Two-Year Outcomes After Pediatric In-Office Tympanostomy Using Lidocaine/Epinephrine Iontophoresis and an Automated Tube Delivery System.

OBJECTIVE: Evaluate 2-year outcomes after lidocaine/epinephrine iontophoresis and tympanostomy using an automated tube delivery system for pediatric tube placement in-office. STUDY DESIGN: Prospective, single-arm. SETTING: Eighteen otolaryngology practices. METHODS: Children age 6 months to 12 years indicated for tympanostomy were enrolled between October 2017 and February 2019. Local anesthesia of the tympanic membrane was achieved via lidocaine/epinephrine iontophoresis and tympanostomy was completed using an automated tube delivery system (the Tula® System). An additional Lead-In cohort of patients underwent tube placement in the operating room (OR) under general anesthesia using only the tube delivery system. Patients were followed for 2 years or until tube extrusion, whichever occurred first. Otoscopy and tympanometry were performed at 3 weeks, and 6, 12, 18, and 24 months. Tube retention, patency, and safety were evaluated. RESULTS: Tubes were placed in-office for 269 patients (449 ears) and in the OR for 68 patients (131 ears) (mean age, 4.5 years). The median and mean times to tube extrusion for the combined OR and In-Office cohorts were 15.82 (95% confidence interval [CI]: 15.41-19.05) and 16.79 (95% CI: 16.16-17.42) months, respectively. Sequelae included ongoing perforation for 1.9% of ears (11/580) and medial tube displacement for 0.2% (1/580) observed at 18 months. Over a mean follow-up of 14.3 months, 30.3% (176/580) of ears had otorrhea and 14.3% (83/580) had occluded tubes. CONCLUSION: In-office pediatric tympanostomy using lidocaine/epinephrine iontophoresis and automated tube delivery results in tube retention within the ranges described for similar grommet-type tubes and complication rates consistent with traditional tube placement in the OR.

In-Office Tympanostomy Tube Placement Using Iontophoresis and Automated Tube Delivery Systems.

OBJECTIVES: (1) To evaluate safety, tolerability, and technical success of lidocaine iontophoresis and a tympanostomy tube placement system for adults in an office setting and (2) to meet regulatory evidence requirements for new drugs and devices. STUDY DESIGN: Prospective, multicenter, single arm. SETTING: Patients were recruited in 8 community-based practices in the United States between June and September 2017. SUBJECTS AND METHODS: This study evaluated tympanic membrane anesthesia and tube placement in 30 adults. Anesthesia was achieved via iontophoresis of a lidocaine/epinephrine solution. Tube placement was conducted using an integrated myringotomy and tube delivery system. Tolerability of tube placement was measured using a patient-reported visual analog scale from 0 mm (no pain) to 100 mm (worst possible pain). Mean pain score was compared to a performance goal of 45 mm, where statistical superiority represents mild pain or less. Technical success and safety through 3 weeks postprocedure were evaluated. RESULTS: Twenty-nine (29/30, 96.7%) patients had tube(s) successfully placed in all indicated ears. One patient demonstrated inadequate tympanic membrane anesthesia, and no tube placement was attempted. The mean (SD) pain score of 9.4 (15.7) mm was statistically superior to the performance goal. There were no serious adverse events. Seven nonserious events were related to device, procedure, or drug: inadequate anesthesia (1), vertigo (1), and dizziness (1) at the time of procedure and ear discomfort (1), tube occlusion (2), and medial tube migration (1) postprocedure. CONCLUSION: Lidocaine iontophoresis provides acceptable tympanic membrane anesthesia for safe, tolerable, and successful in-office tube placement using an integrated myringotomy and tube delivery system.

In-Office Tympanostomy Tube Placement in Children Using Iontophoresis and Automated Tube Delivery.

