Where Nae + and Ke + are total exchangeable quantities of these cations, and TBW is total body water . Therefore, hyponatremia can develop by an increase in total body water, a decrease in Na+ and K+ or a combination of both .
Development of hyponatremia
Hyponatremia is a condition of water excess relative to Na+. In a normal individual, hyponatremia does not develop unless water intake is greater than renal excretion. A defect in renal water excretion in the presence of normal water intake is a prerequisite for the development of hyponatremia. This defect in water excretion is due to high circulating levels of antidiuretic hormone (ADH) . With retention of water, hyponatremic patients are unable to lower their urine osmolality < 100 mOsm/kg H2O with the exception of those with psychogenic polydipsia and reset osmostat .
Approach to the Patient with Hyponatremia
Step 1. Measure Serum Osmolality
Hypoosmolality rules out pseudo (factitious)- and hypertonic hyponatremia. Hypotonic hyponatremia is called true hyponatremia (Fig. 12.1).
Fig. 12.1
Osmolality in a hyponatremia patient
Step 2. Estimate volume status
History
Assess fluid loss (diarrhea, vomiting)
Review medications such as oral hypoglycemics, antihypertensives, antidepressants, opiates, etc.)
Review medical conditions such as psychiatric illness, cancer, cardiovascular, thyroid, renal, and liver, including adrenal disease
Check intravenous (i.v.) fluids for maintenance and medication use
Physical Examination
Vital signs with orthostatic changes (very important and mandatory)
Exam of neck, lungs, heart, and lower extremities for fluid status
Evaluation of mental status is extremely important
Based on volume status, classify hypotonic hyponatremia into (Fig. 12.2):
Fig. 12.2
Classification, causes, and diagnosis of hypotonic hyponatremia. AKI acute kidney injury, CKD chronic kidney disease, NSIAD Nephrogenic syndrome of inappropriate antidiuresis, SIADH syndrome of inappropriate secretion of ADH
1.
Hypovolemic hyponatremia (relatively more Na+ than water loss)
2.
Hypervolemic hyponatremia (relatively more water than Na+ gain)
3.
Normovolemic hyponatremia (relatively more water relative to Na+)
Step 3. Obtain Pertinent Laboratory Tests
Serum chemistry, uric acid, and lipid panel
Complete blood count
Serum and urine osmolalities and urine Na+ plus K+
Fractional excretion of Na+, uric acid, and phosphate is needed occasionally
Check liver, thyroid, and adrenal tests
Step 4. Know More About Pseudo or Factitious Hyponatremia
Occasionally serum [Na+] is artifactually low in patients with severe hyperlipidemia or hyperproteinemia
Reduction in [Na+] is due to displacement of serum water by excess lipid or protein but the serum osmolality is normal
This condition is called pseudohyponatremia
These patients are asymptomatic because their serum osmolality is normal. Therefore, pseudohyponatremia is called isotonic hyponatremia
Correction of underlying causes for increased lipids and protein corrects hyponatremia. Therefore, no treatment for isotonic hyponatremia is required
In this context, it is important to know how serum Na+ is determined. Serum Na+ is determined by ion-selective electrode (potentiometric) method. The determination is done in two ways: indirect and direct. The indirect method involves dilution of serum, whereas the direct method does not require dilution of serum
Note that pseudohyponatremia is observed only if serum Na+ is determined by the indirect ion-selective electrode method, and not by the direct method
Step 5. Know More About Hypertonic (Translocational) Hyponatremia
Severe hyperglycemia also lowers serum [Na+] due to water movement from intracellular to extracellular compartment (translocation)
Serum [Na+] decreases by 1.6 mEq/L for each 100 mg/dL glucose above normal glucose level (i.e., 100 mg/dL). This correction factor applies to glucose levels up to 400 mg/dL. If serum glucose level is > 400 mg/dL, serum [Na+] decreases by 2.4 mEq/L. However, the correction factor of 1.6 mEq/L should be used until more studies are available to confirm the correction factor of 2.4 mEq/L. Because of hyperglycemia, the serum osmolality is high, and the condition is called hypertonic hyponatremia
Correction of hyperglycemia corrects hyponatremia
Mannitol, sucrose, glycerol, glycine, and maltose also cause hypertonic hyponatremia. These solutes also increase osmolal gap. Osmolal gap is defined as the difference between the measured and calculated serum osmolality. Generally, the measured osmolality is 10 mOsm higher than the calculated osmolality. Values > 15 mOsm represent the presence of an osmolal gap
Elevated osmolal gap suggests the presence of osmotically active substances that are not included in the calculation of osmolality, but are measured in the assay
Step 6. Rule Out Causes Other than Glucose that Increase Plasma Osmolality
Urea, methanol, ethanol, and ethylene glycol can also increase plasma osmolality. Calculation of osmolal gap is helpful. These solutes are ineffective osmolytes, and are cell permeable. Therefore, they do not cause translocation of water
Pathophysiology of hyponatremia
Table 12.1 summarizes the possible mechanisms underlying the generation of hyponatremia. As evident, hyponatremia develops due to an increase in ADH secretion and activity and the kidneys’ inability to dilute urine maximally due to impaired water excretion .
