Case Presentation
A 41-year-old man with a history of ethanol abuse was found on the streets with his
clothing saturated with fecal material. In the emergency department (ED), he was confused
and had an unsteady gait. He was sleepy and slow in responding, although easily arousable.
He admitted to being depressed and said that he tried to commit suicide by consuming
vodka and “Blue Thunder”, a fuel for radio-controlled racing cars that he had purchased
from a hobby shop the day before presentation. He denied any other drug ingestion
or previous medical history and was not taking any medications. He did not have any
focal neurological symptoms, visual disturbance, gastrointestinal symptoms such as
nausea or vomiting, or chest discomfort.
His vital signs were within normal limits: temperature 36.4°C, blood pressure 145/87 mm Hg,
heart rate 95/min, respiratory rate 16/min and pulse oximetry saturation 97% on room
air. His physical examination was unremarkable except for an unsteady gait. His cranial
nerves, motor, and sensory findings were grossly intact. As he had attempted to leave
the ED several times despite being ataxic, he was placed in restraints and sedated
with intravenous boluses of lorazepam and admitted for further workup.
Computed tomography of his brain did not show any gross abnormalities. Initial laboratory
data included: sodium 135 mmol/L, potassium 3.8 mmol/L, chloride 97 mmol/L, bicarbonate
21 mmol/L, blood urea nitrogen 7.9 mmol/L (22.0 mg/dL), creatinine 8,270 μmol/L (93.6 mg/dL),
and glucose 6.5 mmol/L (117 mg/dL). The anion gap was 17 mmol/L. Lactic acid and hepatic
enzymes were within normal limits. The serum ethanol, acetaminophen, and salicylate
levels were below detection limits. Urinalysis was normal with a pH of 5.5. Serum
samples were referred to an outside laboratory for methanol, ethylene glycol, acetone,
isopropyl alcohol, and paraldehyde levels. After 4 h of supportive treatment including
intravenous fluids, repeat laboratory results were: sodium 134 mmol/L, potassium 3.8 mmol/L,
chloride 98 mmol/L, bicarbonate 23 mmol/L, blood urea nitrogen 6.9 mmol/L (19.0 mg/dL),
and glucose 6.5 mmol/L (117 mg/dL).
The laboratory had independently decided that nitromethane was an interfering substance
and did not repeat the creatinine level. The anion gap was now 13 mmol/L and the calculated
osmolality [1] was 282 mmol/kg. Serum osmolality determined by freezing point depression
was 430 mmol/kg (reference range 275-295 mmol/kg). The osmolar gap was estimated to
be 148 mmol/kg.
Is this Patient’s Presentation Consistent with Methanol Poisoning?
After ingestion, the hepatic enzyme alcohol dehydrogenase converts methanol to formaldehyde,
which is then converted to formic acid by formaldehyde dehydrogenase [2]. Although
formaldehyde is more toxic than formic acid, it does not accumulate during poisoning
on account of its short half-life of about 1.5 min [3, 4]. Formic acid, an inhibitor
of cytochrome oxidases c and aa3, primarily contributes to the toxic sequelae of methanol
poisoning, including ocular toxicity and the fall in plasma bicarbonate concentration
and consequent increase in anion gap [5]. Ocular toxicity essentially identical to
that produced in methanol poisoning has been described after formate administration
in animals [4]. Also, results suggest that formaldehyde is not a major factor in the
toxic syndrome produced by methanol [6]. The clinical manifestations of methanol ingestion
include headache, dizziness, nausea, vomiting, weakness, and epigastric pain, as well
as developing an elevated anion gap acidosis. The severity of symptoms secondary to
methanol poisoning appears to correlate with the degree of metabolic acidosis [7,
8]. Mortality correlates with the severity of acidosis and the formate concentration
rather than with serum methanol concentration [9].
Although metabolic acidosis is a characteristic feature of methanol poisoning, its
onset may be delayed for 18-24 h, or even longer (up to 72 h [10]) with concurrent
ethanol ingestion [11–16], due to competition for the enzyme alcohol dehydrogenase.
