Acid Base Disorders: Key Core Concepts

Thomas DuBose M.D., MACP, FASN ASN Board Review Course Online Resource Material 2014

Speaker Disclosure

I, Thomas DuBose, M.D., have no financial relationships or affiliations with industry to disclose. Basic Concepts of Acid-Base Balance • Henderson-Hasselbach Equation:

- pHa = 6.1 + log10 (HCO3 /PaCO2 X 0.0301)

• pH maintained between 7.35 & 7.45 and pHi 7.0-7.3. Fine tuned regulation occurs in face of continuous production of acid metabolites and is accomplished by intracellular and extracellular buffers in conjunction with respiratory and renal regulatory mechanisms. Primary Disturbance and Compensatory Responses - pH pCO2 HCO3

Metabolic acidosis 2o 1o

Metabolic alkalosis 2o 1o

Respiratory acidosis 1o 2o

Respiratory alkalosis 1o 2o

Compensatory Responses for Simple Acid- Base Disorders*

(Winter Equation)

*DuBose TD, Acidosis and Alkalosis, in HPIM ED 19, Chapt 66, 2014 Derivation of Winter Equation A Simpler Approach to Predict Respiratory Compensation in and Metabolic Alkalosis • In range of serum of 10-40 mEq/L - Add 15 to patient’s [HCO3 ] to predict PCO2 Examples: - HCO3 Predicted PCO2 15 30 35 50 • Compare predicted and measured values Types of Acid-Base Disturbances 1. Simple Respiratory acidosis alkalosis Metabolic acidosis alkalosis 2. Mixed Mixed Acid-Base Disturbances

• Definition – Combination of two or more of the 4 simple disturbances • Examples – Mixed respiratory-metabolic disorders – Mixed metabolic disorders Key Board Review Point: Step-wise evaluation of acid-base disorders 1. Always analyze acid-base disturbance with both ABG and Venous Panel (BMP) 2. Verify accuracy - Compare calculated [HCO3 ] on arterial blood gas with - measured [HCO3 ] on electrolyte panel 3. Calculate ; but correct for deviation of Palb from normal (4.0 Gm/dL) 4. Calculate predicted respiratory or metabolic compensation 5. Know Causes of HAG and NAG acidosis - 6. Compare Δ HCO3 with D AG 7. Compare D Na+ with D Cl- 8. Calculate Serum Osmolar Gap when cause of HAG not known or toxic alcohol ingestion suspected

The Anion Gap

+ - - AG = Na − (Cl + HCO3 ) Normal Value 6 -12 mEq/L

Represents unmeasured anions present in serum including anionic , phosphate, sulfate, and organic anions. Major assumption is that ECFV is “normal” or that Hct and

Palb are “normal”. If not must correct AG for deviation of Palb from normal value of 4.0 Gm/dL. Anatomy of the Anion Gap

Protein 16 K 5 mEq/L Ca 5 Organic acid 4

Mg 2 PO4/SO4 2 HCO 25 These cations = 12 3 These anions = 22

Na+ Cl- Anion gap is Unmeasured 140 105 Anion gap is calculated as Na - anions - Unmeasured (Cl + HCO ) or cations or 3 140-130 = 10 22-12 = 10

Cations Anions Correction of the AG for PAlb For each 1 Gm/dL DECREASE in albumin below 4.0mEq/L the reported AG will be factitiously reduced by 2.5mEq/L For each 1 Gm/dL INCREASE in albumin above 4.0mEq/L the reporteded AG will be factitiously increased by 2.5mEq/L

Example: if PAlb is 2 and AG is 15, to correct AG add 2.5 X 2 = 5 to 15 Corrected AG = 20 mEq/L

Illustration of Method

• Na 140, K 4.9, Cl 106, HCO3 14, BUN 23, Cr 1.1, Alb 4.0

• pH 7.39, PaCO2 24, PaO2 90, HCO3 13 • Apply the step-wise approach to answer next question: Question: What is the precise acid- base diagnosis in the previous example? 1. Metabolic acidosis with overcompensation 2. High anion gap metabolic acidosis 3. Mixed metabolic acidosis + respiratory alkalosis 4. Mixed metabolic acidosis + respiratory acidosis Stepwise solution for diagnosis

• Measured and calculated HCO3 similar • AG = 20, defines presence of a high anion gap acidosis • What is predicted respiratory compensation in this case?: – Winter equation: 1.5 X 14 + 8 = 29 – 29 ≠ 24 • Therefore, correct answer? – (next slide) Correct Answer, # 3

