Scand 3 Infect Dis 18:65-70, 1986

Effective Treatment of Diarrhoeal Dehydration

with an Oral Rehydration Solution
Containing Citrate
SYED M. AHMED, MOHAMMED R. ISLAM
and THOMAS BUTLER
From the Inremationat Centre f o r Diarrhoeal Disease Research, Dhuka, Bangladesh
and the Departmenr of Medicine, Case Wesrern Reserve University,
Cleveland, Ohio, USA
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To compare the clinical efficacy of oral rehydration salts (ORS) from effervescent tablets
containing citrate with the WHO recommended ORS for the treatment of dehydration due to
acute diarrhoea, a randomized clinical trial was carried out in 57 adults and 58 children.
These patients had mild or moderate degrees of dehydration and acidosis due to acute watery
diarrhoea that was caused by enterotoxigenic Escherichia coli in 4 3 4 7 % of the cases.
EffEcacies were compared by measuring oral fluid intake, stool output, gain in body weight,
decrease in serum specific gravity and correction of acidosis during treatment. Successful
rehydration and maintenance of hydration was achieved in 25 adults and 24 children treated
with citrate containing ORS and 25 adults and 24 children treated with WHO ORS. The mean
intake of ORSkg body weight in children receiving WHO ORS was greater @<0.05) and
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correction of acidosis was faster than the citrate group during the initial 24 h of therapy
(jK0.05). By 48 h, however, both groups showed satisfactory and comparable intake of ORS
and correction of acidosis. Thus ORS from effervescent tablets containing sodium citrate base
is effective for management of diarrhoea in both adults and children and is a convenient stable
form of ORS for use in the home and for travelers.
T. Butler, MD, Department of Medicine, University Hospitals, Cleveland, Ohio 44J06, USA

INTRODUCTION
From the observation that glucose-stimulated sodium absorption remains normal in chol-
era (1) and other diarrhoea1 diseases, the concept of oral rehydration solutions (ORS) was
developed. In both developing countries and developed countries, the use of ORS for the
correction of dehydration during diarrhoea has been demonstrated to be feasible and
preferred to intravenous rehydration in most instances ( 2 , 3). There are problems, never-
theless, with the propagation of ORS use. The WHO-recommended ORS packet contains
bicarbonate which has a short shelf-life because the ingredients form lumps in humid
climates. Citrate has been used as an alternative to bicarbonate and is more stable. Animal
experiments have shown that citrate is actively absorbed by rabbit ileum via an ouabain-
sensitive chloride-independent mechanism and stimulates absorption of sodium and chlo-
ride via a chloride-dependent mechanism (4). Other experiments have shown that sodium
citrate enhances absorption of sodium ( 5 ) . Clinical studies have already suggested that
sodium citrate can substitute satisfactorily for sodium bicarbonate in the rehydration and
correction of acidosis in diarrhoea (6).
Travelers to developing countries, as well as the inhabitants of these countries, are at
high risk of developing diarrhoea and will require a convenient compact form of rehydra-
tion salts. In this study, we have compared the efficacy of an effervescent tablet of ORS
containing citrate with that of WHO recommended ORS containing bicarbonate in the
usual powdered form for the treatment of acute diarrhoea in both adults and children.

5-86855 1
 66 S . M . Ahmed et al. Scand J Infect Dis 18 (1986)

Table I. Clinical characteristics of patients at the time of admission treated with Citrate
ORS or WHO ORS (means k SO)

Children (<5 years) Adults

Citrate ORS WHO ORS Citrate ORS WHO ORS

(n=29) (n=29) (n=28) (n=29)

Age in years 1.3k I .O 1.2f 1.1 27.9k9.5 28.0k9.9

Sex (male/female) 19/10 2118 2117 2217
Duration of diarrhoea
prior to admission (h) 40.5k25.3 45.1524.5 I4.0k 14.0 12.1k14.5
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Body weight (kg) 7.15k1.86 6.47k 1.94 42.49k6.14 41.33k7.49

