Application In Pediatric Population Research Articles

Predicting mortality in pediatric sepsis: A nationwide data analysis using a pediatric sepsis surveillance method

IntroductionA sepsis surveillance method using electronic health records is increasingly used to describe the epidemiology of adult sepsis. However, its application in pediatric populations has been limited, and real-world epidemiology of pediatric sepsis remains unknown. We aimed to determine whether this surveillance method could identify children with sepsis at high-risk of mortality. Patients and methodsFrom a nationwide inpatient database in Japan, we included children who underwent blood culture and received antimicrobials for ≥ 4 days between 2014 and 2021. We stratified these children into those with sepsis or without sepsis by the presence of organ dysfunction. We evaluated the discrimination for in-hospital mortality by the sepsis diagnosis and the number of organ dysfunction. ResultsAmong 6553 eligible children, in-hospital mortality was 7.2 % in 875 children with sepsis and 0.2 % in 5678 children without sepsis. Sepsis diagnosis discriminated in-hospital mortality with a sensitivity of 0.84 and a specificity of 0.87. The area under the curve for mortality based on the number of organ dysfunction was 0.88 (95 % confidence interval:0.84 to 0.93). In-hospital mortality incrementally increased with the number of organ dysfunction; zero, 0.2 %; one, 3.4 %; two, 12.7 %; three, 20.9 %; four, 33.3 %; and five, 50.0 %. ConclusionsThe surveillance method effectively identified children with sepsis with high-risk of mortality and demonstrated strong discrimination of mortality.

Neonatal Pharmacokinetics and Biodistribution of Polymeric Nanoparticles and Effect of Surfactant.

The development of therapeutics for pediatric use has advanced in the last few decades, yet the off-label use of adult medications in pediatrics remains a significant clinical problem. Nano-based medicines are important drug delivery systems that can improve the bioavailability of a range of therapeutics. However, the use of nano-based medicines for application in pediatric populations is challenged by the lack of pharmacokinetic (PK) data in this population. To address this data gap, we investigated the PK of polymer-based nanoparticles in term-equivalent neonatal rats. We used poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles, which are polymer nanoparticles that have been extensively studied in adult populations but less commonly applied in neonates and pediatrics. We quantified the PK parameters and biodistribution of PLGA-PEG nanoparticles in term-equivalent healthy rats and revealed the PK and biodistribution of polymeric nanoparticles in neonatal rats. We further explored the effects of surfactant used to stabilize PLGA-PEG particles on PK and biodistribution. We showed that 4 h post intraperitoneal injection, nanoparticles had the highest accumulation in serum, at 54.0% of the injected dose for particles with Pluronic® F127 (F127) as the stabilizer and at 54.6% of the injected dose for particles with Poloxamer 188 (P80) as the stabilizer. The half-life of the F127-formulated PLGA-PEG particles was 5.9 h, which was significantly longer than the 1.7 h half-life of P80-formulated PLGA-PEG particles. Among all organs, the liver had the highest nanoparticle accumulation. At 24 h after administration, the accumulation of F127-formulated PLGA-PEG particles was at 26.2% of the injected dose, and the accumulation of P80-formulated particles was at 24.1% of the injected dose. Less than 1% of the injected nanoparticles was observed in healthy rat brain for both F127- and P80-formulated particles. These PK data inform the use of polymer nanoparticle applications in the neonate and provide a foundation for the translation of polymer nanoparticles for drug delivery in pediatric populations.

Comprehensive Pediatric Reference Limits for High-Sensitivity Cardiac Troponin I and NT-proBNP in the CALIPER Cohort.

