This CoSTR is a final version prepared by ILCOR and is labelled “draft” to allow for public comments and to comply with copyright rules of journals. The ‘draft label’ will be removed from this website once a summary article has been published in a scientific journal.
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
Nicholson TC, Hirsch K, Berg KM, Drennan I, Lavonas E, on behalf of the Advanced Life Support Task Force.
Effect of Seizure Treatment for Adults and Children following Cardiac Arrest on Patient Outcomes: A Systematic Review
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 prophylaxis and treatment of seizures on outcomes for adult and paediatric patients post-cardiac arrest (Nicholson/Scholefield 2024, pg No – PROSPERO CRD42023460746 and CRD42023463581), by clinical content experts of the Adult and Paediatric Task Forces of ILCOR, with assistance from Jessie Cunningham, Information Specialist at The Hospital for Sick Children, Toronto, Canada. Evidence for adult and paediatric literature was sought and considered by members of the Advanced Life Support Task Force and the Pediatric 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 paediatric 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/functional outcome at discharge, 30 days, 60 days, 180 days, and/or 1 year (all critical)
Survival at discharge, 30 days, 60 days, 180 days, and/or 1 year (all critical)
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, we identified two prospective RCTs {BRCT Study Group 1986 397; Longstreth 2002 506} 1,2 involving a total of 562 subjects which provided very low-certainty evidence (downgraded for risk of bias, indirectness and imprecision) of no benefit from prophylactic anti-seizure medication administration. One study (BRCT Study Group 1986 397) of 262 patients found no difference in good neurological outcome at 12 months for treatment with thiopentone vs standard care, (RR 1.30 [95% CI 0.76 to 2.21]; or 46 more survivors per 1,000 patients [95% CI from 37 fewer to 185 more]). One study (Longstreth 2002 506) found no difference in survival with good neurological outcome at 3 months for treatment with magnesium compared with placebo (RR 1.37 [95% CI 0.83 to 2.25]; or 94 more survivors per 1,000 patients [95% CI from 43 fewer to 317 more]). The study also found no difference in survival with good neurological outcome at 3 months for treatment with diazepam compared with placebo (RR 0.68 [95% CI 0.36 to 1.28]; or 81 fewer survivors per 1,000 patients [95% CI from 162 fewer to 71 more]); and no difference in survival with good neurological outcome at 3 months for combined treatment with magnesium and diazepam compared with placebo (RR 0.68 [95% CI 0.36 to 1.28]; or 81 fewer survivors per 1,000 patients [95% CI from 162 fewer to 71 more]).
We also identified one non-randomized prospective clinical trial (Monsalve 1987 244)3 of 107 patients with historic controls, that provided very low-certainty evidence (downgraded for risk of bias, indirectness, and imprecision) of no improvement in neurological outcome at hospital discharge with the additional treatment of thiopentcome compared with standard care (RR 1.41 [95% CI 0.88 to 2.27]; 137 more survivors per 1,000 patients [95% CI from 40 fewer to 423 more]).
For the critical outcome of survival to hospital discharge/30 days or longer, we found one non-randomized prospective clinical trial (Monsalve 1987 244)3 of 107 subjects with historic controls, that provided very low-certainty evidence (downgraded for risk of bias, indirectness, and imprecision) of no benefit in survival with the addition of thiopentone compared to standard care (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 outcomes of survival with favourable neurological outcome (CPC Score or 1 or 2), or survival at discharge/ 30 days or longer, we identified no RCTs or nonrandomized studies that addressed the effect of treatment of clinical seizures post-cardiac arrest, compared with no seizure treatment on clinical outcomes.
For the critical outcome of survival with favourable neurological outcome at 3 months (CPC score 1 or 2), we identified one RCT {Ruijter 2022 724)4 of low-certainty evidence (downgraded two levels for very serious imprecision) involving 172 patients, that addressed the effect of treatment of rhythmic and periodic EEG patterns in comatose patients post-cardiac arrest, compared with no treatment. The study found no significant difference for the intervention (administration of anti-seizure medications for generalized- periodic discharges (GPDs)) compared with standard care (RR 1.21 [95% CI 0.47 to 3.10]; or 20 more survivors per 1000 patients, [95% CI from 70 fewer to 110 more]).
For the critical outcome of survival to 3 months, we identified low-certainty evidence (downgraded two levels for very serious imprecision) from one RCT {Ruijter 2022 724)4 involving 172 patients, that found no significant effect of treatment of rhythmic and periodic EEG patterns in comatose patients post-cardiac arrest, compared with no treatment (RR 0.14 [95% CI 0.62 to 2.12]; or 30 more survivors per 1000 patients, [95% CI from 90 fewer to 140 more]).
Treatment Recommendations
This treatment recommendation has been updated from 2020.
We suggest against the use of prophylactic anti-seizure medication in adults post-cardiac arrest (weak recommendation, very low-certainty evidence).
We suggest treatment of clinically apparent and electrographic (EEG) seizures in adults post-cardiac arrest (Good practice statement).
