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CHEST

Postgraduate Education Corner


CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

Severe Hypoxemic Respiratory Failure


Part 1Ventilatory Strategies
Adebayo Esan, MD; Dean R. Hess, PhD, RRT, FCCP; Suhail Raoof, MD, FCCP;
Liziamma George, MD, FCCP; and Curtis N. Sessler, MD, FCCP

Approximately 16% of deaths in patients with ARDS results from refractory hypoxemia, which
is the inability to achieve adequate arterial oxygenation despite high levels of inspired oxygen
or the development of barotrauma. A number of ventilator-focused rescue therapies that can
be used when conventional mechanical ventilation does not achieve a specific target level of
oxygenation are discussed. A literature search was conducted and narrative review written to
summarize the use of high levels of positive end-expiratory pressure, recruitment maneuvers,
airway pressure-release ventilation, and high-frequency ventilation. Each therapy reviewed
has been reported to improve oxygenation in patients with ARDS. However, none of them
have been shown to improve survival when studied in heterogeneous populations of patients
with ARDS. Moreover, none of the therapies has been reported to be superior to another for
the goal of improving oxygenation. The goal of improving oxygenation must always be balanced against the risk of further lung injury. The optimal time to initiate rescue therapies, if
needed, is within 96 h of the onset of ARDS, a time when alveolar recruitment potential is the
greatest. A variety of ventilatory approaches are available to improve oxygenation in the setting of
refractory hypoxemia and ARDS. Which, if any, of these approaches should be used is often
determined by the availability of equipment and clinician bias.
CHEST 2010; 137(5):12031216
Abbreviations: ALI 5 acute lung injury; APRV 5 airway pressure-release ventilation; CPAP 5 continuous positive
airway pressure; HFOV 5 high-frequency oscillatory ventilation; HFPV 5 high-frequency percussive ventilation;
IBW 5 ideal body weight; mPaw 5 mean airway pressure; OI 5 oxygenation index; DP 5 pressure amplitude of oscillation;
PCIRV 5 pressure-controlled inverse-ratio ventilation; PCV 5 pressure-controlled ventilation; PEEP 5 positive endexpiratory pressure; Pplat 5 plateau pressure; RCT 5 randomized controlled trial; VCV 5 volume-controlled
ventilation

American-European Consensus Conference


Theon ARDS
standardized the definition of acute
1

lung injury (ALI) and ARDS on the basis of the following clinical parameters: acute onset of severe
respiratory distress; bilateral infiltrates on frontal chest
radiograph; absence of left atrial hypertension, a pulmonary capillary wedge pressure 18 mm Hg, or no
clinical signs of left heart failure; and severe hypoxemia (ALI, PaO2FIO2 ratio 300 mm Hg; ARDS,
PaO2FIO2 ratio 200 mm Hg). The definition does
not take into consideration, however, the etiology
(pulmonary or extrapulmonary) or the level of positive
end-expiratory pressure (PEEP) required. More than
80% of patients with ARDS require intubation and
mechanical ventilation.2 A lung-protective ventilation
strategy should be used with a tidal volume of 4 to
8 mLkg ideal body weight (IBW), a plateau pressure
(Pplat) of 30 cm H2O, and modest levels of PEEP.
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Such an approach affords a survival benefit and is


standard care.3
Patients with ARDS who are placed on lungprotective mechanical ventilation may have an
improvement in oxygenation and disease severity
within 24 h; their mortality is 13% to 23%4,5; and
they should be continued on lung-protective ventilator settings. In patients with little improvement in
PaO2 FIO2 ratio in the first 24 h after instituting
mechanical ventilation, the observed mortality is significantly higher and varies from 53% to 68%.4,5 In
one study, setting PEEP at 10 cm H2O allowed better
differentiation of ARDS and ALI. After the PEEP
trial, about one-third of patients initially classified as
having ARDS were reclassified as having ALI, and
9% had a PaO2FIO2 ratio of . 300 mm Hg. The
mortality rates for reclassified categories were 45%
for ARDS, 20% for ALI, and 6% for others.6
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1203

Another parameter that may identify patients with


severe ARDS is a PEEP requirement of 15 cm H2O.
to maintain adequate oxygenation. Indirect evidence
for this parameter comes from Kallet and Branson,7
who reviewed data for 197 patients from 16 studies.
They determined that 84% of patients with ARDS
had a lower inflection point of 15 cm H2O on
the pressure-volume curve, suggesting that a PEEP
of 15 cm H2O may identify severe ARDS. In a
series of 47 patients with ARDS, refractory hypoxemia was associated with a 16% mortality rate
among ARDS deaths.8 In the same vein, Luhr et al2
reported that patients with a PaO2FIO2 ratio of
, 100 mm Hg required more aggressive therapy
for oxygenation.
The oxygenation index (OI) incorporates the
severity of oxygenation impairment (PaO2FIO2 ratio)
and mean airway pressure into a single variable:
OI 5 (FIO2 3 mPaw 3 100)/PaO2
(where mPaw 5 mean airway pressure). The OI is used
more commonly in neonatal and pediatric patients but
also has been used in adults with ARDS and may be a
better predictor of poor outcome than the PaO2FIO2
ratio.9-12 A high OI 12 to 24 h after the onset of ARDS
and rising values of OI from persistent ARDS have
been shown to be independent risk factors for
mortality.10-12 An OI of . 30 is reported to represent
failure of conventional ventilation and may be considered an indication for nonconventional modes of
ventilation.9,13-16
For the purpose of this article, we have used the following definition of refractory hypoxemia: PaO2FIO2
ratio of , 100 mm Hg or inability to maintain Pplat
, 30 cm H2O despite a tidal volume of 4 mLkg IBW
or the development of barotrauma. An OI of . 30 also
categorizes a patient as having refractory hypoxemic
respiratory failure. We define high ventilator requirement as an FIO2 of 0.7 mm Hg and a PEEP of
. 15 cm H2O or Pplat . 30 cm H2O with a tidal volume
of , 6 mLkg IBW. This requirement should be recManuscript received October 9, 2009; revision accepted January
14, 2010.
Affiliations: From the New York Methodist Hospital (Drs Esan,
Raoof, and George), Division of Pulmonary and Critical Care
Medicine, Brooklyn, NY; Respiratory Care Services (Dr Hess),
Massachusetts General Hospital, Boston, MA; and Pulmonary
and Critical Care Medicine (Dr Sessler), Virginia Commonwealth
University, Richmond, VA.
Correspondence to: Suhail Raoof, MD, FCCP, Division of Pulmonary 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.org
sitemiscreprints.xhtml).
DOI: 10.1378/chest.09-2415
1204

