Abstract
Objective
A pilot study was performed to investigate the utility of basic fibroblast growth factor (bFGF) in the repair of blast-induced total or near-total tympanic membrane perforations (TMPs).
Study design
Prospective clinical study.
Setting
Tertiary university hospital.
Subjects and methods
Patients who fulfilled the inclusion criteria were treated with 0.10–0.15 mL of bFGF solution applied directly to total or near-total TMPs once daily until the perforations closed or for a maximum of 6 months. The treatment response was monitored via serial otoendoscopy, and audiometric outcomes were evaluated.
Results
Complete TMP closure was achieved in 16 of 17 patients with a blast-induced total or near-total TMP. The mean closure time was 28.4 ± 10.9 days. The improvement in hearing from pre- to post-treatment was statistically significant. There were no complications or adverse outcomes.
Conclusions
The direct application of bFGF to blast-induced total or near-total TMPs is a promising, minimally invasive alternative to conventional tympanoplasty, with a comparable success rate. As reported in the literature, the closure rate was higher than achieved with spontaneous healing. There was no effect of the inverted edge on healing outcome. The use of bFGF in this setting has immediate therapeutic applications for military personnel with blast-induced TMPs who are stationed in isolated, remote environments.
1
Introduction
Tympanic membrane perforation (TMP) is a common clinical sign in blast injury. Without timely closure, TMPs may result in tinnitus and hearing loss, and thus negatively affect a patient’s quality of life. Although traumatic TMPs tend to heal spontaneously, blast-induced TMPs are difficult to repair, with a spontaneous closure rate of 29–38% after 6–12 months . Early tympanoplasty is the standard treatment for blast-induced total or near-total TMPs . However, tympanoplasty is expensive, requires hospitalization and anesthesia, and has an associated surgical risk. Moreover, tympanoplasty may not be possible for military personnel stationed in remote, isolated regions (especially under wartime conditions).
In animal studies, the topical application of basic fibroblast growth factor (bFGF) has been shown to promote the proliferation and migration of fibroblasts and epithelial cells as well as angiogenesis, resulting in accelerated TMP closure . A clinical study of chronic TMPs found that the topical application of bFGF improved the membrane closure rate . Our group recently performed a series of clinical randomized controlled trials of bFGF for the treatment of non-explosive-induced traumatic TMPs. The results showed that bFGF, when applied either directly or in combination with gelfoam, significantly shortened the membrane closure time and improved the membrane closure rate . However, there are few reports in the literature on the effectiveness of topical bFGF for blast-induced TMPs. Blast-induced TMPs differ from non-explosive TMPs in that in most cases the former are total or near-total TMPs, accompanied by inverted edges, foreign bodies, and bloody otorrhea . Our early clinical studies did not include patients with blast-induced TMPs. However, based on further research and testing, we consider the direct application of bFGF appropriate for the treatment of blast-induced total or near-total TMPs. In China, blast-induced TMPs are almost always caused by the explosion of fireworks and firecrackers, but the lighting of firecrackers and private use of fireworks have been gradually prohibited. Consequently, blast-induced total or near-total TMPs are rarely seen nowadays. Therefore, rather than a full-scale clinical study we performed a pilot study to investigate the utility of bFGF in the treatment of blast-induced total or near-total TMPs.
2
Materials and methods
This study was reviewed and approved by the institutional ethics review board of Wenzhou Medical College-Affiliated Yiwu Hospital (Yiwu, China). All work was performed in compliance with the Declaration of Helsinki. Informed consent was obtained from all participants. The patients were recruited from consecutive patients diagnosed with a blast-induced traumatic TMP who visited the Hospital’s Department of Otorhinolaryngology and Head and Neck Surgery between March 2012 and January 2014. The inclusion criteria were: (1) a traumatic TMP involving ≥ 75% of the entire tympanic membrane (TM) and caused by a blast explosion, (2) regular follow-up, and (3) no middle ear infection at the time of the hospital visit. A patient was excluded if granulation tissue or purulent otorrhea was evident in the ear, if the patient had persistent severe vertigo, and/or if a skull base fracture or ossicular disruption was suspected upon physical examination or imaging.
Age, sex, date of injury, right vs. left ear, TMP size, and presence or absence of otorrhea were recorded at the time of the first visit. All patients were examined endoscopically after cerumen or blood clots were removed from the external auditory canal (EAC) as detailed below. At that time, the site and size of the perforation were documented. A near-total TMP was defined as involving ≥ 75% of the entire TM, as determined using ImageJ software (National Institutes of Health, Bethesda, MD). Each tympanic cavity was carefully examined for the presence of a foreign body and dislocation or fracture of the ossicular chain. All detected foreign bodies were removed. Standard pure-tone audiometric testing was performed at the initial and final visits or 6 months after treatment. Pure-tone averages of air and bone conduction were determined at 500, 1000, 2000, and 4000 Hz.
