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Neurol Clin 26 (2008) 385408

Updates in the Management of Seizures and Status Epilepticus in Critically Ill Patients
Karine J. Abou Khaled, MD, Lawrence J. Hirsch, MD*
Department of Neurology, Comprehensive Epilepsy Center, Columbia University, 7th oor, 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 intensive care unit (ICU) because of continuous or repetitive seizures requiring aggressive treatment, and patients admitted for medical or surgical reasons who develop seizures during the course of their ICU stay. This article is a revision and update of a previously published in Critical Care Clinics in 2006 [1], which provided recent concepts of seizures and SE in the adult ICU. This revision follows the structure of the original article and starts with a brief review of SE epidemiology, denition, classication, etiologies, diagnosis, and prognosis. Then, the systemic and neurologic eects of seizures and SE are discussed. Finally, the authors propose strategic therapeutic steps and focus on the treatment of seizures and SE in patients with specic organ failures or after organ transplantation. Epidemiology and denition SE remains a serious, life-threatening emergency. De Lorenzo and colleagues [2] estimated that it aects 152,000 individuals in the United States per year and causes 42,000 deaths. The rst attempt to dene SE was in 1962, when the tenth European Conference on Epileptology and Clinical Neurophysiology dened SE as a condition characterized by an epileptic seizure which is so frequently repeated or so prolonged as to create
This is an updated version of an article that originally appeared in Critical Care Clinics, volume 22, issue 4. * Corresponding author. E-mail address: ljh3@columbia.edu (L.J. Hirsch). 0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2008.03.017 neurologic.theclinics.com

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a xed and lasting epileptic condition [3]. The International Classication of Epileptic 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 [3]. The rationale for choosing 30 minutes was based on the minimum duration thought to result in neuronal injury in animal models. Bleck [4] dened SE as continuous or repeated seizures lasting more than 20 minutes. More recently, Lowenstein and colleagues [5] suggested that dening SE based on the theoretic onset of neuronal injury is of questionable value because of the complexity of this relation in human beings. They suggested that we should not wait 10 minutes or longer before instituting a treatment protocol for SE [5]. Treiman and colleagues [6] dened 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. Classication of status epilepticus In 1967, Gastaut [3] rst distinguished two major types of SE based exclusively on seizure semiology. The rst type is generalized SE, which is subdivided into two groups: (1) generalized convulsive SE (GCSE), which is tonic-clonic SE or grand mal SE, tonic SE, clonic SE, or myoclonic SE; and (2) nonconvulsive generalized SE, including petit mal status. The second type is partial SE, which is subdivided into two groups: simple partial SE (eg, somatomotor or aphasic SE) and 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 classication of nonconvulsive status epilepticus (NCSE). In clinical practice, it is often impossible to differentiate between NCSE of generalized onset and NCSE of partial onset with bilateral spread. The authors divide SE into convulsive SE and NCSE or subtle SE. The authors reserve the term absence SE for patients with idiopathic primary 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 comatose or 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 dier among centers, patient population, and age. Box 1 summarizes these by categories. Lowenstein and Alldredge [7] evaluated 154 patients treated for

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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 Anoxia Brain 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 well Vitamin deciency: 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

generalized SE, 93% of whom had an onset preceding hospital admission. The two leading etiologies were anticonvulsant drug withdrawal or noncompliance (almost all were noncompliant with their prescribed regimen) and alcohol-related. These results were similar to what was found by Amino and Simon [8]. 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 Veterans Aairs cooperative study [6]. In another study, the leading etiologies for adult SE cases were low antiepileptic drug (AEDs) levels

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(34%), followed by remote symptomatic events (25%), and stroke (22%) [2]. In a series of patients with NCSE, Towne and associates [9] identied hypoxia or anoxia as the most frequent etiology (42%) followed by cerebrovascular accident (22%). Neuroinfectious etiologies are more common, in places such as India particularly neurocysticercosis and tuberculosis [10,11]. Treatment of the underlying cause may be crucial to managing seizures successfully, especially when caused by a toxic or metabolic origin. It is often dicult, however, to identify a single etiology because of the presence of multiple 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 dicult to dene 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 [12]. This nding highlighted the possibility that imipenem was a confounding variable, a marker of severity of illness and infection, rather than a contributor to the seizures. Box 2 lists the major categories of medications that have been incriminated in contributing to seizures.

