Hyperglycemia is strongly correlated with

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1 LITERATURE REVIEW Perioperative Hyperglycemia: A Literature Review Tammy S. Peacock, MAPSY, BSN, RN, NEA-BC, CENP, CPPS, CLSSBB ABSTRACT The purpose of this literature review is to examine current evidence and determine the effects of stress hyperglycemia on patient outcomes during the perioperative period. This review summarizes the pathophysiology of stress hyperglycemia, the population it affects, and strategies for optimal treatment to reduce the potential for postoperative complications. A literature search produced 16 of the most current studies on the effect of stress hyperglycemia in both the diabetic and nondiabetic populations. The evidence presented indicates the need to maintain tight glucose control in the perioperative patient. Although there are varying approaches to managing stress hyperglycemia, there is compelling agreement that stress hyperglycemia should be treated in all surgical patients. Key words: stress hyperglycemia, glucose control, surgical site infection, insulin resistance. Hyperglycemia is strongly correlated with increased mortality and morbidity in patients undergoing surgery In addition, undiagnosed insulin resistance is progressively more common on the day of surgery. 13 Perioperative hyperglycemia is a normal response to surgery and affects diabetic patients more than nondiabetic patients. 2 Perioperative- induced stress hyperglycemia has been linked to several postoperative complications, including sepsis, myocardial infarction, surgical site infection (SSI), and death. 2 Perioperative stress hyperglycemia can occur in patients admitted for various types of surgical procedures, including general, cardiac, vascular, and orthopedic surgery. 2 Insulin administration may attenuate some of the perioperative risks of hyperglycemia; however, target perioperative blood glucose levels remain controversial. 14 Tight perioperative glucose control with insulin may cause hypoglycemic events, which also are related to poor clinical outcomes and mortality. 9 Although hypoglycemia can be treated, it is sometimes a complicated condition because the signs are difficult to notice under anesthesia. 15 Current studies address intraoperative and postoperative periods, but limited research has been done to address preoperative glucose management or the glucose management of outpatient surgical patients. PURPOSE This literature review critically appraises and synthesizes the evidence regarding the effects of stress hyperglycemia in the perioperative period, reviews hyperglycemic treatment modalities, and correlates hyperglycemia with surgical complications using the most recent randomized control studies from the past five years. The research question was as follows: What are the recommended treatment options for perioperative stress hyperglycemia in inpatients and outpatients? RESEARCH METHODS I used key words to guide the search on October 20, 2017, for each of the following databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, and Scopus. I entered subject subheadings and word truncations according to the individual database requirements and limited the search to literature published in English 80 AORN Journal AORN, Inc, 2019

2 January 2019, Vol. 109, No. 1 Perioperative Hyperglycemia from September 2011 through September The following individual search terms were used and included: stress hyperglycemia, glucose control, surgery, perioperative, surgical complications, tight glucose control, preoperative, inpatient, outpatient, morbidity, and mortality. For this review, I limited eligible studies to those that compared any type of glucose control in adult surgical patients with surgical complications. I excluded animal studies, laboratory-only studies, editorials, and conference presentations. The original search yielded 279 full-text articles. I removed duplicates, compared the remaining articles against the exclusion criteria, and removed additional studies that did not meet the inclusion criteria (Figure 1). The remaining 16 studies were included in this review. I evaluated and appraised these studies according to the strength and quality of the evidence using the AORN Research and Non- Research Evidence Appraisal Tools, 16 and assigned an appraisal score for each article (Supplementary Table 1). PATHOPHYSIOLOGY OF STRESS HYPERGLYCEMIA The causes of hyperglycemia in the perioperative period are multifactorial. An increase in sympathetic stimulation in addition to a rise in cortisol, glucagon, catecholamines, and growth hormone occurs during physiologic stress, causing disproportionate release of inflammatory cytokines. 