CLINICAL PRACTICE GUIDELINE Guidance for the Clinician in Rendering Pediatric Care

Clinical Practice Guideline:

Maintenance Intravenous
Fluids in Children
Leonard G. Feld, MD, PhD, MMM, FAAP,​a Daniel R. Neuspiel, MD, MPH, FAAP,​b Byron A. Foster, MD, MPH, FAAP,​c
Michael G. Leu, MD, MS, MHS, FAAP,​d Matthew D. Garber, MD, FHM, FAAP,​e Kelly Austin, MD, MS, FAAP,
FACS,​f Rajit K. Basu, MD, MS, FCCM,​g,​h Edward E. Conway Jr, MD, MS, FAAP,​i James J. Fehr, MD, FAAP,​j
Clare Hawkins, MD,​k Ron L. Kaplan, MD, FAAP,​l Echo V. Rowe, MD, FAAP,​m Muhammad Waseem, MD, MS,
FAAP, FACEP,​n Michael L. Moritz, MD, FAAP,​o SUBCOMMITTEE ON FLUID AND ELECTROLYTE THERAPY

Maintenance intravenous fluids (IVFs) are used to provide critical supportive abstract
care for children who are acutely ill. IVFs are required if sufficient fluids
cannot be provided by using enteral administration for reasons such as
gastrointestinal illness, respiratory compromise, neurologic impairment,
a perioperative state, or being moribund from an acute or chronic illness.
aRetired, Nicklaus Children's Health System, Miami, Florida; bRetired,
Despite the common use of maintenance IVFs, there is high variability in
Levine Children’s Hospital, Charlotte, North Carolina; cOregon
fluid prescribing practices and a lack of guidelines for fluid composition Health and Science University, Portland, Oregon; lDepartment of
Pediatric Emergency Medicine, dSchool of Medicine, University of
administration and electrolyte monitoring. The administration of hypotonic Washington and Seattle Children’s Hospital, Seattle, Washington;
eDepartment of Pediatrics, College of Medicine – Jacksonville,
IVFs has been the standard in pediatrics. Concerns have been raised
University of Florida, Jacksonville, Florida; Departments of fSurgery
that this approach results in a high incidence of hyponatremia and that and oPediatrics, University of Pittsburgh School of Medicine, Children's
Hospital of Pittsburgh, Pittsburgh, Pennsylvania; gDivision of Critical
isotonic IVFs could prevent the development of hyponatremia. Our goal in Care Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia;
this guideline is to provide an evidence-based approach for choosing the hDepartment of Pediatrics, School of Medicine, Emory University,

Atlanta, Georgia; iDivision of Pediatric Critical Care Medicine,

tonicity of maintenance IVFs in most patients from 28 days to 18 years of Department of Pediatrics, Jacobi Medical Center, Bronx, New
age who require maintenance IVFs. This guideline applies to children in York; Departments of jAnesthesiology and Pediatrics, Washington
University in St Louis, St Louis, Missouri; kDepartment of Family
surgical (postoperative) and medical acute-care settings, including critical Medicine, Houston Methodist Hospital, Houston, Texas; mDepartment
of Anesthesia, Stanford University School of Medicine, Stanford,
care and the general inpatient ward. Patients with neurosurgical disorders, California; and nLincoln Medical Center, Bronx, New York
congenital or acquired cardiac disease, hepatic disease, cancer, renal
This document is copyrighted and is property of the American
dysfunction, diabetes insipidus, voluminous watery diarrhea, or severe Academy of Pediatrics and its Board of Directors. All authors have
filed conflict of interest statements with the American Academy
burns; neonates who are younger than 28 days old or in the NICU; and of Pediatrics. Any conflicts have been resolved through a process
adolescents older than 18 years old are excluded. We specifically address the approved by the Board of Directors. The American Academy of
Pediatrics has neither solicited nor accepted any commercial
tonicity of maintenance IVFs in children. involvement in the development of the content of this publication.

The Key Action Statement of the subcommittee is as follows: The guidance in this report does not indicate an exclusive course of
treatment or serve as a standard of medical care. Variations, taking
1A: The American Academy of Pediatrics recommends that patients 28 into account individual circumstances, may be appropriate.
days to 18 years of age requiring maintenance IVFs should receive isotonic
solutions with appropriate potassium chloride and dextrose because they To cite: Feld LG, Neuspiel DR, Foster BA, et al. Clinical Practice
significantly decrease the risk of developing hyponatremia (evidence quality: Guideline: Maintenance Intravenous Fluids in Children.
A; recommendation strength: strong) Pediatrics. 2018;142(6):e20183083

