preoperative oral granisetron for the prevention of vomiting following paediatric surgery

Preoperative oral granisetron for the preventionof vomiting following paediatric surgery

YOSHITAKA FUJII M DM D AND HIRITOSHI TANAKA M DM D

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

SummaryBackground: We evaluated the ef®cacy of granisetron, 5-hydroxytryp-

tamine type 3 receptor antagonist, given orally, preoperatively, for

the prevention of postoperative vomiting in children undergoing general

anaesthesia for surgery (inguinal hernia, phimosis-circumcision).

Methods: In a randomized, double-blinded manner, 100 children, ASA

physical status I, aged 4±11 years, received orally placebo or gra-

nisetron at three different doses (20 lg�kg±1, 40 lg�kg±1, 80 lg�kg±1)

60 min before surgery (n � 25 of each). The same standard general

anaesthetic technique was used.

Results: The percentage of patients being emesis-free during 0±6 h after

anaesthesia was 56% with placebo, 64% with graniseron 20 lg�kg±1

(P � 0.773), 88% with granisetron 40 lg�kg±1 (P � 0.027) and 92%

with granisetron 80 lg�kg±1 (P � 0.01); the corresponding rate during

6±24 h after anaesthesia was 60%, 68% (P � 0.768), 92% (P � 0.02)

and 92% (P � 0.02) (P-values versus placebo). No clinically serious

adverse events were observed in any of the groups.

Conclusions: In summary, preoperative oral granisetron 40 lg�kg±1

is effective for the prevention of vomiting following paediatric surgery

(inguinal hernia, phimosis-circumcision). Increasing the doses to

80 lg�kg±1 provides no demonstrable additional bene®t.

Keywords: complications: vomiting; pharmacology, antiemetics:

granisetron; surgery: inguinal hernia, phimosis, circumcision

Introduction

Postoperative vomiting (POV) is an important

adverse event of general anaesthesia in children as

well as in adults (1). Sometimes, it may result in a

prolonged stay in the recovery room, ¯uid and

electrolyte imbalance and unanticipated admission.

Pharmacological approaches, including butyrophe-

nones (e.g. droperidol) and dopamine receptor

antagonists (e.g. metoclopramide), prevent POV in

children, but are associated with undesirable

adverse effects, such as excessive sedation and

extrapyramidal symptoms (2). Granisetron, similar

to ondansetron, is a selective 5-hydroxytryptamine

type 3 (5-HT3) receptor antagonist, and has a more

potent and longer acting activity against cisplatin-

induced emesis than ondansetron (3). It is also

effective for the prevention of POV in children

Correspondence to: Yoshitaka Fujii, Department of Anaesthesiology,University of Tsukuba, Institute of Clinical Medicine, 2-1-1,Amakubo, Tsukuba City, Ibaraki 305-8576, Japan (e-mail: [email protected]).

Paediatric Anaesthesia 2002 12: 267±271

Ó 2002 Blackwell Science Ltd 267

undergoing general anaesthesia for surgery (inguinal

hernia, phimosis), with a relatively high incidence of

POV (4). However, granisetron (US$ 33.40 for 1 mg)

as well as ondansetron (US$ 33.43 for 1 mg) are

much more expensive than traditional antiemetics,

such as droperidol (US$ 1.80 for 2.5 mg) and

metoclopramide (US$ 0.60 for 10 mg). This may

delay wide-spread use as an antiemetic regimen. An

oral graniserton preparation (US$ 12.60 for 1 mg)

that is less expensive and is effective for the control

of emesis induced by cancer chemotherapy is now

available (5). We conducted a prospective, random-

ized, double-blinded, placebo-controlled trial to

evaluate the ef®cacy of oral granisetron for the

prevention of POV following paediatric surgery

(inguinal hernia, phimosis-circumcision) in children.

Methods

The study was approved by our instituional ethics

committee, and informed consent was obtained from

the parents of 100 children, ASA physical status I,

aged 4±11 years, who were undergoing general

anaesthesia for surgery (inguinal hernia, phimosis).

Patients who had a history of motion sickness and/

or previous POV and those who had received

antiemetics within 24 h before surgery were exclu-

ded from the study. Patients were not allowed to

have solid food after midnight before surgery. Clear

liquids were permitted up to 3 h before surgery.

