combination of granisetron and droperidol for the prevention of vomiting after paediatric strabismus...

Paediatric Anaesthesia 1999 9: 329–333

Combination of granisetron and droperidol forthe prevention of vomiting after paediatricstrabismus surgery

YOSHITAKA FUJII MD, YUHJI SAITOH MD∗ , HIROYOSHI

TANAKA MD† AND HIDENORI TOYOOKA MD

Department of Anaesthesiology, University of Tsukuba Institute of Clinical Medicine,Tsukuba City, Ibaraki, Japan, ∗Department of Anaesthesiology and Critical Care Medicine,Tokyo Medical and Dental University School of Medicine, Bunkyo-ku, Tokyo, Japan and†Department of Anaesthesiology, Toride Kyodo General Hospital, Toride City, Ibaraki, Japan

SummaryThis study was undertaken to compare the efficacy of granisetron

plus droperidol with each antiemetic alone for the prevention of

vomiting after paediatric strabismus surgery. In a prospective,

randomized, double-blinded trial, 120 ASA physical status I

children, aged 4–10 years, received granisetron 40 lg.kg− 1,

droperidol 50 lg.kg− 1, granisetron 40 lg.kg− 1 plus droperidol

50 lg.kg− 1 (n=40 of each) intravenously after an inhalation

induction of anaesthesia. A complete response, defined as no

vomiting, no retching and no need for another rescue antiemetic

medication, during 0–3 h after anaesthesia was 80% with

granisetron, 45% with droperidol and 98% with granisetron plus

droperidol, respectively; the corresponding incidence during 3–24 h

after anaesthesia was 78%, 38% and 98% (P< 0.05; overall chi-

squared test with Yates continuity correction). No clinically

important adverse events were observed in any of the groups. In

conclusion, a combination of granisetron and droperidol was more

effective than granisetron or droperidol as a sole antiemetic for the

prevention of postoperative vomiting in children undergoing

strabismus repair.

Keywords: vomiting: antiemetics; granisetron; droperidol; surgery:

strabismus repair

Introduction approaches, including antihistamines (e.g.

hydroxyzine), butyrophenones (e.g. droperidol) andPostoperative vomiting (POV) is a commonly

dopamine receptor antagonists (e.g.observed adverse event after strabismus surgery in

metoclopramide), have been investigated in thechildren (1,2). A number of pharmacological

prevention and treatment of POV, but undesirable

side-effects, such as excessive sedation, hypotension,

dry mouth, dysphoria, hallucinations andCorrespondence to: Y. Fujii, Department of Anaesthesiology,

University of Tsukuba Institute of Clinical Medicine, 2–1–1, extrapyramidal symptoms, have been noted (3).Amakubo, Tsukuba City, Ibaraki 305, Japan. Granisetron as well as ondansetron is a selective

329 1999 Blackwell Science Ltd

330 Y. FUJII ET AL.

5-hydroxytryptamine type 3 (5-HT3) receptor concentration). Ventilation was controlled

mechanically and was adjusted to keep an endtidalantagonist and has a more potent and longer acting

activity against cisplatin-induced emesis than CO2 tension between 4.6 kPa and 5.2 kPa as measured

by an anaesthetic/respiratory gas analyser (UltimaTM,ondansetron (4). It has also been reported that

granisetron is effective for the prevention of POV in Datex, Helsinki, Finland). Muscle relaxation was

achieved with vecuronium and reversed by apaediatric patients undergoing strabismus repair (5).

None of the available antiemetics entirely control combination of atropine 0.02 mg.kg− 1 i.v. and

neostigmine 0.04 mg.kg− 1 i.v. at the completion ofPOV, probably because most of them act through

the blockade of one receptor (6). We have recently surgery. The trachea was extubated when the patient

was awake. Orogastric tube was not used. Rectaldemonstrated that a granisetron/droperidol

combination is more effective than each antiemetic temperature was monitored and maintained at

37±1 °C using hot water pads throughout surgery.for the prevention of postoperative emesis after

gynaecological surgery (7). This prospective, Postoperatively, all patients were admitted to the

hospital and remained for a couple of days. Clearrandomized, double-blinded study was designed to

compare the efficacy of granisetron plus droperidol liquids were offered only if the patient requested,

and other oral intake was not allowed for 4 h afterwith each drug alone for the prevention of POV in

children undergoing strabismus surgery. recovery from anaesthesia. If two or more episodes

of vomiting occurred during the first 24 h after

anaesthesia, another rescue antiemetic (e.g.Materials and methodsdomperidone pr) was given. Postoperative analgesia

