BMH Medical Journal

BMH Med. J. 2020; 7(Suppl): Early Online. Geriatrics & Gerontology Initiative: International Workshop on Care of the Elderly

Hyponatremia is a common and serious electrolyte abnormality particularly in the elderly. It is often overlooked and is associated with a wide range of deleterious manifestations affecting different systems and is encountered in hospitalised and out-patients. Since the level of sodium is the determinant of the osmolality of the ECF, changes in the level affect the internal milieu. It is the most common electrolyte disorder encountered in clinical practice affecting 15-30% of hospitalised patients at some time during hospital stay although, many may be asymptomatic. In institutionalised geriatric patients, the incidence may be as high as 50%. It is important to look for the same since it is an independent risk factor for morbidity and mortality. Pre-operative chronic asymptomatic hyponatremia is associated with increased perioperative complication rate and higher 30 day morbidity and mortality. The risk of death in a patient admitted to ICU with hyponatremia is at least 2 times higher than those admitted with normal levels of sodium. Increased mortality has been documented in patients with heart failure and cirrhosis when associated with hyponatremia. Abnormalities in gait and instability in walking observed in some elderly hyponatremic patients have been corrected following correction of hyponatremia. The gait instability translates into increased incidence of falls and fractures. The observation that elderly patients with fracture of pelvis and femur have intractable hyponatremia really raises questions on which occurred first? - hyponatremia or the fracture. The elderly have higher incidence of diabetes, hypertension and other co-morbidities which predispose to hyponatremia. They also have higher chances of hypopituitarism and secondary hypo-adrenalism. Elderly patients with cerebrovascular accidents develop ‘cerebral salt wasting’ characterised by loss of excessive sodium in urine resulting in hyponatremia.

Abnormaliies of sodium, both hypo and hypernatremia are actually disorders of water homeostasis. The sodium level in plasma is maintained at 140 +/- 5 mmol/L. Hyponatremia is defined as sodium < 135 mmol/L and is labelled severe if sodium is < 125 mmol/L. Before confirming the diagnosis on the basis of laboratory report, it is necessary to determine whether it is ‘True’ hyponatremia. The calculation/ measurement of osmolality help in this distinction.

Understanding osmolality

Osmolality is the number of osmotically active solutes in a solution. 1 gm molecular weight of a substance in 1 Litre of water = 1 Osm or 1000 mOsm. In the case of sodium, 1 mmol is equal to 1 mEq sodium and contributes to 1 mOsm. Sodium in plasma is in combination with an anion like chloride or bicarbonate. Therefore, every mmol of sodium contributes to osmolality of 2 mmol/L [1 each for sodium and accompanying anion]. So, 140 mmol/L sodium in plasma contributes to 280 mOsm/L. The other important osmotically active solutes in normal conditions are urea (molecular weight 60 - So, 60 gram urea in 1 Litre is 1 Mole and 30 mg% = 5 mmol/L) and glucose (molecular weight 180 – So, 180 gram glucose in 1 L is 1 mole and 90 mg% = 5 mmol/L).

If blood urea and blood sugars are expressed as mmol units:

Osmolality = (Serum Sodium x 2) + Urea mmol + Blood Glucose mmol

If the above results are in mg%, the following formula may be used:

Osmolality = (Serum Sodium x 2) + (BUN mg% ÷ 2.8) + (Blood Glucose mg% ÷ 18)

Osmolality can also be measured using an osmometer which determines the freezing point of a solution and derives the actual osmolality from the degree of depression of freezing point. The difference between the measured and calculated osmolality represents abnormal osmotically active substances in the blood like alcohol, ethyelene glycol etc and is a useful test to detect such poisonings.

Hyponatremia

Hyponatremia may be associated with high, normal or low osmolality of serum and termed hypo-osmolar, iso-osmolar or hyper-osmolar hyponatremia. Level of sodium in the ECF is the main determinant of the osmolality. In the serum, osmolality is maintained in the range of 287-295 mOsm/Kg. In true hyponatremia, the osmolality is low. In pseudohyponatremia, osmolality is normal. It is often normal or high in translocational hyponatremia.

