[ Contemporary Reviews in Critical Care Medicine ]

Update in Management of Severe

Hypoxemic Respiratory Failure
Dharani Kumari Narendra, MD, FCCP; Dean R. Hess, PhD, RRT; Curtis N. Sessler, MD, FCCP; Habtamu M. Belete, MD;
Kalpalatha K. Guntupalli, Master FCCP; Felix Khusid, RRT-ACCS, RRT-NPS, RPFT, FCCP; Charles Mark Carpati, MD;
Mark Elton Astiz, MD; and Suhail Raoof, MD, Master FCCP

Mortality related to severe-moderate and severe ARDS remains high. We searched

the literature to update this topic. We dened severe hypoxemic respiratory failure as
PaO2/FIO2 < 150 mm Hg (ie, severe-moderate and severe ARDS). For these patients, we support
setting the ventilator to a tidal volume of 4 to 8 mL/kg predicted body weight (PBW), with
plateau pressure (Pplat) # 30 cm H2O, and initial positive end-expiratory pressure (PEEP) of 10
to 12 cm H2O. To promote alveolar recruitment, we propose increasing PEEP in increments of 2
to 3 cm provided that Pplat remains # 30 cm H2O and driving pressure does not increase. A
uid-restricted strategy is recommended, and nonrespiratory causes of hypoxemia should be
considered. For patients who remain hypoxemic after PEEP optimization, neuromuscular
blockade and prone positioning should be considered. Profound refractory hypoxemia (PaO2/
FIO2 < 80 mm Hg) after PEEP titration is an indication to consider extracorporeal life support.
This may necessitate early transfer to a center with expertise in these techniques. Inhaled
vasodilators and nontraditional ventilator modes may improve oxygenation, but evidence for
improved outcomes is weak. CHEST 2017; 152(4):867-879

KEY WORDS: acute hypoxemic respiratory failure; ARDS; nonventilatory strategies in ARDS; prone
positioning in ARDS; ventilatory strategies in ARDS

ARDS, a life-threatening condition, is an hypoxemic patients, both in the selection of

important cause of acute hypoxemic
respiratory failure and accounts for
approximately 10% of ICU admissions and
25% of patients who require mechanical
ventilation.1 Currently, there is controversy
about the management of severely
rescue strategies and the sequence in which
they are used. To provide greater clarity in
the management of such patients, we
conducted a PubMed search (severe
hypoxemic respiratory failure, prevention of
ARDS, ventilator management, recruitment

ABBREVIATIONS: APRV = airway pressure release ventilation; DP =
driving pressure; ECMO = extracorporeal membrane oxygenation;
HFOV = high-frequency oscillatory ventilation; HFPV = high-fre-
quency percussive ventilation; NIV = noninvasive ventilation;
NMBA = neuromuscular blocking agent; PBW = predicted body
weight; PEEP = positive end-expiratory pressure; PP = prone posi-
tioning; Pplat = plateau pressure; P-SILI = patient self-inicted lung
injury; RCT = randomized controlled trial; RHC = right heart cathe-
terization; RV = right ventricular; VV ECMO = venovenous extra-
corporeal membrane oxygenation
AFFILIATIONS: From the Section of Pulmonary, Critical Care and
Sleep Medicine (Drs Narendra and Guntupalli), Department of
Medicine, Baylor College of Medicine, Houston, TX; Massachusetts
General Hospital and Harvard Medical School (Dr Hess), Boston, MA;
the Division of Pulmonary Diseases and Critical Care Medicine
(Dr Sessler), Virginia Commonwealth University Health System,
Richmond, VA; Department of Medicine (Dr Belete), Lenox Hill and
Northwell Hofstra School of Medicine, New York, NY; the Respiratory
Therapy and Pulmonary Physiology Center (Mr Khusid), New York
Presbyterian Brooklyn Methodist Hospital, Brooklyn; the Surgical ICU
(Dr Carpati), the Departments of Internal Medicine and Critical Care
Medicine (Dr Astiz), and the Division of Pulmonary Medicine (Dr
Raoof), Lenox Hill Hospital, and Hofstra Northwell School of Medi-
cine, New York, NY.
CORRESPONDENCE TO: Suhail Raoof, MD, Master FCCP, 2178 Kirby
Lane, Muttontown, New York, NY 11791; e-mail: suhailraoof@gmail.
com
Copyright 2017 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: http://dx.doi.org/10.1016/j.chest.2017.06.039

