Emergency Medicine Australasia (2008) 20, 294–305 doi: 10.1111/j.1742-6723.2008.01086.

REVIEW ARTICLE

Review article: Hypertonic saline use in the

emergency department
Colin J Banks and Jeremy S Furyk
Emergency Department, The Townsville Hospital, Douglas, Queensland, Australia

Abstract

Hypertonic saline (HS) is being increasingly used for the management of a variety of
conditions, most notably raised intracranial pressure. This article reviews the available
evidence on HS solutions as they relate to emergency medicine, and develops a set of
recommendations for its use. To conclude, HS is recommended as an alternative to man-
nitol for treating raised intracranial pressure in traumatic brain injury. HS is also recom-
mended for treating severe and symptomatic hyponatremia, and is worth considering for
both recalcitrant tricyclic antidepressant toxicity and for cerebral oedema complicating
paediatric diabetic ketoacidosis. HS is not recommended for hypovolaemic resuscitation.
Key words: brain injury, hypertonic, hyponatremia, intracranial hypertension, resuscitation,
saline solution.

Introduction
Hypertonic saline (HS) is an old therapy that has
enjoyed a recent resurgence. From the first study in
1919 by Weed and McKibben that demonstrated a
reduction of brain volume in cats,1 it has now become
routine care in many institutions for the treatment of
traumatic brain injury (TBI). HS, in combination with
colloid, has been used in Europe for trauma resuscita-
tion for many years. HS has also been used in other
diverse fields, such as toxicology and hyponatraemia
and, more recently, for cardiac arrest. The aim of this
review is to examine and present the available evidence
behind this resurgence, and then develop a set of rec-
ommendations for the use of HS solutions by emergency
physicians.
Methods
A search was conducted of the electronic databases
MEDLINE (1966 to August 2007), EMBASE (1977
to August 2007) and CINAHL (1982 to August 2007),
using the terms ‘exp saline solutions, hypertonic/’
AND ‘exp brain oedema/OR exp intracranial
hypertension/OR exp brain injuries/OR exp multiple
trauma/OR exp burns/OR exp resuscitation/OR exp
hyponatremia/OR exp sepsis/OR exp antidepressive
agents, tricyclic/OR exp shock/’. The results were
limited to humans. All titles and abstracts were read,
relevant articles were identified and full texts were
obtained. A hand search of the references was also
conducted. This was done independently by both
authors.

Correspondence: Dr Colin J Banks, c/o Emergency Department, The Townsville Hospital, 100 Angus Smith Dr, Douglas, Qld 4814,
Australia. Email: colinbanks@yahoo.com
Colin J Banks, MB BS, Emergency Registrar; Jeremy S Furyk, MB BS FACEM, Staff Specialist.

© 2008 The Authors

Journal compilation © 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine

Table 1. NHMRC guidelines for level of evidence2
Level Description
I Systematic review of level II studies
II A randomized controlled trial
III-1 A pseudorandomized control trial
III-2 A comparative study with concurrent controls
III-3 A comparative study without concurrent controls
IV Case series
NHMRC, National Health and Medical Research Council.
2
Table 2. NHMRC guidelines for grading of recommendations
Grade Description
A Body of evidence can be trusted to guide practice
B Body of evidence can be trusted to guide practice in
most situations
C Body of evidence provides some support for
recommendation but care should be taken in its
application
D Body of evidence is weak and recommendation must be
applied with caution
NHMRC, National Health and Medical Research Council.
Articles retained for selection were those original
research papers of relevance to emergency medicine.
Perioperative studies and case reports were excluded
unless they offered something unique or they were the
best evidence in that area. All HS solutions were incor-
porated, with solutions ranging from 1.6% to 30%,
including those mixed with different colloids. Final
inclusion was decided by author consensus.
The level of evidence and the grading of recommen-
dations for each area were assessed using the Austra-
lian National Health and Medical Research Council
guidelines.2 These are summarized in Tables 1 and 2.
