W McKay, E Surtie, M Al-Rawwaf, T McLaren
W McKay, E Surtie, M Al-Rawwaf, T McLaren. A pilot randomised controlled trial of chlorpromazine to prevent postoperative nausea and vomiting. The Internet Journal of Anesthesiology. 2009 Volume 24 Number 2.
PURPOSE: Safety and efficacy of a small dose of chlorpromazine to prevent postoperative nausea and vomiting (PONV) was studied to enable design of a larger trial. Since phenothiazines may prolong the electrocardiogram QT interval and cause dangerous arrhythmias, we focussed on this side effect. METHODS: A double-blind randomised controlled trial was conducted in a tertiary care teaching hospital comparing chlorpromazine 10mg IV at anesthetic induction to saline with primary outcome prevention of PONV (defined as nausea and/or vomiting and/or retching at any time) in laparoscopic surgery, and secondary outcomes cardiac and other side effects. With University Research Ethics Board approval, 120 subjects were recruited. PONV was assessed in the Post-anesthetic Care Unit and 24 hours later.RESULTS: Group demographics were not different. For incidence of PONV, the chlorpromazine group (incidence; ratio; [95%Confidence Interval]: 33/60; 0.55 [0.42 to 0.68]) was not significantly different from placebo (40/60; 0.67 [0.55 to 0.79]. There was no difference in corrected QT or Tp-e intervals. One subject in each group was sleepier than expected; one in the CPZ group had lower blood pressure than expected after anesthesia induction, which was easily corrected.CONCLUSION: Although not statistically significant, PONV occurred more often in the placebo group than the treated group. A larger dose may be efficacious. Chlorpromazine is inexpensive and, at this dose, appears to be safe in the context of anesthesia practice. This study permitted sample size estimation (n = 100/arm) for a definitive study.
This study was funded by a grant from The Royal University Hospital Foundation.
No author has any commercial or other affiliation that might constitute a conflict of interest.
This study was a pilot exploration of safety, efficacy, problems, side effects, and ease of use, of chlorpromazine (CPZ) in the operating room for prevention of postoperative nausea and vomiting (PONV). It was conducted with a view to deciding about the wisdom of, and the design for, a larger dose-ranging study. A conservative dose of 10mg intravenously (IV) was chosen as likely to be safe. Subjects received CPZ or saline placebo intravenously before a standardised anesthetic regimen. PONV during the first 24 hours post-operatively was recorded as emetic episodes (episodes of vomiting or retching) and incidence of nausea.
CPZ, a phenothiazine drug, has a pharmacologic profile that suggests that it might be useful in prevention and treatment of postoperative nausea and vomiting (PONV).[ , ] Five neurotransmitter receptors are of primary importance in PONV: acetylcholine, dopamine-2, histamine-1, serotonin-3, and neurokinin-1. Of candidate drugs for PONV, CPZ is the only drug that has activity at the first four of these receptors.[ , ] It is inexpensive (US$1.80 for a 50mg ampoule).[ ] CPZ has been used extensively in cancer chemotherapy to prevent and treat nausea and vomiting.[ , ] The usual and recommended dose for this purpose is 25 or 50mg orally (PO).[ ] It is used by some anesthesiologists for PONV prophylaxis (personal communication), usually in the dose of 10 to 25mg IV.
Our study focussed on cardiac adverse effects because we felt that significant electrocardiogram (ECG) changes should prohibit further studies. Although the Chlorpromazine CPhA Monograph makes no specific mention of torsade de pointes, phenothiazines may prolong the QT interval.[ ] Recently it has been shown that risk of torsade de points is associated, not with QT prolongation
The ethical question of using placebo control was addressed by giving all subjects midazolam and by proscribing N2O to help prevent PONV.[ ]
The primary outcome hypothesis was that the incidence of PONV, defined as any report of nausea or vomiting during the first 24 hours after surgery, will be different between subjects given 10mg of CPZ IV and those given saline placebo IV at the onset of anesthesia for laparoscopic surgery. Secondary outcomes were severity of nausea (numerical rating score: NRS) in the Post Anesthesia Care Unit (PACU); length of stay in PACU (min); effects of study drug on QTc and Tp-e intervals; and any reported adverse effects.
