Hyponatremia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Overview

Hyponatremia, serum sodium < 135 mEq/L, is the most common electrolyte disturbances in the clinical encounter. Treatment of hyponatremia based on the etiologies is the best approach because in most cases, hyponatremia resolves with the treatment of underlying causes.

The rate of correction for hyponatremia is very important to prevent the syndrome of osmotic demyelination.

Medical Therapy

Hyponatremia must be corrected slowly in order to lessen the chance of the development of Osmotic demyelination syndrome or central pontine myelinolysis (CPM), a severe neurological disease. In fact, overly rapid correction of hyponatremia is the most common cause of that potentially devastating disorder. During treatment of hyponatremia, the serum sodium should not be allowed to rise by more than 8 mmol/l over 24 hours (i.e. 0.33 mmol/l/h rate of rise). In practice, rapid correction of hyponatremia and then CPM is most likely to occur during the treatment of hypovolemic hyponatremia. In particular, once the hypovolemic state has been corrected, the signal for ADH release disappears. At that point, there will be an abrupt water diuresis (since there is no longer any ADH acting to retain the water). A rapid and profound rise in serum sodium can then occur. Should the rate of rising of serum sodium exceed 0.33  mmol/l/h over several hours, vasopressin may be administered to prevent ongoing rapid water diuresis.

Treatment based on the conditions :

Conditions	Treatment
Pseudohyponatremia	Hyperglycemia: Insulin, IV fluids, isotonic saline Hyperproteinemia: Chemotherapy (multiple myeloma), Stop IVIG Hyperglycemia: Statin therapy Lab error: Repeat the test
Hypovolemic Hyponatremia	Gastrointestinal loss:Intravenous fluids Renal loss Osmotic diuresis: Correct glucose level, stop mannitol use Renal tubular acidosis : Correct acidosis, sodium bicarbonate Salt-wasting nephropathies : Correct underlying cause Diuretic use : Stop diuretic therapy Mineralocorticoid deficiency : Steroid replacement therapy, isotonic saline Third spacing : Intravenous fluids, treat the underlying cause Cerebral salt-wasting syndrome : Isotonic or hypertonic saline, fludrocortisone rarely
Hypervolemic hyponatremia	Heart failure : Diuretics, angiotensin-converting enzyme inhibitors, beta blockers, vaptans Hepatic failure/cirrhosis : Furosemide (Lasix), spironolactone (Aldactone), transplant, vaptans (not tolvaptan for cirrhosis) Renal failure (acute or chronic), Nephrotic syndrome : Correct underlying disease with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers,treat underlying cause for nephrotic syndrome
Euvolemic Hyponatremia	Drugs : Stop causative medications SIADH/SIAD : Fluid restriction, demeclocycline, consider vaptans (second line), oral salt tablets, urea Nephrogenic SIAD : Fluid restriction, loop diuretics, oral salt tablets, urea Hight fluid intake : Diuresis Hypothyriodism : Thyroid replacement therapy Glucocorticoid deficiency : Steroid replacement therapy Reset osmostat : Treat underlying disease
Rate of correction	Goal: Raise the serum sodium concentration by 4 to 6 mEq/L in a 24-hour period Maximum: Should be ≤ 8 mEq/L in any 24-hour period, pediatric: rates ≤ 9 mEq/ L
Acute hyponatremia	For severe symptoms : Adult: 100 mL of 3% saline (NaCl) infused intravenously over 10 minutes X 3 ( if needed) in 30 minutes Pediatric: 3 to 5 mL/kg of 3 % saline is the suggested initial therapy For mild to moderate symptoms : Adult: 3% saline infused at 0.5-2 mL / kg / h, with a low risk of herniation Pediatric: 6 to 8 mEq/L over 24 hours (The rate of correction need not be restricted in patients with true acute hyponatremia, nor is relowering of excessive corrections indicated, however, if there is any uncertainty as to whether the hyponatremia is chronic versus acute, then the limits for correction of chronic hyponatremia should be followed)
Chronic hyponatremia	Asymptomatic: Primary management ‡ Mild to moderate symptoms : With intracranial pathology:100 mL bolus of 3 % saline x 2 (to a total dose of 300 mL) in 30 minutes Without intracranial pathology: Severe hyponatremia (< 120 mEq/L): 3 % saline at 15 to 30 mL/ h + desmopressin in patients with risk of overcorrection and osmotic demyelination syndrome Mild to moderate hyponatremia (120-129 mEq/L): Primary management ‡ Severe symptoms : 100 mL of 3% saline infused intravenously over 10 minutes X 3 ( if needed ) in 30 minutes Pediatric: Treat based on the cause, 6 to 8 mEq/L over 24 hours Primary management ‡ Hyponatremic sodium deficit = Current total body water (TBW) x (desired plasma sodium - actual sodium) ( TBW= 0.6 x weight)
Management of overcorrection	Baseline Serum Na ≥ 120 mmol/L: probably unnecessary, start once limit is exceeded Baseline Serum Na < 120 mmol/L: start relowering with electrolyte-free water or desmopressin after correction exceeds 6–8 mmol/L per d

