Midazolam Adjunct Therapy for Prevention of PONV in Gynecological Laparoscopy (MIDOD)

Effect of Adding Midazolam to Dual Prophylaxis of Dexamethasone and Ondansetron for Preventing Postoperative Nausea and Vomiting (PONV)

This randomized controlled trial was conducted to evaluate the efficacy of adding midazolam to standard dual antiemetic prophylaxis with dexamethasone and ondansetron for the prevention of postoperative nausea and vomiting (PONV) in patients undergoing elective gynecological laparoscopic surgery.

PONV is a common postoperative complication that significantly affects patient comfort, delays recovery, and may prolong hospital stay. Despite the use of established dual prophylaxis with dexamethasone and ondansetron, a considerable proportion of patients continue to experience nausea and vomiting, particularly in high-risk populations such as females undergoing laparoscopic gynecological procedures. Midazolam, a short-acting benzodiazepine, has shown potential antiemetic properties in recent studies, but its role as an adjunct in standard prophylactic regimens remains controversial.

The study was conducted in the Department of Anesthesiology at Hameed Latif Hospital, Lahore, over a period of six months from 02-12-2025 to 01-06-2026. A total of 300 eligible patients aged 19-65 years with ASA physical status I-II undergoing elective gynecological laparoscopic surgery were enrolled after obtaining informed written consent. Patients with significant comorbidities, contraindications to study drugs, or factors influencing PONV assessment were excluded.

Participants were randomly allocated into two equal groups (150 patients each) using a computer-generated randomization sequence with allocation concealment through sealed opaque envelopes. Group A received standard prophylaxis with dexamethasone and ondansetron along with intravenous normal saline. Group B received the same dual prophylaxis in addition to intravenous midazolam at a dose of 0.05 mg/kg administered after preoxygenation and before induction of anesthesia. Blinding was maintained by using identical syringes, and drug administration was performed by an anesthesiologist not involved in outcome assessment.

All patients received standardized general anesthesia, including induction with propofol, fentanyl, and atracurium, and maintenance with isoflurane in oxygen/air mixture. Neuromuscular blockade was reversed appropriately at the end of the procedure. Postoperative care and analgesia were standardized for all patients.

The primary outcome was the efficacy of antiemetic prophylaxis, defined as a postoperative nausea and vomiting visual numeric rating scale (VNRS) score of less than 4. PONV was assessed at 0 (post-anesthesia care unit), 6, 12, and 24 hours postoperatively. Secondary outcomes included comparison of VNRS scores over time and requirement of rescue antiemetics. Rescue antiemetics were administered as per protocol when clinically indicated.

Data were analyzed using SPSS version 26.0. Continuous variables were expressed as mean ± standard deviation, and categorical variables as frequency and percentages. The Shapiro-Wilk test was used to assess normality. Group comparisons were performed using Chi-square or Fisher's exact test, with a p-value ≤0.05 considered statistically significant. Stratified analysis was also conducted for age, body mass index, ASA status, and type of surgical procedure.

Study Overview

• Status: Completed
• Conditions: Anesthesia Complications; Postoperative Nausea and Vomiting (PONV); Gynecological Laparoscopic Surgery
• Intervention / Treatment: Drug: Midazolam 0.05 mg/kg IV as adjunct to dexamethasone and ondansetron for PONV prevention

Detailed Description

Postoperative nausea and vomiting (PONV) is one of the most frequent and distressing complications following general anesthesia, particularly in patients undergoing laparoscopic and gynecological surgical procedures. Despite advances in anesthetic techniques and routine use of prophylactic antiemetic agents, PONV continues to affect a significant proportion of surgical patients. It is associated with considerable discomfort, delayed recovery, prolonged post-anesthesia care unit (PACU) stay, increased healthcare utilization, risk of dehydration and electrolyte imbalance, and in severe cases may lead to aspiration, wound complications, or disruption of surgical repair. The multifactorial nature of PONV involves patient-related, anesthetic-related, and surgical factors. Female gender, non-smoking status, use of volatile anesthetics, perioperative opioid administration, and laparoscopic procedures are well-established risk factors, making gynecological laparoscopic surgery one of the highest-risk categories for PONV.

Even though dual prophylaxis using dexamethasone and ondansetron has become a widely accepted standard regimen due to their complementary mechanisms of action, complete prevention of PONV is still not achieved in a substantial subset of patients. Dexamethasone exerts its antiemetic effect through anti-inflammatory action and possible central inhibition of prostaglandin synthesis, while ondansetron acts as a selective 5-HT3 receptor antagonist blocking serotonin-mediated emetogenic pathways in both the central nervous system and gastrointestinal tract. However, because PONV is mediated through multiple overlapping pathways including dopaminergic, histaminergic, cholinergic, and neurokinin systems, targeting only two pathways may not provide sufficient protection in high-risk individuals.

