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From the Department of Anesthesiology, Hôpital de l'Enfant-Jésus du Centre hospitalier affilié universitaire de Québec (CHA), Laval University, Québec, Québec, Canada.
Address correspondence to: Dr. Pierre C. Nicole, Département d'anesthésie-réanimation, Hôpital de l'Enfant-Jésus du Centre hospitalier affilié universitaire de Québec (CHA), 1401, 18ième rue, Québec, Québec. G1J 1Z4, Canada. Phone: 418-649-0252; Fax: 418-649-5918; E-mail: piernicol{at}sympatico.ca
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Abstract |
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Methods: Forty-eight consecutive women undergoing outpatient laparoscopic tubal ligation were enrolled in this prospective, cumulative case-control study. The study compared serotonin activity in 15 patients totally free of emetic symptoms (asymptomatic group) and, among patients with PONV (n = 33), those 15 who presented the most severe symptoms (PONV group). Patients were anesthetized with a regimen including sufentanil (0.1–0.3 µg•kg-1) plus thiopental (3–5 mg·kg-1) for induction and isoflurane (0.6–1%) in nitrous oxide (60%) for maintenance. Peripheral serotonin activity was assessed by measurement with high-performance liquid chromatography of serotonin's principal urinary metabolite: 5-hydroxyindoacetic acid (5-HIAA) corrected for urinary creatinine.
Results: The preoperative and postoperative urinary 5-HIAA:creatinine ratios were 6.9 ng•µg-1 (confidence interval; CI 95%, 2.7–11.0) and 5.9 ng•µg-1 (CI 95%, 2.4–9.4) respectively in the asymptomatic group (P = 0.69), and were 5.1 ng•µg-1 (CI 95%, 2.5–7.7) and 5.6 ng•µg-1 (CI 95%, 3.4–7.7) respectively in the PONV group (P = 0.75). There was also no difference between groups in the variation of 5-HIAA:creatinine ratios from the preoperative to the postoperative period (P = 0.21).
Conclusion: PONV after laparoscopic tubal ligation are not associated with an increased urinary excretion of serotonin metabolites. Patients with severe PONV present a peripheral serotonin release comparable to asymptomatic patients.
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Introduction |
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Selective 5-HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron and dolasetron are also effective for the prevention and treatment of PONV.8–11 It has been speculated that some surgical procedures, such as those requiring the establishment of a pneumoperitoneum, might trigger a serotonin release from the gut.11 However it has not been investigated whether PONV is associated with such a peripheral release of serotonin.
The working hypothesis of this study was that patients suffering PONV have a pattern of peripheral serotonin release different (increased) from those who do not present this complication. This hypothesis was tested by the measurement of perioperative urinary levels of 5-hydroxyindoacetic acid (5-HIAA), the principal metabolite of serotonin, in outpatients scheduled for laparoscopic tubal ligation.
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Methods |
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The following anesthetic protocol was used. Patients received no premedication. Anesthesia was induced with sufentanil 0.1–0.3 µg•kg-1 and thiopental 3–5 mg·kg-1. The trachea was intubated with the help of rocuronium bromide 0.45–1 mg•kg-1. An orogastric tube was inserted in all patients. Isoflurane (expired fraction 0.6–1%) in a mixture of N2O/O2 (60/40%) was used for maintenance. At the end of surgery, residual neuromuscular blockade was reversed with neostigmine 40–70 µg•kg-1 and glycopyrrolate 7–15 µg•kg-1 if needed. The endotracheal tube was removed when the patient was fully awake. Postoperative pain was controlled with ketorolac 30–60 mg iv. If patients remained in pain, meperidine 0.5–1 mg•kg-1 im was given. Episodes of nausea and vomiting were treated first by metoclopramide 10 mg iv. If symptoms persisted, droperidol 0.625–1.25 mg iv was then given, followed by ondansetron 4 mg iv if required.
