Therapy Intensive Insulin Therapy in Critically ill Patients
This review may be edited
Summary
Posted By:	Anthony Delaney
E-Mail:	drtoze@hotmail.com
Posted Date:	13/12/01
Title:	Intensive Insulin Therapy in Critically ill Patients
Authors:	Van den Berghe G, Wouters P, Weekers F et al.
Reference:	N Engl J Med 2001;345:1359-1367
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	Background:- Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. Methods:- We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter and maintenance of glucose at a level between 180 and 200 mg per deciliter). Results:- At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy; P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care. Conclusions:- Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes, the authors relate the use of sealed envelopes and the patients were stratified for the type of critical illness and balanced in permuted blocks of 10.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Yes, follow up data is presented for all patients through until hospital discharge.
2b. Were patients analyzed in the groups to which they were randomized?
	Yes, the authors state that “all analyses were performed on an intention to treat basis” which means that patients were analyzed in the groups to which they were randomized.
3. Were patients, health workers, and study personnel blind to treatment?
	No. Blinding was not possible for the clinician at the bedside however, nursing staff adjusted the insulin according to a strict algorithm with help if needed from a non-treating clinician. Laboratory staff measuring BSL, EMG electrophysiologist and the pathologists were blinded to treatment allocation
4. Were the groups similar at the start of the trial?
	Unknown! The authors state that “ the clinical and demographic characteristics of the treatment groups were similar at randomisation.” However the Apache II score and TISS scores are presented for the first 24 and 48 hours, which is after the trial interventions have commenced, so it is not possible to conclude that the groups were really equal before the interventions commenced. Furthermore, although the trialist state that randomization was "stratified based on type of critical illness (Table 1)", it is possible that there was an imbalance in patients who were admitted to the trial with "abdominal surgery or peritonitis" (58 in the control arm and 45 in the treatment arm).
5. Aside from the experimental intervention, were the groups treated equally?
	Perhaps. It is impossible to ascertain what the feeding regimes were with regards to the relative contributions of parenteral v’s enteral nutrition in each of the arms of the sudy. The treatment group received less antibiotic therapy, than the control group, which may have been due to the beneficial effect of the therapy.
What are the Results?
1. How large was the treatment effect?
	For the primary outcome measure ICU mortality: control 8.0% v’s treatment 4.6% Relative risk reduction 42.5% Absolute risk reduction 3.4% NNT = 29 The authors also report a number of secondary outcome meausres:- Patients who spent >5 days in ICU: control 20.2% v’s treatment 10.6% Death from MSOF with proven septic focus: 33 v’s 8 patients In hospital mortality all patients: control 10.9% v’s treatment 7.2% In hospital mortality for patients who spent >5 days ICU: 26.3% v’s treatment 16.8%.
2. How precise was the estimate of the treatment effect?
	The “apparent” risk reduction is 42% with 95% confidence intervals from 22-62% The median unbiased estimate of mortality 32% 95% confidence intervals 2-55% Absolute risk reduction is 3.4% with 95% confidence interval 1-6%
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	Qualified Yes. The inclusion criteria were quite wide. The patients included a large percentage of cardiac surgical patients, and the overall APACHE scores were relatively low. The feeding protocol was not specified, so may be different to local protocols.
2. Were all clinically important outcomes considered?
	There were some outcomes that were not reported, including the nursingtime and input into making the protocol safe, the relative use of parenteral nutritition in the two groups. Hypoglycaemia occurred in 39 patients in the treatment group, 2 of whom were symptomatic, with no reports of adverse sequelae, v’s 6 in the control group Lots of morbidity data of various sorts was collected and reported including indices of cardiac, renal, respiratory and neuromuscular failure.
3. Are the likely treatment benefits worth the potential harms and costs?
	Benefits include:- lower mortality, less need for prolonged ventilatory support, fewer episodes of septicaemia (7.8 v 4.2),less need for RRT (8.2 v 4.8%), less CIP (51.9% v 28.7%),less patients with a prolonged stay in the ICU. Costs include:-risk of hypoglycaemia, need for increased blood tests, drain on nursing time,? need for a strict feeding regime If the results are able to be reproduced in a general ICU population this seems like a simple, ? cheap, ? easy to administer therapy that offers some potential benefits to our patients.
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