see also: [[IV Fluids]], [[Osmolality and Osmolarity]] See: [deranged physiology - hyponatremia](https://derangedphysiology.com/main/required-reading/electrolyte-disorders/Chapter-531/hyponatremia-lazy-mans-classification), [Geekymedics - hyponatraemia](https://geekymedics.com/hyponatraemia/), [Harrison's - hyponatremia](x-devonthink-item://D7D7DEE3-8F19-43B8-9F8B-9722C906DAB6?page=381) > **heuristic**: 3mL/kg of 3% saline raises Na ~3mmol/L > [!key points] > - The most common causes of severe hyponatremia in adults are therapy with thiazides, the postoperative state, the syndrome of inappropriate secretion of antidiuretic hormone ([[#SIADH]]), psychogenic polydipsia, exercise-associated hyponatremia, and unintentional water intoxication. > - Gastrointestinal fluid loss, ingestion of overly dilute formula, accidental ingestion of excessive water, and receipt of multiple tap water enemas are the main causes of severe hyponatremia in infants and children > > > ***When to treat*** > > 1. Severe but asymptomatic hyponatremia with a sodium level of *110* mEq/L or less > > 2. Acute symptomatic hyponatremia (acute alterations in mental status, [[Seizures]], or new focal findings due to hyponatremia) with a sodium level below *120* mEq/L. > > > ***Treatment*** > > Severe hyponatremia should be corrected by no more than **8 mEq** in the first 24 hours, but if **seizures** then aim to increase by *4-6 meq/L in 30 min* then slowly thereafter > >- ==100 mL of 3% hypertonic saline infused over 10 minutes endpoint resolution of symptom eg seizures==. > >- Measure Na after each infusion > >- Stop infusion when sx improve, or target of 5meq/L increase in Na > >- Can repeat 100mL 3% to total of 3 doses or total of 300mL of 3% - mild - Na 130 - 135 - moderate - 125 - 129 - severe - <125 Hayes' has moderate 110-125 # causes of ↓ Na ***Hypovolaemic***:  - renal losses (diuretics, nephropathy), [[Adrenal insufficiency|Addison's disease]].   - extra-renal losses: diarrhea/vomiting, [[Heat-related illness|Heat Stroke]] ***Euvolaemia***: - SIADH - psychogenic polydipsia - glucocorticoid deficit - MDMA - hypokalemia - antipsychotics ***Hypervolaemia***: - CHF - cirrhosis - nephrotic syndrome - CKD - liver failure/hypoalbuminaemia # hyponatremia flow charts ![[Pasted image 20250322220435.png]] ![[Pasted image 20240206190531.png| tintinalli]] ![[Pasted image 20240206192621.png| harrisons]] ![[Pasted image 20240207051643.png]] ![[Pasted image 20230408195212.png]] ![[Pasted image 20240206193711.png| Rosens urine sodium interpretation]] # Effects The most important symptoms of hyponatremia are due to its effects on the brain; symptoms can be divided into moderately severe and severe - Moderately severe symptoms often start when a plasma \[Na] is <130 mEq/L and consist of headache, nausea, disorientation, confusion, agitation, ataxia, and areflexia. - When \[Na+ ] reach levels <120 mEq/L, severe symptoms may develop including intractable vomiting, seizures, coma, and ultimately respiratory arrest due to brainstem herniation. Brain injury may become irreversible. - The symptoms of hyponatremia can be due to many other conditions, need toconsider other aetiologies before making treatment decisions. - The presence of hyponatremia-related symptoms is directly related to the rapidity of onset. After a certain period, brain cells begin to adapt to hyponatremia. Initially the hypo-osmolality drives water into the brain cells yielding swelling. - Due to the rigid skull, intracranial hypertension occurs and the described symptoms begin. After 48 hours, the brain cells start to adapt by extruding Na+ , K+ , Cl– , and organic osmolytes like glycine and taurine from the cells, reducing cell osmolality and preventing further water uptake. In several clinical or physiologic conditions, this adaptation