This limitation has led to increasing interest in multimodal antiemetic strategies incorporating drugs with different pharmacological mechanisms. Midazolam, a short-acting benzodiazepine, is primarily used for anxiolysis, sedation, and induction of anesthesia through potentiation of gamma-aminobutyric acid (GABA) receptors in the central nervous system. In addition to its sedative properties, emerging evidence suggests that midazolam may possess antiemetic effects. The proposed mechanisms include reduction of preoperative anxiety, modulation of central dopaminergic pathways, inhibition of cortical and vestibular input to the vomiting center, and attenuation of the emotional component of nausea perception. Some studies also suggest that benzodiazepines may reduce dopamine release in the chemoreceptor trigger zone, thereby contributing to antiemetic action. However, clinical evidence remains inconsistent, with some trials demonstrating significant reductions in PONV incidence and others showing only marginal or statistically non-significant effects.

Given these conflicting findings, the present randomized controlled trial was designed to evaluate whether adding midazolam to standard dual prophylaxis with dexamethasone and ondansetron provides superior protection against postoperative nausea and vomiting in patients undergoing elective gynecological laparoscopic surgery. The study was conducted at the Department of Anesthesiology, Hameed Latif Hospital, Lahore, over a period of six months from 02-12-2025 to 01-06-2026 after obtaining ethical approval from the institutional ethics committee.

A total of 300 female patients aged between 19 and 65 years with American Society of Anesthesiologists (ASA) physical status I and II scheduled for elective gynecological laparoscopic procedures were enrolled in the study after obtaining written informed consent. Patients with significant comorbidities that could influence PONV assessment or drug metabolism were excluded. Exclusion criteria included a history of chemotherapy, chronic opioid use, recent antiemetic administration within 24 hours, known allergy to study drugs, hepatic dysfunction defined as liver enzymes greater than twice the normal upper limit, renal impairment with serum creatinine greater than 1.6 mg/dl, pregnancy or lactation, conversion to laparotomy during surgery, BMI greater than 35 kg/m², QTc prolongation above 450 ms, alcohol or substance abuse, and inability to reliably assess postoperative nausea and vomiting.

The sample size of 300 patients (150 in each group) was calculated using 80% statistical power and a 95% confidence interval, assuming an expected efficacy rate of 65% in the control group and 78% in the intervention group based on previously published literature. This ensured adequate power to detect a clinically meaningful difference between groups.

Randomization was performed using a computer-generated random number sequence in a 1:1 allocation ratio. Allocation concealment was ensured using sealed opaque envelopes that were opened just before drug administration. Patients were assigned to either Group A or Group B accordingly. Group A received standard dual prophylaxis consisting of dexamethasone (0.1 mg/kg intravenously after induction of anesthesia) and ondansetron (0.1 mg/kg intravenously at the end of surgery) along with normal saline placebo administered after preoxygenation. Group B received the same dual prophylaxis with the addition of intravenous midazolam at a dose of 0.05 mg/kg administered after preoxygenation and prior to induction of anesthesia. Identical syringes were used for midazolam and placebo to ensure blinding of both patients and outcome assessors. Drug preparation and administration were performed by an anesthesiologist not involved in data collection or postoperative assessment.

All patients received a standardized general anesthesia protocol to minimize confounding variables. Preoxygenation was performed for three minutes prior to induction. Anesthesia was induced with intravenous propofol at 2 mg/kg, fentanyl at 1 µg/kg, and atracurium at 0.5 mg/kg to facilitate tracheal intubation. Following intubation, anesthesia was maintained using isoflurane in a mixture of oxygen and air (approximately 40% oxygen). Mechanical ventilation was adjusted to maintain end-tidal carbon dioxide between 35 and 40 mmHg throughout the procedure. Hemodynamic parameters were monitored continuously, and anesthetic depth was adjusted as required. Neuromuscular blockade was reversed at the end of surgery using pyridostigmine and glycopyrrolate in appropriate doses. Patients were extubated once standard recovery criteria were met and then transferred to the post-anesthesia care unit for monitoring.

Postoperative management was standardized for all patients. Pain management protocols were kept consistent to avoid confounding effects of analgesics on nausea and vomiting. Patients were observed in PACU and later transferred to the ward once they achieved a modified Aldrete score indicating adequate recovery. No additional sedative or antiemetic medications were given unless required as rescue therapy according to protocol.

