Definition, Presentation, and Clinical Manifestations

Hyponatremia, defined as a serum sodium concentration below 135 mEq/L, reflects a relative excess of water in relation to serum (ECF) sodium. In an attempt to maintain osmotic equilibrium, a net movement of water from the ECF to the ICF results in intracellular volume expansion. Changes in cell water content are of greatest consequence in the brain, where increased cell and tissue volume meet the rigid calvarium and elevated intracranial pressure ensues, risking cerebral herniation. Increased cellular water content can also impair normal intracellular metabolic processes.

Neurologic symptoms usually do not occur until the serum sodium concentration falls below 125 mEq/L, when patients typically complain of anorexia, nausea, or generalized malaise. These symptoms can progress to headache, lethargy, confusion, agitation, and obtundation. If cerebral edema is severe, seizures, coma, respiratory arrest, and death can occur. The morbidity and mortality associated with hyponatremia are influenced by the magnitude and rate of development of the hyponatremia, the age and gender of the patient, and the nature and severity of underlying diseases. At particular risk are the very young and very old, premenopausal women, patients with pneumonia, patients with heart failure, cirrhotics, and chronic alcoholics.

Symptoms generally resolve with correction of the hyponatremia unless moderate to severe hyponatremia has developed in less than 24 hours. In that case, hyponatremia can be associated with residual neurologic deficits and a mortality rate as high as 50%. In contrast, when hyponatremia develops more gradually, symptoms are less frequent and less severe, such that some patients with profound chronic hyponatremia may remain completely asymptomatic.

1 Does the Patient Have Hypotonic Hyponatremia?

Hypotonic hyponatremia (sometimes referred to as true hyponatremia) is associated with plasma hypo-osmolality and relative TBW excess. This is distinct from isotonic hyponatremia and hypertonic hyponatremia, which are not hypo-osmolal states.

When the body is in water balance, the serum sodium concentration is stable and water outputs are being matched by water input. Osmoreceptors in the hypothalamus monitor the plasma osmolality (largely determined by the serum sodium concentration) and maintain osmolality or attempt to correct it through control of thirst and ADH output.

Response to free water addition: When water is added to the body, the fall in plasma osmolality (or development of even mild hyponatremia) should abolish thirst and suppress ADH secretion. In the absence of ADH, the kidney eliminates the excess water by producing dilute urine (approximately 50 to 100 mOsm/kg). A healthy kidney can excrete up to 20 liters of “free” water (the equivalent of solute free water) per day, which exceeds the amount of water most people consume. Hyponatremia (a net increase in TBW) occurs when the kidneys’ ability to excrete water is impaired or exceeded.

Response to free water loss: A healthy individual experiences obligatory daily water losses (outputs) in the stool and urine. Also, evaporative losses occur from the skin and respiratory tract, equal to ∼500 mL/day. This evaporative loss is minimal when the patient is mechanically ventilated, because the ventilator delivers an inspiratory air mixture that is heated and close to fully humidified. These losses must be balanced by water intake to maintain water homeostasis and a stable serum sodium concentration. If the body loses water and it is not replaced, plasma osmolality rises (and hypernatremia develops). This stimulates thirst and increases ADH secretion. ADH minimizes renal water elimination, resulting in concentrated urine (∼1000 to 1200 mOsm/kg). Although this can diminish water loss from the kidney, the original water deficit cannot be corrected without supplementing oral or intravenous water.

To fully comprehend the pathophysiology of abnormal water status, one must account for both (1) net water gain or loss and (2) the renal response to the abnormality in water status. As noted in the preceding example, when hypernatremia occurs from water loss, even a completely normal kidney cannot restore serum sodium to normal unless more water is added. An abnormal renal response may exacerbate the hypernatremia. Similarly, although hyponatremia occurs from a net addition of water to the body, hypo-osmolality is often sustained by insufficient renal water excretion.

Quantifying urinary free water excretion can help answer three key questions: (1) How did the patient develop this dysnatremia? (2) Will the patient self-correct the disorder? and (3) How fast will changes in water content occur? Quantification of water excretion identifies how the kidneys are handling water during a specific time frame. This relies on the theoretic separation of the urine into an isotonic compartment (relative to the serum) and a water (i.e., solute-free) compartment. The quantity of water in this model may be a negative or positive number, representing the net addition to or subtraction from TBW, respectively. This theoretic quantity, the urinary electrolyte-free and solute-free water clearance, offers the optimal way to both conceptualize and quantify urine water.

In hypertonic hyponatremia, large amounts of solutes restricted to the ECF (such as glucose and mannitol) result in water movement out of the cells. The redistribution of water to the ECF thereby reduces the sodium concentration, as commonly seen in severe hyperglycemia. For every 100-mg/dL increase in the serum glucose concentration above 400 mg/dL, one can expect a 2.4-mEq/L reduction in the serum sodium concentration. (Or alternatively, as stated in Chapter 82, every 100 mg/dL of glucose greater than 100 mg/dL decreases the serum sodium by ∼1.6 mEq/L.) Two common scenarios where this is seen are (1) uncontrolled diabetes (see Chapter 82) and (2) iatrogenic delivery of a high solute load (e.g., intravenous immune globulin [IVIG] is commonly delivered in a fluid with high sugar content). In this case, unlike hypotonic hyponatremia, cells are dehydrated. Treatment focuses on correcting the underlying cause of increased serum osmolality (e.g., insulin).

