Association between increased 5-HIAA plasma concentrations and postoperative nausea and vomiting in patients undergoing general anaesthesia for surgery

EDITOR: Prevention of postoperative nausea and vomiting (PONV) by 5-HT3 antagonists suggests that 5-hydroxytryptamine (5-HT) contributes to the biochemical mechanisms of PONV [1–3]. As 5-HT is rapidly removed from plasma by platelets, endothelium and the liver, peripheral 5-HT release is reflected by analysing its major metabolite 5-hydroxyindole acetic acid (5-HIAA). Besides direct central activation of the vomiting system, a variability to onset of vomiting within the first 2 h up to 24 h after surgery points towards peripheral stimulation of 5-HT turnover as a trigger of PONV. Furthermore, volatile anaesthetics may increase peripheral 5-HT release [4]. Therefore, we investigated whether an increase of peripheral 5-HIAA concentrations is associated with PONV in patients with general anaesthesia for surgery. Before recommending a large clinical trial, we decided to investigate the hypothesis in an ongoing trial, where our hospital was one of the study centres. We considered 152 records for patients (80 female patients) participating in a randomized, double-blind, placebo-controlled trial investigating the prevention of PONV by the 5-HT3 antagonists tropisetron and ondansetron in patients undergoing surgery with general anaesthesia for ENT surgery [5]. According to the original protocol, patients had been included who were between 18 and 74 years with an ASA physical status I–III. Approval was given by the Institutional Ethics Committee and informed consent was obtained from patients. Exclusion criteria were: pregnant or lactating women, patients with a history of alcohol or drug abuse, intake of any concomitant medication known to influence gastrointestinal motility, vomiting or motion sickness, or any other drugs interfering with 5-HT receptors or 5-HT metabolism, patients expected to have a gastric tube in situ after surgery or had a previous history of subileus or ileus. Patients received balanced meals without food that increases serotonin levels and fasted for a minimum of 6 h prior to operation. Thirty to 60 min after oral midazolam (0.1 mg kg–1), 5-HT3 receptor antagonists or placebo were given intravenously (i.v.) over 30 s immediately before the induction of anaesthesia. One-hundred-and-three patients received either tropisetron (2 mg) or ondansetron (4 mg); 49 received placebo. Anaesthesia was induced with etomidate (0.2 mg kg–1), sufentanil (0.3 μg kg–1), vecuronium (0.08 mg kg–1) and maintained with 0.5–1.5 vol% isoflurane with 66% nitrous oxide in oxygen. Postoperative analgesia was provided by opioid analgesics. Postoperatively the development of PONV during the first 24 h after surgery was recorded by nursing staff, by a patient questionnaire for self-assessment and by an interview of the patient by the investigator, at 6 and 24 h. The 24-h period started when the patient entered the recovery room and was capable of responding (eye opening) to a verbal command. We decided to measure 5-HIAA concentrations in plasma not in the urine. Urinary ratio of 5-HIAA/creatinine as a measure of 5-HT turnover can be misleading due to drug interactions at the tubular transport system with the 5-HIAA excretion and cannot be controlled [6]. 5-HIAA and 5-HT plasma concentrations were analysed from EDTA plasma using a validated high performance liquid chromatography (HPLC) assay with electrochemical detection according to Cubeddu [7] and Recipe (München, Germany). Blood samples were centrifuged at 800 g for 20 min at 4°C. An aliquot of the supernatant was counted for platelets. Intra-assay variance of 5-HT and 5-HIAA amounted to 7.0% and 9.2%, respectively, and inter-assay variance to 13.5% and 13.7%, respectively. Values given are means ± SD, or only means if the standard deviations are illustrated in the tables. Univariate analyses were performed in patients with and without PONV using t-test for unpaired observations. The software package SAS PHREG 6.07 [8] was used for all statistical analyses. Appropriate time points of blood sampling were estimated