TOC |
Neurology 
Epilepsy - Seizure Disorders
See also Status-epilepticus-Rx |
General-Rx-Approach |
Drug of Choice |
Epilepsy Drugs 2009
Old Clinical Classification:
International
Classification:
Localized (focal, partial) seizure:
Generalized epilepsies & synd.
Status epilepticus 2009 RX REF: DynaMed 2009
Treatment overview:
Treatment general guidelines
Treatment alternative approach
Medications:
Intravenous medications:
" lorazepam preferred as more effective than phenytoin and easier to use than phenobarbital and diazepam/phenytoin
o 570 patients with generalized convulsive status epilepticus randomized to 1 of 4 IV regimens
o successful treatment defined as all motor and EEG seizure activity ceased within 20 minutes after beginning of drug infusion and no recurrence over next 40 minutes
o comparing diazepam then phenytoin vs. lorazepam vs. phenobarbital vs. phenytoin
" 55.8% vs. 64.9% vs. 58.2% vs. 43.6% success rates among 384 patients with verified diagnosis of overt generalized convulsive status epilepticus
" no statistically significant differences in 8.3% vs. 17.9% vs. 24.2% vs. 7.7% success rates among 134 patients with verified diagnosis of subtle generalized convulsive status epilepticus (coma and ictal discharges on EEG)
" combined results in 518 patients with verified diagnosis showed 43.1% vs. 52.2% vs. 49.2% vs. 36.8% success rates and similar but non-significant results in all 570 patients
o Reference - N Engl J Med 1998 Sep 17;339(12):792
Diazepam (Valium)/phenytoin (Dilantin) combination
" fosphenytoin
o fosphenytoin may have a role in treatment of status epilepticus
" fosphenytoin at least as effective as phenytoin for response and control of status epilepticus
" fosphenytoin can be infused more rapidly than phenytoin
" fosphenytoin may have lower rate of vascular adverse events
" Reference - review of 4 randomized trials (Core Evidence 2005;1(1):65)
o editorial discussion supporting use of fosphenytoin (written by author who has received pharmaceutical company funds) can be found in BMJ 2000 Apr 8;320(7240):953
" limited and inconsistent evidence comparing valproate and phenytoin for status epilepticus
o valproate and phenytoin may have similar efficacy for benzodiazepine-refractory status epilepticus (level 2 [mid-level] evidence)
" based on randomized trial with wide confidence intervals
" 100 patients with status epilepticus refractory to benzodiazepine were randomized to IV valproate vs. IV phenytoin
" 12 patients with inadequate seizure control crossed over to other group
" no significant difference in success rate (88% vs. 84%) defined as no seizure activity within 20 minutes after starting study drug and no return of seizure activity for 12 hours
" no significant differences in adverse events or recurrences at 7 days
" Reference - Seizure 2007 Sep;16(6):527
o sodium valproate may be more effective than phenytoin for seizure cessation (level 2 [mid-level] evidence)
" based on randomized trial with borderline statistical significance
" 68 patients aged 1-85 years with convulsive status epilepticus were randomized to sodium valproate 30 mg/kg IV over 15 minutes vs. phenytoin sodium 18 mg/kg IV at 50 mg/minute
" comparing valproate vs. phenytoin
" 66% vs. 42% had status epilepticus aborted (p = 0.046, NNT 8)
" 15 of 19 (79%) vs. 3 of 12 (25%) refractory patients had no seizures in following 24 hours (NNT 2)
" no deaths within 24 hours of treatment, but 19 patients died during hospital stay
" Reference - Neurology 2006 Jul 25;67(2):340
" alternative - phenobarbital 100 mg/minute IV until seizures stop or total dose of 10 mg/kg, then 50 mg/minute until total dose of 20 mg/kg; can be given as 120-240 mg bolus every 15 minutes
" if phenytoin loading dose not given, status epilepticus is likely to recur when benzodiazepine wears off and anticonvulsant effect can wear off much more quickly than sedating effect
Buccal medications:
" buccal midazolam may be more effective than rectal diazepam for seizure cessation in children (level 2 [mid-level] evidence)
o based on 3 randomized trials with methodologic limitations
o in single-blind randomized trial
