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Feb 8, 2014 - However, Mesna cannot be an alternative method for the application of ventilation tubes. Keywords Mesna · Myringotomy · Ventilation tube.
Eur Arch Otorhinolaryngol (2015) 272:1099–1102 DOI 10.1007/s00405-014-2906-9

OTOLOGY

After myringotomy, can topical Mesna application be an alternative method to ventilation tube application? Rifat Karli · Fatih Ilkaya · Arzu Karli · Emre Gunbey · Harun Kucuk · Hasan Guzel · Emre Ayhan 

Received: 6 November 2013 / Accepted: 21 January 2014 / Published online: 8 February 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract Sodium-2-mercaptoethanesulfonate (Mesna) is a mucolytic substance that is also used for chemically assisted tissue dissection in otological surgery. We investigated the effects of Mesna as a chemical agent on the closing time of perforation of the eardrum in an experimental animal model. We performed simple myringotomy with a knife on 44 tympanic membranes of 22 rats. Four rats were excluded from the study because of serosity in their ears. Rats were divided into two study groups and a control group. These groups were the Mesna-administered group (Group A) (8 rats, 15 tympanic membranes), the saline-administered group (Group B) (8 rats, 14 tympanic membranes) and the control (native) group (6 rats, 11 tympanic membranes) (Group C). We applied Mesna locally for 20 min following myringotomy. Examination was made with an otoendoscope on days 1, 2, 3, 5, and 7, and patency rates were recorded. According to our results, we found that the closing time of the tympanic membrane was significantly longer in the Mesna group than in the saline administrated and native group. After myringotomy procedure, the application of a single dose of Mesna may contribute to the recovery duration of middle-ear pathologies by delaying the closing time of tympanic membrane perforation.

R. Karli (*) · E. Gunbey · H. Kucuk · E. Ayhan  Department of Otorhinolaryngology, School of Medicine, Ondokuz Mayis University, Samsun, Turkey e-mail: [email protected]; [email protected] F. Ilkaya · H. Guzel  Department of Medical Pharmacology, School of Medicine, Ondokuz Mayis University, Samsun, Turkey A. Karli  Department of Pediatric Infection, School of Medicine, Ondokuz Mayis University, Samsun, Turkey

However, Mesna cannot be an alternative method for the application of ventilation tubes. Keywords  Mesna · Myringotomy · Ventilation tube

Introduction Myringotomy and ventilation tube application are the most commonly performed surgical procedures in otolaryngologic head and neck surgery practicals. The purpose of ventilation tubes is to provide enough air into the middle ear to allow for healing of middle-ear pathologies. However, the ventilation tube procedure can include some perioperative and post-operative complications. In the perioperative period, these complications include loss of the ventilation tube into the middle ear and some implantation difficulties; in the post-operative period, otorrhea, permanent eardrum perforation, cholesteatoma, and tympanosclerosis are the most likely complications [1]. To prevent these events after myringotomy, some alternative methods by doing clinical and experimental studies could prolong the closure time of eardrum perforation without the application of a ventilation tube in the literatüre [2–4]. Adhesions between the different layers of tissues are rich in disulfide bonds. These bonds may be physiological or pathological. Some drugs are capable of destroying these bonds. Sodium 2-mercaptoethanesulfonate (C2H5NaO3S2: Mesna) is a chemical substance that can break the bonds between fibrous tissues. Mesna is a synthetic sulfur compound that induces mucolysis by destroying the disulfide bonds of the mucous polypeptide chains. In fact, Mesna is usually used to prevent urothelial damage induced by some antineoplastic agents because it inactivates metabolites in patients with bladder cancer. These metabolites can

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Eur Arch Otorhinolaryngol (2015) 272:1099–1102

Table 1  Statistical analysis according to the groups’ closing time of the myringotomies Group

Number

Mean recover (day)

SD

95 % confidence interval for mean (day) Minimum/ Maximum

Minimum recover (day)

Maximum recovery (day)

