The aim of this review is to present the information a clinician will need when considering alpelisib therapy for a patient diagnosed with PIK3CA-related overgrowth spectrum (PROS). PROS is a condition caused by a somatic recessive gain-of-function mutation in the gene encoding phosphatidylinositol-3-kinase (PI3K). PROS is rare, affecting approximately 14 births per 1 million. PROS affects many different tissues including skin, bone, vascular, adipose, and connective tissues, thus its presentations vary widely. The presentation of PROS is often described as mosaic, as the disease typically does not affect all cells in the body. For patients two years of age and older requiring systemic therapy, alpelisib is an option which was recently granted accelerated approval by the US Food and Drug Administration (FDA) on April 5, 2022. Alpelisib is an inhibitor of PI3K, slowing the progression of existing lesions and preventing new lesions in patients with PROS. Important drug interactions exist with both CYP3A4 inducers and CYP2C9 substrates. Additionally, providers of patients receiving alpelisib should be aware of potential side effects including hypersensitivity, severe cutaneous adverse reactions, hyperglycemia, pneumonitis, diarrhea, and embryo-fetal toxicity. Despite the potential for adverse events, alpelisib has provided clinical benefit to many patients with PROS as evidenced by the current literature. This review collects and summarizes the currently available evidence, including a recently published case series and multiple case reports. Alpelisib is a promising new option for patients with PROS.
With a limited number of child and adolescent psychiatrists available to see youth patients, many common psychiatric problems in youth are managed by other providers. Clinical pearls from experts in child and adolescent psychiatry can help general practitioners with this management. Some common issues are discussed here for which practical guidance is offered, ranging from approaches to assessment and how to start and titrate medications for the treatment of attention deficit hyperactivity disorder, depression, and sleep problems.
Therapeutic drug monitoring in pediatric inflammatory bowel disease (IBD) has been used to achieve and maintain remission. Few guidelines exist to aid clinicians in the adjustment of anti–tumor necrosis factor therapies. The objective was to assess the agreement between real-world postinduction and posteriori analysis of retrospective data, using 2 novel pharmacokinetic (PK) models for adalimumab. A retrospective chart review was conducted in pediatric IBD patients treated with adalimumab. A Bayesian clinical decision support tool (InsightRX) was used. Postinduction serum concentration measurements of adalimumab were performed by drug-tolerant, homogenous shift mobility assay. Predicted serum adalimumab concentrations from both models were compared to the actual serum concentrations through a Bland-Altman analysis. Paired sample t test was used for equivalence. A total of 47 patients were included. Forty-one patients (87%) had Crohn disease, and 30 (64%) were male. Most were induced with 160 mg of adalimumab and maintained on 40 mg biweekly. No significant difference resulted between the de Klaver average prediction and mean population concentration (p = 0.294). Significant difference was observed between Ternant and mean population serum adalimumab concentration (p < 0.001). The Bland-Altman plot for the de Klaver method showed no proportional bias. Additionally, 49% of patients required a dose adjustment during maintenance therapy. The de Klaver model was able to provide less bias than the Ternant model and may aid in predicting serum adalimumab concentrations. Approximately half of the patients required dose adjustment during maintenance therapy to obtain a therapeutic drug concentration or achieve clinical remission.OBJECTIVES
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Provision of pulmonary blood flow with a systemic-to–pulmonary artery shunt is essential in some patients with cyanotic congenital heart disease. Traditionally, aspirin (ASA) has been used to prevent thrombosis. We evaluated ASA dosing with 2 separate antiplatelet monitoring tests for accuracy and reliability. This is a retrospective, pre-post intervention single center study. Two cohorts were evaluated; the pre-intervention group used thromboelastography platelet mapping (TPM) and post-intervention used VerifyNow aspirin reactivity unit (ARU) monitoring. The primary endpoint was to compare therapeutic effect of TPM and ARU with regard to platelet inhibition. Inadequate platelet inhibition was defined as TPM <50% inhibition and ARU >550. Data from 49 patients were analyzed: 25 in the TPM group and 24 in the ARU group. Baseline characteristics were similar amongst the cohorts. The TPM group had significantly more patients with inadequate platelet inhibition (14 [56%] vs 2 [8%]; p = 0.0006) and required escalation with additional thromboprophylaxis (15 [60%] vs 5 [21%]). There was no difference in shunt thrombosis (1 [2%] vs 0 [0%]; p = 0.32), cyanosis requiring early re-intervention (9 [36%] vs 14 [58%]; p = 0.11), or bleeding (15 [60%] vs 14 [58%]; p = 0.66). With similar cohorts and the same ASA-dosing nomogram, ARU monitoring resulted in a reduced need for escalation of care and concomitant thromboprophylaxis with no difference in adverse outcomes. Our study suggests ARU monitoring compared with TPM may be a more reliable therapeutic platelet inhibition test for determining ASA sensitivity in children with congenital heart disease requiring systemic-to–pulmonary artery shunt.OBJECTIVES