Box 2. Medications associated with decreased seizure threshold Antidepressants, mostly bupropion and maprotiline Neuroleptics, 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 withdrawal Benzodiazepine 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. [110112].

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Diagnosis NCSE is underdiagnosed. It can present in many ways, including mild personality changes, lethargy, agitation, blinking, confusion, facial twitching, automatisms, and coma [13,14]. After convulsive SE, nonconvulsive seizures may continue, even after clinical seizures have ceased. In the Richmond study, 14% of subjects with convulsive SE who stopped seizing clinically showed persistent electrographic SE on electroencephalogram (EEG), and 48% had intermittent electrographic seizures [15]. Nonconvulsive seizures have been reported in 34% of neurologic ICU patients [16], 16% of severe head trauma patients [17], and 8% of comatose patients who had no prior seizures or subtle clinical evidence of seizures [9]. In the authors series of 570 consecutive in-patients undergoing continuous EEG Monitoring at Columbia, 110 (19%) had seizures, and 101 of these 110 subjects (92%) had purely nonconvulsive seizures that could be detected only by EEG. Only half of these subjects had their rst seizure within the rst hour of recording; even a prolonged routine EEG would not have identied the nonconvulsive seizures in half the subjects. The authors concluded that 24 hours was a reasonable screen for nonconvulsive seizures in noncomatose patients (95% of noncomatose patients had their rst seizure by 24 hours), but that 48 hours or more may be needed in comatose patients (only 80% had their rst seizure by 24 hours) [18].

Prognosis The overall mortality after SE is similar in the two largest known United States studies: 21% in Rochester, Minnesota [19], and 22% in Richmond, Virginia [20] (but higher in the elderly population, 38%) [21]. Towne and colleagues [22] 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. Mortality was increased in patients older than 70 years of age. Recently, Koubeissi and Alshekhlee [23] found an overall in-hospital mortality of 3.45% in a study of 11,580 hospitalized patient cohort with GCSE in the United States. Of those who survived, about 20% of patients were discharged to rehabilitation facilities and 76% discharged home. Mechanical ventilation was associated with tripled mortality compared with those who did not require it. This study also conrmed that advancing age was associated with higher mortality rate, as demonstrated by the Richmond study in 1996 [20]. Conicting data exist regarding mortality and morbidity of NCSE, depending primarily on patient selection. The highest reported mortality rates have been 52% [9,24]. Shneker and Fountain [25] found that 18% of patients with NCSE died. Patients in the acute medical group (dened as acute neurologic or systemic problems or both) had signicantly higher mortality rates (27%) than patients in the cryptogenic (18%) or epilepsy (3%) group.

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Worse outcome also was associated in patients with severely impaired mental status.

Sequelae of status epilepticus Cerebral changes Lothman and colleagues [26] developed and characterized the selfsustaining 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 spontaneous recurrent partial seizures that persist for more than 1 year. This model suggests 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. In a rat model of low dose pilocarpine-induced NCSE, Krsek and colleagues [27] found longterm motor decits and histologic damage 2 months after NCSE. In the rats with NCSE, they also noted disturbances in social behavior, and impairment of gamma-aminobutyric acid (GABA) ergic mediated inhibition in the hippocampus. What about sequelae of recurrent seizures in humans? Biological markers such as serum neuron-specic enolase (a glycolytic enzyme found primarily within neurons), are being investigated as markers of neuronal injury. In the animal literature, neuron-specic enolase correlates with the amount of histologic injury in rats after lithium-pilocarpineinduced SE [28]. Elevated levels of serum neuron-specic enolase have been documented in patients after nonconvulsive SE, including in cases without any demonstrable acute brain injury [2932]. The subtype of SE that was associated with the highest serum neuron-specic enolase levels was subclinical SE in critically ill patients [30]. These acute seizure-related changes can also be shown by dierent magnetic 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 temporal sclerosis [3335]. Pathologic and histologic changes also have been shown. DeGiorgio and colleagues [36] used a case-control approach and cell-density quantication to analyze changes in the hippocampus of ve patients who died after GCSE. They found signicant pyramidal cell loss in these patients compared with a control group. Changes attributable directly to the occurrence of GCSE are dicult to determine because pathologic alterations could have been present as a result of prior history of repetitive seizures or other acute processes. Chronic sequelae result from cell loss or altered physiology or synaptic connectivity. Focal or diuse cortical damage has been described. The latter accounts for general cognitive

