasible and safe.70 The findings of
significant and persistent (up to 10 days) improve-
ment in Pao2ⲐFio2 ratio during prone positioning, but
without impact on survival or days on mechanical
ventilation, was confirmed in a metaanalysis by
Alsaghir and Martin.73 Interestingly, the incidence of
ventilator-associated pneumonia showed a reduction
in the French trial,69 which was not borne out in the
metaanalysis.73
In a post hoc analysis of the patients with ARDS,
Gattinoni et al68 found a significantly lower 10-day
mortality rate in the patients in the quartile with the
lowest Pao2ⲐFio2 ratio ( ⱕ 88 mm Hg; 23.1% vs
47.2%; relative risk of death 0.49; 95% CI, 0.25-0.95)
ventilated in the prone position as compared with the
supine position. When pooled with similar results by
Mancebo et al,70 mortality was reduced in patients
Postgraduate Education Corner
 Table 1—Summary of Four Randomized Trials on Prone Position

Gattinoni et al68 Guerin et al69 Mancebo et al70 Taccone et al71

No. of patients 304 791 136 343
Prone 152 413 76 168
Supine 152 378 60 174
Enrollment criteria ALI ALI ARDS ARDS
Pao2ⲐFio2 , 300 Pao2ⲐFio2 , 300 Pao2ⲐFio2 , 200 Pao2ⲐFio2 , 200
Daily proning
Planned . 6 hⲐd . 8 hⲐd 20 hⲐd 20 hⲐd
Actual 7 hⲐd 8 hⲐd 13 hⲐd 18-20 hⲐd
Number of days 10 d 4d 10 d 28 d
Oxygenation Improved Improved Improved Improved
VAP Not assessed Reduced Not reduced Not assessed
Primary end point 10-d mortality 28-d mortality ICU mortality 28-d mortality
Prone vs supine 21.1% vs 25% 32.4% vs 31.5% 43% vs 58% 31.0% vs 32.8%
RR, 0.84 RR, 0.97 RR, 0.74 RR, 0.97
95% CI, 0.56-1.27 95% CI, 0.79-1.19 95% CI, 0.53-1.04 95% CI, 0.84-1.13
P 5 .50 P 5 .77 P 5 .12 P 5 .72
ALI 5 acute lung injury; RR 5 relative risk; VAP 5ventilator-associated pneumonia.

with higher illness severity (OR 5 0.29; 95% CI, 0.12-
0.70).73 Based on these findings in patients with
ARDS with the most severe hypoxemia, a recently
published unblinded RCT71 was performed to detect
the potential survival benefit of prone positioning.
This trial was performed while avoiding known limi-
tations from previous trials68-70 that had been sug-
gested as possible reasons for the negative results.
This trial only included patients with ARDS who
were randomized into prone and supine groups and
further stratified into moderate hypoxemia (Pao2Ⲑ
Fio2 100-200 mm Hg) and severe hypoxemia (Pao2Ⲑ
Fio2 , 100 mm Hg) patient subgroups. In addition,
mechanical ventilation was implemented using a pre-
specified protocol in both study groups that limited
tidal volume to a maximum of 8 mLⲐkg of ideal body
weight and airway plateau pressures to 30 cm H2O.
Furthermore, daily proning was performed in the
prone position group for up to 20 h. However, despite
the measures taken, namely, use of a standardized
mechanical ventilation protocol, early application
(within 72 h) of prone position, and the 20 h spent
on prone position, there was no survival benefit
between the prone and supine groups. This was
reported in both the general population (prone vs
supine: 31.0% vs 32.8%; relative risk of death 0.97;
95% CI, 0.84-1.13; P 5 .72) as well as the predefined
study subgroups (moderate hypoxemia: 25.5% vs
22.5%; relative risk of death 1.04; 95% CI, 0.89-
1.22; P 5 .62; and severe hypoxemia: 37.8% vs 46.1%;
relative risk of death 0.87; 95% CI, 0.66-1.14; P 5 .31).
Notably, the proportion of patients with complica-
tions as well as the incidence of a majority of the com-
plications was significantly higher in the prone group.
Nevertheless, there was reported a statistically non-
significant 10% difference in mortality favoring the
prone patients in the severe hypoxemia subgroup.
