Efficacy of Prophylactic Ondansetron in a Patient-controlled Analgesia Environment

The Journal of International Medical Research 2004; 32: 160 165 Efficacy of Prophylactic Ondansetron in a Patient-controlled Analgesia Environment SH HAN, YJ LIM, YJ RO, SC LEE, YS PARK AND YC KIM Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, 28 Yongon-Dong, Chongno-Gu, Seoul, 110-744, Korea We conducted a prospective, randomized, double-blind, placebo-controlled trial to examine the efficacy of prophylactic ondansetron on post-operative nausea and vomiting (PONV) during opioid patientcontrolled analgesia (PCA). In total, 374 patients using opioid PCA, but otherwise considered to be low risk for PONV, were randomly allocated to ondansetron (4 mg given intravenously and 16 mg added into the PCA pump) or saline (control group). PONV was evaluated in terms of nausea graded on a visual analogue scale, and the number of patients who experienced emetic episodes or needed rescue anti-emetics in the 48-h post-operative period. Patient satisfaction for PCA was scored at the end of the evaluation period. The only difference between the two groups was the higher number of headaches in the ondansetron group. In patients using opioid PCA, but with no other high risk factors for PONV, prophylactic ondansetron does not have any clinical benefit. KEY WORDS: POST-OPERATIVE NAUSEA AND VOMITING; PATIENT-CONTROLLED ANALGESIA; ONDANSETRON Introduction It is well known that post-operative nausea and vomiting (PONV) are common and distressing post-operative complications. 1,2 Risk factors for PONV may be patient-related (e.g. female gender, non-smoker) or surgical (e.g. intra-abdominal and urological procedures). 3 5 Another important known risk factor is opioid patient-controlled analgesia (PCA). 6,7 The use of prophylactic anti-emetics during PCA has been suggested by many investigators. 8 13 Most of these investigations, however, were carried out on patients who were at high risk for PONV with regard to patient-related and/or surgical factors. Taking into account the cost 14 and the possibility of adverse effects, 15 routine use of prophylactic anti-emetics with PCA use should therefore be reconsidered. We conducted a prospective, randomized, double-blind, placebo-controlled study to examine the anti-emetic efficacy of ondansetron during intravenous opioid PCA (IV-PCA) in patients otherwise regarded as low risk for PONV. Patients and methods PATIENTS Local ethics committee approval and written informed consent from patients were obtained. Patients scheduled for elective 160

surgery under general anaesthesia were enrolled in this placebo-controlled, doubleblind study. Patients were excluded if they: (i) Were under 61 years of age; 3,4 were female; 3,5,16 had a history of motion sickness, migraine or previous PONV, 1,5,16 had a body mass index 3,17 > 27 kg/m 2 ; and/or were non-smokers; (ii) Were undergoing surgery of more than 3 h duration, a laparoscopic procedure, craniotomy 4,5 or a known highly emetogenic procedure such as a dental, otolaryngological, urological or intraabdominal surgery; (iii) Had systemic disease such as hepatic or renal dysfunction, a known allergy to ondansetron, fentanyl or ketorolac, or were unable to control the PCA system. At the pre-anaesthetic visit, patients were given instructions on how to use the PCA system and mark the 100-mm visual analogue scale (VAS). ANAESTHESIA AND DRUG ADMINISTRATION Anaesthesia was given by one of many anaesthesiologists who were blinded to the study protocol. Fifteen minutes before the end of anaesthesia, 4 mg of ondansetron or the same volume of saline (prepared in identical syringes) was administered intravenously. The syringes were prepared by a nurse using computer-generated random numbers. To achieve double-blinding, no other staff were aware of the syringe contents. Following transfer to the recovery room, 0.5 µg/kg of fentanyl was injected intravenously if a patient complained of pain. The same dose of fentanyl was given at 15-min intervals thereafter up to a maximum dose of 2 µg/kg, if necessary. After injecting the fentanyl as required, the patients were started on IV-PCA using an infusor at a basal rate of 0.5 ml/h, with a 15 min lockout time and a 0.5 ml bolus (PC1955 and C1079, Baxter Healthcare, Deerfield, IL, USA). The PCA infusor contained 1200 1700 µg of fentanyl and 150 270 mg of ketorolac (total volume including saline: 60 ml). The dosage of fentanyl and ketorolac was tailored by the attending anaesthesiologist to our regimen, which has been described previously, 18 and the patient s condition. Either 16 mg of ondansetron or the same volume of saline was added to the PCA pump by the nurse who prepared the syringes. Patients not complaining of pain in the recovery room were started on IV-PCA within the first postoperative hour. Rescue anti-emetics (2 mg of intravenous ondansetron) were given on request. PARAMETERS ANALYSED The severity of nausea was evaluated 2 h, 8 h, 16 h, 24 h, 32 h, 40 h and 48 h postoperatively. Patients were asked to grade the nausea using the 100-mm VAS. The incidence of emetic episodes (retching and vomiting were considered as emetic episodes and were assessed as present or absent) was recorded as the number of patients experiencing emetic episodes at any time during each evaluation period (0 2 h, 2 8 h, 8 16 h, 16 48 h post-operatively). The number of patients who needed rescue anti-emetics during each evaluation period was also recorded. Other variables recorded were total fentanyl consumption and opioid- or ondansetron-related side-effects. After the postoperative 48-h evaluation period, patients were asked to rate their overall satisfaction with the PCA therapy using a numerical rating scale (1 = very dissatisfied, 2 = dissatisfied, 3 = neither dissatisfied nor satisfied, 4 = satisfied, 5 = very satisfied). 161

