Insulin therapy in the intensive care unit should be targeted to maintain blood glucose between 4.4 mmol/l and 6.1 mmol/l

Hyperglycaemia has been repeatedly associated with risk of mortality and morbidity in the intensive care unit (ICU). However, establishing a causal relationship between hyperglycaemia and adverse outcome requires randomised controlled trials assessing the impact of treating/preventing hyperglycaemia in this condition. The only two randomised controlled studies that have addressed this question so far targeted normoglycaemia (4.4–6.1 mmol/l) in ICUs and showed that the link indeed appears causal. The evidence currently available is thus in favour of a ‘normal ≤6.1 mmol/l’ level for blood glucose control in ICUs and is not supportive of J. Miles’s viewpoint in this debate [1], as studies on any other level have not been performed. The first randomised controlled trial from Leuven included adult patients admitted to ICU after extensive, complicated surgery or trauma, or after medical complications of major surgical procedures [2]. In the intervention group, glucose levels were targeted to 4.4–6.1 mmol/l with a continuous intravenous insulin infusion, resulting in average blood glucose levels of 5.5 mmol/l (normoglycaemia). The control group was treated ‘conventionally’ (only insulin for hyperglycaemia >11.2 mmol/l) and had average blood glucose levels of 8.8 mmol/l. At the start of the study, there were no data available on the size of the expected benefit, and thus interim analysis was performed for safety reasons. The study was stopped after inclusion of 1,548 patients. In the intention-to-treat (ITT) population, the intervention lowered ICU mortality rate from 8.0 to 4.6% [absolute risk reduction (ARR) 3.4%] and in-hospital mortality rate from 10.9 to 7.2% (ARR 3.7%). The benefit was larger in the target population of long-stay patients, with a reduction of ICUmortality rate from 20.2 to 10.6% (ARR 9.6%) and of in-hospital mortality rate from 26.3 to 16.8% (ARR 9.5%). In retrospect, it appeared indeed that the impact of the intervention increased with the duration of its application and that there was a substantial benefit clearly present from 3 days of intensive insulin therapy onwards. Besides saving lives, maintaining normoglycaemia prevented organ failure and shortened time on the ventilator and in the ICU. Maintaining normoglycaemia protected the central and peripheral nervous system and improved longterm rehabilitation of patients with brain injury [3], and evoked substantial cost-savings [4]. A 4 year follow-up of the cardiac surgery patients showed that it also improved long-term outcome with maintenance of the survival rate benefit without inducing additional need for medical care [5]. Subsequently, an observational study in a heterogeneous medical/surgical patient population (n=1,600) confirmed the clinical and cost-saving impact of a tight glucose management protocol in ‘real life’ intensive care [6, 7]. Thereafter, two multi-centre randomised controlled trials were started, but stopped early. The first one was designed as a four-arm study to assess the impact of two types of Diabetologia (2008) 51:911–915 DOI 10.1007/s00125-007-0878-7