Recruitment Maneuvers for Acute Lung Injury

A 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
1 Interdepartmental 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 conicting data regarding the safety and efcacy 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: Systematic review 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 significantly increased after an RM (PaO2: 106 versus 193 mm Hg, P 5 0.001; and PaO2/FIO2 ratio: 139 versus 251 mm Hg, P , 0.001). There were no persistent, clinically signicant changes in hemodynamic parameters after an RM. Ventilatory parameters (32 studies; 548 patients) were not signicantly altered by an RM, except for higher PEEP postRM (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 signicant 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 benet of transient oxygenation improvements in patients with ALI and the lack of information on their inuence on clinical outcomes, the routine use of RMs cannot 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: articial respiration; adult respiratory distress syndrome; respiratory physiology; systematic review

AT A GLANCE COMMENTARY
Scientic Knowledge on the Subject

Conicting data exist regarding the safety and efcacy of recruitment maneuvers in patients with acute lung injury. Recruitment maneuvers lead to a signicant increase in oxygenation, with few serious adverse events.
What this Study Adds to the Field

Given the uncertain benet of transient oxygenation improvements in patients with ALI and the lack of information on their inuence on clinical outcomes, the routine use of RMs cannot 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.

Acute lung injury (ALI) is characterized by the acute onset of hypoxemia (PaO2/FIO2 <300 mm Hg) with bilateral inltrates on a frontal chest radiograph not explained by the presence of left atrial hypertension (1). ALI associated with the most severe hypoxemia (PaO2/FIO2 ratio <200 mm Hg) is termed acute respiratory distress syndrome (ARDS). Various pulmonary and extrapulmonary insults may lead to ALI/ARDS, most frequently pneumonia and extrapulmonary sepsis (2). ALI and ARDS are common, with a crude incidence of 78.9 and 58.7 cases per 100,000 persons per year, respectively, resulting in
(Received in original form February 25, 2008; accepted in nal form August 29, 2008) Supported by a Canadian Institutes of Health Research Fellowship Award (E.F.), an RCT Mentoring Program Salary Award (N.D.F.), and a Royal College of Physicians and Surgeons of Canada Detweiler Traveling Fellowship (E.F.). Correspondence and requests for reprints should be addressed to Niall D. Ferguson, M.D., M.Sc., Toronto Western Hospital, 399 Bathurst Street, 2MCL-411M Toronto, Ontario, Canada M5T 2S8. E-mail: n.ferguson@utoronto.ca This article has an online supplement, which is accessible from this issues table of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 178. pp 11561163, 2008 Originally Published in Press as DOI: 10.1164/rccm.200802-335OC on September 5, 2008 Internet address: www.atsjournals.org

an associated signicant economic burden (3). Mortality from ALI/ARDS is substantial, ranging from 34 to 58% in recent observational studies (2, 4). The only intervention found to reduce mortality from ALI is an approach to mechanical ventilation that uses relatively small tidal volumes and low airway pressures (58). In addition to pressure and volume limitation, recruitment maneuvers (RMs) may be an important component of a lung protective ventilation strategy. Recruitment refers to the dynamic process of reopening unstable airless alveoli through an intentional transient increase in transpulmonary pressure. This process can be accomplished through a variety of methods (9). The rationale for the use of RMs in ALI is to promote alveolar recruitment, leading to increased end-expiratory lung volume. An increase in end-expiratory lung volume may improve gas exchange and attenuate ventilator-induced lung injury (VILI) by preventing repetitive opening and closing of unstable lung units (9, 10). Moreover, by increasing the number of aerated lung units, recruitment may reduce VILI from the selective overdistention of relatively healthy alveolar units (11, 12). However, RMs may directly overdistend aerated lung units and could, paradoxically, lead to increased VILI (912). Clinical studies of RMs in ALI have yielded variable results (1315). Factors such as the duration (e.g., early versus late) and underlying etiology of ALI (e.g., pulmonary versus extrapulmonary) may be important determinants of the potential for alveolar recruitment and associated physiologic responses (16, 17). Furthermore, the methods of the RM (e.g., sustained ination versus incremental positive end-expiratory pressure [PEEP]) may inuence the effects (18), and the optimal pressure, duration, and frequency of RMs have not been determined or tested in large clinical trials. Finally, although transient hypotension and oxygen desaturation are the most common adverse events related to RMs, serious side effects,

Fan, Wilcox, Brower, et al.: Recruitment Maneuvers in ALI

1157

such as barotrauma (e.g., pneumothorax), arrhythmias, and bacterial translocation, may occur (15, 19, 20). Due to the conicting results regarding the efcacy and safety of RMs in ALI, we undertook this systematic review to synthesize knowledge from published studies. Specically, we intended to summarize the physiologic effects (i.e., changes in respiratory variables) and adverse events (during and after RMs) in adult patients with ALI receiving RMs.

MATERIALS AND METHODS

Data Sources and Searches
We searched Medline (May 1950 to Week 3, 2008), AMED (1985 to May 2008), CENTRAL (second quarter 2008), EMBASE (1980 to Week 22, 2008), CINAHL (May 1985 to Week 5, 2008), and HEALTHSTAR (1975 to April 2008) using a sensitive search strategy (21) combining Medical Subject Headings and keywords where appropriate (see the online supplement for details). We examined bibliographies of all selected articles and all relevant review articles and hand searched abstracts from recent (20032007) major conferences (American Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine) for additional relevant studies.

