Status epilepticus is seizure activity so frequent or prolonged as to be a lasting condition and a medical emergency.  Continuous generalized tonic/clonic seizure activity of at least 30 minutes duration or intermittent seizure activity (2 or more seizures) where the patient fails to regain consciousness between seizures is generalized convulsive status epilepticus (GCSE);  and when exact time of seizure onset is unknown, status epilepticus must be suspected with any tonic/clonic seizure activity in an emergency setting.  It makes little sense to wait around for half an hour to make sure a patient qualifies, so treatment is recommended no later than 10 minutes after confirmed onset of even suspect seizures. 

 Classification
     The rule of 30-minute duration or intermittent seizures without regaining consciousness applies not only to GCSE, but also to focal, complex partial, absence, and other convulsive seizures.  SE can include nonconvulsive seizures, but convulsive seizures cause more systemic effects and are far more lethal.Partial seizures originating in one cerebral hemisphere can progress to generalized seizures with activity from both hemispheres.  Onset is usually characterized by muscular rigidity (tonus) that progresses to convulsions (clonus) of upper and lower extremities that can be either symmetrical or asymmetrical. 
     Convulsions can subside without a return to consciousness, and this “subtle” seizure activity can be monitored by electroencephalograph.As the duration of acute seizures escalates, they become more dangerous.  While many experts advocate designation of SE after 10 minutes of seizure activity, many others insist that aggressive measures to terminate seizure activity be initiated within the first five minutes of onset. 
     Greater rates of survival and full recovery are generally associated with earlier recognition and intervention.  Overall mortality rate is as high as 32% for SE that continues for an hour, but only 2.7% for shorter durations.Clinically, it is often wise to treat the occurrence of at least 3 discrete convulsive episodes within 1 hour as SE.
    Incidence is highest among the young and old, and the elderly suffer the highest mortality at 38% of patients over the age of 70, since they are more vulnerable to ischemic insults involving the central nervous system.  While associated injuries like dislocations, lacerations of the tongue, and trauma of the face and head are significant concerns with convulsive disorders, immediate survival and neurological damage are generally of greater urgency.  Outcome and prognosis are functions of cause as well as comorbid conditions and overall health of the patient.

 Why It’s Deadly
     Elevated sympathetic outflow and convulsive muscular activity increase metabolic demands dramatically, raising heart rate, blood pressure, cardiac output, cortisol production, plasma glucose levels, and cerebral blood flow.  Initial elevation in blood pressure tends to decline as SE continues, but remains high enough to make the blood/brain barrier more permeable and vulnerable to metabolic byproducts (elevated serum lactic acid, decreased arterial pH, and increased serum glucose, for instance) and increase the risk of stroke.  Increases in the production of bronchial secretions, autonomic responses (along with profuse sweating), can compromise respiratory function, increasing the risks of hypoxia, hypercapnea, and neural damage.
     Death occurs in some 20% of up to 200,000 affected patients per year, so prompt and appropriate therapy is essential, beginning with ensuring airway patency and circulation.  Airway obstruction leading to hypoxia and aspiration pneumonia is not uncommon, with vomitus and secretions, clenched jaw, and uncoordinated breathing, typical contributing factors.  Bradycardia, hypotension, and poor perfusion generally indicate severe hypoxia.  Oxygen should generally be administered and the patient intubated if necessary, and an IV should generally be started with saline to ensure compatibility with available anticonvulsant agents.
     Since determination of cause is critical, drug screen, serum chemistry, and CBC should generally be obtained as quickly as possible, along with arterial blood gas in cases where respiration may be impaired.  Withdrawal from either alcohol or drugs (including anticonvulsant medications), and low levels of Ca++, Mg++, Na+, or glucose can all be precipitating or contributory factors. 
     Correction of any possible abnormalities to eliminate causes is a priority, so IV access is usually essential.  Inability to quickly establish IV access can be a rate-limiting factor in seizure control and profoundly affect outcome.

 Some Common Causes of Status Epilepticus

·        About 30% of all cases are the initial seizure in the onset of seizure disorder.

