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 » Introduction
 » Methods
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  Table of Contents  
Year : 2021  |  Volume : 58  |  Issue : 3  |  Page : 349-354

Effect of multimodal analgesia on perioperative insulin resistance in patients with colon cancer

Department of Anesthesiology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China

Date of Submission06-Mar-2019
Date of Decision16-Apr-2020
Date of Acceptance17-May-2020
Date of Web Publication02-Jul-2021

Correspondence Address:
Guiping Xu
Department of Anesthesiology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_197_19

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 » Abstract 

Background: High risk of post-surgery complications have always been related with uncontrolled blood glucose, while the relationship between blood glucose and analgesia has not been compared on radical resection of colon cancer. The aim of this study is to investigate the effects of multimodal analgesia on perioperative insulin resistance in patients undergoing radical resection of colon cancer.
Methods: Sixty patients with colon cancer scheduled for radical resection surgery were equally divided into two groups randomly, the control group (TAP group) received general anesthesia and the transversus abdominis plane block analgesia, and the experimental group (GEA group) received extra epidural anesthesia. The analgesic efficacy was evaluated with visual analog scale (VAS). Insulin resistance indicators like fasting plasma glucose (FPG), resistin (RESIS), fasting insulin (FINS), homeostasis model assessment (HOMA) levels, and inflammation indicator interleukin-6 (IL-6) were evaluated during the surgery.
Results: IL-6 increase was significant in the TAP group than that in GEA group (P < 0.01). The insulin resistance increased significantly in TAP group than that in GEA group including HOMA (P < 0.05) and FPG (P < 0.05). There was no significant difference in RESIS levels and VAS scores in the two groups.
Conclusion: Epidural anesthesia leads to less inflammation in radical resection of colon cancer and the insulin level and insulin resistance increased after the surgeries based on FINS and HOMA..

Keywords: Colon cancer surgery, insulin resistance, multimodal analgesia, perioperative nursing
Key Message Epidural anesthesia combined with general anesthesia and postoperative epidural analgesia would decrease the insulin resistance for the patients with colon cancer.

How to cite this article:
Zhang Y, Su T, Li R, Yan Q, Zhang W, Xu G. Effect of multimodal analgesia on perioperative insulin resistance in patients with colon cancer. Indian J Cancer 2021;58:349-54

How to cite this URL:
Zhang Y, Su T, Li R, Yan Q, Zhang W, Xu G. Effect of multimodal analgesia on perioperative insulin resistance in patients with colon cancer. Indian J Cancer [serial online] 2021 [cited 2021 Oct 27];58:349-54. Available from: https://www.indianjcancer.com/text.asp?2021/58/3/349/320436

 » Introduction Top

Postoperative pain is an important factor that limits recovery after colon surgery and different analgesia combines with different outcome, including the patient's feel and complications.[1],[2] There is a high risk of complications associated with uncontrolled blood glucose levels, which may be associated with cancer itself and surgery trauma.[3],[4],[5],[6] Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms of this relationship remains unclear.

In addition, hyperglycemia following major trauma is a well-known phenomenon related to stress-induced systemic reaction[7] and one of the reasons is related to insulin resistance (IR). IR is always a major risk factor for diseases, such as type-2 diabetes mellitus and metabolic syndrome, and can lead to higher insulin dosage and poor control of blood glucose level.[8] IR is defined as a state of reduced reactivity to insulin in target tissues, such as the liver, muscle, and adipose tissue. Furthermore, it is known to be a major factor in various physiological dysfunctions, such as metabolic syndrome,[9] usually caused by obesity and oxidative stress, which could be caused by stress after surgical trauma.[10] Surgery usually causes insulin resistance which may lead to high blood glucose.[11] Thus, it has drawn considerable attention in recent years. The intensity of IR is not only related to the extent of the surgery but also to the mode of anesthesia. However, there is no perioperative IR reported on the colon cancer surgery receiving multimodal analgesia. This study used different multimodal analgesia programs to investigate the effects of multimodal analgesia on the perioperative IR in patients with colon cancer to find means to reduce the postoperative IR from anesthesia.

 » Methods Top

case selection

The American Society of Anesthesiologists I–III patients who were confirmed of the diagnosis of colon cancer by colonoscopic biopsy and had no distal metastasis as confirmed by computed tomography were included in this study. All the patients were scheduled for radical resection, and they underwent elective surgery or limited surgery under general anesthesia. The patients who had no endocrine or metabolic diseases before surgery, had never taken any drugs that could affect carbohydrate metabolism and insulin function, had no liver or kidney diseases, and had normal or slightly decreased pulmonary function. All patients or their relatives provided written informed consent in advance and the hospital ethics committee had approved this study.