Thus, the patient may be relatively asymptomatic during the latent period [17]. Our
patient had no measurable ethanol level, yet his acidosis was very mild with an anion
gap of only 17 mmol/L and a bicarbonate level of 21 mmol/L. A significant anion gap
may not be present early in the course of methanol intoxication. In a review of 113
acute methanol exposures reported to a poison center, metabolic acidosis was reported
in only 26 cases (23%) [18]. Therefore, the absence of acidosis does not rule out
methanol ingestion.
Possible reasons for our patient not developing worsening or severe acidosis may include
an inaccurate history of ingestion. He might have ingested only a small amount of
methanol, or ingested it shortly before being found. He may also have co-ingested
ethanol or other types of alcohols that are metabolized by alcohol dehydrogenase,
such that the metabolism of methanol to formate was blocked. Such other alcohols might
include ethylene glycol or isopropanol. However, ethanol was not detected and there
was no nail polish remover-like odor detected in the patient, which would be present
when isopropyl alcohol is metabolized to acetone. There was improvement in our patient’s
anion-gap acidosis simply with hydration, which also argues against ethylene glycol
and methanol ingestions.
Thus, even though our patient currently appears relatively well, it is possible that
he ingested methanol. It would be prudent to manage him as for methanol ingestion,
given the history of ingestion and the very large osmolal gap. Nevertheless, it is
unusual that our patient’s anion gap and acidosis improved in the short duration of
supportive management with intravenous fluids alone.
What is Nitromethane and What is its Toxicity?
Nitromethane is a popular solvent in organic and electroanalytical chemistry [19].
It is also used as a fuel in racing, particularly drag racing, to enhance combustion
[20]. The oxygen content of nitromethane enables it to burn with much less atmospheric
oxygen in comparison to hydrocarbons such as gasoline. In model aircraft and remote-controlled
car fuels such as “Blue Thunder”, the primary ingredient is generally methanol with
some nitromethane (up to 65%, but rarely over 30% since nitromethane is expensive
compared to methanol) and 10-20% lubricants (usually castor oil or a synthetic oil).
During combustion, this fuel produces a characteristic blue smoke [20]. Nitromethane
is highly lipid soluble, and acute exposures tend to be inadvertent dermal or ocular
exposures which generally result in local irritation but no apparent sequelae [21].
The American Conference of Governmental Industrial Hygienists lists the adverse health
effects of nitromethane as including dermal irritation, central nervous system depression,
liver and thyroid toxicity, blood dyscrasias, and neuropathy [22].
Following acute inhalational exposure, animal studies suggest a relatively low toxicity
of nitromethane [23, 24]. Rats and mice were exposed to nitromethane at a variety
of concentrations for 6 h per day, 5 days per week, from 16 days to 2 years. In the
16-day study of rats, all those exposed to 1,500 ppm showed loss of coordination in
the hindlimbs. Sciatic nerve degeneration was found in all rats exposed to 375 ppm
and above. In the 13-week study, hindlimb paralysis was seen in all rats in the 1,500-ppm
group. Rats exposed to 375 ppm of nitromethane or greater had minimal to mild degeneration
of the spinal cord and sciatic nerve. In contrast, mice demonstrated no neurologic
abnormalities in any of the studies [25]. Unfortunately, oral toxicity data in animals
is limited.
In a human case report, a 20-year-old woman who had worked for 2 years using a mixture
of trichlorotrifluoroethane (94%), methanol (6%), and nitromethane (0.25%) developed
Parkinsonism in the absence of other potential etiologies [26]. The authors concluded
that exposure to nitromethane could have been the cause of the Parkinsonism. A 19-year-old
man developed a primary, symmetric demyelinating polyneuropathy after a 2-month exposure
to an industrial solvent composed primarily of 1-bromopropane, but also containing
nitromethane and other components [27]. The authors attributed the neuropathy to the
1-bromopropane exposure.
The limited acute toxicity of nitromethane suggests that exposures require only supportive
care with no specific therapy [21]. Although different racing car fuels contain varying
concentrations of nitromethane and methanol, management of this mixed poisoning should
focus on the appropriate treatment for methanol toxicity.
Why is There a False Elevation of Creatinine with Nitromethane?