STATISTICAL ANALYSIS Parametric data were compared using Student s t-test and non-parametric data using the χ 2 test. P < 0.05 was considered to be statistically significant. Results From a total of 374 patients, 187 were allocated to group O (the group given ondansetron) and 187 to group C (control group). Twenty-four patients were excluded from the final analysis for the following reasons: unable to mark the VAS properly (seven patients in group C and 10 patients in group O); or stopping PCA before the completion of the study because of severe nausea and/or vomiting (three patients in group C and four patients in group O). There were no significant differences between the two groups with regard to demographic data (Table 1), the severity of nausea measured with the 100-mm VAS at each post-operative evaluation time (Fig. 1), or the number of patients needing rescue anti-emetics or experiencing emetic episodes (Table 2). Total consumption of fentanyl was similar in the two groups (group O = 742 ± 35.1 µg and group O = 763.6 ± 19.7 µg). One patient in group O and two in group C complained of itching. Four patients in group O complained of a mild headache, but none in group C. In both groups, no patient rated very dissatisfied on the patient satisfaction scale, and the overall satisfaction rate was similar in the two groups (Table 3). Discussion We found no indication of improvement in patient satisfaction or a reduction in the incidence or severity of PONV with prophylactic ondansetron during opioid PCA use. This contrasts with previous reports. 8 13 The only difference noted was the higher number of patients who complained of headache in group O compared with group C, which may have been related to sideeffects of ondansetron. 19 In previous studies, 8 13 the incidence of PONV in the control group was as high as TABLE 1: Demographic data, fentanyl consumption and duration of anaesthesia (mean ± SD), and type of surgery (number of patients) for the patients in the control (C) and ondansetron (O) groups using opioid patient-controlled analgesia who completed the study Group C (n = 177) Group O (n = 173) Age (y) 67.4 ± 6.4 67.8 ± 5.5 Height (cm) 160.2 ± 8.2 160.0 ± 8.7 Weight (kg) 63.2 ± 9.6 63.0 ± 8.8 Type of surgery Hip surgery 88 84 Knee surgery 38 42 Fracture, ankle or elbow 29 22 Carpal tunnel release 13 11 Varicose vein striping 7 9 Miscellaneous 2 5 Intra-operative fentanyl (µg) 68.2 ± 36.8 76.9 ± 35.3 Duration of anaesthesia (min) 158.9 ± 35.2 168.2 ± 21.6 162

