Inflammation/Hormones Increase Adverse Outcomes
Hyperglycemia and glucose intolerance are common manifestations of perioperative stress in many hospitalized patients. Diabetic patients have more frequent, more prolonged, and more expensive hospital admissions that result in increased morbidity and mortality than nondiabetics. Diabetic patients also require more frequent surgical interventions and are more often admitted to the intensive care unit (ICU). Moreover, it is common for even nondiabetic surgical and ICU patients to develop acute hyperglycemia during stress. This hyperglycemia is mediated by the release of proinflammatory cytokines (e.g., TNF-alpha and IL-6) and elevated concentrations of catecholamines, growth hormone, glucagon, and glucocorticoids. These mediators induce metabolic alterations in carbohydrate balance that alter peripheral glucose uptake and utilization, increase gluconeogenesis, depress glycogenesis, and induce glucose intolerance and insulin resistance.
Hyperglycemia produces deleterious effects on the immune system, neutrophil function, and on the response to endotoxin. As a consequence, acute hyperglycemia adversely affects patient outcomes. Diabetic patients undergoing cardiac surgery managed with tight perioperative glycemic control have a lower rate of sternal wound infection and hospital mortality.2–4 In a large nonrandomized study, 2,467 diabetic cardiac surgical patients were classified in 2 sequential groups, the control group with “usual” sliding scale insulin glucose control and the study group with continuous intravenous insulin infusion to maintain blood glucose <200 mg/dL.2 Continuous insulin infusion resulted in lower glucose levels and was associated with significantly lower incidence of sternal wound infection (0.8 vs. 2%) and lower postoperative mortality (2.5 vs. 5.3%). In a subsequent analysis of 4,864 diabetic patients who underwent open-heart procedures, the investigators reported that a 3-day continuous insulin infusion that kept glucose levels <150 mg/dL was a key factor in improved outcomes.4 Modulation of the metabolic state during cardiac ischemia and inhibition of lipolysis by insulin stimulates nitric oxide production and may confer cardiac protection. For instance, in a prospective randomized study of 141 coronary artery bypass graft (CABG) patients, Lazar and colleagues found that tight glycemic control (serum glucose, 125–200 mg/dL) decreased the incidence of recurrent wound infections, episodes of recurrent ischemia, atrial fibrillation, and postoperative length of stay.5 Outcome in patients without diabetes undergoing cardiac surgery also improved with tight glycemic control.6–9 An increase of only 20 mg/dL in the mean intraoperative glucose was linked to an increase of more than 30% in adverse outcomes.8
ICU and Similar Patient Groups
Numerous prospective, randomized trials confirm that maintenance of normoglycemia in critically ill patients (plasma glucose between 80–110 mg/dL) improves ICU outcomes.6–14 Euglycemia can be achieved in ICU patients with insulin infusion protocols and reduces
- ICU mortality (–32%)
- in-hospital mortality (–34%)
- serious infections rate
- onset of acute renal failure
- duration of ventilatory dependence.10,11
While these benefits are more difficult to document in medical ICU patients,12 it is clear that appropriate use of insulin decreases complications from hyperglycemia associated with the response to acute disease, with or without a direct impact on the primary disease process itself.12–14
Other patients with acute illness and hyperglycemia are also at risk. The Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) study revealed that intensive glycemic control during the peri-infarction period reduced long-term mortality rate (1 year, –28%; 3.4 years, –25%).15 That benefit was evident regardless of the antidiabetic regimen used (DIGAMI 2) emphasizing the importance of maintaining euglycemia.16 Acute stroke patients have higher mortality rates and poorer recovery when blood glucose exceeds 110 mg/dL.17 Thus, evidence supports the use of aggressive insulin protocols to manage hyperglycemia in patients admitted to acute care hospitals for myocardial infarction, stroke, those with a previous diagnosis of diabetes, and those patients undergoing surgery.18,19
Tight glucose control demands frequent measurement (at least hourly initially) of glucose concentration and a consistent approach to management. Ideally, a glucose control protocol must fulfill these criteria:
- Ability to make rapid, precise, consistent modifications in blood sugar
- Ability to maintain, increase, or decrease blood sugar depending on clinical situation
- Ability to monitor glucose levels quickly, close to real time with trend detection to allow preemptive glucose management. (See the appendix below for a protocol example from the University of Minnesota.)
