New European Guidelines Address

Hyponatremia Management
Laurie Barclay, MD, and Lisa Nainggolan

February 26, 2014

New guidelines on the diagnosis, classification, and treatment of true hypotonic

hyponatremia have been published online in the European Journal of Endocrinology. The
guidelines focus on managing patients, rather than on treating absolute sodium levels, the
authors emphasize.

"Hyponatremia, defined as a serum sodium concentration of less than 135 mmol/L, is the
most common disorder of body fluid and electrolyte balance encountered in clinical
practice," write Goce Spasovski, MD, PhD, from the State University Hospital Skopje,
Macedonia, and colleagues from the Hyponatremia Guideline Development Group.

"It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life-
threatening, and is associated with increased mortality, morbidity, and length of hospital
stay in patients presenting with a range of conditions. Despite this, the management of
patients remains problematic," they stress.

The guidelines recommend that any hospital-based clinician must be able to accurately
diagnose, classify, and treat hyponatremia, which occurs in up to 30% of hospitalized
patients.

The excess of body water compared with sodium and potassium results in cellular edema,
particularly in the brain.

Because of the potential for brain damage, severe cases are medical emergencies. And
complications of milder cases of hyponatremia may include impaired mobility and
cognition, as well as osteoporosis and fracture.

A wide range of conditions can cause hyponatremia — including heart failure, nausea and
vomiting, adrenal failure, and ectopic vasopressin secretion as part of a malignancy —
and, as a result, it is managed by clinicians from a broad spectrum of backgrounds. This
has resulted in a variety of approaches to its diagnosis and treatment, the authors say.

In an attempt to standardize management, the new recommendations have been

developed jointly by the European Society of Intensive Care Medicine (ESICM), the
European Society of Endocrinology (ESE) and the European Renal Association–
European Dialysis and Transplant Association (ERA–EDTA), represented by European
Renal Best Practice (ERBP).
"The scope of clinical situations in which one might encounter hyponatremia was
recognized from the outset," guidelines coauthor Stephen Ball, FRCP, PhD, MBBS, a
consultant endocrinologist at Newcastle Hospitals NHS Trust, United Kingdom, told
Medscape Medical News. "This meant we needed to make sure the guidance was fit for
the purposes of any doctor on a hospital ward or indeed in a community setting,
[maintaining] a style that was user-friendly and gave practical advice throughout."

The guidelines specifically address the management of hyponatremia in adults only. They
do not cover hyponatraemia in children because the guideline group judged that this
represents "a specific area of expertise."

Treat Serious Hyponatremia First; Avoid Overcorrection

Dr. Ball believes the greatest impact on clinical practice will come from new advice to
manage the patient, rather than simply looking at the sodium level.

"Highlighting a situation that requires urgent management independent of the underlying

cause is a key point within the guidance. We think this should allow for more timely
intervention and consequently save lives. Intervention is more important than
investigation until the patient is stabilized," he stressed.

Another author, Bruno Allolio, MD, from the University of Würzburg, Germany, told
Medscape Medical News that the first indication of hyponatremia often will come from a
low serum sodium concentration performed as part of a routine laboratory assessment.
"Mild" hyponatremia is defined as a serum sodium concentration between 130 and 135
mmol/L, "moderate" between 125 and 129 mmol/L, and "profound" hyponatremia as less
than 125 mmol/L.

If hyponatremia is serious and symptomatic, it is "life-threatening" because it can cause

brain edema, Dr. Allolio explained. In this instance, the first line of treatment will be
prompt intravenous infusion of hypertonic saline, with a target increase of 6 mmol/L over
24 hours (and not exceeding 12 mmol/L) and an additional 8 mmol/L during every 24
hours thereafter until the serum sodium concentration reaches 130 mmol/L.

However, one difficulty is that treating serious hyponatremia entails walking a very fine
line, said Dr. Allolio, because overcorrection represents a real danger too.

Overcorrection of hyponatremia can result in osmotic demyelination syndrome (ODS),

which has "disastrous consequences for the brain that may persist for the rest of life," he
cautioned. For this reason, the use of hypertonic saline to correct serious hyponatremia
"must be performed on the ward with very close monitoring," he stressed.

Guidance Stresses Measures of Urine Osmolarity and Urine Sodium

Once a crisis of serious, symptomatic hyponatremia is under control, the next issue is to
investigate the underlying cause of hyponatremia. Also, the recognition, investigation,
and appropriate treatment of patients with less severe hyponatremia is important, given
that this is much more prevalent, the guideline authors say.

"There is a big misconception. People see hyponatremia as a lack of sodium, whereas

instead it is an excess of water," Dr. Allolio observes. "You can have low, normal, or high
sodium for the body, but relative to that there is too much water on board."

