Optimal Dose of Granisetron for Prophylaxis Against
`Postoperative Emesis After Gynecological Surgery
`Katsuya Mikawa, MD, Yumiko Takao, MD, Kahoru Nishina, MD, Makoto Shiga, MD,
`Nobuhiro Maekawa, MD, and Hidefumi Obara, MD
`Departments of Anaesthesiology and Intensive Care, Kobe University School of Medicine, Chuo-ku, Kobe, Japan
`
`We previously reported that 20 and 40 ILgl kg of granis-
`etron given during anesthesia prevented postoperative
`emesis with no severe complications. The aim of the
`current study was to determine the optimal dose of
`granisetron for the prevention of postoperative nausea
`and vomiting (PONV) after gynecological surgery. Two
`hundred female patients (ASA physical status I) were
`randomly allocated to one of five groups (n = 40 for
`each): saline (as a control), granisetron 2 ~-tglkg, granis-
`etron 5 ~-tg I kg, granisetron 10 ~-tg I kg, and granisetron
`20 1-tg/kg. Saline or granisetron was given intrave-
`nously immediately after. induction of anesthesia.
`PONY was assessed 24 h after surgery. The percentage
`of emesis-free patients was significantly greater in the
`5- to 20-p.g/kg granisetron groups than in the control
`and 2-p.g/kg granisetron groups (18%, 23%, 68%,78%,
`and 75% of patients receiving saline or granisetron
`2 p.g/kg, 5 ~-tglkg, 10 ~-tglkg, and 20 ~-tg/kg, respective-
`ly). Granisetron doses of 5 p.glkg or larger were also
`superior to the saline and 2-p.g/kg granisetron treat-
`ment for the prevention of nausea over the 24-h study
`
`period (nausea visual analog scales 24 h after surgery:
`49, 41, 18, 16, and 14 mm in the control and granisetron
`2 ~-tg/kg, 5 ~-tg/kg, 10 ~-tg/kg, and 20 J.Lg/kg groups,
`respectively). A smaller proportion of patients received
`"rescue" antiemetic in the 5-p.g/kg or larger granis-
`etron groups than in the control and 2-p.glkg granis-
`etron groups (48%, 40%, 18%, 13%, and 10% of patients
`in the control and granisetron 2 p.gl kg, 5 p.g/ kg, 10 p.gl
`kg, and 20 p.g/ kg groups, respectively). The antiemetic
`effect of granisetron was similar among the groups who
`received 5-~-tg/kg or larger doses. In conclusion, we
`suggest that the optimal dose of granisetron is 5 p.glkg
`for the prevention of !PONV after gynecological sur-
`gery. Implications: Nausea and vomiting postopera-
`tively after gynecologic surgery is a significant prob-
`lem. The authors found that granisetron, a selective
`antagonist of serotonin, markedly dec!'eases the inci-
`dence of postoperative nausea and vomiting at doses of
`5 p.g I kg or larger.
`
`(Anesth Analg 1997;85:652-6)
`
`Postoperative nausea and vomiting (PONV) is
`
`one of the most unpleasant experiences associ-
`ated with surgery (1 ). A variety of pharmacolog-
`ical modalities have been advocated to prevent PONV,
`including antihistamines, anticholinergics, and dopa-
`mine receiPtor antagonists (2). We previously reported
`that 20 or 40 p.g/kg of granisetron, a selective antag-
`onist of 5-hydroxytryptamine type 3 (5-HT3) recep-
`tors, is effective in the prevention of these postopera-
`tive complications without severe adverse effects, and
`that the efficacy was similar between the two doses (3).
`However, smaller doses of granisetron may be effective
`and less expensive for prophylaxis against PONV be-
`cause 10 ~-tg/kg of the drug decreases the incidence of
`cisplatin-induced nausea and vomiting (4). To test this
`hypothesis, we assessed in a prospective, randomized,
`
`Accepted for publication June 4, 1997.
