Abstract
We describe two suicides due to phenytoin and pentobarbital intoxications using a commercially available veterinary euthanasia preparation (Euthasol), which is a combination of the two medications. The role of the circumstances and toxicology findings and testing are described. The detection of this combination of medications should cause the death investigator to consider suicide and to look for occupational access to this preparation.
Introduction
Intentional intoxications are common methods of suicide. These intoxications may include prescription or over-the-counter medications and/or other toxic substances. Most of these substances are administered by ingestion. People with the intent to commit suicide often will use a method that is readily available. We describe two fatalities due to intentional intoxications by pentobarbital and phenytoin. These two medications are combined in a single injectable preparation that is commercially available to euthanize animals. The detection of these two substances should alert the medical examiner/coroner (ME/C) to the likelihood of suicide and the need to search for the source of the drug. An occupational history of laboratory research or veterinarian work may point toward the source of the drug.
CASE 1
A 34-year-old woman with a history of stage IV breast cancer metastatic to brain and spine was admitted to the hospital for nausea and poor oral intake. After refusing further treatment she was hydrated with intravenous fluids and prepared for discharge to home. On the evening prior to discharge, a group of friends visited. She was found unresponsive by a nurse shortly after the visitors' departure. She had been well-appearing and active earlier in the evening. Her past medical history included depression with suicidal ideation. An external examination revealed no trauma. She had a peripheral intravenous catheter and had been receiving normal saline. Her prescribed medications included oxycodone, omeprazole, dexamethasone, and fluoxetine. Autopsy subclavian blood was collected for toxicological analysis, which detected pentobarbital (285.8 mg/L) and phenytoin (34.0 mg/L) in addition to the prescribed oxycodone (<0.1 mg/L), fluoxetine (0.7 mg/L), and its active metabolite norfluoxetine (0.4 mg/L).
Further investigation revealed that she had worked in a veterinarian's office and the visiting friends included former coworkers. A pentobarbitol/phenytoin product was used in this office to euthanize animals. No hypodermic syringes were identified in the room.
The cause of death was certified as acute intoxication by the combined effects of pentobarbital and phenytoin. The manner of death was homicide. The "how injury occurred" section was "direct or assisted intravenous administration of the above listed agents."
CASE 2
A 41-year-old male was found dead on a couch in his apartment during a well-being check. His past medical history included hypertension and a remote history of depression after the deaths of his parents. Scene investigation revealed an open bottle of liquor in the kitchen, but no drugs or medications. There was no history of a seizure disorder.
At autopsy, the 72 in, 220 lb (body mass index, 29.8 kg/m2) man had pink posterior fixed lividity and marbling of the lower abdomen with skin slippage. On internal examination, the heart weighed 490 g; the coronary arteries and myocardium were unremarkable. The right and left lungs weighed 870 g and 740 g, respectively.
Initial toxicological analysis of the decedent's blood detected ethanol (101 mg/dL) and pentobarbital (23 mg/L). Subsequent investigation revealed that the decedent worked in an academic laboratory with mice. When the history of decedent's laboratory work was obtained, additional testing for phenytoin was requested. This expanded analysis detected phenytoin (2.7 mg/L).
Further investigation revealed that a pentobarbital/phenytoin product was used in his research laboratory to euthanize mice. The decedent had access to this medication and had created cover stories for his family and colleagues to avoid rescue. No hypodermic syringes were identified in the apartment.
The cause of death was certified as acute pentobarbital and phenytoin intoxication. The manner of death was suicide.
Discussion
Pentobarbital is a short-acting barbiturate with sedative and hypnotic effects due to potentiation of GABA receptors; it is prescribed for sleep induction and is usually given orally due to effective gastrointestinal tract absorption. When taken orally, the plasma concentration of pentobarbital peaks in 30–60 minutes while the hypnotic effect peaks in one to four hours; when given intravenously, the onset of action occurs within one minute and peak plasma concentrations occur by 15 minutes. Plasma concentrations greater than 10 mg/L may result in deep coma while plasma concentrations above 30 mg/L are potentially lethal. Following absorption, the distribution of barbiturates depends upon lipid solubility with distribution to all bodily tissues and fluids. The highest concentrations are in the liver and brain (
1).
Phenytoin is an inhibitor of voltage-gated sodium channels and is commonly used as an anticonvulsant for seizures. It also has indications for use as an anti-arrhythmic and muscle relaxant, however, use has been limited due to a narrow therapeutic window and adverse effects including atrioventricular conduction disruption, ventricular fibrillation, central nervous system depression (somnolence, confusion, slurred speech, decreased coordination), toxic hepatitis, gingival hyperplasia, pancytopenia, megaloblastic anemia, and lymph node hyperplasia, among others (
2).
