Epidemiology

Limited data are available on the epidemiology of seizures in the ICU. A 10-year retrospective study of all ICU patients with seizures at the Mayo Clinic revealed that 7 patients had seizures per 1000 ICU admissions.⁹ Our 2-year prospective study of medical ICU patients identified 35 with seizures per 1000 admissions.¹ These two studies are not exactly comparable, as the patient populations and methods of detection differed. A recent series found 8% of comatose patients without clinical signs of seizure activity to be in electrographic status epilepticus.¹⁰

Up to 34% of hospital in-patients experiencing a seizure die during their hospitalization.¹ Our prospective study of neurologic complications in medical ICU patients showed that having even one seizure while in the ICU for a non-neurologic reason doubled in-hospital mortality.¹⁰ Incidence estimates for generalized convulsive status epilepticus in the United States vary from 50,000 cases per year¹¹ to 195,000 cases per year.¹² Some portion of this difference can be accounted for by different definitions; however, the latter estimate represents the only population-based data available and may be more accurate. Mortality estimates similarly vary from 1% to 2% in the former study to 22% in the latter. This disagreement follows from a conceptual discordance: the smaller number describes mortality the authors directly attribute to status epilepticus, whereas the larger figure estimates the overall mortality rate, even though death was frequently caused by the underlying disease rather than by status epilepticus itself. The elderly have an incidence of status epilepticus almost twice that of the general population and the highest associated mortality rate of any age group at 38%.¹³

Table 36-1 summarizes the most common causes of status epilepticus in adults in the community. Almost 50% of the cases were attributed to cerebral vascular disease.¹¹ Garzon and colleagues¹⁴ found antiepileptic drug noncompliance as the main cause of status epilepticus in patients with a prior history of epilepsy, and CNS infection, stroke, and metabolic disturbances predominated in the group without previous seizures.

TABLE36-1 Causes of Status Epilepticus in Adults Presenting from the Community

CNS, central nervous system.

Three major factors determine outcome in patients with status epilepticus: the type of status epilepticus, its cause, and its duration. Generalized convulsive status epilepticus has the worst prognosis for neurologic recovery; myoclonic status epilepticus following an anoxic episode carries a very poor prognosis for survival. Complex partial status epilepticus can produce limbic system damage, usually manifested as a memory disturbance. Causes associated with increased mortality included anoxia, intracranial hemorrhages, tumors, infections, and trauma. The mortality of patients with nonconvulsive status epilepticus has been reported as high as 33%¹⁵ and correlates with the underlying cause, severe impairment of mental status, and the development of acute complications, especially respiratory failure and infection.¹⁶ Data strongly suggest that prolonged seizure duration is a negative prognostic factor. A study of 253 adult status epilepticus patients demonstrated a 30-day mortality rate of 2.7% in patients with seizures lasting 30 to 59 minutes, compared with 32% in those with seizures of 60 minutes or longer.¹⁷

Limited data are available concerning the functional abilities of generalized convulsive status epilepticus survivors, and no data reliably permit a distinction between the effects of status epilepticus and effects of its causes. One review concluded that intellectual ability declined as a consequence of status epilepticus.¹⁸ Survivors of status epilepticus frequently seem to have memory and behavioral disorders out of proportion to the structural damage produced by the cause of their seizures. Case reports of severe memory deficits following prolonged complex partial status epilepticus have been published.¹⁹ Conversely, one prospective study of 180 children with febrile status epilepticus demonstrated no deaths and no cases of new cognitive or motor handicap.²⁰ Experimental animal²¹ and human epidemiologic²² studies suggest that status epilepticus may be a risk factor in the development of future seizures. Whether treatment of prolonged seizures reduces the risk of subsequent epilepsy remains uncertain.

Classification

The most frequently used classification scheme is that of the International League Against Epilepsy (Box 36-1).²³ This scheme allows classification on clinical criteria without inferring cause. Simple partial seizures start focally in the cerebral cortex without invading other structures. The patient is aware throughout the episode and appears otherwise unchanged. Bilateral limbic dysfunction produces a complex partial seizure; awareness and ability to interact are diminished (but may not be completely abolished). Automatisms (movements a patient makes without awareness) may occur. Secondary generalization results from invasion by epileptic electrical activity of the other hemisphere or subcortical structures.

