Abstract
Background
A combination of antiemetic drugs could be an effective method to prevent severe postoperative nausea and vomiting (PONV). Therefore, we exam-ined the prophylactic effect of haloperidol plus ondansetron on PONV.
Methods
We enrolled 210 patients (n = 70 in each of 3 groups) undergoing elective laparoscopic cholecystectomy for this randomized double-blind study. Patients were randomized to intravenous saline 2 mL and intramuscular haloperidol 2 mg (Group H), intravenous ondansetron 4 mg and intramuscular saline 2 mL (Group O), or intravenous ondansetron 4 mg and intramuscular haloperidol 2 mg (Group H + O), administered after
induction of general anesthesia and 30 minutes before the conclusion of surgery.
We compared the complete response rates, incidence of PONV, nausea scores, the need for rescue medication, patient satisfaction scores, and adverse events during the 24-hour study.
Results
The H + O group had the highest complete response rate to treatment (79%) compared with group H (61%) and group O (62%) (p < 0.05 for both). Patient satisfaction scores were significantly higher in the H + O group (8.3 ± 1.8) than in the H (7.0 ± 2.4) and O (7.2 ± 2.5) groups (p < 0.05 for both). In addition, nausea scores were significantly lower in the H + O group (1.2 ± 2.6) than in the H (2.5 ± 3.3) and O (2.2 ± 3.1) groups (p < 0.05 for both).
Conclusion
We conclude that the combination of prophylactic haloperidol (2 mg) plus ondansetron (4 mg) provides a higher complete response rate and greater patient sati-sfaction after laparoscopic cholecystectomy than either drug used alone.
Keywords
cholecystectomy; haloperidol; laparoscopic surgery; ondansetron; postoperative nausea and vomiting;
1. Introduction
Despite advances in anesthetic techniques and the introduction of new antiemetics in recent decades, postoperative nausea and vomiting (PONV) is still common after anesthesia.1 Although PONV is rarely fatal, it can result in serious complications such as aspiration pneumonitis, dehydration, and disruption of surgical sutures. Even mild PONV can sometimes delay hospital discharge, decrease patient satisfaction, and increase the use of medical resources.1
Risk factors of PONV include female gender, nonsmoking, history of PONV/motion sickness, use of vol atile anesthetics, postoperative analgesia with opioids, and type of surgery such as hysterectomy and cholecystectomy.2,3 Although prophylaxis against PONV is not routinely used, single drug prophylaxis for PONV is usually suggested for patients with mild to moderate risk (1−2 risk factors). For patients with moderate-to-high risk (3−4 risk factors), a combination of two antiemetics with different sites of action is commonly recommended.2−4
Haloperidol, a butyrophenone and a major tranquilizer with a D2 receptor antagonist effect, has been used as an antiemetic in palliation of nausea and vomiting for more than 40 years.5 Recently, a meta-analysis and some clinical and experimental studies6−9 have revealed that haloperidol is clinically effective for preventing PONV because of its rapid onset, safety in low doses, and low cost.7−9 However, only two studies10,11 have evaluated the effect of a combination of haloperidol with dexamethasone, and only one study has investigated the effect of haloperidol plus ondansetron, a popular 5-hydroxytryptamine (HT) 3 receptor blocking antiemetic.12 There is still no study that aims to evaluate the effect of haloperidol combined with ondansetron in preventing PONV. Based on the advantageous effect of droperidol in combination with ondansetron in the prevention of PONV,13,14 it would be expected that haloperidol in combination with ondansetron would offer greater prophylaxis of PONV than haloperidol or ondansetron alone.
Our aim was to evaluate the prophylactic effect of haloperidol plus ondansetron on PONV. We hypothesized that prophylactic haloperidol plus ondansetron would provide an increase in the complete response rate (no PONV and no rescue with antiemetics) and a decrease in the incidence of PONV than either drug used alone.
2. Methods
We conducted a double-blind, randomized, controlled study in patients undergoing elective laparoscopic cholecystectomy (LC). The study protocol was approved by the Institutional Review Board of Human Research, Chi-Mei Medical Center, and written informed consent was obtained from all 210 ASA class I or II patients enrolled in the study. A medical history concerning cigarette smoking, previous motion sick ness, and prior PONV was recorded along with demo graphic information with regard to age, weight, height, and gender. The exclusion criteria were clinical evidence of a difficult airway, obesity (body mass index > 35 kg/m2 ), pregnancy, psychia tric illness, clinically significant major organic disease, preoperative QTc interval > 440 ms or consumption of a drug with antiemetic properties within 24 hours of the study.
