1. Metabolic Acidosis Residents’ Conference 11/1/01 Romulo E. Colindres, MD

2. Primary Acid-Base Disorders Disorder pHHCO 3 - pCO 2 Metabolic Acidosis Metabolic Alkalosis Respiratory Acidosis Respiratory Alkalosis

3. Compensatory Responses to Primary Acid-Base Disorders

4. SERUM ANION GAP [ Na + K] + Unmeasured Cations = [Cl + HCO3] + Unmeasured Anions [Na + K] - [Cl + HCO3] = Unmeasured Anions (UC) - Unmeasured Cations (UC). CAN OMIT K. [Na] - [Cl + HCO3) = UA-UC; Normal Value: 10+/- 2mEq/L. Increase in anion gap usually indicates an increase in unmeasured anions: albumin, PO4, SO4, anions of organic acids.

5. Anion Gap Na+ 140 HCO 3 - 24 Cl- 104 Proteins 16 Organic Acids 5 PO 4 SO 4 3 K 5 Ca 5 Mg 2 Cations Anions Na+ 140 HCO 3 - 24 Cl- 104 AG 12 AG = Na+ - (Cl+HCO 3 )

6. CAUSES OF METABOLIC ACIDOSIS 1Excessive Acid Production Endogenous Exogenous 2Bicarbonate Wasting Diarrhea Renal (Type 2 RTA) 3Decreased Excretion of Acid (Impaired NH4+ excretion) Renal Failure Impaired Distal Acidification (RTA 1) Hypoaldosteronism (RTA 4) 4Combination of Above

7. METABOLIC ACIDOSIS: INDICIS OF SEVERITY pH <7.2 [HCO3] < 10mEq/L Massive continuous production of acid Poor respiratory compensation ( pCO2 fall less than 1.25 mm Hg for each mEq/L fall in HCO3 concentration)

8. Acid Production Carbohydrates/Fats  15,000 mmol/d CO 2 (Volatile acid) CO 2 + H 2 0  H 2 CO 3  H + + HCO 3 - Lungs Proteins  50-100 mEq/d H 2 SO 4 (Fixed Acid) –H + + HCO 3 -  H 2 CO 3 –H + + Intracellular Base-  HBase –H+ excretion in the kidney Limits rise in [H+]

9. RENAL EXCRETION OF ACID The kidneys must excrete 50 to 100 mEq of acid to regenerate the bicarbonate used to buffer the fixed acid generated from metabolism each day The daily acid load cannot be excreted unless all of the filtered HCO3 is reabsorbed Excretion of an acid urine is a necessary but not sufficient condition to excrete the daily acid load: free H+ concentration in the urine is very low (<0.05mEq/L) in a maximally acid urine Acid excretion comes from H+ secretion and binding to NH4+ and phosphate

10. Proximal Tubule: Bicarbonate Reabsorption 3Na + 2K + Peritubular capillary Tubular lumen ATPase H+H+ OH - + CO 2 H2OH2O HCO 3 - CA Na + H+H+ HCO 3 - + H 2 CO 3 CO 2 + H 2 O CA Na + HCO 3 -

11. Proximal Tubule: Titratable Acid 3Na + 2K + Peritubular capillary Tubular lumen ATPase H+H+ OH - + CO 2 H2OH2O HCO 3 - CA Na + H+H+ HCO 3 - HPO 4 2- + H 2 PO 4 -

14. 3Na + 2K + Peritubular capillary Tubular lumen NH 4 + Na + NH 4 + Glutamine Glutamate- Glutaminase Na + NH 4 + 2Cl- NH 4 + 3 ATPase H+ NH 3 + 4 + Ammonia Synthesis and Transport ATPase

15. Renal Acid-Base Regulation 4000 mEq HCO 3 - filtered in proximal tubule must be reabsorbed - no net acid excretion Minimal urine pH is 4.5  only 40-80  mol per day can be excreted as free H+; Excretion of the daily acid load as free H+ would require 2000 liters of urine output/day –H + is excreted in the form of urinary buffers, H 2 PO 4 - and NH 4 +

16. METABOLIC ACIDOSIS WITH INCREASED ANION GAP NaHCO3 + Lactic acid--->Na Lactate + CO3H2----> [Na] - [Cl +HCO3 + Lactate] Usually caused by increased production of endogenous or exogenous organic acid Salt (anion) may be quickly metabolized or excreted yielding a hyperchloremic acidosis

17.  Gap Metabolic Acidosis Due to Presence of Ketoacids Na+ 140 Cl- 105 HCO 3 10 Ketoacid 13 Pr, OA, P,S 12 Anion Gap = 25 pH = 7.25 HCO 3 = 10 pCO 2 = 25 AG = 25

18. Differential Diagnosis of  AG Metabolic Acidosis Methanol poisoning Uremia (advanced, SO 4, PO 4 ) Diabetic ketoacidosis-Other ketoses EtOH Starvation Paraldehyde (rare) Ischemia-Lactate Ethylene glycol Salicylate toxicity

