Intensive anti-seizure treatment ineffective in comatose survivors of cardiac arrest
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Intensive anti-seizure treatment suppressing rhythmic and periodic electroencephalographic patterns in comatose survivors of cardiac arrest did not result in fewer poor outcomes at 3 months vs. standard treatment, researchers reported.
“Rhythmic and periodic electroencephalographic (EEG) patterns that may reflect electrographic seizures have been reported in 10% to 35% of comatose patients after cardiac arrest,” B.J. Ruijter, PhD, a postdoctoral researcher in the department of clinical neurophysiology at the University of Twente in Enschede, the Netherlands, and colleagues wrote in the study background. “Unequivocal electrographic or clinical seizures are infrequent, whereas generalized periodic discharges are common in these patients and have generally been associated with a poor neurologic outcome. Whether rhythmic and periodic EEG patterns should be treated with anti-seizure medications, with the goal of improving the neurologic outcome, is unclear.”
In the TELSTAR open-label trial, Ruijter and colleagues analyzed data from 172 comatose survivors of cardiac arrest randomly assigned to a stepwise strategy of anti-seizure medications to suppress rhythmic and periodic EEG patterns detected on continuous EEG monitoring for at least 48 consecutive hours plus standard care (anti-seizure treatment group; n = 88) or to standard care alone (control group; n = 84). Standard care included targeted temperature management in both groups. The primary outcome was neurologic outcome according to the Cerebral Performance Category (CPC) scale at 3 months, defined as a good outcome (CPC score indicating no, mild or moderate disability) or poor outcome (CPC score indicating severe disability, coma or death). Secondary outcomes were mortality, length of ICU stay and duration of mechanical ventilation.
The findings were published in The New England Journal of Medicine.
Within the cohort, rhythmic or periodic EEG activity was detected a median of 35 hours after cardiac arrest and 62% of patients with available data had myoclonus. Complete suppression of rhythmic and periodic EEG activity for 48 consecutive hours occurred in 56% of patients in the anti-seizure treatment group and in 2% of controls.
At 3 months, 90% of patients in the anti-seizure treatment group and 92% of controls had a poor outcome (difference, 2 percentage points; 95% CI, –7 to 11; P = .68). Mortality at 3 months was 80% in the anti-seizure treatment group and 82% in the control group. The mean length of ICU stay and mean duration of mechanical ventilation were slightly longer in the anti-seizure treatment group compared with the control group.
The researchers noted that intensive anti-seizure treatment did not improve neurologic outcomes at 3 months, but the wide CI for the primary outcome “may not rule out modest benefit or harm.”
“Exploratory subgroup analyses suggested that there may have been fewer good outcomes with the anti-seizure intervention in patients with generalized periodic discharges than in those with other patterns,” the researchers wrote. “However, no conclusions can be drawn from these results, because the trial was underpowered for these analyses.”
Perspective
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Jonathan Elmer, MD, MS
This was an important and well-done clinical trial addressing an unanswered question in post-arrest care — whether seizures and related epileptiform activity are simply a marker of severe brain injury or if they are a treatment-responsive cause of secondary injury. A randomized controlled trial is really the only way to elucidate whether treating these EEG patterns aggressively can improve patient outcomes.
The findings were neutral, with no evidence of benefit with the aggressive treatment protocol in improving CPC, their outcome scale. That is not surprising and it resonates with our clinical experience and some of the observational analyses we and other groups have published.
An open question is whether, even within the somewhat narrow cohort of patients enrolled, there is heterogeneity of treatment responsiveness. There is a suggestion of that when you look at the authors’ prespecified subgroup analyses; however, as the authors note the study was not powered to detect these differences. In analyses stratified by EEG background continuity, it is notable that survival was 0% in both arms of the discontinuous and suppressed groups. That suggests they may be categories of patients for whom these EEG patterns are simply a marker of severe brain injury rather than treatment responsive.
CPC as an outcome category is imperfect; there may be other important neurocognitive outcomes that varied across arms and simply were not captured by this crude scale. I am confident knowing these investigators that those secondary analyses are coming and I look forward to those findings.
These data add to a narrative that we need to be more precise in our characterization of injury phenotypes after cardiac arrest to identify treatment responders in at the bedside.
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