Evaluation of Subjective Tinnitus Severity and Distortion Product Otoacoustic Emissions and Extended High-Frequency Audiometry.

OBJECTIVE: Tinnitus is a multifactorial phenomenon with quality-of-life detriments for those affected by it. We aim to establish a relationship between subjective tinnitus severity with objective audiometric data in the extended high frequency (EHF) from 9 to 16 khz and with distortion product otoacoustic emissions (DPOAE). We hypothesize that severe subjective tinnitus as measured by the Tinnitus Handicap Inventory (THI) does not correlate with increased hearing thresholds in the EHF range. STUDY DESIGN: Prospective. SETTING: Single Tertiary Care Center. METHODS: Patients identified with tinnitus and normal hearing thresholds within standard frequency range (250-8000 Hz) were consented for participation. Those with underlying otologic disease, trauma, radiotherapy, or ototoxic drug use were excluded. The THI questionnaire was given to eligible patients and audiometric test results were collected. THI scores were categorized by severity groups. An n = 20 to 30 was determined to have an effect size of 0.7 with a significance level of P = .05. RESULTS: THI and audiometric data were collected for 38 patients and categorized into mild (n = 18, 47.4%), moderate (n = 8, 21.1%), slight (n = 7, 18.4%), and severe (n = 5, 13.2%) tinnitus severity groups. Mean THI score was 32.3 ± 19.6 with a statistically significant difference in scores by assigned THI severity group (P < .01). There were no significant differences or linear relationship among hearing thresholds in EHF range or DPOAE stratified by subjective tinnitus group (P = .49, r2 = 0.10) CONCLUSION: Subjective tinnitus severity is not predictive of audiometric outcomes. This finding can be used as a counseling tool to help tinnitus patients manage symptoms, expectations, and overall treatment outcomes.

Modified Frailty Index Associates With Transoral Robotic Surgery Complications and Survival: A National Database Study.

OBJECTIVE: The modified frailty index (mFI-5) is a National Surgical Quality Improvement Program-derived 5-factor index that has been proven to reflect frailty and predict morbidity and mortality. We hypothesize that mFI-5 is a valid predictive measure in the transoral robotic surgery (TORS) population. METHODS: Retrospective study utilizing the TriNetX US-collaborative health records network querying for TORS patients. Cohorts were stratified by mFI-5 score which uses five ICD-10 codes: nonindependent functional status, hypertension, obstructive respiratory disease, heart failure, and diabetes mellitus. Cohorts were matched by age using propensity score matching. Outcome measures included survival, infection, pneumonia, tracheostomy dependence, and percutaneous endoscopic gastrostomy dependence. Reported odds ratios were normalized to mFI-5 = 0. RESULTS: A total of 9,081 patients were included in the final analysis. Greater mFI-5 scores predicted decreased survival and increased incidence of postoperative infection and pneumonia. Odds of 5-year mortality were 1.93 (p = 0.0003) for mFI-5 = 2 and 1.90 (p = 0.0002) for mFI-5 = 3. Odds of 2-year mortality were 1.25 (p = 0.0125) for mFI-5 = 1, 1.58 (p = 0.0002) for mFI-5 = 2, and 1.87 (p = 0.003) for mFI-5 = 3. Odds of postoperative infection were 1.51 (p = 0.02) for mFI-5 = 2 and 1.78 (p = 0.05) for mFI-5 = 3. Two-year odds of developing pneumonia were 1.69 (p = 0.0001) for mFI-5 = 2 and 2.84 (p < 0.0001) for mFI-5 = 3. Two-month odds of pneumonia were 1.50 (p = 0.0259) for mFI-5 = 2 and 2.55 (p = 0.0037) for mFI-5 = 3. mFI-5 = 4 or 5 had too few patients to analyze. Using polynomial regression to model age versus incident 5-year post-TORS death (R2 = 0.99), mFI-5 scores better predicted survival than age alone. CONCLUSION: This study demonstrates that mFI-5 predicts mortality, pneumonia, and postoperative infection independently of age. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Cognitive and language outcomes for pediatric hearing loss with otologic surgery.

