Sodium and Water: What Laboratory Scientists Need to Know

1. Sodium and Water: What Laboratory Scientists Need to Know Graham Jones Staff Specialist in Chemical Pathology St Vincent’s Hospital, Sydney Presented RCPA/AACB Chemical Pathology training Course, February 2004, Adelaide

2. Objectives • Measurement • Physiology • Pathology • Lab-based knowledge

3. Sodium Measurement • Most Australian Laboratories use Ion Sensitive Electrodes (ISE) • May be direct or indirect • Indirect • Dilution of the sample • Most automated analysers • Affected by lipid and protein concentrations • Direct • No dilution of the sample • Blood gas machines • Vitros analysers

4. What we measure • Analyte: Sodium • Measurand: • activity of sodium ions per volume of sample (indirect) • Activity of sodium ions per mass of water* (concentration) * expressed per volume of plasma

5. Sodium Measurement: Interferences • Analytical • Electrodes are very specific • In the presence of increased amounts of non-aqueous components we get reduced values with indirect methods (pseudohyponatraemia) • Pre-analytical • Drip-arm • Wrong patient • Gross haemolysis (dilution with intracellular fluid)

6. Drip arm contamination • Common diluents: • Normal saline: 154 mmol/L Na and Cl • 5% dextrose: 278 mmol/L glucose • 4% & 1/5th saline: 222 mmol/L gluc, 31 Na & Cl • Results tend to values in diluent • eg Na of 170 unlikely to be drip-arm • Osmolality tends to be normal • Measuring glucose, albumin and protein helpful

7. Artefacts: examples * * * * * * * * * * Questions: Could it be pathology? Could it be artefact?

8. How good are we • Average analytical CV about 1% • Gives SD of about 1.4 mmol/L for normal result • 95% of results in a 5.6 mmol/L range (+/- 2SD) • Biological variation • Within person 0.6 % • Between person variation 0.6% • Acceptable CV is <0.75 x within person CV • Not acceptable!!

9. Water Measurement • Clinical • Weight (change in weight) • Physical examination: pulse, blood pressure, JVP, lung auscultation, oedema • Concentration of blood components • High albumin#, high sodium may mean low water content of samples. • # or prolonged tourniquet for albumin • Low albumin or low sodium may mean high water concentration of samples • 5% dehydration highly significant

10. Water and electrolytes: Other Tests • Serum • Urea, Creatinine • Glucose • Osmolality (and osmolar gap) • Albumin, Total Protein • Lipids • Urea • Sodium • Osmolality • Creatinine

11. Physiology

12. Body Sodium • Sodium: major extracellular cation • Approx 10 mmol/L intracellularly • 140 mmol/L extracellularly • Intake: 100 - 200 mmol/day • Excretion: • Faecal: 10 mmol/d • Sweat: 10-20 mmol/d • Renal: the rest (ie matches intake) • Equally distributed in extracellular fluid • ie drain fluid • except urine and gastro-intestinal fluid!

13. Sodium and Water • Sodium and Water homeostasis are inextricably linked • “where sodium goes, water follows” • Measure sodium concentration • Affected by changes in water and sodium • Clinical effects due to movement of water in and out of cells

14. Salt and Water regulation • Water • Thirst (regulates input) • Vasopressin (ADH) (regulates output) • Sodium • Renin-Angiotensin-Aldosterone (RAA) • Natriuretic peptides • Both regulate output

15. Vasopressin (ADH) • Hormone from Posterior pituitary • Released in response to high osmolality • Released in response to low volume • Low volume over-rides low osmolality • Increases permeability of kidney distal tubule • Controls renal WATER excretion • Low ADH -> high urine volume, low urine osmo • High ADH -> low urine volume, high urine osmo • Also potent vasocontrictor

16. Vasopressin (ADH) Hypernatraemia(Increased osmolality) Dehydration Reduced BP ADH Release Reduced renal water loss Vasocontriction ConcentratedUrine Euvolaemia

17. Renin-angiotensin-aldosterone (RAA) • Low renal perfusion -> renin release • eg hypovolaemia, heart failure, shock. • Renin converts Angiotensinogen to Angiotensin I • ACE converts AI to AII • AII releases Aldosterone from adrenal gland • Aldosterone acts in proximal tubule • resorbs sodium, excretes potassium • Controls urine SODIUM excretion

18. RAA Response to Dehydration Dehydration Vasocontriction Reduced Renal Perfusion Renin release Angiotensin I Production ACEI Aldosterone release Angiotensin II Production Renal Sodium resorption Low urine sodium Incr Plasma osmolality, ADH, thirst Euvolaemia

