|Year : 2019 | Volume
| Issue : 4 | Page : 1185-1190
Hyperinsulinemic–normoglycemic technique in patients with cirrhosis undergoing hepatic resection: a randomized controlled trial
Magdy K Khalil1, Mohammed H Afifi1, Maha L El-Sheikh1, Mohammed Z Khalil2
1 Department of Intensive Care Unit, Faculty of Medicine, Menoufia University, Shebeen El-Kom, Egypt
2 Department of Intensive Care Unit, Faculty of Medicine, Benha University, Benha, Egypt
|Date of Submission||29-Jan-2018|
|Date of Decision||16-Mar-2018|
|Date of Acceptance||17-Mar-2018|
|Date of Web Publication||31-Dec-2019|
Mohammed Z Khalil
El-Gomohorya Street, Menoufia 11711
Source of Support: None, Conflict of Interest: None
To evaluate the efficacy of hyperinsulinemic–normoglycemic clamp technique (HNCT) versus the insulin sliding scale for glycemic control in patients with cirrhosis undergoing hepatic resection.
There is a consensus in the published literature about the increased risk of hyperglycemia among patients undergoing hepatic resection. Previous reports have established the significant association between hyperglycemia and the extent of hepatic injury in hepatectomized patients.
Patients and methods
A randomized controlled trial was conducted on 60 patients with cirrhosis who underwent hepatic resection. Patients were randomly assigned to either HNCT group control (n = 30) or insulin sliding scale group (n = 30). The postoperative liver function was assessed by the score proposed, and patients were followed for 1 week postoperatively.
The mean operative durations of HNCT study and control groups were 4.4 and 4.3 h, respectively. Moreover, 60% of the study group had a focal resection, whereas 60% of the control group had multiple resection operation. Postoperatively, HNCT group showed a statistically significant marked reduction in Schindl score compared with the control group (P < 0.001). In addition, HNCT group showed a marked improvement in postoperative liver parameters compared with the control group (P < 0.001).
HNCT significantly attenuates hepatic dysfunction and improves clinical outcomes postoperatively.
Keywords: glycemic control, hepatic failure, hyperinsulinism, liver cirrhosis, liver surgery
|How to cite this article:|
Khalil MK, Afifi MH, El-Sheikh ML, Khalil MZ. Hyperinsulinemic–normoglycemic technique in patients with cirrhosis undergoing hepatic resection: a randomized controlled trial. Menoufia Med J 2019;32:1185-90
|How to cite this URL:|
Khalil MK, Afifi MH, El-Sheikh ML, Khalil MZ. Hyperinsulinemic–normoglycemic technique in patients with cirrhosis undergoing hepatic resection: a randomized controlled trial. Menoufia Med J [serial online] 2019 [cited 2020 Feb 16];32:1185-90. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1185/274224
| Introduction|| |
HNCT significantly attenuates hepatic dysfunction and improves clinical outcomes postoperatively. Liver resection is one of the most commonly used therapeutic approaches for the management of different hepatic malignancies . Current evidence suggested that liver resection is associated with longer survival duration and more favorable outcomes compared with other modalities, given the great capacity of the liver to regenerate after major hepatic resection . With the recent advances in the operative care and imaging techniques, the current statistics show a marked reduction in hepatic surgery-related mortality to less than 2%. However, the postoperative morbidity rates remain as high as 20–50% .
There is a growing body of evidence that linked the postoperative liver status with the severity of the surgical stress response and the levels of glycogen stored in the hepatocytes . Following surgical trauma, an inflammatory response is provoked with the release of a large number of proinflammatory mediators such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-8, IL-10, C-reactive protein (CRP), and monocyte chemoattractant protein-1 . This upregulation of the cytokines leads to immune system suppression and hepatic dysfunction, with a high risk of postoperative infection, morbidity, and mortality . The exaggerated proinflammatory response may diminish the hepatic energy stores as well, leading to hyperglycemia and postoperative liver dysfunction with increased morbidity, especially infections .
Consequently, better glucose management was reported to be accompanied by reduced postoperative liver dysfunction and overall complications. The current literature shows different strategies to achieve tight glucose control in hepatic resection patients. Although having widespread use, insulin sliding scale techniques were reported to be largely ineffective in the management of postoperative hepatic dysfunction . On the contrary, strict maintenance of normoglycemia by intensive insulin therapy has been shown to reduce mortality and to attenuate liver, kidney, and endothelial dysfunction in critically ill patients . Okabayashi et al.  reported that intensive insulin therapy through a closed-loop glycemic control system ameliorated liver dysfunction after hepatic resection; however, the mean blood glucose level remained above the target range of 90–110 mg/dl.
Previous reports showed a wide variation in glucose concentration during liver resection, in which hyperglycemia is not the only problem; patients undergoing hepatic resection were reported to be at increased risk of hypoglycemic episodes, which increase the risk of death . Hyperinsulinemic–normoglycemic clamp technique (HNCT) is a new technique that is based on preoperative carbohydrate loading combined with insulin therapy to maintain normoglycemic status .