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 INTRODUCTION cardiac disease, hepatic disease, The buffer in plasma is bicarbonate,
cancer, renal dysfunction, diabetes but buffers in commercially
Maintenance intravenous fluids
insipidus, voluminous watery available solutions include various
(IVFs) are used to provide critical
diarrhea, or severe burns; neonates concentrations of lactate, acetate,
supportive care for children who
who are younger than 28 days old and gluconate. Multiple balanced
are acutely ill. IVFs are required if
or in the NICU; or adolescents older salt solutions can be compared with
sufficient fluids cannot be provided
than 18 years old. normal saline (0.9% saline), which
by using enteral administration for
has the same sodium concentration
reasons such as gastrointestinal
as plasma but has a supraphysiologic
illness, respiratory compromise, BACKGROUND chloride concentration.
neurologic impairment, a
perioperative state, or being Phases of Fluid Therapy
Effect of Dextrose on Tonicity
moribund from an acute or chronic Recent literature has emerged in
illness. For the purposes of this Tonicity is used to describe the net
which researchers describe the
document, specifying appropriate vector of force on cells relative to
context-dependent use of IVFs, which
maintenance IVFs includes the a semipermeable membrane when
should be prescribed, ordered, dosed,
composition of IVF needed to in solution. Physiologic relevance
and delivered like any other drug.‍5–‍ 7‍
preserve a child’s extracellular occurs with tonicity studied in vivo
Four distinct physiology-driven time
volume while simultaneously (eg, as IVF is infused intravascularly).
periods exist for children requiring
minimizing the risk of developing Infused isotonic fluids do not result in
IVFs. The resuscitative phase is the
volume depletion, fluid overload, osmotic shifts; the cells stay the same
acute presentation window, when
or electrolyte disturbances, such as size. Cellular expansion occurs during
IVFs are needed to restore adequate
hyponatremia or hypernatremia. immersion in hypotonic fluids as free
tissue perfusion and prevent or
Because maintenance IVFs may have water, in higher relative abundance
mitigate end-organ injury. The
both potential benefits and harms, in the extracellular environment,
titration phase is the time when IVFs
they should only be administered and crosses the semipermeable
are transitioned from boluses to
when clinically indicated. The membrane. The converse happens
maintenance; this is a critical window
administration of hypotonic IVF in hypertonic fluid immersion: free
to determine what intravascular
has been the standard in pediatrics. water shifts out of the cells, leading
repletion has been achieved and
Concerns have been raised that this to cellular contraction. A distinct
the trajectory of fluid gains versus
approach results in a high incidence but related concept is the concept of
losses in children who are acutely
of hyponatremia and that isotonic osmolality. Osmolality is measured
ill. The maintenance phase accounts
IVF could prevent the development as osmoles of solute per kilogram
for fluids administered during the
of hyponatremia. Guidelines for of solvent. Serum osmolality can be
previous 2 stabilization phases and is
maintenance IVF therapy in children estimated by the following formula:
a time when fluids should be supplied
have primarily been opinion based, to achieve a precise homeostatic
​2 × Na​​(​​mEq / L​)​​​
and evidence-based consensus balance between needs and losses. + BUN (mg / dL)/2.8+glucose (mg/dL)/18​
guidelines are lacking. Finally, the convalescent phase
reflects the period when exogenous Osmolality is distinct from tonicity
fluid administration is stopped, and (effective osmolality) in that tonicity
OBJECTIVE the patient returns to intrinsic fluid relates to both the effect on a cell of
regulation. The dose of fluid during a fluid (dependent on the selective
Despite the common use of
these 4 phases of fluid therapy needs permeability of the membrane) and
maintenance IVFs, there is high
to be adjusted on the basis of the the osmolality of the fluid. In the
variability in fluid prescribing
unique physiologic needs of each plasma, urea affects osmolality but
practices and a lack of guidelines for
patient, and a specific protocoled not tonicity because urea moves
fluid composition and electrolyte
dose is not able to be applied to all freely across cell membranes with no
monitoring.‍1–‍‍ 4‍ Our goal in this
patients.‍8,​9 effect on tonicity. The tonicity of IVF
guideline is to provide an evidence-
is primarily affected by the sodium
based approach for choosing the A variety of IVFs are commercially
and potassium concentration.
tonicity of maintenance IVFs in most available for use in infants and
patients from 28 days to 18 years of children. These solutions principally Dextrose (D-glucose) can be added
age who require maintenance IVFs. vary by their specific electrolyte to IVFs (‍Table 1). Although dextrose
These recommendations do not composition, the addition of a buffer, affects the osmolarity of IVFs, it is
apply to patients with neurosurgical and whether they contain glucose not a significant contributor to the
disorders, congenital or acquired (‍Table 1).‍10 plasma osmotic pressure or tonicity

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 TABLE 1 Composition of Commonly Used Maintenance IVFs
Fluid Glucose, Sodium Chloride Potassium, Calcium Magnesium Buffer Osmolarity,​a
g/dL mEq/L mOsm/L
Human plasma 0.07–0.11 135–145 95–105 3.5–5.3 4.4–5.2 1.6–2.4 23–30 308b
bicarbonate
Hypotonic solutions
D5 0.2% NaCl 5 34 34 0 0 0 0 78
D5 0.45% NaCl 5 77 77 0 0 0 0 154
Isotonic and/or near-
isotonic solutions
D5 0.9% NaCl 5 154 154 0 0 0 0 308
D5 lactated Ringer 5 130 109 4 3 0 28 lactate 273
PlasmaLytec,​d 0 140 98 5 0 3 27 acetate 294
and 23
gluconate
a The osmolarity calculation excludes the dextrose in the solution because dextrose is rapidly metabolized on infusion.
b The osmolality for plasma is 275–295 mOsm/kg.
c Multiple electrolytes injection, type 1 United States Pharmacopeia, is the generic name for PlasmaLyte.
d PlasmaLyte with 5% dextrose is not available in the United States from Baxter Healthcare Corporation in Deerfield, Illinois.

