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Hyponatremia in heart failure

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Hyponatremia in HF

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Hyponatremia in heart failure

  1. 1. OUTLINE  Introduction  Pathophysiology Of Hyponatremia  Prognostic Significance Of Hyponatremia  Clinical Features  Approach To Hyponatremia  Differentiating Depletional Vs Dilutional Hyponatremia  Management  Conclusion
  2. 2. INTRODUCTION  Hyponatremia serum sodium (Na) concentration <135 mEq/l most common electrolyte disorder in hospitalized patients with decompensated heart failure.  Both admission and hospital acquired hyponatremia are associated with an increased risk for adverse outcomes.
  3. 3.  Approximately 20–30% of patients with chronic heart failure NYHA) classes III and IV have hyponatraemia .  It is associated with more severe heart failure and an increased risk of death, independent of other comorbid conditions .  the incidence of hospital-acquired hyponatremia during decongestive treatment for ADHF is 15% to 25%  It is important to differentiate dilutional from depletional hyponatremia
  4. 4.  Even mild hyponatremia among patients with ADHF, regardless of ventricular function, is associated with increased in-hospital and postdischarge mortality, prolonged hospital length of stay, and frequent rehospitalization.
  5. 5. Classification of hyponatremia based on sodium concentration hyponatraemia Mild --- 130 and 135 mmol/L moderate ---125 and 129 mmol/L Profound --- < 125 mmol/L
  6. 6. plasma osmolality  are primarily determined by changes in the serum concentration of sodium and its associated anions.  Normal value: 285 -295 mOsm/l.  Total osmolality is defined as the concentration of all solutes in a given weight of water (mOsm/kg), regardless of whether or not the osmoles can move across biological membranes.  Effective osmolality or tonicity refers to the number of osmoles that contribute water movement between the intracellular and extracellular compartment. function of the relative solute permeability properties
  7. 7. Dilutional vs depletional hyponatremia
  8. 8. PATHOPHYSIOLOGY OF HYPONATREMIA DILUTIONAL HYPONATREMIA  hyponatremia due to impaired water excretion rather than Na depletion  Causes of increased water retention are  increased nonosmotic release of arginine vasopressin (AVP)  insufficient tubular flow through diluting (distal) segments of the nephron
  9. 9.  The ability of the kidneys to excrete free water depend on 1) the relatively low water permeability of the distal segment of nephron 2) the amount of tubular fluid in the distal nephron
  10. 10. AVP  key regulator of water homeostasis.  AVP is synthesized in large-diameter neurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus.  After axonal transport into nerve terminals within the posterior lobe of the pituitary  AVP is released into the bloodstream in response to plasma Hypertonicity from the posterior lobe of pituitary  Normally circulating AVP levels are very low (1 pg/ml) because of its rapid degradation and excretion by the liver and kidneys (t1/2 = 15 -20 min)  hepatic dysfunction and renal insufficiency causes increased plasma levels of AVP in HF
  11. 11. Mechanism of action of AVP Antidiuresis effect  Stimulate high-affinity V2 receptors in the collecting ducts of the nephron increases aquaporin-2 channels on the luminal side of these collecting ducts 
  12. 12.  At higher concentrations stimulate low-affinity V1a receptor, which is expressed in the liver, collecting ducts, and vasa recta of the nephron, enhances hypertonicity in the renal interstitium by hepatic urea production, improved medullary urea reabsorption in the collecting ducts, reduced blood flow through the vasa recta
  13. 13.  Diuretic action (minimal effect)  another effect of V1a receptor stimulation is  promotion of prostaglandin synthesis in the collecting ducts which counteracts V2 effects on aquaporin-2.  This latter effect may explain why some heart failure patients demonstrate a normal response to water loading, with production of adequately diluted urine, despite having elevated plasma AVP levels
  14. 14. Nonosmotic AVP release in heart failure decreased effective circulatory volume Baroreceptor activitation supressed sympathetic overdrive, increase angiotensin II, nonosmotic AVP release increase the sensitivity of osmotic AVP release increase thirst
  15. 15. Osmotic AVP release: Neurohumoral activation increases the amount of AVP release for any given plasma osmolality it moves the set-point of total AVP suppression to a lower plasma osmolality, hence promoting hypotonicity.
