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A Randomized Clinical Trial of a Single Dose of Ramosetron for the Prevention of Vomiting After Strabismus Surgery in Children
A Dose-Ranging Study
Yoshitaka Fujii, MD;
Hiroyoshi Tanaka, MD;
Mutsuko Ito, MD
Arch Ophthalmol. 2005;123:25-28.
ABSTRACT
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Background Postoperative vomiting (POV) after pediatric strabismus surgery remains a major problem.
Objective To evaluate the efficacy and safety of a single dose of ramosetron, a new serotonin antagonist, for preventing POV in children undergoing strabismus surgery.
Method In a prospective, randomized, double-masked, placebo-controlled study, 80 children (38 boys and 42 girls), aged 4 to 10 years, scheduled for strabismus surgery, received intravenously either placebo or ramosetron at 1 of 3 different doses (3 µg/kg, 6 µg/kg, or 12 µg/kg) (n = 20 each) at the end of the surgical procedure. A standard general anesthetic technique was used.
Main Outcome Measures Emetic episodes were recorded and safety assessments performed during the first and second 24-hour periods (ie, 0-24 and 24-48 hours) after receiving anesthesia.
Results The rate of patients who were emesis-free (defined as no retching and no vomiting), during the 0- to 24-hour period after anesthesia was 35% with 3 µg/kg of ramosetron (P = .37), 90% with 6 µg/kg of ramosetron (P = .001), and 90% with 12 µg/kg of ramosetron (P = .001) compared with placebo (25%). The corresponding rate during the 24- to 48-hour period after anesthesia was 40% (P = .371), 90% (P = .001), and 90% (P = .001), respectively, compared with placebo (30%). No clinically important adverse events were observed in any group.
Conclusions A 6-µg/kg dose of ramosetron is sufficient, but a 3-µg/kg dose is insufficient for preventing POV during the 0- to 48-hour period after anesthesia in children undergoing strabismus surgery. Increasing the dose to 12 µg/kg of ramosetron provides no demonstrable additional benefit.
INTRODUCTION
Postoperative vomiting (POV) is an important adverse effect of general anesthesia and surgery in children and adults.1 Pediatric patients undergoing strabismus surgery may be especially at risk of experiencing POV.2-3 Sometimes POV may result in a prolonged recovery room stay, fluid and electrolyte imbalance, and an unanticipated hospital admission.1 A variety of pharmacological approaches (antihistamines, butyrophenones, dopamine receptor antagonists) have been investigated for preventing POV but occasionally cause undesirable adverse effects, such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extrapyramidal signs.1 Granisetron, a serotonin receptor antagonist, reduces the incidence of POV in children undergoing strabismus surgery.4 Ramosetron, (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazol hydrochloride (Nasea; Yamanouchi Pharmaceutical Co Ltd, Tokyo, Japan), a new antagonist of serotonin receptors, is effective for the treatment of nausea and vomiting induced by anticancer drugs.5 Ramosetron is more potent and longer acting than granisetron for the control of cisplatin-induced emesis.6 Recently, we have shown that ramosetron, like granisetron, is effective for preventing POV after strabismus surgery in children.7 However, to our knowledge there have been no dose-response data available that establish the best dose as an antiemetic in this population. We conducted a prospective, randomized, double-masked, placebo-controlled trial to evaluate the sufficient dose of ramosetron for preventing POV in children undergoing strabismus surgery.
METHODS
PATIENTS
After approval by our institutional ethics committee and receiving informed consents from parents, we studied 80 children (38 boys and 42 girls), who were classified as having American Society of Anesthesiologists physical status I (no organic, physiologic biochemical, or psychiatric disturbance),8 aged 4 to 10 years who were scheduled for strabismus surgery (ie, operative procedure for eye muscles advancement [resection] and/or recession). Patients who had a history of motion sickness, previous POV, gastrointestinal tract disorders, or administration of antiemetics within 24 hours before surgery were excluded from participation, because of patient-related factors contributing to POV.1
Patients were randomly allocated to 1 of 4 groups (n = 20 each) to receive intravenously (IV) either placebo (an isotonic sodium chloride solution) or ramosetron at 3 different doses (3 µg/kg, 6 µg/kg, or 12 µg/kg) at the end of the surgical procedure. A randomization list was generated, and identical syringes containing each drug were prepared by personnel not involved in the study, according to the list.
