1. Nephrology Lecture Acid - Base Balance Presented by Anas Diab MD US Board Certified in Nephrology University of Michigan Graduate

2. Acid – Base Balance Each day approximately 15,000 mmol of carbon dioxide form,from oxidation of carbohydrates, amino acids, and fatty acids, and this can rapidly excreted by the lung. 60-70 meq or approximately 1 meq/kg body weight,of fixed nonvolatile acid (mineral acid) mostly sulfuric acid, derived from the metabolism of sulfur-containing amino acids), and phosphate. The concentration of free hydrogen ion in body fluid is 40 nanoequivalents /L, so adding 60-70 meq of hydrogen ion produced daily would be rapidly fatal, if not immediately buffered 40 nanoequivalents /L, so adding 60-70 meq of hydrogen ion produced daily would be rapidly fatal, if not immediately buffered Acid-base balance is maintained to the normal by renal excretion of acid, through a number of intra and extra cellular buffers.

3. Assessment of Acid – Base Balance Bicarbonate-carbon dioxide buffer system: Dissolved CO2 +H2O Dissolved CO2 +H2O H2CO3 HCO3- + H+ The Henderson - Hasselbalch equation: pH = 6.10 + log ([HCO3- ] ÷ [0.03 x PCO2]) pH = 6.10 + log ([HCO3- ] ÷ [0.03 x PCO2])

4. Renal excretion of acid One third of net acid secretion involves the combination of hydrogen ions with urinary titratable acids, particularly phosphate (HPO4 + H+ —> H2PO4). Two third of net acid secretion involves the excretion of excess hydrogen ions as Amonium ions. Electroneutrality is preserved by coupling amonium ions to chloride forming Amonium chloride, and the end result that appropriate titration of renal acidity should result in high levels of urinary chloride.

5. DEFINITIONS Acidosis — A process that tends to lower the extracellular fluid pH : this can be induced by a fall in the extracellular (or plasma ) bicarbonate concentration or by an elevation in the PCO2. this can be induced by a fall in the extracellular (or plasma ) bicarbonate concentration or by an elevation in the PCO2. Alkalosis — A process that tends to raise the extracellular fluid pH this can be induced by an elevation in the extracellular (or plasma ) bicarbonate concentration or by a fall in the PCO2. this can be induced by an elevation in the extracellular (or plasma ) bicarbonate concentration or by a fall in the PCO2.

6. Type of Acidosis Metabolic acidosis — A disorder associated with a low pH and low bicarbonate concentration. Respiratory acidosis — A disorder associated with a low pH and high PCO2.

7. Type of Alkalosis Metabolic alkalosis — A disorder associated with a high pH and high bicarbonate concentration. Respiratory alkalosis — A disorder associated with a high pH and low PCO2.

8. Causes of Metabolic Acidosis Overproduction of Endogenous acid (Diabetic Ketoacidosis) Loss of Alkali stores (Diarrhea or Renal Tubular Acidosis) Failure of Renal Acid Secretion or base synthesis ( Renal Failure)

10. Compensatory responses Each of the simple acid-base disorders is also associated with a compensatory response. The Henderson-Hasselbalch equation shows that the pH is determined by the ratio between the HCO3 concentration and PCO2, not by the value of either one alone. The body responds to an acid-base disorder by making compensatory respiratory or renal responses in an attempt to normalize the pH. This response is mediated at least in part by parallel alterations in regulatory cell (renal tubular or respiratory center) pH

11. Compensation in Met. Acidosis Ventilation is increased, resulting in a fall in PCO2, which tends to raise the pH toward normal. Note that protection of the HCO3/PCO2 ratio and therefore the pH requires a compensatory response that varies in the same direction as the primary disorder (low bicarbonate leads to low PCO2). The respiratory compensation results in a 1.2 mmHg fall in the PCO2 for every 1 meq/L reduction in the plasma bicarbonate concentration. This response begins in the first hour, and is complete by 12 to 24 hours.

12. Compensation in Met. Alkalosis The respiratory compensation tends to raise the PCO2 by 0.7 mmHg for every 1 meq/L elevation in the plasma bicarbonate concentration This response may not be seen in all patients because of concurrent problems. For example, diuretics tend to induce metabolic alkalosis in heart failure or cirrhosis; both of these disorders, however, are associated with hyperventilation and a low PCO2. Thus, the expected rise in PCO2 with metabolic alkalosis may not be seen due to the underlying respiratory alkalosis.

