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Recruitment Maneuvers for Acute Lung InjuryA Systematic Review

Eddy Fan1,2, M. Elizabeth Wilcox1, Roy G. Brower2, Thomas E. Stewart1, Sangeeta Mehta1, Stephen E. Lapinsky1,Maureen O. Meade3, and Niall D. Ferguson1

1Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada; 2Division of Pulmonary and Critical Care

Medicine, Johns Hopkins University, Baltimore, Maryland; and 3Departments of Clinical Epidemiology and Biostatistics, and Medicine, McMaster

University, Hamilton, Ontario, Canada

Rationale: There are conflicting data regarding the safety and

efficacy of recruitment maneuvers(RMs) in patients with acute lung

injury (ALI).

Objectives: To summarize the physiologic effects and adverse events

in adult patients with ALI receiving RMs.

Methods: Systematicreview of case series,observational studies,and

randomized clinical trials with pooling of study-level data.

Measurements and Main Results: Forty studies (1,185 patients) met

inclusion criteria. Oxygenation (31 studies; 636 patients) was signif-

icantly increasedafteranRM (PaO2:106versus193mmHg,P50.001;

andPaO2/FIO2 ratio:139versus251mmHg, P,0.001).There were no

persistent, clinically significant changes in hemodynamic parame-

ters after an RM. Ventilatory parameters (32 studies; 548 patients)

were notsignificantly alteredby an RM,except forhigher PEEPpost-

RM (11 versus 16 cm H2O; P 5 0.02). Hypotension (12%) and

desaturation (9%) were the most common adverse events (31

studies; 985 patients). Serious adverse events (e.g., barotrauma

[1%]and arrhythmias [1%]) were infrequent. Only 10 (1%) patients

had their RMs terminated prematurely due to adverse events.

Conclusions: Adult patients with ALI receiving RMs experienced

a significant increase in oxygenation, with few serious adverse

events. Transient hypotension and desaturation during RMs is

common but is self-limited without serious short-term sequelae.

Given the uncertain benefitof transient oxygenationimprovements

in patients with ALIand thelack of information on their influence on

clinicaloutcomes,the routine useof RMscannot be recommended or

discouraged at this time. RMs should be considered for use on an

individualized basis in patients with ALI who have life-threatening

hypoxemia.

Keywords: artificial respiration; adult respiratory distress syndrome;respiratory physiology; systematic review

Acute lung injury (ALI) is characterized by the acute onset ofhypoxemia (PaO

2/FIO

2

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such as barotrauma (e.g., pneumothorax), arrhythmias, andbacterial translocation, may occur (15, 19, 20). Due to the con-flicting results regarding the efficacy and safety of RMs in ALI,we undertook this systematic review to synthesize knowledgefrom published studies. Specifically, we intended to summarizethe physiologic effects (i.e., changes in respiratory variables)and adverse events (during and after RMs) in adult patientswith ALI receiving RMs.

MATERIALS AND METHODS

Data Sources and Searches

We searched Medline (May 1950 to Week 3, 2008), AMED (1985 toMay 2008), CENTRAL (second quarter 2008), EMBASE (1980 toWeek 22, 2008), CINAHL (May 1985 to Week 5, 2008), andHEALTHSTAR (1975 to April 2008) using a sensitive search strategy(21) combining Medical Subject Headings and keywords where appro-priate (see the online supplement for details). We examined biblio-graphies of all selected articles and all relevant review articles and handsearched abstracts from recent (20032007) major conferences (Amer-ican Thoracic Society, European Society of Intensive Care Medicine,and Society of Critical Care Medicine) for additional relevant studies.

Study Selection and Data AbstractionWe selected studies meeting the following inclusion criteria: (1)randomized clinical trial or controlled observational study or clinicalcase series (study design), (2) exclusively adult patients at least 18 yearsof age (study population), and (3) undergoing a recruitment maneuverlasting less than 30 minutes and that may be repeated. No languagerestrictions were used. We specified that recruitment maneuvers betransient (,30 minutes) to exclude studies that used a fixed ventilationstrategy (e.g., high versus low PEEP) for recruitment. We excludedclinical studies that met the selection criteria but did not report onphysiologic or adverse effects.