Rates of absorption vary among manufacturers, but Phenytoin and its sodium salt are usually slowly and completely absorbed from the gastrointestinal tract allowing for oral administration. Approximately 1% of therapeutic doses are excreted unchanged in urine while in toxic doses, up to 10% may appear unchanged in urine. Following absorption, phenytoin is distributed into cerebrospinal fluid, saliva, semen, gastrointestinal fluids, and bile (
3). Peak plasma concentrations in living subjects following a single 100 mg oral dose of phenytoin of 1.6–2.8 mg/L were observed two to four hours after ingestion (
2). Death due to cardiac arrhythmias following rapid intravenous injection have been reported.
Euthasol is a commercial preparation used in the rapid, painless euthanasia of canines and is not approved for human use. Federal law restricts use of this drug to licensed veterinarians. It is given intravenously and 1 mL contains an admixture of pentobarbital sodium (390 mg), phenytoin sodium (50 mg), 10% ethyl alcohol, 18% propylene glycol, rhodamine B (0.003688 mg), and benzyl alcohol (preservative). Euthanasia occurs through respiratory arrest and circulatory collapse resulting in cerebral ischemia/hypoxia prior to cessation of cardiac activity. At anesthetic doses, there is rapid onset of unconsciousness. At elevated doses, there is depression of medullary respiratory and vasomotor centers. Rapid intravenous administration of phenytoin sodium may result in cardiovascular collapse and/or central nervous system depression including hypotension. The typical clinical sequence following intravenous injection of Euthasol results in unconsciousness within seconds (
4). This is rapidly followed by deep anesthesia and hypotension. On the order of seconds later, breathing stops, encephalographic activity becomes isoelectric, and then cardiac activity ceases (
4). Phenytoin sodium has cardiotoxic properties that hasten the cessation of electrical activity of the heart. Ethanol was not detected in the first instance, which could be dependent on the dose given and/or the levels of detection. Propylene glycol testing was not performed.
The postmortem blood concentrations in case 1 were markedly high. The concentrations in case 2 were not as high. This may be related to the route of administration or the different postmortem interval. Given that patient 1 was receiving intravenous fluid, it is likely that the medication was administered by this route. The precise route of administration in patient 2 is unknown. A determination of the death due to an intoxication requires three factors. First, the autopsy must fail to disclose a disease or physical injury whose extent or severity is inconsistent with life. Second, the concentrations must be in the range typically encountered in such deaths. And third, the history and circumstances must be consistent with a death due to an intoxication.
For case 1, there was advanced disease that was capable of explaining death. The compelling circumstances and toxicology results, however, trump this disease. The circumstances and toxicology result support an intoxication death.
A nonfatal accidental intoxication by phenytoin and phenobarbital (not pentobarbital) has been reported (
5). In this instance, a mentally challenged woman had taken an unknown amount of a friend's medications. Despite treatment with gastric lavage, activated charcoal, and magnesium citrate, the patient's condition worsened over the ensuing days with increased lethargy and ultimately coma. Her peak serum phenytoin concentration during medical treatment was 95 mg/L.
Depending upon the extent of toxicology screening, phenytoin may not be detected while pentobarbital may. Forensic toxicology analysis often includes a barbiturate screen with an enzyme-linked immunosorbent assay but does not always screen for phenytoin. Phenytoin is detected by high performance liquid chromatography. Therefore, it is important to be familiar with specific laboratory protocols with regard to what is and what is not included in routine screening. As in the second case, identification of pentobarbital without phenytoin may occur because phenytoin testing was not included in the initial screen. In case 1, the in-house laboratory's protocol included phenytoin screening in all cases. Since forensic toxicology laboratories may offer different testing panels (basic, advanced, expanded), it is important that forensic pathologists and toxicologists are aware of each other's limitations and concerns. Given the marked shift in prescriptions for benzodiazepines instead of barbiturates, it has become uncommon to detect pentobarbital in forensic practice. The detection of pentobarbital should result in consideration of phenytoin testing and the possibility of a suicide.
The first case was certified as a homicide. This was because there was direct or assisted administration of the drug by another. Even though the patient may have been willing to commit suicide, this was a criminal act at the hand of another that resulted in death, which lead to the homicide certification.
A variety of other methods are approved for euthanasia in animals (
6). Tributame euthanasia solution is a combination of embutramide, chloroquine, and lidocaine. It has a teal blue color with a bittering agent to discourage ingestion. Embutramide is a derivative of γ-hydroxybutyrate with marked cardiovascular effects. Chloroquine, an antimalarial drug, is added to hasten the cardiovascular effects of embutramide as it also has depressive cardiovascular effects.
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