Retrospective evaluation of the effects and outcome of bromethalin ingestion: 192 Dogs (2010-2016).

OBJECTIVE: To evaluate the frequency of clinical signs, dose ingested, and outcome in a large group of dogs with bromethalin ingestion. DESIGN: Retrospective cohort study of dogs from 2010 to 2016. SETTING: Three university teaching hospitals and 1 private practice. ANIMALS: A total of 192 dogs with bromethalin ingestion. MEASUREMENTS AND MAIN RESULTS: Total 192 cases were identified, of which 25 dogs developed clinical signs. Five cases initially had severe neurological signs and were euthanized. A sum of 187 dogs survived to discharge. The total ingested dose was recorded in 59 dogs with a median (interquartile range) 0.2 mg/kg (0.28 mg/kg). The remaining 133 dogs had confirmed ingestion reported by owners (witnessed ingestion or colored feces) but the total dose could not be calculated. The median (interquartile range) time to presentation for all dogs was 2 hours (4.8 h). A majority of patients were treated on an outpatient basis (121/192) and 71 of 192 were treated as inpatients with 58 of 71 receiving fluid diuresis. Decontamination was performed in 179 dogs including emesis induction (14), activated charcoal administration (42), and both (123). Emesis was successful in 128 dogs and apomorphine was the most common emetic agent (121). Mild to severe clinical signs at admission were reported in 19 cases including vomiting (6), tremors (5), lethargy (4), ataxia (3), weakness (2), diarrhea (2), collapse (2), and and anorexia (2). One case developed ataxia and tremors within 72 hours of admission. CONCLUSIONS AND CLINICAL RELEVANCE: Symptoms of bromethalin toxicosis are uncommon, and most ingested doses are well below the reported dose expected to cause clinical signs. In this patient population, prognosis was excellent unless severe clinical signs were noted, which carried a high euthanasia rate. Effects of treatment on outcome could not be evaluated due to the low number of patients that developed clinical signs.

Successful Management of Severe Bromethalin Toxicosis in a Dog.

ABSTRACT The use of bromethalin rodenticides has risen since 2011, and in some states, it is the most common rodenticide ingestion reported to poison control. Although intravenous lipid emulsion (ILE) has been previously reported to lower serum desmethylbromethalin levels in an asymptomatic dog, and repeated mannitol has been investigated in a laboratory setting, there are no published reports of successful treatment of symptomatic bromethalin toxicosis in dogs. A 9 yr old castrated male Norwich terrier was evaluated for obtunded mentation, seizures, cranial nerve deficits, and tetraparesis secondary to bromethalin toxicosis. The patient was treated with ILE, mannitol, and ginkgo biloba and returned to normal neurological function. Bromethalin exposure was confirmed by serum desmethylbromethalin levels. Previous literature indicates that the prognosis for patients who suffer from symptomatic bromethalin toxicosis is poor to grave, and the return to normal neurological function after severe toxicosis has not been reported. ILE, mannitol, and ginkgo biloba are readily available and relatively inexpensive, and in combination may be of benefit in symptomatic bromethalin intoxication.

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.

Fatal bromethalin intoxication in 3 cats and 2 dogs with minimal or no histologic central nervous system spongiform change.

Use of the neurotoxic rodenticide bromethalin has steadily increased since 2011, resulting in an increased incidence of bromethalin intoxications in pets. Presumptive diagnosis of bromethalin toxicosis relies on history of possible rodenticide exposure coupled with compatible neurologic signs or sudden death, and postmortem examination findings that eliminate other causes of death. Diagnosis is confirmed by detecting the metabolite desmethylbromethalin (DMB) in tissues. In experimental models, spongiform change in white matter of the central nervous system (CNS) is the hallmark histologic feature of bromethalin poisoning. We describe fatal bromethalin intoxication in 3 cats and 2 dogs with equivocal or no CNS white matter spongiform change, illustrating that the lesions described in models can be absent in clinical cases of bromethalin intoxication. Cases with history and clinical signs compatible with bromethalin intoxication warrant tissue analysis for DMB even when CNS lesions are not evident.

[Accidental severe poisoning with methemoglobinogenic substance: A case report]. / Zatrucie substancja methemoglobinotwórcza o ciezkim przebiegu ­ opis przypadku.

