JUAN MIGUEL GIL R. ORTIZ, MD, FPCP, FPSN University of Santo Tomas Hospital

JUAN MIGUEL GIL R. ORTIZ, MD, FPCP, FPSN University of Santo Tomas Hospital

HYPONATREMIA Hb 88 Creatinine 7 Na 130 K 5.8

Nonhypotonic Hyponatremia 1. Pseudohyponatremia 2. Presence of non-na effective osmole -presence of an osmolar gap (meas)posm - (calc)posm (2[Na]+BUN/2.8+CHO/18)

Sodium s biologic effects are determined by its concentration in plasma water 7% Decreased [Na] in aqueous phase of plasma (93% water, 7% proteins and lipids)

Pseudohyponatremia 7% 14% 140 in 930cc 151mEq/L 130 in 860cc 151mEq/L Automated lab report an artifactually low [Na] despite a normal [Na] in plasma water

Indirect ion-sensitive electrodes vs Direct ISE Est plasma water %: =99.1 (0.1xL) (0.07xP) L=Lipid P=Protein

Hyponatremia in end stage liver disease with hypergammaglobulinemia i-stat Na 119 meq/l Osm gap 29 POsm 290 mosm/kg total CHON 11.7 g/dl directise Na 128 meq/l (Osm gap 11) Combination of true hyponatremia and pseudohyponatremia Garibaldi J Gen Intern Med 2008

Calculating the patient s plasma aqueous volume was found to be 0.90 rather than 0.93 Using the dilution factor based on plasma water content of 93% underestimated [Na] when indirect ISE was utilized.

Hypertonic hyponatremia abnormally high concentrations of an effective osmole diluting [Na] by osmotically attracting water from cells Hyperglycemia, hypertonic mannitol infusion, Ig infusion containing maltose and sucrose

Isotonic hyponatremia isosmotic or hypo-osmotic irrigants abruptly enter circulation via disrupted venous plexuses Transurethral prostate surgery and endoscopic intrauterine surgery glucose,mannitol, glycine, sorbitol: nonconducting electrolytes (electrocautery) solute is absorbed with water so POsm is not increased and there is no water shift from cells

Although hypertonic and isotonic hyponatremia are true hyponatremia in the sense that they represent [Na] that are low in the ECF in vivo, therapeutic measures to increase PNa are not indicated. Not shown to cause cerebral edema Palmer 2009

Brain Responses to Hyponatremia Hyponatremia associated with swelling of all body cells particularly harmful to brain due to skull

Brain Responses to Hyponatremia Incr in hydrostatic P increases flow of Na-rich interstitial fluid into the CSF to the general circulation

Osmolytes involved in volume regulatory decrease (RVD): K+, Cl- and organic osmolytes (nonperturbing solutes) taurine, glutamate, glycine, GABA sorbitol, myoinositol creatine, phosphoethanolamine, glycerophosphorylcholine N-acetyl aspartate

Brain response to correction of hyponatremia depletion of organic osmolytes permits survival in chronic hyponatremia downregulation of transporters organic osmolytes are slow to return to the cells Osmotic demyelination syndrome (ODS)

Vascular endothelial cell shrinkage Tight junction disruption Opening blood brain barrier Entry of complement, cytokine, lymphocytes apoptosis Oligodendrocyte damage and demyelination

Uremia associated with resistance to myelinolysis enhanced reuptake of osmolytes (myoinositol)

Chronic Hyponatremia brain adaptation to hyponatremia is completed within 48 h - thus chronic if 48 h and acute if developed more rapidly

Duration of hyponatremia developing outside the hospital cannot be known Presume hyponatremia is chronic. Chronic hyponatremia is rarely fatal. Little evidence that chronic hyponatremia leads to permanent sequelae even if Na < 105 meq/l

Prolonged hyponatremia cannot occur unless with sustained defect in water excretion.

