• Electively admitted: Pharmacologic concerns
• Electively admitted: Treating seizures
• Emergently admitted: Pharmacologic concerns
• Emergently admitted: treating seizures
• References

• IV phenytoin should best be given via high-flow (preferably, central venous) access, owing to the risk of thrombophlebitis with peripheral IV administration.31,32
• Central access is not required for administration of fosphenytoin, which can be injected more rapidly intravenously or intramuscularly, has a lower reported incidence of thrombophlebitis and other adverse reactions, and is preferable to IV phenytoin in all circumstances.

If the time period off of medications is brief, another option is to place the patient on round-the-clock doses of benzodiazepines as bridge therapy, after which the patient’s regular AED can be resumed. This may only involve a few doses of lorazepam, chlorazepate, or clonazepam. A benzodiazepine with a relatively long antiepileptic half-life, such as lorazepam, may be best.

Once the patient has been moved into the recovery room or more central ICU area, the choice of AED remains a function of how long the patient’s typical AED regimen is interrupted and which routes of therapy are available for administration.

Will the patient be able to swallow after surgery? Will there be some other access to the gastrointestinal tract? Will enteral nutrition be given?

Using the patient’s normally functioning GI tract is almost always preferable to IV administration, but there are several potential pitfalls. Nasogastric tube (NGT) feedings, for example, raise stomach pH and can interfere with absorption of AEDs that require an acidic environment. For example, phenytoin levels can plummet after NGT feedings are initiated.33 One solution for this problem is to bolus-feed the patient when possible, limiting the patient to a number of boluses of nutrition per day, more closely mimicking normal eating. Holding continuous NGT feedings for several hours before and after administration of phenytoin elixir can help, but serum levels must be monitored carefully to assess the effect on absorption.

Administration of AEDs through feeding tubes can pose difficulties. The patient's usual oral medication often can be used, but levels may fluctuate widely if an appropriate preparation is not used correctly. Suspensions (e.g., phenytoin and carbamazepine) must be vigorously shaken before they are administered. AED levels may plummet if they are not. Preparations of AEDs that are designed to be chewed or mixed in with food, such as valproate (Depakote) sprinkles and the coated carbamazepine beads emptied out of Carbatrol capsules, can be given via enteric tubes.34 These preparations of valproic acid and carbamazepine are preferable to crushed enteric-coated oral preparations of these drugs. Whether they are preferable to the liquid form of these medications is not clear.

Table: Antiepileptic Drug Preparations Delivered Via Enteric Tubes lists preparations of standard AEDs that can be administered through gastric or intestinal tubes with reasonable expectations of absorption. In general, sustained-release and enteric-coated preparations should not be used for this purpose. Chewable preparations are acceptable for crushing and administering through enteric tubes, although they may result in more rapid serum peak levels than slower-to-dissolve preparations. Specific medication preparations need to be judged individually. Those marked “Do not crush, chew, or break” on the package insert can be assumed to result in erratic absorption when these directions are ignored. It is also vital to flush feeding tubes to be sure that the full dose of medication is delivered to the patient.

A common problem with assessing the efficacy of AED delivery strategies in the ICU is waiting for changes in the daily level, as it often results in prolonged periods of underdosing while assessing a variety of ineffective strategies.

Does the patient require medications that can alter the seizure threshold or the absorption, metabolism, or excretion of AEDs?

Several medications, most commonly antacids and histamine 2 blockers, can affect absorption of AEDs into the blood stream through the alimentary tract. Through lowering gastric pH, these medications can interfere with absorption of many AEDs, most notably phenytoin. In this case, AED dosing should be timed away from the administration of these agents, when possible. If this does not help to maintain levels, it may be necessary to change to an IV agent. Increasing the dose of medication may be useful in some cases, but the response should be assessed through peak serum levels after a dose of medication.

(Also see Procedures in epilepsy patients.)

