V 20TH ANNIVERSARY
11 November 1999
CE Refereed Peer Review
FOCAL POINT
★The pathologic effects and
associated clinical signs of acute
ethylene glycol (EG) intoxication,
including hyperosmolality,
metabolic acidosis, and acute
renal failure, are caused by both
EG and the products of its
metabolism.
KEY FACTS
■ Ingestion of as little as 4.4 to
6.6 ml/kg of EG in dogs and
1.5 ml/kg in cats may be
lethal.
■ The metabolites of EG,
particularly glycolate, are
responsible for most of the
associated clinical toxicity.
■ The clinical syndrome of acute
EG intoxication occurs in three
stages; however, the onset and
progression of these stages are
variable and unpredictable.
■ Acute oliguric renal failure can
occur as early as 12 and 24
hours after ingestion of EG in
cats and dogs, respectively.
Vol. 21, No.
Acute Ethylene Glycol
Intoxication. Part I.
Pathophysiology and
Clinical Stages
Tufts University
Alison R. Gaynor, DVM
Nishi Dhupa, BVM, MRCVS
ABSTRACT: Acute ethylene glycol (EG) intoxication is a life-threatening medical emergency
characterized by hyperosmolality, profound high anion gap metabolic acidosis, and oliguric or
anuric renal failure. Toxic effects and associated clinical signs of this syndrome are caused by
both EG and its metabolites, particularly glycolate; however, there is confusion in the medical
(human and veterinary) literature regarding the various metabolites of EG and their putative
roles in the pathophysiology of this devastating syndrome.
A
serious medical emergency in both veterinary and human medicine,
ethylene glycol (EG) intoxication is characterized by hyperosmolality,
profound metabolic acidosis, and oliguric or anuric renal failure. Also
known as 1,2-ethanediol,1–4 EG is a clear, colorless, odorless, water-soluble liquid
that is commonly used as a permanent-type antifreeze.5–7 The compound is also
widely used as an industrial solvent for manufacturing detergents, paints, lac-
quers, pharmaceuticals, polishes, and cosmetics.8,9 Most common antifreeze
products contain approximately 95% EG.10 The widespread availability of EG as
well as environmental contamination from improper disposal and storage pose a
danger to many animals. This article, which is Part I of a two-part presentation,
reviews the pathophysiology, clinical stages, and clinicopathologic findings of
EG intoxication. Part II will discuss diagnosis, treatment, prognosis and preven-
tion.
Ethylene glycol reportedly has a pleasant, sweet or bittersweet taste5,9–12 and im-
parts a warming sensation to the tongue and esophagus when swallowed.5 The
sweet taste is often quoted as being the reason dogs and cats ingest EG10–13; how-
ever, one study suggested that antifreeze (at least in the concentrations usually
available) is not particularly attractive to dogs.14 Dogs and cats confined without
water may ingest EG voluntarily.15 Other reasons for EG ingestion include curios-
ity,10 if it is the only available liquid when temperatures are below freezing, and
intentional poisoning.
Compendium November 1999 20TH ANNIVERSARY
Accidental EG intoxication in humans was first re-
ported in 1930.16 The earliest clinical cases of EG in-
toxication in dogs and cats were reported in 195117 and
1957,15 respectively. The toxicity of EG is partly related
to species susceptibility—cats and humans are among
the most highly susceptible. Individual tolerance may
also be a determining factor in the amount of EG that
can be safely consumed.7 In dogs, the reported mini-
mum lethal dose of undiluted EG is 4.4 to 6.6 ml/
kg7,18; however, it is as low as 1.5 ml/kg (the equivalent
of 1 tablespoon of EG diluted 50:50 with water) in
cats12,19 and humans.1
Reports of the incidence of EG intoxication in ani-
mals are sparse. A review of necropsy records at the
Minnesota Veterinary Diagnostic Laboratory from 1969
to 1978 revealed 72 histopathologically confirmed cases
of EG intoxication in dogs (n = 47) and cats (n = 25).20
Barton and Oehme21 reported 23 cases of EG intoxica-
tion in dogs and cats seen at Kansas State University
from 1975 to 1980, with case-fatality rates of 59% and
100%, respectively. At Colorado State University, EG
poisoning was the second most commonly diagnosed
type of intoxication from 1979 to 1986 (30 of 104 cas-
es) and had the highest overall case-fatality rate
(43.3%) of all intoxications; from 1968 to 1986, the
