Post-cardiac arrest seizure prophylaxis and treatment (ALS): Systematic Review

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This Review is a draft version prepared by ILCOR, with the purpose to allow the public to comment and is labeled “Draft for Public Comment". The comments will be considered by ILCOR. The next version will be labelled “draft" to comply with copyright rules of journals. The final Review will be published on this website once a summary article has been published in a scientific Journal and labeled as “final”.

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. Tobias Cronberg co-authored some of the works considered by the task force in the discussion, although none of these works were included in the systematic review There were no other declared conflicts of interest, intellectual or otherwise, by task force members or authors.

CoSTR Citation

Cronberg T, Skrifvars M, Nolan J, Andersen LW, Berg KM, Böttiger BW, Callaway CW, Deakin CD, Donnino MW, Drennan I, Hsu C, Morely P, Nicholson TC, O’Neil BJ, Paiva EF, Parr MJ, Reynolds JC, Sandroni C, Soar J, Wang TL, Welsford M, Neumar RW.

Post-Cardiac Arrest Seizure Prophylaxis and Treatment Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2020 January 5th. Available from: http://ilcor.org

Methodological Preamble

The continuous evidence evaluation process for the production of this updated 2015 Consensus on Science with Treatment Recommendations (CoSTR) started with a focused systematic review of post-cardiac arrest seizure prophylaxis and treatment publications since 2014 conducted by Tobias Cronberg and Robert Neumar with involvement of clinical content experts Markus Skrifvars and Jerry Nolan. Evidence for adult literature was sought and considered by the Advanced Life Support Task Force. These data were taken into account when formulating the Treatment Recommendations.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Unresponsive adults (>18 years old) with sustained return of spontaneous circulation (ROSC) after cardiac arrest in any setting (in-hospital or out-of-hospital).

Intervention: One strategy for seizure prophylaxis or treatment.

Comparators: Another strategy or no seizure prophylaxis or treatment.

Outcomes: Survival with favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year. Survival at discharge, 30 days, 60 days, 180 days AND/OR 1 year. Seizure incidence during index hospitalization (for seizure prophylaxis only).

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.

Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search updated to September 26th, 2019.

Search was based on 2015 CoSTR and SR approved by ILCOR SAC Representative on 3 October 2019

Consensus on Science

Post-Cardiac Arrest Seizure Prophylaxis

For the critical outcomes of survival with favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year and survival at discharge, 30 days, 60 days, 180 days AND/OR 1 year, 2 prospective randomized clinical trials involving a total of 562 subjects provided very low-certainty evidence (downgraded for risk of bias, indirectness and imprecision)(BRCT Investigators 1986 397;Longstreth 2002 506) of no benefit from seizure prophylaxis. One nonrandomized prospective clinical trial that used historic controls with 107 subjects provided very low-certainty evidence (downgraded for risk of bias, indirectness, and imprecision) of no benefit.(Monsalve 1987 244) In 1 block randomized trial,(Longstreth 2002 506) OHCA patients with ROSC received either placebo, diazepam, magnesium sulfate, or diazepam plus magnesium sulfate. The percentage of patients independent at 3 months was 25.3% (19/75) in the placebo group, 34.7% (26/75) in the magnesium group, 17.3% (13/75) in the diazepam group, and 17.3% (13/75) in the diazepam plus magnesium group (for magnesium: RR, 1.37; 95% CI, 0.83–2.25). After adjusting for baseline imbalances, outcomes did not differ between groups. In a trial of thiopental versus placebo within 1 hour of ROSC,(BRCT Investigators 1986 397) 1-year survival with good cerebral function was 15% (20/131) in the placebo group and 20% (26/131) in the thiopental group (RR, 1.30; 95% CI, 0.76–2.21). A nonrandomized clinical trial (Monsalve 1987 244) showed no benefit of barbiturate therapy in comatose post–cardiac arrest patients using a combination of thiopental and phenobarbital when compared with historic controls. In this study, survival to hospital discharge with favorable neurologic outcome was 47% (25/53) in the barbiturate group and 33% (18/54) in the historic control group (RR 1.41; 95% CI 0.88 to 2.27).

