Research

Original Investigation

Comparison of Isotonic and Hypotonic

Intravenous Maintenance Fluids
A Randomized Clinical Trial
Jeremy N. Friedman, MBChB, FRCP; Carolyn E. Beck, MD, MSc, FRCP; Julie DeGroot, MSc; Denis
F. Geary, MBChB, FRCP; Daniel J. Sklansky, MD; Stephen B. Freedman, MDCM, MSc, FRCP

Journal Club Slides and

IMPORTANCE Use of hypotonic intravenous fluids for maintenance requirements is Supplemental content at
jamapediatrics.com
associated with increased risk of hyponatremia that results in morbidity and mortality in
children. Clinical trial data comparing isotonic and hypotonic maintenance fluids in CME Quiz at
nonsurgical hospitalized pediatric patients outside intensive care units are lacking. jamanetworkcme.com and
CME Questions page 511
OBJECTIVE To compare isotonic (sodium chloride, 0.9%, and dextrose, 5%) with
hypotonic (sodium chloride, 0.45%, and dextrose, 5%) intravenous maintenance fluids in a
hospitalized general pediatric population.

DESIGN, SETTING, AND PARTICIPANTS In this double-blind randomized clinical trial, we

recruited 110 children admitted to a general pediatric unit of a tertiary care children’s
hospital from March 1, 2008, through August 31, 2012 (age range, 1 month to 18 years),
with normal baseline serum sodium levels who were anticipated to require intravenous
maintenance fluids for 48 hours or longer (intent-to-treat analyses). Children with
diagnoses that required specific fluid tonicity and volumes were excluded.

INTERVENTIONS Patients were randomized to receive isotonic or hypotonic intravenous

fluid at maintenance rates for 48 hours.

MAIN OUTCOMES AND MEASURES The primary outcome was mean serum sodium level at 48
hours. The secondary outcomes were mean sodium level at 24 hours, hyponatremia and
hypernatremia, weight gain, hypertension, and edema. Confounding variables were included in
multiple regression models. Post hoc analyses included change from baseline sodium level at
24 and 48 hours and subgroup analysis of children with primary respiratory diagnosis.

RESULTS Of 110 enrolled patients, 54 received isotonic fluids and 56 received hypotonic fluids.
Author Affiliations: Division of
The mean (SD) sodium level at 48 hours was 139.9 (2.7) mEq/L in the isotonic group and 139.6 Paediatric Medicine, Paediatric
(2.6) mEq/L in the hypotonic group (95% CI of the difference, −0.94 to 1.74 mEq/L; Outcomes Research Team, The
P = .60). Two patients in the hypotonic group developed hyponatremia, 1 in each group Hospital for Sick Children, University of
Toronto, Toronto, Ontario, Canada
developed hypernatremia, 2 in each group developed hypertension, and 2 in the isotonic
(Friedman, Beck, DeGroot); Division of
group developed edema. Mean (SD) change from baseline to 48-hour sodium level was Nephrology, The Hospital for Sick
+1.3 (2.9) vs −0.12 (2.8) mEq/L, respectively (absolute difference, 1.4 mEq/L; 95% Children, University of Toronto,
Toronto, Ontario, Canada (Geary);
CI of the difference, −0.01 to 2.8 mEq/L; P = .05).
Division of Pediatrics, University of
Wisconsin School of Medicine and
CONCLUSIONS AND RELEVANCE Our study results support the notion that isotonic Public Health, Madison (Sklansky);
maintenance fluid administration is safe in general pediatric patients and may result in Sections of Pediatric Emergency
Medicine and Gastroenterology,
fewer cases of hyponatremia.
Department of Paediatrics, Alberta
Children’s Hospital, Alberta Children’s
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00632775 Hospital Research Institute, University
of Calgary, Calgary, Alberta, Canada
(Freedman).
Corresponding Author: Jeremy N.
Friedman, MBChB, FRCP, Department
of Paediatrics, Paediatric Outcomes
Research Team, The Hospital for Sick
Children, 555 University Ave, Toronto,
JAMA Pediatr. 2015;169(5):445-451. ON M5G 1X8, Canada
doi:10.1001/jamapediatrics.2014.3809 Published online March 9, 2015. (jeremy.friedman@sickkids.ca).

