Status epilepticus (SE) is a medical emergency that requires immediate and vigorous treatment directed at stopping all behavioral and electrical seizure activity. Physiologic changes occur during the course of SE that may result in severe systemic complications and also may damage or kill cerebral neurons. Physiologically, SE is defined as recurrent seizures without complete normalization of neurochemical and physiologic homeostasis in the brain between seizures. This physiologic definition makes clear the rationale for the operational definition of SE as recurrent seizures without full recovery of neurologic function between seizures. In this chapter, we consider goals and general principles in the management of SE and review general measures and specific pharmacotherapy for the successful management of SE.

The goal in the management of SE is simple: To stop seizure activity as quickly as possible. By doing so, neurons are less likely to be damaged, physiologic consequences are less likely to cause organ failure, and patients are more likely to recover fully from the episode of SE. Ideally, SE should be stopped within 30 minutes from the start of the episode. Meldrum³² and subsequently others^11,12,56 made a distinction between early SE (the first 30 minutes) and late SE (after 30 minutes). They found that physiologic changes occur in late SE that produce systemic complications and put neurons in jeopardy of permanent damage or death (Table 1). Furthermore, the longer SE persists, the more likely that neurons will be damaged by exposure of N-methyl-D-aspartate (NMDA) receptors to the excitatory amino acid neurotransmitter glutamate. Activation of NMDA receptors results in an opening of their cation channels to calcium. The marked increase in intercellular calcium that results sets up a cascade of intercellular biochemical events that damages or kills the cell.^17,31 Sustained seizure activity also results in a progressive reduction of γ-aminobutyric acid (GABA)–mediated inhibition.²⁰ These progressive physiologic and neurochemical changes may provide an explanation for the experimental and clinical observations that the longer the duration of the episode of SE, the more subtle will be the motor manifestations^50,57 and the more refractory the episode will be to pharmacotherapy.^26,50,57

In most patients with SE, ongoing seizure activity is more likely to cause permanent neurologic damage than systemic factors.³³ Although systemic stress from hypoxia, hyperthermia, and hypotension can augment neuronal injury³³ and must be managed effectively, it is most imperative that early efforts focus on cessation of electrical and behavioral seizure activity. This can be accomplished by initiating treatment as soon as the diagnosis of SE is made and then monitoring the patient’s electroencephalogram (EEG) during management. Treatment should never be delayed while awaiting the arrival of the EEG machine. EEG recording may be necessary, however, to confirm successful treatment of the episode. If behavioral seizures stop and the patient is observed progressively to recover consciousness, no EEG recording is needed. If behavioral seizure activity stops but the patient remains in a coma or in an impaired state of consciousness, however, EEG evaluation is essential to determine whether electrical seizure activity has ended. Treiman⁴⁹ reviewed the electroclinical aspects of various types of SE. He suggested that a variety of patterns can be considered ictal, including periodic epileptiform discharges, and proposed that all such epileptiform activity be stopped before the patient is considered successfully treated.⁴⁹ See Chapter 58 for a more detailed discussion of EEG changes during generalized convulsive SE and for EEG examples of ictal patterns.

The management of SE can be divided into general measures and specific pharmacotherapy. General measures include the immediate evaluation and correction of physiologic abnormalities that may occur as a consequence of the episode of SE and concurrent evaluation for potential causes of the event.

The initial evaluation of any medical emergency, including SE, is focused on stabilization of airway, breathing, and circulation. Often, the most effective way to manage the airway is to terminate the seizures pharmacologically (see later discussion). If it is essential to establish a patent airway, insert an oral airway or an endotracheal tube. If neuromuscular junction blockade is required for intubation, a nondepolarizing agent should usually be chosen unless the patient lacks any risk factors for the development of hyperkalemia with a depolarizing agent. Respiratory effort also must be assessed and supported if insufficient. Arterial blood gas analysis and transcutaneous saturation monitoring are useful to guide airway management and determine whether supplemental oxygen is needed. Blood pressure must be evaluated and supported. Early in SE, blood pressure is usually elevated attendant to the rise in circulating catecholamines. With prolonged SE or administration of intravenous medications (particularly phenytoin, propofol, or barbiturates), however, hypotension may develop. If this occurs, vasopressor agents should be administered. Vasopressors and inotropes are almost invariably needed in prolonged status epilepticus. Once initial emergency evaluation is completed and the patient’s airway, respiratory status, and circulatory status are stabilized, blood should be obtained for evaluation of hematologic and biochemical parameters, toxicology screen, and determination of antiseizure drug concentrations. An intravenous line should be placed, preferably in a large vein, and kept open with normal saline. Dextrose-containing solutions should not be used in institutions that use intravenous phenytoin because of the
potential for precipitation. This caveat need not be considered in institutions that have replaced parenteral phenytoin with fosphenytoin.

