Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

41. Status Epilepticus

Stephanie J. Phelps and James W. Wheless


KEY CONCEPTS

 Images Status epilepticus (SE) is a neurologic emergency that is associated with significant morbidity and mortality.

 Images Generalized convulsive status epilepticus (GCSE) is defined as any recurrent or continuous seizure activity lasting longer than 30 minutes in which the patient does not regain baseline mental status. Any seizure that does not stop within 5 minutes should be treated as impending SE.

 Images There are two types of SE, GCSE and nonconvulsive status epilepticus (NCSE). GCSE is the most common type.

 Images Most GCSE develops in patients with no history of epilepsy; however, a patient with preexisting epilepsy may experience GCSE as a result of acute anticonvulsant withdrawal, metabolic disorder, concurrent illness, or progression of neurologic disease.

 Images Although the pathophysiology of GCSE is unknown, experimental models have shown that there is a dramatic decrease in γ-aminobutyric acid–mediated inhibitory synaptic transmission and that glutamatergic excitatory synaptic transmission sustains the seizures.

 Images General treatment includes patient stabilization, adequate oxygenation, preservation of cardiorespiratory function, management of systemic complications, and aggressive assessment of underlying causes.

 Images The main purpose of treatment is to prevent or decrease morbidity and mortality of prolonged seizures. Pharmacologic treatment needs to be rapid and aimed at terminating both electrical and clinical seizures. The probability of poorer outcomes increases with increased length of electrographic seizure activity.

 Images Lorazepam is the preferred benzodiazepine in treatment of GCSE because of its efficacy and long duration of action in the CNS. Midazolam is the preferred benzodiazepine for intramuscular (IM) administration.

 Images Currently, the hydantoins (phenytoin and fosphenytoin) are the long-acting anticonvulsants used most frequently. Either phenytoin or fosphenytoin should be given concurrently with benzodiazepines.

 Images The maximum rate of infusion for phenytoin and fosphenytoin in adults is 50 mg/min and 150 mg PE/min, respectively.

 Images If GCSE is not controlled by two first-line agents (benzodiazepine plus hydantoin or phenobarbital), the GCSE is considered to be refractory. In these cases, anesthetic doses of midazolam, pentobarbital, or propofol may be used.


INTRODUCTION

Images Status epilepticus (SE) is a common neurologic emergency that is associated with brain damage and death. Images The traditional definition defines SE as (a) any seizure lasting longer than 30 minutes whether or not consciousness is impaired or (b) recurrent seizures without an intervening period of consciousness between seizures.1 Clinically, this definition has limited use, as the average seizure is less than 2 minutes; and only 40% of seizures lasting 10 to 29 minutes cease without treatment.2,3 Pharmacoresistance4 and mortality3 significantly increase with prolonged seizure duration. Images Therefore, aggressive treatment of seizures lasting 5 minutes or more is strongly recommended. ImagesSE can present in several forms (Table 41-1), including generalized convulsive status epilepticus (GCSE) and nonconvulsive status epilepticus (NCSE).1

TABLE 41-1 International Classification of Status Epilepticus

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NCSE occurs in 25% of those with SE and is characterized by a fluctuating or continuous “epileptic twilight” state that produces altered consciousness and/or behavior (e.g., lethargy, decreased mental function). An electroencephalogram (EEG) is the most important diagnostic and management tool.5 In most instances, a benzodiazepine and/or valproate remain drugs of choice.5 Although IV hydantoin, levetiracetam, or phenobarbital can be tried in nonresponders, general anesthesia is usually not appropriate.5

This chapter will focus on GCSE, which is the most common and severe form of SE. It is characterized by repeated primary or secondary generalized seizures that involve both hemispheres of the brain and are associated with a persistent postictal state.4

EPIDEMIOLOGY

The worldwide and United States incidence ranges between 1.2 to 5 million and 100,000 to 152,000 cases each year, respectively.4 GCSE has no predilection for gender or socioeconomic status but does occur more frequently in nonwhites across all ages.6 Most GCSE occurs in individuals with no history of epilepsy; however, approximately 5% of adults and 10% to 25% of children with epilepsy will develop GCSE.7 The incidence of GCSE is highest in those younger than 1 year of age and in those older than 60 years of age.

ETIOLOGY

Precipitating events for GCSE vary and generally reflect different populations and referral patterns. Images Most episodes in individuals with epilepsy occur because of acute anticonvulsant withdrawal, a metabolic disorder or concurrent illness, or progression of a preexisting neurologic disease. Common etiologies and mortality rates are shown in Table 41-2.6,8 Precipitating events are divided into those with and without neurologic structural lesions or those with a precipitating injury or insult. Cases with structural lesions or those with a specific neurologic insult are associated with a poor prognosis.