Primary generalized seizures arise from the cerebral cortex and diencephalon at the same time; no focal phenomena are visible, and consciousness is lost at the onset. Absence seizures are frequently confined to childhood; they consist of the abrupt onset of a blank stare that usually lasts 5 to 15 seconds, after which the patient abruptly returns to normal. Atypical absence seizures occur in children with the Lennox-Gastaut syndrome. Myoclonic seizures start with brief synchronous jerks without alteration of consciousness, initially followed by a generalized convulsion. They frequently occur in patients with genetic epilepsy; in the ICU, they commonly follow anoxia or metabolic disturbances.²⁴ Tonic-clonic seizures start with tonic extension, evolve to bilaterally synchronous clonus, and conclude with a postictal phase. Clinical judgment is required to apply this system in the ICU. In patients in whom consciousness has already been altered by drugs, hypotension, sepsis, or intracranial pathologic lesion, the nature of partial seizures may be difficult to classify.

Status epilepticus is classified by a similar system that has been altered to match observable clinical phenomena (Box 36-2).²⁵ Generalized convulsive status epilepticus is the most common type encountered in the ICU and poses the greatest risk to the patient. It may either be primarily generalized, as in the drug-intoxicated patient, or secondarily generalized, as in the brain abscess patient who develops generalized convulsive status epilepticus. Nonconvulsive status epilepticus in the ICU frequently follows partially treated generalized convulsive status epilepticus. Some practitioners use the term for all cases of status epilepticus that involve altered consciousness without convulsive movements; this blurs the distinctions among absence status epilepticus, partially treated generalized convulsive status epilepticus, and complex partial status epilepticus, which have different causes and treatments. Epilepsia partialis continua (a special form of partial status epilepticus in which repetitive movements affect a small area of the body) sometimes continues for months or years.

The International League Against Epilepsy continues to work toward revising and updating the current classification system. The goal is a multi-axis diagnostic scheme that incorporates anatomic, etiologic, therapeutic, and prognostic implications. For the most recent information regarding this ongoing project, refer to www.epilepsy.org.²⁶

Pathogenesis and Pathophysiology

The causes and effects of status epilepticus at the cellular, brain, and systemic levels are interrelated, but their individual analysis is useful for understanding them and their therapeutic implications. The ionic events of a seizure follow the opening of ion channels coupled to excitatory amino acid receptors. From the standpoint of the intensivist, three channels are particularly important, because their activation may raise intracellular free calcium to toxic concentrations: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and metabotropic channels. These excitatory amino acid systems are crucial for learning and memory. Many drugs that block these systems are available but are too toxic for chronic use. Counter-regulatory ionic events are triggered by the epileptiform discharge as well, such as the activation of inhibitory interneurons which suppress excited neurons via GABA_A synapses.

The cellular effects of excessive excitatory amino acid channel activity include (1) generation of toxic concentrations of intracellular free calcium; (2) activation of autolytic enzyme systems; (3) production of oxygen free radicals; (4) generation of nitric oxide, which both enhances subsequent excitation and serves as a toxin; (5) phosphorylation of enzyme and receptor systems, making seizures more likely; and (6) an increase in intracellular osmolality, which produces neuronal swelling. If adenosine triphosphate production fails, membrane ion exchange ceases, and neurons swell further. These events produce the neuronal damage associated with status epilepticus. Longer status epilepticus duration produces more profound alterations and an increasing likelihood of permanence and of becoming refractory to treatment.²⁷ The processes involved in a single seizure and the transition to status epilepticus have been reviewed.²⁸

Many other biophysical and biochemical alterations occur during and after status epilepticus. The intense neuronal activity activates immediate-early genes and produces heat shock proteins, providing indications of the deleterious effects of status epilepticus and insight into the mechanisms of neuronal protection.²⁹ The mechanisms by which status epilepticus damages the nervous system have been reviewed.³⁰ Absence status epilepticus is an exception among these conditions; it consists of rhythmically increased inhibition and does not produce clinical or pathologic abnormalities.

