Sensitive and simultaneous determination of nine anticoagulant rodenticides in human blood by UPLC-MS-MS with phospholipid removal pretreatment.

A sensitive and rapid method for the simultaneous determination of nine anticoagulant rodenticides (ARs) in human blood is reported herein. The method involves phospholipid removal pretreatment for reduced matrix effect (ME) and detection with ultra-performance liquid chromatography coupled with tandem mass spectrometry. Satisfactory recoveries were achieved ranging from 80.6% to 113.1% for the nine analytes, with the intra-day relative standard deviations (RSDs) in the range of 3.4-7.9% and inter-day RSDs in the range of 4.1-8.3%, indicating good precision. Linear relationships with correlation coefficients above 0.998 (n = 6) were found in the range of 1-2,000 ng/mL. High sensitivity was achieved with limits of detection ranging from 0.02 to 0.3. The application of phospholipid removal step significantly optimized the ME, and the reduction of ME ranged from 6.1% to 15.5%. This method was successfully applied to the determination of ARs for blood samples from real forensic cases. These results prove that this method is reliable for rapid forensic and clinical diagnosis. The removal capabilities for five representative phospholipids that are abundant in blood were evaluated individually with Phree™ phospholipid removal plates. While significant capabilities for phospholipid removal were confirmed, the results showed that the removal capability for certain phospholipid could be improved.

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.

Deliberate self-poisoning with long-acting anticoagulant rodenticides.

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 deliberate self-poisoning with long-acting anticoagulant rodenticides presenting with haematuria and coagulation values above measurable limits. This case is important as it required immediate and maintenance therapy in order to prevent profound bleeding, as well as the evaluation of the patient's psychosocial factors to ensure medical compliance and to prevent refractory complications or repeated self-harm.

[Overdose in Vitamin K antagonists administration in Dakar: epidemiological, clinical and evolutionary aspects]. / Les surdosages aux antivitamines K à Dakar: aspects épidémiologiques, cliniques et évolutifs.

Vitamin K antagonists (VKA) are widely used for the prevention and curative treatment of thromboembolic events. This study aims to describe the epidemiological, clinical and evolutionary aspects of overdose in Vitamin K antagonists administration and determine its hemorrhagic factors. We conducted a monocentric cross-sectional descriptive study at the Principal Hospital in Dakar. All patients with an INR greater than 5 were included. We studied patients' gender and age, VKA used, drug use period, indications, INR value, associated drugs, presence of hemorrhage, immediate management and evolution. We enrolled 154 patients. Acenocoumarol was the most prescribed VKA. Sex ratio favoured women. The average age was 63 years. Overdose was asymptomatic in 43% of patients. Hemorrhagic symptoms were mainly represented by gingival bleeding, epistaxis. Major bleeding episodes were found in 8.6% of patients and they were represented by melena in 6 patients (3.9%), deep muscle hematoma in 2 patients (1.3%) and intracerebral parenchymal hematoma in 2 patients. Two patients had cardiovascular collapse associated with deglobulisation. Nonsteroidal anti-inflammatory drugs (NSAIDs) assumption was noted in 21% of patients. VKA assumption was suspended transiently in all patients. Mortality was 2%, due to intracranial hemorrhage. The reduction in VKA overdose requires caregivers to manage overdose factors and provide proper patient education.

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.

Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning.

Superwarfarins (brodifacoum, difenacoum, bromodialone and chlorphacinone) are anticoagulant rodenticides that were developed in 1970s to overcome resistance to warfarin in rats. A 26-year-old previously healthy man was admitted to the emergency department with epigastric pain, severe upper and lower gastrointestinal haemorrhage, gingival bleeding and melena. The patient stated that he had been healthy with no prior hospital admissions and no personal or family history of bleeding diathesis. The patient, who later admitted attempted suicide, stated that he had taken 400 g rodenticide including brodifacoum orally for five days prior to admission to hospital. He had oral mucosal bleeding, numerous bruises over the arms, legs and abdomen, and an abdominal tenderness, together with melena. Laboratory tests revealed a haemoglobin level of 12.3 g/dl, leucocyte count of 9.1 × 10(9) /l, haematocrit of 28% and platelet count of 280 × 10(9) /l. The prothrombin time (PT) was > 200 s (normal range 10.5-15.2 s) and the activated partial thromboplastin time (aPTT) was 91 s (normal range 20-45 s). The INR (International normalised ratio) was reported to be > 17 (normal range 0.8-1.2). The thrombin time and plasma fibrinogen levels were in the normal range. The results showed the presence of brodifacoum at a concentration of 61 ng/ml, detected by reversed-phase liquid chromatography.

Ten years of latrogenic intoxications from the Spanish poison control center.

Iatrogenic incidents involving drugs are the main type of nosocomial intoxications reported to the Spanish Poison Control Center. We examined 231 such incidences from January 1991 to December 2000; 46.1% were route errors, 42.4% overdoses and 7.3% administration to the wrong patient. The most important cause of error in hospitals and dentist consults was route confusions and overdoses in primary health care units. In 56.2% of the dose errors the patient was a child < 2y old in a pediatric inpatient setting, involving the iv route; the common administered drugs were anti-infectives, anticoagulants, analgesics and sedatives. Poison Control Centers have an important role in the prevention of iatrogenic intoxications.