Tight glycemic control in acutely ill patients: low evidence of benefit, high evidence of harm!

In 1878 Claude Bernard described hyperglycemia during hemorrhagic shock [1]. It is now well known that acute illness or injury may result in hyperglycemia, insulin resistance, and glucose intolerance, collectively termed stress hyperglycemia [2]. Stress hyperglycemia is an evolutionarily preserved adaptive response which provides the nervous and immune system with an immediate source of energy at a time of crisis. Insects, worms, and all vertebrates develop stress hyperglycemia when exposed to stress [2]. Stress hyperglycemia is a component of the stereotypic and coordinated response to stress referred to by Hans Selye as the “general adaption syndrome” which until 2001 was believed to be a beneficial host response which enhanced the host’s chances of survival [3]. On 8 November 2001, Van den Berghe and colleagues published a study entitled “Intensive insulin therapy in critically ill patients” in which they randomized 1548 surgical ICU patients (63 % who had undergone cardiac surgery) to an intensive insulin therapy (IIT) protocol targeting a blood glucose of 80–110 mg/dl or a control arm in which patients only received insulin when the blood glucose exceeded 215 mg/dl with a target of 180–200 mg/ dl (Leuven I study) [4]. Hospital mortality was 7.2 % in the IIT group as compared to 10.9 % in the control group (p = 0.01); in addition IIT reduced length of stay and patient morbidities. This study was supported by retrospective cohort studies in acutely ill patients demonstrating an association between increasing hyperglycemia and poor clinical outcomes. The findings of the Leuven study were widely embraced and endorsed by the Institute for Health Care Improvement, the American College of Endocrinology as well as other national and international organizations and soon became considered the standard of care for ICU patients around the world. In 2006, Van den Berghe and colleagues repeated their study in medical ICU patients (Leuven II study) [5]. Although failing to reproduce the improvement in survival in the entire set of patients, this study demonstrated a reduction in morbidity in the patients randomized to IIT with a reduction in mortality in the subset of patients with an ICU stay of 3 days or more. Using a similar study design these authors repeated their study in a pediatric ICU (mostly cardiac surgery patients) and demonstrated an outcome very similar to the Leuven I study [6]. Following the Leuven I study, 14 randomized controlled trials in various patient populations including mixed ICUs, neurosurgical, neurological, coronary, trauma, and pediatric ICUs have been performed (see Table 1). Without exception all of these studies demonstrated no outcome benefit (NOB) from tight glycemic control in acutely ill patients. NICE-SUGAR, the largest trial to date (n = 6022), demonstrated a 2.6 % absolute increase in 90-day mortality in patients randomized to IIT (p = 0.02) [7]. Three of these studies demonstrated harm, with almost all of the studies demonstrating a significant increase in the risk of both moderate and severe hypoglycemia. Even mild hypoglycemia in ICU patients is associated with an increased risk of death [8]. The mechanism(s) by which hypoglycemia increases the risk of death in critically ill patients has (have) not been investigated. However, it is likely that hypoglycemia increases the risk of fatal arrhythmias [9]. Furthermore, cell death *Correspondence: marikpe@evms.edu 2 Eastern Virginia Medical School, 825 Fairfax Av, Suite 410, Norfolk, VA 23507, USA Full author information is available at the end of the article