The Quality of Preoperative Glycemic Control Predicts Insulin Sensitivity During Major Upper Abdominal Surgery: A Case-Control Study : Annals of Surgery Open

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Original Study

The Quality of Preoperative Glycemic Control Predicts Insulin Sensitivity During Major Upper Abdominal Surgery: A Case-Control Study

Omiya, Keisuke MD; Sato, Hiroaki MD, PhD; Sato, Tamaki MD; Nooh, Abdulwahaab MD; Koo, Bon-Wook MD, PhD; Kandelman, Stanislas MD; Schricker, Thomas MD, PhD

Author Information
Annals of Surgery Open 4(1):p e234, March 2023. | DOI: 10.1097/AS9.0000000000000234

INTRODUCTION

Impaired insulin sensitivity and, as a consequence, the acute increase in blood glucose are typical features of the body’s metabolic and endocrine response to surgical tissue trauma. Numerous studies showed that hyperglycemia is independently associated with morbidity and mortality after major surgery.1,2 More recent evidence indicates that the degree of insulin resistance also predicts outcomes in patients undergoing cardiac procedures.3 Furthermore, a significant association between the quality of preoperative glycemic control (glycated hemoglobin A1c [HbA1c]) and intraoperative insulin resistance could be observed in diabetic patients suggesting a role of glycated hemoglobin as an outcome predictor in cardiac surgery.3

The purpose of this study was to examine the relationship between preoperative glycemic control and insulin sensitivity during major upper abdominal surgery and its potential impact on outcome.

METHODS

Study Participants

This study is a post hoc exploratory analysis of the first 170 patients participating in a randomized-controlled on the hyperinsulinemic-normoglycemic clamp (HNC) as a potential intervention to reduce the incidence of surgical site infections (ClinicalTrials.gov NCT01528189; registered on February 7, 2012). Patients of this substudy were studied at the Royal Victoria Hospital (McGill University Health Centre, Montreal, QCc, Canada) between October 2018 and May 2022.

With approval from the institutional ethics review board, written informed consent was obtained from patients scheduled for elective liver resection. Patients <18 years, with severe liver disease (Child-Pugh grade B or C) or on dialysis and steroids were excluded. Only patients in the study’s treatment arm receiving the HNC were analyzed.

Anesthetic Care

As the type of anesthesia has significant impact on glucose homeostasis, anesthesia care in this study was standardized.2 All patients received combined general and epidural anesthesia. Epidural anesthesia between L1 and T4 was established with bupivacaine after inserting epidural catheters at the thoracic level between Th7 and 10. Correct catheter placement was verified by epidural wave form analysis.4 General anesthesia was provided by intravenous propofol, fentanyl, and volatile anesthetics. Patients were paralyzed using intravenous rocuronium. To keep mean blood pressure above 65 mm Hg, norepinephrine was administered intravenously. Normal saline was infused at 4 to 6 mL/kg/h. Albumin 5% was used for volume replacement.

Intraoperative Insulin Sensitivity

Insulin sensitivity was determined by the HNC technique. A 2 U bolus of intravenous insulin was given if the baseline blood glucose level was higher than 6.0 mmol/L, followed by the infusion of 2 mU/kg/min. The 2 mU/kg/min of insulin typically results in plasma insulin levels of 200 µU/mL, sufficient to completely suppress endogenous glucose production.5 The 20% dextrose was titrated to maintain glycemia between 4.0 and 6.0 mmol/L. Arterial blood glucose levels were measured at 5- to 30-minute intervals to ensure normoglycemia. The average of 3 consecutive infusion rates during steady state (coefficient of variation of the dextrose infusion rate < 5%), typically after 90 to 120 minutes, was used as a measure of insulin sensitivity. The 3 consecutive infusion rates were measured in every 5 minutes. The insulin sensitivity was measured before the cancer was resected and, in patients who received the Pringle maneuver, before the intervention. At the end of surgery, the insulin infusion was stopped and the dextrose infusion was weaned off in the postanesthesia care unit (PACU).

Postoperative Clinical Pathway

In the PACU, patients were allowed to take clear liquids accompanied by intravenous hydration with normal saline and 5% dextrose. The central venous catheter and nasogastric tube were removed after patients resumed a regular diet, normally within the first 12 and 24 postoperative hours. Drains were removed within postoperative day 2 unless a bile leak was detected. Early mobilization was encouraged.

