Intraoperative nausea and vomiting (IONV) during cesarean delivery (CD) under regional anesthesia remains a challenge in clinical practice. These events are not only distressing and uncomfortable for the patient, but also interfere with the surgical procedure. The etiologies of IONV during CD, most of which are unique to this surgical procedure, include hypotension, vagal hyperactivity, systemic opioids, uterotonic drugs, surgical stimuli, and motion (1). Ideally, strict control of these etiological factors by appropriate anesthetic and surgical techniques should be the goal to prevent any IONV during CD. However, in clinical practice, some IONV remains due to lack of standardization and some deficiencies in our techniques. Different studies have shown beneficial effects of prophylactic antiemetics in this setting; however, the frequent incidence of IONV in their control groups suggests inadequate control of the multiple causative factors (1). Moreover, the majority of such studies focus on postoperative, rather than intraoperative, prevention of nausea and vomiting. Thus the optimal therapeutic strategy for preventing IONV during CD remains controversial.
In recent years, with the introduction of 5-hydroxy-tryptamine3 (5HT3, serotonin3)-receptor antagonists, the management of nausea and vomiting has improved greatly, especially in the settings of chemotherapy-induced, radiation-induced, and postoperative nausea and vomiting (PONV) (2,3). Granisetron is a potent 5HT3 receptor antagonist with minimal adverse effects when compared with other antiemetics.
We hypothesized that prophylactic granisetron, administered after cord clamping, would be effective in reducing the incidence of postdelivery IONV during CD under standardized anesthetic conditions.
After obtaining approval from the Research Ethics Board at Mount Sinai Hospital, a randomized, double-blind, placebo-controlled clinical trial was performed during the period May 2, 2005 to November 21, 2005. The study was conducted in 176 nonlaboring women undergoing elective CD under spinal anesthesia. A written informed consent was obtained from the patients before enrollment in the study.
Inclusion criteria were patients with ASA Physical Status I and II with full term, singleton pregnancies. Exclusion criteria included patients with allergy or hypersensitivity to granisetron, fentanyl or morphine; history of nausea or vomiting within 24 h before CD; history of gastrointestinal or psychiatric disease, motion sickness, smoking, PONV; morbid obesity; and consumption of drugs such as opioids, antiemetics, H2 antagonists, phenothiazines and/or corticosteroids within 24 h before the study period.
In the preadmission unit, baseline arterial blood pressure (BP) and heart rate were recorded as the mean of three readings, taken 1 min apart using an automated noninvasive BP device. Sodium citrate 0.3 M, 30 mL was administered orally, 10–15 min before the administration of anesthesia. After administration of 10 mL/kg of lactated Ringer’s solution, spinal anesthesia was administered using a 27-gauge Whitacre spinal needle at the L3–L4 interspace with the patient in the sitting position. Anesthetic solution containing 0.75% hyperbaric bupivacaine 15 mg (12 mg if height <152.4 cm) mixed with preservative-free fentanyl 10 μg and morphine 100 μg, was injected over 60 s to achieve a bilateral sensory blockade up to the T4 dermatomal level. The patient was then positioned supine, with left uterine displacement using a wedge under the right hip. Supplemental oxygen was administered at the rate of 4 L/min via nasal prongs until the delivery of the infant. Standard monitoring included electrocardiography, noninvasive BP, and pulse oximetry.
The patients were randomized via a computer-generated list into one of the two study groups. Patients in the granisetron group received 1 mg granisetron, and those in the control group received 1 mL normal saline. The study solution was prepared by a research assistant not participating in the study. Each patient received one of the two previously prepared study solutions of 1 mL volume IV over 30 s, immediately after delivery of the infant and clamping of the umbilical cord. The attending anesthesiologist, the patient and the obstetrician were blinded to the study drug.
BP measurements were recorded every minute until the end of surgery. Systolic BP was maintained strictly at or above baseline values with aliquots of phenylephrine 0.1 mg IV throughout the surgery. Hypotension was defined as a decrease in systolic BP below 80% of baseline despite the use of prophylactic vasopressors.
Oxytocin 0.5 IU was administered IV after delivery of the infant, followed by a maintenance infusion of 40 mU/min. Cefazoline 1 g (diluted in 10 mL normal saline) and ketorolac 30 mg were also given IV. The technique of uterine repair (either exteriorized or in situ) and its duration were recorded.