445

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 Research Original Investigation
H yponatremia is an increasingly recognized cause of morbidity
and mortality in hospitalized children.1-6 The provision of
hypotonic intravenous (IV) mainte-
nance fluids is based on work from the 1950s7 that outlines the fluid and
electrolyte requirements in healthy children based on energy
expenditure and milk composition. Hypotonic IV maintenance fluids
have generally remained the standard of care.8,9 However, there is
increasing recognition that many hos-pitalized children secrete
increased antidiuretic hormone. The administration of hypotonic IV
maintenance fluids to such chil-dren can result in iatrogenic
hyponatremia.10-12
During the past decade, evidence has accumulated sug-gesting that
hypotonic IV maintenance fluid administration in hospitalized children
increases the risk of hyponatremia11 and that hospital-acquired
hyponatremia can lead to seizures, neu-rologic impairment, and death.1-
6,11,12
Despite this increasing body of evidence, a multi-institutional
survey conducted in the United Kingdom8 revealed that 78% of children
receiving IV maintenance fluids were administered hypotonic fluids. A
survey of US pediatric residents9 similarly revealed that 78% routinely
prescribe hypotonic IV maintenance fluids. The rea-sons for the
continued use of hypotonic IV maintenance flu-ids are unclear but may
be explained in part by the lack of stud-ies of hospitalized nonsurgical
children outside the intensive care unit (ICU) setting.
To avoid the development of hyponatremia, it has been suggested
that isotonic replace hypotonic fluids as the stan-dard maintenance IV
fluid.13,14 However, concerns have been raised that isotonic fluids may
15,16
result in hypernatremia and fluid overload, and their use in blinded
clinical trials in children outside the ICU or postoperative period has not
been studied.
Our objective was to compare isotonic (sodium chloride, 0.9%, and
dextrose, 5%) with hypotonic (sodium chloride, 0.45%, and dextrose,
5%) IV maintenance fluids in a hospital-ized general pediatric
population. We hypothesized that, in children administered an isotonic
fluid compared with those given a hypotonic fluid, the former group
would have a higher mean serum sodium level 48 hours after the
initiation of IV maintenance fluid administration. We additionally
hypoth-esized that children administered an isotonic fluid would be less
likely to develop hyponatremia without developing clini-cally
significant serum sodium increases or symptomatic fluid overload.
Methods
Patients
Eligible children aged 1 month to 18 years were initially evalu-ated in
the emergency department (ED) of The Hospital for Sick Children
(Toronto, Ontario, Canada) from March 1, 2008, through August 31,
2012, and were deemed to require admis-sion to the general pediatric
unit. On admission, families of eli-gible children were approached to
discuss study participa-tion; if they agreed, a study investigator (J.N.F.,
C.E.B., or D.J.S.) or qualified designate obtained written informed
consent from the caregivers and participant assent when appropriate.
En-
446 JAMA Pediatrics May 2015 Volume 169, Number 5
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Intravenous Maintenance Fluids
rollment occurred Monday through Friday during daytime hours when
a dedicated research assistant was available. The Hospital for Sick
Children Research Ethics Board approved the study. The trial protocol
can be found in the Supplement.
Participants had a normal initial serum sodium level (135-145
mEq/L [to convert to millimoles per liter, multiply by 1]), a management
plan that included IV fluid administration at 80% to 120% of
maintenance as defined by the Holliday-Segar method,7 and an
anticipated requirement for IV fluids of 48 hours or longer. Children
diagnosed as having or clini-cally suspected of having any of the
following were excluded because these conditions usually have specific
fluid require-ments: dehydration with ongoing fluid losses; cardiac,
renal, or hepatic failure; hemoglobin level less than 6 g/dL (to con-vert
to grams per liter, multiply by 10); portal hypertension with ascites;
metabolic disease; diabetes insipidus or mellitus; hy-pertension; adrenal
insufficiency; nephritic or nephrotic syn-drome; and Kawasaki disease.
Children were also excluded if they were edematous, were taking
diuretic medications, had a serum glucose level greater than 270 mg/dL
(to convert to mil-limoles per liter, multiply by 0.0555), or required ICU
care. Chil-dren remained eligible if they received an IV bolus of an iso-
tonic fluid before enrollment as long as they were considered euvolemic
and only required IV maintenance fluids with no additional rehydration
after enrollment.
Randomization and Blinding
Master randomization tables were prepared and held by the institution’s
Research Support Pharmacy. Patients were allo-cated in a 1:1 ratio to
treatment with a maintenance IV fluid that contained 154 mEq/L of
sodium (sodium chloride, 0.9%, and dextrose, 5%) or 77 mEq/L of
sodium (sodium chloride, 0.45%, and dextrose, 5%), respectively. The
randomization se-quence was computer generated, using balanced
blocks of 4 and stratified by age (<2.5 vs ≥2.5 years). The randomization
code remained secure until enrollment and data entry were complete.
Blinding was accomplished by the placement of an opaque amber
plastic sleeve over the 1-L study IV fluid bags by the research
pharmacist before its dispensing. This pro-cess enabled us to conceal
the identity of the IV fluid from the patient, family, nurses, physicians,
and research team.
Patients taking oral fluids before the 48-hour study end point had
their IV rate reduced to aim for a total fluid intake in keeping with
standard total daily maintenance fluid vol-umes (ie, Holliday-Segar
method7). Potassium was ordered as 0, 20, or 40 mEq/L as entered by
the responsible physician into a computer physician order entry system.
This procedure en-abled the Research Support Pharmacy to add the
potassium requested before distribution to the inpatient unit.
Monitoring
Serum sodium, potassium, chloride, urea, creatinine, glu-cose, and total
