1. ACID-BASE- CLINICAL PHYSIOLOGY Jayson Rapoport Faculty of Medicine, Hebrew University, Jerusalem Department of Nephrology, Kaplan Medical Center, Rehovot

2. Acid-Base: Physiology (1) [H + ] maintained within relatively narrow limits: Normal [H + ] = 40nM/L (40 x 10 -9 M/l) (compare to [Na + ]: 140mM/l, or 140 x 10 -3 M/l.) pH Usually expressed as pH pH = -log [H + ] = -log [40 x 10 -9 ] = 7.4

3. Acid-Base: Physiology (2) Maintenance of constant pH is important because H + is very reactive, especially with proteins, and reaction changes protein function – Probably most important are proteins in brain

4. Acid-Base: Physiology (3) Definitions: ACID ACID: substance that donates H + BASE BASE: substance that accepts H + ACIDBASE H 2 CO 3 H + + HCO 3 - HCl H + + Cl - NH4 + H + + NH 3

5. Acid-Base: Physiology (4) 2 types of acid produced in body: 1.CARBONIC: produced by metabolism of CO 2 and fats: 15,000mM of CO 2. This acid is excreted via lungs. 2.NON-CARBONIC (FIXED) ACIDS: produced by metabolism of proteins: 50-100mM produced/day (or about 1mM/kg body weight). These H + must be excreted in urine.

6. Stages of acid-base balance 1.Acid synthesis: -S-containing AA, phosphoesters (H 3 PO 4 ), organic acids from foods (Total production 1-1.5meg/kg/day) 2. Buffering: -HCO 3 -H 2 CO 3 -Albumin -Hemoglobin 3. Renal Acid Secretion -H + secretion -Titration of urinary buffers (And reabsorption of filtered buffer) Total acid secretion 1-1.5meq/kg/day

7. Acid-Base: Physiology (6) Since homeostatic mechanisms of body cannot allow large changes in pH, acid produced must be buffered. BUFFERS: BUFFERS: Weak acids which can release or take up H +. e.g. HCl + Na 2 HPO4 NaCl + NaH 2 PO 4 NaOH + Na 2 HPO 4 NaH 2 PO 4 + H 2 O

9. Acid-Base: Physiology (7) Bicarbonate system: H 2 CO 3 H + + HCO 3 - Most important system because: H 2 CO 3 CO 2 + H 2 O HCO 3 - present in high concentrations (24mM/l)

10. Acid-Base: Physiology (8) Henderson-Hasselbalch Eqn: pH = pK + log [HCO 3 ] [H 2 CO 3 ] = 6.1 + log [HCO3] [0.03pCO 2 ] But Henderson Eqn. much more useful: [H + ] = 24 x pCO 2 [HCO 3 - ]

11. Relationship between pH and H + Concentration in the physiologic range pHH +, (nanomol/L) 7.816 7.720 7.626 7.532 7.440 7.350 7.263 7.180 7.0100 6.9125 6.8160

12. Acid-Base: Physiology (9) [H+] = 24 x pCO 2 [HCO 3 ] e.g. 40 = 24 x 40 [HCO 3 ] [HCO 3 ] = 24 pK = 6.1 (far from normal pH of 7.4). However, this system is efficient because pCO 2 controlled by ventilation

13. Acid-Base: Physiology (10) ISOHYDRIC PRINCIPLE All buffers in solution are in equilibrium: [H+] = k 1 [pCO 2 ] = k 2 [H 2 PO 4 ] = k 3 [HA] [HCO 3 - ] [HPO 4 2- ] [ A - ] Thus, all extracellular buffers are consumed at an equal rate

14. Acid-Base: Physiology (11) Extracellular buffers: Bicarbonate most important: H 2 SO 4 + 2NaHCO 3 Na 2 SO 4 + H 2 CO 3 2CO 2 + 2H 2 O HCO 3 - cannot buffer H 2 CO 3 : H 2 CO 3 + HCO 3 - HCO 3 - + H 2 CO 3 Thus, H 2 CO 3 is buffered by intracellular buffers. Other extracellular buffers: HPO 4 2- (1mM/l) Plasma proteins: H + + Pr - HPr

15. Acid-Base: Physiology (12) Intracellular and bone buffers: Proteins, organic and inorganic phosphates, Hb in erythrocytes: H + + Hb - HHb Also HCO 3 (12mmol/L) Bone is important IC buffer (40% of buffering of acute acid load) Uptake of H + in exchange for surface Na + and K +, and dissolution of bone mineral releasing NaHCO 3 and KHCO 3, and then CaCO 3 and CaHPO 4.

