Paediatric Anaesthesia 1998 8: 149–153

Prophylactic therapy with granisetron in theprevention of vomiting after paediatric surgery. Arandomized, double-blind comparison withdroperidol and metoclopramide

YOSHITAKA FUJII MD AND HIROYOSHI TANAKA MD

Department of Anaesthesiology, Toride Kyodo General Hospital, Toride City, Ibaraki, Japan

SummaryThe antiemetic efficacy of droperidol, metoclopramide andgranisetron was compared with placebo in the reduction ofvomiting after paediatric surgery (the extremities; inguinal hernia;and phimosis) during general inhalational anaesthesia. One hundredchildren, ASA physical status I, 4–10 years of age, were enrolled in aprospectively, randomized, double-blind investigation and assignedto one of four treatment regimens: placebo (saline, n=25),droperidol (50 lg·kg1, n=25), metoclopramide (0.25 mg·kg-1, n=25)or granisetron (40 lg·kg-1, n=25). These drugs were administeredintravenously (iv) after inhalation induction of anaesthesia. Acomplete response, defined as no emesis and no need for anotherrescue antiemetic during the first 24 h after anaesthesia, occurred in60%, 76%, 68% and 88% of patients who had received placebo,droperidol, metoclopramide and granisetron, respectively (P<0.05;overall Fisher’s exact probability test). The incidence of adverseevents postoperatively was not different among the treatmentgroups. In conclusion, granisetron 40 lg·kg-1 is a better antiemeticthan droperidol and metoclopramide when compared to placebo forthe prevention of postoperative emesis in children.

Keywords: complications: vomiting; antiemetics; droperidol,metoclopramide, granisetron

Introduction unanticipated admission. Different regimens havebeen tried to prevent and treat vomiting post-

Postoperative vomiting is an important adverse effectoperatively, with variable success (2,3). Undesirable

of general anaesthesia in children as well as in adultsside-effects, such as excessive sedation and extra-(1). Sometimes it may result in prolonged stay inpyramidal symptoms, have also been noted (4). Itrecovery room, fluid and electrolyte imbalance, andhas been reported that ondansetron, one of the newclass of 5-hydroxytryptamine type 3 (5-HT3) receptorantagonists, is effective in the prevention of post-

Correspondence to: Dr Y. Fujii, Department of Anaesthesiology,operative emesis in children (5). Granisetron, anotherUniversity of Tsukuba Institute of Clinical Medicine, 2-1-1,

Amakubo, Tsukuba City, Ibaraki 305, Japan. 5-HT3 receptor antagonist, has a more potent and

149 1998 Blackwell Science Ltd

150 Y. FUJII & H. TANAKA

longer activity against vomiting related to chemo- Ultima, Datex, Finland). Muscle relaxation wasachieved with vecuronium and reversed by atherapy than ondansetron (6). We have recently

demonstrated that this pharmacological agent combination of atropine 0.02 mg·kg−1 iv andneostigmine 0.04 mg·kg−1 iv at the completion ofreduces vomiting after strabismus repair and

tonsillectomy in children (7). However, no studies surgery. The trachea was extubated when the patientwas awake. Rectal temperature was monitored andup to date have examined the prophylactic use of

granisetron for preventing postoperative vomiting in maintained at 37±1°C using hot water padsthroughout surgery. Postoperatively, all patientspaediatric patients undergoing other surgicalremained in hospital for a couple of days. Clearprocedures, such as the extremities, inguinal hernialiquids were offered only if the patient requested,and phimosis, with a relatively high incidence ofand other oral intake was not allowed for 4 h afteremesis postoperatively (8). We conducted arecovery from anaesthesia. If two or more episodesprospective, randomized, double-blind, placebo-of vomiting occurred during the first 24 h aftercontrolled study to examine the efficacy ofanaesthesia, another rescue antiemetic (e.g.droperidol, metoclopramide and granisetron fordomperidone pr) was given. Postoperative analgesiapreventing postoperative vomiting in this paediatricwas provided by acetaminophen 10–25 mg·kg−1 prpopulation.for mild pain and pentazocine 0.3 mg·kg−1 iv forsevere pain.Methods Postoperatively, all episodes of retching andvomiting during the first 24 h after anaesthesia wereAfter obtaining institutional review board approvalrecorded by nursing staff who did not know whichfrom Toride Kyodo General Hospital, as well astreatment each patient had received. Vomiting wasinformed consents from each parent, we studied 100defined as the forceful expulsion of gastric contentsotherwise healthy paediatric patients (ASA physicalfrom the mouth, whereas retching was defined asstatus I) aged 4–10 year undergoing elective surgerythe laboured, spasmodic, rhythmic contractions offor the extremities (e.g. resection of superficialthe respiratory muscles without the expulsion oftumour, inguinal hernia and phimosis). Patientsgastric contents (4). Nausea was not assessed as awho had a history of motion sickness or previousseparate entity in this study because of the youngpostoperative vomiting, and those who had takenage of the patients. For the purpose of analysis inantiemetic medication within 24 h before surgerythis study, the act of retching was considered to thewere excluded. Patients were not allowed to havesame as vomiting. A complete response (i.e. emesis-solid food after midnight before surgery. Clear liquidsfree) was defined as no emesis and no need forwere permitted up to 3 h before operation.another rescue antiemetic during the first 24 h afterNo preoperative medications were administered.anaesthesia. The details of any adverse effect wereThe patients received, in a randomized, double-blindalso recorded by a designated follow-up nurse whomanner, a single dose of either placebo (saline, n=interviewed the parents of each patient.25), droperidol (50 lg·kg−1, n=25), metoclopramide