Patients were randomly assigned to one of four

groups (n � 25 of each) to receive orally placebo or

granisetron at three different doses (20 lg�kg±1,

40 lg�kg±1, 80 lg�kg±1) 60 min before surgery. A

randomization list was generated, and syrups with

placebo or granisetron were prepared for each study

group by a pharmacist. The doses of granisetron

used in the current study were based on those from

our previous study (6).

No preoperative medications were administered.

Anaesthesia was induced via mask by administer-

ing increasing concentration of sevo¯urane in 66%

nitrous oxide (N2O) and oxygen (O2). After an inha-

lation induction of anaesthesia, atropine 0.01 mg�kg±1

was administered intravenously (i.v) and then tra-

cheal intubation was facilitated with vecuronium

0.1 mg�kg±1 i.v. After tracheal intubation, anaesthesia

was maintained with N2O/O2 (2 : 1) and sevo¯urane

0.5±3.0% (inspired concentration). Ventilation was

controlled and was adjusted to keep an endtidal CO2

tension at 4.6±5.2 kPa (35±40 mmHg) with an anaes-

thetic/respiratory gas analyser (UltimaTM, Datex-

Omeda, Helsinki, Finland). Local anaesthetics were

not used during surgery. At the termination of

surgery, muscle relaxation was reversed by a combi-

nation of atropine 0.02 mg�kg±1 i.v. and neostigmine

0.04 mg�kg±1 i.v. The trachea was extubated when the

patient was awake. Rectal temperature was monit-

ored and maintained at 37 °C using hot water pads

throughout surgery. Postoperatively, all patients

were admitted to the hospital and remained for

2 days. Clear liquids were offered only if requested

by the patient, and other oral intake was not allowed

for 4 h after recover from anaesthesia. Postopera-

tive analgesia was provided with acetaminophen

10±15 mg�kg±1 rectally for mild pain and pentazocine

0.3 mg�kg±1 i.v. for severe pain.

All episodes of emetic symptoms (retching, vom-

iting) during the ®rst 24 h after anaesthesia were

recorded by nursing staff who did not know which

treatment each patient had received. Retching was

de®ned as the laboured, spasmodic, rhythmic con-

tractions of respiratory muscles without the expul-

sion of gastric contents, and vomiting was de®ned as

the forceful expulsion of gastric contents from the

mouth (2). Because of the young age of the patients,

nausea was not assessed as a separate entity and

patient satisfaction for the study drug was also not

evaluated in the present study. The details of any

adverse effects were recorded by follow-up nurses.

At the end of the observation period, levels of

sedation were graded on a 3-point scale and were

assessed as 0 � awake, 1 � drowsy and 2 � asleep/

excessive sedation.

Statistical analyses of data among the treatment

groups were performed by ANOVAANOVA with Bonferroni's

correction for multiple comparison, chi-square test

with a Yates' continuity correction, or Kruskal±

Wallis rank test, as appropriate (StatView 5.0 for

windows, SAS, Cary, NC, USA). The number nee-

ded to treat (NTT), a useful estimate of clinical

relevance of treatment effect, was calculated (7).

Values were mean (SDSD), median (range) or number

(%). Power analysis was used to determine the

number of patients in the study based on the

assumptions that (i) the rate of no emetic symptoms

in patients who had received placebo would be

60%; (ii) an improvement from 60% to 90% was

268 Y. FUJII & H. TANAKA

Ó 2002 Blackwell Science Ltd, Paediatric Anaesthesia, 12, 267±271

considered of clinical importance; and (iii) a � 0.05

with a power (1 ± b) of 0.8. Based on these assump-

tions, 25 patients per group were required.