Table 12.1
Possible mechanisms of hyponatremia
Cause | Mechanism |
|---|---|
Diarrhea and vomiting | Volume depletion→ ↑ADH→ decreased water excretion |
Diuretics | Volume depletion→ ↑ADH→ decreased water excretion. Hypokalemia. K+ moves out of cells into ECF causing Na+ movement into cells to maintain electroneutrality. Thiazides have some other effects |
Mineralocorticoid deficiency | Volume depletion→ ↑ADH→ decreased water excretion, ↑Na+ excretion |
Salt-losing nephropathies | ↑Na+ excretion, ↑ADH→ decreased water excretion |
Cerebral salt wasting | Volume depletion→ ↑ADH→ decreased water excretion, ↑Na+ excretion |
Decompensated CHF | ↓EABV→ increased AII-SNS→ ↑Na+ and water reabsorption→ decreased delivery to diluting segments and ↑ADH→ decreased water excretion, ↑AQP2 expression |
Cirrhosis | Same as earlier |
Nephrotic syndrome (hypovolemic) | ↓water excretion (children) |
Nephrotic syndrome (hypervolemic) | Intrarenal mechanisms, leading to Na+ and water reabsorption,↓AQP2 expression |
Renal failure | ↓RBF→ ↓GFR→ decreased Na+ and water filtration→ decreased water excretion |
Psychogenic polydipsia | Water intake exceeds its excretion.↓ADH and AQP2 expression |
Hypothyroidism | ↑ADH→ decreased water excretion |
Glucocorticoid deficiency | ↑ADH→ water excretion,↑Na/K/2Cl, and ENaC activity→ increased Na+ and water reabsorption, ↑AQP2 expression |
Drugs | ↑ADH secretion and/or potentiation of ADH activity→ decreased water excretion |
SIADH | ↑ADH→ decreased water excretion |
Nephrogenic syndrome of antidiuresis | Mutation in ADH receptor 2→ increased ADH receptor activity→ decreased water excretion, ADH undetectable |
Specific Causes of Hyponatremia
It is not possible to discuss all causes of hypotonic hyponatremia. However, it is important to focus on some conditions that are frequently associated with hyponatremia.
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia in hospitalized children
Usually caused by central nervous system (CNS) disorders, pulmonary disorders, malignancies, and drugs
The diagnostic criteria of SIADH are:
1.
Hypotonic hyponatremia (plasma osmolality < 270 mOsm/kg H2O)
2.
Inappropriate urinary concentration (> 100 mOsm/kg H2O) or inability to dilute urine osmolality below 100 mOsm/kg H2O
3.
Urinary Na+ > 30 mEq/L on regular diet
4.
Euvolemia
5.
Absence of thyroid, adrenal, liver, cardiac, and renal disease
Thus, SIADH is a disease of exclusion
Besides hyponatremia, patients with SIADH have low uric acid, low blood urea nitrogen (BUN), low renin, and aldosterone levels. Urine [Na+] and FENa as well as FEuric acid are elevated
Edema is absent and blood pressure is normal
Cerebral Salt Wasting or Renal Salt Wasting Syndrome
Cerebral salt wasting (CSW) is similar to SIADH in many aspects except for hemodynamic status and treatment
Like SIADH, CSW is associated with CNS diseases
CSW was originally described in patients with subarachnoid hemorrhage. Subsequently, it was described in patients with tuberculosis and other infections
The Table 12.2 summarizes similarities and differences between CSW and SIADH .
