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abstract
KEY WORDS
intravenous uid, hypotonic uid, isotonic uid, hyponatremia,
children
ABBREVIATIONS
ADHantidiuretic hormone
CIcondence interval
IVintravenous
pNaplasma sodium
PRISMAPreferred Reporting Items for Systematic Reviews and
Meta-Analyses
RCTrandomized controlled trial
RRrelative risk
Dr Wang designed the study, searched databases, selected
studies, extracted raw data, assessed risk of bias, carried out
the analysis, and drafted the manuscript; Dr Xu helped with raw
data extraction, independently assessed risk of bias, helped with
analysis, and critically reviewed the manuscript; Dr Xiao
designed the study, independently selected studies, helped with
analysis, and reviewed and revised the manuscript; and all
authors approved the nal manuscript as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2013-2041
doi:10.1542/peds.2013-2041
Accepted for publication Oct 19, 2013
Address correspondence to Yanfeng Xiao, MD, PhD, Department
of Pediatrics, Second Afliated Hospital of Medical School of Xian
Jiaotong University, 157 Xiwu Rd, Xian, Shaanxi 710004, China.
E-mail: xiaoyanfeng.xjtu@gmail.com
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
METHODS: We searched PubMed, Embase, Cochrane Library, and clinicaltrials.gov (up to April 11, 2013) for RCTs that compared isotonic to
hypotonic maintenance IV uid therapy in hospitalized children. Relative risk (RR), weighted mean differences, and 95% condence intervals (CIs) were calculated based on the effects on plasma sodium
(pNa). The risk of developing hyponatremia (pNa ,136 mmol/L),
severe hyponatremia (pNa ,130 mmol/L), and hypernatremia (pNa
.145 mmol/L) was evaluated. We adopted a random-effects model in
all meta-analyses. Sensitivity analyses by missing data were also
performed.
RESULTS: Ten RCTs were included in this review. The meta-analysis
showed signicantly higher risk of hypotonic IV uids for developing
hyponatremia (RR 2.24, 95% CI 1.52 to 3.31) and severe hyponatremia
(RR 5.29, 95% CI 1.74 to 16.06). There was a signicantly greater fall
in pNa in children who received hypotonic IV uids (3.49 mmol/L
versus isotonic IV uids, 95% CI 5.63 to 1.35). No signicant difference
was found between the 2 interventions in the risk of hypernatremia (RR
0.73, 95% CI 0.22 to 2.48). None of the ndings was sensitive to imputation
of missing data.
CONCLUSIONS: Isotonic uids are safer than hypotonic uids in hospitalized children requiring maintenance IV uid therapy in terms of
pNa. Pediatrics 2014;133:105113
105
METHODS
We followed the Preferred Reporting
Items for Systematic Reviews and MetaAnalyses (PRISMA) statement for reporting of this meta-analysis.25
Search Strategy
We searched PubMed, Embase, Cochrane
Controlled Clinical Trials Register, and
ClinicalTrials.gov (up to April 11, 2013)
for potentially relevant publications
without any language restriction. We
modied the search strategy from
a previous systematic review. 6 The
detailed search strategy is presented
in the Supplemental Information. We
also screened references of previous
systematic reviews and identied relevant articles.
Study Selection
Two authors independently screened
the titles and abstracts of potentially
relevant citations. They then read the
full texts of citations needing additional
evaluation. Discrepancies were resolved through group discussion. The
inclusion criteria were as follows:1
studies on RCTs,2 studies on hospitalized children aged from 1 month to 17
years,3 and studies comparing isotonic
and hypotonic maintenance IV uid
therapy. Solutions were classied as
isotonic if they had the same or near
osmotic pressure as blood (eg, 0.9%
saline, Hartmanns solution, or Ringers
solution) or hypotonic if they had a
lower osmotic pressure than blood
(eg, 0.45% saline, 0.3% saline, or 0.18%
saline). Exclusion criteria were1 non-RCT
studies,2 letters and case reports,3
studies published as abstracts only,4
studies involving neonates,5 studies of
uid resuscitation or rehydration,6 and
patients with preexisting hyponatremia
Data Extraction
A standard reporting form developed by
PRISMA25 was used to extract data. One
author extracted data, and another
checked all forms. We extracted the
following information: methods of the
study (as per assessment of risk of
bias), characteristics of study population (number, age, and diagnosis),
description of the interventions and
comparisons, and outcomes. The primary outcome was hyponatremia (pNa
,136 mmol/L). Secondary outcomes
were severe or symptomatic hyponatremia (pNa ,130 mmol/L), pNa and
pNa changes after IV uid therapy,
hypernatremia (pNa .145 mmol/L),
and adverse events attributable to IV
uid administration and/or pNa
derangements (death, cerebral edema,
seizures, hypertension, and length of
stay).
