1. HYPONATREMIA DIAGNOSIS AND MANAGEMENT

2. INTRODUCTION:PATHOPHYSIOLOGY SYMPTOMS WORK-UP TREATMENT CARDIOLOGIST`S PERSPECTIVE AQUARETICS OSMOTIC DEMYELINATION SYNDROME TAKE HOME MESSAGE 3. INTRODUCTION Defined as sodium concentration < 135 mEq/L. mild 135-130/moderate 130-120/severe or = 300 mosmol/k 22. o Valuesabove this level indicate an inability to normally excrete free water (i.e. continued secretion of ADH)oNormal urine osmolality: 400-500 mM Maximal dilution 50-100 mM (USG 1.002-1.003) Maximal concentration 900-1200 mM (USG 1.0301.040) Concentrated Urine: > 500 mM (at least!), USG > 1.017oThus, UOSM > POSM is not enough to R/O Diabetes Insipiduso 23. oUrine Osm < 100 with hyponatremia is seen in conditions o Psychogenic Polydipsia o Massive H2O intake overwhelms H2O excretion oBeer Drinkers Potomania (aka Tea & Toast diet), malnutrition o dietary solute intake such as Na, K, protein is decreased o therefore solute excretion is so low that the rate of H2O excretion is markedly diminished even though urinary dilution is intactoReset osmostat 24. Increased urine osmolality: Addison's disease (rare) Congestive heart failure Dehydration Glycosuria Renal artery stenosis Shock Syndrome of inappropriate ADH secretion Decreased urine osmolality: Aldosteronism (very rare) Diabetes insipidus (rare) Excess fluid intake(psychogenic polydipsia) Kidney failure Renal tubular necrosis Severe pyelonephritis 25. URINE SPECIFIC GRAVITY USG Estimates solute concentration of urine on basis of weightas compared with an equal volume of distilled water Normal Posm is 0.8-1.0% heavier than water so PSG = 1.0081.010 Each in UOSM 30-35 mM USG by 0.1% (0.001) Therefore, USG of 1.010 ~ UOSM 300-350 mM Larger Molecular Weight urinary OSM (glucose, radiocontrast, carbenicillin) if present will falsely elevate USG Nothing falsely lowers USG 26. URINE SODIUM CONCENTRATION used to distinguish b/n hypovolemic and euvolemic hyponatremia. UNa < 30 implies hypovolemic or reduced effective circulationvolume Kidneys reabsorb solutes to retain water and volume unless there is renal salt-wasting: diuretic therapy(most often ) adrenal insufficiency (infrequently) cerebral salt-wasting UNa > 30 seen in the euvolemic types usually above 40 meq/L in patients with the SIADH who are normovolemic and whose rate of sodium excretion is determined by sodium intake, as it is in normal subjects. 27. oMost hyponatremic patients have a relatively marked impairment in urinary dilution that is sufficient to maintain the urine Osm > or = 300 mosmol/koserial monitoring of the urine [Na] may be helpful in selected cases in which the correct diagnosis may not be apparent If hypovolemic, isotonic saline should suppress the hypovolemic stimulus to ADH releaseIf SIADH urine osmolality remains high but urine Na excretion is promoted by volume expansion and often rises above 40 mEq/L 28. ADDITIONAL LAB TESTS FeNA PLASMA URIC ACID oinitial water retention and volume expansion in the SIADH is frequently associated with hypouricemia (due to increased uric acid excretion in the urine).oUric acid is increased in patients with hypovolemia PLASMA UREA oHypervolemia also increases urea clearance such that hyponatremia of SIADH usually is associated with a BUN of < 5 mg/dL (1.8 mmol/L). caution in older patients as BUN is seldom this low secondary to decreased FeBUN that occurs with aging. i.e the absence of a low BUN cannot be used to exclude SIADH in older patients 29. ACID-BASE AND POTASSIUM BALANCE, E.g: oMetabolic alkalosis and hypokalemia Diuretic use or vomitingoMetabolic acidosis and hypokalemia Diarrhea or laxative abuse,oMetabolic acidosis and hyperkalemia Adrenal insufficiency BRAIN NATRIURETIC PEPTIDE: elevation of BNP provides useful lab evidence ofhypervolemia 30. INTRODUCTION PATHOPHYSIOLOGY SYMPTOMS WORK-UP TREATMENT:CARDIOLOGIST`S PERSPECTIVE AQUARETICS OSMOTIC