Hyponatremia is clinically defined as a serum sodium concentration (S[Na+]) <136 mmol/L. Plasma sodium concentration (P[Na+]) refers to sodium concentration [Na+] in the plasma in vivo or in the plasma of anticoagulated blood ex vivo. S[Na+] refers to [Na+] measured in the serum extracted from coagulated blood ex vivo. P[Na+] and S[Na+] may herein be used interchangeably.
AVP or ADH is synthesized in the paraventricular neurons of the hypothalamus as pre-pro-AVP and proteolytically cleaved into vasopressin + neurophysin II + copeptin (Fig. 1.1).
FIGURE 1.1 Proteolysis of pre-pro-AVP. Abbreviation: AVP, vasopressin.
These molecules are stored in secretory granules in the posterior pituitary and released upon osmotic (e.g., hyperosmolality) and nonosmotic stimuli (e.g., stress, drug induced, nausea, and pain).
ADH may be seen as a “pituitary bright spot” or hyperintense T1 signal within the posterior pituitary on brain MRI. The loss of this “pituitary bright spot” suggests the lack of ADH, and thus the diagnosis of central diabetes insipidus (cDI). However, one-third of patients with cDI may have normal brain MRI. Thickening or enlargement of the pituitary stalk may also be seen in cDI.
Copeptin as a surrogate for ADH:
Copeptin is the C-terminal segment of pro-AVP that is released in equivalent amounts as AVP.
Blood level of copeptin is more easily measured than that of ADH (greater stability than ADH) and has been suggested to be a good ADH surrogate.
The osmotic threshold for both ADH and copeptin release is 282 ± 4.3 mOsm/kg.
Copeptin levels parallel ADH levels in various clinical settings:
Reduced levels in cDI
Copeptin level has been shown to increase earlier than troponin in acute myocardial infarction and has been suggested to be used as an early marker for its diagnosis.
Na+ and K+: both Na+ and K+ are effective exchangeable solutes.
The early Edelman equation predicts P[Na+] is directly proportional to (Na+e + K+e) as follows:
P[Na+] = 1.11 × (Na+e + K+e)/(total body water) – 25.6
where (Na+e + K+e) represents the sum of total body exchangeable Na+ and K+ and the constant 25.6 represents the pool of osmotically inactive Na+ and K+ (e.g., “inexchangeable” Na+ and K+ sequestered in bones, nonfluid phase).
Over the years, modifications to the Edelman equation have been derived, partly because the complete equivalence of Na+ and K+ have been questioned. Although newer equations may be more factually accurate, older equations are sufficiently accurate in predicting P[Na+] in the clinical setting.
Key point to remember from Edelman equation for routine clinical purposes:
Equimolar amounts of exchangeable Na+ and K+ have similar effect on raising P[Na+]. That is, giving a patient 50 mmol of Na+ increases P[Na+] similarly as giving the same patient 50 mmol of K+.
Increased all-cause mortality reported in various settings (e.g., ambulatory setting, emergency department, intensive care unit, geriatric patients, patients
with HF or ST-elevation myocardial infarction, patients with cirrhosis, patients receiving kidney replacement therapies)
FIGURE 1.2 Mechanisms whereby potassium administration can increase serum sodium concentration (S[Na+]). (1) Potassium enters cells in exchange for sodium, which increases S[Na+]; (2) potassium enters cells along with chloride to maintain electrical neutrality, which leads to increased intracellular osmolality and subsequent intracellular water shift. The reduced extracellular water volume leads to increased S[Na+]; or (3) potassium enters cells in exchange for a proton. While potassium entry increases intracellular osmolality, therefore intracellular water shift and subsequent increase in S[Na+], the extracellular proton shift is taken up by the extracellular buffer system and does not affect extracellular osmolality. Abbreviations: osm, osmolality; S[Na+], serum sodium concentration.
Increased postoperative morbidities (major coronary events, wound infections, pneumonia, acute kidney injury [AKI] requiring dialysis, length of hospital stay)
Predictor of hepatorenal syndrome (HRS), hepatic encephalopathy in patients with liver disease
Increased risks for osteoporosis, gait instability, fall, and fracture
Risk and severity of neurologic effects depend on the rate of change of S[Na+]. In acute and severe hyponatremia, free water shifts into brain cells and potentially causes brain edema. Severe neurologic complications and death can follow due to the confinement of the brain within the skull.