100 Group C Group O 100-mm VAS 30 20 10 0 2 8 16 24 32 40 48 Post-operative time (h) FIGURE 1: Change in the severity of nausea as measured by a 100-mm visual analogue scale (VAS) (mean ± SD) during the post-operative period by patients using opioid patient-controlled analgesia in the control (C; n = 177) and ondansetron (O; n = 173) groups 30 70%. In our study, however, the number of emetic episodes in the control group was much lower; a maximum of 10.8% of patients suffered from emetic episodes during the evaluation period. The difference between the results of the present study which demonstrates the inefficacy of routine prophylactic anti-emetic use during opioid PCA and those of previous investigations may be related to patient selection and the TABLE 2: Number (%) of patients using opioid patient-controlled analgesia in the control (C) and ondansetron (O) groups who experienced an emetic episode (EE) or required rescue antiemetics (RESCUE) Post-operative evaluation period Group C (n = 177) Group O (n = 173) 0 2 h EE 21 (11.8) 17 (9.8) RESCUE 5 (2.8) 7 (4.0) 2 8 h EE 18 (10.2) 13 (7.5) RESCUE 6 (3.4) 2 (1.2) 8 16 h EE 6 (3.4) 5 (2.9) RESCUE 1 (0.6) 2 (1.2) 16 48h EE 2 (1.1) 1 (0.6) RESCUE 163

TABLE 3: Rating of satisfaction with patient-controlled analgesia therapy: for each score number (%) as assessed by patients in the control (C) and ondansetron (O) groups Group C (n = 177) Group O (n = 173) Very dissatisfied Dissatisfied 5 (2.8) 6 (3.5) Neither dissatisfied nor satisfied 28 (15.8) 32 (18.5) Satisfied 68 (38.4) 66 (38.1) Very satisfied 76 (42.9) 69 (39.9) underlying risk for PONV. The former studies included patients who had other risk factors for PONV besides using opioid PCA. Specifically, these were young female patients 8 13 who underwent a gynaecological procedure 8,10,12,13 or major breast reconstruction. 11 In contrast, we only included patients who were at low risk of PONV 1,3 5,16,17 but using opioid PCA. The addition of ketorolac to the PCA infusor may also account, in part, for the lower degree of PONV observed in our study. This is because adjunctive non-steroidal antiinflammatory drugs are known to reduce opioid PCA requirement and vomiting. 20,21 In the treatment group (group O) in our study, 4 mg of ondansetron was used as a loading dose and 16 mg of ondansetron was added into a PCA pump containing 1200 1700 µg fentanyl. Although higher doses may be more effective, 19 4 mg has been widely used as an intravenous dose for preventing PONV. 8,22 24 The dosage of ondansetron added to the PCA pump was appropriate since in previous investigations, 8,11,25,26 similar or smaller doses mixed in the PCA pump led to reductions in PONV. We therefore consider patient selection rather than drug dosage to be the reason why there was no improvement in PONV with ondansetron. In conclusion, in patients with no other high risk factors for PONV, the prophylactic administration of ondansetron was not found to be beneficial during use of opioid PCA. Acknowledgement We thank all members of the Statistical Data Analysis Laboratory at Hanyang University College of Natural Sciences for their expert statistical analysis. Received for publication 24 October 2003 Accepted subject to revision 11 November 2003 Revised accepted 5 January 2004 Copyright 2004 Cambridge Medical Publications References 1 Palazzo MG, Strunin L: Anaesthesia and emesis. I: Etiology. Can Anaesth Soc J 1984; 31: 178 187. 2 Oztekin S, Ozzeybek D, Tasdogen A, Kilercik H, Kara HC: Comparison of the antiemetic efficacy of tropisetron and droperidol with patient-given tramadol. J Int Med Res 2003; 31: 267 271. 3 Bellville JW, Bross ID, Howlands WS: Postoperative nausea and vomiting. 4, Factors related to postoperative nausea and vomiting. Anesthesiology 1960; 21: 186 193. 4 Sinclair DR, Chung F, Mezei G: Can postoperative nausea and vomiting be predicted? Anesthesiology 1999; 91: 109 118. 5 Stadler M, Bardiau F, Seidel L, Albert A, 164

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