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Seizures and status epilepticus (SE) in the intensive care setting can be
seen in two main groups of patients: patients admitted to the ICU because
of continuous or repetitive seizures requiring aggressive treatment and pa-
tients admitted for medical or surgical reasons who develop seizures during
the course of their ICU stay. This article discusses new concepts of seizures
and SE in the adult ICU, including nonconvulsive seizures. First, SE epide-
miology, definition, classification, etiologies, diagnosis, and prognosis are
briefly reviewed. Systemic and neurologic effects of seizures and SE are dis-
cussed. Finally, the authors propose strategic therapeutic steps and focus on
the treatment of seizures and SE in patients with specific organ failures or
after organ transplantation.
* Corresponding author.
E-mail address: ljh3@columbia.edu (L.J. Hirsch).
0749-0704/07/$ - see front matter ! 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2006.06.004 criticalcare.theclinics.com
638 ABOU KHALED & HIRSCH
Etiologies
Seizures in the ICU can arise from various etiologies. Etiologies differ
among centers, patient population, and age. Box 1 summarizes these by cat-
egories. Lowenstein and Alldredge [6] evaluated 154 patients treated for
SEIZURES AND STATUS EPILEPTICUS 639
patients with NCSE, Towne and associates [7] identified hypoxia/anoxia as the
most frequent etiology (42%) followed by cerebrovascular accident (22%).
Treatment of the underlying cause may be crucial to managing seizures
successfully, especially when due to a toxic/metabolic origin. It is often dif-
ficult, however, to identify a single etiology because of the presence of mul-
tiple factors lowering the seizure threshold, including the acute medical or
neurologic process, medications, renal or hepatic failure, infection, fever,
hypoxia, metabolic abnormalities, or alkalosis. Because of this complexity,
it is difficult to define the incidence of drug-induced seizures in ICU patients.
Imipenem commonly is cited for its association with seizures. One study
found that imipenem use was associated with an increased risk for seizures,
but most of these occurred when the patient was not taking imipenem [8].
This finding highlighted the possibility that imipenem was a confounding
variable, a marker of severity of illness and infection, rather than a contrib-
utor to the seizures. Box 2 lists the major categories of medications that have
been incriminated in contributing to seizures.
Diagnosis
NCSE is underdiagnosed. It can present in many ways, including
mild personality changes, lethargy, agitation, blinking, confusion, facial
SEIZURES AND STATUS EPILEPTICUS 641
Prognosis
The overall mortality after SE is similar in the two largest known US
studies: 21% in Rochester, Minnesota [15], and 22% in Richmond, Virginia
[16] (but higher in the elderly population, 38% [17]).Towne and colleagues
[18] reported 1-month outcome of 253 adult patients with SE and showed
that the mortality rate of patients with prolonged SE (O60 minutes) was
32% compared with 2.7% in patients whose SE was 30 to 59 minutes. Mor-
tality was increased in patients older than 70 years of age. Conflicting data
exist regarding mortality and morbidity of NCSE, depending primarily on
patient selection. The highest reported mortality rates have been 52%
[7,19]. Shneker and Fountain [20] found that 18% of patients with NCSE
died. Patients in the acute medical group (defined as acute neurologic or sys-
temic problems or both) had significantly higher mortality rates (27%) than
patients in the cryptogenic (18%) or epilepsy (3%) group. Worse outcome
also was associated with severely impaired mental status.
! Systemic blood pressure increases early in SE, but tends to fall to normal
or below normal later in GCSE.
! Cardiac arrhythmias can be life-threatening in SE. Boggs and associates
[34] reported specific electrocardiogram (ECG) abnormalities not pres-
ent at baseline, including in 58.3% of patients in SE. The most fre-
quently observed abnormalities were ischemic changes. They also found
that patients with ECG abnormalities had a higher mortality (37%
versus 12% in patients without ECG changes). Excessive endogenous
epinephrine release has been implicated in cardiac contraction band
necrosis. Manno and colleagues [35] reviewed the cardiac pathologic
slides of 11 patients who died during an episode of SE and found
contraction band necrosis in 8 of them compared with 5 of 22 control
patients (P ! .05).
! Pulmonary arterial pressures increase in SE, and pulmonary edema
might occur in the setting of sympathetic hyperactivity [32].