Two urinary samples were obtained from each patient. A preoperative sample was obtained by spontaneous micturition just before surgery and completed by bladder catheterization at the time of anesthesia induction. The postoperative sample was obtained by spontaneous micturition before discharge from the ambulatory surgery unit (ASU). Urine samples were diluted with 0.1 M perchloric acid (1:50 vol/vol), mixed and centrifugated. An aliquot (2 mL) of this solution was immediately frozen at -30°C for ulterior assay. Urinary 5-HIAA concentration was measured by high performance liquid chromatography with electrochemical detection.6 For each sample, urinary creatinine concentration was also measured using a Synchron LX System® which determines creatinine concentration in urine by the Jaffe rate method (Beckman Coulter, Fullerton, CA, USA). To compensate for differences in urine concentration during the perioperative period, the urinary 5-HIAA concentration was corrected for urinary creatinine concentration.
The following data were collected in the postanesthesia care unit (PACU) and the ASU: episodes of nausea and their severity (light, moderate, severe), episodes of retching or vomiting and episodes of arterial hypotension (systolic blood pressure lower than 90 mmHg). Data on the use of analgesic and antiemetic drugs were also collected. The following day, during a telephone interview, patients were questioned about the occurrence of nausea and vomiting after discharge.
All data were collected either by a research nurse or one of the investigators (P.C.N.). The laboratory personnel who performed the 5-HIAA and creatinine assays were unaware of the purpose of the study. Using type I (
) and type II (ß) errors of 0.05 and 0.2 respectively, and considering a twofold increase of postoperative urinary 5HIAA:creatinine ratio in the PONV group compared to the asymptomatic group as the minimal relevant difference,7 we calculated that a sample of 15 patients per group would be necessary. The student t test and the alternate Welch t test for paired and unpaired data were used for parametric data. Fisher's exact test was used for proportions. All tests were two-tailed and P < 0.05 was considered significant. Results are reported as mean with 95% confidence interval (CI 95%).
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Results |
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). The duration of anesthesia, the dose of intraoperative sufentanil received, and the number of patients who received neuromuscular blockade reversal agents at the end of anesthesia or meperidine in the PACU were also comparable for the two groups (Table II). No episode of arterial hypotension was observed during the postoperative period.
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). The preoperative and postoperative 5-HIAA:creatinine ratios were 6.9 ng•µg-1 (CI 95%, 2.7–11.0) and 5.9 ng·µg-1 (CI 95%, 2.4–9.4) respectively in the asymptomatic group (P = 0.69), and were 5.1 ng•µg-1 (CI 95%, 2.5–7.7) and 5.6 ng•µg-1 (CI 95%, 3.4–7.7) respectively in the PONV group (P = 0.75). There was also no difference between groups in the variation of 5-HIAA:creatinine ratios from the preoperative sampling to the postoperative sampling (P = 0.21).
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Discussion |
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Our results suggest that the pathophysiology of PONV is different from cisplatin-induced nausea and vomiting. Cubeddu et al. have shown that an increase of 5-HIAA: creatinine ratio from 7.0 to 17.5 ng•µg-1 four to six hours after administration of cisplatin correlated with a significant increase in the incidence of nausea and vomiting.7 In the same study, prophylactic administration of ondansetron, a selective antagonist of 5-HT3 receptor, markedly decreased the incidence of nausea and vomiting. These data are consistent with a peripheral mechanism involving serotonin in the gastrointestinal mucosa as a mediator of emesis. Our results, along with the limited efficacy of 5-HT3 receptor antagonists in PONV compared to the almost complete response in cisplatin-induced nausea and vomiting, suggest that this pathway is not an important mechanism in the production of PONV.7,11,12 However, it cannot be excluded that a perioperative serotonin increase might occur in the central nervous system and have a role in the pathophysiology of PONV.
Some have suggested that compression of the gastrointestinal mucosa by the surgical pneumoperitoneum could induce intestinal ischemia and trigger a serotonin release that could lead to PONV.12 On the other hand, Borgeat et al. reported recently that laparoscopy and laparotomy were associated with similar perioperative 5-HIAA urinary levels, and found no difference between patients presenting PONV and those without symptom.13 However the anesthesia regimen was based on propofol, which has been shown to decrease plasma serotonin activity.14 The present study yielded similar results with an anesthetic protocol, both for induction and maintenance, usually associated with a higher incidence of PONV.
A selection bias was introduced voluntarily when patients with the more severe symptoms were chosen to form the PONV group. With respect to the study hypothesis, this selection bias was considered desirable. This selection bias allowed the comparison of two well differentiated groups according to their PONV status, strengthening interpretation of the data. The fact that both the asymptomatic patients and those with the more severe symptoms had a similar serotonin release pattern reinforces the conclusion that, in the population studied, PONV is not related to a peripheral release of serotonin. It must be stated that our results may not necessarily apply to other populations. Indeed it cannot be ruled out that different surgical procedures might result in different serotonin release patterns.
