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CASE REPORT intoxication in adults: an update on bromadiolone, , and

MARÍA LUISA IGLESIAS LEPINE 1,2 , F RANCISCO EPELDE GONZALO 1, F RANCISCO CASAÑAS FERRER 1, EMILI GENÉ TOUS 1,3 1Servicio 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.

CORRESPONDENCE : We report 3 cases in which adults used a superwarfarin rodenticide (bromadiolone, María Luisa Iglesias Lepine brodifacoum, or difethialone) to attempt suicide. No patient developed coagulation Servicio de Urgencias abnormalities or significant clinical problems, and all were dischanged alive from the Hospital de Sabadell emergency department (2 to home, 1 to a psychiatric facility). An updated action plan Parc Taulí, s/n based on case reports published in the last 10 years is also provided. [Emergencias 08208 Sabadell 2013;25:201-203] Barcelona, Spain E-mail: [email protected] Keywords: Superwarfarin . 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 ry of unwanted 8-week pregnancy, dissociative crises and difficulty in handling stress. She con - In Spain, 416 formulated rodenticides are current - sulted for ingestion of two packets of 0.005% ly registered 1 and those most widely used are potent bromadiolone with suicidal intent. The total dose . They are classified into two groups ingested was 2.5 mg some 6-8 h before arrival at according to their chemical composition: the ED. Blood pressure (BP) was 154/86 mmHg derivatives (brodifacoum, bromadiolone, coumatetra - and heart rate (HR) 83 beats per minute (lpm). lyl, , difethialone, and war - Physical examination, laboratory tests including farin) constituting 87.4% and indandione derivatives coagulation tests were normal. The patient was (diphacinone and ) constitute the re - prophylactically administered 20 mg phytomena -

maining 12.6%. However, it is clinically useful to clas - dione (VK 1) by intravenous (IV) route and kept sify them by their half-life: first generation or short under observation for 48 h with monitoring of duration rodenticide (eg, ) and second-gen - prothrombin time (PT) every 24 h. No significant eration or long duration rodenticides (i.e. bromadi - alterations appeared and she was discharged olone). The aim of this clinical note is to present home. three cases of poisoning by ingestion of superwar - Case 2 was a 57 year-old with a history of farín rodenticides in adults as well as to provide an bipolar disorder receiving lithium treatment. The update on the plan of action to be followed. 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

Clinical cases was 100/60 mm / Hg, heart rate 70 bpm and O 2 saturation 99% (with an inspired fraction of Case 1 was a 21 year-old woman with a histo - 26%). On examination, there was evidence of

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M. L. Iglesias-Lepine et al.

epistaxis which required anterior tamponade. Lab - and weigh the various superwarfarin compounds oratory tests, coagulation tests, lithium levels and using chromatographic techniques 5,8,9,11-14 . Individ -

ECG were normal. VK 1 20 mg IV was administered ual metabolism (genetic variability within popula - every 24 h and the patient was kept under obser - tions) of each product guides the clinician on vation for 48 h with 12 h monitoring of PT. No what action to take. Thus the kinetic model of significant alterations were observed, the epistaxis bromadiolone elimination from the blood is bi- was deemed not to be related with a bleeding compartmental, with an initial phase of rapid disorder, and the patient was admitted to the psy - elimination (3.5 / 6 days in plasma / blood, re - chiatric ward. spectively), followed by a slower terminal phase Case 3 was a 43 year-old man with a history (10-13/24 days plasma / blood 9,13,15 . By contrast of personality disorder, alcohol and benzodi - that of brodifacoum is 20-209 days in azepine dependence. He consulted after ingesting serum 2,12,16,17 . Being multi-compartmental it follows four 25 g packets of 0.0025% difethialone with a first-order kinetic model that becomes zero or - suicidal intent. Total dose ingested was 2.5 mg in der when intake is significant 7,18 . It has been the preceding 3 days. The last use was 8 hours demonstrated that 10 ng / mL bromadiolone in before arrival at the ED. BP was 110/73 mm / Hg, plasma and and 4-10 ng / mL brodifacoum in 7,9,18 heart rate of 112 bpm and O 2 saturation 97% serum do not require specific treatment , so (with an inspired fraction of 26%). Laboratory not all require ingested doses treatment. The sec - tests, coagulation tests, ECG and chest X-ray were ond step is to find out the time since the last in -

