Asian Cardiovasc Thorac Ann 2007;15:534-538
© 2007 Asia Publishing EXchange Ltd
Importance of Perioperative Blood Glucose Management in Cardiac Surgical Patients
Timothy SJ Shine, MD,
Mihoko Uchikado, MD,
Claudia C Crawford, MD,
Michael J Murray, MD
Department of Anesthesiology, Mayo Clinic Jacksonville, USA
For reprint information contact: Michael J Murray, MD Tel: 1 480 301 1800 Fax: 1 480 301 2319 Email: murray.michael{at}mayo.edu, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
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ABSTRACT
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Tight blood glucose control has become a therapeutic goal for anesthetic management of patients undergoing cardiovascular surgery. We discuss the evidence for a link between blood glucose levels and rates of morbidity and mortality in cardiac surgical patients in the intensive care unit. Hyperglycemia per se has been associated with higher rates of deep wound infection, neurologic, renal, and cardiac complications following surgery, as well as longer intensive care unit stay. We review the specifics of glucose management in patients undergoing cardiac surgery and hypothermic cardiopulmonary bypass, including the role that insulin may play in regulating blood glucose levels intraoperatively and the relationship between insulin and outcome.
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INTRODUCTION
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Along with hemodynamic stability and ventilatory support, the maintenance of more physiologic blood glucose levels can be added to the list of goals for the anesthesiologist caring for a patient undergoing cardiac surgery. The link between better blood glucose control and decreased mortality and morbidity has been established in the cardiac surgical intensive care unit (ICU) setting.1 Clinicians are using these data to justify better intraoperative management of glucose in patients undergoing cardiovascular surgery.2–4 The US government’s proposal to link financial reimbursement to outcome has increased even further the emphasis on tighter control of blood glucose levels during cardiac surgery.5,6 One suggestion has been to link reimbursement to the maintenance of blood glucose levels < 11.1 mmol·L–1 (200 mg·dL–1) throughout the perioperative cardiovascular surgical period. Medical insurers in the US, both private and public, are increasingly turning to such incentives to achieve clinical objectives.
In this review, we will first discuss the literature showing an association between elevated blood glucose levels and increased morbidity and mortality in patients in the ICU. We will then review the literature suggesting that there is an association between morbidity and mortality rates and intraoperative blood glucose levels in patients having cardiovascular surgery. In this context, we will review some of the specifics relating to patients undergoing cardiac surgical procedures that predispose them to insulin resistance and hyperglycemia. We will also make recommendations on how best to control blood glucose during cardiac operations.
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EVIDENCE FOR HYPERGLYCEMIA AND INCREASED MORBIDITY AND MORTALITY
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Before defining hyperglycemia, one must first understand how glucose is measured. If a finger stick technique is used intraoperatively, with the result measured in the operating room, blood glucose is measured. If one draws blood and sends it to the laboratory, plasma or serum glucose is reported. As whole blood stands in a test tube, glucose levels decrease as blood cells metabolize glucose. Laboratories avoid this problem by initially centrifuging the test tube to pellet the blood cells, and subsequently measure the plasma or serum glucose, depending on how the blood was collected. The difference is usually small, 7%–8%, and for the purposes of this paper, we will discuss hyperglycemia based on blood glucose measurements.7,8
Umpierrez and colleagues9 recently reviewed the relationship between blood glucose concentration on hospital admission and hospital mortality in 2,030 patients with myocardial infarction or acute stroke, dividing them into 3 groups: normoglycemic patients (fasting blood glucose levels of 7 mmol·L–1; 126 mg·dL–1), known diabetics, and new hyperglycemic patients. In this latter group, the hyperglycemia may be a result of acute stress, medications (steroids), or a manifestation of new-onset diabetes. Those with a new onset of hyperglycemia had a higher hospital mortality rate of 16% compared to 3% in patients with a history of diabetes and 1.7% in patients with normal blood glucose. The new-onset hyperglycemic patients also had a higher rate of admission to the ICU and a longer hospital stay.9 Malmberg10 studied patients with acute myocardial infarction and followed them for at least 3 years. The patients were stratified for risks of congestive heart failure and previous myocardial infarction. Those who had intensive metabolic treatment, receiving insulin infusion for at least 24 hours followed by multidose insulin treatment 4-times daily for at least 3 months, showed improved long-term survival rates compared to those who did not receive intensive insulin therapy. More recently, van den Berghe and colleagues1 examined the use of intensive insulin therapy in ICU patients that began when blood glucose was > 6.1 mmol·L–1 (109.9 mg·dL–1) versus therapy that started when blood glucose was > 11.9 mmol·L–1 (214.4 mg·dL–1). Patients who received intensive insulin therapy were less likely to require ventilator support, had a shorter ICU stay, less renal failure requiring dialysis or hemofiltration, and lower rates of blood stream infections. They concluded that intensive insulin therapy in critically ill patients normalized blood glucose levels and reduced mortality and morbidity.1