Study Selection and Data Abstraction

We selected studies meeting the following inclusion criteria: (1) randomized clinical trial or controlled observational study or clinical case series (study design), (2) exclusively adult patients at least 18 years of age (study population), and (3) undergoing a recruitment maneuver lasting less than 30 minutes and that may be repeated. No language restrictions were used. We specied that recruitment maneuvers be transient (,30 minutes) to exclude studies that used a xed ventilation strategy (e.g., high versus low PEEP) for recruitment. We excluded clinical studies that met the selection criteria but did not report on physiologic or adverse effects. Figure 1 summarizes the study selection process. Two reviewers (EF and NDF) independently assessed the eligibility of each study and resolved disagreements by consensus. We used the kappa statistic to measure 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-tested forms. 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 physiologic and ventilatory variables were abstracted from studies at a minimum of two time points: pre-RM (i.e., at baseline or before the start of RM) and post-RM (i.e., the rst reported values after RM).

Figure 1. Literature review schematic illustrating the number of articles identied at each stage of the review process for potential inclusion in the systematic review. Iterative review of titles, abstracts, and fulllength articles yielded 40 unique studies, which are included in this review.

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

RESULTS
Study Search and Selection

Statistical Analysis
Descriptive statistics from individual studies were reported using proportions and mean 6 SD unless otherwise stated. We pooled available data using an n-weighted mean 6 SD based on study size. We compared proportions using Fishers exact test. Continuous variables 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/or ventilatory data 30 minutes or less post-RM (to capture transient effects related to RMs), and (3) studies using sustained ination (e.g., continuous positive airway pressure [CPAP] 3040 cm H2O for 3040 seconds) (RM type). We also performed three a priori subgroup analyses: (1) studies with a pre-to-postRM PEEP difference 5 cm H2O or less versus greater than 5 cm H2O, (2) baseline PaO2/FIO2 ratio less than 150 mm Hg (lower) versus 150 mm Hg or greater (higher), and (3) baseline respiratory system compliance less than 30 mL/cm H2O (lower) versus 30 mL/cm H2O or greater (higher). All analyses were performed using Microsoft Excel 2004 (Microsoft Corporation, Redmond, WA) and Stata 10.0 statistical software (Stata Corporation, College Station, TX). A nominal P value less than 0.05 was used to determine statistical signicance. Due to the heterogeneity in study

The initial search generated 248 citations, of which 91 were duplicate reports from multiple databases. Iterative review of titles, abstracts, and full-length articles yielded 40 unique studies, which are included in this review (Figure 1). These studies had a mean sample size of 30 (range, 8366) and included a total of 1,185 patients. Agreement on study selection was near perfect, 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 four were 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 specifically for experimental purposes (i.e., designed with the explicit purpose of examining outcomes after the use of RMs), as compared with those conducted in the context of usual clinical care (Tables 1 and 2). Sustained ination was the most common (45%) type of RM used.

1158 TABLE 1. STUDY CHARACTERISTICS

Characteristic Study years, range No. patients receiving RMs Total Per study, mean (SD) Number of centers Total Mean (SD) Study duration, h Total Mean (SD) Study design/purpose,* n (%) Randomized controlled trial Clinical Experimental Prospective cohort study Clinical Experimental Retrospective cohort study Clinical Experimental Type of RM used, n (%) Sustained ination High pressure-controlled ventilation Incremental positive end-expiratory pressure High VT/sigh Other RM performed with FIO2 5 1.0, n (%) Yes No Sometimes Not reported RM performed on paralysis, n (%) Yes No Sometimes Not reported

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178

2008

Studies (n 5 40) 19992007 1,185 30 (56) 98 2.5 (5.4) 387 11 (29) 4 1 3 32 5 27 4 3 1 18 9 8 4 1 11 13 0 16 22 6 2 10 (10) (25) (75) (80) (16) (84) (10) (75) (25) (45) (23) (20) (10) (2) (28) (32) (0) (40) (55) (15) (5) (25)

pressure, pulmonary capillary wedge pressure, cardiac output/ index, and mixed venous oxygen saturation, were not signicantly changed after an RM. Ventilatory parameters were reported in 32 studies (548 patients) and were not signicantly altered by an RM, except for higher PEEP post-RM (11 versus 16 cm H2O; P 5 0.02). Respiratory system compliance was marginally higher after an RM (34 versus 35 mL/cm H2O; P 5 0.03).
Adverse Events and Mortality

Thirty-one studies evaluated adverse events (985 patients). The majority of these events occurred during an RM, with hypotension (12%) and desaturation (8%) being the most common complications (Table 5). Serious adverse events, such as barotrauma (1%) and arrhythmias (1%), were infrequent. Only 10 (1%) patients were reported to have had RMs terminated prematurely due to adverse events. Seventeen studies (287 patients) reported no adverse events from RMs. Overall mortality was reported in 20 studies (409 patients) and was 38%.
Sensitivity Analyses

Denition 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.

