Convulsions and Anti Epileptic Drugs

Convulsions and Anti-Epileptic Drugs

Akram M Fayed, MD, ABIM

Associate Professor, Department of Critical Care Medicine

Faculty of MedicineUniversity of Alexandria

12/08/20221

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Although exact definitions vary, the term status epilepticus generally refers to the occurrence of a single unremitting seizure with a duration longer than 5 to 10 minutes or frequent clinical seizures without an interictal return to the baseline clinical state

Introduction

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It is estimated that there are 100,000 to 200,000 episodes of status epilepticus in the United States annually

Refractory status epilepticus, defined as ongoing seizures following first- and second-line drug therapy, was noted in nearly 30 to 43 percent of patients with status epilepticus

Although not associated with increased mortality, refractory status epilepticus was linked to prolonged hospitalization and poorer functional outcomes

EPIDEMIOLOGY

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Encephalitis was associated significantly more often with refractory than with nonrefractory status epilepticus (22 versus 4 percent, respectively).

In contrast, inadequate serum levels of antiepileptic drugs (AEDs) were associated significantly more often with nonrefractory than with refractory status epilepticus (28 versus 0 percent, respectively).

Also, generalized tonic-clonic status was less likely to be refractory than nonconvulsive or focal motor status

EPIDEMIOLOGY

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Optimal management of status epilepticus requires identification and correction, if possible, of any predisposing factors that are present.

Virtually any acute or chronic brain injury, as well as a number of toxic-metabolic insults, can cause status epilepticus

Some of the more common predisposing factors include:

Antiepileptic drug noncompliance or discontinuation

Withdrawal syndromes associated with the discontinuation of alcohol, barbiturates, baclofen, or benzodiazepines (particularly alprazolam)

ETIOLOGY

http://www.uptodate.com/online/content/topic.do?topicKey=drug_a_k/26656&source=see_link


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Remote or longstanding structural injury (eg, prior head injury, cerebral palsy, previous neurosurgery, perinatal cerebral ischemia, arteriovenous malformations)

Metabolic abnormalities (eg, hypoglycemia, hepatic encephalopathy, uremia, pyridoxine deficiency, hyponatremia, hyperglycemia, hypocalcemia, hypomagnesemia)

Use of, or overdose with drugs that lower the seizure threshold (eg, theophylline, imipenem, high dose penicillin G, quinolone antibiotics, metronidazole, isoniazid, tricyclic antidepressants (especially bupropion), lithium, clozapine, flumazenil, cyclosporine, lidocaine, bupivacaine, metrizamide, and, to a lesser extent, phenothiazines)

Chronic epilepsy; status epilepticus may represent part of a patient's underlying epileptic syndrome (as with the Landau-Kleffner syndrome or Rasmussen's encephalitis), or may be associated with any of the generalized epilepsiesNew onset refractory status epilepticus (NORSE) is a syndrome described in a number of reports of patients who present with severe generalized seizures of unclear etiology in the setting of a prodromal febrile illness [8-11]. Patients typically do not respond to AEDs and mortality and morbidity are high

ETIOLOGY

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http://www.uptodate.com/online/content/abstract.do?topicKey=epil_eeg/2440&refNum=8-11

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Chronic epilepsy; status epilepticus may represent part of a patient's underlying epileptic syndrome (as with the Landau-Kleffner syndrome or Rasmussen's encephalitis), or may be associated with any of the generalized epilepsies

New onset refractory status epilepticus (NORSE) is a syndrome described in a number of reports of patients who present with severe generalized seizures of unclear etiology in the setting of a prodromal febrile illness

Patients typically do not respond to AEDs and mortality and morbidity are high

ETIOLOGY

12/08/20228

The mortality rate for adults who present with a first episode of status epilepticus is roughly 20 percent

Estimates vary widely, mainly as a function of the underlying etiology and whether status epilepticus following cerebral anoxia is included in the study

The mortality for status epilepticus after anoxia ranges from 69 to 81 percent

COMPLICATIONS AND OUTCOME

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Older age, medical comorbidity, and high initial APACHE-II scores are also independent risk factors for mortality

Many of the other underlying causes of status epilepticus are associated with significant morbidity and mortality, even in the absence of seizures.

