Q: Which patients should be included on the mandatory ESETT screening logs?  Are there specific required criteria?  Does the log have to contain all children with status epilepticus?  (NEW 7/18/18)

A: To accommodate existing practices at the sites that are already doing this, we allow sites to set their own criteria for entry on a screening log.   For example, here at UM, we include anyone placed in a resuscitation bay with the chief complaint of seizure.  Other sites include any patient treated with levetiracetam, fosphenytoin, or valproate in the ED.  All children with a diagnosis of status could also work.  We are flexible.  It should be something that helps sites investigate and identify possible misses, or helps them confirm that there have not been misses.  Similarly, you can determine the level of PHI needed to be useful.

Q: Does trans-mucosal midazolam count toward the adequate dosing for eligibility?

A: For purposes of the trial eligibility, trans-mucosal midazolam (intranasal or buccal) can be considered as equivalent to intramuscular midazolam toward a cumulative adequate benzodiazepine dose.

Q. Is a patient who is hypotensive prior to enrollment eligible for enrollment?  Should they be enrolled with a slower rate of infusion?

A. Hypotension is not a specific exclusion criterion.  However, if one of the study drugs is deemed contraindicated for a particular patient by clinical team then that patient is not eligible and should not be enrolled, based upon the exclusion criterion “Known allergy or other known contraindication to FOS, PHT, LEV, or VPA”. So, if the clinical team feels, for example, that FOS would be specifically contraindicated because of pre-existing hypotension, then the patient should not be enrolled. Reduction in the rate of infusion is indicated for medication-induced hypotension, not hypotension in general. Do not initiate treatment at a reduced rate of infusion.

Q. Is a patient who gets some form of advanced airway, but is not endotracheally intubated, excluded from enrollment in ESETT?

A. Patients that are endotracheally intubated are not enrolled in ESETT because intubation and mechanical ventilation typically require the use of induction and sedation agents with confounding anticonvulsant properties, and because there is no benefit to 2nd line anticonvulsants over 3rd line anticonvulsants in those already intubated.  Patients treated transiently only with a supraglottic airway may still be eligible.  Those treated with supraglottic devices such as an oropharyngeal airway, nasopharyngeal airway, laryngeal mask airway (LMA), SALT, i-gel, King, Combitube, or similar, but who have these devices removed without subsequent transition to an endotracheal tube, and who are not treated with excluded induction agents, are still eligible for the study.  Obviously those requiring surgical airways are endotracheally intubated and are not eligible. 

Q.  Does having a chronic tracheostomy exclude an otherwise eligible patient from enrollment in ESETT? 

A.  Usually not, but sometimes yes.  The relevant exclusion criteria is related to endotracheal intubation.  The question is whether a chronic trach is like an endotracheal tube for purposes of eligibility.  In the protocol, Section 4.2 Table 2, provides the rationale for excluding intubation, which is “Prevents evaluation of patient for responsiveness.”  We interpret the chronic trach as an exclusion, akin to endotracheal intubation, when the same rationale applies.  A trach is an exclusion when it indicates the same kind of unresponsiveness that is usually indicated by endotracheal intubation.  That is, a patient who has a trach because they are chronically comatose or persistently vegetative are those that will not wake up even when they return to baseline after a seizure.  In such patients the trach indicates inability to evaluate responsiveness just like an ET tube and they are excluded by the ET tube criterion.  Most often, however, patients with chronic trach’s are not persistently unresponsive at baseline.  A patient with a chronic trach who is normally awake at baseline would not be an excluded by this criterion. 

Q. Please provide rationale for not specifically excluding patient’s with Dravet syndrome and other disorders that preclude them from receiving certain antiepileptics.

A. Valproate and leviteracetam are often used in children with Dravet, even chronically.  While sodium channel blockers such as phenytoin are not used in Dravet cases for chronic therapy, phenytoin or fosphenytoin continue to be the first line therapy for convulsive status for children with Dravet.   The same is true of other disorders such as Lennox-Gastaut syndrome, where we avoid phenytoin as chronic therapy but use it as first line for convulsive SE.   The treatment of convulsive SE in these syndromes is identical to treatment of SE for other children . A benzo followed by one of the ESETT agents.

In general, the evidence about not using certain drugs for some syndromes, which is largely anecdotal, pertains to chronic usage and does not apply to single doses in context of abortive therapy.   While we do not use phenytoin or carbamazepine in children with Dravet for chronic dosing, there is no evidence that treatment of convulsive SE should be different.    Please note that while Dravet children frequently have status, they represent a tiny fraction of children over age 2 who present with SE.

The protocol for convulsive SE is the same for these syndromes as for other children with SE.  In addition, there is no data to suggest that treatment of convulsive SE, unlike chronic therapy, is syndrome specific.

Q.  Can you confirm that pediatric patients do not have to be admitted?  A lot of our status patients are transferred out after stabilized, but never within first hour.

A.  Patients on ESETT do not have to be admitted.  Sites may follow standard process after stabilization, including transfer.  NOTE: Patients could be followed if transferred to a ESETT participating hospital.

Q. When referring to “generalized convulsive seizure” as a requirement for enrollment, is this inclusive of seizures other than GTC seizures?

A.  The inclusion criteria are intended to include those whose clinical syndrome is Generalized Convulsive Status Epilepticus (GCSE).  It is not intended to define a narrow or specific semiology.  So, for example, there is no reason to exclude a patient with GCSE whose presentation evolves to hemiclonic convulsion, but we would not include a conscious and alert patient with isolated focal seizures.

