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<< Seizures and Status Epilepticus: Diagnosis and Management in the Emergency Department
Management Of Status Epilepticus
Stabilization
Generalized convulsive status epilepticus (GCSE) is a medical emergency with mortality, associated with duration of the event. Mortality estimates range from 10 to 40%, and are related to the underlying etiology. For example, refractory GCSE associated with bacterial meningitis has higher mortality than GCSE due to AED or alcohol withdrawal. Early termination of SE is of the highest priority, since prolonged seizure activity is associated with difficult seizure termination, morbidity, and mortality. 12, 81, 82 Early termination also allows rapid diagnostic evaluation and early initiation of appropriate therapy for the underlying cause. Interestingly, mortality rates of partial and GCSE were not significantly different, perhaps indicating that combination of focal brain injury and partial status epilepticus contributed to the high mortality.88
In general, the patients that are most often recognized in the ED to be in status epilepticus are those with GCSE. These may be primary generalized or secondary generalized, but, for the purpose of stabilization, treatment, and work-up, they are approached the same. It is important to remember that, after initiation of treatment with benzodiazepines and as the muscles fatigue, the full tonicclonic movements may be attenuated and thus subtler in their clinical presentation (subtle SE).
In true emergency medicine fashion, the emergrency physician must approach SE from multiple directions at once. Consider the treatable etiologies, see Table 5. Protect the airway and ensure oxygenation and obtain intravenous access and diagnostic studies, while initiating pharmacologic interventions and planning the diagnostic work-up.
Intravenous access is best secured with a non-dextrose solution since dextrose will precipitate phenytoin if administered concurrently (fosphenytoin can be safely administered with dextrose solutions). The goal of therapy is to control seizure activity before neuronal injury occurs. Neuronal injury occurs between 20 minutes and one hour in experimental SE, despite adequate oxygenation and ventilation. Patients in status should be monitored by continuous pulse oximetry to detect seizure-related hypoxia. If, at any time, breathing appears compromised, rapid sequence intubation is recommended using lidocaine (as a pretreatment drug), an induction agent, followed by paralysis with a short acting agent, such as succinylcholine. A sedative agent is not often needed because the patient should have received high dose benzodiazepines by this time. While measures should be taken to minimize raising the intracranial pressure, these considerations should not delay securing the airway.
Long acting paralyzing agents are contraindicated unless bedside EEG monitoring becomes available. Prolonged pharmacologic paralysis can mask persistent electrical status of the brain, lulling the physician into a false sense of security. While vecuronium may render the body quiescent, the untreated electrical status may cause further damage to the brain.83 This is thought to be due to the release of excitatory amino acids and to calcium influx. A bedside serum glucose should be obtained early, and IV dextrose should be given if the level is low: 50 cc of 50% dextrose intravenously in adults or 2 mL/kg of 25% dextrose in children (excluding neonates) is the standard dose. Thiamine 100 mg, is recommended with dextrose boluses in patients who either appear malnourished or abuse alcohol.
When infection is suspected, consider early (empiric) antibiotics, since obtaining a head CT and performing a lumbar puncture may be delayed pending patient stabilization. Likewise, prompt administration of activated charcoal 1 gm/kg is a consideration in cases of suspected acute overdose, though this is controversial and should only be done after securing the airway.
A non-contrast head computed tomogram (CT) is recommended for all patients without a prior history of seizure once they have been stabilized. If the seizures cannot be controlled after aggressive use of AEDs, a short acting paralytic can be used to expedite a non-contrast head CT in order to exclude surgically reversible etiologies, such as an epidural hemorrhage. Rocuronium (1 mg/kg) is favored due its short duration of action. Longer acting paralytic agents should be avoided due to the danger of masking epileptic activity.
While an EEG is not typically necessary in status epilepticus for initial diagnosis, it plays an important role in monitoring patients after treatment, particularly in refractory status epilepticus. Recurrent seizures after initial control are common, and undetected persistent epileptic activity has been documented in a number of studies.74, 75, 84 An emergency EEG is indicated in unexplained altered awareness (to exclude NCSE), neuromuscular paralysis for SE, high-dose suppressive therapy for refractory SE, or when there is no improvement or return to baseline mental status after controlling overt convulsive movements (to exclude NCSE).75, 90
Traditionally, therapy of SE has been divided into first-, second-, and third-line therapies. A more practical way to categorize these is as medications that are used upon initial presentation which include benzodiazepines, phenytoin, and valproic acid. After that, if the seizure continues, it should be considered “refractory” GCSE and a protocol for the administration of high doses (anesthetic levels) of midazolam, pentobarbital, or propofol must be given.
