Not all patients who have seizures require anticonvulsant therapy. Making the decision to administer anticonvulsants to a hospitalized patient who experiences one or a few seizures mandates consideration of a provisional cause, estimation of the likelihood of recurrence, and recognition of the utility and limitations of anticonvulsants. For example, seizures due to ethanol or other hypnosedative withdrawal do not need chronic treatment, but short-term therapy with benzodiazepines for repeated or prolonged seizures may be warranted (Table 85-2). Seizures caused by metabolic disturbances such as hyponatremia are often refractory to conventional anticonvulsant medications such as phenytoin, and are best treated with correction of the underlying disorder (benzodiazepines may be useful for seizure suppression if needed while the metabolic problem is being corrected). Seizures related to nonketotic hyperglycemia respond best to correction of hyperglycemia with insulin and rehydration.57
Drugs for the Treatment of Acute Convulsive Status Epilepticus
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Drugs for the Treatment of Acute Convulsive Status Epilepticus
|Drug ||Dose ||Rate ||Advantages ||Disadvantages |
|Diazepam ||0.15 mg/kg ||IV push ||Quick onset of action ||Respiratory depression |
|Fosphenytoin ||20 mg/kg ||<150 mg/min ||Easy transition to chronic administration ||Delay to onset of action; prolonged loading time; hypotension |
|Lorazepam ||0.1 mg/kg ||IV push diluted 1 : 1 ||Quick onset of action; may prevent early recurrence ||Respiratory depression |
|Midazolam ||0.2 mg/kg ||IV/IM push ||Can be given IM; quick onset of action ||Respiratory depression |
|Phenobarbital ||10-20 mg/kg ||50-100 mg/min ||Readily available ||Prolonged loading time; hypotension |
|Phenytoin ||20 mg/kg ||<50 mg/min ||Readily available ||Prolonged loading time; cardiac arrhythmias; necrosis if extravasation occurs; hypotension; incompatible with dextrose-containing solutions |
|Valproate ||25 mg/kg ||12-200 mg/min diluted 2 : 1 ||Appears safe in children ||Not well studied in status epilepticus |
A patient with CNS disease who has even one seizure should receive anticonvulsant therapy because the risk of seizure recurrence is very high. However, this treatment should be reviewed before discharge. Initiating this treatment after the first unprovoked seizure may help delay the appearance of subsequent seizures,66 but probably does not influence whether epilepsy subsequently develops.67 Prophylactic therapy in patients at high risk for seizure, especially if the condition was seriously complicated by a convulsion, is not unreasonable. Patients with traumatic brain injury, intracerebral hemorrhages, and subarachnoid hemorrhages are frequently placed on anticonvulsants immediately upon admission, although no prospective randomized trials have proven a positive effect on outcome.
In the ICU setting, phenytoin is often the first drug selected due to ease of administration and rapid assessment of blood levels. While the efficacy of phenytoin in the control of seizures is well established, several inherent properties of the drug limit its tolerability. In order to improve aqueous solubility, phenytoin is suspended in a highly alkaline solution that is comprised of 40% propylene glycol.68 The propylene glycol vehicle has been linked to hypotension and cardiac arrhythmias during phenytoin infusion; however, phenytoin itself may be partly responsible for hemodynamic instability. The caustic pH of the parenteral formulation can cause injection site reactions that can range from burning at the IV site to necrosis in the event of extravasation.
The phenytoin prodrug fosphenytoin is water soluble; therefore the parenteral formulation is more neutral than that of phenytoin and contains no organic solvents. Cardiovascular side effects were initially thought to be less common with fosphenytoin, but subsequent experience suggests that hypotension and arrhythmias may follow its infusion. Pain at the infusion site is significantly less common with fosphenytoin than with phenytoin.69 In patients without IV access, fosphenytoin can be safely administered intramuscularly. IM doses of fosphenytoin are well tolerated, require no cardiac monitoring, and are completely absorbed. Fosphenytoin is rapidly converted to phenytoin in vivo and free phenytoin levels after fosphenytoin administration are not markedly different compared to phenytoin, although the time to reach the peak level after IM administration is several hours.
