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I have completed bits of my EM training from India. Currently I am boarded with credentials from Christian Medical College, Vellore and also from the prestigious Royal College of Emergency Medicine, UK.  I am currently working in London as an A&E doctor, trying to appreciate the differences in the practise and culture of Emergency Medicine across different healthcare systems. I have always been an avid FOAMed supporter because FOAMed played an indispensable role during the days of my initial training. Through this blog, I aspire to disseminate knowledge and stay up to date with the EM literature. 

Monday, March 7, 2016

Status Epilepticus - Rapid Review


Background
Status Epilepticus (SE) is the second-most frequent life-threatening neurological emergency after stroke that bears considerable risks of morbidity and mortality. SE requires emergent, targeted treatment to reduce patient morbidity and mortality but the treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. Rapid control of seizures is fundamental to the emergency treatment of SE. Adverse effects may include systemic problems arising from seizures (e.g., impaired ventilation, pulmonary aspiration, and metabolic aberrations) or due to direct neuronal cellular injury from excitotoxicity. 



Definition and Classification
  • SE is defined as 5 min or more of continuous clinical and/or electrographic seizure activity or recurrent seizure activity without recovery between seizures
  • SE is further classified as either convulsive SE (convulsions that are associated with rhythmic jerking of the extremities) or non-convulsive SE (seizure activity seen on EEG without the clinical findings associated with convulsive SE)
  • Refractory SE (RSE) should be defined as SE that does not respond to the standard treatment regimens, such as an initial benzodiazepine followed by another AED. Although some experts consider failure of the first drug i.e. BZD to terminate seizure as RSE.

Rationale for changing the traditional 30 minutes definition to 5 minutes 
Animal data suggests that permanent neuronal injury may occur before the traditional definition of 30 min of continuous seizure activity have passed. Evidence also demonstrates that seizures that do not cease in 5-10 minutes are less likely to terminate without intervention (Pharmacoresistance).
  


Pathophysiology

In short - excess excitation and reduced inhibition. However, the failure of inhibitory processes is increasingly thought to be the major mechanism leading to SE.

Excitatory neurotransmitters: Glutamate, NMDA
Inhibitory neurotransmitters: GABA


Most seizures terminate spontaneously within several minutes but with continuing seizures, inhibitory GABA receptors are internalized in clathrin coated vesicles and at the same time, excitatory N-methyl-d-aspartate (NMDA) receptors may be mobilized to the membrane. This receptor trafficking results in a decreased inhibitory control and increased excitation that may lead to continuing status epileptics. The internalization of GABA receptors may explain the clinical finding that benzodiazepines are less effective as seizure durations increase.

Possible Etilogy
  • AED Non-Compliance
  • Stroke 
  • Hypoxic injury, Traumatic Brain Injury
  • Drugs and Toxins (eg, cocaine, theophylline, INH)
  • Withdrawal (Opioid, BZD, Barbiturates, Alcohol)
  • Electrolyte abnormalities 
  • Renal Failure, Liver Failure
  • Neoplasms
  • CNS infections (eg, meningitis, brain abscess, encephalitis)
  • Autoimmune Encephalitis


Management 

All patients need a 
  • Fingerstick glucose
  • Vital signs monitoring
  • Head computed tomography (CT) scan is required for most
  • Order laboratory test: blood glucose, complete blood count, basic metabolic panel, calcium (total and ionized), magnesium, AED levels. 
  • Continuous electroencephalograph (EEG) monitoring

Consider these based on clinical presentation
  • Brain magnetic resonance imaging (MRI)
  • Lumbar puncture (LP)
  • Comprehensive toxicology panel including toxins that frequently cause seizures (i.e. isoniazid, tricyclic antidepressants, theophylline, cocaine, sympathomimetics, alcohol, organophosphates, and cyclosporine)
  • Other laboratory tests: liver function tests, arterial blood gas, AED levels, toxicology screen (urine and blood), and inborn errors of metabolism.

The treatment of convulsive SE should occur rapidly and continue sequentially until clinical seizures are halted. The goal of treatment is to stop the seizures (both clinical and electrographic) as soon as possible. The initial treatment strategy includes simultaneous assessment and management of airway, breathing, and circulation (obtain IV access, administer O2, and securing the airway as needed), seizure abortive drug treatment, screening for the underlying cause of SE, and immediate treatment of life-threatening causes of SE (e.g., meningitis).


Benzodiazepines are the drugs of choiceLorazepam is the drug of choice for IV administration and Midazolam is the drug of choice for IM administration. Early intubation is advisable if continuous intravenous AEDs are necessary. 