The electrical phenomena of status epilepticus at the whole brain level, as seen in the scalp electroencephalogram (EEG), reflect the seizure type that initiates status epilepticus (e.g., absence status epilepticus begins with a 3-Hz wave-and-spike pattern). During status epilepticus, this rhythm slows, but the wave-and-spike characteristic remains. Generalized convulsive status epilepticus goes through a sequence of electrographic changes (Table 36-2).³¹ The initial discharge becomes less well formed, implying that neuronal firing loses synchrony. The sustained depolarizations that characterize status epilepticus alter the extracellular milieu, most importantly by raising extracellular potassium. The excess potassium ejected during status epilepticus exceeds the buffering ability of astrocytes.

TABLE36-2 Electrographic-Clinical Correlations in Generalized Convulsive Status Epilepticus

^* Clinical manifestations may vary considerably depending on the underlying neuropathophysiologic process (and its anatomy), systemic diseases, and medications. In particular, stages of the electrographic progression may be sufficiently brief to be overlooked. Partially treating status epilepticus may dissociate the clinical and electrographic features.

Data from Treiman DM. Generalized convulsive status epilepticus in the adult. Epilepsia 1993;34: S2-11.

The increased cellular activity of status epilepticus elevates demand for oxygen and glucose, and cerebral blood flow initially increases. After approximately 20 minutes, however, energy supplies are exhausted, causing local catabolism to support ion pumps (in an attempt to restore the internal milieu); this is a major cause of epileptic brain damage. In addition to damaging the CNS, generalized convulsive status epilepticus produces life-threatening systemic effects.³² Excess secretion of epinephrine and cortisol cause systemic and pulmonary arterial pressures to rise dramatically at seizure onset and also produce hyperglycemia. Muscular work raises blood lactate levels. Both airway obstruction and abnormal diaphragmatic contractions impair respiration. Carbon dioxide excretion falls while its production increases markedly. Muscular work accelerates heat production, raising core body temperature.

The combined respiratory and metabolic acidoses frequently reduce the arterial blood pH to 6.9 or lower. The acidemia may produce hyperkalemia; in addition to its deleterious effects on cardiac electrophysiology, the elevated extracellular potassium level helps propagate seizure activity. Coupled with hypoxemia and the elevation of circulating catecholamine concentrations, these conditions rarely can produce cardiac arrest. This sequence probably accounts for some cases of epileptic sudden death; neurogenic pulmonary edema is the likely cause of many others. The severity of the acidosis may prompt consideration of bicarbonate administration. When this is attempted, however, the likelihood of the occurrence of pulmonary edema is inordinately high. Rapid termination of seizure activity is the most appropriate treatment; the restitution of ventilation and the metabolism of lactate quickly restore a normal pH.

After approximately 30 minutes of continuous convulsions, motor activity may diminish while electrographic seizures persist. Hypotension and hyperthermia ensue, and gluconeogenesis can fail, resulting in hypoglycemia. Generalized convulsive status epilepticus patients often aspirate oral or gastric contents, producing chemical pneumonitis or bacterial pneumonia. Rhabdomyolysis is common and may lead to renal failure. Compression fractures, joint dislocations, and tendon avulsions are other serious sequelae.

The mechanisms that terminate seizure activity are poorly understood. The leading candidates are inhibitory mechanisms, primarily GABA-ergic interneurons and inhibitory thalamic neurons.

Clinical Manifestations

Three problems complicate seizure recognition: (1) the occurrence of complex partial seizures in the setting of impaired awareness, (2) the occurrence of seizures in patients receiving pharmacologically induced paralysis and/or sedation, and (3) misinterpretation of other abnormal movements as seizures. ICU patients often have depressed consciousness in the absence of seizures owing to their disease, its complications (such as hepatic³³ or septic³⁴ encephalopathy), or drug administration. A further decline in alertness may reflect a seizure; an EEG is required to confirm that one has occurred.

Patients receiving neuromuscular junction blocking agents do not manifest the usual signs of seizures. Patients with increased intracranial pressure (ICP) from primary brain injury, hepatic encephalopathy, or other critical illnesses may be both paralyzed and sedated, making identification of seizures particularly challenging. Tachycardia, tachypnea, and hypertension are signs of seizure that can be misinterpreted as evidence of inadequate sedation. Continuous EEG monitoring is warranted in this population if seizures are suspected.

