Postoperative vomiting is a frequent complication in children after adenotonsillectomy, with an incidence ranging from 40% to 88%(1–3). Prophylactic administration of ondansetron, a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, decreases the incidence of this complication without significant side effects (1,4–7). The elimination half-life of ondansetron is relatively short (2.8 ± 0.6 h). This may be one reason that the antiemetic efficacy of this drug is limited to the predischarge period and does not extend into the 24-h postdischarge period (4,8). Dolasetron mesylate is a relatively new 5-HT3 receptor antagonist that is rapidly reduced to its active metabolite hydrodolasetron. The half-life of hydrodolasetron is 8 h (9,10). Theoretically, therefore, dolasetron may decrease the incidence of postoperative vomiting, both before discharge and during the 24 h postdischarge.
In a previous study at this institution, the administration of dexamethasone IV at anesthetic induction in children undergoing ambulatory adenotonsillectomy significantly reduced the incidence of vomiting during the 24 h postdischarge, but not before discharge, when compared with saline placebo (2). The incidence of vomiting during delayed recovery, however, was 24%, which is a clinically significant incidence with respect to postoperative morbidity.
The objective of this study was to compare the antiemetic efficacy of a single dose of ondansetron or dolasetron administered prophylactically at induction in dexamethasone pretreated patients. We hypothesized that dolasetron may have extended antiemetic activity and may, therefore, reduce vomiting both before and after home discharge. Specifically, therefore, this study attempted to compare the complete response rate, defined as no retching/vomiting and no antiemetics for 48 h, in the two drug treatment groups as compared with a placebo (saline plus dexamethasone) group.
After IRB approval, 150 children, 2–12 yr old, ASA physical status I or II, who were scheduled for ambulatory tonsillectomy and adenotonsillectomy in a free-standing surgery center, were enrolled in the study. Written, informed parental consent was obtained in all cases. The study design was randomized, double-blinded, and placebo controlled. Children who received antiemetics, antihistaminics, or psychoactive drugs within 24 h before surgery were excluded. Also excluded were children who had a history of diabetes and those who required an IV induction, i.e., those with gastroesophageal reflux, obese children (>150% of ideal body weight), and children with a known history of allergy to any of the drugs used in the study.
All the children enrolled in the study received standard premedication and anesthetic. Solid foods were permitted until midnight before the day of surgery, and clear liquids were permitted until 3 h before the start of the expected surgery. All children received oral premedication consisting of midazolam 0.5–0.6 mg/kg (maximum 20 mg), 20–30 min before the anticipated induction. After standard ASA monitors were placed, general anesthesia was induced with sevoflurane in 100% oxygen by face mask with spontaneous ventilation. After induction, IV access was established. The amount of IV fluid administered was standardized to 25–30 mL/kg of lactated Ringer’s solution during surgery, followed by a maintenance-rate infusion until discharge. Endotracheal intubation was facilitated with mivacurium 0.2 mg/kg. Anesthesia was maintained with 60% nitrous oxide and sevoflurane adjusted to maintain heart rate and blood pressure values within 20% of the baseline induction value. Each patient received an acetaminophen 30 mg/kg suppository per rectum, fentanyl 1 μg/kg IV, and dexamethasone 1 mg/kg (maximum 25 mg) IV before the start of surgery.
Children were randomized into three study medication groups: Group 1, ondansetron 0.15 mg/kg, maximum 4 mg; Group 2, dolasetron 0.5 mg/kg, maximum 25 mg; and Group 3, normal saline placebo. In each patient, the study medication was administered immediately after endotracheal intubation. In each case, the study medication was diluted in normal saline so that each patient received exactly the same volume of study medication (5 mL).
All tonsillectomies were performed with an electrodissection technique under the supervision of two attending surgeons (AJH and AP). At the conclusion of surgery, gastric contents were suctioned via an orogastric tube. Muscle-relaxant antagonists were not used. Children were tracheally extubated when they had demonstrated satisfactory motor recovery and wakefulness. The children were observed in the recovery unit for at least 180 min after surgery. Children were considered ready for home discharge when they met institutional criteria, i.e., awake, alert, comfortable, able to swallow without difficulty, stable vital signs, and no retching or vomiting. Parents or caretakers participated in the child’s care for the entire recovery period.