Mild: S[Na+] ≥125 mmol/L: usually asymptomatic to minimally symptomatic
Moderate: impaired attention, poor mentation, lethargy, headaches, nausea/vomiting, disorientation, muscle cramps, reduced reflexes
Severe: hyponatremic encephalopathy, seizures, coma, respiratory arrest, brain stem herniation, death. Hospitalized premenstrual women are thought to be at increased risk for hyponatremic encephalopathy compared to men and postmenopausal women.
Refers to falsely low S[Na+]. Flame photometric assay is an old method used to detect sodium content via intensity of flame color divided by serum volume. In patients with falsely elevated serum volume due to space-occupying
paraproteins or lipids, the S[Na+], defined as sodium content divided by the serum volume, will be falsely low. Newer methods of measuring S[Na+] are now widely used to avoid pseudohyponatremia:
Ion-specific electrodes that measure [Na+] directly from the serum
Supracentrifugation of serum to remove paraproteins/lipids prior to measuring S[Na+]
Conditions with falsely high plasma volume leading to “pseudohyponatremia”:
Hyperparaproteinemia (multiple myeloma, Waldenstrom macroglobulinemia)
Extracellular H2O shift: transient hyponatremia due to extracellular free H2O shift in the presence of osmotically active agents in the extracellular space
Sucrose, maltose (mixed in intravenous immunoglobulin G [IgG] solutions)
True hyponatremia: truly low Na+ content per unit water volume, due to increased free water retention, excessive Na+ loss, or both leading to a hypoosmolar state
Mechanism of hypovolemic hyponatremia: appropriate increase in ADH secretion due to volume depletion + H2O intake
Conditions associated with hypovolemic hyponatremia:
FIGURE 1.3 Differential diagnoses and clinical evaluation of hyponatremia. Abbreviations: ADH, antidiuretic hormone; GFR, glomerular filtration rate; KF, kidney failure; MOA, mechanism of action; NSIAD, nephrogenic syndrome of inappropriate antidiuresis; SIADH, syndrome of inappropriate antidiuretic hormone secretion; UNa, urine sodium concentration. *Blood loss, diarrhea, vomitus, sweats.
Bodily fluid loss, chronic diuretics (thiazides), third-spacing
Typical presentation: hypovolemia; urine Na+ concentration (UNa) < 20 mmol/L, urine osmolality (UOSM) typically >300 mOsm/kg.
Renal salt wasting: acute or recent diuretic use, tubulointerstial diseases, mineralocorticoid insufficiency (typically with adrenal insufficiency), cerebral salt wasting (CSW)
Typical presentation: hypovolemia, UNa > 20 to 30 mmol/L, UOSM typically >300 mOsm/kg
In patients with any cause of hypovolemic hyponatremia and advanced kidney failure, tubular reabsorption of sodium and concentrating capacity may be reduced, in which case UNa may be >20 mmol/L and UOSM may not be concentrated to above 300 to 400 mOsm/kg.
Mechanism of ADH-dependent euvolemic hyponatremia: ADH secretion is inappropriate (i.e., ADH is NOT secreted in response to volume loss or hyperosmolar state) + H2O intake.
Conditions associated with “inappropriate” ADH euvolemic hyponatremia:
SIADH: central nervous system (CNS) or pulmonary pathology, drugs affecting the CNS, antipsychotics, antiepileptics, antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclophosphamide, acute pain, nausea/vomiting, hypoglycemia, symptomatic HIV
Severe hypothyroidism (myxedema coma or thyroid-stimulating hormone > 50 mIU/mL): mechanisms unclear, thought to be due to both ADH-dependent and possibly ADH-independent mechanisms. ADH-dependent mechanism is thought to reflect reduced cardiac output and hypoperfusion of the kidneys.
Hypocortisolism leads to increased synthesis of corticotropin-releasing hormone, which is coexpressed with ADH and, thus, increased ADH level.