! Blood chemistry changes observed in SE include the following:
! Severe metabolic acidosis may be seen secondary to excess anaerobic
metabolic activity.
! Hyperkalemia may be seen secondary to acidosis and muscle necrosis.
! Hyperglycemia resulting from increased catecholamines, but with pro-
longed SE increased insulin secretion may result in hypoglycemia,
! Increased creatine kinase levels resulting from rhabdomyolysis can be
seen after prolonged convulsions and might lead to acute renal failure.
! Increased prolactin level 10 to 20 minutes after a suspected event has
been documented to be useful in differentiating epileptic from nonepi-
leptic convulsions, but there is no evidence of the level being useful in
SE [36].
! Leukocytosis from demargination but should not be attributed to SE,
unless infectious etiologies are ruled out.
! In a series of 138 patients who had cerebrospinal fluid analysis during
SE, Barry and Hauser [37] found that 22.5% had abnormal cerebrospi-
nal fluid white blood cell count or differential. The highest white blood
cell count in patients with no acute insult was 28 " 106/L. A mild tran-
sient increase in protein content also may be observed, possibly reflect-
ing breakdown of the blood-brain barrier [38].
Pharmacologic therapy
Early initiation of therapeutic intervention is much more important than
the choice of agent used. Mazarati and colleagues [39] showed in animal ex-
periments that the efficacy of phenytoin decreased dramatically with time,
and proposed that the failure of diazepam and phenytoin to abort self-sus-
taining SE during its maintenance phase implies that ‘‘seizures evolve certain
mechanisms that cause refractoriness to antiepileptic drugs.’’ Although phe-
nytoin and benzodiazepines become less effective, glutamate antagonists,
such as ketamine (an N-methyl-D-aspartate [NMDA] antagonist), are inef-
fective initially, but become effective in later stages in animals. In humans,
intervention within the first 30 minutes of seizure onset was associated
with 80% response to first-line drugs. The response rate declined with longer
intervals such that more than 60% of the patients who were in SE for more
than 2 hours before initiation of treatment failed to respond to the first-line
treatment [6]. AEDs should be selected in consideration of the patients’
prior history, medications, allergies, hemodynamic status, and hepatic and
renal function and the physician’s experience and preference.
Only a few randomized controlled trials have compared treatment strat-
egies in SE. The most important one was the VA Status Epilepticus Coop-
erative Study [5], which compared the efficacy of four drugs for the
treatment of GCSE. A total of 518 patients were randomly assigned to
SEIZURES AND STATUS EPILEPTICUS 645
Table 1
Status epilepticus d adult treatment protocola
Time min Action
0–5 Diagnose; give O2; ABCs; obtain IV access; begin ECG monitoring; draw blood
for Chem-7, magnesium, calcium, phosphate, CBC, LFTs, AED levels, ABG,
troponin; toxicology screen (urine and blood)
6–10 Thiamine 100 mg IV; 50 mL of D50 IV unless adequate glucose known.
Lorazepam 4 mg IV over 2 min; if still seizing, repeat X 1 in 5 min. If no rapid IV
access, give diazepam 20 mg PR or midazolam 10 mg intranasally, buccally
or IMb.
10–20 If seizures persist, begin fosphenytoin 20 mg/kg IV at 150 mg/min, with blood
pressure and ECG monitoring. This step can be skipped initially, especially if
proceeding to midazolam or propofol, or can be performed simultaneously with
the next step; if done simultaneously, administration rate can be slowed
10–60 If seizures persist, give one of the following (intubation necessary except for
valproate):
CIV midazolam: Load: 0.2 mg/kg; repeat 0.2–0.4 mg/kg boluses every 5 min until
seizures stop, up to a maximum total loading dose of 2 mg/kg. Initial CIV rate:
0.1 mg/kg/h. CIV dose range: 0.05–2.9 mg/kg/h, titrate to EEG seizure control
or burst suppression. If still seizing, add or switch to propofol or pentobarbital.
or
CIV propofol: Load: 1–2 mg/kg; repeat 1–2 mg/kg boluses every 3–5 min until
seizures stop, up to maximum total loading dose of 10 mg/kg. Initial CIV rate:
2 mg/kg/h. CIV dose range: 1–15 mg/kg/h, titrate to EEG seizure control or
burst suppression. If still seizing, add or switch to midazolam or pentobarbital.
