Spurious Elevation in Serum Creatinine Caused by Ingestion of Nitromethane: Implication for the Diagnosis and Treatment of Methanol Intoxication

Clinical History 

A 22-year-old woman was seen in the emergency department 30 hours after reporting she ingested 16 ounces of model airplane fuel. The patient ingested this substance after an argument with her father and subsequently fell asleep. Two years previously, she had also ingested model airplane fuel. She was admitted to the hospital at that time and treated with hemodialysis. She recovered from the incident without sequelae and had been in good health subsequently.

The patient denied abdominal pain, nausea, vomiting, visual disturbances, or headache. She denied using any other medication, chemicals, or alcohol in the period before being seen. She had no history of renal, cardiac, neurological, or hepatic disease. Renal function and blood chemistry test results were normal 6 months earlier.

Physical examination in the emergency department showed temperature of 37.2°C, regular pulse of 100 beats/min, blood pressure of 132/50 mm Hg in the sitting position, and respiratory rate of 16 breaths/min. Lungs were clear to auscultation and percussion. Cardiac examination showed no murmurs or gallops, and abdominal examination showed no tenderness. There was no peripheral edema. She was alert and responsive without focal neurological signs.

Additional Investigations 

Results of blood work performed during her hospitalization are listed in Table 1. On urinalysis, there was trace protein and 1+ ketones. Urinalysis showed no cells or crystals. Urine myoglobin level was less than 1 mg/L. Serum acetaminophen, ethyl alcohol, acetone, and isopropyl alcohol were undetectable. A renal ultrasound showed normal-sized kidney without abnormalities.

Table 1. Laboratory Studies During Hospitalization

	Test	Admission	17 Hours After Admission	Day 2	Day 3
	Sodium (mEq/L)	141	140	143	142
	Potassium (mEq/L)	3.5	3.2	3.8	3.6
	Chloride (mEq/L)	111	104	109	112
	Total carbon dioxide (mEq/L)	18	28	25	25
	Blood urea nitrogen (mg/dL)	14	5	7	4
	Serum creatinine (mg/dL)⁎	23.7	10	8.4	6
	Creatinine kinase (U/L)†	150
	Anion gap (mEq/L)	11	8	9	5
	Serum osmolality (mOsm/kg H2O)	357	303	303	303
	Osmolal gap (mOsm/kg H2O)	70
	Methanol (mg/dL)	71	26

Note: Dialysis was performed on admission and on days 2 and 3. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; urea nitrogen in mg/dL to mmol/L, multiply by 0.357. Sodium, potassium, chloride, and total carbon dioxide levels in mEq/L are equivalent to levels expressed in mmol/L. Anion gap, serum osmolality, and osmolal gap amounts in mOsm/kg are equivalent to levels expressed in mmol/kg.

⁎ Values obtained using the Jaffé reaction. † Normal range is 12 to 180 U/L.

Diagnosis 

On the basis of a history of ingestion of the airplane fuel; serum osmolal gap of approximately 70 mOsm/kg H2O (70 mmol/kg H2O); undetectable blood acetaminophen, ethyl alcohol, and isopropyl alcohol; and normal blood glucose concentration, a presumptive diagnosis of methanol intoxication was made.

Clinical Follow-up 

The patient was treated initially with fomepizole therapy and 4 hours of hemodialysis. She subsequently was dialyzed on 2 other occasions. Fomepizole therapy was continued throughout this period with the following regimen: 1,200 mg every 12 hours for 3 doses and 700 mg every 12 hours for 3 doses. On the second day after admission, repeated laboratory studies (Table 1) showed a serum creatinine level that decreased to 8.4 mg/dL (743 μmol/L) with the Jaffé reaction and serum osmolality of 303 mOsm/kg H2O (303 mmol/kg H2O). Serum methanol concentration obtained on admission was 71 mg/dL (22.15 mmol/L; value reported 48 hours after admission). Serum methanol concentration from the second day of admission, after hemodialysis and fomepizole treatment, was 26 mg/dL (8.11 mmol/L). Because of recognition that 1 of the components of model airplane fuel interferes with measurement of serum creatinine when performed using the Jaffé reaction, blood obtained on admission was retested using an enzymatic assay and showed a serum creatinine concentration of 0.5 mg/dL (44 μmol/L).

The patient remained alert without evidence of neurological, visual, or abdominal abnormalities throughout her hospital course. Serum electrolyte levels and renal function were normal at the time of discharge.

Epidemiological Characteristics of Methanol Intoxication 

Methanol, or wood alcohol, is used to make such products as plastic, plywood, and paint. It is present in windshield wiper fluid, antifreeze, and model airplane fuel. It is colorless and described as either odorless or having a faint pungent odor. These physical properties make its detection difficult.

