Remimazolam and Postoperative Nausea and Vomiting in High-risk Patients

Postoperative Nausea and Vomiting Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04861337
• Other study ID #: 2020-429
• Status: Completed
• Phase: Phase 4
• Start date: May 19, 2021
• Est. completion date: April 22, 2023

Study information

• Verified date: December 2023
• Source: Peking University First Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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), i.e., women, non-smokers, history of PONV, and postoperative use of opioids.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 552
• Est. completion date: April 22, 2023
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age =18 years old;

2. Scheduled to undergo elective surgery under general anesthesia;

3. 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:

1. Refuse to participate;

2. Previous history of schizophrenia, epilepsy, Parkinson's disease or myasthenia gravis;

3. Severe liver dysfunction (Child-Pugh class C);

4. Severe renal dysfunction (dialysis required);

5. Patients of the American Society of Anesthesiologists (ASA) grade 4 and above;

6. Emergency surgery;

7. Continuously taking benzodiazepines for more than 1 week before surgery;

8. Any other circumstances that are considered unsuitable for study participation by attending physicians or investigators.

Related Conditions & MeSH terms

• Benzodiazepine
• High-risk Patients
• Nausea
• Postoperative Nausea and Vomiting
• Vomiting

Intervention

Drug:
• Remimazolam
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.
• Placebo
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.

Locations

Country	Name	City	State
China	Beijing Hospital of the Ministry of Health	Beijing	Beijing
China	Beijing YouAn Hospital, Capital Medical University	Beijing	Beijing
China	Fuwai Hospital Chinese Academy of Medical Sciences	Beijing	Beijing
China	Peking University First Hospital	Beijing	Beijing
China	Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)	Hangzhou	Zhejiang
China	The First Affiliated Hospital, Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	Suzhou Municipal Hospital	Suzhou	Jiangsu
China	Tianjin Medical University Cancer Institute & Hospital	Tianjin	Tianjin
China	Tongji Hospital, Tongji Medical College of HUST	Wuhan	Hubei
China	Wuhan Puai Hospital	Wuhan	Hubei

Sponsors (1)

Lead Sponsor	Collaborator
Peking University First Hospital

Country where clinical trial is conducted

China, 

References & Publications (18)

Ahn 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. — View Citation

Barends 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. — View Citation

Brice DD, Hetherington RR, Utting JE. A simple study of awareness and dreaming during anaesthesia. Br J Anaesth. 1970 Jun;42(6):535-42. doi: 10.1093/bja/42.6.535. No abstract available. — View Citation

Burkhardt 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. — View Citation

de 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. — View Citation

Dewinter 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. — View Citation

Gan 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. Erratum In: Anesth Analg. 2020 Nov;131(5):e241. — View Citation

Gan 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. Erratum In: Anesth Analg. 2014 Mar;118(3):689. Anesth Analg. 2015 Feb;120(2):494. — View Citation

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. — View Citation

Grant 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. — View Citation

Hines S, Steels E, Chang A, Gibbons K. Aromatherapy for treatment of postoperative nausea and vomiting. Cochrane Database Syst Rev. 2018 Mar 10;3(3):CD007598. doi: 10.1002/14651858.CD007598.pub3. — View Citation

Horiguchi 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. — View Citation

Horn 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. — View Citation

Joo 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. — View Citation

Laufenberg-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. — View Citation

Li 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. — View Citation

Pym 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. — View Citation

Wesolowski AM, Zaccagnino MP, Malapero RJ, Kaye AD, Urman RD. Remimazolam: Pharmacologic Considerations and Clinical Role in Anesthesiology. Pharmacotherapy. 2016 Sep;36(9):1021-7. doi: 10.1002/phar.1806. Epub 2016 Sep 1. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of intraoperative awareness	Intraoperative awareness is assessed with the modified Brice questionnaire during PACU stay and on the first postoperative day	Up to 24 hours after surgery
Other	Incidence of dreaming during general anesthesia	Assessed with the modified Brice questionnaire on the first day after surgery. Record whether the patient can recall the content of the dream (divided into clear, unclear, and forget) and the impact of the dream on the patient's subjective feelings (divided into pleasure, normal, sad, and nightmares)	Up to 24 hours after surgery
Primary	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	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
Secondary	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
Secondary	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).	Up to 3 days after surgery
Secondary	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
Secondary	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
Secondary	Length of stay in hospital after surgery	Length of stay in hospital after surgery	Up to 30 days after surgery