ESETT Trial

Status epilepticus poses a significant challenge to intensive care physicians. There is lots of uncertainty about the treatment options and correct dosing. In this podcast, we discuss the landmark ESETT trial published in NEJM which explores this dilemma but rather helping us to solve the problem, this trial asks more questions.

Status epilepticus and refractory status epilepticus represent some of the most complex conditions encountered in the neurological intensive care unit. Challenges in management are common as treatment options become limited and prolonged hospital courses are accompanied by complications and worsening patient outcomes. Antiepileptic drug treatments have become increasingly complex. Rational polytherapy should consider the pharmacodynamics and kinetics of medications.   In the United States, SE represents 0.07% of hospital admissions but accounts for a larger proportion of hospital costs, including $4 billion in direct inpatient costs annually with a mean length of stay of 14 days. In those who fail to respond to conventional treatments, costs increase exponentially in proportion to treatment intensity. RSE provides diagnostic, management, and ethical challenges as treatment options become limited. The definition of status epilepticus as a prolonged seizure or a series of seizures with an incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizure is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace.

The uses of benzodiazepines as the initial treatment for status epilepticus; however, seizures do not respond to benzodiazepines in up to a third of patients. The treatment for this type of benzodiazepine- refractory status epilepticus has not been well studied. Of the three medications most commonly used to treat benzodiazepine refractory status epilepticus — levetiracetam, fosphenytoin, and valproate — only fosphenytoin is labelled by the Food and Drug Administration (FDA) for this indication in adults, and none has been approved for children. Early termination of convulsive status epilepticus decreases the risk of cardiac and respiratory complications and is associated with a reduced risk of admission to an intensive care unit (ICU) and decreased mortality among children.8 Convulsive and nonconvulsive status epilepticus are also associated with neuroimaging evidence of brain injury. Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety.

What’s Known – 

Previous, mostly observational studies that used varying definitions of cessation of status epilepticus. Adult patients with benzodiazepine-refractory status epilepticus who were not randomly assigned to a drug treatment, the percentage of patients in whom seizures were stopped was 51.7% with levetiracetam, and the percentages with valproate

and phenytoin (74.6% and 59.6%, A meta-analysis of 22 studies showed higher effectiveness with levetiracetam (68.5%) and valproate (75.7%) than was seen in our trial but similar effectiveness with phenytoin (50.2%).

The Established Status Epilepticus Treatment Trial (ESETT) was conducted by the Neurological Emergencies Treatment Trials (NETT) Network and the Pediatric Emergency Care Applied Research Network (PECARN). The trial was developed through a program funded by the National Institutes of Health and the FDA.

Design

Multicentric, randomized, blinded trial that compared the effectiveness of levetiracetam, fosphenytoin, and valproate for the treatment of patients who presented with status epilepticus to the emergency department. Conducted across 57 emergency departments in the US. 

Population

Inclusion criteria: 

Patients older than 2 years treated with a standard dose benzodiazepines (midazolam 10 mg, diazepam 10 mg, or lorazepam 4 mg corresponding dose based on body weight in children) for generalized convulsive seizures lasting more than 5 minutes; continued to have convulsions in the emergency department even after 5 minutes of the last dose of benzodiazepine (5 minutes was allowed as the time to onset of action of the benzodiazepine)

Included patients who were taking long-term anticonvulsants for seizure control. 

Not included:  

Persistence of seizures even after 30 minutes of benzodiazepines. 

Seizures due to major trauma, hypoglycemia, hyperglycemia, cardiac arrest, or post-anoxia

If anticonvulsants other than benzodiazepines were used 

Patients who were intubated

Patients with known allergy or contraindications to the trial drugs

After 300 patients were assigned to a treatment group, response-adaptive randomization was initiated. (Response-adaptive randomization is an adaptive trial design in which the randomization ratio of patients assigned to the experimental treatment arm versus the control treatment arm changes from 1:1:1 over time to randomly assigning a higher proportion of patients to the arm that is doing better. A higher proportion of patients are likely to be randomized to the most effective treatment arm following interim analysis while generally using fewer total patients and offers higher power than an analogous trial with fixed randomization). Interim analyses planned after the enrollment of 400, 500, 600, and 700 patients, at which times the trial could be stopped early for success or futility.

