Critical Care Perspective

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1 Critical Care Perspective Meta-Analysis of Acute Lung Injury and Acute Respiratory Distress Syndrome Trials Testing Low Tidal Volumes Peter Q. Eichacker, Eric P. Gerstenberger, Steven M. Banks, Xizhong Cui, and Charles Natanson Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland The use of low tidal volumes (5 7 ml/kg measured body into two groups that were different from one another (p 0.017). weight) as a protective lung strategy is becoming widely rec- Two trials showed significant increases in the odds ratio for ommended for patients with acute lung injury (ALI) and survival of patients treated with low versus control tidal volume acute respiratory distress syndrome (ARDS) requiring me- (henceforth referred to as the two beneficial trials) (3, 4) chanical ventilation (1 4). However, clinical trials testing low (Figure 1). In contrast, the other three trials showed a nonsigtidal volumes in ALI and ARDS have not shown uniform nificant decrease in the odds ratio for this relationship (henceresults (5 7). This has led some experts to recommend forth referred to as the three nonbeneficial trials) (5 7). avoiding high tidal volumes during mechanical ventilation in To explore this difference, we compared tidal volumes and these patients (6, 8), whereas other experts advocate using plateau airway pressures from each of the five trials (3 7). Four very low tidal volumes (1 4). Our concern, shared by others different methods were used to adjust tidal volumes to body (9), was that trials showing low tidal volumes to be beneficial weight in the five trials (3 7), which were not readily convertible, did not use control arms that reflected the current best prac- thus precluding direct comparisons (Table 1). However, a pritice standards at the time. Instead, the trials compared very mary goal for lowering tidal volumes was to reduce excessive low tidal volumes (5 7 ml/kg measured body weight) with inspiratory airway pressures, thereby reducing mortality rates traditional tidal volumes (10 ml/kg or more), which were related to overdistension and injury of compliant lung regions higher than those routinely used (8 9 ml/kg) (10 13). As a (1 7). Therefore, we investigated whether or not differences in result, those studies were inconclusive. We performed a meta- treatment effect could be explained by differences in plateau analysis to investigate why five randomized, prospective clini- airway pressures associated with either the control or low tidal cal trials produced disparate results and to critically evaluate volumes. the basis for recommending low tidal volume ventilation in We first describe the tidal volumes selected and then compare ALI and ARDS (3 7). In this analysis, we demonstrate that the resultant plateau airway pressures in the control groups there is a significant difference in the effects of low tidal (Table 1, Figure 2A). In the two beneficial trials (3, 4), tidal volume on survival among the five trials. We then compare volumes (ml) reported in control patients just before randomizathe tidal volumes and plateau airway pressures from the five tion were similar (mean SE, [3] and [4], trials to determine whether these account for differences in respectively; p NS), as were plateau airway pressures (cm survival. In contrast to previous explanations based on the H 2 O) ( [3] and [4, 10], respectively; p low tidal volumes tested (4), this meta-analysis demonstrates NS). These control patients were then randomized to a single that significant differences in the control arms can account targeted tidal volume of 12 ml/kg based either on measured for the discrepant results among these five trials. body weight (3) or predicted body weight (4) (Table 1). This change represented a 17 5% increase (3) and a 18 3% METHODS AND RESULTS increase (4) (both p 0.001) in tidal volume and resulted in mean plateau airway pressures over the 7 days of study of 36.3 From 1990 to 2001, five clinical trials testing mechanical ventila- 1.0 (3) and (4) cm H 2 O (Figure 2A). Thus, before tion with low tidal volumes in patients with ALI and ARDS study entry, clinical practice was to ventilate patients with tidal were identified, using the search terms mechanical ventilation, volumes that produced plateau airway pressures averaging 29 tidal volume, clinical trial, and ALI and ARDS in Embase to 31 cm H 2 O. However, after entry into the studies, these same or Medline (3 7) (Table 1). The five trials demonstrated suffipatients had plateau airway pressures that were significantly cient heterogeneity in patient outcome to preclude reporting a higher (p 0.001) (34 to 37 cm H 2 O) (3, 4, 8) (Figure 2A) than single odds ratio describing the treatment effect of lowered tidal prerandomization levels. volumes (p 0.06, Breslow Day test). Rather, the trials fell In the three nonbeneficial trials, participating