Postoperative glycemic control in cardiac surgery patients

Abstract

Glycemic control in postoperative cardiac patients is necessary to improve outcomes in wound infection and overall mortality. In recent years, clinical trials evaluating blood glucose control in critically ill patients advocated for intense blood glucose management and found a significant reduction in morbidity and mortality. Some organizations published recommendations regarding blood glucose management in critically ill patients reflecting this information. However, recent clinical trials evaluating blood glucose target ranges in critically ill patients have found conflicting results, which has prompted reevaluation of current goals and guidelines, allowing for less stringent blood glucose target ranges. With the inconsistency of clinical trials evaluating a target blood glucose range for critically ill patients, specifically postoperative cardiac surgery patients, the target blood glucose range is still not clearly defined. Additional comparisons of specific glucose ranges would allow for a clearer definition of recommended blood glucose goals to target in postoperative cardiac patients.

Blood glucose management in critically ill patients remains an ongoing controversy. In recent years, clinical trials evaluating blood glucose control in critically ill patients advocated for intense blood glucose management, with target blood glucose levels between 80 and 110 mg/dL (1). Intense blood glucose control resulted in a reduction in morbidity and mortality in the critically ill patient population, with a large portion of these patients being cardiovascular surgery patients. Clinical trials evaluating other patient populations have shown a reduction in morbidity with a lesser impact on mortality using tight blood glucose control (2). Additional clinical trials conducted to evaluate the benefit of tight blood glucose control have shown a negative impact on mortality due to hypoglycemia and contribute to the body of evidence disputing the need for tight blood glucose control (3). Given the conflicting results from these recent trials, the target blood glucose range for critically ill patients, specifically postoperative cardiac surgery patients, is still not clearly defined.

Blood glucose disturbances from cardiac bypass pump exposure are well documented (4). However, the ability of hyperglycemia to impair leukocyte function via impaired phagocytosis and bacterial killing and lead to infection—specifically surgical or sternal wound infections—was not well established until later (5). Postoperative blood glucose management has been evaluated in diabetic patients, and recent literature includes both diabetic and nondiabetic patients undergoing cardiac surgery. These studies attempt to define optimal postoperative blood glucose goal ranges in both populations.

Initial research assessed benefits of blood glucose management for prevention of sternal wound infection in diabetic patients undergoing open heart surgery (6). An early study by Zerr et al compared an insulin infusion protocol to maintain postoperative blood glucose <200 mg/dL to usual blood glucose control (6). The study involved 1585 diabetic patients: 990 patients before the insulin infusion protocol from 1987 to 1991 and 595 patients after protocol initiation from 1991 to 1993. The average blood glucose value in the protocol arm was 172 mg/dL compared with 206 mg/dL in the control arm. On postoperative day 2, the average blood glucose was 176 mg/dL in the protocol arm and 195 mg/dL in the control arm. The incidence of deep wound infections, including both the sternal site and the leg incision, decreased from 2.4% in the control arm to 1.5% in the treatment arm (P < 0.02); for the sternal site alone, the rates were 2.8% and 0.74%, respectively. Elevated mean blood glucose levels within the first 48 hours after surgery were found to be associated with deep sternal wound infections and to be an independent risk factor for deep sternal wound development (6).

Furnary et al conducted a follow-up study evaluating deep sternal wound infections in diabetic patients undergoing cardiac surgery; the standard arm received sliding-scale insulin every 4 hours to maintain blood glucose <200 mg/dL, and the study arm received a continuous insulin infusion to maintain blood glucose <200 mg/dL (7). The researchers found a significant decrease in deep sternal wound infections in the study arm (P = 0.005).

Another study by the same investigators evaluated hospital mortality in diabetic patients undergoing coronary artery bypass graft surgery (CABG) (8). Subjects in the study arm received an insulin infusion for 72 hours after surgery to maintain blood glucose, and those in the control arm received sliding-scale insulin to maintain blood glucose. Blood glucose goals were gradually lowered throughout the study: from 1991 to 1998, the goal was 150 to 200 mg/dL (group 1); from 1999 to 2000, 125 to 175 mg/dL (group 2); and in 2001, 100 to 150 mg/dL (group 3). The overall mortality in the continuous insulin infusion arm, including all three groups, was 2.5% compared with 5.3% in the control group (P < 0.0001). The blood glucose goals were gradually decreased within each range to allow nurses to become comfortable with the protocol as well as to ensure patient safety. Overall mortality was decreased in the insulin infusion group; however, it was unclear if mortality decreased with each incremental decrease in blood glucose goals.