Theoretically, true isotonic hyponatremia occurs if an isotonic solution without sodium is added to the ECF (e.g., glycine irrigation solution). The solutes in such a solution must be restricted to the ECF for hyponatremia to be sustained. In the past, isotonic hyponatremia was considered pseudohyponatremia, a laboratory artifact, in the setting of hyperlipidemia or paraproteinemia. Newer laboratory techniques directly measure serum sodium and avoid this error. The distinction between hypotonic, isotonic, and hypertonic hyponatremia can be made by measuring the serum osmolality.

2 In Hypotonic Hyponatremia, Are Renal Diluting Mechanisms Functioning at Capacity?

The normal response to water ingestion producing even slight hyponatremia is the excretion of dilute urine (urine osmolality < 100 mOsm/kg). Hence, a urine osmolality less than 100 mOsm/kg points to an appropriate renal response to hyponatremia, as seen clinically with excess water intake (e.g., polydipsia) or a low solute diet (e.g., beer potomania). When the urine osmolality exceeds 100 mOsm/kg during hyponatremia, an impairment of renal diluting ability limits water excretion by the kidney.

3 Why Is Renal Diluting Ability Impaired (as Evidenced by an Inappropriately Elevated Urine Osmolality)?

Impaired urine dilution (urine osmolality > 100 mOsm/kg) may result from (1) decreased delivery of fluid to the renal diluting segment (decrease in GFR or increased proximal tubular reabsorption of glomerular filtrate as a result of volume contraction), (2) abnormalities in dilution of the filtrate in the diluting segment (ascending limb of the loop of Henle and early distal convoluted tubule), or (3) persistently elevated vasopressin (ADH) activity. Of these mechanisms, increased ADH activity (from increased ADH levels or increased sensitivity to ADH) is the most important and most common underlying pathophysiology in ICU patients. Elevated ADH activity often results from low effective arterial blood volume (EABV), as seen in states of whole body hypovolemia or whole body volume excess (e.g., cirrhosis, congestive heart failure, or nephrosis).

Normally, hypo-osmolality potently inhibits ADH release. However, the homeostatic defense against volume contraction supersedes the regulation of serum osmolality: to maintain intravascular volume, the body retains water accepting lowering tonicity. With low EABV, carotid baroreceptors initiate a neural pathway triggering nonosmotic ADH release. ADH increases the collecting duct permeability to water, which facilitates water reabsorption. If the alert patient drinks excessive water through nonosmotic stimulation of thirst (from hypovolemia), or the patient ingests even a “normal” or subnormal amount of water, hyponatremia can progress further. Causes of low EABV are divided into whole body hypovolemic states and hypervolemic states.

Hypovolemia can result from renal or extrarenal volume losses. The patient may exhibit overt signs of volume depletion such as tachycardia, orthostatic hypotension, and organ hypoperfusion. Laboratory indices such as an elevated BUN to creatinine ratio (BUN:creatinine > 20) or an elevated serum uric acid level may help identify subclinical volume loss in ICU patients. With extrarenal volume loss, the urine sodium is typically below 20 mmol/kg. Common causes for extrarenal volume loss include vomiting, diarrhea, bleeding, and “third-spacing” of fluids (e.g., pancreatitis, trauma, sepsis-induced increased vascular permeability).

A serum sample contains both aqueous and nonaqueous components. The actual sodium concentration is based on the amount of sodium and water in the aqueous component. However, with one method of measuring sodium, the reported sodium concentration is based on the amount of sodium per volume of total serum (aqueous and nonaqueous). Therefore, if the nonaqueous part of the serum is increased from marked hypertriglyceridemia or paraproteinemia, the aqueous component of the serum is decreased and the total amount of sodium in that total serum sample volume is decreased.

Renal volume loss occurs from diuretic use, hypoaldosteronism, metabolic alkalosis, sodium- wasting nephropathies, or cerebral salt wasting. In each of these causes, urine sodium typically exceeds 20 mmol/kg. Cerebral salt wasting (CSW) has emerged as an important clinical entity in neurosurgical patients with intracranial pathology. This diagnosis is made based on evidence of defective renal sodium transport, inappropriate urinary salt wasting, and decreased EABV (negative sodium balance). This volume contraction distinguishes CSW from the syndrome of inappropriate antidiuretic hormone (SIADH), which usually represents a slightly volume- expanded state.

The administration of intravenous fluids to patients with intracranial disease can make the volume status and renal sodium excretion difficult to interpret. However, demonstration of inappropriately negative salt balance argues for CSW. One theoretic mechanism for CSW suggests that CNS injury disrupts the autonomic nervous system stimulation of basal proximal tubular sodium and urate reabsorption. Another theory posits that injured CNS cells elaborate brain natriuretic peptide (BNP), which inhibits renal sodium reabsorption. Elevated BNP levels have been demonstrated in patients with subarachnoid hemorrhage. Details regarding the diagnosis and pathophysiology of CSW remain controversial. Clinically, distinguishing CSW from SIADH is important because the management differs dramatically. CSW treatment focuses on correcting hypovolemia, whereas SIADH treatment includes water restriction, increasing free water excretion, and correcting the renal diluting defect.

Low EABV can also occur in conditions where the patient is whole body volume overloaded. Congestive heart failure (CHF), cirrhosis, and nephrotic syndrome each typify this scenario. Excess fluid accumulates in the interstitial spaces (“third spacing”) and peritoneal cavity; the EABV, necessary to establish a mean arterial pressure and perfuse organs, remains relatively low. This can result from a poor cardiac output (CHF), vascular dilation and blood volume redistribution into systemic arteriovenous fistulae (cirrhosis), or low oncotic pressure from hypoalbuminemia (nephrotic syndrome). In each of these processes, the decrease in EABV leads to (1) nonosmotic stimulation of ADH release, (2) decreased GFR and decreased delivery of fluid to the distal nephron, and (3) potential nonosmotic stimulation of thirst.