Hyponatremia

1. Hyponatremia Charles Cline MD, PhD Medical Director Otsuka Pharma Scandinavia

2. Hyponatremia • Physiology of salt & water regulation • Classification • Pathophysiology • Symptoms and diagnosis • SIADH • Tolvaptan (SamscaTM)

3. Hyponatremia is the most common electrolyte disorder of hospitalized patients, with incidences from 2-28% depending on the serum [Na+] level used to define hyponatremia: [Na+] <135: 13-28% incidence1,2 [Na+] <130: 2-4% incidence1,3,4 1. Flear et al. Lancet 2:26-31, 1981 2. Hawkins. Clin Chim Acta 337:169-172, 2003 3. Natkunam et al. J Med 22:83-96, 1991 4. Berghmans et al. Support Care Cancer 8:192-197, 2000

4. VP is synthesised in the hypothalamus, stored in and released from the posterior pituitary • Osmoreceptors • Pituitary • Posterior • lobe • Baroreceptors Vasopressin Secretion

5. Control of Sodium Balance • P-Na+ = 135-145 mmol/l • Na+,Cl-, HCO3-= 86% extracellular fluid osmolality • P-Osmol = 285-295 mosm/kg • P-Osmol = 2× [Na]mmol/l + [urea]mmol.l + [glucose]mmol/l • Main determinant of P-Na+ is plasma water content • Water content = intake + “insensible” losses + urinary dilution • Urinary dilution most important, determined by vasopressin

6. The Kidney

7. Vasopressin V2 receptor activation Free water resorbtion

8. Signaling mechanisms involved in aquaporin-2 (AQP-2) regulation

9. Classification of hyponatremia • Hypovolemic • Hypervolemic • Euvolemic (normovolemic)

10. Hypovolemic Extrarenal loss, urine sodium <30 mmol/l • Dermal losses, such as burns, sweating • Gastrointestinal losses, such as vomiting, diarrhoea • Pancreatitis Renal loss, urine sodium >30 mmol/l • Diuretics • Salt wasting nephropathy • Cerebral salt wasting • Mineralocorticoid deficiency (Addison's disease)

11. Hypervolemic* Urine sodium <30 mmol/l • Congestive cardiac failure • Cirrhosis with ascites • Nephrotic syndrome Urine sodium >30 mmol/l • Chronic renal failure *Paradoxical retention of sodium and water despite a total body excess of each; baroreceptors in the arterial circulation perceive hypoperfusion, triggering an increase in vasopressin release and net water retention

12. Euvolemic Urine sodium >30 mmol/l • Syndrome of inappropriate antidiuretic hormone secretion (SIADH)† • Hypothyroidism • Hypopituitarism (glucocorticoid deficiency) • Water intoxication: Primary polydipsia • Excessive administration of parenteral hypotonic fluids • Post-transurethral prostatectomy †SIADH is a diagnosis of exclusion

13. hyponatremia can be caused by depletion from electrolyte losses in excess of water, or by dilution from retained water

14. Levels of hyponatremia • 130-135 mmol/l = Mild hyponatremia: Usually asymptomatic • <125-130 mmol/l = Moderate hyponatremia: Nausea, malaise • <115-120 mmol/l = Severe hyponatremia: Headache, lethargy, restlessness, disorientation follow, as the sodium concentration falls below • Severe and rapidly evolving hyponatremia: seizure, coma, permanent brain damage, respiratory arrest, brain stem herniation, death

15. Hyponatremia - neurological manifestations • headache • irritability • nausea/vomiting • mental slowing • confusion/delerium • disorientation • stupor/coma • convulsions • respiratory arrest symptomatic but less impaired; usually chronic life-threatening, usually acute

16. Neurological symptoms and P-Na concentrations Arieff et al., Medicine 55:121-129, 1976

17. Symptoms A B • Related to severity and rapidity of fall in P-Na • Creates osmotic gradient between extracellular and intracellular fluid in brain cells, causing movement of water into cells, increasing intracellular volume, and resulting in tissue edema, raised intracranial pressure, and neurological symptoms