  16. 16. osmotic AVP release, increases linearly and with very small changes in serum osmolality, nonosmotic AVP release is exponential
  17. 17. Distribution of Plasma AVP levels in the patients with HF Funayama, H,et al., Kidney Int. 2004, 66, 1387–1392.;
  18. 18. Insufficient tubular flow through the distal nephron  urine dilution depends on Distal tubular function of the nephron (i.e., distal convoluted tubules and collecting ducts).  These segments have low water permeability so free water excretion is achieved by continued solute reabsorption through  thiazide-sensitive Na/Cl co transporter  aldosterone-sensitive epithelial sodium channels(ENaCs)
  19. 19.  low tubular flow less sodium is reabsorbed by ENaCs , irrespective of aldosterone levels more sodium is retained in the tubular lumen, free water excretion is restricted
  20. 20. Maximal diuresis in HF cases
  21. 21. DEPLETIONAL HYPONATREMIA  Na depletion is relatively rare in heart failure Causes combination of very low dietary sodium intake and exaggerated losses osmotic diuresis because of hyperglycemia Loop diuretic-induced hyponatremia
  22. 22. Loop diuretics  Thick ascending limb of Henle’s loop action  Na/K/ Cl transport -- lead to hypertonicity of the renal interstitium  low water permeability  Loop diuretics block the Na/K/Cl cotransporter and interfereing with the generation of hypertonicity in the renal interstitium and decreasing the osmotic gradient that promotes water reabsorption.  increased diuresis (relative protection against hyponatremia)
  23. 23. Loop diuretics causing hyponatremia  In profound volume depletion with strong neurohumoral activation and compromised renal blood flow, loop diuretic agents will fail to elicit adequate water diuresis.  GFR and distal nephron flow will become depressed in the presence of strongly up-regulated AVP, causing hyponatremia development
  24. 24. Thiazide –type diuretics & Mineralocorticoid receptor antagonists (MRAs)  Thiazide type diuretics act on Na/Cl cotransporters, in the distal convoluted tubules  MRAs act on ENaCs in the collecting ducts .  As both have a negligible contribution to the hypertonicity achieved in the renal interstitium, these agents do not interfere with the water reabsorption gradient.  Na and Cl reabsorption in the relatively water-impermeable distal nephron is the mechanism of urinary dilution, this process is impaired, resulting in a higher urinary tonicity and, hence, lower free water excretion even without pronounced hypovolemia
  25. 25.  so it is better avoid their use in any patient with hyponatremia and to prefer a proximally acting diuretic (e.g., acetazolamide) in cases with volume overload and diuretic resistance
  26. 26. Potassium and magnesium depletion  Loop and thiazide-type diuretic agents are a major cause of potassium and magnesium wasting in HF.  higher risk of arrhythmic death  potassium depletion shifts Na towards the intracellular compartment to preserve cellular volume homeostasis, contribute to development of hyponatremia  magnesium is critical for functioning of the Na/potassium ATPase that pumps Na out of cells --- hypomagnesemia may also exacerbate extracellular Na depletion.
  27. 27. Hyponatremia in ADHF: Prognostic Significance  Regardless of the ventricular function (depressed or preserved), hyponatremia in HF is associated with adverse short-term and long-term morbidity and mortality  The one exception to this finding is when hyponatremia occurs in the setting of hyperglycemia. serum Na has no prognostic significance.
  28. 28. Lee WH, Packer M. Circulation 1986; 73:257.
  29. 29. Hyponatremia with Hyperkalemia in advance heart failure  Patients whose serum Na levels < 125 meq/L solely as a result of heart failure usually have near end-stage disease and also frequently have hyperkalemia.  Distal sodium and water delivery are so low in advanced cardiac disease that potassium excretion (primarily dependent upon distal potassium secretion) falls below the level of intake.