To help explain mechanisms of action, some animal
and perioperative trials were quoted, but these were not
used in formulating any recommendations.
Results
The above search yielded: MEDLINE 395 titles,
EMBASE 179 titles, CINAHL 55 titles. After dupli-
cates were removed, all abstracts were read. Of those,
121 were considered potentially relevant and full texts
were obtained. A further 22 papers were identified
from hand-searching references. From the 143 full-text
articles, 91 were included in the final manuscript and
these are discussed in the main body of the text. The 52
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Journal compilation © 2008 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
Hypertonic saline
excluded articles were case reports, perioperative trials
or those felt not to be relevant after detailed examina-
tion by the authors.
Mechanisms of action
Haemodynamic effects
HS infusion causes plasma expansion through a redis-
tribution of fluid from the extravascular space. This
results in an increase in mean arterial pressure (MAP)
with the need for less volume than with isotonic fluids.
This has been shown in both animal and human
models.3–6 There is also a decrease in systemic vascular
resistance,4,5 which might be in part secondary to release
of endothelin-derived relaxing factor.7
There have been conflicting results as to whether
HS directly improves cardiac contractility, with some
studies demonstrating an increase,5,8 and others no
effect.3,9
Endothelial swelling occurs in the early stages of
shock, resulting in capillary narrowing and hypoperfu-
sion. HS infusion has been shown in animal models to
reduce this swelling and also that of the red blood cell,
thereby improving the microcirculation.10,11
Intracranial pressure effects
HS has been shown in many studies to decrease cerebral
water content,12,13 and reduce intracranial pressure
(ICP),12,14–18 having at least the same efficacy as manni-
tol.12,14,15 Two of these studies found that whereas
HS decreased ICP, it did not improve cerebral blood
flow.12,17 However, neither did isotonic fluids12,17 nor
mannitol.12 A more recent study in dogs showed that HS
reversed transtentorial herniation with improved cere-
bral blood flow.18 In terms of duration, Qureshi et al.
showed that the effect of rapidly infused 3% HS lasted
120 min which was longer than both isoosmolar doses
of 23.4% HS and mannitol.12
The blood brain barrier (BBB) reflection coefficient
is higher for HS (1.0) than for mannitol (0.9), which
means that more mannitol will cross the intact BBB.
However, the BBB gets disrupted in TBI. This might
in part explain Lescot et al.’s recent finding that the
volume of contused areas actually increases post HS
infusion.13 However, the overall cerebral volume was
reduced as the decrease in non-contused areas was
greater.
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 CJ Banks and JS Furyk
Table 3. Electrolyte changes post HS infusion
Dose given of HS Na (mmol/L) Cl (mmol/L)
20 min 60 min 20 min
40
4 mL/kg 7.5% † ↑ 11 ↑9 ↑ 12
300 mL of 3%41 ↑5 ↑3 ↑6
†Values measured from graphs of mean changes. Cl, chloride; HS, hypertonic saline; K, potassium; Na, sodium.
Immunological/inflammation effects
HS in the animal model decreases haemorrhage-induced
neutrophil activation, protecting against acute lung
injury.19,20 Suggested mechanisms are by decreasing
chemotaxis,21 endothelial adhesion,22,23 vascular perme-
ability,24 exocytosis25 and mesenteric lymph activation
of neutrophils.26,27 Timing of administration might be of
importance with studies showing that early administra-
tion of HS decreases the neutrophil response, but that
later administration actually augments it.21,28 HS has
also been shown to augment T-cell function,29,30 decrease
liver and intestinal apoptosis,31 increase release of
cortisol and adrenocorticotrophic hormone32 and
decrease post-traumatic sepsis.33
There are two recent randomized controlled trials
examining the immune response in hypotensive
trauma patients who received either 7.5% HS/6%
dextran (HS/D) or isotonic crystalloid.34,35 Both trials
reported that HS/D decreased trauma-induced neutro-
phil and monocyte activation for up to 1235 and 24 h,34
respectively.