ognized early in the course of ARDS (, 96 h) when


the potential for alveolar recruitment is greatest.17-20
Consideration also should be given to transferring
patients with refractory hypoxemia to a center with
established expertise in caring for such patients.21-23
What is the physiologic basis for rescue therapies
in severe ARDS? In the lungs of patients with ARDS,
there are alveoli that are relatively normal, that
are collapsed but recruitable, and that are nonrecruitable.24 Rescue methods are used to recruit the
collapsed, but potentially recruitable alveoli. Alveolar
recruitment reduces the shunt fraction, reduces dead
space, and improves compliance. Another important
physiologic concept is optimally matching ventilation
and perfusion.
The primary focus should be on prevention of
refractory hypoxemia rather than on reversing it after
it develops. If small tidal volumes and adequate levels
of PEEP are used and careful attention given to fluid
status and patient-ventilator synchrony, the need for
rescue therapy may be obviated in many cases.25 Rescue therapies can be categorized arbitrarily as ventilatory and nonventilatory strategies. Nonventilatory
interventions, such as neuromuscular blockade, inhaled
vasodilator therapy, prone positioning, and extracorporeal life support, are discussed in a companion
article forthcoming in the June 2010 issue of CHEST,26
whereas ventilatory approaches are addressed here.
Use of rescue therapies is controversial, as, to our
knowledge, none to date has been shown to reduce
mortality when studied in large heterogeneous populations of patients with ARDS. However, some rescue
therapies have been shown to improve oxygenation,
which may be important as a short-term goal in the
16% of patients deteriorating with hypoxemic respiratory failure.8 When instituting rescue strategies, an
attempt should be made to assess for alveolar recruitment. If alveolar recruitment is demonstrated, higher
levels of PEEP should be considered.27-30 Other rescue therapies include airway pressure release ventilation (APRV),31 high-frequency oscillatory ventilation
(HFOV),32 and high-frequency percussive ventilation
(HFPV).33,34 In patients demonstrating very severe
hypoxemic respiratory failure, defined as a PaO2
FIO2 ratio of , 60 mm Hg,27 consideration of extracorporeal life support,35 HFOV, or HFPV may be
appropriate.
Because there are no data establishing the superiority of one rescue mode over another,36 the choice of
rescue therapy is based on equipment availability and
clinician expertise. Some clinicians may choose not to
use a rescue therapy, which is legitimate on the basis
of the level of available evidence. If a rescue therapy
does not result in improved oxygenation or if complications from the therapy occur, that rescue therapy
should be abandoned.
Postgraduate Education Corner

Thus, a reasonable evidence-based approach might


be one in which lung-protective ventilation is used
(volume and pressure limitation with modest PEEP).
This approach may require permissive hypercapnia
(ie, a higher-than-normal PaCO2)37 and permissive
hypoxemia (ie, a lower-than-normal PaO2).38 If a clinical decision is made to implement rescue therapy for
the patient with ARDS and refractory hypoxemia,
one or more of the strategies described in this article
can be used.
In this narrative review, we discuss ventilatory
techniques that have been used in the setting of
refractory hypoxemia in patients with ARDS. A
PubMed search was conducted, with each strategy
used as a key term. We narrowed the search to articles published in English and those that studied
human subjects. We broadened the search to include
additional articles, as appropriate, from the reference
lists of those identified from our primary search.
Positive End-Expiratory Pressure
Increasing the level of PEEP often is the first consideration when the clinician is faced with a patient
with refractory hypoxemia. If PEEP results in alveolar recruitment, the shunt is reduced, and PaO2
increases. Three randomized controlled trials (RCTs)
have evaluated modest vs high levels of PEEP in
patients with ALI and ARDS (Table 1).27,28,39 Although
none of these studies reported a survival advantage for use of higher PEEP, each reported a higher
PaO2FIO2 ratio in the higher PEEP group. Moreover, two of the studies reported lower rates of refractory hypoxemia, death with refractory hypoxemia,
and use of rescue therapies.27,28 Gattinoni and
Caironi40 argued for the use of higher PEEP on the
basis of fewer pulmonary deaths and absence of
reported complications with this strategy.
The National Heart, Lung, and Blood Institute ARDS
Clinical Trials Network39 and Meade et al27 set individualized PEEP using a table of FIO2-PEEP combinations based on oxygenation. Mercat et al28 individualized PEEP to a level set to reach a plateau pressure of
28 to 30 cm H2O. Post hoc analysis of data from their
study suggested that compared with ARDS, mild lung
injury may be associated with less benefit and more
adverse effects from higher levels of PEEP. Thus, a
strategy of a higher PEEP and lower tidal volume with
a plateau pressure target of 28 to 30 cm H2O should
not be used in patients with ALI. Moreover, critics
have argued that the low PEEP (5-9 cm H2O) used in
the control group in Mercat et al may have been excessively conservative and a suboptimal control.
The benefit of PEEP in patients with refractory hypoxemia might depend on the potential for alveolar
recruitment.24 If the recruitment potential is low, then
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an increase in PEEP will have a marginal effect on


