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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 5  |  Issue : 2  |  Page : 33-35

Iatrogenic phenytoin toxicity – Newer lessons learnt


1 Department of Anesthesia, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Anesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission26-Jul-2020
Date of Decision02-Mar-2021
Date of Acceptance11-May-2021
Date of Web Publication24-Jun-2021

Correspondence Address:
Anjishnujit Bandyopadhyay
Department of Anesthesia, Level 4, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sccj.sccj_33_20

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  Abstract 


Phenytoin is a widely prescribed anti-epileptic drug (AED), but overdoses are common given its narrow therapeutic index. A 24-year-old male, a previously diagnosed case of seizure disorder on multiple AEDs, including phenytoin presented with breakthrough seizures to the medical emergency. The subsequent medical management of this patient led to an inadvertent iatrogenic overdose of phenytoin resulting in encephalopathy in this patient. Given our experience in this patient, we suggest using a newer class of AED for seizure control in a patient already on phenytoin, particularly if immediate therapeutic plasma phenytoin level monitoring is not readily available.

Keywords: Anti epileptics, case report, phenytoin toxicity, status epilepticus


How to cite this article:
Bandyopadhyay A, Kannamani B, Saini V, Ashok V. Iatrogenic phenytoin toxicity – Newer lessons learnt. Saudi Crit Care J 2021;5:33-5

How to cite this URL:
Bandyopadhyay A, Kannamani B, Saini V, Ashok V. Iatrogenic phenytoin toxicity – Newer lessons learnt. Saudi Crit Care J [serial online] 2021 [cited 2021 Jul 27];5:33-5. Available from: https://www.sccj-sa.org/text.asp?2021/5/2/33/319310




  Introduction Top


Phenytoin is one of the most widely prescribed anti-epileptic drug (AED) and has been a cornerstone of epilepsy treatment. It is a broad-spectrum anti-epileptic with good efficacy in partial seizures and generalized tonic-clonic seizures (GTCS). This drug has a narrow therapeutic index and overdoses are common. Phenytoin metabolism is dose dependent with elimination following a predictable first-order kinetics at low drug concentrations and zero-order kinetics at higher drug concentrations.[1] Acute phenytoin toxicity usually manifests with seizures (paradoxically), bradyarrhythmias, and coma, but these can be managed with prompt withdrawal of the drug and supportive intensive care measures.

We hereby report the case of a 24-year-old male with known seizure disorder on multiple AEDs including phenytoin who presented with GTCS and subsequently developed iatrogenic acute phenytoin toxicity. While phenytoin-induced encephalopathy reversed with the discontinuation of the drug, hypotonia caused by acute phenytoin toxicity persisted, leading to prolonging of duration of mechanical ventilation and subsequent tracheostomy. Written consent was obtained from the family for the publication. We present the following case in accordance with CARE reporting checklist.


  Case Report Top


A 24-year-old male with a history of seizure disorder on multiple AED in various combinations and doses since 12 years of age, presented to the medical emergency with recurrent seizures and altered sensorium over the past 1 day. The patient had been on levetiracetam 1 gm BD, carbamazepine 200 mg BD, phenytoin 100 mg times a day (TDS), and lacosamide 100 mg BD, and he was compliant with the treatment.

In the emergency department, the patient was hemodynamically stable, maintaining his own airway, breathing adequately and a Glasgow Coma Scale of E4V2M6 with equally reacting pupils, absent deep-tendon reflexes, hypotonia, and no focal neurological deficit. He was started on valproate 500 mg BD intravenously, phenytoin 300 mg TDS oral, phenobarbitone 30 mg BD intravenously, and carbamazepine 300 mg BD oral. With the above-mentioned medications, the patient was admitted and shifted to ward for further evaluation. On day 2 in the ward, the patient developed fever, hypotension requiring vasopressor support, and deterioration of his mental status to E1V1M1 requiring urgent endotracheal intubation and controlled mechanical ventilation.

The patient was then shifted to the medical intensive care unit (MICU), after a non-contrast commuted tomography (NCCT) head and contrast-enhanced magnetic resonance imaging (CE-MRI) brain for the further management. On receiving in MICU, the patient was E1VtM1 with B/L pupils reacting equally and stable hemodynamics on nor-epinephrine (0.2 μg/kg/min) and vasopressin (2 U/h). Broad-spectrum empirical antibiotics were started in view of suspected bacterial meningitis. After adequate fluid resuscitation, hemodynamic stability was achieved, and vasopressors were tapered off.

The NCCT scan and CE-MRI revealed a right frontal granuloma along with bilateral cerebellar atrophy with no evidence of meningeal enhancement or basal exudates. Analysis of the cerebrospinal fluid did not reveal any abnormality. An electroencephalogram was done to rule out non convulsive status epilepticus, and it revealed diffuse slowing of all brain waves suggestive of encephalopathy. Subsequently, we performed therapeutic drug monitoring (high-performance liquid chromatography) specifically for AEDs that revealed a serum phenytoin level of 45 μg/ml (toxic level) and serum phenobarbitone level of 11 μg/ml (sub-therapeutic level).