mechanism is impaired, as in the syndrome of inappropriate ADH secretion, in children, in menstruating women, and in hypoxia. In such cases, symptoms are more severe and persistent. ## CNS Central nervous system (CNS) damage due to hyponatremia may be caused by - cerebral oedema and increased intracranial pressure - osmotic fluid shifts during overly aggressive treatment - or by both # SIADH see also: [[hyponatremia (paeds)|paediatric SIADH]], [[#Cerebral salt-wasting syndrome]] **Diagnostic criteria** - hypotonic hyponatremia: - Serum osmolality <275 mOsm/kg H2O - inappropriately elevated urine osmolality (usually >200 mOsm/kg) - elevated urine Na >20 mEq/L - clinical *euvolemia* - normal adrenal, renal, cardiac, hepatic, and thyroid functions ## Causes of SIADH see: [NEJM - The Syndrome of Inappropriate Antidiuresis](https://www.nejm.org/doi/full/10.1056/NEJMcp066837) - [Bookends link](bookends://sonnysoftware.com/ref/DL/235091) - neuologic and psychiatric disorders - infection: meningitis, encephalitis, brain abscess - vascular: thrombosis, [[Subarachnoid haemorrhage|SAH]] and SDH, [[Giant Cell Arteritis|GCA]], CVA - malignancy: primary or metastatic - delirium tremens - Guillain-barre - neurosurgery - Drugs - carbamazepine - [Thiazide](https://pmc.ncbi.nlm.nih.gov/articles/PMC3041494/) (HCTZ) - vinca alkaloids - haloperidol, largactil - SSRI and SNRI - amiodarone - narcotics - desmopressin - lung diseases - [[Tuberculosis]] - lung empyema - acute resp failure - lung carcinoma (SCC) -- paraneoplastic syndrome, duodenum, pancreas, thymus, prostate, uterus - lymphoma/leukema - sarcoma ![[Pasted image 20250415234906.png]] ## Treatment SIADH - fluid restrict - +/- urea eg 15g/day - Urea corrects hyponatremia by promoting osmotic diuresis without causing significant fluid shifts # Cerebral salt-wasting syndrome > Not to be confused with [[Diabetes insipidus]], which generally has ↑ Na - patients with a cerebral lesion and excess renal loss of sodium and chloride - exact aetiology unclear - suspect in pts with a cerebral lesion (eg [[Subarachnoid haemorrhage|SAH]], [[traumatic brain injury|TBI]], or tumor), with ==elevated urine output, and elevated urine sodium in absence of physiological cause for increased sodium excretion== - **Treatment:** - exclude other causes of hyponatremia and increased urine output, replace sodium and fluid losses - +/- fludrocortisone ## Cerebral salt wasting vs SIADH > **cerebral salt-wasting** can be differentiated from **SIADH** because patients with cerebral salt wasting have evidence of extracellular fluid *depletion* (eg negative fluid balance, tachycardia, increased urea, low central venous pressure) as opposed to SIADH, where ECF is *normal* or slighlty expanded > > **note:** do not confuse with [[Diabetes insipidus|Central Neurogenic Diabetes Insipidus]], which has increased urine output due to TBI, but this is dilute urine and [[hypernatremia|hyper-na]] in serum. # Control of osmolality * mostly from **antidiuretic hormone** (vasopressin) * increases H2O reabsorption and stimulates thirst * secretion increased by stimulation of osmoreceptors in hypothalamus and serotonin * SHOULD be suppressed by hyponatremia (eg if urinary osmol <100, suggests appropriate suppression of ADH) # pseudohyponatremia see also: [[Blood gas#correct Na for glucose]] The key questions to answer here are 1. When do I used the "corrected sodium" (eg in the presence of hyperglycaemia) vs when do I use the actual measured sodium (eg calculating [[Osmolality and Osmolarity|osmolality]] or [[Blood gas#anion gap|anion gap]]. 