Effectiveness of tight glycemic control on mortality and morbidity of patients undergoing cardiac surgery in hospital: a systematic review protocol

Review question/objective Broadly, the overall objective of this review is to identify the effectiveness of tight glycemic control on mortality and morbidity of patients undergoing cardiac surgery. Additional objectives are to identify: The effectiveness of tight glycemic control on mortality and morbidity of adult (young adult and aged) patients during the intra and post-operative period after cardiac surgery in hospital. The effectiveness of tight glycemic control on mortality and morbidity among diabetic patients during the intra and post-operative period after cardiac surgery in hospital. Background Historically, diabetes mellitus (DM) has been associated with a poor clinical outcome after cardiac surgery, including a higher incidence of morbidity (wound infections, ischemic events, cardiac arrhythmias, cardiac pacing, length of stay in the intensive care unit (ICU), neurological and renal complications) and mortality.1-5 Over the last decade, the incidence of DM has increased markedly in developed countries. Knowledge of the patient's diabetic status preoperatively has led to advances in perioperative clinical management, including active and continuous blood glucose control (BGC) resulting in improved clinical outcome.6 Nevertheless, derangement of glucose metabolism after surgery is not specific to patients with DM.7,8 It has been reported that up to 90% of patient without DM also have problems with their blood glucose homeostasis as a result of various surgical stresses.7,8 In such patients, the disturbances in blood glucose homeostasis have been attributed to insulin resistance and/or a failure of pancreatic-cell function caused by the systemic inflammatory response syndrome after cardiopulmonary bypass (CPB) and its effects on systemic temperature.9-11 Hyperglycemia is a well-documented common response to critical illness and metabolic stress after cardiac surgery.12,13 Stress-induced release of counter regulatory hormones such as cortisol, glucagon, epinephrine and growth hormone leads to upregulation in hepatic gluconeogenesis and glycogenolysis despite hyperinsulinemia and compromised insulin-regulated peripheral glucose uptake.14-17 Interestingly, total body glucose uptake is increased but occurs primarily in insulin- independent tissues such as the brain and red blood cells.17 Glucose uptake and glycogen synthesis in skeletal muscle is decreased, primarily due to a defect in the glucose transporter-4 (GLUT4).18 Historically, hyperglycemia in critical illness was considered a beneficial adaptation intended to supply energy to vital organs. However, evidence refutes this notion instead proving that hyperglycemia is an independent risk factor for morbidity and mortality in the perioperative period.1,19 Although the adaptive rationale for the hyperglycemic response is not well understood, acute hyperglycemia has many deleterious effects, including decreased vasodilation, impaired reactive endothelial nitric oxide generation, decreased complement function, increased expression of leukocyte and endothelial adhesion molecules, increased cytokine levels, and impaired neutrophil chemotaxis and phagocytosis, leading to increased inflammation, vulnerability to infection, and multiorgan system dysfunction.32 Intensive insulin therapy(IIT) ameliorates some of the injurious effects of hyperglycemia through the reduction of endothelial activation viadecreasing circulating levels of intercellular adhesion molecule (ICAM-1) and E-selectin,21 protecting hepatocyte mitochondrial ultrastructure,22 stimulating peripheral glucose uptake by increasing transcription of glucose transporter type 4(GLUT-4) and hexokinase,23 normalizing C-peptide and circulating adiponectin levels,24and improving the serum lipid profile by increasing low-density lipoprotein and high-density lipoprotein levels while decreasing serum triglycerides.23 Patients with hyperglycemia also have high circulating levels of proinflammatory cytokines, which in turn can lead to organ injury. Most prominent among these cytokines is tumor necrosis factor-α, which is well documented to cause both lung and renal injury.25 Esposito et al. demonstrated increased tumor necrosis factor-α, interleukin-1β, and interleukin-8 plasma levels during acute hyperglycemia, with a reduction in these inflammatory cytokines after insulin administration.26 The relationship between inflammatory cytokines and glucose metabolism is complex; in fact, hyperglycemia itself could be caused by cytokines via induction of peripheral insulin resistance. This association is witnessed clinically as patients with severe sepsis often require high doses of intravenous insulin to maintain normoglycemia.27 Hyperglycemia has been identified as a risk factor for perioperative morbidity and mortality. In 2001, Van den Berghe etal. published the first Leuven study, a randomized controlled trial (RCT) of more than 1500 surgical ICU patients in which IIT (target blood glucose [BG], 80-110 mg/dL) reduced in-hospital mortality by 34% when compared to standard therapy (target BG, 180-200 mg/dL) and significantly decreased morbidity, including bloodstream infections, acute renal failure, red-cell transfusions and critical-illness polyneuropathy.28 Other studies have shown that tight glycemic control during cardiac surgery is associated with decreased infection rates and improved survival,29,30 postoperative glycemic control in cadaveric renal transplantation decreases allograft rejection,31 and intensive insulin improves outcomes in the setting of acute neurologic injury32,33 and acute myocardial infarction.34 However, more recently, there has been considerable controversy over the safety and efficacy of IIT. The second Leuven study showed that medical ICU patients may not benefit from IIT in the same way as their surgical counterparts,35 and two studies were stopped early by data safety monitoring boards due to the high incidence of severe hypoglycemic events (BG ≤ 40 mg/dL) and other serious adverse events.36,37 Intraoperative IIT during cardiac surgery may increase the incidence of death and stroke.38 Furthermore, the use of insulin, in general, is not without its risks; along with anticoagulants, opiates, potassium chloride, and hypertonic saline, insulin