The sample size was calculated by the following formula: N = Z2 × [P × (1-P)]/E2, with Z = 1.64, E = 20%, P = 0.5, and N = 60. The patients were randomly divided into two groups by random digits table method as follows: the control group (TAP group, n = 30) and the experimental group (GEA group, n = 30). TAP group underwent general anesthesia and the transversus abdominis plane block analgesia, while GEA group underwent general anesthesia and epidural analgesia. These two groups were admitted in different wards but the procedure was not blinded to doctors and the patients.

Anesthesia methods

All patients underwent radial artery and central venous puncture and intubation. Intraoperative monitoring of radial artery blood pressure, heart rate, blood oxygen saturation, electrocardiogram, and end-tidal carbon dioxide partial pressure was performed. The bispectral index (BIS) was also monitored to control the anesthetic depth and the dosage of narcotic drugs was adjusted according to the BIS values. Induction of the general anesthesia was performed using target-controlled infusion of remifentanil with the target level of 4–8 ng/mL in the effect site and target-controlled infusion of propofol with the target effect-site concentration of 3–4 g/mL and 0.15 mg/kg of cisatracurium. The endotracheal tube was inserted and fixed after correct positioning. Mechanical ventilation was then performed with tidal volume of 6–8 mL/kg, respiratory frequency of 12–15 times/minute, and inspiratory/expiratory ratio from 1:1.5 to 1:2. The target-controlled infusion of propofol and remifentanil was continued during the surgery for the maintenance of anesthesia, and the dosage of anesthetics was adjusted according to the BIS values to maintain this value between 45 and 50. Train-of-four stimulation was applied to stimulate the ulnar nerve for monitoring the muscle relaxation, which was maintained by intermittent infusion of 0.03 mg/kg cisatracurium according to the monitoring results. The patients in the TAP group received the bilateral transversus abdominis plane block, followed by general anesthesia. The patients in the GEA group received T8–T11 epidural space puncture according to the type of surgery and upward intubation for placing the 5 cm epidural catheter. After the intubation position, the anesthesia plane was tested by 3 mL of 1% lidocaine, and general anesthesia was induced. The induction and maintenance of intraoperative anesthesia was similar to the TAP group. 15 minutes before the surgery, 5–10 mL of 0.5% ropivacaine was injected through the epidural catheter and this was repeated after 2–3 hours of the beginning of the surgery, with an epidural analgesia pump containing 250 mL of 0.15% ropivacaine with a lock time of 15 minutes and a speed of 5 mL/hour. All patients were given 0.05 mg/kg tropisetron at the completion of the surgery to prevent nausea and vomiting. After the surgery, the epidural drug was administered through the patient-controlled analgesia pump.

Principle of fluid infusion

The patients in both the groups received fluid infusion of sodium lactate Ringer's injection and succinylated gelatin injection. Fluid infusion was maintained with other non-sugar liquids, 24 hours after the surgery.

Analgesic methods

The patients in the TAP group received intravenous injection of 40 mg parecoxib sodium and the bilateral transversus abdominis plane block at 30 minutes before the induction of anesthesia. The postoperative visual analog scale (VAS) score in patients was kept at ≤4. If the VAS score was higher than 4, another nerve block was performed according to the time interval and medication of the previous block until 48 hours after the surgery.[12]

The patients in the GEA group received intravenous injection of 40 mg parecoxib sodium at 30 min before the induction of anesthesia and infusion of 5 mL of 0.15% ropivacaine through the epidural catheter at 30 min before the completion of the surgery. Then, an epidural analgesia pump containing 250 mL of 0.15% ropivacaine and 2 mL bolus was connected to the epidural catheter with a lock time of 15 min and a speed of 5 mL/hour.

Sample collection and detection

Approximately 5 mL fasting venous blood was collected from all the patients, a day before anesthesia, immediately after postoperative extubation, and the first and second postoperative mornings. The fasting plasma glucose (FPG), fasting insulin (FINS), interleukin-6 (IL-6), and resistin (RESIS) levels were measured using enzyme-linked immunosorbent assay on an automatic biochemical analyzer (BECKMAN AU5800). All surgeries strictly followed the instructions provided by the manufacturers and were completed by the same medical team. According to the test results, the homeostasis model assessment-insulin resistance index (HOMA-IR) level was calculated by the formula as follows: HOMA-IR = FPG × FINS/22.5. In the formula, the unit of FPG is mmol/L and the unit of FINS is μU/mL.