chestjournal.org 867
maneuver, ECMO, prone positioning, neuromuscular
blocking agents, inhaled prostaglandins, nitric oxide,
nutrition, and ARDS), limited to the past 6 years to
provide an update for our previously published
papers.2,3 This search was supplemented by appropriate
cross-references and our individual familiarity with the
topic. Through this narrative review, we aim to provide a
concise overview of the denition, diagnosis,
recognition, prevention, and treatment of severe
hypoxemic respiratory failure.
Denition of Severe Hypoxemic Respiratory
Failure
The Berlin denition incorporates the timing and origin
of pulmonary edema and categorizes severity based on
the degree of hypoxemia with a minimum positive end-
expiratory pressure (PEEP) of 5 cm H2O.4 Severe ARDS
is dened as a PaO2/FIO2 # 100 mm Hg, and moderate
ARDS is dened as a PaO2/FIO2 of 100 to 200 mm Hg.2
Several recent studies5,6 have focused on patients with
ARDS in whom the PaO2/FIO2 is < 150 mm Hg (severe-
moderate and severe ARDS) as the population most
likely to respond to interventions such as prone
positioning (PP) and neuromuscular blockade.
Consistent with these trials and for the purpose of this
review, we dene severe hypoxemic respiratory failure as
a PaO2/FIO2 of < 150 mm Hg.
Impact of Severe ARDS
Increased ventilator days, length of ICU stay, and
mortality as high as 52% have been reported in severe
ARDS.4 Among patients with ARDS, the prevalence of
severe hypoxemic respiratory failure (PaO2/FIO2 <
100 mm Hg) is about 23%, with a 46% mortality.7
Conversely, many patients with mild ARDS go
unrecognized and therefore fail to receive appropriate
lung-protective ventilation.7 In such cases, ventilator-
induced lung injury may perpetuate lung damage.
Prevention of ARDS
Strategies to prevent ARDS should be used whenever
possible. The Lung Injury Prediction Score was
developed to stratify patients at high risk for ARDS.
Sepsis and pneumonia are two high-risk conditions that
predispose to ARDS.8,9 The Checklist for Lung Injury
Prediction8 was developed to allow earlier recognition of
patients at high risk for the development of lung injury
for the purpose of instituting early preventive measures.
This includes restrictive blood transfusions, appropriate
and timely antimicrobial agents, diligent perioperative
868 Contemporary Reviews in Critical Care Medicine
care, adherence to lung-protective ventilation, aspiration
precautions, and appropriate management of shock,
pancreatitis, and trauma.
The term patient self-inicted lung injury (P-SILI) was
recently introduced.10 In spontaneously breathing
patients with a high respiratory drive, there may be large
tidal volumes and potentially injurious transpulmonary
pressure swings. This can occur with pressure control,
pressure support, airway pressure release ventilation
(APRV), and even with noninvasive ventilatory support.
Due to pendelluft, a strong effort can induce
intrapulmonary redistribution of gas, even before the
start of ination.11 Due to the potential for P-SILI,
clinicians must be cognizant of adverse effects from
excess spontaneous breathing in patients with moderate
and severe ARDS and consider remedial measures such
as sedation and paralysis.12
Ventilatory Strategies
Ventilator-Induced Lung Injury and Prevention
For patients with severe hypoxemic respiratory failure,
invasive ventilation is preferred over noninvasive
ventilation (NIV), as poor outcomes have been reported
in patients treated with NIV.13 Provided that the tenets
of lung-protective ventilation are followed, usually
volume-control or pressure-control ventilation can be
used.14,15 Setting limits to tidal volume and to alveolar
distending pressure should be routinely performed.16
Specically, the tidal volume target should be 4 to
8 mL/kg predicted body weight (PBW)17 and reduced
to as low as 4 mL/kg PBW if plateau pressure (Pplat)
targets are not achieved. Pplat should not exceed 30 cm
H2O provided that chest wall effects are normal. When
the chest wall exerts a collapsing effect on the lungs
(eg, morbid obesity, abdominal hypertension, chest
wall deformity), Pplat > 30 cm H2O might be safe
provided that transpulmonary pressure is acceptable.
Gattinoni et al18 proposed that transpulmonary
pressure (stress) should not exceed 22 to 23 cm H2O.
Given the inhomogeneity in the lungs of patients with
ARDS and the magnifying effect of stress raisers, a
conservative approach of limiting transpulmonary
pressure to < 20 cm H2O seems reasonable. In the setting
of elevated pleural pressure, esophageal manometry
might be useful to establish a safe ventilating pressure.
The authors of recently published evidence-based
