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Anesth Analg 1999;88:1346
© 1999 International Anesthesia Research Society

OBSTETRIC ANESTHESIA

Granisetron/Dexamethasone Combination for Reducing Nausea and Vomiting During and After Spinal Anesthesia for Cesarean Section

Yoshitaka Fujii, MD*, Yuhji Saitoh, MD{dagger}, Hiroyoshi Tanaka, MD{dagger}, and Hidenori Toyooka, MD*

*Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine; and {dagger}Department of Anesthesiology, Toride Kyodo General Hospital, Toride City, Ibaraki, Japan

Address correspondence and reprint requests to Y. Fujii, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki 305, Japan.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We compared the efficacy of granisetron plus dexamethasone with that of granisetron alone for preventing nausea and vomiting in parturients undergoing cesarean section under spinal anesthesia. In a randomized, double-blinded manner, 120 patients received either granisetron 3 mg (Group I, n = 60) or granisetron 3 mg plus dexamethasone 8 mg (Group II, n = 60) IV immediately after clamping of the fetal umbilical cord. A complete response, defined as no emetic symptoms and no need for another rescue antiemetic medication in the intraoperative, postdelivery period was 83% in Group I and 98% in Group II (P = 0.008); the corresponding rates during the first 24 h after surgery was 85% and 98% (P = 0.016). No clinically serious adverse events were observed in any of the groups. In conclusion, the prophylactic use of a granisetron/dexameth- asone combination is more effective than granisetron alone for reducing nausea and vomiting in patients during and after spinal anesthesia for cesarean section.

Implications: Intraoperative, postdelivery, and postoperative nausea and vomiting are distressing to patients undergoing cesarean section under spinal anesthesia. The combination of granisetron plus dexamethasone was evaluated and found to be effective for preventing these emetic symptoms.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Nausea and vomiting occur frequently during and after cesarean section under regional anesthesia when no prophylactic antiemetic is given (1–3). A variety of pharmacological approaches, including butyrophenones (e.g., droperidol) and dopamine receptor antagonists (e.g., metoclopramide), have been reported to be effective for preventing these emetic symptoms in patients undergoing spinal anesthesia for cesarean section (1,3). However, these drugs may produce undesirable adverse effects, such as drowsiness, restlessness, dystonic reactions, and extrapyramidal signs (4). Ondansetron, a selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, has been used prophylactically to reduce the incidence of intraoperative nausea and vomiting in patients undergoing cesarean section (5). Granisetron, another new 5-HT3 receptor antagonist, is more potent and has longer acting properties against cisplatin-induced emesis than ondansetron (6). We previously demonstrated that granisetron is effective for preventing emetic symptoms during and after spinal anesthesia for cesarean section (7,8) and that its efficacy is superior to other commonly used and well established antiemetics, such as droperidol and metoclopramide, for preventing postoperative nausea and vomiting in patients undergoing cesarean section (8). However, granisetron cannot entirely control emetic symptoms in this population. Dexamethasone decreases chemotherapy-induced emesis when added to an antiemetic regimen (9). We hypothesized that a granisetron/dexamethasone combination is more effective than granisetron alone in reducing the incidence of these emetic symptoms. To test this hypothesis, we compared the efficacy of granisetron plus dexamethasone with granisetron alone for preventing nausea and vomiting during and after spinal anesthesia for cesarean section in parturients.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After institutional review board approval and obtaining informed consent, we studied 120 ASA physical status I or II parturients between the ages of 24 and 38 yr undergoing spinal anesthesia for elective cesarean section. Patients who had gastrointestinal diseases, those who had a history of motion sickness and/or previous postoperative emesis, and those who had taken an antiemetic medication within 24 h before surgery were excluded from the study.

Patients were randomly allocated to one of two treatment regimens: granisetron 3 mg (Group I) or granisetron 3 mg plus dexamethasone 8 mg (Group II) (n = 60 in each group). A randomization list was generated, and identical syringes containing each drug were prepared by personnel blinded to the study, according to the list. These drugs were administered IV over 2–5 min immediately after clamping of the umbilical cord.

