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* From the Department of Anesthesiology,
and Department of Obstetrics and Gynecology, Tri-Service General Hospital,
National Defense Medical Center, Taipei;
the Department of
Anesthesiology, Chi-Mei Medical Center, Tainan;
the Department
of Anesthesiology, Municipal Women's and Children's General Hospital, Kaohsiung,
Taiwan.
Address correspondence to: Dr. Jhi-Joung Wang, Department of Anesthesiology, Chi-Mei Medical Center, No. 901, Chung-Hwa Rd., Yung - Kang City, Tainan Hsien, Taiwan. Phone: 886-2-87927125; Fax: 886-2-87927130; E-mail: painlab{at}tpts5.seed.net.tw
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Abstract |
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Method: One hundred and eighty parturients (n=45 in each of four groups) requiring epidural morphine for post-Cesarean analgesia were enrolled in this randomized, double-blinded, placebo-controlled study. At the end of surgery, parturients received either dexamethasone, at doses of 10 mg, 5 mg, 2.5 mg, or saline iv. Three milligrams epidural morphine were given to all parturients for postoperative analgesia. The incidence of PONV and side effects were estimated for 24 hr after delivery by blinded, trained nurse anesthetists.
Results: Parturients who received dexamethasone, either 10 mg or 5 mg were different from those who received saline alone in the following parameters: the total incidence of nausea and vomiting, incidence of > 4 vomiting episodes, number the of parturients requiring rescue antiemetics, and the total number of parturients with no vomiting and/or no antiemetic medication (P < 0.05 to P < 0.01 ). The differences between dexamethasone 10 mg and 5 mg were not significant. Dexamethasone 2.5 mg was partially effective.
Conclusion: Dexamethasone, 5 mg iv, is suggested as the minimum effective dose in preventing nausea and vomiting associated with epidural morphine for post-Cesarean analgesia.
EPIDURAL morphine has a potent and long-acting analgesic effect for postoperative pain when compared with epidural fentanyl and meperidine.1–5 It is very convenient for clinical use and is widely accepted for postoperative analgesia, e.g., post-Cesarean analgesia.1,4,5 However, despite its excellent analgesia properties, a high incidence of nausea and vomiting (30-65%) has been reported.6–8 Among the antiemetics currently used, serotonin subtype 3 (5-HT3) antagonists (e.g., ondansetron, granisetron) possess good efficacy, but high cost limits their widespread clinical application.9,10 Other currently used antiemetics (e.g., anticholinergics, dopamine receptor antagonists, antihistamines) have side effects (e.g., restlessness, dry mouth, changes in blood pressure, and extrapyramidal symptoms).6,7,11,12
Dexamethasone is an effective antiemetic agent with minimal side effects after single dose administration.13–18 It is effective in preventing chemotherapy-related emesis and postoperative nausea and vomiting (PONV).18 Recently, we also found that dexamethasone (8 mg) was effective in preventing nausea and vomiting associated with epidural morphine for post-Cesarean analgesia.14 Although effective, the minimum effective dose of dexamethasone for this purpose has not been determined. We, therefore, performed a randomized and double-blinded study to evaluate three doses of dexamethasone, compared with saline, in preventing epidural morphine-related nausea and vomiting in parturients undergoing Cesarean delivery.
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Methods |
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At the end of surgery, parturients were randomly assigned to four groups of 45 parturients to receive dexamethasone, at doses of 10 mg, 5 mg or 2.5 mg, or saline iv. The drug for injection was prepared as a 2 ml clear solution in identical syringes. One minute after injection, all parturients received 3 mg preservative-free morphine in 10 ml isotonic sodium chloride solution through the epidural catheter for postoperative analgesia. The randomization process and the identity of the study drugs were blinded from the parturients, the anesthesiologists during surgery, and the investigators who collected the postoperative data.
Postoperatively, parturients were observed for 24 hr. A team of trained nurse anesthetists without knowledge of which drugs the parturients had received collected the postoperative data. During the observation period, arterial blood pressure, heart rate, and respiratory rate were monitored every four hours except when parturients were sleep.
Nausea and vomiting was evaluated by the following parameters: the incidences of nausea and vomiting, episodes of vomiting, rescue antiemetics and successful prevention. For the purpose of data collection, retching (same as vomiting but without expulsion of gastric content) was considered as vomiting. A vomiting episode was defined by events of vomiting that occurred in a rapid sequence (<1 min between events). If the vomiting were separated by more than one minute, they were considered to be separate episodes. Vomiting which occurred more than four times within 24 hr was considered as severe vomiting. Rescue antiemetics (4 mg ondansetron iv) were given if vomiting occurred, or at the parturients' request. The treatment was repeated if necessary. No vomiting and no antiemetic medication during the 24-hr postoperative period was defined as successful prevention. This was also the primary efficacy end point of the study. The data of nausea and vomiting were collected every four hours, except when parturients were sleep, by direct questioning by a team of specially trained nurse anesthetists or by spontaneous complaint of the parturients.