Side-effects
Overly rapid correction of chronic hyponatraemia with
hypertonic and even isotonic saline can result in osmotic
demyelination syndrome (ODS).36 There is only one
reported case when a HS solution used in trauma resus-
citation or ICP control has resulted in ODS.37 This was
in a trauma patient who received 1250 mL of 7.5%
HS/7.2% hydroxyethyl starch (HES) over 6–7 h. This
was the only occurrence in this study which examined
all adverse reactions to HS/HES over 10 years and at
least 18 000 patients. The same study also found three
cases of anaphylactic/anapyhlactoid reaction to the
HES, none of which was fatal.
A concern with prolonged use of HS is that sodium
levels will eventually equilibrate across the BBB and
that when HS is ceased, serum sodium will drop and
free water will be drawn across the BBB into the brain.
Most studies have not reported this, but a rebound
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K (mmol/L) pH
60 min 20 min 60 min 20 min 60 min
↑ 12 ↓ 0.1 ↑ 0.6 ↓ 0.05 ↓ 0.05
↑4 ↓ 0.3 ↓ 0.1 ↓ 0.016 ↓ 0.007
increase in ICP has been found in one animal study.16
There are two case reports of late malignant cerebral
oedema despite prolonged HS therapy in patients with
intracerebral haemorrhage.38 The authors felt that this
was not consistent with the natural history of the
disease and postulated that it might have been second-
ary to the HS.
A single case of fatal hypernatraemic haemorrhagic
encephalopathy (HHE) was reported in 1979 when a
12-year-old diabetic boy (weight not mentioned) with
diabetic ketoacidosis (DKA) was inadvertently given
500 mL of 5% HS.39 His sodium increased from 135 to
172 mmol/L. No other studies have reported a case
of HHE.
HS administration raises both serum sodium and
chloride which can result in a hyperchloraemic meta-
bolic acidosis. Potassium levels drop initially then rise.
Table 3 shows mean electrolyte changes from two
studies.40,41
HS has been shown to be anticoagulant in vitro when
5–10% of blood has been replaced with 7.5% HS.42–44
This equates to an approximate dose of 3.5–7 mL/kg
of 7.5% HS. In two of these studies,42,43 HS was being
compared with normal saline which itself has been
shown to be procoagulant in small doses.45
In one study, 3–5 mL/kg of 7.5% HS solutions given
to 10 volunteers through a peripheral vein caused
painful irritation in four and subsequent thrombophle-
bitis in two.6 However, in a clinical trial of trauma
patients, none of the 23 patients given a similar dose
developed phlebitis.46
Clinical applications
Hypovolaemic resuscitation
HS was first used for resuscitation in humans in a case
series in 1980 by de Felippe et al.47 They gave repeated
50 mL boluses of 7.5% HS to 12 patients in hypovol-
aemic shock that was refractory to dopamine and fluids.
Shock was reversed in 11 patients.
© 2008 The Authors

In 1991, Chavez-Negrete et al. randomized 49 patients
to receive either 250 mL of HS/D or lactated Ringer’s
solution (LRS) for upper gastrointestinal haemorrhage
and a systolic blood pressure less than 90 mmHg.48
They found improved blood pressure, urine output and
conscious state with the HS/D group that were statisti-
cally significant.
