Approach to hyponatremia

simple n strategic approach to hypo natremia

1. APPROACH TO A PATIENT OF HYPONATREMIA -DR MAHENDRA M MASKE

2. Introduction Hyponatremia -Most common abnormality 15-30% of hospitalized pnts Independent predictor of mortality Acute – 50 %; Chronic- 10-20% Challenge among physicians > CAUSE Basically a water imbalance.

3. Total Body Water - 60 % of body weight in Male - 50% of body weight in Female Fat holds less water, obese will have proportionately less body water.

4. Electrolyte Composition

5. Plasma Osmolality { mOsm /kg } Normal Plasma Osmolarity > 275-295 mOsm /kg

6. Effective Osmolality Effective Osmolality { mOsm /Kg } = 2 x Na + Glucose 18 Determine by those solutes which does not permeate cell membrane & act to hold water within ECF. Lipid soluble substances like Urea can cross cell membrane, does not contribute to Osmotic pressure gradient b/w ECF & ICF.

7. SODIUM 11 Na 23 Na major ECF cation { 140 mEq /l ECF vs 25 mEq /l intracellular} Total body Na > 5000mEq 85-90% Na extra-cellular Responsible for > 90% total osmolarity of ECF. Maintain ECF volume & hence Blood pressure. Daily requirement > 100 mEq i.e. 6 gm salt. 1 gm of NaCl contains 17.1 mEq of Na. from Latin :  natrium

8. Hyponatremia Plasma Na + concentration <135 m M The concentration of sodium in ECF is a reflection of the tonicity of body fluids, not of total body sodium content. Hyponatremia can be associated with low, normal or high tonicity.

9. Pseudo- hyponatremia > associated with normal or increased tonicity. Isotonic hyponatremia expansion of extracellular fluid with isotonic fluids that do not contain Na there is no transcellular shift of water but the [Na+] decreases Ex- hypertriglyceridemia hyperproteinemia ( as in Multiple Myeloma) rise in plasma lipids of 4.6 g/L or plasma protein concentrations greater than 10 g/ dL will decrease the sodium concentration by approximately 1 mEq /L.

10. Hypertonic hyponatremia Seen when there is increase in effective osmoles in the extracellular fluid Shift of water from the cells to the ECF and thus causing translocational hyponatremia Ex- hyperglycaemia in DM {plasma Na + falls by 2 mEq /l for every 100-mg/ dL increase in Glucose b/w 200-400 mg/dl; and by 4 mEq /l at Glucose > 400mg/dl} hypertonic mannitol

11. Hypotonic Hyponatremia Hypotonic hyponatremia is the most common form of hyponatremia Hypotonic hyponatremia occurs by two mechanisms 1) impaired renal water excretion 2) excess water intake Hypotonic hyponatremia can be classified as hypovolemic, euvolemic and hypervolemic on the basis of ECF volume as assessed clinically by changes in blood pressure and heart rate, edema , jugular venous distension, skin turgor , mucous membranes.

12. Hypovolemic Hyponatremia Total body water Total body Na Conditions with UNa > 20 The renal causes of hypovolemic hyponatremia inappropriate loss of Na + - Cl – in the urine volume depletion and an increase in circulating AVP; Mineralocorticoid deficiency Hyperkalemia hyponatremia hypotensive and/or hypovolemic patient with high urine Na + concentration (much >20 m M )

13. Salt-losing nephropathies -sodium intake is reduced due to impaired renal tubular function reflux nephropathy interstitial nephropathies post-obstructive uropathy medullary cystic disease the recovery phase of acute tubular necrosis. Diuretics Excess Thiazides Loop diuretics > blunting the countercurrent mechanism {Water diuresis > Natriuresis }

14. Osmotic diuresis Excretion of osmotically active nonreabsorbable or poorly reabsorbable solute glycosuria , ketonuria (e.g., in starvation or in diabetic or alcoholic ketoacidosis ), and bicarbonaturia (e.g., in renal tubular acidosis or metabolic alkalosis, in which the associated bicarbonaturia leads to loss of Na.

15. Cerebral salt wasting Rare cause of hypovolemic hyponatremia, hyponatremia clinical hypovolemia inappropriate natriuresis Intracranial disease SAH, trauma, craniotomy, encephalitis and meningitis. Release of BNP {brain natriuretic peptide} in cerebral dysfunction D/D syndrome of inappropriate antidiuresis (SIAD) Cerebral salt wasting typically responds to aggressive Na + - Cl – repletion.