Statistical analyses of data among the treatment(0.25 mg·kg−1, n=25) or granisetron (40 lg·kg−1, n=groups were performed by one-way analysis of25) intravenously (iv) over 2–5 min after inhalationvariance (ANOVA) with Bonferroni correction forinduction of anaesthesia and prior to the surgicalmultiple comparison, chi-squared test, or Fisher’sprocedure. Anaesthesia was induced with sevo-exact probability test, as appropriate. A P-value offlurane in 66% nitrous oxide (N2O) and oxygen (O2)<0.05 was considered significant. All values werevia mask. Tracheal intubation was facilitated withexpressed as mean±SD, median (range) or numbervecuronium 0.1 mg·kg−1 iv. After tracheal intubation,(%).anaesthesia was maintained with N2O/O2 (2:1) and

sevoflurane 0.5%–3.0% (inspired concentration).ResultsVentilation was controlled mechanically and was

adjusted to keep an endtidal CO2 tension between Patient demographics, types of surgery, and4.6 kPa and 5.2 kPa (35–40 mmHg) with an anaesthetic or postoperative management were

comparable among the treatment groups (Table 1).anaesthetic/respiratory gas analyser (Capnomac

1998 Blackwell Science Ltd, Paediatric Anaesthesia, 8, 149–153

PROPHYLACTIC THERAPY WITH GRANISETRON 151

Table 1Patient demographics

Placebo Droperidol Metoclopramide Granisetron(n=25) (n=25) (n=25) (n=25)

Age (yr) 6.8±2.3 6.3±2.1 6.5±2.1 6.6±2.1Sex (male/female) 14/11 14/11 14/11 14/11Height (cm) 120.1±12.5 119.2±12.7 118.3±9.5 120.0±11.0Weight (kg) 24.0±6.3 24.0±5.9 23.6±6.3 24.5±7.2Duration of operation (min) 50 (10–156) 65 (11–195) 56 (16–165) 52 (15–184)Duration of anaesthesia (min) 70 (25–185) 81 (30–220) 80 (40–180) 70 (30–220)Types of surgery (n)

Extremities 4 4 4 4Inguinal hernia 10 10 11 11Phimosis 11 11 10 10

Postoperative management (n)Acetaminophen 21 20 21 21Pentazocine 3 4 3 3

Values are ±SD, median (range) or number. There were no significant differences among the treatment groups.

Table 2Number (%) of patients experienced emesis-free and required another rescue antiemetic during the first 24 h after anaesthesia

Placebo Droperidol Metoclopramide Granisetron(n=25) (n=25) ∗P values (n=25) ∗P values (n=25) ∗P values

No. (%) of patients experiencedemesis-free 15 (60%) 19 (76%) P=0.182 17 (68%) P=0.384 22 (88%) P=0.025

No. (%) of patients requiredanother rescue antiemetic 8 (32%) 3 (12%) P=0.085 6 (24%) P=0.377 o (o%) P=0.002

∗ Study drug compared with placebo by Fisher’s exact probability test.