" 330 children aged 3 months to 12 years presenting with seizure to emergency room in Uganda were randomized to buccal midazolam plus rectal placebo vs. rectal diazepam plus buccal placebo (weight-based dosing)
" 67.3% diganosed with malaria
" 71.5% had documented temperature ? 37.5°C (100°F)
" primary outcome cessation of visible seizure activity within 10 minutes without recurrence in subsequent hour
" comparing buccal midazolam vs. rectal diazepam
" overall seizure cessation in 69.7% vs. 57% (p = 0.016, NNT 8)
" seizure cessation in subgroup with malaria in 68.2% vs. 64.2% (p = 0.0534)
" seizure cessation in subgroup without malaria in 55.9% vs 26.5% (p = 0.002, NNT 4)
" Reference - Pediatrics 2008 Jan;121(1):e58
o in randomized trial without allocation concealment or intention-to-treat analysis
" 219 seizures (presumed generalized tonic-clonic) presenting to emergency department in 177 children > 6 months old without IV access were randomized to buccal midazolam vs. rectal diazepam
" randomization by assigning study center which treatment to use on a weekly basis and allocation was not concealed
" dosing approximated 0.5 mg/kg by using 2.5 mg at age 6-12 months, 5 mg at age 1-4 years, 7.5 mg at age 5-9 years and 10 mg at age 10 years and older
" 35% were febrile seizures, results not separately reported
" results were per protocol and not intention-to-treat
" therapeutic success defined as cessation of seizures within 10 minutes and for at least 1 hour without respiratory depression requiring intervention
" comparing midazolam vs. diazepam
" therapeutic success in 56% vs. 27% (NNT 4 in per-seizure analysis)
" therapeutic success in 53% vs. 28% (NNT 4 in per-patient analysis using first episode)
" seizure stopped within 10 minutes in 65% vs. 41% (NNT 5 in per-seizure analysis)
" seizure stopped within 10 minutes in 60% vs. 42% (NNT 6 in analysis of initial episodes)
" respiratory depression in 5% vs. 6% (not significant)
" Reference - Lancet 2005 Jul 16;366(9481):205 EBSCOhost Full Text, editorial can be found in Lancet 2005 Jul 16-22;366(9481):182 EBSCOhost Full Text
o in small unblinded randomized trial
" 42 young persons with severe epilepsy at a residential school and continuous seizures > 5 minutes were randomized to buccal midazolam vs. rectal diazepam
" additional medication given at physician discretion for seizure > 10 minutes
" comparing buccal midazolam vs. rectal diazepam
" 40 seizures treated in 14 students vs. 39 seizures treated in 14 students
" seizures stopped in 75% vs. 59% seizures (not significant)
" Reference - Lancet 1999 Feb 20;353(9153):623 EBSCOhost Full Text, editorial can be found in Lancet 1999 Feb 20;353(9153):608 EBSCOhost Full Text, commentary can be found in Lancet 1999 May 22;353(9166):1796 EBSCOhost Full Text
" nurse administered midazolam and medical care available in this study, so results may not be generalizable to community setting; seizures (not patients) were randomized and 50% seizures occurred in 2 patients; long seizures treated, not status epilepticus (ACP J Club 2000 Jan-Feb;132(1):22)
Rectal medications:
" rectal diazepam gel (Diastat) appears effective for acute repetitive seizures in adults and children (level 2 [mid-level] evidence)
o baed on 2 randomized placebo-controlled trials reported as combined subgroup analyses
o adults and children with acute repetitive seizures randomized to rectal diazepam vs. placebo in 2 trials
o 1 trial used single dose, 1 trial used second dose at 4 hours
o 96 adults enrolled
" 70 adults who had siezures were treated and analyzed
" comparing rectal diazepam vs. placebo
" median number of seizures/hour over 12 hours 0 vs. 0.13
" seizure-free rate over 12 hours 71% vs. 28% (NNT 3)
" adverse events in 32% vs. 23% (NNH 11)
" Reference - Arch Neurol 2002 Dec;59(12):1915
o 133 children enrolled
" comparing rectal diazepam vs. placebo
" median number of seizures/hour over 12 hours 0 vs. 0.25
" seizure-free rate over 12 hours 59% vs. 31% (NNT 4)
" somnolence in 25% vs. 7.7% (NNH 5)
" Reference - Pediatr Neurol 1999 Apr;20(4):282