The risk of hypoglycemia and difficulty of attaining normoglycemia with a tight glycemic control protocol is an important safety concern in both cardiac and other ICU patients.20 In 2 recent studies, a novel approach, the hyperinsulinemic normoglycemic clamp technique, achieved normoglycemia even during especially high stress such as cardiac surgery. This technique involves a fixed, relatively high-dose infusion of insulin and then uses a variable rate of glucose infusion to “clamp” the blood glucose concentration at an appropriate level.21–23 However, this methodology is incredibly labor and time intensive, too.
Although the methodology for administering insulin and glucose may be debated, the clinical end-point is not. The American College of Endocrinology position statement recommends maintaining blood glucose ≤110 mg/dL (<6.1 mM) in intensive care patients to decrease perioperative complications and in-hospital morbidity and mortality.24 Most insulin protocols for ICU patients target glucose levels in the physiologic range of 80–110 mg/dL.10–12 However, we still need to elucidate the exact biochemical mechanisms by which the benefit of normoglycemia is actually conferred.6 Indeed, although insulin is the primary agent available to lower blood sugar, recently available pharmacologic agents, such as the incretin mimetics, amylin and exenatide, which can actually lower glucagon release, may confer metabolic advantages distinct from insulin treatment alone. Other strategies to ameliorate the perioperative “stress response” in surgical patients include interventions like epidural or spinal blockade to reduce catecholamine secretion and improve insulin responsiveness.
In summary, we believe that whenever hyperglycemia and/or insulin resistance occur, early detection and effective insulin therapy is indicated. Clearly, the potential of hypoglycemia remains the most serious safety issue. Recent clinical reports suggest hypoglycemia may be associated with multiple factors, including misunderstanding of the insulin administration protocol, rebound response from concomitant intravenous bolus of corticosteroids, and other complex insulin and drug-patient interactions. Therefore, there is intense interest in continuous glucose level monitoring technology, which promises a means of avoiding, undiagnosed and untreated hypoglycemia. We also await the findings of additional important clinical studies regarding these issues.25
Dr. Apostolidou is Associate Professor of Anesthesiology at the University of Minnesota in Minneapolis, MN. Dr. Prielipp is Professor and Chair of the Department of Anesthesiology at the University of Minnesota in Minneapolis, MN. Dr. Prielipp is also Chair of the APSF Committee on Education and Training and a member of the APSF Executive Committee.
GOAL: Maintain glucose level between 80–100 mg/dL. Start protocol only if glucose >110 mg/dL x 2. This protocol is not to be used for patients in Diabetic Ketoacidosis (DKA).
- Discontinue all currently active insulin orders.
- Insulin infusions will be provided as 1 unit of regular insulin/mL in 0.9% Sodium Chloride, in 30 mL syringes, unless otherwise requested.
- If patients are on Parenteral Nutrition/Enteral Feeding, and they are held or cycled, contact MD for specific instructions regarding the insulin infusion.
- If subcutaneous insulin (correction scale or scheduled) is ordered, discontinue the insulin infusion 2 hours after the first dose of Sub-Q insulin.
- Discontinue this protocol when the patient has achieved glycemic control, and is being transitioned to subcutaneous insulin or no longer requires insulin therapy. See Transition Insulin Orders.
- Bedside glucose monitor (whole blood glucose) Q1H until glucose is stable within 80–110 mg/dL x 4, then Q2H until insulin infusion is discontinued. If subsequent glucose values are outside the 80–110 mg/dL range, measure whole blood glucose Q1H.
- Obtain a STAT plasma glucose for changes in mental status, diaphoresis, or unexplained tachycardia.
