CONTENTS

• Symptoms
• Causes
  • [1] Non-hypotonic hyponatremia
  • [2] {Water intake > solute intake}
  • [3] Hypovolemic hyponatremia
  • [4] Euvolemic hyponatremia
  • [5] Hypervolemic hyponatremia
• Initial investigation & treatment
  • 🚨 Initial hyponatremia package
  • Interpretation of hyponatremia labs
    • Serum osmolality
    • Urine osmolality
    • Urine sodium
  • Determining the cause of hyponatremia
  • Risk stratification
  • Target rate of increase
• Subsequent therapeutic strategies
  • DDAVP clamp-bolus technique
    • When to use the DDAVP clamp
    • How to perform DDAVP clamp-bolus
  • Aquaresis using oral urea
• Common causes of hyponatremia:
  • SIAD
    • Diagnosis of SIAD
    • Causes of SIAD
    • Treatment of SIAD
  • Heart failure
  • Cirrhosis
  • Hypokalemic hyponatremia
• Other topics:
  • Why not to use vaptans
  • Emergent tx with oral soy sauce
• Podcast
• Questions & discussion
• Pitfalls

---

symptoms of hyponatremia

(back to contents)

---

the presence of symptoms is extremely important:

• Even mild symptoms are an indication for IV hypertonic fluid. ⚡️
• Symptoms generally imply one of the following:
  • [1] Acute hyponatremia.
  • [2] Chronic hyponatremia that is severe (e.g., Na<115 mM). (Irwin 2023)

severe & moderately severe symptoms

• Seizure.
• Delirium that may progress to coma and brain death (herniation).
• Neurogenic pulmonary edema 📖, especially following endurance sports or intoxication with 3,4-methylenedioxymethamphetamine (ecstasy). (figure below)
• Vomiting. (This is worrisome since it may reflect elevated intracranial pressure. Additionally, vomiting may cause SIAD and hypovolemia, thereby exacerbating the hyponatremia). (35852524)
• Headache.

non-severe symptoms

• Malaise, lethargy.
• Nausea without vomiting.
• Dizziness, gait instability.
• Tremor, multifocal myoclonus.
• Muscle cramps, myalgia.

---

causes

(back to contents)

---

---

[1/5] non-hypotonic hyponatremia (serum osmolality >275 mOsm)

causes of non-hypotonic hyponatremia

• Large amounts of other osmoles (translocational hyponatremia): (In this case, sodium is truly reduced. The sodium reduction is due to other osmoles that pull water into the plasma – so the plasma tonicity is not low.)
  • Severe hyperglycemia.
  • Mannitol administration.
  • Maltose (from IVIG).
  • Hypertonic contrast dye.
  • Sorbitol/glycine irrigation (for transurethral resection of the prostate) or histidine-tryptophan-ketoglutarate irrigation (for cardiac surgery). (36974717)
  • Ethanol intoxication. (This is somewhat unique. Ethanol is not an effective osmole, so that ethanol will elevate the measured osmolality but not the clinically relevant tonicity.)
• Pseudohyponatremia: (In this case, the plasma osmolality and sodium concentration are usually normal. A reduction in the liquid phase of the blood causes a laboratory artifact when sodium is measured following dilution of the blood sample.)
  • Hypertriglyceridemia  (>1,500 mg/dL).
  • Hyperproteinemia:
    • Multiple myeloma.
    • Waldenstrom macroglobulinemia.
    • Therapy with IVIG.
  • Hypercholesterolemia (lipoprotein X in cholestasis). (37822230)

diagnosis of non-hypotonic hyponatremia

• History may often be suggestive:
  • Hyperglycemic crisis (e.g., DKA or HHS).
  • Administration of mannitol or IVIG.
  • Surgical procedures involving irrigation.
• Laboratory findings:
  • Serum osmolality ≧275 mOsm is the critical finding.
  • If the lab reports that blood is lipemic, this should suggest the possibility of hypertriglyceridemia.
  • Pseudohyponatremia is usually associated with a normal sodium measurement using point-of-care assays or blood gas analyzers (which don't involve specimen dilution). (37822230)

management

• Large amounts of other osmoles:
  • Hyperglycemic crises should be treated per usual protocols.
  • Sorbitol/glycine poisoning with elevated serum osmolality may require emergent administration of free water to reduce the tonicity towards a normal value.
• Pseudohyponatremia:
  • The tonicity is normal, so no therapy is required to address the tonicity.
  • Underlying disease processes should be treated.

---

[2/5] rare situations where {water intake > solute intake} 

causes of {water intake > solute intake}

• Beer potomania (the combination of excessive beer intake with reduced solute intake).
• Low solute intake diet, e.g.:
  • Elderly patients who eat a “tea-and-toast” diet.
  • Anorexia nervosa.
• Very rapid water intake:
  • Fraternity hazing.
  • Water loading prior to a drug screen.
  • Multiple tap water enemas.
  • Freshwater drowning.
• Primary polydipsia (often in schizophrenia).

diagnosis

• History is often helpful.
• The key finding is that the kidney is producing maximally dilute urine:
  • Urine osmolality <100 mOsm.
  • Urine specific gravity < 1.003
• Sodium will generally auto-correct rapidly, following minimal intervention.

treatment

• Sodium usually corrects very rapidly after removal of the cause.
• There is a high risk for over-correction; consider using the DDAVP clamp for patients who are at risk of osmotic demyelination syndrome.

