Anesth Analg 2004;98:1660-1664
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000117288.76432.7F
AMBULATORY ANESTHESIA
Paul F. White Section Editor
Prophylaxis of Postoperative Nausea and Vomiting with Oral, Long-Acting Dimenhydrinate in Gynecologic Outpatient Laparoscopy
Kim E. Turner, MD*,
Joel L. Parlow, MD*,
Nicole D. Avery, MSc*,
Deborah A. Tod, RN*, and
Andrew G. Day, MSc
*Department of Anesthesiology and
Clinical Research Unit, Queen’s University, Kingston, Ontario, Canada
Address correspondence and reprint requests to Kim E. Turner, MD, Department of Anesthesiology, Kingston General Hospital, 76 Stuart St., Kingston, Ontario, Canada, K7L 2S6. Address e-mail to ket1{at}post.queensu.ca
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Abstract
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Dimenhydrinate is an inexpensive antiemetic with few side effects available as an oral, long-acting (LA) formulation (Gravol L/A) containing 25 mg of immediate and 50 mg of sustained release drug. We designed this double-blind comparison trial to assess the efficacy of dimenhydrinate LA versus droperidol alone and the combination for prophylaxis of nausea, vomiting, and retching in outpatient gynecologic laparoscopy. One-hundred-forty-one women were randomized into 3 groups: 1) droperidol (placebo capsule preoperatively and IV droperidol 0.625 mg before induction), 2) dimenhydrinate LA preoperatively and IV placebo before induction, or 3) combination. Information regarding nausea, vomiting, retching, pain, and sedation was recorded in the postanesthesia care unit (PACU) and collected by telephone for the presence of symptoms: on arrival home; at bedtime; upon arising, and at lunchtime the following day. The overall incidence of complete treatment failure (rescue medication in PACU or nausea, vomiting, or retching at any time point) was 28 of 46 (61%), 28 of 48 (58%), and 22 of 47 (47%); and for treatment failure vomiting (rescue medication in PACU or vomiting or retching at any time point) was 16 of 46 (35%), 11 of 48 (23%), and 5 of 47 (11%), for the droperidol, dimenhydrinate, and combination groups, respectively (P = 0.007 for droperidol versus combination). There were no differences in sedation or pain. Preoperative administration of an oral dose of LA dimenhydrinate in combination with droperidol when compared with droperidol alone effectively reduced the incidence of vomiting but not nausea in women undergoing elective outpatient gynecologic laparoscopy.
IMPLICATIONS: Dimenhydrinate is an inexpensive antiemetic with few side effects available as a long-acting oral formulation. Women undergoing outpatient gynecologic laparoscopy were given droperidol, an effective antiemetic, dimenhydrinate alone, or the combination of the two drugs. Dimenhydrinate plus droperidol significantly reduced the overall incidence of vomiting, but not nausea, when compared with droperidol alone.
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Introduction
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Dimenhydrinate is an antiemetic available as an inexpensive oral long-acting (LA) formulation containing 25 mg of immediate and 50 mg of sustained release drug (Gravol L/A; Carter-Horner Inc., Mississauga, Ontario, Canada). Therapeutic serum concentrations of this LA oral formulation are achieved in fasting volunteers within <2 h and maintained for just over 9 h.1 The cost is $0.21/capsule (pharmacy acquisition cost, Canadian dollars at time of writing).
Outpatient gynecologic laparoscopy is associated with a high risk of postoperative nausea and vomiting (PONV), particularly after discharge from hospital. Dimenhydrinate’s original antiemetic effect was recognized in patients with motion sickness (1) which may make its use desirable in patients traveling home after surgery. Droperidol is an effective antiemetic (2) that was used in our institution at the time the study was commenced. We hypothesized that a single oral dose of LA dimenhydrinate alone or in combination with droperidol would reduce complete treatment failure (CTF) and in particular treatment failure for vomiting (TFV), when compared with droperidol alone, in patients undergoing outpatient gynecologic laparoscopy.
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Methods
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After Research Ethics Board approval and written informed consent, women scheduled for elective outpatient gynecologic laparoscopic surgery at Kingston General Hospital were randomized using a computer-generated randomization table, in a stratified manner, according to presence or absence of history of PONV. Eligible patients were randomized to receive: 1) droperidol (placebo capsule preoperatively and IV droperidol [Sabex, Inc., Boucherville, Quebec, Canada] 0.625 mg before induction), 2) dimenhydrinate (GLA [Gravol L/A; Carter-Horner Inc.] capsule preoperatively and IV placebo before induction, or 3) combination (GLA capsule preoperatively and IV droperidol 0.625 mg before induction). Patients were ineligible if they were: pregnant; intolerant or allergic to any of the drugs used in the study protocol; had underlying gastrointestinal disease requiring active treatment; known history of vomiting or use of antiemetic drugs in the last 24 h; body mass index >35; concurrent use of antihistamines, phenothiazines or drugs with known antiemetic effect; inability to ingest oral medication with a sip (approximately 30 mL) of water.
