Paediatrics and International Child Health

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Isotonic versus hypotonic saline as maintenance

intravenous fluid therapy in children under 5 years
of age admitted to general paediatric wards: a
randomised controlled trial

Manish Kumar, Kaustav Mitra & Rahul Jain

To cite this article: Manish Kumar, Kaustav Mitra & Rahul Jain (2019): Isotonic versus hypotonic
saline as maintenance intravenous fluid therapy in children under 5 years of age admitted to
general paediatric wards: a randomised controlled trial, Paediatrics and International Child Health,
DOI: 10.1080/20469047.2019.1619059

To link to this article: https://doi.org/10.1080/20469047.2019.1619059

Published online: 29 May 2019.

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PAEDIATRICS AND INTERNATIONAL CHILD HEALTH
https://doi.org/10.1080/20469047.2019.1619059

Isotonic versus hypotonic saline as maintenance intravenous fluid therapy in

children under 5 years of age admitted to general paediatric wards: a
randomised controlled trial
Manish Kumar, Kaustav Mitra and Rahul Jain
Department of Paediatrics, Chacha Nehru Bal Chikitsalaya, New Delhi, India

ABSTRACT ARTICLE HISTORY

Background: To prevent the risk of iatrogenic hyponatraemia in hospitalised children, Received 9 January 2019
isotonic fluid has been recommended as maintenance intravenous fluid (IVF). There are few Accepted 9 May 2019
studies which compare half normal saline with normal saline as maintenance IVF in general KEYWORDS
paediatric wards. Hypotonic fluid; isotonic
Aim: To compare the safety and efficacy of half normal saline with normal saline as main- fluid; saline; hyponatraemia
tenance IVF in general paediatric wards.
Methods: Children aged between 3 months and 5 years with an anticipated requirement for
IVF for 24 h were randomised to receive either half normal saline (0.45% saline in 5%
dextrose) or normal saline (0.9% saline in 5% dextrose). The primary objective was to compare
the incidence of hyponatraemia (serum sodium <135 mmol/L with a decrease from baseline
of at least 4 mmol/L) at 24 h in children receiving half normal saline with those receiving
normal saline. Secondary objectives were to compare the incidence of moderate (sodium
<130 mmol/L), severe (sodium <125 mmol/L) and symptomatic hyponatraemia, change in
serum sodium level from baseline and the incidence of hypernatraemia.
Results: A total of 168 children were randomised to receive either normal saline (n = 84) or half
normal saline (n = 84). More than two-thirds of the children were suffering from respiratory
diseases (pneumonia and bronchiolitis) and diseases of the nervous system (meningoencepha-
litis, febrile seizures and epilepsy). The incidence of hyponatraemia at 12 h in children receiving
half normal saline was similar to that in those receiving normal saline (6 vs 4.8%; Relative risk
(RR) 1.2; 95% CI 0.3.0–4.8; p = 0.73). Although the incidence of hyponatraemia at 24 h in children
receiving half normal saline was higher than in those receiving normal saline, the difference
was not statistically significant (14.3 vs 6%; RR 2.6; 95% CI 0.9–7.8; p = 0.07). One child in the
isotonic group and one in the hypotonic group developed moderate and severe hyponatrae-
mia, respectively. There was no significant difference in the incidence of hypernatraemia
between two groups (RR 0.7; 95% CI 0.16–3.3).
Conclusion: Half-normal saline as maintenance IVF does not result in a significantly increased
risk of hyponatraemia in general paediatric ward patients under 5 years of age.