The pharmacologic treatment of status epilepticus has changed in the past 20 years with increasing evidence supporting the use of benzodiazepines and less on phenobarbital. In addition, fosphenytoin and intravenous valproic acid have become available in the US and are developing roles in many protocols.
Benzodiazepines
Early and aggressive therapy with benzodiazepines has confirmed benefit in the management of status epilepticus.3, 85 IV lorazepam has been shown to be equally effective at terminating seizures to phenobarbital and superior to using phenytoin alone.4
Intravenous benzodiazepines remain the first drugs of choice for status epilepticus. Lorazepam is generally preferred up to a dose of 0.1 mg/kg given at 2 mg/min. Lorazepam and diazepam (0.2 mg/kg IV given at 5 mg/min) are equally effective at terminating the initial seizure. However, lorazepam has a smaller volume of distribution, and thus the anticonvulsant activity of lorazepam lasts up to twelve hours while that of diazepam only lasts for 20 minutes. 86 In a metanalysis, the Cochrane Database found that IV lorazepam was superior to IV diazepam for cessation of seizure and preventing recurrence/continuation of seizure requiring an additional drug or anesthesia.87 IV midazolam is less extensively studied, but a number of small studies seem to show a trend toward superior efficacy and decreased incidence of adverse outcomes compared to lorazepam88 and diazepam.89
In a patient with no intravenous access, the options are IM lorazepam or midazolam or rectal diazepam. Of these, IM midazolam is probably thebest option.112 This drug is water soluble, nonirritating, and rapidly absorbed. At least one trial has shown that it as effective as IV diazepam with no additional adverse outcomes.111 Rectal diazepam is another alternative for the patient with no intravenous access; the recommended dose in adults is 30 mg.3, 90, 91 It can be given per rectum either using the standard intravenous form, or as a gel formulated for this purpose (Diastat™). In a systemic review of available data, rectal diazepam is recommended when monitoring is not available.93
Phenytoin
In the ED setting, phenytoin has been used as a first line drug in status epilepticus since 1956 due to it’s availability in parenteral preparation and because it can rapidly achieve therapeutic levels. It is limited by the rate at which it can be delivered, as well as known adverse effects.
Phenytoin slows the recovery of voltage activated sodium channels thus decreasing repetitive action potentials in neurons. This effect on the myocardium can also lead to QT prolongation and arrhythmias. This is very rare, but cardiac monitoring is still recommended during infusion.92 A more common effect is hypotension which occurs 3.5% of the time. Its incidence is directly related to the total dose and the rate of infusion.93, 94
The recommended dose of phenytoin is 20 mg/kg administered in a non-glucose solution. For a 70 kg person this would be much higher than the common “one gram” often given in practice.Based on observational studies and consensus, a second dose of 10 mg/kg is recommended for patients who continue to seize.22, 95, 96 The infusion rate is limited to 50 mg/min in order to avoid hypotension caused by the propylene glycol diluent. The infusion rate should be no faster than 25 mg/min in patients with cardiac disease to minimize the risk of hypotension as well as the direct cardiac effects of phenytoin which can lead to bradycardia and heart blocks.
Due to specific properties of phenytoin, administration is a non-trivial consideration.99, 100 To maintain phenytoin soluble, it is formulated in solution with a pH of 12, making it extremely toxic to the vascular walls and soft tissue. It must be given through a large and well-secured vein, a potential challenge in some actively seizing patients. Infusion can cause distal limb edema, discoloration, and ischemia. Extravasation can be disastrous for the patient, resulting in extensive necrosis (i.e., ‘the purple glove’ syndrome).97, 98, 99
Because of its side effects, cardiac monitoring is necessary during phenytoin infusions. Reports of sudden cardiac death in patients receiving the intravenous form of the drug were most likely the result of rapid infusion of propylene glycol and/or ethanol, the vehicle used for phenytoin.100, 101, 102 Other, relatively minor side effects include confusion and ataxia, both of which usually resolve with supportive care. Fosphenytoin is a parenteral phenytoin precursor with an added phosphoryl group that has the same pharmacological activity as phenytoin in the treatment of seizures.113 Fosphenytoin has the advantage of being more water soluble and having a lower pH (8.6-9) than phenytoin, obviating the need for the propylene glycol vehicle. These characteristics make it preferable to phenytoin in a number of ways.103
When IV access is not available, fosphenytoin can be given IM with rapid achievement of therapeutic serum drug levels within one hour and within 30 minutes in 40% of patients.104, 105, 106, 107 For dosing ease, fosphenytoin is measured in phenytoin equivalents (PE) and can be infused at a rate up to 150 mg PE/min. 108 The manufacturer still recommends cardiac and blood pressure monitoring because hypotension, though rare, does occur. The lower pH decreases vascular irritation and decreases tissue toxicity allowing for IM administration with rapid bioavailability. The conversion half-life is 8 to 15 minutes. 113, 109 Fosphenytoin reaches a peak serum level within approximately one hour of intramuscular administration and at six minutes after intravenous loading.
