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1 30th January 15:34
pureheart
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Default Ethylene Glycol Intoxication: Case Report and Pharmacokinetic Perspectives (lactate dehydrogenase)


Ethylene Glycol Intoxication: Case Report and Pharmacokinetic
Perspectives
Posted 02/20/2004
Nina Vasavada, M.D.; Craig Williams, Pharm.D.; Richard N. Hellman,
M.D.
Abstract and Introduction
Abstract

A 42-year-old man was brought to the emergency department with
ethylene glycol intoxication. He was hemodynamically stable and had
normal renal function. His serum ethylene glycol concentration was
284 mg/dl approximately 1 hour after ethylene glycol consumption. The
patient was treated with fomepizole and forced diuresis. Elimination
of ethylene glycol in this patient followed first-order
pharmacokinetics. Elimination pharmacokinetics in this patient were
compared with that in a patient who received fomepizole and
hemodialysis. Fomepizole monotherapy can be given in patients without
renal failure or metabolic acidosis even with serum ethylene glycol
concentrations greater than 50 mg/dl. However, cost estimates based
on this case suggest that if the patient is treated adequately with a
single hemodialysis session and 24-hour hospitalization, then
fomepizole monotherapy may be more expensive than the combination
regimen of fomepizole and hemodialysis.

Introduction

Ethylene glycol is an odorless volatile alcohol found in automotive
products such as antifreeze. Adults generally ingest ethylene glycol
as a source of inebriation or as a means of attempted suicide.

In 2001, 5833 ethylene glycol exposures were reported to the American
Association of Poison Control Centers. Of these, 850 occurred in
children younger than 6 years. Seven hundred eighty-six exposures
occurred in individuals aged 6-19 years, and 4131 exposures occurred
in adults older than 19 years. Age of the individual was not reported
for 66 of the exposures. Two hundred twenty-two individuals (3.8%)
experienced a major outcome, defined as signs or symptoms resulting
from the exposure that were life-threatening or caused significant
residual disability or disfigurement. Thirty-four individuals died as
a result of the exposure or related complications.[1]

Treatment recommendations for ethylene glycol intoxication include
inhibition of alcohol dehydrogenase (ADH) with or without accelerated
blood clearance by hemodialysis. Hemodialysis is recommended if severe
metabolic acidosis (pH < 7.3) unresponsive to therapy or renal failure
exists, or if the ethylene glycol concentration is greater than 50
mg/dl unless fomepizole is being administered and the patient is
asymptomatic with a normal arterial pH.[2]

Traditionally, ethanol has been administered to inhibit ADH. The
target plasma ethanol concen-tration that provides ADH inhibition is
100-125 mg/dl.[3] The serum ethanol concentration must be measured
frequently, as the rate of ethanol metabolism is unpredictable.[4]
Ethanol therapy may result in inebriation, hypoglycemia, obtundation,
or myocardial depression; hence, patients must be monitored closely in
an intensive care unit. In addition, patients with ethylene glycol
toxicity may have underlying alcoholic cardiomyopathy or liver
disease, both relative contraindications for therapy with ethanol.

Fomepizole (4-methylpyrazole, Antizol; Orphan Medical, Minnetonka, MN)
is a competitive inhibitor of ADH and was approved by the United
States Food and Drug Administration in 1997 for the treatment of
ethylene glycol poisoning. Alcohol dehydrogenase has an 8000-fold
greater affinity for fomepizole than for ethanol.[5] The presence of
ethanol has no significant effect on the elimination of ethylene
glycol in the presence of fomepizole,[6] demonstrating the high degree
of competitive inhibition of ADH by fomepizole.

Ethylene glycol follows first-order elimination pharmacokinetics in
the presence of ADH inhibition, with an elimination half-life of 16.8
hours in patients with normal renal function.[6] Renal clearance is
proportional to creatinine clearance, with a fractional excretion of
ethylene glycol of 26%, which allows the use of serum creatinine level
on presentation to determine which patients may need hemodialysis to
accelerate elimination.[6]

Hemodialysis clears ethylene glycol but imposes risk, such as that of
hypotension[7] or dialyzer reactions,[8] as well as expense.
Hemodialysis traditionally has been recommended for patients with
plasma ethylene glycol concentrations greater than 50 mg/dl.[2]
However, recent pharmacokinetic evaluations suggest that hemodialysis
may not be necessary in all patients with serum ethylene glycol
concentrations in this range.[6] We report a case of acute ethylene
glycol intoxication in a 42-year-old man who at presentation had a
serum concentration of 284 mg/dl, hemodynamic stability, normal renal
function, and absence of metabolic acidosis. The patient demonstrated
resolution of toxicity with fomepizole monotherapy. This clinical
experience exemplifies the efficacy of fomepizole monotherapy for
ethylene glycol toxicity in selected patients.

