The Veterinary Journal 251 (2019) 105349

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The Veterinary Journal

journal homepage: www.elsevier.com/locate/tvjl

Clinical manifestations, laboratory findings, treatment and outcome of

acute organophosphate or carbamate intoxication in 102 dogs:
Aretrospective study
S. Klainbarta,c,d,* , M. Grabernika,c,d , E. Kelmera,c,d , O. Chaia,c,d , O. Cuneahb,c,d,
G. Segeva,c,d , I. Arocha,c,d
a
Department of Small Animal Emergency and Critical Care, The Veterinary Teaching Hospital, Koret School of Veterinary Medicine, The Hebrew University of
Jerusalem, P.O. Box 12, Rehovot, 761001, Israel
b
Department of Small Animal Neurology, The Veterinary Teaching Hospital, Koret School of Veterinary Medicine, The Hebrew University of Jerusalem,
P.O. Box 12, Rehovot, 761001, Israel
c
Department of Toxicology, Kimron Veterinary Institute, Bet Dagan, 5025000, Israel
d
Department of Small Animal Internal Medicine, The Veterinary Teaching Hospital, Koret School of Veterinary Medicine, The Hebrew University of Jerusalem,
P.O. Box 12, Rehovot, 761001, Israel

A R T I C L E I N F O A B S T R A C T

Article history: Organophosphates (OP) and carbamates are commonly used insecticides and important intoxication
Accepted 25 July 2019 sources of humans and animals. Nevertheless, large scale studies of these intoxications in dogs are
unavailable. The medical records of dogs presented to a veterinary hospital were reviewed
Keywords: retrospectively. The study included 102 dogs definitely diagnosed with acute OP or carbamate
Acetylcholine esterase intoxication.
Butyrylcholine esterase The most common presenting clinical signs included muscle tremor, hypersalivation, miosis, weakness,
Mechanical ventilation
vomiting and diarrhea. Hypersalivation, muscle tremor and tachypnea were significantly (P < 0.05)
Poisoning
Toxicity
associated with survival to discharge; while weakness, mental dullness, anorexia, pale mucous
membranes and paddling were significantly associated with death. Common laboratory abnormalities
included decreased butyrylcholine esterase activity, acidemia, increased total plasma protein,
leukocytosis, hypochloridemia, hyperbilirubinemia, increased creatinine and alanine transaminase
(ALT), aspartate transaminase (AST) and creatine kinase activities, and prolonged activated partial
thromboplastin time (aPTT). Compared to the survivors, the non-survivors showed significantly: higher
frequencies of thrombocytopenia, hypocarbemia, prolonged prothrombin time (PT), hypernatremia,
hyperkalemia, hypocholesterolemia, hypoproteinemia, hypertriglyceridemia, increased ALT activity and
increased urea concentration; lower median concentrations of venous blood bicarbonate, serum chloride
and total CO2; and higher medians of PT, serum total bilirubin and urea concentrations, and ALT and AST
activities. Intoxicated dogs were commonly treated with diphenhydramine, atropine-sulfate, antibiotics,
diazepam and pralidoxime, while some (19.2%) required general anesthesia and mechanical ventilation.
The survival rate of dogs treated by gastric lavage was higher (P = 0.041) compared to that of the
remaining dogs. Development of respiratory failure and mechanical ventilation requirement were
significantly associated (P < 0.001) with death. The mortality rate was 17%.
© 2019 Elsevier Ltd. All rights reserved.

Introduction environment, and important intoxication sources of humans, dogs

Carbamates and organophosphates (OPs) are organic insecti-
cides commonly used in agriculture, industry and home
* Corresponding author at: Department of Small Animal Emergency and Critical
Care, The Veterinary Teaching Hospital, Koret School of Veterinary Medicine, The
Hebrew University of Jerusalem, P.O. Box 12, Rehovot, 761001, Israel.
E-mail address: klainbart@gmail.com (S. Klainbart).
and cats (Marrs, 1993; Bardin et al., 1994; Frazier et al., 1999; De
Bosschere et al., 2001; Berny et al., 2010). OPs are phosphoric
(H3PO4) or thiophosphoric acid (H3PO3S) derivatives, and carba-
mates are mostly phosphorus-free carbamic acid (NH2COOH)
derivatives (Marrs, 1993; Bardin et al., 1994; Rotenberg et al., 1995).
Both competitively bind to the anionic and esteric sites of
acetylcholine esterase (AChE) and butyrylcholine esterase (BuChE),
thereby inhibiting them (Fukuto, 1990; Marrs, 1993; Bardin et al.,
1994). Acetylcholine is a neurotransmitter in cholinergic nerve

