Development of a survival animal model for subglottic stenosis.

OBJECTIVE: To develop a reproducible survival animal model for subglottic stenosis. STUDY DESIGN: Prospective study. METHODS: We evaluated five methods of inducing airway injury in 30 New Zealand white rabbits to produce a subglottic stenosis model. Experimental groups comprised: group 1 (n = 5), which underwent 4-hour intubation; group 2 (n = 5), which underwent induced subglottic injury with a nylon brush; group 3 (n = 10), which underwent subglottic injury with a nylon brush, followed by 4-hour intubation; group 4 (n = 5), which underwent subglottic injury with Bugbee cautery in 50% of the subglottic circumference, followed by 4-hour intubation; and group 5 (n = 5), which underwent subglottic injury with Bugbee cautery in 75% of the subglottic circumference, followed by 4-hour intubation. Five animals were used as controls. Endoscopy of the airway and sacrifice of animals were planned at an interval of 14 days postinjury. Histologic measurements were analyzed. RESULTS: No animals in groups 1 or 2 developed stenosis. In group 3, 50% of animals developed symptomatic grade 3 subglottic and tracheal stenosis, necessitating early endoscopy and sacrifice in three animals. Four animals in group 4 developed grade 1 subglottic stenosis, and four in group 5 developed grade 2 subglottic stenosis. Histologic measurements of lumen areas within each of these two groups were similar; all animals survived the follow-up period. CONCLUSION: We successfully developed a reproducible survival model for induced subglottic stenosis using a combination of cautery-induced subglottic injury followed by 4-hour intubation. This model lays the foundation for future studies that evaluate endoscopic interventions for the management of subglottic stenosis. LEVEL OF EVIDENCE: NA Laryngoscope, 129:989-994, 2019.

A randomized controlled trial of Velcro versus standard twill ties following pediatric tracheotomy.

OBJECTIVES/HYPOTHESIS: Tracheotomy is a common procedure. A reliable method of securing the tracheotomy tube is essential to minimize accidental decannulation. However, skin breakdown has been reported in ∼30% of patients. We sought to evaluate rates of skin-related complications and accidental decannulation with the use of Velcro ties compared to twill ties. STUDY DESIGN: A nonblinded, randomized controlled trial comparing Velcro versus twill ties in patients undergoing tracheotomy between July 1, 2014 and January 31, 2016. METHODS: Patients ≤21 years of age were recruited and randomized to receive either Velcro or twill ties. The primary outcome measure was skin-related complications. The secondary outcome measure was accidental decannulation. Outcome measures were followed through postoperative day 5. RESULTS: Ninety-three patients were eligible, and 63 were enrolled. No patients were withdrawn. Fifty-seven patients were included in the analysis. Twenty-seven (47.4%) received Velcro, and 30 (52.6%) received twill. Five enrolled patients did not undergo tracheotomy (one Velcro, four twill). One was diagnosed with a genetic skin condition after enrollment but prior to undergoing tracheotomy. Patient characteristics were similar between groups. No significant differences were found with respect to skin-related complications (P = .59). Six patients (20%) with twill ties required early tie change compared to two (7.4%) with Velcro ties (P = .5). Two accidental decannulations occurred in the twill group compared to one in the Velcro group (P = 1.0). CONCLUSIONS: Our study demonstrated no differences in skin-related complications or accidental decannulation between Velcro and twill tracheotomy ties in the immediate postoperative period following tracheotomy. Our study suggests that Velcro ties are a viable alternative to twill ties. LEVEL OF EVIDENCE: 1b Laryngoscope, 127:1996-2001, 2017.

Combination therapies using an intratympanic polymer gel delivery system in the guinea pig animal model: A safety study.

OBJECTIVES: High dose antivirals have been shown to cause hearing loss when applied via the intratympanic route. The aim of this study was to determine if a combination therapy using dexamethasone (DXA) with either Cidofovir (CDV) or Ganciclovir (GCV), in solution or in PLGA-PEG-PLGA (PPP) hydrogel, is innocuous to the inner ear. METHODS: Cytomegalovirus (CMV)-free guinea pigs were separated into four principal study groups and treated via intratympanic injection (IT) of CDV/DXA solution, CDV/DXA Hydrogel, GCV/DXA solution and GCV/DXA hydrogel. Hearing thresholds were evaluated with pretreatment ABR and post injection weekly ABRs for a total follow up of 28 days. Temporal bone tissue was harvested and stained with Hematoxylin and Eosin for histologic analysis. RESULTS: ABR analysis revealed that GCV/DXA in solution and in hydrogel led to a mild hearing loss at days 7-21 but returned to baseline by day 28 When administered via PPP hydrogel, CDV/DXA demonstrated mild persistent hearing loss at 32kHz at 28 days. An inflammatory response was identified in the cochlear specimen of the CDV/DXA/PPP hydrogel group, in concert with mild hearing loss, at days 21 and 28. CONCLUSION: Results of this study support the safe intratympanic use of higher concentrations of antivirals when combined with DXA, both in solution and when applied via PPP hydrogel.

Radioprotective Effect of Aminothiol PrC-210 on Irradiated Inner Ear of Guinea Pig.