The best therapeutic study on GCSE management is the VA Cooperative Study.4 This was a headto- head trial comparing four treatment arms:
diazepam (0.15 mg/kg) followed by phenytoin (18 mg/kg), lorazepam alone (0.1 mg/kg), phenytoin alone (18 mg/kg), and phenobarbital alone (15 mg/kg). This well designed, randomized, double blind study found no outcome difference between the four treatments; however, lorazepam was the easiest to administer and the authors recommended it as the first line agent in GCSE management. Because of the high seizure recurrence rate in patients treated with diazepam, phenytoin should always be administered after diazepam; this is not necessarily the case when lorazepam is used and depends on the underlying etiology of the seizure.
Valproic Acid
Valproic acid is unique among older antiepileptic drugs because it is effective in treating all forms of seizures, including absence, partial, and primary generalized. Its mechanism is similar to phenytoin and carbamazepine in that it prolongs recovery of voltage activated sodium channels from inactivation. The drug has recently become available in the US in IV form,110 although experience in status epilepticus is limited to small studies in adults and pediatrics which show an efficacy rate of 42 to 80%.111, 112 The recommended loading dose for valproic acid is 15-20 mg/kg at a rate of 3-6 mg/kg/min, although more rapid bolus infusions have been safely administered. 113, 114, 115, 116
Valproate has some promise due to its generally excellent safety profile.120, 121, 117 It is generally well tolerated with mild side effects. The notable exception is hepatotoxicity, which usually develops with chronic use over the first six months of therapy. There is also an incidence of an occasional rare fatal idiosyncratic hepatoxicity in 1/49,000 adults and 1/800 children. 123, 118 Therefore, the drug is contraindicated in patients with hepatic dysfunction.
Further study is needed, but parenteral valproate is an alternative in cases where benzodiazepine or phenytoin use is limited by hypotension or hypersensitivity, as well as in patients who are in status as a result of valproic acid withdrawal.
Phenobarbital
Introduced in 1912, Phenobarbital is the oldest antiepileptic drug still in use. It is notable as being the only barbiturate that possesses anticonvulsant properties at sub-hypnotic doses. It has been advocated in the past as a first line intervention, but has fallen out of favor today. Phenobarbital works on the GABA receptor similar to the mechanism of benzodiazepines and has generally shown the same efficacy as a first line agent in the combination of diazepam and phenytoin119 or with lorazepam alone.4 The main drawback of phenobarbital is its potential to induce profound respiratory depression and hypotension from its vasodilatatory and cardiodepressant effects. The respiratory depressant effects are compounded when used - as it typically is - after treatment with benzodiazepine. It also has a long half-life, which can make complications and titration difficult to manage.25 It is therefore generally held as a second line antiepileptic drug due to significant side effects. Many reserve this drug for patients who continue to seize despite benzodiazepine and phenytoin loading.125
Phenobarbital is dosed at 20 mg/kg administered at 100 mg/min. For refractory GCSE, it can be given in even higher doses of up to 30 mg/kg or more. However, in such doses, it is likely to cause hypotension and suppress respirations particularly during rapid infusion or co-existing benzodiazepine. Refractory GCSE: Current literature supports the use of continuous IV midazolam, anesthetic barbiturates (pentobarbital), or propofol in the management of refractory status epilepticus. Inhalational anesthetics do not have a well-defined role and can be considered along with other potentially useful, but less well studied medications, such as lidocaine, chloral hydrate, adenosine, and etomidate.
There is very little empiric data to guide the choice of therapy in an evidence-based fashion. Treatment modality is often based upon expert opinion and available resources (e.g., IV midazolam may be preferred as it is more readily available in the ED than pentobarbital) and the patient’s hemodynamic status.120
A recent systematic review98 did not find sufficientevidence to support the superiority of pentobarbital, propofol, or midazolam. Pentobarbital had less treatment failure but caused more hypotension than either propofol or midazolam, but this was based on a total of 28 patients over different study conditions. Midazolam and propofol are medications that are more familiar to most emergency medicine and critical care physicians, and are, therefore, often recommended due to the ease of access and familiarity.