Either with abnormal hemodynamics Or independent of hemodynamic stimuli Hemodynamically-mediated AVP secretion and hyponatremia advanced heart failure cirrhosis easily recognized clinically (sodium retention and edema)

Korean J Crit Care Med. 2008 Dec;23(2):67-74

Greater challenge: sodium depletion vs euvolemic hyponatremia (SIADH) Hypoosmolality Maximally dilute urine (UOsm>100) Absence of diuretics, clinical signs of volume depletion or edema UNa > 30mEq/L (or >40mEq/L on adeq diet) Response of hyponatremia with water restriction Absence of severely impaired renal function

Presence of antidiuretic hormone cannot always be proved in cases of euvolemic hyponatremia: Syndrome of Inappropriate Diuresis (SIAD)

Most definitive test: Assessment of the response to isotonic saline: ECF volume expansion Vasopressin suppression Dilute urine

Spot urine Na < 30mEq/L in saline-responsive > 30mEq/L in SIAD Problem : elderly slow to adapt to hypovolemia, some UNa as high as 50-60mEq/L FENa = UNa/PNa/Ucrea/Pcrea (<0.5% depletion)

Feurea = Uurea/Purea/Pcreat/Ucreat FENa >0.15% and FEurea >45% - SIAD A rapid incr in FENa >0.5% after 2L saline without correction of PNa SIAD Change in [Na] with saline dependent on UOsm

Cerebral salt wasting Inappropriate urinary salt loss + reduced effective arterial blood volume in Neurologic Patient Volume restriction exacerbates cerebral vasospasm and ischemia - deleterious Isotonic saline prevents volume depletion but does not correct hyponatremia (hypertonic urine) Hypertonic saline is treatment

Beer Potomania / Pyschogenic Polydipsia Drug-induced (Thiazide, SSRI, NSAID) Addison s Disease / Hypothyroidism Cirrhosis NSIAD Cardiac (CHF) Tumor-related (Lung CA)

Serum potassium and acid-base disturbance Hyperkalemia and acidosis Addison s Disease and CKD Hypokalemia and alkalosis Hypovolemia from thiazide, vomiting SIADH no acid-base or potassium disturbance Korean J Crit Care Med. 2008 Dec;23(2):67-74

Korean J Crit Care Med. 2008 Dec;23(2):67-74

Treatment General measures [Na] should not be allowed to fall any further symptoms attributable to hyponatremia should be alleviated by partial correction therapeutic complications should be avoided reversible causes should be eliminated

Limit correction over 48 h to 18 meq/l For a 24 h limit: 6 meq/l in 1 st 24 hr 10 meq/l in 1 st 24 h then 8 meq/l every 24 thereafter until 130mEq/L* (and even lower for high risk patients : liver disease, malnutrition, alcoholism) Recommended target for acute hyponatremia : 5mEq/L* *Spasovsky EJE European Guidelines 2014

Water restriction -effective in mildly symptomatic chronic hyponatremia -UOsm>300 (more than POsm) - negative free water -UOsm<300 (less than POsm) - positive free water

U(Na+K) / P(Na+K) x urine flow rate Spot urine U(Na+K) / P(Na+K) practical Ratio > 1 (water restriction alone may not work) due to negative free water clearance Ratio 0.5 1.0 (water restriction of up to 500 ml)

Ratio< 0.5 (water restriction of up to 1 liter may be sufficient) Augmenting by increasing solute intake For any given UOsm, solute excretion sets the ceiling how much water is actually excreted

Uosm 664 mosm/l from SIAD lung CA Diet : 600 mosm/d PNa : 120 meq/l If U(Na+K) is 166 meq/l - negative free water balance Water restriction not effective Double solute load to 1200 mosm/d would double urine flow and dilute Ulytes by half

Large dietary protein not achievable High salt intake + restriction : result to matched ingested and urine electrolyte conc only Add furosemide to decrease UOsm

Fluid Therapy Δ [Na] =[Na + K]infusate Serum Na Total body water + 1 Δ [Na] =Serum Na [Na + K]fl Total body water - 1 Infusate formula Adrogue-Madias Fluid loss formula

60 kg woman with Na 110 TBW 30L (0.5 x 60) What is expected change in [Na] if 1L 3% NaCl is infused? (1) SIADH with moderately severe neurologic symptoms and oliguria Retention of 1 L of 3% NaCl is projected to increase [Na + ] s by 13 meq/l ([513 110]/[30 + 1]). For a targeted increase in [Na + ] s of 4 meq/l over 6 hours, 308 ml of 3% NaCl [(1000/13) 4], or 51 ml/h (308/6) is required. Δ [Na] =[Na + K]infusate Serum Na Total body water + 1