17. Acid-Base: Physiology (13) RESPONSE TO METABOLIC AND RESPIRATORY ACID LOADS Buffering by plasma HCO 3 - occurs immediately Intracellular buffering of CO 2 : 15mins Entry of H + into cells: 2-4h

18. Acid-Base: Physiology (14) Buffering of CO 2 is intracellular: CO 2 + H 2 O H 2 CO 3 HCO 3 - + H + CO 2 CO 2 + H 2 O H 2 CO 3 + Hb - HHb + HCO 3 - HCO 3 -

19. Acid-Base: Physiology (15) RESPIRATORY COMPENSATION In the case of metabolic acidosis: pCO 2 = 1.5HCO 3 - + 8 i.e. If HCO 3 - 14, expected pCO2 = (1.5 x 14) + 8 = 29 H + = 24 x 29 = 50 pH = 7.3 14 If there were no change in pCO2: H + = 24 x 40 = 68.5 pH ~ 7.17 14 Thus: RESPIRATORY COMPENSATION VERY IMPORTANT

20. Acid-Base: Physiology (16) Buffering of acid-base loads: 1.Chemical buffering 2.Changes in ventilation to control pCO 2 3.Alterations in renal H + excretion to regulate plasma [HCO3 - ]. Renal H + excretion: 1.Kidneys must excrete 50-100mM H + generated each day 2.All HCO 3 - filtered must be reabsorbed (since loss of HCO 3 - from body is equivalent to adding H +. 3.H + secreted by proximal tubules and collecting tubules (by different mechanisms). 4.Daily acid load cannot be excreted as free acid, and thus must be buffered in urine, by phosphate or NH 3.

25. NH 4 + Na + Solution: “proton acceptors” Proton Acceptor #1: NH 3 H+H+ H+H+ Na + NH 3 NH 4 + HCO 3 - Glutamine NH 3 + CO 2 + H 2 O Glutaminase Proximal tubule How to get rid of H + ?

26. NH 4 + NH 4 + undergoes counter-current multiplication-1

27. NH 4 + NH 3 H+H+ H+H+ NH 4 + undergoes counter-current multiplication-2 NH 4 +

28.  IC cell Na + H+H+ ATP ADP + P i NH 3 NH 4 + H+H+ NH 3 NH 4 + undergoes counter-current multiplication-3

29. Proton Acceptor #2: HPO 4 -- urine H + + HPO 4 --  H 2 PO 4 - pKa = 6.8 Location pH HPO 4 -- H 2 PO 4 - amt buffered Consider 50 millimoles of phosphate in the glomerular filtrate: filtrate 7.4 40 10 0 end prox 6.8 25 25 15 urine 4.8 0.5 49.5 39.5

30. The Four Cardinal Acid Base Disorders M acidosis M alkalosis R acidosis R alkalosis Disorder pHpCO 2 [HCO 3 - ]            

31. Acid-Base Disorders (1) Evaluation begins with pH: this indicates main disorder. e.g. pH = 7.3 (H + = 50). HCO 3 - = 15 pCO 2 = 30 H + = 24 x pCO2 = 24 x 30 = 48 HCO 3 - 15 i.e. Pure metabolic acidosis with respiratory compensation But: pH = 7.4 (H + = 40) HCO 3 - =14 pCO 2 = 23 The expected pCO 2 for HCO 3 - of 14 would be (14 x 1.5 + 8) = 29. Thus, this is a mixed metabolic acidosis and respiratory alkalosis, e.g. salicylate poisoning.

32. Acid-Base Disorders (1) (Cont) pH = 7.35 pCO 2 = 50 HCO 3 - = 27 This is a chronic respiratory acidosis with renal compensation Compensatory changes never return pH to normal. Thus, if pH is normal with alterations in HCO 3 - and pCO 2, a mixed disorder is present.

