Hypertonic Saline For Sever Symptomatic Hyponatraemia - Real-World Findings From The UK

M F Arshad, A Iqbal et al.
Hypertonic saline use in 11:5 e220007

severe hyponatraemia
RESEARCH
Hypertonic saline for severe symptomatic

hyponatraemia: real-world findings from the UK
Muhammad Fahad Arshad , Ahmed Iqbal1,2,*, James Weeks1, Ines Fonseca1, Alia Munir1 and William Bennet1
1,2,*
Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals, Sheffield, UK

1
Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield, UK
2
Correspondence should be addressed to M F Arshad: [email protected]
*(M F Arshad and A Iqbal contributed equally to this work)
Abstract
Objective: To evaluate ‘real-world’ safety and efficacy of the European Society of Key Words
Endocrinology guidelines for the treatment of severe symptomatic hyponatraemia using ff hyponatraemia
hypertonic saline (HTS). ff hypertonic saline
Design: Retrospective, observational, cohort study, examining the use of HTS for severe ff overcorrection
symptomatic hyponatraemia at Sheffield Teaching Hospitals between 2017 and 2020. ff osmotic demyelination
Methods: Patients were identified from pharmacy records and demographic, clinical, and syndrome
treatment data extracted.
Results: Out of 112 patients (females:males = 61:51), the mean age ± s.d. was 66.3±
16.0 years and mean pre-treatment serum sodium ± s.d. was 113.8 ± 6.4 mmol/L.
Overall, overcorrection rates at 24 and 48 h (>10 and >18 mmol/L) were 44.9 and
19.6%, respectively, while 19.6% of patients were treated for overcorrection. Above-
target rise in sodium (>5 mmol/L) after first and second boluses was noted in 22.6 and
34.6% of patients, respectively. In-hospital and 12-month mortality was 7.1 and 18.7%,
respectively, with no cases of osmotic demyelination. The mean venous blood gas (VBG)
sodium was 1.9 mmol/L lower than paired serum sodium (n = 36) (113.6 ± 6.6 vs 115.7 ±
7.8 mmol/L).
Conclusion: We report real-world data demonstrating that a significant number of patients
overcorrected using current guidelines. Also, several patients had above-target rise in
sodium after one bolus of HTS, and sodium measurement should be considered before
the second bolus unless ongoing severe symptoms persist. A point of care VBG sodium
concentration was useful for this purpose. In addition to careful monitoring, a cautious but
Endocrine Connections
anticipatory overcorrection prevention strategy should be considered in the first 24 h. (2022) 11, e220007
Introduction
Hyponatraemia (serum sodium concentration <135 Clinical manifestations of hyponatraemia are on a
mmol/L) is the most frequently encountered electrolyte clinical spectrum, ranging from being asymptomatic to
abnormality in clinical practice, occurring in up to one- seizures (5). Symptoms of hyponatraemia are typically more
third of all hospitalised patients (1). While hyponatraemia is striking when the fall of serum sodium is acute (over hours)
driven by multiple causes, several studies have consistently or is large (5, 6). Awareness of the chronicity of change can
demonstrated an association between hyponatraemia and be essential. Rapid correction of serum sodium is required
adverse patient outcomes irrespective of the aetiology when hyponatraemia causes severe symptoms as the latter
(2, 3, 4). can indicate cerebral oedema. Here, expeditious treatment
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M F Arshad, A Iqbal et al. Hypertonic saline use in 11:5 e220007
is required to prevent progression to cerebral herniation the use of HTS for the treatment of severe symptomatic
and death (7, 8). This has to be balanced against the risk of hyponatraemia. The aim of this study was to evaluate the
overcorrection which increases the possibility of osmotic safety and efficacy of the ESE guidelines in a ‘real-world’
demyelination syndrome (ODS). This highlights the setting.
importance of rapid yet controlled correction of sodium
to mitigate the deleterious effects of overcorrection on the
CNS (1).
Materials and methods
Hypertonic saline (HTS) has been used in marathon
runners who develop acute exercise-associated We conducted a retrospective, observational, cohort study
hyponatraemia (9, 10, 11). It is also an effective treatment for that examined the use of HTS for severe symptomatic
severe symptomatic hyponatraemia of any other aetiology hyponatraemia at Sheffield Teaching Hospitals (Northern
(12). Several clinical treatment guidelines published in the General Hospital & Royal Hallamshire Hospital) United
last few years have aimed to standardise the administration Kingdom between January 2017 and March 2020. The
of HTS in severe symptomatic hyponatraemia (1, 13, 14, study was registered with Sheffield Teaching Hospitals
15). A common aim of these guidelines has been to achieve Clinical Effectiveness Unit (reference number 9757) as a
a quicker (or rapid) initial rise in sodium and the need to service improvement project. Thus, all data collected as
monitor and avoid overcorrection is also emphasised. Most part of this observational study reflect routine clinical care,
recommend the use of small, frequent boluses of HTS to and ethical approval was not required.
achieve the desired quicker rise in sodium as opposed to the Patients who were issued with a prescription for HTS
more steady rise in sodium seen with continuous infusion were identified using centralised pharmacy electronic
of HTS (16). The evidence for a dose-response relationship records (JAC Medicines Management version 2016).
underpinning these guidelines is, however, limited. Inclusion criteria were age of 18 years or more and evidence
Recently, an observational study from Germany compared of at least one bolus of HTS for hyponatraemia. This was
the use of conventional treatment with HTS in severe and confirmed by a review of the electronic and/or paper notes
moderately symptomatic hyponatraemia (n = 62 total; and biochemical results.
n = 36 HTS and n = 26 conventional) (17). They found that Exclusion criteria were administration of HTS for
with 150 mL boluses of 3% HTS, the rate of overcorrection reasons other than hyponatraemia and lack of clear
at 24 h in severely symptomatic hyponatraemia was as documentation to confirm HTS administration. For those
high as 38%. Another single-centre, retrospective study, who met the inclusion criteria, demographic, clinical and
examined the use of 150 mL aliquots of 3% HTS for the laboratory data were extracted from electronic and paper
treatment of acute decompensated heart failure and case notes. This was recorded in a password-protected Excel
measured serum sodium levels as a safety parameter (18). spreadsheet and stored securely on a Trust computer in line
In 40 patients with diuretic-resistant heart failure, 3% HTS with national governance protocols. Data extraction was
use resulted in a median serum sodium rise of 2 mmol/L at performed by one team of investigators using a standard
24 h with no reported adverse neurological outcomes. operating procedure with quality checks to minimise
The European Society of Endocrinology (ESE) missing data and ensure accuracy.
published guidelines for the management of A history of alcohol excess was defined as a
hyponatraemia (2014), and these are now in routine documented diagnosis of active or past alcohol excess.
clinical use (1). For the first-hour management of severe Being underweight was defined as having a BMI of <18.0
symptomatic hyponatraemia, ESE guidelines recommend kg/m2. Sodium levels were considered to be post-HTS only
an intravenous infusion of two boluses of 150 mL 3% HTS if blood was drawn within one hour of the initiation of
with an aim to raise serum sodium concentration by 5 the bolus. Serum sodium concentrations were analysed
mmol/L. These guidelines also recommend checking the using a fully automated system (Cobas® system, Roche
serum sodium in between the first two boluses, however, Diagnostics). The intermediate precision coefficients
not waiting for this result before administering the second of variation (CV) for this system at mean sodium
bolus. As acknowledged by the authors, the evidence base concentrations of 88.7, 120.6, and 175.8 mmol/L were
for these recommendations is limited to case reports and 1.1, 0.7, and 0.6%, respectively. Heparinised venous blood
series, and to small observational studies with fewer than gas (VBG) sodium concentrations were analysed on point
100 participants (1). The ESE guidelines were adopted of care test machines (Siemens RAPIDPoint®500 Blood
at Sheffield Teaching Hospitals in 2017 to harmonise Gas Analyser). The intermediate precision CV at a mean

