CLIN.CHEM.39/9, 1922-1925 (1993)
Severe Isopropanolemia without Acetonemia or Clinical Manifestations of Isopropanol
Intoxication
Kwok-Ming
Chan,1 Edward
T. Wong,
and W. Stephen
This is the first reported case of severe isopropanolemia
in a patient who did not experience associated clinical
manifestationsand acetonemia.
The patient
was found
lyingface down in a hotel lobby but at admission was alert
and oriented to place and person. Toxicological analysis
of the patient’s serum revealed the presence of isopropanol at a concentration of 72 mmol/L. An increased
serum osmolal gap (81 mOsm/kg) was also observed.
The serum concentration of isopropanol decreased to 9.5
mmol/L 15.5 h after admission with an estimated half-life
of elimination of 5-7 h. No serum acetone was detected
throughout the patient’s hospitalization.
The identity of
isopropanol was confirmed by gas chromatography/mass
spectrometry. The patient remained awake and alert while
in the hospital and was discharged 5 days after admission. These unusual findings raise some fundamental
questions about the role of isopropanol conversion to
acetone in the manifestation of symptoms usually associated with isopropanol intoxication.
Terms: tox,cology
mass spectrometly
Indexing
.
acetone
g
chromatography!
Isopropanol
is a clear, colorless, volatile liquid commonly found in various concentrations
in many household
and industrial
products,
including antifreeze preparations
and rubbing alcohol (1). Isopropanol
intoxication
can result from (a) accidental ingestion,
especially
among young
children;
(b) suicide attempts; (c) using rubbing alcohol as
an ethanol substitute
(2-4); and (d) inhalation
and (or)
absorption
during
topical use for fever control (5-9). Isopropanol is rapidly metabolized
to acetone (2, 4, 10, 11).
Serum isopropanol
concentrations
>25 mmol/L may result in coma and death (12), although patients with serum
isopropanol
concentration
of 66.7 mmol/L have survived
after hemodialysis
(13).2 Here we present a case involving
a patient with a serum isopropanol
concentration
of 72
mmol/L but devoid of acetonemia
and the clinical manifestations associated with severe isopropanol intoxication.
Department of Pathology and Laboratory Medicine, Los Angeles
County-University
of Southern California Medical Center, and
University of Southern California School of Medicine, Los Angeles,
CA 90033.
‘Mdress
correspondence
to this author at Box 118, General
Hospital, Los Angeles County-University
of Southern California
Medical Center, 1200 N. State St., Los Angeles, CA 90033. Fax
213-226-2685.
2bepano1#{149}1 mmol/L = 60 mg/L (6 mg/dL).
Received November 11, 1992; accepted March 23, 1993.
1922 CLINICAL CHEMISTRY, Vol. 39, No. 9, 1993
Matthews
Case Report
A 28-year-old
Japanese
man was admitted
to the
Emergency
Department
at 1050 after being found face
down on a hotel floor. At admission,
his temperature
was 36.3 #{176}C,
pulse rate 72/mm, respiratory
rate 16/mm,
and blood pressure
112/76 mmHg.
The patient was
awake and oriented to place and person, but appeared to
be lethargic
and disoriented
in relation to time. Shortly
after admission,
the patient became agitated
and began
yelling mathematical
equations.
He vomited once, and
had episodes of diarrhea
with brown liquid stools during
his admission.
There were no signs of trauma
or unusual breath odor. A computerized
tomographical
scan
of the head was normal. Neurological
examination
revealed
bilaterally
dilated pupils, which were equally
responsive
to light, and 2+ deep-tendon
reflexes. The
remainder
of the physical examination,
including
cardiovascular
examination,
was unremarkable.
Through an interpreter,
a brief past medical history
was obtained from the patient and his father via telephone in Japan. The patient suffered a mental breakdown at age 13 and has since been treated for schizophrenia.
In the patient’s possession was an unidentified
package of Japanese medicine.
There was no previous
hospitalization
and the patient denied having allergies
or using drugs or alcohol.
The patient’s serum chemistry
values at the time of
admission
were normal.
Toxicological
analysis
of the
patient’s serum revealed only isopropanol
at a concentration of 72 mmol/L. Additional
serum assays indicated
<0.7 molIL for acetaminophen,
<0.3 mmol/L for salicylates, and negative results for acetone, barbiturates,
ethanol, hypnotics, and methanol. Headspace
gas-chromatographic
analysis
of the patient’s serum specimen
for hydrocarbons
and volatiles by a reference laboratory
confirmed
the presence of only isopropanol
and was negative for aromatics
(benzene, ethylbenzene,
cyclobenzene, cyclopropane,
toluene,
and xylene),
aliphatics
(heptane,
hexane, and pentane),
other alcohols
(butanols,
ethanol, isoamyl alcohol, methanol,
and propanol), aldehydes (acetaldehyde,
acetone, methyl ethyl
ketone), and esters and ethers (amyl acetate, butyl acetate, ethyl acetate,
ethyl ether, and isopropyl ether).