Between 1987 and 1993, 10 randomized controlled
(level II) trials were published comparing the adminis-
tration of 250 mL of 7.5% HS/6% D with isotonic crys-
talloid in hypotensive trauma patients.46,49–57 Three of
the trials55–57 are not examined further as they were
reporting on interim data that were reported in two
larger studies.49,54 In all trials, HS/D was administered
as part of overall resuscitation with further isotonic
fluid or blood given as necessary. One of the studies
was of penetrating trauma only.46 Hypotension was
variably defined as <80 mmHg,53,54 <90 mmHg46,50–52 and
<100 mmHg.49 Most of the studies showed that HS/D
raised blood pressure significantly more than isotonic
crystalloid.49–53 No study found a statistically significant
survival advantage. No significant side-effects were
reported. Three of the studies also compared HS with
HS/D and found no additional effect of dextran.51–53
Subgroup analysis revealed that some patients might
benefit from HS/D. Vassar et al. found that those
patients with a severe head injury who received HS/D
had an improved survival rate (32% vs 16%, P = 0.04).49
Mattox et al. stated that the subgroup of patients with
penetrating trauma requiring surgery who received
HS/D had improved 24 h survival (89% vs 82%,
P = 0.02).50 These are post-hoc conclusions and need
to be interpreted with caution.
Younes et al., in a double-blinded randomized control
trial in 1997, did find a survival benefit with HS/D.58 A
total of 212 patients in the ED received either 250 mL
of 7.5% HS/6% D or normal saline if the treating physi-
cian diagnosed haemorrhagic hypovolaemia, irrespec-
tive of blood pressure. Survival was significantly
improved in the HS/D group at both 24 h (87% vs 72%,
P < 0.01) and 30 days (73% vs 64%, P < 0.03). Further
evaluation showed that HS/D seemed to offer most
benefit to those patients with a MAP < 70 mmHg.
CE Wade was the first author of three separate
manufacture-supported meta-analyses in 1997 of the
above trauma trials.59–61 The first used 100 mmHg as the
cut-off for hypotension.59 The conclusion was that HS
was no different to isotonic crystalloid and that HS/D
was likely to be more effective. The quoted increase in
survival for HS/D was 3.5%, but was not statistically
significant (P = 0.14). The second meta-analysis used
© 2008 The Authors
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Hypertonic saline
90 mmHg as a cut-off and found a benefit in survival
expressed as an odds ratio (OR) of 1.47 (95% CI, 1.04–
2.08) for patients treated with HS/D as compared with
isotonic crystalloid.60 The third meta-analysis examined
patients with TBI which is discussed later with the
other TBI trials.61 In 2003, Wade et al. also published a
re-examination of the data reported by Mattox et al.50
who had already found a survival advantage for the
subgroup of patients with penetrating trauma requiring
surgery.62 They found that patients with penetrating
trauma to the torso requiring surgery and treated with
HS/D had a survival benefit (84.5% vs 67.1%, P = 0.01).
Five other trials of varying design have found that
HS solutions improved haemodynamic parameters,63–66
or decreased overall fluid requirements,67 but they did
not examine mortality.
A Cochrane review in 2004 examined hypertonic
crystalloid in trauma patients and found the pooled
relative risk of death to be 0.84 (95% CI 0.69–1.04).68 The
conclusion was that there was no evidence to suggest
that HS is better than isotonic crystalloid.
The evidence suggests that HS solutions are safe, and
will improve haemodynamics in hypovolaemic resusci-
tation. However, resuscitation end points are currently
being debated with a move towards hypotensive resus-
citation in some circumstances.69,70 The evidence for
increased survival with use of HS solutions is inconclu-
sive. It is possible that certain subgroups might benefit
from HS solutions, but further research is required.
With the current evidence, HS solutions are not
recommended over isotonic solutions for resuscitation
in hypovolaemic patients.
Traumatic brain injury
Reducing ICP
Retrospective studies have demonstrated that HS in
varying concentrations is safe71 and effective in reduc-
ing ICP in both paediatric72 and adult73 settings.
