Key Point

Researchers outlined the advantages and disadvantages of using corticosteroids to treat septic shock at the Society of Critical Care Medicine’s 37th Critical Care Congress.

HONOLULU—In a pro–con debate at the Society of Critical Care Medicine’s 37th Critical Care Congress, Djillali Annane, MD, PhD, defended the use of corticosteroids in septic shock treatment. He said that steroids provide several important benefits, especially for the most severely ill patients. Dr. Annane’s opponent in the debate was Charles L. Sprung, MD. Drs. Sprung and Annane were coauthors of a study published earlier this year in the New England Journal of Medicine reporting the results of the Corticosteroid Therapy of Septic Shock (CORTICUS) study.

“In the CORTICUS trial, it was obvious that the use of corticosteroids resulted in a shortening of the duration of shock,” pointed out Dr. Annane, Professor in the Section of Critical Care Medicine at the University of Versailles Saint Quentin in Garches, France. In addition, when the results of all randomized controlled trials of low-dose corticosteroids in septic shock are combined, he said, these trials show a nearly 40% increase in the likelihood of stopping vasopressor therapy and of the reversal of shock after one week.

IMPROVES IMMUNE RESPONSE

Corticosteroid therapy has demonstrated positive effects on the immune response of septic shock patients at one week, added Dr. Annane. These effects included down-regulation of all proinflammatory cytokines in the serum and tissues.

“This is also true for the late inflammatory mediators, such as macrophage migration inhibitory factor,” Dr. Annane said. Interestingly, he noted, hydrocortisone does not appear to produce immune suppression, at least when measured by levels of interleukin 10 or by tumor necrosis factor α–receptor down-regulation.

The positive hemodynamic and immune system responses of septic shock patients taking corticosteroids translate into favorable effects on organ dysfunction. “There is more rapid resolution of organ dysfunction,” explained Dr. Annane. This effect was observed in the CORTICUS trial and in several other studies, including a well-known French trial completed in the mid-1990s.

Other favorable outcomes associated with corticosteroids in the CORTICUS trial included more rapid extubation and, in meta-analyses of randomized controlled trials, improved survival. There was no heterogeneity across the studies in the meta-analyses, indicating that all of the studies had consistent findings.

MOST BENEFICIAL TO THE SICKEST OF PATIENTS

“In the CORTICUS trial, there was no significant difference between the steroid and placebo groups,” acknowledged Dr. Annane. This may be due in part to several factors: The CORTICUS trial was not very large (251 patients with septic shock in the treatment group and 248 in the placebo group), and acuity was relatively low overall, making it less likely that the trial would find corticosteroids beneficial.

However, there was a subgroup of the sickest patients in the CORTICUS trial that mimicked the patients in an earlier French trial. Similar to the results of the French trial, analysis of this subgroup associated placebo with a 54% mortality rate and corticosteroids with a 10% absolute mortality reduction. Thus, corticosteroid treatment appears most likely to be effective in treating the sickest septic shock patients.

Importantly, among septic shock patients, there were no differences between steroids and placebo in the rates of catheter-related superinfection (relative risk [RR], 0.99), lung infection (RR, 1.12), gastrointestinal infection (RR, 1.15), and a variety of other types of infection, Dr. Annane claimed. “What is different is the percentage of patients who have new septic shock or repeat shock,” he said. That percentage is somewhat higher among corticosteroid recipients (RR, 2.78 and 1.25, respectively).

After a 2002 study by Dr. Annane and colleagues, there has been increased interest in adding fludrocortisone to hydrocortisone for septic shock. In the study, this combination improved 28-day survival by 33% compared with placebo in septic shock patients with relative adrenal insufficiency, but a direct comparison with hydrocortisone alone was not made. Further evaluation of the fludrocortisone/hydrocortisone combination is under way in US and French trials, and the results of these investigations are expected in about two years, said Dr. Annane.

ROUTINE USE NOT RECOMMENDED

“I have been a believer in the use of steroids every time I started a trial,” admitted Dr. Sprung, Professor in the Department of Anesthesiology and Critical Care Medicine at the Hadassah University Hospital in Ein-Karem, Jerusalem. “But then the data show that steroids do not work.”

Dr. Sprung pointed out that the results of Dr. Annane’s 2002 trial did much to encourage practitioners to use corticosteroids in septic shock. “But as Dr. Annane said, these were patients in refractory shock,” Dr. Sprung observed, “and it is necessary to look at the single most important criteria used in that study—a systolic blood pressure of less than 90 for more than an hour despite fluid and vasopressor therapy. I do not know about you, but it rarely happens that I cannot raise a patient’s blood pressure after an hour of aggressive fluid resuscitation and vasopressor therapy.”

Furthermore, the trial only showed a trend toward a benefit from corticosteroids with regard to 28-day mortality among corticotropin test nonresponders. “However, that was not their end point,” Dr. Sprung remarked. “They were looking at 28-day survival.”

But while survival was shown to be greater among steroid-treated patients, “that was pretty much driven by the 77% of patients who were nonresponders,” said Dr. Sprung. “If you look at the responders, you can see that the placebo group does better. So should you be using it for responders? Maybe not, even in refractory shock.”

The CORTICUS data did not support corticosteroid use in septic shock, either, he maintained. These data showed no overall difference in 28-day mortality between corticosteroid and placebo recipients. This finding applied to corticotropin test responders and to the patient group of primary interest—nonresponders—who, if anything, showed slightly higher mortality when treated with corticosteroids, related Dr. Sprung.

Clearly, shock reversal (not improved survival) is the main reason that clinicians give corticosteroids in septic shock. Reversal occurs in approximately 80% of septic shock patients after steroid delivery.

“But if you wait before giving treatment, 74% of patients who do not receive steroids also experience reversal of shock,” Dr. Sprung stressed. “Placebo is very effective at reversing shock,” he quipped.

Dr. Sprung conceded that septic shock patients generally can be taken off vasopressor therapy about 2.5 days sooner when treated with corticosteroids than when they are not. But the benefit of corticosteroid use does not offset the increased mortality likely to result from a higher incidence of steroid-related new sepsis (RR, 2.97), septic shock, and overall superinfection (RR, 1.27), he argued.

He reiterated the advice of the CORTICUS Study Group—that hydrocortisone cannot be recommended as routine adjuvant therapy for septic shock. “You all did not see that recommendation, I guess, because you are all still using steroids,” Dr. Sprung said in jest to the clinicians in the audience, many of whom had indicated previously by a show of hand using steroids in septic shock.

In addition, Dr. Sprung cited the revised Surviving Sepsis guidelines from Dellinger et al that “suggest intravenous hydrocortisone be given only to adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy.” He asserted that the only group of septic shock patients in which corticosteroids may have a role is the group with refractory shock—as indicated by hypotension that persists for more than one hour despite high-dose vasopressor therapy and fluid resuscitation.

If hydrocortisone were being submitted to the FDA as a septic shock therapy, it is unlikely that the FDA would ever approve it, based on the available data, speculated Dr. Sprung. “So if the FDA would never approve it, why are you all using it?” he asked.

—Timothy Begany

Suggested Reading
Dellinger RP, Levy MN, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for the management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327.
Sprung CL, Annane D, Keh D, et al, for the CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124.

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