case-fatality rate from EG intoxication was 70.4% for
dogs and 96% for cats.22 From 1993 to 1998, 114 cases
of EG intoxication in dogs (n = 91) and cats (n = 23)
were seen by the veterinary emergency services of Tufts
University and the University of Pennsylvania, with
combined case-fatality rates of 43.9% for dogs and
78.2% for cats.23 This apparently increased incidence
may partly reflect improved clinician and owner aware-
ness of the dangers of EG.
METABOLISM AND PATHOPHYSIOLOGY
Knowledge of the metabolic pathways of EG is criti-
cal to understanding the mechanisms of its toxicity and
the rationale behind therapy. EG is rapidly absorbed
from the gastrointestinal tract and is readily distributed
throughout all body tissues.8,24 Although ingestion with
food may delay absorption,25 serum EG levels rise rap-
idly by 1 hour after ingestion and are highest at 3 hours
after ingestion in both dogs11,25,26 and cats.27 These lev-
els remain significantly elevated for at least 12 hours
and are usually undetectable 48 hours after inges-
tion.11,25 Unmetabolized EG is excreted through the
kidneys2; the amount depends on the species and the
dose ingested.1,8 In dogs, urine EG levels peak 6 hours
after ingestion.25
The metabolism of EG occurs primarily in the liver,
where the first step involves the oxidation of EG to gly-
coaldehyde by the cytosolic enzyme alcohol dehydroge-
LETHAL DOSE ■ ALDEHYDES ■ GLYCOLATE ACCUMULATION
Small Animal/Exotics
nase (ADH; Figure 1).1,28,29 Glycoaldehyde is then rap-
idly oxidized to glycolate by mitochondrial aldehyde
dehydrogenase1,8; small amounts of glyoxal may also be
formed.1,8 The oxidation of glycolate to glyoxylate is an
important rate-limiting step in EG metabolism, allow-
ing for the accumulation of potentially high levels of
glycolate in serum.3,30,31 Glyoxylate is then rapidly me-
tabolized to oxalate.1,30 Alternative pathways for glyoxy-
late metabolism include reversible transamination to
glycine, which requires pyridoxine as a cofactor,1 and
condensation to α-hydroxy, β-ketoadipate, which re-
quires thiamine as a cofactor.9 The quantitative impor-
tance of these latter pathways is unknown.
Because of species differences in EG metabolism, ear-
ly investigators suggested that EG itself might be toxic
in some species.1,10,28 EG causes an ethanol-like central
nervous system (CNS) depression5,7,10,32,33 and increased
serum osmolality.25,27,34–37 However, studies using ADH
inhibitors in animals7,11,12,18,30,32,34 and humans6,38 have
shown that inhibition of EG metabolism reduces toxi-
city, confirming the primary role of metabolites. Gly-
oxylate and glycoaldehyde are more toxic than are any
of the other compounds on a per-weight basis.8,24,28,30
Effects of these aldehydes at the mitochondrial level in-
clude inhibition of the citric acid cycle and of sub-
strate-level phosphorylation; they may also uncouple
oxidative phosphorylation.24 Glycolate, which also pos-
sesses an aldehyde group, may act similarly.9,30 These
aldehydes may also depress serotonin metabolism and
alter CNS amine levels.9
The contribution of glyoxylate and glycoaldehyde to
clinical toxicity is unclear; because of their very short
half-lives, these compounds are present in only minute
amounts.8,24,30 Alternatively, the degree of glycolate ac-
cumulation has been shown to correlate with the pro-
found high anion gap metabolic acidosis that is a hall-
mark of EG intoxication.3,27,30,31,39 Glycolate is thought
to be the most likely major mediator of EG toxicity,30
although it is unclear whether glycolate is toxic only be-
cause it lowers the pH in body fluids or because the
glycolate anion itself has toxic properties. Lactate accu-
mulation, secondary to the increased cytoplasmic ratio
of reduced nicotinamide adenine dinucleotide
(NADH) to NAD+ resulting from EG oxidation3,9,40,41
and to the inhibition of pyruvate metabolism by alde-
hydes, is also thought by some investigators to play a
role in the development of metabolic acidosis, at least
in human intoxication.9,40,41 Hypoperfusion will also
lead to lactate accumulation. Lactate levels have not
been specifically evaluated in EG-intoxicated dogs and
cats. Hippuric acid, which is thought to be produced
from glycine in the presence of exogenous benzoic acid
(a preservative in some antifreeze preparations),41 does
Small Animal/Exotics 20TH ANNIVERSARY Compendium November 1999