Pseudohyponatremia is a condition where the plasma sodium measured by ‘flame photometry’ is low. Normally, plasma contains 93 % water and 7% solutes (mainly lipids and proteins). In situations of hyperlipidemia and abnormally increased protein level, the liquid portion of the plasma is lesser and the flame photmeteric test measures only the sodium in the reduced quantity of the available plasma. This gives rise to falsely low sodium level. Thus, if the results are obtained by flame photometry, pseudo-hyponatremia due to hyperlipidemia or abnormally high serum protein level should be ruled out before confirming the diagnosis as hyponatremia. This error can be overcome by using ion selective electrodes (ISE) which measures only the sodium in the liquid phase of the plasma and the report will be indicated this by the abbreviation ‘ISE’. If the laboratory has reported sodium as – 128 mmol/L (ISE), pseudohyponatremia can be ruled out.

Translocational hyponatremia is a condition associated with severe hyperglycemia. When the blood sugar levels increase in a diabetic, the glucose does not move into the intracellular compartment due to lack of insulin effect. The high blood sugar causes increase in ECF osmolality leading to osmotic difference between ECF and ICF. The water from intracellular compartment moves out and the dilution in ECF causes low sodium. Between 100 and 400 mg blood sugar range, the sodium decreases by 1.6 mmol/L for every 100 mg% increase in sugar level. Beyond 400 mg, the fall in sodium is 2.4 mmol/L for every 100 mg rise. Therefore, if a patient has blood sugar value of 700 mg% and the serum sodium is 130 mmol/L, it is likely to be translocational hyponatremia. In such cases, sodium level should be rechecked after blood sugar levels are controlled.

True hyponatremia is hypoosmolar and is further classified based on the volume status of the patient as hypovolemic, hypervolemic and isovolemic. The causes of different types of true hyponatremia are given below:

Hypovolemic

• Gastrointestinal loss (diarrhoea/vomiting)
• Sequestration of fluid into ‘third space (peritoneal cavity – {peritonitis, pancreatitis}/bowel lumen – {paralytic ileus})
• Diuresis – Thiazides {most common cause in the elderly}, Other diuretics/Mannitol {osmotic diuretic}
• Renal loss – post obstructive diuresis/diuretics/ early stages of chronic kidney disease
• Cutaneous loss (Excessive sweating/burns)
• Mineralocorticoid deficiency (hypoaldosteronism - {Hypovolemia, hyperkalemia and hyponatremia})
• Salt losing nephropathy (Chronic interstitial disease)
• Cerebral salt wasting (Sub-arachnoid haemorrhage – ?Brain natriuretic peptide)

Hypervolemic

• Congestive cardiac failure
• Cirrhosis liver
• Nephrotic syndrome
• Stage 4/5 chronic kidney disease

Euvolemic

• Syndrome of inappropriate antidiuresis (SIAD) {earlier known as SIADH – syndrome of inappropriate antidiuretic hormone secretion}
• Glucocorticoid deficiency {primary or secondary adrenal insufficiency}
• Hypothyroidism
• Drugs: (Thiazides/cyclophosphamide/vincristine/Antidepressants {SSRIs - Citalopram, Escitalopram, Fluoxetine, Sertraline})
• Cerebral salt wasting.
• Post-operative (use of mainly glucose based IV fluid replacement + stress induced vasopressin release)

Clinical manifestations

Clinical manifestations are extremely variable and depend on the onset (acute < 48 hours or chronic > 48 hours), severity and whether symptomatic or asymptomatic. Chronic and mild degrees of hyponatremia are often asymptomatic. Symptoms occur in younger individuals only when the sodium level is less than125 mmol/L whereas, older individuals may develop symptoms, with sodium levels of 135 mmol/L.

