Inpatient hyperglycemia

What next?

Before 2001, hospital hyperglycemia was often neglected. This approach changed dramatically when tight glycemic control came to the forefront of hospital medicine after a single-center, randomized controlled trial (RCT) in Leuven, Belgium, of more than 1,500 patients in a surgical intensive care unit (ICU) reported a 42 percent reduction in mortality rate with use of intensive insulin therapy. Since then, massive efforts have been made worldwide to achieve these goals, with intensive insulin therapy becoming a benchmark in critically ill patients.

Gunjan Y. Gandhi, M.D., of the Division of Endocrinology at Mayo Clinic in Jacksonville, Fla., says: "Clinicians realized there are substantial challenges to achieving such ambitious goals in practice:

• Multifold increased risk of hypoglycemia
• Increased utilization of resources
• Considerable revamping of infrastructure to implement glycemic management protocols
• Additional personnel training
• Need for intense coordination among varied involved specialties

"Although laudable efforts have been undertaken, from the tertiary care academic centers to small community hospitals, for the seamless implementation of insulin protocols, subsequent clinical studies in varied ICU settings did not replicate the amazing benefits reported in the study from Leuven, Belgium."

In addition, some concern started to emerge regarding possible harm. Dr. Gandhi explains: "At Mayo Clinic, we conducted what still is the only RCT to assess the role of tight glycemic control (blood glucose between 80 and 100 mg/dL) intraoperatively in cardiac surgery patients. While we did not see any improvement in patient-important outcomes, we did see an increased risk of deaths and strokes in the group with tightly controlled glucose compared with the group that was treated conventionally."

The much-awaited results of the multicenter, international Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial (of which Mayo Clinic in Rochester, Minn., was the only site in the United States) recently reported definitive and not entirely surprising evidence that there is no benefit of tightening glucose control to normal levels compared with a reasonable and achievable goal of 140 to 180 mg/dL in a heterogeneous group of critically ill patients (N>6,000).

The results differ from the Leuven trial in that there was an increase in the primary endpoint (death at 90 days) with intensive glucose control. Severe hypoglycemia occurred in more patients in the intensive control group.

Dr. Gandhi highlights: "A meta-analysis incorporated the NICE-SUGAR trial and the Leuven study among many other, smaller studies to attempt to resolve the disparate results and answer the question of whether we are helping or hurting patients with tight glycemic control.

"The outcome of the pooled data for these 13,000 critically ill patients tells us that the truth may lie somewhere in between, and tight glycemic control may not actually have any effect on mortality rate at all.

"The relationship between hyperglycemia in critically ill patients (the majority of whom do not have underlying diabetes mellitus) and worse outcomes in most previous observational studies is probably not causal but a reflection of the severity of illness. Thus, attempting to reverse a normal stress response of shunting energy to critical organs may be deleterious."

Role of hypoglycemia

Fear of hypoglycemia is one of the key barriers for the implementation of targeted glucose control. Dr. Gandhi says: "Although not shown by available data, unrecognized hypoglycemia may very well be the major culprit for the increased mortality rate, especially in critically ill patients who are sedated and connected to a mechanical ventilator.

"Hypoglycemia is associated with increased risk of death and prolonged hospital stay in various hospitalized patient populations. Recent studies, however, suggest that episodic in-hospital hypoglycemia may be a marker of greater illness severity, rather than a mediator of adverse events. Although these findings offer some reassurance to clinicians in their efforts to control glucose levels, hypoglycemic events are associated with potential for harm and should be avoided."

Clinical implications

Dr Gandhi suggests the following guiding principles:

• Do not neglect glycemic control in critically ill patients because studies have not tested tight vs. no or poor control, but rather they have compared tight vs. good control. The former question needs to be answered — but until then, summative evidence suggests that reduction of severe hyperglycemia reduces morbidity, especially from infectious complications.
• Use evidence-based glucose control protocols with a demonstrated safety record, establish hospitalwide policies that provide guidance on identification of high-risk patients, and standardize procedures for detection and treatment of hypoglycemia across nursing units. A system for tracking the frequency and severity of all hypoglycemic and hyperglycemic events allows for timely and ongoing analysis of the safety of a glycemic management program.
• There is no additional benefit in outcomes obtained through achieving normoglycemia compared with reasonable glycemic control. A moderate approach to managing critical illness-related hyperglycemia seems most prudent at this juncture (for example, goal blood glucose concentrations between 140 and 180 mg/dL). Professional organizations, such as the American Association of Clinical Endocrinologists and the American Diabetes Association, have come full circle on this issue and now recommend a more moderate approach to treating hyperglycemia in the critically ill patient. ICUs should make efforts to adjust to these goals.
• There is harm from overt and unrecognized hypoglycemia with intensive insulin therapy. Thus, strict goals cannot be achieved safely given the limitations of current technology in monitoring glucose levels. It remains to be seen whether there is benefit in tight glucose control once hypoglycemia is minimized with technological advances, such as continuous glucose monitoring systems.

Future directions

Underlying mechanisms behind stress hyperglycemia

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The underlying pathophysiologic mechanisms behind stress hyperglycemia need to be characterized further in an attempt to prevent its adverse consequences.

Dr. Gandhi concludes: "Although glycemic goals have been set in a moderate range, it may be that certain subsets of patients would benefit from different glycemic goals. Further studies will need to be completed to determine whether there is a need to individualize glycemic targets depending on the patient and his or her type of critical illness.

"Future research should also focus on hospital-related hyperglycemia in patients on the general medical-surgical floors, where patients with blood glucose concentrations greater than 200 mg/dL are still being treated with sliding-scale insulin."