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Meta-Analysis of Acute Lung Injury and Acute Respiratory Distress Syndrome Trials Testing Low Tidal Volumes

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Peter Q. Eichacker, M.D., Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Drive, Building 10, Room 7D43, Bethesda, MD 20892. E-mail: peichacker{at}nih.gov

	INTRODUCTION

TOP INTRODUCTION METHODS AND RESULTS DISCUSSION REFERENCES

 
The use of low tidal volumes (5–7 ml/kg measured body weight) as a protective lung strategy is becoming widely recommended for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation (1–4). However, clinical trials testing low tidal volumes in ALI and ARDS have not shown uniform results (5–7). This has led some experts to recommend avoiding high tidal volumes during mechanical ventilation in these patients (6, 8), whereas other experts advocate using very low tidal volumes (1–4). Our concern, shared by others (9), was that trials showing low tidal volumes to be beneficial did not use control arms that reflected the current best practice standards at the time. Instead, the trials compared very low tidal volumes (5–7 ml/kg measured body weight) with "traditional" tidal volumes (10 ml/kg or more), which were higher than those routinely used (8–9 ml/kg) (10–13). As a result, those studies were inconclusive. We performed a meta-analysis to investigate why five randomized, prospective clinical trials produced disparate results and to critically evaluate the basis for recommending low tidal volume ventilation in ALI and ARDS (3–7). In this analysis, we demonstrate that there is a significant difference in the effects of low tidal volume on survival among the five trials. We then compare the tidal volumes and plateau airway pressures from the five trials to determine whether these account for differences in survival. In contrast to previous explanations based on the low tidal volumes tested (4), this meta-analysis demonstrates that significant differences in the control arms can account for the discrepant results among these five trials.

	METHODS AND RESULTS

TOP INTRODUCTION METHODS AND RESULTS DISCUSSION REFERENCES

 
From 1990 to 2001, five clinical trials testing mechanical ventilation with low tidal volumes in patients with ALI and ARDS were identified, using the search terms "mechanical ventilation," "tidal volume," "clinical trial," and "ALI and ARDS" in Embase or Medline (3–7) (Table 1). The five trials demonstrated sufficient heterogeneity in patient outcome to preclude reporting a single odds ratio describing the treatment effect of lowered tidal volumes (p = 0.06, Breslow–Day test). Rather, the trials fell into two groups that were different from one another (p = 0.017). Two trials showed significant increases in the odds ratio for survival of patients treated with low versus control tidal volume (henceforth referred to as the two beneficial trials) (3, 4) (Figure 1). In contrast, the other three trials showed a nonsignificant decrease in the odds ratio for this relationship (henceforth referred to as the three nonbeneficial trials) (5–7).

View larger version (13K): [in this window] [in a new window]   Figure 1. Odds ratio (± SEM) for survival, comparing low with high tidal volumes. This partitions the five studies into one group of three studies, in which low tidal volumes were nonbeneficial, with individual odds ratios of 0.70 (0.48, 1.02) (6), 0.89 (0.62, 1.28) (5), and 0.85 (0.49, 1.48) (7), and another group of two studies, in which low tidal volumes were beneficial, with individual odds ratios of 1.47 (1.28, 1.70) (4) and 3.97 (2.20, 7.17) (3).

We first describe the tidal volumes selected and then compare the resultant plateau airway pressures in the control groups (Table 1, Figure 2A). In the two beneficial trials (3, 4), tidal volumes (ml) reported in control patients just before randomization were similar (mean ± SE, 665 ± 125 [3] and 646 ± 24 [4], respectively; p = NS), as were plateau airway pressures (cm H₂O) (29.5 ± 1.5 [3] and 30.3 ± 0.6 [4, 10], respectively; p = NS). These control patients were then randomized to a single targeted tidal volume of 12 ml/kg based either on measured body weight (3) or predicted body weight (4) (Table 1). This change represented a 17 ± 5% increase (3) and a 18 ± 3% 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 ± 1.0 (3) and 34.1 ± 0.4 (4) cm H₂O (Figure 2A). Thus, before study entry, clinical practice was to ventilate patients with tidal volumes that produced plateau airway pressures averaging 29 to 31 cm H₂O. However, after entry into the studies, these same patients had plateau airway pressures that were significantly higher (p < 0.001) (34 to 37 cm H₂O) (3, 4, 8) (Figure 2A) than prerandomization levels.

