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Osmolal gap without anion gap in a 43-year-old man.

CASE DESCRIPTION

A 43-year-old man presented to the emergency department (ED) (3) 2 h after ingesting 10 oz of antifreeze mixed with Gatorade in a suicide attempt. The antifreeze was green, of an unknown brand, and purchased at a local gas station. He subsequently confessed to his wife, who brought him to a community hospital ED. He denied abdominal pain, nausea, vomiting, urinary symptoms, or visual changes. Initial laboratory tests (Table 1) were clinically relevant for the following: arterial whole-blood pH, 7.34; [Pco.sub.2], 33 mmHg (4.4 kPa); serum bicarbonate, 18 mmol/L; serum ethanol, 10 mg/dL (2.17 mmol/L); and serum anion gap, 18 mmol/L. The serum osmolal gap (75 mOsm/kg) was calculated as follows: Osmolal gap = freezing-point depression osmometer value --(2 X [[Na.sup.+]] + [glucose]/18 + [blood urea nitrogen]/2.8 + [ethanol]/4.6), where the [Na.sup.+] concentration is in millimoles per liter and the glucose, blood urea nitrogen, and ethanol concentrations are in milligrams per deciliter.

With the advice of the local Poison Control Center, the patient was given 15 mg/kg fomepizole intravenously. He was placed on suicide precautions and transferred to a tertiary care center for further evaluation and treatment. On arrival at the tertiary care ED 8 h after ingestion and 3 h after fomepizole administration, the patient had a normal mental status and normal vital signs. Thiamine (100 mg), folic acid (50 mg), and pyridoxine (50 mg) were administered intravenously as cofactors for secondary metabolic pathways. At that time, laboratory test results (Table 1) were clinically relevant for the following: arterial whole-blood pH, 7.39; [Pco.sub.2], 28 mmHg (3.7 kPa); serum bicarbonate, 18 mmol/L; creatinine, 1.1 mg/dL (97.2 [micro]mol/L); lactate, 5.3 mmol/L; anion gap, 14 mmol/L; and osmolal gap, 72 mOsm/kg. No crystals were visible in the urine.

CASE FOLLOW-UP

Given the improving anion gap and the lack of clinically relevant acidemia, there was debate about whether this patient had actually ingested ethylene glycol (EG) or had instead ingested propylene glycol (found in "safer" antifreezes) or isopropyl alcohol. Therefore, a test for the serum concentration of EG was ordered for confirmation. The sample for measurement of EG by gas chromatography had to be sent by courier to the closest clinical laboratory offering the test, with the results expected in 4-8 h. While the sample was en route for testing by gas chromatography, the hospital pathologist performed a modified version of a commercially available veterinary enzymatic assay. This test had been validated by our laboratory, and the results of these studies have been published (1). The serum concentration of EG (Table 1) measured by enzymatic assay was 308 mg/dL (49.6 mmol/L). On the basis of this information, the patient was continued on fomepizole, and plans were made for hemodialysis. Ten hours after admission, the gas chromatography result indicated an EG concentration of 315 mg/dL (50.9 mmol/L), in close agreement with the results of the enzymatic assay (the gas chromatography results were negative for methanol and isopropyl alcohol). After hemodialysis was performed, the patient's postdialysis serum showed an osmolal gap of 6 mOsm/kg and an EG concentration of 50 mg/dL (8.2 mmol/L). After a second hemodialysis course, the EG concentration according to the enzymatic assay was 1.4 mg/dL (0.2 mmol/L); the fomepizole treatment was then discontinued. The patient's renal function remained normal, and he recovered completely. He was discharged from the hospital to a psychiatric treatment facility.

DISCUSSION

EG is a sweet-tasting, colorless liquid found in antifreeze and airplane-deicing solutions. EG ingestions led to 6241 calls to US Poison Control Centers in 2011, including 7 deaths (2). The toxicity of EG is due to the production of the organic-acid metabolites glycolic acid, glyoxylic acid, and oxalic acid. The first, and rate-limiting, step in this metabolic pathway is catalyzed by alcohol dehydrogenase, the same enzyme responsible for ethanol metabolism (3). As these acids accumulate, an anion gap metabolic acidosis ensues, with subsequent organ and metabolic dysfunction. In addition to severe acidemia, oxalic acid combines with calcium to form calcium oxalate crystals, which deposit in the renal tubules to lead to renal injury and hypocalcemia.