Introduction IVF in children aged from 1 month to 18 years as it

significantly reduces the risk of hyponatraemia [14].
Addressing the treatment of hospital-acquired hypona-
As most of the studies have been conducted in
traemia with hypotonic maintenance fluid, Moritz and
post-operative and critically ill children using hypo-
Ayus recommended 0.9% saline in dextrose as mainte-
tonic solution with variable sodium concentrations
nance intravenous fluid (IVF) in children [1]. However,
varying from 0.2% to 0.45% saline [15], the recom-
concerns were raised about the increased risk of hyperna-
mendation of isotonic saline as maintenance IVF can-
traemia with isotonic saline, and a physiologically based
not be generalised to all hospitalised children. There
fluid protocol was suggested to avoid hyponatraemia [2].
are few studies which compare 0.45% saline with
As a compromise between traditional 0.18% saline and
0.9% saline as maintenance IVF in order to assess
complete switching to isotonic solution, The National
the risk of hyponatraemia [8–10], and, to the best of
Patient Safety Agency, UK recommended 0.45% saline
our knowledge, only one such study has been exclu-
as standard maintenance fluid to avoid the risk of severe
sively done in general paediatric ward patients using
hyponatraemia [3]. Since then, many trials and reviews
0.45% saline as hypotonic fluid [9].
have demonstrated a significantly increased risk of hypo-
This study aimed to determine the safety and effi-
natraemia in children receiving hypotonic maintenance
cacy of isotonic normal saline compared with hypo-
fluid [4–13]. A recent clinical practice guideline on main-
tonic half normal saline as maintenance IFV in general
tenance fluid in children by the American Academy of
paediatric ward patients.
Pediatrics recommended isotonic saline as maintenance

CONTACT Manish Kumar manishkp75@yahoo.com

© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 M. KUMAR ET AL.
Subjects and methods
This open-label, randomised controlled trial was con-
ducted from November 2015 to October 2016 in
Chacha Nehru Bal Chikitsalaya, a tertiary-care children’s
hospital in Delhi. Children aged from 3 months to 5 years
attending the paediatric emergency department with an
anticipated requirement for IVF for 24 h were enrolled.
The following were excluded from the study: children
who had received IVF in the last 24 h, those with baseline
hyponatraemia (serum sodium <135 mmol/L) or hyper-
natraemia (serum sodium>145 mmol/L), dehydration
requiring fluid boluses, haemodynamic instability, severe
acute malnutrition and renal or hepatic disorders or con-
gestive cardiac failure. Haemodynamic instability was
defined as the presence of shock at admission requiring
fluid boluses with or without inotropes. Severe acute
malnutrition was defined according to WHO criteria as
weight-for-length/height <−3 SD score.
The primary outcome variable was to compare the
incidence of hyponatraemia in children receiving
0.45% saline in 5% dextrose with those receiving
0.9% saline in 5% dextrose (subsequently referred to
as half normal saline and normal saline, respectively).
Hyponatraemia was defined as serum sodium
<135 mmol/L with a decrease of at least 4 mmol/L
from baseline [9]. ‘Hypotonic’ and ‘isotonic’ will be
used for half normal saline and normal saline, respec-
tively. The secondary outcome variables were compar-
ison of the incidence of moderate (serum sodium
<130 mmol/L), severe (serum sodium <125 mmol/L)
and symptomatic hyponatraemia (lethargy, altered
sensorium or seizures), difference in mean serum
sodium level at 12 and 24 h, change in serum sodium