16. Conditions with Una < 20 Nonrenal causes of hypovolemic hyponatremia gastrointestinal (GI) loss vomiting, diarrhoea, tube drainage, etc. Third space loss of fluids. Ex- pancreatitis, burns a rapid increase in plasma Na + concentration in response to intravenous normal saline. saline induces a water diuresis in this setting, as circulating AVP levels decreases.

17. Euvolemic Hyponatremia Hyponatremia with normal ECF volume is seen in Syndrome of inappropriate antidiuresis (SIAD) Endocrine deficiency -hypothyroidism -adrenal insufficiency

18. SIAD Syndrome of inappropriate antidiuresis (SIAD) SIAD more accurate term ADH is inappropriately elevated in SIAD by a variety of mechanisms enhanced and unregulated ADH secretion (by tumor or hypothalamus) elevated secretion of ADH in basal state and in response to hypertonicity Reset osmostat Activating mutation of the V2 receptor permitting reabsorption of water in absence of ADH. Natriuresis (increases ANP) in presence of water retention leads to inappropriately concentrated urine.

19. Diagnostic Criteria for SIADH: plasma sodium concentration <135 mmol /l plasma osmolality <280 mOsmol /kg urine osmolality > 100  mOsmol /kg urinary sodium concentration >20mEq/L patient clinically euvolaemic absence of clinical or biochemical features of adrenal and thyroid dysfunction

20. Serum uric acid is often low (<4 mg/ dL ) in patients with SIAD, consistent with suppressed proximal tubular transport in the setting of increased distal tubular Na + - Cl – and water transport. In contrast, patients with hypovolemic hyponatremia are often hyperuricemic due to a shared activation of proximal tubular Na + - Cl – and urate transport.

21. Endocrine deficiency Hypothyroidism or adrenal insufficiency - impairs reduced cardiac output > ADH release. Isolated glucocorticoid deficiency -through corticotropin releasing factor mediated release of ADH. Correction of these hormonal deficits corrects for the water excretion defect and hyponatremia .

22. Hypervolemic Hyponatremia Causative disorders can be separated by the effect on urine Na + concentration U Na > 20 -Acute renal failure (ARF) -Chronic renal failure (CRF) U Na < 20 -congestive heart failure - nephrotic syndrome -hepatic cirrhosis Low intraarterial filling Movement of water from the vascular to the interstitial space –due to hypoalbuminemia Activation of the neurohormonal compensatory mechanisms

23. Exercise induced hyponatremia Marathon runners Females and with low body weight. Excessive drinking of hypotonic solutions (>1.5 l/hour of water or hypotonic sport drinks) and Inappropriate secretion of ADH due to muscle derived interleukin-6 .

24. Primary polydipsia (compulsive water drinking 10-15 liter /day) psychiatric patients -schizophrenia. central defect in thirst regulation excessive secretion or renal action of ADH and Antipsychotic drugs by anticholinergic action. Low Solute Intake A low dietary solute intake ( tea-toast diet , extreme vegetarian diets.) as in debilitated residents in nursing homes or chronic alcohol ingestion ( beer potomania ) causes hyponatremia by decreasing the ability of the kidney to excrete water. Water intake above this renal and insensible water loss will cause hyponatremia Beer is very low in protein and salt content, containing only 1–2 millimole per liter of Na + . Associated with low urine osmolality , <100–200 mosmol /kg, with a urine Na + concentration that is <10–20 m M .

25. Clinical diagnosis The symptoms primarily neurologic Development of cerebral edema within a rigid skull. headache, lethargy, confusion, gait disorder, nausea, vomiting and in severe hyponatremia as seizures, coma, brain-stem herniation , permanent brain damage or death. Hypo- natremia < 135 mild <130 moderate < 120 severe

26. Severe hyponatremia (Na+<120meq/l) and rapid development of hyponatremia (<48 hours) A key complication is normocapnic or hypercapnic respiratory failure. Normocapnic respiratory failure is noncardiogenic , neurogenic pulmonary edema , with a normal pulmonary capillary wedge pressure.