Preanesthetic medication was limited to 30 mL of orally administered 0.3 M sodium citrate. Each patient received 20 mL/kg of lactated Ringer's solution (up to a maximum of 2 L) before the induction of spinal anesthesia. As per our standard routine, tetracaine (8–10 mg in dextrose) was injected through a 25-gauge spinal needle (Top Spinal Needle®; Iwai City, Ibaraki, Japan) inserted at the L2-3 or L3-4 interspace. The blocks were performed with the patient in the right lateral decubitus position. After injection of the anesthetic solution, the patient was turned to the supine position with a 15° wedge under the right hip for left uterine displacement. Oxygen 3 L/min was administered via a face mask. Blood pressure was measured by an automated cuff blood pressure monitor. Maternal hypotension was defined as a decrease in systolic blood pressure of >20% from baseline values and/or <80 mm Hg immediately after spinal injection (7,8), and it was treated by increasing the rate of IV fluid administration, by exaggerating the uterine tilt, and by injecting ephedrine 5–10 mg IV. The level of analgesia was assessed by pinprick before surgical incision. Patients in all groups were allowed to receive up to 100 µg of fentanyl IV if required for pain relief after the delivery of the fetus. Subarachnoid fentanyl is not routinely administered in Japan and was therefore not offered to our patients. Immediately after surgery, patients were transferred to the postanesthesia unit, where they remained until discharge criteria were met. Postoperative analgesia was provided by indomethacin 50 mg given rectally for moderate pain and pentazocin 15 mg IM for severe pain.

Intraoperative, postdelivery, and postoperative emetic episodes were recorded by two anesthesiologists blinded to which antiemetic the patients had received. Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit; retching was defined as the labored, spasmodic, rhythmic contractions of the respiratory muscles without the expulsion of gastric contents; vomiting was defined as the forceful expulsion of gastric contents from the mouth (4). Complete response (i.e., emesis-free) was also defined as no emetic symptoms and no need for another rescue antiemetic medication. If two or more episodes of emesis occurred in each observation period, another rescue antiemetic (e.g., domperidone rectally) was given. At the end of the surgical procedure and 24 h after surgery, the patients evaluated the severity of nausea and general satisfaction, and the anesthesiologists evaluated the sedation of the patients. The evaluations were performed with 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 noted throughout the study after general questioning of the patients by the anesthesiologists or spontaneous mention by the patients.

Statistical analyses of data between the treatment groups were performed by using analysis of variance with Bonferroni correction for multiple comparison, {chi}2 test, two-tailed Fisher's exact probability test, or the Mann-Whitney U-test, as appropriate. A P value of <0.05 was considered significant. All values are expressed as mean ± SD, median (ranges) or number (%). We set {alpha} = 0.05 and ß = 0.2 and used a large magnitude of effect (effective size 0.8) to estimate a sufficient sample size. The analysis showed that 60 patients per group would be sufficient.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The treatment groups were comparable with regard to maternal demographics (Table 1) and operative management (Table 2). The level of anesthesia was sufficient for the surgical procedure, and no patient had a sensory level below T3-5 (midclavicular line) as tested by pinprick. Despite this, several patients required supplementation with fentanyl when the peritoneum was being manipulated. The amount of fentanyl for pain relief was not different between the groups. The amount of ephedrine administered for the treatment of hypotension was similar between the groups.


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  		Table 1. Maternal Demographics
 

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  		Table 2. Operative Management
 
In the intraoperative postdelivery period, a complete response (no emesis, no rescue) was seen in 83% of patients in Group I and in 98% of those in Group II. The corresponding rates during the first 24 h after surgery were 85% and 98%. Thus, complete response during and after surgery was greater in Group II than in Group I (P < 0.05). The severity of nausea was not different between the groups. The treatment groups were comparable with respect to satisfaction with the study drugs (Group I 0 [0–9], Group II 0 [0–7]). No difference in sedation was observed between the groups (Table 3).


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  		Table 3. Patients Having a Complete Response, Nausea, Retching, Vomiting, Requiring Rescue Antiemetic Medication, the Severity of Nausea and Sedation
 
The most frequently reported adverse events were headache and dizziness, which were mild. There were no differences in the incidence of adverse effects between the groups (Table 4).


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  		Table 4. Adverse Events
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The incidence of nausea and vomiting after regional anesthesia for cesarean section is relatively high when no prophylactic antiemetic is provided (1–3). We found the incidence of intraoperative, postdelivery, and/or postoperative emetic episodes to be as high as 60% in parturients undergoing cesarean section under spinal anesthesia with tetracaine (7,8). This incidence may justify the use of prophylactic antiemetic medication for the prevention of nausea and vomiting during and after spinal anesthesia for cesarean section.