In 2005, Gandhi and colleagues4 at the Mayo Clinic reported on 409 patients undergoing cardiac surgery and found that intraoperative hyperglycemia was associated with postoperative morbidity and mortality. When the blood glucose concentration was > 5.55 mmol·L–1 (100 mg·dL–1), a 1.11 mmol·L–1 (20 mg·dL–1) increase in glucose concentration was associated with a 34% increase in the number of postoperative adverse events. In 141 patients undergoing coronary artery bypass grafting, Lazar and colleagues11 demonstrated that clinical outcome was improved by actively maintaining tight glucose control during cardiac surgery. Patients received one of two treatments: either an intravenous solution of glucose, insulin, and potassium to maintain blood glucose between 6.9 and 11.1 mmol·L–1 (125–200 mg·dL–1) or standard therapy using intermittent subcutaneous insulin to maintain blood glucose levels < 13.9 mmol·L–1 (250 mg·dL–1). Patients who received intravenous insulin had lower blood glucose, less atrial fibrillation, fewer episodes of recurrent ischemia, and a shorter length of postoperative hospital stay.11
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RELATIONSHIP BETWEEN HYPERGLYCEMIA, DIABETES, AND OUTCOME
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Diabetic patients have an increased incidence and prevalence of atherosclerosis, and clinicians initially assumed that the patients with hyperglycemia had undiagnosed long-standing diabetes and their worse outcomes were due to poor tissue perfusion because of atherosclerosis. Gray and colleagues12 described the prognostic significance of elevated blood glucose levels in patients with hyperglycemia who had a stroke. Many of their patients were diabetic, but a significant number had stress hyperglycemia without evidence of diabetes, and they concluded that elevated blood glucose per se correlated with a worse outcome. Wingard and colleagues13 examined patients who were diabetic and either euglycemic or hyperglycemic: those with long-standing, poorly treated hyperglycemia had the worst outcome; non-diabetic euglycemic patients had the best outcome; and diabetic patients with normoglycemia on admission were in between.
As physicians have recognized the effect of hyperglycemia per se, anesthetic practice has changed. For example, after Lanier and colleagues14 observed worse outcomes in non-human primates who were hyperglycemic following a neurologic injury, glucose was removed from all intravenous solutions administered intraoperatively at the Mayo Clinic in Rochester, Minnesota. McCowen and colleagues15 found that patients who had blood glucose > 220 mg·dL–1 within 24 hours of surgery had a higher incidence of serious infection, and nutritional support practices began to change. This occurred about the same time that Malmberg10 published the results of the DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) study, showing that glucose-insulin infusions have decreased morbidity and mortality in the last 5 years. This was followed by other studies showing that controlling blood glucose in patients in the ICU improved outcome.1,3,16 These studies have changed practice in the ICU;17 and we believe other studies will change practice in the operating room.2–4
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GLUCOSE REGULATION
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Hyperglycemia is a normal response to stress, providing the brain with glucose during the flight-or-fight response. Normally, insulin release is stimulated by elevated levels of glucose. Insulin suppresses gluconeogenesis and promotes glucose uptake in muscle tissue where it is used in the Krebs cycle to produce energy or stored as glycogen to be released when necessary to maintain glucose homeostasis. When blood glucose levels fall, the counter-regulatory hormones (epinephrine, glucagon, growth hormone, and cortisol) facilitate glycolysis, releasing glucose from hepatic stores and promoting gluconeogenesis in peripheral tissues. During times of stress, such as during surgery, there is an increase in the levels of counter-regulatory hormones and inflammatory cytokines, such as tumor necrosis factor and interleukins, which results in increased hepatic glucose production, impaired peripheral glucose utilization, relative insulin deficiency, and hyperglycemia.18 In a healthy individual, hyperglycemia during stress may be beneficial, but as discussed, hyperglycemia in a critically ill patient or during surgery may be detrimental.
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INSULIN RESISTANCE
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Treating hyperglycemia in the operating room or ICU is complicated by the fact that many cardiac surgical patients have insulin resistance. While the molecular mechanisms underlying this insulin resistance are not fully known, defects in a transmembrane protein (facilitative glucose transporter protein) may play a role.19 The interaction of insulin with glucose transporter protein is a critical step in glucose utilization. A decrease in insulin receptor signaling and impaired insulin receptor binding may also play a role in insulin resistance or insensitivity.
