British Journal of Anaesthesia 1990; 65: 456-460
EFFECTS OF RANITIDINE AND METOCLOPRAMIDE ON
GASTRIC FLUID pH AND VOLUME IN CHILDREN!
S. CHRISTENSEN, A. FARROW-GILLESPIE AND J. LERMAN
H2 receptor antagonists, reduces the risk of lung
damage by decreasing gastric acid secretion
To determine the effects of ranitidine and meto- without affecting lower oesophageal sphincter
clopramide on gastric fluid in children, 40 healthy tone1 or gastrointestinal motility. In a dose of 2 mg
children (aged 2-8 yr) were allocated randomly kg" , it increases gastric fluid pH and decreases
to groups of 10 to receive one of four oral gastric fluid volume without affecting gastric
premedications 4 h before surgery: no premedi- emptying [6, 7, 11]. In contrast, metoclopramide,
cation, metoclopramide 0.1 mg kg'1, ranitidine a benzamide derivative, reduces the risk of lung
2 mg kg~1 and metoclopramide 0.1 mg kg'1 with damage by increasing lower oesophageal sphincter
ranitidine 2 mg kg'1. After tracheal intubation, tone, enhancing gastric emptying and augmenting
gastric fluid was aspirated and analysed for pH intestinal motility without altering gastric acid
and total fluid volume. Ranitidine, with or secretion [8-10]. Although metoclopramide has
without metoclopramide, increased gastric fluid been shown to decrease the incidence of vomiting
pH significantly compared with control (P after chemotherapy and the severity of reflux
< 0.05). Gastric fluid volume did not change oesophagitis in children [9, 12, 13], its effect on
gastric fluid pH and volume in healthy children
significantly.
undergoing elective surgery is unknown. In order
to compare the effects of these two drugs on
KEY WORDS
gastric fluid pH and volume, we designed the
Anaesthesia: paediatric. Gastrointestinal tract: gastric fluid
following randomized, controlled and doublevolume, gastric pH. Premedication: metoclopramide, ranblinded study.
itidine.
SUMMARY
The severity of lung damage following gastric
fluid aspiration is determined often by the pH and
volume of the fluid aspirated [1,2]. Evidence
from animal studies indicates that the lung
damage is most severe when the pH of the
aspirated fluid is < 2.5 and volume > 0.4 ml kg"1
[3]. If these criteria hold true for humans also,
then those patients with a gastric fluid pH < 2.5
and volume > 0.4 ml kg"1 are at risk of severe
lung damage following gastric fluid aspiration.
Several studies have shown that 75 % of healthy
children who fast before elective surgery have a
gastric fluid pH < 2.5 and volume > 0.4 ml kg"1
[4, 5]. In these children, aspiration of gastric fluid
may cause severe lung damage.
Recent efforts to minimize the severity of lung
damage following aspiration of gastric fluid have
focused on two groups of drugs: histamine type 2
(H,) receptor antagonists [6, 7] and benzamide
derivatives [8-10]. Ranitidine, one of the newer
PATIENTS AND METHODS
With approval from the Human Subjects Review
Committee, written informed consent was obtained from the parents of 40 children, aged 2-8 yr
and ASA grade I—II undergoing elective inpatient surgery. These children were allocated
randomly to groups of 10 to receive one of four
oral premedications: control (no premedication),
metoclopramide O.lmgkg"1, ranitidine 2 mg
SCOTT CHJUSTBNSEN, M.D.; ALAN FARROW-GILLESPIB, M.D.;
JBRKOLD LERMAN,* M.D., F.R.c.P.c; Department of Anaesthesia and the Research Institute, The Hospital for Sick
Children, University of Toronto, Toronto, Ontario. Accepted
for Publication: March 13, 1990.
*Address for correspondence: Department of Anaesthesia,
The Hospital for Sick Children, 555 University Avenue,
Toronto, M5G 1X8 Ontario, Canada.
fPresented in part at the annual meeting of the American
Society of Anesthesiologists, October 1988, San Francisco,
California.