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Limited data exist comparing indomethacin and ibuprofen for the treatment of patent ductus arteriosus (PDA). The objective was to compare the safety and efficacy of indomethacin and ibuprofen for treatment of PDA closure. This single-center, pre-test/post-test quasi-experiment included preterm infants admitted to the neonatal intensive care unit who received indomethacin (July 1, 2013–September 30, 2015) or ibuprofen (December 1, 2015–July 31, 2019) for PDA. Patients were excluded if they were thrombocytopenic, had existing kidney injury, unresolved intraventricular hemorrhage (IVH) or necrotizing enterocolitis (NEC) at treatment initiation. Data were obtained from the electronic health record. Study outcomes were complete PDA closure, degree of PDA closure, resolution of symptoms, and new-onset acute kidney injury (AKI), IVH, or NEC. A total of 114 patients were included: 44 (39%) received indomethacin and 70 (61%) received ibuprofen. Twenty-one (21%) patients experienced successful PDA closure within 1 week: 13 (32%) indomethacin patients and 8 (13%) ibuprofen patients (p = 0.023). PDA size reduction occurred in 43 (46%) patients with 29 (25%) experiencing complete symptom resolution. Significantly more indomethacin patients compared with ibuprofen patients experienced new-onset AKI (48% vs 17%; p < 0.001) and received concomitant nephrotoxins (68% vs 39%; p = 0.002). There were no significant differences in new-onset IVH or NEC. Indomethacin administration successfully closed the PDA in more neonates than ibuprofen but resulted in higher rates of AKI. However, this was confounded by more frequent administration of concomitant nephrotoxins. Larger trials are needed to help elucidate the optimal drug for closure of the PDA in neonates.OBJECTIVE
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Preterm newborns (PTNBs) often require sedation and analgesia. Dexmedetomidine (DEX) is used to provide sedation in extremely PTNBs, even though information on such use is limited. The objective of this research is to describe the use of DEX in these patients in a single academic center. This is a retrospective study of PTNBs receiving DEX from January 1, 2010, through December 31, 2018, at the Cleveland Clinic Children’s Hospital, a tertiary academic center operating 2 Level III and 1 Level IV neonatal intensive care units (NICUs). Inclusion criteria were gestational age (GA) <36 weeks and receipt of DEX for >2 days. Adequacy of clinical response was based on achieving Neonatal Pain, Agitation and Sedation Scale (N-PASS) scores <3. Hypotension, bradycardia, and respiratory depression were recorded as the incidence as adverse events. A total of 105 patients were included. The birth weight median was 870 g (IQR, 615–1507); the GA median was 26 weeks (IQR, 24–31). The duration of DEX infusion averaged 7 days. The DEX dose averaged 0.4 mcg/kg (IQR, 0.3–0.45). Bradycardia was observed in 35 patients (57%) weighting <1 kg and in 7 patients (18%) >1 kg (p < 0.01). There was no difference in the incidence of other adverse events between these groups. However, infants <1 kg required more pharmacologic interventions to maintain N-PASS score <3. DEX was well tolerated overall and provided adequate sedation to PTNBs in this cohort. From this study, we recommend a starting dose of 0.2 to 0.4 mcg/kg/hr and titrating up hourly until adequate sedation is achieved.OBJECTIVE
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Sleep deprivation is a risk factor for delirium development, which is a frequent complication of intensive care unit admission. Melatonin has been used for both delirium prevention and treatment. Melatonin safety, efficacy, and dosing information in neonates and infants is lacking. The purpose of this study was to describe melatonin use in infants regarding indication, dosing, efficacy, and safety. This descriptive, retrospective study included infants <12 months of age admitted to an intensive care unit receiving melatonin. Data collection included demographics, melatonin regimen, sedative and analgesic agents, antipsychotics, and delirium-causing medications. The primary objective was to identify the melatonin indication and median dose. The secondary objectives included change in delirium, pain, and sedation scores; change in dosing of analgesic and sedative agents; and adverse event identification. Wilcoxon signed rank tests and linear mixed models were employed with significance defined at p < 0.05. Fifty-five patients were included, with a median age of 5.5 months (IQR, 3.9–8.2). Most (n = 29; 52.7%) received melatonin for sleep promotion. The median body weight–based dose was 0.31 mg/kg/dose (IQR, 0.20–0.45). There was a statistical reduction in cumulative morphine equivalent dosing 72 hours after melatonin administration versus before, 17.1 versus 21.4 mg/kg (p = 0.049). No adverse events were noted. Most patients (n = 29; 52.7%) received melatonin for sleep promotion at a median dose was 0.31 mg/kg/dose. Initiation of melatonin was associated with a reduction of opioid exposure; however, there was no reduction in pain/sedation scores.OBJECTIVES
