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Anesth Analg 2000;90:1004-1007
© 2000 International Anesthesia Research Society

LETTERS TO THE EDITOR

Reported Data on Granisetron and Postoperative Nausea and Vomiting by Fujii et al. Are Incredibly Nice!

Peter Kranke, Christian C. Apfel, MD, and Norbert Roewer, MD

Department of Anesthesiology University of Würzburg Würzburg, Germany

We read with interest the recent article of Fujii et al. (1) about granisetron in the prevention of postoperative nausea and vomiting (PONV). With increasing amazement, we noticed that the results reported by Fujii et al. are incredibly nice and we became skeptical when we realized that side effects were almost always identical in all groups.

During 1994–1999, 47 articles have been published by Fujii et al. (http://www.nlm.nih.gov/> search "Fujii-Y and granisetron") (1–47). In 21 articles, the most frequently reported side effect, headache, is given for the overall 24-h period of observation (Table 1). In 13 articles, the frequency of headache was reported to be identical in all groups (5,7–11,15,16,19,20,29,40,43), while this side effect differed, at most, by one patient per group in the remaining 8 papers (4,6,12–14,27,28,32). Surely, assuming that the study drug has no impact on a side effect, one would expect similar results between the groups. However, identical results are still relatively rare as binominal distribution causes a certain variability in reality. Thus, we tested the null hypothesis that the reported identical incidences could have occurred by chance with the alternative hypothesis that an underlying reason lead to such identical results.


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  		Table 1. Incidence of Headache per Group in the Investigated Publications and Calculated Probabilities of Obtaining Identical Groups
 
First, the incidence of headache (p) was calculated by the total number of patients with headache (n = 186) divided by the total number of patients (n = 2369) in the 21 studies, resulting in an incidence (with lower to upper 95% confidence intervals) of p = 0.0785 (0.0681 to 0.09).

Second, the probability (P) that x out of n patients will experience headache will generally be calculated according to formula for the binominal distribution P = (n!/(x!(n - x)!)) x px x (1 - p)n-x (48). Third, for each study, the probability that all (z) groups have identical results with x patients suffering from headache is calculated by P = Pz. These calculations were done for x between 0 and 10 as the probabilities for x > 10 were too small to have any impact on the calculation (Table 1).

Fourth, the joint probability that a study results in any identical number of patients is calculated by the sum of the single probabilities for x = 0, 1, 2, ... 10, also given in Table 1.

Fifth, the joint probabilities of all 18 separate studies with more than two groups–all three studies with two groups had identical results anyway–was in the range of P = 0.0002 to 0.0548. To make it safe and simple, the hypothesis that 10 of 18 studies will result in identical numbers was tested by applying again the above mentioned formula for the binominal distribution with the highest probability of 0.0548. This resulted in a final probability (Pfinal) that 10 of those 18 studies will have identical results by chance of Pfinal = 6.78 x 10-9!

Thus, we have to reject the null hypothesis that the frequency of identical results simply occurred because of the assumption that the incidence of headache is not affected by the intervention, and we have to conclude that there must be an underlying influence causing such incredibly nice data reported by Fujii et al.

