Disorders of Water and Sodium Balance

Richard H. Sterns, MD, FACP
Medical University of Rochester School of Medicine and Dentistry

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Low plasma sodium concentration
• Usually associated with low plasma osmolality level and body fluids that are too dilute

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Differential Diagnosis

• Hyperglycemia
• Intravenous hypertonic mannitol therapy
• Intravenous γ-globulin therapy
• Irrigant absorption (prostatectomy or intrauterine surgery)
• Pseudohyponatremia
  • Severe hyperlipidemia
  • Multiple myeloma
  • Macroglobulinemia

• Neurologic syndrome that develops when large volumes of water are retained within a short period (< 48 hr)
  • Headaches
  • Weakness
  • Nervousness
  • Vomiting
  • Progresses to disorientation, delirium, tremulousness, convulsions, and coma
  • Dilated pupils
  • Bilateral Babinski signs may appear
  • Hemiparesis may appear
• Causes
  • Postoperative stress; can be fatal in women and young children
  • Oxytocin infusion
  • Cyclophosphamide
  • Psychotic self-induced water intoxication
  • Marathon running
  • Ecstasy (MDMA) use
• Best Tests
  • Serum electrolytes
    • Serum sodium concentration < 130 mEq/L
    • Arterial sodium concentration may be lower than the venous
  • CT scan: shows cerebral edema in severe cases, rules out other causes of neurologic findings
• Best Therapy
  • Severe symptoms: do not delay therapy while awaiting imaging
  • Increase plasma sodium concentration by 4–6 mEq/L to decrease cerebral edema and stop seizures
  • Stop free-water intake
  • Hypertonic 3% saline
    • Dose: 1–2 ml/kg of body weight to raise plasma sodium by 1–2 mEq/L/hr for 2–3 hrs; for severe neurological symptoms give 100 100 ml by bolus infusion repeated in 10 minutes x 2 if no clinical improvement
    • Best infused in 100 ml containers to avoid excessive dose
    • Avoid increasing plasma sodium concentration by > 12 mEq/L in first day of therapy or by > 6 mEq/L/day thereafter
  • Concurrent loop diuretic 40 mg I.V.
    • Furosemide
    • Bumetanide
    • Torsemide

• Hyponatremia that evolves over the course of ≥ 48 hr
• Abnormality in vasopressin secretion, except in renal failure
• Rarely fatal
• May become life-threatening if patient rapidly ingests large volume of water
• Patients may have gait disturbances and an increased risk of falls at plasma sodium concentrations less than 128 mEq/L
• Plasma sodium concentrations < 115–120 mEq/L produce the following symptoms:
  • Anorexia
  • Nausea
  • Vomiting
  • Muscle weakness
  • Muscle cramps
  • Irritability
  • Personality changes
  • Slow response
• Plasma sodium concentrations < 110 mEq/L produce the following symptoms:
  • Stupor
  • Tremulousness
  • More rarely, seizures
• Causes
  • Advanced renal failure
  • Thiazide diuretics
  • Hypovolemia, including Addison disease
  • Obsessive consumption of beer
  • Edematous conditions, including the following:
    • Congestive heart failure
    • Cirrhosis
    • Nephrotic syndrome
  • AIDS
  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH) (water is retained without abnormal sodium balance, volume depletion, or edema); may indicate the following:
    • Malignancy
    • Chest infection
    • Tuberculosis
    • Pneumonia
    • Hypopituitarism with glucocorticoid deficiency
    • Hypothyroidism
  • NSAIDs may exacerbate other causes of hyponatremia

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Best Tests

• Exclude disorders that can lower plasma sodium concentration without causing hypotonicity
• Diet, fluid intake, GI fluid losses, and use of diuretics, antidepressants, or other antidiuretic drugs
• Signs of volume depletion or edema
• Check for signs of disorders known to cause SIADH
• Evaluate severity of neurologic symptoms to determine the need for urgent therapy