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Etoposide, a topoisomerase II inhibitor used clinically to treat cancer, has been associated with severe anaphylactic infusion related adverse drug reactions (ADRs). In a previous study we identified a hydrophilic polyethersulfone filter as a possible cause of increased rates of pediatric etoposide infusion reactions. In this multidisciplinary follow-up analytical study, we aimed to assess the chemical structure of etoposide after passing through the same hydrophilic polyethersulfone filter. An etoposide 0.4 mg/mL infusion was prepared under aseptic conditions and then passed through a standard IV infusion set with an in-line filter in place. Samples were taken in triplicate using a needle-less access system to include sampling sites directly from the IV bag port and from the IV tubing both before and after the in-line filter. Samples were diluted into mobile phase, then an aliquot was injected into a high-performance liquid chromatography mass spectrometry HPLC-MS (Thermo TSQ Quantum Ultra) system coupled to a Diode Array Detector (DAD) (Thermo Dionex Ultimate 3000). Etoposide was monitored using a selected reaction monitoring scan (SRM) of 606.2/228.8 and wavelengths of 210, 220, 254, and 280 nm for 30 minutes. No detectable differences were observed upon comparing the three samples. Based on these results, a chemical change in etoposide resulting from an in-line filter is unlikely to be the primary cause of increased rates of infusion reactions. Pharmacists working in healthcare systems, observe many ADRs, but rarely have the resources necessary to investigate the potential etiology or causality. This report highlights importance of multi-disciplinary collaboration to investigate serious ADRs.PURPOSE
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The objective was to complete a single hospital quality assessment to characterize the use, safety, and outcomes of the 5 specialty medications (infliximab, adalimumab, tofacitinib, ustekinumab, and vedolizumab) used for the treatment of pediatric inflammatory bowel disease following admission due to a disease flare. This was a single-center, retrospective, quality assessment of the current clinical practice. The electronic medical record was queried to identify patients ages 0 to 18 years admitted to our institution during a 2-year period from September 1, 2019, to September 30, 2021, who received infliximab, adalimumab, tofacitinib, ustekinumab, and/or vedolizumab for the treatment of Crohn’s disease or ulcerative colitis followed by manual data collection and cohort analysis. The total population comprised 20 patients during 23 encounters. The biologic-naive group included 12 patients during 12 encounters, 2 of which are also included in the biologic-experienced group, which captured a total of 10 patients during 11 encounters. In the biologic-naive group, infliximab monotherapy comprised the largest percentage of therapy plans across encounters (91.6%), with a statistically significant greater number of readmissions within 6 months of discharge (p = 0.00031). The biologic-experienced cohort had a statistically significant longer duration of intravenous corticosteroid administration (p = 0.016) and a large variety of therapy plans. The diversity of practice observed within our institution supports the need for guidelines to define standard of therapy or guide selection of second-line therapies based on patient-specific factors.OBJECTIVES
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Midazolam is a commonly used, well-tolerated, anxiolytic, sedative, anesthesia induction agent, and an adjunct for procedural sedation that is used widely in the emergency department. The ability to administer midazolam via multiple routes, including intranasal, makes it a particularly common choice for use in children. Intranasal administration is safe, easy, and well tolerated and has been shown to be an effective method of obtaining anxiolysis and/or sedation. Adverse drug reactions, including allergic reactions, can occur with any medication. However, anaphylaxis is an uncommon phenomenon from midazolam. Despite being one of the most common medications used in the emergency department and operating room, there are only a handful of unequivocal cases of anaphylaxis secondary to midazolam. The rarity of this presentation may lead to delays in care and potential adverse outcomes as a result. We present one such case of a 10-year-old patient who experienced anaphylaxis after administration of intranasal midazolam to facilitate a computed tomography scan.