clinicians selected tidal volumes for individual control patients based not on a single targeted number but rather on a range of values (5 7). The ranges were 10 to 15 ml/kg, based on ideal (5) or dry (6) (Received in original form June 27, 2002; accepted in final form August 21, 2002) body weight in two trials and 10 to 12 ml/kg based on predicted Correspondence and requests for reprints should be addressed to Peter Q. Ei- (7) body weight in the third. On average, the tidal volumes chacker, M.D., Critical Care Medicine Department, Clinical Center, National Insti- selected in all three trials were close to the lower limit (10.0 ml/ tutes of Health, 10 Center Drive, Building 10, Room 7D43, Bethesda, MD kg) of these ranges (5 7) (Table 1). One of these trials also peichacker@nih.gov excluded any patient exposed to peak airway pressures greater Am J Respir Crit Care Med Vol 166. pp , 2002 Originally Published in Press as DOI: /rccm OC on August 28, 2002 than 30 cm H 2 O for more than 2 hours before randomization Internet address: (5). As a result, control patients in these trials had plateau airway

2 Critical Care Perspective 1511 TABLE 1. NUMBER OF PATIENTS, TIDAL VOLUMES STUDIED, AND MORTALITY RATES IN FIVE RANDOMIZED CLINICAL TRIALS Number of Patients Tidal Volume Mortality Rate Reported Mortality Low Tidal Low Tidal Volume* Control* Low Tidal Volume Control Difference Author (Ref.) Volume Control (ml/kg) (ml/kg) (%) (%) (p Value) Amato and coworkers (3) Stewart and coworkers (5) Brochard and coworkers (6) Brower and coworkers (7) ARDSNet (4) Definition of abbreviation: ARDSNet Acute Respiratory Distress Syndrome Network. * Summary data (means SEM). To estimate the actual mean tidal volume per kilogram body weight administered, we used the fact that in the first hour 6- and 12-ml/kg tidal volumes were targeted and assumed that weight was constant over the 7 days. Measured body weight. Ideal body weight 25 [(height in meters) 2 ]. Dry weight measured weight minus estimated weight gain from salt and water retention. Predicted body weight 50 (for males) or 45.5 (for females) 2.3[(height in inches) 60]. pressures over the 5 to 7 days after randomization of sures with low tidal volumes cannot explain the significant increase in the odds ratio of survival in the two beneficial trials (6), (5), and (7) cm H 2 O. The pressures in the three trials (28 to 32 cm H 2 O) were similar to prerandom- compared with the three nonbeneficial trials (3 7) (Figure 1). ization values (29 to 31 cm H 2 O) reported in the two beneficial trials (3, 4) (p NS). Importantly, mean plateau airway pressures DISCUSSION in the two beneficial trials were higher after randomization (34 to 37 cm H Opinions differ as to why low tidal volumes (5 to 7 ml/kg mea- 2 O) (p 0.001) (Figure 2A) compared with those in the three nonbeneficial trials and near a threshold level (35 cm sured body weight) (3 7) have not produced consistent beneficial H effects in clinical trials of patients with ALI and ARDS. This 2 O) above which airway pressures were thought by many to be harmful (14). analysis suggests that there were important postrandomization Finally, we describe the tidal volumes selected and compare differences in airway pressures in the control arms of the five the resultant plateau airway pressures in patients receiving ventithree nonbeneficial trials used control tidal volumes that resulted trials (Figure 3) to explain the discrepant results (Figure 1). The lation with low tidal volumes (Table 1, Figure 2B). In the two beneficial trials, tidal volumes were lowered to (3) or in lower airway pressures (28 to 32 cm H 2 O), consistent with (4) ml/kg based on actual (3) or predicted (4) body routine care at the time of the studies (29 to 31 cm H 2 O) (10). weight (all p versus values before randomization) Compared with these control pressures, low tidal volumes did (Table 1). These decreases in tidal volume resulted in plateau not improve outcomes. However, the two beneficial trials comairway pressures over the 7 days after randomization of 28.8 pared low tidal volume ventilation with control arms with airway 1.2 (3) and (4) cm H pressures high enough (34 to 37 cm H 2 O) to potentially increase 2 O (Figure 2B). In the three nonbeneficial trials, the low tidal volumes employed were 7.2 control mortality rates. In this setting, low tidal volumes may 0.8 (5), (6), and (7) ml/kg based on ideal (5), mistakenly appear beneficial. dry (6), or predicted (7) body weight (Table 1). After randomizathese trials with the prerandomization data (i.e., routine care by Further comparison of the control tidal volumes studied in tion, these tidal volumes resulted in plateau airway pressures of (5), (6), and (7) cm H 2 O enrolling physicians at the participating institutions) provides (Figure 2B). In comparing the beneficial with the nonbeneficial additional insight. As noted, the control tidal volumes in the trials, plateau