After obtaining our institutional review board was provided by acetaminophen 10–25 mg.kg− 1 prapproval and informed consent from each parent, for mild pain and pentazocine 0.3 mg.kg− 1 i.v. forwe studied 120 otherwise healthy children (ASA severe pain.physical status I) aged 4–10 years undergoing Postoperatively, all episodes of retching andstrabismus surgery (i.e. operative procedure for eye vomiting during the first 24 h after anaesthesia (i.e.muscles). Patients who had a history of motion 0–3 h in the postanaesthesia care unit and 3–21 h insickness and/or previous POV and those who had the ward) were recorded by nursing staff who did

received antiemetics within 24 h before surgery were not know which treatment each patient had received.

excluded from the study. Patients were not allowed Nausea was not assessed as a separate entity in this

to have solid food after midnight before surgery. study because of the young age of the patients.

Clear liquids were permitted up to 3 h before surgery. A complete response, defined as no vomiting, no

Patients were randomly allocated to receive one retching and no need for another rescue antiemetic,

of three treatment regimens: granisetron 40 lg.kg−1was recorded during the first 24 h after anaesthesia.

(group G), droperidol 50 lg.kg− 1 (group D), or The details of any adverse events were recorded by

granisetron 40 lg.kg−1 plus droperidol 50 lg.kg− 1 follow-up nurses who interviewed the parents of

(group GD) (n=40 of each). These drugs were each patient. The level of sedation was also graded

administered intravenously (iv) after an inhalation on a three-point scale and was assessed as 0=awake,

induction of anaesthesia and prior to the surgical 1=drowsy and 2=asleep/excessive sedation.

procedure. A randomization list was generated, and Statistical analysis was performed by anova with

identical syringes containing each antiemetic were Bonferroni correction for multiple comparison and

prepared by personnel blinded to the study, v2 test, as appropriate (Stat View 4.0; Macintosh). The

according to the list. number-needed-to-treat (NNT), a useful estimate of

No preoperative medications were administered. clinical relevance of treatment effect, was also

Anaesthesia was induced by increasing concentration calculated (8). A P-value of < 0.05 was considered

of sevoflurane in 66% nitrous oxide (N2O) and oxygen significant. All values were expressed as mean±sd,

(O2) via mask. Tracheal intubation was facilitated numbers (%), medians and ranges. Power analysis

with vecuronium 0.1 mg.kg− 1 i.v. After tracheal was used to determine the number of patients in the

intubation, anaesthesia was maintained with N2O/ study based on the assumptions that (a) the incidence

of emesis in patients receiving droperidol aloneO2 (2:1) and sevoflurane 0.5–3.0% (inspired

1999 Blackwell Science Ltd, Paediatric Anaesthesia, 9, 329–333

PREVENTION OF VOMITING AFTER STRABISMUS SURGERY 331

Table 1Patient details Group G (n=40) Group D (n=40) Group GD (n=40)

Age (years) 7.0±2.4 6.8±2.2 6.7±2.2

Sex (male/female) 18/22 19/21 19/21

Height (cm) 121.4±11.7 120.3±10.6 120.2±11.5

Weight (kg) 24.6±6.4 25.1±8.0 24.2±5.9

Duration of operation (min) 50 (30–65) 48 (30–67) 48 (30–66)

Duration of anaesthesia (min) 70 (50–87 70 (45–90) 70 (55–95)

Analgesics used postoperatively (n)

Acetaminophen 28 27 28

Pentazocine 7 6 6

Values are mean ± sd, numbers, medians or ranges. Group G, granisetron; group D, droperidol,

∗ group GD, granisetron plus droperidol. No differences were observed amont the treatment

groups.

would be 60%, (b) an improvement from 60% to 80% period. The most frequently reported adverse events

were headache, drowsiness and constipation. Therewas considered of clinical importance, and (c) a=0.05 and a power (1−b)=0.8. Based on these were no differences in the incidence of adverse effects

among the groups (Table 3). Excessive sedation andassumptions, 40 patients per group were required.

The analysis showed 35 patients per group would extrapyramidal symptoms were not observed in any

of the groups.be sufficient.

Results Discussion

The reported incidence of vomiting after strabismusPatient profile and information on surgery and

anaesthesia are summarized in Table 1. There were surgery in children varies from 48% to 85% when no

antiemetic treatment is given (1,2). This incidence isno differences in patient demographics among the

treatment groups. higher than that associated with other paediatric

surgical procedures (3). The aetiology of vomitingA complete response (no vomiting, no rescue)

during 0–3 h after anaesthesia was 80%, 45% and following strabismus repair remains unclear, but is

probably multifactorial (3). A number of factors,98% in groups G, D and GD, respectively; the

corresponding incidence during 3–24 h after including age, sex, obesity, a history of motion

sickness and/or previous POV, surgical procedure,anaesthesia was 78%, 38% and 98%. Thus, in the first

24-h postanaesthetic period, it was greater in group anaesthetic technique and postoperative pain (3).