Patients with metabolic disturbances, anoxia, and other types of nervous system injury may demonstrate abnormal movements that can be confused with seizure. Asterixis is a brief asynchronous loss of tone at the wrist or hip joints that can appear in the setting of hepatic dysfunction. Stimulus-sensitive massive myoclonus after anoxia can be dramatic but usually self-abates in a few days. Controversy exists as to the epileptic origin of this disorder, and postanoxic myoclonus has been reported in the presence of almost total cortical suppression.³⁵ Brain-injured patients may manifest paroxysmal episodes of sympathetic hyperactivity and associated rigidity or decerebrate posturing. These “hypothalamic seizures” can sometimes be distinguished from epileptic seizures with observation. Patients with tetanus are awake during their spasms and flex rather than extend their arms as seizure patients do. Psychiatric disturbances in the ICU occasionally resemble complex partial seizures. If doubt about the nature of abnormal movements persists, an EEG should be obtained.

The manifestations of status epilepticus depend on the type and, for partial status epilepticus, the cortical area of abnormality. Box 36-2 presents the types of status epilepticus encountered and focuses on those seen most frequently in the ICU.

Primary generalized convulsive status epilepticus begins as tonic extension of the trunk and extremities without preceding focal activity. No aura is reported, and consciousness is immediately lost. After several seconds of tonic extension, the extremities start to vibrate; clonic (rhythmic) extension of the extremities quickly follows. This phase wanes in intensity over a few minutes. The patient may then repeat the cycle of tonus followed by clonic movements or continue to have intermittent bursts of clonic activity without recovery. Myoclonic status epilepticus (bursts of myoclonic jerks that increase in intensity and lead to a generalized convulsion) is a less common form of generalized convulsive status epilepticus usually associated with anoxic coma.

Secondarily generalized status epilepticus begins with a partial seizure and progresses to a convulsive activity. The initial focal clinical activity may be overlooked. This seizure type implies a structural lesion, so care must be taken to elicit evidence of lateralized movements.

Of the several forms of generalized nonconvulsive status epilepticus, the one of greatest importance to intensivists is nonconvulsive status epilepticus as a sequela of inadequately treated generalized convulsive status epilepticus. When a patient with generalized convulsive status epilepticus is treated with anticonvulsants in inadequate doses, visible convulsive activity may stop, but the electrochemical seizure continues. Patients begin to awaken within 15 to 20 minutes after the successful termination of status epilepticus; many regain consciousness much faster. Patients who do not start to awaken after 20 minutes should be assumed to have entered nonconvulsive status epilepticus. Careful observation may disclose slight clonic activity. Nonconvulsive status epilepticus is an extremely dangerous problem because the destructive effects of status epilepticus continue even without obvious motor activity. Nonconvulsive status epilepticus demands emergency treatment guided by EEG monitoring to prevent further cerebral damage, since there are no clinical criteria to indicate whether therapy is effective.

Failure to recognize nonconvulsive status epilepticus is common in patients presenting with nonspecific neurobehavioral abnormalities such as delirium, lethargy, bizarre behavior, cataplexy, or mutism.³⁶ Patients may present in nonconvulsive status epilepticus without an inciting episode of generalized convulsive status epilepticus. A high suspicion for this disorder should be maintained in patients with unexplained alteration in level of consciousness or cognition admitted to the ICU.

Partial status epilepticus in ICU patients often follows a stroke or occurs with the rapid expansion of brain masses. Clonic motor activity is most easily recognized, but the seizure takes on the characteristics of adjacent functional tissue. Therefore, somatosensory or special sensory manifestations occur, and the ICU patient may be unable to report such symptoms. Aphasic status epilepticus occurs when a seizure begins in a language area and may resemble a stroke. Epilepsia partialis continua involves repetitive movements confined to a small region of the body. It may be seen with nonketotic hyperglycemia³⁷ or with focal brain disease; anticonvulsant treatment is seldom useful. Complex partial status epilepticus manifests with diminished awareness. The diagnosis often comes as a surprise when an EEG is obtained.

Diagnostic Approach

When an ICU patient has a seizure, one has a natural tendency to try to stop the event. This leads to both diagnostic obscuration and iatrogenic complications. Beyond protecting the patient from harm, very little can be done rapidly to influence the course of the seizure. Padded tongue blades, or similar items, should not be placed in the mouth; they are more likely to obstruct the airway than to preserve it. The seizures of most patients stop before any medication can reach the brain in an effective concentration.

