Postoperative nausea and vomiting (PONV) remains in 1999 the most frequent and feared side-effect observed in the recovery room. The application of the 5-HT3 antagonists in patients receiving cancer chemotherapy has shown promising results (1) which were either confirmed (2) or not (3) in the postoperative period. However, the precise mechanism of action of these drugs in this setting is still not clearly elucidated.
Serotonin (5-hydroxytryptamine - 5-HT) is a widely distributed endogenous vasoactive substance that also serves as an inhibitory neurotransmitter in the central nervous system. About 90% of endogenous serotonin is present in enterochromaffin cells of the gastrointestinal tract. The remaining serotonin is present principally in the central nervous system and in platelets. The principal metabolite, 5-hydroxyindoleacetic acid (5-HIAA) is excreted in the urine (2-10mg/24h) in the normal adult. Measurement of this substance in urine is utilized clinically as an indicator of the level of endogenous 5-HT metabolism in the body. Different 5-HT receptors have been identified and nowadays up to eleven receptors have been cloned and purified by genetic engineering techniques.
Animal studies have indicated that 5-HT mediates its emetic sequel by acting on 5-HT3 receptors located both centrally, in the area postrema (4) and peripherally on the nerve plexus (vagal and splanchnic) within the wall of the small intestine (5). The discovery and use of 5-HT3 receptor antagonists such as ondansetron, granisetron or tropisetron has revolutionized the management of chemotherapy-induced vomiting. Indeed, Cubeddu et al. (1) measured the excretion of 5-HIAA in patients receiving cisplatin chemotherapy. They observed in all patients an increase of 5-HIAA excretion two to six hours after they received cisplatin, and the increases paralleled the episodes of emesis. In the same study, the authors showed that the administration of ondansetron markedly decreased the incidence of nausea and vomiting as compared to those who received a placebo. It is known that cisplatin causes damage to intestinal mucosa (6) resulting in the release of the 5-HT. The administration of 5-HT3 antagonists in patients receiving cancer chemotherapy was confirmed to decrease the incidence of nausea and vomiting within the first 24 hours, but their efficacy in preventing the delayed nausea and vomiting remains elusive. Wilder-Smith et al. (7) investigated the profile of 5-HIAA excretion during a 48-hour period following cisplatin chemotherapy. They found that 5-HIAA showed a peak 6 hours after induction of chemotherapy and a return to baseline 16 hours after. No other peaks of 5-HIAA were observed until the end of the study period.
Recently the 5-HT3 antagonists were introduced in anesthesiology to prevent or treat PONV. Most studies in the literature have shown a beneficial effect of prophylactic 5-HT3 antagonist administration in this clinical context (2), but different results have also been noted. However, Snaidach and Alberts (3) were not able to find a difference in the incidence of vomiting in a randomized, prospective, double-blind study comparing ondansetron 4mg and droperidol 20mg/kg given at the induction of anesthesia to women undergoing elective outpatient gynecology laparoscopy. Koivuranta et al. (8) compared ondansetron 4mg with placebo in a randomized, double-blind fashion in patients undergoing laparoscopic cholecystecomy. No difference was found between the two groups in terms of nausea and vomiting episodes during the first 24h postoperatively. Interestingly, the 5-HT3 antagonists are very effective during the first 24h of cisplatin-induced vomiting, when the urinary 5-HIAA levels are increased (1), but their efficacy is greatly reduced during the delay phase (> 24h) when the urinary 5-HIAA has normalized (9). The link between surgery and the secretion of serotonin on the excretion of serotonin metabolites, as well as the consequences of the pneumoperitoneum necessary for gynecological or digestive procedures - both procedures being associated with a very high incidence of PONV, have not been investigated. Borgeat et al. (10) investigated the effect of laparoscopic gynecological surgery on the urinary excretion of 5-HIAA. In a prospective study the excretion of 5-HIAA was compared in 40 women undergoing either gynecological laparoscopic surgery or traditional open laparotomy surgery. The authors did not find any difference in the excretion of 5-HIAA corrected to the excretion of creatinine between the two groups during the first eight postoperative hours. The excretion of 5-HIAA/creatinine was comparable in patients of both groups among those who vomited and those who did not. It was concluded that the creation of a pneumoperitoneum during gynecologic laparoscopic surgery is not associated with an increase of 5-HIAA excretion and this mechanism may not explain the high incidence of PONV observed in this type of surgery. The same group (11) investigated the relation between the excretion of serotonin and the hyperemesis gravidarum. The authors compared the excretion of 5-HIAA between 23 gravid women with hyperemesis gravidarum, 10 gravid women without nausea and vomiting - both groups within the first 3 months of pregnancy - and 10 nongravid women of similar age not taking contraceptive pills. No significant difference in the urinary excretion of 5-HIAA was found among the groups.
The role of serotonin in PONV is still unclear. The relation between the different types of surgery and the metabolism of serotonin has not yet been investigated. A peripheral mechanism may not explain the nausea and vomiting associated with laparoscopic surgery; the beneficial effect of the 5-HT3 agonists after gynecological laparoscopic surgery are most likely by some interactions in the central nervous system on the 5-HT3 receptor, possibly within the nucleus tractus solitarius. Until now this mechanism seemed to be the major one to explain the beneficial effects of the 5-HT3 antagonists on PONV. The central action of the 5-HT3 antagonists is non-specific (as compared to the peripheral blockade of the receptors) and may explain the wide discrepancies of the results noted in the literature.
References
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