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THE ROLE OF INSULIN
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Furnary and colleagues3 showed that patients treated with a continuous insulin infusion had a reduced rate of postoperative deep surgical site infection, compared to controls who received intermittent subcutaneous insulin. Patients undergoing CABG who received continuous insulin had a 2.5% mortality rate (65/2615 patients), compared to a 5.3% mortality rate (50/942 patients) in those who received subcutaneous insulin. Glucose control was much improved with continuous insulin infusion: 9.8 ± 1.65 mmol·L–1 (177 ± 30 mg·dL–1) vs 11.8 ± 1.71 mmol·L–1 (213 ± 31 mg·dL–1); it was concluded that continuous insulin infusion normalized hospital mortality for patients with diabetes undergoing CABG.3 They also speculated that continuous insulin infusions might provide a protective effect through the efficient metabolic use of excess glucose, by favorably altering pathways of myocardial adenosine triphosphate production. It was recommended that continuous insulin infusion become standard therapy for glucose control in patients with diabetes undergoing CABG.3
Is the protective effect of normoglycemia solely due to lower blood glucose or does insulin per se play a direct role in the improved outcome, independent of glucose levels? Rao and colleagues20 studied primary cardiomyocyte cultures from patients undergoing repair of tetralogy of Fallot. They found that the presence of insulin increased pyruvate dehydrogenase activity which enhanced myocardial metabolic recovery and reduced extracellular lactate production. They concluded that insulin protects the human cardiomyocyte from ischemia.20 Insulin promotes glucose transport across the cell membrane and reduces the rate of lipolysis from fat tissue by depressing hormone-sensitive lipase. When there is insufficient insulin, lipase is active, triglycerides are hydrolyzed, and fatty acids are released; these fatty acids are used instead of glucose for energy. In contrast, Finney and colleagues21 observed in a clinical study that increased insulin administration was positively associated with death in the ICU, regardless of the prevailing blood glucose. Their conclusion was that blood glucose level accounted for the mortality benefit rather than the absolute level of insulin. Administration of large amounts of insulin was found to be an independent risk factor for hospital mortality.22 Thus the mechanisms by which insulin alters mortality and morbidity in patients in the ICU or operating room are not clear at present.
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EFFECTS OF CARDIOPULMONARY BYPASS ON GLUCOSE CONTROL
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Blood glucose is difficult to control during cardiac surgery. Chaney and colleagues23 concluded that tight blood glucose control during cardiopulmonary bypass (CPB) was not easily achievable, as 40% of patients needed treatment for hypoglycemia (3.33 mmol·L–1; 60 mg·dL–1) in the cardiac ICU after surgery. Insulin resistance is aggravated during CPB. Lehot and colleagues24 examined the disturbance in blood glucose homeostasis and demonstrated that during hypothermic CPB, glucose levels increased and insulin levels decreased. On rewarming, blood glucose levels continued to increase, but insulin levels rose by more than 300%, associated with a concomitant increase in catecholamine, cortisol, and growth hormone levels. In patients in the ICU, Wasmuth and colleagues25 showed increasing levels of inflammatory cytokines were associated with insulin resistance. This insulin resistance observed during hypothermia is aggravated by the absorption of insulin by plastic material in the extracorporeal circuit, ongoing glucose administration in the cardioplegia solution, and steroids that are used to ameliorate the inflammatory response to CPB. During rewarming, blood glucose values continued to increase, associated with an increase in glucagon, growth hormone, and catecholamines.
During anesthesia, because patients cannot communicate the early warning signs of hypoglycemia (headache, lack of concentration, tremor, muscle weakness, visual disturbances, hunger, sweating, irritation), blood glucose levels may need to be checked frequently, with dextrose infusion immediately available to treat hypoglycemia. The majority of anesthesiologists administer dextrose when blood glucose levels decrease below 3.3 mmol·L–1 (60 mg·dL–1).
Maintenance of glucose levels with intravenous insulin is also associated with a risk of hypokalemia. Potassium is transported intracellularly with glucose and insulin; therefore, it is prudent to check serum potassium concentrations when measuring blood glucose, and treat accordingly. Glucose and potassium monitoring should be continued into the postoperative period, in the post-anesthesia care unit or ICU. As the patient continues to rewarm, insulin resistance declines, and there is further potential for hypoglycemia.
