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Hyponatremia navin`s ppt


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hynonatremia symptoms and management in cardiology practice

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Hyponatremia navin`s ppt

  3. 3. INTRODUCTION • Defined as sodium concentration < 135 mEq/L. mild 135- 130/moderate 130-120/severe <120. • Generally considered a disorder of water as opposed to disorder of salt usually Results from increased water retention  Hyponatremia, the most common electrolyte disorder in hospitalized patients present seen in 15%-22% patients at admission
  4. 4. • Normal physiologic measures allow a person to excrete up to 10 liters of water per day which protects against hyponatremia • Thus, in most cases, some impairment of renal excretion of water is present  Maximum concentrating ability of kidney is approximately 800-1600mOsm/kg Verbalis et al Hyponatremia Treatment Guidelines 2007/The American Journal of Medicine (2007) Vol 120 (11A), S1–S21
  5. 5.  Because they impair distal tubule–diluting capacity without affecting urinary concentration , thiazide drugs are the predominant cause of diuretic induced hyponatremia(73% cases)  Furosemide-related hyponatremia tends to occur after many months of therapy, often when an intercurrent illness develops, whereas thiazide-related hyponatremia frequently occurs within a few days or weeks after initiation of therapy. Verbalis et al Hyponatremia Treatment Guidelines 2007/The American Journal of Medicine (2007) Vol 120 (11A), S1–S21
  6. 6.  Patients with thiazide-induced hyponatremia typically are elderly women. In 1 study, the mean age was 76.4 +/- 9.6 years, 90% of those affected were aged 65years, and 70% were women  Serum uric acid levels, which typically rise with volume depletion, were lower in patients with thiazide-induced hyponatremia as compared with normonatremic patients taking thiazides suggesting a role for abnormal thirst and water intake Verbalis et al Hyponatremia Treatment Guidelines 2007/The American Journal of Medicine (2007) Vol 120 (11A), S1–S21
  7. 7.  Max. ADH effect decreases urine output to approximately 500 cc/day  No ADH release increases urine output to 15-20 Liters per day. U osm = 40 – 80 mOsm/kg H2O  The risk of death associated with hyponatremia appears to be particularly strong in patients with cardiovascular disease, cancer, and those undergoing orthopaedic procedures
  9. 9. Am J Cardiol 2005;95(suppl):8B–13B
  10. 10. Clinical Findings Type I, Hypervolemic Type II, Hypovolemic Type IIIA, Euvolemic Type IIIB, Euvolemic (SIAD) CHF, cirrhosis, or nephrosis Yes No No No Salt and water loss No Yes No No ACTH–cortisol deficiency and/or nausea and vomiting No No Yes No Generalized edema, ascites Yes No No No Postural hypotension Maybe Maybe Maybea No BUN, creatinine High-normal High-normal Low-normal Low-normal Uric acid High-normal High-normal Low-normal Low-normal Serum potassium Low-normal Low-normalb Normalc Normal Serum albumin Low-normal High-normal Normal Normal Serum cortisol Normal-high Normal-highd Lowe Normal Plasma renin activity High High Lowf Low Urinary sodium (meq unit of time)g Low Lowh Highi Highi History Physical examination Laboratory
  11. 11. The American Journal of Medicine, Vol 120 (11A), November 2007
  12. 12. The American Journal of Medicine, Vol 120 (11A), November 2007
  14. 14. WHO HAS SYMPTOMS….?  Depends on rate of development  Symptoms universal if [Na] < 120 is acute  Chronic hyponatremia is less likely to be symptomatic  Young and old are more likely to be symptomatic
  15. 15. WHAT ARE THE SYMPTOMS….? ACUTE: 121-130 mEq/L Nausea, malaise, headache, lethargy, muscle cramps, disorientation, restlessness <120 mEq/L Obtundation, seizures, respiratory arrest, coma,death CHRONIC: (developed over days) Usually Asymptomatic / Non-Specific Nausea, gait disturbance, forgetfulness, muscle cramps confusion, lethargy, fatigue Palmer, Biff F., John R. Gates, and Malcolm Lader. "Causes and Management of Hyponatremia." The Annals of Pharmacotherapy 37 (2003): 1694-701.