  30. 30.  Hyponatremic patients are also at increased risk for worsening of cardiac and renal function after the administration of NSAIDs  In this setting of advanced heart failure with a high level of circulating vasoconstrictors, there is increased renal secretion of vasodilator prostaglandins which act to preserve renal perfusion and to lower SVR  Decreasing prostaglandin synthesis with an NSAID in such a patient is likely to cause renal ischemia, a rise in the serum creatinine concentration, and a fall in cardiac output due to increased afterload
  31. 31. Clinical features  Because of a difference in effective osmolality between brain and plasma water moves from the extracellular to the intracellular compartment leading swelling of brain cells  Severe symptoms of hyponatraemia are caused by brain oedema and increased intracranial pressure.
  32. 32.  Brain oedema occur more frequently when hyponatraemia develops in< 48 h  brain needs approximately 48 h to adapt to a hypotonic environment, achieved mainly by extruding Na,K,Cl and organic osmoles from its cells , in an attempt to restore the brain volume  This process takes about 24–48 hrs
  33. 33. Classification based on duration and speed of development  Development of hyponatremia < 48 h -- acute hyponatremia > 48hrs -- chronic hyponatraemia duration unknown-- chronic hyponatremia
  34. 34.  once adaptation is completed, brain cells can again sustain damage if the serum sodium concentration increases too rapidly.  Breakdown of the myelin sheath insulating individual neurons can result in what is called the osmotic demyelination syndrome .  It is important to distinguish between acute and chronic hyponatraemia  acute hyponatremia cause brain oedema  Rapid correction of hyponatremia in chronic hyponatremia cause osmotic demyelination .
  35. 35. Clinical manifestations of acute hyponatremia  Nausea and malaise -- earliest findings(Na= 125 to 130 meq/L)  Na < 115-120meq/L Headache lethargy obtundation seizures coma respiratory arrest
  36. 36. Symptoms of chronic hyponatraemia  The degree of cerebral edema and the severity of neurologic symptoms are much less with chronic hyponatremia  The cerebral adaptation permits patients with chronic hyponatremia to appear to be asymptomatic despite a serum sodium concentration below 120 mmol/L.  When symptoms occur they are nonspecific like  Fatigue & lethargy  Nausea  Dizziness  Gait disturbances  Forgetfulness  Confusion  Muscle cramp  osteoporosis (loss of bone Na)
  37. 37. APPROACH TO HYPONATREMIA IN HF
  38. 38. assess plasma osmolality  Calculation  Posm (mmol/kg) = (2 x S. Na) + (S.glucose]/18) + (BUN/2.8)  Indications: serum Na < 130meq/l symptomatic hyponatremia  reference value: 285 -295 mOsm/l.
  39. 39.  If Plasma osmolality ≥285 mOsm/L  Pseudohyponatremia Falsely low serum Na+ concentrations caused by laboratory artefacts (elevated triglyceride/cholesterol levels)  Increased plasma osmolality caused by hyperglycemia, urea hyperosmolar radio-contrast media
  40. 40. Estimates of the serum sodium concentration corrected for the presence of hyperglycaemia serum Na concentration decreases by approximately 2.4 mEq/l per 100 mg/dl increase in serum glucose above a standard serum glucose concentration of 100 mg/dL.
