Before 2001, the hyperglycemia found in most critically ill patients was considered to be a component of the stress response. Current understanding was completely changed by the publication of the seminal study by van den Berghe et al. in 2001. This investigation compared an intensive insulin regimen targeting a blood glucose level between 80 and 110 mg/dL with a “conventional” management cohort in which blood glucose was treated only when above 200 mg/dL. The authors of the study demonstrated a 4% decrease in the absolute mortality of critically ill patients randomized to intensive insulin therapy. These unexpectedly impressive results triggered a huge wave of enthusiasm. Recommendations to implement tight glucose control in intensive care units (ICUs) were rapidly issued by several health-care agencies (Joint Commission on Accreditation of Healthcare Organization, the Institute for Healthcare Improvement, and the Volunteer Hospital Organization). Simultaneously, several different teams tried to reproduce the results and to examine the underlying mechanisms of the findings of the Leuven team. Overall, the results of the first Leuven study have not been reproduced. Nonetheless, these follow-up studies have given rise to several controversies and raised important but as yet unanswered questions for the physicians taking care of critically ill patients: What is the optimal value of blood glucose? What are the risks associated with hypoglycemia? What categories of patient might benefit from tight glucose control by intensive insulin therapy?
Pathophysiology and Mechanism of Action
It has long been recognized that critically ill patients tend to be hyperglycemic. For many years, this was attributed to stress and was thought to be a part of the host response to critical illness. The Leuven studies started with the hypothesis that hyperglycemia was not just a biomarker. Rather, these investigators postulated that elevations in serum glucose contributed to the pathophysiology of critical illness. This proposal spawned the current field of investigation. The initial question might be reframed as, “What is the optimal blood glucose concentration in the critically ill patient?” Further exploration and investigation of this question are warranted.
The physiology behind “stress hyperglycemia” is complex. The elaboration of glucose, primarily by the liver, is known to be an essential component of the host’s response. Gluconeogenesis reflects the energy demand that results from injury, ischemia, or other deleterious processes. White blood cells, the main effectors of the inflammatory response, are more or less obligate glucose users. Because the blood supply to injured tissue often has been interrupted or diminished, delivery is primarily through mass action across the intracellular matrix. Increases in concentration facilitate this movement. Gluconeogenesis, the process by which the liver synthesizes glucose, is driven primarily by the direct action of glucagon and epinephrine on hepatocytes. This is enhanced by cortisol and perhaps by inflammatory cytokines. In addition, these hormones, and the cytokines to some degree, limit the peripheral response to insulin. This latter effect has been termed insulin resistance, although there are no data in nonseptic patients or animals to indicate that the direct responses of the insulin signaling pathway are impaired. At some point, the process becomes maladaptive in the critically ill patient. This is especially true in sepsis and multiple-organ dysfunction. Thus the previously asked question must be expanded to examine the time course of stress hyperglycemia and the actual glucose concentration.
In experimental conditions, concentrations of glucose higher than 300 mg/dL are clearly deleterious. Furthermore, new insights into the cellular mechanisms of glucose toxicity suggest a link among glucose, cytopathic hypoxia, and the production of reactive oxygen and nitrogen species. However, it is essential to recognize that only clinical data can be used to define the optimal value for tight glucose control. Indeed, the ultimate proof that hyperglycemia is an independent risk factor for poor outcome in critically ill patients is lacking. Importantly, insulin exerts effects other than the promotion of glucose metabolism and utilization. These include vasodilatory, anti-inflammatory, and antiapoptotic activities most easily viewed as homeostatic control mechanisms that limit some of the processes that occur in inflammation and other potentially injurious responses. Such a role for insulin might explain some of the beneficial but unexpected effects of intensive insulin therapy.
Presentation of Available Data Based on Systematic Review
It has been difficult to replicate the results of the Leuven study. This inability leaves several practical questions unanswered. First, it is unclear just what constitutes “normoglycemia” in critical illness. Retrospective data and the two Leuven studies clearly indicate that a blood glucose higher than 180 mg/dL cannot be considered acceptable. However, the optimal target for blood glucose concentration remains unknown. Interestingly, several retrospective trials found that patients in whom blood glucose was below 150 mg/dL had a better outcome than those with higher levels.