Table 12.2
Similarities and differences between CSW and SIADH
Parameter
CSW
SIADH
Hypotonic hyponatremia
Yes
Yes
Volume status
Low
Normal to high
CVP/PCWP
Low
Normal
Othostatic BP/pulse changes
Yes
No
Hematocrit
High
Normal
Seum uric acid
Low
Low
BUN
High
Low
FEuric acid
High
High
FEuric acid after disease correction
High (persists)
Normal
FEphosphate
High
Normal
Urine [Na+]
High
High
FENa
High
High
Urine osmolality
High
High
Urine volume
High
Low
Plasma ADH
Normal to high
High
Atrial natriuretic peptide
Normal to high
Normal
Brain natriuretic peptide
Normal to high
Normal
Treatment
Salt, fludrocortisone
Water restriction, 3 % saline, loop diuretics, demeclocycline, urea, vaptans
Nephrogenic Syndrome of Inappropriate Antidiuresis
Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is similar to SIADH, but rare
First described in 2005 in infants with hyponatremia and high urine osmolality
Unlike SIADH, patients with NSIAD have undetectable or extremely low ADH levels
NSIAD is a gain of function mutation in vasopressin V2 receptor
Treatment is fluid restriction, urea, and vaptans
Reset Osmostat
Rest osmostat is a variant of SIADH because of euvolemia and hyponatremia
Patients with reset osmostat are asymptomatic and their kidneys demonstrate normal function. When patients are challenged with water load, they can lower urine osmolality to < 100 mOsm/kg H2O
Fluid restriction raises urine osmolality
Pathogenesis is unclear
Patients with alcoholism, malnutrition, spinal cord injury, and cerebral palsy are prone to develop reset osmostat
Thiazide Diuretics
Hyponatremia is a well-documented complication of thiazide diuretics
The major reason for hyponatremia is inability to dilute urine maximally with urine osmolality > 100 mOsm/kg H2O
Urine concentrating ability is preserved
Other mechanisms of hyponatremia include: (1) volume contraction; (2) early diuretic-induced inactivation of tubuloglomerular feedback system; (3) decreased glomerular filtration rate (GFR) due to earlier two mechanisms; (4) increased release of ADH and increased water reabsorption; and (5) relative decrease in vasodilatory prostaglandin (PG) synthesis in elderly subjects with unopposed ADH action
Diuretic-induced hypokalemia may further exacerbate hyponatremia by transcellular cation exchange, in which K+ moves out of the cell to improve hypokalemia and Na+ moves into the cell to maintain electroneutrality
Ecstacy
Ecstasy is a popular name for a ring-substituted form of methamphetamine
It gained the popularity of a “club drug” among adolescents, young adults, and subjects attending “rave” parties
Among other side effects such as rhabdomyolysis, arrhythmias, and renal failure. It causes symptomatic hyponatremia and sudden death
Ecstasy induces ADH secretion and retention of water in the stomach and intestine by decreasing gastrointestinal (GI) motility. Hyponatremia develops as a result of excess water intake and reabsorption from the GI tract in the presence of high ADH levels .
Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for depression
Drugs such as setraline, paroxetine, duloxetine inhibit the reuptake of serotonin, and improve depression
SSRIs have few side effects compared to other antidepressants
Hyponatremia is due to SIADH
Mechanisms include: (1) stimulation of AVP secretion; (2) augmentation of AVP action in the renal medulla; (3) resetting the osmostat that lowers the threshold for ADH secretion; and (4) interaction of SSRIs with other medications via p450 enzymes, resulting in enhanced action of ADH
Exercise-Induced Hyponatremia
Exercise-induced hyponatremia (EIH) is a serious condition in marathon runners.
