AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hyponatremia is defined as serum sodium (Na) concentration of less than 135 mEq/L. Whereas hypernatremia always denotes hypertonicity, hyponatremia can be associated with low, normal, or high tonicity. Hyponatremia is the most common electrolyte abnormality encountered in clinical practice, with an incidence of 1.5% of all pediatric hospital admissions.

Symptoms and signs of hyponatremia are related to the absolute level and to the rate at which serum Na levels decrease from baseline. Symptoms are not correlated with specific serum Na levels. However, they most frequently occur when the serum Na concentration is less than 125 mEq/L. Although morbidity varies widely in severity, serious complications can arise from the disorder itself or during treatment. Understanding the pathophysiology and treatment options is important because the morbidity and mortality of untreated hyponatremia are clinically significant.

Pathophysiology

Hyponatremia can develop because of (1) excessive free water, which mostly happens in hospitalized patients; (2) excessive renal or extrarenal loss of Na; or, in rare cases, (3) deficient intake of Na.

Under normal circumstances, the human body is able to maintain serum Na in normal range (135-145 mEq/L) despite wide fluctuations in fluid intake. The body's defense against developing hyponatremia is the kidney's ability to generate a dilute urine and excrete free water. Whenever the ability of the kidney to concentrate urine is affected or overwhelmed, hyponatremia develops.

Deficient intake rarely causes hyponatremia. In children, the most common cause of hyponatremia is loss of Na from the GI tract. Diarrhea is responsible for most incidents of hyponatremia in children. Na loss also occurs in the kidneys. Diuretics are the most common culprit, followed by other causes, such as salt-losing nephritis, mineralocorticoid deficiency, and cerebral salt-wasting syndrome (CSWS).

Excessive antidiuretic hormone (ADH) secretion causes water retention and subsequent dilutional hyponatremia. ADH is secreted from supraoptic nuclei in response to hyperosmolality and hypovolemia. Secretion of ADH also occurs in response to pain, nausea, vomiting, and morphine intake in postoperative patients. In certain clinical conditions, ADH secretion occurs without any physiologic stimuli, hence the term syndrome of inappropriate ADH secretion (SIADH). In patients with cirrhosis, cardiac failure, or renal failure, hyponatremia may be caused by mechanisms, such as water retention, diuretic use, and decreased Na intake.

Clinical manifestations vary from an asymptomatic state to severe neurologic dysfunction. CNS symptoms predominate in hyponatremia, though cardiovascular and musculoskeletal findings may be present. Factors that contribute to CNS symptoms are (1) the rate at which serum Na levels change, (2) the serum Na level, (3) the duration of the abnormal serum Na level, (4) the presence of risk factors, and the presence of excessive ADH levels.

CNS effects

When serum Na declines, the decrease in serum osmolality results in an osmotic gradient across the blood-brain barrier that causes water to move into the brain intracellular space. The resultant edema is responsible for symptoms such as headache, nausea, vomiting, irritability, and seizures.

Animal studies demonstrated that the brain swells by as much as 46% of the predicted level for a particular level of serum Na compared with other tissues after 6 hours of hyponatremia. This discrepancy increases with time. This response of the brain tissue indicates a clinically significant degree of adaptation to hypo-osmolality. Therefore, the subsequent amount of brain swelling is less than expected when osmotic gradient alone is considered. Cerebral adaptation to hyponatremia is accomplished by means of 2 mechanisms: (1) loss of interstitial fluid into the CSF and (2) loss of cellular solute and organic osmolytes.

When water moves into the brain, increasing hydrostatic pressure shifts interstitial fluid into CSF, which is subsequently absorbed through the arachnoid villi. The interstitial fluid is rich in Na, and, by removing this fluid, the brain equilibrates the osmolar gradient. In addition, intracellular solutes (eg, potassium) act similarly with a maximal response occurring in 24 hours. If hyponatremia lasts longer than this, intracellular amino acids are extruded to maintain the osmolar gradient. This shift of solutes and organic osmolytes plays an important role in protecting the brain from cerebral edema. The resultant hypo-osmolar state makes the brain vulnerable to dehydration secondary to rapid correction of hyponatremia during treatment.

The optimal speed of correction is unknown. However, rapid correction of fully compensated chronic hyponatremia results in a demyelinating lesion in the pons. This lesion was previously known as central pontine myelinosis (CPM) and is now called osmotic demyelination syndrome (ODS) because the pathology also involves extrapontine areas.