·        Another 30% are acute exacerbations of existing seizure disorder, often due to poor adherence to medication regimens.

The remaining cases fall into a wide variety other causes that include:

·        Stroke, especially in the elderly

·        Trauma

·        Hypoxia

·        Intoxications, including theophylline, isoniazid, and cocaine

·        Systemic infections or those involving the central nervous system

·        Electrolyte imbalances

·        Subarachnoid hemorrhage

·        Space-occupying lesionsComplicated febrile seizuresDegenerative diseases

Sample Treatment Protocol (Adults) – While protocols differ among institutions, most are very similar, with little scientific support for significant differences.
* Establish and maintain patent airway, and ensure adequate oxygenation.
* Establish IV access, monitor vital signs, and begin electroencephalographic monitoring. 
* Ascertain baseline blood values:  CBC, Na, Ca, Mg, serum glucose, BUN, LFTs, toxicology screen, blood alcohol, anticonvulsant levels, and blood gasses.
* Bedside blood glucose level will determine whether IV dextrose is indicated or not, as rapid correction of any abnormalities is essential.  Metabolic acidosis and blood gasses quickly revert to normal upon cessation of seizure activity, so bicarbonate is generally unnecessary unless control is unsuccessful or severely delayed.
* Administer thiamine 100mg IV to prevent Wernicke-Korsakoff encephalopathy. 
* A number of protocols prefer to treat initially as alcohol withdrawal with IV glucose 25-50gm, thiamine 100mg, magnesium 2gm, and multivitamins.
* Aggressive treatment of hyperthermia may be necessary to minimize neural damage.
* Rapidly terminate seizure activity, usually with a rapid-onset benzodiazepine followed by a longer-acting agent.
* While rhabdomyolysis is relatively uncommon, its consequences are severe.  Muscular stress and dumping of intracellular contents into extracellular spaces causes dark urine that indicates myoglobinuria.  Elevations in phosphate, calcium, and potassium and BUN:creatnine ratio over 10 are both diagnostic and problematic.  Elevations can be seen in alkaline phosphatase, lactate dehydrogenase, creatine phosphate kinase, and aldolase as necrosis of muscle tissues.
* Evaluation and follow-up -- long-term management (epilepsy, substance abuse, diabetes) or short-term management (infection, electrolyte imbalances) of underlying causes, when appropriate.