in the absence of uncontrolled states, which lead to water retention relationship with the administration
diabetes because it is rapidly followed by a physiologic natriuresis of hypotonic IVFs.‍11,​19,​
‍ 20 The
metabolized after entering the blood in which fluid balance is maintained most serious complication of
stream. Thus, although dextrose will at the expense of plasma sodium. hospital-acquired hyponatremia is
affect the osmolarity of solutions, for hyponatremic encephalopathy, which
patients in whom maintenance IVFs Children have historically been is a medical emergency that can be
are needed, the dextrose component administered hypotonic maintenance fatal or lead to irreversible brain
generally is not believed to affect the IVFs.‍3,​4‍ This practice is based on injury if inadequately treated.‍21–‍‍ 24
‍
tonicity of solutions. theoretical calculations from the The reports of hospital‐acquired
1950s.‍16 The water requirement was
hyponatremic encephalopathy have
Historical Maintenance IVF Practice based on the energy expenditure of
occurred primarily in otherwise
and Hyponatremia healthy children, with 1 mL of fluid
healthy children who were receiving
provided for each kilocalorie (kcal)
Hyponatremia (serum sodium hypotonic IVFs, in many cases after
expended, or 1500 mL/m2 per day.
concentration <135 mEq/L) is minor surgical procedures.21,​23‍
The resting energy expenditure in
the most common electrolyte Patients with hospital‐acquired
healthy children is vastly different
abnormality in patients who are hyponatremia are at particular risk
in those with an acute disease and/
hospitalized, affecting approximately for hyponatremic encephalopathy,
or illness or after surgery. When
15% to 30% of children and which usually develops acutely in
using calorimetric methods, energy
adults.‍11,​12
‍ Patients who are acutely less than 48 hours, leaving little time
expenditure in these patients is
ill frequently have disease states for the brain to adapt. Children are at
closer to the basal metabolic rate
associated with arginine vasopressin particularly high risk of developing
proposed by Talbot,​‍17 which averages
(AVP) excess that can impair symptomatic hyponatremia because
50 to 60 kcal/kg per day.18 The
free-water excretion and place of their larger brain/skull size ratio.‍24
electrolyte concentration of IVFs was
the patient at risk for developing Symptoms of hyponatremia can be
estimated to reflect the composition
hyponatremia when a source of nonspecific, including fussiness,
of human and cow milk. The final
electrolyte-free water is supplied, headache, nausea, vomiting,
composition consisted of 3 mEq of
as in hypotonic fluids.‍10 Nonosmotic confusion, lethargy, and muscle
sodium and 2 mEq of potassium per
stimuli of AVP release include pain, cramps, making prompt diagnosis
100 kcal metabolized.‍16
nausea, stress, a postoperative difficult.
state, hypovolemia, medications, Most hyponatremia in patients who
and pulmonary and central nervous are hospitalized is hospital acquired After reports of severe hyponatremia
system (CNS) disorders, including and related to the administration and associated neurologic injury
common childhood conditions such of hypotonic IVFs in the setting of were reported in 1992, a significant
as pneumonia and meningitis.‍13–15 ‍ elevated AVP concentrations.‍10,​11
‍ debate emerged regarding the
These conditions can lead to Studies in which researchers appropriateness of administering
the syndrome of inappropriate evaluated hospital‐acquired hypotonic maintenance IVFs
antidiuresis (SIAD) or SIAD-like hyponatremia have revealed a to children.‍21 In 2003, it was

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 recommended that isotonic fluids subcommittee composed of primary plots for all included randomized
be administered to children who are care clinicians and experts in the controlled trials (RCTs) in which
acutely ill and require maintenance fields of general pediatrics, hospital researchers used random-effects
IVFs to prevent the development medicine, emergency medicine, models and Mantel-Haenzel
of hyponatremia.‍24 Since then, the critical care medicine, nephrology, (M-H) statistics with the outcome
Institute for Safe Medical Practices anesthesiology, surgery, and quality of hyponatremia are shown in
of both the United States‍25 and improvement. The subcommittee also Supplemental Figs 2–4.
Canada‍26 released reports on included a guideline methodologist To appraise the methodology of
deaths from severe hyponatremia and/or informatician and an the included studies, a risk-of-bias
in patients who were hospitalized epidemiologist who were skilled assessment was completed by using
and received hypotonic IVFs. The in systematic reviews. All panel the Cochrane Handbook risk of bias
United Kingdom released a national members declared potential conflicts assessment framework.‍45 Using
safety alert reporting 4 deaths and on the basis of the AAP policy on this framework, raters placed a
1 near miss from hospital-acquired conflicts of interest and voluntary value of low, high, or unclear risk
hyponatremia,​27 and 50 cases of disclosure. Subcommittee members of bias for each article in the areas
serious injury or child death from repeated this process annually and of selection bias (both random-
hypotonic IVFs were reported in the on publication of the guideline. All sequence generation and allocation
international literature.‍22 potential conflicts of interest are concealment), performance bias,
listed at the end of this document. detection bias, attrition bias,
After the recognition of hospital-
The project was funded by the AAP. and reporting bias. Two authors
acquired hyponatremia in patients
receiving hypotonic IVFs and independently reviewed each study
The subcommittee initiated its identified in the systematic review
recommendations for avoiding
literature review by combining and made an independent judgment.
them,​‍24 the use of 0.2% saline has
the search strategies in 7 recent Differences in assessment were
declined with an increase in the use
systematic reviews of clinical resolved via discussion.
of 0.45% and 0.9% saline.‍3,​28 ‍ There
trials of maintenance IVFs in
have been concerns raised about the
children and adolescents, which The resulting systematic review
safety of the proposed use of isotonic
consisted of 11 clinical trials was used to develop the guideline
maintenance IVFs in children who
involving 1139 patients.‍9,​33,​ ‍ –‍ 42
‍ 34,​
‍ 39 ‍ recommendations by following
are acutely ill for the prevention of
The subcommittee then used the Policy Statement from the AAP
hospital-acquired hyponatremia.‍18
this combined search strategy to Steering Committee on Quality
Some believe that this approach
discover 7 additional clinical trials Improvement and Management,
could lead to complications such
of maintenance IVFs involving 1316 “Classifying Recommendations
as hypernatremia, fluid overload
children and adolescents (ages 28 for Clinical Practice Guidelines.”‍46
with edema and hypertension, and
days to 18 years) published since Decisions and the strength of
hyperchloremic acidosis.29 In the past
2013 (the last year included in the recommendations were based on a
15 years, there have been a multitude
previous 6 systematic reviews) in systematic grading of the quality of
of clinical trials and systematic
the PubMed, Cumulative Index to evidence from the updated literature
reviews in which researchers
Nursing and Allied Health Literature, review by the subcommittee with
have attempted to address this
and Cochrane Library databases. guidance by the epidemiologist.
debate.‍30–‍‍‍ 35
‍ Authors of textbooks and
All articles that were initially Expert consensus was used when
review articles in the United States
identified were back searched for definitive data were not available.
continue to recommend hypotonic
other relevant publications. Studies If committee members disagreed
fluids.‍36–‍ 38
‍ Conversely, the National
published as of March 15, 2016, with the consensus, they were
Clinical Guideline Centre in the
were included. Three independent encouraged to voice their concerns
United Kingdom published evidence-
reviewers from the subcommittee until full agreement was reached.
based guidelines for IVF therapy in
then critically appraised the full text Full agreement was reached on the
children younger than 16 years old
of each identified article (n = 17) clinical recommendations below.
and recommended isotonic IVFs.34
using a structured data collection
form that was based on published Clinical recommendations were
guidelines for evaluating medical entered into Bridge-Wiz 2.1 for AAP
METHODS
literature.‍43,​44
‍ These reviews were software (Building Recommendations
In April 2016, the American integrated into an evidence table by in a Developers Guideline Editor),
Academy of Pediatrics (AAP) the subcommittee epidemiologist an interactive software tool that is
convened a multidisciplinary (Supplemental Table 3). Forest used to lead guideline development