---

[3/5] hypovolemic hyponatremia

causes of hypovolemic hyponatremia

• Hypovolemic hyponatremia without active renal sodium wasting (urine sodium <20-30 mM):
  • GI loss:
    • Vomiting or gastric tube drainage (later stages).
    •  Diarrhea.
  • Hemorrhage.
  • Sweating.
  • Poor oral intake.
  • Third space fluid sequestration:
    • Pancreatitis.
    • Bowel obstruction.
    • Peritonitis.
    • Burns.
    • Massive trauma.
• Hypovolemic hyponatremia with active renal sodium wasting (urine sodium >20-30 mM):
  • Diuretics (especially thiazides).
  • Salt-wasting nephropathy (e.g., post-obstructive diuresis).
  • Hypoaldosteronism or late adrenal insufficiency.
  • Osmotic diuresis, e.g.:
    • Glucosuria in uncontrolled diabetes. (35852524)
    • Urea.
    • Mannitol.
  • Bicarbonaturia:
    • Renal tubular acidosis.
    • Vomiting (early stage).
  • Ketonuria.
  • Cerebral salt wasting (possibly a form of hypoaldosteronism).

treatment

• Treat the underlying disorder.
• Monitor for sodium overcorrection and consider DDAVP clamp if needed.

---

[4/5] euvolemic hyponatremia

causes of euvolemic hyponatremia

• SIAD (causes listed below ⚡️).
• Adrenal insufficiency (early).
• (Hypothyroidism is often listed as a cause of hyponatremia, but this does not appear to be evidence-based. Hypothyroidism itself doesn't appear to cause hyponatremia. Hypothyroidism may cause heart failure, which subsequently leads to hyponatremia.) (23902827, 23902827)

management

• Adrenal insufficiency: provide replacement hormone. 📖
• SIAD: treatment is discussed below: ⚡️

---

[5/5] hypervolemic hyponatremia

causes of hypervolemic hyponatremia 

• Heart failure with reduced systemic perfusion.
• Cirrhosis with reduced systemic perfusion (hepatorenal physiology).
• Nephrotic syndrome.
• Renal failure (GFR <~20-25 ml/min). (37822230)
  • Acute kidney injury.
  • Chronic kidney disease.
• Pregnancy.

treatment

• Treatment of heart failure with hyponatremia: ⚡️
• Treatment of cirrhosis with hyponatremia: ⚡️

---

initial hyponatremia package

(back to contents)

---

Initial management is pretty simple.

[1] order the hyponatremia lab package 

• 📦 Repeat serum electrolytes (including Ca/Mg/Phos and glucose).
• 📦 Serum osmolality.
• 📦 Serum random cortisol level.
• 📦 Urine osmolality & urine sodium.

[2] limit further water intake

• Restrict oral fluid intake (for severe hyponatremia, NPO is safest initially).
• Avoid fluid administration (unless needed for hypovolemic shock).

[3] consider the need for IV hypertonic therapy

• Indications for immediate IV hypertonic therapy:
  • [a] Symptomatic hyponatremia (symptoms may be subtle; discussed here: ⚡️)
  • [b] Profound hyponatremia (any further worsening could be life-threatening).
  • [c] Hyponatremia of known duration <24-48 hours. (37822230)
• Hypertonic bicarbonate is often the easiest:
  • Hypertonic bicarbonate (1 mEq/ml) is usually found in 50-ml ampules on crash carts.  It has the same tonicity as 6% NaCl. It's immediately available everywhere.
  • A typical dose is two ampules (100ml) of hypertonic bicarbonate (equivalent to giving ~200 ml of 3% saline, raising the serum sodium by ~3 mM). For smaller patients, 1-1.5 ampules (50-75 ml) might be better.
• Hypertonic saline (3%) is another option (preferred in metabolic alkalosis):
  • 3% saline may be provided in a dose of 2 ml/kg body weight (e.g., ~150 ml).
  • Please note that 3% saline is safe to administer through a peripheral line. 3% saline does NOT require the placement of a central line. (30745195, 29472509, 28372499, 27965228).

[4] repeat electrolytes after hypertonic bolus

• The goal is to increase the sodium by ~4-6 mM (which should cause clinical improvement).
• If symptoms persist:
  • If the sodium has increased by <5 mM, then additional hypertonic therapy may be needed. (35870366)
  • If the sodium has increased by ~6 mM and the symptoms have not resolved, then consider an alternative cause of the symptoms.