Observation is the most important activity to perform when a patient has a single seizure. This is the time to collect evidence of a partial onset to implicate structural brain disease. The postictal examination is similarly valuable; language, motor, sensory, or reflex abnormalities after an apparently generalized seizure are evidence of focal pathology.

Seizures in ICU patients have several potential causes that must be investigated. Drugs are a major cause of ICU seizures, especially in the setting of diminished renal or hepatic function or when the blood-brain barrier is breached. Theophylline frequently produces seizures or status epilepticus if it has been rapidly loaded or if high concentrations of the drug occur; occasionally, however, these complications arise at “therapeutic” levels. Imipenem-cilastatin³⁸ and fluoroquinolones³⁹ have substantial potential to lower the seizure threshold, especially in patients with renal dysfunction. They should be avoided if possible in patients already at risk for seizure. Other antibiotics, especially β-lactams, are occasionally implicated.⁴⁰ Sevoflurane, a volatile anesthetic agent, is dose-dependently epileptogenic in patients with no predisposition to seizures.⁴¹

Recreational drugs are frequently overlooked offenders in patients presenting to the ICU. Acute cocaine or methamphetamine intoxication is characterized by a state of hypersympathetic activity followed by seizures.⁴² Although ethanol withdrawal is a common cause of seizures, discontinuing any hypnosedative agent may prompt convulsions 1 to 3 days later. One report suggests that narcotic withdrawal may produce seizures in the critically ill.¹ In the absence of other clear causes for seizure, complete toxicologic screening should be performed.

Serum glucose, electrolyte concentrations, and serum osmolality should also be measured. Nonketotic hyperglycemia^43,44 and hyponatremia can precipitate both focal and generalized seizures. Seizure activity may infrequently be the first presenting sign of diabetes mellitus. However, hypocalcemia rarely causes seizures beyond the neonatal period; its identification on analysis must not signal the end of the diagnostic workup. Hypomagnesemia has an equally unwarranted reputation as the cause of seizures in malnourished alcoholic patients.

The physical examination should emphasize assessment for both global and focal abnormalities of the CNS. Evidence of cardiovascular disease or systemic infection should be sought and the skin and fundi examined closely.

The need for imaging studies in these patients has been an area of uncertainty. A prospective study of neurologic complications in medical ICU patients determined that 38 of 61 patients (62%) had a vascular, infectious, or neoplastic explanation for their seizures.⁴⁵ Hence, head computed tomography (CT) or magnetic resonance imaging (MRI) should be performed on ICU patients with new seizures. With current technology, there are almost no patients who cannot undergo CT scanning, and MRI is particularly helpful in detecting evidence of acute ischemic stroke and encephalitis. MRI cannot be performed on patients with pacemakers. Many ICP monitor catheters are compatible with MRI provided the device is not coiled when it is secured to the scalp. Patients who need cerebrospinal fluid analysis always require imaging of the brain first. When CNS infection is suspected, empirical antibiotic treatment should be started while these studies are being performed.

Electroencephalography is a vital diagnostic tool for evaluating the seizure patient. Partial seizures usually show EEG abnormalities that begin in the area of cortex that produces seizures. Primary generalized seizures appear to start over the entire cortex simultaneously. Postictal slowing or depressed amplitude provides clues as to the focal cause of the seizures, and epileptiform activity helps classify the type of seizure and guide treatment. An emergency EEG is necessary to exclude nonconvulsive status epilepticus in those patients who do not begin to awaken soon after seizures have apparently been controlled (Figure 36-1).

Figure 36-1 Electroencephalographic recording during status epilepticus. First panel illustrates onset of seizure; subsequent panels show its evolution. Montage: longitudinal bipolar; channels 1-4, left temporal, and channels 5-8, left parasagittal. Calibration: vertical, 50 µV; horizontal, 1 sec.

In contrast to the patient with a single or a few seizures, the status epilepticus patient requires concomitant diagnostic and therapeutic efforts. Although 30 minutes of continuous or recurrent seizure activity usually define status epilepticus, one should not stand by waiting for this period to pass to start treatment. Since most seizures in critically ill patients stop within 2 to 3 minutes, it is reasonable to start treatment after 5 minutes of continuous seizure activity or after the second or third seizure occurs without recovery between the spells.

