Ethylene Glycol and Other Glycols

Abstract

Ethylene glycol is a colorless, almost nonvolatile liquid with an aromatic odor that is recognizable on the breath of some victims. It is used widely as antifreeze in internal combustion engines and as a solvent in various manufacturing processes.

Full text

Ethylene Glycol and Other Glycols
Knut Erik Hovda, Kenneth McMartin, and Dag Jacobsen
Contents
Ethylene Glycol ...................................... 2
Biochemistry and Clinical Pharmacology ............ 2
Pathophysiology of Toxic Effects ..................... 2
Clinical Presentation and Life-Threatening
Complications . . . .................................. 4
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . .. .. . 5
Treatment . . . ........................................... 6
Prognosis . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Diethylene Glycol .................................... 11
Pathophysiology of Toxic Effects . . . . . .. . . . . . . . . . . . . . . 12
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . .. .. . 12
Treatment .......................... .................... 13
Polyethylene Glycol .................................. 13
Treatment .......................... .................... 14
Propylene Glycol . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 14
Treatment .......................... .................... 14
Alkyl Ethers of Ethylene Glycol (Cellosolves) . . . . . 15
Treatment .......................... .................... 15
References ............................................ 15
K.E. Hovda (*)
The Norwegian CBRNE Centre of Medicine, Department
of Acute Medicine, Oslo University Hospital, Oslo,
Norway
e-mail: knuterikhovda@gmail.com
K. McMartin (*)
Pharmacology, Toxicology & Neuroscience, Louisiana
State University Health Sciences Center-Shreveport,
Shreveport, LA, USA
e-mail: KMcmar@lsuhsc.edu
D. Jacobsen (*)
Department of Acute Medicine, Oslo University Hospital,
Oslo, Norway
e-mail: UXDAJA@ous-hf.no
#Springer International Publishing Switzerland 2016
J. Brent et al. (eds.), Critical Care Toxicology,
DOI 10.1007/978-3-319-20790-2_77-1
1

Ethylene Glycol
Ethylene glycol is a colorless, almost nonvolatile
liquid with an aromatic odor that is recognizable
on the breath of some victims. It is used widely as
antifreeze in internal combustion engines and as a
solvent in various manufacturing processes.
There are many similarities between the patho-
physiologies of ethylene glycol and methanol poi-
soning (see “▶Methanol”chapter). Although
little comparable epidemiologic data exist, ethyl-
ene glycol poisoning seems to be more frequent
than methanol intoxication in the developed
world, whereas methanol poisonings are far
more frequent in the developing world. Besides
being the “poor man’s”substitute for ethanol,
ethylene glycol has also been used as suicidal
agent –sometimes in “copy-cat”epidemics
among young people [1,2].
Biochemistry and Clinical
Pharmacology
Ethylene glycol is rapidly and completely
absorbed after oral administration. The volume
of distribution is approximately 0.7 L/kg based
on studies in two male patients [3], although
values of 0.54 L/kg [4] and 0.83 L/kg [5] also
have been reported in men.
The elimination kinetic profile of ethylene glycol
has not been completely clarified. There is evidence
for a saturable elimination with linear (first-order)
elimination for low-to-moderate plasma concentra-
tions (<40 mmol/L [<250 mg/dL]) with a half-life
of 6 h [4]. For higher plasma concentrations, the
elimination seems to approach nonlinear (zero-
order) kinetics.
In one male patient, the volume of distribution
of glycolate, the major circulating ethylene glycol
metabolite, was calculated to be 0.6 L/kg, with an
estimated intrinsic half-life of 6 h over the con-
centration range studied [4]. When ethylene gly-
col metabolism was inhibited by fomepizole, the
mean endogenous half-life of ethylene glycol was
10 h and the mean elimination rate was 1.1 mmol/
L/h (6.8 mg/dL/h; n=4) [6]. In one patient who
was admitted numerous times, a median ethylene
glycol half-life of 12.9 h (range 10.0–17.3 h) was
found during antidote treatment and normal renal
function, indicating both glomerular filtration and
tubular secretion of ethylene glycol in the kidneys
[7]. The half-life of ethylene glycol during inter-
mittent hemodialysis was 2.4 h, whereas the
glycolate half-life in two admissions were calcu-
lated to 2.4 and 3.9 h, respectively. The latter were
slightly shorter than elsewhere reported: 10.4 !
7.9 h (n=4) [6], 7 h (n=1) [4], and 4.5 h (n=
1) [8].
Pharmacokinetics of Ethylene Glycol
Volume of distribution: 0.7 L/kg
Protein binding: none
Mechanisms of clearance: hepatic and
renal
Active metabolites: glycolic acid and oxalic
acid far more toxic than the parent compound
Methods to enhance clearance:
hemodialysis
Pathophysiology of Toxic Effects
The potentially lethal dose of ethylene glycol in
untreated patients is not well established, but
100 mL is the most frequently cited approxima-
tion. A value of 1–2 mL/kg seems reasonable [9].
The primary enzyme in ethylene glycol metab-
olism is alcohol dehydrogenase (ADH) (Fig. 1).
Similar to methanol, the toxicity of ethylene gly-
col is mediated by its metabolites. In contrast to
methanol, ethylene glycol causes central nervous
system (CNS) depression and inebriation in a
manner similar to ethanol.
The mechanisms for the toxicity of ethylene
glycol are not completely resolved. The role of
oxalate (see Fig. 1) was originally based on the
visualization of oxalate-like crystals in the urine
(see Fig. 2a, b) and the development of acute renal
failure. Later, it was suggested that the aldehyde
metabolites –mainly glycolaldehyde –were
responsible for the toxic syndrome. It has been
shown experimentally that these aldehydes were
2 K.E. Hovda et al.