Adapted from: Kolb SJ and Litt B. Management of epilepsy and comorbid disorders in the emergency room and intensive care unit. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;515–535.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The patient should be treated with the hospital’s status epilepticus protocol if a tonic-clonic seizure persists for more than 3 minutes. Table: Protocol for Treatment of SE Rapid treatment with low-dose benzodiazepines, such as 1 mg of lorazepam, may protect the patient for a brief period while the initial assessment takes place. IV diazepam, although effective for treating acute seizures, undergoes rapid redistribution in body fat after initial rapid penetration into the brain. It has an effective antiepileptic half-life of approximately 30 minutes, whereas lorazepam’s half-life lasts hours.35 If brief altered consciousness due to benzodiazepines may interfere with assessment, such as in neurosurgical patients, then the patient must be carefully evaluated before this medication is administered.

Alternatively, a long-term AED can be administered first. AED levels should be measured immediately, and a bolus of the patient’s standing medication should be given if there is strong suspicion of medication withdrawal as a cause of seizures. The downside, a transiently elevated AED level, usually has a low morbidity in the ICU setting.

Immediate bedside serum glucose testing is required in these patients. It is also vital to send serum for electrolytes (particularly sodium, magnesium, and calcium), CBC, glucose, coagulation studies, and any other laboratory tests that may be pertinent to the patient’s particular condition.

Low serum AED levels are often the cause of such seizures. Assess other possible causes of seizures, such as withdrawal from alcohol and nonprescription medications (perhaps not reported, e.g., chronic benzodiazepines), infection, and illicit drug use. Concomitant medications should be assessed for interactions with AEDs or the potential to lower the seizure threshold. Among common drugs that can lower seizure threshold are:

• Aminophylline or other xanthines
• Butyrophenones (e.g., haloperidol)
• Phenothiazines (e.g., Thorazine, Compazine)
• Tricyclics (less potent)
• Penicillin antibiotics
• Quinolone antibiotics
• Narcotic analgesic (Demerol): epileptogenic metabolite accumulates to higher levels in renal failure
• Cyclosporine (seizures often associated with parietooccipital white matter abnormalities)

Nonconvulsive status epilepticus

If the patient does not rapidly recover to baseline, consider nonconvulsive status epilepticus (NCSE). If seizures recur, treat for status epilepticus if the appropriate criteria are met. The initial approach to the patient with NCSE is similar to the treatment for convulsive status epilepticus.

Philosophically, the difference is in deciding when and how to proceed to aggressive treatment after initial trials of benzodiazepines and phenytoin (or, preferably, fosphenytoin). Whether prolonged complex partial status epilepticus causes brain injury is controversial.50-52 There is not convincing evidence that the benefits of further treating these individuals aggressively with barbiturate-induced coma always outweigh the risks. The decision must be made on a case-by-case basis. When approaching these patients, consider the patient’s overall condition and the circumstances responsible for its occurrence. For example, in the patient with severe anoxic-ischemic encephalopathy and continuous seizure activity, the use of aggressive therapy is unclear and, perhaps, less likely to definitively affect outcome in most cases. Alternatively, the patient with well-controlled complex partial epilepsy who presents with complex partial status epilepticus after an acute precipitant may well benefit from more aggressive therapy, similar to the protocol for convulsive status epilepticus. Between these two cases might be a frail elderly person with NCSE who is at high risk for potentially fatal complications if intubated and placed into barbiturate coma. In this case, one might try a more gradual approach, with gradually escalating oral or lower-dose IV therapy, even over days, if required, in the hope of stopping seizures and, at the same time, preventing iatrogenic complications.

Seizure prophylaxis with AEDs

The topic of AED prophylaxis in the ICU is controversial, often driven by tradition, not data. There are several primary scenarios in which AED prophylaxis is used often in this setting:

• after invasive procedures affecting the brain
• after injuries with penetrating head injury
• during the first week after closed head trauma
• when the potential morbidity associated with a single seizure is high

Most neurosurgeons routinely administer prophylactic AEDs during and after resective surgery for focal lesions (e.g., tumors, vascular anomalies, evacuation of hematomas) or other procedures associated with potential injury (e.g., prolonged retraction) of cortical structures. In these cases, AED therapy is usually tapered off weeks to a few months after the procedure.