INITIATION OF CONTINUOUS INSULIN INFUSION PROTOCOL
STEP ONE. For initial glucose value, start insulin infusion according to scale below:
|Initial glucose value||Action taken|
|111–140 mg/dL||Start insulin infusion @ 1 unit/hour.|
|141–175 mg/dL||Start insulin infusion @ 2 units/hour.|
|176–220 mg/dL||Give 2 units IV bolus of regular insulin and start insulin infusion @ 2 units/hour.|
|221–300 mg/dL||Give 4 units IV bolus of regular insulin and start insulin infusion @ 3 units/hour.|
|301–400 mg/dL||Give 10 units IV bolus of regular insulin and start insulin infusion @ 4 units/hour.|
STEP TWO. For second blood glucose value, adjust insulin infusion according to scale below:
|Second glucose value||Action taken|
|<80 mg/dL||Follow instructions for blood glucose value in Step Three.|
|80–110 mg/dL||No changes. Continue current infusion rate.|
|111–400 mg/dL||Increase insulin infusion BY 2 units / hour.|
|>400 mg/dL||Notify MD.|
STEP THREE. For all blood glucose values after the second reading, adjust insulin infusion according to scale below:
|Blood glucose value||Action taken|
|<40 mg/dL||Hold insulin infusion. Notify MD. Give 50 mL IV of Dextrose 50%. Recheck blood glucose in 15 min. If <80 mg/dL, repeat 50 ml Dextrose 50%. If recheck glucose >80 mg/dL, then restart insulin infusion at half previous rate.|
|40–59 mg/dL||Hold insulin infusion. Give 25 mL IV of Dextrose 50%. Recheck blood glucose in 15 minutes. If <80 mg/dL, repeat 25 mL of Dextrose 50%. If recheck glucose >80 mg/dL, then restart insulin infusion at half previous rate.|
|60–79 mg/dL||Hold insulin infusion. Recheck blood glucose in 1 hour. If <80 mg/dL, follow STEP 3 protocol. If recheck glucose >80 mg/dL, then restart infusion at half previous rate.|
|80–110 mg/dL||No changes if blood glucose stable within range. If blood glucose is fluctuating within range, titrate in 0.5 unit increments based on patient response to keep within range.|
|111–175 mg/dL||Increase insulin infusion BY 0.5–1 unit/hour.|
|176–220 mg/dL||Increase insulin infusion BY 1–2 units/hour.|
|221–260 mg/dL||Increase insulin infusion BY 2–3 units/hour.|
|261–300 mg/dL||Increase insulin infusion BY 4 units/hour.|
|301–350 mg/dL||Increase insulin infusion BY 5 units/hour.|
|351–400 mg/dL||Increase insulin infusion BY 6 units/hour.|
|>400 mg/dL||Notify MD.|
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- Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg 1999;67:352–60.
- Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003;125:1007–21.
- Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocr Pract 2004;10(Suppl 2):21–33.
- Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation 2004;109:1497–502.
- Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J Clin Invest 2004;114:1187–95.
- Latham R, Lancaster AD, Covington JF, et al. The association of diabetes and glucose control with surgical-site infections among cardiothoracic surgery patients. Infect Control Hosp Epidemiol 2001;22:607–12.
- Gandhi GY, Nuttall GA, Abel MD, et al. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc 2005;80:862–6.
- Doenst T, Wijeysundera D, Karkouti K, et al. Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2005;130:1144.
- Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill hospitalized patients: a meta-analysis of randomized controlled trials. Arch Intern Med 2004;164:2005–11.
- Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–67.
- Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449–61.
- Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc 2003;78:1471–8.
- Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 2004;79:992–1000. Aug;80(8):1101.
- Malmberg K, Norhammar A, Wedel H, Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999;99:2626–32.
- Malmberg K, Ryden L, Wedel H, et al.; DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650–61.
- Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001;32:2426–32.
- Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87:978–82.
- Clement S, Braithwaite SS, Magee MF, et al; American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004;27:553–91.
- 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.
- Smith CE, Styn NR, Kalhan S, et al. Intraoperative glucose control in diabetic and nondiabetic patients during cardiac surgery. J Cardiothorac Vasc Anesth 2005;19:201–8.
- Carvalho G, Moore A, Qizilbash B, et al. Maintenance of normoglycemia during cardiac surgery. Anesth Analg 2004;99:319–24.
- Coursin DB, Prielipp RC. The new anesthesia diet plan: keeping perioperative carbs in check. Anesth Analg 2004;99:316–8.
- Garber AJ, Moghissi ES, Bransome ED Jr, et al.; American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control. American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract 2004;10:77–82.
- Bellomo R, Egi M. Glycemic control in the intensive care unit: why we should wait for NICE-SUGAR. May Clin Proc 2005;80:1546–1548.