Original article
Incidence and pathophysiology of severe
1
Department of Academic
Endocrinology, Beaumont
Hospital, Dublin, Ireland;
2
Department of Neurosurgery,
Beaumont Hospital, Dublin,
Ireland; 3 Department of
Chemical Pathology, Beaumont
Hospital, Dublin, Ireland
Correspondence to:
Dr C Thompson, Department of
Academic Endocrinology,
Beaumont Hospital, Dublin 9,
Republic of Ireland;
christhompson@beaumont.ie
Received 2 July 2008
Accepted 5 January 2009
Postgrad Med J 2009;85:171–175. doi:10.1136/pgmj.2008.072819
hyponatraemia in neurosurgical patients
M Sherlock,1 E O’Sullivan,1 A Agha,1 L A Behan,1 D Owens,1 F Finucane,1 D Rawluk,2
W Tormey,3 C J Thompson1
ABSTRACT
Background: Hyponatraemia is a well-recognised com-
plication of neurosurgical conditions, but the incidence
and implications have not been well documented.
Objective: To define the incidence, pathophysiology and
clinical implications of significant hyponatraemia in several
neurosurgical conditions.
Methods: All patients admitted to the Irish National
Neurosciences Centre at Beaumont Hospital, Dublin with
traumatic brain injury, subarachnoid haemorrhage, intra-
cranial neoplasm, pituitary disorders and spinal disorders
who developed significant hyponatraemia (plasma sodium
,130 mmol/l) from January 2002 to September 2003
were identified from computerised laboratory records.
Data were collected by retrospective case note analysis.
Results: Hyponatraemia was more common in patients
with pituitary disorders (5/81, 6.25%; p = 0.004),
traumatic brain injury (44/457, 9.6%; p,0.001), intra-
cranial neoplasm (56/355, 15.8%; p,0.001) and sub-
arachnoid haemorrhage (62/316, 19.6%; p,0.001) than
in those with spinal disorders (4/489, 0.81%). The
pathophysiology of hyponatraemia was: syndrome of
inappropriate antidiuretic hormone secretion (SIADH) in
116 cases (62%) (31 (16.6%) drug-associated), hypo-
volaemic hyponatraemia in 50 cases (26.7%) (which
included patients with insufficient data to assign to the
cerebral salt-wasting group (CSWS)), CSWS in nine cases
(4.8%), intravenous fluids in seven cases (3.7%) and
mixed SIADH/CSWS in five cases (2.7%). Hyponatraemic
patients with cerebral irritation had significantly lower
plasma sodium concentrations (mean (SD) 124.8
(0.34) mmol/l) than asymptomatic patients (126.6
(0.29) mmol/l) (p,0.0001). Hyponatraemic patients had
a significantly longer hospital stay (median 19 days
(interquartile range (IQR) 12–28)) than normonatraemic
patients (median 12 days (IQR 10.5–15)) (p,0.001).
Conclusions: Hyponatraemia is common in intracerebral
disorders and is associated with a longer hospital stay.
Cerebral irritation is associated with more severe
hyponatraemia. SIADH is the most common cause of
hyponatraemia and is often drug-associated.
Hyponatraemia is the most common electrolyte
abnormality encountered in neurosurgical patients1
and has been reported in most neurosurgical
conditions including subarachnoid haemorrhage
(SAH),2 3 intracranial neoplasms,4 pituitary adeno-
mas5 and traumatic brain injury (TBI).6 There are,
however, very few data on the relative incidence of
hyponatraemia in different neurosurgical condi-
tions and the clinical implications of this
electrolyte abnormality. There are also contra-
dictory data on the aetiology of hyponatraemia in
neurosurgical patients, with some groups reporting
that hyponatraemia in neurosurgical patients is
usually due to the syndrome of inappropriate
antidiuretic hormone secretion (SIADH),7 whereas
other groups suggest that cerebral salt-wasting
syndrome (CSWS) is the most common pathophy-
siology.8 The appropriate diagnosis of hyponatrae-
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mia is crucial in determining the correct treatment,
as the managements of SIADH and CSWS are
polar opposites, with the treatment of SIADH
being fluid restriction and that of CSWS being
aggressive intravenous administration of 0.9%
NaCl9 to replace losses. Misdiagnosis leads to
inappropriate treatment and potential worsening
of hyponatraemia, leading to both acute and
chronic neurological sequelae.9
We performed a retrospective case note analysis
of patients attending the Irish National
Neurosciences Centre at Beaumont Hospital,
Dublin, in order to identify the incidence, patho-
physiology and clinical implications of developing
hyponatraemia in a large heterogeneous cohort of
neurosurgical patients.