13. Compensation in Respiratory acidosis Compensation in Respiratory acidosis The compensatory response to respiratory acid-base disorders occurs in two stages: 1- Cell buffering that acts within minutes to hours 2- The renal compensation that is not complete for 3 to 5 days. As a result, different responses are seen with acute and chronic disorders. In acute respiratory acidosis, The [HCO 3 ] will increase by 1 mmol/l for every 10 mmHg elevation in pCO 2 above 40 mmHg. Expected [HCO 3 ] = 24 + { (Actual pCO 2 - 40) / 10 } In chronic respiratory acidosis The [HCO3] will increase by 4 mmol/l for every 10 mmHg elevation in pCO2 above 40mmHg. Expected [HCO3] = 24 + 4 { (Actual pCO2 - 40) / 10} The renal response is carefully regulated, so that administering extra bicarbonate results in the urinary excretion of the excess alkali without elevation in the plasma bicarbonate concentration

14. Compensation in Respiratory alkalosis In acute respiratory alkalosis, The [HCO3] will decrease by 2 mmol/l for every 10 mmHg decrease in pCO2 below 40 mmHg. Expected [HCO3] = 24 - 2 { ( 40 - Actual pCO2) / 10 } Expected [HCO3] = 24 - 2 { ( 40 - Actual pCO2) / 10 } In chronic respiratory alkalosis, The [HCO3] will decrease by 5 mmol/l for every 10 mmHg decrease in pCO2 below 40 mmHg. In chronic respiratory alkalosis, The [HCO3] will decrease by 5 mmol/l for every 10 mmHg decrease in pCO2 below 40 mmHg. Expected [HCO3] =24 - 5 { ( 40 - Actual pCO2) / 10 } ( range: +/- 2) Expected [HCO3] =24 - 5 { ( 40 - Actual pCO2) / 10 } ( range: +/- 2) Reductions in both bicarbonate reabsorption and in ammonium excretion contribute to the compensatory reduction in the plasma bicarbonate concentration

16. MIXED ACID-BASE DISORDERS Some patients have two or more acid-base disorders. An understanding of the approach to this problem requires knowledge of the renal and respiratory compensations that have been empirically observed in patients with simple acid-base disorders. Values substantially different from those that are expected indicates the presence of a mixed disturbance

17. How to reach a diagnosis? Evaluation of an acid-base disorder begins with measurement of the extra cellular pH Measurement of the plasma bicarbonate concentration, Measurement of the plasma bicarbonate concentration, A low plasma bicarbonate concentration can be seen as the primary change in metabolic acidosis and as the compensatory response in respiratory alkalosis. Once the primary change is determined, the degree of compensation should then be assessed. You can not over- compensate, as a golden rule.

18. Establishing a diagnosis requires a careful history : Diarrhea would suggest metabolic acidosis Vomiting would suggest metabolic alkalosis History of COPD would suggest respiratory acidosis History of Psychosis would suggest respiratory alkalosis.

19. Normal Anion Gap Metabolic Acidosis Defined in terms of the serum potassium concentration: Hypokalemic : - Diarrhea, Ureteral diversion, Use of Carbonic inhydrase inhibitors - Renal Tubular Acidosis: Type I, or Type II Hyperkalemic : Total parenteral nutrition oral Calcium chloride, obstructive uropathy, addison disease, Type IV RTA.

20. High Anion Gap Metabolic Acidosis MUDPILES : Methanol, Uremia, Diabetic Ketoacidosis, Paraldehyde, Isoniazide, Lactic Acidosis, Ethanol Ethylene glycole, Salicylates. In chronic renal failure the anion gap is less than 25, if more than 25 we should think about ingestion of poison.

21. When to measure The Anion Gap Anion Gap = NA –(Cloride+Bicarb) We measure it in each case of metabolic acidosis Normal anion gap 10-14mEq/L Elevated in cases of overproduction of endogenously produced organic acids such Keto Acidosis or Lactic Acidosis, or the ingestion of certain toxins such as Salicylate, Metanol, or Ethylene Glycol. In advance renal failure because decreased ability of the kidneys to regenerate bicarbonate through the Amoniagenesis.

