Page 1732 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 124: Toxicology in Adults 1201

TABLE 124-14 Selected Drugs Associated With an Elevated Anion Gap TABLE 124-16 Drugs/Toxins Associated With an Elevated Osmol Gap
Metabolic Acidosis Ethanol (if not included in the formula)
Amiloride Ketamine Ethylene glycol/glycolaldehyde
Ascorbic acid Metformin Glycerol
Carbon monoxide Methanol Glycine
Chloramphenicol Niacin Intravenous immunoglobulin (maltose)
Colchicine Nitroprusside Isopropanol/acetone
Cyanide NSAIDs Mannitol
Dapsone Papaverine Methanol/formaldehyde
Epinephrine Paraldehyde (hippuric acid) Propylene glycol
Ethanol Phenformin Radiocontrast media
Ethylene glycol Propofol Sorbitol
Formaldehyde Salicylates
Hydrogen sulfide Terbutaline
Iron Tetracycline (outdated) (blood urea nitrogen) and glucose are divided by 2.8 and 18, respectively,
to convert mg/dL into mmol/L. Dividing ethanol concentration by 4.6
Isoniazid Toluene (hippuric acid)
accounts for the effect of a measured plasma ethanol concentration (in
Verapamil mg/dL) on calculated plasma osmolarity. Of note, measured osmolality
NSAIDs, nonsteroidal anti-inflammatory drugs. has units of mOsm/kg and calculated osmolarity has units of mOsm/L;
subtracting one from the other, however, generally does not cause a criti-
Rarely, toxic ingestion decreases the anion gap (<6 mEq/L). Causes cal error in analysis because 1 L ∼ 1 kg in human serum. Further note
of decreased anion gap are listed in Table 124-15. Note the presence of that spuriously low serum sodium values (pseudohyponatremia) due to
lithium on this list. hyperlipidemia or hyperproteinemia may cause a factitious osmol gap.
Methanol and ethylene glycol are unique in producing both severe
Osmol Gap: Certain drugs and toxins of low molecular weight metabolic acidosis with elevated anion gap and an elevated osmol gap.
(Table 124-16) produce a discrepancy between measured osmolality Isopropanol intoxication can elevate the osmol gap and cause ketonemia
and calculated plasma osmolarity, commonly referred to as the osmol and ketonuria (owing to its metabolism to acetone) without elevation of
gap (osmol gap equals measured osmolality minus calculated osmo- the anion gap or acidosis. Through CNS and cardiac effects, isopropanol
larity). The plasma osmol gap can thus be used to detect the presence may cause respiratory acidosis and lactic acidosis, respectively.
of these toxins in the blood. Normal plasma osmolarity, determined Caution must be used when interpreting the osmol gap. First, mea-
by the concentrations of major solutes in plasma, is approximately 285 surement of osmolality by vapor pressure osmometry does not detect
to 295 mOsm/L and is calculated as: volatile alcohols such as ethanol and methanol (but does detect ethyl-
Calculated Osmolarity = 2[Na ] + [BUN]/2.8 + [Glucose]/18 ene glycol); freezing point depression osmometry does measure these
+
+ [Ethanol]/4.6 solutes. 35,36 Although 10 mOsm/L is often used as the upper limit of
normal, osmol gaps may range from −9 mOsm/L to +5 mOsm/L in
where Na (in mmol/L) is multiplied by 2 to account for accompany- normal individuals (using the standard formula for calculations).
+
37
ing anions (chloride and bicarbonate), and the concentrations of BUN Thus, an osmol gap of 10 mOsm/L in a patient whose baseline value is
−2 mOsm/L could represent the presence of significant amounts of low-
molecular-weight substances (eg, ethylene glycol level over 70 mg/dL). 38,39
TABLE 124-15 Causes of Decreased Anion Gap
In one study, the range of osmolal gaps measured in 300 consecutive
Increased unmeasured cations patients presenting to Bellevue Hospital in New York (with indications
Hyperkalemia for measurement of electrolytes and ethanol) was −2 ± 6 mOsm/L using
Hypercalcemia the standard formula, including the contribution of measured ethanol
40
concentrations. Large variations existed in the range of osmol gap that
Hypermagnesemia was very dependent on the equation used. Because of the large range of
Acute lithium intoxication values, the authors noted that small osmol gaps in no way exclude the
Elevated IgG (myeloma; cationic paraprotein) possibility of toxic alcohol ingestion. Furthermore, as ethylene glycol/
glycoaldehyde and methanol/formaldehyde are metabolized, the osmol
Decreased unmeasured anions
gap may fall into the normal range in the continued presence of toxic
Hypoalbuminemia metabolites. By contrast, concurrent ethanol ingestion may prevent
41
Drugs early development of metabolic acidosis, so that the presence of an
osmol gap greater than expected from the measured ethanol level may
Bromide
be the only clue to the presence of a nonethanol alcohol. Lactic acidosis
42
Iodide and ketoacidosis have also been reported to cause elevation of the osmol
43
Lithium gap. Finally, chronic (but not acute) renal failure is a cause of increased
osmol gap, a phenomenon corrected by dialysis. 44
Polymyxin B
In summary, the presence of an elevated anion gap metabolic
Tromethamine acidosis, even in the presence of an apparent clinical explanation,
Analytical artifact warrants consideration of intoxication. The additional presence of an
Hypernatremia (>170 mEq/L) elevated osmol gap, particularly of large magnitude (>25 mOsm/L),
is indicative of methanol or ethylene glycol intoxication (see below).
Hyperlipidemia The converse is not true, in that serious intoxications with either agent

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