Understanding ACEP’s Clinical Policy on Seizures

In January, 2014, the American College of Emergency Physicians revised its policy on ‘ED Evaluation and Management of Seizures in Adults’. Dr. Rhonda Cadena, a neurointensivist and emergency physician educator at UNC, breaks down the critical updates.

In January, 2014, the American College of Emergency Physicians revised its policy on ‘ED Evaluation and Management of Seizures in Adults’. Dr. Rhonda Cadena, a neurointensivist and emergency physician educator at UNC, breaks down the critical updates.

ACEP CLINICAL POLICY REVIEW: A NEW FEATURE IN EPM

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ACEP clinical policies are important for our practice. We have great respect for our colleagues who have carefully and stringently reviewed the available literature using the methods of evidence-based medicine when developing clinical policies. Although EBM is an important tool, its methods have important drawbacks that affect clinical practice recommendations, especially for complex conditions. There are sometimes insufficient robust clinical investigations from which to draw conclusions, and guidelines that are typically developed using carefully selected clinical protocols may be difficult to extrapolate to individual patients or to the variety of ED settings in which we practice. Practical experience and clinical judgment are part of our clinical decision-making (1) but are unrecognized by EBM methodology, and EBM is not able to address the clinical uncertainty inherent in many ED evaluations. So, with this new feature, we are going to give our best shot to put new ACEP policies into a practical clinical context.

-Judith Tintinalli, MD

Editor-in-Chief of Emergency Physicians Monthly

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In January, 2014, ACEP revised its 2004 seizure policy. One element not addressed in the 2014 revision but discussed in the 2004 ACEP guidelines warrants reviewing: Which new-onset seizure patients who have returned to a normal baseline require a head computed tomography (CT) scan in the emergency department? The 2004 ACEP seizure clinical policy stated that a CT head should be performed on patients with a first time seizure in the ED when feasible, allowing for deferred outpatient neuroimaging when reliable follow-up is available. While the 2004 policy might have been directed by concerns about ED resource utilization, the realities of ED practice (including easy access to CT in the ED, uncertainty about patient follow-up, cost to the patient at follow-up, and diagnostic uncertainty when evaluating a first-time seizure in the ED) would support CT scan in the ED rather than deferral to follow-up. Recently, the American Academy of Neurology (AAN) released a revision to their 1996 guidelines on neuroimaging (Kromholz, Harden) and stated that a CT head in the emergency department is probably useful (class III) due to the findings that imaging changed management in a significant percentage of patients presenting with the first seizure.

For these reasons, it has become common practice to perform a non-contrast head CT on first-time seizure patients in the ED, and the guidelines should affirm this practice, since imaging results may affect patient management.

Below is a point-by-point commentary on the critical questions addressed by the 2014 seizure policy.

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“In patients with a first generalized convulsive seizure who have returned to baseline clinical status, should an antiepileptic drug be initiated in the ED to prevent additional seizures? There is insufficient evidence to tell us what is best (level C).”

Data on short-term seizure recurrence for unprovoked seizures is scant but does not appear to be beneficial in low risk patients (FSTG, Marson) Therefore, EPs do not need to not start antiepileptic drugs on patients with a first unprovoked seizure who return to baseline, but should obtain a careful history and exam to rule out high risk factors for recurrence such as previous structural brain injury, multiple seizures at presentation, underlying neurologic disorder or prior unprovoked seizures. For provoked seizures the definitive treatment involves treating the source, although short-term agents might be warranted for initial seizure control. Consult with a neurologist when thinking about starting medication, since there are many drug options and each drug has advantages and disadvantages (Schmidt 2014).

“In patients with a first unprovoked seizure who have returned to their baseline clinical status in the ed, should the patient be admitted to the hospital to prevent adverse events? There is insufficient evidence to tell us what is best (level C).”

If there are no high risk factors, there is no need to admit the healthy individual with the first unprovoked seizure and a normal non-contrast head CT scan who is now back to baseline.

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In patients with a known seizure disorder in which resuming antiepileptic medication in the ED is appropriate, does the route of administration impact recurrence of seizures? There is insufficient evidence-based literature to tell us what is best (level C).