normal. The patient was administered 20 mg VK 1 gestion for the possible manifestations that ap - IV prophylactically and kept under observation for pear at 24-48 h after PT drops below 20% 2-6,8-20 , 48 h with 24 h PT monitoring. No significant i.e. epistaxis, gingival bleeding, hematuria, ecchy - changes were observed and the patient was dis - mosis, hemoptysis, vaginal bleeding, pulmonary charged home. or gastrointestinal bleeding, etc. Specific and adjuvant treatment, as for any acute intoxication, is digestive decontamination Discussion with activated carbon or polyethylene glycol solu - tion depending on the time elapsed since inges - Rodenticide poisoning with superwarfarín has tion. If PT is abnormal (50 - 80%), it is advisable

increased in the last decade in countries like the to administer 10 mg orally or IV VK 1 and PT con - U.S. and China 2,3 , as opposed to Spain where trol every 24 h. If PT is Յ 50% and the patient prevalence is low 4. These products are character - has some sort of bleeding, the recommendation is

ized by their rapid and complete absorption rate VK 1 0.1-3 mg / kg / day every 6-8 h by oral or IV 2-4,7-10,12,16,19,20 18 and long elimination half-life. As VK 1 antagonists, route . Bruno et al demonstrated in an they inhibit VK 1 enzymes, 2-3-epoxide reductase animal model that the ideal dose of VK 1 is 3.5 mg and VK 1 reductase and decrease production of vi - / kg / day every 6 hours for at least 48 h by oral tamin K-dependent coagulation factors (II, VII, IX route. Today it may be administered intravenously and X) 5-7 . Protein binding is 99%, and their vol - since the solvent that once caused anaphylaxis ume of distribution is 11-12% of bodyweight. has been modified. If the situation is life threaten - They accumulate in the liver due to high lipid sol - ing, one can add prothrombin complex 6,13 and / ubility, present enterohepatic circulation and are or fresh frozen plasma 2-20 . Once stabilized, if chro - eliminated in feces and urine 5,6 . matography to identify and quantify the swal - The approach to probable / possible rodenti - lowed product is not available, the recommenda -

cide poisoning for emergency department (ED) tion is to orally administer 10 mg VK 1 every 24 professionals is detailed below. The first step is to h2-20 during weeks / months, with weekly PT con - identify the product and the dose ingested. Prod - trol 8. uct catalogs only specify toxic doses for animals In our review of published cases we found that and not humans. From a review of published case it takes a significant amount of the product to reports, the toxic dose of brodifacoum is 0.1 to produce symptoms in humans, so one should on- 0.27 mg/kg 1,8 and 0.17 mg/Kg 9 for bromadiolone. ly intervene if the dose ingested is actually toxic 2-20 ,

There are no data on difethialone toxic values. and prophylactic VK 1 is not recommended if PT In countries like the U.S. with its American As - shows no significant alterations at 48 h after in - sociation of Poison Control Center 8, EDs have gestion 8,11,18 . In all three cases presented here, it

screening test for warfarin compounds (Ratio VK 1- was unknown whether the dose was toxic for hu - 2, 3 epoxide/K1) 10 and can also identify, quantify mans. PT was requested every 12 - 24 h during

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SUPERWARFARIN RODENTICIDE INTOXICATION IN ADULTS : AN UPDATE ON BROMADIOLONE , BRODIFACOUM , AND DIFETHIALONE