Cardiac biomarkers have increasing application in pediatric populations, including congenital heart disease, myocarditis, and heart failure. Clinical practice is limited by evidence gaps in pediatric reference limits to inform clinical decision-making. The current study aimed to establish comprehensive pediatric reference limits for N-terminal (NT)-pro hormone brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI) in the CALIPER cohort of healthy children and adolescents. Analytical immunoassay performance was assessed through precision, linearity, and method comparison (Abbott Alinity ci system). Subsequently, approximately 200 serum samples collected from apparently healthy children (birth to 18 years) were analyzed for hs-cTnI and NT-proBNP. Reference limits (2.5th, 97.5th, and 99th percentiles) were established as per Clinical and Laboratory Standards Institute EP-28A3c guidelines with associated 90% confidence intervals. Of all pediatric serum samples analyzed, 46% had detectable hs-cTnI concentrations (limit of detection: 1.3 ng/L). Both hs-cTnI and NT-proBNP demonstrated markedly elevated neonatal concentrations with 99th percentiles of 55.8 and 1785 ng/L, respectively. No statistically significant age-specific differences were observed beyond 1 year of age across all cardiac biomarkers examined. No sex-specific association was observed between hs-cTnI and NT-proBNP concentration and adolescence. We report age-specific reference limits for hs-cTnI and NT-proBNP in a healthy Canadian cohort of children and adolescents measured using Alinity immunoassays for the first time. These data support the need for pediatric-specific interpretation to reduce misinformed clinical decision-making and calls to action larger cohort studies such that reference limits can be more robustly defined.

Conversion Rate in Pediatric Robotic-Assisted Surgery: Looking for the Culprit.

Introduction: Robotic-assisted surgery (RAS) is increasingly used in adulthood but its application in pediatric population is limited. We report our initial experience in pediatric RAS, focusing on conversions to analyze their causes. Methods: All pediatric patients who underwent RAS between June 2015 and April 2019 were included, analyzing demographics, comorbidities, previous surgery, and intraoperative surgical and anesthetic parameters. A three-arms robotic technique was used in all cases. Additional laparoscopic ports were added, when needed. The surgical team did not change during the program, whereas the anesthesiology team varied. Results: Thirty-nine patients (23 females, 16 males; mean age ± SD = 9.33 ± 4.73 years [range = 1-16]; mean weight ± SD = 35.2 ± 20.0 kg [range = 9-85]) underwent 40 different procedures (18 gastrointestinal, 15 urogynecological, 5 oncological, and 2 miscellaneous). Three procedures (7.5%) were converted to open surgery for inadequate working space (two marked bowel distension and one insufficient hepatic retraction). Converted patients were of significant lower age (mean ± standard error of mean [SEM] = 2.97 ± 1.03 versus 9.83 ± 0.77 years, P = .01) and lower weight (mean ± SEM = 11.83 ± 1.74 versus 35.47 ± 3.16 kg, P = .03). The two groups did not differ statistically for duration of facial mask ventilation before intubation (mean ± SEM = converted 10.67 ± 2.33 versus completed 10.31 ± 0.91 minutes), neuromuscular block dosage (rocuronium; mean ± SEM = converted 0.46 ± 0.06 mg/kg versus completed 0.62 ± 0.03 mg/kg) and in the type of bowel preparation (mechanical and/or pharmacological). Discussion: Conversion rate in initial pediatric RAS program is acceptable. In children, the need for conversion is mainly because of inadequate working space, particularly in smaller children, but it seems not to be influenced by measurable anesthetic factors or different regimen for bowel preparation.

Validation of Peek Acuity application in pediatric screening programs in Paraguay.