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sodium concentration of 114 mmol/L was 0.3% and at 153 variables: age, sex, BMI, pre-treatment baseline serum
mmol/L it was 0.6%. sodium, history of alcohol excess, and being underweight.
Overcorrection at 24 and 48 h was defined as a rise in Analyses were conducted in SPSS version 26 and in all
serum sodium levels of >10 and >18 mmol/L respectively, as analyses, a P-value of <0.05 was considered statistically
defined in the ESE guidelines (1). An above-target rise after significant.
first and second HTS boluses was defined as an increase in
serum sodium of >5 mmol/L from baseline. The primary
outcome was to establish the incidence of overcorrection
Results
rates at 24- and 48-h post-HTS. Early time points were
the rate of above-target rise in sodium after the first and The total number of patients identified was 134. Of these,
second HTS boluses. Secondary outcomes were incidence 4 patients had a duplicate entry, 17 patients were identified
of ODS and early (same admission) and late all-cause as having been issued HTS from the pharmacy, however,
mortality at 12 months follow-up. This was performed by this was not administered later on clinical grounds,
a review of death certificates. While more stringent cut- and one patient’s notes could not be located to confirm
offs for overcorrection may be used by clinicians when inclusion/exclusion criteria. Thus, a total of 112 patients
treating those at particularly high risk of ODS for example met the inclusion criteria and were included in the final
in individuals underweight or those consuming excess analysis (Fig. 1).
alcohol, these cut-offs were not analysed in this study. This
was because ESE guidelines do not make a distinction in
Baseline characteristics
overcorrection cut-offs for these groups and our aim was to
evaluate the guidelines in the real world. ODS was defined The mean age was 66.3 ± 16.0 years with a mean BMI of
as new neurological findings on clinical examination 24.8 ± 5.6 kg/m2. Mean sodium at baseline was 113.8 ± 6.4
confirmed by MRI post-HTS in-hospital or within 12 mmol/L and on average, there were 3.7 ± 1.8 serum sodium
months follow-up. We also conducted further analyses to measurements after administration of any number of
determine if there was a relationship between admission HTS boluses in the first 24 h. The most common cause
demographic (age and sex), anthropometric, and clinical of hyponatraemia in our cohort was syndrome of
variables with the risk of sodium overcorrection post-HTS. inappropriate antidiuresis (SIAD), either in combination
The ESE guidelines recommend the use of HTS for with offending drugs (32.1%) or alone (26.8%). Other
both severe symptoms (vomiting, cardiorespiratory commonly reported aetiologies were hypovolemia (20.5%),
distress, seizures, Glasgow coma scale ≤8, and deep drug-induced only (8.9%), and others (1.8%). Histories of
somnolence) and moderately severe symptoms (nausea, alcohol excess or being underweight were noted in 29.5
confusion, and headache). However, as a matter of policy, and 8.0%, respectively. The most common symptom was
our local guidelines recommend HTS only for severely acute confusion (49.1%), while a significant proportion
symptomatic patients as defined in the ESE guidelines as of patients presented with signs of severe hyponatraemia
non-specific symptoms such as nausea, chronic confusion, including seizures or vomiting (24.1% each). The decision
and headache are extremely common and likely to be to administer HTS was solely based on the biochemical
benign when hyponatraemia develops insidiously (19). severity of hyponatraemia in 17.9% of our cohort, not in
Also, our local guidelines recommend using 2.7% saline line with hospital guidelines. In these patients, the mean
infusion bottles (Fresenius Kabi Ltd, Runcorn, UK) as the baseline sodium was comparable to the overall cohort
3% preparation is unavailable locally. However, to keep the (113.3 ± 6.5 mmol/L vs 113.8 ± 6.4 mmol/L), however, in
sodium chloride dose equivalent to the ESE guidelines (77 most of these cases, sodium levels were on a downward
mEq), the infusion volume for each bolus was increased to trajectory despite the initiation of aetiology-specific
170 mL providing 78 mEq sodium chloride. treatment. They did not have severe symptoms per se but
Continuous variables are represented as mean and s.d. their onset was anticipated given the sodium trajectory,
while categorical variables are represented by the number so treatment with HTS was commenced based on clinical
of cases (n) and a percentage (%) of the total. Categorical judgement.
variables were analysed using the chi-squared (χ2) test. Table 1 summarises baseline characteristics for the
Possible predictive variables for sodium overcorrection post study population. The majority of patients had either
first HTS bolus were explored using bivariate regression one (37.5%) or two (38.4%) boluses of HTS, but, 24.1%
analysis incorporating the following at admission received ≥3 boluses. HTS was administered most frequently