DEMYELINATION SYNDROME TAKE HOME MESSAGE 31. THERAPYADVANTAGESDISADVANTAGESFluid restrictionGenerally effective; inexpensiveNoncomplianceDemeclocyclineConsistently effectiveReversible azotemia and nephrotoxicity; polyuriaLithiumEffective in some patientsInconsistent effectiveness; significant adverse effectsLoop diuretics (e.g. furosemide) plus increased salt intakeEffective in some patientsImbalance between diuretic action and salt ingestion can lead to volume depletion or overloadUreaConsistently effectivePoor palatability; gastrointestinal adverse effects; development of azotemia at higher dosesHypertonic (3% or 5%) saline with or without coadministration of loop diureticsCorrects serum [Na+]Rate of correction is variable and difficult to control; overly rapid correction is associated with myelinolysisVAPTANSCorrects sodium consistentlyExpensive, no long term mortality benefit 32. GENERAL GUIDELINES Na deficit = 0.6 x wt(kg) x (desired [Na] - actual [Na]) (mmol) When do you need to Rx quickly? Acute (1, indicating that the actual increase exceeded the predicted increase. 35. The Adrogue -Madias formula underestimates increase in sodiumconcentration after hypertonic saline therapy esp.in patients with ECF depletion and psychogenic polydipsia Hypertonic saline should be infused at rates lower than thosepredicted by formulas with close monitoring of serum sodium and urine output. Total body water is estimated as total body weight X 0.6 in children and nonelderly men, X 0.5 in nonelderly women and elderly men X 0.45 in elderly women. Other formulas are Barsoum-Levine and the Nguyen-Kurtz 36. Total body water can be determined using Flowingafterglow mass spectrometry FA-MS measurement of . deuterium abundance in breath samples from individuals after ingestion of D2O Another method of determining total body waterpercentage (TBW%) is via Bioelectrical Impedance Analysis (BIA). . BIA has emerged as a promising technique because of its simplicity, low cost, high reproducibility and non-invasiveness 37. Karen E. Yeates, Michael Singer, CMAJ FEB. 3, 2004; 170 (3) 38. Adrogue: NEJM, Volume 342(21).May 25, 2000.1581-1589 39. INTRODUCTION AND PATHOPHYSIOLOGY SYMPTOMS WORK-UP TREATMENT CARDIOLOGIST`S PERSPECTIVE:AQUARETICS OSMOTIC DEMYELINATION SYNDROME TAKE HOME MESSAGE 40. Approximately 5% of CHF patients have hyponatremia. Predominantly dilutional hyponatremia Total extracellular sodium is higher than normal Predicted as 1 of the predictors of mortality in OPTIME-CHF Study as also in ACTIV-CHF. In the OPTIMIZE-HF registry, the risk of death duringfollow-up of 60 to 90 days increased by 10% for each 3mmol/L decrease in baseline serum sodium 140 mmol/L.3 Marker of neurohormonal activation 41. Am J Cardiol 2005;95(suppl):8B13B 42. Am J Cardiol 2005;95(suppl):8B13B 43. AJCVOL. 95 (9A) MAY 2, 2005 44. Am J Cardiol 2009;103:405 410 45. MANAGEMENT Improvement in cardiac function Control of factors causing exacerbation of cardiacdysfunction Fluid restriction Controlled use of diuretics causing free waterclearance/avoidance of thiazides Use of hypertonic saline and aquaretics as indicated 46. MAJOR TRIALS OF VAPTANS ACTIV IN CHF:-(319 pts),Tolvaptan(doses 30/60/90 mg)produced weight reduction and correction of hyponatremia without electrolyte imbalance and worsening of renal function. No effect on heart failure outcomes at 60 days. METEOR:-(240 pts)Showed no beneficial effects of tolvaptanon LV remodeling EVEREST:-(4133 pts)Tolavaptan had no significant mortalitybenefit and decrease of hospitalization if drug is continued after discharge.However dyspnoea ,body weight and edema were decreased 47. SALT1/2:-multicentre placebo controlled trial on 448 ptswith conivaptan in euvolemic/hypervolemic hyponatremia demonstrated benefit ADVANCE:-343 PTS in NYHA class 2-4 were givenconivaptan for 12 weeks. Quality of life and exercise capacity of the pts did not improve VICTOR:-83 pts in NYHA class 2-3 with signs of congestionwere given Tolvaptan in addition to furosemide. Euvolemia and normonatremia was better achieved in pts given Tolavaptan BALANCE:-650 pts multicenter RCT in pts withdecompensated Heart Failure. study completed.results not published as yet 48. Circulation. 