ADH levels are increased despite hyponatremia
Water consumption > 3 L, body mass index < 20 kg/m2, excess loss of sweat, nonsteroidal drugs, running time > 4 h, and postmarathon weight gain may precipitate hyponatremia
Oral supplements or sports drinks rarely cause EIH
Beer Potomania
A syndrome characterized by a history of alcohol abuse, hyponatremia, signs and symptoms of water intoxication, protein malnutrition (chronic alcoholics), low solute intake, and no evidence of diuretic or steroid use
Urine osmolality may be < 50 mOsm/kg H2O or higher
ADH levels may be suppressed or high at initial presentation
Development of hyponatremia depends on solute (e.g., protein, salt) intake
An example: If solute intake per day is 250 mOsm and urine osmolality is 50 mOsm/kg H2O, beer intake > 5 L can induce hyponatremia
Alcoholics with or without hypokalemia are at high risk for osmotic demyelination syndrome (ODS) with rapid correction of hyponatremia
Poor Oral Intake
Poor oral intake of protein and electrolytes or tea and toast diet can induce hyponatremia similar to that of beer ptotomania or crash diet potomania with low solute intake
Urine osmolality may be < 50 mOsm/kg H2O or higher
Protein and salt intake improve both hyponatremia and urine osmolality
Postoperative Hyponatremia
Common in hospitalized patients
Hypotonic fluids, drugs for pain, and nonosmotic release of ADH are frequent causes
Hyponatremia may also occur with normal saline due to retention of water in the presence of ADH. This process is called desalination. When normal saline is infused and intravascular volume is expanded, the kidneys excrete administered NaCl with retention of water, resulting in hyponatremia
Patients undergoing hysterectomy or prostate surgery may develop hyponatremia due to irrigation fluids such as glycine
Young menstruating women are at risk postoperatively for ODS
Diagnosis of hyponatremia
Figure 12.2 shows the two most important urinary tests in the evaluation of hypotonic hyponatremia:
1.
UNa
2.
Urine osmolality
It is emphasized that UNa is < 10 mEq/L only in vomiting, diarrhea, and decompensated congestive heart failure (CHF), cirrhosis, and nephrotic syndrome. Acute kidney injury due to volume depletion also causes low urinary Na+. Fractional excretion of Na+ follows that of UNa. Urine osmolality is always > 100 mOsm/kg H2O in all conditions that cause hypotonic hyponatremia except in those conditions of psychogenic polydipsia and reset osmostat .
Signs and symptoms of hyponatremia
Patients with plasma [Na+] > 130 mEq/L are generally asymptomatic. Symptoms are primarily neurologic, which are related to the severity and rapidity of development of hyponatremia. Gastrointestinal symptoms such as nausea may be the earliest findings, followed by headache, yawning, lethargy, restlessness, disorientation, ataxia, and depressed reflexes with [Na+] < 125 mEq/L. In patients with rapidly evolving hyponatremia, seizures, coma, respiratory arrest, permanent brain damage, and death may occur.
Consequences of hyponatremia
Cerebral Edema
Most of the signs and symptoms of hyponatremia are neurologic due to cerebral edema. When plasma osmolality is low, water moves into the brain, causing cerebral edema. Because brain expansion is limited due to the rigid skull, intracranial hypertension develops and neurologic symptoms start to appear. However, the symptoms slowly disappear as the brain begins to adapt to hyponatremia. The major defense mechanism is the extrusion of Na+, Cl−, K+, and organic osmolytes (myoinositol, taurine, glycine, etc.) from the brain cell. This results in the reduction of intracellular osmolality, and further water movement into the cell is prevented. Subsequently, the brain volume returns to baseline even in the presence of severe hyponatremia (Fig. 12.3). This adaptation is nearly complete after 48 h. Many factors may impair brain adaptation to hyponatremia. Table 12.3 shows these factors and their possible mechanisms for impairment of brain adaptation .
Fig. 12.3
Adaptation of brain volume to hyponatremia
Table 12.3
Mechanisms that impair brain adaptation
Factor | Mechanism |
|---|---|
Children | High brain to skull ratio, as brain development is complete before skull development |
Young menstruating females | Estrogen inhibition of Na/K-ATPase causing decreased extrusion of Na+ |
Hypoxia | ↓cerebral blood flow in the presence of hyponatremia, ↓ATP production,↑lactate production →low intracellular pH |
Increased ADH levels | Cerebral vasoconstriction, hypoperfusion |
Osmotic Demyelination Syndrome
Osmotic demyelination syndrome, previously called central pontine myelinolysis, is a complication of treatment of hyponatremia. It occurs due to rapid correction of chronic hyponatremia because the recovery of brain osmolytes during correction of hyponatremia is much slower than the loss of these osmolytes during the adaptation of brain volume. When serum [Na+] is rapidly raised, the plasma osmolality becomes hypertonic to the brain with resultant water movement from the brain. This cerebral dehydration probably causes myelinolysis and ODS.