17 Cortisol stimulates protein catabolism and hepatic glucose production. This increase in counter- regulatory hormones (ie, glucagon, growth hormones, cortisol) initiates a proliferation in endogenous glucose production via gluconeogenesis (Figure 2). 3 During the perioperative period, impaired insulin signaling and transient insulin resistance are believed to contribute to hyperglycemia in patients with and without diabetes mellitus. 3 This period of impaired insulin signaling and transient insulin resistance is believed to occur because of counter- regulatory hormone production and an excess of circulating proinflammatory cytokines. 3 The literature indicates that transient hyperglycemia is the body s response to decreased circulating insulin levels and is most prominent on the first day after an operation; however, it may continue for days. 3 Surgeries involving the abdomen and thorax have been correlated with a more prolonged and pronounced degree of hyperglycemia. Furthermore, less invasive (eg, laparoscopic) procedures have been related to less increase in insulin resistance. 3 Preoperative carbohydrate loading as advocated by the Enhanced Recovery After Surgery program may counteract the state of insulin resistance in surgical patients. 14 The use of carbohydrate- rich drinks avoids the catabolic rate associated with starvation. Carbohydrate loading also has been shown to increase insulin sensitivity, which decreases the risk of postoperative hyperglycemia. 18 A neuroendocrine stress response, which releases counterregulatory hormones, is a result of anesthesia and the surgical procedure. The scale of this counter- regulatory response is weighted by the type of anesthesia and the severity of the surgical procedure. 19 FINDINGS The studies in this review pertained to treating perioperative hyperglycemia, assessing the appropriate target level of blood glucose, and monitoring patient outcomes of hyperglycemia induced by surgical stress. Some of the studies were performed in patients with diabetes and some in patients without diabetes, and some studied both populations simultaneously. Figure 1. Flow chart showing the different phases of the systematic review. In 2008, Umpierrez et al 4 initiated a randomized controlled trial (RCT) that compared the efficacy of types of perioperative hyperglycemic control and documented the outcomes of study participants. Participants were excluded if AORN Journal 81

3 Peacock January 2019, Vol. 109, No. 1 Figure 2. Chart detailing the hormonal response to surgical stress. they were pregnant, had liver disease, had impaired renal function, underwent cardiac surgery, had a history of diabetic ketoacidosis, or had any mental condition that made them unable to consent. The group was randomized into two different groups. The researchers compared the inpatient management of general surgery patients with type 2 diabetes who were treated with basal- bolus glargine once daily and glulisine before meals if they were able to eat with a similar group of patients who were treated with sliding scale insulin four times a day. The results revealed that basal- bolus glargine showed significantly better glycemic control in patients with type 2 diabetes. The trial also showed a lower frequency of postoperative complications (eg, systemic or localized infections, organ failure) for this group. 4 In 2015, Umpierrez et al 5 conducted an RCT to determine the optimal goal for glycemic control in patients undergoing coronary artery bypass graft surgery. The researchers randomized a pool of 302 patients into two equal- sized groups: an intensive control group with a glucose target of 100 mg/deciliter (dl) to 140 mg/dl and a conservative control group with a glucose target of 141 mg/dl to 180 mg/dl. Findings from the study showed little significant difference in the rate of complications among the two groups of the diabetic population (49% for the intensive, 48% for conservative, P =.87). The study indicated that complications among patients without diabetes were significantly lower in the intensive control group using a target glucose level of between 100 mg/dl and 140 mg/dl compared with the conservative control group using a target glucose level of between 141 mg/dl and 180 mg/dl (34% and 55% respectively, P =.008). 5 Bláha et al 6 also looked specifically at tight glucose control (TGC) in nondiabetic patients aged 18 to 90 years who underwent major cardiac surgery between 2007 and There were two study groups: the perioperative group (n = 1134) and postoperative group (n = 1249). There also were two target ranges for blood glucose control: TGC (blood glucose of 4.4 millimoles [mmol]/l to 6.1 mmol/l) and glucose control (blood glucose of 4.4 mmol/l to 8.3 mmol/l). 6 The perioperative group showed a marked decrease (23.2%) in postoperative morbidity compared with the postoperative study group (34.1%; relative risk, 0.68; 95% CI, 0.60 to 0.78). The reduction in postoperative morbidity connected with the intraoperative initiation of TGC was predominately driven by nondiabetic patients. 6 Akbarzadeh et al 7 conducted an RCT that investigated the effect of a new metabolic conditioning supplement on nondiabetic coronary artery bypass patient 82 AORN Journal

