vs ondansetron (Zofran). A randomized, prospective trial in patients undergoing laparoscopic cholecystectomy. S. N~ Kothari, W. C. Boyd, M. L. Bottcher, P. J. ...
Surg Endosc (2000) 14:926-929 DOI: l 0.1007/s004640080055
Surgical Endoscopy Ultrasound and Interventional Techniques 9 Springer-VerlagNew York [no. 2fKh3
Antiemetic efficacy of prophylactic dimenhydrinate (Dramamine) vs ondansetron (Zofran) A
randomized, prospective trial in patients undergoing laparoscopic cholecystectomy
S. N~ Kothari, W. C. Boyd, M. L. Bottcher, P. J.
Lambert
Departments of S~gery and Anesthesiology,Gundersen Lutheran. 1836 South Avenue,La Crosse, Wl 54601, USA Received: 1 March 20001Accepted: et April 2000/Online publication:29 August 2000
Abstract Background: The prophylactic administration of dimenhydrinate (Dramamine) is as effective as the use of ondansetron (Zofran) in preventing postoperative nausea and vomiting (PONV) in patients undergoing elective laparoscopic cholecystectomy. A prospective double-blind randomized study was performed in a tertiary care referral center. Methods:For this study, 128 American Society of Anesthesiology (ASA) physical statuses I, II, and III patients were randomly assigned to receive either ondansetron 4 mg intravenously (IV) at $17 per dose (group 1) or dimenhydrinate 50 mg IV at $2.50 per dose (group 2) before induction of anesthesia. The end points evaluated were frequency of PONV, need for rescue antiemetics, need for overnight hospitalization secondary to persistent nausea and vomiting, and frequency PONV 24 h after discharge. Results: Chi-square tests and student's t-test were used to determine the significance of differences among groups. Of the 128 patients enrolled in this study, 20 were excluded: 15 patients received an additional antiemetic preoperative; 4 were converted to open cholecystectomies; and 1 procedure was aborted due to carcinomatosis. Of the 108 remaining participants, 50 received ondansetron (group 1) and 58 received dimenhydrinate (group 2). Both groups were well matched for demographics including gender, A S A class, and history of motion sickness. The need for rescue antiemetics occurred in 34% of group 1 and 29% of Group 2 (t7 = 0.376), postoperative vomiting in 6% of group 1 and 12% of group 2 (p = 0.228), and postoperative nausea in 42% of group t and 34% of group 2 (p = 0.422). One group i patient and two group 2 patients required overnight hospitalization for persistent nausea, a difference that was not significant. Rates of PONV 24 h after discharge were similar between groups 1 and 2 (i0% vs 14%, p = 0.397 and 2% vs 5%, p = 0.375, respectively).
Corre~77otutence to: W. C. Boyd
Conclusions: Prophylactic administration of dimenhydrinate is as effective as the use of ondansetron in preventing PONV in patients undergoing elective laparoscopic cholecystectomy. Dimenhydrinate is the preferred drug because it is tess expensive. With more than 500,000 laparoscopic cholecystectomies performed in the United States each year, the potential drug cost savings from the prophylactic administration of dimenhydrinate instead of ondansetron exceed $7.25 million per year.
Key w o r d s : Prophylactic dimenhydrinate - - Dramamine - - Ondansetron - - Zofran
More than 500,000 laparoscopic cholecystectomies are performed in the United States each year [12]. Postoperative nausea and vomiting (PONV) are among the most common symptoms occurring after laparoscopic surgery, and the symptom of persistent nausea and vomiting is one of the most common reasons lbr hospital admission after same day surgical procedures [4]. In an attempt to address these problems, attention has turned to the administration of antiemetic drugs before surgery to prevent PONV and decrease admission rates. A varied spectrum of drugs has emerged to prevent PONV. However, many of these drugs are associated with side effects including sedation, dry mouth, dysphoria, and extrapyramidal reactions [18]. Ondansetron (Zofran), a 5-hydroxytryptomine type 3 (5 HT3) receptor antagonist with a minimal side effect profile h a s emerged as an effective, but costly, antiemetic in the prevention of PONV after laparoscopic procedures [8, 9, i I, 15]. Recently, we had exceptional anecdotal success with dimenhydrinate (Dramamine), an antihistamine, as a rescue drug in alleviating PONV after laparoscopic cholecystectomy. Because dimenhydrinate is significantly less expensive, offering potential for significant cost savings, we decided to compare dimenhydrinate to ondansetron. We hypothesized
927 that the p r o p h y l a c t i c a d m i n i s t r a t i o n o f d i m e n h y d r i n a t e is as e f f e c t i v e as the use o f o n d a n s e t r o n in p r e v e n t i n g P O N V in patients u n d e r g o i n g elective l a p a r o s c o p i c c h o l e c y s t e c t o m y .