CLINICAL STAGES
HO-CH2-CH2-OH The clinical syndrome of
Lactate Ethylene glycol EG intoxication is classically
NAD+
Alcohol
described in three fairly dis-
dehydrogenase tinct stages.5,9,13,44 Clinical signs
and their severity are dose and
NADH
time related, however, and thus
Pyruvate HO-CH2-C O
H the onset and progression of
Glycoaldehyde stages are not always straight-
NAD+
Citric acid cycle Glucose forward or predictable.
Aldehyde
dehydrogenase

Glyoxal Stage 1
NADH
The first stage occurs 30 min-
HO-CH2-C O utes to 12 hours after ingestion
OH
Glycolate and is associated with CNS dis-
orders; signs may resemble those
of alcohol intoxication.5,7,10,32,33
Early signs include CNS de-
pression and incoordination
O C-C O α-Hydroxy, β-ketoadipate that progress to ataxia and pare-
H OH cofa
c tor sis; somnolence; and sometimes
mine (especially when large amounts
Thia
Glyoxylate
Pyrid of EG are ingested) to focal or
oxine
cofac
tor Glycine generalized seizures, coma, and
Benzoate
death.11–13,18,34 Cats may become
unresponsive within 9 hours af-
O O Hippurate ter ingestion.27 Other less com-
C-C mon signs include muscle fas-
HO OH
ciculations, head tremors, and
Oxalate nystagmus.45 Hypothermia is a
common finding, especially in
Figure 1—Ethylene glycol metabolic pathways. Solid arrows indicate the quantitatively most
important steps; broken arrows indicate postulated metabolic pathways. Pathways may vary
cats,27,45 and may be secondary
according to species. to CNS depression, hypoperfu-
sion, and possibly exposure to
low ambient temperatures. 45
not appear to play a role in the development of meta- Vomiting is also seen frequently and may be secondary
bolic acidosis. to direct gastric mucosal irritation from EG7,9,13 or the
The role of oxalate accumulation in the toxicity of EG, acute rise in serum osmolality. After the initial CNS de-
and particularly in the development of acute renal failure, pression, many animals often seem to recover but then
has not been clarified. Depending on the species, 0.05% rapidly deteriorate.19,31
1
to 3.79% of ingested EG is excreted in urine as oxalate ; Serum osmolality and osmolal gaps are significantly
cats are thought to produce more oxalate than do other increased by 1 hour after EG ingestion in both cats27
species.1 Oxalate combines with calcium in the blood to and dogs,25,34,36,37 paralleling serum EG concentrations.
form a soluble calcium oxalate complex that precipitates In dogs, serum hyperosmolality peaks 6 hours after in-
in the renal tubules and, to a lesser extent, in vasculature gestion and both it and cerebrospinal fluid osmolality37
5,9,10,18,19,28
of the brain, heart, and other organs. Some in- remain elevated for at least 12 hours.25,36,37 A severe nor-
vestigators believe that renal tubular epithelial damage mochloremic metabolic acidosis with a high anion gap
and subsequent renal failure may result from the precipi- occurs within 3 hours of ingestion and may persist for
tation of calcium oxalate crystals per se,18,38,42 whereas oth- at least 12 hours.25,34,36,45
ers believe that nephrotoxicosis is caused by direct cyto- Intoxicated dogs, but not cats, exhibit marked and
toxic effects of either oxalate5,19,43 or the other metabolites progressive polydipsia within 1 hour of EG ingestion7,25
of EG.9,11,26,28,30 The exact mechanism of renal tubular ep- that is thought to result from stimulation of the thirst
ithelial necrosis and failure remains unknown. mechanism by the acute rise in serum osmolality. Se-