`Address correspondence and reprint requests to Dr. K. Mikawa,
`Department of Anaesthesiology, Intensive Care Unit, Kobe Univer-
`sity School of Medicine, Kusunoki-cho 7, Chuo-ku, Kobe 650, Japan.
`
`and double-blind study, the prophylactic effects of
`smaller doses (2, 5, and 10 J.Lg/kg) of granisetron on
`PONY in patients who were scheduled to undergo gy-
`necological surgery. This population has a great likeli-
`hood of experiencing these complications (5,6). Granis-
`etron produces several adverse effects,
`including
`headache, rash, diarrhea, and liver dysfunction. We also
`examined whether smaller doses of granisetron may
`reduce the incidence of untoward side effects in this
`setting.
`
`Methods
`We studied 200 otherwise healthy inpatients (ASA
`physical status 1) aged 20- 67 yr un dergoing elective
`gynecological surgery after obtaining institutional ap-
`proval and the informed consent of all patients. Ex-
`clusion criteria included antiemetic medication within
`24 h before surgery, gastrointestinal disease, preg-
`nancy, obesity (more than 25% heavier than ideal
`
`652 Anesth Analg 1997;85:652-6
`
`Dr. Reddy's Laboratories, Ltd., et al.
`V.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1049
`
`

`
`Optimal Dose of Granisetron for Prophylaxis Against
`Postoperative Emesis After Gynecological Surgery
`Katsuya Mikawa, MD, Yumiko Takao, MD, Kahoru Nishina, MD, Makoto Shiga, MD,
`Nobuhiro Maekawa, MD, and Hidefumi Obara, MD
`Departments of Anaesthesiology and Intensive Care, Kobe University School of Medicine, Chuo-ku, Kobe, Japan
`
`We previously reported that 20 and 40 ILgl kg of granis-
`etron given during anesthesia prevented postoperative
`emesis with no severe complications. The aim of the
`current study was to determine the optimal dose of
`granisetron for the prevention of postoperative nausea
`and vomiting (PONV) after gynecological surgery. Two
`hundred female patients (ASA physical status I) were
`randomly allocated to one of five groups (n = 40 for
`each): saline (as a control), granisetron 2 ~-tglkg, granis-
`etron 5 ~-tg I kg, granisetron 10 ~-tg I kg, and granisetron
`20 1-tg/kg. Saline or granisetron was given intrave-
`nously immediately after. induction of anesthesia.
`PONY was assessed 24 h after surgery. The percentage
`of emesis-free patients was significantly greater in the
`5- to 20-p.g/kg granisetron groups than in the control
`and 2-p.g/ kg granisetron groups (18%, 23%, 68%,78%,
`and 75% of patients receiving saline or granisetron
`2 p.g/kg, 5 ~-tglkg, 10 ~-tglkg, and 20 ~-tg / kg, respective-
`ly). Granisetron doses of 5 p.glkg or larger were also
`superior to the saline and 2-p.g/kg granisetron treat-
`ment for the prevention of nausea over the 24-h study
`
`period (nausea visual analog scales 24 h after surgery:
`49, 41, 18, 16, and 14 mm in the control and granisetron
`2 ~-tg/kg, 5 ~-tg/kg, 10 ~-tg / kg, and 20 J.Lg/kg groups,
`respectively). A smaller proportion of patients received
`"rescue" antiemetic in the 5-p.g/kg or larger granis-
`etron groups than in the control and 2-p.glkg granis-
`etron groups (48%, 40%, 18%, 13%, and 10% of patients
`in the control and granisetron 2 p.gl kg, 5 p.g/ kg, 10 p.gl
`kg, and 20 p.g/ kg groups, respectively). The antiemetic
`effect of granisetron was similar among the groups who
`received 5-~-tg/kg or larger doses. In conclusion, we
`suggest that the optimal dose of granisetron is 5 p.glkg
`for the prevention of !PONV after gynecological sur-
`gery. Implications: Nausea and vomiting postopera-
`tively after gynecologic surgery is a significant prob-
`lem. The authors found that granisetron, a selective
`antagonist of serotonin, markedly dec!'eases the inci-
`dence of postoperative nausea and vomiting at doses of
`5 p.g I kg or larger.
