Recommendations for the Management of Initial and Refractory Pediatric Status Dystonicus.

Status dystonicus is the most severe form of dystonia with life-threatening complications if not treated promptly. We present consensus recommendations for the initial management of acutely worsening dystonia (including pre-status dystonicus and status dystonicus), as well as refractory status dystonicus in children. This guideline provides a stepwise approach to assessment, triage, interdisciplinary treatment, and monitoring of status dystonicus. The clinical pathways aim to: (1) facilitate timely recognition/triage of worsening dystonia, (2) standardize supportive and dystonia-directed therapies, (3) provide structure for interdisciplinary cooperation, (4) integrate advances in genomics and neuromodulation, (5) enable multicenter quality improvement and research, and (6) improve outcomes. © 2024 International Parkinson and Movement Disorder Society.

Weaning Dexmedetomidine in Non-ICU Areas: An Implementation Effort.

OBJECTIVES: To develop and implement clinical practice guidelines for safely weaning dexmedetomidine infusions in non-ICU areas. DESIGN: Development, implementation, and analysis of effectiveness of clinical practice guidelines. SETTING: Quaternary care academic free-standing pediatric hospital. PATIENTS: Children, otherwise medically ready for transfer to non-ICU areas, who were undergoing a planned wean of a dexmedetomidine infusion. INTERVENTIONS: Subject matter experts developed evidence-based guidelines for weaning dexmedetomidine in patients whose critical phase of illness had resolved. MEASUREMENTS AND MAIN RESULTS: Searches identified no prospective studies of dexmedetomidine weaning. We identified two retrospective reviews of withdrawal symptoms and one on the use of clonidine. There were case studies on withdrawal symptoms. Guidelines were piloted on a cohort of 24 patients while in the ICU. The guidelines were then implemented in non-ICU areas for patients undergoing dexmedetomidine weaning after ICU transfer. Over a 2-year period (October 1, 2018, to September 30, 2020), 63 patients (1 mo to 18 yr old) successfully weaned dexmedetomidine in non-ICU areas. The median time to discontinuation of dexmedetomidine after transfer to non-ICU areas was 5.8 days (interquartile range, 4.75-15 d). Fifty-eight percent (n = 41) of all patients were considered high risk for dexmedetomidine withdrawal based on the dose, duration of exposure, and the risk of experiencing physiologic detriment with more than mild withdrawal. Twenty-nine patients (46%) exhibited no signs or symptoms of withdrawal while weaning per guidelines. For those with signs and symptoms of withdrawal, the most common were tachycardia (n = 26, 40%), agitation (n = 9, 14%), and hypertension (n = 9, 11%). CONCLUSIONS: Weaning dexmedetomidine in non-ICU areas is feasible and can be accomplished safely even among pediatric patients at high risk for withdrawal using standardized weaning guidelines. At our institution, implementation was associated with reduced ICU length of stay for patients recovering from critical illness.

Patients dispensed medications with actionable pharmacogenomic biomarkers: rates and characteristics.

PURPOSE: Pharmacogenomic biomarkers are increasingly listed on medication labels and authoritative guidelines but pharmacogenomic-guided prescribing is not yet common. Our objective was to assess the potential for incorporating knowledge of patients' genomic characteristics into prescribing practices. METHODS: We performed a retrospective analysis of claims data for 2,096,971 beneficiaries with pharmacy coverage from a national, commercial health insurance plan between January 2017 and December 2019. Children between 0 and 17 years comprised 21% of the cohort. Adults were age 18 to 64. Medications with actionable pharmacogenomic biomarkers (MAPBs) were identified using public information from the US Food and Drug Administration (FDA), Clinical Pharmacogenomics Implementation Consortium (CPIC), and PharmGKB. RESULTS: MAPBs were dispensed to 63% of the adults and 29% of the children in the cohort. Most frequently dispensed were ibuprofen, ondansetron, codeine, and oxycodone. Most common were medications with CYP2D6, G6PD, or CYPC19 pharmacogenomic biomarkers. Ten percent of the cohort were codispensed more than one MAPB for at least 30 days. CONCLUSION: The number of people who might benefit from pharmacogenomic-guided prescribing is substantial. Future work should address obstacles to integrating genomic data into prescriber workflows, complex factors contributing to the magnitude of benefit, and the clinical availability of reliable on-demand or pre-emptive pharmacogenomic testing.

Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism.

SLC1A2 is a trimeric transporter essential for clearing glutamate from neuronal synapses. Recurrent de novo SLC1A2 missense variants cause a severe, early onset developmental and epileptic encephalopathy via an unclear mechanism. We demonstrate that all 3 variants implicated in this condition localize to the trimerization domain of SLC1A2, and that the Leu85Pro variant acts via a dominant negative mechanism to reduce, but not eliminate, wild-type SLC1A2 protein localization and function. Finally, we demonstrate that treatment of a 20-month-old SLC1A2-related epilepsy patient with the SLC1A2-modulating agent ceftriaxone did not result in a significant change in daily spasm count. ANN NEUROL 2019;85:921-926.

Off-label use of prescription analgesics among hospitalized children in the United States.

PURPOSE: Analgesics are the most frequently administered medications among hospitalized children. However, current analgesic prescribing patterns have not been well defined among hospitalized children. In addition, it is unknown what proportion of prescription analgesics is approved for use in children and what proportion is used "off-label." METHODS: Nationally representative data from 52 tertiary care children's hospitals in the Pediatric Health Information System were queried to determine prescribing rates of analgesic medications. We analyzed hospitalizations for children <18 years occurring between 1 April 2010 and 30 June 2018. Food and Drug Administration (FDA) drug labels were reviewed for pediatric information, and prescriptions were classified as on- or off-label based on age, route, and formulation. RESULTS: Among 4.9 million hospitalizations, 1.8 million (37.6%, 95% confidence interval [CI] = 37.6-37.7) were associated with use of a prescription analgesic. Overall, 36.7% (95% CI = 36.7-36.7) of hospitalizations included off-label analgesic therapy, with 26.4% (95% CI = 26.4-26.5) associated with two or more off-label analgesics. Off-label analgesic use was higher among hospitalizations in the intensive care unit (61.5%) or with an operating room procedure (92.8%). Rates of off-label prescribing increased with age, peaking at 50.5% for adolescents. Prescription analgesics administered most frequently were morphine, fentanyl, and ketorolac, with off-label use occurring in 24.5%, 23.1%, and 11.3% of hospitalizations, respectively. CONCLUSIONS: Over a third of pediatric hospitalizations were associated with the administration of prescription analgesics that have not been labeled for use in children. Our findings highlight the critical need to ensure that safe and effective analgesics are developed for children and that pediatric labeling is expanded for existing analgesics to inform treatment decisions.

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.

BACKGROUND: Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. METHODS: To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. RESULTS: By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients. CONCLUSIONS: Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

Initial Pain Management in Pediatric Acute Pancreatitis: Opioid Versus Non-opioid.

Nearly all patients with acute pancreatitis (AP) experience some degree of abdominal pain that is severe enough to prompt medical evaluation and necessitate analgesia. Effective analgesia is a priority in caring for such patients. Despite its importance, strategies for pain management in AP have been poorly studied, particularly in the field of pediatrics. Presently, no published data examine the management of pain because of AP in children at the time of initial presentation. Management approaches are often extrapolated from adult practice and based on anecdotal experience in the absence of objective data. The aim of our study was to examine the initial provision of analgesia to children who presented to a pediatric emergency department with AP.

Pharmacist Outpatient Prescription Review in the Emergency Department: A Pediatric Tertiary Hospital Experience.