---

interpretation of hyponatremia labs

(back to contents)

---

The hyponatremia lab package 📦 is listed above ⚡️.

Evaluation of hyponatremia labs involves three sequential considerations, as listed below:

---

[1] consider serum osmolality

• Serum osmolality is normally 275-295 mOsm.
• Serum osmolality ≧275 mOsm reveals rare patients with non-hypotonic hyponatremia (see the section above: ⚡️). (35919925) 
• Serum osmolality <270-275 mOsm (hypoosmolar hyponatremia) is seen in the vast majority of patients with hyponatremia.

---

[2] consider urine osmolality

dilute urine (urine osmolality <100 mOsm; specific gravity <1.003)

• Physiologically this indicates that the kidney is functioning properly and ADH (antidiuretic hormone) is absent.
• Causes of dilute urine:
  • [1] Hyponatremia due to {water intake > solute intake}. ⚡️
  • [2] Patient is in the recovery phase (e.g., the patient initially had hypovolemic hyponatremia, received volume resuscitation prior to urinalysis, and is currently auto-correcting their own sodium levels.)
  • (Renal failure may cause mildly dilute urine, but usually the urine osmolality will not be <100 mOsm.)
• Treatment implications: The patient is likely to auto-correct their sodium rapidly within the coming hours. For patients at risk of osmotic demyelination, consider initiation of the DDAVP clamp. ⚡️

inappropriately concentrated urine (urine >100 mOsm; specific gravity >1.003)

• Physiologically
  • Elevated osmolality indicates the presence of endogenous ADH (antidiuretic hormone). This includes inappropriate ADH secretion (i.e., SIAD), or “appropriate” ADH secretion in response to systemic hypoperfusion (e.g., due to hypovolemia, heart failure, or cirrhosis).
  • In the presence of endogenous ADH, the kidneys will retain water.
• Causes of concentrated urine:
  • This is nonspecific.
  • Concentrated urine is found in most hyponatremic patients (including the three most common types of hyponatremia: hypovolemic hyponatremia, euvolemic hyponatremia, and hypervolemic hyponatremia).
• Treatment implications:
  • The patient is unlikely to auto-correct their sodium rapidly.
  • The higher the urine osmolality is, the more likely the patient is to resist treatment of hyponatremia (especially in the context of SIAD).

---

[3] consider urine sodium

low urine sodium (<20-30* mEq/L)

• Physiologically: Low urine sodium indicates activity of the RAAS (renin-angiotensin-aldosterone system) that is causing sodium retention.
• Causes of low urine sodium:
  • Hypovolemic hyponatremia without active renal sodium wasting (see above ⚡️).
  • Hypervolemic:
    • Heart failure.
    • Cirrhosis.
    • Nephrotic syndrome.

high urine sodium (>20-30* mEq/L)

• Physiologically: Elevated urine sodium implies either inactivity of the renin-angiotensin-aldosterone system, or renal salt wasting.
• Causes of elevated urine sodium:
  • SIAD.
  • Adrenal insufficiency.
  • Renal failure (acute kidney injury or chronic kidney disease). (35852524)
  • Hypovolemic hyponatremia with active renal sodium wasting (see above ⚡️).

*20-30 mEq/L is a grey area. Some articles use 20 mEq/L as a cutoff, (37822230) whereas others use 30 mEq/L. (35852524)

---

determination of the etiology of hyponatremia

(back to contents)

---

why this is difficult: 

• Patients are increasingly multimorbid, so multifactorial hyponatremia is increasingly common. Multifactorial hyponatremia may defy any simple categorization scheme.
• Urine electrolytes are rarely collected prior to initiation of therapy.
• Urine sodium may fall into a grey zone.
• Unequivocal classification of volume status is frequently impossible.

consider three main pieces of information

• [1] Volume status & cardiac function:
  • Factors to help sort out volume status:
    • POCUS (which may also evaluate for heart failure ⚡️). (36036229)
    • Weight change (if serial weights are known).
    • History of diarrhea, emesis, poor oral intake, diuresis, etc.
    • Examination findings of peripheral edema.
  • Frank hypovolemia suggests hypovolemic hyponatremia ⚡️, whereas frank hypervolemia suggests hypervolemic hyponatremia. ⚡️
• [2] Hyponatremia labs:
  • Serum osmolality >275 mOsm is essential to sort out non-hypotonic hyponatremia. ⚡️
  • Urine osmolality <100 mOSm and/or urine specific gravity <1.003 can help reveal rare causes of {water intake > solute intake}. ⚡️
  • Urine sodium ⚡️ can provide helpful hints it's clearly low (<20 mM) or high (>30 mM).
• [3] History:
  • Evaluate the medication list carefully drugs causing SIAD. ⚡️
  • Evaluate for diuretic use (especially thiazides).
  • Archival laboratory values may help differentiate acute from chronic hyponatremia.
  • Recent historical events may be illuminative.