" rectal diazepam gel useful in home settings for acute repetitive seizures; acute repetitive seizures distinguished from unpredictable seizures or those provoked by specific cause in that they had predictable pattern such as aura or prodrome, type, frequency, severity or duration; 114 patients with acute repetitive seizures (mostly on other seizure medications) and epileptic seizure type including primary-generalized, complex-partial or simple-partial seizures with motor component randomized to diazepam rectal gel vs. placebo rectal gel; in 12 hours after administration, median number of seizures 0 vs. 2, 55% vs. 34% seizure free, increased rate of somnolence with diazepam (not statistically significant) (Neurology 1998 Nov;51(5):1274 in Am Fam Physician 1999 Feb 15;59(4):972)
" limited evidence for rectal medications for treatment of acute tonic-clonic convulsive episode (including status epilepticus) in children (level 2 [mid-level] evidence)
o based on Cochrane review of trials without blinding
o systematic review of 4 randomized and quasi-randomized trials evaluating anticonvulsant drugs in 383 children with acute tonic-clonic convulsion (including status epilepticus)
o all trials were unblinded
o 2 trials evaluated rectal benzodiazepines
o rectal lorazepam appeared more effective than rectal diazepam for controlling episodes of acute tonic-clonic convulsions (100% vs. 31%, p < 0.05, NNT 2) in 1 trial with 25 patients
o buccal midazolam appeared more effective than rectal diazepam for controlling episodes of acute tonic-clonic convulsions (56% vs. 27%, p < 0.05, NNT 4) in 1 trial with 219 patients
o Reference - Cochrane Database Syst Rev 2008 Jul 16;(3):CD001905
" diazepam rectal gel (Diastat AcuDial) should be returned if applicator has cracks at base of plastic tip, may result in partial dosing (FDA MedWatch 2006 Mar 30); applicator tip should be inspected for cracks at least once per month without removing cap during inspection (FDA Press Release 2006 Apr 3)
Intranasal medications:
" intranasal benzodiazepines appear effective for treatment of acute tonic-clonic convulsive episode (including status epilepticus) in children (level 2 [mid-level] evidence)
o based on Cochrane review of trials without blinding
o systematic review of 4 randomized and quasi-randomized trials evaluating anticonvulsant drugs in 383 children with acute tonic-clonic convulsion (including status epilepticus)
o all trials were unblinded
o 2 trials evaluated intranasal benzodiazepines
o intranasal midazolam appeared as effective an intravenous diazepam in 1 trial in 52 patients with prolonged febrile convulsions
o intranasal lorazepam appeared more effective than intramuscular paraldehyde in 1 trial in 160 patients with acute tonic-clonic convulsions
o Reference - Cochrane Database Syst Rev 2008 Jul 16;(3):CD001905
" intranasal lorazepam appears effective and less invasive than intramuscular paraldehyde for seizure cessation in children (level 2 [mid-level] evidence)
o 160 children > 2 months old with seizures > 5 minutes in Malawi pediatric emergency department were randomized to open-label intranasal lorazepam 100 mcg/kg vs. intramuscular paraldehyde 0.2 mL/kg
o 75% lorazepam vs. 61% paraldehyde group had cessation of presenting seizure within 10 minutes of dosing
o no clinically important cardiorespiratory events occurred in either group
o Reference - BMJ 2006 May 13;367(9522):1591 EBSCOhost Full Text, editorial can be found in BMJ 2006 May 13;367(9522):1555 EBSCOhost Full Text
" intranasal midazolam effective in uncontrolled study; 20 children 1 month-16 years old with generalized motor seizures lasting 10-25 minutes given midazolam 5 mg/mL solution at 0.2 mg/kg drops into both nostrils, mean time to seizure control 3.5 minutes with no recurrences at 60 minutes, 1 patient required IV diazepam for continued seizures at 10 minutes (Lancet 1998 Aug 22;352(9128):620 EBSCOhost Full Text); lack of placebo control group makes true efficacy unknown (DynaMed commentary), intranasal midazolam not yet FDA approved for use in US (J Watch 2000 Sep 1;20(17):139)
" review of intranasal midazolam for pediatric status epilepticus can be found in Am J Emerg Med 2006 May;24(3):343
Additional considerations:
