This study demonstrated that significant hyperglycemia in diabetic patients during non-cardiac surgery confers an increased MINS and mortality incidence. The estimated threshold for intraoperative blood glucose level related to MINS was 149mg/dL. Our findings suggest that managing for an adequate intraoperative blood glucose level may be beneficial for the prevention of MINS.
Perioperative hyperglycemia is common as a result of transient body glucose elevation in response to physiological stress among patients undergoing surgery. The stress of surgery and anesthesia causes the release of counter-regulatory hormones, leading to reduced insulin production and increased lipolysis.4 Sustained hyperglycemia triggers insulin resistance by impairment of the insulin signal transduction pathway, resulting in cardiovascular events such as myocardial injury.14,26 Perioperative hyperglycemia is also associated with numerous other adverse outcomes including longer postoperative hospital duration, surgical site infection, higher overall morbidity, and mortality.1,27 By inducing acute changes in cellular metabolism, such as an increase in polyol pathway activation and hexosamine pathway flux, activation of protein kinase C, formation of advanced glycation end products, and hyperglycemia leads to tissue damage, vascular inflammation, fibrosis, and injury by overproduction of reactive oxygen species.28
Our study focused on the effect of transient hyperglycemia superimposed on diabetic patients who were already at risk for various adverse clinical outcomes and complications related to diabetes itself. According to our result, intraoperative hyperglycemia was associated with an increased risk of MINS. This result is consistent with our previous finding that MINS was associated with preoperative glucose level rather than hemoglobin A1c level, which reflects more of a long-term glucose status.15 Both results stress the association between short-term glycemic control and the incidence of MINS.
The mediation of reactive oxygen species could explain the mechanism behind the association between hyperglycemia and MINS. The imbalance between free radical generation and elimination plays a key role in the pathophysiology of myocardial injury.28 During the perioperative period, oxidative stress due to hyperglycemia and insulin resistance contributes to the cellular structure and functions of diabetic myocardium.29,30 Furthermore, surgical hypercoagulability, bleeding, and inflammation can also predispose patients to ischemic injuries.31
In this study, we divided the patients according to intraoperative blood glucose level above 180 mg/dL, while the estimated threshold associated with MINS incidence was 149mg/dL. Stress hyperglycemia has been consistently related to adverse outcomes in both diabetic and non-diabetic patients.27,32 In a previous study, even modest glucose elevation (140–179 mg/dL) was strongly related to mortality only in non-diabetic patients, but more severe hyperglycemia (glucose > 180 mg/dL) was a risk factor for mortality among diabetic patients2. Because the purpose of this study was to evaluate the effect of stress-induced hyperglycemia in diabetic patients, we stratified patients into the hyperglycemia group even with a single intraoperative glucose level over 180 mg/dL. Therefore, our results also need to be validated in patients without diabetes. Of note, the subgroup analysis showed that the observed association between hyperglycemia and MINS was not significant in patients with hypertension, chronic renal failure, active cancer, and for those undergoing high-risk surgery. In addition, the threshold of intraoperative blood glucose associated with MIN had an area under the ROC curve of 0.57 with relatively low sensitivity and specificity; therefore, further investigation regarding more precise cutoff value for intraoperative blood glucose level is required.
For intraoperative blood glucose control, the 2019 ADA guidelines recommend a range between 80–200mg/dL (4.4 -10.0mmol/L),33 based on numerous studies suggesting tight glycemic control during surgery.6,34 On the other hand, conflicting results have also been reported, suggesting that aggressive intraoperative treatment of hyperglycemia did not improve outcome; in some instances, such treatment actually increased mortality and postoperative stroke.16,30 For the patients of the present study, regular insulin was used to treat hyperglycemia during the surgical period. The use of regular insulin is known to have anti-inflammatory, anti-thrombotic, and anti-atherogenic properties with a favorable effect on myocardium.35,36 However, an accurate blood glucose target during surgery was not identified in this study and therefore needs further investigation.
There are several limitations to be addressed. Due to the nature of a retrospective study, perioperative cTn I and intraoperative blood glucose levels were not measured in all the patients undergoing non-cardiac surgery; In addition, as they were selectively performed selectively in high-risk patients, our results may have been exaggerated due to selection bias. Second, a unifying treatment protocol for perioperative hyperglycemic management was absent. Anesthesia was provided by many different anesthesiologists; therefore, a therapeutic approach to hyperglycemia such as the dose of insulin given and at which glucose level the treatment initiation has taken place may have varied, thereby possibly influencing the results. Lastly, our study could not fully address the question of adequate blood glucose level or whether treatment of hyperglycemia with insulin may reduce the incidence of MINS or mortality. Despite these limitations, this study showed that MINS in diabetic patients was associated with intraoperative blood glucose level, highlighting the importance of glycemic control during surgical procedures.