Approach To The Surgical Patient With Hyperglycemia

Diabetic and non-diabetic patients develop hyperglycemia during surgery and medical illness due to enhanced hepatic gluconeogenesis, relative insulin deficiency, and decreased sensitivity of the liver, skeletal muscle, and adipose tissue to the actions of insulin (1-3). While clinical evidence suggests a direct association between hyperglycemia and adverse outcome in patients undergoing vascular and cardiac surgery, there is little prospective data available to indicate that glucose control improves outcome in the average hyperglycemic patient undergoing other types of surgical procedures (4-13). The adverse effects of hyperglycemia are mediated in large part by enhanced oxidative stress, which is not counter-balanced by endogenous antioxidants.

The optimal range of blood glucose (BG) control in a specific patient population remains controversial. The fear of hypoglycemia (change in mental status, seizure, coma, myocardial ischemia, arrhythmia, and death) dictates the psychology of diabetes management in the hospital setting. Nurses and physicians err on the side of hyperglycemia to avoid the consequences of low BG levels (14-17). Current therapeutic methods that attempt to maintain tight control (80-110 mg/dL) are associated with fluctuation in BG levels beyond the desired range and a high incidence of hypoglycemia (4,5,18). The incidence and severity of hypoglycemia are significantly increased when attempting to achieve tight BG control using intensive insulin therapy (5,19).

The BG range 100 to 180 mg/dL has traditionally been recommended to minimize the risk for hypoglycemia and the sequellae of hyperglycemia. Levels above 180mg/exceed the renal threshold for glucose and increase the risk for dehydration and electrolyte imbalance (14-17). Levels above 200 mg/dL increase the risk of infection and worst clinical outcome following cerebral and myocardial ischemia. Even brief periods of hyperglycemia have been shown to adversely effect cellular and humoral immunity (7-8). Acute hyperglycemia delays gastric emptying and may increase the risk for aspiration pneumonia (21). Recent evidence suggests that high glycemic variability may be associated with increased morbidity and mortality (18).

The results of a landmark study performed by Van den Berghe etal. highlighted the importance of glucose control in an ICU population of medical and postoperative cardiac surgical patients. The prospective randomized trial was designed to determine a difference in clinical outcome resulting from an intravenous infusion of insulin titrated to achieve normal BG control (< 110 mg/dL) versus insulin titrated to achieve moderate hyperglycemia (180-200 mg/dL). End-organ complications were decreased and long-term survival increased when BG levels were maintained < 110 mg/dL. Mortality in the group of patients who required ICU care for more than five days decreased from 20.2% in the conventional-treatment group to 10.6% in the intensive-treatment group at 12 months post discharge. Death in the intensive care unit decreased from 8.0% to 4.6% (43% relative reduction). Intensive insulin therapy and tight glucose control provided the greatest protection from death by decreasing the incidence and severity of systemic infection (multiple-organ failure with a proven septic focus). The intensive-treatment group had an overall 34% reduction in hospital mortality, 46% reduction in bloodstream infections, 41% reduction in renal failure requiring dialysis, 50% reduction in the median number of red blood cell transfusions, and a reduction in the need for prolonged mechanical ventilation. Hypoglycemia, defined as a BG level less than 40 mg/dL, occurred in 39 patients in the intensive-treatment group (N= 765) and six patients in the conventional-treatment group (N= 783) (4).

Van den Berghe performed an identical prospective study in a cohort of medical patients requiring long-term intensive care. Similar to the original study, major adverse events were significantly reduced in patients treated aggressively with insulin. Mortality was significantly reduced in those hyperglycemic patients treated intensively with insulin (BG < 110 mg/dL) for three of more days. Although hypoglycemia (BG < 40 mg/dL) occurred in 22% of the patients treated with intensive insulin therapy, serious adverse events related to hypoglycemia were not reported (5).

A retrospective review of medical and surgical inpatients by Umpierrez etal. found a 38% prevalence of hyperglycemia. Patients that developed hyperglycemia had an 18-fold increase in (in-hospital) mortality, increased rate of infection, length of stay, and overall cost (22). A retrospective study of medical and surgical ICU patients by Krinsley etal. showed a close association between hyperglycemia and mortality. A follow-up prospective study by the same investigators documented a marked decrease in mortality, organ dysfunction, length of stay, and cost in ICU patients treated with intensive insulin therapy and tight BG control (10,11).

Furnary et al. studied the effects of intensive insulin therapy and tight BG control over 15 years in more than 3500 cardiac surgery patients. Subcutaneous tissue insulin injections were replaced by intravenous infusions of insulin, resulting in a decrease in the average BG from > 180 mg/dL to < 120 mg/dL. Risk-adjusted mortality was decreased significantly when the three-day average BG level was maintained < 150 mg/dL. The incidence of atrial fibrillation, deep sternal wound infection, length of stay, and overall cost were significantly reduced when glucose levels were aggressively controlled with intravenous insulin in the SCCU and surgical floor (6,7).

Two retrospective studies of patients undergoing cardiac surgery using an IV insulin infusion protocol revealed a close association with hyperglycemia and increased morbidity/ mortality (8,9). Kalin etal studied CABG patients treated with an intravenous infusion of insulin. In-hospital mortality in the intensively managed group was similar to the mortality rate in a matched group of 876 patients without diabetes (1.75% vs. 1.71%) (23).

A position statement released by the American College of Clinical Endocrinologists in 2005 endorsed the prevention of hyperglycemia in all hospitalized patients, regardless of prior diabetic status. The multidisciplinary team of physicians recommended that insulin be aggressively titrated to keep BG levels < 110 mg/dL in medical ICU patients and cardiac surgery patients. Non-ICU patients should be maintained < 110 mg/dL pre-prandial and

< 180 mg/dL post-prandial. The team also recommended that BG levels be maintained

< 100 mg/dL during labor and delivery of term pregnancies (24). The risk/benefit ratio of tight BG control should be determined on an individual patient basis.

Tight glucose control has been achieved with a variety of regimens. A variable-rate intravenous infusion of regular insulin has been shown to be the most effective method of providing tight BG control in surgical patients with diabetes and stress induced hyperglycemia (4-11). Insulin dose algorithms are based upon physiological principles and the pharmacokinetic/dynamic profiles of intravenous insulin. An accurate bedside glucose meter, properly trained nurses, and frequent glucose monitoring are mandatory for the safe and effective application of intensive-insulin therapy. Higher glycemic goals are required in patients that experience hypoglycemia unawareness and when nursing issues prevent an adequate frequency of BG monitoring and bedside vigilance (14-17).

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