Download Fatal Caffeine Intoxication in a Dog M. Hensel1, M. Pashmakova2

Fatal Caffeine Intoxication in a Dog
M. Hensel1, M. Pashmakova2, and B.F. Porter*.
1
Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical
Sciences, Texas A&M University, College Station, TX, USA
2
Department of Veterinary Small Animal Clinical Sciences, College of Veterinary Medicine and
Biomedical Sciences, Texas A&M University, College Station, TX, USA.
Correspondence to B. Porter ([email protected])
Phone number: (979) 847-8541
4467 TAMU
College Station, TX. 77843
2
1
Abstract: An 8-month-old male Yorkshire terrier was presented for
2
ingestion of 800 mg of an over-the-counter caffeine supplement.
3
Clinical signs included extreme tachycardia, facial fasciculation,
4
coma/stupor and flailing. Due to the lack of response to medical
5
therapies, humane euthanasia was elected. Microscopically,
6
necrotic neurons were scattered throughout the hippocampus,
7
olfactory cortex, pyriform lobe, amygdala, and basal nuclei, with
8
relative sparing of the caudate nuclei. In addition, mild skeletal
9
myocyte necrosis and mural necrosis of cardiac arterioles in the
10
left and right ventricles were noted. This is the first report of the
11
microscopic lesions associated with caffeine intoxication in a dog.
12
Key words: Caffeine toxicity; neuron necrosis
13
Introduction
14
Caffeine is a natural plant alkaloid found in more than 60
15
plant species and many beverage and food products, over the
16
counter dietary supplements, and medications (9). Caffeine is the
17
common name for the chemical 1,3,7-trimethylxanthine, which is
18
absorbed through the gastrointestinal tract and metabolized by the
19
liver (5,9). Caffeine is generally considered a safe compound
20
because it has a high threshold of toxicity and is a gastric irritant
21
with emetic properties (20). Reports of toxicosis in the medical
22
literature have been attributed to both accidental and intentional
23
overdose (3,4,7,14,26,27). The few case reports in dogs have been
24
related to accidental ingestion or presumptive malicious poisoning
25
(6,12,16,24,25). To the best of our knowledge, this is the first
26
detailed description of the pathologic findings in canine caffeine
27
intoxication.
28
Case Report
29
An 8-month-old, male, 1.5 kg Yorkshire terrier presented to
30
an emergency hospital with an acute onset of extreme tachycardia
31
(HR= 220 bpm) after witnessed ingestion of 4 x 200 mg (800 mg)
32
caffeine tablets between 6 to 8 hours previously. The only active
33
ingredient in the over the counter caffeine supplement was
34
caffeine. Due to rapid absorption of the toxin and presentation with
35
clinical signs of cardiovascular and neurologic instability, gastric
36
decontamination was deemed unsafe and therefore not performed.
37
During hospitalization, the dog experienced 3 tonic seizures, which
38
progressed to alternating periods of stupor/coma and flailing with
39
facial fasciculation for the next 2 days. Tachycardia was
40
moderately controlled with beta-blockers; however, the patient was
41
refractory to pharmaceutical management of intracranial signs
42
including cluster seizures, inappropriate mentation, and eventual
43
display of intracranial hypertension as evidenced by a Cushing
44
reflex. Serial bloodwork from 24 hours after ingestion and at 48
45
hours revealed progressively increasing aspartate aminotransferase
46
(AST) 1126 U/L to 1768 U/L (10-34 U/L) and alanine
4
47
aminotransferase (ALT) 217 U/L to 490 U/L (10-130 U/L).
48
Creatine kinase (CK) remained >16,000 U/L (68-400 U/L), and
49
cardiac troponin was severely increased (3.306 ng/ml [0-0.06]).
50
Urinalysis revealed myoglobinuria. The dog developed ptyalism,
51
loss of gag reflex, possible aspiration pneumonia, and ultimately
52
humane euthanasia was elected 2 days after ingestion of caffeine.
53
A complete necropsy was performed, and no gross lesions
54
were observed. Sections of heart, kidney, liver, lung, pancreas,
55
spleen, urinary bladder, thyroid gland, parathyroid gland, skeletal
56
muscle, stomach, small intestine, colon, cerebrum, thalamus,
57
hippocampus, cerebellum, midbrain, and medulla oblongata were
58
fixed in 10% neutral buffered formalin, processed routinely,
59
embedded in paraffin, and stained by hematoxylin and eosin (HE)
60
for light microscopy. Due to the witnessed ingestion of caffeine
61
supplements and the lack of exposure to any other toxin, blood or
62
tissue were not assessed for caffeine levels in this case.
