Metabolic Acidosis A Review by George B. Buczko MD FRCP(C) A Review by George B. Buczko MD FRCP(C)

Case Presentation 1 54 year old man with fever and abnormal liver function for liver biopsy 54 year old man with fever and abnormal liver function for liver biopsy Biopsy “well tolerated” until 3 hours afterwards when he developed abdominal distension, with systolic BP 40 and Hg 4.6 Biopsy “well tolerated” until 3 hours afterwards when he developed abdominal distension, with systolic BP 40 and Hg year old man with fever and abnormal liver function for liver biopsy 54 year old man with fever and abnormal liver function for liver biopsy Biopsy “well tolerated” until 3 hours afterwards when he developed abdominal distension, with systolic BP 40 and Hg 4.6 Biopsy “well tolerated” until 3 hours afterwards when he developed abdominal distension, with systolic BP 40 and Hg 4.6

Vasopressin and bicarbonate infusions and blood transfusion restored BP to 85/40 Vasopressin and bicarbonate infusions and blood transfusion restored BP to 85/40 The patient was rushed to the OR for exploratory laparotomy The patient was rushed to the OR for exploratory laparotomy Vasopressin and bicarbonate infusions and blood transfusion restored BP to 85/40 Vasopressin and bicarbonate infusions and blood transfusion restored BP to 85/40 The patient was rushed to the OR for exploratory laparotomy The patient was rushed to the OR for exploratory laparotomy Case Presentation 2

Arterial blood analysis: pH 6.95, p a O 2 337, p a CO 2 44, TCO 2 10 H + 102nM Na 142, K 6.3, Cl 106 anion gap 26 Albumin 1.2g/dl Expected anion gap 6 because of low albumin Anion gap 20 above expected Lactate 18.3meq/l Minute ventilation 6.4 liters Arterial blood analysis: pH 6.95, p a O 2 337, p a CO 2 44, TCO 2 10 H + 102nM Na 142, K 6.3, Cl 106 anion gap 26 Albumin 1.2g/dl Expected anion gap 6 because of low albumin Anion gap 20 above expected Lactate 18.3meq/l Minute ventilation 6.4 liters Case Presentation 3

The problem: high H + The problem: high H + Cerebral enzyme dysfunction Cerebral enzyme dysfunction Cardiac enzyme dysfunction Cardiac enzyme dysfunction Myocardial dysfunction in the face of hemorrhagic shock Myocardial dysfunction in the face of hemorrhagic shock Downward spiral from more than just blood loss Downward spiral from more than just blood loss The problem: high H + The problem: high H + Cerebral enzyme dysfunction Cerebral enzyme dysfunction Cardiac enzyme dysfunction Cardiac enzyme dysfunction Myocardial dysfunction in the face of hemorrhagic shock Myocardial dysfunction in the face of hemorrhagic shock Downward spiral from more than just blood loss Downward spiral from more than just blood loss Case Presentation 4

Metabolic Acidosis Definition Definition Acid-Base physiology Acid-Base physiology Anion gap Anion gap Differential diagnosis of metabolic acidosis with high anion gap Differential diagnosis of metabolic acidosis with high anion gap Lactic acidosis Lactic acidosis Oxidative phosphorylation Oxidative phosphorylation Types of Lactic acidosis Types of Lactic acidosis Treatment of Lactic Acidosis Treatment of Lactic Acidosis Definition Definition Acid-Base physiology Acid-Base physiology Anion gap Anion gap Differential diagnosis of metabolic acidosis with high anion gap Differential diagnosis of metabolic acidosis with high anion gap Lactic acidosis Lactic acidosis Oxidative phosphorylation Oxidative phosphorylation Types of Lactic acidosis Types of Lactic acidosis Treatment of Lactic Acidosis Treatment of Lactic Acidosis

A condition that causes a primary fall in serum bicarbonate level A condition that causes a primary fall in serum bicarbonate level H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 A condition that causes a primary fall in serum bicarbonate level A condition that causes a primary fall in serum bicarbonate level H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 Metabolic Acidosis (primary fall in serum bicarbonate)

H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 According to the above, a fall in HCO 3 - will result from: According to the above, a fall in HCO 3 - will result from: 1. Addition of H + (shift right:  in HCO 3 - ) 2. Loss of bicarbonate (shift left:  in H+) Increase in H + occurs in both situations Increase in H + occurs in both situations H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 According to the above, a fall in HCO 3 - will result from: According to the above, a fall in HCO 3 - will result from: 1. Addition of H + (shift right:  in HCO 3 - ) 2. Loss of bicarbonate (shift left:  in H+) Increase in H + occurs in both situations Increase in H + occurs in both situations

Increase in H + : Enzyme dysfunction which leads to Enzyme dysfunction which leads to Organ dysfunction Organ dysfunctionHeart/Brain Increase in H + : Enzyme dysfunction which leads to Enzyme dysfunction which leads to Organ dysfunction Organ dysfunctionHeart/Brain Metabolic Acidosis (primary fall in serum bicarbonate)

