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University of Tennessee Health Science Center, Memphis, TN Thomas Jefferson University, Philadelphia, PA Memorial Sloan-Kettering Cancer Center, New York, NY Universite de Versailes Saint-Quentin en Yvelines, Garches, France
Correspondence to: G. Umberto Meduri, MD, FCCP, University of Tennessee Health Science Center, Division of Pulmonary Division of Pulmonary, Critical Care, and Sleep Medicine, 956 Court Ave, Room H316, Memphis, TN 38163; e-mail: umeduri{at}utmem.edu
To the Editor:
The review article by Calfee and Matthay (March 2007)1 provides an incomplete picture of the recent literature on prolonged glucocorticoid treatment in ARDS. Five randomized trials (n = 518) have been published investigating prolonged glucocorticoid (hydrocortisone, 200 to 240 mg/d; methylprednisolone, 1 mg/kg/d) treatment in early acute lung injury (ALI) [PaO2/fraction of inspired oxygen (FIO2) < 300],2 early ARDS (PaO2/FIO2 < 200),34 and unresolving ARDS (methylprednisolone, 2 mg/kg/d).56 These trials consistently reported that prolonged glucocorticoid treatment was associated with significant improvement in PaO2/FIO2,23456 and a significant reduction in markers of systemic inflammation,23456 BAL neutrophilia,67 duration of mechanical ventilation,23456 and ICU stay.2456 The magnitude of reduction in duration of mechanical ventilation (ventilator-free days) is shown in Table 1 , and is far greater than the reduction observed with the recommended low-tidal-volume ventilation8 or conservative strategy of fluid management.9
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Finally, the conclusion of the ARDS network trial6 that methylprednisolone treatment increases mortality in patients randomized after day 14 is challenged by the large imbalances in baseline characteristics (control vs methylprednisolone) in this small subgroup of patients for age (45 ± 13 years vs 52 ± 24 years), male gender (56% vs 35%), trauma (20% vs 13%), pneumonia (28% vs 44%), serum creatinine (1.0 ± 0.8 mg/dL vs 1.3 ± 1.3 mg/dL), APACHE (acute physiology and chronic health evaluation) III score (79 ± 22 vs 87 ± 25), compliance (26 ± 15 cm H2O vs 18 ± 7 cm H2O; p = 0.02), and lung injury score (2.7 ± 1.2 vs 3.7 ± 0.87; p = 0.001) [mean ± SD] that likely accounted for the uncharacteristically low mortality in the control group (8% vs 36%). These factors should be taken into consideration in analyzing the role of glucocorticoid treatment in ARDS, and should stimulate additional clinical investigation of this inexpensive and highly effective antiinflammatory therapy.
Footnotes
The authors have no conflicts of interest to disclose.
The authors have no conflicts of interest to disclose.
References
Division of Pulmonary and Critical Care Medicine, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA
Correspondence to: Carolyn S. Calfee, MD, University of California, San Francisco, Pulmonary and Critical Care Division, 505 Parnassus Ave, San Francisco, CA 94143-0130; e-mail: carolyn.calfee{at}ucsf.edu
To the Editor:
Meduri et al highlight the nature of the ongoing debate over the value of corticosteroids in acute lung injury/ARDS. The study by Confalonieri and colleagues1 was not included in our review because the study population had severe pneumonia, not ARDS. The retrospective study by Annane et al2 was a secondary analysis of a randomized controlled trial of corticosteroids in septic shock; benefit was noted in the subgroup of patients with sepsis-associated ARDS who failed to respond to a corticotropin stimulation test. The benefits of corticosteroids in this group likely derive from their beneficial effects in the overall population of nonresponders in this study rather than from an effect specific to ARDS; no statistical test of interaction between corticosteroid therapy and ARDS was reported in the article. In addition, while post hoc subgroup analysis may be useful for hypothesis generation, generalizing the findings to patient treatment can be perilous.3 The 2007 study by Meduri et al was not published at the time of our review; however, this trial4 has significant limitations as well. For one, the majority of patients randomized to placebo who remained on mechanical ventilation at day 9 of the study were crossed over to open-label methylprednisolone, making outcomes analysis after that point (such as mortality and ventilator-free days) very difficult to interpret. In our review,5 we focused on the largest and most rigorous trial on this issue: the prospective, randomized controlled trial performed by the ARDS Network, which demonstrated no mortality benefit to corticosteroids.6 We agree that the size of the subgroup of patients randomized after day 14 in this study is small, and that conclusions drawn from this subgroup, albeit a prespecified one, should be tempered by this consideration; however, most of the baseline imbalances cited by the letter were not statistically significant.
We also question the validity of the authors’ approach of pooling data from the five studies cited in their letter. Since the trials did not have similar inclusion criteria (ie, ARDS vs pneumonia, early vs late ARDS), they would be poor candidates for a traditional metaanalysis.7 Moreover, the authors do not describe their meta-analysis methods (ie, fixed vs random-effects model, statistical tests for heterogeneity). For these reasons, we also disagree with their calculation of a number needed to treat based on this data. The heterogeneity of prior studies was a primary driving force behind the creation of the ARDS Network’s large randomized controlled trial, which has rendered the most definitive verdict in this field.
References
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