Effect of two dose versus single dose dexamethasone on pain and post-operative inflammatory response in patients undergoing major abdominal surgery: A double- blinded randomised controlled trial.

Effect of two dose versus single dose dexamethasone on pain and post-operative inflammatory response in patients undergoing major abdominal surgery: A double- blinded randomised controlled trial.

 BACKGROUND

Excessive post-operative inflammatory response may lead to post-operative systemic inflammatory dysregulation – a state of dysregulated host response to surgical injury, in which progression to SIRS and infectious complications is more likely.1 Therefore, attenuation of the post-operative inflammatory response may help reduce post-operative morbidity and mortality. Evidence suggests that dexamethasone, through its anti-inflammatory action, reduces post-operative ileus and enhances functional gut recovery after major bowel surgery.2 The role of dexamethasone is reducing post-operative pain and nausea vomiting is well established.3,4

Dexamethasone has a long biological half-life of approximately 36-54 hours.5 However, as post-operative inflammatory response usually peaks on the third post-operative day,2 a single dose of dexamethasone at induction of anaesthesia, as is the current practice, may not be adequate for effectively suppressing post-operative inflammation.

 We hypothesize that two doses of dexamethasone, one administered at the induction of anaesthesia, followed by a second dose 12 hours after the initial dose, will be more effective in attenuating the post-operative inflammatory response, pain, and functional gastrointestinal recovery, compared to a single dose of dexamethasone at anaesthesia induction, without increasing adverse effects.

METHODS

After obtaining informed written consent, patients will be randomly allocated into:

·       Group 1: Single dose dexamethasone (0.2 mg/kg immediately following induction)

·       Group 2: Two-dose dexamethasone (0.2 mg/kg immediately following induction, and second dose 12 hours after the initial dose)

Intravenous access will be secured, and baseline blood sample (5 ml) will be obtained prior to induction. Further blood samples (5 ml each) will be obtained on post-operative day 1, 3 and 5.

Standard technique of anaesthesia for major abdominal laparotomies will be followed. All patients will receive general anaesthesia along with thoracic epidural infusion of local anaesthetic during the intra-operative period. Post-operative analgesia will be maintained with epidural morphine 50 mcg/kg every 12 hours for 48 hours along with IV paracetamol (15mg/kg every 6 hours). IV tramadol (1mg/kg) will be used for rescue analgesia. All patients will receive post-operative nausea and vomiting (PONV) prophylaxis with IV ondansetron 0.1 mg/kg at the end of surgery.

Blood sugar will be monitored every 2 hours during the intra-operative period and every 6 hours in the post-operative period for 48 hours. Hyperglycemia (BS > 180 g/dl) will be treated with insulin infusion. All patients will receive peri-operative stress ulcer prophylaxis with pantoprazole 40 mg IV once daily.

 The schedule of the intervention drug or placebo will be as follows:

Group 1

Group 2

|At anaesthesia induction

IV infusion of 0.2 mg/kg dexamethasone in 100 ml of normal saline

|12-hours after initial dose

IV infusion of 100 ml of normal saline (PLACEBO)

IV infusion of 0.2 mg/kg dexamethasone in 100 ml of normal saline

 Sample size calculation:

Minimum required sample size has been calculated separately for each primary outcome. Sample size for CRP level is based on a two-sided T-test model with an expected mean (± SD) post-operative CRP level in single dose dexamethasone group as 125 (± 50) mg/L,6 and a 25% reduction in CRP level considered clinically significant. With an alpha error of 0.05 and power of study at 80%, the required minimum sample size is 41 in each group.

Sample size for mean VAS score has been calculated based on a two-sided T-test model with an expected mean (± SD) post-operative VAS score in single dose dexamethasone group as 3 (± 2),2 and a reduction in VAS score by 1 considered clinically significant. With an alpha error of 0.05 and power of study at 80%, the required minimum sample size is 63 in each group.

Therefore, it has been decided to recruit a total of 130 patient in the study.

 Statistical analysis:

Quantitative data will be assessed using Mann-Whitney U-test or student’s t-test, and qualitative data will be assessed using chi-square test or Fischer’s exact test. A p value of less than 0.05 will be considered statistically significant.

 REFERENCES

1. Bain CR, Myles PS, Corcoran T, Dieleman JM. Postoperative systemic inflammatory dysregulation and corticosteroids: a narrative review. Anaesthesia. 2023;78(3):356-370. doi:10.1111/anae.15896

2. Zhang T, Xu Y, Yao Y, et al. Randomized Controlled Trial: Perioperative Dexamethasone Reduces Excessive Postoperative Inflammatory Response and Ileus After Surgery for Inflammatory Bowel Disease. Inflamm Bowel Dis. 2021;27(11):1756-1765. doi:10.1093/ibd/izab065

3. De Oliveira GS, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology. 2011;115(3):575-588. doi:10.1097/ALN.0b013e31822a24c2

4. Waldron NH, Jones CA, Gan TJ, Allen TK, Habib AS. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. Br J Anaesth. 2013;110(2):191-200. doi:10.1093/bja/aes431

5. Drug vignettes: Dexamethasone. The Centre for Evidence-Based Medicine. Accessed April 29, 2023. https://www.cebm.net/covid-19/dexamethasone/

6. Straatman J, Cuesta MA, Tuynman JB, Veenhof AAFA, Bemelman WA, van der Peet DL. C-reactive protein in predicting major postoperative complications are there differences in open and minimally invasive colorectal surgery? Substudy from a randomized clinical trial. Surg Endosc. 2018;32(6):2877-2885. doi:10.1007/s00464-017-5996-9