Hyponatremic encephalopathy

Risk factors for hyponatremic encephalopathy include age, sex, and hypoxia (hypoxemia).

Children and adolescents younger than 16 years are at increased risk for hyponatremic encephalopathy because of their relatively high ratio of brain size to intracranial volume compared with that of adults. The pediatric brain reaches adult size by 6 years of age, whereas the skull does not reach adult size until 16 years of age. As a consequence, children can develop symptomatic hyponatremia with Na concentrations higher than those observed in adults.

Recent epidemiologic data have shown that the risk for developing permanent neurologic sequelae or death from hyponatremic encephalopathy is substantially higher in menstruating women than in men or postmenopausal women (Moritz, 2003). The relative risk of death or permanent neurologic damage due to hyponatremic encephalopathy is about 30 times greater for women than for men and about 25 times greater for menstruating women than for postmenopausal women. Premenopausal women are at high risk for developing hyponatremic encephalopathy because of the inhibitory effects of sex hormones and the effects of vasopressin on the cerebral circulation.

Hypoxia or hypoxemia is a major risk factor for hyponatremic encephalopathy. The combination of systemic hypoxemia and hyponatremia is more deleterious than either factor alone because hypoxemia impairs the ability of the brain to adapt to hyponatremia, leading to a vicious cycle of worsening hyponatremic encephalopathy that exacerbates hypoxemia.

Patients with symptomatic hyponatremia can develop hypoxemia by means of at least 2 different mechanisms: noncardiogenic pulmonary edema and hypercapnic respiratory failure. Respiratory failure can be of sudden onset in patients with symptomatic hyponatremia. Recent data showed that hypoxia is the strongest predictor of mortality in patients with symptomatic hyponatremia (Moritz, 2003).

Cardiovascular response to hyponatremia

Arterial blood volume may be increased, decreased, or normal depending on the type of hyponatremia, such as hypervolemic, hypovolemic, or euvolemic. The distribution of water and solute in the intracellular and extracellular spaces determine the intravascular volume. Fluid shifts from the extracellular space to the intracellular space with a subsequent decrease in arterial blood volume. This reduction in volume may result in hypotension. Because of this fluid shift, hyponatremia causes hemodynamic disturbance more pronounced than that expected for the degree of dehydration.

Frequency

United States

The frequency is 1.5% among hospitalized pediatric patients.

International

In India, the frequency of hyponatremia is 29.8% (Prasad, 1994). It is more frequent in summer (36%) than in winter (24%).

Sex

Incidences of hyponatremia are equal in both sexes. However, CNS complications are most likely to occur among premenopausal women.

Age

Hyponatremia is most common at the extremes of age. Neonates and infants are most likely to develop hyponatremia because they depend on their caregivers for their water intake.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Feeding with hypotonic formula or free water during infancy
• Conditions causing GI fluid loss, such as the following:
• • Diarrhea
  • Vomiting
  • Fistulas
• Renal disorders, including the following:
• • Salt-losing nephropathy
  • Acute renal failure
  • Chronic renal failure
• Postoperative states
• Psychiatric conditions
• Coma
• Drug use
• CNS and pulmonary diseases
• Hypothyroidism
• Adrenal insufficiency
• Cirrhosis
• Congestive heart failure
• Acquired immunodeficiency syndrome

Physical

• CNS findings
• • Early signs include the following:
    • Anorexia
    • Headache
    • Nausea
    • Emesis
  • Advanced signs include the following:
    • Impaired response to verbal stimuli
    • Impaired response to painful stimuli
    • Bizarre behavior
    • Hallucinations
    • Obtundation
    • Incontinence
    • Respiratory insufficiency
  • Far-advanced signs include the following:
    • Decorticate or decerebrate posturing
    • Bradycardia
    • Hypertension or hypotension
    • Altered temperature regulation
    • Dilated pupils
    • Seizure activity
    • Respiratory arrest
    • Coma
• Cardiovascular findings
• • Hypotension
  • Tachycardia
• Musculoskeletal findings
• • Weakness
  • Muscular cramps

