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Hyponatremia
HYPONATREMIA Ajay K. Singh, MBBS, FRCP
Hyponatremia is defined as a plasma sodium level ⬍135 mEq/L (135 mmol/L) and is the most commonly encountered electrolyte abnormality in hospitalized patients (prevalence of approximately 2.5%). Acute or symptomatic hyponatremia can lead to significant rates of morbidity and mortality. A. Clinical features depend on the degree of hyponatremia and the rapidity with which they develop. An abrupt (over 24–48 hours) decrease in the sodium concentration may be associated with symptoms that range from mild anorexia, headache, and muscle cramps to significant alteration in mental status, including obtundation, coma, or status epilepticus. The key diagnostic challenge is to clinically predict total body sodium content. Patients who are hypervolemic have increased total body sodium; patients who are euvolemic have normal body sodium; and patients who are hypovolemic have low body sodium. Hypovolemic hyponatremia develops as sodium (and free water) are lost and replaced by inappropriately hypotonic fluids. Sodium can be lost through renal or nonrenal routes. Nonrenal routes include GI losses, excessive sweating, third spacing of fluids (e.g., ascites, peritonitis, pancreatitis, burns), and cerebral salt-wasting syndrome. Euvolemic hyponatremia is characterized by normal total body sodium and a total body excess of free water. This occurs in patients who take in excess fluids. The most common causes are psychogenic polydipsia, administration of hypotonic intravenously, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hypervolemic hyponatremia occurs in patients with excessive total body sodium (e.g., with congestive heart failure). B. SIADH is characterized by maximally dilute urine in the face of hypoosmolality and hyponatremia. SIADH is the most common cause of normovolemic (euvolemic) hyponatremia and the most common cause of hyponatremia. SIADH is caused by an increase of arginine vasopressin (AVP) secretion resulting in impairment of water excretion. AVP secretion in these patients is caused by a nonphysiologic release of AVP from the posterior pituitary or another ectopic source. The most common causes of SIADH include neuropsychiatric and pulmonary disease, malignant tumors, major surgery (postoperative pain), and pharmacologic agents. Hyponatremia of SIADH can be explained by the inappropriate secretion of AVP. AVP or antidiuretic hormone (ADH) increases water resorption through the renal tubules in order to
376
conserve water. A pathologic increase of AVP often leads to excessive retention of water. Renal free water excretion is impaired, whereas the regulation of sodium balance is unaffected. In addition, a high volume of water intake is required for significant development of hyponatremia because a high level of AVP alone is usually insufficient to produce hyponatremia. Malignancies may secrete AVP. Also, tumors may cause SIADH secretion by interfering with the normal osmoregulation of AVP secretion from the neurohypophysis through direct invasion of the vagus nerve, metastatic implants in the hypothalamus, or some other more generalized neuropathic changes. Many drugs may also increase production of AVP either directly or indirectly by acting on the kidneys. Examples include chlorpropamide, clofibrate, carbamazepineoxcarbazepine, vincristine, nicotine, narcotics, and antipsychotic/antidepressant drugs. The most important diagnostic criterion for SIADH is the excretion of inappropriately concentrated urine (⬎300 mOsm/kg H2O) despite hypoosmolality and hyponatremia. The absence of any renal, adrenal, or thyroid abnormalities also is important. Appropriate renal response to hypoosmolality is to excrete the maximum volume of dilute urine (i.e., urine osmolality and specific gravity of ⬍100 mOsm/kg and 1.003, respectively). Patients with primary polydipsia will have an appropriate response to the water loading. An inappropriate renal response often implies AVP action on the kidneys. Patients with SIADH tend to be mildly volume expanded secondary to water retention and have a urine sodium excretion rate equal to intake (urine sodium concentration usually ⬎40 mmol/L). Hypouricemia may be an accompanying finding because of the volume expansion (in contrast to hypovolemic hyponatremia). Evaluate for an underlying malignancy (SIADH may precede diagnosis of malignancy by several months). For treatment of mild hyponatremia, water restriction of 1000 ml/day should be adequate. However, patient compliance may be difficult because of the lengthy periods of water restriction that may be required. Pharmacologic agents that antagonize AVP action and maneuvers that increase solute excretion may allow patients with SIADH secretion to drink more water (e.g., demeclocycline). The recommended demeclocycline dose is between 600 and 1200 mg/day with restoration of serum sodium in 5–14 days without restricting water intake. Patients with cirrhosis require dosage adjustments because of fear of developing toxicity. For severe symptomatic hyponatremia 3% hypertonic saline is recommended.
377 Patient with HYPONATREMIA
A Determine plasma osmolality*
Assessment of extracellular fluid volume by history and physical examination
Measure urine Na concentration
B Exclude renal failure, hypothyroidism, and adrenal insufficiency
C Body Na: low
Body Na: normal
Body Na: High
*Osmolality ⫽ 2 (Na⫹) ⫹ Plasma glucose/18 ⫹ BUN/2.8 mOsm/kg.