A 20-mg/kg loading dose of phenytoin brings most patients to the desired concentration of 20 µg/mL (corresponding to an unbound or free concentration of 2 µg/mL). Fosphenytoin is dosed by phenytoin-equivalent units (PE); therefore no dosage adjustments are needed when converting patients from phenytoin to fosphenytoin. Fosphenytoin can be administered via intravenous infusion at rates of up to 150 mg PE/min, compared with a maximum rate of 50 mg/min for phenytoin. Both of these drug infusions should be started at a lower rate and increased as tolerated. When loading doses of fosphenytoin are given IM, two divided doses of 10 mg/kg each are recommended. After fosphenytoin administration, phenytoin concentrations should not be measured until the biologic conversion to phenytoin is complete and the drug has equilibrated throughout the body, about 2 hours after an intravenous infusion or 4 hours after an intramuscular injection of fosphenytoin. Phenytoin is approximately 90% protein bound in normal hosts, but the unbound fraction is the active component. Patients with renal or hepatic dysfunction or those taking drugs that compete for protein binding may benefit from measuring the free (unbound) serum phenytoin concentration before increasing phenytoin doses due to apparently subtherapeutic total phenytoin concentrations.
The maintenance dose for phenytoin is typically in the range of 5 to 7 mg/kg per day, but is highly variable because of individual differences in metabolism and interactions with other drugs metabolized via the cytochrome P450 system. Maintenance doses can be given either enterally or parenterally. Maintenance doses of IV or enteral liquid suspension phenytoin must be given in twice-daily divided doses since their half-life is less than 24 hours. Extended-release capsules can be given once a day. However, patients often do not tolerate more than 300 or 400 mg of phenytoin enterally in any one dose secondary to nausea. Therefore, patients requiring more than this amount in capsules should usually receive divided doses.
Hypersensitivity is the major adverse effect of concern to the intensivist. This may manifest itself solely as fever, but commonly includes rash, eosinophilia, and elevated liver enzymes. Adverse reactions to phenytoin and other anticonvulsants have been reviewed elsewhere.70 Over the recent years, levetiracetam has become increasingly popular as antiepileptic drug in the inpatient setting. Levetiracetam was originally approved in 1999 as add-on therapy for the treatment of partial-onset seizures in adults; by now, labeled use additionally includes myoclonic, and/or primary generalized tonic-clonic seizures. While the precise mechanism of action is unknown, inhibition of high-voltage-activated Ca2+ channels and enhanced activity of potassium channels that maintain the resting membrane potential seem to be involved.71 Levetiracetam can be administered as infusion or as oral solution or tablet. Its half-life is 6 to 8 hours. The bioavailability of levetiracetam is not dependent on food, it does not affect the protein binding of other drugs, and its distribution volume is close to that of total body water.72 It is primarily metabolized by enzymatic hydrolysis, and renally excreted. Dose adjustment is needed in decreased renal function, and approximately half of the drug is removed during hemodialysis, so that extra dosing is required after dialysis.73,74 Furthermore, lack of hepatic metabolism or interactions with other medications and few cardiac or peripheral venous effects are advantageous to levetiracetam, especially when compared with phenytoin.75 Its low incidence of serious adverse reactions (as low as 1% for acute drug reactions76) and the lack of drug-drug interactions make levetiracetam a safe medication in the elderly or multimorbid patient population.77 Patients treated with levetiracetam monotherapy in a neurological intensive care setting had lower complication rates78 when compared to other antiepileptic drugs. When used for prophylaxis after neurological injury, patients treated with levetiracetam had better outcomes at 3 months compared to patients treated with phenytoin.79 Levetiracetam is found at least as effective as phenytoin in the prevention of seizures after neurological injury or neurosurgery76,79,80 In the adult patient, effective doses of levetiracetam range from 500 to 3000 mg/d.
Phenobarbital remains a useful anticonvulsant for those intolerant to phenytoin or those who have persistent seizures after adequate phenytoin administration. The loading IV dose is 15 to 20 mg/kg, and the target serum concentration is 20 to 40 µg/mL. The serum concentration may be altered by hepatic and renal dysfunction. Furthermore, phenobarbital can also induce P450-related metabolism, thereby affecting the metabolism of other drugs that undergo hepatic clearance. Since the usual clearance half-life of phenobarbital is about 96 hours, maintenance doses of this agent should be given once a day. A steady-state level takes about 3 weeks to become established. Sedation is the major adverse effect; allergy to the drug occurs rarely.
Carbamazepine is rarely initiated in the ICU because it is not available in parenteral form and absorption from the gastrointestinal tract is relatively slow. Carbamazepine has significant interactions with many drugs that are used in hospitalized patients, such as corticosteroids, theophylline, warfarin, and cimetidine. Adjusting blood levels of carbamazepine in the setting of polypharmacy can be unpredictable. Carbamazepine and the newer anticonvulsant oxcarbazepine can both cause hyponatremia with chronic use, probably due to a combination of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and salt-wasting nephropathy.