level from baseline and the incidence of hypernatrae-
mia (serum sodium >145 mmol/L) in the two groups.
Assuming a 20% incidence of hyponatraemia with
hypotonic saline, it was hypothesised that the incidence
of hyponatraemia would be decreased to 5% with the
use of isotonic normal saline [16]. A sample size of 76 was
calculated in each group at an alpha level of 0.05 and
power of 80%. Given a drop-out rate of 10%, it was
decided to enrol 84 children for each group.
Block randomisation was undertaken with randomly
permuted blocks of variable sizes using www.randomisa
tion.com, and a randomisation sequence was generated.
This randomisation sequence was transcribed to sequen-
tially numbered opaque sealed envelopes (SNOSE)
labelled as treatment Group 1 or 2 by a person not
directly involved in the study. At the time of enrolment,
the envelope pertaining to the sequence number of the
patient was opened and group allocation was done
according to the treatment arm written inside the envel-
ope. Children allocated to Group 1 received isotonic
normal saline and those in Group 2 received hypotonic
half normal saline, both at a standard maintenance rate.
Baseline demographic, clinical diagnosis, anthropome-
try and laboratory parameters were recorded.
Subsequent serum sodium levels were measured at 12
and 24 h. Serum sodium was measured by the direct ion
selective method with an Escheweler Combi Line analy-
ser. Children were monitored for signs of dysnatraemia
(drowsiness, encephalopathy, seizure and vomiting) and
features of fluid overload (facial puffiness or oedema).
Intervention fluid was stopped before 24 h if serum
sodium decreased to <130 mmol/L or increased to
>150 mmol/L, oral intake improved or features of fluid
overload appeared. Clinical monitoring was continued
and sodium measured at 24 h, even after stopping IVF.
Statistical analysis
Statistical analysis was undertaken using SPSS version
23. Descriptive statistics were calculated by frequency
with percentages, mean (SD) or median (IQR), as
applicable. Pearson’s χ2 or Fischer’s Exact test were
employed to test the significance of difference
between two proportions. The independent sample
t-test and Mann–Whitney U-tests were used to test
the significance between two means and medians,
respectively. Significance of difference in the same
group was analysed by the paired t-test, and
p < 0.05 was considered statistically significant.
Ethics approval
The study protocol was approved by the institution’s
Ethics Committee and informed consent was given by
all the parents. The trial was registered with the
Clinical Trials Registry, India (CTRI/2017/09/009639).
Results
Of the 805 children screened, 380 met the inclusion
criteria and were enrolled for the study (Figure 1), 212
children were excluded for various reasons and the
remaining 168 were equally randomised into two
groups: isotonic normal saline (n = 84) and hypotonic
half normal saline (n = 84). IVF was discontinued
before 24 h in six and eight children receiving normal
saline and half normal saline, respectively, because of
clinical improvement and better oral acceptance.
Intervention fluid was stopped and changed to nor-
mal saline in one child receiving half normal saline
owing to the development of severe hyponatremia
(serum sodium 124 mmol/L) at 12 h of fluid therapy.
None of the children developed features of fluid over-
load. Final analysis was undertaken according to
intention-to-treat. Per-protocol analysis was also
undertaken after excluding the 15 children who
showed trial deviation as they failed to complete
24 h of intervention fluid as per group allocation.
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH 3