View larger version (24K): [in this window] [in a new window]   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).

Finally, we describe the tidal volumes selected and compare the resultant plateau airway pressures in patients receiving ventilation with low tidal volumes (Table 1, Figure 2B). In the two beneficial trials, tidal volumes were lowered to 6.1 ± 0.2 (3) or 6.3 ± 0.1 (4) ml/kg based on actual (3) or predicted (4) body weight (all p < 0.0001 versus values before randomization) (Table 1). These decreases in tidal volume resulted in plateau airway pressures over the 7 days after randomization of 28.8 ± 1.2 (3) and 25.6 ± 0.3 (4) cm H₂O (Figure 2B). In the three nonbeneficial trials, the low tidal volumes employed were 7.2 ± 0.8 (5), 7.1 ± 0.2 (6), and 7.3 ± 0.1 (7) ml/kg based on ideal (5), dry (6), or predicted (7) body weight (Table 1). After randomization, these tidal volumes resulted in plateau airway pressures of 21.8 ± 0.6 (5), 25.1 ± 0.7 (6), and 24.9 ± 1.6 (7) cm H₂O (Figure 2B). In comparing the beneficial with the nonbeneficial trials, plateau airway pressures were similar or lower in the three nonbeneficial trials (Figure 2B). Thus, lower plateau airway pressures with low tidal volumes cannot explain the significant increase in the odds ratio of survival in the two beneficial trials compared with the three nonbeneficial trials (3–7) (Figure 1).

	DISCUSSION

TOP INTRODUCTION METHODS AND RESULTS DISCUSSION REFERENCES

 
Opinions differ as to why low tidal volumes (5 to 7 ml/kg measured body weight) (3–7) have not produced consistent beneficial effects in clinical trials of patients with ALI and ARDS. This analysis suggests that there were important postrandomization differences in airway pressures in the control arms of the five trials (Figure 3) to explain the discrepant results (Figure 1). The three nonbeneficial trials used control tidal volumes that resulted in lower airway pressures (28 to 32 cm H₂O), consistent with routine care at the time of the studies (29 to 31 cm H₂O) (10). Compared with these control pressures, low tidal volumes did not improve outcomes. However, the two beneficial trials compared low tidal volume ventilation with control arms with airway pressures high enough (34 to 37 cm H₂O) to potentially increase control mortality rates. In this setting, low tidal volumes may mistakenly appear beneficial.

View larger version (16K): [in this window] [in a new window]   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).

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 the contradictory findings in these five trials (Figure 3). Both high and low tidal volumes and airway pressures may be associated with increased mortality rate compared with common clinical practice. Consistent with this relationship, a survey of outcomes 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 increases and decreases in tidal volume and airway pressure correlated 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 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 pressures 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], 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.

