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Obstetrics & Gynecology:
Original Research

Dose‐Range Effects of Propofol for Reducing Emetic Symptoms During Cesarean Delivery

Fujii, Yoshitaka MD; Numazaki, Mitsuko MD

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Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba City, Ibaraki, Japan.

Address reprint requests to: Yoshitaka Fujii, MD, University of Tsukuba Institute of Clinical Medicine, Department of Anesthesiology, 2–1‐1 Amakubo, Tsukuba City, Ibaraki 305–8576, Japan; E‐mail: yfujii@igaku.md.tsukuba.ac.jp.

Received May 25, 2001. Received in revised form August 15, 2001. Accepted August 30, 2001.

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Abstract

OBJECTIVE: To evaluate the efficacy and safety of propofol at subhypnotic doses for reducing emetic symptoms in parturients undergoing cesarean delivery under spinal anesthesia.

METHODS: In a randomized, double‐masked trial, 80 patients received lidocaine intravenously 0.1 mg/kg (for injection pain relief) followed by either placebo or propofol at three different doses (0.5 mg/kg per hour, 1.0 mg/kg per hour, 2.0 mg/kg per hour) (n = 20 in each group) immediately after clamping of the umbilical cord. Emetic episodes and safety assessments were performed during spinal anesthesia for cesarean delivery. To estimate a sufficient sample size, it was calculated that 20 patients per group would be required with α = .05 and β = .2.

RESULTS: The rate of patients experiencing no emetic symptoms in an intraoperative, postdelivery period was 45% with propofol 0.5 mg/kg per hour (P = .5), 80% with propofol 1.0 mg/kg per hour (P = .011), and 80% with propofol 2.0 mg/kg per hour (P = .011), compared with placebo (40%). No clinically serious adverse events caused by the study drugs were observed.

CONCLUSION: Propofol 1.0 mg/kg per hour is the minimum effective subhypnotic dose for reducing emetic symptoms during cesarean delivery. Increasing the dose to 2.0 mg/kg per hour provides no further benefit.

Nausea and vomiting during cesarean delivery are distressing to the patients and are a disturbance to the surgeon. The reported incidence of nausea and vomiting during cesarean performed under regional anesthesia varies from 50% to 80% when no prophylactic antiemetic is given.1,2 Most of the currently used antiemetics (antihistamine, butyrophenones, dopamine receptor antagonists) have undesirable adverse effects, such as excessive sedation, hypotension, dry mouth, dysphoria, restlessness, and extrapyramidal symptoms.3 Propofol is believed to be an antiemetic and therefore useful to decrease the incidence of postoperative nausea and vomiting when used at a subhypnotic dose.4,5 However, a bolus injection of low‐dose (10 mg) propofol is not effective for the prevention of nausea and vomiting during cesarean because of the short duration of propofol administered before the onset of emesis, and/or the dose of propofol used may be insufficient.6 In a recent study,7 continuous infusion of a subhypnotic dose (1.0 mg/kg per hour) of propofol was effective for reducing emetic symptoms during cesarean delivery without clinically serious adverse events. We have found no report to determine the minimum effective subhypnotic dose of propofol for control against nausea and vomiting in an intraoperative, postdelivery period. We therefore conducted a prospective, randomized, double‐masked trial to evaluate the efficacy and safety of propofol at three different doses (0.5 mg/kg per hour, 1.0 mg/kg per hour, 2.0 mg/kg per hour) for preventing emetic symptoms in patients undergoing cesarean under spinal anesthesia.

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MATERIALS AND METHODS

The study was approved by our institutional ethics committee, and the procedures followed were in accordance with the ethical standards for human experimentation established by the Declaration of Helsinki of 1975, revised in 1983. After obtaining informed consent, 80 American Society of Anesthesiologists physical status 1 parturients, between the ages of 23 and 36, scheduled for elective cesarean delivery were enrolled. Patients who had gastrointestinal diseases, those who had a history of motion sickness and/or previous emesis in an intraoperative, postdelivery period, and those who had taken antiemetics within 24 hours before surgery were excluded from the study.

