Abstract
Background and Aims:
Patients undergoing neurosurgical procedures are at a high risk of post-operative nausea and vomiting (PONV). Amisulpride, a dopamine (D2, D3) receptor antagonist, has been recently approved for intravenous use in antiemesis and has demonstrated safety and efficacy in managing PONV in non-neurosurgical settings. We hypothesised that amisulpride would be non-inferior to ondansetron in preventing PONV.
Methods:
Adult patients scheduled for elective supratentorial craniotomy for tumour surgery under general anaesthesia were randomised to receive either intravenous amisulpride (5 mg) or intravenous ondansetron (4 mg) intra-operatively, administered 30 minutes before skin closure. Patients were then assessed for PONV in the post-operative intensive care unit. The primary objective was to evaluate the incidence of nausea and vomiting in the first 24 hours post-operatively. Secondary outcomes included nausea severity, the need for rescue antiemetic medications, and treatment-related adverse events. Incidence of PONV was compared using the Chi-square test. Secondary outcomes like severity of nausea, rescue medications, and adverse events were tested using Chi-square/Fisher’s exact test. Non-inferiority of amisulpride to ondansetron was assessed using the pre-specified absolute non-inferiority margin of 20%.
Results:
A total of 100 patients were included in the final analysis. The incidence of nausea and vomiting was significantly lower in the amisulpride group (22% and 8%) compared to the ondansetron group (36% and 8%) (P = 0.032 and P = 0.045, respectively). Nausea severity was also significantly lower in the amisulpride group during the first four post-operative hours (P < 0.05). Additionally, patients receiving amisulpride required fewer rescue antiemetics. No treatment-related adverse events were observed in the amisulpride group.
Conclusion:
A single intra-operative intravenous dose of amisulpride (5 mg) at the end of the surgery was found to be non-inferior to 4 mg intravenous ondansetron in reducing the incidence and severity of PONV in patients undergoing supratentorial craniotomy.
Keywords: Amisulpride, anaesthesia, craniotomy, intravenous, neurosurgery, ondansetron, PONV, post-operative nausea and vomiting, supratentorial tumour surgery
INTRODUCTION
Post-operative nausea and vomiting (PONV) is one of the most common post-operative complications in neurosurgical patients, with an incidence ranging from 22% to 70%.[1] The aetiology of PONV following craniotomy is likely multifactorial, with established risk factors including age, gender, and a history of motion sickness, or PONV.[2] Additionally, neurosurgical factors such as tumour location, midline shift, and mass effect can influence its incidence. PONV is most prevalent within the first 24 hours after craniotomy.[3]
Ondansetron and dexamethasone are routinely used for PONV prevention; however, ondansetron has been associated with an increased risk of QT prolongation and arrhythmias, particularly in brain-injured patients[4] and individuals over 50 years of age.[5] Amisulpride, a dopamine (D2, D3) receptor antagonist, has demonstrated safety and efficacy in managing PONV in non-neurosurgical settings.[6,7,8] Previous studies primarily focussed on its enteral administration, but the recent Food and Drug Administration (FDA) approval of intravenous (IV) amisulpride has opened new possibilities for its use. However, there is limited literature on the role of IV amisulpride in neurosurgical patients.
We conducted this study to compare the efficacy and safety of IV amisulpride (5 mg) with those of IV ondansetron (4 mg) in patients undergoing craniotomy for supratentorial tumour surgery. The primary objective was to evaluate whether a single intra-operative dose of IV amisulpride (5 mg) administered 30 minutes before skin closure is non-inferior to IV ondansetron (4 mg) in reducing the incidence of PONV within the first 24 hours post-operatively in adult patients undergoing elective supratentorial craniotomy for brain tumour surgery under general anaesthesia. The secondary objectives were to compare the severity of nausea between amisulpride and ondansetron at specified post-operative intervals (1, 2, 4, 8, and 24 hours) within the first 24 hours, to assess the need for rescue antiemetic medications (number of doses and total dose) between the two groups within the first 24 hours, and to evaluate treatment-related adverse events between the two groups within the first 24 hours. The hypothesis of the study was that IV amisulpride (5 mg) is non-inferior to IV ondansetron (4 mg) in preventing PONV in neurosurgical patients.