There are potential limitations and other possible interpretations of these data. Most importantly, the number of trials available for analysis was relatively small, as was the overall patient enrollment. Lack of availability and small sample sizes made comparison of many potentially important variables difficult, including the following: failure of randomization, differences in outcome time points, censoring, differences in the severity of illness and lung injury scores, methods of mechanical ventilation, and differences in adjunctive treatments. Plateau airway pressure was the primary variable employed in our analysis because it was a uniform measure available from all studies and is associated with ventilator-induced lung injury. However, plateau airway pressure values were determined by different methods across the five trials. Furthermore, other factors that may influence airway pressures, such as chest wall stiffness, may have varied among trials. Despite these limitations, the fact remains that three statistically different mechanical ventilation strategies were used in the two beneficial trials. All patients started the trial with average tidal volumes of 8 to 9 ml/kg (measured body weight) and then were randomized into two groups that not only differed significantly from one another but also differed significantly from this prestudy strategy. One group received low tidal volumes of 5 to 6 ml/kg while the other received increased tidal volumes greater than 10 ml/kg. Ultimate survival data are available only for the low- and high-tidal volume groups, but not for the prerandomization treatment strategy reflecting current best practice standards by participating physicians at the study sites. We show in this analysis why such Phase III study designs are seriously flawed. It is possible both treatments could have a worse outcome than routine care, yet this could not be detected. On the basis of experience and without a formal analysis, some clinicians recognized that not controlling for conventional practice was a flaw in the study design of the beneficial trials (9).

The Acute Respiratory Distress Syndrome Network (ARDSNet) trial, one of the two beneficial studies, represented the majority (72%) of patients in this meta-analysis and was the most recent of these five trials to be conducted. Overall control and treatment mortality rates noted in this trial did appear lower than in the other trials, possibly reflecting the progressive improvement in outcome that has been noted in patients with ALI and ARDS (22). The significant decrease in mortality rate noted with low tidal volumes within this trial has been the primary impetus for recommendations to lower tidal volumes to very low levels (5–7 ml/kg measured body weight) in patients with ALI and ARDS. It is therefore relevant and problematic that the control treatment chosen in this trial represented the "traditional" (4) rather than the common practice employed by participating pulmonologists and intensivists at the time. This practice standard appears to have been widespread, as determined on the basis both of surveys done before or close to the time most of the five trials began (11–13) and of data generated by the trials themselves (3–7).

In a study conducted in 1992, nearly half of 1,023 critical care physicians surveyed reported using tidal volumes in patients with ALI and ARDS that were similar to the tidal volumes patients received prerandomization in the ARDSNet trial begun 4 years later (4, 12). Importantly, 96% of all respondents in this survey said that the level of airway pressure would influence their choice of tidal volume (12), suggesting that most clinicians by that time were already decreasing tidal volumes if airway pressures were high. Even as early as 1990, in the first low tidal volume trial, patients received tidal volumes that resulted in plateau airway pressures of 29.5 ± 1.5 cm H₂O (3) prerandomization. One of the three nonbeneficial trials specifically excluded patients whose airway pressures with control treatment might rise to more than 30 cm H₂O (5). An international survey of more than 300 intensive care units was completed during the ARDSNet trial and showed that a subset of more than 200 patients with ALI and ARDS requiring mechanical ventilation had initial mean (± SEM) plateau airway pressures of 28 ± 0.5 cm H₂O (12). Finally, patients from the 10 medical centers, including 24 hospitals, and more than 70 intensive care units participating in the ARDSNet trial received tidal volumes before study enrollment that produced a mean plateau airway pressure of 30.3 ± 0.6 cm H₂O (4, 10), significantly lower than those given to control patients after randomization.

In the ARDSNet trial, the protocol not only specified a "traditional" high tidal volume for control subjects rather than current practice in the study centers, but also restricted the physician's ability to adjust tidal volumes unless airway pressures were very high. In contrast, airway pressures were lower in studies where physicians could more freely vary tidal volumes (i.e., in all the above-described surveys, the three nonbeneficial trials, and in patients before randomization in the ARDSNet trial itself). Adjustment of tidal volumes was possible only in control subjects from the ARDSNet trial if airway pressures were greater than 50 cm H₂O. Although evidence of barotrauma did not differ between groups in this trial, mortality rates did appear to increase with decreasing compliance in the control arm but not in the low tidal volume groups (4). Overall, this study design may have resulted in substantial numbers of control patients receiving inferior treatment in the ARDSNet trial (23). Definitive Phase III clinical trials enrolling large numbers of patients need a control arm that represents what is believed by participating physicians to be the best current care (23). Such a control requires no assumptions to determine whether or not an experimental therapy is resulting in harm during a trial (24), and it is the only control that provides clear evidence that the new therapy will actually improve and not worsen current practice. This is particularly important when studying rapidly lethal diseases, during which treatment toxicities can be masked by disease progression. Of note, the ARDSNet is currently enrolling patients with ARDS to evaluate two different fluid regimens. The protocol explicitly states that each of these regimens is "thought to have potential benefit...but may also have risks" and that "the net balance of these potential opposing risks and benefits is not known." Further, the protocol states that "there may be potential benefit [of one or both of the regimens]...(relative to ‘routine’ care)"; yet the trial does not contain an arm that represents routine care, the group against which researchers ultimately want to make comparisons (25).