Patients were randomized prospectively to receive lidocaine intravenously 0.1 mg/kg (for injection pain relief) followed by either placebo or propofol at three different doses (0.5 mg/kg per hour, 1.0 mg/kg per hour, 2.0 mg/kg per hour) immediately after clamping of the umbilical cord (n = 20 in each group). Propofol is formulated as a 1% solution in a fat emulsion containing 10% of soybean oil (long‐chain triglycerides). The drug administration was stopped at the end of the surgical procedure (ie, skin‐suture) to avoid delayed discharge from the operating room. A randomization list was prepared according to a list of computer‐generated numbers. According to the group allocation, identical syringes containing each drug were prepared by personnel masked to the study.

As preanesthetic medication, patients received oral ranitidine 150 mg 90 minutes before surgery. Each patient received 20 mL/kg of lactated Ringer's solution (up to a maximum of 2000 mL) before the induction of spinal anesthesia. Tetracaine (8–10 mg in dextrose) was injected through a 25‐gauge needle inserted at the L3–4 interspace. The blocks were performed with the patient in the right lateral decubitus position. After the injection of anesthetic solution, the patients were turned to the supine position with a 15‐degree wedge under the right hip for left uterine displacement. Oxygen 3 L per minute was administered by face mask. Blood pressure was measured by an automated cuff monitor. The decrease in systolic blood pressure (more than 20% from baseline values and/or less than 100 mm Hg) immediately after spinal injection was treated by increasing the rate of fluid administration, by exaggerating the uterine tilt, and by injecting ephedrine 5–10 mg intravenously. Thus, maternal hypotension related to emetic symptoms before and after clamping the umbilical cord was avoided.8,9 The level of anesthesia was assessed by pinprick before surgical incision. Patients in all groups were allowed to receive up to 100 μg of fentanyl intravenously, if required for pain relief, after the delivery of the fetus. The same anesthetic technique was performed by a staff anesthesiologist (YF).

Intraoperatively, postdelivery emetic episodes were recorded by a research anesthesiologist (MN), who had no knowledge of which antiemetic the patients had received. Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit.3 Retching was defined as the labored spasmodic, rhythmic contraction of the respiratory muscles without the expulsion of gastric contents.3 Vomiting was defined as the forceful expulsion of gastric contents from the mouth.3 The patients evaluated the severity of nausea and satisfaction with the study drug, and the research anesthesiologist evaluated sedation of the patients at the end of the observation period. The evaluations were performed on a linear numerical scale ranging from 0 (no nausea, complete satisfaction, no sedation) to 10 (severe nausea, complete dissatisfaction, extreme sedation). The details of any other adverse effects were recorded. Postoperatively, when patients were wide awake, they were transferred to the postanesthesia care unit and remained there before being moved to the ward.

Patient demographic data were analyzed by analysis of variance with Bonferroni correction for multiple comparison and χ2 test. The number of patients experiencing no emetic symptoms, nausea, retching, or vomiting, and the incidence of adverse events were compared with Fisher exact probability test. The severity of nausea, patient satisfaction, and sedation assessed by the research anesthesiologist were analyzed using Kruskal‐Wallis rank test. A P value of < .05 was considered significant. Values were mean ± standard deviation, n (%), or median (range). To estimate a sufficient sample size, power analysis in this clinical trial was based on the assumption that the incidence of no emetic symptoms (which was regarded as the primary endpoint) in patients receiving placebo would be 40%, an improvement from 40% to 80% was considered of clinical importance with α = .05 and β = .2. Based on these assumptions, 20 patients per group would be sufficient. However, its analysis was not adequate to detect differences in safety.