Number of children screened for eligibility (n=805) Consent refused (n=39)

Met at least 1 exclusion
criteria (n=173)
Number of children meeting eligibility criteria (n=380) • Hyponatraemia 25
• Hypernatraemia 5
• Dehydration 49
• Required boluses 31
Number of children excluded (n=212) • Haemodynamic instability
25
• Renal failure 4
• Heart failure 10
• Severe acute malnutrition
Number of children enrolled (n=168) 7
• Received IV fluids in last
24 hours 15
• Received diuretics in last 7
Randomized (n=168)
days 2

GROUP 1- Isotonic fluid (0.9% normal saline with 5% GROUP 2- Hypotonic fluid (0.45% normal saline with 5%
dextrose) (n=84) Allocation dextrose) (n=84)

Number of children who received maintenance IVF < 24 Number of children who received maintenance IVF < 24
hours (n=6) Follow-up hours (n=8)

Number of children finally analyzed for study (n= 84) Analysis Number of children finally analyzed for study (n= 84)

Figure 1. Study flow chart.

Table 1. Baseline clinical, demographic and laboratory parameters.

Isotonic fluid Hypotonic fluid
Parameters n = 84 n = 84 p-value
*Age, months, median (IQR) 16 (7–30) 11 (5–28.5) 0.12
Age group, months, n (%)
3–6, n=44 18 (21.4) 26 (31.0) 0.14
6–12, n=48 22 (26.2) 26 (31.0)
12–24, n=33 22 (26.2) 11 (13.1)
24–60, n=43 22 (26.2) 21 (25)
Male, n =110 (%) 59 (70) 51 (61)
Diagnosis at admission, n (%)
Respiratory diseases, n=88 44 (52.4) 44 (52.4) 0.58
CNS diseases, n=39 20 (23.8) 19 (22.6)
Gastrointestinal, n=7 4 (4.8) 3 (3.6)
Poisoning, n=11 5 (6.0) 6 (7.1)
Metabolic, n=13 4 (4.8) 9 (10.7)
Others, n=10 7 (8.3) 3 (3.6)
Weight, kg, mean (SD)
3–6 months 5.3 (0.9) 5.2 (0.70) 0.96
6–12 months 7.3 (0.8) 7.6 (1.2) 0.36
12–24 months 9.9 (1.3) 9.8 (1.5) 0.75
24–60 months 13.4 (1.8) 14.3 (1.8) 0.15
Haemoglobin, g/dL 9.9 (1.8) 10 (1.8) 0.77
Total leucocyte count, 109/L 12.7 (5.9) 13.7 (6.4) 0.31
Platelet count, 109/L 373 (173) 366 (145) 0.78
Blood urea, mg/dl 28.3 (20.8) 25.6 (18.4) 0.37
Serum creatinine, mg/dl 0.6 (0.1) 0.6 (0.1) 0.06
Serum sodium, mmol/L 137.2 (2.1) 137.9 (2.8) 0.07
Volume of IVF received, ml/kg/day 93.3 (11.0) 93.8 (9.5) 0.78
IVF, intravenous fluid.
All variables are expressed as mean (SD) except* median (IQR).

Baseline characteristics were similar in the two
groups except that more children aged between 12
and 24 months were allocated to the isotonic group
(Table 1). More than half of the children had respiratory
diseases (n=88), followed by neurological diseases
(n=39). Pneumonia was the most common respiratory
system disease (n=61), followed by bronchiolitis (n=11),
empyema (n=8), acute episodic wheeze (n=4), asthma
(n=2), pneumothorax (n=1) and pulmonary tuberculosis
(n=1). On the other hand, febrile seizure (n=14) and
meningitis (n=13) were the most common neurological
diseases, followed by epilepsy (n=5), encephalitis (n=2),
intracranial tumour (n=1), stroke (n=1), neurocysticerco-
sis (n=1) and post-diphtheric palatal palsy (n=1). Mean
4 M. KUMAR ET AL.

Table 2. Primary and secondary outcomes in two study groups.

Isotonic fluid Hypotonic fluid RR, 95% CI;
Outcome n = 84 n = 84 or mean difference, CI p-value
Primary outcome
Incidence of hyponatraemia at 12 h 4 (4.8%) 5 (6.0%) 1.2 (0.3–4.8) 0.73
Incidence of hyponatraemia at 24 h 5 (6.0%) 12 (14.3%) 2.6 (0.9–7.8) 0.07
Secondary outcome
Serum sodium at 12 h, mean (SD) 138.1 (2.7) 137.4 (3.2) 0.74 (−0.2–1.65)* 0.11
Serum sodium at 24 h, mean (SD) 139.3 (4.4) 137.6 (4.0) 1.7 (0.4–2.9)* 0.01
Change in serum sodium at 12 h from baseline 0.94 (2.9) −0.49 (4.0) 1.43 (0.35–2.5)* 0.009
Change in serum sodium at 24 h from baseline 2.14 (4.7) −0.24 (4.8) 2.38 (0.9–3.8)* 0.002
Incidence of hypernatraemia at 12 hrs 1 (1.2%) 0 1 (0.96–1.01) 1.0
Incidence of hypernatraemia at 24 hrs 3 (3.6%) 4 (4.8%) 0.7 (0.16–3.3) 1.0
p-values in bold type are statistically significant.
Hyponatraemia: serum sodium <135 mmol/L; hypernatraemia: serum sodium >145 mmol/L.
CI, confidence interval; RR, relative risk.
*Mean difference and confidence interval.