2. Is it unsafe to rapidly correct the measured sodium if the corrected sodium is not correcting too quickly, eg if hyperglycaemia ? see [[#3. Relationship with osmolality]] ## Explanation ### 1. "pseudohyponatremia" refers to a lab error when there is ↑ protein or triglycerides in the plasma see: [Acute care testing - pseudohyponatremia](https://acutecaretesting.org/en/articles/pseudohyponatremia) Plasma has an aqueous phase and a solid (nonaqueous) phase. small electrolytes like Na are confined to the aqueous phase, while larger molecules like lipids and proteins are located in the solid phase. The clinical laboratory measures both phases of plasma, and ∴ the measured plasma sodium could underestimate the actual (aqueous) sodium level. Because most of the plasma is H2O (aqueous phase), there is usually little difference between the measured and actual sodium concentrations. However, if there is a significant increase in *protein or lipid* levels in the blood, there is an increase in the nonaqueous phase of plasma, which will *decrease the measured plasma sodium concentration*, while the actual (aqueous phase) sodium concentration is unchanged. This pseudohyponatraemia becomes significant when plasma protein levels are 12 g/dL (normal 5.5-8 g/dL) or triglycerides increase to 1500 mg/dL (normal 25-175 mg/dL). The concentration of sodium in plasma water is the physiologically relevant parameter. Consider two patients with the same concentration of sodium in plasma water (150 mmol/L is normal given that plasma is about 93% H2O), but one patient's plasma is 80% H2O and 20 % proteins; the second patient's measured Na would be 120 mmol/L, even though the actual aqueous Na is normal. > In real pseudohyponatremia (i.e. not caused by hyperglycaemia), the patient has a physiologically normal plasma water sodium concentration but a reduced measured plasma sodium concentration. In these cases, it is an artifact that should not be treated. ***causes:*** - hyperprotinemia - HIV - immunoglobulin infusions (IVIG) - multiple myeloma and other monoclonal gammopathies - waldenstrom's macroglobulinaemia - hypertriglyceridemia - [[Alcohol-related disease|EtOH abuse]] - [[DKA]] → not just from hyperglycaemia! can also have severe hyperlipidemia! - hyperlipidemia - [[pancreatitis]] - poorly-controlled DM2 - hypercholesterolemia - biliary obstruction - [[Hepatitis]] - intrahepatic cholestasis - primary biliary cirrhosis ### 2. Hyperglycaemia causes spurious hyponatremia from dilution; the "corrected" Na does not mean the measurement of Na in serum is incorrect When glucose does not readily enter cells, the resultant hyperglycaemia draws fluid out of cells. this increases the aqueous phase of plasma, and has a *dilutional effect on sodium*. This is different from the above pseudohyponatremia because the aqueous Na concentration is actually a lower concentration due to dilution. This **hyperosmolar hyponatremia** is often seen in [[Hyperglycaemic Hyperosmolar state|HHS]] and occasionally in [[DKA]]. other causes are mannitol (although generally develops hypernatremia quickly because it is an osmotic diuretic that clears free water), and high serum ethanol concentrations. > for every 5.6 mmol/L of glucose, there is a 1.6 mmol/L ↓ in sodium > - BSL 14 : Na drops by 4mmol/L > - BSL 28 : Na drops by 8 mmol/L > - BSL 56 : Na drops by 16 mmol/L **The Corrected Na is what is left if we got rid of all the extra glucose.** However, unlike in pseudohyponatremia, the sodium concentration reported by the lab is the accurate concentration of sodium in the body fluids. and all other ions in the body fluids are diluted to the same extent. this is why we use the **uncorrected** Na when calculating the anion gap. ### 3. Relationship with osmolality High sodium and high glucose both cause [[Osmolality and Osmolarity|hyperosmolality]]. The risk of osmotic demyelination relates to re-acumulation of osmolytes in the brain which were lost as an adaptation to protect from cerebral oedema during periods of