Remimazolam is a new type of ultra-short-acting benzodiazepine that acts on the central GABAA receptor, opening the channel and increasing the inward flow of chloride ions, causing hyperpolarization of the nerve cell membrane and thus inhibiting neuronal activity, producing sedation and amnesia etc. Remimazolam combines some of the properties of both remifentanil and midazolam. It is derived from the parent compound midazolam and incorporates the pharmacokinetic properties of remifentanil, which is metabolised by tissue esterases to an inactive compound CNS 7054. It has three times the total drug clearance of midazolam and is characterised by a rapid onset of action and mild respiratory and circulatory depression. However, it does not have the analgesic effect of opioids and often needs to be used in combination with other opioid analgesics. Continuous infusion of 3 h of context-sensitive half-time (CSHT) is similar to that of propofol (7.5 min) and significantly shorter than that of midazolam. There are specific antagonists for remimazolam. In 2020, remimazolam was approved for induction and maintenance of general anesthesia in Japan and in March 2021, remimazolam besylate was approved for induction and maintenance of general anesthesia in China. Studies have confirmed that remimazolam (0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg) is a safe and effective sedative drug with few side effects during induction of anesthesia in ASAI-II patients and provides stable hemodynamics compared to propofol; remimazolam can be used safely and effectively instead of propofol for induction of anesthesia for valve replacement. In this study, induction and maintenance of anesthesia was performed according to a regimen of 6 mg/kg/h initial infusion of remimazolam induction and 1 mg/kg/h maintenance.[12,13]
A large body of literature confirms that the incidence of PONV is approximately 25 ~ 50% and that post-discharge nausea and vomiting (PDNV) occurs in 30% of patients. Despite the widespread use of anti-emetic drugs, short-acting anesthetic drugs and minimally invasive surgery in the clinic, the incidence of PONV is still 20 ~ 40%[16,17] and up to 80% in high-risk groups, mainly associated with increased day surgery and early activity and discharge after minor/major surgery. High risk factors for early PONV in the PACU are opioid administration, female gender, BMI > 35, major surgery, and duration of anesthesia over 60 min. The Apfel score of the PONV risk scale is a better predictor of the risk of PONV occurrence. The Apfel score for PONV risk assessment in the three groups of patients in this study was 2–3, which is an intermediate to high risk of PONV. There were no statistically significant differences in basic information such as age, weight, BMI, ASA grade and type of surgery among the three groups of patients. There were no statistically significant differences in the intraoperative administration of alfentanil and remimazolam and the duration of surgery, so the baseline information of the three groups of patients was comparable.
The incidence of PONV in the PACU in this study was 14.5% in the dexamethasone combined with droperidol group, 26.7% in the dexamethasone combined with tropisetron group and 50% in the dexamethasone alone group. the incidence of PONV within 24 h was 44.7% in the dexamethasone combined with droperidol group, 45.1% in the dexamethasone combined with tropisetron group and 51% in the dexamethasone alone group. The incidence of PONV falls within the normal incidence range reported in the literature.
Dexamethasone is a corticosteroid antiemetic that is currently widely used in clinical practice and may be associated with anti-infective effects and stabilization of cell membranes. Dexamethasone 4–12 mg given intravenously was effective in preventing PONV. Because of the slow onset of action of dexamethasone, this study followed the recommendation to administer it at the start of surgery. Perioperative use of dexamethasone did not reduce the incidence of PONV in the PACU in a multi-centre study, but did reduce PDNV. 5-HT3 receptors are closely related to PONV and can act from the cerebral cortex, chemical trigger band, vomiting centre and visceral afferent nerves. Droperidol has strong Dopamine receptor antagonism, and low dose (0.625–1.25 mg) can effectively prevent PONV. Dexamethasone combined with ondansetron can effectively prevent early and late PONV. The combination of different types of antiemetic drugs can block a variety of central nervous system receptors and have a better preventive effect than single drugs. Combination therapy is recommended to prevent PONV. The use of the least effective dose also reduced the incidence of side effects for each drug. Habib et al.found in a multi-centre randomized controlled trial that the combination of a 5-HT3 receptor antagonist and dexamethasone was significantly more effective than the 5-HT3 receptor antagonist alone in preventing PONV. Dexamethasone, ondansetron and droperidol were used in combination at doses not exceeding 8 mg, 4 mg and 1.25 mg, and intravenous administration in this study was within the recommended dose. 5-HT3 combined with droperidol and droperidol combined with dexamethasone did not differ, and 5-HT3 receptor inhibitors, dexamethasone and droperidol were effective in preventing PONV with few side effects. This study confirmed that either droperidol or tropisetron combined with dexamethasone reduced the incidence of PONV in the PACU better than dexamethasone alone, but whether droperidol was superior to tropisetron combined with dexamethasone (26.7% & 14.5%) may not be statistically different due to the sample size. There is no conclusive evidence on the most optimal drug combination and dose selection.
