Avances en el tratamiento del estado epil+®ptico en el paciente cr+¡tico (2007)

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Advances in the Management

of Seizures and Status Epilepticus

in Critically Ill Patients

Karine J. Abou Khaled, MD, Lawrence J. Hirsch, MD*

Comprehensive Epilepsy Center, Department of Neurology, Columbia University

Neurological Institute, 7th floor, 710 West 168th Street, New York, NY 10032, USA

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 eff ects 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.

Epidemiology and definition

SE remains a serious, life-threatening emergency. De Lorenzo and col-leagues [1] estimated that it aff ects 152,000 individuals in the United States

per year and causes 42,000 deaths. The first attempt to define SE was in

1962, when the tenth European conference on epileptology and clinical neu-

rophysiology defined SE as ‘‘a condition characterized by an epileptic

seizure which is so frequently repeated or so prolonged as to create a fixed

and lasting epileptic condition’’ [2]. The International Classification of Ep-

ileptic Seizures, along with a general consensus, described SE as any seizure

lasting more than 30 minutes or intermittent seizures from which the patient

did not regain consciousness lasting for more than 30 minutes [2]. The ratio-nale for choosing 30 minutes was based on the minimum duration thought

* Corresponding author.

E-mail address: [email protected] (L.J. Hirsch).

0749-0704/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.ccc.2006.06.004 criticalcare.theclinics.com

Crit Care Clin 22 (2007) 637–659

mailto:[email protected]

mailto:[email protected]



to result in neuronal injury in animal models. Bleck [3] defined SE as con-

tinuous or repeated seizures lasting more than 20 minutes. More recently,

Lowenstein and colleagues [4] suggested that defining SE based on the the-oretical onset of neuronal injury is of questionable value because of the com-

plexity of this relation in humans. They suggested that ‘‘we should not wait

10 minutes or longer before instituting a treatment protocol for SE’’ [4].

Treiman and coworkers [5] defined overt convulsive SE as two or more

generalized convulsions without full recovery of consciousness between

seizures, or continuous convulsive activity for more than 10 minutes. For

practical purposes, SE should be considered if a seizure persists more

than 5 minutes because very few single seizures last this long.

Classification of status epilepticus

In 1967, Gastaut [2] first distinguished two major types of SE based

exclusively on seizure semiology. The first type is generalized SE, which is

subdivided into two groups:

1. Generalized convulsive SE (GCSE) (tonic-clonic SE or grand mal SE,

tonic SE, clonic SE, myoclonic SE)

2. Nonconvulsive generalized SE, including petit mal status

The second type is partial SE, which is subdivided into two groups:

1. Simple partial SE (eg, somatomotor or aphasic SE)

2. Complex partial SE

Gastaut separately distinguished a unilateral SE, seen only in infants and

very young children, and erratic SE, seen in neonates.

There is no recent consensus on further classification of nonconvulsive

status epilepticus (NCSE). In clinical practice, it often is impossible to dif-

ferentiate between NCSE of generalized onset and NCSE of partial onsetwith bilateral spread. The authors divide SE into convulsive SE and

NCSE or subtle SE. The authors reserve the term absence SE for patients

with chronic primary or symptomatic generalized epilepsy. There are two

distinct clinical scenarios involving NCSE: that in ambulatory patients

with confusion who have a good prognosis and often respond quickly and

dramatically to treatment in the emergency department, and that in coma-

tose/stuporous patients who have a more guarded prognosis and rarely

awaken rapidly with treatment. The latter situation is discussed further in

this article.

Etiologies

Seizures in the ICU can arise from various etiologies. Etiologies diff er

among centers, patient population, and age. Box 1 summarizes these by cat-

egories. Lowenstein and Alldredge [6] evaluated 154 patients treated for

638 ABOU KHALED & HIRSCH



generalized SE, 93% of whom had an onset preceding hospital admission.