airway pressures were similar or lower in the three three nonbeneficial trials (5 7) produced airway pressures (28 nonbeneficial trials (Figure 2B). Thus, lower plateau airway pres- to 32 cm H 2 O) close to prerandomization values (29 to 31 cm H 2 O) (3, 4, 10) (Figure 2, Table 1). Although not significant, in each of these trials low tidal volumes were associated with increased mortality rates (Table 1). The possibility that all three of these trials (5 7) would have shown an effect with low tidal volumes on the side of harm by chance alone is only 1 in 8 (Figure 1). Moreover, the combined odds ratio of survival with low tidal volume treatment in the three trials was 0.80 with a 90% confidence interval extending from 0.54 to If not actually harmful, then any beneficial effect with low tidal volumes missed by chance in these three trials must have been small. In contrast to the three nonbeneficial trials, the two beneficial trials randomized patients to high tidal volumes that were Figure 1. Odds ratio ( SEM) for survival, comparing low with high significantly increased from those routinely used by the physitidal volumes. This partitions the five studies into one group of three cians in these trials (3, 4, 10) (Figures 2A and 2B). Without a studies, in which low tidal volumes were nonbeneficial, with individual comparison with this standard, it is not possible to determine odds ratios of 0.70 (0.48, 1.02) (6), 0.89 (0.62, 1.28) (5), and 0.85 directly whether the significant increase in the odds ratio of (0.49, 1.48) (7), and another group of two studies, in which low tidal survival to 1.56 in the two beneficial trials was because lowering volumes were beneficial, with individual odds ratios of 1.47 (1.28, 1.70) tidal volumes and airway pressures in the treatment group de- (4) and 3.97 (2.20, 7.17) (3). creased or raising tidal volume and airway pressures in the

3 1512 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 2. Serial mean ( SEM) plateau airway pressures before and after randomization to control (high) tidal volumes (A) or low tidal volumes (B) in five prospective randomized trials (3 7). All values after initiation of treatment were used to calculate the mean, represented by the clear line between each pair of colored bars ( SEM), except for Day 14 values reported in a single study (6). The results would not change if this value were included. The solid circles represent the individual mean plateau airway pressures reported for each study. After randomization they are connected over time by a solid line. See Table 1 for the study references indicated by the first author names shown above the curves, and for the mean ( SEM) tidal volumes used in each of these studies and calculated in a similar manner to the mean plateau airway pressures. One study (7) provided a mean value averaged over 5 days, but individual day mean values were shown only graphically; these have been transposed onto this figure. Finally, only two studies published prerandomization plateau airway pressures (3, 4, 10). the contradictory findings in these five trials (Figure 3). Both high and low tidal volumes and airway pressures may be associ- ated with increased mortality rate compared with common clini- cal practice. Consistent with this relationship, a survey of out- comes with mechanical ventilation in adults, including those with ALI and ARDS, found that low or high tidal volumes were both associated with increased mortality rates compared with intermediate mortality rates (13). Animal studies in which in- creases and decreases in tidal volume and airway pressure corre- lated with worsened lung function and outcome further validate this relationship (15, 16). Increased mortality rates seen with low tidal volumes may also be related to the higher doses of sedatives and narcotics necessary to maintain patient comfort, the addition of neuromuscular blockade or higher carbon dioxide levels, all of which could adversely affect hemodynamics and physiologic function (17 21). Despite contradictory results, these five trials can provide some clinical guidance. Because the two beneficial trials failed to use control arms representing current practice by participating physicians (Figures 2A and 2B) (3, 4, 10), they could not determine whether either therapy tested was superior to that practice. However, they could determine which of the two therapies tested produced a worse outcome and they clearly showed that high tidal volumes (e.g., 12 ml/kg based on predicted or measured body weight) associated with high airway pressures (34 cm H 2 O or more) were harmful and should be avoided (3, 4). In contrast, the three nonbeneficial trials (5 7) employed control arms that closely reflected current practice of physicians studying and treating patients with ALI and ARDS (3, 4, 10 13). These trials established that, as long as tidal volumes produce airway pressures between 28 and 