This study confirmed that the incidence of PONV in the three groups was 44.7–63.8% within 24 h postoperatively, with no difference, which may be related to the short duration of the antiemetic effect of a single administration of droperidol or tropisetron, thus necessitating further research into postoperative interventions for PONV.
As to whether remimazolam itself has a preventive effect on PONV, it has been suggested in the literature that midazolam can reduce the incidence of PONV when applied either at the induction of anesthesia or at the end of surgery; Midazolam 2 mg given 30 min before the end of surgery can effectively prevent PONV and is equivalent to ondansetron 4 mg. Hari Y et al. found that remimazolam reduced the incidence of early postoperative nausea and vomiting compared with desflurane in gynaecological laparoscopic surgery, with no difference for PONV 24 h after surgery.
The pathogenesis of PONV is complex, and understanding the risk factors of PONV, the effectiveness of various antiemetic drugs and non-pharmacological treatment countermeasures will enable us to further understand PONV, optimise anesthetic management methods to reduce the risk factors for PONV under the premise of meeting surgical needs, and use antiemetics early and appropriately for high-risk patients or supplement with other non-pharmacological treatments.
Inadequacies of this study: The three groups of patients with Apfel scores of 2–3 were at moderate to high risk of PONV, and for ethical reasons there was no blank control group, so it was not possible to determine whether dexamethasone alone could reduce the incidence of PONV after anesthesia for this type of procedure. For the incidence of PONV within 24 h being significantly higher than the incidence of PONV in the PACU, are there any factors related to the patient's change in position and premature discharge activity? As we found that patients in the PACU were prone to PONV during position change. No combination of the three drugs was taken for high-risk patients., and 5-HT3 receptor inhibitors have been shown to work best in combination with droperidol and dexamethasone. The gold standard for determining the effectiveness of clinical control of PONV is to achieve 24 h effectiveness and complete absence of nausea and vomiting, so it is important to choose antiemetic drugs and timing of administration appropriately. This study protocol did not achieve effective prevention of PONV at 24 h and further optimization of the protocol is required. It is also uncertain whether the short-acting benzodiazepine remimazolam also has a preventive effect against PONV in this study. Further studies are therefore needed for the postoperative PONV of remimazolam and the interaction with opioids.
In conclusion, droperidol or tropisetron combined with dexamethasone was effective in reducing the incidence of PONV in the remimazolam combined with alfentanil PACU compared to dexamethasone alone, but had no effect on the incidence of PONV in 24 h after surgery.
All authors thank Cuihuan Zhang, Shirong Fang, Xuelian Ji, Li Jing, Yanxia Lin, who served as nurse in PACU. They thank to Xiaobo Sun, Mingming Liu, Haiqiang Liu, Min Fu, who provided trial monitor in PACU.
This study was self-financed.
Availability of data and materials
The datasets generated and analysed during the current study are not publicly available due to institutional restrictions but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
This study was approved by the Clinical Research Ethics Committee of Weifang People's Hospital (2021029) and registered at https://www.chictr.org.cn (ChiCTR2100053316). The study protocol followed the CONSORT guidelines. The study protocol was performed in the relevant guidelines. Written informed consent was obtained from all patients.
Consent for publication
All authors declare that they have no conflicts of interest.
BMC Anesthesiol. 2022;22(292) © 2022 BioMed Central, Ltd.