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

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Presentation on theme: "Hyponatremia Charles Cline MD, PhD Medical Director Otsuka Pharma Scandinavia."— Presentation transcript:

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 (Samsca TM )

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% incidence 1,2 [Na + ] <130: 2-4% incidence 1,3,4 1. Flear et al. Lancet 2:26-31, Hawkins. Clin Chim Acta 337: , Natkunam et al. J Med 22:83-96, Berghmans et al. Support Care Cancer 8: , 2000

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

5 Control of Sodium Balance P-Na + = mmol/l Na +,Cl -, HCO3 - = 86% extracellular fluid osmolality P-Osmol = 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 V 2 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 mmol/l = Mild hyponatremia: Usually asymptomatic < mmol/l = Moderate hyponatremia: Nausea, malaise < 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 life-threatening, usually acute symptomatic but less impaired; usually chronic

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

17 Symptoms 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 AB

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 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: , 1979 Central Pontine Myelinolysis

21 Examination in patient with hyponatremia 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

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 100 mosm/kg), in a euvolaemic patient after exclusion of hypothyroidism and glucocorticoid deficiency).

23 Robertson et al. Am J Med 72: , 1982 P-AVP levels are inappropriately elevated in most patients with SIADH Plasma Osmolality (mOsm/kg) Plasma Vasopressin (pg/mL) Normal Range

24 Causes of SIADH CancersPulmonary diseases CNS disordersDrugsOther Carcinomas (eg. lung, oropharynx, gastro-intestinal tract, genitourinary tract) Lymphomas Sarcomas Infections (eg. pneumonia, abscess, tuberculosis) Asthma Cystic fibrosis COPD Acute respiratory failure Positive-pressure ventilation Infection (eg. encephalitis, meningitis) Bleeding and masses (eg. SAH, brain tumours, head trauma) Other (eg. multiple sclerosis, Guillain- Barre syndrome) Stimulation of vasopressin release or enhancement of its action (eg. chlorpropamide, SSRIs, carbamazepine, anti-psychotic drugs Vasopressin analogues (eg. desmopressin, oxytocin, vasopressin) Hereditary Idiopathic Transient (eg. endurance exercise, general anaesthesia) AIDS Ellison DH, et al. N Engl J Med. 2007;356: Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21. AIDS = Acquired immune deficiency syndrome; CNS = Central nervous system; COPD = Chronic obstructive pulmonary disease; SAH = Subarachnoid haemorrhage; SSRIs = selective serotonin reuptake inhibitors

25 Diagnosing SIADH Essential and supplemental diagnostic criteria for SIADH Essential 1,2 Hyponatraemia < 135 mmol/l Plasma hypo-osmolality < 275 mOsm/Kg Urine osmolality > 100 mOsm/Kg Clinical euvolaemia No clinical signs of hypovolaemia (orthostatic decreases in blood pressure, tachycardia, decreased skin turgor, dry mucous membranes) No clinical signs of hypervolaemia (oedema, ascites) Increased urinary sodium excretion with normal salt and water intake 30 mmol/l Absence of other potential causes of euvolaemic hypo-osmolality Exclude hypothyroidism, hypocortisolism, renal disease and recent diuretic use Supplemental 1,3 Failure to correct hyponatraemia after 0.9% saline infusion Correction of hyponatraemia through fluid restriction Abnormal water load test over 4 hours Plasma vasopressin inappropriately elevated relative to plasma osmolality Ellison DH, et al. N Engl J Med. 2007;356: Janicic N, et al. Endocrinol Metab Clin N Am. 2003;32: Verbalis JG, et al. Am J Med. 2007;120(11A):S1-S21.

26 Types of SIADH Plasma osmolality (mOsm/kg) Plasma AVP (pmol/l) A B C

27 Assessing and managing hyponatremia

28 Disadvantages of conventional treatments TreatmentMechanism 1-3 Disadvantage 1-3 Fluid restriction Induces negative water balance Increases plasma osmolality and plasma sodium Poor patient compliance Slow onset of action (2-3 days, may prevent discharge) Hypertonic saline Increases water excretion and replaces sodiumDifficult to administer (IV) Complex calculations needed to estimate appropriate rate of sodium correction Risk of overly rapid sodium correction leading to osmotic demyelination syndrome Demeclocycline Impairs vasopressin action at renal tubules Induces nephrogenic diabetes insipidus Unpredictable response (may cause hypernatraemia) Renal and liver toxicities Slow onset of action (3-4 days) Urea Decreases sodium excretionRenal and liver toxicities Poor compliance due to bad taste Lithium Impairs vasopressin action at renal tubulesInconsistent results Rarely used due to toxicity Loop diuretics Increase water excretion by inhibiting sodium and chloride re-absorption in the loop of Henle and distal tubule Electrolyte imbalance (eg. hypokalaemia, exacerbation of hyponatraemia) 1. Verbalis J, et al. Am J Med. 2007; 120(11 Suppl 1): S Douglas I. Cleve Clin J Med. 2006; 73 Suppl 3: S Ellison DH, et al. N Engl J Med. 2007;356:

29 SIADH Intracerebral aneurysm plasma Na + mmols/L 3% NaClN-saline Fluid restrict


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