We present a case of bidirectional ventricular tachycardia in a 15-year-old boy asymptomatic for arrhythmias, whose major complaint was muscle weakness. At our first evaluation he was receiving sotalol for his ventricular arrhythmias. In addition to bidirectional tachycardia, electrocardiogram during sinus rhythm showed prominent U waves and prolonged QT-U interval. These electrocardiographic signs, along with the evidence of clinodactyly and mild hypertelorism, led us to the diagnosis of Andersen-Tawil syndrome, confirmed by genetic analysis that revealed a “de novo” missense mutation of KCNJ2 gene. Monotherapy with flecainide was rapidly effective and almost eliminated ventricular arrhythmias. After a 4-year follow-up there were no adverse events, flecainide has been well tolerated without significant modification of the QRS or repolarization, and ventricular arrhythmias have not been relapsed to date. The case highlights the importance of a correct clinical diagnosis, which is crucial for the optimal selection of the most appropriate drug therapy, which is expected not to be harmful, before being beneficial.
Bradycardic Arrest in a Child with Complex Congenital Heart Disease Due to Sugammadex Administration
The neuromuscular blocking drugs rocuronium and vecuronium are often used during general anesthesia. These drugs temporarily paralyze the patient and thus both facilitate placement of an endotracheal tube and prevent any patient movement during surgery. Reversal of neuromuscular blockade is necessary at the end of surgery to avoid postoperative weakness and adverse respiratory events in the recovery room. Neostigmine, the traditional reversal agent, may not completely restore muscle strength. Sugammadex is a reversal agent that is more effective and quicker acting than neostigmine. In adults, sugammadex administration has rarely been associated with bradycardia and cardiac arrest. In healthy children, the bradycardia that occurs after sugammadex administration is benign and does not require intervention. There is 1 case report of a 10- to 15-second bradycardic arrest after sugammadex administration to a 10-year-old child with heart disease. The present case report describes an 8-month-old child with complex congenital heart disease who experienced a 10-minute bradycardic arrest after the administration of sugammadex. Pediatric anesthesiologists should be aware that sugammadex administration to children with heart disease may cause hemodynamically significant bradycardia.
Chemotherapies and biologic agents are known to cause hypersensitivity reactions (HSRs). It is imperative that pediatric patients receive these agents to treat their cancer or other rare condition, as oftentimes there are no available therapeutic alternatives. Successful medication desensitization has been described previously with a 12-step method using 3 intravenous (IV) infusion bags of varying concentrations. However, this 12-step process is time and resource intensive and increases the risk for medication errors. A recent study successfully used a simplified 12-step method with a single IV infusion bag for a paclitaxel desensitization. From the results of this study, our institution used this single IV infusion bag method for desensitization with 3 different medications. Two of these experiences were successful. We share those 3 experiences in this report.
The American Academy of Pediatrics (AAP) recommends Vitamin K prophylaxis to all newborns irrespective of their gestational age.1 The recommended dose of Vitamin K for infants less than 1500 g is 0.3 to 0.5 mg/kg. The commercially manufactured Vitamin K is available as a single-use 1 mg/0.5 mL concentration. Dosage forms include an ampule, vial (manufactured by Hospira, Inc, Lake Forest, IL), or a prefilled syringe (Prefilled Syringe with safety device (Saf-T-Jet) International Medication Systems, Ltd, South El Monte, CA, An Amphastar Pharmaceuticals Company; See Supplemental Figure). The advantage of the prefilled syringe is that it