shunt and PaO2, and it may contribute to overdistension
of already-open alveoli,41 which could lead to increased
risk for ventilator-induced lung injury and increased
dead space and might potentially result in redistribution of pulmonary blood flow to nonventilated regions
of the lungs. If an increase in PEEP results in alveolar
recruitment, then the strain (distribution of pressure) in
the lungs is reduced. On the other hand, if an increase
in PEEP increases transpulmonary pressure, then the
stress (change in size of the lungs during inflation) on
the lungs is increased. PEEP may adversely affect PaO2
in the presence of unilateral lung disease.42
The potential for recruitment can be identified in
an individual patient by use of a short (30-min) trial
of increased PEEP. If an increase in PEEP results in
minimal improvement (or worsening) of PaO2, an
increase in dead space (increased PaCO2) with stable
minute ventilation, and worsening compliance, then
alveolar recruitment is minimal.43 Conversely, if an
increase in PEEP results in a large increase in PaO2,
a decrease in PaCO2, and improved compliance, it suggests significant recruitment. Some have suggested a
decremental rather than an incremental PEEP trial.44,45
With this approach, PEEP is set to 20 cm H2O and
then decreased to identify the level that produces the
best PaO2 and compliance.
The stress index was recently proposed to assess
the level of PEEP to avoid overdistension.29 This
approach uses the shape of the pressure-time curve
during tidal volume delivery. Worsening compliance
as the lungs are inflated (upward concavity; stress index,
. 1) suggests overdistension, and the recommendation is to decrease PEEP (Fig 1). Improving compliance as the lungs are inflated (downward concavity;
stress index, , 1) suggests tidal recruitment and potential for additional recruitment, thus a recommendation to increase PEEP.
The use of an esophageal balloon to assess intrapleural pressure has been advocated to allow more
precise setting of PEEP.30,46 If pleural pressure is high
relative to alveolar pressure (ie, PEEP), there may be
potential for alveolar derecruitment, which is most
likely seen with a decrease in chest wall compliance,
such as occurs with abdominal compartment syndrome,
pleural effusion, or obesity. In this case, it is desirable
to keep PEEP greater than pleural pressure. Unfortunately, artifacts in esophageal pressure, especially
in supine patients who are critically ill, make it very
difficult to measure absolute pleural pressure
accurately.47-50 Although it is important to consider
pleural pressure when setting PEEP, the use of an
esophageal balloon may not be required. In patients
with abdominal compartment syndrome, bladder
pressure may be useful to assess intraabdominal pressure, the potential collapsing effect on the lungs, and
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Figure 1. Graphic representation of the stress index. Flow and


airway pressure vs time are displayed for three examples of stress
index categories. The ventilator is set for constant-flow inflation.
The stress index is derived from the airway pressure waveform
between the dashed lines. For stress index values , 1, the airway
pressure curve presents a downward concavity, suggesting a continuous decrease in elastance (or increase in compliance) during
constant-flow inflation, and further recruitment of alveoli is likely.
For stress index values . 1, the curve presents an upward concavity, suggesting a continuous increase in elastance (decrease
in compliance), and excessive positive end-expiratory pressure
may be present. Finally, for a stress index value 5 1, the curve is
straight, suggesting the absence of tidal variations in elastance.
Pao 5 airway pressure. (Reprinted with permission from the
American Thoracic Society.29)

the amount of PEEP necessary to counterbalance


this effect.48
The available evidence does not clearly indicate
the best method to select PEEP in patients with
ARDS. Various options are listed in Table 2. A PEEP
setting of 0 cm H2O generally is accepted to be
harmful in the patient with ARDS. A PEEP setting of
8 to 15 cm H2O is appropriate in most patients with
ARDS. Higher levels of PEEP should be used in
patients for whom a greater potential for recruitment
can be demonstrated. Care must be taken to avoid
overdistension when PEEP is set. Higher PEEP settings may be required in patients with refractory hypoxemia; however, a PEEP of . 24 cm H2O seldom is
required. In the decision-making for each patient,
the potential benefit of high levels of PEEP should
be balanced against the risk of harm (ventilatorinduced lung injury, barotrauma, hypotension).
Lung Recruitment Maneuvers
A recruitment maneuver is a transient increase
in transpulmonary pressure intended to promote
reopening of collapsed alveoli 52-54 and has been
shown to open collapsed alveoli, thereby improving
gas exchange.17,18,55-58 However, to our knowledge,
there have been no RCTs demonstrating a mortality
benefit from this improvement in gas exchange.
A variety of techniques have been described as
recruitment maneuvers (Table 3).52,54 One approach
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involves a sustained high-pressure inflation using