We suggest treatment of rhythmic and periodic EEG patterns that are on the ictal-interictal continuum in comatose adults post-cardiac arrest (weak recommendation, low-certainty evidence).
Justification and Evidence to Decision Framework Highlights
Prophylactic Anti-Seizure Medication
The task force decision to suggest against the use of prophylactic anti-seizure medication post- cardiac arrest was primarily based on the absence of direct evidence that prophylactic anti-seizure medication prevents seizures or improves important outcomes in adult comatose cardiac arrest patients. However, the task force did recognize the very low certainty of the evidence from the included RCTs. The task force also considered that the administration of prophylactic anti-seizure medication in other forms of acute brain injury is not associated with improved outcomes, and that most prophylactic anti-seizure medications can have significant side effects. Finally, the task force acknowledged that most comatose post-cardiac arrest patients routinely receive sedatives such as propofol or benzodiazepines that are known to have antiseizure effects. However, the task force identified no controlled studies that examined whether different sedation strategies or choices of sedation drugs had an impact on the incidence of post-cardiac arrest seizures.
Seizure Treatment
In 2021, The American Clinical Neurophysiology Society (ACNS) published updated criteria for electrographic seizures, electrographic status epilepticus, and the ictal-interictal continuum.5 In practice, seizures may be classified as clinical, electrographic, or electroclinical. The ictal-intercital continuum describes an EEG pattern that “does not qualify as an electrographic seizure or electrographic status epilepticus, but there is a reasonable chance that it may be contributing to impaired alertness, causing other clinical symptoms, and/or contributing to neuronal injury.”
Table 1
ACNS Standardized Critical Care EEG Terminology 2021 for Electrographic and Electroclinical Seizures
Electrographic seizure (ESz)
Either:
A.Epileptiform discharges averaging >2.5 Hz for ≥10 s (>25 discharges in 10 s), OR
B.Any pattern with definite evolution as defined above and lasting ≥10 s.
Electrographic status epilepticus (ESE)
A.An electrographic seizure for >10 continuous minutes, OR
B.A total duration of >20% of any 60-minute period of recording.
Electroclinical seizure (ECSz)
Any EEG pattern with either:
A.Definite clinical correlate time-locked to the pattern (of any duration), OR
B.EEG AND clinical improvement with a parenteral (typically IV) anti-seizure medication.
Electroclinical status epilepticus (ECSE)
An electroclinical seizure for either
A. ≥10 continuous minutes, OR
B. A total duration of ≥20% of any 60-minute period of recording, OR
C. ≥5 continuous minutes if the seizure is convulsive (i.e.with bilateral tonic-clonic (BTC) motor activity) In any other clinical situation, the minimum duration to qualify as SE is >10 mins. Possible ECSE: An RPP that qualifies for the IIC (see below) that is present for ≥10 continuous minutes or for a total duration of >20% of any 60- minute period of recording, which shows EEG improvement with a parenteral anti-seizure medication BUT without clinical improvement.
Ictal-Interictal Continuum (IIC)
1. Any periodic discharge (PD) or spike wave (SW) pattern that averages >1.0 Hz and <2.5 Hz over 10 s (>10 and < 25 discharges in 10 sec); OR
2. Any PD or SW pattern that averages >0.5 Hz and <1 Hz over 10 s (>5 and <10 discharges in 10 sec), and has a plus modifier or fluctuation; OR 3. Any lateralized RDA averaging >1 Hz for at least 10 s (at least 10 waves in 10 s) with a plus modifier or fluctuation
AND
4. Does not qualify as an ESz or ESE.
These distinctions rely on EEG monitoring and correlating EEG patterns with clinical manifestations and thus require the skilled interpretation of video EEG. Untreated clinical seizure activity is thought to potentially cause additional brain injury, and thus treatment of clinical seizures is recommended despite the lack of high-certainty evidence. Rhythmic and period EEG patterns and other activities that do not meet criteria for electrographic seizures are of unclear significance in patients who are comatose after cardiac arrest. It is not clear if they represent a marker of an injured brain or if they are an abnormal pattern whose treatment may improve outcomes. Given the pathophysiologic concerns that electrographic seizures and discharges on the Ictal-Interictal Continuum may cause secondary brain injury, treatment of such waveforms
(including electrographic status epilepticus) is suggested. The TELSTAR trial randomized 172 subjects to protocolized tiered treatment targeting suppression of electroencephalographic rhythmic or periodic patterns in adults with GCS<8 after cardiac arrest. However, the majority (~80%) of the EEG patterns treated were not electrographic seizures nor findings that met criteria for the IIC but were generalized period discharges of 0.5 – 2.5Hz without evolution. Whether such rhythmic or periodic EEG patterns deserve treatment is unknown. Of note however, though the numbers involved in the post-hoc subgroup analysis of TELSTAR were too small to be anything other than exploratory, they were suggestive of a beneficial effect for the treatment of electrographic seizures, but not for treatment of periodic discharges.
