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Status Epilepticus      
 

Status Epilepticus                                                                                                                     REF:  UpToDate 2006  | DynaMed 2009  
  RX | Predisposing Factors |  Seizure Classification  |  Drugs    
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 to 43 % of patients with status epilepticus.

  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
Treatment of Status Epilepticus 2009          REF: DynaMed 2009

           

  • at  0-10 min:  
    Check ABC (Airway, Breathing, Circulation- Pulse,BP) , IV line, O2 supplement;
    If suspect hypoglycemia, Thiamine 100mg IV (esp in thiamine-deficient alcoholic patients), then IV Glucose 50ml D50W
    Consider give thiamine first, 100 mg intravenously, to avoid precipitating Wernicke disease in thiamine-deficient alcoholic patients.

    Stat lab tests: blood glucose, lytes, CBC, ABG, EKG, anticonvulsant level, toxicology, check oxymetry.
    Identify & correct precipitating cause
  • at 10-20 min:  
    Ativan/Lorazepam  IV ~ 2 to 4 mg bolus over 2 min (0.05-0.1 mg/kg ) to a max of 8 mg    , may repeat every 5 -10 minutes x 2
    - can be given in 1-2 mg boluses or as continuous infusion
    - if IV unavailable, consider IM route as an option.

    Other Options:
    Valium/Diazepam IV  ~ 5 to 10 mg every 10-15 min (at rate 2 mg/minute IV ), up to max of 30 mg total dose or until seizures stop.  
    - if IV unavailable, consider IM route as an option.   May repeat regimen again in 2 - 4 hours.
    Valium/Diazepam gel rectally 15-20 mg (0.2mg/kg) syringe in pt without IV access.  
    * It is short-acting 15-20 min.
    * If diazepam is used to terminate seizures, a long-acting Anti-Epilepsy Drugs such as fosphenytoin or phenytoin (on separate IV line) must be administered.  
       Even if seizures terminate after the initial lorazepam dose, therapy with phenytoin or fosphenytoin is generally indicated to prevent the recurrence of seizures.
    * Both of these drugs can cause depression of breathing and even apnea, so ventilation must be supported, and intubation may be necessary.        

    Midazolam (Versed) 0.1-0.2 mg/kg IV load slowly for status epilepticus may be substituted if lorazepam is not available.
    For sedation/anxiolysis/amnesia:  the dose is 1 - 2.5 mg (max 5 mg) IV over 2 min.
  • at 20-35 min:
    IV Dilantin/phenytoin 18 mg/kg IV infusion , rate < 5 mg/kg/minute (Max 50 mg/minute) -  Should Monitor ECG and BP!
    For 50 kg patient:  750-1000 mg IV loading;  For 60 kg patient:  900-1200 mg IV loading;  For 70 kg patient:  1050 mg-1400 mg IV loading.

    Other Options:
    Fosphenytoin/Cerebyx  IV: 15–20 mg PE/kg at rate of 100–150 mg PE/minute    , followed by maintenance doses of fosphenytoin sodium or parenteral or oral doses of phenytoin.
    Concomitant therapy with an IV benzodiazepine usually is necessary for initial control of status epilepticus.  (PE= phenytoin sodium equivalents)
  • at 35-45 min:
    Repeat IV Dilantin/phenytoin 5-10 mg/kg infusion
    Daily maintenance dose: 4-6 mg/kg   (Therapeutic level: 10-20 mg/L)
  • at 45-60 min:
    IV Phenobarbital IV 20-25 mg/kg    , consider intubation; may repeat IV phenobarbital to maximum 40 mg/kg  
  • after 60 min:  
    ICU, intubate, consider barbiturate coma, EEG monitoring  

* 205 adults with repetitive generalized convulsive seizures for > 5 minutes randomized to Ativan/Lorazepam 2 mg vs. Valilm/Diazepam 5 mg vs. placebo IV, second injection given if needed, 59% vs. 43% vs. 21% had termination of status epilepticus on arrival to emergency department (p = 0.001, NNT 3 for lorazepam)

* Ativan/Lorazepam preferred as more effective than phenytoin and easier to use than phenobarbital and diazepam/phenytoin

Treatment of refractory seizures  - ICU & Call Neurologist for assistance !
If a patient fails to regain consciousness or continues to have seizures after first-line therapy,
neurologic consultation is required. Such a patient requires urgent & continuous EEG recording, and anesthesia must be considered.  The patient must be intubated to provide adequate ventilatory support, and appropriate intensive care monitoring established. Patients are maintained in anesthetic coma for variable periods.