The elimination pharmacokinetics of ethylene glycol from a similar
patient treated with both fomepizole and hemodialysis are given for
comparison and highlight the expected rapidity of blood clearance of
ethylene glycol with hemodialysis. The accelerated blood clearance by
hemodialysis provides for a shorter hospital stay and fewer required
doses of ADH inhibitors. Cost estimates of these differences based on
our patient reveal lower expense when hemodialysis is given with ADH
inhibition if hospitalization and ADH inhibition are required for only
24 hours and if a single session of hemodialysis adequately clears the
blood of ethylene glycol.


Case Report

A 42-year-old Caucasian man was found intoxicated under a bridge and
was brought to a local emergency department. The patient admitted to
consuming approximately 1 pint of vodka followed by approximately 1
pint of antifreeze in a suicide attempt 1 hour before coming to the
emergency department. He denied other toxic ingestions, nausea, or
vomiting and voiced no other physical complaints. His medical history
revealed hepatitis C, depression, anxiety, and polysubstance abuse
including tobacco, ethanol, and cocaine (in the past). His only
routine drug therapy was buspirone. Initial vital signs revealed a
temperature of 97.5F, heart rate 94 beats/minute, blood pressure
139/81 mm Hg, and respiratory rate 16 breaths/minute. The patient's
height was 70 inches and weight was 85 kg. Physical examination was
significant for rotary nystagmus and mild hepatomegaly. Kussmaul
respirations, fruity odor, rash, cardiac gallops, pericardial rub,
pulmonary rales, abdominal tenderness, peripheral edema, and tetanic
contractions were absent.

Initial laboratory data obtained from serum revealed the following:
ethanol concentration 181 mg/dl, ethylene glycol concentration 284
mg/dl, sodium 143 mEq/L (normal range 137-145 mEq/L), potassium 3.7
mEq/L (3.5-5.5 mEq/L), carbon dioxide 23 mEq/L (22-27 mEq/L), urea
nitrogen 8 mg/dl (5-20 mg/dl), creatinine 1.0 mg/dl (0.8-1.4 mg/dl),
calcium 7.9 mg/dl (8.4-10.6 mg/dl), albumin 3.8 g/dl (3.5-5.0 g/dl),
and glucose 153 mg/dl (65-110 mg/dl). Neither an arterial nor a venous
blood gas measurement was performed. Calculated serum osmolarity was
297 mOsm/L and measured serum osmolality 425 mOsm/kg, yielding an
osmol gap of 128. Serum and urine toxicology screens were negative for
cocaine, salicylates, barbiturates, benzodiazepines, and other
volatile alcohols. Microscopic examination of the urine did not reveal
calcium oxalate crystals. An electrocardiogram demonstrated sinus
tachycardia at 105 beats/minute with a corrected QT interval of 387
msec.

On arrival to the emergency department, the patient received
fomepizole 15 mg/kg as an intravenous loading dose, followed by
10-mg/kg maintenance doses every 12 hours for a total of four doses,
then one additional 15-mg/kg dose 12 hours later. The patient did not
receive any intravenous infusions such as lorazepam, which contain
propylene glycol as an additive. The patient was administered isotonic
saline on hospital days 2 and 3, and each day produced a minimum urine
output of 90 ml/hour. Other therapies consisted of multivitamins. At
no point did the patient receive any form of dialysis. His serum
creatinine level consistently remained from 0.8-1.0 mg/dl, and serum
bicarbonate remained 22-24 mEq/L. Relevant laboratory values during
the patient's hospitalization are shown in Table 1. Elimination of
ethylene glycol from the blood followed first-order pharmacokinetics,
as shown in Figure 1. On hospital day 4, the patient was discharged to
an inpatient psychiatric facility for further care.

Discussion

The successful medical management of ethylene glycol toxicity is based
on early recognition of the extent of toxicity of metabolites of
ethylene glycol in the individual patient. This assessment is critical
in determining the necessity of ADH inhibition and hemodialysis.
Similar treatment guidelines apply after the ingestion of other toxic
alcohols such as methanol. Our comparative ****ysis of care options at
an urban inner city hospital demonstrates cost differences among
various the****utic approaches.
Ethylene Glycol Pharmacokinetics and Toxicity

Ethylene glycol is highly miscible in water, with an oral
bioavailability of 92-100% in animal studies.[9] It distributes into
the total body water with a volume of distribution of 0.5-0.8 L/kg.[2]
The toxicity of ethylene glycol relates to its metabolism by ADH to
various acidic metabolites. Ethylene glycol itself exerts no obvious
cytotoxicity on either isolated murine proximal tubular cells
(measured by cellular release of lactate dehydrogenase [LDH]) or to
cultured human proximal tubular cells.[10] Observational studies have
not demonstrated a predictable relationship between serum ethylene
glycol concentration and anion gap, pH, or bicarbonate
concentration.[11]