before and within 1 h after surgery by investigating nine patients of the placebo group who developed PONV. 5-HIAA plasma concentrations increased by 1.24 ng mL–1 (5.96 ± 2.11 before to 7.20 ± 1.90 ng mL–1, P < 0.05 Wilcoxon test for matched pairs) within 1 h after the patients had entered the recovery room and did not increase further when patients developed emesis (7.04 ± 2.08). They returned to baseline values within 24 h after induction of anaesthesia (5.20 ± 1.59). A minimum of 120 patients was required to provide sufficient power (80%) to detect this 5-HIAA difference of 1.24 ng mL–1 assuming 22% emetic episodes in the placebo group and 11% in the treatment group with a two-tailed t-test of alpha level 0.05. We analysed blood samples in a total of 152 patients before and within 1 h after surgery for 5-HIAA and 5-HT. The results are shown in Table 1. Thirty-five out of 152 patients had developed PONV. The difference in 5-HIAA plasma concentrations between post- and preoperation was 4.4-fold higher in patients with PONV compared with patients without PONV (3.45 vs. 0.79, P < 0.05). In contrast, pre- and postoperative 5-HT plasma concentrations and 5-HT content per platelet revealed no difference, regardless of whether patients experienced PONV or not (preoperative: 20.6 ± 19.8; postoperative: 19.5 ± 17.4; nmol (109)–1 platelets). Thus, the release of 5-HT was not large enough to spill over into the systemic circulation.Table 1: Differences of 5-HIAA plasma concentrations before and after surgery under general anaesthesiaTo control for potential risk factors, e.g. gender, age, body weight, history of previous PONV, use of postoperative opioids, prophylactic use of 5-HT3 antagonists and duration of anaesthesia, multiple logistic regression analyses were carried out (Table 2) and resulted in odds ratios (ORs) for the difference in 5-HIAA concentrations of 1.40 and a confidence interval that does not cover the one (1.15; 1.71, Table 2). Therefore, an increase in 5-HIAA concentrations was an independent prognostic risk factor for the development of PONV suggesting that the probability of having PONV increases by 40% with respect to the reference group when 5-HIAA concentrations increase by 1 ng mL–1 during surgery.Table 2: Multiple logistic regression models of the association between PONV and differences in 5-HIAA concentrationsAccording to the study protocol of the randomized clinical trial, the use of 5-HT3 receptor antagonists in part of the study population could confound the effect of serotonin on the 5-HT3 receptor. Subgroup analyses for the placebo group and the drug treatment group were performed (Table 1). They confirmed a higher increase in the difference of 5-HIAA concentrations (ng mL–1) in 103 patients of the drug treatment group in patients with PONV compared with those without PONV (3.85 vs. 0.84, P < 0.05). However, in the placebo group of only 49 patients this difference was borderline significant with a P-value of 0.094 (2.84 vs. 0.68). Adjusting for the risk factors in a multiple logistic regression analysis, the differences in 5-HIAA plasma concentrations became a prognostic risk factor for PONV with an OR of 1.37 (1.01; 1.87, Table 2). Thus, the overall analyses are confirmed by subgroup analyses. Furthermore, 5-HT3 antagonists had no influence on 5-HIAA plasma concentrations as they were comparable between placebo and the antiemetic treatment group (in ng mL–1 preoperative 7.26 ± 2.60 vs. 6.84 ± 2.61; postoperative 8.71 ± 3.89 vs. 8.14 ± 3.79). To our knowledge, this is the first study reporting on an association between increased peripheral 5-HIAA concentrations in blood and PONV after surgery under general anaesthesia. As an explanation may serve that many of the drugs used in anaesthesia, e.g. halothane, isoflurane, enflurane or nitrous oxide are thought to be able to stimulate peripheral 5-HT turnover [4,9] and were found to be associated with a similar incidence of PONV [10]. Whether the magnitude of change in 5-HIAA concentrations is associated with the degree or severity of PONV, must be investigated in a prospective trial.

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