pressures of 30 to 50 cm H2O for 20 to 40 s.51,56 A sustained inflation usually is achieved by changing to a
continuous positive airway pressure (CPAP) mode
and setting the pressure to the desired level. Pressurecontrolled breaths can be applied in addition to the
sustained high pressure.18,57 Another approach is to
use intermittent sighs, using three consecutive sighs
set at a pressure of 45 cm H2O.59 An extended sigh
also has been used in which there is a stepwise increase
in PEEP and a decrease in tidal volume over 2 min to
a CPAP level of 30 cm H2O for 30 s.60 Another method
applies an intermittent increase in PEEP for 2 breaths
min.55 Pressure-controlled ventilation (PCV) of 10 to
15 cm H2O with PEEP of 25 to 30 cm H2O to reach a
peak inspiratory pressure of 40 to 45 cm H2O for 2 min
also has been used as a recruitment maneuver.57 Prone
positioning61 and HFOV62 also have been used to
improve alveolar recruitment.
Just as it is unclear which, if any, recruitment
maneuver is superior to another, the optimal pressure,
duration, and frequency of recruitment maneuvers has
not been established. Many patients require increased
sedation, paralysis, or both during the application of a
recruitment maneuver. Studies using a decremental
PEEP trial after a recruitment maneuver have reported
significant oxygenation benefits for at least 4 to 6 h.18,44
However, it is unclear whether this finding was due to
the recruitment maneuver, the PEEP titration strategy,
or both. An improvement in oxygenation with a
recruitment maneuver may indicate that the level of
PEEP is too low. A recruitment maneuver may be of
limited benefit when higher levels of PEEP are used.63
A recent systematic review reported the acute
physiologic effects of a recruitment maneuver in
approximately 1,200 patients.52 Oxygenation was significantly increased after a recruitment maneuver
(Fig 2). Hypotension (12%) and desaturation (8%)
were the most common complications of recruitment
maneuvers. Serious adverse events, such as barotrauma
(1%) and arrhythmia (1%), were infrequent. The overall
mortality was similar to observational studies of
patients with ALI (38%). The finding of improved
oxygenation was more common in the following subgroups: difference between pre- and post-recruitment
maneuver PEEP ( 5 cm H2O vs . 5 cm H2O), baseline
PaO2FIO2 ratio (, 150 mm Hg vs 150 mm Hg), and
baseline respiratory system compliance (, 30 mLcm
H2O vs 30 mLcm H2O).
Many of the studies of recruitment maneuvers
reported a rapid decline in oxygenation gains, some
within 15 to 20 min of the maneuver.52 The application of higher levels of PEEP after a recruitment
maneuver may affect the sustainability of the effect.
Whether improvements in oxygenation associated with
recruitment maneuvers result in reduced lung injury
Postgraduate Education Corner

Table 1Summary of Results of Three Randomized Controlled Trials of Lower vs Higher Levels of PEEP
Study

Control Group
39

Experimental Group

ALVEOLI

Volume assist-control. Vt 5 6 mLkg


Volume assist-control. Vt 5 6 mLkg
IBW; Pplat 30 cm H2O. Combinations
IBW; Pplat 30 cm H2O.
of PEEP and Fio2 to maintain Pao2
Combinations of PEEP and Fio2
(55-80 mm Hg) or SpO2 (88%-95%).
to maintain Pao2 (55-80 mm Hg) or
PEEP on days 1-4 was 8.3 6 3.2 cm
Spo2 (88%-95%). PEEP on days 1-4
H2O. n 5 273
was 13.2 6 3.5 cm H2O. In the first
80 patients, recruitment maneuvers
of 35-40 cm H2O for 30 s. n 5 276

LOV27

Pressure control. Vt 5 6 mLkg


Volume assist-control. Vt 5 6 mLkg
IBW; Pplat 40 cm H2O.
IBW; Pplat 30 cm H2O. Combinations
of PEEP and Fio2 to maintain Pao2
Combinations of PEEP and Fio2
(55-80 mm Hg) or Spo2 (88%-93%).
to maintain Pao2 (55-80 mm Hg) or
PEEP on days 1-3 was 9.8 6 2.7 cm
Spo2 (88%-93%). PEEP on days 1-4
H2O. n 5 508
was 14.6 6 3.4 cm H2O. Recruitment
maneuvers after each disconnect
from the ventilator of 40 cm H2O
for 40 s. n 5 475

EXPRESS28

Volume assist-control. Vt 5 6 mLkg


IBW. Moderate PEEP (5-9 cm H2O).
n 5 382

Volume assist-control. Vt 5 6 mLkg


IBW. PEEP set to reach Pplat of
28-30 cm H2O (14.6 6 3.2 cm H2O)
on day 1. n 5 385

Major Findings
Higher Pao2Fio2 ratio in high PEEP group
(220 6 89 vs 168 6 66) on day 1. Higher
compliance in the higher-PEEP group
(39 6 34 vs 31 6 15 mLcm H2O) on day 1.
Mortality before hospital discharge (low
PEEP, 24.9%; high PEEP, 27.5%; P 5 .48).
Ventilator-free days (low PEEP, 14.5 6 10.4 d;
high PEEP, 13.8 6 10.6 d; P 5 .50). Incidence
of barotrauma (low PEEP, 10%; high
PEEP, 11%; P 5 .51).
Higher Pao2Fio2 ratio in higher-PEEP group
(187 6 69 vs 149 6 61) on day 1. Higher
Pplat in the high-PEEP group (30.2 6 6.3
vs 24.9 6 5.1). The higher-PEEP group had
lower rates of refractory hypoxemia (4.6%
vs 10.2%; P 5 .01), death with refractory
hypoxemia (4.2% vs 8.9%; P 5 .03), and
previously defined eligible use of rescue
therapies (5.1% vs 9.3%; P 5 .045). Twentyeight day mortality (high PEEP, 28.4%;
low PEEP, 32.3%; P 5 .2). Incidence of
barotrauma (high PEEP, 11.2%; low PEEP,
9.1%; P 5 .33).
Higher Pao2Fio2 ratio in higher-PEEP group
(218 6 97 vs 150 6 69) on day 1. Higher
compliance in the high-PEEP group
(37.2 6 22.7 mLcm H2O vs 33.7 6 14.3
mLcm H2O) on day 1. The increased
PEEP group had higher median number
of ventilator-free days (7 d vs 3 d; P 5 .04),
organ failure-free days (6 d vs 2 d; P 5 .04),
and use of adjunctive therapies. Incidence
of barotraumas (high PEEP, 6.8%; low
PEEP, 5.8%; P 5 .57).