METABOLIC PATHWAYS ■ OXALATE ACCUMULATION ■ CNS DISORDERS

Compendium November 1999 20TH ANNIVERSARY Small Animal/Exotics

vere polyuria is common in both species and can lead
to serious dehydration and hypoperfusion. Because the
canine proximal convoluted tubule is not permeable to
EG,2 a marked osmotic diuresis occurs. In addition, be-
cause of the structural similarity between EG and
ethanol, it has been suggested that EG may inhibit the
release of vasopressin in a manner similar to that of
ethanol.25,46 Serum hyperosmolality is normally a strong
stimulus for vasopressin release and renal water conser-
vation.
Acute CNS signs have been attributed to the actions
of the aldehyde metabolites of EG9,13,45 as well as to
serum hyperosmolality and metabolic acidosis.3,37,45 In-
creases in effective extracellular fluid osmolality result
in cellular dehydration and can cause depression,
lethargy, and weakness that may progress to seizures,
coma, and death in severe cases.47 Alternatively, brain
metabolism and regulation of brain volume are im-
paired by severe acidemia, resulting in progressive ob-
tundation and coma.48
Stage 2
Cardiac and pulmonary manifestations occur in the
second clinical stage, 12 to 24 hours after EG ingestion.
Tachypnea and tachycardia are fairly common signs in
dogs7,13,18 and may also be noted in cats19; these signs
may be partially attributable to the severe metabolic aci-
dosis. Cardiopulmonary manifestations appear to be
recognized less often in cats and dogs than in humans.
Pulmonary edema has been described in human pa-
tients,5,9,49 only some of whom had concurrent myocar-
dial damage and congestive heart failure.49,50 Congestive
heart failure has not been reported in cats or dogs with
EG toxicosis, although myocardial dilation has been de-
scribed in cats.19 Pulmonary edema and congestion are,
however, fairly common postmortem findings in small
animals.7,11,13,19 The cause of noncardiogenic pulmonary
edema in EG intoxication is unclear; a neurogenic ori-
gin was suggested as early as 1957,5 and adult respirato-
ry distress syndrome has been suggested by hemody-
namic monitoring in at least one human patient. 49
Severe acidemia may also predispose to pulmonary con-
gestion via direct venoconstrictive effects.48
Stage 3
The third clinical stage, onset of oliguric renal failure,
generally occurs 24 to 72 hours after ingestion of EG in
dogs but may be seen as early as 12 hours after inges-
tion in cats.27 Most cats and dogs are presented at this
stage of intoxication, when most of the EG has already
been metabolized. Manifestations include depression,
anorexia, vomiting, azotemia or uremia, and minimal

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Small Animal/Exotics 20TH ANNIVERSARY Compendium November 1999