RANITIDINE AND METOCLOPRAMIDE IN CHILDREN
457
1
kg , and the combination of metoclopramide
O.lmgkg"1 and ranitidine 2 mg kg"1. Oral ranitidine was prepared by suspending the i.v.
formulation in a fruit syrup (ISmgml" 1 ). Oral
metoclopramide was administered as a suspension
(1 mg ml"1). The volumes of the premedicants
were 0.13 ml kg"1 for ranitidine and 0.1 ml kg"1
for metoclopramide. All children received also
water 2 ml kg"1 approximately 4 h before surgery.
No other premedicants were administered.
After administration of i.v. atropine 0.02 mg
kg"1, anaesthesia was induced with thiopentone
4-7 mg kg"1. Tracheal intubation was facilitated
with i.v. suxamethonium 2 mg kg"1 and anaesthesia was maintained with either halothane or
isoflurane and nitrous oxide in oxygen.
After tracheal intubation but before surgical
incision, an orogastric tube (Salem 16 gauge) was
inserted into the stomach. The position of the
orogastric tube was verified by injecting air into
the tube and auscultating over the epigastrium.
The pH of a 2-ml sample of gastric fluid aspirate
was determined using a pHM62 Radiometer pH
meter. The pH meter was calibrated using three
standard pH solutions: 1.0,4.01 and 7 before each
measurement. Several attempts were made to
remove all the gastric fluid by blind aspiration. To
facilitate this, pressure was applied over the
epigastrium with the patient in the left lateral
decubitus position while gentle suction was applied manually to the orogastric tube. Gastric
fluid volume was defined as the total volume of
fluid aspirated. Gastric fluid pH and volumes
were determined by one of the authors who was
blinded to the patient's premedication.
The patient's age, weight, fasting interval and
C
M
R M+R
Treatment
FIG. 1. Mean (SD) gastric fluid pH. *Significantly greater in
the ranitidine groups with or without metoclopramide compared with control (P < 0.05).
pH and volume of the gastric fluid aspirate were
recorded.
The frequency distributions of gastric fluid pH
and volume for each group were tested for
deviation from normality with the KolmogorovSmirnov test. Statistical significance (P < 0.05)
was determined using one-way analysis of variance and the Tukey test [14] for multiple pairwise
comparisons for age, weight, fasting interval, and
gastric fluid pH and volume. Power analysis was
applied to negative results using standard techniques [15]. All data are presented as means (SD).
RESULTS
The ages, weights and fasting intervals of the four
groups did not differ significantly (table I).
Gastric fluid was obtained from all 40 patients.
Gastric fluid pH in the control group did not
TABLE I. Details of patients studied {mean (SD)). $ Time interval from last fluids and premedication until gastric fluid sampling.
P < 0.05: *compared with control; \ compared with metoclopramide
Treatment group
Control
Number of patients
Age(yr)
Weight (kg)
Fasting interval (h)J
Gastric fluid
PH
Volume (ml kg l )
Children with pH < 2.5 and
volume > 0.4 ml kg*1 (%)
Metoclopramide
0.1 mgkg"1
Ranitidine
2mgkg"1
Metoclopramide 0.1 mg kg '
and ranitidine 2 mg kg"1
10
10
10
10
4.41 (2.39)
18.9 (8.5)
5.23(1.64)
5.63(1.75)
21.5(6.6)
4.26 (0.95)
4.62 (1.58)
17.2 (3.5)
4.14(0.41)
5.65(2.17)
21.8(9.8)
4.29 (0.63)
1.90(0.87)
0.43(0.11)
2.41 (1.4)
0.49 (0.33)
4.76 (2.2)*f
0.47 (0.29)
4.07 (2.0)*
0.40(0.19)
50
40
10
20
BRITISH JOURNAL OF ANAESTHESIA
458
OB
I OB
^
0.4
£
0.2
0.0
M
R
Treatment
M+R
FIG. 2. Mean (SD) gastric fluid volume. No significant difference in the ranitidine, metoclopramide and combination
groups compared with control.
differ significantly from that in the metoclopramide group (table I, fig. 1). However, gastric
fluid pH was significantly greater in both the
ranitidine and ranitidine-metoclopramide groups
compared with the control group (P < 0.05).