Q.  Consider a patient who gets a dose of benzodiazepines and stops convulsing, then 35 minutes later convulses again and is given an additional dose of benzodiazepines. The cumulative benzodiazepine dose is adequate, but the patient is still convulsing 5 minutes after the second dose. Is this patient eligible?

A.  Yes.

Q.  Are patients on daily levetiracetam, phenytoin, or valproic acid excluded if they took their med that day?

A.  No.  Patients are excluded if they were given levetiracetam, phenytoin, or valproic acid as emergency treatment for the current episode of SE.  Patients are not excluded because they take one of these medications orally as daily anticonvulsive therapy.   

Q.  Does the exclusion criterion ‘metabolic disease’ refer to patients with diabetes?

A.  No.  “Metabolic disease” does not refer to either diabetes nor to the so-called pre-diabetic “metabolic syndrome”.  Rather, the term “metabolic disease” is an exclusion based upon a warning on the FDA label for VPA referring to certain rare inborn errors of metabolism in children less than 2 years old.  

Q.  Whom are the patients that are intended to be excluded by the ‘metabolic disease’ criteria?

A.  Investigators may use their clinical judgment in interpreting this exclusion based upon the FDA warning on the label for VPA referring to congenital but unspecified conditions occurring mostly in children less than two.  All children under age 2 are already excluded from ESETT.  It is thought that the warning refers only to the inborn errors related to the six urea cycle disorders (deficiencies of NAGS, N-acetylglutamate synthase deficiency, ASL, arginosuccinate lyase, CPS1, carbamyl phosphate synthetase, AS, argininosuccinic acid, OTC, ornithine carbamoyltransferase, and citrullinemia).  It may also be appropriate to exclude those with known mitochondrial DNA polymerase-gamma (POLG) gene mutations (e.g., Alpers Huttenlocher Syndrome), tyrosinemia, porphyria, MELAS and Gaucher disease.  This exclusion only applies to those with known and already established diagnoses.  It is neither necessary nor feasible to test for these conditions prior to treatment in patients presenting with convulsive status epilepticus.  These suggestions supersede a misleading list of examples of congenital conditions mentioned in a previous version of an FAQ.  

Q. An IRB requested that “known or suspected overdose/poisoning be included as an exclusion criteria since all three of the study drugs would be contraindicated in that scenario.”  The site study team opined that the exclusion for “other known contraindication to FOS, PHT, LEV or VPA” covers this situation.  The IRB responded that this should be added as a local exclusion, especially for our adult population, as this is often a factor in adult seizure patients.  They thought it should be more directly addressed for each screening/enrollment rather than “other known contraindication”.

A. The ESETT study team does not object to the site adding this as a local exclusion.  We agree with the site study team that this exclusion is adequately covered by the “other known contraindications” exclusion criterion.  We agree with the IRB that in many cases seizures known to be caused by identified drug overdoses require specific antidotes in preference to second line anticonvulsants and should not be enrolled, however, such cases are rare.  In the prior NETT and PECARN status epilepticus emergency treatment trials, known drug overdoses other than alcohol were identified in less ½ of one percent of enrollments.  Most of these responded to benzodiazepines and do not reflect subjects that would be eligible for ESETT anyway.     

Q.  How is the word “known” to be interpreted in the ESETT eligibility criteria?

A.  Five of the ESETT exclusion criteria include “known” as a qualifier on the item described.  We recognize that this term is ambiguous and therefore offer the following clarification.  The term “known” is ambiguous in this context because it is does not indicate to whom the information is known, or when it was known.  In these eligibility criteria “known” is intended to indicate information already possessed by the clinical team or the study team at the time of enrollment.  Criteria qualified with “known” are not violated by a subsequent discovery, after enrollment, of a new or existing diagnosis or condition of which the clinical or study team was not aware at enrollment. 

For example, a patient in SE should not be enrolled if she is obviously gravid on exam or if someone accompanying the patient at presentation provides a history that the patient is pregnant, because known pregnancy is an exclusion criterion.  If a patient in SE is enrolled, however, and during the subsequent portion of the ED visit or hospitalization is found by history or laboratory evaluation to be pregnant, this would not be considered an eligibility violation.  It does not matter whether or not the pregnancy was known to the patient or others; it is not a violation if it was not information readily available to the treating team at enrollment. 

Contrast the use of “known” as it relates to pregnancy in the prior example with another exclusion that is not qualified by the word “known”.  Consider a subject enrolled after being transferred for SE from another institution.  The patient was enrolled because the treatment team was told that the patient had only received benzodiazepines at the referring ED.  Review of medical records faxed over from the referring ED after the enrollment indicate that the patient had also already been treated with LEV prior to transfer.  Although understandable and potentially unavoidable, this is an eligibility violation even though it was unknown at the time of enrollment.  This is because the exclusion is “treatment with a second line anticonvulsant for this episode of SE” rather than “known treatment with….” 

We acknowledge the potential subtlety of this distinction, and are happy to work through specific situations with sites as they arise.  Note that the goal of this distinction is derived from the rational for the exclusion criteria in Table 2 of the study protocol (section 4.2), and how the collection of eligibility data is intended to be used.  Interpretation does not consider real or perceived leniency or fairness related to the enrolling teams.