ALVEOLI 5 Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury Trial; EXPRESS 5 Expiratory
Pressure Trial; IBW 5 ideal body weight; LOV 5 Lung Open Ventilation Trial; PEEP 5 positive end-expiratory pressure; Pplat 5 plateau pressure;
SpO2 5 oxygenation by pulse oximetry; Vt 5 tidal volume.

and improved outcomes remains to be determined.


Some studies have shown a survival advantage with a
lung-protective ventilation strategy incorporating
recruitment maneuvers,51,64 whereas others have
not.27 The potential for lung recruitment likely varies
considerably among patients,24 which likely affects
the response to a recruitment maneuver.
The routine use of recruitment maneuvers is not
recommended at this time. Given that they pose little
risk of harm if the patient is carefully monitored
during their application and that some patients may
have a dramatic improvement in oxygenation with
their application,57 recruitment maneuvers may play
a role in patients who develop life-threatening refractory hypoxemia. It is prudent to avoid the use of
recruitment maneuvers in patients with hemodynamic compromise and those at risk for barotrauma.65
If the application of a recruitment maneuver results
in an important improvement in oxygenation, higher
levels of PEEP should be used to maintain recruitwww.chestpubs.org

ment. However, caution must be exercised to avoid


overdistension with excessive levels of PEEP.
Pressure-Controlled Ventilation
In patients with severe ARDS, some clinicians
choose PCV as an alternative to volume-controlled
ventilation (VCV) based on several lines of reasoning. First, the peak inspiratory pressure is lower
on PCV, but this is related to the flow pattern
during pressure control and, for the same tidal volume delivery, there is no difference in plateau pressure for PCV and VCV. Second, patient-ventilator
synchrony is believed to be better with PCV.
However, Kallet et al66 reported that the work of
breathing is not better with PCV than with VCV
during lung-protective ventilation in patients who
are actively breathing. Moreover, the active inspiratory effort resulted in an increase in tidal volume such that lung-protective ventilation may have
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Table 2Methods for Selecting PEEP


Method

Description
3,27,39

Incremental PEEP

This approach uses combinations of PEEP and Fio2 to achieve the


desired level of oxygenation or the highest compliance.
This approach begins with a high level of PEEP (eg, 20 cm H2O), after
which PEEP is decreased in a stepwise fashion until derecruitment
occurs, typically with a decrease in Pao2 and decrease in compliance.
The pressure-time curve is observed during constant-flow inhalation
for signs of tidal recruitment and overdistension.
This method estimates the intrapleural pressure by using an esophageal
balloon to measure the esophageal pressure and subsequently
determine the optimal level of PEEP required.
PEEP is set slightly greater than the lower inflection point.

Decremental PEEP44,45

Stress index measurement29


Esophageal pressure measurement30,46

Pressure-volume curve guidance51


See Table 1 for expansion of the abbreviation.

been violated in many patients.66 Third, some clinicians expect an improvement in gas exchange with
PCV. With PCV, the pressure waveform approximates a rectangle, and flow decreases during the
inspiratory phase. The resulting increased mean
airway pressure and lower end-inspiratory flow
theoretically should improve gas exchange. However,
on many current-generation ventilators, a descending ramp of flow can be used with VCV, and this may
result in similar findings with PCV and VCV with a
descending ramp waveform.67-70 With careful attention to tidal volume, plateau pressure, PEEP, and
inspiratory time, the differences between PCV and
VCV are minor, and neither is clearly superior to the
other. It is also worth pointing out that the ARDSNet
trial was conducted with VCV.3

enthusiasm for this ventilatory approach, a number


of subsequent controlled studies reported no benefit or marginal benefit of PCIRV over more conventional approaches to ventilatory support in patients
with ARDS.68,77-80 The elevated mean airway pressure and auto-PEEP that occur with PCIRV also
may adversely affect hemodynamics. Because this
approach can be very uncomfortable for the patient,
sedation and paralysis often are required. On the
basis of the available evidence, there is no clear benefit for PCIRV in the management of patients with
ARDS. The likelihood of an improvement in oxygenation with PCIRV is small, and the risk of auto-PEEP
and hemodynamic compromise is great.81-83

Pressure-Controlled Inverse-Ratio
Ventilation

APRV is a mode of ventilation designed to allow


patients to breathe spontaneously while receiving
high airway pressure with an intermittent pressure
release (Fig 3). The high airway pressure maintains
adequate alveolar recruitment. Oxygenation is determined by high airway pressure and FIO2. The timing
and duration of the pressure release (low airway pressure) as well as the patients spontaneous breathing
determine alveolar ventilation (PaCO2). The ventilatordetermined tidal volume depends on lung compliance, airway resistance, and the duration and timing
of the pressure-release maneuver.

Following reports71-75 of improved oxygenation


with pressure-controlled inverse-ratio ventilation
(PCIRV) published 20 years ago, considerable enthusiasm for this method was generated. The approach
to PCIRV is to use an inspiratory time greater than the
expiratory time to increase mean airway pressure
and, thus, improve arterial oxygenation. PCIRV most
often is used with PCV, although VCV with inverse
ratio also has been described.76 Following the initial

Airway Pressure Release Ventilation

Table 3Different Lung Recruitment Maneuvers


Recruitment Maneuver

Method
51,56

Sustained high-pressure inflation


Intermittent sigh59
Extended sigh60
Intermittent PEEP increase55
Pressure control 1 PEEP57

Sustained inflation delivered by increasing PEEP to 30-50 cm H2O for 20-40 s


Three consecutive sighsmin with the tidal volume reaching a Pplat of 45 cm H2O
Stepwise increase in PEEP by 5 cm H2O above baseline with a simultaneous stepwise decrease
in tidal volume over 2 min leading to implementing a CPAP level of 30 cm H2O for 30 s
Intermittent increase in PEEP from baseline to set level for 2 consecutive breathsmin
Pressure control ventilation of 10-15 cm H2O with PEEP of 25-30 cm H2O to reach a peak
inspiratory pressure of 40-45 cm H2O for 2 min

