Conflict of Interest Declaration
The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. No Task Force members were recused from the discussion due to declaration of a conflict of interest.
No Task Force members declared an intellectual conflict of interest.
CoSTR Citation
Scholefield B, Nicholson TC, Topjian A, Rech L, Bach A, Hahn C, Morrison LJ on behalf of the Pediatric Life Support Task Force.
Effect of Prophylactic Anti-Seizure Medication and Seizure Treatment for Children following Cardiac Arrest on Patient Outcomes: Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2024. Available from: http://ilcor.org
Methodological Preamble and Link to Published Systematic Review
The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of the effect of prophylactic anti-seizure medication and treatment of seizures on outcomes for adult and pediatric patients post cardiac arrest (Nicholson/Scholefield 2023, pg No – PROSPERO CRD42023460746 and CRD42023463581), by clinical content experts of the Adult and Pediatric Life Support Task Forces of ILCOR, with assistance from Jessie Cunningham, Information Specialist at The Hospital for Sick Children, Toronto, Canada. Evidence for adult and pediatric literature was sought and considered by members of the Advanced Life Support Task Force and the Pediatric Life Support Task Force groups respectively.
Systematic Review
Nicholson et al, Effect of Seizure Treatment for Adults and Children following Cardiac Arrest on Patient Outcomes: A Systematic Review (in preparation)
Rech/Bach... Nicholson/Scholefield et al, Effect of Prophylactic Anti-Seizure Medication for Adults and Children following Cardiac Arrest on Patient Outcomes: A Systematic Review (in preparation)
PICOST
The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)
Population: Adults or pediatric patients in any setting (in-hospital or out-of-hospital) with (cardiac arrest) and return of spontaneous circulation (ROSC).
Intervention: One strategy for prophylactic anti-seizure medication OR seizure treatment
Comparators: Another strategy or no prophylactic anti-seizure medication OR seizure treatment
Outcomes: Survival with favourable neurological outcome as per Pediatric Core Outcome Set for Cardiac Arrest (1)
Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols) are excluded. All relevant publications in any language are included if there is an English abstract.
In case of there being insufficient studies from which to draw a conclusion, case series may be included in the initial search if they include a comparator group.
Timeframe: Literature search include all years up to Sept 11th 2023.
PROSPERO Registrations CRD42023460746 and CRD42023463581.
Consensus on Science
Prophylactic Anti-Seizure Medication
For the critical outcome of survival with favourable neurological outcome at discharge/30 days or longer, no pediatric RCTs nor non-randomized comparative studies were identified.
Indirect evidence from adult patients was identified.
For the critical outcome of survival with favourable neurological outcome at discharge; Two prospective RCTs (BRCT Study Group 1986, 397; Longstreth 2002 506) involving a total of 562 comatose adults post-arrest provided very low-certainty evidence (downgraded for risk of bias, indirectness and imprecision) of no benefit from prophylactic anti-seizure medication administration. For the BRCT study, good neurological outcome for treatment with thiopentone vs standard care (no prophylactic anti-seizure medication) had a RR of 1.3 [95% CI 0.76 to 2.21; 46 more survivors per 1,000 patients [95% CI from 37 fewer to 185 more). For the Longstreth study: for treatment with intravenous magnesium versus placebo, RR for improved outcome was 1.37 [95% CI 0.83 to 2.25]; 94 more survivors per 1,000 patients [95% CI from 43 fewer to 317 more]; for treatment with intravenous diazepam versus placebo, RR for improved outcome was 0.68 [95% CI 0.36 to 1.28]; 81 fewer survivors per 1,000 patients [95% CI from 162 fewer to 71 more]; for treatment with intravenous magnesium and diazepam versus placebo, RR for improved outcome was 0.68 [95% CI 0.36 to 1.28]; 81 fewer survivors per 1,000 patients [95% CI from 162 fewer to 71 more].
One non-randomized prospective clinical trial (Monsalve 1987, 244) with 107 adults compared patients who received a bolus and continuous infusion of thiopentone and phenobarbital compared to historic controls, provided very low-certainty evidence (downgraded for risk of bias, indirectness, and imprecision) of no benefit (RR 1.41 [95% CI 0.88 to 2.27]; 137 more survivors per 1,000 adults [95% CI from 40 fewer to 423 more]).
For the critical outcome of survival to hospital discharge/30 days or longer; One non-randomized prospective clinical trial (Monsalve 1987, 244) with 107 adults compared patients who received a bolus and continuous infusion of thiopentone and phenobarbital compared to historic controls, provided very low-certainty evidence (downgraded for risk of bias, indirectness, and imprecision) of no benefit (RR 1.40 [95% CI 0.83 to 2.36]; 119 more survivors per 1,000 patients [95% CI from 50 fewer to 403 more].
Treatment of Seizures
For the critical outcome of survival with favourable neurological outcome at discharge/30 days or longer, no pediatric RCTs or non-randomized comparative studies were identified.
Indirect evidence from adults were identified.
For the critical outcome of survival with favourable neurological outcome at discharge/30 days or longer; One RCT (Ruijter 2022, 724) that addressed the effect of treatment of rhythmic and periodic discharges with anti-seizure medication in 172 comatose adults post-cardiac arrest, compared with no seizure treatment on the critical outcome of survival with favourable neurological outcome at 3 months (CPC score 1 or 2). This study provided low level certainty evidence (downgraded for imprecision and indirectness) of no significant difference for the intervention (administration of anti-seizure medication for rhythmic and periodic EEG patterns) compared with standard care (RR 1.21 [95% CI 0.47 to 3.10; 2 more survivors per 100 patients, [95% CI from 7 fewer to 11 more]).