---

risk stratification

(back to contents)

---

risk factors for seizures/herniation due to hyponatremia 🤯

• Symptoms of hyponatremia (especially severe symptoms). ⚡️
• Hyperacute hyponatremia due to a specific exposure:
  • Massive water ingestion.
  • MDMA (ecstasy).
  • Postoperative hyponatremia.
  • Exercise-associated hyponatremia. (Schmidt 2024)
• Brain substrate:
  • Premenopausal women. (These patients are most frequently affected by catastrophic herniation due to hyponatremia. This may relate to hormonally mediated reduction in the efficiency of osmotic adaptation.) (Irwin 2023)
  • Intracranial pathology (e.g., space-occupying lesion, pre-existing cerebral edema).
  • Known seizure disorder.

risk factors for ODS (osmotic demyelination syndrome) 

• Sodium <120 mM (osmotic demyelination is rare if the initial sodium is >120-125 mM). (31601554)
• Hypokalemia.
• Cirrhosis.
• Alcohol use disorder.
• Malnutrition. (30181129)

---

target rate of increase

(back to contents)

---

target rate for chronic hyponatremia

• Excessively rapid correction might increase the risk of osmotic demyelination. Several recent studies have questioned whether rapid correction actually causes osmotic demyelination, or whether this is merely a correlation (e.g., severe hyponatremia correlates with both osmotic demyelination and rapid correction).
• Currently it may remain prudent to target lower rates of sodium correction. European guidelines recommend the following: (24569125)
  • Limit the increase in sodium to ≦10 mM in the first 24 hours.
  • Limit the increase in sodium to ≦8 mM per 24 hours subsequently.
• The key is the net rate of correction. If the sodium corrects too rapidly, it should be lowered back to it's target value.

target rate for acute hyponatremia (<48 hours)

• Faster rates of sodium correction are safe.
• For example, acute hyponatremia occuring during a marathon or following MDMA intoxication should probably be rapidly corrected.

the physiology of sodium overcorrection

• Over-correcting the sodium is almost never due to the practitioner's giving too much sodium chloride.  Instead, common causes of over-correction include:
• [1] The underlying cause of hyponatremia is reversed. This causes the body to suddenly excrete a lot of free water, thereby causing the sodium to rise. This form of auto-correction is by far the most common cause of over-correction. The DDAVP clamp may be used to avoid this (next section).
• [2] KCl administration, without taking into account the effect this will have on sodium (more on this below).

use caution with predictive equations

• Equations can be used to predict the effect of a fluid on the patient's sodium level (e.g. MDCalc here).
• These equations treat the body as a passive receptacle which receives IV fluid and does nothing with it (i.e., they ignore water excretion by the kidney). This works well in a few situations:
  • [1] Anuric renal failure.
  • [2] Patients on a DDAVP clamp (which blocks urine excretion of water).
• Predictive equations will fail among patients whose kidneys are actively excreting water.

---

DDAVP clamp-bolus technique

(back to contents)

---

---

when to use the DDAVP clamp

basics of the DDAVP clamp

• Administration of DDAVP prevents the kidneys from secreting free water. This takes the kidneys out of the equation, preventing the patient from auto-correcting. The patient acts like a passive container, with very predictable behavior:
  • Administration of hypotonic fluid (e.g., water, juice) will cause the sodium to decrease.
  • Administration of hypertonic fluids (e.g., 3% saline, potassium tablets) will cause the sodium to increase.
  • If there are no inputs, the sodium should stay roughly stable.

the DDAVP clamp may be useful if both of the following are present: 

• [1] Patient is at risk for osmotic demyelination, so they require a controlled sodium rise:
  • Baseline sodium <120 mM.
  • Risk factors for osmotic demyelination are discussed further above. ⚡️
• [2] Cause of hyponatremia has the capacity to auto-correct, e.g.:
  • {Water intake > solute intake} ⚡️
  • Hypovolemic hyponatremia: ⚡️
  • SIAD due to a reversible etiology.
  • Thiazide-induced hyponatremia.
  • Adrenal insufficiency. (Koyner 2021)

pragmatically, when to start the DDAVP clamp

• [1] Proactive DDAVP clamp: immediately starting the DDAVP clamp may be useful in occasional situations with the following characteristics:
  • [1] The etiology of the hyponatremia is obvious.
  • [2] This etiology is associated with a high risk of rapid correction.
  • [3] The patient is at high risk of osmotic demyelination syndrome.
• [2] Delayed initiation of the DDAVP clamp (reactive strategy) may be useful if the etiology of hyponatremia isn't clear.  In many cases, observing how the sodium responds to interventions (e.g., volume resuscitation) may help clarify the etiology of the hyponatremia.

---

how to perform the DDAVP clamp-bolus technique 

[1] initiate the DDAVP clamp

• Order DDAVP 2 mcg IV q8hrs scheduled (with a potential dose range of 2-4 micrograms IV q6-8 hours). (37822230, 35852524)
• Restrict free water intake (<1 liter/day).
• Avoid IV fluids as much as possible.
• ⚠️ With DDAVP on board, the patient will aggressively retain water.