METHODS
This single-centre, double-blind, randomised, non-inferiority study was conducted between October 2024 and December 2024 after getting approval from the institutional ethics committee (vide approval number SCT/IEC/2213/March 2024, dated 05/04/2024) and registration with the Clinical Trials Registry-India (vide registration number CTRI/2024/09/073589, accessible at https://ctri.nic.in). It was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2013 and Good Clinical Practice guidelines. Written informed consent was obtained from each participant or their legal representative before enrolment for participation in the study and use of the patient data for research and educational purposes.
Patients of either gender aged 18 to 65 years with the American Society of Anesthesiologists (ASA) physical status classification I-II scheduled to undergo elective supratentorial craniotomy for brain tumour surgeries were included. Exclusion criteria were patient refusal, patients with a history of drug or alcohol abuse, history of nausea or vomiting, pregnant or lactating women, chemotherapy or radiation therapy during the previous month, history of psychiatric illness or Glasgow coma scale score < 13 pre-operatively, and patients on multiple antiepileptic drugs.
All participants were pre-medicated with oral pantoprazole 40 mg the night before and on the morning of the surgery. The volumetric measurements of the tumour mass and peritumour oedema were assessed using the method described by Kienzler et al.[2] As per our institutional protocol for supratentorial tumour surgeries, all patients received oral dexamethasone 4 mg twice daily pre-operatively. Standard ASA monitors, including heart rate, non-invasive blood pressure, and pulse oximetry, were instituted upon arrival at the operating room. Additionally, the bispectral index (BIS) was used to monitor the depth of anaesthesia (DOA). After pre-oxygenation with 100% oxygen for 3 minutes, anaesthesia was induced with IV fentanyl 1–2 µg/kg and IV propofol 2–3 mg/kg. Endotracheal intubation was facilitated by a bolus dose of IV vecuronium 0.1 mg/kg, and anaesthesia was maintained with sevoflurane (0.8–1 minimum alveolar concentration) in an air–oxygen (1:1) mixture or propofol total IV anaesthesia as per the discretion of the attending anaesthesiologist, with the DOA titrated to a BIS value of 40–50.
Additionally, IV infusion of atracurium 0.01 mg/kg/min and fentanyl 1–2 µg/kg/h was used to maintain the anaesthesia. Mechanical ventilation was titrated to maintain an end-tidal partial pressure of carbon dioxide between 30 and 35 mm of Hg, and a positive end-expiratory pressure of 5 cm of water was used. After induction of anaesthesia, a radial artery catheter was inserted to facilitate invasive blood pressure monitoring and blood sampling. A central line, if indicated, was inserted in the right internal jugular vein for fluid replacement and the administration of vasopressors or inotropes if needed. Additional monitoring included end-tidal sevoflurane concentration monitoring. Half an hour before the skin closure, PONV prophylaxis was administered as per the following protocol.
Patients were randomised into two groups, A and B, using a computer-generated block randomisation method (simple block randomisation with a fixed block size of four and a 1:1 allocation ratio) using WINPEPI (PEPI for Windows) developed by Abramson JH. The random allocation sequence was generated by an independent statistician not involved in patient care or data collection using the online software Sealed Envelope (Sealed Envelope Ltd., London, United Kingdom). Allocation concealment was achieved using sequentially numbered, opaque, sealed envelopes (SNOSEs) containing the group assignment. These envelopes were opened only at the time of drug preparation by the research coordinator, ensuring that the allocation remained hidden from the enroling investigator, patients, anaesthesiologists, and outcome assessors until study completion. Participant enrolment was performed by the principal investigator, who screened and obtained consent from eligible patients.
