Long-acting Anticoagulant Rodenticides Research Articles

Treatment of a long-acting anticoagulant rodenticide poisoning cohort with vitamin K1 during the maintenance period.

Currently, there are few guidelines for the use of vitamin K1 in the maintenance treatment of long-acting anticoagulant rodenticide (LAAR) poisonings. We explored factors in the treatment of LAAR poisoning during the maintenance period in order to suggest feasible treatment models.Data from 24 cases of anticoagulant rodenticide poisoning in our hospital were collected from January 2013 to May 2016. The patients' sex, age, coagulation function, total time from poisoning to treatment with vitamin K1 (prehospital time), vitamin K1 sustained treatment time (VKSTT), anticoagulant rodenticide category, and specific poison dosage were collected. Multivariate analysis was used to evaluate the correlation between vitamin K1 dosage and other factors during the maintenance period.Only VKSTT (partial regression coefficient -1.133, 0.59, P = 0.035) had an obvious influence on the therapeutic dose of vitamin K1 required during the maintenance period.After an initial pulse therapy, the bleeding and coagulation functions were stabilized, and the patients were subsequently treated with vitamin K1 during the maintenance period. Over time, the maintenance dose of vitamin K1 (10-120 mg/d, intravenous drip) was gradually decreased and was not related to toxicant concentration.

Human bromethalin exposures reported to a U.S. Statewide Poison Control System

Background: Bromethalin is an increasingly used alternative to long-acting anticoagulant and cholecalciferol rodenticides. There are few reports of human exposures, and no existing professional society guidelines on medical management of bromethalin ingestions. The aim of this retrospective data review is to characterize bromethalin exposures reported to the California Poison Control System (CPCS) between 1997 and 2014. Methods: This is an observational retrospective case review of our statewide poison control system’s electronic medical records. Following Institutional Board Review and Research Committee approvals, poison center exposures related to bromethalin were extracted using substance code and free text search strategies. Case notes of bromethalin exposures were reviewed for demographic, clinical, laboratory, and outcome information; inclusion criteria for the study was single-substance, human exposure to bromethalin. Results: There were 129 calls related to human bromethalin exposures (three cases met exclusion criteria). The age range of cases was 7 months–90 years old, with the majority of exposures (89 cases; 70.6%), occurring in children younger than 5 years of age (median age of 2 years). Most exposures occurred in the pediatric population as a result of exploratory oral exposure. One hundred and thirteen patients (89.7%) had no effects post exposure, while 10 patients (7.9%) had a minor outcome. Adverse effects were minor, self-limited, and mostly gastrointestinal upset. There were no moderate, major, or fatal effects in our study population. The approximate ingested dose, available in six cases, ranged from 0.067 mg/kg to 0.3 mg/kg (milligrams of bromethalin ingested per kilogram of body weight), and no dose-symptom threshold could be established from this series. Exposures were not confirmed through urine or serum laboratory testing. Discussion: The prognosis for most accidental ingestions appears to be excellent. However, bromethalin exposures may result in a higher number of symptomatic patients than long-acting anticoagulant agents. Parents, physicians and poison control specialists are encouraged to maintain a high index of suspicion for bromethalin-related complications in all cases of rodenticide exposures. Conclusions: Accidental bromethalin exposures in children appear to be self-limited in toxicity. Additional studies are warranted to determine whether more severe effects are precipitated when larger amounts are involved, particularly in suicidal ingestion.

