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The Effect of Timing of Ondansetron Administration in Outpatients Undergoing Otolaryngologic Surgery

Sun, Rui MD, PhD; Klein, Kevin W. MD; White, Paul F. PhD, MD, FANCZA

Ambulatory Anesthesia
Free
SDC

A randomized, double-blind, placebo-controlled study was designed to compare the relative efficacy of prophylactic ondansetron, 4 mg intravenously (IV), when administered before induction of anesthesia or at the end of surgery to an outpatient population at high risk of developing postoperative nausea and vomiting (PONV). Patients undergoing otolaryngologic surgery were randomly assigned to one of three different treatment groups: Group I (placebo) received saline 5 mL prior to induction of anesthesia and again at the end of surgery; Group II received ondansetron 4 mg in 5 mL prior to induction of anesthesia and saline 5 mL at the end of surgery; and Group III received saline 5 mL prior to induction of anesthesia and ondansetron 4 mg at the end of surgery. All patients received the same general anesthetic technique. A standardized regimen of rescue antiemetics was administered in the recovery room to patients with >or=to2 emetic episodes or at the patient's request for persistent nausea. Episodes of nausea and vomiting, as well as the need for rescue antiemetics, were recorded for 24 h after the operation. The incidences of nausea and emesis in the recovery room after prophylactic ondansetron, 4 mg IV, administered either before induction (68% and 20%, respectively) or at the end of surgery (60% and 4%, respectively) were not significantly decreased compared to the placebo control group (80% and 12%, respectively). However, when ondansetron was administered at the end of the operation, it significantly reduced the need for rescue antiemetics in the recovery room (36% vs 64% in the control group). The postanesthesia care unit and hospital discharge times were similar in all three study groups. One patient in Group II and one patient in Group III were hospitalized because of intractable symptoms related to PONV. After discharge from the ambulatory surgery unit, the incidence of nausea, vomiting, and the need for rescue antiemetic drugs were similar in all three treatment groups. In conclusion, ondansetron (4 mg IV) was more effective in reducing the need for rescue antiemetics in the recovery room when administered at the end versus prior to the start of otolaryngologic surgery. Therefore, when ondansetron is used for antiemetic prophylaxis in outpatients undergoing otolaryngologic procedures, it should be administered at the end of the operation rather than prior to induction of anesthesia.

(Anesth Analg 1997;84:331-6)

The Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas.

Accepted for publication October 30, 1996.

Address correspondence and reprint requests to Paul F. White, PhD, MD, FANCZA, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9068. Address e-mail to rsanch@mednet.swmed.edu.

Ondansetron is a highly effective antiemetic that has been used successfully for both the prophylaxis and treatment of postoperative nausea and vomiting (PONV) in high-risk outpatient surgical populations [1-5]. In most studies evaluating the efficacy of ondansetron as a prophylactic antiemetic, investigators have administered the drug immediately before induction of anesthesia [6-12]. Yet there are no well-controlled studies evaluating the effect of timing of ondansetron administration on its efficacy as a prophylactic antiemetic.

Given the relatively short elimination half-life of ondansetron (3-4 h) [13], we hypothesized that the timing of its administration may be an important determinant of its antiemetic efficacy. Therefore, we designed a study to compare the relative efficacy of ondansetron (4 mg intravenously [IV]) when it was administered prior to induction of anesthesia or at the end of surgery in preventing PONV after otolaryngologic surgery.

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Methods

Seventy-five healthy consenting adult ASA physical status I and II patients, aged 20-70 yr, and undergoing ambulatory otolaryngologic procedures consisting of endoscopic sinus, middle ear, or mastoid surgery, were randomly assigned to one of three antiemetic treatment groups according to a randomized, double-blind, placebo-controlled protocol approved by the local institutional review board. The patients were excluded if they had received any prophylactic antiemetics within 24 h before surgery, had any preexisting abnormalities involving major organ systems, had a history of drug abuse, were pregnant, or were more than 100% above their ideal body weight. The study medications were prepared by the pharmacy in two numbered syringes (containing 5 mL of either saline or ondansetron 4 mg) and were administered IV just before induction of anesthesia (Syringe 1) and at the end of the operation (Syringe 2). Group I received saline (Syringe 1) and saline (Syringe 2), Group II received ondansetron 4 mg (Syringe 1) and saline (Syringe 2), and Group III received saline (Syringe 1) and ondansetron 4 mg (Syringe 2).