To validate the Peek Acuity mobile phone application in pediatric populations and compare its utility, both economic and diagnostic, against conventional screening methods using a pediatric ophthalmologist examination as the gold standard. A cohort of 393 subjects from Fernando de la Mora, Paraguay (ages 6-16y) were enrolled in the study. Subjects were randomly assigned a starting screening modality among: Peek Acuity, a single line of tumbling E optotypes set at 20/40, and Spot Vision Screener. Once completing the first screening modality, the subjects completed the two remaining techniques. Referral criteria were established based on the most current American Association of Pediatric Ophthalmology and Strabismus (AAPOS) recommendations: 20/40 for Peek Acuity and the tumbling E, and refractive error detection for the Spot Vision Screener. Subjects that failed to achieve the cut-off for any of the three screening techniques or subjects that passed the screening but were randomly selected to perform a comprehensive eye exam to determine the false negative rate, were evaluated by a pediatric ophthalmologist. This evaluation was considered the gold standard, and included vision assessment by a Snellen chart, strabismus evaluation, and cycloplegic refraction with dilated fundoscopy. We obtained 48% sensitivity, 83% specificity, 43% positive predictive value, and 86% negative predictive value for Peek Acuity's ability to refer compared to evaluation by a pediatric ophthalmologist, failing to achieve a desired sensitivity for implementation. Peek Acuity trended to overestimate the subject's visual acuity, providing a higher visual acuity that would not indicate referral for a comprehensive eye examination. However, its high specificity accurately predicted a significant number of children who did not need further evaluation. When comparing the three screening methods, no single screening modality outperformed the others. Peek Acuity represented a technology that was economically feasible compared to other screening modalities in low income settings, due to the prevalence of cell phone use. Peek Acuity represents an efficient tool that has potential for implementation in school screenings with different strategies aimed at pediatric populations due to its low cost and high specificity. An increase in sensitivity would improve detection of children with refractive errors.

Advances in clinical application of adaptive support ventilation

Mechanical ventilation is one of the most commonly used respiratory treatments in intensive care unit.New ventilation modes are developed to reduce the occurrence of mechanical ventilation complications, and adaptive support ventilation (ASV) is one of them.ASV is a newer form of closed-loop controlled ventilation which provides automated selection of initial ventilator parameters based on measurements of patient lung mechanics and breathing effort.Now, the basic theory, parameter setting, advantages and disadvantages of ASV were summarized, and the clinical application in pediatric population was also concluded. Key words: Adaptive support ventilation; Closed-loop controlled ventilation; Clinical application

Foreign body removal in children and adults: review of available techniques and emerging technologies

In adults, clinical manifestations of foreign body aspiration range from sudden onset of asphyxia and respiratory failure due to central airway obstruction to subacute and even chronic worsening of non-specific pulmonary complaints. Given a wide range of often non-specific clinical symptoms associated with foreign body aspiration, high index of suspicion is required to avoid delay in diagnosis. In this review article we describe risk factors, clinical presentation, evaluation and management of foreign body aspiration in adult and pediatric patient populations. We will review several bronchoscopic techniques for foreign body extraction and describe the use of a flexible cryoprobe and its novel application in pediatric populations to aid in foreign body removal. Finally we will highlight potential complications that may be encountered during foreign body removal.

The Free Anterolateral Thigh (ALT) Flap for Microsurgical Reconstruction of Traumatic Defects in Pediatric Foot

Objective: Microsurgery has found early application in pediatric population despite the initial concerns on the technically challenging microanastomosis. Complex injuries of lower extremities in children have not received the same attention in the international literature, but some specific accidental foot injuries seem to have a particularly high frequency in that age group. The muscle flaps were initially the choice for the coverage of distal lower limb deficits; however, the donor site morbidity and the bulky appearance attracted attention to more delicate flaps, with the fasciocutaneous anterolateral thigh (ALT) flap becoming a basic reconstructive option. The present study considered all journal abstracts and articles on the use of free flaps in children’s extremities in order to evaluate the use of the free ALT flap in pediatric patients. The literature search was performed with “PubMed” and “MEDLINE” databases according to PRISMA guidelines with the systematic review clustering eventually the results of 12 different studies. We investigated the use of 102 free ALT flaps for the reconstruction of traumatic foot defects in children with 95.1% flap survival rate and only 2 complete flap losses noted due to venous thrombosis; 6 flaps went for urgent re-exploration resulting in the unavoidable loss of one flap and the partial necrosis of 3 others. In the vast majority of cases the reconstruction was delayed and the total complication rate was 21.57%. It is reaffirmed that hypertrophic scarring tends to be more common in pediatric patients and split thickness skin graft should be avoided whenever primary closure without extensive tension is possible. More than a quarter (27.27%) of the children necessitated a secondary revision surgery, as the child’s growth and the additional fat tissue make secondary debulking procedures really common. Special perioperative care, atraumatic dissection technique, and well established microsurgical experience are absolutely required when performing a free flap reconstruction in children. Nevertheless, the good functional outcome and the high survival rate of our review highlight the reliability of the free ALT flap for traumatic defects in pediatric foot.