Pregnancy: reduced threshold for ADH secretion + increased thirst
Typical presentation for conditions associated with “inappropriate” ADH secretion:
Clinical criteria: euvolemia, U[Na+] > 20 to 30 mmol/L (on normal dietary water and sodium intake), UOSM > 150 mOsm/kg, and low serum uric acid
In addition to the clinical criteria above, hypothyroidism, hypocortisolism, diuretic use (particularly thiazides), and reduced kidney function must also be ruled out prior to making the diagnosis of SIADH.
Other tests that may be considered in the diagnosis of SIADH:
Fractional excretion of uric acid: A level >12% has been suggested to provide a positive predictive value of 100% for the diagnosis of SIADH, whereas a value of <8% excludes the diagnosis.
Water loading test: In equivocal cases of SIADH, a water loading test may be considered. This test may only be performed in patients with mild hyponatremia (not in those with moderate or severe hyponatremia). In this test, normal individuals will dilute the urine to UOSM < 100 mOsm/kg and appropriately excrete >90% of a free water load (given at 20 mL/kg body weight) within 4 hours, whereas patients with SIADH will inappropriately hold on to the free water load. See Appendix A for protocol.
Mechanism of disease: lower osmotic threshold for ADH release
Conditions associated with reset osmostat: normal variant, hypothalamic injury, malnutrition
Mechanism for hyponatremia: water load exceeds the capacity of the kidneys to excrete free water ingestion
Conditions associated with primary polydipsia: psychiatric patients ± phenothiazines with associated dry mouth, hypothalamic infiltrative disease such as sarcoidosis affecting thirst center, use of mouth-drying medications (e.g., anticholinergic agents, decongestants)
Tea and toast syndrome, beer potomania:
Mechanism of hyponatremia: insufficient solute intake to provide the necessary solute load required by the kidneys to excrete water. Kidneys cannot excrete pure free water. Kidneys need a minimum of 50 to 100 mOsm of solute to excrete every 1 L of water. The “maximal diluting capacity” of healthy kidneys is typically 50 to 100 mOsm/kg. Patients with poor kidney function have reduced “maximal diluting capacity”; therefore, UOSM may be on the higher range of 100 to 150 mOsm/kg.
Increased H2O reabsorption from the use of irrigation fluids with various genitourinary procedures (e.g., transurethral resection, hysteroscopy, nephrolithotomy) may lead to hyponatremia for the following reasons:
1.5% glycine solution:
Solution is hypotonic: osmolality = 200 mOsm/kg
Glycine may also directly stimulate ADH secretion.
Typical presentation for all ADH-independent conditions above: euvolemia, U[Na+] is variable depending on sodium intake; UOSM < 100 to 150 mOsm/kg (kidneys appropriately dilute urine to excrete free H2O).
Nephrogenic syndrome of inappropriate antidiuresis (NSIAD)
Mechanism of disease: X-linked gain-of-function mutation of vasopressin 2 receptor (AVP2R); these receptors are constitutively activated in the absence of ADH.
Hyponatremia (female carriers may be asymptomatic with mild hyponatremia), decreased thirst, infrequent voiding (due to increased tubular H2O reabsorption)
Laboratory findings are similar to those seen with SIADH, but ADH level is undetectable (in contrast to SIADH where ADH levels are high).
Definitive diagnosis requires sequencing of the AVP2R gene.
Exercise-induced hyponatremia (e.g., marathon runner hyponatremia):
Volume status is variable.
Mechanisms of hyponatremia: (1) excess free water ingestion relative to salt and water loss from sweating and (2) concurrent increased ADH level associated with muscle injury during heavy exercise
To avoid exercise-induced hyponatremia, heavy exercisers should be advised to only drink per thirst.
Drugs affecting both sodium and H2O homeostasis: diuretics (thiazides, indapamide, amiloride, furosemide)
Drugs affecting H2O homeostasis:
Increase hypothalamic ADH production: antidepressants (amitriptyline, protriptyline, desipramine, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors), antipsychotics (thioridazine, trifluoperazine, haloperidol), antiepileptics (carbamazepine, oxcarbazepine, sodium valproate),
chemotherapeutic agents (vincristine, vinblastine, IV cyclophosphamide, melphalan, ifosfamide, methotrexate, interferon α and γ, levamisole, pentostatin, monoclonal antibodies), opiates
Potentiate ADH effect: antiepileptics (carbamazepine, lamotrigine), antidiabetics (chlorpropamide, tolbutamide), anticancer agents (IV cyclophosphamide), NSAIDs
Desmopressin (DDAVP): Hyponatremia may easily occur in patients with excessive free water intake while receiving DDAVP for various reasons (e.g., enuresis, cDI, or von Willebrand disease). Patients must be instructed to only drink water with thirst, adjust DDAVP dose per urine volume, and recognize signs and symptoms of hyponatremia.