Statistical analysis

Data are expressed as mean ± standard deviation. Intra group comparisons were performed using analysis of variance for randomized block design, while both the groups were compared using independent samples t-test. Enumeration data were compared using chi-square test. The relationships between HOMA and various cytokines levels were analyzed by multiple linear regressions. The difference was statistically significant at P < 0.05.

 » Results Top

General data

There were no significant differences in age, body mass index, surgery time, and other general data between the two groups [Table 1].
Table 1: Comparisons of the general data of the two groups

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Comparisons of high-sensitivity C-reactive protein, IL-6, RESIS, FINS, and FPG

The blood levels of IL-6, a day after surgery in both the groups, were significantly increased as compared with those before induction of anesthesia and immediately after the surgery (P < 0.01, [Table 2]). The levels of FINS in both the groups were significantly higher, a day after the surgery, than those before induction of anesthesia and immediately after the surgery (P < 0.05 and P < 0.01, in the TAP and GEA groups respectively; [Table 2]). The levels of FPG in both the groups immediately after surgery and 1 day after surgery were significantly different from those before induction of anesthesia (P < 0.01, [Table 2]). Furthermore, there were also significant differences of the HOMA values between the two groups (P < 0.05, [Table 2]). The HOMA values in both the groups displayed significant differences between 1 day after surgery and before induction of anesthesia (P < 0.01, [Table 2]). The HOMA value in the GEA group, a day after the surgery, was not different from that of the immediately after the surgery (P > 0.05, [Table 2]), but was significantly lower than that in TAP group (P < 0.05, [Table 2]). There was no significant difference in RESIS level between the two groups. Furthermore, no statistical differences were found among the time points in both groups [Table 2].
Table 2: Comparisons of IL-6, RESIS, FINS, FPG, and HOMA values between the two groups

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 » Discussion Top

Several concepts have been developed to improve postoperative pain management, such as preemptive analgesia, preventive analgesia, and multimodal analgesia.[13] It has been demonstrated that the post traumatic IR occurrs soon after surgical trauma in rats.[14] Furthermore, in humans, post operative insulin IR increases according to the magnitude of surgical invasion and extent of surgical trauma.[15] In fact, IR not only can cause high catabolism and negative nitrogen balance but also can cause infectious complications.[16] IR is the decrease in the ability of FINS to assist the target cells to absorb and utilize glucose. It usually occurs at the beginning of the surgery and reaches the peak within 24 hours after the surgery. Anesthesia has certain effect on it. The surgery of gastrointestinal tumor is an extensive one in the department of general surgery.[17] Therefore, this study included the patients with standard incision for radical resection of colon cancer.

The results showed that both IL-6 and high-sensitivity C-reactive protein were significantly higher at 1 day after surgery than before induction of anesthesia and immediately after the surgery. IL-6 is an immunoregulatory factor that plays an important regulatory role in destructive stimulus. Thus, the tissue injury or inflammation can increase the production of IL-6. The increase of IL-6 (980% to 1100%), a day after surgery, can reflect the degree of injury in open intestinal surgery, which also indicates that IL-6 is a sensitive index reflecting tissue damage. No significant change in RESIS level was found between, before and after surgery in this study.

The gold standard for the evaluation of IR is glucose clamp test. However, this method needs special requirement and is expensive, which limits its clinical application. Researches have shown that the HOMA value has a good correlation with the gold standard. The natural logarithm of the HOMA value may have the best correlation with the results of glucose clamp test; therefore, the HOMA-IR level was used for analysis.[18] This study showed that the HOMA value, a day after surgery, was increased as compared with that before induction of anesthesia and immediately after surgery, which increased by 75% in TAP group and by 46% in GEA group.