19. Renal Water & Sodium Handling Sodium: 25 mol/d Water: 150 L/d Sodium: Aldosterone-sensitive Water: ADH-sensitive Active sodium Passive water Sodium only(no water) Makes dilute urine Sodium: 100-200 mmol/d Water: 1-2 L/d

20. Additional Mechanisms • Thirst • Responds to high osmolality and low volume • Powerful but slow regulator • Natrurietic Peptides • Atrial (ANP, atrium); Brain (BNP, ventricle) • Respond to stretch (over filling) • Causes renal sodium and water loss • Blocks RAA, causes vasodilation • Markers of heart failure, HT

21. Pathology

22. Sodium and Water balance • In normals: • Sodium in = sodium out • Water in = water out • With changes: • Systems try to correct changes • eg dehydration -> water retention • With defects in systems: • other mechanisms try and correct defect • eg DI, thirst can correct body interior

23. Clinical Derangements • Water • Too much, too little, just right • Sodium • Too much, too little just right • Combination leads to sodium concentration

24. Sodium - Clinical Effects • Hypernatraemia - draws water out of cells • Hyponatraemia - water drawn into cells • Main effects on brain!! >160 twitching, siezures, coma >150 weakness, lethargy <130 nausea, drowsiness <120 vomiting, confusion <110 convulsions, coma Depends on rate of change and other factors

25. Hyponatraemia

26. Hyponatraemia: Important Diagnoses • Diuretics • Renal Failure • Addison’s disease • Hypothyroidism • Liver failure • Heart Failure • SIADH • Artefacts

27. Hyponatraemia diagnosis Hyponatraemia Exclude common drugs, eg diuretics Measure plasma osmolality Increased Hypertonic Hyponatraemia: - Hyperglycaemia - Hyperglycinaemia (post TURP) Normal Drip-arm Pseudohyponatraemia: - Hyperlipidaemia - Hyperproteinaemia Decreased True Hyponatraemia Measure Urine Sodium and osmolality, state of hydration Urine sodium >20 mmol/L Urine sodium <20 mmol/L

28. Hyponatraemia diagnosis Hyponatraemia Exclude common drugs, eg diuretics Measure plasma osmolality Increased Hypertonic Hyponatraemia: - Hyperglycaemia - Hyperglycinaemia (post TURP) Normal Drip-arm Pseudohyponatraemia: - Hyperlipidaemia - Hyperproteinaemia Decreased True Hyponatraemia Measure Urine Sodium and osmolality, state of hydration Urine sodium >20 mmol/L Urine sodium <20 mmol/L

29. Drugs and Hyponatraemia • Diuretics (sodium loss) • Eg thiazides, frusemide, indapamide • Potentiate ADH secretion (water retention) • barbiturates; narcotics; oral hypoglycaemics; antineoplastics; anticonvulsants, antidepressants • miscellaneous (clofibrate, isoprenaline, nicotine derivatives) • Potentiate ADH action (water retention) • Chlorpropamide, paracetamol, indomethacin

30. Hyponatraemia diagnosis Hyponatraemia Exclude common drugs, eg diuretics Measure plasma osmolality Normal Drip-arm Pseudohyponatraemia: - Hyperlipidaemia - Hyperproteinaemia Decreased True Hyponatraemia Increased Hypertonic Hyponatraemia: - Hyperglycaemia - Hyperglycinaemia (post TURP) Measure Urine Sodium and osmolality, state of hydration Urine sodium >20 mmol/L Urine sodium <20 mmol/L

31. Low Sodium and Normal Osmolality • Normal Osmolar gap • Drip Arm • Glucose high, included in osmolar gap calculation • High Osmolar Gap • Pseudohyponatraemia • High total protein (>100 g/L) • High Lipids • Triglycerides • Lipoprotein X

32. Pseudohyponatraemia • Reduced measured sodium (and other analytes) in indirect measurements • Caused by increase in non-aqueous components • Triglycerides > 30 mmol/L • Protein > 100 g/L • Sodium molality is normal • Sodium molarity is low • Normal measured osmolality (high osmolar gap) • Normal result in blood gas analyser • BODY THINKS SODIUM IS NORMAL

33. Hyperosmolar Hyponatraemia(dilutional hyponatraemia) * * * * * * * * * * * • High extracellular osmolality • Glucose (normal osmolar gap) • Glycine (raised osmolar gap) • Occurs after TURP • Draws water out of cells • With treatment glucose returns into cells • Water follows glucose into cells • Sodium level increases • Sodium rise = glucose(mmol/L)/4 • Eg Sodium 125 mmol/L Glucose 40 mmol/L * * * * * * * * * * * * * * * * * * * * * * *

34. True Hyponatraemia • Low osmolality • Normal osmolar gap • Further investigation indicated • Clinical evaluation of state of hydration • Spot urine sample • sodium • Osmolality