32 cm H 2 O, there is no benefit from using low tidal volumes (i.e., 6 to 7 ml/kg based on either ideal [5], predicted [7], or dry [6] body weight), and it may be harmful. Further clinical trials are necessary to determine whether lowered tidal volumes produce a survival benefit when compared with the intermediate tidal volumes (8 9 ml/kg) routinely used by participating physicians at the time of these trials. control group increased the number of ventilator-associated deaths. However, because the three nonbeneficial trials used controls consistent with the standard practice reported in the two beneficial trials (Figure 2), those results can be reviewed to find the likeliest explanation. Statistically, there is only a 5% chance that the three nonbeneficial trials could produce a beneficial effect with an odds ratio of survival greater than 1.18 when comparing low tidal volumes with standard practice. Thus, the greater odds ratio of 1.56 in the two beneficial trials (3, 4) most likely represents a significant increase in the number of ventilator-associated deaths in the control arms of those studies. On the basis of this meta-analysis, a parabolic relationship between mortality rates and changes in tidal volumes and resultant plateau airway pressures could provide an explanation for Figure 3. Hypothetical model representing the relationship between tidal volumes and resultant plateau airway pressure and mortality rates. Mortality rates first decrease and then increase as tidal volume and plateau airway pressure decreases. On the basis of the data provided in each trial, this model may account for the disparate results of the five trials (3 7).

4 Critical Care Perspective 1513 There are potential limitations and other possible interpreta- 30 cm H 2 O (5). An international survey of more than 300 intensive tions of these data. Most importantly, the number of trials available care units was completed during the ARDSNet trial and for analysis was relatively small, as was the overall patient showed that a subset of more than 200 patients with ALI and enrollment. Lack of availability and small sample sizes made ARDS requiring mechanical ventilation had initial mean comparison of many potentially important variables difficult, ( SEM) plateau airway pressures of cm H 2 O (12). including the following: failure of randomization, differences in Finally, patients from the 10 medical centers, including 24 hospi- outcome time points, censoring, differences in the severity of tals, and more than 70 intensive care units participating in the illness and lung injury scores, methods of mechanical ventilation, ARDSNet trial received tidal volumes before study enrollment and differences in adjunctive treatments. Plateau airway pressure that produced a mean plateau airway pressure of cm was the primary variable employed in our analysis because it H 2 O (4, 10), significantly lower than those given to control pa- was a uniform measure available from all studies and is associ- tients after randomization. ated with ventilator-induced lung injury. However, plateau airway In the ARDSNet trial, the protocol not only specified a tradi- pressure values were determined by different methods tional high tidal volume for control subjects rather than current across the five trials. Furthermore, other factors that may influence practice in the study centers, but also restricted the physician s airway pressures, such as chest wall stiffness, may have ability to adjust tidal volumes unless airway pressures were very varied among trials. Despite these limitations, the fact remains high. In contrast, airway pressures were lower in studies where that three statistically different mechanical ventilation strategies physicians could more freely vary tidal volumes (i.e., in all the were used in the two beneficial trials. All patients started the above-described surveys, the three nonbeneficial trials, and in trial with average tidal volumes of 8 to 9 ml/kg (measured body patients before randomization in the ARDSNet trial itself). Adjustment weight) and then were randomized into two groups that not of tidal volumes was possible only in control subjects only differed significantly from one another but also differed from the ARDSNet trial if airway pressures were greater than significantly from this prestudy strategy. One group received low 50 cm H 2 O. Although evidence of barotrauma did not differ tidal volumes of 5 to 6 ml/kg while the other received increased between groups in this trial, mortality rates did appear to increase tidal volumes greater than 10 ml/kg. Ultimate survival data are with decreasing compliance in the control arm but not in the available only for the low- and high-tidal volume groups, but low tidal volume groups (4). Overall, this study design may have not for the prerandomization treatment strategy reflecting current resulted in substantial numbers of control patients receiving