NEUROLOGY OF COMMON ELECTROLYTE DISORDERS

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CHAPTER 116 NEUROLOGY OF COMMON ELECTROLYTE DISORDERS

Martin A. Samuels, Julian L. Seifter

HYPEROSMOLALITY AND HYPERTONICITY

Normal serum, and therefore body fluid, osmolality is in the range of 275 to 295 mOsm/kg; clinically significant effects are generally seen at levels greater than 325 mOsm/kg. Osmolality may be measured directly by the freezing point depression or calculated as serum osmolarity in milliosmoles per liter with the following formula, which accounts for the millimolar quantities of major serum solutes (where BUN is blood urea nitrogen):

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Effective hyperosmolality is called hypertonicity and indicates the effect of increased extracellular osmoles to draw water from cells by osmosis. If hyperosmolality is caused by hypernatremia, cells initially shrink until adaptive mechanisms allow cell volume to recover. Similarly, a diabetic patient with hyperglycemia loses cell water and develops a hypertonic syndrome. In contrast, azotemia (i.e., an elevated BUN level) may cause hyperosmolality but not hypertonicity, because the high permeability of urea allows solute movement into cells so that cell water does not leave by osmosis. The difference between hyperglycemia (glucose cannot enter cells) and azotemia is seen by the effect on the serum sodium concentration. Water leaving cells in the hyperglycemic patient lowers serum [Na], whereas serum sodium [Na] is not altered by a rise in BUN. Addition of extrinsic osmoles such as mannitol, like glucose, causes hyperosmolality, hypertonicity, loss of cell water, and hyponatremia. On the other hand, added alcohols that quickly permeate cells, such as ethanol, ethylene glycol, isopropyl glycol, and methanol, act more like azotemia, causing hyperosmolality but not hypertonicity or hyponatremia. Because measured osmolality is increased with addition of these extrinsic solutes but sodium, glucose, and urea are not, there is an osmolal gap, defined as the difference between measured and calculated osmolality. The osmolal gap should be less than 10 mOsm/L.

Hypernatremia is defined as a serum sodium concentration higher than 145 mEq/L. In all tissues, hypernatremia leads to loss of intracellular water, which in turn leads to cell shrinkage. The nervous system is unique in that it is capable of generating (or accumulating from the extracellular fluid) solutes referred to as idiogenic osmoles, such as amino acids (glutamine, taurine, glutamate), polyols (myoinositol), and methylamines (glycerophosphorylcholine and choline), to minimize cell shrinkage, a process that is complete in 1 to 2 days. When hypernatremia is unusually severe (serum sodium level exceeds 160 mEq/L), these mechanisms fail, which leads to encephalopathy. When hypernatremia occurs, antidiuretic hormone (ADH) is released and thirst increases, which lead to renal retention of ingested water and thereby lower the serum sodium level toward normal. Hypernatremia is thus caused by a defect in thirst or inability to access water, inadequate release or effect of ADH, loss of hypotonic fluid, or addition of concentrated sodium.

Hyperglycemia is nearly always caused by diabetes mellitus, which results from either inadequate insulin production or insulin resistance. In patients with neurological disease, this is often precipitated by stress, infection, or the therapeutic use of glucocorticoids.

Azotemia is caused by renal failure or inadequate renal perfusion (prerenal azotemia).

Hyperosmolar agents such as mannitol or glycerol are often used in patients with neurological disease to treat increased intracranial pressure and may result in hyperosmolality.

Hyperosmolality usually produces a generalized encephalopathy without localizing or lateralizing features, but an underlying focal lesion (e.g., stroke, multiple sclerosis, neoplasm) could become symptomatic under the metabolic stress of a hyperosmolar state. The prognosis of the hyperosmolality itself is good, but the long-term outlook depends on the cause. For unknown reasons, hyperosmolality alone, particularly when caused by hyperglycemia, may lead to continuous partial seizures, and even careful studies may fail to uncover any underlying lesion. These seizures generally respond promptly to lowering of the serum glucose level.

The treatment of hyperosmolality requires calculation of apparent water losses:

1. The normal total body water (NTBW) is calculated as body weight (in kilograms) × 0.6.
2. The total body solute (sodium + potassium) is estimated as NTBW × 140 mEq/L. Note that 140 mEq/L is normal serum [Na] but is approximately equal to intracellular [K] needed to estimate total body solutes.
3. The patient’s body water is calculated as total body solute/patients serum [Na].
4. The patient’s water deficit is calculated as NTBW – patient’s body water.
5. Apart from deficit correction, large ongoing losses in the urine (osmotic diuresis or diabetes insipidus) or sweat (fever) are estimated and replaced.