Materials and Methods
and subjects' written informed consent, 120 adult patients requiring general anesthesia for elective laparoscopic abdominal procedures were studied prospectively in a randomized, double-blinded, placebo-controlled trial.
Postoperatively, the patients were accompanied to the PACU by investigators who reminded PACU nurses about the study in order to assure accurate charting of the occurrence and treatment of PONV. The incidence of PONV (defined as nausea, vomiting, or retching) and an 11-point (0 to 10) numerical rating scale (NRS) of worst nausea during the PACU stay was recorded at the end of the subjects' stay in the PACU. At this time the attending nurse was asked about any side effects, and specifically about excessive sedation and dysphoria. Inpatients were visited by investigators next day; outpatients telephoned, and PACU incidence and nausea NRS of worst nausea recorded. Additional episodes of PONV were identified by review of the medical chart. Emetic episodes were episodes of vomiting and episodes of retching. Narrative descriptions of any adverse effects were sought from anesthesiologists and PACU nurses.
Dimenhydrinate (25-50 mg IV) was given as rescue treatment for PONV as deemed needed by the nurse or requested by the patient. Additional treatment was ordered by the anesthesiologist when needed. Morphine (1-5 mg IV) was given for pain as needed or requested by the patients. Use of antiemetics on the ward was not recorded as part of the study because surgical nurses were in the habit of always giving dimenhydrinate with every dose of opiate.
Demographic data is presented in Table 1. Sixty subjects were recruited to each group. All but one subject, who had an unplanned admission to the intensive care unit (placebo group) completed the study until leaving PACU, with no protocol violations. One subject in the placebo group could not be contacted subsequently. She had no nausea or vomiting up to discharge from PACU and was analysed in the placebo group as intent-to-treat. Significantly more subjects smoked than expected: 40% of subjects smoked, compared to 20% of adult Canadians in 2004; P = 0.028.
It has long been stated that phenothiazines prolong the QTc interval, with no distinction made among different phenothiazines.[ , ] It was concerning therefore that CPZ might induce torsade de pointes, a potentially fatal arrhythmia. Our study shows no effect at the small dose of CPZ used, but how safe would it be to study larger doses? Other phenothiazines (promethazine, perphenazine and prochlorperazine) are recommended for PONV prophylaxis and treatment. [18 ] Is the risk of arrhythmias from CPZ and other phenothiazines different?
A literature search reveals only three case reports of torsade de pointes associated with CPZ, and seven reports of other ventricular arrhythmias.[ , ] Torsades occurred with chronic use of 100, 900, and 1600mg per day of CPZ given over more than a year. The three patients had low potassium, calcium, or both. On the one hand, torsade de pointes associated with CPZ is likely to be under-reported. On the other hand, CPZ has been used for more than fifty years by millions of psychiatric and oncology patients.[ ] Thus, if torsade de pointes occurs in significant numbers of CPZ users, more than three reports would be expected.
Further evidence that CPZ is unlike other phenothiazines with respect to risk of torsade de pointes emerges from two observational studies. First, in a study of patients with drug overdoses, 171 patients with CPZ overdose did not have QTc prolongation, while 65 patients with thioridazine overdose had prolongation, and had a correlation of QTc with dose.[ ] Second, a study of 495 psychiatric patients and 101 healthy reference individuals found that thioridazine, droperidol, and tricyclic antidepressants resulted in QTc prolongation, but CPZ did not.[ ] Thus, it seems reasonably safe to study CPZ for PONV prophylaxis in larger doses.
We are grateful for the assistance of Dr Kotoo Meguro in translating the Japanese article.