Four non-comparative prospective trials found HS
to be effective as rescue therapy when mannitol has
failed.74–77
Two non-comparative prospective trials studied HS
as an alternative agent to mannitol. Munar et al. used
1.5 mL/kg of 7.2% HS for elevations in ICP above
15 mmHg and achieved a reduction of about 30%
(P < 0.01).78 Huang et al. used 300 mL of 3% HS for rises
in ICP over 20 mmHg and achieved a mean reduction of
6–7 mmHg (P < 0.01).41
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 CJ Banks and JS Furyk
Three small trials have compared HS with isotonic or
hypotonic crystalloid. Fisher et al. produced a double-
blinded cross-over study comparing 3% HS with normal
saline in 18 paediatric patients with TBI.79 A bolus of
10 mL/kg was given for rising ICP or falling CPP. They
showed that HS reduced ICP from 20 to 16 mmHg
(P < 0.01) over a 2 h study period, whereas normal saline
did not. Simma et al. compared 1.6% HS with LRS as the
only crystalloid used in 32 paediatric patients in the first
3 days post TBI.80 They found an inverse correlation
between sodium level and ICP. The HS group required
fewer interventions to maintain a low ICP (P < 0.01) and
had a shorter intensive care stay (8.0 vs 11.6 days,
P = 0.04). Shackford et al. randomized 34 adult patients
with TBI to a hypertonic or a hypotonic group.81
However, no conclusions could be reached as the hyper-
tonic group had more serious head injuries on admission.
Comparison with mannitol
Four trials have compared HS solutions with mannitol in
TBI, including three randomized trials. Ware et al. pub-
lished a retrospective chart review of 13 patients who
had received both 23.4% HS and 20% mannitol.82 They
concluded that HS and mannitol caused an equivalent
decrease in ICP. Vialet et al. randomized 20 adult patients
to receive either 2 mL/kg of 7.5% HS or 2 mL/kg of 20%
mannitol for elevations in ICP over 25 mmHg.83 The HS
group had less elevations per day (6.8 vs 13.3, P = 0.02)
and less overall minutes per day over 25 mmHg (62 vs
95 min, P = 0.04). However, the osmotic load of HS was
higher than for mannitol (2400 vs 1160 mOsm/kg water).
Harutjunyan et al. randomized 32 neurosurgical patients
(10 with TBI) to receive either 7.2% HS/HES or 15%
mannitol for rises in ICP.84 The solutions were given
at a predetermined rate until ICP returned to below
15 mmHg. They found that less HS/HES was required
(1.4 vs 1.8 mL/kg, P < 0.05), although again the osmotic
load was much higher for the HS. Battison et al. in
a prospective cross-over trial compared equimolar
amounts of 7.5% HS/6% D (100 mL) with 20% mannitol
(200 mL).85 There were nine adult patients with TBI
or subarachnoid haemorrhage (SAH). HS/D caused a
greater reduction in ICP (13 vs 7.5 mmHg, P = 0.01) and
for a longer duration (148 vs 95 min, P = 0.04).
In-hospital survival
In terms of mortality, Qureshi et al. performed a retro-
spective chart review of 36 adult patients with isolated
severe TBI, defined as a Glasgow Coma Score (GCS) <9.
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Those admitted before a certain date received normal
saline as maintenance fluid and those after received 2%
or 3% HS/acetate solution.86 Mean duration of infusion
was 72 h. Both groups received boluses of HS when
needed. They found an increase in hospital mortality
for the hypertonic group (OR 3.1, 95% CI 1.1–10.2).
However, the hypertonic group had a higher incidence
of both penetrating trauma (36% vs 17%, P = 0.07) and
a mass lesion on initial computerized tomography (CT)
scan (72% vs 50%, P = 0.07).
TBI with hypotension
Wade et al. produced a meta-analysis selecting all
the TBI patients from six trials which had compared
HS/D with isotonic crystalloid in hypotensive trauma
patients.61 The dose in all trials was 250 mL of HS/D.
A total of 223 patients were identified. They found
that patients treated with HS/D had a trend towards
improved survival to discharge (38% vs 27%, P = 0.08).
