DYSELECTROLYTEMIA Maintaining proper levels of sodium, potassium, calcium, chloride, magnesium, and phosphate is crucial for overall health.

Sodium, the principal extracellular cation and solute, is essential for generation of action potentials in neurologic and cardiac tissues
Regulation of total body sodium and [Na*] is accomplished primarily by the endocrine and renal systems
Secretion of aldosterone control total body sodium.
ADH, which is secreted in response to increased osmolality or decreased blood pressure, primarily regulates [Na*]

1. DYSELECTROLYTEMIA PRESENTER Dr VISHAL G MODERARTOR: DR NARASHIMHA REDDY

2. SODIUM

3. Physiologic role Sodium, the principal extracellular cation and solute, is essential for generation of action potentials in neurologic and cardiac tissues Regulation of total body sodium and [Na*] is accomplished primarily by the endocrine and renal systems Secretion of aldosterone control total body sodium. ADH, which is secreted in response to increased osmolality or decreased blood pressure, primarily regulates [Na*]

4. HYPONATREMIA Hyponatremia is defined as a serum sodium concentration <135 mEq /L. Normal serum sodium levels are between approximately 135 and 145 mEq /L. • Hyponatremia is classified into 3 types based on the ECF volume status: Euvolemic, hypovolemic, and hypervolemic

5. Causes of Hyponatremia Euvolemic hyponatremia • SIADH (syndrome of inappropriate antidiuretic hormone secretion) • Glucocorticoid deficiency • Hypothyroidism • Stress • Drugs (barbiturates, carbamazepine, clofibrate, opioids, vincristine, NSAIDs)

6. Hypovolemic hyponatremia • Integumentary loss: Sweating, burns • Gastrointestinal loss: Vomiting, diarrhea • Renal loss: Diuretics, osmotic diuresis, salt-wasting nephropathy, mineralocorticoid deficiency. Third space loss: Pancreatitis, intestinal obstruction, peritonitis • Cerebral salt wasting syndrome Hypervolemic hyponatremia • Congestive heart failure • Renal failure • Cirrhosis

7. Pathophysiology of Hyponatremia • Most causes of hyponatremia are associated with low serum osmolality. In general, hypotonic hyponatremia is due to either a primary water gain or a primary sodium loss • Isotonic hyponatremia may complicate transurethral resection of the prostate because large volumes of isoosmotic (mannitol) or hypoosmotic (sorbitol or glycine) bladder irrigation solution can be absorbed and result in a dilutional hyponatremia. • Hypertonic hyponatremia is usually due to hyperglycemia or, occasionally, intravenous administration of mannitol.Glucose is an effective osmole and draws water from muscle cells, resulting in hyponatremia. Plasma Na concentration falls by 1.4 mmol/L for every 100 mg/dl rise in the plasma glucose concentration. •Diuretic-induced hyponatremia is almost always due to thiazide diuretics, because loop diuretics decrease the tonicity of the medullary interstitium and impairs maximal urinary concentrating capacity. This limits the ability of ADH to promote water retention.

8. Effects of Hyponatremia on Brain • The fall in serum osmolality due to hyponatremia creates an osmolar gradient that favors water movement into the cells, leading to brain edema. • Hyponatremia-induced cerebral edema occurs primarily with rapidly (over one to three days) developing hypo-natremia. In slowly developing hyponatremia, there is time for adaptation of neuronal cells and hence, this can be clinically asymptomatic.

9. Clinical Manifestations • Mild hyponatremia (plasma sodium level >120 mEq /L) is usually asymptomatic. Nausea and malaise are the earliest findings seen with mild hyponatremia. • Headache, lethargy, obtundation, seizures, coma, and respiratory arrest may be seen at sodium level below 115 mEq /L. • Chronic hyponatremia may be asymptomatic or associated with nonspecific features such as fatigue, nausea, dizziness, gait disturbances, forgetfulness, confusion, lethargy, and muscle cramps.

10. Investigations • Serum sodium level is less than 135 mEq /L. • Urine sodium and urine osmolality is inappropriately increased in SIADH. •Appropriate tests to rule out cardiac, renal, or liverdisease . Thyroid function tests and cortisol levels.

