Pharmacologic Treatment for Pediatric Gastroparesis: A Review of the Literature

There have been a number of agents that have been tried for treatment of gastroparesis over the past 3 decades, with varying levels of success. Guidelines exist for the management of gastroparesis in adults; however, even though the cause of gastroparesis in children is similar to that in adults, no guidelines exist for treating pediatric gastroparesis as studies on the topic are limited. With what little information we have on pediatric gastroparesis, medications used in children's studies do not seem to demonstrate the same results as in adult patients with gastroparesis; thus, future studies of whether certain medications are effective for treating pediatric gastroparesis and at what dose still need to be conducted. Pharmacological treatment options for pediatric gastroparesis do not show a clear correlation of resolving or even maintaining gastroparesis-associated symptoms or disease state. This article reviews the available studies of drugs that have shown some efficacy, with an emphasis on pediatric studies

Evaluating and Mitigating Risk of Acute Kidney Injury with the Combination of Vancomycin and Piperacillin-Tazobactam in Children

The antibiotic combination of vancomycin (VAN) and piperacillin-tazobactam (PTZ) has been associated with an increased risk of acute kidney injury (AKI) in both adult and pediatric patients. In this review, we highlight some of the limitations of existing pediatric studies evaluating the combination of VAN/PTZ, focusing on AKI risk in specific pediatric patient populations. We also review the variability in defining AKI in children and provide guidance to clinicians for use of prospective surveillance and stewardship in mitigating the risk of AKI in pediatric patients treated with combination of VAN/PTZ. Based on review of available pediatric studies, if the combination of VAN/PTZ is selected as an empirical antibiotic combination, it should be used in those at low risk for AKI and should be used with extreme caution in patients with additional nephrotoxic risks. Systems should be in place to monitor the use of VAN/PTZ and associated renal function in those receiving this antibiotic combination

Nephrotoxicity in a Patient With Inadequate Pain Control: Potential Role of Pharmacogenetic Testing for Cytochrome P450 2D6 and Apolipoprotein L1

A case is presented which demonstrates the perils of opioid inefficacy and how pharmacogenomic testing may have prevented nonsteroidal anti-inflammatory drug (NSAID)-induced nephrotoxicity and progression to chronic kidney disease (CKD). A 62 year-old female with back pain was treated with tramadol and hydrocodone; however, neither proved effective. Consequently, to control her pain, she resorted to cocaine, marijuana, and high dose nonsteroidal anti-inflammatory drugs (NSAIDs). She eventually developed CKD. To identify CKD contributors, she underwent genotyping for Apolipoprotein L1 (APOL1), a known risk factor of CKD, as well as relevant pharmacogenomic genes. Her APOL1 genotype was *G1(GM)/*G1(GM), placing her at increased risk of CKD progression. Her CYP2D6 genotype was *5/*17, consistent with intermediate metabolism, making opioid drugs reliant on CYP2D6 activation, such as tramadol and hydrocodone, relatively ineffective in this patient. Thus, this patient was at genetic risk for CKD and reduced opioid efficacy. We conclude that this genetic combination likely contributed to opioid inefficacy and the eventual progression to CKD

Enhancing Pediatric Adverse Drug Reaction Documentation in the Electronic Medical Record

Adverse drug reactions (ADRs) often go unreported or are inaccurately documented in the electronic medical recorded (EMR), even when they are severe and life-threatening. Incomplete reporting can lead to future prescribing challenges and ADR reoccurrence. The aim of this study was to evaluate the documentation of ADRs within the EMR and determine specific factors associated with appropriate and timely ADR documentation. Retrospective data were collected from a pediatric hospital system ADR reports from October 2010 to November 2018. Data included implicated medication, type, and severity of reaction, treatment location, the presence or absence of ADR documentation in the EMR alert profile within 24 hours of the ADR hospital or clinic encounter discharge, ADR identification method, and the presence or absence of pharmacovigilance oversight at the facility where the ADR was treated. A linear regression model was applied to identify factors contributing to optimal ADR documentation. A total of 3065 ADRs requiring medical care were identified. Of these, 961 ADRs (31%) did not have appropriate documentation added to the EMR alert profile prior to discharge. ADRs were documented in the EMR 87% of the time with the presence of pharmacovigilance oversight and only 61% without prospective pharmacovigilance (P < .01). Severity of ADR was not a predictor of ADR documentation in the EMR, yet the implicated medication and location of treatment did impact reporting. An active pharmacovigilance service significantly improved pediatric ADR documentation. Further work is needed to assure timely, accurate ADR documentation

A pilot study of ADRA2A genotype association with doses of dexmedetomidine for sedation in pediatric patients.

STUDY OBJECTIVE: Dexmedetomidine is titrated to achieve sedation in the pediatric and cardiovascular intensive care units (PICU and CVICU). In adults, dexmedetomidine response has been associated with an ADRA2A polymorphism (rs1800544); CC genotype is associated with an increased sedative response compared with GC and GG. To date, this has not been studied in children. DESIGN: We conducted a pilot study to determine whether ADRA2A genotype is associated with dexmedetomidine dose in children. MEASUREMENTS AND MAIN RESULTS: Forty intubated PICU or CVICU patients who received dexmedetomidine as a continuous infusion for at least 2 days were genotyped for ADRA2A with a custom-designed TaqMan® Assay. Ten (25%) subjects were wildtype (GG), 15 (37.5%) were heterozygous (GC), and 15 (37.5%) were homozygous (CC) variant. The maximum dexmedetomidine doses (mCg/kg/h) were not different between genotype groups CC (1, 0.3-1.2), GC (1, 0.3-1.3), and GG (0.8, 0.3-1.2), (p = 0.37); neither were mean dexmedetomidine doses for these respective genotype groups 0.68 (0.24-1.07), 0.72 (0.22-0.98), 0.58 (0.3-0.94), (p = 0.67). CONCLUSIONS: These findings did not confirm the results from adult studies where ADRA2A polymorphisms correlate with dexmedetomidine response, therefore highlighting the need for pediatric studies to validate PGx findings in adults prior to implementation in pediatrics