None of these drugs have shown clear superiority over the other but it is well known that delays in controlling the seizure lead to worse outcomes. Continuous benzodiazepine infusion: Even after maximum dosing of lorazepam or diazepam, continuous infusions of midazolam or lorazepan have been reported to be effective in terminating refractory GCSE in small case series. Midazolam is water soluble and continuous infusion allows for high CNS penetration. It has a short duration of action and it is easy to titrate. The loading dose is 0.2 mg/kg, and this is followed by an infusion of 0.05 – 2.0 mg/kg/hour.121, 122 When compared to propofol or pentobarbital in a meta-analysis for refractory status epilepticus, IV midazolam was effective in 80% of cases. While this was less effective than propofol or pentobarbital, it was also associated with less hypotension than the other two medications. 123 Lorazepam .3 to 9 mg/hour can also be given as a continuous IV infusion; however, there is limited data on its use in status and its long half-life makes withdrawal more difficult.124
Propofol
Propofol is a global CNS depressant; it acts as a direct GABA agonist as well as an NMDA antagonist. There are limited studies of its efficacy in status epilepticus, but there is evidence that it provides almost immediate suppression of seizure activity after a bolus infusion. 125 It is rapidly metabolized and studies report rapid recovery from the propofol when the infusion is discontinued. Propofol is dosed with a bolus of 3-5 mg/kg followed by a continuous infusion at 30-100 mcg/kg/min.22, 126 Limiting factors in its long term and high dose use is the “propofol infusion syndrome” of hypotension, lipidemia, and metabolic acidosis in both adults and children.126, 127 Propofol can cause non-seizure jerking movements and even induce seizures, so EEG monitoring should be strongly considered.128 In one small, retrospective study of IV midazolam and propofol, the mortality was 57% in the propofol group and 17% in the IV midazolam group, though the study had only 14 patients, was not randomized, and did not have the power to demonstrate significance in this difference.129
Barbiturates
Pentobarbital and thiopental are much shorter acting than phenobarbital. Thiopental is rapidly metabolized to pentobarbital. Both agents are highly lipid soluble and will accumulate in fat stores, leading to prolonged elimination. In a recent series of 12 ICU patients in status epilepticus, high dose thiopental terminated seizures in all of the patients. However, one-third of the patients needed either dobutamine or norepinephrine to support their mean arterial pressure during therapy. The authors also noted prolonged recovery time from the medication after the seizures had been suppressed.130
Thiopental has a less favorable side-effect profile than pentobarbital. It is more lipid soluble and the metabolic pathway can become saturated, leading to an accumulation of thiopental and delays in recovery when stopped. For these reasons, pentobarbital is preferred when a barbiturate is used to manage refractory status.22 Pentobarbital is dosed with a loading dose of 3 to 5 mg/kg followed by an infusion of 0.5 to 3 mg/kg/hr. Pentobarbital can compromise cardiovascular status, and its use necessitates EEG monitoring since motor activity will be suppressed. Use fluid boluses to treat pentobarbitalinduced hypotension and consider dopamine in case of persistent hypotension.131, 132
Other agents
Other medications that have been used to treat status epilepticus in case series include lidocaine,133, 134 chloral hydrate,135 and etomidate.136 As of yet, these medications have not been validated for general use and should only be considered when other, more standard, therapies have failed.
Putting it all together: When a patient presents with GCSE, the time to termination of seizure maybecome dependent upon the time it takes for the physician to chose a drug and for the nurse to administer it. Thus, the ability of an emergency department to provide the rapid resources needed to treat status epilepticus depends upon development of a prearranged treatment algorithm, see Clinical Pathway. Pre-selection of medications for first-line use and those for refractory status epilepticus use will prevent delays when patients present. With a lack of strong evidence to select a preferred treatment for refractory status epilepticus, individual departments may make choices in conjunction with their neurology and critical care services, based upon drug availability and upon nursing familiarity with the given drugs.
Treatment in the prehospital arena begins with either IV lorazepam or diazepam. Upon presentation to the ED, continued seizure treatment begins with the stabilization of airway and vital functions. Initial medication choice is IV lorazepam (0.1 mg/kg), IV midazolam (0.2 mg/kg) or diazepam (0.15 mg/kg), taking into account the dose of the medication given in the field. If diazepam terminates the seizure, it should be followed by phenytoin or fosphenytoin (20 mg/kg or 20 PE/kg, respectively). If a benzodiazepine does not terminate seizure activity, phenytoin or fosphenytoin should be given with consideration to a second half load in refractory cases. Intravenous valproic acid might be considered if the patient is known to have been on valproic acid in the past.
If seizure activity continues, the patient is considered to be in refractory status epilepticus. Management choices include infusions of a benzodiazepine, propofol, and pentobarbital.
