Intraoperative Antiemetic Efficacy of Prophylactic Ondansetron Versus Droperidol for Cesarean Section Patients Under Epidural Anesthesia

OBSTETRIC

ANESTHESIA

SECTION EDITOR

BETH GLOSTEN

lntraoperative Antiemetic Efficacy of Prophylactic Ondansetron Versus Droperidol for Cesarean Section Patients Under Epidural Anesthesia Peter H. Pan, Department

MD,

and Charles H. Moore, Pm

of Anesthesiology,

Medical

College

of Virginia,

The efficacy of ondansetron and droperidol were evaluated for prophylactic treatment of nausea and vomiting in cesarean section patients under epidural anesthesia. Forty-eight ASA physical status I-II parturients requiring nonemergent cesarean section gave their consent and were randomly assigned into one of three treatment groups (n = 16 each) according to a doubleblind, placebo-controlled protocol. When the fetal umbilical cord was clamped, patients received intravenously 8 mg of ondansetron or 0.625 mg of droperidol or saline depending on their treatment group. Ninetyfour percent of the ondansetron group, 88% of the droperidol group, and 56% of the placebo group were emesis free. Sixty-nine percent of the ondansetron group, 75% of the droperidol group, and 31% of the

N

ausea and vomiting occur frequently during cesarean section under regional anesthesia, especially when the uterus is exteriorized (1,2). These symptoms are distressing and uncomfortable for the patient and may interfere with the surgical procedure. Droperidol and metoclopramide have been reported to reduce the incidence of emetic symptoms in these patients (l-3). However, sedation, respiratory depression, delayed anxiety, extrapyramidal symptoms, acute dystonic reactions, and exaggerated stress-induced tachycardia have been reported as possible side effects associated with either droperidol or metoclopramide (2-10). Both animal experiments and studies in humans have shown ondansetron to be effective in preventing nausea and vomiting associated with chemotherapy, radiation therapy,

Presented in part as an abstract at the 1994 Annual Meeting of the American Society of Anesthesiologists, San Francisco, October 1994. Accepted for publication July 11, 1996. Address correspondence to Peter H. Pan, MD, Division of Obstetrical Anesthesiology, Department of Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 0695, Richmond, VA 23298-0695.

Virginia

Commonwealth

Anesth

Analg

1996;83:982-6

Richmond,

Virginia

placebo group were nausea free. This study showed a significantly lower incidence of nausea and vomiting and a tendency toward less severe emetic symptoms in the ondansetron and the droperidol groups than in the placebo group, but the ondansetron group was not statistically different from the droperidol group. This study is the first to report the antiemetic efficacy of prophylactic ondansetron in cesarean section patients or in patients under epidural anesthesia for abdominal surgery. Both prophylactic ondansetron and droperidol were similarly effective, and significantly better than placebo, in reducing the incidence and severity of intraoperative emetic symptoms in cesarean section patients under epidural anesthesia. (Anesth Analg 1996;83:982-6)

ambulatory surgery, gynecological surgery, and strabismus surgery (11-15). Ondansetron is a serotonin antagonist that selectively inhibits 5-HT, receptors and is devoid of dopamine, histamine, cholinergic, or adrenergic receptor activity. Serotonin receptors of the 5-HT, type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema (16,17), a site known to be associated with nausea and vomiting. It is possible that ondansetron may act at these sites to reduce emesis. Abdominal surgery and its associated physical disruption and manipulation of abdominal viscera may cause the release of humoral substances including 5-HT, which could stimulate 5-HT, receptors on the afferent vagus nerves, triggering the emetic reflex especially in awake patients. Efficacy of ondansetron as a treatment or prophylaxis has not been studied in term pregnant patients or in patients having abdominal surgery under regional anesthesia, such as in cesarean section. Therefore, we designed a randomized, double-blind, placebo-controlled clinical study to evaluate the intraoperative efficacy of prophylactic ondansetron and droperidol in preventing nausea and vomiting in cesarean section patients under epidural anesthesia. 01996