Increase in H + : H + is accompanied by an anion in order to maintain electrical neutrality H + is accompanied by an anion in order to maintain electrical neutrality The anion may be Cl - (HCl administration) The anion may be Cl - (HCl administration) The anion may be LACTATE, a KETONE, PHOSPHATE, SULPHATE, or an ingested anion The anion may be LACTATE, a KETONE, PHOSPHATE, SULPHATE, or an ingested anion Increase in H + : H + is accompanied by an anion in order to maintain electrical neutrality H + is accompanied by an anion in order to maintain electrical neutrality The anion may be Cl - (HCl administration) The anion may be Cl - (HCl administration) The anion may be LACTATE, a KETONE, PHOSPHATE, SULPHATE, or an ingested anion The anion may be LACTATE, a KETONE, PHOSPHATE, SULPHATE, or an ingested anion

Metabolic Acidosis (primary fall in serum bicarbonate) The Anion Gap: In the body In the body cations = anions Not all of the anions are measured in routine laboratory analysis Not all of the anions are measured in routine laboratory analysis [Na + ] – ( [Cl - ] + [HCO3 - ] ) = 12 [Na + ] – ( [Cl - ] + [HCO3 - ] ) = 12 The Anion Gap: In the body In the body cations = anions Not all of the anions are measured in routine laboratory analysis Not all of the anions are measured in routine laboratory analysis [Na + ] – ( [Cl - ] + [HCO3 - ] ) = 12 [Na + ] – ( [Cl - ] + [HCO3 - ] ) = 12

Metabolic Acidosis (primary fall in serum bicarbonate) The Anion Gap: The usual unmeasured anions that account for the “gap” are: The usual unmeasured anions that account for the “gap” are:AlbuminPhosphatesSulphates The Anion Gap: The usual unmeasured anions that account for the “gap” are: The usual unmeasured anions that account for the “gap” are:AlbuminPhosphatesSulphates

Metabolic Acidosis (primary fall in serum bicarbonate) The Anion Gap: The Anion Gap:  anion gap in the presence of  [H] is a marker for the presence of anions that accompany H but are not routinely measured  anion gap in the presence of  [H + ] is a marker for the presence of anions that accompany H + but are not routinely measured The Anion Gap: The Anion Gap:  anion gap in the presence of  [H] is a marker for the presence of anions that accompany H but are not routinely measured  anion gap in the presence of  [H + ] is a marker for the presence of anions that accompany H + but are not routinely measured

Metabolic Acidosis (primary fall in serum bicarbonate) High Anion Gap Acidosis: TypeAnion: Lactic lactate Lactic lactate Diabeticketones Diabeticketones Uremiasulphate/phosphate Uremiasulphate/phosphate ASAsalicylate ASAsalicylate Methanolformate Methanolformate E. Glycoloxalate E. Glycoloxalate High Anion Gap Acidosis: TypeAnion: Lactic lactate Lactic lactate Diabeticketones Diabeticketones Uremiasulphate/phosphate Uremiasulphate/phosphate ASAsalicylate ASAsalicylate Methanolformate Methanolformate E. Glycoloxalate E. Glycoloxalate

Lactic Acidosis Why do we need oxygen? For oxidative phosphorylation For oxidative phosphorylation What is oxidative phosphorylation? ADP + P i = ATP (requires energy) ADP + P i = ATP (requires energy) The formation of ATP The formation of ATP What does the oxygen do? Why do we need oxygen? For oxidative phosphorylation For oxidative phosphorylation What is oxidative phosphorylation? ADP + P i = ATP (requires energy) ADP + P i = ATP (requires energy) The formation of ATP The formation of ATP What does the oxygen do?

Lactic Acidosis Glycolysis: Glucose  Pyruvate  Acetyl CoA Kreb’s: Acetyl CoA  NADH & FADH Electron transport chain (ETC) NADH & FADH  ATP Glycolysis: Glucose  Pyruvate  Acetyl CoA Kreb’s: Acetyl CoA  NADH & FADH Electron transport chain (ETC) NADH & FADH  ATP

Lactic Acidosis Lactic Acidosis The bulk of ATP is generated in the electron transport chain (ETC) in the mitochondrion The bulk of ATP is generated in the electron transport chain (ETC) in the mitochondrion The energy for creating the high- energy phosphate bond is generated at several points in the ETC. So are hydrogen ions The energy for creating the high- energy phosphate bond is generated at several points in the ETC. So are hydrogen ions The bulk of ATP is generated in the electron transport chain (ETC) in the mitochondrion The bulk of ATP is generated in the electron transport chain (ETC) in the mitochondrion The energy for creating the high- energy phosphate bond is generated at several points in the ETC. So are hydrogen ions The energy for creating the high- energy phosphate bond is generated at several points in the ETC. So are hydrogen ions