" consider intraosseous injection in children
Options if seizure activity > 30-40 minutes:
" intubate, monitor EEG
" phenobarbital 100 mg/minute IV to maximum 20 mg/kg OR
" add phenytoin or lorazepam if not previously given
Options if seizure activity > 50-80 minutes:
" isoflurane or halothane and neuromuscular junction blockade by anesthesiologist
" pentobarbital IV, loading dose 15 mg/kg over 1 hour, maintenance 1-2 mg/kg/hour until seizures stop or EEG burst suppression
" thiopentone 2 mg/minute in normal saline, reduce dose to 0.5 mg/minute when controlled, increase dose if necessary, monitor EEG for burst suppression
" midazolam 200 mcg/kg IV bolus then 0.75-11 mcg/kg/minute infusion lasting 8 hours to 10 days reported as successful in 4 patients; cessation of seizures within minutes, no significant side effects, all patients recovered (Neurology 1994 Oct;44(10):1837)
o for midazolam protocol Click for Details
" 1. Use midazolam protocol only after full loading doses of lorazepam, phenytoin and phenobarbital. Monitor vital signs and hyperthermia. Treat underlying cause.
" 2. If still seizing, intubate using short-acting paralytic agent, ventilate and transfer to ICU.
" 3. If comatose, begin EEG monitoring. Proceed with midazolam if convulsions or seizure activity on EEG. Consider arterial line and central venous monitoring.
" 4. Give midazolam 200 mcg/kg as slow IV bolus, then 0.75-10 mcg/kg/minute continuous IV infusion. Higher doses may be necessary due to tachyphylaxis. Adjust maintenance dose to stop EEG seizure activity. Monitor EEG continuously for first 1-2 hours then for 30-60 minutes every 2 hours during maintenance phase. Stop therapy upon suppression of EEG seizures.
" 5. Continue maintenance doses of phenytoin and phenobarbital. Follow levels to determine optimal doses.
" 6. Use IV fluids and low-dose dopamine (up to 10 mcgg/kg/minute) to treat hypotension. Add low-dose dobutamine if necessary. Decrease midazolam dose if cardiovascular compromise.
" 7. Discontinue midazolam at 12 hours while monitoring EEG and observe for seizure activity. If seizures recur, restart infusion and repeat this step every 12-24 hours.
" case report of successful continuous propofol infusion, high dose required possibly due to tolerance and other enzyme-inducing agents (Anesthesia and Analgesia 1994;78(6):1193)
General Rx Approach
to seizures:
Drugs of Choice for
major epilepsy:
Symptomatic partial epilepsy
Idiopathic generalized epilepsy
(AIM 3-1-94. p 413)
Drug Treatment of Seizures
| Seizures Type | Drugs |
Daily Adult Dose | Therapeutic level |
| Primary Generalized Tonic-Clonic (Grand-mal type) |
Valproate (Depakene) | 1000-3000 mg | 50-120 ug/mL |
| . | Phenytoin (Dilantin) | 3300-400 mg | 10-20 ug/mL |
| . | Carbamazepine (Tegretol, Carbatrol) |
800-1600 mg | 6-12 ug/mL |
| Alternative: | Lamotrigine (Lamictal) | 100-500 mg | . |
| . | Primidone (Mysoline) | 750-1250 mg | 6-12 ug/m |
| . | Phenobarbital | 90-150 mg | L15-35 ug/mL |
| . | . | . | . |
2008
SYMPOSIUM ON SEIZURE MANAGEMENT - Postgraduate Medicine January 2002
Status Epilepticus on E-Medicine 7-2002
REF: UpToDate 2006
The term status epilepticus generally refers to the occurrence of a single unremitting seizure with a duration longer than 30 minutes or frequent clinical seizures without an interictal return to the baseline clinical state
Refractory status epilepticus, defined as ongoing seizures following first- and second-line drug therapy, was noted in nearly 30 [8] to 43 [9] percent of patients with 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)
Acute structural injury (eg, encephalitis, tumor, stroke, head trauma, subarachnoid hemorrhage, cerebral anoxia or hypoxia)
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 epilepsies
CLASSIFICATION — 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:
Simple partial — Simple partial status epilepticus is characterized by continuous or repeated focal motor seizures (eg, twitching of one thumb), focal sensory symptoms (eg, the sensation of flashing lights in one visual field), or cognitive symptoms (eg, aphasia) without impaired consciousness.
