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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 ϭ 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 nonsig- tidal volumes in ALI and ARDS have not shown uniform nificant decrease in the odds ratio for this relationship (hence- results (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 pri- tice 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 randomiza- the tidal volumes and plateau airway pressures from the five tion were similar (mean Ϯ SE, 665 Ϯ 125 [3] and 646 Ϯ 24 [4], trials to determine whether these account for differences in respectively; p ϭ NS), as were plateau airway pressures (cm survival. In contrast to previous explanations based on the H2O) (29.5 Ϯ 1.5 [3] and 30.3 Ϯ 0.6 [4, 10], respectively; p ϭ 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 Ϯ 5% increase (3) and a 18 Ϯ 3% increase (4) (both p Ͻ 0.001) in tidal volume and resulted inMETHODS AND RESULTS mean plateau airway pressures over the 7 days of study of 36.3 Ϯ From 1990 to 2001, five clinical trials testing mechanical ventila- 1.0 (3) and 34.1 Ϯ 0.4 (4) cm H2O (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 H2O. However, after entry into the studies, these same or Medline (3–7) (Table 1). The five trials demonstrated suffi- patients had plateau airway pressures that were significantly cient heterogeneity in patient outcome to preclude reporting a higher (p Ͻ 0.001) (34 to 37 cm H2O) (3, 4, 8) (Figure 2A) than single odds ratio describing the treatment effect of lowered tidal prerandomization levels. volumes (p ϭ 0.06, Breslow–Day test). Rather, the trials fell In the three nonbeneficial trials, participating clinicians se- lected 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 20892. kg) of these ranges (5–7) (Table 1). One of these trials also E-mail: peichacker@nih.gov excluded any patient exposed to peak airway pressures greater Am J Respir Crit Care Med Vol 166. pp 1510–1514, 2002 than 30 cm H2O for more than 2 hours before randomizationOriginally Published in Press as DOI: 10.1164/rccm.200208-956OC on August 28, 2002 Internet address: www.atsjournals.org (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) 29 24 6.1 Ϯ 0.2†‡ 11.9 Ϯ 0.5†‡ 38 71 Ͻ 0.001 Stewart and coworkers (5) 60 60 7.2 Ϯ 0.8§ 10.6 Ϯ 0.2§ 50 47 0.72 Brochard and coworkers (6) 58 58 7.2 Ϯ 0.2 10.4 Ϯ 0.2 47 38 0.38 Brower and coworkers (7) 26 26 7.3 Ϯ 0.1¶ 10.2 Ϯ 0.1¶ 50 46 0.60 ARDSNet (4) 432 429 6.3 Ϯ 0.1¶ 11.7 Ϯ 0.1¶ 31 40 0.007 Definition of abbreviation: ARDSNet ϭ Acute Respiratory Distress Syndrome Network. * Summary data (means Ϯ 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 ϭ 25 ϫ [(height in meters)2 ]. Dry weight ϭ measured weight minus estimated weight gain from salt and water retention. ¶ Predicted body weight ϭ 50 (for males) or 45.5 (for females) ϩ 2.3[(height in inches) Ϫ 60]. pressures over the 5 to 7 days after randomization of 31.6 Ϯ 1.1 sures with low tidal volumes cannot explain the significant in- crease in the odds ratio of survival in the two beneficial trials(6), 27.8 Ϯ 0.9 (5), and 30.6 Ϯ 1.7 (7) cm H2O. The pressures in the three trials (28 to 32 cm H2O) were similar to prerandom- compared with the three nonbeneficial trials (3–7) (Figure 1). ization values (29 to 31 cm H2O) reported in the two beneficial trials (3, 4) (p ϭ NS). Importantly, mean plateau airway pressures DISCUSSION in the two beneficial trials were higher after randomization (34 Opinions differ as to why low tidal volumes (5 to 7 ml/kg mea-to 37 cm H2O) (p Ͻ 0.001) (Figure 2A) compared with those in sured body weight) (3–7) have not produced consistent beneficialthe three nonbeneficial trials and near a threshold level (35 cm effects in clinical trials of patients with ALI and ARDS. ThisH2O) above which airway pressures were thought by many to analysis suggests that there were important postrandomizationbe harmful (14). differences in airway pressures in the control arms of the fiveFinally, we describe the tidal volumes selected and compare trials (Figure 3) to explain the discrepant results (Figure 1). Thethe resultant plateau airway pressures in patients receiving venti- three nonbeneficial trials used control tidal volumes that resultedlation with low tidal volumes (Table 1, Figure 2B). In the two in lower airway pressures (28 to 32 cm H2O), consistent withbeneficial trials, tidal volumes were lowered to 6.1 Ϯ 0.2 (3) or routine care at the time of the studies (29 to 31 cm H2O) (10).6.3 Ϯ 0.1 (4) ml/kg based on actual (3) or predicted (4) body Compared with these control pressures, low tidal volumes didweight (all p Ͻ 0.0001 versus values