clinical practice guidelines recommend that patients with
ARDS receive mechanical ventilation with strategies
that limit tidal volumes (4-8 mL/kg PBW) and Pplat
[ 152#4 CHEST OCTOBER 2017 ]
(< 30 cm H2O) (strong recommendation, moderate
condence in effect estimates).17 Since high tidal volumes
might be an important determinant for the development
of ARDS19 and because ARDS is frequently unrecognized,7
a reasonable recommendation is to limit volume and
pressure in all mechanically ventilated patients.
An emerging concept is that ventilator driving pressure
(DP), the difference between Pplat and PEEP, may be
correlated with outcome. Relative risk of death was > 1
when DP was more than 15 cm H2O in a secondary
analysis of data from randomized controlled trials
(RCTs).20 Although the simplicity of choosing ventilator
settings based on DP makes it attractive, the concept
should be conrmed21 in prospective clinical trials.
Positive End-Expiratory Pressure
Optimizing PEEP is the rst consideration in a patient
with refractory hypoxemia due to diffuse parenchymal
lung disease such as ARDS. Although individual RCTs did
not nd a mortality benet for higher PEEP,22-24 each trial
reported better oxygenation in the higher PEEP group.
Using individual patient data from these three trials, Briel
et al25 found that in subjects with moderate and severe
ARDS, hospital mortality was 34% with higher PEEP and
39% with lower PEEP. In subjects with mild ARDS,
hospital mortality was 27% with higher PEEP and
19% with lower PEEP. In another analysis of the same
data used by Briel et al,25 Kasenda et al26 found that for
patients with a PaO2/FIO2 of 100 to 150 mm Hg, higher
PEEP was associated with lower hospital mortality, but
the benecial effect appeared to plateau for patients with
severe ARDS. Patients with mild ARDS (PaO2/FIO2 >
200 mm Hg) did not benet from higher PEEP, and it
might be harmful. The results of these studies25,26 suggest
that higher PEEP should be reserved for those with
severe-moderate and severe ARDS. The authors of
recently published evidence-based clinical practice
guidelines suggest that patients with moderate or severe
ARDS receive higher rather than lower levels of PEEP
(conditional recommendation, moderate condence in
effect estimates).17
An important practical question is the necessary wait time
after PEEP is changed to assess the response. Chiumello
et al27 found that when performing a PEEP titration,
changes in oxygenation after 5 min might be used to judge
the direction of change (improving or worsening), but the
full effect might take 60 min or longer.
A variety of approaches have been suggested to
determine appropriate PEEP for an individual patient
chestjournal.org
(Table 1).28-31 In a physiological crossover study of
51 patients with ARDS, Chiumello et al32 compared
PEEP selection by lung mechanics24 (or stress index),
esophageal manometry, and oxygenation (higher PEEP
table of the Lung Open Ventilation Study,23 similar to
the high PEEP table of the ARDS Network22). When
patients were classied according to ARDS severity, the
approach using the PEEP/FIO2 table was the only one
that resulted in lower PEEP in mild and moderate ARDS
compared with severe ARDS.
We have previously argued that the benet of PEEP in
patients with refractory hypoxemia might depend on the
potential for alveolar recruitment.2 Gattinoni et al33
suggest that similar PEEP is required in patients with
higher and lower potential for recruitment and that
PEEP selection methods based on PEEP/FIO2 tables were
the only discriminating factors between patients with
higher recruitability and those with lower recruitability.
Gattinoni et al33 also recommend selecting PEEP
according to the ARDS severity: 5 to 10 cm H2O with
mild ARDS, 10 to 15 cm H2O with moderate ARDS, and
15 to 20 cm H2O with severe ARDS. Use of this
approach or a PEEP/FIO2 table (Table 2) can be used for
any patient with ARDS, regardless of expertise and
available technology. Advanced methods such as stress
index, esophageal manometry, ultrasonography, and
electrical impedance tomography should be reserved for
hospitals with the necessary equipment and expertise.
The selection of PEEP is always a balance between
recruitment and overdistention. Goligher et al34 reported
that an increase in PaO2/FIO2 with an increase in PEEP
(presumably the result of recruitment) was associated
with lower mortality, whereas a decrease in PaO2/FIO2
after an increase in PEEP (presumably the result of
overdistention) was associated with a higher mortality.
Applying PEEP that results in a Pplat > 30 cm H2O or a
DP > 15 cm H2O is not recommended. Applying an