TABLE 41-2 Etiology and Mortality for Pediatric and Adult Cases of Status Epilepticus

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There are major differences in etiologies for pediatric and adult patients (see Table 41-2). During their first few weeks of life, infants who are born to addicted mothers can develop drug withdrawal seizures. Other neonates can develop GCSE because of pyridoxine deficiency, which should resolve within hours following IV pyridoxine (100 mg). Acute encephalopathy and metabolic disorders are the major causes of GCSE in those younger than 1 year of age. In young children, the cause is often a nonspecific illness such as fever and/or a viral illness. The most frequent precipitating events in adults are cerebrovascular disease, rapid anticonvulsant withdrawal, and low anticonvulsant serum concentrations. Cerebrovascular disease is the leading cause in those who have their first seizures after age 60. Prescription, over-the-counter, and recreational drugs should be considered in anyone with new-onset GCSE.

MORBIDITY AND MORTALITY

GCSE is harmful to the brain. While most contend that the GCSE is responsible for the damage, it is unknown if the morbidity results from the underlying etiology or the GCSE. Regardless of the inducing stimulus, neuronal damage in animal models is evident following 30 to 60 minutes of GCSE, and most progress to develop epilepsy following a prolonged seizure. Interestingly, inhibiting the seizure-induced neuronal damage does not prevent the development of epilepsy, suggesting that the seizures themselves may be harmful. It is hard to establish a relationship between GCSE and long-term outcomes because it is difficult to weigh the effects of seizure type, etiology, duration, concurrent physiologic events, and therapy or lack thereof. It has been shown that patients with a history of prolonged febrile seizures who later developed epilepsy share similar histopathologic changes (i.e., hippocampal sclerosis) to those found in animal models of GCSE.9,10 In these cases, the period between the initial GCSE and the first epileptic seizure may be months to decades, suggesting a possible link between GCSE and the development of epilepsy. Importantly, studies of GCSE show that the currently available anticonvulsants do not reproducibly prevent the development of epilepsy following prolonged seizures.9,11

Patients who develop epilepsy following prolonged GCSE are less likely to experience remission of their seizures and may have decreased cognitive and memory function, mental retardation, or neurologic deficits when compared to those who develop epilepsy and subsequently have GCSE.4 Most studies have found that younger children, the elderly, and those with preexisting epilepsy have a higher propensity for sequelae. Unless accompanied by an underlying neurologic abnormality, febrile status epilepticus is less likely to be associated with sequelae.

Estimated mortality in the United States following GCSE ranges between 22,000 and 42,000 individuals per year,8 with rates up to 16% in children,12 20% in adults,4 and 38% in the elderly.6 When compared with other populations, neonates have a higher mortality and more neurologic sequelae.

Table 41-2 summarizes the etiology and corresponding mortality rates for GCSE.6,8 Interestingly, the mortality associated with many etiologies is significantly greater in adults than in children. Unresponsive patients may die from GCSE, but more frequently they die from the acute illness that precipitated the GCSE. For example, patients with serious CNS structural changes (e.g., hemorrhage, stroke) have a poor prognosis, compared to those with no structural lesion.

Outcome is affected by the time between onset of GCSE and the initiation of treatment and the duration of the seizure. Mortality significantly increases with increased seizure duration (e.g., 2.6% for seizures 10 to 29 minutes, 19% for seizures lasting >30 minutes, and 32% for seizures lasting greater than 60 minutes).2,8 Mortality has decreased over the past decade and probably reflects a recognition of the need to initiate sequenced therapy using large doses as soon as possible.

PATHOGENESIS

Seizures occur when the excitatory neurotransmission overcomes inhibitory impulses in one or more brain regions. Most seizures are brief (less than 5 minutes), largely because the brain’s inhibitory mechanisms restore the balance of normal neurotransmission.4 Although it is unknown why the mechanisms that control normal brain homeostasis fail, when seizures occur in close succession or the magnitude of the proconvulsant stimulus is severe, compensatory mechanisms can be overwhelmed.

Images While the exact cellular mechanisms are unknown, it appears that seizure initiation is caused by an imbalance between excitatory (e.g., glutamate, calcium, sodium, substance P, and neurokinin B) and inhibitory neurotransmission (e.g., γ-aminobutyric acid [GABA], adenosine, potassium, neuropeptide Y, opioid peptides, and galanin).13

Most of what is known has focused on gated ion channels.13 GCSE is largely caused by glutamate acting on postsynaptic N-methyl-D-aspartate (NMDA) and ε-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)/kainate receptors. During GCSE, glutamate activation of the NMDA and AMPA receptors causes opening of the gated calcium and sodium channels, which lead to neuronal depolarization. Sustained depolarization may maintain GCSE and eventually cause neuronal death through calcium-, free radical-, and kinase-mediated events.9 Although drugs acting as NMDA and AMPA receptor antagonists seem attractive, it is likely that glutamate is not the sole mechanism for GCSE and that other mechanisms become increasingly important as the duration of seizures increases.

