Ammonium Chloride (see Ammonium Chloride): intravenous ammonium chloride is a systemic and urinary acidifying agent, which is converted to ammonia and hydrochloric acid through hepatic oxidation
Calcium Chloride (see Calcium Chloride): generates hydrogen chloride
D-Lactic Acidosis with Normal Renal Function (see Lactic Acidosis)
Mechanism: the proximal tubule sodium/L-lactate co-transporter is stereospecific and does not transport D-lactate
Therefore, filtered D-lactate is rapidly excreted in the urine (assuming normal renal function)
Diagnosis: delta anion gap/delta bicarbonate ratio is 1 or <1 (obviously, as the delta anion gap/delta bicarbonate ratio approaches zero, this would be observed as a non-anion gap metabolic acidosis)
This is in contrast with L-lactic acidosis, where the delta anion gap/delta bicarbonate ratio is typically between 1.1-1.6
Rapid Infusion of Bicarbonate-Free (and Lactate-Free) Normal Saline (see Normal Saline)
Physiology: dilutional metabolic acidosis results predominantly from an expansion in the extracellular fluid volume by fluids that are bicarbonate-free or contain no organic acid salts that could potentially be metabolized to bicarbonate (such as lactate or acetate)
Mechanisms Favoring the Development of Dilutional Metabolic Acidosis
Narrowing of strong ion difference between sodium and chloride
Mechanisms Countering the Development of Dilutional Metabolic Acidosis
Movement of bicarbonate from bone and intracellular stores into the extracellular space
Binding of hydrogen ions by proteins (albumin, hemoglobin)
Clinical Significance: however, in a dog model with a 28% expansion of the extracellular volume with isotonic saline, the serum bicarbonate only decreased 10% [MEDLINE] -> this suggests that dilutional acidosis is unlikely to occur unless extremely large amounts of bicarbonate-free intravenous fluids are administered
Normal Anion Gap Values: laboratory-dependent (so, the laboratory should publish their normal range) and patient-dependent (so, it is important to know the patient’s baseline anion gap prior to the onset of their disease process)
Correction of the Serum Anion Gap
Correction of Anion Gap for Serum Albumin: since albumin represents the major unmeasured anion responsible for the anion gap (with a net negative charge at physiologic pH), the expected anion gap must be corrected for serum albumin
Anion Gap Decreases 2.3-2.5 mEq/L for Each 1 g/dL Decrease in the Serum Albumin: Corrected Anion Gap = (Measured Anion Gap) + [2.5 x (4.5 – Serum Albumin)]
Correction of Anion Gap for Hyperkalemia: since potassium is an unmeasured cation
For example, serum potassium of 6.0 mEq/L will decrease the anion gap by 2 mEq/L
Correction of Anion Gap for Hypercalcemia: since calcium is an unmeasured cation, hypercalcemia decreases the anion gap
Correction of Anion Gap for Hypermagnesemia: since magnesium is an unmeasured cation, hypermagnesemia decreases the anion gap
Delta Gap/Delta Bicarbonate Ratio
General Comments: in simple acid-base disturbances, there is a significant variability in the delta gap/delta bicarb ratio between patients [MEDLINE]
Mechanism: hypovolemia changes the renal excretion of ketoacids in DKA, significantly altering the delta gap/delta bicarb ratio
Recommendation: the delta gap/delta bicarb ratio should be used with caution in diagnosing a mixed acid-base disturbance in any individual patient
L-Lactic Acidosis -> Delta Anion Gap/Delta Bicarbonate Ratio is Typically Around 1.6 (see Lactic Acidosis)
Mechanisms
Most of the lactate anions which enter the extracellular space remain in that space
Urinary lactate excretion is decreased due to associated renal hypoperfusion/dysfunction
Lactate does not usually enter the intracellular fluid space
Over 50% of hydrogen ions are buffered in the cells and bone (even more so when the acidosis is severe): when hydrogen ions are buffered in cells/bone, the serum bicarbonate does not decrease -> therefore, anion gap increases more than the serum bicarbonate decreases
Clinical Time Course: since hydrogen ion buffering in cells and bone may take several hours to equilibrate, the ratio may initially be 1.1 and increase over time toward the ratio of 1.6
Exercise-Induced Lactic Acidosis -> Delta Anion Gap/Delta Bicarbonate Ratio Varies Based on Serum Lactate and pH (see Lactic Acidosis)
Mechanism: may be due to better buffering by nonbicarbonate buffers (such as hemoglobin) at lower pH values
Clinical
Serum Lactate <15 mEq/L: delta gap/delta bicarb ratio is around 1
Serum Lactate >15 mEq/L (with pH <7/15): delta gap/delta bicarb ratio increases to >1
D-Lactic Acidosis -> Delta Anion Gap/Delta Bicarbonate Ratio is Typically Around 1 (or <1) (see Lactic Acidosis)