63
Microscopic brain lesions were largely limited to the
64
telencephalon and diencephalon. Scattered areas of neuronal
65
necrosis, varying from minimal to severe, were evident throughout
66
all cerebral lobes. Necrotic neurons were shrunken and angular
67
with hypereosinophilic cytoplasm and pyknotic nuclei. Necrosis
68
was severe in the hippocampus, olfactory cortex, pyriform lobe,
69
amygdala, and basal nuclei, with relative sparing of the caudate
5
70
nuclei. Both the pyramidal layer (CA1-CA4) and dentate layer of
71
the hippocampus were severely and diffusely affected (Fig. A). In
72
the cerebral cortex, necrotic neurons were evident in superficial,
73
middle, and deep layers without a clear laminar pattern. Necrotic
74
neurons and occasional swollen axons (spheroids) were evident in
75
the thalamus, most notably in the lateral geniculate nucleus (Fig.
76
B). The dorsal thalamus was more affected than the ventral
77
thalamus. A few necrotic neurons had multiple basophilic
78
incrustations along their cell membrane (Fig. C, inset). Necrotic
79
neurons and adjacent blood vessels were often surrounded by clear
80
space interpreted as cytotoxic edema (Fig. C). Other vessel
81
changes in affected areas included hypertrophy of endothelial cells
82
and occasional mitotic figures. Rare Purkinje cell necrosis was
83
seen in the cerebellum. The midbrain and medulla oblongata were
84
within normal limits. Additional microscopic findings of this case
85
included scattered necrotic skeletal myocytes and mural necrosis of
86
arterioles in the left and right ventricles (Fig. D).
87
Discussion
88
The dog weighed 1.5 kg and ingested approximately 800
89
mg of pure caffeine (533 mg/kg). The toxic dose for dogs is
90
reported to be 140-150 mg/kg (20). The diagnosis of caffeine
91
intoxication is based on history of caffeine ingestion with
92
corresponding caffeine levels in blood or tissue samples
6
93
(4,7,14,27). Reported pathologic findings in human cases of
94
caffeine intoxication include pulmonary edema, visceral
95
congestion, myocardial infarction, rhabdomyolysis, and mild
96
gastric erosion with hemorrhage (4,7,26,27). Lesions in the central
97
nervous system are limited to cerebral edema, although most
98
reports do not include brain histology (27). The pathology of
99
caffeine toxicosis in dogs is poorly characterized. Necropsies were
100
not performed in most of the reported cases nor were caffeine
101
levels in the blood or tissues evaluated (12,16,19,25). Two cases
102
that received necropsies reported no gross findings, and
103
histopathology was not done in either case (6,24).
104
While caffeine intoxication is the most likely diagnosis,
105
similar microscopic lesions have been attributed to seizure activity
106
in epileptic dogs and are also seen in dogs with cardiac arrest,
107
cranial trauma, and hypoglycemia (11,13,17,18). The dog did not
108
have a previous history of epilepsy and lacked gross lesions or a
109
history of cranial trauma. In a study of epileptic beagles, the
110
distribution and nature of the lesions was similar to this case,
111
involving the cerebral cortex, basal nuclei, claustrum, amygdala,
112
septal nuclei, dorsal thalamic nuclei, isthmus of the pyriform lobe,
113
and hippocampus (13). The rostral cerebrum was most severely
114
affected, specifically the medial aspect of the frontal lobes and the
115
cingulate gyrus, a finding not appreciated in this case. The beagles
7
116
had infrequent cerebellar Purkinje cell necrosis, neuronal necrosis
117
in the thalamus, and frequent neuronal incrustation, all similar to
118
this case. Incrustations are a change that has been attributed to
119
dense pockets of neuronal cytoplasm caused by impingement of
120
swollen astrocyte processes on the neuronal cell membrane (21).
121
Hippocampal necrosis was seen in CA1-CA4 in the beagle study,
122
but did not involve the dentate gyrus, as it did in this case. Another
123
change not mentioned in the epileptic beagles but seen in this case
124
is the presence of spheroids within the thalamus, particularly the
125
lateral geniculate nucleus.
126
The prominent histologic findings of neuronal necrosis and
127
cytotoxic edema could be entirely due to seizure activity or
128
hypoxia resulting from cardiovascular collapse, rather than from
129
any direct toxic effects of caffeine. Caffeine increases the rate of
130
metabolism of structures within the extrapyramidal motor system,
131
thalamic nuclei, and hippocampus, resulting in relative
132
hypoperfusion of these areas (15). Caffeine also causes transient
133
vasoconstriction, which could contribute to relative hypoperfusion
134
(15). The lesions in this dog could be secondary to the inherent
135
vasoconstrictive properties of caffeine and increased glucose
136
utilization within the central nervous system.