In one series, 89 percent of deaths in patients with status epilepticus were attributed to the underlying etiology


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Another study suggested that acute symptomatic status epilepticus is associated with a six-fold increased risk of mortality from status epilepticus compared to individuals with status epilepticus arising from chronic epilepsy

Mortality is also lower in individuals who have previously survived an episode of status epilepticus (4.8 versus 15.6 percent in one study), again suggesting that the underlying etiology is a major determinant of outcome in status epilepticus


12/08/202211

The mortality of status epilepticus is in part due to the metabolic stress of repeated muscular convulsions

Rhabdomyolysis, lactic acidosis, aspiration pneumonitis, neurogenic pulmonary edema, and respiratory failure may complicate convulsions

In one analysis, patients who received mechanical ventilation had a three-fold increase in mortality

Cardiac injury due to massive release of catecholamines may also contribute to injury


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In addition, neuronal death can occur under certain circumstances after as little as 30 to 60 minutes of continuous seizure activity

The pathologic hallmark of this phenomenon, cortical laminar necrosis, may also be seen on brain MRI as a persistent, high intensity lesion on T1- or diffusion-weighted images, which follows the gyral anatomy of the cerebral cortex


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Clinically, this effect manifests in increasing neurologic morbidity with increasing seizure duration, even after the effects of etiology are eliminated

Consequently, survivors of status epilepticus are at significant risk for recurrent seizures, and up to 10 percent may be left with disabling neurologic deficits


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Status epilepticus will recur in approximately one-third of patients, according to one population-based study that followed patients for 10 years

When patients with progressive neurologic disease were excluded, the risk was 25 percent and was similar among other etiologic subgroups

Female gender and a failure to respond to the first drug administered for status epilepticus were risk factors for recurrence


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The diagnosis of status epilepticus is often straightforward, but may be more complicated when symptoms are continuous and affect focal cognitive functions like language.

The diagnosis of status epilepticus rests primarily upon the neurologic examination and the electroencephalogram (EEG)

DIAGNOSIS

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Although the diagnosis of tonic-clonic status epilepticus may be obvious, a neurologic examination can be critical in making the diagnosis in nonconvulsive status epilepticus

Particularly important are assessment of the level of consciousness, observations for automatic movements or myoclonus, and any asymmetric features on examination that may indicate a focal structural lesion

DIAGNOSIS Neurologic examination

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The EEG is an extremely valuable tool in evaluating the patient with suspected status epilepticus

An EEG that reveals continuous seizure activity is diagnostic of status epilepticus

Many cases of status epilepticus can be diagnosed on the basis of the neurologic examination alone, but EEG data are invaluable in diagnosing complex cases

DIAGNOSIS Electroencephalogram

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However, there are some limitations to the use of the EEG in this context:

Clear ictal activity may not be seen during simple partial status epilepticus

Some ictal EEG patterns are difficult to recognize or are controversial

An EEG obtained over a short period of time and between seizures can miss intermittent ictal activity


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Certain EEG patterns in unresponsive patients are diagnostic of status epilepticus, including patterns that show temporal evolution.

The meaning of other patterns, such as periodic lateralized epileptiform discharges (PLEDS) remains controversial, although aggressive pharmacologic treatment in a patient whose EEG shows only PLEDS without evolution and whose examination reveals no clinical seizures should generally be avoided

Continuous EEG recordings may be helpful if the initial study is not diagnostic


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Single photon emission computed tomography (SPECT) may demonstrate areas of increased perfusion during status epilepticus that can persist for weeks after the termination of seizures

SPECT may be helpful in diagnosing status epilepticus when the EEG is equivocal

However, good studies of sensitivity and specificity are not available, and results should be interpreted in conjunction with clinical and EEG findings

DIAGNOSIS SPECT

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Magnetic resonance imaging (MRI) is the best tool to reveal the structural lesions that may trigger status epilepticus, but MRI is not a first-line test for diagnosing status epilepticus