Causes

• Hypervolemic hyponatremia
• • Congestive heart failure
  • Cirrhosis
  • Nephrotic syndrome
  • Acute or chronic renal failure
• Hypovolemic hyponatremia due to renal loss
• • Diuretic excess
  • Osmotic diuresis
  • Salt-wasting diuresis
  • Adrenal insufficiency
  • Metabolic alkalosis
  • Pseudohypoaldosteronism
• Hypovolemic hyponatremia due to extrarenal loss
• • GI conditions, such as the following:
    • Vomiting
    • Diarrhea
    • Tubes
    • Fistula
  • Sweat
  • CSWS
  • Third-spacing conditions, such as the following:
    • Pancreatitis
    • Burns
    • Muscle trauma
    • Peritonitis
    • Effusions
    • Ascites
• Normovolemic hyponatremia
• • SIADH
    • Tumors - Adenocarcinoma of the duodenum, adenocarcinoma of the pancreas, carcinoma of the ureter, carcinoma of the prostate, Hodgkin disease, thymoma, acute leukemia, lymphosarcoma, or histiocytic lymphoma
    • Chest disorders - Infection (eg, tuberculosis or bacterial, mycoplasmal, viral, or fungal infection), positive-pressure ventilation, decreased left atrial pressure (eg, due to pneumothorax, atelectasis, asthma, cystic fibrosis, mitral valve commissurotomy, ligation of the patent ductus arteriosus ligation), or malignancy
    • CNS disorders - Infection (eg, tuberculous meningitis, bacterial meningitis, encephalitis), trauma, hypoxia-ischemia, psychosis, brain tumor, or miscellaneous CNS disorders (eg, Guillain-Barré syndrome, ventriculoatrial shunt obstruction, acute intermittent porphyria, cavernous sinus thrombosis, multiple sclerosis, anatomic abnormalities, vasculitis, stress, idiopathic causes)
    • Drugs - Chlorpropamide, vincristine, vinblastine, diuretics, clofibrate, carbamazepine, fluphenazine, amitriptyline, morphine, isoproterenol, nicotine, adenine arabinoside, colchicine, or barbiturates
  • Reset osmostat
  • Glucocorticoid deficiency
  • Hypothyroidism
  • Water intoxication due to intravenous (IV) therapy, tap-water enema, or psychogenic water drinking

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Verify the accuracy of laboratory results.
• Exclude pseudohyponatremia.
• • Findings on flame emission spectrophotometry
    • If Na measurement is performed by using flame emission spectrophotometry, hyponatremia is falsely low in patients with hyperproteinemia and hypertriglyceridemia.
    • Raised proteins and lipid levels increase the nonaqueous portion of plasma, which normally forms 7% of the plasma.
    • However, new ion-specific Na electrodes measure Na from only the aqueous phase, enabling accurate estimation of serum Na concentrations.
  • Correction factors for raised proteins and lipids
    • Triglycerides (in milligrams per deciliter) X 0.002 = decrease in plasma Na level (in milliequivalents per liter)
    • (Plasma protein level [in grams per deciliter] - 8) X 0.25 = decrease in plasma Na (in milliequivalents per liter)
• Exclude distributive hyponatremia.
  • Distributive hyponatremia occurs when the plasma glucose concentration exceeds 100 mg/dL.
  • Each 100-mg/dL increase in the glucose level above 100 mg/dL leads to a 1.6-mEq/L decrease in the Na concentration.
• Obtain routine laboratory studies to assess the following:
• • Serum Na level
  • Serum osmolality
  • BUN and creatinine levels
  • Urine osmolality
  • Urine Na level
• Urine Na level changes according to the type of hyponatremia.
• • Hypovolemic hyponatremia
    • Renal losses caused by diuretic excess, osmotic diuresis, salt-wasting nephropathy, adrenal insufficiency, proximal renal tubular acidosis, metabolic alkalosis, or pseudohypoaldosteronism result in a urine Na concentration of more than 20 mEq/L.
    • Extrarenal losses caused by vomiting, diarrhea, sweat, or third spacing result in a urine Na concentration of less than 20 mEq/L secondary to increased tubular reabsorption of Na.
  • Normovolemic hyponatremia: When hyponatremia is caused by SIADH, reset osmostat, glucocorticoid deficiency, hypothyroidism, or water intoxication, the urine Na concentration is more than 20 mEq/L.
  • Hypervolemic hyponatremia
    • If hyponatremia is caused by an edema-forming state (eg, congestive heart failure, cirrhosis, nephrotic syndrome), the urine Na concentration is l20 mEq/L because effective arterial perfusion is low despite an increase in total body water.
    • If hyponatremia is caused by acute or chronic renal failure, the urine Na concentration is more than 40 mEq/L.
• Special laboratory studies include tests of the following:
• • Aldosterone level
  • Cortisol level
  • Thyroid function
  • Corticotropic hormone level
  • ADH level