increase in PEEP that results in a decrease in DP
TABLE 1 ] Techniques Used to Determine Best
PEEP28-31
Gas exchange: oxygenation: PEEP/FIO2 tables, dead
space
Respiratory mechanics: compliance, driving pressure,
pressure-volume curve, stress index, esophageal
manometry.
Imaging: electrical impedance tomography,
ultrasonography, chest CT imaging
PEEP positive end-expiratory pressure.
869
TABLE 2 ] Tables Used to Set combinations of FIO2 and PEEP to Achieve an Spo2 of 88% to 95%a
See Table 1 legend for expansion of abbreviations.
a
The lower PEEP table might be used for mild ARDS, whereas the higher PEEP table might be used for moderate and severe ARDS. Adapted from
Brower et al.22
suggests recruitment. However, applying an increase in
PEEP that results in an increase in DP suggests that
overdistention has occurred, and PEEP should be
decreased to the previous level. The exception is the
patient with abnormal chest wall mechanics (eg, obesity,
abdominal hypertension) in whom PEEP is necessary to
counterbalance the collapsing effect of the chest wall. In
this setting, esophageal manometry is recommended to
estimate transpulmonary pressure.28,31
Recruitment Maneuvers
A recruitment maneuver is a transient increase in
transpulmonary pressure to promote the reopening of
collapsed alveoli, thereby improving gas exchange and
the distribution of volume in the lungs.28,35 Approaches
include the following:
1. Sustained high-pressure ination using pressures of
30 to 40 cm H2O for 30-40 s (eg, 40 cm H2O for 40 s)
2. A stepwise increase in PEEP with a constant DP (eg,
15 cm H2O) or a xed tidal volume (eg, 4-8 mL/kg
PBW)
Keenan et al36 and Marini37 suggest that stepwise
recruitment maneuvers are more effective for lung
recruitment than abrupt applications of high peak
pressure, with less adverse hemodynamic effects
(Fig 1). Suzumura et al38 conducted a meta-analysis of
10 RCTs assessing the effect of recruitment maneuvers
on mortality and reported a risk ratio (RR) of 0.84
(95% CI, 0.74-0.95) favoring recruitment. In a
Cochrane review,39 data from ve trials showed a lower
ICU mortality (RR, 0.83; 95% CI, 0.72-0.97; P .02)
but no difference in 28-day mortality (RR, 0.86;
95% CI, 0.74-1.01; P .06). The analysis found no
differences in barotrauma. In both these meta-analyses,
the authors commented that the results were
contaminated by cointerventions in patients receiving
recruitment maneuvers. The authors of recently
published evidence-based clinical practice guidelines
870 Contemporary Reviews in Critical Care Medicine
suggest that patients with ARDS receive recruitment
maneuvers (conditional recommendation, low to
moderate condence in the effect estimates).17
An approach to setting PEEP is to perform a recruitment
maneuver followed by a decremental PEEP titration
(open lung approach).40,41 Decremental PEEP titration is
performed by setting the PEEP to 20 to 25 cm H2O, and
then decreasing it in 2 to 3 cm H2O steps every 2 to 3 min.
PEEP is maintained at the level that maintains
oxygenation and respiratory system compliance. This
often results in a PEEP set higher than that before the
recruitment maneuver.
Nonconventional Ventilator Modes
Nontraditional ventilator modes used in the setting of
severe hypoxemic respiratory failure include high-
frequency oscillatory ventilation (HFOV), high-
frequency percussive ventilation (HFPV), and APRV.
The technical features of these modes have been
described elsewhere.2,42-44 Each mode can result in
improved oxygenation, and each has passionate
advocates, but none of these modes has received
widespread acceptance, most likely due to limited high-
level evidence supporting improved outcomes. It is
important to appreciate that ventilator approaches
resulting in better gas exchange might not result in
better survival. In a pivotal ARDS Network study,45 for
example, subjects in the low-tidal-volume group had
worse gas exchange but better survival, indicating that
oxygenation may be a awed surrogate for outcome.
High-Frequency Oscillatory Ventilation
HFOV delivers very low tidal volume (1-2 mL/kg) at high
frequencies (3-15 Hz). Enthusiasm for HFOV was
dampened after two RCTs failed to show a survival
benet.46,47 The authors of a Cochrane review48 suggested
that HFOV does not reduce hospital and 30-day mortality
in patients with ARDS, and thus these ndings do not
[ 152#4 CHEST OCTOBER 2017 ]
 A
50
FIO2: 1
VT: 0.3 L
45
P: 14 cm H2O
FIO2: 1 SpO2: 96%
40 VT: 0.3 L FIO2: 0.6
FIO2: 1 P: 13 cm H2O
PEEP and Pplat (cm H2O)
VT: 0.3 L VT: 0.3 L
35 SpO2: 80% P: 10 cm H2O
FIO2: 1 P: 14 cm H2O
VT: 0.3 L SpO2: 79% SpO2: 96%
30 P: 15 cm H2O
SpO2: 79%
25