Surgical factors also include the impulses from theGD than in groups D and G (P< 0.05). Nine of 40

(23%, during 0–3 h after anaesthesia) and nine of 40 extrinsic eye muscles related to the vestibular nuclei

via nuclei III, IV, and VI of the medial longitudinal(23%, during 3–24 h after anaesthesia) patients who

had received droperidol required another rescue fasciculi (9). These vestibular nuclei lie in the

brainstem reticular formation and are closelyantiemetic (e.g. domperidone) for the treatment of

two or more episodes of POV, compared with none associated anatomically with the vomiting centre.

In this study, however, the treatment groups werewho had received granisetron or granisetron plus

droperidol (P< 0.05) (Table 2). The NNT estimated comparable with regard to patient demographics,

operative procedure, anaesthetics administered and2.0 and 1.7 during 0–3 h and 3–24 h after anaesthesia,

respectively, to prevent postoperative emetic analgesics used postoperatively. Therefore, the

differences in a complete response among the groupsepisodes with combined granisetron and droperidol

compared with droperidol alone. Thus, a can be attributed to the differences in the antiemetics

administered.combination of granisetron and droperidol showed

a more favourable effect on a complete response than Granisetron has been reported to be effective for

the treatment of vomiting in patients receivingdroperidol alone in the first 24-h postanaesthetic


332 Y. FUJII ET AL.

Table 2Patients having complete response (no vomiting, no retching, no rescue) or requiring another rescue antiemetic medication during the

first 3 h (0–3 h) and the next 21 h (3–24 h) after anaesthesia

Group G (n=40) Group d (n=40) Group GD (n=40) P1 P2 P3

0–3 h after anaesthesia

Complete response 32 (80%) 18 (45%) 39 (98%) 0.003 0.034 0.001

Vomiting 7 (18%) 18 (45%) 1 (3%) 0.016 0.062 0.001

Retching 2 (5%) 5 (13%) 0 (0%) 0.429 0.474 0.065

Rescue 0 (0%) 9 (23%) 0 (0%) 0.005 1.0 0.005


Complete response 31 (78%) 15 (38%) 39 (98%) 0.001 0.018 0.001

Vomiting 8 (20%) 20 (50%) 1 (3%) 0.01 0.034 0.001

Retching 2 (5%) 5 (13%) 0 (0%) 0.429 0.474 0.065

Rescue 0 (0%) 9 (23%) 0 (0%) 0.005 1.0 0.005

Values are numbers (%). Group G, granisetron; group D, droperidol; group GD, granisetron plus droperidol. P1, group G vs group D; P2,

group G vs group GD; P3, group D vs group GD.

Table 3Adverse events Group G (n=40) Group D (n=40) Group GD (n=40)


Headache 2 (5%) 2 (5%) 2 (5%)

Drowsiness 1 (3%) 1 (3%) 1 (3%)

Constipation 2 (5%) 2 (5%) 2 (5%)


Headache 3 (8%) 2 (5%) 3 (9%)

Drowsiness 1 (3%) 1 (3%) 1 (3%)

Constipation 2 (5%) 2 (5%) 2 (5%)

Values are numbers (%). Group G, granisetron; group D, droperidol; group GD, granisetron plus

droperidol. No differences were observed among the treatment groups.

cytotoxic drugs (10). We have recently demonstrated droperidol was better than granisetron or droperidol

given as a sole antiemetic in the prevention of POV.that it reduces the incidence of POV in children

undergoing strabismus surgery (5). The precise The advantages of combining granisetron and

droperidol are considered to be based on theirmechanism for preventing POV remains unclear, but

it has been suggested that granisetron may act on different mechanism of antiemetic activity and their

efficacy when used alone.sites containing 5-HT3 receptors with demonstrated

antiemetic effects (11). Droperidol is a major The effective doses of granisetron are between

40 lg.kg− 1 and 80 lg.kg− 1 for the treatment of cancertranquillizing drug that possess antiemetic activity

as a result of its antagonistic property at dopamine therapy-induced emesis (12). We have recently

demonstrated that granisetron 40 lg.kg−1 is thereceptors (3). There were no published studies to

compare a combination of granisetron and droperidol minimum effective dose for preventing POV after

strabismus surgery in children (13). For thewith each antiemetic alone for the prevention of POV

following strabismus repair. This study showed that prevention of POV in paediatric patients undergoing

strabismus repair, droperidol 50 lg.kg− 1 has oftena complete response during the first 3 h and the next

21 h after anaesthesia was greater in patients who been used (3). Higher doses of this antiemetic

is associated with sedative activity and extra-had received granisetron plus droperidol (98%) was

greater than in those who had received granisetron pyramidal symptoms (4). In this study, therefore,

granisetron 40 lg.kg−1 or droperidol 50 lg.kg−1 wasalone (78–80%) or droperidol alone (38–45%)

(P< 0.05). Thus, a combination of granisetron and administered.


