Seizures & status epilepticus in the intensive care

Seizures & Status Epilepticus
in the Intensive Care Unit
Dr. Kaveh Kazemian.
Pharm-D.
Board Certified of Clinical Pharmacy
Fellowship of Critical Care Pharmacotherapy

 Persistent seizures and failure to regain consciousness following
witnessed seizure activity require emergency neurological
consultation. Although outcome is largely dependent on underlying
cause, early maximal anticonvulsant therapy is critical to reducing
morbidity.
Dr. Kaveh Kazemian. Pharm-D. BCCP. Pharmacotherapy FCCM assistant 2

• Reported risk of seizures as a complication or as the principal reason
for ICU admission is 3.3%, although the actual incidence is likely to
be significantly higher
• The primary cause of seizures in the ICU:
Antiepileptic drug (AED) withdrawal
Alcohol withdrawal
• (Stroke, Anoxic brain injury, Central nervous system infection, Head trauma, Sepsis, Metabolic
disorders)

• Status epilepticus in the critically ill patient is most often caused by
the acute illness in patients who did not previously have seizures
• Non-convulsive status epilepticus 8 to 34% of neurological ICU
patients in comatose states

• In elderly populations, the mortality from nonconvulsive status
epilepticus is as high as 57%.

 Hypersynchronous paroxysmal cortical discharges of neurons that
interfere with normal function
 Single or recurrent
 Status epilepticus : Continuous state of seizures or multiple seizures,
without return to baseline for at least 30 minutes
Dr. Kaveh Kazemian. Pharm-D. BCCP. Pharmacotherapy FCCM assistant
DEFINITIONS
10

 Generalized status epilepticus :
 Generalized convulsive status epilepticus
 Tonic clonic status epilepticus (grand mal status epilepticus)
 Tonic status epilepticus
 Clonic status epilepticus or myoclonic status epilepticus
 Nonconvulsive status epilepticus

 Partial status epilepticus :
 Simple partial status epilepticus either motor (epilepsia partialis
continua), sensory, or aphasic
 Complex partial status epilepticus.

 Nonconvulsive status epilepticus based on EEG criteria:
(1) Generalized nonconvulsive status epilepticus
(2) Focal nonconvulsive status epilepticus

 Clinical patterns of nonconvulsive status epilepticus
 In ambulatory patients with confusion
 In patients with coma or stupor

 Toxic, metabolic, infectious encephalopathies
 Benzodiazepine withdrawal, encephalopathy, lithium toxicity, and
psychogenic states.
 Serotonin syndrome, neuroleptic malignant syndrome, and tiagabine
encephalopathy.
All of these can be differentiated from nonconvulsive status epilepticus with the help of EEG.

• Nonconvulsive status epilepticus should be considered
In elderly patients + major irreversible brain injury, after sudden
withdrawal of AEDs, after sudden withdrawal of benzodiazepines or
propofol

• Nonconvulsive status epilepticus typically presents as an
(Ictal impairment of cognition, subtle facial or limb twitches, eyes-open mutism, head or eye
deviation, automatisms, and behavioral change)
• In the elderly, diagnosis is often delayed and mistaken for delirium,
stupor, or other causes of confusion

• Typical clinical features :
Mutism
Agitation
Emotional lability
Aggressiveness
Hallucinosis with face, eye, and limb myoclonus

Factors reducing the seizure threshold:
 Multisystem organ dysfunction
 Metabolic abnormalities
 Sedatives and paralytics
 Therapeutic drugs that lower the seizure threshold
MANAGEMENT
20

• Up to 83% of patients successfully treated for convulsive status
epilepticus and 100% treated for nonconvulsive status epilepticus
remain comatose 12 hours after initiation of therapy
• Between 25 and 42% of patients presenting with status epilepticus
have nonconvulsive status epilepticus, which would otherwise have
been missed without EEG

• Only half of patients had the first seizure within the first hour of
recording and only 80% had their first seizure by 24 hours.
• It is recommended to provide at least 48 hours of EEG in comatose
patients in whom seizures may be contributing to altered mental status

• cEEG is instrumental in the diagnosis and management of
nonconvulsive seizures and status epilepticus, detection of cerebral
ischemia, prognostication of outcomes after cardiorespiratory arrest,
and evaluation of abnormal movements and altered mental status