Group A received amisulpride 5 mg and paracetamol 1 gm intravenously, and Group B received ondansetron 4 mg and paracetamol 1 gm IV. This was a double-blind study (participant and outcome assessor blinded). Blinding was ensured by preparing the study drugs in identical, unlabelled syringes by a qualified anaesthesiologist, who was not involved in patient care and data collection. The syringes were labelled only with the patient’s study ID. Patients were blinded as they received the drugs intra-operatively under anaesthesia. The attending anaesthesiologists, surgeons, and intensive care unit clinicians were blinded to group allocation. Outcome assessors were blinded through the use of de-identified data sheets and had no access to the allocation sequence or drug preparation records. Blinding was maintained until data analysis was complete, with emergency unblinding provisions available only for serious adverse events.
Following surgery, a neurological assessment was done in all patients. They were shifted, intubated for non-contrast computed tomography, and then transferred to the neurosurgery intensive care unit (NSICU). Once the extubation criteria were met, the patients were extubated.
Management of patients in the NSICU was as per our institute protocol. Rescue antiemetic therapy with IV ondansetron 4 mg was given at the patient’s request. If PONV persisted, despite the rescue dose of IV ondansetron, IV dexamethasone 4 mg was administered. All patients were on dexamethasone 4 mg IV, twice a day, for the prevention of post-operative cerebral oedema. Post-operative pain was managed with paracetamol 1 gm, three times a day. Rescue analgesia, if needed, was managed with IV fentanyl 1 µg/kg or IV morphine 0.1 mg/kg.
The primary outcome was to evaluate the incidence of PONV following intra-operative administration of amisulpride (5 mg) versus ondansetron (4 mg) in adult patients undergoing elective supratentorial craniotomy within the first 24 hours post-operatively. PONV was defined as any episode of nausea (subjective unpleasant sensation associated with the urge to vomit) or vomiting (forceful expulsion of gastric contents) reported by the patient or observed by staff. Secondary outcomes included assessment of severity of nausea, which was assessed using a 4-point numerical rating scale (0 = no nausea; 1 = mild nausea not interfering with activities; 2 = moderate nausea requiring intervention; 3 = severe nausea with frequent vomiting; 4 = continuous vomiting) measured at 1, 2, 4, 8, and 24 hours post-operatively, the need for rescue antiemetic medications, which was defined as the number of rescue doses administered (first-line: ondansetron 4 mg IV; second-line: dexamethasone 4 mg IV if PONV persisted) and total dose per patient, recorded from NSICU charts administered whenever requested by the patient or indicated by symptoms within 24 hours and treatment-related adverse events, which was defined as any drug-attributable events (e.g. QTc prolongation >500 ms on the electrocardiogram (ECG), bradycardia <50 beats per minute requiring intervention, allergic reactions like rash/itching, extrapyramidal symptoms, or psychological disturbances), monitored continuously via vital signs, ECG, and clinical observation in the first 24 hours, with documentation in the patient’s record.
Post-operative pain was assessed using the visual analogue scale (VAS), where 0 score represents no pain, and a maximum score of 10 represents the worst imaginable pain. The total dose of opioids administered was also recorded.
The 100-sample size, with 50 participants in each group, was calculated using n master software, version 2.0 (developed by the Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India), considering an alpha error of 5%, a power of 80%, the observed difference in the proportion of 4%[9] for PONV, and a non-inferiority margin of 0.2.
Statistical analysis was performed using International Business Machine, Statistical Package for the Social Sciences (IBM SPSS), Statistics version 23 (IBM Corporation, Armonk, New York, United States of America). Data normality was assessed using the Kolmogorov–Smirnov test for continuous variables. Normally distributed continuous variables (age, body mass index, tumour mass, duration of surgery and anaesthesia, pain score) were presented as mean (standard deviation). Categorical variables (gender, mode of anaesthesia, incidence of hypertension and hypotension, incidence of nausea and vomiting, need for rescue medication) were presented as frequencies (percentages). For the primary outcome (PONV incidence), groups were compared using the Chi-square test. Secondary outcomes like nausea severity scale, rescue medications, and adverse events were compared using Chi-square/Fisher’s exact test. The comparison of pain score and post-operative opioid requirement was tested using an independent samples t-test. The significance level was set at P < 0.05.