before randomization) not improve outcomes. However, the two beneficial trials com-(Table 1). These decreases in tidal volume resulted in plateau pared low tidal volume ventilation with control arms with airwayairway pressures over the 7 days after randomization of 28.8 Ϯ pressures high enough (34 to 37 cm H2O) to potentially increase1.2 (3) and 25.6 Ϯ 0.3 (4) cm H2O (Figure 2B). In the three control mortality rates. In this setting, low tidal volumes maynonbeneficial trials, the low tidal volumes employed were 7.2 Ϯ mistakenly appear beneficial.0.8 (5), 7.1 Ϯ 0.2 (6), and 7.3 Ϯ 0.1 (7) ml/kg based on ideal (5), Further comparison of the control tidal volumes studied indry (6), or predicted (7) body weight (Table 1). After randomiza- these trials with the prerandomization data (i.e., routine care bytion, these tidal volumes resulted in plateau airway pressures of enrolling physicians at the participating institutions) provides21.8 Ϯ 0.6 (5), 25.1 Ϯ 0.7 (6), and 24.9 Ϯ 1.6 (7) cm H2O additional insight. As noted, the control tidal volumes in the(Figure 2B). In comparing the beneficial with the nonbeneficial three nonbeneficial trials (5–7) produced airway pressures (28trials, plateau airway pressures were similar or lower in the three to 32 cm H2O) close to prerandomization values (29 to 31 cmnonbeneficial trials (Figure 2B). Thus, lower plateau airway pres- H2O) (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 1.18. If not actually harmful, then any beneficial effect with low tidal vol- umes missed by chance in these three trials must have been small. In contrast to the three nonbeneficial trials, the two bene- ficial trials randomized patients to high tidal volumes that were significantly increased from those routinely used by the physi-Figure 1. Odds ratio (Ϯ SEM) for survival, comparing low with high cians in these trials (3, 4, 10) (Figures 2A and 2B). Without atidal volumes. This partitions the five studies into one group of three comparison with this standard, it is not possible to determinestudies, in which low tidal volumes were nonbeneficial, with individual directly whether the significant increase in the odds ratio ofodds ratios of 0.70 (0.48, 1.02) (6), 0.89 (0.62, 1.28) (5), and 0.85 survival to 1.56 in the two beneficial trials was because lowering(0.49, 1.48) (7), and another group of two studies, in which low tidal tidal volumes and airway pressures in the treatment group de-volumes were beneficial, with individual odds ratios of 1.47 (1.28, 1.70) (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 166 2002 Figure 2. Serial mean (Ϯ 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 cal- culate the mean, represented by the clear line between each pair of colored bars (Ϯ SEM), except for Day 14 values re- ported 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 con- nected over time by a solid line. See Table 1 for the study refer- ences indicated by the first au- thor names shown above the curves, and for the mean (Ϯ 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). control group increased—the number of ventilator-associated the contradictory findings in these five trials (Figure 3). Both deaths. However, because the three nonbeneficial trials used high and low tidal volumes and airway pressures may be associ- controls consistent with the standard practice reported in the ated with increased mortality rate compared with common clini- two beneficial trials (Figure 2), those results can be reviewed to cal practice. Consistent with this relationship, a survey of out- find the likeliest explanation. Statistically, there is only a 5% comes with mechanical ventilation in adults, including those with chance that the three nonbeneficial trials could produce a bene- ALI and ARDS, found that low or high tidal volumes were ficial effect with an odds ratio of survival greater than 1.18 when both associated with increased mortality rates compared with comparing low tidal volumes with standard practice. Thus, the intermediate mortality rates (13). Animal studies in which in- greater odds ratio of 1.56 in the two beneficial trials (3, 4) most creases and decreases in tidal volume and airway pressure corre- likely represents a significant increase in the number of ventila- lated with worsened lung function and outcome further validate tor-associated deaths in the control arms of those studies. this relationship (15, 16). Increased mortality rates seen with On the basis of this meta-analysis, a parabolic relationship low tidal volumes may also be related to the higher doses of between mortality rates and changes in tidal volumes and resul- sedatives and narcotics