Published ahead of print on September 5, 2008, doi:10.1164/rccm.200802-335OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200802-335OC
Recruitment Maneuvers for Acute Lung InjuryA Systematic Review1 Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada; 2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland; and 3 Departments of Clinical Epidemiology and Biostatistics, and Medicine, McMaster University, Hamilton, Ontario, Canada 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{at}utoronto.ca
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: 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 = 0.001; and PaO2/FIO2 ratio: 139 versus 251 mm Hg, P < 0.001). There were no persistent, clinically significant changes in hemodynamic parameters after an RM. Ventilatory parameters (32 studies; 548 patients) were not significantly altered by an RM, except for higher PEEP post-RM (11 versus 16 cm H2O; P = 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 benefit of transient oxygenation improvements in patients with ALI and the lack of information on their influence 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.
Key Words: artificial respiration • adult respiratory distress syndrome • respiratory physiology • systematic review
Acute lung injury (ALI) is characterized by the acute onset of hypoxemia (PaO2/FIO2  300 mm Hg) with bilateral infiltrates 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 an associated significant 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 (5–8). 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 (9–12). Clinical studies of RMs in ALI have yielded variable results (13–15). 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 inflation versus incremental positive end-expiratory pressure [PEEP]) may influence 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, such as barotrauma (e.g., pneumothorax), arrhythmias, and bacterial translocation, may occur (15, 19, 20). Due to the conflicting results regarding the efficacy and safety of RMs in ALI, we undertook this systematic review to synthesize knowledge from published studies. Specifically, 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.
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 (2003–2007) 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 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 first reported values after RM).
Statistical Analysis
Study Search and Selection 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, 8–366) 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
The baseline characteristics of the study patients are presented in Table 3. Across studies, patients had a mean age of 52 ± 9.5 years, with mean APACHE II score 21 ± 3.3 and mean Lung Injury Score of 3.0 ± 0.26. Patients were ventilated at baseline, with a mean plateau pressure 28 ± 4.8 cm H2O, mean VT of 7.0 ± 1.2 mL/kg body weight (as reported by each study), and mean PEEP of 12 ± 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. Co-interventions were reported in 16 studies (327 patients), with prone positioning used most frequently (22%).
Physiologic and Ventilatory Variables Thirty-one studies reported on the acute physiologic effects of an RM in 636 patients (Table 4). Oxygenation was significantly increased after an RM (PaO2: 106 versus 193 mm Hg; P = 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 = 0.04), pH (7.34 versus 7.30; P = 0.04), and central venous pressure (CVP) (13 versus 16 mm Hg; P = 0.009) were statistically significantly higher post-RM, although the clinical significance of these changes is questionable. Other hemodynamic parameters, including mean arterial pressure, pulmonary capillary wedge pressure, cardiac output/index, and mixed venous oxygen saturation, were not significantly changed after an RM. Ventilatory parameters were reported in 32 studies (548 patients) and were not significantly altered by an RM, except for higher PEEP post-RM (11 versus 16 cm H2O; P = 0.02). Respiratory system compliance was marginally higher after an RM (34 versus 35 mL/cm H2O; P = 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 Sensitivity analyses restricted to prospective studies (32 studies) yielded results similar to the main analysis, with significantly 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 = 0.04), pH (7.33 versus 7.30; P = 0.04), CVP (13 versus 16 mm Hg; P = 0.009), and respiratory system compliance (34 versus 35 mL/cm H2O; P = 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 significant 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, 3–120 minutes). In sensitivity analyses restricted to studies that reported data 30 minutes or less post-RM (25 studies), there continued to be significant increases in oxygenation (PaO2: 106 versus 214 mm Hg; P = 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 = 0.01) and PEEP (11 versus 17 cm H2O; P = 0.01). There were no significant 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 inflation (18 studies) as compared with other RM types (e.g., sigh/high VT), only the change in the PaO2/FIO2 ratio remained significant (149 versus 235; P = 0.005). Point estimates for other variables were similar to those in the main analysis, but the findings were not statistically significant. There were no significant differences in the rates of any adverse events during RMs between sustained inflation versus other RM type groups.
Subgroup Analyses
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 = 0.02 and PaO2/FIO2 ratio: 128 versus 245 mm Hg; P = 0.002) and higher group (PaO2/FIO2 ratio
In the subgroup of patients with lower baseline respiratory system compliance (<30 mL/cm H2O), there were no significant differences in any physiologic or ventilatory parameters after an RM. However, patients with higher baseline respiratory system compliance (
In this systematic review of nearly 1,200 adult patients with ALI, the use of RMs was associated with significant, albeit transient, increases in oxygenation (as measured by PaO2 and PaO2/FIO2 ratio). There were no clinically significant 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 findings (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, 50–53, 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 inflation versus high pressure-controlled ventilation) may also influence 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 difficult to confirm these results. The importance of these transient effects is questionable because there are conflicting 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 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 benefit the minority of patients with ALI who develop life-threatening refractory hypoxemia. Given the uncertain importance of transient oxygenation benefits 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 difficult 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 long-term 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-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, 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 inflation 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 significant oxygenation benefits for at least 4 to 6 hours (41, 46). It remains unclear whether prolonged benefits in oxygenation, perhaps using different RM techniques, have an impact on important clinical outcomes in patients with ALI. Finally, it is impossible within the confines 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 conflicting data on the oxygenation benefit from RMs based on baseline ALI severity. Patients with a lower baseline PaO2/FIO2 ratio experienced a significant oxygenation improvement, whereas those with lower baseline respiratory system compliance did not. The lack of oxygenation benefit 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 benefits. Although hypotension has been reported to be more common in patients with poor chest wall compliance and limited RM-induced oxygenation benefit (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 ± 16 mL/cm H2O; PaO2/FIO2 ratio 220 ± 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 difficult to attribute our findings of improved oxygenation to successful RMs alone. Changes in oxygenation alone may not directly reflect recruitment because oxygenation may be influenced by other factors affected by RMs, such as cardiac output. However, cardiac output (or index) did not change significantly 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), RM-induced 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 findings of transient RM-induced oxygenation effects, our inclusion of a wide range of reported data at the post-RM time point may not accurately reflect the true effect of RMs. However, by including data up to 120 minutes post-RM, this would have biased our results toward finding no significant 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 significant 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 benefits in patients with ALI who have low baseline respiratory system compliance, although these findings require confirmation in future studies. Given the uncertain benefit 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.
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.). This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200802-335OC on September 5, 2008 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form February 25, 2008; accepted in final form August 29, 2008
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
AT A GLANCE COMMENTARY
150 mm Hg) (PaO2: 153 versus 236 mm Hg; P = 0.03 and PaO2/FIO2 ratio: 180 versus 229 mm Hg; P = 0.04). CVP was also significantly higher post-RM in the lower PaO2/FIO2 ratio subgroup (13 versus 15 mm Hg; P = 0.02). 
