Clinical Assessment—Laboratory Tests

Course: WB 4342
CE Original Date: March 20, 2020
CE Expiration Date: March 20, 2022
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Learning Objectives

After completing this section, you will be able to

  • identify the abnormal laboratory findings associated with ethylene glycol poisoning, and
  • list three measurements that can assist with diagnosis of ethylene glycol poisoning.
Introduction

Ethylene glycol is a relatively common cause of overdose treated in U.S. emergency departments. Among the thousands of cases of ethylene glycol poisoning reported in the United States each year, several deaths occur.

Timely and accurate measurement of ethylene glycol is vital to establish the correct diagnosis.

Serum Analysis

Diagnosis of ethylene glycol poisoning usually depends on the detection of the toxicant or toxic metabolites in serum or plasma. The most commonly used analytic methods for detection and quantification of ethylene glycol use gas chromatography (GC) coupled to flame ionization detection (FID) or mass spectrometric detectors [Juenke et al. 2011]. However, many hospitals do not have this testing capacity. In fact, in many hospitals these are only available as “send out” tests, so results arrive too late for meaningful clinical decision making (Goldfrank LR et al 2019).

An elevated serum level of ethylene glycol confirms ethylene glycol poisoning. Significant toxicity is often associated with levels greater than 25 milligrams per deciliter (mg/dL) (Goldfrank LR FN 1998; Hall AH 1992). However, potentially toxic serum concentrations of ethylene glycol (≥20–30 mg/dL) do not always produce early symptoms in children or adults. Therefore, the lack of symptoms does not exclude a potentially toxic ingestion (Caravati et al. 2005).

False Positives

Communication with the laboratory is critical in poisoning cases for several reasons:

  • 2,3-butanediol, often found in the plasma of alcoholics, mistakenly can be identified as ethylene glycol when the analysis is performed by gas chromatography (Jones AW et al. 1991).
  • Propylene glycol can interfere with some ethylene glycol assays (Apple et al. 1993; Hilliard et al. 2004; Robinson et al. 1983).
  • Laboratory results can show an inherited metabolic disorder as ethylene glycol intoxication [(Pien et al. 2002).
  • Some blood gas analyzers might mistake elevated serum glycolic acid as elevated lactic acid, leading to a false positive lactic acid result (Marwick et al. 2012; Meng et al. 2010).
Routine Tests

All patients with known or suspected ethylene glycol ingestion require the following tests:

  • Arterial or venous blood gas
  • Blood glucose
  • Serum electrolytes (including calcium and magnesium)
  • Blood urea nitrogen (BUN) and creatinine
  • Liver function tests
  • Serum acetaminophen and salicylate concentrations
  • Urinalysis with microscopic evaluation for crystals
  • Blood ethanol
  • Measured serum osmolality (sample must be obtained from the same blood draw used to obtain serum electrolytes)
  • Samples for a serum volatile acid screen (which will test for methanol and isopropanol) and serum ethylene glycol should also be collected and sent. Note that many hospitals must send these samples to a reference laboratory, and results are not usually available in time to guide initial clinical management. Check with your hospital’s laboratory for specific instructions on how to order these necessary tests.
Ethanol, Methanol, Ketoacidosis

A blood or serum ethanol level will establish whether ethanol is contributing to the initial CNS symptoms. If present, ethanol will substantially affect metabolism and influence therapy. Patients who have suspected ethylene glycol exposure also should be assessed with serum methanol tests. If alcoholic ketoacidosis is suspected, serum lactate and β-hydroxybutyrate levels might help identify alcoholic patients.

Anion and Osmolal Gaps

The presence of metabolic acidosis with anion and osmolal gaps is an important clue to the diagnosis (Friedman et al. 1962; Parry and Wallach 1974; Szerlip 1999). Numerous toxic substances are associated with an elevated anion gap (Table 3) (Goldfrank LR FN 1998). An elevated osmolal gap suggests the presence of a low-molecular weight substance.

A measured osmolality by the freezing point depression method is needed to detect an osmolal gap. Results of this test are used to calculate the osmolal gap (Figure 2).

Metabolic acidosis might be inhibited or delayed when large quantities of ethanol and ethylene glycol are ingested concurrently. In such cases, an elevated anion-gap metabolic acidosis will take longer to develop than if ethylene glycol alone were ingested. This is because aldehyde dehydrogenase (ADH) has a higher affinity for ethanol than for ethylene glycol. The presence of ethanol delays the metabolism of ethylene glycol to its acidic metabolites.

