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ACID-BASECLINICAL PHYSIOLOGY Jayson Rapoport Faculty of Medicine, Hebrew University, Jerusalem Department of Nephrology, Kaplan Medical Center, Rehovot Acid-Base: Physiology (1) [H+] maintained within relatively narrow limits: Normal [H+] = 40nM/L (40 x 10-9M/l) (compare to [Na+]: 140mM/l, or 140 x 10-3M/l.) Usually expressed as pH pH = -log [H+] = -log [40 x 10-9] = 7.4 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 Acid-Base: Physiology (3) Definitions: ACID: substance that donates H+ BASE: substance that accepts H+ ACID H2CO3 HCl NH4+ BASE H+ + HCO3H+ + ClH+ + NH3 Acid-Base: Physiology (4) 2 types of acid produced in body: 1. CARBONIC: produced by metabolism of CO2 and fats: 15,000mM of CO2. 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. Stages of acid-base balance 1. Acid synthesis: -S-containing AA, phosphoesters (H3PO4), organic acids from foods (Total production 1-1.5meg/kg/day) 2. Buffering: -HCO3-H2CO3 -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 Acid-Base: Physiology (6) Since homeostatic mechanisms of body cannot allow large changes in pH, acid produced must be buffered. BUFFERS: Weak acids which can release or take up H+. e.g. HCl + Na2HPO4 NaCl + NaH2PO4 NaOH + Na2HPO4 NaH2PO4 + H2O Acid-Base: Physiology (7) Bicarbonate system: H2CO3 H+ + HCO3Most important system because: • H2CO3 CO2 + H2O • HCO3- present in high concentrations (24mM/l) Acid-Base: Physiology (8) Henderson-Hasselbalch Eqn: pH = pK + log [HCO3] [H2CO3] = 6.1 + log [HCO3] [0.03pCO2] But Henderson Eqn. much more useful: [H+] = 24 x pCO2 [HCO3-] Relationship between pH and H+ Concentration in the physiologic range pH H+, (nanomol/L) 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 16 20 26 32 40 50 63 80 100 125 160 Acid-Base: Physiology (9) [H+] = 24 x pCO2 [HCO3] e.g. 40 = 24 x 40 [HCO3] [HCO3] = 24 pK = 6.1 (far from normal pH of 7.4). However, this system is efficient because pCO2 controlled by ventilation Acid-Base: Physiology (10) ISOHYDRIC PRINCIPLE All buffers in solution are in equilibrium: [H+] = k1 [pCO2] = k2 [H2PO4] [HCO3-] [HPO42-] = k3 [HA] [ A -] Thus, all extracellular buffers are consumed at an equal rate Acid-Base: Physiology (11) Extracellular buffers: Bicarbonate most important: H2SO4 + 2NaHCO3 2H2O Na2SO4 + H2CO3 HCO3- cannot buffer H2CO3: H2CO3 + HCO3HCO3- + H2CO3 Thus, H2CO3 is buffered by intracellular buffers. Other extracellular buffers: • HPO42- (1mM/l) • Plasma proteins: H+ + PrHPr 2CO2 + Acid-Base: Physiology (12) Intracellular and bone buffers: Proteins, organic and inorganic phosphates, Hb in erythrocytes: H+ + HbHHb Also HCO3 (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 NaHCO3 and KHCO3, and then CaCO3 and CaHPO4. Acid-Base: Physiology (13) RESPONSE TO METABOLIC AND RESPIRATORY ACID LOADS • Buffering by plasma HCO3- occurs immediately • Intracellular buffering of CO2 : 15mins • Entry of H+ into cells: 2-4h Acid-Base: Physiology (14) Buffering of CO2 is intracellular: CO2 + H2O H2CO3 CO2 HCO3- + H+ CO2 + H2O H2CO3 + HbHHb + HCO3- HCO3- Acid-Base: Physiology (15) RESPIRATORY COMPENSATION In the case of metabolic acidosis: pCO2 = 1.5HCO3- + 8 i.e. If HCO3- 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 Acid-Base: Physiology (16) Buffering of acid-base loads: 1. Chemical buffering 2. Changes in ventilation to control pCO2 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 HCO3- filtered must be reabsorbed (since loss of HCO3from 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 NH3. How to get rid of H+ ? Solution: “proton acceptors” Proton Acceptor #1: NH3 Glutamine NH4+ Glutaminase H+ Na+ H+ NH3 NH3 NH3 + CO2 + H2O HCO3- NH4+ Na+ NH4+ Proximal tubule NH4+ undergoes counter-current multiplication-1 NH4+ NH4+ undergoes counter-current multiplication-2 H+ NH4+ H+ NH3 NH4+ NH3 NH4+ NH4+ undergoes counter-current multiplication-3 NH3 NH3 Na+ NH4+ NH3 H+ NH3 ATP H+ ADP + Pi a IC cell NH4+ Proton Acceptor #2: HPO4-urine H+ + HPO4-- H2PO4- pKa = 6.8 Consider 50 millimoles of phosphate in the glomerular filtrate: Location pH HPO4-- H2PO4- filtrate 7.4 40 10 0 end prox 6.8 25 25 15 urine 4.8 0.5 49.5 amt buffered 39.5 The Four Cardinal Acid Base Disorders pCO2 [HCO3-] Disorder pH M acidosis M alkalosis R acidosis R alkalosis Acid-Base Disorders (1) Evaluation begins with pH: this indicates main disorder. e.g. pH = 7.3 (H+= 50). HCO3- = 15 pCO2 = 30 H+ = 24 x pCO2 = 24 x 30 = 48 HCO315 i.e. Pure metabolic acidosis with respiratory compensation But: pH = 7.4 (H+= 40) HCO3-=14 pCO2= 23 The expected pCO2 for HCO3- of 14 would be (14 x 1.5 + 8) = 29. Thus, this is a mixed metabolic acidosis and respiratory alkalosis, e.g. salicylate poisoning. Acid-Base Disorders (1) (Cont) pH = 7.35 pCO2 = 50 HCO3- = 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 HCO3- and pCO2, a mixed disorder is present. Acid-Base Disorders (2) Respiratory Acidosis 15,000mM CO2 produced every day CO2 + H2O H2CO3 HCO3- + H+ H+ combines with intracellular buffers: H2CO3 + HbHHb + HCO3Thus, metabolically generated CO2 is carried in bloodstream as HCO3-, with little change in pH. Hypercapnia and respiratory acidosis usually due to reduction in effective respiratory ventilation, not increase in CO2 production. BUT: Respiratory Acidosis In conditions of hypovolemia, there is reduced muscle blood flow, and thus reduced clearance of CO2 from muscle. Thus pCO2 rises and pH falls, without change in respiration Acid-Base Disorders (2) Respiratory Acidosis Compensation (slow, because it is renal) • Acute: 1meq/l increase in HCO3 /10mmHg rise in pCO2 • Chronic: 3.5meq/l increase in HCO3 /10mmHg rise in pCO2 Acid-Base Disorders (5) Respiratory Alkalosis Primary decrease in pCO2. Compensation requires lowering of HCO3-. H+ moves from cells into ECF: H+ + HCO3H2CO3 CO2 + H2O (H+ derived from HBuf H+ + Buf -) HCO3- falls 2meq/l for each 10mmHg fall in pCO2. Chronic respiratory alkalosis Compensatory decrease in renal H+ excretion which begins within 2h but is not complete for 2-3 days. Thus HCO3- falls 4meq/l for each 10mmHg fall in pCO2. 