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© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. in the clinic Hyponatremia

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What is hyponatremia?  Disorder of water balance  Occurs when more water ingested than kidneys can excrete  Ability to excrete a large volume of dilute urine is compromised  Kidney disease  Diuretics  Low protein intake  Presence of arginine vasopressin  Amount of free water excreted is determined by urine volume, sodium, and potassium  Free water is excreted if urinary sodium + potassium < plasma sodium

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. Who is at risk for hyponatremia?  Endurance athletes  Institutionalized patients with schizophrenia  People who consume large quantities of fluid but little protein  People with severe kidney disease  Certain drugs (diuretics, particularly thiazide; SSRIs; SNRIs)  If posterior pituitary secretes AVP despite low plasma sodium  Hypovolemia or heart or liver disease  AVP secretion without osmotic and hemodynamic stimulus  Syndrome of inappropriate antidiuretic hormone secretion  Common in hospitalized patients  Hospitalized children receiving hypotonic fluids

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What potential measures can prevent or limit the severity of hyponatremia?  Encourage runners to drink fluids only when thirsty  Monitor body weight to avoid weight gain during exercise  Check plasma sodium after initiating thiazides, SNRIs, SSRIs  Check 1 to 2 weeks after initiating therapy  Avoid thiazides in persons with high fluid or low protein intake and during acute illness  Measure plasma sodium in hospitalized patients on admission  Treat low sodium based on the underlying cause  Avoid hypotonic fluids and thiazides  Monitor daily in patients with hyponatremia and in those at increased risk

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. CLINICAL BOTTOM LINE: Prevention...  Hyponatremia is common in patients who:  Participate in endurance exercise  Receive thiazides, SSRIs, or SNRIs  Have congestive heart failure, cirrhosis, or pneumonia  Admitted to the ICU  Elderly patients  Avoid hypotonic fluids in hospitalized patients at increased risk

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What characteristic symptoms or physical findings should alert clinicians to the diagnosis of hyponatremia?  Mild hyponatremia  Subtle neurocognitive deficits  Deficits improve when plasma sodium is normalized  Moderate hyponatremia  Nausea, confusion, headache, vomiting  Severe hyponatremia  Delirium; impaired consciousness; seizures  Rarely: cardiorespiratory arrest  Consider hyponatremia in the differential diagnosis of patients with osteoporosis, falls, and hip fractures

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What conditions should clinicians consider when evaluating patients with hyponatremia? Major Causes of Hyponatremia Based on Volume Status  Hypovolemia: Extrarenal losses  Vomiting, diarrhea, sweating  Pancreatitis  Small bowel obstruction  Hypovolemia: Renal losses  Diuretics, osmotic diuresis  Cerebral salt wasting, salt-losing nephritis  Addison disease —continued

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. Hypervolemia  Heart failure  Liver disease with cirrhosis  Nephrotic syndrome  Chronic kidney disease Euvolemia  Primary polydipsia  Decreased solute excretion  Diuretics  Hypothyroidism  Cortisol deficiency  Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. Essential  Decreased effective osmolality of the extracellular fluid  Inappropriate urinary concentration in presence of decreased effective serum osmolality  Clinical euvolemia, as defined by the absence of signs of hypovolemia or hypervolemia  Absence of urinary sodium conservation when salt and water intake are normal  Absence of other potential causes of euvolemic hypoosmolality: hypothyroidism, hypocortisolism, diuretics —continued Criteria for the Diagnosis of SIADH

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. Supplemental  Plasma uric acid <4 mg/dL  Blood urea nitrogen <10 mg/dL  Fractional sodium excretion >1%; fractional urea excretion >55%  Abnormal water load test  Plasma AVP level inappropriately elevated relative to plasma osmolality  No significant correction of plasma sodium with volume expansion but improvement after fluid restriction

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. Common Causes of SIADH Tumors  Pulmonary/mediastinal (e.g., small cell carcinoma)  Other cancers (e.g., duodenal, stomach, pancreatic, bladder)  Lymphoma  Ewing sarcoma Central nervous system disorders  Mass lesions (e.g., tumors, brain abscesses)  Inflammatory diseases (e.g., encephalitis, meningitis)  Degenerative or demyelinating diseases  Miscellaneous: subarachnoid hemorrhage, head trauma, psychosis, delirium tremens, pituitary stalk section, transsphenoidal adenomectomy, hydrocephalus, cerebrovascular accident, cavernous sinus thrombosis —continued