In this study, as well as in others, serotonin could not be measured directly. Serotonin released from the gastrointestinal mucosa has a high hepatic extraction ratio and is almost entirely transformed to 5-HIAA during its hepatic first pass. Therefore, plasma serotonin half-life is extremely short and the measurement of its urinary metabolite 5-HIAA is the standard method to assess plasma serotonin activity. In order to compensate for any difference in hydration and urine concentration during the perioperative period, a correction factor using urinary creatinine concentrations must be applied. Cubbedu et al. used a similar protocol to study chemotherapy-induced emesis.3,7 In the present study, the sampling protocol used covered the intraoperative and the postoperative periods in the PACU and the ASU. These are periods when serotonin release might be expected. However only two urinary samples were obtained during the observation period. Ideally, sequential urinary samples should have been collected. Although a 5-HIAA urinary peak may have been missed due to the limited number of samples, it is unlikely that a large increase, of the same magnitude as that observed with cisplatin, was missed.
In conclusion, PONV after laparoscopic tubal ligation was not associated with an increased urinary excretion of 5-HIAA. Patients with PONV present a peripheral serotonin release pattern similar to asymptomatic patients. Our study suggests that PONV is not related to a peripheral release of serotonin.
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Acknowledgments |
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Revision received February 12, 2002. Accepted for publication December 7, 2001.
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References |
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2 Bunce KT, Tyers MB. The role of 5-HT in postoperative nausea and vomiting. Br J Anaesth 1992; 69(Suppl. 1): 60S–2S.
3 Cubeddu LX, Hoffmann IS, Fuenmayor NT, Malave JJ. Changes in serotonin metabolism in cancer patients: its relationship to nausea and vomiting induced by chemotherapeutic drugs. Br J Cancer 1992; 66: 198–203.[Medline]
4 Kilpatrick GJ, Jones BJ, Tyers MB. Binding of the 5-HT3 ligand, [3H]GR65630, to rat area postrema, vagus nerve and the brains of several species. Eur J Pharmacol 1989; 159: 157–64.[Medline]
5 Read NW, Gwee K-A. The importance of 5-hydroxytryptamine receptors in the gut. Pharmac Ther 1994; 62: 159–73.[Medline]
6 Cubeddu LX. Serotonin mechanisms in chemotherapy-induced emesis in cancer patients. Oncology 1996; 53(Suppl 1): 18–25.
7 Cubeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med 1990; 322: 810–6.[Abstract]
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Larijani GE, Gratz I, Afshar M, Minassian S. Treatment of postoperative nausea and vomiting with ondansetron: a randomized, double-blind comparison with placebo. Anesth Analg 1991; 73: 246–9.
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Ang C, Habre W, Sims C. Tropisetron reduces vomiting after tonsillectomy in children. Br J Anaesth 1998; 80: 761–3.
10 Mikawa K, Takao Y, Nishina K, Shiga M, Maekawa N, Obara H. Optimal dose of granisetron for prophylaxis against postoperative emesis after gynecological surgery. Anesth Analg 1997; 85: 652–6.[Abstract]
11 Kovac AL, Scuderi PE, Boerner TF, et al. Treatment of postoperative nausea and vomiting with single intravenous doses of dolasetron mesylate: a multicenter trial. Anesth Analg 1997; 85: 546–52.[Abstract]
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Goll V, Akça O, Greif R, et al. Ondansetron is no more effective than supplemental intraoperative oxygen for prevention of postoperative nausea and vomiting. Anesth Analg 2001; 92: 112–7.
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Borgeat A, Hasler P, Fahti M. Gynecologic laparoscopic surgery is not associated with an increase of serotonin metabolites excretion. Anesth Analg 1998; 87: 1104–8.
14 Grouzmann E, Borgeat A, Fathi M, Gaillard RC, Ravussin P. Plasma and cerebrospinal fluid concentration of neuropeptid Y, serotonin, and catecholamines in patients under propofol or isoflurane anesthesia. Can J Physiol Pharmacol 2000; 78: 100–7.[Medline]
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