137
138
Diffuse brain hypoxia from cardiopulmonary dysfunction is
another possible explanation for the brain lesions. Myocardial
8
139
infarction and cardiac arrest have been reported after massive
140
ingestion of caffeine, resulting in abnormal electrocardiograph
141
(ECG) findings and elevated cardiac troponin levels (3,7). Cardiac
142
arrest with resulting global ischemia is a well-known cause of
143
neurologic deficits. In a research model utilizing pigs, cardiac
144
arrest of 7 or 10 minutes duration resulted in varying degrees of
145
neuronal necrosis and cerebral edema within the cerebral cortex,
146
caudate nucleus, putamen, hippocampus, thalamus, and cerebellar
147
median fissure (10). Necrotic neurons were found in layers III and
148
V of the 7 minute group and progressed to diffuse involvement by
149
10 minutes. The lesions reported in these pigs are similar to those
150
described in this case. The dog did not experience cardiac arrest,
151
but elevated cardiac troponin and mural necrosis of epicardial
152
arterioles of the left and right ventricles suggests compromised
153
myocardial function. Vascular necrosis has apparently not been
154
observed in previous cases of canine or human caffeine toxicity.
155
Caffeine is quickly absorbed after ingestion and reaches
156
peak serum levels within 1 hour (2,20). Clinical signs include
157
gastrointestinal derangements (vomiting, diarrhea), cardiovascular
158
instability (hypertension or hypotension, tachycardia), and
159
neurologic effects (delusions, hallucinations, and seizures) (14,20).
160
Caffeine’s effects are mediated through competitive antagonism of
161
adenosine receptors, which are found in the cardiovascular,
9
162
respiratory, renal, gastrointestinal, and central nervous systems
163
(1,2).
164
Caffeine is structurally similar to the methylxanthines
165
theobromine and theophylline. Due to its presence in chocolate
166
products, theobromine toxicosis is well recognized in dogs. In an
167
experimental study of canine theobromine intoxication, clinical
168
signs included restlessness, panting, and muscle tremors (8).
169
Lesions were limited to necrosis of cardiac muscle in the right
170
auricle with thickening of adjacent arterioles, presumably due to
171
smooth muscle hyperplasia and perivascular fibrosis. The brain
172
was apparently not examined in this study. With the exception of
173
renal tubular necrosis in one case, histopathologic lesions have not
174
been reported in natural cases of canine theobromine toxicosis
175
(22,23). The clinical signs in an experimental study of canine
176
theophylline intoxication included vomiting, erythema, a
177
staggering gait, hyperpnea, spasms, salivation, excitement, and
178
convulsions (22). The brain was not examined in the study, and
179
myocardial necrosis was the only lesion described.
180
Caffeine is a potent stimulant. Although toxicity is rare in
181
dogs, the drug can induce severe pathologic changes in the species.
182
The extent to which the lesions reported herein are due to seizure
183
activity, cardiopulmonary dysfunction, or some other mechanism
184
remains to be determined.
10
185
No conflicts of interest have been declared.
186
Acknowledgements
187
188
The authors wish to thank Dr. Brian Summers for consulting on
this case.
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
Literature Cited
1 ABBOTT PJ. Caffeine: a toxicological overview. Med. J. Aust.,
1986, 145, 10, 518-521.
2 BENOWITZ NL. Clinical pharmacology of caffeine. Annu.
Rev. Med., 1990, 41, 277-288.
3 BERGER AJ, ALFORD K. Cardiac arrest in a young man
following excess consumption of caffeinated "energy
drinks". Med. J. Aust., 2009, 190, 1, 41-43.
4 CAMPANA C, GRIFFIN PL, SIMON EL: Caffeine overdose
resulting in severe rhabdomyolysis and acute renal failure.
Am. J. Emerg. Med., 2014, 32, 1, 113-114.
5 DARRAGH A, KENNY M, LAMBE RF, O'KELLY DA.
Adverse effects of caffeine. Ir. J. Med. Sci., 1981, 150, 2,
47-53.
6 FOOR J, STOWE CM. Acute fatal caffeine toxicosis in a dog. J.
Am. Vet. Med. Assoc., 1975, 167, 5, 379.
7 FORMAN J, AIZER A, YOUNG CR. Myocardial infarction
resulting from caffeine overdose in an anorectic woman.
Ann. Emerg. Med., 1997, 29, 1, 178-180.
8 GANS JH, KORSON R, CATER MR, ACKERLY CC. Effects
of short-term and long-term theobromine administration to
male dogs. Toxicol. Appl. Pharmacol., 1980, 53, 3, 481496.
9 HECKMAN MA, WEIL J, GONZALEZ DE MEJIA E. Caffeine
(1, 3, 7-trimethylxanthine) in foods: a comprehensive
review on consumption, functionality, safety, and
regulatory matters. J. Food Sci., 2010, 75, 3, R77-87.
10 HOGLER S, STERZ F, SIPOS W, SCHRATTER A, WEIHS
W, HOLZER M. Distribution of neuropathological lesions
in pig brains after different durations of cardiac arrest.
Resuscitation., 2010, 81, 11, 1577-1583.
11 KROOK K, RM. Central nervous system lesions in dogs with
metastasizing islet cell carcinoma. Cornell Vet., 1962, 52,
385-415.
12 MICHAEL S. Caffeine poisoning in a dog. J. Am. Vet. Med.
Assoc., 1961, 139.
11
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
13 MONTGOMERY DL, LEE AC. Brain damage in the epileptic
beagle dog. Vet. Pathol., 1983, 20, 2, 160-169.
14 MRVOS RM, REILLY PE, DEAN BS, KRENZELOK EP.
Massive caffeine ingestion resulting in death. Vet. Hum.
Toxicol., 1989, 31, 6, 571-572.
15 NEHLIG A, DAVAL JL, DEBRY G. Caffeine and the central
nervous system: mechanisms of action, biochemical,
metabolic and psychostimulant effects. Brain Res. Rev.,
1992, 17, 2, 139-170.
16 OOMS TG, KHAN SA, MEANS C. Suspected caffeine and
ephedrine toxicosis resulting from ingestion of an herbal
supplement containing guarana and ma huang in dogs: 47
cases (1997-1999). J. Am. Vet. Med. Assoc., 2001, 218, 2,
225-229.
17 PALMER AC. The accident case--IV. The significance and
estimation of damage to the central nervous system. J.
Small Anim. Pract., 1964, 5, 25-33.
18 PALMER AC, WALKER RG. The neuropathological effects
of cardiac arrest in animals: a study of five cases. J. Small
Anim. Pract., 1970, 11, 12, 779-791.
19 PATTERSON R. Lethal caffeine poisoning in a dog. Canine
Pract. 1975, 2, 3, 51-52.
20 PETERS J. Factors affecting caffeine toxicity: a review of the
literature. J. Clin. Pharmacol. and the J. New Drugs.,
1967, 7, 3, 131-141.
21 PULSINELLI WA. Selective neuronal vulnerability and
infarction in cerebrovascular disease. Ann. N. Y. Acad.
Sci., 1997, 104-107.
22 SHIBATA M, WACHI M, KAGAWA M, KOJIMA J,
ONODERA K. Acute and subacute toxicities of
theophylline are directly reflected by its plasma
concentration in dogs. Methods Find. Exp. Clin.
Pharmacol., 2000, 22, 3, 173-178.
23 SUTTON RH. Cocoa poisoning in a dog. Vet. Rec., 1981, 109,
25-26, 563-564.
24 TAWDE SN, PUSCHNER B, ALBIN T, STUMP S,
POPPENGA RH. Death by caffeine: presumptive
malicious poisoning of a dog by incorporation in ground
meat. J. Med. Toxicol., 2012, 8, 4, 436-440.
25 WIDGERSON F. Accidental caffeine poisoning in a dog. J.
Am. Vet. Med. Assoc., 1956, 134.
26 WRENN KD, OSCHNER I. Rhabdomyolysis induced by a
caffeine overdose. Ann. Emerg. Med., 1989, 18, 94-97.
27 YAMAMOTO T, YOSHIZAWA K, KUBO S, EMOTO Y,
HARA K, WATERS B. Autopsy report for a caffeine
12
271
272
intoxication case and review of the current literature. J.
Toxicol. Pathol., 2015, 28, 1, 33-36.
273
274
275
276
277
278
279
280
Fig. 1. Hippocampus. Hypereosinophilic and shrunken neurons in
the dentate layer (*) and within the pyramidal layer (arrows). HE.
Bar, 70 m.
281
282
Fig. 2. Thalamus. Multifocal swollen axons (arrows) in the lateral
geniculate nucleus. HE. Bar, 35 m.
283
284
285
286
287
Fig. 3. Cerebrum. The perivascular space is expanded by cytotoxic
edema (*). Multifocally, neurons are necrotic (solid arrow). HE.
Bar, 70 m. Upper inset. Some neurons have basophilic
incrustations along the cell membrane (open arrow). HE. Bar, 20
m.
288
289
Fig. 4. Heart. Mural fibrinoid necrosis (*) in an epicardial arteriole.
HE. Bar, 20 m.
13