Clinical Review - Hyponatraemia

Contributed by Dr Roderick Warren, specialist registrar, and Dr Mark Strachan, consultant physician, at the Metabolic Unit, Western General Hospital, Edinburgh.

Ankle swelling oedema may be present with hyponatraemia
Ankle swelling oedema may be present with hyponatraemia

Section 1: Epidemiology and aetiology
Hyponatraemia is typically defined as a serum sodium concentration less than 135mmol/L, though local reference ranges may vary.

Hyponatraemia is common, and is seen in around 5 per cent of hospital inpatients1 and 2-3 per cent of biochemistry specimens sent from primary care.2

In our experience in a specialist endocrine unit, it is frequently difficult to make clear diagnoses and management plans, and that challenge is even greater in primary care.

Often, hyponatraemia is a consequence of another illness and resolves with its treatment.

The challenge is to be pragmatic without being complacent, as hyponatraemia can be harmful or fatal if not treated, or caused by a disease which would be harmful or fatal if missed.

Aetiology
Categorising by volume status is helpful in understanding causes and treatment. In practice, cases may be multifactorial. Hyponatraemia may be exacerbated by low solute diets that are often inadvertently administered during illness (tea and toast).

Hypovolaemic hyponatraemia
In hypovolaemic states there is sodium depletion and fluid depletion. Sodium loss is usually the primary problem; inadequate salt intake is really only seen in people with eating disorders, alcoholism or anorexia.

In the majority of cases, sodium is lost from the GI tract (e.g. diarrhoea), or from the kidneys (e.g. diuretics). In this context, urine sodium measurement is helpful: a low concentration strongly suggests a GI problem.

Hypervolaemic hyponatraemia
Hypervolaemic hyponatraemia is paradoxically similar to hypovolaemic states, because intravascular volume is reduced.

In heart failure, inadequate pumping results in venous stasis and leakage from capillaries (oedema). In liver failure and nephrotic syndrome, leakage is due to hypoalbuminaemia.

The intravascular volume depletion induces hormonal changes that retain both water and sodium, but proportionally more water resulting in hyponatraemia.

Euvolaemic hyponatraemia
The main problem in euvolaemic hyponatraemia is impaired excretion of free water. This causes water retention, but other mechanisms are activated to excrete sodium and water.

The most common cause of this is syndrome of inappropriate ADH secretion (SIADH), often due to medication or infection. Free water excretion is also impaired in glucocorticoid deficiency (e.g. pituitary disease).

Erroneous causes

Erroneous or over-diagnosed causes of hyponatraemia:

Pseudohyponatraemia

Rare with modern laboratories, but may still occur when triglyceride or cholesterol levels are very high.

Pseudohyponatraemia due to hyperglycaemia

The hyponatraemia seen with very high glucose levels is genuine, not a laboratory artefact. It improves with correction of hyperglycaemia

Hypothyroidism
Although widely reported as causing hyponatraemia, there is strong evidence that it does not in usual clinical practice.

Section 2: Diagnosis
Although causes are categorised by volume status, volume deficiency or excess may be subtle.

Clinical assessment may be little better than guessing in patients without obvious oedema or dehydration.3

We therefore present a pragmatic approach to the diagnosis of hyponatraemia.

Clinical questions
1. Is there obvious dehydration?

This is associated with hyponatraemia with hypovolaemia. Urea is usually elevated.

2.Is there oedema or ascites?

Hyponatraemia is probably due to fluid overload. A history of heart failure or liver disease is supportive.

Serum albumin is often low.

3. Does the patient have another illness?

Hyponatraemia often accompanies other illnesses, particularly in the elderly.

4. Is there a history of vomiting, diarrhoea, anorexia or bulimia?

Hyponatraemia is probably due to GI losses. Low urine sodium is supportive.

5. Is the patient taking diuretics?

A diagnosis of diuretic-induced hyponatraemia is reasonable, unless hyponatraemia has developed acutely with a stable dose. Review the diagnosis if hyponatraemia persists after cessation or dose reduction.

6. Is the patient taking another culpable drug?

Such drugs include tricyclic antidepressants, SSRIs opioids, antipsychotics, nicotine, NSAIDs and ACE inhibitors.

Review the diagnosis if hyponatraemia persists after cessation.