Drugs that reset osmostat: antidepressants (venlafaxine), antiepileptics (carbamazepine)
Angiotensin-converting enzyme inhibitors (ACEI): ACEI inhibits the conversion of angiotensin I (AI) to II (AII) in peripheral tissue, but not in brain. In the brain, AI continues to be converted to AII, which can stimulate thirst and ADH release. Use of ACEI increases AI levels, hence increased brain AII. ACEI may also induce increased ADH secretion by delaying bradykinin degradation.
Intravenous immune globulins (IV Ig) mixed in maltose or sucrose: Hyponatremia may occur via (1) pseudohyponatremia, if measured by flame photometric assay due to large amount of space-occupying globulins; (2) dilutional hyponatremia, due to extracellular free water shift with accumulation of maltose or sucrose (important if poor kidney function and reduced excretion of maltose or sucrose)
Amphetamines: 3,4-methylenedioxymethylamphetamine (i.e., “ecstasy”): increase hypothalamic ADH secretion and excessive water intake due to associated hyperthermia and thirst
Less common causes: nicotine patch, colchicine poisoning, dopaminergic agents, unfractionated heparin, hydroxyurea, azithromycin, clonidine, glipizide, tacrolimus, cotrimoxazole, theophylline, proton pump inhibitors
Provide adequate oxygenation, mechanical ventilation support if necessary. Hypoxemia may exacerbate hyponatremic encephalopathy.
Potassium and sodium are equivalent effective exchangeable osmoles. Any K+ given during the treatment of hyponatremia will correct S[Na+] exactly as if the same amount of Na+ was given. See Figure 1.2 for mechanisms.
Example: If a patient needs 200 mmol of Na+ to raise his or her hyponatremia to goal, but also needs 75 mmol K+ for concurrent hypokalemia, the clinician should give:
125 mmol of Na+ + 75 mmol of K+ = 200 mmol total of Na+ + K+ instead of 200 mmol of Na+ + 75 mmol K+ = 275 mmol total of Na+ + K+. The latter combination would overshoot the goal S[Na+].
Monitor urine output: Hypotonic polyuria can easily overcorrect hyponatremia if not recognized. Hypotonic polyuria may be seen during the treatment of hyponatremia with the following conditions: postpituitary infarction, glucocorticoid replacement in patient with cortisol insufficiency, discontinuation of DDAVP in patients with chronic use (e.g., for cDI), recovery from acute respiratory failure, withdrawal of thiazides, water deprivation in primary polydipsia, rapid volume expansion with boluses of intravenous saline. (Normal saline [NS] boluses should be reserved for hemodynamically unstable patients.)
Cases of osmotic demyelination syndrome (ODS) have been reported in patients with concurrent hypokalemia, hypomagnesemia, hypophosphatemia, thiamine deficiencies, or any combination of these deficiencies independent of the rate of Na+ correction. It is important to monitor and correct these deficiencies during the management of hyponatremia.
A 5% increase in S[Na+] should substantially reduce cerebral edema.
Rapid correction can lead to ODS, previously known as central pontine myelinolysis (CPM), due to insufficient time allowed for brain synthesis of organic osmolytes or “idiogenic osmoles” to counteract the acute rise in extracellular osmolality. Major brain organic osmolytes include glutamine, glutamate, taurine, myo-inositol, among others.
High risks for ODS: S[Na+] < 105 mmol/L, alcoholism, malnutrition, advanced liver disease, hypokalemia
Clinical manifestations of ODS:
1 to 2 days: generalized encephalopathy
2 to 3 days: behavioral changes, cranial nerve palsies, progressive weakness, quadriplegia, “locked-in” syndrome; death is possible.
