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patients.4,5 In 2003, we introduced the concept Box 1 Clinical settings in which production of arginine vasopressin
of using 0.9% sodium chloride (NaCl) as a main- is increased.
tenance parenteral fluid for the prevention of
Hemodynamic stimuli (decreased effective circulatory volume)
hospital-acquired hyponatremia in children.1 Hypovolemia
This concept caused controversy in the pedi-
■ Vomiting
atric literature about the most appropriate fluid
therapy for children.6–10 The Royal College of ■ Diarrhea
Pediatrics has since issued a warning regarding ■ Diuretics
the use of 0.18% NaCl,11 and critics have now ■ Renal salt wasting
conceded that hypotonic fluids are overused and
■ Hypoaldosteronism
can be dangerous.12 Avoidance of hypotonic
fluids, and use of 0.9% NaCl as prophylaxis Hypervolemia
against hospital-acquired hyponatremia, are ■ Nephrosis
equally relevant to adults and children.13 In this
■ Cirrhosis
Review, we explore the question of why admin-
istration of hypotonic fluids is unphysiologic ■ Congestive heart failure
and potentially dangerous, the settings in which ■ Hypoalbuminemia
isotonic fluids should be administered to prevent
Hypotension
hyponatremia, and the appropriate management
of hyponatremic encephalopathy. Nonhemodynamic stimuli (syndrome of inappropriate antidiuretic hormone
production)
Euvolemia
WHY ARE HYPOTONIC FLUIDS USED?
Hypotonic fluids are still the parenteral fluid ■ Central nervous system disturbances such as meningitis, encephalitis,
most commonly administered to both pedi- stroke, brain tumor, brain abscess, head injury and hypoxic brain injury
atric and adult hospitalized patients. The ■ Pulmonary diseases such as pneumonia, asthma, tuberculosis, empyema,
pediatric literature specifically addresses the topic chronic obstructive pulmonary disease and acute respiratory failure
of maintenance parenteral fluid therapy and ■ Cancers of the lung, brain, central nervous system, head, neck, breast,
recommends hypotonic fluid.14 The adult litera- gastrointestinal tract, genitourinary tract, and leukemia, lymphoma, thymoma
ture does not specifically address maintenance and melanoma
parenteral therapy but does make recommen-
■ Medications such as cyclophosphamide, vincristine, morphine, selective
dations for hypotonic fluids in total parenteral
serotonin reuptake inhibitors and carbamazepine
nutrition and in the perioperative setting.15,16
We queried the adult inpatient pharmacy of ■ Nausea, emesis, pain and stress
the University of Pittsburgh Medical Center, ■ Postoperative state
and found that 0.45% NaCl with 20 mmol/l
■ Cortisol deficiency
potassium chloride in 5% dextrose is the most
commonly prescribed fluid for parenteral
therapy. This practice seems to be common for
adult patients throughout the world. The WHO
recommends using 5% dextrose in water in the tolerances for sodium and water in parenteral
postoperative setting for one-third of main- fluids, based on the ranges of normal renal
tenance fluids in patients unable to drink.17 concentration and dilution. Their recommen-
In the UK, 0.18% NaCl in 4% dextrose is the dation at the time was to use 40 mmol/l NaCl for
most commonly used parenteral fluid.18–20 In maintenance fluid therapy. Hypotonic fluid use
a Brazilian study, about 50% of postoperative in children is partly based on recommendations
patients received 5% dextrose in water.21 In a made by Holliday and Segar in 1957.24 These
recent Case Record of the Massachusetts General authors recommended 30 mmol/l NaCl for main-
Hospital, 0.45% NaCl was administered to a tenance fluid in children. Their guidance was
patient with a central nervous system disorder based in part on the recommendations of others,
and a serum sodium level of 131 mmol/l.22 and also on the fact that 30 mmol/l NaCl approx-
The use of hypotonic fluids in adults origi- imates the sodium composition of human breast
nated in part from recommendations made by and cow’s milk. Both Talbot’s and Holliday’s
