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From the Department of Anaesthesiology, University of Ulm, Germany, D-89070 Ulm, Germany.
Address correspondence to: Dr. Leopold Eberhart. Phone: ++49-731-502-7931; Fax: ++49-731-502-7917; E-mail: leopold.eberhart{at}medizin.uni-ulm.de
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Abstract |
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Methods: One hundred and sixty male inpatients undergoing endonasal surgery were randomized to receive one of four antiemetic regimens in a double-blind manner: placebo, 1 mg•kg–1 dimenhydrinate, 0.3 mg•kg–1 metoclopramide, or the combination of both drugs was administered after induction of anesthesia. Patients received a second dose of these drugs six hours after the first administration to mitigate their short half-life. Standardized general anesthesia included benzodiazepine premedication, propofol, desflurane in N2O/O2 vecuronium, and a continuous infusion of remifentanil. Postoperative analgesia and antiemetic rescue medication were standardized. Episodes of vomiting, retching, nausea, and the need for additional antiemetics were recorded for 24 hr. The incidences of PONV were analyzed with Fisher's Exact test and the severity of PONV (rated by a standardized scoring algorithm) with the Jonckheere-Terpestra-test.
Results: The incidence of patients free from PONV was 62.5% in the placebo-group and increased to 72.5% in the metoclopramide-group (P = 0.54), 75.0% in the dimenhydrinate-group (P = 0.34), and 85.0% in the combination-group (P = 0.025). In the latter group, the severity of PONV was reduced compared with placebo treatment (P = 0.017; Jonckheere-Terpestra-test).
Conclusion: Dimenhydrinate and metoclopramide were ineffective in reducing the incidence and the severity of PONV. Their combination reduced the incidence of PONV compared with placebo.
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Introduction |
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Both drugs are used routinely although data describing the efficacy of dimenhydrinate is virtually nonexistent for adults1,2 or inconsistent.3,4 However, when asked about useful combinations of different antiemetics, the combination of dimenhydrinate and metoclopramide was mentioned frequently by anesthesiologists participating in a German survey attributing personal concerns of PONV.5 However, this combination has only been proven for chemotherapy associated vomiting.6,7
Thus, the aim of this randomized, double blind, placebo-controlled trial was to evaluate the antiemetic efficacy of a metoclopramide-dimenhydrinate combination vs both drugs alone.
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: 0.05; ß: 0.2) when the incidence of PONV in the placebo-group is 40% (this incidence was assumed from previous studies). Thus, a total of 160 ASA 1-2 men undergoing endonasal surgery (e.g. septoplasty, rhinoplasty, and septorhinoplasty) were enrolled into the study. According to a computer generated randomization plan, they were chosen to receive one of four treatments in a double-blind manner. The following drugs were administered intravenously immediately after induction of anesthesia: 1.Placebo group:saline
2.Metoclopramide-group:0.3 mg•kg–1 metoclopramide
3.Dimenhydrinate-group:1 mg•kg–1 dimenhydrinate
4.Combination-group:1 mg•kg–1 dimenhydrinate + 0.3 mg•kg–1 metoclopramide
Six hours after the first administration of the study medication, a second dose of the same drug was administered intravenously. Metoclopramide and dimenhydrinate can be diluted together in 100 ml saline. This mixture is chemically and physically stable for at least 24 hr (results of a gas chromatographic analysis [unpublished observation]).
The day before surgery, patients were interviewed for risk factors that might contribute to PONV (e.g. previous PONV, susceptibility to motion sickness, smoking habits). Patients receiving antiemetics, or suffering from nausea or vomiting in the two weeks before surgery, or those with known allergy against any of the drugs used were excluded from the study.
All patients fasted starting at 10:00 p.m., the night before surgery and received premedication with oral dipotassium clorazepate in the evening and in the morning before surgery.
General anesthesia was standardized: after insertion of the iv canula, a continuous infusion of remifentanil, 10-20 g.•kg–1•hr–1, was established. Propofol, 2 mg•kg–1, was used for induction of anesthesia. Tracheal intubation was facilitated with 0.1 mg•kg–1 vecuronium. Anesthesia was maintained using desflurane in end-expiratory concentrations of 2-3%. The lungs were ventilated with N2O/O2 using a fresh gas flow of 1 l•min–1. Intraoperatively, remifentanil infusion was adjusted to keep mean arterial blood pressure within a range of 60-75 mmHg. Before surgery, local anesthesia with mepivacaine combined with adrenaline as a vasoconstrictor to minimize intraoperative bleeding was applied by the surgeon. Postoperatively the nasal passages were packed. No throat pack or gastric tube was used. Since no neuromuscular blocker was repeated intraoperatively, no reversal agents were used at the end of surgery.
Postoperative analgesia was achieved with 100 mg diclofenac pr or, when contraindicated, with 1 g metamizole iv. Additionally, 0.05-0.1 mg•kg–1 piritramide iv was given on demand.