(SD) volumes of IVF administered to the hypotonic and
isotonic groups were 93.8 (9.5) and 93.3 (11) ml/kg/day,
respectively (p=0.78).
The incidence of hyponatraemia at 12 h in children
receiving half normal saline was similar to that in those
receiving normal saline (6 vs 4.8%; RR 1.2; 95% CI 0.3–4.8;
p=0.73). Although the incidence of hyponatraemia at
24 h in children receiving half normal saline was higher
than in those receiving isotonic saline (14.3 vs 6%), the
difference was not statistically significant (RR 2.6; 95% CI
0.9–7.8; p=0.07) (Table 2). There was one case each of
moderate (serum sodium <130 mmol/L) and severe
(serum sodium <125 mmol/L) hyponatraemia at 24 and
12 h of fluid therapy in the isotonic and hypotonic
groups, respectively. The child who developed moderate
hyponatraemia had a baseline serum sodium level of
138 mmol/L which decreased to 131 and 126 mmol/L
at 12 and 24 h of fluid therapy, respectively. The other
child who developed severe hyponatraemia had
a baseline serum sodium level of 141 mmol/L which
subsequently decreased to 124 mmol/L at 12 h of fluid
therapy. The IVF was changed to isotonic saline, and the
serum sodium level at 24 h was 133 mmol/L. None of the
children in either group developed features of sympto-
matic hyponatraemia. Per-protocol analysis of the inci-
dence of hyponatremia at 24 h of fluid therapy was
undertaken after excluding 15 trial deviants and the
results were similar to those of the intention-to-treat
analysis. The incidences of hyponatremia at 24 h were
14.9 and 6.3% in children receiving hypotonic and iso-
tonic fluid, respectively (RR 2.6; 95% CI 0.9–8.3; p = 0.08).
The mean (SD) serum sodium levels at 12 h in the
hypotonic and isotonic groups were 137.4 (3.2) and 138.1
(2.7) mmol/L, respectively, but the difference was not
statistically significant. However, the mean (SD) serum
sodium level at 24 h in the hypotonic group was signifi-
cantly lower than in the isotonic group [137.6 (4.0) vs
139.3 (4.4) mmol/L; p = 0.012] (Figure 2).
At 12 h, the serum sodium level in the isotonic
group had increased from baseline by 0.94 mmol/L,
whereas it had decreased by 0.49 mmol/L in the hypo-
tonic group (mean change in serum sodium from

Figure 2. Serum sodium levels at 0, 12 and 24 h of fluid therapy in the two groups.

