Detection of ingested nitromethane and reliable creatinine assessment using multiple common analytical methods.

AIM: Nitromethane, found in fuels used for short distance racing, model cars, and model airplanes, produces a falsely elevated serum creatinine with standard creatinine analysis via the Jaffé method. Erroneous creatinine elevation often triggers extensive testing, leads to inaccurate diagnoses, and delayed or inappropriate medical interventions. Multiple reports in the literature identify "enzymatic assays" as an alternative method to detect the true value of creatinine, but this ambiguity does not help providers translate what type of enzymatic assay testing can be done in real time to determine if there is indeed false elevation. METHODS: We report seven cases of ingested nitromethane where creatinine was determined via Beckman Coulter® analyser using the Jaffé method, Vitros® analyser, or i-Stat® point-of-care testing. Nitromethane was detected and semi-quantified using a common clinical toxic alcohol analysis method, and quantified by headspace-gas chromatography-mass spectrometry. RESULTS: When creatinine was determined using i-Stat® point-of-care testing or a Vitros® analyser, levels were within the normal range. Comparatively, all initial creatinine levels obtained via the Jaffé method were elevated. Nitromethane concentrations ranged from 42 to 310 µg/mL. CONCLUSIONS: These cases demonstrate reliable assessment of creatinine through other enzymatic methods using a Vitros® analyser or i-STAT®. Additionally, nitromethane is detectable and quantifiable using routine alcohols gas chromatography analysis and by headspace-gas chromatography-mass spectrometry.

Point of care testing provides an accurate measurement of creatinine, anion gap, and osmolal gap in ex-vivo whole blood samples with nitromethane.

CONTEXT: Nitromethane interferes with Jaffé measurements of creatinine, potentially mimicking acute kidney injury. OBJECTIVES: We determined the proportional contribution of nitromethane in blood samples to creatinine measured by the Jaffé colorimetric and the point-of-care (POC) reactions and determined whether the difference can reliably estimate the concentration of nitromethane. Additionally, we determined whether the presence of nitromethane interferes with anion/osmolal gaps and ascertained the stability of nitromethane in serum after 7 days. METHODS: Nitromethane was added to whole blood from four healthy volunteers to achieve concentrations of 0, 0.25, 0.5, 1, and 2 mmol/L. The following tests were performed: creatinine (Jaffé and POC), electrolytes (associated with Jaffé and POC), osmolality and nitromethane concentration (gas chromatography [GC]). Remaining samples were refrigerated and reanalyzed using GC at 7 days. Anion and osmolal gaps were calculated. Proportional recovery and degradation of nitromethane were measured using GC. Data were analyzed for agreement with single-factor ANOVA (p = 0.05). RESULTS: Mean creatinine for POC and Jaff methods were 0.93 vs. 0.76 mg/dL, respectively. Jaff creatinine concentrations increased linearly with increasing nitromethane concentrations (R(2) = 1, p = 0.01): measured creatinine (mg/dL) = 7.1*nitromethane (mmol/L) = 0.79. POC creatinine remained unchanged across the range of nitromethane concentrations (p = 0.99). Anion and osmolal gaps also remained unchanged. Nitromethane was reliably identified in all sample concentrations using GC on Day 0. Detection of 0.25 mmol/L nitromethane was not consistently recovered on Day 7. Nitromethane degradation was most pronounced at 2 mmol/L concentrations (81% recovery). CONCLUSIONS: Nitromethane alters apparent concentration of creatinine using the Jaffé reaction in a linear fashion but not when using the POC reaction. Measured difference between Jaffé and POC creatinine may identify the presence and estimate concentration of nitromethane. Presence of nitromethane did not alter the anion or osmolal gap; thus it would not potentially interfere with the diagnosis of co-exposure to a toxic alcohol.

Method for quantifying nitromethane in blood as a potential biomarker of halonitromethane exposure.