2008;118:410-421.) 49. Circulation. 2008;118:410-421. 50. INTRODUCTION AND PATHOPHYSIOLOGY SYMPTOMS WORK-UP TREATMENT CARDIOLOGIST`S PERSPECTIVE AQUARETICS:OSMOTIC DEMYELINATION SYNDROME TAKE HOME MESSAGE 51. THINGS TO KNOW ABOUT VAPTANS Vasopressin receptor antagonists can cause an electrolyte-free aquaresis, reduce urine osmolality, & raise serum Na Use in euvolemic/hypervolemic hyponatremia Contraindicated in hypovolemic hyponatremia Vaptans are not suitable for hyponatremia due to cerebralsalt wasting and psychogenic polydipsia where the ADH level is appropriate. 52. Avoid in pregnant women Aquaresis delayed 1-2 h Promotes slow aquaresis/Risk of overly rapid correction ofhyponatremia seems low Adverse Effects: Thirst 8-16%; dry mouth 4-13% Hypernatremia develops in 5% Correction rate > 12 mmol/L/24h-3% 53. If rate of correction too rapid use water or DDAVP Not studied in acute hyponatremia Not studied in patients with sNa < 115 mmol/L Role in hyponatremia due to over treated DI? No reduction in Mortality/Morbidity with long term use inheart failure 54. Possibility of hypotension & variceal bleeding incirrhotics if given a V1aR blocker ? Bleeding complications from V2R inhibition in vascularendothelium Metabolized by CYP3A4 Tachyphylaxis does not seem to occur Heart failure decreases clearance Risks v/s benefit? 55. AJC VOL. 95 (9A) MAY 2, 2005 56. The AJC Vol 96 (12A) December 19, 2005 57. PHARMACOKINETICS The VaptansConivaptanTolvaptanConvenience Mech Of ActionIV non-selective(10:1)PO Selective(29:1)Efficacy/OnsetMean Increases: 40 mg/day: 6.3mEq/L 80 mg/day: 9.4 mEq/L Lost effect at end of tx As early as 10 hr in the 80mg arm, increase >=4mEq/LMean increases ~6.2 mEq/L (end of 30 day treatment) Lost effect at end of tx At day 4,~4mEq/L increase was achievedSafetyInfusion site reactions, phlebitis, cardiac effectsLimited to v2 antagonism RashDrug InteractionsStrong CYP3A4 Inhibitor/substrateP-glycoprotein Substrate 58. OTHER USES OF VAPTANS POLYCYSTIC KIDNEY DISEASE polycystin defects may promote cyst development b/c they increases in intracellular cAMP (a second messenger for AVP acting at the V2R) therefore, V2R antagonists may reduced cyst volume CONGENITAL NEPHROGENIC DIABETES INSIPIDUS type 2 V2R mutations cause misfolding & interfere w/ trafficking ofthe receptor from the ER to the cell membrane VRA can bind to misfolded intracellular V2R & improve transport to the cell membrane 59. INTRODUCTION PATHOPHYSIOLOGY SYMPTOMS WORK-UP TREATMENT CARDIOLOGIST`S PERSPECTIVE AQUARETICS OSMOTIC DEMYELINATION SYNDROME:TAKE HOME MESSAGE 60. OSMOTIC DEMYELINATION SYNDROME OR CENTRAL PONTINE MYELINOLYSIS First described by Adams et al. in 1959 RISK FACTORS: alcoholism chronically ill patients Elderly/malnourished Cirrhosis predisposes to demyelination (due to depletion of intracellular organic solutes) Hypokalemia is a strong predictor 61. Demyelination can be diffuse and not involve the pons Symptom onset can be delayed for weeks Rate of correction over 24 hours more important than rate ofcorrection in any one particular hour More common if sodium increases by more than 20 mEq/L in24 hours 62. Very uncommon if sodium increases by 12 mEq/L or less in 24hours CT but preferably MRI to diagnose demyelination if suspected,though imaging studies may not be positive for up to 4 weeks after initial correction Symptoms generally occur 2-6 days after elevation of sodiumand usually either irreversible or only partially reversibleThe AJM, Vol 120 (11A), November 2007 63. PRESENTATION Dysarthria