Status epilepticus is a medical emergency. While proper diagnosis of the cause is critical, the most important initial goal is to expeditiously stop the clinical and electrographic seizures. The likelihood of successfully treating SE is inversely related to the duration of seizures; the longer seizures last, the more difficult they are to terminate. Administration of antiepileptic drugs within 5 to 10 minutes has been shown essential to limit the emergence of status epilepticus and related neuronal damage and permanent cerebral injury,81 as well as further systemic complications. Aggressive and rapid management is warranted, particularly when considering that only two-thirds of patients in SE respond to the first treatment.82
The preferred agents used for first-line treatment of SE are benzodiazepines (especially lorazepam, diazepam, and midazolam), phenytoin, phenobarbital, levetiracetam, and valproate sodium. The Veterans Affairs Status Epilepticus Cooperative Study Group trial compared four regimens for the initial treatment of GCSE and demonstrated that lorazepam was more efficacious than phenytoin, and easier to use than phenobarbital or phenytoin plus diazepam.82 Lorazepam has been our agent of first choice for terminating SE for many years and remains so with support from this study.
The major advantage of lorazepam over diazepam is its longer duration of action, thereby limiting seizure recurrence. Lorazepam has traditionally been given in 2-mg doses repeated at 5-minute intervals if seizures do not terminate. Since this is often an inadequate dose and valuable time passes before definitive treatment is instituted, we recommend instead a single IV dose of 0.1 mg/kg of lorazepam. If lorazepam is not available, a single IV dose of 0.15 mg/kg of diazepam is an alternative. However, another agent such as phenytoin or phenobarbital should be started immediately, as the duration of action of diazepam against SE is only about 20 minutes. In the event that IV access is unattainable, 0.2 mg/kg of midazolam administered IM will be rapidly and reliably absorbed. The use of midazolam in refractory SE will be discussed below. All benzodiazepines carry a risk of hypotension and respiratory depression. However, these are also sequelae of prolonged or inadequately treated SE. The intensivist should be prepared to intubate or use vasopressors if necessary.
RAMPART, a recently published double-blind, randomized trial comparing intramuscular midazolam with intravenous lorazepam in the prehospital treatment of SE, found that intramuscular midazolam was at least equally safe as intravenous lorazepam, particularly regarding the need for endotracheal intubation. Seizure termination was at least as effective with intramuscular midazolam, the time-to-treatment being significantly shorter for the intramuscular treatment likely playing a significant role.83 Phenytoin is an effective anti-SE agent; however, the constraint on the rate of intravenous administration is of concern when treating SE. Fosphenytoin may be a better drug for use in SE since it can be loaded up to three times faster, although its 7-minute conversion half-life means that the serum phenytoin level does not reach its target much faster. Phenytoin has a long duration of action when an adequate dose is given (a 20-mg/kg dose produces a serum level above 20 mg/mL for 24 hours). Adding an additional 5 mg/kg if the initial load fails to stop SE may be useful. Intramuscular injection of fosphenytoin in SE patients may be supported by the known pharmacokinetics of this route, but it should not be considered to be acceptable therapy for SE and should be reserved for only those rare circumstances in which IV access cannot be obtained.
Levetiracetam is increasingly used as anti-SE agent, either as primary agent or as adjunct medication, due to its ease of use, the ease of rapid intravenous infusion (15 minutes) and the tolerability in critically ill patients due to very few serious adverse events and drug-drug interactions.84 Common dosing is a 500- to 2000-mg bolus followed by 2000 to 3000 mg daily maintenance dose. The efficacy to abort SE has been found to be higher when loading with a bolus, and when initiated earlier during the course of SE.85 Several smaller series found intravenous levetiracetam highly effective in patients with SE refractory to benzodiazepines or other initial therapy.73,75
Phenobarbital in the management of acute SE is not routinely recommended, except when phenytoin is contraindicated. However, the Veterans Affairs study showed no difference in efficacy between lorazepam and phenobarbital as first-line agents in SE, but phenobarbital took longer to administer.82 Furthermore, in the patients that did not respond to lorazepam or phenytoin, the response rate to phenobarbital was only 2.1% (unpublished data). We therefore recommend pursuing a more definitive treatment strategy for patients who have entered refractory SE (RSE).