Plasma specific gravity 1.0274k0.0034 1.0282kO.OO31 1.0305kO.OO34 I .0314kO.O042
TC02 (mmol/l) 13.1f 3 . 4 13.8f2.8 17.6f3.4 16.124.6

MATERIALS AND METHODS

This study was camed out during the period of January-April, 1983 at International Centre for
Diarrhoeal Disease Research, Bangladesh. 57 adults and 58 children below 5 years of age who
attended the centre for acute diarrhoea, were selected for the study. Of these patients 28 adults and 29
children were treated with effervescent ORS tablets containing citrate; 29 adults and 29 children were
treated with WHO ORS containing bicarbonate. These patients had mild or moderate degrees of
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dehydration and acidosis due to acute uncomplicated diarrhoea. The degree of dehydration was
assessed by WHO guidelines; mild dehydration was considered as increased thirst without physical
signs of dehydration and moderate dehydration as diminished skin turgor with a weak radial pulse (7).
They had not taken any antibiotics prior to admission. Patients were randomly assigned to the two
treatment regimens of ORS using sealed envelopes.

Table 11. Comparison of intake of ORS and milk, output of stool and urine (mean t SD) of
patients treated successfully with Citrate ORS or WHO ORS

Children (<5 years) Adults

Citrate ORS WHO ORS Citrate ORS WHO ORS

(n=24) (n=24) (n=25) (n=25)

Intake (mVkg)
ORS
0-24 h 234.7f67.5 331.5k156.2" 149.1k53.4 147.8f41.4
2448 h l88.6kllO.O 187.0k 107.2 84.3k44.6 67.5k44.0
Milk and plain water
0-24 h 59.9534.7 61 S f 4 4 . 6 11.0f4.5 10.5f4.9
2448 h 70.1k34.9 51.4k31.1 6.3k3.1 5.5k0.9

Output (mYkg)
Stool
&24 h 141.0f103.9 185.3f127.0 41.5248.8 34.9f31.5
2448 h 140.5k 87.6 142.5f83.2 30.3k38.9 26.6f38.7
Urine
0-24 h 20.4k13.36 23.3f13.1 4 1.6k 28.3 32.4f23.2
2448 h 25.9k 16.0 30.4k 19.3 52.6k41.4 56.0k35.0

a Children in the WHO ORS group consumed significantly more fluid than children in the Citrate
ORS group (p<0.05).
 Scand J Infect Dis 18 (1986) Diarrhoea1 rehydration with citrate 67

Table 111. Progress of rehydration and body weight change and correction of acidosis
(mean SD) in patients treated successfully with Citrate ORS or WHO ORS
+_

_ _ _ _ _ _ _ ~

Children (4
years) Adults

Citrate ORS WHO ORS Citrate ORS WHO ORS

(n=24) (n=24) ( n = 25) (n=25)

Plasma sp. gravity

Admission 1.0269f0.0027 1.0281f0.0039 1.0301f0.0033 1.0310f0.0042
At 24 h I ,0247f0.0021 1 ,02402 0 .OO 1 2 1.0254k0.0026 1.0250f0.0017
At 48 h 1.0238+0.0015 1.0237+0.0019 1.0263f0.0028 1.0256f0.002l
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Body weight (kg)

Admission 6.8+ I .4 6.2k1.8 42.5 k6.0 41.327.6
At 24 h 7 . 0 f 1.6 6.7f2.0 44.6k5.8 43.7f 8.2
At 48 h 7.lf1.7 6.7f2.0 44.5f6.1 43.9f8.5

K O 2 (mmolfl)
Admission 13.0f3.1 14.0f4.1 18.0k3.2 15.8f 4.7
At 24 h 14.6f4.0 17.7f 4 .OR 23.7f3.6 22.8f3.9
At 48 h 16.7f4.1 18.9f4.8 23.9f 3.8 24.253.2

a Acidosis was corrected significantly better at 24 h in children receiving WHO ORS than in children
receiving Citrate ORS ( p ~ 0 . 0 5 ) .
For personal use only.

