Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup.

The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence-based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence = C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning.

Integrating the Forensic Sciences in Wildlife Case Investigations: A Case Report of Pentobarbital and Phenytoin Toxicosis in a Bald Eagle (Haliaeetus leucocephalus).

The application of medical knowledge to the purpose of law is the foundation of forensic pathology. A forensic postmortem examination often involves the expertise of multiple scientific disciplines to reconstruct the full story surrounding the death of an animal. Wildlife poses additional challenges in forensic investigations due to little or no associated history, and the disruptive effects of decomposition. To illustrate the multidisciplinary nature of wildlife forensic medicine, the authors outline a case of secondary pentobarbital/phenytoin toxicosis in a bald eagle (Haliaeetus leucocephalus). The eagle was the single fatality in a group of 8 birds that fed on euthanized domestic cat remains that had been improperly disposed of in a landfill. Cooperation between responding law enforcement officers, pathologists, and other forensic scientists led to the successful diagnosis and resolution of the case.

Acute onset of a tonic seizure in a phenytoin-overdosed patient who had taken phenytoin and levetiracetam daily.

The 42-year-old woman who had been taking 300 mg phenytoin and 2,000 mg levetiracetam daily took 28.6 g of phenytoin and was transferred to our critical care center. The blood phenytoin concentration was 67.9 µg/mL on admission and decreased to 53.4 µg/mL on hospital day 2. Tonic seizures occurred several times on hospital day 2; thus, we resumed levetiracetam via a nasogastric tube. Thereafter, no further seizures were observed. We thought the seizure to have been caused by temporary withdrawal of levetiracetam because it did not occur on the day when the blood phenytoin concentration peaked and stopped altogether after resumption of levetiracetam. We considered that to treat the convulsion attack resulting from an overdose of the other antiepileptic drug with a different action mechanism, it was necessary to promptly restart the administration of the antiepileptic drug, which the patient was usually administered.

Novel method for rapid reversal of drug toxicity: a case report.

Drug toxicity is traditionally treated by reducing the amount of the drug absorbed, enhancing elimination, and providing supportive care. Once the drug has been absorbed, there are few methods that help decrease morbidity and mortality caused by a toxic drug level. Albumin infusion is a new approach that changes that, as it can rapidly reverse a toxic drug level back to a therapeutic level. It is believed with most drugs that the toxic effects are related to the total amount of the free drug. In this method, albumin binds to the free drug and acts as a reservoir or depot from which the drug is slowly released to the free form, thereby limiting the effects of drug toxicity. In this case report, an elderly female patient who experienced phenytoin toxicity was treated with albumin infusion, after which her phenytoin level returned to a therapeutic level with corresponding improvements in her symptoms. Based on our calculations, it was predicted that a small amount of albumin would reverse the patient's toxic symptoms. With this approach, the patient's toxic symptoms improved when free phenytoin levels dropped from 15 to 8 µmol/L. Albumin infusion is a promising new therapy that can rapidly reverse a toxic drug level back to a therapeutic level by binding the free drug to albumin.

Free phenytoin toxicity.

Phenytoin has a narrow therapeutic window, and when managing cases of toxicity, clinicians are very wary of this fact. Typically, if patient presents with symptoms suggestive of phenytoin toxicity, total serum phenytoin is promptly ordered. That could be falsely low especially in elderly or critically ill patients, which may lead to a low albumin level resulting in this discrepancy. The free phenytoin can be best estimated using the Sheiner-Tozer equation. Herein, we describe a case of an elderly male patient who presented with drowsiness, gait changes, and elevated liver enzymes and a normal total serum phenytoin level of 18 ng/dL (normal, 10-20 ng/dL).After taking his albumin level into account, his free phenytoin level was calculated to be 27 ng/dL, and the phenytoin was discontinued leading to resolution of his symptoms as well as a return of his liver function panel values to baseline.

Acute leukoencephalopathy possibly induced by phenytoin intoxication in an adult patient with methylenetetrahydrofolate reductase deficiency.