OBJECTIVES: This study aimed to assess the frequency, type, and potential severity of errors intercepted by pharmacists on review of discharge prescriptions in a pediatric emergency department (ED). METHODS: This was a retrospective, observational study conducted in the ED of a pediatric teaching hospital. A daily report of prescriptions from the previous day was reviewed by a pharmacist for safety and efficacy. If an intervention was deemed necessary, the prescriber was contacted for clarification. In situations where patient harm could occur, the physician performing follow-ups was contacted by phone. The interventions were categorized based on type and potential severity. Physician response rates and intervention acceptance rates were assessed. RESULTS: Approximately 23,600 prescriptions were reviewed during a 1-year period with 60 interventions (0.25% intervention rate). Of the 60 interventions, 3% were estimated to have no severity, 80% were estimated to have minor, 12% moderate, and 5% major potential severity. The most common types of interventions were optimization of therapy, drug overdose, or dose omission at 33%, 32%, and 14%, respectively. Eighty-five percent of physicians responded; 73% accepted the intervention whereas 27% provided a rationale for their decision. More importantly, valuable information was gained, allowing for implementation of system fixes to prevent future errors. On an average, pharmacists spent 45 minutes reviewing and clarifying prescriptions each day. CONCLUSIONS: Pharmacists in the ED can provide a valuable service by reviewing discharge prescriptions. A small amount of time dedicated to this service can lead to detection of clinically significant preventable medication errors and optimization of prescription therapy.

Lacerations and Embedded Needles Caused by Epinephrine Autoinjector Use in Children.

STUDY OBJECTIVE: Epinephrine autoinjector use for anaphylaxis is increasing. There are reports of digit injections because of incorrect autoinjector use, but no previous reports of lacerations, to our knowledge. We report complications of epinephrine autoinjector use in children and discuss features of these devices, and their instructions for use, and how these may contribute to injuries. METHODS: We queried emergency medicine e-mail discussion lists and social media allergy groups to identify epinephrine autoinjector injuries involving children. RESULTS: Twenty-two cases of epinephrine autoinjector-related injuries are described. Twenty-one occurred during intentional use for the child's allergic reaction. Seventeen children experienced lacerations. In 4 cases, the needle stuck in the child's limb. In 1 case, the device lacerated a nurse's finger. The device associated with the injury was operated by health care providers (6 cases), the patient's parent (12 cases, including 2 nurses), educators (3 cases), and the patient (1 case). Of the 3 epinephrine autoinjectors currently available in North America, none include instructions to immobilize the child's leg. Only 1 has a needle that self-retracts; the others have needles that remain in the thigh during the 10 seconds that the user is instructed to hold the device against the leg. Instructions do not caution against reinjection if the needle is dislodged during these 10 seconds. CONCLUSION: Epinephrine autoinjectors are lifesaving devices in the management of anaphylaxis. However, some have caused lacerations and other injuries in children. Minimizing needle injection time, improving device design, and providing instructions to immobilize the leg before use may decrease the risk of these injuries.

Electronic medication reconciliation and medication errors.

OBJECTIVE: To measure the impact of electronic medication reconciliation implementation on reports of admission medication reconciliation errors (MREs). DESIGN: Quality improvement project with time-series design. SETTING: A large, urban, tertiary care children's hospital. PARTICIPANTS: All admitted patients from 2011 and 2012. INTERVENTIONS: Implementation of an electronic medication reconciliation tool for hospital admissions and regular compliance reporting to inpatient units. The tool encourages active reconciliation by displaying the pre-admission medication list and admission medication orders side-by-side. MAIN OUTCOME MEASURE: Rate of non-intercepted admission MREs identified via a voluntary reporting system. RESULTS: During the study period, there were 33 070 hospital admissions. The pre-admission medication list was consistently recorded electronically throughout the study period. In the post-intervention period, the use of the electronic medication reconciliation tool increased to 84%. Reports identified 146 admission MREs during the study period, including 95 non-intercepted errors. Pre- to post-intervention, the rate of non-intercepted errors decreased by 53% (P = 0.02). Reported errors were categorized as intercepted potential adverse drug events (ADEs) (35%), non-intercepted potential ADEs (42%), minor ADEs (22%) or moderate ADEs (1%). There were no reported MREs that resulted in major or catastrophic ADEs. CONCLUSIONS: We successfully implemented an electronic process for admission medication reconciliation, which was associated with a reduction in reports of non-intercepted admission MREs.