  41. 41. Differentiate Between Depletional And Dilutional Hyponatremia.  Depletional hyponatremia Clinical presentation: Hypovolemia  Caused by:  Use of powerful Na+-wasting loop diuretics  Use of thiazide-type or combinational diuretics  Salt-restricted diets  Acute gastro-intestinal or third-space losses
  42. 42.  Dilutional hyponatremia  Clinical presentation: Hypervolemia (Edema, ascites, pleural effusion) Caused by:  Non-osmotic release of arginine vasopressin (AVP)  Insufficient tubular flow through diluting segments of the distal nephron
  43. 43. parameters to diagnose causes of hypotonic hyponatremia Assess urine osmolality urine osmolality <100 mOsm/l --depletional hyponatremia >100 mOsm/l -- dilutional hyponatremia
  44. 44. Treatment of hyponatremia  There is no evidence that correction of hyponatremia improves the hemodynamic abnormalities associated with the severe underlying chronic heart failure or that it improves clinical outcomes.  indications severe hyponatremia < 120 meq/L) symptomatic hyponatremia
  45. 45. Treatment of hyponatremia  In any patient with hypotonic hyponatremia, Avoid thiazide-type diuretic agents, Mineralocorticoid receptor antagonist ENaC blockers (e.g., amiloride) These interfere directly with the kidneys’ capacity to produce hypotonic urine.  Potassium and Magnesium stores should be replenished if serum levels are low. AIM serum K > 4 mEq/l Mg > 1.7 mEq/l
  46. 46. What is the optimal rate of correction of Hyponatremia ?  Is hyponatremia acute or chronic Does the patient have severe symptoms
  47. 47. Acute versus chronic hyponatremia  Most commonly the duration of hyponatremia is often unknown  Patients with chronic hyponatremia may develop acute reductions in the serum Na concentration  The clinical approach to the patient should be primarily determined by the severity of symptoms
  48. 48. How aggressive the hyponatremia should be corrected ?  Severe symptoms – Seizures, obtundation, respiratory distress, coma  infusion of hypertonic saline to increase serum sodium by 1-2 mEq/L per hour until symptoms subside. The critical link of hypervolemia and hyponatremia in heart failure and the potential role of AVP antagonists.Ghali JK, Tam SW .J Card Fail. 2010 May; 16(5):419-31.
  49. 49. TREATMENT OF DEPLETIONAL HYPONATREMIA  Isotonic saline  Hypertonic saline (normovolemic hyponatremia)  correct the serum Na concentration 5 mEq/l per day 10 mEq/l per day if s.Na <125 mEq/l  Correction of Na >10 mEq/l in 24 h should be avoided because of the risk of central pontinemyelinolysis
  50. 50.  change in serum Na concentration with 1 l of infusate TBW = α x body weight (kg) α = 0.6 (children & nonelderly men) 0.5 ( nonelderly women& elderly men) 0.45 ( elderly women) Inf : potassium should be supplemented along with normal saline to increase Na concentration . Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342:1493–9.
  51. 51. Adrogue: NEJM, Volume 342(21).May 25, 2000.1581-1589
  52. 52. TREATMENT OF ACUTE SYMPTOMATIC HYPONATREMIA  In acute symptomatic hyponatremia with severe neurologic symptoms (for example seizures and/or obtundation) immediate treatment is required to reduce the risk of neurologic complications. Recommended treatment Severe symptomatic patients  100 mL of 3% NaCl infused intravenously over 10 minutes × 3 as needed Mild to moderate symptoms, in patients at low risk for herniation: 3% NaCl infused at 0.5–2 mL/kg/h Verbalis JG, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013 Oct. 126
  53. 53. TREATMENT OF CHRONIC HYPONATREMIA  To avoid osmotic demyelination syndrome (ODS) in patients with chronic hyponatremia (known duration >48 hours), the recommendations include the following :  Minimum correction of serum sodium by 4-8 mmol/L per day, with a lower goal of 4-6 mmol/L per day if the risk of ODS is high  For patients at high risk of ODS: maximum correction of 8 mmol/L in any 24-hour period  For patients at normal risk of ODS: maximum correction of 10- 12 mmol/L in any 24-hour period; 18 mmol/L in any 48-hour period Verbalis JG, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013 Oct. 126
  54. 54. Central pontine myelinolysis  is a neurological disease caused by the rapid rise in serum sodium levels during treatment in individuals with hyponatremia.  It is characterised by severe damage of the myelin sheath of nerve cells in the pons area in the brainstem, leading to confusion, horizontal gaze paralysis, spastic quadriplegia, dysphagia, dysarthria .  The neurologic deterioration occurs 48-72 h after the rapid correction of hyponatremia.  Death is common, but if the patient survives chronic neurologic deficits including locked-in syndrome and spastic quadriparesis are usually observed  Brain magnetic resonance imaging is used to reveal the demyelination in the brainstem pons.