The etiology of nausea and vomiting in parturients undergoing spinal anesthesia for cesarean section is complex and is dependent on a variety of factors, including maternal demographics, operative procedure, and anesthetic technique (4). Regardless of the cause, maternal hypotension after the induction of spinal anesthesia is associated with an increased incidence of intraoperative postdelivery emetic symptoms (10). This hypotension may cause brainstem hypoxemia and thus trigger the vomiting center to induce emesis (11). In this study, rapid fluid infusion, left uterine displacement, or administration of ephedrine were performed, if necessary, for the prevention or early treatment of this hypotension. A number of factors, including age, gender, pain, surgical procedure, anesthetic management, and postoperative pain, are considered to affect the incidence of nausea and vomiting (4). However, in this study, these factors were well balanced among the groups, so that the difference in a complete response during and after cesarean section under spinal anesthesia can be attributed to the study drug.

Granisetron has been reported to be effective for the treatment of emesis induced by cancer chemotherapy (12). We previously demonstrated that granisetron 40 µg/kg reduces the incidence of intraoperative postdelivery emetic symptoms in patients undergoing cesarean section under spinal anesthesia, and we have also shown that the efficacy of granisetron 40 µg/kg is similar to that of granisetron 80 µg/kg for preventing emesis in this population (7). The dose of granisetron 3 mg (40–50 µg/kg) chosen in this study was within the effective dose ranges (40–80 µg/kg). Dexamethasone 8 mg decreases chemotherapy-induced emesis when added to an antiemetic regimen (9). In this study, therefore, the same dose of dexamethasone was added to granisetron 3 mg (i.e., therapeutic dose).

Droperidol and metoclopramide have both been reported to reduce the incidence of emetic symptoms in patients undergoing cesarean section (1–3). We previously compared the efficacy of droperidol, metoclopramide, and granisetron for preventing nausea and vomiting during and after spinal anesthesia for cesarean section (8). Although droperidol and metoclopramide are effective for preventing intraoperative postdelivery emesis, they are not effective in reducing the incidence of postoperative emesis. Granisetron, however, is highly effective in preventing nausea and vomiting both during and after the surgical procedure in patients undergoing cesarean section.

In this study, we demonstrated that a complete response (no emesis, no rescue) in each observation period was greater in patients who had received granisetron plus dexamethasone than in those who had received granisetron alone (P < 0.05). This suggests that prophylactic antiemetic therapy with a combination of granisetron and dexamethasone is more effective than granisetron alone for preventing nausea and vomiting during and after spinal anesthesia for cesarean section.

The precise mechanism by which dexamethasone increases the effectiveness of granisetron is not known, but it seems that dexamethasone enhances the efficacy of granisetron for the prevention of emetic symptoms. This is based on the suggestion that granisetron may act on sites containing 5-HT3 receptors with demonstrated antiemetic effects (13) and that dexamethasone may inhibit stimulation of 5-HT3 receptors (14).

The major deficiency in this study design is the failure to include a control group receiving placebo. We previously demonstrated that the antiemetic efficacy of granisetron is superior to that of placebo against nausea and vomiting during and after spinal anesthesia for cesarean section (7,8). Aspinall and Goodman (15) have also shown that there is a poor quality of clinical information in placebo-controlled trials of another 5-HT3 receptor antagonist, ondansetron, for preventing postoperative nausea and vomiting. Therefore, a control group was not included in this study.

We have previously demonstrated that the prophylactic use of granisetron is effective for preventing intraoperative, postdelivery, and postoperative emetic symptoms without clinically serious adverse events in patients undergoing cesarean section under spinal anesthesia (7,8). Adverse events observed in this study were not serious, and there were no differences in the incidence of headache and dizziness between the groups. Thus, dexamethasone did not increase the incidence of adverse effects when added to granisetron.