     In most cases, acute cessation of seizure activity by administration of a benzodiazepine should be attempted within the first five minutes of presentation, as better prognosis is associated with earlier control.  Isoniazid overdose is a noted exception, requiring pyridoxine as a first-line agent – 5gm IV every 10 to 20 minutes until seizures are controlled.  Benzodiazepines are normally viable first-line options for seizures associated with cocaine or alcohol, and phenytoin is generally of minimal utility in such cases. 
     Unless dealing with a febrile seizure relieved with the first dose of benzodiazepine, this should generally be followed by a longer-acting agent in a loading dose.  Fosphenytoin is the current first choice for a longer-acting agent.  Rapidly converted to phenytoin upon injection, it precludes the liabilities of injectable phenytoin, which is solublized in propylene glycol;  but it usually require 10 to 30 minutes to achieve anti-seizure activity.  Administration of opiates like phenobarbital, especially in conjunction with other agents with the tendency to cause respiratory depression, increases the likelihood of respiratory depression dramatically. 
     Since repeated doses or continuous infusion of benzodiazepine may be necessary to control acute seizure activity, this is an important consideration.  Benzodiazepines, especially shorter-acting agents, are frequently started with an IV bolus followed by continuous infusion;  and while longer-acting benzodiazepines (clonazepam, lorazepam) prolong seizure control, they also can complicate therapy by prolonging respiratory depression in the face of treatment failure and the necessity of adding barbiturates.
     While lorazepam remains the official benzodiazepine of choice in the hospital setting, largely due to its lower tendency to cause respiratory depression than diazepam, rectal diazepam may be preferable in an EMS situation, since it doesn’t require refrigeration.  Ease of administration compared to the IV route makes it more convenient in settings where IV administration is more difficult, but only midazolam can be administered IM. 
     Midazolam is increasing in popularity due to its rapid onset, short duration of action, and efficacy in this application.  Recent studies have shown it at least as effective as rectal diazepam with either rectal or buccal administration.  Since outcome typically improves with earlier benzodiazepine treatment before arrival in the emergency room, one study involving patients in a residential school evaluated rectal diazepam against buccal midazolam.  Buccal midazolam administered within about 2 minutes of seizure discovery relieved 75% of the seizures on which it was tried, compared with 59% relieved by rectal diazepam in the same time interval, and response time was about equal.  Since buccal administration is far easier and socially acceptable, this is a distinct advantage.  Intranasal administration has also been studied, but buccal administration seems more effective.
     Seizure control is often compromised by lack of or difficulty in achieving IV access, especially in the neonatal or pediatric patient;  and while buccal and rectal administration have their advantages in such cases and in pre-hospital settings, midazolam’s efficacy when injected intramuscularly sets it apart from other therapeutic options.  Less local irritation is seen with it, both IV and IM, than with agents requiring organic solvents.
     Since efficacy of benzodiazepines in this application depends upon short onset of action, the concept of receptor affinity must also be examined.  Midazolam, clonazepam, and lorazepam show greater affinity for benzodiazepine receptors in the central nervous system than diazepam so they generally produce more rapid results.  The longer duration of action of lorazepam, while an advantage with respect to continued seizure control, is countered by quick recovery to facilitate neurological evaluation with shorter-acting agents.  One study showed midazolam to be the most rapidly-effective among benzodiazepines, and another shows more-rapid recovery after seizure control.

Comparison of Benzodiazepines Commonly Used for SE

     While unusual when used alone, all of these benzodiazepines share the liability of hypotension and respiratory depression, especially in elderly patients; so careful monitoring of the patient’s blood pressure and respiratory function is essential.  Administration of flumazenil to counter these problems is associated with recurrent seizure activity and may perpetuate SE and reduce the efficacy of treatment attempts.

Diazepam

·        Its greater lipophilicity is both an asset and a liability, as it quickly enters the central nervous system to terminate seizure activity, generally within about 3 minutes.  It has a short duration of action at about 30 minutes, though, since it is readily distributed away from the CNS to other tissue compartments.  Thus, initial bolus must be followed by continuous infusion or repeated bolus dosing (possibly leading to accumulation), or more preferably by a longer-acting agent like phenytoin.

·        Though relatively stable in glass containers of NS, D5W, or LR at concentrations below 0.1mg/ml for immediate continuous infusion, sorption is a problem for both PVC and plastic tubing.

·        It does not require refrigeration in any dosage form, facilitating easy storage for quick use, which makes it particularly valuable in pre-hospital settings as a rectal gel dosage form, reducing utilization of emergency facilities.

·        Unconsciousness is usually not a problem.

 

Lorazepam

·        While taking up to 10 minutes to terminate seizure activity, its anti-seizure effects can endure for 12 to 72 hours, eliminating the need for continuous IV or repeat dosing and reducing the risk of accumulation seen with diazepam.

·        It requires refrigeration and IV administration – other means of administration are of little use in SE.

·        Drug-induced unconsciousness is usually not a problem.

 

Midazolam

·        Termination of seizure activity is usually seen within 5 minutes. 

·        Though short duration of action requires continuous infusion or addition of longer –acting agents, accumulation is less likely;  recovery from sedation is relatively quick;  and IV and compounding for continuous infusion obviates the precautions necessary with diazepam.

·        It is water-soluble, eliminating the need for propylene glycol as a solvent (with its own toxicity and rate-limiting IV administration), and enabling effective IM injection with less pain at the injection site than diazepam.  It is generally less irritating than other benzodiazepines upon IV administration for this reason.

·        It can be administered buccally or even nasally in the pre-hospital setting.

·        Distribution to the CNS decreases as pH decreases (metabolic acidosis seen with prolonged SE).

