Saturday May 3, 2008
Steroids in sepsis controversy - what 'Guru' thinks !
Here is a very well rounded commentary on steroids in sepsis from internationally famed Critical Care master Dr. Jean-Louis Vincent. We are just posting important points from commentary due to space constrain. You can read full text with references by clicking at link below:
"............Forty years ago, high-dose steroids were used in the belief that, because sepsis is an inflammatory response, the anti-inflammatory properties of steroids could be useful. Initial studies were encouraging, with Schumer demonstrating that treatment with one or two doses of intravenous dexamethasone (3 mg/kg) or methylprednisolone (30 mg/kg) was associated with reduced mortality compared with saline treatment in patients with septic shock. Two large, double-blind, randomized controlled trials later failed to confirm these findings, however, and two meta-analyses in the mid 1990s concluded that steroids were ineffective or indeed were potentially harmful in sepsis.
Then, in the late 1990s, several studies were published suggesting a role for much smaller, so-called stress, doses of steroids in reducing vasopressor requirements in patients with septic shock. These results led to a study by Annane and colleagues in which patients with relative adrenal insufficiency – as assessed by nonresponse to a corticotropin test – who were treated with hydrocortisone (50 mg intravenously every 6 hours) and fludrocortisone (50 μg orally daily) for 7 days had a reduced mortality compared with nonresponders treated with placebo. Despite concerns regarding the lack of statistical significance in overall mortality rates at 28 days, the results from this study led to steroids being recommended in the treatment of patients with septic shock. Steroid use was also incorporated into the so-called sepsis bundles, with the recommendation that all patients with septic shock should receive low-dose corticosteroids within 24 hours of diagnosis.
Doubts remained, however, and a large, international, multicenter study was conducted to confirm the results of the earlier study. The Corticus – Corticosteroid Therapy of Septic Shock – study, which included close to 500 patients, recently showed that hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not respond to a corticotropin test. The results from the Corticus study were somewhat disappointing, and, in the accompanying editorial, Dr Finfer suggested the need for a further study to explore the effects of steroids in septic shock in a much larger population. With no signal from the Corticus study, however, merely increasing the size of the study is unlikely to show mortality differences.
Importantly, apart from the differences in effects on outcome, there were other notable differences between the Corticus study and Annane and colleagues' study, including the larger number of postoperative patients, the more common abdominal source of the sepsis, and, in particular, the lower severity of illness in the Corticus study. This latter factor is particularly important and can be explained by the fact that many patients with severe septic shock were treated with steroids in accordance with guidelines current at the time of the study, and hence were excluded from enrollment – so the included population, by definition, consisted of less severely ill patients. As a result of this lower severity of illness, the mortality rate in the Corticus study was about one-half that of Annane and colleagues' study. It is therefore still possible that steroids may decrease mortality in very ill patients, just not in those with moderately severe shock.
Similar observations were made with activated protein C, another adjunct therapy for sepsis, which was shown to reduce mortality in very ill patients but not in those patients with a lower risk of death. I believe we do need another trial of steroids in sepsis, but specifically in patients with severe septic shock rather than just in a larger general population of septic shock patients.
...................Perhaps the time has come to take a step back and reflect on past efforts so that future clinical trials will be conducted in an optimal manner to limit the pendulum effect and to provide results that stand up to scrutiny and can be immediately introduced into clinical practice to the benefit of our patients."
Reference: Steroids in sepsis: another swing of the pendulum in our clinical trials, Jean-Louis Vincent, Department of Intensive Care, Université libre de Bruxelles, Erasme Hospital, Brussels, Belgium, Critical Care 2008, 12:141