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changes, whereas hippocampal neuronal loss can explain the subsequent decits in memory that are sometimes seen [37]. Changes in systemic physiology The rst 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 [38]. The most important physiologic 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 and rule out infection before attributing fever to SE, especially if associated with increased white blood cells in blood or cerebrospinal uid. Meldrum and colleagues [39] found that increased temperature correlated with severity of cerebellar 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 [40] reported specic electrocardiogram (ECG) abnormalities not present at baseline in 58.3% of patients in SE. The most frequently 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 [41] 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 [38]. 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 prolonged 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 dierentiating epileptic from nonepileptic convulsions, but there is no evidence of the level being useful in SE [42].

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Leukocytosis from demargination, but this should not be attributed to SE unless infectious etiologies are ruled out. In a series of 138 patients who had cerebrospinal uid analysis during SE, Barry and Hauser [43] found that 22.5% had abnormal cerebrospinal uid white blood cell count or dierential. The highest white blood cell count in patients with no acute insult was 28 per mm3. A mild transient increase in protein content also may be observed, possibly reecting breakdown of the blood-brain barrier [8]. Treatment of acute seizures and status epilepticus Management of SE should begin within 5 minutes of seizure activity or after 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 hypertension and tachycardia would be dangerous. General supportive measures for seizures and SE are reviewed rst. Subsequently, specic treatments and choice of AEDs are reviewed. Treatment in special situations, including organ failure and immunosuppression, conditions commonly encountered in the ICU, is also 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 barbiturates, frequently are introduced, and intravenous uid resuscitation and vasopressors may become necessary. Refractory GCSE and the use of agents such as midazolam, propofol, and pentobarbital generally mandate securing 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 presentation, additional tests might be necessary when the patient is stabilized, including 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 [44] showed in animal

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Table 1 Status epilepticus: adult treatment protocol, Columbia University Comprehensive Epilepsy Center 2006 Time, minutes 05 Action Diagnose; give oxygen; 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). Thiamine 100 mg IV; 50 mL of D50 IV unless adequate glucose known. Lorazepam 4 mg IV over 2 mins; if still seizing, repeat 1 in 5 mins. If no rapid IV access, give diazepam 20 mg PR or midazolam 10 mg intranasally, buccally or IMa 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 performed simultaneously with the next step; if done simultaneously, administration rate can be slowed. IV valproate is a reasonable alternative to fosphenytoin at this point as well (dosing below). If seizures persist, give one of the following (intubation usually necessary except for valproate): CIV midazolam: Load: 0.2 mg/kg; repeat 0.2 mg/kg0.4 mg/kg boluses every 5 minutes until seizures stop, up to a maximum total loading dose of 2 mg/kg. Initial CIV rate: 0.1 mg/kg per hr. CIV dose range: 0.05 mg/kg2.9 mg/kg per hr, titrate to EEG seizure control or burst suppression. If still seizing, add or switch to propofol or pentobarbital. or CIV propofol: Load: 1 mg/kg2 mg/kg; repeat 1 mg/kg2 mg/kg boluses every 35 minutes until seizures stop, up to maximum total loading dose of 10 mg/kg. Initial cIV rate: 2 mg/kg per hr. CIV dose range: 1 mg/kg 15 mg/kg per hr titrate to EEG seizure control or burst suppression. If still seizing, add or switch to midazolam or pentobarbital. Avoid using O5 mg/kg per hr for multiple days to minimize risk of propofol infusion syndrome. Follow CPK, triglycerides, acid-base status closely. or IV valproate: 30 mg/kg40 mg/kg over approximately 10 minutes. If still seizing, additional 20 mg/kg over approximately 5 minutes. If still seizing, add or switch to CIV midazolam or propofol. or IV Phenobarbital: 20 mg/kg IV at 50 mg100 mg per min. If still seizing, add or switch to CIV midazolam, propofol, or pentobarbital. CIV Pentobarbital. Load: 5 mg/kg at up to 50 mg per min; repeat 5 mg/kg boluses until seizures stop. Initial CIV rate: 1 mg/kg per hr. CIV-dose range: 0.5 mg/kg10 mg/kg per hr; traditionally titrated to suppressionburst 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.