982

University,

by the International

Anesthesia

Research Society 0003.2999/96/$5.00

ANESTH ANALG 1996;83:982-6

Methods After approval from our institutional review board, 48 healthy ASA class I or II parturients scheduled to undergo nonemergent cesarean section gave informed consent to participate in the study. Nursing patients, patients with psychiatric diseases, or patients with a history of motion sickness were excluded from the study. Preanesthetic medication was limited to 30 mL of orally administered 0.3 M sodium citrate. Each patient received 25 mL/kg of lactated Ringer’s solution (up to a maximum of 2 L) prior to dosing of the epidural catheter for cesarean section. The epidural catheter was placed at the L2-3 or L3-4 level. Epidural dosing was administered in 5-mL increments of 2% lidocaine with 1:200,000 epinephrine plus 50 PLgof fentanyl to achieve a bilateral cephalad sensory T-4 dermatomal level. Oxygen, 2 L/min, via nasal cannula was given to patients. Bolus intravenous (IV) lactated Ringer’s solution and ephedrine in lo-mg increments were given if systolic blood pressure decreased more than 20% from baseline pressure or if systolic blood pressure was less than 90 mm Hg. Arterial blood pressure was measured by an automated cuff blood pressure monitor every l-3 min. Aortocaval compression was avoided by keeping the patient in a left tilt position. Standard monitors included electrocardiogram, automated blood pressure, nasal end-tidal CO,, respiratory rate, pulse oximetry, mental status, and level of sensory and motor blockade. Immediately after clamping of the umbilical cord, each patient received one of the three study drugs IV over 2 min according to a computer-generated, randomized assignment in a double-blind fashion. Group I patients received 8 mg of ondansetron (Glaxo, Research Triangle Park, NC) freshly prepared by the pharmacy. Group II patients received 0.625 mg of droperidol (American Regent Laboratories, Shirley, NY), and Group III patients received normal saline. All three study solutions were diluted to a lo-mL volume with normal saline. After administration of the study solution, patients in all three groups also received an additional 50 pg of epidural fentanyl and additional 2% lidocaine with epinephrine, if needed. Patients in all three groups were allowed to receive up to 100 pg of fentanyl intravenously, if needed, after the delivery of the fetus. Postoperative analgesia was started after arrival in the recovery room with epidural patient-controlled analgesia with fentanyl. Each patient was questioned during the surgery every 5 min while in the operating room until 15 min after arrival in the recovery room. Parturients were specifically asked by the anesthesiologist whether they had emetic symptoms, nausea, or vomiting. The same anesthesiologist, who was unaware of the type of study solution the patient

PROPHYLACTIC

Table

OBSTETRIC ANESTHESIA PAN AND MOORE ONDANSETRON FOR CESAREAN SECTION

1. Maternal

Age (yr) Weight (kg) Height (cm) Multiparous Parity (median) Parity (range) Gestational age

983

Characteristics Ondansetron (Group I)

Droperidol (Group II)

30 ? 6 87 -c 16 164 t 6 12/16 1 o-3 39 + 2

27 2 6 85 k 14 162 ? 7 12/16 1 o-3 39 2 2

Placebo (Group III) 27 5 82 -c 161 2 11/16 1 o-2 39 f

8 19 7

2

(wk) Data are rounded off to nearest whole number as appropriate. Data are expressed as mean k SD expect for parity, which is expressed as median and range, and multiparous, which is expressed as number over sample size. There were no statistical differences among the three groups.

received, rated the severity of each episode of nausea and vomiting based on a four-point scale (0 = no symptoms, 1 = mild, 2 = moderate, and 3 = severe). The incidence and the number of nausea and vomiting episodes during the study period were recorded. To determine the severity of nausea or vomiting, a cumulative nausea or vomiting score was calculated for each patient. The cumulative nausea or vomiting score is defined as the sum of the nausea or vomiting scores of all episodes of nausea or vomiting, respectively, for each patient (e.g., if a patient has three episodes of vomiting, with vomiting scores of 3, 1, and 2, the cumulative vomiting score for this patient is equal to 3 + 1 + 2 = 6). The cumulative score is further normalized for the duration of surgery to give a normalized cumulative score per unit hour of surgery. Statistical analysis consisted of unpaired t-test, 2, Fisher exact test, and analysis of variance as appropriate. P < 0.05 was considered significant.