Table 1. Patient demographics
Patient characteristics
Methods After Institutional Review Board approval and intbrmed consent were obtained, 128 American Society of Anesthesiology (ASA) classes I and II patients and l0 ASA class HI patients undergoing elective laparoscopic chotecystectomy were enrolled in the study. Randomization was performed using a computer-generated randomized list. Patients were pretreated with either 4 mg of ondansetron IV at $17/dose or 50 mg of dimenhydrinate IV at $2.50/dose before the induction of anesthesia. All the patients were premedica~ed with 30 ml of sodium citrate and 2 m 3 mg IV of midazolam. Anesthetic induction was performed with propofo3 and maintained with sevoflurane after intubation. Before completion of the procedure, patients younger than 65 years of age received 30 mg IV of Toradol, and those older than 65 years received 15 rag. All the laparoscopic cholecystectomies were performed by general surgery residents under direct staff supervision. Nurses blinded to which antiemetic the patients had received recorded all episodes of nausea, vomiting, and retching in the recovery room by direct questioning, spontaneous complaint of the patient, or side effects. Patients were discharged after their surgery when they were able to tolerate liquids, void, and ambulate with minimal discomfort. Phone calls were then made to patients by nurses the day after discharge to assess any further nausea or vomiting. For the patients who experienced nausea, the severity of the nausea was rated on a scale of t (mild) to 5 (most severe). Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit. Retching was defined as labored, spasmotic, rhythmic contraction of the respiratory muscles, and vomiting was defined as the forceful expulsion of gastric contents from the mouth. The end points evaluated included the following: frequency of postoperative nausea, vomiting, and retching; need for rescue antiemetics because of persistent nausea or vomiting for 15 rain or more, with patients given their choice of antiemetic at the discretion of the anesthesiologist; a need for overnight hospitalization because of persistent nausea and vomiting; and frequency of nausea and vomiting 24 h al~er discharge. End-point data analysis was conducted using a chi-square test for the discrete variables. Follow-up evaluation used a nonparametric proportional analysis, in which ondansetron was the standard and dimenhydrinate was compared to that norm. Mann-Whitney analysis also was used for two independent groups across nonparametric variables. Continuous variables were analyzed using Student's t-test to determine whether any significant differences existed between the means of the two groups. A p value less than 0.05 was considered statistically significant.
Group 1 Ondansetron n = 50
Group 2 Dimenhydrinate n = 58
p
47.9 14136 22 24 4
49,7 t5/43 25 27 6
0.08 0.80 0.91 0.9t 0.91
12 65.1 165.8 87.5
13 61.1 165.7 85.1
0.84 0.53 0.194 0.79t
Age (years) Gender (M/F) ASA Class [ ASA Class II ASA Class III Prior episodes of motion sickness Duration of operation Height (cm) Weight (kg)
ASA, American Society of Anesthesiology
Table 2. Patient demographics Indications Biliary colic Gallbladder polyps Biliary dyskinesia Porcelain gallbladder Biliary colic and polyps Total
Group 1 Ondansetron
Group 2 Dimenhydrinate
Total
47 1 2 0
49 2 5 1 1 58
96 3 7 1 I 108
50
Table 3. Postoperative nausea
Need for rescue antiemetics Postoperative vomiting Postoperative nausea Postoperative retching
Group 1
Group 2
p value
34% 6% 42% 6%
29% 12% 34% 9%
.376 .228 .422 .604
Group 1, Ondansetron Group 2, Dimehydrinate
( p = 0.397). M e a n n a u s e a s c o r e s on the day after d i s c h a r g e
Results F r o m N o v e m b e r 1, 1998 to June l, 1999 128, c o n s e c u t i v e patients w e r e e n r o l l e d in the study. O f the 20 patients excluded, 15 had r e c e i v e d an additional a n t i e m e t i c p r e o p e r a tively 4 were c o n v e r t e d to o p e n c h o l e c y s t e c t o m y , a n d the case o f 1 was a b o r t e d b e c a u s e o f t h e i n t r a o p e r a t i v e f i n d i n g o f c a r c i n o m a t o s i s . O f the 108 r e m a i n i n g patients available for analysis, 50 w h o m w e r e r a n d o m i z e d to r e c e i v e o n d a n s e tron (group l) and 58 to r e c e i v e d i m e n h y d r i n a t e ( g r o u p 2). P a t i e n t d e m o g r a p h i c s w e r e similar in b o t h t r e a t m