Generalized convulsive status epilepticus (GCSE) is a medical emergency with mortality, associated with duration of the event. Mortality estimates range from 10 to 40%, and are related to the underlying etiology. For example, refractory GCSE associated with bacterial meningitis has higher mortality than GCSE due to AED or alcohol withdrawal. Early termination of SE is of the highest priority, since prolonged seizure activity is associated with difficult seizure termination, morbidity, and mortality. 12, 81, 82 Early termination also allows rapid diagnostic evaluation and early initiation of appropriate therapy for the underlying cause. Interestingly, mortality rates of partial and GCSE were not significantly different, perhaps indicating that combination of focal brain injury and partial status epilepticus contributed to the high mortality.88
In general, the patients that are most often recognized in the ED to be in status epilepticus are those with GCSE. These may be primary generalized or secondary generalized, but, for the purpose of stabilization, treatment, and work-up, they are approached the same. It is important to remember that, after initiation of treatment with benzodiazepines and as the muscles fatigue, the full tonicclonic movements may be attenuated and thus subtler in their clinical presentation (subtle SE).
In true emergency medicine fashion, the emergrency physician must approach SE from multiple directions at once. Consider the treatable etiologies, see Table 5. Protect the airway and ensure oxygenation and obtain intravenous access and diagnostic studies, while initiating pharmacologic interventions and planning the diagnostic work-up.
Intravenous access is best secured with a non-dextrose solution since dextrose will precipitate phenytoin if administered concurrently (fosphenytoin can be safely administered with dextrose solutions). The goal of therapy is to control seizure activity before neuronal injury occurs. Neuronal injury occurs between 20 minutes and one hour in experimental SE, despite adequate oxygenation and ventilation. Patients in status should be monitored by continuous pulse oximetry to detect seizure-related hypoxia. If, at any time, breathing appears compromised, rapid sequence intubation is recommended using lidocaine (as a pretreatment drug), an induction agent, followed by paralysis with a short acting agent, such as succinylcholine. A sedative agent is not often needed because the patient should have received high dose benzodiazepines by this time. While measures should be taken to minimize raising the intracranial pressure, these considerations should not delay securing the airway.
Long acting paralyzing agents are contraindicated unless bedside EEG monitoring becomes available. Prolonged pharmacologic paralysis can mask persistent electrical status of the brain, lulling the physician into a false sense of security. While vecuronium may render the body quiescent, the untreated electrical status may cause further damage to the brain.83 This is thought to be due to the release of excitatory amino acids and to calcium influx. A bedside serum glucose should be obtained early, and IV dextrose should be given if the level is low: 50 cc of 50% dextrose intravenously in adults or 2 mL/kg of 25% dextrose in children (excluding neonates) is the standard dose. Thiamine 100 mg, is recommended with dextrose boluses in patients who either appear malnourished or abuse alcohol.
When infection is suspected, consider early (empiric) antibiotics, since obtaining a head CT and performing a lumbar puncture may be delayed pending patient stabilization. Likewise, prompt administration of activated charcoal 1 gm/kg is a consideration in cases of suspected acute overdose, though this is controversial and should only be done after securing the airway.
A non-contrast head computed tomogram (CT) is recommended for all patients without a prior history of seizure once they have been stabilized. If the seizures cannot be controlled after aggressive use of AEDs, a short acting paralytic can be used to expedite a non-contrast head CT in order to exclude surgically reversible etiologies, such as an epidural hemorrhage. Rocuronium (1 mg/kg) is favored due its short duration of action. Longer acting paralytic agents should be avoided due to the danger of masking epileptic activity.
While an EEG is not typically necessary in status epilepticus for initial diagnosis, it plays an important role in monitoring patients after treatment, particularly in refractory status epilepticus. Recurrent seizures after initial control are common, and undetected persistent epileptic activity has been documented in a number of studies.74, 75, 84 An emergency EEG is indicated in unexplained altered awareness (to exclude NCSE), neuromuscular paralysis for SE, high-dose suppressive therapy for refractory SE, or when there is no improvement or return to baseline mental status after controlling overt convulsive movements (to exclude NCSE).75, 90
Traditionally, therapy of SE has been divided into first-, second-, and third-line therapies. A more practical way to categorize these is as medications that are used upon initial presentation which include benzodiazepines, phenytoin, and valproic acid. After that, if the seizure continues, it should be considered “refractory” GCSE and a protocol for the administration of high doses (anesthetic levels) of midazolam, pentobarbital, or propofol must be given.