Nitromethane cause spurious elevations of the serum creatinine when the Jaffe colorimetric
method is used to determine serum creatinine concentration [28–33]. This method involves
injecting a sample of the patient’s serum into an alkaline picrate solution. Creatinine
in the sample combines with alkaline picrate to form a red-colored complex or chromophore,
the light absorbance of which can then be measured in the 470-550 nm range using a
double-beam spectrophotometer. The rate of absorbance is directly proportional to
the creatinine concentration in the serum [29]. Nitromethane also forms a red chromophore
with alkaline picrate with an absorbance similar to that of the creatinine-picrate
chromophore [30]. Thus, when nitromethane is present in a patient’s serum, the reaction
of both creatinine and nitromethane with alkaline picrate can result in a significantly
but spuriously elevated creatinine concentration [33].
Can the Degree of Cross-reactivity Predict the Nitromethane Level?
There is a linear relationship between the concentration of nitromethane and the rise
in serum creatinine concentration measured by the Jaffe method [21, 28]. This correlation
could provide a surrogate marker for significant methanol exposure in those who ingest
racing car fuel [32]. Analysis by least-squares linear regression of ten serum samples
containing nitromethane showed the following relationship [29]:
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\begin{document}$$ {\hbox{Apparent}}\,\left[ {{\hbox{creatinine}},\,{{\hbox{mmol}}
\mathord{\left/{\vphantom {{\hbox{mmol}} {\hbox{L}}}} \right.} {\hbox{L}}}} \right]
= 0.99\left[ {{\hbox{nitromethane}},\,{{\hbox{mmol}} \mathord{\left/{\vphantom {{\hbox{mmol}}
{\hbox{L}}}} \right.} {\hbox{L}}}} \right] + 0.21\left( {\pm 0.013} \right) $$\end{document}
Using this equation in our patient, with a creatinine of 8,270 μmol/L (93.6 mg/dl),
we estimated a nitromethane level of approximately 8 mmol/L:
Apparent (creatinine, mmol/L) = 0.99 (nitromethane, mmol/L) + 0.21 (±0.013)
8.27 mmol/L = 0.99 (nitromethane, mmol/L) + 0.21 (±0.013)
(Nitromethane) = (8.27-0.21(±0.013))/0.99 = 8.13-8.15 mmol/L
A nitromethane level of 8 mmol/L would be expected to contribute only about eight
to the osmol gap, leaving a residual, unexplained osmol gap of about 140. Assuming
the remaining osmol gap is due to methanol alone, the estimated serum methanol level
would be around 400 mg/dL, if multiplied by a conversion factor of 3.2 (one-tenth
the molecular weight of methanol) [34].
The fatal oral dose of methanol is estimated to be 30-240 mL (20-150 g). The minimum
toxic dose is approximately 100 mg/kg [35]. Serum methanol concentrations greater
than 20 mg/dL (>6.24 mmol/L) are considered potentially toxic [36], and concentrations
of greater than 40 mg/dL (>12.4 mmol/L) can be fatal, but individual sensitivity varies
[37]. Based on these estimated levels, and without the benefit of a rapid analysis
for methanol, it was decided that our patient had ingested a significant amount of
methanol and he was initially treated with a loading dose of 15 mg/kg intravenous
fomepizole and 2 hours of hemodialysis.
Are There Other Causes of a Falsely Elevated Serum Creatinine Level?
The concentration of creatinine in serum is the most widely used and commonly accepted
measure of renal function in clinical medicine. In renal failure, deterioration of
renal function, results in the accumulation of nitrogenous waste products, including
creatinine [38].
In the absence of renal failure, elevated creatinine levels may be due to factors
influencing creatine production as well as elimination. The total muscle mass is the
most important determinant of the creatine pool size and thereby of creatinine production
[39]. Hence serum creatinine is increased in people with increased muscle mass, those
with a high-meat diet, users of anabolic steroids, and weight lifters [38]. Trauma
or febrile states have been associated with significant increases in the excretion
of creatinine [40–43].
Rhabdomyolysis or extensive crush injury may result in an increase of serum creatinine,
at times exceeding what can be accounted for by the decrement in renal function [44],
the excess creatinine is generally assumed to derive from injured muscle. But it was
found that phosphocreatine was present in muscle in sufficient amounts to serve as
a direct intermediate in the conversion of phosphocreatine to creatinine [45].