The patient’s urine tested negative for amphetamines,
cocaine metabolites,
opiates, and phencycidine.
The patient was evaluated by a psychiatric consultant
and was found to have no clinical problems other than
the aforementioned
schizophrenia.
At the suggestion of
the psychiatric
consultant,
the patient was started
on
haloperidol
(Haldol), benztropune
mesylate
(Cogentin),
and lorazepam
(Ativan). Because of the patient’s agitation, he was confined in a two-point restraint.
On 2nd day of admission,
the patient was awake,
alert, and calm. The serum isopropanol
concentration
had decreased
to 9.5 mmol/L within
15.5 h after admission, and stifi no serum acetone was detected. The patient continued to improve and was discharged
to his
father on the 5th day after admission.
MaterIals and Methods
Volatiles
(acetone, ethanol, isopropanol,
and methanol) were measured
by gas chromatography
with a
headspace
analysis
technique.
n-Propanol
was used as
an internal standard. A Hewlett-Packard
(HP; Lawndale, CA) Model 19395A headspace
sampler
was used
with an HP Model 5890 gas chromatograph
equipped
with a 180 cm x 2 mm (i.d.) Carbopack
B/5% Carbowax
20M column (Supelco, Bellefonte,
PA) and a flame-ionization detector.
The analysis
was performed
isothermally at 80#{176}C
at a helium carrier-gas
flow rate of 30-40
mLlmin with an injector
and detector temperature
of
150 #{176}C.
For gas chromatographic/mass
spectrometric
(GC/
MS) confirmation
of isopropanol,
a 200-L aliquot of the
patient’s diluted serum specimen or a 33.3 mmol/L isopropanol standard
was mixed with an equal volume of
the internal
standard,
n-propanol
(26.7 mmol/L),
in
headspace
vials. The vials were crimp-sealed
and incubated at 70#{176}C
for 15 miii, and 100 pL of the headspace
was injected into the GC/MS. The injector temperature
was 150 #{176}C,
and the oven temperature
was 50#{176}C
initiallyfor 2 miii, increased to 200 #{176}C
at 30 #{176}C/min,
and
maintained
at 200 #{176}C
for 2 miii, with a total run time of
9 mm. Isopropanol
in the patient’s
serum sample was
confirmed by comparing
both the relative retention time
and the mass spectrum
for the peak of interest with the
peak for the isopropanol
standard.
For GC/MS analysis
of acidic, neutral,
and basic extracts from the patient’s serum specimen,
2 mL of the
patient’s diluted serum was acidified
to -pH 6.0 with 2
mL of 3 moliL phosphate
buffer and mixed with 20 mL
of chloroform. After separation,
the aqueous
phase,
which contained
the basic drugs, was alkalinized
to pH
10 with saturated
ammonium
chloride and sodium hydroxide, and mixed with chloroform
to extract
the basic
drugs. The initial chloroform layer, which contained the
acidic, neutral, and weakly basic drugs, was alksiliniied
with 0.45 mol/L NaOH and mixed again to separate the
neutral
and weak basic drugs, which partitioned
into
the chloroform layer, from the acidic drugs, which partitioned into the aqueous
layer. After acidifying
the
aqueous layer with 2 mol/L hydrochloricacid, the acidic
drugs were back-extracted
into chloroform. All the chloroform extracts were evaporated
to dryness and reconstituted
in methanol
before GC/MS analysis. The injector temperature
was 250 #{176}C,
and the oven temperature
was initially
90#{176}C
for 2 miii, increased
to 300 #{176}C
at
15 #{176}C/min,
and stayed at 300 #{176}C
for 4 min, with a total
run time of 20 mm. Unknown
peaks were identified by
comparing
their mass spectra with those in the Pfleger
library.
An HP 5970B mass spectrometer
was used with the
HP 5890 gas chromatograph,
which was equipped
with
a 25 m x 0.2 mm (i.d.) HP-i fused-silica
capillary
colu.mn (HP no. i9lOZ-i02),
coated with 5% methyl silicone gum. The helium flow rate was 0.65 mL/min. The
MS detector was operated
in the electron impact mode
with the ion source at 70 eV and an interface temperature of 280 #{176}C.