All patients received a standardized general anesthetic technique consisting of midazolam 0.02 mg/kg IV for premedication, sufentanil 0.5 micro g/kg IV, propofol 1.5 mg/kg IV, lidocaine 0.5 mg/kg IV, and vecuronium 0.1 mg/kg IV for induction of anesthesia, followed by desflurane 2%-5% in combination with 50% nitrous oxide (0.5 L/min) in oxygen (0.5 L/min) for maintenance of anesthesia. Neostigmine 3-5 mg IV and glycopyrrolate 0.6-1.0 mg IV were given to all patients for reversal of residual neuromuscular blockade at the end of surgery. Desflurane and N2 O were discontinued upon completion of the surgical procedure (including placement of the bandage).

Demographic data were obtained including gender, weight, age, type of otolaryngologic procedure, history of PONV, motion sickness, or dizziness, as well as duration of surgery (from incision to application of the bandage) and anesthesia (from induction to discontinuation of the inhaled anesthetics). In addition, emergence time (from discontinuation of the inhaled anesthestics to eye opening), the volume of IV fluid administered during surgery and in the PACU, duration of stay in the PACU (time from PACU arrival until PACU discharge), as well as hospital discharge time (from PACU arrival until discharge from the ambulatory surgery unit) were recorded.

The incidence of PONV was assessed at 30-min intervals in the postanesthesia care unit (PACU) by an investigator who was blinded to the prophylactic antiemetic treatment. An emetic episode was defined as vomiting or retching occurring in a 2-min interval [6]. Of the rescue antiemetic drugs, ondansetron (4 mg IV) was administered as the initial "rescue" antiemetic for the treatment of PONV. If ondansetron was ineffective, droperidol 1.25 mg IV followed by promethazine 12.5 mg IV were administered. The criteria for administering a rescue antiemetic was either repeated (> two) episodes of retching/vomiting or a request by the patient for the treatment of their emetic symptoms. The administration of rescue antiemetic drugs was determined by the PACU nurse who was blinded to the prophylactic antiemetic treatment. A second rescue antiemetic was administered only when the symptoms of PONV persisted for 10 min or more after the first rescue antiemetic therapy. Postoperative pain relief in the PACU was provided with fentanyl 12.5-25 micro g IV. A follow-up telephone call was made to all patients at 24 h after surgery to determine the incidence of PONV after discharge.

A sample size of 25 for each group was determined by a power analysis based on the following assumptions: (a) more than 50% of the patients not receiving a prophylactic antiemetic would experience PONV [14]; (b) with effective antiemetic prophylaxis, a decrease of 40% (e.g., from 50% to 10%) would be considered of clinical importance [15,16]; and (c) alpha = 0.05, with beta = 0.20. Statistical analysis was performed using Fisher's exact test for categorical data and analysis of variance, with Tukey's multiple-comparison test for continuous data. Data are expressed as mean values +/- SD unless otherwise stated, with P values < 0.05 considered statistically significant.

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Results

Seventy-five patients (25 in each group) were studied, and the three treatment groups were similar with respect to their demographic characteristics, except that fewer patients in Group II (versus Group III) had a history of prior PONV (P < 0.05) (Table 1). In addition, there were no significant differences among the three groups in the amount of IV fluid administered during the perioperative period, total dose of opioid (i.e., sufentanil and fentanyl) in the perioperative period, emergence times (mean +/- SD 8.7 +/- 4.9, 9.8 +/- 4.9, and 9.4 +/- 5.9 min in Groups I, II, and III, respectively), PACU recovery times (66 +/- 21, 73 +/- 19, and 63 +/- 18 min in Groups I, II, and III, respectively), and hospital discharge times (203 +/- 68, 225 +/- 85, and 188 +/- 85 min in Groups I, II, and III, respectively).

