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Ramosetron for Preventing Postoperative Nausea and Vomiting in Women Undergoing Gynecological Surgery

Fujii, Yoshitaka MD*; Saitoh, Yuhji MD; Tanaka, Hiroyoshi MD; Toyooka, Hidenori MD*

doi: 10.1213/00000539-200002000-00043
GENERAL ARTICLES
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In a prospective, randomized, double-blinded, placebo-controlled trial, we evaluated the efficacy of ramosetron at three different doses (0.15, 0.3, and 0.6 mg) for the prevention of postoperative nausea and vomiting (PONV) after gynecological surgery. One hundred twenty women, ASA physical status I or II, aged 21–63 yr, received IV either placebo or ramosetron 0.15, 0.3, or 0.6 mg (n = 30 of each) at the completion of surgery. A standard general anesthetic technique and postoperative analgesia were used. A complete response, defined as no PONV and no need for another rescue antiemetic, during 0–3 h after anesthesia occurred in 40%, 47%, 87%, and 90% of patients who had received placebo and ramosetron 0.15, 0.3, and 0.6 mg, respectively. Corresponding results during 3–24 h after anesthesia were 43%, 50%, 87%, and 90%, and 24–48 h after anesthesia were 50%, 53%, 90%, and 93% (P < 0.05). Patients who had received ramosetron 0.3 or 0.6 mg were satisfied compared with those who had received placebo (P < 0.05). There were no serious clinical adverse events caused by the study drug in any of the groups. In conclusion, ramosetron 0.3 mg is an effective antiemetic for preventing PONV during 0–48 h after anesthesia in female patients undergoing gynecological surgery. Increasing the dose to 0.6 mg provided no further benefit.

Implications This randomized, double-blinded, placebo-controlled trial in 120 women found the effective dose of ramosetron for preventing postoperative nausea and vomiting after gynecological surgery to be 0.3 mg.

*Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, Tsukuba City; and †Department of Anesthesiology, Toride Kyodo General Hospital, Toride City, Ibaraki, Japan

October 5, 1999.

Address correspondence and reprint requests to Y. Fujii, MD, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1, Amakubo, Tsukuba City, Ibaraki 305, Japan.

Postoperative nausea and vomiting (PONV) are distressing adverse effects of anesthesia and surgery, with a remarkably high incidence in women undergoing major gynecological surgery (1). We showed that granisetron, a selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, reduces the incidence of PONV after gynecological surgery (2) and showed that granisetron is a better antiemetic than other com- monly used and well established antiemetics, such as droperidol and metoclopramide (2,3). Ramosetron, (R)-5-[(1-methyl-3-indolyl)cardonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, (Nasea®; Yamanouchi, Tokyo, Japan) is another selective antagonist of the 5-HT3 receptor, and is effective for the treatment of nausea and vomiting induced by anticancer drugs (4). Ramosetron has more potent and longer acting properties against cisplatin-induced emesis than granisetron (4). We recently demonstrated that ramosetron 0.3 mg compared with granisetron 2.5 mg is effective for preventing PONV within a 48-h postanesthetic period (5). However, little is known about the minimal effective doses for the prevention of PONV with ramosetron. Furthermore, an overdose of this antiemetic may cause undesirable adverse effects, such as severe headache (6). We conducted a prospective, randomized, double-blinded, placebo-controlled study to determine the effective dose of ramosetron for preventing PONV in female patients undergoing major gynecological surgery.

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Methods

After obtaining institutional review board approval and informed consent, we studied 120 ASA physical status I or II patients, aged 21–63 yr, undergoing major gynecological surgery. Patients who had gastrointestinal disease, those who had a history of motion sickness and/or previous PONV, and those who had received any antiemetic medication within 24 h before surgery were excluded.

Patients were allocated randomly to one of four groups (n = 30 in each) to receive placebo or ramosetron at three different doses (0.15 mg, 0.3 mg, or 0.6 mg) IV at the completion of surgery. A randomization list was generated, and identical syringes containing each drug were prepared by personnel not involved in the study, according to the list.

Patients received no preanesthetic medication. Standard monitoring was used. An epidural catheter was inserted at the L2-3 or L3-4 level and was placed cephalad (approximately 5 cm). Correct placement of the catheter was confirmed by administering 2 mL of lidocaine 1.5% plus epinephrine (i.e., test dose). Anesthesia was induced with thiopentone 5 mg/kg IV and fentanyl 2 μg/kg IV, and vecuronium 0.2 mg/kg IV was used to facilitate tracheal intubation. After intubation of the trachea, anesthesia was maintained with 0.5%–2.0% isoflurane (inspired concentration) and 66% nitrous oxide in oxygen with controlled ventilation adjusted to maintain PETCO2 between 35 and 40 mm Hg throughout surgery, as measured by an anesthetic/respiratory gas analyzer. When hemodynamic variables were stable, 10–15 mL of lidocaine 1.5% was injected through the epidural catheter during surgery. Neuromuscular block was achieved with vecuronium as required. A nasogastric tube was inserted, and suction was applied to empty the stomach of air and other contents. Before extubation of the trachea, the nasogastric tube was again suctioned and then removed. At the completion of surgery, atropine 0.02 mg/kg IV and neostigmine 0.04 mg/kg IV were administered for reversal of muscle relaxation, and the trachea was extubated when the patient was awake. Rectal temperature was monitored and maintained at 37° ± 1°C by using a warming pad. Intraoperative hydration was set at 10 ml · kg−1 · h−1. Postoperative analgesia was provided with a mixture of 100 mL of bupivacaine 0.25%, and morphine 0.1 mg/mL was started after surgery at a rate of 2 mL/h with an infusion balloon catheter. Patients in all groups received indomethacin 50 mg rectally when they complained of intolerable pain.

