Abstract Objective To assess the first lithium coin‐cell battery (CCB) technology on the consumer market with ingestion burn protection claims in context of medical management practices. Study Design Cadaveric porcine esophageal model. Setting Tertiary care children's hospital research institute and third‐party laboratory. Methods Anterior‐posterior X‐ray imaging was performed. Using in vitro porcine tissue segments, traditional CCBs and protective CCBs were assessed for visible appearance and surface pH over 60 minutes; another group was assessed for 24 hours. A separate experiment evaluated existing protocols to administer honey/sucralfate and perform 0.25% acetic acid irrigation. Results All protective CCBs demonstrated diagnostic double‐ring/halo sign on X‐ray. Traditional CCBs demonstrated diffusely highly alkaline pH of 13 and significant tissue necrosis. For protective CCBs, regions of tissue pH increased to 12‐13; however, substantially reduced tissue injury without obvious necrosis was noted. At 24 hours, protective CCBs compared to traditional CCBs maintained reduced visible tissue injury at both positive and negative poles. Honey, sucralfate or 0.25% acetic acid irrigations effectively neutralized pH. Conclusion To our knowledge, this is the first study in the medical literature to assess recently marketed protective CCBs. X‐ray diagnosis, preremoval honey/sucralfate use, emergent removal for esophageal lodgment, postremoval 0.25% acetic acid esophageal irrigation practices should not change. While protective CCBs showed substantial reduction of injury severity, the highly alkaline pH at negative pole still warrants neutralization treatments and further study. Widespread adoption of advanced technologies for child safety across the battery, electronics, and consumer goods industries could prevent severe injuries or deaths.

Severe subglottic stenosis develops in over 20,000 infants per year and requires laryngotracheal reconstruction to enlarge the airway by implanting autologous cartilage from a rib graft. However, young children often lack sufficiently sized costal cartilage for this procedure, resulting in increased donor site morbidity and operative time, as well as an elevated risk for airway restenosis, necessitating revision surgery. To overcome these limitations, we create a scaffold based on porcine meniscal cartilage decellularization - which we term MEND - by selectively digesting away the elastin and blood vessels uniquely present in the meniscus; this creates microchannels that support cellular re-invasion. Here we demonstrate that MEND can be fully recellularized in 3 days with ear-derived cartilage progenitor cells and reaches structural and functional maturation suitable for implant within 3 weeks of chondrogenic differentiation, a time frame compatible with clinical translation. To further this therapy toward clinical translation, we validate the ear-derived cartilage progenitor cell-MEND grafts in a New Zealand white rabbit laryngotracheal reconstruction model. Our results demonstrate airway expansion, graft re-epithelialization, neocartilage formation, and integration with adjacent native laryngotracheal cartilage at 3 months. Notably, MEND implants perform better in all outcomes than autologous costal cartilage, the standard of care. No instances of adverse events such as extrusion, granulation, infection, or calcification are observed in any of the 38 rabbits in our study. These results demonstrate the feasibility of our translational tissue engineering approach to laryngotracheal reconstruction and could overcome the autograft-associated limitations in pediatric patients, decreasing the need for invasive revision surgery.

OBJECTIVE:To prospectively compare outcomes and complications of the two most common techniques for closure of tracheocutaneous fistulas (TCFs): surgical excision of the tract with primary closure (PC), and de-epithelialization with healing by secondary intention (SI). STUDY DESIGN:Prospective cohort study. SETTING:Tertiary academic center. METHODS:All patients who underwent closure of a TCF between 5/1/2022 and 5/30/2023 were eligible for inclusion in the study. Data was prospectively collected and included demographics, tracheostomy history, intraoperative data (including fistula size and closure technique), postoperative recovery and any complications. RESULTS:There were 15 patients who underwent PC, and 10 patients who underwent closure by SI. Both cohorts were premature and had tracheostomies for at least 2 years prior to decannulation. The length of time from decannulation to closure was longer in the primary vs secondary group (p = .01). The operative time was significantly longer in the PC group (p = .002) and the PC group experienced a significantly higher number of postoperative respiratory complications (p = .05) during their postoperative admission. The average TCF size was larger in the SI group compared to the PC group (p < 0.001). CONCLUSION:This prospective study demonstrated fewer postoperative respiratory complications for SI closure of TCFs compared to PC.