`
`(Anesth Analg 1997;85:652-6)
`
`Postoperative nausea and vomiting (PONV) is
`
`one of the most unpleasant experiences associ-
`ated with surgery (1 ). A variety of pharmacolog-
`ical modalities have been advocated to prevent PONV,
`including antihistamines, anticholinergics, and dopa-
`mine receiPtor antagonists (2). We previously reported
`that 20 or 40 p.g/kg of granisetron, a selective antag-
`onist of 5-hydroxytryptamine type 3 (5-HT3) recep-
`tors, is effective in the prevention of these postopera-
`tive complications without severe adverse effects, and
`that the efficacy was similar between the two doses (3).
`However, smaller doses of granisetron may be effective
`and less expensive for prophylaxis against PONV be-
`cause 10 ~-tg/kg of the drug decreases the incidence of
`cisplatin-induced nausea and vomiting (4). To test this
`hypothesis, we assessed in a prospective, randomized,
`
`Accepted for publication June 4, 1997.
`Address correspondence and reprint requests to Dr. K. Mikawa,
`Department of Anaesthesiology, Intensive Care Unit, Kobe Univer-
`sity School of Medicine, Kusunoki-cho 7, Chuo-ku, Kobe 650, Japan.
`
`652 Anesth Analg 1997;85:652-6
`
`and double-blind study, the prophylactic effects of
`smaller doses (2, 5, and 10 J.Lg/kg) of granisetron on
`PONY in patients who were scheduled to undergo gy-
`necological surgery. This population has a great likeli-
`hood of experiencing these complications (5,6). Granis-
`etron produces several adverse effects,
`including
`headache, rash, diarrhea, and liver dysfunction. We also
`examined whether smaller doses of granisetron may
`reduce the incidence of untoward side effects in this
`setting.
`
`Methods
`We studied 200 otherwise healthy inpatients (ASA
`physical status 1) aged 20- 67 yr undergoing elective
`gynecological surgery after obtaining institutional ap-
`proval and the informed consent of all patients. Ex-
`clusion criteria included antiemetic medication within
`24 h before surgery, gastrointestinal disease, preg-
`nancy, obesity (more than 25% heavier than ideal
`
`©1997 by the International Anesthesia Research Society
`0003-2999/97/$5.00
`
`Exh. 1049
`
`

`
`ANESTH ANALG
`1997;85:652-6
`
`MIKAWA ET AL.
`GRANISETRON AND POSTOPERATIVE ANTIEMFSIS
`
`653
`
`body weight), liver and/ or renal dysfunction, vomit-
`ing in the 24 h preceding surgery, and need for post-
`operative nasogastric tube. None of the patients un-
`derwent laparoscopic techniques.
`The patients were randomly assigned to one of five
`groups (n = 40 for each grouj) to receive saline (con-
`trol) or granisetron (Kytril ; SmithKiine Beecham
`Seiyaku, Tokyo, Japan) at four different doses (2 p..g/
`kg, 5 J.Lg/kg, 10 J.Lg/kg, or 20 p..g/kg). Saline or gran-
`isetron was administered intravenously over 5 min
`immediately after the induction of anesthesia (imme-
`diately before surgery) by anesthetists who were
`blinded to the nature of treatment. These medications
`had been prepared beforehand in equivalent volume
`by an assistant. Vital signs (arterial blood pressure and
`heart rate) were recorded at 1-min intervals for the
`first 10 min and subsequently at 2.5-min intervals for
`30 min after administration of the study drugs.