  17. 17. WORKUP FOR HYPONATREMIA • 4 mandatory lab tests – Serum Osmolality – Urine Osmolality – Urine specific gravity – Urine Sodium Concentration • Additional labs depending on clinical suspicion – TSH, cortisol (Hypothryoidism or Adrenal insufficiency) – Albumin, triglycerides (psuedohyponatremia, cirrhosis), MM – Plasma urea and uric acid – Acid base balance
  18. 18. HYPONATREMIA FLOW CHART Urine Osmolality
  19. 19. PLASMA OSMOLALITY  Distribution of water:- due to osmotic forces  Serum osmol = 2(Na)+ BUN/2.8 + Gluc/18  Normal:- 275 to 290 mosmol/kg  reduced in most hyponatremic patients, because it is primarily determined by the plasma [Na] and accompanying anion  Mechanisms for regulation  If osmol↑ → 1. thirst mechanism, 2. ADH↑  ↓Effective circulating volume→ ADH↑ The American Journal of Medicine, Vol 120 (11A), November 2007
  20. 20.  NORMAL OSMOLALITY (ISO-OSMOLAR)  aka Pseudohyponatremia with hyperlipidemia or hyperproteinemia  HYPEROSMOLAR HYPONATREMIA  Gap (measured - calculated) > 10 indicates osmotic substance that is not Na, Glucose, or BUN  Normal Serum Osm Gap is -14 to +10.  Endogenous substances:-Acetone, Renal Failure, Lactate  Exogenous substances:-Methanol, Ethylene Glycol, Ethanol, Glycine, Mannitol
  21. 21. URINE OSMOLALITY o used to distinguish between impaired water excretion (which is present in almost all cases) and primary polydipsia o Remember: problem is too much water o normal response to hyponatremia is to completely suppress ADH secretion  results in excretion of a maximally dilute urine with an osm below 100 mosmol/kg and a SpG ≤1.003  Most hyponatremic patients have a relatively marked impairment in urinary dilution that is sufficient to maintain the urine Osm > or = 300 mosmol/k
  22. 22. o Values above this level indicate an inability to normally excrete free water (i.e. continued secretion of ADH) o Normal 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 > 1.017 o Thus, UOSM > POSM is not enough to R/O Diabetes Insipidus o
  23. 23. o Urine Osm < 100 with hyponatremia is seen in conditions o Psychogenic Polydipsia o Massive H2O intake overwhelms H2O excretion o Beer 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 intact o Reset osmostat
  24. 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. 25. URINE SPECIFIC GRAVITY USG  Estimates solute concentration of urine on basis of weight as 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, radio contrast, carbenicillin) if present will falsely elevate USG  Nothing falsely lowers USG
  26. 26. URINE SODIUM CONCENTRATION • used to distinguish b/n hypovolemic and euvolemic hyponatremia.  UNa < 30 implies hypovolemic or reduced effective circulation volume  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. 27. o Most hyponatremic patients have a relatively marked impairment in urinary dilution that is sufficient to maintain the urine Osm > or = 300 mosmol/k o serial 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 release  If SIADH urine osmolality remains high but urine Na excretion is promoted by volume expansion and often rises above 40 mEq/L
  28. 28. ADDITIONAL LAB TESTS • FeNA • PLASMA URIC ACID o initial water retention and volume expansion in the SIADH is frequently associated with hypouricemia (due to increased uric acid excretion in the urine). o Uric acid is increased in patients with hypovolemia • PLASMA UREA o Hypervolemia 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. 29. • ACID-BASE AND POTASSIUM BALANCE, • E.g: o Metabolic alkalosis and hypokalemia  Diuretic use or vomiting o Metabolic acidosis and hypokalemia  Diarrhea or laxative abuse, o Metabolic acidosis and hyperkalemia  Adrenal insufficiency • BRAIN NATRIURETIC PEPTIDE:• elevation of BNP provides useful lab evidence of hypervolemia