The pharmacologic treatment of status epilepticus has changed in the past 20 years with increasing evidence supporting the use of benzodiazepines and less on phenobarbital. In addition, fosphenytoin and intravenous valproic acid have become available in the US and are developing roles in many protocols.
Benzodiazepines
Early and aggressive therapy with benzodiazepines has confirmed benefit in the management of status epilepticus.3, 85 IV lorazepam has been shown to be equally effective at terminating seizures to phenobarbital and superior to using phenytoin alone.4
Intravenous benzodiazepines remain the first drugs of choice for status epilepticus. Lorazepam is generally preferred up to a dose of 0.1 mg/kg given at 2 mg/min. Lorazepam and diazepam (0.2 mg/kg IV given at 5 mg/min) are equally effective at terminating the initial seizure. However, lorazepam has a smaller volume of distribution, and thus the anticonvulsant activity of lorazepam lasts up to twelve hours while that of diazepam only lasts for 20 minutes. 86 In a metanalysis, the Cochrane Database found that IV lorazepam was superior to IV diazepam for cessation of seizure and preventing recurrence/continuation of seizure requiring an additional drug or anesthesia.87 IV midazolam is less extensively studied, but a number of small studies seem to show a trend toward superior efficacy and decreased incidence of adverse outcomes compared to lorazepam88 and diazepam.89
In a patient with no intravenous access, the options are IM lorazepam or midazolam or rectal diazepam. Of these, IM midazolam is probably thebest option.112 This drug is water soluble, nonirritating, and rapidly absorbed. At least one trial has shown that it as effective as IV diazepam with no additional adverse outcomes.111 Rectal diazepam is another alternative for the patient with no intravenous access; the recommended dose in adults is 30 mg.3, 90, 91 It can be given per rectum either using the standard intravenous form, or as a gel formulated for this purpose (Diastat™). In a systemic review of available data, rectal diazepam is recommended when monitoring is not available.93
Phenytoin
In the ED setting, phenytoin has been used as a first line drug in status epilepticus since 1956 due to it’s availability in parenteral preparation and because it can rapidly achieve therapeutic levels. It is limited by the rate at which it can be delivered, as well as known adverse effects.
Phenytoin slows the recovery of voltage activated sodium channels thus decreasing repetitive action potentials in neurons. This effect on the myocardium can also lead to QT prolongation and arrhythmias. This is very rare, but cardiac monitoring is still recommended during infusion.92 A more common effect is hypotension which occurs 3.5% of the time. Its incidence is directly related to the total dose and the rate of infusion.93, 94
The recommended dose of phenytoin is 20 mg/kg administered in a non-glucose solution. For a 70 kg person this would be much higher than the common “one gram” often given in practice.Based on observational studies and consensus, a second dose of 10 mg/kg is recommended for patients who continue to seize.22, 95, 96 The infusion rate is limited to 50 mg/min in order to avoid hypotension caused by the propylene glycol diluent. The infusion rate should be no faster than 25 mg/min in patients with cardiac disease to minimize the risk of hypotension as well as the direct cardiac effects of phenytoin which can lead to bradycardia and heart blocks.
Due to specific properties of phenytoin, administration is a non-trivial consideration.99, 100 To maintain phenytoin soluble, it is formulated in solution with a pH of 12, making it extremely toxic to the vascular walls and soft tissue. It must be given through a large and well-secured vein, a potential challenge in some actively seizing patients. Infusion can cause distal limb edema, discoloration, and ischemia. Extravasation can be disastrous for the patient, resulting in extensive necrosis (i.e., ‘the purple glove’ syndrome).97, 98, 99
Because of its side effects, cardiac monitoring is necessary during phenytoin infusions. Reports of sudden cardiac death in patients receiving the intravenous form of the drug were most likely the result of rapid infusion of propylene glycol and/or ethanol, the vehicle used for phenytoin.100, 101, 102 Other, relatively minor side effects include confusion and ataxia, both of which usually resolve with supportive care. Fosphenytoin is a parenteral phenytoin precursor with an added phosphoryl group that has the same pharmacological activity as phenytoin in the treatment of seizures.113 Fosphenytoin has the advantage of being more water soluble and having a lower pH (8.6-9) than phenytoin, obviating the need for the propylene glycol vehicle. These characteristics make it preferable to phenytoin in a number of ways.103
When IV access is not available, fosphenytoin can be given IM with rapid achievement of therapeutic serum drug levels within one hour and within 30 minutes in 40% of patients.104, 105, 106, 107 For dosing ease, fosphenytoin is measured in phenytoin equivalents (PE) and can be infused at a rate up to 150 mg PE/min. 108 The manufacturer still recommends cardiac and blood pressure monitoring because hypotension, though rare, does occur. The lower pH decreases vascular irritation and decreases tissue toxicity allowing for IM administration with rapid bioavailability. The conversion half-life is 8 to 15 minutes. 113, 109 Fosphenytoin reaches a peak serum level within approximately one hour of intramuscular administration and at six minutes after intravenous loading.