`Premedication included diazepam 4-6 mg per os
`and atropine 0.5 mg intramuscularly. All patients un-
`derwent endotracheal intubation and received the
`same anesthetic technique, consisting of thiopental
`5 mg/kg for induction and 60% nitrous oxide and
`1%-2% isoflurane in oxygen for the maintenance of
`anesthesia .. Isoflurane concentrations were adjusted to
`maintain arterial blood pressure and heart rate within
`20% of preinduction values. This anesthetic manage-
`ment is our routine technique. Muscle relaxation was
`achieved with vecuronium and reversed by a combi-
`nation of neostigmine and atropine. Body temperature
`was measured at the tympanic membrane and main-
`tained between 36.0 and 37.5°C. An epidural catheter
`was inserted into all patients before surgery, but no
`drug was given through the catheter during surgery.
`Placement of the epidural catheter was confirmed us-
`ing 4-5 mL of 1% lidocaine with epinephrine. Postop-
`erative analgesia was provided by an epidural bolus
`injection of 0.2 mg buprenorphine (diluted with 10 mL
`of saline) at the end of surgery, followed by continu-
`ous epidural administration of buprenorphine (10 p..g/
`mL) and bupivacaine (2.5 mg/mL) mixture (1.25 mL/
`h). We used this timing of the postoperative analgesics
`to minimize the influence of buprenorphine on nausea
`or vomiting at emergence from anesthesia. No pa-
`tients received blood transfusion or narcotics (IV or
`IM), or had hypotension (defined as systolic blood
`pressure <80 mm Hg) throughout the study. Patients
`who had undergone hysterectomy received carbazo-
`chrome 100 mg and tranexamic acid 500 mg to prevent
`hemostasis, as routine postoperative management in
`our hospital. As a postoperative analgesic supple-
`ment, 5-11 patients in each group received a diclofe-
`nac suppository.
`Blind observers monitored patients for emetic epi-
`sodes, severity of nausea, and vital signs for a 24-h
`period that began when patients responded to a vocal
`
`command after surgery. Adverse events (rash, head-
`ache, and diarrhea) within 24 h after surgery were
`assessed by questionnaire. At the completion of the
`study period, patients provided blood samples to be
`assessed for hematologic, blood chemistry, and renal
`and hepatic variables.
`No distinction was made between vomiting and
`retching for data collection. Vomiting was defined as
`the expulsion of stomach contents through the mouth.
`Retching was defined as an involuntary attempt to
`vomit that did not produce stomach contents. An
`emetic episode was defined as a vomiting or retching
`event or any combination of these events that occurred
`in rapid succession (less than a 1-min interval between
`events). A patient who had no emetic episodes during
`the specified time period was described as emesis-free.
`Nau sea was rated on linear vertical visual analog
`scale (nausea VAS) (0 = no nausea, 100 = severe
`nausea). Nausea assessment was made preopera-
`tively, postoperatively (immediately after tracheal ex-
`tubation), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h
`thereafter. Those patients who scored their nausea as 0
`(no nausea) over the specified time period were
`termed nausea-free.
`The efficacy of the study medication was assessed in
`terms of the number of emetic episodes, the percent-
`age of emesis-free patients, and the percentage of
`nausea-free patients during the 24 hr postoperative
`period, and in terms of the mean nausea VAS score.
`Metoclopramide 10 mg/kg IV was given as a "rescue"
`antiemetic for vomiting or persistent nausea at the
`discretion of a physician blinded to group classifica-
`tion or at the patient's request.
`Comparisons of data between the groups were
`made using the one-way analysis of variance with
`Bonferroni's correction for multiple comparisons of
`parametric data (age, weight, height, last menstrual
`cycle, duration of anesthesia, duration of surgery,
`blood loss, infusion volume, and awakening time
`[time from the end of surgery to eye opening sponta-
`neously or in response to verbal stimuJi]). Nonpara-
`metric data (no history of general anesthesia or post-
`operative nausea or vomiting, incidence of the adverse
`effects, and types of surgery) were analyzed using the
`j- test and Fisher's exact test. The Wilcoxon ranked
`sum test was used to compare treatments with respect
`to the number of emetic episodes. The >( test a.nd
`Fisher's exact test were used to compare the study
`groups with regard to the proportion of emesis-free
`and nausea-free patients over the 24-h study period,
`and the number of patients withdrawn for rescue
`medication. The mean nausea VAS scores were com-
`pared using analysis of variance. In the analysis of
`nausea VAS data, the data of the patients who were
`withdrawn from the study due to administration of
`the rescue antiemetic were excluded. P < 0.05 was
`deemed statistically significant.