CPAP 5 continuous positive air pressure. See Table 1 legend for expansion of other abbreviation.
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Postgraduate Education Corner

Figure 2. The relationship between oxygenation (Pao2Fio2 ratio)


after the application of a recruitment maneuver (post-RM) with
baseline (pre-RM) oxygenation in each individual study presented.
Oxygenation was significantly increased post-RM (Pao2Fio2 ratio,
139 mm Hg vs 251 mm Hg; P , .001). PF 5 Pao2Fio2. (Reprinted
with permission from the American Thoracic Society.52)

An active exhalation valve allows the patient to


breathe spontaneously throughout the ventilatorimposed pressures, although spontaneous breathing
typically occurs only during high airway pressure
due to the short time at low airway pressure. Diaphragmatic contraction associated with spontaneous
breaths during APRV may recruit dependent (dorsal)
juxtadiaphragmatic alveoli, thus reducing shunt and
improving oxygenation. Because high airway pressure usually is much longer than low airway pressure, APRV is functionally the same as PCIRV in
the absence of spontaneous breathing. Because the
patients ability to breathe spontaneously is preserved, APRV allows for a prolonged inspiratory
phase without the need for heavy sedation and
paralysis.
Various time ratios for high-to-low airway pressure have been used with APRV, ranging from 1:1 to
9:1 in different studies.84-88 In order to sustain optimal recruitment, the greater part of the total time
cycle (80%-95%) occurs at high airway pressure. In
order to minimize derecruitment, the time spent at
low airway pressure is brief (0.2-0.8 s in adults).89
Neumann et al88 demonstrated that spontaneous
inspiratory and expiratory time intervals are independent of the time at high to low airway pressure cycle
because patients who are breathing spontaneously
can maintain their innate respiratory drive during
high and low airway pressure; thus, the release phase
does not reflect the only expiratory time. If the time
at low airway pressure is too short, expiration may
be incomplete, and intrinsic PEEP may result.88
However, creating intrinsic PEEP is, by design,
required with some approaches to APRV in which
low airway pressure is set to 0 cm H2O.89 With this
approach, the time at low airway pressure is set such
www.chestpubs.org

that the expiratory flow reaches 50% to 75% of the


peak expiratory flow.
Crossover studies have reported improvements
in physiologic end points with APRV.31,85,86,90-92 These
studies reported that APRV required lower inflation
pressure and less sedation and often produced
better oxygenation than other forms of mechanical
ventilation. Putensen et al87 randomized 30 trauma
patients to APRV or PCV. With APRV, the inotropic
support was lower, and the duration of ventilatory
support and length of ICU stay were shorter. However, these findings are debatable because patients
randomized to the conventional ventilation group
were paralyzed for the initial 72 h of support. The
largest RCT of APRV84 was terminated early for
futility after recruiting 58 out of a targeted 80 subjects. At 28 days, there were no statistical differences
in the number of ventilator-free days. In addition,
mortality at 28 days and at 1 year was similar. However, the authors used prone positioning in both
arms, which is known to improve the oxygenation in
60% to 70% of patients; thus, prone position may
have eclipsed any oxygenation differences between
the two groups. Additionally, the ventilator used to
provide APRV in the test group is not designed
to provide APRV and required modification to the
expiratory limb.
Spontaneous breathing during high airway pressure has the potential to generate negative pleural
pressures that may add to the stretch applied from
the ventilator. This situation must be considered
when evaluating the maximal stretch to which the
lungs are exposed. Neumann et al88 reported tidal
volumes of approximately 1 L and large pleural pressure swings with APRV. There is concern that these
relatively large tidal volumes and transpulmonary
pressures could contribute to the risk of ventilatorinduced lung injury. The potential benefits of
improved oxygenation and reduced need for sedation
make APRV an attractive ventilator mode.89 However,
without RCTs demonstrating improved patient outcomes, routine use of this mode cannot be recommended. If APRV is used, auto-PEEP and tidal volume must be closely monitored.
High-Frequency Oscillatory Ventilation
High-frequency ventilation is any application of
mechanical ventilation with a respiratory rate of . 100
breathsmin. This can be achieved with a small tidal
volume and rapid respiratory rate with conventional mechanical ventilation, various forms of external chest wall oscillation, HFPV, high-frequency jet
ventilation, or HFOV, which currently is the form of
high-frequency ventilation most widely used in adult
critical care.62,93-95 It delivers a small tidal volume by
CHEST / 137 / 5 / MAY, 2010

1209

oscillating a bias gas flow in the airway. The oscillator


has an active inspiratory and expiratory phase. A
frequency of 3 to 15 Hz can be used, although lower
rates (3-6 Hz) are used in adults. Nevertheless, higher
rates are feasible and may result in smaller tidal
volumes and decreased risk for lung injury.96
HFOV oscillates the gas delivered to pressures
above and below the mean airway pressure(mPaw).
The mPaw and FIO2 are the primary determinants
of oxygenation, whereas the pressure amplitude of
oscillation (DP) and the respiratory frequency are the
determinants of CO2 elimination. The tidal volume
varies directly with DP and inversely with frequency.95
The mPaw is initially set to a level approximately
5 cm H2O above that with conventional ventilation,
and DP is set to induce wiggle, which is visible to
the patients mid-thigh.96,97 Much of the pressure
applied to the airway is attenuated by proximal
airways and does not reach the alveoli, resulting in a
small tidal volume that may be less than dead
space.98,99 The delivery of a small tidal volume and a

high mPaw may result in improved alveolar recruitment with less risk of overdistension, thus providing
improved gas exchange and lung protection. HFOV
also has been combined with other strategies, such as
recruitment maneuvers,100 inhaled nitric oxide,101 and
prone positioning.102
Most of the evidence for HFOV has been from
small observational studies,9,19,103,104 often in the setting of refractory hypoxemia. These studies have
shown that HFOV is safe and effective, resulting in
improvements in oxygenation and providing ample
ventilation in adult patients with severe ARDS.
There have been only two RCTs of HFOV in adult
patients with ARDS.32,105 Derdak et al32 randomized 148 patients to receive either HFOV or conventional ventilation. The HFOV group showed an early
improvement in the PaO2FIO2 ratio, but this was
not sustained beyond 24 h. There was a nonsignificant trend toward a lower 30-day mortality in the
HFOV group (37% vs 52%; P 5 .102). A criticism of
this trial is that patients in the conventional ventilation