The diagnosis of EG toxicity is made via a combination of the patient's history, the clinical picture, and a laboratory analysis showing an anion gap metabolic acidosis with an increased osmolal gap. The analysis of the laboratory findings requires consideration of the time of ingestion and the interval between ingestion and presentation to the ED (4). There is a delay between the time of ingestion and the development of the anion gap metabolic acidosis, because the anion gap reflects the presence of the organic-acid metabolites. In addition, the osmolal gap, a reflection of the presence of the parent compound, can be diminished if the patient presents late and has already metabolized most of the parent compound into its organic-acid metabolites. Therefore, the diagnosis can be confusing when a patient presents very early or very late, owing to the time-dependent nature of the anion and osmolal gaps. Confirmatory serum concentrations can be obtained via gas chromatography; however, the lack of this capability in most hospital clinical laboratories often leads to diagnostic delays.

In addition to confirming the diagnosis, serum EG concentrations are useful to guide treatment. The mainstay of treatment for EG toxicity is to inhibit alcohol dehydrogenase with fomepizole (5, 6, 7). Hemodialysis is often used to enhance the elimination of the parent compound and its toxic metabolites and to correct the acidemia. Traditionally, these treatments are continued until the EG concentration decreases to <20 mg/dL (<3.2 mmol/L) (7). Because of the difficulty in obtaining EG concentrations, an osmolal gap of <10 mOsm/kg is often used as a surrogate marker for when it is safe to stop treatment. Such values can be misleading, however, because a "normal" osmolal gap of 10 mOsm/kg can represent a potentially toxic EG concentration of up to 75 mg/dL (12.1 mmol/L) (8, 9). In the present case, the patient's osmolal gap was 5 mOsm/kg after the first hemodialysis session, but the enzymatic EG concentration was 50 mg/dL (8.2 mmol/L), still far greater than the concentration considered safe to stop treatment. If treatment had then been discontinued, the patient could have developed acidemia and acute kidney injury. Furthermore, when our laboratory had previously performed a validation study for an internal reference interval for normal values for the osmolal gap, the highest osmolal gap we obtained among 40 healthy outpatients was only 2 mOsm/kg. This finding suggests the published clinical threshold of 10 mOsm/kg is an overestimate.

Confirmatory testing of serum EG concentrations is traditionally performed via gas chromatography with flame ionization detection or mass spectrometry at specialized laboratories (1). Depending on distances and courier availability, results can take hours to return, potentially delaying diagnosis and management. An alternative method that uses a modified veterinary enzymatic assay has been developed and validated (1). This veterinary enzymatic assay had been rejected for use with human samples because of concern over interference by propylene glycol and various butanediols, some of which may be increased in chronic alcohol users (10). The development in 2011 of a modified assay that uses kinetic rate analysis has improved the assay's analytic specificity and has eliminated most false-positive results. This modification also decreased the labor time by 85% and the turnaround time by 10 h (1). The availability of the enzymatic assay in the present case allowed the treating team to rapidly verify the diagnosis and to direct treatment in a safe and efficient manner.

The patient in this case ingested a toxic and dangerous amount of EG. Because he presented early, the initial test results showed a large osmolal gap, but the patient had not yet developed an anion gap acidosis. If the history had been obfuscated, the correct diagnosis would likely have been missed, especially given that serum osmolality tests are often ordered only when there is a high suspicion of toxic-alcohol ingestion or an unexplained anion gap acidosis. The appropriate treatment would have been delayed, and the patient would have developed clinically important renal injury. In properly caring for this patient, we found the availability of an assay that not only measured the EG concentration but also had a rapid turnaround time to be very helpful in confirming the diagnosis and determining the duration of therapy.

QUESTIONS TO CONSIDER

1. What are the major ingredients found in antifreeze that can contribute to toxicity after ingestion?

2. In a patient with an increased osmolal gap and normal anion gap, can EG poisoning be ruled out?

3. What are some factors that may cause a normal anion gap in EG poisoning?

4. Can a normal osmolal gap be used to determine when fomepizole therapy should be discontinued?

POINTS TO REMEMBER

* Depending solely on the anion and osmolal gaps to diagnose and guide treatment of patients poisoned by EG can be misleading.

* Patients who have ingested toxic amounts of EG but who present early after ingestion and receive prompt treatment with fomepizole may never manifest an increased anion gap or clinically relevant acidemia.

* Modification of an enzymatic assay for detecting serum EG concentrations can improve diagnosis and treatment of patients with EG poisoning.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, oranalysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

References

(1.) Juenke JM, Hardy L, McMillin GA, Horowitz GL. Rapid and specific quantification of ethylene glycol levels: adaptation of a commercial enzymatic assay to automated chemistry analyzers. Am J Clin Pathol 2011;136:318-24.