hyponatraemia/hypoosmolality. Most discussion of ODS relates to hypoosmolar hyponatraemia, which is to say, hyponatraemia in the setting of hyperglycaemia may not be such a hypoosmolar state. However, it is noted that low corrected Na in the setting of hyperglycaemia is associated with [higher 90 day mortality](https://pmc.ncbi.nlm.nih.gov/articles/PMC7478195/). There is little information about whether the rate of sodium correction should be titrated to measured or calculated Na, but it stands to reason that if there is severe hyperglycaemia, then perhaps titrating to the *osmolality* (i.e. not correcting the sugar OR the sodium too quickly) is the safest way to go. eg 2xNa + glucose and aim to correct by ~3mosmol per hour or so. The above assertion is supported by case reports that rapidly correcting hyperglycaemia can be a risk factor for osmotic demyelination syndrome. this can occur in [[Hyperglycaemic Hyperosmolar state|HHS]] in particular, see [(1)](https://www.ccjm.org/content/85/7/511), [(2)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9981549/), and [(3)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9630894/). # Treatment ## hypertonic saline > [!doses] volume of Na to raise serum sodium by x > the volume of a saline solution required to raise serum sodium the desired amount can be calculated in two steps: > 1. calculate expected change in serum Na from infusion of a litre of saline solution (see [[IV Fluids]] for chart of mmol/L) > 2. determine portion of the litre required to raise the sodium the desired amount > **Expected change in serum Na+** = $\frac{infusate~Na^{+} -serum~Na^{+}}{TBW + 1}$ > infusate Na - ( serum Na/(TBW +1) ) > > TBW = 60% weight of children and men, 50% of women > > **Example** > - 3% NaCl contains 513 mEq/L of Na > - 68 yo, 70kg M with Na 108 and seizures > - *TBW* = 0.5 x 70 = 35L > > *Δ in Na expected* = > (513 - 108)/(35 +1) = 11.25 mEq rise if given 1000mL of 3% hypertonic saline > The fraction of litre of 3% hypertonic saline to raise sodium by 5meQ/L would be 444 mL of 3% NaCl see [[traumatic brain injury#Hypertonic saline]] If seizures, then 2-3 mL/kg of 3% NaCl over 20-30 min (aka can give 100mL over 10 min) - For relatively asymptomatic patients with sodium values of *115 to 135* mEq/L, **free water restriction** is typically the most important treatment. - In more severe cases when the sodium value is 120 mEq/L or less and the patient has alterations in mental status, has focal findings, or is seizing, **3% hypertonic saline** (513 mEq/L of sodium) is indicated. - Correction of hyponatremia by *4 to 6 mEq/L within 6 hours*, with bolus infusions of 3% saline if necessary, is sufficient to manage the most severe manifestations of hyponatremia. - Initially, ==100 mL of 3% hypertonic saline should be infused over 10 minutes.== If a second bolus is required, an additional 100 mL of the 3% solution may be administered during the next 50 minutes. - To minimize the likelihood of ODS, it is essential that symptomatic patients with severe hyponatremia have serum sodium levels raised slowly. Previous guidelines endorsed the safety of raising the serum sodium by up to 10 to 12 mEq within the first 24 hours. However, in patients believed to have been hyponatremic for more than 48 hours, **severe hyponatremia should be corrected by no more than 8 mEq in the first 24 hours** - aggressively replace [[hypokalemia|potassium deficits]] > [!Hypertonic saline Dunn's]- > - only indicated for severe hyponatremia with acute cerebral sx > - aim to raise Na to about 120 above seizure threshold within 1h, then correct Na concentration over next 48-72 h (eg 5-8 mmol/L/day > - aim to raise Na by 5 mmol/L over 30 min > - remeasure Na after first 20 min infusion has finished to minotor progress and adjust second infusion dose as required > - if seizures present can do 250 mmol over 10 min ## treatment for other causes of hyponatraemia ![[Pasted image 20240207052433.png]] ## hypovolaemic hyponatremia - rehydration - if hypotensive → 0.9% NaCl 500-1000mL/H until BP normal, then slowed 200 mL/h with frequent sodium checks - if Na < 120, aim increase by 8 meq/day until 120 - identify and treat underlying cause ## hypervolaemic hyponatremia - restrict fluid and sodium (Saline can cause pulm oedema) - patients with CHF benefit from diuretics ## Osmotic demyelination syndrome aka *central pontine myelinolysis* > Note that rapidly correcting hyponatraemia is generally considered to be higher risk for osmotic demyelination syndrome than rapid correction of hypernatremia is for cerebral oedema *in adults*. However, rapid correction is risky in both directions for paeds. **Mechanism (completely not relevant for the exam)** Chronic hyponatraemia → loss of osmotically active osmolytes (eg glutamate, glutamine) from astrocytes, which provides protection against brain swelling / cerebral oedema. As brain volume begins to shrink in response to the correction of hyponatraemia, these osmolytes cannot be as quickly replaced, and brain volume can quickly fall from being somewhat above normal to smaller than normal with rapid correction of hyponatraemia. demyelination primarily occurs in areas of the brain that are slowest in reaccumulating osmolytes after rapid correction of hyponatraemia (eg the pons). Fall in brain volume results in demyelination from direct injury to astrocytes and oligodendrocytes that are crucial for normal myelination and maintenance of the blood brain barrier. After rapid correction of hyponatremia, reduction in cell H2O coupled with movement of Na and K back into cells leads to an initial increase in cell cation concentration before repletion of organic osmolytes, then protein aggregation, DNA fragmentation, and programmed cell death. **Risk factors** - Na < 105 ; rare if Na > 120 - duration of hyponatraemia -- ODS rarely occurs if Hypo Na occurs quickly over only a few hours or a day (eg polydipsia quickly) - rapid correction: increase over 24 hours more important than hour-by-hour correction - save 24 hour rise generally about 5 mmol/L/day - Other risks - **alcoholism** - malnutrition - liver disease - **geriatric** - hypokalaemia - burns **Symptoms** - Main symptoms are dysarthria, dysphagia, lethargy, paraparesis or quadriparesis, seizures, coma, and death ***Pontine myelinolysis***: - dysarthria - dysphagia - flaccid quadraparesis ***Extrapontine myelinolysis***: - tremor - ataxia - mutism - dystonia - catatonia > If a patient develops symptoms of ODS during therapy, all sodium-containing fluids should be stopped and **D5W administered immediately** to tem- porarily lower sodium values. > - give at rate 5% dextrose @ 3 mL/kg/h ![[Pasted image 20240208083427.png|adaptation of brain volume to hyponatremia and correction]] # Disposition - Na >125: outpatient management - Na 115-125: - admit if symptomatic - close OPD f/u if asymptomatic and repeat Na within 72 h - Na <115: - usually requires ICU admission # Related Questions ## hyponatraemia - [x] 7Q: [Seizure and hyponatraemia](x-devonthink-item://5DD7C01C-AB9B-4F0E-9CC4-266700BD94E8?page=15) -- [Answer](x-devonthink-item://7CE81625-E4A6-40C1-BAEB-7E44C75B1E60?page=18) - [ ] 8Q: [Hyponatraemia](x-devonthink-item://D6654B01-83AA-4553-94F0-791FD96A636D?page=2) -- [Answer](x-devonthink-item://00427DF6-6D28-4FEB-A0CA-DF96DBBBCE97?page=1) -- [prop](x-devonthink-item://AB9BDA6D-9CA8-4E73-9D15-B6105225A1B4?page=2) ## osmotic demyelination syndrome - [x] DUPLICATE Q: [Seizure and hyponatraemia](x-devonthink-item://5DD7C01C-AB9B-4F0E-9CC4-266700BD94E8?page=15) -- [Answer](x-devonthink-item://7CE81625-E4A6-40C1-BAEB-7E44C75B1E60?page=18)