able to inhibit oxidative phosphorylation, glucose
metabolism, protein synthesis, DNA replication,
and RNA synthesis; these aldehydes may also be
able to oxidize intracellular sulfhydryl
groups [10].
The mechanism for the renal toxicity of ethyl-
ene glycol is clearly associated with the accumu-
lation of calcium oxalate monohydrate (COM)
crystals in the kidney [11,12]. Although older
human case studies [13] and studies in animals
[14] appeared to show tubular necrosis without
the appearance of crystals, recent human [15] and
animal studies [16] have confirmed that the insol-
uble COM is deposited in the renal tubules and
causes the kidney damage with evidence of prox-
imal tubular necrosis. Microscopically, necrotic
damage is observed only in the presence of
COM [15,16], and metabolically, damage is
most severe in kidneys with the highest accumu-
lation of COM [16]. In vitro studies of the toxicity
of COM, glycolate, glycolaldehyde, and
glyoxylate in normal human proximal tubule
cells showed that only COM induced renal cell
death at relevant concentrations [17], whereas
none of the other metabolites including the oxa-
late ion had an effect on cellular viability.
As judged from experimental studies, there
may be no major differences in the way rodents
and humans handle ethylene glycol. This idea is
based on the fact that both become acidotic and
display kidney injury after exposure. As such, the
measurement of the ethylene glycol metabolites in
rodents may also have some validity in humans
[18]. In experimental studies with ethylene
Fig. 1 The complex metabolism of ethylene glycol. Solid
arrows represent major routes or pathways. Dotted arrows
are theoretical or less important routes. Direct renal
excretion of ethylene glycol is a major pathway of elimi-
nation, provided that normal renal function is present. ADH
alcohol dehydrogenase
Ethylene Glycol and Other Glycols 3

glycol–intoxicated rats, dogs, and monkeys, nei-
ther circulating glycolaldehyde nor glyoxylate
was detected using gas chromatography–mass
spectrometry techniques [18–20]. In addition, in
six patients poisoned with ethylene glycol, plasma
glyoxylate levels were less than 1.2 mg/dL
(<0.2 mmol/L), and the glycolate concentrations
ranged from 100 to 175 mg/dL (17–29 mmol/L),
demonstrating that of the relevant metabolites,
only glycolic acid is present in the blood in
amounts significant to produce the metabolic
acidosis [21].
In summary, the toxicity of ethylene glycol is
most probably due to a combination of the severe
metabolic acidosis caused by glycolic acid and the
precipitation of calcium oxalate crystals resulting
in impaired organ function, especially in the kid-
neys (see Fig. 1). The toxicity of glycolate is
probably less than that of formate, the major
toxic metabolite in methanol poisoning [9,
22]. Hypocalcemia and the resulting tetany and
seizures are probably less important mechanisms
of toxicity (see Fig. 1).
Clinical Presentation and Life-
Threatening Complications
Many authors describe the clinical syndrome of
ethylene glycol poisoning in three stages: (1) CNS
depression, (2) cardiopulmonary complications,
and (3) renal failure. Although there is some sup-
port for this classification, especially for the
understanding of the pathophysiology, there is
considerable clinical overlap between stages.
Ethylene glycol poisoning is characterized by
an initial CNS depression phase associated with
inebriation progressing to coma. After 4–12 h,
signs and symptoms resulting from the metabo-
lites appear if ethanol has not been coingested.
The increasing accumulation of glycolic acid
leads to metabolic acidosis, which may be severe,
and to compensatory hyperventilation. In contrast
to methanol poisoning, these patients are usually
comatose when hyperventilation is pronounced,
so there is most often no subjective feeling
of dyspnea. Also, for unknown reasons,
leucocytosis, elevated blood pressure, and tachy-
cardia are usually prominent features.
For the first 12–18 h postingestion, urine out-
put is generally still adequate, and if proper treat-
ment is started at this stage, full recovery is
usually seen, although the patient may have
some degree of acute kidney injury (AKI) as
evidenced by elevation of serum creatinine. How-
ever, in most cases, the AKI will have a good
prognosis in the long run. Another complication
of calcium oxalate precipitation, such as
hypocalcemia-induced tetanic contractions, may
occur. The prognosis of acute renal failure is good
due to dialysis therapy, although the plasma cre-
atinine may not return to normal for weeks to
months [9,23].
Without adequate treatment, seriously poi-
soned patients rapidly deteriorate. In addition to
CNS depression possibly associated with the
inebriating effects of ethylene glycol (similar to
ethanol), cerebral edema, convulsions, oliguric
Fig. 2 Typical needle-shaped calcium oxalate
monohydrate (COM) crystals in the urine during ethylene
glycol poisoning (a) (Regular HE-staining). Envelope-
shaped calcium oxalate dihydrate crystals (b) are less fre-
quent but may occur in early stages of poisoning (Polarized
light) [4]
4 K.E. Hovda et al.

