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Department of Anesthesiology, Queen’s University, Kingston, Ontario
Address correspondence and reprint requests to Joel L. Parlow, MD, Department of Anesthesiology, Kingston General Hospital, 76 Stuart St., Kingston, Ontario, K7L 2V7. Address e-mail to parlowj{at}post.queensu.ca
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Abstract |
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IMPLICATIONS: In this randomized, double-blinded, placebo-controlled trial, a single, small IM dose of haloperidol 1 mg or 2 mg reduced the incidence of postoperative nausea and vomiting after spinal anesthesia with local anesthetic and intrathecal morphine.
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Introduction |
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The objective of this study was to evaluate the use of haloperidol for antiemetic prophylaxis in patients receiving intrathecal morphine during spinal anesthesia. We hypothesized that a single dose of IM haloperidol after spinal anesthesia with local anesthetic and morphine would significantly decrease the incidence of PONV during the first 24 h after surgery.
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Methods |
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Usual monitoring was used. Lumbar spinal anesthesia was established using either 0.5% bupivacaine, 0.75% bupivacaine, or 0.75% tetracaine at a dose chosen by the attending anesthesiologist. Preservative-free morphine (0.3 mg) was added to the local anesthetic syringe before the injection.
Patients were not premedicated. Midazolam was administered IV in 0.5-mg increments for intraoperative sedation at the discretion of the anesthesiologist. After the spinal block was established, the study drug was administered IM into an anesthetized area (gluteus muscle). Patients were randomized to receive one of three study drugs, according to a computer-generated randomization code held by the hospital research pharmacist. Study drugs were prepared to equal volumes in identical syringes containing saline placebo (group P), haloperidol 1 mg (group H1), or haloperidol 2 mg (group H2).
Demographic data were collected for each patient including age, sex, height, weight, type of surgery, regular medications, significant medical history, timing in menstrual cycle, history of previous PONV or motion sickness, and history of smoking and alcohol use. Rescue antiemetic was provided at patients’ request using dimenhydrinate 50 mg IV. If ineffective, patients were offered prochlorperazine 10 mg IV, followed by ondansetron 4 mg IV.
The primary outcome was treatment failure, defined as a nausea score of 1 or more, any episodes of vomiting, or request for rescue antiemetic at any time. Outcome measures were recorded at 1 and 2 h after surgery in the recovery room and then every 4 h for a total follow-up period of 24 h from the time of the spinal anesthetic. At each time period, both patient- and nurse-observer–derived scores were collected. Patient self assessment consisted of a 10-cm visual analog scale for nausea. Scales used to obtain data (Appendix 1) by the observers included: (a) 5-point descriptor score for nausea using Melzack Overall Nausea Index (23); (b) episodes of vomiting; (c) use of rescue antiemetics; (d) 10-point pain score; (e) 5-point descriptor score for sedation; (f) 3-point descriptor score for pruritus; and (g) presence of extrapyramidal side effects.
Using a predicted failure rate in the placebo arm of 70% for the primary outcome (1,2), 31 subjects per group were calculated to be required to yield a reduction in incidence of 50% with a power of 80% and 
error of 0.05. Incidence data were analyzed using 
2. Dose-related linear trends were assessed using the Cochran-Armitage Trend Test, which detects increasing or decreasing probabilities of response when a categorical exposure is ordered (24). Multiple logistic regression was used to predict the occurrence of PONV by treatment arm while controlling for preoperative demographic variables.
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Results |
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1 for nausea: 53% P, 39% H1, and 32% H2; P = 0.033; descriptor score 1: 65% P, 47% H1, and 42% H2; P = 0.029) and for vomiting at 12 h only (P = 0.05). There were no outcome differences determined between the two haloperidol doses when compared alone, and both doses were effective at reducing PONV, particularly during the first 12 h of follow up (Table 2). There was, however, a nonsignificant trend to a greater efficacy of the 2-mg dose over the entire 24 h period versus the first 12 h.
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Discussion |
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In addition to its well known antipsychotic properties, haloperidol is an effective antiemetic in the setting of opioid-induced nausea and vomiting. This is likely because of its central effects at dopamine D2 receptors (18,19,22). Its effectiveness and duration of action as an antiemetic has been documented in volunteers challenged with apomorphine (21). More recently, haloperidol has become a first-line antiemetic in the setting of palliative care medicine (15,16). In the postoperative setting after general anesthesia, haloperidol has been shown to be effective and well tolerated when given prophylactically (12,14) or therapeutically (13). The current study demonstrates a potential for the use of haloperidol for PONV prophylaxis after spinal anesthesia, including intrathecal opioids.