OBJECTIVES: To test the hypothesis that surgical otologic intervention for any type of pediatric hearing loss decreases the odds for incident adverse cognitive and linguistic developmental outcomes. STUDY DESIGN: Retrospective cohort database study. METHODS: Electronic medical record data from the TriNetX Research Network were queried for children with congenital, sensorineural, conductive, and mixed hearing loss (HL) between ages 0 and 5 years. Patients were further stratified by presence (HL + surgery) or absence (HL-surgery) of surgical intervention at any point following diagnosis, including cochlear implantation, tympanoplasty with or without mastoidectomy, and tympanostomy. Primary outcomes were defined as odds for new adverse cognitive or linguistic outcomes at any point given HL treatment status [odds ratio with 95% confidence interval, (OR; 95%CI, p-value)]. Cohorts were balanced using propensity-score matching (PSM) based on US census-defined demographics and clinically relevant congenital conditions. RESULTS: Of 457,636 total patients included in the study, 118,576 underwent surgery (HL + surgery cohort) and 339,060 did not (HL-surgery). In matched cohorts, surgical otologic intervention significantly decreased the odds of developing cognitive disorders including scholastic, motor, psychological developmental disorders, and pervasive developmental delays (p < 0.01). CONCLUSIONS: Surgical interventions for treatment of pediatric HL including cochlear implantation, tympanoplasty with or without mastoidectomy, and tympanostomy should be considered as they may prevent delays in development.

The Effect of Postoperative Naloxone in Certain Otolaryngologic Surgeries.

OBJECTIVE: To evaluate the association of postoperative naloxone with the development of new substance use disorder (SUD), overdose, and death within 6 months of otolaryngologic surgery. STUDY DESIGN: Retrospective cohort database study on TriNetX. METHODS: Adult patients who underwent tonsil surgery (noncancerous), thyroid/parathyroid, septorhinoplasty, otology/neurotology, sinus/anterior skull base, and head and neck cancer surgeries between January 2003 and April 2023. Patients were excluded if they had an instance of SUD or overdose recorded in their charts prior to surgery, or had undergone another surgery within that 6-month time frame. We hypothesized that patients prescribed naloxone postoperatively would have decreased odds for experiencing new SUD, overdose, and/or death within 6 months of surgery compared to patients who did not receive naloxone. P < .01 was considered statistically significant. RESULTS: There were 2,305,655 patients in this study. The average age was 36.7 ± 19.5 years old, with 46% female patients. Before matching, cohorts showed equivocal odds for developing new SUD, increased odds for overdose, and mixed odds for dying. After matching for demographic variables and comorbidities such as other substance use, opioid use for other pathologies, and psychiatric conditions, these effects diminished (P > .01). CONCLUSION: Our results suggest that postoperative naloxone may not significantly affect development of new SUD and incident overdose and death in certain otolaryngologic surgeries after controlling for prior SUD and psychiatric conditions. Clinicians should be aware of these comorbidities when considering their postoperative pain management protocol, which may or may not include naloxone.

Association of Smoke and Nicotine Product Consumption With Sensorineural Hearing Loss: A Population-Level Analysis.

OBJECTIVE: To test the hypothesis that use of cigarettes or other products with either cigarette-like smoke profile or high nicotine content by young populations increases the odds of developing sensorineural hearing loss (SNHL). STUDY DESIGN: Retrospective cohort study. SETTING: TriNetX US Collaborative Network (2003-2022). PATIENTS: Approximately 3.6 million patients at least 18 years old. INTERVENTION: None. MAIN OUTCOME MEASURES: The primary outcome of interest was diagnosis of SNHL, defined using medical billing codes ( International Classification of Diseases, Tenth Revision , Current Procedural Terminology , etc.). Cohort inclusion criteria included electronic health record entry after 2003, age 18 to 54 or 55+ years at index, and status of cigarette, noncigarette nicotine, or cannabis use. Covariates were controlled via 1:1 propensity score matching for SNHL-related conditions, including diabetes mellitus and ischemic diseases. Odds for developing SNHL were calculated against control subjects aged 18 to 54 years who have no record of nicotine/cannabis use. RESULTS: Odds for developing SNHL are higher for people 18 to 54 years old who use any nicotine product (odds ratio [95% confidence interval], 5.91 [5.71-6.13]), cigarettes only (4.00 [3.69-4.33]), chewing tobacco only (9.04 [7.09-11.63]), or cannabis only (3.99 [3.60-4.44]) compared with control. People 55+ years old who use no products also showed increased odds for SNHL (4.73 [4.63-4.85]). CONCLUSIONS: Both nicotine and smoke exposure seem to be strongly associated with increased odds for developing SNHL, with chewing tobacco having the strongest association.