Talbot et al. in 1953.23 These authors generated groups appreciated that AVP excess could
a theoretical model of maximal and minimal impair water handling and that symptomatic
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have, however, occurred at fluid volumes less 0.9% NaCl AS PROPHYLAXIS AGAINST
than or equal to standard maintenance doses. HYPONATREMIA
In a prospective study by Coulthard et al., post- Several prospective studies in children and adults
operative administration of one-third normal have shown that administration of 0.9% NaCl is
saline at two-thirds of the standard maintenance effective prophylaxis against the development of
dose caused serum sodium levels to drop; 37% hyponatremia.42–49 Even in patients with SIADH
of patients developed hyponatremia.32 and hyponatremia, administration of normal
Our group used data collected since 2000 to saline does not aggravate hyponatremia.50 We
evaluate the risk factors for death or neuro- conducted a meta-analysis of 550 postoperative
logical impairment from hyponatremic patients, 50 of whom were children, managed
encephalopathy.33 We found hospital-acquired with either 0.9% NaCl or a more-hypotonic
hyponatremia caused by hypotonic fluid admin- fluid. Hyponatremia was effectively prevented
istration to be one of the primary risk factors. by 0.9% NaCl, whereas more-hypotonic
Virtually all reports of hospital-acquired fluids—including Ringer’s lactate—consistently
hyponatremic encephalopathy in children caused a drop in serum sodium level.51 Ringer’s
are of cases in which hypotonic fluids were lactate, which has a sodium concentration of
administered.5,34,35 Even a small amount of 130 mmol/l, is hypotonic to plasma water and
supplemental hypotonic fluid can produce can produce hyponatremia.52 Avoidance of
hyponatremia. A prospective study of jaundiced hypotonic fluids, and administration of 0.9%
neonates revealed that 8 h of supplementation NaCl when parenteral fluids are required, is the
with 50 ml/kg body weight of 0.18% NaCl most physiologic approach to preventing hypo-
resulted in acute hyponatremia.36,37 natremia. Administration of 0.9% NaCl is safe;
There is evidence to suggest that hypotonic there has never been a report of neurological
fluid administration is the primary factor complications of hyponatremia resulting from
leading to hospital-acquired hyponatremia use of 0.9% NaCl in non-neurosurgical patients.
and hyponatremic encephalopathy in adult Neurosurgical patients can develop cerebral salt
patients. In three studies of patients with wasting. In such cases, 0.9% NaCl might not be
neurological sequelae from hospital-acquired sufficient for prophylaxis against hyponatremia,
hyponatremic encephalo pathy, most had and 3% NaCl might need to be administered in
received hypotonic parenteral fluids with a order to maintain normal serum sodium levels.
sodium concentration of ≤77 mmol/l.38–40 In Hyponatremia is not a benign condition.
a series of 15 women with hyponatremia and Several studies have shown that mortality and
permanent neurological impairment following hospitalization rates are elevated in patients
elective surgery, 11 had received 5% dextrose with hyponatremia.53 Mortality is highest in
in water.38 In a series of 65 postoperative patients with hospital-acquired hyponatremia.
patients with hyponatremic encephalopathy, Active measures must be taken to prevent hypo-
all had received hypotonic fluids.39 In a series natremia in patients at risk for AVP excess
of 30 patients with noncardiogenic pulmo- (Box 1). In these disease states, parenteral fluid
nary edema as a complication of postoperative therapy should consist of normal saline rather
hyponatremic encephalopathy, all had received than a more-hypotonic fluid. There are certain
hypotonic fluids.40 These results are consistent subsets of patients for whom adaptation of the
with those of a prospective study by Chung brain to hyponatremia is impaired and even
et al., which revealed that 94% of patients with mild hyponatremia can be lethal (Table 1).