4 January 2019, Vol. 109, No. 1 Perioperative Hyperglycemia outcomes. The supplement was composed of L- carnitine (3 g), vitamin C (750 mg), glutamine (15 g), selenium (150 μg), and vitamin E (250 mg), and was designed exclusively for this study. For this RCT, 89 nondiabetic patients with an ejection fraction greater than 30% and who were scheduled for coronary artery bypass grafting were divided into four groups. Groups received either the supplement, a placebo, or a combination of supplement and placebo before and after surgery. 7 The groups were assigned as follows: 1. supplement before surgery and placebo after surgery (n = 27), 2. placebo before surgery and supplement after surgery (n = 26), 3. supplement both before and after surgery (n = 26), and 4. placebo both before and after surgery (n = 26). These researchers found that when they compared the results of the groups, all showed an increase in glucose postoperatively; however, the placebo group showed the highest increase. The patients who used the supplement both before and after maintained better controlled blood glucose levels during the perioperative period (P =.004). 7 Treatment Recommendations There are many different recommendations about glucose control in the literature, and some of the recommendations vary regarding the appropriate level of glucose control. The University of Washington Medical Center used a very tight glycemic control protocol that began with an insulin infusion with a glucose concentration of greater than 140 mg/dl to maintain a target glucose level of 100 mg/dl to 140 mg/dl. The protocol used four separate algorithms: one for type 1 diabetic patients, one for type 2 diabetic patients, and two for patients in which the target glucose level did not decrease by a prescribed amount. Intraoperative glucose was measured by a point- of- care test completed by anesthesia providers. 8,21 There are many different recommendations about glucose control in the literature, and some of the recommendations vary regarding the appropriate level of glucose control. Patient Outcomes of Stress- Induced Hyperglycemia Richards et al 11 studied the relationship between stressinduced hyperglycemia and postoperative infections of 187 trauma patients who sustained orthopedic injuries. The patient population they studied did not have a history of diabetes and the target blood glucose level for these intensive care unit patients was between 80 mg/dl and 110 mg/dl. Results of this study indicated that the risk for an SSI was increased in patients with hyperglycemia being treated for orthopedic injuries (P =.047). 11 Kiran et al 20 studied the effect of hyperglycemia in a nondiabetic colorectal surgery patient population. This study was retrospective and included 16,404 postoperative glucose measurements in 2,447 patients. Of this group, 66% showed elevated glucose levels above 125 mg/dl. This study showed septic complications and mortality were associated with hyperglycemia. Hyperglycemia also was associated with both infectious and noninfectious complications, with correlation increasing for patients with an increasing American Society of Anesthesiologists class and the severity of blood loss. 20 A study by Takesue and Tsuchida 9 at the Hyogo College of Medicine divided a patient population into surgical patients and critically ill surgical patients. The goal for the surgical patients was to maintain a glucose level of 110 mg/dl to 150 mg/dl, and for critically ill patients, the goal was a glucose level of 140 mg/dl to 180 mg/dl. This study resulted in a recommendation for both groups of patients to start an insulin infusion when the patient s glucose reached >150 mg/dl. 9 Evans et al 10 reviewed studies completed between 2001 and 2008 and differentiated between noncritically ill and critically ill surgical patients. Based on the information from the studies, these researchers recommended the use of subcutaneous insulin bolus therapy with a sliding scale to maintain blood glucose between 140 mg/dl and 180 mg/dl in the noncritically ill surgical patients when the fasting blood glucose was greater than 140 mg/dl or random blood glucose was greater than 180 mg/dl. The researchers recommended that the insulin infusion for critically ill patients should be started with a blood glucose level greater than 180 mg/dl with the goal of a blood glucose of 140 mg/dl to 180 mg/dl. 10 Researchers investigated another treatment option for perioperative AORN Journal 83

