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© 1999 International Anesthesia Research Society
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Abstract |
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In a prospective, randomized, double-blinded trial, we evaluated the efficacy of two antiemetics given orally, granisetron and perphenazine, for preventing postoperative vomiting after tonsillectomy with or without adenoidectomy in children. One hundred pediatric patients, ASA physical status I, aged 4–10 yr, received either granisetron 40 µg/kg or perphenazine 70 µg/kg (n = 50 each) orally 1 h before surgery. We used a standard general anesthetic technique. The rate of complete response, defined as no emesis and no need for rescue antiemetic medication, during 0–3 h after anesthesia was 86% with granisetron and 60% with perphenazine; the corresponding rate 3–24 h after anesthesia was 86% and 62%, respectively (P < 0.05). No serious adverse events were observed in any of the groups. In conclusion, preoperative oral granisetron is more effective than perphenazine for preventing postoperative vomiting in children undergoing tonsillectomy with or without adenoidectomy.
Implications: We compared the efficacy of granisetron and perphenazine given orally for preventing postoperative vomiting after tonsillectomy with or without adenoidectomy in children. Preoperative oral granisetron was more effective than perphenazine.
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Introduction |
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Children undergoing tonsillectomy are considered to be at a relatively high risk for developing postoperative vomiting (1). Most of the currently used antiemetics (antihistamines, butyrophenones, dopamine receptor antagonists) have been reported to cause undesirable adverse effects, such as excessive sedation, hypotension, dry mouth, dysphoria, restlessness, and extrapyramidal symptoms (2). Ondansetron, a recently introduced selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, is effective for preventing postoperative vomiting after tonsillectomy in children (3,4). Granisetron, another new 5-HT3 receptor antagonist, has more potent and longer acting properties against cisplatin-induced emesis than ondansetron (5), and it reduces the incidence of postoperative vomiting in pediatric patients undergoing tonsillectomy (6,7). However, this 5-HT3 receptor antagonist is more expensive than other antiemetics that prevent postoperative emesis, such as droperidol and metoclopramide. An oral granisetron preparation that is less expensive and is effective in reducing emesis induced by cancer chemotherapy is now available (8). We recently demonstrated that granisetron given orally prevents postoperative vomiting in children (9). However, there have been no studies to compare its efficacy with the commonly used and well established oral antiemetic perphenazine for preventing postoperative emesis in pediatric patients. We designed this prospective, randomized, double-blinded trial to assess the efficacy of granisetron and perphenazine in the prevention of postoperative vomiting in children undergoing tonsillectomy with or without adenoidectomy.
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Methods |
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After approval by our institutional ethics committee and informed parental consent, we studied 100 ASA physical status I children, aged 4–10 yr, undergoing general anesthesia for tonsillectomy with or without adenoidectomy. Patients who had experienced postoperative vomiting after a previous anesthetic, those who had taken an antiemetic medication within 24 h before surgery, and those who had a history of motion sickness were excluded from the study.
Patients were randomly assigned to receive orally either granisetron 40 µg/kg or perphenazine 70 µg/kg (n = 50 each) 1 h before surgery. A randomization list was generated, and syrups with either granisetron or perphenazine were prepared by personnel not involved in the study, according to the list. The doses of graniserton or perphenazine chosen in this study were referred to in previous studies by us (7) and Naganuma (10).
Patients were not allowed to have solid food after midnight before surgery. Clear liquids were permitted up to 3 h before surgery. No preanesthetic medications were administered. Anesthesia was induced by increasing concentration of sevoflurane in 66% nitrous oxide (N2O) and oxygen (O2) via a mask. After an inhaled induction of anesthesia, atropine 0.01 mg/kg IV was administered, followed by fentanyl 1 µg/kg IV, and tracheal intubation was facilitated with vecuronium 0.1 mg/kg IV. After tracheal intubation, anesthesia was maintained with N2O/O2 (2:1) and sevoflurane 0.5%–3.0% (inspired concentration). Ventilation was controlled mechanically and was adjusted to maintain PETCO2 35–40 mmHg as measured by using an anesthetic/respiratory gas analyzer (UltimaTM; Datex, Helsinki, Finland). Muscle relaxation was achieved with vecuronium, and residual neuromuscular blockade was antagonized by a combination of atropine 0.02 mg/kg IV and neostigmine 0.04 mg/kg IV at the end of surgery. The trachea was extubated when the patient was awake. Rectal temperature was monitored and maintained at 37 ± 1°C throughout surgery. Postoperatively, all patients were admitted to the hospital and remained there for 2 days (i.e., 0–3 h in the postanesthesia care unit, 3–24 h in the postoperative ward, and 24–48 h in the general ward). Clear liquids were offered only if the patient requested them, and other oral intake was not allowed for 4 h after recovery from anesthesia. Postoperative analgesia was provided by acetaminophen 10–25 mg/kg rectally for mild pain and pentazocine 0.3 mg/kg IV for severe pain.