Figure 1 summarizes the study selection process. Two reviewers(EF and NDF) independently assessed the eligibility of each study andresolved disagreements by consensus. We used the kappa statistic tomeasure agreement in these assessments between the two reviewershe.

Data from included studies were abstracted in duplicate (EF,

MEW, RGB, TES, SM, SEL, and NDF) using customized, pilot-testedforms. The reviewers abstracted the data on description of the cohort,study design and methods, physiologic and ventilatory variables,adverse events, and patient survival. Reported aggregated physiologicand ventilatory variables were abstracted from studies at a minimum oftwo time points: pre-RM (i.e., at baseline or before the start of RM)and post-RM (i.e., the first reported values after RM).

Statistical Analysis

Descriptive statistics from individual studies were reported usingproportions and mean 6 SD unless otherwise stated. We pooledavailable data using an n-weighted mean 6 SD based on study size.We compared proportions using Fishers exact test. Continuousvariables were compared using the Wilcoxon signed rank-sum test.We performed sensitivity analyses for all outcomes restricted to: (1)prospective studies, (2) studies that reported physiologic and/orventilatory data 30 minutes or less post-RM (to capture transienteffects related to RMs), and (3) studies using sustained inflation (e.g.,continuous positive airway pressure [CPAP] 3040 cm H2O for 3040seconds) (RM type). We also performed three a priori subgroupanalyses: (1) studies with a pre-to-postRM PEEP difference 5 cmH2O or less versus greater than 5 cm H2O, (2) baseline PaO

2/FIO

2ratio

less than 150 mm Hg (lower) versus 150 mm Hg or greater (higher),and (3) baseline respiratory system compliance less than 30 mL/cmH2O (lower) versus 30 mL/cm H2O or greater (higher). All analyseswere performed using Microsoft Excel 2004 (Microsoft Corporation,Redmond, WA) and Stata 10.0 statistical software (Stata Corporation,College Station, TX). A nominal Pvalue less than 0.05 was used todetermine statistical significance. Due to the heterogeneity in study

populations, interventions, and reported outcomes, a quantitativemeta-analysis of effect sizes was not performed.

RESULTS

Study Search and Selection

The initial search generated 248 citations, of which 91 wereduplicate reports from multiple databases. Iterative review oftitles, abstracts, and full-length articles yielded 40 unique stu-dies, which are included in this review (Figure 1). These studieshad a mean sample size of 30 (range, 8366) and included a totalof 1,185 patients. Agreement on study selection was nearperfect, with a kappa statistic of 0.90 (22).

Study Characteristics

Of the 40 studies, 32 were prospective studies (1417, 2252),four were randomized controlled trials (15, 20, 53, 54), and fourwere retrospective cohort studies (5558). Seventeen studies(43%) enrolled consecutive eligible and consenting patients,and 17 (43%) did not report on patient enrollment procedures.In the majority of studies (78%), RMs were conducted specif-ically for experimental purposes (i.e., designed with the explicitpurpose of examining outcomes after the use of RMs), ascompared with those conducted in the context of usual clinicalcare (Tables 1 and 2). Sustained inflation was the most common(45%) type of RM used.

Figure 1. Literature review schematic illustrating the number of articles

identified at each stage of the review process for potential inclusion in

the systematic review. Iterative review of titles, abstracts, and full-length articles yielded 40 unique studies, which are included in thisreview.

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The baseline characteristics of the study patients are pre-sented in Table 3. Across studies, patients had a mean age of526 9.5 years, with mean APACHE II score 21 6 3.3 and meanLung Injury Score of 3.0 6 0.26. Patients were ventilated atbaseline, with a mean plateau pressure 28 6 4.8 cm H2O, meanVTof 7.0 6 1.2 mL/kg body weight (as reported by each study),and mean PEEP of 12 6 2.1 cm H2O. The etiologic risk factorfor ALI was reported in 36 studies (786 patients); 43% of thesepatients developed ALI from a direct pulmonary insult. Co-interventions were reported in 16 studies (327 patients), withprone positioning used most frequently (22%).

