Blood glucose variability in critical illness: Is it time to cast a wider net?

Alterations in glucose homeostasis are common in critical illness, even in the absence of underlying diabetes mellitus (1). In the past, this was largely ignored or considered to represent an adaptive response to critical illness. It is becoming increasingly obvious that stress hyperglycemia of critical illness is associated with poor outcomes (2, 3). More recently, evidence has emerged that hypoglycemia in critical illness may also be independently associated with poor outcomes (4, 5). A new paradigm that is being explored is the impact of blood glucose variability on outcomes from critical illness (6, 7), a concept that attempts to describe the complex temporal fluctuation of blood glucose concentrations between extremes of high and low levels during the evolution of critical illness. Why might blood glucose variability be an important consideration when evaluating the impact of blood glucose concentrations on outcomes from critical illness? During states of health, blood glucose concentrations are closely regulated via homeostatic mechanisms in the body. During the acute phase of illness, variability in blood glucose concentrations may initially represent an allostatic or adaptive state involving changes in the neuroendocrine axis as well as cell signaling machinery to prolong survival (8). However, in chronic critical illness, the stressors may overwhelm these compensatory mechanisms. Consequently, the allostatic load rapidly progresses to allostatic overload, resulting in greater fluctuations in blood glucose concentrations, involving both hyperglycemia and hypoglycemia (8). In such circumstances, blood glucose variability may very well serve as a more discriminating marker of poor outcomes, a fascinating paradigm that deserves greater scrutiny. In this issue of Pediatric Critical Care Medicine, Dr. Hirshberg and colleagues (9) add to the growing body of literature on the impact of altered glucose homeostasis on outcomes in critically ill children. The authors describe the association of hyperglycemia, hypoglycemia, and blood glucose variability with mortality, hospital length of stay, and nosocomial infections in critically ill children in the absence of insulin therapy. The authors retrospectively analyzed data for 863 children admitted to the pediatric intensive care unit (PICU) over a 12-month period for 24 hrs with at least one blood glucose measurement in the PICU. The authors excluded children with preexisting disorders of glucose metabolism, such as diabetes mellitus, primary hypoglycemia, and fatty acid oxidation defects. The authors also specified that no blood glucose management protocols were in place in the PICU during this period. Thus, they attempted to correlate the “wild landscape” of blood glucose concentrations with outcomes in critically ill children, in an effort to gain important insights into the natural patterns and variations in blood glucose concentrations during critical illness. The authors observed that hyperglycemia (blood glucose 150 mg/dL [ 8.3 mmol/L]) was extremely common during PICU stay, occurring in approximately 56% of subjects, similar to previously published studies (3). In addition to confirming the association between hyperglycemia and mortality (odds ratio 9.6; 95% confidence interval, 1.2–77.2), the authors observed a trend between hyperglycemia and nosocomial infections. Hypoglycemia (blood glucose 60 mg/dL [ 3.3 mmol/L]) occurred in approximately 10% of all patients, in the absence of insulin therapy and blood glucose management protocols, and was more common in younger children. Interestingly, blood glucose variability (defined by the authors as hyperglycemia and hypoglycemia occurring in the same patient) was more strongly associated with mortality (odds ratio 40.5; 95% confidence interval, 4.6–358.7) and nosocomial infections (odds ratio 4.9; 95% confidence interval, 1.9– 12.7) than was either hyperglycemia or hypoglycemia alone. Blood glucose variability may have a much bigger role to play in critical illness than hitherto recognized and may serve as an important marker of poor outcomes. Egi et al. (10) observed that blood glucose variability (expressed as SD or coefficient of variation) was independently associated with intensive care unit and hospital mortality in adults after adjustment for potential confounders. Similarly, Wintergerst et al. (11) reported an association between index of glucose variability and mortality rates in critically ill children. Recent data from patients with diabetes indicate that fluctuations in blood glucose concentrations increase cellular damage via oxidative stress, with toxicity being most pronounced when the concentrations changed rapidly from normal to elevated (12). Children in the PICU are at increased risk for significant fluctuations in blood glucose concentrations due to numerous stressors, such as mechanical ventilation, vasoactive infusions, sedation, neuromuscular blockade, steroids, and parenteral nutrition, several of which were not accounted for in the present study. The authors defined blood glucose variability rather simplistically and did not examine more widely used definitions, such as average daily risk range or mean amplitude of glycemic excursion, to capture more subtle variations (13). The authors also acknowledge detection bias in blood glucose measurement resulting from intermittent sampling that might have underestimated the true extent of fluctuation of blood glucose concentrations. Newer techniques of continuous sampling can potentially de*See also p. 361.