In addition, for the critical outcome of survival to 3 months, we identified low certainty evidence (downgraded for imprecision, indirectness) from one RCT (Ruijter 2022, 724) for no significant effect of treatment of rhythmic and periodic EEG patterns in 172 comatose adults post-cardiac arrest, compared with no seizure treatment (RR 0.14 [95% CI 0.62 to 2.12; 3 more survivors per 100 adults, [95% CI from 9 fewer to 14 more].
Treatment Recommendations
Prophylactic Anti-Seizure Medication
There is insufficient evidence to make a treatment recommendation for or against the use of prophylactic anti-seizure medication in children post-cardiac arrest.
We suggest against the routine use of prophylactic anti-seizure medication in children post-cardiac arrest (Good Practice Statement).
Seizure Treatment
There is insufficient evidence to make a treatment recommendation for or against the treatment of seizures in children post-cardiac arrest.
We suggest for the treatment of seizures in children post-cardiac arrest (Good Practice Statement).
Justification and Evidence to Decision Framework Highlights
Prophylactic Anti-Seizure Medication
Due to the lack of direct evidence in children post-cardiac arrest, and very low certainty of the indirect evidence from adults, the Task Force was unable to make a treatment recommendation. The Task Force decision to provide a Good Practice Statement suggesting against post-cardiac arrest prophylactic anti-seizure medication was based on the absence of in-direct evidence from adult comatose cardiac arrest survivors that prophylactic therapy with anti-seizure medication prevents seizures or improves important outcomes. However, the Task Force did recognize the very low certainty of the evidence from RCTs. The Task Force also considered that the administration of prophylactic anti-seizure medication in other forms of acute brain injury (e.g. neonatal hypoxic-ischemic encephalopathy) (Young 2016, 1) is not associated with improved long-term outcomes. Although prophylactic anti-seizure medication is recommended following traumatic brain injury in children (Kochanek 2019, 1172), the evidence of benefit for early seizure prevention is very-low certainty and there is no evidence of improved long-term outcomes (Liesemer 2011, 755)
The medication used for anti-seizure prophylaxis in the included trials (e.g. barbiturates) can have significant side effects although the cardiac side-effects seen in adults may be less common in children. The Task Force acknowledged that newer anti-seizure medication have not been evaluated and their efficacy and side effect profile may differ. Further evaluation is encouraged.
Seizure Treatment
No direct pediatric evidence of the effects of treating seizures in children after cardiac arrest was identified and the Task Force was unable to make a treatment recommendation.
High seizure burden in children has been associated with poor neurological outcome (Payne 213, 1429, Srinivasakumar 2015, e1302). There are safe and effective anti-seizure medications that can reduce seizure burden in children with status epilepticus which in turn may benefit longer term outcomes (Dalziel 2019 2135, Kapur 2019, 2103, Lyttle, 2019, 2125). Therefore, the Task Force decided to make the Good Practice Statement suggesting for the treatment of seizures in children post-cardiac arrest.
The Task Force acknowledges the challenge of seizure diagnosis and the important role of confirmatory electroencephalographic (EEG) in addition to clinical signs of seizure to increase certainty of diagnosis. The potential risk of treating suspected seizures in settings without access to EEG confirmation needs to be balanced with potential harm of anti-seizure medications. EEG confirmation remains the gold-standard approach for seizure diagnosis; however, EEG may not be available in many clinical settings as it requires significant resources, including neurophysiology equipment, training and expertise. Continuous EEG monitoring is labor intensive and likely to add significant cost to patient care. The cost-effectiveness of this approach is controversial and may depend on the setting. The relative benefit of continuous EEG compared with intermittent EEG monitoring was not reviewed.
There is insufficient evidence to suggest for or against the treatment of rhythmic and periodic EEG patterns in children post-cardiac arrest. One adult RCT (Ruijter 2022 724) did not find a difference in the primary outcome with one therapeutic approach to treatment of rhythmic and periodic EEG patterns. However, no significant harm was noted in adults assigned to the treatment or control arm. Further research is required in children to evaluate the impact on treating specific EEG patterns and electrographic seizures.
Medication for sedation (e.g. benzodiazepines and propofol) and targeted temperature management use after cardiac arrest may also affect seizure burden and timing. Evaluation of the use of prophylactic anti-seizure medication and seizure treatment in the context of these therapies is important.
Knowledge Gaps
There is no pediatric data for the use of prophylactic anti-seizure medication post-cardiac arrest. We encourage the assessment of newer anti-seizure medication and the role of sedative medication with anti-seizure properties used in the post-cardiac arrest period.
There is no pediatric data for the use of anti-seizure medication to treat seizures on important clinical outcomes post-cardiac arrest. We encourage research in this field.
EEG diagnosis remains the gold standard for seizure diagnosis. Risks and benefits of treating seizures without EEG and the importance of EEG monitoring post-cardiac arrest is a high priority with an important focus on cost effectiveness. This includes the role of continuous EEG, quantitative EEG and intermittent EEG.
Attachment: Pediatric Prophylaxis and Rx of Seizures PLS 4210 02 Et D
References
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{Liesemer, 2011 #8685;Srinivasakumar, 2015 #8681;Young, 2016 #8684;Kochanek, 2019 #2938;Lyttle, 2019 #8686;Topjian, 2021 #6016}