Physiologic and Ventilatory Variables

Thirty-one studies reported on the acute physiologic effects ofan RM in 636 patients (Table 4). Oxygenation was significantlyincreased after an RM (PaO

2: 106 versus 193 mm Hg; P5 0.001

and PaO2/FIO

2ratio: 139 versus 251 mm Hg; P, 0.001) (Figure

2). Few studies reported oxygenation beyond a 3- to 6-hourpost-RM (30, 36, 43, 46, 54), with many studies reporting a rapiddecline in oxygenation gains, some within 15 to 20 minutes ofthe RM (14, 25, 26, 30, 34, 36, 42, 46, 52, 53). Heart rate (104versus 105 beats per minute; P 5 0.04), pH (7.34 versus 7.30;P5 0.04), and central venous pressure (CVP) (13 versus 16 mmHg; P5 0.009) were statistically significantly higher post-RM,although the clinical significance of these changes is question-able. Other hemodynamic parameters, including mean arterial

pressure, pulmonary capillary wedge pressure, cardiac output/index, and mixed venous oxygen saturation, were not signifi-cantly changed after an RM. Ventilatory parameters werereported in 32 studies (548 patients) and were not significantlyaltered by an RM, except for higher PEEP post-RM (11 versus 16cm H2O; P5 0.02).Respiratorysystem compliance was marginallyhigher after an RM (34 versus 35 mL/cm H2O;P5 0.03).

Adverse Events and Mortality

Thirty-one studies evaluated adverse events (985 patients). Themajority of these events occurred during an RM, with hypo-tension (12%) and desaturation (8%) being the most commoncomplications (Table 5). Serious adverse events, such as baro-trauma (1%) and arrhythmias (1%), were infrequent. Only 10(1%) patients were reported to have had RMs terminatedprematurely due to adverse events. Seventeen studies (287patients) reported no adverse events from RMs. Overall mortal-ity was reported in 20 studies (409 patients) and was 38%.

Sensitivity Analyses

Sensitivity analyses restricted to prospective studies (32 studies)yielded results similar to the main analysis, with significantlyincreased oxygenation (PaO

2: 105 versus 190 mm Hg; P, 0.001

and PaO2

/FIO2

ratio: 142 versus 224 mm Hg; P , 0.001) andmodest changes in heart rate (104 versus 105 beats per minute;P 5 0.04), pH (7.33 versus 7.30; P 5 0.04), CVP (13 versus16 mm Hg; P50.009), and respiratory system compliance (34versus 35 mL/cm H2O;P5 0.03). Hypotension (11 versus 19%;P,0.001) and desaturation (7 versus 18%; P, 0.001) duringRMs were reported less frequently. There were no significantdifferences in barotrauma rates between prospective and retro-spective studies.

Studies have reported data on physiologic and ventilatoryparameters at varying times after an RM (range, 3120 minutes).In sensitivity analyses restricted to studies that reported data30 minutes or less post-RM (25 studies), there continued to besignificant increases in oxygenation (PaO

2: 106 versus 214 mm Hg;

P5 0.005 and PaO2/FIO

2ratio: 138 versus 254 mm Hg;P, 0.001),

with modest increases in CVP (13 versus 16 mm Hg; P5 0.01)and PEEP (11 versus 17 cm H2O; P 5 0.01). There were nosignificant differences in the rates of any adverse events betweengroups with data 30 minutes or less post-RM versus more than30 minutes post-RM.

When restricted to studies using sustained inflation (18studies) as compared with other RM types (e.g., sigh/highVT), only the change in the PaO

2/FIO

2ratio remained significant

(149 versus 235; P5 0.005). Point estimates for other variableswere similar to those in the main analysis, but the findings werenot statistically significant. There were no significant differencesin the rates of any adverse events during RMs between sus-tained inflation versus other RM type groups.