Patients were not allowed to have solid food after midnight before surgery. Clear liquids were permitted up to 3 hours before surgery. No patient was given preanesthetic medication. Anesthesia was induced via mask by administering increasing concentrations of sevoflurane in 66% nitrous oxide (N2O) and oxygen (O2). After an inhalation induction of anesthesia, 0.01 mg/kg of atropine was administered IV, and then tracheal intubation was facilitated with 0.1 mg/kg of vecuronium IV. After tracheal intubation, anesthesia was maintained with N2O/O2 (2:1) and 1.0% to 3.0% (inspired concentration) sevoflurane. Ventilation was mechanically controlled and adjusted to keep an end-tidal concentration of carbon dioxide at 35 to 40 mm Hg with an anesthetic-respiratory gas analyzer (Ultima; Datex-Ohmeda Division, Instrumentarium Corp, Helsinki, Finland). Muscle relaxation was achieved with vecuronium and reversed by a combination of IV 0.02 mg/kg of atropine and 0.04 mg/kg of neostigmine at the end of surgery. The trachea was extubated when the patient was awake. Rectal temperature was monitored at 36.5°C; to 37.0°C; using a warming pad throughout surgery. Postoperatively, all patients were admitted to the hospital and remained for a couple of days. Clear liquids were offered only if requested by the patient, and other oral intake was not allowed for 4 hours after recovery from anesthesia. Postoperative analgesia was provided with acetaminophen, 15 to 20 mg/kg, rectally for mild pain and by 0.3 mg/kg of pentazocine IV for severe pain.
All episodes of emetic symptoms (retching, vomiting) during the first 24-hour period and the second 24-hour period after anesthesia were recorded by nursing staff who did not know which treatment the patients had received. Retching was defined as the labored, spasmodic, rhythmic contractions of respiratory muscles without the expulsion of gastric contents, and vomiting was defined as the forceful expulsion of gastric contents from the mouth.1 Because of the young age of the patients, nausea was not assessed as a separate entity in this study. If 2 or more episodes of emetic symptoms were recorded within a 48-hour postanesthetic period, another rescue antiemetic (domperidone) was given. The details of any other adverse events were also recorded by questioning the children, interviewing the parents of patients, or observation by the nursing staff.
STATISTICAL ANALYSIS
Patient demographics were analyzed by analysis of variance with Bonferroni adjustment for multiple comparison and  2 test. The rate of patients who were emesis free (defined as no retching or vomiting), those who experienced retching or vomiting, and the incidence of adverse events were compared using the Fisher exact probability test. P<.05 was considered statistically significant. Values were mean (SD) or number (percentage). Power analysis was used to determine the number of patients in this study based on the assumptions that: (1) the rate of an emesis-free episode in patients who had received placebo would be 30%; (2) an improvement from 30% to 90% was considered of clinical importance; and (3)  = .05 with a power (1 –  ) = .80. Based on these assumptions, 20 patients per group would be sufficient.
RESULTS
Patient demographics, types of surgery, and anesthetic and/or postoperative management were comparable among the treatment groups (Table 1). The rate of patients who were emesis free (no retching, no vomiting) during the first 24-hour period (0-24 hours) after anesthesia was 25% with placebo, 35% with 3 µg/kg of ramosetron (P = .37), 90% with 6 µg/kg of ramosetron (P = .001), and 90% with 12 µg/kg of ramosetron (P = .001), respectively. The corresponding rate during the second 24-hour period (24-48 hours) after anesthesia was 30%, 40% (P = .37), 90% (P = .001), and 95% (P = .001) (P values vs placebo), respectively. Within a 48-hour postanesthetic period, 5 or 6 patients who had received placebo or 3 µg/kg of ramosetron required another rescue antiemetic whereas none who had received 6 µg/kg or 12 µg/kg of ramosetron required rescue (P<.05) (Table 2). Clinically serious adverse events that include excessive sedation and extrapyramidal signs caused by traditional antiemetics (eg, droperidol) were not observed in any group.
