Abstract
Objective
To investigate the feasibility of direct application of basic fibroblast growth factor (bFGF) without edge trimming on human subacute traumatic tympanic membrane perforation (TMP).
Methods
A total of 29 patients with traumatic TMPs beyond 1 month after trauma were enrolled. Patients were placed into two groups: an observation group (n = 17) and a bFGF-treated group (n = 12). The bFGF-treated group was treated by direct application of bFGF, in which the margin of the perforation was not trimmed. All patients were followed at least once per week until the perforation was completely closed or for up to 6 months. The closure rate and closure time were estimated.
Results
At 6 months, 11/12 (91.7%) perforations achieved complete closure after bFGF treatment. The mean closure time was 18.1 ± 11.4 days (range = 3–65 days). Purulent otorrhea was found after treatment in five patients, but resolved after oral amoxicillin and ofloxacin ear drops. Of these five patients, four achieved complete closure. However, only 9/17 (52.9%) perforations achieved complete spontaneous closure in the observation group. FGF-treated groups had significantly improved closure rates compared to the observation group (91.7% vs. 52.9%, respectively, P = 0.03).
Conclusions
Although the margin of the perforation was not trimmed, direct application of bFGF on human subacute TMP was feasible, and it could significantly improve the closure rate of the subacute TMPs. The technique was simple and convenient. Thus, direct application of bFGF should be recommended pre-myringoplasty.
1
Introduction
Traumatic tympanic membrane perforation (TMP) is commonly encountered in the otic clinic. It can result in tinnitus, fullness, and conductive hearing loss. Most patients visit the hospital in a timely manner post-trauma, but some may delay a hospital visit for various reasons. Additionally, most traumatic TMPs tend to heal spontaneously, although a few fail to heal, resulting in chronic TMP requiring a myringoplasty.
The use of bFGF on traumatic TMPs has been demonstrated in the clinic and in experiments; the ototoxicity of bFGF has also been widely investigated . However, previous studies have concentrated mainly on acute traumatic TMPs, within 7 or 14 days ; few studies have involved chronic or subacute traumatic TMPs. Although Kato’s experimental study showed that topical application of bFGF improved the rate of chronic TMP healing, the chronic TMP in that study was similar to clinical subacute traumatic TMP, not chronic otitis media with perforation. Santa Maria et al. pointed out that a rat model of chronic tympanic perforation does not exist, only delayed models of healing. In recent years, some scholars have reported that bFGF combined with gelfoam or atelocollagen closed chronic TMPs in adults and children . However, the perforation margin was trimmed to create a fresh edge in those studies. The objective of our study was to investigate the feasibility of direct application of bFGF without trimming of the margin on human subacute TMPs.
2
Materials and methods
The present study was approved by the institutional ethical review board of Wenzhou Medical College-Affiliated Yiwu Hospital in Yiwu, Zhejiang, China. Informed consent was obtained from all participants.
Study subjects were recruited from consecutive patients diagnosed with traumatic TMP who visited the Department of Otorhinolaryngology, Head and Neck Surgery, at the Affiliated Yiwu Hospital of Wenzhou Medical College between September 2008 and December 2013. The inclusion criteria were: (1) traumatic TMPs, (2) the injury time exceeded 30 days after the trauma, (3) a perforation size of at least one-eighth of the pars tensa, and (4) no middle ear infection at the time of the hospital visit.
Age, gender, date of injury, cause of traumatic injury, size of TMP and presence or absence of otorrhea were recorded at the time of the visit. All patients were examined with an endoscope after cleaning cerumen or blood clots from the external auditory canal (EAC), using a cotton bud soaked in povidone-iodine solution, and the site and size of the perforation were documented. Perforation size was graded into two (medium and large) categories that were, respectively, 1/8–1/4 and > 1/4 of the eardrum. Subacute traumatic TMP was defined as the perforation failing to close completely after 30 days post-injury in this study.
Treatment methods and their advantages and disadvantages were carefully described by the clinician when patients visited for the first time. Next, patients were separated into the following two groups: an observation group (n = 17) and a bFGF-treated group (n = 12).
2.1
Observation group
These patients received no further treatment other than continuing to keep the ear dry.
2.2
bFGF-treated group
The EAC was cleaned with a cotton bud soaked in povidone-iodine solution. Approximately 0.1–0.15 mL (2–3 drops) of recombinant bovine bFGF solution (21,000 IU/5 mL; Yi Sheng) was applied onto the eardrum along the EAC once daily to keep the eardrum moist; none of the margin of the perforation was trimmed and no scaffolding material was used.
All patients were followed at least once per week, until the perforation closed completely or for up to 6 months following treatment. In the bFGF-treated group, the first application of bFGF drops was carried out by the physician. Subsequently, the drops were applied by the patients themselves at home, as instructed, until complete perforation closure was confirmed by the physician. The physician determined whether self-application of bFGF by patients at home was correct and whether purulent otorrhea developed during the 2–3 days following the start of treatment. The eardrop dose was adjusted as needed to keep the eardrum moist (not excessively wet or dry). Incorrect application was corrected. The patient was advised to discontinue eardrops if the ear symptoms disappeared or purulent otorrhea occurred. Oral amoxicillin and ofloxacin otic drops were administered simultaneously if purulent otorrhea occurred. To reduce clinician bias, tympanic membrane closure and the occurrence of otorrhea were photo-documented (color pictures) during each follow-up visit.
2
Materials and methods
The present study was approved by the institutional ethical review board of Wenzhou Medical College-Affiliated Yiwu Hospital in Yiwu, Zhejiang, China. Informed consent was obtained from all participants.
