Counterpoint : Inpatient Glucose

R ecently, the attention of the diabetes community has shifted to glycemic management in the inpatient setting, where there has been a rising chorus in support of stricter blood glucose control. We applaud the spirit of the current American College of Endocrinology (ACE) recommendations, which attempt to improve the hospital management of hyperglycemia (1). However, as we examine the very limited evidence upon which these guidelines are based, we are concerned about such prematurely stringent glucose targets. Indeed, there is a paucity of well-controlled randomized trials in which the feasibility and safety of specific insulin strategies in the variety of inpatient settings have been validated. Moreover, few have assessed actual outcomes at different glycemic ranges. We all recognize that several crosssectional studies have consistently demonstrated that hyperglycemia correlates with increased morbidity and mortality in the acutely ill, particularly in the critically ill and in the perioperative setting (2–4). This association holds for both patients with previously diagnosed diabetes and those with newly recognized hyperglycemia (5). However, the directionality of this relationship remains controversial. Does acute hyperglycemia lead to poor clinical outcomes or is it a reflection of sicker patients, due to increased counterregulatory forces that simply manifest their stress in the form of elevated blood glucose? Is an elevated blood glucose a marker or a pathogenic mechanism of disease in these patients? Experimental evidence has clearly supported a cause-and-effect relationship. Leukocyte action, immunoglobulin production, wound healing, collagen production, endothelial function, cardiac performance, and fluid balance are each impaired in the setting of hyperglycemia, particularly when severe (6,7). Admittedly, most data stem from in vitro observations and from in vivo investigations employing animal models (8–10). Moreover, these studies were typically designed to contrast markedly elevated versus normal ambient glucose concentrations (8–10). And, because insulin has beneficial vascular and anti-inflammatory effects (11), it is even less clear whether hyperglycemia or relative insulin deficiency was the major contributor to the increased risk in the in vivo models. There have been only two wellregarded randomized clinical trials indicating benefit from short-term strict glucose control in hospitalized patients (12,13). In addition, uncontrolled nonrandomized interventional reports in cardiothoracic surgical patients showed improved outcomes with intensive insulin regimens and better glycemic control (14,15). In light of these studies, the ACE sponsored a consensus conference that was cosponsored by several other professional organizations, including the American Diabetes Association (ADA) and the Endocrine Society. Subsequently, the ACE published a position statement (1) with very specific stringent targets for the inpatient management of the hyperglycemic patient. According to the ACE, blood glucose concentrations for intensive care unit (ICU) patients should be maintained at 110 mg/dl. In the noncritically ill, the upper limit for preprandial glucose is 110 mg/dl, with no peak postprandial reading to rise above 180 mg/dl. It is most important to clarify that these recommendations arose specifically from the ACE, not from the ADA or the Endocrine Society. In the case of the ADA, not even a technical review as good and comprehensive as the recent one devoted to the management of hyperglycemia and diabetes in hospitals (16) has the authority to make such critical recommendations. Only the ADA Professional Practice Committee, after rigorously interpreting the evidence and weighing the risk-benefit ratio as well as the burden and societal costs, has the authority to issue the Clinical Practice Recommendations, which are published in Diabetes Care each January. Given that in most hospitals such targets are a significant departure from the status quo, the recommendations have led to enormous concern among hospital officials and administrators, as they have quickly come to the realization that glucose management has been essentially ignored for decades in most institutions. This increased awareness is clearly a good thing; at the very least, poor glycemic control in the hospital is bad care and probably increases length of stay. At worst, as suggested by these studies, poor glycemic control may worsen shortand perhaps even long-term outcomes. Diabetologists, who have long been frustrated about the care received by their previously well-controlled patients once admitted to the hospital, are finally being asked to assist in quality improvement projects. Committee meetings, protocol development, and teaching exercises concerning inpatient glucose management are now a component of many endocrinologists’ work week. So, how strong is the evidence basis for said guidelines? The often-cited but uncontrolled study by Furnary et al. (14), implemented an insulin infusion protocol in the cardiothoracic ICU that is conservative by the standards now being recommended, with a glucose target of 150– 200 mg/dl. Over the years of the study, the glycemic target was gradually reduced, making the results more difficult to interpret. In addition, infectious outcomes in treated patients were compared with those of a historical control group in a study that spanned nearly 15 years. Clearly, many additional factors may have contributed to the benefit ascribed to insulin infusion, including improved surgical and anesthetic expert ise, the availability of more powerful antibiotics, and other hospital-related quality improvements. In a recent update from this group (15), a reduced mortality was reP o i n t C o u n t e r p o i n t