`
`Exh. 1049
`
`

`
`654 MIKA WA ET AL.
`GRANISETRON AND POSTOPERATIVE ANTfEMESIS
`
`ANESTH ANALG
`1997;85:652-6
`
`Table 1. Demographic Data
`
`Saline (control)
`40
`48 ± 13
`57 ± 9
`157 ± 6
`15 ± 3 [24]
`34
`3
`
`2
`
`40
`46 ± 12
`55 ± 8
`155 ± 5
`16 ± 3 [26]
`33
`2
`
`Patients (n)
`Age (yr)
`Weight (kg)
`Height (em)
`Last menstrual cycle (days) [n]"
`No previous general anesthesia
`History of PONV
`Type of surgery
`AH
`AH with salpingo-oophorectomy
`Oophorectomy
`Duration of anesthesia (min)
`Duration of surgery (min)
`Blood loss (mL)
`Fluid infused (mL)
`Awakening time (min)
`Data are expressed as mean :!: SD.
`There were no significant differences among the groups.
`PONY = postoperative nausea and vomiting. AH = a bdominal hysterectomy.
`"Patients who had experienced the menopause were excluded.
`b Time from the end of surgery to eye opening.
`
`34
`4
`1
`159 ± 46
`119 ± 35
`340 ± 170
`1210 ± 330
`8±4
`
`33
`5
`2
`151 ± 43
`112 ± 32
`330 ± 160
`1210 ± 320
`7±3
`
`Granisetron (JLg I kg)
`10
`5
`
`40
`44 ± 12
`59± 9
`159 ± 7
`15 ± 4 [2.8]
`32
`4
`
`40
`48 ± 12
`57± 9
`156 ± 7
`16 ± 4 [23]
`33
`3
`
`33
`4
`3
`147 ± 39
`109 ± 34
`310 ± 150
`1170 ± 300
`8 ± 4
`
`36
`2
`2
`161 ± 42
`122 ± 41
`360 ± 180
`1250 ± 350
`7 ± 3
`
`20
`
`40
`43 ± 11
`58± 9
`156 ± 5
`16 ± 3 [29]
`32
`2
`
`35
`5
`0
`156 ± 42
`114 ± 37
`310 ± 150
`1190 ± 300
`8±3
`
`Power analysis revealed that sample size (n = 40 for
`each group) in the current study was sufficient to
`detect antiemetic effects of small doses of granisetron
`(moderate differences in efficacy [d= (p,1-p2)/s
`0.6-0.7]) provided that the power is 70%-80% (7).
`
`ResuHs
`The study groups were comparable with respect to
`characteristics of patients and surgery (Table 1 ).
`Patients receiving 5-20 p,g/kg of granisetron expe-
`rienced significantly fewer emetic episodes than those
`receiving saline or 2 p,g I kg of granisetron over the
`entire 24-h study period (Table 2). More patients
`treated with 5-p,g/kg or larger doses of granisetron
`were emesis-free during the 24 h after surgery corn-
`pared with the saline- or granisetron 2 1-1-g/kg-treated
`patients. The frequency distribution of emetic epi-
`sodes and the number of emesis-free patients were
`similar between the 5-, 10-, and 20-J.Lg/kg granisetron
`groups. There was a decreased need for rescue anti-
`emetic medication in the patients who received
`5-20 p,g I kg granisetron compared with those who
`received saline (Table 2). The number of patients who
`required postoperative rnetoclopramide was similar
`between the granisetron 2 p,g/kg and control groups.