35. Hyponatraemia: further investigation Measure Urine sodium and osmolality, determine state of hydration Urine sodium > 20 mmol/L Urine sodium < 20 mmol/L Patient Overloaded Renal failure - acute, chronic Patient Hypovolaemic Renal losses (UPO>1) - Diuretic therapy - Addisons Disease - Salt-losing nephritis - Proximal RTA Osmotic diuresis (UPO1) - glucose, urea Patient Euvolaemic Chronic water overload - SIADH (U osmo>200) - Hypothyroidism - Cortisol deficiency (UPO>1) Acute Water Overload - Stress, post surgery - Psychogenic polydipsia (UPO<1)

36. Hyponatremia: low Urine sodium Measure Urine sodium and osmolality, determine state of hydration Urine sodium < 20 mmol/L Urine sodium > 20 mmol/L Patient Hypovolaemic Extra-renal losses (UPO>1) - vomiting, diarrhoea - skin loss, pancreatitis Patient Euvolaemic Fluid depletion and hypotonic replacement SIADH with fluid restriction Patient Oedematous Renal sodium retent’n - cirrhosis, CCF - nephrotic synd.

37. Sodium in urine • Vital investigation for sodium abnormalities • Spot urine most useful • Normal range: NOT USEFUL • Decision point: 20 mmol/L • Only when patient has true hyponatraemia • Consider effects of salt (RAA) and water (ADH) • 24 hour urine • In normals reflects daily intake • Can be useful for assessing replacement

38. Hyponatraemia: Important Diagnoses • Diuretics - History • Renal Failure - creatinine • Addison’s disease - Cortisol, Synacthen test • Hypothyroidism - TFTs • Liver failure - LFTs • Heart Failure – History, BNP • SIADH

39. SIADH • True Hyponatramia • Euvolaemic (slight overload) • Urine sodium > 20 mmol/L (RAAS not on) • Urine osmolality > 200 (ADH present) • No renal, cardiac, liver or adrenal problems • Response to water restriction • CNS lesions, lung lesions, cancer

40. SIADH Increased ADH Water retention in Kidney Hypervolaemia (not dehydrated) Inhibition of RAAS Urine osmolality high (>200 mosm/kg) Hyponatraemia Urine sodium > 20 mmol/L

41. Hypernatraemia

42. Hypernatraemia diagnosis “Dehydration until proven otherwise” 1. Exclude artefact (drip arm) 2. Not enough water • Not enough in • too sick, old, young, restrained; thirst center lesion • Too much out • DI, GIT, renal 3. Too much salt • Iatrogenic, sea water drowning, Conn’s

43. Hypernatraemia Determine state of hydration and measure urine sodium and osmolality. Patient Dehydrated Patient Euvolaemic Patient Hypervolaemic U Na < 10 mmol/LInadequate intake (U osmo > 800) - too young, too old, too sick, prevented, oesophageal stricture, thirst centre damage Non-renal water loss (Uosmo > 800) - GI loss, skin loss Diabetes insipidus with inadequate fluid intake (U osmo < 300) U osmo < 800 Diabetes insipidus - central - nephrogenic U Na > 20 mmol/L Salt ingestion (tablets, sea water, iv hypertonic saline or Na Bicarbonate) Mineralocorticoid excess syndromes (only with inadequate fluid intake) U osmo > 800 Insensible water losses - lung - skin U Na > 20 mmol/L Renal Sodium loss - osmotic diuresis (UPO  1) - diuretics with decreased water intake - renal disease

44. Polyuria

45. Polyuria • Distinguish from urinary frequency • Timed collection can be useful • High Urine osmo makes polyuria unlikely 2. Consider causes • Diabetes mellitus (osmotic) • Drugs: Diuretics, lithium • Diabetes insipidus (insufficient ADH) • Psychogenic polydipsia (depressed ADH) • Renal failure (polyuria)

46. Polyuria investigation • Urine osmolality • >400: not present at time of testing • Approx 300: osmotic, eg diabetes, renal • <200: Diabetes Insipidus, Psychogenic polydipsia • Biochemically indistinguishable • Needs water deprivation test

47. Laboratory Knowledge • Laboratory • Type of assay • Alternatives (blood gas, osmolality) • What drip-arm sample look like • Hyponatraemia • Interpretation of serum osmolality • Pseudohyponatraemia, dilutional hyponatraemia • Importance of drugs • Requires spot urine Na and osmo • “Reference intervals” are not required for urine sodium • Hypernatraemia usually dehydration • Polyuria • Spot urine • Cannot separate DI and polydipsia

48. Closing thoughts • Sodium measurements very common • Sodium and water must be considered together • Diagnosis of disorders requires both clinical and laboratory investigation • Drug history and urine samples are vital • www.sydpath.com.au