Long-acting Anticoagulant Rodenticides Research Articles

Bromadiolone may cause severe acute kidney injury through severe disorder of coagulation: a case report

BackgroundBromadiolone is a wide-use long-acting anticoagulant rodenticide known to cause severe coagulation dysfunction. At present, there have been no detailed reports of acute kidney injury (AKI) resulting from bromadiolone poisoning.Case presentationA 27-year-old woman was admitted to the hospital due to severe coagulopathy and severe AKI. Coagulation test revealed a prothrombin time exceeding 120 s and an international normalized ratio (INR) greater than 10. Further examination for coagulation factors showed significantly reduced level of factors II, VII, IX and X, indicating a vitamin K deficiency. The AKI was non-oliguric and characterized by gross dysmorphic hematuria. Following the onset of the disease, the patient’s serum creatinine rose from 0.86 to 6.96 mg/dL. Suspecting anticoagulant rodenticide poisoning, plasma bromadiolone was identified at a concentration of 117 ng/mL via gas chromatography/mass spectrometry. All other potential causes of AKI were excluded, except for the presence of a horseshoe kidney. The patient’s kidney function fully recovered after the coagulopathy was corrected with high doses of vitamin K and plasma transfusion. At a follow-up 160 days post-discharge, the coagulation function had normalized, and the serum creatinine had returned to 0.51 mg/dL.ConclusionBromadiolone can induce AKI through a severe and prolonged coagulation disorder. Kidney function can be restored within days following treatment with high-dose vitamin K1.

Non-adherence with long-term oral vitamin K1 therapy in acute long-acting anticoagulant rodenticides poisoning: a call for action

Non-adherence with long-term oral vitamin K1 therapy in acute long-acting anticoagulant rodenticides poisoning: a call for action

Short-term treatment with cholestyramine increases long-acting anticoagulant rodenticide clearance from rabbits without affecting plasma vitamin K1 levels or blood coagulation.

Administration of high-dose vitamin K1 (VK1) overcomes coagulopathy and bleeding elicited by acute poisoning with long-acting anticoagulant rodenticides (LAARs). However, long-term (months) treatment is required due to long LAAR biological half-lives that may lead to poor compliance and recurrent coagulopathy. The half-lives of LAARs are extended by slow metabolism, and similar to warfarin, are thought to undergo enterohepatic recirculation. We now show that treatment with the bile acid sequestrant cholestyramine (CSA) administered concomitantly with VK1 decreases plasma LAAR levels and increases LAAR fecal excretion. Daily CSA treatment for 14 days did not reduce plasma VK1 levels, or increase prothrombin time. Collectively, these data show that CSA accelerates LAAR clearance from rabbits without adverse effects on VK1 anticoagulation, and could provide an additional therapeutic option for treatment of LAAR poisoning.

Toxic substances in the household - cases of poisoning, therapy, complications

There are many toxic substances used in our houses. Rodent poisons are not the most common group of substances, but cases of poisoning still occur. Long-acting anticoagulant rodenticides, also called superwarfarins, are known for their greater potency, longer half-life and delayed onset of symptoms. Cases of superwarfarin poisoning can pose a diagnostic and clinical challenge due to a wide array of presentations and prolonged severe coagulopathy requiring months of high-dose oral vitamin K therapy. The most common presentation of long-acting anticoagulant rodenticide poisoning is mucocutaneous bleeding, with other common presentations including haematuria, gingival bleeding, epistaxis and gastrointestinal bleeding.We discuss a case of self-poisoning with long-acting anticoagulant rodenticides with a little presentation of sympthoms and disscus about another cases based on the found articles.

Retrospective analysis of clinical characteristics of and treatment strategies for patients with long-acting anticoagulant rodenticide poisoning.

