An Algorithmic Approach to the Patient with Metabolic Acidosis

A 67 year-old man has a history of COPD and diabetic kidney disease and is admitted with worsening kidney failure, altered mental status and fluid overload. Among his labs include venous blood gases, showing pO₂ 37 torr, pCO₂ 40 torr, pH 7.22 and HCO₃^- 16 mEq/L. His blood chemistries include: Glucose 153 mg/dl, Na⁺ 130mEq/L K⁺ 5.3 mEq/L Cl^- 102 mEq/L HCO₃^- 16 mEq/L albumin 2.4 g/dl BUN 40 mg/dl Cr 2.8 mg/dl.

Applying the algorithm, the patient definitely has a metabolic acidosis. The estimated appropriate respiratory compensation for a serum HCO₃ of 16 mEq/L would be (1.5 X 16=24) + 8 =32. Since this patient’s measured pCO₂ is actually 40 torr, this represents an additional respiratory acidosis, probably related to his COPD. The patient’s anion gap is 12, and if one were not aware that the normal anion gap in healthy individuals was approximately 6, one might be tempted to refer to this as a normal anion gap acidosis. In addition, it is recalled that each gram/dl diminution of the serum albumin reduces the anion gap by about 2.5, so the anion gap may be artificially reduced by about (1.6 X 2.5) =4 in this case, resulting in a ‘actual’ anion gap of 16.

The resultant delta ratio would then be approximately 10/10=1.0 again suggestive of a elevated anion gap metabolic acidosis, as well as the patient’s respiratory acidosis. The patient had a serum lactate of 1.7 mEq/L and negative serum ketones, so the unmeasured anions much be inorganic acids or minor organic acids accumulating in renal failure. In this case, the patient’s serum phosphorus was measured at 8.2 mg/dl=5.33 mEq/L, explaining much of the patient’s elevated anion gap.

A 37 year-old woman with a history of Type I diabetes mellitus is admitted with flu-like symptoms for a few days and non-compliance with her insulin dosing. She appears clinically dehydrated and is breathing deeply and rapidly. Her venous blood gases show pO₂ 40 torr pCO₂ 11 torr pH 6.97 HCO₃^- 2 mEq/L . Her blood chemistries include Na⁺ 117 mEq/L K⁺ 4.6 mEq/L Cl^- 85 mEq/L HCO₃^-2 mEq/L Albumin 4.0g/dl BUN 23 mg/dl Cr 1.6 mg/dl Glucose 910 mg/dl.

Applying the algorithm, the patient clearly has a severe metabolic acidosis. Winter’s formula for respiratory compensation of metabolic acidosis becomes less valid at such an extreme level, yet a pCO₂ of 11 torr certainly is near the maximum ability of respiratory compensation. The patient’s anion gap is 30, so this is, of course an elevated anion gap acidosis. The delta ratio is approximately 24/24=1.0, which is typical for diabetic ketoacidosis.

In diabetic ketoacidosis (DKA), the lack of insulin forces the body to metabolize lipids and amino acids for energy [11]. Free fatty acids are formed and these are further metabolized to ketones, which are strong organic acids. The major acidic ketones are beta-hydroxybutyrate (B^-OH) and acetoacetate and the ratio between the two varies according with the degree of acidosis (NADH/NAD⁺). In the usual patient with DKA, most of the acidic ketone is B^-OH, but the amount of acetoacetate may also be significant. This is important, because acetoacetate is not measured in most clinical laboratory evaluation of ketones. Acetone is electrically without charge and would not enter into our formulas.

In addition, patients with DKA may also, as in this case, have a degree of lactic acidosis. This may relate to dehydration and poor tissue perfusion, but also to altered glucose metabolism.

The patient’s serum ketones were measured at 12.11 mEq/L and her serum lactate was 3.1 mEq/L, which adds up to 15.2 out of the patient’s excess anion gap of 24. Since the patient has some degree of renal dysfunction, there may be a contribution of inorganic acids, such as sulfates and phosphate, as well as acetoacetate, noted above.

The patient was treated for her DKA with an insulin infusion and saline hydration. A day later, she was clinically much better. Her labs, then, included:
Venous gases:
pO₂ 41 torr pCO₂ 33 torr HCO₃^- 16 mEq/L pH 7.31, and her chemistries showed: Glucose 143 mg/dl Na⁺132 mEq/L Cl^- 108 mEq/L CO₂ 16 mEq/L.