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Figure 1
Flow diagram listing the total number of patients
identified from pharmacy records and all
exclusions to arrive at the final number of
patients in the analysis (created with BioRender.
com).
in a general ward (67%), followed by the accident and increase of 5.17 ± 2.25 mmol/L. We further analysed the
emergency department (20.5%), and intensive/high relative contribution of those overshooting the desired
dependency care units (12.5%). Re-lowering treatments for initial 5 mmol/L target after first and second boluses to
sodium overcorrection were used in 19.6% (n = 22) of the those who overcorrected at 24 and 48 h. Our analyses
total cohort (i.v. dextrose = 17, desmopressin = 2, both = 3). showed that overshooting after first and second boluses
These were mostly provided outside of general wards, was associated with overcorrection at 24 hours (P = 0.024
especially desmopressin which was given exclusively and 0.009, respectively), but not at 48 h (P = 0.264 and
in high dependency/intensive care units. Details of 0.066, respectively).
the patients who received dextrose infusion and/or Table 2 compares the characteristics of patients that
desmopressin are summarised in Supplementary Table 1 achieved target at 24 h that is, responders (n = 44) with
(see section on supplementary materials given at the end non-responders (n = 15) and those who overcorrected (n =
of this article). HTS administration, except within high 48). Our analyses were unable to delineate any significant
dependency areas, was only via peripheral intravenous demographic or biochemical characteristics at baseline
cannulae with no reported major extravasation injury. that distinguish non-responders from responders. None
of the non-responders had a reduced consciousness at
baseline compared to 25% of those who did respond to
Sodium overcorrection
HTS (P = 0.028). Numbers in the non-responder sub-group
The number of patients who had overcorrection at 24 and were low (n = 15) limiting statistical power to robustly
48 h was 48/107 (44.9%) and 22/97 (19.6%), respectively explore sub-group differences. On the other hand, patients
with mean increases in sodium of 10.0 ± 5.5 at 24 h and who overcorrected had a significantly shorter hospital
13.4 ± 7.0 mmol/L at 48 h (Fig. 2). Data were available length of stay compared to responders (11.4 days vs 18.4
for 53 patients who had serum sodium checked within days; P = 0.022). We speculate this was on account of a
1 h of starting the first bolus of HTS infusion; of these, more rapid resolution of hyponatraemia facilitating earlier
12 patients (22.6%) had a rise of >5 mmol/L from the discharge in those who overcorrected. Overcorrectors had
pre-treatment baseline. For the second bolus, data were a more severe clinical phenotype on admission with a
available for 26 patients who had serum sodium checked greater proportion presenting with seizures (overcorrector
within 1 h of starting the second bolus of HTS; of these seizures 37.5% vs responder seizures 15.9%; P = 0.020)
nine patients (34.6%) had above-target rise (Fig. 3). despite comparable baseline sodium (mean overcorrector
Likewise, 5/12 patients (41.7%) breached the 5 mmol/L Na+ at baseline 112.3 vs responder Na+ at baseline 113.7;
threshold after the third bolus with a mean sodium P = 0.381). Further, those with overcorrection were more