The baseline characteristics of the study patients are presented in Table 3. Across studies, patients had a mean age of 52 6 9.5 years, with mean APACHE II score 21 6 3.3 and mean Lung Injury Score of 3.0 6 0.26. Patients were ventilated at baseline, with a mean plateau pressure 28 6 4.8 cm H2O, mean VT of 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 factor for ALI was reported in 36 studies (786 patients); 43% of these patients developed ALI from a direct pulmonary insult. Cointerventions were reported in 16 studies (327 patients), with prone positioning used most frequently (22%).
Physiologic and Ventilatory Variables

Sensitivity analyses restricted to prospective studies (32 studies) yielded results similar to the main analysis, with signicantly increased oxygenation (PaO2: 105 versus 190 mm Hg; P , 0.001 and PaO2/FIO2 ratio: 142 versus 224 mm Hg; P , 0.001) and modest 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 versus 16 mm Hg; P 5 0.009), and respiratory system compliance (34 versus 35 mL/cm H2O; P 5 0.03). Hypotension (11 versus 19%; P , 0.001) and desaturation (7 versus 18%; P , 0.001) during RMs were reported less frequently. There were no signicant differences in barotrauma rates between prospective and retrospective studies. Studies have reported data on physiologic and ventilatory parameters at varying times after an RM (range, 3120 minutes). In sensitivity analyses restricted to studies that reported data 30 minutes or less post-RM (25 studies), there continued to be signicant increases in oxygenation (PaO2: 106 versus 214 mm Hg; P 5 0.005 and PaO2/FIO2 ratio: 138 versus 254 mm Hg; P , 0.001), with modest increases in CVP (13 versus 16 mm Hg; P 5 0.01) and PEEP (11 versus 17 cm H2O; P 5 0.01). There were no signicant differences in the rates of any adverse events between groups with data 30 minutes or less post-RM versus more than 30 minutes post-RM. When restricted to studies using sustained ination (18 studies) as compared with other RM types (e.g., sigh/high VT), only the change in the PaO2/FIO2 ratio remained signicant (149 versus 235; P 5 0.005). Point estimates for other variables were similar to those in the main analysis, but the ndings were not statistically signicant. There were no signicant differences in the rates of any adverse events during RMs between sustained ination versus other RM type groups.
Subgroup Analyses

Thirty-one studies reported on the acute physiologic effects of an RM in 636 patients (Table 4). Oxygenation was signicantly increased after an RM (PaO2: 106 versus 193 mm Hg; P 5 0.001 and PaO2/FIO2 ratio: 139 versus 251 mm Hg; P , 0.001) (Figure 2). Few studies reported oxygenation beyond a 3- to 6-hour post-RM (30, 36, 43, 46, 54), with many studies reporting a rapid decline in oxygenation gains, some within 15 to 20 minutes of the RM (14, 25, 26, 30, 34, 36, 42, 46, 52, 53). Heart rate (104 versus 105 beats per minute; P 5 0.04), pH (7.34 versus 7.30; P 5 0.04), and central venous pressure (CVP) (13 versus 16 mm Hg; P 5 0.009) were statistically signicantly higher post-RM, although the clinical signicance of these changes is questionable. Other hemodynamic parameters, including mean arterial

Patients with a pre- to post-RM PEEP difference 5 cm H2O or less still had a signicant increase in oxygenation (PaO2: 102 versus 125 mm Hg; P 5 0.02 and PaO2/FIO2 ratio: 145 versus 210 mm Hg; P 5 0.04), with a modest change in respiratory system compliance (35 versus 38 mL/cm H2O; P 5 0.04). There were no signicant differences in the rates of any adverse events during RMs in the groups with pre- to post-RM PEEP difference 5 cm H2O or less versus greater than 5 cm H2O. Oxygenation improved after RMs irrespective of baseline PaO2/FIO2 ratio: lower group (PaO2/FIO2 ratio ,150 mm Hg) (PaO2: 84 versus 181 mm Hg; P 5 0.02 and PaO2/FIO2 ratio: 128 versus 245 mm Hg; P 5 0.002) and higher group (PaO2/FIO2

Fan, Wilcox, Brower, et al.: Recruitment Maneuvers in ALI TABLE 2. RANDOMIZED CONTROLLED TRIALS OF RECRUITMENT MANEUVERS
Trial ARDSNet (15) n 57 Type of RM Used Sustained ination (CPAP 3540 cm H2O for 30 s) Frequency of RM Every other day (alternating with sham RMs) Main Outcome Measures Greater increase in SpO2 with 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 signicantly different up to 8 h from RM or sham RM No net effect on oxygenation or pulmonary mechanics after rst or subsequent RMs Adverse Events

1159

Meade (54)

28

Sustained ination (CPAP 3540 cm H2O for 2040 s)

Twice daily

Oczenski (53)

30

Sustained ination (CPAP 50 cm H2O for 30 s)

Once

Stewart (20)

366

Sustained ination (CPAP 40 cm H2O for 40 s)

Up to four times daily

Signicant 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 signicant differences in P/F ratio between RM and control group at baseline and after 30 min None reported

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 RM Ventilator dysynchrony (ve patients), barotraumas requiring intervention (four patients), appeared uncomfortable (two patients), transient hypotension (two patients) No change in any hemodynamic variables at 3 min post-RM compared with baseline values; no signicant differences between groups in any hemodynamic variables detected at 30 min compared with baseline values 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%])