Treatment for status epilepticus should not be delayed to obtain an EEG. However, a prospective evaluation of 164 patients demonstrated that nearly half manifested persistent electrographic seizures in the 24 hours after clinical control of convulsive status epilepticus.⁴⁶ These data suggest that EEG monitoring after control of convulsive status epilepticus can be essential in directing the course of treatment. A variety of findings may be present on the EEG, depending on the type of status epilepticus and its duration (see Table 36-2). Complex partial status epilepticus patients are often without such organized discharges of generalized convulsive status epilepticus; instead, they have waxing and waning rhythmic activity in one or several brain regions. A diagnostic trial of intravenous (IV) benzodiazepine therapy is often necessary to diagnose complex partial status epilepticus. Patients developing refractory status epilepticus or having seizures during neuromuscular junction blockade require continuous EEG monitoring.

The availability of continuous paperless EEG monitoring allows for detection of seizure activity over a long period.⁴⁷ Subclinical seizures have been observed to occur in patients receiving aggressive treatment for status epilepticus and even in patients treated with barbiturates to a burst-suppression EEG pattern. The clinical significance of these subclinical seizures, and their effect on prognosis, remains uncertain.

Management Approach

Treating Status Epilepticus

Generalized convulsive status epilepticus obviously constitutes a medical emergency; however, nonconvulsive status epilepticus and complex partial status epilepticus are also emergencies but are more difficult to recognize. In each circumstance, one must act quickly to prevent additional cerebral damage. Figure 36-2 shows a management algorithm for status epilepticus and Box 36-3 presents a sample management protocol for drug administration.⁵⁴ Patients with simple partial status epilepticus or epilepsia partialis continua are at less risk for the development of widespread cerebral damage and are also less likely to respond to the aggressive approach outlined in Box 36-3. In these patients, correcting underlying problems such as nonketotic hyperosmolar hyperglycemia is crucial. Errors in terminating status epilepticus include inadequate dosing of effective drugs and continued use of drugs that are ineffective in the patient being treated.

Figure 36-2 Management algorithm for status epilepticus. CPSE, complex partial status epilepticus; GSCE, generalized convulsive status epilepticus; NCSE, nonconvulsive status epilepticus; SE, status epilepticus.

Box 36-3

Suggested Protocol for Treating Status Epilepticus

1 Establish an airway, provide oxygen, and ensure ventilation. If neuromuscular junction blockade is required for intubation, use a short-acting agent (e.g., succinylcholine or vecuronium).

2 Determine blood pressure. If the patient is hypotensive, begin volume replacement or administration of vasoactive agents (or both), as indicated. Generalized convulsive status epilepticus patients who present with hypotension will usually require admission to a critical care unit. Hypertension should not be treated until status epilepticus is controlled, since terminating status epilepticus usually substantially corrects it, and many of the agents used to terminate status epilepticus can produce hypotension.

3 Unless the patient is known to be normo- or hyperglycemic, administer dextrose (1 g/kg) and thiamine (1 mg/kg).

4 Terminate status epilepticus. The following sequence is recommended (see text for details); be cognizant of the potential of these drugs to eliminate the visible convulsive movements of generalized convulsive status epilepticus when leaving the patient in nonconvulsive status epilepticus. Patients who do not begin to respond to external stimuli 15 minutes after the apparent termination of generalized convulsive status epilepticus should be considered at risk for nonconvulsive status epilepticus and should undergo emergent EEG monitoring.

A Give lorazepam, 0.1 mg/kg, at a rate of 0.04 mg/kg/min. This drug should be diluted in an equal volume of the solution being used for intravenous infusion, as it is quite viscous. Most adult patients who respond do so by a total administered dose of 8 mg. The latency of effect is debated, but lack of response after 5 minutes should indicate failure.

B If status epilepticus persists after lorazepam administration, consider phenytoin at up to 50 mg/min; or fosphenytoin, 20 mg/kg, at up to 150 mg/min (dosed by phenytoin equivalent). Many investigators believe an additional 5 mg/kg dose of phenytoin equivalent should be administered before the next line of therapy is attempted. However, this step may have more value for preventing status epilepticus recurrence than for its initial control.

C If status epilepticus persists, administer midazolam, 0.2 mg/kg as a bolus, followed by an infusion of 0.1-2 mg/kg/h to achieve seizure control (as determined by EEG monitoring). Intubate the patient at this stage if this has not already been accomplished. A patient reaching this stage should be treated in a critical care unit.