60 kg woman with Na 110 TBW 30L (0.5 x 60) What is change in Na if 1L of urine is allowed to pass out? (2) Primary polydipsia with severe neurologic symptoms and large aquaresis (500 ml/h); [Na + + K + ] is 20 meq/l). Loss of 1 L of urine is estimated to increase [Na + ] s by 3.1 meq/l ([110 20]/[30 1]). A targeted increase in [Na + ] s of 4 meq/l requires 1.3 L of urine (4/3.1) and will be achieved in 2.6 hours (1.3/0.5). At the 3-hour mark [Na + ] s is 115 meq/l. To prevent overcorrection of hyponatremia, desmopressin is prescribed. Δ [Na] =Serum Na [Na + K]fl Total body water - 1

60 kg woman with Na 110 TBW 30L (0.5 x 60) What change in Na if corrected with 1L saline and 30 meq KCl added? (3) Hypovolemic hyponatremia with mild neurologic symptoms and oliguria. [K + ] s is 3.0 meq/l. Retention of 1 L of 0.9% NaCl + 30 meq of KCl is projected to increase [Na + ] s by 2.4 meq/l ([184 110]/[30 + 1]). After administration of this infusate at 250 ml/h for 6 hours, [Na + ] s is 114 meq/l and [K + ] s is 3.4 meq/l. Urine output has increased and at the 6-hour mark is 150 ml/h; urine [Na + + K + ] is 20 meq/l. Loss of 1 L of such urine is estimated to increase [Na + ] s by 3.2 meq/l ([114 20]/[30 1]). To prevent overcorrection of hyponatremia, the infusate is changed to 0.45% NaCl. ([77-114]/[30+1]) will decrease [Na] by 1.1 meq/l per liter infused.)

Estimated effect of infusates and fluid losses of different electrolyte composition on [Na + ] s a [Na + + K + ] (meq/l) Infusate Effect on [Na + ] s per 1 L (meq/l) [Na + + K + ] (meq/l) Fluid Loss Effect on [Na + ] s per 1 L (meq/l) 3% NaCl 513 13.0 Aquaresis (e.g., primary polydipsia) 0.9% NaCl 154 1.4 Natriuresis (e.g., furosemide) 20 3.1 55 1.9 0.9% NaCl + 30 meq KCl per L 184 2.4 Viral/bacterial diarrhea 90 0.7 Ringer s lactate 135 0.8 Osmotic diarrhea 40 2.4 0.45% NaCl 77 1.1 Gastric fluid 70 1.4 5% dextrose 0 3.5 Adrogue JASN 2012

Drugs with nephrogenic diabetes insipidus like effect: Demeclocycline (nausea, photosensitivity, nephrotoxicity) Lithium (tubulointerstitial disease, ESRD)

Hyponatremia in ESRD Use low Na dialysis solution (130mEq/L, 120-130mEq/L) Shorten duration Limit blood flow (50ml/min) SLEDD / Venovenous HF

Vaptans Vasopressin receptor antagonists Conivaptan 20mg IV/d 4days? Lixivaptan Tolvaptan 15/30mg? Satavaptan

Vasopressin V1a receptor Vascular tone and platelet activity Conivaptan Tolvaptan Water reabsorption V2 receptor Upregulates aquaporin2 expression in collecting ducts

Vaptans Vasopressin receptor antagonists Hypervolemic and Euvolemic Hyponatremia Issue of Hepatotoxicity Initiation in-hospital to monitor for overcorrection Extent and duration Cost of therapy

Urea Ineffective osmole in plasma, effective urinary osmole In powder or capsule form, 15mg and 30mg Bitter taste Protects against brain damage and myelinolysis Antioxidant properties protect against hyperosmotic stress leading to astrocyte apoptosis

Expected osmotic effects of rapid administration of 30 g (500 mosmol) of urea to a 50-kg woman with 25 liters of total body water, serum sodium 120 mmol/l, and urine osmolarity 500 mosmol/l. Sterns Kidney International (2015) 87, 268 270

Mild Moderate Profound 130-135 125-129 <125 Moderate Severe (Sx) Goals/Thresholds: 10mEq in 24h 18mEq in 48h 5mEq for acute Sx Nondilutional lab methods POsm UOsm and UNa Urea? Vaptans Spasovsky EJE European Guidelines 2014

Algorithm for the diagnosis of hyponatraemia. Goce Spasovski et al. Eur J Endocrinol 2014;170:G1-G47 2014 European Society of Endocrinology, European Society of Intensive Care Medicine,

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