Complex partial — Complex partial status 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 [20]. Other symptoms, such as automatisms and behavioral disturbances, may also occur.
Generalized tonic-clonic — 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.
Less common varieties — In addition to the three major types of status epilepticus listed above, there are a number of less common but important forms to recognize:
Absence — 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 epilepsy and frequently requires EEG for confirmation.
Myoclonic — Myoclonic status epilepticus is characterized by frequent myoclonic jerks 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. 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.
Psychogenic — 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.
Initial pharmacologic therapy
Lorazepam 0.02 to 0.03 mg/kg should be administered intravenously and approximately 1 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. 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 of refractory seizures — Status epilepticus that is refractory to first line anticonvulsants is a feared complication that requires management in an intensive care unit. The first approach to refractory seizures is to infuse another 10 mg/kg of phenytoin (or 10 mg/kg PE of fosphenytoin) and consider another 0.05 mg/kg of lorazepam if the patient is stable. Metabolic derangements from initial laboratory studies should be appropriately treated. 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 EEG recordings are desirable [42].
The primary drugs used in this setting are phenobarbital, pentobarbital, midazolam, and propofol; however, 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 [42]. Overall mortality was 48 percent, but there was no association between drug selection and the risk of death. 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).
Further pharmacologic therapy at this point is based primarily upon the patient's hemodynamic stability and the risk for prolonged mechanical ventilation.
PHARMACOLOGIC AGENTS —
There are four main categories of drugs used to treat status epilepticus:
benzodiazepines,
phenytoin (or fosphenytoin),
barbiturates, and
propofol.
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. 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 [21].
Benzodiazepines — Benzodiazepines remain the first-line treatment for status epilepticus because they can rapidly control seizures [22]. 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 [23].
Diazepam — 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. However, because of subsequent redistribution of the drug into adipose tissue, the duration of diazepam's acute anticonvulsant effect is typically <20 minutes.
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.
Lorazepam — 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 2 minutes. The clinical advantage of lorazepam is that the effective duration of action against seizures is as long as 4 to 6 hours because of its less pronounced redistribution into adipose tissue. Effective initial intravenous doses of lorazepam are 0.02 to 0.2 mg/kg.
One study randomized 570 patients with a verified diagnosis of status epilepticus to one of four initial regimens [24]: lorazepam (0.1 mg/kg), phenytoin (18 mg/kg), diazepam (0.15 mg/mL) plus phenytoin (18 mg/kg), or phenobarbital (15 mg/kg). In the subgroup of 384 patients with overt generalized convulsive status epilepticus, treatment with lorazepam alone was most effective in terminating seizures within 20 minutes and maintaining a seizure-free state in the first 60 minutes after treatment (65 percent versus 58 percent with phenobarbital, 56 percent with diazepam plus phenytoin, and 44 percent with phenytoin alone). No significant differences in the success rates of the different regimens were observed in the 134 patients with subtle generalized convulsive status epilepticus, and overall there were no significant differences in seizure recurrence during the 12 hour study period, outcome at 30 days, or in the incidence of adverse events.
Midazolam — 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 [23]. Effective initial intravenous doses of midazolam are a 0.2 mg/kg bolus, followed by continuous infusion at rates of 0.75 to 10 µg/kg per minute.
A continuous midazolam infusion is probably 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. Nasally administered midazolam may be useful in the rapid termination of seizures when IV access is difficult [25], but additional studies are needed before this can be recommended.
Clonazepam — 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.