2.1
Statistical analyses
Student’s t -test and the Wilcoxon signed rank test were used to analyze the audiometric outcome in successfully treated patients. P < 0.05 was considered to indicate statistical significance.
2.2
Technique
The EAC was cleaned with a cotton bud soaked in povidone iodine solution. The EAC and middle ear were carefully examined by endoscopy for the presence of a foreign body, which was then removed. The TM was treated once daily by the direct application of 0.10–0.15 mL (2–3 drops) of recombinant bovine bFGF solution (21000 IU/5 mL) (Yi Sheng, Zhuhai City, China). The surface and edge of the TM were kept slightly moist. The edge of the perforation was not approximated, and no scaffolding material was used. The first bFGF application was performed by a physician. Thereafter, the drops were applied daily at home by the patients themselves, as instructed, until complete closure of the perforation was confirmed by a physician. In patients with profound sensorineural hearing loss, intravenous steroids and vasodilators were administered simultaneously for 7–10 days.
Oral amoxicillin was prescribed for all patients for 1 week. All patients were followed-up twice a week during the 2 weeks following treatment and at least once a week thereafter until either complete closure of the perforation was evident or for up to 6 months. Any ear symptom (e.g., purulent otorrhea, otalgia, and/or vertigo) that developed during follow-up was recorded. The bFGF dose was adjusted as needed to ensure that the surface of the eardrum was moist (not excessively wet or dry). The TM was examined endoscopically at all follow-up visits to evaluate the perforation size. A computed tomography (CT) scan of the temporal bone was obtained 6 months after closure to determine whether granulation tissue or a cholesteatoma was evident in the middle ear.
2
Materials and methods
This study was reviewed and approved by the institutional ethics review board of Wenzhou Medical College-Affiliated Yiwu Hospital (Yiwu, China). All work was performed in compliance with the Declaration of Helsinki. Informed consent was obtained from all participants. The patients were recruited from consecutive patients diagnosed with a blast-induced traumatic TMP who visited the Hospital’s Department of Otorhinolaryngology and Head and Neck Surgery between March 2012 and January 2014. The inclusion criteria were: (1) a traumatic TMP involving ≥ 75% of the entire tympanic membrane (TM) and caused by a blast explosion, (2) regular follow-up, and (3) no middle ear infection at the time of the hospital visit. A patient was excluded if granulation tissue or purulent otorrhea was evident in the ear, if the patient had persistent severe vertigo, and/or if a skull base fracture or ossicular disruption was suspected upon physical examination or imaging.
Age, sex, date of injury, right vs. left ear, TMP size, and presence or absence of otorrhea were recorded at the time of the first visit. All patients were examined endoscopically after cerumen or blood clots were removed from the external auditory canal (EAC) as detailed below. At that time, the site and size of the perforation were documented. A near-total TMP was defined as involving ≥ 75% of the entire TM, as determined using ImageJ software (National Institutes of Health, Bethesda, MD). Each tympanic cavity was carefully examined for the presence of a foreign body and dislocation or fracture of the ossicular chain. All detected foreign bodies were removed. Standard pure-tone audiometric testing was performed at the initial and final visits or 6 months after treatment. Pure-tone averages of air and bone conduction were determined at 500, 1000, 2000, and 4000 Hz.
2.1
Statistical analyses
Student’s t -test and the Wilcoxon signed rank test were used to analyze the audiometric outcome in successfully treated patients. P < 0.05 was considered to indicate statistical significance.
2.2
Technique
The EAC was cleaned with a cotton bud soaked in povidone iodine solution. The EAC and middle ear were carefully examined by endoscopy for the presence of a foreign body, which was then removed. The TM was treated once daily by the direct application of 0.10–0.15 mL (2–3 drops) of recombinant bovine bFGF solution (21000 IU/5 mL) (Yi Sheng, Zhuhai City, China). The surface and edge of the TM were kept slightly moist. The edge of the perforation was not approximated, and no scaffolding material was used. The first bFGF application was performed by a physician. Thereafter, the drops were applied daily at home by the patients themselves, as instructed, until complete closure of the perforation was confirmed by a physician. In patients with profound sensorineural hearing loss, intravenous steroids and vasodilators were administered simultaneously for 7–10 days.
Oral amoxicillin was prescribed for all patients for 1 week. All patients were followed-up twice a week during the 2 weeks following treatment and at least once a week thereafter until either complete closure of the perforation was evident or for up to 6 months. Any ear symptom (e.g., purulent otorrhea, otalgia, and/or vertigo) that developed during follow-up was recorded. The bFGF dose was adjusted as needed to ensure that the surface of the eardrum was moist (not excessively wet or dry). The TM was examined endoscopically at all follow-up visits to evaluate the perforation size. A computed tomography (CT) scan of the temporal bone was obtained 6 months after closure to determine whether granulation tissue or a cholesteatoma was evident in the middle ear.
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