Postoperative nausea and vomiting (PONV) is common in children after strabismus surgery performed under general anaesthesia.1 It causes restlessness and delays discharge from the post-anaesthetic room or day surgery unit. Serotonin receptor antagonists can reduce the incidence of PONV2,3 but not block it completely; a combination of antiemetics may be more effective.4,5 Midazolam is frequently used as an antiemetic in children,6,7 and is also effective in preventing agitation on emergence,8 which is especially problematic after sevoflurane anaesthesia in children. Midazolam might, therefore, be an attractive candidate for combination therapy after sevoflurane anaesthesia in children.
In this clinical study, we hypothesised that a serotonin receptor antagonist combined with midazolam might be more effective in reducing the incidence of PONV than a serotonin receptor antagonist alone after strabismus surgery under sevoflurane anaesthesia.
We undertook a prospective, double-blind study after obtaining Ethical Committee approval from the Seoul National University Hospital, Seoul, Korea (Chairperson Professor B. Yoon; Ethical Committee 0909-025-294; 4 December 2009). Informed consent was obtained from parents or guardians of children (American Society of Anesthesiologists physical status I or II) aged from 4 to 12 years who were to undergo strabismus surgery. Exclusion criteria were a history of motion sickness, previous PONV, gastro-intestinal tract disorders or administration of antiemetic in the 24 h before surgery.
Recruited patients were randomly allocated into one of two groups using sealed envelopes prepared by the study coordinator. Patients fasted according to local guidelines (at least 8 h for solid food and 2 h for clear fluids) and were hydrated appropriately. Patients arrived in the operating room without premedication. After recording non-invasive blood pressure, heart rate and peripheral oxygen saturation, they received ramosetron 6 μg kg−1 (ramosetron group) or the same dose of ramosetron and midazolam 0.1 mg kg−1 (ramosetron and midazolam group) intravenously. Anaesthesia was induced with thiopental 6 mg kg−1 and atropine 0.02 mg kg−1 and the patients’ lungs were ventilated with sevoflurane 8% in oxygen via a facemask after loss of consciousness. Once patients were fully anaesthetised, a laryngeal mask airway (LMA) of appropriate size was inserted. Anaesthesia was maintained with sevoflurane 2–2.5% in equal parts of nitrous oxide and oxygen at a fresh gas flow rate of 3 l min−1. If the patient became hypercapnic, the anaesthesiologist assisted ventilation to maintain the end-tidal concentration of carbon dioxide within the predetermined limits (4.7–5.3 kPa). During anaesthesia, lactated Ringer's solution was administered at 8 ml kg−1 h−1. The incidence of the oculocardiac reflex (defined as a decrease in heart rate > 20% from baseline) during surgery was noted. At the end of surgery, the LMA was removed and patients were awakened. Once they opened their eyes to verbal command they were transferred to the post-anaesthetic care unit (PACU) and then returned to the day surgery unit after staying in the PACU for 30–60 min. If patients reported pain, ketorolac 0.5 mg kg−1 intravenously or ibuprofen 0.5 mg kg−1 orally was administered.
While in hospital, all episodes of nausea, retching or vomiting during the first 6 h after surgery were recorded by an investigator blinded to patient group allocation and episodes during 6–24 h and the second 24 h at home were recorded by an anaesthetic nurse blinded to group allocation by telephone interview. In the hospital, metoclopramide was used as a rescue antiemetic. Nausea was defined as a patient report that they felt nauseated, that is, ‘I feel like vomiting or a sensation like motion sickness’. Retching was defined as the laboured, spasmodic, rhythmic contractions of respiratory muscles without the expulsion of gastric contents, and vomiting was defined as the forceful expulsion of gastric contents. Other adverse events such as headache or dizziness were recorded. The degree of agitation was assessed in the PACU by a nurse blinded to the patient group using the Pediatric Anesthesia Emergence Delirium (PAED) Scale (Table 1)9 on arrival and 30 min after arrival.
The primary outcomes were the incidences of nausea, retching or vomiting and the secondary outcome was the degree of agitation. Sample size was determined using a power analysis. We aimed for a study with an 80% chance (β = 0.2) of detecting a 50% reduction in PONV from a basal incidence of 20%, with a significance level (α) of 0.05. The calculated minimum sample size was 200 patients in each group; a larger number was recruited to allow for possible incomplete data collection or patient dropout. Statistical analysis was performed using SPSS for Windows (Version 18.0, SPSS Inc., Chicago, Illinois, USA). Demographic data were analysed by Student's t-test, the incidences of nausea, retching or vomiting or other adverse effects were analysed by χ2-tests and PAED scores were compared using repeated measures analysis of variance. A P value less than 0.05 was considered significant.
In total, 446 patients were recruited; 41 patients were excluded because they were lost to follow-up and we analysed data from the remaining 405 patients (ramosetron, n = 202; ramosetron and midazolam, n = 203). There was no difference in patient characteristics and other clinical data between groups (Fig. 1; Table 2). The number of muscles operated on, the duration of surgery and the duration of anaesthesia were similar in the two groups.