The aim of the present study is to evaluate the efficacy of HNCT versus the insulin sliding scale for glycemic control in patients with cirrhosis undergoing hepatic resection.
| Patients and Methods|| |
We followed Consolidated Standards of Reporting Trials guidelines during the preparation of this randomized controlled trial (Supplementary file no. 1). The present trial obtained the approval of the local ethics and research committee of anesthesia, ICU and Pain Management Department, and Liver Institute of Menoufiya University.
This was a parallel prospective open-label randomized controlled trial. Adult patients were included if they fulfilled the following criteria: (a) patients who were scheduled to undergo resection of one segment or more of the liver, (b) patients with Child A with model for end-stage liver disease less than 10, and ASA II or III, and (c) patients who did not show intraoperative events (e.g., massive bleeding and hypothermia).
Patients were excluded if they were type 1 diabetic patients with uncontrolled blood glucose levels (fasting level >180 mg/dl), patients with chronic liver disease (Child–Pugh B or C), and patients with anemia with hemoglobin concentration less than 10 g/dl. Patients were also excluded if they underwent a simultaneous resection of other viscera or were unable to give written consent. Diabetic patients on oral hypoglycemics were asked to discontinue their therapy 24 h before surgery, and those on insulin were asked to omit their evening dose.
The sample size was calculated using EpiInfo version 3.5.4 (Center of diseases control and infection 1600 Clifton Rd, Atlanta, GA 30333, United States) based on the following assumptions: power of 80%, α = 0.05, and the mean difference in the Schindl score between the two groups is equal to 1. According to these assumptions, 60 patients were decided to be included. Patients were allocated randomly upon study entry by study investigators using computerized randomization schedule with allocation ratio of 1 : 1 (MedCalc Software bv. Acacialaan 22 8400 Ostend Belgium).
Preoperatively, patients received high-calorie, carbohydrate-rich meals the day before the operation (35 kcal/kg, 60% CHO). The meals were divided into three meals 5 h apart and the last one at 8 p.m. This was followed by intravenous dextrose (2 mg/kg/min) for ideal body weight for 8 h starting from midnight until arrival at the operating room. Random blood sugar (RBS) was measured every 3 h and followed the scale shown in [Table 1].
Intraoperatively, insulin therapy was initiated in these patients by administration of 0.12 U/kg/h just after induction of anesthesia. RBS will be measured every 15 min and the dextrose infusion rate will be adjusted to maintain arterial glycemia between 63 and 110 mg/dl according to the scale shown in [Table 2].
Postoperatively on arrival to ICU, the dose of insulin will be halved (0.06 U/kg/h), the blood glucose will be measured hourly for 48 h, and the dextrose infusion rate will be modified by the attending nurse following the same protocol as the intraoperative one.
Blood samples will be collected in the morning just before surgery and then 12, 24, 48 h, and 7 days postoperatively for measurements of complete blood count (CBC), alanine transaminase (ALT), aspartate transaminase (AST), bilirubin, albumin, prothrombin time (PT), INR, fibrinogen, serum lactate, serum electrolytes, renal function test, and CRP cholesterol level.
The postoperative liver function was assessed by the score proposed by Schindl et al. , evaluating total serum bilirubin and plasma lactate concentrations, PT, and the grade of encephalopathy.
Data entry, processing, and statistical analysis were carried out using MedCalc version 15.8. Tests of significance (χ2, Student's t-test, Mann–Whitney's U-test, Friedman's, Wilcoxon test, repeated measures analysis of variance, and regression) were used. Data were presented, and suitable analysis was done according to the type of data (parametric and nonparametric) obtained for each variable. P values less than 0.05 (5%) was considered to be statistically significant.
| Results|| |
A total of 76 patients were assessed for eligibility, from which 60 patients were included in the trial. The demographic and clinical variables of 60 hepatic patients who were included in the study are shown in [Table 3]. Most patients were males (80% in HNCT and 73.3% in control group), and the mean age of patients was 58.9 and 60.6 years, respectively. The mean operative duration of patients was 4.4 ± 0.49 hours in HNCT group and 4.33 ± 0.47 hours in control group. However, the mean preoperative Schindl scores were 0.73 ± 0.69 in HNCT group and 0.66 ± 0.6 in control group. Moreover, 60% of HNCT group had a focal resection, whereas 60% of the control group had multiple resection operation. The HNCT group showed a statistically significant lower RBS, albumin, ALT, Sodium (Na), and cholesterol levels compared with control group, but both groups showed comparable total protein, ammonia, and total leucocytic count levels.
Postoperatively, the HNCT group showed a marked reduction in Schindl score after the operation, and the difference was statistically significant (P = 0.0004). On the contrary, the control group showed a marked elevation in Schindl score after the operation. The difference between the HNCT and control group was statistically significant (P < 0.001).