renal failure, and respiratory problems may
develop. Pulmonary infiltrates may be observed
radiologically, but these changes are thought to be
noninfectious in origin. Calcium oxalate crystals
have been observed in the lungs of patients who
have died from ethylene glycol poisoning, as well
as in brain tissue on autopsy. Given this observa-
tion, one could postulate that these changes may
be an inflammatory reaction related to this precip-
itation. Although “cardiogenic pulmonary
edema”is claimed to occur in ethylene glycol
poisoning, this is not frequent. While the cardiac
ejection fraction may be lowered (to about 40 % in
severely poisoned patients), this is not the major
cause of the pulmonary infiltrates seen in these
cases. The pulmonary capillary wedge pressure is
often normal in this situation; as such, the diag-
nostic criteria for acute respiratory distress syn-
drome (ARDS) are fulfilled. The concomitant
ingestion of ethanol may inhibit the metabolism
of ethylene glycol to its toxic metabolites, thereby
prolonging the initial CNS phase of inebriation
and delaying the onset of the other clinical fea-
tures of toxicity.
Patients admitted “in extremis”may survive
with adequate treatment. These patients should
undergo computed tomography or magnetic reso-
nance imaging of the head to evaluate the degree
of brain damage. Some of these patients develop
(large) cerebral infarcts or cerebral edema
resulting in brain death [3,9], whereas patients
without these findings may have excellent prog-
nosis in spite of weeks in a coma. There are a few
reports of ocular manifestations and methemoglo-
binemia associated with ethylene glycol poison-
ing [24,25]. No analytic investigations were
performed, however, to rule out methanol contam-
ination of the liquid ingested. One ethylene
glycol–intoxicated patient developed visual
dyspraxia as a result of cerebral infarcts [3]. No
objective ocular complications were observed.
Diagnosis
Ethylene glycol in biologic fluids can be deter-
mined easily by enzymatic methods [26], or by
gas chromatography [27]. Simultaneous determi-
nation of ethylene glycol and glycolate is also
possible [28].
If specific analysis is not available, the use of
the anion and osmolal gaps may suggest the diag-
nosis (see chapters “▶Methanol and
Formaldehype”and ▶“Acid Base Balance in the
Poisoned Patient”)[23,29,30]. An ethylene gly-
col concentration of 100 mg/dL (16 mmol/L)
increases the osmolal gap by 16/0.93, or
17 mOsm/kg H
2
O (see “▶Methanol and Formal-
dehyde,”Table 1). Osmometry uses osmolality,
which is expressed as milliosmoles per kilogram
of water (mOsm/kgH
2
O). Osmolarity is expressed
as milliosmoles per liter (mOsm/L). Because
serum consists of 93 % water, one has to divide
serum osmolarity by 0.93 to compare these two
parameters. Theoretically the sensitivity of the
osmolal gap should be low at ethylene glycol
concentrations less than 50 mg/dL (8 mmol/L).
However, for unknown reasons, the osmolal gap
tends to be higher than expected from the molar
contribution of ethylene glycol at such low levels.
A possible explanation for this could be that bicar-
bonate is replaced by glycolate in the “anion side”
of the Gamble diagram, and this may increase the
dissociation coefficient (1.86) used in the
caluculations of osmolality. At low ethylene gly-
col concentrations, the patients are usually most
acidotic, and more bicarbonate is replaced by
glycolate in the “anion side”(see “▶Methanol
and Formaldehyde,”Fig. 4).
Serum osmolality measurement must be
performed by the freezing point depression
method, not by the vapor pressure method. If
ethanol is coingested, there may be no metabolic
acidosis, or anion gap, before the ethanol is
metabolized. The details of the calculation of the
osmolal gap are given in chapters “▶Methanol
and Formaldehype”and ▶“Acid Base Balance in
the Poisoned Patient”If ethanol is present, calcu-
lation of the osmolal and anion gaps must be
repeated periodically. In late stages of ethylene
glycol poisoning, most of the parent compound
is metabolized to glycolic acid. In this situation,
the anion gap may be increased considerably, but
the osmolal gap may be close to normal. As such,
Ethylene Glycol and Other Glycols 5

a small or normal osmolal gap does not eliminate
the possibility of toxic alcohol ingestion, espe-
cially in the presence of metabolic acidosis and
significant anion gap [23]. (see “▶Methanol and
Formaldehyde,”Fig. 4)
Many arterial blood gas analyzers use lactate
oxidase for the enzymatic reaction, which can
give a falsely elevated lactate concentration in the
presence of glycolate. By subtracting the “real”
level of lactate (as found by chromatography
methods or by the use of lactate dehydrogenase),
this “lactate gap”will indirectly indicate the pres-
ence of glycolate, hence ethylene glycol poisoning
[31,32].
Urine microscopy may reveal envelope-shaped
calcium oxalate dihydrate crystals (typically in
early stage) or needle-shaped calcium oxalate
monohydrate crystals (typically in late stages)
(Fig. 2a, b). These findings may be delayed, and
a negative microscopy should be repeated if diag-
nosis is still unclear. About half of patients present
with crystalluria on admission, and most, but not
all, develop this sign later. The crystalluria may be
massive and easy to detect, even by an inexperi-
enced microscopist. In addition, there usually are
erythrocytes, leukocytes, and different casts in the
urine sediment [3,33].
Treatment
Treatment of ethylene glycol poisoning should
follow the well-established principles of support-
ive care. Activated charcoal is of no value in
ethylene glycol poisoning.
Metabolic Acidosis
Although not studied in a formal clinical trial, it is
generally accepted that the metabolic acidosis
associated with ethylene glycol poisoning, partic-
ularly if severe, should be treated aggressively by
infusion of sodium bicarbonate. In the first few
hours, 600–800 mmol (milliequivalents) of bicar-
bonate may be needed, especially if antidotal ther-
apy has not been initiated. Because ethylene
glycol is metabolized faster than methanol, the
acidosis develops more rapidly if an ADH inhib-
itor (ethanol or fomepizole) is not given, in which
case a so-called bicarbonate-resistant metabolic
acidosis may develop. The rapid correction of
acidosis in these patients may provoke tetanic
signs, especially when hypocalcemia already is
present.
Inhibition of Alcohol Dehydrogenase
For ethylene glycol-poisoned patients, it is criti-
cal that ethanol or fomepizole be given to inhibit
the generation of toxic metabolites by ADH.
(Grade II-1 recommendation) The major advan-
tage of fomepizole compared with ethanol is its
documented effectiveness, lack of CNS depres-
sion, ease of administration, and ability to reduce
the need for hemodialysis [22,34]. If fomepizole
is given to a patient with ethylene glycol poison-
ing before renal failure develops, hemodialysis
may not be necessary [34–36]. Fomepizole
(molecular weight 82 g/mol) is removed by
hemodialysis with a dialysance close to that of
urea [37]. No drug concentration monitoring is
necessary, however, during this procedure. There
are only anecdotal reports defining the threshold
for antidote use in ethylene glycol poisonings.
However, a recent review suggests an ethylene
glycol level of 10 mmol/L (62 mg/dL) as a rea-
sonable cut-off value given no or only mild met-
abolic acidosis [22]. In conventional acidotic
patients or patients with renal impairment,
20 mg/dL (3 mmol/L) seems appropriate,
although this has not been validated. If no
serum ethylene glycol concentration is available,
the degree of metabolic acidosis should be con-
sidered. ADH inhibition should be undertaken if
the base deficit is greater than 10 mmol/L or a
progressive decrease in serum bicarbonate is
seen in serial measurements. In borderline situa-
tions, one loading dose of ethanol (e.g., healthy
adult with a serum ethylene glycol concentration
<62 mg/dL (10 mmol/L) and base deficit
<10 mmol/L) may be preferred over fomepizole,
which is usually more expensive [22]. In serious
ethylene glycol poisoning, however, fomepizole
is the preferred antidote.
6 K.E. Hovda et al.