REFRACTORY STATUS EPILEPTICUS
Refractory status epilepticus evolves in 31% to 44% of patients in SE.86 Failure of a first-line anticonvulsant drug to terminate SE usually requires the use of a definitive therapy in anesthetic doses that are highly likely to cause significant respiratory suppression and hypotension. Therefore, mechanical ventilation is necessary, and invasive hemodynamic monitoring is frequently required. Concomitant continuous EEG monitoring is also mandatory to confirm treatment success and monitor depth of sedation. The traditional goal of therapy is burst-suppression pattern on EEG for 12 to 24 hours prior to any attempts to wean medication. Since the available data suggest that successful treatment and improved outcome probably required seizure suppression regardless of background EEG activity,87 we recommend cessation of electrographic seizures as the goal instead.
The agents used most frequently include propofol, midazolam, and barbiturates.88 Propofol is an intravenous anesthetic agent that acts primarily on the GABAA receptor. Smaller series and case reports documenting its efficacy in RSE are abundant,89 but studies examining direct comparisons with other agents have had mixed results.90-92 An initial bolus of 1 to 2 mg/kg should be followed with a maintenance infusion at 1 to 15 mg/kg per hour. Propofol is fast acting, highly lipid soluble, and has little propensity to accumulate even with prolonged infusions.93 Because of its rapid clearance, propofol should not be abruptly discontinued, but instead tapered gradually. Respiratory depression and hypotension are extremely common, especially after the initial bolus. Nutritional support must be adjusted in the setting of propofol infusion due to the high lipid and calorie content of the solution. Acidosis and rhabdomyolysis have been reported in both adults94 and children.95 Careful monitoring of creatine kinase and blood pH are prudent.
Midazolam is a water-soluble benzodiazepine that has demonstrated high efficacy in refractory SE in adults and children.96-98 Midazolam is loaded at 0.2 mg/kg followed by continuous infusion of 0.05 to 2.0 mg/kg per hour. Respiratory depression may be encountered less frequently than with other hypnosedatives, but should be anticipated. Since most patients with RSE are already intubated, concern for respiratory effects should not limit use. Clinically significant hypotension is rare even at the very high doses that are often required to address tachyphylaxis.99 Sedation is quickly reversed after short-term infusions are discontinued. However, terminal half-lives of three to eight times normal have been reported with extended administration.100 In addition, prolonged elimination times have been associated with critical illness and hepatorenal dysfunction. High-dose barbiturates, most commonly pentobarbital, are extremely useful in RSE when used as third-line therapeutic choice,101 but side effects can be severe and may limit use (Table 85-3). Hypotension can be refractory to initial resuscitative efforts, and the patient may benefit from pulmonary artery catheterization to plan fluid and vasopressor management. Pulmonary infection is common due to prolonged intubation and impaired function of both respiratory cilia and leukocytes. The intensivist must be vigilant in monitoring for infection since barbiturate-induced poikilothermia may mask fever. Despite these side effects, barbiturate anesthesia should not be rapidly discontinued if it is successful in terminating refractory SE. Continuing therapy for at least 48 hours, gradual tapering of the infusion dose, and the administration of phenobarbital during the drug taper are recommended.93 Pentobarbital is loaded at 5 to 12 mg/kg followed by an infusion of 1 to 10 mg/kg per hour. As an alternative, thiopental sodium may be given in 75- to 125-mg IV boluses followed by infusion rates of 1 to 5 mg/kg per hour. Both medications rapidly redistribute into adipose tissue; recovery of consciousness usually takes much longer after thiopental infusions than after pentobarbital. Elimination times can be greatly increased in obese patients after prolonged infusions.90-100
Drugs for the Treatment of Refractory Status Epilepticus
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Drugs for the Treatment of Refractory Status Epilepticus
|Drug ||IV Loading Dose ||Maintenance Dose ||Advantages ||Disadvantages |
|Ketamine ||4-5 mg/kg over 2-4 minutes ||1-5 mg/kg per hour ||Unlikely to cause hemodynamic instability ||Not well studied for status epilepticus |
|Midazolam ||0.2 mg/kg IV bolus ||0.05-2 mg/kg per hour ||Fast onset of action ||Tachyphylaxis |
|Pentobarbital ||5-12 mg/kg at 50 mg/min ||1-10 mg/kg per hour ||Readily available ||Hypotension; immune suppression |
|Propofol ||1-2 mg/kg IV bolus ||1-15 mg/kg per hour ||Easy to adjust ||High lipid and calorie content; “propofol infusion syndrome” (metabolic acidosis, and on occasion rhabdomyolysis, with doses greater than 5 mg/kg per hour) |
