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Correspondence |

Corticosteroids in ARDSResponse: A Counterpoint FREE TO VIEW

G. Umberto Meduri, MD, FCCP; Paul E. Marik, MD, FCCP; Stephen M. Pastores, MD, FCCP; Djillali Annane, MD, PhD
Author and Funding Information

Affiliations: 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,  Division of Pulmonary and Critical Care Medicine, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA

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@utmem.edu



Chest. 2007;132(3):1093-1094. doi:10.1378/chest.07-0714
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Published online

The review article by Calfee and Matthay (March 2007)1provides 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),4 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,,26 and a significant reduction in markers of systemic inflammation,26 BAL neutrophilia,67 duration of mechanical ventilation,26 and ICU stay.2,46 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 ventilation,8or conservative strategy of fluid management.9

Overall, glucocorticoid treatment appears most effective when started at a lower dosage (1 mg/kg/d) early in the course of ALI-ARDS.2,4 Mortality is overall improved with prolonged glucocorticoid treatment (91 of 276 patients; 33%; vs 111 of 242 patients; 46%; relative risk [RR], 0.76; 95% confidence interval [CI], 0.62 to 0.93; p = 0.007), and the benefits are more significant when treatment is initiated before day 14 of ARDS (84 of 252 patients; 33%; vs 108 of 216 patients; 50%; RR, 0.71; 95% CI, 0.50 to 0.87; p = 0.001). The mortality benefit with glucocorticoid treatment is greater than the benefit observed with low-tidal-volume ventilation (9%),8 with number needed to treat to save one life of 6 for treatment initiated before day 14.

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.

The authors have no conflicts of interest to disclose.

Table Graphic Jump Location
Table 1. Effect of Glucocorticoid Treatment on Ventilator-Free Days to Day 28*
* 

Data are presented as mean ± SD.

 

NHLBI ARDS = National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network.

The authors have no conflicts of interest to disclose.

Calfee, CS, Matthay, M (2007) Nonventilatory treatment for acute lung injury and ARDS.Chest131,913-920. [PubMed] [CrossRef]
 
Confalonieri, M, Urbino, R, Potena, A, et al Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study.Am J Respir Crit Care Med2005;171,242-248. [PubMed]
 
Annane, D, Sebille, V, Bellissant, E Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome.Crit Care Med2006;34,22-30. [PubMed]
 
Meduri, GU, Golden, E, Freire, AX, et al Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial.Chest2007;131,954-963. [PubMed]
 
Meduri, GU, Headley, S, Golden, E, et al Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial.JAMA1998;280,159-165. [PubMed]
 
The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.N Engl J Med2006;354,1671-1684. [PubMed]
 
Sinclair, S, Bijoy, J, Golden, E, et al Interleukin-8 and soluble intercellular adhesion molecule-1 during acute respiratory distress syndrome and in response to prolonged methylprednisolone Treatment.Minerva Pneumologica2006;45,93-104
 
Bower, G, Matthay, M Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome: the Acute Respiratory Distress Syndrome Network.N Engl J Med2000;342,1301-1308. [PubMed]
 
Wiedemann, HP, Wheeler, AP, Bernard, GR, et al Comparison of two fluid-management strategies in acute lung injury.N Engl J Med2006;354,2564-2575. [PubMed]
 
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 colleagues1was not included in our review because the study population had severe pneumonia, not ARDS. The retrospective study by Annane et al2was 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 trial4has 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,5we 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
Confalonieri, M, Urbino, R, Potena, A, et al Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study.Am J Respir Crit Care Med2005;171,242-248. [PubMed]
 
Annane, D, Sebille, V, Bellissant, E Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome.Crit Care Med2006;34,22-30. [PubMed] [CrossRef]
 
Assmann, SF, Pocock, SJ, Enos, LE, et al Subgroup analysis and other (mis)uses of baseline data in clinical trials.Lancet2000;355,1064-1069. [PubMed]
 
Meduri, GU, Golden, E, Freire, AX, et al Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial.Chest2007;131,954-963. [PubMed]
 
Calfee, CS, Matthay, MA Non-ventilatory management of acute lung injury and the acute respiratory distress syndrome.Chest2007;131,913-920. [PubMed]
 
The Acute Respiratory Distress Syndrome Network.. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.N Engl J Med2006;354,1671-1684. [PubMed]
 
Bent, S, Shojania, KG, Saint, S The use of systematic reviews and meta-analyses in infection control and hospital epidemiology.Am J Infect Control2004;32,246-254. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Effect of Glucocorticoid Treatment on Ventilator-Free Days to Day 28*
* 

Data are presented as mean ± SD.

 

NHLBI ARDS = National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network.

References

Calfee, CS, Matthay, M (2007) Nonventilatory treatment for acute lung injury and ARDS.Chest131,913-920. [PubMed] [CrossRef]
 
Confalonieri, M, Urbino, R, Potena, A, et al Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study.Am J Respir Crit Care Med2005;171,242-248. [PubMed]
 
Annane, D, Sebille, V, Bellissant, E Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome.Crit Care Med2006;34,22-30. [PubMed]
 
Meduri, GU, Golden, E, Freire, AX, et al Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial.Chest2007;131,954-963. [PubMed]
 
Meduri, GU, Headley, S, Golden, E, et al Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial.JAMA1998;280,159-165. [PubMed]
 
The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.N Engl J Med2006;354,1671-1684. [PubMed]
 
Sinclair, S, Bijoy, J, Golden, E, et al Interleukin-8 and soluble intercellular adhesion molecule-1 during acute respiratory distress syndrome and in response to prolonged methylprednisolone Treatment.Minerva Pneumologica2006;45,93-104
 
Bower, G, Matthay, M Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome: the Acute Respiratory Distress Syndrome Network.N Engl J Med2000;342,1301-1308. [PubMed]
 
Wiedemann, HP, Wheeler, AP, Bernard, GR, et al Comparison of two fluid-management strategies in acute lung injury.N Engl J Med2006;354,2564-2575. [PubMed]
 
Confalonieri, M, Urbino, R, Potena, A, et al Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study.Am J Respir Crit Care Med2005;171,242-248. [PubMed]
 
Annane, D, Sebille, V, Bellissant, E Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome.Crit Care Med2006;34,22-30. [PubMed] [CrossRef]
 
Assmann, SF, Pocock, SJ, Enos, LE, et al Subgroup analysis and other (mis)uses of baseline data in clinical trials.Lancet2000;355,1064-1069. [PubMed]
 
Meduri, GU, Golden, E, Freire, AX, et al Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial.Chest2007;131,954-963. [PubMed]
 
Calfee, CS, Matthay, MA Non-ventilatory management of acute lung injury and the acute respiratory distress syndrome.Chest2007;131,913-920. [PubMed]
 
The Acute Respiratory Distress Syndrome Network.. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.N Engl J Med2006;354,1671-1684. [PubMed]
 
Bent, S, Shojania, KG, Saint, S The use of systematic reviews and meta-analyses in infection control and hospital epidemiology.Am J Infect Control2004;32,246-254. [PubMed]
 
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