Epidemiology and symptomatology of long acting anticoagulant rodenticide poisoning

Background: Long acting anticoagulant rodenticides (LAARs) are widely used pesticides that initiate anticoagulation through avitamin K antagonist (VKA) mechanism. Human exposures produce presentations ranging from asymptomatic to fatal. Methods: A comprehensive literature search and search of relevant databases was conducted. Data related to epidemiology ofLAAR exposure as well as clinical manifestations of LAAR poisoning and clinical management were extracted. Results: Between 1987 and 2012, 315,951 total exposures were reported to the American Association of Poison ControlCenters. Of these, 95.6% were unintentional and 88.9% occurred in children under the age of six. Moderate or major effectsoccurred in only 0.6% of human LAAR exposures. Of reviewed case reports, the most common hemorrhagic manifestationswere mucocutaneous. Fatalities were most commonly associated with intracranial hemorrhage and intentional misuse. Multipleroutes of exposure have been reported including oral, percutaneous, and inhalational. Treatment courses required prolongedadministration of high dose vitamin K. Conclusions: Most instances represent unintentional LAAR exposures among children. Although the majority of exposures areasymptomatic, serious coagulopathy may occur, and LAAR poisoning may not immediately be considered as an etiology. Aheightened awareness for this entity and awareness of diagnosis and treatment principles are critical to appropriate management.

Long-Acting Anticoagulant Rodenticide (Superwarfarin) Poisoning: A Review of Its Historical Development, Epidemiology, and Clinical Management.

Long-acting anticoagulant rodenticides (LAARs) inhibit vitamin K epoxide reductase (VKOR). Related bleeding may present a diagnostic challenge and require administration of blood component therapy, hemostatic agents, and vitamin K. This article intends to provide the reader a comprehensive understanding of LAAR poisoning. An exhaustive literature search of PubMed, Science Direct, US National Library of Medicine Toxicology Data Network, and Google Scholar yielded 174 reported cases of LAAR poisoning from which clinical data were extracted and reviewed. In addition, 25 years of epidemiologic data from the American Association of Poison Control Centers was reviewed. In the United States, on average, there were 10413 exposures reported with 2750 patients treated annually. For 25 years, there were 315951 exposures reported with nearly 90% among children and more than 100000 patients treated in a health care facility. Fortunately, only 2% of all exposures result in morbidity or mortality. Inhalational, transcutaneous, and oral routes of exposure have been documented. Most exposures are unintentional. The most frequently reported bleeding sites are mucocutaneous, with hematuria being the most common feature. Deaths were most commonly associated with intracranial hemorrhage. Long-acting anticoagulant rodenticide-induced paradoxical thrombosis and thrombotic complications accompanying hemostatic therapy have also been observed. Most patients present with coagulation assay values beyond measurable limits. Long-acting anticoagulant rodenticides have an extremely high affinity for VKOR compared with warfarin, characterized by rebound coagulopathy and bleeding after initial treatment and the need for high-dose, long-term therapy with vitamin K1. Treatment of acute hemorrhagic symptoms often required intravenous vitamin K1 in excess of 50 to 100 mg; chronic maintenance with 100 mg PO vitamin K1 daily was the most frequently used dose required to suppress coagulopathy. Treatment courses averaged 168 days. Adjunctive hemostatic therapy with recombinant factor VIIa and prothrombin complex concentrate has been reported, and phenobarbital has been used to expedite LAAR metabolism.

When Is "Pseudo-Ludwig's Angina" Associated With Coagulopathy Also a "Pseudo" Hemorrhage?

Sublingual hematoma secondary to short-acting anticoagulants such as warfarin has been labeled “pseudo–Ludwig’s angina” to distinguish it from the classic syndrome of localized infection and swelling involving the upper airway. Sublingual hematoma with airway compromise secondary to brodifacoum, a common long-acting anticoagulant rodenticide, has only been reported in the veterinary literature. We report a case of massive tongue swelling and impending airway compromise in the context of an intentional long-acting anticoagulant ingestion leading to coagulopathy. The swelling was initially presumed to be due either to infection or hemorrhage, but this was not supported by computed tomography scan imaging. Instead, the patient’s clinical course was consistent with corticosteroid-responsive angioedema, temporally associated with the ingested brodifacoum.

TOXIC POTENTIAL OF SUPERWARFARIN: BRODIFACOUM

Summary Brodifacoum, a commercially available, long-acting anticoagulant rodenticide, is a highly toxic compound. Structurally it is similar to warfarin, but it is many times more potent, with the ability to cause severe bleeding in humans. Most of the health hazards of brodifacoum are associated with accidental ingestion. Superwarfarin intoxication may have no signs or symptoms other than bleeding at various sites. Brodifacoum has the potential to be used as a chemical warfare agent because of its high potency and long duration of action.