Temkin et al. reported that AED prophylaxis after closed head trauma significantly reduces the incidence of seizures during the first week after head injury but not after that point.36

One situation in which the potential morbidity associated with a single seizure is high enough to require prophylactic AED therapy is subarachnoid hemorrhage due to aneurysm rupture (before surgical repair). An increase in arterial blood pressure during a seizure may induce rebleeding from the aneurysm.

Another example is any condition in which intracranial pressure is elevated with coincident risk of seizure. In this case, increased intracranial pressure due to a single seizure could cause brain stem herniation.

In these settings, prophylactic AED therapy is usually tapered within weeks to months after the acute period, unless side effects or adverse reactions dictate earlier termination. Even in cases in which a single acute seizure occurs during high-risk states, tapering of AED therapy usually proceeds in a similar fashion. Should seizures be repetitive, particularly even after the acute phase of the illness, medication taper is often delayed.

The timing of when to stop prophylactic AED treatment is arbitrary. Many epileptologists advocate using the EEG to help to predict the probability of relapse, which is increased when focal epileptiform activity is found.

Adapted from: Kolb SJ and Litt B. Management of epilepsy and comorbid disorders in the emergency room and intensive care unit. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;515–535.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The principles of care described for patients with epilepsy admitted electively to the intensive care unit (ICU) also apply to emergent ICU admissions. Efforts should be made to continue the patient’s outpatient antiepileptic drug (AED) regimen. Some of the newer agents may be administered via nasogastric tubes or other alimentary tubes (Table: Antiepileptic drug preparations that can be delivered via enteric tubes with reliable kinetics). The choices of IV substitutes for newer AEDs are limited, and it may be necessary to deliver periodic doses of benzodiazepines in the short-term interval while loading the patient with an acceptable IV medication preparation. Targets for serum levels should be in the therapeutic range (e.g., 10–20 mg/dL for phenytoin, 10–20 mg/dL for phenobarbital, and 50–100 mg/dL for valproic acid).

Acutely, it is usually more important to establish adequate levels of a therapeutic AED rapidly than to make an optimal choice for long-term therapy. Considerations about interactions with other medications are more important during chronic treatment than in the ICU. Nevertheless, several pharmacologic principles must be taken into account when treating individuals with epilepsy in the ICU:

• Lowering of seizure threshold. The point is not absolutely to avoid medications that can lower seizure threshold, but rather to be aware of this association during their use. Several drugs and drug classes commonly encountered in the ICU were listed in the discussion of treating seizures in electively admitted patients.



• Protein binding. Many AEDs (e.g., phenytoin, phenobarbital, valproic acid) are highly protein bound, and most agents have some protein binding. Free levels of these agents are increased in the setting of low albumin, which frequently occurs with malnutrition in the ICU. In addition, medications or conditions that compete with these medications for binding to albumin increase free levels. The most common of these conditions is uremia, in which blood urea nitrogen displaces other agents bound to albumin. In these settings, monitor free serum levels of AEDs to adjust medication doses. Notable exceptions to this rule are gabapentin and levetiracetam, which are not metabolized hepatically or significantly protein bound.



• Increased metabolism, autoinduction, and tolerance. These phenomena usually occur only after a number of days or, more commonly, weeks of AED therapy. In the ICU, they generally are a major concern only for individuals with tremendous hepatic induction or tolerance induced before ICU admission. Drugs such as phenytoin, carbamazepine, and phenobarbital cause autoinduction of hepatic enzymes, and individuals with a recent history of taking these medications may require higher-than-typical doses of these medications. Subjects with a history of significant chronic use of alcohol or benzodiazepines often require much higher doses of benzodiazepines than usual to achieve an antiepileptic effect. Finally, many patients are rapid acetylators, in whom it can be difficult to achieve therapeutic AED levels, despite large doses.37 This condition is usually apparent early after initiation of therapy and is best addressed by changing to another AED that is not dependent on the affected enzyme system for metabolism. Large increases in medication dose help in this situation, but doses may be difficult to titrate, with shifts from subtherapeutic to toxic levels. In our experience, this often results in wasted time and prolonged periods in which the patient has low serum levels of AED.

