Management of Hyperglycemia in the Critically Ill

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Chapter 51 Management of Hyperglycemia in the Critically Ill

Matthew P. Gilbert, DO, MPH , Alison Schneider, MD

1 Who is at risk for development of hyperglycemia?

Hyperglycemia can occur in patients with known or undiagnosed diabetes mellitus. Hyperglycemia during acute illness can also occur in patients with previously normal glucose tolerance, a condition called stress hyperglycemia.

2 How common is hyperglycemia in critically ill patients?

Acute hyperglycemia is common in critically ill patients. It is estimated that in 90% of all patients blood glucose concentrations >110 mg/dL develop during critical illness. Stress-induced hyperglycemia has been associated with adverse clinical outcomes in patients with trauma, acute myocardial infarction, and subarachnoid hemorrhage.

3 What causes hyperglycemia in critically ill patients?

In healthy individuals, blood glucose concentrations are tightly regulated within a narrow range. The cause of hyperglycemia in critically ill patients is multifactorial. Physiologic and emotional stress leads to intense activation of counterregulatory hormones such as cortisol and epinephrine. The release of inflammatory cytokines causes an increase in peripheral insulin resistance and hepatic glucose production. The use of glucocorticoids and parenteral and enteral nutrition is an important contributor to hyperglycemia.

4 What is the relationship between hyperglycemia and acute illness?

The relationship between hyperglycemia and acute illness is complex. Severe hyperglycemia (>250 mg/dL) has been shown to have a negative impact on the vascular, hemodynamic, and immune systems. Hyperglycemia can also lead to electrolyte imbalance, mitochondrial injury, and both neutrophil and endothelial dysfunction. Acute illness increases the risk for hyperglycemia through the release of counterregulatory hormones, increased insulin resistance, and immobility. Figure 51-1 illustrates the relationship between acute illness and hyperglycemia.

Figure 51-1 Hyperglycemia and acute illness.

5 Should oral medications used to treat diabetes be continued in the intensive care unit (ICU)?

Given the high incidence of renal and hepatic impairment, oral medication to treat diabetes should not be continued in the ICU. Medications such as metformin are contraindicated in patients with renal or hepatic dysfunction and congestive heart failure. Long-acting formulations of sulfonylureas have been associated with episodes of prolonged severe hypoglycemia in hospitalized patients. Oral medications are not easily titrated to meet glycemic targets and may take weeks to effectively lower blood glucose levels.

6 Should injectable, noninsulin medications be used in the ICU?

Noninsulin, injectable medications such as exenatide, liraglutide, and pramlintide have similar limitations as oral agents and should not be used in the ICU setting.

7 What is the most effective way to treat hyperglycemia in the ICU?

An intravenous insulin infusion is the safest and most effective way to treat hyperglycemia in critically ill patients. Because of the short half-life of circulating insulin (minutes), an insulin infusion can be frequently adjusted to match the often-variable insulin requirements of critically ill patients. Intravenous insulin therapy should be administered by validated written or computerized protocols that outline predefined adjustments in the insulin dose based on frequent measurement of blood glucose concentrations.

8 When should treatment with an intravenous insulin infusion be initiated?

Intravenous insulin therapy should be initiated for the treatment of persistent hyperglycemia starting at a blood glucose concentration of no greater than 180 mg/dL.

9 What is the appropriate glycemic target for critically ill patients?

Recognizing the importance of glycemic control in critically ill patients, a number of professional societies have developed treatment guidelines and/or consensus statements that provide evidence-based glycemic targets. Although the glycemic targets are not identical, all of the groups advocate for good glycemic control while avoiding hypoglycemia (see Table 51-1).

^{Table 51-1} Summary of glycemic targets from the medical literature

Professional society/consensus statement	Glycemic target for critically ill patients
American Diabetes Association	140-180 mg/dL
American Association of Clinical Endocrinologists	140-180 mg/dL
Surviving Sepsis Campaign	150-180 mg/dL
American College of Physicians	140-200 mg/dL
American Thoracic Society	<180 mg/dL (in patients undergoing cardiac surgery)

10 What is the evidence supporting the current glycemic targets?

The first randomized controlled trial (RCT) comparing tight glycemic control (target blood glucose concentration of 80-110 mg/dL) with conventional insulin therapy (target blood glucose concentration of 180-200 mg/dL) was conducted by Van den Berghe and colleagues (2001) in a population of surgical ICU patients. The single-center trial enrolled more than 1500 patients and showed a 34% reduction in mortality associated with tight glycemic control. However, subsequent studies in both medical and surgical ICU populations have not shown consistent reductions in mortality with tight glycemic control. A recent meta-analysis of RCTs that included 8432 critically ill adult patients did not show a significant difference in mortality between tight glycemic control and control groups.