Outcomes

Primary outcome was the association between HbA1c and intraoperative insulin sensitivity. Secondary outcome was the association between body mass index (BMI), postoperative morbidity within 30 days of surgery and insulin sensitivity.

Statistical Analysis

Sample size was calculated on the basis of the primary study hypothesis assuming a negative correlation between HbA1c and insulin sensitivity. A sample size of 33 achieves 80% power to detect a slope 0.5 under the alternative hypothesis when the SD of HbA1c is 1, the SD of the dextrose infusion rate is 1, and the significance level is 0.05.

Continuous data were analyzed by the unpaired t test or Mann-Whitney U test and proportions were analyzed by Fisher exact test. The relationship of HbA1c, BMI, and insulin sensitivity was analyzed by simple regression analysis. A logistic regression model assessed the relationship between insulin sensitivity and postoperative complications. Two-sided P values <0.05 were considered statistically significant. All statistical analyses were performed using GraphPad Prism version 8 for Windows (GraphPad Software, San Diego, CA).

RESULTS

Patient characteristics are shown in Table 1.

TABLE 1. - Patient Characteristics
Non-DM (n = 24) DM (n = 10) P
Age (y) 61.8 ± 11.5 62.1 ± 11.8 0.94
Female, n (%) 10 (42) 4 (40) >0.99
BMI (kg/m2) 27.0 ± 5.1 29.3 ± 5.9 0.25
Hypertension, n (%) 9 (38) 5 (50) 0.70
Dyslipidemia, n (%) 8 (33) 4 (40) 0.71
HbA1c (%) 5.6 ± 0.4 7.2 ± 1.1 <0.001
Fasting time before surgery (h) 13.4 ± 2.6 14.5 ± 2.7 0.27
Blood glucose levels before surgery (mmol/L) 5.8 ± 0.8 7.1 ± 1.8 0.04
No. segments resected 2.0 ± 1.0 2.4 ± 1.1 0.31
Pringle maneuver, n (%) 1 (4) 1 (10) 0.51
Duration of pringle maneuver (min) 27.0 ± 0.0 17.0 ± 0.0 -
Duration of surgery (min) 170.9 ± 62.3 222.1 ± 79.2 0.06
Estimated blood loss (mL) 625.0 ± 537.7 865.0 ± 530.2 0.24
Crystalloids (mL) 1729.2 ± 658.4 2300.0 ± 1099.5 0.20
Artificial colloids (mL) 41.7 ± 141.2 150.0 ± 337.5 0.43
5% albumin (mL) 362.5 ± 276.7 350.0 ± 210.8 0.90
RBC (units) 0.8 ± 2.6 1.8 ± 2.7 0.29
FFP (units) 0.3 ± 1.6 1.2 ± 2.7 0.20
Norepinephrine (μg/kg/min) 0.05 ± 0.04 0.05 ± 0.04 0.90
Insulin sensitivity (mg/kg/min) 2.0 ± 0.9 0.8 ± 0.6 <0.001
Hospital stay (d) 5.4 ± 1.7 5.9 ± 2.3 0.51
Data are expressed as mean ± standard deviation, n (%). The average of three consecutive dextrose infusion rates during steady state (90–120 min after starting HNC) was used as a measure of insulin sensitivity. The infusion rate of norepinephrine was the average of three consecutive data when insulin sensitivity was measured.
FFP indicates fresh–frozen plasma; RBC, red blood cells.

Mean insulin sensitivity in diabetic patients was lower than in patients without diabetes (DM) (0.8 ± 0.6 vs 2.0 ± 0.9 mg/kg/min, P < 0.001, Table 1).

The HbA1c level (Y = −0.52X + 4.8, P < 0.001, R2 = 0.29, Fig. 1A) and BMI (Y = −0.12X + 5.0, P < 0.001, R2 = 0.43, Fig. 1B) negatively correlated with insulin sensitivity during surgery. There was no significant correlation between HbA1c and BMI (Y = 1.26X + 20.0, P = 0.18, R2 = 0.06, Fig. 1C).