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Table 1 Baseline clinical characteristics of 112 patients treated for severe symptomatic hyponatraemia using HTS.
Mean age ± s.d. (years) 66.38 ± 16.04 112

Weight ± s.d. (kg) 68.88 ± 16.30 105
Height ± s.d. (m2) 1.67 ± 0.09 102
BMI ± s.d. (kg/m2) 24.80 ± 5.62 102
Sex Females= 61; males =51 112
Mean Na+ at baseline ± s.d. (mmol/L) 113.82 ± 6.41 112
Mean number of Na+ readings in first 24 h after infusion ± s.d. 3.71 ± 1.84 112
Aetiology 112
SIAD 30 (26.8%)
SIAD and drug-induced 36 (32.1%)
Hypovolemia 12 (10.7%)
Hypovolemia and drug-induced 11 (9.8%)
Drug-induced only 10 (8.9%)
Hypervolemia 6 (5.4%)
Others 2 (1.8%)
Unknown 5 (4.5%)
Symptoms
Acute confusion (%) 55 (49.1%) 112
Seizures (%) 27 (24.1%) 112
Reduced consciousness (%) 26 (23.2%) 112
Vomiting (%) 27 (24.1%) 112
Biochemical severity of hyponatraemia only (%) 20 (17.9%) 112
Location
Ward (%) 72 (67%) 112
High dependency or intensive care units (%) 14 (12.5%) 112
A&E (%) 23 (20.5%) 112
Number of boluses
1 (%) 42 (37.5%) 112
2 (%) 43 (38.4%) 112
3 or more (%) 27 (24.1%) 112
History of alcohol excess (%) 33 (29.5%) 112

Underweight (%) 9 (8.0%) 112
Length of stay (days) 15.7 ± 14.7 112
Overcorrection treatment
Use of desmopressin (%) 5 (4.5%) 112
Use of dextrose (%) 20 (17.9%) 112
Investigations
Serum osmolality (%) 110 (98.2%) 112
Urine osmolality and Na (%) 103 (92%) 112
Cortisol (%) 97 (86.6%) 112
TSH (%) 103 (92%) 112
Aetiology-specific treatment (%) 110 (98.2%)
Type of specific treatment
Fluid restriction (%) 75 (67.0%) 112
Intravenous normal saline (%) 38 (33.9%) 112
Hold-offending drugs (%) 57 (50.9%) 112
Tolvaptan (%) 1 (0.9%) 112
Demeclocycline (%) 4 (3.6%) 112
Slow sodium tablets (%) 12 (10.7%) 112
Specialist endocrine opinion (%) 92 (82.1%) 112
Type of hypertonic saline
2.7% (%) 109 (97.3%) 112
1.8% (%) 3 (2.7%) 112
A&E, Accident and Emergency department; BMI, body mass index; SIAD, syndrome of inappropriate antidiuresis; TSH, thyroid-stimulating hormone.