5 Peacock January 2019, Vol. 109, No. 1 Key Takeaways Stress hyperglycemia not only affects postoperative morbidity and mortality in diabetic perioperative patients, but also in nondiabetic perioperative patients. Tight glucose control during the perioperative period is supported by available evidence. Perioperative hyperglycemia may be treated with either subcutaneous insulin or an IV insulin infusion. Additional research is needed to develop hyperglycemia treatment recommendations for both inpatients and outpatients. hyperglycemia in which they did not divide the patients, but treated patients with a blood glucose of 140 mg/dl to 180 mg/dl with subcutaneous insulin and then initiated insulin infusion for those with a blood glucose greater than 180 mg/dl. 5 DISCUSSION The evidence presented in these studies shows a clear relationship between the level of glycemic control and complications after surgery. Most studies were based on cardiac, complex general, and orthopedic surgeries. In the orthopedic study, musculoskeletal trauma suggests a greater effect on hyperglycemia and increased rate of SSIs. 11 The studies that investigated outcomes of hyperglycemia concluded that nondiabetic patients were at greater risk for poorer outcomes than diabetic patients. Even with evidence to provide glucose control, compliance among anesthesia professionals is poor, possibly because of fear of a hypoglycemic effect. 8,21 Many of the studies supported the need for perioperative glucose monitoring, 1,2,5,6,8,10,14,20,21 and additional studies showed a correlation between random elevated blood glucose readings and postoperative complications. 12,20 Perioperative nurses and leaders continue to struggle with the question of how to encourage compliance with blood glucose monitoring and initiation of treatment when the evidence shows that the risk of adverse outcomes is significant for both diabetic and nondiabetic populations. Additional research is needed to reach a consensus on standardizing treatment practice for perioperative hyperglycemia. Standardized treatment recommendations may provide better guidance for providers to comply with protocols to treat hyperglycemia. Currently there are operational challenges with using IV insulin. More surgeries are being moved to outpatient facilities, which may not have the resources to assess and treat hyperglycemia. The existing protocols are directed toward inpatient facilities and have great variation on the best methodology of glucose control. As the number of inpatient surgeries moving to the outpatient arena increases, the need for facility leaders to develop outpatient perioperative hyperglycemic management protocols to decrease the risk of postoperative complications also increases. There is a need for more hyperglycemic research in the outpatient environment. Akbarzadeh et al 7 discussed the effect that glutamine and arginine can have on controlling insulin resistance by metabolic regulation and postoperatively by decreased cell injury, increased peripheral glucose utilization, and increased antioxidant capacity. A newly recognized L- carnitine, which is used as an adjunct therapy for type 2 diabetes, showed efficacy in controlling insulin resistance by means of increased fatty acid oxidation. 7 This therapy might have a positive effect on the treatment of outpatient surgical patients because it may provide adequate glycemic control without interfering with the operational needs of the perioperative space. LIMITATIONS This literature review had some limitations, including a small sample size, single institution used, first study for a newly developed medication, limitations on surgery type, and a single researcher reviewing and scoring articles. Another limitation of this review was the exclusion of non English language literature because of the lack of interpretation services. In addition, one study that was conducted more than five years ago was included in this review because it is considered an important reference to perioperative hyperglycemia. 84 AORN Journal

6 January 2019, Vol. 109, No. 1 Perioperative Hyperglycemia CONCLUSION Perioperative hyperglycemia has a significant correlation with adverse surgical outcomes, and blood glucose should be monitored in both the diabetic and nondiabetic surgical patient populations. The literature shows a need for a standard treatment protocol for perioperative hyperglycemia in all surgical patients regardless of surgical specialty. Whether critically ill patients should have different treatment standards than the general population is unknown. Standards for the treatment of hyperglycemia could increase compliance with treatment protocols and lessen the fear of hypoglycemia. The literature lacked any recommendations for outpatient surgical patients, which is a concern because of the increase in surgical procedures being performed in outpatient settings. The risk