The two leading etiologies were anticonvulsant drug withdrawal/noncompli-

ance (almost all were noncompliant with their prescribed regimen) and alco-

hol-related. These results were similar to what was found by Aminoff andSimon [36]. Other etiologies included stroke, drug toxicities, central nervous

system infection, tumor, and metabolic etiologies. A remote neurologic

cause was found in 70% of the overt SE group and 34% of the subtle SE

group in the VA cooperative study [5]. In another study, the leading etiolo-

gies for adult SE cases were low antiepileptic drugs (AEDs) (34%) followed

by remote symptomatic events (25%) and stroke (22%) [1]. In a series of

Box 1. Etiologies of seizures in critically ill patients

Exacerbation of preexisting epilepsy AED withdrawal

Acute neurologic insult

Cerebrovascular disease: infarct, hemorrhage (including

subarachnoid, subdural, parenchymal, intraventricular),

vasculitis

Infection: meningitis, encephalitis, brain abscess

Head trauma

AnoxiaBrain tumors

Demyelinating disorders

Supratentorial neurosurgical procedure

Acute systemic insult

Electrolytes imbalances: hyponatremia, hypocalcemia,

hypomagnesemia, hypophosphatemia (especially in

alcoholics)

Hypoglycemia; hyperglycemia with hyperosmolar state; both

can cause focal seizures as wellVitamin deficiency: pyridoxine

Illicit drug use, especially cocaine

Toxins

Hypertensive encephalopathy/eclampsia/posterior reversible

encephalopathy syndrome

Hypotension

Organ failure: renal, hepatic

Multisystem illness such as systemic lupus erythematosus

Medications: side effects/toxicity (see Box 2), withdrawal(benzodiazepines, barbiturates)

Alcohol related

Systemic infection/sepsis

639SEIZURES AND STATUS EPILEPTICUS



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

Box 2. Medications associated with decreased seizure threshold

Antidepressants, mostly bupropion and maprotilineNeuroleptics, mostly phenothiazines and clozapine

Lithium

Baclofen

Withdrawal of AEDs

Phenytoin at supratherapeutic levels (including very high free

levels)

Theophylline

Analgesics: meperidine, fentanyl, and tramadol

Opioid withdrawalBenzodiazepine withdrawal

Barbiturate withdrawal

Antibiotics: b-lactams (cefazolin), carbapenems (imipenem),

quinolones, isoniazid (treat with vitamin B6), metronidazole

Antiarrhythmic medications: mexiletine, lidocaine, digoxin

Radiographic contrast agents

Immunomodulators: cyclosporine, tacrolimus, interferons

Chemotherapeutic agents: alkylating agents such as

chlorambucil and busulfan

Data from refs. [91–93].




twitching, automatisms, and coma [9,10]. Nonconvulsive seizures may con-

tinue even after clinical seizures have ceased. In the Richmond study, 14%

of patients who stopped seizing clinically showed persistent electrographicSE on electroencephalogram (EEG), and 48% had intermittent electro-

graphic seizures [11]. Nonconvulsive seizures have been reported in 34%

of neurologic ICU patients [12], 16% of severe head trauma patients [13],

and 8% of comatose patients who had no prior seizures or subtle clinical

evidence of seizures [7]. In the authors’ series of 570 consecutive inpatients

undergoing continuous EEG monitoring at Columbia, 110 (19%) had sei-

zures, and 101 of these 110 patients (92%) had purely nonconvulsive sei-

zures that could be detected only by EEG. Only half of these patients had

their first seizure within the first hour of recording; even a prolonged routineEEG would not have identified the nonconvulsive seizures in half the

patients. The authors concluded that 24 hours was a reasonable screen for

nonconvulsive seizures in noncomatose patients (95% of noncomatose

patients had their first seizure by 24 hours), but that 48 hours or more

may be needed in comatose patients (only 80% had their first seizure by

24 hours) [14].

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.

Sequelae of status epilepticus

Cerebral changes

Lothman and colleagues [21] developed and characterized the self-sus-

taining limbic SE electrogenic animal model using continuous hippocampal

stimulation. As SE progresses, the animals show fewer motor manifestations

despite ongoing electrographic seizure activity. Self-sustaining limbic SE

stops spontaneously after several hours, and the animals gradually recover




to normal alertness. Approximately 9 months later, they begin to have spon-

taneous recurrent partial seizures that persist for more than 1 year. This

model shows that acute SE can lead to long-term epilepsy.Recurrent spontaneous seizures are frequent sequelae of GCSE and are

present after induced SE in several animal models. What about sequelae

of recurrent seizures in humans? New markers, such as serum neuron-spe-

cific enolase (a glycolytic enzyme found primarily within neurons), are being

investigated as markers of neuronal injury. In the animal literature, neuron-

specific enolase correlates with the amount of histologic injury in rats after

lithium-pilocarpine–induced SE [22]. Elevated levels of serum neuron-spe-

cific enolase have been documented in patients after nonconvulsive SE, in-

cluding in cases without any radiographically demonstrable acute braininjury [23–26]. The subtype of SE that was associated with the highest serum

neuron-specific enolase levels was subclinical SE in critically ill patients [24].