1. Metabolic acidosis with overcompensation 2. High anion gap metabolic acidosis 3. Mixed metabolic acidosis – respiratory alkalosis 4. Mixed metabolic acidosis – respiratory acidosis Example of stepwise approach using D values (step 6)

• A patient is admitted with a history of vomiting for 2 days and orthostatic hypotension. PMH of CKD secondary to DM, baseline Cr 3. - • Laboratory: Na 140, K 3.7, Cl 95, HCO3 25, BUN 80, Cr 7.9, glucose 130, pH 7.40, PaCO2 39, PO2 92, Albumin 4.0

• Consider the AG, and the DHCO3 vs. DAG Using D values • AG = 20, DAG = 10

• DHCO3 = 0

• Therefore, DAG > DHCO3, defines a mixed high anion gap metabolic acidosis plus metabolic alkalosis

Mixed Metabolic Acidosis- Alkalosis Electrolyte Values (mEq/L) MA and Serum High Gap MA Normal MA (Vomiting) 140 140 140 Chloride 105 105 95 Bicarbonate 25 15 25 Anion gap 10 20 20 DAG +10 +10 - DC  -10 0

Step 5: Causes of High Anion Gap Acidosis • Ketoacidosis – Diabetic ketoacidosis – Alcoholic ketoacidosis – Starvation ketoacidosis • Lactic Acidosis – L-Lactic acidosis  Type A  Type B – D-Lactic acidosis

Causes of High Anion Gap Acidosis - continued • Renal Failure – Acute and Chronic • Toxins – Ethylene glycol – High Osmolar Gap – Methyl alcohol – High Osmolar Gap – Propylene glycol – High Osmolar Gap – Salicylates – high salicylate level – Pyroglutamic acid or 5- oxoprolene (glutathione depletion) Gold Mark: Modern Mnemonic for Anion Gap Acidosis GOLD MARK Glycols (ethylene and propylene) Oxoproline L-lactate D-lactate Methanol Aspirin Renal failure Ketoacidosis

Mehta, AN, Emmett,JB and Emmett, M. The Lancet, 2008; 372: 892 Useful Ancillary Tests in the Diagnosis of High AG Metabolic Acidosis • Serum and ketones • Serum • Serum L-lactate (consider D-lactate) • Serum osmolality to calculate osmolar gap • Serum toxic alcohols • Pyroglutamic acid (5-oxoproline) • Urine microscopy for crystals

Osmolar Gap in Diagnosis of Toxin- Induced Anion Gap Acidosis Compare measured and calculated osmolality det cal Gaposm = Posm - Posm cal + Posm = 2Na + BUN/2.8 + Glu/18

Key Point: Gaposm > 10 mOsm/kg. in setting of possible toxin ingestion suggests methyl alcohol, ethylene glycol, or propylene glycol intoxication UNDERSTANDING NON-GAP METABOLIC ACIDOSIS

Overview of Renal Distinguishing Renal from Non-Renal Forms Role of the Kidney in the Defense Against Metabolic Acidosis Role of the Kidney in Regulation of Acid-Base Balance: 2 Components • Reclamation of Filtered Bicarbonate –Proximal Tubule –Distal Nephron - • Regeneration of ECF [HCO3 ] consumed by net acid production –Ammonia production and excretion increases with dietary acid load Definition of Non-Gap Acidosis

• Low Bicarbonate, low pH • Normal Anion Gap (~8-10 mEq/L) – Note Albumin – correct to 4 Gm/dL

• Compensatory decrease in PCO2 – Predicting Respiratory Compensation: - • Winter Equation: PCO2 = 1.5 (HCO3 ) + 8 ± 2 - • Add 15 to Patient’s [HCO3 ] • Example: Clinical Examples: NAG Acidosis Electrolyte Values (mEq/L) NAG - MA Serum + High Electrolytes Normal NAG - MA AG - MA S o dium 1 4 0 1 4 0 1 4 0 Chlo ride 1 05 1 1 5 1 1 5 Bicarbonate 25 15 5 Ani o n gap 10 10 20 AG 0 +10

C   - 10 - 20

Causes of Non-Gap Acidoses (step 5) . Diarrhea or other GI losses of alkali (e.g., tube drainage) . Ureteral diversion (e.g., ileal loop, ureterosigmoidostomy) . Posttreatment of ketoacidosis (dilutional) . Progressive chronic kidney disease . Toluene ingestion (excretion of hippurate) . Drugs . Carbonic anhydrase inhibitors: acetazolamide, topiramate, sulfamyalon . Amphotericin B