Diagnosis: presence of nonenhancing and hyperintense pontine and extrapontine lesions on T2-weighted MRI. A time lag of up to 2 weeks for the presence of MRI abnormalities is possible.
ODS may be reversible, even in some cases with severe symptoms at presentation.
Reversal of overcorrection with hypotonic fluids and DDAVP has been shown to be beneficial in rats and human case reports.
Correction rate for acute symptomatic hyponatremia (known duration < 24 to 48 hours):
Urgent correction by 4 to 6 mmol/L to prevent brain herniation and cerebral ischemia
No need to restrict correction rate if truly acute
For severe symptoms (e.g., seizures, coma): infuse 100 mL of 3% NaCl over 10 minutes × 3 as needed
For mild to moderate symptoms: infuse 3% NaCl at 0.5 to 2 mL/kg/h. Must monitor change in S[Na+] closely and specify duration of treatment to avoid overcorrection.
Correction rate for hyponatremia with associated seizures or coma, presence of intracranial pathology, or increased intracranial pressure and unknown duration:
Urgent correction by 4 to 6 mmol/L
After urgent correction above, treat based on total daily correction rate limits used for chronic hyponatremia mentioned below.
Correction rate for chronic hyponatremia (lasting ≥48 hours):
Fluid restriction may be considered for euvolemic or hypervolemic patients.
“Fluid” implies all fluid consumed by drinking and food source, not just water.
Restriction volume should be aimed at 500 mL below the patient’s average daily urine volume.
However, fluid restriction is often ineffective, particularly in patients with severe SIADH.
Predictors of likely failure with fluid restriction alone:
Table 1.1 Treatment options in the management of hyponatremia
Indications and Comments
Sodium chloride tablets
Volume depletion; avoid boluses unless patients are hemodynamically unstable.
Severe neurologic complications, severe salt wasting (e.g., renal or cerebral salt wasting), severe SIADH with urine osmolality >> 300 mOsm/kg + severe hyponatremia and unclear volume status
Patients with concurrent hypokalemia. Note that potassium supplement increases S[Na+] exactly as if the same amount of sodium is given.
Free H2O restriction
Reduce free water intake to 500 mL below urine output
Therapy failure predictors: baseline urine output < 1,500 mL/d; (UNa + UK)/SNa > 1; UOSM > 500 mOsm/kg
Volume overload (e.g., heart failure, cirrhosis, nephrotic syndrome)
Increase free H2O excretion
SIADH, heart failure (not suggested in patients with cirrhosis or those with severe neurologic complications); concurrent use with loop diuretic not recommended
SIADH (contraindicated during pregnancy and children due to interference with bone development, nephrotoxicity, photosensitivity)
Increase solute load (e.g., protein drinks, urea)
Poor solute intake or malnutrition. Consider nutrition consult.
Maintain adequate oxygenation/airway if altered mental status; follow serum magnesium, phosphorus, potassium levels, and replete as needed.
Abbreviation: SIADH, syndrome of inappropriate antidiuretic hormone secretion.
NS or salt-balanced solution: recommended for hypovolemic patients. Avoid boluses unless hemodynamically unstable. Rapid volume expansion can lead to high-volume aquaresis, and therefore rapid overcorrection of hyponatremia.
Indicated for patients who are severely symptomatic (e.g., seizures, severely depressed mental status): 100 mL 3% bolus every 10 minutes as needed to break seizures or up to a total of three boluses, whichever comes first
May also be considered at low infusion rates for:
Example: Imagine a patient with severe SIADH, whose kidneys always concentrate the urine to an osmolality of ˜600 mOsm/kg. Conceptually, this is essentially equivalent to 600 mOsm/1 L of urine.
If this patient receives 1 L of NS, he or she receives a solution consisting of 308 mOsm of solutes (154 mmol Na + 154 mmol Cl) + 1 L of free water, which is approximately 300 mOsm of solutes + 1 L of free water.
Kidneys would see 1 L of NS as:: 300 mOsm of solutes + 1 L of free water
Kidneys’ task: excrete urine with an osmolality of 600 mOsm/kg ˜600 mOsm/L
Kidneys will use up all 300 mOsm of solutes, but only 500 mL of water from the fluid administered to make urine with osmolality 600 mOsm/kg.
