EPISODE #4:  

To be or not to be — The Scary B’s of Brain Death Tox

Written by Theresa Kim, MD

Outline

1)     Cases of overdoses imitating brain death

2)     Review of neurologic criteria for brain death

3)     Pharmacogenetics

 

Cases of overdoses imitating brain death

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• Case report of barbiturate overdose from the Neavyn article
  
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  • A 53 year old woman with a history of depression and seizure disorder overdoses on phenobarbital
    
  • Given the absence of brainstem reflexes, the ICU team declares her brain dead
    
  • The poison control center is consulted regarding termination of care
    
    • 
      
    •  They advise the team regarding “early closure bias†(prematurely declaring brain death when a potentially reversible cause such as overdose may be confounding the exam)
      
    • Case report from Syracuse, NY
      
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      • A 41 year old woman is brought to a NY state hospital after being found unresponsive at home
        
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        • Benedryl, baclofen, and xanax bottles are found at the scene
          
        
        
        
      
      
      
    
    
    
  
  
  
• On arrival the pt is unresponsive with a GCS=3, flaccid extremities, and fixed dilated pupils
  
• Initial tests: drug screen is positive for benzodiazepines and opiates, and head CT is normal
  
• The patient is admitted to the ICU where neurology is consulted
  
  • 
    
  • They diagnose the patient with severe anoxic encephalopathy from cardiopulmonary arrest despite no documented cardiac arrest or prolonged hypotension
    
  
  
  
• Day 4: the patient exhibits a normal Babinski reflex and begins breathing over the ventilator
  
  • 
    
  • Ativan is given
    
  
  
  
• At midnight the patient is taken to the operating room to have her organs harvested for donation
  
• On the operating room table she opens her eyes spontaneously and the operation is cancelled
  
• The patient later awakes and admits to taking a massive baclofen overdose
  
• Another case report of baclofen overdose
  
  • 
    
  • A 51 year old woman is found unresponsive with a suicide note at home
    
    • 
      
    • Medication list: clorazepate, hydroxyzine, paroxetine, phenobarbital, phenytoin, digoxin, warfarin, and baclofen
      
    
    
    
  
  
  
• Initial presentation: temperature 95°F, systolic blood pressure 70 mmHg, fixed dilated pupils
  
• Initial tests: CBC, CMP, and head CT are unremarkable; phenobarbital, phenytoin, and digoxin are at therapeutic levels
  
• Day 5: since the patient continues to be deeply comatose, neurology is consulted to perform a brain death examination
  
  • 
    
  • The evaluation is delayed until after the weekend
    
  
  
  
• Day 7: neurology exam cancelled because over the weekend the becomes more alert
  
• Later baclofen level results return from day 1: 2.7mcg/ml (therapeutic .080-.400mcg/ml)
  
• A general rule of thumb is that at therapeutic doses drugs takes ~3-5 half lives to be cleared from the system
  
  • 
    
  • Key point: half lives are determined by volunteers at therapeutic doses
    
    • 
      
    • In contrast, the toxicokinetics in overdose are unknown and not clearly studied
      
    
    
    
  • Therefore, multiple factors such as altered pharmacokinetics, therapeutic hypothermia after arrest, pharmacogenetics, etc can alter metabolism and thus confound this general rule of thumb
    
  
  
  
• The scary B’s that can mimic brain death: baclofen, barbiturate, benzodiazepine
  

Review of neurologic determination of brain death

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• Definition of neurologic brain death
  
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  • American vs. Canadian
    
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    • American requires death of all areas of the brain
      
    • Canadian is a clinical one of either whole brain or brainstem death
      
    • Timing of exam for brain death
      
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      • Australian and New Zealand: > 4 hours
        
      • American Academy of Neurology: unclear
        
      • Canadian: 24 hours post resuscitation
        
      • Who can perform the assessment
        
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        • Technically all physicians who are licensed can perform
          
        • Some hospitals or states differ in policy, however, and may require a neurologist or ICU specialist
          
        • Clinical evaluation
          
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          • Established cause of irreversible coma
            