postoperative hyponatremia (Na+ concentra- In these groups of patients, prophylaxis with
tion <130 mmol/l) were receiving hypotonic normal saline is crucial.
fluids.41 A prospective study by Aronson
and colleagues showed that the amount of Postoperative setting
electrolyte-free water administered was the Most of the deaths and neurological dysfunction
most predictive factor for the development of resulting from hyponatremic encephalopathy in
clinically significant hyponatremia following both children and adults have occurred in post-
cardiac catheterization.42 The odds ratio for surgical patients. Postoperative patients have
developing hyponatremia was 3.7 for each multiple nonosmotic stimuli for AVP produc-
liter of electrolyte-free water administered to tion, such as subclinical volume depletion, pain,
a 70 kg patient. stress, nausea and vomiting, narcotic use and
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Table 1 Risk factors for development of hyponatremic encephalopathy. The serum sodium level of patients with neuro-
logical deterioration was only 2 mmol/l less
Risk factor Pathophysiologic mechanism
than that of those without deterioration (131.9
Childhood Higher brain-to-intracranial volume ratio vs 133.8 mmol/l). A drop in serum sodium
Female sex Sex steroids (estrogens) inhibit adaptation of brain to hyponatremia concentration of only 4 mmol/l resulted in neuro-
Higher arginine vasopressin levels than males logical deterioration. There is no ‘safe’ degree of
Cerebral vasoconstriction
Hypoperfusion of brain tissue hyponatremia in patients with brain injury, and
0.9% NaCl is one of the most important prophy-
Hypoxemia Impairs adaptation of brain to hyponatremia
Decreased cerebral perfusion lactic measures for prevention of hyponatremia
Causes brain injury in this population.
Brain injury Vasogenic cerebral edema
Cytotoxic cerebral edema Pulmonary disease (hypoxemic states)
Hyponatremia is common in patients with
pulmonary disease, affecting approximately 25%
of patients with pneumonia.57 Hyponatremia
third spacing, which puts them at risk for hypo- markedly increases the risk of death from
natremia. Premenopausal females are at highest community-acquired pneumonia.58 The under-
risk of developing hyponatremic encephalo- lying mechanism is probably hypoxia, a major
pathy, as their postoperative AVP levels are 40 risk factor for the development of hyponatremic
times those of young males.54 The relative risk encephalopathy. The majority of neurological
of death or permanent neurological dysfunction morbidity in patients with hyponatremia has
is approximately 30 times greater for women been in those who experienced a respiratory
than for men, and about 25 times greater for arrest.59–61 Recent studies have found respira-
menstruant females than for postmenopausal tory compromise to be a comorbidity factor
females.39 Children under the age of 16 years in patients with hyponatremia.5,62,63 Studies
are also at high risk of developing postoperative of hyponatremic animals have revealed that
hyponatremic encephalopathy, as seizures hypoxia impairs volume regulation of brain
occur at higher serum sodium concentrations cells, decreases cerebral perfusion, and increases
in this group than in adults. This phenomenon the probability of neuronal lesions developing.64
occurs because children have a larger brain- Adaptation of the brain to hyponatremia largely
to-intracranial volume ratio than adults. There depends on extrusion of sodium from the intra-
can be no justification for administering electro- cellular space via sodium–potassium ATPase
lyte-free water, including Ringer’s lactate, in the pumps. This energy-dependent process is
postoperative setting.3 impaired under hypoxic conditions. The combi-
nation of systemic hypoxia and hyponatremia