RESULTS
A total of 124 patients were screened for eligibility, with 11 excluded based on the exclusion criteria. Consequently, 113 patients underwent block randomisation into one of the two study groups. During follow-up, 13 patients dropped out, leaving 100 patients for the final analysis [Figure 1]. The demographic and baseline clinical characteristics were comparable between the groups [Table 1].
Figure 1.
Consolidated standards of reporting trials (CONSORT) flow diagram of the enroled patients. n=number of patients
Table 1.
Demographic and clinical characteristics of the study population
| Characteristics | Amisulpride Group A (n=50) | Ondansetron Group B (n=50) | P |
|---|---|---|---|
| Age (years) | |||
| Mean (SD) (95% CI) | 44.28 (13.43) (95% CI: 40.46, 48.10) | 41.42 (12.08) (95% CI: 37.99, 44.85) | 0.266 |
| Male/female n (%) | 27 (54)/23 (46) | 27 (54)/23 (46)) | 1.00 |
| BMI (kg/m2) | |||
| Mean (SD) (95% CI) | 24.1 (0.41) (95% CI: 23.98, 24.22) | 24.9 (0.52) (95% CI: 24.75, 25.05) | 0.229 |
| Tumour mass (cm3) | |||
| Mean (SD) (95% CI) | 12.78 (4.8) (95% CI: 11.42, 14.14) | 11.5 (4.2) (95% CI: 10.31, 12.69) | 0.186 |
| Duration of surgery (min) | |||
| Mean (SD) (95% CI) | 347.6 (54.23) (95% CI: 332.19, 363.01) | 356.3 (45.6) (95% CI: 343.34, 369.26) | 0.18 |
| Duration of anaesthesia (min) | |||
| Mean (SD) (95% CI) | 369.76 (54.2) (95% CI: 354.36, 385.16) | 341.3 (40.6) (95% CI: 329.76, 352.84) | 0.512 |
| Intraoperative opioid requirement (μg) | |||
| Mean (SD) (95% CI) | 632.6 (156.73) (95% CI: 588.06, 677.14) | 576 (169.45) (95% CI: 527.84, 624.16) | 0.086 |
| Mode of anaesthesia | |||
| (INHA/TIVA) n (%) | 27 (54)/23 (46) | 30 (60)/20 (40) | 0.545 |
| Vasopressor use n (%) | 16 (32%) | 18 (36%) | 0.378 |
| Incidence of hypertension n (%) | 4 (8) | 5 (10) | 0.628 |
| Incidence of Hypotension n (%) | 8 (16) | 7 (14) | 0.525 |
| Intraoperative Fluid (L) | |||
| Mean (SD) (95% CI) | 2.4 (0.5) (95% CI: 2.26, 2.54) | 0.2.8 (0.3) (95% CI: 2.71, 2.89) | 0.321 |
| Blood loss (ml) | |||
| Mean (SD) (95% CI) | 400 (125) (95% CI: 364.48, 435.52) | 420 (110) (95% CI: 388.74, 451.26) | 0.454 |
| Apfel score | |||
| Mean (SD) (95% CI) | 1 (0.925) (95% CI: 0.74, 1.26) | 1.26 (0.633) (95% CI: 1.08, 1.44) | 0.98 |
Data presented as mean (SD) (95% CI) or number (%), BMI=Body mass index, TIVA=Total intravenous anaesthesia, INHA=Inhalational anaesthesia, SD=Standard deviation, CI=Confidence interval
In our study, significant differences were observed between the two groups in terms of the episodes of nausea and vomiting (P = 0.032 and P = 0.045, respectively); the nausea severity scale at 0–1 h (P = 0.046), 1–2 h (P = 0.021), and 2–4 h (P = 0.011); and the need for rescue medications (P = 0.037) [Table 2]. In the amisulpride group, four patients required rescue ondansetron, while in the ondansetron group, five patients required rescue ondansetron. Additionally, one patient in the amisulpride group and three in the ondansetron group required a rescue dose of ondansetron and dexamethasone. Two patients in the ondansetron group experienced QTc prolongation, which was successfully managed with a labetalol 0.2–0.5 mg/kg/h infusion. One patient developed bradycardia and was treated with IV atropine, and another had an allergic reaction (rashes and itching) to ondansetron, managed with IV hydrocortisone and pheniramine maleate (P = 0.042). Adverse events happened with the initial dose of ondansetron in all these patients. In contrast, no treatment-related side effects were observed in the amisulpride group. Furthermore, there was no evidence of adverse effects typically associated with D2-antagonists, such as cardiotoxicity, extrapyramidal symptoms, or psychological effects, at the administered dose in our study.