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RESULTS

Excluding the total dose of propofol administered, there were no differences among the treatment groups with regard to maternal demographics (Table 1) and operative management (Table 2). The level of analgesia was sufficient for the surgical procedure because no patient had a sensory level below T4–5. No differences were observed among the groups with regard to the number of patients with only nausea, retching, or vomiting. The only difference was found in the rate of patients experiencing no emetic symptoms in an intraoperative, postdelivery period, which occurred in eight (40%), nine (45%), 16 (80%), and 16 (80%) of 20 patients who had received placebo, propofol 0.5 mg/kg per hour, propofol 1.0 mg/kg per hour, and propofol 2.0 mg/kg per hour, respectively. Thus, no emetic symptoms were greater in patients who had received propofol 1.0 mg/kg per hour or propofol 2.0 mg/kg per hour than in those who had received placebo (P < .05). The severity of nausea was less in patients who had received propofol 1.0 mg/kg per hour or propofol 2.0 mg/kg per hour than in those who had received placebo (P < .05). Patients who had received propofol 1.0 mg/kg per hour or propofol 2.0 mg/kg per hour were more satisfied than were those who had received placebo (P < .05). However, there were no differences in the rate of patients experiencing no emetic symptoms, the severity of nausea, and the satisfaction with the study drug between the propofol 0.5 mg/kg per hour and placebo groups. No difference in being sedated was observed among the groups (Table 3). After discontinuation of the study drug, all patients were wide awake in less than 5 minutes. There were no clinically important adverse events (eg, extrapyramidal signs) in any of the groups.

Table 1
Table 1
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Table 2
Table 2
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Table 3
Table 3
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DISCUSSION

Nausea and vomiting during regional anesthesia for cesarean delivery have a complex and multifactorial etiology. A number of factors, including age, sex, pain, operative procedure, and anesthetic technique are considered to influence the incidence of emesis.3 In this clinical trial, however, the treatment groups were similar with regard to maternal demographics and operative management, and patients with a history of motion sickness and/or previous emesis during cesarean were excluded because they had a relatively high incidence of emetic symptoms.3 The rate of patients who were emesis free observed in the current study would be changed if such patient‐related factors were not controlled.

Subhypnotic doses of propofol are effective for the prevention of postoperative nausea and vomiting,5 but the efficacy of propofol as an antiemetic is still debated. Low‐dose (1.0 mg/kg per hour) propofol by continuous infusion does not decrease the incidence of nausea and vomiting after major gynecologic surgery or laparoscopy.10,11 In this study, the efficacy of propofol 1.0 mg/kg per hour or propofol 2.0 mg/kg per hour was superior to that of placebo for the prevention of emetic symptoms during cesarean under spinal anesthesia. The precise reason for this difference is not known, but may be related to the difference in surgical procedure, anesthetic technique, and observation period.

In a recent report,7 propofol at a subhypnotic dose (1.0 mg/kg per hour) reduced the incidence of intraoperative, postdelivery nausea, and vomiting in patients undergoing spinal anesthesia for cesarean. The exact mechanism by which propofol acts as an antiemetic remains unclear, but propofol is not considered to have vagolytic properties.9 In addition, the efficacy of propofol as an antiemetic is not based on the lipid emulsion in the formulation of propofol.12 Hammas et al13 have evaluated the effect of propofol on nausea and vomiting induced by ipecacuanha known to release 5‐hydroxytryptamine type 3 (5‐HT3) and have demonstrated that propofol reduces the intensity of retching after ipecacuanha administration, suggesting that propofol may have a weak 5‐HT3 antagonistic effect.

We found no report to determine the effective dose of propofol for the prevention of emetic symptoms in parturients undergoing spinal anesthesia for cesarean. We demonstrated that propofol 1.0 mg/kg per hour was as effective as propofol 2.0 mg/kg per hour for the control of emesis in an intraoperative, postdelivery period and showed no difference in the rate of emesis‐free episodes between patients who had received propofol 0.5 mg/kg per hour and those who had received placebo. In addition, patients who had received propofol in doses greater than 1.0 mg/kg per hour were more satisfied than those who had received placebo. These results suggest that propofol in a minimum effective subhypnotic dose of 1.0 mg/kg per hour may be effective for the prevention of nausea and vomiting in patients undergoing spinal anesthesia for cesarean delivery.

