Therapy Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial
This review may be edited
Summary
Posted By:	Elizabeth Sweetman
E-Mail:	easweetm@nsccahs.health.nsw.gov.au
Posted Date:	27/04/10
Title:	Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial
Authors:	COIITSS Study Investigators
Reference:	JAMA. 2010 Jan 27;303(4):341-8
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	CONTEXT: Corticosteroid therapy induces potentially detrimental hyperglycemia in septic shock. In addition, the benefit of adding fludrocortisone in this setting is unclear. OBJECTIVES: To test the efficacy of intensive insulin therapy in patients whose septic shock was treated with hydrocortisone and to assess, as a secondary objective, the benefit of fludrocortisone. DESIGN, SETTING, AND PATIENTS: A multicenter, 2 x 2 factorial, randomized trial, involving 509 adults with septic shock who presented with multiple organ dysfunction, as defined by a Sequential Organ Failure Assessment score of 8 or more, and who had received hydrocortisone treatment was conducted from January 2006 to January 2009 in 11 intensive care units in France. INTERVENTIONS: Patients were randomly assigned to 1 of 4 groups: continuous intravenous insulin infusion with hydrocortisone alone, continuous intravenous insulin infusion with hydrocortisone plus fludrocortisone, conventional insulin therapy with hydrocortisone alone, or conventional insulin therapy with intravenous hydrocortisone plus fludrocortisone. Hydrocortisone was administered in a 50-mg bolus every 6 hours, and fludrocortisone was administered orally in 50-microg tablets once a day, each for 7 days. MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: Of the 255 patients treated with intensive insulin, 117 (45.9%), and 109 of 254 (42.9%) treated with conventional insulin therapy died (relative risk [RR], 1.07; 95% confidence interval [CI], 0.88-1.30; P = .50). Patients treated with intensive insulin experienced significantly more episodes of severe hypoglycemia (<40 mg/dL) than those in the conventional-treatment group, with a difference in mean number of episodes per patient of 0.15 (95% CI, 0.02-0.28; P = .003). At hospital discharge, 105 of 245 patients treated with fludrocortisone (42.9%) died and 121 of 264 (45.8%) in the control group died (RR, 0.94; 95% CI, 0.77-1.14; P = .50). CONCLUSIONS: Compared with conventional insulin therapy, intensive insulin therapy did not improve in-hospital mortality among patients who were treated with hydrocortisone for septic shock. The addition of oral fludrocortisone did not result in a statistically significant improvement in in-hospital mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00320099.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Allocation concealment was maintained by a centralised secure website. Study patients were randomly allocated to receive 1 of the 4 following treatment combinations; 1. Intensive insulin treatment + Hydrocortisone 2. Intensive insulin treatment + Hydrocortisone and Fludrocortisone 3. Conventional glucose control + Hydrocortisone 4. Conventional glucose control + Hydrocortisone and Fludrocortisone
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Yes all patients entered into this RCT were accounted for in the study results. The statistical analysis was conducted according to the intention to treat and no study participants were excluded from the analysis.
2b. Were patients analyzed in the groups to which they were randomized?
	Yes. As this is a 2x2 factorial trial (comparing intensive insulin therapy vs conventional blood glucose control and as a secondary objective hydrocortisone vs hydrocortisone + fludrocortisone) and no evidence of significant interaction (P=0.31) existed between Insulin and Fludrocortisone, the two comparison groups were analyzed separately (see the results section of this paper).
3. Were patients, health workers, and study personnel blind to treatment?
	Physicians and nurses were not blinded when administering fludrocortisone (p. 347). The authors did not mention blinding of intervention and/or outcomes in the Glucose control study.
4. Were the groups similar at the start of the trial?
	Yes (Baseline characteristics presented in Table 1, page 343).
5. Aside from the experimental intervention, were the groups treated equally?
	Not sure about this. Aside from the baseline characteristics table they don't present a table of the other therapies that the patients receive during the conduct of the trial.
What are the Results?
1. How large was the treatment effect?
	Glucose Control Trial Primary Outcome - In hospital mortality (or day 90 Mortality, which ever occurred first) Result: No significant difference in hospital death rates between Intensive Insulin vs Conventional Glucose Control (45.9% vs 42.9%, adjusted P = 0.37(3% Rate Difference, 95% CI -5.6% to 11.6%). Fludrocortisone Trial Primary Outcome - In hospital mortality (or day 90 Mortality, which ever occurred first) Result: No significant difference in hospital death rates between Fludrocortisone vs control (42.9% vs 45.8%, adjusted P = .91 (-2.9 Rate Difference, 95% CI -11.5% to 5.7%).
2. How precise was the estimate of the treatment effect?
	See above for 95% Confidence Intervals around the absolute risk differences.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	The 95% confidence intervals around the treatment effects do not rule out meaningful benefits for any comparison groups.
2. Were all clinically important outcomes considered?
	Yes. They considered in hospital or 90 day mortality whichever occured first. Secondary outcomes included Day 28, 90, 180, number of vasopressor and mechanical ventilation free days, ICU and hospital length of stay.
3. Are the likely treatment benefits worth the potential harms and costs?
	Not sure. Confidence intervals are too wide however the harm observed with the NICE trial is consistent with the IIT results.
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