Antiepileptic Drug Management in the Pediatric Intensive Care Unit

Children with epilepsy have high rates of hospitalization as well as medical comorbidities and need careful management of their medication regimens to maintain seizure control during hospitalization. In this article, pediatric epilepsy specialists respond to 6 questions about the common approaches, challenges, and pitfalls associated with the management and treatment of epilepsy in the pediatric intensive care unit (PICU). In addition to discussing such topics as drug interactions and strategies to reduce the risk of oversedation, the authors address system-based challenges, including medication shortages and the need for multidisciplinary coordination of care. Throughout, the authors weave their own clinical experience from the Cincinnati Children’s Hospital Medical Center.

What Are the Primary Challenges Associated With Antiepileptic Drug Management in the PICU?

Children with epilepsy have high rates of medical comorbidities, hospitalizations, and risk for readmission,¹ and it is not uncommon for our PICU consult team to see several children per week who are experiencing breakthrough seizures in the PICU. Common challenges arise in treatment of these individuals.

Systems-based challenges affect antiepileptic drug (AED) management (eg, timely administration of medications, awareness of missed medication doses during transportation and admission processes, availability of home AED that are not on the hospital formulary). Missing and delayed medication administration was the second largest cause of medication incidents in a national review.² Our hospital pharmacy team reviews the medication profile of all admitted children and verifies doses and timing with parents; this step is in addition to the expected medication reconciliation performed upon hospital admission.

Many genetic epilepsies are treated with uncommon, expensive, and difficult-to-obtain medications (eg, vigabatrin, adrenocorticotropic hormone for spasms, fenfluramine, stiripentol for Dravet syndrome, nicotine patches for pathogenic CHRNA4 and CHRNB2 variants encoding the nicotinic acetylcholine receptor), which, if not on formulary, parents may not always have on hand at the time of admission. Timely identification of medication needs is of utmost importance for individuals with complex, refractory epilepsy.

Many antiseizure medications and dosing strategies can further stress an already strained respiratory or cardiovascular system when doses are increased, especially in conjunction with the physiologic effects of increased seizures and intercurrent illness. Children may be more somnolent or have increased oral secretions or difficulty managing oral secretions, weak cough, or altered mental status. Increased attention must be paid to risk for aspiration, need for additional pulmonary toilet or airway clearance maneuvers, and risk for constipation (with midazolam and pentobarbital infusions being the primary offenders). If individuals develop new or worsening organ dysfunction, such as renal or hepatic impairment, medications may need to be dose-adjusted or switched; if children begin to experience new side effects on stable AED doses, it is imperative to consider altered drug metabolism.

How Can the Practitioner Decrease the Risk of Oversedation with Increases or Changes in AED?

Many children, particularly those with genetic epilepsies, experience a high seizure burden in their everyday lives, and parents are accustomed to increased seizures in the setting of illness, particularly in temperature-sensitive epilepsies such as Dravet syndrome or PCDH19-associated epilepsy. Families of children with complex epilepsies are aware of the tradeoff of seizure control versus side effects³ as they have experienced titrating medications to therapeutic effect or side effect threshold and are easily engaged in contingency planning for breakthrough seizures. Management of physiologic or environmental triggers (eg, treating fever with antipyretic, use of Blanketrol [Gentherm Medical; Cincinnati, OH] or other technologies), delirium precautions, and sleep aids if necessary all should be considered for at-risk individuals.⁴ Acute seizure action plans are vital to lay a framework for in-hospital treatment of seizures, particularly for individuals who may have multiple seizure types requiring different treatment, have had adverse reactions to AED in the past, or have experienced prolonged intubations in the past related to excess sedation or seizures.

“Bridge plans,” which are temporary medication changes to address breakthrough seizures, typically involve benzodiazepines, given their quick time of onset, but should be used judiciously if the individual is already on a sedating AED or there are concerns for respiratory compromise. When appropriate, we use ketamine as a first-line or second-line treatment to mitigate the respiratory and hemodynamic side effects of increased benzodiazepines or barbiturates. Intravenous ketamine is on our status epilepticus protocol in addition to midazolam, and we have growing experience using enteral ketamine for cluster seizures.

How Should Drug–Drug Interactions and Nonpharmacologic Interventions Be Managed in the PICU?