A research nurse who was blinded to the treatment group recorded study variables. Because nausea is difficult to assess in children, only retching and vomiting episodes were documented. Episodes of retching or vomiting occurring <5 min apart were considered one single episode. A rescue antiemetic consisting of IV ondansetron 0.15 mg/kg (maximum dose, 4 mg) was administered if children experienced two episodes of retching or vomiting. If retching or vomiting persisted for 20 min after the administration of ondansetron, a second rescue antiemetic consisting of IV droperidol 0.015 mg/kg (minimum, 0.625 mg; maximum, 1.25 mg) was administered.
The need for postoperative pain medication was assessed by the postanesthesia care unit (PACU) nurse after the children were awake and reunited with their parents or caretaker. IV fentanyl in increments of 0.5 μg/kg was administered for pain (child restless, crying, or unresponsive to tender loving care) during early recovery until the child was comfortable. Once children demonstrated the ability to swallow, they were given acetaminophen with codeine elixir (0.75–1.0 mg/kg of codeine) to control pain. Children were offered liquids 45 min after arrival in the PACU. The quality of oral intake was judged as follows: excellent, child requests it; good, child accepts it when offered; fair, child accepts it when coaxed; and poor, child refuses.
All patients were discharged home with a prescription for acetaminophen with codeine and plain acetaminophen elixir, to be taken concurrently every 4 h while awake. Parents were instructed to follow the pain medication schedule. An evaluation diary/log book was provided to the parents, and they were instructed to record oral intake (graded in a manner similar to that of the PACU), number of episodes of retching and vomiting, compliance with oral pain medications, and state of hydration (frequency of voiding). Parents were instructed to call the surgeon if the child experienced more than two episodes of vomiting or had poor oral intake because of nausea and retching and failure to void the morning after the surgery. A rescue antiemetic (trimethobenzamide hydrochloride suppository, 200 mg for children >15 kg and 100 mg for children <15 kg) was prescribed for the children whose parents called the surgeon for more than two episodes of retching and vomiting or if the child refused oral fluids because of nausea and retching. The research nurse contacted the parents via telephone at 24 and 48 h after discharge to document the postdischarge recovery data.
These variables were documented in each case: age, weight, duration of anesthesia and surgery, duration of PACU stay, analgesic requirements in the PACU, incidence of retching and vomiting, need for rescue antiemetics, quality of oral intake in the PACU, quality of oral intake after home discharge, frequency of phone calls to the surgeons, and hospital returns.
In a previous study at this institution, the complete response rate, i.e., no retching/vomiting and no antiemetics for 24 h after adenotonsillectomy in dexamethasone-pretreated children, was 52%. This incidence was taken into consideration when the patient sample size was selected for this study. An increase in the complete response rate by 50% in the drug treatment groups compared with a placebo group (saline plus dexamethasone) was considered to be clinically relevant. It was desired that this be detected with a P value of ≤0.05 at a power of 80%. This study, therefore, was targeted for a patient sample size of 150 (50 in each treatment group).
The data were analyzed with analysis of variance, with pairwise multiple comparisons, Student’s t-test, and the Pearson χ2 test as appropriate. The primary end-point considered in the study was a complete response, defined as no emesis and no antiemetics administered during the 48-h period after surgery. If a significant difference was found, a post hoc comparison was conducted by using Tukey’s significant differences test to determine the nature of the specific group differences, i.e., placebo versus ondansetron and dolasetron, and ondansetron versus dolasetron. A P value of <0.05 was considered to be statistically significant. The data are presented as mean ± sd.