11. Management. .• Mild hyponatremia (Na >120) has high morbidity due to cerebral edema, and . It is generally safe to correct this relatively rapidly using hypertonic saline infusions (1.6% or 3% saline). • rapid correction of hyponatremia which has developed slowly (over weeks to months) can be hazardous to the brain. in chronic hyponatremia, correction should be slow and not exceed 10 mEq /L/day. For hypovolemic patients, intravenous saline infusion. SIADH requires fluid restriction and treatment with demeclocycline to enhance water excretion . Conivaptan or tolvaptan which are ADH receptor antagonists are also useful in SIADH. Hypervolemic patients (due to CF) are treated with a combination of diuretics and fluid restriction.

12. A 60 kg man with sodium 110meq/l Hyponatremia is corrected using 3 percent hypertonic saline Hence the formula {513-110}/{60*0.6+1}=10mmol/l Hence one litre of this solution will increase sodium by 10mmol/l

13. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) In SIADH, increased (inappropriate) ADH release occurs without any physiologic stimulation. Hypovolemia and hyperosmolality are physiological stimulations for ADH secretion, Inappropriate ADH secretion leads to water retention leading to hyponatremia. •Normal regulation of ADH release occurs from both CNS and chest via baroreceptors and neural input. Hence, disorders affecting CNS and lungs commonly produce SIADH.

14. CNS disorders • Head trauma, stroke, subarachnoid hemorrhage , brain.tumor , encephalitis, meningitis Lung diseases • Tuberculosis, pneumonia, bronchiectasis, neoplasms Malignancies • Bronchogenic carcinoma, malignant lymphoma, leukemia Drugs • Carbamazepine, phenytoin, haloperidol,cyclophosphamide,chlorpropamide Other s• Postoperative state, sustained pain, stress, nausea, AIDS, idiopathic

15. Diagnosis of SIADH • Hyponatremia • Low plasma osmolality <270 mmol/kg. • Urine osmolality >150 mmol/kg. Normally urine should be maximally dilute in the presence of low serum osmolality, but is typically >150 in SIADH, i.e. inappropriately concentrated due to ADH action. • Urine sodium concentration >30 mmol/1.Normal renal function tests, uric acid.

16. Treatment • Severe symptomatic hyponatremia should be corrected using hypertonic saline. • Fluid restriction to 600-1000 ml/day. •.Demeclocycline (600-900 mg/day) may enhance water excretion, by interfering with collecting duct responsiveness to ADH.. Oral urea therapy (30-45 g/day) can provide a soluteload to promote water excretion. • ADH receptor antagonists are the new drugs available to treat SIADH. These are conivaptan and tolvaptan.They promote the excretion of free water ( aquaretics ).

17. Hypernatremia. Serum sodium level of >145 mEq /L is called hypernatremia. Hypernatremia is either due to excess water loss from the body or due to excess sodium intake. Most of the cases are due to excess free water loss from the body. • An intact thirst mechanism usually prevents hyper-natremia. hypernatremia occurs only if adequate water intake is not possible, as with unconscious patients.

18. Causes • Excessive diuretic therapy due to relatively more water loss than sodium loss. • Primary water loss due to diarrhea or excessive sweating. • Diabetes insipidus (central or nephrogenic). • Excess sodium intake (IV or oral salt administration).

19. Clinical Features • Hyperthermia delirium coma may be seen with severe hypernatremia.

20. HYPOVOLEMIC HYPERNATREMIA -MANAGEMENT Volume Resuscitation- signs of a low flow state (e.g., cold extremities, a decrease in blood pressure or urine output) - immediate volume resuscitation with isotonic saline Free Water Replacement- Current TBW=Normal TBW*140/Current sodium Once the current TBW is calculated, the free water deficit is the difference between the normal and current TBW. Water deficit=normal TBW-current TBW

21. REPLACEMENT VOLUME- Free water deficits are corrected with sodium-containing fluids such as 0.45% NaCL Replacement volume=water deficit*140/[Na]in IV fluid RATE OF REPLACEMENT- To limit the risk of cerebral edema, the decrease in plasma [Na+] should not exceed 0.5 mEq /L per hour during free water replacement