However, MRI may reveal areas of increased signal intensity on FLAIR, T2-, or diffusion-weighted images in the presence of status epilepticus

These findings are believed to represent seizure-induced cellular edema and are seen in cortical and limbic structures, particularly the hippocampus

DIAGNOSIS MRI

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They may persist for days to weeks, especially if seizures are prolonged, and either ultimately resolve or evolve into focal atrophy and sclerosis

These lesions are nonspecific and can be associated with many other processes

DIAGNOSIS MRI

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Classifying the type of status epilepticus is important because it is a major factor in determining morbidity and, therefore, the aggressiveness of treatment that is required; generalized tonic-clonic or partial-complex status epilepticus poses the greatest risk.

The three most common forms of status epilepticus are

CLASSIFICATION

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Simple partial status epilepticus is characterized by continuous or repeated focal motor seizures (e.g. twitching of one thumb), focal sensory symptoms (e.g. the sensation of flashing lights in one visual field), or cognitive symptoms (e.g. aphasia) without impaired consciousness

CLASSIFICATION Simple partial

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Complex partial status (nonconvulsive) epilepticus is characterized by continuous or repeated episodes of focal motor, sensory, or cognitive symptoms with impaired consciousness, and should be considered in the differential diagnosis of acute confusional states

Other symptoms, such as automatisms and behavioral disturbances, may also occur

CLASSIFICATION Complex partial

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Generalized tonic-clonic status epilepticus is always associated with impaired consciousness.

Tonic-clonic seizures may be the initial manifestation of status epilepticus, or may represent secondary generalization from other seizure types

CLASSIFICATION Generalized tonic-clonic

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Absence (petit mal) status epilepticus is characterized by altered awareness, but not necessarily unconsciousness

Patients are typically confused or stuporous, and there may be associated myoclonus, eye blinking, perseveration, altered motor performance, language difficulty, or other symptoms

Absence status epilepticus typically occurs in patients with chronic idiopathic epilepsy and frequently requires EEG for confirmation

CLASSIFICATION Absence

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Myoclonic status epilepticus is characterized by frequent myoclonic jerks, usually in the setting of altered mental status

This typically occurs in patients with one of the generalized epilepsies, such as juvenile myoclonic epilepsy

The term has also been applied by some authors to the myoclonus seen in the patient who has experienced global cerebral ischemia

CLASSIFICATION Myoclonic

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However, this myoclonus should not be considered in the same category as myoclonic status epilepticus unless EEG recordings demonstrate actual seizure activity and not simply a burst-suppression pattern

Overall, patients with myoclonus and altered consciousness are far more likely to be suffering from a metabolic encephalopathy (particularly uremic or hepatic encephalopathy) than from true myoclonic status epilepticus

CLASSIFICATION Myoclonic

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Although relatively rare, psychogenic status epilepticus should be considered in situations where there are bilateral motor movements with preserved consciousness

An EEG recording during one of the patient's typical clinical events can help establish this diagnosis, although the EEG may also appear relatively normal during simple partial status epilepticus

CLASSIFICATION Psychogenic

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Although prolactin levels drawn shortly after the onset of a seizure may help differentiate epileptic and non-epileptic events, prolactin levels normalize during prolonged seizures and so are not helpful in the diagnosis of status epilepticus


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Creatine kinase levels are typically markedly elevated after generalized convulsive epileptic seizures and are only rarely and mildly elevated after psychogenic seizures even when motor features are pronounced

This test is of most value when motor features are very prominent

Also, there may be a delay in peak concentrations, limiting the value of this test somewhat in the emergency setting


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There are four main categories of drugs used to treat status epilepticus:

benzodiazepines,

phenytoin (or fosphenytoin),

barbiturates, and

propofol

PHARMACOLOGIC AGENTS




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Other treatments with drugs such as lidocaine, paraldehyde (which is no longer available in the United States for intravenous infusion), chloral hydrate, ketamine, carbamazepine, or etomidate are less efficacious or less well studied and should not be considered part of the routine management of status epilepticus







12/08/202236

Similarly, general anesthesia with isoflurane or other inhalational agents may be temporarily effective in stopping seizures but is used only in extreme circumstances because of logistical problems

Other agents such as chlormethiazole are used in other countries but are not available in the United States



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Benzodiazepines remain the first-line treatment for status epilepticus because they can rapidly control seizures

A number of studies have addressed the different uses and pharmacology of the three most commonly used benzodiazepines for status epilepticus: diazepam, lorazepam, and midazolam.

