Learning Objectives: After participating in this activity, the physician should be better able to:
- Evaluate the increased incidence of sepsis.
- Analyze the latest data to determine whether to administer corticosteroids to treat septic patients.
- Examine the methodological limitations of the CORTICUS trial.
Article from the 2010 LLSA Reading List
Hydrocortisone Therapy for Patients with Septic Shock
Sprung CL, et al
N Engl J Med
It is no wonder that the American Board of Emergency Medicine picked the CORTICUS trial (Corticosteroid Therapy for Septic Shock) for our reading pleasure. The trial is perhaps the most controversial and widely discussed study in the critical care literature for the past five years. This large study was intended to end the controversy once and for all on corticosteroid use in septic patients. The authors of the study attempted to evaluate the efficacy and safety of low-dose hydrocortisone therapy in a broad population of patients with septic shock, particularly patients who responded to a corticotropin test.
The second author of the CORTICUS trial, Djillali Annane, MD, previously published a similar study showing that septic shock patients with relative adrenal insufficiency, as shown by a negative response to a corticotropin stimulation test, had a decreased 28-day mortality rate when given corticosteroids. (JAMA 2002;288:862.)
To determine whether steroids decrease mortality in a broad population with septic shock, the authors enrolled 499 adult patients in 52 participating ICUs. Inclusion criteria included clinical evidence of infection, evidence of a systemic response to infection, onset of shock within 72 hours of enrollment, and hypoperfusion or end-organ dysfunction due to sepsis. Shock was defined as a systolic blood pressure of less than 90 mm Hg despite fluid resuscitation or the need for vasopressors for at least one hour. Exclusion criteria included life expectancy of less than 24 hours, underlying disease with a poor prognosis such as widely metastatic cancer, immunosuppression, and long-term corticosteroid therapy.
Of the 499 patients enrolled, 251 patients received 50 mg intravenous hydrocortisone therapy, and 248 received placebo for 11 days. All patients in the study underwent a corticotropin stimulation test to assess for relative adrenal insufficiency. Of the 499 enrolled patients, 233 (46.7%) did not have a response to the corticotropin stimulation test while 254 (50.9%) did.
The primary endpoint of the study was mortality at 28 days in patients who did not have a response to corticotropin. Secondary endpoints included mortality in patients who had a response to corticotropin, all-cause mortality at one year, length of hospitalization, and the reversal of shock. For the primary endpoint, there was no difference in mortality between patients who received hydrocortisone or placebo (39.2% vs. 36.1%; p=0.69). Similarly in the group that responded to corticotropin, there was no difference in mortality between patients who received hydrocortisone or placebo (28.8% vs. 28.7%; p=1.00). The number of patients who had a reversal of shock was similar in both the study and placebo groups. The duration of time until reversal of shock was 3.3 days in the hydrocortisone group compared with 5.8 days in the placebo group. Finally, in the hydrocortisone group, there was an increased incidence of new infections, and new episodes of sepsis with an odds ratio of 1.37 when compared with placebo.
Based on these results, the authors conclude that the use of hydrocortisone in septic patients regardless of adrenal response to corticotropin, did not affect the mortality rate at 28 days. The proportion of patients who had reversal of shock was the same in both groups, although the time to reversal of shock was shorter in patients receiving hydrocortisone. As part of monitoring for adverse events in the trial, there was an increased incidence of hyponatremia and hypoglycemia in the hydrocortisone group. Finally, the authors conclude they cannot recommend steroids be given empirically to vasopressor responsive patients in septic shock. The paper also calls into question the usefulness of the routine ICU practice of obtaining a corticotropin stimulation test on patients admitted with septic shock.
COMMENT: The incidence of sepsis has risen dramatically from about 164,000 cases in 1979 to 660,000 cases in 2000. (N Engl J Med 2003;348: 1546.) Some of the increase can be attributed to more refined case definitions and an increased general awareness of sepsis. Interestingly, the overall severity of sepsis has increased with a dramatic rise in the number of cases due to fungal organisms. Age-adjusted rates of hospitalization for severe sepsis have increased from 66 per 100,000 population to 132 per 100,000 population over the past decade. During the same time, population-based mortality for sepsis increased from 30.3 per 100,000 population to 49.7 per 100,000 population. (Crit Care Med 2007;35:1244.) Almost 10 years ago, it was estimated that each case of sepsis cost $22,000 with an overall in-hospital mortality rate of 28 percent, figures that will continue to rise given the soaring cost of medical care and the aging population in the United States. (Crit Care Med 2001;29:1303.)
Over the past decade, numerous interventions to reverse the course of severe sepsis such as activated Protein C and early goal-directed management with invasive hemodynamic monitoring have been advocated with unsatisfying degrees of success. Although giving academia and methodology mavens much to critique in the wake of each new important study, not much has changed besides copious fluids and appropriate antibiotics.
The CORTICUS trial was widely expected to answer whether corticosteroids should be used in a wide variety of septic patients. Instead, it conflicted with the previous study by Annane (JAMA 2002;288:862) which showed improved survival and reversal of shock in corticotropin nonresponders who received corticosteroids. The CORTICUS trial authors admit that patients were much sicker in the earlier Annane study. Notably, the placebo group in the Annane trial had a much higher death rate at 28 days (61%) than the CORTICUS placebo group (32%).
In assessing the literature on this topic, the emergency physician should consider when patients were enrolled in each of these studies. In the Annane study, patients were enrolled within eight hours of study eligibility versus 72 hours for the CORTICUS trial. There has been widespread criticism of the CORTICUS trial for this unexplained delay in starting hydrocortisone after meeting inclusion criteria. That's right: These critically ill patients, who often have hour-to-hour changes in clinical course, may not have received hydrocortisone (or placebo) for up to three days after the episode that triggered enrollment. As of this writing, the authors have not reported the mean time delay from eligibility to drug administration. Without knowing how many patients were close to the 72-hour window, the results of the study have limited utility for the emergency physician. We need to know if starting steroids early on, while the patient is in the ED, will make a difference.
Another major criticism of the CORTICUS trial comes from the lack of standardization in treatment. Fluid resuscitation, monitoring of hemodynamics, and choice of antibiotic agent were not controlled and left to individual clinicians. Additionally, a fairly large proportion of patients received inappropriate antibiotics in both the hydrocortisone and placebo groups (72.8% vs. 78.8%) as determined by the study authors.
Finally, the biggest criticism of the CORTICUS trial comes from the authors themselves. Prior to initiating enrollment, they calculated 800 patients would be needed to achieve a statistical power of 80 percent to detect a 10 percent decrease in mortality. Only 500 patients were recruited. Enrollment ended prematurely due to slow recruitment, termination of funding, and expiration of study medication. The authors concluded that continued enrollment of 300 more patients would likely not show a difference, but without the extra data, this remains to be seen.
Given the results of CORTICUS, should emergency physicians give steroids to septic patients? The answer probably has not changed too much. We need an adequately powered trial looking at the benefit of very early corticosteroid therapy in patients resistant to vasopressors and intravenous fluids. Until then, corticosteroids should not be given to all patients with septic shock, but instead be reserved for patients with vasopressor and fluid resistant shock, regardless of the results of a corticotropin stimulation test.
Luis M. Lovato, MD, an Associate Professor at the David Geffen School of Medicine at UCLA, the Director of Critical Care in the Department of Emergency Medicine at Olive View-UCLA Medical Center, and an instructor for the National MegaLLSA Review Course (www.megallsa.com), serves as the medical editor of this column.
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