EXPERIMENTAL
Patients and methods
All admissions to the National Neurosciences
Centre of Ireland at Beaumont Hospital (catch-
ment population of 3 million patients) with TBI,
SAH, intracranial neoplasm, pituitary disorders
and spinal disorders between January 2002 and
September 2003 who developed hyponatraemia
were identified from computerised laboratory
archives. The study was approved by the hospital
research ethics committee. The neurosurgical con-
dition that precipitated hospital admission was
defined by the hospital coding system, according to
ICD-9 diagnostic criteria. Case notes of patients
who developed hyponatraemia during their hospi-
tal admission were perused for the following: age,
sex, admission Glasgow Coma Scale (GCS), mor-
tality, prescribed drugs, symptoms and complica-
tions of hyponatraemia, treatment of underlying
neurosurgical condition, length of hospital stay,
and severity and timing of development of
hyponatraemia after either the initial insult or
surgical intervention. In non-neurosurgical
patients, a plasma sodium concentration (pNa+)
,125 mmol/l would be considered as severe
hyponatraemia. We defined severe hyponatraemia
in our neurosurgical patients as pNa+ ,130 mmol/l.
This is based on data from this unit, which
showed no difference in seizure frequency in two
groups of patients with SAH, one with pNa+
125–130 mmol/l and the other with pNa+
,125 mmol/l.2 Cerebral irritation was considered
171
 Original article
to be present if evidence of seizure or a decrease in GCS/
cognition during the hyponatraemic period was documented.
A diagnosis of SIADH required the patient to be euvolaemic,
with inappropriate urine concentration (urine osmolality
.100 mOsm/kg), low urine volume and natriuresis (urinary
Na+ raised), with exclusion of hypocortisolaemia and hypothyr-
oidism10 (table 1). In contrast, CSWS9 was defined when
hypovolaemic hyponatraemia, with low central venous pres-
sure, occurred concurrently with diuresis (.250 ml urine/h) and
natriuresis (urinary Na+ raised) (table 1). In patients thought to
be hypovolaemic on the basis of hypotension and/or raised
blood urea, if central venous pressure readings were unavailable
or there was no documented diuresis, it was deemed that there
was insufficient evidence to make a firm diagnosis of CSWS,
and the patient was assigned the diagnosis of hypovolaemic
hyponatraemia. Intravenous fluid administration was consid-
ered the underlying cause when there was clinical evidence of
fluid overload or if hypotonic solutes such as dextrose, 0.45%
NaCl or compound sodium lactate had been administered. If the
patient displayed evidence of SIADH followed by CSWS, this
was recorded as mixed SIADH/CSWS.
Assays
Plasma and urine osmolality was measured by the depression of
freezing point method (2400 Osmometer; Fiske, Norwood,
Massachusetts, USA). Plasma and urine sodium were measured
by the indirect ion-specific electrode method (Olympus 2700;
Olympus, Tokyo, Japan; interassay and intrassay coefficients of
variation are ,0.5% and ,0.5%, respectively). Serum urea was
measured by standard laboratory methods (Olympus 2700).