11 What was the NICE-SUGAR study?

The Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) was a multicenter, multinational RCT that evaluated the effect of tight glycemic control (target glucose level of 81-108 mg/dL) on a number of clinical outcomes in 6104 critically ill adults. Greater than 95% of the patients in the trial required mechanical ventilation. The 90-day mortality was significantly higher in the tight glycemic control group (78 more deaths; 27.5% vs. 24.9%; P = 0.02). Cardiovascular mortality and severe hypoglycemic events were also more common in the tight glycemic control group.

It is important to note that studies have not evaluated tight glycemic control versus poor glycemic control but rather have compared tight control versus good control. Given the limitations of current technology in the monitoring of blood glucose levels, tight glycemic control with intensive insulin therapy cannot be achieved safely. Advances in technology, particularly continuous glucose monitoring systems, will be needed to better evaluate the risks and benefits of tight glycemic control in critically ill adults.

12 How should patients be transitioned from an intravenous insulin infusion to subcutaneous insulin therapy?

Patients should be transitioned from an insulin infusion to a subcutaneous insulin program when clinically stable. In patients who are eating, the use of once- or twice-daily administered basal insulin in combination with scheduled mealtime rapid-acting insulin and a supplemental (correction) component has been shown to maintain adequate glycemic control without clinically significant hypoglycemia. Subcutaneous insulin therapy should be initiated at least 2 hours before the discontinuation of the insulin infusion to reduce the risk of hyperglycemia. The use of a sliding-scale insulin regimen as the sole means of treatment of hyperglycemia is ineffective and should be avoided.

13 How is hypoglycemia defined?

Hypoglycemia is defined as any blood glucose level <70 mg/dL. This level correlates with the initial release of counterregulatory hormones. Cognitive impairment begins at a blood glucose concentration of approximately 50 mg/dL, and severe hypoglycemia occurs when blood glucose concentrations are <40 mg/dL.

14 What is the clinical impact of hypoglycemia?

The incidence of severe hypoglycemia in the tight glycemic arm of the NICE-SUGAR trial was significantly higher (relative risk of 13.7). However, a clear link between the increased 90-day mortality rate and incidence of severe hypoglycemia in the tight glycemic control group has not yet been established. Recent observational studies illustrate a relationship between mild to severe hypoglycemia and death. Hypoglycemia has been associated with increased risk for cardiovascular death and death due to infectious disease after adjustment for insulin therapy. In addition, hypoglycemia has also been shown to prolong hospital stay for various patient populations. Some have hypothesized that hypoglycemia may be a marker of the severity of illness, rather than a mediator of poor clinical outcomes.

15 How do we prevent severe hypoglycemic events in the ICU?

Critically ill patients are not likely able to report symptoms of hypoglycemia; thus it is important that patients be closely monitored. Early recognition and treatment of mild hypoglycemia can prevent the adverse outcomes associated with severe hypoglycemia. The establishment of a system for documenting the frequency and severity of hypoglycemic events and the implementation of policies that standardize the treatment of hypoglycemia are essential components of an effective glycemic management program.

16 Is intensive treatment of hyperglycemia cost-effective?

Intensive treatment of hyperglycemia not only reduces morbidity and mortality but is also cost-effective. The cost savings have been attributed to reductions in laboratory and radiology cost, decreased ventilator days, and reductions in ICU and hospital length of stay.

Key Points Management of hyperglycemia in critically ill patients

1. Hyperglycemia is common in critically ill patients and has been independently associated with increased ICU mortality.

2. Oral medications and noninsulin injectable therapies should not be used to treat hyperglycemia in critically ill patients.

3. An intravenous insulin infusion is the safest and most effective way to treat hyperglycemia in critically ill patients.

4. A glycemic target of 140 to 180 mg/dL is recommended for critically ill patients.

5. Early recognition and treatment of mild hypoglycemia can prevent the adverse outcomes associated with severe hypoglycemia.

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8 Lazar H., McDonnnell M., Chipkin S., et al. The Society of Thoracic Surgeons practice guideline series: blood glucose management during adult cardiac surgery. Ann Thorac Surg. 2009;87:663–669.

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11 Moghissi E., Korytkowski M., DiNardo M., et al. AACE/ADA consensus statement on inpatient glycemic control. Endocr Pract. 2009;15(4):1–17.

12 Qaseem A., Humphrey L.L., Chou R., et al. Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2011;154:260–267.

13 Umpierrez G., Smiley M., Zisman A., et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 Trial). Diabetes Care. 2007;30:2181–2186.

14 Van den Berghe G., Wouters P., Weekers F., et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359–1367.

15 Wiener R., Wiener D., Larson R. Benefits and risk of tight glucose control in critically ill adults: a meta-analysis. JAMA. 2008;300:933–944.

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