Intrathecal opioids are safe and highly effective for the management of pain after cesarean delivery. Unfortunately, their use is associated with a 30%–70% incidence of postoperative nausea and vomiting (PONV), which is partially dose-dependent (1,2). Because consensus guidelines suggest that prophylactic antiemetic medications are useful in moderate-to-high risk groups (3), for most anesthesiologists this incidence may justify the use of prophylactic antiemetic medication for the prevention of PONV in this setting.
A variety of pharmacological approaches, including droperidol, metoclopramide, cyclizine, ondansetron, and dexamethasone, have been reported to be effective for preventing these symptoms of PONV in patients undergoing cesarean delivery under spinal anesthesia (2,4–7). However, these drugs may produce undesirable adverse side effects, such as drowsiness, restlessness, dystonic reactions, and extrapyramidal signs. Transdermal scopolamine (TDS), which is highly effective in the management of motion sickness, was approved in 1997 by the Food and Drug Administration for the prevention of nausea and vomiting related to anesthesia. The patch contains 1.5 mg of scopolamine delivered at 5 μg/h for 72 h and provides sustained therapeutic concentrations of the drug and is compatible with breastfeeding (8). Kotelko et al. (9) reported a decreased incidence of PONV with the preoperative application of scopolamine in patients undergoing elective cesarean delivery under epidural anesthesia with the addition of epidural morphine for postoperative analgesia. However, despite this study, preoperative application of the TDS patch in the setting of cesarean delivery has not gained widespread clinical acceptance, perhaps because of perceived potential exposure to the fetus and concerns of potential side effects such as dry mouth and dizziness.
We thus chose to compare the prophylactic antiemetic efficacy of scopolamine and placebo, with the study drugs delivered after delivery of the fetus, during the first 24 h postoperatively in patients who had spinal morphine for postoperative analgesia after cesarean delivery, by observing the visual analog scale (VAS) for nausea, the incidence of vomiting and retching, and use of rescue antiemetics. We chose to include a group receiving IV ondansetron as well, as this was the drug of choice in our institution for those who administered prophylactic medication in this setting. We hypothesized that TDS would reduce emesis when compared with placebo, in the 24 h after cesarean delivery under spinal anesthesia including intrathecal morphine.
The Brigham and Women’s Hospital Committee for Protection of Human Subjects approved this protocol, and all subjects gave their written, informed consent before participation. Two-hundred forty healthy patients scheduled for elective cesarean delivery were entered into this study. All subjects were ASA I, free of major systemic disease and pregnancy complications, at term gestation (>38 wk), and not in labor. Subjects were excluded if they had a history of PONV or motion sickness, had taken antiemetic medication in the previous week, or had a history of hyperemesis gravidarum. Patients gave their consent in the preoperative holding area before anesthesia and surgery.
Subjects were randomized with the aid of a computer-generated scheme (four blocks of 60 subjects with 20 subjects in each group per block) to receive one of three treatments in a double-blind manner. Spinal anesthesia was performed in our standard fashion with 1.6 mL hyperbaric bupivacaine 0.75% (12 mg), fentanyl 10 μg, and preservative-free morphine, 0.2 mg. Cesarean delivery was then performed. After clamping of the umbilical cord, the randomly assigned antiemetic treatment was administered. Group S received an active scopolamine patch 1.5 mg released over 72 h (Novartis Consumer Health, NJ) behind one ear and an injection of 10 mL of IV normal saline. Group O received a placebo patch (identical in appearance to active patch) and 4 mg IV ondansetron diluted to 10 mL with normal saline. Group P received both a placebo patch and an injection of 10 mL of IV saline.
Hypotension during cesarean delivery, defined as systolic blood pressure <100 mm Hg or >20% below prespinal baseline was treated with boluses of ephedrine, 10 mg; if >3 doses of ephedrine were given, the anesthesiologist could substitute phenylephrine, 40– 80 μg boluses, for ephedrine. Emesis during the operation was treated with ondansetron 1 mg or metoclopramide 10 mg, at the discretion of the attending anesthesiologist. Pain during cesarean delivery was treated, at the anesthesiologist’s discretion, with IV fentanyl 50–100 μg. Oxytocin, 20 IU was added to the first liter of IV lactated Ringer’s solution after cord clamping. Rescue therapy in the postanesthesia care unit for nausea, vomiting, and retching was ondansetron 1 mg or metoclopramide 10 mg IV, at the discretion of the attending anesthesiologist. Pain was treated at patient request and was treated initially with ibuprofen 600 mg, followed by oxycodone 5 mg if necessary. Treatment for pruritus was with IV nalbuphine 5 mg. The treating anesthesiologist remained blinded to group allocation.