Little is known about second messenger systems (e.g., metabotropic glutamate receptors) and the development of GCSE. GABAA postsynaptic receptors control chloride channels to produce hyperpolarization (inhibition) of the postsynaptic cell membrane. These receptors have binding sites for GABA and select anticonvulsants (e.g., phenobarbital and benzodiazepines) and enhance GABAA-mediated chloride inhibitory currents. It was previously thought that a decrease in presynaptic GABA led to prolonged seizures; however, it is currently held that GABA concentrations increase during the early phases of GCSE and continue to be elevated during late GCSE. Prolonged seizures lead to decreased inhibitory GABAA-receptor density because of postsynaptic receptor endocytosis. Additionally, modification of GABAAreceptors during SE may decrease response to both endogenous GABA and GABA agonists.10 Clinically, the relative potencies of benzodiazepines and phenobarbital can be reduced up to 10-fold if seizures persist for more than 30 minutes.10 A similar phenomenon occurs with sodium channel antagonists (phenytoin); however, the magnitude of resistance is less.

PATHOPHYSIOLOGY

As GCSE persists, there are systemic alterations, progression of motor phenomena, and development of specific EEG findings.14 Two distinct and predictable phases have been identified. Phase I occurs during the first 30 minutes of seizure activity, and phase II immediately follows. Although these systemic complications affect the prognosis of GCSE, a prolonged seizure can destroy neurons independent of these events.9 In fact, the systemic effects of induced seizures in animals can be blocked, but the damage to the neocortex, cerebellum, and hippocampus persists.

During phase I, each seizure markedly increases plasma epinephrine, norepinephrine, and steroid concentrations, which can cause hypertension, tachycardia, and cardiac arrhythmias.15 Within minutes, arterial systolic pressures can rise to above 200 mm Hg, and heart rate can increase by 83 beats per minute. Mean arterial pressure does not fall below 60 mm Hg; hence, cerebral perfusion pressure is not compromised. In animals, cerebral blood flow is also increased, thereby protecting neurons from hypoxic injury.

In the presence of a hypoxic myocardium, seizure-induced increases in sympathetic and parasympathetic stimulation of the heart can result in ventricular arrhythmias. Autonomic neuron stimulation can cause a release of insulin and glucagon. Concurrently, circulating catecholamines cause an elevation of hepatic cyclic adenosine monophosphate, producing glycogenolysis. Although the patient can be hyperglycemic initially, serum glucose begins to fall.

Seizure-induced muscular contractions and hypoxia cause lactic acid release, which can produce severe acidosis that maybe accompanied by hypotension and shock. Muscle contractions can be so severe that rhabdomyolysis with secondary hyperkalemia and acute tubular necrosis can occur. The airway can be obstructed, causing the patient to become cyanotic or hypoxic. Additionally, an increase in salivation and tracheal and pulmonary secretions can cause aspiration pneumonia. Although transient pleocytosis can develop, it should not be attributed to SE until infectious causes have been eliminated. Between seizures, the EEG slows, and blood pressure normalizes. Although metabolic demands are increased, the brain is able to adequately compensate.

When seizures exceed 30 minutes (phase II), the EEG ictal discharge and clonic motor activity become continuous, and the patient begins to decompensate. Despite elevated levels of catecholamines, the patient can become hypotensive. During this time, autoregulation of cerebral blood flow becomes dependent on mean arterial pressure and begins to fail. There continues to be an excessive consumption of oxygen and glucose; however, compensatory mechanisms are no longer able to meet demands.

During Phase II, the serum glucose concentration may be normal or decreased. Profound hypoglycemia, secondary to hyperinsulinemia, can occur in those with hepatic dysfunction or reduced glycogen stores. Hyperthermia and respiratory deterioration with hypoxia and ventilatory failure can develop. Metabolic and biochemical complications, including respiratory and metabolic acidosis, hyperkalemia, hyponatremia, and azotemia, may develop. There is increased sweating and salivation.

CLINICAL PRESENTATION AND DIAGNOSIS

Accurate diagnosis requires observation, physical examination, laboratory assessment, EEG, and neurologic imaging. The nature and duration of the seizure should be obtained, but a diagnosis of GCSE should not be made until a clinician has observed a seizure. Most patients have an altered consciousness that ranges from obtunded to marked lethargy and somnolence with pronounced eyes-open unresponsiveness and waxy rigidity. Motor features can include muscle contractions, extensor or flexor posturing, and spasms. Over time, the clinical manifestations become less apparent. This has important ramifications in that seizures appear to have terminated without treatment or when an ineffective therapy is given.

In addition to an assessment of language and cognitive abilities, the physical and neurological examinations should assess motor, sensory, and reflex abnormalities, pupillary response, asymmetry, and posturing. The patient should also be examined for secondary injuries (e.g., tongue lacerations, shoulder dislocations, and head and facial trauma).