The data system for the GC/MS included
an HP 300 computer
with an HP 7957B Winchester
hard drive and an HP 9144 tape drive. The instrument
was autotuned
with perfluorotributylamune.
Data acquisition was performed in the scan mode for masses of
10 to 200 atomic mass units (amu) for volatiles and 50 to
500 amu for organic extracts, with a solvent delay of 0.7
mm.
DIscussIon
Symptoms
of isopropanol
intoxication
usually occur
within 30 mm of ingestion.
Depending
on the amount
ingested,
symptoms
may range from gastrointestinal
manifestations
such as nausea,
vomiting,
abdominal
pain, gastritis, and hematemesis to central nervous system effects, including dizziness,
headaches, confusion,
stupor, and coma (14). Hypotension,
coma, and death
may occur in severe intoxications
(15). Attempts
have
been made to correlate
the severity of the clinical outcome with the blood isopropanol
concentrations.
It has
been suggested that blood isopropanol
concentrations of
>25 mmol/L often result in deep coma, and concentrations >33.3 mmolJL are rarely compatible
with life (12).
Moreover,
isopropanol
concentrations
of <25 mmol/L
have also been noted in some fatal cases (12). Alexander
et al. (12) proposed that the combined concentrations
of
isopropanol
and its metabolite,
acetone, may provide
greater accuracy in predicting
the clinical course of the
intoxication
in specific patients.
On the basis of data
from a retrospective
study, they suggested
that a combined isopropanol/acetone
content >18.5 mmol/L correlated better
with potentially
lethal situations
(12).
The patient described
in this study had a serum isopropanol concentration
of 72 mmol/L at admission.
Only
two cases have been reported
with higher serum isopropanol concentrations
(12,13).
One of those patients died
(12) and the other survived (after hemodialysis)
(13).
The surviving
patient initially
presented
with the characteristic
symptoms
of isopropanol
intoxication,
but
subsequently
became
hypotensive and comatose.
However, in our case study, despite his high concentration
of
serum isopropanol,
the patient was awake, alert, and
normotensive,
and was without the symptoms of central
nervous system depression
commonly
associated
with
severe isopropanol
intoxication.
About 80% of the ingested isopropanol
is normally
metabolized
by alcohol dehydrogenase
(EC 1.1.1.1) to
acetone in the liver, with the remaining
20% being
eliminated
unchanged by the kidneys. Acetone generCLINICAL CHEMISTRY, Vol. 39, No. 9, 1993 1923
ally appears in the serum 3-4 h after isopropanol
ingestion (2). The half-life of serum isopropanol
ranges from
<2 to 7.3 h (2,4, 10). The half-life of serum isopropanol
from the patient in this study approximated
5 h and
agreed with half-life values reported
in the literature,
even though the decrease in isopropanol
was not accompanied by its expected metabolism
to acetone. In fact,
the serum
acetone
concentration
remained
negative
throughout
his entire hospitalization.
There are several possible explanations
for the presence of isopropanol
but absence of serum acetone in this
patient: (a) an incorrect
identification
of isopropanol;
(b)
ingestion of an unknown compound that, when analyzed
by GC, yielded isopropanol
as a pyrolysis product; or (c)
failure of the liver to convert isopropanol to acetone due
to either anomalous
or deficient alcohol dehydrogenase
activity or inhibition of the alcohol dehydrogenase
activity by compounds
ingested by the patient.
Incorrect
identification
of isopropanol
was ruled out
because (a) the measured osmolality was 350 mOsm/kg
and the calculated osmolality was 269 mOsm/kg with an
osmolality gap of 81 mOsmlkg
this approximated
the
73.4 mOsm/kg increase in osmolality attributed
to isopropanol at 72 mmol/L; (b) isopropanol
was identified by
headspace
gas chromatography
in both the authors’ laboratory and by a reference laboratory; and (c) isopropanol was confirmed by CC/MS (Figure 1). The total ion
chromatogram
of the headspace
from a mixture of the
patient’s diluted serum and an n-propanol
internal standard demonstrated
only two distinct peaks (Figure IA).
The retention times of these two peaks matched
the
retention times of the two peaks from the headapace of a
mixture
containing
only isopropanol and n-propanol
standards (Figure 1B). Furthermore,
the mass spectrum
of the unknown
peak from the patient’s total ion chromatogram
correlated
with the mass spectrum
for the
isopropanol
standard.