In the recovery room, the patients were monitored for the occurrence of nausea and emetic episodes (retching or vomiting). The patients were visited on the ward 2, 5, 8, and 24 hr after surgery by two of the authors (LE & BU). Both the patients and the nursing staff were asked whether an emetic episode had occurred. Patients rated nausea using a four-point scale (none-mild-moderate-severe).
Droperidol, 0.5-1 mg, was administered when the patient suffered moderate or severe nausea or had two or more emetic episodes within two hours. This was followed by 12.5 mg dolasetron when droperidol was ineffective.
Statistical analysis
The main outcome variable of this study was the number of men free from nausea and vomiting (= "no PONV"). This was defined as absence of any emetic episode and no nausea throughout the postoperative observation period. Significance was calculated with the 2-test with the Fisher-Yates' correction. Fisher's Exact test was used for post-hoc analysis.
According to Korttila,8 an additional analysis of the severity of PONV was performed. For this purpose, the severity of PONV during the 24 hr observation interval was categorized into four degrees using the following standardized scoring algorithm that has been used in similar trials:2
"no PONV": Absence of any emetic episode and nausea (as defined above).
"mild PONV": 1) the patient had only mild nausea. 2) one emetic episode or short lasting nausea of any severity (<10 min) occurred, but was triggered by an exogenous stimulus, e.g. drinking, eating, or postoperative movement. After this event, nausea was diminished and the patient felt well again throughout the entire observation period. No antiemetic drug was necessary.
"moderate PONV": 1) the patient had 1-2 emetic episodes or moderate or severe nausea without exogenous stimulus. 2) the patient required antiemetic therapy once.
"severe PONV": The patient had more than two emetic episodes or was nauseated more than twice (moderate or severe). The administration of at least one antiemetic was necessary.
The results of this categorization (a 4x9;4 contingency table, see Table III
) were analyzed using the procedure described by Jonckheere.9 This test is very similar to the non-parametric Kruskal-Wallis-test but is optimized to detect trends within the data with ordered categories. The asymptotic version of the test was calculated by a recursive procedure performed with the StatXact statistical package (CYTEL Software Corporation, Cambridge, MA 02139, USA). All other analyses were performed with StatView 4.5 (Abacus Concepts, Inc. Berkeley, CA 94704, USA). For all tests, a level of = 0.05 was considered statistically significant.
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) and anesthetic and surgical parameters (Table II) showed no difference among the groups. There were also no differences among the groups concerning risk factors for PONV.
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). This could be proven by calculating the table of ordered severity of PONV using the procedure of Jonckheere.9 The P-value for the two-tailed asymptotic test was P = 0.017 for placebo-group vs the combination-group. The reduction of the severity of PONV induced by metoclopramide or dimenhydrinate alone was not statistically significant (metoclopramide vs placebo: P = 0.27; dimenhydrinate vs placebo: P = 0.12). The incidences of side effects were the same in all four groups. Dry mouth (placebo: n=8 ; metoclopramide: n=7 ; dimenhydrinate n=10 ; combination: n=9) and headache (placebo: n=5; metoclopramide: n=3 ; dimenhydrinate n=5 ; combination: n=5) were most frequent. No other relevant side effects were observed.
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Discussion |
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Many studies have been performed using metoclopramide as an antiemetic. Rowbotham10 reviewed several of these and concluded that there is a trend towards increased effectiveness when higher doses of the drug are used (e.g. 20 mg instead of 10 mg). However, metoclopramide showed less effectiveness than droperidol and 5-HT3- receptor antagonists.11–13 In several other studies, metoclopramide was found to be ineffective in preventing PONV.14 This was attributed to the short duration of effect of the drug.10,14 Thus, we decided to give a second dose of both drugs six hours after the first administration since the plasma half life of both drugs, metoclopramide and dimenhydrinate, is similar (about 4-6 hr15,16).
However, when analyzing our data retrospectively, we found that patients in the placebo group very rarely developed PONV eight or more hours postoperatively. Thus, it can be speculated whether the second administration of the antiemetic was necessary. Instead of repeating the drugs it would have been more appropriate and less complicated to administer the drugs at the end of surgery than during induction of anesthesia.
Since there were no exclusion criteria with regard to the patients' proneness to develop PONV, the likelihood to suffer from PONV without antiemetic prophylaxis was calculated using a risk score for prediction of PONV.17 Applying a logistic regression analysis to six main risk factors developed this score. In short these are gender, age, smoking habits, history of motion sickness and previous PONV, and duration of surgery. For each patient the individual risk for suffering from PONV was calculated. The results suggest that patients in all four groups had the same baseline risk (without antiemetic prophylaxis) of developing PONV (Table I). A homogenous group of male patients was studied to avoid interference with differences regarding the hormonal status and menstrual cycle in females.