Oral study medication was administered with 30 mL of water 1 h before the anticipated procedure time and IV study medication was given before induction. All study drug packages were prepared in pharmacy to contain active GLA capsules or an identical placebo and a preloaded syringe containing IV droperidol 0.625 mg or an identical syringe of saline. Patients, study and hospital personnel were blinded to the medication received.
All patients received a general anesthetic with endotracheal intubation and ventilation. Anesthesia was induced with propofol 1.5–2.5 mg/kg, intubation was facilitated with succinylcholine 1.0–1.5 mg/kg or rocuronium 0.6 mg/kg, and anesthesia was maintained with nitrous oxide 70%, isoflurane <1%, and fentanyl 25-µg increments to a maximum of 3 µg/kg. Patients received 10 mL/kg NaCl or Ringer’s lactate solution (crystalloid) on IV insertion to replace existing fluid deficit and an additional 2 mL · kg–1 · h–1 maintenance and 3 mL of crystalloid/mL blood loss if required. Neuromuscular blockade was reversed as deemed appropriate by the attending anesthesiologist with neostigmine 2.5 mg IV and glycopyrrolate 0.4 mg or atropine 1.2 mg IV. All patients received indomethacin 100 mg and acetaminophen 1300 mg rectally before surgical start. Patients received ondansetron as a rescue antiemetic in the postanesthetic care unit (PACU) if requested or if deemed necessary by PACU staff.
Demographic information was collected upon patient enrollment, including age, weight, height, history of PONV or motion sickness, and duration of trip home. Information recorded by nurses in the PACU included use of rescue medication, vomiting in PACU (retching was defined as a vomiting episode), and patients’ self-report of their average pain (none, mild, moderate, severe), nausea or upset stomach (none, mild, moderate, severe), and sedation or drowsiness (wide awake, slightly drowsy, dozing frequently, and mainly sleeping). All patients were given a take-home patient diary to complete, for which they had received instructions upon enrollment into the study. Patients were informed about the availability of rescue medication for nausea, vomiting, or retching in the PACU. Patients were asked to record the time at which they arrived home. Patients were instructed to record episodes of vomiting or retching, and their perception of their average pain, nausea or upset stomach, and sedation or drowsiness using the same descriptors as used in the PACU. These variables were recorded on arrival home, at bedtime, the following morning, and at lunch time the following day when participation in the study was considered over. Patients were also asked whether they were able to return to their normal daily activities (yes fully, somewhat, or not at all) at the end of the study period and, if not, what had limited their activities (pain, nausea, drowsiness). Trained study personnel collected all information recorded in the patient diaries via telephone interview.
The primary outcome of our study was CTF defined as the administration of rescue medication in PACU or nausea, vomiting, or retching at any time point during the study. The secondary outcome was TFV defined as the administration of rescue medication in PACU or vomiting or retching at any time point during the study. Based on previously published data (3), we estimated that the incidence of CTF in the droperidol alone group would be approximately 35%. We considered an absolute risk reduction of 25% (from 35% to 10%) with dimenhydrinate, either alone or in combination with droperidol, to be of clinical importance. A sample size of approximately 40 subjects per group was estimated to provide approximately 80% power to detect such a difference using a 2-sided test at 
= 0.05. A larger number of patients were randomized to each group to allow for possible incomplete data collection or protocol violations. Continuous data were analyzed using analysis of variance and Fisher’s exact test was used to compare proportions across groups and P < 0.05 was considered statistically significant. The analysis was performed in SAS version 8.2 (SAS Institute, Cary, NC) and SPSS 9.0 (SPSS Inc., Chicago, IL).
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Results
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There were no significant differences among the three groups with respect to demographics, type of surgery, or anesthetic medications (Table 1), except that body mass index was significantly greater in the combination group (P < 0.05). There were no significant differences in reported pain or sedation among groups. One patient in the droperidol group, four in the dimenhydrinate group, and three in the combination group received rescue medication in the PACU; this difference was not statistically different. All patients who received rescue medication were analyzed as treatment failures.
There was no statistical difference in severity of nausea among groups. Nausea and vomiting were therefore dichotomized into presence or absence for the final analysis. The primary outcome of CTF was not significantly different among the three treatment groups (Table 2). The secondary outcome of TFV was significantly less in the combination group versus droperidol (P = 0.007). The TFV in patients receiving dimenhydrinate LA alone was less than with droperidol (35% versus 25%) but was not statistically significant. All patients who vomited or retched except one in each treatment group also reported nausea. The CTF and TFV are shown as cumulative incidence over time in Figures 1 and 2 .
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Figure 1. Cumulative incidence complete treatment failure (CTF). CTF = administration of rescue medication in the postanesthesia care unit (PACU) or nausea, vomiting, or retching. Values are % ± SE.
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Figure 2. Cumulative incidence treatment failure for vomiting (TFV). TFV = administration of rescue medication in the postanesthesia care unit (PACU) or vomiting or retching. Values are % ± SE.