Postoperative nausea and vomiting was assessed using an 11-point visual numeric rating scale (VNRS), where 0 represented no nausea and 10 represented the worst possible nausea. Scores were categorized as mild (1-3), moderate (4-6), and severe (7-10). A VNRS score of 4 or more was considered clinically significant PONV. Assessments were conducted at predefined time intervals: immediately in the post-anesthesia care unit (0 hours), at 6 hours, 12 hours, and 24 hours postoperatively. The highest VNRS score recorded during each time period was used for statistical analysis. Vomiting episodes and retching were also recorded separately. Rescue antiemetic therapy was administered according to protocol, including metoclopramide 10 mg intravenously as first-line rescue treatment, and chlorpheniramine 4 mg intravenously as second-line therapy if symptoms persisted or recurred.

Data were entered and analyzed using SPSS version 26.0. Continuous variables were expressed as mean ± standard deviation, while categorical variables were presented as frequencies and percentages. Normality of continuous data such as age and body mass index was assessed using the Shapiro-Wilk test, which confirmed that the data were normally distributed. Independent sample t-test was applied for continuous variables, while Chi-square test or Fisher's exact test was used for comparison of categorical variables. A p-value of less than or equal to 0.05 was considered statistically significant. Stratified analysis was performed to control for potential confounders including age groups, body mass index categories, ASA physical status, and type of surgical procedure.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 2

Contacts and Locations

Study Locations

• Pakistan
  • Punjab Province
    • Lahore, Punjab Province, Pakistan, 54590
      • Department of Anaesthesiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged between 19 to 65 years with an American society of Anesthesiologists (ASA) physical status of < III.
• Patients planned for elective gynecologic laparoscopic procedures'
• Female patients.

Exclusion Criteria:

• Patients with a history of anticancer chemotherapy, alcohol or drug abuse, chronic opioid use, antiemetic intake within 24 hours prior to laparoscopy, or allergy to study drugs.
• Hepatic impairment (liver enzymes >2 times normal value) or renal insufficiency (serum creatinine >1.6 mg/dl).
• Conversion of laparoscopic procedure to laparotomy.
• Pregnancy or breastfeeding (childbearing or lactating women).
• Borderline QTc prolongation (>450 ms).
• Patients with history of diabetes mellitus, infectious diseases, gastritis, or gastric ulcer.
• Body mass index >35 kg/m².
• Patients unable to reliably assess PONV or pain scores.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard dual prophylaxis (dexamethasone + ondansetron + placebo); Participants in this arm received standard antiemetic prophylaxis consisting of intravenous dexamethasone 0.1 mg/kg administered after induction of anesthesia and ondansetron 0.1 mg/kg administered at the end of surgery. In addition, an equivalent volume of normal saline (placebo) was administered intravenously after preoxygenation prior to induction. All patients underwent standardized general anesthesia. This arm served as the control group to compare the efficacy of dual prophylaxis alone in preventing postoperative nausea and vomiting (PONV).	Drug: Midazolam 0.05 mg/kg IV as adjunct to dexamethasone and ondansetron for PONV prevention; Placebo (0.9% normal saline) with dexamethasone and ondansetron for PONV prevention; Other Names: Placebo (0.9% normal saline) with dexamethasone and ondansetron for PONV prevention
Experimental: Midazolam + dexamethasone + ondansetron (intervention group); Participants in this arm received intravenous midazolam 0.05 mg/kg administered after preoxygenation and before induction of anesthesia, in addition to standard dual antiemetic prophylaxis consisting of dexamethasone 0.1 mg/kg after induction and ondansetron 0.1 mg/kg at the end of surgery. All patients underwent standardized general anesthesia. This arm evaluated the added effect of midazolam as an adjunct to dual prophylaxis for prevention of postoperative nausea and vomiting (PONV) in patients undergoing gynecological laparoscopic surgery.	Drug: Midazolam 0.05 mg/kg IV as adjunct to dexamethasone and ondansetron for PONV prevention; Placebo (0.9% normal saline) with dexamethasone and ondansetron for PONV prevention; Other Names: Placebo (0.9% normal saline) with dexamethasone and ondansetron for PONV prevention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of antiemetic prophylaxis in prevention of postoperative nausea and vomiting (PONV)	The primary outcome was the efficacy of antiemetic prophylaxis, defined as the proportion of patients achieving a visual numeric rating scale (VNRS) score of less than 4 for postoperative nausea at 6, 12, and 24 hours after surgery. VNRS ranged from 0 (no nausea) to 10 (worst possible nausea), with scores ≥4 considered clinically significant PONV. Assessments were performed at predefined time intervals in the post-anesthesia care unit, and at 6, 12, and 24 hours postoperatively. The comparison was made between patients receiving standard dual prophylaxis (dexamethasone and ondansetron with placebo) and those receiving additional intravenous midazolam. The outcome measured the overall effectiveness of the intervention in reducing clinically significant postoperative nausea and vomiting.	6 hours, 12 hours, and 24 hours postoperatively