These acute seizure-related changes also can be shown by diff erent mag-

netic resonance neuroimaging modalities. There are several reported cases of

SE with clear development of acute hippocampal swelling on MRI followed

by later hippocampal atrophy and abnormal signal, evidence of mesial tem-

poral sclerosis [27–29]. Pathologic and histologic changes also have been

shown. DeGiorgio and colleagues [30] used a case-control approach and

cell-density quantification to analyze changes in the hippocampus of fivepatients who died after GCSE. They found significant pyramidal cell loss

in these patients compared with a control group. Changes attributable

directly to the occurrence of GCSE are difficult to determine because path-

ologic alterations could have been present as a result of prior history of re-

petitive seizures or other acute processes. Chronic sequelae result from cell

loss or altered physiology or synaptic connectivity. Focal or diff use cortical

damage has been described. The latter accounts for general cognitive

changes, whereas hippocampal neuronal loss can explain the subsequent

deficits in memory that are sometimes seen [31].

Changes in systemic physiology

The first 30 minutes of GCSE are dominated by sympathetic overdrive,

probably mediated by increased circulating catecholamines, following which

physiologic changes begin to normalize or move in the opposite direction, as

a result of failure of homeostatic mechanisms [32]. The most important phys-

iologic perturbations are fever, blood pressure changes, cardiac arrhythmias,

pulmonary vascular pressure changes, and alterations in blood chemistries.

Fever is common secondary to sustained muscle activity. Clinicians

should be cautious in ruling out infection before attributing fever to

SE, especially if associated with increased white blood cells in blood

or cerebrospinal fluid. Meldrum and coworkers [33] found that in-

creased temperature correlated with severity of cerebral injury and

found that neuromuscular blockade prevented both.




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 controlpatients (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 diff erentiating 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 duringSE, Barry and Hauser [37] found that 22.5% had abnormal cerebrospi-

nal fluid white blood cell count or diff erential. The highest white blood

cell count in patients with no acute insult was 28 Â 106/L. A mild tran-

sient increase in protein content also may be observed, possibly reflect-

ing breakdown of the blood-brain barrier [38].

Treatment of acute seizures and status epilepticus

Management of SE should begin within 5 minutes of seizure activity orafter two seizures without full recovery in between. In the setting of acute

brain injury, treatment usually should be initiated after a single self-limited

seizure, at least for the short-term, and especially in patients with increased

intracranial pressure or patients in whom an episode of marked hyperten-

sion and tachycardia would be dangerous. General supportive measures

for seizures and SE are reviewed first. Subsequently, specific treatments




and choice of AEDs are reviewed. Treatment in special situations, including

organ failure and immunosuppression, conditions commonly encountered

in the ICU, also is addressed.

General supportive measures

General supportive measures begin with basic life support measures and

adequate monitoring of vital signs and ECG. A proposed timetable and

treatment protocol is represented in Table 1.

Blood pressure should be monitored closely, especially if seizures persist for

more than 30 minutes, at which point cerebral autoregulation starts to fail,

and cerebral perfusion becomes increasingly dependent on systemic blood

pressure. At this point, intravenous drugs, such as propofol, benzodiazepines,

and phenobarbital, frequently are introduced, and intravenous fluid resuscita-

tion and vasopressors may become necessary. Refractory GCSE and the use of

agents such as midazolam, propofol, and pentobarbital generally mandate se-

curing the airway and instituting mechanical ventilation.

The treatment should aim to correct all underlying potential causes and

stop the seizures simultaneously. In at least half of cases of SE, there is some

acute etiology that warrants attention. Depending on the clinical presenta-

tion, additional tests might be necessary when the patient is stabilized, in-

cluding lumbar puncture and head CT or MRI, to rule out acute

structural or potentially treatable etiologies.