Several antiemetics have been examined in the prevention and treatment of PONV induced by spinal opioids with mixed results. The combination of metoclopramide and ondansetron was ineffective in preventing PONV after intrathecal morphine (3). The 5-hydroxytryptamine-3 inhibitor tropisetron was also ineffective (2), suggesting a limited role for this class of antiemetics in this clinical situation. In contrast, a combination of oral promethazine and transdermal scopolamine reduced PONV after intrathecal morphine (4), as did a subhypnotic infusion dose of propofol (5,6). Droperidol, the antiemetic that is most pharmacologically similar to haloperidol, has been used frequently to combat nausea and vomiting related to systemic morphine (7,8,25), as well as neuraxial opioids (9,10). However, recent concerns regarding cases of fatal arrhythmias related to prolonged QT interval after the administration of droperidol have all but eliminated its routine use in North American practice (11).
Haloperidol reduced the incidence of nausea in our study, although it remained somewhat frequent. In the current study, haloperidol doses were limited to 1 or 2 mg to avoid extrapyramidal effects, which were not reported by any of our study patients. Extrapyramidal reactions are rare in small doses (12,13). In patients receiving one of a range of doses of prophylactic IM haloperidol (0.5 to 4 mg), only 1 of 357 patients (4-mg group) experienced a mild extrapyramidal reaction (12). Similarly, no extrapyramidal reactions were observed in 62 patients given a single IM dose of haloperidol 1 mg for treatment of PONV after general anesthesia (13) or after haloperidol 0.03 mg/kg in volunteers challenged with apomorphine (21). It is unlikely that larger doses of haloperidol would decrease the incidence of PONV further, in that in a previous dose-finding study, all doses of haloperidol from 0.5 to 4 mg were more effective than placebo (12). In the current study, the value of using the larger (2 mg) dose may have been in extending the duration of effect, rather than improving efficacy.
Another possible cause for the incomplete response to haloperidol is the dose of intrathecal morphine used. More recently, investigators have demonstrated good postoperative pain relief with smaller doses of morphine. Intrathecal morphine 0.1 mg was found to be as effective as 0.2 mg for analgesia, without a difference in the incidence of PONV (1), whereas in another study, a dose of 0.05 mg led to a similar analgesic effect to 0.1 and 0.2 mg but with a decreased incidence of PONV and pruritus (26). Interestingly, one investigator found that patients receiving morphine 0.2 mg with bupivacaine for lower limb joint surgery had the same incidence of PONV as those receiving bupivacaine alone (27). Although this study used a large sample size, there was no randomization or blinding, which may have skewed results. However, this study did suggest the possibility that the mechanisms involved in PONV after spinal anesthesia may be multifactorial. For example, delayed gastric emptying has been postoperatively demonstrated in a group of patients who received a large dose of intrathecal morphine (0.6 mg) versus placebo with bupivacaine for hip arthroplasty (28). This was not associated with an increase in PONV, although the follow-up period in that study was only four hours. However, drugs that improve gastric motility have not generally been shown to reduce PONV after spinal anesthesia (1,3). In the current study, most of the patients underwent orthopedic procedures, with no intraabdominal surgery being included, to limit additional potential causes for PONV. Although untested, a multimodal approach to postoperative PONV prevention after spinal anesthesia may provide greater efficacy, as has been demonstrated after general anesthesia (20).
The methodology of measurement of nausea also differs markedly between different studies (23). Thus, the efficacy of antiemetic modalities will vary according to the criteria established to detect treatment failure (29). In the current study, a liberal definition of failure rate was established (nausea more than 1 on either scale and any vomiting or antiemetic use), which may have led to a lower threshold for treatment failure than in some other investigations.
In summary, a single IM dose of haloperidol 1 or 2 mg offers an inexpensive, safe approach to PONV prophylaxis after spinal anesthesia using intrathecal morphine. However, a substantial number of patients in the treatment arms still experienced PONV. Further reduction in the incidence of PONV might be achieved with the use of smaller doses of intrathecal morphine and with a multimodal approach to PONV.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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