Prone positioning has been associated with compli-
cations that include pressure sores, endotracheal tube
obstruction, unplanned extubation, loss of central
venous access, and increased use of sedation.68-71
Despite these limitations, Girard and Bernard61 con-
cluded that prone positioning may be considered
a reasonable short-term therapy for patients with
ARDS requiring high Fio2 (. 0.6) or elevated pla-
teau pressure (. 30 cm H2O). In light of recent find-
ings,68,70,71 we recommend that prone positioning be
considered in the subgroup of patients with severe
refractory hypoxemia.
Extracorporeal Life Support
Extracorporeal life support (ECLS), also called
extracorporeal membrane oxygenation, is used in
specialized centers for neonatal, pediatric, and adult
respiratory and cardiac failure. The goal of ECLS is
to support gas exchange, allowing the intensity of
mechanical ventilation to be reduced and thus
decreasing the potentially injurious effects of ventilator-
induced lung injury until recovery. Furthermore,
ECLS might be considered the definitive rescue
therapy for refractory life-threatening hypoxemia
since pulmonary gas exchange is not required. Evidence
supports its use in the neonatal population, but its use
is controversial in adult respiratory failure.
ECLS is a technique that removes blood from the
patient and circulates it through an artificial lung with
a pump. Through 2008, registry data suggest that
only about 2,000 adults have been treated with ECLS
at 145 centers around the world.74 Venoarterial access
can be used, but venovenous access is favored for
treating respiratory failure.75-77 In centers performing
ECLS for respiratory failure, typical treatment crite-
ria include severe respiratory failure from potentially

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 reversible causes, limited time receiving mechanical
ventilation (ie , 7 days), absence of significant comor-
bidities, age , 65 years, and no contraindication to
anticoagulation.74
An early RCT of venoarterial ECLS for acute
respiratory failure reported a 10% survival in patients
who received either ECLS or conventional ventila-
tion.78 Another major RCT using venovenous ECLS
also reported no significant difference in survival with
ECLS compared with mechanical ventilation.79 An
RCT of 180 patients comparing ECLS to conven-
tional ventilation (the Conventional Ventilatory Sup-
port vs Extracorporeal Membrane Oxygenation for
Severe Adult Respiratory Failure, or CESAR, trial)
was recently completed in the United Kingdom.80
Patients randomized to ECLS were transferred to a
single ECLS center to receive treatment, whereas
patients randomized to conventional ventilation
remained in regional hospitals. Survival without dis-
ability in the group randomized to receive ECLS was
63% at 6 months (regardless of whether they received
ECLS) compared with 47% in patients in the control
group (P 5 .03). This was an intention-to-treat analysis,
and only 68 of 90 patients who were randomized to
receive ECLS actually received this therapy because
of clinical improvement prior to initiating ECLS
(n 5 16), death during transfer or within 48 h of transfer
(n 5 5), or contraindication to heparin (n 5 1). An
important criticism of this study is the lack of stan-
dardized management of patients in the control group,
whereas many aspects of care, including adherence
to low tidal volume ventilation, were protocolized in
the ECLS group with significantly higher adherence.
We conclude that because of the multiple confounding
factors in trial design and implementation, firm con-
clusions about the value of ECLS cannot be drawn
from this trial.
In addition to the RCTs, there are observational
reports of the benefit of ECLS in adults with severe
hypoxemic respiratory failure.81-83 One hospital with
nonneonatal ECLS therapy recently reported sur-
vival of 53%. Survival with ECLS therapy was strongly
correlated with the cause of respiratory failure, with
the highest survival seen in those with viral or bacte-
rial pneumonia. Older age, multiple organ failure,
prolonged ventilation prior to ECLS initiation, and
long ECLS runs were associated with decreased
survival.84
The role of ECLS in the treatment of patients with
refractory hypoxemia is likely to remain controver-
sial. A modest number of centers around the world
are able to provide this therapy. It is invasive, it carries
the risk of complications from anticoagulation, and it
is expensive. Newer, less complex technical systems
may make ECLS more attractive and less risky in the
future.85-87 In our management algorithm (Fig 1), we
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include ECLS as an option for life-threatening hyp-
oxemia, reserving it for cases with profound hypox-
emia that is refractory to other ventilatory and non-
ventilatory interventions. Clinicians should weigh
patient characteristics associated with likelihood of
survival as noted above, feasibility and safety of trans-
port and implementation, and the inconclusive out-
comes data currently in the literature, when consid-
ering ECLS in this setting.