is considered a “high-alert medication”, one that has the highest risk of causing injury when misused.39 Hypoglycemia can also be detrimental because the brain is an obligate glucose metabolizer. Severe hypoglycemia causes neuronal necrosis via increased concentrations of excitatory amino acids, with a predilection for the neurons of the superficial layers of the cortex and the dentate gyrus of the hippocampus; however, the cerebellum and brainstem are spared injury.40 Low BG levels also lead to increased secretion of glucagon, epinephrine, growth hormone, and cortisol. In diabetic patients, hypoglycemia is associated with neurogenic and neuroglycopenic symptoms including: seizure, coma, or even death.42One Case reports describe seizures and comas after severe, prolonged hypoglycemia in ICU patients; however, little is known about the effects of short-term accidental hypoglycemia in this population.42 Observational studies have documented that hyperglycemia after cardiothoracicsurgical procedures is associated with higher rates (approximately two-fold) of wound infection.43,44 Interventions to reduce hyperglycemia in this setting through IV insulin therapy, decrease infection rates2,5,45 and cardiac-related mortality,46 in comparison with historical control subjects. Intensive insulin therapy targeting arterial glucose levels of 80-110 mg/dl (4.4-6.1 mmol/l) in a surgical ICU patient population resulted in significant decrease in morbidity and mortality.28 However, implementation of the identical protocol in 1,200 medical ICU patients by the same investigators in the same institution diminished morbidity but failed to reduce mortality. A sixfold increase in severe hypoglycemic events (BG < 40 mg/dl [2.2 mmol/l]) was observed in the intensively treated group (18.7 vs. 3.1%), and hypoglycemia was identified as an independent risk factor for mortality.35 The largest study to date, Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR), a multicenter, multinational RCT, tested the effect of tight glycemic control on outcomes among 6,104 critically ill participants, the majority of whom (>95%) required mechanical ventilation.47 The 90-day mortality was significantly higher in the intensively treated versus the conventionally treated group (78 more deaths; 27.5 vs. 24.9%; P = 0.02) in both surgical and medical patients. Mortality from cardiovascular causes was more common in the intensively treated group (76 more deaths; 41.6 vs. 35.8%; P=0.02). Severe hypoglycemia was also more common in the intensively treated group (6.8 vs. 0.5%; P < 0.001).48 A recent meta-analysis of RCTs reported comparisons between IIT with glycemic targets of 72-126 mg/dl (4.0-7.0 mmol/l) (commonly, 80 to 110 mg/dl [4.4-6.1 mmol/l]) and less intensive therapy with targets of <150 to 220 mg/dl (<8.3-12.2 mmol/l) (commonly, 180 to 200 mg/dl [10.0-11.1 mmol/l]). Among the 8,432 critically ill patients, there was no significant difference in mortality between intensive therapy and control groups (21.6 vs. 23.3%, respectively).49 A decrease in septicemia and a fivefold increase in hypoglycemia (13.7 vs. 2.5%) were observed. In a second meta-analysis48 including 13,567 critically ill patients, a favorable effect of intensive therapy on mortality was noted only in surgical ICU patients (relative risk, 0.63; CI, 0.44 to 0.91). There was a sixfold increase in the rate of occurrence of hypoglycemia with use of intensive therapy in all ICU patients.50 Hyperglycemia is defined as any BG value>140 mg/dl (>7.8 mmol/l). Levels that are significantly and persistently above this may necessitate treatment in hospitalized patients. In patients without a previous diagnosis of diabetes, elevated BG concentrations may be due to stress hyperglycemia, a condition that can be established by a review of prior medical records or measurement of A1C. A1C values of >6.5-7.0% suggest that diabetes preceded hospitalization.51 Hypoglycemia is defined as any BG level<70 mg/dl (<3.9 mmol/l).52 This is the standard definition in outpatients and correlates with the initial threshold for the release of counter regulatory hormone.53 Severe hypoglycemia in hospitalized patients has been defined by many clinicians as <40 mg/dl (<2.2 mmol/l), although this value is lower than the approximate 50 mg/dl (2.8 mmol/l) level at which cognitive impairment begins in normal individuals.54 As with usual hyperglycemia, hypoglycemia among inpatients is also associated with adverse short-term and long-term outcomes. Early recognition and treatment of mild to moderate hypoglycemia (40 and 69 mg/dl [2.2 and 3.8 mmol/l], respectively) can prevent deterioration to a more severe episode with potential adverse sequelae.55,56 Bedside BG monitoring with use of point-of-care (POC) glucose meters is performed before meals and at bedtime in most inpatients who are eating usual meals. It is important to avoid routine use of correction insulin at bedtime. In patients who are receiving continuous enteral or parenteral nutrition, glucose monitoring is optimally performed every four to six hours. In patients who are receiving cycled enteral nutrition or parenteral nutrition, the schedule for glucose monitoring can be individualized but should be frequent enough to detect hyperglycemia during feedings and the risk of hypoglycemia when feedings are interrupted.57,58 More frequent BG testing, ranging from every 30 min to every two hours, is required for patients receiving IV insulin infusions.59 A search was done of the JBI and Cochrane libraries in addition to PubMed to determine if there were any recent systematic reviews that had been conducted on this topic.A systematic review and meta- analysis was performed by Haga et al in 2011 evaluating the effect of tight glycemic control during and after cardiac surgery on patient mortality and morbidity. That review is out of date as it was performed in 2011.The meta-analysis used only published literature and there was no subgroup analysis on diabetic patients. More outcomes could be included (for example acute renal failure, stroke, deep sternal infection, re-infarction).Furthermore, there is no critical appraisal performed.60 This systematic review will synthesize all available evidence to determine whether tight glycemic control is effective in patients undergoing cardiac surgery to improve their peri and postoperative outcomes (mortality and morbidity).