Assessment of Risk of Bias
We addressed the methodologic quality
of included studies using the Cochrane
risk-of-bias tool, which includes domains for sequence generation, allocation sequence concealment,
blinding, incomplete outcome data,
selective outcome reporting, and other
potential sources of bias.26 Discrepancies were resolved through group
discussion.
Analysis
If .1 study reported the same outcome, statistical pooling was adopted
to estimate the intervention effects. For
dichotomous outcomes, we used relative risk (RR) and 95% condence
intervals (CIs). For continuous outcomes, we used weighted mean differences and 95% CIs. All pooled
estimates of the intervention effects
WANG et al
REVIEW ARTICLE
RESULTS
Study Selection
Figure 1 shows the process of study selection. We identied 10 studies comparing
isotonic and hypotonic maintenance IV
uid therapy in hospitalized children
FIGURE 1
Flow diagram of study selection.
107
TABLE 1 Characteristics of Included RCTs of Hypotonic Versus Isotonic Maintenance IV Fluid Therapy in Hospitalized Children
Study
Condition
Follow-up, h
Hypotonic
Na
Isotonic
Age,b y
Solution
Na
5
Adolescent
13
11
58
5.3 (0.912)
15.4 (10.815.9)
3.0 (1.07.0)
31c
9.4 (1.014.9)
31c
8.4 (0.614.9)
128
63e
9.2 6 5.5
4.9 (2.010.6)
16
41
8.2 (2.814.3)
11.3 (4.313.9)
Brazel 1996
Surgical
$72
Adolescent
Yung 2009a
Yung 2009b
Kannan 2010
$12
$12
$24
15
11
56
4.7 (1.48.9)
3.7 (1.514.7)
4.0 (1.16.0)
0.3% S and 3% D;
0.18% S and 4% D
0.18% S and 4% D
0.18% S and 4% D
0.18% S and 5% D at full rate
Neville 2010a
align
Surgical
$24
$8
53
31c
3.0 (0.85.5)
9.9 (2.015.0)
Neville 2010b
Surgical
$8
31
9.1 (0.914.9)
Choong 2011
Rey 2011
Surgical
Surgical and medical
$24
$12
130
62d
9.2 6 5.7
4.7 (1.79.9)
Saba 2011
Coulthard 2012
$8
$16
21
41
8.9 (1.716.5)
11.5 (6.014.1)
Age,b y
Solution
Hartmans solution
0.9% S
0.9% S
0.9% S and 5%
D at full rate
0.9% S and 5%
D at half rate
0.9% S and 2.5%
D at full rate
0.9% S and 5% D
136 mmol/L NaCl
and 20 mmol/L KCl
0.9% S and 5% D
Hartmanns and 5% D
Adequate Sequence
Generation
Allocation
Concealment
Brazel 1996
Yung 2009a
Yung 2009b
Kannan 2010
Neville 2010a
Unclear
Yes
Yes
Yes
Unclear
Unclear
Yes
Yes
Yes
Yes
Neville 2010b
Unclear
Choong 2011
Rey 2011
Incomplete Outcome
Data Addressed
Free of Selective
Reporting
No
Yes
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Unclear
No
No
Yes
Unclear
Unclear
Unclear
Unclear
Unclear
No
Yes
No
Yes
Unclear
No
Yes
Yes
Yes
Unclear
Yes
No
Yes
Yes
Yes
Unclear
Unclear
No
Saba 2011
Yes
Yes
Yes
No
Yes
Unclear
Coulthard 2012
Yes
Yes
Unclear
Yes
Yes
Unclear
signicantly lower than those who received isotonic IV uids (2.09 mmol/L,
95% CI 2.91 to 1.28, P ,.00001, I2 =
47%; Fig 4). Furthermore, the fall in pNa
was also signicantly greater in children who received hypotonic IV uids
(3.49 mmol/L, 95% CI 5.63 to 1.35,
P = .001, I2 = 87%; Fig 5). However, our
analysis showed no signicant difference between the 2 interventions in the
risk of hypernatremia with or without
inclusion of the study by Kannan et al,14