Data analysis
Using the data collected, including symptoms and complica-
tions of hyponatraemia, treatment of underlying neurosurgical
condition, length of hospital stay, severity and timing of
development of hyponatraemia after either the initial insult or
surgical intervention, and time to normalisation of pNa+, we
were able to assess a number of factors. These included data on
the severity of the hyponatraemic nadir, the incidence of
hyponatraemia according to neurosurgical diagnosis, the patho-
physiology of hyponatraemia, and the implications of hypona-
traemia in neurosurgical patients.
Data are presented as mean (SD) or median (interquartile
range (IQR)) unless otherwise stated. All parametric data were
analysed using the Student t test. All non-parametric data were
analysed using the Wilcoxon rank sum test. Correlations
between non-parametric data are reported as Spearman
coefficients. Differences between relative incidences were
assessed using the x2 test. Results were deemed significant at
p,0.05. Analysis was performed using the statistical package
GraphPad Prism.
Table 1 Characteristics of syndrome of inappropriate
antidiuretic hormone secretion (SIADH) compared with
cerebral salt-wasting syndrome (CSWS)
SIADH CSWS
+
Plasma Na Low Low
Blood urea Normal/low Raised
Blood pressure Normal Normal/postural fall
Urine volume Low High
Urinary Na+ Raised Raised
CVP Normal Low
CVP, central venous pressure.
172
RESULTS
In total, there were 1698 patients admitted to the Irish National
Neurosciences Centre at Beaumont Hospital, Dublin with TBI,
SAH, intracranial neoplasm, pituitary disorders or spinal
disorders who developed significant hyponatraemia (pNa+
,130 mmol/l) between January 2002 and September 2003. Of
these, 187 (11%) developed pNa+ ,130 mmol/l during their
hospital stay. In the hyponatraemic group, 52.9% of patients
were male, and 53.2% in the normonatraemic group were male
(p = 0.8). The hyponatraemic group were older (55.6 years (IQR
44–69)) than the normonatraemic group (41.7 years (IQR 35–45))
(p,0.01). Age correlated negatively with length of stay
(r = 20.23, p = 0.002) and positively with time to normalisation
of hyponatraemia (r = 0.22, p = 0.003). There was no correlation
between age and severity of the hyponatraemic nadir (p = 0.49).
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Hyponatraemia developed 6.7 (5.1) days after the initial insult
(eg, haemorrhage or trauma) and 5.8 (4.1) days after the
intervention. The median time to normalisation of pNa+ was
3 days (IQR 1–4).
Severity of the hyponatraemic nadir
A total of 187 (11%) patients developed a pNa+ ,130 mmol/l
during their hospital stay: 126–130 mmol/l in 136 (72.7%);
121–125 mmol/l in 41 (21.9%); (120 mmol/l in 10 (5.4%) (fig 1).
Incidence of hyponatraemia and neurosurgical diagnosis/
intervention
The incidence of hyponatraemia was greater in patients with
SAH (62/316, 19.6%; p,0.001), intracranial tumours (56/355,
15.8%; p,0.001), TBI (44/457, 9.6%; p,0.001) and pituitary
surgery (5/81, 6.2%; p = 0.004) than other neurosurgical
conditions such as spinal surgery/disease (4/489, 0.81%)
(table 2). Other miscellaneous diagnoses (n = 16) included brain
abscesses (n = 5; including one patient with hyperosmolar non-
ketotic comas), epilepsy surgery (n = 6), ventriculoperitoneal
shunt surgery (n = 4), and other central nervous system
infections (n = 1). In the TBI group, 27.3% had no surgical
intervention and 72.7% had a craniotomy, and in the
intracranial tumour group, 14.3% had no treatment, 78.6%
had a craniotomy and 7.1% had pituitary surgery. In the SAH
group, 18% had no intervention, 44.2% had a craniotomy and
aneurysm clipping, 32.8% had coiling and 5% had both clipping
and coiling of intracranial aneurysms.
Figure 1 Severity of the hyponatraemic nadir in the total cohort of 187
neurosurgical patients with hyponatraemia.