A 45-year-old male patient was admitted to the Regional Poison Center because of poisoning with dimethyloaniline contained in a toxic resin-curing dimethyl aniline-based formulation ingested inadvertently. Intoxication happened at workplace. The patient was then transferred to the Toxicology Clinic, where he stayed for 3 weeks. During the hospitalization, the primary method of treatment involved administration of methylene blue, which is the antidote of choice in such cases. During the intensive care and treatment of the patient massive intravascular hemolysis was seen. In that case treatment with blood products was required. He also showed signs of liver dysfunction due to cholestatic liver damage and jaundice. The reported case shows that severe organ damage may result from poisoning with even a small amount of the toxicant. Med Pr 2017;68(6):795-801.

Intravenous Lipid Emulsion Therapy for Bromethalin Toxicity in a Dog.

Bromethalin is a central nervous system toxin currently incorporated into several different rodenticides. In 2008, the EPA requested that manufacturers phase out second-generation anticoagulant rodenticides. In response, manufacturers began to increase production of bromethalin-based rodenticides. It is likely that pet exposure to bromethalin will increase in the future. Bromethalin has no known antidote and tends to deposit in fat. Intravenous lipid emulsions (ILEs) are being used with increasing frequency in both human and veterinary medicine to treat numerous acute systemic toxicities. A 4 yr old spayed female Pit bull terrier was presented following witnessed ingestion of bromethalin rodenticide by the owners. Decontamination was unsuccessful and ILE was started. Serum was frozen at -80°C before and 1 hr after completion of ILE. In rats, the half-life of desmethylbromethalin, the toxic metabolite, has been reported at 5.6 days and 6 days, and it is likely to be similar in dogs. The only intervention between the pre-lipid serum sample and the post-lipid serum sample was the administration of ILE, and the serum desmethylbromethalin levels were reduced by 75% (from 4 ppb to 1 ppb) during this time. To the authors' knowledge, this is the first report describing treatment of bromethalin ingestion with ILE.

[Peculiarities of detection of 4-nitro-3-(trifluoromethyl)-aniline in the biological material].

The objective of the present work was to study peculiarities of detection of 4-nitro-3-(trifluoromethyl)-aniline in the biological material with the use of TLC, GC-MS, and electron spectrophotometry. We have proposed the rationale for the application of acetone as an insulating agent for the extraction of 4-nitro-3-(trifluoromethyl)-aniline from the cadaveric hepatic tissue and biological fluids. It was shown that this compound is possible to separate from endogenous biomaterials on the silicagel L column (40/100 mcm). The results of the quantitative evaluation of different amounts of 4-nitro-3-(trifluoromethyl)-aniline in the cadaveric hepatic tissue, blood, plasma, and urine are presented. The proposed method makes it possible to determine a minimum of 0.12 mg of 4-nitro-3-(trifluoromethyl)-aniline in 100 g of the biological material (cadaveric hepatic tissue), 0.09 mg in 100 g of blood, 0.06 mg and 0.05 mg in 100 u of plasma and urine respectively.

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.

Atypical bromethalin intoxication in a dog: pathologic features and identification of an isomeric breakdown product.

BACKGROUND: Definitive post mortem confirmation of intoxication by the neurotoxic rodenticide bromethalin can be challenging. Brain lesions are not specific and detection of bromethalin and its metabolites are unpredictable due to rapid photodegradation and inconsistent behavior in tissues. CASE PRESENTATION: A 2-year-old dog presented with rapid onset of severe muscle tremors and death within hours after a known ingestion of a reportedly low dosage of bromethalin and subsequent decontamination using activated charcoal. Marked meningeal hemorrhages and multifocal myelin sheath vacuolation were observed in the brain. A marked reactive astrocytosis and neuronal hypoxia/necrosis were identified using immunohistochemistry (IHC) for glial fibrillary acidic protein (GFAP) and for neuron specific protein (NeuN). Bromethalin exposure and tissue absorption was confirmed by identification of one of two isomeric 543.7 molecular weight (MW) breakdown products in the patient's adipose and kidney samples using gas chromatography (GC) combined with tandem quadrupole mass spectrometry (MS/MS). CONCLUSIONS: The severity of clinical signs and subsequent death of this dog was not expected with the low dosage of bromethalin reportedly ingested, and the use of activated charcoal possibly precipitated a hypernatremic status. Meningeal hemorrhages are atypical of bromethalin intoxication, and might have been caused by hyperthermia, secondary to tremors or hypernatremia. Identification of one of two isomeric breakdown products in the adipose tissue and kidney provides an additional molecule to the toxicologic testing regime for bromethalin intoxication.