The primary outcome of this study was the incidence of all emesis in the 24 h after surgery. We defined vomiting as emesis with expulsion of gastric contents, retching as emesis without expulsion of gastric contents, and “all emesis” as vomiting, retching, or both. The incidence of nausea, vomiting, and retching intraoperatively was recorded as a dichotomous variable (yes/no). After the operative procedure, measurements were taken at three time points, each at the end of the observation period: 0–2 h, 2–6 h, and 6–24 h. A VAS measurement of nausea, pain, and pruritus was recorded on a 100-mm unlabeled scale. In addition, the incidence of vomiting and retching and use of rescue antiemetics, antipruritics, and analgesics were recorded for each time period. The overall incidence of antiemetic use and vomiting and retching for the entire study period (0–24 h postoperatively) was calculated for each group.
Patient demographics were compared among the groups by χ2 for discrete variables, and ANOVA for continuous variables. Apgar scores of the infants were compared among groups with the Kruskal–Wallis test. VAS scores were compared with ANOVA, with Fisher’s protected least significant difference for individual between-group comparisons. Discrete outcomes were compared with χ2, with Tukey adjustment for multiple comparisons (10). Number needed to treat (NNT) for antiemetics was calculated as the reciprocal of the absolute risk reduction. When exact P values or 95% confidence intervals (CIs) are not shown P < 0.05 was considered significant. The required sample size was estimated based on an assumption of 35% incidence of emesis in the control group. To demonstrate a reduction in incidence in either treatment group to 17% with a power of 80% and an α of 0.017 (0.05 corrected for multiple comparisons), we estimated 76 patients per group. Eighty subjects per group were enrolled to allow for possible protocol violations.
The subjects were similar with regard to baseline characteristics and risk for PONV, intraoperative management, and intraoperative symptoms of nausea and vomiting (Table 1). Intraoperative use of fentanyl did not differ among groups, nor did use of antiemetics (metoclopramide, ondansetron) or vasopressors (ephedrine, phenylephrine). Other adjunctive drugs, including anticholinergic drugs (atropine, n = 5, glycopyrrolate, n = 1), sedatives (midazolam, n = 5; ketamine, n = 2), and methylergonovine (n = 3), were used rarely and their use did not vary among groups. Fetal status at delivery (Apgar scores) did not differ among groups. Postoperative analgesic requirements did not differ among groups (Table 2). Rescue antiemetics were the same for all three groups: ondansetron was used more frequently (approximately 75%), but the frequency with which metoclopramide versus ondansetron was used did not differ among groups at any time point.
The VAS for nausea (at the 2–6 h time period) and the incidence of vomiting, and all emesis (at the 6–24 h time period) were reduced in subjects receiving scopolamine, compared with those receiving placebo (Figs. 1–3). The effect was most pronounced for vomiting and all emesis (Figs. 2 and 3) and was strongest in the 6–24 h time period. Retching did not differ among groups (Fig. 4). Excluding the 55 patients who received intraoperative antiemetics did not significantly change the results for retching, vomiting, or all emesis.
Overall rates of all emesis were 59.3% in the placebo group and were reduced by both drugs, to 40% in the scopolamine group and 41.8% in the ondansetron group (P = 0.025). The corresponding NNT was 5.2 (95% CI: 2.9–24.4) for scopolamine and 5.7 (95% CI: 3.1–44.8) for ondansetron.
Rescue antiemetics were used in 35%–45% of patients overall in the first 24 h. There was a trend toward less use in the scopolamine group at 2–6 h and 6–24 h (0.05 < P < 0.1).
Side effects did not lead to discontinuation of drug use in any subject. Dizziness varied significantly among groups, but the relative incidence was not consistent across time intervals (Table 3). Dry mouth was somewhat more common in the scopolamine group in the 6–24 h interval (9% in placebo group, 4% in ondansetron group, 19% in scopolamine group, P < 0.05 for scopolamine vs placebo) but not in the earlier time periods. Similarly, blurry vision was more common in the scopolamine group than placebo at 6–24 h (6% vs 0%, Fisher’s exact test, P = 0.03), though this difference did not persist after correction for multiple comparisons. Lethargy occurred in <10% of subjects at all time points and did not differ among groups (Table 3).