Indications for ICU Admission in Ethylene Glycol
Poisoning
There should be a low threshold for patients
with pronounced metabolic acidosis
(>20 mmol/L base deficit). Patients may dete-
riorate rapidly, and early treatment with “many
nurse hands”is essential for outcome. Treat-
ment is complicated (bicarbonate, antidote,
treatment of seizures); patients without “nor-
mal admission criteria”also should be consid-
ered for the intensive care unit in cases of
significant poisoning, especially if ethanol is
the antidote in use.
Dosing of Fomepizole
A loading dose of 15 mg/kg should be admin-
istered, followed by doses of 10 mg/kg every
12 h for four doses, then 15 mg/kg every 12 h
thereafter until ethylene glycol levels have
been reduced to <62 mg/dL (10 mmol/L).
All doses should be given as a slow intrave-
nous infusion over 30 min (dissolved in, e.g.,
100 mL of isotonic saline or dextrose), or it can
be given orally at the same doses. During
hemodialysis, the frequency of dosing should
be increased to every 4 h, whereas every 8 h is
a likely sufficient dosing frequency during
continuous dialysis modalities, continuous
renal replacement therapy (CRRT)/continuous
veno-venous hemodialysis (CVVHD)/contin-
uous veno-venous hemodiafiltration
(CVVHDF). (Grade III recommendation)
To reach a therapeutic blood ethanol level
of 100 mg/dL (22 mmol/L) –see suggested
dosing regimen in “▶Methanol and Formal-
dehyde,”Table 3. The maintenance infusion
should be increased or decreased according to
measured blood ethanol concentrations.
If ethanol is used as an antidote, it should be
given as in methanol poisoning (see chapter
“▶Methanol and Formaldehyde”). The serum
ethylene glycol concentration threshold for stop-
ping antidotal therapy has been set arbitrarily at
less than 40 mg/dL (<6 mmol/L). If an ethylene
glycol concentration is not readily available, an
osmolal gap less than 10 mOsm/kg H
2
O may be
an indicative substitute value for stopping therapy,
provided no metabolic acidosis or indication of
renal dysfunction is present. Although the affinity
of ADH for ethylene glycol is lower than that for
methanol [38,39], this makes little practical dif-
ference in therapeutic dosing.
Several studies have indicated that ethanol can
significantly inhibit ethylene glycol elimination [4,
5,8,40]. Ethylene glycol is renally excreted. An
apparent elimination half-life for ethylene glycol of
14–17 h during ethanol therapy has been shown in
patients without renal failure [40], compared with
an elimination half-life of 6 h without ethanol
administration [4]. Similar half-lives were
observed using fomepizole instead of ethanol in
patients without kidney failure [7,41]. The appar-
ent half-life of ethylene glycol during antidotal
therapy depends on urine output and the degree of
renal impairment. Although fomepizole in many
places has replaced ethanol as the antidote of
choice in ethylene glycol poisoning [34,35,42],
ethanol still may be used in some hospitals.
Patients with CNS depression must be closely
monitored if ethanol is given because this admin-
istration has been associated with respiratory arrest
[40]. The American Academy of Clinical Toxicol-
ogy published practice guidelines indicating that
fomepizole should be the first-line ADH inhibitor
in the treatment of serious ethylene glycol poison-
ing. Ethanol should be reserved for cases in which
fomepizole is not available or the patient is allergic
to fomepizole [43]. Note that celecoxib has a
pyrazole structure as does fomepizole. It is
unknown if there are cross reactions between the
two in cases of allergic reaction to one or the other.
In the case of patients who have had a significant
reaction to celecoxib, fomepizole should, if
needed, be administered with appropriate caution
and preparation for a possible allergic reaction.
Hemodialysis
The dialysance of ethylene glycol is well
documented [3,5,34]. As should be expected
Ethylene Glycol and Other Glycols 7