Laboratory Tests

• Plasma sodium concentration
• Urinary sodium and/or chloride concentration
  • Urinary sodium < 20 mEq/L without edema indicates hypovolemia
  • Urinary chloride < 20 mEq/L without edema indicates hypovolemia in patients with metabolic alkalosis due to gastric fluid losses (urinary sodium may be > 20 mEq/L)
  • Urinary sodium > 40 mEq/L with normal renal function and in the absence of diuretics indicates SIADH
• BUN and serum uric acid
  • Elevated in hemodynamic abnormalities, low in SIADH
• Uric acid
  • More reliable indicator of volume status than BUN
• Serum potassium and bicarbonate
  • Levels are normal in SIADH
• Hypokalemia and metabolic alkalosis
  • Suggest diuretic therapy or vomiting
• Hypokalemia and acidosis
  • Suggest diarrhea or laxative abuse
• Hyperkalemia and acidosis
  • Suggest adrenal insufficiency

• Exclude another cause for hyponatremia before attributing electrolyte disturbance to a drug
• To diagnose drug-induced hyponatremia, eliminate the drug and see if water excretion returns to normal (may take 1–2 wk in thiazide-induced hyponatremia)

• Patients with subclinical edematous conditions retain the sodium and develop edema
• Volume-depleted patients
  • Water diuresis (dilute urine) emerges and hyponatremia improves; avoid overly rapid correction
• Patients with SIADH
  • Hyponatremia persists and may worsen; seek a specific etiology and follow up carefully if no cause for SIADH is found

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Best Therapy

• Increase plasma sodium concentration by at least 4 mEq/L/day
• Restrict free water until plasma sodium begins to increase
• Limit oral fluid intake to 500–1,000 ml/day, depending on the severity of electrolyte disturbance
• Avoid thiazides
• Excessive correction of chronic hyponatremia may cause neurologic injury (osmotic demyelination syndrome)
  • Confusion
  • Psychotic or catatonic behavior
  • Pathologic crying
  • Movement disorderSwallowing dysfunction
  • Progressive unresponsiveness
  • Spastic quadriparesis
  • Avoid by maintaining rates of correction < 10–12 mEq/L/day and 18 mEq/L/48 hr
  • Aim for an increase of serum sodium concentration by 8 mEq/L/day or less
• Hyponatremic seizures
  • Treat with hypertonic saline and anticonvulsants
  • Initial correction by 1 to 2 mEq/L/hr with total correction < 10 to 12 mEq/L/day

• Hypovolemic hyponatremia
  • 0.9% sodium chloride I.V.
  • Discontinue once hypovolemia is corrected and plasma sodium concentration begins to increase
  • Use saline cautiously, if at all, in hypokalemic patients who require potassium replacement
  • Potassium replacement raises plasma sodium concentration
• Diuretic-induced hyponatremia
  • Easily corrected by the following:
    • Adequate diet
    • Replacement of potassium deficits
    • Discontinuance of thiazide diuretics
  • I.V. saline usually not required
• Severe hyponatremia
  • Monitor plasma sodium concentration every 6–8 hr during first 2–3 days of therapy
  • If water diuresis threatens to increase plasma sodium too much, give oral water or 5% dextrose in water to slow the rate of correction or administer desmopressin to stop the water diuresis

• SIADH
  • Water restriction alone is slow to resolve hyponatremia
  • Furosemide is a useful adjunct: 20 mg p.o., b.i.d. (or equivalent dose of bumetanide or torsemide)
  • Oral salt or slow infusion of 3% saline (approximately 15 ml/hr)
  • Demeclocycline: high cost and long duration of action limit its effectiveness
    • Dose: 600 to 1,200 mg/day
  • Conivaptan: intravenous vasopressin receptor antagonist to induce an "aquaresis" (increased urinary water losses without change in urinary sodium and potassium losses) in hospitalized patients
• Edematous conditions
  • Do not give saline
    • Will not improve hyponatremia and worsens edema
  • Loop diuretics plus ACE inhibitor
    • Particularly effective in patients with congestive heart failure

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Best References

Adrogue HJ, et al: N Engl J Med 342:1581, 2000 [PMID 10824078]

Sterns RH, et al: QJM 96:549, 2003 [PMID 12897339]

Ellison DH, Berl T: N Engl J Med 356:2064, 2007 [PMID 17507705]