  31. 31. THERAPY ADVANTAGES DISADVANTAGES Fluid restriction Generally effective; inexpensive Noncompliance Demeclocycline Consistently effective Reversible azotemia and nephrotoxicity; polyuria Lithium Effective in some patients Inconsistent effectiveness; significant adverse effects Loop diuretics (e.g. furosemide) plus increased salt intake Effective in some patients Imbalance between diuretic action and salt ingestion can lead to volume depletion or overload Urea Consistently effective Poor palatability; gastrointestinal adverse effects; development of azotemia at higher doses Hypertonic (3% or 5%) saline with or without coadministration of loop diuretics Corrects serum [Na+] Rate of correction is variable and difficult to control; overly rapid correction is associated with myelinolysis VAPTANS Corrects sodium consistently Expensive, no long term mortality benefit
  32. 32. GENERAL GUIDELINES  Na deficit = 0.6 x wt(kg) x (desired [Na] - actual [Na]) (mmol)  When do you need to Rx quickly?  Acute (<24h) severe (< 120 mEq/L) Hyponatremia  Prevent brain swelling or Rx brain swelling  Symptomatic Hyponatremia (Seizures, coma, etc.)  Alleviate symptoms  Initially treat“Quickly”: 3% NS, 1-2 mEq/L/h until:   Symptoms stop 3-4h elapsed and/or Serum Na has reached 120 mEq/L  Then SLOW down correction to 0.5 mEq/L/h with 0.9% NS or simply fluid restriction.  Aim for overall 24h correction to be < 10-12 mEq/L/d to prevent myelinolysis
  33. 33. Rx Hyponatremia (Example)  Na deficit (mmol) = 0.6 x wt(kg) x (desired [Na] - actual [Na])  60 kg woman, serum Na 107, seizure and other symptoms  Na deficit = 0.6 x (60) x (120 – 107) = 468 mEq  Want to correct at rate 1.5 mEq/L/h: 13/1.5 = 8.7h  468 mEq / 8.7h = 54 mEq/h  3% NaCl has 513 mEq/L of Na  54 mEq/h = 513 mEq x 1L  x = rate of 3% NaCl = 105 cc/h over 8.7h to correct serum Na to 120 mEq/h  Note: Calculations are always at best estimates, and anyone getting hyponatremia corrected by IV saline (0.9% or 3%) needs frequent serum electrolyte monitoring (q1h if on 3NS).
  34. 34. ADROGUE MADIAS FORMULA  Ratio of actual to expected rise in sodium is calculated using the Adrogue-Madias formula.  A value of 1 indicates that the entire increase in serum sodium concentration can be accounted for by the administered hypertonic saline.  In 74.2% of the patients with preinfusion sodium 120 mEq/L, the ratio was >1, indicating that the actual increase exceeded the predicted increase.
  35. 35.  The Adrogue -Madias formula underestimates increase in sodium concentration after hypertonic saline therapy patients with ECF depletion and psychogenic polydipsia  Hypertonic saline should be infused at rates lower than those predicted 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. 36.  Total body water can be determined using Flowing afterglow mass spectrometry FA-MS measurement of . deuterium abundance in breath samples from individuals after ingestion of D2O  Another method of determining total body water percentage (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. 37. Karen E. Yeates, Michael Singer, CMAJ • FEB. 3, 2004; 170 (3)
  38. 38. Adrogue: NEJM, Volume 342(21).May 25, 2000.1581-1589
  40. 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 during follow-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. 41. Am J Cardiol 2005;95(suppl):8B–13B
  42. 42. Am J Cardiol 2005;95(suppl):8B–13B
  43. 43. AJCVOL. 95 (9A) MAY 2, 2005
  44. 44. Am J Cardiol 2009;103:405– 410
  45. 45. MANAGEMENT  Improvement in cardiac function  Control of factors causing exacerbation of cardiac dysfunction  Fluid restriction  Controlled use of diuretics causing free water clearance/avoidance of thiazides  Use of hypertonic saline and aquaretics as indicated
  46. 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 tolvaptan on LV remodeling  EVEREST:-(4133 pts)Tolavaptan had no significant mortality benefit and decrease of hospitalization if drug is continued after discharge.However dyspnoea ,body weight and edema were decreased
  47. 47.  SALT1/2:-multicentre placebo controlled trial on 448 pts with conivaptan in euvolemic/hypervolemic hyponatremia demonstrated benefit  ADVANCE:-343 PTS in NYHA class 2-4 were given conivaptan 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 congestion were given Tolvaptan in addition to furosemide. Euvolemia and normonatremia was better achieved in pts given Tolavaptan  BALANCE:-650 pts multicenter RCT in pts with decompensated Heart Failure. study completed.results not published as yet
  48. 48. Circulation. 2008;118:410-421.)