Moreover, after the application of epidural anesthesia and analgesia, the HOMA value in the GEA group was significantly lower than that in the TAP group, suggesting that epidural anesthesia and analgesia can effectively reduce the postoperative HOMA value. The decrease of the HOMA value was not caused by the decrease of RESIS secretion, which is consistent with the related literature.[19],[20] The FPG level in both the groups immediately after surgery was significantly elevated than that before the induction of anesthesia. Although the FPG level was decreased slightly, a day after surgery, it was significantly higher than that before induction of anesthesia. However, the FPG level in the GEA group was significantly lower than that in the TAP group immediately and a day after surgery. There was no significant difference in pain score between the two groups after surgery, which could exclude the difference caused by postoperative pain, indicating that epidural anesthesia and analgesia can significantly reduce the elevated postoperative FPG level. These results were consistent with the results reported in the relevant literatures.[21] A large number of studies show that epidural anesthesia can reduce the high-FPG reaction during the surgery by limiting glucose production.[22] General anesthesia combined with thoracic epidural anesthesia, the preemptive analgesia induced by epidural block before the surgery combined with the intraoperative general anesthesia could inhibit the upward conduction of nociceptive stimulus.[23] Epidural local anesthetics could block the conduction of pain nerve in thoracic sympathetic nerve and somatic nerve, which could significantly reduce the tension of sympathetic nervous system, the release of catecholamine, and relieve surgical stress reaction.[24] However, the transversus abdominis plane block had no effect on the stress reaction caused by the stimulation of stretching the organs because it only provided analgesia on the abdominal incision.

In this study, heart rate was observed to be reduced in GEA group than that in TAP group during anesthesia. In addition, besides the correlation with the FPG level, the HOMA value was correlated with the FINS level. The FINS levels in both the groups decreased at the end of the surgery but increased significantly, a day after the surgery, indicating that FINS changes slower than the change of FPG. With the increase of FPG, FINS levels increased correspondingly. The FINS levels, a day after surgery in both the groups, were significantly higher than those immediately after surgery (increased by 52.8% and 46.4% in TAP and GEA groups, respectively). The body improved glucose conversion through increasing FINS secretion. Therefore, the results showed that the decrease of HOMA value in the GEA group a day after surgery, is directly related to the decrease of postoperative plasma glucose level and the relative low level of postoperative FINS level.

Donatelli et al. believed that the HOMA value higher than 2.1 predicts the existence of IR.[25] In this study, the mean value of HOMA in the TAP group was 2.29 a day after surgery, indicating the existence IR; while it was 1.97 in GEA group, suggesting no IR phenomenon appeared in the GEA group, which indicates that general anesthesia combined with epidural anesthesia and analgesia can reduce IR.

