Postoperative Nausea and VomitingPhase 4NCT04861337
Remimazolam and Postoperative Nausea and Vomiting in High-risk Patients
A Phase 4 study testing Remimazolam in people with Postoperative Nausea and Vomiting and Benzodiazepine, run by Peking University First Hospital at 10 sites in China.
Trial summary
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)… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Postoperative Nausea and Vomiting, Benzodiazepine, High-risk Patients
- What is being tested?
- Remimazolam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 552 participants
- Where
- 10 sitesChina
- Study dates
- 19 May 2021to 22 Apr 2023
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
China10 sites
Peking University First Hospital
Beijing, Beijing Municipality, 100034
Beijing Hospital of the Ministry of Health
Beijing, Beijing Municipality
Beijing YouAn Hospital, Capital Medical University
Beijing, Beijing Municipality
Fuwai Hospital Chinese Academy of Medical Sciences
Beijing, Beijing Municipality
Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)
Hangzhou, Zhejiang
The First Affiliated Hospital, Zhejiang University School of Medicine
Hangzhou, Zhejiang
Suzhou Municipal Hospital
Suzhou, Jiangsu
Tianjin Medical University Cancer Institute & Hospital
Tianjin, Tianjin Municipality
Tongji Hospital, Tongji Medical College of HUST
Wuhan, Hubei
Wuhan Puai Hospital
Wuhan, Hubei
About this study
Official title: 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
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.
Read the detailed description
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.
- Being tested
- Remimazolam, Placebo
- Keywords
- Postoperative nausea and vomiting, Benzodiazepines, High-risk patients
- Medical subject headings
- Postoperative Nausea and Vomiting
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RemimazolamDrug
Also called Remimazolam group
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.
PlaceboDrug
Also called Placebo group
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.
| Study group | Role | What they receive |
|---|---|---|
| Remimazolam Group | Experimental | 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. Receives: Drug: Remimazolam |
| Placebo Group | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 24 hours after surgery
Secondary outcomes (6)
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.
Measured: 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.
Measured: Up to 30 days after surgery
Subjective sleep quality score within 3 days after surgery
Subjective sleep quality was evaluated with the NRS (an 11-point scale where 0=the worst night sleep and 10=the best night sleep).
Measured: 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.
Measured: 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.
Measured: Up to 3 days after surgery
Length of stay in hospital after surgery
Length of stay in hospital after surgery
Measured: Up to 30 days after surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Apr 2021
- Study start19 May 2021
- Primary completion31 Dec 2022
- Study completion22 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (18)Papers the sponsor has linked to this study.
- Other trials for Postoperative Nausea and VomitingStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 552 participants (actual)
Sponsor and investigators
- Lead sponsor
- Peking University First Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dong-Xin Wang, Peking University First Hospital
- Investigators
- Dong-Xin Wang, MD, PhD, Principal investigator, Peking University First Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04861337
- Sponsor's protocol ID
- 2020-429
- Status last verified
- Dec 2023
- First submitted
- 24 Apr 2021
- Last updated
- 3 Jan 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Geng ZY, Liu YF, Wang SS, Wang DX. Intra-operative dexmedetomidine reduces early postoperative nausea but not vomiting in adult patients after gynaecological laparoscopic surgery: A randomised controlled trial. Eur J Anaesthesiol. 2016 Oct;33(10):761-6. doi: 10.1097/EJA.0000000000000491.
PubMed 27307217Dewinter G, Staelens W, Veef E, Teunkens A, Van de Velde M, Rex S. Simplified algorithm for the prevention of postoperative nausea and vomiting: a before-and-after study. Br J Anaesth. 2018 Jan;120(1):156-163. doi: 10.1016/j.bja.2017.08.003. Epub 2017 Nov 23.
PubMed 29397124Gan TJ, Diemunsch P, Habib AS, Kovac A, Kranke P, Meyer TA, Watcha M, Chung F, Angus S, Apfel CC, Bergese SD, Candiotti KA, Chan MT, Davis PJ, Hooper VD, Lagoo-Deenadayalan S, Myles P, Nezat G, Philip BK, Tramer MR; Society for Ambulatory Anesthesia. Consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2014 Jan;118(1):85-113. doi: 10.1213/ANE.0000000000000002.