4 Rodrigo P, Rodríguez V, García JM, Aguilera I. Intento autolítico con 48 h, VK 1 was administered prophylactic ally and superwarfarinas. Rev Esp Anestesiol Reanim. 2005;52:506-7. observation time was 48 h. In the second case 5 Olmos V, Lenzken SC, Paz MC, Olivera NM, Clara SD, López M, et prophylaxis was also deemed necessary because al. Cuantificación de brodifacoum, bromadiolone y difenacoum en suero humano por HPLC con detección ultravioleta y fluorométrica. of the episode of epistaxis and the prolonged Acta Toxicol Arg. 2004;12:9. consumption. However, in light of this review, 6 Watt BE, Proudfoot AT, Bradberry SM, Vale JA. rodenti - cides. Toxicol Rev. 2005;24:259-69. none of the three required VK 1 prophylaxis since 7 North Dakota Poison Center. Long-Acting Anticoagulant Rodentici - none showed PT alterations, and furthermore, the des. Newsletters and Reviews. (Consultado 10 Julio 2011). Disponi - ble en: http://www.ndpoison.org/index.asp?pageID=150. dose administered was twice that recommended. 8 Dolin EK, Baker DL, Buck SC. A 44-year-old woman with hemateme - In conclusion, superwarfarin rodenticides are sis and cutaneous hemorrhages as a result f superwarfarin poisoning. J Am Osteopath Assoc. 2006;106:280-4. over-the-counter products despite their deadly 9 Lo VM, Ching CK, Chan AY, Mak TW. Bromadiolone toxicokinetics: diagnosis and treatment implications. Clin Toxicol (Phila). potential. The concept of a toxic dose enunciated 2008;46:703-10. by Paracelsus (1493-1541), dosis sola facit ve - 10 Tsutaoka BT, Miller M, Fung SM, Patel MM, Olson KR. Superwarfarin nenum, remains valid today, so therapy should not and glass ingestion with prolonged coagulopathy requiring high-do - se 1 therapy. Pharmacotherapy. 2003;23:1186-9. be applied in cases of a non-toxic dose. If neces - 11 Chua JD, Friedenberg WR. Superwarfarin Poisoning. Arch Intern Med. 1998;158:1929-32. sary, VK 1 treatment should be adjusted on the ba - 12 Olmos V, López CM. Brodifacoum poisoning with toxicokinetics da - sis of coagulation test results. All patientsvisiting ta. Clin Toxicol (Phila). 2007;45:487-9. 13 Grobosch T, Angelow B, Schönberg L, Lampe D. Acute bromadiolo - the ED with a coagulation disorder of unknown ne intoxication. J Anal Toxicol. 2006;30:281-6. origen should be screened for a warfarin com - 14 Jin MC, Ren YP, Xu XM, Chen XH. Determination of bromadiolone in whole blood by high-performance liquid chromatography cou - pound. And if chromatographic techniques are pled with electrospray ionization tandem mass spectrometry. Foren - available, quantification of the product will help sic Sci Int. 2007;17:52-6. 15 Vindenes V, Karinen R, Hasvoid I, Bernard HP, Morland JG, Christo - avoid unnecessary therapies and fatal outcomes. phersen AS. Bromadiolone poisoning: LC-MS method and pharma - cokinetic data. Forensic Sci. 2008;53:993-6. 16 Spahr JE, Maul JS, Rodgers GM. Superwarfarin poisoning: a report of two cases and review of the literature. Am J Hematol. 2007;82:656- References 60. 17 Pavlu J, Harrington DJ, Voong K, Savidge GF, Jan-Mohamed S, Kacz - marski R. Superfarfaring poisoning. Lancet. 2005;365:628. 1 Moreno J, López J, Jiménez R. El control de los roedores: revisión de 18 Bruno GR, Howland MA, McMeeking A, Hoffman R. Long-Acting An - los rodenticidas registrados en el ámbito de la sanidad ambiental en ticoagulant Overdose: Brodifacoum Kinetics and Optimal Vitamin K. España. Rev Esp Salud Pública. 2004;78:5-16. Ann Emerg Med. 2000;36:262-7. 2 Nelson AT, Hartzell JD, More K, Durming SJ. Ingestion of Superwar - 19 Laposata M, Van Cott E, Lev MH. Case 1-2007: A 40 years-Old Wo - farin Leading to Coagulopathy: A Case Report and Review of the li - man with Epixtasis, Hematemesis and Altered Mental Status. N Engl terature. Med Gen Med. 2006;8:41. J Med. 2007;356:174-82. 3 Shu-Lei Z, Peng L, Ming J, Ye Z, Shu-Tian Z. Upper gastrointestinal 20 Conte G, Torres C, Alfaro J, Marianela V. Intoxicación por rodentici - hemorrhage caused by superwarfarin poisoning. Wold J Gastroente - da-superwarfarina: Descripción de un caso clínico. Revista Hospital rology. 2010;16:1680-2. Clínico Universidad de Chile. 2004;15:209-12.

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, bro - difacoum 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 psi - quiatría). Se realiza una puesta al día del plan de actuación a seguir, en base a los casos clínicos publicados en los últi - mos diez años. [Emergencias 2013;25:201-203]

Palabras clave: Rodenticidas superwarfarínicos. Bromadiolona. Brodifacoum y difetialona.

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