which dened hypernatremia as pNa
108
Blinding
Comments
WANG et al
REVIEW ARTICLE
TABLE 3 Extracted Data From Included Studies for Meta-Analysis of Outcomes Relating to pNA Levels
Study
Brazel 1996
Kannan 2010a
Yung 2009a
Yung 2009b
Neville 2010ab
Neville 2010bb
Choong 2011
Rey 2011c
Saba 2011d
Coulthard 2012
Hypotonic
Isotonic
pNa Changes
pNa End
Hypo
Severe Hypo
Hyper
pNa Changes
pNa End
Hypo
Severe Hypo
Hyper
7 (7)
56 (56)
53 (53)
15
11 (12)
31 (37)
31 (37)
112 (130)
39 (43)
21 (32)
40 (41)
212.5 6 2.8
NA
NA
23 6 3.3
24.9 6 4.0
21.9 6 2.0
21.5 6 2.3
NA
NA
1.1 6 3.0
NA
129.0 6 3.8
NA
NA
NA
NA
136 6 2.1
136 6 2.1
NA
134.5 6 2.7
138.1 6 2.4
136.7 6 2.7
7
8
2
NA
NA
10
9
47
19
1
7
4
8
2
NA
NA
NA
NA
7
3
0
0
0
2
4
NA
NA
0
0
4
NA
0
0
5 (5)
58 (58)
22.0 6 1.9
NA
138.0 6 6.5
NA
1
1
0
1
0
2
13 (15)
11 (12)
31 (37)
31 (37)
106 (128)
45 (50)
16 (27)
39 (41)
20.2 6 3.5
21.5 6 4.3
20.1 6 3.2
0.6 6 2.2
NA
NA
2.4 6 3.1
NA
NA
NA
138 6 3.6
138 6 1.9
NA
137.6 6 3.2
139.4 6 3.0
138.1 6 1.9
NA
NA
5
1
26
8
1
0
NA
NA
NA
NA
1
1
0
0
NA
NA
2
0
3
NA
1
0
Hyper, hypernatremia; Hypo, hyponatremia; N, number of participants expressed as available cases (randomized cases); NA, not available; pNa end, pNa after IV uids; pNa changes, pNa
changes after IV uids.
a Hyponatremia dened as sodium ,130 mmol/L; hypernatremia dened as .150 mmol/L.
b Data at 8 h.
c Data at 12 h for continuous outcomes, data throughout the study period for categorical outcomes. We assumed that all withdrawn cases were from those without preexisting hyponatremia.
d Data interpreted from gures.
FIGURE 2
Meta-analysis of data for the outcome of hyponatremia comparing hypotonic with isotonic IV maintenance uids in hospitalized children.
FIGURE 3
Meta-analysis of data for the outcome of severe hyponatremia comparing hypotonic with isotonic IV
maintenance uids in hospitalized children.
averaged 1 mmol/L lower than the observed data itself. The results were
similar to those from the analysis of
available cases (Table 4).
109
DISCUSSION
FIGURE 4
Meta-analysis of data for the outcome of pNa level after hypotonic versus isotonic IV maintenance uids
in hospitalized children.
FIGURE 5
Meta-analysis of data for the outcome of change in pNa level after hypotonic versus isotonic IV
maintenance uids in hospitalized children.
Data Source
Hyponatremia
Severe
hyponatremia
Hypernatremia
pNa after IV uid
pNa change
ACA
ITT
ACA
ITT
ACA
ITT
ACA
Imputation
ACA
Imputation
281
327
267
273
325
214
2.24
2.23
5.29
4
3
3
6
11c
6
11c
289
164
199
168
196
115
140
241
153
192
167
197
107
133
5.36
0.73
0.76
22.09
21.54
23.49
22.24
95% CI
ACA, available case analysis; ITT, intention to treat; WMD, weighted mean difference.
a Number of children receiving hypotonic IV solutions.
b Number of children receiving isotonic IV solutions.
c Imputed missing data were analyzed as separate studies.
WANG et al
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111
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113
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