`More patients receiving 5-p,g/kg or larger doses of
`granisetron reported no nausea over the entire 24-h
`study period than those receiving saline or 2 p,g I kg
`granisetron (3, 4, 19, 21, and 22 patients in the control,
`2-p,g/kg, 5-p,g/kg, 10-p,g /kg, and 20-~-tg/kg granis-
`etron groups, respectively). The patients who received
`
`less nausea
`~5 JLg/kg of granisetron reported
`throughout the study period than did those who re-
`ceived saline or 2 p,g/kg granisetron (Figure 1). The
`nausea VAS scores in the 5- to 20-~-tg/kg granisetron
`groups were similar.
`The adverse events in the granisetron groups were
`similar to those in the control group. One to three
`patients in each group experienced a headache of mild
`severity. No rash or diarrhea was observed in any
`patient. None of the patients had tachycardia or hy-
`potension during or after any dose of granisetron.
`Changes in vital signs were similar and remained
`within the clinically acceptable ranges in all groups.
`We found no significant changes in postoperative lab-
`oratory values among the five study groups.
`
`Discussion
`The incidence of PONV in female patients undergoing
`gynecological surgery varies from 24% to 75% (8- 11).
`Although various antiemetics (e.g., anticholinergics,
`antihistamines, dopamine receptor antagonists) are
`available to treat PONV, their use is limited by unto-
`ward side effects (12). Granisetron is a potent anti-
`emetic with high selectivity for 5-HT3 receptor, result-
`ing in fewer adverse side effects than other antiemetics
`(13). Several studies have shown that granisetron at
`doses of 20-40 p,g/kg successfully prevent PONV
`(3,14). However, the high cost of these doses may
`result in an undesirable cost/ effectiveness ratio in gy-
`necological surgery. Granisetron, 1 rng (approximate-
`ly 16 p,g/kg), has recently been reported to be more
`
`Exh. 1049
`
`

`
`A \1[51'11 ANAl C
`1 '.197;8~:6~2 (!
`
`\IIKAWA I I AI
`(,RANI'>tii\ON ~\ND I'Cl'>IOI'LI{\11\E •\\.TII·\Ihl'>
`
`655
`
`Table 2. Distribution of the • umber of Emetic Epi!>ode!> over 24 I lour., for l:.Mh 1 rl'c1tment Group
`Grc1n1~ctron (JJ.g/ kg)
`
`P.1tient., (11)
`Patient<; pN no. ot emetic episodes (11 (0~)J
`0
`I
`2
`3
`4
`Patients withd rawn for rescue medication
`'" (%)1
`
`Saline (control)
`-lO
`
`7 (18)
`5 (13)
`6 (1 "i)
`3 (8}
`0 (0)
`19 (48)
`
`-lO
`
`9 (23)
`6 ( 15}
`"i ( 13)
`3 (8}
`I (3)
`16(-J.O)
`
`40
`
`27 (68)
`4 ( 10)
`2 ('i)
`0 (0)
`0 (0)
`7 (18)t
`
`20
`
`10
`
`-tO
`
`31 (78)
`3 (8)
`I (3)
`0 (0)
`0 (0)
`5 (13)t
`
`30 (75)"
`5 (13)
`I (3)
`0 (0)
`0 (0)
`4 (lOt
`
`100
`
`20
`
`0
`
`D
`Saline (control)
`0
`Gr.rni~elron 2 1.1g/kg
`~ Gr.rn1setron 5 IJg/kg
`Grani~etron 10 1.1g/kg
`-
`W Gr.rn1setron 20 1.1g/kg
`
`n 40 40 40 40 40
`pre-
`operation
`
`40 40 40 4() 40
`0 hr
`
`36 18 .19 40 <10
`I hr
`
`12 1$ 18 40 19
`2 hr
`
`26 2<) \ol 17 17
`4 hr
`Post-operation
`
`22 26 II 16 17
`S hr
`
`21 25 3.1 I~ .16
`12 hr
`
`21 2A .11 ~~ l6
`24 hr
`
`T ime
`,1u~c.1 v i~u.11 an:~log sc.1le scores (mean ::: SEM) during the 24-h sludy ~Wr 1 od . ()
`'il:\'l'rl". *P . 0.05 \'l'r~u;. rontrol
`11011l' lo 100
`Figure I.