References

  1. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Comparison of ramosetron and granisetron for preventing postoperative nausea and vomiting after gynecologic surgery. Anesth Analg 1999;89:476–9.[Abstract/Free Full Text]
  2. Fujii Y, Tanaka H, Toyooka H. Optimal anti-emetic dose of granisetron for preventing postoperative nausea and vomiting. Can J Anaesth 1994;41:794–7.[Web of Science][Medline]
  3. Fujii Y, Tanaka H, Toyooka H. Reduction of postoperative nausea and vomiting with granisetron. Can J Anaesth 1994;41:291–4.[Web of Science][Medline]
  4. Fujii Y, Tanaka H, Toyooka H. Prevention of postoperative nausea and vomiting with granisetron: a randomized, double-blind comparison with droperidol. Can J Anaesth 1995;42:852–6.[Web of Science][Medline]
  5. Fujii Y, Tanaka H, Toyooka H. Granisetron-dexamethasone combination reduces postoperative nausea and vomiting. Can J Anaesth 1995;42:387–90.[Web of Science][Medline]
  6. Fujii Y, Toyooka H, Tanaka H. Antiemetic efficacy of granisetron and metoclopramide in children undergoing ophthalmic or ENT surgery. Can J Anaesth 1996;43:1095–9.[Web of Science][Medline]
  7. Fujii Y, Tanaka H, Toyooka H. Granistron and dexamethasone provide more improved prevention of postoperative emesis than granistron alone in children. Can J Anaesth 1996;43:1229–32.[Web of Science][Medline]
  8. Fujii Y, Toyooka H, Tanaka H. Antiemetic effects of granisetron on postoperative nausea and vomiting in patients with and without motion sickness. Can J Anaesth 1996;43:110–4.[Web of Science][Medline]
  9. Fujii Y, Tanaka H, Toyooka H. Granisetron reduces vomiting after strabismus surgery and tonsillectomy in children. Can J Anaesth 1996;43:35–8.[Web of Science][Medline]
  10. Fujii Y, Toyooka H, Tanaka H. Effective dose of granisetron for preventing postoperative emesis in children. Can J Anaesth 1996;43:660–4.[Web of Science][Medline]
  11. Fujii Y, Tanaka H, Toyooka H. Granisetron reduces incidence of nausea and vomiting after breast surgery. Acta Anaesthesiol Scand 1997;41:746–9.[Web of Science][Medline]
  12. Fujii Y, Toyooka H, Tanaka H. Prevention of PONV with granisetron, droperidol and metoclopramide in female patients with history of motion sickness. Can J Anaesth 1997;44:820–4.[Web of Science][Medline]
  13. Fujii Y, Tanaka H, Toyooka H. Prophylactic antiemetic efficacy of granisetron in patients with and without previous postoperative emesis. Can J Anaesth 1997;44:273–7.[Web of Science][Medline]
  14. Fujii Y, Tanaka H, Toyooka H. Granisetron reduces postoperative nausea and vomiting throughout menstrual cycle. Can J Anaesth 1997;44:489–93.[Web of Science][Medline]
  15. Fujii Y, Tanaka H, Toyooka H. Effective dose of granisetron in the reduction of nausea and vomiting after breast surgery. Acta Anaesthesiol Scand 1997;41:1167–70.[Web of Science][Medline]
  16. Fujii Y, Tanaka H, Toyooka H. The effects of dexamethasone on antiemetics in female patients undergoing gynecologic surgery. Anesth Analg 1997;85:913–7.[Abstract]
  17. Fujii Y, Tanaka H, Toyooka H. Granisetron reduces the incidence and severity of nausea and vomiting after laparoscopic cholecystectomy. Can J Anaesth 1997;44:396–400.[Web of Science][Medline]
  18. Fujii Y, Toyooka H, Tanaka H. Granisetron reduces the incidence of nausea and vomiting after middle ear surgery. Br J Anaesth 1997;79:539–40.[Abstract/Free Full Text]
  19. Fujii Y, Toyooka H, Tanaka H. Oral granisetron prevents postoperative vomiting in children. Anaesth 1998;81:390–2.
  20. Fujii Y, Toyooka H, Tanaka H. Granisetron-droperidol combination for the prevention of postoperative nausea and vomiting in female patients undergoing breast surgery. Anaesth 1998;81:387–9.
  21. Fujii Y, Toyooka H, Tanaka H. A granisetron-droperidol combination prevents postoperative vomiting in children. Anesth Analg 1998;87:761–5.[Abstract/Free Full Text]
  22. Fujii Y, Toyooka H, Tanaka H. Prophylactic antiemetic therapy with a combination of granisetron and dexamethasone in patients undergoing middle ear surgery. Br J Anaesth 1998;81:754–6.[Abstract/Free Full Text]
  23. Fujii Y, Toyooka H, Tanaka H. Prophylactic anti-emetic therapy with granisetron, droperidol and metoclopramide in female patients undergoing middle ear surgery. Anaesthesia 1998;53:1165–8.[Web of Science][Medline]
  24. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Prophylactic oral antiemetics for preventing postoperative nausea and vomiting: granisetron versus domperidone. Anesth Analg 1998;87:1404–7.[Abstract/Free Full Text]
  25. Fujii Y, Tanaka H, Toyooka H. Prevention of nausea and vomiting with granisetron, droperidol and metoclopramide during and after spinal anaesthesia for caesarean section: a randomized, double-blind, placebo-controlled trial. Acta Anaesthesiol Scand 1998;42:921–5.[Web of Science][Medline]