Is top-down therapy a more effective alternative to conventional step-up therapy for Crohn's disease?

The management of Crohn’s disease involves immunosuppressive protocols in a step-up approach that progresses through a therapeutic pyramid with several tiers of medication. Medications at the top are considered more potent but present greater risk. A new top-down approach to therapy inverts this procedure, using top-tier drugs for initial treatment. A critical appraisal of the current literature relating to top-down therapy was performed to evaluate its merit. A literature search was conducted on PubMed, Ovid, and PubMed Central to identify studies of the efficacy of top-down therapy. Papers were appraised critically using the Scottish Intercollegiate Guidelines Network score to evaluate current evidence for the use of top-down therapy. Nineteen studies were identified, including six randomized controlled trials, thirteen cohort studies, and two cost-benefit studies. Early combined therapy involving both biologics and immunomodulators was found to be effective at improving patient outcomes; however, early biologics alone were not shown to have a clear benefit over step-up therapy. Likewise, the early use of immunomodulators alone showed inconsistent results with respect to efficacy in terms of both remission and surgical outcomes. Evidence for application in pediatric populations was also inconclusive. The cost-benefit analyses found that top-down therapy merits investigation, as it proved to be economical given current data. Top-down therapy has the potential of being a viable alternative to step-up therapy, but further studies are needed to determine the most appropriate patients to receive this treatment.

Determination of the Accuracy of Ultrasound for Detecting Stenosis in Tissue Engineered Vascular Grafts in a Murine Model

Determination of the Accuracy of Ultrasound for Detecting Stenosis in Tissue Engineered Vascular Grafts in a Murine Model Tissue-engineered vascular grafts (TEVGs) offer a viable solution to the complications derived from using synthetic materials for correction of congenital cardiovascular defects. Our TEVGs possess the ability to grow with a patient, thus making them well suited for application in pediatric populations. In our clinical trial involving patients with congenital heart disease, the TEVGs demonstrated the ability to grow with a patient without significant morbidity due to graft-related complications; however, stenosis development remained a substantial drawback in long term neovessel performance, affecting up to 24% of patients who underwent the operation. We developed a mouse model of inferior vena cava (IVC) interposition graft implantation in order to study cellular and molecular mechanisms of nonissue formation, to investigate factors that contribute to stenosis development, and to evaluate new strategies to prevent stenosis. Graft explanation and subsequent histological evaluation has been considered the definitive gold standard for analysis of neovessel patency in this model. Histology requires animal sacrifice at each observational time point, consequently prohibiting the serial follows up of the same animals at future time points. This is a significant deterrent to the usefulness of the model, as its intended purpose is to provide insights into the long-term performance of TEVGs, ultimately leading to the creation of an improved second-generation vascular graft. In addition, grafts that are used for histology cannot be used for other methods of characterization that require unfixed tissue samples, such as mechanical testing, western blotting, flow cytometry, and PCR. An accurate, noninvasive monitoring technique is therefore required to enable serial monitoring of TEVG implants over a time course that spans scaffold degradation and neo-vessel remodeling. Clinically, ultrasound has long been accepted as a highly accurate method for detecting vascular graft stenosis or occlusion in patient populations. In addition, ultrasonography has been used to successfully monitor TEVG performance in larger animal models. The use of this common imaging modality in a mouse model is difficult due to decreased vessel and graft size. Although we have previously used ultrasound to evaluate TEVG remodeling in the mouse, no detailed analysis has been performed to evaluate the efficacy of its use in this model. In the current report, we perform a detailed retrospective analysis of mouse TEVG ultrasound data to verify the accuracy of this technique in monitoring TEVG performance. Our aim is to determine whether ultrasound is an accurate and reliable method to serially monitor TEVG remodeling in the mouse. This analysis will have significant implications for the design of future experiments.

