1 University Department of Anaesthesia, Critical Care and Pain Management, Leicester University, University Hospitals of Leicester NHS Trust, Leicester General Hospital, Leicester LE5 4PW, UK. 2 The Mater Misericordiae Hospital, Dublin 7, Republic of Ireland
Corresponding author. E-mail: donal.buggy{at}nbsp.ie
Accepted for publication: January 16, 2003
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Abstract |
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Methods. Ninety-nine women undergoing elective Caesarean section under spinal anaesthesia were allocated randomly, in a double-blind study design, to receive either cyclizine 50 mg, dexamethasone 8 mg, or placebo as a single-dose infusion in saline 0.9%, 100 ml on completion of surgery. Spinal anaesthesia consisted of: hyperbaric bupivacaine 0.5%, 2.0 ml; fentanyl 10 µg; and spinal morphine 0.2 mg. The primary outcome measure was the incidence of nausea.
Results. The incidence of nausea was significantly less in patients receiving cyclizine compared with dexamethasone and placebo (33 vs 60 and 67%, respectively, P<0.05). Severity of nausea and number of vomiting episodes were also less at 36 h in cyclizine patients. Overall satisfaction with postoperative care at 24 h, expressed on a 100 mm visual analogue scale, was greater in cyclizine [78 (28)] than either dexamethasone [58 (31), P=0.03] or placebo [51 (28), P=0.008].
Conclusion. We conclude that following spinal morphine 0.2 mg and fentanyl 10 µg analgesia for Caesarean section, cyclizine 50 mg i.v. reduces the incidence of nausea compared with dexamethasone 8 mg i.v. or placebo. It also lessens the severity of nausea and vomiting, and increases maternal satisfaction in the early postoperative period.
Br J Anaesth 2003; 90: 66570
Keywords: anaesthetic techniques, subarachnoid; analgesics, morphine; vomiting, antiemetics, cyclizine; vomiting, antiemetics, dexamethasone; vomiting, nausea
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Introduction |
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Among a number of antiemetic agents available for PONV after Caesarean section is dexamethasone, a corticosteroid with proven antiemetic efficacy after single-dose administration in chemotherapy and for PONV associated with general anaesthesia.48 It has also been demonstrably effective in reducing PONV in women receiving epidural morphine for pelvic surgery, including Caesarean section.911 However, there are no reports investigating dexamethasone antiemetic therapy after spinal morphine for Caesarean section. Furthermore, cyclizine, a long-established, safe antiemetic with antihistamine and anticholinergic effects, has not been evaluated in this clinical setting either.
Therefore, we undertook a randomized, double-blind, placebo-controlled, clinical trial comparing standard, single-dose dexamethasone and cyclizine, in terms of their preventive efficacy for PONV and adverse effects, in women receiving spinal morphine for Caesarean section under regional anaesthesia.
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Methods |
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A histamine (H2) antagonist (oral ranitidine 150 mg) was given the evening before and the morning of surgery. Surgical anaesthesia to T4 dermatome level was provided by: hyperbaric bupivacaine 0.5%, 2.0 ml; fentanyl 0.2 ml (10 µg); and preservative-free morphine 0.2 ml (0.2 mg) for spinal injection, given via a 26G Whitacre pencil point needle, as part of a combined spinal epidural technique. The L34 or L45 intervertebral space was identified by loss of resistance to saline using a Tuohy 16G needle under aseptic conditions. Hartmanns solution 500 ml was infused before surgery and estimated fluid deficit and maintenance fluid requirements were infused as required during the case. If supplementary analgesia was required during surgery, lidocaine 2%, 35 ml was administered via the epidural catheter as required. Dermatomal sensory level was determined by ethyl chloride spray 1015 min after the intrathecal injection. All patients received ephedrine 36 mg i.v. as required for hypotension at the discretion of the anaesthetist and also oxytocin 10 international units and i.v. antibiotics (augmentin 1.2 g, erythromycin 1 g if allergic to penicillins) after delivery. Finally, all patients received rectal diclofenac 100 mg at the end of surgery.