Without inhibition of ADH, hepatic metabolism accounts for
approximately 80% of ethylene glycol elimination, with the remaining
20% being eliminated unchanged in urine.[2] Elimination of ethylene
glycol has been demonstrated to follow first-order pharmacokinetics
between serum concentrations of 3.5 and 211 mg/dl.[6] Patients with
abnormal kidney function (mean SD serum creatinine level 2.24 0.21
mg/dl) experience a longer elimination half-life (48.9 5.7 hrs) than
that of patients with normal kidney function (16.8 0.8 hrs).[6]

An overview of the metabolism of ethylene glycol is illustrated in
Figure 2. In the first step of metabolism, ADH oxidizes ethylene
glycol to glycoaldehyde. The addition of glycoaldehyde to cultured
murine and human proximal tubular cells demonstrates cytotoxicity
through increasing LDH release, decreasing adenosine triphosphate
(ATP) concentration, and altering plasma membrane phospholipids.[10]

Aldehyde dehydrogenase converts glycoaldehyde to glycolate, which
subsequently is converted to glyoxylate in the rate-limiting step of
ethylene glycol metabolism. The ac***ulation of glycolate induces the
metabolic acidosis associated with ethylene glycol toxicity.[10] The
endogenous elimination half-life of glycolate is 7 hours; hemodialysis
reduces this to 2.4-3.6 hours.[12] A predictable relationship has been
observed between initial serum glycolate concentration and anion gap,
but not pH or bicarbonate.[12] The toxicity of glycolate is unclear.
In vivo studies correlate serum glycolate concentrations with central
nervous system toxicity and acute renal failure.[11] In vitro studies,
however, demonstrate a lack of significant cytotoxicity based on LDH
release by isolated murine proximal tubular cells and cultured human
proximal tubular cells.[10]

The next metabolite, glyoxylate, induces cytotoxicity to isolated
murine proximal tubular cells, as measured by LDH release and
reduction in cellular ATP content, as well as to cultured human
proximal tubular cells.[10] In vivo toxicity remains undefined.

Glyoxylate is metabolized to the final product, oxalate. In vitro
toxicity of oxalate remains unclear. Some studies found that oxalate
exerted cytotoxicity to human proximal tubular cell cultures.[13] A
more recent in vitro study demonstrated that oxalate additions were
not cytotoxic to isolated murine proximal tubular cells or to cultured
human proximal tubular cells.[10] This discrepancy suggests that
oxalate may cause acute renal failure through cast formation rather
than direct cytotoxicity.[10] A common histologic abnormality of
ethylene glycol-induced acute renal failure is intraluminal oxalate
crystal ac***ulation. The observation that proximal tubular cell
injury correlates poorly with intensity of oxalate deposition suggests
toxicity of precursor metabolites.

In vivo, oxalate has the potential to exert numerous toxicities.
Gastrointestinal irritation may occur by means of calcium oxalate
deposits in the intestinal mucosa. As with ethanol, central nervous
system depression may occur. Deposition of calcium oxalate crystals in
the myocardium, along with interstitial edema and acidosis, may cause
myocardial dysfunction. Oxalate chelates calcium, which may result in
hypocalcemia with subsequent seizures and electrocardiographic
abnormalities such as QT interval prolongation, which predispose the
patient to ventricular arrhythmias.[2] Anion gap metabolic acidosis
develops from the formation of acidic metabolites, as well as the
ac***ulation of lactate. The oxidative metabolism of ethylene glycol
depletes the oxidized form of nicotinamide adenine dinucleotide (NAD+)
and reduces the biologically significant ratio of NAD+: nicotinamide
adenine dinucleotide. This reduction inhibits the citric acid cycle
and increases lactic acid production through anaerobic metabolism.
The****utic Strategies

Alcohol dehydrogenase inhibition is a cornerstone of therapy whenever
serum ethylene glycol levels are above 20 mg/dl, as this implies the
risk for generating toxic quantities of metabolites. Alcohol
dehydrogenase inhibitors should be administered during the treatment
of ethylene glycol poisoning if one the following three criteria
exist: do***ented plasma ethylene glycol concentration greater than 20
mg/dl, do***ented recent (hrs) history of ingesting toxic amounts of
ethylene glycol and an osmol gap greater than 10, history or strong
clinical suspicion of ethylene glycol poisoning. In addition, at least
two of the following criteria should be present: arterial pH less than
7.3, serum bicarbonate less than 20 mEq/L, osmol gap greater than 10,
or presence of urinary calcium oxalate crystals.[2] Administration of
the ADH inhibitor should continue until the serum ethylene glycol
concentration is less than 20 mg/dl and the patient is asymptomatic
with normal arterial pH.[2]