  26. Fujii Y, Toyooka H, Tanaka H. Granisetron in the prevention of nausea and vomiting after middle-ear surgery: a dose-ranging study. Br J Anaesth 1998;80:764–6.[Abstract/Free Full Text]
  27. Fujii Y, Tanaka H, Toyooka H. Preoperative oral granisetron prevents postoperative nausea and vomiting. Acta Anaesthesiol Scand 1998;42:653–7.[Web of Science][Medline]
  28. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Prophylactic antiemetic therapy with granisetron-droperidol combination in patients undergoing laparoscopic cholecystectomy. Can J Anaesth 1998;45:541–4.[Web of Science][Medline]
  29. Fujii Y, Tanaka H, Toyooka H. Prevention of nausea and vomiting in female patients undergoing breast surgery: a comparison with granisetron, droperidol, metoclopramide and placebo. Anaesthesiol Scand 1998;42:220–4.
  30. Fujii Y, Toyooka H, Tanaka H. Prevention of postoperative nausea and vomiting with a combination of granisetron and droperidol. Anesth Analg 1998;86:613–6.[Abstract]
  31. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Comparison of granisetron and droperidol in the prevention of vomiting after strabismus surgery or tonsillectomy in children. Paed Anaesth 1998;8:241–4.[Web of Science][Medline]
  32. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Prevention of PONV with granisetron, droperidol or metoclopramide in patients with postoperative emesis. Can J Anaesth 1998;45:153–6.[Web of Science][Medline]
  33. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Anti-emetic efficacy of prophylactic granisetron, droperidol and metoclopramide in the prevention of nausea and vomiting after laparoscopic cholecystectomy: a randomized, double-blind, placebo-controlled trial. Eur J Anaesthesiol 1998;15:166–71.[Web of Science][Medline]
  34. Fujii Y, Tanaka H. Prophylactic therapy with granisetron in the prevention of vomiting after paediatric surgery: a randomized, double-blind comparison with droperidol and metoclopramide. Paed Anaesth 1998;8:149–53.[Web of Science][Medline]
  35. Fujii Y, Tanaka H, Toyooka H. Granisetron prevents nausea and vomiting during spinal anaesthesia for caesarean section. Acta Anaesthesiol Scand 1998;42:312–5.[Web of Science][Medline]
  36. Fujii Y, Tanaka H, Toyooka H. Prophylactic antiemetic therapy with granisetron-dexamethasone combination in women undergoing breast surgery. Acta Anaesthesiol Scand 1998;42:1038–42.[Web of Science][Medline]
  37. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Prophylactic antiemetic therapy with granisetron in women undergoing thyroidectomy. Br J Anaesth 1998;81:526–8.[Abstract/Free Full Text]
  38. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Effective dose of granisetron for the prevention of post-operative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. Eur J Anaesthesiol 1998;15:287–91.[Web of Science][Medline]
  39. Fujii Y, Toyooka H, Tanaka H. Prevention of postoperative nausea and vomiting in female patients during menstruation: comparison of droperidol, metoclopramide and granisetron. Br J Anaesth 1998;80:248–9.[Abstract/Free Full Text]
  40. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Prophylactic therapy with combined granisetron and dexamethasone for the prevention of post-operative vomiting in children. Eur J Anaesthesiol 1999;16:376–9.[Web of Science][Medline]
  41. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Anti-emetic efficacy of prophylactic granisetron compared with perphenazine for the prevention of postoperative vomiting in children. Anaesthesiol 1999;16:304–7.
  42. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Combination of granisetron and droperidol in the prevention of nausea and vomiting after middle ear surgery. J Clin Anesth 1999;11:108–12.[Web of Science][Medline]
  43. Fujii Y, Tanaka H. Granisetron reduces post-operative vomiting in children: a dose-ranging study. Eur J Anaesthesiol 1999;16:62–5.[Web of Science][Medline]
  44. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Granisetron/dexamethasone combination for reducing nausea and vomiting during and after spinal anesthesia for cesarean section. Anesth Analg 1999;88:1346–50.[Abstract/Free Full Text]
  45. Fujii Y, Saitoh Y, Tanaka H, Hidenori T. Preoperative oral antiemetics for reducing postoperative vomiting after tonsillectomy in children: granisetron versus perphenazine. Anesth Analg 1999;88:1298–301.[Abstract/Free Full Text]
  46. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Combination of granisetron and droperidol for the prevention of vomiting after paediatric strabismus surgery. Paed Anaesth 1999;9:329–33.[Web of Science][Medline]
  47. Fujii Y, Tanaka H, Kobayashi N. Granisetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting after thyroidectomy. Laryngoscope 1999;109:664–7.[Web of Science][Medline]
  48. Cruickshank S. Mathematics and statistics in anaesthesia. Oxford, New York:Oxford University Press, 1998.
 