ObjectivePediatric subglottic stenosis (SGS) is characterized by subglottic narrowing which occurs when pathological fibroblasts deposit extracellular matrix that reduces airway patency. Recent clinical observations have suggested that azithromycin may have favorable impacts on SGS reduction while treating airway infections; furthermore, our recent work in mice demonstrated that the airway microbiome influences SGS. In this work, we characterize the protective effect of azithromycin as an immunomodulatory and antibacterial therapeutic against subglottic stenosis.MethodsImmunomodulatory and antifibrotic effects of azithromycin were assessed on TGF‐β1‐stimulated airway fibroblasts at 10 μg/mL for 5 days. Changes in gene expression were quantified by RT‐qPCR and myofibroblast differentiation by α‐SMA immunostaining. Murine airways were pretreated (2‐weeks) with intranasal azithromycin before SGS injury by a twisted wire brush. Disease severity and immune response were characterized by histology and immunostaining for immune cells.ResultsIn vitro, azithromycin treatment of TGF‐β1‐stimulated fibroblasts exhibited strong reductions in extracellular matrix (COL1A1, LOX) and myofibroblast‐related gene expression (ACTA2). Notably, there was a significant reduction in pro‐fibrotic expression, which was observed with 10 μg/mL azithromycin. Immunostaining of fibroblasts for α‐SMA revealed strong reductions in the number of positive‐staining cells and the intensity of each positive cell. In vivo, azithromycin exhibited a significant decrease in lamina propria thickness indicative of reduced stenosis with associated changes in T‐cell infiltration.ConclusionsOverall, we show azithromycin prevents pro‐fibrotic gene expression and myofibroblast differentiation and can help protect mice from developing SGS. This introduces azithromycin as a potential treatment for SGS.Level of EvidenceNA Laryngoscope, 2024

Objective Subglottic stenosis (SGS) may result from prolonged intubation where fibrotic scar tissue narrows the airway. The scar forms by differentiated myofibroblasts secreting excessive extracellular matrix (ECM). TGF‐β1 is widely accepted as a regulator of fibrosis; however, it is unclear how biomechanical pathways co‐regulate fibrosis. Therefore, we phenotyped fibroblasts from pediatric patients with SGS to explore how key signaling pathways, TGF‐β and Hippo, impact scarring and assess the impact of inhibiting these pathways with potential therapeutic small molecules SB525334 and DRD1 agonist dihydrexidine hydrochloride (DHX). Methods Laryngeal fibroblasts isolated from subglottic as well as distal control biopsies of patients with evolving and maturing subglottic stenosis were assessed by α‐smooth muscle actin immunostaining and gene expression for α‐SMA, FN, HGF, and CTGF markers. TGF‐β and Hippo signaling pathways were modulated during TGF‐β1‐induced fibrosis using the inhibitor SB525334 or DHX and analyzed by RT‐qPCR for differential gene expression and atomic force microscopy for ECM stiffness. Results SGS fibroblasts exhibited higher α‐SMA staining and greater inflammatory cytokine and fibrotic marker expression upon TGF‐β1 stimulation ( p < 0.05). SB525334 restored levels to baseline by reducing SMAD2/3 nuclear translocation ( p < 0.0001) and pro‐fibrotic gene expression ( p < 0.05). ECM stiffness of stenotic fibroblasts was greater than healthy fibroblasts and was restored to baseline by Hippo pathway modulation using SB525334 and DHX ( p < 0.01). Conclusion We demonstrate that distinct fibroblast phenotypes from diseased and healthy regions of pediatric SGS patients respond differently to TGF‐β1 stimulation, and SB525334 has the superior potential for subglottic stenosis treatment by simultaneously modulating TGF‐β and Hippo signaling pathways. Level of Evidence NA Laryngoscope , 134:287–296, 2024