Differences in Functional and Survival Outcomes Between Patients Receiving Primary Surgery vs Chemoradiation Therapy for Treatment of T1-T2 Oropharyngeal Squamous Cell Carcinoma.

Importance: Due to lack of data from high-powered randomized clinical trials, the differences in functional and survival outcomes for patients with oropharyngeal squamous cell carcinoma (OPSCC) undergoing primary transoral robotic surgery (TORS) vs primary radiation therapy and/or chemoradiation therapy (RT/CRT) are unclear. Objectives: To compare 5-year functional (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) and survivorship outcomes in patients with T1-T2 OPSCC receiving primary TORS vs RT/CRT. Design, Setting, and Population: This national multicenter cohort study used data from a global health network (TriNetX) to identify differences in functional and survival outcomes among patients with OPSCC who underwent primary TORS or RT/CRT in 2002 to 2022. After propensity matching, 726 patients with OPSCC met inclusion criteria. In the TORS group, 363 (50%) patients had undergone primary surgery, and in the RT/CRT group, 363 (50%) patients had received primary RT/CRT. Data analyses were performed from December 2022 to January 2023 using the TriNetX platform. Exposure: Primary surgery with TORS or primary treatment with radiation therapy and/or chemoradiation therapy. Main Outcomes and Measures: Propensity score matching was used to balance the 2 groups. Functional outcomes were measured at 6 months, 1 year, 3 years, 5 years, and more than 5 years posttreatment and included dysphagia, gastrostomy tube dependence, and tracheostomy dependence according to standard medical codes. Five-year overall survivorship was compared between patients undergoing primary TORS vs RT/CRT. Results: Propensity score matching allowed a study sample with 2 cohorts comprising statistically similar parameters with 363 (50%) patients in each. Patients in the TORS cohort had a mean (SD) age of 68.5 (9.9) vs 68.8 (9.7) years in RT/CRT cohort; 86% and 88% were White individuals, respectively; 79% of patients were men in both cohorts. Primary TORS was associated with clinically meaningful increased risk of dysphagia at 6 months (OR, 1.37; 95% CI, 1.01-1.84) and 1 year posttreatment (OR, 1.71; 95% CI, 1.22-2.39) compared with primary RT/CRT. Patients receiving surgery were less likely to be gastrostomy tube dependent at 6 months (OR, 0.46; 95% CI, 0.21-1.00) and 5 years posttreatment (risk difference, -0.05; 95% CI, -0.07 to -0.02). Differences in overall rates of tracheostomy dependence (OR, 0.97; 95% CI, 0.51-1.82) between groups were not clinically meaningful. Patients with OPSCC, unmatched for cancer stage or human papillomavirus status, who received RT/CRT had worse 5-year overall survival than those who underwent primary surgery (70.2% vs 58.4%; hazard ratio, 0.56; 95% CI, 0.40-0.79). Conclusions and Relevance: This national multicenter cohort study of patients undergoing primary TORS vs primary RT/CRT for T1-T2 OPSCC found that primary TORS was associated with a clinically meaningful increased risk of short-term dysphagia. Patients treated with primary RT/CRT had an increased risk of short- and long-term gastrostomy tube dependence and worse 5-year overall survival than those who underwent surgery.

Evaluating the impact of hemodynamic support measures on head and neck free tissue transfer outcomes: A population-based analysis.