Utility of a dedicated pediatric cardiac anticoagulation program: the Boston Children's Hospital experience.

Congenital heart disease is the leading cause of stroke in children. Warfarin therapy can be difficult to manage safely in this population because of its narrow therapeutic index, multiple drug and dietary interactions, small patient size, high-risk cardiac indications, and lack of data to support anticoagulation recommendations. We sought to describe our institution's effort to develop a dedicated cardiac anticoagulation service to address the special needs of this population and to review the literature. In 2009, in response to Joint Commission National Patient Safety Goals for Anticoagulation, Boston Children's Hospital created a dedicated pediatric Cardiac Anticoagulation Monitoring Program (CAMP). The primary purpose was to provide centralized management of outpatient anticoagulation to cardiac patients, to serve as a disease-specific resource to families and providers, and to devise strategies to evolve clinical care with rapidly emerging trends in anticoagulation care. Over 5 years the CAMP Service, staffed by a primary pediatric cardiology attending, a full-time nurse practitioner, and administrative assistant with dedicated support from pharmacy and nutrition, has enrolled over 240 patients ranging in age from 5 months to 55 years. The most common indications include a prosthetic valve (34 %), Fontan prophylaxis (20 %), atrial arrhythmias (11 %), cardiomyopathy (10 %), Kawasaki disease (7 %), and a ventricular assist device (2 %). A patient-centered multi-disciplinary cardiac anticoagulation clinic was created in 2012. Overall program international normalized ratio (INR) time in therapeutic range (TTR) is favorable at 67 % (81 % with a 0.2 margin) and has improved steadily over 5 years. Pediatric-specific guidelines for VKOR1 and CYP2C9 pharmacogenomics testing, procedural bridging with enoxaparin, novel anticoagulant use, and quality metrics have been developed. Program satisfaction is rated highly among families and providers. A dedicated pediatric cardiac anticoagulation program offers a safe and effective strategy to standardize anticoagulation care for pediatric cardiology patients, is associated with high patient and provider satisfaction, and is capable of evolving care strategies with emerging trends in anticoagulation.

Dispensing Medications at the Hospital Upon Discharge From an Emergency Department.

Although most health care services can be provided in the medical home, children will be referred or require visits to the emergency department (ED) for a variety of conditions ranging from nonurgent to emergent. Continuation of medical care after discharge from an ED is dependent on parents or caregivers' understanding of follow-up instructions and adherence to medication administration recommendations. Barriers to obtaining medications after ED visits include lack of access because of pharmacy hours, affordability, and lack of understanding the importance of medication as part of treatment. ED visits often occur at times when community-based pharmacies are closed. Caregivers are typically concerned with getting their ill or injured child directly home once discharged from the ED. Approximately one-third of patients fail to obtain priority medications from a pharmacy after discharge from an ED. The option of judiciously dispensing medications at ED discharge from the outpatient pharmacy within the health care facility is a major convenience that helps to overcome this obstacle, improving the likelihood of medication adherence. Emergency care encounters should routinely be followed by visits to the primary care provider medical home to ensure complete and comprehensive care.

Experience of pharmacy involvement in a disaster simulation exercise within a pediatric hospital emergency department: A pilot project.