baseline +1.5 mmol/L; p = 0.009). At 24 h, serum
sodium levels in the isotonic group had increased by
2.14 mmol/L, but had decreased by 0.24 mmol/L in the
hypotonic group (mean change in serum sodium from
baseline +2.38 mmol/L; p = 0.002) (Table 2). A post-hoc
analysis to measure changes in the serum sodium level
from baseline in individual groups showed a significant
change in the isotonic group at 12 h (+0.94 mmol/L;
p = 0.005) and 24 h (+2.1 mmol/L; p < 0.001), whereas
there was no significant change in the hypotonic group
at 12 h (−0.49 mmol/L; p = 0.26) and 24 h (−0.24 mmol/
L; p = 0.63).
There was one case of hypernatraemia (sodium
>145 mmol/L) in the isotonic group and none in
the hypotonic group at 12 h. However, at 24 h,
there were three and four cases of hypernatraemia
in the isotonic and hypotonic groups, respectively
(RR 0.7; 95% CI 0.16–3.3). One child in the hypotonic
group had a serum sodium level of 150 mmol/L and
one in the isotonic group a level of 158 mmol/L.
Another five children with hypernatraemia had
serum sodium levels which varied between 146 and
149 mmol/L.
Discussion
When compared with isotonic normal saline, hypotonic
half normal saline as maintenance IVF in children under
5 years of age admitted to the general paediatric wards
did not result in a significantly increased risk of hypona-
traemia. In contrast, most recent trials and reviews have
demonstrated a significantly increased risk of hyponatrae-
mia with hypotonic saline and favour isotonic saline as
maintenance IVF [4–13]. The increased risk of hyponatrae-
mia in earlier studies could be owing to a heterogeneous
study population, mainly post-operative and critically ill
children, and varying rate and tonicity of hypotonic fluid
(0.18–0.45%). Moreover, similar to earlier studies, an
increased risk of moderate, severe or symptomatic hypo-
natraemia was not observed in children receiving hypo-
tonic fluid [9,10]. In contrast, in a meta-analysis in 2014,
hypotonic fluid was associated with a significantly
increased risk of moderate and severe hyponatraemia [7].
In this study, the incidence of hyponatraemia at 24 h
was 14.3% in the hypotonic group, which is similar to
another Indian study [5]; however, the study population,
definition of hyponatraemia and tonicity of fluid were
different from this study. Similarly, in one of the most
recent and largest randomised controlled trials under-
taken in Australia, the incidence of hyponatraemia was
11% in children receiving maintenance fluid containing
77 mmol/L of sodium [10]. In contrast, a higher incidence
of hyponatraemia (48–60%) with the use of hypotonic
fluid (0.2–0.45% saline with varying infusion rate) was
reported in other Indian studies [11–13] of children with
pneumonia and meningitis which are known to be asso-
ciated with increased secretion of anti-diuretic hormone
PAEDIATRICS AND INTERNATIONAL CHILD HEALTH 5
(ADH), resulting in impaired water excretion and
hyponatraemia.
In this study, neither group demonstrated a significant
difference in mean serum sodium levels at 12 h, similar to
an earlier study [8]. However, a significant difference
between the two groups in serum sodium level was
observed at 24 h which resulted from a significant rise in
serum sodium in the isotonic group rather than
a significant fall in serum sodium in the hypotonic
group. In contrast, no significant difference in serum
sodium at 24 h was observed between two groups in
two previous studies, both of which used 0.45% saline as
hypotonic fluid [9,10].
An important finding in this study was the absence of
a significant decrease in serum sodium levels from base-
line at 12 and 24 h in the hypotonic group which is similar
to two earlier studies [8,9] which also reported no sig-
nificant change in rate and absolute serum sodium level
in the hypotonic group. However, isotonic saline in this
study resulted in a significant increase in serum sodium
from baseline but not a significantly increased risk of
hypernatraemia, similar to earlier studies [4–6,8–10].
The study was conducted in general paediatric ward
patients using half normal saline compared with normal
saline which was a more realistic and practical scenario.
Limitations of the study include not measuring oral fluid
intake, urine output and weight after fluid therapy as
a measure of fluid overload, and children were not fol-
lowed up beyond 24 h of fluid therapy to detect the
occurrence of hyponatraemia or hypernatraemia. Non-
estimation of serum ADH levels and serum and urine
osmolality were other limitations.
Half normal saline as maintenance IVF in children
under 5 years of age in general paediatric wards does
not result in a significantly increased risk of hyponatrae-
mia compared with isotonic normal saline. However,
more studies with a larger sample size are needed to
assess the safety of half normal saline as maintenance
IVF in general the paediatric population. Children receiv-
ing normal saline as maintenance fluid beyond 24 h need
to be monitored iatrogenic hypernatraemia. Multi-centre
studies with adequate sample sizes are needed to detect
the incidence of moderate and severe hyponatraemia in
children receiving half normal saline compared with iso-
tonic saline.
What is already known?
Compared with hypotonic fluid, isotonic normal saline
as maintenance IVF in hospitalised children reduces
the risk of hyponatraemia.
What this study adds?
Half normal saline as maintenance IVF does not result
in a significantly increased risk of hyponatraemia in
general paediatric patients under 5 years of age.
6 M. KUMAR ET AL.
MK and RJ conceptualised the study. KM enrolled the
patients, collected the data and was involved in patient
management. MK prepared the initial draft and under-
took the analysis and interpretation of data. MK and RJ
revised the draft. All the authors approved the final ver-
sion of the manuscript. MK will act as guarantor for the
manuscript.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
None.
Notes on contributors
Dr. Manish Kumar is an Associate Professor in Department
of PediatricsChacha Nehru Bal Chikitsalaya (CNBC), An
Autonomous Institute under Govt. of NCT of Delhi.
Dr. Kaustav Mitra M.B.B.S. (BACHELOR OF MEDICINE &
BACHELOR OF SURGERY) in Calcutta National Medical
College & Hospital.
Dr. RAHUL JAIN is an Assistant Professor at Pediatrics
Maulana Azad Medical College & Associated LN Hospital,
New Delhi, India-110002.
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