Dysphagia Parkinsonism Catatonia (2 case reports) Locked-in syndrome Lethargy and coma Seizures Nystagmus Ataxia emotional lability akinetic mutism gait disturbance myoclonus Behavioral disturbances Paraparesis or quadriparesis 64. PATHOPHYSIOLOGY Exact pathophysiology unknown. Possibly due to disturbance of blood brain barrier and damageby cytokines Or due to influx of potassium triggering apoptosis brain regions that are slowest to recover osmolytes are themost severely affectedby myelinolysis Uremia protects against myelinolysis 65. EVALUATION MRI may not show changes for weeks Appears as symmetric area of myelin disruption Extrapontine areas include: cerebellar and neocortical white/gray junctional areas thalamus subthalamus amygdala globus pallidus Putamen Caudate and lateral geniculate bodies 66. TREATMENT No effective therapy Case reports of improvement with aggressive plasmapheresisimmediately after diagnosis Case reports of treatment with thyrotropin-releasing hormone infusion of myoinositol (a major osmolyte lost in the adaptationto hyponatremia)protects against mortality and myelinolysis from rapid correctionof hyponatremia Am J Med. 2006;119(suppl 1):S12S16 67. PROGNOSIS Changes can be irreversible Old statistics shows 50% mortality Milder cases now diagnosed more often 68. INTRODUCTION PATHOPHYSIOLOGY SYMPTOMS WORK-UP TREATMENT CARDIOLOGIST`S PERSPECTIVE AQUARETICS OSMOTIC DEMYELINATION SYNDROME TAKE HOME MESSAGE:- 69. TAKE HOME MESSAGE Hyponatremia needs to be taken seriously in patientswith heart failure being a marker of neurohormonal activity Do not ascribe muscle cramps always to Hypokalemia.Think about hyponatremia as well!! WORK UP:-4 mandatory lab tests Serum Osmolality Urine Osmolality Urine specific gravity Urine Sodium Concentration 70. CORRECTION FORMULA: Na deficit = 0.6 x wt(kg) x (desired [Na] - actual [Na]) (mmol) Use of aquaretics is a relatively safe and effective methodfor hyponatremia correction with no long term mortality benefit Thiazide diuretics cause hyponatremia much morecommonly than loop diuretics. Onset is earlier and is predominantly seen in elderly females. 71. Overzealous correction of hyponatremia needs to beavoided lest CPM develops Pontine myelinolysis not necessarily involves pons MRI change may take upto 4 weeks to occur Less severe forms of CPM are much more common Essentially CPM has no t/t 72. Neoplasms Carcinomas Lung Duodenum Pancreas Ovary Bladder, ureter Other neoplasms Thymoma Mesothelioma Bronchial adenoma Carcinoid Gangliocytoma Ewing's sarcoma Head trauma (closed and penetrating) Infections Pneumonia, bacterial or viral Abscess, lung or brain Cavitation (aspergillosis) Tuberculosis, lung or brain Meningitis, bacterial or viral Encephalitis AIDS Vascular Cerebrovascular occlusions, hemorrhage Cavernous sinus thrombosisNeurologic Guillain-Barr syndrome Multiple sclerosis Delirium tremens Amyotrophic lateral sclerosis Hydrocephalus Psychosis Peripheral neuropathy Congenital malformations Agenesis corpus callosum Cleft lip/palate Other midline defects Metabolic Acute intermittent porphyria Pulmonary Asthma Pneumothorax Positive-pressure respiration Drugs Vasopressin or desmopressin Chlorpropamide Oxytocin, high dose Vincristine Carbamazepine Nicotine Phenothiazines Cyclophosphamide Tricyclic antidepressants Monoamine oxidase inhibitors Serotonin reuptake inhibitors 73. http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=10935&searchStr=hyponatremia 74. Syndrome of Inappropriate ADH Release (Bartters Criteria) Hyponatremia and true hypoosmolality bydefinition Euvolemia clinical Urine less than maximally dilute (urinary osmolality usually > 200 mOsm/kg of H2O) Normal renal, cardiac, hepatic, adrenal, pituitary,and thyroid function No history of antidiuretic drugs No emotional or physical stress Urinary sodium > 20 mEq/litera a Urinary sodium may be