[2] plot a course of the desired sodium

• The usual course is:
  • First day: target 8 mM rise (max 10 mM).
  • Subsequent days: target 6 mM rise (max 8 mM).
• If the patient deviates from this course, the goal is always to get back on the original desired trajectory.

[3] repeat serum sodium q4-q6 hours and raise/lower the sodium with boluses of D5W or hypertonic therapy

• It sodium needs to be raised, bolus with 3% saline or hypertonic bicarbonate to increase the sodium to goal.
  • 3% saline: The Madias equation can be used, with this calculator from MDCalc. 🧮 The calculator can be set to determine the volume of 3% saline required to increase the sodium by 1 mM. This can be scaled up to match the desired increase in sodium. Boluses should usually be limited to ≦250 ml.
  • Hypertonic bicarbonate (1 mEq/ml): This has the same tonicity as 6% NaCl. Start by calculating the volume of 3% saline that would be required, as described above. Then divide by two to obtain the equivalent volume of hypertonic bicarbonate.
• If the sodium needs to be lowered, bolus with D5W to reduce the sodium to goal.
  • The volume of water may be calculated using the free water deficit (setting the desired sodium level as the patient's goal sodium at that point in time). 🧮
• 💡 Make sure to administer the full bolus before to the next sodium check. This allows you to see the response to therapy and re-adjust as needed (in a tight, real-time feedback loop).

[4] removing the DDAVP clamp

• Once the sodium is close to normal (e.g., >125 mM), the DDAVP clamp may be discontinued. About 10 hours later, the patient's diet may be gradually liberalized.
• Observe the sodium carefully for its behavior off DDAVP.  For example:
  • If the cause of hyponatremia has been eliminated (e.g., hypovolemia), then the sodium will rapidly increase to normal and stay there.
  • If the patient has a persistent cause of hyponatremia (e.g., SIAD), their sodium may start falling. In that case, they may require maintenance therapy for SIAD (e.g., oral urea).

---

aquaresis using oral urea

(back to contents)

---

indications for aquaresis with oral urea

• SIAD:
  • Oral urea is emerging as a front-line therapy for SIAD.
  • Oral urea has been used for SIAD for decades in Europe, and has long been recommended by the European guidelines. Oral urea became available in the United States around ~2018 (brand name UreNa). Recently, several studies have confirmed that oral urea is a safe and effective therapy for SIAD. (22378162, 30181129, 30614552, 30868608).
• Heart failure. ⚡️
• Cirrhosis (as second or third-line therapy; discussed further below ⚡️).

contraindications to urea

• Inability to tolerate PO intake.
• Cirrhosis with hepatic encephalopathy.
• Severe renal failure.
• Hypovolemia.

oral urea dosing

• Initial dose is usually 30 grams daily. (36974717) The starting dose may also be assessed based on the patient's weight and urine osmolality, using the formula below.
• The dose range is usually 15-60 grams daily cumulative dose (but may be as wide as  7.5-90 grams daily cumulative dose).

general strategy for using oral urea

• Initial therapy:
  • [1] Restrict free water intake (urea only causes a finite amount of water excretion).
  • [2] Starting dose is ~15-30 grams oral urea (dose discussed above).
• Repeat sodium level after 12 hours, to determine efficacy. With oral urea the target is often a gradual and controlled increase in sodium (e.g., ~3-6 mEq/day increase).
  • Urea is generally cleared from the body within ~12 hours.
• Titrate urea and water intake to effect:
  • Sodium rise is inadequate:
    • Consider re-dosing and/or increasing the dose.
    • If still refractory, consider the addition of scheduled low-dose furosemide to reduce the renal concentration gradient (e.g., 20 mg furosemide q6hr). This is analogous to the use of oral salt tablets plus furosemide for the treatment of SIAD. (Irwin 2023) 
  • Sodium rise is adequate → continue oral urea.
  • Sodium rise is excessive → administer free water to lower the sodium, consider dose reduction in urea, also consider whether oral urea is still appropriate (if the urine osmolality is <300 mOsm the patient may have recovered and is now auto-correcting, so oral urea is inappropriate).

(The physiology behind aquaresis is discussed here: 🌊)

---

SIAD

(back to contents)

---

SIAD (syndrome of inappropriate antidiuresis) is the new name for SIADH (syndrome of inappropriate antidiuretic hormone secretion).