necessary to maintain patient comfort, tant plateau airway pressures could provide an explanation for 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 deter- mine 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 H2O 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 pres- sures between 28 and 32 cm H2O, there is no benefit from using low tidal volumes (i.e., 6 to 7 ml/kg based on either ideal [5],Figure 3. Hypothetical model representing the relationship between predicted [7], or dry [6] body weight), and it may be harmful.tidal volumes and resultant plateau airway pressure and mortality rates. Further clinical trials are necessary to determine whether low-Mortality rates first decrease and then increase as tidal volume and ered tidal volumes produce a survival benefit when comparedplateau airway pressure decreases. On the basis of the data provided with the intermediate tidal volumes (8–9 ml/kg) routinely usedin each trial, this model may account for the disparate results of the five trials (3–7). by participating physicians at the time of these trials.
  • 4. Critical Care Perspective 1513 There are potential limitations and other possible interpreta- 30 cm H2O (5). An international survey of more than 300 inten- sive care units was completed during the ARDSNet trial andtions of these data. Most importantly, the number of trials avail- able for analysis was relatively small, as was the overall patient showed that a subset of more than 200 patients with ALI and ARDS requiring mechanical ventilation had initial meanenrollment. Lack of availability and small sample sizes made comparison of many potentially important variables difficult, (Ϯ SEM) plateau airway pressures of 28 Ϯ 0.5 cm H2O (12). Finally, patients from the 10 medical centers, including 24 hospi-including the following: failure of randomization, differences in outcome time points, censoring, differences in the severity of tals, and more than 70 intensive care units participating in the ARDSNet trial received tidal volumes before study enrollmentillness and lung injury scores, methods of mechanical ventilation, and differences in adjunctive treatments. Plateau airway pressure that produced a mean plateau airway pressure of 30.3 Ϯ 0.6 cm H2O (4, 10), significantly lower than those given to control pa-was the primary variable employed in our analysis because it was a uniform measure available from all studies and is associ- tients after randomization. In the ARDSNet trial, the protocol not only specified a “tradi-ated with ventilator-induced lung injury. However, plateau air- way pressure values were determined by different methods tional” high tidal volume for control subjects rather than current practice in the study centers, but also restricted the physician’sacross the five trials. Furthermore, other factors that may influ- ence airway pressures, such as chest wall stiffness, may have ability to adjust tidal volumes unless airway pressures were very high. In contrast, airway pressures were lower in studies wherevaried among trials. Despite these limitations, the fact remains that three statistically different mechanical ventilation strategies physicians could more freely vary tidal volumes (i.e., in all the above-described surveys, the three nonbeneficial trials, and inwere used in the two beneficial trials. All patients started the trial with average tidal volumes of 8 to 9 ml/kg (measured body patients before randomization in the ARDSNet trial itself). Ad- justment of tidal volumes was possible only in control subjectsweight) and then were randomized into two groups that not only differed significantly from one another but also differed from the ARDSNet trial if airway pressures were greater than 50 cm H2O. Although evidence of barotrauma did not differsignificantly from this prestudy strategy. One group received low tidal volumes of 5 to 6 ml/kg while the other received increased between groups in this trial, mortality rates did appear to increase with decreasing compliance in the control arm but not in thetidal volumes greater than 10 ml/kg. Ultimate survival data are available only for the low- and high-tidal volume groups, but low tidal volume groups (4). Overall, this study design may have resulted in substantial numbers of control patients receivingnot for the prerandomization treatment strategy reflecting cur- rent best practice standards by participating physicians at the inferior treatment in the ARDSNet trial (23). Definitive Phase III clinical trials enrolling large numbers of patients need astudy sites. We show in this analysis why such Phase III study designs are seriously flawed. It is possible