  55. 55. Central pontine myelinolysis
  56. 56. ACUTE TREATMENT OF DILUTIONAL HYPONATREMIA  aim is to promote free water excretion prevent a positive free water balance  Free water excretion – increasing flow to distal nephron AVP levels should be lowered, or effects should be antagonized
  57. 57. free water excretion  Loop diuretic agents reduce hypertonicity of the renal interstitium increases the amount of tubular fluid presented to the distal nephron
  58. 58.  Diuresis begins 30-60 min with oral vs 5 min with IV administration
  59. 59. Free water diuresis with hypertonic saline with loop diuretics  Hypertonic saline augments intravascular filling, decreases vascular resistance, increases preload, improves cardiac performance, and suppresses vasoconstrictor hormones  increase urodilatin, a natriuretic renal peptide,which increases urine flow and Na excretion.  Hypertonic saline increase renal blood flow, may facilitate the action of furosemide and help overcome the established furosemide resistance.  Indicated in refractory heart failure with hyponatremia .
  60. 60. Acetazolamide  reversible inhibitor of the carbonic anhydrase enzyme  increased renal excretion of sodium, potassium, bicarbonate, and water  combining with loop diuretic agents and acetazolamide ensures minimal tubular Na reabsorption proximal from the macula densa and maximal flow through the distal nephron  Useful in loop diuretic resistance in HF
  61. 61.  AVP antagonists directly promote free water excretion by decreasing in aquaporin-2 channel availability in the collecting ducts of the nephron
  62. 62. Trials on vaptans role in AHF
  63. 63.  Conivaptan is restricted to the shortterm treatment (of up to 4 days) for hospitalised patients. The loading dose is 20 mg over 30 minutes, followed by a continuous infusion of 20 -40mg/day.  Tolvaptan starting dose 7.5 mg once daily; maximum dose 30-60 mg
  64. 64. Tolvaptan  avoid use in patients with underlying liver & renal failure .  patients treated with both tolvaptan and digoxin should be monitored for excessive digoxin effects  Its use is contraindicated if the patient is unable to sense or appropriately respond to thirst.  If the patient has limited capacity to drink (e.g. oral/GI disease), glucose 5% may need to be initiated along with initiation of tolvaptan.
  65. 65.  serum sodium is monitored frequently (4,6,12hrly ) on day 1 of therapy ,to exclude rapid correction of hyponatraemia (if by 6hrs, the sodium has risen by 6 mmol/L then it is likely to rise by more than 10 mmol/L by hour 24. In such cases, water orally or glucose 5% intravenously should be given at 6hrs of treatment to slow down the rate of increase in serum sodium)  should be discontinued once symptoms resolve AND/OR serum sodium normalises.
  66. 66. LONG-TERM MANAGEMENT OF HYPOTONIC DILUTIONAL HYPONATREMIA  Fluid restriction :Restriction of fluid intake to 1000 mL/day is the least invasive therapy, and, consequently, a first-line treatment for patients with hypervolemic hyponatremia.  When fluid intake is restricted to 800 mL/day, the serum sodium concentration is increased by 1 to 2 mmol/L per day
  67. 67.  Maintain positive free water balance  AVP antagonists – better for short term treatment  Renin-angiotensin system blockers increase renal blood flow and decrease proximal tubular sodium reabsorption
  68. 68.  Inotropes and vasodilator therapy hypothesis :Increasing the effective circulatory volume in heart failure is expected to result in less nonosmotic AVP release and better renal blood flow  afterload reduction increase the effective circulatory volume nitroprusside (IV) hydralazine and nitrates (oral) new drug under trials--- serelaxin  effects of both inotropes and vasodilator therapy on hyponatremia remain insufficiently elucidated.
  69. 69. Conclusions  Differentiate depltional from dilutional hyponatremia by measuring plasma osmolality, urine osmolality,urine sodium levels  Avoid thiazides and MRAs and amiloride in hyponatremia  Correct hypokalemia and hypomagnesemia.  Agressive correction of hyponatremia only in profund symptomatic hyponatremia.  Saline infusion in depletional hyponatremia  small volume of Hypertonic saline with high dose of loop diuretics in refractory heart failure with hyponatremia  Use of Vaptans in symptomatic hyponatremia for short period.
  70. 70. THANK U

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