Imaging Studies

• Neuroimaging
• • CT scanning is useful for evaluating causative intracranial pathologies, such as tumors, hydrocephalus, and hemorrhage. It is also useful for detecting cerebral edema and demyelinating lesions that occur during treatment. CT scanning is superior to MRI in delineating hemorrhage and calcifications.
  • MRI is sensitive for detecting tumors and demyelination.
• Abdominal imaging
• • Ultrasonography may be performed to detect abdominal masses, such as those due to bilateral adrenal hyperplasia, and adrenal tumors.
  • CT and MRI may help in further delineating the tumor.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Principles of treatment
• • The most common and devastating effects of hyponatremia are of CNS origin. Therefore, being aware of the risk factors that lead to hyponatremia and hyponatremic encephalopathy is important.
  • Optimal treatment of hypotonic hyponatremia requires balancing the risks associated with treating and preventing cerebral edema while avoiding osmotic demyelination.
  • Although cerebral adaptation to low serum Na occurs slowly, it prevents deleterious effects of hypo-osmolality. However, this protective mechanism leaves the brain susceptible to dehydration during treatment, especially in persons with chronic hyponatremia, if the correction is rapid.
• Equations used in managing hyponatremia:
  • To estimate the effect of 1 L of any infusate on serum Na concentration: Change in Na concentration = (infusate Na level - serum Na level)/(total body water + 1)
  • To estimate the effect of 1 L of any infusate containing Na and potassium (K) on serum Na concentration: Change in serum Na level = [(infusate Na level + infusate K level) - serum Na level]/(total body water + 1)
• Na concentrations of various fluids used in pediatric practice are as follows:

  Solution	Na Concentration, mEq/L
  5% NaCl in water	855
  3% NaCl in water	513
  0.9% NaCl in water	154
  Ringer's lactate	130
  0.45% NaCl in water	77
  0.2% NaCl in water	34
  5% Dextrose in water	0

• Management of hypovolemic hyponatremia
  • The immediate goal is to correct volume depletion with normal NaCl solution. As soon as the patient's blood pressure becomes normal, hyponatremia should be corrected. In patients with seizure, 3% NaCl should be given while volume depletion is corrected.
  • No consensus has been reached about the optimal treatment of symptomatic hyponatremia. Physiologic considerations indicate that a relatively small increase in the serum Na concentration, on the order of 5%, should substantially reduce cerebral edema. The available evidence indicates that even a 9-mEq/L increase in serum Na concentration over 24 hours can result in demyelinating lesions. Given the risk of demyelinating lesions, the recommended rate of correction should not exceed 8 mEq/L/d. Even hyponatremia-induced seizures can be stopped with mean changes in serum Na concentration of only 3-7 mEq/L.
  • Treatment if normovolemic hyponatremia due to SIADH requires the administration of 3% NaCl, fluid restriction, and IV administration of furosemide. Furosemide is given to offset the volume expansion created by the 3% Na infusion. As previously discussed, the plan is to raise the serum Na concentration by 3-7 mEq/L to stop symptoms. Then closely monitor electrolyte levels so that the correction does not exceed 8 mEq/L/d.
  • In patients with hypervolemic hyponatremia, administer 3% NaCl to stop the symptoms, as previously discussed, and treat the cause.
• Management of asymptomatic hyponatremia
• • In individuals with hypovolemic hyponatremia, the clinical should not rush to correct hyponatremia. The main principle is to avoid hypotonic fluids and to slowly correct Na levels, especially when hyponatremia has been present for 48 hours or longer. When the duration of hyponatremia is unknown, hyponatremia in outpatients as chronic hyponatremia (>48 h). Closely monitor electrolyte values, and the rate of correction should not exceed 8 mEq/L/d.
  • In patients with normovolemic hyponatremia, restriction of fluids to two-thirds (or less) of the volume needed for maintenance is the mainstay of treatment. Diuretics can be administered with fluid restriction to remove free water. Once again, the change in Na levels should not exceed 8 mEq/L/d.
  • In recalcitrant euvolemic hyponatremia, one can use demeclocycline to induce therapeutic nephrogenic diabetes insipidus, which might help eliminate excessive water. However, one must remember that total correction should not exceed the established goal. In patients with hypervolemic hyponatremia, restrict fluids, and treat the underlying cause.