610

1020

1060

O 60 minutes

Abbreviations: ABCs, stabilize airway, breathing and circulation; ABG, arterial blood gas; ASAP, as soon as possible; CBC, complete blood cell count; CIV, continuous intravenous; CPK, creatine kinase; IV, intravenously; IM, initramuscularly; LFT, liver function test; PR, per rectum. a The IV solution of diazepam can be given rectally if Diastat is not available; the IV solution of midazolam can be given by any of these routes.

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experiments that the ecacy of phenytoin decreased dramatically with time, and proposed that the failure of diazepam and phenytoin to abort selfsustaining SE during its maintenance phase implies that seizures evolve certain mechanisms that cause refractoriness to antiepileptic drugs. Although phenytoin and benzodiazepines become less eective, glutamate antagonists, such as ketamine (an N-methyl-D-aspartate or NMDA antagonist), are ineective initially, but become eective in later stages in animals. In human beings, intervention within the rst 30 minutes of seizure onset was associated with 80% response to rst-line drugs. The response rate declined with longer intervals to treat, 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 rst-line treatment [7]. AEDs should be selected in consideration of the patients prior history, medications, allergies, hemodynamic status, and hepatic and renal function, and the physicians experience and preference. Only a few randomized, controlled trials have compared treatment strategies in SE. The most important one was the Veterans Aairs (VA) Status Epilepticus Cooperative Study [6], which compared the ecacy of four drugs for the treatment of GCSE. A total of 518 subjects 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 rst regimen chosen was successful in 55.5% of subjects with overt status, but only 14.9% of subjects with subtle SE (coma and ictal discharges on EEG with or without subtle movements). In subjects with overt status, intravenous lorazepam was most eective. It stopped SE in 65% of the cases; phenobarbital, 58%; diazepam plus phenytoin, 56%; and phenytoin alone, 44%. The only statistically signicant dierences were between phenytoin alone and lorazepam. Hypotension requiring treatment occurred more often in subjects with subtle SE, but there were no dierences between the medications. Overall mortality was twice as high for subjects whose SE was not controlled with the rst drug as for subjects who had successful response to the rst regimen. In the VA cooperative study, subjects who failed the rst treatment rarely responded to the second (7%) or third (2.3%), raising the question of the ecacy of a second and third drug [6,45]. Lorazepam has many advantages over other drugs. It can be given quickly and has a duration of antiseizure eect of 12 to 24 hours [46]. Leppik and colleagues [46] compared lorazepam with diazepam for the treatment of SE in 78 subjects enrolled in a double-blind, randomized trial. Time of onset of the two drugs was almost the same. Seizures were controlled in 89% of the episodes treated with lorazepam and in 76% treated with diazepam. These results, combined with the more recent and more denitive VA cooperative study, have led to intravenous lorazepam (0.1 mg/kg) becoming a clear drug of choice for initial treatment of SE. Phenytoin or fosphenytoin is the most frequently recommended agent used following benzodiazepines [12,47], but recent data indicate that IV

