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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
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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Table 1Summary of Results of Three Randomized Controlled Trials of Lower vs Higher Levels of PEEP
Study
Control Group
39
Experimental Group
ALVEOLI
LOV27
EXPRESS28
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.
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Description
3,27,39
Incremental PEEP
Decremental PEEP44,45
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
Pressure-Controlled Inverse-Ratio
Ventilation
Method
51,56
CPAP 5 continuous positive air pressure. See Table 1 legend for expansion of other abbreviation.
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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)
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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.
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.
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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-
ARDS/ALI
Conventional Management
g
of ARDS/ALI
ARDSnet Guidelines
Non-ventilatory strategies
to improve PaO2
(Part 2)
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)
no
yes
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.
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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
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