Definition  

Hyponatremia is defined as a serum [Na+] <135 mmol/L and can be acute or chronic. The treatment of hyponatremia is guided by severity, chronicity, and etiology – so determination of all of these factors is paramount.

• Acute: <48 hours since development of hyponatremia.
• Chronic: >48 hours since development of hyponatremia.
  • Note: hyponatremia should be considered chronic whenever the duration is unknown.
• Mild: serum [Na+] 130-134 mmol/L.
• Moderate: serum [Na+] 120-129 mmol/L.
• Severe: serum [Na+] <120 mmol/L.

Hyponatremia is the most common electrolyte abnormality in hospitalized patients (estimated to occur in 10-30% of all hospitalized patients). Recognition and safe treatment are extremely important. Hyponatremia and its mismanagement can cause serious, sudden, and irreversible neurological problems and is associated with increased mortality.

Etiology

• Hyponatremia represents an excess of free water and should be considered a disorder of water balance.
• Excess free water can result from:
  • High intake (e.g. polydipsia).
  • Impaired free water excretion.
    • Low GFR or diminished diluting capacity of the kidney (e.g. dialysis patients).
    • High ADH (e.g. heart failure, SIADH).
    • Inadequate solute intake (e.g. tea and toast diet).
  • A combination of high intake & low excretion.

Evaluation

Helpful tips

• Remember that free water balance (urine osmolality) is regulated by ADH.
• Sodium excretion (urine sodium) is regulated by aldosterone. 
  • If a patient has end-stage kidney disease, the cause of hyponatremia is excess free water intake in the setting of impaired kidney water excretion, and is not mediated by ADH.

Step 1: differentiate true hyponatremia from pseudohyponatremia.

• A normal or elevated effective serum osmolality (280 mOsm/kg or greater) suggests pseudohyponatremia. 
• Hypertonic states, like hyperglycemia or mannitol use, can cause hyponatremia by drawing water extracellularly and lowering serum sodium concentration. This is technically a true (not pseudo) hyponatremia. Serum osmolality will be high; sodium should normalize with correction of hypertonic state (insulin for hyperglycemia, excretion of mannitol, etc.).
  • Correction formula for hyperglycemia: corrected Na = measured Na + [(serum glucose – 100)/100]*1.6
    • Hyperlipidemia or increased protein can also cause a lab error that results in a falsely low sodium result. Blood gas analyzers are typically not subject to this error.

Step 2: is ADH high or low? Compare serum osmolality to urine osmolality.

• If serum osm > urine osm, then ADH is low (kidneys are appropriately responding by maximizing water excretion, i.e. maximally dilute urine). The problem is excess water intake or inadequate solute intake. A urine osm <100 also suggests normal free water excretion. 
  • Check for iatrogenesis: are there high rates of hypotonic solution infusing?
    • Look at what medications are mixed in (e.g. IV bactrim in 500 ml D5W 4x/day = 2L of free water).
    • Check volume of free water flushes in patients getting tube feeds or other hypotonic oral intake. 
  • Consider primary polydipsia (formerly known as “psychogenic polydipsia”).
  • Causes of inadequate solute intake include tea and toast diet and beer potomania (high alcohol intake relative to solute intake).
    • Because urine osm cannot be 0, there is always some obligate solute excreted with urine. Even if maximally dilute at 50 mOsm/L, if a person only eats 100 mOsm and drinks 3L of water in a day, they can only eliminate 100/50 = 2L of that water and 1L is retained. This dilutes the serum sodium.
    • Carbohydrates and fat metabolize to water and CO2, so do not count as solute. Protein and electrolytes (e.g., sodium) are solutes. Hence, as diets, toast and beer contain insufficient solute.
• If serum osm < urine osm, ADH is high. Proceed to Step 3.

Step 3: if ADH is high, what is the volume status?