In the preoperative holding area, patients were randomly assigned to one of three study groups using a computer-generated random number table (n= 70 in each): (1) Group H patients were given intramuscular (i.m.) haloperidol (2 mg) plus intravenous (i.v.) saline (2 mL); (2) Group O patients were given i.v. ondansetron (4 mg) plus i.m. saline (2 mL); (3) Group H + O patients were given i.m. haloperidol (2 mg) plus i.v. ondansetron (4 mg). The study medications diluted with 2 mL saline were prepared by a nurse anesthetist in two syringes labeled “i.m.” or “i.v.”. Each patient was given the test drug i.v. after induction of general anesthesia and another dose of test drug at the completion of gallbladder resection, about 30 minutes before the conclusion of surgery. Patients and the investigators who collected the postoperative data were blinded to the drugs given.
Anesthesia, standardized in all patients, was induced with fentanyl (2 μg/kg, i.v.), lidocaine (1 mg/ kg, i.v.), and propofol (2 mg/kg, i.v.). Laryngoscopy and endotracheal intubation were facilitated with rocuronium (1 mg/kg, i.v.). Anesthesia was maintained with 8−12% (inspired concentration) desflurane in oxygen. Additional opioid designated as 50 μg fentanyl was given if the heart rate or blood pressure increased more than 20% from the preoperative value during surgery. Ventilation was controlled mechanically and adjusted to maintain end-tidal CO2 at 30−35 mmHg throughout the surgery. Additional rocuronium was given as required. A nasogastric tube was inserted to empty the gastric contents. LC was done via three openings in the abdomen. At the end of surgery, the residual neuromuscular blockade was reversed with neostigmine (0.04 mg/kg, i.v.) and atropine (0.02 mg/ kg, i.v.), and the tra chea was extubated after the patient had resumed spontaneous respiration and become conscious. The nasogastric tube was removed before the patient was transferred to the recovery room.
During anesthesia, a standard lead II electrocardiogram (ECG) was recorded before and every minute after the drug was injected for a 10-minute observation period. The QT intervals were measured manually from the onset of the QRS complexes to the end of the T wave and corrected for the patient’s heart rate using a previously published formula.15 A corrected QT interval (QTc) was then obtained. In addition, a complete 12-lead ECG was done before each patient was discharged from the postanesthesia care unit (PACU). A QTc interval > 470 ms was considered as significant prolongation16 and the incidence was recorded and compared.
After surgery, all patients were observed for 24 hours. They were first transferred to the PACU where they stayed for 2 hours. Then they were returned to the ward. Three parameters—(1) incidence and severity of PONV, (2) severity of postoperative pain, and (3) occurrence of postoperative adverse effects, i.e. sedation and extrapyramidal symptoms (EPS)—were monitored every 15 minutes in the PACU and thereafter every 4 hours from 8:00 a.m. to 10:00 p.m. in the ward. Furthermore, each patient gave a satisfaction score (0−10) 24 hours after surgery on the anesthetic technique and the administered drug.
The severity and extent of PONV were evaluated with regard to five specific entities, namely: (1) incidence of nausea; (2) incidence of vomiting; (3) incidence of nausea and vomiting; (4) rescue antiemetics used; and (5) nausea score. An episode of vomiting was defined as either expulsion of stomach contents or retching, an involuntary attempt to vomit without actual expulsion of stomach contents. Repeated retching or vomiting occurring in a space of less than 5 minutes was considered as a single episode. A combination of nausea and vomiting was considered as one entity under the category of vomiting. Vomiting alone, vomiting with nausea, and retching were all considered as vomiting. Nausea was scored with a verbal rating scale (from 0 = no nausea to 10 = worst nausea). A rescue antiemetic (metoclopramide, 10 mg, i.m.) was given if the nausea was rated > 5, if actual vomiting occurred, or at any time if requested by the patient. Nausea and vomiting assessments were made 30 minutes after a patient had been given rescue medication. The treatment could be repeated if the PONV symptoms did not improve. A complete response was defined as absence of PONV without antiemetic rescue during the 0−24-hour postoperative period. Complete response and the patients’ satisfaction scores were the primary end points of the study. The secondary end points of the study were the proportion of patients with nausea or vomiting, the proportion needing antiemetic rescue, the nausea scores, and the side-effects of each treatment. For ethical reasons, we did not have a placebo group for comparison. Instead, we calculated the predicted incidence of PONV based on Apfel et al’s risk score.17 The observed incidence was compared with the predicted incidence and between groups.
