Making Polypharmacy Safer for Children with Medical Complexity

Case Vignette:

A 14-year-old patient who has severe cerebral palsy and seizures, requested that his parents speak to his pediatrician about a medication to help with sleep. He already uses 13 other medications, including anticonvulsants, analgesics, and respiratory medications, and 5 additional as needed (PRN) medications (Figure 1). He has a vagal nerve stimulator and a gastrostomy tube. His parents had researched several sleep medications, and they were interested in discussing trazodone therapy for his sleep issues. Clinicians who prescribe medications to children with medical complexity (CMC) frequently must consider the question: How does one safely prescribe a patient like ours a new medication, like the sleep medication trazodone, amidst an already complex background of polypharmacy?

Introduction:

Optimal health for CMC frequently depends on the chronic use of multiple medications.(1–8) CMC live with lifelong complex chronic conditions (CCCs), such as neurological, congenital, or genetic conditions, and CMC often depend on technology, like gastrostomy tubes. Many CMC are frequently exposed to chronic daily polypharmacy (≥5 medications), with complex medication regimens that span multiple therapeutic classes and include high-risk medications.(5–9) Though polypharmacy is often necessary for symptom and disease management in CMC, major opportunities exist to improve medication use practices (Figure 2). Polypharmacy is not simple or straightforward to manage for clinicians or for parents and can lead to adverse drug events that interfere with optimal patient outcomes.(10, 11) Clinicians have limited high-quality evidence for many of the medications used to treat children, and potentially less evidence for how those medications interact. Furthermore, in the home setting, parents must administer complex dosing schedules, use various dosage forms, and follow specialized instructions for off-label medications. Unneeded, incorrectly administered, or self-discontinued medications can lead to poor symptom management or adverse drug events, resulting in emergency department (ED) visits or hospitalizations.(12) Yet, during routine clinical care for CMC, polypharmacy is infrequently assessed and rarely managed comprehensively.(12, 13) To ensure medication safety and effectiveness, clinicians need to treat pediatric polypharmacy as a chronic medical condition itself that requires ongoing attention, dedicated time, and careful management.

Figure 2: The Outpatient Medication Use System for Children with Medical Complexity and Select Associated Vulnerabilities.

Each circle represents a major step in the outpatient medication use system. Select vulnerabilities are listed beside each step.

The Epidemiology of Pediatric Polypharmacy:

Before even considering the specific effects of a new medication a clinician may think more generally about the impact of adding another chronic medication specifically in the context of existing polypharmacy. Knowing that the background milieu of polypharmacy can change over time, safe pediatric prescribing begins with an up-to-date knowledge of the epidemiology of polypharmacy. Is our patient’s polypharmacy typical? Is it expected to continue to escalate as he ages? What other medications might he use over time? Where and when are additional medications prescribed? By leveraging population-level data to understand the expected course of polypharmacy for a patient like this, problems can be anticipated and managed before polypharmacy escalates.

Who Gets Polypharmacy?

In a large study of 240,000 children enrolled in Colorado Medicaid, children with the highest levels of sustained annual polypharmacy were older (13–18 years old), had ≥1 CCC, and had technology dependence.(8) CMC with these characteristics, like our patient were 6 to 7 times more likely to experience high levels of polypharmacy for months on end.(8) Even within the population of CMC, certain groups are at higher risk. In another study of 4.5 million U.S. children, those with technology dependence or organ transplantation had by far the highest levels of chronic polypharmacy.(1) Even though children with transplants are often monitored by dedicated transplant pharmacists, CMC with respiratory, gastrointestinal, and neuromuscular CCCs can also experience substantial polypharmacy, and they do not have as routine or coordinated supervision.(1, 2) Because so many CMC are likely to develop polypharmacy over time, clinicians must be judicious when prescribing even just the first or second medication for CMC.

Why Does Polypharmacy Occur?

CMC, particularly children like our patient with severe neurological conditions, have medical comorbidities that involve many other body systems.(3, 4, 14) These comorbidities start early in life and accrue over time.(14) The presence of multiple symptoms, ranging from life-threatening issues like seizures or respiratory issues, to very impactful symptoms, like constipation, is strongly associated with use of ≥10 medications per day; CMC with the highest symptom burdens use ≥20 medications per day.(3, 5, 14) Although it may seem logical that more symptoms equals more medications, it isn’t always that straightforward. Among 123 CMC with severe neurological conditions, their polypharmacy regimens did not necessarily reflect need.(3) For example, more than half of children with polypharmacy had parent-reported pain in the past 7 days, but only 61% of these children had some type of pain medication prescribed.(3) Among the same children, this also occurred simultaneously with other symptoms, like constipation. Although many comorbidities are chronic or lifelong, a patient’s symptoms can change over shorter periods of time, which can lead to constantly changing medication regimens, underscoring the need for ongoing reassessment.