The water losses are replaced, with water or 5% dextrose in water, so that the serum sodium level falls no faster than 2 mEq/L/hour. In the hypotensive or volume-depleted patient, normal saline may first be needed to correct blood pressure. In patients with renal failure, dialysis may be required. Insulin is administered, with frequent blood glucose testing, if there is hyperglycemia. Intramuscular and subcutaneous insulin may be unpredictably absorbed, particularly in hypovolemic patients, because of poor tissue perfusion. Rapid-acting insulin, 0.1 U/kg by rapid intravenous infusion followed by 0.05 U/kg/hour by continuous intravenous infusion, is usually sufficient to reduce the blood glucose level adequately and safely, but the mainstay of hyperglycemia correction in the patient with hyperosmolar type II diabetes is volume expansion, which leads to urinary glucose clearance. Rapid reduction of extreme elevations of glucose should be avoided.

Diabetes insipidus is recognized as hypernatremia (>292 Osm) with simultaneous submaximal concentration of the urine. A subcutaneous dose of vasopressin and subsequent measurement of serum ADH level help distinguish central from nephrogenic diabetes insipidus. Treatments include deamino-D-arginine vasopressin, an ADH analog used in the treatment of central diabetes insipidus. Salt restriction and even thiazide diuretics may help in treating nephrogenic diabetes insipidus.

HYPONATREMIA

Hyponatremia is defined as a serum sodium level lower than 135 mEq/L, but it may be asymptomatic at levels less than 125 mEq/L in chronic, slowly developing cases. Hypotonicity is always associated with hyponatremia, but hyponatremia may be isotonic (e.g., as an artifact in hyperlipidemia or hyperproteinemia), hypertonic (e.g., hyperglycemia; mannitol), or hypotonic (with impairment of free water excretion in low cardiac output states or the syndrome of inappropriate antidiuretic hormone [SIADH] or with an enormous free water load, as in psychogenic water drinking). Osmolality is estimated by use of the formula given previously (see discussion of hyperosmolality) and may be measured in the clinical laboratory. The difference between the calculated and measured osmolality (the osmolal gap) should not exceed 10 mOsm/L. The finding of factitious hyponatremia is caused by a laboratory artifact in diluted samples when the solids of plasma are increased (e.g., hyperlipidemia, severe hyperproteinemia as in myeloma). Measurements of the undiluted serum [Na] by the blood gas machine and of the osmolality are not similarly affected.

The prognosis of hyponatremia depends on the rate and magnitude and the cause of the fall in serum sodium. In acute hyponatremia (a few hours or less), seizures and severe cerebral edema may be rapidly life-threatening at serum sodium levels as high as 125 mEq/L, whereas patients may tolerate very low serum sodium levels (even below 110 mEq/L) if the process develops over days or more. Rapid correction of acute hyponatremia may be lifesaving, whereas rapid correction of chronic hyponatremia may be dangerous. Nervous system cells initially swell in hypotonic states but then compensate for chronic hyponatremia by losing solute to the extracellular space, followed by water, to restore normal cell volume. If the serum sodium level rapidly rises after cells regain normal volume, brain cells can rapidly shrink, causing osmotic demyelination (formerly known as central pontine myelinolysis). The clinical picture of osmotic demyelination ranges from mild spasticity to coma, depending on the extent of the demyelinating lesions. The pons is particularly susceptible, possibly simply because the crossing and descending fiber tracts produce a tight grid that does not tolerate fluid shifts as well as does the rest of the brain. The process, however, is not restricted to the pons; it may affect the cerebral white matter as well, leading to the evolution of the name for this disorder from central pontine myelinolysis to pontine and extrapontine myelinolysis to the preferred modern term osmotic demyelination.

The cause of hypotonic hyponatremia is best determined by dividing all possibilities into three categories on the basis of the clinical estimate of the state of the extracellular fluid space. Blood pressure and heart rate with orthostatic measurements, the central venous pressure (neck vein distention), and the presence or absence of edema allow all cases of hypotonic hyponatremia to be categorized into three types: hypovolemic (reduced effective blood volume with hypotension, tachycar-dia and orthostatic intolerance), hypervolemic (edematous states), and isovolemic (retention of free water, no apparent edema).