D Should the patient’s condition not be controlled with midazolam, administer propofol or pentobarbital. Propofol is given as a continuous infusion at a rate of 1-15 mg/kg/h to achieve seizure control (as determined by EEG monitoring). A bolus dose of propofol (3 mg/kg) is often given but may increase the occurrence of hypotension. Pentobarbital is given as a bolus dose of 12 mg/kg at a rate of 0.2-0.4 mg/kg/min as tolerated, followed by an infusion of 0.25-2 mg/kg/h, as determined by EEG monitoring (with an initial goal of burst-suppression; in some cases, an isoelectric electroencephalogram may be required to eliminate all electrical seizures). Most patients require systemic and pulmonary arterial catheterization, with fluid and vasoactive drug therapy as indicated to maintain blood pressure. Other complications of this treatment are discussed in the text.

5 Prevent recurrence of status epilepticus. The choice of drugs depends greatly on the cause of status epilepticus and the patient’s medical and social situation. In general, patients not previously receiving anticonvulsants whose status epilepticus is easily controlled often respond well to chronic treatment with phenytoin or carbamazepine. In contrast, others (e.g., patients with acute encephalitis) will require two or three anticonvulsants at “toxic” levels (e.g., phenobarbital at greater than 100 µg/mL) to be weaned from midazolam or pentobarbital and may still have occasional seizures.

6 Treat complications.

A Rhabdomyolysis should be treated with a vigorous saline diuresis to prevent acute renal failure; urinary alkalinization may be a useful adjunct. If definitive treatment of generalized convulsive status epilepticus takes longer than expected because of hypotension or arrhythmias, neuromuscular junction blockade under EEG monitoring might be considered.

B Hyperthermia usually remits rapidly after termination of status epilepticus. External cooling usually suffices if the core temperature remains elevated. In rare instances, cool peritoneal lavage or extracorporeal blood cooling may be required. High-dose pentobarbital generally produces poikilothermia.

C Treatment of cerebral edema occurring secondary to status epilepticus has not been well studied. When substantial edema is present, one should suspect that status epilepticus and cerebral edema are both manifestations of the same underlying condition. Mannitol and mild hyperventilation may be valuable if edema is life threatening. If substantial cerebral edema is present, ICP monitoring should be strongly considered. Edema due to status epilepticus is vasogenic in origin; thus, steroids may be useful as well, but they have not been studied in this setting.

The conventional agents used as first-line treatment of status epilepticus are the benzodiazepines (especially lorazepam, diazepam, and midazolam), phenytoin, and phenobarbital. Status epilepticus that is refractory to the traditional agents is treated with continuous infusions of the short-acting barbiturates, midazolam, or propofol. A major multicenter clinical trial⁵⁵ that compared lorazepam alone, phenytoin alone, diazepam followed by phenytoin, and phenobarbital alone as initial drug treatment for generalized convulsive status epilepticus showed that the highest rate of successful treatment of “overt” generalized convulsive status epilepticus was achieved with lorazepam. There was no demonstrable difference among these four drug regimens in the initial treatment of “subtle” generalized convulsive status epilepticus. Lorazepam has been our agent of first choice for terminating status epilepticus for many years and remains so with support from this study.

Advantages of lorazepam over diazepam are its duration of action against status epilepticus (4 to 14 hours as opposed to 20 minutes) and its higher initial response rate. European practitioners often use midazolam or clonazepam initially. In patients in whom IV access is difficult to attain, 0.2 mg/kg of midazolam administered intramuscularly will be rapidly and reliably absorbed. The use of midazolam in refractory status will be discussed later. Respiratory depression is the major adverse effect of the benzodiazepines, especially when they are given together with barbiturates or paraldehyde.

Phenytoin is a less effective agent in the treatment of status epilepticus; in addition, the constraint on the rate of IV administration is of concern. Phenytoin has a long duration of action when an adequate dose is given (a 20 mg/kg dose produces a serum level above 20 µg/mL for 24 hours). Adding 5 mg/kg if the first 20 mg/kg load fails to stop status epilepticus may be useful. Fosphenytoin can be administered by a more rapid IV infusion, but the brain concentration of the phenytoin derived from it does not appear to rise faster than with the native drug. Free phenytoin levels reach a therapeutic range 10 to 20 minutes after an infusion of fosphenytoin is started.^56,57 Intramuscular injection of fosphenytoin in patients with status epilepticus should not be considered acceptable therapy and should be reserved for only those rare circumstances in which IV access cannot be obtained.