OBJECTIVES: This study sought to analyze the effects of perioperative blood transfusions and vasopressors on 30-day surgical complications and 1-year mortality after reconstructive surgery in head and neck free tissue transfer (FTT) and to identify predictors of administration of perioperative blood transfusions or vasopressors. MATERIALS AND METHODS: TriNetX (TriNetX LLC, Cambridge, USA), an international population-level electronic health record database, was queried to identify subjects that underwent FTT requiring perioperative (intraoperative to postoperative day 7) vasopressors or blood transfusions. Primary dependent variables were 30-day surgical complications and 1-year mortality. Propensity score matching was used to control for population differences, and covariate analysis was used to identify preoperative comorbidities associated with perioperative vasopressor or transfusion requirements. RESULTS: 7,631 patients met inclusion criteria. Preoperative malnutrition was associated with increased odds of perioperative transfusion (p = 0.002) and vasopressor requirement (p < 0.001). Perioperative blood transfusion (n = 941) was associated with increased odds of any surgical complication (p = 0.041) within 30 days postoperatively and specifically increased odds of wound dehiscence (p = 0.008) and FTT failure (p = 0.002), respectively. Perioperative vasopressor was (n = 197) was not associated with 30-day surgical complications. Vasopressor requirement was associated with increased hazards-ratio of mortality at 1-year (p = 0.0031). CONCLUSION: Perioperative blood transfusion in FTT is associated with increased odds for surgical complications. Judicious use as a hemodynamic support measure should be considered. Perioperative vasopressor use was associated with an increased risk of one-year mortality. Malnutrition is a modifiable risk factor for perioperative transfusion and vasopressor requirement. These data warrant further investigation to assess causation and potential opportunity for practice improvement.

Trends in Endoscopic and Microscopic Approaches to Transsphenoidal Pituitary Surgery in the US.

OBJECTIVES: Among the transsphenoidal (TSS) approaches to pituitary tumors, the microscopic approach (MA) has historically been the predominant technique with the increasing adoption of the endoscopic approach (EA). This study investigates national trends in TSS approaches and postoperative outcomes for MA and EA through 2021. METHODS: The TriNetX database was queried for patients undergoing TSS (MA and EA) between 2010 and 2021. Data were collected on demographics, geographic distribution of surgical centers, postoperative complications, stereotactic radiosurgery (SRT), repeat surgery, and postoperative emergency department (ED) visits. RESULTS: 8644 TSS cases were queried between 2010 and 2021. MA rates were highest until 2013 when rates of EA (52%) surpassed MA (48%) and continued to increase through 2021 (81%). From 2010 to 2015 EA had higher odds of a postoperative CSF leak (OR 3.40) and diabetes insipidus (DI (OR 2.30)) versus MA (p < 0.05); from 2016 to 2021 differences were not significant. Although there was no significant difference among approaches from 2010 to 2015 for syndrome of inappropriate antidiuretic hormone (SIADH), hyponatremia, or bacterial meningitis, from 2016 to 2021 EA had lower odds of SIADH (OR 0.54) and hyponatremia (OR 0.71), and higher odds of meningitis (OR 1.79) versus MA (p < 0.05). EA had higher odds of additional surgery (either EA or MA) after initial surgery from 2010 to 2021. From 2010 to 2015 EA had lower odds of postoperative SRT compared to MA, whereas in 2016-2021 there was no statistical difference among approaches. CONCLUSION: This study demonstrates increasing EA adoption for TSS in the United States since 2013. Complication rates have overall improved for EA compared to MA, potentially as a result of improving surgeon familiarity and experience. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2135-2140, 2023.

Federated Electronic Health Record Database via a Public-Private Partnership to Enhance Health Care Equity by Disparity Discovery and Equitable Clinical Trial Recruitment.

Despite increasingly stringent requirements from regulatory agencies, clinical trials often fail to recruit study populations representative of real-world demographics and disease prevalence and are often skewed away from racial/ethnic minorities. Consequently, data produced by such trials can result in treatment guidelines and outcome expectations that do not apply to racial/ethnic minorities, further widening health disparities. In this study, we describe a new tool, the TriNetX Diversity Lens ("Diversity Lens"), which augments the existing electronic health record querying functionality of TriNetX and allows clinical trial sponsors to rapidly evaluate the potential impact of inclusion and exclusion criteria on the eligibility rates of different racial and ethnic groups. We describe the development of Diversity Lens in collaboration with public and private stakeholders. Additionally, we feature examples of how Diversity Lens can bring to the surface insights into existing health disparities and prospectively explore the impact of study criteria on the eligibility of racial/ethnic minorities.