Brain injury and infection is more deleterious than is either condition
Hyponatremia is poorly tolerated in patients with alone, because hypoxia impairs the ability of
brain injury. Even a small drop in serum sodium the brain to adapt to hyponatremia, worsening
level can aggravate cerebral edema.22,35,55 Brain hyponatremic encephalopathy.61
injury can produce cerebral edema via vasogenic
and cytotoxic mechanisms. Vasogenic edema is POTENTIAL COMPLICATIONS OF 0.9% NaCl
accumulation of fluid in the extracellular brain No single fluid therapy will be optimal for all
parenchyma following disruption of the blood– patients. Patients with ongoing urinary free
brain barrier by, for example, a brain tumor or water losses resulting from renal concentrating
abscess. Cytotoxic cerebral edema is accumu- defects, or extrarenal free water losses secondary
lation of fluid in the intracellular space, as in to diarrhea or fever, will probably require a more-
hypoxic brain injury or hyponatremia.56 These hypotonic fluid. Patients with hypernatremia
mechanisms are not mutually exclusive. Volume will need a more-hypotonic fluid to correct
regulation of brain cells is impaired in patients the free water deficit. In general, normal saline
with brain injury, and the movement of addi- will not cause hypernatremia, as the kidney can
tional water into the brain as a result of even mild generate free water by producing hypertonic
hyponatremia can be lethal. In a study of children urine. Prolonged administration of normal
with Lacrosse encephalitis, mild hyponatremia saline to a patient who is avidly fluid restricted
was associated with neurological deterioration.35 could cause hypernatremia. Administration of
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0.9% NaCl can be dangerous in the setting of a There is a misconception that administration
renal concentrating defect, especially diabetes of 0.9% NaCl as a maintenance fluid will result in
insipidus. Patients with head injuries might acidosis. This solution has a pH of 5 (which does
initially require 0.9% NaCl to prevent hypo- not differ from that of 0.45% or 0.2% NaCl) and
natremia; however, if central diabetes insipidus is not more likely to produce acidosis than is a
develops, 0.9% NaCl can result in severe hyper- more-hypotonic parenteral fluid. Administration
natremia. Patients at risk of developing central of 0.9% NaCl in large volumes for fluid resusci-
diabetes insipidus should be monitored closely tation can result in a dilutional acidosis. Ringer’s
for the development of hyperosmolality while lactate does have an advantage over normal
they are receiving fluid therapy. In patients with saline in that the lactate can be metabolized
a fixed inability to excrete free water and a urine to bicarbonate; however, Ringer’s lactate is a
osmolality greater than 500 mmol/kg H2O, slightly hypotonic fluid that, in cases of severe
even 0.9% NaCl can cause serum sodium levels liver disease, sepsis or severe hypoperfusion,
to drop.50 can contribute to lactic acidosis. There are
The optimal fluid therapy for patients with currently no FDA-approved parenteral fluids
congestive heart failure or cirrhosis is a matter containing bicarbonate because of the instability
of debate. Excessive sodium administration of bicarbonate in solution. Acidosis can develop
can lead to fluid overload, but hypotonic fluid following administration of any parenteral fluid
administration can also lead to hyponatremia, to a patient with renal dysfunction or multi-
which increases the risk of mortality.65,66 system organ failure. Additional prospective
Sodium and water need to be avidly restricted in studies are needed to assess the safety and efficacy
patients with these conditions. Either 0.9% NaCl of administering 0.9% NaCl.