best practice standards by participating physicians at the inferior treatment in the ARDSNet trial (23). Definitive Phase study sites. We show in this analysis why such Phase III study III clinical trials enrolling large numbers of patients need a designs are seriously flawed. It is possible both treatments could control arm that represents what is believed by participating have a worse outcome than routine care, yet this could not be physicians to be the best current care (23). Such a control re- detected. On the basis of experience and without a formal analy- quires no assumptions to determine whether or not an experimental sis, some clinicians recognized that not controlling for conventional therapy is resulting in harm during a trial (24), and it is practice was a flaw in the study design of the beneficial the only control that provides clear evidence that the new therapy trials (9). will actually improve and not worsen current practice. This The Acute Respiratory Distress Syndrome Network (ARDS- is particularly important when studying rapidly lethal diseases, Net) trial, one of the two beneficial studies, represented the during which treatment toxicities can be masked by disease promajority (72%) of patients in this meta-analysis and was the gression. Of note, the ARDSNet is currently enrolling patients most recent of these five trials to be conducted. Overall control with ARDS to evaluate two different fluid regimens. The proto- and treatment mortality rates noted in this trial did appear lower col explicitly states that each of these regimens is thought to than in the other trials, possibly reflecting the progressive improvement have potential benefit but may also have risks and that the in outcome that has been noted in patients with ALI net balance of these potential opposing risks and benefits is not and ARDS (22). The significant decrease in mortality rate noted known. Further, the protocol states that there may be potential with low tidal volumes within this trial has been the primary benefit [of one or both of the regimens] (relative to routine impetus for recommendations to lower tidal volumes to very care) ; yet the trial does not contain an arm that represents low levels (5 7 ml/kg measured body weight) in patients with routine care, the group against which researchers ultimately want ALI and ARDS. It is therefore relevant and problematic that to make comparisons (25). the control treatment chosen in this trial represented the tradi- In conclusion, significant differences in the control arms provide tional (4) rather than the common practice employed by participating a basis for the contradictory results of these five trials (3 7). pulmonologists and intensivists at the time. This practice In three trials (5 7), control patients received tidal volumes standard appears to have been widespread, as determined on that produced airway pressures considered safe and that closely the basis both of surveys done before or close to the time most represented routine practice by physicians studying ALI and of the five trials began (11 13) and of data generated by the ARDS (10 13) (Figure 1). Compared with the control arm in trials themselves (3 7). these trials, low tidal volumes were ineffective or potentially In a study conducted in 1992, nearly half of 1,023 critical care harmful. However, in two other clinical trials, control subjects physicians surveyed reported using tidal volumes in patients with received traditional tidal volumes higher than routine treatment ALI and ARDS that were similar to the tidal volumes patients (Figure 2) (3, 4, 10). As a result, neither of these two trials received prerandomization in the ARDSNet trial begun 4 years can determine whether raising tidal volumes and airway pressure later (4, 12). Importantly, 96% of all respondents in this survey worsened or lowering tidal volume and airway pressures im- said that the level of airway pressure would influence their choice proved outcome compared with the practice that was current of tidal volume (12), suggesting that most clinicians by that time among participating physicians at study centers. We conclude were already decreasing tidal volumes if airway pressures were that none of these trials provides a scientific basis for the use high. Even as early as 1990, in the first low tidal volume trial, of low tidal volumes as routine treatment for patients with ALI patients received tidal volumes that resulted in plateau airway and ARDS, as long as plateau pressure is maintained between pressures of cm H 2 O (3) prerandomization. One of 28 and 32 cm H 2 O. Until such a basis is provided, low tidal the three nonbeneficial trials specifically excluded patients whose volumes (5 7 ml/kg measured body weight) should not be standard airway pressures with control treatment might rise to more than for patients with ALI and ARDS.

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