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. Drug-induced  Stimulated AVP release (narcotics, nicotine, phenothiazines)  Direct renal effects or potentiation of AVP antidiuretic effects (desmopressin, oxytocin, prostaglandin synthesis inhibitors)  Mixed/uncertain actions (carbamazepine, chlorpropamide, SSRI, clofibrate, clozapine, cyclophosphamide, ecstasy, vincristine) Pulmonary diseases  Infections  Mechanical or ventilatory (e.g., acute respiratory failure, asthma) Other  Rocky Mountain spotted fever  AIDS and AIDS-related complex  Nausea, pain, stress, prolonged strenuous exercise  Mutations of the aquaretic vasopressin receptor Idiopathic

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What is the overall approach to the diagnosis of hyponatremia?  Initial evaluation  Measure plasma osmolality, glucose, urea, creatinine, and potassium  Measure urine osmolality, sodium, and chloride (if the patient is vomiting)  Base further diagnostic workup on initial evaluation results  Identifying cause of hyponatremia is often difficult

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What is the role of volume status, urine osmolality, and urinary sodium in the evaluation of patients with hyponatremia?  Measure urine osmolality in hypotonic hyponatremia  <100 mOsm/kg H2O: polydipsia, decreased solute excretion usual cause  <100 mOsm/kg H2O: may also occur after volume resuscitation with hypovolemic hyponatremia (if measured after administration of isotonic saline)  >200 mOsm/kg H2O: AVP playing a role if kidney function normal and patient not receiving diuretics  Determine cause of AVP secretion  Classify volume status based on history and physical: hypovolemia, clinical euvolemia, or hypervolemia  Subdivide hypovolemia: extrarenal or renal sodium losses —continued

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1.  Clinical euvolemia vs. mild hypovolemia  Water retention may make patient seem euvolemic  Hypovolemia: urinary sodium <30 mEq/L  Euvolemia: urinary sodium >30 mEq/L  Hypovolemic hyponatremia vs. SIADH with salt depletion  If urinary sodium 20 mEq/L or <40 mEq/L  Hypovolemic hyponatremia: improves after normal saline  Salt-depleted SIADH: plasma sodium doesn’t normalize after administration of normal saline  Hypervolemia due to HF, cirrhosis, nephrotic syndrome  Base diagnosis on history and physical exam  Urinary sodium <30 mEq/L unless on diuretics

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What is the role of imaging studies in the diagnosis of hyponatremia?  Chest radiography  Unexplained SIADH: to identify potential underlying cause  Chest computed tomography  Consider for smokers  Magnetic resonance imaging of the brain  If physical exam reveals neurologic abnormalities after plasma sodium is normalized

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. When should clinicians consult with a nephrologist or endocrinologist?  Cause of hyponatremia is unknown  Guidance for evaluation of SIADH  Guidance on use of normal saline in patients with possible SIADH and plasma sodium levels <120 mEq/L

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. CLINICAL BOTTOM LINE: Diagnosis...  Identifying the cause of hyponatremia can be challenging  Often difficult to distinguish whether patient is slightly volume depleted or euvolemic  If volume status uncertain, saline infusion may be useful  Before diagnosing SIADH  Stop thiazides to determine effect on plasma sodium  Rule out secondary adrenal insufficiency and hypothyroidism

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What is the overall approach to treatment of hyponatremia?  Acute: duration known to be <48 h  Endurance exercise, psychogenic polydipsia, drug use, colonoscopy preparation, and postoperative states  Can lead to cerebral edema with risk for brain herniation  Urgent normalization of sodium levels is needed  Chronic: duration unknown or >48 h  Patients predisposed to brain damage if hyponatremia corrected too rapidly  Hyponatremia severity classification (mEq/L)  U.S.: mild: , moderate , severe <120  European: mild ; moderate , severe <125

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. How should sodium levels be corrected in acute and severely symptomatic hyponatremia?  Difficult to predict rate of correction of plasma sodium  Acute or severely symptomatic chronic hyponatremia  Rapidly reverse cerebral edema by increasing plasma sodium by 5 mEq/L  Chronic hyponatremia  Do not raise plasma sodium level >10 mEq/L within 24 h and/or >18 mEq/L within 48 h  Set goal of therapy well below therapeutic limit  Recommended rates of correction in patients at high risk for osmotic demyelination: 4-6 mEq/L per day