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 TABLE 2 Key Action Statement 1A
Aggregate Evidence Quality Grade A
Benefits More physiologic fluid, less hyponatremia
Risks, harm, cost Potential harms of hypernatremia, fluid overload, hypertension, hyperchloremic metabolic acidosis, and acute kidney injury
have not been found to be of increased risk with isotonic maintenance fluids.
Benefit-harm assessment Decreased risk of hyponatremia
Intentional vagueness None
Role of patient preferences None
Exclusions Patients with neurosurgical disorders, congenital or acquired cardiac disease, hepatic disease, cancer, renal dysfunction,
diabetes insipidus, voluminous watery diarrhea, or severe burns; neonates who are <28 d old or in the NICU; or
adolescents >18 y old
Strength Strong recommendation
Key references ‍9,​‍33,​‍39‍–‍42

teams through a series of questions of each recommendation per the On the basis of the reviewed
that are intended to create clear, guidance in ‍Fig 1. literature, this guideline applies
transparent, and actionable Key to children 28 days to 18 years of
Action Statements.‍47 The committee Before formal approval by the age in surgical (postoperative) and
was actively involved while the AAP, this guideline underwent medical acute-care settings, including
software was used and solicited a comprehensive review by critical care and the general inpatient
the inputs of this program, which stakeholders, including AAP councils, ward. This guideline DOES NOT
included strength of evidence and committees, and sections; selected apply to children with neurosurgical
balance of benefits versus harms, and outside stakeholder organizations; disorders, congenital or acquired
chose which sentences recommended and individuals who were identified cardiac disease, hepatic disease,
by the program to use as part of the by the subcommittee as experts cancer, renal dysfunction, diabetes
guideline. Bridge-Wiz also integrates in the field. All comments were insipidus, voluminous watery
the quality of available evidence and reviewed by the subcommittee and diarrhea, or severe burns; neonates
a benefit-harm assessment into the incorporated into the final guideline who are younger than 28 days
final determination of the strength when appropriate. old or in the NICU; or adolescents
older than 18 years old because
the majority of the researchers in
the prospective studies reviewed
in this guideline excluded these
subsets of patients or did not include
patients with these specific high-risk
diagnoses.

RESULTS

Key Action Statement

The Key Action Statement is as

follows:

1. Composition of Maintenance IVFs

1A: The AAP recommends that

patients 28 days to 18 years of age
requiring maintenance IVFs should
receive isotonic solutions with
appropriate potassium chloride
(KCl) and dextrose because they
significantly decrease the risk of
developing hyponatremia (evidence
FIGURE 1 quality: A; recommendation
AAP rating of evidence and recommendations. strength: strong; ‍Table 2).