The HNCT group showed a marked increase in postoperative total protein, albumin, Na, and cholesterol levels and showed a marked decrease in ALT, ammonia, and total leucocytic count compared with control group with a high significant difference (P < 0.0001); however, both groups showed comparable results regarding postoperative RBS (P > 0.05). In addition, the HNCT group showed a marked decrease in postoperative total and direct bilirubin, Gamma-glutamyl transferase (GGT), alkaline phosphatase, urea, creatinine, CRP, Lactic dehydrogenase (LDH), International Ratio (INR), PT, activated partial thromboplastin time (aPTT), and lactate levels, and showed a marked increase in Potassium (K), Calcium (Ca), phosphorus (Ph), hemoglobin, hematocrit, and platelets compared with control group, with a highly significant difference (P < 0.001); however, both groups showed comparable results regarding postoperative Magnasium (Mg) and AST (P > 0.05). [Table 4] shows the postoperative laboratory measurements.
After applying the multiple linear regression (enter method), total protein, albumin, AST, ALT, GGT, Na, and K had an independent effect on the postoperative Schindl score in HNCT group with a statistically significant difference (P < 0.05), whereas other preoperative laboratory variables had no effect.
| Discussion|| |
There is a consensus in the published literature about the increased risk of hyperglycemia among patients undergoing hepatic resection . Previous reports have established the significant association between hyperglycemia and the extent of hepatic injury in hepatectomized patients . Similar reports showed a wide variation in glucose concentration during liver resection, in which hyperglycemia is not the only problem; patients undergoing hepatic resection were reported to be at increased risk of hypoglycemic episodes, which increase the risk of death . In the present randomized controlled trial, we included 60 patients undergoing hepatic resection to evaluate the safety and effectiveness of HNCT compared with the standard glucose control in improving postoperative hyperglycemia and hepatic dysfunction.
As mentioned, hepatic resection may be followed by postoperative hepatic dysfunction, with incidence rates ranging from 20 to 70% . Schindl et al.  score is a prognostic scoring system for hepatic dysfunction that divides the patients into three groups based on their calculated score, namely, the good, moderate, and poor prognosis groups. In the present prospective study, HNCT group showed a statistically significant reduction in Schindl score postoperatively, and the postoperative score was significantly lower than the control group. Our findings showed a statistically significant effect of HNCT in maintaining normal hepatic function among patients undergoing hepatic resection.
In concordance with our results, Hassanain and colleagues conducted a randomized controlled trial on 56 diabetic patients scheduled for hepatic resection, and compared between the HNCT group and standard therapy. They reported a greater hepatic dysfunction in the control cohort than HNCT group.
A subsequent subset analysis on 30 patients by Fisette et al.  evaluated the mechanisms through which HNCT induced better clinical outcomes in patients undergoing hepatic resection. The study showed that the HNCT reduced postoperative liver dysfunction by suppressing apoptosis and increasing hepatic energy stores.
As liver enzymes retained in hepatocytes, AST and ALT, are well-known surrogate parameters for structural injury of hepatocytes cell barrier or necrosis , recent studies further suggested that perioperative changes in serum concentration of the enzymes are correlated with clinical outcomes like liver synthetic function, regeneration, and biliary complication . In the present trial, liver enzymes levels decreased significantly postoperatively in HNCT group. In addition, the liver enzymes levels in this groups were significantly lower than the control group. Similarly, Hassanain et al. , reported a significantly lower level in the liver enzymes among HNCT compared with standard care group.
The current body of evidence suggested that the extent of the hepatic injury, postoperatively, shows a huge variation in the population based on a number of preoperative factors. It would be advocated that knowing the relationship between preoperative factors and the extent of hepatocytes injury will lead to potential improvement in postoperative clinical outcomes .
Han et al.  assessed the relationship between intraoperative hyperglycemia and hepatocytes injury and evaluated the contributors for hyperglycemia during liver resection. They reported that the intraoperative hyperglycemia was associated with the extent of hepatocytes injury. In addition, perioperative transaminase rise, cirrhosis, lower PT, greater serum total cholesterol, and prolonged hepatic ischemia were determined as contributing factors for the development of intraoperative hyperglycemia.
In the present clinical trial, we found that the preoperative liver enzymes and albumin levels were independent predictors of the postoperative hepatic dysfunction in HNCT group. However, bilirubin and GGT level may be independent predictors for postoperative hepatocytes injury in control group. Similar to our results, a previous report showed that preoperative and postoperative levels of alkaline phosphatase, platelet count, and serum IL-8 level were independently associated with HNCT technique group .
The present trial has a number of strength points. We conducted a randomized controlled study which is the gold standard research method. In addition, the included participants were comparable regarding the baseline characteristics. However, we acknowledge several limitations of our study. The present trial was an open-label study which may increase the risk of performance bias . HNCT is also associated with constant dextrose infusion, so the blood glucose was easily maintained constant by reducing the dextrose infusion rate. On the contrary, the standard therapy has a too slow rate of change in insulin infusion to counteract the glucose load from transfused blood products, leading to hyperglycemia, which is then corrected over hours.
The present randomized controlled trial showed that the HNCT protocol significantly attenuates hepatic dysfunction and improves clinical outcomes postoperatively. Preoperative liver function measurements may be independent predictors of the extent of postoperative liver injuries. Further clinical trials are still needed to establish the beneficial effect of HNCT.
| Conclusion|| |
HNCT significantly attenuates hepatic dysfunction and improves clinical outcomes postoperatively.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]