Indication of cEEG:
I. After seizures, if impaired consciousness persists after initial
treatment
II. In cases of unexplained alteration of mental status without known
acute brain injury
III. When specific EEG patterns are recognized on routine recording:
generalized periodic discharges (GPDs), lateralized periodic
discharges (LPDs), or BIPDs (bilateral independent periodic
discharges)
IV. In comatose patients after acute brain injury
V. When neuromuscular blocking drugs (NMBD) are used in high risk
patients

• Recording for at least 24 h is recommended
• About 80–95% of patients with non-convulsive seizures can be
identified within 24–48 h
• In case of absence of epileptiform abnormalities during the first 15
min recording, the 72-h seizure probability was less than 10%, and
less than 5% if no abnormality was present during the first 2 h
recording
Duration of cEEG Monitoring
25

• EEG is very sensitive in detecting changes in cerebral blood flow
• DCI after SAH in 20–30% of cases
• EEG is able to detect electrical changes before structural damage occurs
• 10% reduction in the alpha-delta power ratio, lasting 6 h, had a sensitivity
of 100% for DCI, with a specificity of 76%
• 50% decrements in the alpha-delta ratio for 2 h , 89% sensitivity and 84%
specificity
• EEG changes appearing before ischemia were identified in around 70% of
cases ( 5 to 60 h ).
Diagnosis of Ischemia

• Prognostic evaluation in comatose patients for sleep architecture, the
presence of a sleep/awake cycle, reactivity to external stimuli, and
detection of epileptiform changes
• Absence of EEG reactivity to external stimuli and the presence of
burst-suppression or status epilepticus at 72 h after cardiac arrest
significantly predict poor outcome, defined as severe neurological
disability, persistent vegetative state or death

• Claassen et al. reported that outcome was poor in all patients with
absent EEG reactivity, GPDs, or BIPDs, and in 92% of patients with
NCSE

• Administration of effective AEDs within 5 to 10 minutes has been
shown to be essential to prevent the emergence of status epilepticus
and its associated neuronal damage and permanent cerebral injury
• The efficacy of AEDs is highest (80% response rate) when treatment is
initiated within 30 minutes, and their effectiveness declines
progressively as treatment is increasingly delayed
• Early treatment of seizures is associated with better outcomes

Treatment algorithm
30

• Failure of first and second-line anticonvulsant agents to terminate
status
• Should lead to the use of definitive infusion therapy in general
anesthetic doses in association with endotracheal intubation
• Only 7% of patients will respond to a loading dose of a third agent
• Refractory status epilepticus develops in 31 to 44% of all patients with
status epilepticus
Refractory Convulsive Status Epilepticus
32

• Midazolam, propofol, and pentobarbital are most frequently used
• Alternatives : ketamine, thiopental, and isoflurane, other halogenated
hydrocarbon anesthetic gases
• Intubation for patients with generalized convulsive status epilepticus
usually requires neuromuscular blockade.
(rocuronium bromide or vecuronium is preferred over succinylcholine chloride)

• Sudden unexpected death in epilepsy rarely occurs and is thought to be
due to sympathetically mediated cardiac arrhythmias
• Hypoxemia secondary to apnea, airway obstruction, aspiration or
neurogenic pulmonary edema is common, and most patients will
require intubation after large doses of benzodiazepines

• Resistance to anticonvulsants follows a similar time-dependent course
• After the first 30 minutes of status epilepticus, the potency of
benzodiazepines decreases 20 times, whereas phenytoin potency
decreases more slowly
• In established self-sustaining status epilepticus, seizures can only be
terminated by a few agents that mostly inhibit glutamatergic
transmission such as ketamine

• N-methyl-D-aspartic acid blockers are not effective in the initial 10 to
15 minutes of seizures, but become more effective later in the course
of status epilepticus
• Pathophysiologically, the transition from seizures to status epilepticus
is associated with endocytosis and a decrease in functional
hippocampal GABAA receptors

• Recruitment of N-methyl-D-aspartic acid receptor subunits occurs
from subsynaptic sites to the synaptic membrane enhancing the
proconvulsant state and possibly explaining the improved potency of
N-methyl-Daspartate(NMDA) blockers late in the course of status
epilepticus

• It would seem optimal to choose AEDs initially with potent GABAA
receptor activity and then add an agent with NMDA antagonism if
seizures become refractory

• GABAA agonist, is shorter acting than barbiturates with less hypotension than either
barbiturates or propofol and is a reasonable first choice
• usually terminating status epilepticus in less than 1 hour.
• Doses typically range from 0.1 to 0.4 mg/kg/h after a loading dose of 0.2 mg/kg IV.
• The initial half-life is 1.5 to 3.5 hours
• with prolonged use, persistent escalation of dose is needed due to tolerance and
tachyphylaxis and the half-life increases up to several days.
• The EEG cannot be fully suppressed with midazolam
Midazolam
39