e n t g r o u p s (Tables 1 and 2). T h e n e e d for r e s c u e a n t i e m e t i c s o c c u r r e d in 3 4 % o f g r o u p 1 and 29% o f g r o u p 2 (p -= 0.376). P o s t o p e r a t i v e v o m i t i n g o c c u r r e d in 6 % o f g r o u p 1 and 12% o f g r o u p 2 (p = 0.228), p o s t o p e r a t i v e n a u s e a in 4 2 % o f g r o u p 1 a n d 3 4 % o f g r o u p 2 (p = 0.422), and p o s t o p e r a t i v e r e t c h i n g in 6 % o f g r o u p 1 and 9 % o f g r o u p 2 (p = 0.604) (Table 3). T h e m e a n p o s t o p e r a t i v e n a u s e a s c o r e s w e r e 2.33 for g r o u p 1 and 2.52 for g o u p 2 (p = 0.643). P o s t o p e r a t i v e n a u s e a 24 h after d i s c h a r g e o c c u r r e d in 10% o f g r o u p 1 ,and 14% o f g r o u p 2
w e r e 2.60 in g r o u p l and 1.75 in g r o u p 2 (p = 0.060). P o s t o p e r a t i v e v o m i t i n g 24 h after d i s c h a r g e o c c u r r e d in 2 % o f g r o u p 1 and 5% o f g r o u p 2 (p = 0.0375). M o r e total c o m p l a i n t s w e r e r e g i s t e r e d by g r o u p 2 patients (n = [4) than b y g r o u p I patients (n = 2) (p = 0.050) (Table 4). H o w e v e r , the various t y p e s o f c o m p l a i n t s w e r e too f e w in n u m b e r for any c o n c l u s i o n s to be d r a w n f r o m c h i - s q u a r e analysis. O n e p a t i e n t w h o r e c e i v e d o n d a n s e t r o n and two patients w h o r e c e i v e d d i m e n h y d r i n a t e r e q u i r e d o v e r n i g h t h o s p i t a l i z a t i o n for p e r s i s t e n t n a u s e a o r v o m i t i n g (Table 5).
Discussion P o s t o p e r a t i v e n a u s e a a n d v o m i t i n g r e m a i n s the n u m b e r o n e r e a s o n for hospitalization after s a m e day surgicaI p r o c e d u r e s [4]. T h e i n t r o d u c t i o n o f l a p a r o s c o p i c t e c h n i q u e s t b r c h o l e c y s t e c t o m y have m a d e it a s a m e day surgical p r o c e dure. L a p a r o s c o p y , h o w e v e r , is an e s t a b l i s h e d risk factor t b r P O N V . N a g u i b e t a l . [1 1] was the first to report the inci-
928 Table 4, Patient complaints Complaints
Headache Dizziness Drowsiness Total
Group 1 Ondansetron
Group 2 Dimenhydrinate
p
2 0 0 2
4 6 4 14
0.050
Table 5. Patient hospitalization Reason for Hospitalization
Group 1 Group 2 Ondansetron Dimenhydrinate p
Persistent nausea or vomiting l Urinary retention l Pain control 1 Observation of cardiac status Febrile Drain placement Need for ERCP Hypotension Total 3
2 1 5 3 1 1 2 1 16
0.861
ERCP, endoscopicretrogradecholangiopancreatography
dence of PONV (72%) in placebo-treated patients after laparoscopic cholecystectomy. The high incidence of PONV in patients undergoing taparoscopic procedures, most of which are outpatient procedures, can have a significant impact on both the patient and the provider. Patients with PONV may require additional time in the recovery room as well as additional nursing support, supplies, and medications. Although more difficult to quantify, indirect costs extend PONV after discharge, from lost wages because of missed work, to the debilitating impact on the patient [6]. As a result, attention has turned to the administration of antiemetics before laparoscopic procedures in an attempt to reduce the incidence of PONV. We chose to evaluate the effectiveness of dimenhydrinate, a low-priced antihistamine, against that of the much higher-priced ondansetron in preventing PONV after elective laparoscopic cholecystectomy. Ondansetron is a 5-hydroxytryptomine type 3 receptor antagonist with a half-life of approximately 4 h. Studies on the use of ondansetron, consisting mainly of women undergoing laparoscopic procedures, have shown a decrease in the incidence of postoperative emetic episodes from 54% to 25% (p < 0.001), and a decrease in the incidence of nausea from 71% to 58% (p < 0.00 l) [3]. Pearman [ 13] showed that ondansetron 4 mg IV given to women undergoing outpatient laparoscopic surgery reduced the incidence of emesis from 54% to 24% as compared with a placebo. Helmy [5] showed that the prophylactic administration of ondansetron 4 mg IV in patients undergoing laparoscopic cholecystectomy under total IV anesthesia reduced the incidence of vomiting from 47.5% to 7.5% over the 24-h study period. Naguib et al. [1 i] showed that ondansetron 4 mg IV administered before taparoscopic cholecystectomy reduced the incidence of PONV from 72% to 35% as compared with a placebo.