Review of records from poison control centers in the United States showed that approximately 1,000 to 2,000 cases of methanol intoxication are reported each year.2 Similar outbreaks of methanol intoxication also were reported throughout the world.3 The majority of cases of methanol intoxication are caused by ingestion of ethanol adulterated with methanol, accidental ingestion by children, or its use in suicide attempts.

Mortality rates of patients with methanol intoxication are variable: in the 1953 epidemic, it was approximately 8%,9 and in 1 recent outbreak in Sweden, it was approximately 28%.3 Mortality and complications are related to severity of metabolic acidosis upon presentation. In 2 studies composed of more than 370 patients, serum bicarbonate concentration less than 10 mEq/L (<10 mmol/L) or blood pH less than 7.0 was associated with a mortality rate of 50% to 89%.9, 10 Furthermore, development of irreversible blindness and neurological complications also was more frequent in patients with severe metabolic acidosis.5, 10 Thus, early recognition of the disorder is important.

Review of the MEDLINE database showed only 4 case reports of coingestion of methanol and nitromethane contained in model airplane fuel, similar to this patient.8, 11, 12, 13 In 2 other cases, nitromethane was absorbed from race car fuel after a car accident, although methanol was not detected in the blood.13, 14 Salient characteristics of these patients are listed in Table 2. As a consequence, clinicians might not be aware of the possible impact of nitromethane on serum creatinine concentration, which could have important ramifications for the diagnosis and treatment of methanol intoxication.

Table 2. Cases of Combined Nitromethane and Methanol Exposure

	Patient	Method of Intoxication⁎	Serum Creatinine (mg/dL)		Treatment	Reference
			Jaffé	Enzymatic
	22-year-old woman	Ingestion of model airplane fuel	23.7	0.5	Fomepizole, hemodialysis	Present report
	2-year 9- month-old boy	Ingestion of model airplane fuel	6.0†	—	Supportive care	Booth et al11
			1.4‡	0.56‡
	25-year-old man	Absorption through skin of fuel (95% nitromethane, 5% methanol) after car crash	8.6	Normal§	Supportive care	Gabrielli and Hammett-Stabler14
	39-year-old man	Ingestion of model airplane fuel (70% methanol, 30% nitromethane)	9.0	1.0	Ethanol, hemodialysis	De Leacy et al8
	23-year-old woman	Ingestion of model airplane fuel	17.9	—	Ethanol, hemodialysis	Mullins and Hammett-Stabler13
	25-year-old man	Absorption through skin of fuel	17.5	1.0	Supportive care	Mullins and Hammett-Stabler13
	4-year-old girl	Ingestion of model airplane fuel	4.0	Normal§	Fomepizole	Leonard and Akhtar12

Note: To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4.

⁎ Proportion of methanol and nitromethane present shown if available. † Initial measurement. ‡ Second measurement during treatment. § Actual values for creatinine with enzymatic assay not given.

Metabolism of Methanol 

As shown in Fig 1, methanol is metabolized in the liver by the enzyme alcohol dehydrogenase to formaldehyde. Formaldehyde is then converted to formic acid, a process catalyzed by the enzyme formaldehyde dehydrogenase, and finally to carbon dioxide and water.

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Figure 1. Metabolic pathway for methanol. Methanol is metabolized to formaldehyde under the influence of the enzyme alcohol dehydrogenase (ADH). Formaldehyde is then converted to formic acid under the influence of formaldehyde dehydrogenase (FMD) and finally to carbon dioxide (CO2) and water (H2O). Abbreviations: NAD, nicotinamide-adenine dinucleotide; NADH, the reduced form of NAD.

The metabolism of methanol can be delayed substantially by the presence of ethanol or other substance with a greater affinity for the enzyme alcohol dehydrogenase. In our patient, the strikingly increased serum osmolality (explained only in part by increased serum methanol levels) predicted an increase in serum osmolality of 24 mOsm/kg (24 mmol/kg) and mild metabolic acidosis found 30 hours after the ingestion is consistent with delayed metabolism of methanol. The delay in metabolism presumably is caused by substances in the airplane fuel that effectively compete with methanol for binding to alcohol dehydrogenase. Of the compounds present in the airplane fuel, polyalkaline glycol seems the most likely candidate.