Subgroup AnalysesPatients with a pre- to post-RM PEEP difference 5 cm H2O orless still had a significant increase in oxygenation (PaO

2: 102

versus 125 mm Hg; P5 0.02 and PaO2/FIO

2ratio: 145 versus 210

mm Hg;P5 0.04), with a modest change in respiratory systemcompliance (35 versus 38 mL/cm H2O;P5 0.04). There were nosignificant differences in the rates of any adverse events duringRMs in the groups with pre- to post-RM PEEP difference 5 cmH2O or less versus greater than 5 cm H2O.

Oxygenation improved after RMs irrespective of baselinePaO

2/FIO

2ratio: lower group (PaO

2/FIO

2ratio ,150 mm Hg)

(PaO2: 84 versus 181 mm Hg; P 5 0.02 and PaO

2/FIO

2ratio:

128 versus 245 mm Hg; P5 0.002) and higher group (PaO2/FIO

2

TABLE 1. STUDY CHARACTERISTICS

Characteristic Studies (n 5 40)

Study years, range 19992007

No. patients receiving RMs

Total 1,185

Per study, mean (SD) 30 (56)

Number of centers

Total 98

Mean (SD) 2.5 (5.4)

Study duration, h

Total 387Mean (SD) 11 (29)

Study design/purpose,*n (%)

Randomized controlled trial 4 (10)

Clinical 1 (25)

Experimental 3 (75)

Prospective cohort study 32 (80)

Clinical 5 (16)

Experimental 27 (84)

Retrospective cohort study 4 (10)

Clinical 3 (75)

Experimental 1 (25)

Type of RM used, n (%)

Sustained inflation 18 (45)

High pressure-controlled ventilation 9 (23)

Incremental positive end-ex pi ratory press ure 8 (20)

High VT/sigh 4 (10)

Other 1 (2)

RM performed with FIO2 5 1.0, n (%)

Yes 11 (28)

No 13 (32)

Sometimes 0 (0)

Not reported 16 (40)

RM performed on paralysis,n (%)

Yes 22 (55)

No 6 (15)

Sometimes 2 (5)

Not reported 10 (25)

Definition of abbreviation: RM 5 recruitment maneuver.

* Percentage reported for study design is proportion of all studies (n 5 37);

percentage reported for study purpose is proportion of preceding study design.

1158 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178 2008

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ratio>

150 mm Hg) (PaO2: 153 versus 236 mm Hg;

P50.03 andPaO

2/FIO

2ratio: 180 versus 229 mm Hg; P5 0.04). CVP was also

significantly higher post-RM in the lower PaO2/FIO

2ratio sub-

group (13 versus 15 mm Hg; P5 0.02).In the subgroup of patients with lower baseline respiratory

system compliance (,30 mL/cm H2O), there were no significantdifferences in any physiologic or ventilatory parameters after anRM. However, patients with higher baseline respiratory systemcompliance (>30 mL/cm H2O) had a significantly higher PaO

2/

FIO2

ratio after an RM (130 versus 180 mm Hg;P5 0.02). Therewere no significant differences in any adverse events duringRMs in either subgroup (pre- versus post-RM).

DISCUSSION

In this systematic review of nearly 1,200 adult patients withALI, the use of RMs was associated with significant, albeittransient, increases in oxygenation (as measured by PaO

2and

PaO2/FIO

2ratio). There were no clinically significant changes in

short-term hemodynamic or ventilatory variables, except for asmall increase in CVP post-RM. Hypotension and desaturationwere the most common adverse events during RMs, but therewere few serious short-term adverse events (e.g., barotraumasor arrhythmias), and an extremely small number of RMs wereterminated early due to adverse events. Overall mortality wassimilar to previous observational studies of patients with ALI. Ingeneral, these findings (oxygenation, adverse events) were robustacross our sensitivity and subgroup analyses.