Table 1

Table 1

In the recovery room, there were no significant differences in the incidence of postoperative nausea (Group I 80%, Group II 68%, and Group III 60%). Although fewer patients in Group III developed emesis (4% compared with 12% in Group I and 20% in Group II), this difference did not achieve statistical significance (P > 0.05). However, when ondansetron, 4 mg IV, was administered at the end of the operation, it significantly reduced the need for rescue antiemetics in the PACU (Figure 1). Prophylactic ondansetron given prior to induction of anesthesia did not significantly reduce the need for rescue antiemetic therapy in the recovery room. Of the patients who required a rescue antiemetic in the recovery room, fewer in Group III (44%) were treated within 30 min after the operation than in Groups I (75%) or II (71%). After the first-line rescue antiemetic, ondansetron 4 mg IV, 7 of 16, 6 of 14, and 6 of 9 patients in Groups I, II, and III, respectively, required the back-up rescue antiemetic, droperidol 1.25 mg IV. Subsequently, two of seven, four of six, and two of six patients in Groups I, II, and III, respectively, were administered promethazine 12.5 mg IV. The need for additional antiemetic therapy after the first-line rescue antiemetic did not differ among the three groups. In Groups I and III, more female than male patients required rescue antiemetics (Figure 2), and more female than male patients in Group III experienced nausea (83% vs 38%, P < 0.05). Compared with male patients in all three treatment groups, the overall incidences of postoperative nausea (83% vs 58%, P < 0.05) and the need for rescue antiemetics (71% vs 35%, P < 0.01) in the recovery room were significantly higher in females. Only two patients, one in Group II and one in Group III, were admitted to the hospital because of intractable symptoms related to PONV.

Figure 1

Figure 1

Figure 2

Figure 2

Complete 24-h follow-up data were available for 63 patients. After discharge from the ambulatory surgery unit, the incidences of nausea (6 of 20, 5 of 20, and 6 of 23 in Groups I, II, and III, respectively), vomiting (1 of 20, 0 of 20, and 2 of 23 in Groups I, II, and III, respectively), and the need for rescue antiemetics (1 of 20, 2 of 20, and 2 of 23 in Groups I, II, and III, respectively) were similar in all three treatment groups.

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Discussion

After otolaryngologic surgery, PONV is very common [14] and has been attributed to both direct and indirect stimulation of afferent fibers in the vestibular apparatus. Ondansetron, a selective 5-hydroxytryptamine type 3 antagonist, has been shown to be effective in preventing nausea and vomiting during the perioperative period. A recent review by Naylor and Inall [17] discussed the importance of 5-hydroxytryptamine in the vomiting reflex and the effectiveness of ondansetron in the prevention of PONV. These authors and others have recommended that prophylactic ondansetron, 4-8 mg IV, be given prior to induction of anesthesia [2,4,6,8-10]. However, the effect of timing of the dose of prophylactic ondansetron has not been investigated previously.

Since outpatients undergoing otolaryngologic procedures experience potent emetogenic stimuli during the perioperative period, they are at high risk of developing PONV. Stimulation of the vestibular labyrinthine system and the sensory afferent fibers of the trigeminal nerve, which terminate at the nucleus tractus solitarius, can provoke severe, intractable PONV, leading to unanticipated hospitalizations after ambulatory surgery [17]. Although 5-hydroxytryptamine type 3 receptors are abundant in the vicinity of the trigeminal nerve and the vestibular labyrinthine system, there have been no published studies demonstrating a significant benefit associated with prophylactic ondansetron administration prior to or during otolaryngologic procedures.

Our data would suggest that the relatively short elimination half-life of ondansetron, three to four hours [13], may contribute to the drug's relative ineffectiveness when administered prior to the start of otolaryngologic procedures. In addition, Khalil et al. [18] have found that the duration of ondansetron's antiemetic efficacy is dose-related. However, the optimum dose of ondansetron for the prevention of PONV in adults is alleged to be 4 mg, since there was no difference between 4 mg and 8 mg of ondansetron with respect to overall antiemetic efficacy [11].

Recently, it was reported that propofol-based anesthesia was associated with a lower incidence of PONV than a standard propofol-isoflurane-nitrous oxide anesthesia after middle ear surgery [15]. In addition, patients undergoing gynecologic laparoscopy with propofol-desflurane-nitrous oxide anesthesia experienced less PONV when ondansetron was administered before induction of anesthesia [19]. Yet, the current study revealed that despite prophylactic ondansetron, over 60% of this outpatient population developed nausea in the PACU when the otolaryngologic procedures were performed under propofol-desflurane-nitrous oxide anesthesia. Therefore, this study failed to demonstrate the effectiveness of prophylactic ondansetron (4 mg IV) in reducing PONV after otolaryngologic procedures, regardless of whether it was administered prior to induction of anesthesia or at the end of surgery. The high overall incidence of PONV in this outpatient population resulted in part from preexisting risk factors (i.e., history of motion sickness or previous PONV), and the type of surgical stimulation (e.g., middle ear surgery) [17], as well as the use of desflurane and nitrous oxide [15], neostigmine-glycopyrrolate [20], and the opioid analgesics, sufentanil and fentanyl [21].