22. Hints An elevated Anion Gap always strongly suggests a Metabolic Acidosis. If AG is 20-30 then high chance (67%) of metabolic acidosis If AG is > 30 then a metabolic acidosis is definitely present

23. The delta anion gap / delta bicarbonate in metabolic acidosis We use this concept to determine a mix acid base disorder. The delta /delta ratio in an uncomplicated high AG metabolic acidosis should be between 1 and 2. The delta /delta ratio in an uncomplicated high AG metabolic acidosis should be between 1 and 2. A lower value (in which the delta AG is less than expected from the delta HCO3) reflects either urinary ketone losses (as in diabetic ketoacidosis)or in CKD. or a combined high and normal AG acidosis, as might occur if diarrhea were superimposed upon chronic renal failure a delta /delta ratio above 2 indicates the plasma HCO3 is lower than expected from the rise in the AG; this usually reflects a concurrent metabolic alkalosis, as with vomiting.

24. If a metabolic acidosis is diagnosed, then the Delta Ratio should be checked Delta Ratio Assessment Guidelines in patients with a metabolic acidosis : < 0.4 - Hyperchloraemic normal anion gap acidosis 0.4 to 0.8 - Combined high AG and normal AG acidosis 1 - Common in DKA due to urinary ketone loss 1 to 2 - Typical pattern in high anion gap metabolic acidosis > 2 Check for either a co-existing Metabolic Alkalosis (which would elevate [HCO3]) or a co-existing Chronic Respiratory Acidosis (which results in compensatory elevation of [HCO3])

25. Urinary Anion gap In metabolic acidosis with a normal serum Anion Gap we have to determine weather the loss in Bicarbonate is renal or extra renal from GI loss as in Diarrhea. Urinary Anion Gap= Ur Cl- (Ur Na + Ur K) It estimates the Amonium Excretion. If it is more negative than -30 it reflect normal response to severe GI loss If it is positive it means impaired urinary Acidification as in Type I RTA

27. Osmolal Gap Serum Osm= 2X(NA)+ glu/18 +BUN/2.8 Osmolal Gap = Measured Osm-Calculated Osm. An elevated Osmolal gap in the setting of a metabolic acidosis with elevated Anion Gap suggests intoxication with a low molecular-weight substance such as Methanol or Ethylene glycol.

28. Indication to use bicarbonate therapy Reserved for patient with severe metabolic acidosis pH less than 7.15, or serum bicarb less than 12 mEq/L. Most beneficial in cases of loss of bicarb as in diarrhea Not indicated if in lactic acidosis. Calculated based on the Serum bicarb to be corrected to 15 Bicarb needs = body weight X volume of distribution X ( 15 – the measured bicarb) 50% of the calculated bicarb dose should be administered bollus, and the rest over 6-12 hours.

29. Case study- 1 A patient with diarrhea has an arterial pH of 7.23, bicarbonate concentration of 10 meq/L, and PCO2 of 23 mmHg What is your diagnosis? The low pH indicates acidemia, and the low plasma bicarbonate concentration indicates metabolic acidosis. The plasma bicarbonate concentration is 14 meq/L below normal, which should lead to a 17 mmHg fall in the PCO2 (14 x 1.2 = 17) from 40 to 23 mmHg.

30. Case study 1 cont. This patient has a simple metabolic acidosis. A PCO2 significantly higher than this level would indicate a concurrent respiratory acidosis. If, on the other hand, the PCO2 were lower than 20 mmHg, then a concurrent respiratory alkalosis would be present, as might be seen with salicylate intoxication.

31. Case study 2 D.D is a 56 Y/O smoker 1PP/D for 25 years has the following arterial blood values: pH equals 7.27; PCO2 equals 70 mmHg; and bicarbonate concentration equals 31 meq/L. What is your diagnosis?

32. The low pH and hypercapnia indicate that the patient has some form of respiratory acidosis. In view of the 30 mmHg rise in the PCO2, the plasma bicarbonate concentration should be elevated by 3 meq/L (to 27 meq/L) in with acute hypercapnia, and by 11 meq/L (to 35 meq/L) with chronic hypercapnia.

