Bicarbonate Therapy in Severe Metabolic Acidosis

1. Bicarbonate Therapy in Severe Metabolic Acidosis Neil A. Kurtzman, MD Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas 79430

2. Metabolic acidosis: A primary fall in the bicarbonate concentration • Due to either a gain of acid or a loss of base (usually HCO3) • Acidemia refers solely to a fall in pH

3. Gain of Acid • Exogenous (eg, NH4Cl) • Endogenous • Abnormal lipid metabolism DKA • Abnormal CHO metabolism Lactic acidosis • Normal protein metabolism Uremic acidosis

4. Kraut and Kurtz did an online (Clin Exp Neprol 10:111-117, 2006) survey of how intensivists and nephrologists gave HCO3 to patients with metabolic acidosis • Forty percent of the intensivists would not give bicarbonate unless the pH was less than 7.0 • Only 6% of nephrologists wait until pH gets this low (p < 0.01)

5. More than 80% of nephrologists consider the pCO2 in making their decision to treat • Only 59% of intensivists do (p<0.02) • In patients with lactic acidosis, 86% of nephrologists treat with bicarbonate • Two-thirds of intensivists give bicarbonate (p< 0.05)

6. 60% of nephrologists treat DKA with bicarbonate • 28% of intensivists give bicarbonate to patients with DKA (p<0.01) • Both would administer bicarbonate by constant infusion, targeting an arterial pH of 7.2 • Seventy-five percent of nephrologists calculate the amount of bicarbonate required, while only one-third of intensivists do so

7. Metabolic acidosis results from a loss of bicarbonate (eg diarrhea) • Or from its titration to an anionic base that often can be converted back to bicarbonate (eg DKA or lactic acidosis) • This non-bicarbonate base anion is commonly termed “potential” bicarbonate

8. Giving bicarbonate to a patient with a true bicarbonate deficit is not controversial • Controversy arises when the decrease in bicarbonate concentration is the result of its conversion to another base which, given time, can be converted back to bicarbonate

9. In considering acute bicarbonate replacement four questions should be considered 1. What are the deleterious effects of acidemia and when are they manifest? 2. When is acidemia severe enough to warrant therapy?

10. 3. How much bicarbonate should be given and how is that amount calculated? 4. What are the deleterious effects of bicarbonate therapy?

11. Deleterious effects of acidemia • Decreased myocardial contractility • Fall in cardiac output • Fall in BP • Pulmonary venoconstriction

12. Deleterious effects of acidemia • Decreased binding of norepinephrine to its receptors • Acidemia may adversely affect cell functions such as enzymatic reactions, ATP generation, fatty acid biosynthesis, and bone formation/resorption

13. Deleterious effects of acidemia • Drugs which are salts of weak acids are more active during acidemia • More receptor binding • More entry to cells • Best example is ASA

14. tolbutamide • methotrexate • phenobarbital • phenytoin

15. Optimal extracelluar pH 7.4 • Optimal intracellular pH 7.1 • Deviations from normal pH will obviously decrease the efficiency of all reactions

16. Acidemia protects the central nervous system against seizures, it sensitizes the myocardium to arrhythmias • Extracellular pH is a surrogate for intracellular pH

17. When is acidemia severe enough to warrant therapy? • Most authorities in acid-base physiology would give bicarbonate to a patient with an arterial pH < 7.1 • Not a hard and fast rule • More on this later

18. How much bicarbonate should be given and how is that amount calculated? • The volume of distribution of bicarbonate is approximately that of total body water • In patients with metabolic acidosis it is said to vary from 50% to greater than 100%, depending on the severity of the acidemia

19. How much bicarbonate should be given and how is that amount calculated? • Any calculated amount is approximate • Fernandez et al have derived a formula for calculating the bicarbonate space (KI 36:747-752, 1989) • (0.4 + 2.6 / pHCO3) (body weight)

20. How much bicarbonate should be given and how is that amount calculated? • At a pCO2 of 13 mm Hg and HCO3 of 4 mEq/l, the arterial pH is 7.1 • Raise the HCO3 to only to 8 mEq/L the blood pH will increase to 7.4 • This assumes the pCO2 doesn’t change

21. How much bicarbonate should be given and how is that amount calculated? • If the bicarbonate concentration rises only 1 mEq/L the pH would be above 7.2 • Arterial pCO2 typically however does not remain the same after bicarbonate infusion • In severely acidotic patients it rises 6.7 ± 1.8 mm Hg when an infusion of sodium bicarbonate is given (1.5 mmol/kg over 5min)