Phenytoin — Phenytoin is one of the most commonly used treatments for status epilepticus, despite the trial described above which showed that initial treatment of generalized convulsive status epilepticus with lorazepam alone was more effective than treatment with diazepam and phenytoin [24]. The principal advantage of phenytoin derives from its efficacy in preventing the recurrence of status epilepticus for extended periods of time.
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. 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.
Fosphenytoin — 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/min with phenytoin). 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.
Since propylene glycol is not required to solubilize fosphenytoin, the cardiovascular side effects of fosphenytoin may be less frequent and severe than those of phenytoin. However, at least two studies have suggested that the incidence of adverse hemodynamic effects with fosphenytoin and phenytoin infusions is similar [26,27].
Since 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. 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 PE's; as an example, 20 mg/kg PE load at a rate of 100 to 150 mg PE/minute. Cardiac monitoring is required during the infusion of fosphenytoin or phenytoin.
Barbiturates — 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 [28]. 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.
Phenobarbital — 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 [24,29].
Despite its efficacy, phenobarbital is generally not used as a first-line
treatment in adults because it carries a higher risk of hypoventilation and
hypotension than benzodiazepines or phenytoin.
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.
Pentobarbital — 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 [30]. 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, and pulmonary artery catheterization may
be required to optimize volume status and facilitate vasopressor management.
(See "Physiology and principles of the use of vasopressors and inotropes"
and see "Swan-Ganz catheterization: Indications and complications").
Thiopental — Some centers use thiopental instead of pentobarbital
for refractory status epilepticus, but there are a number of problems with
this approach [21]. 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. Thiopental may
also have immunosuppressive effects on neutrophil function and mucociliary
clearance [31,32].
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 [33]. 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.
Propofol — 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.
Experience with propofol in the treatment of status epilepticus is limited, but promising results have been reported in several small trials [12,34,35]. As an example, one study compared the results of treatment with propofol or high dose barbiturates in 16 patients with refractory status epilepticus [36]. 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).
Valproic acid — The use of intravenous (IV) valproic acid (Depacon) in the treatment of status epilepticus has been limited in part because the US Food and Drug Administration (FDA) approved it only for slow infusion rates (up to 20 mg/min). However, accumulating evidence suggests that more rapid infusion rates and higher intravenous loading doses of valproate are safe and well tolerated. (See "Pharmacology of antiepileptic drugs", section on Valproate).
The limited available data suggest that valproate may be useful in treating acute status epilepticus [37-39], but questions remain about the relative effectiveness of IV valproate compared with other AEDs that are first-line agents for treating status. In addition, the risk of hyperammonemic encephalopathy due to valproate, may pose diagnostic challenges in the postictal setting [40]. (See "Management of valproic acid intoxication"). Further clinical trial data are needed to define the role of IV valproate in this setting.
Further pharmacologic therapy at this point is based primarily upon the patient's hemodynamic stability and the risk for prolonged mechanical ventilation.
Hemodynamically stable patients — Treatment with high-dose barbiturates (pentobarbital or phenobarbital) remains commonplace in this setting because of the greatest experience with its use [30]. However, propofol is gaining some acceptance in this setting for patients who are already intubated. 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. (See "Physiology and principles of the use of vasopressors and inotropes").
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 seizures stop (and the EEG shows burst-suppression). Almost all patients at this point will require vasopressor support (typically phenylephrine or dopamine) as well as crystalloid infusions. 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. 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.
Hemodynamically unstable patients — Treatment with barbiturates or propofol may significantly worsen the hemodynamics of unstable patients. Therefore, one option is to proceed with a midazolam infusion because it is the best tolerated treatment in this setting [3,23]. Generally, therapy is initiated with a 0.2 mg/kg bolus, followed by a continuous infusion of 0.05 to 0.5 mg/kg per hour. If this is unsuccessful within 45 to 60 minutes, a propofol or pentobarbital infusion should be started.
Patients at high risk for respiratory failure — 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 [36]. Pressors should be ready at the bedside, and blood pressure and EEG 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. Infusion rates up to 10 to 12 mg/kg/hour may be required.
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. 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. 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.
Out-of-hospital treatment — 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 [43]. 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).
2009