Title: Prevention of hospital-acquired
hyponatremia: a case for using isotonic saline.
Date: 2/1/2003; Publication: Pediatrics; Author:
Ayus, Juan Carlos
current standard of care in pediatrics is to administer hypotonic
saline in maintenance parenteral fluids. The safety of this approach
has never been evaluated.
review of the literature reveals that the administration of
hypotonic fluids is potentially dangerous and may not be physiologic
for the hospitalized child.
have been >50 reported cases of neurologic morbidity and mortality,
including 26 deaths, in the past 10 years resulting from
hospital-acquired hyponatremia in children who were receiving
hypotonic parenteral fluids. Common childhood conditions requiring
parenteral fluids, such as pulmonary and central nervous system
infections, dehydration, and the postoperative state, are associated
with a nonosmotic stimulus for antidiuretic hormone production,
which can lead to free water retention and hyponatremia. Children
are at particularly high risk of developing symptomatic hyponatremia
as they have a larger brain-to-skull size ratio.
The administration of isotonic saline in maintenance parenteral
fluids is the most important prophylactic measure that can be taken
to prevent the development of hyponatremia in children who receive
parenteral fluids. Pediatrics 2003;111:227-230; hyponatremia, child,
treatment, fluid, intravenous, encephalopathy.
ADH, antidiuretic hormone; SIADH, syndrome of inappropriate
secretion of antidiuretic hormone.
principles for prescribing maintenance parenteral fluids in children
were laid down in the 1940s and 1950s and culminated with Holliday
and Segar's landmark paper in 1957 (1) describing a simple formula
for determining the maintenance need for water in children and
recommending the use of a hypotonic saline solution, equivalent to
0.2% sodium chloride in 5% dextrose in water. Since that time,
recommendations for prescribing maintenance parenteral fluid therapy
have remained unchanged. (2) Although Holliday and Segar's formula
for determining water needs clearly has passed the test of time,
their recommendations for prescribing hypotonic saline need to be
reassessed. Increasing evidence has shown that hypotonic maintenance
fluids can lead to potentially fatal hyponatremia in cases of excess
antidiuretic hormone (ADH) production. (3-6) Although it is
well-established that isotonic saline should be used for fluid
resuscitation in children to raise circulatory volume while
preventing the development of hyponatremia, (7) it has not been an
accepted practice to use isotonic saline as a maintenance fluid. We
review the evidence supporting our view that isotonic saline should
be used in favor of hypotonic saline in maintenance fluids in
hospitalized children, who are prone to have an increase in ADH
production, as this is least likely to result in hyponatremia.
MAINTENANCE PARENTERAL FLUIDS ARE CURRENTLY USED
needs for water in children have been shown to parallel energy
metabolism. (8-10) Maintenance requirements for electrolytes are
less clear. Holliday and Segar (1) conceded this point, writing,
"With respect to maintenance needs for electrolytes, less precise
data are available and figures considerably in excess of minimum
requirements are readily handled." In 1953, Talbot et al (11)
recognized the potential danger of administering hypotonic fluid in
states of ADH excess, stating that the "administration of dextrose
in water solution at a rate of more than approximately 1100 mL/[M.sup.2]/24
hrs may induce water intoxication" and that the "risk of water
intoxication may be reduced to small proportions by the
administration of 100 or more mosm of organic solute to each liter
of solution." The safety of administering maintenance hypotonic
parenteral fluids has never been evaluated prospectively, and
Holliday and Segar noted that approximately one third of children
and adults receiving parenteral therapy had urinary concentration
outside of a desirable range.
basis for the current recommendation of prescribing 3.0 and 2.0
mEq/100 kcal/24 h sodium and potassium, respectively, in maintenance
fluids is that this roughly reflects the electrolyte composition of
breast and cow milk. (1,8-10) This electrolyte composition will also
result in a urine osmolality of approximately 400
mOsm/kg/[H.sub.2]O, which was believed to be ideal, as it is between
the range of urinary concentrating capacity. (11) Although it has
been well-established that isotonic saline could be tolerated
without any adverse effects, the use of isotonic saline has been
avoided to prevent excess urinary water losses in conditions with
impaired renal concentrating ability and to prevent the development
of postoperative edema. (9-11) Whereas these recommendations may be
appropriate for the healthy child, they may not apply to ill
children, who are much more likely to have a nonosmotic stimulus for
ADH production (Table 1). At the time that these recommendations
were made, it was not yet fully appreciated that many conditions
could lead to impaired free water excretion as a result of ADH
excess. It is our intent to alert physicians to the potential
dangers of using hypotonic maintenance fluids in children who may
have an impaired ability to excrete free water, as this can lead to
clinically significant hyponatremia.