http://dx.doi.org/10.1016/j.tvjl.2019.105349
1090-0233/© 2019 Elsevier Ltd. All rights reserved.
2 S. Klainbart et al. / The Veterinary Journal 251 (2019) 105349
endings and neuromuscular junctions (NMJ), hydrolyzed by AChE
(Peper et al., 1982). BuChE is synthesized by the liver, and
hydrolyzes various esteric compounds, including butyrylcholine
and acetylcholine, and is present mostly in the plasma, but also in
the liver, pancreas, brain, and intestinal mucosa (Chatonne and
Oksana, 1989; Lockridge, 2015). Removal of a hydroxyl ion from
serine in the AChE active site by OP or carbamate exposure inhibits
acetylcholine hydrolysis, leading to its synaptic accumulation,
muscarinic and nicotinic post-synaptic receptor overstimulation,
and ultimately signals transmission disruption within the central
and peripheral nervous systems (Fukuto, 1990; Marrs, 1993; Bardin
et al., 1994).
Carbamates and OPs differ in several characteristics. Some OPs
require cytochrome P450 activation, while carbamates are active
immediately upon absorption (Fukuto, 1990; Marrs, 1993; Bardin
et al., 1994; Rotenberg et al., 1995). Carbamates poorly penetrate
the blood-brain barrier, intoxication is of shorter duration, and is
usually less severe than OP intoxication; although some carba-
mates may lead to severe, potentially fatal syndromes (Tafuri and
Roberts, 1987; Fukuto, 1990; Rotenberg et al., 1995). Most
importantly, most OPs can bind irreversibly to AChE through a
process termed “aging”, necessitating de-novo AChE synthesis
(which occurs at a daily rate of 1%) for neural function recovery.
Aging is a process where hydrolysis of the phosphorous-bound
alkyl group of the OP strengthens the bond between the phosphate
and the active site serine of AChE to which it is also bound, forming
a stable conjugate and resulting in permanent enzyme function
loss. Conversely, most carbamates have much lower affinity to
AChE, their binding is reversible and does not induce carbamate-
ChE complex “aging”. Carbamates spontaneously dissociate from
AChE with reaction half-lives ranging between 30 to 40 min (Tafuri
and Roberts, 1987; Minton and Murray, 1988; Fukuto, 1990; Baron,
1991; Marrs, 1993; Bardin et al., 1994; Rotenberg et al., 1995).
Both OP and carbamate intoxication leads to several neurologi-
cal syndromes, that are indistinguishable, including acute cholin-
ergic crisis (ACC; type-1 syndrome; Tafuri and Roberts, 1987;
Minton and Murray, 1988; Baron, 1991; Marrs, 1993; Bardin et al.,
1994), intermediate syndrome (IS; type-2 syndrome; De Bleecker
et al., 1993; De Bleecker, 1995; Hopper et al., 2002; Merbl et al.,
2011) and OP-induced delayed polyneuropathy (OPIDP), myopathy
and central nervous system (CNS) impairment (Lotti and Moretto,
2005; Jokanovi c et al., 2011).The clinical signs of OP intoxication
result from parasympathetic and somatic nerve overstimulation,
and differ between the neurologic syndromes. ACC is the most
common syndrome in animals, occurring mostly through gastro-
intestinal exposure, with clinical signs occurring within minutes to
hours post-exposure (Gupta and Milatovic, 2012). ACC may also be
seen with carbamate intoxication (Gupta and Milatovic, 2012).
Parasympathetic (muscarinic) overstimulation signs include hy-
persalivation, bronchorrhea, lacrimation, miosis, urination, defe-
cation, bradypnea, bradycardia, cough, dyspnea, gastrointestinal
hypermotility, diarrhea, abdominal pain and anorexia. Nicotinic
signs follow, due to neuromuscular junction synaptic overstimu-
lation, and include tremors, muscle spasm (facial and/or general-
ized), weakness, and eventually, spastic paralysis, sometimes
including the diaphragm and respiratory muscles, potentially
leading to respiratory failure. CNS signs occur last, including
anxiety, restlessness, hyperactivity, depression, twitching, seiz-
ures, respiratory center depression and coma (Gupta and Milatovic,
2012).
OP and carbamate intoxications are diagnosed based on a
history of exposure, the characteristic clinical signs, with their
improvement with atropine-sulfate and pralidoxime therapy,
decreased red blood cell (RBC) AChE or serum BuChE activity,
and identifying the toxic compound in gastric contents (Namba
et al., 1971). There are different cholinesterase activity
measurement methods. Whole blood RBC AChE activity can be
measured, and when decreasedto less than 50% of the lower limit
of the reference interval (RI) is considered suspicious of intoxica-
tion, and when decreased to less than 25% of the lower limit of the
RI it is confirmatory (Lodgett, 2001; Bajgar, 2005). Alternatively,
serum BuChE activity can be measured, which is more sensitive,
but less specific for confirming intoxication (Bajgar, 2005).
To the best of our knowledge, there are no published large-scale
studies of OP and carbamate intoxications in dogs. The aim of this
large-scale retrospective study was to describe the clinical,
neurological and laboratory findings, treatment and outcome of
ACC due to such intoxications in dogs.
Materials and methods
Selection of dogs and data collection
This retrospective medical records study included dogs presented to the
Hebrew University Veterinary Teaching Hospital (2000–2015), and definitely
diagnosed with acute OP or carbamate intoxication. The diagnosis was based on
compatible history and clinical signs, and at least one of the following: decreased
serum BuChE or RBC AChE activities, positive toxicological analysis of stomach
contents and solid evidence of exposure to toxic compounds (i.e. dogs observed
ingesting the toxin or were administered toxin-containing preparations). Dogs were
excluded when their owners declined treatment due to purely financial constraints.
Dogs discharged alive from the hospital were considered survivors, while those that
died or were euthanased due to deterioration during hospitalization, were defined
as non-survivors.
Laboratory tests
Blood samples collected in potassium-EDTA tubes for complete blood count
(CBC) were analyzed within 15 min of collection (Abacus, Arcus or Abacus Junior
Vet, Diatron; Advia 120, Siemens). Blood smears stained with modified-Wright
staining solution were used for confirming the platelet count. The packed cell
volume (PCV) was measured by centrifugation of heparinized blood in a capillary
tube, and the total plasma protein (TPP) was determined using a clinical
refractometer (Atago). Samples for serum biochemistry, including BuChE activity,
were collected in tubes with gel separators containing no anticoagulant (allowed to
clot, centrifuged, and separated). Sera were either analyzed within 60 min, or stored
at 4
C and analyzed within 24 h of collection (Cobas-Mira or Cobas Integra 400 Plus,
Roche; at 37
C). Electrolytes were measured in serum or heparinized whole blood
(Nova 8, Nova Biomedical; OmniC or Cobas b221, Roche). Blood samples for
hemostatic function tests (i.e. activated partial thromboplastin time (aPTT),
prothrombin time (PT) and fibrinogen concentration) were collected in 3.2%
potassium-citrate tubes. Centrifuged and separated plasma was analyzed within
30 min of collection (KC 1A Micro; ACL 200 or ACL-9000, IL, Milano, Italy). Venous
blood gas (VBG) analysis was performed within 10 min of collection in blood
samples collected in sealed heparinized syringes (Phox, Nova Biomedical; OmniC or
Cobas b221, Roche).
BuChE activity was measured based on BuCh hydrolysis to butyrate and
thiocholine, which converts yellow hexacyanoferrate III to colorless hexacyano-
ferrate II. The decrease in absorbance at 410 nm is directly proportional to sample
cholinesterase activity.1 AChE activity was measured using Michel’s method
(Michel, 1949). Briefly, heparinized whole blood was incubated for 60 min with
acetylcholine-chloride in buffer solution (pH 8.1, at 37
C). Hydrolysis of
acetylcholine acidifies the solution. AChE activity is proportional to the pre- to
post-incubation pH difference.
Stomach content of OPs and carbamates was identified using gas chromatog-
raphy mass spectrometry (GCMS; 7890A gas chromatograph; 5975C VL-MSD and
nitrogen phosphorus detector). Stomach content (5 g) was extracted into
acetonitrile and cleaned using an adapted QuEChERS protocol (Anastassiades
et al., 2007). The final ethyl-acetate extract (1 mL) was injected into the GCMS
analyzer, which was set in full scan mode with electron ionization, and selected ion
monitoring and nitrogen phosphorus detector data were collected. The scan data
were deconvoluted using Deconvolution Reporting Software (Agilent Technologies,
Santa Clara, CA). Selected ion monitoring data were used to identify low-level
compounds, which were not identified in the scan mode. The data analysis was
made referring to the retention time-locked Agilent Forensic Toxicology Database
and the NIST 2.0f library (Anonymous, 2008). The insecticides identified by the
libraries (i.e., chlorpyriphos and carbamates) were validated against known
samples that served as standards.
1
See: Cobas Integra 400 Plus Insert. https://usdiagnostics.roche.com/products/
04498577190/PARAM14/overlay.html. (Accessed 9 October, 2018).
 S. Klainbart et al. / The Veterinary Journal 251 (2019) 105349 3

Statistical analysis Table 2

Clinical signs reported by owners and recorded at presentation to the hospital in
The distribution pattern of quantitative variables was assessed using the 102 dogs acutely intoxicated by organophosphates or carbamates.
Shapiro–Wilk test. Quantitative variables were compared between groups using the
Student’s t test or Mann–Whitney U-test, for normally and non-normally P Non-survivors Survivors All dogs Clinical sign
distributed variables, respectively. Categorical variables were compared between n (%) n (%) n (%)
groups using the chi-squared or Fisher’s exact tests, as appropriate. Associations Based on the history
between two normally-distributed quantitative variables were examined by 0.535 10 (59) 56 (67) 66 (65) “Shivers”
Pearson’s correlation method. All tests were two-tailed, and P < 0.05 was 0.004 5 (29) 56 (67) 61 (60) Hypersalivation
considered significant. Analyses were performed using a statistical software 0.116 13 (77) 47 (56) 60 (59) Weakness
package (SPSS 22.0, SPSS Inc. Chicago, IL). 0.121 5 (29) 42 (50) 47 (47) Vomiting
0.626 6 (35) 35 (42) 41 (41) Diarrhea
Results 0.079 6 (38) 35 (42) 41 (41) Ataxia
0.183 9 (53) 30 (36) 39 (39) Apathy
0.328 8 (47) 29 (35) 37 (37) Recumbent
The study included 102 dogs. Their residential area, signalment, 0.053 2 (12) 30 (36) 32 (32) Foamy oral discharge
body weight, and the season in which they were presented are 0.309 3 (18) 25 (30) 28 (28) Muscle spasms
provided in Table 1. The exposure route to the toxin included: the 0.028 8 (53) 18 (21) 26 (27) Anorexia
0.848 4 (24) 18 (21) 22 (22) Involuntary urination
skin (26 dogs; 18 survivors), gastrointestinal tract (GIT; 22 dogs;
0.218 1 (6) 15 (18) 16 (16) Tachypnea
20 survivors), skin and GIT (one dog; survivor), or was unknown 0.784 2 (12) 12 (14) 14 (14) Dyspnea
(53 dogs; 46 survivors). The exposure route was unassociated with 0.651 0 (0) 1 (1) 1 (1) Mydriasis
death (P = 0.192). The identified toxic compounds included
chlorpyrifos (22 dog; 16 survivors), carbamates (three dogs; all Based on the physical examination at presentation to the hospital
0.005 4 (25) 53 (63) 57 (57) Tremors
survivors) and a carbamate-chlorpyrifos mixture (one dog; a
0.005 3 (20) 49 (59) 52 (53) Hypersalivation
survivor), and were unknown in the remaining cases (76 dogs, 0.497 7 (44) 44 (53) 48 (49) Miosis
74.5% total; 66 survivors). 0.040 11 (73) 37 (45) 48 (49) Weakness
The median time from the intoxication to presentation to the 0.073 4 (27) 43 (52) 47 (48) Diarrhea
0.029 3 (20) 41 (49) 45 (46) Tachypneaa
hospital (n = 97) was 3 h (range 0.25–720 h), and was not
0.018 10 (63) 26 (31) 36 (36) Depression
associated (P = 0.26) with death (survivors, n = 80, median 3 h, 0.205 7 (50) 27 (33) 34 (35) Hyperemia
range 0.25–720 h vs. non-survivors, n = 17, median 10 h, range 0.334 7 (44) 26 (31) 33 (33) Recumbent
0.3–188 h). The median hospitalization period was 1.8 days (range 0.107 2 (13) 27 (33) 29 (29) Tachycardiab
0.0–13.0 days). The mortality rate was 16.7% (17 dogs), including 0.072 1 (7) 24 (29) 25 (25) Vomiting
0.659 3 (19) 20 (24) 23 (23) Seizures
four dogs (4%) euthanased due to deterioration.
0.427 4 (29) 16 (19) 20 (21) Dyspnea
The median heart rate (HR; 120 beats/min; range 52–200 beats/ 0.733 2 (13) 14 (17) 16 (16) Dehydration
min), median respiratory rate (40 breaths/min; range 9–160 beats/ 0.035 5 (33) 10 (12) 15 (15) Pale mucous membranes
min) and median rectal temperature (39.0
C; range, 35–42
C) at 0.909 2 (13) 12 (14) 14 (14) Ataxia
presentation were not associated with death (P = 0.302, P = 0.512, 0.088 0 (0) 14 (17) 14 (14) Foamy oral discharge
0.100 0 (0) 13 (16) 13 (13) Lacrimation
P = 0.865, respectively). The common historical and presenting 0.085 4 (25) 8 (10) 12 (12) Bradycardiac
clinical signs included muscle tremors, hypersalivation, miosis, 0.535 1 (7) 10 (12) 11 (11) Capillary refill time <0.5 s
weakness, vomiting and diarrhea (Table 2). Hypersalivation 0.728 2 (12) 8 (10) 10 (10) Abdominal pain
(P = 0.005), tremor (P = 0.005) and tachypnea (P = 0.029) were more 0.938 1 (7) 6 (7) 7 (7) Hypertonia
0.206 2 (13) 4 (5) 6 (6) Dry mucous membranes
frequent, while weakness (P = 0.04), mental dullness (P = 0.018),
0.924 1 (7) 5 (6) 6 (6) Absent menace reflex
anorexia (P = 0.028) and pale mucous membranes (P = 0.035) were 0.924 1 (7) 5 (6) 6 (6) Hyperesthesia
less frequent among the survivors compared to the non-survivors. 0.302 0 (0) 5 (6) 5 (5) Miosis
0.582 1 (7) 3 (4) 4 (4) Capillary refill time >3 s
0.373 0 (0) 4 (5) 4 (4) Mydriasis
0.385 0 (0) 4 (5) 4 (4) Nystagmus
0.669 0 (0) 1 (1) 1 (1) Hypermetria
Table 1 0.018 1 (7) 0 (0) 1 (1) Paddling
Signalment, body weight, season presented, and residential environment of 0.656 2 (13) 15 (18) 17 (17) SLUDGE
102 dogs acutely intoxicated by organophosphates or carbamates.
N, number of dogs; SLUDGE, Salivation, Lacrimation, Urination, Defecation,
Variable Gastrointestinal distress, Emesis; MM, mucous membranes; CRT, capillary refill
Age time.
a
Median (range) in months 48.0 (1.5–168.0) >40 breaths per min.
b
>120 breaths per min.
c
Body weight <70 breaths per min.
Median (range, kg) 20 (1–50)

Sex
Neutered male n = 5 (4.9%) At time of presentation RBC AChE activity was measured in
Intact male n = 49 (48.0%) eight dogs, while serum BuChE activity was measured in 94 dogs.
Neutered female n = 28 (27.5%)
The common laboratory abnormalities (Tables 3 and 4) included
Intact female n = 20 (19.6%)
decreased BuChE activity (93%), hyperbilirubinemia (65%), acid-
Season presented emia (64%), prolonged aPTT (64%), hypochloridemia (56%),
Summer (June–August) n = 34 (33.3%) increased TPP concentration (55%), leukocytosis (54%), azotemia
Spring (March–May) n = 28 (27.4%)
(52%), hyponatremia (32.5%) and increased aspartate transaminase
Autumn (September–November) n = 23 (22.5%)
Winter (December–February) n = 17 (16.7%)
(AST; 89%), creatine kinase (CK; 65%), alanine transaminase (ALT;
55%) and alkaline phosphatase (ALP; 43%) activities. There were
Residential environment significant weak correlations between serum bilirubin concentra-
Rural n = 57 (55.9%) tion and ALP (r = 0.519; P < 0.0001) and ALT (r = 0.488; P < 0.0001)
Urban n = 45 (44.1%)
activities.
4 S. Klainbart et al. / The Veterinary Journal 251 (2019) 105349

RI, Reference interval; BE, base excess; PCV, packed cell volume; TPP, total plasma protein (measured by refractometry); RBC, red blood cells; MCV, mean corpuscular volume; MCHC, mean corpuscular hemoglobin concentration; PT,
Compared to the survivors, the non-survivors showed signifi-

0.900

0.263
0.022

0.240
0.061
0.379

0.378
0.876

0.701
0.031
0.743
0.718

0.011

0.147
cantly (P < 0.05) higher frequencies of thrombocytopenia,
Pb

hypocarbemia, prolonged PT, hypernatremia, hypercalcemia,

hypocholesterolemia, hypoproteinemia, hypertriglyceridemia, in-

0.646

0.454
0.996
0.894

0.405
0.467
0.097

0.061
0.378

0.021
0.010

0.747
0.717

0.181
creased ALT activity, and increased urea concentration; lower
Pa

median concentrations of bicarbonate, chloride and total CO2

n (%) > RI

(TCO2); higher median concentrations of total bilirubin and urea,

Venous bicarbonate concentration, base excess and pH, hematological and hemostatic analytes recorded at presentation to the hospital in dogs acutely intoxicated by organophosphates or carbamates.

(33)

(33)
(53)
(29)

(36)

(86)
(27)

(57)
ALT and AST activities, and PT (Tables 3 and 4).

(7)
(0)
(0)

(0)

(0)

(0)
All dogs received intravenous fluid therapy. The other most
3

4
5
8
4

5
4
6
0
0

0
common medications and treatments administered in hospital
n (%) < RI

(Table 5) included: diphenhydramine (80.2%), atropine-sulfate

(77.8)
(56)

(36)
(43)
(33)
(67)

(13)
(14)

(66.3%), antibiotics (65.3%), diazepam (53.5%), 2-pyridine aldoxime

(7)

(7)

(7)
(0)
(0)
(0)
methyl chloride pralidoxime (2-PAM; 51.5%) and general anesthe-
3
6
7
5
1
2
2
1
5
6
1
0
0
0
sia (propofol, 43%; isoflurane, 36%). Dogs that had seizures were
treated more frequently (P < 0.001) with mannitol compared to the
7.3 (19.6–19.3)

66.0 (35.0–75.0)

0.22 (0.21–0.27)
40.5 (27.2–48.3)

13.6 (10.8–20.7)

0.46 (0.14–0.78)

23.0 (17.0–56.0)
Median (range)

339 (255–387)

remaining dogs. Survivors were more likely to receive gastric

11.1 (4.7–30.6)
8.6 (6.0–15.0)
7.3 (2.8–11.0)

212 (17–500)
78 (40–110)
7.1 (7.0–7.4)

lavage compared to the non-survivors (P = 0.041) or activated

charcoal (P = 0.08); they were less likely to receive atropine-sulfate
Non-survivors

(P = 0.036), mannitol (P = 0.034) or mechanical ventilation

(P < 0.001).
15
15
14
14
14
14
14
n
9
9
9
9

7
7
3

Discussion
n (%) > RI

Insecticides, particularly OPs and carbamates, are important

45 (56)
28 (35)

56 (58)
22 (27)

15 (58)
11 (46)

11 (14)
5 (22)
8 (33)

3 (33)
3 (12)
4 (17)

6 (8)
0 (0)

intoxicants of dogs (Gfeller and Messonnier, 1998; Frazier et al.,

1999). Intoxications occur through farmland spraying in rural
areas, direct in-habitat contact, direct spraying, or malicious
n (%) < RI

poisoning. Intoxications lead to high morbidity and mortality in

20 (25)
15 (63)

12 (15)
5 (22)

2 (22)
5 (21)

5 (21)

9 (11)
3 (4)
2 (3)

5 (6)

2 (3)
0 (0)
0 (0)

both resource-poor settings and well-developed countries (De

Bosschere et al., 2001; Hrabetz et al., 2013). Nevertheless, there is
paucity of clinical studies of such intoxications in dogs. This
0.36 (0.08–0.89)
3.5 (12.2–11.5)
20.9 (14.4–38.5)

66.0 (41.0–76.9)
0.50 (0.14–0.71)
40.6 (21.2–81.9)

18.5 (11.0–36.0)
Median (range)

retrospective study of such intoxications, to the best of our

14.9 (4.9–43.6)
332 (284–385)

7.6 (6.0–12.0)
8.0 (2.3–11.5)

301 (0–875)
78 (50–120)
7.3 (7.1–7.5)

knowledge, is the largest one.

The clinical signs recorded herein were highly varied, but the
most common ones included muscle tremor, hypersalivation,
Survivors

weakness, vomiting, diarrhea, miosis, and tachypnea, combining

muscarinic and nicotinic signs, in agreement with previous reports
24
24
23
24
81

79

25
26
80
80
80
80

80

in dogs (Anastasio and Sharp, 2011) and humans (Lifshitz et al.,

n

1994, 1997; Lee and Tai, 2001; Sungur and Güven, 2001; El-Naggar
n (%) > RI

et al., 2009). In our study, presence of hypersalivation, tremor and

53 (55)
32 (34)
27 (28)

21 (64)
15 (46)

51 (54)
11 (33)

11 (12)

7 (22)

3 (25)
4 (12)
5 (16)

tachypnea were significantly associated with survival. Although,

7 (7)
0 (0)

prothrombin time; aPTT, activated partial thromboplastin time; NA, non-applicable.

diarrhea, ataxia and vomiting were also more frequently noted in

P value for comparisons of the frequencies of distribution in respect to the RI.

survivors, significance was not achieved. In contrast, presence of

n (%) < RI

weakness, mental dullness, anorexia, pale mucous membranes and

25 (27)
21 (64)
12 (38)
10 (30)

11 (12)
8 (24)

18 (1)

2 (17)

paddling were significantly associated with death. It therefore

4 (4)
4 (4)

6 (6)

3 (3)
0 (0)
0 (0)

Groups compared by the Student's t-test or Mann–Whitney U-test.

seems that the prognosis of dogs presenting with “classical”

muscarinic signs of intoxication was more favorable, while for dogs
3.0 (19.6–19.3)

0.27 (0.08–0.89)
66.0 (35.0–76.9)
19.9 (10.8–38.5)

0.50 (0.14–0.78)
40.5 (21.2–81.9)

19.0 (11.0–56.0)

presenting with signs of weakness and shock, the prognosis was

Median (range)

333 (255–38.7)

14.9 (4.7–43.6)
7.9 (6.0–15.0)
7.9 (2.3–11.5)

less favorable. Similarly, dogs presenting with more severe or

301 (0–875)
78 (40–120)
7.3 (7.0–7.5)

advanced signs of intoxication, suggestive of neurological and

cardiovascular derangement or shock (manifested as decreased
arterial blood pressure, pale mucous membranes, hypothermia
All dogs

and cold extremities) had poorer outcomes.

33
33
32
33
96
95
94
94
94
93
94
32
33
12

Numerous laboratory abnormalities were recorded in the

n

intoxicated dogs in this study. Leukocytosis was commonly

(54%) observed herein, in agreement with findings in humans
0.37–0.55
7.35–7.45

320–360
150–500

11–17.4
5.5–8.5

0.2–0.4
55–75
35–45

60–77

intoxicated with OPs (El-Naggar et al., 2009), possibly due to stress,

18–23

6–8.4
6–14
0–4

anxiety, or inflammation (e.g., pancreatitis and aspiration pneu-

RI

monia).
The median platelet count of both outcome groups was within
Leukocytes (109/L)
Platelets (109/L)

RI; however, thrombocytopenia was significantly more frequently

HCO3 (mmol/L)

Fibrinogen (g/L)
PCO2 (mmHg)

RBC (1012/L)

noted among the non-survivors. Thrombocytopenia was reported

BE (mmol/L)

MCHC (g/L)

in a human patient intoxicated with OP (Pechuho et al., 2014), but

PCV (L/L)
TPP (g/L)

MCV (fL)

aPTT (s)
Analyte

was not reported in previous studies of intoxicated dogs.

PT (s)
Table 3

Thrombocytopenia possibly resulted from direct toxin effects on

pH

b
a

platelets (Ziemen, 1984; Petroianu et al., 1999), or was due to low-

Table 4
Serum chemistry results and butyrylcholine esterase activity at presentation to the hospital of dogs acutely intoxicated by organophosphates or carbamates.

Analyte RI All dogs Survivors Non-survivors Pa Pb

n Median (range) n (%) <RI n (%)>RI n Median (range) n (%) <RI n (%) >RI n Median (range) n (%) <RI n (%) >RI

S. Klainbart et al. / The Veterinary Journal 251 (2019) 105349

Sodium (mmol/L) 145–154 80 146 (87–166) 26 (32.5) 6(7.5) 66 146 (131–162) 19 (29) 4 (6) 14 143 (87–166) 7 (50) 2 (14) 0.115 0.045
Potassium (mmol/L) 3.6–5.3 80 4.0 (2.0–7.0) 28 (35) 3 (4) 68 4.0 (3.0–6.0) 24 (35) 1 (2) 12 4.0 (2.0–7.0) 4 (33) 2 (17) 0.936 0.052
Chloride (mmol/L) 108–118 54 107 (75–129) 30 (56) 3 (6) 42 108 (75–124) 21 (50) 2 (5) 12 1038 (93–129) 9 (75) 1 (8) 0.021 0.200
Ionised calcium (mmol/L) 0.9–1.35 57 1.2 (1.0–1.0) 2 (4) 1 (2) 51 1.2 (1.0–1.0) 2 (4) 0 (0) 6 1.2(1.0–1.0) 0 (0) 1 (14) 0.101 0.024
Total calcium (mmol/L) 2.43–2.88 63 2.48 (1.73–3.13) 27 (43) 5 (8) 54 2.48 (1.73–3.13) 22 (41) 5 (9) 9 2.4 (1.85–2.78) 5 (56) 0 (0) 0.731 0.528
Albumin (g/L) 30–44 64 33 (15–57) 23 (36) 6 (9) 54 34 (20–57) 18 (33) 5 (9) 10 30 (15–46) 5 (50) 1 (10) 0.523 0.599
Total protein (g/L) 54–76 65 71 (41–119) 10 (15) 23 (35) 54 71 (48–119) 6 (11) 18 (33) 11 73 (41–106) 4 (36) 5 (46) 0.713 0.034
Total bilirubin (mmol/L) 0–3.42 65 5.13 (0–66.71) NA 42 (65) 54 5.13 (0–17.10) NA 33 (61) 11 11.97 (1.71–66.71) NA 9 (82) 0.043 0.190
Cholesterol (mmol/L) 3.50–9.35 65 5.72 (1.97–13.52) 6 (9) 5 (8) 54 5.72 (1.97–12.33) 2 (4) 3 (6) 11 5.44(2.46–13.52) 4 (37) 2 (18) 0.993 0.001
Total CO2 (mmol/L) 16–26 43 21.0 (0–42.0) 16 (37) 12 (28) 35 22.0 (5.0–38.0) 11 (31) 11(31) 8 11.1(0.0–42.0) 5 (63) 1 (13) 0.046 0.247
Triglycerides (mmol/L) 0.219–1.50 59 0.87 (0.23–14.38) 0 (0) 17 (29) 48 0.81 (0.33–6.00) 0 (0) 9 (19) 11 2.46(0.23–14.38) 0 (0) 8 (73) 0.056 0.001
Phosphorus (mmol/L) 0.97–2.00 65 1.42 (0.45–5.43) 11 (17) 9 (14) 54 1.39 (0.45–5.43) 10 (19) 7 (13) 11 1.58 (0.84–4.49) 1 (9) 2 (18) 0.255 0.711
Creatinine (mmmol/L) 26.4–105.6 65 105.6 (0–836.0) 0 (0) 34 (52) 54 105.6 (26.4–299.2) 0 (0) 27 (50) 11 52.8 (0.0–836.0) 0 (0) 7 (64) 0.062 0.409
Urea (mmol/L) 3.82–19.10 66 16.21 (3.64–125.4) 0 (0) 19 (29) 55 15.8 (3.64–82.11) 0(0) 13 (24) 11 26.95 (8.78–125.4) 0 (0) 6 (55) 0.022 0.039
Glucose (mmol/L) 3.55–6.83 61 5.77 (2.55–19.43) 3 (5) 16 (26) 49 5.55 (2.55–19.43) 3 (6) 13 (27) 12 5.88(3.89–14.04) 0 (0) 3 (25) 0.723 0.662
Amylase (U/L) 103–1510 64 967 (27–16,466) 1 (2) 21 (32) 53 899 (27–16,466) 1 (2) 15 (28) 11 1737 (521–7987) 0 (0) 6 (55) 0.102 0.214
DGGR-lipase (U/L) 5–107 4 71 (48–415) NA NA 3 66 (48.0–76) NA NA 1 415 (415.0–415) NA NA 0.180 NA
ALP (U/L) 21–170 65 153 (15–1330) 0 (0) 28 (43) 54 153 (15–1330) 0 (0) 22 (41) 11 169 (23–738) 0 (0) 6 (55) 0.786 0.399
AST (U/L) 19–42 64 86 (6–1625) 1 (2) 57 (89) 53 73 (6–1099) 1 (2) 47 (89) 11 374 (41–1625) 0 (0) 10 (91) 0.008 0.881
ALT (U/L) 19–67 67 77 (19–1273) 0 (0) 37 (55) 56 67 (19–1273) 0 (0) 28 (50) 11 183 (27–543) 0 (0) 9 (82) 0.002 0.046
GGT (U/L) 0–6 65 2.6 (0–16.2) NA 14 (22) 54 2.6 (0–16.2) NA 11 (20) 11 2.8 (0.0–15.5) NA 3 (27) 0.484 0.612
CK (U/L) 51–339 65 5888 (31–211,343) 0 (0) 42 (65) 54 5883 (31–211,343) 0 (0) 36 (67) 11 3823 (60–20,565) 0 (0) 6 (55) 0.495 0.443
BuChE(U/L) 2660–11,000 94 616 (0–6954) 86(91) NA 77 621 (0–6954) 69 (90) NA 17 601 (0–2576) 17 (100) NA 0.507 0.187

RI, reference interval; DGGR, 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(60 -methylresorufin) ester; ALP, alkaline phosphatase; AST, aspartate transaminase; ALT, alanine aminotransferase; GGT, g-glutamyltranspeptidase; CK,
creatine kinase; BuChE, butyrylcholine esterase; NA, not applicable.
a
Groups compared using the Student’s t-test or Mann–Whitney U-test.
b
Groups compared using the chi-squared or Fisher’s exact tests.

5
6 S. Klainbart et al. / The Veterinary Journal 251 (2019) 105349

Table 5
Treatments administered to dogs with acute organophosphate or carbamate toxicity.

Treatment administered n ALL DOGS n (%) SURVIVORS n (%) NON-SURVIVORS n (%) P

Treated Not treated Treated Not treated Treated Not treated

Activated charcoala 101 34 (33.7) 67 (66.3) 33 (39.3) 51 (60.7) 1 (5.9) 16 (94.1) 0.008
Antibiotics 101 66 (65.3) 35 (34.7) 53 (63.1) 31 (36.9) 13 (76.5) 4 (23.5) 0.291
Atropinesulfateb 101 67 (66.3) 34 (33.7) 52 (61.9) 32 (38.1) 15 (88.2) 2 (11.8) 0.036
Body wash 101 13 (12.9) 88 (87.1) 12 (14.3) 72 (85.7) 1 (5.9) 16 (94.1) 0.345
Diazepamc 101 54 (53.5) 47 (46.5) 44 (52.4) 40 (47.6) 10 (58.8) 7 (41.2) 0.627
Diphenhydramined 101 81 (80.2) 20 (19.8) 67 (79.8) 17 (20.2) 14 (82.4) 3 (17.6) 0.807
Gastric lavage 100 33 (33.0) 67 (67.0) 31 (37.3) 52 (62.7) 2 (11.8) 15 (88.2) 0.041
H2 receptor blockere 101 35 (34.7) 66 (65.3) 27 (32.1) 57 (67.9) 8 (47.1) 9 (52.9) 0.239
Isofluranef 101 36 (35.6) 65 (64.4) 30 (35.7) 54 (64.3) 6 (35.3) 11 (64.7) 0.974
Mannitolg 101 22 (21.8) 79 (78.2) 15 (17.9) 69 (82.1) 7 (41.2) 10 (58.8) 0.034
Methocarbamoleh 28 6 (21.4) 22 (78.6) 6 (27.3) 16 (72.7) 0 (0) 6 (100.0) 0.149
Metoclopramidei 101 50 (49.5) 51 (50.5) 38 (45.2) 46 (54.8) 12 (70.6) 5 (29.4) 0.057
Phenobarbitalj 101 33 (32.7) 68 (67.3) 26 (31.0) 58 (69.0) 7 (41.2) 10 (58.8) 0.412
Propofolk 101 43 (42.6) 58 (57.4) 36 (42.9) 48 (57.1) 7 (41.2) 10 (58.8) 0.898
2-PAMl 101 52 (51.5) 49 (48.5) 41 (48.8) 43 (51.2) 11 (64.7) 6 (35.3) 0.232
Mechanical ventilation 102 20 (19.6) 82 (80.4) 11 (12.9) 74 (87.1) 9 (52.9) 8 (47.1) <0.001
a
Chrcdote, Pharmascience INC., Montréal, Canada.
b
Atropine-sulfate, Teva Pharmaceutical Works Private Limited Company, Hungary.
c
Diazepam; Hameln Pharmaceuticals, Gloucester, UK.
d
Diphenhydramine hydrochloridium, Fagron, Capelleaan den IJssel, Netherlands.
e
Famotidine, West-Ward, Eatontown, NJ, USA.
f
Isoflurane, Pirmal, Bethlehem, PA, USA.
g
20% Osmitrol, Baxter, Deerfield, IL, USA.
h
Ortoton, Recordati pharma, Ulm, Germany.
i
Pramin, Rafa Laboratories, Jerusalem, Israel.
j
Luminal, Kern pharma, Barcelona, Spain.
k
Lipuro 1%, B. Braun, Melsungen, Germany.
l
2-PAM; 2-pyridine aldoxime methyl chloride, (Pralidoxime).Pyridine-2 Aldoxime methochloride, Sigma-Aldrich, Schnelldorf, Germany.

grade consumptive coagulopathy in the non-survivors, which is
also supported by their significantly prolonged PT and their
prolonged, but not statistically increased aPTT, compared to the
survivors. To the best of our knowledge, hemostatic findings were
not reported in previous studies of dogs intoxicated by OPs. The
present results suggest that hemostatic derangement does occur in
more severe intoxications in dogs, warranting future studies.
Venous blood pH below reference interval was very frequent
among the survivors and non-survivors alike. However, median
venous blood bicarbonate concentration was significantly lower in
the latter, supporting a more severe metabolic acidosis in this
group. This agrees with previous findings in experimental and
clinical acute OP and carbamate intoxications in dogs (Cordoba
et al., 1983; Anastasio and Sharp, 2011), as well as in humans,
where acidemia is a major outcome predictor, reflecting the
severity of intoxication (Liu et al., 2008; Gunduz et al., 2015). In the
study by Anastasio and Sharp (2011), the most common laboratory
abnormality among dogs with acute carbamate toxicity, was lactic
acidosis, attributed to multifactorial mechanisms, including
hypovolemia with reduced tissue perfusion (secondary to ptya-
lism, vomiting, and diarrhea) and increased tissue oxygen demand
resulting from tremors. Interestingly, sodium bicarbonate is
occasionally used for the treatment of OP poisoning in humans
in certain countries, instead of oximes (Wong et al., 2000; Balali-
Mood et al., 2005). Elevation in blood pH (up to 7.45–7.55) has been
reported to improve outcome in dogs through an unknown
mechanism (Cordoba et al., 1983); however, a Cochrane review
(Roberts and Buckley, 2005) concluded that there is insufficient
evidence to establish whether sodium bicarbonate should be used
in humans poisoned with OP.
Hypertriglyceridemia was significantly more common among
the non-survivors than the survivors. OPs induce hypertriglycer-
idemia in mice via single or dual endocannabinoid hydrolyzing
enzyme inhibition (Suzuki et al., 2014). Hypertriglyceridemia was
also recorded in rats and fish intoxicated by OPs (Abdel-Daim et al.,
2015; Akande et al., 2016; Narra et al., 2017). Moreover, this present
finding agrees with previous findings in humans intoxicated by
highly lipophilic OP herbicides, where serum triglycerides
concentration is increased, and is a useful prognostic predictor
(Han et al., 2016). The possible mechanisms responsible for this
hypertriglyceridemia include receptor or enzyme (e.g., hormone
sensitive lipase) inhibition or activation, specific toxin character-
istics (i.e., fat solubility), body fat content, and development of
acute pancreatitis (Evans, 2011). This retrospective study cannot
provide the mechanism of the hypertriglyceridemia or its
association with death in the intoxication, but the present results
warrant future studies.
Increased serum hepatocellular enzyme (ALT and AST) activities
and hyperbilirubinemia were commonly noted in this cohort, and
were significantly more frequent among the non-survivors. These
abnormalities were reported in both experimental OP and
carbamate intoxications in animals and in intoxications in humans.
In the latter, ALT and AST activities were significantly higher in
more severe cases of intoxication (Reena et al., 1989; Gomes et al.,
1999; Rao, 2006; Amanvermez et al., 2010). Their increased activity
possibly resulted from both hepatocellular and muscular injury.
The latter is likely, as serum CK activity was commonly
concurrently increased herein, as reported in OP intoxications in
rats and humans (Vanneste and Lison, 1993; John et al., 2003;
Bhattacharyya et al., 2011; Hall and Bender, 2011), likely due to
seizures, muscle fasciculations and tremors (Hall and Bender,
2011). Hyperbilirubinemia, noted in 65% of the dogs in this cohort,
suggests liver dysfunction or post-hepatic cholestasis, possibly
secondary to low-grade pancreatitis (Reena et al., 1989; Gomes
et al., 1999; Awad et al., 2014; Vanaja and Palanimuthu, 2014). This
is supported by the correlations between serum bilirubin
concentration and ALP and ALT activities, and by the relatively
common (32%) occurrence of hyperamylasemia in this cohort,
respectively.
Hypochloridemia, possibly secondary to acute vomiting and
diarrhea, was common, and was significantly more severe in the
non-survivors. Nevertheless, the median corrected chloride
 S. Klainbart et al. / The Veterinary Journal 251 (2019) 105349
concentration was within reference interval in the entire cohort as
well as among the non-survivors. Serum urea and creatinine
concentrations were higher among the non-survivors than the
survivors, possibly due to more severe dehydration, hypovolemia
and developing acute kidney injury (AKI) in the former. This agrees
with findings of severe OP intoxications in humans, where the
occurrence and risk of AKI are increased (Cavari et al., 2013; Lee
et al., 2015).
Serum BuChE activity was measured in 94 dogs at presentation
herein, and was reduced below RI in 86 dogs (92%), although in
eight it was within the reference interval. Nevertheless, in these
eight dogs with normal BuChE activities, solid evidence of toxin
exposure and typical clinical signs of intoxication existed. The
hospital’s laboratory BuChE activity reference interval in dogs is
wide (2660–11000 U/L), thereby decreasing its sensitivity.
Intoxicated humans have also been reported to present with
BuChE activity within the reference interval (Hodgson and
Parkinson, 1985; Midtling et al., 1985; Tafuri and Roberts, 1987).
This wide BuChE reference interval, which results in low
sensitivity, possibly contributed to the lack of difference in BuChE
activity between the outcome groups in the present study. This
present finding is also in agreement with previous findings, where
the severity of the typical clinical signs of OP intoxication was not
reflected by the absolute decrease in AChE activity, but rather by
the rate of its decrease (Summerford et al., 1953; Midtling et al.,
1985).
Organophosphate or carbamate poisoning is diagnosed based
on RBC AChE or serum BuChE activity, identifying the toxic
compound in gastric contents or history of ingestion or other
exposure to such toxins (Namba et al., 1971; Tafuri and Roberts,
1987). When this information is unavailable, establishing a
diagnosis on a clinical evaluation alone is arduous. In mild to
moderate intoxications, gastroenteritis, asthma, venomous arthro-
pod bite (e.g., black widow and scorpion), non-specific viral
infection or progressive peripheral neuropathies (e.g., polyradi-
culoneuritis, Guillain-Barré syndrome in humans, fulminant
myasthenia gravis) are differential diagnoses. In intoxications
presenting with severe clinical signs, the differential diagnoses
may also include hypoglycemia, drug overdose (e.g., opiates,
phencyclidine, meprobamate, phenothiazines, clonidine, or cho-
linergic drugs overdose, such as pilocarpine, carbachol, bethane-
chol or methacholine) and severe pyrethroid insecticide
intoxication. Consumption of muscarine-containing mushrooms
(e.g. some species of the Inocybe genus, Clitocybe genus, and ‘red-
pored Boletes’ group) will cause classic cholinergic crisis, but will
lack clinical signs associated with nicotinic signs. Nicotine
intoxication might be difficult to differentiate from OP or
carbamate poisoning, although, in severe nicotine poisoning,
mydriasis is usually present. Metabolic and infectious etiologies of
coma, including myxedema coma, diabetic ketoacidosis, sepsis,
meningitis and encephalitis, as well as major structural neurologi-
cal etiologies of coma should also be considered (Tafuri and
Roberts, 1987).2
None of the eight dogs where BuChE activity was within
reference interval were exposed to drugs or toxins other than OPs
or carbamates. With exception of one, all of these dogs were
intoxicated in the spring or summer (i.e., the dry season), and as
such, there was no chance of environmental exposure to mush-
rooms. As all eight dogs underwent full physical exam and CBC, and
in all, partial (2/8 dogs) or full (6/8 dogs) serum chemistry was
2
See: Heide, E.A., 2012. Cholinesterase inhibitors: including insecticides and
chemical warfare nerve agents Part 5: The intermediate syndrome. Agency for toxic
substances and disease registry (ATSDR).http://www.atsdr.cdc.gov/csem/csem.asp.
(Accessed 22 July, 2019).
7
available, metabolic, infectious, and neurologic etiologies were
excluded to the best of our ability.
The treatments of the dogs in this cohort varied. Atropine-
sulfate is the mainstay antidotal treatment for ACC, to combat its
muscarinic signs (Gfeller and Messonnier, 1998; Meerdink, 2004).
It was more frequently administered to the non-survivors
compared to the survivors, possibly because the former presented
with more severe muscarinic signs, and were therefore, more likely
to die. The nicotinic signs of ACC can be treated with 2-PAM, which
has little effect on muscarinic and CNS signs. In the present cohort,
approximately 50% of the dogs received 2-PAM, and the drug was
unassociated with the outcome. The use of 2-PAM in carbamate
intoxication is controversial (Rosman et al., 2009). First, it is
claimed that oxime therapy is unwarranted, because carbamates
do not permanently inhibit AChE and mostly result in moderate,
reversible intoxication that responds well to atropine and
supportive therapy. Second, in some experimental carbamate
intoxications in animals, particularly those involving carbaryl,
oxime therapy exacerbated toxicity (Natoff and Reiff, 1973; Harris
et al., 1989; Galloway and Smallridge, 1994). However, it is argued
that in these studies the administered oxime doses were
themselves toxic, and not in line with current clinical practice
(Mercurio-Zappala et al., 2007). Furthermore, additional data
support the potential beneficial effects of oximes in intoxications
by most carbamate compounds, in both animal studies and in
clinical case reports in humans (Natoff and Reiff, 1973; Harris et al.,
1989; Ekins and Geller, 1994; Galloway and Smallridge, 1994;
Rosman et al., 2009).
Diphenhydramine was very frequently used in this cohort, due
to its antinicotinic effects, and when administered to mice and rats
with experimentally induced acute OP intoxication decreased their
mortality rate (Mohammad et al., 1989; Faris and Mohammad,
1997; Bird et al., 2002). Nevertheless, diphenhydramine is not
considered standard therapy in OP intoxication in humans. Its use
did not differ between the outcome groups herein. We therefore
cannot recommend its use or disuse in such intoxications in dogs.
Mannitol was administered significantly more frequently to the
non-survivors than the survivors, and to dogs presenting with
seizures compared to other dogs. This association between
mannitol treatment and increased risk of death is likely biased,
resulting from its indication to lower intracranial pressure in dogs
presenting with severe CNS abnormalities (e.g. seizures), which
were also associated with increased risk of death and very likely
reflected more severe intoxications.
Gastric lavage and activated charcoal treatment were both
administered more frequently to the survivors compared to the
non-survivors. The veterinary literature recommends one or both
of these measures, depending on the time lag from toxin ingestion
to presentation for care, for the management of oral intoxications
in general, based on sound rationale (Arnot et al., 2011; Gupta and
Milatovic, 2012; Lee, 2013). Nevertheless, high-quality evidence
supporting their use in managing intoxications, and particularly in
OP or carbamate intoxications, is lacking (Tomimaru et al., 1996;
Chyka and Seger, 1997; Li et al., 2009; Benson et al., 2013). The
present findings therefore provide supporting evidence of the
beneficial effects of both these measures in dogs orally and acutely
intoxicated with OPs.
Mechanical ventilation was applied to 20% of our dogs, which
was comparable to OP (with or without carbamate) intoxication in
humans (17–75% required mechanical ventilation; Tsao et al., 1990;
Chuang et al., 1996; Saadeh et al., 1996, 1997; Emerson et al., 1999;
Lee and Tai, 2001; Sungur and Güven, 2001; Verhulst et al., 2002;
Sungurtekin and Balcy, 2003; Sungurtekin et al., 2006; Noshad
et al., 2007). It has several indications in OP intoxication. First,
bronchoconstriction and bronchial hypersecretion, common mus-
carinic toxin effects, often result in dyspnea, hypoxemia and
8 S. Klainbart et al. / The Veterinary Journal 251 (2019) 105349
respiratory failure, potentially leading to asphyxia and aspiration
pneumonia. Second, the nicotinic effects of OPs lead to muscle
weakness, potentially with respiratory muscle fatigue and
ineffective respiration, while CNS depression might aggravate
the progression to respiratory failure (Tsao et al., 1990; Noshad
et al., 2007). Of the 17 non-survivors in this cohort, nine (53%) had
sustained respiratory failure requiring mechanical ventilation (45%
of the mechanically-ventilated dogs herein). It is highly likely that
dogs requiring mechanical ventilation sustained more severe
intoxications, which therefore led to their significantly higher
mortality rate compared to other dogs. The mortality rate of the
ventilated dogs in our study was comparable to the mortality rate
of ventilated human patients (34–51%; Tsao et al., 1990; Chuang
et al., 1996; Saadeh et al., 1996, 1997; Emerson et al., 1999; Lee and
Tai, 2001; Sungur and Güven, 2001; Verhulst et al., 2002;
Sungurtekin and Balcy, 2003; Sungurtekin et al., 2006; Noshad
et al., 2007) and dogs (ventilated for any reason; 32%–59%; Hopper
et al., 2007).
This retrospective clinical study has several inherent limita-
tions. Firstly, some data were missing from the medical records,
and certain laboratory tests were not performed for some dogs,
oftentimes due to financial constraints, weakening the power of
certain statistical analyses. This is a common limitation in clinical
retrospective studies, which we have tried to minimize the impact
of by investigating a relatively large cohort. Secondly, cause and
effect relationship cannot sometimes be determined retrospec-
tively. Thirdly, the methods used to diagnose intoxication varied,
and more often, the exact toxic compound was undetermined.
Fourthly, serum BuChE activity was the most common laboratory
diagnostic method of intoxication. BuChE activity is an indicator of
OP poisoning or simple exposure to OP, but individual levels need
to be interpreted with caution. The interpretation of the results of
such measurements is complex for several reasons, particularly
when the changes in BuChE activity are small (World Health
Organization (WHO), 1985; McQuee, 1995; Rosenman and Guss,
1997; Aygun et al., 2002; Stefanidou et al., 2009) the dose-response
relation in vivo is modified by absorption, distribution, metabolism
and excretion of each individual OP or carbamate; the cholines-
terase activity levels apply only to the time when the blood sample
was drawn, and offer no indication of any trend; the wide BuChE
activity reference interval in non-exposed dogs makes it difficult to
detect small degrees of inhibition; levels of enzyme activity may
vary for causes other than inhibition (i.e. inherited, physiological,
metabolic, acquired and iatrogenic conditions); inhibition is not
measured directly, but only by reference to a ‘normal’ value,
ignoring inter- and intra-individual variations; the degree of
inhibition of BuChE activity does not reflect precisely the inhibition
of cholinesterase within the nervous system, nor does it give any
indication of the extent or severity of functional changes in other
body systems; and finally, in the case of carbamate esters, the
faster reversibility of the cholinesterase inhibitor complex may
produce a ‘false negative’ result. Nevertheless, the diagnosis of OP
or carbamate intoxication in the present study was based on
compatible history and clinical signs along with BuChE activity
measurements, and most studies agree that measurement of
BuChE activity can be used as a sensitive marker of exposure to
most organophosphorus compounds or other cholinesterase-
inhibiting compounds, and for measuring organophosphorus
elimination from the body (Namba et al., 1971; Tafuri and Roberts,
1987; Eddleston et al., 2008; Stefanidou et al., 2009). Lastly, this
study comprised clinical data from a single teaching referral
hospital over a relatively long time-period. Due to advances made
in veterinary medicine over this time-frame the latter undoubtedly
introduced some variance and could have influenced the clinical
outcome of individual cases. Our results should therefore be
applied cautiously to other clinical settings.
Conclusions
This large-scale retrospective study of acute OP and carbamate
intoxications in dogs describes the common clinical and laboratory
findings at presentation and has identified several prognostic factors.
The overall mortality rate was 17%, and death was most often
associated with respiratory failure and mechanical ventilation.
Conflict of interest statement
None of the authors has any financial or personal relationships
that could inappropriately influence or bias the content of the
paper.
Acknowledgements
A portion of this manuscript includes some results of a DVM
dissertation, submitted by Dr M. Grabernik to the Koret School of
Veterinary Medicine, Hebrew University of Jerusalem, Israel. Some
of the results were presented as an abstract at the 28th European
College of Veterinary Internal Medicine – Companion Animals
(ECVIM-CA) Congress; Rotterdam, September 2018.
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