A 19-year-old university student with no personal or family history of neurologic disorders developed convulsions and was administered phenytoin. Two months later, he developed lower limb-dominant acute demyelinating polyneuropathy, from which he recovered within 2 months. At age 20, he rapidly developed visual disturbances and paraplegia from phenytoin intoxication. Cranial magnetic resonance imaging (MRI) revealed leukoencephalopathy with no evidence of thrombosis or vasoconstriction. Hyperhomocysteinemia, hypomethioninemia, low serum folate concentration, and an absence of megaloblastic anemia were consistent with the diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency. A genomic DNA sequence analysis demonstrated compound heterozygosity for two missense mutations in the MTHFR gene, namely, [458G>T + 459C>T] (Gly149Val) and 358G>A (Ala116Thr), both of which are known pathogenic mutations. An absence of leukoencephalopathic changes on MRI scans performed 9 months previously strongly suggested that phenytoin intoxication caused acute leukoencephalopathy. Therefore, phenytoin may be an aggravating factor of remethylation defects in patients with MTHFR deficiency.

Successful hemodialysis in a phenytoin overdose: case report and review of the literature.

We describe the case of a 42-year-old female who presented to our care 1 hour after ingesting 3.6 g of phenytoin. She was stuporous 48 hours after admission despite supportive therapy. She was treated with hemodialysis (HD) for nearly 6 hours in order to remove phenytoin. Her level of consciousness improved markedly during the procedure. During HD, phenytoin levels decreased by 47% and measured half-life was 6.8 hours as compared to 116 hours when not on HD. Finally, we were able to remove 547 mg of phenytoin (directly measured from the dialysate), representing approximately a third of estimated body stores. The use of extracorporeal therapy in phenytoin overdose is reviewed here. We believe that in severe cases of phenytoin intoxication, hemodialysis can be used to accelerate total body burden of the drug, even if protein binding is significant.

Cardiac Collapse Secondary to Phenytoin Toxicity in a Neonate Treated with Extracorporeal Membrane Oxygenation Support (ECMO).

INTRODUCTION: Although medication toxicity is uncommon in neonates, there are several medications used in this population that pose a risk. Phenytoin has an increased risk of toxicity given its narrow therapeutic window and variations in drug elimination. CASE REPORT: We describe the case of a 3-day-old male infant who developed cardiovascular collapse secondary to severe phenytoin toxicity (max phenytoin level 86 µg/mL) and was placed on extracorporeal membrane oxygenation support (ECMO). Several ancillary treatments were utilized in an attempt to decrease serum phenytoin concentrations and limit toxicity including albumin boluses, phenobarbital administration, intravenous lipid infusion, and folic acid supplementation. DISCUSSION: Although uncommon, drug toxicity should be considered in patients with acute changes who are exposed to medications with potential toxicity. With elevated levels of phenytoin, the half-life can be prolonged resulting in longer exposure to elevated levels of the drug as seen in our patient. This case report highlights the importance of ECMO utilization for cardiac support in neonates with medication toxicity and other potential ancillary treatments to decrease serum phenytoin concentrations.

Enhanced clearance of highly protein-bound drugs by albumin-supplemented dialysate during modeled continuous hemodialysis.

BACKGROUND: In 2006, there were 16 796 toxic exposures attributed to valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) reported to the US Toxic Exposure Surveillance System. Of these, 30% (5046) were treated in a health care facility with 12 cases resulting in death. These drugs are highly protein bound and poorly dialyzable; however, it has been suggested that albumin-supplemented dialysate may enhance dialytic clearance. We investigated whether the addition of albumin to dialysate affects dialytic clearance of VPA, CBZ and PHT. METHODS: VPA, CBZ and PHT were added to a bovine blood-based in vitro continuous hemodialysis circuit, which included a polysulfone or an AN69 hemodialyzer. VPA, CBZ and PHT clearances were calculated from spent dialysate and pre-dialyzer plasma concentrations. VPA, CBZ and PHT clearances with control (albumin-free) dialysate were compared to clearances achieved with 2.5% or 5% human albumin-containing dialysate. The influences of blood flow (180 and 270 mL/min) and dialysate flow (1, 2 and 4 L/h) on dialysis clearance were also assessed. RESULTS: The addition of 2.5% albumin to dialysate significantly enhanced dialytic clearance of VPA and CBZ, but not PHT. Use of 5% albumin dialysate further increased VPA and CBZ clearance. Overall, drug clearance was related directly to dialysate flow but independent of blood flow. CONCLUSION: Continuous hemodialysis with albumin-supplemented dialysate significantly enhanced VPA and CBZ, but not PHT, clearance compared to control dialysate. Continuous hemodialysis with albumin-supplemented dialysate may be a promising therapy to enhance dialytic clearance of selected highly protein-bound drugs.