To solve the issues of the external validity of the Leuven study and the optimal blood glucose target, large single-center and multicenter prospective trials of tight glucose control using intensive insulin therapy comparing two ranges of blood glucose were launched. The designs of these trials ( Table 21-1 ) were similar. All aimed to compare the effects of insulin therapy titrated to restore and maintain blood glucose between 80 and 110 mg/dL for adult studies and between 72 and 126 mg/dL for one study conducted in several mixed pediatric ICUs. They differed in the target range of blood glucose for the control (nonintensive insulin therapy) group. The Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation (NICE-SUGAR) and GluControl trials used a target value of 140 to 180 mg/dL. Both of the Leuven studies, the VISEP (Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis) study, and two other single-center large-scale trials used a target value of 180 to 200 mg/dL. The CGAO-REA (Computerized Glucose Control in Critically Ill Patients) study used a target value of less than 180 mg/dL, and the pediatric study has a target of 180 and 215 mg/dL.
| Study | No. of Subjects (Intervention/No Intervention) | Study Design | Intervention (Blood Glucose Target) | Control (Blood Glucose Target) | Primary Outcome Variable | |
|---|---|---|---|---|---|---|
| Single center | van der Bergeh et al. (Leuven I), 2001 | 765/783 | Single-blind | 80–110 mg/dL | 180–200 mg/dL | ICU mortality |
| van der Bergeh et al. (Leuven II), 2006 | 595/605 | Single-blind | 80–110 mg/dL | 180–200 mg/dL | ICU mortality | |
| Arabi, 2008 | 266/257 | Single-blind | 80–110 mg/dL | 180–200 mg/dL | ICU mortality | |
| De La Rosa | 254/250 | Single-blind | 80–110 mg/dL | 180–200 mg/dL | 28-day mortality | |
| Multicenter | Brunkhorst et al., 2008 (VISEP) | 247/289 | Single-blind | 80–110 mg/dL | 180–200 mg/dL | 28-day mortality and SOFA |
| Finfer et al., 2009 (NICE-SUGAR) | 3054/3050 | Single-blind | 80–110 mg/dL | 140–180 mg/dL | 90-day mortality | |
| Preiser et al., 2009 (GluControl) | 542/536 | Single-blind | 80–110 mg/dL | 140–180 mg/dL | ICU mortality | |
| Kaflon et al., 2014 | 1336/1312 | Single-blind | 80–110 mg/dL | <180 mg/dL | 90-day mortality | |
| Macrae et al., 2014 | 694/675 | Single-blind | 72–126 mg/dL | 180–215 mg/dL | Number of days alive and free |
The results of these trials are summarized in Table 21-1 . Basically, there were no significant differences in the vital outcomes between the two groups, with the notable exceptions of the Leuven I study and the NICE-SUGAR study, in opposite directions. Not surprisingly, tight glucose control by intensive insulin therapy is associated with a fourfold to sixfold increase in the incidence of hypoglycemia. This represents the major concern when starting intensive insulin therapy and leads to a major increase in the workload placed on the ICU care team. A post hoc analysis of the NICE-SUGAR study revealed a strong, dose-dependent association between the risk of death and moderate (41 to 70 mg/dL) and severe (<40 mg/dL) hypoglycemia. Although Macrae and associates were unable to demonstrate an improvement of the primary outcome (number of days alive and free from mechanical ventilation at 30 days), they found a shortening of the length of stay and a decrease in health-care costs. In the VISEP and GluControl studies, the rate of hypoglycemia and the mortality in the patients who experienced at least one such episode (defined as blood glucose <40 mg/dL) were higher than in patients who did not experience hypoglycemia. In contrast, in both Leuven studies, patients with hypoglycemia had no detectable differences in outcome compared with patients who had no hypoglycemic episodes. This does not exclude the possibility that long-lasting hypoglycemia, with consequent decreases in glucose availability for tissues that are glucose dependent, may be deleterious or even life threatening. An accurate understanding of the consequences of hypoglycemia in critically ill patients clearly requires further investigation.
Systematic reviews and meta-analyses including data on glucose control recorded in the ICU and in other patients are also available. The design and main results of the seven meta-analyses are summarized in Table 21-2 . These analyses yielded different results, including the overall effects on mortality. The meta-analyses by Pittas and colleagues and Gandhi and associates revealed decreased short-term mortality (respective relative risks [95% confidence interval] of 0.85 [0.75 to 0.97] and 0.69 [0.51 to 0.94]). In contrast, the five other studies showed no significant effect on mortality and an increased risk of hypoglycemia.
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