The patient’s blood glucose concentration should be determined by finger stick. If hypoglycemia is detected, the patient should be given an intravenous bolus dose of glucose. The usual dose for hypoglycemia in adults is 50 mL of 50% glucose; the dose for children is 2 mL/kg of 25% glucose. Any adult who could be thiamine deficient (e.g., alcoholics or malnourished individuals) should be given 100 mg of thiamine intravenously before or simultaneously with the glucose in order to avoid Wernicke encephalopathy. Historically, it was common to administer a bolus of glucose to all patients with SE in case the episode had been precipitated by hypoglycemia. However, hyperglycemia may exacerbate neuronal damage caused by cerebral ischemia and SE.^8,18,48 Therefore, the blood glucose should be determined at the bedside and a dose of glucose only given if the concentration is ≤70 mg/dL (3.9 mmol/L).

The next step is to determine the cause of the event. SE may occur in persons with epilepsy (low antiseizure drug concentrations and alcohol are two common causes), as the initial manifestation of epilepsy, or as a consequence of a severe neurologic or systemic insult. The prognosis in the former situations is far better than in the latter.⁴³ In a patient with epilepsy in whom SE has been precipitated by withdrawal or reduction of maintenance antiseizure drug therapy, the rapid reintroduction of the relevant drug will usually terminate SE (the drug should be given intravenously if possible). In some instances, such as SE caused by metabolic derangements or medication overdose, specific treatments are available to address the underlying precipitant. For example, SE caused by hyponatremia may respond to gradual sodium replacement; SE caused by isoniazid overdose often responds to intravenous (IV) pyridoxine. In infants developing status epilepticus, IV pyridoxine is routinely given. In many cases, however, the immediate cause of SE is not apparent or etiology-specific treatment is not available. Even when there is no specific treatment for the cause of SE, the information is useful because neurologic outcome is largely dependent on the etiology. It is usually wise also to save 50 mL of serum in a patient in whom the cause is not obvious, for later analysis.

Medical complications should be identified and treated. The most common are cerebral complications (venous thrombosis, hemorrhage, infarction), cardiovascular complications (notably hypotension, cardiac arrhythmia, cardiorespiratory failure, pulmonary edema), and systemic complications (hepatic failure, renal failure, pancreatitis, electrolyte disturbance, disseminated intravascular coagulation, rhabdomyolysis, thrombophlebitis, and infections).⁴⁴

Pharmacotherapy (discussed later) is indicated for patients who experience two or more seizures without full recovery of consciousness or who exhibit continuous seizure activity (either behaviorally or electrically) for 5 minutes or longer.^2,27,28,51 Simultaneously, other general measures should be considered. Hyperthermia is common during SE and may markedly exacerbate neuronal damage caused by ongoing electrical seizure activity.³² Rectal temperature should be monitored during an episode of SE, and fever should be corrected quickly using passive cooling measures.⁶ Acidosis from impaired ventilation and lactate release is common during SE and often does not need pharmacologic correction.⁴⁵ In the past, some advocated the use of bicarbonate to normalize the pH, but there is no evidence that transient SE-induced acidosis, even with serum pH ≤7.0, results in permanent injury. Generally, once SE is stopped, the serum pH normalizes rapidly. If large amounts of bicarbonate have been administered, however, this may result in iatrogenic metabolic alkalosis once SE is controlled.

The utility of steroids in reducing intracerebral edema during SE has not been proven, nor has the value of monitoring for increased intracranial pressure. Muscle paralysis is rarely indicated in the management of SE (except to facilitate intubation and in certain postoperative situations) and should never be used without ongoing EEG monitoring to detect ongoing seizures.

An ideal drug for the treatment of SE would be easy to administer, have immediate and long-lasting antiseizure effects, and would not cause adverse effects on respiratory drive, cardiovascular function, or level of consciousness. Intravenous therapy is always preferred because drugs administered by this route are completely bioavailable and have minimal delay in attaining a therapeutic effect. However, alternate routes of administration (e.g., rectal, buccal, and intranasal routes), have utility when intravenous access is not feasible, particularly in the out-of-hospital setting, and in selected situations for infants and children.^29,30,40 Thus, the choice of treatments for SE is based on efficacy, pharmacokinetic features, toxicity, and relative ease of use. Drugs useful for the termination of SE are most effective when given early in an episode. In one retrospective study, first-line therapy (usually a benzodiazepine followed by phenytoin) was effective in 80% of patients when administered within 30 minutes of the onset of SE. When treatment was delayed by 2 hours or more, however, ≤40% of patients responded.²⁶ Altered sensitivity of drug targets to antiseizure therapies may contribute to this reduction in pharmacoresponsiveness. In animals, GABA_A receptors from dentate granule cells become progressively less sensitive to diazepam during 45 minutes of continuous pilocarpine-induced seizures. This plasticity in GABA_A-receptor function appears to be drug specific because sensitivity to pentobarbital was preserved over this same time interval.²² These observations suggest a possible mechanism for reduced pharmacoresponse
during prolonged SE in humans, and suggest that future approaches to therapy may need to be tailored to the specific functional state of drug targets as opposed to the “one protocol fits all” approach to SE management that has been used historically.²⁵