Overall, in this study in patients receiving spinal bupivacaine plus morphine 0.2 mg for cesarean delivery, we demonstrated that postoperative vomiting and all emesis in the 24 h after cesarean delivery was reduced by approximately 1/3, from nearly 60% in the placebo group to 40% with scopolamine (NNT = 5.2) and 42% with ondansetron (NNT = 5.7). Nausea was significantly reduced in subjects receiving scopolamine, compared to those receiving placebo or ondansetron in the 2–6 h time period. During the 6–24 h postoperative time interval, there was a significant reduction in the incidence of vomiting and all emesis in the scopolamine group when compared with the placebo group. There was a trend toward a reduction in the use of rescue antiemetics in the scopolamine group when compared with those receiving placebo at 2–6 h and 6–24 h (0.05 < P < 0.1).
The frequency of PONV is influenced by the surgical procedure, age, sex of patient, and medications administered, but the overall frequency, as defined by large-scale studies, has been estimated to be 20%–30% (11). In the present study we found that the total incidence of vomiting and retching was 59.3% in the placebo group, which is comparable to the results by Nortcliffe et al. (2) who reported the incidence of vomiting to be 60% in the placebo group of their study in patients receiving intrathecal morphine undergoing cesarean delivery. Conceivably, techniques such as reduced dose of intrathecal morphine might reduce this incidence even without prophylactic antiemetics, but we chose to study the effectiveness of scopolamine in the setting of the usual dose of analgesics used in our institution.
Our results demonstrated differences among study groups during two time intervals. In the 2–6 h time period, nausea VAS was reduced in the scopolamine group relative to placebo or ondansetron, and there was a trend toward a modest reduction of vomiting and all emesis during this time period (0.5 < P < 1.0). In the 6–24 h time period, the effect of scopolamine was stronger, and vomiting and all emesis were significantly reduced versus placebo, an effect not seen with ondansetron (Figs. 2 and 3). The difference between drug effects at different time periods may be related to both differences in drug pharmacokinetics and pharmacodynamics (i.e., differing effects on nausea and vomiting). Moreover, neuraxial morphine causes earlier nausea and later vomiting (12). It is thought that this results from the widespread dispersion of morphine throughout the subarachnoid and cerebrospinal fluid (12).
During the 0–2 h postoperative time interval, there were no differences in the VAS for nausea nor the incidence of vomiting, retching, or all emesis. These are similar findings to those of Kotelko et al. (9) who found no difference between groups in incidence of nausea or vomiting in the first 2 h postoperatively despite the preoperative application of the scopolamine patch. This is not unexpected, as it takes 3–4 h to achieve therapeutic blood levels after application of the TDS patch (13). However, ondansetron was also ineffective in this time period. This is unlike previous reports of the effectiveness of ondansetron in the early postoperative period in other types of surgery (14). However, the emetogenic stimuli in our population are perhaps different; postcesarean patients are more likely to have visceral and sympathetic stimulation as well as the emetogenic effect of intrathecal morphine as causative factors.
The cost to the hospital per TDS patch is $6 when compared with $12 for 4 mg of ondansetron. However, a single TDS patch lasts for up to 72 h. The cost-effectiveness of various antiemetics is a determinant of their popularity. Although prophylactic ondansetron has been shown to decrease the incidence of intrathecal and epidural-induced PONV after cesarean delivery (6,7), treatment of PONV with ondansetron has been shown to be more cost-effective than prevention, even in a moderate-to-high risk setting (15). We suggest that TDS’s low cost and long duration of action make it an attractive drug.
Given the time required for initial transdermal transfer of scopolamine, there is negligible potential for fetal exposure if administered preoperatively; almost a decade ago, Kotelko et al. did report an overall decreased incidence of PONV, when applied before surgery (9). Despite this study, scopolamine use in the setting of cesarean delivery has not gained widespread clinical acceptance, perhaps because of the perceived requirement of applying the patch preoperatively, and therefore the potential exposure to the baby. We therefore chose not to administer the study drugs until after delivery of the baby to overcome this concern. Our results show that scopolamine is nonetheless as effective as conventional drugs when used in this way.