PURPOSE: In this descriptive report, we describe a unique trial of pharmacist participation in a multidisciplinary pediatric emergency department disaster simulation exercise. With the number of disasters increasing worldwide, the role of pharmacists in disaster response is of particular interest to the profession. SUMMARY: This observational study describes pharmacist participation in a disaster simulation exercise. An evaluation tool was developed to assess participants' performance in the following domains: communication, pharmacotherapy, problem solving/decision making, and teamwork/organization. The observers used a rating scale of "concise/prompt," "needs improvement," or "not done" to evaluate performance on each objective. The participants' self-perceived knowledge of disaster response was assessed with pre- and postsimulation surveys using Likert scales. Five simulation exercises were held from June to October 2019, with 2 pharmacists participating in each simulation. Within the problem solving/decision making and communication domains, pharmacists were concise/prompt 66% of the time, while they were concise/prompt for 88.8% and 92.5% of tasks in the teamwork/organization and pharmacotherapy domains, respectively. Surveys of self-perceived knowledge revealed that while only 10% of pharmacists felt "moderately prepared" prior to the simulation exercise, 80% of pharmacists felt moderately prepared to care for patients during a disaster event after the simulation exercise. CONCLUSION: This report describes a unique approach of including emergency department-trained pharmacists in disaster simulation exercises to enhance their professional development, improve team dynamics in a mass casualty scenario, and increase their own reported level of preparedness to effectively manage a surge in critically ill pediatric patients.

Adverse drug event presentation and tracking (ADEPT): semiautomated, high throughput pharmacovigilance using real-world data.

OBJECTIVE: To advance use of real-world data (RWD) for pharmacovigilance, we sought to integrate a high-sensitivity natural language processing (NLP) pipeline for detecting potential adverse drug events (ADEs) with easily interpretable output for high-efficiency human review and adjudication of true ADEs. MATERIALS AND METHODS: The adverse drug event presentation and tracking (ADEPT) system employs an open source NLP pipeline to identify in clinical notes mentions of medications and signs and symptoms potentially indicative of ADEs. ADEPT presents the output to human reviewers by highlighting these drug-event pairs within the context of the clinical note. To measure incidence of seizures associated with sildenafil, we applied ADEPT to 149 029 notes for 982 patients with pediatric pulmonary hypertension. RESULTS: Of 416 patients identified as taking sildenafil, NLP found 72 [17%, 95% confidence interval (CI) 14-21] with seizures as a potential ADE. Upon human review and adjudication, only 4 (0.96%, 95% CI 0.37-2.4) patients with seizures were determined to have true ADEs. Reviewers using ADEPT required a median of 89 s (interquartile range 57-142 s) per patient to review potential ADEs. DISCUSSION: ADEPT combines high throughput NLP to increase sensitivity of ADE detection and human review, to increase specificity by differentiating true ADEs from signs and symptoms related to comorbidities, effects of other medications, or other confounders. CONCLUSION: ADEPT is a promising tool for creating gold standard, patient-level labels for advancing NLP-based pharmacovigilance. ADEPT is a potentially time savings platform for computer-assisted pharmacovigilance based on RWD.

Adverse drug event rates in pediatric pulmonary hypertension: a comparison of real-world data sources.

OBJECTIVE: Real-world data (RWD) are increasingly used for pharmacoepidemiology and regulatory innovation. Our objective was to compare adverse drug event (ADE) rates determined from two RWD sources, electronic health records and administrative claims data, among children treated with drugs for pulmonary hypertension. MATERIALS AND METHODS: Textual mentions of medications and signs/symptoms that may represent ADEs were identified in clinical notes using natural language processing. Diagnostic codes for the same signs/symptoms were identified in our electronic data warehouse for the patients with textual evidence of taking pulmonary hypertension-targeted drugs. We compared rates of ADEs identified in clinical notes to those identified from diagnostic code data. In addition, we compared putative ADE rates from clinical notes to those from a healthcare claims dataset from a large, national insurer. RESULTS: Analysis of clinical notes identified up to 7-fold higher ADE rates than those ascertained from diagnostic codes. However, certain ADEs (eg, hearing loss) were more often identified in diagnostic code data. Similar results were found when ADE rates ascertained from clinical notes and national claims data were compared. DISCUSSION: While administrative claims and clinical notes are both increasingly used for RWD-based pharmacovigilance, ADE rates substantially differ depending on data source. CONCLUSION: Pharmacovigilance based on RWD may lead to discrepant results depending on the data source analyzed. Further work is needed to confirm the validity of identified ADEs, to distinguish them from disease effects, and to understand tradeoffs in sensitivity and specificity between data sources.