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What is the treatment of patients with chronic asymptomatic hyponatremia?  Hypovolemia due to GI losses and sweating  Isotonic saline; consider concomitant desmopressin  Diuretics  Discontinue; if no improvement administer isotonic saline  Addison disease  Isotonic saline; glucocorticoid and mineralocorticoid replacement  Glucocorticoid insufficiency  Glucocorticoid replacement —continued

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1.  Primary polydipsia  Restrict water; discontinue diuretics and any drug known to cause SIADH  If volume-depleted or decreased solute excretion, cautiously administer isotonic saline and consider desmopressin (if no access to fluids) initially or if rapid increase in urine output and/or plasma sodium  Decreased solute intake  Same treatment as for polydipsia  Additionally: increase electrolytes and protein in the diet  Heart failure  Restrict water, salt; loop diuretics in fluid overload cases  Cirrhosis with ascites  Restrict water and salt; administer diuretics; possible albumin infusion with diuretics —continued

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1.  Nephrotic syndrome  Restrict water and salt; diuretics  If clinically decreased effective circulating volume, administer albumin with diuretics  Chronic kidney disease  Restrict water, salt; loop diuretics if fluid overload present  SIADH  Discontinue diuretics and any drug known to cause SIADH  Restrict water but not salt; consider oral urea, salt tablets, furosemide with salt tablets, and demeclocycline if water restriction ineffective  Don’t use vaptans unless benefit is greater than risk and only approved for 1 month of use (FDA guidelines)

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What are manifestations of the osmotic demyelination syndrome and who is at risk?  If chronic hyponatremia is corrected too rapidly  Brain unable to rapidly recover organic solutes lost in adaptation to hyponatremia  Neurologic symptoms occur 2-6 days after correction  Risk factors  Initial plasma sodium <105 mEq/L; hypokalemia  History of alcoholism, malnutrition, advanced liver disease  Increase in plasma sodium >10 mEq/L within 24 h and >18 mEq/L within 48 h  If cause of hyponatremia reversible, plasma sodium may increase more than intended

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. When should patients be hospitalized for management of hyponatremia?  Hyponatremic patients who are symptomatic  Confusion, headache, vomiting, and seizures  Acute hyponatremia  Plasma sodium level <125 mEq/L  Risk factors for ODS

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. How should clinicians counsel patients about salt and fluid intake and when to seek clinical care?  Treatment of hypervolemic hyponatremia due to HF  Restrict dietary salt to 1.5 to 3.0 g/day  Restrict fluids to 1.5 to 2 L/day unless hyponatremia worsens  Treatment of SIADH  Limit fluids ≈800 mL/day  Do not restrict salt intake  Patients should seek care if they experience altered mental status, falls, or persistent nausea

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. What other therapies are used in the management of hyponatremia?  Sodium chloride tablets  Furosemide (Lasix)  Urea  Demeclocycline  Tolvaptan

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1.  If fluid restriction unsuccessful in managing plasma sodium in hyponatremia  Concerns about increased risk for rapid correction of plasma sodium and lack of mortality benefit  Concerns about hepatotoxicity  US FDA: Limit use to 1-month  US FDA: Limit use with plasma sodium <125 mEq/L unless symptomatic + no response to fluid restriction  To avoid overcorrection, use vaptans alone  Not in conjunction with other treatment for hyponatremia  Check plasma sodium levels every 6-8 h during initiation and don’t initially restrict fluid intake When should clinicians consider use of vasopressin-receptor antagonists?

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. When should clinicians consult a nephrologist or endocrinologist for treatment of hyponatremia?  Considering administration of hypertonic saline or vaptans  Hyponatremia is acute, severe, or symptomatic  Patients have risk factors for ODS  Patients have had overly rapid correction  Patients require long-term therapy

© Copyright Annals of Internal Medicine, 2015 Ann Int Med. 163 (3): ITC3-1. CLINICAL BOTTOM LINE: Treatment...  Hospitalization  Patients with acute or severe hyponatremia  Patients with moderate to severe symptoms  Acute hyponatremia  Administer hypertonic saline to rapidly correct plasma sodium levels even if asymptomatic  Monitor closely  Don’t increase >10 mEq/L within 24 h or 18 mEq/L within 48 h  Use lower rates of sodium correction in those at risk for ODS  Risk factors for ODS  Initial plasma sodium level <105 mEq/L  Hypokalemia  Alcoholism or malnutrition  Advanced liver disease