Postoperative pain at the surgical wound was assessed with a 10-cm visual analog scale (VAS; 0= no pain to 10= most severe pain) score. When parturients complained of pain and requested analgesia, 20 mg tenoxicam iv (every 12 hr) was given. Pruritus was assessed on a three-point ordinal scale (0= none, 1= pruritus but only in a small area of the body, 2= generalized pruritus). Pruritus was treated with im diphenhydramine (20 mg every four hours as needed).
The occurrence of side effects accompanying dexamethasone usage, such as wound infection or delayed wound healing during their stay in hospital was evaluated and reported by an obstetrician (Dr. Liu). Any other side effects were also recorded. Duration of hospital stay was recorded too.
Sample size was predetermined by using a power analysis based on the assumptions that (a) the total
incidence of nausea and vomiting in the saline group would be 50%,14 (b) a 40% reduction in the total incidence of nausea and vomiting
(from 50% to 30%) in the treatment group would be of clinical relevance, and (c) 
=0.05,
ß=0.2.19 The analysis showed that 40
parturients per group would be sufficient to detect the antiemetic effect of small dose of
dexamethasone (2.5 mg).19 A series of one-way
analyses of variance were conducted to examine differences among the four groups with respect to
parametric variables. If a significant difference was found, the Bonferroni t-test was used to detect
the intergroup differences. The Kruskal-Wallis test was used to determine differences among the four
groups with respect to nonparametric variables, followed by the Mann-Whitney U test for
intergroup differences. Categorical variables were analyzed by using a series of 4 x
2P2 tests to determine differences among the four groups, followed by 2 x
2P2 tests or Fisher's exact tests, as appropriate, for intergroup
differences. All follow-up analyses were corrected for the number of simultaneous contrasts using the
Bonferroni adjustments. A P value < 0.05 was considered statistically significant.
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Results |
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).
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).
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). The differences between dexamethasone 10 mg and 5 mg were not
statistically significant. Dexamethasone 2.5 mg was only partially effective.
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Discussion |
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We also found that dexamethasone did not influence the efficacy of epidural morphine-related analgesia. Parturients receiving 2.5 mg, 5 mg or 10 mg dexamethasone requested similar amounts of rescue analgesic and reported similar intensities of postoperative pain. Besides, dexamethasone did not influence the occurrence of pruritus related to epidural morphine for post-Cesarean analgesia.
The exact mechanism by which epidural morphine exerts an emetic action is alleged to be activation of opioid receptors in the chemoreceptor trigger zone of the fourth ventricle caused by cephalad migration of the morphine.8 However, the exact mechanism by which dexamethasone, a glucocorticoid, exerts an antiemetic action after epidural morphine is not known.18 Glucocorticoids have been shown to have various effects on the central nervous system; they regulate transmitter levels, receptor densities, signal transduction, and neuronal configuration.20,21 In the nucleus of the solitary tract, the nucleus of raphe, and the area postrema, numerous glucocoriticoid receptors are found.21,22 These nuclei are well known to have considerable neuronal activities on the regulation of nauseating and vomiting responses.8,23 Dexamethasone may exert its antiemetic action through these nuclei.
Some factors which may interfere with the interpretation of the study result, such as consumptions of ephedrine, midazolam, diphenhydramine and iv fluid, were also evaluated in our study.23,24 We found that the intraoperative consumptions of ephedrine, midazolam and iv fluid were similar among groups. In addition, the use of diphenhydramine among groups for the treatment of pruritus was also similar. Therefore, differences in the occurrence of nausea and vomiting among the groups can be attributed to the study drugs.
In a previous study, we found that iv dexamethasone has a delayed onset of action for both nausea and vomiting.25 The lag time was about two hours.25 In patients receiving epidural morphine, the occurrence of nausea and vomiting is usually two to four hours after medication.1,8 In our study, iv dexamethasone was given one minute before the administration of epidural morphine. Under this design, dexamethasone was considered to be an active antiemetic if the dosage was appropriate.
Multiple-dose corticosteroid therapy (>1 week) may cause side effects, such as increased risk of infection, glucose intolerance, delayed wound healing, superficial ulceration of gastric mucosa, avascular necrosis of femoral head, and adrenal supression.20,26 However, these side effects are not found after a single dose of dexamethasone therapy.13–18 In the current study, a single dose of 2.5 to 10 mg dexamethasone did not cause wound infection or delay wound healing. In addition, no other side effects were also found after the usage of a single dose of dexamethasone.
In conclusion, 10 mg and 5 mg dexamethasone were more effective than saline in preventing epidural morphine-related nausea and vomiting in parturients undergoing Cesarean delivery. The difference between dexamethasone 10 mg and 5 mg was not significant. Dexamethasone 2.5 mg was partial effective. We suggest that dexamethasone 5 mg iv is the minimum effective dose for this purpose.
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Footnotes |
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Accepted for publication November 9, 2000.
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References |
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