• Tips: 
  • If ADH is activated, urine osmolality is usually >100. 
  • Urine sodium can help you determine RAAS activation, which can narrow your differential in cases where volume status is not clear. A low urine sodium suggests RAAS activation, as seen in hyper- or hypovolemia; a high urine sodium may suggest SIADH. 
• Hypervolemic: ADH is released in response to low effective arterial blood volume (EABV) due to third spacing or poor forward flow.  
  • Ddx: CHF, nephrotic syndrome, liver failure.
  • Urine Na will be low, since the RAAS system is also activated in response to low EABV.
• Hypovolemic: ADH is being released in response to low EABV due to fluid loss.
  • Extrarenal losses, like GI loss: urine Na will be low, since aldosterone will also be on.
  • Renal salt wasting: urine Na will be high. Causes include salt-wasting nephropathy, adrenal insufficiency, cisplatin, and thiazide diuretic use.
• Euvolemic:  
  • Hypothyroidism: check TSH.
  • Glucocorticoid deficiency: check AM cortisol.
  • SIADH: inappropriate release of ADH independent of EABV/osmolality or release of ADH at a lower osm level (“reset osmostat”). Urine Na will be high, since aldosterone is low.
    • Etiology: pain/nausea, pulmonary disease, CNS disease, malignancy, drugs (SSRI, MDMA/ecstasy, opioids, chemotherapy [e.g. cyclophosphamide, vincristine]). 
    • SIADH is a diagnosis of exclusion with the following features:
      • Clinical euvolemia.
      • Normal thyroid and adrenal function, no recent diuretic use.
      • Lab findings:
        • Urine osmolality >150 mOsm.
        • Serum osmolality <275 mOsm.
        • Urine Na >20 mmol/L with normal dietary salt intake.
      • Corroborating features (sometimes but not always present).
        • Serum uric acid <4mg/dl.
        • BUN <10 mg/dL.
        • FENa >2% or FEUrea >45%.
  • Refractory or worsening hyponatremia after isotonic fluid infusion. 

Management

• Evaluate and treat severe symptoms emergently in all patients.
  • Check for signs of cerebral edema: visual changes, neurologic deficits, encephalopathy, and seizures. The presence of these signs suggest cerebral edema and necessitates rapid treatment.
    • To acutely relieve cerebral edema, sodium can be raised using 3% hypertonic saline (100 mL bolus given over 10 minutes, may be repeated up to 2 times).
    • Goal is resolution of severe symptoms, typically with [Na+] rise of 4-6 mEq/L.
    • Usual rate limit of correction still applies, i.e. if the goal is 6 mEq/L/day, and acute treatment for severe symptoms has already increased [Na+] by 6 mEq/L, then that level of sodium should be maintained for the following 24 hours.
• Calculate desired rate of correction.
  • The brain adapts to hypotonic hyponatremia with intracellular osmolar shifts over approximately 48 hours.
  • For acute hyponatremia (<48 hours), rapid correction is appropriate and safe. 
  • Chronic hyponatremia (>48 hours or unknown duration) requires slower correction (no more than 6-8 mEq/L/day) to minimize the risk of osmotic demyelination syndrome (ODS). If the duration of hyponatremia is unknown, always assume it is chronic and use slower correction goals.
  • Risk factors for ODS: lower sodium (<105 mEq/L), hypokalemia, malnutrition, alcohol use, liver disease.

Select treatment approach based on volume status, severity, and etiology. 

• Hypovolemia: the cornerstone of treatment is volume expansion with isotonic crystalloid to increase EABV.
  • Caution: once volume status is corrected, a brisk aquaresis may ensue and cause overcorrection; thus, strict urine output and frequent sodium monitoring is critical. The earliest and most concerning indication of overcorrection is brisk urine output and/or a decrease in urine osmolality. For patients with high risk of ODS, nephrology consultation is recommended to consider mitigating strategies (e.g. preemptive DDAVP). These strategies could be considered and implemented ideally before treatment is initiated.
• SIADH: 
  • Treatment of underlying cause/withdrawal of causative agents as possible. 
  • Start with fluid restriction 1-1.5L/day. However, restriction alone is often inadequate for SIADH. Do not restrict beyond 1L, as that is unlikely to add additional benefit and can cause significant discomfort.
  • Use urine electrolytes (UNa + UK) to guide therapy:
    • Based on the concept of electrolyte free water clearance (EFWC), this is a way to determine whether the kidneys are still excreting water, or whether the urine is so concentrated that all free water is reabsorbed. You do not need the full EFWC equation, instead compare UNa and UK to plasma Na. (Na and K are the main osmotically active electrolytes in the urine, but K serum concentration is low relative to Na and is not included in the equations.) 
    • UNa + UK < serum Na: positive free water clearance, i.e., patient is still urinating out free water (but perhaps not enough to improve hyponatremia unless water intake is substantially limited with fluid restriction). This suggests fluid restriction will be an effective treatment.
    • UNa + UK > serum Na: negative free water clearance, i.e., all free water is reabsorbed and any urination will continue to lower serum [Na+]. This suggests osmole supplementation (e.g. hypertonic saline or salt tabs) is needed to treat hyponatremia. 
    • Any IV fluids with Na content less than UNa + UK will result in worsening hyponatremia. This process is sometimes called desalination because the kidney is able to excrete the solute but reabsorb the free water from the infused solution. Therefore, UNa + UK > 154 is typically an indication that hypertonic saline is needed to correct hyponatremia.
  • Additional therapies for SIADH:
    • Hypertonic saline
      • Effective (3% = 513 mEq/L), necessary when UNa + UK is very high.
      • Requires good venous access (some centers only allow sustained infusion with central access, but there is scant evidence of adverse events with appropriate peripheral access).
      • Not a long term therapy.
    • Loop diuretics
      • In theory, wash out medullary concentrating gradient (lowering maximal urine concentration), but efficacy is often limited.
      • However, may be useful as an adjunct to NaCl tabs to counteract volume overload.
    • NaCl tabs (1g NaCl tab = 17 mEq Na+ and 17 mEq Cl-)
      • Not a very high osm load per tab (typically need upwards of 2g TID).
      • Difficult pill burden, can stimulate thirst counteracting fluid restriction and cause GI upset.
    • Oral urea (tabs or powder): 15g = 250 mOsm.
      • Osmotic diuretic effect to eliminate free water.
      • Efficient way to deliver a large osmole load.
      • Will not cause volume overload, excellent safety margin.
• Hypervolemia:
  • Free water restriction (1-1.5 L/day).
  • Loop diuretics to optimize volume status.
  • Hypertonic saline and salt tabs generally NOT recommended as they will worsen volume overload. 