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 certainmechanisms that cause refractoriness to antiepileptic drugs.’’ Although phe-

nytoin and benzodiazepines become less eff ective, glutamate antagonists,

such as ketamine (an N -methyl-D-aspartate [NMDA] antagonist), are inef-

fective initially, but become eff ective 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




receive phenobarbital (15 mg/kg), phenytoin (18 mg/kg), diazepam (0.15

mg/kg) plus phenytoin (18 mg/kg), or lorazepam (0.1 mg/kg). The first reg-

imen chosen was successful in 55.5% of patients with ‘‘overt status,’’ but

only 14.9% of patients with ‘‘subtle SE’’ (coma and ictal discharges on

Table 1

Status epilepticus d adult treatment protocola

Time min Action0–5 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 eff ective. It stopped SE in 65% of the cases;

phenobarbital, 58%; diazepam plus phenytoin, 56%; and phenytoin alone,44%. The only statistically significant diff erences were between phenytoin

alone and lorazepam. Hypotension requiring treatment occurred more often

in patients with subtle SE, but there were no diff erences 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 givenquickly and has a duration of antiseizure eff ect 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-linetherapy, 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 inthe 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




concurrently. This problem may be overcome if parenteral nutrition is with-

held temporarily before and after administration of oral phenytoin to these

patients.An alternative as second-line therapy is phenobarbital with a loading

dose of 15 to 20 mg/kg. Maximum rate is 50 to 100 mg/min. Recommended

serum levels in SE are greater than 30 mg/mL. It has a prolonged half-life in

adults ranging from 50 to 150 hours and is a powerful sedative that may

contribute to coma and mask the evolution of the neurologic examination

in critically ill patients. In addition, phenobarbital may cause respiratory de-

pression and hypotension via vasodilation and cardiac depression. The main

advantages are intravenous availability, prolonged eff ect, and good efficacy

in controlling SE.Interest in VPA for the treatment of SE has increased with the availability

of an intravenous formulation. It is highly bound to plasma protein, similar to

phenytoin, with similar caveats about its use. It diff ers from older generation

AEDs in being an enzyme inhibitor, rather than inducer; one must be vigilant

for increased levels or eff ect of concomitant P-450-metabolized medications.

There is a dramatic fall of its level after addition of antibiotics such as mero-

penem or amikacin, possibly owing to accelerated renal excretion [44].

Valproate has broad-spectrum activity against all types of seizures, in-

cluding postanoxic myoclonus. A major advantage is not causing sedationor hypotension, which renders it a drug of choice in patients with a ‘‘do

not intubate’’ status or phenytoin allergy (although it has not been approved

for use in SE). Intravenous VPA has been used in open-label studies with

approximately 80% seizure control [45,46]. Giroud and colleagues [46]

found that intravenous VPA stopped SE in 19 of 23 patients within 20 min-

utes. Sinha and Naritoku [47] reviewed hospital records of 13 elderly pa-

tients with SE and cardiovascular instability who received intravenous

valproate therapy. A loading dose of valproate of 25.1 Æ 5 mg/kg (range

14.7–32.7 mg/kg), at a rate of 36.6 Æ 25.1 mg/min (range 6.3–100 mg/min), was used. There were no significant changes in blood pressure, pulse,

or increases of vasopressor dosages. All patients died as a result of their un-

derlying medical illness or withdrawal of life support. Peters and Pohlmann-

Eden [48] reported a series of 102 adult patients who received standardized

high-dose intravenous VPA in various situations, including 35 patients who

were in SE; 85.6% had interruption of clinical seizure activity within less

than 15 minutes, followed by freedom from seizure during intravenous ther-

apy for at least 12 hours. Subgroup analysis showed efficacy of intravenous

VPA in 27 of 35 patients with SE (77.1%). None had serious side eff ects, in-cluding sedation or hypotension.

Adverse eff ects from valproate include hyperammonemic encephalopa-

thy, pancreatitis, parkinsonism, rare liver failure, and not-so-rare thrombo-

cytopenia, which is usually dose related and benign. Other types of

VPA-associated bleeding diathesis have been observed, including platelet

dysfunction and hypofibrinogenemia.