Difficulties associated with specific AEDs

Vigilant monitoring for particular side effects or difficulties associated with the use of specific AEDs is important in the ICU. All AEDs can cause allergic reactions, hepatic dysfunction, and encephalopathy. The ICU must also be aware of specific side effects or medication-associated challenges presented by specific AEDs:

• Valproic acid can cause thrombocytopenia and increased risk of bleeding. This agent is often avoided when active bleeding or increased risk of bleeding is a problem, although the magnitude of these risks is difficult to assess.37 Valproate also carries with it an increased risk of hyperammonemia and encephalopathy in the elderly, which can be difficult to recognize in ICU patients unless one is specifically aware of this difficulty.38,39
  
  
• Carbamazepine and oxcarbazepine can cause leukopenia and hyponatremia. These side effects may be dose-related or idiosyncratic. Both types of side effects may be severe, but usually are not. Hyponatremia, when due to carbamazepine, is usually due to inappropriate antidiuretic hormone section and may respond, to some degree, to fluid restriction.



• Phenytoin can cause zero-order kinetics after a level of more than 10–12 ìg/mL. The metabolizing enzyme becomes saturated, and levels may rise dramatically in response to a small increase in dose. Phenytoin is highly protein bound. Monitor free levels in uremia, hypoalbuminemia, and pregnancy.



• Topiramate can cause acute psychosis, depression, decreased ability to speak clearly, and nephrolithiasis.



• Lamotrigine may cause a rash leading to erythema multiforme if rapidly titrated. This problem is exacerbated by simultaneous administration of valproic acid. Risks of severe allergic reaction leading to erythema multiforme are increased in those under 16 years of age.



• Phenobarbital can cause prolonged sedation at high levels owing to its long half-life. Large amounts of protein binding may result in elevated free levels in uremia and hypoalbuminemia. The half-life may be prolonged in hepatic failure.



• Benzodiazepines may cause prolonged sedation with extended infusion, owing to storage and slow release from adipose tissue.

Adapted from: Kolb SJ and Litt B. Management of epilepsy and comorbid disorders in the emergency room and intensive care unit. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;515–535. With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Treating seizures in the intensive care unit (ICU) has much in common with treatment in the emergency department, but seizure care in the ICU branches out from acute assessment, emergent therapy, and triage to more prolonged care, in-depth diagnosis, prognostication, and definitive care planning. (See Approach to epilepsy)

The goal of therapy in the ICU is to suppress seizures and obtain a good patient outcome. The over-riding principle of ICU seizure care is that, barring therapeutic misadventure, the outcome ultimately is determined by how sick the patient is rather than by nuances of care. The ICU patient is subjected to factors that lower the seizure threshold. Although aggressive treatment with antiepileptic drugs (AEDs) reverses this, some conditions (e.g., end-stage organ failure) can only be treated by improving or compensating for decreased organ function. In acute renal failure, for instance, rapid recovery of function or emergent hemodialysis must occur if seizures are to be stopped. In cases in which recovery or replacement of function is not an option, such as status epilepticus and fulminant hepatic failure in patients who are not candidates for liver transplantation, physicians may still choose to follow treatment protocols for status epilepticus, although with little hope of ultimately affecting outcome.

Protocols for the treatment of status epilepticus are discussed elsewhere. Challenges to seizure care that are uncommon outside of the ICU include sepsis, acute brain injury, organ failure, and coma.