Long-acting anticoagulant rodenticide (LAAR) poisoning remains a serious public health problem. The aim of this study was to explore the clinical characteristics of different LAARs and a method of making a decision on the VK1 treatment course and the time to stop VK1 treatment safely. This retrospective study compared the clinical characteristics of two LAARs poisoning patients and used multivariate regression method to explore the relationship between blood LAAR concentration and vitamin K1 dose/treatment time. A total of 115 patients with LAAR poisoning were included in this study after screening. Of these, 50 patients attempted to commit suicide. The median LAAR concentration of the patients at admission was 409 (157-1174)ng/mL, and the VK1 treatment duration was 14 (8-34)days. The total VK1 treatment time in patients with LAAR poisoning was positively correlated with admission LAAR concentration. During the maintenance treatment period, the VK1 dosage was positively correlated with blood LAAR concentration. Low dose of VK1 during the maintenance period is indicative of the blood LAAR concentration being relatively low. This provides a basis for judging the LAAR content in the body during the maintenance treatment period.

Severe Vitamin K-dependent Coagulopathy from Rodenticide-contaminated Synthetic Cannabinoids: Emergency Department Presentations.

IntroductionSynthetic cannabinoids are a rapidly expanding subset of designer drugs widely available in the United States since 2008. In Illinois during the spring of 2018, over 160 documented cases of bleeding and prolonged coagulopathy occurred secondary to contaminated synthetic cannabinoids.MethodsWe conducted a retrospective cohort study consisting of 38 patients to describe the initial emergency department (ED) presentation, diagnosis, and treatment.ResultsThrough serum testing we found that three long-acting anticoagulant rodenticides (LAAR) were detected in patients who had inhaled these tainted products: brodifacoum, difenacoum, and bromodialone.DiscussionThis study encompasses the largest ED presentation of LAAR poisoning via the inhalational route known to date.ConclusionThe emergency physician should be aware of the potential for tainted coingestants as the cause of undifferentiated coagulopathy.

Unmet clinical laboratory need in patients hospitalized for acute poisoning from long-acting anticoagulant rodenticides

The importance of real-time, quantitative toxicology data available for physicians treating poisoned patients was illustrated during the 2018 outbreak in Illinois of severe coagulopathy caused by inhaling illicit synthetic cannabinoids products contaminated with commercially-available brodifacoum, difenacoum, and bromadiolone, three potent, long-acting anticoagulant rodenticides (LAARs). Identification and quantification of these life-threatening toxins in blood samples of hospitalized patients required toxicology testing with liquid chromatography-tandem mass spectrometry (LC-MS/MS) that was not available in clinical laboratories of hospitals at the time of the outbreak. This highly-sensitive, quantitative assay can provide critical information to guide patient care during and after hospitalization, including identification of offending LAARs, estimates of the ingested dose, and dosage and discontinuation of oral vitamin K1 therapy after hospital discharge once plasma LAARs concentrations decreased to a safe level (<10 ng/mL). Accordingly, we propose an action plan to enable treating physicians to quantify plasma concentrations of several LAARs simultaneously in poisoned patients. It involves rapid (<15 min), sensitive, and validated LC-MS/MS methods developed, tested and validated in our laboratory. This will allow treating physicians to request quantitative plasma LAARs testing, report test results in the patient’s hospital discharge summary, and recommend regular monitoring of plasma LAARs concentrations in the outpatient setting.

Brodifacoum pharmacokinetics in acute human poisoning: implications for estimating duration of vitamin K therapy

Standard of care follow-up therapy for patients poisoned by long-acting anticoagulant rodenticides (LAARs) is daily high-dose (up to 100 mg per day) oral vitamin K1 (VK1) for weeks to months to over a year. The availability of CLIA-certified quantitative testing for plasma LAAR concentrations can now assist health care providers in determining when to safely discontinue VK1 therapy. We present estimates of treatment duration required to reach safe concentrations (< =10ng/ml) using serial measurements of plasma brodifacoum (BDF, a potent LAAR) concentrations obtained from patients poisoned after inhaling synthetic cannabinoids containing BDF. We fit the data to zero-order (linear) and first-order (exponential) curves, the latter to account for enterohepatic circulation of BDF. The results show that estimates of therapy duration are significantly longer when exponential clearance is assumed. Accordingly, we recommend that plasma BDF concentrations be monitored simultaneously with international normalization ratio (INR) during follow-up of poisoned patients, and that concentrations be determined after VK1 therapy is discontinued to document persistence of safe concentrations.