Most symptoms of acute hyponatremia are related to cell swelling. Cell swelling occurs because, the osmotic gradient between low extracellular and relatively normal intracellular osmotic forces cause movement of water from ECF to ICF. The manifestations are mainly neurological because, the brain tissue has no space to swell within the skull and may even develop tentorial herniation. The early symptoms of cerebral odema may be head ache, yawning, lethargy, nausea, unsteady gait, irrelevant talk, psychosis, coma or in severe cases even convulsions. If tentorial herniation occurs, respiratory paralysis and even death may occur. Therefore, severe symptomatic hyponatremia is a medical emergency and is associated with high mortality. The brain readjusts itself to the low ECF osmolality in about 48 hours by eliminating osmotically active intracellular electrolytes (osmolytes) through the CSF thereby establishing a new osmotic equilibrium. This is the stage of chronic hyponatremia (Figure 1 a,b,c,d)

Figure 1a: Normal – ECF and ICF osmolality are normal and there is osmotic equilibrium.

Figure 1b: Brain swelling in acute hyponatremia due to low ECF osmolality and shift of water into the cell (cell swelling)

Figure 1c: Removal of osmotically active intracellular electrolytes (osmolytes) - Brain swelling subsides - New osmotic equilibrium in chronic hyponatremia.

Figure 1d: Rapid correction of chronic hyponatremia – New osmotic equilibrium disturbed leading to cell shrinkage and osmotic demyelination

In the stage of chronic hyponatremia, since the cell swelling subsides, the neurologic symptoms improve although other manifestations may persist. It is important to realise that in this stage of chronic hyponatremia, the ICF compartment has adapted itself to a new osmotic equilibrium with lower level of osmolality, rapid correction of ECF osmolality will be associated with disturbances of osmotic forces in such a way that water moves out of the ICF causing cell dehydration. When neuronal cells undergo such shrinkage, demylination occurs and the patient may develop ‘osmotic demyelination’ often in the Pons (central pontine myelinolysis) (Figure 2) or extrapontine regions.

Figure 2: MRI of brain in osmotic demyelination. {Note the lesion in the central part of pons (arrow)}

Clinical suspicion of hyponatremia

Hyponatremia can be suspected clinically from the history and circumstances under which the patient presents to the hospital. The following are some of the predisposing factors for the development of hyponatremia and its complications:

1. Elderly patients
2. Hypothyroidism
3. Hypopituitarism
4. Heart failure
5. Malignancy
6. Liver disease
7. Alcoholism
8. Malnutrition
9. Hypokalemia
10. Adrenal insufficiency
11. Low body mass index
12. Female gender
13. Low baseline sodium
14. Concomitant use of:

a. Antidepressants [benzodiazepines, serotonin reuptake inhibitors [SSRIs], Mirtazapine, Tricyclic antidepressants]
b. Antipsychotic drugs [phenothiazines, butyrophenones]
c. Diuretics,
d. NSAIDs,
e. Proton-pump inhibitors,
f. Angiotensin-converting enzyme inhibitors

In the case of loss from intravascular compartment, manifestations depend on the degree of loss of blood volume. Up to 15% blood volume reduction is usually tolerated by normal healthy adults. Older individuals and those on treatment or on multiple drugs like NSAIDs will not tolerate even smaller degrees of volume loss. When the loss is 15-30%, tachycardia, tachypnoea and reduction in urine flow rate occurs. If the loss is between 30-40%, persistant hypotension tachypnoea, confusion and drowsiness, may occur and if >40% fluid loss occurs the patient will be in shock with anuria and mental changes. At this stage, even fluid replacement may be futile. Interstitial fluid depletion is usually associated with some degree of intravascular loss as well. When interstitial fluid depletion is present, in addition to the above features, dryness of tongue and mucous membrane, decreased skin turgor and sunken eyeballs may be present. In more severe cases, sweating, cold clammy skin, reduced eyeball tension and persistent hypotension or shock may supervene. Intracellular dehydration occurs in combination with the others. The cardinal symptom of intracellular dehydration is thirst which is due to increase in extracellular osmolality. The manifestations are mainly neurological with altered sensorium, convulsions and even coma.