This means that the remaining 500 mL of water gets reabsorbed into the patient. This leads to worsening of the patient’s existing hyponatremia.
In effect, the kidneys “desalinate” or remove all NaCl from the NS to make urine with the high osmolality dictated by the patient’s degree of SIADH. The “leftover” water gets reabsorbed into the patient.
By the same reasoning, imagine another patient with moderate SIADH with a typical UOSM of 300 mOsm/kg. The use of NS would never correct the patient’s hyponatremia because this patient’s kidneys typically excrete urine with the same osmolality as NS. Since there is no salt gained or lost from the NS infusion, there will be no change in the existing hyponatremia.
Bottom line: Any saline solution used in a patient with SIADH for the sole purpose of increasing S[Na+] must have higher osmolality than that of urine.
FIGURE 1.4 Desalination with syndrome of inappropriate secretion of antidiuretic hormone (ADH). Panel 1. Patient with low level of ADH: there is low level of aquaporin 2 (AQP2) expression, thus minimal free water reabsorption. Urine volume and tonicity remain relatively high and dilute, respectively. Panel 2. Patient with syndrome of inappropriate secretion of antidiuretic hormone (SIADH): There is increased aquaporin 2 expression that allows for avid water reabsorption. Imagine a patient with known SIADH who can concentrate urine up to 600 mOsm/kg. If this patient is given 1,000 mL of NS with approximate tonicity of 300 mOsm/kg, the kidneys will reabsorb 500 mL of free water and excrete 500 mL of urine with tonicity of 600 mOsm/kg. The high volume of free water reabsorbed results in worsening of existing hyponatremia and the excretion of a highly concentrated urine (desalination of the administered fluid).
May be used in patients with severe salt wasting (e.g., patients with severe CSW or renal wasting associated with cisplatin)
Salt tablets: may be preferred over strict fluid restriction in stable euvolemic patients with SIADH and terminal conditions (i.e., metastatic malignancy for better quality of life—authors’ opinion)
Increase solute load if poor nutrition: parenteral feeding, encourage high oral solute intake (salt and protein)
Urea (0.5 to 1.0 g/kg/d or higher as needed) may also be used as an osmotic diuretic agent to increase free water excretion in patients with chronic hyponatremia due to SIADH.
Vasopressin (ADH) antagonists:
Demeclocycline: inhibits ADH by inhibiting adenylyl cyclase activation
Contraindicated in children and during pregnancy due to interference with bone development, teeth discoloration
Should not be used in liver patients; hepatitis and liver failure may occur with demeclocycline
Other complications: photosensitive rash, nephrotoxicity
Vasopressin receptor antagonists (i.e., vaptans, aquaretics): for euvolemic and hypervolemic hyponatremic patients with dysregulated ADH or SIADH.
Conivaptan: intravenous formulation only; combined V1a and V2 receptor antagonist; limit use to 4 days due to significant drug interactions with other agents metabolized by CYP3A4.
Tolvaptan: oral formulation; V2 receptor antagonist
Both agents improve free water excretion and improve S[Na+] without altering 24-hour sodium excretion.
Vaptans have not been shown to improve long-term outcome in the treatment of hyponatremia.
Use of vaptans is not recommended immediately following cessation of other treatments of hyponatremia, particularly 3% saline.
Vaptans are ineffective in patients with reduced kidney function (i.e., SCr > 3 mg/dL)
Major side effects and risks: thirst, transaminitis, gastrointestinal bleed
Overly rapid correction leading to ODS is possible particularly if used concurrently with diuretics or in patients without access to free water (e.g., patients who are mechanically ventilated or debilitated, bed bound). Relowering of S[Na+] should be considered in cases with overly rapid corrections.
Data are lacking to recommend use of vaptans in severe asymptomatic hyponatremia—that is, S[Na+] < 120 mmol/L.
Vaptans should not be used in patients with symptomatic acute hyponatremia, particularly in those with neurologic symptoms due to its delayed onset of action. Hypertonic 3% saline infusion is the treatment of choice in such cases.