Avoid using O5 mg/kg/h for multiple days to minimize risk of propofol
infusion syndrome. Follow CPK, triglycerides, acid-base status closely.
or
IV valproate: 30–40 mg/kg over w10 min. If still seizing, additional 20 mg/kg
over w5 min. If still seizing, add or switch to CIV midazolam or propofol.
or
IV phenobarbital: 20 mg/kg IV at 50–100 mg/min. If still seizing, add or switch to
CIV midazolam, propofol, or pentobarbital.
O60 CIV pentobarbital. Load: 5 mg/kg up to 50 mg/min; repeat 5 mg/kg boluses until
seizures stop. Initial CIV rate: 1 mg/kg/h. CIV-dose range: 0.5–10 mg/kg/h;
traditionally titrated to suppression-burst on EEG, but titrating to seizure
suppression is reasonable as well
Begin EEG monitoring ASAP if patient does not rapidly awaken or if any CIV
treatment is used.
Abbreviations: CIV, continuous intravenous; ABCs, stabilize airway, breathing and circula-
tion; ASAP, as soon as possible.
a
Columbia University Comprehensive Epilepsy Center, 2006.
b
The IV solution of diazepam can be given rectally if Diastat is not available; the IV solu-
tion of midazolam can be given by any of these routes.
Courtesy of the Columbia University Comprehensive Epilepsy Center, New York, NY.
EEG with or without subtle movements). In patients with ‘‘overt status,’’ in-
travenous lorazepam was most effective. It stopped SE in 65% of the cases;
phenobarbital, 58%; diazepam plus phenytoin, 56%; and phenytoin alone,
44%. The only statistically significant differences were between phenytoin
alone and lorazepam. Hypotension requiring treatment occurred more often
in patients with subtle SE, but there were no differences between the medi-
cations. Overall mortality was twice as high for patients whose SE was not
controlled with the first drug as for patients who had successful response to
the first regimen. In the VA cooperative study, patients who failed the first
treatment rarely responded to the second (7%) or third (2.3%), raising the
question of the efficacy of a second and third drug [5,40].
Lorazepam has many advantages over other drugs. It can be given
quickly and has a duration of antiseizure effect of 12 to 24 hours [41]. Lep-
pik and colleagues [41] compared lorazepam with diazepam for the treat-
ment of SE in 78 patients enrolled in a double-blind, randomized trial.
Time of onset of the two drugs was almost the same. Seizures were con-
trolled in 89% of the episodes treated with lorazepam and in 76% treated
with diazepam. These results, combined with the more recent and more de-
finitive VA cooperative study, have led to intravenous lorazepam (0.1 mg/kg)
becoming a clear drug of choice for initial treatment of SE.
No randomized controlled studies have been conducted for second-line
therapy, but phenytoin or fosphenytoin is the most frequently recommended
agent [9,42]. A loading dose of 18 to 20 mg/kg intravenously is recommen-
ded. Phenytoin solution is highly caustic to veins and may cause tissue ne-
crosis in case of extravasation, limiting the rate of administration to
a maximum of 50 mg/min. Fast administration carries the risk of hypoten-
sion and cardiac arrhythmias and requires close monitoring of blood pres-
sure and ECG. Fosphenytoin sodium is a phenytoin prodrug, preferred
over phenytoin because of its water solubility, allowing faster administra-
tion with less risk of venous irritation. It is rapidly dephosphorylated in
the bloodstream to phenytoin, with a half-life of 10 to 15 minutes, reaching
therapeutic free phenytoin levels slightly faster than intravenous phenytoin.
Cardiac complications and hypotension still can occur with fosphenytoin
(owing to the phenytoin).