(2.) Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual report of the American Association of Poison Control Centers' National Poison Data System: 29th Annual Report. Clin Toxicol (Phila) 2012;50:911-1164. See Table 22A.

(3.) Faroon O, Tylenda C, Harper CC, Yu D, Cadore A. Ethylene Glycol. Atlanta, GA: Agency for Toxic Substances and Disease Registry, Division of Toxicology and Environmental Medicine, Centers for Disease Control and Prevention; 2010. p 123-6.

(4.) Hovda KE, Hunderi OH, Rudberg N, Froyshov S, Jacobsen D. Anion and osmolal gaps in the diagnosis of methanol poisoning: clinical study in 28 patients. Intensive Care Med 2004;30:1842-6.

(5.) Patil N, Lai Becker MW, Ganetsky M. Toxic alcohols: not always a clear cut diagnosis. Emerg Med Pract 2010;11:1-8.

(6.) Verelst S, Vermeersch P, Desmet K. Ethylene glycol poisoning presenting with falsely elevated lactate level. Clin Toxicol (Phila) 2009;47:236-8.

(7.) Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol 2008;1:208-25.

(8.) Glaser DS. Utility of the serum osmol gap in the diagnosis of methanol or ethylene glycol ingestion. Ann Emerg Med 1996;27:343-6.

(9.) Smithline N, Garner KD. Gaps--anionic and osmolal. JAMA 1976;236:1594-7.

(10.) Rutstein DD, Veech RL, Nickerson RJ, Felver ME, Vernon AA, Needham LL, Kishore P, Thacker SB. 2,3-butanediol: an unusual metabolite in the serum of severely alcoholic men during acute intoxication. Lancet 1983;2:534-7.

Commentary

This case of a patient with ethylene glycol poisoning illustrates the difficulty of diagnosing the ingestion of this toxic alcohol. Traditionally, such poisoning is recognized by ethylene glycol's tendency to cause an increase in the serum osmolal gap with and without an increase in the serum anion gap. The increase in the osmolal gap is due to accumulation of the parent alcohol, whereas the increase in the serum anion gap is due to accumulation of the organic-acid metabolites. Therefore, early on in the course of poisoning (before extensive metabolism of the alcohol), only an increase in the osmolal gap might be observed. Subsequently, increased osmolal and anion gaps can be observed as the alcohol is metabolized. Finally, when the bulk of the alcohol has been metabolized, only an increased anion gap might be seen.

Additional factors that can affect the pattern of the osmolal and anion gaps include their baseline values. The authors correctly identify that the baseline osmolal gap in an individual can be low. Individuals with a very low gap might have a large concentration of the alcohol without the osmolal gap increasing above the upper reference limit. One issue not addressed by the authors was the possibility that the 18-mmol/L anion gap at presentation might be increased although remaining within the normal range. The reference range of the anion gap is wide, spanning 10 mmol/L from low to high (1). Therefore, an individual with a value at the low range of normal could have a large accumulation of organic acids without a detectable increase in the anion gap.

Be that as it may, the authors correctly identify the difficulty of diagnosing a toxic-alcohol exposure, the need for early use of an analytically sensitive test to detect its presence, and the importance of having a high level of suspicion for toxic-alcohol exposure for all patients.

Jeffrey A. Kraut *

Medical and Research Services VHAGLA Healthcare System, UCLA Membrane Biology Laboratory, and Division of Nephrology, VHAGLA Healthcare System and David Geffen School of Medicine, Los Angeles, CA.

* Address correspondence to the author at: Division of Nephrology, VHAGLA Healthcare System, 11301 Wilshire Blvd., Los Angeles, CA 90073. E-mail jkraut@ucla.edu.

Received August 12, 2013; accepted August 22, 2013.

DOI: 10.1373/clinchem.2013.214247

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, oranalysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Reference

(1.) Kraut JA, Nagami GT. The serum anion gap in the evaluation of acid-base disorders: what are its limitations and can its effectiveness be improved? Clin JAm Soc Nephrol 2013;8:2018-24.

Commentary

One of the best-known mnemonics in medicine is MUDPILES (for methanol, uremia, diabetic ketoacidosis, propylene glycol, isoniazid, lactic acidosis, ethylene glycol, salicylates), which helps us remember causes of increased anion gap metabolic acidosis. Less well known is ME DIE (for methanol, ethanol, diuretics such as mannitol, isopropyl alcohol, ethylene glycol), which helps us remember causes of increased osmolal gaps.