Of the 150 children enrolled in the study, 1 child (in Group 2) was excluded because of protocol violation. Two patients, one each in Groups 1 and 3, were lost to follow-up after discharge. The predischarge recovery data, therefore, are representative of 149 cases, and postdischarge recovery data represent 147 cases (49 cases in each of the 3 groups).
There were no significant differences among the three groups with respect to age, weight, sex distribution, ASA physical status, or the duration of anesthesia and surgery (Table 1). The distribution of patients in the three study groups was also comparable with respect to blood loss and the volume of IV crystalloids infused perioperatively.
Table 2 depicts the incidence of postoperative vomiting and the need for rescue antiemetics in the postoperative period, from the end of surgery to 48 h after discharge. The incidence of retching and/or vomiting before the discharge (PACU stay) did not differ significantly between Groups 1 and 2, and this incidence was less than that of Group 3 (saline placebo). The need for rescue antiemetics was also significantly larger in Group 3 compared with Groups 1 and 2. During the first 24-h period after discharge, the incidence of retching/vomiting was also significantly more frequent in Group 3 as compared with Group 1. The incidence of retching and/or vomiting in Group 1, however, was not significantly different from that in Group 2. None of the children in any of the three groups required rescue antiemetics during the 24 h after discharge. During the 24–48 h after discharge, the incidence of vomiting was not significantly different between Groups 1 and 2, and this incidence was significantly less than that of Group 3. One patient in the dolasetron group (Group 2) and one in the placebo group (Group 3) required rescue antiemetic trimethobenzamide during the 24- to 48-h postoperative period.
The incidence of complete response, defined as no retching/vomiting and no antiemetics for 48 h, was significantly less in Group 3 compared with Groups 1 and 2. There was no significant difference between Groups 1 and 2 with respect to the incidence of complete response. The overall use of antiemetics over the 48-h postoperative period was also significantly larger in Group 3 compared with Groups 1 and 2 (Table 2).
Table 3 depicts the recovery characteristics of patients in each group. The three groups were comparable with respect to analgesic interventions (fentanyl and codeine), time to first oral intake, and time to home discharge from PACU. The quality of oral intake was also comparable in the three groups for the entire 48-h period after surgery. The number of emergency room visits and hospital admissions for vomiting and poor oral intake was very small (a total of four admissions: one each for Groups 1 and 3 and two for Group 2).
To minimize postoperative vomiting and related morbidity, anesthesiologists may elect to administer anesthetic drugs with minimal emetic potential or administer various antiemetic drugs. Ondansetron, a 5-HT3 receptor antagonist, is a better prophylactic antiemetic than droperidol and metoclopramide in children undergoing tonsillectomy (4,11). Published studies, however, suggest that the antiemetic efficacy of ondansetron does not extend beyond home discharge (4,8). We hypothesized that dolasetron, because of the longer elimination half-life of its active metabolite, may have antiemetic efficacy that extends beyond discharge (9,10).
Data from this study indicate that in dexamethasone-pretreated children, the additional administration of a single dose of ondansetron or dolasetron significantly reduces the incidence of postoperative vomiting compared with placebo before, as well as during, the 48 hours after discharge. The proposed hypothesis was not found to be true because dolasetron, in this study, did not offer any advantage over ondansetron with respect to the incidence of postoperative vomiting, the need for therapeutic intervention for postoperative vomiting, or the postoperative recovery profiles for 48 hours after surgery. The complete response rate in the two drug treatment groups was comparable and was significantly larger than in the placebo group.
The dose of ondansetron used in this study was similar to that used in several of the previously published studies (1,4,12). The dose of dolasetron was extrapolated from several drug dose-response studies in adults (12–14). Dolasetron doses ranging from 12.5 to 100 mg were used in these studies, without significant side effects. The dose of dolasetron recommended by the manufacturer in the package insert is 0.35 mg/kg in adults. Dose recommendations are not available from the manufacturer for the pediatric patients. We elected to use 0.5 mg/kg in our pediatric population for two reasons: (a) the volume of distribution for water-soluble drugs is larger in pediatric patients, and (b) larger doses (up to 50 mg) of dolasetron are more effective for the prevention of vomiting in adults compared with smaller doses consisting of 25 mg (12).
