Does Tight Blood Glucose Control during Cardiac Surgery Improve Patient Outcome?

Intensive insulin therapy to maintain normal levels of blood glucose (4.4 to 6.1 mmol/L [80 to 110 mg/dL]) during intensive care improves survival and reduces morbidity of critically ill patients after complicated, high-risk, or extensive surgery or trauma (1). Clear benefit from this intervention requires maintenance of tight blood glucose control for at least a few days (2). The mechanism by which maintaining normoglycemia prevents adverse outcomes is not fully understood. One possibility is that avoiding sustained cellular glucose overload and toxicity in certain cell types reduces the likelihood for vital organ dysfunction (3). Avoiding glucose toxicity seems to prevent damage to the mitochondrion, the organelle that generates energy for cellular functions (4). The first observation of this clinical effect took place in a randomized trial performed in Belgium (1) in which a large number of the study patients were admitted to the intensive care unit (ICU) after high-risk cardiac surgery. These cardiac patients had a mean EuroSCORE of 6.0 and thus a high predicted risk of death (9.9%) (5); few were known to have diabetes before the operation. This subgroup of cardiac patients had substantially better outcomes when randomly assigned to tight blood glucose control, with an in-hospital mortality rate of 3.4% (vs.7.5% in control patients) and lower morbidity (5). These results were consistent with an observational study (6) in which patients had a history of diabetes mellitus (6). The short-term mortality rate in the Belgian study (1, 5) persisted for up to 4 years (5), and patients in the intervention group did not require more postdischarge medical care than patients in the control group (5). The success of this postsurgical intervention raised the possibility that targeting normal levels of blood glucose during cardiac surgery, for patients with or without diabetes, could further improve patient outcomes. In this issue, Gandhi and colleagues report the results of a randomized, controlled study that specifically addresses this question (7). These authors previously reported the results of an observational study (8) in which they noted that intraoperative hyperglycemia in cardiac surgical patients was an independent predictor of a composite end point of morbidity and death. They performed this observational study in 2002, a time when intensive care specialists tolerated elevated blood glucose levels averaging around 10 mmol/L (180 mg/dL) during the postoperative intensive care phase (8). This study led to the hypothesis that normalizing blood glucose levels during surgery would improve outcomes (7). Based on a hypothesized 40% relative reduction of a composite end point (death, stroke, deep sternal infection, heart block requiring pacemaker, new atrial fibrillation, acute renal failure, or intubation for more than 24 hours), the authors calculated a sample size of 400. They randomly assigned 400 patients to intensive insulin therapy during surgery, targeting blood glucose levels of 4.4 to 5.5 mmol/L (80 to 100 mg/dL) or conventional therapy (7). By the time of this randomized, controlled study, however, they had changed the postoperative routine management in their ICU to include postoperative tight blood glucose control (targeting 4.4 to 5.5 mmol/L [80 to 100 mg/dL]) for all patients. Therefore, patients in both groups had a different blood glucose level only from the time they were weaned from extracorporeal circulation until 2 to 3 hours after admission to the ICU. After analysis of the 371 study patients who received the randomly assigned intervention, the authors concluded that starting tight blood glucose control during surgery had no benefit compared with starting it after surgery. This study was well planned and rigorously performed. However, readers should be aware of a few important limitations that affect the interpretation of the results. The authors did not blind patients and investigators to study treatment, and they performed the study at only 1 site. Also, they found a relatively small difference in blood glucose differences between study groups and a low mortality rate for the cohort compared with their observational study (1% vs. 3%). The authors have acknowledged these limitations and discussed them appropriately. The most important limitation of the study is the implementation of an ICU policy of postoperative tight blood glucose control between the time of the observational study and the prospective, randomized, intervention study. This limitation requires additional discussion. Postoperative tight glucose control has such a strong effect on the outcome of cardiac surgical patients that any additional effect of tight blood glucose control initiated only a few hours earlier, during an operation, is likely to be quite small. The authors' study design was appropriate to test the hypothesis that intraoperative tight blood glucose control would improve outcomes when added to postoperative tight control. However, the authors based their power calculation on a 40% reduction in the composite end point. They should have anticipated a smaller effect. Previous studies have shown that the impact of tight blood glucose control depends on the length of time it is applied. Specifically, 3 days of tight control are required for a sizable benefit of morbidity, death, or both (1, 2, 5, 6, 9, 10). The authors should have anticipated that 3 to 4 hours more of tight blood glucose control would have much less than a relative 40% reduction in the composite end point. The results of the study, which show a relative risk of 1.0 (95% CI, 0.8 to 1.2) for an event of the composite end point, are statistically compatible with anything between a 20% reduction and a 20% increase in the composite end point. For example, to prove or exclude a 10% relative reduction of the composite end pointa more reasonable, albeit perhaps still optimistic estimate of the effect of the intervention given its brevitywith an -error less than 0.05 and a power of 80% or 90%, the study should have had 2500 to 3500 patients, respectively. This sample is probably unrealistically large for a single-center study. So what are clinicians to do with the results from this study by Gandhi and colleagues? What are the clinical implications, if any? The study clearly shows that adding tight blood glucose control during surgery does not cause a large additional benefit compared with starting tight blood glucose control in intensive care. If clinicians require a large benefit to change clinical practice, they should not implement tight glucose control during surgery. That the 4 deaths in the study all occurred in the intervention group, although this is possibly due to a chance occurrence given the small sample size and the low overall mortality rate, further supports caution about adopting intraoperative tight glucose control. However, a reliable test to prove or exclude that intraoperative tight blood glucose control has a small effect on the outcome of cardiac surgical patients would require a much larger study than Gandhi and colleagues performed. Perhaps someone will do such a study. Until then, we should regard tight glucose control during cardiac surgery as experimental and confine its use to clinical trials.