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valproate may be as good and perhaps even better [10,11]. A phenytoin load of 18 mg/kg to 20 mg/kg intravenously is recommended. Phenytoin solution is highly caustic to veins and may cause tissue necrosis in case of extravasation, limiting the rate of administration to a maximum of 50 mg/min. Fast administration carries the risk of hypotension and cardiac arrhythmias and requires close monitoring of blood pressure and ECG. Fosphenytoin sodium is a phenytoin prodrug, preferred over phenytoin because of its water solubility, allowing faster administration 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 mg/mL to 2.5 mg/mL, which is equivalent to a total phenytoin level of 15 mg/mL to 25 mg/mL in the presence of normal protein binding [13]. Free levels may be excessively high in the presence of low albumin or coadministration of highly protein bound drugs (eg, valproic acid), and this may confuse the clinical presentation by worsening encephalopathy or paradoxically exacerbating seizures. 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 subsequent poor seizure control. In a study by Bauer [48], phenytoin serum levels decreased an average of 71.6% when parenteral nutrition was given concurrently. This problem may be overcome if parenteral nutrition is withheld 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 mg/kg to 20 mg/kg. Maximum rate is 50 mg to 100 mg per minute. 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 depression and hypotension via vasodilation and cardiac depression. The main advantages are intravenous availability, prolonged eect, and good ecacy in controlling SE. Interest in valproic acid (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 diers from older generation AEDs in being an enzyme inhibitor, rather than inducer; one must be vigilant for increased levels or eect of concomitant P-450-metabolized medications. There is a dramatic fall of its level after addition of antibiotics, such as meropenem or amikacin, possibly owing to accelerated renal excretion [49]. Valproate has broad-spectrum activity against all types of seizures, including postanoxic myoclonus. A major advantage is not causing sedation or hypotension, which renders it a drug of choice in patients with a do

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not intubate status or phenytoin allergy (although it has not been approved by the United States Food and Drug Administration for use in SE). Intravenous VPA has been used in open-label studies with seizure control in approximately 80% of cases [50,51]. Giroud and colleagues [51] found that intravenous VPA stopped SE in 19 of 23 patients within 20 minutes. Sinha and Naritoku [52] reviewed hospital records of 13 elderly patients with SE and cardiovascular instability who received intravenous valproate therapy. A loading dose of valproate of 25.1 plus or minus 5 mg/kg (range 14.7 mg/kg32.7 mg/kg), at a rate of 36.6 plus or minus 25.1 mg per minute (range 6.3 mg100 mg per minute), was used. There were no signicant changes in blood pressure, pulse, or increases of vasopressor dosages. All patients died as a result of their underlying medical illness or withdrawal of life support. Peters and Pohlmann-Eden [53] 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 therapy for at least 12 hours. Subgroup analysis showed ecacy of intravenous VPA in 27 of 35 patients with SE (77.1%). None had serious side eects, including sedation or hypotension. Adverse eects from valproate include hyperammonemic encephalopathy, pancreatitis, parkinsonism, rare liver failure, and not-so-rare thrombocytopenia, which is usually dose related and benign. Other types of VPA-associated bleeding diatheses have been observed, including platelet dysfunction and hypobrinogenemia. Two recent prospective, randomized trials compared the ecacy and tolerance of IV valproate to IV phenytoin (PHT) in patients with SE. In one of the studies, Agarwal and colleagues [10] randomized 100 subjects in SE who had persistant seizures after IV diazepam to either IV VPA or IV PHT (20 mg/kg load for both). No dierence in ecacy or tolerance was detected between the two drugs. The other study by Misra and colleagues [11] was a randomized controlled trial that compared IV VPA (30 mg/kg given over 15 minutes) and IV PHT (18 mg/kg) as rst line treatment for convulsive SE (no benzodiazepines were used before this); if the given drug failed, they were switched over to the other agent. The investigators found that VPA was more eective in controlling the SE, both as the initial drug (66% versus 42%, P .046), and even more dramatically as the second drug (79% versus 25 %, P .004). 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 consensus has been reached regarding the degree or duration of the required EEG suppression. In a retrospective review, Rossetti and colleagues [54] 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

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and colleagues [55] did a systematic review of the literature on use of pentobarbital, propofol, and midazolam in refractory SE and found that most patients already had been treated with phenytoin, benzodiazepines, and phenobarbital before continuous intravenous therapy. Duration of infusion was longest with midazolam and shortest with pentobarbital. Continuous EEG monitoring was performed signicantly less often in patients treated with pentobarbital (27%) than in patients treated with midazolam or propofol, possibly explaining its seemingly higher ecacy. Continuous EEG is recommended because most seizures in patients with refractory SE are nonconvulsive and unnoticeable at the bedside [18]. Commonly used therapies for refractory SE include the following. Barbiturates Acting on GABA receptors, eects of barbiturates include cerebral and respiratory depression, myocardial depression, vasodilation, hypotension, and ileus. Administration of continuous intravenous barbiturates requires support with mechanical ventilation, intravenous uids 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 preferred drugs for treating SE in the ICU in the United Kingdom after failure of the initial treatment [56]. The recommended dose is 2 mg/kg to 4 mg/kg bolus, followed by infusion of 3 mg/kg to 5 mg/kg per hour, although higher doses commonly are used. Thiopental is metabolized by the liver and should be withdrawn slowly 24 hours after resolution of electrographic 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 concentrations are maintained longer. The loading dose is 5 mg/kg and should be repeated until seizures stop, with a maximum bolus rate of 25 mg to 50 mg per minute. Infusion rates are 0.5 mg/kg to 10 mg/kg per hour, 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 halflife is longer than thiopental (2030 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 during pentobarbital 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