Several investigations have demonstrated that prophylactic therapy with droperidol or metoclopramide reduces the incidence of emetic symptoms in cesarean patients under spinal anesthesia.1,2 However, these drugs occasionally cause undesirable adverse effects, such as excessive sedation, restlessness, dystonic reactions, and extrapyramidal signs.3 Unlike these antiemetics, propofol at subhypnotic doses lacks these adverse effects.4 In this study, sedation level was comparable among the treatment groups, and all patients were wide awake in less than 5 minutes after discontinuation of the study drug. In addition, there were no clinically important adverse events (eg, extrapyramidal signs) in any of the groups.

Pan and Moore14 have shown that ondansetron, a selective 5‐HT3 receptor antagonist, is effective for reducing the incidence of intraoperative emetic symptoms in cesarean patients under epidural anesthesia. However, some investigators have criticized 5‐HT3 receptor antagonists because of their high cost.15,16 In Japan, ondansetron (US $102.00 for 3 mg) is much more expensive than other commonly used and well‐established antiemetics, such as droperidol (US $1.80 for 1.25 mg) and metoclopramide (US $0.60 for 10 mg), and routine prophylactic ondansetron administration has been limited. Our hospital pharmacy pays US $4.20 for propofol 25 mg, which is less expensive than ondansetron.

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REFERENCES

1. Santos A, Datta S. Prophylactic uses of droperidol for control of nausea and vomiting during spinal anesthesia for caesarean section. Anesth Analg 1984;63:85–7.

2. Lussos SA, Bader AM, Thornhill ML, Datta S. The antiemetic efficacy and safety of prophylactic metoclopramide for elective cesarean section delivery during spinal anesthesia. Reg Anesth 1992;17:126–30.

3. Watcha MF, White PF. Postoperative nausea and vomiting. Its etiology, treatment, and prevention. Anesthesiology 1992;77:162–84.

4. Smith I, White PF, Nathanson M, Gouldson R. Propofol. An update on its clinical use. Anesthesiology 1994;81:1005–43.

5. Borgeat A, Winder-Smith OHG, Saiah M, Rifat K. Subhypnotic dose of propofol possess direct antiemetic properties. Anesth Analg 1992;74:539–41.

6. Shi JJ, Wang YP, Sun WZ, Hung CP, Cherng YG, Lin SY, et al. The effect of low dose propofol for prevention of nausea and vomiting during spinal anesthesia for cesarean section. Acta Anaesthesiol Sin 1994;32:95–8.

7. Numazaki M, Fujii Y. Subhypnotic dose of propofol for the prevention of nausea and vomiting during spinal anaesthesia for caesarean section. Anaesth Intens Care 2000;28:262–5.

8. 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.

9. Patra CK, Badola RP, Bhargava KP. A study of factors concerned in emesis during spinal anaesthesia. Br J Anaesth 1972;44:1208–11.

10. Montgomery JE, Sutherland CJ, Kestin IG, Sneyd JR. Infusion of subhypnotic doses of propofol for the prevention of postoperative nausea and vomiting. Anaesthesia 1996;51:554–7.

11. Scuderi PE, D'Angelo R, Harris L, Mims GR III, Weeks DB, James RL. Small-dose propofol by continuous infusion does not prevent postoperative vomiting in females undergoing outpatient laparoscopy. Anesth Analg 1997; 84:71–5.

12. Ostman PL, Faure E, Glosten B, Kemen M, Robert MK, Bedwell S. Is the antiemetic effect of the emulsion formation of propofol due to the lipid emulsion? Anesth Analg 1990;71:536–40.

13. Hammas B, Hvarfner A, Thorn SE, Wattwil M. Effects of propofol on ipecacuanha-induced nausea and vomiting. Acta Anaesthesiol Scand 1998;42:447–51.

14. 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.

15. White PF, Watcha MF. Are new drugs cost-effective for patients undergoing ambulatory surgery? Anesthesiology 1993;78:2–5.

16. Lerman J. Are antiemetics cost-effective for children? Can J Anaesth 1995;42:263–6.

© 2002 by The American College of Obstetricians and Gynecologists.

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