Bicarbonate Therapy in Severe Bicarbonate Therapy in Severe Metabolic AcidosisMetabolic Acidosis

Neil A. Kurtzman, MDNeil A. Kurtzman, MDDepartment of Internal Medicine,Department of Internal Medicine,

Texas Tech University Health Sciences Texas Tech University Health Sciences Center,Center,

Lubbock, Texas 79430Lubbock, Texas 79430

• Metabolic acidosis: A primary fall in the Metabolic acidosis: A primary fall in the bicarbonate concentrationbicarbonate concentration

• Due to either a gain of acid or a loss of base Due to either a gain of acid or a loss of base (usually HCO(usually HCO33))

• Acidemia refers solely to a fall in pHAcidemia refers solely to a fall in pH

• Exogenous (eg, NHExogenous (eg, NH44Cl) Cl) • Endogenous Endogenous

• Abnormal lipid metabolismAbnormal lipid metabolismDKADKA

• Abnormal CHO metabolismAbnormal CHO metabolismLactic acidosisLactic acidosis

• Normal protein metabolismNormal protein metabolismUremic acidosisUremic acidosis

Gain of AcidGain of Acid

• Kraut and Kurtz did an online (Clin Exp Neprol Kraut and Kurtz did an online (Clin Exp Neprol 10:111-117, 2006) survey of how intensivists and 10:111-117, 2006) survey of how intensivists and nephrologists gave HCOnephrologists gave HCO3 3 to patients with metabolic to patients with metabolic

acidosisacidosis

• Forty percent of the intensivists would not give Forty percent of the intensivists would not give bicarbonate unless the pH was less than 7.0bicarbonate unless the pH was less than 7.0

• Only 6% of nephrologists wait until pH gets this Only 6% of nephrologists wait until pH gets this low (p < 0.01)low (p < 0.01)

• More than 80% of nephrologists consider the More than 80% of nephrologists consider the pCOpCO22 in making their decision to treat in making their decision to treat

• Only 59% of intensivists do (p<0.02) Only 59% of intensivists do (p<0.02)

• In patients with lactic acidosis, 86% of In patients with lactic acidosis, 86% of nephrologists treat with bicarbonate nephrologists treat with bicarbonate

• Two-thirds of intensivists give bicarbonate Two-thirds of intensivists give bicarbonate (p< 0.05)(p< 0.05)

• 60% of nephrologists treat DKA with 60% of nephrologists treat DKA with bicarbonate bicarbonate

• 28% of intensivists give bicarbonate to patients 28% of intensivists give bicarbonate to patients with DKA (p<0.01) with DKA (p<0.01)

• Both would administer bicarbonate by constant Both would administer bicarbonate by constant infusion, targeting an arterial pH of 7.2infusion, targeting an arterial pH of 7.2

• Seventy-five percent of nephrologists calculate Seventy-five percent of nephrologists calculate the amount of bicarbonate required, while only the amount of bicarbonate required, while only one-third of intensivists do soone-third of intensivists do so

• Metabolic acidosis results from a loss of bicarbonate Metabolic acidosis results from a loss of bicarbonate (eg diarrhea)(eg diarrhea)

• Or from its titration to an anionic base that often can Or from its titration to an anionic base that often can be converted back to bicarbonate (eg DKA or lactic be converted back to bicarbonate (eg DKA or lactic acidosis)acidosis)

• This non-bicarbonate base anion is commonly This non-bicarbonate base anion is commonly termed “potential” bicarbonatetermed “potential” bicarbonate

• Giving bicarbonate to a patient with a true Giving bicarbonate to a patient with a true bicarbonate deficit is not controversial bicarbonate deficit is not controversial

• Controversy arises when the decrease in Controversy arises when the decrease in bicarbonate concentration is the result of its bicarbonate concentration is the result of its conversion to another base which, given time, conversion to another base which, given time, can be converted back to bicarbonate can be converted back to bicarbonate

1. What are the deleterious effects of acidemia 1. What are the deleterious effects of acidemia and when are they manifest? and when are they manifest?

2. When is acidemia severe enough to warrant 2. When is acidemia severe enough to warrant therapy? therapy?

In considering acute bicarbonate replacement four In considering acute bicarbonate replacement four questions should be consideredquestions should be considered

3. How much bicarbonate should be given and 3. How much bicarbonate should be given and how is that amount calculated? how is that amount calculated?