F1
FIGURE 1.:
Relationship between HbA1c, BMI and insulin sensitivity in all patients (n = 34). The average of three consecutive dextrose infusion rates during steady state (90–120 minutes after starting HNC) was used as a measure of insulin sensitivity. Relationships were analyzed by simple regression analysis. A, The relationship between HbA1c and insulin sensitivity: Y = −0.52X + 4.8 (P < 0.001, R 2 = 0.29), B, The relationship between BMI and insulin sensitivity: Y = −0.12X + 5.0 (P < 0.001, R 2 = 0.43), C, The relationship between HbA1c and BMI: Y = 1.26X + 20.0 (P = 0.18, R 2 = 0.06).

The odds ratio of postoperative complications within 30 days of surgery for every increase in insulin sensitivity by 1 mg/kg/min was 0.22 (95% confidential interval, 0.06–0.59; P = 0.009).

The details of the postoperative complications are available in Supplemental Table 1, https://links.lww.com/AOSO/A200.

DISCUSSION

The results of this study demonstrate a significant correlation between the quality of preoperative glycemic control as assessed by circulating HbA1c levels and insulin sensitivity during upper abdominal surgery. Furthermore, intraoperative insulin resistance was associated with an increased risk of postoperative morbidity.

Surgical patients are exposed to stereotypical metabolic and endocrine alterations, often called the diabetes of the injury.6 This stress response is characterized by increased plasma concentrations of catabolic hormones such as cortisol, catecholamines, and glucagon, leading to a state of insulin resistance7 and hyperglycemia.8 The degree of insulin resistance has been shown to depend on the magnitude of surgical tissue trauma. Although insulin sensitivity after colorectal surgery decreased by 70% and by almost 50% after open cholecystectomy, the impairment of insulin function was significantly less pronounced in patients undergoing inguinal hernia repairs or laparoscopic procedures.9 Furthermore, insulin itself may improve insulin resistance. In patients undergoing open hepatectomy, intraoperative insulin infusion reduced postoperative insulin resistance.10

Intraoperative insulin resistance in the present study showed a significant correlation with postoperative morbidity supporting previous observations of a significant impact of decreased insulin sensitivity on outcome.9 Data from Sweden showed a correlation between the decrease in postoperative insulin sensitivity and the patients’ length of hospital stay.9 In patients undergoing cardiac surgery requiring cardiopulmonary bypass, for each 20% decrease in insulin sensitivity during the procedure the risk of serious complications more than doubled.3

Taking into account that surgical stress induces inflammatory responses with potential impact on outcome and the fact that insulin possesses strong immune enhancing properties immunomodulatory effects of insulin may be, at least partly responsible, for this association.11–16

Considering the link between the body’s insulin sensitivity and glycemia, our finding of a significant correlation between preoperative HbA1c levels and intraoperative insulin resistance was not unexpected. The predictive outcome value of HbA1c, an indicator of the quality of glycemic control over the preceding 3 months, has been extensively studied in the nonsurgical diabetic patient population.17,18 Its potential role in surgery, however, has received less attention. Recent evidence suggests that patients with elevated HbA1c levels have an increased risk to develop serious complications after major colorectal surgery,19 open heart, and vascular procedures.20–24 If it is true that poor glycemic control predicts the risk of postoperative morbidity, further studies are warranted to examine whether its timely improvement before surgery can be beneficial as already demonstrated in medical patients.25

In the present study, the patient’s BMI also negatively correlated with insulin sensitivity during liver resection. This observation is in agreement with previous results obtained in cardiac surgery26 further illustrating the relationship between body weight and glucose homeostasis in the context of surgery.27

We acknowledge several limitations of this study. Because of the relatively small sample size, we could not establish significant links between intraoperative insulin sensitivity and specific complications such as infections, cardiovascular problems, and organ dysfunction. Second, perioperative administration of dextrose and insulin as part of the HNC may have per se influenced the clinical outcome. Larger, prospective protocols are needed to confirm the clinical findings of this case-control study.

In conclusion, in patients undergoing major upper abdominal surgery, the quality of preoperative glycemic control and BMI-predicted intraoperative insulin sensitivity. Insulin resistance during surgery was associated with postoperative morbidity.

ACKNOWLEDGMENT

We thank the nursing staff at the operating room for their help in the execution of the experiments.

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Keywords:

body mass index; diabetes; glycated hemoglobin A1c; intraoperative insulin sensitivity; postoperative morbidity

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