Clinical Manifestations
1.
Paraparesis or quadriparesis
2.
Pseudobulbar symptoms (dysarthria or dysphagia)
3.
Locked-in syndrome (preserved intellectual capacity without expression), and
4.
Movement or behavioral disorders
Diagnostic Test
Magnetic resonance imaging (MRI) of brain. Initially the MRI findings are normal, but may be found 3–4 weeks later after repeat MRI.
Precipitating Factors
Several risk factors for precipitation of ODS have been identified. These are:
1.
Chronic hyponatremia
2.
Serum [Na+] < 105 mEq/L
3.
Chronic alcoholism
4.
Malnutrition
5.
Hypokalemia
6.
Severe liver disease
7.
Elderly women on thiazide diuretics
Management and Prognosis
Management is supportive. Four treatment modalities have been reported with variable success: (1) thyrotropin-releasing hormone, (2) methylprednisolone, (3) plasma pheresis, and (4) i.v. immunoglobulins. Early reports showed 100 % mortality. Current reports document milder clinical course without substantial neurologic deficits in survivors .
Falls, Fractures, and Osteoporosis
Even mild chronic hyponatremia is not without complications. Studies have shown cognitive impairment, falls, fractures, and osteoporosis in individuals with serum [Na+] between 126 and 134 mEq/L .
Treatment of hyponatremia
Hyponatremia is classically defined as acute (< 48 h duration) or chronic (> 48 h duration), and further characterized as asymptomatic or symptomatic. This classification is important in terms of treatment. Thus, the treatment of hyponatremia depends on four factors:
1.
Severity of hyponatremia,
2.
Duration of hyponatremia,
3.
Signs and symptoms of hyponatremia, and
4.
Volume status
Treatment of Acute Symptomatic Hyponatremia
1.
Acute symptomatic hyponatremia (seizures, respiratory distress, etc.) is a medical emergency.
2.
Patients at risk for acute symptomatic hyponatremia are postoperative patients receiving hypotonic fluids, psychogenic polydipsic patients, patients taking ecstacy, and marathon runners.
3.
Select an i.v. fluid that has a higher urine osmolality than that of the patient.
4.
3 % NaCl is the fluid of choice, because it has high osmolality than most of the patients’ urine osmolality. Also, its infusion raises serum [Na+] to a desired level and prevents cerebral edema. Rarely, 5 % saline is required.
5.
Raise serum Na+ 1–2 mEq/h for 3 h up to 6 mEq from baseline. Then hold 3 % NaCl. If symptoms persist, give another bolus of 100 ml of 3 % NaCl. The rate of increase in serum Na+ is 6–8 mEq in a 24-h period. This can be achieved by giving 1–2 ml/kg/h or 100 ml boluses of 3 % NaCl. Repeat these boluses 2–3 times as needed. Assuming no urine excretion of Na+, a bolus of 100 ml raises serum [Na+] by 1 mEq.
6.
To avoid overcorrection, it is useful to calculate the amount of Na+ required to achieve the desired level. If the patient weighs 70 kg and serum [Na+] is 110 mEq/L, and you wish to increase it to 118 mEq/L, use the following simple formula:
1 L of 3 % NaCl contains 513 mEq of Na+
336 mEq = 665 mL 3 % NaCl. If the patient receives 100–200 mL during the 1st 3 h to a total of 400–600 mL, and serum [Na+] reaches 116 mEq, you can stop 3 % NaCl.
7.
Note that these calculations are based on the assumption that the patient is not losing any Na+ in the urine. This is not possible in clinical medicine unless the patient is anuric.
8.
Therefore, measure urine volume and urine Na+ and K+ simultaneously with serum Na+ every 2 h until the symptoms improve. Replace urinary loss of Na+ with either 3 % or 0.9 % saline, as needed, to achieve the target Na+.
9.
NEVER correct serum Na+ levels above 8 mEq in a 24-h period from baseline.
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