All are thought to increase chloride conductance in central nervous system GABA(A) receptors and thus decrease neuronal excitability

PHARMACOLOGIC AGENTS Benzodiazepines




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Diazepam has a high lipid solubility and therefore an ability to rapidly cross the blood-brain barrier; it is highly effective in rapidly terminating seizures when administered at doses of 0.1 to 0.3 mg/kg intravenously

An effect upon seizure activity can be seen as early as 10 to 20 seconds after administration, and cerebrospinal fluid (CSF) concentrations reach half of their maximum value in three minutes

PHARMACOLOGIC AGENTS Diazepam


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However, because of subsequent redistribution of the drug into adipose tissue, the duration of diazepam's acute anticonvulsant effect is typically <20 minutes.

Initial termination of seizure activity with intravenous diazepam is seen in 50 to 80 percent of patients, but if no other medication is provided, there is a 50 percent chance of seizure recurrence within the next two hours


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Nonetheless, diazepam remains the drug of first choice in many settings because it is stable in liquid form for long periods at room temperature

Therefore, diazepam is available in resuscitation kits in premixed form, while lorazepam, midazolam, and phenytoin are not

A rectal gel formulation of diazepam is also marketed and provides rapid delivery when intravenous access is problematic, or for at home use in patients who have frequent repetitive or prolonged seizures






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Although lorazepam is as effective as diazepam in terminating seizures, the time from its injection to its maximum effect against seizures is as long as two minutes

The clinical advantage of lorazepam is that the effective duration of action against seizures is as long as four to six hours because of its less pronounced redistribution into adipose tissue

PHARMACOLOGIC AGENTS Lorazepam



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Like lorazepam and diazepam, midazolam is very effective in acutely terminating seizures (frequently in less than one minute), but it has a short half-life in the central nervous system

The advantage of midazolam over the other two benzodiazepines is that its use as a continuous infusion for refractory status epilepticus has been more thoroughly investigated and is associated with minimal cardiovascular side effects

PHARMACOLOGIC AGENTS Midazolam




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Effective initial intravenous doses of midazolam are a 0.2 mg/kg bolus, followed by continuous infusion at rates of 0.75 to 10 mcg/kg per minute

Some use higher doses


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A continuous midazolam infusion may be less effective than high dose barbiturates or propofol for the treatment of refractory status epilepticus, although high quality studies directly comparing these treatments have not been performed

Nasal and buccal administration midazolam may be useful in the rapid termination of seizures when IV access is difficult




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Clonazepam has been used to treat status epilepticus outside the United States in settings where intravenous formulations are available

It has effects similar to those of other benzodiazepines, with a rapidity of onset that is intermediate between that of lorazepam and that of diazepam

Its duration of activity is more prolonged than that of diazepam

PHARMACOLOGIC AGENTS Clonazepam





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Phenytoin is one of the most commonly used treatments for status epilepticus,

A trial showed that initial treatment of generalized convulsive status epilepticus with lorazepam alone was more effective than treatment with diazepam and phenytoin

The principal advantage of phenytoin derives from its efficacy in preventing the recurrence of status epilepticus for extended periods of time

PHARMACOLOGIC AGENTS Phenytoin




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Phenytoin is generally infused at a rate of up to 50 mg/minute to a total dose of 20 mg/kg, but it is critical to modify the infusion rate in the presence of hypotension or other adverse cardiovascular events

The risks of hypotension and cardiac arrhythmias increase with higher infusion rates, partly due to the propylene glycol used to solubilize phenytoin



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In addition, the risks of local pain and injury (including venous thrombosis and the purple glove syndrome) increase with more rapid rates of infusion

Cardiac monitoring during the initial infusion is mandatory because bradyarrhythmias or tachyarrhythmias may occur

Phenytoin and fosphenytoin are reported to intensify seizures caused by cocaine, other local anesthetics, theophylline, or lindane






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Fosphenytoin is a pro-drug of phenytoin that is hydrolyzed into phenytoin by serum phosphatases.