Nonventilatory Interventions Associated
With Gradual Improvement in Oxygenation
Conservative Fluid Management
Fluid administration increases hydrostatic pressure
in the lungs and promotes fluid filtration and edema
formation, particularly in states of increased micro-
vascular permeability, such as ARDS.88,89 Addition-
ally, the administration of blood products can con-
tribute to circulatory overload or pulmonary edema
as a result of ALI (ie, transfusion-related ALI). Wors-
ening pulmonary edema is associated with progres-
sive hypoxemia. Patients with ARDS generally accu-
mulate about 1 L of fluid per day with conventional
management.90,91 In RCTs, a conservative fluid-
management strategy for patients with ARDS or
ALI resulted in lower intravascular pressures and
higher oncotic pressure,90 less extravascular lung
water,92 shorter duration of mechanical ventilation,
and shorter ICU LOS.90,92,93 Interestingly, in a multi-
center RCT, conservative fluid management that
achieved a net even fluid balance over 7 days resulted
in only modest improvements in oxygenation, aver-
aging a 15% increase in Pao2ⲐFio2 over 7 days, com-
pared with an 8% increase with liberal fluid manage-
ment (P 5 .07).90
There is evidence that the concomitant adminis-
tration of colloid (albumin) infusions in concert with
diuretics allows for more effective fluid removal
and better oxygenation, at least in hypoproteinemic
patients.94,95 In a small placebo-controlled RCT,
Martin et al94 found that a 5-day protocol of albumin
infusions every 8 h and continuous furosemide infu-
sion led to a 10-kg weight loss over 7 days and
increases in Pao2ⲐFio2 of 40% within 24 h, with the
oxygenation benefit persisting for 7 days. Somewhat
surprisingly, they observed no difference in oxygena-
tion compared with the placebo group after 7 days. In
a subsequent study, the combination of albumin and
furosemide over 72 h was associated with greater
negative fluid balance, more stable hemodynamic
status, and significantly better oxygenation through
72 h in comparison with furosemide alone.95 The
improvement in Pao2ⲐFio2 averaged 30% to 35% higher
than baseline from day 1 to day 7. In a subset analysis
of patients with ARDS taken from a very large RCT,
Postgraduate Education Corner
 Figure 1. Nonventilatory strategies that can be used in patients with ALIⲐARDS with refractory
hypoxemia. These strategies supplement the ventilator strategies and should be reserved for centers
familiar with their use. “Conventional Management of ARDSⲐALI” includes conservative fluid manage-
ment, consideration of use of corticosteroids, and consideration of use of nutritional supplementation—
other measures that may improve oxygenation. ALI 5 acute lung injury; IBW 5 ideal body weight;
iNO 5 inhaled nitric oxide; Pplat 5 plateau pressure; Vt 5 tidal volume.

randomization to albumin rather than normal saline
was not associated with survival benefit.96
The ideal fluid-management strategy remains to be
defined. However, many experts recommend using a
conservative approach that uses diuresis unless the
patient meets one of the following conditions: (1) is
hypotensive, (2) has recently (, 12 h) received vaso-
pressors, (3) has a very low central venous pressure
(, 4 mm Hg), or (4) is oliguric and has a central
venous pressure of 4 to 8 mm Hg.90,91,97 The addition
of albumin for hypoproteinemic patients is also
supported by evidence of moderate strength for
improving oxygenation and hemodynamic status.94,95
Corticosteroid Therapy
The role of corticosteroids in the management of
ARDS and ALI has been controversial since the
1980s and continues to incite debate. Studies con-
ducted in the past decade have assessed the impact
of corticosteroids administered in low-to-moderate
doses (ie, , 2.5 mgⲐkgⲐd of methylprednisolone, or

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 equivalent) for prolonged duration (ie, 4 weeks).