27. Persistent, chronic hyponatremia efflux of organic osmolytes ( creatine , betaine , glutamate, myo -inositol , and taurine ) from brain cells > intracellular osmolality > water entry. complete within 48 h, time period defines chronic hyponatremia vomiting, nausea confusion and seizures subtle gait and cognitive defects increases risk of falls risk of bony fractures

28. Diagnostic Evaluation of Hyponatremia Clinical assessment underlying cause detailed drug history volume status multifactorial , Consider all the possible causes

29. Laboratory Serum osmolality , Na, K BUN and creatinine Serum glucose, uric acid Urine Na, K Urine Osmolarity Serum proteins & Lipid profile Thyroid, adrenal, and pituitary function Radiology CXR-PA CT Thorax & Brain

30. Hyponatremia Na < 125 mEq /l Sr. Osmolarity >280 mOsm /k Sr Osm < 280 mOsm /kg Pseudo- Hyponatremia { Iso /Hyper tonic } Primary Polydipsia Low solute intake Una <2 U na >2 Renal causes Extra-Renal causes 0.9% NS Urine Osmolarity < 100 mOsm /kg H20 SIAD HYPOTHY-ROIDISM Adrenal insufficiency CHF Cirrhosis Nephrotic syndrome Fluid restriction Demeclocycline Fluid Restriction Furosemide

31. Management Three major considerations to guide therapy for hyponatremia. Severity of symptoms Risk for ODS Highly unpredictable response Once the urgency in correcting the plasma Na + concentration has been established and appropriate therapy instituted, the focus should be on treatment or withdrawal of the underlying cause .

32. Acute Symptomatic hyponatremia – medical emergency. Rate of correction 1.5-2 meq /l/h for the first 3-4 hours; total 8-12 meq /l/day Na + deficit = 0.6 x body weight x (target Na + conc – starting Na + conc ). Hypertonic saline (3% NaCl ) @ 1-2 ml/kg/hour For mild symptoms @ 0.5 ml/kg/hour + lasix 20-40 mg IV For seizures & coma @ 2-4 ml/kg/hour + lasix 20-40 mg IV Monitored every 2–4 h Vaptans - no role

33. Chronic or slowly developing hyponatremia 0.5 meq /l/h total 8-12 meq /l/day or < 10 mMol in 1 st 24 hrs, < 18 mMol in 48 hrs Water Restriction The urine:plasma electrolyte ratio (urinary [Na + ]+[K + ]/plasma [Na + ]) indicator of electrolyte-free water excretion >1 restricted more aggressively (<500 mL /d), 1 restricted to 500–700 mL /d, <1 restricted to <1 L/d. In hypokalemic pnts > inj KCl or Pottasium supplements. By this, generally Na levels are corrected. Oral salt tablets oral furosemide 20 mg bd plus oral salt tablets Demeclocycline 600 to 1200 mg/day Vaptans

34. Equations are available to help calculate the initial rate of fluids to be administered. A widely used formula is the Adrogue-Madias formula. Change in serum Na+ with infusing solution= [ infusate (Na + K)]-serum Na (total body water +1) Infusate Na+ is the [Na+] in the infused fluid (154meq/l in 0.9%NS, 513meq/l in 3%NS, 77meq/l in 0.45%NS & 0 meq /l in D5W). The above equation predicts the amount of [Na+] change by 1 liter of infusate . Dividing the targeted change in Sr Na by the result of above equation gives volume of infusate required & thus the rate of infusion.

35. For ex 60 kg female with Na- 110 m Eq /l. Correction using 3% NaCl (513 mEq /l) – (513-110 ) / 30 +1 = 400 /31 = 13 mEq /l So infusion of 1 L of 3% NaCl in this pnt will raise Na by 13 mEq /l. Since correction to be done at 2 mEq /hr, 1 litre of 3% NaCl should be infused over 6.5 hrs. i.e. 154 ml/hour or 2.5 ml/min @ 40 macrodrops /min or 150 udrops /min. Other formulae Barsoum -Levine Nguyen-Kurtz

36. Euvolemic and hypervolemic hyponatremia Fluid restriction ( upto 800-1000ml/day) furosemide > excretion of 70-80meq/l urine Na+ and K+ (tonicity similar to 0.45NS). Replacement of these electrolyte losses with 0.9NS would require a volume equal to half the urine output, with the resulting net free water clearance being half the total urine volume.

37. OSMOTIC DEMYELINATION SYNDROME Rapid correction movement of water out of the edematous neurons, causing shrinkage and disruption myelin sheaths. Predisposed - chronic alcohol abuse, hepatic failure and malnutrition. Central pontine myelinolysis (CPM) - quadriplegia - pseudobulbar palsy - seizures - coma and death. Extra- pontine Myelinolysis Cerebellum Lateral geniculate body Thalamus Putamen Cerebral cortex Hyponatremia reinduced by Desmopressin acetate (DDAVP) and/or the administration of free water, typically intravenous D5W; Goal is to prevent or reverse the development of ODS.