18. Adaptive response to hyponatremia • Rapid adaptation hours to days transport out of NaCl and K • Slow adaptation loss of organic solutes including glutamate, taurine, myo-inositol, and glutamine from intracellular to extracellular compartments. Induces water loss and ameliorates brain swelling

19. Central Pontine Myelinolysis • Blood-brain barrier becomes permeable, rapid correction of hyponatremia and allows complement mediated oligodendrocyte toxicity (can occur widely in the brain) • Alcoholics with malnutrition, premenopausal or elderly women on thiazide diuretics, and patients with hypokalaemia or burns are at increased risk • Neurological injury is typically delayed 2 to 6 days after elevation of Na concentration • Neurological symptoms generally irreversible (dysarthria, dysphagia, spastic paraparesis, lethargy, seizures, coma, death)

20. Central Pontine Myelinolysis White areas in the middle of the pons indicate massive demyelination of descending axons (corticobulbar and corticospinal tracts), usually associated with overly rapid correction of hyponatremia using hypertonic saline Wright, Laureno, Victor . Brain 102:361-385, 1979

21. Evaluation of volume status Skin turgor Pulse rate Postural blood pressure Jugular venous pressure Consider central venous pressure monitoring Examination of fluid balance charts General examination for underlying illness Congestive cardiac failure Cirrhosis Nephrotic syndrome Addison's disease Hypopituitarism Hypothyroidism Examination in patient with hyponatremia

22. Investigations in patient with hyponatremia • Urinary sodium • Plasma glucose and lipids* • Renal function • Thyroid function • Peak cortisol during short synacthen test† • Plasma and urine osmolality‡ • If indicated: chest x ray, and computed tomography and magnetic resonance imaging of head and thorax *Pseudohyponatraemia due to artefactual reduction in plasma sodium in the presence of marked elevation of plasma lipids or proteins should no longer be seen with the measurement of sodium by ion specific electrodes; hyperglycaemia causes true hyponatraemia, irrespective of laboratory method. †May be unhelpful in pituitary apoplexy, in which patients may still “pass” the test. ‡For SIADH: plasma osmolality < 270 mosm/kg with inappropriate urinary concentration (> 100 mosm/kg), in a euvolaemic patient after exclusion of hypothyroidism and glucocorticoid deficiency).

23. P-AVP levels are inappropriately elevated in most patients with SIADH 11 10 9 8 Normal Range 7 Plasma Vasopressin (pg/mL) 6 5 4 3 2 1 0 230 240 250 260 270 280 290 300 310 Plasma Osmolality (mOsm/kg) Robertson et al. Am J Med 72:339-353, 1982

24. Causes of SIADH AIDS = Acquired immune deficiency syndrome; CNS = Central nervous system; COPD = Chronic obstructive pulmonary disease; SAH = Subarachnoid haemorrhage; SSRIs = selective serotonin reuptake inhibitors Ellison DH, et al. N Engl J Med. 2007;356:2064-72. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.

25. Diagnosing SIADH Ellison DH, et al. N Engl J Med. 2007;356:2064-2072. Janicic N, et al. Endocrinol Metab Clin N Am. 2003;32:459-481. Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.

26. 20 15 10 A Plasma AVP (pmol/l) 5 B C 280 290 300 310 320 Plasma osmolality (mOsm/kg) Types of SIADH

27. Assessing and managing hyponatremia

28. Disadvantages of conventional treatments 28 3. Ellison DH, et al. N Engl J Med. 2007;356:2064-2072. 1. Verbalis J, et al. Am J Med. 2007; 120(11 Suppl 1): S1-21. 2. Douglas I. Cleve Clin J Med. 2006; 73 Suppl 3: S4-12.

29. 135 125 120 115 Fluid restrict N-saline 3% NaCl plasma Na+mmols/L SIADHIntracerebralaneurysm