Although these clinical trials generally focused on
critical outcomes, such as survival, ICU and hospital
LOS, andⲐor duration of mechanical ventilation, there
is also evidence that corticosteroid treatment is asso-
ciated with improved oxygenation. Corticosteroids
are commonly administered to patients with ARDS,
including 40% to 50% of patients enrolled in large
international RCTs.1,2
Improvement in oxygenation with corticosteroid
therapy was demonstrated for patients with ARDS
who had persistent respiratory failure despite at
least 7 days of mechanical ventilation. In an RCT of
patients with severe persistent ARDS, those who
received methylprednisolone (2 mgⲐkgⲐd initially,
then tapered over 32 days) demonstrated improved
Pao2ⲐFio2 ratio, from an average of 110 mm Hg to
262 mm Hg, on study day 10.98 This improvement
was significantly (P , .001) greater than with placebo.98
In a subsequent multicenter RCT conducted by the
ARDS Network investigators in which patients with
persistent ARDS were randomized to methylpred-
nisolone or placebo, significantly higher Pao2ⲐFio2
ratio was observed in the methylprednisolone group
on days 3 and 14 after enrollment.99 Patients random-
ized to methylprednisolone also had significantly
more ventilator-free days and shock-failure-free days,
but no difference in mortality compared with
placebo.95 The timing of initiation of therapy may be
important since mortality was higher with methyl-
prednisolone compared with placebo in the small
subset of patients in whom randomization occurred
. 13 days after ARDS onset.99
A more recent RCT extended the observation of
oxygenation benefit with methylprednisolone in
ARDS to early treatment, being initiated within 72 h
of ARDS onset.100 Patients randomized to receive
methylprednisolone had an average increase in Pao2Ⲑ
Fio2 ratio from 118 mm Hg to 256 mm Hg on study
day 7, significantly (P 5 .006) higher than 179 mm Hg
(increased from 126 mm Hg at baseline) for patients
who received placebo. A recent metaanalysis that
included six clinical trials that examined low-to-
moderate dose corticosteroids in ARDS confirmed
significantly (P 5 .01) higher Pa o2ⲐFio2 ratios with
corticosteroids compared with control.101 Although
there is evidence that corticosteroid therapy can result
in improved oxygenation, decisions regarding whether
to administer low-dose long-duration corticosteroid
treatment should weigh important outcome measures.
The authors of the recent metaanalysis also demon-
strated a lower overall relative risk for death, as well
as improvement in ventilator-free days, ICU LOS,
and multiple organ dysfunction scale score, with no
increase in infection, neuromyopathy, or major com-
plications with corticosteroids.101 The authors of an
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international consensus statement conclude that
moderate-dose glucocorticoids should be considered
in the management strategy of patients with early
severe ARDS and before day 14 for patients with
unresolving ARDS, giving this a 2B (weak) recom-
mendation supported by moderate-quality evidence.102
We concur with these recommendations.
Nutritional Supplementation Therapy
There has been accumulating evidence that the
use of a nutritional product rich in antioxidants and
supplemented with v-3 fatty acids, such as eicosap-
entaenoic acid (EPA) and g-linoleic acid (GLA), can
modulate proinflammatory properties in patients
with ARDS and septic shock, resulting in improved
oxygenation and favorable outcomes. Recent results
of a multicenter placebo-controlled RCT performed
by the ARDS Network investigators that was stopped
after enrollment of 272 patients, however, lacked
evidence that v-3 and antioxidant supplementation
has any benefit and showed trends for worse results
regarding survival, ventilator-free days, and ICU-free
days (Todd Rice, MD, personal communication).
