pilepticus after R
A. Bouwes1, J.M. Binnekade1, J.H.T.M. Koelman2, A. Hijdra3, J. Horn1
1Dept of Intensive Care AMC, 2Dept of Clinical Neurophysiology AMC, 3Dept of Neu-
J. Horn, Intensive Care, Academic Medical Center, Meibergdreef 9, 1105 AZ, Am-
Table of contents
4.6 Statistical analysis and power calculation
In the Netherlands, each year approximately 7500 patients are admitted after cardiopulmon-
ary resuscitation (CPR) (1). During cardiac arrest and resuscitation, cerebral blood flow is
temporarily absent or seriously decreased, leading to cerebral damage. In 70% of successful
resuscitations this cerebral damage results in a post anoxic coma. The chances of recovery
from this type of coma are small, after 6 months almost 90% of the patients has died or are in
a persistent vegetative state (2). In 10-20% of the patients who remain in coma after CPR,
epileptic seizures or a status epilepticus (SE) are the cause of coma. Symptoms of epilepsy
can sometimes be found during physical examination, in other cases the epilepsy is diag-
nosed during electroencephalogram (eeg) (2;3). A post-anoxic status epilepticus (PSE) is
considered to have a poor prognosis, 90-95% of these patients will never regain conscious-
ness or will die. Uncertainty exists about the optimal treatment of this condition. Some doc-
tors do not start anti-epileptic treatment, because this is not considered a worthwhile inter-
vention. Others do start treatment, but there is no general agreement about the optimal
treatment regimen. Many manuscripts have been published about the treatment of a SE in
general, but most of these studies are retrospective and the number of patients with a PSE in
these groups is relatively small (4;5). Recently, Dutch and European guidelines for treatment
of status epilepticus have been published (6;7), but patients with PSE are not always treated
in accordance with these guidelines, despite the fact that this might increase their chance for
a good neurological outcome. In this study the neurological outcome of patients with a PSE,
all treated in accordance with a strict protocol, will be evaluated.
A) Can treatment in accordance to a strict protocol improve the neurological outcome of pa-
B) In which percentage of patients will SE recur after adequate treatment with propofol
C) Are there specific eeg-characteristics which could predict neurological outcome?
A) Prove that optimal treatment of patients with PSE improves neurological outcome in com-
parison with a control group (historical controls from literature).
B) Prove that with optimal treatment a PSE on eeg can be suppressed adequately.
C) Define the eeg-characteristics which can predict neurological outcome.
Generalized status epilepticus after non-traumatic cardiopulmonary resuscitation. This SE
can be diagnosed clinically or by eeg, which often means that the patient has a non-
convulsive SE. Status epilepticus on an eeg is defined as continuous epileptic activity
(spikes, spike-wave complexes or sharp waves), or >2 electro-encephalographic attacks dur-
ing 30 minutes of eeg recording. Both hemispheres should be involved.
Age < 18 years, myoclonus status (clinical diagnosis, defined as spontaneous or soundsensi-
tive, repetitive, irregular brief jerks in both face and limb) after resuscitation, trauma leading
to CPR, other than neurological reasons to withdraw supportive treatment, comorbidity with
diminished life expectancy of < 6 months, severe disability before CPR, known allergy for any
When the treating physicians decide not to treat the SE, we also would like to be informed
and will collect data (patient characteristics, reasons for withdrawal / withholding of support)
In this study patients with PSE are treated conform the national and international guidelines.
The effect of this treatment in this specific population is registered precisely. As no experi-
mental treatment is administered, informed consent is not necessary. The Medical Ethics
Committee of the Academic Medical Center has agreed on this approach.
Patients will be treated according to a protocol based on the European and Dutch guidelines
A benzodiazepine (options to choose from)
a. lorazepam 4 mg + repeated gifts if needed, maximum dose 12 mg/24 hours
b. midazolam 10 mg + repeated gifts if needed (or continuous administration),
phenytoin, loading dose 10-15 mg/kg intravenously administered in 30 minutes, fol-
lowed by intravenous administration, guided by serum levels (including free fraction
If the SE has not subsided (either clinically or on the eeg performed within 24 hours) after the
loading dose of phenytoin, the started medication (benzodiazepine and phenytoin) will be
continued. In addition to this treatment a burst-suppression eeg will be induced with propofol.
Propofol will be administered continuously, guided by the eeg or a neurotrack system.