Postoperative pain was scored 2 and 24 hours after surgery using a 10-cm visual analog scale (VAS; from 0 = no pain to 10 = most severe pain). We gave ketorolac (30 mg, i.v.) for pain relief if the VAS score exceeded 5 or if the patient complained of pain and requested an analgesic. If pain persisted for 15 minutes after ketorolac, meperidine (25 mg, i.v.) was given instead.
The level of sedation was classified as: 1 = awake; 2 = drowsy, responds to verbal commands; 3 = asleep, responds to touch or pain stimuli; 4 = totally unresponsive. It was evaluated 30 minutes after a patient arrived in the PACU. All EPS (motor restlessness, acute dystonia, or tardive dyskinesia) during the 24-hour observation period were recorded and then treated with diphenhydramine hydrochloride (30 mg, i.v.).
The sample size was predetermined using a power analysis based on two assumptions: first, the complete response rate to ondansetron would be 50%,18 and, second, a 25% increase in the response rate (from 50% to 75%) would be clinically relevant [α= 0.05 (two-sided) and β= 0.2 (power = 80%)]. The calculated minimum sample size was 62 patients in each group. One-way analysis of variance was done to examine the differences in the parametric variables between the three groups. If a significant difference was found, Tukey’s Honestly Significant Difference test was used to detect intergroup differences. The Kruskal-Wallis test was used to determine differences in the nonparametric variables between groups, and then the Mann-Whitney rank sum test was used to detect intergroup differences. Categorical variables were analyzed using a series of 2 ˜ 3 χ2 tests or Fisher’s exact test to detect differences between groups, and then a 2 ˜ 2 χ2 test or Fisher’s exact test was used to detect intergroup differences as appropriate. Statistical significance was set at p< 0.05.
3. Results
Eighteen of the 210 patients enrolled in the study were excluded from the analysis, of whom 10 required an exploratory laparotomy, and eight had incomplete data collected. The data obtained from the remaining 192 patients were analyzed. Patients’ characteristics such as age, weight, height, history of PONV and motion sickness, durations of surgery and anesthesia were not different between the three groups (Table 1).
The H + O group had the highest complete response rate (0−24 hours), highest patient satisfaction (24 hours), the lowest incidence of total PONV (2−24 and 0−24 hours) and the lowest nausea score (2−24 hours) (Table 2). In addition, the H + O group needed less rescue analgesics than the other two groups (0−24 hours) (Table 2). On the other hand, we found no differences between the H and O groups in these aspects (Table 2). Moreover, the incidence of total PONV in all three groups [39% (H), 38% (O), and 21% (H + O)] was significantly less than the predicted values based on the patients’ underlying risks [58% (H), 58% (O), and 56% (H + O)] (Table 3). The mean VAS pain scores in all groups were between 2 and 4 during the 2−24-hour postoperative observation period. The intensity of postoperative pain and the use of ketorolac and meperidine were not different among groups (Table 4). The levels of sedation were between 1 and 2 in all groups 30 minutes after the patients arrived in the PACU, and there were no significant differences in sedation levels among groups.
Although the QTc interval lengthened after the administration of induction agents in all groups, it did not increase further compared with the preinjection value after the test antiemetic medication had been given (Table 5). The incidence of QTc > 470 ms was not significantly different among groups (Table 5). The mean values of QTc intervals in all groups during two 10-minute observation periods (i.v. test drug after general anesthesia induction and i.m. test drug before the end of surgery) were not significantly different.