22. For an adult male with a lean body weight of 70 kg and a plasma [Na] of 160 mEq /L, the normal TBW is 0.5×70 = 35 L, the current TBW is 35×(140/160) = 30.5 L, H2O deficit is 35 – 30.5 = 4.5 L. , if the replacement fluid is 0.45% NaCL ([Na+] = 77 mEq /L), the replacement volume is 4.5×(140/77) = 8.1 liters

23. HYPERNATREMIA WITHOUT HYPOVOLEMIA Hypernatremia with a normal ECV is the result of free water loss with no net sodium loss Diabetes insipidus (DI), is a disorder of renal water conservation, and is characterized by loss of urine Management- the replacement strategy is aimed at replacing free water deficits and limiting the rate of sodium correction to ″ 0.5 mEq /L per hour VASOPRESSIN: vasopressin administration is also required to prevent ongoing free water losses. The usual dose is 2 to 5 Units of aqueous vasopressin given subcutaneously every 4 to 6 hours

24. Hypervolemic Hypernatremia Hypernatremia with a high ECV is uncommon, Seen in sodium bicarbonate infusions for metabolic acidosis , use of hypertonic saline to treat increased intracranial pressure, . Excessive ingestion of table salt seen in psychiatric disorder Management- In patients with normal renal function, excess sodium and water are excreted rapidly. When renal sodium excretion is impaired,increase renal sodium excretion with a diuretic (e.g., furo-semide ).

25. POTASSIUM

26. Physiologic role Potassium plays an important role in cell membrane physiology Maintaining resting membrane potentials and in generating action potentials in the central nervous system and heart Potassium is actively transported into cells by a Na/K adenosine triphosphatase (ATPase) pump, which maintains an intracellular [K*] that is at least 30-fold greater than extracellular [K*]. Intracellular potassium concentration is normally 150 mEq /L, while the extracellular concentration is only 3.5 to5 mEq /L.

27. The primary mechanism that maintains potassium inside cells is the negative voltage created by the transport of three sodium ions out of the cell for every two potassium ions transported. insulin promote potassium entry into cells Metabolic and respiratory acidosis tend to shift potassium out of cells, while metabolic and respiratory alkalosis favor movement into cells.

28. REGULATION Usual potassium intake varies between 50 and 150 mEq /day. Freely filtered at the glomerulus, most potassium excretion is urinary, with some fecal elimination. Of potassium which are filtered , of which 85% to 90% is reabsorbed in the proximal convoluted tubule and loop of Henle. The remaining 10% to 15% reaches the distal convoluted tubule, which is the major site at which potassium excretion

29. The two most important regulators of potassium excretion are plasma [K] and aldosterone. Potassium secretion into the distal convoluted tubules and cortical collecting ducts is increased by hyperkalemia, aldosterone, alkalemia, increased delivery of sodium to the distal tubule and collecting duct, high urinary flow rates sodium reabsorption increases, the electrical driving force opposing reabsorption of potassium is also increased Aldosterone increases sodium reabsorption by inducing a more opening epithelial sodium channel; potassium-sparing diuretics (amiloride and triamterene) and trimethoprim block the epithelial sodium channel, thereby increasing potassium reabsorption

30. HYPOKALEMIA Hypokalemia is defined as plasma K* concentration of <3.5  mEq /L. Etiology Reduced intake • Diet containing less K*, starvation, potassium free IV fluids. Urinary loss • Diuretics, polyuria, primary mineralocorticoid excess, metabolic acidosis, hypomagnesemia, amphotericin-B, salt-wasting nephropathies Gastrointestinal loss • Vomiting, diarrhea , tube aspiration of gastric contents, laxative abuse, villous adenoma. Increased entry into cells • Alkalosis, increased availability of insulin, B, agonists, hypokalemic periodic paralysis.

31. Clinical Features Muscular weakness and paralysis. Respiratory muscle weakness can lead to respiratory failure and death. Gastrointestinal muscle weakness leads to paralytic ileus. Cardiac arrhythmias include ectopic beats, sinus bradycardia, paroxysmal atrial or junctional tachycardia, atrioventricular block, and ventricular tachycardia fibrillation. Muscle cramps leading to rhabdomyolysis and myoglobinuria.

32. Investigations Serum electrolytes, Urine potassium excretion is increased in hypokalemia due to renal loss and decreased in extrarenal loss ECG changes - depression of ST segment, flattening or inversion of T wave, and presence of U waves at the end of the T wave. U waves are often seen in leads V4 to V6.