ORS effervescent tablet (Servidrat, Ciba-Geigy, Basle, Switzerland) is a vanilla flavoured glucose
electrolyte mixture, which contains anhydrous glucose 2 182 mg, sodium chloride 421 mg, potassium
chloride 180 mg, citric acid 691 mg, sodium bicarbonate 302 mg, and saccharin sodium 50 mg to be
dissolved in 120 mg HzO. The formulation listed refers to the tablet in the dry form. In solution COz is
given off, hence the effervescence and sodium citrate is formed. The composition of dissolved
solution in terms of mmoYl is sodium 90,potassium 20, chloride 80, citrate 30 and glucose 100. This
composition is identical to that of WHO ORS with the exception that WHO ORS contains bicarbonate
30 mmoM in place of citrate.
To assess the acceptability of the ORS effervescent tablet, adult patients and children through their
mothers were asked to grade the taste of the solution after 24 h therapy as good, neutral, unpleasant,
or very bad.
No intravenous fluid was given to the patients. All patients were given ORS in a volume of 50 ml/kg
body weight for mild dehydration and 100 ml/kg for moderate dehydration for the initial rehydration
that was accomplished within 6 h. Oral rehydration therapy was continued to match stool output until
diarrhoea stopped. The effect of treatment was assessed by measuring the amount of ORS intake,
purging and vomiting rate, gain in body weight and rate of correction of acidosis. Patients were
observed carefully by attending physicians and trained nurses regularly at the clinical study ward. All
intakes and outputs were measured at 8 h intervals. Blood samples were drawn for hematocrit, plasma
specific gravity and electrolytes on admission and at 24 and 48 h after the start of oral therapy. A stool
sample was obtained for isolation of Salmonella sp., Shigella sp. and Vibrio sp. Enterotoxigenic
Eschenchia coli were tested for LT (9) and ST enterotoxins (lo), and rotavirus was detected by the
ELISA method (11). Breast milk and diluted cows milk (1: I ) were allowed ad libitum from the
beginning of the study for children. In adults free water was allowed ad libitum.
Those who failed to be rehydrated due to persistent vomiting or non-acceptability of ORS were
considered as oral therapy failures and were treated with intravenous fluid.
Statistical analyses were performed using the 2-tailed “t” test and Chi-square test.

RESULTS
The two groups of adults and children were comparable in respect to age, weight, duration
of diarrhoea before admission, and degree of dehydration and acidosis reflected by plasma
 68 S . M . Ahmed et al. Scand J Infect Dis 18 (1986)

Table IV. Serum sodium and potassium values (mean meqll k S D ) in patients before and
during therapy with Citrate ORS or WHO ORS

Children (4
years) Adults

Citrate ORS WHO ORS Citrate ORS WHO ORS

(n=24) (n=24) (n=25) (n=25)

Sodium
Admission 135.827.0 133.755.9 134.923.5 136.053.6
At 24 h 138.4k5.3 137.7f4.2 137.6t4.4 139.4k3.9
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At 48 h 138.7f6.5 138.6t4.9 136.425. I 139.5k2.8

Potassium
Admission 4.423.2 3.950.9 4.4f0.6 4 . 8 f 1.2
At 24 h 3 . 9 2 1 .O 3.9f1.0 4.3t0.5 4.2k0.4
At 48 h 3 . 8 5 1. I 4.3k1.0 4. I t 0 . 5 4.350.4