PubMed 24356162Li CJ, Wang BJ, Mu DL, Hu J, Guo C, Li XY, Ma D, Wang DX. Randomized clinical trial of intraoperative dexmedetomidine to prevent delirium in the elderly undergoing major non-cardiac surgery. Br J Surg. 2020 Jan;107(2):e123-e132. doi: 10.1002/bjs.11354.
PubMed 31903588Joo J, Park S, Park HJ, Shin SY. Ramosetron versus ondansetron for postoperative nausea and vomiting in strabismus surgery patients. BMC Anesthesiol. 2016 Jul 22;16(1):41. doi: 10.1186/s12871-016-0210-5.
PubMed 27449404Pym A, Ben-Menachem E. The effect of a multifaceted postoperative nausea and vomiting reduction strategy on prophylaxis administration amongst higher-risk adult surgical patients. Anaesth Intensive Care. 2018 Mar;46(2):185-189. doi: 10.1177/0310057X1804600207.
PubMed 29519221Burkhardt T, Czorlich P, Mende KC, Treitz A, Kiefmann R, Westphal M, Schmidt NO. Postoperative Nausea and Vomiting Following Craniotomy: Risk Factors and Complications in Context of Perioperative High-dose Dexamethasone Application. J Neurol Surg A Cent Eur Neurosurg. 2019 Sep;80(5):381-386. doi: 10.1055/s-0039-1685194. Epub 2019 May 10.
PubMed 31075810Laufenberg-Feldmann R, Muller M, Ferner M, Engelhard K, Kappis B. Is 'anxiety sensitivity' predictive of postoperative nausea and vomiting?: A prospective observational study. Eur J Anaesthesiol. 2019 May;36(5):369-374. doi: 10.1097/EJA.0000000000000979.
PubMed 30865002de Boer HD, Detriche O, Forget P. Opioid-related side effects: Postoperative ileus, urinary retention, nausea and vomiting, and shivering. A review of the literature. Best Pract Res Clin Anaesthesiol. 2017 Dec;31(4):499-504. doi: 10.1016/j.bpa.2017.07.002. Epub 2017 Jul 8.
PubMed 29739538Horn CC, Wallisch WJ, Homanics GE, Williams JP. Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting. Eur J Pharmacol. 2014 Jan 5;722:55-66. doi: 10.1016/j.ejphar.2013.10.037. Epub 2013 Oct 26.
PubMed 24495419Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, Jin Z, Kovac AL, Meyer TA, Urman RD, Apfel CC, Ayad S, Beagley L, Candiotti K, Englesakis M, Hedrick TL, Kranke P, Lee S, Lipman D, Minkowitz HS, Morton J, Philip BK. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg. 2020 Aug;131(2):411-448. doi: 10.1213/ANE.0000000000004833.
PubMed 32467512Grant MC, Kim J, Page AJ, Hobson D, Wick E, Wu CL. The Effect of Intravenous Midazolam on Postoperative Nausea and Vomiting: A Meta-Analysis. Anesth Analg. 2016 Mar;122(3):656-663. doi: 10.1213/ANE.0000000000000941.
PubMed 26332858Ahn EJ, Kang H, Choi GJ, Baek CW, Jung YH, Woo YC. The Effectiveness of Midazolam for Preventing Postoperative Nausea and Vomiting: A Systematic Review and Meta-Analysis. Anesth Analg. 2016 Mar;122(3):664-676. doi: 10.1213/ANE.0000000000001062.
PubMed 26516802Barends CRM, Absalom AR, Struys MMRF. Drug selection for ambulatory procedural sedation. Curr Opin Anaesthesiol. 2018 Dec;31(6):673-678. doi: 10.1097/ACO.0000000000000652.
PubMed 30124543Horiguchi Y, Ohta N, Yamamoto S, Koide M, Fujino Y. Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling. Int Immunopharmacol. 2019 Jan;66:373-382. doi: 10.1016/j.intimp.2018.11.050. Epub 2018 Dec 5.
PubMed 30530051