Consultations

• Transfer patients with symptomatic hyponatremia to a pediatric intensive care unit for appropriate treatment and close monitoring.
• Consult an endocrinologist when patients have hypothyroidism or adrenal insufficiency.
• Consult a nephrologist when patients have salt-losing nephropathy, renal failure, or recalcitrant hyponatremia.

Diet

• Patients with salt-wasting disorders (eg, salt-losing nephropathies) need Na supplementation throughout the period of continued loss of excessive Na.
• Patients with SIADH and renal failure require fluid restriction.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical therapy includes the administration of 3% Na chloride (Na 513 mEq/L), normal Na chloride solution (Na 154 mEq/L), diuretics, and other drugs used to treat SIADH (eg, lithium carbonate, demeclocycline, ethanol, phenytoin, vasopressin analogs).

Drug Category: Diuretics

These agents promote renal excretion of water and electrolytes. They are used to treat heart failure or hepatic, renal, or pulmonary disease when Na and water retention results in edema or ascites. They may be used as monotherapy or combination therapy for hypertension.

Drug Category: ADH inhibitors

These agents produce diuresis by inhibiting ADH-induced water reabsorption.

Drug Name	Demeclocycline (Declomycin)
Description	Only tetracycline used to treat SIADH. Produces diuresis by inhibiting ADH-induced water reabsorption in distal portion of convoluted tubules and collecting ducts of kidneys. Effects observed within 5 d and are reversed 2-6 d after cessation of therapy. Administer 1 h before or 2-3 h after ingestion of milk or food.
Adult Dose	600-1200 mg PO divided tid/qid
Pediatric Dose	>8 years: 7-13 mg/kg PO divided bid/qid
Contraindications	Documented hypersensitivity; do not use in children <8 y; do not use sodium bicarbonate concurrently because of increased gastric pH unless administration of each agent can be separated by 1-3 h
Interactions	Antacids reduce absorption; calcium salts and magnesium salts in foods and dairy products can form chelates with tetracyclines and impair absorption; ferrous sulfate and other iron salts can affect absorption of demeclocycline or iron product; may increase action of warfarin; concomitant use of PO contraceptives containing estrogen may reduce their effect and increase incidence of breakthrough bleeding; methoxyflurane can increase potential for demeclocycline-induced nephrotoxicity; potentiates neuromuscular effects of nondepolarizing neuromuscular blockers
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in breastfeeding women; adverse effects include increased intracranial pressure, diarrhea, nausea, vomiting, epigastric distress and anorexia, hepatotoxicity, candidiasis (oral, rectal, or vaginal), photosensitivity, rashes, discolored nails, erythema multiforme, tooth discoloration, enamel hypoplasia, teratogenesis, neutropenia, eosinophilia, and Fanconi syndrome

Drug Name	Phenytoin (Dilantin)
Description	Inhibits secretion of ADH.
Adult Dose	Loading: 15-20 mg/kg PO/IV Maintenance: 5-8 mg/kg PO/IV q8h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; sinoatrial block, second-degree and third-degree atrioventricular (AV) block, sinus bradycardia, or Adams-Stokes syndrome (unless pacemaker present)
Interactions	Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity Effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (long-term ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in hematologic dental disease, intermittent porphyria, hepatic disease, renal failure, radiation therapy, hypothyroidism, and systemic lupus erythematosus Rapid IV infusion can result in arrhythmias, marked hypotension, and cardiac arrest; infusion not to exceed 1 mg/kg/min CNS reactions include dizziness, drowsiness, nystagmus, ataxia, lethargy, coma, seizures, choreoathetosis, and dystonic reaction; severity increases as serum concentrations increase; lethargy, dizziness, and drowsiness may occur at therapeutic serum concentrations, but ataxia, coma, and drug-induced seizures usually occur at supratherapeutic concentrations GI effects include nausea, vomiting, constipation, abdominal pain, and gingival hyperplasia Dermatologic reactions include maculopapular rash and more serious responses (eg, bullous rash, exfoliative dermatitis, purpura, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis); can produce hypertrichosis or hirsutism (unusual growth of hair) in some patients Lupuslike symptoms have been described with use Lymph node reactions include lymphoid hyperplasia, pseudolymphoma, pseudo-pseudolymphoma, and lymphoma Blood dyscrasias (eg, thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia, macrocytosis, megaloblastic anemia) Long-term therapy can lead to osteomalacia secondary to interference with vitamin D metabolism Has been associated with sexual dysfunction (eg, decreased libido, impotence, priapism) Injection contains 40% propylene glycol, which caused cardiac arrhythmias when infused into dogs; never administer IM because phenytoin precipitates at injection site, producing delayed and erratic absorption Teratogenic agent; fetal hydantoin syndrome and manifestations include craniofacial features (eg, strabismus, broad and/or depressed nasal bridge, high-arched palate, smaller head circumference)