What does polypharmacy look like?

Because of the diversity of comorbidities and symptoms that children experience, CMC are also exposed to a diversity of medications.(1, 5, 7, 8) Examining the medication regimens for more than 2,300 children taking ≥10 concurrent medications, two-thirds of children were simultaneously exposed to systemic antibiotics, respiratory agents, gastrointestinal agents, and psychotropic medications, with a huge variety of other less common medications.(8) Additionally, CMC frequently use high-risk pediatric medications that require careful monitoring regardless of the level of polypharmacy, including opioids, anticoagulants, antiepileptics, and sleep aids.(6) Finally, many of the medications that CMC use are filled as chronic medications (≥90 day supply).(1) With several thousand individual medications available, and approximately 20 to 30 new drugs entering the market every year, this emphasizes the need for clinicians to be very familiar with the set of medications they prescribe personally and to know how those medications interface with the other typical medications a child with polypharmacy may use, either currently or in the future.

Where and when does polypharmacy occur?

Even though medical complexity is often equated with inpatient care, after the first year of life, CMC receive most of their care in the less supervised outpatient setting.(15) In a longitudinal 5-year study of approximately 14,000 CMC with severe neurological conditions, almost all CMC filled outpatient prescriptions starting in the first year of life and persisting throughout the 5-year follow up period.(15) These CMC were largely cared for in the outpatient setting, punctuated by ED visits and inpatient admissions, suggesting that the outpatient medical home is where medication management efforts should be coordinated. Does coordinated monitoring occur? Another study of CMC examined where follow up occurred after high-risk opioids were prescribed during subspeciality, ED, surgical, or inpatient visits.(2) Only a third of children had any in-person follow-up with the healthcare system within 7-days and it wasn’t necessarily with a primary care or specialty clinician familiar with that child’s care, which can set a child up for adverse drug events.(2)

The Adverse Consequences of Pediatric Polypharmacy:

Two weeks after initiating a trial of trazodone, our patient’s parents brought him to the ED for concerns about noisy, labored breathing. His mother noted that his secretions had thickened substantially, and he was requiring frequent deep suctioning and supplemental oxygen at home. In the ED, he was evaluated for respiratory distress, and he had a thorough medical evaluation, including a chest x-ray, complete blood count, C-reactive protein level, and viral respiratory panel, which were all within normal limits. In absence of another cause, it was thought that his symptoms may have been caused by one or more of his many medications. He was discharged home with a primary care appointment the next day.

Unfortunately, pediatric adverse drug events do occur and can result in actual emergency-level care.(11) An adverse drug event is defined as “Any harm experienced by a patient as a result of exposure to a medication.” An adverse drug event can happen as a direct result of the medication itself, like oversedation by a central nervous system agent or through a drug interaction with another medication, and most commonly manifests as a dermatologic, gastrointestinal, or respiratory symptom.(7, 11, 16) Or an adverse drug event could happen as a consequence of administration, like a mismeasured dose or improperly prepared liquid medication, which has been associated with undertreated symptoms among CMC, like seizures or pain.(12) Among 144 million ED visits by U.S. children, 0.5% of all annual visits, or 700,000 visits a year, were associated with an adverse drug event.(11) In particular, CMC had 5 times the risk of adverse drug event-related visits compared with children without medical complexity.(11)

Knowledge-Related Medication Problems:

An adverse drug event may be straightforward to determine for a child taking a single medication, but—as in the case of our patient—it’s much more difficult to identify in the setting of polypharmacy. Considering that most medication monographs list multiple side-effects or adverse symptoms (many of which are theoretical, understudied, or extrapolated to children), when multiplied across 10 or 15 medications, this leaves clinicians searching for a proverbial needle in the haystack. At a minimum, implicating a drug requires that an event is a known response to a suspected medication, the event is not otherwise explained by the child’s medical conditions, and the timing makes sense. Whenever a parent of a child with polypharmacy reports a new or unwanted symptom, it’s imperative to consider an adverse drug event as part of the differential diagnosis. Given the rarity of pediatric adverse drug events, especially in CMC with already rare conditions, the only way we can generate better knowledge about adverse drug events is by capturing reliable data. Parents and clinicians should be encouraged to voluntarily report adverse events, which can be done easily and quickly by entering basic details about a suspected adverse drug event through the U.S. Food and Drug Administration’s online MedWatch portal, which aggregates adverse drug events nationally.(17)