INTRODUCTION:Button batteries (BB) are a source of significant morbidity and mortality in young children. Little data is available regarding associations between esophageal impaction location and outcomes or need for surveillance imaging. METHODS:All patients treated at a single institution following BB ingestion between 2018 and 2022 were included for retrospective chart review. RESULTS:Twenty patients were treated at our institution BBs were located, or most significant damage observed, in the cervical esophagus (n = 10, 50 %), followed by thoracic esophagus (n = 6, 30 %), and abdominal esophagus (n = 4, 20 %). Patients with cervical esophageal impaction were younger (482 [370-866] days), than those with thoracic (1395 [871-2369] days) or abdominal esophageal impaction (2021.5 [1230.5-3419.5] days) (p = 0.003). Zargar Mucosal Injury Grade was significantly more severe in patients with cervical button battery impaction; 8/10 (80 %) had a ≥Grade IIIB injury, compared to 2/6 (33.3 %) thoracic impactions and 0/4 (0 %) abdominal impactions (p = 0.002). All patients who developed persistent esophageal stenosis (n = 6) had cervical battery impactions (6, 60 %, p = 0.015). Both TEFs (2/2) had anterior facing anode, while both (2/2) esophageal perforations had posterior. Only 1/20 (5 %) patients, and 1/7 (14.3 %) with serious complications, had a serious complication detected on routine, rather than clinically indicated follow-up surveillance. CONCLUSIONS:In our population, cervical BB impaction occurred more frequently in younger children, was associated with more severe mucosal injury, and had higher risk of stenosis. Nearly all complications were detected on clinically indicated rather than postoperative surveillance imaging.

Pediatric subglottic stenosis (SGS) results from prolonged intubation where scar tissue leads to airway narrowing that requires invasive surgery. We have recently discovered that modulating the laryngotracheal microbiome can prevent SGS. Herein, we show how our patent-pending antimicrobial peptide-eluting endotracheal tube (AMP-ET) effectively modulates the local airway microbiota resulting in reduced inflammation and stenosis resolution. We fabricated mouse-sized ETs coated with a polymeric AMP-eluting layer, quantified AMP release over 10 days, and validated bactericidal activity for both planktonic and biofilm-resident bacteria against Staphylococcus aureus and Pseudomonas aeruginosa. Ex vivo testing: we inserted AMP-ETs and ET controls into excised laryngotracheal complexes (LTCs) of C57BL/6 mice and assessed biofilm formation after 24 h. In vivo testing: AMP-ETs and ET controls were inserted in sham or SGS-induced LTCs, which were then implanted subcutaneously in receptor mice, and assessed for immune response and SGS severity after 7 days. We achieved reproducible, linear AMP release at 1.16 µg/day resulting in strong bacterial inhibition in vitro and ex vivo. In vivo, SGS-induced LTCs exhibited a thickened scar tissue typical of stenosis, while the use of AMP-ETs abrogated stenosis. Notably, SGS airways exhibited high infiltration of T cells and macrophages, which was reversed with AMP-ET treatment. This suggests that by modulating the microbiome, AMP-ETs reduce macrophage activation and antigen specific T cell responses resolving stenosis progression. We developed an AMP-ET platform that reduces T cell and macrophage responses and reduces SGS in vivo via airway microbiome modulation.

Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate (MTX) was evaluated in children and young adults with NF1 and PN. Patients ≤ 25 years of age with progressive and/or inoperable NF1-PN received VBL 6 mg/m2 and MTX 30 mg/m2 weekly for 26 weeks, followed by every 2 weeks for 26 weeks. Objective response rate was the primary endpoint. Of 25 participants enrolled, 23 were evaluable. The median age of participants was 6.6 years (range 0.3–20.7). The most frequent toxicities were neutropenia and elevation of transaminases. On two-dimensional (2D) imaging, 20 participants (87%) had stable tumor, with a median time to progression of 41.5 months (95% confidence interval 16.9, 64.9). Two of eight participants (25%) with airway involvement demonstrated functional improvements including decreased positive pressure requirements and apnea-hypopnea index. A post hoc three-dimensional (3D) analysis of PN volumes was completed on 15 participants with amenable imaging; 7 participants (46%) had progressive disease on or by the end of therapy. VBL/MTX was well-tolerated but did not result in objective volumetric response. Furthermore, 3D volumetric analysis highlighted the lack of sensitivity of 2D imaging for PN response evaluation.

OBJECTIVE:Severe subglottic stenosis develops as a response to intubation in 1% of the >200,000 neonatal intensive care unit infants per year and may require laryngotracheal reconstruction (LTR) with autologous hyaline cartilage. Although effective, LTR is limited by comorbidities, severity of stenosis, and graft integration. In children, there is a significant incidence of restenosis requiring revision surgery. Tissue engineering has been proposed to develop alterative grafting options to improve outcomes and eliminate donor-site morbidity. Our objective is to engineer a decellularized, channel-laden xenogeneic cartilage graft, that we deployed in a proof-of-concept, neonatal porcine LTR model. METHODS:Meniscal porcine cartilage was freeze-thawed and washed with pepsin/elastase to decellularize and create microchannels. A 6 × 10-mm decellularized cartilage graft was then implanted in 4 infant pigs in an anterior cricoid split. Airway patency and host response were monitored endoscopically until sacrifice at 12 weeks, when the construct phenotype, cricoid expansion, mechanics, and histomorphometry were evaluated. RESULTS:The selective digestion of meniscal components yielded decellularized cartilage with cell-size channels. After LTR with decellularized meniscus, neonatal pigs were monitored via periodic endoscopy observing re-epithelization, integration, and neocartilage formation. At 12 weeks, the graft appeared integrated and exhibited airway expansion of 4 mm in micro-CT and endoscopy. Micro-CT revealed a larger lumen compared with age-matched controls. Finally, histology showed significant neocartilage formation. CONCLUSION:Our neonatal porcine LTR model with a decellularized cartilage graft is a novel approach to tissue engineered pediatric LTR. This pilot study sets the stage for "off-the-shelf" graft procurement and future optimization of MEND for LTR. LEVEL OF EVIDENCE:NA Laryngoscope, 134:807-814, 2024.

Introduction: Comorbidities such as chronic lung disease and gastroesophageal reflux (GERD), prematurity, and numerous other conditions may impact the success of LTR. Single-center studies are limited in terms of patient numbers and may be underpowered. Objectives: To analyze the impact of specific comorbidities on the operation-specific and overall surgical success of LTR in a large multicenter cohort and validate a predictive model for surgical success. Methods: A large retrospective multicenter 10-year review was undertaken to validate the data of a previous single-center study (Wertz et al. Laryngoscope 2020) which identified specific predictive comorbidities which impacted LTR outcomes. A Monte Carlo simulation based on the previous data set suggested that 300-400 cases would be needed to optimize the statistical power of a Bayesian model developed from the single-center data to predict surgical success. An IRB-approved data-sharing agreement was executed for 4 large U.S. centers. A virtual REDCap (R) data entry form inquired about patient characteristics that best predicted surgical success in the singlecenter model. These included demographics, surgical approaches, cardiac, airway, genetic, endocrine, musculoskeletal, gastrointestinal, and pulmonary comorbidities; details of the surgical procedures, and results of esophagogastroduodenoscopy (EGD), esophageal pH/impedance and flexible bronchoscopy with bronchioalveolar lavage (BAL) were included. Surgical success defined as successful decannulation or resolution of airway symptoms was recorded as single surgery success and overall success following open surgical revision surgery. Multivariate Bayesian analysis, logistical regression, and Kaplan-Meier analysis were performed. Results: 542 patients were identified, including 165 from the single-center study and an additional 377 patients from the multicenter group. The median age was 36 months at the time of the most recent surgery. 70.9% of the LTRs were double-staged procedures. The overall success rate was 86.4% and operation-specific success rate was 69.2%. The specific comorbidities and aerodigestive test results that impacted success based on univariate analysis included staging, bronchiectasis, pulmonary hypertension, GERD, ASD, PDA, grade of stenosis, advanced levels of stenosis, Trisomy 21, MRSA, prior open surgery at another hospital, and gross appearance on EGD. Bayesian model averaging with backward selection was used to validate and refine a predictive model for surgical success with favorable receiver operating curve characteristics - AUC values of 0.827 for single surgery success and 0.797 for overall success. Discussion: With over 500 patients reviewed, this was the largest multicenter study of LTR to date, which elucidated the impact of comorbidities on success with LTR and was able to improve upon the predictive