The best therapeutic study on GCSE management is the VA Cooperative Study.4 This was a headto- head trial comparing four treatment arms:
diazepam (0.15 mg/kg) followed by phenytoin (18 mg/kg), lorazepam alone (0.1 mg/kg), phenytoin alone (18 mg/kg), and phenobarbital alone (15 mg/kg). This well designed, randomized, double blind study found no outcome difference between the four treatments; however, lorazepam was the easiest to administer and the authors recommended it as the first line agent in GCSE management. Because of the high seizure recurrence rate in patients treated with diazepam, phenytoin should always be administered after diazepam; this is not necessarily the case when lorazepam is used and depends on the underlying etiology of the seizure.
Valproic Acid
Valproic acid is unique among older antiepileptic drugs because it is effective in treating all forms of seizures, including absence, partial, and primary generalized. Its mechanism is similar to phenytoin and carbamazepine in that it prolongs recovery of voltage activated sodium channels from inactivation. The drug has recently become available in the US in IV form,110 although experience in status epilepticus is limited to small studies in adults and pediatrics which show an efficacy rate of 42 to 80%.111, 112 The recommended loading dose for valproic acid is 15-20 mg/kg at a rate of 3-6 mg/kg/min, although more rapid bolus infusions have been safely administered. 113, 114, 115, 116
Valproate has some promise due to its generally excellent safety profile.120, 121, 117 It is generally well tolerated with mild side effects. The notable exception is hepatotoxicity, which usually develops with chronic use over the first six months of therapy. There is also an incidence of an occasional rare fatal idiosyncratic hepatoxicity in 1/49,000 adults and 1/800 children. 123, 118 Therefore, the drug is contraindicated in patients with hepatic dysfunction.
Further study is needed, but parenteral valproate is an alternative in cases where benzodiazepine or phenytoin use is limited by hypotension or hypersensitivity, as well as in patients who are in status as a result of valproic acid withdrawal.
Phenobarbital
Introduced in 1912, Phenobarbital is the oldest antiepileptic drug still in use. It is notable as being the only barbiturate that possesses anticonvulsant properties at sub-hypnotic doses. It has been advocated in the past as a first line intervention, but has fallen out of favor today. Phenobarbital works on the GABA receptor similar to the mechanism of benzodiazepines and has generally shown the same efficacy as a first line agent in the combination of diazepam and phenytoin119 or with lorazepam alone.4 The main drawback of phenobarbital is its potential to induce profound respiratory depression and hypotension from its vasodilatatory and cardiodepressant effects. The respiratory depressant effects are compounded when used - as it typically is - after treatment with benzodiazepine. It also has a long half-life, which can make complications and titration difficult to manage.25 It is therefore generally held as a second line antiepileptic drug due to significant side effects. Many reserve this drug for patients who continue to seize despite benzodiazepine and phenytoin loading.125
Phenobarbital is dosed at 20 mg/kg administered at 100 mg/min. For refractory GCSE, it can be given in even higher doses of up to 30 mg/kg or more. However, in such doses, it is likely to cause hypotension and suppress respirations particularly during rapid infusion or co-existing benzodiazepine. Refractory GCSE: Current literature supports the use of continuous IV midazolam, anesthetic barbiturates (pentobarbital), or propofol in the management of refractory status epilepticus. Inhalational anesthetics do not have a well-defined role and can be considered along with other potentially useful, but less well studied medications, such as lidocaine, chloral hydrate, adenosine, and etomidate.
There is very little empiric data to guide the choice of therapy in an evidence-based fashion. Treatment modality is often based upon expert opinion and available resources (e.g., IV midazolam may be preferred as it is more readily available in the ED than pentobarbital) and the patient’s hemodynamic status.120
A recent systematic review98 did not find sufficientevidence to support the superiority of pentobarbital, propofol, or midazolam. Pentobarbital had less treatment failure but caused more hypotension than either propofol or midazolam, but this was based on a total of 28 patients over different study conditions. Midazolam and propofol are medications that are more familiar to most emergency medicine and critical care physicians, and are, therefore, often recommended due to the ease of access and familiarity.