For the important outcome of seizure prevention, we identified very low-certainty evidence (downgraded for risk of bias and indirectness and imprecision) from 2 prospective double-blinded RCTs (BRCT Study Group 1986 397; Longstreth 2002 506) showing no benefit of seizure prophylaxis. In 1 trial of thiopental treatment,( BRCT Study Group 1986 397) 21% (28/131) of control subjects and 13% (17/131) of thiopental-treated subjects had seizures (RR 0.61; 95%CI 0.35-1.05). The overall incidence of seizures in a second trial (Longstreth 2002 506) was 11.9% and reported to be not different between the 4 groups (double placebo, magnesium plus placebo, diazepam plus placebo, and diazepam plus magnesium).

Post-Cardiac Arrest Seizure Treatment

For the critical outcomes of survival with favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year and survival at discharge, 30 days, 60 days, 180 days AND/OR 1 year we identified no randomized controlled trials (RCTs) or non-randomized that addressed post-cardac arrest seizure treatment.

Treatment Recommendations

Post-Cardiac Arrest Seizure Prophylaxis

We suggest against seizure prophylaxis in adult post–cardiac arrest survivors (weak recommendation, very low certainty of evidence).

Post-Cardiac Arrest Seizure Treatment

We suggest treatment of seizures in adult post–cardiac arrest survivors (weak recommendation, very low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

Cardiac arrest, both in the out-of-hospital and in-hospital setting, is relatively common and has a very high mortality, with post-cardiac arrest brain injury as a common cause of death. Clinical convulsions (mainly myoclonus) and epileptiform activity in the EEG are common manifestations of post-cardiac arrest brain injury with substantial overlap and an approximate incidence of 20-30% (Seder 2015 965, Lybeck 2017 146, Backman 2017 681, Beretta 2018 e2153). A broad range of outcomes have been reported in post-cardiac arrest patients with seizures who are treated with antiepileptic drugs (Hofmeijer 2014 39, Backman 2017 128, Beretta 2018 e2153 ). Patients with post-cardiac arrest seizures who have good outcomes are usually, but not always treated aggressively with antiepileptic drugs and they usually have a delayed awakening (Dragancea 2015 173, Aica Rapun 2017 169).

Subgroups of patients with either potentially favorable or poor prognosis have been identified in several retrospective studies. A continuous EEG-background preceding the start of status epilepticus, reactive background and later start of status epilepticus are factors associated with a potentially favorable outcome. Conversely, early onset of status epilepticus in the EEG (<24 hours), a preceding burst-suppression pattern, lack of EEG-background and EEG-background reactivity are EEG-features associated with a poor prognosis (Rossetti 2009 744, Backman 2017 128, Elmer 2016 175). In addition, reliable prognosticators of poor outcome other than EEG may identify patients who are not likely to benefit from prolonged treatment (Dragancea 2015 173, Beretta 2018 e2153).

The Task Force decision to suggest against post-cardiac arrest seizure prophylaxis was primarily based on the absence of direct evidence that prophylactic therapy with antiepileptic drugs prevents seizures or improves important outcomes in adult comatose cardiac arrest survivors. However, the task force did recognize the very low certainty of the evidence from randomized clinical trials. The task force also considered that seizure prophylaxis in other forms of acute brain injuries is not associated with improved outcomes, and that most drugs used for seizure prophylaxis have significant side effects. Finally, the task force acknowledged that most comatose cardiac arrest surivors routinely receive sedatives such as propofol or benzodiazepines that are known to have antiepileptic effects. However we identified no controlled studies that examined whether different sedation strategies or choice of sedation drugs had an impact on the incidence of post-cardiac arrest seizures.