Indirect evidence from case series suggests that sedatives such as propofol are effective in suppressing both clinical and electrographic seizures in these patients. A retrospective study provides some evidence that conventional antiseizure medications (specifically valproate and levetiracetam) also have an effect in suppressing epileptiform activity in the EEG.6
There is no direct evidence of undesirable effects of antiseizure medications in comatose post-cardiac arrest patients. Treatment with sedatives and conventional antiseizure medications in high doses has the potential to delay awakening, prolong the need for mechanical ventilation, and increase critical care days. The task force also discussed the potential cost of delayed neurological prognostication and prolonged ICU care associated with active treatment of seizures because of the need to continue sedation.
The relative benefit of continuous EEG compared with intermittent EEG monitoring was not specifically reviewed. Continuous EEG monitoring is labour intensive and likely to add significant cost to patient care. The cost-effectiveness of this approach is controversial and may depend substantially on the setting. The Continuous EEG Randomized Trial in Adults (CERTA) study 7 evaluated continuous vs intermittent EEG in critically ill adults with impaired consciousness, and approximately one third of the subjects had been resuscitated from cardiac arrest. No difference was found in outcome (6 month mortality) though the continuous EEG group had increased seizure detection and more frequent changes to antiseizure medications. Additional studies are needed in post-cardiac arrest patients patients to determine the optimal timing and method(s) of EEG monitoring.
Knowledge Gaps
There is no high-certainty evidence of a positive effect of anti-seizure medications on the outcome of post-cardiac arrest patients with either rhythmic and periodic EEG patterns or clinical seizures.
There are inadequate data about the timing, duration, dosing, and choice of antiseizure medications for seizure prophylaxis in comatose post-cardiac arrest patients.
EEG monitoring in the diagnosis and treatment of seizures in comatose post- cardiac arrest patients is unknown.
The threshold for treating rhythmic and period EEG activity is poorly defined.
The value of using volatile anesthetics to treat refractory status epilepticus on post-cardiac arrest patients is currently unknown.
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References
Backman S, Westhall E, Dragancea I, Friberg H, Rundgren M, Ullén S, Cronberg T. Electroencephalographic characteristics of status epilepticus after cardiac arrest. Clin Neurophysiol. 2017 Apr;128(4):681-688. doi: 10.1016/j.clinph.2017.01.002. Epub 2017 Jan 21. PMID: 28169132.
BRAIN RESUSCITATION CLINICAL TRIAL I STUDY GROUP (BRCT Group). Randomized Clinical Study of Thiopental loading in comatose survivors of Cardiac Arrest. N Engl J Med 1986; 314:397-403. Hirsch L.J., Fong M.W., Leitinger M., LaRoche S.M. , Beniczky S et al . American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2021 Version
J Clin Neurophysiol. 2021 Jan 1;38(1):1-29. doi: 10.1097/WNP.0000000000000806.
Longstreth WT, Fahrenbruch CE, Olsufka M, Walsh TR, Copass MK, Cobb LA. Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest . NEUROLOGY 2002;59:506–514
Lybeck A, Friberg H, Aneman A, Hassager C, Horn J, Kjærgaard J, Kuiper M, Nielsen N, Ullén S, Wise MP, Westhall E, Cronberg T; TTM-trial Investigators. Prognostic significance of clinical seizures after cardiac arrest and target temperature management. Resuscitation. 2017
May;114:146-151. doi: 10.1016/j.resuscitation.2017.01.017. Epub 2017 Feb 3. PMID: 28163232.
Monsalve F, Rucabado L, Ruano M, Cunat J, Lacueva V and Vinauales A. The Neurological Effect of Thiopental Therapy after Cardiac Arrest. Intensive Care Medicine (1987) 13:244-248.
Rossetti A.O.; Schindler K.; Sutter R.S.; Zubler F.; Novy J. et al. Continuous vs Routine Electroencephalogram in Critically Ill Adults With Altered Consciousness and No Recent Seizure : a Multicenter Randomized Clinical Trial . JAMA neurology 2020;77(10):1225. DOI:10.1001/jamaneurol.2020.2264
Ruijter B.J.; Keijzer H.M.; Tjepkema-Cloostermans M.C.; Blans M.J.; Beishuizen A et al. Telstar Investigators. Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest . New England Journal of Medicine 2022;386(8):724. DOI: 10.1056/NEJMoa2115998
Seder DB, Sunde K, Rubertsson S, Mooney M, Stammet P, Riker RR, Kern KB, Unger B, Cronberg T, Dziodzio J, Nielsen N; International Cardiac Arrest Registry. Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest.Crit Care Med. 2015 May;43(5):965-72. doi: 10.1097/CCM.0000000000000880.PMID: 25654176
Solanki P, Coppler PJ, Kvaløy JT, et al. Association of antiepileptic drugs with resolution of epileptiform activity after cardiac arrest. Resuscitation 2019;142:82 90, doi:http://dx.doi.org/10.1016/j. resuscitation.2019.07.007.
Waak M, Laing J, Nagarajan L, Lawn N, Simon Harvey A. Continuous electroencephalography in the intensive care unit: A critical review and position statement from an Australian and New Zealand perspective. Crit Care Resusc. 2023 May 23;25(1):9-19. doi: 10.1016/j.ccrj.2023.04.004. PMID: 37876987; PMC