Follow-Up Phone Interviews and Attendance Motivation From A Free Head and Neck Cancer Screening.

INTRODUCTION: Head and Neck Cancer Awareness and Screening Programs (HNCASP) are popular community outreach events hosted by academic and community otolaryngology departments. However, long-term follow-up of participants is lacking. PATIENTS AND METHODS: Participants of a HNCASP held at an academic cancer center prospectively filled out demographic and risk factor surveys followed by HNC screening examination. A phone interview was conducted for participants between 2012 and 2016 with suspicious findings to assess outcomes. RESULTS: Participants were largely Caucasian, female, and had health insurance, reflecting the setting at an academic medical center. Despite this, there were 156 (16.8%) positive screenings; 47 of these completed follow up interviews. Twelve (1.1% of all participants) cancer cases were confirmed. DISCUSSION: A significant proportion of HNCASP participants benefited from this screening opportunity. Education regarding HNC is the primary benefit and motivational factor for attendance of HNCASPs, although a significant subset of patients was identified that needed follow-up, and several cancers were detected.

Toll-like Receptor 4 Signaling and Downstream Neutrophilic Inflammation Mediate Endotoxemia-Enhanced Blood-Labyrinth Barrier Trafficking.

HYPOTHESIS: Both toll-like receptor 4 (TLR4) and downstream neutrophil activity are required for endotoxemia-enhanced blood-labyrinth barrier (BLB) trafficking. BACKGROUND: Aminoglycoside and cisplatin are valuable clinical therapies; however, these drugs often cause life-long hearing loss. Endotoxemia enhances the ototoxicity of aminoglycosides and cisplatin in a TLR4 dependent mechanism for which downstream proinflammatory signaling orchestrates effector immune cells including neutrophils. Neutrophil-mediated vascular injury (NMVI) can enhance molecular trafficking across endothelial barriers and may contribute to endotoxemia-enhanced drug-induced ototoxicity. METHODS: Lipopolysaccharide (LPS) hypo-responsive TLR4-KO mice and congenitally neutropenic granulocyte colony-stimulating factor (GCSF) GCSF-KO mice were studied to investigate the relative contributions of TLR4 signaling and downstream neutrophil activity to endotoxemia-enhanced BLB trafficking. C57Bl/6 wild-type mice were used as a positive control. Mice were treated with LPS and 24 hours later cochleae were analyzed for gene transcription of innate inflammatory cytokine/chemokine signaling molecules, neutrophil recruitment, and vascular trafficking of the paracellular tracer biocytin-TMR. RESULTS: Cochlear transcription of innate proinflammatory cytokines/chemokines was increased in endotoxemic C57Bl/6 and GCSF-KO, but not in TLR4-KO mice. More neutrophils were recruited to endotoxemic C57Bl/6 cochleae compared with both TLR4 and GCSF-KO cochleae. Endotoxemia enhanced BLB trafficking of biocytin-TMR in endotoxemic C57Bl/6 cochleae and this was attenuated in both TLR4 and GCSF-KO mice. CONCLUSION: Together these results suggest that TLR4-mediated innate immunity cytokine/chemokine signaling alone is not sufficient for endotoxemia-enhanced trafficking of biocytin-TMR and that downstream neutrophil activity is required to enhance BLB trafficking. Clinically, targeting neutrophilic inflammation could protect hearing during aminoglycoside, cisplatin, or other ototoxic drug therapies.

Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.

BACKGROUND: Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy. METHODS: Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200 mg/kg NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15 min post NAC. Twenty-eight subjects (15 men; mean age 72.2 ± 6.8 years) received NAC IV (N = 13) or IA (N = 15). RESULTS: The first participant to experience grade 4 toxicity was at the 600 mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450 mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450 mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p < 0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3 mM concentration which seemed to be nephroprotective in previous preclinical studies. CONCLUSIONS: In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450 mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: https://eudract.ema.europa.eu . Unique identifier: 2011-000887-92.

Effect of sepsis and systemic inflammatory response syndrome on neonatal hearing screening outcomes following gentamicin exposure.