  • 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.

  • Pentobarbital (Nembutal)  
    Ty    pically with a loading dose of 5-10 mg/kg infused  slowly at a rate of up to 50 mg/minute. The ultimate infusion rate is determined by the amount of drug required to terminate status epilepticus  (burst suppression pattern is seen on EEG), 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.  Use only in consultation with Neurologist.

    Phenobarbital  
    20mg/kg at<100mg/min IV if status epilepticus persists, give until seizure stops or max. dose of 20mg/kg.  Usual initial loading 300-800mg.  Maintenance: 90-120mg/day PO or IV.  
    * When give phenobarb after Valium, sedation may result, and apnea is a risk, particularly if the patient has taken benzodiazepines as Valium or Ativan.   Blood pressure monitoring is critical; hypotension responds to slowing the rate of administration.

  • Propofol (Diprivan)  1 to 2 mg/kg with 2 to 10 mg/kg/hr,  or

  • Midazolam (Versed)  0.2 mg/kg administered by slow I.V. bolus injection followed by 0.75 to 10 µg/kg/min,
    replacing pentobarbital as the drugs of choice.

  • Metabolic derangements from initial laboratory studies should be appropriately treated.

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. Overall mortality was 48 percent, but there was no association between drug selection and the risk of death. Pentobarbital  (Nembutal) 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).

   
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
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

   
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
CLASSIFICATION
-  Generalized tonic-clonic or partial-complex status epilepticus poses the greatest risk.

The three most common forms of status epilepticus are:

  1. 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.

  2. 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 distuy also occur.

  3. 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.

   
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
PHARMACOLOGIC AGENTS —

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

  1. benzodiazepines

  2. phenytoin (or fosphenytoin)

  3. barbiturates

  4. propofol (Diprivan)

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.

 
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
Benzodiazepines
— Benzodiazepines remain the first-line treatment for status epilepticus because they can rapidly control seizures.

Lorazepam  (Ativan) IV 0.02 to 0.2 mg/kg the effective initial IV doses
— Onset of action: 2 minutes; the effective duration of action against seizures is as long as 4 to 6 hours.

Diazepam (Valium) IV 0.1 to 0.3 mg/kg intravenously
— Onset of action: as early as 10 to 20 seconds after administration;  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.

Midazolam  (Versed) IV 0.2 mg/kg bolus, followed by continuous infusion at rates of 0.75 to 10 µg/kg per minute the effective initial IV doses.
— Onset of action: frequently in less than one minute.
- 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.
- A continuous midazolam infusion is probably less effective than high dose barbiturates or propofol for the treatment of refractory status epilepticus.
- Nasally administered midazolam may be useful in the rapid termination of seizures when IV access is difficult, but additional studies are needed before this can be recommended.

Clonazepam (Klonopin) PO 0.125 to 0.5 mg 2 to 3 times  per day prn anxiety orpanic disorder.
— 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.

   
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
Phenytoin (Dilantin)  
— 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 . 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 (Cerebyx)
— 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.
Cardiac monitoring is required during the infusion of fosphenytoin or phenytoin.

   
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
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.

  1. 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. 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.

  2. Pentobarbital (Nembutal)
    — 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. 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.

  3. Thiopental
    — 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. 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. 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.

   
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
Propofol (Diprivan)
— 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. As an example, 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).

Valproic acid (Depacon)
— 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.

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

   
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  
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. 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.

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. 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. 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. 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).

   
  RX | Predisposing Factors |  Seizure Classification  |  Drugs  

       

REF:  UpToDate 2006 | ACP Medicine 2006 | DynaMed 2009  
REF:  Cochran Database Syst Rev 2005; (4): CD 003723  

        2009