Denition of abbreviations: CPAP 5 continuous positive airway pressure; P/F ratio 5 ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; PEEP 5 positive end-expiratory pressure; RM 5 recruitment maneuver.

ratio >150 mm Hg) (PaO2: 153 versus 236 mm Hg; P 5 0.03 and PaO2/FIO2 ratio: 180 versus 229 mm Hg; P 5 0.04). CVP was also signicantly higher post-RM in the lower PaO2/FIO2 ratio subgroup (13 versus 15 mm Hg; P 5 0.02). In the subgroup of patients with lower baseline respiratory system compliance (,30 mL/cm H2O), there were no signicant differences in any physiologic or ventilatory parameters after an RM. However, patients with higher baseline respiratory system compliance (>30 mL/cm H2O) had a signicantly higher PaO2/ FIO2 ratio after an RM (130 versus 180 mm Hg; P 5 0.02). There were no signicant differences in any adverse events during RMs in either subgroup (pre- versus post-RM).

DISCUSSION
In this systematic review of nearly 1,200 adult patients with ALI, the use of RMs was associated with signicant, albeit transient, increases in oxygenation (as measured by PaO2 and PaO2/FIO2 ratio). There were no clinically signicant changes in short-term hemodynamic or ventilatory variables, except for a small increase in CVP post-RM. Hypotension and desaturation were the most common adverse events during RMs, but there were few serious short-term adverse events (e.g., barotraumas or arrhythmias), and an extremely small number of RMs were terminated early due to adverse events. Overall mortality was similar to previous observational studies of patients with ALI. In general, these ndings (oxygenation, adverse events) were robust across our sensitivity and subgroup analyses.

Improvements in oxygenation after an RM have been demonstrated in many studies (14, 23, 27, 28, 31, 32, 34, 35, 37, 39, 40, 42, 44, 47, 48, 5053, 55). However, many studies report a rapid decline in these oxygenation gains over the subsequent 24 hours, some within 15 to 20 minutes of the RM (14, 26, 27, 31, 35, 37, 43, 47, 52, 53). Animal models suggest that the type of RM used (e.g., sustained ination versus high pressure-controlled ventilation) may also inuence the durability of RM-induced oxygenation (18). In addition, the application of higher levels of PEEP after an RM may affect the sustainability of the effect (17, 41). Few studies included in our systematic review reported oxygenation beyond 6 hours, making it difcult to conrm these results. The importance of these transient effects is questionable because there are conicting data from observational studies regarding the association between oxygenation and mortality in ALI (59). Furthermore, despite having reduced oxygenation on Day 1 (as compared with the control group), patients randomized to low VT ventilation in the ARDS Network study ultimately derived a survival advantage from this intervention (7). However, the ARDS Network study used a ventilation strategy in the control group that resulted in sustained higher tidal volumes and increased airway pressures, as opposed to the transient nature of the RMs being studied in this review. Improving oxygenation is unlikely to be inherently harmful; rather, it seems likely that it is the manner in which this is achieved that is important. Whether improvements in oxygenation with RMs are associated with reduced VILI and improved clinically important outcomes

1160 TABLE 3. BASELINE CHARACTERISTICS*

Characteristic Age, yr Female, n Severity of illness (APACHE II Score) Severity of ALI Lung injury score PaO2/FIO2 ratio, mm Hg Respiratory system compliance, mL/cm H2O ALI risk factor Pulmonary, n (%) Pneumonia Aspiration Other Extrapulmonary, n (%) Sepsis Pancreatitis Trauma Burns Transfusion-related acute lung injury Other Ventilatory parameters Peak inspiratory pressure, cm H2O Plateau pressure, cm H2O Positive end-expiratory pressure, cm H2O VT, mL VT, mL/kg Respiratory rate, breaths per minute _ E, L/min V Co-interventions, no. (%) Prone positioning High-frequency oscillatory ventilation Inhaled nitric oxide High-dose corticosteroids None

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178 TABLE 4. PHYSIOLOGIC AND VENTILATORY VARIABLES*
Variable 52 (9.5) 8 (6.4) 21 (3.3) 3.0 (0.26) 142 (39) 34 (5.5) 336 212 64 60 450 170 25 113 5 5 132 29 28 12 508 7.0 19 9.9 82 0 19 0 9 (43) (27) (8) (8) (57) (22) (3) (14) (1) (1) (16) (3.7) (4.8) (2.1) (58) (1.2) (4.5) (2.2) (22) (0) (5) (0) (2) Hemodynamics Mean arterial blood pressure, mm Hg Heart rate, beats per minute Central venous pressure, mm Hg Pulmonary capillary wedge pressure, mm Hg Q, L/min Cardiac index, L/min/m2 Mixed venous oxygen saturation, % Arterial blood gas pH PaO2, mm Hg PaCO2, mm Hg Arterial oxygen saturation, % Ventilatory settings Peak inspiratory pressure, cm H2O Plateau pressure, cm H2O Mean airway pressure, cm H2O Positive end-expiratory pressure, cm H2O VT, mL VT, mL/kg FIO2, % Respiratory mechanics Respiratory system compliance, mL/cm H2O PaO2/FIO2 Ratio, mm Hg