Laboratory tests are essential to the diagnosis of various etiologies. Hypoglycemia, hyponatremia, hypernatremia, hypomagnesemia, hypocalcemia, and renal failure all can cause seizures. A urine drug screen can help eliminate illicit drug use or drug overdose. Serum drug concentration(s) should be obtained in those on chronic anticonvulsants, as low concentrations can reflect partial adherence or rapid drug withdrawal. A baseline serum concentration is necessary to determine whether a loading dose of a specific anticonvulsant is required. Assessment of other laboratory parameters (e.g., hematology and chemistries to include albumin, renal function, and hepatic function) that affect anticonvulsant dosing also can be useful. An EEG is a valuable diagnostic tool, particularly in those with prolonged GCSE in whom clinically apparent seizures are not always evident, but therapy should not be delayed while awaiting testing or results.


CLINICAL PRESENTATION GCSE

Symptoms

    • Impaired consciousness (e.g., lethargy to coma)

    • Disorientation once GCSE is controlled

    • Pain associated with injuries (e.g., tongue lacerations, shoulder dislocations, back pain, myalgias, headache, head trauma)

Early Signs

    • Generalized convulsions

    • Acute injuries or CNS insults that cause extensor or flexor posturing

    • Hypothermia or fever suggestive of intercurrent illnesses (e.g., sepsis or meningitis)

    • Incontinence

    • Normal blood pressure or hypotension and respiratory compromise

Late Signs

    • Clinical seizures may or may not be apparent

    • Pulmonary edema with respiratory failure

    • Cardiac failure (dysrhythmias, arrest, cardiogenic shock)

    • Hypotension or hypertension

    • Disseminated intravascular coagulation, multisystem organ failure

    • Rhabdomyolysis

    • Hyperpyrexia

Initial Laboratory Tests

    • Complete blood count (CBC) with differential

    • Serum chemistry profile (e.g., electrolytes, calcium, magnesium, glucose, serum creatinine, alanine aminotransferase [ALT], aspartate aminotransferase [AST])

    • Urine drug/alcohol screen

    • Blood cultures

    • Arterial blood gas to assess for metabolic and respiratory acidosis, oxygenation

    • Serum drug concentration if previous anticonvulsant suspected or known

Other Diagnostic Tests

    • Spinal tap if CNS infection suspected

    • EEG should be obtained on presentation and once clinical seizures are controlled

    • CT with and without contrast

    • MRI

    • Radiograph if indicated to diagnose fractures

Once seizures have stopped, it is important to determine if the patient is febrile or has a systemic or CNS infection. Many physiologic consequences of GCSE (e.g., leukocytosis, pleocytosis, and hyperthermia) produce symptoms that can be confused with other conditions. If a CNS infection is suspected, a spinal tap should be performed, and empiric antibiotics should be started. If vascular, neoplastic, or infectious etiologies are suspected, computed tomography (CT) or magnetic resonance imaging (MRI) should be obtained once the seizures are controlled.

TREATMENT

Various treatments are available for the management of GCSE. These range from abortion of impending SE with rescue medications to the use of pharmacologic and nonpharmacologic therapies for GCSE and refractory/resistant SE.

Desired Outcomes

Short-term desired outcomes include (a) immediate termination of all clinical and electrical seizure activity, (b) no clinically significant adverse effects, and (c) lack of recurrent seizure activity. The long-term outcomes involve minimizing or avoiding pharmacoresistant epilepsy and/or the development of neurologic sequelae that significantly impact quality of life.

Nonpharmacologic Therapy

The time of seizure onset should be noted. Vital signs should be assessed, an adequate and protected airway should be established, ventilation should be maintained, and oxygen should be administered. Frequent arterial blood gas determinations should assess for metabolic acidosis, which should be treated with sodium bicarbonate if the pH is less than 7.2. Assisted ventilation should be used to correct respiratory acidosis. Hyperthermia, if present, should be aggressively treated (e.g., rectal acetaminophen, cooling blanket).

Because electrical seizures may persist in the absence of overt clinical motor manifestations, an EEG should be performed in anyone who continues to have altered consciousness after clinical control of their seizures. Although hypoglycemia rarely causes GCSE, adults and children with a blood glucose less than 60 mg/dL (less than 3.3 mmol/L) should receive 50 mL of a 50% dextrose solution, and 1 mL/kg of a 25% dextrose solution, respectively.4,7Because Wernicke’s encephalopathy can develop in alcoholics, adults should receive IV thiamine (100 mg) prior to glucose.4 Serum glucose concentration should be determined to assess the need for further supplementation.

Pharmacologic Therapy

When a seizure does not stop within 5 minutes, or when doubt exists regarding the diagnosis, patients should be treated as if they have GCSE (Fig. 41-1). Images Images There are four immediate goals: (a) patient stabilization, including adequate oxygenation, preservation of cardiorespiratory function, and management of systemic complications; (b) accurate diagnosis of the subtype of GCSE and identification of precipitating factors; (c) termination of clinical and electrical seizures as early as possible; and (d) prevention of seizure recurrence. The benzodiazepines, hydantoins, and barbiturates are the most commonly used classes of anticonvulsants for the initial treatment of GCSE.