Metabolic Acidosis (primary fall in serum bicarbonate) High - Oxygen allows for ATP formation in an electrically-neutral biologically safe manner

Metabolic Acidosis (primary fall in serum bicarbonate) Lactic Acidosis Type A:failure of oxidative phosphorylation ( Pyruvate  Lactate ) Type A:failure of oxidative phosphorylation ( Pyruvate  Lactate ) Type B:lactate production overwhelms lactate metabolism Type B:lactate production overwhelms lactate metabolism Lactic Acidosis Type A:failure of oxidative phosphorylation ( Pyruvate  Lactate ) Type A:failure of oxidative phosphorylation ( Pyruvate  Lactate ) Type B:lactate production overwhelms lactate metabolism Type B:lactate production overwhelms lactate metabolism

Lactic Acidosis Type A (more severe) Failure of ETC: Decreased Oxygen delivery Shock of any type Severe hypoxemia Severe Anemia Inhibitors (CO, CN) Failure of ETC: Decreased Oxygen delivery Shock of any type Severe hypoxemia Severe Anemia Inhibitors (CO, CN)

Lactate production overwhelms lactate metabolism (not anaerobic) Malignancies (after chemotherapy) Malignancies (after chemotherapy) Hepatic failure Hepatic failure Drugs (biguanides, AZT, INH) Drugs (biguanides, AZT, INH) Lactate production overwhelms lactate metabolism (not anaerobic) Malignancies (after chemotherapy) Malignancies (after chemotherapy) Hepatic failure Hepatic failure Drugs (biguanides, AZT, INH) Drugs (biguanides, AZT, INH) Lactic Acidosis Type B (less severe)

Back to original case Arterial blood analysis: pH 6.95, p a O 2 337, p a CO 2 44, TCO 2 10 H + 102nM Na 142, K 6.3, Cl 106 anion gap 26 Albumin 1.2g/dl Expected anion gap 6 because of low albumin Anion gap 20 above expected Lactate 18.3meq/l Minute ventilation 6.4 liters Arterial blood analysis: pH 6.95, p a O 2 337, p a CO 2 44, TCO 2 10 H + 102nM Na 142, K 6.3, Cl 106 anion gap 26 Albumin 1.2g/dl Expected anion gap 6 because of low albumin Anion gap 20 above expected Lactate 18.3meq/l Minute ventilation 6.4 liters

Lactic Acidosis: Treatment Treat the underlying cause Treat the underlying cause Lower the H + concentration Lower the H + concentration Treat the underlying cause Treat the underlying cause Lower the H + concentration Lower the H + concentration

Underlying cause in this case: Profound rapid blood loss Transfusion of blood and products Circulatory support Underlying cause in this case: Profound rapid blood loss Transfusion of blood and products Circulatory support Lactic Acidosis: Treatment

Lower the H + concentration H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 Lower the p a CO 2 by increasing minute ventilation Lower the H + concentration H + + HCO 3 -  H 2 CO 3  H 2 O + CO 2 Lower the p a CO 2 by increasing minute ventilation Lactic Acidosis: Treatment

Lower the p a CO 2 by increasing minute ventilation

For every 1meq/l drop in HCO 3 - from 25, p a CO 2 should decrease by ~ 1 torr “Normal” p a CO 2 in the face of HCO is 25 (40 – 15) and not 40 torr For every 1meq/l drop in HCO 3 - from 25, p a CO 2 should decrease by ~ 1 torr “Normal” p a CO 2 in the face of HCO is 25 (40 – 15) and not 40 torr Lactic Acidosis: Treatment

Intravenous bicarbonate administration: Pro:lowers H + concentration (  pH) improves pressor response improves myocardial function Con:worsens intracellular acidosis may worsen outcome hypertonic

Lactic Acidosis: Treatment Bottom line: If there is adequate circulation and if minute ventilation is appropriate, some bicarbonate administration is warranted. Don’t aim for full correction, continue arterial blood analysis

Definition Definition Acid-Base physiology Acid-Base physiology Anion gap Anion gap Differential diagnosis of metabolic acidosis with high anion gap Differential diagnosis of metabolic acidosis with high anion gap Lactic acidosis Lactic acidosis Oxidative phosphorylation Oxidative phosphorylation Types of Lactic acidosis Types of Lactic acidosis Treatment of Lactic Acidosis Treatment of Lactic Acidosis Definition Definition Acid-Base physiology Acid-Base physiology Anion gap Anion gap Differential diagnosis of metabolic acidosis with high anion gap Differential diagnosis of metabolic acidosis with high anion gap Lactic acidosis Lactic acidosis Oxidative phosphorylation Oxidative phosphorylation Types of Lactic acidosis Types of Lactic acidosis Treatment of Lactic Acidosis Treatment of Lactic Acidosis Metabolic Acidosis: Summary

Lactic Acidosis take-home points With hemodynamic instability: Severe acute bleed SepsisTrauma Increase minute ventilation Analyze arterial blood Judicious intravenous NaHCO 3 -