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Hypernatremia

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Loss of water not adequately replaced or excessive salt intake
• Causes
  • Electrolyte-free water losses through skin and lungs
  • Diabetes insipidus
  • Electrolyte abnormalities
  • Drugs
  • Pregnancy
  • Excess urea excretion
    • Protein feeding
    • Catabolism
    • Resolution of renal failure
  • Hypotonic losses
    • Sweat
    • Vomiting
    • Cathartics
    • Glycosuria
    • Diuretics
  • Salt poisoning (oral or parenteral)
• Acute onset (salt poisoning)
  • Neurologic symptoms
    • Seizures
    • Coma
    • Hyperventilation
    • Hyperreflexia
    • Hypertonia
    • High fever
  • Plasma sodium levels > 170 mEq/L often fatal
• Chronic hypernatremia
  • Lethargy to coma, depending on severity of electrolyte disturbance
  • Signs and symptoms of extracellular fluid volume depletion

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Differential Diagnosis

• Impaired thirst
• Excessive insensible or GI water losses
• Osmotic diuresis
• Diabetes insipidus

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Best Tests

• Serum electrolytes
• Water deficit = normal body water (1 - serum [Na⁺]/140) (amount of water that will return the serum sodium concentration to normal)
  • Diabetic patients with hyperglycemic dehydration need more

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Best Therapy

• Correct severe volume depletion before correcting hypernatremia
• Hypotensive patient: rapid infusion of isotonic saline
• Hemodynamically stable patient: pure-water replacement
• Edematous patient: diuretics plus electrolyte-free water
  • Electrolyte-free water I.V. in a 5% dextrose solution (D5W) at < 500 ml/hr for patients who cannot drink
  • Monitor serum sodium concentration and urine output frequently and adjust fluids appropriately
• Correcting hypernatremia too rapidly can cause cerebral edema
• Reduce serum sodium concentration by ≤ 10–12 mEq/L/day
• Electrolyte-free water intake should exceed free-water losses by ≤ 2 L daily
• Acute salt poisoning: rapid infusions of electrolyte-free water plus a loop diuretic (without waiting for serum electrolyte test) may prevent irreversible brain injury
• Diabetic dehydration
  • Prevent hypovolemia following correction of hyperglycemia
    • 1–2 L 0.45% isotonic saline at a rate that exceeds urine output
  • Carefully monitor serum sodium concentration, blood glucose level, and urine output to tailor fluid replacement to needs
  • Avoid rapid correction of hypertonicity in severe hyperglycemia to prevent cerebral edema

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Best References

Adrogue HJ, et al: N Engl J Med 342:1493, 2000 [PMID 10816188]

Fried LF, et al: Med Clin North Am 81:585, 1997 [PMID 9167647]

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Diabetes Insipidus (DI)

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• A disorder of water conservation
  • Neurogenic: deficient secretion of vasopressin
  • Nephrogenic: unresponsiveness of kidneys to normally secreted hormone
• Polyuria (> 3–4 L of urine/day)
• Nocturia
• Polydipsia

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Differential Diagnosis

• Primary polydipsia

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Best Tests

• Urine osmolality level: < 250 mOsm/kg in DI despite hypernatremia
• Serum osmolality level
• Serum sodium concentration
• MRI of the brain: bright spot on posterior pituitary is absent or greatly diminished in pituitary DI

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Best Therapy

• Water replacement

• 1-desamino-8-D-arginine vasopressin (DDAVP), parenteral or intranasal
• Chlorpropamide: 125 to 250 mg once or twice a day (higher doses risk hypoglycemia)
• Carbamazepine: 100 to 300 mg twice daily
• Thiazide diuretics: for patients with mild disease
• Limit dietary salt and protein

• Limit dietary salt and protein
• Thiazide diuretics
• Indomethacin: 2 mg/kg/day
• Amiloride: for prevention of lithium-induced nephrogenic DI

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Best References

Verbalis JG: Rev Endocr Metab Disord 4:177, 2003 [PMID 12766546]

Sands JM, et al: Ann Intern Med 144:186, 2006 [PMID 16461963]

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Edema

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Swelling of the soft tissues caused by excess saltwater in the extracellular space
• Retention of dietary or infused sodium with impaired ability to excrete saltwater

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Differential Diagnosis

• Renal disease (nephrotic syndrome, nephritic disease)
• Congestive heart failure
• Cirrhosis
• Premenstrual fluid retention
• Long-term diuretic or cathartic use
• Idiopathic edema