Options for RSI meds include Propofol and Ketamine and this is a scenario where you might consider skipping the paralytics. If you are using them, beware of succinyl choline induced hyperkalemia in prolonged seizures or a chronic neurological illness. If you are using Rocuronium, get the continuous EEG to pick convulsions in a paralysed patient. 
The diagnostic labs are selected depending on the patient’s history and physical examination. Not every diagnostic study is required in every patient. For instance, a lumbar puncture is needed if there is any suspicion of a central nervous system (CNS) infection, but may not be required if patients gives a history of AED non-compliance.






Dosing and Considerations when using second and third line agents 



Dosing of continuous infusion AEDs for RSE should be titrated to cessation of electrographic seizures or burst suppression.
                                                                                                                                                   
                     

Propofol comes with issues like severe hypotension and propofol related infusion syndrome. Midazolam appears to be safer and less hypotensive. Be prepared to start a vasopressor drip to maintain blood pressure or switch to ketamine.

Alternative therapies: Reserve these therapies for patients in RSE
  • Ketamine (3 mg/kg IV followed by an infusion of at least 1 mg/kg/hr up to 10 mg/kg/hr.)
  • Hypothermia
  • Inhales Anesthetics (Isoflurane)
  • Ketogenic Diet
  • Steroids, ACTH
  • Immunomodulation (IVIG or Plasma Exchange)
  • Electroconvulsive therapy
  • Vagus Nerve Stimulation
  • Repetitive Transcranial Magnetic Stimulation
  • Surgical Management

     Medications are more likely to terminate seizures when given closer to the seizure onset and they decrease in effectiveness as seizure duration increases, most likely related to changes in the neuronal gamma aminobutyric acid (GABA) receptor subunit composition as a function of time. 

Rationale for using Ketamine 
There is growing evidence that increasing refractoriness to treatment is partly the result of progressive impairment of GABA mediated inhibition as a result of internalization of GABA receptors under conditions of sustained excitability. Due to this internalisation  , GABAergic drugs dare less likely to work for sustained SE. There is also evidence for increased numbers of N-methyl-D-aspartic acid (NMDA) receptors at the synaptic membrane that results in increased sensitivity to excitatory neurotransmitters. The rationale behind using Ketamine is an attempt to antagonise the excitatory NMDA system as GABAergic system is impaired. 


Take Home

  • Seizure onset to drug delivery time is more important then debating which BZD works better. Be aggressive while treating SE because pharmacoresistance develops over minutes.
  • Never forget that NCSE can present as coma and maintain a low threshold for obtaining a bedside EEG. 
  • Ketamine is definitely an option for refractory status epilepticus. 

Further Reading:

  1. Shinnar S, Berg AT, Moshe SL, Shinnar R. How long do new-onset seizures in children last? Ann Neurol 2001;49:659-64. 
  2. Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multi-center study. Epilepsia. 2013;54(8):1498-1503. doi:10.1111/epi.12247.
  3. Treatment of Refractory Status Epilepticus: Literature Review and a Proposed Protocol Nicholas S. Abend, MD and Dennis J. Dlugos
  4. Glauser, Tracy, et al. "Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society." Epilepsy Currents 16.1 (2016): 48-61.
  5. Rossetti, Andrea O., and Thomas P. Bleck. "What's new in status epilepticus?." Intensive care medicine 40.9 (2014): 1359.
  6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731413/pdf/nihms481665.pdf
  7. Emergency Medicine Practice - Evidence Based Medicine - Clinical Decision Making In Seizures And Status Epilepticus 
  8. Lowenstein, Daniel H., and Brian K. Alldredge. "Status epilepticus." New England Journal of Medicine 338.14 (1998): 970-976.
  9. www.neurocriticalcare.org
  10. Brophy, Gretchen M., et al. "Guidelines for the evaluation and management of status epilepticus." Neurocritical care 17.1 (2012): 3-23.
Other FOAMed thoughts on Status Epilepticus: 
http://first10em.com/2015/11/16/status-epilepticus/
http://emlyceum.com/2014/12/09/seizure-answers/

16 comments:

  1. Thank you, Sir. Very Nice Compiled info.

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  2. Very nice article dr lakhshay..keep.up.the good work.. Njoyed reading about SE

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  3. Very helpful, thankx lakahay.

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  4. Lakahay. You are pushing FOAMed into the subcontinent. Congrats on your innovative work and textbook approach to the blog post

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    Replies
    1. Thank you so much Andrew. Appreciate you reading.

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  5. CARL EM Resident ChicagoMarch 7, 2016 at 12:04 PM

    excellent post

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  6. Nice treatment flow chart sir.thanx for it

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    Replies
    1. Thanks Shiva. Hope you are doing well.

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