‡ Primary management:

• Treat the underlying cause of hyponatremia
• Discontinue responsible drugs unless there is no other substitute
• Treat chronic hyponatremia and SIADH with loop diuretics, oral salt tablets, urea
• Reduce intake of electrolyte-free water(IV fluid, oral intake)

Medications	Clinical use
Salt tablets	Dose: 5-15 gr daily Side effects: Hypernatremia, fluid overload Indications: SIAD combined with furosemide
Furosemide	Dose:20-80 mg daily Side effects: Orthostatic hypotension, impaired glucose tolerance, hyperuricemia, azotemia, ototoxicity, pancreatitis Indications: SIAD, CHF, and liver disease with ascites
Urea	Dose: 15–30 g daily Side effects: Too rapid an increase in serum sodium, azotemia Indications: SIAD, hyponatremia of heart failure
Demeclocycline	Dose: 600–1200 mg total daily dose, dosed 3 to 4 times daily Side effects: CNS side effects, nausea, vomiting, diarrhea, photosensitivity, azotemia, acute renal failure, hematologic effects with long-term therapy Indications: SIAD

Practical approach to treatment of hyponatremia

Duration of hyponatremia • Acute hyponatremia develops < 48 hours • Chronic hyponatremia > 48hours or unknown duration

Hospitalize the patients if • The patient is symptomatic regardless of duration • Serum sodium < 125 mEq/L • Acute hyponatremia

Chronic

Acute

Is the patient symptomatic ( Whether mild, moderate, severe)

Hospitalize the patient and check for symptoms of hyponatremia ( Whether mild, moderate, severe)

Asymptomatic but serum Na < 120 mEq/L

Symptomatic patients must be admitted

No symptoms

Are the symptoms severe?

Recheck serum Na if the patient is hyponatremic ( incase of water diuresis autocorrectiom may happen

Yes

Yes

Yes

No

No

Manage the patient in the hospital • Primary management ‡ • Monitor serum Na every 4 hours to ensure appropriate rate of correction ≤ 8 mEq/L in 24 hours

Therapy • 100 ml bolus of 3% saline,repeat as needed if symptoms persist • Monitor serum Na hourly till it is increased by 4 to 6 mEq/L • Primary management‡

• Primary management ‡ • Monitor serum Na every 4 hour (Na rise ≤ 8 mEq/L in 24 h)

If no, Primary management ‡

Yes

Is there any history of intracranial pathology?Trauma, surgery, hemorrhage, neoplasm, space occupying lesions

Treatment • Monitor serum Na hourly till it is increased by 4 to 6 mEq/L • Further decline in serum Na means delayed water absorbtion • If serum Na declines give 50ml bolus of 3% saline • Primary management‡

No

Yes

Is the serum Na < 120 mEq/L?

Yes

No

Is the hyponatremia due to self-induced water intoxication?

