Diagnosis and management of hyponatraemia: AGREEing the guidelines

Hypotonic hyponatraemia (serum sodium concentration 135 mmol/L with low osmolality)
is the most common electrolyte abnormality in hospitalised adult patients 1]. The diagnosis and management of hyponatraemia may be complex, costly, and controversial.
Hyponatraemia has diverse aetiologies and is additionally defined clinically by its
duration, “acute” (48 hours) versus “chronic” (48 hours), and by the presence or
absence of symptoms. Management can be challenging particularly in the emergency setting
where different treatment options may help or indeed harm individual patients. It
is perhaps surprising that management of this electrolyte disorder has a limited evidence
base in part due to the paucity of high quality randomised controlled trials. Multiple
clinical practice and consensus guidelines for the diagnosis and management of hyponatraemia
have been published by local, national, and international organisations. These guidelines
represent genuine efforts to address the diagnostic challenges and controversies in
its management, particularly in relation to the rate of correction for the serum sodium
concentration. The systematic review by Nagler et al. 2], reviewing the quality of recent published guidelines and consensus statements for
diagnosis and treatment of hyponatraemia, has highlighted important variations in
both their development and recommendations.

Guidelines of hyponatraemia treatment

Hypotonic hyponatraemia is a clinical state where there is a relative excess of water
to sodium content in the extracellular fluid 3]. Acute hyponatraemia is clinically important as it can cause significant morbidity
and mortality associated with rapid development of symptomatic cerebral oedema. Prompt
treatment to raise the serum sodium concentration in this setting is life-saving.
Chronic hyponatraemia, even if asymptomatic, is associated with many adverse outcomes
including prolonged hospitalisation, gait instability, falls, fractures, and increased
bone loss 4],5]. Diverse strategies to correct chronic hyponatraemia have been recommended and success
of such treatment is dependent on the underlying aetiology for hyponatraemia. Overly
rapid correction of chronic hyponatraemia may trigger an osmotic demyelination syndrome
resulting in serious neurological deficits and death 6].

The methodological quality of guideline development and consensus statements can be
assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II)
process 7]. This tool is used to systematically evaluate six guideline domains including scope,
stakeholder involvement, editorial independence, rigour of development, clarity, and
applicability. Nagler et al. identified five clinical practice guidelines and five
consensus statements after a comprehensive search of English and non-English publications,
guideline databases, and professional society websites 2]. Their recommendations differed with respect to classification of hyponatraemia,
diagnostic tests, doses of saline to use for correction, limits for the rise in serum
sodium concentration, and the most appropriate second line therapies for management.
The overall quality of these publications (measured by the AGREE tool) was mixed.

Should we be surprised that individual hyponatraemia guidelines “failed” this test
of quality? Arguably, the diagnosis and management of hyponatraemia cannot be subjected
to this sort of rigorous analysis because of the low level of evidence available to
help various expert panels and guideline groups write internationally consistent advice.
For example, hyponatraemia occurring within 48 hours is an arbitrary cut-off for determining
the presence of acute hyponatraemia, the desired rate of correction for hyponatraemia
in most settings is not universally agreed, availability of certain recommended therapies
is country dependent and impacted by differing regulatory indications for drugs, and
even the biochemical threshold for defining hyponatraemia varies widely in the literature.
Furthermore, many of the clinical algorithms require initial assessment of the extracellular
fluid volume to determine if a hyponatraemic patient is hypovolaemic, euvolaemic,
or hypervolaemic. In practice, this physical examination of fluid balance can be subject
to misinterpretation if the clinical signs are subtle.

The applicability of guidelines remains a major issue. The target audience are the
clinicians who may infrequently encounter an ill patient with either acute symptomatic
hyponatraemia requiring urgent correction or a patient with profound chronic hyponatraemia
and additional risk factors (malnourished, hypokalaemia, history of alcoholism) for
the osmotic demyelination syndrome. It is improbable that clinicians would always
be able to quickly access or indeed assimilate the comprehensive advice in scholarly
recent publications on diagnosis and treatment of hyponatraemia. For instance, Spasovski
et al. (European Guideline Development Group) produced a 39 page clinical practice
guideline 8] and Verbalis et al. (Expert Panel Recommendations) published an extensive narrative
review running to 42 pages 9]. These guidelines are freely available but have several important differences, particularly
in relation to the drug treatment of chronic hyponatraemia, which may lead to some
confusion for clinicians. If appropriate, fluid restriction is used in the management
of chronic hyponatraemia but this is frequently of limited efficacy. Additional pharmacological
agents have been used, including demeclocycline, lithium, urea, loop diuretics, and
vaptan drugs (conivaptan and tolvaptan) 8],9]. Tolvaptan has been used more extensively in the USA for the treatment of hypervolaemic
and euvolaemic hyponatraemia compared to Europe, where tolvaptan’s licence is restricted
to hyponatraemia caused by the syndrome of inappropriate anti-diuretic hormone 10]. The European clinical practice guideline has been widely endorsed by European specialist
societies for nephrologists, endocrinologists, and intensive care medicine clinicians.

In the “real world”, the non-expert doctor who initially recognises and responds to
severe hyponatraemia (serum sodium concentration 120 mmol/L) in a critically ill
patient will often be a junior trainee working “out of routine office hours”. In this
emergency setting, the doctor may have limited immediate access to important additional
diagnostic tests, e.g., serum and urine osmolality and urine electrolytes. Urgent
treatment decisions may need to be taken to manage symptoms such as confusion and
seizures, with incomplete patient history and diagnostic information. There is a general
consensus that hypertonic saline is effective in the immediate management of acute
symptomatic hyponatraemia but available guidelines differ on the volumes and rates
of saline infusion. Ultimately, it is clinical judgement rather than adherence to
a particular guideline that will determine an individual patient’s treatment. Intuitive
clinical algorithms, with proven efficacy, would help to encourage “best practice”
in the diagnosis and management of hyponatraemia.