20

15

10

0 Stepwise Recruitment Maneuver

B FIO2: 1
50 VT: 0.23 L
FIO2: 1 SpO2: 96% FIO2: 1
45 VT: 0.25 L VT: 0.25 L
FIO2: 1 SpO2: 80% SpO2: 96% FIO2: 1
40 VT: 0.27 L VT: 0.27 L FIO2: 0.6
PEEP and Pplat (cm H2O)

FIO2: 1 SpO2: 79% SpO2: 98% VT: 0.3 L

35 VT: 0.3 L P: 12 cm H2O FIO2: 0.6
SpO2: 79% SpO2: 96% VT: 0.32 L
30 P: 10 cm H2O
SpO2: 95%
25

20

15

10

0 Stepwise Recruitment Maneuver

Figure 1 Examples of stepwise recruitment maneuvers with decremental PEEP titration for constant tidal volume (A) and constant driving pressure
(B). DP driving pressure; PEEP positive end-expiratory pressure; Pplat plateau pressure; SpO2 oxygen saturation measured by pulse oximetry;
VT tidal volume.

support the use of HFOV as a rst-line strategy in patients
undergoing mechanical ventilation for ARDS. The
authors of recently published evidence-based clinical
practice guidelines recommend that HFOV not be used
routinely in patients with moderate or severe ARDS
(strong recommendation, moderate to high condence in
effect estimates).17A recent meta-analysis49 reported that
HFOV was harmful in patients with moderate ARDS,
whereas it showed possible benet in patients with severe
hypoxemia. Meade et al49 state that HFOV might be
considered in patients with severe ARDS who remain
hypoxemic after optimizing conventional lung-protective
ventilation or when approaches such as PP and
extracorporeal membrane oxygenation (ECMO) are
either contraindicated or unavailable.
High-Frequency Percussive Ventilation
HFPV consists of pneumatically powered, pressure-
limited, time-cycled, and ow-interrupted breaths with
biphasic percussions. It generates minibursts or pulses
of subtidal volume, resulting in the production of
intrapulmonary percussive waves. Percussive breaths
are purported to facilitate clearance of respiratory
secretions, facilitate lung recruitment, and reduce the
need for sedation.50
In observational studies, HFPV has been reported to
improve oxygenation for patients with hypoxemic
respiratory failure.51-54 One study reported less time on
ECMO when HFPV was combined with ECMO.55 Chung
et al56 conducted a single-center RCT comparing HFPV