from its higher molecular weight than that of
methanol (62 d vs. 32 d), ethylene glycol is less
dialyzable than the latter (130 mL/min
vs. 160 mL/min, using a 1.6 m
2
dialyzer at blood
flow of 200 mL/min) [3,9]. The dialysance of the
toxic metabolite glycolate has also been
documented [6,21]. Because ethylene glycol has
no significant pulmonary elimination, hemodialy-
sis becomes the major route of its elimination if
renal failure is present and ADH metabolism is
blocked. Hemodialysis offers the additional pos-
sibility of eliminating the toxic metabolites, par-
ticularly glycolate, and correcting the metabolic
and electrolyte disturbances seen in these patients.
There are no studies comparing the various dialy-
sis modalities in ethylene glycol-poisoned
patients, but intermittent hemodialysis is probably
more effective than continuous renal replacement
theraphy (CRRT), as is seen in methanol poison-
ing [44]. In patients admitted late with established
renal failure and low serum ethylene glycol levels
or low osmolal gaps, CRRT may be considered
especially if the patient is hemodynamically
unstable.
If the patient is seen at an early stage (i.e.,
before severe metabolic acidosis and renal impair-
ment have developed), hemodialysis may not be
necessary, especially if fomepizole is the antidote
used [7,34,36]. Under such circumstances, fur-
ther metabolism of the glycol to its toxic metabo-
lites is inhibited, and the glycol is excreted rapidly
through the kidneys (half-life of 12–17 h). The
onset of acute renal failure may require hemodi-
alysis, CRRT, or peritoneal dialysis. The anion
glycolate may have a moderate toxicity by itself,
but it is a precursor for the nephrotoxic anion
oxalate. As such, the degree of metabolic acidosis
(reflecting glycolate levels) is an important indi-
cator of the need for dialysis and glycolate
removal [21].
As is evident from this discussion, it is not
possible to establish strict indications for hemodi-
alysis in ethylene glycol poisoning. This decision
is difficult, and an experienced clinical toxicolo-
gist should be consulted. Hemodialysis may not
be easily available in rural areas, and transport
complications associated with critically ill
patients must be taken into consideration,
especially if ethanol is the antidote given. The
introduction of fomepizole also limits the need
for hemodialysis. Because hemodialysis also
removes glycolate, the degree of metabolic acido-
sis and the renal status of the patient are more
important than the serum ethylene glycol concen-
tration as such. Most patients with normal renal
function and moderate metabolic acidosis (base
deficit <20 mmol/L) are best treated with bicar-
bonate and fomepizole, even in patients with high
serum ethylene glycol concentrations. The renal
function of these patients must be monitored
closely, however, because hemodialysis may be
necessary later if oliguric or nonoliguric renal
impairment develops. Patients with serum ethyl-
ene glycol levels of 558 mg/dL (90 mmol/L) and
moderate metabolic acidosis [36] and in one case
a patient with 700 mg/dL, a metabolic acidosis,
and a high anion gap [45] have been treated with
bicarbonate and fomepizole alone. Dialysis was,
however, claimed to be necessary to avoid com-
plications related to hyperosmolality in a case
with serum ethylene glycol of >1000 mg/dL
(161 mmol/L) [46].
When initiated, hemodialysis should be con-
tinued until the serum ethylene glycol concentra-
tion is less than 62 mg/dL (<10 mmol/L) and
there are no acid–base disturbances. (Grade III
recommendation). If blood ethylene glycol con-
centrations are not available, hemodialysis
should be continued for at least 8 h, and longer
if the acidosis is not corrected. If ethanol is used
as an antidote, persisting acidosis indicates that
too little ethanol is being given during hemodi-
alysis. If hemodialysis is not available, peritoneal
dialysis also removes ethylene glycol [47],
although far less efficiently. Hemoperfusion has
no role in the management of ethylene glycol
poisoning.
Criteria for ICU Discharge in Ethylene Glycol
Poisoning
Resolution of metabolic acidosis
Hemodynamic stability
If ethanol-treated, that treatment must be
stopped, and the patient should be not
inebriated
8 K.E. Hovda et al.

The effectiveness of fomepizole and hemodi-
alysis in an ethylene glycol poisoned patient is
shown in Fig. 3. The possibility to treat an ethyl-
ene glycol-poisoned patient with normal renal
function without hemodialysis during ongoing
fomepizole treatment is shown in Fig. 4. The
effectiveness of hemodialysis in a patient with
acute renal injury and the difficulty of dosing
ethanol is illustrated in Fig. 5.
Hypocalcemia and Seizures
The hypocalcemia associated with ethylene gly-
col poisoning may cause tetany and seizures,
which should be treated with intravenous calcium
gluconate (or chloride), usually 5 mmol IV each
time. Calcium should not be given for hypocalce-
mia per se, however, because this may increase
precipitation of calcium oxalate crystals in the
tissues (see Fig. 1). If calcium therapy is not
effective, convulsions can be treated
conventionally with benzodiazepines, or
propofol/barbiturates in the most severe cases.
Pyridoxine and Thiamine
Pyridoxine and thiamine are thought to promote
the alternative metabolism of glyoxylic acid to
nontoxic metabolites (see Fig. 1). Data supporting
this antidotal effect are sparse, however, and their
use is not routinely recommended.
Prognosis
Outcomes are excellent for ethylene glycol-
poisoned patients with early diagnosis and aggres-
sive treatment. If acute oliguric or nonoliguric
renal failure develops, the prognosis for the renal
function is always good with normalization of
serum creatinine within 2–3 weeks (rarely
months). In severe cases, patients with late
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Plasma gycolate (mmol/L)
Plasma fomepizole levels (µmol/L)
Hours
Urinar
y
oxalate levels (mmol/L)
Plasma ETOH and ethylene glycol (mg/dL)
Dose 1
Dose 3
Dose 4
Dose 2
Ethanol
Fomepizole
Ethylene glycol
Glycolate
Oxalate
Hemodialysis
Fig. 3 Serial plasma glycolate, fomepizole, ethanol, and
ethylene glycol concentrations and urinary oxalate excre-
tion in a 35-year-old woman who presented 6 h after
ingesting antifreeze in an attempt at suicide. Her initial
arterial pH was 7.42. She was treated with fomepizole,
underwent hemodialysis twice (initially for 4 h and subse-
quently for 2 h), and recovered uneventfully. To convert
the values for plasma ethylene glycol to millimoles per
liter, multiply by 0.161. To convert the values for plasma
glycolate to millimoles per liter, multiply by 0.132. To
convert the values for serum creatinine to micromoles per
liter, multiply by 88.4. To convert the values for plasma
ethanol to millimoles per liter, multiply by 0.217 (From
Brent et al. [34], 832–839)
Ethylene Glycol and Other Glycols 9

