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From the Department of Anesthesiology and Critical Care, Medicine, Klinikum, Ludwigshafen, Ludwigshafen, Germany.
Address correspondence to: Dr. Swen N. Piper, Department of Anesthesiology and Critical Care Medicine, Klinikum Ludwigshafen, Bremserstraße 79, D-67063 Ludwigshafen, Germany. Phone: 0049/621/503-3000; Fax: 0049/621/503-3024; E-mail: swen.n.piper{at}t-online.de
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Abstract |
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Methods: In a randomized, placebo-controlled, double-blinded trial we evaluated the efficacy of 12.5 mg dolasetron iv and 20 mg metoclopramide (MCP) iv in preventing PONV in 387 patients (ASA I–III) undergoing laparoscopic cholecystectomy. Patients were allocated randomly to one of three main groups: Group D (n = 129) received 12.5 mg dolasetron iv, Group MCP (n = 129) 20 mg MCP iv, and Group C (n = 129) saline as placebo iv. Using a multifactorial study design, one third of each main group (n = 43) was further randomized to receive either general anesthesia with desflurane, isoflurane or IVA with propofol and remifentanil. PONV, postoperative piritramide and droperidol consumption were documented.
Results: Independent from the anesthesia regimen chosen, dolasetron reduced PONV (19%) significantly compared to MCP (45%) and placebo (46%). Furthermore we could show a significant difference in the incidence of PONV between IVA (28%) and isoflurane (46%), but not in comparison to desflurane (36%). Patients receiving IVA had a higher postoperative piritramide consumption compared to the two other groups.
Conclusions: The results of our study suggest that dolasetron was more effective than MCP and placebo in preventing PONV. This action is independent of the anesthetic technique used.
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Methods |
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Patients were randomly assigned to one of three main groups (each group: n = 129): patients of Group D received 12.5 mg dolasetron, Group MCP 20 mg metoclopramide and Group C 0.9% saline as placebo intravenously. Randomization was performed with closed envelopes containing the study assignment. The envelopes were opened after inclusion of the patient in the study. All study drugs were diluted to a fixed volume of 50 mL and were administered intravenously over ten minutes in a double-blinded fashion. Forty-three patients of each main group were randomly assigned to maintenance of general anesthesia with desflurane (0.7–1.5 MAC), isoflurane (0.7–1.5 MAC) or IVA with propofol (4–10 mg•kg-1•hr-1) and remifentanil (0.2–0.25 µg•kg-1•min-1). The subgroup assignment was not double-blinded for practical and legal reasons. In the isoflurane and desflurane groups anesthesia was induced with thiopental (5 mg•kg-1) and fentanyl (3 µg•kg-1). Patients of the IVA group received 1.5 mg•kg-1 propofol and remifentanil 1.5 µg•kg-1 for induction of anesthesia. In all groups rocuronium (0.5 mg•kg-1) was given to facilitate orotracheal intubation. Nitrous oxide, 60% in oxygen 40%, was used in all patients. Mechanical ventilation (Julian®, Dräger, Lübeck, Germany) was used in all patients with a positive end-expiratory pressure of 5 cm H20 and controlled to maintain an end-tidal carbon dioxide tension at 30–36 mmHg. The fresh gas flow was set at 2 L•min-1. A nasogastric tube was inserted in all patients and suction applied to empty the stomach of air and secretions. Before tracheal extubation, the nasogastric tube was suctioned and removed.
Patients were monitored for 24 hr after surgery. On arrival in the postanesthesia care unit (PACU), 30, 60 min postoperatively, upon leaving the PACU, and four and 24 hr postoperatively, the patients were asked to score the occurrence of nausea using the following scale: 0 = no nausea, 1 = nausea, 2 = retching, 3 = single vomiting, 4 = multiple vomiting. If two score-points or more were reached or if patients specifically demanded antiemetics, increments of 1.25 mg droperidol (DHB) were given intravenously. Patients in all groups were given diclofenac (100 mg) rectally or iv doses of the opioid piritramide (increments of 3.75 mg) to treat pain. The postoperative inquiry of patients and the evaluation of patients’ PONV-score were carried out by an anesthesiologist who was unaware of group assignment.