4. What are the deleterious effects of bicarbonate 4. What are the deleterious effects of bicarbonate therapy? therapy?

• Decreased myocardial contractility Decreased myocardial contractility

• Fall in cardiac output Fall in cardiac output

• Fall in BPFall in BP

• Pulmonary venoconstrictionPulmonary venoconstriction

Deleterious effects of Deleterious effects of acidemiaacidemia

• Decreased binding of norepinephrine to its Decreased binding of norepinephrine to its receptors receptors

• Acidemia may adversely affect cell functions Acidemia may adversely affect cell functions such as enzymatic reactions, ATP generation, such as enzymatic reactions, ATP generation, fatty acid biosynthesis, and bone fatty acid biosynthesis, and bone formation/resorption formation/resorption

Deleterious effects of Deleterious effects of acidemiaacidemia

• Drugs which are salts of weak acids are more Drugs which are salts of weak acids are more active during acidemiaactive during acidemia

• More receptor binding More receptor binding

• More entry to cellsMore entry to cells

• Best example is ASA Best example is ASA

Deleterious effects of Deleterious effects of acidemiaacidemia

• tolbutamidetolbutamide

• methotrexatemethotrexate

• phenobarbitalphenobarbital

• phenytoinphenytoin

• Optimal extracelluar pH 7.4Optimal extracelluar pH 7.4

• Optimal intracellular pH 7.1Optimal intracellular pH 7.1

• Deviations from normal pH will obviously Deviations from normal pH will obviously decrease the efficiency of all reactionsdecrease the efficiency of all reactions

• Acidemia protects the central nervous system Acidemia protects the central nervous system against seizures, it sensitizes the myocardium against seizures, it sensitizes the myocardium to arrhythmias to arrhythmias

• Extracellular pH is a surrogate for intracellular Extracellular pH is a surrogate for intracellular pHpH

• Most authorities in acid-base physiology Most authorities in acid-base physiology would give bicarbonate to a patient with an would give bicarbonate to a patient with an arterial pH < 7.1 arterial pH < 7.1

• Not a hard and fast ruleNot a hard and fast rule

• More on this laterMore on this later

When is acidemia severe enough to warrant therapy?When is acidemia severe enough to warrant therapy?

• The volume of distribution of bicarbonate is The volume of distribution of bicarbonate is approximately that of total body water approximately that of total body water

• In patients with metabolic acidosis it is said to In patients with metabolic acidosis it is said to vary from 50% to greater than 100%, vary from 50% to greater than 100%, depending on the severity of the acidemia depending on the severity of the acidemia

How much bicarbonate should be given and How much bicarbonate should be given and how is that amount calculatedhow is that amount calculated??

• Any calculated amount is approximate Any calculated amount is approximate

• Fernandez et al have derived a formula for Fernandez et al have derived a formula for calculating the bicarbonate space (KI 36:747-calculating the bicarbonate space (KI 36:747-752, 1989) 752, 1989)

• (0.4 + 2.6 / pHCO3) (body weight) (0.4 + 2.6 / pHCO3) (body weight)

How much bicarbonate should be given and how is How much bicarbonate should be given and how is that amount calculated?that amount calculated?

• At a pCOAt a pCO22 of 13 mm Hg and HCO of 13 mm Hg and HCO33 of 4 mEq/l, of 4 mEq/l,

the arterial pH is 7.1 the arterial pH is 7.1

• Raise the HCORaise the HCO33 to only to 8 mEq/L the blood to only to 8 mEq/L the blood

pH will increase to 7.4pH will increase to 7.4

• This assumes the pCOThis assumes the pCO22 doesn’t change doesn’t change

How much bicarbonate should be given and How much bicarbonate should be given and how is that amount calculated?how is that amount calculated?

• If the bicarbonate concentration rises only If the bicarbonate concentration rises only 1 mEq/L the pH would be above 7.2 1 mEq/L the pH would be above 7.2

• Arterial pCOArterial pCO22 typically however does not typically however does not

remain the same after bicarbonate infusionremain the same after bicarbonate infusion

• In severely acidotic patients it rises 6.7 ± 1.8 In severely acidotic patients it rises 6.7 ± 1.8

mm Hg when an infusion of sodium mm Hg when an infusion of sodium bicarbonate is given (1.5 mmol/kg over 5min) bicarbonate is given (1.5 mmol/kg over 5min)

How much bicarbonate should be given How much bicarbonate should be given and how is that amount calculated?and how is that amount calculated?