chestjournal.org 871
with low-tidal-volume ventilation in patients who were
admitted to a burn ICU with respiratory failure. Patients
receiving HFPV had higher oxygenation compared with
low tidal volume; however, this did not translate to more
ventilator-free days or reduction in mortality.
Airway Pressure Release Ventilation
APRV is a mode of mechanical ventilation that uses two
levels of airway pressure: (Phigh) and (Plow). APRV
intermittently switches between two levels of CPAP
while allowing the patient to breathe spontaneously
throughout both cycles. APRV has been shown to
improve oxygenation in observational studies, but few
RCTs have been conducted.57,58 In a secondary analysis
of an observational study in 349 ICUs in 23 countries,
Gonzalez et al59 could not demonstrate any improvement
in outcomes with APRV compared with conventional
ventilation. In an RCT, Varpula et al60 compared APRV
and synchronized intermittent mandatory ventilation
with pressure support; they did not nd signicant
differences in clinically relevant outcomes. In an RCT
comparing APRV with conventional low-tidal-volume
ventilation, Maxwell et al61 reported no difference in
mortality and trends for subjects receiving APRV to have
increased ventilator days, ICU length of stay, and
ventilatory associated pneumonia.
Of concern in the study by Maxwell et al and another
by Maung and Kaplan62 is that APRV may increase
ventilator days in trauma patients. This raises the
possibility that APRV could potentiate lung injury.
Specically, spontaneous breathing during the
application of high pressures can result in alveolar
overdistention; similarly, low pressures during the
release phase might result in collapse of alveoli with low
compliance (producing opening/closing injury).58
Further, APRV is associated with generation of tidal
volumes in excess of 6 mL/kg PBW. The brief exhalation
time (often < 0.6 s) virtually guarantees the presence of
intrinsic PEEP, which is difcult to measure and control.
Controversy will continue to surround APRV in the
setting of hypoxemic respiratory failure until a
multicenter RCT with an appropriately designed control
group is able to assess patient-related outcomes.
Nonventilatory Strategies
Neuromuscular Blockade
Neuromuscular blocking agents (NMBAs) are frequently
used in the management of patients with ARDS who have
severe hypoxemia. In the Large Observational Study to
872 Contemporary Reviews in Critical Care Medicine
Understand the Global Impact of Severe Acute
Respiratory Failure (LUNG SAFE) study,7 neuromuscular
blockade was used in about 22% of patients, including
about 38% of patients with a PaO2/FIO2 < 100 mm Hg. A
common indication for NMBAs is hypoxemia in a patient
who exhibits poor ventilator synchrony despite deep
sedation. Improvement in oxygenation has been
demonstrated in placebo-controlled RCTs.6,63-65
Perhaps more important, there is evidence that routine
use of NMBAs for patients with severe ARDS likely
improves outcomes. In a meta-analysis of three placebo-
controlled RCTs, patients with ARDS and a PaO2/
FIO2 < 150 mm Hg who were randomized to continuous
infusion of cisatracurium had lower ICU mortality
(31% vs 45%; RR, 0.71; 95% CI, 0.55-0.90), lower 28-day
mortality (23% vs 34%; RR, 0.68; 95% CI, 0.51-0.92), more
ventilator-free days (6.8 vs 5.2 days; P .02), and less
barotrauma (4.0% vs 9.6%; RR, 0.45; 95% CI, 0.22-0.92).65
Several caveats are worth considering when interpreting
these results,66 particularly those from the largest RCT
by Papazian et al.6 First, although patients with PaO2/
FIO2 < 150 were enrolled in this RCT, post hoc analysis
demonstrated that the mortality benet was limited to
patients with PaO2/FIO2 < 120 at baseline. Second, the
average PEEP administered was lower than in nearly all
other modern-era ARDS clinical trials and might
inuence patient selection and generalizability. Third,
> 50% of patients randomized to receive placebo infusion
received as-needed doses of NMBA. Fourth, all RCTs
used cisatracurium for NMBA and were conducted or led
(or both) by the same group of investigators, potentially
limiting generalizability until more data are available.
The mechanism for improvement in outcomes
associated with NMBA is subject to speculation.67
In an observational study, Beitler et al68 reported that
neuromuscular blockade prevented breath-stacking
asynchrony, ensuring the provision of the intended
lung-protective strategy. Forel et al63 demonstrated that
patients with ARDS who were randomized to receive
cisatracurium had decreasing levels of proinammatory
cytokines in BAL uid and in serum, suggesting that
NMBAs might reduce ventilator-induced biotrauma.
Other potential mechanisms for the effects of
cisatracurium include reduced oxygen consumption,
improved ventilation-perfusion relationships,
prevention of the pendelluft effect,11 and a direct anti-
inammatory effect of the agent.
Despite concerns about prolonged weakness after
neuromuscular blockade, objective evidence of excessive
[ 152#4 CHEST OCTOBER 2017 ]
weakness has not been demonstrated. Using the Medical
Research Councils muscle power scale on day 28 and at
ICU discharge, the scores were identical for patients
randomized to cisatracurium and those randomized to
placebo.7 It is possible that the excellent safety prole of
cisatracurium does not extend to steroid nucleus
NMBAs such as vecuronium, which may produce a
higher incidence of prolonged neuromuscular blockade
or muscle weakness, or both, particularly among
patients with renal or hepatic failure, or both.66
In its recently published guidelines for sustained
neuromuscular blockade, the Society of Critical Care
Medicine69 made a weak recommendation that an
NMBA be administered by continuous IV infusion
early in the course of ARDS for patients with a PaO2/
FIO2 < 150. Since all the RCTs were conducted using
cisatracurium, the recommendation for use of an NMBA
in ARDS is limited to cisatracurium. A multicenter RCT
is now under way in the United States to re-evaluate
the hypothesis that neuromuscular blockade with
cisatracurium improves outcomes in severe ARDS
(ClinicalTrials.gov: NCT02509078).
Prone Positioning
The physiological rationale for PP in ARDS has been
established (Table 3), making this therapy appealing.70,71
Following several negative RCTs,5,72 Guerin et al5
reported benet with PP in severe ARDS in a
multicenter RCT. In this study, there was a signicant
mortality benet for PP (16% absolute risk reduction,
51% relative risk reduction with number needed to treat
of six). Subjects with a PaO2/FIO2 # 150, an FIO2 $ 0.6,
and PEEP $ 5 cm H2O were enrolled.
A criticism of this study is that the PEEP levels were
relatively low when subjects were enrolled; on average,
TABLE 3 ] Potential Physiological Benets for Prone
Positioning77
More homogeneous pleural pressure
Dorsal lung is better perfused and aerated, thereby
decreasing intrapulmonary shunting
Improving ventilation-perfusion matching
Improved lung recruitment
Less ventilator-induced lung injury
Decreased release of proinammatory cytokines
Improves PaO2 and decreases PaCO2 and Pplat by