Images

FIGURE 41-1 Algorithm for the treatment of GCSE. (BP, blood pressure; CBC, complete blood count; EEG, electroencephalogram; GCSE, generalized convulsive status epilepticus; HR, heart rate; PR, per rectum; RR, respiratory rate.) aBecause variability exists in dosing, monitor serum concentration. bIf seizure is controlled, begin maintenance doses and optimize using serum concentration monitoring.

Benzodiazepines

The benzodiazepines are effective initial therapy in most patients and should be administered as soon as possible. Generally, one or two IV doses will terminate seizures within 2 to 3 minutes.4 All benzodiazepines are effective; therefore, preference is determined by differences in pharmacokinetics, route of administration, pharmacoeconomics, adverse-effect profile, and current availability.

Diazepam is extremely lipophilic with a large volume of distribution (1 to 2 L/kg).15 Although it initially distributes into the brain within seconds, it rapidly redistributes into fat, causing its CNS half-life to be less than 1 hour and its duration of effect to be less than 30 minutes.15 The rapid decrease in brain concentration can cause seizure recurrence; hence, a longer-acting anticonvulsant (e.g., phenytoin or phenobarbital) should also be given immediately after diazepam. Dosing can be found in Table 41-3.

TABLE 41-3 Dosing of Medications Used in the Initial Treatment of GCSE

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Images Most practitioners consider IV-administered lorazepam the benzodiazepine of choice (Table 41-3).4,15 A Cochrane Database Review concluded that lorazepam is as effective, but safer than diazepam in children.16 It is less lipid soluble than diazepam and takes longer to achieve peak concentrations in the brain; however, its minimal redistribution into fat results in a longer duration of action in the CNS, which can provide seizure protection for up to 24 hours.4,15 It also has a higher-affinity binding to the benzodiazepine receptor than diazepam.

Patients chronically on a benzodiazepine (e.g., clobazam, clonazepam) might have developed tolerance and could require large doses. Diazepam and lorazepam contain propylene glycol, which can cause dysrhythmia and hypotension if administered too rapidly (Table 41-4).15 They also cause vein irritation; therefore, the parenteral product should be diluted with an equal volume of compatible diluent before administration. Because of slow and erratic absorption, standard parenteral formulations should not be given IM.

TABLE 41-4 Adverse Drug Reactions and Monitoring of Patients Receiving Drugs for GCSE

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Unfortunately, midazolam has an extremely short half-life, and maintenance doses must be given by continuous infusion (Table 41-3). When IV access cannot be established, buccal, IM, and intranasal administration have been used successfully to terminate seizures. Because of its increased solubility, midazolam has a more reliable IM absorption than either diazepam or lorazepam. A recent study showed that when IM midazolam is given by emergency personnel as first-line treatment in the prehospital setting, it is as effective as IV lorazepam.17 Buccal administration is easily accomplished, the volume of fluid is small enough (e.g., 2 to 5 mL) that aspiration is unlikely. A recent Cochrane Database Review concluded that buccal midazolam is more effective than rectal diazepam in children.16


Clinical Controversy…

The positioning of midazolam among the medications used to treat GCSE is changing. It is now recommended that midazolam be a first-line anticonvulsant for IM administration, when IV access cannot be established. It is also recommended for refractory GCSE. Options for out-of-hospital treatment now include rectal diazepam, buccal midazolam, and IM midazolam. Currently, no pharmacoeconomic studies are available to guide the decision as to which therapy to use.

Although rare, brief cardiorespiratory depression can necessitate assisted ventilation or require intubation (Table 41-4). This is especially true if a benzodiazepine is used concomitantly with a barbiturate; however, cardiorespiratory depression is more likely due to ongoing seizures than benzodiazepines. Hypotension secondary to a reduction in vasomotor tone can occur following large doses.4


Clinical Controversy…

The choice of long-acting anticonvulsant to give following the initial benzodiazepine is controversial. According to the Working Group on Status Epilepticus, phenytoin should be used in seizures that recur after treatment with a benzodiazepine.15 Although this has been the practice for decades; no studies have documented the superiority of a hydantoin over other anticonvulsants. Thus, it is questionable if a hydantoin should be administered alone, in larger doses, or at all when seizures recur following benzodiazepine administration. This issue is further complicated by the frequent shortage of some of these medications, and emerging data suggesting that valproate may be as effective.