carbon dioxide were measured at the time of IV fluid administration and
subsequently every 24 hours. Blood was drawn by peripheral venous
sampling. All sodium mea-surements were performed by the hospital
clinical laboratory using the VITROS 5600 integrated system (Ortho-
Clinical Di-agnostics) with an SD of 0.7 mEq/L and coefficient of varia-
jamapediatrics.com
 Intravenous Maintenance Fluids
tion of 0.7%. Total IV fluids administered and the type and quantity of
oral fluid intake were recorded. Daily weights were obtained every 24
hours with the same scale and clothing. A research assistant performed
a daily standardized assess-ment of edema. Blood pressure was
monitored every 8 hours.
Study Termination
Each patient’s study period terminated if or when any of the following
end points occurred: (1) 48 hours after enrollment,
(2) plasma sodium level greater than 145 mEq/L with a change of 4
mEq/L or more from baseline sodium level, (3) plasma sodium level
less than 135 mEq/L with a change of 4 mEq/L or greater from baseline
sodium level, (4) weight gain of more than 10% body weight compared
with admission weight, (5) blood pressure increase greater than 20%
diastolic or systolic compared with baseline on 3 consecutive readings
for 2 hours and greater than 95th percentile for age,17 or (6) admission
to the ICU.
Outcome Measurements
Primary Outcome
The primary outcome was mean serum sodium level 48 hours after
initiation of therapy. This outcome was selected be-cause dysnatremias
are too uncommon to study with this de-sign. Mean serum sodium level
could enable the identifica-tion of a trend toward dysnatremia
development and could potentially justify the conduct of very large
studies that fo-cused on clinically significant hyponatremic events.
Confound-ing variables, including age and baseline sodium level, were
identified a priori and placed into a multiple regression model for
analysis.
Secondary Outcomes
Secondary outcomes included the following: (1) mean serum sodium
level 24 hours after initiation of therapy; (2) develop-ment of
hyponatremia, defined as serum sodium level less than 135 mEq/L
associated with sodium decrease of 4 mEq/L or more from baseline; (3)
development of hypernatremia, defined as serum sodium level greater
than 145 mEq/L associated with sodium increase of 4 mEq/L or more
from baseline; and (4) signs of fluid overload a priori defined as any of
the follow-ing: mean and percent change in weight from baseline (in-
crease >10% from weight at admission), development of hy-pertension
(increase >20% diastolic or systolic compared with baseline),17 or
edema.
We performed a post hoc subgroup analysis based on pre-senting
diagnosis, comparing only those children with a pri-mary respiratory
diagnosis (eg, pneumonia, asthma, or bron-chiolitis). We also
performed a post hoc analysis calculating the mean change from
baseline to 24- and 48-hour serum so-dium levels between the 2 groups.
Sample Size
Enrolling 110 children would provide 90% power to detect a 2.5-mEq/L
difference in mean serum sodium levels at 48 hours given a 2-sided type
I error probability of .05 and an SD of 3 mEq/L. The minimal important
difference was selected based on expert opinion, biochemical accuracy,
and previous
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Original Investigation Research
studies.18 Our sample size calculation included a 25% adjust-ment for
losses to follow-up, withdrawals, early termination, and missing data.
Statistical Analysis
All analyses were undertaken by the intent-to-treat principle except for
adverse events, for which the as-treated principle was used. Analyses
were performed with SAS statistical soft-ware, version 9.3 (SAS
Institute Inc). To adjust for multiple test-ing, the .01 significance level
was selected for secondary out-come measures.
Baseline characteristics were compared between random-ization
groups using descriptive statistics. Discrete variables were compared
using frequency counts and percentages and continuous variables using
means, medians, SDs, and inter-quartile ranges. If a nonnormal
distribution was detected (through use of Q-Q plots), between-group
comparisons used nonparametric tests.
An unadjusted 2-sample t test was used to examine the dif-ference
in the primary outcome between groups and sub-groups and for the
continuous, secondary outcome, 24-hour serum sodium levels. We used
the Fisher exact test to exam-ine the difference between groups for the
dichotomous sec-ondary outcomes of hyponatremia or hypernatremia
and fluid overload. The 48-hour mean serum sodium levels were also
analyzed using linear regression models. Potential covariates identified
a priori were age and baseline serum sodium level, which were included
in all regression analyses.
All adverse events were reported to the The Hospital for Sick
Children Research Ethics Board according to the hospi-tal’s adverse
event reporting requirements. A data and safety monitoring committee
reviewed the data after entry of 35 patients in a masked manner and
evaluated all adverse events.
Results
Participants
Of the 186 potentially eligible children identified in the ED, 110 were
enrolled (Figure). The median age was 4.5 years (range, 0.1-17.2 years).
The most common diagnoses were pneumo-nia, sickle cell disease,
infections, asthma, and vomiting (Table 1). No significant differences
were found between the groups in terms of age, sex, baseline weight,
baseline sodium level, or diagnoses. While participating in the study,
patients in both groups received similar total volumes of IV and oral flu-
ids (Table 1). There were no known compromises in the blind-ing
procedures.
Primary Outcome
The mean (SD) 48-hour serum sodium level was 139.9 (2.7) mEq/L in
the isotonic group and 139.6 (2.6) mEq/L in the hy-potonic group
(absolute difference, 0.3 mEq/L; 95% CI of the difference, −0.94 to 1.74
mEq/L; P = .60). After adjustment for a priori identified covariates, the
48-hour serum sodium lev-els did not differ significantly (95% CI of the
difference, −2.0 to 0.57 mEq/L; P = .27) (Table 2).
JAMA Pediatrics May 2015
Volume 169, Number 5 447
 Research Original Investigation Intravenous Maintenance Fluids