All episodes of PONV (nausea, retching, and vomiting) were recorded within the first 48 h after anesthesia covering three time periods, 0–3 h in the postanesthesia care unit, 3–24 h in the postoperative ward, and 24–48 h in the general ward. Specifically trained nurses performed the questioning, and they were blinded to study groups. Nausea was defined as the subjectively unpleasant sensation associated with awareness of the urge to vomit; retching was defined as the labored, spastic, rhythmic contraction of the respiratory muscles without the expulsion of the gastric contents; and vomiting was defined as the forceful expulsion of gastric contents from the mouth (7). Complete response (i.e., emesis-free) was also defined as no PONV and no need for another rescue antiemetic medication. If two or more episodes of PONV occurred during the first 48 h after anesthesia, another rescue antiemetic (e.g., domperidone rectally) was given. At the end of each observation period, patients evaluated general satisfaction using a linear numerical scale ranging from 0 (complete dissatisfaction) to 10 (complete satisfaction) (5). The severity of nausea was also graded ranging from 0 (no nausea) to 10 (severe nausea) (5). The details of any other adverse effects were recorded by the nurses who interviewed the patients and recorded complaints.

Statistical analyses of data among the groups were performed by using analysis of variance with Bonferroni’s correction for multiple comparison, χ2 test, two-tailed Fisher’s exact probability test, or Mann-Whitney U-test, as appropriate. A P value of < 0.05 was considered significant. Values were expressed as mean ± SD, number (%), or median (range). Based on a previous study by us (5), it was calculated that 30 patients per group would be required to demonstrate a 30% difference in values for a complete response (no PONV, no rescue) (which was regarded as the primary endpoint) α=0.05 with a power (1-β) of 80%.

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Results

There were no differences in patient demographics among the treatment groups (Table 1).

Table 1

Table 1

A complete response (no PONV, no rescue) during 0–3 h after anesthesia was 40% with placebo, 47% with ramosetron 0.15 mg, 87% with ramosetron 0.3 mg, and 90% with ramosetron 0.6 mg, respectively; corresponding incidence during 3–24 h after anesthesia was 43%, 50%, 87%, and 90%; corresponding incidence during 24–48 h after anesthesia was 50%, 53%, 90%, and 93%. Thus, significantly more patients had a complete response within the first 48 h after anesthesia who received ramosetron 0.3 mg and ramosetron 0.6 mg compared with those who received placebo (P < 0.05). There were no differences between patients who received ramosetron 0.15 mg and those who received placebo (Table 2).

Table 2

Table 2

In each observation period, severity of nausea was less in patients who had received ramosetron 0.3 mg or ramosetron 0.6 mg than in those who had received placebo (P < 0.05). Patients who had received ramosetron 0.3 mg or ramosetron 0.6 mg were more satisfied compared with those who had received placebo (P < 0.05).

The most common adverse events in the four groups were headache, dizziness, and drowsiness. There were no differences in the incidence of these events during 0–3 h, 3–24 h, and 24–48 h after anesthesia among the treatment groups.

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Discussion

Patients undergoing major gynecologic surgery have a remarkably high incidence of PONV when no prophylactic antiemetic is given (1). This problem is multifactorial in origin, and includes age, obesity, a history of motion sickness and/or previous PONV, menstrual cycle, surgical procedure, anesthetic technique, and postoperative pain (7). In this study, however, these factors were well balanced among the treatment groups, and patients with a history of motion sickness and/or previous PONV were excluded because they had a relatively high incidence of PONV (7). Therefore, the difference in a complete response (no PONV, no rescue) can be attributed to the study drug.

Ramosetron is effective for the treatment of nausea and vomiting induced by cancer chemotherapy (6). We demonstrated that ramosetron 0.3 mg prevents PONV in patients undergoing major gynecologic surgery (5). The exact mechanism of ramosetron is not known, but it is possible that ramosetron may act on sites containing 5-HT3 receptors with demonstrated antiemetic effects (6).

We could not find any report to determine the effective dose of ramosetron for preventing PONV after major gynecological surgery. We demonstrated that ramosetron 0.3 mg was as effective as ramosetron 0.6 mg for preventing PONV and showed no difference in a complete response between patients who received placebo and those who received ramosetron 0.15 mg. These results suggest that ramosetron 0.3 mg is the minimal effective dose for preventing PONV in patients undergoing major gynecological surgery.

Ramosetron lacks the sedative, dystrophic, and extrapyramidal symptoms associated with other non-5-HT3 antiemetics, such as droperidol and metoclopramide (6,7). A previous study by us (5) demonstrated that ramosetron is relatively free of adverse effects and was safe for the control of PONV after major gynecological surgery. No differences in the incidence of adverse events, such as headache, dizziness, and drowsiness, were observed among the four groups in this clinical trial.

In conclusion, ramosetron 0.3 mg appears to be the minimal effective dose for preventing PONV in patients undergoing major gynecological surgery. A double dose of 0.6 mg does not add any therapeutic advantage compared with ramosetron 0.3 mg.

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References

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