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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 612-613, (2003)
© 2003 American Thoracic Society

Correspondence

Metaanalysis of Tidal Volume in ARDS

To the Editor:

In their recent commentary and letter in AJRCCM, Eichacker and coworkers (1) suggested that the tidal volumes used in both of the study groups in the National Institutes of Health (NIH) Acute Respiratory Distress Syndrome Network trial (2) and the Brazilian trial (3) (6 and 12 ml/kg) were detrimental and exposed patients to unjustifiable risks. We think a more accurate assessment of data does not support their conclusions.

In their analysis, Eichacker and coworkers (1) compared pooled odds ratios for survival of the lower tidal volume study groups in the three nonbeneficial trials (4–6) to the pooled odds ratios for the two beneficial trials (2, 3). In the three nonbeneficial trials, the higher tidal volume study groups received tidal volumes of 10 ml/kg (4–6) instead of 12 ml/kg. The comparison of the pooled odds ratios for the three nonbeneficial trials to the two beneficial trials (see Figure 1 in Reference 1) suggests that the 6 ml/kg strategies in the NIH and Brazilian studies are not protective, but instead that the 12 ml/kg arms are detrimental.



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  		Figure 1. Using the framework of Eichacker and coworkers (1), we replotted the pooled odds ratio ± 95% confidence intervals for the three nonbeneficial trials. After model adjustments for baseline imbalances, the odds ratio for survival does not suggest a detrimental effect of the lower tidal volume strategies. The same behavior was observed when using a multivariate Cox proportional hazard model, pointing out an adjusted odds ratio or relative risk greater than 1. * The best adjusted model included APACHE-II scores and the PaO2/FIO2 ratios at study entry. When considering only the three nonbeneficial studies, arterial pH and respiratory system compliance at entry were also significantly correlated with survival in multivariate forward and backward selection. Their inclusion moved the odds ratio further to the right (odds ratio = 1.10; 95% confidence interval: 0.64–1.88).

 
We reviewed the raw data for the three nonbeneficial trials and recalculated odds ratios for survival for the pooled tidal volume study groups (n = 288, with 144 patients pooled in each arm). Our findings include the following:
  1. The authors' original presentation of standard error of mean confidence intervals (instead of the standard 95% confidence intervals) produced some visual impact, which risks misleading readers. In Figure 1, we show the more appropriate 95% confidence intervals, which demonstrate that the presumed trend is rather weak.
  2. By using multivariate analysis, in which we adjust the model for baseline variables significantly correlated with mortality rates (APACHE-II score and PaO2/FIO2), the goodness-of-fit of the model improved and the pooled odds ratio for survival for the lower tidal volume groups of the three nonbeneficial studies moved away from detrimental effect. The difference between our adjusted pooled odds ratio and the odds ratio presented by Eichacker and coworkers (1) suggests that the negative results of the three nonbeneficial studies were caused by unfavorable "signal-to-noise" ratios.

We conclude that there is no evidence for harm of the lower tidal volume strategies in these studies. The odds ratios shown in Figure 3 of the analysis by Eichacker and colleagues (1) suggests an interesting hypothesis, but it is not confirmed by an individual metaanalysis.

Marcelo Amatoa, Laurent Brochardb, Thomas Stewartc and Roy Browerd

a Hospital das Clínicas—Universidade de São Paulo São Paulo, Brazil
b Service de Réanimation Médicale—Hôpital Henri Mondor—University Paris Créteil, France
c Mount Sinai Hospital University Health Network University of Toronto Toronto, Ontario, Canada
d Johns Hopkins University Baltimore, Maryland

FOOTNOTES

Conflict of Interest Statement: M.A., L.B., T.S., and R.B. have no declared conflict of interest.

REFERENCES

  1. Eichacker PQ, Gerstenberger EP, Banks SM, Cui X, Natanson C. Metaanalysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 2002;166:1510–1514.[Free Full Text]
  2. ARDSNet. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308.[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. 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. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 1998;338:355–361.[Abstract/Free Full Text]
  5. 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. The multicenter trial group on tidal volume reduction in ARDS. Am J Respir Crit Care Med 1998;158:1831–1838.[Abstract/Free Full Text]
  6. Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P Jr, Wiener CM, Teeter JG, Dodd-o 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]
 

From the Authors:

We agree with Amato and colleagues that decreasing tidal volumes in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) to 6 ml/kg predicted body weight has not been proven to be significantly "detrimental" (1). However, inspection of the two 95% confidence intervals provided by Amato and colleagues (see Figure) shows that a good portion of both reside on the side in which low tidal volumes produce increases in mortality rates. Even the "best adjusted" 95% confidence intervals suggest there is a one in three chance that low tidal volumes produce an increase in mortality rates. Therefore, this practice also has not been proven to be safe. Even in the hands of skilled pulmonologists and intensivists, such low tidal volumes often require increased levels of sedation, which has been associated with worsened outcome, and result in respiratory acidosis, which also may have adverse effects (2–6). The risks of increased sedative use and respiratory acidosis may outweigh any potential benefit of markedly decreasing tidal volumes, particularly if plateau airway pressures were not high to begin with (7–9). Before routinely decreasing tidal volumes to 6 ml/kg predicted body weight in all patients with ALI or ARDS, it should be proven in a clinical trial to be a safe practice.

Peter Q. Eichacker, Steven M. Banks and Charles Natanson

Critical Care Medicine Department National Institutes of Health Bethesda, Maryland

FOOTNOTES

Conflict of Interest Statement: P.E. has no declared conflict of interest. S.B. has no declared conflict of interest. C.N. has no declared conflict of interest.

REFERENCES

  1. Eichacker PQ, Gerstenberger EP, Banks SM, Cui X, Natanson C. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 2002;166:1510–1514.
  2. 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]
  3. 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]
  4. Feihl F, Perret C. Permissive hypercapnia: how permissive should we be? Am J Respir Crit Care Med 1994;150:1722–1737.[Medline]
  5. 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]
  6. 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]
  7. 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. The multicenter trial group on tidal volume reduction in ARDS. Am J Respir Crit Care Med 1998;158:1831–1838.
  8. 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.
  9. 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.



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