Gastric fluid pH in the ranitidine group did not
differ statistically from that in the ranitidinemetoclopramide group.
There was no difference between the groups
with regard to gastric fluid volume (table I, fig.
2).
The percentage of children with a gastric fluid
pH < 2.5 and volume > 0.4 mg kg"1 was 50 % in
the control group and 10% in the ranitidine
group. This difference was not statistically significant, but the power of this comparison was
only 0.54. To achieve a power of 0.8, 18 children
would be required in each group.
There were no side effects associated with the
administration of ranitidine, metoclopramide or
the combination of drugs.
DISCUSSION
The results of this study indicate that oral
ranitidine 2 mg kg"1 with or without metoclopramide 0.10 mg kg"1 increased significantly
the gastric fluid pH, but did not affect gastric fluid
volume in fasted children undergoing elective
surgery. The results for ranitidine are consistent
with data published previously for children [6],
while the results for metoclopramide support the
suggestion that oral metoclopramide 0.1 mg kg"1
given 4 h before surgery affects neither gastric
acid secretion nor gastric fluid emptying in
children.
We administered oral ranitidine 2 mg kg"1 4 h
before surgery in an attempt to suppress gastric
acid secretions completely. The dose of ranitidine
was based on the results of two studies in which
oral ranitidine 1.25-1.90 mg kg"1 suppressed gastric acid secretions effectively [16] and oral
ranitidine 2 mg kg"1 increased gastric fluid pH
and decreased gastric fluid volume in children as
effectively as larger doses of ranitidine [6]. The
time interval between oral ranitidine and gastric
fluid measurements is an important determinant
of the extent of gastric acid suppression. Blumer
and others reported that the serum concentration
of ranitidine was greatest, and the gastric acid
secretions were least, 2 h after oral ranitidine in a
group of children (mean age 12.6 (SD 3.7) yr) [16].
Although comparable data in younger children
are not available, preliminary pharmacokinetic
data suggest that blood concentrations of ranitidine in younger children are similar to those in
older children [17]. In order to minimize gastric
acid secretions in all children who received
ranitidine in this study, we administered all
premedicants 4 h before induction of anaesthesia.
The primary mechanism of action of metoclopramide on gastric fluid characteristics is
believed to be a direct action on gastrointestinal
motility. It increases lower oesophageal sphincter
tone and enhances gastric fluid emptying [18].
However, two studies suggested that metoclopramide increases gastric fluid pH also. This
effect was observed after a single oral dose of
metoclopramide 0.15 mg kg"1 was given 2-2.5 h
before gastric fluid aspiration [19, 20]. Although
the mechanism by which metoclopramide increases gastric fluid pH is unclear, Manchikanti
and colleagues suggested that metoclopramide
diluted the residual acid-containing fluid in the
stomach by non-acid-containing secretions [19].
Our inability to demonstrate an effect of metoclopramide on gastric fluid pH in this study may
be attributed to four factors. First, the small
sample size (« = 10) and low power (0.25) of our
study. (To achieve a power of 0.80, the sample size
should be increased to 65 children per group
[15].) Second, an inadequate dose of metoclopramide may have been used. Third, the longer
time interval between administration of the drug
and aspiration of gastric fluid may have been a
factor and, finally, metoclopramide may lack any
direct effect on gastric fluid pH [21]. The dose of
metoclopramide in this study (O.lOmgkg"1) is
less than that which has been reported to increase
RANITIDINE AND METOCLOPRAMIDE IN CHILDREN
1
gastric fluid pH in adults (0.15 mg kg" ) [19, 20].
We selected the dose of metoclopramide in
consultation with the local manufacturer (AH
Robins, Canada Ltd) in order to minimize the risk
of side effects. These data suggest that metoclopramide alone neither decreased gastric fluid
volume nor increased gastric fluid pH.
Concern has been expressed on the risks of
extrapyramidal side effects after administration of
metoclopramide to children. Such side effects
have been reported in children who received large
doses of metoclopramide (1.0 mg kg"1 or greater)
repeatedly for nausea and emesis during chemotherapy [22,23]. In this study, none of the 20
children who received a single oral dose of
metoclopramide 0.1 mg kg"1 experienced any side
effects. Indeed, there have been no reports of
extrapyramidal side effects in healthy unpremedicated children after a single oral dose of metoclopramide. These data indicate that single dose
oral metoclopramide 0.1 mg kg"1 may be safe for
use in children [18].