For a patient taking an antiepileptic drug who experiences a breakthrough seizure due to non-compliance or low therapeutic drug levels, provide a loading dose to reach therapeutic levels before the patient leaves the ED. The data does not discuss replacement with the oral or parental routes, and leave the route up to clinical judgment. If the patient has returned to baseline and can safely tolerate PO meds without an aspiration risk, an oral load is appropriate. If the highest oral dose that can be administered at one time is not feasible in the ED, for example, the phenytoin max dose is 400mg PO, IV supplementation may be needed to provide a full loading dose. For some drugs in which drug levels are not available in the ED, such as levetiracetam and lacosamide, and history suggests noncompliance or a missed dose, give the home dose in the ED prior to discharge as long as the patient is at neurological baseline.

In ED patients with generalized convulsive status epilepticus who continue to have seizures despite receiving optimal dosing of a benzodiazepine, which agent or agents should be administered next to terminate seizures?

While the recommendations are clear on the need to administer additional drugs after benzodiazepines (level A), the traditional drugs phentoin, fosphenytoin and valproate are listed as level B, and the agent levetiracetam (along with propofol or barbiturates) are listed as level C, giving us insufficient clinical guidance.

Most seizures are self-limiting and last seconds, most are resolved by 3 minutes and, if proceed longer than 5 minutes with no signs of stopping, are considered status epilepticus. Benzodiazepines, which bind to the GABAA receptor, are the first line treatment for seizures. However, data suggests that there is uptake of the GABAA receptors as the seizure progresses (Chen 2006) making it more difficult to treat with standard first line agents as time progresses. For this reasons, it is important to quickly move to a second agent for seizure cessation. Administer another drug within 5-10 minutes if the patient continues to seize and give a 3rd agent if seizures last more than 20 minutes. If a 3rd agent is started, intubation and a continuous infusion is necessary. For second line agents, there are several options included in the 2014 ACEP policy, your choice depends on availability in your ED, ease of administration, comfort of the EP with dosing, side effect profile of the drug, and the time to administer the drug. Phenytoin is the most common second line agent and most EPs typically feel comfortable with the dosing and monitoring of side effects. Phenytoin is commonly under dosed; the usual dose for status epilepticus is 20mg/kg which is close to 1.5 gram for an average sized patient instead of the standard 1 gram that is commonly administered. The most significant adverse event involves hemodynamic instability during administration requiring a slower infusion; the maximum dosing rate is recommended at 50 mg/min but a slower rate of 25mg/min is required if the patient becomes hypotensive. Fosphenytoin is more commonly used for phenytoin loading due less hemodynamic adverse events and therefore, faster infusion. It is given as a dose of 20mg PE/kg and run at an infusion rate of 150mg/min and can be given over 10-15 minutes. Valproate is a recommended second line drug that is comparable to phenytoin. It does appear safe and does not cause hypotension but has been associated with adverse effects which include hepatic toxicity that has resulted in death, teratogenic effects, pancreatitis, and thrombocytopenia. There are multiple drug-drug interactions and should not be administered with phenytoin. Valproate can be given as a load of 20mg/kg with a maximum infusion rate of 20mg/min. Leviteracetam is a newer agent that is showing a lot of favor with epileptologists, neurointensivists, and emergency physicians. It is easy and quick to administer, has few drug-drug interactions, few side effects, and does not require monitoring of levels. In the literature, data is still limited but so far small studies have shown it to be effective as a first line for status epilepticus (Fattouch), equivalent to lorazepam for control of status epilepticus with decreased seizure recurrence (Misra), equivalent to valproate (Liu), and effective as a second line drug if given early (Aiguabella). For a patient in status epilepticus, a 15-20mg/kg load, approximately 1500mg IV infusion for an average size adult, can be administered over 15 minutes. You should be familiar with this drug, as you will likely be seeing more of it – it’s regrettable that 2014 guidelines can only give a Level C recommendation for its use. Lacosamide is another newer agent that is safe with few drug-drug interactions. It has only been approved since 2008 for the treatment of seizures but so far the limited data shows promise in the treatment of status epilepticus (Kellinghaus, Santamarina). At this time, cost and inexperience limits its use, but when available, a 200mg IV dose can be given over 15 minutes. You will likely see more of this drug used in the future as well.