Results

Patient demographics and types of surgery were not

different among the treatment groups (Table 1). The

percentage of patients being emesis-free during 0±6 h

after anaesthesia was 56% with placebo, 64% with

graniseron 20 lg�kg±1 (P � 0.773), 88% with granise-

tron 40 lg�kg±1 (P � 0.027) and 92% with granisetron

80 lg�kg±1 (P � 0.01); the corresponding rate during

6±24 h after anaesthesia was 60%, 68% (P � 0.768),

92% (P � 0.02) and 92% (P � 0.02) (P-values versus

placebo) (Table 2). The NTT estimated to be 12.5, 3.1,

2.8 during 0±6 h after anaesthesia and 12.5, 3.1, 3.1

during 6±24 h after anaesthesia to prevent POV by

administering granisetron at 20 lg�kg±1, 40 lg�kg±1,

80 lg�kg±1, respectively, compared with placebo.

Thus, granisetron 40 lg�kg±1 or 80 lg�kg±1 showed a

more favourable effect on emetic symptoms in the

®rst 24-h postanaesthetic period. No clinically serious

adverse events (e.g. extrapyramidal signs) were

observed in any of the groups. The levels of sedation

were not different among the groups (Table 2).

Table 1Patient demographics

Placebo(n � 25)

Granisetron20 lg�kg)1

(n � 25)


(n � 25)


(n � 25)

Age (years) 6.9 � 2.5 6.6 � 1.9 6.7 � 2.5 6.8 � 2.1Sex (male/female) 15/10 14/11 15/10 15/10Height (cm) 122.6 � 11.9 121.8 � 11.3 118.9 � 9.1 121.1 � 10.4Weight (kg) 24.6 � 6.6 24.2 � 6.6 25.7 � 6.8 23.8 � 6.9Duration of operation (min) 43 (17±73) 45 (20±75) 51 (20±75) 48 (16±70)Duration of anaesthesia (min) 60 (30±95) 60 (35±90) 70 (30±90) 65 (30±95)

Types of surgery (n)Inguinal hernia 17 17 18 18Phimosis-circumcision 6 7 5 6Both 2 1 2 1

Postoperative management (n)Acetaminophen 20 21 21 20Pentazocine 2 1 2 1

Values are mean � SDSD, median (range), or number. There were no signi®cant differences among the treatment groups.

Table 2Number (%) of patients experiencing emesis-free, retching, or vomiting and sedation assessed by nurses during the ®rst 24 h afteranaesthesia

PlaceboGranisetron 20 lg�kg)1 Granisetron 40 lg�kg)1 Granisetron 80 lg�kg)1

(n � 25) (n � 25) P (n � 25) P (n � 25) P

Early (0±6 h) phaseEmesis-free 14 (56%) 16 (64%) 0.773 22 (88%) 0.027 23 (92%) 0.01Retching 6 (24%) 4 (16%) 0.724 1 (4%) 0.103 1 (4%) 0.103Vomiting 7 (28%) 5 (20%) 0.741 2 (8%) 0.141 2 (8%) 0.141Sedation (2/1/0) assessed by nurses 0/2/23 0/3/22 0.641 0/3/22 0.641 0/3/22 0.641

Late (6±24 h) phaseEmesis-free 15 (60%) 17 (68%) 0.768 23 (92%) 0.02 23 (92%) 0.02Retching 5 (20%) 3 (12%) 0.7 2 (8%) 0.209 1 (4%) 0.192Vomiting 7 (28%) 5 (20%) 0.741 2 (8%) 0.141 2 (4%) 0.141Sedation (2/1/0) assessed by nurses 0/2/23 0/2/23 1.0 0/2/23 1.0 0/3/22 0.641

Values are number (%). P-values (vs. placebo).

PREVENTION OF VOMITING FOLLOWING PAEDIATRIC SURGERY 269


Discussion

The incidence of vomiting following surgery for

inguinal hernia and/or phimosis in children is

relatively high when no prophylactic antiemetic is

provided (8). The incidence of emetic symptoms

(retching, vomiting) in the present study was

approximately 40% in paediatric patients who had

received placebo, which was in agreement with a

previous study by us (4). Thus, the relatively high

incidence of emetic symptoms following these pae-

diatric surgical procedures justi®es prophylactic

therapy with antiemetics for the prevention of POV.

The aetiology of POV after paediatric surgery for

inguinal hernia and/or phimosis is not known, but

is probably complex and depends on a variety of

factors including age, gender, a history of motion

sickness and/or previous POV, operative procedure,

anaesthetic technique and postoperative pain (2). In

this trial, the treatment groups were similar with

respect to patient demographics, surgical procedure,

anaesthetics administered and analgesics used post-

operatively. Therefore, the difference in the rate of

patients experiencing emesis-free among the groups

can be attributed to the drug tested.