2008

Pre-RM 83 104 13 14 (5.4) (12.5) (3.6) (1.2)

Post-RM 84 105 16 14 (5.2) (12.5) (5.0) (0.8)

P value 0.53 0.04 0.009 0.85 0.58 0.19 0.07 0.04 0.001 0.87 0.17 0.07 0.53 0.12 0.02 0.56 0.84 0.09 0.03

8.6 (2.0) 4.4 (1.0) 70 (10) 7.34 106 46 92 31 27 18 11 506 8.1 81 (0.08) (51.3) (6.8) (3.7) (2.8) (3.8) (1.7) (3.1) (57) (2.6) (18)

8.6 (2.0) 4.1 (1.0) 77 (11) 7.30 193 48 95 34 31 22 16 470 6.6 72 (0.15) (133) (13.8) (2.1) (4.7) (6.4) (5.2) (5.9) (251) (4.2) (23)

34 (4.5) 139 (31.3)

35 (8.1)

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)

Denition of abbreviations: ALI 5 acute lung injury; APACHE 5 Acute Physiology 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).

remains to be determined, although a few studies have shown a survival advantage with a lung protective ventilation strategy incorporating RMs (6, 8). In the interim, RMs may also benet the minority of patients with ALI who develop life-threatening refractory hypoxemia. Given the uncertain importance of transient oxygenation benets derived from RMs, any important risks would be critical in decision-making around their use in patients with ALI. Adverse events (e.g., hypotension and desaturation) were most common during the performance of RMs and were generally transient 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 uncommon. Though difcult to quantify, it is possible that even a transient increase in transpulmonary pressure during an RM may lead to enhanced VILI due to overdistention of relatively healthy lung units. Furthermore, given that most patients require increased sedation and/or paralysis during the use of RMs, there is a potential for indirect adverse effects on longterm outcomes (e.g., neurocognitive and neuromuscular function) (60). Although our results suggest that RMs are generally well tolerated, the risks and sequelae of RMs may differ substantially from patient to patient because even transient events may be detrimental in severely ill patients. Because increased PEEP alone can lead to direct increases in oxygenation, we conducted a subgroup analysis with studies that had a pre- to post-RM PEEP change of 5 cm H2O or less (versus .5 cm H2O) in an attempt to isolate RM-specic

effects. RMs led to improved oxygenation in both subgroups, although the changes were not statistically signicant in the preto post-RM PEEP change greater than 5 cm H2O group, likely due to the small number of studies (and patients) in that subgroup. The level of post-RM PEEP may be critical in stabilizing and maintaining alveoli opened by the preceding RM; failure to maintain ination of recruited alveoli post-RM may potentiate VILI further through cyclic recruitment-derecruitment 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 an optimal level of post-RM PEEP have maintained signicant

Figure 2. Oxygenation (PaO2/FIO2 ratio) pre- and postrecruitment maneuver by study (20 studies). The relationship between oxygenation (P/F ratio) after the application of a recruitment maneuver (RM) (postRM) with baseline (pre-RM) oxygenation in each individual study is presented. Oxygenation was signicantly increased after an RM (PaO2/ FIO2 ratio: 139 versus 251 mm Hg; P , 0.001).

Fan, Wilcox, Brower, et al.: Recruitment Maneuvers in ALI TABLE 5. ADVERSE EVENTS AND MORTALITY
Adverse Event or Outcome Cardiovascular,* no. (%) Cardiac arrest Arrhythmia Myocardial ischemia/infarction Hypertension Hypotension Other cardiovascular Respiratory,* no. (%) Desaturation Barotrauma Refractory respiratory acidosis Other respiratory Other (noncardiovascular, nonrespiratory),* n (%) Studies with no adverse events, n (no. of patients) Studies that did not report adverse events, n (no. of patients) RMs terminated due to adverse events, n (%) Mortality, n (%) Studies that did not report mortality, n (no. of patients) Pre-RM During RM Post-RM 0 0 0 0 0 0 1 (0) 0 0 0 0 0 8 (1) 0 0 114 (12) 24 (2) 82 (8) 9 (1) 0 5 (1) 4 (1) 17 (287) 9 (201) 10 (1) 157 (38) 20 (736) 0 0 0 0 0 0 0 9 (1) 0 0 0

1161

Denition 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).