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Figure 2
Serum sodium (Na+) kinetics at 24 (n = 107) and 48 h (n = 97) post-HTS.
Length of bars represents proportion (%) of patients who overcorrected
(dark bars) or those within target correction (light bars) or non-
responders (checkered bars).
likely to need treatment with desmopressin or dextrose and

were more likely to require a specialist endocrine opinion.
Mortality and osmotic demyelination syndrome
In-hospital mortality in this cohort was 7.1% (n = 8).

Causes of death as reported on the death certificates were
as follows: pneumonia/chest infection n = 3, congestive
cardiac failure n = 2, cancer n = 2, and pulmonary
hypertension due to congenital heart disease n = 1. The
patients who died during the same admission were older
than the cohort average (mean age 69.9 years vs 66.3 years)
and had several co-morbidities. Mean baseline serum
sodium in these patients was higher than the cohort
average (116.7 mmol/L vs 113.8 mmol/L) and rates of
overcorrection at 24 h were lower (14.3% vs 44.9% for the
whole cohort). Total mortality (death due to any cause) at
12 months was 18.7% (n = 21). No case of ODS was reported
during the in-hospital stay or at 12 months follow-up.
Admission factors associated with sodium

overshooting post first HTS bolus
As a significant number of patients (22.6%) were noted to

have exceeded the 5 mmol/L target cut-off, an exploratory
bivariate regression analysis including age, sex, BMI, pre-
treatment baseline serum sodium, history of alcohol excess,
and being underweight was performed to potentially
identify those at higher risk of overshooting (Table 3). Figure 3
Serum sodium (Na+) kinetics post first (A), second (B), and third (C)
While younger age appeared to be linked with an above-
boluses of 170 mL 2.7% HTS. The x-axis represents the change in serum
target rise in the univariate analysis, a multivariate analysis sodium from the pre-treatment baseline and the y-axis represents the
was unable to statistically stratify a high-risk group. number of patients.

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Table 2 Characteristics of responders vs overcorrectors and non-responders at 24 h. (responders = achieving sodium rise
between 5 and 10 mmol/L at 24 h, overcorrectors= achieving sodium rise >10 mmol/L at 24 h, and non-responder= achieving
sodium rise <5 mmol/L at 24 h).
Responders Overcorrectors P value Non-responders P value

(n = 44) (A) (n = 48) (B) (A and B) n =15 (C) (A and C)
Mean age ± s.d. (years) 72.23 ± 15.24 60.17 ± 13.47 0.237 70.02 ± 16.64 0.637
Weight ± s.d. (kg) 71.28 ± 15.64 67.23 ± 17.72 0.179 67.34 ± 15.36 0.414
Height ± s.d. (m2) 1.66 ± 0.08 1.68 ± 0.10 0.090 1.66 ± 0.10 0.415
BMI ± s.d. (kg/m2) 26.17 ± 5.62 23.79 ± 5.58 0.741 24.45 ± 6.03 0.336
Sex Females= 26 Females= 24 0.382 Females= 9 0.951
Males= 18 Males= 24 Males= 6
Mean Na+ at baseline ± s.d. (mmol/L) 113.7 ± 5.82 112.31 ± 6.37 0.381 116.27 ± 5.63 0.143
Mean number of Na+ readings in 3.68 ± 1.57 3.94 ± 1.77 0.918 3.53 ± 2.56 0.790
first 24 h after infusion ± s.d.
Aetiology
SIAD 14 (31.8%) 12 (25%) 0.206 4 (26.7%) 0.384
SIAD and drug-induced 16 (36.4%) 13 (27.1%) 7 (46.7%)
Hypovolemia 3 (6.8%) 5 (10.4%) 2 (13.3%)
Hypovolemia and drug-induced 5 (11.4%) 6 (12.5%) 0 (0%)
Drug-induced only 2 (4.5%) 6 (12.5%) 0 (0%)
Hypervolemia 4 (9.1%) 1 (2.1%) 1 (6.7%)
Others 0 (0%) 2 (4.2%) 0 (0%)
Unknown 0 (0%) 3 (6.3%) 1 (6.7%)
Length of stay (days) 18.4 ± 15.4 11.4 ± 9.1 0.022 21.53 ± 19.95 0.527
Symptoms
Acute confusion (%) 22 (50%) 24 (50%) 1.000 6 (40%) 0.203
Seizures (%) 7 (15.9%) 18 (37.5%) 0.020 1 (6.7%) 0.161
Reduced consciousness (%) 11 (25%) 13 (27.1%) 0.820 0 (0%) 0.028
Vomiting (%) 11 (25%) 10 (20.8%) 0.634 5 (33%) 0.168
Biochemical severity of 10 (22.7%) 8 (16.7%) 0.464 2 (13.3%) 0.180
hyponatraemia only (%)
Location
Ward (%) 29 (65.9%) 28 (58.4%) 0.426 14 (93.3%) 0.136
High dependency or intensive 4 (9.1%) 10 (20.8%) 0 (0%)
care units (%)
A&E (%) 11 (25%) 10 (20.8%) 1 (6.7%)
Number of boluses
1 (%) 12 (27.3%) 21 (43.8%) 0.461 5 (33.3%) 0.518
2 (%) 20 (45.5%) 18 (37.5%) 5 (33.3%)
3 or more (%) 12 (31.9%) 9 (18.8%) 5 (33.3%)
History of alcohol excess (%) 10 (22.7%) 18 (37.5%) 0.124 3 (20%) 0.826
Underweight (%) 2 (4.5%) 5 (10.4%) 0.289 2 (13.3%) 0.242
Overcorrection treatment
Use of desmopressin (%) 0 (0%) 5 (10.4%) 0.028 0 (0%) N/A
Use of dextrose (%) 5 (11.4%) 15 (31.3%) 0.021 0 (0%) 0.172
Specialist endocrine opinion (%) 34 (77.3%) 45 (93.8%) 0.023 11 (73.3%) 0.757
Death during same admission 2 (4.5%) 1 (2.1%) 0.507 3 (20%) 0.063
12-month mortality 8 (18.2%) 8 (16.7%) 0.848 3 (20%) 0.876
A&E, accident and emergency department; SIAD, syndrome of inappropriate antidiuresis; TSH, thyroid-stimulating hormone.
Bold indicates statistical significance, P < 0.05.
Comparison of post-HTS laboratory serum sodium to guide further HTS boluses in severe symptomatic
with VBG sodium hyponatraemia. We compared all available (n = 36)
simultaneous VBG and serum sodium data post-HTS
We assessed point of care VBG sodium concentrations bolus. We found that mean sodium in VBG samples was,
vs formal laboratory serum sodium concentrations to on average, 1.9 mmol/L lower than for serum (VBG sodium
determine whether VBG sodium can be reliably used 113.6 ± 6.6 vs serum sodium 115.7 ± 7.8 mmol/L).