Improvements in oxygenation after an RM have beendemonstrated in many studies (14, 23, 27, 28, 31, 32, 34, 35,37, 39, 40, 42, 44, 47, 48, 5053, 55). However, many studiesreport a rapid decline in these oxygenation gains over thesubsequent 24 hours, some within 15 to 20 minutes of the RM(14, 26, 27, 31, 35, 37, 43, 47, 52, 53). Animal models suggestthat the type of RM used (e.g., sustained inflation versus highpressure-controlled ventilation) may also influence the durabil-ity of RM-induced oxygenation (18). In addition, the applica-tion of higher levels of PEEP after an RM may affect thesustainability of the effect (17, 41). Few studies included in oursystematic review reported oxygenation beyond 6 hours, mak-ing it difficult to confirm these results. The importance of thesetransient effects is questionable because there are conflictingdata from observational studies regarding the association be-

tween oxygenation and mortality in ALI (59). Furthermore,despite having reduced oxygenation on Day 1 (as comparedwith the control group), patients randomized to low VTventilation in the ARDS Network study ultimately deriveda survival advantage from this intervention (7). However, theARDS Network study used a ventilation strategy in the controlgroup that resulted in sustained higher tidal volumes andincreased airway pressures, as opposed to the transient natureof the RMs being studied in this review. Improving oxygenationis unlikely to be inherently harmful; rather, it seems likely that itis the manner in which this is achieved that is important.Whether improvements in oxygenation with RMs are associatedwith reduced VILI and improved clinically important outcomes

TABLE 2. RANDOMIZED CONTROLLED TRIALS OF RECRUITMENT MANEUVERS

Trial n Type of RM Used Frequency of RM Main Outcome Measures Adverse Events

ARDSNet (15) 57 Sustained inflation (CPAP

3540 cm H2O for 30 s)

Every other day (alternating

with sham RMs)

Greater increase in SpO2with RM vs. sham RM

(1.7% 6 0.2% vs. 0.6%

6 0.3%; P, 0.01);

changes in FIO2/PEEP

requirements were not

significantly different up

to 8 h from RM or sham RM

Greater decrease in SBP

with RM vs. sham RM

(29.4 6 1.1 vs. 23.1 6

1.1 mm Hg; P, 0.01);

three RMs terminated

early due to transient

hypotension or desaturation;

new barotraumas after

one RM and one sham RMMe ade ( 54) 28 Sustain ed i nflation (CPAP

3540 cm H2O for 2040 s)

Twice daily No net effect on oxygenation

or pulmonary mechanics

after first or subsequent RMs

Ventilator dysynchrony

(five patients),

barotraumas requiring

intervention (four

patients), appeared

uncomfortable (two

patients), transient

hypotension (two patients)

Oczenski (53) 30 Sustained inflation (CPAP

50 cm H2O for 30 s)

Once Significant increase in

P/F ratio at 3 min post-RM

(139 6 46 vs. 246 6

111 mm Hg, P, 0.001)

with return to baseline

values by 30 min; no

significant differences in

P/F ratio between RM and

control group at baseline

and after 30 min

No change in any

hemodynamic variables

at 3 min post-RM compared

with baseline values; no

significant differences

between groups in any

hemodynamic

variables detected

at 30 min compared

with baseline values

Stewart (20) 366 Sustained inflation (CPAP

40 cm H2O for 40 s)

Up to four times daily None reported 81 (22%) patients

with complications from

151 (11%) RMs: hypotension

(61 [5%]), desaturation

(58 [4%]), tachycardia/

bradycardia (24 [2%]),

new air leak (4 [0.3%]),

new arrhythmia (4 [0.3%])

Definition of abbreviations: CPAP 5 continuous positive airway pressure; P/F ratio5 ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; PEEP5

positive end-expiratory pressure; RM 5 recruitment maneuver.