oxygenation benets for at least 4 to 6 hours (41, 46). It remains unclear whether prolonged benets in oxygenation, perhaps using different RM techniques, have an impact on important clinical outcomes in patients with ALI. Finally, it is impossible within the connes of this systematic review to isolate RM- and PEEP-independent effects on oxygenation, which would require an experimental design (i.e., a controlled clinical trial). However, we believe that this analysis is hypothesis generating for testing in future studies. Our study provides conicting data on the oxygenation benet from RMs based on baseline ALI severity. Patients with a lower baseline PaO2/FIO2 ratio experienced a signicant oxygenation improvement, whereas those with lower baseline respiratory system compliance did not. The lack of oxygenation benet in patients with lower baseline respiratory system compliance may be consistent with a subgroup of patients with ALI who are not easily recruitable and in whom the risks of RMs may outweigh the potential benets. Although hypotension has been reported to be more common in patients with poor chest wall compliance and limited RM-induced oxygenation benet (61), we did not observe any difference in hypotension in a similar subgroup of patients in our study with low baseline respiratory system compliance. In contrast, Gattinoni and colleagues demonstrated that patients with ALI who had lower baseline ALI disease severity (respiratory system compliance 49 6 16 mL/cm H2O; PaO2/FIO2 ratio 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). Patients included in our systematic review had more severe ALI at baseline (as measured by baseline respiratory system compliance and PaO2/FiO2 ratio), which may explain these divergent results. Our study has other potential limitations. First, because the studies were heterogeneous in design, type of RM used, and outcomes measured and reported, we could not perform a quantitative meta-analysis with true effect sizes (i.e., relative risk or odds ratio). Furthermore, too few randomized controlled trials of RMs have been conducted to allow a summary of the effects of RMs as compared with placebo (or sham) in patients

with ALI. However, the results of our analysis are similar to the few randomized controlled trials that have been reported (15, 20, 53, 54). Second, most studies did not directly measure alveolar recruitment, making it difcult to attribute our ndings of improved oxygenation to successful RMs alone. Changes in oxygenation alone may not directly reect recruitment because oxygenation may be inuenced by other factors affected by RMs, such as cardiac output. However, cardiac output (or index) did not change signicantly after an RM in studies that reported these parameters. Because shunt from airless lung regions is a major cause of arterial hypoxemia in ALI (1), RMinduced recruitment is likely the cause of the transient oxygenation improvements. Furthermore, our results were robust in the subgroup of patients with a pre- to post-RM PEEP difference of 5 cm H2O or less. Third, given the previous ndings of transient RM-induced oxygenation effects, our inclusion of a wide range of reported data at the post-RM time point may not accurately reect the true effect of RMs. However, by including data up to 120 minutes post-RM, this would have biased our results toward nding no signicant difference in oxygenation pre- to post-RM. In addition, our results were robust in a sensitivity analysis restricted to data reported less than 30 minutes post-RM. Finally, the results from our subgroup analyses based on baseline ALI severity may differ depending on the thresholds chosen for PaO2/FIO2 ratio and respiratory system compliance. Both thresholds were chosen to balance clinical and practical considerations; for the latter, this allowed enough patients to be included in each subgroup to make a meaningful comparison. In conclusion, adult patients with ALI receiving RMs experienced a signicant increase in short-term oxygenation, with few serious short-term adverse events. Transient hypotension and desaturation during RMs is common, although likely self-limited without serious sequelae. The risks of RMs may outweigh the potential benets in patients with ALI who have low baseline respiratory system compliance, although these ndings require conrmation in future studies. Given the uncertain benet of transient oxygenation improvements in patients with ALI and the lack of information on their clinical outcome effects, the routine use of RMs cannot be recommended or discouraged at this time. RMs should be considered on an individualized basis in patients with ALI with life-threatening refractory hypoxemia.
Conict of Interest Statement: None of the authors has a nancial relationship with a commercial entity that has an interest in the subject of this manuscript.

References
1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:13341349. 2. Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007;131:554562. 3. Rubenfeld GD, Caldwell MS, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:16851693. 4. Esteban A, Anzueto A, Frutos F, Alia I, Brochard L, Stewart TE, Benito S, Epstein SK, Apezteguia C, Nightingale P, et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA 2002;287:345355. 5. Fan E, Needham DM, Stewart TE. Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA 2005;294: 28892896. 6. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338:347354.