---

definition & diagnosis of SIAD

diagnostic criteria for SIAD:

1. Hyponatremia.
2. Hypotonia (serum osmolality <270-275 mOsm).
3. Urine osmolality >100 mOsm. (However, the urine osmolality is generally >300 mOsm, so an osmolality of ~100-300 mOsm may place the diagnosis in some question.) (35870366)
4. Urine sodium >20-30 mM.
5. Clinical appears euvolemic.
6. Hyponatremia isn't explainable by renal failure (precise GFR cutoffs aren't well defined, but renal failure alone doesn't generally cause hyponatremia until GFR is <20-25 ml/min). (37822230)
7. Exclusion of adrenal insufficiency.
8. Absence of recent exposure to diuretics, especially thiazides (e.g., within a week). (35919925)

---

causes of SIAD

medications (~20%)

• ADH agonists: (These don't technically stimulate ADH release, but rather directly stimulate ADH receptors.)
  • DDAVP.
  • Oxytocin.
  • Terlipressin. (less frequent because it is a selective V1-agonist)
  • Vasopressin.
• Antidepressants.
  • SSRIs and SNRIs.
  • Tricyclic antidepressants.
  • MAO inhibitors.
  • Venlafaxine.
• Antipsychotics.
  • Butyrophenones (e.g., haloperidol)
  • Clozapine.
  • Phenothiazines (e.g., chlorpromazine).
• Antiseizure medications.
  • Carbamazepine.
  • Lamotrigine.
  • Levetiracetam. (rare but can occur)
  • Oxcarbazepine.
  • Valproate.
• Chemotherapeutics:
  • Cyclophosphamide.
  • Ifosfamide.
  • Interferon.
  • Melphalan.
  • Methotrexate.
  • Platins (cisplatin, carboplatin).
  • Vinblastine, vincristine.
• NSAIDs (because prostaglandins block ADH effect).
• Opioids.
• Miscellaneous:
  • Amiodarone.
  • Bromocriptine.
  • First-generation sulfonylureas (chlorpropamide, tolbutamide).
  • Nicotine.
  • Prostaglandin synthetase inhibitors. (Koyner 2021, 36974717)

malignancy (~25%)

• SCLC (small cell lung carcinoma) – most commonly.
• Squamous cell carcinoma of the head and neck.
• Olfactory neuroblastoma.
• Gastrointestinal.
• Genitourinary.
• Lymphoma.
• Mesothelioma.
• Sarcoma. (Koyner 2021, Schmidt 2022)

neuropsychiatric disorders (~10%)

• Mass lesions (e.g., tumor, abscess, hematoma)
• Inflammatory conditions, e.g.:
  • Encephalitis.
  • Meningitis.
  • anti-LGL1 limbic encephalitis.
• Infection.
• Guillain-Barre Syndrome.
• Stroke.
• Traumatic brain injury.
• Acute psychosis.
• Delirium tremens.

pulmonary conditions (~10%)

• Pneumonia of all etiologies. (37851876)
• Obstructive lung disease:
  • Asthma.
  • COPD.
  • Cystic fibrosis.
• Acute respiratory failure.
• Positive pressure ventilation.

other exposures & specific situations (~10%)

• MDMA (ecstasy).
• Extreme exercise (e.g., marathons, especially when combined with aggressive water drinking).
• Pain.
• Severe nausea.
• General anesthesia & postoperative state.

idiopathic (~30%)

• Idiopathic SIAD is more likely in the elderly.
• Features arguing against idiopathic SIAD include: (37822230)
  • Aget <70 years old.
  • New onset hyponatremia.
  • Urine osmolality >340 mOsm.

---

investigation of SIAD

• Review medications and exposures.
• Check early AM cortisol level to exclude adrenal insufficiency (if this hasn't been checked).
• Imaging to exclude malignancy (e.g., CT scan head/chest/abdomen/pelvis). (37851876)

---

treatment of SIAD

basic treatment strategy

• [1] Basics:
  • Address any reversible causes of SIAD.
  • Promote adequate protein and salt intake.
• [2] Fluid restriction:
  • Fluid restriction alone can be effective in about half of patients, but it is difficult to maintain compliance. Most studies evaluate fluid restriction to <500-1000 ml/day, which is tough. (36974717)
  • If urine osmolality is >500 mOsm and/or urine sodium is >130 mM, fluid restriction is unlikely to work as the sole therapy. (37851876, 36974717)
• [2] Second line therapies:
  • Oral urea ⚡️ is a front-line therapy for SIAD.
  • SGLT2 inhibitors have demonstrated efficacy and safety in randomized controlled trials. (32019783, 36396331, 36656532) Note that the dose may be higher than usual (25 mg/day empagliflozin). Further discussion on SGLT2 inhibitors: 💉
• [3] Other treatments:
  • ADH inhibitors (vaptans) may be useful for outpatient therapy in patients who are unable to receive oral urea.
  • If urea is contraindicated, a less desirable strategy is salt tablets (see below).