33. Acid-Base Disorders (2) Respiratory Acidosis 15,000mM CO 2 produced every day CO 2 + H 2 O H 2 CO 3 HCO 3 - + H + H+ combines with intracellular buffers: H 2 CO 3 + Hb - HHb + HCO 3 - Thus, metabolically generated CO 2 is carried in bloodstream as HCO 3 -, with little change in pH. Hypercapnia and respiratory acidosis usually due to reduction in effective respiratory ventilation, not increase in CO 2 production. BUT:

34. Respiratory Acidosis In conditions of hypovolemia, there is reduced muscle blood flow, and thus reduced clearance of CO 2 from muscle. Thus pCO2 rises and pH falls, without change in respiration

35. Acid-Base Disorders (2) Respiratory Acidosis Compensation (slow, because it is renal) Acute: 1meq/l increase in HCO 3 /10mmHg rise in pCO 2 Chronic: 3.5meq/l increase in HCO 3 /10mmHg rise in pCO 2

36. Acid-Base Disorders (5) Respiratory Alkalosis Primary decrease in pCO 2. Compensation requires lowering of HCO 3 -. H + moves from cells into ECF: H + + HCO 3 - H 2 CO 3 CO 2 + H 2 O (H + derived from HBuf H + + Buf - ) HCO 3 - falls 2meq/l for each 10mmHg fall in pCO 2. Chronic respiratory alkalosis Compensatory decrease in renal H + excretion which begins within 2h but is not complete for 2-3 days. Thus HCO 3 - falls 4meq/l for each 10mmHg fall in pCO 2. Usually caused by primary hypoxemia, e.g. pulmonary disease, CHF, severe anemia; or direct stimulation of respiratory center: Gram Neg. sepsis, salicylate poisoning; mechanical ventilation

37. Causes of Respiratory Alkalosis Chronic 10 mm Hg  pCO 2  3-5 mEq/L  HCO 3 - Acute 10 mm Hg  pCO 2  2 mEq/L  HCO 3 - Fear Pain Acid-base exams… Anxiety Altitude; Psychosis Sepsis; Stiff lungs Liver failure Salicylates Pregnancy Neurological Iatrogenic (wrong ventilator setting)

38. Acid-Base Disorders (6) METABOLIC ACIDOSIS Low pH, low HCO 3 -, compensatory hyperventilation. HCO 3 - less than 10 always indicates metabolic acidosis, since renal compensation for chronic hypercapnia cannot reduce HCO 3 - to this extent. H + + HCO 3 - H 2 CO 3 CO 2 + H 2 O Thus metabolic acidosis can be produced by addition of H + or loss of HCO 3 -. Buffering: Extracellular buffering (HCO 3 - ) very efficient. Intracellular buffering: 55-60% of acid load. K+ moves out of cells. Thus metabolic acidosis often associated with hyperkalemia (0.6meq/l rise in K+ for every 0.1pH unit fall in pH). Does not occur in organic acidosis (lactic, ketosis).

39. Pathogenesis of Metabolic Acidosis Acidosis-induced decrease in Bicarbonate Acid production can be: 1.Normal Under-excretion of acid (acute or chronic renal failure, renal tubular acidosis) Bicarbonate wasting (renal or GI) 2. Excessive Endogenous acid (lactic, ketone, amino, phophoric) Exogenous acid (salicylate, methanol, ethylene glycol, HCl)

40. Acid-Base Disorders (7) METABOLIC ACIDOSIS (cont) Respiratory compensation is important in acute metabolic acidosis, but not in chronic metabolic acidosis (fall in pCO 2 reduces Respiratory compensation is important in acute metabolic acidosis, but not in chronic metabolic acidosis (fall in pCO 2 reduces HCO 3 - reabsorption in kidney). Renal buffering: H + + HPO 4 2- H 2 PO 4 - H + + NH 3 NH 4 + Decreased H + excretion (e.g. CRF, RTA) causes slowly developing acidosis. Acute increase in acid load can overwhelm renal secretory capacity and cause rapid onset of severe metabolic acidosis.

41. Acid-Base Disorders (8) METABOLIC ACIDOSIS (cont) ANION GAP A.G. = [Na + ] – ([Cl - + [HCO 3 - ]) A.G. = [Na + ] – ([Cl - ] + [HCO 3 - ]) = 140 – (105 + 24) = 11 A.G. = 12 + 2 Usually caused by increase in unmeasured anions. e.g. If acid is HCl: HCl + NaHCO 3 NaCl + H 2 CO 3 CO 2 + H 2 O HCO 3 - replaced by HCl; thus no change in A.G. If acid HA: HA + NaHCO 3 NaA + H 2 CO 3 CO 2 + H 2 O Accumulation of A - (not usually measured) leads to increase in A.G.