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 Isotonic Solutions Versus Hypotonic of whether isotonic or hypotonic Surgical (Postoperative Patients)
Solutions fluids should be used in children Surgical or postoperative patients
who are hospitalized. Sixteen of the have been specifically studied in 7
Isotonic fluid has a sodium
studies revealed that isotonic fluids studies‍20,​48,​
‍ 49,​
‍ 51,​
‍ 54,​56,​
‍ 57‍ that included
concentration similar to plasma
were superior to hypotonic fluids 529 patients. McNab‍30 showed
(135–144 mEq/L). Plasma is
in preventing hyponatremia. There a pooled risk ratio of 0.48 (95%
approximately 93% aqueous and
have also been 7 systematic reviews confidence interval [CI], 0.38–0.60)
7% anhydrous with a sodium
over the past 11 years in which for the outcome of hyponatremia in
concentration in the aqueous
researchers have synthesized favor of isotonic fluids.
phase of plasma of 154 mEq/L and
various combinations of the above
osmolarity of 308 mOsm/L, similar
RCTs.‍9,​33,​ ‍ –‍‍ 42
‍ 34,​39 ‍ The number needed Medical (Nonsurgical Patients)
to that of 0.9% sodium chloride
to treat with isotonic fluids to Medical patients are defined here as
(NaCl). Conversely, hypotonic fluid
prevent hyponatremia (sodium <135 children who are hospitalized in an
has a sodium concentration lower
mEq/L) was 7.5 across all included acute-care setting with no indication
than that of the aqueous phase of
studies and 27.8 for moderate for a surgical operation and no
plasma. In the studies evaluated in
hyponatremia (sodium <130 mEq/L). immediate history of a surgical
the formulation of these guidelines,
there is some heterogeneity in both operation. For these patients, there
Study appraisal for risk of bias are 4 randomized clinical trials‍32,​52,​
‍ 55,​
‍ 58
‍
the isotonic and hypotonic fluids
(Supplemental Table 4) revealed in which researchers enrolled only
used. The sodium concentration
the reviewed studies in total to be medical patients and 6 randomized
of isotonic fluids ranged from
methodologically sound. Most types clinical trials50,​51,​
‍ 53,​
‍ 56,​
‍ 57,​
‍ 59 in which
131 to 154 mEq/L. Hartmann
of bias were found to be of low risk in researchers enrolled both medical
solution (sodium concentration 131
all but 2 studies. There was 1 study and surgical patients. Some of the
mEq/L; osmolality 279 mOsm/L)
with 2 bias types of potentially high mixed studies in which researchers
was used in only 46 patients.‍48,​49
‍
risk and 11 studies with 1 or more looked at both medical and surgical
PlasmaLyte (sodium concentration
unclear bias areas. patients include outcomes for only
140 mEq/L; osmolarity 294
mOsm/L) was used in 346 patients.‍35 medical patients, whereas most
Researchers in the majority of Inclusion and Exclusion Criteria: include combined outcomes for both
the studies used either 0.9% NaCl Rationale for Specific Subgroups groups.
(sodium concentration 154 mEq/L;
Age Varying Acuity (ICU Versus General
osmolarity 308 mOsm/L) or a fluid of Ward)
equivalent tonicity. Hypotonic fluids
The specific age groups from which There are 6 randomized clinical
ranged from 30 to 100 mEq/L.‍33
data are available from randomized trials‍31,​49,​
‍ 50,​
‍ 53,​
‍ 56,​59
‍ in which
Lactated Ringer solution (sodium
clinical trials range from 1 day (1 researchers enrolled only ICU
concentration 130 mEq/L; osmolarity
trial) to 18 years. Given this broad patients, and all but one‍50 revealed
273 mOsm/L), a slightly hypotonic
age range, we specifically evaluated a significant difference favoring
solution, was not involved in any of
whether there was variability in the isotonic IVFs for the prevention of
the clinical trials. For the purposes
outcomes by age, particularly for the hyponatremia. Researchers in 8
of this guideline, isotonic solutions
lower age range. McNab et al‍33 randomized clinical trials enrolled
have a sodium concentration
examined this question in their exclusively patients in a general ward
similar to PlasmaLyte, or 0.9% NaCl.
systematic review and found 100 setting,​‍32,​51,​
‍ 52,​54,​
‍ 55,​
‍ 57,​
‍ 58,​
‍ 60 and those
Recommendations are not made
children studied at younger than 32,​57
in all but 2‍ ‍ found a significant
regarding the safety of lactated
1 year of age, 243 children studied reduction in hyponatremia among
Ringer solution. Researchers in the
between the ages of 1 and 5 years, those receiving isotonic IVFs. McNab
majority of studies added dextrose
and 465 children studied at older et al‍35 enrolled patients in both
(2.5%–5%) to the intravenous (IV)
than 5 years of age. They showed a the ICU and general surgical ward,
solution.
significant benefit of isotonic IVFs and they were at similar risk for
The search revealed 17 randomized in each age group stratum. There developing hyponatremia.
clinical trials‍20,​31,​
‍ 32,​‍ 48–‍‍‍‍‍‍‍‍‍ 60
‍ 35,​ ‍ that have been 7 additional studies in
met the search criteria, including a which researchers have also included Exclusion of Specific Populations Not
total 2455 patients (2313 patients children younger than 1 year old, Studied
had primary outcome data for although there are not specific Patients with neurosurgical
analysis in Supplemental Figs outcome data reported for this age disorders, congenital or acquired
2–4), to help evaluate the question group.‍31,​32,​
‍ 35,​
‍ 50,​51,​
‍ 55,​
‍ 58
‍ cardiac disease, hepatic disease,