An osmolal gap is often cited as indirect evidence of an exogenous alcohol or glycol, but other substances or conditions also can cause an increased osmolal gap. Conversely, failure to find an elevated osmolal gap might lead to a wrong assumption that no exogenous substances are present. Even a small osmolal gap might represent a significant ethylene glycol level.

The point is, use caution when interpreting the osmolal gap. Recent reviews have argued that using the osmolal gap as a screening tool for ethylene glycol has significant limitations and remains hypothetical (Glaser 1996; Koga et al. 2004; Purssell et al. 2004).

Urinary Crystals

Calcium oxalate or hippurate crystals in the urine, together with an elevated anion gap or osmolal gap, strongly suggest ethylene glycol poisoning (Albertson 1999). Urinary crystals result from

  • the precipitation of calcium by the oxalic acid metabolite of ethylene glycol, and
  • the reaction of the glycine metabolite with benzoic acid, which forms hippuric acid.

Urinary crystals can take many forms:

  • Dumbbells
  • Envelopes
  • Needles (most commonly) (Jacobsen et al. 1988).

Absence of urinary crystals, however, does not rule out poisoning. Many studies have shown that renal damage can occur after ethylene glycol ingestion, without deposition of calcium oxalate crystals in the kidney (Hall AH 1992; Vale 1979).

Urine Fluorescence

Urine from an exposed person might fluoresce under a Wood’s lamp because some antifreeze products contain fluorescein. Still, false positives and negatives often occur. An expert panel has concluded that using an out-of-hospital ultraviolet light to diagnose ethylene glycol ingestion by urine fluorescence is unreliable and contraindicated (Caravati et al. 2005).

Table 3. A few examples of toxic agents associated with an elevated anion gap.
Substance CNS Depression Metabolic Acidosis Ketosis Increased Osmolality Characteristic Findings
Methanol + ++ +
  • Blindness and pink edematous optic disk (delayed findings)
  • Metabolic acidosis
Ethanol + + + +
  • Alcoholic ketoacidosis
Ethylene glycol + ++ +
  • Renal failure
  • Calcium oxalate and hippurate crystals
  • CNS depression
  • Tachycardia
  • Tachypnea
Isopropanol + ++ +
  • Hemorrhagic tracheobronchitis
  • Gastritis
Salicylates + + +
  • Vomiting
  • Tinnitus
  • Hyperthermia

Adapted from (Goldfrank LR FN 1998).

Figure 2. Formulas for calculating anion and osmolal gaps.
(Goldfrank LR 2015)

An ethylene glycol level (in mg/dL) might be estimated from the osmolal gap (OG) if it is the only osmotically active poison present and levels are taken early in the course. This is most accurate if the ethylene glycol level is between 50 to 100 mg/dL:

Estimated ethylene glycol level = OG × 6.2.

The serum anion gap (AG) is determined from serum electrolytes measured in mEq/L and may be defined by the formula:

AG = ( Na+ + K+) – ( Cl + HCO3)

(Normal anion gap: 12 to 16)

The serum osmolal gap (OG) is most commonly approximated by the formula:

OG = osmolality (measured)*


+
+

2Na+ + [BUN divided by 2.8]
[glucose divided by 18]
[BAT (ethanol) divided by 4.6 (if present)]

OG = osmolality (measured)*
– 2Na+ + [BUN divided by 2.8]
+ [glucose divided by 18]
+ [BAT (ethanol) divided by 4.6 (if present)]

(Normal osmolal gap: –14 to +10)

*In this formula, osmolality (measured) is obtained by the freezing-point–depression method and expressed in milliosmoles per liter (mOsm/L); Na+ in mEq/L; BUN and glucose in mg/dL; blood alcohol test (BAT) in mg/dL.

Key Points
  • Ethylene glycol poisoning is strongly suggested by
    • an elevated anion-gap metabolic acidosis,
    • an elevated osmolal gap, and
    • urinary calcium oxalate or hippuric acid crystals.
  • Measurement of serum ethylene glycol levels can confirm poisoning.

To review relevant content, see “Serum Analysis” in this section.

Page last reviewed: October 7, 2020