Medical treatments provided in the PICU, such as extracorporeal membrane oxygenation, molecular adsorbent recirculating system, plasmapheresis, continuous renal replacement therapy, and dialysis, may affect the clearance of antiseizure medications, with subsequent alterations of therapeutic concentrations.^5,6 Extracorporeal membrane oxygenation may remove or sequester significant amounts of ketamine, midazolam, phenobarbital, phenytoin, and propofol, and require higher dosing. Some medications need dose adjustment and may need to be dosed after dialysis (eg, lacosamide, levetiracetam, phenobarbital). Phenytoin, fosphenytoin, phenobarbital, and pentobarbital have decreased clearance and increased exposure during therapeutic hypothermia. Frequent blood level monitoring and titrating based on clinical observations is often necessary.

The ketogenic diet requires hypervigilance to avoid inadvertent administration of dextrose or other carbohydrates in intravenous infusions or liquid oral suspensions.⁷ Years ago, our hospital began an initiative to use normal saline instead of D5W (ie, dextrose solution) as the standard diluent for all intravenous antiseizure medications, many antibiotics, and continuous infusions. The electronic medical record (EMR) uses redundant alerts and warnings for providers and pharmacists with respect to parenteral dextrose administration in individuals on the ketogenic diet to minimize or prevent these errors. If dextrose is unable to be avoided (such as with corticosteroid administration), bridges or escalations of existing medications may be required temporarily, as we anticipate individuals will exit ketosis temporarily.

How Should AED Treatment Proceed in Patients Who Require Additional Medications?

Upon the identification of a potential or realized drug–drug interaction, the stakeholders, including pharmacy, must determine whether to avoid or carefully manage the interaction. As an example, the interaction between carbapenem antibiotics and valproic acid will cause valproic acid levels to be subtherapeutic for the course of antibiotic use plus several days afterward; therefore, if no other antibiotics can be used, a bridging plan for seizures needs to be implemented and valproic acid should be held.⁸ Inducers such as rifampin may cause breakthrough seizures in a person with otherwise stable epilepsy, and review of the medication list is warranted for individuals who have seizure recurrence during the hospitalization. We create redundant warnings in our EMR and surveillance system when these interactions occur so that the issue can be addressed preemptively. The risks and benefits of specific maintenance antiseizure medications with enzyme induction effects (strong or moderate) or other effects on drug clearance need to be considered for individuals in whom potential therapeutic failure can occur (eg, chemotherapy, immunosuppression, antibiotic or antifungal treatment).

On occasion, there may be situations where an antiseizure medication should be held. Everolimus, an mTOR (mechanistic target of rapamycin) inhibitor commonly used in tuberous sclerosis, is an immunosuppressant associated with increased rates of infection in initial clinic trials, and may put individuals at risk for difficulty overcoming infection.⁹ Our institutional practice is to hold everolimus in the setting of fever and illness symptoms (eg, cough, congestion) until 24 hours fever-free or when off antibiotics (whichever is later, if antibiotics were indicated), or in the case of surgery, when the risk of wound dehiscence and postsurgical infection has passed (typically 1 to 2 weeks after open surgery), or upon discussion with the surgical team.

The AED regimen should be evaluated in individuals with new concerns for bleeding disorder or for whom anticoagulation is started; there has been concern that older AED (ie, phenytoin, phenobarbital, carbamazepine) may alter the metabolism of non–vitamin K oral antagonists.¹⁰ Valproic acid may affect hemostasis with a variety of laboratory abnormalities reported (eg, platelet count, aggregation, low fibrinogen levels) which may not correlate with therapy duration, dosage, or plasma concentration. When this affects surgical planning, medication bridges with benzodiazepines or other antiseizure medications can be considered.

What Challenges Are Associated With NPO Orders? What Strategies Can Be Used to Address These Challenges?

Nothing by mouth (NPO) diet orders may be in place for multiple reasons: anticipation of sedated procedures, risk of respiratory decline with possible intubation, or development of gastrointestinal symptoms or disorders (eg, ileus, recurrent emesis, pancreatitis) for which NPO is part of the treatment strategy. This may interfere with AED medication administration or dietary therapies (eg, ketogenic diet, modified Atkins diet). This is a common consult question for our team.