Spectrum of patients intentionally poisoned with an emulsified concentrate pendimethalin herbicide.

OBJECTIVE: Studies on the acute toxicity of pendimethalin herbicide in humans are limited. Therefore, this study investigated the clinical characteristics of acute intentional pendimethalin herbicide poisoning. MATERIAL AND METHOD: A retrospective observational case series was conducted involving 17 patients with a history of intentional pendimethalin herbicide ingestion. Data were collected on clinical manifestations, management and final outcome. RESULT: The mortality rate was 0%; however, four patients (23.5%) exhibited metabolic acidosis, hypotension or respiratory failure within the first 24 h after ingestion and required admission to the intensive care unit. The most common complication was respiratory failure, followed by hypotension. Complicated patients tended to show an altered mental state and X-ray abnormalities at presentation. DISCUSSION AND CONCLUSIONS: Physicians should be aware that patients who have been poisoned with pendimethalin herbicide, and particularly patients with a depressed mental state and X-ray abnormalities at presentation, may exhibit metabolic acidosis, hypotension, respiratory failure or pancreatitis.

Paranitroanaline poisoning: a failure in basic prevention?

The Occupational Medicine Forum is prepared by the ACOEM Occupational and Environmental Medical Practice Committee and does not necessarily represent an official ACOEM position. The Forum is intended for health professionals and is not intended to provide medical or legal advice, including illness prevention, diagnosis or treatment, or regulatory compliance. Such advice should be obtained directly from a physician and/or attorney.

Bromethalin.

Bromethalin is a potent neurotoxin capable of inducing fatal cerebral edema in companion animals. Bromethalin decreases adenosine triphosphate production resulting in cerebral edema. Toxicosis can be seen in cats and dogs with oral exposures as low as 0.3 and 2.5mg/kg, respectively. High doses produce severe muscle tremors, hyperthermia, seizures, and death within a couple hours postingestion. The usual presentation after moderate to low exposure develops over 12-24 hours with progressive ataxia, paresis, and hindlimb paralysis. Central nervous system depression continues to semicoma or coma. Diagnosis is based upon history of exposure, development of progressive appropriate clinical signs and chemical confirmation in tissues. Treatment relies heavily upon early emesis induction and prolonged decontamination with pulse dosing of activated charcoal. There is no specific antidote; attempts to control cerebral edema with diuretics and corticosteroids have met with limited success. Significant supportive care is usually required, often including seizure management, nutritional support, and defense against decubital ulceration. Prognosis is guarded to poor.

Common rodenticide toxicoses in small animals.

This article focuses on the 3 most commonly used rodenticide types: anticoagulants, bromethalin, and cholecalciferol. It is important to verify the active ingredient in any rodenticide exposure. Many animal owners may use the term "D-con" to refer to any rodenticide regardless of the actual brand name or type of rodenticide. The EPA released their final ruling on rodenticide risk mitigation measures in 2008 and all the products on the market had to be compliant by June 2011, changing to consumer products containing either first-generation anticoagulants or nonanticoagulants including bromethalin and cholecalciferol. These regulations are likely to cause an increase in the number of bromethalin and cholecalciferol cases.

Severe methemoglobinemia and hemolytic anemia from aniline purchased as 2C-E (4-ethyl-2,5-dimethoxyphenethylamine), a recreational drug, on the Internet - Oregon, 2011.

In August 2011, two men in Oregon drank a liquid they believed to be 2C-E (4-ethyl-2,5-dimethoxyphenethylamine), a psychoactive stimulant used as a recreational drug, after purchasing it on the Internet. Fifteen minutes after ingestion, the men became cyanotic and subsequently were treated for refractory methemoglobinemia and hemolytic anemia. The Oregon Poison Center, Oregon Public Health Division, Drug Enforcement Administration (DEA), and Food and Drug Administration (FDA) jointly investigated to determine the cause of the poisoning and identify other cases. The Oregon Poison Center and Oregon Public Health Division promptly alerted health-care providers and public health agencies and searched for additional cases. DEA confiscated all product remaining in the men's possession, and FDA identified the substance as aniline, an industrial solvent known to cause methemoglobinemia. One patient reported purchasing the substance from the Internet site of a Chinese chemical company. No additional cases were identified by investigators. Purchase of chemicals from unregulated Internet sources poses a serious risk to purchasers from product contamination and substitution.