Should routine premedication be administered
to all fasted children who are scheduled for
elective surgery ? The incidence of regurgitation
and gastric fluid aspiration is approximately
1:10000 [24]. Because the incidence of side effects
from prophylactic therapy may exceed the incidence of pneumonitis following aspiration, there
is insufficient evidence to support routine premedication at this time. Nonetheless, there is a
group of children who are at increased risk of
regurgitation and aspiration, including those with
hiatus hernia, hyperacidity syndrome and gastrooesophageal dysmotility. These children may
benefit from prophylactic premedication to prevent aspiration pneumonitis, as we demonstrated
that ranitidine reduced the percentage of children
with a pH < 2.5 and volume > 0.4 mg kg"1 from
50% to 10%.
Gastric fluid volume is difficult to measure
accurately in children. There are two techniques
that are used commonly to estimate gastric fluid
volume: the aspiration and dye dilution techniques. Although the former technique is used
commonly, it may underestimate gastric fluid
volume by emptying the stomach incompletely.
This concern is supported by recent data in adults
in whom blind aspiration yielded gastric fluid
volumes that were only 50 % of those obtained by
direct endoscopic examination for residual fluids
[25]. However, several authors have presented
conflicting views on the accuracy of blind as-
459
piration in adults [25-27]. The accuracy of blind
aspiration as an estimate of the actual gastric fluid
volume in children remains uncertain. The second
technique available is the dye dilution technique.
This technique may overestimate gastric fluid
volume [28] because of incomplete mixing of dye
with gastric fluid and passage of dye into the
duodenum or oesophagus. We believe that both
blind aspiration and dye dilution techniques may
be associated with inherent errors that could be
exaggerated in children who have small gastric
fluid volumes.
In conclusion, we found that oral ranitidine
2 mg kg"1 with or without metoclopramide
0.10 mg kg"1 increased gastric fluid pH without
affecting gastric fluid volume in healthy children
scheduled for elective surgery under general
anaesthesia. In view of the low risk of aspiration,
we do not recommend the routine use of H s
receptor blockers in healthy children undergoing
elective surgery.
ACKNOWLEDGEMENT
Supported in part by a grant from Glaxo Canada Inc.
REFERENCES
1. Awe WC, Fletcher WS, Jacob SW. The pathophysiology
of aspiration pneumonitis. Surgery 1966; 60: 232—239.
2. Roberts RB, Shirley MA. Reducing the risk of acid
aspiration during Cesarean section. Anesthesia and Analgesia 1974; S3: 859-868.
3. James CF, Modell JH, Gibbs CP, Kuck LJ, Ruiz BC.
Pulmonary aspiration—effects of volume and pH in the
rat. Anesthesia and Analgesia 1984; 63: 665-668.
4. Cote CJ, Goudsouzian NG, Liu LMP, Dedrick DF,
Szyfelbein SK. Assessment of risk factors related to the
acid aspiration syndrome in pediatric patients—gastric pH
and residual volume. Anesthesiology 1982; 56: 70-72.
5. Christensen S, Farrow-Gillespie A, Lerman J. Effect of
the fasting interval on gastric fluid pH and volume in
children. Anesthesia and Analgesia 1988; 67: S59.
6. Goudsouzian NG, Young ET. The efficacy of ranitidine
in children. Acta Anaesthesiologica Scandinavica 1987;
31: 387-390.
7. Sandhar BK, Maltby JR, Goresky G, Strunin L. Preoperative fluids and ranitidine in children. British Journal
of Anaesthesia 1987; 59: 324-325P.
8. Olsson GL, Hallen B. Pharmacological evacuation of the
stomach with metoclopramide. Acta Anaesthesiologica
Scandinavica 1982; 26: 417-420.
9. Byrne W, Marino LR. Metoclopramide increases lower
oesophageal sphincter pressure and reduces the number of
episodes and duration of reflux in infants with gastroesophageal reflex. Pediatric Research 1984; 18: 191A.