In the recovery room, patients were allocated randomly to receive a 100 ml infusion of trial medication over 10 min according to one of three group allocations. Blocked randomization in groups of nine was used, with each patients group allocation placed in a consecutively numbered scaled envelope. Patients allocated to cyclizine therapy received cyclizine 50 mg in saline 0.9%, 100 ml. Patients allocated to dexamethasone received dexamethasone 8 mg in saline 0.9%, 100 ml, while control patients received an infusion of saline 0.9%, 100 ml as placebo. These infusions were prepared by the anaesthetist in charge of the case, but out of sight of the patient. This anaesthetist took no further part in the data collection, and patients were therefore unaware to which group they had been allocated. The randomization process and identity of study drugs were also blinded from the research nursing staff that gathered the outcome data. Sedation was assessed by the researchers using the scale provided, severity of nausea and vomiting was defined by the patient using the scale provided, rescue antiemetic use was checked on the drug chart and patient satisfaction by asking the patient to use the scale provided. Patients experiencing a persistent nausea score of more than 1 or who had two or more vomiting episodes received prochlorperazine 12.5 mg i.m. rescue antiemetic medication on demand at 4 h intervals.
The primary outcome measure was the incidence of nausea in the first 24 h after surgery. Secondary outcome measures included the incidence of vomiting, incidence of requirement for rescue antiemetic medication, patient satisfaction with overall postoperative care at 24 h (measured on a 100 mm visual analogue scale (VAS), where 0 mm indicated total dissatisfaction and 100 mm indicated total satisfaction during the first 24 h of postnatal care). Nausea was defined as a subjectively unpleasant sensation associated with awareness of the urge to vomit; vomiting was defined as rhythmic contractions of the abdominal muscles with or without expulsion of gastric contents from the mouth (i.e. including retching). Secondary outcome measures were quantitatively documented as follows: severity of nausea (measured on a four point scale: 0=no nausea; 1=mild; 2=moderate; and 3=severe nausea); number of vomiting episodes; pain intensity, which was measured on a 100-mm VAS, 0 mm=no pain and 100 mm=intolerable pain. If rescue analgesia was required, patients received a single tablet containing codeine 300 mg and paracetamol 500 mg combined. Pruritus was measured on a four point categorical scale similar to that for nausea (0=no pruritus, 1=mild, 2=moderate, 3=severe pruritus). If treatment was needed, chlorpheniramine 4 mg orally was given. Sedation was also evaluated on a four-point scale (0=awake; 1=mild, eyes closed occasionally; 2=asleep, eyes closed unless spoken to; 3=severe sedation, requiring physical arousal to open eyes). Data were recorded by staff unaware of the group allocations at the end of the 3, 6, 12, and 24 h time slots after surgery. Patients were asked to report any adverse event (e.g. vomiting) that had occurred in the time periods 03, 36, 612, and 1224 h, not just their present state at the particular time they were seen on the ward.
Sample size was determined prospectively. Because nausea is more prevalent than vomiting after spinal morphine, in the region of 60%,13 we decided that a 35% reduction in the proportion of patients with any incidence of nausea would be clinically significant. The -error (two-sided) was set at 0.05, the ß-error at 0.1 (study power 90%). Therefore, we calculated that n=33 patients would be required in each group. Data were inspected for distribution using scattergrams and the KolmogorovSmirnov test. Statistical analysis was conducted using SPSS v9 for Windows. Non-normally distributed data (severity of nausea, number of vomiting episodes, pruritus, sedation patient characteristics, VAS pain scores, arterial pressure and ventilatory frequency) were compared by the Kruskal Wallis test to identify differences between the three groups with post-hoc MannWhitney tests to detect differences between pairs of groups. Categorical variables (incidence of nausea, vomiting and requirement for rescue medication) were analysed by
2 analysis of 3x2 contingency tables or Fishers exact test as appropriate, followed by similar analysis 2x2 tables for intergroup differences.
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Results |
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Discussion |
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Although use of intrathecal morphine is associated with a high incidence of PONV, it provides excellent, safe analgesia for up to 24 h after surgery.13 We allowed an untreated placebo group because this was the first use of intrathecal opioids in our unit, and this study has helped to provide local baseline data for the incidence of nausea and vomiting in this clinical setting. There is emerging evidence that the incidence of PONV is reduced, without compromising the quality of analgesia, by using lower intrathecal doses of morphine, in the region of 0.1 mg.20
The mechanism of the antiemetic effects of dexamethasone is unclear. Glucocorticoid receptors are found in the nucleus of the solitary tract, the raphe nucleus, and the area postrema,13 all of which are involved in the regulation of nausea and vomiting.14 It is conceivable therefore that dexamethasone may affect PONV by modulating neurotransmission or receptor density in these nuclei.