These findings contrast with earlier reports. Special
nutritional products with these characteristics have
been compared in prospective trials to standard tube
feeds in critically ill mechanically ventilated adults.103-107
Gadek et al103 performed a multicenter placebo-
controlled RCT in which patients who received
nutrition containing antioxidants and EPAⲐGLA had
improved gas exchange, decreased ICU LOS, and
decreased organ failures in comparison with patients
receiving a standard tube feed. Increases of 35% and
25% in Pao2ⲐFio2 ratio were noted by day 4 and day
7, respectively. A multicenter, double-blind, placebo-
controlled RCT evaluated the impact of a tube feeding
rich in EPA, GLA, and antioxidants on mortality in
patients with sepsis requiring mechanical ventilation
and found improvement in predefined hospital out-
comes and lower mortality rates.104 Improvements
in Pao2ⲐFio2 ratio by about 45% were noted at day
4 and day 7 among patients treated with EPAⲐGLA-
supplemented nutrition, whereas patients who
received standard nutrition had no change in Pao2Ⲑ
Fio2 ratio at either time point. Similarly, in a study of
100 trauma and surgery patients with ALI, Pao2ⲐFio2
ratio was significantly higher at days 4 and 7 with v-3-
based nutrition vs standard nutrition.105 In a metaanal-
ysis of these three studies, EPA 1 GLA nutrition was
associated with significantly (P ⱕ .001 for all) higher
Pao2ⲐFio2 ratios, more ventilator-free and ICU-free
days, as well as lower mortality in comparison with
standard nutrition.106 Although a careful review of the
peer-reviewed paper of the recent ARDS Network
study is needed to more fully compare these results
Postgraduate Education Corner
 to those of previous RCTs, these new findings suggest
lack of benefit and do not exclude the potential for
harm with such supplements, thus dampening
enthusiasm for such an approach until full review is
possible. Accordingly, we withhold recommendation
for or against use of nutritional supplementation with
v-3 fatty acids and antioxidants until these new data
are available for careful review.
IV infusion of antioxidant-enriched parenteral
nutrition has also been tested in a limited scope.107
A small prospective, randomized, double-blind study
consisting of 16 consecutive patients with ARDS
demonstrated the safety of infusing a lipid emulsion
enriched with v-3 fatty acids.107 The study did not
show any significant change in hemodynamic and gas
exchange parameters, but the infusion was maintained
for only 12 h.
Summary
Figure 1 summarizes a proposed algorithmic non-
ventilatory approach to management of severe hyp-
oxemic respiratory failure. Severe refractory hypox-
emia is a common challenge in the management of
patients with ARDS. Adjustments to mechanical ven-
tilation and nonventilatory interventions can produce
improvements in oxygenation that may be life saving.
The use of NMBAs, iNO, prone positioning, andⲐor
ECLS may improve oxygenation in some patients.
Given the risk of adverse effects andⲐor high cost of
these interventions, demonstration of clinically sig-
nificant improvement in life-threatening hypoxemia
should guide decisions to initiate or continue these
potential rescue therapies. Vasoactive agents can
affect oxygenation, and nonselective vasodilators that
might worsen intrapulmonary shunting should be
avoided. A variety of other nonventilatory interven-
tions can have an impact on oxygenation in patients
with ARDS but typically in a more gradual fashion.
Conservative fluid management with diuresis, plus
albumin for hypoproteinemic patients, is associated
with modest improvements in oxygenation and other
benefits and is endorsed. Although controversial,
administration of intravenous corticosteroids in low-
to-moderate doses for prolonged duration has been
associated with improved oxygenation when initiated
, 14 days after onset of ARDS; this has been recom-
mended by an international group of experts and may
be considered. Although earlier RCTs demonstrated
positive outcomes as well as improved oxygenation
with enteral feeding containing v-3 fatty acids and
antioxidants, new research is not supportive of the
benefit of v-3 fatty acid and antioxidant-rich nutri-
tional supplementation. Decisions regarding imple-
mentation of these interventions should be driven by
clinically important outcomes, such as more rapid
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recovery and reduced duration of hospitalization,
rather than oxygenation benefits per se. The treat-
ments included in this review specifically address
severe ARDS and may not be applicable to other causes
of refractory hypoxemia, such as lobar pneumonia,
intracardiac shunt, massive pulmonary embolism, large
pneumothorax, or atelectasis.
Acknowledgments
FinancialⲐnonfinancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Dr Hess has received
royalties from Impact. He was a consultant for Respironics and
Pari. He also has relationships with Cardinal (CaseFusion) and
Ikaria. Drs Raoof, Esan, Goulet, and Sessler report that no poten-
tial conflicts of interest exist with any companiesⲐorganizations
whose products or services may be discussed in this article.
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