7. Should lung cancer be suspected?

A chest X-ray is indicated in cases of persistent hyponatraemia, but especially with features such as smoking history, weight loss or haemoptysis. A CT scan may reveal a lung carcinoma.

8. Should adrenal insufficiency be suspected?

Suspect Addison's disease in a child or young adult, particularly with hyperkalaemia, fatigue, weight loss, dizziness, pigmentation or autoimmune disease. Consider adrenal metastasis in advanced cancer. Consider adrenocorticotrophic hormone (ACTH) deficiency in known pituitary disease, or patients previously on long-term steroid therapy.

Investigations
Urine sodium concentration is very useful. In stable hyponatraemia, urinary sodium excretion equals dietary intake, minus losses from the GI tract.

A low spot urine sodium (defined as <20 or <30 mmol/L) indicates low intake or GI loss.

Ideally, the sample should be obtained before treatment, as total body sodium is no longer stable when hyponatraemia is being corrected.

Higher urine sodium concentrations should be regarded as 'non-low', and are compatible with all other causes of hyponatraemia.

Plasma osmolality rarely helps: if sodium is low, osmolality is usually also low.

A normal or high osmolality implies another solute - most commonly glucose or ethanol, but very occasionally, a toxin such as ethylene glycol.

Urine osmolality rarely helps, unless <100mOsm/kg, in which case SIADH can be excluded.

Laboratory and radiological investigations

Routine:

  • Serum U&E, chloride, bicarbonate (or total CO2).
  • Spot urine sodium and osmolality (before any corrective treatment).
  • Plasma osmolality.
  • Glucose, lipids and thyroid function.

Optional or additional:

  • Random or early morning serum cortisol (result above 460 nmol/L excludes adrenal insufficiency, though local guidelines may vary; early morning result below 100 nmol/L is diagnostic).
  • Pituitary function (TFTs, prolactin, FSH/LH, testosterone in men) if pituitary disease is a possibility.
  • Short synacthen test.
  • Chest X-ray (if clinical suspicion of chest sepsis or malignancy).

Section 3: Management
The effects of hyponatraemia depend on severity and rapidity of onset.4

Cerebral oedema may result if severe hyponatraemia develops over less than 48 hours. A sodium level of 130-135 mmol/L is usually asymptomatic.

Non-specific malaise may be seen below 130 mmol/L, confusion or headache below about 120 mmol/L, and depressed consciousness, seizures and death with lower levels. Rapid correction of acute hyponatraemia is safe, and mandatory in severe cases.

Adaptation to chronic hyponatraemia means very few signs may be evident - some patients with sodium <110 mmol/L may be to all appearances well. In chronic hyponatraemia, and in the absence of neurological effects, sodium should not be corrected faster than 8-10 mmol/L per day to minimise the risk of central pontine myelinolysis.

Severe hyponatraemia with neurological complications is a life-threatening condition, for which there is evidence that active treatment with hypertonic saline improves outcome.5

Is admission required?
Neurological signs presenting with new or worse hyponatraemia require hospital referral.

Decisions are primarily based on overall condition. Broadly, we would expect hospital admission for many patients with acute hyponatraemia <130 mmol/L, and virtually all with sodium <125 mmol/L. In chronic cases, a pragmatic interpretation is required.

Consider if there is dehydration or renal impairment. Hypovolaemic states causing renal impairment require hospital admission.

Also consider if adrenal insufficiency is suspected. With features such as hypotension, tachycardia, hyperkalaemia or renal impairment, immediate administration of IM or IV glucocorticoid is required, followed by hospital admission.

In a stable patient, urgent outpatient testing is reasonable. An early morning cortisol may confirm or exclude (see box, section two), but usually referral to endocrine or medical outpatients for a synacthen test is required.

Drug-induced hyponatraemia
If possible, stop culpable drugs.

If drugs causing SIADH cannot be stopped (e.g. due to psychotic illness) strategies such as fluid restriction may be employed.

Hypervolaemic hyponatraemia
In cardiac failure or cirrhosis, stopping diuretics may be impossible. Other treatments for the underlying condition, such as manual drainage of ascites and restriction of fluid and salt intake, may help.

SIADH
Fluid restriction is the first-line treatment for SIADH, but it is not entirely safe, and could be catastrophic if hypovolaemic hyponatraemia is misdiagnosed as SIADH.

Dehydration frequently complicates illness, especially in the elderly.