42. Most important anion is Pr -. For every 1g reduction in serum albumin, AG falls by 2.3mmol/l. IgG cationic, IgA anionic UC 13 UA 25

44. Acid-Base Disorders (9) METABOLIC ACIDOSIS (cont) A - usually lactate, ketones, HCOOH or (COOH) 2 A - usually lactate, ketones, HCOOH or (COOH) 2. e.g. A 27 year old diabetic presents in coma: Na + 140pH 7.1 K + 7.0pCO 2 20 Cl - 105 HCO 3 - 6 Glucose 800Ketones 4+ A.G. 29 Decrement in HCO 3 - =18 Increase in A.G. =18

45. Acid-Base Disorders (10) METABOLIC ACIDOSIS (cont) Anion Gap in diarrhea: Loss of HCO 3 - Thus: Normal A.G. Anion Gap in renal failure: Retention of H +, SO 4 2- Thus: Raised A.G. Anion Gap in Lactic Acidosis: Increased production of Lactate - : Thus, raised A.G.

46. ANION GAP H + X - + NaHCO 3 = Na + X - + CO 2 + H 2 O AG = Na + + {Cl - + HCO 3 } = 12+2 mmol NORMAL NORMAL HIGH AG ACIDOSIS AG ACIDOSIS Na+ 140 140140 Cl- 105 115105 HCO3 25 15 15 AG 10 10 20  HCO3 -10 -10  AG 0 10 LACT. 1 10  LACT. 0 +10 (D = change from normal)

47. CAUSES OF KETOACIDOSIS 1.Starvation4. Enzyme Deficiences 2.Diabetes Mellitus -G-6 Phosphatase 3.Alcoholic -F-1,6 Diphosphatase 5.False Positives -Paraldehyde -Antabuse + ETOH -Captopril -Isopropyl (rubbing alcohol)

50. DIAGNOSIS OF LACTIC ACIDOSIS HCO3, pCO2, pH: all low Anion gap increased > 12 Ketotest Neg; BUN < 40mg/dl No intoxication Serum [lactate] increased > 2mM. -------------------------------------------------------------------------------------------------- CLINICAL EVALUATION OF TISSUE OXYGENATION: Type A: Clinically apparent hypoxia (cyanosis, hypotension, hypoxemia) -CAUSES: CHF, SHOCK, ANEMIA, SEVERE HYPOXEMIA Type B: Clinically well oxygenated (pink periphery, normal BP) -CAUSES: a) Common: liver damage, sepsis, seizures, sepsis, DM, malignancy b) Drugs & Toxins: Ethanol, methanol, biguanides c) Hereditary disorders: von Gierke’s disease, pyruvate D-H def. d) Miscellaneous: D-lactic acidosis

52. Uremia is indicated by BUN, creatinine (chronicity by kidney size and Hct). Methanol - presents with ± abdominal pain, vomiting, headache; CT: BL putamen infarcts visual disturbance (optic neuritis)

53. TOXIC ALCOHOLS

54. ETHANOL & LACTIC ACIDOSIS

55. TOXIC ALCOHOLS

56. Normal retina (left); optic neuritis (right) Methanol intoxication: neurological effects Putamen infarcts

57. Ethylene glycol - presents with ± CNS disturbances, cardiovascular collapse, respiratory failure, renal failure Oxalate crystals (octahedral or dumbell) in urine are diagnostic Anion gap may be > 50 Osmolal gap > 10 mOsm

61. NORMAL ANION GAP ACIDOSIS 2 Main Causes: 1. Diarrhea 2. Renal Tubular Acidosis

63. Pancreas Ileum Colon Pancreas Ileum Colon Diarrhea Causes Loss of HCO 3 - And a Normal Anion Gap Acidosis And Hypokalemia HCO 3 - Cl - HCO 3 - Cl - K+K+ HCO 3 - NormalDiarrhea Cl -

64. (TYPE IV)

70. Distal RTA Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - Aldosterone amphotericin Auto-immune

74. Hypo- kalemia in distal RTA: H + no longer shunts Na + current so K + must do so Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - Aldosterone

80. Hyporenin- hypo aldosteronism Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - Aldosterone Diabetes is the main cause

81. Urine pH generally < 5.5 as if the H + gradient is OK but the H + “throughput” is poor Plasma [HCO 3 - ] usually above 15 mEq/L Major problem: hyperkalemia suppresses ammoniagenesis Hypoaldosteronism (“Type IV RTA”)