If seizures persist, intubation becomes required if not performed yet, and

continuous intravenous drugs become necessary to control the SE. Only

a few agents are available for control of refractory SE, and no consensushas been reached regarding the degree or duration of the required EEG sup-

pression. In a retrospective review, Rossetti and coworkers [49] showed that

achievement of burst suppression on EEG did not correlate with a better

outcome. Further studies are needed to evaluate the relationships between

the depth of burst suppression, duration of therapy, and outcomes. Claassen

and colleagues [50] did a systematic review of the literature on use of pento-

barbital, propofol, and midazolam in refractory SE and found that most pa-

tients already had been treated with phenytoin, benzodiazepines, and

phenobarbital before continuous intravenous therapy. Duration of infusionwas longest with midazolam and shortest with pentobarbital. Continuous

EEG monitoring was performed significantly less often in patients treated

with pentobarbital (27%) than in patients treated with midazolam or pro-

pofol, possibly explaining its seemingly higher efficacy. Continuous EEG

is recommended because most seizures in patients with refractory SE are

nonconvulsive and unnoticeable at the bedside [14]. Commonly used thera-

pies for refractory SE include the following.

BarbituratesBarbiturates are direct GABA agonists. Eff ects 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 to50 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




have been observed on EEG on withdrawal; these patterns sometimes

resolve without intervention as the withdrawal of barbiturate continues.

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

eff ect lasting minutes to hours. Respiratory depression and hypotension are

common side eff ects.

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 aff ects cellular

metabolism, causing a biochemical break in the respiratory chain that leads

to lactic acidosis and multiple organ dysfunction. It is prudent to avoid




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 eff ective 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.

Other antiepileptic drugsIn recent years, there has been increasing use of enterally administered lev-

etiracetam in ICU patients. Levetiracetam, whose mechanism of action is not

well understood, has the advantages of rapid titration and a good safety pro-

file. It is less than 10% protein bound, with a plasma half-life of 6 to 8 hours. It

is not metabolized by the liver, making it an excellent choice (as are gabapentin

and pregabalin) in patients with hepatic failure. Dosage should be reduced in

the presence of renal impairment, and supplemental doses should be given af-

ter dialysis (approximately 50% of the pool of levitiracetam in the body is re-

moved during a standard 4-hour hemodialysis procedure).There are onlya few reports on its use in SE [58,59]. An intravenous formulation of levetira-

cetam is expected to be available shortly.

Topiramate, administered via the nasogastic route, is reported to be eff ec-

tive in aborting SE [60], possibly owing to the multiple mechanisms of ac-

tion. There is evidence of a neuroprotective eff ect of topiramate, with

attenuation of seizure-induced neuronal injury noted in experimental SE

[61]. Several other oral AEDs have been used for refractory seizures or

SE in the ICU, but there are no comparative data to help select one over

the other. If topiramate or zonisamide is used, one should remain vigilantfor metabolic acidosis (particularly in combination with propofol) because

they are both carbonic anhydrase inhibitors. If carbamazepine or oxcarba-

zepine is used, one should be attentive to hyponatremia.

Ketamine is an anesthetic and NMDA receptor antagonist that has been

used in refractory SE with success in animal models [62–64]. Borris and as-

sociates [62] showed that in contrast to its failure to control early SE, ket-

amine is more eff ective in treatment of prolonged SE, the opposite of

phenobarbital in an animal model of SE (rats who underwent electrical stim-

ulation of the hippocampus). There is evidence that it also may be an ago-nist at the GABA-A receptor [64], that it has neuroprotective eff ects, and

that it does not compromise the hemodynamic status of ICU patients. A

few case reports have been reported in humans [65,66], but no clear evidence

supports its use in SE at this point. Severe neurotoxicity has been reported

secondary to NMDA-receptor antagonism, so further studies and extreme

caution are needed before its widespread use in SE.




The efficacy of isoflurane, an inhalational anesthetic agent, in aborting sei-

zures in nine patients with refractory SE was shown in a report by Kofke and

colleagues [67], who also noted that seizures could recur on discontinuation.They recommended its use only when other agents have failed. Mirsattari

and colleagues [68] described seven patients with refractory SE who received

isoflurane with or without desflurane with a goal of burst suppression on

EEG to control SE. Four patients had good outcomes, and three died; all ex-

perienced hypotension. Other complications included atelectasis and ileus.