Collaborators and Investigators

• Sponsor: Hameed Latif Hospital, Lahore

Publications and helpful links

General Publications

• 1. Kanya K, Tayung RP, Das KK. An observational study on the incidence and risk factors of postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic surgeries. Eur J Cardiovasc Med. 2025;15(3):510-2. doi:10.5083/ejcm/25-05-91. 2. Zhao X, Liao W, Chen C, Zheng Y, Li L, Chang Q, et al. Postoperative nausea and vomiting: translating pathophysiological mechanisms into clinical management. Perioper Med. 2025;14(1):140. doi: 10.1186/s13741-025-00626-5. 3. Timerga S, Befkadu A. Prevalence and associated factors of postoperative nausea and vomiting among adult patients undergoing elective surgery. Ann Med Surg. 2024;86(3):1304-8. doi:10.1097/MS9.0000000000001678. 4. Mieszczański P, Jurczak M, Cylke R, Ziemiański P, Trzebicki J. Evidence-based perioperative prevention of postoperative nausea and vomiting (PONV) in Patients undergoing laparoscopic bariatric surgery: a scoping review. J Clin Med. 2025;14(19):6901. 5. Hailu S, Mekonen S, Shiferaw A. Prevention and management of postoperative nausea and vomiting after cesarean section: a systematic literature review. Ann Med Surg. 2022;75(1):103433. doi:10.1016/j.amsu.2022.103433. 6. Schlesinger T, Meybohm P, Kranke P. Postoperative nausea and vomiting: risk factors, prediction tools, and algorithms. Curr Opin Anesthesiol. 2023;36(1):117-23. doi: 10.1097/ACO.0000000000001220. 7. Lin C, Li J, Wu Q, Luo T, Zheng Z. Postoperative nausea and vomiting in female patients undergoing laparoscopic gastrointestinal surgery with double prophylactic therapy. Surg J. 2024;10(02):e25-30. doi: 10.1055/s-0044-1787305. 8. Hu B, Zhou H, Zou X, Shi J, Li X, Tan L. A comparison of dexmedetomidine and midazolam for the prevention of postoperative nausea and vomiting caused by hemabate in cesarean delivery: a randomized controlled trial. Drug Design Develop Ther. 2020;28:2127-33. doi:10.2147/DDDT.S251525. 9. Singh MP, Gupta A, Bhardwaj S. Continuum-based postoperative nausea and vomiting prophylaxis protocol: development and real-w

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2025
• Primary Completion (Actual): June 1, 2026
• Study Completion (Actual): June 1, 2026

Study Registration Dates

• First Submitted: June 13, 2026
• First Submitted That Met QC Criteria: June 23, 2026
• First Posted (Actual): June 25, 2026

Study Record Updates

• Last Update Posted (Actual): June 25, 2026
• Last Update Submitted That Met QC Criteria: June 23, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Ondansetron; Dexamethasone; Midazolam; Postoperative nausea vomiting; PONV prevention; Multimodal analgesia / antiemesis; Anti-emetic prophylaxis
• Additional Relevant MeSH Terms: Postoperative Complications; Pathologic Processes; Signs and Symptoms, Digestive; Vomiting; Nausea; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Postoperative Nausea and Vomiting; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Azoles; Imidazoles; Indoles; Crystalloid Solutions; Isotonic Solutions; Solutions; Benzazepines; Benzodiazepines; Heterocyclic Compounds, 3-Ring; Carbazoles; Midazolam; Ondansetron; Saline Solution
• Other Study ID Numbers: HameedLatif

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared due to institutional and ethical restrictions governing patient confidentiality and data protection. The dataset contains sensitive perioperative clinical information collected from surgical patients, and there is no formal data-sharing agreement or approved repository for external access. Additionally, the informed consent obtained from participants did not include provisions for public data sharing. The data will remain securely stored within the Department of Anesthesiology, Hameed Latif Hospital, Lahore, and will be used solely for the purposes of statistical analysis and publication of study findings. Access to raw data may be granted only upon reasonable request from regulatory authorities or the institutional ethics committee.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No