Table 2.
Incidence of nausea and vomiting, nausea severity, rescue medication requirement, pain scores, post-operative opioid consumption, and treatment-related adverse events in both groups
| Amisulpride Group A (n=50) | Ondansetron Group B (n=50) | P (95% Confidence Interval) | |||
|---|---|---|---|---|---|
| Incidence of nausea n (%) | 11 (22%) | 18 (36%) | 0.032 | ||
| Episode of nausea (n) – 1/2/≥3 | 5/3/3/ | 6/4/8 | |||
|
| |||||
|
Nausea severity scale
| |||||
| Postoperative time | Number of patients | Severity | Number of patients | Severity | P-value |
|
| |||||
| 0-1 h n (%) | 4 (8%) | Mild: 1 | 9 (18%) | Mild: 4 | 0.046* |
| Moderate: 1 | Moderate: 3 | ||||
| Severe: 2 | Severe: 2 | ||||
| 1-2 h n (%) | 6 (12%) | Mild: 3 | 12 (24%) | Mild: 5 | 0.021 |
| Moderate: 2 | Moderate: 5 | ||||
| Severe: 1 | Severe: 2 | ||||
| 2-4 h n (%) | 2 (4%) | Mild: 1 | 8 (16%) | Mild: 4 | 0.011 |
| Moderate: 1 | Moderate: 3 | ||||
| Severe: 0 | Severe: 1 | ||||
| 4-8 h n (%) | 2 (2%) | Mild: 2 | 4 (8%) | Mild: 2 | 0.565 |
| Moderate: 0 | Moderate: 2 | ||||
| Severe: 0 | Severe: 0 | ||||
| 8-24 h n (%) | 0 | Mild: 0 | 0 | Mild: 0 | 0.99 |
| Moderate: 0 | Moderate: 0 | ||||
| Severe: 0 | Severe: 0 | ||||
| Incidence of vomiting n (%) | 4 (8%) | 9 (18%) | 0.045 | ||
| Episodes of vomiting (n)– 1/2/≥3 | 2/2/0 | 3/2/4 | |||
| Rescue medications n (%) | 5 (10%) | 8 (16%) | 0.037 | ||
| Pain Score (VAS) Mean (SD) (95% CI) |
4 (2) (95% CI: 3.43, 4.57) | 5 (1) (95% CI: 4.72, 5.28) | 0.767 | ||
| Post-operative opioid requirement (Morphine equivalent dose-mg) Mean (SD) (95% CI) |
7.5 (3) (95% CI: 6.65, 8.35) | 7 (4.5) (95% CI: 5.72, 8.28) | 0.642 | ||
| Adverse events n (%) | 0 | 4 (8%) | 0.042 | ||
Data presented as mean (SD) (95% CI) or number (%). VAS=Visual analogue scale, SD=Standard deviation, CI=Confidence interval
DISCUSSION
Our study found that a single intra-operative prophylactic dose of IV amisulpride significantly reduced the incidence of PONV compared to ondansetron in patients undergoing elective supratentorial craniotomy.
Key factors influencing PONV incidence and severity, including gender, Apfel score[10] (female gender, history of PONV or motion sickness, non-smoking status, and opioid use in the post-operative period), perioperative opioid requirements, choice of anaesthesia, tumour volume, and peritumoral oedema were comparable between both groups.