Following this, phenytoin was stopped and Levetiracetam added. The dose of phenobarbitone was increased to 30 mg TDS. Serum phenytoin levels were sent on alternate day and are as described in [Table 1].
Table 1: Trends of serum phenytoin levels in intensive care unit

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Once phenytoin was stopped, sensorium gradually improved and by day 7 in the MICU, the patient was E4VtM6. Despite improvement in sensorium, the patient continued to be hypotonic. Thus, in view of expected extubation failure, a bedside percutaneous dilatational tracheotomy was performed. We were then able to wean him off mechanical ventilation and he was transferred out of MICU to the neurology ward on day 14 on room air. The total duration of mechanical ventilation was 12 days.


  Discussion Top


Phenytoin is a very commonly prescribed antiepileptic medication with a very narrow therapeutic range (10–20 μg/ml). As the serum levels of phenytoin go above 20 μg/ml elimination shifts from first-order kinetics to zero-order kinetics. Toxicity is well correlated with the serum levels of phenytoin. Serum concentrations of phenytoin are monitored by measuring the total phenytoin concentration. Ninety percent of total phenytoin is bound to albumin, and only the unbound form is pharmacologically active.[2]

Toxicity depends on the route of exposure (oral versus parenteral), duration of exposure (acute overdose versus chronic), dosage, and metabolism. Oral overdose of phenytoin usually causes neurological effects, whereas parenteral overdose will mainly involve cardiovascular systems.[3],[4] Chronic toxicity can cause cerebellar atrophy leading to progressive hypotonia. It may also cause other central nervous system effects such as behavioral changes and increased seizure activity. Megaloblastic anemia, gastrointestinal symptoms, hirsutism, and hyperplasia of gums are also common. Acute oral toxicity of phenytoin causes nystagmus, seizures, coma, and even death at levels more than 50 μg/ml.[2]

In our case, the patient presented with seizures despite being on multiple anti-epileptics including phenytoin following which the total dose per day of phenytoin was tripled. This most likely precipitated encephalopathy in this patient. Improvement in sensorium started after 48 h of stopping the drug, once the levels started to come down. There is no specific antidote for phenytoin toxicity and treatment recommendations are only supportive. High-protein binding of phenytoin makes it unamenable to haemodialysis. There a few reports of hemoperfusion and molecular adsorbents recirculating system (MARS) being used to decrease phenytoin levels, but as of now the evidence is mostly anecdotal.[5] Thus, with supportive ICU care and mechanical ventilation we were able to manage our case successfully.

This case gave us some useful new insights into the management of a patient with seizure disorder who presents with recurrent seizures. First, in low- and middle-income countries like ours, routine monitoring of serum phenytoin levels is not sometimes readily available. In this scenario it might be prudent to start a newer class of AED rather than escalating the dose of phenytoin. Second, inadvertent iatrogenic phenytoin overdose causes a spectrum of disorders, most of which are reversible with stoppage of drug and supportive care. However, in our patient, hypotonia was persistent even after the resolution of signs and symptoms of acute phenytoin toxicity, leading to weaning failure and subsequent tracheostomy. This is potentially something that critical care physicians may need to be aware of while managing patients with seizure disorders in the intensive care unit.

To conclude, routine monitoring of serum levels of AEDs is recommended, especially in patients on multiple AEDs. Additionally, if a patient who is already on AEDs which have narrow therapeutic index like phenytoin, presents with seizures, it might be advisable to start an AED of another class rather than increase the dose of phenytoin, particularly when immediate therapeutic drug monitoring is not available.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Ethical Statement

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Written informed consent was obtained from the patient for publication of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Shaikh AS, Li Y, Cao L, Guo R. Analysis of phenytoin drug concentration for evaluation of clinical response, uncontrolled seizures and toxicity. Pak J Pharm Sci 2018;31:1697-700.  Back to cited text no. 1
    
2.
Iorga A, Horowitz BZ. Phenytoin toxicity. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482444/. [Last updated on 2019 Feb 28].  Back to cited text no. 2
    
3.
Hamed SA. The auditory and vestibular toxicities induced by antiepileptic drugs. Expert Opin Drug Saf 2017;16:1281-94.  Back to cited text no. 3
    
4.
Guldiken B, Rémi J, Noachtar S. Cardiovascular adverse effects of phenytoin. J Neurol 2016;263:861-70.  Back to cited text no. 4
    
5.
Sen S, Ratnaraj N, Davies NA, Mookerjee RP, Cooper CE, Patsalos PN, et al. Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS). Epilepsia 2003;44:265-7.  Back to cited text no. 5
    



 
 
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