© 2005 American Thoracic Society
"Stop Right There...I Gotta Know Right Now!" Do Steroids Really Help for CAP?From the Authors:The letter from Dr. Scales and colleagues includes many perceptive observations on the imbalance between treated and control groups at study entry (1). We do agree with most of the observations, but should clarify that the PaO2:FIO2 ratio and chest radiograph score reported at study entry were obtained prior to instituting mechanical ventilation and, therefore, were not affected by the application of PEEP. In the discussion section of the paper, we included a review of potential imbalances, including preexisting comorbidities and mechanical ventilation, and underscored additional limitations of this study. The purpose of our study was to evaluate the effect of hydrocortisone infusion on organ dysfunction associated with pulmonary and systemic inflammation. Reduction in mortality was not the primary endpoint of the study and was not used to terminate the study. The study tested (1) a pathophysiologic model that placed dysregulated inflammation at the core of severe sepsis caused by community-acquired pneumonia, and (2) the effect of anti-inflammatory treatment on biological and physiological responses related to inflammation (2). The surrogate markers for pulmonary and systemic inflammation included PaO2:FIO2 ratio and chest radiograph score, C-reactive protein levels, septic shock, and multiple organ dysfunction syndrome (MODS). Dr. Scales and colleagues note the relationship between improvement in PaO2:FIO2 and mortality in three recent randomized trials that investigated a pharmacologic intervention (3) and two ventilatory strategies (4, 5) in patients with ARDS. In the first two studies, improvement in gas exchange was not associated with improvement in other relevant clinical parameters, such as duration of mechanical ventilation or resolution of MODS. In these studies, the intervention affected the functional consequences of the disease (hypoxemia) but did not significantly affect its core pathogenetic process (inflammation). The ARDS Network study (6), similar to prior reports (2), found that severity of inflammation (plasma interleukin-6, interleukin-8, and interleukin-10) in the first three days of the study predicted a poor outcome. The lower tidal volume strategy was associated with significant attenuation of inflammation, more pulmonary and nonpulmonary organ failure-free days, and a 9% absolute reduction in mortality despite a lower PaO2:FIO2 ratio in the first 3 days of the study. In our study, a progressive increase in PaO2:FIO2 ratio was observed throughout hydrocortisone infusion and was associated with increased ventilator-free days; these findings are similar to those we reported in patients with unresolving ARDS (7) and the NIH ARDS Network Late Steroid Rescue Study (data presented at the 2005 Society of Critical Care meeting in Phoenix, AZ) (6). Most important, both ARDS trials showed that earlier introduction of prolonged corticosteroid treatment was associated with improved results, indicating that early intervention is more likely to be effective. In our study, introducing hydrocortisone early in severe community-acquired pneumonia accelerated clinical resolution and prevented development of sepsis-related complications. Finally, Dr. Scales and colleagues refer to an excellent study from the Canadian Critical Care Trials Group evaluating 1-year outcomes of ARDS (8). In this study, treatment with corticosteroids during ICU admission was associated, in a multivariate regression analysis, with shorter distance walked at 3 months. This association was not observed at 6 and 12 months. Although the criteria for corticosteroid use, dose, and duration were not described, it is likely that the sickest patients in the study received corticosteroids. The only factor associated with improved performance at 12 months was rapid resolution of lung injury and MODS scores. In our study, hydrocortisone treatment was associated with rapid resolution of pulmonary and extrapulmonary organ dysfunction and a reduction in complications. We believe that our study supports the original hypothesis. We continue to believe that a larger trial of hydrocortisone therapy in severe community-acquired pneumonia, incorporating the suggestions made in the discussion section of our study, should be conducted to address mortality as a primary aim.
a University of Tennessee Health Science Center, Memphis, Tennessee FOOTNOTES Conflict of Interest Statement: G.U.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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