(SIAD treatment with NaCL plus loop diuretic)

• General concept:
  • (i) These patients are usually in sodium balance, so they shouldn't retain sodium. As sodium is excreted, it will pull water out of the body along with it. The amount of water loss is equal to the osmotic load of the sodium divided by the urine osmolarity.
  • (ii) Continuous exposure to a loop diuretic will wash out the concentration gradient in the kidney, causing the urine osmolarity to decrease. Thus, even though the kidney is “trying” to retain water, it's less able to achieve that. Washing out the kidney concentration gradient will increase the amount of water which is pulled out of the body due to sodium administration (in part #i).
• Nuts and bolts:
  • (1) Loop diuretic (e.g. furosemide) should be given frequently enough so that the kidney doesn't escape in between doses (e.g. 20 mg IV furosemide q6hr). As patients stabilize, this may be weaned down or off (furosemide will augment the efficacy of the NaCl, but it's not mandatory for it to work).
  • (2) Sodium intake is increased.
    • In acutely ill patients, this is usually achieved with a 3% NaCl infusion.
    • In less emergent situations, oral salt tabs may also be used (a typical dose would be ~3 grams TID with meals). (35919925)
  • (3) Monitor fluid balance, to make sure that the patient doesn't become volume overloaded or depleted.
• The primary problem with salt tablets is that they have low potency. 30 grams of urea is equivalent to 15,000 mg of NaCl tablets (a much higher dose than is generally utilized). (36974717)
• Evidentiary basis: An outpatient study found this strategy to be ineffective (with an increased risk of hypokalemia and acute kidney injury). (32199708) Overall this isn't generally a preferred therapy for SIAD, but it may occasionally be utilized among inpatients, with close monitoring of electrolytes and renal function.

---

heart failure

(back to contents)

---

general comments

• Sodium is usually fairly stable, around ~120-135 mM.
• Exactly when treatment is beneficial is unclear. The best approach to chronic, asymptomatic hyponatremia is often to provide no specific therapy for the hyponatremia. Instead, the primary focus of therapy should remain the heart failure.
  • There is a risk of focusing too much energy on treating the hyponatremia, and not enough energy on treating the underlying heart failure. For example: It's counter-productive for a cardiology service to refuse admission of a heart failure patient solely due to moderate hyponatremia.

physiology

• Inadequate cerebral perfusion stimulates the brain to produce antidiuretic hormone (ADH), leading to water retention.
• Thus, hyponatremia in heart failure is a reflection of poor systemic perfusion.

treatments

• Optimize systemic perfusion: Occasionally hypoperfusion requires direct intervention (e.g., volume resuscitation for hypovolemia, inotrope infusion, coronary revascularization, or mechanical circulatory support 📖).
• SGLT2 inhibitors 💉 are indicated for patients with heart failure. Aside from causing improvements in heart failure, SGLT2 inhibitors may cause a mild increase in serum sodium levels.
• Loop diuretics (e.g., furosemide) are an excellent therapy for patients with significant volume overload. Furosemide stimulates the production of dilute urine, causing loss of both water and sodium (but generally more water than sodium). This will treat hypervolemia and hyponatremia. However, excessive doses of loop diuretics may cause volume depletion, which may exacerbate hyponatremia. (35852524)
• Oral urea could be a consideration for patients with substantial hyponatremia who are close to euvolemia. Urea will cause a pure water loss (aquaresis), so it will increase the sodium level with less volume loss.
• Hyperdiuresis could be considered for patients with hyponatremia and severe refractory congestion that doesn't respond to conventional diuretics (further discussion: 📖).

---

cirrhosis

(back to contents)

---

general comments

• Cirrhosis causes hyponatremia due to impaired systemic perfusion, as a manifestation of hepatorenal physiology. This is an indication of advanced cirrhosis.
• Cirrhosis rarely causes severe hyponatremia. Similar to heart failure, there is usually a fairly stable sodium of ~120-135 mM.

treatment

• Exactly when treatment is beneficial is unclear. The best approach to chronic, mild asymptomatic hyponatremia could be careful observation.
• Hemodynamic assessment:
  • As in heart failure, careful assessment of perfusion and volume status should be performed.
  • Rare patients may be hypovolemic, in which case judicious volume resuscitation may be considered.
• Furosemide diuresis is often a good option for patients with volume overload. Furosemide stimulates the production of dilute urine, causing loss of both water and sodium (but generally more water than sodium).
• Oral lactulose is an excellent option for patients with hyponatremia and hepatic encephalopathy. Lactulose causes wasting of water via the gut (which will improve the hyponatremia), while simultaneously treating hepatic encephalopathy. 🌊
• Oral urea might be considered in patients without any history of hepatic encephalopathy, but its use in cirrhosis is controversial. There is concern that urea could be converted into ammonia by gut bacteria, promoting the development of hepatic encephalopathy. Overall, urea is probably a 2nd or 3rd line agent here (likely inferior to lactulose). If urea is used, it should be closely monitored.

