Remimazolam and Postoperative Nausea and Vomiting in High-risk Patients

Study Overview
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Brief Summary
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This trial aims to explore whether the intraoperative use of remimazolam can reduce the incidence of postoperative nausea and vomiting (PONV) in high-risk patients. According to the Apfel's simplified score, patients with 3 or more of the following factors are at high risk of postoperative nausea and vomiting (PONV), i.e., women, non-smokers, history of PONV, and postoperative use of opioids.

Detailed Description
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Postoperative nausea and vomiting (PONV) is a common adverse event after general anesthesia. The incidence of PONV within 2 hours after surgery was approximately 14% in patients undergoing laparoscopic gynecological procedure and it could be about 22%-33% within 24 hours and as high as 80% in high-risk patients. Even with prophylaxis and treatment, such as 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, the incidence of PONV is still about 7%-10%. PONV is an important clinical problem that impact the recovery of patients. Firstly, it can be a highly distress experience to patients and reduce their satisfaction with medical services. Secondly, PONV is associated with prolonged stay in the postanesthesia care unit and hospital, and increase medical expenditures. Thirdly, PONV increases the risk of reflux aspiration and lung infection. Risk factors for PONV in adults include anxiety, opioid use, and inflammation. A cohort study showed that patients with anxiety before surgery have a 5-fold increase in the risk of PONV. Opioids are one of the main causes of PONV, and the incidence of PONV increases with the increasing dose of opioids. Inflammation is also considered to be a potential molecular mechanism leading to PONV. Animal studies have shown that surgery can cause inflammation throughout the body and central nervous system, and stimulate the vomiting center , which leads to PONV. Several clinical studies reported that midazolam decreased PONV. In a meta-analysis included 12 randomized trials (841 patients), the use of midazolam during the perioperative period reduced the risk of PONV by about 55%. Another Meta-analysis involving 16 randomized controlled studies also reported similar results. The use of midazolam during the perioperative period reduced the risk of PONV by approximately 45%. The mechanism by which benzodiazepines reduce PONV is not fully understood, but may include the following. Benzodiazepines can reduce the incidence of anxiety and reduce the severity of anxiety. On the other hand, studies have shown that the use of remimazolam enhances the analgesic effect of remifentanil and may reduce the dose of opioids. Another aspect is benzodiazepines may suppress the inflammatory response. Remimazolam is an ultra-short-acting benzodiazepine sedative. It has a more predictable fast onset, short duration of sedative action, and rapid recovery profile, but there is no clinical study on whether remimazolam has an effect on the incidence of PONV. The investigators speculate that remimazolam as a supplement anesthetic during general anesthesia can reduce the incidence of PONV.

Official Title
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Effect of Remimazolam on Incidence of Postoperative Nausea and Vomiting Following General Anesthesia in High-risk Patients: a Multicenter, Double-blinded, Placebo-controlled Randomized Trial

Conditions
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Postoperative Nausea and Vomiting, Benzodiazepine, High-risk Patients

Intervention / Treatment
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* Drug: Remimazolam
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years old; Scheduled to undergo elective surgery under general anesthesia; Judged to be at high risk of postoperative nausea and vomiting. According to the Apfel's simplified score, patients with 3 or more of the following factors are at high-risk: women, non-smokers, history of PONV, postoperative use of opioids. Exclusion Criteria: Refuse to participate; Previous history of schizophrenia, epilepsy, Parkinson's disease or myasthenia gravis; Severe liver dysfunction (Child-Pugh class C); Severe renal dysfunction (dialysis required); Patients of the American Society of Anesthesiologists (ASA) grade 4 and above; Emergency surgery; Continuously taking benzodiazepines for more than 1 week before surgery; Any other circumstances that are considered unsuitable for study participation by attending physicians or investigators.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remimazolam Group<br>Remimazolam infusion is initiated after induction of general anesthesia at a rate of 0.25 mg/kg/h and stopped 15 minutes before the end of surgery. | Drug: Remimazolam<br>* Remimazolam is infused at a rate of 0.25 mg/kg/h from end of anesthesia induction until 15 minutes before the end of surgery.<br>* Other names: Remimazolam group;|
| Placebo Comparator: Placebo Group<br>Placebo (0.9% saline) infusion is initiated after induction of general anesthesia at the same rate as in the remimazolam group and stopped 15 minutes before the end of surgery. | Drug: Placebo<br>* Normal saline is infused at a rate same as in the remimazolam group from end of anesthesia induction until 15 minutes before the end of surgery.<br>* Other names: Placebo group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of postoperative nausea and vomiting (PONV) within 24 hours following surgery | Nausea is diagnosed when the patient has gastrointestinal symptoms but does not vomit stomach contents. The severity of nausea is assessed using a digital subjective score scale (the scale ranges from 0 to 10, where 0 points represent no nausea, and 10 points represent the most severe nausea). Vomiting is diagnosed when the patient has gastrointestinal symptoms and retching or vomits gastric contents. Retching refers to the act of vomiting, but no stomach contents are vomited out. | Up to 24 hours after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of PONV within 48 hours after surgery | Nausea is diagnosed when the patient has gastrointestinal symptoms but does not vomit stomach contents. The severity of nausea is assessed using a digital subjective score scale (the scale ranges from 0 to 10, where 0 points represent no nausea, and 10 points represent the most severe nausea). Vomiting is diagnosed when the patient has gastrointestinal symptoms and retching or vomits gastric contents. Retching refers to the act of vomiting, but no stomach contents are vomited out. | Up to 48 hours after surgery | 
| Incidence of complications within 30 days after surgery | Postoperative complications are defined as new-onset medical events that are harmful to patients' recovery and required therapeutic intervention, i.e., grade II or above on the Clavien-Dindo classification. | Up to 30 days after surgery | 
| Subjective sleep quality score within 3 days after surgery | The Richards-Campbell Sleep Questionnaire (RSCQ) scale was used for evaluation. This is a five-item, visual analogue scale designed to assess subjective sleep quality. The scale for each item ranges from 0 to 100, with higher score indicating better quality. | Up to 3 days after surgery | 
| Incidence of emergence delirium (ED) | Delirium is assessed with the Confusion Assessment Method for the Intensive Care Unit. The assessments are performed at 10 minutes and 30 minutes after admission to the post-anesthesia care unit (PACU), or before leaving the PACU. | Up to 30 minutes after surgery or during the stay in PACU | 
| Incidence of delirium within 3 days after surgery | Delirium is assessed with the Three-dimensional Confusion Assessment Method (3D-CAM) twice daily (between 8-10 am and 18-20 pm) during the first 3 days after surgery. | Up to 3 days after surgery | 
| Length of stay in hospital after surgery | Length of stay in hospital after surgery | Up to 30 days after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postoperative nausea and vomiting, Benzodiazepines, High-risk patients