diagnosis and treatment may experience cerebral
infarcts [9,48].
It is important to note that in some severe cases,
the prognosis may seem to be rather poor based on
the overall clinical situation. If proper treatment is
provided, especially dialysis in the acute stage
with correction of acidosis (and removal of toxic
metabolites), prognosis may be good even after
weeks on mechanical ventilation and dialysis for
acute renal failure. Treatment in the ICU must
therefore not be discontinued early in these
patients. A possible explanation for this could be
that the extravascular precipitation of oxalate
crystals causes a massive tissue edema (also in
the brain) and that it takes time for this to resolve.
Also, the crystals in the tissue and the cells may
dissolve over time [49], which may partly explain
the pathophysiology.
Special Populations
The toxicity of ethylene glycol in pediatric
patients should generally be treated in a manner
similar to that in adults. The experience with
fomepizole in children is limited, but cases have
been published, and ethanol [8] and fomepizole
both seem to be effective antidotes in children [47,
50,51]. Use of new drugs such as fomepizole is
generally discouraged in the first trimester of
pregnancy, but in a study in pregnant rats [52],
no adverse effects of fomepizole were reported.
However, the alternative antidote ethanol has
documented ability to cause fetal harm. In a preg-
nant woman with severe ethylene glycol poison-
ing, an antidote is obligatory, and either could be
used –with a preference for fomepizole
[22]. (Grade III recommendation)
Common Errors in Ethylene Glycol Poisoning
Delayed diagnosis because of failing to con-
sider ethylene glycol poisoning in the differ-
ential diagnosis of high anion gap metabolic
acidosis of unknown origin
Failure to appreciate that the absence of
early clinical features and the presence of nor-
mal anion or osmolal gaps do not exclude a
potentially toxic ethylene glycol ingestion
(continued)
Fig. 4 S-ethylene glycol in healthy female treated with
fomepizole and bicarbonate alone [7]. Note probable ongo-
ing absorption due to early admission. Note also increasing
S-glycolate before –and declining S-glycolate after –
fomepizole administration. Half-lives of S-ethylene glycol
and S-glycolate during ADH inhibition were 10 and 2.4 h,
respectively. The excellent correlation between S-ethylene
glycol and osmolal gaps is also illustrated. Conversion
factor mg/dL to mmol/L: EG: 0.016, glycolic acid: 0.013
(Reprinted with permission from Hovda et al. [7])
10 K.E. Hovda et al.

Failure to give enough ethanol, if this is the
antidote chosen, especially during
hemodialysis
Failure to closely monitor blood ethanol
concentrations, if this antidote is used
Failure to appreciate that prognosis may be
good even in critically ill patients and over
long periods if correct treatment is given
Failure to stay at the bedside until bicarbon-
ate and antidotal therapy have been initiated
because time is critical in severely poisoned
patients
Key Points in Ethylene Glycol Poisoning
1. Ethylene glycol toxicity is caused by its
metabolites.
2. The initial step in ethylene glycol metabo-
lism is catalysis by alcohol dehydrogenase.
3. Treatment is based on inhibition of alcohol
dehydrogenase, correction of metabolic
acidosis, and removal of glycol and toxic
metabolites by dialysis.
Diethylene Glycol
The clinical course and the pathologic features of
poisoning with diethylene glycol (Fig. 6) have
been described in some reports, among which
“the 1937 sulfanilamide Massengill disaster”is
probably the best known [53]. In that instance,
diethylene glycol (73 %) was used, because of a
lack of knowledge of its toxicity, as the vehicle for
preparing a liquid formulation of 10 %
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0
5
10
15
20
25
30
35
0 10 20 30 40 50
Serum ethylene glycol (mmol/L)
Serum ethanol (g/L)
Time from admission (hours)
S-ethylene glycol (mmol/L) HDEthanol infusion S-Ethanol (g/L)
HD
Ethanol infusion
Fig. 5 Healthy adult male presenting with metabolic aci-
dosis of unknown origin (gave no history). Elevated osmo-
lal (30) and anion gaps (42; base deficit 21 mmol/L) and
oxalate crystalluria indicated diagnosis (ethylene glycol
measured later). He was treated with bicarbonate, ethanol
and hemodialysis (HD) with uneventful recovery. Note
dosing problems and variations in S-ethanol during
dialysis. Also note long half-life of S-ethylene glycol
after terminated dialysis (ongoing ADH inhibition)
because of transient acute kidney injury (AKI; no further
dialysis necessary). As such, buffer and ADH inhibition
would not have been sufficient treatment in this case with
AKI. Conversion factor mg/dL to mmol/L: EG: 0.016
Ethylene Glycol and Other Glycols 11