10. Harrington RA, Hamilton CW, Brogden RN, Linkewich
JA, Romankiewicz JA, Heel RC. Metoclopramide: an
460
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
update review of its pharmacological properties and
clinical use. Drugs 1983; 25: 451^t94.
Manchikanti L, Kraus JW, Edds SP. Cimetidine and
related drugs in anesthesia. Anesthesia and Analgesia
1982; 61: 595-608.
Leung AK.C, Lai PCW. Use of metoclopramide for the
treatment of gastro-esophageal reflux in infants and
children. Current Therapeutic Research 1984;36: 911-915.
Howric D L , Felix C, Wollman M, Juhl RP, Blatt J.
Metoclopramide as an antiemeuc agent in pediatric
oncology patients. Drug Intelligence and Clinical Pharmacology 1986; 20: 122-124.
Zar JH. Biostatistical Analysis, 2nd Edn. EnglewoodCliffs: Prentice-Hall, 1984; 162-171, 185-190.
Cohen J. Statistical Power Analysis for the Behavioral
Sciences, revised Edn. Orlando: Academic Press, 1977;
19-60.
Blumer JL, Rothstein FC, Kaplan BS, Yamashita TS,
Eshelman FN, Myers CM, Reid MD. Pharmacokinetic
determination of ranitidine. Pharmacodynamics in
pediatric ulcer disease. Journal of Pediatrics 1985; 107:
301-306.
Leeder JS, Brill-Edwards M, Chin T, Tesoro A, MacLeod SM. Pharmacokinetics of ranitidine in pediatric
patients. Ada Pharmacologica and Toxica 1986; 59: 79. .
Schulze-Delrieu K. Metoclopramide. New England Journal of Medicine 1981; 305: 28-32.
Manchikanti L, Colliver JA, Marrero TC, Rousch JR.
Ranitidine and metoclopramide for prophylaxis of aspiration pneumonitis in elective surgery. Anesthesia and
Analgesia 1984; 63: 903-910.
Manchikanti L, Marrcro TC, Rousch JR. Preanesthetic
cimetidine and metoclopramide for acid aspiration prophylaxis in elective surgery. Anesthesiology 1984; 61: 48-54.
BRITISH JOURNAL OF ANAESTHESIA
21. Rao TLK, Madhavareddy S, Chinthagada M, El-Err AA.
Metoclopramide and cimetidine to reduce gastric fluid pH
and volume. Anesthesia and Analgesia 1984; 63: 10141016.
22. Bateman D N , Craft AW, Nicholson E, Pearson ADJ.
Dystonic reactions and the pharmacokinetics of metoclopramide in children. European Journal of Clinical
Pharmacology 1983; 15: 557-559.
23. Allen JC, Gralla R, Reilly L, Kellick M, Young C.
Metoclopramide: dose-related toxicity and preliminary
antiemetic studies in children receiving cancer chemotherapy. Journal of Clinical Oncology 1985; 3: 1136-1141.
24. Tiret L, Nivoche Y, Hatton F, Desmonds JM, Vourch G.
Complications related to anaesthesia in infants and
children: a prospective study of 40240 anaesthetics.
British Journal of Anaesthesia 1988; 61: 263-269.
25. Taylor WJ, Champion MC, Barry AW, Hurtig JB.
Measuring gastric contents during general anaesthesia:
evaluation of blind gastric aspiration. Canadian Journal of
Anaesthesia 1989; 36: 51-54.
26. Hardy JF, Plourde G, LeBrun M, Dube S, Cote C.
Measuring the volume of gastric contents under general
anaesthesia: evaluation of two clinical methods. Canadian
Anaesthetists Society Journal 1986; 33: 119-120.
27. Adelhoj B, Petring OU, Hagelsten JO. Inaccuracy of
peranaesthetic gastric intubations for emptying liquid
stomach contents. Ada Anaesthesiologica Scandinavica
1986; 30: 4 1 ^ 3 .
28. Ong G, Palahniuk RJ, Cummings M. Gastric volume and
pH in outpatients. Canadian Anaesthetists Society Journal
1978; 25: 36-39.