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

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