 » Conclusion Top

In this study, the HOMA value showed that the application of nonsteroidal anti-inflammatory drugs combined with epidural continuous analgesia during the surgery of colon cancer can reduce the incidence of IR within 1–2 days after surgery, while nonsteroidal anti-inflammatory drugs combined with the transversus abdominis plane block can provide satisfactory postoperative analgesia but cannot reduce the incidence of IR after colon cancer surgery.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Harrington B, Halaszynski T, Marino J. Multimodal Analgesia. Berlin: Springer International Publishing; 2016.  Back to cited text no. 1
Gebhart GF, Schmidt RF. Multimodal Analgesia. Berlin: Springer Berlin Heidelberg; 2013.  Back to cited text no. 2
Bashandy GM, Abbas DN. Pectoral nerves I and II blocks in multimodal analgesia for breast cancer surgery: A randomized clinical trial. Reg Anesth Pain Med 2015;40:68-74.  Back to cited text no. 3
Ziemann-Gimmel P, Hensel P, Koppman J, Marema R. Multimodal analgesia reduces narcotic requirements and antiemetic rescue medication in laparoscopic Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis 2013;9:975-80.  Back to cited text no. 4
Adeniji AO, Atanda OO. Randomized comparison of effectiveness of unimodal opioid analgesia with multimodal analgesia in post-cesarean section pain management. J Pain Res 2013;6:419-24.  Back to cited text no. 5
Krych AJ, Baran S, Kuzma SA, Smith HM, Johnson RL, Levy BA. Utility of multimodal analgesia with fascia iliaca blockade for acute pain management following hip arthroscopy. Knee Surg Sports Traumatol Arthrosc 2014;22:843-7.  Back to cited text no. 6
Bonizzoli M, Zagli G, Lazzeri c, Degl'Innocenti S, Gensini G, Peris A. Early insulin resistance in severe trauma without head injury as outcome predictor? A prospective, monocentric pilot study. Scand J Trauma Resusc Emerg Med 2012;20:69.  Back to cited text no. 7
Clark JL, Taylor CG, Zahradka P. Rebelling against the (Insulin) resistance: A review of the proposed insulin-sensitizing actions of soybeans, chickpeas, and their bioactive compounds. Nutrients 2018;10:E434.  Back to cited text no. 8
Cho YN, Lee KO, Jeong J, Park HJ, Kim SM, Shin HY, et al. The role of insulin resistance in diabetic neuropathy in Koreans with type 2 diabetes mellitus: A 6-year follow-up study. Yonsei Med J 2014;55:700-8.  Back to cited text no. 9
Mukherjee K, Sowards KJ, Brooks SE, Norris PR, Boord JB, May AK. Insulin resistance increases before ventilator-associated pneumonia in euglycemic trauma patients. Surg Infect (Larchmt) 2014;15:713-20.  Back to cited text no. 10
Baban B, Thorell A, Nygren J, Bratt A, Ljungqvist O. Determination of insulin resistance in surgery: The choice of method is crucial. Clin Nutr 2015;34:123-8.  Back to cited text no. 11
Rausch M, Zehetleitner M. A comparison between a visual analogue scale and a four point scale as measures of conscious experience of motion. Conscious Cogn 2014;28:126-40.  Back to cited text no. 12
Rosero EB, Joshi GP. Preemptive, preventive, multimodal analgesia: What do they really mean? Plast Reconstr Surg 2014;134:85S-93S.  Back to cited text no. 13
Jiang Y, Wu GH, Zhang B, Han YS, Zhuang QL. Acute insulin resistance following surgical trauma in rats. Exp Clin Endocrinol Diabetes 2012;120:315-22.  Back to cited text no. 14
Fujino H, Itoda S, Esaki K, Tsukamoto M, Sako S, Matsuo K, et al. Intra-operative administration of low-dose IV glucose attenuates post-operative insulin resistance. Asia Pac J Clin Nutr 2014;23:400-7.  Back to cited text no. 15
Ljungqvist O, Jonathan E. Rhoads lecture 2011: Insulin resistance and enhanced recovery after surgery. JPEN J Parenter Enteral Nutr 2012;36:389-98.  Back to cited text no. 16
Hsu AR. Comment on “multimodal analgesia therapy reduces length of hospitalization in patients undergoing fusions of the ankle and hindfoot”. Foot Ankle Int 2013;34:1747-8.  Back to cited text no. 17
Demirhan A, Tekelioglu UY, Akkaya A, Bilgi M, Apuhan T, Karabekmez FE, et al. Effect of pregabalin and dexamethasone addition to multimodal analgesia on postoperative analgesia following rhinoplasty surgery. Aesthetic Plast Surg 2013;37:1100-6.  Back to cited text no. 18
Tewari N, Awad S, Macdonald IA, Lobo DN. Obesity-related insulin resistance: Implications for the surgical patient. Int J Obes (Lond) 2015;39:1575-88.  Back to cited text no. 19
Das P, Biswas S, Mukherjee S, Bandyopadhyay SK. Association of oxidative stress and obesity with insulin resistance in type 2 diabetes mellitus. Mymensingh Med J 2016;25:148-52.  Back to cited text no. 20
Rafiq S, Steinbrüchel DA, Wanscher MJ, Andersen LW, Navne A, Lilleoer NB, et al. Multimodal analgesia versus traditional opiate based analgesia after cardiac surgery, a randomized controlled trial. J Cardiothorac Surg 2014;9:52.  Back to cited text no. 21
Steagall PV, Monteiro-Steagall BP. Multimodal analgesia for perioperative pain in three cats. J Feline Med Surg 2013;15:737-43.  Back to cited text no. 22
Niraj G, Kelkar A, Hart E, Horst C, Malik D, Yeow C, et al. Comparison of analgesic efficacy of four-quadrant transversus abdominis plane (TAP) block and continuous posterior TAP analgesia with epidural analgesia in patients undergoing laparoscopic colorectal surgery: An open-label, randomised, non-inferiority trial. Anaesthesia 2014;69:348-55.  Back to cited text no. 23
Sircuta C, Lazar A, Azamfirei L, Baranyi M, Vizi ES, Borbély Z. Correlation between the increased release of catecholamines evoked by local anesthetics and their analgesic and adverse effects: Role of K(+) channel inhibition. Brain Res Bull 2016;124:21-6.  Back to cited text no. 24
Donatelli F, Vavassori A, Bonfanti S, Parrella P, Lorini L, Fumagalli R, et al. Epidural anesthesia and analgesia decrease the postoperative incidence of insulin resistance in preoperative insulin-resistant subjects only. Anesth Analg 2007;104:1587-93.  Back to cited text no. 25

Please see the related commentary [Gupta A, Gupta N. Epidural or TAP block to curtail insulin resistance in colorectal cancer surgeries: The jury is out! Indian J Cancer 2021;58:471-2]


  [Table 1], [Table 2]


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