84. CAUSES OF METABOLIC ALKALOSIS  VOLUME CONTRACTION  Vomiting, N/G suction  Renal loss of H +, Cl - and K + : diuretics, drug anions.  VOLUME EXPANSION, HTN, K + - DEFICIENCY  High renin (RAS)  Low renin (Primary hyperaldosteronism)

86. GASTRIC JUICE Vomitus/Gastric drainage: Volume: 0.00 to 3.00 L/d Na + :20 to 100 mmol/L K + :10 to 15 mmol/L Cl - :120 to 160 mmol/L

87. PATHOPHYSIOLOGY: PHASES OF METABOLIC ALKALOSIS DUE TO VOMITING  GENERATIVE PHASE  LOSS OF ACID  GAIN OF HCO 3 -  LOSS OF Cl -  MAINTENANCE PHASE (KIDNEY LOSES ABILITY TO EXCRETE HCO 3 - EFFICIENTLY )  VOLUME CONTRACTION  LOW GFR  Cl- DEPLETION  K+ DEPLETION

91. SYNDROME OF ECF CONTRACTION, NORMAL BP, K+ DEFICIENCY & SECONDARY HYPERALDOSTERONISM  GI ORIGIN  VOMITING & NG SUCTION  VILLOUS ADENOMA  RENAL ORIGIN  DIURETICS, EDEMATOUS STATES  K+ DEPLETION  BARTTER & GITELMAN SYNDROME  NON-REABSORBABLE ANIONS (PENICILLIN & CARBENICILLIN)

92. Collecting Duct Acidification Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - pH min = 5

97. PROBLEMS IN ACID-BASE (1) אשה בת 35 מגיעה לחדר מיון מחוסרת הכרה. התלוננה על חולשה הולכת וגוברת במשל חודשיים. בבדיקה: ירידה בהחזרים גידיים. Na135meq/L K1.5meq/L Cl118meq/L HCO 3 7 Anion Gap 10meq/L ABG:pH6.88 (H + 132) pCO 2 40 Urine:pH6.5

98. PROBLEMS IN ACID-BASE (2) אשה בת 68 מגיעה לחדר מיון לאחר שלשולים במשך שבוע ימים. משקל גוף 60 ק''ג. לחץ דם 100/60 פרקדן, 70/40 בעמידה. ירידה ניכרת בטורגור של העור. Creatinine3.5mg/dl Na133meq/L K2.5meq/L Cl118meq/L HCO35 Anion Gap10meq/L ABG:pCO212 H+57neq/L pH7.24

99. PROBLEMS IN ACID-BASE (3) אלכוהוליסט בן 36 אושפז בבי''ח עקב הקאות במשך 5 ימים. בבדיקה: לחץ דם 120.80, ערפול הכרה. Urea80mg/dl Creatinine1.9mg/dl Na135meq/L K5.2meq/L Cl85meq/L HCO 3 25meq/L Anion Gap25meq/L Ketones:Weakly Positive ABG:pCO 2 40 H + 40 (pH 7.4)

100. PROBLEMS IN ACID-BASE (4) אצל אשה בת 47, בד''כ בבריאות טובה, נמצאת K של 3.0. ללא אנמנזה של יתר לחץ דם, הקאות או שימוש בדיורטיקה. קיבלה תוספות של K, אך היפוקלמיה חזרה כאשר התוספות הופסקו. אושפזה לשם בירור. בדיקה פיזיקלית: ב.מ.פ. לחץ דם תקין. Urea 30mg/dl Creatinine0.8mg/dl Na142meq/L K2.7meq/L Cl98meq/L HCO334meq/L Anion Gap10meq/L 24h Urinary Excretion:Na85meq(Renin: High) K85meq(Aldosterone: High) Cl65meq

101. PROBLEMS IN ACID-BASE (5) אשה בת 74 אושפזה בבי''ח עקב בלבול, חולשה וירידה בהחזרים. לא ניתן לקבל אנמנזה. Urea 76mg/dl Creatinine1.6mg/dl Na145meq/L K2.4meq/L Cl86meq/L HCO 3 45meq/L Anion Gap14meq/L 24h Urinary Excretion:Na30meq K65meq Cl2meq ABG:pCO 2 49 H + 26 (pH 7.58)