Clinical and Laboratory Findings With Methanol Intoxication 

Visual disturbances, abdominal pain, and headache are common with methanol intoxication.3, 9 In one study of 51 patients, 49% of patients manifested abdominal pain and 37% had visual disturbances.3 Visual disturbances were attributed to the effect of formic acid.5

The development of clinical and laboratory abnormalities with methanol intoxication can take many hours, particularly if ethanol or other substances are ingested that compete with methanol for the enzyme.15 In a large series of more than 300 patients ingesting bootlegged whiskey, the period before overt symptoms developed averaged 24 hours, with some patients manifesting symptoms later than 72 hours.9 Similarly, the metabolic acidosis associated with methanol intoxication, which is primarily caused by formic acid generation, may not develop for many hours.1, 3, 5 In our patient, the absence of clinical findings, mildness of the metabolic acidosis (serum bicarbonate, 18 mEq/L [18 mmol/L]), the minimal increase in serum anion gap (change in anion gap of 6 mEq/L [6 mmol/L] compared with value obtained at discharge), and the minimal increase in serum lactate concentration (lactate generation was attributed to inhibition of cellular respiration by formate) are additional evidence that the bulk of the methanol remained unmetabolized at presentation.

Diagnosis of Methanol Intoxication 

The diagnosis of methanol intoxication is classically considered in a patient with high-anion-gap metabolic acidosis and increased serum osmolal gap.16 The increment in serum osmolality is related to both the concentration and molecular weight of methanol. Because the molecular weight of methanol is 32.04, serum osmolality will be increased by 3.3 mOsm/kg H2O for every 10-mg/dL increase in serum methanol concentration. Serum methanol concentration in this patient was 71 mg/dL, which should have caused a serum osmolal gap of only 20 mOsm/kg H2O (20 mmol/kg H2O). However, the serum osmolal gap was 70 mOsm/kg H2O (70 mmol/kg H2O). This disparity between the predicted serum osmolal gap (based on the serum concentration of methanol) and the measured osmolal gap indicates the presence of other low-molecular-weight substances in the blood. Substances contained in the model airplane fuel that could increase serum osmolality include polyalkaline glycol (molecular weight, 102.3) and nitromethane (molecular weight, 61.01).

If a history of methanol ingestion is not available, osmolal gap and high-anion-gap metabolic acidosis are important clues to the diagnosis of methanol intoxication. In our patient, the increase in serum osmolality was striking, whereas the decrease in serum bicarbonate level and increase in anion gap was modest. As noted, this constellation of laboratory findings is not unusual with methanol or other alcohol-related intoxications. Several reports of methanol intoxication showed that within the first few hours after ingestion of methanol, there was marked discordance between the increment in serum osmolality, decrease in serum bicarbonate concentration, and change in anion gap.3, 17 Subsequently, as methanol is metabolized to formic acid, serum osmolality will decrease while serum anion gap increases. Several hours after the ingestion, when most of the methanol is converted into formic acid, serum osmolality will decrease substantially, resulting in a high-anion-gap metabolic acidosis with correction of serum osmolality. Thus, hyperosmolality alone, hyperosmolality with high-anion-gap metabolic acidosis, or high-anion-gap metabolic acidosis with little change in osmolality are all consistent with the diagnosis of methanol intoxication.

Several other alcohol intoxications can produce clinical and laboratory abnormalities that mimic methanol intoxication, including ethylene glycol intoxication, diethylene glycol intoxication, propylene glycol intoxication, isopropanol intoxication, and alcoholic ketoacidosis.18 Although certain aspects of treatment of these disorders may be similar to those of methanol intoxication, differentiation between methanol intoxication and these disorders is important to be able to quickly provide appropriate therapy. Important diagnostic clues and major methods of treatment for each of these disorders are listed in Table 3.

Table 3. Differential Diagnosis of Toxic Alcohol Intoxications

	Disorder	Diagnostic Clues⁎	Treatment†
	Methanol intoxication	Hyperosmolality with osmolal gap	Fomepizole or alcohol
		High-anion-gap metabolic acidosis	Dialysis
		Optic papillitis	Folic acid
			Base
	Ethylene glycol intoxication	Hyperosmolality with osmolal gap	Fomepizole or alcohol
		High-anion-gap metabolic acidosis	Dialysis
		Calcium oxalate crystals in urine	Thiamine
		Acute renal failure	Pyridoxine
			Base
	Diethylene glycol intoxication	Hyperosmolality with osmolal gap	Fomepizole or alcohol
		High-anion-gap metabolic acidosis	Dialysis
		Acute renal failure	Base
		History of cohort with similar abnormalities
	Propylene glycol intoxication	Hyperosmolality with osmolal gap	Discontinuation of medication with propylene glycol usually sufficient
		Lactic acidosis
		History of administration of medication containing propylene glycol	Dialysis in selected cases with severe lactic acidosis or extremely high serum propylene glycol levels
	Isopropanol intoxication	Hyperosmolality and osmolal gap	Supportive care; consider dialysis with serum concentration > 400 mg/dL
		Metabolic acidosis uncommon without hypotension
	Alcoholic ketoacidosis	High-anion-gap metabolic acidosis	Supportive care
		Positive ketones in blood or urine that become more prominent with H2O2	Administration of saline and glucose
			Insulin with significant hyperglycemia
		Osmolality can be increased, but often normal	Base treatment with severe metabolic acidosis
		History of binge drinking

⁎ Appearance of increased serum osmolality and high-anion-gap metabolic acidosis will depend on duration elapsing after ingestion and presence of other substances that affect alcohol dehydrogenase. † Treatment measures depend on severity of disorder, time after ingestion, and comorbid conditions. See reference18 for fuller details.