Control SF Mesna

11 14 15

2,1818 2,3571 5,6000

0,87386 0,64584 2,16465

1,5947 1,4069 4,4013

2,7689 3,3074 6,7987

1,00 1,00 2,00

3,00 7,00 7,00

Total

40

3,5250

2,33136

2,7794

4,2706

1,00

7,00

irritate mucous membranes and lead to urotoxicity [5, 6]. At the same time, Mesna has been used in a variety of other disorders. For example, in recent years, the drug has been administered for abdominal myomectomies and excision of endometrial cysts, as well as in ear, skull base, and head and neck diseases. It can be used in outpatient and/or operating room settings and simplifies the treatment without side effect [7]. As in other surgery areas, Mesna usage in otolaryngology is growing. In our study, we investigated the effect of a single topical administration of Mesna on closure time of eardrum perforation. If this application method was to prolong the recovery time of tympanic membrane perforation, it may be an alternative to the ventilation tube application.

Materials and methods This study was approved by the Animal Experiments Local Ethical Committee of Ondokuz Mayis University. Rats were bought from the Laboratory Animals Research and Application Center of Ondokuz Mayis University. The surgical portion of the study and the drug applications were performed in the same center. Rats were anesthetized using 100 mg/kg ketamine and 0.75 mg/kg chlorpromazine intraperitoneally; under automicroscopic observation, a 1-mm standard myringotomy was performed on both eardrums using ear speculums and sterile picks. Myringotomies were performed using a straight otologic pick with tip diameter of 1 mm. All the perforations were made as the diameter of the peak. Therefore, standardization has been achieved [16]. Next, Mesna and saline were administered topically according to the respective groups (Group A, B). No substance was administered to the native (control) group (Group C). If the eardrums were normal in one rat, these eardrums were studied. One eardrum in the control group, two eardrums in the saline group, and one eardrum in the Mesna group were excluded from the study because of serous otitis. In the Myringotomy (Group C, n  = 6), only standard myringotomy was performed on 11 eardrums. In the Myringotomy + Saline group (Group B, n  = 8), 14

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eardrums underwent myringotomy, and then gel foam absorbed saline was applied for 20 min to the perforated area. Fifteen eardrums in the Myringotomy + Mesna (Group A, n = 8) group were subjected to myringotomy, and then we applied gel foam absorbed 20 % Mesna (100 mg/ml) to the perforated area for 20 min. Examinations were conducted with an otoendoscope on days 1, 2, 3, 5, and 7, and patency rates were recorded.

Statistical method Data analyses were performed with the Statistical Package for the Social Sciences (SPSS for Windows, version 15.0) software. Distributions of the data were analyzed with the One Sample Kolmogorov Smirnow Test. Our comparison between groups was performed with the Kruskal– Wallis Test due to a non-parametric distribution in the Mesna group. We performed binary comparisons of the three groups using the Mann–Whitney U Test. Estimated p values were divided by three, which was the comparison count.

Results In the Mesna group, closure time of eardrum perforation was statistically increased in comparison to the saline and native (control) groups. There was no significant difference between the saline and native (control) groups (Table 1) (Fig. 1).

Discussion In this study, Mesna significantly increased the closing time of eardrum perforation in comparison to the control group. So far, several studies have examined the effects of antineoplastic agents in conjunction with myringotomy applied using laser and radiofrequency on tympanic membrane perforation recovery time. In these studies is reported, the

Eur Arch Otorhinolaryngol (2015) 272:1099–1102

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12 Control Group

Saline Group

Mesna Group

10 8 6 4 2 0 CT:1 day

CT:2 day

CT:3 day

CT:5 day

RT:7 day

Fig. 1  Distribution according to groups’ closing time of the tympanic membrane after myringotomy, CT Closing Time. (1) column, Control group; (2) column, Saline group; (3) column, Mesna group