Agents given for ADH inhibition include fomepizole and ethanol.
Fomepizole is preferred over ethanol when the patient has ingested
multiple substances and has a depressed level of consciousness, the
patient has altered consciousness, or the hospital has inadequate
intensive care staffing or laboratory support to monitor ethanol
administration. Relative contraindications to ethanol include a
critically ill patient with anion gap metabolic acidosis of unknown
cause or patients with active hepatic disease, alcoholic
cardiomyopathy, or chronic heart failure. Ethanol is advocated over
fomepizole when a known hypersensitivity to fomepizole exists. In the
presence of fomepizole, the elimination half-life of ethylene glycol
is 19.7 hours.[6]

Accelerated blood clearance of ethylene glycol and its metabolites by
hemodialysis is indicated when there is severe metabolic acidosis (pH
< 7.3) unresponsive to medical therapy, renal failure, or a serum
ethylene glycol concentration greater than 50 mg/dl. Hemodialysis is
unnecessary if fomepizole is being administered and the patient is
asymptomatic with normal arterial pH. Supportive measures include
correcting fluid deficits, forced diuresis, correcting acidosis (pH <
7.3) with intravenous bicarbonate, and replacing magnesium, thiamine,
and pyridoxine in depleted patients. In addition, close monitoring is
required if an ethanol infusion is to be given. Patients should be
placed in an intensive care unit or similar setting and monitored for
metabolic acidosis, alterations in vital signs, and abnormal serum
laboratory values including glucose and electrolytes. Also, serum
ethanol concentrations must be monitored.[2] Hemodialysis accelerates
blood clearance of ethylene glycol, yielding an elimination half-life
of 2.68 0.22 hours.[6]
Comparative Pharmacokinetics and Cost Estimation

The elimination pharmacokinetics in our patient were compared with
those in a second patient admitted to our institution who received
fomepizole with hemodialysis after antifreeze ingestion. This second
patient was a 45-year-old man who came to the emergency department 15
hours after having consumed approximately 600 ml of antifreeze in a
suicide attempt. Nine hours after ingesting the antifreeze, the
patient consumed several servings of ethanol as well. He was
hemodynamically stable and weighed 53 kg. On admission, he received
fomepizole 15 mg/kg and underwent hemodialysis with an F80 dialyzer
(Fresenius Medical Care North America, Lexington, MA) for 6 hours at a
blood flow rate of 400 ml/minute through a temporary femoral venous
hemodialysis catheter. The patient subsequently received fomepizole 10
mg/kg during hemodialysis at 5 and 9 hours after presentation and was
discharged 2 days after admission. As demonstrated in Table 2,
hemodialysis dramatically shortened the elimination half-life of
ethylene glycol from 15.3 to 3.15 hours.

Table 3 demonstrates cost estimates based on our initial patient had
he been treated with various the****utic modalities. Data estimating
duration of hemodialysis required for blood clearance of ethylene
glycol are calculated based on the initial serum concentration, type
of dialyzer used, and total body water.[14] Cost data were obtained
from an inner city county hospital. As illustrated in Table 3, in the
selected setting of a hemodynamically stable patient with normal renal
function and arterial pH, fomepizole monotherapy provides an
alternative therapy for ethylene glycol intoxication compared with ADH
inhibition (ethanol or fomepizole) with hemodialysis, although cost is
higher due to longer duration of hospitalization and ADH inhibition.

Patient consumption of ethanol at the time of ethylene glycol intake
limits our ****ysis. It is possible that the patient's
self-administration of ethanol inhibited ADH, subsequently minimizing
the development of acidosis and toxicity by metabolites of ethylene
glycol. The ethylene glycol and ethanol serum concentrations on
presentation do not fully account for the measured serum osmolality,
which may reflect laboratory error or unmeasured osmotically active
substances.[15]

Conclusion

This clinical experience illustrates the efficacy of fomepizole
monotherapy in a patient with elevated serum ethylene glycol
concentration, normal kidney function, hemodynamic stability, and
absence of acidosis at presentation. This case reaffirms recent data
about the safety and efficacy of fomepizole therapy even in patients
with serum ethylene glycol concentrations greater than 50 mg/dl.[16]
Cost factors may favor ADH inhibition in conjunction with hemodialysis
if only one session of hemodialysis and one day of hospitalization are
required.

Acknowledgements

We thank Dr. Mary Margolis for sharing case material and Dr. Bruce
Molitoris for his helpful comments on the manuscript.
Reprint Address

Address reprint requests to Nina Vasavada, M.D., 10733 Worthington
Lane, Prospect, KY 40059; e-mail: nina_vasavada_panchal@hotmail.com.

http://www.medscape.com/viewarticle/465881?mpid=25381
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