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Renad Abu-Sawwa, PharmD, BCPPS
University of Florida, College of Pharmacy

“When you adjust for hypoalbuminemia, his phenytoin level was therapeutic at 17.5 mcg/mL following his fosphenytoin load. In addition to starting maintenance phenytoin, I would recommend initiating ketamine rather than pentobarbital as adjunctive therapy given that he is in refractory status epilepticus (RSE).  Unlike pentobarbital, ketamine does not have propylene glycol or other carbohydrates, thus it will maintain his state of ketosis.”

This is just one example of a recommendation I made for a two year old male with Lennox-Gastaut Syndrome maintained on a ketogenic diet, clobazam, levetiracetam, and cannabidiol, who presented in status epilepticus secondary to medication nonadherence. After administration of intermittent benzodiazepines, loading with levetiracetam and fosphenytoin and initiation of a high-dose midazolam infusion, pediatric neurology was consulted for further management. As the pharmacist consulting with the pediatric neurology service, my role was to provide recommendations for optimizing the pharmacological management of this patient’s RSE.

Clinical pharmacy is a consult service. Pharmacists are trained to be medication experts and in practice, are expected to have extensive knowledge regarding numerous medications treating countless conditions. However, as the number of new medications coming to market grows exponentially, the need for highly specialized clinical pharmacy services is becoming more apparent. The need is especially evident in the realm of pediatric pharmacotherapy which includes patients of all ages with diverse conditions (including adult patients who continue to be followed for underlying childhood conditions) and in every healthcare setting (ambulatory, emergency medicine, critical care, and acute care).

I was fortunate to have the opportunity to establish pediatric neurology/neurocritical care services at a children’s hospital. Initially, my pediatric neurology pharmacy service was established in the outpatient pediatric clinics caring for patients in conjunction with general neurologists, epileptologists, and neuromuscular specialists. Over time, it developed into a consultation service on patients that were admitted inpatient on acute or critical care units or for observation in the epilepsy monitoring unit.

As illustrated in the aforementioned scenario, pediatric neurology/neurocritical care, while being further specialized, encompasses all levels of acuity of care. My responsibilities include medication selection, optimization, dosing, management of drug-drug interactions and polypharmacy challenges, therapeutic drug monitoring (TDM), medication access, enrollment in clinical trials, patient counseling, and didactic and experiential education for multidisciplinary learners.

It is well-established that the incorporation of pharmacist-led medication management and TDM correlates with reductions in complications and improved patient outcomes. Multidisciplinary teams value the collaboration and contribution that pharmacists provide to their services. When it comes to initiating and modifying pharmacotherapy, three key components should be considered: (1) efficacy, (2) toxicity, and (3) medication access (e.g. formulation, cost, attainment). Each of these have many nuances that need to be factored in the realm of pediatric neurology/neurocritical care.

Pediatric neurology is one of the more robust specialties in terms of pharmacotherapy, as it requires extensive knowledge of neuropharmacology and disease pathology to determine efficacy. In epilepsy, one of the most common pediatric neurological disorders, less than half of patients respond to the first medication initiated, with even lower response rates that decline further with each subsequent agent. Up to one-half of patients develop medically refractory epilepsy due to disease progression, thus demonstrating the importance of medication selection and optimization in polypharmacotherapeutic regimens. Treatment of these refractory seizure disorders are medically complex, requiring a multimodal approach including the combination of pharmacological and nonpharmacological therapy (e.g. ketogenic diets, surgical interventions). The increased medical complexity of these patients correlates with the risk of concomitant comorbidities and a requirement for more specialized care.