In addition to the direct effects of a medication itself, polypharmacy increases the risk of potential drug-drug interactions (PDDIs) that can also cause adverse drug events. The same holds true for drug-food, drug-supplement, and drug-disease interactions, and again exceedingly little real-world pediatric data exists to inform these types of interactions. To determine the prevalence of pediatric PDDIs, researchers used the Pediatric Health Information System to examine PDDIs in hospitalized children.(7) For each patient day, every possible 2-drug interaction was analyzed by severity, mechanism of harm, and the affected organ system. Among 500,000 hospitalizations that resulted in nearly 4.5 million PDDIs, major PDDIs occurred in 41% of pediatric hospitalizations and CMC were at the highest risk for PDDIs.(7) The most common implicated drugs included psychotropic medications and opioids, and the most common potential adverse drug events were severe respiratory depression, increased risk of bleeding, and cardiac issues such as long QT syndrome.(7, 8) Although PDDIs can be easily identified by non-pharmacist clinicians using reliable online drug interaction checking software from public and commercial sources, the utility of these interaction checkers is limited by the pediatric-specific information they contain.(18) For our patient when prescribing the trazodone, the electronic health record (EHR) presented multiple alerts for interactions with the potential for central nervous system depression, but no alerts directly related to the thickened secretions that our patient subsequently experienced.

Without real-world evidence to support whether PDDIs have actual consequences, PDDI may continue to go unnoticed. For example, CMC commonly are exposed to multiple anticholinergic medications, but little pediatric-specific evidence exists linking anticholinergic PDDIs to actual anticholinergic symptoms. In a recent study of medications and parent-reported symptoms among 123 CMC, parents were 3 times more likely to report anticholinergic symptoms (drowsiness, constipation, concentration problems, dry mouth, and urinary problems) in children taking multiple anticholinergic medications compared with those without, suggesting that these drug interactions have a real consequence.(19) Regarding our patient, even though trazodone is technically a weak anticholinergic medication, in conjunction with the other medications he was taking (including PRN medications administered by his parents), the additive anticholinergic effects may have been more pronounced than expected.

Administration-Related Medication Problems:

Medication safety can also be compromised by issues related to the home administration of complex polypharmacy regimens. Our patient’s parent remarked, “We are sent home with care routines that would challenge nurses in the intensive care unit, and yet we never get to clock out and we still have to fulfill all the other responsibilities as a parent.” Indeed, in a cross-sectional study of 123 CMC with neurological impairment, children were prescribed a median of 31 total daily doses of medication, 7 different dose frequencies, 6 unique dosage forms, and 5 different specialized instructions.(5) Dose frequencies were the primary driver of pediatric medication regimen complexity, highlighting the need for clinicians to simplify dosing schedules when appropriate.(5) But some of those medications were also prescribed as PRN medications and up to a third of PRN medications did not have a specified dose frequency, potentially leaving parents without clearly defined administration instructions.(5)

Finally, other aspects of pediatric medication administration can increase complexity and the risk for harm. For unique patients, clinicians often need to use unique medications that can introduce additional safety concerns. Compounded medications, liquid medications, alternative routes of administration (e.g., gastrostomy tube), and unregulated nutritional supplements all carry additional risks.(20) Any time a liquid is chosen over a solid dosage form, it results in the potential for calculation errors, and requires careful selection of drug concentrations at all transitions of care. Many children rely on gastric or jejunal feeding tubes to deliver nutrition and medications; manipulating medications for such administration isn’t always easy or appropriate. There are some medications that might not be absorbed correctly depending on the position of an enteral feeding tube, and that detail isn’t always considered or researched. Our patient’s parents had to crush, dissolve, and administer his trazodone through the gastrostomy tube. The correct 75mg dose required them to dissolve 1.5 tabs, amidst all our patient’s other daily care activities.

When all these complexities are added together and parents are expected to simply “do it all correctly,” parents are not set up for success. In a study involving over 150 parents of CMC, parents reported high confidence in their ability to manage their child’s medications.(6) But when it came to demonstrating actual medication abilities, 1 in 4 parents were unable to match medications to indication, over half were unable to recall dosing instructions, and nearly half committed errors while measuring liquid doses.(6) This is not a shortcoming of those parents, but rather, it reinforces the need for clinicians to support parents with better medication education, especially when polypharmacy is present.