---

hypokalemic hyponatremia

(back to contents)

---

potassium increases tonicity as much as sodium does

• Administration of KCl will increase the sodium concentration just as much as NaCl would (they have the same impact on tonicity).
  • This is a bit counterintuitive, because the potassium levels don't increase much. However, potassium entry into cells is paired with the exit of sodium, such that the sodium levels will rise.
  • 50 mEq of oral KCl will have about the same effect as 100 ml of 3% NaCl.
• The effect of intravenous forms of potassium will depend on exactly how they are formulated.

estimating the effect of oral KCl supplementation on serum sodium

• The impact of oral potassium tablets on serum sodium can be estimated as above (if we approximate the total body water as roughly equal to 55% of the patient's weight).
• This effect can be more than expected, for example:
  • In a very small 40-kg patient, an oral dose of 40 mEq KCl could increase the sodium by ~2 mEq/L.
  • The potassium deficit increases exponentially as potassium levels fall (explored further here). Thus, a 70-kg patient with a potassium of 2.5 mM could have a potassium deficit of ~500 mEq. Administration of this quantity of KCl orally would increase sodium by ~12 mM!

clinical significance

• Oral repletion of KCl will have a greater impact on serum sodium than we generally recognize. This should be accounted for in patients with significant hypokalemia.
  • Failure to consider the osmotic effect of KCl is one driver of unexpected overcorrection of hyponatremia.
• In some patients with moderate hyponatremia and moderate hypokalemia, oral repletion of KCl will simultaneously address both problems.

---

why not to use vaptans

(back to contents)

---

Historically, folks have often been afraid of using 3% saline (yet felt more comfortable using vaptans). This is completely backwards. 3% saline is actually extremely safe. Meanwhile, vaptans have a unique capacity to cause runaway water loss and overcorrection. This is why the European guidelines for hyponatremia recommend against vaptan use. There is no reason to use vaptans in a modern ICU with access to therapies described above.

vaptans induce a state of uncontrolled diabetes insipidus

• Vaptans block aquaporin water channels in the kidneys, causing uncontrolled excretion of water by the kidneys. This will mimic nephrogenic diabetes insipidus. Giving a vaptan is thus the opposite strategy compared to the DDAVP clamp.
• There are several problems with this:
  • Water loss is uncontrolled and unpredictable. Patients can correct their sodium much faster than would be desired.
  • Patients may develop overshoot hypernatremia. This is particularly dangerous regarding the risk of osmotic demyelination.
• Vaptans are also extremely expensive and some may be potentially hepatotoxic. But these problems pale in comparison to the simple truth that the mechanism of action of vaptans is inherently dangerous and uncontrolled.

---

emergency treatment of hyponatremia with oral soy sauce

(back to contents)

---

indications for enteral soy sauce

• Need for emergent hypertonic therapy (discussed above: ⚡️).
• -PLUS-
• Either:
  • [1] Lack of intravenous access.
  • [2] Lack of access to hypertonic solutions (e.g., 3% NaCl or hypertonic bicarbonate ampules).

cautions about enteral soy sauce

• The main problem is that the pharmacokinetics of sodium absorption are unclear. The effects should likely be seen within a few hours, but there is no solid evidentiary basis for this. Consequently, it's not well defined exactly when sodium should be re-checked to assess the effectiveness of the oral sodium dose.
• If additional doses of sodium are administered before absorption of the first dose, this could lead to dose-stacking with excessive sodium administration.
• To avoid dose-stacking, it's probably best to give a single, large dose of oral sodium (for an average-sized person, this could be roughly equivalent to ~250 ml 3% saline).

pharmacology of soy sauce

• ⚠️ Make sure not to use low-sodium soy sauce. Check the label, there should be ~1,000 mg sodium per tablespoon.
• 1 Tablespoon Kikkoman soy sauce (15 ml) = 960 mg sodium.
• 960 mg sodium / (23 grams = molecular wt of sodium) = 42 mEq sodium.
• 42 mEq sodium / (0.513 mEq sodium per ml 3%) = equivalent to 82 ml 3%.
• So:
  • 1 Tablespoon Kikkoman soy sauce ~ 82 ml of 3% saline.
  • Kikkoman soy sauce is equivalent to 16% NaCl.

summary of standard soy sauce dosing (~1,000 mg Na/tablespoon)

• 3 tablespoons = 45 ml soy sauce = 246 ml 3% saline.
• 6 packets containing 6 ml per packet = 36 ml soy sauce = 197 ml 3% saline.

---

podcast

(back to contents)

---

Follow us on iTunes

---

questions & discussion

(back to contents)

---

To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Don't forget to implement free water restriction for all hyponatremic patients (at least early on, while the dust is settling).
• Don't use vaptans. It's that simple, just don't use them.
• If you use the DDAVP clamp, be sure to restrict the patient's fluid intake. The combination of DDAVP plus unrestricted fluid intake can worsen the patient's hyponatremia.
• Patients with symptomatic hyponatremia should be treated with hypertonic fluid (either 3% saline or hypertonic sodium bicarbonate). Don't use normal saline here, because if the patient has SIAD this may exacerbate their hyponatremia.
• If the patient's sodium rises too quickly, don't give up (“well the patient's ok, they seem to have tolerated it”). Patients may look OK for a while, but later develop osmotic demyelination. If the patient's sodium over-corrects, give them DDAVP and water, and reduce the sodium to the appropriate target.

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• = Link to supplemental media.