In conclusion, significant differences in the control arms provide a basis for the contradictory results of these five trials (3–7). In three trials (5–7), control patients received tidal volumes that produced airway pressures considered safe and that closely represented routine practice by physicians studying ALI and ARDS (10–13) (Figure 1). Compared with the control arm in these trials, low tidal volumes were ineffective or potentially harmful. However, in two other clinical trials, control subjects received "traditional" tidal volumes higher than routine treatment (Figure 2) (3, 4, 10). As a result, neither of these two trials can determine whether raising tidal volumes and airway pressure worsened or lowering tidal volume and airway pressures improved outcome compared with the practice that was current among participating physicians at study centers. We conclude that none of these trials provides a scientific basis for the use of low tidal volumes as routine treatment for patients with ALI and ARDS, as long as plateau pressure is maintained between 28 and 32 cm H₂O. Until such a basis is provided, low tidal volumes (5–7 ml/kg measured body weight) should not be standard for patients with ALI and ARDS.

Received in original form June 27, 2002; accepted in final form August 21, 2002

	REFERENCES

TOP INTRODUCTION METHODS AND RESULTS DISCUSSION REFERENCES

 

1. Brower RG, Fessler HE. Mechanical ventilation in acute lung injury and acute respiratory distress syndrome. Clin Chest Med 2000;21:491–510.[CrossRef][Medline]
2. Brower RG, Ware LB, Berthiaume Y, Matthay MA. Treatment of ALI and ARDS. Chest 2001;120:1347–1367.[Abstract/Free Full Text]
3. 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;338:347–354.[Abstract/Free Full Text]
4. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308.[Abstract/Free Full Text]
5. Stewart TE, Meade MO, Cook DJ, Granton JT, Hodder RV, Lapinsky SE, Mazer CD, McLean RF, Rogovein TS, Schouten BD, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998;338:355–361.[Abstract/Free Full Text]
6. Brochard L, Roudot-Thoraval F, Roupie E, Delclaux C, Chastre J, Fernandez-Mondejar E, Clementi E, Mancebo J, Factor P, Matamis D, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. Multicenter Trial Group on Tidal Volume Reduction in ARDS. Am J Respir Crit Care Med 1998;158:1831–1838.[Abstract/Free Full Text]
7. Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P Jr, Wiener CM, Teeter JG, Doddo JM, Almog Y, Piantadosi S. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999;27:1492–1498.[CrossRef][Medline]
8. Tobin MJ. Culmination of an era in research on the acute respiratory distress syndrome. N Engl J Med 2000;342:1360–1361.[Free Full Text]
9. Oba Y, Salzman GA. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury. N Engl J Med 2000;343:813.
10. Thompson BT, Hayden D, Matthay MA, Brower R, Parsons PE. Clinicians' approaches to mechanical ventilation in acute lung injury and ARDS. Chest 2001;120:1622–1627.[Abstract/Free Full Text]
11. Esteban A, Anzueto A, Alia I, Gordo F, Apezteguia C, Palizas F, Cide D, Goldwaser R, Soto L, Bugedo G, et al. How is mechanical ventilation employed in the intensive care unit? An international utilization review. Am J Respir Crit Care Med 2000;161:1450–1458.[Abstract/Free Full Text]
12. Carmichael LC, Dorinsky PM, Higgins SB, Bernard GR, Dupont WD, Swindell B, Wheeler AP. Diagnosis and treatment of acute respiratory distress syndrome in adults: an international survey. J Crit Care 1996;11:9–18.[CrossRef][Medline]