Improving the Management of Pediatric Polypharmacy:

The integration of pharmacy support is an important component that can address many of the existing vulnerabilities in the medication use system (Figure 2) and can provide a consistent point of contact for families and clinicians, especially at times of transition, like after our patient’s acute ED visit. When our patient followed up in the complex care clinic, a pediatric pharmacist worked with his parents to perform a comprehensive medication review. The pharmacist determined that our patient’s total anticholinergic burden was high, and it was unpredictable because many of his PRN medications also had anticholinergic activity. The trazodone had tipped the scale just enough to dry up and thicken his oral secretions, which ultimately manifested as unwanted respiratory symptoms. Multiple opportunities exist that could have improved the safe and effective prescribing, administration, and monitoring of a new medication for CMC with polypharmacy (Table I).

Table 1.

Best Practices at the Prescriber-Level and System-Level to Make Polypharmacy Safer for Children with Medical Complexity

Activity	Prescriber-Level	System-Level
Prescribing	• Verify current medications, including over the counter medications and nutritional supplements • Review best available evidence for indicated use • Check for drug-drug interactions • Consider ease of preparation and administration when selecting dosage form and dose frequency • Consider cost/insurance issues	• Integrated pharmacist support • Comprehensive medication review • Improved real-world evidence for prescribing in special populations • EHR based comprehensive drug interaction checking • Medication therapy management at least annually
Administering	• Provide tailored anticipatory guidance, education, and instructions for all caregivers who will prepare or administer medications • Consolidate administrations • Identify potential home administration issues (e.g., safe storage, refrigeration, etc.)	• EHR-based standardization of caregiver resources (e.g., auto-populated dosing calendars, administration instructions and diagrams) • Technology/telehealth-based education/observation • Medication therapy management
Monitoring	• Define parameters for treatment success/failure • Provide education about possible side effects or adverse drug events and how/when they might present • Consider laboratory monitoring for safety/efficacy • Schedule follow-up to assess response (e.g., visit, call, EHR patient portal message) • Modify, discontinue, or switch therapy as needed	• Improved population-level adverse drug event monitoring • EHR-based communication/coordination between multiple prescribers across multiple systems of care • EHR-based symptom inventories and tracking • Technology/telehealth-based pharmacist involvement • Medication therapy management

Improving Prescribing Practices:

During the prescribing stage, off-label medication use, polypharmacy, and unique disease-specific considerations can complicate the selection of the safest and most effective medications. For our patient who had sleep problems, a review of the relevant literature for recommendations about sleep medications in CMC yielded several common themes: “Additional data are needed” or “Prescribers must rely on clinical expertise.” Safe prescribing requires evidence of real-world safety and effectiveness. This is perhaps the toughest aspect to address because it requires the most work. Like trazodone, there are many other commonly used individual drugs that each deserve their own study of real-world effectiveness and outcomes in children. The National Institute for Child Health and Human Development leads the Best Pharmaceuticals for Children Act, which helps the NIH prioritize therapeutic areas and sponsor clinical trials for medications that need further study in children.(21) The annual list of prioritized medications often highlights knowledge gaps about therapeutics for CMC.(21) Clinicians who routinely prescribe medications off-label to CMC, whether in the ED, inpatient, or outpatient setting, can nominate such medications for prioritization using a brief online form. This has led to, for example, further study of the safety and efficacy of oral baclofen for use by children with cerebral palsy.(21)

Improving Medication Administration:

Parents must function at home as a “parent pharmacist” where they administer complex medication regimens. How can clinicians best support parents? Interventions to improve medication safety must be acceptable to and inclusive of parents from all levels of health literacy and should minimize additional caregiving burdens. First, clinicians should attempt to reduce medication regimen complexity by choosing medications with optimal dose frequencies or thinking critically about opportunities to de-prescribe medications.(22) When clinically appropriate, dosing schedules for multiple medications can be aligned to consolidate medication administrations. Second, clinicians need to proactively identify potential home medication administration issues, perhaps enhanced by periodic comprehensive medication review with a pediatric pharmacist and enabled by mobile technology or even telehealth pharmacist encounters. Finally, clinicians can provide anticipatory guidance, education, and instructions tailored for a patient’s unique medication regimen. Our patient’s parents recommended that: “If there are medications prescribed with special instructions, we need actual instruction on how to prepare and administer it—not just a printout. Show us on a baby doll, show with an empty syringe.”

