Primary versus secondary closure of tracheocutaneous fistula in pediatric patients.

OBJECTIVE: Up to 50% of pediatric patients have a persistent tracheocutaneous fistula (TCF) after tracheostomy decannulation. Classically these fistula tracts were excised and completely closed in a multilayered fashion, but recently closure by secondary intention has become the standard of care. However, variations in postoperative care still exist. The primary objectives of this study were to compare outcomes between patients who had a primary closure versus closure by secondary intention after excision of a TCF in children with a tracheostomy placement at one year old or less and to determine if closure by secondary intention will be equally efficacious compared to traditional primary closure. METHODS: Patients ages 0-21 years who had a primary or secondary closure of a TCF at a tertiary care children's hospital following decannulation of a tracheostomy tube were reviewed and those with a tracheostomy placement ≤1 year old were included. Demographic information, comorbidities, and surgical information were extracted from inpatient and outpatient charts. Mann-Whitney U test, Fisher's Exact test, and logistic regression to compare outcomes across the two TCF surgical groups. RESULTS: A total of 64 patients met inclusion with primary closures in 25 (39.1%) patients and secondary closures in 39(60.9%) patients. Patients who underwent secondary closure had a significantly shorter surgery duration (p < .001), shorter ICU length of stay (p < .001), and shorter postop LOS (p < .001). There were no differences in cardiac complications, respiratory complications, and the need for additional closure surgery between the two techniques, p > .05. Time from decannulation to TCF in months increased with primary closure, p = .010. CONCLUSION: Closure of tracheocutaneous fistula by secondary intention is safe and effective and can allow for shorter hospital stays in children with a tracheostomy placement at a year old or less.

Subglottic hemangioma: Understanding the association with facial segmental hemangioma in a beard distribution.

OBJECTIVE: A subglottic hemangioma (SGH) is a benign tumor of infancy that can cause severe obstruction of the airway. Infantile hemangiomas, in general, are the most common head and neck tumor in children, affecting 4-5% of the pediatric population. This retrospective cohort study characterizes subglottic infantile hemangiomas at a single vascular anomaly center over a 5-year period (2013-2017) during the era of propranolol treatment. METHODS: Queried the Vascular Anomaly Database at Children's Hospital of Pittsburgh for all infantile hemangioma(s) and then identified case of subglottic hemangiomas. Characterized key features of presentation, natural history and management for subglottic hemangiomas. A secondary differentiation focused on differences between subglottic hemangiomas associated with Beard Distribution (BD) vs not (NBD). RESULTS: Analysis of 761 cases of infantile hemangiomas demonstrated only 13 patients with subglottic hemangiomas (1.7%). Of those 13 patients, only 4 patients (30%) had BD while 2 patients (15%) had other cutaneous hemangiomas and 7 patients (55%) had no cutaneous hemangiomas. Secondarily, a total of 31 case of beard distribution cutaneous hemangiomas with 11 patients having oropharyngeal involvement (35%) but only 4 patients with subglottic hemangiomas (13%). Interestingly, 2 of the 4 BD patients had treatment failure on propranolol and required second line treatment with steroids or surgical excision while only 1 of 9 NBD patients failed propranolol treatment. As well the same 2 BD patients which failed propranolol also had PHACES syndrome. CONCLUSION: Subglottic hemangiomas are a rare presentation of infantile hemangiomas but with significant morbidity. While the classic teaching that a segmental beard distribution hemangioma raises concern for a subglottic hemangioma, this cohort indicates subglottic hemangiomas occur in a NBD presentation (1.3%), and demonstrated only an approximate 10% incidence rate with a beard distribution. But more importantly, this study raises the question that beard distribution in setting of PHACES syndrome may herald a more recalcitrant and complicated natural history for a subglottic hemangioma. This is of significant concern as risk for CVA in setting of PHACES is highest with use of steroid treatment. None of our patients had high risk extra or intra cranial vascular arterial anomalies and no CVA were noted.

Quercetin increases cystic fibrosis transmembrane conductance regulator-mediated chloride transport and ciliary beat frequency: therapeutic implications for chronic rhinosinusitis.