·        Its tendency to cause hemodynamic side effects is somewhat lower than the other two agents

 

Some Important Drug Interactions Involving Midazolam

Most of the drug interactions involving midazolam are pharmacokinetic in nature and involve changes in its normal rate of elimination.  Since it, like the other benzodiazepines alprazolam, diazepam, and triazolam, is metabolized by the cytochrome P450 enzyme system, other agents that either induce or inhibit CYP3A4 enzymes will logically affect midazolam’s rate of elimination.  As a substrate of this subsystem, its elimination can also be affected by other substrates that compete for these same enzymes.

Since use of midazolam is generally limited to acute administration over short periods, as in sedative/anesthetic applications or for status epilepticus, such interactions are limited in scope, so only a few are considered clinically significant.  Nevertheless, since patients subject to midazolam use may already be severely compromised by illness and/or trauma, and perhaps already on complicated medication regimens, interaction potential can be very significant.  Consideration of continued infusion, as in longer-term maintenance of seizure activity, must take any interaction potential into account.  In any case, induction of general anesthesia or conscious sedation, even with an agent with such a generally favorable safety profile, is a serious undertaking.  Every effort should be made to screen the patient for potential interaction problems in order to minimize the risks of complications.

Most of the clinically significant interactions relate to midazolam’s sedative properties and it’s tendency to cause respiratory depression.  While the risk of respiratory depression is generally very low when midazolam is used alone, that risk escalates markedly when midazolam is used with other depressants.  The obvious interactions in this category involve potentiation of these properties by other agents known to cause sedation and respiratory depression, which includes many drugs of abuse as well as other agents used for sedation, anesthesia, or seizure control, all of significance in the emergency setting as well as both out-patient and in-patient anesthesia.  Not only do these various agents complicate an intoxication problem, but they can obviously reduce the amount of midazolam required to achieve its desired effects.  A variety of other agents are used in conjunction with midazolam to facilitate sedation, anesthesia, and amnesia, all with varying effects that enable usage of lower doses of all utilized.  Respiratory support is an essential consideration in these circumstances, and these interactions affect other benzodiazepines as well.

Most of the significant interactions involving the CYP3A4 subsystem, though, involve concomitant therapy with other medications, and they can affect clearance of midazolam, triazolam, alprazolam, and diazepam similarly to prolong sedation and increase the risk of respiratory depression.  Here again, clinical significance varies with the patient’s medical condition(s) and their severities.  The most noteworthy offenders in this category are strong inhibitors of the CYP3A4 enzymes, most specifically cimetidine, erythromycin, ketaconazole, itraconazole, diltiazem, and verapamil.  The decision to utilize any of these four benzodiazepines in patients on any of those CYP3A4 inhibitors should be made cautiously, with the knowledge that dosage should be adjusted to minimize anticipated prolonged sedation and increased risk of respiratory depression and hypotension.  This caution extends to other CYP3A4 inhibitors.

Table of CYP3A4 Inhibitors of Clinical Significance

Macrolide antibiotics:  erythromycin, clarithromycin, and troleandomycin

Azole antifungals:  itraconazole, ketoconazole, and miconazole

HIV protease inhibitors:  indinavir, nelfinavir, ritonavir, and saquinavir

SSRIs:  fluoxetine, nefazodone, and fluvoxamine

Calcium-channel blockers:  mibefradil, verapamil, diltiazem

Amiodarone

Grapefruit juice

Cimetidine

Oral contraceptives

In contrast, inducers of the CYP3A4 enzymes can increase clearance and decrease elimination half-life and effects of midazolam, diazepam, alprazolam, and triazolam.  The most notable include rifampin, rifabutin, carbamazepine, phenytoin, phenobarbital, and troglitazone, and even St. John’s wart also bear this potential.

Theophyllines antagonize the actions of midazolam by competing for common binding sites, and several other agents impede hepatic metabolism of midazolam by mechanisms other than CYP3A4 systems, like valproic acid, probenecid, and omeprazole.ANTIEPILEPTIC AGENTS