1162

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178

2008

7. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:13011308. 8. Villar J, Kacmarek RM, Perez-Mendez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 2006;34:13111318. 9. Lapinsky SE, Mehta S. Bench-to-bedside review: recruitment and recruiting maneuvers. Crit Care 2005;9:6065. 10. Trembley LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med 2006;32:2433. 11. Gattinoni L, Pesenti A. The concept of baby lung. Intensive Care Med 2005;31:776784. 12. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998;157:294323. 13. Lapinsky SE, Aubin M, Mehta S, Boiteau P, Slutsky A. Safety and efcacy of a sustained ination for alveolar recruitment in adults with respiratory failure. Intensive Care Med 1999;25:12971301. 14. Pelosi P, Cadringher P, Bottino N, Panigada M, Carrieri F, Riva E, Lissoni A, Gattinoni L. Sigh in acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;159:872880. 15. The ARDS Clinical Trials Network. Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure. Crit Care Med 2003;31:25922597. 16. Pelosi P, DOnofrio D, Chiumello D, Paolo S, Chiara G, Capelozzi VL, Barbas CS, Chiaranda M, Gattinoni L. Pulmonary and extrapulmonary acute respiratory distress syndrome are different. Eur Respir J Suppl 2003;42:48S56S. 17. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM, Quintel M, Russo S, Patroniti N, Cornejo R, Bugedo G. Lung recruitment in patients with acute respiratory distress syndrome. N Engl J Med 2006; 354:17751786. 18. Lim SC, Adams AB, Simonson DA, Dries DJ, Broccard AF, Hotchkiss JR, Marini JJ. Intercomparison of recruitment maneuver efcacy in three models of acute lung injury. Crit Care Med 2003;32:23712377. 19. Cakar N, Akinci O, Tugrul S, Ozcan PE, Esen F, Eraksoy H, Cagatay A, Telci L, Nahum A. Recruitment maneuver: does it promote bacterial translocation? Crit Care Med 2002;30:21032106. 20. Stewart TE, Cooper J, Laufer B, Lapinsky SE, Langevin S, Granton JT, Muscedere J, Ward M, Woolfe C, Lesur O. Complications of recruitment maneuvers in a multicenter trial of lung protective ventilation in ALI/ARDS. Am J Respir Crit Care Med 2007;175:A943. 21. Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions 5.0.0 [updated February 2008; accessed July 27, 2008]. Available from: http://www.cochrane-handbook.org/. 22. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159174. 23. Bugedo G, Bruhn A, Hernandez G, Rojas G, Varela C, Tapia JC, Castillo L. Lung computed tomography during a lung recruitment maneuver in patients with acute lung injury. Intensive Care Med 2003; 29:218225. 24. Claesson J, Lehtipalo S, Winso O. Do lung recruitment maneuvers decrease gastric mucosal perfusion? Intensive Care Med 2003;29: 13141321. 25. Ferguson ND, Chiche J-D, Kacmarek RM, Hallett DC, Mehta S, Findlay GP, Granton JT, Slutsky AS, Stewart TE. Combining high-frequency oscillatory ventilation and recruitment maneuvers in adults with early acute respiratory distress syndrome: The Treatment with Oscillation and an Open Lung Strategy (TOOLS) Trial pilot study. Crit Care Med 2005;33:479486. 26. Foti G, Cereda M, Sparacino ME, De Marchi L, Villa F, Pesenti A. Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated acute respiratory distress syndrome (ARDS) patients. Intensive Care Med 2000;26:501507. 27. Grasso S, Mascia L, Del Turco M, Malacarne P, Giunta F, Brochard L, Slutsky AS, Marco Ranieri V. Effects of recruiting maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology 2002;96:795802. 28. Johannigman JA, Miller SL, Davis BR, Davis K Jr, Campbell RS, Branson RD. Inuence of low tidal volumes on gas exchange in acute respiratory distress syndrome and the role of recruitment maneuvers. J Trauma 2003;54:320325. 29. Lim C-M, Jung H, Koh Y, Lee JS, Shim TS, Lee SD, Kim WS, Kim DS, Kim WD. Effect of alveolar recruitment maneuver in early acute

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40. 41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

respiratory distress syndrome according to antiderecruitment strategy, etiological category of diffuse lung injury, and body position of patient. Crit Care Med 2003;31:411418. Lim C-M, Koh Y, Park W, Chin JY, Shim TS, Lee SD, Kim WS, Kim DS, Kim WD. Mechanistic scheme and effect of extended sigh as a recruitment maneuver in patients with acute respiratory distress syndrome: a preliminary study. Crit Care Med 2001;29:12551260. Oczenski W, Hormann C, Keller C, Lorenzi N, Kepka A, Schwarz S, Fitzgerald RD. Recruitment maneuvers during prone positioning in patients with acute respiratory distress syndrome. Crit Care Med 2005; 33:5461. Park KJ, Lee YJ, Oh YJ, Lee KS, Sheen SS, Hwang SC. Combined effects of inhaled nitric oxide and a recruitment maneuver in patients with acute respiratory distress syndrome. Yonsei Med J 2003;44:219226. Patroniti N, Fot G, Cortinovis B, Maggioni E, Bigatello LM, Cereda M, Pesenti A. Sigh improves gas exchange and lung volume in patients wth acute respiratory distress syndrome undergoing pressure support ventilation. Anesthesiology 2002;96:788794. Pelosi P, Bottino N, Chiumello D, Caironi P, Panigada M, Gamberoni C, Colombo G, Bigatello LM, Gattinoni L. Sign in supine and prone position during acute respiratory distress syndrome. Am J Respir Crit Care Med 2003;167:521527. Povoa P, Almeida E, Fernandes A, Mealha R, Moreira P, Sabino H. Evaluation of a recruitment maneuver with positive inspiratory pressure and high PEEP in patients with severe ARDS. Acta Anaesthesiol Scand 2004;48:287293. Richard J-C, Maggiore SM, Jonson B, Mancebo J, Lemaire F, Brochard L. Inuence of tidal volume on alveolar recruitment. Am J Respir Crit Care Med 2001;163:16091613. Schreiter D, Reske A, Scheibner L, Glien C, Katscher S, Josten C. The open lung concept: a clinical trial in severe chest trauma. Chuirg 2002; 73:353359. Takeuchi M, Imanaka H, Tachibana K, Ogino H, Ando M, Nishimura M. Recruitment maneuver and high positive end-expiratory pressure improve hypoxemia in patients after pulmonary thromboendarterectomy for chronic pulmonary throboembolism. Crit Care Med 2005;33: 20102014. Villagra A, Ochagavia A, Vatua S, Murias G, Del Mar Fernandez M, Lopez Aguilar J, Fernandez R, Blanch L. Recruitment maneuvers during lung protective ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:165170. Wauer VH, Groll G, Krausch D, Lehmann C, Kox WJ. Clinical experiences with the open lung concept. Anaesthesiol Reanim 2003;28:844. Borges JB, Okamoto VN, Matos GF, Caramez MP, Arantes PR, Barros F, Souza CE, Victorino JA, Kacmarek RM, Barbas CS, et al. Reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome. Am J Respir Crit Care Med 2006;174:268278. Galiatsou E, Kostanti E, Svarna E, Kitsakos A, Koulouras V, Efremidis SC, Nakos G. Prone position augments recruitment and prevents alveolar overination in acute lung injury. Am J Respir Crit Care Med 2006;174:187197. Lapinsky SE, Aubin M, Mehta S, Boiteau P, Slutsky AS. Safety and efcacy of a sustained ination for alveolar recruitment in adults with respiratory failure. Intensive Care Med 1999;25:12971301. Puls A, Pollok-Kopp B, Wrigge H, Quintel M, Neumann P. Effects of a single-lung recruitment maneuver on the systemic release of inammatory mediators. Intensive Care Med 2006;32:10801085. Antonaglia V, Pascotto S, De Simoni L, Zin WA. Effects of a sigh on the respiratory mechanical properties in ALI patients. J Clin Monit Comput 2006;20:243249. Girgis K, Hamed H, Khater Y, Kacmarek RM. A decremental PEEP trial identies the PEEP level that maintains oxygenation after lung recruitment. Respir Care 2006;51:11321139. Li M-Q, Zhang Z, Li S-M, Shi ZX, Xu JY, Lu F, Li L, Wang HM. Comparative study on recruitment maneuvers in acute respiratory distress syndrome with pulmonary and extrapulmonary origin. Chin Crit Care Med 2006;18:355358. Yi H-M, Cai C-J, Lu M-Q, Wang GS, Yi SH, Yang Y, Xu C, Li H, Chen GH. The treatment strategy of early ALI after liver transplantation. Chin J Surg 2006;44:889893. Constantin J-M, Cayot-Constantin S, Roszyk L, Futier E, Saphin V, Dastugue B, Bazin JE, Rouby JJ. Response to recruitment maneuver inuences net alveolar uid clearance in acute respiratory distress syndrome. Anesthesiology 2007;106:944951. Tugrul S, Akinci O, Ozcan PE, Ince S, Esen F, Telci L, Akpir K, Cakar N. Effects of sustained ination and postination positive end-

