One size does not fit all: genetic variability of mu-opioid receptor and postoperative morphine consumption.

BLOOD glucose has only recently emerged as an important variable in critical care. In the past, this biologic marker has been largely ignored or considered as adaptive to the stress conditions observed in critically ill patients. In this issue of ANESTHESIOLOGY, Egi et al. report observations from a large database that included 7,049 critically ill patients in whom blood glucose was frequently monitored. They observed that variability of blood glucose concentration was an independent predictor of intensive care unit (ICU) and hospital mortality. It is now obvious that blood glucose plays a key role in both the shortand long-term consequences of neurologic injury. In the heart, high blood glucose level abolishes ischemic preconditioning, amplifies reperfusion injuries, and provokes coronary endothelial dysfunction and thus further increases the incidence of myocardial ischemic events. Numerous clinical studies have identified diabetes mellitus as an independent risk factor for perioperative morbidity and mortality, and there is compelling evidence that perioperative glycemic control improves early clinical outcome of diabetic patients. In a randomized study in critically ill patients, Van der Berghe et al. reported that intensive insulin therapy is associated with a lower mortality. In patients undergoing coronary artery bypass surgery, we have recently demonstrated that a poor intraoperative glucose control despite intensive insulin therapy is associated with a worsened hospital outcome in diabetic patients. As emphasized recently by Malhotra, the days of ignoring blood glucose levels or tolerating marked hyperglycemia in the ICU are over. In the report by Egi et al., blood glucose was closely monitored; on average, glucose was measured every 4 h. The mean measures were 24 per patient, and the variability of blood glucose predicted ICU and hospital mortality. In multivariate analyses, the odds ratio associated with blood glucose variability (1.28 per 1 mM of SD) and that associated with mean blood glucose (1.21 per 1 mM) were comparable in predicting ICU mortality. The results were comparable when considering hospital mortality. These results should be considered with caution because this was a retrospective study and we cannot rule out the possibility of hidden bias. Although these results are impressive and the methodology used is appropriate, including a very large number of critically ill patients, it should be noted that these associations were observed; however, this does, in itself, not prove causality. Therefore, the study from Egi et al. should be considered as the first important step toward a new paradigm concerning the prognostic value of blood glucose concentrations: Not only the level of blood glucose but also its variability might be of paramount importance. This study constitutes a unique opportunity to orient future research, both experimental and clinical, to test this new hypothesis. If blood glucose variability is as important as blood glucose level, some recent findings should be reconsidered. For example, using intensive insulin therapy in the ICU, the first study by Van der Berghe et al. showed a reduction in mortality, whereas a second large trial did not. Many factors might explain this discrepancy. However, it should be pointed out that neither of these clinical trials assessed blood glucose variability, which might have played a crucial role. Two large ongoing randomized trials on intensive insulin therapy in the ICU might also consider blood glucose variability as an important factor. *† Blood glucose variability has been simply assessed by the SD (or the coefficient of variation) in the study by Egi et al. However, this variable is in fact a very complex factor that could encompass several pathophysiologic processes: variation of blood glucose around abnormal high values, variation of blood glucose between abnormal high (hyperglycemia) and low (hypoglycemia) values. Future research should be also directed to assess the more appropriate definition of blood glucose variability and to delineate the possible pathophysiologic mechanisms involved. The initial results of blood glucose variability as insulin treatment is initiated should probably be discarded. Also, this may depend on the therapeutic effort to maintain blood glucose using intensive insulin therapy. The mode of administration of insulin may affect blood glucose variability; continuous intravenous administration is better than continuous and bolus subcutaneous administration, which is better than intravenous bolus administration. Insulin itself may also induce biologic effects aside from glyThis Editorial View accompanies the following article: Egi M, Bellomo R, Stachowski E, French CJ, Hart G: Variability of blood glucose concentration and short-term mortality in critically ill patients. ANESTHESIOLOGY 2006; 105:244–52.