Loop diuretic (e.g., furosemide): may be used in patients with hypervolemia. Concurrent use with vaptan is not recommended due to the risk of rapid free H2O excretion and overly rapid correction of hyponatremia.
Conservative therapy: water restriction, increase in salt intake combined with loop diuretic, oral urea (if available)
The use of vaptan is ineffective in all cases with Arg137Cys (arginine to cysteine substitution at amino acid 137) mutation but effective in F229V (phenylalanine to valine substitution at amino acid 229) mutation. The ineffectiveness of vaptans in specific NSIAD mutations is thought to be due to the inability of vaptans to deactivate the constitutively activated AVP receptor.
Commonly used equations to calculate expected S[Na+] (Na2), given initial S[Na+] (Na1), total body water volume, input and output volumes (Volinput/Volinf, Volout) and their respective sodium and potassium concentrations (Na + K)out, (Na + K)in, and net volume change ΔVol (Volinput – Volout)
For calculations involving multiple sources of input and output and estimates for both fluid tonicity and rate administration, see Curbside Consultant App (available 2021).
Correction of hyponatremia in the dialysis patient:
Uremic patients are thought to be relatively protected from ODS with rapid correction of hyponatremia during hemodialysis. Although the mechanism is not known, it has been speculated that the simultaneous removal of uremic solutes offsets the rapid rise in S[Na+]. Nonetheless, it must be cautioned that ODS has been reported in hemodialysis patients.
Correction rates should therefore follow the same guidelines for nonuremic patients.
Calculations of blood flow to correct hyponatremia with intermittent hemodialysis (IHD): See Appendix A.
For acute water intoxication, relowering of sodium is not necessary.
For patients with presenting S[Na+] < 120 mmol/L, relowering of S[Na+] should be considered (particularly in patients with high risks for ODS):
Replace water losses with intravenous 5% dextrose water or oral water to achieve desired goal—For adult patients with hyperglycemia who cannot tolerate high dose of dextrose and cannot drink water (e.g., patients with high serum glucose), 2.5% dextrose water may be used.
Administer DDAVP 2 to 4 µg intravenously q8h as needed (per Hyponatremia Expert Panel). In our experience, 2 µg DDAVP q12h to q24h is typically sufficient.
If patient was given vaptan, hold the next dose if correction exceeds 8 mmol/L/24 h. In case of unsafe overcorrection, administer free water and DDAVP as above.
Monitor S[Na+] closely.
Consider administration of high-dose glucocorticoids to reduce ODS risk in case of severe overcorrection (e.g., dexamethasone 4 mg q6h for 24 to 48 hours).
Treat underlying condition that causes SIADH.
Hyponatremia in patients with HF:
For mild to moderate symptoms:
Begin with fluid restriction 1 L/d. Add loop diuretic as needed for volume overload.
Tolvaptan may be considered, but must be closely monitored to assess long-term need. Combined loop diuretic and vaptan should be avoided to prevent rapid and excessive overcorrection.
For severely symptomatic patients with severe hyponatremia, consider the administration of 3% NaCl plus loop diuretics. Close monitoring is required.
For primary polydipsia:
Consider behavioral therapy.
Avoid anticholinergic agents, antihistamines, decongestants.
Consider atypical antipsychotics in patients with psychogenic polydipsia (limited data): clozapine, olanzapine, risperidone.
Discontinue thirst- or hyponatremia-inducing drugs. See Other Noteworthy Causes of Hyponatremia above.
A typical osmolar clearance is <3 L/d.
COSM > 3 L/d generally indicates the presence of a solute diuresis.
FWC or CH2O may be calculated as:
Conceptually, FWC is the urine volume with osmolality of zero that remains after the portion of urine normalized to serum osmolality has been extracted/removed from the initial total urine volume. Depending on the urine and serum osmolalities, FWC may be positive or negative.
A positive FWC indicates that a patient makes urine that is hypoosmolar to the plasma, thereby losing free water and increasing plasma osmolality, whereas a negative FWC indicates that a patient makes urine that is hyperosmolar to the plasma, thereby gaining free water and lowering plasma osmolality. The change in plasma osmolality does not necessarily imply a similar change in S[Na+]. Any change in S[Na+] depends on the actual amount of salt loss or gain per unit of urine volume relative to that of the plasma.
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