The possibility
that the patient might have ingested a
substance
that when analyzed
by CC yielded isopropanol as a pyrolysis
product is unlikely because (a)
when the patient’s serum was analyzed
by headapace
CC/MS in the authors’ laboratory,
there were no other
peaks on the chromatogram
after the n-propanol
internal standard
for the remaining
7.5 miii of the run; (b)
when the patient’s serum was analyzed
by headapace
CC in a reference laboratory,
isopropanol
was the only
compound identified:
no aromatics, aliphatics,
other alcohols, esters, or ethers were detected;
and (c) when
acidic, neutral, and basic extracts of the patient’s serum
were analyzed by CC/MS. the mnjor substances
present
were fattyacids and relatedcompounds. Although minor compounds
with unidentifiable
spectra
were detected, their spectra did not match the spectra for the
4-substituted
pyrazoles in the Pfleger mass spectral library.
Thus, with the finding that isopropanol
was unlikely
to be a pyrolytic
or breakdown
product of another ingested compound,
and given the apparent
lack of its
metabolism
to acetone, we think it is surprising
that the
isopropanol
half-life of elimination
in this patient was
1924
CLINICAL
CHEMISTRY,
Vol. 39,
No.9, 1993
A
Total Ion Chromatograni
npropanol
6.0E8
.
f\.
4.05.8
20E+L
1:5
‘14
lime (mil.)
Mass Spectrum of Unknown Peak
2.OE+8
45
27
1928/
1.05+8
0.05.0
37
43\
59
.
“lI
10
20
30
40
50
60
B
Total Ion Chromatogram
InoI
12E#{247}7
8OE.4
4.0E6
0.OE+0
La..
n-popanol
._
Time (mm.)
Mass Spectrum of Isopropanol
4.05.8
46
2.05.8
u.ut+u
1926/
1
I
10
i
20
27
43
535950
‘H
\
30
i
40
50
60
Mass/crge
Fig. 1. Total ion chromatograms and mass spectra of headspace
from patient’s serum mixed with an internal
standard,
n-propanol (A),
and a mixture of Isopropanol standard and n-propanol (B)
consistent
with those reported
in the literature
(2, 4,
10): Unchanged
isopropanol
is believed to be ordinarily
eliminated
only slowly via renal excretion
because of
renal reabsorption.
Because
alternative
pathways
of
metabolism
and elimination
could not be identified, we
postulate
that most of the isopropanol
was cleared from
this patient by renal excretion. Unfortunately,
the presence of isopropanol
in the patient’s urine could not be
established
because the patient had been discharged
by
the time the case was identified and no more of his urine
was available.
We consider that the most plausible cause of the lack
of isopropanol
metabolism
in this patient was a failure
of the patient’s liver to convert isopropanol
to acetone.
Because no alternative
pathway of metabolism
other
than by alcohol dehydrogenase has been identified, the
lack of isopropanol
metabolism
could be attributed
to
either (a) anomalous
or deficient alcohol dehydrogenase
activity, or (b) inhibition
of the alcohol dehydrogenase
activity by substances
ingested by the patient. Although
we have found no reports of a complete deficiency of
alcohol dehydrogenase,
polymorphisms
do occur in this
enzyme and in aldehyde dehydrogenase, both of which
are responsible
for ethanol degradation
in humans (16).
An inactive
form of the aldehyde dehydrogenase
isoenzyme has been known to exist in the Oriental
population. Expression
of the inactive form of this isoenzyme
affects ethanol metabolism
by impairing the metabolism of acetaldehyde
and accounts for the initial facial
flushing in Orientals
after alcohol ingestion
(17). Conceivably, lack of or anomalous
alcohol dehydrogenase
activity could account for the lack of conversion of isopropanol
to acetone. Likewise,
the possibility
that the
patient might have ingested a compound that inhibited
the alcohol dehydrogenase
activity cannot be ruled out.
However, the CC/MS analysis of acidic, neutral,
and
basic extracts
from the patient’s serum revealed
only
fatty acids and related compounds.
Unfortunately, discharge of the patient from the hospital
precluded
us
from obtaining
a sample of the patient’s unidentified
package of Japanese
medicine for analysis.
The mechanism
of intoxication
by isopropanol
is ifi
defined. Both isopropanol
and its metabolite,
acetone,
have been suggested
as causative agents for the clinical
manifestations
associated
with
isopropanol
intoxication. Isopropanol
has been reported to be at least twice
as potent a central nervous system depressant
as ethanol (18). Similarly, acetone has been described as toxic
and perhaps a more potent anesthetic than ethanol (12).