Postoperatively, all episodes of retching and vomiting during the first 24 h after anesthesia (i.e., 0–3 h in the postanesthesia care unit and 3–24 h in the ward) were recorded by nursing staff who did not know which treatment each patient had received. Vomiting was defined as the forceful expulsion of gastric contents from the mouth; retching was defined as the labored, spasmic, rhythmic contraction of the respiratory muscles, including the diaphragm, chest wall, and abdominal wall muscles, without the expulsion of gastric contents (2). Nausea was not assessed as a separate entity in this study because of the young age of the patients. A complete response—defined as no vomiting, no retching, and no need for rescue antiemetic medication—was recorded during the first 24 h after anesthesia. If two or more episodes of vomiting occurred during the first 24 h after anesthesia, another rescue antiemetic (e.g., domperidone rectally) was given. At the end of every observation period, the nurses asked the parents about their children's postanesthetic condition and problems (i.e., adverse events due to the study drugs). A trained research nurse evaluated sedation of the patients. The evaluations were performed with a linear numerical scale ranging from 0 (no sedation) to 10 (extreme sedation).
Statistical analyses of data between the groups were performed by using analysis of variance with Bonferroni's correction for multiple comparison, 
2 test, two-tailed Fisher's exact probability test, or the Mann-Whitney U-test, where appropriate. The number needed to treat (NTT), a useful estimate of clinical relevance of treatment effect, was also calculated (11). A P value of <0.05 was considered significant. All values are expressed as mean ± SD, n (%), or median (range). The primary end point of the study was a complete response to antiemetic therapy, defined as no emetic symptoms or no need for another rescue medication. Power analysis was used to determine the number of patients in the study based on the assumptions that (a) the incidence of emesis in patients receiving oral perphenazine would be 40% based on data from the use of IV perphenazine (12); (b) an improvement from 60% to 85% was considered of clinical importance; and (c) 
= 0.05 and a power (1-ß) = 0.8. Based on these assumption, 50 patients per group were required.
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Results |
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There were no differences in patient demographics between the treatment groups (Table 1). A complete response (no emesis, no rescue) 0–3 h after anesthesia was 86% with granisetron and 60% with perphenazine; the corresponding incidence 3–24 h after anesthesia was 86% and 62%, respectively. Thus, the number of patients having a complete response within the first 24-h period after anesthesia in patients who had received granisetron was greater than in those who had received perphenazine (P < 0.05). The research nurse found no differences in sedation between the two groups (Table 2). The NTT estimated 3.8 and 4.0 at 0–3 h and 3–24 h after anesthesia, respectively, to prevent postoperative emesis with granisetron compared with perphenazine. Thus, granisetron showed a more favorable effect on a complete response than perphenazine within the 24-h postoperative period.
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The most frequently reported adverse event was headache. There was no difference in the incidence of this symptom between the two groups (0–3 h: granisetron 6% versus perphenazine 6%; 3–24 h: granisetron 4% versus perphenazine 4%).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Postoperative vomiting is among the most common complications after anesthesia and surgery, with a relatively high incidence after tonsillectomy with or without adenoidectomy in children (1). The etiology of postoperative vomiting after pediatric tonsillectomy performed under general anesthesia is not known, but it is probably multifactorial (2). Age, obesity, history of motion sickness and/or previous postoperative emesis, surgical procedure, anesthetic technique, and postoperative pain are considered to affect the incidence of postoperative vomiting. In this study, however, there were no differences between the groups with regard to patient demographics, types of operation, anesthetics administered, and analgesics used postoperatively. Patients with a history of motion sickness and/or postoperative emesis were excluded from the study because they had a relatively high incidence of postoperative vomiting (2). Therefore, the difference in a complete response (no emesis, no rescue) can be attributed to the difference in the study drug.
Granisetron is effective for the treatment of vomiting in patients receiving cytotoxic drugs (13), and we recently demonstrated that it reduces the incidence of vomiting after tonsillectomy, with or without adenoidectomy, in children (6,7). The precise mechanism of granisetron for preventing postoperative vomiting is not known, but it may act on sites containing 5-HT3 receptors (14).
The fact that granisetron is much more expensive than other antiemetics for IV injection may delay its widespread use as an antiemetic medication. With oral administration, this difference in cost may be reduced (8). Our hospital pharmacy pays $12.60 for PO granisetron 1 mg, compared with $33.40 for IV granisetron 1 mg. We recently evaluated the efficacy of granisetron given orally for preventing postoperative vomiting after pediatric tonsillectomy with or without adenoidectomy and demonstrated that preoperative oral granisetron in a minimal dose of 40 µg/kg provides effective antiemetic prophylaxis (9). Therefore, the same dose (i.e., 40 µg/kg) of granisetron was chosen in this study.
Perphenazine is a phenothiazine with potent antiemetic effects. Its antiemetic action has been attributed to its ability to block receptors in the chemoreceptor trigger zone, specifically the dopaminergic receptors (2). Perphenazine 70 µg/kg IV reportedly reduces the incidence of postoperative vomiting in children undergoing tonsillectomy, with an antiemetic efficacy similar to that of ondansetron (12). The dose of oral perphenazine to be used in children is not well established but has been extrapolated from the dosage used in adult investigations. Pherphenazine 70 µg/kg given orally in this study is comparable to the recommended adult dosage of 2–8 mg (10). Further studies regarding dose-response curve available for the antiemetic effect of oral perphenazine are needed.