sulfanilamide to treat infections. A total of
105 deaths due to renal failure were related to
this sulfonamide formulation. No oxalate crystals
were reported found in the kidneys or other organs
of these victims, but the variety of the oxalate
crystals (not only the envelope form) was proba-
bly not known for most clinicians before 1980
[33,54]. Except for the lack of oxalate crystals,
the pathologic findings in the various organs of
these victims were similar to those found in eth-
ylene glycol-poisoned victims.
In the 1995 Haitian episode, diethylene glycol-
contaminated acetaminophen syrup caused renal
failure in more than 100 children with a high
mortality rate [55]. A similar episode also
occurred in India [56] and in Panama in 2006
where an estimated minimum of 78 deaths were
associated with consumption of a diethylene
glycol-contaminated cough syrup [57]. The clini-
cal features were renal failure, hepatitis, pancrea-
titis, bilateral peripheral neuropathy, and coma
before death. Diethylene glycol is also found in
brake fluids and other consumer products, such
that sporadic ingestions also occur [58]. Because
of the acute renal failure, it is difficult to relate the
metabolic acidosis reported in some cases [59] to
possible acidic metabolites of diethylene glycol
metabolism by ADH. In one case report, there is
an indication of a positive effect from hemodialy-
sis for the removal of diethylene glycol [50]. In
another case report, the use of fomepizole was
associated with correction of the metabolic acido-
sis [60]. Topical application of silver sulfadiazine
contaminated with diethylene glycol to patients
with burns resulted in increased anion gap meta-
bolic acidosis and acute renal failure. All five
patients in this report died despite supportive
treatment and bicarbonate replacement
[61]. Autopsy was performed in one patient and
no calcium oxalate crystals were observed.
Pathophysiology of Toxic Effects
Experimental studies in rats exposed to diethylene
glycol showed similarities to ethylene glycol tox-
icity [62,63]. The animals developed metabolic
acidosis, as in ethylene glycol toxicity. Mortality
was reduced if the animals were treated with
bicarbonate, while administration of ethanol or
fomepizole both prevented metabolic acidosis
and reduced mortality to nil. Later studies in ani-
mals have demonstrated that diethylene glycol is
metabolized to 2-hydroxyethoxyacetic acid,
which is responsible for the metabolic acidosis
[62] and further to diglycolic acid (DGA), which
accumulates markedly in the kidney and is the
nephrotoxic metabolite [64]. No evidence that
oxalate deposition actually occurs was noted,
likely because the ether is generally resistant to
metabolic degradation. During the Panama epi-
demic, urine and serum samples were collected
as part of a case–control study such that the sam-
ples were collected late in the course (post case
definition) [65]. These serum and urine samples
were analyzed for concentrations of diethylene
glycol and its metabolites –DGA was the only
metabolite that was statistically related to case
status. The serum and urine samples showed no
evidence of conversion of diethylene glycol to
ethylene glycol in humans. As such, DGA is of
likely importance in human cases also.
Clinical Presentation and Life-
Threatening Complications
In humans exposed to diethylene glycol, the pres-
ence of acidosis was earlier questioned, but this
may be due to the fact that these fatal cases were
reported by pathologists with less emphasis on the
clinical and metabolic features present prior to
death [66]. Later studies have shown metabolic
acidosis and gastrointestinal features followed by
acute kidney injury after 1–3 days. In survivors,
neurological features such as bilateral facial nerve
palsy and peripheral neuropathy, coma, and death
may develop after 5–7 days [67].
Diagnosis
If there is no history of ingestion of diethylene
glycol, diagnosing this condition is difficult.
There is no general laboratory analysis pointing
to this diagnosis, except for specific analysis,
which is rarely available in hospital laboratories.
Clinical features that may suggest diethylene
12 K.E. Hovda et al.

glycol would include acute kidney injury or bilat-
eral facial nerve palsy or other neurological fea-
tures. These patients should be observed for the
development of metabolic acidosis (elevated
anion gap), which should trigger treatment.
Since the molecular weight is higher (106 g/mol,
1 g/L =9 mmol/L which increases the osmolal
gap with only 10 mOsm/kg H
2
O) than for the
other alcohols that form toxic metabolites (meth-
anol and ethylene glycol), calculation of the
osmolal gap is likely less useful (see “▶Methanol
and Formaldehyde,”Table 1).
Treatment
The toxicities of ethylene glycol and diethylene
glycol are similar in that the metabolic acidosis
and kidney injury result from metabolism of the
parent compound via ADH. At present, treatment
of diethylene glycol poisoning should be as for
ethylene glycol poisonings: bicarbonate and
ADH inhibition should be given if metabolic aci-
dosis is moderate or severe (base deficit >
10 mmol/L) (Grade III recommendation); hemo-
dialysis should be performed in severely poisoned
patients, especially if metabolic acidosis is pro-
nounced (base deficit >15–20 mmol/L) or with
evidence of renal injury. Assuming no protein
binding of diethylene glycol and a volume of
distribution close to 0.6 L/kg, this compound
(MW 106 g/mol) should be removed by hemodi-
alysis, which will correct acidosis and likely
remove toxic metabolites. Because no strict treat-
ment recommendations can be given, physicians
dealing with these patients should consult a med-
ical toxicologist or a poison center. Further treat-
ment is supportive. Although not documented,
thiamine should be given to protect the patient
from neurological complications –especially if
ethanol abuse is present.
Polyethylene Glycol
The polyethylene glycols (see Fig. 6) (molecular
weight approximately 400–4000 g/mol) can be
liquids, but are solid when the molecular weight
is greater than 1000 g/mol. The toxicity decreases
with increasing molecular weight, probably as a
result of poor absorption of the solid forms. In
general, the toxicity is low but may be significant
for the glycols with low-molecular weight. The
polyethylene glycols are used as solvents or
excipients for different purposes. They also are
used, and well tolerated, in the electrolyte solution
recommended for whole-bowel irrigation [68].
Little is known about the clinical features of
polyethylene glycol poisonings, because few
cases have been reported in peer-reviewed
Fig. 6 Chemical structures
of common glycols and
glycol ethers
Ethylene Glycol and Other Glycols 13