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 cancer, renal dysfunction, diabetes <135 mEq/L and <130 mEq/L, researchers evaluated moderate
insipidus, voluminous watery respectively) to be >2 and >5, hyponatremia revealed benefits
diarrhea, or severe burns; neonates respectively. The risk related to of isotonic versus hypotonic IVFs
who were younger than 28 days hyponatremia persisted regardless (Supplemental Figs 2 and 4).
old or in the NICU (researchers of age, medical versus surgical status, Furthermore, hypotonic solutions
in the majority of prospective and intensive care versus general have been associated with a larger
studies reviewed in this guideline pediatric ward setting. These data decrease in serum sodium. Also, the
excluded this subset of patients); strongly reveal an increased risk true effects of hypotonic IVFs may
and adolescents older than 18 of hyponatremia when children have been underestimated because
years old were excluded. Patients receive hypotonic versus isotonic many of the studies also included
with congenital or acquired heart IVFs. This association is reinforced rigorous monitoring of sodium,
disease have been either explicitly by the observations that increased during which patients were removed
excluded from every study listed hyponatremia occurs in (1) children from the study if mild hyponatremia
previously or were not described, so with normal sodium at baseline developed. Numerous studies of
no conclusions may be drawn related (hospital-acquired hyponatremia) adults have revealed that mild
to this specific population. Similarly, and (2) children who have a low and asymptomatic hyponatremia
patients with known liver or renal sodium concentration at baseline is associated with deleterious
disease or adrenal insufficiency (hospital-aggravated hyponatremia). consequences, is an independent
have also been excluded from most This association has been found risk factor for mortality,​‍62,​63
‍
of the studies listed, limiting any when using both 0.2% saline and leads to increased length of
conclusions for these patients as (sodium 34 mEq/L) and 0.45% saline hospitalization and increases in
well. Neurosurgical patients and (sodium 77 mEq/L). The risk for costs of hospitalization.‍64,​65
‍ Thus,
those with traumatic brain injury hyponatremia with hypotonic fluids the subcommittee believes that
were excluded from most studies. persisted in the subgroup of patients hyponatremia is an appropriate
Oncology patients have been who received fluids at a restricted indicator of potential harm.
included in some of the randomized rate.‍49,​54,​
‍ 58,​
‍ 59
‍ A sensitivity analysis
trials, but no specific subanalysis in which the Shamim et al58 study Hypernatremia
for them has been completed, and was excluded given the anomalous One of the concerns when providing
data are not available separately to number of events in both arms a higher level of sodium in IVFs is
conduct one. Many patients receiving revealed no change in the overall the development of hypernatremia
chemotherapy receive high volumes estimated relative risk (0.43; 95% (serum sodium >145 mEq/L). This
of fluids to prevent renal injury, CI, 0.35–0.53) compared with that was evaluated in the most recently
and there are reports of clinically of all the studies included (0.46; published systematic review.‍33 Those
significant hyponatremia, which is 95% CI, 0.37–0.57; Supplemental authors identified that there was
possibly associated with the fluid Fig 2). In the clinical trials in which no evidence of an increased risk of
type.‍61 Further study is needed to researchers assessed the possible hypernatremia associated with the
evaluate the fluid type, rate, and risk mechanism for this finding, elevated administration of isotonic fluids,
of renal injury and hyponatremia antidiuretic hormone (ADH) although the quality of evidence was
for this population. The committee concentration was found to play a judged to be low, primarily given
did not specifically review literature putative role.‍54 the low incidence of hypernatremia
for those with the following care in the studies included. To be clear,
needs: patients with significant There is heterogeneity in the design there was not evidence of no risk; the
renal concentrating defects, such as of the above studies in the types risk is unclear from the meta-analysis
nephrogenic diabetes insipidus, and of patients enrolled, IVF rate and results. The estimated risk ratio from
patients with voluminous diarrhea type, frequency of plasma sodium that meta-analysis was 1.24 (95%
or severe burns who may have monitoring, and study duration. CI, 0.65–2.38), drawn from 9 studies
significant ongoing free-water losses. Despite this heterogeneity, the with 937 patients, although 3 studies
increased risk of hyponatremia with had no events and did not contribute
Complications hypotonic IVFs is consistent. Some to the estimate. Researchers in 2
may argue that mild hyponatremia large studies published since the
Hyponatremia
(plasma sodium 130–134 mEq/L) meta-analysis did not find evidence
The reviewed studies revealed the and moderate hyponatremia (plasma of an increased risk of hypernatremia
relative risk of developing mild and sodium 125–129 mEq/L) may not with isotonic IVFs. In the study by
moderate hyponatremia (defined be clinically significant or constitute Friedman et al,​‍32 there was 1 patient
as a serum sodium concentration harm. However, the studies in which in each randomized group (N = 110)