Free phenytoin levels should be monitored with a goal of 1.5 to 2.5 mg/
mL, which is equivalent to a total phenytoin level of 15 to 25 mg/mL in
the presence of normal protein binding [9]. Free levels may be excessively
high in the presence of low albumin or coadministration of highly protein
bound drugs (eg, valproic acid [VPA]), and this may confuse the clinical pre-
sentation by worsening encephalopathy or paradoxically exacerbating sei-
zures. Another common problem in ICU patients who are receiving
parenteral nutrition is decreased enteral phenytoin absorption and blood
levels after conversion of intravenous phenytoin to oral phenytoin with sub-
sequent poor seizure control. In a study by Bauer [43], phenytoin serum
levels decreased an average of 71.6% when parenteral nutrition was given
SEIZURES AND STATUS EPILEPTICUS 647
Barbiturates
Barbiturates are direct GABA agonists. Effects of barbiturates include
cerebral and respiratory depression, myocardial depression, vasodilation,
hypotension, and ileus. Administration of continuous intravenous barbitu-
rates requires support with mechanical ventilation, intravenous fluids and
vasopressors, and continuous EEG monitoring (or frequent prolonged
checks if continuous EEG is unavailable) to identify breakthrough seizures
and to assess the level of suppression.
Thiopental is one the most preferred drugs for treating SE in the ICU in
the United Kingdom after failure of the initial treatment [51]. The recom-
mended dose is 2 to 4 mg/kg bolus, followed by infusion of 3 to 5 mg/kg/h,
although higher doses commonly are used. Thiopental is metabolized by the
liver and should be withdrawn slowly 24 hours after resolution of electro-
graphic seizures. At serum levels less than 30 mg/L, the elimination half-
life is 3 to 11 hours, but this may increase to 60 hours with higher serum
levels and result in a prolonged recovery time.
Pentobarbital has a slower action than thiopental, but cerebral concen-
trations are maintained longer. The loading dose is 5 mg/kg and should
be repeated until seizures stop, with a maximum bolus rate of 25 to
50 mg/min. Infusion rates are 0.5 to 10 mg/kg/h, traditionally titrated to
burst suppression on EEG. In some patients, seizures still can occur from
a suppression-burst background, and in other patients seizures are fully
controlled without reaching suppression burst. The half-life is 20–30 hours.
On drug withdrawal, seizures may recur. Although not clearly investigated,
several paroxysmal or periodic patterns on the ictal-interictal continuum
SEIZURES AND STATUS EPILEPTICUS 649
Benzodiazepines
Midazolam, which also acts on the GABA-A receptor, is increasingly
used as an alternative to intravenous barbiturates because it is shorter acting
and causes fewer hemodynamic disturbances. The recommended loading
dose is 0.2 mg/kg, and boluses should be repeated every 5 minutes until sei-
zures stop, up to a maximum total loading dose of 2 to 3 mg/kg. The initial
rate is 0.1 mg/kg/h with a continuous dose range of 0.05 to 2.9 mg/kg/h (this
is higher than in older literature, and even higher doses are occasionally
used). The elimination half-life is 1.5 to 3.5 hours initially; with prolonged
use, there may be tolerance, tachyphylaxis, and significant prolongation of
half-life, up to days. Naritoku and Sinha [52] reported slow clearance of
midazolam in two patients after several days of continuous therapy, proba-
bly related to accumulation of midazolam in peripheral compartments
(adipose tissue) with subsequent redistribution back to the central compart-
ment. The time to stop SE is usually less than 1 hour with a duration of
effect lasting minutes to hours. Respiratory depression and hypotension are
common side effects.
Propofol
Also a GABA-A receptor agonist, propofol has a rapid onset of action of
less than 3 minutes, quick redistribution into body compartments, and easy
reversibility, which has led to widespread use for the sedation of critically ill
patients. The recommended dose for SE is a bolus of 1 to 2 mg/kg, followed
by a continuous infusion of 1 to 15 mg/kg/h with a recommended maximum
dosage of 5 mg/kg/h if used for any length of time There is no consensus
regarding total duration of induced coma when seizures are controlled,
but 12 to 24 hours seems to be the most commonly used duration. Side ef-
fects include respiratory depression, hypotension, bradycardia, and the
more recently recognized ‘‘propofol infusion syndrome,’’ consisting of met-
abolic acidosis, cardiac failure, rhabdomyolysis, hypotension, and death. In
2001, the US Food and Drug Administration communicated that pediatric
ICU patients given propofol for sedation had higher death rates that pa-
tients who received other standard anesthetic agents. In recent years, case
reports regarding propofol infusion syndrome in adults also have emerged.
Risk factors were mostly prolonged infusion (O48 hours), high doses
(O5mg/kg/h) [53,54], severe head injury [55], lean mass, and concurrent
use of catecholamines or steroids [54]. It has been suggested that concomi-
tant use of propofol with catecholamines may precipitate this syndrome.