33. Case study 2 cont. The observed value of 31 meq/L is between these expected levels and could be explained by one of three disorders : 1-Chronic respiratory acidosis with superimposed metabolic acidosis to lower the plasma bicarbonate concentration, as might occur in a patient with chronic obstructive pulmonary disease who develops diarrhea due to viral gastroenteritis. 2- Acute respiratory acidosis with superimposed metabolic alkalosis to elevate the plasma bicarbonate concentration, as might occur in a patient with vomiting due to theophylline toxicity who then develops an acute asthmatic attack. theophylline Acute, superimposed on mild chronic respiratory acidosis, as can be induced by pneumonia in a patient with chronic hypercapnia.

34. Case study 2-cont. Thus, the correct diagnosis in a primary respiratory acid- base disorder can be established only when correlated with the clinical history. This is true even when the arterial blood values appear to represent a simple disorder. If, for example, the plasma bicarbonate concentration had been 35 meq/L then the results would have been compatible with an uncomplicated chronic respiratory acidosis. However, similar findings could have been induced by the combination of acute hypercapnia and metabolic alkalosis. The history should allow these possibilities to be distinguished.

35. Case Presentation A 28 Y/O woman presents for evaluation of malaise fatigue and weakness she is always thirsty and her eyes are gritty. The serum levels of electrolytes are as follows : Na 135 mEq/l, K 1.2 mEq/l, Cl 118 mEq/L, Bicarb 10 mEq/L, BUN 12 mg/dl, Cr 1.2 mg/dl. ABG’s pH 7.28 PaCo2 25 mm hg. Urinalysis shows pH 6.6, U.Na 35 mEq/l, U.K 20 mEq/L U.Cl 50 mEq/L. What should be your next recommendation? 1- Order diuretic screen 1- Order diuretic screen 2- Order psychiatric consult 2- Order psychiatric consult 3- Order stool electrolytes 3- Order stool electrolytes 4- Begin sodium bicarbonate 450 mEq tablets 2 tabs orally X 4/d 4- Begin sodium bicarbonate 450 mEq tablets 2 tabs orally X 4/d 5- Initiate potassium repletion, followed by potassium ctrate. 5- Initiate potassium repletion, followed by potassium ctrate.

36. The answer is potassium repletion The patient has Sicca complex and Renal Tubular Acidosis likely due to Sjogren syndrome Normal Anion gap Metabolic acidosis Urinary Anion Gap is positive Repletion of potassium is foremost in these situation because a potential disastrous exacerbation of this patient’s hypokalemia may occur with base supplementation alone. Diuretic abuse often leads to hypokalemia but not metabolic acidosis, except with Acetazolamide.

37. Quick Case select the correct interpretation for the given arterial blood gas set: pH 7.51, pCO2 40, HCO3- 31: pH 7.51, pCO2 40, HCO3- 31: a. Normal b. Uncompensated metabolic alkalosis c. Partially compensated respiratory acidosis d. Uncompensated respiratory alkalosis

38. Quick case pH 7.33, pCO2 29, HCO3- 16: a. Uncompensated respiratory alkalosis b. Uncompensated metabolic acidosis c. Partially compensated respiratory acidosis d. Partially compensated metabolic acidosis

39. Quick case pH 7.40, pCO2 40, HCO3- 24: pH 7.40, pCO2 40, HCO3- 24: a. Normal b. Uncompensated metabolic acidosis c. Partially compensated respiratory acidosis d. Partially compensated metabolic acidosis

40. Quick case pH 7.12, pCO2 60, HCO3- 29: pH 7.12, pCO2 60, HCO3- 29: a. Uncompensated metabolic acidosis b. Uncompensated respiratory acidosis c. Partially compensated respiratory acidosis d. Partially compensated metabolic acidosis

41. Quick case pH 7.48, pCO2 30, HCO3- 23: pH 7.48, pCO2 30, HCO3- 23: a. Uncompensated metabolic alkalosis b. Uncompensated respiratory alkalosis c. Partially compensated respiratory alkalosis d. Partially compensated metabolic alkalosis

42. Quick case pH 7.62, pCO2 47, HCO3- 30: pH 7.62, pCO2 47, HCO3- 30: a. Uncompensated metabolic alkalosis b. Uncompensated respiratory alkalosis c. Partially compensated respiratory alkalosis d. Partially compensated metabolic alkalosis

43. Last case pH 7.30, pCO2 59. HCO3- 28: pH 7.30, pCO2 59. HCO3- 28: a. Uncompensated metabolic acidosis b. Uncompensated respiratory acidosis c. Partially compensated respiratory acidosis d. Partially compensated metabolic acidosis