. CaCl2, MgSO4, Cholestyramine . Acid loads (NH4Cl, acidic amino acids -TPN, sulfur) . For Hyperkalemia: amiloride, triamterenene, spironolactone, TMP . Post - hypocapnic state . RTA’s – proximal, classical distal, mixed, type 4 Mnemonic for Non-Gap Acidosis • HAARDUPS – Hyperalimentation – Acetazolamide or any CA Inhibitor – Amphotericin B – RTA – Diarrhea – Ureterosigmoidostomy – Post hypocapneic state, pancreatic fistula – Sulfamyalon

Types of Renal Acidoses • Hypokalemic Forms – Proximal RTA (Type 2) – Classical Distal RTA (Type 1) • Hyperkalemic Forms – Aldosterone Deficiency or Resistance (Type 4) – Non-mineralocorticoid Voltage Defect • Normokalemic – RTA of CKD 2-4 – Uremic Acidosis Distinction between Non-Renal and Renal Origin of NAG Acidosis; Use of the Urine Anion Gap: Pathophysiological Response of Kidney to Acidosis Renal Origin vs. Non Renal Origin

• Estimate Urine Ammonium (spot urine lytes)

–Urine Anion Gap is Surrogate for UAm

–UAG = [UNa + UK] -UCl • Interpretation: – Negative Value: Non-Renal Origin (Ammonium Adequate) – Positive Value: Renal Origin (Ammonium Low) Clinical Recognition of Renal Response To Non-Gap Metabolic Acidosis • Non-Renal + –Increase in NH4 Excretion (kidney response appropriate) • Negative Urine Anion Gap • Acid urine pH (<5.5) - exceptions • Renal + –Inability to increase NH4 Excretion (inappropriate kidney response) • Positive Urine Anion Gap • Urine pH typically > 5.5 but more variable in Type 4 Tests useful in the Differential Diagnosis of NAG Metabolic Acidosis • Serum • Serum creatinine • Urine electrolytes

– TTKG or FEK

– FEHCO3- • and urine osmolar gap • Urine pH Mixed High Anion Gap and Normal Anion Gap Metabolic Acidosis in a Patient with Severe Diarrhea Electrolyte Values (mEq/L) NAG-MA Serum + High Electrolytes Normal NAG-MA AG-MA Sodium 140 140 140 Chloride 105 115 115 Bicarbonate 25 15 5 Anion gap 10 10 20 DAG 0 +10 - DC  -10 -20

Adverse Consequences Severe Acidemia • Cardiovascular – Impaired contractility, vasodilatation, venoconstriction, decreased C.O., sensitization to arrhythmias, decreased responsiveness to pressors. • Respiratory – Hyperventilation, respiratory muscle fatigue, dyspnea • Metabolic – Insulin resistance, inhibition of anaerobic glycolysis, degradation, decreased ATP synthesis, hyperkalemia. Complications of Bicarbonate Therapy • Overshoot alkalosis:

–Exogenously administered NaHCO3 must be added to endogenously produced by metabolism of ketones, lactate, etc. • Increase in lactate generation • Volume expansion with ARF or ESRD

• Increased CO2 production • Hypocalcemia • Cardiac depression When to Give NaHCO3

• In ESRD, CKD stage 2-4 keep HCO3>22 to avoid osteopenia, hypercalciuria, natriuresis, sarcopenia, and to help slow progression of CKD. • In DKA, almost never; extreme acidosis? (pH<6.9), never for children? – Treat the underlying cause with regular insulin + i.v. fluid replacement • In L-lactic acid acidosis, pH < 7 – Treat the underlying cause

– Give no more NaHCO3 than needed to increase pH to 7.1 – Consequence of NaHCO3 in lactic acidosis: increase in lactate production

Summary: Solving Acid-base Problems • If metabolic acidosis: – For Non-gap Acidoses • Distinguish renal from non-renal forms • Calculate urine anion gap and/or urine osmolar gap and note urine pH – For High AG Acidoses • Know causes of high anion gap metabolic acidosis • If toxin suspected: calculate Osmolar Gap • If hypokalemia:

– Calculate TTKG or FE K+ to determine if K loss of renal origin • If metabolic alkalosis: – Look at urine [Cl-] and separate into two categories: Cl responsive and Cl unresponsive