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dose is 0.2 mg/kg, and boluses should be repeated every 5 minutes until seizures stop, up to a maximum total loading dose of about 2 mg/kg. The initial rate is 0.1 mg/kg per hour with a continuous dose range: 0.05 mg/ kg to 2.9 mg/kg per hour (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 signicant prolongation of half-life, up to days. Naritoku and Sinha [57] reported slow clearance of midazolam in two patients after several days of continuous therapy, probably related to accumulation of midazolam in peripheral compartments (adipose tissue) with subsequent redistribution back to the central compartment. The time to stop SE is usually well under 1 hour, with a duration of eect lasting minutes to hours. Respiratory depression and hypotension are common side eects. 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 is a bolus of 1 mg/kg to 2 mg/kg, followed by a continuous infusion of 1 mg/kg to 15 mg/kg per hour with a recommended maximum dosage of 5 mg/kg per hour if maintained for days. 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 eects include respiratory depression, hypotension, bradycardia, and the more recently recognized propofol infusion syndrome, consisting of metabolic acidosis, cardiac failure, rhabdomyolysis, hypotension, and death. In 2001, the United States Food and Drug Administration communicated that pediatric ICU patients given propofol for sedation had higher death rates that patients 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 (O5 mg/kg per hour) [58,59], severe head injury [60], lean mass, and concurrent use of catecholamines or steroids [59]. It has been suggested that concomitant use of propofol with catecholamines may precipitate this syndrome. Cray [61] proposed that either propofol or its lipid soluent aects 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 per hour), and once used creatine kinase and lactic acid should be followed closely. Rossetti and colleagues [62] used concomitant intravenous clonazepam and propofol at the lowest eective dose. In their group of 31 patients 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

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rst published series of SE patients treated with propofol in which there was not a very high mortality rate. Other antiepileptic drugs There has been increasing use of levetiracetam in ICU patients. Levetiracetam, the mechanism of action of which is not well understood but involves binding to the synaptic vesicle protein SV2A, has the advantages of rapid titration, no drug interactions, and a good safety prole. It is less than 10% protein bound, with a plasma half-life of 6 to 8 hours. The liver does not metabolize levetiracetam, thus making it an excellent choice in patients with hepatic failure. Dosage should be reduced in the presence of renal impairment, and supplemental doses should be given after dialysis (approximately 50% of the pool of levetiracetam in the body is removed during a standard 4-hour hemodialysis procedure) [63,64]. The recent introduction of the intravenous formulation makes it use more ideal in the ICU. Intravenous levetiracetam with a mean loading dose of 944 mg was studied byKnake and colleagues [65] in 18 subjects with benzodiazepine-refractory focal SE. SE was controlled in all subjects, with only 2 of the 18 subjects requiring additional antiepileptic drugs following the IV levetiracetam. No severe adverse eects were noted. Topiramate, administered via the nasogastric route, is reported to be effective in aborting SE [66], possibly owing to the multiple mechanisms of action. There is evidence of a neuroprotective eect of topiramate, with attenuation of seizure-induced neuronal injury noted in experimental SE [67]. 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 vigilant for metabolic acidosis (particularly in combination with propofol) because they are both carbonic anhydrase inhibitors. If carbamazepine or oxcarbazepine 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 [6870]. Borris and associates [68] showed that in contrast to its failure to control early SE, ketamine is more eective in treatment of prolonged SE, the opposite of phenobarbital, in an animal model of SE (rats who underwent electrical stimulation of the hippocampus). There is evidence that it also may be an agonist at the GABA-A receptor [70], that it has neuroprotective eects, and that it does not compromise the hemodynamic status of ICU patients. Few cases have been reported in human beings [71,72], 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 caution are needed before its widespread use in SE. The ecacy of isourane, an inhalational anesthetic agent, in aborting seizures in nine patients with refractory SE was shown in an article by Kofke and colleagues [73], who also noted that seizures tended to recur on

