ANION GAP METABOLIC ACIDOSIS More then just a mud pile Anne Peery, MD July 29, 2008

Metabolic acidosis  Overproduction or ingestion of fixed acid or loss of base which produces an increase in arterial pH (an acidemia)  HCO3 is used to buffer the extra fixed acid.  As a result, the arterial HCO3 decreases.  Acidemia causes hyperventilation (Kussmaul breathing), which is the respiratory compensation for metabolic acidosis.

The anion gap  An estimate of the unmeasured anions.  Used to determine if a metabolic acidosis is due to an accumulation of non-volatile acids (e.g. lactic acid) OR a net loss of bicarbonate (e.g. diarrhea)  Anion gap = Na – (Cl + HCO3)

The influence of albumin  Albumin is a major source of unmeasured anions!  If a patient’s serum albumin is low, then the patient has more unmeasured anions then the anion gap predicts.  Corrected AG = Observed AG x (4.5 – measured albumin)

More then one problem?  The “gap-gap” or “delta-delta”  In the presence of a high AG metabolic acidosis, it is possible to detect another metabolic acid base disorder by comparing the AG excess to the HCO3 deficit  Delta-Delta = (Measured AG – 12)/(24-measured HCO3)

Mixed Disorders  When a fixed acid accumulates in extracelluar fluid, the decrease in serum HCO3 is equivalent to the increase in AG and the gap-gap ratio = 1  When a hypercholemic acidosis appears, the decrease in HCO3 is greater then the increase in AG, and the gap-gap <1 (i.e. coexistent metabolic acidosis)  When alkali is added in presence of high AG acidosis, the decrease in bicarbonate is less then increase in AG and the gap-gap > 1 (i.e. coexistent metabolic alkalosis)

Differential for AG Metabolic Acidosis 1. Ketoacidosis 2. Lactic acid acidosis 3. Toxin-induced metabolic acidosis 4. Renal failure acidosis

Ketosis  Occurs in conditions of reduced nutritient intake, adipose tissues release free fatty acids, which are taken up in the liver and metabolized to form the ketones, acetoacetate and B-hydroxybutyrate.  The ACETEST a nitroprusside reaction detects acetoacetate NOT hydroxybutyrate.

Ketosis  Diabetic ketoacidosis  Alcoholic ketoacidosis  Starvation ketosis

Alcoholic Ketoacidosis  Some chronic alcoholics, esp binge drinkers, who discontinue solid food intake while continuing EtOH consumption develop this form of ketoacidosis when EtOH ingestion is curtailed abruptly.  Metabolic acidosis may be severe but is accompanied by only a modest derangement in glucose levels (usually low but may be slightly elevated).

Alcoholic Ketoacidosis  Presentation may be complex because a mixed disorder is often present  Metabolic alkalosis from emesis  Respiratory alkalosis from EtOH liver disease  Lactic acid acidosis from hypoperfusion  Therapy includes IV glucose and saline  Check electrolytes frequently  High potential for refeeding syndrome

Lactic Acid Acidosis  Lactic acid can exist in two forms: L-lactate and D- Lactate. In mammals, only the levorotary form is a product of metabolism.  D-Lactate can accumulate in humans as a byproduct of metabolism by bacteria, which accumulate and overgrow in the GI tract with jejunal bypass or short bowel syndrome.  The lab measures only L-lactate!

L-Lactic Acidosis  Tissue underperfusion (Type A)  Shock, shock, shock  Hypoxia  Asthma  CO poisoning  Severe anemia

L-Lactic Acidosis  Medical conditions (w/o tissue hypoxia)  Hepatic failure  Thiamine deficiency (co-factor for pyruvate dehyrogenase)  Malignancy  Bowel ischemia  Seizures  Heat stroke  Tumor lysis  Drugs/Toxins Metformin (particulary associated with hypovolemia and dye) NRTI (especially stavudine and zidovudine) Propofol Nitroprusside

L-Lactic Acidosis  Propylene Glycol toxicity  An alcohol used to enhance water solubility of many hydrophobic IV medications (lorazepam, diazepam, esmolol, nitroglycerin)  Propylene glycocol toxicity from solvent accumulation has been reported in 19% to 66% of ICU patients receiving high dose lorazepam or diazepam for more then 2 days.  Signs of toxicity—agitation, coma, seizures, tachycardia, hypotension

Toxic-Induced Metabolic Acidosis  Salicylates  More common in children then in adults  May result in high AG metabolic acidosis  Most commonly associated with respiratory alkalosis due to direct stimulation of the respiratory center

Osmolar Gap  Under most physiologic conditions, Na, urea and glucose generate the osmotic pressure of blood.  Serum OSM = 2 (Na) + BUN/2.8 + glc/18  Calculated and determined OSM should agree within 10 to 15 mOsm/kg.  If not, then serum Na may be spuriously low OR osmolytes other then Na, glc or urea have accumulated.  The osmolar gap is a reliable and helpful tool when screening for toxin-associated high AG acidosis.

Toxic-Induced Metabolic Acidosis  Ethanol  In general does not cause high AG metabolic acidosis  Oxidized to acetaldehyde, acetyl CoA and CO2  Acetaldehyde levels increase significantly if acetaldehyde dehydrogenase inhibited by disulfiram, insecticides or a sulfonurea.  Paraldehyde  Very rare

Toxic-Induced Metabolic Acidosis  Methanol  Causes metabolic acidosis in addition to severe optic nerve and CNS manifestations  High osmolar gap  Ethylene Glycol  Leads to high AG metabolic acidosis in addition to severe CNS, cardiopulmonary and renal damage.  Recognizing oxalate crystals in urine facilitates diagnosis.  High osmolar gap

Uremia  At a GFR < 20 mL/min, the inability to excrete H+ with retention of acid anions such as phosphate and sulfate results in an increased anion gap acidosis, which RARELY is severe.  The unmeasured anions “replace” bicarbonate (which is consumed as a buffer).  Hyperchloremic normal anion gap acidosis develops in milder cases of renal insufficiency.

References  Marino, P The ICU Book. 3 rd Edition. Philadelphia. Lippincott.  Brenner and Rector The Kidney. 8 th Edition. New York. Saunders.  McPhee S andPapadakis M Current Medial Diagnosis and Treatment. New York. McGraw-Hill.  Up to Date 2008.