Applying the algorithm, the patient continues to have a significant metabolic acidosis, though, of course, improved. The respiratory compensation for a serum HCO₃ of 16 mEq/L would be estimated at (1.5 X 16=24)+8=32, so that would be appropriate. The anion gap is 8 with would be considered at the upper edge of normal for the anion gap and the delta ratio is approximately: 2/10=0.2.

Therefore, the patient, primarily, has a non-anion gap or hyperchloremic acidosis. This is common on recovery from diabetic ketoacidosis because ketones, which are strong organic acids, are excreted into the urine with a cation to maintain electrical neutrality. This is sometime referred to as ‘loss of potential bicarbonate’. Therefore, HCO₃^- may be replaced by Cl^- in the patient’s blood, especially, as in this case, when the patient has already received large volumes of chloride containing IV solutions for resuscitation. This results in replacement of a severe elevated anion-gap acidosis with a less severe non-anion gap acidosis.

A 77 year-old man was seen in the ED because of mental confusion and gait difficulties, present over the last few days. The patient had a history of multiple intestinal resections for bowel obstructions and had been left with a short gut, for which he had previously been on total parenteral nutrition for a few months. The total parenteral nutrition had eventually been weaned and discontinued, so that he was able to tolerate a normal diet with mild diarrhea. He was on no medications, though he had recently finished a course of clindamycin for a dental infection.

His laboratory work included a set of venous blood gases, showing pO₂ 37 torr pCO₂ 30 torr pH 7.31 and HCO₃ 15 mEq/L. Blood chemistries showed a Na⁺ 144 mEq/L K⁺ 4.1 mEq/L Cl^- 102 mEq/L HCO₃ 15 mEq/L BUN 12 mg/dl Cr 1.0 mg/dl Glucose 132 mg/dl Phosphorus 2.6 mg/dl (1.69 mEq/L) Albumin 3.9 g/dl , ketone 0.51 mEq/L and serum lactate 1.12 mEq/L. Acetaminophen and salicylate levels and blood ethanol levels were zero and his serum osmolality was 298 mmole/kg.

Applying the algorithm, the patient is significantly acidotic. The predicted pCO₂ from respiratory compensation would be approximately (1.5 X 15= 22.5) +8= 30.5 torr, so that is appropriate. The anion gap is calculated at 17, which is significantly elevated.

What is (are) the unmeasured anion? Since the serum albumin is normal, the unmeasured anion(s) must be inorganic or organic acids. The patient’s renal functions are normal, as is the phosphorus level, so it is unlikely that we are dealing with an inorganic acidosis. Therefore, the unmeasured anion is likely to be a truly unmeasured organic acid, especially with the serum lactate and ketone levels low. That is, the patient most likely suffers from an undiagnosed toxic organic acid; most likely a toxic substance metabolized to an organic acid or acids.

Examples of this situation would include intoxication with ethylene glycol (metabolized to oxalic acid and glycolic acid) or methanol (metabolized to formic acid) but these are probably ruled out by the patient’s normal serum osmolality.

The patient’s serum was sent to a reference laboratory, where his D-lactate level was found to be 7.9 mEq/L. The typical serum lactate assay performed in clinical laboratories uses the L-lactate dehydrogenase enzyme and generally measures only L-Lactate, which was normal in this case. D-Lactic acidosis is a syndrome of elevated anion-gap acidosis and neurologic debility occurring in patients with a short gut, usually after jejunal-ileal bypass surgery [12]. In this condition, ingested carbohydrates and metabolized by colonic lactobacilli to D-Lactate. In this case, the patient’s recent antibiotic exposure may have led to overgrowth of colonic bacteria. This case illustrates that organic molecules occur as stereoisomers and may differ in their testing as well as clinical importance.

A 78 year-old white man is recently diagnosed with multiple myeloma. His laboratory work includes venous blood gases: pO₂ 39 torr pCO₂ 38 torr pH 7.29 and HCO₃ 18 mEq/L. Among the rest of his labs are: Na⁺ 129 mEq/L K⁺ 5.0 mEq/L Cl^-100 mEq/L HCO₃^- 18 mEq/L , BUN 32 mg/dl Cr 2.9 mg/dl Total protein 12.0 g/dl albumin 2.2 g/dl Calcium 12.4 mg/dl (6.2 mEq/L) , and Phosphorus 6.2 mg/dl (4.0 mEq/L).