Patients were instructed, before the administration of anesthesia, to report the presence of nausea at any time during the surgery. The patients were not asked directly about nausea during the course of the surgery, but its incidence was recorded when spontaneously reported. Vomiting was recorded as observed by the investigator. The primary outcome was the presence of postdelivery IONV. If the patient had persistent nausea or an episode of vomiting, an unblinded rescue antiemetic, dimenhydrinate 50 mg, was administered IV. The secondary outcomes were severity of nausea, requirement for rescue antiemetic, intraoperative hypotension, pain and adverse effects. The severity of nausea was assessed shortly after its reporting by the patient, and rated by a verbal rating scale of 1–10 (1 = least nausea and 10 = worse nausea).
Based on the results of a randomized control trial performed at our institution, we considered the incidence of IONV as 38% in the control group (4). Assuming 50% reduction in the incidence of IONV with prophylactic granisetron, α error level or confidence level at 5%, and β error level or statistical power (1-β) at 80%, we concluded that the sample size required to achieve a statistically significant difference between these groups was 88 patients per group. Data for continuous outcome variables were analyzed using the independent sample t-test or the Mann–Whitney nonparametric test, as appropriate. χ2 and Fisher’s exact test were used for testing the association between categorical variables. A P value of <0.05 was considered statistically significant.
During the recruitment period of 7 mo, 264 patients were approached, of whom 71 refused to participate due to various reasons, including refusal to receive unnecessary medication (29 patients), refusal to participate in the study (20 patients), absence of IONV during previous CD (12 patients), willingness to receive prophylactic antiemetic (9 patients), and concerns regarding the side effects of granisetron (1 patient). Fourteen patients did not meet the inclusion criteria and three who consented were withdrawn from the study due to breach of protocol.
The two groups were comparable with regard to maternal demographics and obstetric data (Table 1). There was no significant difference between the two groups with respect to intraoperative events, mode and duration of uterine repair, and tubal ligation (Table 1).
The overall incidence of postdelivery IONV was 18%, distributed as 18 patients (20.4%) in the granisetron group and 15 (17.0%) in the control group (P = 0.56, NS). Nausea was reported by 16 patients (18.2%) in the granisetron group and 14 (15.9%) in the control group. The verbal rating scale for nausea [median (range)] was 5 (2–9) in the granisetron and 6 (4–10) in the control group. Vomiting occurred in 3.4% and 4.6% of patients in the granisetron (three patients) and in the control (four patients) groups respectively. Rescue antiemetic improved symptoms in 77% of patients and was required in 8% and 6.8% of patients in the granisetron and control groups respectively (Table 2).
Despite the use of prophylactic vasopressors, 7.9% of patients in the granisetron group and 4.5% in the control group had intraoperative hypotension postdelivery. Intraoperative pain not requiring opioid supplementation was reported by 2.2% and 4.5% of patients in the granisetron and control groups respectively (Table 2). Three patients had IONV during transfer to the stretcher. The overall incidence of IONV in cases where uterine repair was performed with exteriorization was 20.4%, and in in situ cases was 14.8%, the difference being statistically insignificant (P = 0.37). The majority of IONV events were seen after uterine repair (12.5%) rather than during uterine repair (7.4%). The requirement for oxytocin and vasopressor was similar in both groups. None of the patients received transfusion of blood or blood products. Postdelivery adverse effects are shown in Table 3. There was no statistically significant difference in the incidence of adverse effects between the two groups.
The overall incidence of IONV during regional anesthesia for CD is extremely variable, up to 80%, depending on the anesthetic technique and the preventive and therapeutic measures taken (1). Various studies have shown reduction in the incidence of IONV during CD by 22%–55% with the use of prophylactic antiemetics. However, the incidence of IONV in the control groups of these studies is remarkably high, ranging from 40% to 80%, which suggests a bias against the control of causative factors (5–14). The etiological factors of IONV during CD under regional anesthesia have already been described (1). To minimize the influence of such factors on our results, each of them was strictly controlled and monitored in our study. As a result, the incidence of IONV in the control group of our study was considerably lower (17%) in comparison to other studies investigating the efficacy of prophylactic antiemetics. The incidence of IONV might have been under-estimated in our study, because nausea was not directly asked about but rather reported by our patients spontaneously. Further, with the exclusion of patients with a history of PONV and motion sickness, the baseline risk for IONV in our patients was lower. We found no difference in the incidence of nausea and vomiting between the granisetron group (20.4%) and the control group (17%), suggesting that the commonly believed prophylactic role of antiemetics may not be clinically significant, at least intraoperatively, provided all the causative factors are well controlled. It is possible that granisetron may have a role in reducing PONV; however, our study was not extended into the postoperative period, and therefore no such conclusion can be drawn.