Results There were a total of 48 patients, with 16 patients in each of the three groups. The three groups were similar with regard to maternal characteristics (Table 1) and operative management (Table 2). All patients had an adequate level of surgical anesthesia (T-5 to T-3 sensory level) before incision. The number of emetic and nausea episodes were the @mar-y efficacy variable in the study. As shown in Table 3, ondansetrontreated and droperidol-treated patients experienced significantly fewer emetic and nausea episodes than saline-treated patients. One patient (6.3%) in the ondansetron group, two patients (12.5%) in the droperido1 group, and seven patients (43.8%) in the saline placebo group experienced vomiting (P < 0.02 ondansetron or droperidol group versus saline group). The frequency distribution of nausea and vomiting episodes in the ondansetron-treated group was similar to that in the droperidol-treated group. Among those

984

OBSTETRIC ANESTHESIA PAN AND MOORE PROPHYLACTIC ONDANSETRON FOR CESAREAN

Table

2. Operative

ANESTH ANALG 1996;83:982-6

SECTION

Management Ondansetron (Group I)

Droperidol (Group II)

Placebo (saline) (Group III)

62 + 18 50% 19% 15/16 19 + 6 19 + 10 146 + 76 14 + 13 69%

58 2 24 56% 19% 15/16 17+ 7 15 + 7 142 + 102 12 + 13 50%

56 2 16 38% 13% 15/16 17? 9 14 ? 5 146 f 83 11?9 63%

Operative time (min) History of previous cesarean section Tubal ligation performed Uterus exteriorized Uterus exteriorize time (min) I-D interval (mix-r) U-D interval (s) Total ephedrine (mg) Surgery done between 7 AM and noon

I-D interval = interval from skin incision to delivery of fetus; U-D interval = interval from uterine incision to delivery of fetus. Data are rounded off to nearest whole number as appropriate. Data are expressed as mean t SD except for cesarean section, tubal ligation, which are percentages, and uterus exteriorized, which is shown as number over sample size. There were no &tistical differences among the three groups.

Table 3. Distribution of the Number Postdelivery Emetic Episodes

Ondansetron (Group I) (n = 16) Number of nausea episodes 0 1 2 3 or more Number of vomiting episodes 0 1 2 3 or more * P < 0.02 t P < 0.02 There was the droperidol

of Intraoperative

Droperidol (Group II) (n = 16)

Placebo (saline control) (Group III)

(n = 16)

12 4 0 0

(75%Y+ (25%) (0%) (0%)

5 2 7 2

(31%) (13%) (44%) (13%)

15 (94%)t 1(6%) 0 (0%) 0 (0%)

14 2 0 0

(88%)-t (13%) (0%) (0%)

9 5 2 0

(56%) (31%) (13%) (0%)

the ondansetron

done,

Discussion

11 (69%)” 4 (25%) 1(6%) 0 (0%)

vs control placebo group. vs control placebo group. no significant difference between group.

and surgery

group

and

who had nausea or vomiting episodes, the normalized cumulative nausea scores (median with range in parentheses) were 1.9 (0.9-3.1), 2.0 (l.l-2.2), and 5.2 (1.6-8.9) for the ondansetron, droperidol, and placebo groups, respectively; the normalized cumulative vomiting scores were 1.6 for the one patient who vomited in the ondansetron group, 1.9 and 2.2 for the two patients who vomited in the droperidol group, and a median of 4.4 with a range of 0.8-6.7 for the seven patients who vomited in the placebo group. The mean amount of ephedrine used was similar among the three groups. There were no observed instances of acute extrapyramidal reactions, excessive drowsiness, or clinically significant respiratory depression in any of the study patients. One patient in the ondansetron group complained of mild transient headache lasting for less than 10 min.