33. Management . Potassium replacement this can be done by oral or IV potassium chloride supplementation. For mild hypokalemia (K >3 mEq /L), about 20 to 80 mEq per day of oral potassium chloride is given in 3 to 4 divided doses. In moderate hypokalemia (K+ <3.0 mEq /L), about 120 mEg oral potassium chloride is given in 3 to 4 divided doses. For severe or symptomatic hypokalemia , intravenous potassium chloride is given. IV potassium is administered along with IV fluids at a concentration of 20 to 40 mEq per liter of fluid. Potassium sparing diuretics- such as spironolactone or amiloride can be used along with other measures to correct  hypokalemia .

34. HYPERKALEMIA Hyperkalemia is defined as a plasma K+ concentration of >5.5 mEq /L. Causes Excess intake- potassium rich foods, Impaired excretion • Acute and chronic renal failure, Addison's disease, hypo-aldosteronism, drugs (K+ sparing diuretics, ACE inhibitors, NSAIDs). Release of intracellular K*• Hemolysis , rhabdomyolysis, crush injury, burns, tumor lysis syndrome. Shift of K+ out of cell • Metabolic acidosis, hyperosmolality, insulin deficiency, hyperkalemic periodic paralysis, succinylcholine, digitalis. Pseudohyperkalemia • Hemolysed blood sample, repeated fist clenching during phlebotomy, with release of K* from forearm muscles, specimen drawn from arm with K+ infusion.

35. Clinical Features Symptoms generally do not occur until the plasma potassium concentration exceeds 7 mEq /L, unless the rise in potassium concentration has been very rapid. • Hyperkalemia interferes with normal neuromuscular function and causes muscle weakness, and rarely, flaccid paralysis. This happens repeatedly in hyperkalemic periodic paralysis. Paralytic ileus and abdominal distension may occur. • Hyperkalemia causes depolarization, leading to decreased cardiac excitability, hypotension, and bradycardia. Ventricular fibrillation and cardiac arrest are terminal events. • ECG changes : Tall peaked T waves with shortened QT interval. progressive lengthening of the PR interval and QRS duration. The P wave may disappear, and QRS widens giving rise to "sine wave" pattern.

36. Treatment Calcium gluconate decreases membrane excitability and prevents cardiac arrhythmias. The usual dose is 10 ml of a 10% solution intravenously over 2-3 mins. Insulin plus dextrose infusion shifts K+ into the cells and temporarily lowers the plasma K* concentration. 50 ml of 50% dextrose plus 10 units of regular insulin is given every 6 to 8th hourly. Sodium bicarbonate increases blood pH and results in a shift of K* into cells. 1-2 ampoules can be given intra-venously. B-adrenergic agonists such as salbutamol promote cellular uptake of K*. They can be given parenterally or in nebulized form every 4 to 6th hourly.

37. K* excretion can be enhanced by diuretics (frusemide, thiazides) and cation-exchange resin. Sodium polystyrene sulfonate (e.g. K-BIND) is a cation-exchange resin that binds to K+ in the gastrointestinal tract which is then excreted in the stool Hemodialysis is the most rapid way of removing the K+ from the body. It is indicated in patients with renal failure and those with severe hyperkalemia unresponsive to other measures. Peritoneal dialysis also removes K+ but is less effective.

38. CALCIUM

39. Calcium is a divalent cation found primarily in the extracellular fluid. The free calcium concentration in ECV is approximately 1 mM, The free calcium concentration  in the ICV approximates 100  mM,

40. FUNCTIONS Essential for normal excitation-contraction coupling calcium is also necessary for proper function of muscle tissue, ciliary movement mitosis neurotransmitter release enzyme secretion hormonal secretion Cyclic adenosine monophosphate (CAMP, which are major second messenger regulating cellular metabolism, function primarily through the regulation of calcium movement. Activation of numerous intracellular enzyme systems requires calcium. generation of the cardiac pacemaker activity and for generation of the cardiac action potential

41. REGULATION Parathyroid hormone (PTH) and calcitriol, the most important neurohumoral mediators of serum calcium mobilize calcium from bone, increase renal tubular reabsorption of calcium, and enhance intestinal absorption of calcium. Vitamin D, after ingestion or cutaneous manufacture under the stimulus of ultraviolet light, is 25-hydroxylated to calcidiol in the liver and then is1-hydroxylated to calcitriol, the active metabolite, in the kidney. PTH and vitamin D can maintain a normal circulating calcium by mobilizing calcium from bone.. The receptor activator of nuclear factor KB (RANK), RANK ligand (RANKL), and osteoprotegerin play key molecular roles; binding of RANKL to RANK stimulates osteoclast activity, binding of RANKL to osteoprotegerin,disrupts binding to RANK. 