A complete response occurred in 15 of 25 (60%) Discussionpatients who had received placebo vs. 19 of 25 (76%)

Vomiting is one of the common and unpleasantthose who had received droperidol (P=0.182), 17 ofconsequences of general anaesthesia in children (1).25 (68%) those who had received metoclopramideIts incidence is highly variable, with reported rates(P=0.384), or 22 of 25 (88%) those who had receivedaveraging 60%–70% in paediatric patients under-granisetron (P=0.025) (Table 2).going strabismus repair or tonsillectomy (9,10). ThisEight children who had received placebo, three ofstudy demonstrated that ten of 25 (40%) patientsthose who had received droperidol and six of thosewho had received placebo experienced emesis afterwho had received metoclopramide required anothersurgery for the extremities, inguinal hernia andrescue antiemetic for the treatment of two orphimosis. The exact reason for this difference is notmore episodes of vomiting, whereas none who hadknown, but may be attributed to the difference inreceived granisetron needed it (P=0.002) (Table 2).surgical procedure. The difference in ethnicity,The most common untoward adverse events wereanaesthetics administered (sevoflurane), or exclusionheadache and drowsiness, which were relativelyof high risk patients who had a history of motionmild. There were no differences in the incidencesickness or previous postoperative vomiting may alsoof adverse effects among the treatment groupsbe associated with the difference of the incidence of(placebo; 20%, droperidol; 24%, metoclopramide;vomiting. In this study, however, the relatively high20%, granisetron; 25%). No extrapyramidal symptom

was observed in any group. incidence of postoperative symptom justifies the use

1998 Blackwell Science Ltd, Paediatric Anaesthesia, 8, 149–153

152 Y. FUJII & H. TANAKA

of prophylactic antiemetics for preventing emesis For the prevention of postoperative emesis inpaediatric patients undergoing strabismus repair orafter these types of surgery.tonsillectomy, droperidol 50 lg·kg−1 or meto-The aetiology of vomiting after surgery for theclopramide 0.25 mg·kg−1 has often been used (4).extremities, inguinal hernia and phimosis, is notHigher doses of these antiemetics are associatedknown, but is probably multifactorial (4). Awith sedative activity and extrapyramidal symptomsnumber of recognized contributing factors include(4). In this study therefore droperidol 50 lg·kg−1 orage, sex, obesity, a history of motion sickness ormetoclopramide 0.25 mg·kg−1 was administered. Weprevious postoperative emesis, operative procedure,could not find any report to examine the efficacy ofanaesthetic technique and postoperative pain.these drugs for preventing emesis after paediatricIn this study, however, there were no differencessurgery for the extremities, inguinal hernia andamong the groups with regard to patientphimosis. The results of this study demonstrateddemographics, types of operation and anaestheticthat droperidol 50 lg·kg−1 or metoclopramideor postoperative management. Therefore, the0.25 mg·kg−1 were not effective for preventingdifference in the incidence of patients being emesis-postoperative emesis in this population.free and those requiring another rescue antiemetic

This study also showed that eight children whoduring the first 24 h after anaesthesia among thehad received placebo, three of those who had receivedgroups can be attributed to the difference in thedroperidol and six those who had receivedantiemetics tested.metoclopramide required another rescue antiemeticGranisetron has already been shown to be anfor the treatment of severe vomiting (i.e. two oreffective treatment of cisplatin-induced nausea andmore episodes of vomiting), whereas none who hadvomiting (11). It has been recently reported thatreceived granisetron needed it (P=0.002). Thus, it isthis pharmacological agent is effective in reducingsuggested that granisetron reduces the severity ofthe incidence of postoperative emesis in childrenemesis after surgery for the extremities, inguinalundergoing strabismus surgery and tonsillectomy (7).hernia and phimosis.

This study also demonstrated that the incidence ofIn this study, there were no differences in the

emesis-free after surgery for the extremities, inguinalincidence of adverse events among the groups.

hernia and phimosis, in patients who had receivedExtrapyramidal symptoms were not observed in

granisetron was higher than in those who had either group, but the use of droperidol orreceived placebo (P=0.024). The precise mechanism metoclopramide has been described to be associatedof granisetron in the reduction of postoperative with these symptoms (4). It has been reported thatemesis remains unclear, but this antiemetic may act granisetron lacks the sedative and extrapyramidalat the area postrema and the nucleus tractus solitarius side effects (16). Thus, unlike these antiemetics,which contain a number of 5-HT3 receptors with granisetron is considered to be relatively free ofdemonstrated antiemetic effects (12,13). adverse effects.