Role of DDAVP (ADH analog) for management of hyponatremia

• DDAVP (dosed 1-2mcg IV or SC q6h-q8h) will reduce urine water output to a minimum (minimize “aquaresis”), thus preventing a rapid rise in serum sodium with resolution of ADH stimulus. This facilitates a more controlled correction, and is often used with hypertonic saline. 
• Typically DDAVP is considered as a proactive measure in situations when ODS risk is high and brisk aquaresis is expected, such as in:
  • Hypovolemic hyponatremia: the volume stimulus for ADH is removed promptly by fluid resuscitation.
  • Poor solute intake: when the provision of solute (i.e., 308 mOsm from 1L of NS) enables significant aquaresis (if UOsm is 50, then 1L of NS will enable 6L of urine output).
  • SIADH: when the stimulus for ADH is removed suddenly or unpredictably (rarely the case).
• DDAVP may also be used as a reactive measure to “put the brakes” on overcorrection, either as an alternative or an adjunct to giving back D5W/free water.
• Do NOT use DDAVP in patients with volume overload (CHF, cirrhosis) or patients who may continue to drink water/hypotonic fluids (e.g. primary polydipsia and/or severe thirst).

If the serum sodium has been overcorrected:

• IV D5W alone or with DDAVP, as above.
  • Can give 3mL/kg/hour D5W to lower [Na+] by approximately 1 mEq/L/hour if overcorrected.
  • Pay attention to ongoing losses: if urine output is brisk (>150 mL/hour) and dilute, the patient is losing free water rapidly and it is raising serum [Na+] rapidly; reactive boluses of D5W may be inadequate to keep up. Suggest nephrology consultation to assist with safe correction strategies (e.g., titrating D5W drip to a % of urine output or using DDAVP to inhibit the aquaresis).

Key Points

• Hypotonic hyponatremia is due to excess free water, which may be a result of excess water intake and/or impaired water excretion. 
• Severe symptoms of hyponatremia represent an emergency and should be treated with hypertonic saline to immediately raise [Na+] and resolve symptoms.
• The recommended correction rate is 6-8 mEq/L/day for chronic hyponatremia.
• If there is high risk for ODS or if considering the need for DDAVP, hypertonic infusion (other than emergent use for severe symptoms), or vaptan therapy, a nephrology consult is advised.
• Hypovolemic, low solute, and hypervolemic hyponatremia are treated by correcting the underlying cause. Urine output monitoring is critical as it is the earliest sign of overly rapid correction.
• SIADH is treated by addressing the underlying cause (if possible) but often requires chronic therapy to maintain normonatremia. Urine Na + K can be used to assess severity of SIADH and guide therapy.

Seay NW, Lehrich RW, Greenberg A. Diagnosis and Management of Disorders of Body Tonicity—Hyponatremia and Hypernatremia: Core Curriculum 2020. Am J Kidney Dis 

2019;75(2):272-286.

Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170(3):G1-47. Doi:10.1530/EJE-13-1020