Fosphenytoin is highly water soluble and therefore unlikely to precipitate during intravenous administration

The risk of local irritation at the site of infusion is significantly reduced compared with phenytoin; fosphenytoin can therefore be infused much more rapidly (up to 150 mg/minute versus 50 mg/minute with phenytoin)

PHARMACOLOGIC AGENTS Fosphenytoin



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In addition, the increased water solubility of fosphenytoin makes intramuscular (IM) administration possible if intravenous (IV) access cannot be obtained

However, IM administration will yield less predictable levels and a longer time to onset of effect than IV administration


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Because fosphenytoin is converted on a 1:1 molar basis to phenytoin, the dosing of fosphenytoin in terms of moles is identical

However, the molecular weight of fosphenytoin is greater than that of phenytoin; hence, a greater weight of fosphenytoin must be given in order to yield the same concentration of phenytoin




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To eliminate this problem, the manufacturer recommends prescribing of fosphenytoin as milligrams of phenytoin equivalent (PE).

Orders for fosphenytoin should be written in terms of PEs; as an example, 20 mg/kg PE load at a rate of 100 to 150 mg PE/minute

Cardiac monitoring and frequent vital signs are required during the infusion of fosphenytoin or phenytoin


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Barbiturates are similar to benzodiazepines in that they also bind to the GABA(A) receptor, amplifying the actions of GABA by extending GABA-mediated chloride channel openings

This process permits an increasing flow of chloride ions across the membrane, causing neuronal hyperpolarization (eg, membrane inhibition to depolarization)

Phenobarbital and pentobarbital are the most useful barbiturates in the treatment of status epilepticus

PHARMACOLOGIC AGENTS Barbiturates



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Phenobarbital is an excellent anticonvulsant, especially in the acute stage of managing seizures.

Various studies have shown a rate of seizure control of approximately 60 percent when phenobarbital is used alone; this rate is similar to that seen with lorazepam alone or the combination of phenytoin and diazepam

Despite its efficacy, phenobarbital is generally not used as a first-line treatment in adults because, administration is slow, it causes prolonged sedation, and it is believed to carry a higher risk of hypoventilation and hypotension than benzodiazepines or phenytoin

PHARMACOLOGIC AGENTS Phenobarbital





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Initial doses of 20 mg/kg infused at a rate of 30 to 50 mg/minute are generally used, but slower infusion rates should be used in the elderly

Careful monitoring of respiratory and cardiac status is mandatory. It is often necessary to intubate patients in order to provide a secure airway and minimize the risk of aspiration if phenobarbital is administered following benzodiazepines

The risk of prolonged sedation with phenobarbital is greater than with the other anticonvulsants because of its half-life of 87 to 100 hours

PHARMACOLOGIC AGENTS Phenobarbital


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Pentobarbital is used primarily in the treatment of refractory status epilepticus, typically with a loading dose of 10 mg/kg infused at a rate of up to 100 mg/minute

After the loading dose is administered, it is often necessary to use a continuous infusion of pentobarbital ranging from 1 to 4 mg/kg/hour in order to maintain the patient in a seizure-free state

PHARMACOLOGIC AGENTS Pentobarbital


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The ultimate infusion rate is determined by the amount of drug required to terminate status epilepticus, but can be limited by hypotension due to the drug's adverse inotropic and vasodilatory effects

Vasopressors are almost universally required during high dose pentobarbital infusions

PHARMACOLOGIC AGENTS Pentobarbital

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Some centers use thiopental instead of pentobarbital for refractory status epilepticus, but there are a number of problems with this approach

Animal studies suggest that thiopental carries a higher incidence of adverse cardiovascular effects than pentobarbital