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Best Tests

• History and physical examination
  • Signs and symptoms depend on underlying cause
  • Dyspnea on exertion, orthopnea indicate left ventricular failure or nephritic edema
  • Large volumes may cause shortness of breath, gastric reflux, or infection
  • Tissues can be indented or pitted by the examiner's fingers
  • Seek signs of heart, renal, or liver disease
• Urinalysis
• Serum albumin
• Liver function tests
• Chest x-ray
• Plasma B-type natriuretic peptide (BNP): levels are increased in heart failure

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Best Therapy

• Dietary salt restriction
• Diuretics
  • Define effective dose early
  • Induce fluid loss gradually, increasing the dose until desired weight is reached
  • Inpatients can be managed more precisely with continuous infusion
  • Diuretic resistance
    • Loop diuretics plus thiazide or metolazone and/or acetazolamide
    • Monitor carefully to avoid large potassium and sodium losses
    • Loop diuretics can predispose to hearing loss, particularly at high doses via bolus injection in patients receiving other ototoxic drugs
  • Complications
    • Azotemia
    • Volume depletion
    • Thiazides and loop diuretics can cause the following:
      • Hypokalemic alkalosis
      • Hyperglycemia
      • Hyperuricemia (sometimes with clinical gout)
    • Thiazides can cause hypercalcemia in patients with underlying conditions that increase calcium absorption (e.g., sarcoidosis) or bone reabsorption (e.g., hyperparathyroidism)
    • Avoid thiazides in patients with high fluid intake
    • Potassium-sparing agents (e.g., triamterene, amiloride, spironolactone) may cause hyperkalemia
      • Do not give with potassium supplements
      • Use with caution in patients with renal insufficiency and those taking ACE inhibitors or angiotensin II blocking agents
• Cirrhotic patients with ascites but no peripheral edema
  • Limit weight loss to 0.5 kg/day
• Repeated large-volume paracenteses plus I.V. albumin
  • Alternative to diuretics
  • Avoids intravascular volume depletion
  • Afterward, diuretics can prevent reaccumulation of ascitic fluid

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Best References

Brater DC: N Engl J Med 339:387, 1998 [PMID 9691107]

O'Brien JG, et al: Am Fam Physician 71:2111, 2005 [PMID 15952439]

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Volume Depletion

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Loss of saltwater from the extracellular fluid at a rate that exceeds intake
• Characterized by the following:
  • Increased heart rate
  • Fatigue
  • Thirst
  • Muscle cramps
  • Rapid weight loss
  • Low jugular venous pulse rate
  • Hypotension on standing or during physical exertion
  • Hypotension in recumbency
  • Tissue ischemia
  • Shock in severe cases

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Differential Diagnosis

• Diarrhea
• Fluid sequestrated in the abdominal cavity (pancreatitis or peritonitis) or in the soft tissues (crush injuries with rhabdomyolysis or burns)
• Renal salt wasting from diuretics
• Osmotic diuresis caused by glycosuria
• Recovery phases of acute tubular necrosis or obstructive uropathy
• Toxic nephropathies
• Adrenal insufficiency

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Best Tests

• Hematocrit: increases in proportion to the contraction of plasma volume
• Serum albumin: may be increased
• Urinary sodium: usually < 20 mEq/L except in metabolic alkalosis (in which the urine chloride is low) or when renal sodium wasting is the cause of the condition
• Serum creatinine: changes very little
• BUN: increased disproportionately to the increase in creatinine
• Azotemia may be blunted in patients with a poor dietary protein intake and may be exacerbated in patients who are catabolic, bleeding, or receiving steroid therapy

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Best Therapy

• Increase dietary intake of salt
• Oral solutions containing electrolytes, sugar, and amino acids
• I.V. fluids when fluids cannot be taken orally
• Hypotensive patients: isotonic saline given as rapidly as possible until tissue perfusion is adequate

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Best References

McGee S, et al: JAMA 281:1022, 1999 [PMID 10086438]

Greenberg A: Ann J Med Sci 319:10, 2000 [PMID 10653441]

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The author has received honoraria from Astellas, the manufacturer of Conivaptan.

February 2009