Metabolic Alkalosis

Brief introduction of metabolic alkalosis, causes, investigations and management.

1. Metabolic Alkalosis Dr. Muhammad Usama Azhar PGR Medicine

2. Objectives Definition Classification Causes Compensatory Mechanism Clinical Presentation History and Examination Investigations Management

3. Definition Metabolic alkalosis is a primary acid–base disturbance due to either loss of acid (H) or gain of HCO3 in the ECF . The blood has a pH of >7.4 and plasma HCO of >26–28 mEq/L The increase in pH that results from the elevation in (HCO3 − ) induces hypoventilation, producing a secondary increase in arterial CO2 tension (PaCo2 ). Thus , metabolic alkalosis is characterized by coexisting elevations in serum HCO3 − , arterial pH, and PaCO2.

4. Causes Exogenous Administration of Alkali ECF contraction (Secondary Hyper-aldosteronism) ECF expansion (Primary Hyper-aldosteronism ) Miscellaneous

5. Exogenous Administration of Alkali IV HCO3 overload Acute alkali administration Milk alkali syndrome

6. ECF contraction (Secondary Hyper-aldosteronism ) Gastrointestinal origin Vomiting Gastric aspiration Congenital chloride diarrhoea Villous adenoma Renal origin Diuretcs Posthypercapnic stage Hypercalcemia/hypoparathyroidism Recovery from lactic acidosis or ketoacidosis Delivery of nonreabsorbable anions including Penicillin, Carbenicilline Hypomagnesemia Bartter’s syndrome Gitelman’s syndrome

7. ECF expansion (Primary Hyper-aldosteronism ) High renin Renal artery stenosis Accelerated hypertension Renin secreting tumor Oestrogen therapy Low renin Primary aldosteronism (adenoma, hyperplasia, carcinoma ) Adrenal enzyme defects (11 B hydroxylase deficiency, 17 a-hydroxylase deficiency ) Cushing’s syndrome or disease

8. Miscellaneous Liddle’s syndrome Cystic fibrosis Ingestion of licorice, carbenolone, chewer’s tobacco Hypokalemia Hypomagnesemia

9. Causes associated with contracted ECF volume

10. Vomiting or nasogastric suction Results in the loss of hydrochloric acid with the stomach contents. Loss of fluid and NaCl in vomitus results in contraction of ECF and increased secretion of renin and aldosterone . Severe vomiting also causes loss of potassium (hypokalaemia) and sodium (hyponatremia ). The kidneys compensate for these losses by retaining sodium in the collecting ducts at the expense of hydrogen ions by the action of aldosterone, leading to metabolic alkalosis.

11. Congenital chloridorrhea Rare autosomal recessive disorder which causes severe diarrhea, fecal acid loss and HCO3 retention. The main mechanism is loss of ileal HCO3/Cl anion exchange mechanism which results in decreased Cl reabsorption . Na + /H + exchange mechanism remains normal so normal H + is secreted in stool which causes Na and HCO 3 - to be retained. This results in metabolic alkalosis.

12. Villous adenoma High adenoma derived K secretory rate. Colonic secretion is alkaline K + and volume depletion most probably causes alkalosis

13. Diuretics Loop diuretics and thiazide reduce the ECF without affecting the total body bicarbonate content . Diuretics blocks Na+ and Cl- channels More Na + is delivered to DCT Na + exchange with K + under the effect of aldosterone Kaliuresis and hypokalemia occurs Depleted ECF causes contraction alkalosis Hypokalemia augments renal ammoniagenesis

14. Post-hypercapnic State During respiratory acidosis prolonged CO 2 retention occurs (chronic hypoventilation and hypercapnia) resulting in increased plasma HCO 3 - concentration Due to increased reasbsorption and generation of HCO 3 - When hypercapnia resolves increased HCO 3 - content and associated ECF contraction will cause metabolic alkalosis Alkalosis persists until chloride supplementation is given

15. Non-reabsorbable anions Administration of large amount of non reabsorbable anions like penicillin or carbenicillin can enhance distal acidification and K+ excretion. H + secretion occurs without Cl- dependant HCO3 secretion . Mg deficiency also results in hypokalemic alkalosis by enhancing distal acidification by stimulation of renin and hence aldosterone secretion .