Clinical analysis of 12 patients caused by long-acting anticoagulant rodenticide occult poisoning.

To explore the clinical characteristics and diagnosis and treatment of occult poisoning caused by long-acting anticoagulant rodenticides. Records of 12 patients from July 2008 to April 2011 diagnosed as anticoagulant rodenticide occult poisoning, who had been misdiagnosed initially at other hospitals were analyzed retrospectively. Elements from the records included clinical symptoms and signs, laboratory findings for prothrombin time (PT) and activated partial prothrombin time (APTT), and initial misdiagnosis and treatment outcome at our hospital. The clinical presentations of patients were insidious and serious, often presented as skin ecchymose, hematuria, menorrhagia and gastrointestine bleeding. Laboratory examinations showed prolonged PT and APTT; bleeding was controlled effectively by administoring vitamin K1 daily. There were statistical difference between PT and APTT before and after the treatment (P<0.01). Coagulation disorders might be caused by the reduced acquisition in vitamin K dependent coagulation factors, which tends to be neglected due to a hidden medical history, delayed signs of poisoning, and various organs involved. A detailed patient history and systematic review may improve the diagnostic accuracy. Once diagnosed is made, vitamin K1 should be given as soon as possible.

Management of intentional superwarfarin poisoning with long-term vitamin K and brodifacoum levels

Context. Brodifacoum is a widely available superwarfarin used as a commercial rodenticide. Toxicity from long-acting anticoagulant rodenticides, primarily from uncontrolled bleeding, has been reported. Very little published toxicokinetic data are available for human brodifacoum poisoning. Management is also contentious with uncertainty over the dose, frequency, and duration of antidote treatment with vitamin K. The role of brodifacoum levels in guiding management is not entirely established. Methods. A novel, highly sensitive method was developed for measuring all commercially available rodenticide-hydroxycoumarin anti-coagulants. Monthly brodifacoum levels were performed in two patients to determine half-life and expected time for levels to fall below 10 μg/L. Results. We report two concurrent cases at our clinical toxicology service that required prolonged treatment with oral vitamin K to achieve normalisation of coagulation studies. Brodifacoum elimination appears to follow first-order kinetics. Case 1 had a brodifacoum elimination half-life of 33 days and was treated with vitamin K (100 mg) for 6 months. Case 2 was treated with vitamin K (100 mg) for 3 months with a half-life of 15 days. Discussion. Our cases illustrate the positive experience in the utility of brodifacoum levels to confirm diagnosis and aid in directing antidote therapy. Large ingestions of brodifacoum-containing rodenticides are likely to require high-dose oral vitamin K administered daily. A brodifacoum level below 10 μg/L was associated with a normal coagulation profile following completion of vitamin K1 therapy in our cases; this level may prove to be a safe treatment cessation threshold.