Figure. Study Profile

186 Approached for participation

76 Excluded
4 Did not meet inclusion criteria
72 Declined to participate

110 Randomized

54 Allocated to sodium chloride, 0.9% 56 Allocated to sodium chloride, 0.45%

52 Received sodium chloride, 0.9% 54 Received sodium chloride, 0.45%
2 Did not receive sodium chloride, 0.9% 2 Did not receive sodium chloride, 0.45%
2 Withdrew consent 2 Withdrew consent

48 Completed 24 hours 50 Completed 24 hours

1 Remained in the study but had no 5 Remained in the study but had no
24-hour blood work 24-hour blood work
4 Discontinued from study 2 Discontinued from study
4 IV fluids discontinued 1 IV fluids discontinued
1 IV rate changes

30 Completed 48 hours 35 Completed 48 hours

2 Completed study but had no 48-hour 3 Completed study but had no 48-hour
blood work blood work
18 Discontinued from study 15 Discontinued from study
10 IV fluids discontinued 10 IV fluids discontinued
4 IV rate changes 1 IV rate changes
1 Increased BP 2 Hyponatremia
1 Hypernatremia 1 Hypernatremia
1 Edema 1 Transferred to ICU
BP indicates blood pressure;
1 Transferred to ICU
ICU, intensive care unit;
IV, intravenous.