In 1957, the
same year that Holliday and Segar published their paper on
maintenance water needs, Schwartz et al (12) described the first
case of "the syndrome of inappropriate Secretion of antidiuretic
hormone" (SIADH). (13) SIADH is a disorder that can lead to
hyponatremia as a result of the nonphysiologic secretion of ADH,
which leads to free water retention followed by a natriuresis that
maintains fluid balance at the expense of serum osmolality. SIADH is
1 of the most common causes of hyponatremia in both children and
adults in a hospital setting. (14) It has been reported in numerous
conditions but primarily affects children with central nervous
system and pulmonary disorders and as a side effect of medications.
Many common childhood conditions that require parenteral fluids
cause SIADH, such as pneumonia, (15) bronchiolitis, (16) asthma,
(17) positive pressure ventilation, CNS infections, (18) and head
trauma. (19) Other stimuli for ADH release that can lead to
hyponatremia in children are emesis, pain, stress, and hypoxia. (20)
There are many clinical settings where children are at risk for
developing hyponatremia as a result of nonosmotic stimuli for ADH
release (Table 1).
A common reason
that hospitalized children receive parenteral fluids is to treat
isotonic dehydration. Although isotonic saline is recommended for
acute volume expansion, hypotonic fluids with 0.45% sodium chloride
are currently recommended for the remainder of the deficit therapy.
(21) Volume depletion is a potent stimulus for ADH production. The
administration of hypotonic fluids to children with dehydration can
result in acute hyponatremia secondary to free water retention. (22)
Hypotonic fluids are even recommended as parenteral fluid therapy in
children with meningitis. (23) Such children frequently have
dehydration in addition to other nonosmotic stimuli for ADH
production, and the administration of hypotonic fluids can lead to
worsening neurologic deterioration secondary to the development of
children are at especially high risk for developing hyponatremia,
and there have been many associated fatalities. (3,17,24-30)
Contributing factors to hyponatremia in the postoperative setting
comprise a combination of nonosmotic stimuli for ADH release, such
as subclinical volume depletion, pain, nausea, stress, edema-forming
conditions, and the administration of hypotonic fluids. The
postoperative nonosmotic stimuli for ADH release typically resolve
by the third postoperative day but can last until the fifth
postoperative day. (17) The most important factors that lead to
postoperative hyponatremia are the failure to recognize the
compromised ability of the patient to maintain water balance and the
administration of hypotonic fluids.
There have been
>50 reported cases of neurologic morbidity and mortality, including
26 deaths, resulting from hospital-acquired hyponatremia in children
who were receiving hypotonic fluids. (3-5,15,26-29,31-34) More than
half of these cases occurred in the postoperative setting in
previously healthy children who underwent minor surgery. Arieff et
al (13) reported on 16 previously healthy children who died or
experienced permanent neurologic damage as a result of hyponatremic
encephalopathy soon after receiving hypotonic fluids after minor
surgical procedures or for the treatment of common childhood
infections. McJunkin et als and Moritz and Ayus (6) noted that the
major factor that results in neurologic deterioration in children
with La Crosse encephalitis was mild hyponatremia developing after
the administration of hypotonic fluid. Halberthal et al (4) reported
on 23 children, without an underlying disease that impaired water
handling, who developed acute symptomatic hyponatremia after the
administration of hypotonic fluids. Hyponatremia in these cases
seemed to be attributable to a combination of hypotonic fluid
administration and ADH excess. The above authors and others (30,35)
have cautioned against the routine use of hypotonic maintenance
fluids in children.
Children are at
particularly high risk for developing symptomatic hyponatremia as
they develop hyponatremic encephalopathy at higher serum sodium
concentrations than adults and have a poor prognosis if timely
therapy is not instituted. This seems to be attributable to the
higher brain-to-skull size ratio in children, which leaves less room
for brain expansion. (3,36) Children achieve adult brain size by 6
years of age, whereas full skull size is not achieved until 16 years
of age. Female adolescents may also be at increased risk of
developing hyponatremic encephalopathy, as women of reproductive age
are >30 times more likely to develop hyponatremic encephalopathy
than are men, as a result of diminished ability to adapt to
hyponatremia by decreasing brain volume. (36,37)
encephalopathy can be difficult to recognize in children, as the
symptoms can be variable and do not correlate with either the serum
sodium concentration or the rapidity of development of hyponatremia.