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Table 3 Impact of admission variables on overshooting after first HTS bolus (>5 mmol/L) by univariate and multivariate logistic
regression analyses.
Univariate Multivariate
Parameters OR (95% CI) P value OR (95% CI) P value
Age 0.95 (0.90–0.99) 0.02 0.98 (0.91–1.06) 0.68
BMI 0.88 (0.74–1.06) 0.19 0.70 (0.41–1.11) 0.13
Female sex 0.29 (0.07–1.12) 0.07 0.67 (0.12–3.85) 0.66
History of alcohol excess 0.51 (0.13–1.96) 0.33 0.43 (0.07–2.63) 0.36
Underweight 0.87 (0.08–9.20) 0.91 4.03 (0.077–213.84) 0.49
Baseline Na+ 1.06 (0.95–1.18) 0.31 1.20 (1.00–1.44) 0.06
OR, odds radio.
Discussion comparing the use of bolus vs continuous infusion of

HTS were identified. The largest of these, a multi-centre,
In this largest real-world study to date, we aimed to evaluate randomised trial, was an open-label study recently
the safety, response to treatment, and clinical outcomes published from South Korea (n = 178). In this Efficacy and
in 112 patients treated with HTS for severe symptomatic Safety of Rapid Intermittent Correction Compared With
hyponatraemia as recommended by ESE guidelines. We Slow Continuous Correction With Hypertonic Saline in
have shown that the use of these guidelines in a busy Patients With Moderately Severe or Severe Symptomatic
tertiary hospital resulted in significant overcorrection at 24 Hyponatremia (SALSA) trial (20, 21), investigators
and 48 h, despite adequate monitoring. While the majority reported a similar rate of overcorrection in both groups
of patients in this study were administered HTS on a (17.2% rapid intermittent bolus vs 24.2% slow continuous
general ward compared to higher-level care areas, it must infusion). However, in this study, the overcorrection at
be noted that overcorrection rates were not lower among 24 h was defined as a rise in sodium of >12 mmol/L. The
those in intensive/high-dependency care units. The study overcorrection rates in the SALSA trial were lower than our
results demonstrate that the administration of one bolus cohort despite the study regimen being more aggressive
of HTS can raise serum sodium by more than 5 mmol/L than recommended in ESE guidelines for which there are
in more than one in five patients. Thus, in adopting ESE several possible explanations. First, in addition to a more
guidelines, a significant proportion of patients would relaxed cut-off at 24 h, aggressive use of overcorrection
receive a second bolus despite achieving the initially treatments (41% for bolus and 52% for continuous infusion
intended improvement in sodium level. We were not able vs 19.6% in our cohort) and a strict clinical trial protocol-
to identify patient-specific risk factors for overshooting driven approach compared to our real-world data may
after the first bolus of HTS. Our findings support recently explain the difference in overcorrection rates. Secondly,
published observational data from Germany where 150 ml compared to SALSA, our cohort had factors associated
3% HTS boluses were used for the treatment of symptomatic with more overcorrection including lower baseline
hyponatraemia (17). Here, key findings were that patients sodium (mean 113.8 mmol/L vs 118 mmol/L), a higher
treated with even a single bolus of HTS were susceptible burden of severe symptoms (27 patients with seizures vs
to overcorrection, HTS use resulting in overcorrection 2 with seizures), and a higher proportion with a history
rates between 28 and 38% at 24 h. They also report higher of alcohol excess (33 vs 5). The second prospective study
overcorrection in those with severe symptoms, but there (n = 50) evaluated 100 mL 3% HTS bolus administration vs
were no reported cases of ODS. We have extended their continuous HTS infusion in the treatment of symptomatic
findings in a larger cohort (n = 112 in our study vs n = 36), hyponatraemia due to SIAD (16). The reported rates of
demonstrating safety more robustly by means of a longer overcorrection are again lower compared to our study for
follow-up period. Additionally, we detailed causes of similar reasons (overcorrection cut-off >12 mmol/L, more
in-hospital mortality using death certificate data and have overcorrection treatment, higher sodium nadir, and fewer
included practically useful data by comparing VBG sodium patients with alcohol excess) (16). However, in keeping
to serum sodium when using HTS. with our data, there were no reported clinical cases of ODS
There is a dearth of prospective studies evaluating in either of these studies. One explanation for this may be
the safety and efficacy of HTS for the treatment of severe the use of overcorrection treatments (dextrose infusion or
symptomatic hyponatraemia. Only two such studies desmopressin) in overcorrectors who would have otherwise

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developed ODS. However, in the absence of rigorous daily to substantially reduce intracranial pressure and herniation
neurological examinations and formal MRI imaging of risk (19, 22). However, even on state-of-the-art automated
all patients with biochemical evidence of overcorrection biochemistry platforms, as used in our hospitals, serum