Secondary Outcomes
Mean (SD) serum sodium levels at 24 hours did not differ be-tween the
groups (140.5 [2.7] vs 139.6 [2.7] mEq/L, respec-tively; 95% CI of the
difference, −0.22 to 2.02 mEq/L; P = .14). Two patients in the hypotonic
group developed hyponatre-mia; both had serum sodium levels of 134
mEq/L after 24 hours and were terminated from the study. These
patients included a child with pneumonia and a baseline sodium level of
141 mEq/L and a child with sickle cell disease who had a baseline
sodium level of 138 mEq/L. One patient in each group devel-oped
hypernatremia with sodium levels of 147 mEq/L at 24 hours; these
patients included a child in the isotonic group with bronchiolitis and an
initial sodium level of 139 mEq/L and a child with asthma in the
hypotonic group who had a baseline sodium level of 143 mEq/L (Table
2).
The change in weight between baseline and 48 hours did not differ
between the groups. Two patients in each group de-veloped
hypertension, and 2 patients in the isotonic group de-veloped edema.
was 1.9 (3.1) mEq/L in the isotonic group compared with –0.02 (3.1)
mEq/L in the hypotonic group (absolute difference, 1.9 mEq/L; 95% CI
of the difference, 0.6-3.1 mEq/L; P = .004).
The subgroup analysis of children with a primary respira-tory
diagnosis revealed a mean change from baseline to 48-hour sodium
level of 2.5 mEq/L (95% CI, 0.76-4.2 mEq/L) in the isotonic group
compared with −0.21 mEq/L (95% CI, −1.8 to 1.4 mEq/L) in the
hypotonic group (absolute difference, 2.7 mEq/L; 95% CI of the
difference, 0.34-5.1 mEq/L; P = .05) (Table 2).
Adverse Events
No significant adverse events were attributed to the study in-tervention.
Two patients (1 from each group) required trans-fer to the ICU for
increasing respiratory distress that was deemed to be unrelated to the
volume and type of IV fluids ad-ministered. One patient in the isotonic
group had a self-resolving episode of bradycardia of unknown origin.

Post Hoc Exploratory Analysis
The mean (SD) change from baseline to 48-hour sodium level was 1.3
(2.9) mEq/L in the isotonic group compared with −0.12 (2.8) mEq/L in
the hypotonic group (absolute difference, 1.4 mEq/L; 95% CI of the
difference, −0.01 to 2.8 mEq/L; P = .05). The mean (SD) change from
baseline to 24-hour sodium level
Discussion
In a population of general pediatric patients outside the ICU, there was
no significant difference in mean serum sodium lev-els at 24 and 48
hours between those administered isotonic or hypotonic IV maintenance
fluids. Although our study was not powered to detect a statistical
difference in any of the second-

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 Intravenous Maintenance Fluids Original Investigation Research