Only two patients (one each in the H and H + O groups) reported EPS (restlessness), which were relieved within 15 minutes after they had been given diphenhydramine hydrochloride (30 mg, i.v.). The EPS case in the H group was found during the PACU stay and the other case (in the H + O group) developed restlessness 6 hours postoperatively after metoclopramide rescue was given twice. No untoward long-term events were observed. No differences were found in the incidence of EPS among the three groups.
4. Discussion
This is the first clinical study to compare coadministration of haloperidol and ondansetron in the prevention of PONV. We found that a combination of haloperidol (2 mg) and ondansetron (4 mg) produced a greater reduction in the incidence of PONV and provided increased patient satisfaction after anesthesia than did either drug alone. In addition, adverse outcomes, such as QTc prolongation, over-sedation, EPS, postoperative pain, and headache did not increase.
Many antiemetics have been used in the prophylaxis and treatment of PONV. None of the available antiemetics, however, provide total prevention of PONV.19 Although the precise etiology of PONV is not clear, the origin is multifactorial, principally relating to the patient per se, the drugs and the surgery. Multiple receptors, such as dopamine type 2, 5-HT type 3, histamine type 1, muscarinic cholinergic type 1, and neurokinin type 1, are involved.20−22 Most of the antiemetics act by blocking only one kind of receptor. Thus, using a combination of antiemetics with different mechanisms of action has gained favor for preventing and treating PONV in high risk patients.19
Droperidol, dexamethasone, and ondansetron have often been tested in combination for treating PONV.4,13,14,23 However, there has only been a single clinical study that tested the efficacy of a combination of haloperidol and dexamethasone or droperidol and dexamethasone for antiemetic prophylaxis in elective LC.11 Either haloperidol or droperidol in combination with dexamethasone is more effective than dexamethasone alone for antiemetic prophylaxis after LC. In addition, in one of our studies,10 haloperidol (2 mg) plus dexamethasone (4 mg) was superior to either drug used alone, and also to droperidol (1.25 mg) in women undergoing laparoscopic-assisted vaginal hysterectomy. Recently, Grecu et al12 reported that the antiemetic effect of haloperidol (1 mg) combined with ondansetron (4 mg) was effective and longer lasting than ondansetron alone in a mixed surgical population. However, in our study, we compared haloperidol plus ondansetron with either drug alone in one specific surgery—LC. Our favorable results add new evidence that the combination of haloperidol and ondansetron can be considered as a good choice for the prophylaxis of PONV. We speculate that the advantage of haloperidol plus ondansetron is based on their different mechanisms of action.
Although it is possible that the incidence of adverse events will increase in patients who take two anti-nausea and vomiting prophylactic drugs, we found no significant differences between the single- and combined-drug groups. Our result is consistent with those of many studies using haloperidol-dexamethasone, droperidol-dexamethasone, droperidol-ondansetron, or ondansetrondexamethasone combinations.10,23,24
Very recently, based on some sporadic case reports, the US Food and Drug Administration has issued a warning that haloperidol could cause QT prolongation and torsades de pointes, especially when given i.v. or in higher doses than recommended.25 Here, we used a low dose (< 5 mg) and administered it i.m. The QTc interval prolonged significantly after induction of general anesthesia. However, during the two 10-minute observation periods after the tested drug was administered (after induction and before the end of surgery), the QTc intervals were not significantly different from the preinjection value. Our previous and other similar studies also demonstrated that the QTc interval was not affected during the observation period.7,10
Many drugs used in anesthesia, for example, thiopental, muscle relaxants, and gas inhalation agents, are reported to cause prolongation of the QTc interval. Moreover, a recent review6 of 1397 patients receiving haloperidol (0.25−5 mg) revealed that cardiac-related side effects were absent. Hence, we believe that there is little chance of QTc prolongation when using a low dose of haloperidol.
Since the occurrence of PONV in patients undergoing LC without use of prophylaxis could be rather high,26 it would not be ethical to use a placebo drug as a control in a study of efficacy with highrisk patients. To overcome this problem, we used, for each group, the Apfel risk score17 as a predictor to determine the development of PONV without prophylaxis,27 in lieu of a placebo control group.
In conclusion, prophylactic treatment with a combination of haloperidol (2 mg) and ondansetron (4 mg) provides a higher response rate, greater patient satis faction, and a larger reduction in the incidence of PONV than either drug used alone, and the combination does not increase adverse outcomes.