Phenytoin

Images A hydantoin is the second-line agent in GCSE that is unresponsive to the benzodiazepines or in seizures that recur after successful treatment with a benzodiazepine.4 Although it is effective in terminating seizures in 40% to 91% of patients,15 it can be inferior to lorazepam, phenobarbital, or diazepam plus phenytoin at stopping GCSE within 20 minutes of their infusion.18,19

Phenytoin has a long half-life (20 to 36 hours) and causes less respiratory depression and sedation than the benzodiazepines or phenobarbital15; however, it cannot be delivered rapidly enough to be considered a first-line single agent. Injectable phenytoin should be diluted to less than or equal to 5 mg/mL in normal saline. Microcrystals will precipitate if it is mixed in a glucose-containing solution. The vehicle (40% propylene glycol) can cause administration-related hypotension and cardiac arrhythmias (Table 41-4).15 Images For this reason, the maximum rate of infusion is limited (Table 41-3).4

Suggested IV loading doses are provided in Table 41-3.15 A reduction in the loading dose is recommended for elderly patients,15 and a larger loading dose is required in obese individuals.20 If the patient has been on phenytoin prior to admission and the serum concentration is known, this should be considered in determining a loading dose. Although some advocate the administration of an additional 5 mg/kg in those with unresponsive GCSE, there is no evidence that this will be beneficial. This practice can cause concentrations to exceed the reference range and produce toxicity. Because phenytoin has poor lipid solubility and enters the brain slowly, it can take up to 60 minutes before the pharmacodynamic effect is apparent. This delay is important when considering administration of a second loading dose. Therapeutic serum concentrations, 10 to 20 mg/L (40 to 79 μmol/L), generally do not persist more than 24 hours; hence, maintenance doses (see Table 41-3) should be started within 12 to 24 hours of the loading dose.

Phenytoin has an alkaline pH, which may cause pain and burning during infusion; phlebitis can occur with chronic infusion, and tissue necrosis is likely on infiltration. IM administration is not recommended because absorption is delayed and erratic, and phenytoin can crystallize in tissue. Although oral loading doses have been used in patients not actively seizing, it may take 4 to 12 hours before adequate serum concentrations are obtained; thus, this practice is not recommended.

Fosphenytoin

Fosphenytoin, a water-soluble phosphate ester, has no known pharmacologic activity.21 It is converted rapidly (7 to 15 minutes) and completely (100%) to phenytoin by blood and tissue phosphatases after IV and IM dosing.21 The conversion delay was a concern initially; however, this time is offset by high protein binding, saturable binding at high concentrations, and the rapid rate of infusion.21 It does not contain propylene glycol and is compatible with most common IV fluids.

Fosphenytoin should be dosed using phenytoin equivalents (PE), thereby obviating the need for interconversion between phenytoin and fosphenytoin. The loading dose and rates of administration of fosphenytoin can be found in Table 41-3. Because of delays in achieving adequate phenytoin serum concentrations, a loading dose should not be given IM unless IV access is impossible.

Fosphenytoin serum concentrations have no value. Serum phenytoin concentrations should be used for therapeutic drug monitoring, and the desired serum concentration range is the same as that for phenytoin. Fosphenytoin cross reacts with some phenytoin immunoassays causing an overestimation of phenytoin concentration; hence, blood should not be obtained for at least 2 hours after IV and 4 hours after IM administration.21


Clinical Controversy…

The debate continues as to which hydantoin is preferred in GCSE. Although phenytoin has been used for decades, it is associated with a variety of problems related to its formulation. Conversely, fosphenytoin is associated with less infusion pain and IV-site complications and fewer hemodynamic effects than phenytoin. Although most practitioners believe that fosphenytoin is clearly a “better” formulation, many struggle with the advantages of fosphenytoin, given its cost.

Phenobarbital

Phenobarbital has biphasic distribution into body organs.22 During phase I, the drug distributes into highly vascular organs, but does not distribute into the brain. With the exception of fat, phenobarbital distributes throughout the body during phase II22; hence, lean body mass should be used in calculating doses in obese patients.22 Although the highest brain concentrations occur 12 to 60 minutes after an IV dose,22 seizures are controlled within minutes of the loading dose.19 Despite two studies that found phenobarbital to be as effective as phenytoin, lorazepam, or diazepam plus phenytoin in patients with GCSE,18 the Working Group on Status Epilepticus recommends that phenobarbital be given after a benzodiazepine plus phenytoin has failed.15

The loading and maintenance dose are given in Table 41-3. When necessary, larger loading doses (30 mg/kg) have been used in neonates without adverse effects. If the initial loading dose does not stop the seizures within 20 to 30 minutes, an additional 10 to 20 mg/kg can be given. If seizures continue, a third 10 mg/kg load can be given.23 Phenobarbital exhibits first-order linear pharmacokinetics, and there is no maximum dose beyond which further doses are likely to be ineffective.23 Once GCSE is controlled, the maintenance dose should be started within 12 to 24 hours.