or a more-hypotonic fluid could be used safely,
provided that there is adequate fluid restriction TREATMENT OF HYPONATREMIC
and patient monitoring. ENCEPHALOPATHY
Parenteral fluid therapy, including 0.9% Hyponatremic encephalopathy is a medical emer-
NaCl, should not be thought of as benign, as gency that requires early recognition and treat-
serious complications can develop. Continuous ment. Neurological sequelae of hyponatremic
fluid administration in excess of standard encephalopathy are the result of inadequate
maintenance doses—generally accepted to be therapy rather than rapid correction.59,60 This
1,600 ml/m2/day—should be avoided. Volume fact has been confirmed by three recent studies
depletion is best corrected by administering in adults, which found a poor outcome to be
0.9% NaCl as bolus therapy until volume reple- associated with inadequate therapy.62,63,67 We
tion, rather than via prolonged administration have studied risk factors for poor neurological
of parenteral fluids at a rate in excess of stan- outcome in hyponatremic encephalopathy in
dard maintenance. Even standard maintenance children, and have found lack of therapy to be
therapy can result in fluid overload in patients the main contributory factor.33
with advanced chronic renal failure, oliguric Treatment of hyponatremia should be based
acute renal failure, acute glomerulonephritis or on neurological symptoms and not on the
an edematous state such as nephrosis, cirrhosis absolute serum sodium concentration. Patients
or congestive heart failure. The monitoring of with symptomatic hyponatremia need aggres-
patients who are receiving parenteral fluids sive management with 3% NaCl (513 mmol/l;
should take the form of daily weights, frequent Figure 1). Fluid restriction alone has no role in
vitals, strict intake and output measures, and the management of symptomatic hyponatremia.
daily chemistries, and is especially important Treatment of hyponatremic encephalopathy
within the first 72 h of fluid therapy. Prolonged should precede any neuroimaging studies to
administration of parenteral fluids should be confirm cerebral edema and should occur in
avoided unless there is a specific indication. In a monitored setting in which the airway can
patients requiring prolonged administration of be secured and serum sodium level measured
parenteral fluids (such as those receiving total every 2 h until the patient is stable. Patients with
parenteral nutrition), a more-hypotonic fluid severe symptoms such as seizures, respiratory
could be used and monitoring performed less arrest or neurogenic pulmonary edema should
frequently, provided there is no acute illness receive 100 ml of 3% NaCl as a bolus over 10 min
resulting in AVP excess. in order to rapidly reverse brain edema.68 This
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Symptomatic hyponatremia
avoiding normonatremia and hypernatremia
High-risk patients/clinical settings are: in the first 48 h. In general, 1 ml/kg body weight
■ Children of 3% NaCl will increase the serum sodium level
■ Premenopausal females by about 1 mmol/l. A continuous infusion of 3%
■ Postoperative patients
■ Brain injury or infection NaCl at a rate of 50–100 ml/h administered over
■ Pulmonary disease 4 h is usually sufficient to reverse symptoms. In
■ Hypoxia children with acute hyponatremic encephalo-
pathy, 12 ml/kg body weight of 3% NaCl infused
over 4 h has been used without apparent neuro-
logical sequelae.69,70 Much of the change in
serum sodium level is a function of the renal
Hyponatremic encephalopathy
response to therapy, making formulae unreliable
Impending herniation
■ Active seizures ■ Headache for predicting the change in serum sodium.
■ Neurogenic pulmonary edema ■ Nausea Patients with SIADH are at low risk of over-
■ Hypercapnic respiratory failure ■ Vomiting correction of hyponatremia. Patients with hypo-
■ Obtundation ■ Altered mental status
■ Hyperemesis ■ Seizures natremia resulting from diuretics or psychogenic
■ Decorticate or decerebrate polydipsia will have a brisk free water diuresis
posturing Treatment during therapy and are prone to overcorrection.3
■ Dilated pupils 1 3% NaCl via infusion pump in In these patients, active measures might be
a monitored setting (adults
Treatment 50–100 ml/h; children 1 ml/kg needed to prevent overcorrection of hypo-
1 3% NaCl bolus over 10 min body weight/h) natremia, including a switch to hypotonic fluids
(adults 100 ml; children 2 ml/kg 2 Check serum sodium level or DDAVP (desmopressin). Administration of
body weight) every 2 h
3 Stop 3% NaCl infusion when
DDAVP will stop the free water diuresis, and
2 Repeat bolus once or twice as
required until symptoms either: the patient is symptom a controlled rate of sodium correction can be
improve; aim for a 2–4 mmol/l free (that is, awake, alert, achieved with a combination of fluid restric-
increase in serum sodium level responding to commands, tion, 0.9% NaCl and 3% NaCl as needed.