The half-life of thiopental is shorter than that of pentobarbital, but this is counterbalanced by the fact that thiopental is degraded to active metabolites (including pentobarbital), which accumulate with longer term infusions

PHARMACOLOGIC AGENTS Thiopental



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Thiopental may also have immunosuppressive effects on neutrophil function and mucociliary clearance

An uncontrolled series of 10 consecutive adults presenting with status epilepticus noted that high-dose thiopental therapy effectively terminated clinical and electrophysiological evidence of seizures



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However, therapy was associated with systemic hypotension; each patient required fluid resuscitation with an average of 2.6 L of crystalloid in the first 24 hours

High-dose thiopental resulted in delayed recovery from anesthesia, and six patients developed S. aureus pneumonia, resulting in prolonged intubation


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Propofol is a hindered phenolic compound with anticonvulsant properties.

The drug is unrelated to any of the currently used barbiturate, opioid, benzodiazepine, arylcyclohexylamine, or imidazole intravenous anesthetic agents.

Hypotension and respiratory depression may complicate its use

PHARMACOLOGIC AGENTS Propofol



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Propofol is a hindered phenolic compound with anticonvulsant properties.

The drug is unrelated to any of the currently used barbiturate, opioid, benzodiazepine, arylcyclohexylamine, or imidazole intravenous anesthetic agents.

Hypotension and respiratory depression may complicate its use




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Experience with propofol in the treatment of status epilepticus is limited, but promising results have been reported in several small trials

One study compared the results of treatment with propofol

or high dose barbiturates in 16 patients with refractory status epilepticus

Termination of seizures was significantly faster among successfully treated patients in the propofol group (mean 3 versus 123 minutes), but there was a nonsignificant trend toward higher overall success rates in barbiturate-treated patients (82 versus 63 percent)



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Propofol is associated with rare but serious, potentially fatal adverse effects including a syndrome of metabolic acidosis, rhabdomyolysis, renal failure, and cardiac dysfunction

This may be mitigated by avoiding high doses for more than two days and laboratory monitoring



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The use of intravenous (IV) valproic acid (Depacon) is increasingly used in the treatment of status epilepticus.

(FDA) approved it only for slow infusion rates (up to 20 mg/min).

Accumulating evidence suggests that IV valproate can be safely infused at rates up to 10 mg/kg per minute in adults without adverse effects on blood pressure or heart rate

Rapid IV loading may be desirable as a way to achieve serum concentrations >100 mcg/mL quickly

PHARMACOLOGIC AGENTS Valproic acid

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The limited available data suggest that valproate may be useful in treating acute status epilepticus

As an example, an unblinded, randomized trial in 68 patients with convulsive status epilepticus suggested that high-dose valproate infusions (30 mg/kg over 15 minutes) terminated seizures more quickly than phenytoin infusions (18 mg/kg at 50 mg/min)



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In another randomized study, valproate and phenytoin infusions were similarly effective, but valproate was better tolerated

The risk of hyperammonemic encephalopathy due to valproate may pose diagnostic challenges in the postictal setting


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Topiramate is a broad spectrum antiepileptic drug.

Topiramate, administered via nasogastric tube, may have some efficacy in refractory status epilepticus as reported in some case reports and small case series

Further prospective study is needed to define a role for topiramate in the treatment of status epilepticus.

Its use is not recommended at this time

PHARMACOLOGIC AGENTS Newer AEDs


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Case series of 18 to 43 patients with status epilepticus refractory to benzodiazepines and/or other AEDs who were treated with intravenous levetiracetam suggests that this is a safe and effective treatment

However, the efficacy of levetiracetam relative to other agents has yet to be studied in prospective controlled studies

PHARMACOLOGIC AGENTS Newer AEDs


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Any patient with possible status epilepticus requires rapid evaluation and treatment

There are many possible pharmacologic approaches to status epilepticus; successful approaches to management have been developed empirically, since there are few controlled trials comparing different regimens

Although there are differences in efficacy and side effect profile among effective agents, it is important to become familiar with and primarily use one reasonable treatment method

TREATMENT

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A rapid neurologic examination should be performed to provide a preliminary classification of the type of status epilepticus and its probable etiology

The patient should also undergo a rapid general evaluation, with particular attention to respiratory and circulatory status, and supportive therapy (eg, oxygen, mechanical ventilation) should be instituted as needed

TREATMENT Assessment and support

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During this time, intravenous catheters should be placed and blood obtained for electrolyte, serum glucose, and toxicology studies, a complete blood count, and a rapid "finger-stick" glucose

Measurement of arterial blood gases is often valuable and may suggest a need for intubation and mechanical ventilatory support

Cardiac monitoring, frequent measurement of blood pressure, and pulse oximetry should be instituted.