Although injectable phenobarbital contains propylene glycol, it can be given more rapidly than phenytoin (see Table 41-3). It can be given IM, but its rate of absorption is too slow to be effective. Adverse drug reactions and monitoring can be found in Table 41-4.4,15


Clinical Controversy…

There are three different opinions regarding the use of phenobarbital in GCSE. Because barbiturates cause CNS and respiratory depression, as well as hypotension, most contend that phenobarbital should be the third-line agent when a benzodiazepine plus phenytoin has failed. Others suggest that the barbiturates are as safe and effective as other anticonvulsants and should be the drug of choice following a benzodiazepine. Still others support continuous-infusion midazolam as the third-line anticonvulsant before the barbiturates. Currently, most practitioners agree that phenobarbital is the long-acting anticonvulsant of choice in patients with hypersensitivity to the hydantoins or in those with cardiac conduction abnormalities.

Refractory GCSE

Images When adequate doses of a benzodiazepine, hydantoin, or barbiturate have failed, the condition is termed refractory. Approximately 10% to 15% of patients will develop refractory GCSE, and approximately 30% whose seizures are “clinically” controlled will have persistent electrical manifestations after administration of these anticonvulsants. When a patient develops refractory GCSE, an intense search should be performed for an acute or progressive cause.

While the goal is to stop electrical epileptiform activity, there is no consensus regarding the anticonvulsant of choice, sequencing of therapy, or treatment of refractory GCSE. Most recommend the administration of anesthetic doses of midazolam, pentobarbital, or propofol, while other approaches include the continuous infusion of a benzodiazepine, valproate, lacosamide, levetiracetam, topiramate, or lidocaine. Doses for these agents can be found in Table 41-5. A meta-analysis compared midazolam, propofol, and pentobarbital in refractory GCSE.24 Overall response rates were significantly greater in those treated with pentobarbital (92%) compared to midazolam (80%) and propofol (73%). Seizure recurrence was more commonly observed with midazolam (51%) versus propofol (15%) and pentobarbital (12%). Although pentobarbital had a greater response rate, clinically significant hypotension was more common. Mortality rates were similar for the three drugs.

TABLE 41-5 Dosing of Medications Used to Treat Refractory GCSE

Images

Benzodiazepines

Some advocate that anesthetic doses of midazolam should be the first-line agent in refractory GCSE. Table 41-5 shows the loading and maintenance doses of midazolam.24 Most patients respond to these doses within an hour. Successful discontinuation is enhanced by maintaining the patient’s phenytoin and phenobarbital serum concentration(s) above 20 mg/L (79 μmol/L) and 40 mg/L (172 μmol/L), respectively. Because of midazolam’s short half-life, patients can return to consciousness more rapidly than those receiving larger doses of more sedating anticonvulsants (e.g., phenytoin, phenobarbital). Generally, continuous-infusion midazolam has been well tolerated, with few cases of hypotension and respiratory depression. Hypotension and poikilothermia can occur and can require supportive therapies.

Large-dose continuous-infusion lorazepam also has been used successfully,25 but can be associated with adverse drug reactions due to propylene glycol.26

Pentobarbital

If there is an inadequate response to large doses of midazolam, anesthetizing the patient to suppress the cerebral ictal discharge is recommended.15,27 Although it is likely that the patient is already being mechanically ventilated, intubation and respiratory support are mandatory during barbiturate coma, along with continuous EEG monitoring (Table 41-4). A short-acting barbiturate (usually either pentobarbital or thiopental) generally is preferred because it allows a more rapid reversal of coma.

Several sources note that the initial loading dose of pentobarbital is 5 mg/kg.15 However, this dose is inadequate to achieve the serum concentrations (40 mg/L; 172 μmoL/L) necessary to induce an isoelectric EEG (Table 41-5).27Although the duration of barbiturate coma in most studies has been 2 to 3 days, it has been used safely for 53 days in an 18-year-old patient.28 To avoid complications (e.g., pneumonia, pulmonary edema), the pentobarbital should be discontinued as soon as possible. It is important to have other anticonvulsants at therapeutic amounts before pentobarbital is withdrawn so that the risk of seizure recurrence is minimized. Because pentobarbital is a potent hepatic enzyme inducer, doses of most concurrent anticonvulsants will need to be larger than usual maintenance doses. The patient will need to be monitored for side effects as deinduction occurs and anticonvulsant concentrations increase. This can take up to a month after pentobarbital’s discontinuation.

Propofol

Propofol is extremely lipid soluble, has a large volume of distribution, and has a very rapid onset of action. Its extremely short half-life promotes rapid awakening on drug discontinuation. Propofol’s efficacy is comparable to midazolam for refractory GCSE.27,29 Adverse drug reactions and doses can be found in Tables 41-4 and 41-5,30 respectively. Finally, a normal adult dose can provide over 1,000 calories (4,186 J) per day as lipid at a cost to the patient that may exceed $800 per day.