Pharmacogenomics of acetaminophen in pediatric populations: a moving target.

Acetaminophen (APAP) is widely used as an over-the-counter fever reducer and pain reliever. However, the current therapeutic use of APAP is not optimal. The inter-patient variability in both efficacy and toxicity limits the use of this drug. This is particularly an issue in pediatric populations, where tools for predicting drug efficacy and developmental toxicity are not well established. Variability in toxicity between age groups may be accounted for by differences in metabolism, transport, and the genetics behind those differences. While pharmacogenomics has been revolutionizing the paradigm of pharmacotherapy for many drugs, its application in pediatric populations faces significant challenges given the dynamic ontogenic changes in cellular and systems physiology. In this review we focused on the ontogenesis of the regulatory pathways involved in the disposition of APAP and on the variability between pediatric, adolescent, and adult patients. We also summarize important polymorphisms of the pharmacogenes associated with APAP metabolism. Pharmacogenetic studies in pediatric APAP treatment are also reviewed. We conclude that while a consensus in pharmacogenetic management of APAP in pediatric populations has not been achieved, a systems biology based strategy for comprehensively understanding the ontogenic regulatory pathway as well as the interaction between age and genetic variations are particularly necessary in order to address this question.

Prospective open-label pilot trial of mirtazapine in children and adolescents with social phobia

Mirtazapine is indicated for major depression and used for anxiety in adults; however, little is known about its application in pediatric populations. This is an 8-week open-label pilot study of mirtazapine in children with social phobia age 8–17 years. Primary outcomes were symptom improvement based on clinician rating and self-report, as well as tolerability based on rates of discontinuation due to adverse effects. Fifty-six percent (10/18) responded to treatment, 17% (3/18) achieved full remission. Social phobia symptoms improved significantly during the first 2 weeks of treatment, as did comorbid symptoms of depression and anxiety. Eleven patients (61%) did not complete all 8 weeks of treatment; four patients (22%) discontinued due to adverse effects including fatigue and irritability. The others discontinued due to study burden (28%), insufficient response (6%), or to pursue herbal treatment (6%). Significant weight gain was observed. Larger controlled trials are needed to further evaluate efficacy and safety.

Diffusion tensor imaging in children and adolescents: Reproducibility, hemispheric, and age-related differences

We evaluated intra-rater, inter-rater, and between-scan reproducibility, hemispheric differences, and the effect of age on apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in healthy children (age range 5.5–19.1 years) examined with a clinical diffusion tensor imaging (DTI) protocol at 1.5 T, using a region of interest (ROI) methodology. Measures of reliability and precision were assessed in six ROIs using two different ROI shapes (polygonal and ellipsoidal). Results: Highly reproducible values of ADC and FA were obtained with the polygonal method on intra-rater (coefficients of variation ≤ 2.7%) and inter-rater (coefficients of variation ≤ 4.8%) reproducibility. For between-scan reproducibility, the coefficients of variation were ≤ 5.0%. Mean asymmetry indices were in the range from − 4% to 9% for FA and from − 6% to 3% for ADC. ADC showed significant negative correlation with age in 13 of 15 examined fiber tracts and FA increased significantly in three fiber tracts. Our results show that the evaluated DTI protocol is suitable for clinical application in pediatric population.