Some practitioners advocate the use of phenobarbital as a first-line drug,⁵⁸ but it has typically been used as a third-line agent after administration of a benzodiazepine and phenytoin.⁵⁹ Although this approach has been widely accepted by the neurologic community, we rarely use phenobarbital for two reasons. First, only a small percentage of patients who have failed treatment with the first anticonvulsant drug respond to a second or third conventional agent⁶⁰; second, at least an additional 20 minutes are required to obtain control in the few patients who do respond. Phenobarbital remains an important drug in the management of simple partial status epilepticus and for those patients who are being weaned from high-dose midazolam or anesthetic barbiturates.

Pentobarbital and thiopental infusions are usually reserved for refractory status epilepticus.⁵⁶ Although these drugs are effective in sufficiently large doses, their side effects can limit their use and may be fatal.⁶¹ However, they are important when other modalities have failed (see Box 36-3). Endotracheal intubation and mechanical ventilation are mandatory when high-dose barbiturates are used, and both continuous EEG and invasive hemodynamic monitoring are highly recommended. Severe hypotension is the most frequent side effect of pentobarbital therapy, and its occurrence is associated with increased mortality.⁶² An increased occurrence of nosocomial respiratory tract infection has been reported in patients treated with pentobarbital infusion.⁶³ An inhibitory effect on leukocyte chemotaxis and paralysis of respiratory cilia by the barbiturates have been postulated. Despite these side effects, barbiturate anesthesia should not be rapidly discontinued if it is successful in terminating refractory status epilepticus; rather, continuing therapy for at least 48 hours, gradual tapering of the infusion dose, and the administration of phenobarbital during the drug taper are recommended.⁶⁴

Midazolam is a water-soluble benzodiazepine that has demonstrated high efficacy in refractory status in adults and children.^65,66 At our institution, this agent is used as a second-line drug after lorazepam has failed to control status epilepticus. Clinically significant hypotension is rare even at very high doses that are often required to address tachyphylaxis. Respiratory depression is uncommon after a loading dose but should be anticipated with infusions of any duration. Sedation is quickly reversed after short-term infusions are discontinued. However, terminal half-lives of three to eight times normal have been reported with extended administration.⁶⁷ In addition, prolonged elimination times have been associated with critical illness and hepatorenal dysfunction. Others have recently discussed its use in this setting.⁶⁸

Isoflurane, an inhaled anesthetic, controls refractory status epilepticus; however, it is difficult to deliver such a gas outside of the operating suite or the recovery area. It has no known advantage over IV anticonvulsants and can raise ICP.

Propofol has been reported to be effective in the treatment of refractory status epilepticus, but direct comparisons with other agents have shown mixed results.^69,70 It may offer a lower risk of ventilatory depression and promote more rapid awakening compared with other drugs when it is discontinued. Early fears of a possible proconvulsant effect appear to be unfounded, although withdrawal convulsions may occur if the drug is abruptly terminated. A dosage range of 1 to 15 mg/kg/h has been studied,⁷¹ although the actual upper limit is not known. Acidosis and oxygenation difficulties have been reported in children.⁷² Mortality with its use appears to be greater than with midazolam.⁷⁰ Careful monitoring of creatine kinase and oxygen saturation would be prudent.⁷³

Levetiracetam is emerging as a very commonly used IV and enteral antiseizure drug in critical care. Unfortunately, no organized dose-finding has been undertaken in critically ill patients; published series have included loading doses between 1 and 6 grams, with a wide range of maintenance doses.⁷⁴ Levetiracetam has been used for prophylaxis after head trauma, but the higher mortality in the patients receiving this drug in comparison to those receiving phenytoin argues for some caution.⁷⁵

IV valproate has emerged as an important drug for the treatment of several forms of status epilepticus.⁷⁶ IV lacosamide is also available, but information about its use in status is limited. Topiramate may also be useful for refractory status epilepticus⁷⁷ but lacks an IV form. Levetiracetam (1 gm loading dose, 1-9 gm/d maintenance) or lacosamide (300-400 mg loading dose, 300-400 mg/d maintenance) may also be useful.