Other substances that can cause false elevations of the measured serum creatinine
determined by the Jaffe method include ketoacids, acetone, pyruvate, glucose, uric
acid, proteins, creatine, ascorbic acid, dopamine, and certain cephalosporins [46,
47]. High concentrations of bilirubin can falsely lower the serum creatinine concentration
determined by the Jaffe method [46, 47]. Enzymatic methods for determining serum creatinine
concentration are not affected by the presence of nitromethane in serum [21, 30, 47].
Substances that can interfere with this enzymatic method when present in the serum
include creatine, bilirubin, dopamine, dobutamine, ascorbic acid, and calcium dobesilate
[38, 46, 47].
What are Some Other Common Laboratory Analysis Cross-reactivities of Interest to Toxicologists?
The techniques for detecting the presence of drugs include a variety of chromatographic
methods, immunoassays, and chemical and spectrometric techniques. A number of interferences
resulting in “false-positive” results have been reported [48]. Some common, important
interferences resulting in false-positive results are listed in Table 1.
Table 1
Examples of false-positive results in toxicology testing
Drug
Some reported cause(s) of a false positive result
Amphetamines (urine)
Cross-reacting stimulant drugs (MDMA, pseudoephedrine, etc.); cross-reacting non-stimulant
drugs (bupropion, labetalol, ranitidine, sertraline, and trazodone); drugs metabolized
to amphetamines (benzphetamine, selegiline)
Ethylene glycol
Other glycols; elevated triglycerides
Lithium
Use of a green-top Vacutainer specimen tube (contains lithium heparin, may raise Li
level by 6-8 mEq/L)
Methadone (urine)
Diphenhydramine, verapamil
Opiates (urine)
May be triggered by ingestion of poppy seeds.
Osmolality
Use of a gray-top Vacutainer specimen tube (contains fluoride-oxalate) can raise measured
osmolality by up to 150 mOsm/kg
Phencyclidine (urine)
Diphenhydramine, dextromethorphan, venlafaxine
Tricyclic antidepressants
Carbamazepine, cyclobenzaprine, quetiapine
Adapted from Osterloh J and Haller CA, “Toxicology Testing,” in Poisoning and Drug
Overdose, 5th edition, McGraw-Hill, 2007, pp. 43-44
Case Continuation
Based on the history of ingestion of “Blue Thunder” fuel which may contain varying
amounts of methanol (43-77%) and nitromethane (5-35%) and the presence of a large
osmolal gap even after accounting for the contribution of the nitromethane, we recommended
treatment with fomepizole, thiamine (the patient was suspected to be an alcoholic),
folate, and transfer to a facility with dialysis capabilities.
Two days later, the reference laboratory that the patient’s serum was sent out to
reported the initial serum methanol concentration to be 399 mg/dL (124 mmol/L). The
methanol concentration decreased to 47 mg/dL (1.47 mmol/L) approximately after completing
2 h after dialysis, while the apparent creatinine concentration decreased to 66.8 mg/dL.
Ethylene glycol, acetone, isopropyl alcohol, acetaldehyde, and paraldehyde were not
detected in the initial serum specimen. The patient continued to have daily dialysis
(approximately 19 h of dialysis in total) until the osmolal gap narrowed and his apparent
creatinine level was reduced to 168 μmol/L (1.9 mg/dL). He was also treated orally
with folic acid 1 mg, thiamine 100 mg, and a multivitamin daily. Although the patient
had no visual disturbances or any significant metabolic acidosis, he had auditory
hallucinations thought to be related to alcohol withdrawal, which was treated with
benzodiazepines. He was discharged to a psychiatric facility after 9 days of hospitalization.
Conclusion
Toy racing car and other nitromethane-containing fuel additives often contain significant
concentrations of methanol. Unfortunately, most hospitals are not able to perform
a rapid quantitative test for methanol. In addition, nitromethane causes a marked
false elevation of the serum creatinine level when measured by the Jaffe method, which
can be exploited to estimate the nitromethane level. If the relative concentrations
of nitromethane and methanol in the fuel are known, then the estimated methanol level
can be extrapolated. If the relative concentrations are not known, the nitromethane
level can be subtracted from the osmolal gap to provide a residual estimate of the
methanol level. Based on the extrapolated methanol level, appropriate treatment with
fomepizole and hemodialysis can be recommended.