In 2004, Cooper et al. published a double-blinded ran-
domized controlled trial that compared pre-hospital
administration of 250 mL of 7.5% HS with LRS for
patients with severe TBI and hypotension.87 This was
defined as a GCS of <9 and a systolic blood pressure of
<100 mmHg. A total of 229 patients were enrolled. The
primary outcome measure was neurological function
at 6 months, measured using the extended Glasgow
Outcome Score (GOSE). The median GOSE at 6 months
(with interquartile range) was 5 (3–6) for the HS group
and 5 (5–6) for the control group (P = 0.45). Survival at 6
months was 55% for the HS group and 47% for the
control group (P = 0.23). There was a trend towards a
lower initial ICP in the HS group (10 vs 15 mmHg,
P = 0.08).
HS has been shown to reliably decrease ICP in
patients with TBI (level II evidence). In comparative
trials with mannitol, it is at least as effective. Systemic
hypotension and raised ICP are both associated with
increased mortality, and current Brain Trauma
Foundation guidelines suggest treating an ICP greater
than 20–25 mmHg and maintaining a CPP of at least
50–70 mmHg.88,89 Osmotherapy is one of many modali-
ties to reduce ICP. Both HS and mannitol will reduce
ICP, yet neither has good evidence showing an outcome
benefit. Both options have potential side-effects. Manni-
tol can cause volume depletion, renal toxicity and
rebound cerebral oedema.90,91 As a grade C recommen-
dation, HS is an alternative to mannitol as osmotherapy
for treating raised ICP in TBI. A suggested dose is
© 2008 The Authors

5 mL/kg of 3% HS given as a bolus or rapid infusion
which can be repeated if necessary.
Burns
In burns resuscitation, HS solutions have been used in an
attempt to minimize overall volume required, in particu-
lar, lactated hypertonic saline (LHS). The earlier studies
and those without controls found that the use of LHS
resulted in less fluid volume being required than pre-
dicted by various formulae,92–94 and that LHS was safe.95
Most comparative trials found that the volume require-
ment for HS solutions was significantly less than for
isotonic fluid,96–105 but three found no such effect.106–108
Other interesting findings were that in the trial by
Murphy et al., the hypertonic group had a significantly
lower troponin level at 24 h despite no difference in
fluid requirements.107 Oda et al. reported a significant
decrease in intra-abdominal pressure and subsequent
abdominal compartment syndrome for those treated
with LHS solution.102 However, there was a degree of
selection bias in that patients transferred from other
centres received isotonic crystalloid whereas the direct
presentations were given LHS.
One study found HS solutions to be harmful. Huang
et al. in a retrospective study found a fourfold increase
in acute renal failure (P < 0.01) and a doubling of mor-
tality (P < 0.01) for 65 patients resuscitated with HS
solutions compared with 109 patients resuscitated with
isotonic crystalloid.103 This is the only trial that found
a mortality difference.
A Cochrane review in 2004 found that for burns,
the relative risk of death with use of HS solutions was
1.49 (95% CI 0.56–3.95), suggesting a trend towards
increased mortality.68
Although it appears that HS solutions might reduce
fluid requirements in burns resuscitation, there is
concern regarding increased mortality. Consequently,
they cannot be recommended.
Cardiac arrest
Bender et al. in 2007 published a randomized control
trial for patients with out-of-hospital cardiac arrest.109
The two groups were randomized to receive either 7.2%
HS/6% HES or 6% HES given at a rate of 2 mL/kg/
10 min. The number of patients enrolled was 66. The
proportion in each group with ventricular fibrillation
was identical. The rates of return of spontaneous circu-
lation were remarkably high for both groups; 66.7% for
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Hypertonic saline
the HS group and 51.5% for the colloid-only group
(P = 0.21).
This is the first human trial in this field and the
results warrant further evaluation, but no recommenda-
tion can be made at this stage.