Laryngomalacia is usually a benign condition that improves on its own in most cases. A small percentage of patients develop severe symptoms and require surgical intervention with supraglottoplasty either hot (laser) or cold to improve the symptoms. Severe laryngomalacia may result in failure to thrive, sleep apnea, stridor, respiratory distress, and in specific cases may require surgical intervention. Laryngomalacia is usually a benign condition that improves on its own in most cases. A small percentage of patients develop severe symptoms and require surgical intervention with supraglottoplasty either hot (laser) or cold to improve the symptoms. Severe laryngomalacia may result in failure to thrive, sleep apnea, stridor, respiratory distress, and in specific cases may require surgical intervention.

Objectives/HypothesisSubglottic stenosis (SGS) results from dysregulated extracellular matrix deposition by laryngotracheal fibroblasts causing scar tissue formation following intubation. Recent work has highlighted a relationship between this inflammatory state and imbalances in the upper airway microbiome. Herein, we engineer novel drug‐eluting endotracheal (ET) tubes to deliver a model antimicrobial peptide Lasioglossin‐III (Lasio) for the local modulation of the microbiome during intubation.Study DesignControlled in vitro study.MethodsET tubes were coated with a water‐in‐oil (w/o) emulsion of Lasio in poly(d,l‐lactide‐co‐glycolide) (PLGA) by dipping thrice. Peptide release was quantified over 2 weeks via fluorometric peptide assays. The antibacterial activity was tested against airway microbes (Staphylococcus epidermidis, Streptococcus pneumoniae, and pooled human microbiome samples) by placing Lasio/PLGA‐coated tubes and appropriate controls in 48 well plates with diluted bacteria. Bacterial inhibition and tube adhesion were tested by measuring optical density and colony formation after tube culture, respectively. Biocompatibility was tested against laryngotracheal fibroblasts and lung epithelial cells.ResultsWe achieved a homogeneous coating of ET tubes with Lasio in a PLGA matrix that yields a prolonged, linear release over 1 week (typical timeframe before the ET tube is changed). We observed significant antibacterial activity against S. epidermidis, S. pneumoniae, and human microbiome samples, and prevention of bacterial adherence to the tube. Additionally, the released Lasio did not cause any cytotoxicity toward laryngotracheal fibroblasts or lung epithelial cells in vitro.ConclusionOverall, we demonstrate the design of an effective‐eluting ET tube to modulate upper‐airway bacterial infections during intubation which could be deployed to help prevent SGS.Level of EvidenceNA Laryngoscope, 132:1356–1363, 2022