16. Bartter’s Syndrome Autosomal recessive disorder involving impaired Thick Ascending Limb salt reabsorption. Results in salt wasting, volume depletion, and activation of renin-angiotensin system. It is associated with metabolic alkalosis, hypokalemia and normal to low blood pressure. NSAIDs  reduce polyuria and salt wasting in Bartter’s syndrome (increased renal  PGE2  production in Bartter’s).

17. Gitelman Syndrome Autosomal recessive disorder Characterised by metabolic alkalosis, hypokalemia , hypocalciuria and hypomagnesemia. It is caused by loss of function of the thiazide sensitive sodium-chloride symporter located in the distal convoluted tubule.

18. Causes associated with increased ECF volume

19. High Renin States with high renin may be accompanied by hyperaldosteronism and alkalosis. Renin levels may be increased due to increased renin secretion or decreased circulating blood volume. Examples of high renin are accelerated hypertension and renovascular hypertension. Estrogen increase renin substrate and hence angiotensin II formation. Primary tumor causing overproduction of renin can also cause Metabolic alkalosis

20. Low Renin I . Hyperaldosternism Adenoma , carcinoma and hyperplasia of adrenal gland results in aldosterone overproduction Adrenal enzyme defects (11 B hydroxylase deficiency, 17 ahydroxylase deficiency ) Aldosterone causes hypokalemia which results in an increased indirect reabsorption of HCO3 via the rise in proximal tubular intracellular H + Hypokalemia reduces GFR and thereby maintains the elevated blood HCO3

21. Low Renin II. Cushing’s syndrome or disease Abnormally high glucocorticoid hormone production caused by adrenal gland adenoma or carcinoma or ectopic corticotrophin production can cause metabolic alkalosis

22. Liddle Syndrome Autosomal dominant disorder Continuous activation of  ENaC  in collecting duct leading to increased Na absorption Early and severe hypertension with low renin and aldosterone Hypokalemia and metabolic alkalosis Amiloride or triamterene block ENaC (basis of treatment)

23. Hypokalemia & Metabolic Alkalosis Hypokalemia results in the shift of hydrogen ions intracellularly. The resulting intracellular acidosis enhances bicarbonate re-absorption in the collecting duct.

24. Hypokalemia & Metabolic Alkalosis Hypokalemia stimulates the apical H+ /K+ ATPase in the collecting duct

25. Hypokalemia & Metabolic Alkalosis Hypokalemia stimulates renal ammonia genesis and alphaketoglutarate is produced, the metabolism of which generates bicarbonate that is returned to the systemic circulation.

26. Hypokalemia & Metabolic Alkalosis It leads to impaired chloride ion re-absorption in the distal nephron. This results in an increase in luminal electronegativity, with subsequent enhancement of hydrogen ion secretion

27. Consequences Cardiovascular Arteriolar vasoconstriction Decreased coronary blood flow Cecreased myocardial contractility Increased risk of arrhythmia Respiratory Hypoventilation Metabolic Decreased K+ , Ca+ , Mg + , PO4 Neurological Seizures

28. Compensation Respiratory Compensation Renal Compensation

29. Respiratory Compensation Respiratory compensation for metabolic alkalosis is less predictable than that for metabolic acidosis. PaCO2 can be estimated by adding 15 to the HCO3 when HCO3 range is from 25 to 40 mEq/L Further elevation in PaCO2 is limited by hypoxemia and to some extent hypokalemia, which normally accompanies metabolic alkalosis. PaCO2 usually does not increase beyond 55mmHg, because further bradypnea will cause hypoxemia.

30. Respiratory Compensation Compensation for metabolic alkalosis occurs mainly in the lungs, which retain carbon dioxide (CO2 ) through hypoventilation . CO2 is then consumed toward the formation of the carbonic acid, thus decreasing pH . The decrease in H+ suppresses the peripheral chemoreceptors, which are sensitive to pH . But , because respiration slows, there's an increase in PCO2 which offsets the depression because of the action of the central chemoreceptors which are sensitive to the partial pressure of CO2 in the cerebral spinal fluid. So , because of the central chemoreceptors, respiration rate would be increased .