C. The therapeutic strategy for hyponatremia is dictated by the underlying cause of the disorder. It is important to consider the presence or absence of symptoms, the duration of the disorder, and the risk of neurologic complication. It is ideal to raise the plasma sodium concentration by restricting water and increasing water loss. Ultimately, the goal of treatment is to correct the underlying disorder causing hyponatremia, if possible. Symptomatic hyponatremia always requires treatment regardless of severity of the hyponatremia. The issue of how rapid the correction is still of great controversy. For patients who are acute (⬍48 hours) and severely symptomatic, it is typically recommended to raise the sodium concentration no more than 1–2 mEq/L/hr for the first 3–4 hours with a limit at 15 mEq/L but preferably at 12 mEq/L during the first 24 hours with hypertonic saline. Once symptoms have subsided, the rate of correction can be switched to water restriction. As long as the osmolality of the fluid administered is higher than that of the level of plasma, sodium increases. The quantity of sodium required to increase the plasma sodium concentration by a given amount can be estimated by multiplying the deficit in plasma sodium concentration by the total body water. The treatment of a patient with asymptomatic hyponatremia is less controversial. In patients with chronic hyponatremia, water restriction alone is usually effective. A free water restriction of 1000 ml/day is adequate to achieve negative water balance. In some patients, an even greater restriction of water intake may be necessary because this volume of restriction exceeds total renal and extrarenal water losses. The use of furosemide (40 mg/day) and high salt intake (200 mEq/day), an extension of the treatment of
acute symptomatic hyponatremia to the chronic management of euvolemic hyponatremia, has also been reported to be successful. Patients with hypervolemic hyponatremia, secondary to heart failure or liver cirrhosis, are often asymptomatic. These patients require strict sodium and water restriction and correction of any other electrolyte and metabolic alterations. Patients who have a hypovolemic type of hyponatremia may be treated with isotonic saline in an attempt to replete sodium and remove the hemodynamic stimulus for AVP release. The most important complication in the treatment of severe hyponatremia is central pontine myelinolysis (osmotic demyelination syndrome). Demyelinating syndrome is most likely to occur in patients whose hyponatremia is more chronic and is rapidly corrected once the adaptive process has set in. Diagnosis can be difficult with small lesions, but more extensive disease is associated with flaccid paralysis, dysarthria, and dysphagia. There is no specific treatment for this disorder, causing a high mortality and morbidity. Because the rate and magnitude of correction seem to play a critical role, it is important to adhere to the suggested rate of correction as stated previously.
References Adrogué HJ. Consequences of inadequate management of hyponatremia. Am J Nephrol 2005;25(3):240–249. Epub 2005 May 25. Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342(21): 1581–1589. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med 2006;119(7 Suppl 1):S30–S35.
Hyponatremia is defined as a plasma sodium level ⬍135 mEq/L (135 mmol/L) and is the most commonly encountered electrolyte abnormality in hospitalized patients (prevalence of approximately 2.5%). Acute or symptomatic hyponatremia can lead to significant rates of morbidity and mortality. A. Clinical features depend on the degree of hyponatremia and the rapidity with which they develop. An abrupt (over 24–48 hours) decrease in the sodium concentration may be associated with symptoms that range from mild anorexia, headache, and muscle cramps to significant alteration in mental status, including obtundation, coma, or status epilepticus. The key diagnostic challenge is to clinically predict total body sodium content. Patients who are hypervolemic have increased total body sodium; patients who are euvolemic have normal body sodium; and patients who are hypovolemic have low body sodium. Hypovolemic hyponatremia develops as sodium (and free water) are lost and replaced by inappropriately hypotonic fluids. Sodium can be lost through renal or nonrenal routes. Nonrenal routes include GI losses, excessive sweating, third spacing of fluids (e.g., ascites, peritonitis, pancreatitis, burns), and cerebral salt-wasting syndrome. Euvolemic hyponatremia is characterized by normal total body sodium and a total body excess of free water. This occurs in patients who take in excess fluids. The most common causes are psychogenic polydipsia, administration of hypotonic intravenously, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hypervolemic hyponatremia occurs in patients with excessive total body sodium (e.g., with congestive heart failure). B. SIADH is characterized by maximally dilute urine in the face of hypoosmolality and hyponatremia. SIADH is the most common cause of normovolemic (euvolemic) hyponatremia and the most common cause of hyponatremia. SIADH is caused by an increase of arginine vasopressin (AVP) secretion resulting in impairment of water excretion. AVP secretion in these patients is caused by a nonphysiologic release of AVP from the posterior pituitary or another ectopic source. The most common causes of SIADH include neuropsychiatric and pulmonary disease, malignant tumors, major surgery (postoperative pain), and pharmacologic agents. Hyponatremia of SIADH can be explained by the inappropriate secretion of AVP. AVP or antidiuretic hormone (ADH) increases water resorption through the renal tubules in order to
376