for perioperative hyperglycemia exists in all patients and should be monitored and treated to prevent adverse surgical complications. Editor s notes: CINAHL, Cumulative Index to Nursing and Allied Health Literature, is a registered trademark of EBSCO Industries, Birmingham, AL. PubMed is a registered trademark of the US National Library of Medicine, Bethesda, MD. SCOPUS is a registered trademark of Elsevier BV, Amsterdam, the Netherlands. SUPPORTING INFORMATION Additional information may be found online in the supporting information tab for this article. REFERENCES 1. Kwon S, Thompson R, Dellinger P, Yanez D, Farrohki E, Flum D. Importance of perioperative glycemic control in general surgery: a report from the Surgical Care and Outcomes Assessment Program. Ann Surg. 2013;257(1): Mohan S, Kaoutzanis C, Welch KB, et al. Postoperative hyperglycemia and adverse outcomes in patients undergoing colorectal surgery: results from the Michigan surgical quality collaborative database. Int J Colorectal Dis. 2015;30(11): Palermo NE, Gianchandani RY, McDonnell ME, Alexanian SM. Stress hyperglycemia during surgery and anesthesia: pathogenesis and clinical implications. Curr Diab Rep. 2016;16(3): Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal- bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care. 2011;34(2): Umpierrez G, Cardona S, Pasquel F, et al. Randomized controlled trial of intensive versus conservative glucose control in patients undergoing coronary artery bypass graft surgery: GLUCO- CABG trial. Diabetes Care. 2015;38(9): Bláha J, Mráz M, Kopecký P, et al. Perioperative tight glucose control reduces postoperative adverse events in nondiabetic cardiac surgery patients. J Clin Endocrinol Metab. 2015;100(8): Akbarzadeh M, Eftekhari MH, Shafa M, Alipour S, Hassanzadeh J. Effects of a new metabolic conditioning supplement on perioperative metabolic stress and clinical outcomes: a randomized, placebocontrolled trial. Iran Red Crescent Med J. 2016;18(1): e Grunzweig K, Nair BG, Peterson GN, et al. Decisional practices and patterns of intraoperative glucose management in an academic medical center. J Clin Anesth. 2016;32: Takesue Y, Tschida T. Strict glycemic control to prevent surgical site infections in gastroenterological surgery. Ann Gastroenterol Surg. 2017;1: Evans CH, Lee J, Ruhlman MK. Optimal glucose management in the perioperative period. Surg Clin North Am. 2015;95(2): Richards JE, Kauffmann RM, Obremskey WT, May AK. Stress- induced hyperglycemia as a risk factor for surgical- site infection in nondiabetic orthopedic trauma patients admitted to the intensive care unit. J Orthop Trauma. 2013;27(1): Wang R, Panizales MT, Hudson MS, Rogers SO, Schnipper JL. Preoperative glucose as a screening tool in patients without diabetes. J Surg Res. 2014;186(1): Frisch A, Chandra P, Smiley D, et al. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care. 2010;33(8): Duggan EW, Carlson K, Umpierrez GE. Perioperative hyperglycemia management: an update. Anesthesiology. 2017;126(3): AORN Journal 85

7 Peacock January 2019, Vol. 109, No Akhtar S, Barash PG, Inzucchi SE. Scientific principles and clinical implications of perioperative glucose regulation and control. Anesth Analg. 2010;110(2): Spruce L, Van Wicklin SA, Wood A. AORN s revised model for evidence appraisal and rating. AORN J. 2016;103(1): Barth E, Albuszies G, Baumgart K, et al. Glucose metabolism and catecholamines. Crit Care Med. 2007;35(9 suppl):s508 S Tamura T, Yatabe T, Kitagawa H, Yamashita K, Hanazaki K, Yokoyama M. Oral carbohydrate loading with 18% carbohydrate beverage alleviates insulin resistance. Asia Pac J Clin Nutr. 2013;22(1): Dobyns JB. General anaesthesia tutorial #327: perioperative insulin management. Anesthesia Tutorial of the Week. com_virtual_library/media/aa40c611099b3913bc ce8b2535-Perioperative-insulin-management. pdf. Published March 18, Accessed October 1, Kiran RP, Turina M, Hammel J, Fazio V. The clinical significance of an elevated postoperative glucose value in nondiabetic patients after colorectal surgery: evidence for the need for tight glucose control? Ann Surg. 2013;258(4): Nair BG, Grunzweig K, Peterson GN, et al. Intraoperative blood glucose management: impact of a real- time decision support system on adherence to institutional protocol. J Clin Monit Comput. 2016;30(3): Tammy S. Peacock, Master of Arts in Health Psychology (MAPSY), BSN, RN, Nursing Executive Advanced, Board Certified (NEA- BC), Certified Executive in Nursing Practice (CENP), Certified Professional in Patient Safety (CPPS), Certified Lean Six Sigma Black Belt (CLSSBB), is the surgical outcomes improvement leader at Kaiser Permanente in Oakland, CA. Ms Peacock has no declared affiliation that could be perceived as posing a potential conflict of interest in the publication of this article. 86 AORN Journal