In 1991, the American College of Cardiology (ACC) and American Heart Association (AHA) Guidelines for Coronary Artery Bypass Graft Surgery made no recommendations related to blood glucose control in CABG patients, although the increased risk of sternal wound infections in diabetics was noted (9). In the 1999 version, the guidelines recommended an insulin infusion maintaining blood glucose <200 mg/dL (10).

One of the first trials evaluating intensive blood glucose control, blood glucose 80 to 110 mg/dL, produced significant benefits. The trial was conducted by van den Berghe et al. Approximately 1500 critically ill patients were included in this randomized trial, consisting of both diabetic and nondiabetic patients, the majority of whom underwent cardiac surgery. A continuous insulin infusion was used to maintain blood glucose at two different levels: from 80 to 110 mg/dL in the intensive treatment arm and from 180 and 200 mg/dL in the conventional arm. The average blood glucose levels in the intensive and conventional treatment arms were 143 and 173 mg/dL, respectively. There was a significant reduction in overall mortality in the intensive arm (4.6%) compared with the conventional arm (8%) (P < 0.04), in addition to decreases in the incidence of septicemia, number of blood transfusions, length of stay in the intensive care unit (ICU), incidence of renal failure, number of bloodstream infections, and other morbidities (1). This trial showed the largest positive impact on mortality and led to further trials evaluating various blood glucose goals in cardiac surgery patients; however, none were able to recreate such a widely noticeable impact on patient outcomes.

Another study assessing effects of tight blood glucose control, 120 to 200 mg/dL, using continuous insulin infusion in diabetic patients after cardiac surgery reported decreases in length of stay and deep surgical wound infections; however, the differences were not significant (11). A study by Carr et al evaluating the effect of lower blood glucose goals (<130 mg/dL) demonstrated a significant benefit with intensive blood glucose control in patient morbidity outcomes; however, mortality was not assessed (12). In that study, both diabetic and nondiabetic patients were included, with a continuous insulin infusion initiated at decreasing blood glucose ranges set over specified time periods. In the last two phases of the study, insulin infusions were initiated when blood glucose was >125 mg/dL and 110 mg/dL. Patient glucose levels were considered well controlled if they were <130 mg/dL for more than 50% of the time. A reduction in the incidence of sternal wound infections was observed (0.4% to 0%) when the insulin infusion was initiated at a blood glucose of >125 mg/dL. The same rate of sternal wound infections was maintained in the final phase of the study when the insulin infusion was initiated at a blood glucose >110 mg/dL (12).

A trial by LeComte et al evaluated additional endpoints, including incidence of renal failure in patients with intensive blood glucose control utilizing an insulin infusion (80–110 mg/dL) versus those patients without intensive blood glucose control. To maintain blood glucose, all patients were initiated intraoperatively on fluids that contained dextrose. A significant decrease in the incidence of postoperative renal injury and renal failure was found, but only in nondiabetic patients (13). In the nondiabetic patients, 30-day mortality was also decreased (P < 0.05).

Based on much of the new information at that time, the AHA/ACC guidelines were reevaluated in 2004, and recommendations similar to those published in 1999 were maintained, that blood glucose should be <200 mg/dL (10, 14). These guidelines did not recommend intensive blood glucose control (80–100 mg/dL). However, in 2007, guidelines from the American Association of Clinical Endocrinologists (AACE) for in-hospital management of blood glucose in critically ill patients suggested a goal blood sugar of 80 to 110 mg/dL (15). This was a significant decrease in the suggested blood glucose target range. The recommendations seem to be based upon known deleterious outcomes of patients with elevated blood glucose (16–19) as well as many other studies showing benefit in patients undergoing cardiac surgery with controlled blood glucose and the studies showing survival rates with various glucose ranges (1, 6, 8, 11–13, 20, 21).

The Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial compared intensive blood glucose control (81–108 mg/dL) with conventional control (<180 mg/dL) (3). The trial included critically ill patients; approximately 37% were operative admissions to the ICU. The number of cardiovascular surgery patients was not defined. Approximately 6000 critically ill patients admitted to the ICU were enrolled, with 3054 in the intensive arm and 3050 in the conventional arm. Within the conventional arm, a continuous insulin drip was initiated if blood glucose rose above 180 mg/dL and was discontinued if the blood glucose fell below 144 mg/dL. A similar percentage of patients in both arms had a history of diabetes at baseline. At 90 days, the primary outcome was assessed, and mortality was greater in the intensive glucose control arm—28% compared with 25% in the conventional arm (P = 0.02). The absolute difference in mortality was 2.6%. The results were drastically different than previous evidence supporting the practice of intensive glucose control and prompted reevaluation of blood glucose goals for critically ill patients. The NICE-SUGAR trial provided evidence against intensive blood glucose control due to increased mortality in these patients. However, only a minority of the patients were operative admissions, and even fewer were postoperative cardiac patients.