• Bicarbonate therapy is associated with an Bicarbonate therapy is associated with an increase in mortality increase in mortality

• True in humans and experimental animals True in humans and experimental animals under a variety of acidemic conditions under a variety of acidemic conditions

• Fall in blood pressure and cardiac output Fall in blood pressure and cardiac output

What are the deleterious effects of bicarbonate What are the deleterious effects of bicarbonate therapy?therapy?

• Shifts in ionized calciumShifts in ionized calcium

• In strong acid acidosis potassium also shifts In strong acid acidosis potassium also shifts out of the cell out of the cell

• Sensitizes the heart to abnormal electrical Sensitizes the heart to abnormal electrical activity and subsequent arrhythmiasactivity and subsequent arrhythmias

What are the deleterious effects of bicarbonate What are the deleterious effects of bicarbonate therapy? therapy?

• ““Paradoxical” intracellular acidosis – COParadoxical” intracellular acidosis – CO22 shifts shifts

into cellsinto cells

• Both volume expansion and hypernatremia can Both volume expansion and hypernatremia can occur occur

• Fulminate congestive heart failure with flash Fulminate congestive heart failure with flash pulmonary edema may result pulmonary edema may result

What are the deleterious effects of bicarbonate What are the deleterious effects of bicarbonate therapy?therapy?

• In vitroIn vitro studies show that intracellular studies show that intracellular alkalinization hastens cell death following anoxiaalkalinization hastens cell death following anoxia

• Stimulates superoxide formation, increases pro-Stimulates superoxide formation, increases pro-inflammatory cytokine release, and enhances inflammatory cytokine release, and enhances apoptosisapoptosis

• Relationship to human disorders unknownRelationship to human disorders unknown

What are the deleterious effects of bicarbonate What are the deleterious effects of bicarbonate therapy?therapy?

• Rebound alkalemia – especially with low Rebound alkalemia – especially with low arterial pCOarterial pCO22

• Blood lactate and ketone bodies increaseBlood lactate and ketone bodies increase

• This “potential” bicarbonate will be converted This “potential” bicarbonate will be converted back to actual bicarbonate unless it lost in the back to actual bicarbonate unless it lost in the urine urine

What are the deleterious effects of bicarbonate What are the deleterious effects of bicarbonate therapy?therapy?

• Acetoacetate and beta-hydroxybutyrate are Acetoacetate and beta-hydroxybutyrate are lost in the urine before the patient arrives at lost in the urine before the patient arrives at the hospital the hospital

• The patient is truly bicarbonate deficient The patient is truly bicarbonate deficient

• More urinary loss of ketone bodies occurs More urinary loss of ketone bodies occurs following fluid administration and volume following fluid administration and volume repletion repletion

DKADKA

• Hyperchloremic metabolic acidosis the day Hyperchloremic metabolic acidosis the day after insulin therapy after insulin therapy

• Almost never necessary to give bicarbonate Almost never necessary to give bicarbonate even though the patient is bicarbonate even though the patient is bicarbonate deficient unless renal function is permanently deficient unless renal function is permanently impaired impaired

• Bicarbonate therapy markedly increases blood Bicarbonate therapy markedly increases blood acetoacetate and beta-hydroxybutyrate levelsacetoacetate and beta-hydroxybutyrate levels

DKADKA

• Bicarbonate therapy delays the removal of Bicarbonate therapy delays the removal of ketone bodies from the blood ketone bodies from the blood

• Bicarbonate therapy markedly increases blood Bicarbonate therapy markedly increases blood acetoacetate and beta-hydroxybutyrate levels acetoacetate and beta-hydroxybutyrate levels

DKADKA

• Mortality greater than 80%Mortality greater than 80%

• Outcome depends on the treatment of its causeOutcome depends on the treatment of its cause

• Cardiogenic or hemorrhagic shock Cardiogenic or hemorrhagic shock

• Exogenous toxins such as cyanide or metforminExogenous toxins such as cyanide or metformin