Response

Yoshitaka Fujii, , MD

Department of Anesthesiology University of Tsukuba Institute of Clinical Medicine Ibaraki, Japan

Thank you for the opportunity to answer the questions by a reader of Anesthesia & Analgesia. As previously described in the first report by us (1), we evaluated the efficacy and safety of granisetron, a selective 5-hydroxytryptamine Type 3 (5-HT3) receptor antagonist, for preventing postoperative nausea and vomiting (PONV) in women undergoing major gynecologic surgery. Consequently, granisetron was effective for the control of PONV after major gynecologic surgery, with little adverse event. Since then, we have investigated to assess the prophylactic antiemetic therapy with granisetron for preventing PONV after various types of surgery, such as pediatric tonsillectomy, breast surgery, middle ear surgery, and thyroidectomy, with a relatively high incidence of PONV when no prophylactic antiemetic is given.

Granisetron lacks the sedative, dyspholic, and extrapyramidal symptoms associated with non-5-HT3 receptor antagonist (e.g., droperidol, metoclopramide) (2,3). Mild headache occurs in patients receiving granisetron for preventing chemotherapy-induced emesis (4). Similarly, in a number of our studies regarding granisetron and PONV, we found that several patients who had received granisetron experienced mild headache and that an incidence of headache was approximately 10%. Consequently, an incidence of headache seems to be identical, but it was true. How much evidence is required to provide adequate proof about antiemetics’ adverse events introduced recently by several investigators?

Acknowledgments

We thank Horst Fassl, Emeritus Professor of Medical Statistics (Nieder-Olm, Germany) and Herbert Vogt, Professor of Mathematics (Dept. of Applied Mathematics, University of Wuerzburg, Germany) for their statistical advice.

References

  1. Fujii Y, Tanaka H, Toyooka H. Reduction of postoperative nausea and vomiting with granisetron. Can J Anaesth 1994;41:291–4.
  2. Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment, and prevention. Anesthesiology 1992;77:162–84.[Web of Science][Medline]
  3. Yarker YE, McTavish D. Granisetron: an update of its therapeutic use in nausea and vomiting induced by antineoplastic therapy. Drugs 1994;48:761–93.[Web of Science][Medline]
  4. Falkson G, vanZyl AJ. A phase I study of a new 5HT3 receptor antagonist, BRL 43694A, an agent for the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol 1989;24:193–6.[Web of Science][Medline]




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press