Prognostic significance of clinical seizures after cardiac arrest and target temperature management

doi:10.1016/j.resuscitation.2017.01.017

Resuscitation

Volume 114, May 2017, Pages 146-151

https://doi.org/10.1016/j.resuscitation.2017.01.017 Get rights and content

Abstract

Aim

Clinical seizures are common after cardiac arrest and predictive of a poor neurological outcome. Seizures may be myoclonic, tonic-clonic or a combination of seizure types. This study reports the incidence and prognostic significance of clinical seizures in the target temperature management (TTM) after cardiac arrest trial. Our hypotheses were that seizures are associated with a poor prognosis and that the incidence of seizures is not affected by the target temperature.

Methods

Post-hoc analysis of reported clinical seizures during day 1–7 in the TTM-trial including their treatment, EEG-findings, and long-term neurological outcome. The trial randomised 939 comatose survivors to TTM at 33 °C or 36 °C with strict criteria for withdrawal of life-sustaining therapies. Sensitivity, specificity and false positive rate for poor outcome were reported for different types of seizures.

Results

Clinical seizures were registered in 268 patients (29%), similarly distributed in both intervention arms. Early and late seizures were equally predictive of poor outcome. Myoclonic seizures were the most common (240 patients, 26%) and the most predictive of a poor outcome (sensitivity 36.1%, false positive rate 4.3%). Two patients with status myoclonus regained consciousness, one with a good neurological outcome, generating a false positive rate of poor outcome of 0.2% (95%CI 0.0–1.0).

Conclusion

Clinical seizures are common after cardiac arrest and indicate poor outcome with limited specificity. Prolonged seizures are a very grave sign but occasional patients may have a good outcome. The level of the target temperature does not affect the prevalence or prognostic significance of seizures.

Introduction

Clinical seizures are common manifestations of neurological injury after cardiac arrest and may be classified as focal or generalised, myoclonic or tonic-clonic or a combination of seizure types.¹ Clinical seizures may or may not be epileptic and other involuntary movements may be misdiagnosed as seizures.²

Myoclonic seizures are sudden, brief, involuntary muscle jerks that may be focal, multifocal or generalised, and occur with or without epileptiform activity on the electroencephalogram (EEG).3, 4, 5, 6 Status myoclonus defined as >30 min of generalised myoclonus is a severe form with a grave prognosis.7, 8 Overall, myoclonus is associated with poor prognosis but good outcomes occur.5, 6, 9, 10 Status myoclonus of early onset (<24 h after cardiac arrest) was previously considered a reliable sign of poor prognosis, but good outcomes have been reported in patients treated with TTM. 5, 6, 11, 12, 13 Action myoclonus persisting after awakening (Lance-Adams syndrome) compatible with otherwise good outcome may occur on rare occasions mainly after cardiac arrest of primarily hypoxic origin.6, 14, 15 Tonic-clonic seizures are less common than myoclonic seizures but are also associated with a poor outcome.16, 17

It is unknown whether post-anoxic electrographic seizures cause further neurological damage or are simply a sign of post-anoxic encephalopathy.18, 19 Since epileptic activity can increase the metabolic rate and thereby inflict further neuronal injury, treatment of clinical seizures is generally recommended.7, 20 These recommendations are based on expert advice awaiting evidence from randomised trials.²¹ Myoclonic seizures are often possible to suppress by propofol, but this has not been found to improve outcome.²²

This post hoc analysis of the Target Temperature Management trial (TTM-trial) reports the incidence and prognostic significance of clinical seizures during the first 7 days in the ICU, interaction with TTM and EEG findings.²³ Our hypotheses were that seizures are associated with a poor prognosis, late occurring seizures are associated with a better prognosis and that the incidence of seizures is not affected by the level of TTM.

Section snippets

Study population

The TTM-trial, was an international, randomised, parallel group, assessor-blinded trial designed to evaluate outcome after temperature management at either 33 °C (TTM33) or 36 °C (TTM36) in unconscious patients after out-of-hospital cardiac arrest of presumed cardiac origin.²³ It enrolled 950 adult (≥18 years) patients in 26 months 2010–2013. The modified intention to treat group included 473 patients at 33 °C and 476 at 36 °C. Trial data were obtained from 36 intensive care units in Europe and

Baseline and cardiac arrest characteristics

Patients with clinical seizures were older, less likely to have a witnessed arrest, receive bystander cardiopulmonary resuscitation (CPR), and have a first monitored shockable rhythm and their time to ROSC was longer (Table 1). The duration of day 1 was similarly distributed. Within the groups of patients with or without seizures, there was no difference in background characteristics between the two intervention groups TTM33 and TTM36 (Supplementary data 1).