These tasks may require one to five minutes and may

overlap with the next phase of treatment

TREATMENT Assessment and support

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Lorazepam 0.02 to 0.03 mg/kg should be administered intravenously and approximately one minute allowed to assess its effect

Diazepam 0.1 mg/kg IV or midazolam 0.05 mg/kg IV may be substituted if lorazepam is not available

If seizures continue at this point, additional doses of lorazepam (up to a cumulative dose of 0.1 mg/kg) should be infused at a maximum rate of 2 mg/minute, and a second intravenous catheter placed in order to begin a concomitant phenytoin (or fosphenytoin) loading infusion

TREATMENT Initial pharmacologic therapy






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Even if seizures terminate after the initial lorazepam dose, therapy with phenytoin or fosphenytoin is generally indicated to prevent the recurrence of seizures

Phenytoin and any of the benzodiazepines are incompatible and will precipitate if infused through the same intravenous line

A phenytoin infusion of 20 mg/kg (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) should be started at 25 to 50 mg/min (or 100 mg PE/minute for fosphenytoin) and reduced if significant adverse effects of the infusion are seen

This phase of treatment usually lasts approximately 30 minutes

TREATMENT Initial pharmacologic therapy



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Status epilepticus that is refractory to first line anticonvulsants indicates a grave prognosis and requires management in an intensive care setting

After failure of the first line therapy discussed above, the next step is to consider infusion of another 10 mg/kg of phenytoin (or 10 mg/kg PE of fosphenytoin) and up to another 0.05 mg/kg of lorazepam if the patient is stable

Metabolic derangements from initial laboratory studies should be appropriately treated

TREATMENT Treatment of refractory seizures




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Further measures are required if seizures continue, but whereas there is reasonable agreement upon treatment up to this point, the optimal therapy of refractory status epilepticus is less well defined

Regardless of the specifics of pharmacologic therapy, it is critical to provide adequate ventilatory and hemodynamic support

Patients with refractory seizures should be endotracheally intubated, and continuous electroencephalogram (EEG) recordings are desirable


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The primary drugs used for refractory status epilepticus are phenobarbital, pentobarbital, midazolam, and propofol.

There is no consensus about which should be used first.

A systematic review of drug therapy for refractory status epilepticus assessed data on 193 patients from 28 trials in an attempt to clarify this issue

Overall mortality was 48 percent, but there was no association between drug selection and the risk of death






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Pentobarbital was more effective than either propofol or midazolam in preventing breakthrough seizures (12 versus 42 percent), but was associated with a significantly increased incidence of hypotension, defined as a systolic blood pressure below 100 mmHg (77 versus 34 percent)

Another study of 107 patients failed to show an influence of the therapy used on the outcome of refractory status

Further pharmacologic therapy at this point is based primarily upon the patient's hemodynamic stability and the risk for prolonged mechanical ventilation


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Treatment with high-dose barbiturates (pentobarbital or phenobarbital) remains common in this setting because of the greatest experience with its use

However, propofol is gaining some acceptance in this setting for patients who are already intubated because response to therapy is very rapid, allowing a rapid change to another regimen if propofol infusion is unsuccessful

Continuous EEG monitoring should be instituted, if possible, along with continuous pulse oximetry and blood pressure monitoring via an arterial catheter

Vasopressors should be available at the bedside

TREATMENT Hemodynamically stable patients




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An initial dose of 20 mg/kg of phenobarbital should be infused at a maximum rate of 100 mg/minute.