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remains to be determined, although a few studies have showna survival advantage with a lung protective ventilation strategyincorporating RMs (6, 8). In the interim, RMs may also benefitthe minority of patients with ALI who develop life-threateningrefractory hypoxemia.

Given the uncertain importance of transient oxygenationbenefits derived from RMs, any important risks would be criticalin decision-making around their use in patients with ALI.Adverse events (e.g., hypotension and desaturation) were mostcommon during the performance of RMs and were generallytransient and self-limited, given the small proportion of patients(1%) that had RMs terminated early due to adverse events.Serious complications (e.g., barotrauma, arrhythmia) were un-common. Though difficult to quantify, it is possible that evena transient increase in transpulmonary pressure during an RM

may lead to enhanced VILI due to overdistention of relativelyhealthy lung units. Furthermore, given that most patientsrequire increased sedation and/or paralysis during the use ofRMs, there is a potential for indirect adverse effects on long-term outcomes (e.g., neurocognitive and neuromuscular func-tion) (60). Although our results suggest that RMs are generallywell tolerated, the risks and sequelae of RMs may differsubstantially from patient to patient because even transientevents may be detrimental in severely ill patients.

Because increased PEEP alone can lead to direct increasesin oxygenation, we conducted a subgroup analysis with studiesthat had a pre- to post-RM PEEP change of 5 cm H2O or less(versus .5 c m H2O) in an attempt to isolate RM-specific

effects. RMs led to improved oxygenation in both subgroups,although the changes were not statistically significant in the pre-to post-RM PEEP change greater than 5 cm H2O group, likelydue to the small number of studies (and patients) in thatsubgroup. The level of post-RM PEEP may be critical instabilizing and maintaining alveoli opened by the precedingRM; failure to maintain inflation of recruited alveoli post-RMmay potentiate VILI further through cyclic recruitment-dere-cruitment and may explain the lack of a durable oxygenation

response seen in many studies (14, 26, 27, 31, 35, 37, 39, 43, 47,52, 53). Studies using a decremental PEEP trial to identify anoptimal level of post-RM PEEP have maintained significant

Figure 2. Oxygenation (PaO2/FIO

2ratio) pre- and postrecruitment

maneuver by study (20 studies). The relationship between oxygenation(P/F ratio) after the application of a recruitment maneuver (RM) (post-

RM) with baseline (pre-RM) oxygenation in each individual study is

presented. Oxygenation was significantly increased after an RM (PaO2/

FIO2

ratio: 139 versus 251 mm Hg;P,0.001).

TABLE 3. BASELINE CHARACTERISTICS*

Characteristic

Age, yr 52 (9.5)

Female,n 8 (6.4)

Severity of illness (APACHE II Score) 21 (3.3)

Severity of ALI

Lung injury score 3.0 (0.26)

PaO2/FIO2 ratio, mm Hg 142 (39)

Respiratory system compliance, mL/cm H2O 34 (5.5)

ALI risk factor

Pulmonary,n (%) 336 (43)Pneumonia 212 (27)

Aspiration 64 (8)

Other 60 (8)

Extrapulmonary,n (%) 450 (57)

Sepsis 170 (22)

Pancreatitis 25 (3)

Trauma 113 (14)

Burns 5 (1)

Transfusion-related acute lung injury 5 (1)

Other 132 (16)

Ventilatory parameters

Peak inspiratory pressure, cm H2O 29 (3.7)

Plateau pressure, cm H2O 28 (4.8)

Positive end-expiratory pressure, cm H2O 12 (2.1)

VT, mL 508 (58)

VT, mL/kg 7.0 (1.2)

Respiratory rate, breaths per minute 19 (4.5)_VE, L/min 9.9 (2.2)

Co-interventions, no. (%)

Prone positioning 82 (22)

High-frequency oscillatory ventilation 0 (0)

Inhaled nitric oxide 19 (5)

High-dose corticosteroids 0 (0)

None 9 (2)

Definition of abbreviations: ALI 5 acute lung injury; APACHE 5 Acute Physiol-

ogy and Chronic Health Evaluation; FRM 5 recruitment maneuver.