Cray [56] proposed that either propofol or its lipid soluent affects cellular
metabolism, causing a biochemical break in the respiratory chain that leads
to lactic acidosis and multiple organ dysfunction. It is prudent to avoid
650 ABOU KHALED & HIRSCH
prolonged use of propofol (O48 hours) at higher doses (O5 mg/kg/h), and
once used, the authors recommend close monitoring of creatine kinase and
lactic acid. Rossetti and colleagues [57] used concomitant intravenous clona-
zepam and propofol at the lowest effective dose. In their group of 31 pa-
tients with refractory SE, none had evidence of propofol infusion
syndrome, and only one had isolated hyperlipidemia. Overall mortality
was 22%, which is low for patients with refractory SE, and there were no
neurologic sequelae in 20 of the 25 patients who survived. This was the first
published series of SE patients treated with propofol who did not have very
high mortality.
in 3 (15%) and 10 (45%) patients of the treated and control groups, respec-
tively. Autopsy examinations available in 19 patients showed signs of cere-
bral edema in only 22% of the phenytoin-treated patients compared with
70% of the controls (P ! .033). This study emphasizes the importance of
continuous brain monitoring in the critically ill as outlined earlier, although
we recommend performing EEG with a full set of electrodes to allow accu-
rate diagnosis and differentiation of seizures from other patterns, such as tri-
phasic waves, artifact, and high-voltage slowing. Even with a full set of
electrodes and board-certified epilepsy specialists, this differentiation can
be challenging or impossible [31,75–77].
The overall therapeutic approach of seizures and SE in these patients
does not differ from others except that special considerations should be
made with use of AEDs metabolized by the liver. The degree of hepatic fail-
ure might affect the AEDs’ metabolism; in early hepatitis, there may be in-
creased blood flow to the liver with relatively normal hepatic function,
a situation that may increase hepatic clearance of the drugs. In more
advanced hepatic failure with necrosis, hepatocellular tissue decreases, and
serum levels of drugs cleared by the liver may increase [78]. Hypoalbumine-
mia, also encountered in malnutrition and infectious, renal, or neoplastic
diseases, can lead to increased free blood levels of some AEDs that are
highly bound to protein, such as phenytoin and VPA. Monitoring free levels
of these drugs, especially phenytoin, avoids toxicity (which can include
worsening encephalopathy and myoclonus). Other AEDs favored in this sit-
uation would be drugs with low or no protein binding effect or with primar-
ily renal metabolism, such as gabapentin, pregabalin, and levetiracetam. To
this date, these drugs are available only in the oral form, but an intravenous
form of levetiracetam is expected to be available soon. In a study in animal
models, Gibbs and associates [79] showed that levetiracetam has neuropro-
tective effect against mitochondrial dysfunction and oxidative stress seen
after SE. This effect also has been reported with topiramate [61,80], but
further studies are needed for both of these agents.
Table 2
Seizures after transplantation
Organ transplanted Incidence of seizures (%)
Liver 25 [86]–30 [87]
Kidney 1 [94]–5 [95]–31 [96]
Heart 2 [97,98]–6.5 [99]–15 [100]
Lung 22 [101]–27 [102]
Bone marrow 3 [103]–7.5 [104]–12.5 [105]
Pancreas 13 [106]
654 ABOU KHALED & HIRSCH
Summary
Seizures occur in critically ill patients in variable conditions. In all situa-
tions, it is crucial to identify potential causes or contributors, particularly
reversible factors, such as metabolic disturbances, fever, hypoxia, and med-
ications. For SE, it is imperative to begin treatment as soon as possible and
to treat until success is verified with EEG or the patient returns to normal
mental status.
Nonconvulsive seizures are underdiagnosed. Most seizures in critically ill
patients are nonconvulsive and can be detected only with EEG monitoring.
The authors recommend continuous EEG monitoring in critically ill pa-
tients with alteration of mental status, especially if there is concurrent acute
brain injury, prior epilepsy, a prior clinical seizure or SE, fluctuating mental
status, coma, abnormal eye movements, or subtle twitching. Nonconvulsive
SEIZURES AND STATUS EPILEPTICUS 655
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