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 Causes of Respiratory Alkalosis Acute Chronic 10 mm Hg pCO2 2 mEq/L HCO3- 10 mm Hg pCO2 3-5 mEq/L HCO3- Fear Altitude; Psychosis Pain Salicylates Liver failure Anxiety Sepsis; Stiff lungs Acid-base exams… Pregnancy Neurological Iatrogenic (wrong ventilator setting) Acid-Base Disorders (6) METABOLIC ACIDOSIS Low pH, low HCO3- , compensatory hyperventilation. HCO3- less than 10 always indicates metabolic acidosis, since renal compensation for chronic hypercapnia cannot reduce HCO3- to this extent. H+ + HCO3H2CO3 CO2 + H2O Thus metabolic acidosis can be produced by addition of H+ or loss of HCO3-. Buffering: • Extracellular buffering (HCO3-) 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). 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) Acid-Base Disorders (7) METABOLIC ACIDOSIS (cont) Respiratory compensation is important in acute metabolic acidosis, but not in chronic metabolic acidosis (fall in pCO2 reduces HCO3- reabsorption in kidney). Renal buffering: H+ + HPO42- H2PO4- H+ + NH3 NH4+ 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. Acid-Base Disorders (8) METABOLIC ACIDOSIS (cont) ANION GAP = [Na+] – ([Cl-] + [HCO3-]) = 140 – (105 + 24) = 11 A.G. = 12 + 2 Usually caused by increase in unmeasured anions. e.g. If acid is HCl: HCl + NaHCO3 NaCl + H2CO3 CO2 + H2O HCO3- replaced by HCl; thus no change in A.G. If acid HA: HA + NaHCO3 NaA + H2CO3 CO2 + H2O Accumulation of A- (not usually measured) leads to increase in A.G. A.G. UC 13 UA 25 Most important anion is Pr-. For every 1g reduction in serum albumin, AG falls by 2.3mmol/l. IgG cationic, IgA anionic Acid-Base Disorders (9) METABOLIC ACIDOSIS (cont) A- usually lactate, ketones, HCOOH or (COOH)2. e.g. A 27 year old diabetic presents in coma: Na+ 140 pH 7.1 K+ 7.0 pCO2 20 Cl105 HCO3- 6 Glucose 800 Ketones 4+ A.G. 29 Decrement in HCO3- =18 Increase in A.G. =18 Acid-Base Disorders (10) METABOLIC ACIDOSIS (cont) • • • Loss of HCO3Thus: Normal A.G. Anion Gap in renal failure: Retention of H+, SO42Thus: Raised A.G. Anion Gap in Lactic Acidosis: Increased production of Lactate-: Thus, raised A.G. Anion Gap in diarrhea: ANION GAP H+X- + NaHCO3 = Na+X- + CO2 + H2O AG = Na+ + {Cl- + HCO3} = 12+2 mmol NORMAL Na+ 140 Cl105 HCO3 25 AG 10 DHCO3 DAG LACT. DLACT. (D = change from normal) NORMAL AG ACIDOSIS 140 115 15 10 -10 0 1 0 HIGH AG ACIDOSIS 140 105 15 20 -10 10 10 +10 CAUSES OF KETOACIDOSIS 1. Starvation 4. Enzyme Deficiences 2. Diabetes Mellitus -G-6 Phosphatase 3. Alcoholic -F-1,6 Diphosphatase 5.False Positives -Paraldehyde -Antabuse + ETOH -Captopril -Isopropyl (rubbing alcohol) 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 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) TOXIC ALCOHOLS ETHANOL & LACTIC ACIDOSIS TOXIC ALCOHOLS Methanol intoxication: neurological effects Normal retina (left); optic neuritis (right) Putamen infarcts 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 