Many or all these clinical activities can be performed during formal medication therapy management visits with a pharmacist. Pharmacist-led medication therapy management is a proven and cost-effective tool for improving polypharmacy-related outcomes, safety, and adherence in adult and geriatric populations.(23) In partnership with the patient and parents, pediatric medication therapy management consists of a comprehensive medication review, optimizations of the medication regimen, and creation of a written medication action plan.(10) In a study of the potential benefits of pediatric medication therapy management, pharmacists performed comprehensive medication review for 100 children with polypharmacy to see what types of issues could be addressed by medication therapy management.(10) Opportunities to improve are abundant, with children having an average of 3 medication-related problems, such as inappropriate therapy, PDDIs, or duplications of therapy, with 97% of patients having opportunities for potential interventions.(10) From the perspective of a clinician who has a long list of topics to address during a clinical visit, this type of partnership with pharmacists can improve efficiency, even when caring for CMC with the most complex polypharmacy. Furthermore, because adult medication therapy management can be delivered by contracted providers and is reimbursable by Medicare, similar models could allow pediatric practices to access centralized pediatric medication therapy management services for CMC.

Improving Medication Monitoring:

How can clinicians do a better job of working with parents in the home setting to make sure that a medication is working? Longitudinal medication monitoring strategies are needed to determine the relationship between symptoms and medications. Clinicians need to know about symptoms so that they might act upon them. In a study of symptoms experienced by CMC, parent-reported symptoms endorsed before a visit were compared with symptoms noted by a clinician during the visit, either in their clinical notes or in the related orders.(4) There was high agreement when severe symptoms were present, like seizures or breathing difficulties.(4) But for other important and prevalent symptoms reported by parents, like itching, fatigue, or irritability, there was lower recognition or related orders of adverse drug events by a clinician.(4) Enhanced communication between parents and clinicians after medications are started or changed—especially at times of transition between ED, inpatient, and outpatient settings—can enable the identification of medication-related issues as they come up in real time.(4) In a currently ongoing study, when a CMC is prescribed a medication of interest anywhere within a healthcare system—for example, a high-risk psychotropic medication—parents are sent an online symptom inventory at key timepoints.(24) The symptoms can then be tracked over time, for example to see if a symptom improves, and the information is available to clinicians familiar with the child, who can then react. With our patient if this type of data had been available, changes in symptom trajectories might have been detected before they worsened, perhaps preventing his ED visit.

Conclusion:

In the case of our patient, the pharmacist-led medication therapy management session resulted in adjustments to several of his other anticholinergic medications (both scheduled and PRN) and the trazodone subsequently improved the quality and duration of his sleep without affecting his oral secretions or breathing. For CMC like our patient some degree of polypharmacy for CMC is always going to be necessary and inevitable, but this is not simple or straightforward to manage for clinicians or for parents. There are many vulnerabilities, especially in the outpatient and home settings. Because of this, clinicians need to treat polypharmacy itself as a chronic medical condition that requires ongoing attention, dedicated time, and careful management. Clinicians can implement several practical strategies to make pediatric polypharmacy safer (Table I).

Consider Real-World Constraints:

When prescribing a new medication to a patient who already has polypharmacy, clinicians must think about how to make that medication safest and most effective in the home setting. What real-world evidence exists to support using this medication for this specific child? Are there any major PDDIs with a child’s existing regimen? Can the dosing schedule be minimized? Are formulations available that are easier for a parent to prepare and store alongside 10 or 15 other medications? Are there cost or insurance constraints that will impact a family’s ability to fill the prescription?

Choose Discrete Endpoints:

Clinicians should work with the parent to educate them about what to expect and when to expect it. That means reviewing what the possible side effects might be or how an adverse drug event might present. That also means, right up front, discussing what defines a treatment failure and over which time frame, so that a medication can promptly be discontinued if it’s not achieving its desired effect.

Proactively Monitor for Response:

Knowing the realities of how busy life can be for families and for clinicians, set up some type of a scheduled monitoring plan. That could be a return visit, a call with clinical support staff, or a EHR patient portal message at a specified time to ask about a child’s response to a medication.

Discontinue/Deprescribe:

When a medication is not working, or when there is an opportunity to trial off a legacy medication, it is worth a discussion with parents to see if a medication can be removed. It might seem negligible to remove a chronic cetirizine prescription, but that’s one less medication that needs to be administered for many years of a child’s future life.

Early and frequent collaborations with inpatient and outpatient pharmacists can be tremendously valuable. Pediatric pharmacists can perform comprehensive medication reviews, research medications and PDDIs in greater detail, lead medication therapy management visits to coordinate and manage even the most complex polypharmacy regimens, and provide tailored education for both parents and clinicians, ultimately improving pediatric medication safety and effectiveness.

Figure 1: Typical Outpatient Polypharmacy for a Child with Medical Complexity.

This photograph depicts our patient’s home medication regimen.

Abbreviations:

CCC

complex chronic condition

CMC

children with medical complexity

ED

Emergency Department

EHR

electronic health record

PDDI

potential drug-drug interaction

PRN

pro re nata (as needed)