OBJECTIVES: Hearing loss in neonatal intensive care unit (NICU) graduates range from 2% to 15% compared to 0.3% in full-term births, and the etiology of this discrepancy remains unknown. The majority of NICU admissions receive potentially ototoxic aminoglycoside therapy, such as gentamicin, for presumed sepsis. Endotoxemia and inflammation are associated with increased cochlear uptake of aminoglycosides and potentiated ototoxicity in mice. We tested the hypothesis that sepsis or systemic inflammatory response syndrome (SIRS) and intravenous gentamicin exposure increases the risk of hearing loss in NICU admissions. METHODS: The Institutional Review Board at Oregon Health & Science University (OHSU) approved this study design. Two hundred and eight infants met initial criteria, and written, informed consent were obtained from parents or guardians of 103 subjects ultimately enrolled in this study. Prospective data from 91 of the enrolled subjects at OHSU Doernbecher Children's Hospital Neonatal Care Center were processed. Distortion product otoacoustic emissions (DPOAEs; f2 frequency range: 2063-10,031 Hz) were obtained prior to discharge to assess auditory performance. To pass the DPOAE screen, normal responses in >6 of 10 frequencies in both ears were required; otherwise the subject was considered a "referral" for a diagnostic hearing evaluation after discharge. Cumulative dosing data and diagnosis of neonatal sepsis or SIRS were obtained from OHSU's electronic health record system, and the data processed to obtain risk ratios. RESULTS: Using these DPOAE screening criteria, 36 (39.5%) subjects would be referred. Seventy-four (81%) subjects had intravenous gentamicin exposure. Twenty (22%) had ≥4 days of gentamicin, and 71 (78%) had <4 days. The risk ratio (RR) of referral with ≥4 days of gentamicin was 1.92 (p=0.01). Eighteen subjects had sepsis or met neonatal SIRS criteria, 9 of whom had ≥5 days of gentamicin and a DPOAE referral risk ratio of 2.12 (p=0.02) compared to all other subjects. Combining subjects with either vancomycin or furosemide overlap with gentamicin treatment yielded an almost significant risk ratio (RR=1.77, p=0.05) compared to the rest of the cohort. CONCLUSIONS: We report an increased risk of referral with DPOAE screening for those receiving ≥4 days of intravenous gentamicin administration that may contribute to the greater prevalence of hearing loss in NICU graduates. We propose an expanded prospective study to gather a larger cohort of subjects, identifying those with sepsis or neonatal SIRS, to increase the statistical power of this study design. Subsequent studies also need to obtain follow-up diagnostic audiological data to verify whether the outcomes of DPOAE screening, in addition to the standard AABR screen, is a reliable predictor of permanent hearing loss following gentamicin exposure in the NICU.

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity.

The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB) or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.

Thin and open vessel windows for intra-vital fluorescence imaging of murine cochlear blood flow.

Normal microvessel structure and function in the cochlea is essential for maintaining the ionic and metabolic homeostasis required for hearing function. Abnormal cochlear microcirculation has long been considered an etiologic factor in hearing disorders. A better understanding of cochlear blood flow (CoBF) will enable more effective amelioration of hearing disorders that result from aberrant blood flow. However, establishing the direct relationship between CoBF and other cellular events in the lateral wall and response to physio-pathological stress remains a challenge due to the lack of feasible interrogation methods and difficulty in accessing the inner ear. Here we report on new methods for studying the CoBF in a mouse model using a thin or open vessel-window in combination with fluorescence intra-vital microscopy (IVM). An open vessel-window enables investigation of vascular cell biology and blood flow permeability, including pericyte (PC) contractility, bone marrow cell migration, and endothelial barrier leakage, in wild type and fluorescent protein-labeled transgenic mouse models with high spatial and temporal resolution. Alternatively, the thin vessel-window method minimizes disruption of the homeostatic balance in the lateral wall and enables study CoBF under relatively intact physiological conditions. A thin vessel-window method can also be used for time-based studies of physiological and pathological processes. Although the small size of the mouse cochlea makes surgery difficult, the methods are sufficiently developed for studying the structural and functional changes in CoBF under normal and pathological conditions.