|Thiopental sodium ||75-125 mg IV bolus ||1-5 mg/kg per hour ||Fast onset of action ||Can have prolonged effects after extended infusions due to absorption into adipose tissue |
The efficacy of alternative regimens needs further evaluation to define their role in the treatment of seizure emergencies. While there are many case reports, no convincing evidence or randomized trials are available to support early initiation of these interventions.6
In brain tumor patients with RSE, the use of phenytoin, levetiracetam, and pregabalin to abort RSE has been found safe and highly effective.102
Lacosamide, a modulator of voltage-gated sodium channels,103 has also gained attention for the use in refractory SE. It has been reported effective as an adjunct in refractory NCSE, especially focal SE104; however, other series have not been able to confirm its efficacy in RSE.105 It is available intravenously, and is easy to administer.103 Common dosing is a loading dose of 200 to 300 mg IV, followed by 100 to 200 mg maintenance every 12 hours. Success in the termination of RSE has also been reported for isoflurane, intravenous valproate, ketamine, and topiramate. Ketamine in particular is often described, probably at least partly due to its lack of cardiosuppressive side effects, and its potential neuroprotective capacity given its structure as NMDA antagonist.106
Emerging insight into antibody-induced seizures and SE, mainly NMDA-receptor antibodies, has also triggered exploration of emergency treatment of SE with immunosuppressants in selected cases, with high dose methylprednisolone and/or intravenous immunoglobulin.106
The application of therapeutic hypothermia, the use of which in RSE has anecdotally been reported successful,107 lacks data on a larger scale. Once SE is addressed, one must manage the major systemic complications of SE. Patients with GCSE should be screened for rhabdomyolysis with urine myoglobin and serum creatin kinase (CK) determination. If myoglobinuria is present or if the CK concentration is more than 10 times the upper limit of normal, rehydration and urinary alkalinization should be instituted.81 Prolonged or severe hyperthermia should be aggressively treated with cooling blankets, ice packs, or other cooling modalities.
SPECIAL CONSIDERATIONS FOR CHILDREN
Treatment of seizures or SE in critically ill children generally parallels that for adults. Intravenous access is often more difficult to achieve in children. Lorazepam and diazepam can both be administered by the rectal route (usually 0.5 mg/kg per rectum for both agents) and midazolam (0.2 mg/kg) via the IM, nasal, or buccal routes. Lorazepam is probably the first-line drug of choice for terminating SE in children as for adults. One study of 86 children presenting with seizure found that those who received lorazepam had a higher incidence of termination of seizure activity and less frequent respiratory depression than those treated with diazepam.108
Midazolam administered by continuous infusion appears effective in RSE in children.97,109,110 Although all eight patients in one study were mechanically ventilated, none demonstrated cardiovascular instability despite midazolam doses resulting in burst suppression.108
As with adults, rapid control of SE in children achieved with benzodiazepines should be followed by administration of a longer-acting agent such as phenytoin (20 mg/kg IV), fosphenytoin (20 mg PE/kg IV), or phenobarbital (10-20 mg/kg IV).111 The rate of conversion of fosphenytoin to phenytoin is probably the same in children as in adults. Intramuscular injection of fosphenytoin may be particularly advantageous for prevention of recurrent seizures in children without IV access. The use of IV fosphenytoin over IV phenytoin is prudent in infants and neonates, whose small limbs are at especially high risk of extensive necrosis and amputation in the event of a phenytoin extravasation.
Similarly to the treatment of seizures and SE in adults, there is growing evidence to support the use of levetiracetam. In the neonatal period, intravenous levetiracetam has been found useful and safe as monotherapy or as an adjunct in acute seizure management.112 When administered within half an hour of seizure onset in children at a dose of 29.4 ± 13.5 mg/kg, 89% of patients were seizure free at 1 hour.113 When given with a bolus dose of 25 to 50 mg/kg followed by maintenance as adjunct or monotherapy for status epilepticus or exacerbation of seizure disorder, response rates were as well favorable.114
Intravenous valproate appears to be safe and effective in children.115 Several retrospective and prospective series have reported seizure termination after infusion of valproate in loading doses between 25 and 30 mg/kg, with response rates between 65% and 100% and without occurrence of serious adverse events.115-117
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