None of these drugs have shown clear superiority over the other but it is well known that delays in controlling the seizure lead to worse outcomes. Continuous benzodiazepine infusion: Even after maximum dosing of lorazepam or diazepam, continuous infusions of midazolam or lorazepan have been reported to be effective in terminating refractory GCSE in small case series. Midazolam is water soluble and continuous infusion allows for high CNS penetration. It has a short duration of action and it is easy to titrate. The loading dose is 0.2 mg/kg, and this is followed by an infusion of 0.05 – 2.0 mg/kg/hour.121, 122 When compared to propofol or pentobarbital in a meta-analysis for refractory status epilepticus, IV midazolam was effective in 80% of cases. While this was less effective than propofol or pentobarbital, it was also associated with less hypotension than the other two medications. 123 Lorazepam .3 to 9 mg/hour can also be given as a continuous IV infusion; however, there is limited data on its use in status and its long half-life makes withdrawal more difficult.124
Propofol
Propofol is a global CNS depressant; it acts as a direct GABA agonist as well as an NMDA antagonist. There are limited studies of its efficacy in status epilepticus, but there is evidence that it provides almost immediate suppression of seizure activity after a bolus infusion. 125 It is rapidly metabolized and studies report rapid recovery from the propofol when the infusion is discontinued. Propofol is dosed with a bolus of 3-5 mg/kg followed by a continuous infusion at 30-100 mcg/kg/min.22, 126 Limiting factors in its long term and high dose use is the “propofol infusion syndrome” of hypotension, lipidemia, and metabolic acidosis in both adults and children.126, 127 Propofol can cause non-seizure jerking movements and even induce seizures, so EEG monitoring should be strongly considered.128 In one small, retrospective study of IV midazolam and propofol, the mortality was 57% in the propofol group and 17% in the IV midazolam group, though the study had only 14 patients, was not randomized, and did not have the power to demonstrate significance in this difference.129
Barbiturates
Pentobarbital and thiopental are much shorter acting than phenobarbital. Thiopental is rapidly metabolized to pentobarbital. Both agents are highly lipid soluble and will accumulate in fat stores, leading to prolonged elimination. In a recent series of 12 ICU patients in status epilepticus, high dose thiopental terminated seizures in all of the patients. However, one-third of the patients needed either dobutamine or norepinephrine to support their mean arterial pressure during therapy. The authors also noted prolonged recovery time from the medication after the seizures had been suppressed.130
Thiopental has a less favorable side-effect profile than pentobarbital. It is more lipid soluble and the metabolic pathway can become saturated, leading to an accumulation of thiopental and delays in recovery when stopped. For these reasons, pentobarbital is preferred when a barbiturate is used to manage refractory status.22 Pentobarbital is dosed with a loading dose of 3 to 5 mg/kg followed by an infusion of 0.5 to 3 mg/kg/hr. Pentobarbital can compromise cardiovascular status, and its use necessitates EEG monitoring since motor activity will be suppressed. Use fluid boluses to treat pentobarbitalinduced hypotension and consider dopamine in case of persistent hypotension.131, 132
Other agents
Other medications that have been used to treat status epilepticus in case series include lidocaine,133, 134 chloral hydrate,135 and etomidate.136 As of yet, these medications have not been validated for general use and should only be considered when other, more standard, therapies have failed.
Putting it all together: When a patient presents with GCSE, the time to termination of seizure maybecome dependent upon the time it takes for the physician to chose a drug and for the nurse to administer it. Thus, the ability of an emergency department to provide the rapid resources needed to treat status epilepticus depends upon development of a prearranged treatment algorithm, see Clinical Pathway. Pre-selection of medications for first-line use and those for refractory status epilepticus use will prevent delays when patients present. With a lack of strong evidence to select a preferred treatment for refractory status epilepticus, individual departments may make choices in conjunction with their neurology and critical care services, based upon drug availability and upon nursing familiarity with the given drugs.
Treatment in the prehospital arena begins with either IV lorazepam or diazepam. Upon presentation to the ED, continued seizure treatment begins with the stabilization of airway and vital functions. Initial medication choice is IV lorazepam (0.1 mg/kg), IV midazolam (0.2 mg/kg) or diazepam (0.15 mg/kg), taking into account the dose of the medication given in the field. If diazepam terminates the seizure, it should be followed by phenytoin or fosphenytoin (20 mg/kg or 20 PE/kg, respectively). If a benzodiazepine does not terminate seizure activity, phenytoin or fosphenytoin should be given with consideration to a second half load in refractory cases. Intravenous valproic acid might be considered if the patient is known to have been on valproic acid in the past.
If seizure activity continues, the patient is considered to be in refractory status epilepticus. Management choices include infusions of a benzodiazepine, propofol, and pentobarbital.
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