Medications used in pediatric neurology, specifically antiseizure medications (ASMs), have a broad toxicity profile with the potential for numerous adverse effects and drug interactions and may require extensive monitoring, including TDM. Schoenenberger et al. evaluated TDM management of ASMs not managed by clinical pharmacy specialists (CPS) in adult patients in the inpatient setting and found that only 27% of levels ordered had appropriate indications that could impact patient care (e.g., seizure recurrence or suspected toxicity) [1]. Of those with appropriate indications, only 51% were sampled correctly, thus effectively decreasing overall appropriateness to a rate of 14% and roughly $300,000 in unnecessary medical expenses [1]. Pharmacist involvement in ASM TDM significantly increased the proportion of appropriate TDM lab assays (97.7%, p = 0.001), sampling times (79.1%, p = 0.0023), and application (83.7%, p = 0.0293), and decreased overall total healthcare expenses, including laboratory monitoring costs. [2-3] These results highlight the potential for a neurology/neurocritical care CPS-led collaborative practice.

In addition to the potential for improved safety and efficacy outcomes in these medically refractory patients, a pediatric neurology/neurocritical care CPS can also aid in access to medications, both inpatient and outpatient. ASMs are within the top 5 highest volume of prescriptions paid for by Medicaid, and yet not all patients have easy access to these critical medications due to modifications in formulary coverage, high insurance deductible/premiums, and/or lengthy drug utilization review processes. Ultimately these hurdles lead to interruptions in medication therapy, disease progression, and potentially increased healthcare cost due to preventable emergency room visits and hospital admissions. Across 36 children’s hospitals nationwide, almost one-third of children that are hospitalized with refractory epilepsy will change insurance within 5 years [4]. Patients with private insurance are more likely to transition insurances, which further increases the risk for hospitalization and emergency department visits subsequent to coverage gaps. These prolonged and/or recurrent gaps in coverage increase the risk for medically refractory epilepsy and polypharmacy, compounding the costs to the patient and healthcare system (estimated at $15,414 per person with an additional $9399 when uncontrolled) [5]. The incorporation of CPS with experience managing the complexities of medication coverage and the ability to provide supportive documentation to gain insurance coverage approval can increase approval and attainment of these specialty medications.

In my discussion with the pediatric neurology service, the aforementioned patient was transitioned to oral rufinamide upon discharge from the hospital. My involvement was essential in selecting the most appropriate dosage form given his concomitant ketogenic diet tube feeds, providing education for the family on administration, side effects, monitoring, and ensuring that the medication was obtained prior to discharge to minimize the likelihood of readmission secondary to medication nonadherence. Having a dedicated pediatric neurology/neurocritical care pharmacist aids in the transitions of care of patients not only through the healthcare system, but also transitioning from pediatric to adult care as warranted. Based on the limited literature available and my personal experience, it is my belief that the incorporation of a pediatric neurology/neurocritical care CPS has the potential to provide more effective care to a patient population that is incredibly medically complex and nuanced in a wide variety of settings.

References

1. Schoenenberger, Ronald A. et al. “Appropriateness of antiepileptic drug level monitoring.” JAMA 274 20 (1995): 1622-6 .
2. Ratanajamit C, Kaewpibal P, Setthawacharavanich S, Faroongsarng D. Effect of pharmacist participation in the health care team on therapeutic drug monitoring utilization for antiepileptic drugs. J Med Assoc Thai. 2009 Nov;92(11):1500-7.
3.  Lertsinudom S, Chaiyakum A, Tuntapakul S, Sawanyawisuth K, Tiamkao S, Tiamkao S; Integrated Epilepsy Research Group. Therapeutic drug monitoring in epilepsy clinic: a multi-disciplinary approach. Neurol Int. 2014 Dec 16;6(4):5620.
4. Pan, I-Wen & Lam, Sandi & Clarke, Dave & Shih, Ya-Chen. Insurance transitions and healthcare utilization for children with refractory epilepsy. Epilepsy & Behavior. 2018; 89. 48-54. 10.1016/j.yebeh.2018.09.042.
5. Examining the Economic Impact and Implications of Epilepsy. American Journal of Managed Care.Supplements and Featured Publications. 2020