Effect of Adding Midazolam to Dual Prophylaxis of Dexamethasone and Ondansetron for Preventing Postoperative Nausea and Vomiting (PONV)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 300
- 试验地点
- 1
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Care Provider)
盲法说明
In addition to participants, care providers, and outcome assessors, masking was extended to the anesthesiologist responsible for postoperative data recording and ward-based assessment of PONV outcomes. Drug preparation was performed by a separate anesthesiologist who was not involved in patient management, data collection, or outcome evaluation to ensure allocation concealment. Study medications (midazolam and placebo normal saline) were prepared in identical syringes to maintain blinding. The surgical team, postoperative nursing staff involved in routine care, and statisticians analyzing the data were also kept blinded to group allocation to minimize performance and assessment bias throughout the study period.
入排标准
- 年龄范围
- 19 Years 至 65 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究者
Dr. Abdullah Saad
Dr. Abdullah Saad
Hameed Latif Hospital, Lahore