Associations between cannabis use, polygenic liability for schizophrenia, and cannabis-related experiences in a sample of cannabis users

BACKGROUND AND HYPOTHESIS: Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. STUDY DESIGN: We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). STUDY RESULTS: Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. CONCLUSIONS: Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use

Risks and mitigation strategies to prevent etoposide infusion-related reactions in children

Etoposide is an antineoplastic agent widely used for treatment of many pediatric cancers. Etoposide has been associated with infusion-related reactions. In this brief report, we compare etoposide infusion-related reactions that occurred over a 10-year period at two freestanding pediatric hospitals. Infusion reactions occurred in 1% of patients at two hospitals across the study period. Rates of 4.8%, 3.4%, and 7.9% were observed at Children's Mercy Hospital during 2018, 2019, and 2020, respectively, after the implementation of in-line filters during etoposide infusions in late 2017. Of the 32 patients who experienced adverse reactions, 41% were rechallenged after the reaction and all were able to tolerate at least one future dose with either pre-treatment or extending infusion duration. This work highlights the importance of a multicenter approach to investigating adverse drug reactions (ADRs) as variation in practice can provide key information about ADRs and potential risk factors

Variability of Dosing and Number of Medications Needed to Achieve Adequate Sedation in Mechanically Ventilated Pediatric Intensive Care Patients.

Children admitted to the pediatric intensive care unit (PICU) often require multiple medications to achieve comfort and sedation. Although starting doses are available, these medications are typically titrated to the desired effect. Both oversedation and undersedation are associated with adverse events. The aim of this retrospective study was to evaluate cumulative medication burden necessary to achieve comfort in patients in the PICU and determine relevant predictors of medication needs. In order to account for all of the sedative medications, z-scores were used to assess the population average dose of each medication and compare each patient day to this population average. Sedation regimens for 130 patients in the PICU were evaluated. Mean overall infusion rates of fentanyl, morphine, and hydromorphone were 1.67 ± 0.81 µg/kg/hour, 0.12 ± 0.08 mg/kg/hour, and 17.84 ± 13.4 µg/kg/hour, respectively. The mean infusion rate of dexmedetomidine was 0.59 ± 0.28 µg/kg/hour, and midazolam was 0.14 ± 0.1 mg/kg/hour. Summation z-sores were used to rank the amount of sedation medication needed to achieve comfort for each individual patient for his/her PICU stay in relation to the entire sample. Patient age, weight, and length of mechanical ventilation were all significant predictors of sedation requirement. This study will provide data necessary to develop a model of cumulative medication burden needed to achieve appropriate sedation in this population. This descriptive model in appropriately ranking patients based on sedative needs is the first step in exploring potential genetic factors that may provide an insight into homing in on the appropriate sedation regimen

Opportunity for pharmacogenomic testing in patients with cystic fibrosis

Background Patients with cystic fibrosis (CF) are exposed to many drugs in their lifetime and many of these drugs have Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines that are available to guide dosing. Contemporary CF treatments are targeted to specific mutations in the CF transmembrane conductance regulator (CFTR) gene, and thus, require patients to have genetic testing before initiation of modulator therapy. However, aside from CFTR genetic testing, pharmacogenomic testing is not standard of care for CF patients. Aim The aim of this study is to determine the number of non-CFTR modulator medications with CPIC guidelines that are prescribed to patients with CF. Materials & Methods We identified all patients with a diagnosis of CF and queried our hospital electronic medical records (EMR) for all orders, including inpatient and prescriptions, for all drugs or drug classes that have CPIC actionable guidelines for drug–gene pairs that can be used to guide therapy. Results We identified 576 patients with a diagnosis of CF that were treated at our institution during this 16-year period between June 2005 and May 2021. Of these patients, 504 patients (87.5%) received at least one drug that could have been dosed according to CPIC guidelines if pharmacogenomic results would have been available. Conclusions Patients with CF have high utilization of drugs with CPIC guidelines, therefore preemptive pharmacogenomic testing should be considered in CF patients at the time of CFTR genetic testing

Tracheal Aspirate as an Alternative Biologic Sample for Pharmacogenomics Testing in Mechanically Ventilated Pediatric Patients

Patients in the pediatric intensive care unit are exposed to multiple medications and are at high risk for adverse drug reactions. Pharmacogenomic (PGx) testing could help decrease their risk of adverse reactions. Although whole blood is preferred for PGx testing, blood volume in this population is often limited. However, for patients on mechanical ventilation, tracheal secretions are abundant, frequently suctioned, and discarded. Thus, the aim of this pilot study was to determine if tracheal aspirates could be used as a source of human genomic DNA for PGx testing. We successfully extracted DNA from tracheal secretions of all 23 patients in the study. The samples were successfully genotyped for 10 clinically actionable single nucleotide variants across 3 cytochrome P450 genes (CYP2D6, CYP2C19, and CYP3A5). Using DNA from whole blood samples in 11 of the patients, we confirmed the accuracy of the genotyping with 100% concordance. Therefore, our results support the use of tracheal aspirates from mechanically ventilated children as an adequate biospecimen for clinical genetic testing