ReviewThe role of hyperglycemia in acute illness: Supporting evidence and its limitations
Introduction
Hyperglycemia is common during acute illness in patients with and without diabetes. Although once considered an adaptive response to physiologic stress, a substantial accumulation of evidence now links hyperglycemia in hospitalized patients to poor outcomes. Furthermore, correcting hyperglycemia has been shown to decrease morbidity and mortality. Current guidelines from various professional organizations recommend the treatment of inpatient hyperglycemia regardless of prior diagnosis of diabetes [1], [2], [3]; however, the exact glycemic targets and widespread implementation of glucose-lowering practices remain controversial. The purpose of this article is to review the evidence regarding consequences of hyperglycemia and treatment targets in hospitalized patients and to describe potential mechanisms that cause abnormal glucose metabolism in acutely ill populations.
Section snippets
Hospital-related hyperglycemia and adverse outcomes
Hyperglycemia has been associated with increased mortality and morbidity for a variety of medical conditions and patient populations [4], [5]. Collectively, numerous studies conducted in the settings of acute myocardial infarction [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], stroke [17], [18], critical illness [19], [20], coronary artery bypass graft surgery [21], [22], trauma [5], [23], [24], [25], [26], [27], cerebral endarterectomy [28], congestive heart failure [29], [30],
Randomized controlled trials of intravenous insulin intervention for hyperglycemia
The strongest evidence to support normalizing blood glucose in the intensive care unit (ICU) remains the Leuven study of 1,548 surgical patients in the ICU that examined the effects of continuous insulin infusion to achieve a target glucose range of 80–110 mg/dL. In this study, Van den Berghe et al. [38] demonstrated substantial decreases in hospital and ICU mortality, bloodstream infections, renal insufficiency, and need for mechanical ventilation and blood transfusions. A subsequent study
Meta-analyses of intravenous insulin treatment for hyperglycemia
Initial meta-analyses aimed at assessing the benefits and risks of glucose control in critically ill adults include a diverse array of trials with different target glucose levels and insulin preparations [45], [46]. Subsequent meta-analyses have been able to analyze data derived from studies examining normoglycemia, including large trials such as NICE-SUGAR. One recent systematic review is particularly informative because it includes only trials in which glucose control was the goal and
Limitations of trials and systematic reviews of insulin therapy in hospitalized patients
A consistent factor limiting studies of intensive glycemic control is that many have been terminated early due to excessive hypoglycemia. Hypoglycemia is the most common complication associated with inpatient insulin therapy. Risk of hypoglycemia remains a barrier to the implementation of inpatient diabetes care strategies and the increased likelihood of hypoglycemia associated with glucose-lowering intervention extends to the setting of clinical trials [42], [44], [49].
Perhaps equally relevant
Hypoglycemia and glucose variability
Hypoglycemia is an important and common adverse event related to inpatient glycemic control, the consequences of which are still unclear [57], [58], [59]. In a recent meta-analysis by Griesdale et al. [47], among the trials that reported hypoglycemia, the pooled relative risk with intensive insulin therapy was 6.0 (95% confidence interval 4.5–8.0). A retrospective chart review of 863 pediatric patients in the ICU showed that 9.7% had at least one blood glucose measurement lower than 60 mg/dL in
Causes of hospital-related hyperglycemia
Hyperglycemia is common in hospitalized patients and is not limited to those with a known diagnosis of diabetes. Stress-induced hyperglycemia is a term used to describe a transient physiologic response to the stress of an acute illness or injury. During illness, the action of counter-regulatory hormones such as glucagon, catecholamines, growth hormone, glucocorticoids, and cytokines result in increased hepatic gluconeogenesis and insulin resistance [69]. However, stress-induced hyperglycemia
Mechanisms underlying detrimental effects of hyperglycemia and improved outcomes with insulin intervention
The detrimental effects of hyperglycemia in the context of acute illness are postulated to act through a variety of mechanisms. Fluid and electrolyte shifts contribute to direct toxicity to vulnerable tissues. Additional deleterious factors include: immune dysfunction caused by impaired reactivity of leukocyte and mononuclear cell responsiveness, increased inflammatory response with release of reactive oxygen species, and promotion of coagulation associated with abnormal endothelial function
Conclusion
Hyperglycemia in hospitalized patients is common and associated with adverse outcomes including increased mortality. Treatment of hyperglycemia has proven beneficial, however, establishing evidence-based guidelines has been challenging because insulin infusion interventions have varied in the questions they have addressed, glucose levels studied, and quality of methodology. Ongoing research of the mechanisms underlying the detrimental effects of hyperglycemia and the beneficial effects of
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