Serum creatinine level increased strikingly in this patient. Renal failure in the absence of hypotension is not common in patients with methanol intoxication, in contrast to ethylene glycol intoxication, in which crystalluria and calcium oxalate deposition can induce renal failure.18, 19 There was no evidence of rhabdomyolysis, reflected by increased creatine kinase values to explain the increased serum creatinine concentration. Therefore, had a history of ingestion of airplane fuel not been obtained, a diagnosis of acute renal failure could have been made. However, spurious increases in serum creatinine levels have been reported with ingestion of glow fuel or other model airplane fuel. Glow fuel contains nitromethane (CH3NO2), a highly lipid-soluble moiety that interferes with the measurement of serum creatinine when determined using the Jaffé reaction.8, 13

Measurement of creatinine in blood using the Jaffé reaction is accomplished when it reacts with picrate ion formed in an alkaline medium to develop a red-orange color. The color produced from the sample is then examined in a colorimeter at a wavelength of 505 nm. The reading found is compared with standards determined by using a known amount of creatinine under the same conditions. The Jaffé reaction is known to be nonspecific. Many compounds, including protein, glucose, ascorbic acid, acetone, and keto acids, can react with picrate and cause overestimation of creatinine level in plasma. Similarly, nitromethane reacts with picrate, causing overestimation of serum creatinine concentration.8 In the presence of nitromethane, despite normal serum creatinine concentrations, values as high as 18 to 20 times the upper limit of normal were reported.8 In this regard, De Leacy et al8 found a direct linear relationship between levels of nitromethane and creatinine in blood when determined using the Jaffé method. However, nitromethane does not interfere with the measurement of serum creatinine when it is done using an enzymatic assay.8 In the present case, determination of serum creatinine simultaneously using the Jaffé reaction and enzymatic assay showed a marked discrepancy. Serum creatinine level was only 0.5 mg/dL (44 μmol/L) with the enzymatic assay at a time when it measured 23.7 mg/dL (2,095 μmol/L) with the Jaffé reaction.

Treatment of Methanol Intoxication 

The consensus statement of the American Academy of Clinical Toxicology published in 20025 recommends that ethanol or fomepizole, inhibitors of alcohol dehydrogenase, be administered for the treatment of patients with methanol intoxication when plasma methanol concentration is greater than 20 mg/dL, there is a recent history of ingestion of methanol in association with a serum osmolal gap greater than 10 mOsm/kg H2O (>10 mmol/kg H2O), or there is strong clinical suspicion of methanol poisoning with at least 2 of the following findings: arterial pH less than 7.3, serum bicarbonate level less than 20 mEq/L (<20 mmol/L), and osmolal gap greater than 20 mOsm/kg H2O (>20 mmol/kg H2O).5, 18, 20 Thus, this patient met criteria for treatment with fomepizole.

Hemodialysis, in addition to fomepizole, is recommended by some for presumed methanol intoxication when serum concentration is greater than 50 mg/dL (15.60 mmo/L) or in the presence of metabolic acidosis (blood pH 7.25 to 7.30), visual abnormalities, renal failure, or electrolyte imbalance unresponsive to conventional therapy.5 However, others showed that patients with methanol concentrations greater than 50 mg/dL (15.60 mmo/L) who are not acidemic or in renal failure can be treated with fomepizole therapy alone without hemodialysis.21 Because this patient was not acidemic and measurement of serum creatinine using an enzymatic method showed she did not have acute renal failure, she might have been treated with fomepizole alone rather than being dialyzed. Although the decision to dialyze this patient was based on the presumed severity of the methanol intoxication irrespective of serum creatinine concentration, appreciation of the potential impact of nitromethane on serum creatinine concentration could be a factor in the choice of treatment modalities.

In summary, methanol intoxication should be considered in individuals with high-anion-gap metabolic acidosis, hyperosmolal states, or changes in mentation without an obvious cause. To this group of findings as possible clues to the presence of methanol intoxication should be added an increased serum creatinine concentration in the absence of other stigmata of renal failure.22