`and grani~l'lron 2/tg/ kg. Dat,l .ll 0.5, 1.5, 3, and 6 halter sur~ery were om1tll'd. l lw numbl•rs lwlow the '<-<1\IS denote the number ol p.ltiL'Ill'•
`u-.ed for tlw ,lJM I)'"i~.
`
`effective than 0. 1 mg (approximately 1.6 1--lg/kg) in
`preventing PONV (15). In this previous research, the
`efficacy of doe between 1.6 Mg/ kg and 16 Mg/ kg
`was not evaluated. In the current study, 5 1--lg/ kg of
`granisetron "'as as effective a~ 20 Mg/kg in the pre-
`' ention of P01 V \\ ithout any severe untoward side
`effect ; 2 p.g/ J...g failed to provide effective pro phylaxis
`again!>! thc~c complications. These findings suggest
`that the optimal do!.e of granisetron as a prophylaxis
`against PO V is 5 Mg/ kg. I [owever, in pediatric out-
`patient<; undergoing tonsillo- adenoidectomy, strabis-
`mus surgery, or dental rehabilitation, 10 1--lg/ kg of
`granisetron has been shown to be ineffective in pre-
`venting PONV ( 16). T his inconsistency may be due to
`difference~ in pa tients' age and types of surgery.
`Cost-cffcclivcness analysis of antiemetic therapy for
`ambulatory surgery by Watcha a nd Smith (17) indi-
`cated that prophy lactic use of droperidol was more
`
`favorable than ond<ln~etron, another 5-llT1 recep tor
`antagonist, although tlwre was less incidence of
`PO V in the patients receiving ondansetron (17). An-
`tiemetic prophylaxis with ondansetron (4 mg) has
`been reported to be comparable with that of grani.,-
`etron (3 mg) in laparo~copic surgery (18). Granisetron,
`40 1--lg/ J...g, hclS been ~hown to be su perior to dropcri-
`dol (l.'l or 25 mg) in the pre\ention of PO. V in
`gynecological ~u rgery without coc;t-effeclivcncss anal-
`ysis ( I-n The multifactorial etiology of PO 'V includes
`the type and dur<1lion of su rgery (6). Because moder-
`ate doses of granisctron arc rather costly, the proph)-
`lactic U'>e of granisetron may be less cost-effective than
`dropcridol in surgeries that are expected to have lo\'
`incidence of PO V, despite the high efficacy of gran-
`isclron. In contra!>!, in gynelological SLifgery, in which
`,, high incidence of PONV is cxpeclcd, an antiemetic
`with more potent and longer action (e.g., granisctron)
`
`Exh. 1049
`
`

`
`656 MIKAWA ET AL.
`GRANISETRON AND POSTOPERATIVE ANTIEMESIS
`
`ANESTH ANALG
`1997;85:652-6
`
`may provide a more desirable cost/ effectiveness ratio
`than an antiemetic with less potent and shorter action
`(e.g., droperidol), regardless of their costs.
`In conclusion, we have shown that granisetron at
`doses of 5 and 10 J.Lg/kg given immediately before
`operation successfully prevented PONV in gynecolog-
`ical surgery, and the efficacy of these doses was sim-
`ilar to that of 20 J.Lg/kg granisetron. Furthermore,
`granisetron at 2 J.Lg/kg failed to prevent PONV. Se-
`vere adverse effects were not found at any dose. We
`conclude that the optimal dose of the drug is 5 J.Lg/kg
`in this setting.
`
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