Study subjects were recruited from consecutive patients diagnosed with traumatic TMP who visited the Department of Otorhinolaryngology, Head and Neck Surgery, at the Affiliated Yiwu Hospital of Wenzhou Medical College between September 2008 and December 2013. The inclusion criteria were: (1) traumatic TMPs, (2) the injury time exceeded 30 days after the trauma, (3) a perforation size of at least one-eighth of the pars tensa, and (4) no middle ear infection at the time of the hospital visit.
Age, gender, date of injury, cause of traumatic injury, size of TMP and presence or absence of otorrhea were recorded at the time of the visit. All patients were examined with an endoscope after cleaning cerumen or blood clots from the external auditory canal (EAC), using a cotton bud soaked in povidone-iodine solution, and the site and size of the perforation were documented. Perforation size was graded into two (medium and large) categories that were, respectively, 1/8–1/4 and > 1/4 of the eardrum. Subacute traumatic TMP was defined as the perforation failing to close completely after 30 days post-injury in this study.
Treatment methods and their advantages and disadvantages were carefully described by the clinician when patients visited for the first time. Next, patients were separated into the following two groups: an observation group (n = 17) and a bFGF-treated group (n = 12).
2.1
Observation group
These patients received no further treatment other than continuing to keep the ear dry.
2.2
bFGF-treated group
The EAC was cleaned with a cotton bud soaked in povidone-iodine solution. Approximately 0.1–0.15 mL (2–3 drops) of recombinant bovine bFGF solution (21,000 IU/5 mL; Yi Sheng) was applied onto the eardrum along the EAC once daily to keep the eardrum moist; none of the margin of the perforation was trimmed and no scaffolding material was used.
All patients were followed at least once per week, until the perforation closed completely or for up to 6 months following treatment. In the bFGF-treated group, the first application of bFGF drops was carried out by the physician. Subsequently, the drops were applied by the patients themselves at home, as instructed, until complete perforation closure was confirmed by the physician. The physician determined whether self-application of bFGF by patients at home was correct and whether purulent otorrhea developed during the 2–3 days following the start of treatment. The eardrop dose was adjusted as needed to keep the eardrum moist (not excessively wet or dry). Incorrect application was corrected. The patient was advised to discontinue eardrops if the ear symptoms disappeared or purulent otorrhea occurred. Oral amoxicillin and ofloxacin otic drops were administered simultaneously if purulent otorrhea occurred. To reduce clinician bias, tympanic membrane closure and the occurrence of otorrhea were photo-documented (color pictures) during each follow-up visit.
3
Results
A total of 29 patients (14 males, 15 females) met the inclusion criteria; their average age was 37.4 ± 5.9 years (range = 16–61 years). The age, sex, size of the perforation, cause, duration of perforation, side of the ear, site of perforation, presence or absence of previous middle ear disease or pre-existing myringosclerosis and closure time following commencement of treatment are summarized in Table 1 (observation group) and Table 2 (bFGF-treated group). There were no statistically significant differences between the two groups with regard to age, sex, size of perforation, and time course to presentation ( Table 3 ). Table 1 shows that 9/17 (52.9%) perforations achieved complete spontaneous closure. The mean closure time was 9.2 ± 2.9 days (range = 6–16 days). However, Table 2 shows that 11/12 (91.7%) perforations achieved complete closure after bFGF treatment ( Figs. 1 and 2 ). The mean closure time was 18.1 ± 11.4 days (range = 3–65 days). Fig. 3 shows that one large perforation (No. 3) in the observation group failed to close spontaneously within 2 years. Purulent otorrhea was found after treatment in five patients, but resolved with oral amoxicillin and ofloxacin ear drops. Of these five patients, four achieved complete closure. Patients in the bFGF-treated group had significantly improved closure rates compared with those in the observation group (91.7% vs. 52.9%, respectively; chi-square test, P = 0.03).
| No. | Sex | Age, years | cause | side | Size | location | Duration time, days | history of previous middle ear disease or preexisting myringosclerosis | Closure time, days |
|---|---|---|---|---|---|---|---|---|---|
| 1 | M | 56 | PT | R | ME | AI | 41 | N | 16 |
| 2 | F | 26 | S | L | ME | PI | 57 | Y | NH |
| 3 | F | 22 | S | L | LA | AP | 55 | N | NH |
| 4 | F | 56 | B | L | ME | AS | 43 | Y | NH |
| 5 | F | 27 | S | L | LA | KS | 41 | N | NH |
| 6 | F | 42 | S | L | LA | KS | 31 | Y | NH |
| 7 | F | 46 | S | L | ME | AI | 41 | Y | 7 |
| 8 | F | 33 | S | L | ME | AS | 51 | N | NH |
| 9 | F | 39 | S | L | LA | AP | 57 | N | NH |
| 10 | F | 20 | S | L | ME | AI | 33 | N | 8 |
| 11 | F | 45 | S | L | ME | AI | 31 | N | 9 |
| 12 | M | 42 | S | L | ME | AP | 41 | N | 5 |
| 13 | M | 32 | S | L | ME | PS | 62 | N | NH |
| 14 | M | 32 | S | L | ME | AI | 31 | N | 7 |
| 15 | M | 41 | B | L | ME | AI | 37 | N | 12 |
| 16 | M | 33 | S | L | ME | PS | 35 | N | 6 |
| 17 | F | 17 | S | R | ME | AI | 41 | N | 13 |
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