The diagnosis is made with a measurement of the serum sodium, followed by an assessment of extracellular volume. The major diagnoses in each category are hypotonic hypovolemic hyponatremia (gastrointestinal sodium losses; hemorrhage; renal salt wasting, including the cerebral salt wasting syndrome; diuretic excess; and adrenal insufficiency), hypotonic hypervolemic hyponatremia (congestive heart failure, hepatic failure with ascites, nephrotic syndrome), and hypotonic isovolemic hyponatremia (SIADH, psychogenic water drinking, hypothyroidism, and resetting of the osmostat). The treatment depends on the type of hyponatremia. In hypertonic hyponatremia, the underlying disorder (e.g., hyperglycemia, exposure to mannitol) is treated, and only the estimated salt losses are replaced. Factitious hyponatremic disorders (e.g., hyperlipidemia, hyperproteinemia) do not necessitate osmotic treatment, and in fact it may be dangerous to subject such patients to fluid restriction. In hypovolemic hypotonic hyponatremia, volume is replaced with isotonic saline; the underlying renal, adrenal, and gastroenterological conditions are treated, and the cases of cerebral salt wasting (e.g., intracerebral or subarachnoid hemorrhage) are recognized and treated. In hypervolemic hypotonic hyponatremia, free water restriction is used while the underlying edematous disorders (e.g. congestive heart failure, liver failure, nephrotic syndrome) are treated. In isovolemic hypotonic hyponatremia, the chronicity of the syndrome must be considered. In chronic, slowly developing cases of isovolemic hyponatremia, water restriction is used. Antagonism of ADH action in SIADH with demeclocycline may be useful if water restriction alone fails. In acute (less than 48 hours) rapidly developing isovolemic hyponatremia, 3% saline (containing 513 mEq/L of sodium) is used. This solution contains about 0.5 mEq sodium/mL, and because total body water is about 50% body weight, then infusions of 3% saline at 1 to 2 mL/kg raises the serum [Na] by 1 to 2 mEq/L. In an acutely hyponatremic patient, raising the [Na] by 4 to 6 meq/L may be of immediate value, but serum [Na] should not be raised to normal. The correction rate is then slowed to less than 10 mEq/L/24 hours. This is followed by free water restriction.

Some patients with SIADH may become more hyponatremic with saline infusion as the water is retained and the salt excreted. This response can be predicted if the urinary [Na + K] level exceeds the serum [Na] level. In such a case, furosemide may be a useful adjunct for diluting the urine.

HYPOKALEMIA

Hypokalemia is defined as a serum potassium level below 3.5 mEq/L. The serum potassium level may be low because of abnormal distribution between intracellular and extracellular potassium or because of excessive potassium losses (renal or extrarenal). Hypokalemia caused by excessive cellular potassium uptake may be caused by insulin, catecholamines (β2-adrenergic agonists), hypokalemic periodic paralysis, alkalosis, and hypothermia. Extrarenal potassium loss (urine potassium level less than 20 mEq/day) may be caused by diarrhea (low serum bicarbonate), cathartic agents, sweating (normal serum bicarbonate), or starvation (anorexia). Renal potassium loss (urine potassium level more than 20 mEq/day) may be caused by hyperreninemia, hyperaldosteronism, renal tubular acidosis, diuretic use, and hypomagnesemia. Vomiting, by causing metabolic alkalosis, actually causes renal potassium losses.

Severe hypokalemia (serum potassium less than 3 mEq/L) may be life-threatening because it can cause cardiac arrhythmia and severe muscle weakness or paralysis.

The diagnosis of hypokalemia is made with a serum potassium measurement. Urinary potassium measurement may help determine whether the potassium loss is renal or extrarenal, but it should be borne in mind that such measurements are valid only in the presence of normal dietary and urinary sodium levels, inasmuch as sodium restriction may result in some masking of renal potassium wastage. The blood pressure and measured serum sodium, bicarbonate, plasma renin, plasma aldosterone, and urinary chloride levels may also help in the differential diagnosis of the cause of hypokalemia. The treatment of hypokalemia depends on the cause. Potassium balance problems should be corrected, if possible (e.g., by reducing dosages of β2-adrenergic agonists). Dietary sodium restriction (less than 80 mEq/day) reduces renal potassium losses. Oral potassium chloride is used to supplement high-potassium diets in resistant cases of hypokalemia (30 to 50 mEq/day). For severe (less than 3.0 mEq/L) hypokalemia, especially with cardiac arrhythmias and/or severe muscle weakness, intravenous potassium chloride may be administered with continuous cardiac monitoring. Potassium infusions in excess of 20 mEq/hour should also be restricted, to guard against possible hyperkalemic complications.