Statistical analysis
The size of the study was independent of the multifactorial design chosen to allow a subgroup analysis with sufficient power and was determined as follows: we expected an incidence of PONV in the placebo groups of desflurane and isoflurane of at least 50% and a reduction of the incidence to about 20% with an effective medication such as dolasetron. Consequently, the present study was powered to detect such a reduction in incidence of PONV from 50% to 20% with an 
-error of 0.05 (two-sided) and a ß-error of 0.2. Based on that assumption, a minimum of 39 patients per group were required. We decided to enroll 43 patients per group to allow dropouts.
Demographic data, duration of surgery and anesthesia, intraoperative blood loss and fluid balance, recovery time from end of anesthesia and to extubation and time in the PACU were analyzed with Student’s t test. The incidences of PONV and vomiting were analyzed with Fishers’exact test. The ranked sum test of Raatz16 was used to analyze the PONV-score, as well as the postoperative piritramide, diclofenac and DHB consumption. The Raatz-test is a modified rank order test with corrections for multiple ties to be used for values that fall into classes (e.g., scores). All values are expressed as mean (standard deviation, SD) or as median (range). Only a Bonferroni corrected P-value of 0.05/3 (P < 0.016) was considered significant.
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). More patients with IVA received piritramide postoperatively, compared to patients who received isoflurane (P < 0.000002) or desflurane (P < 0.000003; Table IIb).
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PONV comparing the anesthetic regimens (Table IIc)
Patients in whom anesthesia was maintained with isoflurane (46%) had more PONV than patients who received IVA (28%, P < 0.01). We found no significant difference between desflurane- and IVA-based anesthesia. Vomiting did not differ significantly between the groups. The severity of PONV was also significantly reduced in IVA patients compared to isoflurane patients (P < 0.01). No significant difference was observed between desflurane and IVA with respect to PONV-score.
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Discussion |
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PONV does not only cause patient discomfort, but can also lead to prolongation of stay in the PACU and to serious complications, including electrolyte imbalance, aspiration, increased bleeding and wound dehiscence.14,17,18 Patients who suffer from PONV require additional health care professional time and material resources.18 This increases the amount of nursing resources and leads to higher costs.19,20 However, avoiding PONV while minimizing adverse events still remains a challenge. Metoclopramide (MCP) has been used for almost 40 years to prevent PONV.21 The affinity for dopaminergic D2-receptors explains the antiemetic effect of MCP.13 Although it may provoke extrapyramidal symptoms, MCP is still used in clinical practice.15,21 In adults, the most often studied regimen to prevent PONV is 10 mg MCP iv. However, in a meta-analysis by Henzi et al., it has been shown that this dose had no significant anti-nausea effect.21 Therefore, we decided to administer 20 mg MCP.
The use of 5-HT3 receptor antagonists has become more frequent as the drugs have shown a good efficacy in preventing PONV.6–14 Two mechanisms should be considered in the antiemetic effect of these drugs: firstly, blocking the 5-HT3 receptors in the area postrema and the nucleus tractus solitarius and secondly, blocking peripherally afferent vagal impulses originating from 5-HT3 receptors in the mucosa of the gastrointestinal tract.22 Dolasetron is a 5-HT3 receptor antagonist with a high selectivity in vitro and in vivo.23 It is rapidly converted in vivo to its active metabolite, hydrodolasetron, which appears to be largely responsible for its antiemetic activity.23,24 However, the major aim of our study was not only to compare the efficacy of two antiemetic drugs. By using a multifactorial study design, we also tried to investigate the influence of different anesthetic techniques on the incidence of PONV in a high risk population.