tympanic membrane closure time to be longer than normal after myringotomy [2–4]. In our study, we used Mesna, a synthetic sulfur compound. This substance acts by breaking sulfite bonds [8]. In recent years, Mesna has been used for tissue dissection in surgical and invasive procedures due to its chemical properties [7]. In otolaryngology practicals, particularly for adhesive otitis and atelectatic eardrums, Mesna has been used in chemodissection for adhesions between the tympanic membrane and the middle ear mucosa [9]. Some drugs administered topically into the middle ear may lead to ototoxic effects due to the permeability of the round window membrane to many substances. The ototoxic effects of many ototopically applied substances are well-documented in experimental animal models [10, 11]. It is important to determine whether the topical application of Mesna has a toxic effect like some other administered preperates to the middle ear. However, obtaining an effective result after a single administration of Mesna may be accepted as an advantage despite the risk of toxicity. In otologic surgery, neurotoxic or systemic effects are rare because of the local nature of procedures. We generally use 20 % Mesna in adhesive otitis surgery. We applied a single dose of Mesna transmembranally through the nonretracted part of the tympanic membrane or to the middle ear through the antrum using a dental needle. After the application of Mesna, we waited until the retracted part achieved a mature position. This time period took approximately 4–6 min. In a study by Yilmaz and his colleagues, Mesna was applied to 42 ears of 39 patients with diagnoses of retraction pockets fixed to the incudostapedial joint, stapes or promontorium, and adhesive otitis media. They reported that Mesna application facilitated the surgical operation and increased surgical success and reliability. In their study, they observed

no sensorineural hearing loss [9]. In the literature, few studies have used experimental animals to research the ototoxic effect of Mesna. In one of these studies, the toxicity of Mesna was assessed using transmission electron microscopy, scanning electron microscopy, and auditory brainstem response testing. This study revealed that these tests were normal and did not show any toxic effect on cochlear morphology [12]. In another study, which was done by Van Spaendonck and his colleagues, interference contrast microscopy and scanning electron microscopy were used. These researchers observed no macroscopic signs of middle-ear inflammation in any of the treated ears and no morphological and quantitative differences in the cochlea. As a result, they determined that the single ototopical application of Mesna has no ototoxic effects on guinea pig cochlear hair cells [13]. In our experimental myringotomy model, we found that Mesna had a negative effect on the recovery of the tympanic membrane due to its disturbing effect of protein building. It has been demonstrated that the proliferation and migration of the tympanic membrane cell layer at the perforation area and size may affect the healing process and outcome [14, 15]. Therefore, in our study, the process always the same localization and size of the tympanic membrane (anterior quadrant) by the same surgeon were made. Our study rats showed a homogeneous distribution in terms of physiological characteristics (age, weight, sex). We think that the most important factor of closure of perforation of the eardrum is the location and size of the perforation. Other reasons are minimal impacts on the closure time of the tympanic membrane. Therefore, treatment and control groups were formed separately. A lot of experimental study has been applied with this method which related to mringotomy in the literature [16, 17]. In recent years, many studies have been done to try to delay the recovery time of tympanic membrane perforation using various drugs and methods. Mesna is a pharmacologic drug that has been growing in usage for chemodissection in many clinics in recent years. Mesna usage is increasing in otologic surgery, especially for adhesive otitis, but we could not find any information in the literature about its effect on the closing time of tympanic membrane perforation. According to our results, Mesna delayed closing time of tympanic membrane. Therefore, Mesna may be positive contribution to the improvement of middle-ear pathology by extending the closing time of tympanic membrane. We cannot recommend its usage in recurrent doses because no studies have researched its ototoxic and systemic effects on the body.

Conclusion The application of Mesna as a single dose significantly delayed the closing time of tympanic membrane perforation

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in comparison to the control group in rats. However, this single administration cannot be an alternative method for the application of ventilation tubes. Following myringotomy, the application of a single dose of Mesna may contribute to the recovery duration of middle-ear pathologies by delaying the closing time of tympanic membrane perforation. Acknowledgments  Supports for this study were not received from any public or private institutions. Conflict of interest  The authors declare no conflicts of interest in preparing this article.

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