31. Renal Compensation Renal compensation for metabolic alkalosis consists of increased excretion of HCO3 – Filtered load of HCO3 - exceeds the ability of the renal tubule to reabsorb it . The development of metabolic alkalosis hence means the failure of kidneys to eliminate HCO3 at normal capacity

32. Clinical Presentation Symptom of metabolic alkalosis are not specific . It depends on etiology and severity of disease. Include changes in central and peripheral nervous system function Hypoventilation develops because of inhibition of the respiratory center in the medulla .

33. Clinical Presentation Mental confusion, obtundation, predisposition to seizure is common. Aggravation of arrhythmia and hypoxemia in COPD may also be seen . Symptoms of hypokalemia like muscle cramps, myalgia and muscle weakness may also be seen . Symptoms of hypocalcemia (eg, jitteriness, perioral tingling, muscle spasms) may be present .

34. Background History History of congential adrenal hypoplasia History of cystic fibrosis History of CCF (suggesting chronic exposure to diuretics) History of uncontrolled hypertension (malignant hypertension or renal artery stenosis ) Deafness , Recurrent dehydration (bartter syndrome) Hypertension (hypermineralocorticoid state)

35. Recent History Recent antacid consumption Recent use of calcium supplements β- lactam antibiotic use Massive abuse of licorice History of diarrhoea (villous adenoma) or vomiting (chloride loss) History of recent hypercapneic respiratory failure Intake of sodabicarbonate Massive blood transfusion, (citrate bicarbonate) Total parenteral nutrition (TPN) ( acetate bicarbonate) 

36. Examination Clinically , findings consistent with severe hypertension (eg. retinal changes ) Renal artery stenosis bruit Peripheral oedema (suggesting chronic exposure to diuretics)

37. ABGs in Metabolic Alkalosis Arterial pH increased (> 7.45 ) Serum bicarbonate increased (> 26meq/l ) PaCO2 increased PaCO2 rises 7 mmHg per 10 meq/L bicarbonate rise The anion gap is frequently elevated to a modest degree in metabolic alkalosis because of the increase in the negative charge of albumin and the enhanced production of lactate .

38. ABGs in Metabolic Alkalosis Normally, arterial PaCO2 increases by 0.5-0.7 mm Hg for every 1 mEq/L increase in plasma bicarbonate concentration. If the change in PaCO2 is not within this range, then a mixed acid-base disturbance occurs . If the increase in PaCO2 is more than 0.7 times the increase in bicarbonate, then metabolic alkalosis coexists with primary respiratory acidosis . If the increase in PaCO2 is less than the expected change, then a primary respiratory alkalosis is also present.

39. Approach to Metabolic Alkalosis

40. Approach to Metabolic Alkalosis

41. Investigations Urinary chloride ↑ Renin & ↑ aldosterone → Renovascular hypertension Renin secreting tumor ↓ Renin & ↑ aldosterone → Adrenal adenoma Glucocorticoid usage ↓ Renin & ↓ aldosterone → Cushing & Liddle syndrome Licorice Elevated 24 hour urinary cortisol → Cushing syndrome Elevated 11 de-oxycortisol → 17 alpha hydro.deficiency, 11 beta hydro.deficiency

42. Management Chloride-Responsive Metabolic Alkalosis Re-expand volume with n ormal saline (primary therapy) Supplement with Potassium to treat hypokalemia (alkalosis associated with severe hypokalemia will be resistant to volume resuscitation until K + is repleted ) H + blockers or PPIs if vomiting/NG suction to prevent further losses in H + ions

43. Management Chloride-Responsive Metabolic Alkalosis Discontinue diuretics Acetazolamide if normal saline is contraindicated due to CHF. (Monitor for hypokalemia) NH 4 Cl ( 100 meq/L per 20 mL vial) 1-2 vials in 1000 mL of normal saline. Hemodialysis in patients with marked renal failure

44. Management Chloride–Unresponsive Metabolic Alkalosis Surgical removal of mineralocorticoid producing tumor Aldosterone inhibitors ACE inhibitors Discontinue corticosteroids Potassium repletion (only intervention needed to treat the alkalosis)