22. What are the deleterious effects of bicarbonate therapy? • Bicarbonate therapy is associated with an increase in mortality • True in humans and experimental animals under a variety of acidemic conditions • Fall in blood pressure and cardiac output

23. What are the deleterious effects of bicarbonate therapy? • Shifts in ionized calcium • In strong acid acidosis potassium also shifts out of the cell • Sensitizes the heart to abnormal electrical activity and subsequent arrhythmias

24. What are the deleterious effects of bicarbonate therapy? • “Paradoxical” intracellular acidosis – CO2 shifts into cells • Both volume expansion and hypernatremia can occur • Fulminate congestive heart failure with flash pulmonary edema may result

25. What are the deleterious effects of bicarbonate therapy? • In vitro studies show that intracellular alkalinization hastens cell death following anoxia • Stimulates superoxide formation, increases pro-inflammatory cytokine release, and enhances apoptosis • Relationship to human disorders unknown

26. What are the deleterious effects of bicarbonate therapy? • Rebound alkalemia – especially with low arterial pCO2 • Blood lactate and ketone bodies increase • This “potential” bicarbonate will be converted back to actual bicarbonate unless it lost in the urine

28. DKA • Acetoacetate and beta-hydroxybutyrate are lost in the urine before the patient arrives at the hospital • The patient is truly bicarbonate deficient • More urinary loss of ketone bodies occurs following fluid administration and volume repletion

29. DKA • Hyperchloremic metabolic acidosis the day after insulin therapy • Almost never necessary to give bicarbonate even though the patient is bicarbonate deficient unless renal function is permanently impaired • Bicarbonate therapy markedly increases blood acetoacetate and beta-hydroxybutyrate levels

30. DKA • Bicarbonate therapy delays the removal of ketone bodies from the blood • Bicarbonate therapy markedly increases blood acetoacetate and beta-hydroxybutyrate levels

31. Lactic Acidosis • Mortality greater than 80% • Outcome depends on the treatment of its cause • Cardiogenic or hemorrhagic shock • Exogenous toxins such as cyanide or metformin

32. CASE #1: A 20 year-old man with a five-year history of type 1 diabetes mellitus was admitted for the ninth time in diabetic ketoacidosis. He was poorly responsive and had Kussmaul respirations. Before any therapy he had a plasma Na of 140 mEq/L, K 4 mEq/L, Cl 109 mEq/L, CO2 3 mEq/L, and his creatinine was 1 mg/dL. The arterial pH was 6.95, pCO2 14 mm Hg, and the calculated HCO3 was 3 mEq/L.

33. Urine and blood ketones were strongly positive. He was treated with insulin and appropriate fluid and electrolyte replacement. He was not given bicarbonate. The next day he was fully oriented. His plasma Na was 142, K 4, Cl 114 and his CO2 was 18 mEq/L. The remainder of his clinical course was unremarkable.

34. CASE #2: An 80 year old man was admitted with severe congestive heart failure. He was hypotensive and oliguric. He had both pulmonary and peripheral edema. His baseline creatinine was known to be 1.6 mg/dL. On arrival at the emergency room his plasma Na was 135 mEq/L, K 4 mEq/L, Cl 97 mEq/L, CO2 7 mEq/L, and his creatinine was 2.5 mg/dl. His arterial pH was 7.1, pCO2 20 mm Hg, and the calculated HCO3 was 6 mEq/l. The blood lactate level was 20 mmol/L.

35. The patient was intubated and placed on a respirator keeping his pCO2 at 20 mmHg. CVVHD was begun with a bath containing 14 mEq/L of bicarbonate. He was given an infusion of 300 mEq of bicarbonate over two hours; with a total body water of 43 liters, one would aim for a HCO3 of 14 mEq/L: (7 mEq/L X 43 L = 301 mEq). At the end of that time his pH was 7.2 and the HCO3 was 13 mEq/L. Five days later he was transferred out of the intensive care unit, his lactic acidosis resolved.

36. Case #1 got no bicarbonate even though his pH was < 7.0 • Case #2 received bicarbonate though he had a higher pH • Bicarbonate therapy must be individualized

37. Desired HCO3 – observed HCO3 • Use total body water • Assume pCO2 will not change • Give that amount which will raise the pH to 7.2

38. Reevaluate in two hours • Make new plan based on the new data • Correct the underlying cause(s)

39. Sandra Sabatini and Neil A. Kurtzman: Bicarbonate Therapy in Severe Metabolic Acidosis, JASN in press.