Although the timing of administration of ondansetron did not influence the overall incidence of PONV, the need for rescue antiemetic medication in the PACU was significantly decreased in the patients who received ondansetron at the end of surgery. Of interest, requests for antiemetic therapy by the patients who received 4 mg of ondansetron prior to induction of anesthesia were not significantly decreased compared to the placebo group. The need for additional antiemetic therapy after the administration of a rescue dose of ondansetron was also similar among the three groups (7 of 16, 6 of 14, and 6 of 9 in Groups I, II, and III, respectively), indicating that the rescue dose of ondansetron provided no greater benefit in the patients receiving prophylactic ondansetron than those receiving the placebo (saline). These data would suggest that if prophylaxis with ondansetron (4 mg IV) does not adequately control symptoms of PONV, a second rescue dose of ondansetron is unlikely to be effective. Since only patients who complained of persistent nausea or experienced recurrent emesis were given rescue antiemetic in the recovery room, and both patients and PACU nurses were blinded to the prophylactic antiemetic therapy, the requirement for additional medication was considered a valid outcome measure of prophylactic antiemetic treatment.

Compared to male patients undergoing otolaryngologic procedures, the overall incidences of postoperative nausea (83% vs 58%) and the need for rescue antiemetics (71% vs 35%) were significantly greater in females. These data are consistent with many earlier reports suggesting that female gender is a risk factor for PONV, especially during the menstrual period [18,21,22]. A recent retrospective study suggested that prophylactic ondansetron, 4 mg IV, was equally effective in preventing PONV in both menstruating and nonmenstruating women [23]. However, prophylactic ondansetron, 4 mg IV, appears to be less effective in this outpatient otolaryngologic population than in outpatients undergoing gynecologic procedures [2,4,6,8-10].

Even though a lower percentage of high-risk patients were assigned to Group II (e.g., those with a history of prior PONV) [21], prophylactic administration of ondansetron immediately before induction of anesthesia proved less effective than when the antiemetic was administered at the end of surgery. In Groups I and II, 71% to 75% of the patients with intractable nausea and/or persistent emesis required rescue antiemetics within 30 minutes after completion of their operation. In contrast, less than half of the patients in Group III required rescue antiemetics within 30 minutes after surgery. Analogous to other investigations involving prophylactic administration of ondansetron in the ambulatory setting, there was no significant difference in the incidence of PONV after discharge [7,10]. Our inability to demonstrate an effect of ondansetron after discharge may have been related to the fact that ondansetron was used as the rescue antiemetic in all three treatment groups. These findings would suggest that the optimal time for ondansetron to achieve its antiemetic effect is within 30 minutes after its administration and support the concept that prophylactic ondansetron should be administered near the end of the surgical procedure. Given the limited effectiveness of ondansetron in preventing PONV after otolaryngologic surgery, these data would suggest that it may be more cost-effective to use ondansetron for treatment rather than prophylaxis.

Future pharmacoeconomic studies should also compare the cost effectiveness of ondansetron with other less costly antiemetic drugs (e.g., droperidol) when administered at the end of otolaryngologic procedures. Recently, Tang et al [24] reported that droperidol, 0.625 mg IV, was as effective as ondansetron, 4 mg IV, in the prophylaxis of PONV in women undergoing outpatient gynecological surgery. More importantly, since this small dose of droperidol was not associated with an increase in postoperative side effects or prolongation of discharge times compared with a standard prophylactic dose of ondansetron, it would appear to be more cost-effective for routine prophylaxis in outpatients undergoing gynecologic surgery. Similar comparative pharmacoeconomic studies are clearly needed in outpatients undergoing otolaryngologic procedures.

In conclusion, the incidence of PONV was high in outpatients undergoing otolaryngologic surgery with a propofol-desflurane-N2 O anesthetic technique in spite of prophylaxis with ondansetron, 4 mg IV. However, prophylactic ondansetron appeared to be more effective when administered at the end of otolaryngologic surgery than prior to the induction of anesthesia. A repeat dose of ondansetron, 4 mg IV, in the PACU provided no additional benefit in patients who experienced PONV after receiving intraoperative prophylaxis. Future studies should examine the cost effectiveness of ondansetron prophylaxis versus treatment in this patient population.

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