recruitment, which helps to preserve pulmonary
circulation and improve RV dysfunction
Pplat plateau pressure; RV right ventricular.
chestjournal.org
only 10 cm H2O. Beitler et al73 observed that in three
RCTS of PP, the postintervention PEEP was not more
than 5 cm H2O in 17% of subjects and not more than
10 cm H2O in 66% of subjects. Postintervention PEEP
would have been nearly twice the set PEEP had a high-
PEEP strategy been used. We advocate performing
adequate PEEP titration before PP is instituted. PP
has been shown to improve PaO2 and decrease PaCO2
and Pplat by recruitment, which helps to preserve
pulmonary circulation and improve right ventricular
(RV) dysfunction.74
The results of several recent meta-analyses recommended
the use of PP in severely hypoxemic patients. Beitler et al75
concluded that PP was associated with signicantly
reduced mortality from ARDS in the low-tidal-volume
era and that the substantial heterogeneity across studies
can be explained by differences in tidal volume. Sud et al76
also concluded that the use of PP during mechanical
ventilation improves survival in patients with ARDS who
receive protective lung ventilation. The authors of
recently published evidence-based clinical practice
guidelines recommend that patients with severe ARDS
receive PP for more than 12 hours per day (strong
recommendation, moderate to high condence in effect
estimates).17
Use of PP requires commitment from the clinical staff
caring for the patient, including physicians, nurses, and
respiratory therapists. The key aspects of successful
implementation of PP are listed in Table 4.77 It is
important to note that a specialty bed is not required;
although it might reduce staff burden, it will add expense.
TABLE 4 ] Important Aspects for Successful
Implementation of Prone Positioning77
Early application of prone positioning when severe
hypoxemia persists after initial stabilization
Duration of prone positioning more than 12 h/d
Strict adherence to lung-protective ventilation (tidal
volume 6 mL/kg PBW and Pplat < 30 cm H2O).
Judicious use of neuromuscular blocking agents and
sedation
Experienced and specially trained medical staff who are
familiar with prone positioning
Optimization of PEEP for alveolar recruitment
Discontinuation of prone positioning when oxygenation is
improved (Pao2/FIO2 $ 150 with a PEEP # 10 cm H2O,
FIO2 # 0 .6 for at least 4 h in supine position)
PBW predicted body weight. See Table 1 and 3 legends for expansion of
other abbreviations.
873
Potential complications of PP include endotracheal tube
obstruction and dislodgement and pressure ulcer
formation on dependent areas such as the face, chest,
and knees.77 Absolute contraindications for PP are
spinal instability and unmonitored elevated intracranial
pressure. Relative contraindications include open
abdomen, late pregnancy, severe hemodynamic
instability, unstable fractures, and absolute need for
vascular access.
Extracorporeal Membrane Oxygenation
ECMO, also called extracorporeal life support, can
play an important role in the management of severe
hypoxemic respiratory failure. For patients with
respiratory failure, venovenous (VV) ECMO is used.
This is often accomplished using a single dual-lumen
catheter inserted through the internal jugular vein.78
ECMO is restricted to centers that have established
expertise, as a higher volume of cases is associated with
lower in-hospital mortality for adults.79 In the LUNG
SAFE study, about 3% of invasively ventilated patients
with ARDS received ECMO, including almost 7% with
severe ARDS.7 The increased interest in ECMO80 may
be related to successful application during recent
inuenza pandemics and recent clinical trial results.
A multicenter prospective trial reported improved
outcomes among patients with ARDS transferred to a
single ECMO center compared with continuation of
conventional management at regional hospitals
(63% vs 47% 6-month disability-free survival).81
Interestingly, only 68 of the 90 patients referred to the
ECMO center underwent ECMO, as many of the
remaining patients improved with other interventions
after transfer, obviating the need for ECMO. This
supports the potential value of transferring patients with
severe hypoxemic respiratory failure to a center with
TABLE 5 ] Indications, Contraindications, and Adverse Effects of ECMO
Indications Contraindications
Profound hypoxemia (PaO2/FIO2 < 80) Mechanical ventilation > 7 d
on invasive ventilation with CNS catastrophe
appropriate tidal volume and PEEP Irreversible condition in an individual
persisting for > 3-6 h of optimized who is not a lung transplant
mechanical ventilation candidate
Severe uncompensated hypercapnia Absolute contraindications for
with acidemia (pH < 7.15) despite anticoagulation
appropriate ventilation persisting Multiple organ failure
for > 3-6 h of optimized mechanical Age > 70 y
ventilation
ECMO extracorporeal membrane oxygenation. See Table 1 legend for expansion of other abbreviations.
874 Contemporary Reviews in Critical Care Medicine
specialized expertise, including ECMO. The duration of
mechanical ventilation and ICU and hospital length of
stay were longer when ECMO was used than with
conventional management alone. In a recent multicenter
retrospective analysis of patients with severe ARDS,
those who received early VV ECMO had lower odds of
ICU and hospital death but longer ICU and hospital
length of stay.82
The authors of recently published evidence-based
clinical practice guidelines state that additional evidence
is necessary to make a denitive recommendation for or
against the use of ECMO in patients with severe
ARDS.17 ECMO is indicated when there is compromise
to gas exchange that is refractory to optimal mechanical
ventilation and medical therapy, threatens survival,
and is reversible. Indications, contraindications, and
complications are listed in Table 5.83,84 ECMO provides
potentially lifesaving support of gas exchange and allows
lung rest by reducing the intensity of mechanical
ventilation. High DP during ECMO is associated with
worse outcomes.85
Due to the risks and complexity of management that
requires specialty center expertise, VV ECMO for ARDS
is generally considered after conventional management
has been optimized. However, there are benets
associated with early transfer to an ECMO center. Use of
objective scoring systems that incorporate the degree of
impairment of oxygenation and early response to
conventional therapy, estimates of dead space ventilation,
and other factors can help identify the appropriate
candidate for transfer or initiation (or both) of ECMO.83
Managing ECMO effectively requires an experienced
team. A challenge is weaning the patient from ECMO,
which is as much art as science. It is important to
consider that gas exchange using ECMO occurs at the
membrane lung and that the patients arterial
Adverse Effects
Infection
Bleeding (surgical site, cannulation
site, pulmonary site, GI tract,
intracranial site)
Clotting (at oxygenator, circuit)
Hemolysis
Disseminated intravascular
coagulation
Oxygenation failure
[ 152#4 CHEST OCTOBER 2017 ]
 Pao2/FIO2
< 150 mm Hg