Laparoscopic cholecystectomy was selected for this study due to its relatively high incidence of nausea and vomiting. Accordingly, we found a high incidence of PONV in the three placebo (sub) groups (33%–56%), which was independent of the anesthetic regimen used, in agreement with various other studies of patients undergoing laparoscopic cholecystectomy.4,9,25–28 Naguib et al. found that 4 mg ondansetron, another 5-HT3-antagonist was superior in preventing PONV compared to metoclopramide (10 mg) and placebo. In contrast, others found no significant reduction of PONV using ondansetron compared to placebo.26,27 Moreover, two other 5-HT3- antagonists, namely granisetron (3 mg) and tropisetron (5 mg) showed no significant reduction of PONV in patients undergoing laparoscopic cholecystectomy.9 Badaoui et al. reported that dolasetron, the fourth available 5-HT3-antagonist, is superior in preventing PONV compared to prophylaxis with a low dose (10 mg) of MCP.8 In our study we could demonstrate that dolasetron (12.5 mg) is significantly more effective than 20 mg MCP and placebo. Like Wilson et al.,26 we found no significant reduction of PONV comparing MCP with placebo, but MCP reduced vomiting significantly from 22% in untreated placebo patients to 10%. MCP may provoke extrapyramidal symptoms,21 but in spite of using higher doses of MCP (20 mg), no patient suffered such undesirable side-effects. Dolasetron also reduced significantly the need for postoperative rescue medication with DHB compared to MCP and placebo.
Total iv anesthesia showed good recovery characteristics and a reduction in PONV.29 In a meta-analysis of nausea and vomiting following maintenance of anesthesia with propofol and inhalational agents, patients who received maintenance of anesthesia with propofol had a significantly lower incidence of PONV in comparison with inhalational anesthetics regardless of choice of inhalation agent.30 Whether the reduction of PONV is caused by an antiemetic effect of propofol or secondary to the avoidance of the potential emetic effects of volatile anesthetics and nitrous oxide remains controversial.3 Jakobsson et al. found no difference between desflurane and isoflurane in patients undergoing laparoscopic gynecological surgery.31 In our study we showed a reduction of PONV in patients receiving IVA compared to isoflurane, but we found no difference between isoflurane and desflurane and between IVA and desflurane. One reason why we could not show a beneficial effect of IVA on the incidence of PONV compared to desflurane may relate to the higher postoperative opioid consumption in patients receiving IVA. The use of opioids is one of the main risk factors of PONV.3 Remifentanil is a µ-opioid receptor agonist with pharmacodynamic properties like those of fentanyl and its derivates.32 Secondary to a metabolism by non-specific esterases the drug has an extremely high clearance, and therefore offset of effect, which is independent of excretion.32 In contrast, its rapid offset of action necessitates an earlier and a more intensive postoperative pain treatment.33 In our study patients receiving IVA consumed more piritramide postoperatively, compared to both volatile anesthetic groups. In spite of this higher use of opioids we found a decrease of nausea and vomiting in the IVA group compared to isoflurane, but not desflurane. This absence of a difference between IVA and desflurane may relate to the use of nitrous oxide in all patients. The supplementation of general anesthesia with nitrous oxide increases the incidence of PONV.34 Nonetheless, we decided to administer nitrous oxide to all patients since it remains in use in several centres.
Possible limitations of our study include the use of a number of patients insufficient to show a significant difference in the incidence of PONV between the different anesthesia regimes. A post hoc sample size estimation showed that a formal comparison of PONV rates in the IVA vs desflurane and desflurane vs isoflurane would have required in excess of 300 patients per group. The comparison of a priori PONV risks in the various groups is difficult because we did not ask for motion sickness, an important component of prediction scores established in the past years. Also, our study was not stratified for other known risk factors such as sex. This was, however, nearly unavoidable in a factorized design with 3 x 3 groups as further stratification according to a priori risk would have led to at least 18 groups and thus have been unmanageable with the resources of our department. However, we did not find differences in the incidence of a priori risk factors between groups. Finally, it should be kept in mind that the IVA group and the inhalation groups differ not only in the maintenance anesthetic (propofol vs isoflurane or desflurane), but also in the opioid and induction anesthetic used, so that this is not a comparison of propofol vs isoflurane/desflurane, but a comparison of three common anesthesia techniques.
We conclude that 12.5 mg dolasetron iv reduces PONV and the need of a rescue medication in comparison to 20 mg metoclopramide iv and placebo in patients undergoing laparoscopic cholecystectomy. This effect is independent of the anesthetic technique used.
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Footnotes |
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Revision received September 5, 2002. Accepted for publication May 17, 2002.
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2 Buggy D, Higgins P, Moran C, O’Donovan F, McCarroll M. Clonidine at induction reduces shivering after general anaesthesia. Can J Anaesth 1997; 44: 263–7.
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