13. 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;287:345–355.[Abstract/Free Full Text]
14. Slutsky AS. Mechanical ventilation: American College of Chest Physicians' Consensus Conference. Chest 1993;104:1833–1859.
15. Tsuno K, Prato P, Kolobow T. Acute lung injury from mechanical ventilation at moderately high airway pressures. J Appl Physiol 1990;69:956–961.[Abstract/Free Full Text]
16. Muscdere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994;149:1327–1334.[Abstract]
17. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342:1471–1477.[Abstract/Free Full Text]
18. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest 1998;114:541–548.[Abstract/Free Full Text]
19. Feihl F, Perret C. Permissive hypercapnia: how permissive should we be? Am J Respir Crit Care Med 1994;150:1722–1737.[Medline]
20. Thorens JB, Jolliet P, Ritz M, Chevrolet JC. Effects of rapid permissive hypercapnia on hemodynamics, gas exchange, and oxygen transport and consumption during mechanical ventilation for the acute respiratory distress syndrome. Intensive Care Med 1996;22:182–191.[CrossRef][Medline]
21. Puybasset L, Stewart T, Rouby JJ, Cluzel P, Mourgeon E, Belin MF, Arthaud M, Landault C, Viars P. Inhaled nitric oxide reverses the increase in pulmonary vascular resistance induced by permissive hypercapnia in patients with acute respiratory distress syndrome. Anesthesiology 1994;80:1254–1267.[Medline]
22. Steinberg KP, Hudson LD. Acute lung injury and the acute respiratory distress syndrome: the clinical syndrome. Clin Chest Med 2000;21:401–417.[CrossRef][Medline]
23. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects [revised October 7, 2000]. HIV Clin Trials 2001;2:92–95.[CrossRef][Medline]
24. Freeman BD, Danner RL, Banks SM, Natanson C. Safeguarding patients in clinical trials with high mortality rates. Am J Respir Crit Care Med 2001;164:190–192.[Free Full Text]
25. Anonymous. ARDSNet study protocol: prospective, randomized, multi-center trial of "fluid conservative" vs. "fluid liberal" management of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). PAC Study version 1, ARDSNet Study, March 16, 2000, pp. 31–32. http://hedwig.mgh.harvard.edu/ardsnet/factt.pdf

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				C. W. Bollen, C. S. P. M. Uiterwaal, and A. J. van Vught Cumulative Metaanalysis of High-frequency Versus Conventional Ventilation in Premature Neonates Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1150 - 1155. [Full Text] [PDF]

				M. J. Tobin Writing a Review Article for AJRCCM Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 732 - 734. [Full Text] [PDF]

				M. J. Tobin The Role of a Journal in a Scientific Controversy Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 511 - 511. [Full Text] [PDF]

				M. Amato, L. Brochard, T. Stewart, R. Brower, P. Q. Eichacker, S. M. Banks, and C. Natanson Metaanalysis of Tidal Volume in ARDS Am. J. Respir. Crit. Care Med., September 1, 2003; 168(5): 612 - 613. [Full Text]

				O. Stenqvist Practical assessment of respiratory mechanics Br. J. Anaesth., July 1, 2003; 91(1): 92 - 105. [Full Text] [PDF]

				B. Priolet, D. Robert, R. G. Brower, M. A. Matthay, and G. R. Bernard Questions about ARDSNetwork trial of low tidal volume Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1717 - 1717. [Full Text] [PDF]

M. Duggan, C. L. McCaul, P. J. McNamara, D. Engelberts, C. Ackerley, and B. P. Kavanagh