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Few patients were able to return fully to their normal activities at the conclusion of the study period (droperidol 9%, dimenhydrinate 7%, and combination 2%). Many patients reported that they were "not at all" able to return to their normal activities (droperidol 37%, dimenhydrinate 33%, and combination 33%). The most frequently reported factor was pain (droperidol 35%, dimenhydrinate 32%, and combination 34%). No patient reported nausea as the sole limiting factor. The majority of patients would choose the same anesthetic for future surgeries (droperidol 87%, dimenhydrinate 92%, and combination 94%).
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Discussion
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This study demonstrates that a single oral dose of LA dimenhydrinate in combination with droperidol, when compared with droperidol alone, will significantly improve the TFV in patients undergoing outpatient gynecologic laparoscopy, with no difference in sedation. The patients receiving oral LA dimenhydrinate alone or in combination with droperidol did not have a statistically significant improvement in CTF versus droperidol alone.
We did not use a placebo-only arm in our study because a prestudy survey of our department found that our departmental standard of practice was to administer prophylactic antiemetics to women undergoing outpatient gynecologic laparoscopy. At the time this study was done, most of our department used small-dose (<0.625 mg) droperidol in this patient group. Accordingly, based on our departmental beliefs and those expressed in the literature (4), a decision was made that all participants should receive active drug. Droperidol is effective for PONV (3), with few side effects when used in small doses (5). Since this time, droperidol has received a "black box warning" because of concerns regarding cardiovascular toxicity and deaths (6). This study was not designed to demonstrate equivalence of treatments which would have required a much larger sample size. We were not able to demonstrate a statistical difference between dimenhydrinate LA and droperidol alone or in combination for CTF, however we cannot state with certainty that the treatments are equivalent.
Dimenhydrinate is an ethanolamine first-generation H1-antagonist that is a combination of diphenhydramine and 8-chlortheophylline in equal proportions. It is a reversible, competitive H1-antagonist with antimuscarinic activity. It is possible that the anticholinergic properties of H1-antagonists are responsible for the effect on motion sickness. The most frequent side effect is sedation. The mechanism of the H1-blocking activity, antimuscarinic effects, and antiemetic action of H1-blocking drugs is uncertain (7). The effectiveness of dimenhydrinate as an antiemetic was first recognized in 1947 (1) and its perioperative use was described in 1949 (8). The use of dimenhydrinate was studied perioperatively in the 1950s (9–11) with generally favorable results for vomiting.
In more recent years, Eberhart et al. (12) found that in patients undergoing nasal surgery the combination of IV administered dimenhydrinate and droperidol reduced the incidence of PONV, whereas droperidol alone reduced the severity of PONV and dimenhydrinate alone was ineffective. Kothari et al. (13) found that IV dimenhydrinate compared favorably to IV ondansetron in preventing PONV in a trial of patients undergoing laparoscopic cholecystectomy. The same authors suggested a savings of $7.25 million per year in the United States might be realized if dimenhydrinate were to be used instead of ondansetron. Kranke et al. ’s meta-analysis (14), examining dimenhydrinate for prophylaxis of PONV, revealed a reduction in the incidence of both PONV and emesis which was statistically significant, and a reduction in postoperative nausea which did not achieve statistical significance. The studies included in Kranke et al.’s meta-analysis, unlike this study, compared dimenhydrinate with placebo and did not use the oral route of administration.
The overall incidence of treatment failure in this study was very frequent. This is likely a consequence of the selected high-risk group (gynecologic outpatient laparoscopy), the anesthetic technique which included opioids as well as neuromuscular relaxants with subsequent reversal (15), following patients after discharge (16), and accepting occurrence of nausea, vomiting, or retching at any time point as a treatment failure.
The combination of dimenhydrinate and droperidol was more effective in decreasing TFV than CTF. This separation of antiemetic and antinausea effect has also been reported for ondansetron (greater antiemetic effect) and droperidol (greater antinausea effect) (17). In an editorial, Hefferman and Rowbotham (18) recognized the different sites of action of antiemetics, and using the analogy of balanced analgesia, endorsed the concept of combination of drugs with different sites of action for balanced antiemetic therapy. Combination antiemetic therapy alone may not be sufficient to eliminate PONV as is suggested by the striking success of Scuderi et al. (19) using a multimodal management algorithm in outpatient gynecologic laparoscopy.
In conclusion, the combination of a single oral dose of LA dimenhydrinate with droperidol significantly reduced the total TFV, with no differences in sedation when compared with droperidol alone. No difference was found between droperidol and oral LA dimenhydrinate alone or in combination in the incidence of CTF. Dimenhydrinate is an inexpensive antiemetic with few side effects that requires further evaluation to determine its place in future antiemetic regimens.
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Footnotes
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1 Gravol Long Acting, information provided from Carter-Horner Inc. 
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References
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Accepted for publication January 2, 2004.
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Abstract
Introduction