The Task Force decision to suggest treatment of seizures in post-cardiac arrest survivors takes into consideration the absence of direct evidence that seizure treatment improves critical outcomes in this patient population. However, the absence of direct evidence is there are no published controlled clinical studies. Therefore, the Task Force considered that ongoing seizures have the potential to worsen brain injury, and treatment of recurrent seizures and status epilpeticus is the standard of care in other patient populations (Glauser 2016 48). A large randomized trial is currently underway investigating the benefit of systematic antiepileptic drug therapy with the goal of suppressing all epileptiform activity on the EEG vs. standard treatment of clinical seizures only in post-cardiac arrest status epilepticus (TELSTAR trial, NCT02056236).

Indirect evidence from case series suggests that sedatives such as propofol are effective in suppressing both clinical convulsions and epileptiform activity on EEG in these patients (Thömke 2010 1392, Aica Rapun 2017 169, Kotroumanidis 2015 255). A recent retrospective study provides some evidence that conventional antiepileptic drugs (specifically valproate and levetiracetam) also have an effect in suppressing epileptiform activity in the EEG (Solanki 2019 82). In a recent comparison of valproate, levetiracetam and fosphenytoin for convulsive status epilepticus, the three drugs were equally effective but fosphenytoin caused more episodes of hypotension and need for intubation (Kapur 2019 2103).These results suggest that valproate and levetiracetam may be reasonable first line drugs in post-cardiac arrest seizure management.

There is no direct evidence of undesirable effects of antiepileptic drug therapy in comatose post-cardiac arrest survivors. Treatment with sedatives and conventional antiepileptic drugs in high doses has the potential to cause delayed awakening, prolonged need for mechanical ventilation, and increased ICU days. Importantly, generalized myoclonus in combination with epileptiform discharges may be manifestations of Lance-Adams syndrome which is compatible with a good outcome (Elmer 2016 175, Aica-Rapun 2017 169 ). In such cases, overly aggressive sedation and treatment with high doses of conventional antiepileptic drugs may confound the clinical examination and lead to overly pessimistic prognostication.

The relative benefit of continuous EEG compared with routine EEG has not been demonstrated. One retrospective cohort study found no difference in survival with good neurologic outcome (CPC 1-2 at 3 months) in patients monitored with routine EEG vs. continuous EEG (Fatuzzo, 2018 29). In addition to diagnosing seizures, continuous EEG monitoring is used to monitor response to therapy and assess prognosis. Continuous EEG monitoring is labor intensive and likely to add significant cost to patient care. The net cost-effectiveness of this approach is controversial and may depend substantially on the organization (Crepeau 2014 785, Sondag 2017 111 ). There is also the potential cost of delayed neurologic prognostication and prolonged ICU care due to active treatment of seizures.

We identified no studies that addressed health equity of post-cardiac arrest seizure prophylaxis or treatment. However, it is likely that the availability of specific drugs will vary with setting and region.The availability of conventional and continuous EEG monitoring is likely to be limited in low resourced environments.

Knowledge Gaps

  • There is no high certainty evidence for the effect of antiepileptic drugs on the outcome of post-cardiac arrest patients with seizures
  • There are no RCTs specifically designed to evaluate the impact of post-cardiac arrest seizure prophylaxis on the incidence of seizures and neurologic outcome.
  • There are inadequate data regarding the timing, duration, dosing, and choice of antiepileptic drugs for seizure prophylaxis in comatose post–cardiac arrest patients.
  • The utility of continuous EEG versus intermittent EEG monitoring in the diagnosis and treatment of seizures in comatose post–cardiac arrest patients remains controversial due to resource utilization and lack of evidence for improved outcomes.
  • The threshold for treating epileptiform activity other than convulsive seizures (eg, generalized epileptiform discharges) is poorly defined
  • Standardized terminology for classification of epileptiform activity in the EEG of comatose post–cardiac arrest patients is increasingly used. There remains a need to develop consensus on the definition of post cardiac arrest status epilepticus
  • The value of using volatile anesthetics to treat refractory status epilepticus on post-cardiac arrest patients is currently unknown.