19. DIFFERENTIAL DX OF  ANION & OSMOLAR GAP ACIDOSES

20. KETOACIDOSIS EVOLVES FROM HIGH AG  NL. AG ACIDOSIS GFR INSULIN

21. HYPERCHLOREMIC METABOLIC ACIDOSIS HCL + NaHCO3---> NaCl and H2CO3---> CO2 +H2O Therefore: anion gap unchanged since [Na] - (increased [Cl] + decreased [HCO3]). Loss of HCO3 in stool Loss of HCO3 in urine (RTA 2) Decreased excretion of NH4 (RTA 1 and 4 and renal failure) Increased production of acid but prompt excretion of anion (treatment of DKA, toluene)

22. Normal Anion Gap Metabolic Acidosis in a Patient with Diarrhea Na+ 140 HCO 3 15 Cl- 113 AG 12 pH= 7.32 HCO 3 -= 15 pCO 2 = 30 AG= 12

23. URINE ANION GAP:AN INDIRECT MEASUREMENT OF NH4+ EXCRETION IN HYPERCHLOREMIC METABOLIC ACIDOSIS Urine Anion Gap: [Na] + [K] - [Cl] Since: [Na] + [K] + Unmeasured (U) Cations = [Cl] + Unmeasured (U) Anions Therefore, [Na] + [K] - [Cl]= U Anions- U Cations U Anions = Sulfates, Phosphates, etc. U Cation = Mainly NH4+ Normal Value: 0 Hyperchloremic Metabolic Acidosis: -20 to -50 = Appropriately Increased NH4+ Excretion

31. Practical Approach (Hyperchloremic metabolic acidosis) Urine Anion Gap Negative Positive Type 2 RTA Diarrhea DKA/Toluene HCl (Hyperalimentation) Urine pH and Plasma K Urine pH 5.5, K nl/low Urine pH > 5.5, K  Type 4 RTAType 1 (secretory defect Type 1 (voltage) Early CRF or back-leak)

32. METABOLIC ACIDOSIS:BICARBONATE THERAPY Avoid if metabolic acidosis is transient and moderate and renal function is adequate, particularly with increased anion gap acidosis, since anions of organic acids can regenerate HCO3 Only a small inmediate increase (2-3 mEq/L) in plasma [HCO3] is necessary to get patient out of danger if there is normal respiratory compensation

33. Relationship Between pH and [HCO 3 - ] 25 20 15 10 5 7.107.207.307.40 pH [HCO 3 - ] meq/L Small changes in [HCO3-] cause large changes in pH

34. Therapy in Patients with Severe Acidosis Initial goal is to raise the pH to ~7.20 –decreased risk of arrhythmias –improved cardiac contractility and responsiveness to catecholamines Further correction is generally not necessary acutely –may cause volume overload –may reduce O 2 delivery to the tissues –may result in hypercarbia

35. METABOLIC ACIDOSIS:BICARBONATE THERAPY Rapid I.V. administration of HCO3 is important only in patients with severe metabolic acidosis Serial Measurements of [HCO3] Give oral HCO3 if possible Assume volume of distribution of HCO3 to be 50% of lean body weight

36. METABOLIC ACIDOSIS: BICARBONATE THERAPY Chronic renal failure: HCO3, not citrate to avoid Aluminum absorption. Give a large dose for several days to achieve a [HCO3] of approx.20mEq/L. Maintenance dose of about 40 mEq/day Chronic RTA 1: 1-2 mEq/Kg/day of Na-K citrate after increasing [HCO3] to desired level RTA 2: 10-15 mEq/Kg/day RTA 4: Correct hyperkalemia

37. Normal [H+] 40 nanoequivalents per liter  One-millionth the concentration of sodium, potassium and chloride

38. Modified Henderson-Hasselbach Equation [H+] = 24 pCO 2 [HCO 3 -]

39. Bicarb-CO2 System in Response to H+ Load 30 mEq H+ ECF 24 mEq/L HCO 3 - ECF 22 mEq/L HCO 3 - 30 mmol CO 2 = 2 mmol/L CO 2 Dissolved CO 2 1.2 mmol/L + 2 mmol/L = 3.2 mmol/L  pCO 2 107 mmHg [H+] = 24 107 22 = 116 nEq/L  pH = 6.94 [H+] = 24 37 22 = 39 nEq/L  pH = 7.396 No change in V E.  V E.

40. Change in Tubular Fluid pH  pH  0.2 0 0.4 0.8 1.2 0.2 0 0.4 0.8 1.2 1.6 2.0 2.4 0 20 40 60 80 100 Proximal Tubule, % Distal convolution, % 0 100 Ureteral urine GottschalkCW,LassiterWE,MylleM,Am JPhysiol, 198:581, 1960.

41. Decreased Efficacy of Respiratory Compensation with Worsening Acidosis ConditionHCO 3 - pCO 2 H + pH Normal 24 40407.40 Moderately 15 30507.30 Severe Life Threatening 5 201007.00