Steroids, intravenous immunoglobulins, plasmapheresis, and adrenocor-

ticotropic hormone all have been reported to help control seizures, mostly in

the pediatric population or as part of syndromes known to involve immune

mechanisms. More research is needed to clarify the indications and conse-quences of each of these therapies [69].

Extensively used in cardiology, lidocaine’s main advantages are a short

half-life and a relative lack of respiratory and cerebral depressant eff ects.

It is 65% protein bound with a distribution half-life of less than 10 minutes

in adults and rapid hepatic metabolism. Pascual and colleagues [70] reported

42 episodes of SE treated with a lidocaine intravenous bolus dose of 1.5 to

2 mg/kg over 2 minutes; 31 responded to the first injection, but seizures re-

curred in 19. Eleven were nonresponders to the first and second bolus. Ef-

fects are thought to be temporary because of its rapid clearance. It isuseful as a short-term AED, particularly in patients with preexisting respi-

ratory disease as an alternative to benzodiazepines. Toxic eff ects include hy-

potension, sedation, and other neurologic side eff ects such as hallucinations

or exacerbation of seizures.

Acute seizures in special intensive care situations

Seizures and liver disease

The reported incidence of seizures in liver failure ranges from 2% to 33%[71]. Postulated pathophysiologic factors include hyperammonemia; abnor-

mal glutamine metabolism; cerebral ischemia; cerebral edema; accumulation

of toxins; or associated biochemical abnormalities such as hyponatremia,

hypomagnesemia; and renal failure [72–74]. Elevation of endogenous benzo-

diazepines may lower the incidence of seizures in hepatic failure.

Ficker and coworkers [73] reviewed EEGs of 118 patients with hepatic

encephalopathy and identified epileptiform abnormalities in 15%. Twelve

patients had clinical seizures, and most of them died or deteriorated. There

are rare reports of SE [74]. It is important to detect subclinical ictal activityin these patients because seizures increase cerebral oxygen requirements and

may worsen brain edema and prognosis. Ellis and colleagues [72] evaluated

42 patients in grade III or IV hepatic encephalopathy using a bedside cere-

bral function and activity monitor (two-channel, five-lead EEG designed to

study background activity, not seizures). Twenty patients were given phe-

nytoin, and 22 acted as controls. Subclinical seizure activity was reported




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 with70% 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 diff erentiation 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 diff erentiation can

be challenging or impossible [31,75–77].

The overall therapeutic approach of seizures and SE in these patients

does not diff er from others except that special considerations should bemade with use of AEDs metabolized by the liver. The degree of hepatic fail-

ure might aff ect 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 levelsof 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 eff ect 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 eff ect against mitochondrial dysfunction and oxidative stress seen

after SE. This eff ect also has been reported with topiramate [61,80], butfurther studies are needed for both of these agents.

Seizures and renal disease

Acute renal failure is associated with uremic encephalopathy and

seizures, which may result from metabolic abnormalities, such as hyponatre-

mia, calcium disorders, uremia, hypertensive encephalopathy, or dysequili-

brium syndrome seen with hemodialysis. The incidence of seizures in

patients undergoing hemodialysis for renal failure has been estimated at

2% to 10% [81–83].Treatment of these patients may be problematic because of alteration of

AED pharmacokinetics in uremia, decreased albumin, and dialysis eff ects.

AEDs predominantly eliminated by the kidneys, such as gabapentin, prega-

balin, and levetiracetam in particular, but also topiramate and phenobarbi-

tal, should be used at much lower doses in renal failure. Some carbonic

anhydrase inhibitors, such as zonisamide and topiramate, should be avoided




in patients at risk of nephrolithiasis or when the etiology of the renal failure

is unknown because they increase renal bicarbonate loss and stone forma-

tion. As far as dialysis eff ects, drugs that are highly protein bound (phenyt-oin, valproate, tiagabine; moderately high binding with carbamazepine) are

not dialyzed significantly (although the unbound portion is higher than

usual in these patients, so the eff ect is unpredictable) and do not usually

need to be replaced. Some AEDs are moderately aff ected (lamotrigine,

55% protein bound, 20% dialyzable) and might require predialysis and

postdialysis level monitoring to make necessary adjustments (postdialysis

supplementation). AEDs requiring replacement after dialysis are gabapen-

tin, pregabalin, ethosuximide, levetiracetam, phenobarbital, and topiramate.