PREVENTION OF VOMITING AFTER STRABISMUS SURGERY 333

2 Lerman J, Eustis S, Smith DR. Effect of droperidol pretreatmentOne of the important problems with droperidolon postanesthetic vomiting in children undergoing strabismus

for prophylactic antiemetic therapy is the risk ofsurgery. Anesthesiology 1986; 65: 322–325.

undesirable adverse effects, such as excessive 3 Watcha MF, White PF. Postoperative nausea and vomiting. Its

etiology, treatment, and prevention. Anesthesiology 1992; 77:sedation and extrapyramidal signs (3). The adverse162–184.

events observed in this study were not serious, and4 Andrews PLR, Bhandari P, Davey PT, et al. Are All 5–HT3

there were no differences in the incidence of headache Receptor Antagonists the Same? Eur J Cancer 1992; 28: S2–S6.

5 Fujii Y, Tanaka H, Toyooka H. Granisetron reduces vomitingand constipation among the treatment groups.after strabismus surgery and tonsillectomy in children. Can JExcessive sedation and extrapyramidal symptomsAnaesth 1996; 43: 35–38.

were also not observed in any of the groups. Thus, 6 Rowbotham DJ. Current management of postoperative nausea

and vomiting. Br J Anaesth 1992; 69: 46S–59S.the risk of these undesirable side-effects may not be7 Fujii Y, Toyooka H, Tanaka H. Prevention of postoperativeaugmented with added droperidol.

nausea and vomiting with a combination of granisetron andSeveral investigations have criticized new

droperidol. Anesth Analg 1998; 86: 613–616.antiemetics (e.g. ondansetron) because of their high 8 Tramer M, Moore A, McQuay H. Prevention of vomiting after

paediatric strabismus surgery: a systemic review using thecost (13,14). Our hospital pharmacy pays US$102.00numbers-needed-to-treat methods. Br J Anaesth 1995; 75:

for granisetron 3 mg and US$3.60 for droperidol556–561.

2.5 mg. Thus, granisetron plus droperidol is more 9 Warner LO, Rogeres MD, Martino LD, et al. Intravenous

lidocaine reduces the incidence of vomiting in children afterexpensive than granisetron alone. However, on thesurgery to correct strabismus. Anesthesiology 1988; 68: 618–621.basis of our results, combined of granisetron and

10 Bermudez J, Boyle EA, Minter WD, et al. The antiemeticdroperidol was more effective than each antiemetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL

43694. Br J Cancer 1988; 58: 644–650.alone in increasing complete response. Therefore, a11 Carmichael J, Cantwell BMJ, Edwards CM, et al. Adecision about antiemetic medication should not be

pharmacokinetic study of granisetron (BRL 43694A), a selectivelimited to its cost but also consider its efficacy for

5–HT3 receptor antagonist: correlation with anti-emeticthe prevention of POV and the overall cost of care if response. Cancer Chemother Pharmacol 1989; 24: 45–49.

12 Furue H, Oota K, Taguchi T, et al. Clinical evaluation ofPOV were to occur.granisetron against nausea and vomiting induced anticancer

In conclusion, prophylactic therapy with adrugs. Optimal dose-finding study. J Clin Therapy Med 1990; 6:

combination of granisetron and droperidol is 49–61.

13 Fujii Y, Toyooka H, Tanaka H. Effective dose of granisetron forsuperior to that with each antiemetic alone for thepreventing postoperative emesis in children. Can J Anaesthprevention of POV following strabismus surgery in1996; 43: 660–667.

children. 14 White PF, Watcha MF. Are new drugs cost-effective for patients

undergoing ambulatory surgery? Anesthesiology 1984; 78: 2–5.

15 Lerman J. Are antiemetics cost-effective for children? Can JReferences Anaesth 1995; 42: 263–266.

1 Abramobitz MD, Oh TH, Epstein BS, et al. The antiemetic

effect of droperidol following outpatient strabismus surgery

in children. Anesthesiology 1983; 97: 579–583. Accepted 8 October 1998


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