Postgrad Med J 2009;85:171–175. doi:10.1136/pgmj.2008.072819

Pathophysiology of hyponatraemia in neurosurgical patients
The pathophysiology of hyponatraemia was SIADH in 116
patients (62%; 31/116 drug-associated; carbamazepine in seven,
desmopressin acetate in 10, selective serotonin-specific reuptake
inhibitors in 14), hypovolaemic hyponatraemia in 50 (26.7%;
10/50 receiving diuretic therapy (loop diuretic in four, thiazide
diuretic in six)), CSWS in nine (4.8%), intravenous fluids in
seven (3.7%) and mixed SIADH/CSW in five (2.7%) (table 3).
Implications of hyponatraemia in neurosurgical patients
Eighty (42.8%) hyponatraemic patients developed symptoms of
cerebral irritation during the hyponatraemic phase.
Hyponatraemic patients with symptoms of cerebral irritation
had lower pNa+ concentrations (124.8 (0.34) mmol/l than
asymptomatic patients (126.6 (0.29) mmol/l) (p,0.001).
Hyponatraemic patients had a longer hospital stay than
normonatraemic patients (median 19 days (IQR 12–28) vs 12
(IQR 10.5–15); p,0.001). There was no correlation between
baseline GCS and severity of hyponatraemic nadir (p = 0.31).
However, there was a negative correlation between baseline
GCS and length of hospital stay (r = 20.26, p = 0.004). There
was no correlation between severity of hyponatraemic nadir
and length of hospital stay (p = 0.5). Mortality was similar in
the hyponatraemic group (12/187, 6.4%) and normonatraemic
group (134/1511, 8.9%) (p = 0.33).
DISCUSSION
We have shown that hyponatraemia is common in neurosurgi-
cal patients with SAH (which we have reported previously),2
intracranial neoplasms, TBI and pituitary disorders. The most
common pathophysiology of hyponatraemia in neurosurgical
patients is SIADH, which is often associated with medication
taken. Hyponatraemia in neurosurgical patients is associated
with a median 7-day prolongation of hospital stay (despite the
median time to normalisation of pNa+ only being 3 days) and
we feel this is due to increased morbidity in these patients.
Hyponatraemia in patients with acute brain injury leads to
cerebral oedema, which increases intracranial pressure, thus
lowering cerebral perfusion. This decrease in cerebral perfusion
increases the vulnerability to cerebral ischaemia.11
Hyponatraemia has also been shown in animal models to affect
the autoregulation of cerebral perfusion, by decreasing cere-
brovascular reactivity.12 Seizure activity is also more likely in
hyponatraemic patients who have intracranial lesions, particu-
larly if there is coincidental hypoxia or acidosis,9 which is a
commonplace in neurosurgical intensive care units.
Most hyponatraemic patients had a nadir pNa+ of 125–
129 mmol/l, and only 5.4% developed pNa+ (120 mmol/l
(fig 1). This may reflect the unit policy, whereby all
neurosurgical patients have daily electrolyte assessments and,
if hyponatraemic, are reviewed daily by the endocrine service,
thus instigating prompt and accurate diagnosis and treatment.
The method of pNa+ analysis is of great importance. Most
laboratory assays use the indirect ion-specific electrode method,
whereas most blood gas analysers in the intensive care setting
use a direct ion-specific electrode method. There are a number of
important differences between these methods of analysis which
clinicians need to be aware of to allow appropriate interpreta-
tion of results. Abnormal plasma protein concentrations lead to
discrepancy between the two methods of analysis, which may
be large enough to affect clinical diagnosis and decision
making.13 Hypoproteinaemia may lead to spuriously high
pNa+ when measured with indirect ion-specific electrodes (the
Postgrad Med J 2009;85:171–175. doi:10.1136/pgmj.2008.072819
Original article
Table 2 Incidence of hyponatraemia in different
neurosurgical conditions
No of patients
No with
Diagnosis Total pNa+,130 mmol/l
SAH 316 62 (19.6)
Intracranial tumour 355 56 (15.8)
TBI 457 44 (9.6)
Pituitary surgery 81 5 (6.2)
Spinal disease 489 4 (0.8)
Values in parentheses are percentages.