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 who developed hypernatremia, and Fluid Overload insufficiency; neurosurgical patients;
in the study by McNab et al,​‍35 the and patients taking medication
Children receiving IVFs are at risk known to impair free-water
incidence of hypernatremia was 4%
for fluid accumulation leading excretion, such as desmopressin.
in the isotonic IVF group and 6% in
to a positive fluid balance or Data on the efficacy of isotonic fluids
the hypotonic IVF group, with no
volume overload. A combination to prevent hyponatremia and the
significant difference noted between
of excessive fluid and sodium can potential complications related to
the 2 groups (N = 641 with data for
synergistically increase retained isotonic fluids in these patients are
analysis). The available data among
volume, a condition that is lacking. Further studies in which
the meta-analysis discussed above exacerbated in children with chronic
and subsequent large RCTs were researchers evaluate optimal fluid
comorbidities (such as systolic management in these groups of
unable to be used to demonstrate cardiac dysfunction [congestive
an increased risk of hypernatremia patients are necessary. Patients
heart failure (CHF)], cirrhotic with edematous states, such as CHF,
associated with the use of isotonic hepatic failure, chronic kidney
IVFs. cirrhosis, and nephrotic syndrome,
disease, and hepatorenal syndrome)
have an impaired ability to excrete
and metabolic disturbances (such
both free water and sodium and are
Acidosis as hyperaldosteronism and long-
at risk for both volume overload
term steroid use). Researchers in
and hyponatremia. Administering
recent literature, most notably in
A hyperchloremic metabolic isotonic saline at typical maintenance
the critically ill population (adults
acidosis has been associated with rates will likely be excessive and
and children), have attempted to
0.9% NaCl when it is used as a risk volume overload, and IVFs
delineate the causative and outcome
resuscitation fluid. Researchers in should be restricted with close
associations with significant
the majority of studies reviewed monitoring. Renal diseases can
positive fluid accumulation, termed
in this series did not specifically have multiple effects on sodium
“fluid overload.”‍66 In the non-ICU
evaluate the development of acidosis and water homeostasis; patients
population, researchers in only
or report on it as a complication. with glomerulonephritis may
a handful of studies mention an
Researchers in 4 studies involving avidly reabsorb sodium, whereas
association between fluid tonicity
496 patients evaluated the effect those with tubulopathies may have
and volume overload (or “weight
of IVF composition on acid and/or obligatory urinary sodium losses.
gain”).‍20,​59,​
‍ 60‍ Choong et al20
base status,​‍31,​49,​
‍ 54,​
‍ 58‍ and the majority Patients with renal failure have a
reported on “overhydration” as
were not able to demonstrate that relative inability to excrete free water
estimated by using total weight gain,
because of the reduced glomerular
0.9% NaCl resulted in acidosis. finding no significant difference
filtration rate and simultaneously
Two studies in which researchers between isotonic and hypotonic
are unable to produce maximally
compared 0.9% NaCl to 0.45% NaCl IVF administration. In the meta-
concentrated urine. Patients with
involving 357 children found no analyses that encompass 12 different
adrenal insufficiency can have
effect on the development of acidosis RCTs and more than 750 children,
renal salt wasting and an impaired
based on the change in total carbon neither weight nor net fluid balance
ability to excrete free water.
dioxide (Tco2), a measure of plasma is discussed. Increasing scrutiny is
Patients with CNS disorders can
bicarbonate, with a low Tco2 being a being given to fluid management
have multiple conditions that impair
surrogate marker for acidosis rather in the critically ill population.‍33 To
water excretion, including SIAD
than a low pH.31,​54 ‍ Researchers in 1 determine any association in patients
and cerebral salt wasting. Patients
study compared Hartman solution, who are noncritically ill, more
receiving certain medications
which has a base equivalent to 0.45% evidence is required.
are at particularly high risk for
NaCl, involving 79 patients and found developing hyponatremia, such
no effect on the development of Specific Groups That May Be
as desmopressin administered
acidosis based on a change in Tco2.‍49 at Higher Risk for Developing
perioperatively for Von Willebrand
Researchers in 1 study involving
Hyponatremia
disease, antiepileptic medications
60 patients compared 0.9% NaCl Researchers in the RCTs reviewed for (such as carbamazepine), and
to 0.18% NaCl and demonstrated a this statement excluded many groups chemotherapeutic agents (such as IV
decrease in pH from 7.36 to 7.32 in of patients who are at particularly cyclophosphamide and vincristine).
the 0.9% NaCl group compared with high risk for hyponatremia, such as Isotonic IVFs may be the preferred
an increase in pH from 7.36 to 7.38 in those with congenital or acquired fluid composition for these disease
the 0.18% NaCl group (P = .01), but heart disease, liver disease, renal states, but care is needed in dosing
the effect on Tco2 was not reported.‍58 failure or dysfunction, or adrenal the quantity of fluids, and close