conserve water. A pathologic increase of AVP often leads to excessive retention of water. Renal free water excretion is impaired, whereas the regulation of sodium balance is unaffected. In addition, a high volume of water intake is required for significant development of hyponatremia because a high level of AVP alone is usually insufficient to produce hyponatremia. Malignancies may secrete AVP. Also, tumors may cause SIADH secretion by interfering with the normal osmoregulation of AVP secretion from the neurohypophysis through direct invasion of the vagus nerve, metastatic implants in the hypothalamus, or some other more generalized neuropathic changes. Many drugs may also increase production of AVP either directly or indirectly by acting on the kidneys. Examples include chlorpropamide, clofibrate, carbamazepineoxcarbazepine, vincristine, nicotine, narcotics, and antipsychotic/antidepressant drugs. The most important diagnostic criterion for SIADH is the excretion of inappropriately concentrated urine (⬎300 mOsm/kg H2O) despite hypoosmolality and hyponatremia. The absence of any renal, adrenal, or thyroid abnormalities also is important. Appropriate renal response to hypoosmolality is to excrete the maximum volume of dilute urine (i.e., urine osmolality and specific gravity of ⬍100 mOsm/kg and 1.003, respectively). Patients with primary polydipsia will have an appropriate response to the water loading. An inappropriate renal response often implies AVP action on the kidneys. Patients with SIADH tend to be mildly volume expanded secondary to water retention and have a urine sodium excretion rate equal to intake (urine sodium concentration usually ⬎40 mmol/L). Hypouricemia may be an accompanying finding because of the volume expansion (in contrast to hypovolemic hyponatremia). Evaluate for an underlying malignancy (SIADH may precede diagnosis of malignancy by several months). For treatment of mild hyponatremia, water restriction of 1000 ml/day should be adequate. However, patient compliance may be difficult because of the lengthy periods of water restriction that may be required. Pharmacologic agents that antagonize AVP action and maneuvers that increase solute excretion may allow patients with SIADH secretion to drink more water (e.g., demeclocycline). The recommended demeclocycline dose is between 600 and 1200 mg/day with restoration of serum sodium in 5–14 days without restricting water intake. Patients with cirrhosis require dosage adjustments because of fear of developing toxicity. For severe symptomatic hyponatremia 3% hypertonic saline is recommended.
377 Patient with HYPONATREMIA
A Determine plasma osmolality*
Assessment of extracellular fluid volume by history and physical examination
Measure urine Na concentration
B Exclude renal failure, hypothyroidism, and adrenal insufficiency
C Body Na: low
Body Na: normal
Body Na: High
*Osmolality ⫽ 2 (Na⫹) ⫹ Plasma glucose/18 ⫹ BUN/2.8 mOsm/kg.
C. The therapeutic strategy for hyponatremia is dictated by the underlying cause of the disorder. It is important to consider the presence or absence of symptoms, the duration of the disorder, and the risk of neurologic complication. It is ideal to raise the plasma sodium concentration by restricting water and increasing water loss. Ultimately, the goal of treatment is to correct the underlying disorder causing hyponatremia, if possible. Symptomatic hyponatremia always requires treatment regardless of severity of the hyponatremia. The issue of how rapid the correction is still of great controversy. For patients who are acute (⬍48 hours) and severely symptomatic, it is typically recommended to raise the sodium concentration no more than 1–2 mEq/L/hr for the first 3–4 hours with a limit at 15 mEq/L but preferably at 12 mEq/L during the first 24 hours with hypertonic saline. Once symptoms have subsided, the rate of correction can be switched to water restriction. As long as the osmolality of the fluid administered is higher than that of the level of plasma, sodium increases. The quantity of sodium required to increase the plasma sodium concentration by a given amount can be estimated by multiplying the deficit in plasma sodium concentration by the total body water. The treatment of a patient with asymptomatic hyponatremia is less controversial. In patients with chronic hyponatremia, water restriction alone is usually effective. A free water restriction of 1000 ml/day is adequate to achieve negative water balance. In some patients, an even greater restriction of water intake may be necessary because this volume of restriction exceeds total renal and extrarenal water losses. The use of furosemide (40 mg/day) and high salt intake (200 mEq/day), an extension of the treatment of
acute symptomatic hyponatremia to the chronic management of euvolemic hyponatremia, has also been reported to be successful. Patients with hypervolemic hyponatremia, secondary to heart failure or liver cirrhosis, are often asymptomatic. These patients require strict sodium and water restriction and correction of any other electrolyte and metabolic alterations. Patients who have a hypovolemic type of hyponatremia may be treated with isotonic saline in an attempt to replete sodium and remove the hemodynamic stimulus for AVP release. The most important complication in the treatment of severe hyponatremia is central pontine myelinolysis (osmotic demyelination syndrome). Demyelinating syndrome is most likely to occur in patients whose hyponatremia is more chronic and is rapidly corrected once the adaptive process has set in. Diagnosis can be difficult with small lesions, but more extensive disease is associated with flaccid paralysis, dysarthria, and dysphagia. There is no specific treatment for this disorder, causing a high mortality and morbidity. Because the rate and magnitude of correction seem to play a critical role, it is important to adhere to the suggested rate of correction as stated previously.
References Adrogué HJ. Consequences of inadequate management of hyponatremia. Am J Nephrol 2005;25(3):240–249. Epub 2005 May 25. Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342(21): 1581–1589. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med 2006;119(7 Suppl 1):S30–S35.