Intraoperative emetic symptoms during abdominal surgery under regional anesthesia are troublesome and may interfere with the procedure. Emetic symptoms have a complex and multifactorial etiology, and can be influenced by factors such as hormonal changes, gender, age, pain, hypotension, surgical procedure, and weight. An antiemetic therapy effective for one group of surgical patients may not be effective for a different group of patients undergoing a different surgical procedure or anesthetic technique. In this study, we focused on intraoperative postdelivery antiemetic efficacy of prophylactic ondansetron and droperidol in cesarean section patients under regional anesthesia. We excluded nursing parturients and administered the antiemetic drug after clamping of the umbilical cord because the effects of ondansetron and droperidol on fetuses and neonates are unknown. We also ensured that the three groups were comparable in demographics and surgical and anesthetic variables. Maternal hypotension and its associated brainstem hypoxemia (18-20) were aggressively prevented and/or treated with generous prehydration, nasal oxygen, left uterine displacement, and, if necessary, IV ephedrine together with rapid fluid infusion. Without previous published data on ondansetron for cesarean section patients, we consider ondansetron and small-dose droperidol to be clinically and practically useful only if they are at least as effective as other commonly available antiemetic drugs. Droperidol and metoclopramide reduce the emetic symptoms in cesarean section patients from 70%-80% in placebo groups to 14%-46% in treated groups (1,2,4). To show similar drug efficacy in our study, a sample size of 16 per group achieves a power of 0.8 with alpha set at a significant level of 0.05 and beta at 4 times alpha. Our small sample size does not allow us to differentiate small differences between the droperidol and ondansetron groups, but it does establish the intraoperative antiemetic efficacy of ondansetron and small-dose

ANESTH ANALG 1996;83:982-6

droperidol. This study is different from previous ondansetron studies in that the patients were awake while undergoing abdominal surgery when the surgical manipulation of viscera is most intense and most likely to trigger emetic symptoms. We chose 8 mg as our study dose because 1) we anticipated the risk of emetic symptoms to be high; 2) early efficacy studies of ondansetron were done using 8 mg; and 3) we wanted to eliminate the doubt of underdosing of ondansetron, since previous data were not available in this group of patients and our sample size was not large. Several studies (21,22) have demonstrated that ondansetron 4 mg is as effective as 8 mg, but it is used for treating or preventing postoperative emetic symptoms and not intraoperative. Pearman (21) also suggested that 8 mg may have more benefit than 4 mg in females with a high risk of emetic symptoms. With 8 mg ondansetron, one patient in our study complained of mild transient headache lasting 10 minutes shortly after administration of ondansetron. Ondansetron is well tolerated without significant side effects. The most commonly reported side effects are mild headache and constipation with larger doses of ondansetron (23). We did not notice any side effects or excessive sedation with the droperidol group, probably because we used a smaller dose in our study compared with previous reports of associated side effects (1,4,5,24). The incidence of intraoperative postdelivery emetic symptoms in our placebo group is slightly more frequent when compared with previous similar studies (l-3). This is in part due to our active questioning of patients’ emetic symptoms and severity, not interfering with the surgical manipulation (such as not asking the obstetricians to decrease traction on the uterus), not using prophylactic ephedrine, having a higher rate of uterine exteriorization, and using a less dense epidural block than the spinal anesthetic used in previous studies. This study is the first to report that IV ondansetron 8 mg is effective in reducing the incidence and severity of intraoperative emetic symptoms in awake cesarean section patients under epidural anesthesia. We have also shown that small-dose droperidol was equally effective without any untoward side effects, but other authors had reported side effects associated with the use of larger doses of droperidol. Ondansetron would appear to be a promising drug for this group of patients for prevention of emetic symptoms and is devoid of many of the side effects that can be associated with dopamine antagonists. Ondansetron has been compared with established antiemetics in patients undergoing chemotherapy or general anesthesia, but not intraoperatively in patients under regional anesthesia for abdominal surgery. In one study, patients undergoing general anesthesia for dilation and curettage were randomized to receive IV either ondansetron