Several investigators have criticized new antiemetics, 5-HT3 receptor antagonists (e.g., ondansetron), because of their high cost (16,17). In Japan, granisetron ($102.00 for 3 mg) and ondansetron ($103.00 for 3 mg) are much more expensive than other commonly used antiemetics, such as droperidol ($1.80 for 1.25 mg) and metoclopramide ($0.60 for 10 mg). However, the use of droperidol and metoclopramide as antiemetics has been limited because these drugs sometimes cause excessive sedation or extrapyramidal symptoms (4). The combination of granisetron ($102.00) and dexamethasone ($5.30) would slightly increase the cost of antiemetic therapy. In this study, a cost-effective analysis, defined as the cost per unit of success (18), was not performed. However, based on our results, a granisetron/droperidol combination was more effective than granisetron alone in increasing a complete response (no emesis, no rescue) during and after spinal anesthesia for cesarean section. Therefore, a decision about antiemetics should not be limited to these costs but should also consider the outcome of the patients and the overall cost of care if emesis was to occur. The incremental cost of combined granisetron and dexamethasone may be justified by the incremental effectiveness (i.e., antiemetic efficacy).

In conclusion, prophylactic therapy with a combination of granisetron and dexamethasone, although much more expensive than other drugs, was more effective than granisetron alone for preventing intraoperative, postdelivery, and postoperative emetic symptoms in patients undergoing cesarean section.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Santos A, Data S. Prophylactic use of droperidol for control of nausea and vomiting during spinal anesthesia for cesarean section. Anesth Analg 1984;63:85–7.[Free Full Text]
  2. Chestnut DH, Vandewalker CE, 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.[Web of Science][Medline]
  3. 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.[Web of Science][Medline]
  4. Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology 1992;77:162–84.[Web of Science][Medline]
  5. Pan P, Moore CH. Intraoperative antiemetic efficacy of prophylactic ondansetron versus droperidol for cesarean section patients under epidural anesthesia. Analg 1996;83:982–6.[Abstract]
  6. Andrews PLR, Bhandari P, Davey PT, et al. Are all 5-HT3 receptor antagonists the same? Eur J Cancer 1992;28:S2–S6.
  7. Fujii Y, Tanaka H, Toyooka H. Granisetron prevents nausea and vomiting during spinal anaesthesia for caesarean section. Acta Anaesthesiol Scand 1998;42:312–5.[Web of Science][Medline]
  8. Fujii Y, Tanaka H, Toyooka H. Prevention of nausea and vomiting during and after spinal anaesthesia for caesarean section with granisetron, droperidol and metoclopramide: a randomized, double-blind, placebo-controlled trial. Acta Anaesthesiol Scand 1998;42:921–5.[Web of Science][Medline]
  9. Smith DB, Newlands ES, Rustin GJS, et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin containing chemotherapy. Lancet 1991;338:487–90.[Web of Science][Medline]
  10. Datta S, Alper MH, Ostheimer GW, Weiss JB. Methods of ephedrine administration and nausea and hypotension during spinal anesthesia for cesarean section. Anesthesiology 1982;56:68–70.[Web of Science][Medline]
  11. Patra CK, Badola RP, Bhargava KP. A study of factors concerned in spinal anesthesia. Br J Anaesth 1972;44:1208–11.[Abstract/Free Full Text]
  12. Bermudez J, Boyle EA, Minter WD, Sanger GJ. The antiemetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694. Br J Cancer 1988;58:644–50.[Web of Science][Medline]
  13. Carmichael J, Cantwell BMJ, Edwards CM, et al. A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation of anti-emetic response. Cancer Chemother Pharmacol 1989;24:45–9.[Web of Science][Medline]
  14. Aapro BMS, Plezia PM, Alberts DS, et al. Double-blind crossover study of the antiemetic efficacy of high-dose dexamethasone versus high dose metoclopramide. J Clin Oncol 1984;2:466–71.[Abstract]
  15. Aspinall RL, Goodman NW. Denial of effective treatment and poor quality of clinical information in placebo controlled trials of ondansetron for postoperative nausea and vomiting: a review of published trials. BMJ 1995;311:844–6.[Abstract/Free Full Text]
  16. White PF, Watcha MF. Are new drugs cost-effective for patients undergoing ambulatory surgery? Anesthesiology 1993;78:2–5.[Web of Science][Medline]
  17. Lerman J. Are antiemetics cost-effective for children? Can J Anaesth 1995;42:263–6.[Web of Science][Medline]
  18. Watcha MF, White PF. Economics of anesthetic practice. Anesthesiology 1997;86:1170–86.[Web of Science][Medline]
Accepted for publication March 5, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press