Pharmacogenomic Primer for the Pediatrician-What Is Really Important?

Safe prescribing of medications has become increasingly challenging with dozens of new drugs and drug classes added each year. Maximizing the ability to find a medication that will work as intended while minimizing side effects can be difficult, particularly when a patient does not respond as expected. Some of the variability in response may be attributed to the patient's genetics. Pharmacogenomics is the science of examining a patient's genotype in the context of medication selection and dosing. Used correctly, the clinical application of pharmacogenomic data can be useful in decreasing the trial and error approach to medication therapy. [Pediatr Ann. 2018;47(5):e217-e219.].

HLA-A*31:01 and Oxcarbazepine-Induced DRESS in a Patient With Seizures and Complete DCX Deletion.

Oxcarbazepine is an antiepileptic drug (AED) commonly used as a first-line treatment option for focal epilepsy. Several AEDs, including carbamazepine, oxcarbazepine, and phenytoin are associated with various delayed-hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, or toxic epidermal necrolysis. The Food and Drug Administration-approved label for oxcarbazepine currently presents information regarding a pharmacogenomic association with the HLA antigen allele HLA-B*15:02 and hypersensitivity reactions in certain ancestry groups with a high incidence of this allele. However, unlike carbamazepine, screening for the presence of this allele is not routinely recommended before administration of oxcarbazepine. In practice, even with carbamazepine, HLA antigen testing is not always performed before initiating treatment because of lack of physician awareness of the recommendations and because of the desire to initiate treatment without delay. We present the clinical course of a pediatric patient with focal epilepsy refractory to several AEDs who developed drug reaction with eosinophilia and systemic symptoms after oxcarbazepine administration. The pharmacogenomic testing for various HLA antigen alleles was performed post hoc, and results were evaluated for structural similarities between AEDs and their molecular associations with HLA antigen proteins. In addition, we review the population-wide prevalence of various hypersensitivity reactions to AEDs and associated HLA antigen alleles. Finally, we discuss the potential utility of preemptive pharmacogenomic screening of patients before pharmacological treatment of epilepsy to assess the risk of developing hypersensitivity reactions.

Creating a scalable clinical pharmacogenomics service with automated interpretation and medical record result integration - experience from a pediatric tertiary care facility.

OBJECTIVE: This paper outlines the implementation of a comprehensive clinical pharmacogenomics (PGx) service within a pediatric teaching hospital and the integration of clinical decision support in the electronic health record (EHR). MATERIALS AND METHODS: An approach to clinical decision support for medication ordering and dispensing driven by documented PGx variant status in an EHR is described. A web-based platform was created to automatically generate a clinical report from either raw assay results or specified diplotypes, able to parse and combine haplotypes into an interpretation for each individual and compared to the reference lab call for accuracy. RESULTS: Clinical decision support rules built within an EHR provided guidance to providers for 31 patients (100%) who had actionable PGx variants and were written for interacting medications. A breakdown of the PGx alerts by practitioner service, and alert response for the initial cohort of patients tested is described. In 90% (355/394) of the cases, thiopurine methyltranferase genotyping was ordered pre-emptively. DISCUSSION: This paper outlines one approach to implementing a clinical PGx service in a pediatric teaching hospital that cares for a heterogeneous patient population. There is a focus on incorporation of PGx clinical decision support rules and a program to standardize report text within the electronic health record with subsequent exploration of clinician behavior in response to the alerts. CONCLUSION: The incorporation of PGx data at the time of prescribing and dispensing, if done correctly, has the potential to impact the incidence of adverse drug events, a significant cause of morbidity and mortality.