For refractory status epilepticus, if bolus medications described above are not leading to cessation of seizures, continuous infusions are required. Current recommendatins include propofol, midazolam, and pentobarbital. While these drugs are necessary to treat patients in refractory status, they receive only a level C recommendation. All three agents can cause hypotension and require intubation, and may need vasopressors. The most commonly used agents in the ED are propofol and midazolam due to availability and familiarity of the drugs. Propofol can be started at a standard rate and increased to the goal of seizure cessation. Doses can reach 40-80mg/kg/hour which can put the patient at risk of hypotension and propofol infusion syndrome. A midazolam infusion could also be used and started at an initial infusion rate of 0.05-0.4 mg/kg/hour, which is about 4-30mg/hour in an average size adult. These continuous infusions started in the ED are usually continued after arrival to the ICU and therefore, as an intensivist, I prefer propofol due to the short half-life and ease of waking the patient up after the seizure has resolved. Midazolam can accumulate in peripheral tissues with continuous infusion, especially in patients with renal dysfunction, making the patient difficult to arouse and obscures the evaluation of neurological recovery. Although the guidelines suggest pentobarbital as choice, I would recommend against its use by an EP given its side effect profile and the need for EEG monitoring to guide dosing. Instead infuse propofol first, and midazolam as a second choice. At this time, continuous EEG monitoring is also warranted in order to guide dosing and assess for nonconvulsive status epilepticus.

Additional questions not addressed

Of course, there are issues that are not addressed in the ACEP policy but are important to emergency physicians. For example, what is the appropriate time of observation in the ED after a seizure? What if I have problems obtaining neurology follow up? What should I do with patients who are consistently noncompliant with their meds? What if they just can’t afford them? What are the rules for providing discharge instructions for patients about driving, swimming, or work? Am I liable if that patient has an accident? These are all important questions and are clinically significant to us and would benefit being addressed in the future. Rhonda Cadena, MD, is a neurointensivist and emergency physician. She is an assistant professor in the departments of emergency medicine, neurology and neurosurgery at the University of North Carolina

Defining Seizures A seizure can be difficult to confirm and is often based primarily on eyewitness accounts. An unprovoked seizure has no acute precipitating factor, or can result from a remote insult such as stroke, traumatic brain injury, or infection. Provoked seizures occur as a result of an acute precipitating event or within 7 days of the insult. Some common causes include electrolyte disturbances, hypoglycemia, CNS infections, sepsis, medications that alter the seizure threshold, alcohol abuse or withdrawal, toxins, brain lesions and traumatic brain injury, hypoxia, hypertensive encephalopathy, cerebral venous thrombosis, and eclampsia. A seizure mimic includes conditions such as psychogenic motor activity, migraines, drug intoxication, cardiac syncope or myoclonus. Status epilepticus is a seizure that lasts ≥5 minutes or ≥ two seizures without full recovery between the seizures.

Rhonda Cadena, MD, is a neurointensivist and emergency physician. She is an assistant professor in the departments of emergency medicine, neurology and neurosurgery at the University of North Carolina

REFERENCES

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American College of Emergency Physicians. Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Seizures. Annals of Emergency Medicine 2014, 63(4): pp 437-447.

American College of Emergency Physicians (ACEP) Clinical Policies Committee and the Clinical Policies Subcommittee on Seizures. Clinical Policy: Critical issues in the evaluation of adult patients presenting to an emergency department with seizures. Ann Emerg Med 2004;43:605–625.

Braithwaite, RS ‘EBM’s Six Dangerous Words’ JAMA Nov 27, 2013, 310:20, 2149-2150

Schmidt O, Schachter SC. The Epilepsy Research Group, Berlin, and Department of Neurology, BethIsrael Deaconess Hospital, Masachusetts General Hospital, and Harvard Medial School ‘Clinical Review. State of the Art. Status Epilepticus. BMJ 2014; 348; g254 Feb 28 doi: 10.1126/bmj.g254

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