Incidence of clinical seizures

The frequency of myoclonic and

Discussion

This post-hoc analysis of the TTM-trial is to our knowledge the largest prospective study on clinical seizures after cardiac arrest and the first comparison of the impact of two different temperature strategies. The incidence of clinical seizures was 29%, of which 11% had a good outcome. Myoclonic seizures were more common than tonic-clonic seizures and implicated a worse outcome. There was no significant difference in incidence of clinical seizures or outcome between TTM33 and TTM36 and we

Conclusions

Clinical seizures were identified in 29% of patients and were associated with poor outcome, but good outcomes occurred even in patients with early status myoclonus. The incidence and outcome of clinical seizures were not altered by TTM at 33 °C or 36 °C, and we did not find any difference in outcome between early and late onset clinical seizures. Our results support the need for multimodal neuroprognostication in patients with seizures who remain unconscious after cardiac arrest.

Conflict of interest statement

Anna Lybeck, Anders Aneman, Christian Hassanger, Janneke Horn, Jesper Kjaergaard, Michael Kuiper, Susann Ullén, Erik Westhall and Tobias Cronberg have none to declare. Hans Friberg, Niklas Nielsen and Matthew Wise report personal fees from Bard Medical. Hans Friberg is a scientific advisor for QuickCool.

Funding

The TTM-trial and the present study was funded by independent research grants from the non-profit or governmental agencies: Swedish Heart Lung Foundation (grant no. 20090275); Arbetsmarknadens forsakringsaktiebolag AFA-Insurance Foundation (grant no. 100001); The Swedish Research Council(grant no. 134281, 296161, 286321); Regional research support, Region Skane; Governmental funding of clinical research within the Swedish NHS (National Health Services) (grant no. M2010/1837, M2010/1641, 353301

Ethics and patient consent

Australia: Health Ethics Review Committee Protocol No X11-0150 & HREC/11/RPAH/216 – “GI-CCT886. Czeck Republic: Ethics committee of the General University Hospital of Prague, c/j 193-11 S 17.2.2011. Denmark: De vitenskabsetiske Komiteer i Region Hovedstaden, H-1-2010-059. Italy: Comitato Etico Indipendente, Hospedaliera S Maria degli Angeli Pordenone, No 9. Luxembourg: Comité National d’Ethique de Recherche CNER No 201007/05 Ver 1.0. The Netherlands: Medisch Etische Toetsingscommissie MEC

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Of 157 patients, 98 (63%) had myoclonus at inclusion. Myoclonus was not associated with one specific RPP type. However, myoclonus was associated with a smaller probability of a continuous EEG background pattern (48% in patients with vs 75% without myoclonus, odds ratio (OR) 0.31; 95% confidence interval (CI) 0.16–0.64) and earlier onset of RPPs (24% vs 9% within 24 hours after cardiac arrest, OR 3.86;95% CI 1.64–9.11). Myoclonus was associated with poor outcome at three months, but not invariably so (poor neurological outcome in 96% vs 82%, p = 0.004). Anti-seizure medication did not improve outcome, regardless of myoclonus presence (6% good outcome in the intervention group vs 2% in the control group, OR 0.33; 95% CI 0.03–3.32).
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Cardiac arrest (CA) is associated with a low rate of survival with favourable neurologic recovery. The most common mechanism of death after successful resuscitation from CA is withdrawal of life-sustaining measures on the basis of perceived poor neurologic prognosis due to underlying hypoxic-ischemic brain injury. Neuroprognostication is an important component of the care pathway for CA patients admitted to hospital but is complex, challenging, and often guided by limited evidence. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to evaluate the evidence underlying factors or diagnostic modalities available to determine prognosis, recommendations were generated in the following domains: (1) circumstances immediately after CA; (2) focused neurologic exam; (3) myoclonus and seizures; (4) serum biomarkers; (5) neuroimaging; (6) neurophysiologic testing; and (7) multimodal neuroprognostication. This position statement aims to serve as a practical guide to enhance in-hospital care of CA patients and emphasizes the adoption of a systematic, multimodal approach to neuroprognostication. It also highlights evidence gaps.
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^☆: A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2017.01.017.

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Clinical paperPrognostic significance of clinical seizures after cardiac arrest and target temperature management☆

Abstract

Aim

Methods

Results

Conclusion

Introduction

Section snippets

Study population

Baseline and cardiac arrest characteristics

Incidence of clinical seizures

Discussion

Conclusions

Conflict of interest statement

Funding

Ethics and patient consent

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Am Heart J

Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest

Acta Anaesthesiol Scand

What’s shaking in the ICU? The differential diagnosis of seizures in the intensive care setting

Epilepsia

Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus

BMC Neurol

Electroencephalographic findings in posthypoxic myoclonus

J Intensive Care Med

Acute posthypoxic myoclonus after cardiopulmonary resuscitation

BMC Neurol

Clinically distinct electroencephalographic phenotypes of early myoclonus after cardiac arrest

Ann Neurol

Prognostication after cardiac arrest and hypothermia: a prospective study

Ann Neurol

Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest

Crit Care Med

Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology

Neurology.

The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy

Brain

Clinical paper
Prognostic significance of clinical seizures after cardiac arrest and target temperature management☆