Chiral liquid chromatography-tandem mass spectrometry analysis of superwarfarin rodenticide stereoisomers – Bromadiolone, difenacoum and brodifacoum – In human plasma

Superwarfarins are second-generation long-acting anticoagulant rodenticides that can cause unintended human and wildlife toxicity due, in part, to their prolonged half-lives. Commercially available superwarfarin rodenticides are synthesized as racemates with two asymmetric carbons, producing four stereoisomers. To support studies of human plasma half-lives of individual superwarfarin stereoisomers, a method was developed based on LC-MS/MS to separate and quantify stereoisomers of the commercially important superwarfarins bromadiolone, difenacoum and brodifacoum. Human plasma samples were prepared using protein precipitation and centrifugation. Chiral-phase HPLC separation was carried out on-line with tandem mass spectrometric quantitative analysis of the eluting stereoisomers using selected-reaction monitoring with positive ion electrospray on a triple quadrupole mass spectrometer. All four stereoisomers of each superwarfarin were resolved within 12.5 min with calibration curves spanning 2–3 orders of magnitude and lower limits of quantitation between 0.87 and 2.55 ng/mL. This method was used to determine the half-lives of superwarfarin stereoisomers in plasma from patients who had inhaled synthetic cannabinoid products contaminated with superwarfarins. These data may be used to guide the development of safer next generation anticoagulant rodenticides stereoisomers.

Separation and Quantification of Superwarfarin Rodenticide Diastereomers-Bromadiolone, Difenacoum, Flocoumafen, Brodifacoum, and Difethialone-in Human Plasma.

Superwarfarins, second-generation long-acting anticoagulant rodenticides, are 4-hydroxycoumarin analogues of warfarin that contain a large hydrophobic side chain. These compounds contain two chiral centers and are synthesized for commercial use as two pairs of diastereomer. To support studies of superwarfarin pharmacokinetics and other efforts to improve clinical care for poisoning victims, a quantitative assay was developed for the measurement of diastereomer of bromadiolone, difenacoum, flocoumafen, brodifacoum, and difethialone in human plasma. Based on ultrahigh-pressure liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS), this method was validated according to U.S. Food and Drug Administration (FDA) guidelines. Sample preparation involved simple protein precipitation followed by reversed phase UHPLC, which resolved all five pairs of cis/trans diastereomer in less than 10 min. Superwarfarins were measured using negative ion electrospray followed by selected-reaction monitoring on a triple quadrupole mass spectrometer. Calibration curves covered 3-4 orders of magnitude with linear regression coefficients of >0.999. The lower limits of quantitation were from 0.013 to 2.41 ng/mL, and intra-day and inter-day accuracy and precision coefficients of variation were <12%. A 10-min UHPLC-MS/MS assay was developed and validated for the separation and quantitative analysis of the pairs of diastereomer of five superwarfarins in human plasma. This method was used to identify and measure superwarfarins and their cis/trans diastereomers in plasma obtained from patients treated for coagulopathy following consumption of contaminated synthetic cannabinoid products.

An outbreak of severe coagulopathy from synthetic cannabinoids tainted with Long-Acting anticoagulant rodenticides