42. Hypocalcemia Hypocalcemia is an abnormal reduction in serum ionized calcium concentration (<8.8 mg/ dI ).

43. Etiology of Hypocalcemia Hypoparathyroidism • After parathyroid, thyroid, or radical neck surgery • Idiopathic • Infiltration of the parathyroid gland • Pseudohypoparathyroidism Vitamin D deficiency Nutritional deficiency • Intestinal malabsorption • Acute pancreatitis • Vitamin D resistance

44. Miscellaneous • Hyperphosphatemia • Hypomagnesemia (can cause relative PTH deficiency and end-organ resistance to PTH action. • Massive blood transfusion (citrate-anticoagulated blood can decrease the concentration of ionized Ca) • Alkalosis (hyperventilation, excessive vomiting) • Fluoride intoxication • Septic shock (due to suppression of PTH release and decreased conversion of 25(OH)D to 1,25(OH), D)

45. Clinical features Neuromuscular manifestations Hypocalcemia leads to neuromuscular irritability leading to tetany . sensory symptoms such as numbness, paresthesias of the hands and feet are seen. Motor symptoms are stiffness and clumsiness, myalgia, and muscle spasms and cramps. Hand muscle spasm leads to adduction of the thumb, flexion of the metacarpophalangeal joints and wrists, and extension of the fingers. Spasm of the respiratory muscles and of the glottis can cause cyanosis. Autonomic manifestations include diaphoresis, bronchospasm, and biliary colic.

46. Trousseau sign is the induction of carpal spasm by inflation of a sphygmomanometer above systolic blood pressure for three minutes. It can also be induced by hyperventilation for one to two minutes after release of the cuff. Trousseau's sign is due to the ischemia of the nerve trunk under the cuff which increases excitability. Chostek's sign is contraction of the ipsilateral facial muscles when facial nerve is tapped anterior to the ear. This leads to contraction of corner of the mouth, the nose and the eye. Other neurological features are seizures,intellectual impairment, parkinsonism, dystonia,.

47. Psychiatric manifestations- emotional instability anxiety depression confusion hallucinations Psychosis Cardiovascular Hypotension decreased myocardial contractility, heart failure.

48. Skin manifestations- dry skin, hyperpigmentation; dermatitis and eczema, and psoriasis Gastrointestinal- steatorrhea due to impaired pancreatic secretion, Endocrine manifestations- impaired insulin release. Denta l -dental hypoplasia, failure of tooth eruption, defective enamel and root formation, Eye cataracts.

49. Investigations • Serum calcium level is low. • Serum PTH level is low in hypoparathyroidism and elevated in secondary hyperparathyroidism. •Serum vit D level is low in vit D deficiency. • Serum magnesium level-hypomagnesemia causes hypocalcemia by inducing PTH resistance or deficiency. •ECG shows prolonged QT interval.

50. TREATMENT Administer Calcium IV: 10 mL 10% calcium gluconate over 10 min, followed by elemental calcium 0.3-2 mg/kg/hr Oral: 500-100 mg elemental calcium q6h Administer Vitamin D Ergocalciferol, 1,200 mg/day (T1/2 = 30 days) Dihydrotachysterol , 200-400 pg /day (T1/2 = 7 days) 1,25-dihydroxycholecalciferol, 0.25-1 g/day (T/2 = 1 day)

51. HYPERCALCEMIA Etiology of Hypercalcemia Increased bone resorption •Primary hyperparathyroidism • Secondary and tertiary hyperparathyroidism Increased calcium intake Chronic kidney disease • Milk alkali syndrome • Hypervitaminosis D Miscellaneous • Lithium • Pheochromocytoma • Adrenal insufficiency • Rhabdomyolysis and acute renal failure