* All values are mean (SD) unless otherwise indicated. ALI risk factors were reported in 37 studies (786 patients). Co-interventions were reported in 17 studies (378 patients).

TABLE 4. PHYSIOLOGIC AND VENTILATORY VARIABLES*

Variable Pre-RM Post-RM Pvalue

Hemodynamics

Mean arterial blood pressure, mm Hg 83 (5.4) 84 (5.2) 0.53

Heart rate, beats per mi nute 104 (12.5) 105 (12.5) 0.04

Central venous press ure, mm Hg 13 (3.6) 16 (5.0) 0.009

Pulmonary capillary wedge pressure,

mm Hg

14 (1.2) 14 (0.8) 0.85

Q, L/min 8.6 (2.0) 8.6 (2.0) 0.58

Cardiac index, L/min/m2 4.4 (1.0) 4.1 (1.0) 0.19

Mi xed ve nous oxyge n saturat ion, % 70 (10) 77 (11) 0.07Arterial blood gas

pH 7.34 (0.08) 7.30 (0.15) 0.04

PaO2, mm Hg 106 (51.3) 193 (133) 0.001

PaCO2, mm Hg 46 (6.8) 48 (13.8) 0.87

Arterial oxygen saturation, % 92 (3.7) 95 (2.1) 0.17

Ventilatory settings

Peak inspiratory pressure, cm H2O 31 (2.8) 34 (4.7) 0.07

Plateau pressure, cm H2O 27 (3.8) 31 (6.4) 0.53

Mean airway pressure, cm H2O 18 (1.7) 22 (5.2) 0.12

Positive end-expiratory pressure, cm H2O 11 (3.1) 16 (5.9) 0.02

VT, mL 506 (57) 470 (251) 0.56

VT, mL/kg 8.1 (2.6) 6.6 (4.2) 0.84

FIO2, % 81 (18) 72 (23) 0.09

Respiratory mechanics

Respiratory system compliance,

mL/cm H2O

34 (4.5) 35 (8.1) 0.03

PaO2/FIO2 Ratio, mm Hg 139 (31.3) 251 (117.0) ,0.001

* All values are n-weighted mean (SD) unless otherwise indicated. Physiologic variables were reported in 31 studies (636 patients) Ventilatory variables were reported in 32 studies (548 patients)


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oxygenation benefits for at least 4 to 6 hours (41, 46). It remainsunclear whether prolonged benefits in oxygenation, perhapsusing different RM techniques, have an impact on importantclinical outcomes in patients with ALI. Finally, it is impossiblewithin the confines of this systematic review to isolate RM- andPEEP-independent effects on oxygenation, which would re-quire an experimental design (i.e., a controlled clinical trial).However, we believe that this analysis is hypothesis generatingfor testing in future studies.

Our study provides conflicting data on the oxygenationbenefit from RMs based on baseline ALI severity. Patients

with a lower baseline PaO2/F

IO2 ratio experienced a significantoxygenation improvement, whereas those with lower baseline

respiratory system compliance did not. The lack of oxygenationbenefit in patients with lower baseline respiratory system com-pliance may be consistent with a subgroup of patients with ALIwho are not easily recruitable and in whom the risks of RMsmay outweigh the potential benefits. Although hypotension hasbeen reported to be more common in patients with poor chestwall compliance and limited RM-induced oxygenation benefit(61), we did not observe any difference in hypotension in asimilar subgroup of patients in our study with low baselinerespiratory system compliance. In contrast, Gattinoni andcolleagues demonstrated that patients with ALI who had lowerbaseline ALI disease severity (respiratory system compliance 496 16 mL/cm H2O; PaO

2/FIO

2ratio 220 6 70 mm Hg) had a lower

potential for recruitment due to fewer targets available (i.e.,diseased, atelectatic lung units) for recruitment (13). Patientsincluded in our systematic review had more severe ALI atbaseline (as measured by baseline respiratory system compli-ance and PaO