Fan, Wilcox, Brower, et al.: Recruitment Maneuvers in ALI

expiratory pressure in acute respiratory distress syndrome: focusing on pulmonary and extrapulmonary factors. Crit Care Med 2003;31: 738744. Toth I, Leiner T, Mikor A, Szakmany T, Bogar L, Molnar Z. Hemodynamic and respiratory changes during lung recruitment and descending optimal positive end-expiratory pressure titration in patients with acute respiratory distress syndrome. Crit Care Med 2007;35:787793. Talmor D, Sarge T, Legedza A, ODonnell CR, Ritz R, Loring SH, Malhotra A. Cytokine release following recruitment maneuvers. Chest 2007;132:14341439. Oczenski W, Hormann C, Keller C, Lorenzi N, Kepka A, Schwarz S, Fitzgerald RD. Recruitment maneuvers after a positive end-expiratory pressure trial do not induce sustained effects in early adult respiratory distress syndrome. Anesthesiology 2004;101:620625. Meade MO, Guyatt GH, Cook DJ, Lapinsky SE, Hand L, Grifth L, Stewart TE. Physiologic randomized pilot study of a lung recruitment maneuver in acute lung injury. Am J Respir Crit Care Med 2002;165: A683. Richards G, White H, Hopley M. Rapid reduction of oxygenation index by employment of a recruitment technique in patients with severe ARDS. J Intensive Care Med 2001;16:193199.

1163
56. Schreiter D, Reske A, Stichert B, Seiwerts M, Bohm SH, Kloeppel R, Josten C. Alveolar recruitment in combination with sufcient positive end-expiratory pressure increases oxygenation and lung aeration in patients with severe chest trauma. Crit Care Med 2004;32: 968975. 57. Suh GY, Kwon OJ, Yoon JW, Park SJ, Ham HS, Kang SJ, Koh WH, Chung MP, Kim HJ. A practical protocol for titrating optimal PEEP in acute lung injury: recruitment maneuver and PEEP decrement. J Korean Med Sci 2003;18:349354. 58. Yang Z-J, Zhang X-Y, Fan H-R, Jiang X, Wang QX, Shen JF, Chen L. The analysis of 252 episodes of recruitment maneuvers during mechanical ventilation in surgery intensive care unit. Chin Crit Care Med 2007;19:539541. 59. Ware LB. Prognostic determinants of acute respiratory distress syndrome in adults: impact on clinical trial design. Crit Care Med 2005;33:S217S222. 60. Desai SV, Boucher K, Fan E, Needham D. Long-term outcomes after acute lung injury. Contemporary Crit Care 2006;4:110. 61. Rothen HU, Sporre B, Engberg G, Wegenius G, Hogman M, Hedenstierna G. Inuence of gas composition on recurrence of atelectasis after a reexpansion maneuver during general anesthesia. Anesthesiology 1995;82:832842.

51.

52.

53.

54.

55.