OBJECTIVES/HYPOTHESIS: Evaluate technical success, tolerability, and safety of lidocaine iontophoresis and tympanostomy tube placement for children in an office setting. STUDY DESIGN: Prospective individual cohort study. METHODS: This prospective multicenter study evaluated in-office tube placement in children ages 6 months through 12 years of age. Anesthesia was achieved via lidocaine/epinephrine iontophoresis. Tube placement was conducted using an integrated and automated myringotomy and tube delivery system. Anxiolytics, sedation, and papoose board were not used. Technical success and safety were evaluated. Patients 5 to 12 years old self-reported tube placement pain using the Faces Pain Scale-Revised (FPS-R) instrument, which ranges from 0 (no pain) to 10 (very much pain). RESULTS: Children were enrolled into three cohorts with 68, 47, and 222 children in the Operating Room (OR) Lead-In, Office Lead-In, and Pivotal cohorts, respectively. In the Pivotal cohort, there were 120 and 102 children in the <5 and 5- to 12-year-old age groups, respectively, with a mean age of 2.3 and 7.6 years, respectively. Bilateral tube placement was indicated for 94.2% of children <5 and 88.2% of children 5 to 12 years old. Tubes were successfully placed in all indicated ears in 85.8% (103/120) of children <5 and 89.2% (91/102) of children 5 to 12 years old. Mean FPS-R score was 3.30 (standard deviation [SD] = 3.39) for tube placement and 1.69 (SD = 2.43) at 5 minutes postprocedure. There were no serious adverse events. Nonserious adverse events occurred at rates similar to standard tympanostomy procedures. CONCLUSIONS: In-office tube placement in selected patients can be successfully achieved without requiring sedatives, anxiolytics, or papoose restraints via lidocaine iontophoresis local anesthesia and an automated myringotomy and tube delivery system. LEVEL OF EVIDENCE: 2b Laryngoscope, 130:S1-S9, 2020.

Phase 3 Trials of Thermosensitive Ciprofloxacin Gel for Middle Ear Effusion in Children with Tubes.

OBJECTIVE: To investigate the efficacy, safety, and microbiology of a thermosensitive otic suspension of ciprofloxacin (OTO-201) in children with bilateral middle ear effusion undergoing tympanostomy tube placement. STUDY DESIGN: Two randomized, double-blind, sham-controlled phase 3 trials. Patients were randomized to intratympanic OTO-201 or sham. SETTING: Children with bilateral middle ear effusion undergoing tympanostomy tube placement. SUBJECTS/METHODS: Studies evaluated 532 patients (6 months to 17 years old) in a combined analysis of efficacy (treatment failure: presence of otorrhea, otic or systemic antibiotic use, lost to follow-up, missed visits), safety (audiometry, otoscopy, tympanometry), and microbiology. RESULTS: There was a lower cumulative proportion of treatment failures in patients receiving OTO-201 vs tympanostomy tubes alone (1) on days 4, 8, 15, and 29; (2) on day 15, primary end point (23.0% vs 45.1%; age-adjusted odds ratio, 0.341; P < .001; reduction in relative risk, 49%); and (3) on day 15, blinded-assessor otorrhea treatment failure (7.0% vs 19.4%; age-adjusted odds ratio, 0.303; P < .001; reduction in relative risk, 64%). Per-protocol and subgroup analyses (baseline demographics, pathogen type, culture status, effusion type, microbiologic response) supported these findings. There were no drug-related serious adverse events; the most frequent treatment-emergent adverse events in both groups were pyrexia, postoperative pain, nasopharyngitis, cough, and upper respiratory tract infection. OTO-201 administration had no evidence of increased tube occlusion and no negative effect on audiometry, tympanometry, or otoscopy. CONCLUSIONS: Combined analysis of 2 phase 3 trials demonstrated a lower cumulative proportion of treatment failures through day 15 compared with TT alone when OTO-201 was administered intratympanically for otitis media with bilateral middle ear effusion at time of tympanostomy tube placement.

Randomized Clinical Trial of a Sustained-Exposure Ciprofloxacin for Intratympanic Injection During Tympanostomy Tube Surgery.

OBJECTIVE: This exploratory clinical trial evaluated the safety and clinical activity of a novel, sustained-exposure formulation of ciprofloxacin microparticulates in poloxamer (OTO-201) administered during tympanostomy tube placement in children. METHODS: Double-blind, randomized, prospective, placebo- and sham-controlled, multicenter Phase 1b trial in children (6 months to 12 years) with bilateral middle ear effusion requiring tympanostomy tube placement. Patients were randomized to intraoperative OTO-201 (4 mg or 12 mg), placebo, or sham (2:1:1 ratio). RESULTS: Eighty-three patients (52 male/31 female; mean age, 2.80 years) were followed for safety (otoscopic exams, cultures, audiometry, and tympanometry) and clinical activity, defined as treatment failure (physician-documented otorrhea and/or otic or systemic antibiotic use ≥3 days post surgery). At baseline, 14.3% to 36.8% of children showed positive cultures of middle ear effusion samples in at least 1 ear. Through day 15, treatment failures accounted for 14.3%, 15.8%, 45.5%, and 42.9% of patients (OTO-201 4 mg, OTO-201 12 mg, placebo, and sham, respectively); treatment failure reductions for OTO-201 doses were significant compared to pooled control (P values = .023 and .043, respectively). Observed OTO-201 safety profile was indistinguishable from placebo or sham. CONCLUSIONS: Results of this first clinical trial suggest that OTO-201 was well tolerated and shows preliminary clinical activity in treating tympanostomy tube otorrhea.