Objective: To describe a large regional poison center’s experience managing an outbreak of long-acting anticoagulant rodenticide (LAAR) poisoning associated with synthetic cannabinoid (SC) use.Methods: This is a retrospective review of exposures reported to the Illinois Poison Center between March 10 and August 1, 2018. All cases coded as exposure to Δ9-tetrahydrocannabinol homologs were identified. Patients with suspected SC use, positive LAAR testing, and coagulopathy (signs or symptoms of bleeding or international normalized ratio [INR] > 2) were included. If confirmatory LAAR testing was performed and resulted as negative, the patient was excluded from this analysis. In the absence of LAAR testing, patients with suspected SC use, an INR >2, and no alternative explanation of coagulopathy were included. Suspected SC use was defined as use suspected by a member of the treating team or reported by the patient. Presenting signs and symptoms, laboratory findings, management, healthcare utilization, outcomes, and disposition of patients affected by this outbreak were reported.Results: One hundred seventy-eight cases met inclusion criteria. Most patients were male (73%) and young to middle-aged (median age 32, IQR 25–40). Most presented to hospitals in Peoria (35%) and Cook (31%) counties. Median hospitalization was three days (IQR 2–4). Eighty-eight percent of patients presented with an INR >10. Eighteen cases had qualitative anticoagulant testing, all of which were positive for brodifacoum. Other identified LAARs included difenacoum (10/18) and bromadiolone (1/18). Sixty-three percent of patients had back, flank or abdominal pain; 70% of patients presented with hematuria. One hundred six cases received IV vitamin K1; no adverse or anaphylactoid reactions were reported. Forty-one (22%) patients left AMA. Thirty-eight patients (21%) were re-hospitalized during the study period. Patients leaving AMA were 1.6 times more likely to be re-hospitalized than patients with other dispositions. Intracranial hemorrhage, present in 3% of total cases, was present in 4 of 5 fatalities.Conclusions: We describe an outbreak of multiple LAARs contaminating SCs. Patients presented with bleeding from varied sites, often required blood products, factor replacement, and high dose vitamin K1 for stabilization.

Effects of vitamin K1 treatment on plasma concentrations of long-acting anticoagulant rodenticide enantiomers following inhalation of contaminated synthetic cannabinoids

Background: An outbreak of synthetic cannabinoid (SC)-associated coagulopathy and bleeding in Illinois, USA was determined to be due to inhalation of SC contaminated with brodifacoum (BDF), difenacoum (DiF), and bromadiolone (BDL), highly potent long-acting anticoagulant rodenticides (LAARs). Treatment with high-dose vitamin K1 (VK1) prevented mortality; however, plasma LAAR levels were not measured risking recurrence of coagulopathy and bleeding due to premature discontinuation. The goal of this study was to determine if plasma LAAR levels were reduced following standard of care treatment to normalize coagulopathy.Methods: Blood samples were collected from a cohort of 32 patients, and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis used to quantify plasma LAAR levels including enantiomers.Results: BDF was detected in 31 samples; 30 also contained DiF and 18 contained BDL. Initial plasma levels were 581 ± 87, 11.0 ± 1.9, and 14.9 ± 5.9 ng/mL for BDF, DiF, and BDL, respectively (mean ± SE). At discharge plasma, BDF levels remained elevated at 453 ± 68 ng/mL. Plasma half-lives for BDF, DiF, and BDL were 7.5 ± 1.3, 7.2 ± 1.9, and 1.8 ± 0.3 days, respectively. The half-life for trans-BDF enantiomers (5.7 ± 0.8 days) was shorter than for cis-enantiomers (7.6 ± 1.9 days). BDF half-lives were shorter, and coagulopathy normalized faster in patients receiving intravenous VK1 as compared to oral VK1. Patients prescribed VK1 at discharge had fewer re-admittances.Conclusions: These results demonstrate that plasma LAAR levels at discharge were elevated in poisoned patients despite normal coagulation, and that the route of VK1 administration affected LAAR pharmacokinetics and INR normalization. We propose plasma LAAR levels and coagulation be monitored concomitantly during follow-up of patients with LAAR poisoning.KEY POINTSIn patients treated with high-dose vitamin K1 for LAAR poisoning, plasma levels remained 40-fold above safe levels upon discharge from hospital.LAAR half-lives, normalization of coagulopathy, and readmittances were reduced by treatment with intravenous vitamin K1.