The correlation of IONV during CD with the development of hypotension has been well established in the literature (15–18). Ngan Kee et al. (15) found that when phenylephrine is titrated with the aim of maintaining maternal BP at 100% baseline in the predelivery period, the incidence of IONV is only 4%, compared to 16% when the BP is maintained at 90%, and 40%, when it is at 80% of baseline. This implies the importance of strict BP control in preventing IONV. Our study provides additional evidence to support this finding. We controlled hypotension by balancing the use of 10 mL/kg of crystalloid preload, left uterine displacement and prophylactic vasopressors for any decrease in BP below baseline; all done in a standardized manner. Interestingly, Ngan Kee et al. (15) reported a higher incidence of hypotension (29% vs 9.6%), but a lower incidence of IONV (4% vs 13.6%) in the predelivery period in the group aiming for BP at 100% of baseline, when compared with our study. Perhaps continuous infusion of phenylephrine, which was used in their study, is more effective in maintaining cardiac output (not necessarily correlated with BP) when compared with the intermittent boluses used in our study. We also observed that in the predelivery period, hypotension was closely related to IONV; while in the postdelivery period, hypotension was only one of the factors causing IONV.
Intraoperative pain and associated emetic symptoms appear to be strongly related to visceral stimuli arising from uterine exteriorization, peritoneal traction, handling of abdominal viscera and/or tubal ligation, even in the presence of a good conduction block. Siddiqui et al. (4), at our institution, showed that the incidence of IONV is higher when the uterine repair is performed with exteriorization of the uterus as compared to in situ (38% vs 18%). We found no difference in the incidence of IONV between the exteriorized and the in situ uterine repair subgroups (20.4% vs 14.8%). Moreover, the overall incidence of pain in Siddiqui et al.’s study was considerably higher when compared with our study (19% vs 3.4%). The difference between the studies could be due to the use of a higher dose of bupivacaine in our study (15 mg vs 12.5 mg), providing better control of visceral pain arising from uterine exteriorization. Increasing the dose of local anesthetic as well as the addition of intrathecal fentanyl 10–20 μg has been shown to limit the incidence of moderate to severe visceral pain and IONV during spinal anesthesia for CD by improving the quality of block and reducing the requirement for supplemental IV opioids (1,19,20).
Nausea and vomiting can also occur after oxytocin-induced hypotension. When administered in rapid boluses and large doses, oxytocin could be associated with significant hypotension and other hemodynamic consequences (21). Judicious use and administration of oxytocin in the form of infusion can overcome the problem of hypotension and its associated adverse effects (22).
In our study, we attempted to reduce IONV without any therapeutic intervention by fine-tuning the anesthetic technique. Although lack of assessment of patient satisfaction is a limitation of our study, our results are unbiased and strongly support the importance of preventive measures. These measures such as strict control of BP, provision of dense anesthetic block, and the judicious use of uterotonic drugs can enhance our anesthetic technique considerably, especially in circumstances where exteriorization is preferred for uterine repair. Fujii et al. (11) compared three different doses of granisetron during CD and found the incidence of IONV in patients who had received 40 μg/kg (16%) and 80 μg/kg (12%) to be lower than that in those who received 20 μg/kg (52%) and placebo (64%). The fact that the placebo group had a 64% incidence of IONV suggests a bias in their conclusions, possibly due to the variability of confounding factors, mainly hypotension and intraoperative pain, in the three groups.
The Food and Drug Administration approved dosage of granisetron, 1 mg IV over 30 s, is the commonly used dose in clinical practice in North America, and has been reported as the optimum dose for the prophylaxis of PONV in high risk nonobstetric patients (23). It has been suggested that granisetron may be effective in doses as low as 0.1 mg for the prophylaxis of nausea and vomiting; however, the efficacy of this regimen requires further investigation (23). There are currently no dose-finding studies on granisetron in obstetric patients undergoing CD with adequate control of the factors influencing IONV. Further, the transfer of this drug across the human placenta and into the breast milk has not been investigated, and hence for ethical and safety issues, it is administered after delivery and umbilical cord clamping.