3 Begin infusion as for without headache or nausea);
or there is an acute rise in
Recently, vasopressin V2 receptor antagonists
hyponatremic encephalopathy
(see box to the right) serum sodium level of have received FDA approval for the treatment
10 mmol/l in first 5 h of hyponatremia.71 Preliminary data support
4 Total correction in first 48 h:a a role for these agents in the management of
■ Do not exceed 15–20 mmol
of correction asymptomatic euvolemic or hypervolemic hypo-
■ Avoid correction to natremia,72 but there is currently no evidence
normonatremic or to support their use in acute treatment of
hypernatremic levels
symptomatic hyponatremia.
380 NATURE CLINICAL PRACTICE NEPHROLOGY MORITZ AND AYUS JULY 2007 VOL 3 NO 7
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fluid restriction and patient monitoring are 5 Hoorn EJ et al. (2004) Acute hyponatremia related to
intravenous fluid administration in hospitalized children:
adequate. No single fluid composition will work an observational study. Pediatrics 113: 1279–1284
for all patients, and there is no substitute for 6 Hatherill M (2004) Rubbing salt in the wound. Arch Dis
sound physician judgment. Child 89: 414–418
7 Holliday MA et al. (2004) Acute hospital-induced
Further prospective studies are needed to hyponatremia in children: a physiologic approach.
assess the safety and efficacy of 0.9% NaCl in J Pediatr 145: 584–587
a variety of disease states in children, adults 8 Moritz ML and Ayus JC (2005) Hospital-induced
hyponatremia. J Pediatr 147: 273–274
and the elderly. Current literature reveals that 9 Friedman AL (2005) Pediatric hydration therapy:
0.9% NaCl is the safest parenteral fluid; hypo- historical review and a new approach. Kidney Int 67:
tonic fluids have been consistently associated 380–388
10 Moritz ML and Ayus JC (2005) Hypotonic fluids should
with neurological complications due to hypo- not be used in volume-depleted children. Kidney Int 68:
natremia. Administration of parenteral fluids 409–410
11 [No authors listed] Postoperative fluid management
should be thought of as an invasive proce- and hyponatraemia [http://www.ich.ucl.ac.uk/clinserv/
dure requiring close monitoring including anaesthetics/professionals/10postopfluid.html]
daily electrolytes, weight, intake and output (accessed 2 May 2007)
12 Holliday MA et al. (2006) Fluid therapy for children:
measurements, physical examination, and vital facts, fashions and questions. Arch Dis Child
signs. Hypotonic fluids are contraindicated in [doi: 10.1136/adc.2006.106377]
the postoperative setting, in patients with brain 13 Achinger SG et al. (2006) Dysnatremias: why are
patients still dying? South Med J 99: 353–362
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When hyponatremic encephalopathy develops, fluid therapy. Pediatr Rev 22: 380–387
prompt treatment with 3% NaCl is required, as 15 Nathens AB and Maier RV (2003) Perioperative fluids
and electrolytes. In Essential Practice of Surgery: Basic
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Secaucus: Springer-Verlag
16 Driscoll DF and Bistrian BR (2003) Parenteral and
KEY POINTS enteral nutrition in the intensive care unit. In Irwin &
Rippe’s Intensive Care Medicine, edn 5, 2057–2069
■ Hospitalized patients have numerous stimuli for
(Eds Irwin RS and Rippe JM) Philidelphia: Lippincott
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■ Routine administration of hypotonic parenteral (accessed 2 May 2007)
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in the setting of a free water deficit or ongoing
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21 Ferreira da Cunha D et al. (2000) Hyponatremia in
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hyponatremia are children, premenopausal surgical wards. Am J Nephrol 20: 37–41
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with Crohn’s disease and altered mental status. N Engl
brain injury, brain infection or hypoxemia
J Med 354: 2833–2834
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