2/FiO

2ratio), which may explain these divergent

results.Our study has other potential limitations. First, because the

studies were heterogeneous in design, type of RM used, andoutcomes measured and reported, we could not performa quantitative meta-analysis with true effect sizes (i.e., relativerisk or odds ratio). Furthermore, too few randomized controlledtrials of RMs have been conducted to allow a summary of theeffects of RMs as compared with placebo (or sham) in patients

with ALI. However, the results of our analysis are similar to thefew randomized controlled trials that have been reported (15,20, 53, 54). Second, most studies did not directly measurealveolar recruitment, making it difficult to attribute our findingsof improved oxygenation to successful RMs alone. Changes inoxygenation alone may not directly reflect recruitment becauseoxygenation may be influenced by other factors affected byRMs, such as cardiac output. However, cardiac output (orindex) did not change significantly after an RM in studies thatreported these parameters. Because shunt from airless lungregions is a major cause of arterial hypoxemia in ALI (1), RM-induced recruitment is likely the cause of the transient oxygen-ation improvements. Furthermore, our results were robust inthe subgroup of patients with a pre- to post-RM PEEPdifference of 5 cm H2O or less. Third, given the previousfindings of transient RM-induced oxygenation effects, ourinclusion of a wide range of reported data at the post-RM timepoint may not accurately reflect the true effect of RMs.However, by including data up to 120 minutes post-RM, thiswould have biased our results toward finding no significantdifference in oxygenation pre- to post-RM. In addition, ourresults were robust in a sensitivity analysis restricted to datareported less than 30 minutes post-RM. Finally, the results fromour subgroup analyses based on baseline ALI severity may

differ depending on the thresholds chosen for PaO2/FIO2 ratioand respiratory system compliance. Both thresholds werechosen to balance clinical and practical considerations; for thelatter, this allowed enough patients to be included in eachsubgroup to make a meaningful comparison.

In conclusion, adult patients with ALI receiving RMsexperienced a significant increase in short-term oxygenation,with few serious short-term adverse events. Transient hypoten-sion and desaturation during RMs is common, although likelyself-limited without serious sequelae. The risks of RMs mayoutweigh the potential benefits in patients with ALI who havelow baseline respiratory system compliance, although thesefindings require confirmation in future studies. Given the un-certain benefit of transient oxygenation improvements in patients

with ALI and the lack of information on their clinical outcomeeffects, the routine use of RMs cannot be recommended ordiscouraged at this time. RMs should be considered on anindividualized basis in patients with ALI with life-threateningrefractory hypoxemia.

Conflict of Interest Statement: None of the authors has a financial relationshipwith a commercial entity that has an interest in the subject of this manuscript.

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TABLE 5. ADVERSE EVENTS AND MORTALITY

Adverse Event or Outcome Pre-RM During RM Post-RM

Cardiovascular,* no. (%)

Cardiac arrest 0 0 0

Arrhythmia 0 8 (1) 0

Myocardial ischemia/infarction 0 0 0

Hypertension 0 0 0

Hypotension 0 114 (12) 0

Other cardiovascular 0 24 (2) 0

Respiratory,* no. (%)

Desaturation 1 (0) 82 (8) 0Barotrauma 0 9 (1) 9 (1)

Refractory respiratory acidosis 0 0 0

Other respiratory 0 5 (1) 0

Other (noncardiovascular, nonrespiratory),*n (%) 0 4 (1) 0

Studies with no adverse events,

n (no. of patients)

17 (287)

Studies that did not report adverse events,

n (no. of patients)

9 (201)

RMs terminated due to adverse events, n (%) 10 (1)

Mortality, n(%) 157 (38)

Studies that did not report mortality,

n (no. of patients)

20 (736)

Definition of abbreviations: ICU 5 intensive care unit; RM 5 recruitment

maneuver.

* Adverse events were reported in 31 studies (985 patients). Mortality was reported in 20 studies (409 patients).


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