SAH, subarachnoid haemorrhage; TBI, traumatic brain injury; pNa+,
plasma sodium concentration.
reverse is true for hyperproteinaemia). Morimatsu et al14
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reported a significant difference in pNa+ measured by these
two methods, with indirect measurements producing a higher
value than the direct method (140.4 (5.6) vs 138.3 (5.9) mmol/l;
p,0.0001). Therefore, particularly when a patient with
abnormal plasma protein concentrations and documented
hyponatraemia is being followed, only one of these methodol-
ogies should be used and not interchanged, as this may lead to
confusion about clinical progress.
Using standard diagnostic criteria,9 10 we found that SIADH
was the most common cause of hyponatraemia. However, it
should be noted that a considerable percentage of patients were
taking drugs such as carbamazepine,15 serotonin-specific reup-
take inhibitors16 and synthetic vasopressin which are known to
cause SIADH (table 3). This contrasts with the results from
other studies, which documented raised plasma concentrations
of atrial and brain natriuretic peptide and negative sodium
balance, leading to the suggestion that CSWS is the most
common cause of hyponatraemia in neurosurgical patients,
particularly after SAH.8 Using strict criteria, we diagnosed
CSWS in only a small proportion of patients in our study;
however, as this was a retrospective case note study, there were
insufficient data on central venous pressure, diuresis and
natriuresis in some patients, and these were classified as
hypovolaemic hyponatraemia. We may have therefore under-
estimated the incidence of CSWS in our cohort. Distinguishing
the underlying aetiology of hyponatraemia in these patients is
clinically extremely important, as the correct diagnosis is crucial
in determining the correct treatment; the management of
SIADH and CSWS are polar opposites, with the treatment of
SIADH being fluid restriction and CSWS aggressive intravenous
administration of 0.9% NaCl.9 Misdiagnosis leads to inappropri-
ate treatment and may lead to worsening of hyponatraemia
with associated acute and chronic neurological sequelae.9
Sherlock et al2 in a retrospective case note analysis of 316
patients after SAH revealed that 179 (56.6%) patients developed
Table 3 Pathophysiology of hyponatraemia in 187
neurosurgical patients with pNa+ ,130 mmol/l
Pathophysiology No of patients
SIADH 116 (62)
Hypovolaemia 50 (26.7)
CSWS 9 (4.8)
IV fluids 7 (3.7)
SIADH/CSWS 5 (2.7)
Values in parentheses are percentages.
CSWS, cerebral salt-wasting syndrome; IV, intravenous; pNa+,
plasma sodium concentration SIADH, syndrome of inappropriate
antidiuretic hormone secretion.
173
 Original article
Main messages
c Hyponatraemia is common in patients with intracranial
neoplasms, traumatic brain injury, subarachnoid haemorrhage
and pituitary disorders.
c The most common pathophysiology of hyponatraemia in
neurosurgical patients is syndrome of inappropriate
antidiuretic hormone secretion (SIADH) (which is often drug-
associated). However, one must be aware of other causes
such as hypovolaemic hyponatraemia (in particular cerebral
salt-wasting syndrome).
c Hyponatraemic patients have a prolonged length of hospital stay.
c Cerebral irritation does not only occur in neurosurgical patients
with plasma sodium ,120 mmol/l.
pNa+ ,135 mmol/l and 62 (19.6%) developed clinically sig-
nificant hyponatraemia (pNa+ ,130 mmol/l) during their
hospital stay.2 Hyponatraemia was more common after
aneurysmal clipping (66%) or coiling (62%) than in patients
who had conservative treatment (36%) or in whom no
aneurysm was identified (38.8%).