Dimenhydrinate (Dramamine) is an ethanolamine derivative antihistamine. Its pharmacologic effects are believed to be largely attributable to its diphenhydramine moiety. Although the exact antiemetic mechanism is unknown, dimenhydrinate's efficacy is thought to be related to its inhibition of vestibular stimulation and its ability to inhibit acetylcholine. The duration of action is 3 to 6 h [1]. Dimenhydrinate was studied extensively during the 1950s in an attempt to reduce PONV [2, 7, t0]. Since that time, there have been no modern blinded controlled randomized trials in the United States evaluating dimenhydrinate's effectiveness in preventing PONV in patients undergoing laparoscopic cholecystectomy. Consequently, we chose to evaluate the effectiveness of dimenhydrinate against that of ondansetron. We showed that patients receiving prophylactic ondanselxon had a postoperative nausea rate of 42%, as compared with 34% of patients treated with dimenhydrinate. The differences did not achieve statistical significance (p = 0.422). The incidence of postoperative vomiting also was similar between the two treatment groups, with a rate of 6% in the ondansetron group and 12% in the dimenhydrinate group. Rescue antiemetics were needed in 34% of those receiving ondansetron and 29% of those receiving dimenhydrinate. These differences did not reach statistical significance. Some studies suggest that the administration of ondansetron just before the completion of the procedure improves its efficacy [14, 16]. We chose to administer the ondansetron and dimenhydrinate "on call" to the operating room. This method more closely parallels the pharmacology and efficacy of the drugs when they are administered via an oral route preoperatively. A study evaluating the efficacy of oral ondansetron versus oral dimenhydrinate, which avoids the added nursing administration charge to the patient, needs to be performed. One theoretical drawback to the use of dimenhydrinate is the potential for the side effect of drowsiness and the increased time to arousal after general anesthesia. Ondansetron has been shown to have a side effect profile similar to that of a placebo with regard to its sedative effect [t3]. In our study, 4 of 58 (6.9%) patients receiving dimenhydrinate complained of drowsiness as compared with no patients receiving ondansetron. These nmnbers were too small for any significant conclusions to be drawn regarding differences in rates of postoperative drowsiness. Other studies have concluded that the use of dimenhydrinate is not associated with excessive drowsiness [17]. Ideally, an antiemetic should be effective and affordable, with no side effects. At our institution, ondansetron costs $17 per dose compared with $2.50 per dose for dimenhydrinate. The actual cost to the patient will vm2r from institution to institution. Our patient charge is $27.50 for a 4-rag IV dose of ondansetron and $12.73 for a 50-mg IV dose of dimenhydrinate. Besides this markup a nursing charge is added for the IV administration of the medication. Our data support the hypothesis that IV dimenhydrinate is as effective as IV ondansetron in preventing PONV in patients undergoing elective laparoscopic cholecystectomy. Because dimenhydrinate costs less, it is the preferred antiemetic. Ideally, the most aftbrdable route of delivery is oral, which eliminates the nursing administration charge to the
929 patient. Both ondansetron and dimenhydrinate are available in oral forms. Future studies are necessary to establish the efficacy o f oral dimenhydrinate c o m p a r e d with oral Ondansetron in preventing P O N V in patients undergoing elective laparoscopic cholecystectomy.
Conclusion The findings from this study confirm the hypothesis that the prophylactic administration o f dimenhydrinate 50 m g IV is as effective as ondansetron 4 m g IV in preventing P O N V in patients undergoing elective laparoscopic cholecystectomy. Dimenhydrinate is the preferred drug because it is less expensive. With more than 500,000 taparoscopic cholecystectomies performed in the United States each year, the potential cost savings from prophylactic administration o f dimenhydrinate instead o f ondansetron e x c e e d s $ 7 2 5 million per year. Acknowledgments. The authors thank Paul Havlik for statistical ,analysis and/ohanna Berg for assistance with manuscript preparation.
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