The first strategy is always to clarify whether the individual can be NPO except for medications—many routine NPO orders, such as for anticipated sedated procedures, should allow administration of most enteral medications with small amounts of clear liquids. When possible, we advocate for expedited nasogastric tube placement, with administration of the AED in either liquid (Table) or crushed tablet formulation if the child’s cooperation level or mental status is impaired. Medication administration on an empty stomach may trigger nausea or other side effects. If the indication for NPO status affects gastric motility or absorption, medication doses may need to be adjusted, seizure medication levels monitored, and escalation plans in place for breakthrough seizures.

For individuals who must be NPO including medications, we turn to our limited catalogue of intravenous or parenteral antiseizure medication options. We use a standardized note template for AED conversions, which includes all factors considered important for making abrupt medication changes (Figure). We attempt to use intravenous options with similar mechanisms of action among benzodiazepines, barbiturates, sodium channel agents, and carbonic anhydrase inhibitors (eg, replacing oxcarbazepine with a sodium channel agent such as fosphenytoin or lacosamide). For individuals on clobazam, we use a dosing algorithm to help estimate their needs that can be given as scheduled intravenous lorazepam.

Rectal administration is an option, and there have been multiple studies of AED dosing by this route. Rectal administration should be approached with caution in the PICU in people with coagulopathies or immunocompromised states but should be considered in appropriate circumstances. Rectal phenobarbital can be used to administer relatively high doses to individuals on the ketogenic diet to avoid propylene glycol in intravenous formulation. We frequently consider rectal administration of lamotrigine if NPO status is anticipated to be prolonged, and reinitiation would require prolonged uptitration, although absorption is less than with oral dosing.¹¹

Individuals on the ketogenic diet deserve particular attention in this scenario.⁷ The ketogenic diet is not as easily or immediately replaced with ketogenic total parenteral nutrition, which requires dietician and pharmacy expertise for administration. At our institution, individuals on the ketogenic diet are listed as having a dextrose allergy to prevent inadvertent glucose administration, and we have altered monitoring and response to low glucose levels in these individuals. Seizure medications used in the PICU can be counterproductive to ketosis (eg, methylprednisolone, which leads to elevated glucose levels; and pentobarbital, because of its use of propylene glycol as the solvent, which is a substrate for gluconeogenesis).

The goal is always to transition back to the home regimen as quickly as possible. In cases where the NPO period has extended beyond 3 days, we document a titration plan back to goal dosing while weaning the bridging medication we had been using in the PICU. Special consideration is made for clobazam and lamotrigine: clobazam has a substantially longer half-life than the scheduled lorazepam, so we keep the lorazepam scheduled for the first 3 to 5 days of clobazam reinitiation while watching closely for sedating side effects; lamotrigine may require careful retitration to avoid Stevens-Johnson syndrome (typically a concern if off lamotrigine for several days).

How Can a Multidisciplinary Approach Optimize Assessment, Diagnosis, and Treatment of Epilepsy in the PICU?

Children with genetic epilepsy often have longstanding relationships with their primary neurologist or epileptologist, with levels of trust and understanding that cannot be achieved in a PICU setting. However, outpatient neurologists and epileptologists cannot be expected to be available at all times for PICU-related questions. It is the job of the consult service to navigate these cases, providing inpatient expertise for acute situations while supporting the outpatient care plan. Early and direct communication is key to management of complex cases; when possible, rounding with PICU teams and pharmacy is preferred. Because systems-based challenges may put the individual at risk of medication error or missed medications, joint discussion about the risk of breakthrough seizures, medication options, and treatment goals is of utmost importance, with prompt documentation. For example, children undergoing orthopedic procedures (eg, spinal fusion, splinting or casting for hip surgeries) may have increased pain or risk of complications if breakthrough seizures occur, and medication plans must be adjusted accordingly. Clear communication with other services ensures we are working in concert and not counter to our shared goal of safety and healing.

Hospital discharge is a time when errors may be introduced into the record, especially when individuals are discharged from non-neurology services. Errors may occur when medications are sent to new pharmacies, new doses of medications are not double-checked and prior authorizations received, and outpatient follow-up plans are not coordinated. Our sign-off note has a templated format to include discharge medication doses, rescue plans, and follow-up appointment information.

Conclusion

Hospitalized children with epilepsy are at risk of missed medication doses or other challenges in maintaining their AED regimen, which can exacerbate their seizure disorder and complicate their concurrent illness. Management of their illness while preventing breakthrough seizures necessitates careful consideration and balance of their medical therapies, which can be achieved through multidisciplinary discussion and cooperation.