The cytotoxicity and genotoxicity of nitromethane and its halogenated analogues in mammals raise concerns about potential toxicity to humans. This study shows that halonitromethanes are not stable in human blood and undergo dehalogenation to form nitromethane. We quantified nitromethane in human blood using solid-phase microextraction (SPME) headspace sampling coupled with gas chromatography (GC) and high resolution mass spectrometry (HRMS). The limit of detection was 0.01 microg/L with a linear calibration curve spanning 3 orders of magnitude. This method employs isotope dilution to precisely quantify trace amounts of nitromethane (coefficient of variation <6%). At three spiked concentrations of nitromethane, method accuracy ranged from 88 to 99%. We applied this method to blood samples collected from 632 people with no known occupational exposure to nitromethane or halonitromethanes. Nitromethane was detected in all blood samples tested (range: 0.28-3.79 microg/L, median: 0.66 microg/L). Time-course experiments with trichloronitromethane- and tribromonitromethane-spiked blood showed that nitromethane was the major product formed (1 nmole tribromonitromethane formed 0.59 nmole of nitromethane, whereas 1 nmole trichloronitromethane formed 0.77 nmole nitromethane). Nitromethane may form endogenously from peroxynitrite: nitromethane concentrations increased proportionately in blood samples spiked with peroxynitrite. Blood nitromethane can be a biomarker of exposure to both nitromethane and halonitromethanes. This sensitive, accurate, and precise analytical method can be used to determine baseline blood nitromethane level in the general population. It can also be used to study the health impact from exposure to nitromethane and halonitromethanes in occupational environments and to assess trichloronitromethane (chloropicrin) exposure in chemical terrorism investigations.

Co-ingestion of methanol and nitromethane: using falsely elevated creatinine as indicator for methanol antidote use.

OBJECTIVE: To report a case of co-ingestion of methanol and nitromethane in a child in order to heighten the awareness of false elevation of serum creatinine from nitromethane ingestion. DESIGN: Case report. SETTING: Pediatric intensive care unit. PATIENT: A 4-yr-old previously healthy girl ingested an unknown quantity of "Blue Thunder" model-engine fuel, which consisted of methanol and nitromethane. The patient was treated with fomepizole for methanol ingestion using elevated creatinine level as a reason for treatment. RESULTS: The patient was asymptomatic but her creatinine level increased ten-fold (from 0.4 mg/dL to 4 mg/dL) within 6 hrs. Blood urea nitrogen, anion gap, and osmolar gap remained within normal limits. When the serum creatinine level was measured with enzymatic method instead of Jaffe's method, a normal creatinine level was obtained. The falsely elevated creatinine level was due to nitromethane. CONCLUSION: The falsely elevated serum creatinine levels due to nitromethane ingestion can lead to unnecessary therapeutic interventions. We intend to heighten awareness of this potential misstep by reporting this case.

Intoxication with nitromethane-containing fuels: don't be "fueled" by the creatinine.

BACKGROUND: This report describes two patients exposed to nitromethane-containing fuels and the resulting laboratory abnormalities. Patient 1 ingested model airplane fuel on two separate occasions; the second patient had dermal exposure from clothing saturated with fuel in a drag racing accident. After the exposure, both patients had unusually elevated serum creatinine concentrations. METHODS: We determined the cause of the increase in serum creatinine to be due to nitromethane interfering with the Jaffé reaction used to measure this analyte. The interference was determined by both adding increasing quantities of nitromethane to sera and remeasuring the apparent creatinine and by retesting some of the original samples using an enzyme-based creatinine method. RESULTS: We found nitromethane, in the concentrations absorbed or ingested by the patients, increased the apparent creatinine 10- to 20-fold. CONCLUSIONS: Nitromethane interferes with the most widely used colorimetric method used to measure creatinine. Management of this mixed poisoning should focus on the appropriate treatment for methanol toxicity. Extreme, but false, elevations of creatinine do not require hemodialysis when no other significant laboratory abnormality exists.

Nitromethane interferes in assay of creatinine by the Jaffé reaction.

A patient who ingested a methanol/nitromethane mixture (model airplane fuel) showed an apparent plasma creatinine concentration of 8.0 mmol/L by the Jaffé reaction when the actual creatinine concentration, as measured by a specific enzymatic method, was 0.09 mmol/L. This effect was due to nitromethane in the plasma. Interference by nitromethane with the determination of creatinine by reaction with alkaline picrate (the Jaffé reaction) has not previously been reported. When nitromethane was added to plasma, the apparent creatinine measured was linearly related to the amount of nitromethane added. Comparison of spectral changes occurring during creatinine/picrate and nitromethane/picrate reactions show substantial similarity, suggesting a similar structure for the products. Although the findings are of interest for both their toxicological and analytical implications, the main interest lies with their suggestion of a model system for future investigation of the Jaffé reaction.

Fulminant hepatic failure after occupational exposure to 2-nitropropane.

Two construction workers became ill after applying an epoxy resin coating containing 2-nitropropane in the confined space of an underground concrete vault. One man died 10 days later from fulminant hepatic failure. The second man recovered but has had persistently elevated serum aminotransferase activity. The serum concentration of 2-nitropropane on admission of the man who died was 13 mg/L, and was 8.5 mg/L in his coworker. The acute toxicity of 2-nitropropane has not been widely appreciated despite previous reports of death due to hepatic failure after exposure to the compound in confined spaces. These cases show the importance of effective education and protective work practices.