BACKGROUND: Increasing epithelial chloride (Cl(-)) secretion in the upper airways represents a putative method for promoting mucociliary clearance through augmentation of airway surface liquid depth. Several naturally occurring flavonoid compounds, including quercetin, have shown the capacity to increase transepithelial Cl(-) transport. Quercetin exhibits well-known antioxidant and anti-inflammatory activity and is now recognized as a potent activator of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel activity in a fashion largely independent of cyclic adenosine monophosphate signaling. The present study investigates whether this compound activates Cl(-) secretion and ciliary beat frequency (CBF) in well-characterized culture models of sinonasal epithelium. METHODS: Cystic fibrosis and non-cystic fibrosis primary human sinonasal epithelial (HSNE) and murine nasal septal epithelial (MNSE) cultures were studied for transepithelial ion transport in Ussing chambers under voltage clamp conditions and CBF was performed using pharmacologic manipulation. RESULTS: Change in short circuit current (DeltaI(SC), expressed as microamperes per squared centimeter) in response to quercetin were significantly greater than controls in both MNSE (23.23 ± 5.44 versus 2.47 ± 1.62; p < 0.0001) and HSNE (-8.72 ± 1.88 versus -1.88 ± 0.66; p < 0.01) cultures. CBF was significantly increased in quercetin-treated cells (expressed as fold change over baseline) in wild type (1.65 ± 0.13 versus 1.23 ± 0.05 [control]; p < 0.01), but not CFTR(-/-) (1.65 ± 0.29 versus 1.48 ± 0.38; p = 0.23). CONCLUSION: Quercetin significantly increased transepithelial Cl(-) transport and CBF in MNSE and HSNE cultures. Future studies investigating quercetin as a means to promote mucociliary transport in individuals with rhinosinusitis are warranted.

Hesperidin stimulates cystic fibrosis transmembrane conductance regulator-mediated chloride secretion and ciliary beat frequency in sinonasal epithelium.

OBJECTIVE: Pharmacologic agents designed to promote mucociliary clearance (MCC) in chronic rhinosinusitis (CRS) represent a novel therapeutic strategy. The objectives of the present study were to investigate whether the natural bioflavonoid hesperidin 1) increases transepithelial chloride (Cl(-)) secretion in vitro and in vivo, 2) enhances ciliary beat frequency (CBF), and 3) exerts its mechanistic effects through cAMP/PKA-dependent pathways. STUDY DESIGN: In vitro and in vivo study. SETTING: Laboratory. SUBJECTS AND METHODS: Transepithelial Cl(-) transport (Ussing chamber) and CBF were investigated in primary murine nasal septal (MNSE) and human sinonasal epithelial (HSNE) cultures. In vivo activity was measured using the murine nasal potential difference (NPD) assay, cystic fibrosis transmembrane conductance regulator (CFTR) R-domain phosphorylation, and cAMP levels were investigated to rule out a cAMP/PKA-dependent mechanism of activation. RESULTS: Hesperidin significantly increased CFTR-mediated Cl(-) transport (change in short-circuit current, DeltaI(SC)) in both MNSE (13.51 +/- 0.77 vs 4.4 +/- 0.66 [control]; P < 0.05) and HSNE (12.28 +/- 1.08 vs 0.69 +/- 0.32 [control]; P < 0.05). Cl(-) transport across in vivo murine nasal epithelium was also significantly enhanced with hesperidin (-2.3 +/- 1.0 vs -0.8 +/- 0.8 mV [control], P < 0.05). There was no increase in cellular cAMP or phosphorylation of the CFTR R-domain. Hesperidin significantly increased CBF (ratio of pretreatment to post-treatment) with both basal (1.31 +/- 0.07 vs 0.93 +/- 0.06 [control]; P < 0.05), apical (1.72 +/- 0.09 vs 1.40 +/- 0.07 [control]; P < 0.05), and basal + apical delivery (2.26 +/- 0.18 vs 1.60 +/- 0.21, respectively; P < 0.05). CONCLUSION: Our in vitro and in vivo investigations provide strong support for future testing of this robust Cl(-) secretagogue and CBF activator in human clinical trials for CRS.

Exposure to cigarette smoke condensate reduces calcium activated chloride channel transport in primary sinonasal epithelial cultures.