post-HTS, some cases where there was subtle neurology or sodium results are not immediately available to determine
subclinical radiographic changes may have been missed in if a 5 mmol/L rise has been achieved after each bolus of
these studies and our cohort (19). HTS. VBG sodium may have utility in this scenario with
Despite adequate monitoring of sodium in our cohort results available within a few minutes at the point of
(on average 3.7 readings in the first 24 h after initiation of clinical care. One caveat to using this method, however,
treatment), there was a high rate of overcorrection at 24 h, is that VBG sodium appears to underestimate true serum
especially in those treated outside high dependency areas. sodium concentration and consequently osmotic ions
This, however, is manageable if a pre-emptive approach to delivered across the blood– brain barrier. In our platforms,
either avoid overcorrection or to re-lowering is used. Our VBG sodium concentration was on average 1.9 mmol/L
data suggest that once serum sodium is increased by the lower than simultaneously-obtained serum sodium. One
recommended 5 mmol/L with boluses, it is challenging study from two European Hospitals compared sodium
to avoid exceeding the 10 mmol/L cut-off for 24 h. This measurements ascertained via indirect (plasma/serum)
is especially the case if overcorrection treatments are not vs direct (whole blood/VBG) methods in 231 participants
employed, or where aetiology-specific treatment has also undergoing HTS infusion (23). In agreement with our
been started as was the case in 98.2% of our cohort. We findings, sodium measured on blood gas platforms, was,
postulate this is due to the attainment of a negative water on average, 1.9 mmol/L lower than serum/plasma. This
balance given that fluid restriction was the single most phenomenon was also evident in other studies comparing
commonly used aetiology-specific treatment, used for arterial blood gas sodium concentrations with serum values
67.0% of our cohort. The ESE 24-h correction target can only (24, 25). One approach when using HTS would be to factor
be realistically achieved if an anticipatory overcorrection in this approximate 2 mmol/L difference between blood
prevention strategy is adopted. Such a strategy must gas vs serum/plasma sodium concentrations. However,
incorporate a careful review of fluid balance including while this difference is within an acceptable range in
urine output, frequent sodium monitoring, and judicious absolute numerical terms, it is clinically significant in the
use of re-lowering treatments. This will minimise the risk context of HTS use (23). It is thus critical to use a consistent
of adverse neurological events from rapid bidirectional approach in obtaining sodium concentrations when using
fluxes in serum sodium. HTS as opposed to switching between serum/plasma and
At variance with ESE guidelines, our data indicate blood gas sodium. A logical approach would be to only use
that an additional strategy that may prevent or slow a quick turnaround test like VBG sodium to avoid under or
down overcorrection, and reduce the need for re-lowering over-estimation, due to differences in modalities used to
therapies would be to assess sodium concentrations quantify sodium (23).
immediately after the first bolus of HTS before proceeding One strength of our study is that it is the largest to
to the second bolus unless the patient has ongoing seizures, comprehensively perform a real-world evaluation of the
coma or cardiorespiratory instability. This refined bolus ESE guidelines and it is the first undertaken in a major UK
strategy is also supported by the aforementioned data from University Hospital Trust. As well as examining outcomes
Germany where ESE guidelines were in use (17). Other over the entire length of hospital stay, we extended
clinical guidelines including the ones published by Verbalis follow-up to 12 months post-discharge to robustly capture
and colleagues from the United States (14) recommend long-term neurological sequelae of sodium overcorrection.
treatment protocols for severe symptomatic hyponatraemia This study has limitations consequent to the retrospective
using HTS. It is challenging, however, to infer conclusions observational design which makes it susceptible to selection
on overcorrection as reported in this study when using bias and confounding. Our findings are, however, important
HTS as recommended by Verbalis et al. given differences for hypothesis generation and confirmation in prospective
in the volume of HTS boluses (100 mL bolus of 3% HTS randomised clinical trials. Also, while our cohort is larger
in American Verbalis et al guidelines vs 150 mL bolus of than all published observational studies (17, 24, 25, 26, 27,
3% HTS in ESE guidelines) (1, 14). Physiologic principles 28, 29) on HTS use informing the ESE guidelines, we are likely
governing the relationship between cerebral volume and to be statistically underpowered in accurately delineating
intracranial pressure dictate that even a modest 5% increase at admission patient characteristics that predict the risk of
in serum sodium concentration provides sufficient osmoles overcorrection post-HTS. Large, prospective, registry studies