Meanwhile, a second anti-epileptic drug will be added. Our experience is that sometimes
high doses of propofol are necessary to induce burst-suppression. To diminish the risk of
propofol infusion syndrome, a dose > 8 mg/kg/hour must be avoided. This dose is relatively
high, but considered safe, given the limited duration of administration. However, CPK levels
(creatine phosphokinase) and lactate levels should be followed. When no burst-suppression
can be achieved with the maximum dosage of propofol, midazolam can be added (continu-
ous administration, 0.3-0.5 mg/kg/hour). After achievement of burst-suppression eeg this
treatment will be continued for at least 24 hours. After these hours, the propofol (and possibly
For the second anti-epileptic drug, the treating physician can choose between:
a. levetiracetam, 500 mg two times daily intravenously administered. If unsuccessful
b. valproic acid, intravenous loading dose 10-20 mg/kg in 30 min, followed by 15
mg/kg/day divided in two gifts, intravenously or orally administered. Check serum
In the available guidelines, benzodiazepine together with phenytoin are advised for treatment
of SE. It has been shown recently that valproic acid and levetiracetam are also effective in
treatment of SE (8;9). When phenytoin and valproic acid are combined, a decrease in pheny-
toin levels to subtherapeutic levels is often found. Therefore, this combination is not preferred
for these patients. If this combination is used, phenytoin levels (including free fraction serum
level) have to be checked on a regular base. The combination of phenytoin and leveti-
When, after wearing off of propofol (and possibly midazolam), the SE persists (clinically or on
the eeg), again a burst suppression coma will be induced with pentobarbital. Before pento-
barbital is started, serum levels of anti-epileptic drugs are checked and, if necessary doses
Pentobarbital, loading dose 10 mg/kg in 30 minutes, followed by 5 mg/kg/hour for 3
hours. Maintenance dose is adjusted on the results on eeg or neurotrack system re-
After achievement of burst-suppression coma, pentobarbital is continued for 72 hours. Then
the administration of pentobarbital is discontinued. During treatment with pentobarbital, se-
rum levels of anti-epileptic drugs must be checked again, because enzyme induction can
result in subtherapeutic serum levels. At the end of the treatment, a pentobarbital serum level
can be used to predict the moment pentobarbital does no longer influence neurological in-
When, after wearing off of pentobarbital, the SE persists (either clinically or on eeg) despite
treatment with a benzodiazepine and 2 anti-epileptic drugs (with therapeutic doses and/or
serum levels), the decision to continue or withdraw supportive treatment is left to the treating
If the treatment was successful, the serum levels of anti-epileptic drugs must be checked 48
hours after wearing off of pentobarbital, to prevent toxic serum levels (no more enzyme in-
Neurological outcome will be assessed with the Glasgow Outcome Scale (GOS, see appen-
dix II), a five point scale. Poor outcome will be defined as dead, persistent vegetative state or
Secondary outcome measurements: GOS 1 month after CPR, disappearance of status epi-
lepticus on the eeg after burst-suppression coma, prognostic value of eeg characteristics
Patient characteristics (gender, age at admission), resuscitation characteristics (date CPR,
presenting rhythm, time to return of spontaneous circulation), duration of hypothermia treat-
ment, date and time assessment of status epilepticus, eeg results, administered medication
(name, dose), serum levels of medication, GOS at 1 and 6 months after CPR.
4.6) Statistical analysis and power calculation
In the PROPAC study (2), a status epilepticus (clinically or neurophysiologically) was found
in 9 patients (total group size: 407 patients), all patients died. This indicates a poor outcome
of 100% 6 months after resuscitation. Rossetti et al. reported a poor outcome of 97% in 35
patients with a status epilepticus after resuscitation on eeg.
In this study, the effect of treatment will be evaluated after inclusion of 30 patients and every
10 included patients thereafter. Treatment in accordance with this study protocol might lead
to an increase in ICU length of stay and it is possible that the number of patients with a good
neurological outcome does not increase substantially. Therefore, the effectiveness of treat-
ment in accordance with this protocol will have to be evaluated regularly in order to prevent
unnecessary treatment of these patients.
(1) Horn J, Zandbergen EGJ, Koelman JHTM, Hijdra A. Bepalen van de prognose van een coma na
reanimatie. Ned Tijdschr Geneeskd 2008;152(6):308-13.
(2) Zandbergen EGJ, Hijdra A, Koelman JHTM, et al. Prediction of poor outcome within the first 3 days
of postanoxic coma. Neurology 2006;66:62-8.
(3) Rossetti AO, Logroscino G, Liaudet L, et al. Status epilepticus: an independent outcome predictor
after cerebral anoxia. Neurology 2007 Jul 17;69(3):255-60.
(4) Rossetti AO, Reichhart MD, Schaller MD, Despland PA, Bogousslavsky J. Propofol treatment of
refractory status epilepticus: a study of 31 episodes. Epilepsia 2004 Jul;45(7):757-63.
(5) Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized con-
vulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med
(6) Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus.
(7) Nederlandse Vereniging voor Neurologie, Nederlandse Liga tegen Epilepsie. Epilepsie, richtlijnen
voor diagnostiek en behandeling. www.neurologie.nl 2006.
(8) Agarwal P, Kumar N, Chandra R, et al. Randomized study of intravenous valproate and phenytoin
in status epilepticus. Seizure 2007 Sep;16(6):527-32.
(9) Knake S, Gruener J, Hattemer K, et al. Intravenous levetiracetam in the treatment of benzodi-
azepine refractory status epilepticus. J Neurol Neurosurg Psychiatry 2008 May;79(5):588-9.
Appendix I: Flowchart treatment
Report patient to trial bureau IC AMC when
1) it has been decided to initiate treat-
Start treatment: benzodiazepine + phenytoin (+ loading dose)
Continue phenytoin and benzodiazepine; check serum levels
When there is no burst-suppression with maxi-
mum dose of propofol (8 mg/kg/hour), start mi-
Continue both anti-epileptic drugs and benzo-
Check serum levels of anti-epileptic drugs before start pentobarbital Adjust dose if necessary
Start pentobarbital for induction of burst-suppression on eeg (72 hours) and continue anti-epileptic drugs + benzodiazepine
Check serum levels of anti-epileptic drugs 48 hours after start pentobarbi-tal Adjust dose if necessary
Continue both anti-epileptic drugs and benzo-
diazepine; check serum levels 48 hours after
Discuss poor prognosis with family and decide on further treatment
Appendix II: Glasgow Outcome Scale
(follows commands, but unable to live independently)
(able to live without help, but can not return to work of school)
(able to resume activities of daily life as before admission)
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