Studies showing no benefit with intensive blood glucose control raise questions about target blood glucose ranges in cardiac surgery patients. A metaanalysis in 2008 evaluated benefits of intensive blood glucose control in critically ill patients, evaluating intensive control in medical ICU patients, surgical ICU patients, and patients in a combined medical-surgical ICU. The metaanalysis showed no overall benefit in intensive blood glucose goals when all ICUs were included or when only the surgical ICU was evaluated (22). However, the surgical ICU studies included in the metaanalysis were not specifically evaluating cardiac ICU or cardiac surgery patients.

A recent study in 2009 evaluated blood glucose target ranges: a treated range of 80 to 130 mg/dL and a control group of 160 to 200 mg/dL (23). No difference between the two groups was found in various clinical outcomes, including mortality, length of stay, and infection rate.

Intraoperative blood glucose control has been evaluated in patients undergoing cardiopulmonary bypass surgery to determine if elevated blood glucose during bypass affects mortality and if tight blood glucose control during surgery allows for improved glucose control postoperatively. Lazar et al evaluated a glucose-insulin-potassium (GIK) infusion in diabetics during surgery and postoperatively for tight control of blood glucose (goal blood glucose, 125–200 mg/dL) compared with standard therapy with sliding-scale insulin (goal blood glucose, <250 mg/dL). No impact on mortality was found; however, the GIK infusion arm showed a significant decrease in infection rates, length of stay, mechanical ventilator time, and incidence of atrial fibrillation (24). Ouattara et al also evaluated intraoperative blood glucose control and outcomes on multiple morbidities; mortality was not evaluated. An association was found between increased morbidity and poor intraoperative glycemic control (25).

Gandhi et al (26) also evaluated intensive blood glucose control with an insulin infusion (goal blood glucose, 80–100 mg/dL) compared with conventional treatment with an insulin infusion (blood glucose goal, 150–200 mg/dL) in both diabetic and nondiabetic patients. A composite outcome of death, sternal wound infections, prolonged pulmonary ventilation, cardiac arrhythmias, stroke, and acute renal failure within 30 days was evaluated. Mean blood glucose was 123 versus 148 mg/dL during bypass and 114 versus 157 mg/dL postoperatively in the ICU in the intensive control and conventional arms, respectively. There was no significant difference between groups in the primary composite outcome. Individual endpoints were analyzed separately, finding an increase in death, stroke, and heart block requiring pacemaker in the intensive insulin control arm.

With more conflicting evidence and literature reporting poor outcomes with intensive blood glucose control, recommendations regarding blood glucose goals have been revised. In 2007, the AACE recommended a goal blood sugar of 80 to 110 mg/dL in critically ill inpatients (15). However, consensus statements from the AACE and American Diabetes Association (ADA) published in 2009 now recommend utilization of an insulin infusion to maintain blood glucose between 140 and 180 mg/dL in critically ill patients, with possibly increased benefit in maintaining a blood glucose closer to 140 mg/dL. Maintenance of blood glucose below 110 mg/dL is no longer recommended (27). In addition, the Society of Thoracic Surgeons published guidelines regarding blood glucose management during cardiac surgery, recommending maintenance of blood glucose <180 mg/dL utilizing an insulin infusion. In patients who spend >3 days in the ICU, require an intraaortic balloon pump, inotropic medications, or left ventricular assist devices, receive antiarrhythmic drugs, or are on dialysis, a blood glucose level of <150 mg/dL is recommended (28). The Joint Commission and the Surgical Care Improvement Project have also issued requirements that morning blood glucose on postoperative day 1 and 2 be <200 mg/dL (29). These new blood glucose goals are more lenient than the intensive blood sugar goals utilized in many institutions.

Based on recent information, the new Society of Thoracic Surgeons guidelines and the AACE/ADA consensus statement seem appropriate and allay the concern for hypoglycemia with the new recommended range of <180 and 140 to 180 mg/dL. More studies analyzing blood glucose target ranges seem necessary to further recommend an intensive blood glucose goal range of 80 to 110 mg/dL, especially in the cardiac surgery population. Even throughout the Van Den Berghe trials, the average blood sugar of patients in the intensive control arm was approximately 140 mg/dL. Thus, aiming for blood glucose levels around 140 mg/dL appears reasonable. Mortality and morbidity benefits are seen with overall control of hyperglycemia; however, the exact range is still not clearly defined, as previously thought. Additional comparisons of specific glucose ranges would allow for a clearer definition of recommended blood glucose goals in postoperative cardiac patients, resulting in the best outcomes and least incidence of hypoglycemia.