In previous studies with adult patients, the complete response rate (no emetic episodes and no rescue medications for 24 hours) for dolasetron ranged from 28% to 71%(12–14). This wide variability in the incidence of complete response may be related to nonuniform surgical populations with respect to the risk for postoperative nausea and vomiting. In this study, the complete response rate for dolasetron in the first 24 hours after surgery was 74%. This rate was comparable to the complete response rate observed for patients who received ondansetron. The complete response rate for children who received saline placebo and dexamethasone was significantly less (44%).
All children in this study received dexamethasone 1 mg/kg at the time of anesthetic induction. In a previous study at this institution, a 1 mg/kg dose of IV dexamethasone administered at the induction of anesthesia significantly decreased retching/vomiting during the first 24-hour period after discharge in children undergoing ambulatory adenotonsillectomy (dexamethasone 24% versus placebo 63%) (2). The beneficial effect of dexamethasone on the frequency of vomiting was not evident during early recovery (PACU stay), and the complete response rate during the entire 24-hour recovery period was 52%. This study specifically sought to examine whether the addition of dolasetron or ondansetron improves the complete response rate in dexamethasone-pretreated children and whether dolasetron, with its longer-acting active metabolite, is superior to ondansetron in this regard. In this study, ondansetron and dolasetron were comparable with respect to their immediate (predischarge) and long-term (48 hour postdischarge) antiemetic efficacy and recovery profiles.
One may speculate that dexamethasone’s salutary effect on delayed (postdischarge) recovery could confound the recovery data with respect to the incidence of vomiting and quality of recovery, thereby making delineation of the difference between the two drug groups (ondansetron versus dolasetron) difficult. For ethical reasons, dexamethasone was administered to all children because that became standard clinical practice at this institution after the completion of the previous study, which demonstrated beneficial effects of dexamethasone on postdischarge recovery (2). Interestingly, the complete response rate with dexamethasone alone in our previous study, as well as in this study, was comparable (52% vs 44%) (2). The addition of a single dose of ondansetron or dolasetron to dexamethasone for antiemetic prophylaxis significantly increased the complete response rate over a 48-hour recovery period.
McKenzie et al. (5) compared the effectiveness of ondansetron plus placebo (saline) and ondansetron plus dexamethasone for the prevention of postoperative nausea and vomiting in women undergoing major gynecologic surgery. A complete response (no emesis and no rescue antiemetics in the first 24 hours) occurred in 38% of patients in the ondansetron-placebo group and in 52% of patients in the ondansetron-dexamethasone group. The authors concluded that ondansetron with dexamethasone was a more effective regimen for the prevention of nausea and vomiting during the 24-hour recovery period. The data from our study support their conclusion, in that the administration of a single dose of ondansetron or dolasetron in combination with dexamethasone resulted in a very small incidence of postoperative vomiting in the immediate (PACU), as well as the delayed (48-hour), recovery period (Table 2). A complete response rate (no emesis and no antiemetic intervention for 48 hours) of 76% in the ondansetron-dexamethasone group and 74% in the dolasetron-dexamethasone group is a significant improvement over the 40%–88% incidence of postoperative vomiting reported in children undergoing ambulatory tonsillectomy (1–3).
In summary, data from this study suggest that, compared with placebo (saline/dexamethasone), prophylactic antiemetic therapy consisting of a single dose of ondansetron (0.15 mg/kg; maximum, 4 mg) or dolasetron (0.5 mg/kg; maximum, 25 mg), administered in combination with dexamethasone at the induction of anesthesia, significantly reduces the incidence of postoperative retching/vomiting and the need for rescue antiemetics in children undergoing ambulatory adenotonsillectomy. When used in combination with dexamethasone, the beneficial effects of the two drugs on postoperative emesis and recovery profiles were comparable over a 48-hour postoperative observation period. Clinically significant side effects were not observed with the use of either ondansetron or dolasetron.
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