SUPER WARFARIN POISONING AFTER MARIJUANA USE

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Long acting vitamin K antagonists (super warfarins) produce coagulopathy in humans that can last for weeks to months. Exposure to these poisons can be very dangerous, but if recognized early can be effectively treated. CASE PRESENTATION: SW is a 32 year old female with no past medical history who presented to the emergency room due to nausea, vomiting, and abdominal discomfort. Symptoms started suddenly a week prior. Abdominal pain was constant, not associated with food, and was mainly in the upper quadrants with radiation to the flanks. The day of presentation she began to have bright red blood in her emesis as well as gross hematuria. She also noted sudden onset of bruising of her legs bilaterally. Patient was mildly tachycardic with heart rate in the 100s. Initial lab work showed a Hb 14.9 and an INR >29. She stated that she had no allergies, took no medications or herbal supplements, and had no family history of bleeding disorders. She denies any previous history of easy bruising or heavy menses. No previous psychiatric history of depression or suicidality. She denied regular tobacco use and states that she drank alcohol only on rare occasions. She admitted to very rare marijuana use, her last use being a week prior. She had smoked with a friend and this was their first time buying from the specific dealer. She stated the friend was not exhibiting any of the same symptoms. After admission to the ICU she initially received K-Centra which briefly corrected her coagulopathy to an INR 1.1. Over the next 24 hours, however, her INR gradually rose back up to 7.13. After consultation with toxicology the patient was placed on 10mg vitamin K every 8 hours which required escalation to 30mg every 8 hours before the INR remained corrected. An anticoagulant poisoning panel was sent and was positive for brodifacoum and difenacoum. A synthetic cannabinoid panel was run which was negative. She was sent home on this dose of vitamin K with close follow-up scheduled with her PCP. DISCUSSION: Case reports of accidental or intentional exposures to super warfarins have been seen as far back as 1984. They have more recently gained attention due to super warfarins being found mixed with synthetic marijuana. Compared to warfarin, the coagulopathy produced by these agents is more potent and prolonged. Elevated prothrombin time has been reported for weeks to months after ingestion. There is little data on the most optimal treatment algorithm, although case reports have shown large doses of vitamin K are effective for reversing the coagulopathy and maintaining normal INR. CONCLUSIONS: This case shows an occurrence of super warfarin poisoning in conjunction with non-synthetic marijuana use. In cases of significant and prolonged elevation of PT clinicians should keep a low index of suspicion for super warfarin poisoning. Reference #1: Chua JD, Friedenberg WR. Superwarfarin Poisoning. Arch Intern Med. 1998;158(17):1929–1932. https://doi.org/10.1001/archinte.158.17.1929 Reference #2: Long J, Peng X, Luo Y, et al. Treatment of a long-acting anticoagulant rodenticide poisoning cohort with vitamin K1 during the maintenance period. Medicine (Baltimore). 2016;95(51):e5461 DISCLOSURES: No relevant relationships by Jay Patel, source=Web Response No relevant relationships by Rahul Sangani, source=Web Response

Synthetic cannabinoid-associated coagulopathy secondary to long-acting anticoagulant rodenticides: Observational case series and management recommendations.

Synthetic cannabinoids have become increasingly popular drugs of abuse due to low cost and inability to detect these substances on routine drug screenings. In the United States, incidence of synthetic cannabinoid contamination with long-acting anticoagulant rodenticides (LAARs) resulting in coagulopathy and bleeding complications has been described.We sought to describe the natural history, management approach, and outcomes of bleeding secondary to synthetic cannabinoid-associated LAAR toxicity in an observational case series of patients evaluated at an urban academic medical system.We conducted an observational study of patients with suspected exposure to LAAR-contaminated synthetic cannabinoids and associated bleeding treated within the Johns Hopkins Health System.In this 16 subject cohort, hematuria was the most common bleeding symptom at presentation. The majority of the cohort (75%) had international normalized ratio (INR) > 9.6 at presentation. Of the 13 patients with brodifacoum testing, 12/13 (92%) were positive. Twelve patients (75%) had at least 1 INR value below 2 within 24 hours of the first INR measurement. Of this cohort, 1/16 (6%) died in hospital. The median length of hospital stay was 4 days, (interquartile range = 3-6). The average cost of pharmacological treatment for coagulopathy during inpatient hospitalization was $5300 (range, $2241-$8086).In patients presenting with unexplained coagulopathy it is important for emergency department providers to consider LAAR intoxication and consider formal testing for brodifacoum to assist with treatment planning. Use of a standardized management algorithm including intravenous/oral vitamin K, judicious use of blood products and close laboratory monitoring is essential to optimizing outcomes.