Attachments

Evidence-to-Decision Table: ALS Seizure Treatment Prophylaxis ADULT

References

Aicua Rapun I, Novy J, Solari D, Oddo M, Rossetti AO. Early Lance-Adams syndrome after cardiac arrest: Prevalence, time to return to awareness, and outcome in a large cohort. Resuscitation 2017; 115: 169-72.

Backman S, Westhall E, Dragancea I, et al. Electroencephalographic characteristics of status epilepticus after cardiac arrest. Clin Neurophysiol 2017; 128: 681-8.

Beretta S, Coppo A, Bianchi E, et al. Neurologic outcome of postanoxic refractory status epilepticus after aggressive treatment. Neurology 2018; 91: e2153-e62.

Brain Resuscitation Clinical Trial ISG. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med. 1986;314:397-403.

Crepeau AZ, Fugate JE, Mandrekar J, et al. Value analysis of continuous EEG in patients during therapeutic hypothermia after cardiac arrest. Resuscitation 2014.

Dragancea I, Backman S, Westhall E, Rundgren M, Friberg H, Cronberg T. Outcome following postanoxic status epilepticus in patients with targeted temperature management after cardiac arrest. Epilepsy & behavior : E&B 2015; 49: 173-7.

Elmer J, Rittenberger JC, Faro J, et al. Clinically distinct electroencephalographic phenotypes of early myoclonus after cardiac arrest. Ann Neurol 2016; 80: 175-84.

Fatuzzo D, Beuchat I, Alvarez V, Novy J, Oddo M, Rossetti AO. Does continuous EEG influence prognosis in patients after cardiac arrest? Resuscitation. 2018;132:29-32.

Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman DM. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16:48-61.

Hofmeijer J, Tjepkema-Cloostermans MC, Blans MJ, Beishuizen A, van Putten MJ. Unstandardized treatment of electroencephalographic status epilepticus does not improve outcome of comatose patients after cardiac arrest. Front Neurol. 2014 Mar 31;5:39.

Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R, Nett and Investigators P. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019;381:2103-2113.

Koutroumanidis M, Sakellariou D. Low frequency nonevolving generalized periodic epileptiform discharges and the borderland of hypoxic nonconvulsive status epilepticus in comatose patients after cardiac arrest. Epilepsy & behavior : E&B 2015; 49: 255-62.

Longstreth WT Jr1, 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(4):506-514

Lybeck A, Friberg H, Aneman A, et al. Prognostic significance of clinical seizures after cardiac arrest and target temperature management. Resuscitation 2017; 114: 146-51.

Monsalve F, Rucabado L, Ruano M, Cunat J, Lacueva V and Vinuales A. The neurologic effects of thiopental therapy after cardiac arrest. Intensive Care Med. 1987;13:244-8.

Rossetti AO, Oddo M, Liaudet L, Kaplan PW. Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia. Neurology 2009; 72: 744-9.

Ruijter BJ, van Putten MJ, Horn J, Blans MJ, Beishuizen A, van Rootselaar AF, Hofmeijer J; TELSTAR study group. Treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation (TELSTAR): study protocol for a randomized controlled trial. Trials. 2014;15:433

Seder DB, Sunde K, Rubertsson S, et al. Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest. Critical care medicine 2015; 43: 965-72.

Solanki P, Coppler PJ, Kvaloy JT, et al. Association of antiepileptic drugs with resolution of epileptiform activity after cardiac arrest. Resuscitation 2019; 142: 82-90.

Sondag L, Ruijter BJ, Tjepkema-Cloostermans MC, et al. Early EEG for outcome prediction of postanoxic coma: prospective cohort study with cost-minimization analysis. Critical care 2017; 21: 111.

Thomke F, Weilemann SL. Poor prognosis despite successful treatment of postanoxic generalized myoclonus. Neurology 2010; 74: 1392-4.


Task Force Systematic Review

Discussion

GUEST
Ed Amorim (218 posts)
One important caveat is ictal-interictal continuum patterns, e.g. generalized periodic discharges with high frequency. Should clinicians consider anti-seizure medications?
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