Treatment of severe intravenous phenytoin overdose with hemodialysis and hemoperfusion.

BACKGROUND: Phenytoin is a widely used anticonvulsant agent responsible for a number of intentional and unintentional overdoses. However, besides supportive care, specific treatment recommendations to enhance elimination of the parent compound have been discussed controversially and effectiveness of hemoperfusion is under debate. CASE REPORT: A women with a prehistory of cerebral seizures was presented following a severe iatrogenic phenytoin overdose with a peak plasma concentration of 117 mg/L. A Phenytoin overdose could be contributed to both inadequate dosing and missed repeated drug monitoring. Native phenytoin body clearance failed to relevantly lower phenytoin concentration. Thus, three sessions of a four-hour long combination of activated charcoal hemoperfusion and high-flux hemodialysis were performed resulting in considerably reduced half-life during these measures of about 7-13 hours compared to the native half-life wavering between 40-100 hours. This resulted in a substantial clinical improvement in terms of central nervous system toxicity. CONCLUSIONS: Hemodiaperfusion with activated charcoal seems to be a reasonable measure for forced lowering of highly toxic phenytoin plasma concentration and should be considered especially in circumstances following intravenous overdose (e.g. inadequate iatrogenic dosing). Its narrow therapeutic range enforces strictly adequate dosing and subsequent repeated drug monitoring of phenytoin.

Acenocoumarol and phenytoin toxicity in the presence of CYP2C9 mutation.

This case report describes a rare interaction between therapeutic doses of phenytoin and acenocoumarol resulting in both acute phenytoin toxicity and increased international normalized ratio (INR). Interactions between these drugs are due to the pharmacokinetics and the common metabolising pathway by hepatic cytochrome P450 isoenzyme-CYP2C9. Our patient was detected to be homozygous for CYP2C9*3 by PCR-RFLP analysis resulting in markedly decreased metabolism of both the drugs. Given that these two drugs are often given concomitantly in the medical out patient department, and that CYP2C9 polymorphisms are not uncommon, clinicians should be aware of this interaction and suspect this in patients with toxicity to these drugs.

Characterization of drug overdoses in an Ohio incarcerated population.

CONTEXT: Literature exists about drug overdose following release of recently incarcerated individuals and mortality among prisoners in the United States, but little information exists about drug overdoses in the imprisoned population. OBJECTIVE: This study aims to quantify and describe prisoner medication overdose requiring inpatient admission or assessment at a tertiary care facility and to assess the associated hospital charges. MATERIALS AND METHODS: A single-center, retrospective cohort study was conducted on all Ohio Department of Rehabilitation and Correction inmates who presented to The Ohio State University Wexner Medical Center with drug overdose between 15 October 2011 and 14 October 2014. Demographic information, overdose substances, exposure reason, clinical effects, lengths of stay, outcomes, and hospital charges were collected. RESULTS: Of the 130 patients included in the study, there were 100 intentional overdoses, 7 unintentional overdoses, 3 adverse drug reactions, and 20 unknown intentions. The most common drug in prisoner overdose was phenytoin (n = 29, 22%). While anticonvulsants were the most common drug class overall, anticonvulsants, antidepressants, and cardiovascular medications accounted for equal numbers of intensive care unit (ICU) admissions. Most patients exhibited multiple symptoms on arrival, most commonly neurologic, cardiovascular, and gastrointestinal symptoms. Patients were seen from 21 of the 28 Ohio Department of Rehabilitation and Correction facilities, of which five facilities, that largely house minimum and medium security prisoners, accounted for 61% of patients sent to our institution. The total sum of charges was $2,606,942 with 55% of charges from ICU stays. CONCLUSION: Our study shows that drug overdoses within our incarcerated population were largely intentional overdoses of anticonvulsants, cardiovascular drugs, and antidepressants. Opportunities exist to target intentional drug overdoses that accounted for 80% of prisoner overdoses for potential cost-savings.