PROPHYLACTIC

OBSTETRIC ANESTHESIA PAN AND MOORE ONDANSETRON FOR CESAREAN SECTION

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8 mg, droperidol 1.25 mg, or metoclopramide 10 mg. Ondansetron is more effective in prevention of vomiting but not more effective in prevention of nausea episodes (25). Since small-dose droperidol and ondansetron are similarly effective with minimal side effects in this study, one may choose droperidol over ondansetron based on cost. Our hospital costs are $19.76 and $39.52 for 4 mg and 8 mg of IV ondansetron, respectively, and $0.38 for droperidol up to 2.5 mg. However, the cost to the patients in our hospital is $57.22 for ondansetron up to 10 mg IV and $15.73 for droperidol up to 2.5 mg. We did not study the efficacy of oral ondansetron, but our hospital cost for a 4-mg and 8-mg ondansetron tablet is $8.63 and $14.39, respectively; the patient cost is $13.26 and $19.25, respectively. In this study, we focused on establishing the intraoperative efficacy of ondansetron. The incidence and the need for treatment of postoperative and postpartum emetic symptoms were not studied in detail here. Time spent in the recovery room was similar among the three groups. In the recovery room period, one patient in the placebo group, one patient in the droperidol group, and no patients in the ondansetron group reported emetic symptoms, but none required any treatment for the symptoms. Pearman (21) and Claybon (22) showed that single-dose IV ondansetron 4 mg or 8 mg given prior to general anesthesia induction was effective in preventing emetic symptoms for the first 24 postoperative hours. If the antiemetic effect of ondansetron continues through the immediate postoperative period and the early postpartum period, then the cost-effectiveness calculation would be different. In conclusion, we have shown that ondansetron 8 mg and droperidol 0.625 mg given IV after cord clamping were equally effective and superior to placebo in reducing the incidence and severity of intraoperative, postdelivery emetic symptoms in patients undergoing cesarean section with epidural anesthesia.

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16. Hawthorn J, Ostler KJ, Andrews PLR. The role of the abdominal visceral innervation and 5-hydroxytryptamine M-receptor in vomiting induced by the cytotoxic drugs cyclophosphamide and cis-platin in the ferret. Q J Exp Physiol 1988;73:7-21. 17. Kilpatrick GJ, Jones BJ, Tyers MB. The distribution of specific binding of the 5-HT, receptor ligand [3H]GR65630 in rat brain using quantitative autoradiography. Neurosci Lett 1988;94: 156-60. 18. Datta S, Alper MH, Ostheimer GW, Weiss JB. Method of ephedrine administration and nausea and hypotension during spinal anesthesia for cesarean section. Anesthesiology 1982;56:68-70. 19. Kang YG, Abouleish E, Caritis S. Prophylactic intravenous ephedrine infusion during spinal anesthesia for cesarean section. Anesth Analg 1982;61:839-42. 20. Ratra CK, Badola RI’, Bhargava KP. A study of factors concerned in emesis during spinal anesthesia. Br J Anaesth 1972; 44:1208-11. 21. Pearman MH. Single dose intravenous ondansetron in prevention of postoperative nausea and vomiting. Anaesthesia 1994; 49(Suppl):ll-5. 22. Claybon L. Single dose intravenous ondansetron for the 24-hour treatment of postoperative nausea and vomiting. Anaesthesia 1994;49(Suppl):24-9. 23. Castle WM, Jukes AJ, Griffiths CJ, et al. Safety of ondansetron. Eur J Anaesthesiol 1992;9(Suppl 6):63-6. 24. Melnick BM. Extrapyramidal reactions to low dose droperidol. Anesthesiology 1988;69:424-6. 25. Alon E, Himmelseher S. Ondansetron in the treatment of postoperative vomiting: a randomized, double-blind comparison with droperidol and metoclopramide. Anesth Analg 1992;75: 561-5.