Sepsis
We identified three prospective trials in which HS solu-
tions have been used in sepsis resuscitation. All used
haemodynamic parameters as end points, not morbidity
nor mortality. Oliveira et al. randomized 29 patients to
receive either 250 mL of 7.5% HS/8% dextran or normal
saline, and showed an increase in cardiac output with a
decrease in systemic vascular resistance for the hyper-
tonic group.110 Hannemann et al. found that 2–4 mL/kg
of 7.5% HS/6% HES given to 21 stabilized patients
improved cardiac output and increased pulmonary
capillary wedge pressure (PCWP).111 Muller et al. gave
250 mL of 7.5% HS to 12 patients in severe sepsis or
septic shock with a transient increase in cardiac index
and PCWP.112
Although HS solutions improve haemodynamics
transiently, there is no recommendation to use HS
solutions for patients with sepsis.
Paediatric DKA
Cerebral oedema-complicating DKA remains incom-
pletely understood and is associated with poor out-
comes. HS has been suggested by some as an alternative
to mannitol. A case report in 2001 describes a 13-year-
old girl that had CT-proven cerebral oedema in the
setting of DKA.113 She had already received 0.7 g/kg of
20% mannitol, but she kept deteriorating. Her GCS was
7 when a rapid infusion of 5 mL/kg of 3% HS was
given, and her GCS returned to 15 within 5 min. A later
case series showed significant improvement in four chil-
dren with altered mental state in DKA, when 10 mL/kg
of 3% HS was given instead of mannitol.114
The administration of 5–10 mL/kg of 3% HS is now
being offered as a treatment option for cerebral oedema-
complicating DKA in some paediatric reviews.115,116
There is only level IV evidence but, given the lack
of effective alternative treatments for cerebral oedema-
complicating DKA, HS is a grade D recommendation as
an alternative to, or in addition to, mannitol.
Non-traumatic cerebral oedema
Yildizdas et al. published a retrospective study of 67
children with various causes of non-traumatic cerebral
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oedema who were treated with mannitol, HS or both.117
The mannitol-only group had a higher mortality than
the other two groups (50% vs 25% and 20%, P < 0.01).
None of these children had ICP monitoring, with clinical
and/or radiological parameters being used.
A number of studies have demonstrated that HS solu-
tions will reduce ICP in patients with severe SAH,118–122
ischaemic cerebrovascular accidents123,124 and acute
liver failure.125 None of these has measured mortality or
morbidity as outcomes.
HS is likely to reduce ICP across a range of heterog-
enous conditions; however, there is insufficient evidence
to make a recommendation.
Hyponatraemia
There are no level II trials examining the use of HS
in hyponatraemia. Ayus et al. used a prolonged infusion
of 3% HS in seven patients with severe neurological
complications from hyponatraemia.126 Worthley and
Thomas controlled hyponatraemic seizures with 50 mL
of 29.2% HS in five patients.127 Ayus et al., in a prospec-
tive study of 33 patients, successfully and safely treated
symptomatic hyponatraemia with a prolonged infusion
(average of 17 h) of 5% HS.128
Looking at the paediatric population, Sarnaik et al.
published a retrospective study in which 25 paediatric
patients with severe hyponatraemia-causing seizures
received a 4–6 mL/kg bolus of 3% HS.129 Seizures were
terminated in all cases and they concluded HS to be both
safe and efficacious. Sharf reviewed 15 infants under 1
year of age who had hyponatraemic seizures.130 HS did
not protect against a need for ventilation but small
doses were used (most <2 mL/kg of 3% HS), and all
infants who required ventilation post HS had also
received a significant dose of benzodiazepines and/or
barbituates.