Nonetheless, it is surprising that dexamethasone was ineffective after spinal morphine, when it has been consistently effective in reducing PONV after epidural morphine.912 Clearly, higher doses of morphine are used for epidural analgesia than spinal analgesia. Epidural opioids cause a higher incidence of PONV than spinal opioids after Caesarean section,15 therefore it may be easier to demonstrate a reduction in PONV by any effective agent when epidural morphine is used. However, our incidence of PONV after spinal morphine was 6067% in the control group, which is at the upper end of the range quoted for epidural morphine.812 It is noteworthy that dexamethasone was ineffective after intrathecal neostigmine analgesia for inguinal herniorrhaphy.16 Possibly, the mechanism of emesis induced by drugs administered via the intrathecal route differs from drugs given via the epidural route. Perhaps dexamethasones antiemetic effect is greater when brain stem nuclei are stimulated by opioids given via the epidural, rather than the intrathecal route, but this is speculative. Delayed postoperative gastric emptying has been shown in patients receiving spinal morphine and bupivacaine,17 but whether this contributes to emesis after epidural administration of these agents is unknown.
Cyclizine is a long-established, possibly underestimated, antiemetic with antihistaminic and anticholinergic properties, which may cause dry mouth and sedation.14 18 However, our data showed no evidence of increased sedation in patients receiving cyclizine compared with dexamethasone or placebo, although we did not specifically ask about cholinergic adverse effects. Cyclizine is both highly effective and well-tolerated and has been shown to be as effective as ondansetron for PONV after day-case laparoscopy.18 Others have recently confirmed that cyclizine, combined with ondansetron, decreased the incidence of vomiting after gynaecological laparoscopy from 20 to 3%, compared with ondansetron alone, with minimal reported side-effects.19
The incidence of PONV observed in the present study was high (6067%). This may reflect our choice of dose of spinal morphine (0.2 mg), which is at the higher end of the range commonly used clinically. There is conflicting evidence on whether increasing the dose of spinal morphine above 0.1 mg increases the incidence of PONV. A recent meta-analysis suggested spinal morphine 0.1 mg as the optimum dose for balancing analgesic efficacy against dose-related increased incidence of PONV,3 but a dose-finding study in Caesarean section patients where up to 0.5 mg spinal morphine was administered found no increase in PONV compared with lower doses.20 Our study had been approved and was being conducted when this guideline emerged. In practice, many units continue to administer spinal morphine in doses of 0.150.2 mg. Our dose of dexamethasone (8 mg) is also consistent with the recommendation of a dose-finding study for its use after epidural morphine, which indicated that dexamethasone 5 and 10 mg were equally effective.10 We chose not to study 5-HT3 antagonists (e.g. ondansetron and granisetron), which, though effective in PONV, are expensive8 and can also contaminate breast milk.21 The fact that dexamethasones proven efficacy in PONV after general anaesthesia and epidural morphine was not reproduced in our study using spinal morphine, suggests that the efficacy of all antiemetics should be re-evaluated in this clinical scenario. However, our antiemetic drugs were administered in the recovery room and their efficacy assessed for the following 24 h. Dexamethasone is thought to have a late-onset antiemetic effect, which may have contributed to its disappointing lack of efficacy in this instance.
Our finding of significantly lower satisfaction with overall postoperative care in patients receiving placebo or dexamethasone medication, whose PONV was poorly controlled relative to cyclizine patients, is a true outcome measure of the success of PONV therapy11 and is indeed remarkable. It suggests that PONV is a significant contributor to overall satisfaction with their perioperative care for these young, relatively fit patients, which is consistent with satisfaction data from similar populations of patients undergoing day surgery.22
In conclusion, in this randomized, double-blind, placebo-controlled, clinical trial, we found that i.v. cyclizine 50 mg, administered immediately after elective Caesarean section, significantly decreased the incidence and severity of nausea and vomiting, and the need for rescue antiemetic therapy compared with i.v. dexamethasone 8 mg and placebo. It also resulted in significantly higher satisfaction with overall postoperative care and was well tolerated. The proven antiemetic efficacy of dexamethasone after epidural morphine was not observed in this study after spinal morphine.
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Acknowledgements |
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References |
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