urine output with a low to course of intoxication9,45 or

fixed specific gravity.9,11,13,18,25 later in association with olig-
Complete anuria often de- uria and anuria.
velops by 72 to 96 hours af- Hypocalcemia is seen in
ter ingestion. Flank pain is at least 50% of affected dogs
a common finding on ab- and cats13,25,27,36,37,45,51 and is
dominal palpation,13 and oral assumed to be secondary to
ulcerations and seizures may chelation of calcium by ox-
be seen secondary to urem- alate, although this has nev-
ia.7,9,11,18 er been proven. Although
the degree of hypocalcemia
CLINICOPATHOLOGIC can be severe,52 development
FINDINGS Figure 2—Calcium oxalate dihydrate crystals in the urine sed- of clinical signs (e.g., tetany)
Hematologic iment of a dog with ethylene glycol intoxication. (Courtesy is thought to be uncommon
Hematologic findings are of Drs. G. Freden and J. Knoll, Tufts University School of in cats and dogs, possibly
relatively nonspecific in EG Veterinary Medicine.) because the ionized calcium
intoxication. Neutrophilic fraction tends toward nor-
leukocytosis and lympho- mality in the presence of
penia are common9,25,26,36,45,51 metabolic acidosis.45 In hu-
and are attributed to endo- man intoxication, tetany,
genous corticosteroid release seizures, and possibly car-
secondary to vomiting, CNS diac malfunction are consid-
depression, and metabolic ered to be caused by hypo-
acidosis.25,26 The hematocrit, calcemia.9,33,53
total protein, and hemo- Hyperglycemia is also com-
globin concentrations may mon and is seen in more than
be slightly decreased sec- 70% of affected cats and
ondary to volume expansion dogs.27,36,45 Hyperglycemia is
from polydipsia in dogs 25 thought to be caused by inhi-
Figure 3A
but are more often elevated bition of glucose metabolism
45
secondary to dehydration. by aldehyde metabolites of
EG and by an increased re-
Biochemical lease of epinephrine and cor-
Concurrent with the early ticosteroids in response to
development of metabolic stress. 27,33,45 In addition,
acidosis, decreases in blood hypocalcemia may inhibit in-
pH and bicarbonate concen- sulin secretion54 and acidemia
trations on arterial or venous may induce insulin resistance
blood gas evaluation as well and inhibit glycolysis.48
as decreased total carbon di- Increases in blood urea ni-
oxide and an elevated anion trogen and creatinine are
gap on serum chemistry anal- seen with the development
ysis are seen as early as 3 Figure 3B of acute renal failure, al-
hours after ingestion.3,25,27,34,36 Figure 3—Calcium oxalate monohydrate crystals in the urine though severe dehydration
Hyperphosphatemia may oc- sediment of a dog with ethylene glycol intoxication (A and early in the course of intoxi-
cur with the onset of azo- B). The crystals in B are viewed with polarized light. (Cour- cation may cause prerenal
temia and acute renal failure; tesy of Drs. G. Freden and J. Knoll, Tufts University School azotemia.
elevations in inorganic phos- of Veterinary Medicine.)
phorus that occur early in Urinalysis
the course of intoxication are thought to result from the Calcium oxalate crystalluria is a consistent finding in
presence of phosphate-containing rust inhibitors in EG intoxication in all species studied,9,25,28,33,45,53,55,56 ap-
25,51
many antifreeze preparations. Hyperkalemia may be pearing in urine as early as 3 hours after ingestion in
noted, either secondary to metabolic acidosis early in the cats27 and by 4 to 6 hours after ingestion in dogs.11,25,57

HYPERCALCEMIA ■ HYPERGLYCEMIA ■ CALCIUM OXALATE CRYSTALLURIA

 Compendium November 1999 20TH ANNIVERSARY Small Animal/Exotics

Although the well-known dihydrate (weddelite) octahe- epithelial necrosis, remain incompletely understood.
dral or envelope-shaped form may be seen (Figure Knowledge of the EG metabolic pathways is also
2),55,56 the monohydrate (whewellite) form (Figure 3) is necessary in understanding the rationale behind specific
much more commonly observed in cases of EG intoxi- therapy. Rapid diagnosis and early aggressive therapeu-
cation.9,25,28,33,53,55,56 Often misidentified as hippurate tic intervention are essential in the management of EG-
crystals,9,28 x-ray diffraction studies have proven conclu- intoxicated dogs and cats. Part II of this presentation
sively that these spindle or hemp-seed–shaped crystals will address details of diagnosis, therapy, prognosis, and
are indeed calcium oxalate monohydrate crystals.55,56 prevention of acute EG intoxication in dogs and cats.
Dumbbell and budding-crystal forms of the monohy-
drate crystals may also be observed.55 REFERENCES
Isosthenuria may be observed as early as 3 hours after 1. Gessner PK, Parke DV, Williams RT: Studies in detoxica-
EG ingestion.25,36 Glucosuria concurrent with normo- tion. 86. The metabolism of 14 C-labelled ethylene glycol.
Biochem J 79:482–489, 1961.
glycemia has been observed in dogs36,45,52 and humans6 2. Swanson RE, Thompson RB: Renal tubular handling of
and is thought to occur secondary to widespread proxi- glycerol and ethylene glycol in the dog. Am J Physiol 217:
mal tubular damage.55 Normoglycemic glucosuria has 553–562, 1969.
not been observed in cats.27 Aciduria, hematuria, renal 3. Clay KL, Murphy RC: On the metabolic acidosis of ethy-
lene glycol intoxication. Toxicol Appl Pharmacol 39:39–49,
epithelial cells, and cellular and granular casts are other 1977.
frequent urinalysis findings.9,25,27,36,45,51,53 4. Beasley VR, Buck WB: Acute ethylene glycol toxicosis: A re-
view. Vet Hum Toxicol 22:255–263, 1980.
CONCLUSION 5. Berman LB, Schreiner GE, Feys J: The nephrotoxic lesion of
Acute EG intoxication is a rapidly progressive, life- ethylene glycol. Ann Intern Med 46:611–619, 1957.
threatening emergency with a complex pathophysiolo- 6. Wacker WEB, Haynes H, Druyan R, et al: Treatment of
ethylene glycol poisoning with ethyl alcohol. JAMA 194:
gy. Despite improvements in our knowledge of the 1231–1233, 1965.
metabolic pathways of EG and the specific effects of 7. Kersting EJ, Nielson SW: Experimental ethylene glycol poi-
EG and its various metabolites, some of the mecha- soning in the dog. Am J Vet Res 27:574–582, 1966.
nisms of its toxicosis, particularly that of renal tubular 8. McChesney EW, Golberg L, Parekh CK, et al: Reappraisal