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discontinuation. They recommended its use only when other agents have failed. Mirsattari and colleagues [74] described seven patients with refractory SE, who received isourane with or without desurane with a goal of burst suppression on EEG to control SE. Four patients had good outcomes, and three died; all experienced hypotension. Other complications included atelectasis and ileus. Steroids, intravenous immunoglobulins, plasmapheresis, and adrenocorticotropic 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 consequences of each of these therapies [75]. Extensively used in cardiology, lidocaines main advantages are a short halflife and a relative lack of respiratory and cerebral depressant eects. It is 65% protein bound with a distribution half-life of less than 10 minutes in adults and rapid hepatic metabolism. Pascual and colleagues [76] reported 42 episodes of SE treated with a lidocaine intravenous bolus dose of 1.5 mg/kg to 2 mg/kg over 2 minutes; 31 responded to the rst injection, but seizures recurred in 19. Eleven were nonresponders to the rst and second bolus. Eects are thought to be temporary because of its rapid clearance. It is useful as a short-term AED, particularly in patients with preexisting respiratory disease as an alternative to benzodiazepines. Toxic eects include hypotension, sedation, and other neurologic side eects 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% [77]. Postulated pathophysiologic factors include hyperammonemia, abnormal glutamine metabolism, cerebral ischemia, cerebral edema, accumulation of toxins, or associated biochemical abnormalities such as hyponatremia, hypomagnesemia, and renal failure [7880]. Elevation of endogenous benzodiazepines may lower the incidence of seizures in hepatic failure. Ficker and colleagues [79] reviewed EEGs of 118 patients with hepatic encephalopathy and identied epileptiform abnormalities in 15%. Twelve patients had clinical seizures, and most of them died or deteriorated. There are rare reports of SE [80]. It is important to detect subclinical ictal activity in these patients because seizures increase cerebral oxygen requirements and may worsen brain edema and prognosis. Ellis and colleagues [78] evaluated 42 subjects in grade III or IV hepatic encephalopathy using a bedside cerebral function and activity monitor (two-channel, ve-lead EEG designed to study background activity, not seizures). Twenty subjects were given phenytoin, and 22 acted as controls. Subclinical seizure activity was reported in 3 (15%) and 10 (45%) subjects of the treated and control groups. Autopsy examinations available in 19 subjects showed signs of cerebral edema in only 22% of the phenytoin-treated subjects, compared with 70%

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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 accurate diagnosis and dierentiation of seizures from other patterns, such as triphasic waves, artifact, and high-voltage slowing. Even with a full set of electrodes and board-certied electroencephalographers, this dierentiation can be challenging or impossible [37,8183]. The overall therapeutic approach of seizures and SE in these patients does not dier from others except that special considerations should be made with the use of AEDs metabolized by the liver. The degree of hepatic failure might aect the AEDs metabolism; in early hepatitis, there may be increased blood ow 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 [84]. Hypoalbuminemia, also encountered in malnutrition and infectious, renal, or neoplastic diseases, can lead to increased free unbound 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 situation would be drugs with low or no protein binding eect or with primarily renal metabolism, such as gabapentin, pregabalin, and levetiracetam; an intravenous form of levetiracetam is now available. In a study in animal models, Gibbs and colleagues [85] showed that levetiracetam has neuroprotective eect against mitochondrial dysfunction and oxidative stress seen after SE. This eect also has been reported with topiramate [67,86], but further 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 hyponatremia, calcium disorders, uremia, hypertensive encephalopathy, or dysequilibrium syndrome seen with hemodialysis. The incidence of seizures in patients undergoing hemodialysis for renal failure has been estimated at 2% to 10% [8789]. Treatment of these patients may be problematic because of alteration of AED pharmacokinetics in uremia, decreased albumin, and dialysis eects. AEDs predominantly eliminated by the kidneys, such as gabapentin, pregabalin, and levetiracetam in particular, but also topiramate and phenobarbital, should be used at much lower doses in renal failure. Some carbonic anhydrase inhibitors, such as zonisamide and topiramate are relatively contraindicated in patients at risk of nephrolithiasis or when the etiology of the renal failure is unknown because they increase renal bicarbonate loss and stone formation. As far as dialysis eects, drugs that are highly protein bound (phenytoin, valproate, tiagabine; moderately high binding with carbamazepine) are not