Recommendations from recent reviews are to raise
serum sodium by 1–2 mmol/L/h while symptomatic
with a maximal rise of 8–10 mmol/L over the first
24 h.131–133 This should avoid the devastating complica-
tion of ODS. 1–2 mL/kg/h of 3% HS has been suggested
to raise the serum sodium by 1–2 mmol/h.131 Some
authors advocate even higher doses in the setting of
seizures or profound obtundation.129,131
There is a growing body of evidence regarding
exercise-associated hyponatraemia (EAH). We identi-
fied four case series from marathons,134–137 and one from
more moderate exercise138 where HS was used for
symptomatic hyponatraemia. It appears that EAH is
not just a dilutional hyponatraemia, but that there is
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inappropriate secretion of antidiuretic hormone.136 This
might explain cases where isotonic saline and even
1.8% HS have initially failed to increase the sodium
level.135 A consensus statement in 2005 suggested that
3% HS be used for symptomatic patients, either as a
100 mL of rapid infusion followed by 100 mL/h, or at a
rate of 1–2 mL/kg/h.139
As a grade D recommendation, supported by level III
and IV evidence, HS might be used to correct severe and
symptomatic hyponatraemia. A recommended dose is
1–2 mL/kg of 3% HS over 1 h with consideration of
higher doses for patients in extremis.
Tricyclic antidepressant toxicity
Deaths from tricyclic antidepressant (TCA) in overdose
usually arise from dysrhythmias and hypotension,140,141
with the accepted treatment including the administra-
tion of sodium bicarbonate.142 One of the mechanisms is
the overcoming of the sodium channel blockade via
increased serum sodium, and it has been proposed that
HS might have the same effect. Animal models of TCA
overdose have shown HS to be effective in restoring
blood pressure and QRS duration,143,144 comparing
favourably with sodium bicarbonate.143
There are four case reports of severe TCA toxicity
successfully treated with HS. McKinney and Rasmus-
sen described the use of HS to reverse cardiovascular
instability in a patient with a nortriptyline overdose that
was refractory to repeated sodium bicarbonate admin-
istration and high-dose inotropes.145 The patient’s pH
was already between 7.5 and 7.55; 200 mL of 7.5% HS
(2.6 mL/kg) was given with immediate improvement in
blood pressure and narrowing of the QRS complex.
Høegholm and Clementsen published a similar case of
ongoing haemodynamic instability from a prothiaden
overdose that was unresponsive to sodium bicarbonate,
dopamine and lignocaine, but was improved with rapid
infusions of 100–170 mmol of HS.146 The pH was not
mentioned, nor was the concentration of HS used
(100 mmol is approximately 194 mL of 3% HS). Seitz
et al. used 30 mL of 10% HS to reverse a wide complex
tachycardia in a patient with an amitriptyline, diben-
zipine and thioridazine overdose.147 Dolara and Franconi
described a case of a 6-year-old boy with an imipramine
overdose whose ventricular tachycardia ceased with a
combination of HS and lignocaine.148 The precise dose of
HS is unclear.
HS is a reasonable option for treatment in TCA
toxicity resistant to bicarbonate therapy as a grade D
recommendation, supported by level IV evidence.
© 2008 The Authors

Conclusions
HS reduces ICP in TBI and is a grade C recommendation
as an alternative to mannitol when osmotherapy is indi-
cated. A dose of 5 mL/kg of 3% HS given as a bolus or
rapid infusion is reasonable, and can be repeated if
necessary.
Cerebral oedema in paediatric DKA can be treated
with HS in addition to, or as an alternative to, mannitol.
Recalcitrant TCA toxicity can also be treated with HS.
Both of these are grade D recommendations. Again,
a dose of 5 mL/kg of 3% HS seems reasonable.
The use of HS is a grade D recommendation for
treating severe and symptomatic hyponatremia at
1–2 mL/kg of 3% HS over 1 h, with consideration of
higher doses for the patient in extremis.
HS solutions are not recommended for hypovolaemic
resuscitation. Further research in the future might
clarify a subgroup of patients who benefit. HS is not
recommended for use in burns, sepsis, cardiac arrest or
non-traumatic cerebral oedema.
Author contributions
Research was conducted by both authors. The manu-
script was largely written by CB with guidance and
editing from JF. Overall, approximate contribution is
50:50.
Competing interests
There are no competing interests.
Accepted 21 January 2008
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