SIAD or SIADH is the leading cause of severe hyponatremia (serum sodium ≤125 mmol/L) in elderly hospitalized patients.

Diagnosis, evaluation and management

Before embarking on treatment, the following questions should be addressed:

1. Is the report from a reliable source?

2. Whether ‘pseudo-hyponatremia’ and ‘translocational hyponatremia’, have been excluded?

3. Does the patient have any predisposing factor for development of hyponatremia?

4. If it is true hyponatremia, whether it is associated with symptoms and signs of hypovolemia, hypervolemia or isovolemia?

5. Is the patient symptomatic?
6. Is it ‘acute’ (< 48 hours) or ‘chronic’ (> 48 hours)?
7. Will correction lead to worsening rather than improvement?
8. Who are predisposed to complications of rapid correction of chronic hyponatremia

a. Malnourished patients
b. Alcoholics
c. Elderly women on thiazide diuretics
d. Patients on treatment for burns
e. Hypokalemia

The first step is to prevent development of hyponatremia. The important steps are to identify individuals at risk of hyponatremia (see list of predisposing factors above). The next step is to avoid polypharmacy and if necessary use the lowest dose of the suspected drugs or consider alternative drugs. Inadvertent re-administration of the same drug should be avoided.

The rate of correction of hyponatremia is critical. If the patient has severe, acute, symptomatic hyponatremia with convulsions, sodium correction can be upto 2 mmol/L/hour for the first two hours. The rapid correction should not be continued beyond 2 hours and should be changed to gradual correction if convulsions resolve earlier. However, the total correction should not exceed 6-8 mmol/L in 24 hour. Even in symptomatic, acute hyponatremia, the correction should not exceed 6- 8 mmol/L/24 hours. Auto-correction of hyponatremia by body’s homeostatic mechanisms may lead to overcorrection. Therefore, the rate of correction should be closely monitored by periodic serum sodium estimations. Typically, the plan for correction of hyponatremia from 118 mmol/L to 140 mmol/L should be over 4 days (approximately at the rate of 6-8 mmol/L/day).

Note: Here, the rate of correction is important. It must be remembered that hyponatremia auto-corrects in the course of treatment which may be associated with more correction than expected over 24 hour period or even overcorrection. Hence, close monitoring of blood level is necessary.

In hypovolemic hyponatremia, the main treatment is replacement of fluid and sodium deficit by administering salted liquids or oral rehydration solutions (ORS) by mouth or feeding tube. If patient cannot be given adequate quantity of oral fluids, intravenous normal saline infusions may be used and the volume is determined by the clinical status and degree of dehydration. Only in severe hyponatremia with neurologic symptoms, 3% sodium chloride infusions are given with close monitoring plasma sodium levels. Once the deficit is corrected, maintenance can be with 0.45% (’half’) normal saline and glucose.

In hypervolemic hyponatremia, the main treatment modalities are water restriction, treatment of underlying cause [cardiac failure/cirrhosis liver/Nephrotic syndrome] and judicious use of diuretics and/or Vaptans. Among the diuretics, loop diuretics like frusemide should be preferred over thiazides since thiazides cause diuresis with relatively more sodium loss (saliuretic) whereas frusemide causes more water loss (aquaretic). Vaptans are purely aquaretics and they act by blocking vasopressin which is responsible for reabsorption of water in the distal parts of the nephron.

The classical example of euvolemic/isovolemic hyponatremia is syndrome of inappropriate antidiureis (SIAD) or syndrome of inappropriate antidiuretic hormone (SIADH) release. It is a common cause of hyponatremia in the elderly and other hospitalised patients.