It is well-known that granisetron 40–80 lg·kg−1 is It has been demonstrated by several investigatorseffective for the treatment of cancer therapy-induced that a new antiemetic, such as ondansetron, isvomiting (14). We have recently demonstrated that criticized because of its high cost (17,18). Our hospitalgranisetron 40 mg·kg−1 is the optimal effective dose pharmacy pays $100.2 for 3 mg of granisetron. Thus,for preventing emesis after strabismus repair and this antiemetic as well as ondansetron ($100.3 fortonsillectomy in children (15). We found no report 3 mg) is more expensive than others (e.g. $1.75 forto determine the minimum effective dose of this droperidol 2.5 mg, $0.61 for metoclopramide 10 mg).antiemetic in the prevention of emesis after paediatric In this study, however, the efficacy of granisetronsurgery for the extremities, inguinal hernia and was superior to that of droperidol or metoclopramidephimosis. However, the use of this pharmacological when compared to placebo in the prevention ofagent in higher doses may increase adverse effects. emesis after paediatric surgery for the extremities,Therefore, this dose chosen for this study was inguinal hernia and phimosis.40 lg·kg−1 in paediatric patients undergoing these In conclusion, this study suggests that

intraoperative use of granisetron 40 lg·kg−1 is antypes of surgery.

1998 Blackwell Science Ltd, Paediatric Anaesthesia, 8, 149–153

PROPHYLACTIC THERAPY WITH GRANISETRON 153

10 Litman RS, Wu CL, Catanzaro FA. Ondansetron decreaseseffective antiemetic for preventing postoperativeemesis after tonsillectomy in children. Anesth Analges 1994; 78:

emesis in children undergoing surgery for the 478–481.extremities, inguinal hernia and phimosis. 11 Bermudez J, Boyle EA, Minter WD et al. The anti-emetic

potential of the 5-hydroxytryptamine3 receptor antagonist BRL43694. Br J Cancer 1988; 58: 644–650.

References 12 Kilpatrick GJ, Jones BJ, Tyers MB. The distribution of specificbinding of the 5-HT3 receptor ligand [3H] GR65630 in rat brain

1 Cohen MM, Cameron CB, Duncan PG. Pediatric anesthesia using quantitative autoradiography. Neurosci Lett 1988; 94:morbidity and mortality in the postoperative period. Anesth 156–160.Analges 1990; 70: 160–167. 13 Carmicheal J, Cantwell BMJ, Edwards CM et al. A

2 Lerman J, Eustis S, Smith DR. Effect of droperidol pretreatment pharmacokinetic study of granisetron (BRL 43694A), a selectiveon postoperative vomiting in children undergoing strabismus 5-HT3 receptor antagonist: correlation with anti-emeticsurgery. Anesthesiology 1986; 65: 322–325. response. Cancer Chemotherapy Pharmacol 1989; 24: 45–49.

3 Cohen SE, Woods WA, Wyner J. Antiemetic efficacy of 14 Furue H, Oota K, Taguchi T et al. Clinical evaluation ofdroperidol and metoclopramide. Anesthesiology 1984; 60: 67–69. granisetron against nausea and vomiting induced by anticancer

4 Watcha MF, White PF. Postoperative nausea and vomiting. Its drugs. Optimal dose-findings study. J Clin Therapy Med 1990;etiology, treatment, and prevention. Anesthesiology 1992; 77: 6: 49–61 (Japanese).162–184. 15 Fujii Y, Toyooka H, Tanaka H. Effective dose of granisetron for

5 Ummenholfer W, Frei FJ, Urwyler A et al. Effects of ondansetron preventing postoperative emesis in children. Can J Anaesthin the prevention of postoperative nausea and vomiting in 1996; 43: 660–667.children. Anesthesiology 1994; 81: 804–810. 16 Falkson G, van Zyl AJ. A phase I study of new 5-HT3 receptor

6 Andrews PLR, Bhandari P, Davey PT et al. Are all 5-HT3 antagonist, BRL 43694A, an agent for the prevention ofreceptor antagonists the same? Euro J Cancer 1992; 28A: S2–S6. chemotherapy-induced nausea and vomiting. Cancer

Chemotherapy Pharmacol 1989; 24: 193–196.7 Fujii Y, Tanaka H, Toyooka H. Granisetron reduces vomiting17 White PF, Watcha MF. Are new drugs cost-effective for patientsafter strabismus surgery and tonsillectomy in children. Can J

undergoing ambulatory surgery? (Editorial) AnesthesiologyAnaesth 1996; 43: 35–38.1993; 78: 2–5.8 Rowley MP, Brown TCK. Postoperative vomiting in children.

18 Lerman J. Are antiemetics cost-effective for children? (Editorial)Anaesth Intens Care 1982; 10: 309–313.Can J Anaesth 1995; 42: 263–266.9 Rose JB, Martin TM, Corddry DH et al. Ondansetron reduces

the incidence and severity of poststrabismus repair vomitingin children. Anesth Analges 1994; 79: 486–489. Accepted 16 July 1997

1998 Blackwell Science Ltd, Paediatric Anaesthesia, 8, 149–153