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EMERGENCY AND CRITICAL CARE MEDICINE® Expert help fast in a practical and readable format
Feline Hepatic Lipidosis ■ Other abnormalities may be
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In each article you will find:
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Small Animal/Exotics 20TH ANNIVERSARY Compendium November 1999

of the toxicology of ethylene glycol. II. Metabolism studies col intoxication in small animals. Vet Hum Toxicol 24:21–
in laboratory animals. Food Cosmet Toxicol 9:21–38, 1978. 24, 1982.
9. Parry MF, Wallach R: Ethylene glycol poisoning. Am J Med 21. Barton J, Oehme FW: The incidence and characteristics of
57:143–150, 1974. animal poisonings seen at Kansas State University from
10. Kersting EJ, Nielson SW: Ethylene glycol poisoning in small 1975 to 1980. Vet Hum Toxicol 23:101–102, 1981.
animals. JAVMA 146:113–118, 1965. 22. Rowland J: Incidence of ethylene glycol intoxications in
11. Sanyer JL, Oehme FW, McGavin MD: Systematic treat- dogs and cats seen at Colorado State University Teaching
ment of ethylene glycol toxicosis in dogs. Am J Vet Res 34: Hospital. Vet Hum Toxicol 29:41–44, 1987.
527–534, 1973. 23. Gaynor AR: Incidence of ethylene glycol intoxications in
12. Penumarthy L, Oehme FW: Treatment of ethylene glycol dogs and cats at two veterinary teaching hospitals. 1998.
toxicosis in cats. Am J Vet Res 36:209–212, 1975. Unpublished data.
13. Grauer GF, Thrall MA: Ethylene glycol (antifreeze) poison- 24. Bachman E, Golberg L: Reappraisal of the toxicology of
ing in the dog and cat. JAAHA 18:492–497, 1982. ethylene glycol. III. Mitochondrial effects. Food Cosmet Tox-
14. Marshall DA, Doty RL: Taste responses of dogs to ethylene icol 9:39–55, 1971.
glycol, propylene glycol and ethylene glycol based antifreeze. 25. Grauer GF, Thrall MA, Henre BA, et al: Early clinicopatho-
JAVMA 197:1599–1602, 1990. logic findings in dogs ingesting ethylene glycol. Am J Vet Res
45:2299–2303, 1984.
15. Hadlow WJ: Symposium on poisoning—Part 2. Case 9—
26. Nunamaker DM, Medway W, Berg P: Treatment of ethy-
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296–297, 1957.
1971.
16. Anonymous: Possible death from drinking ethylene glycol
27. Dial SM, Hull Thrall MA, Hamar DW: Comparison of
(“Prestone”). Queries and minor notes. JAMA 94:1940,
ethanol and 4-methylpyrazole as treatments for ethylene gly-
1930.
col intoxication in cats. Am J Vet Res 55:1771–1782, 1994.
17. Jacobson D: Ethylene glycol (Prestone) poisoning in a dog. 28. Bove KE: Ethylene glycol toxicity. Am J Clin Pathol 45:
Vet Med/Small Anim Clin 46:118–119, 1951. 46–50, 1966.
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About the Authors
When this paper was submitted for publication, Drs.
Gaynor and Dhupa were affiliated with the Department of
Clinical Sciences, School of Veterinary Medicine, Tufts
University, North Grafton, Massachusetts. Dr. Dhupa is
now affiliated with Angell Memorial Animal Hospital,
Boston, Massachusetts. Both authors are Diplomates of
the American College of Veterinary Internal Medicine, and
Dr. Dhupa is also a Diplomate of the American College of
Veterinary Emergency and Critical Care.