literature. The reported CNS depression, meta-
bolic acidosis, and renal failure may point to
some similarities with ethylene glycol
poisoning [69].
Unexplained increased anion- and osmolal
gaps were observed in three burn patients who
died following a treatment with a polyethylene
glycol-based burn cream. All three patients died
in acute renal failure. The concentrations of eth-
ylene glycol found in the circulation of two
patients (0.4–1.3 mmol/L) were unlikely to
explain the osmolal or anion gaps; no oxalate
crystals were reported in the kidney upon autopsy
[70]. The authors attributed the toxicity to the
effects of polyethylene glycols or their metabo-
lites, not to ethylene glycol per se.
Treatment
The standard measures of gastric decontamination
and supportive care are probably the mainstay of
therapy in these rare poisonings if the patient is
seen within 1 h. The efficacy of hemodialysis is
hampered by the relatively high molecular weight
of this group, but hemodialysis should be done if
low-molecular-weight glycols are ingested
(molecular weight <600 g/mol). If severe meta-
bolic acidosis develops, fomepizole or ethanol
treatment may be administered as in ethylene gly-
col poisoning, but the efficacy of this treatment
has not been documented. Sodium bicarbonate
should be given to correct severe metabolic
acidosis.
Propylene Glycol
The use of propylene glycol (1,2-propanediol)
(see Fig. 6) in various cosmetics has little toxico-
logical significance. Its use as a solvent for intra-
venous drug formulations has shown that this
compound is not completely inert from a toxico-
logical point of view. Renal failure may result in
retention of the glycol, causing CNS depression,
as about 50 % is excreted in unchanged form by
the kidneys, whereas the rest is metabolized
mainly to lactate, acetate, and pyruvate [71]. Met-
abolic acidosis may be pronounced because of its
metabolism to lactate, and concentrations as high
as 24 mmol/L (216 mg/dl) has been described
when iv medications were given with propylene
glycol as a vehicle [72]. One case also reports D-
lactate levels up to 110 mmol/L from an overdose
of propylene glycol [73]. The elimination half-life
is about 19 h [74]. In two children, CNS depres-
sion and seizures were observed after propylene
glycol intoxication [75]. Propylene glycol is also
found as a diluent in many drugs. One 50 year-old
male with a iatrogenic overdose of lorazepam
resulted in severe propylene glycol poisoning
(peak level 659 mg/dL (87 mmol/L), pH 6.9,
bicarbonate 5 mmol/L (5 mEq/L) and lactate
19 mmol/L). He was treated with fomepizole,
continuous renal replacement therapy (CRRT)
and CVVH. His metabolic acidosis resolved, but
he died from anoxic brain injury [76].
Propylene glycol (molecular weight 76 g/mol)
also may raise the osmolal gap (see “▶Methanol
and Formaldehyde,”Table 1). If lactic acidosis
develops, this rare poisoning may raise the osmo-
lal and the anion gaps. Propylene glycol concen-
trations of 760 mg/dL (100 mmol/L) did not cause
CNS depression [77], whereas stupor and meta-
bolic acidosis were present in a patient with serum
propylene glycol concentrations of 70 mg/dL
(9 mmol/L) [78]. In these two cases, the osmolal
gap theoretically would be elevated by about
108 mOsm/kg H
2
O (100/0.93) and 10 mOsm/kg
H
2
O (9/0.93). From these few cases, there does
not seem to be any definite correlation between
serum propylene glycol levels and toxicity.
Treatment
Treatment of propylene glycol poisoning is sup-
portive. The effect of activated charcoal has not
been documented. Hemodialysis will effectively
remove propylene glycol in the rare cases where
propylene glycol can cause severe
poisonings [79].
14 K.E. Hovda et al.

Alkyl Ethers of Ethylene Glycol
(Cellosolves)
The group of alkyl ethers of ethylene glycol con-
sists of the mono alkyl ethers of ethylene glycol –
ethylene glycol butyl ether (butyl glycol, Butyl
Cellosolve), ethylene glycol monomethyl ether
(methyl Cellosolve), and ethylene glycol
monoethyl ether (Cellosolve) (see Fig. 6). These
compounds are used mainly as solvents in hydrau-
lic fluids and in household cleaning products. Few
cases of toxicity from these compounds have been
published, and the mechanisms of toxicity are not
completely understood. Coma, hypotension, and
metabolic acidosis with hyperventilation are typ-
ical clinical signs of intoxication. The abnormal
blood picture, including erythropenia,
granulocytosis, hemolysis, and hemoglobinuria,
seen in animals [80,81] may also be seen in the
clinical situation [82]. Until more data are avail-
able, supportive treatment is considered to be
most important for this group of compounds.
Ethylene glycol butyl ether, also known as
butyl glycol, poisoning has been reported after
the suicidal ingestion of a window-cleaning
agent containing butyl glycol and ethanol
[82]. Coma and hypotension were present on
admission with blood levels of ethylene glycol
butyl ether and ethanol being 432 mg/L and
36 mg/L, respectively. Metabolic acidosis devel-
oped and was confirmed by the presence of the
butyl glycol metabolite butoxyacetic acid and lac-
tate. No increase in urine oxalate content was
observed. The patient was treated with forced
diuresis, bicarbonate, and hemodialysis. There
was a suggestion of ethanol-induced inhibition
of butyl glycol metabolism and a beneficial effect
of hemodialysis in this patient.
In another case without concomitant ethanol
ingestion, metabolic acidosis was accompanied
by coma, hypokalemia, hemoglobinuria, oxaluria,
and a transitory rise in the serum creatinine level
in a patient who survived on supportive therapy
alone [83]. The measured increased urinary excre-
tion of oxalate and butoxyacetic acid in this case
gives an indication of different metabolic
pathways, one of which includes degradation of
ethylene glycol butyl ether to ethylene glycol.
Two patients with methyl Cellosolve ingestion
developed metabolic acidosis and coma [84]. The
patient with the more severe metabolic acidosis
developed slight acute renal failure, and urine
oxalate crystals were observed. The other patient
had no evidence of renal effect or oxalate crystals
in the urine. Both patients had an uneventful
recovery after treatment with bicarbonate and
ethanol.
Treatment
Based on these case reports and overall theoretical
considerations, it seems reasonable to treat these
poisonings with supportive therapy, including
possibly gastric decontamination if the patient is
seen early (within 1 h), and bicarbonate to correct
significant metabolic acidosis (base deficit >
10 mmol/L). Hemodialysis also seems justified if
large doses are ingested and the patient is acidotic.
The role of hemodialysis in these poisonings is
theoretical and lacks empiric validation. The role
of ADH inhibitors is controversial. Until more
data are available, ADH inhibitors should be con-
sidered mostly in rare cases in which metabolic
acidosis develops, to prevent an assumed forma-
tion of toxic metabolites by oxidation of the alco-
hol groups.
Because the role of ADH in the metabolism of
these compounds is not clear, and because
fomepizole is expensive in some countries, some
clinicians may prefer to use ethanol. If ethanol is
used, however, patients must be placed in an
intensive care unit and monitored closely as
described previously.
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