ary outcomes, 2 of the 56 patients in the hypotonic group de-veloped Although patients receiving isotonic maintenance fluids had a
hyponatremia based on our a priori definition (vs nil in the isotonic small increase in serum sodium levels at 24 and 48 hours, these
group) and required study termination at 24 hours. Although they only increases were not clinically significant; there were no increases in the
had mild hyponatremia, we do not know how low their sodium level numbers of children developing clinically rel-evant hypernatremia or
would have been at 48 hours if they had continued to receive hypotonic fluid overload. One case of mild hy-pernatremia occurred in each study
fluids. group. An equal number of patients in each group developed
hypertension.
A post hoc analysis evaluating change in serum sodium from
Table 1. Characteristics of the Study Patientsa baseline found that children receiving isotonic fluids had increased their
Isotonic Group Hypotonic Group sodium level 1.9 mEq/L more than the hypo-tonic group at 24 hours and
Characteristic (n = 54) (n = 56)
1.4 mEq/L more at 48 hours. These differences are likely not clinically
Age, median (IQR), y 3.9 (2.0-6.9) 5.8 (1.4-11.2)
significant. A post hoc analy-sis on the subgroup of children with
Male sex 28 (51.9) 26 (46.4)
primary respiratory di-agnoses revealed an increased absolute
Weight, median (IQR), kg 15.9 (11.3-23.4) 18.3 (9.6-35.7)
difference in sodium of 2.7 mEq/L from baseline to 48 hours, which is
Baseline serum sodium, mean (SD), 138.7 (2.5) 139.5 (2.6)
mEq/L of question-able clinical significance.
Diagnosis
The literature is currently lacking in high-quality studies comparing
Pneumonia 15 (28) 13 (23)
the effect of IV maintenance fluid tonicity on se-rum sodium levels in
Asthma 3 (6) 6 (11)
children admitted to a general pediat-rics inpatient unit.19,20 Two
Bronchiolitis 4 (7) 2 (4)
Sickle Cell 9 (17) 5 (9) systematic reviews21,22 in 2006 and 2007 on the use of IV maintenance
Infections b
5 (9) 7 (13) fluids in hospitalized chil-dren identified a paucity of well-designed
Vomiting 5 (9) 5 (9) studies on which to base the selection of IV maintenance fluids. The
Otherc 13 (24) 18 (32)
identified stud-ies focused on surgical populations and children with
dehy-dration and reported that those administered hypotonic flu-ids
Respiratory subgroup 22 (41) 21 (38)
developed lower serum sodium levels. Since the publication of these
IV fluid volume during study, 2.5 (1.0) 2.3 (1.1)
mean (SD), mL/kg/h reviews, a number of studies23-27 addressing the is-sue of IV fluid
Oral fluid intake, median (IQR), 0.7 (0.1-1.7) 0.7 (0.2-1.2) tonicity and hyponatremia in children in the ICU and/or postoperative
mL/kg/h
settings have been published.
Abbreviations: IQR, interquartile range; IV, intravenous.
SI conversion factor: To convert sodium to millimoles per liter, multiply by 1. Two meta-analyses28,29 published in 2014 reviewed ran-domized
a
Data are presented as number (percentage) of patients unless control trials that compared isotonic and hypotonic IV maintenance
otherwise indicated.
fluids in hospitalized children. Wang et al28 included 10 randomized
b Infections include urinary tract infection, cellulitis, osteomyelitis, viral,
dental, and orbital. control trials that involved 855 chil-dren; all except one19 involved ICU
c Other includes seizures, colitis, erythema multiforme major, or postoperative children. They reported an increased risk of developing
tumor, and apparent life-threatening event. hyponatremia in children prescribed hypotonic maintenance fluids (so-

Table 2. Primary and Secondary Outcomesa

Outcome Isotonic Group Hypotonic Group P Value

Primary Outcome
No. of patients 30 34
Serum sodium at 48 hours, mean (SD), mEq/L 139.9 (2.7) 139.6 (2.6) .60
Secondary Outcomes
No. of patients 47 45
Serum sodium at 24 hours, mean (SD), mEq/L 140.5 (2.7) 139.6 (2.7) .14
Hyponatremia 0 2 (3.6) .26
Hypernatremia 1 (1.9) 1 (1.8) >.99
Weight change at 48 hours, mean (SD), kg 0.9(0.8) 0.2 (0.6) .25
Weight change at 48 hours, mean (SD) 2.4 (4.4) 1.1 (2.5) .23
Developed hypertension 2 (3.7) 2 (3.3) >.99
Developed edema 2 (3.7) 0 .15
Post Hoc Exploratory Analyses
SI conversion factor: To convert
Change in sodium from baseline to 48 hours, mean (SD), mEq/L 1.3 (2.9) −0.12 (2.8) .05 sodium to millimoles per liter,
Change in sodium from baseline to 24 hours, mean (SD), mEq/L 1.9 (3.1) −0.02 (3.1) .004 multiply by 1.
a
Respiratory Diagnosis Subgroup Data are presented as number
(percentage) of patients unless
Change in sodium from baseline to 48 hours, mean (SD), mEq/L 2.5 (1.7) −0.21 (1.6) .05 otherwise indicated.