both treatments could control arm that represents what is believed by participating physicians to be the best current care (23). Such a control re-have a worse outcome than routine care, yet this could not be detected. On the basis of experience and without a formal analy- quires no assumptions to determine whether or not an experi- mental therapy is resulting in harm during a trial (24), and it issis, some clinicians recognized that not controlling for conven- tional practice was a flaw in the study design of the beneficial the only control that provides clear evidence that the new ther- apy will actually improve and not worsen current practice. Thistrials (9). The Acute Respiratory Distress Syndrome Network (ARDS- is particularly important when studying rapidly lethal diseases, during which treatment toxicities can be masked by disease pro-Net) trial, one of the two beneficial studies, represented the majority (72%) of patients in this meta-analysis and was the gression. Of note, the ARDSNet is currently enrolling patients with ARDS to evaluate two different fluid regimens. The proto-most recent of these five trials to be conducted. Overall control and treatment mortality rates noted in this trial did appear lower col explicitly states that each of these regimens is “thought to have potential benefit…but may also have risks” and that “thethan in the other trials, possibly reflecting the progressive im- provement in outcome that has been noted in patients with ALI net balance of these potential opposing risks and benefits is not known.” Further, the protocol states that “there may be potentialand ARDS (22). The significant decrease in mortality rate noted with low tidal volumes within this trial has been the primary benefit [of one or both of the regimens]…(relative to ‘routine’ care)”; yet the trial does not contain an arm that representsimpetus for recommendations to lower tidal volumes to very low levels (5–7 ml/kg measured body weight) in patients with routine care, the group against which researchers ultimately want to make comparisons (25).ALI and ARDS. It is therefore relevant and problematic that the control treatment chosen in this trial represented the “tradi- In conclusion, significant differences in the control arms pro- vide a basis for the contradictory results of these five trials (3–7).tional” (4) rather than the common practice employed by partici- pating pulmonologists and intensivists at the time. This practice In three trials (5–7), control patients received tidal volumes that produced airway pressures considered safe and that closelystandard appears to have been widespread, as determined on the basis both of surveys done before or close to the time most represented routine practice by physicians studying ALI and ARDS (10–13) (Figure 1). Compared with the control arm inof the five trials began (11–13) and of data generated by the trials themselves (3–7). these trials, low tidal volumes were ineffective or potentially harmful. However, in two other clinical trials, control subjectsIn a study conducted in 1992, nearly half of 1,023 critical care physicians surveyed reported using tidal volumes in patients with received “traditional” tidal volumes higher than routine treat- ment (Figure 2) (3, 4, 10). As a result, neither of these two trialsALI and ARDS that were similar to the tidal volumes patients received prerandomization in the ARDSNet trial begun 4 years can determine whether raising tidal volumes and airway pressure worsened or lowering tidal volume and airway pressures im-later (4, 12). Importantly, 96% of all respondents in this survey said that the level of airway pressure would influence their choice proved outcome compared with the practice that was current among participating physicians at study centers. We concludeof tidal volume (12), suggesting that most clinicians by that time were already decreasing tidal volumes if airway pressures were that none of these trials provides a scientific basis for the use of low tidal volumes as routine treatment for patients with ALIhigh. Even as early as 1990, in the first low tidal volume trial, patients received tidal volumes that resulted in plateau airway and ARDS, as long as plateau pressure is maintained between 28 and 32 cm H2O. Until such a basis is provided, low tidalpressures of 29.5 Ϯ 1.5 cm H2O (3) prerandomization. One of the three nonbeneficial trials specifically excluded patients whose volumes (5–7 ml/kg measured body weight) should not be stan- dard for patients with ALI and ARDS.airway pressures with control treatment might rise to more than
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