If seizure activity continues, a dose of 10 mg/kg of pentobarbital should be infused while careful attention is paid to the EEG and hemodynamic status.

Additional doses of pentobarbital at rates up to 100 mg/min should be infused until all seizures stop




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Subclinical seizures may still be evident on the EEG after clinical seizures have stopped

As it is important to stop both clinical and electrographic seizures, EEG monitoring is important in the treatment of refractory status epilepticus

However, it can be difficult to be certain if electrographic patterns are ictal or interictal


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Thus, it is common practice to titrate therapy until the EEG shows a pattern that is clearly not ictal.

A burst suppression pattern is often chosen as an electrographic endpoint because it is clearly not ictal and is easy to recognize

Almost all patients at this point will require vasopressor support (typically phenylephrine or dopamine), as well as crystalloid infusions



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The mortality rate associated with barbiturate coma is high because of adverse hemodynamic effects and the severity of the underlying neurologic process, and reaches 80 percent in patients over 70

If seizures are terminated with pentobarbital, then an infusion at 1 to 4 mg/kg per hour should be maintained for 24 hours and tapered over the following 24 hours



12/08/202285

Some physicians may prolong the duration of high-dose therapy if frequent focal epileptiform discharges remain on the EEG after treatment

During this time, high therapeutic phenytoin and/or phenobarbital concentrations must be maintained




12/08/202286

Patients who are at high risk for prolonged mechanical ventilation (eg, those with severe COPD, severe debilitation, or cancer) should be treated with propofol in an attempt to minimize the duration of sedation

Pressors should be ready at the bedside, and blood pressure and EEG should be monitored closely while propofol infusion is initiated at 1 to 2 mg/kg per hour

This infusion should be titrated over the next 20 to 60 minutes to maintain a seizure-free state and burst suppression on the EEG

TREATMENT Patients at high risk for respiratory failure


12/08/202287

Infusion rates up to 10 to 12 mg/kg/hour may be required, but should not be maintained for more than 18 to 48 hours because of the risk of the propofol infusion syndrome

If seizures are controlled with propofol, the effective infusion rate should be maintained for 24 hours and then tapered at a rate of 5 percent per hour

This prevents rebound seizures that commonly occur with abrupt propofol discontinuation



12/08/202288

It is critical that high therapeutic levels of at least one anticonvulsant (phenytoin levels >25 mg/L [99 µmol/L] or phenobarbital levels >30 mg/L [129 µmol/L]) are obtained prior to tapering the propofol in order to reduce the risk of seizure recurrence

Treatment with propofol should generally be considered unsuccessful if it does not terminate seizure activity within 45 to 60 minutes





12/08/202289

In this case, a high dose barbiturate infusion should be considered

Propofol infusions for refractory status epilepticus are relatively new in comparison with midazolam or high dose barbiturates

However, as clinical experience with propofol sedation in the intensive care setting grows, this agent is increasingly used in patients with refractory status persisting after intubation

It remains critical that propofol be employed cautiously and by individuals familiar with its use in this context



12/08/202290

The term "malignant" status epilepticus has been introduced to refer to status epilepticus that either fails to respond to the therapies discussed above or recurs quickly on tapering these medications

It has been reported that as many as 20 percent of patients with refractory status epilepticus evolve into malignant status epilepticus, a transition that is associated with a very poor prognosis

TREATMENT Malignant status epilepticus

12/08/202291

Treatment of status epilepticus out of hospital by paramedics appears to be safe and effective.

This was illustrated in a randomized, double-blind study of 205 patients with status epilepticus, of whom 66 received lorazepam, 68 received diazepam, and 71 received placebo

TREATMENT Out-of-hospital treatment



12/08/202292

Status epilepticus had been terminated on arrival to the emergency department in more patients treated with lorazepam and diazepam than placebo (59, 43, and 21 percent, respectively).

Active treatment also reduced the rates of respiratory or circulatory complications (10.6, 10.3, and 22.5 percent, respectively)

TREATMENT Out-of-hospital treatment

12/08/202293

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Convulsions and Anti Epileptic Drugs

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