Figure 3. Display of airway pressure and flow vs time during airway pressure-release ventilation.
Spontaneous breaths occur at a high pressure level, leading to a pressure release to a lower pressure
level, as seen in this figure. During this mode, ventilation occurs by intermittent switching between
the two pressure levels while allowing spontaneous breathing to occur in either phase of the ventilator
cycle. Because time at low airway pressure is brief, in practice, spontaneous breathing occurs primarily
during the time of high airway pressure. Maintaining an adequate level of time during a high airway
pressure enhances alveolar recruitment, whereas keeping time short prevents alveolar collapse during
the release to low airway pressure. CPAP 5 continuous positive air pressure; Paw 5 airway pressure;
T High 5 time at high airway pressure; T Low 5 time at low airway pressure; V5 flow. (Reprinted with permission from the Intensive Care On-line Network.89)
1210

Postgraduate Education Corner

group were ventilated with relatively large tidal volumes, which may have contributed to the high mortality in the control group.93 Bollen et al105 reported
no significant difference in mortality between
patients randomized to HFOV and those to conventional ventilation. A post hoc analysis, however, suggested that HFOV might improve mortality in
patients with a higher oxygenation index. Complications reported with HFOV are relatively infrequent
and include barotrauma,19,32,100,104 hemodynamic
compromise,9,104 mucus inspissations resulting in endotracheal tube occlusion or refractory hypercapnia,31
and increased use of sedation or neuromuscular
blocking agents.9,19,32,102,106 In the two RCTs comparing
HFOV with conventional ventilation, Derdak et al
reported no significant effect of HFOV on hemodynamics, barotrauma, or mucus plugging, and Bollen
et al did not report any increased risk of complications with HFOV.

The use of HFOV may improve oxygenation in


patients with refractory hypoxemia. However, there
is not sufficient evidence to conclude that HFOV
reduces mortality or long-term morbidity in patients
with ALI or ARDS.107
High-Frequency Percussive Ventilation
HFPV was introduced in the early 1980s as the
Volumetric Diffusive Respirator (Percussionaire
Corporation; Sandpoint, ID). Compared with HFOV,
only a few studies have investigated the use of HFPV
in adult patients with ARDS.33,108-112 HFPV is a flowregulated, pressure-limited, and time-cycled ventilator that delivers a series of high-frequency (200900 cyclesmin) small volumes in a successive
stepwise stacking pattern, resulting in the formation
of low-frequency (upper limit, 40-60 cyclesmin) convective pressure-limited breathing cycles (Fig 4).34,110,113

Figure 4. High-frequency percussive ventilation. An interplay of the percussive frequency, peak inspiratory pressure (indirectly
modulated by altering the pulsatile flow rate), inspiratory and expiratory times (of both percussive and convective breaths), and the
oscillatory and demand continuous positive air pressure (CPAP) levels either singly or in combination is involved in determining mean
airway pressure as well as the degree of gas exchange. The percussions are of lower amplitude at oscillatory CPAP (baseline oscillations)
during exhalation and are of higher amplitude during inspiration as a result of the selected pulsatile flow rate (see pressure-time display). During inspiration, the lung volumes progressively increase in a cumulative, stepwise manner by continually diminishing subtidal
deliveries that result in stacking of breaths. The peak pressure is reached as a result of modulations in the flow rate of the percussive
breaths. Once an oscillatory pressure peak is reached and sustained, periodic programmed interruptions occur at specific times for
predetermined intervals to allow for the return of airway pressures to baseline oscillatory pressure levels (ie, oscillatory CPAP), thereby
passively emptying the lungs. A 5 pulsatile flow during inspiration at a percussive rate of 655 cyclesmin; B 5 convective pressurelimited breath with low-frequency cycle (14 cyclesmin); C 5 demand CPAP (provides static baseline pressure); D 5 oscillatory CPAP
(provides high-frequency baseline pressure as a mean of the peak and nadir of the oscillations during exhalation); E 5 single percussive
breath; F 5 periodic programmed interruptions signifying the end of inspiration and subsequent onset of exhalation.
www.chestpubs.org

CHEST / 137 / 5 / MAY, 2010

1211

An interplay of the Volume Diffusive Respirator control variables, either singly or in combination, contribute to the determination of mean airway pressure
and gas exhange.34,109,112,114 At high percussion fre-

quencies (300-600 cyclesmin), oxygenation is


enhanced, whereas at low percussion frequencies (180-240 cyclesmin), CO2 elimination is
enhanced.34,109,113

ARDS/ALI
Conventional Management
g
of ARDS/ALI

ARDSnet Guidelines

Non-ventilatory strategies
to improve PaO2
(Part 2)

P O2/FIO2 < 100


PaO
Or
Pplat > 30 cm H2O on VT 4 mL/kg IBW
Or
OI > 30 ?

yes

no

yes
Increase PEEP by 5 - 10 cm H2O to a maximum of 20 cm H2O
and/or
Recruitment maneuver (eg, 30 - 40 cm H2O for 30 - 40 s)