The Public Health Response to a Large Poisoning Outbreak Involving an Illicit Substance: Synthetic Cannabinoids Contaminated With a Long-Acting Anticoagulant Rodenticide, Illinois, March-July, 2018.

During March-July 2018, the Illinois Department of Public Health responded to an acute outbreak of severe coagulopathy among patients with recent synthetic cannabinoid use. Toxicological testing indicated that cases were exposed to brodifacoum, a long-acting anticoagulant rodenticide. A total of 174 confirmed and probable cases, including 5 deaths, were linked to this outbreak. On the basis of the experience of responding to this complex outbreak, we recommend several steps for consideration to improve health department preparation for acute outbreaks involving illicit substances including strengthening communication between public health and law enforcement agencies, reviewing legal authority to investigate noninfectious acute disease outbreaks, continuing strong partnerships with state poison control centers, partnering with substance abuse and mental health agencies to provide services to patients, and determining health department ability to rapidly enter into public-private partnership agreements.

Medical outcomes of bromethalin rodenticide exposures reported to US poison centers after federal restriction of anticoagulants

Background: Exposures to bromethalin rodenticides have increased since restrictions were placed on long acting anticoagulant rodenticide (LAAR) registrations in 2008. Bromethalin works, in part, by uncoupling mitochondrial oxidative phosphorylation. Toxicity in humans is not well characterized and no antidote is available.Methods: This retrospective observational study analyzed data from the National Poison Data System (NPDS). The data set was derived from single substance bromethalin ingestions followed to a known medical outcome that were reported to US poison centers from 01/01/2008 to 12/31/2017.Results: There were 2674 bromethalin exposures in the NPDS database that met inclusion criteria. Of these exposures 2227 (83.28%) were pediatric, aged 16 days–12 years. Within this population, no effects were seen in 2143 (96.38%) of the exposures, 74 (3.32%) had minor effects, and 10 (0.45%) had moderate effects. No major clinical effects or deaths occurred in pediatric patients, although one patient with a major effect was of unknown age. Exposures in patients >12 years encompassed 391 patients aged 13–94 years. No effect was seen amongst 257 (65.73%) of the patients, 100 (25.58%) had minor effects, 23 (5.88%) had moderate effects, nine (2.30%) had major effects, and two (0.51%) patients died. Intentional ingestions among these patients accounted for one (0.25%) death and four (1.02%) major effects. Case details of the intentional ingestion death suggest the possibility of a miscoded long acting coagulant rodenticide.Conclusions: No major effects or deaths were seen in pediatric exposures. A majority of the possible bromethalin exposures involving adults reported to poison centers resulted in minor or no effects, though seizures, death and one questionable case of coagulopathy were documented. This dataset suffers from its retrospective nature, reliance on caller information, selection bias, information bias, and miscoding. It is possible that one or both deaths attributed to bromethalin exposure were not actually due to bromethalin.

The relative toxicity of brodifacoum enantiomers

Brodifacoum (BDF) is a potent, long-acting anticoagulant rodenticide that can cause fatal poisoning in humans. The chemical structure of BDF includes 2 chiral carbons, resulting in 2 pairs of diastereomers, BDF-cis (R/S and S/R) and BDF-trans (R/R and S/S). However, the relative potency of these molecules is not known. The purpose of this study was to compare the in vitro and in vivo toxic effects of the 2 BDF diastereomer pairs. In adult Sprague-Dawley rats BDF-cis was significantly more toxic than BDF-trans (LD50 values of 219 versus 316 μg/kg, respectively) while racemic BDF had intermediate potency (266 μg/kg). In adult New Zealand white rabbits, BDF-cis had a longer half-life than BDF-trans which could contribute to its observed increased toxicity. Lastly, BDF-cis (10 μM), but not BDF-trans, damaged cultured SH-SY5Y human neuroblastoma cells by attenuating mitochondrial reductive capacity. Taken together, these data suggest that different toxic manifestations of BDF poisoning in mammals could be attributed, in part, to differences in relative enantiomer concentrations present in racemic formulations of this commercially-available toxicant.