We could not find any report comparing the efficacy of the two oral antiemetics, granisetron and perphenazine, for preventing postoperative vomiting in children undergoing tonsillectomy with or without adenoidectomy. Our results demonstrated that a complete response (no emesis, no rescue) within the first 24-h period after anesthesia in patients who had received granisetron was greater than that in those who had received perphenazine as an oral antiemetic regimen (P < 0.05). This suggests that prophylactic oral antiemetic therapy with granisetron is more effective than perphenazine for preventing postoperative vomiting after tonsillectomy with or without adenoidectomy in children. However, this suggestion may be limited because there have been no reports that the doses of the two antiemetics, granisetron and perphenazine, given orally are equipotent.
Although the failure to include a control group receiving placebo may be considered a deficiency in our study design, we did not do so because we have already shown that granisetron given orally is a better antiemetic than placebo for preventing postoperative vomiting after pediatric tonsillectomy (9). Moreover, Aspinal and Goodman (15) have shown that there is a lack of reliable clinical information concerning placebo-controlled trials of another 5-HT3 receptor antagonist, ondansetron, for preventing postoperative nausea and vomiting.
The most commonly reported adverse event was headache, the incidence of which was not different between the treatment groups. Excessive sedation was also not observed in any of the groups. Thus, preoperative oral granisetron, as well as perphenazine, is considered to be relatively free of adverse effects for preventing postoperative vomiting in children.
The use of PO compared with IV granisetron reduces the price of antiemetic therapy. In Japan, however, oral granisetron ($12.60 for 1 mg) is still more expensive than oral perphenazine ($0.90 for 2 mg). Thus, using PO granisetron as an antiemetic may be criticized because of its high cost. In this study, a cost-effective analysis was not performed. However, oral granisetron was more effective than oral perphenazine in increasing a complete response. Therefore, the choice of antiemetics should be based on the calculation of costs, but also on the preference of patients.
In conclusion, the efficacy of preoperative oral granisetron 40 µg/kg is superior to oral perphenazine 70 µg/kg for preventing postoperative vomiting in children undergoing tonsillectomy with or without adenoidectomy.
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References |
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- Carithers JS, Gebhart DE, Williams JA. Postoperative risk of pediatric tonsilloadenoidectomy. Laryngoscope 1987;97:422–9.[Web of Science][Medline]
- Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology 1992;77:162–84.[Web of Science][Medline]
- Furst SR, Rodarte A. Prophylactic antiemetic treatment with ondansetron in children undergoing tonsillectomy. Anesthesiology 1994;81:799–803.[Web of Science][Medline]
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Litman RS, Wu CL, Catanzaro FA. Ondansetron decreases emesis after tonsillectomy in children. Analg 1994;78:478–81.
[Abstract/Free Full Text] - Andrews PLR, Bhandari P, Davet PT, et al. Are all 5-HT3 receptor antagonists the same? Eur J Cancer 1992;28:S2–6.
- Fujii Y, Tanaka H, Toyooka H. Granisetron reduces vomiting after strabismus surgery and tonsillectomy in children. Can J Anaesth 1996;43:35–8.[Web of Science][Medline]
- Fujii Y, Tanaka H, Toyooka H. Effective dose of granisetron for preventing postoperative emesis in children. Can J Anaesth 1996;43:660–4.[Web of Science][Medline]
- Maisano R, Adamo V, Settineri N, et al. Efficacy of two oral dose regimens of granisetron. Anticancer Res 1995;15:2287–90.[Web of Science][Medline]
- Fujii Y, Toyooka H, Tanaka H. Oral granisetron prevents postoperative vomiting in children. Anaesth 1998;81:390–2.
- Naganuma G. Perphenazine for the treatment of nausea, vomiting and vertigo. Remedies Ther 1962;64:14–6.
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Tramer M, Moore A, McQuay H. Prevention of vomiting after paediatric strabismus surgery: a systemic review using the numbers-needed-to-treat methods. Br J Anaesth 1995;75:556–61.
[Abstract/Free Full Text] -
Splinter WN, Phine EJ. Prophylaxis for vomiting by children after tonsillectomy: ondansetron compared with perphenazine. Br J Anaesth 1998;80:155–8.
[Abstract/Free Full Text] - Bermudez J, Boyle EA, Minter WD, Sanger GJ. The antiemetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694. Br J Cancer 1988;58:644–50.[Web of Science][Medline]
- Carmichael J, Cantwell BMJ, Edwards CM, et al. A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation of anti-emetic response. Cancer Chemother Pharmacol 1989;24:45–9.[Web of Science][Medline]
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Aspinal RL, Goodman NW. Denial of effective treatment and poor quality of clinical information in placebo controlled trilas of ondansetron for postoperative nausea and vomiting: a review of published trials. BMJ 1995;311:844–6.
[Abstract/Free Full Text]
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