Endonasal surgery is associated with a high incidence of PONV, which is reported between 34% and 65%.18,19 To improve the efficacy of antiemetic prophylaxis, a combination of antiemetic drugs has been suggested since there are at least four major receptor systems involved in the etiology of PONV.10 The combination of metoclopramide and dimenhydrinate is promising. On the one hand, anticholinergic action of the H1-antihistaminic dimenhydrinate can attenuate extrapyramidal side effects induced by antidopaminergic drugs.3,20 On the other hand, the prokinetic properties of metoclopramide can reduce gastroparesis that might be induced by anticholinergic effects of dimenhydrinate.
The incidence of PONV in male inpatients undergoing endonasal surgery under propofol-desflurane-remifentanil anesthesia receiving placebo treatment was about 38% in the present study. Among these, more than 50% suffered from severe PONV (several emetic episodes and the need for antiemetic rescue medication). This incidence of PONV could be reduced to 27.5% and 25% with prophylactic administration of metoclopramide or dimenhydrinate, respectively. However, this reduction was not statistically significant. Only the combination of both antiemetics reduced the incidence and the severity of PONV to a clinically acceptable level (15%).
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Accepted for publication May 6, 2000.
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2 Eberhart LHJ, Seeling W, Bopp TI, Morin AM, Georgieff M. Dimenhydrinate for prevention of post-operative nausea and vomiting in female in-patients. Eur J Anaesthesiol 1999; 16: 284–9.[Medline]
3 Vener DF, Carr AS, Sikich N, Bissonnette B, Lerman J. Dimenhydrinate decreases vomiting after strabismus surgery in children. Anesth Analg 1996; 82: 728–31.[Abstract]
4 Hamid SK, Selby IR, Sikich N, Lerman J. Vomiting after adenotonsillectomy in children: a comparison of ondansetron, dimenhydrinate, and placebo. Anesth Analg 1998; 86: 496–500.[Abstract]
5 Eberhart LHJ, Morin AM, Felbinger TW, Falkner Y, Georgieff M, Seeling W. Results of a survey concerning postoperative nausea and vomiting. (German) AINS 1998; 33: 545–51.
6
Grunberg SM, Ehler E, McDermed JE, Akerley WL. Oral metoclopramide with or without diphenhydramine: potential for prevention of late nausea and vomiting induced by cisplatin. J Natl Cancer Inst 1988; 80: 864–8.
7 Chang T-C, Hsieh F, Lai C-H, et al. Comparison of the efficacy of tropisetron versus a metoclopramide cocktail based on the intensity of cisplatin-induced emesis. Cancer Chemother Pharmacol 1996; 37: 279–85.[Medline]
8 Korttila K. The study of postoperative nausea and vomiting. Br J Anaesth 1992; 69(Suppl1): 20–3.
9 Jonckheere AR. A distribution-free k-sample test against ordered alternatives. Biometrica 1954; 41: 133–45.
10 Rowbotham DJ. Current management of postoperative nausea and vomiting. Br J Anaesth 1992; 69(Suppl1): 46–59.
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Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Prevention of PONV with granisetron, droperidol or metoclopramide in patients with postoperative emesis. Can J Anaesth 1998; 45: 153–6.
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Fujii Y, Toyooka H, Tanaka H. Prevention of PONV with granisetron, droperidol and metoclopramide in female patients with history of motion sickness. Can J Anaesth 1997; 44: 820–4.
13
Naguib M, El Bakry AK, Khoshim MHB, et al. Prophylactic antiemetic therapy with ondansetron, tropisetron, granisetron and metoclopramide in patients undergoing laparoscopic cholecystectomy: a randomized, double-blind comparison with placebo. Can J Anaesth 1996; 43: 226–31.
14 Dundee JW, Clarke RSJ. The premedicant and anti-emetic action of metoclopramide. Postgrad Med J 1973; 48(Suppl 4): 34–7.
15 Harrington RA, Hamilton CW, Brogden RN, Linkewich JA, Romankiewicz JA, Heel RC. Metoclopramide. An updated review of its pharmacological properties and clinical use. Drugs 1983; 25: 451–94.[Medline]
16 Blyden GT, Greenblatt DJ, Scavone JM, Shader RI. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol 1986; 26: 529–33.[Abstract]
17 Apfel CC, Greim CA, Haubitz I, et al. A risk score to predict the probability of postoperative vomiting in adults. Acta Anaesthesiol Scand 1998; 42: 495–501.[Medline]
18 Elhakim M. A comparison of intravenous ketoprofen with pethidine for postoperative pain relief following nasal surgery. Acta Anaesthesiol Scand 1991; 35: 279–82.[Medline]
19 van den Berg AA. The prophylactic antiemetic efficacy of prochlorperazine and ondansetron in nasal septal surgery: a randomized double-blind comparison. Anaesth Intensive Care 1996; 24: 538–45.[Medline]
20
Schreibman DL. Treatment of a delayed reaction to droperidol with diphenhydramine (Letter). Anesth Analg 1990; 71: 105.
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difference between placebo and dimenhydrinate; 
difference between placebo and combination.