Superwarfarin (Long-Acting Anticoagulant Rodenticides) Poisoning: from Pathophysiology to Laboratory-Guided Clinical Management.

Superwarfarins are long-acting anticoagulant rodenticides developed from warfarin. The mechanism of action is by inhibition of vitamin K epoxide reductase, resulting in the inability of the body to recycle vitamin K. Deficiency of vitamin K thereafter leads to inability for the body to synthesise vitamin K-dependent coagulation factors, factor II, VII, IX, and X, leading to prolonged prothrombin time. Due to the bulky aromatic sidechains, superwarfarins have a much longer half-life when compared to warfarin, and exposure to superwarfarins results in a prolonged period of anticoagulation which can result in clinical bleeding. Diagnosis is straightforward in patients with known history of superwarfarin exposure but has proved difficult for patients who did not report superwarfarin intake. Superwarfarin poisoning should therefore be suspected in all patients with unexplained prolongation of prothrombin time, and can be confirmed by their detection in serum. Treatment for superwarfarin poisoning includes rapid correction of factor deficiencies with either 4-factor prothrombin complex concentrate or fresh frozen plasma in patients with active bleeding, and high dose vitamin K therapy given multiple times per day for a prolonged period of weeks to months.

The Bile Sequestrant Cholestyramine Increases Survival in a Rabbit Model of Brodifacoum Poisoning.

Patients exposed to long acting anticoagulant rodenticides (LAARs) are typically administered large amounts of oral vitamin K1 (VK1) to counteract life-threatening anticoagulant effects. Although VK1 treatment effectively prevents mortality, additional methods are needed to reduce the long duration of VK1 treatment which can last for months at high expense. We developed a model of brodifacoum (BDF) poisoning, one of the most potent LAARs, in adult male New Zealand White (NZW) rabbits. The LD50 for oral BDF was determined to be 192 μg/kg, similar to that calculated for adult rats. However, in contrast to rats, NZW rabbits exhibited severe internal hemorrhage including in the brain, symptoms which mimic what occurs in cases of human poisoning. Similar to warfarin, BDF and other LAARs undergo enterohepatic recirculation which contributes to their long half-lives. We therefore tested effects of cholestyramine (CSA), an FDA-approved bile sequestrant, on BDF-induced mortality. When given daily (0.67 g/kg, oral) starting the day of BDF administration, CSA reduced mortality from 67% to 11%. At the same CSA prevented the increase in clotting time, and reduced the decrease in core body temperature due to BDF. Given its excellent safety record and that it is approved for children older than 6 years, these findings suggest CSA could be considered as an adjunct to VK1 for treatment of LAAR poisoning.

Treatment for long acting anticoagulant rodenticide poisoning – beyond INR monitoring?

Poisoning by long acting anti-coagulant rodenticides (LAARs) requires long-term treatment with oral vitamin K1 (VK1). However, discontinuing treatment based on normalization of INR, may leave some patients with serum LAAR concentrations above a level considered safe. To address this, we carried out a retrospective analysis of 21 case reports of LAAR poisoning having at least two serum LAAR concentrations quantified during treatment with oral VK1. We identified the case reports by survey of existing peer-reviewed literature in which a patient presented to emergency department exhibiting bleeding or elevated International Normalized Ratio (INR), and had quantitative measurements of serum LAAR concentrations. Of 21 case reports, measurement of serum LAAR concentrations following VK1 treatment showed that over half (n = 11) had serum LAAR concentrations that were above a concentration considered to be safe (10 ng/mL), despite having received higher daily and total VK1 dosing, over an equivalent treatment duration. Since residual amounts of serum and tissue LAAR could contribute to symptom recurrence and repeated hospitalization, these results indicate that normalization of INR is not a sufficient criterion to discontinue VK1 treatment and that measurements of serum LAAR concentrations should be included to help guide decisions to continue or discontinue VK treatment.