  49. 49. Circulation. 2008;118:410-421.
  51. 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 cerebral salt wasting and psychogenic polydipsia where the ADH level is appropriate.
  52. 52.  Avoid in pregnant women  Aquaresis delayed 1-2 h  Promotes slow aquaresis/Risk of overly rapid correction of hyponatremia seems low  Adverse Effects:  Thirst 8-16%; dry mouth 4-13%  Hypernatremia develops in 5%  Correction rate > 12 mmol/L/24h-3%
  53. 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 in heart failure
  54. 54.  Possibility of hypotension & variceal bleeding in cirrhotics if given a V1aR blocker  ? Bleeding complications from V2R inhibition in vascular endothelium  Metabolized by CYP3A4  Tachyphylaxis does not seem to occur  Heart failure decreases clearance  Risks v/s benefit?
  55. 55. AJC VOL. 95 (9A) MAY 2, 2005
  56. 56. The AJC Vol 96 (12A) December 19, 2005
  57. 57. PHARMACOKINETICS “The Vaptans” Conivaptan Tolvaptan Convenience Mech Of Action IV non-selective(10:1) PO Selective(29:1) Efficacy/Onset Mean 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/L Mean increases ~6.2 mEq/L (end of 30 day treatment) Lost effect at end of tx At day 4,~4mEq/L increase was achieved Safety Infusion site reactions, phlebitis, cardiac effects Limited to v2 antagonism Rash Drug Interactions Strong CYP3A4 Inhibitor/substrate P-glycoprotein Substrate
  58. 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 of the receptor from the ER to the cell membrane – VRA can bind to misfolded intracellular V2R & improve transport to the cell membrane
  60. 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. 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 of correction in any one particular hour • More common if sodium increases by more than 20 mEq/L in 24 hours
  62. 62. • Very uncommon if sodium increases by 12 mEq/L or less in 24 hours • 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 sodium and usually either irreversible or only partially reversible The AJM, Vol 120 (11A), November 2007
  63. 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. 64. PATHOPHYSIOLOGY  Exact pathophysiology unknown.  Possibly due to disturbance of blood brain barrier and damage by cytokines  Or due to influx of potassium triggering apoptosis  brain regions that are slowest to recover osmolytes are the most severely affectedby myelinolysis  Uremia protects against myelinolysis
  65. 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. 66. TREATMENT  No effective therapy  Case reports of improvement with aggressive plasmapheresis immediately after diagnosis  Case reports of treatment with thyrotropin-releasing hormone  infusion of myoinositol (a major osmolyte lost in the adaptation to hyponatremia)protects against mortality and myelinolysis from rapid correctionof hyponatremia Am J Med. 2006;119(suppl 1):S12–S16
  67. 67. PROGNOSIS  Changes can be irreversible  Old statistics shows 50% mortality  Milder cases now diagnosed more often
  69. 69. TAKE HOME MESSAGE  Hyponatremia needs to be taken seriously in patients with 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. 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 method for hyponatremia correction with no long term mortality benefit  Thiazide diuretics cause hyponatremia much more commonly than loop diuretics. Onset is earlier and is predominantly seen in elderly females.
  71. 71.  Overzealous correction of hyponatremia needs to be avoided 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. 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 thrombosis Neurologic Guillain-Barré 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. 73.
  74. 74. Syndrome of Inappropriate ADH Release (Bartter’s 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 <20 mEq/liter if the patient is volume depleted or on low sodium intake.