Challenges to seizure care

Sepsis

Seizures in the septic patient most commonly originate from hypotension, metabolic dysfunction, electrolyte disturbances, infection, or other factors directly related to the cause or consequences of the underlying disorder. In many cases, a patient may have an underlying predisposition to seizures, such as an old cerebral infarct, small-vessel vascular disease, or, less commonly, a neurodegenerative disorder.

As with all ICU patients, the focus should be on addressing the underlying cause or sequela of sepsis rather than on the seizures themselves. The specific choice of AED in these patients is not usually as crucial as the care with which the AED is given. These patients may be exquisitely sensitive to the hypotensive side effects of IV phenytoin or benzodiazepines, so these agents usually must be given much more slowly than in individuals who do not have sepsis. Interactions with steroid medications must be considered, if they have been prescribed. Finally, it is important to be aware of hepatic dysfunction in these individuals early in the course of treatment, as it may alter the choice of AED.

Acute brain injury

Seizures are frequently seen in patients with acute brain injury. Prophylactic therapy with an AED reduces the incidence of seizures, although only in the first week after acute head trauma.36 There has been some interest in investigating the use of AEDs to interfere with epileptogenesis and inhibit the development of spontaneous seizures after acute brain injury, but most of these studies have not yielded encouraging results. Studies of newer AEDs for cerebral protection, such as topiramate, are under consideration.

Other types of brain injury that are associated with a higher incidence of seizures include:

• intracranial hemorrhage
• embolic stroke
• abscess
• meningitis
• encephalitis

It is not common to administer prophylactic therapy to patients with these conditions, unless the risk of harm from a single seizure is quite high, such as with cerebral edema. The risks of administering AEDs to these individuals usually outweigh the benefits, but each patient must be considered individually.

Single or multisystem organ failure

Individuals with organ failure are common in the ICU. This group has a much higher risk of acute seizures. Considerations regarding therapy (especially the choice and dosage of AEDs) must be carefully considered with respect to the particular systems affected.

Survival in these patients is primarily dictated by the underlying causes of the conditions and how ill they are (e.g., the number of organ systems failing), rather than by the aggressiveness of seizure treatment.41 This applies whether the patient is experiencing convulsive or nonconvulsive status epilepticus, intermittent jerking movements, or impaired consciousness with EEG patterns suggestive of seizures. In the most ill patients, benzodiazepine use was statistically associated with an increased mortality, however.

Convulsive or definitive partial seizures usually should be treated with adequate levels of a single AED, with add-on therapy if necessary. Aggressive pharmacologic treatment of more nonspecific, generalized EEG patterns in these patients is not recommended, as it has not been demonstrated to improve clinical outcome.

Coma

The comatose patient provides a great challenge to clinicians, particularly in diagnosing and treating seizures. Mechanical ventilators, continuous sedation, and paralytic agents make it difficult to diagnose seizures, although one study has indicated that the prevalence of undetected seizures and status epilepticus is high.43 The threshold for ordering routine EEGs and bedside, continuous EEG monitoring should be low in these patients, particularly in the case of those with a history of epilepsy or a predisposition to it.

Therapy is aimed first toward suppressing clinical seizures. Then, suppression of electrographic seizures is accomplished, when possible. Escalating therapy to suppress interictal epileptiform activity on the EEG is generally considered counterproductive in these patients, however. Periodic lateralizing epileptiform discharges usually fall into this category, unless they evolve into frank clinical seizures. The risks of aggressive treatment (e.g., AED-induced hypotension, cardiac dysrhythmias, or rash) often outweighs potential benefits when isolated electrographic seizures are:

• focal
• limited to brief periods
• not associated with clinical signs
• occur in the setting of severe critical illness

Adapted from: Kolb SJ and Litt B. Management of epilepsy and comorbid disorders in the emergency room and intensive care unit. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;515–535. With permission from Elsevier (www.elsevier.com).

Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

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Adapted from: Kolb SJ and Litt B. Management of epilepsy and comorbid disorders in the emergency room and intensive care unit. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;515–535.
With permission from Elsevier (www.elsevier.com).

Reviewed May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.