In patients with SAH, fluid restriction for SIADH can be
particularly difficult, and many clinicians are reluctant to fluid-
restrict patients after SAH, especially in those with some degree
of vasospasm. A balance must be reached between fluid
resuscitation for vasospasm and excess fluid resuscitation,
which can aggravate hyponatraemia (which has itself been
associated with alterations in intracranial vessel autoregulation)
due to SIADH.12 For the past 30 years, hypertensive, hyper-
volaemic, haemodilutional therapy (HHHT) has been a
generally accepted treatment strategy for SAH to prevent or
treat vasospasm. There are no randomised, controlled prospec-
tive trials showing that HHHT improves the short-term or long-
term neurological outcome or survival after SAH.17 In fact, one
randomised, controlled study reported that prophylactic HHHT
after SAH does not improve cerebral vasospasm, regional blood
flow or Glasgow Outcome Score at 1 year, but cost and
complications were higher than in the no-HHHT group.18
Muench et al19 have recently reported the findings of a study
assessing the effect of the three components of HHHT on
regional blood flow, intracranial pressure and brain tissue
oxygenation in an experimental pig model, followed by a
clinical study of patients with SAH. Interestingly, in the animal
model, neither hypertension nor hypervolaemia had an effect on
intracranial pressure, brain tissue oxygenation or regional
cerebral blood flow.19 In the patients after SAH, induction of
hypertension increased regional cerebral blood flow and brain
tissue oxygenation at all observation time points.19 In contrast,
hypervolaemia/haemodilution induced only a slight increase in
regional cerebral blood flow, while whole tissue oxygenation did
not improve.19 HHHT failed to improve regional blood flow
more than hypertension alone, and it appeared that the
hypervolaemic/haemodilutional component of HHHT may
have reversed the effect of induced hypertension on brain tissue
oxygenation.19 Although more work needs to be performed in
this area, these results are interesting, as many patients who
have SIADH and cerebral vasospasm may not need the
sometimes large volumes of fluids given as part of HHHT, but
rather may benefit both from a cerebral oxygenation and
sodium viewpoint by the use of vasopressor agents.
Most available information on the occurrence of disorders in
water balance after TBI has been derived from retrospective case
174
Current research questions
c Large prospective studies assessing the role of atrial and brain
natriuretic peptides and vasopressin are required to further
investigate the pathophysiology of hyponatraemia in
neurosurgical patients.
note studies.20 21 Agha et al22 have reported that, of 50 patients
prospectively studied after TBI, seven patients (14%) had acute
hyponatraemia, which was attributed to SIADH and this had
resolved in all at 6 months.
There was no increase in mortality in the hyponatraemic group
compared with the normonatraemic group, which would not be
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in keeping with the classic teaching.23 Recent data, however, have
suggested that, in SAH, hypernatraemia is of more prognostic
significance than hyponatraemia.24 In our study, patients who
developed cerebral irritation had a lower mean pNa+ nadir than
the asymptomatic group, and the mean pNa+ in the symptomatic
group was not as low as one might have expected (124.8 mmol/l).
This highlights the importance of early recognition and appro-
priate diagnosis and treatment of hyponatraemia.
Hyponatraemic patients had a longer hospital stay than
normonatraemic patients, with a median difference in length of
stay of 1 week between the groups (despite a median time to
normalisation of pNa+ of only 3 days). We hypothesise that this
prolongation of hospital stay in the hyponatraemic patients is a
marker of morbidity in these patients. The cerebral oedema and
ischaemia that occurs with hyponatraemia can be multifocal
and may lead to neurological dysfunction or seizure, resulting in
prolongation of hospital stay.
In conclusion, hyponatraemia is common in neurosurgical
patients, particularly in patients after SAH, intracranial
neoplasms and TBI. The pathophysiology of hyponatraemia is
most commonly SIADH and is often confounded by prescribed
medication. Hyponatraemia was associated with a significant
increase in length of hospital stay. This study highlights the
importance of close monitoring of pNa+ in all neurosurgical
patients and the prompt and accurate diagnosis and treatment
of hyponatraemia in this group.
Competing interests: None.
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175