NORMAL ANION GAP ACIDOSIS 2 Main Causes: 1. Diarrhea 2. Renal Tubular Acidosis Diarrhea Causes Loss of HCO3And a Normal Anion Gap Acidosis And Hypokalemia Pancreas Pancreas HCO3- HCO3- Ileum HCO3- Cl- Ileum Cl- Cl- Colon Normal K+ HCO3 Diarrhea - Colon (TYPE IV) Distal RTA Na+ Na+ K+ K+ Auto-immune Principal cell Aldosterone ATP H+ HCO3- ADP + Pi Clamphotericin Cl- a IC cell Cl- Cl- HCO3- ATP H+ ADP + Pi b IC cell Na+ Na+ K+ K+ Hypokalemia in distal RTA: Principal cell Aldosterone ATP H+ HCO3- ADP + Pi Cl- + H no longer shunts Na + current so K+ must do so Cl- a IC cell Cl- Cl- HCO3- ATP H+ ADP + Pi b IC cell Na+ Na+ K+ K+ Hyporeninhypo aldosteronism Principal cell Aldosterone ATP H+ HCO3- ADP + Pi Cl- Diabetes is the main cause Cl- a IC cell Cl- Cl- HCO3- ATP H+ ADP + Pi b IC cell Hypoaldosteronism (“Type IV RTA”) Urine pH generally < 5.5 as if the H+ gradient is OK but the H+ “throughput” is poor Plasma [HCO3-] usually above 15 mEq/L Major problem: hyperkalemia suppresses ammoniagenesis 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) 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 PATHOPHYSIOLOGY: PHASES OF METABOLIC ALKALOSIS DUE TO VOMITING GENERATIVE PHASE LOSS OF ACID GAIN OF HCO3LOSS OF Cl MAINTENANCE PHASE (KIDNEY LOSES ABILITY TO EXCRETE HCO3- EFFICIENTLY) VOLUME CONTRACTION LOW GFR Cl- DEPLETION K+ DEPLETION 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) Na+ Na+ K+ K+ Principal cell ATP Collecting Duct Acidification H+ HCO3- ADP + Pi ClCl- a IC cell Cl- Cl- HCO3- ATP H+ pHmin = 5 ADP + Pi b IC cell )PROBLEMS IN ACID-BASE (1 אשה בת 35מגיעה לחדר מיון מחוסרת הכרה .התלוננה על חולשה הולכת וגוברת במשל חודשיים .בבדיקה :ירידה בהחזרים גידיים. Na 135meq/L K 1.5meq/L Cl 118meq/L HCO3 7 Anion Gap 10meq/L pH )6.88 (H+ 132 pCO2 40 ABG: pH Urine: 6.5 )PROBLEMS IN ACID-BASE (2 אשה בת 68מגיעה לחדר מיון לאחר שלשולים במשך שבוע ימים .משקל גוף 60ק''ג. לחץ דם 100/60פרקדן 70/40 ,בעמידה .ירידה ניכרת בטורגור של העור. Creatinine 3.5mg/dl Na 133meq/L K 2.5meq/L Cl 118meq/L HCO3 5 Anion Gap 10meq/L 12 57neq/L 7.24 pCO2 H+ pH ABG: PROBLEMS IN ACID-BASE (3) ,120.80 לחץ דם: בבדיקה. ימים5 אושפז בבי''ח עקב הקאות במשך36 אלכוהוליסט בן .ערפול הכרה Urea 80mg/dl Creatinine 1.9mg/dl Na 135meq/L K 5.2meq/L Cl 85meq/L HCO3 25meq/L Anion Gap 25meq/L Ketones: Weakly Positive ABG: pCO2 40 H+ 40 (pH 7.4) )PROBLEMS IN ACID-BASE (4 אצל אשה בת ,47בד''כ בבריאות טובה ,נמצאת Kשל .3.0ללא אנמנזה של יתר לחץ דם ,הקאות או שימוש בדיורטיקה .קיבלה תוספות של ,Kאך היפוקלמיה חזרה כאשר התוספות הופסקו .אושפזה לשם בירור .בדיקה פיזיקלית :ב.מ.פ .לחץ דם תקין. Urea 30mg/dl Creatinine 0.8mg/dl Na 142meq/L K 2.7meq/L Cl 98meq/L HCO3 34meq/L Anion Gap 10meq/L (Renin: )High )(Aldosterone: High 85meq 85meq 65meq Na K Cl 24h Urinary Excretion: PROBLEMS IN ACID-BASE (5) . לא ניתן לקבל אנמנזה. חולשה וירידה בהחזרים, אושפזה בבי''ח עקב בלבול74 אשה בת Urea Creatinine Na K Cl HCO3 Anion Gap 76mg/dl 1.6mg/dl 145meq/L 2.4meq/L 86meq/L 45meq/L 14meq/L 24h Urinary Excretion: Na K Cl pCO2 H+ ABG: 30meq 65meq 2meq 49 26 (pH 7.58)