OBJECTIVES:Pediatric esophageal button battery (BB) injury occurs rapidly and continues to be a significant source of morbidity and mortality. Unfortunately, a BB that no longer supplies power to a device can still have enough residual voltage to cause injury within the body. Development of additional prevention strategies for consumers may reduce esophageal injury risk.METHODS:In this study, 24 commercially available button batteries (BBs) were horizontally and vertically wrapped (2 layers, full circumferential coverage, 90° apart) with 6 different types of common household tapes (Scotch®/clear, Scotch®/Magic, masking tape, packing tape/clear, packing tape/brown, black electrical tape) and left at room temperature for 30 days. In addition, 6 of the CR2032 batteries covered with each type of tape were placed in a cadaveric piglet esophageal model for a 4-h period and then compared to controls without tape for tissue pH changes and visible tissue injury.RESULTS:None of the tape-wrapped batteries showed voltage changes nor presented any hazard stemming from BB ingestion. All 6 tape covered batteries placed in the cadaveric piglet esophageal tissue model demonstrated no visible tissue injury and no change in tissue pH in contrast to the controls. Review of BB packaging language from various brands of commercially available CR2032 batteries showed that none had specific disposal recommendations.CONCLUSION:Both BB and electronics manufacturers should consider instructing the use of common household tape options to cover these BB immediately after removal from a device for either recycling or disposal. Such precautions may help to reduce related ingestion injuries in children.

Objective/HypothesisDetermine if diagnostic findings from pre‐operative multidisciplinary evaluations are associated with single surgery or overall success rates in pediatric laryngotracheal reconstruction (LTR).Study DesignRetrospective cohort.MethodsRetrospective cohort study of patients undergoing LTR at a tertiary care children's hospital between January 01, 2008 and December 31, 2017. Success is defined as decannulation rate if tracheostomy present, and resolution of symptoms if tracheostomy not present. Cohorts compared were those who did and did not receive pulmonary and gastrointestinal preoperative testing. Multivariate, logistic regression, and Kaplan Meier analyses performed.ResultsAbout 165 children were included in the study. Median age was 3 years at the time of surgery; 73% of LTRs were double‐stage procedures. Single surgery and overall success rates were 75% and 87%, respectively. After adjusting for severity of stenosis and surgical approach, performing esophagogastroduodenoscopy (EGD) and normal gross appearance on EGD were associated with increased single surgery (P = .01, .005) and overall success (P = .005, .0003). Performing pH probe and normal EGD biopsy results was associated with increased overall success (P = .03, .007). Asthma and musculoskeletal comorbidities, postoperative complications, and need for postoperative balloon dilation were associated with decreased success. No other comorbidities evaluated impacted success.ConclusionsAerodigestive comorbidities are common in children undergoing LTR, and preoperative multidisciplinary workup often results in changes in management. After adjusting for grade and level of stenosis and staged approach, performing EGD and pH/impedance probe as well as normal gross and microscopic EGD findings was independently associated with increased LTR surgical success.Level of Evidence4 (retrospective cohort study) Laryngoscope, 131:E2356–E2362, 2021

Pediatric upper airway disorders are frequently life-threatening and require precise assessment and intervention. Targeting these pathologies remains a challenge for clinicians due to the high complexity of pediatric upper airway anatomy and numerous potential etiologies; the most common treatments include systemic delivery of high dose steroids and antibiotics or complex and invasive surgeries. Furthermore, the majority of innovative airway management technologies are only designed and tested for adults, limiting their widespread implementation in the pediatric population. Here, we provide a comprehensive review of the most recent challenges of managing common pediatric upper airway disorders, describe the limitations of current clinical treatments, and elaborate on how to circumvent those limitations via local controlled drug delivery. Furthermore, we propose future advancements in the field of drug-eluting technologies to improve pediatric upper airway management outcomes.

Thom, Christopher; Deskmukh, Hitesh; Soorikian, Leanne; Jacobs, Ian; Fiadjoe, John; Lioy, Janet Author Information

Foreign bodies ingestion or aspiration events in children can be a source of morbidity and mortality. In most cases, removal by a coordinated endoscopy can be performed when there is the availability of equipment and support staff for pediatric care. Close communication with the anesthesia, surgeon and operating room support staff is essential and rehearsing with a facsimile of the foreign body is useful. In certain cases, such as sharp foreign bodies or button batteries the endoscopy should be performed immediately.