OBJECTIVES/HYPOTHESIS: The cystic fibrosis transmembrane conductance regulator (CFTR) serves as a predominant Cl(-) transport conduit in airway epithelium and is inhibited by cigarette smoke in vitro and in vivo. Activation of secondary Cl(-) transport pathways through calcium-activated Cl(-) channels (CaCC) has been postulated as a mechanism to bypass defects in CFTR-mediated transport. Because it is not known whether CaCCs are also inhibited by tobacco exposure, the current study was designed to investigate the effect of cigarette smoke condensate (CSC) on CaCC transport. STUDY DESIGN: In vitro study. METHODS: Well-characterized primary murine nasal septal epithelial (MNSE) and human sinonasal epithelial (HSNE) cultures were exposed to CSC in Ussing chambers. We monitored CaCC short-circuit current through stimulation of P2Y purinergic receptors with uridine triphosphate or adenosine triphosphate and selective inhibition of the CFTR-dependent secretory pathway. Characterization of CaCC current was also accomplished in primary airway cells derived from transgenic CFTR(-/-) (knockout) murine models. RESULTS: Change in CaCC-mediated current (DeltaI(SC) representing transepithelial Ca-mediated Cl(-) secretion in muA/cm(2)) was significantly decreased in CSC-exposed wild type MNSE when compared to controls (32.8 +/- 4.6 vs. 47.5 +/- 2.3; respectively; P < .02). A similar effect was demonstrated in CFTR(-/-) MNSE cultures (33.4 +/- 2.8 vs. 38.6 +/- 2.0; P < .05>. HSNE cultures also had a significant reduction in I(SC) (16.1 +/- 0.6 vs. 22.7 +/- 0; P = .008). CONCLUSIONS: CSC affects multiple pathways fundamental to airway ion transport, including both cyclic adenosine monophosphate and calcium activated Cl(-) transport. Inhibition of Cl(-) transport may contribute to common diseases of the airways, such as chronic rhinosinusitis and chronic obstructive pulmonary disease.

The bioflavonoid compound, sinupret, stimulates transepithelial chloride transport in vitro and in vivo.

OBJECTIVES/HYPOTHESIS: Dehydration of airway surface liquid (ASL) disrupts normal mucociliary clearance in sinonasal epithelium leading to chronic rhinosinusitis. Abnormal chloride (Cl(-)) transport is one mechanism that contributes to this disorder, as demonstrated by the disease cystic fibrosis. Identifying safe compounds that stimulate transepithelial Cl(-) transport is critical to improving hydration of the ASL and promoting mucociliary transport. Sinupret (Bionorica, LLC, San Clemente, CA), a combination of naturally occurring bioflavonoids, is a widely used treatment for respiratory ailments in Europe. However, the effects of Sinupret on target respiratory epithelium have yet to be fully investigated. The present study evaluated the mechanisms underlying this bioflavonoid therapeutic on transepithelial Cl(-) transport in respiratory epithelium. STUDY DESIGN: In vitro and in vivo investigation. METHODS: Well characterized murine nasal septal epithelial (MNSE) cultures, and murine nasal potential difference (NPD) techniques were used to evaluate the effects of Sinupret on Cl(-) secretion. RESULTS: The change in Sinupret-stimulated current (Delta I(SC) expressed as microA/cm(2)) in MNSE, representing Cl(-) secretion, was significantly increased when compared to controls (19.04 + or - 1.67 microA/cm(2) vs. 1.8 + or - 0.35 microA/cm(2), respectively; P = .00005). Transepithelial Cl(-) transport measured in the murine NPD in vivo assay (n = 42) was also significantly enhanced when compared to controls (-0.8 mV vs. -0.9 mV; P = .0004). Importantly, Sinupret-stimulated Cl(-) transport was substantially more robust in vivo than forskolin, a compound among the strongest known cystic fibrosis transmembrane conductance regulator activators (-3.8 mV vs. -1.65 mV; P = .01). CONCLUSIONS: Sinupret strongly activates transepithelial Cl(-) secretion through a mechanism known to hydrate the ASL of respiratory epithelium. This is one means by which the medication is likely to exert therapeutic benefit.