Tidal Volume 4-8 mL/kg PBW

Pplat < 30 cm H2O

Initial PEEP 10-12 cm H2O

Increase PEEP by 2-3 cm H2O steps; stop with hypotension, desaturation, increased driving pressure, or Pplat > 30 cm H2O.
Consider recruitment maneuver and decremental PEEP titration.

Pao2/FIO2 yes
> 150 mm Hg

no
Consider nonrespiratory causes (eg, PFO)
Fluid restriction and diuresis as necessary

no Pao2/FIO2 yes Daily attempt to decrease

> 150 mm Hg PEEP by 2-3 cm H2O

no
Consider transfer to
Neuromuscular blockade
ECMO facility

no Pao2/FIO2 yes Discontinue neuromuscular

> 150 mm Hg blockade at 48 h

no
Prone positioning

no Pao2/FIO2 yes Daily attempt to discontinue

ECMO > 150 mm Hg prone positioning

no

Consider inhaled vasodilators

Consider nontraditional ventilator modes
(note low level evidence to support these strategies)

no Pao2/FIO2 yes
> 150 mm Hg

Figure 2 A suggested approach to severe hypoxemic respiratory failure based on our view of the available evidence. The dashed lines represent less-
favored alternative approaches. This approach is intended to be reasonable, not rigid. Experienced clinicians might select different priorities, and this
approach might be superseded as new evidence becomes available. ECMO extracorporeal membrane oxygenation; PBW predicted body weight;
PFO patent foramen ovale. See Figure 1 legend for expansion of other abbreviations.

oxygenation is the result of mixing the ECMO blood ow (proportion of cardiac output) of ECMO blood
with the native venous blood. The arterial blood oxygen mixed with the venous return blood oxygen content
content will be dependent on the oxygen content and and ow.86

chestjournal.org 875
ECMO and PP
Limited evidence exists on the combination of
ECMO and PP. Most are retrospective studies and
underpowered clinical trials. Kredel et al87 showed that
the combination of VV-ECMO and PP improved both
oxygenation and respiratory compliance without any
serious adverse events. Kimmoun et al88 noted that
improvement in oxygenation was marked when PP was
applied after 7 days of VV-ECMO, with a marked
decrease in Pplat in patients having difculty reducing
Pplat on ECMO alone.
Miscellaneous Therapies
Fluid Restriction
The 2006 Fluid and Catheter Treatment Trial
(FACTT) trial89 showed that aiming for central venous
pressure < 4 mm Hg and pulmonary artery occlusion
pressure < 8 mm Hg with aggressive uid restriction
and diuretics in ARDS improves lung function and
increases ventilator- and ICU-free days without
increasing nonpulmonary organ failure. There was no
mortality benet seen in this trial. Fluid management
with a simplied conservative protocol in ARDS
(FACTT lite) yielded similar results.90
Inhaled Vasodilators (Prostaglandins and Nitric
Oxide)
Selective pulmonary vasodilators improve oxygenation
and lower pulmonary hypertension but have not been
shown to improve mortality. Of concern is the potential
for renal dysfunction and methemoglobinemia when
inhaled nitric oxide is used.91 Inhaled prostaglandin can
result in hypotension.92 Although they should not be
used routinely, inhaled vasodilators might be used as a
bridge to other therapy such as ECMO.
Additional Considerations
It is important to point out that there are other
important conditions frequently associated with ARDS
that may compound the degree of hypoxemia or
complicate its management. For example, almost 20% of
patients with severe ARDS may have a patent foramen
ovale.93 If hypoxemic respiratory failure is not
responding to the ventilatory and nonventilatory
strategies outlined below, it behooves the treating
clinician to look for this entity and consider a contrast
study using agitated saline with transthoracic or
transesophageal echocardiography.93,94 Another entity
that is occasionally encountered and is potentially
treatable is acute cor pulmonale or acute RV
876 Contemporary Reviews in Critical Care Medicine
dysfunction. It may be seen in up to 25% of patients with
severe ARDS95 and is associated with an increase in
RV afterload.95 RV dysfunction may develop even when
the pulmonary artery pressures remain unchanged.
Although right heart catheterization (RHC) was
initially used to diagnose acute RV dysfunction,
echocardiographic imaging (transthoracic or
transesophageal) has supplanted RHC and become
standard of care. Echocardiographic ndings include the
ratio of right ventricular end-diastolic area over LV end-
diastolic area > 0.6 with septal akinesis (D-sign). A RV
protective approach74 includes limiting Pplat to < 27 cm
H2O and DP to < 17 cm H2O, limiting PaCO2 to <
60 mm Hg, titrating PEEP according to RV function,
and using PP in these patients.
Finally, we would like to point out that for patients who
do not respond to initial treatment of severe hypoxemic
respiratory failure, consideration should be given to
transfer to a unit with expertise in caring for such
patients and where therapies such as ECMO are
available. Kahn et al96 reported that mechanical
ventilation of patients in a hospital with a high case
volume was associated with reduced mortality and that
regionalization of intensive care might improve survival
for patients receiving mechanical ventilation.97
Conclusions
A suggested approach to the management of severe
hypoxemic respiratory failure is shown in Figure 2. The
initial approach should be lung-protective ventilation, with
a tidal volume 4 to 8 mL/kg PBW and adequate PEEP
titration. For patients who remain hypoxemic after PEEP
titration, NMBAs and PP should be used. For patients
who remain severely hypoxemic after these strategies,
ECMO should be considered. Inhaled vasodilators and
nontraditional ventilator modes might be considered,
despite low-level evidence to support their use.
Acknowledgments
Financial/nonnancial disclosures: The authors have reported to
CHEST the following: D. R. H. is a consultant for Philips Respironics
and Ventec Life Systems and has received royalties from Jones and
Bartlett, McGraw-Hill, and UpToDate. He is also on the Pulmonary
Disease Board for the American Board of Internal Medicine, and an
editor for Daedalus Enterprises. None declared (D. K. N., C. N. S.,
H. M. B., K. K. G., F. K., C. M. C., M. E. A., S. R.).
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