(3) The most consistent symptoms of hyponatremia are headache,
nausea, vomiting, emesis, and weakness. Advanced symptoms are signs
of cerebral herniation, with seizures, respiratory arrest,
noncardiogenic pulmonary edema, (38,39) dilated pupils, and
decorticate posturing. (3) Failure to recognize hyponatremic
encephalopathy and initiate appropriate therapy will result in a
poor neurologic outcome. (3,29)
MAINTENANCE PARENTERAL FLUIDS SHOULD BE USED
administration of isotonic maintenance fluids is the most important
prophylactic measure that can be taken to prevent the development of
hyponatremia in children who are receiving parenteral fluids.
Commonly used intravenous fluids have a significant amount of free
water that can contribute to hyponatremia (Table 2); therefore, they
should be used with caution in maintenance fluids, to mix
intravenous medications or to keep a vein open. Even isotonic saline
can lead to hyponatremia if excessive fluid is administered in the
presence of a fixed urine osmolality with impaired urinary dilution.
(40) If an isotonic solution of 300 mOsm/kg/[H.sub.2]O is
administered in a state of excess vasopressin, such as SIADH or the
postoperative state, for which the urine osmolality may be fixed at
500 mOsm/kg/[H.sub.2]O, then a natriuresis that will result in the
generation and retention of free water and the development of
hyponatremia will ensue. An isotonic solution will have
approximately 154 mEq/L monovalent cations, sodium plus potassium,
as the average concentration of sodium plus potassium in the aqueous
phase of plasma is 154 mEq/L. Although no 1 fluid rate or
composition will be appropriate for all children, isotonic saline in
5% dextrose in water seems to be the safest fluid composition in
most hospitalized patients. If potassium chloride is to be added to
the parenteral fluids, then the sodium concentration can be lowered
proportionally to maintain isotonicity. Lactated ringers with 20
mEq/L potassium chloride in 5% dextrose in water would also be an
isotonic fluid. Physicians must assess children carefully to choose
the most appropriate parenteral fluid rate and composition before
initiating therapy. The maintenance fluid requirements of the term
and preterm neonate may differ from the older child as a result of
unique physiologic issues, and our recommendations do not extend to
this group of patients. Children with ongoing free water losses or a
free water deficit will require a more hypotonic fluid. In children
with illnesses that can lead to fluid overload, such as nephrosis,
cirrhosis, congestive heart failure, and glomerulonephritis, both
sodium and fluid restriction is of paramount importance to avoid
worsening fluid overload and the development of hyponatremia.
Hospitalized children who are receiving parenteral fluid therapy
should be considered at risk for developing hyponatremia and
monitored closely through daily weights, fluid balance, blood
pressure, observing for signs of edema, and monitoring the serum
sodium concentration. Isotonic saline seems to be the preferred
fluid for administration to hospitalized patients, as they are at
high risk for developing hyponatremia as a result of factors that
lead to ADH excess.
TABLE 1. Clinical Settings of Increased ADH Release in Children
Hemodynamic Stimuli Nonhemodynamic Stimuli
for ADH Release for ADH Release
Hypovolemia Central nervous system disturbances
Nephrosis Meningitis, encephalitis, brain
Cirrhosis tumors, head injury
Congestive heart failure Pulmonary disease
Hypoaldosteronism Pneumonia, asthma, bronchiolitis
Cytoxan, Vincristine, Morphine
Nausea, emesis, pain, stress
Table 2. Electrolyte-Free Water in Parenteral Fluids
Intravenous Fluid Sodium Osmolality % Electrolyte-
(mEq/L) (mOsm/kg/ Free Water *
5% Dextrose in water 0 252 100
0.2% Sodium chloride in 5% 34 321 78
dextrose in water
0.45% Sodium chloride in 5% 77 406 50
dextrose in water
Lactated Ringer's 130 273 16
5% Dextrose Lactated Ringer's 130 525 16
0.9% Sodium chloride in 5% 154 560 0
dextrose in water
* Based on a sodium plus potassium concentration in the aqueous phase
of plasma of 154 mEq/L, assuming that plasma is 93% water with a serum
sodium of 140 mEq/L and a potassium concentration of 4 mEq/L.
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Moritz MD *, and Juan Carlos Ayus, MD ([double dagger])
From the *
Division of Nephrology, Department of Pediatrics, Children's
Hospital of Pittsburgh, University of Pittsburgh School Medicine,
Pittsburgh, Pennsylvania; and ([double dagger]) Department of
Medicine, University of Texas Health Science Center at San Antonio,
San Antonio, Texas.
publication Mar 25, 2002; accepted Jul 8, 2002.
requests to (M.L.M.) Division of Nephrology, Children's Hospital of
Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2538. E-mail:
American Academy of Pediatrics
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