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Avoid administering hypotonic fluids on a routine basis and in high-risk patients. This pattern of use is the most common error in hospitalized patients.
• Carefully monitor patients receiving drugs that can cause hyponatremia.
• Regularly monitor serum electrolytes in postoperative patients and in those with brain tumors, intracranial infections, pulmonary infections, or head trauma.

Complications

• ODS: Brain damage and cerebral demyelination can develop if the serum Na level changes rapidly. Cerebral demyelinating lesions are rare but recognized complications of hyponatremic therapy.
• • Epidemiology: The exact incidence of ODS is unknown, and data are derived primarily from autopsy series. In 3548 consecutive autopsies in adults with ODS, the typical lesions were found in 9 (0.25%) (Wright, 1979). In another study, Sterns et al (1994) observed myelinolysis in as many as 25% of patients with hyponatremia who were treated with aggressive protocols. The incidence is highest among high-risk groups.
  • Risk factors
  • • Alcoholism (common)
    • Malnutrition (common)
    • After prolonged diuretic use (frequent)
    • Psychogenic polydipsia (rare if acute)
    • Burns (infrequent, and often in context of hypernatremia)
    • Liver transplantation (well recognized)
    • Pituitary surgery (rare)
    • Urologic or gynecologic surgery, especially if it involved glycine infusions (rare)
    • Correcting serum Na into hypernatremic levels
    • Hypoxia
  • Subtypes
  • • CPM: Lesions are confined to the pons.
    • Extrapontine myelinolysis (EPM): Lesions are confined to the basal ganglia, cerebrum, and cerebellum.
    • ODS: CPM and EPM lesion sites are both present.
  • Pathogenesis: The pathogenesis of ODS is unknown. Cells conditioned to hypo-osmotic hyponatremia may have a decreased adaptive capacity to osmotic stress. The predilection for myelinolysis in the pons is thought to be a result of the grid arrangement of the oligodendrocytes in the base of pons, which limits their mechanical flexibility and, therefore, their capacity to swell. During hyponatremia, these cells can adapt only by losing ions instead of swelling. This limitation makes them prone to damage when Na is replaced. The risk factors mentioned above make normal adaptation difficult.
• Clinical manifestations of CPM:
• • Ataxia
  • Coma
  • Depressed or absent reflexes
  • Dysarthria
  • Dysphasia
  • Lethargy
  • Ophthalmoplegia
  • Quadriparesis
• Clinical manifestations of EPM:
• • Akinesis
  • Ataxia
  • Catatonia
  • Choreoathetosis
  • Cogwheel rigidity
  • Disorientation
  • Dysarthria
  • Dystonia
  • Emotional lability
  • Extra pyramidal symptoms
  • Gait disturbance
  • Movement disorders
  • Mutism
  • Myoclonus
  • Myokymia
  • Parkinsonism
  • Rigidity
  • Tremor
• Diagnosis of CPM: The diagnosis of CPM is based on clinical suspicion and confirmed with imaging studies. MRI is the primary method for diagnosis, and it is superior to CT. During the acute phase, symmetrical and hypointense lesions can be identified on a T1-weighted MRI. During the subacute phase, symmetrical and hypointense lesions are seen on T2-weighted images. Lesions on MRI may appear days to weeks after the onset of symptoms; in some cases, these may resolve, over months.
• Management
• • At present, supportive treatment is all that can be recommended with certainty. Therefore, prevention becomes important because hyponatremia is preventable and causes neurologically significant morbidity and mortality.
  • To the authors' knowledge, no trials for the treatment of ODS have been conducted. Small case series or single case reports of treatments, including steroids, IV immunoglobulin, and thyrotrophin-releasing hormone, have all shown good outcomes. However, the results are difficult to interpret because of the lack of clinical trials.