Valproate

The IV dosage form approved by the FDA is not labeled for GCSE. A number of loading and continuous-infusion doses (see Table 41-5) have been used in both adult and pediatric patients.24,31,32 A recent study showed that IV valproate and continuous infusion diazepam were comparable in GCSE. Although the manufacturer originally recommended IV valproate be given no faster than 20 mg/min, much faster rates have been studied (40 mg/min; 2 to 10 mg/kg/min) and are used for administration of the loading dose.24,31 One study suggested the need to consider the effects of enzyme-inducing anticonvulsants when dosing and recommended that the continuous-infusion rate be determined by the presence of concurrent anticonvulsants (no inducers present, 1 mg/kg/h; one or more inducers [e.g., phenytoin, phenobarbital], 2 mg/kg/h; and inducers and pentobarbital coma, 4 mg/kg/h).33 In general, IV valproate has been well tolerated, with no cases of respiratory depression. Hemodynamic instability is extremely rare, but patients’ vital signs should be monitored closely during the loading dose.

Other Agents

Topiramate has been given orally in adults and in children with GCSE (Table 41-5), but may be associated with adverse drug reaction (Table 41-4).13,26,3437 Crushing the tablets and dissolving them in small amounts of water are necessary, as no liquid formulation is available. Response tends to be delayed hours to days. Once seizures are controlled, doses should be tapered to a tolerable maintenance dose.

Oral levetiracetam has been given in case series for GCSE.38 However, IV levetiracetam should be used (Table 41-5), but doses larger than 3,000 mg/day do not add additional efficacy.13,26,3942 Levetiracetam is not hepatically metabolized and is minimally protein bound, which makes drug–drug interactions unlikely. There have been two case reports of lacosamide used in refractory GCSE and NCSE.4244 Like levetiracetam, its lack of effect on the metabolism on other medications makes it attractive for use. Neither levetiracetam nor lacosamide has been associated with toxicities (respiratory depression, hypotension) noted with the older anticonvulsants.

Lidocaine has been used in refractory GCSE, but is not recommended unless other agents have failed.45 It is administered IV (Table 41-5) and has a rapid onset of action. Although the reference serum concentration range for the antiarrhythmic effects of lidocaine is 2 to 6 mg/L (8.5 to 25.6 μmol/L), the reference range for GCSE has not been established. Serum lidocaine concentrations should be monitored to avoid drug accumulation and toxicity (Table 41-4).

Halothane, isoflurane, ketamine, and other inhaled anesthetics can produce EEG suppression; however, these gases are difficult to deliver outside the operating room and require an anesthesiologist. No proven advantages have been shown over traditional anticonvulsants (e.g., barbiturate coma or continuous-infusion benzodiazepine), and these gases can increase intracranial pressure. If used, dosing is titrated to obtain EEG burst suppression. Finally, it is also prudent to validate that the patient does not have a low serum-magnesium concentration, because magnesium deficiency can lower the seizure threshold.

Personalized Pharmacotherapy

If the patient has been on phenytoin, phenobarbital, or valproate prior to admission, a stat serum concentration should be obtained and the results considered in determining a loading dose or redosing. A serum concentration should be obtained in any patient who is unresponsive to therapy or who exhibits concentration-associated adverse drug reactions. Pharmacogenetics produces differences in metabolic pathways and rate of drug metabolism, which can influence efficacy or toxicity. Obviously, a patient who is a poor metabolizer would theoretically have changes in drug metabolism based on expression of specific isoenzymes. For example, many Orientals have decreased CYP 2C19 activity; therefore, they may respond to lower doses of diazepam. If one were concerned about benzodiazepine-associated adverse effects in this population, lorazepam would be preferred.

Although a patient may have an alteration in gene expression that could be important in development of refractory SE or in response to various anticonvulsants, there is no information to support that this is important in GCSE. While HLA-B*1502 has been associated with severe skin reactions in patients receiving phenytoin, this is applicable to chronic and not acute, single dose therapy. Some studies have noted an association between P-glycoprotein and refractory epilepsy; however, no reports have suggested that this finding is important in GCSE. There is currently no evidence to support a change in protocol based on underlying genetics.

EVALUATION OF THERAPEUTIC OUTCOMES

Initial success is defined as termination of all clinical and electrical seizure activity, but ultimate success is measured by the patient’s subsequent quality of life. The morbidity and mortality associated with GCSE are affected by the underlying etiology; however, morbidity and mortality can be minimized by the rapid implementation of a rational therapeutic plan. An EEG is an extremely important tool that not only allows practitioners to determine when abnormal electrical activity has been aborted, but also can assist in determining which anticonvulsant was effective. Because many of the anticonvulsants affect the cardiorespiratory system, it is imperative that vital signs (e.g., heart rate, respiratory rate, and blood pressure) be monitored during drug loading and infusion. Finally, it is imperative that the infusion site be assessed for any evidence of infiltration before and during administration of phenytoin. Information regarding the patient’s past medical and drug history and imaging studies (e.g., MRI) also can help to determine if there is a defined etiology for the original episode of GCSE. This information then can be used to guide future medication therapy, as well as help in determining if the patient is at risk for a poor outcome.

ABBREVIATIONS

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REFERENCES

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