Applying the algorithm to this case, the patient certainly has a metabolic acidosis and since the predicted pCO₂ with a serum HCO₃^- of 18 mEq/L would be approximately (1.5 X 18) + 8=32 torr, there is an element of respiratory acidosis, as well. If one were unaware that the ‘normal’ anion gap is approximately 6, one might refer to this metabolic acidosis as a non-anion gap metabolic acidosis; but the acid-base picture is much more complicated.

First, the serum albumin is about 2 grams lower than normal, which would lower the calculated anion gap by about 5. In addition, the elevated serum calcium level would also lower the anion gap by about 1. This would ‘increase’ the anion gap in this case to 11+5+1= about 17, but that is not the end of the story.

As mentioned, in most cases, the globulin fraction of serum proteins does not exhibit a significant ionic charge and therefore is usually ignored in our calculations of the anion gap (compared to the negatively charged albumin). In malignant and benign paraproteinemias, however, there may be a significant positive charge from the IgG heavy chain and a lesser negative charge from the IgA heavy chain [8,13,14]. The amount of the positive charge associated with the IgG heavy chain is approximately 0.8mEq per gram.

Since this patient’s IgG level was 6.1 grams/dl, the anion gap would be further reduced by 6.1 X 0.8=4.9. Therefore, the patients’ ‘effective anion gap’ would be approximately 17+5=22, demonstrating a significant anion gap metabolic acidosis.

The presence of significant paraproteinemia, such as malignant or benign hematologic dyscrasia may, as noted, lead to an increased level of unmeasured cations and, thereby, a lower or even negative anion gap [13,14]. The presence of a very low or negative anion gap in an otherwise healthy individual, however, is usually of no clinical concern and need not lead to a search for hematologic diseases in most patients [8].

The understanding of human acid-base pathophysiology and use of a simple algorithm are of great help in the evaluation of the acidotic patient.

1. Curthoys NP, Moe OW (2014) Proximal tubule function and response to acidosis. Clin J Am Soc Nephrol 9: 1627-1638.
2. Rose BD, Post TW (2001) Clinical Physiology of Acid-Base and Electrolyte Disorders. In: Rose BD, Post TW (eds). Physiology of Acid-Base Disorders, 5^th edn, McGraw-Hill, New York, USA.
3. http://www.faa.gov/data_research/research/med_humanfacs/oamtechreports/1960s/media/am68-23.pdf
4. Emmett M, Narins RG (1977) Clinical use of the anion gap. Medicine (Baltimore) 56: 38-54.
5. http://www.hcplive.com/contributor/frank-brodkey/2014/09/tales-of-the-anion-gap-part-i
6. Winter SD, Pearson JR, Gabow PA, Schultz AL, Lepoff RB (1990) The fall of the serum anion gap. Arch Intern Med 150: 311-313.
7. Wrenn K (1990) The delta (delta) gap: an approach to mixed acid-base disorders. Ann Emerg Med 19: 1310-1313.
8. Kraut JA, Madias NE (2007) Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2: 162-174.
9. Wilcox (2009) Handbook of Nephrology and Hypertension (6thedn).CBS Publishers & Distributors, new Delhi, India.
10. Martinu T, Menzies D, Dial S (2003) Re-evaluation of acid-base prediction rules in patients with chronic respiratory acidosis. Can Respir J 10: 311-315.
11. http://www.anaesthesiamcq.com/AcidBaseBook/ab8_2.php
12. Kowlgi NG, Chabbra L (2015) D-Lactic Acidosis: An Underrecognized Complication of Short Bowel Syndrome. Gastroenterol Res Pract 2015: 476215.
13. Mansoor S, Siddiqui I, Adil S, Nabi Kakepoto G, Fatmi Z, et al. (2007) Anion gap among patients of multiple myeloma and normal individuals. Clin Biochem 40: 226-229.
14. Paladini G, Sala PG (1979) Anion gap in multiple myeloma. Acta Haematol 62: 148-152.