In hospital, fluid restriction is only instituted after a patient is recovering from acute illness, with frequent reassessment and monitoring of electrolytes.

Therefore, we cannot generally recommend fluid restriction in the community for SIADH associated with acute illness, as it can potentially do more harm than good.

Mild hyponatraemia may be observed with regular review of clinical condition and biochemistry.

Fluid restriction is appropriate in chronic cases, but must be strict to be effective - initially a litre per day, though sometimes less. This runs contrary to folklore that people 'should drink more fluids'.

More importantly, a small decline in renal function may be anticipated and the patient will be thirsty: long-term fluid restriction is hard to enforce.

Demeclocycline is the drug of choice for SIADH. The dose is generally 300-900mg per day.

Side-effects include oral candidiasis, photosensitivity and nephrotoxicity, especially in patients with underlying liver disease.1 Lithium is rarely used due to side-effects.

Newer drugs that block antidiuretic hormone, such as tolvaptan, are efficacious with few or no side-effects.6

Chronic hyponatraemia
In mild and chronic cases, it is less clear that hyponatraemia is harmful. Treatments are poorly tolerated, somewhat toxic or implausibly expensive.

Why then, should a clinician choose one of these treatments with no clear expectation of benefit? The main reason is a general sense that chronic hyponatraemia cannot be good for the patient. In some cases conditions such as epilepsy or cognitive impairment might be improved by correction of hyponatraemia.

However, two reasons to treat 'asymptomatic' hyponatraemia have come to light.

First, evidence shows chronic hyponatraemia is not only associated with falls but causes impairment of gait and cognition.7 Second, there is evidence that hyponatraemia has a causative association with osteoporosis.8

Section 4: Prognosis
The prognosis for patients with hyponatraemia is generally poor - a seven-fold increase in hospital mortality and a two-fold increase in outpatient mortality has been reported.

Hyponatraemia is a poor prognostic indicator in heart failure and cirrhosis.4 These are due to association with frailty, or the severity of the underlying illness.

Acute hyponatraemia
The prognosis for correction of hyponatraemia is good in acute cases, and poor in chronic cases. Acute hyponatraemia resolves with cessation of drugs or treatment of an underlying illness.

Although fluid restriction or demeclocycline may accelerate correction of SIADH in acute illness, most patients are discharged without continuing treatment, indicating that SIADH has resolved.

Chronic hyponatraemia
The long-term efficacy of treatment of chronic hyponatraemia is not well described.

In our experience, patients who develop chronic SIADH tend to have complex medical histories and frequent hospital admissions, and struggle to comply with fluid restriction.

A few stay on long-term demeclocycline, but in most cases it is contraindicated due to impaired renal or hepatic function.

Tolvaptan and related drugs may offer a revolution in treatment, but they will have to fall dramatically in price or demonstrate a specific survival benefit before they can be properly recommended.

Resources

1. Kumar S, Berl T.

Sodium. Lancet 1998; 352: 220-8.

2. Shea AM, Curtis LH, Szczech LA, Schulman KA. Hyponatremia among commercially insured outpatients in the US. BMC Nephrology 2008; 9: 5.

3. Chung HM, Kluge R, Schrier RW, Anderson RJ.

Clinical assessment of extracellular fluid volume in hyponatraemia.

Am J Med 1987; 83: 905-8.

4. Reynolds RM, Seckl JR.

Hyponatraemia for the clinical endocrinologist.

Clin Endocrinol 2005; 63: 366-74.

5. Ayus JC, Arieff AI.

Chronic hyponatremic encephalopathy in postmenopausal women. Association of therapies with morbidity and mortality. JAMA 1999; 281: 2299-304.

6. Schrier RW, Gross P, Gheorghiade M et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist for hyponatremia.

N Engl J Med 2006; 355: 2099-112.

7. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness and attention deficits.

Am J Med 2006; 119: 71.e1-71.e8.

8. Verbalis JG, Barsony J, Sugimura Y et al. Hyponatremia-induced osteoporosis. J Bone Mineral Res 2009 Sep 14 (Epub ahead of print).

FURTHER READING

  • Reynolds RM, Padfield PL, Seckl JR.

Disorders of sodium balance. BMJ 2006; 332: 702-5.

  • Goh KP.

Management of hyponatremia. Am Fam Physician 2004; 69: 2387-94. http://www.aafp.org/afp/2004/0515/p2387.html

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