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are urgently needed to develop admission risk stratification

Author contribution statement
models based on robust clinical endpoints including M F A, A I, A M, and W M B, co-conceived this study. M F A and A I developed
overcorrection rates and ODS post-HTS. Further, despite a the protocol and study data collection tools with contributions from J W
standardised approach to data extraction and meticulous and I F. Data collection was performed by M F A, A I, and J W. Analysis was
performed by M F A. The first draft of the manuscript was jointly prepared
review of available patient records, there was missing data at by M F A and A I with critical input on multiple versions of the manuscript
the source, specifically serum sodium data collected within from all authors. All authors approved the final submitted version. M F A
the first hour after first and second boluses was available and A I are the guarantors of this work, and as such had full access to all
study data and thus take responsibility for data integrity and accuracy of
in only 53 (47%) and 26 (37%) participants, respectively. data analysis.
Further our findings were limited by whether symptoms
resolved after one bolus of HTS and data on chronicity. In
addition, a paucity of clinical assessment of volume status, Acknowledgements
urine output, and neurological symptoms and status infers a The authors would like to acknowledge Dr Godfrey Gillet, Consultant
in Clinical Chemistry & Inherited Metabolic Disease and Dr Kate Earp,
need for a bespoke educational package covering this acute
Consultant in Chemical Pathology at Sheffield Teaching Hospitals for
emergency. Chronicity of hyponatraemia and urine output technical information provided on sodium analytical platforms.
data in particular would have strengthened our analyses
into identifying predictors of overcorrection post-HTS.
Lastly, several in our cohort were treated solely on the basis
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Received in final form 9 April 2022

Accepted 22 April 2022
Accepted Manuscript published online 22 April 2022

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Hypertonic Saline For Sever Symptomatic Hyponatraemia - Real-World Findings From The UK

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M F Arshad, A Iqbal et al.

Hypertonic saline use in 11:5 e220007

Hypertonic saline for severe symptomatic

Department of Diabetes and Endocrinology, Sheffield Teaching Hospitals, Sheffield, UK

Correspondence should be addressed to M F Arshad: [email protected]

*(M F Arshad and A Iqbal contributed equally to this work)

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Mean age ± s.d. (years) 66.38 ± 16.04 112

History of alcohol excess (%) 33 (29.5%) 112

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likely to need treatment with desmopressin or dextrose and

Mortality and osmotic demyelination syndrome

In-hospital mortality in this cohort was 7.1% (n = 8).

Admission factors associated with sodium

As a significant number of patients (22.6%) were noted to

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Responders Overcorrectors P value Non-responders P value

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OR, odds radio.

Discussion comparing the use of bolus vs continuous infusion of

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are urgently needed to develop admission risk stratification

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Received in final form 9 April 2022

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