In SIAD, there is inappropriate release of ADH or ADH like peptides leading to excessive fluid absorption, increase in urine osmolality in relation to plasma osmolality. Thus, the essential criteria for diagnosis of SIAD are:

1. Patient clinically euvolemic. No clinical evidence of hypovolemia (hypotension/tachycardia/dry mucous membranes 0 or hypervolemia (odema/effusion)
2. Low plasma osmolality (< 275 mOsm/Kg)
3. Inappropriately high urine osmolality (>100 mOsm/Kg water)
4. Elevated urine sodium excretion (>20 – 30 mmo/L) while on normal salt and fluid intake
5. Normal thyroid and adrenal functions
6. Normal renal function and no diuretic use

The management principles include, discontinuation of the offending drug and restriction of free water intake. Attempts should be made to eliminate free water through urine. Since frusemide increases excretion of free water, it is used together with restriction of free water intake. The salt replacement varies depending on the urinary salt loss which is to be monitored. Vaptans are drugs which antagonise the antidiuretic action of vasopressin and promote free water loss. Tolvapten available as 30 mg tablet can be used judiciously in chronic, symptomatic, euvolemic, hyponatremic hospitalised patients with SIAD and some cases of hypervolemic hyponatremia. It is avoided in patients with hepatic insufficiency.

NOTE: Antidiuretic hormone (ADH) or vasopressin is a peptide hormone secreted by the posterior pituitary. This hormone is involved in osmoregulation and is stimulated when the plasma osmolality increases (example when the individual is dehydrated). It acts at the collecting tubule causing reabsorption of water and thereby reducing the plasma osmolality, decreasing urine output and increasing urine osmolality.

NOTE: When the ECF is hypoosmolar, the body is expected to reabsorb as much sodium as possible which should result in low urine osmolality and sodium. Here, since ADH is inappropriate, the urine sodium and osmolality are higher than expected.

Take home points

• Hyponatremia is very common in elderly hospitalised patients, institutionalised individuals.
• It may be observed in apparently normal elderly individuals as well.
• It is associated with higher morbidity and mortality.
• Unsteady gait and falls should raise suspicion of hyponatremia in the elderly.
• Use of multiple drugs particularly thiazide diuretics, antidepressants, cause or aggravate hyponatremia.
• Many neurologic disorders cause hyponatremia due to either cerebral salt wasting or syndrome of inappropriate antidiuresis.
• Before confirming hyponatremia, ‘pseudohyponatremia’ and translocational hyponatremia [caused by high sugar] should be excluded.
• True hyponatremia is associated with low serum osmolality [Hypoosmolar hyponatremia].
• Patients with acute symptomatic hyponatremia need aggressive correction [maximum correction should not exceed 6-8 mmol/L in 24 hours.
• Auto-correction by the body may lead to overcorrection.
• Asymptomatic chronic hyponatremia should be corrected slowly in order to avoid complications like osmotic demyelination syndrome.
• Vaptans should be used for selected indications like SIAD or selected cases of hypervolemic hyponatremia.

Suggested reading

1. Berl. T, Sands, JM, Chpter - Disorders of water metabolism in ‘Comprehensive clinical Nephrology’ [6e] editors Feehally J, Floege J, Toelli M, Johnson R. Publisher, Elsevier, New York. [2019].

2. Edwin Fernando M in Chapter - Approach to fluid and electrolyte balance in ‘Essentials of Nephrology’ [3e] editor. R. Kasi Visweswaran, Publisher CBS publishers, New Delhi. [2020]

3. Filippatos TD, Makri A , Elisaf M S, and Liamis G. Clin Interv Aging. 2017; 12: 1957–1965.

4. Verbalis JG, Goldsmith SR, Greenberg A. et. al. Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations American Journal of Medicine: 126, 10, Supplement 1, Pages S1–S 42 [Oct 2013].

Approach To Hyponatremia In The Elderly