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 monitoring of both the volume status use of this guideline differentiates sodium being measured between 6
and electrolytes is required. the applicability to 2 subgroups of hours and 12 hours. The incidence of
children: (1) The guideline applies hyponatremia in patients receiving
Limitations to surgical (postoperative) medical isotonic fluids ranged from 0% to
patients in a critical care setting and 23%, whereas that of hypotonic
The subcommittee’s
the general inpatient ward. (2) The fluids ranged from 5% to 100%. This
recommendation to use isotonic
guideline does not apply to patients large variability was likely related
fluids when maintenance IVFs are
with neurosurgical disorders, to the different study designs. Many
required does not mean that there
congenital or acquired cardiac patients who were hospitalized
are no indications for administering
disease, hepatic disease, cancer, and received isotonic IVFs will be
hypotonic fluids or that isotonic
renal dysfunction, diabetes insipidus, at risk for hyponatremia if they are
fluids will be safe in all patients.
voluminous watery diarrhea, or receiving IV medications containing
Patients with significant renal
severe burns; neonates who are free water or are consuming
concentrating defects, such as
younger than 28 days old or in the additional free water via the enteral
nephrogenic diabetes insipidus, could
NICU; or adolescents older than 18 route. For these reasons, clinicians
develop hypernatremia if they are
years of age (Supplemental Fig 5). should be aware that even patients
administered isotonic fluids. Patients
This guideline is intended for receiving isotonic maintenance IVFs
with voluminous diarrhea or severe
use primarily by clinicians are at sufficient risk for developing
burns may require a hypotonic fluid
providing acute care for children hyponatremia. If an electrolyte
to keep up with ongoing free-water
and adolescents who require abnormality is discovered, this could
losses. Hypotonic fluids may also be
maintenance IVFs. It may be of provide useful information to adjust
required to correct hypernatremia.
interest to parents and payers, but maintenance fluid therapy. If patients
However, for the vast majority of
it is not intended to be used for receiving isotonic maintenance
patients, isotonic fluids are the most
reimbursement or to determine IVFs develop hyponatremia, they
appropriate maintenance IVF and are
insurance coverage. This guideline is should be evaluated to determine if
the least likely to result in a disorder
not intended to be the sole source of they are receiving other sources of
in serum sodium.
guidance in the use of maintenance free water or if they may have SIAD
IVFs but rather is intended to assist and/or an adrenal insufficiency. If
clinicians by providing a framework hypernatremia develops (plasma
CONCLUSIONS
for clinical decision-making. sodium >144 mEq/L), patients
For the past 60 years, the should be evaluated for renal
prescription for maintenance The Key Action Statement is as dysfunction or extrarenal free-water
IVFs for infants and children has follows: losses.
been a hypotonic fluid. These 1A: The AAP recommends that In patients at high risk for developing
recommendations were made on patients 28 days to 18 years electrolyte abnormalities, such as
theoretical grounds and were not of age requiring maintenance those who have undergone major
based on clinical trials. Despite IVFs should receive isotonic surgery, those in the ICU, or those
this accepted dogma, over the past solutions with appropriate with large gastrointestinal losses
decade and longer, there have been KCl and dextrose because they or receiving diuretics, frequent
increasing reports of the deleterious significantly decrease the risk laboratory monitoring may be
effect of hyponatremia in the acute of developing hyponatremia necessary. If neurologic symptoms
care setting with the use of the (evidence quality: A; that could be consistent with
prevailing hypotonic maintenance recommendation strength: hyponatremic encephalopathy are
solutions. Using an evidence-based strong). present, such as unexplained nausea,
approach, recommendations for vomiting, headache, confusion, or
optimal sodium composition of lethargy, electrolytes should be
maintenance IVFs are provided to BIOCHEMICAL LABORATORY
MONITORING measured.
prevent hyponatremia and acute or
permanent neurologic impairment Although the frequency for
related to it. Recommendations are biochemical laboratory monitoring FUTURE QUALITY-IMPROVEMENT
not made regarding the use of an was not specifically addressed in QUESTIONS
isotonic buffered crystalloid solution the 17 RCTs included in the meta-
Future questions are as follows:
versus saline, the optimal rate of fluid analysis, researchers in most of
therapy, or the need for providing the studies obtained serial plasma 1. How frequently is plasma sodium
potassium in maintenance fluids. The sodium values, with the first plasma concentration abnormal, and

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by Chiang Mai University user
 is this abnormality clinically SUBCOMMITTEE ON FLUID AND STAFF
significant? ELECTROLYTE THERAPY Kymika Okechukwu, MPA – Senior Manager,
2. Will the widespread use of Leonard G. Feld, MD, PhD, MMM, FAAP – Chair, Evidence-Based Medicine Initiatives
Pediatric Nephrology
isotonic maintenance IVFs Daniel R. Neuspiel, MD, MPH, FAAP – Pediatric
in the acute-care setting Epidemiologist
significantly reduce or eliminate Byron Alexander Foster, MD, MPH, FAAP –
ABBREVIATIONS
hyponatremia- and hyponatremia- Pediatric Hospitalist
related neurologic events? Matthew D. Garber, MD, FHM, FAAP – Pediatric AAP: A  merican Academy of
Hospitalist; Implementation Scientist Pediatrics
3. Will the widespread use of 0.9% Michael G. Leu, MD, MS, MHS, FAAP – Partnership
ADH: a ntidiuretic hormone
saline for maintenance IVFs in for Policy Implementation
Rajit K. Basu, MD, MS, FCCM – Society of Critical AVP: a rginine vasopressin
the acute care setting increase CHF: c ongestive heart failure
Care Medicine, Pediatric Section
clinically significant metabolic Kelly Austin, MD, MS, FAAP, FACS – American CI: c onfidence interval
acidosis? Pediatric Surgical Association CNS: c entral nervous system
Edward E. Conway, Jr, MD, MS, FAAP – Pediatric
4. Are isotonic-balanced solutions IV: i ntravenous
Critical Care
superior to 0.9% saline for the James J. Fehr, MD, FAAP – Society for Pediatric IVF: i ntravenous fluid
maintenance IVF in the acute-care Anesthesia kcal: kilocalorie
setting? Clare Hawkins, MD – American Academy of Family KCl: potassium chloride
Physicians M-H: Mantel-Haenzel
5. How frequently should clinicians Ron L. Kaplan, MD, FAAP – Pediatric Emergency
NaCl: sodium chloride
monitor the serum sodium Medicine
RCT: r andomized controlled trial
Echo V. Rowe, MD, FAAP – Pediatric Anesthesiology
concentrations when a patient is SIAD: syndrome of inappropriate
and Pain Medicine
receiving maintenance IVFs and Muhammad Waseem, MD, MS, FAAP, FACEP – antidiuresis
for patients who are at high risk of American College of Emergency Physicians Tco2: total carbon dioxide
sodium abnormalities? Michael L. Moritz, MD, FAAP – Pediatric Nephrology

All clinical practice guidelines from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

DOI: https://​doi.​org/​10.​1542/​peds.​2018-​3083

Address correspondence to Leonard G. Feld, MD, PhD, MMM, FAAP. E-mail: feldllc@gmail.com

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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