A multicenter, randomized, double-blind placebo-controlled, single dose trial of the safety and efficacy of intravenous ibuprofen for treatment of pain in pediatric patients undergoing tonsillectomy.

BACKGROUND: Tonsillectomy is one of the most common pediatric procedures in the United States. An optimal perioperative pain control regimen remains a challenge. Intravenous ibuprofen administered at induction of anesthesia may be a safe and efficacious option for postoperative tonsillectomy pain. OBJECTIVES: To determine whether preoperative administration of intravenous ibuprofen (IV-ibuprofen) can significantly decrease the number of doses of postoperative fentanyl when compared with placebo in pediatric tonsillectomy surgical patients. METHODS: This was a multicenter, randomized, double-blind placebo-controlled trial conducted at six hospitals in the United States. A total of 161 pediatric patients aged 6-17 years undergoing tonsillectomy were randomized to receive either a single preoperative dose of 10 mg·kg(-1) IV-ibuprofen or placebo (normal saline). Postoperative pain was managed with intravenous fentanyl (0.5 µg·kg(-1)) on an as needed basis when the visual analog scale (VAS) was >30 mm and deemed appropriate by recovery room nurse/physician. The primary endpoint was the number of doses and amount of postoperative fentanyl administered postoperatively for rescue analgesia. RESULTS: There was a significant reduction in the number of postoperative doses and the amount of fentanyl administered after surgery in the IV-ibuprofen group compared with the placebo group (P = 0.021). There were no differences in the time to first analgesia request or the number of patients who required postoperative analgesia. There were no significant differences in the incidence of serious adverse events, surgical blood loss (P = 0.662), incidence of postoperative bleeding, or a need for surgical re-exploration between the treatment groups. CONCLUSION: Administration of IV-ibuprofen, 10 mg·kg(-1) , significantly reduced fentanyl use in pediatric tonsillectomy patients.

Comparison of clonidine, local anesthetics, and placebo for pain reduction in pediatric tonsillectomy.

OBJECTIVE: To determine if pretonsillectomy injection of local anesthetics with and without clonidine reduces pain following tonsillectomy in children. DESIGN: A prospective, randomized, double-blind, placebo-controlled trial. SETTING: Tertiary care academic medical center. PATIENTS: A total of 120 children, ages 3 to 17 years, presenting for tonsillectomy. INTERVENTIONS: Patients were randomized to 1 of 3 pretonsillectomy injection groups: (1) saline, (2) lidocaine plus bupivacaine, or (3) lidocaine plus bupivacaine plus clonidine. MAIN OUTCOME MEASURES: The total number of analgesic doses consumed on postoperative days (PODs) 1, 3, 5, and 7. Secondary outcome variables included total time and intravenous analgesic doses required in the recovery room, visual analog scale pain scores, and maximum tolerated diet on postoperative days 1, 3, 5, and 7. RESULTS: The total number of analgesic doses on PODs 1, 3, 5, and 7 were not significantly different between the randomization groups (P = .53). The median numbers (interquartile ranges) of analgesic doses were 12.0 (9.0-16.8) for the lidocaine plus bupivacaine plus clonidine group, 12.0 (10.0-16.5) for the lidocaine plus bupivacaine group, and 14.0 (9.0-15) for the placebo group. The placebo group was found to have a more advanced diet on POD 1 (P = .04) and significantly less pain on POD 3 (P = .02). Multivariable analysis showed children in the lidocaine plus bupivacaine plus clonidine group were significantly less likely to need intravenous pain medication in the recovery room compared with children in the placebo group and again showed that the placebo group achieved a significantly more advanced diet and had less pain on PODs 1 and 3. CONCLUSION: Pretonsillectomy injection of lidocaine, 1%, and bupivacaine, 0.5%, with or without clonidine (25 µg) is not recommended for the reduction of posttonsillectomy pain. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00678379.

Contemporary management of intracranial complications of otitis media.

