No additional benefit of intensive insulin therapy in patients treated with hydrocortisone for septic shock

Patients with septic shock who received intensive insulin therapy to counteract elevated blood glucose levels with corticosteroid therapy did not have a reduced risk for in-hospital mortality compared with patients who received conventional insulin therapy, according to data published in JAMA.

Moreover, researchers reported that adding a second corticosteroid treatment — oral fludrocortisone — did not significantly reduce the risk for in-hospital mortality.

Researchers for the randomized, controlled Corticosteroids and Intensive Insulin Therapy for Septic Shock (COIITSS) trial assessed the efficacy of intensive insulin therapy (n=255) vs. conventional insulin therapy (n=245) in adults with septic shock treated with hydrocortisone 50 mg every six hours. Researchers further assessed the additional benefit of oral fludrocortisones 50 mcg once-daily for one week.

All patients presented with septic shock and multiple organ dysfunction (defined as sequential organ failure assessment score of >8) and received treatment from January 2006 to January 2009 at 11 ICUs in France.

The researchers randomly assigned patients to one of four groups: continuous IV insulin infusion with hydrocortisone alone; continuous IV insulin infusion with hydrocortisone plus fludrocortisones; conventional insulin therapy with hydrocortisone alone; or conventional insulin therapy with IV hydrocortisone plus fludrocortisone.

At hospital discharge, 117 of 255 patients (45.9%) assigned to intensive insulin therapy and 109 of 254 patients (42.9%) assigned to conventional insulin therapy died (RR=1.07; 95% CI, 0.88-1.30).

In addition, those assigned to intensive insulin therapy experienced significantly more episodes of severe hypoglycemia (<40 mg/dL) when compared with those assigned to conventional insulin therapy — the difference in mean number of episodes per patient was 0.15 (95% CI, 0.02-0.28).

The researchers reported no significant between-group differences in secondary outcomes such as number of days that surviving patients spent in the ICU, overall length of hospital stay, vasopressor-free days and mechanical ventilation-free days.

When fludrocortisone was added, 42.9% of patients who received additional treatment with fludrocortisone and 45.8% of patients who received conventional insulin therapy died (RR=0.94; 95% CI, 0.77-1.14).

“No significant difference in overall mortality existed between the fludrocortisone-treated patients and controls. Nor did significant differences exist between the two groups for the survivors’ ICU and hospital lengths of stay, for the number of vasopressor-free days and for mechanical ventilation-free days,” the researchers wrote.

They concluded that the current data provide “no evidence to support a strategy of intensive insulin therapy aimed at maintaining blood glucose levels in the range of 80 mg/dL to 110 mg/dL for treating septic shock with corticosteroids.” Further, these results “do not support the routine use of oral fludrocortisone in addition to hydrocortisone when physicians decide to introduce corticosteroids in the management of a patient with septic shock.”

In an accompanying editorial, Greet Van den Berghe, MD, PhD, of Catholic University of Leuven, Belgium, said larger trials regarding the treatment of septic shock are needed.

“Precedent for large-scale international cooperation exists in oncology and cardiology. Given the huge global burden of conditions such as septic shock, which causes hundreds of thousands of deaths in the United States alone each year, international collaboration should and must be achievable,” Van den Berghe said.

“The COIITSS trial results may thus suggest that clinicians should titrate insulin to a blood glucose level of approximately 145 mg/dL in patients with hydrocortisone–treated septic shock, thereby avoiding hypoglycemia,” Van den Berghe said. “However, such a conclusion requires careful consideration of the statistical power of the trial.” – by Jennifer Southall

The COIITSS Study Investigators. JAMA. 2010;303:341-348.

Van den Berghe G. JAMA. 2010;303:341-348.