Radiotherapy of individuals suffering with head & neck or brain tumors subserve the risk of sensorineural hearing loss. Here, we evaluated the protective effect of Aminothiol PrC-210 (3-(methyl-amino)-2-((methylamino)methyl)propane-1-thiol) on the irradiated inner ear of guinea pigs. An intra-peritoneal or intra-tympanic dose of PrC-210 was administered prior to receiving a dose of gamma radiation (3000 cGy) to each ear. Auditory Brainstem Responses (ABRs) were recorded one week and two weeks after the radiation and compared with the sham animal group. ABR thresholds of guinea pigs that received an intra-peritoneal dose of PrC-210 were significantly better compared to the non-treated, control animals at one week post-radiation. Morphologic analysis of the inner ear revealed significant inflammation and degeneration of the spiral ganglion in the irradiated animals not treated with PrC-210. In contrast, when treated with PrC-210 the radiation effect and injury to the spiral ganglion was significantly alleviated. PrC-210 had no apparent cytotoxic effect in vivo and did not affect the morphology or count of cochlear hair cells. These findings suggest that aminothiol PrC-210 attenuated radiation-induced cochlea damage for at least one week and protected hearing.

Preservation of auditory brainstem response thresholds after cochleostomy and titanium microactuator implantation in the lateral wall of cat scala tympani.

HYPOTHESIS: The safety of implanting a titanium microactuator into the lateral wall of cat scala tympani was assessed by comparing preoperative and postoperative auditory brainstem response (ABR) thresholds for 1 to 3 months. BACKGROUND: The safety of directly stimulating cochlear perilymph with an implantable hearing system requires maintaining preoperative hearing levels. This cat study is an essential step in the development of the next generation of fully implantable hearing devices for humans. METHODS: Following GLP surgical standards, a 1-mm cochleostomy was drilled into the lateral wall of the scala tympani, and a nonfunctioning titanium anchor/microactuator assembly was inserted in 8 cats. The scala media was damaged in the 1 cat. ABR thresholds with click and 4- and 8-kHz stimuli were measured preoperatively and compared with postoperative thresholds at 1, 2, and 3 months. Nonimplanted ear thresholds were also measured to establish statistical significance for threshold shifts (>28.4 dB). Two audiologists independently interpreted thresholds. RESULTS: Postoperatively, 7 cats implanted in the scala tympani demonstrated no significant ABR threshold shift for click stimulus; one shifted ABR thresholds to 4- and 8-kHz stimuli. The eighth cat, with surgical damage to the scala media, maintained stable click threshold but had a significant shift to 4- and 8-kHz stimuli. CONCLUSION: This cat study provides no evidence of worsening hearing thresholds after fenestration of the scala tympani and insertion of a titanium anchor/microactuator, provided there is no surgical trauma to the scala media and the implanted device is securely anchored in the cochleostomy. These 2 issues have been resolved in the development of a fully implantable hearing system for humans. The long-term hearing stability (combined with histologic studies) reaffirm that the microactuator is well tolerated by the cat cochlea.

Assessment of PLGA-PEG-PLGA copolymer hydrogel for sustained drug delivery in the ear.

Temperature sensitive copolymer systems were previously studied using modified diffusion cells in vitro for intratympanic injection, and the PLGA-PEG-PLGA copolymer systems were found to provide sustained drug delivery for several days. The objectives of the present study were to assess the safety of PLGA-PEG-PLGA copolymers in intratympanic injection in guinea pigs in vivo and to determine the effects of additives glycerol and poloxamer in PLGA-PEGPLGA upon drug release in the diffusion cells in vitro for sustained inner ear drug delivery. In the experiments, the safety of PLGA-PEG-PLGA copolymers to inner ear was evaluated using auditory brainstem response (ABR). The effects of the additives upon drug release from PLGA-PEG-PLGA hydrogel were investigated in the modified Franz diffusion cells in vitro with cidofovir as the model drug. The phase transition temperatures of the PLGA-PEG-PLGA copolymers in the presence of the additives were also determined. In the ABR safety study, the PLGA-PEG-PLGA copolymer alone did not affect hearing when delivered at 0.05-mL dose but caused hearing loss after 0.1-mL injection. In the drug release study, the incorporation of the bioadhesive additive, poloxamer, in the PLGA-PEG-PLGA formulations was found to decrease the rate of drug release whereas the increase in the concentration of the humectant additive, glycerol, provided the opposite effect. In summary, the PLGA-PEG-PLGA copolymer did not show toxicity to the inner ear at the 0.05-mL dose and could provide sustained release that could be controlled by using the additives for inner ear applications.

Safety of cidofovir by intratympanic delivery technique.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is one of the most common infectious causes of congenital sensorineural hearing loss. To date, a safe and effective therapy for CMV-induced hearing loss does not exist. We hypothesize that the antiviral cidofovir (CDV) can be delivered to the inner ear via intratympanic (IT) injections to safely and effectively mitigate CMV-induced hearing loss. METHODS: To evaluate the safety of CDV IT injections, weanling guinea pigs with normal hearing were injected intratympanically with 3 mg or 5 mg concentrations of CDV and compared to control animals injected with sterile saline. A separate group of weanling guinea pigs were inoculated with CMV and a subset of this group was treated with CDV following inoculation. RESULTS: The 3 mg/ml and 5 mg/ml CDV concentrations resulted in hearing loss following IT injection into uninfected animals. No signs of inflammation or toxicity were noted on histologic analysis and there was no evidence of systemic toxicity in serology. Hearing loss induced as a result of guinea pig CMV infection recovered by day 21 in animals treated with IT injections of 5 mg/ml CDV. CONCLUSIONS: We provide promising evidence demonstrating both the efficacy and safety of IT CDV in the guinea pig animal model. This research further establishes a sound framework upon which ongoing investigations into drug delivery mechanisms for CMV-induced hearing loss will be based.