Granisetron administered i.v. is effective for the

treatment of vomiting in patients receiving cytotoxic

drugs (9). In a previous report by us (4), it reduced

the incidence of POV in children undergoing general

anaesthesia for surgery (inguinal hernia, phimosis).

An oral regimen of granisetron shows a good ef®cacy

for the treatment of chemotherapy-induced emesis

(10). The dose of oral granisetron used in the current

study is not well-established but is extrapolated from

a dose in adults (6). Granisetron given orally at three

different doses (20 lg�kg±1, 40 lg�kg±1, 80 lg�kg±1)

chosen in this clinical trial is comparable with that

used in adult doses (1±4 mg) (4). In the present study,

the rate of no emetic symptoms in patients who had

received oral granisetron 40 lg�kg±1 or granisetron

80 lg�kg±1 were signi®cantly greater than in those

who had received placebo (P < 0.05). The exact

mechanism of granisetron for reducing the incidence

of POV is not known, but there is a possibility that

granisetron acts on sites containing 5-HT3 receptors

with demonstrated antiemetic effects (11).

Effective doses of granisetron administered i.v.

range from 40 lg�kg±1 to 80 lg�kg±1 for the treatment of

cancer chemotherapy-induced emesis (12). We could

®nd no report to determine the minimun effective

dose of oral granisetron for the prevention of POV

following paediatric surgery (inguinal hernia, phi-

mosis). In this study, antiemetic ef®cacy of granise-

tron 40 lg�kg±1 or granisetron 80 lg�kg±1 was

superior to that of placebo (P < 0.05), and there

were no differences in the rate of no emetic symp-

toms between patients who had received granisetron

20 lg�kg±1 and those who had received placebo. This

suggests that granisetron 40 lg�kg±1 given orally is

the minimum effective dose for the prevention of

POV following paediatric surgery (inguinal hernia,

phimosis) in children.

Granisetron lacks the sedative, dysphoric and

extrapyramidal effects associated with traditional

antiemetics, such as droperidol and metoclopramide

(2,13). In the current study, we found no clinically

serious adverse events in any of the groups and no dif-

ferences in sedation scores among the groups. There-

fore, the safety pro®les of oral granisetron at three

different doses (20 lg�kg±1, 40 lg�kg±1, 80 lg�kg±1)

and placebo used in this study were similar.

The fact that intravenous granisetron (US$ 33.40

for 1 mg) as well as intravenous ondansetron (US$

33.43 for 1 mg) is more expensive than other antie-

metics may delay its widespread use as an antie-

metic. However, the results of the current study are

important because of the potential reduction of cost

of prophylactic antiemetic therapy. In our institu-

tion, oral granisetron (US$ 12.60 for 1 mg) is less

expensive than intravenous granisetron (US$ 33.40

for 1 mg). The cost of oral granisetron is still high

compared with traditional antiemetics administered

i.v., droperidol (US$ 1.80 for 2.5 mg) and metoclo-

pramide (US$ 0.60 for 10 mg). In this clinical trial, a

cost-effective analysis, de®ned as the cost per unit of

success (14), was not performed. However, the use

of droperidol and metoclopramide as antiemetics

has been limited because these drugs occasionally

cause excessive sedation and extrapyramidal signs

(2). Furthermore, on the basis of our results, the

mininum effective dose (40 lg�kg±1) of oral granise-

tron would reduce the overall cost of therapy when

emisis occurred.

In summary, preoperative oral granisetron

40 lg�kg±1 is effective for the prevention of vomiting

following paediatric surgery (inguinal hernia, phimo-

sis-circumcision). Increasing the doses to 80 lg�kg±1

provides no demonstrable additional bene®t.

270 Y. FUJII & H. TANAKA


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Accepted 4 September 2001

PREVENTION OF VOMITING FOLLOWING PAEDIATRIC SURGERY 271


preoperative oral granisetron for the prevention of vomiting following paediatric surgery

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