HYPERKALEMIA

Hyperkalemia is defined as a serum potassium concentration of greater than 5.5 mEq/L, but this is rarely problematic unless it exceeds 6 mEq/L. Hyperkalemia may be present in circumstances that do or do not cause an excess of whole body potassium. The causes of hyperkalemia without an excess of potassium are muscle injury (e.g., trauma, persistent seizures, muscle infarction), β2-adrenergic antagonists (e.g., propranolol), insulin resistance, hyperchloremic metabolic acidosis, digitalis poisoning, depolarizing muscle relaxants (e.g., succinylcholine), and hyperkalemic periodic paralysis (muscle sodium channel mutation). Common causes of hyperkalemia caused by whole-body potassium excess include Addison’s disease, aldosterone deficiency (e.g., that caused by hyporeninemia, angiotensin-converting enzyme inhibitor therapy, nonsteroidal anti-inflammatory drugs, heparin), and aldosterone resistance (e.g., renal failure, renal tubular disorders, potassium-sparing diuretics). Pseudohyperkalemia may be seen in states of thrombocytosis, leukemic leukocytosis, or hemolysis in the test tube. A plasma [K] measurement may be helpful in ruling out these diagnoses. Also, poor venous access with a tourniquet that causes local tissue ischemia may artifactually raise the serum [K] level in blood drawn from the affected limb.

The first sign of hyperkalemia is usually peaking of the T wave of the electrocardiogram, which usually occurs with a potassium level of about 6.0 mEq/L. As the potassium level rises, the QRS complex widens, which is followed by reduction in its amplitude and then disappearance of the T wave. Heart block and loss of P waves are noted. Sudden cardiac arrest may occur. Muscle weakness usually develops. Hyperkalemia may be suspected when the characteristic electrocardiographic pattern is seen, particularly in combination with weakness, sometimes with paresthesias. The diagnosis is confirmed with measurement of the serum potassium.

If hyperkalemia is considered life-threatening because it is producing electrocardiographic changes and/or severe muscle weakness, the clinician should treat it by protecting the heart against life-threatening arrhythmias, promoting redistribution of potassium into cells, and enhancing potassium removal. For cardiac protection, calcium gluconate 10% solution should be administered, 20 mL as a rapid intravenous infusion. To promote redistribution of potassium into cells, glucose, 50 g/hour, should be administered intravenously with insulin, 5 U, by rapid intravenous infusion every 15 minutes and with albuterol, 10 to 20 mg, by inhaler. To enhance removal of potassium, sodium polystyrene sulfonate (Kayexalate) may be used: 15-60 g with sorbitol by mouth or 50 to 100 g by retention enema. Loop diuretics, such as furosemide, 40 to 240 mg intravenously over 30 minutes, are useful in the patient undergoing volume expansion. In severe or resistant cases of whole-body potassium excess and in renal failure, hemodialysis may be used.

KEY POINTS

• As can readily be seen from the determinants of osmolality, in most clinical settings, hyperosmolality is caused by hypernatremia, hyperglycemia, azotemia, or the iatrogenic addition of extrinsic osmoles (e.g., mannitol, glycerol).
• Hyperosmolality usually produces a generalized encephalopathy without localizing features, but an underlying focal lesion (e.g., stroke, multiple sclerosis, or neoplasm) could become symptomatic under the metabolic stress of a hyperosmolar state.
• The prognosis of hyponatremia depends on the rate and magnitude of the fall in serum sodium and its cause.
• Nervous system cells compensate for chronic hyponatremia by excreting solute to avoid water retention. If upon this substrate the serum sodium level rapidly rises, brain cells can rapidly shrink, causing osmotic demyelination.
• Serum potassium may be low because of abnormal distribution between intracellular and extracellular potassium or because of excessive potassium losses (renal or extrarenal).
• For severe (less than 3.0 mEq/L) hypokalemia, especially with cardiac arrhythmias and/or severe muscle weakness, intravenous potassium chloride may be administered with continuous cardiac monitoring.
• If hyperkalemia is considered life-threatening because it is producing electrocardiographic changes and/or severe muscle weakness, the clinician should treat it by protecting the heart against life-threatening arrhythmias, promoting redistribution of potassium into cells, and enhancing potassium removal.

Suggested Reading

Ayus JC, Krothapalli RK, Arieff AI. Treatment of symptomatic hyponatremia and its relation to brain damage. A prospective study. N Engl J Med. 1987;317:1190-1195.

Burn DJ, Bates D. Neurology and the kidney. J Neurol Neurosurg Psychiatry. 1998;65:810-821.

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