Anticoagulant Rodenticides

Anticoagulant pesticides are used widely in agricultural and urban rodent control. The emergence of warfarin-resistant strains of rats led to the introduction of a new group of anticoagulant rodenticides variously referred to as 'superwarfarins', 'single dose' or 'long-acting'. This group includes the second generation 4-hydroxycoumarins brodifacoum, bromadiolone, difenacoum, flocoumafen and the indanedione derivatives chlorophacinone and diphacinone. Most cases of anticoagulant rodenticide exposure involve young children and, as a consequence, the amounts ingested are almost invariably small. In contrast, intentional ingestion of large quantities of long-acting anticoagulant rodenticides may cause anticoagulation for several weeks or months. Occupational exposure has also been reported. Anticoagulant rodenticides inhibit vitamin K(1)-2,3 epoxide reductase and thus the synthesis of vitamin K and subsequently clotting factors II, VII, IX and X. The greater potency and duration of action of long-acting anticoagulant rodenticides is attributed to their: (i) greater affinity for vitamin K(1)-2,3-epoxide reductase; (ii) ability to disrupt the vitamin K(1)-epoxide cycle at more than one point; (iii) hepatic accumulation; and (iv) unusually long biological half-lives due to high lipid solubility and enterohepatic circulation. Substantial ingestion produces epistaxis, gingival bleeding, widespread bruising, haematomas, haematuria with flank pain, menorrhagia, gastrointestinal bleeding, rectal bleeding and haemorrhage into any internal organ; anaemia may result. Spontaneous haemoperitoneum has been described. Severe blood loss may result in hypovolaemic shock, coma and death. The first clinical signs of bleeding may be delayed and patients may remain anticoagulated for several days (warfarin) or days, weeks or months (long-acting anticoagulants) after ingestion of large amounts. There are now sufficient data in young children exposed to anticoagulant rodenticides to conclude that routine measurement of the international normalised ratio (INR) is unnecessary. In all other cases, the INR should be measured 36-48 hours post exposure. If the INR is normal at this time, even in the case of long-acting formulations, no further action is required. If active bleeding occurs, prothrombin complex concentrate (which contains factors II, VII, IX and X) 50 units/kg, or recombinant activated factor VII 1.2-4.8 mg or fresh frozen plasma 15 mL/kg (if no concentrate is available) and phytomenadione 10mg intravenously (100 microg/kg bodyweight for a child) should be given. If there is no active bleeding and the INR is < or =4.0, no treatment is required; if the INR is > or =4.0 phytomenadione 10mg should be administered intravenously.

Long-Acting Anticoagulant Overdose: Brodifacoum Kinetics and Optimal Vitamin K Dosing

Ingestion of long-acting anticoagulant rodenticides such as brodifacoum can lead to prolonged and life-threatening coagulopathy. A paucity of conflicting information is available on brodifacoum’s half-life and elimination pharmacokinetics. In addition, the optimal dose, duration, and route of administration of vitamin K1 therapy are unknown. We report the case of a 52-year-old man who ingested eight 43-g boxes of a rodenticide (d-Con Mouse-Prufe II; 0.005% brodifacoum; Reckitt & Colman, Wayne, NJ). This case demonstrates that after stabilization with fresh frozen plasma, high-dose oral vitamin K1 therapy (≅7 mg/kg per 24 hours divided every 6 hours) was effective in treating brodifacoum-induced coagulopathy. The concentration of vitamin K1 required for normal coagulation in this case was less than the accepted value of 1 μg/mL, which is derived from a rabbit model. In this case, brodifacoum appears to follow zero-order elimination pharmacokinetics. In future cases of patients with ingestions of long-acting anticoagulants who present with coagulopathy, it may be useful to obtain serial brodifacoum concentrations to determine elimination curves to help predict the duration of oral vitamin K1 therapy. [Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med. September 2000;36:262-267.]

Superwarfarin Poisoning in Children: A Prospective Study

This prospective study was undertaken to determine the incidence, severity, time of onset, and duration of coagulopathy in children following accidental ingestion of long-acting anticoagulant rodenticides, often called "superwarfarins." Of 110 children, who ingested superwarfarins and in whom one or more prothrombin time values were obtained, 8 had a prothrombin time ratio (patient to control) of greater than or equal to 1.2, indicative of anticoagulation. Prothrombin time values obtained 48 hours after ingestion were more likely to be prolonged (6/34, 17.6%) than values obtained 24 hours after ingestion (2/104, 1.9%) (P less than .005). The occurrence of an abnormal prothrombin time could not be predicted based on the history of amount ingested or on the presence of the characteristic green-blue product dye in or around the child's mouth. Acute toxicity was evidenced by transient abdominal pain, vomiting, and heme positive stools in 2 patients. The duration of prothrombin time prolongation could not be determined because of the few values obtained after 48 hours. To detect all possible abnormal prothrombin time values, 24- and 48-hour determinations are recommended after a child has ingested a superwarfarin.