Post-operative nausea and vomiting prevention with perphenazine: long overdue

Abstract

Editor, With great interest, we read Schnabel et al.1 who presented a quantitative systematic review addressing perphenazine and the prevention of post-operative nausea and vomiting (PONV). Our group began using intravenous perphenazine in 1997; we were forced to switch to oral perphenazine in 2002, as an injectable form was no longer available in the United States. We would like to complement their report with relevant citations that may be valuable, despite our outcomes having occurred outside of typical reports involving randomised trials.2 When we first reported (after knee surgery) routine bypass of the post-anaesthesia care unit (PACU bypass) in 2000,3 and in follow-up knee surgery studies,4–6 perphenazine (2 mg intravenously) and dexamethasone (4 mg intravenously) were the recommended anti-emetics in our clinical pathway. In a separate analysis of n = 449 shoulder surgery out-patients from our institution (94% of whom bypassed PACU), perphenazine–dexamethasone prophylaxis (versus 1 or fewer anti-emetics) was associated with a 50% reduction in the need for in-hospital PONV rescue and faster discharge time to home.7 In our experiences with oral perphenazine (8 mg before surgery), combined with intravenous ondansetron (4 mg) and intravenous dexamethasone (4 mg) during surgery, we reported a 4% PONV incidence after out-patient anterior cruciate ligament construction (n = 233) under spinal anaesthesia.8 In a separate retrospective population study at our institution, orthopaedic patients received the same doses of dexamethasone–ondansetron with (n = 6605) or without (n = 2853) pre-operative oral perphenazine (8 mg). The need for ondansetron rescue in patients not receiving perphenazine was 18%, but only 13% in patients who received perphenazine.9 This 27% reduction matches the classical study by Apfel et al.10 with respect to the anticipated 25% risk reduction achieved with droperidol administration; we are not aware of perphenazine being non-efficacious in men as Apfel et al.10 reported droperidol to be. When perphenazine doses were not repeated, we never encountered an adverse event to our knowledge. This was true, specifically when the intravenous dose was less than or equal to 2 mg, or when the single pre-operative oral dose did not exceed 8 mg. Our criteria for dosing 8 mg orally before surgery includes ages 14–70, patient weight no less than 45 kg, no history of extra-pyramidal reactions to medications (e.g. prochlorperazine), no history of Parkinson's disease, no history of cerebral palsy and no class III anti-dysrhythmic being co-administered for co-existing disease. For patients less than 14 years old, and/or less than 45 kg, we commonly use a 4 mg oral dose (assuming the patient is old enough to swallow pills without chewing). Any low-rate occurrences of extra-pyramidal symptoms after perphenazine dosing (i.e. outside of these guidelines) were immediately treated with diphenhydramine. Our hospital pharmacy archives did not indicate that any of our patients were prescribed benztropin treatment for extra-pyramidal symptoms after any perphenazine dosing for PONV prophylaxis on the day of surgery.9 Finally, owing to the non-sedating characteristics of single-dose perphenazine (when compared with such agents as droperidol, dimenhydrinate, promethazine, prochlorperazine and trans-dermal scopolamine), it should be acknowledged that PACU bypass has not been a traditional end point in most anti-emetic outcome studies, especially those involving multi-modal anti-emetic prophylaxis. Incorporating PACU bypass as a hospital-centred cost–benefit outcome forces all previous PONV-related recommendations to be re-evaluated. The 2007 Society for Ambulatory Anesthesia Consensus Guidelines for PONV11 do not acknowledge PACU bypass as an end point, and calibrated its cost-effectiveness recommendations based on the acquisition costs of still patent-protected ondansetron. In fact, the accompanying editorial by Glass and White12 plainly declared ‘given the high efficacy, low cost, and excellent safety profiles of the most commonly used anti-emetic drugs (e.g., droperidol, dexamethasone, and ondansetron), in our view these drugs should be routinely administered for anti-emetic prophylaxis of all patients receiving general anaesthesia irrespective of their risk classification.’ Following the logic of Glass and White, our reported clinical experience, and now the quantitative systematic review of Schnabel et al.,1 there is little justification not to routinely administer perphenazine, dexamethasone and ondansetron to all patients receiving anaesthesia irrespective of baseline PONV risk (given the aforementioned cautions/exceptions). All future studies of PONV should be required to consider PACU bypass as a secondary outcome in cost-effectiveness analysis, owing to the renaissance of a non-sedating anti-dopaminergic anti-emetic, that being perphenazine.