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Table 1. Patient Characteristics*
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Table 2. Emetic Symptoms and Rescue*
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COMMENT
The postoperative course in children undergoing strabismus surgery is often complicated by vomiting.2-3 The reported incidence was as high as 85% in pediatric patients scheduled for strabismus surgery when no antiemetic treatment is given.2-3 The cause of high incidence of POV following strabismus surgery is unknown but probably is multifactorial.1 Several recognized contributing factors include age, sex, obesity, a history of motion sickness and/or previous POV, operative procedure, anesthetic technique, and postoperative pain.1 In this study, however, the treatment groups were similar for patient demographics, surgical procedure, anesthetic administered, and analgesics used postoperatively. Also, patients with a history of motion sickness and/or previous POV were excluded from the study because they had a remarkably high risk of POV.1 Therefore, by eliminating those factors that may affect POV, the difference in the rate of patients experiencing emesis-free recovery among the groups can be attributed to the study drug.
Ramosetron is effective for the treatment of nausea and vomiting induced by cancer chemotherapy.5-6 Recently, we have shown that prophylactic therapy with ramosetron is effective for preventing POV that lasts up to 48 hours after anesthesia in children undergoing strabismus surgery.7 The exact mechanism of ramosetron remains unclear, but it is possible that ramosetron may act on sites containing serotonin receptors with demonstrated antiemetic effects.8
We could find no reports to determine the sufficient dose of ramosetron that provides prophylaxis against POV in pediatric patients scheduled for strabismus surgery. In the present study, 6 µg/kg of ramosetron was as effective as 12 µg/kg for preventing POV, and both resulted in increasing the rate of patients experiencing emesis-free recovery compared with placebo (P<.05). Also, there were no differences in an emesis-free episode between patients who had received placebo and those who had received 3 µg/kg of ramosetron. This suggests that 6 µg/kg of ramosetron is a sufficient dose, but 3 µg/kg is an insufficient dose, for preventing POV after pediatric strabismus surgery.
In this study, within a 48-hour postanesthetic period, 5 or 6 patients who had received either placebo or 3 µg/kg of ramosetron required another rescue drug (domperidone) for the treatment of severe POV (ie,  2 episodes of POV), whereas none who had received 6 µg/kg or 12 µg/kg of ramosetron required rescue (P<.05). Thus, administration of ramosetron at doses equal to or more than 6 µg/kg attenuates the severity of POV in children undergoing strabismus surgery.
Ramosetron lacks the sedative, dysphoric, and extrapyramidal symptoms associated with traditional antiemetics (eg, droperidol).9 In the present study, we found no clinically important adverse events that include excessive sedation and extrapyramidal signs in any group. Therefore, the safety profiles of ramosetron at 3 different doses (3 µg/kg, 6 µg/kg, and 12 µg/kg) and placebo used in this study were comparable.
Our hospital pharmacy pays US $100 for 0.3 mg of ramosetron and US $103 for 3 mg of granisetron. These serotonin receptor antagonists are much more expensive than traditional antiemetics, US $1.80 for 1.25 mg of droperidol and US $0.60 for 10 mg of metoclopramide [costs given being in 2003 US dollars]. This higher cost may delay the widespread use of ramosetron as an antiemetic. However, the use of traditional antiemetics has been limited because of their undesirable adverse effects, such as excessive sedation and extrapyramidal symptoms.1 Recently, the US Food and Drug Administration issued an adverse effect warning about droperidol because of its dysrhythmogenic effects, such as prolonged QT syndrome.10 Thus, a decision regarding antiemetics should not be limited to the costs but should also consider the outcomes of the patients. Furthermore, on the basis of these results, the use of ramosetron at the lower dose (6 µg/kg) would decrease the cost of antiemetic therapy.
CONCLUSIONS
A 6-µg/kg dose of ramosetron is sufficient, but 3 µg/kg is insufficient, for preventing POV during the first 48-hour period (0-48 hours) after anesthesia in children undergoing strabismus surgery. Increasing the dose to 12 µg/kg provides no demonstrable additional benefit.
AUTHOR INFORMATION
Correspondence: Yoshitaka Fujii, MD, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki 305-8576, Japan (yfujii{at}md.tsukuba.ac.jp).
Submitted for Publication: August 25, 2003; final revision received May 6, 2004; accepted May 27, 2004.
Financial Disclosure: None.
Author Affiliations: Departments of Anesthesiology (Drs Fujii and Tanaka) and Ophthalmology (Dr Ito), Toride Kyodo General Hospital, Toride City, Ibaraki, Japan.
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