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 Accepted 9 May 2019
few studies which compare half normal saline with normal saline as maintenance IVF in KEYWORDS
general paediatric wards. Hypotonic fluid; isotonic
Aim: To compare the safety and efficacy of half normal saline with normal saline as fluid; saline; hyponatraemia
main- 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

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

CONTACT Manish Kumar

© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 M. KUMAR ET
AL.
hypotonic half normal saline, both at a standard
Subjects and methods maintenance rate.
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
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH 3
excluding the 15 children who showed trial
Baseline demographic, clinical diagnosis, deviation as they failed to complete 24 h of
anthropome- try and laboratory parameters were intervention fluid as per group allocation.
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
 Number of children screened for eligibility (n=805) Consent refused (n=39) Met at least 1 exclusion criteria (n=173)
Hyponatraemia 25
Number of children meeting eligibility criteria (n=380) Hypernatraemia 5
Dehydration 49
Required boluses 31
Haemodynamic instability 25
Renal failure 4
Number of children excluded Heart failure 10
(n=212)
Severe acute malnutrition 7
Received IV fluids in last 24 hours 15
Received diuretics in last 7 days 2

Number of children enrolled (n=168)

Randomized (n=168)

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

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

Number of children finally analyzed for study (n= Analysis Number of children finally analyzed for study (n= 84)
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
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 with increased secretion of anti-diuretic hormone
sodium levels in the isotonic group had increased
by
2.14mmol/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
(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
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
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.
Maulana Azad Medical College & Associated LN
Hospital, New Delhi, India-110002.
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