Our study shows that when the known etiological factors for IONV are strictly controlled during CD, 1 mg of granisetron is ineffective in reducing postdelivery nausea and vomiting. This could be because adequate drug levels to cover the intraoperative period are not achieved when this drug is administered in the postdelivery period, or perhaps the etiology of nausea and vomiting during CD is so complex that antiemetics are ineffective and further modifications of the anesthetic and surgical techniques are necessary. Provided the confounding variables for IONV are controlled, we suggest that further investigations with (a) early preoperative administration of this drug, (b) the use of an antiemetic of another class, or (c) multidrug therapy, may prove clinically beneficial.
The authors acknowledge Kristi Downey (research assistant) for recruiting patients for the study and for organizing the database.
1. Balki M, Carvalho JCA. Intraoperative nausea and vomiting during caesarean section under regional anesthesia. Int J Obstet Anesth 2005;14:230–41.
2. Aapro M. Granisetron: an update on its clinical use in the management of nausea and vomiting. Oncologist 2004;9:673–86.
3. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 2003;97:62–71.
4. Siddiqui M, Goldszmidt E, Tharmaratnam U, et al. Complications of exteriorized versus in situ
uterine repair at cesarean section under spinal anesthesia [abstract]. Anesthesiology 2005;102:SOAP A13.
5. 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.
6. Abouleish EI, Rashid S, Haque S, et al. Ondansetron versus placebo for the control of nausea and vomiting during caesarean section under spinal anaesthesia. Anaesthesia 1999;54:479–82.
7. Ure D, James KS, McNeil M. Glycopyrrolate reduces nausea during spinal anaesthesia for caesarean section without affecting neonatal outcome. Br J Anaesth 1999;82:277–9.
8. Pan PH, Moore CH. Intraoperative antiemetic efficacy of prophylactic ondansetron versus droperidol for cesarean section patients under epidural anesthesia. Anesth Analg 1996;83:982–6.
9. Chestnut DH, Vandewalker GE, Owen CL, et al. Administration of metoclopramide for prevention of nausea and vomiting during epidural anesthesia for elective cesarean section. Anesthesiology 1987;66:563–6.
10. 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.
11. Fujii Y, Tanaka H, Toyooka H. Granisetron prevents nausea and vomiting during spinal anesthesia for cesarean section. Acta Anaesthesiol Scand 1998;42:312–15.
12. Fujii Y, Tanaka H, Toyooka H. Prevention of nausea and vomiting with granisetron, droperidol and metoclopramide during and after spinal anaesthesia for caesarean section: a randomized, double-blind, placebo-controlled trial. Acta Anaesthesiol Scand 1998;42:921–5.
13. Stein DJ, Birnbach DJ, Danzer B, et al. Acupressure versus intravenous metoclopramide to prevent nausea and vomiting during spinal anesthesia for cesarean section. Anesth Analg 1997;84:342–5.
14. 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.
15. Ngan Kee WD, Khaw KS, Ng FF. Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anesthesia for cesarean section. Br J Anaesth 2004;92:469–74.
16. Lee A, Ngan Kee WD, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg 2002;94:920–6.
17. Datta S, Alper MH, Ostheimer GW. Method of ephedrine administration and nausea and hypotension during spinal anesthesia for cesarean section. Anesthesiology 1982;56:68–70.
18. Carvalho JCA, Cardoso MMSC, Capelli EL, et al. Prophylactic ephedrine during cesarean delivery under spinal anesthesia: dose-response study of bolus and continuous infusion administration. Braz J Anesthesiol Int Issue 2000;11:32–7.
19. Peterson H, Santos AC, Steinberg ES, et al. Incidence of visceral pain during cesarean section: the effect of varying doses of spinal bupivacaine. Anesth Analg 1989;69:46–9.
20. Hirabayashi Y, Saitoh, Fakuda H, Shimizu R. Visceral pain during cesarean section: the effect of varying doses of spinal amethocaine. Br J Anaesth 1995;75:266–8.
21. Pinder AJ, Dresner M, Calow C. Hemodynamic changes caused by oxytocin during caesarean section. Am J Obstet Gynecol 1999;85:289–94.
22. Carvalho JC, Balki M, Kingdom J, Windrim R. Oxytocin requirements at elective cesarean delivery: a dose-finding study. Obstet Gynecol 2004;104:1005–10.
23. Corman SL, Skledar SJ, Ansani NT. Low-dose granisetron for postoperative nausea and vomiting prophylaxis. Ann Pharmacother 2004;38:710–13.