Lactic AcidosisLactic Acidosis

CASE #1:CASE #1: A 20 year-old man with a five-year A 20 year-old man with a five-year history of type 1 diabetes mellitus was admitted history of type 1 diabetes mellitus was admitted for the ninth time in diabetic ketoacidosis. He for the ninth time in diabetic ketoacidosis. He was poorly responsive and had Kussmaul was poorly responsive and had Kussmaul respirations. Before any therapy he had a respirations. Before any therapy he had a plasma Na of 140 mEq/L, K 4 mEq/L, Cl 109 plasma Na of 140 mEq/L, K 4 mEq/L, Cl 109 mEq/L, COmEq/L, CO22 3 mEq/L, and his creatinine was 1 3 mEq/L, and his creatinine was 1 mg/dL. The arterial pH was 6.95, pCOmg/dL. The arterial pH was 6.95, pCO22 14 mm 14 mm Hg, and the calculated HCO3 was 3 mEq/L. Hg, and the calculated HCO3 was 3 mEq/L.

Urine and blood ketones were strongly Urine and blood ketones were strongly positive. He was treated with insulin and positive. He was treated with insulin and appropriate fluid and electrolyte replacement. appropriate fluid and electrolyte replacement. He was not given bicarbonate. The next day He was not given bicarbonate. The next day he was fully oriented. His plasma Na was 142, he was fully oriented. His plasma Na was 142, K 4, Cl 114 and his COK 4, Cl 114 and his CO22 was 18 mEq/L. The was 18 mEq/L. The

remainder of his clinical course was remainder of his clinical course was unremarkable.unremarkable.

CASE #2: CASE #2: An 80 year old man was admitted An 80 year old man was admitted with severe congestive heart failure. He was with severe congestive heart failure. He was hypotensive and oliguric. He had both hypotensive and oliguric. He had both pulmonary and peripheral edema. His baseline pulmonary and peripheral edema. His baseline creatinine was known to be 1.6 mg/dL. On creatinine was known to be 1.6 mg/dL. On arrival at the emergency room his plasma Na arrival at the emergency room his plasma Na was 135 mEq/L, K 4 mEq/L, Cl 97 mEq/L, was 135 mEq/L, K 4 mEq/L, Cl 97 mEq/L, COCO22 7 mEq/L, and his creatinine was 2.5 7 mEq/L, and his creatinine was 2.5 mg/dl. His arterial pH was 7.1, pCOmg/dl. His arterial pH was 7.1, pCO22 20 mm 20 mm Hg, and the calculated HCOHg, and the calculated HCO33 was 6 mEq/l. was 6 mEq/l. The blood lactate level was 20 mmol/LThe blood lactate level was 20 mmol/L. .

The patient was intubated and placed on a The patient was intubated and placed on a respirator keeping his pCOrespirator keeping his pCO22 at 20 mmHg. at 20 mmHg.

CVVHD was begun with a bath containing 14 CVVHD was begun with a bath containing 14 mEq/L of bicarbonate. He was given an mEq/L of bicarbonate. He was given an infusion of 300 mEq of bicarbonate over two infusion of 300 mEq of bicarbonate over two hours; with a total body water of 43 liters, one hours; with a total body water of 43 liters, one would aim for a HCOwould aim for a HCO33 of 14 mEq/L: (7 mEq/L of 14 mEq/L: (7 mEq/L

X 43 L = 301 mEq). At the end of that time X 43 L = 301 mEq). At the end of that time his pH was 7.2 and the HCOhis pH was 7.2 and the HCO33 was 13 mEq/L. was 13 mEq/L.

Five days later he was transferred out of the Five days later he was transferred out of the intensive care unit, his lactic acidosis resolved.intensive care unit, his lactic acidosis resolved.

• Case #1 got no bicarbonate even though his Case #1 got no bicarbonate even though his pH was < 7.0pH was < 7.0

• Case #2 received bicarbonate though he had a Case #2 received bicarbonate though he had a higher pHhigher pH

• Bicarbonate therapy must be individualizedBicarbonate therapy must be individualized

• Desired HCODesired HCO33 – observed HCO – observed HCO33

• Use total body waterUse total body water

• Assume pCOAssume pCO22 will not change will not change

• Give that amount which will raise the pH toGive that amount which will raise the pH to 7.2 7.2

• Reevaluate in two hoursReevaluate in two hours

• Make new plan based on the new dataMake new plan based on the new data

• Correct the underlying cause(s)Correct the underlying cause(s)

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