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 Research Original Investigation Intravenous Maintenance Fluids

dium <136 mEq/L; relative risk, 2.24; 95% CI, 1.52-3.31) and also of
developing severe hyponatremia (sodium <130 mEq/L; rela-tive risk,
5.29; 95% CI, 1.74-16.06). In keeping with our find-ings, the mean
sodium level in children after receiving hypo-tonic fluids was lower
than in those who received isotonic fluids (−2.09 mEq/L; 95% CI, −2.91
to −1.28 mEq/L), and no differ-ence was found between the 2
interventions in the risk of hy-pernatremia (relative risk, 0.73; 95% CI,
0.22-2.48).
The other meta-analysis29 included an additional 2 ran-domized
clinical trials. Two-thirds of the patients included were postoperative
surgical patients, and half of the studies were conducted in ICUs. In
keeping with the aforemen-tioned review, this review by Foster et al29
reported an increased risk of hyponatremia in those receiving hypotonic
IV maintenance fluids and no differences in the secondary outcomes for
hypernatremia and signs of fluid overload (eg, hypertension and
edema). The authors list among the limita-tions a lack of studies looking
at sodium chloride, 0.45% vs 0.9%, in nonoperative and non-ICU
patients and the use of brief (24 hours) end points. The latter point is
crucial because longer follow-up periods could potentially reveal higher
rates and more clinically significant episodes of dys-natremia. Our study
provides results that will help address both these deficiencies.
The many studies performed in the last decade and ana-lyzed in the
meta-analyses discussed above consistently sug-gest that, compared
with hypotonic IV maintenance fluids, iso-tonic fluids decrease the risk
of developing hyponatremia without increasing the risk of fluid
overload and hypernatre-mia. However, these studies focus on children
who are criti-cally ill in an ICU or who have just undergone a surgical
op-
eration. Thus, these results are not necessarily generalizable to children
admitted to general medical wards.
Our study was powered to detect a difference in serum so-dium
levels at 48 hours of 2.5 mEq/L between the 2 groups. This difference,
which was deemed to be the minimally clinically relevant outcome
using sodium levels as a continuous vari-able, was selected based on a
review of previous studies and expert opinion. To conclusively
determine the risk of develop-ing significant dysnatremias requires an
extremely large sample size that will be challenging to achieve
prospectively. Al-though a number of patients did not complete the full
48-hour study period, we were able to achieve our a priori de-sired
sample size of children with complete data. We excluded children with
conditions that require specific IV fluid prescrip-tions in terms of rate
and tonicity (eg, those with dehydration requiring ongoing rehydration
and/or replacement fluids); therefore, we cannot generalize our findings
to such patients. Finally, our findings are not generalizable to children
admit-ted to an ICU or those who have recently undergone surgery.
Conclusions
We found no clinically significant difference in our primary out-come
of mean serum sodium level at 48 hours after IV fluid administration in
general pediatric patients treated with iso-tonic or hypotonic
maintenance fluids. There were, however, 2 cases of hyponatremia in
the hypotonic group at 24 hours. Our study results support the notion
that isotonic mainte-nance fluid administration is safe in general
pediatric pa-tients and may result in fewer cases of hyponatremia.

ARTICLE INFORMATION approval of the manuscript; and the decision to 7. Holliday MA, Segar WE. The maintenance need
Accepted for Publication: December 19, 2014. submit the manuscript for publication. for water in parenteral fluid therapy. Pediatrics.
1957;19(5):823-832.
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Conflict of Interest Disclosures: None reported. hyponatremia and death in healthy children. August administration in hospitalized children: an
Funding/Support: This study was supported by 13, 2009. http://ismp.org/newsletters/acutecare observational study. Pediatrics. 2004;113(5):1279-
grants from Physicians’ Services Incorporated /articles/20090813.asp. Accessed June 7, 2014. 1284.
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