Type 1 Brugada pattern ECG due to supra-therapeutic phenytoin level.

Brugada syndrome is an inherited arrhythmogenic disease, characterised by a coved-type ST segment elevation in right precordial leads and an increased risk of sudden cardiac death due to ventricular arrhythmia. To unmask or exacerbate a Brugada ECG pattern, class IA or IC antiarrhythmic agents are used, and clinicians can predict sudden cardiac death in a high-risk patient. However, phenytoin, one of the class IB agents, may induce a Brugada pattern ECG at a supra-therapeutic level and this association has rarely been reported. We describe a case of a patient with a phenytoin level about twice as high as the therapeutic level, which led to the emergence of a type 1 Brugada pattern ECG. Awareness should be made between this important association of supra-therapeutic phenytoin level and type 1 Brugada pattern ECG because symptomatic Brugada syndrome can lead to sudden cardiac death.

Phenytoin intoxication in critically ill patients.

Phenytoin intoxication can result in major and possibly life-threatening disorders. Furthermore, the hepatic clearance can become saturated, thus, shifting the elimination from first- to zero-order kinetics. This results in a slow elimination of the compound in case of intoxication. The treatment modalities for phenytoin overdose are limited. Taking into account the high level of protein binding, the molecule is not easily eliminated from the body by means of extracorporal epuration. Although reports exist on the use of MARS (molecular adsorbents recirculating system) dialysis, peritoneal dialysis, and standard dialysis for the elimination, in practice, hemoperfusion, is the most often applied technique. The authors report the case of a hypoalbuminemic patient with severe neurologic signs of phenytoin intoxication (total concentration moderately elevated, free fraction high). A combination of high-flux dialysis and hemoperfusion resulted in a considerable extraction of the drug, accelerating the natural clearance from the body and ameliorating clinical signs of intoxication. In selected patients (with a high free fraction of phenytoin), high-flux dialysis may be a valuable alternative or adjuvant to hemoperfusion.

Charcoal hemoperfusion in the therapy for methsuximide and phenytoin overdose.

Two patients suffered overdoses of anticonvulsant drugs. The first patient took methsuximide and the second, phenytoin. Because of profound CNS depression, both patients underwent hemoperfusion with a cellulose-activated charcoal hemoperfusion column. The primary metabolite of methsuximide, N-desmethylmethsuximide, primarily was responsible for the CNS depression in the first patient. The clearance of N-desmethylmethsuximide by the charcoal column was high, and clinical improvement became apparent during the hemoperfusion period. The clearance of phenytoin, on the other hand, was much lower than that of N-desmethylmethsuximide, and there was no apparent clinical improvement in that patient's condition.

Subacute phenytoin intoxication syndrome.

Phenytoin sodium intoxication of subacute onset may occur in cases of nonepileptic patients who receive phenytoin for suppression of cardiac arrhythmias. The case reported here is of a syndrome that consisted of dementia, cerebellar dysfunction, and peripheral neuropathy. Withdrawal of phenytoin was followed by a slow improvement in the syndrome. Awareness of the features of subacute phenytoin intoxication in cardiac patients is important because this entity may mimic cerebrovascular disease. Periodic monitoring of serum phenytoin concentrations is advisable.

Phenytoin intoxication with no symptoms correlated with serum drug level: a case study.

In high-dose intake of phenytoin, which is used frequently to treat epilepsy, nystagmus, diplopia, nausea-vomiting, lethargy, confusion, seizure, and coma can be observed. In recent studies on phenytoin intoxication, in which seizure and coma were observed in drug levels greater than 50 ug/mL. The serum phenytoin level of a patient, who consumed approximately 100 pcs of 100 mg phenytoin tablets in an effort to commit suicide, and who had no pathological finding in her neurologic examination, was 124 ug/mL. High drug level and the absence of toxic effect (or the absence of toxic effect correlated with the drug level) indicates that cytochrome P450 is functioning, but there can be a mutation in the MDR1 gene. In our case study, we report on phenytoin intoxication in a patient having a high level of phenytoin but no symptoms correlated with serum drug level, as supported by the findings in the literature.