Ethylene glycol appears in both mnemonics; the only other compound with that distinction is methanol. Both are central nervous system depressants in their unmetabolized forms, but their major toxicities occur when they are converted into their strong-acid metabolites. By blocking their metabolism, one prevents their most dire consequences.

Because most clinical laboratories must refer samples elsewhere for measurement of ethylene glycol, and probably methanol, and because delays can only exacerbate their toxicities, treatment, appropriately, is often presumptive. If the concentrations of these alcohols are low, treatment can be discontinued.

While awaiting definitive measurements of these alcohols, clinicians may turn to surrogate tests, such as the anion gap or the osmolal gap. Strong acids produced by metabolism of ethylene glycol and methanol are present in appreciable millimolar concentrations and are detectable as an increased anion gap. Unfortunately, that is not the case for both parent compounds, whose presence is reflected in the osmolal gap, rather than anion gap. Because of their respective molecular weights (32 and 62 mg/mmol) and lethal concentrations (80 and 20 mg/dL), methanol at its lethal concentration will create a sizable osmolal gap (25 mOsm/kg), whereas ethylene glycol will not (3 mOsm/kg).

As reflected in this case, treatment for possible ethylene glycol ingestion should be presumptive to prevent acidosis. A normal osmolal gap should not be used to rule out toxic concentrations, initially or during treatment; genuine ethylene glycol concentrations are needed. Clinical chemists occupy a strategic position to ensure treatment is not delayed while awaiting results and to caution against the use of insensitive surrogate tests.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Diana Felton, [1] *, Michael Ganetsky, [1] and Anders H. Berg [2]

[1] Harvard Medical Toxicology Program, Department of Emergency Medicine, and

[2] Division of Clinical Chemistry, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA.

* Address correspondence to this author at: Harvard Medical Toxicology Program, 300 Longwood Ave., Ida C. Smith Bldg., Rm. 113, Boston, MA 02115. Fax 617-730-0521; e-mail diana.felton@childrens.harvard.edu.

Received April 4, 2013; accepted July 18, 2013.

DOI: 10.1373/clinchem.2013.207597

[3] Nonstandard abbreviations: ED, emergency department; EG, ethylene glycol.
Table 1. The patient's laboratory results on presentation, after
transfer to the tertiary care center, and on hospital day 2 after
hemodialysis. (a)

                             Initial      Tertiary ED      Actual,
                           presentation   (3 h later)   day 2 (after
                                                        hemodialysis)

Sodium, mmol/L                 140            138            141
Potassium, mmol/L                4.0            4.2            3.6
Cloride, mmol/L                104            106            103
Bicarbonate, mmol/L             18             18             32
BUN, (b) mg/dL                  11             10              3
Creatinine, mg/dL                1.13           1.1            0.6
Glucose, mg/dL                 106            107            138
Anion gap, mmol/L               18             14              6
pH                               7.34           7.39           7.46
Lactate, mmol/L            Unavailable          5.3            1.7
Serum osmoles, mOsm            367            358            296
Osmolal gap, mOsm/kg            75             72              6
EG (gas chromatography),
  mg/dL                    Unavailable        315        Unavailable
EG (enzymatic assay),
  mg/dL                    Unavailable        308            50

                           Expected, day 2     Reference
                           (if untreated)      interval

Sodium, mmol/L             Normal               137-145
Potassium, mmol/L          Normal               3.6-5.0
Cloride, mmol/L            Normal                98-107
Bicarbonate, mmol/L        Low                   22-30
BUN, (b) mg/dL             High                   9-20
Creatinine, mg/dL          High                 0.5-1.2
Glucose, mg/dL             Normal                75-110
Anion gap, mmol/L          High                   8-20
pH                         Low                 7.35-7.45
Lactate, mmol/L            High                 0.5-2.0
Serum osmoles, mOsm        Normal to high       275-295
Osmolal gap, mOsm/kg       Normal to high         0-10
EG (gas chromatography),
  mg/dL                    High              Nondetectable
EG (enzymatic assay),
  mg/dL                    High              Nondetectable

(a) For conversion to the SI unit of measure: blood urea nitrogen, 1
mg/dL = 0.36 mmol/L; creatinine, 1 mg/dL = 88.4 [micro]mol/L; lactate,
1 mg/dL = 0.11 mmol/L; EG, 1 mg/dL = 0.16 mmol/L.

(b) BUN, blood urea nitrogen.
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Title Annotation:Clinical Case Study
Author:Felton, Diana; Ganetsky, Michael; Berg, Anders H.
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Mar 1, 2014
Words:3157
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