          • Deep unresponsive coma
            
          • Absent brainstem reflexes
            
          • Absent respiratory efforts
            
          • Absent confounding factors
            
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            • Examples of confounders: hypotensive shock, hypothermia, peripheral nerve or neuromuscular blockade, locked in syndrome, drug effect, metabolic disorders, reversible conditions or conditions that affect the ability to confirm irreversibility
              
            
            
            
          
          
          
        
        
        
      
      
      
    
    
    
  
  
  
• Of note: a comparison of various neurology and neurosurgery centers showed large variations regarding guidelines across centers, as well as compared to established criteria set forth by the American Academy of Neurology (AAN)
  
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  • Need further standardization to avoid prematurely diagnosing brain death
    
  • Ancillary tests
    
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    • Examples: EEG, brain perfusion studies, transcranial Doppler ultrasound, angiography
      
    • Even EEG’s which are required by most standards to be included in brain death evaluations have been shown to be affected by drug overdose and produce false positives
      
    • More research is needed to clarify the specificity and sensitivity of these in drug overdoses
      
    
    
    
  
  
  

 

Pharmacogenetics

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• A 55 year old woman is found unresponsive after ingesting 99 tablets of 25mg amitriptyline and 46 tablets of 1mg alprazolam
  
• The patient continues in a deep comatose states for 6 days with no improvement, and steady elevated TCA levels
  
• Genotyping is sent for CYP2D6, an enzyme involved in the metabolism of TCAs
  
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  • The patient is found to be homozygous for a polymorphism associated with absent activity
    
  • Conclusion: unclear how long to wait before pronouncing brain death as many factors such as pharmacogenetics can alter normal metabolism
    
  
  
  

 

Summary

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• Drug overdose can mimic brain death
  
• Be especially cautious in overdose involving the scary B’s: baclofen, barbiturate, benzodiazepine
  
• The 3-5 half life rule for drug clearance cannot be applied in the cases of overdose
  
  • 
    
  • Half lives are measured at therapeutic levels
    
  • Multiple other factors can alter metabolism in overdoses, such as pharmacogenetics, and cross reactivity with other ingestants
    
  • Consult a toxicologist if there is any question regarding possible overdose in the diagnosis of brain death
    
  
  
  

 NOTE: On the podcast, Leon mistakenly identifies Joe Rotella as @toxtalk. Joe is actually @toxrocks — @toxtalk is the feed from the UMass Division of Toxicology. Both are excellent and well worth following.

Quizzler from episode 3 Kaboom!

Q:  The Guinness World record recently named this pepper the hottest pepper in the world. What is its name and who makes it?

A: Smokin’ Ed’s ‘Carolina Reaper’ by the Puckerbutt Pepper Company rating an average of 1,569,300 Scoville Heat Units

Congratulations Thomas Gilmore!

Current Quizzler

Posted at the end of the podcast

Submit responses and any feedback to toxtrivia@gmail.com

The first correct response wins a $10 amazon gift card and a Poison Review t-shirt (bonus prize!)

Bibliography

 

Neavyn, M.J. (2014). Suicide and the surrogate. Journal of Medical Toxicology. 10(1), 3-6.

O’Brien, J., & Mulder, J.T. (2013). St. Joe’s “dead” patient awoke as docs prepared to remove organs. Syracuse.com News.

Scripko, P.D. & Greer, D.M. (2011). An update on brain death criteria: a simple algorithm with complex questions.

The Neurologist, 17(5), 237-239.

Shappell CN, Frank JI, Husari K, Sanchez M, Goldenberg F, Ardelt A. (2013) Practice variability in brain death determination: a call to action. Neurology. 81(23):2009-14.

Smith, J.C. & Curry, S.C. (2011). Prolonged toxicity after amitriptyline overdose in a patient deficient in CYP2D6 activity. Journal of Medical Toxicology, 7(3), 220-223.

Sullivan, R., Hodgman, M., Kao, L., & Tormoehlen, L.M. (2012). Baclofen overdose mimicking brain death. Clinical Toxicology, 50(2), 141-144.

Teitelbaum, J. & Shemie, S. (2011). Neurologic determination of brain death. Neurologic Clinics, 29(4), 787-799.