There was no difference in the incidence of oculocardiac reflex during the surgery between the two groups. The overall incidences of nausea, retching or vomiting, use of rescue antiemetics and adverse effects of antiemetics are shown in Table 3. The incidence of nausea was similar in the two groups in both the first and second 24 h after surgery. Retching and vomiting were more common than nausea and, again, there were no difference between the two groups during the first or second 24 h after surgery. Only two patients in each group received rescue antiemetics in the hospital, although almost 40 patients in each group reported retching or vomiting at home without medication.
The PAED scores in PACU in the ramosetron group were lower than in the ramosetron and midazolam group (Table 4).
In this study of children after strabismus surgery, the antiemetic effect of ramosetron alone was similar to that of a ramosetron and midazolam combination. The only advantage of the combination was a small reduction in emergence agitation in the PACU after anaesthesia. Of note, we used sevoflurane, which is commonly associated with emergence agitation in children.8,10,11
Strabismus surgery is now mostly performed in day surgery units and it is important to prevent PONV. The incidence after strabismus surgery varies from 37 to 80% without prophylactic antiemetic treatment.12,13 In our institution, the incidence of PONV without antiemetic prophylaxis was about 60%, and we use a serotonin receptor antagonist as prophylaxis.
Ramosetron is a carbazalone derivative that is structurally related to serotonin and possesses specific serotonin receptor antagonist properties, without altering dopamine, histamine, adrenergic or cholinergic receptor activity. It is effective when administered orally and intravenously and has an oral bioavailability of about 50% with therapeutic blood concentrations appearing 30–60 min after administration. Metabolism to inactive metabolites occurs predominantly in the liver and the elimination half-time is 4–5 h.11
Although combination therapy for the prevention of PONV is controversial,14–17 we wished to prevent PONV completely in the PACU and day care unit. We chose midazolam instead of droperidol or dexamethasone because droperidol is not available in our unit and we expected a reduction in emergence agitation with midazolam. Midazolam is commonly used as a premedicant in children. It has been used effectively for prevention of PONV in adults after middle ear surgery and in children after strabismus surgery or tonsillectomy.18,19 However, its mechanism of antiemetic action is unknown. Postulated mechanisms include glycinemimetic inhibitory effects, enhancing the inhibitory effects of γ-amino butyric acid, enhancing adenosinergic effects and inhibition of dopamine release.20,21 It has been hypothesised that midazolam's antiemetic effect is due to an exaggerated adenosine-mediated inhibition of dopamine in the chemoreceptor trigger zone, although the required dose is not known. Splinter et al.19 recommended a dose of 50–75 μg kg−1 for prophylactic antiemetic effect. The dose we used in our study (0.1 mg kg−1) should have been enough to demonstrate an antiemetic effect. The lack of additive effect with ramosetron may be due to the ramosetron effect being fully expressed even though the mechanism of these two drugs is different. A reduction in incidence of PONV might be achieved by use of propofol rather than sevoflurane,22 or alternatively by combination with other antiemetics such as a neurokinin-1 receptor antagonist.15
In the PACU, the PAED delirium score in the combination group was lower than that in the patients receiving ramosetron alone, but the difference was not clinically relevant. A previous study has reported that a combination of midazolam and fentanyl was associated with a lower incidence of emergence agitation than sevoflurane and fentanyl, with a similar incidence of PONV in the two groups.23 This result is compatible with ours.
In this study, only two patients in each group received rescue antiemetics in hospital, although almost 40 children in each group had PONV. Most of the PONV events occurred at home after discharge and in the future we need to consider the use of antiemetics with a longer duration of action or to consider use of a prophylactic antiemetic after discharge.
There were some limitations to our study. First, most patients who had PONV after surgery did not receive antiemetics because these events occurred at home. Second, there was no control group in this study. As we already use antiemetics for strabismus surgery, there might be an ethical problem to include a control group who did not receive any antiemetics. Third, we used nitrous oxide. As nitrous oxide is a potent cause of PONV, this might be an additional factor in the high incidence of PONV in the study. Nevertheless, nitrous oxide was used in all patients and did not bias the results. Fourth, we did not evaluate postoperative pain and focused on the antiemetic effect of ramosetron and midazolam. If we had assessed postoperative pain and PONV together, we might have found a relationship between pain and PONV. Nevertheless, the use of postoperative analgesics was similar in the two groups. Finally, we evaluated the antiemetic effect of ramosetron or midazolam by recording the incidence of nausea or retching or vomiting. In other studies, retching and vomiting have been placed into different categories.2 We did not distinguish between retching and vomiting as these have the same mechanism of action. However, our decision not to distinguish between the two might cause our results to be different from other studies.
In conclusion, we found that combining midazolam with ramosetron had no advantages over ramosetron alone in reducing the incidence of PONV in children undergoing strabismus surgery.
No external funding or conflicts of interest declared.
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Keywords:© 2012 European Society of Anaesthesiology
midazolam; postoperative nausea and vomiting; ramosetron; strabismus surgery