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dialyzed signicantly (although the unbound portion is higher than usual in these patients, so the eect is unpredictable) and do not usually need to be replaced. Some AEDs are moderately aected (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 gabapentin, pregabalin, ethosuximide, levetiracetam, phenobarbital, and topiramate. In general, the serum concentration of these AEDs decreases by 50% after dialysis. Seizures in transplant patients Seizures in transplant patients are frequent and may arise from metabolic abnormalities such as hyponatremia, hyperglycemia or hypoglycemia, neurotoxicity from immunosuppressive agents or other medications (eg, highdose intravenous antibiotics), infections including brain abscess, cerebral edema, cerebral infarction, or postanoxic encephalopathy secondary to hypovolemia or septic shock [90,91]. The incidence of seizures in transplant patients 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 seizures. Some of the reports include encephalopathy as a neurologic complication after transplant without clarifying EEG ndings. One third of liver transplant patients are believed to have seizures [92,93]. Wijdicks and colleagues [105] 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 critically ill patients are now known to be nonconvulsive [13,17,18,106]; 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. Phenytoin eectively treated clinical seizures in all 28 patients and was successfully discontinued in all survivors shortly thereafter. One possible explanation for this timing of seizures is that there is withdrawal from endogenous benzodiazepines in the post transplant setting as hepatic clearance dramatically increases. Immunosuppressant drug neurotoxicity is the most commonly cited etiology, particularly toxicity associated with the calcineurin inhibitors cyclosporine and tacrolimus. These agents are linked to a wide spectrum of
Table 2 Seizures after transplantion Organ transplanted Liver Kidney Heart Lung Bone marrow Pancreas Incidence of seizures 25% [92]30% [93] 1% [94]5% [95]31% [96] 2% [108,109]6.5% [97]15% [98] 22% [99]27% [100] 3% [101]7.5% [102]12.5% [103] 13% [104]

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neurologic abnormalities, particularly in liver transplant patients, including tremor, visual hallucinations, speech diculties, 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 tacrolimus blood levels, and hypomagnesemia. Nonconvulsive SE should be considered in the dierential diagnosis of delirium and agitation in the post-transplant period, and continuous EEG monitoring should be obtained. (A 30- to 60-minute EEG would detect only one third to one half of cases with nonconvulsive seizures [18,106].) In cardiac transplant patients, certain AEDs should be used with caution because of the risks of arrhythmias (phenytoin, carbamazepine), hyponatremia (carbamazepine, oxcarbamazepine), and cardiovascular depression (phenobarbital). Anticonvulsant use is valuable in the short-term, but data are unclear regarding duration of treatment. This should be decided on a case-by-case basis depending on the etiology and the radiologic and electrographic ndings. 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 quickly. Medication interactions constitute another concern in the transplant population. Phenytoin decreases absorption of cyclosporine [107], and all hepatic enzyme inducers (including phenytoin, carbamazepine, and phenobarbital) can increase the clearance of cyclosporine, methylprednisolone, and many other medications dramatically. Summary Seizures occur in critically ill patients in various conditions. In all situations, it is crucial to identify potential causes or contributors, particularly reversible factors, such as metabolic disturbances, fever, hypoxia, and medications. For SE, it is imperative to begin treatment as soon as possible and to treat until success is veried 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 patients with alteration of mental status, especially if there is concurrent acute brain injury, prior epilepsy, a prior clinical seizure or SE, uctuating mental status, coma, abnormal eye movements, or subtle twitching. Nonconvulsive seizures are associated with neuronal metabolic stress, increased edema and mass effect, and worse clinical outcome. Future studies are needed to determine whether greater use of EEG monitoring and early or more aggressive treatment of nonconvulsive seizures would improve the outcome of these patients.

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