To figure out the underlying cause of hyponatremia, doctors must perform 2 simple
measurements that are often overlooked: urine osmolality and urine sodium, the
guidelines state. These can be performed on spot urine samples and do not need to
involve collecting urine for hours, Dr. Allolio pointed out.

"Once you have ruled out very rare things, such as hyperglycemic hyponatremia" —
which can be excluded by measuring the serum glucose concentration and correcting the
measured serum sodium concentration for the serum glucose concentration if the latter is
increased — urine osmolality should be measured, he said.

If urine osmolality is low (<100 mOsm/kg), this is usually caused by the body taking on
too much water (either by overdrinking or low electrolyte infusions).

If urine osmolality is too high, however (defined as being higher than "normal" serum
osmolality, at around 275 mOsm/kg), the cause of hyponatremia is "another reason," such
as too much vasopressin, Dr. Allolio explained.

But equally important in figuring out the underlying cause is a urine sodium check. "I
would say that 90% of people do not measure urine sodium, and if the guidelines help to
establish this, that will be a good thing," he says.

"If you don't measure urine osmolality and urine sodium, the key parameters for
classification are not on board, and you don't know what's going on."

If urine osmolality is higher than 100 mOsm/kg and urine sodium concentration is 30
mmol/L or less, low effective arterial volume may be a cause of the hyponatremia. If
urine sodium concentration is greater than 30 mmol/L, extracellular fluid status and
diuretic use should be assessed.

Dr. Allolio admits that use of diuretics does muddy the waters when trying to ascertain
causes of hyponatremia. "If people are on diuretics, this induces high sodium excretion
whatever their volume status, so it is a bit more complicated."

The new guidelines include an algorithm to help with the diagnosis of hyponatremia.

First-line Treatment Is Water Restriction, Then Urea; No "Vaptans"

Another cause of hyponatremia is the syndrome of inappropriate antidiuretic hormone

secretion (SIADH) — also known as syndrome of inappropriate antidiuresis (SIAD) —
which constitutes about 40% of hyponatremia cases. SIAD is a diagnosis of exclusion
(particularly adrenal insufficiency), and the guidelines do not recommend measuring
vasopressin to confirm the diagnosis, as vasopressin levels are highly variable and confer
little additional information.

For patients with SIAD and moderate or profound hyponatremia, first-line treatment
should be fluid restriction, the guidance indicates. Equal second-line treatments are
increasing solute intake with 0.25–0.50 g/kg per day of urea or a combination of low-
dose loop diuretics and oral sodium chloride.

For those with reduced circulating volume, extracellular volume should be restored with
intravenous infusion of 0.9% saline or a balanced crystalloid solution at 0.5 to 1.0 mL/kg
per hour. In case of hemodynamic instability, the need for rapid fluid resuscitation
outweighs the risk of an overly rapid increase in serum sodium concentration
("overcorrection").

For moderate or profound hyponatremia, the guidelines generally advise against lithium
or demeclocycline. They also do not recommend use of a vasopressin receptor antagonist.

The latter are a new class of drugs, known as the "vaptans," Dr. Allolio said. They include
tolvaptan (Otsuka America Pharmaceuticals), conivaptan (Vaprisol, Astellas), lixivaptan
(Cornerstone Therapeutics), and satavaptan (Sanofi). Some of these are approved for use
in SIAD, while others have hit hurdles. Lixivaptan, for example, was rejected by a US
Food and Drug Administration advisory committee in 2012, and the EU marketing
license for satavaptan was withdrawn in 2008.

The guidelines review all the clinical-trial evidence with the vaptans, he explained,
adding that, in practice, these agents are not widely used. One of the major reasons for
this is the fact that "overcorrection" can occur with their use and has been observed in
clinical trials.

Because this overcorrection can have dire clinical consequences in the form of osmotic
demyelination syndrome, "that makes this drug class difficult to handle," he observes.

In addition, the guideline committee determined that "there are no good outcomes data
[with vaptans], either," he said. "You want to have a benefit beyond just correcting the
sodium, but there are no data on improved survival or improved quality of life."

And while a lack of outcomes data also applies to other treatments for hyponatremia,
with respect to the vaptans, "we have here very potent drugs that can lead to
overcorrection and with no truly important outcome measures."

However, there is a further distinction that can be made when considering the use of these
new agents, he said. "When there is profound hyponatremia, there is a very big risk of
overcorrection, and we would recommend against using vaptans."
But with moderate hyponatremia, "we don't recommend against using them; the use is at
the discretion of the treating physician."

And although the guidelines don't address the issue of cost, these newer drugs are
expensive, and "their price is sometimes unconsciously at the back of decisions made
regarding their use," Dr. Allolio concludes.

The guidelines authors have reported no relevant financial relationships.

Eur J Endocrinol. 2014;170:G1-G47, Abstract

Medscape Medical News © 2014 WebMD, LLC

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Cite this article: New European Guidelines Address Hyponatremia Management.

Medscape. Feb 26, 2014.