There are several classes of antiemetic drugs, including 5-hydroxytryptamine 3 (5-HT3), D2, and neurokinin-1 (NK1) receptor antagonists, corticosteroids, antihistamines, and anticholinergics.[11,12,13,14,15,16,17] In neurosurgical patients, it is preferable to avoid agents with sedative effects, such as anticholinergics, antihistamines, and dopamine antagonists like droperidol, as these patients are already at high risk of developing side effects such as electrocardiographic abnormalities and electrolyte imbalances due to underlying brain injury. The most commonly reported electrocardiographic abnormalities in non-traumatic brain injury include ST-T changes and prolonged QTc, which can progress to lethal arrhythmias like torsades de pointes and cardiac arrest.[18,19] While ondansetron remains a commonly used antiemetic in neurosurgical settings, it is known to increase the risk of arrhythmias in patients with pre-existing QTc prolongation.[20]
Despite prophylactic administration of IV ondansetron, a significant proportion of patients undergoing craniotomy continue to experience PONV. The reported incidence of PONV following craniotomy, even with combined ondansetron and dexamethasone prophylaxis, ranges between 6% and 60%.[1] PONV can contribute to events like intravascular volume depletion, electrolyte imbalances, pulmonary aspiration, and prolonged hospital stay.[21] Additionally, the high intra-abdominal and intrathoracic pressures (>100 mmHg) generated during the ejection phase of vomiting are transmitted to the intracranial space, potentially increasing intracranial pressure and the risk of post-operative cavity bleeding.[22] Neurosurgical patients are particularly vulnerable to aspiration due to pre-existing lower cranial nerve deficits and a depressed level of consciousness.[7]
Amisulpride, a dopamine receptor agonist which was initially used as an atypical antipsychotic in the dose range 600–1200 mg/day, orally, was approved by the FDA in 2020 as an antiemetic. Amisulpride offers a longer duration of action, with a half-life of approximately 12 hours, compared to 6 hours for ondansetron. IV amisulpride (5 mg) has been shown to be more effective than placebo in reducing nausea and vomiting.[23] Amisulpride is not associated with sedation, extrapyramidal side effects, or QTc prolongation at antiemetic doses.[7] When used in combination with other antiemetics, it demonstrates a favourable safety profile comparable to a placebo. Moreover, IV amisulpride has not shown significant drug interactions and does not induce or inhibit cytochrome P450 liver enzymes.[17]
Kranke et al.[7] evaluated different doses of IV amisulpride administered at anaesthesia induction for PONV prevention in non-neurosurgical patients and concluded that 5 mg was the optimal and safest dose. Gupta et al.[9] investigated the efficacy of 25 mg oral amisulpride as part of a multimodal regimen administered 2 hours before surgery. They found that it significantly reduced the incidence and severity of PONV in craniotomy patients. A 2022 survey among anaesthesia providers reported that IV amisulpride has a superior safety profile compared to IV ondansetron.[24]
The study has certain limitations. This study was conducted at a single centre, with the study population consisting of patients undergoing craniotomy. Consequently, we did not assess post-operative headache, a common adverse effect of ondansetron, as distinguishing it from post-craniotomy pain is challenging in this patient group. Additionally, all participants received dexamethasone as part of our institutional protocol, which has inherent antiemetic properties. Therefore, further studies evaluating amisulpride as a standalone antiemetic are warranted.
CONCLUSION
A single intra-operative IV dose of amisulpride (5 mg) at the end of the surgery was found to be non-inferior to (4 mg) IV ondansetron in reducing the incidence and severity of PONV in patients undergoing supratentorial craniotomy.
Study data availability
De-identified data may be requested with reasonable justification from the authors (email to the corresponding author) and shall be shared after approval as per the authors’ institution’s policy.
Disclosure of use of artificial intelligence (AI)-assistive or generative tools
The AI tools or language models have not been utilised in the manuscript, except that software has been used for grammar corrections and references.
Declaration of use of permitted tools
The scales, scores, figures, and tables, such as the nausea severity scale, visual analogue scale, and Apfel score, are freely available and not copyrighted.
Supplementary material
None.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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