In general, the serum concentration of these AEDs decreases by 50% afterdialysis.

Seizures in transplant patients

Seizures in transplant patients are frequent and may arise from metabolic

abnormalities such as hyponatremia, hyperglycemia or hypoglycemia, neu-

rotoxicity from immunosuppressive agents or other medications (eg, high-

dose intravenous antibiotics), infections including brain abscess, cerebral

edema, cerebral infarction, or postanoxic encephalopathy secondary to hy-

povolemia or septic shock [84,85]. The incidence of seizures in transplant pa-tients varies depending on the transplanted organ (Table 2), but the true

proportion is likely underestimated because none of the studies done so

far used continuous EEG in these patients to rule out nonconvulsive sei-

zures. Some of the reports include encephalopathy as a neurologic compli-

cation after transplant without clarifying EEG findings.

One third of liver transplant patients are believed to have seizures

[86,87]. Wijdicks and coworkers [88] reviewed 630 orthotopic liver transplant

recipients and found generalized tonic clonic seizures in 28 (4%), none of

whom had history of seizures before the transplant. Most seizures in criticallyill patients are now known to be nonconvulsive [9,13,14,89]; thus, this is likely

an underestimation of the prevalence of seizures in these patients. Most seizures

occurred in the postoperative period, usually on days 4 to 6 (raising the pos-

sibility that ‘‘withdrawl’’ from high levels of endogenus benzodiazepines plays

a role). Phenytoin eff ectively treated clinical seizures in all 28 patients and was

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]




successfully discontinued in all survivors shortly thereafter. Immunosuppres-

sant drug neurotoxicity is the most commonly cited etiology, particularly tox-

icity associated with the calcineurin inhibitors cyclosporine and tacrolimus.These agents are linked to a wide spectrum of neurologic abnormalities, partic-

ularly in liver transplant patients, including tremor, visual hallucinations,

speech difficulties, cortical blindness, posterior cerebral edema (also known

as posterior reversible encephalopathy syndrome), and seizures. Factors that

may promote the development of serious complications include advanced liver

failure, hypertension, hypocholesterolemia, elevated cyclosporine or tacroli-

mus blood levels, and hypomagnesemia. Nonconvulsive SE should be consid-

ered in the diff erential diagnosis of delirium and agitation in the post-transplant

period, and continuous EEG monitoring should be obtained. (A 30- to 60-min-ute EEG would detect only one third to one half of cases with nonconvulsive

seizures [14,89].) In cardiac transplant patients, AEDs should be used with cau-

tion owing to the risks of arrhythmias (phenytoin, carbamazepine), hyponatre-

mia (carbamazepine, oxcarbamazepine), and cardiovascular depression

(phenobarbital).

Anticonvulsant use is valuable in the short-term, but data are unclear re-

garding duration of treatment. This should be decided on a case-by-case basis

depending on the etiology and the radiologic and electrographic findings. If

there is an acute symptomatic explanation for seizures that has been corrected,there is no indication for prolonged AED use. In liver transplant patients,

phenytoin may be needed for rapid seizure control, and levetiracetam also

may be used as discussed earlier. Gabapentin, pregabalin, and topiramate

are other agents that can be advanced relatively fast.

Medication interactions constitute another concern in the transplant pop-

ulation. Phenytoin decreases absorption of cyclosporine [90], and all hepatic

enzyme inducers (including phenytoin, carbamazpine, and phenobarbital)

can increase the clearance of cyclosporine, methylprednisolone, and many

other medications dramatically.

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 are associated with additional neuronal metabolic stress, increased

edema or mass eff ect, and worse clinical outcome. Future studies are needed

to determine whether greater use of EEG monitoring and early or more ag-gressive treatment of nonconvulsive seizures would improve the outcome of

these patients.

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Avances en el tratamiento del estado epil+®ptico en el paciente cr+¡tico (2007)

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