OBJECTIVES: Intracranial complications as a result of otogenic infections occur even in the antibiotic era. Meningitis is the most common reported intracranial complication, followed by brain abscess and lateral sinus thrombosis. The purpose of this study is to review our experience and management of these serious complications. MATERIALS AND METHODS: A retrospective chart review was performed at a tertiary referral medical center for the period from 1998 to 2007. Charts with acute or chronic otitis media as primary diagnosis were reviewed, and intracranial complications secondary to either were included in the study. Age, sex, clinical presentation, radiographic findings, management, and outcome were studied. Patients with meningitis or petrous apicitis were not included in the study. RESULTS: Ten cases reviewed had intracranial complications. Five patients had brain abscesses, 1 patient had a subdural empyema, and 4 patients had lateral sinus thrombosis. All patients received broad-spectrum intravenous antibiotics for 6 weeks. Mastoidectomy was performed in all patients, but not all patients were treated with direct drainage of the intracranial abscess, especially if clinical and serial radiographic response was favorable. CONCLUSION: Otogenic intracranial complications can be fatal if not managed appropriately. Broad-spectrum intravenous antibiotics for 6 weeks is usually sufficient treatment. Management of the intracranial disease takes precedence, but direct drainage of the abscess may not be necessary if a patient's symptoms, neurologic status, and radiographic findings progress favorably. A high index of suspicion should be maintained on all patients presenting with symptoms not typically seen with routine otitis media.

Biodegradation of Inion fast-absorbing biodegradable plates and screws.

Biodegradable plates and screws are recommended for use in surgery of the craniofacial skeleton of children. To be effective and not interfere with growth of the child's skull, the plates must biodegrade sufficiently to release the holding power of the plate and screw within 1 year. It is also essential that excessive foreign body reaction and cyst formation does not occur when the plates and screws biodegrade. The purpose of this experimental study was to evaluate the rate of biodegradation of Inion CPS Baby biodegradable plates and screws under different clinical circumstances in the rabbit craniofacial skeleton and evaluate their efficacy for use in pediatric craniofacial surgery. Foreign body reaction would be evaluated. Inion baby plates and screws were tested in a rabbit model. Plates were applied to the frontal bone, over a bony defect of the parietal bone, to a nasal bone fracture, and inserted in the subcutaneous space over the occipital bone in thirty 6-week-old rabbits. Six rabbits were euthanized at 9, 12, 15, and 18 months' postoperative time point and examined for residual plates and screws. Bone from each surgical site was excised, fixed by immersion in 10% neutral-buffered formalin, decalcified in Immunocal solution, and examined by 7-microm paraffin sections stained with hematoxylin and eosin. At 9 months, the plates and screws had effectively biodegraded and no longer had holding power on the bones. Fragmentation of the implant material was noted. Residual implant material was still present on gross and histologic examination in rabbits at 9, 12, 15, and 18 months. Residue of a screw was still palpable in 1 rabbit at 18 months. There was no evidence of cyst formation in any of the examined specimens. Macrophages and giant cells were present in most of the specimens at 9, 12, 15, and 18 months. Findings from the current study revealed a relative short resorption time (9 mo) and normal inflammatory sequelae in an adult rabbit model. These findings suggest that these plates may be used safely in fixing the pediatric craniofacial skeleton.

Familial head and neck cancer: molecular analysis of a new clinical entity.

OBJECTIVE: The tumor suppressor gene p16 encodes a cyclin-dependent kinase inhibitor that normally inhibits cell proliferation by causing a G1 cell cycle arrest. The p16 gene is frequently mutated in a variety of somatic tumors, as well as in familial melanoma and familial pancreatic carcinoma. We identified a family with a high incidence of head and neck squamous cell carcinoma (HNSCC) and melanoma. Molecular analyses of the p16 gene locus in blood and tumor DNA from this family was performed to determine whether an association between germline p16 gene mutation and HNSCC exists. STUDY DESIGN: Molecular pedigree analyses. METHODS: Exon 2 of p16 was polymerase chain reaction amplified from blood, tumor, or nontumor DNA isolated from affected and unaffected members, then directly sequenced and compared with consensus p16 sequence. Cell cycle position of cells expressing wild-type or mutant p16 was determined by flow cytometry. RESULTS: Molecular analyses revealed a nonfunctional germline point mutation within exon 2 of the p16 gene that encodes a mutant p16 protein substituting proline at amino acid position 87 for the wild-type arginine (p16R87P). Relative to wild-type p16, p16R87P lost ability to cause a growth arrest following ectopic expression. The mutant (p16R87P) allele segregated with cancer predisposition in tested family members, and analyses of HNSCC tumor tissues demonstrated universal loss of wild-type allele. CONCLUSIONS: Significance of the mutant p16 (p16R87P) in HNSCC tumorigenesis is strongly suggested by its loss of cell cycle arrest activity and its retention in tumor tissue with simultaneous loss of the wild-type allele. Further, the germline p16 mutation segregated with cancer predisposition within the family. In aggregate, these data suggest that there is a direct causal relationship between the germline p16 mutation in this family and HNSCC tumorigenesis. Based on our observations, the spectrum of familial cancers associated with p16 mutations should include a new clinical entity, familial HNSCC.