SpO2 increase > 5%


Or
PaCO2 decrease
Or
Compliance increase

no

Low recruitment potential

yes

High recruitment potential

ECLS (PaO2/FIO2 < 60)


Higher Levels of PEEP (ALVEOLI TRIAL)*
FIO2

0.3
03

0.3
03

0.3
03

0
0.3
3

0
0.3
3

0
0.4
4

0
0.4
4

0
0.5
5

0
0.5
5

PEEP
cm H2O

10

12

14

14

16

16

18

0
0.55
0.8
20

0
0.8
8

0
0.9
9

1
1.0
0

1
1.0
0

22

22

22

24

Reassess in 6 24 hours

PaO2/FIO2 < 60

Consider:
HFOV/HFPV
ECLS

PaO2/FIO2 60 - 100

Consider:
APRV
HFOV/HFPV

Figure 5. Ventilatory strategies for the management of refractory hypoxemic respiratory failure,
showing the alternative ventilator strategies that can be used in patients with acute lung injury or ARDS
with refractory hypoxemia following evaluation of the recruitment potential of the lungs. In patients with
recruitable lungs, higher levels of positive end-expiratory pressure (PEEP) or other methods of setting
appropriate levels of PEEP may be used initially. However, failure of the aforementioned techniques
can result in the use of the alternative ventilatory strategies in centers familiar with their use. 5 other
methods of setting appropriate levels of PEEP include setting PEEP to reach a plateau pressure of
28 to 30 cm H2O using esophageal pressure monitoring or the stress index. ALI 5 acute lung injury;
APRV 5 airway pressure-release ventilation; ECLS 5 extracorporeal life support; ETCO2 5 end-tidal
carbon dioxide; HFOV 5 high-frequency oscillatory ventilation; HFPV 5 high-frequency percussive
ventilation. See Table 1 legend for expansion of other abbreviations.
1212

Postgraduate Education Corner

HFPV has been reported to improve oxygenation


and ventilation in patients with ARDS refractory to
conventional ventilation, although these studies are
small in size, few in number, and nonrandomized. In
a prospective trial of seven patients with ARDS
requiring increased ventilator support on conventional
ventilation, Gallagher et al112 found that when the
patients were switched to HFPV at the same level of
airway pressure and FIO2, the patients had a significant increase in PaO2, a slight reduction in PaCO2,
and no change in cardiac output. In another prospective study comparing HFPV and conventional ventilation in 100 adult patients with acute respiratory failure,
no difference was found between the two groups in
the time to reach the study end points of PaO2FIO2
ratio . 225 or shunt , 20%.114 In the subgroup of
patients with ARDS, HFPV provided equal oxygenation and ventilation at significantly lower airway pressures, although there was no difference in the incidence of barotrauma, ICU days, hospital days, or
mortality.114 In a retrospective series of 32 adult
medical and surgical patients with ARDS unresponsive
to at least 48 h of conventional ventilation, Velmahos
et al33 demonstrated improved oxygenation within 1 h
of being switched to HFPV. Peak inspiratory pressure
decreased with HFPV, but mPaw increased. Although
the peak inspiratory pressure decreased, peak alveolar
pressure was not reported. In 12 patients with ARDS
following blunt trauma who were switched to HFPV
after failure of conventional ventilation, there was an
improvement in oxygenation within 12 to 24 h.108
However, these improvements were not due to a rise
in mPaw because there was no significant change following the switch to HFPV. The mechanisms that
contribute to gas exchange in HFPV and other highfrequency ventilatory techniques have been described
in a review by Krishnan and Brower.98
An additional reported benefit of HFPV is the
enhanced mobilization and drainage of secretions
from the lung periphery to the larger airways, potentially decreasing pulmonary infections.33,109,115 Nonetheless, HFPV has not demonstrated improved outcomes. Unlike other ventilatory strategies that might
be applied in the patient with refractory hypoxemia,
both HFOV and HFPV require a ventilator that is
not available in all hospitals as well as respiratory
therapists and physicians skilled in its use.

Summary
Figure 5 summarizes a proposed algorithmic
approach to ventilator management of refractory
hypoxemia. We recommend that lung-protective ventilation (volume and pressure limitation with moderate levels of PEEP) be instituted in patients with
www.chestpubs.org

ALI and ARDS requiring mechanical ventilation.


Rescue therapies may be considered in patients who
develop refractory hypoxemia, with the use of these
therapies based on a variety of factors, such as the
severity of hypoxemia, likelihood of alveolar recruitment, response to the intervention, and patient characteristics. Rescue strategies are aimed at improving
alveolar recruitment (high PEEP, recruitment maneuvers, APRV, HFOV) and, thereby, oxygenation; however, none of these modalities have been consistently
shown to improve outcome in a critically ill patient
population. Before a trial of rescue therapy is initiated, the target outcome should be established. If the
rescue strategy does not achieve this end point, it
should be abandoned. Nonventilatory rescue strategies, such as inhaled vasodilators, prone positioning,
and extracorporeal life support, may be considered in
conjunction with the ventilatory strategies outlined in
this article. They are discussed in detail in part 2 of
this series, which will appear in the June 2010 issue of
CHEST.26 Further research is needed to elucidate
how these rescue strategies may be better used to
provide an outcome benefit.
Acknowledgments
Financialnonfinancial disclosures: The authors have reported
to the CHEST the following conflicts of interest: Dr Hess
has received royalties from Impact. He was a consultant for
Respironics and Pari. He also discloses relationships with Cardinal
(CaseFusion) and Ikaria. Dr George was a consultant to Eubien,
Boehringer Ingelheim, from 2006 to 2007. She has received money
from AstraZeneca, Pfizer, Penexel, and Talceda. Drs Esan, Raoof,
and Sessler report that no potential conflicts of interest exist with
any companiesorganizations whose products or services may be
discussed in this article.

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