specific gravity and serum carbon dioxide level @>0.05) (Table I). The etiological agents
identified in the citrate-ORS group were enterotoxigenic E. coli in 15/32 stools tested
(47%) and V . cholerae in 2 (4%), and in the WHO-ORS group enterotoxigenic E. coli in
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15/35 stools tested (43 %), V. cholerae in 7 (12%) and Shigella sp. in I (2%). Rotavirus was
detected in 1 of 10 stools tested in children (10%).
Three adults and 5 children in the citrate group and 4 adults and 5 children in the control
group were excluded from study. Most of these patients (71 %) could not be rehydrated
orally due to persistent vomiting. They were considered as oral failures and were treated
with intravenous fluid. The others were excluded because of poor compliance during the
study. The success of rehydration in the remainder of both groups of adults and children
was supported by significant rise in weight and drop in serum specific gravity which were
evaluated at 24 and 48 h respectively after initiation of oral therapy (Table 111).
In those who were successfully treated with ORS alone, there were no signifcant
differences in the intake of ORS and milk or output of stool and urine between the groups
except that children in the WHO-ORS group drank significantly more ORS (p<O.OS)
during initial 24 h therapy (Table 11). There was a higher incidence of vomiting during
initial rehydration in children receiving WHO-ORS, 76 %, than in children receiving the
citrate ORS, 52% (p>0.05). The vomiting, which resulted in added intake of ORS, may
explain the higher mean intake in the WHO-ORS group. All patients passed urine satisfac-
torily within 12 h.
Children treated with WHO-ORS corrected their biochemical acidosis faster than those
treated with citrate ORS during initial 24 h period (Table 111). Serum sodium and potas-
sium concentrations at 0, 24 and 48 h period of treatment showed no significant differences
(Table IV).
Nine adults and 11 children graded the taste of the effervescent oral solution as neutral.
16 adults and 12 children graded it as good. Only 2 children expressed that the solution had
an unpleasant taste.

DISCUSSION
This study confirms that ORS containing citrate is as effective as bicarbonate based WHO
ORS in the management of diarrhoea1 dehydration and associated acidosis in adults.
 Scand J Infect Dis 18 (1986) Diarrhoeal rehydration with citrate 69

Young children also could be rehydrated with the citrate-based ORS equally well as with
WHO ORS. Vomiting was observed more frequently in children treated with WHO ORS.
Thus, these children took more than the calculated amount of ORS for initial rehydration
and this explains why these children took more ORS than did the citrate group. Biochemi-
cal correction of acidosis was found to be delayed in these children treated with citrate-
ORS during the initial 24 h therapy, but correction of acidosis was quite satisfactory by 48
h, and comparable with children treated with WHO ORS. The reason for the delayed
correction of biochemical acidosis in these children treated with citrate ORS is not fully
understood. Citrate metabolism may be interrupted and delayed in the face of assaults
from acute dehydration and malnutrition, which could interfere with normal liver function
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in children of developing countries. Since none of these children showed evidence of

clinical acidosis, this delayed correction of acidosis may have no practical significance.
Advantages of the effervescent tablet form of ORS include a prolonged shelf life,
allowing it to be stored for prolonged periods even in a humid climate. Since one tablet is
dissolved in 120 ml of water, there will be little wastage of prepared ORS. Promotion of
bacterial overgrowth in prepared ORS will also be minimized as patients will receive
freshly prepared ORS each time. These advantages have particular implications in devel-
oping countries where there is a great need of general stock piling of ORS for control of
diarrhoeal disease programme.
Additionally, for travelers to developing countries who anticipate diarrhoeal episodes,
the effervescent tablets present a convenient and compact alternative to the packets of
For personal use only.

ORS ingredients. Travelers’ diarrhoea is frequently caused by enterotoxigenic E. coli (1 1,

12). Our favorable experience with this citrate containing ORS in patients who were
infected frequently with enterotoxigenic E. coli suggests that this form of ORS should be
useful for travelers.

ACKNOWLEDGEMENTS
This research was supported by the International Centre for Diarrhoeal Disease Research, Bangla-
desh (ICDDR, B).
The authors acknowledge with gratitude, the excellent help and co-operation received from Mr H.
B. Ghose, Miss Makhduma Khatun, Mrs Anita Stephen and her clinical research staff. The authors
would like to thank Mr Meer Md. Ramzan Ali for excellent secretarial work.

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For personal use only.