Alexander et al. (12) suggested that the potency of isopropanol as a central nervous system depressant
may be
related to the generation of acetone. The hypothesis that
acetone may be the primary
causative
agent for the
symptoms
of isopropanol
intoxication
is not universally
accepted. In one report, the authors described a patient
who became comatose after drinking
isopropyl alcohol
(700 milL) (2). The patient regained
consciousness
in
10 h despite the fact that the acetone level had peaked
when the isopropanol
concentration
was below the lower
detection limit of the assay (2).
In the current case study, the lack of significant
clinical manifestations
of isopropanol
intoxication
despite a
serum isopropanol
concentration
of 72 mmol/L
is puszling. This unique phenomenon
is inconsistent
with our
current
understanding
of the role of isopropanol
and
acetone in the clinical manifestation
of isopropanol
intoxication
and raises
a myriad
of questions.
Further
delineation
of the mechanism
for isopropanol
intoxica-
tion would require (a) demonstrating
a deficient or
anomalous
alcohol dehydrogenase
activity in such patients, (b) the use of animal models with aberrant expression of the alcohol dehydrogenase
gene, or (c) identi1ring a method to inhibit the alcohol dehydrogenase
activity in vivo while exposing the animals to isopropanol. Proper understanding
of the mechanism
of isopropanol intoxication
may provide an important
basis
for effective treatment
of potentially
fatal isopropanol
intoxications.
We thank Craig Childs for performing the gas chromatographicl
mass spectrometric study on the patient’s serum specimen.
References
1. Goaselin RE, Hodge HC, Smith RP, eds. Clinical toxicolo
of
commercial products. Baltimore: WillbmR & Wilkins, 1984:172-9.
2. Gaudet MP, Fraser GL Isopropanol ingestion: case report with
pharmacokinetic
analysis. Am J Emerg Med 1989;7:297-9.
3. Rosanaky Sd. Isopropyl alcohol poisoning treated with hemodialysis: kinetics of isopropyl alcohol and acetone removal. J Toxicol
Clin Toxicol 1982;19:265-71.
4. Daniel DR., McAnalley BH, Garriott JC. Isopropyl alcohol
metabolism after acute intoxication in humans. J Anal Toxicol
1981;5:11O-2.
5. Barnett JM, Plotnick M, Fine KC. Intoxication after an isopropyl alcohol enema. Ann Intern Med 1990;113:638-9.
6. McGrath RB, Einterz R. Absorption of topical isopropyl alcohol
in an adult. Crit Care Med 1989;11:1233.
7. Arditi M, Kiliner MS. Cases following use of rubbing alcohol for
fever control. Am J Dis Child 1987;141:237-8.
8. McFadden SW, Haddow JE. Coma produced by topical application of isopropanol. Pediatrics 1969;43:622-3.
9. Senz EH, Goldfarb DL. Coma in a child following use of
iaopropyl alcohol in sponging. J Pediatr 1958;53:322-3.
10. Natowicz M, Gorman DL, Kane M, McKisaick J, Shaw L.
Pharmacokinetic analysis of a case of isopropanol intoxication.
Clin Chem 1985;31:326-.8.
11. Lacouture PC, Heldreth DD, Shannon M, Lovejoy F!!. The
generation of acetonemia/acetonuria following ingestion of a subtoxic dose of isopropyl alcohoL Am J Emerg Med 1989;7:38-40.
12. Alexander CB, McBay Ad, Hudson RP. Isopropanol and isopropanol deaths-ten
years’ experience. J Forensic Sd 1982;27:
541-8.
13. King U! Jr, Bradley
KP, Shires DL Jr. Hemodialysis
for
isopropyl alcohol poisoning. JAm Med Assoc 1970;211:1855.
14. Lacouture PC, Wason S, Abrams A, Lovejoy F!!. Acute isopropyl alcohol intoxication. Am J Med 1983;75:680-6.
15. Melson L. Fatal intoxication with isopropyl alcohol (rubbing
alcohol). Am J Clin Pathol 1962;38:144-51.
16. Ehrig T, Bosron WF, Li TK. Alcohol and aldehyde dehydrogenase. Alcohol Alcohol 1990;25:105-16.
17. Agarwal DP, Goedde 11W. Human aldehyde dehydrogenase
isozymes and alcohol sensitivity. Isozymes Curr Top Biol Med Baa
1987;16:21-48.
18. McCord WM, Switzer PK, Brill HI! Jr. Isopropyl alcohol
intoxication. South Med J 1948;41:639-42.
CUNICAL
CHEMISTRY,Vol. 39, No. 9, 1993 1925