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INSULIN INFUSION
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What are the issues to consider when starting intravenous insulin infusion therapy, and what might be the appropriate goals of such treatment? Malmberg10 suggested blood glucose levels < 10 mmol·L–1 (180 mg·dL–1), and the data of Furnary and colleagues3 suggest < 8.3 mmol·L–1 (150 mg·dL–1) is best. An appropriate goal might be an intraoperative glucose level < 10 mmol·L–1 (180 mg·dL–1). An ideal insulin protocol could be easily set up and implemented in the intraoperative period, with minimal risk of symptomatic hypoglycemia. Requirements include an intravenous line with sufficient flow to keep the vein patent and available to treat hypoglycemia. Regular insulin in a concentration of 1.0 or 0.5 units·mL–1 with frequent monitoring of blood glucose levels is required. Whatever algorithm is used, it should be adjusted according to frequently checked blood glucose levels.
Infusion protocols that have been used in ICU settings are complex. In an operating room setting, they risk distracting the anesthesiologist. In the Portland protocol, the initial insulin dose is determined by the clinician, and afterwards one doubles the insulin infusion rates for glucose levels > 11.1 mmol·L–1 (200 mg·dL–1) and halves the infusion rate for glucose levels < 5.5 mmol·L–1 (100 mg·dL–1).3 Carvalho and colleagues26 demonstrated excellent glucose control using a hyperinsulinemic normoglycemic clamp technique involving separate infusions of insulin and glucose, as well as frequent blood sugar determinations. This is a very labor intensive protocol and might even increase the risk to the patient by occupying the attention of an anesthesia provider with myriad duties in a complex cardiac case. A protocol was suggested by Davidson and colleagues27 based on the following formula: units of insulin per hour = (blood glucose – 60) x multiplier. They were inspired by the infusion protocol of White and colleagues28 and after analyzing their data, they found that it yielded a regression line with an intercept of 60 and a slope of 0.02, giving a formula for the insulin infusion rate equal to the blood glucose minus 60 with a multiplier of 0.02, which increased in steps of 0.01 as the insulin resistance increased. We start with a multiplier of 0.03, increasing it to 0.04 if catecholamines or steroids are used. In severely insulin-resistant patients, a multiplier as high as 0.15 has been reported.27 If the blood glucose exceeds 9.9 mmol·L–1 (140 mg·dL–1), one should increase the multiplier by 0.01; if less than 5.5 mmol·L–1 (100 mg·dL–1), decrease it by 0.01; and if less than 7.7 mmol·L–1 (80 mg·dL–1), give 50% dextrose intravenously at a dose of 100 mL – blood glucose x 0.4. Illness or stress-related increases in the insulin requirement need to be corrected, and all components will decrease as the level of stress decreases. The simplicity of the insulin protocol is important. As the protocol becomes more complex, there is a higher risk of error, and less likelihood that anesthesiologists or nurses will use it.
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CONCLUSION
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In the 1980s, observational studies demonstrated that the outcome from stroke was worse in hyperglycemic patients. In the 1990s, nutrition specialists noted that outcome was worse in patients given nutrition support who were hyperglycemic. These observations led to a number of studies in the ICU that have demonstrated that hyperglycemia is associated with a worse outcome, changing the practice of critical care medicine. More recently, there is evidence that hyperglycemia is a common problem during cardiac surgical procedures, because of insulin resistance due to cytokines released during the surgical procedure. Administration of insulin decreases glucose concentrations and is associated with improved outcomes. The intraoperative use of insulin during cardiac surgical procedures is increased, and in doing so, one must choose an algorithm that is easy to implement and easy to follow, and which allows monitoring of patients to avoid the complications of hypoglycemia. It is anticipated that over the next few years, these insulin algorithms will become the norm in managing cardiac surgical patients intraoperatively.
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- Chaney MA, Nikolov MP, Blakeman BP, Bakhos M. Attempting to maintain normoglycemia during cardiopulmonary bypass with insulin may initiate postoperative hypoglycemia. Anesth Analg 1999;89:1091–5.[Abstract/Free Full Text]
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- Wasmuth HE, Kunz D, Graf J, Stanzel S, Purucker EA, Koch A, et al. Hyperglycemia at admission to the intensive care unit is associated with elevated serum concentrations of interleukin-6 and reduced ex vivo secretion of tumor necrosis factor-alpha. Crit Care Med 2004;32:1109–14.[Medline]
- Carvalho G, Moore A, Qizilbash B, Lachapelle K, Schricker T. Maintenance of normoglycemia during cardiac surgery. Anesth Analg 2004;99:319–24.[Abstract/Free Full Text]
- Davidson PC, Steed RD, Bode BW. Glucommander: a computer-directed intravenous insulin system shown to be safe, simple, and effective in 120,618 h of operation. Diabetes Care 2005;28:2418–23.[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION
