Superwarfarin rodenticide intoxication in adults: an

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CASE REPORT
Superwarfarin rodenticide intoxication in adults: an
update on bromadiolone, brodifacoum, and difethialone
MARÍA LUISA IGLESIAS LEPINE1,2, FRANCISCO EPELDE GONZALO1, FRANCISCO CASAÑAS FERRER1,
EMILI GENÉ TOUS1,3
Servicio de Urgencias, Hospital de Sabadell, Corporació Sanitària i Universitària Parc Taulí, Sabadell,
Barcelona, Spain. 2Departamento de Psiquiatría y Medicina Legal (UAB), Barcelona, Spain. 3CIBERehd,
Instituto de Salud Carlos III, Barcelona, Spain.
1
CORRESPONDENCE:
María Luisa Iglesias Lepine
Servicio de Urgencias
Hospital de Sabadell
Parc Taulí, s/n
08208 Sabadell
Barcelona, Spain
E-mail: miglesias@tauli.cat
We report 3 cases in which adults used a superwarfarin rodenticide (bromadiolone,
brodifacoum, or difethialone) to attempt suicide. No patient developed coagulation
abnormalities or significant clinical problems, and all were dischanged alive from the
emergency department (2 to home, 1 to a psychiatric facility). An updated action plan
based on case reports published in the last 10 years is also provided. [Emergencias
2013;25:201-203]
Keywords: Superwarfarin rodenticides. Bromadiolone. Brodifacoum. Difethialone.
RECEIVED:
7-9-2011
ACCEPTED:
20-10-2011
CONFLICT OF INTEREST:
The authors declare no conflict
of interest in relation with the
present article.
Introduction
In Spain, 416 formulated rodenticides are currently registered1 and those most widely used are potent
anticoagulants. They are classified into two groups
according to their chemical composition: coumarin
derivatives (brodifacoum, bromadiolone, coumatetralyl, difenacoum, difethialone, flocoumafen and warfarin) constituting 87.4% and indandione derivatives
(diphacinone and chlorophacinone) constitute the remaining 12.6%. However, it is clinically useful to classify them by their half-life: first generation or short
duration rodenticide (eg, warfarin) and second-generation or long duration rodenticides (i.e. bromadiolone). The aim of this clinical note is to present
three cases of poisoning by ingestion of superwarfarín rodenticides in adults as well as to provide an
update on the plan of action to be followed.
Clinical cases
Case 1 was a 21 year-old woman with a histoEmergencias 2013; 25: 201-203
ry of unwanted 8-week pregnancy, dissociative
crises and difficulty in handling stress. She consulted for ingestion of two packets of 0.005%
bromadiolone with suicidal intent. The total dose
ingested was 2.5 mg some 6-8 h before arrival at
the ED. Blood pressure (BP) was 154/86 mmHg
and heart rate (HR) 83 beats per minute (lpm).
Physical examination, laboratory tests including
coagulation tests were normal. The patient was
prophylactically administered 20 mg phytomenadione (VK 1) by intravenous (IV) route and kept
under observation for 48 h with monitoring of
prothrombin time (PT) every 24 h. No significant
alterations appeared and she was discharged
home.
Case 2 was a 57 year-old with a history of
bipolar disorder receiving lithium treatment. The
patient consulted after ingesting 8 packets of
0.01% brodifacoum with suicidal intent. The total
dose ingested was 5 mg during the last week. BP
was 100/60 mm / Hg, heart rate 70 bpm and O2
saturation 99% (with an inspired fraction of
26%). On examination, there was evidence of
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M. L. Iglesias-Lepine et al.
epistaxis which required anterior tamponade. Laboratory tests, coagulation tests, lithium levels and
ECG were normal. VK1 20 mg IV was administered
every 24 h and the patient was kept under observation for 48 h with 12 h monitoring of PT. No
significant alterations were observed, the epistaxis
was deemed not to be related with a bleeding
disorder, and the patient was admitted to the psychiatric ward.
Case 3 was a 43 year-old man with a history
of personality disorder, alcohol and benzodiazepine dependence. He consulted after ingesting
four 25 g packets of 0.0025% difethialone with
suicidal intent. Total dose ingested was 2.5 mg in
the preceding 3 days. The last use was 8 hours
before arrival at the ED. BP was 110/73 mm / Hg,
heart rate of 112 bpm and O 2 saturation 97%
(with an inspired fraction of 26%). Laboratory
tests, coagulation tests, ECG and chest X-ray were
normal. The patient was administered 20 mg VK1
IV prophylactically and kept under observation for
48 h with 24 h PT monitoring. No significant
changes were observed and the patient was discharged home.
Discussion
Rodenticide poisoning with superwarfarín has
increased in the last decade in countries like the
U.S. and China 2,3, as opposed to Spain where
prevalence is low4. These products are characterized by their rapid and complete absorption rate
and long elimination half-life. As VK1 antagonists,
they inhibit VK1 enzymes, 2-3-epoxide reductase
and VK1 reductase and decrease production of vitamin K-dependent coagulation factors (II, VII, IX
and X)5-7. Protein binding is 99%, and their volume of distribution is 11-12% of bodyweight.
They accumulate in the liver due to high lipid solubility, present enterohepatic circulation and are
eliminated in feces and urine5,6.
The approach to probable / possible rodenticide poisoning for emergency department (ED)
professionals is detailed below. The first step is to
identify the product and the dose ingested. Product catalogs only specify toxic doses for animals
and not humans. From a review of published case
reports, the toxic dose of brodifacoum is 0.1 to
0.27 mg/kg1,8 and 0.17 mg/Kg9 for bromadiolone.
There are no data on difethialone toxic values.
In countries like the U.S. with its American Association of Poison Control Center 8, EDs have
screening test for warfarin compounds (Ratio VK12, 3 epoxide/K1)10 and can also identify, quantify
202
and weigh the various superwarfarin compounds
using chromatographic techniques5,8,9,11-14. Individual metabolism (genetic variability within populations) of each product guides the clinician on
what action to take. Thus the kinetic model of
bromadiolone elimination from the blood is bicompartmental, with an initial phase of rapid
elimination (3.5 / 6 days in plasma / blood, respectively), followed by a slower terminal phase
(10-13/24 days plasma / blood9,13,15. By contrast
that of brodifacoum is 20-209 days in
serum2,12,16,17. Being multi-compartmental it follows
a first-order kinetic model that becomes zero order when intake is significant 7,18 . It has been
demonstrated that 10 ng / mL bromadiolone in
plasma and and 4-10 ng / mL brodifacoum in
serum do not require specific treatment 7,9,18, so
not all require ingested doses treatment. The second step is to find out the time since the last ingestion for the possible manifestations that appear at 24-48 h after PT drops below 20%2-6,8-20,
i.e. epistaxis, gingival bleeding, hematuria, ecchymosis, hemoptysis, vaginal bleeding, pulmonary
or gastrointestinal bleeding, etc.
Specific and adjuvant treatment, as for any
acute intoxication, is digestive decontamination
with activated carbon or polyethylene glycol solution depending on the time elapsed since ingestion. If PT is abnormal (50 - 80%), it is advisable
to administer 10 mg orally or IV VK1 and PT control every 24 h. If PT is ⱕ 50% and the patient
has some sort of bleeding, the recommendation is
VK1 0.1-3 mg / kg / day every 6-8 h by oral or IV
route2-4,7-10,12,16,19,20. Bruno et al18 demonstrated in an
animal model that the ideal dose of VK1 is 3.5 mg
/ kg / day every 6 hours for at least 48 h by oral
route. Today it may be administered intravenously
since the solvent that once caused anaphylaxis
has been modified. If the situation is life threatening, one can add prothrombin complex6,13 and /
or fresh frozen plasma2-20. Once stabilized, if chromatography to identify and quantify the swallowed product is not available, the recommendation is to orally administer 10 mg VK1 every 24
h2-20 during weeks / months, with weekly PT control8.
In our review of published cases we found that
it takes a significant amount of the product to
produce symptoms in humans, so one should only intervene if the dose ingested is actually toxic2-20,
and prophylactic VK1 is not recommended if PT
shows no significant alterations at 48 h after ingestion8,11,18. In all three cases presented here, it
was unknown whether the dose was toxic for humans. PT was requested every 12 - 24 h during
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SUPERWARFARIN RODENTICIDE INTOXICATION IN ADULTS: AN UPDATE ON BROMADIOLONE, BRODIFACOUM, AND DIFETHIALONE
48 h, VK1 was administered prophylactic ally and
observation time was 48 h. In the second case
prophylaxis was also deemed necessary because
of the episode of epistaxis and the prolonged
consumption. However, in light of this review,
none of the three required VK1 prophylaxis since
none showed PT alterations, and furthermore, the
dose administered was twice that recommended.
In conclusion, superwarfarin rodenticides are
over-the-counter products despite their deadly
potential. The concept of a toxic dose enunciated
by Paracelsus (1493-1541), dosis sola facit venenum, remains valid today, so therapy should not
be applied in cases of a non-toxic dose. If necessary, VK1 treatment should be adjusted on the basis of coagulation test results. All patientsvisiting
the ED with a coagulation disorder of unknown
origen should be screened for a warfarin compound. And if chromatographic techniques are
available, quantification of the product will help
avoid unnecessary therapies and fatal outcomes.
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Intoxicación por rodenticidas superwarfarínicos en adultos: bromadiolona, brodifacoum
y difetialona
Iglesias-Lepine ML, Epelde Gonzalo F, Casañas Ferrer F, Gene Tous E
Se presentan tres casos clínicos de tentativas suicidas por ingesta de rodenticidas superwarfarínicos (bromadiolona, brodifacoum y difetialona) en tres pacientes adultos. Ningún paciente presentó alteraciones en la coagulación ni problemas
clínicos relevantes, por lo que fueron dados de alta desde urgencias (2 casos a domicilio y 1 caso con ingreso en psiquiatría). Se realiza una puesta al día del plan de actuación a seguir, en base a los casos clínicos publicados en los últimos diez años. [Emergencias 2013;25:201-203]
Palabras clave: Rodenticidas superwarfarínicos. Bromadiolona. Brodifacoum y difetialona.
Emergencias 2013; 25: 201-203
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