The limitations of our study include, first, the fact that our patients were not asked to keep a diary of episodes of vomiting. Instead we simply interviewed patients at the end of each of the three time intervals, possibly creating recall bias. Second, we did not measure overall satisfaction scores at the end of the study period. This may have been of interest becasue the incidence of side effects such as dry mouth and blurry vision were more common in the scopolamine group at 6–24 h and may have offset the antiemetic benefit. However, it should be recognized that our analysis might have overestimated the clinical significance of various adverse effects because these were evaluated by presence or absence and not by severity. Third, some may criticize the use of ondansetron as one of the rescue antiemetic drugs in the study. Ondansetron was chosen for rescue treatment because ondansetron and metoclopramide are standard drugs for rescue treatment in our institution. Nonetheless, the use of two different classes of antiemetics in the scopolamine group versus a single class in the ondansetron or placebo groups could make the scopolamine group perform better.
In conclusion, in this randomized, double-blind, placebo-controlled, clinical trial, we found that the overall rates for all emesis were reduced by one-third by TDS or ondansetron. However, in the 6–24 h time period, scopolamine use was associated with an increased incidence of side effects such as blurry vision and dry mouth. Scopolamine is an effective drug for use in this setting, even when administered after cord clamping.
1. Dahl JB, Jeppesen IS, Jorgensen H, Wetterslev J, Moiniche S. Intraoperative and postoperative analgesic efficacy and adverse effects of intrathecal opioids in patients undergoing cesarean section with spinal anesthesia. Anesthesiology 1999;91:1919–27
2. Nortcliffe SA, Shah J, Buggy DJ. Prevention of postoperative nausea and vomiting after spinal morphine for caesarean section: comparison of cyclizine, dexamethasone and placebo. Br J Anaesth 2003;90:665–70
3. Gan TJ, Meyer T, Apfel CC, Chung F, Davis PJ, Eubanks S, Kovac A, Philip BK, Sessler DI, Temo J, Tramer MR, Watcha M. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 2003;97:62–71
4. Santos A, Datta S. Prophylactic use of droperidol for control of nausea and vomiting during spinal anesthesia for cesarean section. Anesth Analg 1984;63:85–7
5. Lussos SA, Bader AM, Thornhill ML, Datta S. The antiemetic efficacy and safety of prophylactic metoclopramide for elective cesarean delivery during spinal anesthesia. Reg Anesth 1992;17: 126–30
6. Yazigi A, Chalhoub V, Madi-Jebara S, Haddad F, Hayek G. Prophylactic ondansetron is effective in the treatment of nausea and vomiting but not on pruritus after cesarean delivery with intrathecal sufentanil-morphine. J Clin Anesth 2002;14:183–6
7. Pan PH, Moore CH. Comparing the efficacy of prophylactic metoclopramide, ondansetron, and placebo in cesarean section patients given epidural anesthesia. J Clin Anesth 2001;13:430–5
8. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50
9. Kotelko DM, Rottman RL, Wright WC. Transferal scopolamine decreases nausea and vomiting following cesarean section in patients receiving epidural morphine. Anesthesiology 1989;71: 675–8
10. Zar J. Biostatistical analysis. 4th ed. Englewood Cliffs, NJ: Prentice Hall, 1999:564
11. Lerman J. Surgical and patient factors involved in postoperative nausea and vomiting. Br J Anaesth 1992;69:S24–32
12. Bromage PR, Camporesi EM, Durant PA, Nielsen CH. Nonrespiratory side effects of epidural morphine. Anesth Analg 1982;61:490–5
13. Clissold SP, Heel RC. Transferal hyoscine (Scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 1985;29:189–207
14. Hartsell T, Long D, Kirtsch JR. The efficacy of postoperative ondansetron (Zofran) orally disintegrating tablets for preventing nausea and vomiting after acoustic neuroma surgery. Anesth Analg 2005;101:1492–6
© 2007 International Anesthesia Research Society
15. Tramer MR, Phillips C, Reynolds DJ, McQuay HJ, Moore RA. Cost-effectiveness of ondansetron for postoperative nausea and vomiting. Anaesthesia 1999;54:226–34