52. Clinical Features Renal • Polyuria • Polydipsia • Nephrolithiasis • Nephrocalcinosis • Distal renal tubular acidosis • Nephrogenic diabetes insipidus • Acute and chronic renal insufficiency

53. Gastrointestinal • Nausea, vomiting • Bowel hypomotility and constipation • Pancreatitis • Peptic ulcer disease. Musculoskeletal • Muscle weakness • Bone pain • Osteopenia/osteoporosis

54. Neuropsychiatric • Anxiety, depression • Decreased concentration • Confusion, stupor, coma Cardiovascular • Shortening of the QT interval • Bradycardia • Hypertension Eye • Calcium may precipitate in the corneas ("band keratopathy")

55. TREATMENT Rehydration Administration of calcitonin 4 1U/kg initially and then every 6 to 12 hours. • Bisphosphonates: Zoledronic acid (4 mg IV over 15minutes) or pamidronate (60 to 90 mg over two hours). Steroids: Prednisolone 5-15 mg 6 hourly or hydrocortisone100 mg 6 hourly IV. .• Calcitonin plus saline reduces calcium concentration within 12 to 48 hours whereas bisphosphonates will be effective by the second to fourth day. Hemodialysis should be considered if serum calcium is above 18 mg/dl.

56. MAGNESIUM

57. PHYSIOLOGIC ROLE Magnesium is an important, multifunctional, divalent cation located primarily in the intracellular space typical adult's 24 g of magnesium is located in bone, 12 g is located intracellularly, and less than 1% circulates in the serum. Total magnesium concentration (1.5 to 1.9 mEq /L ) protein-bound (30%), anion-bound (15%), and ionized (55%), of which only ionized magnesium is active.

58. Magnesium is necessary for enzymatic reactions involving DNA and protein synthesis, energy metabolism, glucose utilization, and fatty acid synthesis and breakdown. magnesium stabilizes axonal membranes Magnesium also influences the release of neurotransmitters at the neuromuscular junction by competitively inhibiting the entry of calcium into the presynaptic nerve terminals Magnesium is widely available in foods and is absorbed through the gastrointestinal tract,

59. REGULATION Seventy percent of plasma magnesium is filtered through the glomerular membrane, Of the filtered magnesium, 30% is absorbed in the proximal tubule, 60% in the thick ascending loop of Henle, and 10% to 15% in the distal tubule.

60. Hypomagnesemia. Normal magnesium level in the plasma is 1.4 to 2 mg/ dl.A value less than this is called hypomagnesemia. Causes Decreased intake or absorption • Malnutrition, alcoholism, malabsorption, chronic diarrhea , laxative abuse, gastrointestinal suction, total parenteral nutrition Increased renal loss • Diuretics, hyperaldosteronism, hyperparathyroidism, hyperthyroidism, hypercalcemia, tubulointerstitial diseases Others • Diabetes mellitus, post parathyroidectomy (hungry bone syndrome), respiratory alkalosis, pregnancy

61. Clinical Features Anorexia, nausea, vomiting, lethargy, weakness, and personality change. Tetany (e.g. positive Trousseau's or Chvostek's sign or tration . spontaneous carpopedal spasm, hyperreflexia), and tremor and muscle fasciculations. Severe hypomagnesemia may cause generalized tonic- clonic seizures,.

62. Investigations • Urinary excretion of magnesium- more than 10-30 mg/d indicates renal magnesium loss. • Hypocalcemia and hypokalemia may be present. • ECG shows prolonged QT interval. Treatment Intravenous Mg°: (1-2 g MgSO4) bolus over 1 hr, followed by 2-4 (250-500 mg/hr MgSO4) as continuous infusion Intramuscular Magnesium sulfate can also be given .

63. Hypermagnesemia. Hypermagnesemia is a serum Mg concentration >2.1 mEq /L. It occurs most commonly in patients with renal failure after ingestion of Mg-containing drugs, such as antacids or purgatives Other causes are administration of magnesium sulfate intravenously as a treatment eclampsia and aluminium phosphide poisoning. Symptoms and signs include hyporeflexia, hypotension, respiratory depression, and cardiac arrest. Treatment of severe Mg toxicity consists of intravenous Ca gluconate. IV furosemide can increase Mg excretion when renal function is adequate. Hemodialysis may be considered in severe hypermagnesemia.

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