Mechanisms: proximal tubule sodium/L-lactate co-transporter is stereospecific and does not transport D-lactate -> therefore, filtered D-lactate is rapidly excreted in the urine
Clinical
Normal Renal Function: delta gap/delta bicarb ratio may be 0 (i.e. NAGMA) to <1 (i.e. mild AGMA)
Impaired Renal Function: delta gap/delta bicarb ratio is around 1 (i.e. typical AGMA)
Mechanisms: renal function is typically maintained in most ketoacidoses (except in the case of patients with decreased renal function) with resulting renal loss of ketoacids (acetoacetate, β-hydroxybutyrate) as sodium/potassium salts -> this decreases the anion gap without impacting the serum bicarbonate
Toluene Intoxication -> Delta Anion Gap/Delta Bicarbonate Ratio is Typically <1 (see Toluene)
Mechanism: in the setting of intact renal function, hippurate is efficiently excreted (decreasing the anion gap)
Early or with Impaired Renal Function: AGMA is typical (with delta anion gap/delta bicarbonate ratio <1)
Later or with Normal Renal Function: NAGMA due to type 1 distal RTA (with delta anion gap/delta bicarbonate ratio 0)
Chronic Kidney Disease (CKD) -> Delta Anion Gap/Delta Bicarbonate Ratio is Variable Depending on Stage of Renal Disease (see Chronic Kidney Disease)
Mechanisms
Early Kidney Disease: greater dysfunction in acid excretion than acid anion excretion -> typically have non-anion gap metabolic acidosis or anion gap metabolic acidosis with delta anion gap/delta bicarbonate ratio <1
Later Kidney Disease: typically have anion gap metabolic acidosis with delta anion gap/delta bicarbonate ratio >1
Bicarbonate Deficit
Bicarb Deficit = (0.5 x Wt in Kg)(Desired HCO3-Measured HCO3)
Normal Urine Anion Gap: -20 to -50 mEq/L (as the concentration of unmeasured cations normally exceeds the concentration of unmeasured anions) -> the remainder is NH4+)
Requires urine Na >25 and lack of other unmeasured anions (hydroxybutyrate, etc)
Interpretation of the Urine Anion Gap
Gastrointestinal Bicarbonate Loss: urine anion gap becomes more negative (usually >-50 mEq/L), due to the kidney increasing hydrogen ion (H+) excretion in the form of ammonium (NH4+)
Mechanism
Hypovolemia with decreased sodium delivery to distal nephron
Bicarbonate is replaced by chloride in serum (producing hyperchloremia)
Type 1 or 4 Renal Tubular Acidoses: urine anion gap becomes positive, due to the kidney decreasing H+ excretion in the form of NH4+
Serum Ketones
Nitroprusside Reaction: only detects acetoacetate and, to a far lesser extent, acetone
Acetoacetate
Acetone
Beta Hydroxybutyrate Level
Normal: <0.6 mmol/L
Preferred test in diabetic ketoacidosis (DKA)/hyperosmolar hyperglycemic state (especially for monitoring the therapeutic response), since this is the predominant ketone in severe DKA
Arrhythmias: data come mainly from animal studies with pH <7.1, but human studies are generally not consistent with these findings
Decreased Catecholamine Efficiency: data come mainly from animal studies with pH <7.1, but human studies are generally not consistent with these findings
Myocardial Depression: data come mainly from animal studies with pH <7.1, but human studies are generally not consistent with these findings
Transient decreases in pH to <6.8 in diabetic ketoacidosis do not result in myocardial depression
This is due to the fact that at pH <7.1, small changes in pCO2 and serum bicarbonate result in large changes in the serum pH
Physiology of Bicarbonate Distribution Space: infused bicarbonate rapidly diffuses into the extracellular space (some will enter the intracellular space), some will be titrated by hydrogen ions (released from buffers), and some will be titrated by organic acids (which may occur as part of the primary disease or be formed in response to the bicarbonate load and increased pH)
Administration
Sodium Bicarbonate Intravenous Vials: these are hypertonic (for reference, 100 mEq/50 mL = 2000 mOsm/L)
7.2% Solution (44.6 mEq/50 mL)
8.4% Solution (50 mEq/50 mL)
Sodium Bicarbonate Intravenous Infusion: 3 amps sodium bicarbonate per liter of D5W (gives sodium bicarbonate at approximately 150 mEq/L)
Tromethamine (Tris-Hydroxymethyl Aminomethane, THAM, Trometamol): amino alcohol which buffers hydrogen ions via its amine (NH2) moiety
Indications: has been studied in acidosis associated with diabetic ketoacidosis, sepsis, permissive hypercapnia, renal tubular acidosis, gastroenteritis, and drug intoxications (but not lactic acidosis)
Chronic Metabolic Acidosis
General Considerations
Treatment of Chronic Acidosis May Alleviate Dyspnea
Treatment of Chronic Acidosis May Normalize Skeletal Growth in Children with Chronic Acidosis
Anion gap-bicarbonate relation in diabetic ketoacidosis. Am J Med. 1986 Dec;81(6):995-1000 [MEDLINE]
Use of the DeltaAG/DeltaHCO3- ratio in the diagnosis of mixed acid-base disorders. J Am Soc Nephrol. 2007 Sep;18(9):2429-31. Epub 2007 Jul 26 [MEDLINE]