Prognosis

• Early reports of ODS indicated almost a 100% mortality rate within 3 months after hospital admission.
• Recent studies of ODS showed a relatively mild clinical course without substantial neurologic deficits in survivors.

Patient Education

• Advise parents not to replace diarrheal fluid loss with hypotonic fluids such as tea or soda.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Avoid rapid correction of asymptomatic hyponatremia.
• • In persons with asymptomatic chronic hyponatremia, rapid correction may result in the severe neurologic impairment of CPM.
  • In individuals with acute symptomatic hyponatremia, begin therapy with IV 3% NaCl by using an IV pump with the infusion designed to raise plasma Na concentrations at a rate of approximately 1 mmol/L/h until symptoms abate. After symptoms resolve, correction can proceed at a slow rate.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med. May 25 2000;342(21):1581-9. [Medline].
• Ayus JC, Arieff AI. Pulmonary complications of hyponatremic encephalopathy. Noncardiogenic pulmonary edema and hypercapnic respiratory failure. Chest. Feb 1995;107(2):517-21. [Medline].
• Berry PL, Belsha CW. Hyponatremia. Pediatr Clin North Am. Apr 1990;37(2):351-63. [Medline].
• Brown WD. Osmotic demyelination disorders: central pontine and extrapontine myelinolysis. Curr Opin Neurol. Dec 2000;13(6):691-7. [Medline].
• Fraser CL, Arieff AI. Epidemiology, pathophysiology, and management of hyponatremic encephalopathy. Am J Med. Jan 1997;102(1):67-77. [Medline].
• Gross P. Treatment of severe hyponatremia. Kidney Int. Dec 2001;60(6):2417-27. [Medline].
• Gruskin AB, Sarnaik A. Hyponatremia: pathophysiology and treatment, a pediatric perspective. Pediatr Nephrol. May 1992;6(3):280-6. [Medline].
• Harrigan MR. Cerebral salt wasting syndrome. Crit Care Clin. Jan 2001;17(1):125-38. [Medline].
• Haycock GB. The syndrome of inappropriate secretion of antidiuretic hormone. Pediatr Nephrol. Jun 1995;9(3):375-81. [Medline].
• Lin M, Liu SJ, Lim IT. Disorders of water imbalance. Emerg Med Clin North Am. Aug 2005;23(3):749-70, ix. [Medline].
• Marino PL. Hypertonic and hypotonic syndromes. In: The ICU Book. 2nd ed. Philadelphia, Pa:. Lippincott Williams and Wilkins;1998: 631-46.
• Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry. Sep 2004;75 Suppl 3:iii22-8. [Medline].
• Moritz ML, Ayus JC. The pathophysiology and treatment of hyponatraemic encephalopathy: an update. Nephrol Dial Transplant. Dec 2003;18(12):2486-91. [Medline].
• Moritz ML, Ayus JC. Disorders of water metabolism in children: hyponatremia and hypernatremia. Pediatr Rev. Nov 2002;23(11):371-80. [Medline].
• Musana AK, Yale SH. Central pontine myelinolysis: case series and review. WMJ. Aug 2005;104(6):56-60. [Medline].
• Oh MS, Kim HJ, Carroll HJ. Recommendations for treatment of symptomatic hyponatremia. Nephron. 1995;70(2):143-50. [Medline].
• Prasad SV, Singhi S, Chugh KS. Hyponatremia in sick children seeking pediatric emergency care. Indian Pediatr. Mar 1994;31(3):287-94. [Medline].
• Sterns RH. The treatment of hyponatremia: first, do no harm. Am J Med. Jun 1990;88(6):557-60. [Medline].
• Sterns RH, Cappuccio JD, Silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol. Feb 1994;4(8):1522-30. [Medline].
• Wright DG, Laureno R, Victor M. Pontine and extrapontine myelinolysis. Brain. Jun 1979;102(2):361-85. [Medline].
• Zarinetchi F, Berl T. Evaluation and management of severe hyponatremia. Adv Intern Med. 1996;41:251-83. [Medline].

Article Last Updated: Dec 5, 2006