• Rapid onset of action of <3 minutes
• short half-life (1 to 2 hours after prolonged administration)
• It activates GABAA receptors directly, inhibits the NMDA receptor, and
modulates calcium influx
• It reduces cerebral blood flow and intracranial pressure (ICP), is a potent
antioxidant, and has antiinflammatory and immunomodulatory activity.
• loading dose : 2 mg/kg then infusion 2 to 10 mg/kg/h.
• Vasopressors are usually required to maintain adequate blood pressure.
propofol
40

• It is reasonable to wean off propofol after 24 hours of successful
seizure control
• Propofol should be weaned slowly with continuous EEG monitoring
as both induction and withdrawal of propofol has been associated with
seizures.

 Propofol infusion syndrome :
Acute refractory bradycardia leading to asystole, in the presence of
one or more of the following:
( metabolic acidosis, rhabdomyolysis, hyperlipidemia, and
enlarged or fatty liver )
 Risk factors : High dose (>4 mg/kg/h)
Administration of more than 48 hours duration
Hemodialysis is recommended if this syndrome is suspected.

• Act on GABAA receptors, NMDA antagonists and have an effect on calcium
channels
• Thiopental: loaded at 2 to 4 mg/kg and then infused at 3 to 5 mg/kg/h.
The half-life is 3 to 11 hours at serum levels <30 mg/L,
and up to 60 hours at higher serum concentrations.
• Pentobarbital: loaded repeatedly at 5 mg/kg until seizures stop and
then infused at a rate of 0.5 to 10 mg/kg/h.
With prolonged administration, the half-life (15 to 22
hours vs 14 to 36 hours).
Barbiturates
43

• Hypotension appears to be most profound with barbiturate therapy.
• Increased infection rates

• NMDA receptor antagonist with agonist effects at the GABAA
receptor and neuroprotective properties
• It appears to be more useful in controlling prolonged status epilepticus
(after 1 hour) as opposed to early status epilepticus
• Loading dose : 2 mg/kg then infusion of 10 to 50 mg/kg/min.
• The main hemodynamic effects are hypertension and tachycardia.
• Prolonged infusion may be associated with neurotoxicity (cerebellar
and cortical atrophy
Ketamine
45

 Lidocaine, inhalation anesthetics, and topiramate.
• Lidocaine:
Short half-life and low risk of central nervous system depression
respiratory depression.
Initial intravenous lidocaine dose ranges from 1 to 3 mg/kg
then maintenance infusion after termination of status epilepticus

• Isoflurane with or without desflurane:
Epileptic discharges are effectively stopped and burst
suppression rapidly achieved.
Rapid elimination and the reduced potential for toxic
effects on organs
• For any of the above infusions, patients should have continuous EEG
and close hemodynamic monitoring, and be mechanically ventilated

• Cortical and deep brain stimulation
• Vagal nerve stimulation
• Transcranial magnetic stimulation
• Electroconvulsive therapy
• Plasmapheresis
• Surgical resection
 Hypothermia to a target temperature of 31° to 35° using an endovascular
cooling system
Non-pharmacological and Experimental Therapies
for Status Epilepticus
48

• Two large American studies and one large French study all had similar overall
mortality after status epilepticus of 21 to 22%.125–127 Prolonged status
epilepticus (>60 minutes) was associated with a 30-day mortality rate of 32%,
compared with 2.7% in shorter duration status epilepticus (30 to 59 minutes).128
Nonconvulsive status epilepticus has a reported mortality of 18% when
associated with significant medical comorbidity. In a recent study of 140 adults
with status epilepticus, independent predictors of 30-day mortality were patient
age, initial Glasgow Coma Score (GCS), and seizure severity with continuous,
symptomatic and refractory seizures having the worst prognosis.127 Refractory
status epilepticus is associated with encephalitis and not with insufficient levels
of AEDS.129 Alcohol and drug withdrawal-related status epilepticus has a better
prognosis than etiologies associated with structural brain injury, such as anoxic
brain injury, vascular lesions, and brain tumors, which are all associated with
poorer outcomes.124 Progression to chronic epilepsy occurs in up to 90% of
patients with status epilepticus and develops significantly more often following
refractory status epilepticus.

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