38. Vasopressin antagonists ( vaptans ) highly effective in treating SIAD and hypervolemic hyponatremia due to heart failure or cirrhosis, Aquaretic effects (augmentation of free-water clearance). Important role in circulatory & water homeostsis 3 receptor sub-types: V1a vascular smooth musclevasoconstriction /cardiac hypertrophy V2 renal collecting duct systemresorption of free water V3 (V1b) limbic systemstimulates ACTH & endorphins

39. Tolvaptan oral V 2 antagonist approved by the U.S. Food and Drug Administration. most appropriate for the management of significant and persistent SIAD Dosage- 30 mg, 60 mg od Conivaptan intravenous vaptan a mixed V 1A /V 2 antagonist risk of hypotension due to V 1A receptor inhibition inflammation at infusion sites 20-40 mg/day IV

40. Therapy with vaptans must be initiated in a hospital setting, with a liberalization of fluid restriction (>2 L/d) and close monitoring of plasma Na + concentration. Vaptans are not to be used in hypovolemic hyponatremia acute hyponatremia SIAD caused by activating mutation in vaopressin receptor Cerebral salt wasting Psychogenic polydipsia

41. Other Vaptans V2 selective V1 A selective V1 B selective - Satavaptan - Relcovaptan - Nelivaptan - Lixivaptan - Mozavaptan

42. Vaptans in Cirrhosis Tolvaptan effective in raising Na Conivaptan – increase risk of GI bleed Vaptans in CHF Rapid & sustaine decrease in body weight Normalization of Sr Na with Tolcapone Trend towards lower mortality in patients with congestion, hyponatremia & abnormal renal function No significant difference in worsening of heart failure compared to placebo.

43. Safety of Vaptans ? Trials showed correction of hyponatremia faster than recommended No guidelines for back titration once overcorrection occurs No case of ODS reported till date with vaptans

44. Fallacies in ppt : -no consideration of Heat related hyponatremia -treatment not properly explained -more elaboration of ODS CMDT In severely symptomatic patients, the clinician should calculate the sodium deficit and deliver 3% hypertonic saline. The sodium deficit can be calculated by the following formula:   Sodium deficit = Total body water (TBW) × (Desired serum Na–Actual serum Na)   where TBW is typically 50% of total mass in women and 55% of total mass in men. For example, a nonedematous , severely symptomatic 70 kg woman with a serum sodium of 122 mEq /L should have her serum sodium corrected to approximately 132 mEq /L in the first 24 hours. Her sodium deficit is calculated as:   Sodium deficit = 70 kg × 0.5 × (132 mEq /L – 122 mEq /L) = 350 mEq   3% hypertonic saline has a sodium concentration of 514 mEq /1000 mL. The delivery rate for hypertonic saline can be calculated as:   Delivery rate = Sodium deficit/514 mEq /1000 mL /24 hours   = 350 mEq /514 mEq /1000 mL /24 hours = 28 mL /hour   In general, the 3% hypertonic saline infusion rate should not exceed 0.5 mL /kg body weight/h ; higher rates may represent a miscalculated sodium deficit or a mathematical error. The goal is not to correct the serum sodium by more tha 10–12 mEq /L over the first 24 hours.

45. References Harrison 18 th edition JAPI Hyponatremia and Hypernatremia : Disorders of Water Balance V Agrawal *, M Agarwal Dec 2008; 956-60 Medicine Updates 2012 Medicine updates 2013 Text book of critical care. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia.Am J Kidney Dis 2008; 52 (1) : 144-53. Gennari FJ. Hypo– hypernatraemia : disorders of water balance. In:Davison AM, Cameron JS, Grünfeld JP, Kerr DNS, Ritz E, Winearls CG,eds . Oxford Textbook of Clinical Nephrology, 2nd Edition. Oxford University Press, Oxford, New Y ork , Tokyo: 1998: 175-89. Asadollahi K, Beeching N, Gill G. Hyponatraemia as a risk factor for hospital mortality.QJM 2006;99(12):877-80. Rose BD, Black RM ( eds ): Clinical Problems in Nephrology, ed 1. Boston,Little , Brown, 1996, pp 3-17. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med 2007;356:2064-72.

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