• Primary management ‡ • Monitor serum Na every 6-12 hours

Yes

No

Therapy • Primary management ‡ • Monitor serum Na every 6-12 hours

Is the patient hypervolemic/edematous (CHF,RF,cirrhosis)

Yes

No

Treatment • Primary management ‡ • Infusion of 3% saline at the rate of 15-30 ml/hour plus IV furosemide(40 mg or higher)twice daily • Monitor serum Na frequently to adjust rate of furosemide and saline to achieve 4-6mEq/L rise in serum Na • Discontinue regimen when serum Na is at least 125 mEq/L

Is the cause of hyponatremia reversible? •True hypovolemia •Adrenal insufficiency •Transient SIAD

No

Yes

Evaluate the risk for osmotic demyelination syndrome • Serum Na ≤ 105 mEq/L • Associated hypokalemia • Alcoholic patient • Malnourished patient • Advanced liver disease

No

Yes

Treatment • Primary management ‡ • Infusion of 3% salin at 15-30 ml/hour • Monitor serum Na to achieve rate of correction 4-6 mEq/L • Discontinue regimen when serum Na is at least 125 mEq/L

Treatment • Infusion of 3% saline at 15-30 ml/hour plus IV or subcutaneous desmopressin 1 to 2 mcg every 6-8 hours • Monitor serum Na to achieve rate of correction 4-6 mEq/L • Discontinue regimen when serum Na is atleast 125 mEq/L • Primary management ‡

‡ Primary management:

• Treat the underlying cause of hyponatremia
• Discontinue responsible drugs unless there is no other substitute
• Treat chronic hyponatremia and SIADH with loop diuretics, oral salt tablets, urea
• Reduce intake of electrolyte-free water(IV fluid, oral intake)

Vaptan Drugs

The “vaptan” class of drugs contains a number of compounds with varying selectivity for ADH receptors, several of which are either already in clinical use or in clinical trials. Tolvaptan improves short term survival in most decompensated cirrhotic hyponatremia patients with resolved serum sodium.

Unselective (mixed V1A, V2):

• Conivaptan

V1A selective:

• Relcovaptan

V1B selective:

• Nelivaptan

V2 selective:

• Lixivaptan

• Mozavaptan

• Satavaptan

• Tolvaptan

Name	Characteristics
	Receptors	Route of administration	Urine volume	Urine osmolality	Sodium excretion in 24 hours	Dosage
Conivaptan	V1a/V2	IV	↑	↓	↔	20 mg loading dose followed by a continuous infusion of either 40 or 80 mg/day for four days
Lixivaptan	V2	Oral	↑	↓	↔ at low dose ↑ at high dose	Tial
Satavaptan	V2	Oral	↑	↓	↔	Trial
Tolvaptan	V2	Oral	↑	↓	↔	15 mg once daily then after at least 24 hours, may increase to 30 mg once daily to a maximum of 60 mg once daily titrating at 24-hour intervals to desired serum sodium concentration. Avoid fluid restriction during the first 24 hours of therapy. Do not use for more than 30 days due to the risk of hepatotoxicity

The V2-receptor antagonists tolvaptan and conivaptan allow excretion of electrolyte-free water and are effective in increasing serum sodium in euvolemic and hypervolemic hyponatremia.

Cautions for use Vaptans in hyponatremia:

• Vaptans should not be used in hypovolemic hyponatremia.

• Vaptans should not be used in conjunction with other treatments for hyponatremia.
• Do not start vaptans immediately after cessation of other treatments for hyponatremia, particularly 3% NaCl.
• Monitor serum sodium closely (every 6-8 hours) for the first 24-48 hours after initiating treatment.
• Adequate fluid intake should be maintained during the first 24-48 hours of treatment; hyponatremia may be corrected too quickly with coincidental fluid restriction; in patients with an impaired or inadequate thirst mechanism ( intubated or unconscious patients), sufficient fluid should be provided to prevent overly rapid correction due to overly rapid aquaresis.
• Serum sodium should be monitored frequently to consider stopping the vaptans if there is a deterioration or change in the patient’s condition (NPO status, intubation) that restrict the ability to ingest fluid, request, access.
• Severe, symptomatic hyponatremia should be managed with 3% NaCl, for quicker and more certain correction of serum sodium than vaptans.

• Currently, there are no sufficient data for use of vaptans in severe asymptomatic hyponatremia (serum sodium <120 mmol/L)—caution and more frequent monitoring is necessary for these patients.

• Overcorrection should be treated with re-lowering the serum sodium to safe limits (see Managing Excessive Correction of Chronic Hyponatremia).

Contraindicated medications

Hyponatremia is considered an absolute contraindication to the use of the following medications:

• Acetazolamide

Hypovolemic hyponatremia is considered an absolute contraindication to the use of the following medications:

• Tolvaptan
• Conivaptan