Bayesian analysis to assess the predictive probability of each treatment.  If the predictive probability was greater than 0.975 (corresponds to a p value of less than 0.05), then the trial would be stopped for success; if less than 0.05, it would be stopped for futility.

Primary analysis based on intention to treat 

Also on per protocol basis. 

Interventions

Levetiracetam: 60 mg/kg, maximum dose: 4.5 g

Fosphenytoin: 20 mg PE/kg, maximum dose: 1500 mg PE

Valproate: 40 mg/kg, maximum dose: 3 g

Rescue therapy was administered for persistent or recurrent seizures after 20 minutes from the commencement of the infusion.

Enrollment was discontinued after 384 patients at the recommendation of the data and safety monitoring board after the trial met the predefined futility criteria in a planned interim analysis. There was a 1% chance of showing the most effective or least effective treatment if the trial were to continue to the maximum sample size.

Outcomes

Primary outcome

Absence of clinically apparent seizures (visible generalized tonic–clonic movements, nystagmoid or rhythmic eye movements, generalized or focal myoclonus) and improving responsiveness (purposeful response to noxious stimuli, follows commands, able to verbalize) at 60 minutes after the commencement of the infusion. There should be no requirement for additional anticonvulsant drugs, including drugs to facilitate endotracheal intubation (the need for intubation indicated failure of treatment).

Outcome adjudication by four neurologists

Secondary outcomes 

Time to cessation of seizures: defined as the interval from the commencement of infusion to the cessation of clinically apparent seizures.

ICU admission

ICU and hospital LOS.

Multivariate analysis 

Covariates including age group (<18 years or ≥18 years), weight group (<75 kg or ≥75 kg), final diagnosis, time from seizure onset to enrollment, sex, race (black, white, or other), and ethnic group (Hispanic or non-Hispanic) were evaluated by logistic-regression models; no impact of these variables on the primary outcome

Primary safety outcome

 Composite of life-threatening hypotension (systolic blood pressure remaining below the age-specific thresholds for two consecutive readings at least 10 minutes apart; remaining below the age-specific thresholds for more than 10 minutes after reduction the rate or cessation of the infusion and an intravenous fluid challenge or cardiac arrhythmia (persistent arrhythmia after reducing the rate of infusion of the trial drug and that required chest compressions, pacing, defibrillation, or the use of an antiarrhythmic drug or procedure within 60 minutes of commencement of the infusion). 

Additional safety outcomes

Death before the end of participation in the trial, endotracheal intubation after 60 minutes of commencement of infusion, acute anaphylaxis, acute seizure recurrence (convulsive or electroencephalographic seizure activity requiring further anti- convulsant therapy occurring between 60 minutes and 12 hours after the commencement of infusion). 

Strengths- 

• RCT 
• Relatively large sample of 400 enrollments
• the use of weight-based dosing. 
• used an adaptive statistical design to increase the chance of finding a difference if a true difference existed.

Limitations of this trial included – 

• the unblinding in some instances in order to choose a second anticonvulsant to treat ongoing seizures (occurring after the determination of the primary outcome in most patients)  
• the fact that 10% of the patients enrolled had psychogenic nonepileptic seizures.
• Clinical rather than electroencephalographic criteria were used to determine the primary outcome of seizure cessation.
• It is not possible to distinguish postictal or benzodiazepine- related sedation from continued nonconvulsive status epilepticus
• Fosphenytoin has more restrictions on the maximal rate of infusion than the other agents; the constraint of a 10-minute infusion limited the maximal dose to 1500 mg which may be a submaximal dose in patients with a bodyweight greater than 75 kg.

Summary –

This trial has raised more questions on our current approach and forced us to review our current practices of treating patients with status epilepticus.