Systematic review of ototoxic pre-surgical antiseptic preparations – what is the evidence?

Objective There is uncertainty regarding the safety of surgical antiseptic preparations in the ear. A systematic review of the literature was conducted to assess the evidence regarding ototoxicity of surgical antiseptic preparations. Methods A literature search was conducted using the PRISMA methods. Key words included “ototoxicity” “hearing loss”, “antiseptic”, “surgical preparation”, “tympanoplasty”, “vestibular dysfunction”, “chlorhexidine”, “iodine”, “povidone”, “ethanol”, and “hydrogen peroxide” using Medline, Embase, Cochrane Library, Scopus and Web of Science. We included peer-reviewed papers that 1) objectively measured ototoxicity in humans or animals through hearing, vestibular function or histologic examination, 2) studied topically applied surgical antiseptic preparations, 3) were either in English or had an English abstract. We excluded papers that were 1) in vitro studies, 2) ear trauma studies, 3) studies of ototoxic ear drops intended for therapy, or 4) case reports. Studies included in the final review were screened using the PRISMA method. Current systematic review registration number pending: 83,675. Results Fifty-six papers were identified as using PRISMA criteria. After applying our exclusion criteria, 13 papers met overall study criteria. Of these, six papers reported ototoxicity of iodine based solutions, five papers reported ototoxicity of chlorhexidine and ethanol and two papers assessed hydrogen peroxide. All papers reviewed were animal studies. Iodine based solutions show least harm overall, while chlorhexidine and high concentrations of alcohol based solutions showed most harm. The evidence on hydrogen based solutions was inconclusive. Conclusions The overall evidence for anyone antiseptic solution is weak. There is some evidence that iodine, chlorhexidine, hydrogen peroxide and alcohol based antiseptics have ototoxicity. Conclusive evidence for human ototoxicity from any solution is not strong.


Background
Antiseptic cleaning of skin prior to surgical intervention is the standard of care globally. Pre-surgical antiseptic preparation has been known to reduce the number of wound infections when used adequately [1]. However some standard antiseptic preparations have been shown to cause toxicity to the eyes and ears when used in head and neck surgery [2]. Currently, in otologic surgery, there remains uncertainty regarding the safety of surgical antiseptic preparations in the ear. This has been a long standing area of concern as described in a case series conducted by Bicknell et al. in the early 1960s. Bicknell et al. describe varying degrees of morbidity following tympanoplasty surgery, ranging from high frequency hearing loss to "dead ears" with the main commonality between patients being pre-surgical preparation of the ear with chlorhexidine [3]. The purpose of this study was to conduct a systematic review of the literature to assess the evidence regarding ototoxicity of standard surgical antiseptic preparations. The focus of this study was to review ototoxicity of povidone-iodine, chlorhexidine gluconate, ethanol and hydrogen peroxide.

Methods
A systematic literature review was conducted using various combinations of the following key words: "ototoxicity", "hearing loss", "antiseptic", "surgical preparation", "tympanoplasty", "vestibular dysfunction", "chlorhexidine", "iodine", "povidone", "ethanol", and "hydrogen peroxide" using the databases: Medline, Embase, Cochrane Library, Scopus and Web of Science through September 2016. Further studies were obtained through screening references from relevant articles and the authors' own databases and grey literature including legal proceedings. Criteria for inclusion of a published article in this review were applied to the collected studies by two independent reviewers.
Studies included were peer-reviewed papers that 1) objectively measured ototoxicity in humans or animals through hearing, vestibular function or histologic examination, 2) studied topically applied surgical antiseptic preparations, 3) were either in English or had an English abstract. Excluded studies were 1) in vitro studies, 2) ear trauma studies, 3) studies of ototoxic ear drops intended for therapy and 4) case reports. Studies included in the final review were screened using the PRISMA method [4].
Each paper identified through PRISMA criteria was reviewed for the following data items including: experimental subjects, solutions and concentrations tested and objective measure of ototoxicity. Objective measure of ototoxicity was defined as having any of the following: audiological or vestibular testing done before and after exposure to the solution, histological examinations or gross pathologic examinations. Due to the broad variation in objective measures of ototoxicity, no direct meta-analysis of the data was conducted between studies. However, the data obtained from the final results of studies meeting the set criteria in all studies are summarized in Tables 1, 2 and 3. Sources of error for these studies are further assessed in the discussion section.

Results
Fifty-six studies were identified through database searches and searches of relevant article references. Using pre-set criteria as mentioned above, 43 articles were eliminated as outlined in Fig. 1. Of the final 13 articles included in this review; six pertained to iodine based solutions, five to chlorhexidine and ethanol and two papers to hydrogen peroxide. All papers identified were animal studies.
Of the papers assessing the ototoxicity of povidoneiodine, Aursnes et al. found that povidone-iodine solutions in 70% alcohol with greater then 10 min of middle ear exposure to the solution caused an increase in cochlear damage [5]. Ichibangase et al. assessed ototoxicity of povidone-iodine 10% solution in guinea pigs of varying ages [6]. They found that those animals deemed to be infant or young had increased cochlear toxicity compared to adult guinea pigs. One reason they suggested for this finding was increased permeability of the round window membrane in infant versus adult guinea pigs as the membrane thickens with age [6]. Of the studies pertaining to povidone-iodine scrubs that contain detergents, all studies found that scrubs caused higher ototoxicity than povidone-iodine solutions, suggesting that detergent facilitates entry of the scrub into the inner ear [6][7][8].
In studies assessing chlorhexidine gluconate solutions, Igarashi et al. found that a concentration of 0.05% caused no change in Auditory Brainstem Response (ABR) from baseline after three applications of solution to the middle ear [9]. Perez showed that after three applications of 0.5% chlorhexidine gluconate to the middle ear of sand rats, no ABR were present in previously normal hearing animals [10]. Finally, three applications of chlorhexidine solution at 2.0% concentration caused destruction of outer hair cells on histological examination of the cochlea. Concentrations of 0.05 and 2.0% were shown to cause thick serous middle ear discharge on gross pathological examination. Similarly,. Perez et al. found that 70% Ethyl Alcohol caused gross pathological changes to the middle ear space including erythema and edema. In some animals oedema of the external ear canal was so severe that testing of hearing was not possible [10]. Morizono et al. tested several strengths of ethanol ranging from 0.1 to 100% pure ethanol in the middle ear cavities of chinchillas [11]. They concluded that there was evidence of ototoxicity for ethanol concentrations greater than 10% using cochlear microphonics [11].
Finally, Perez et al. and Nader et al. assessed the ototoxicity of 3% hydrogen peroxide solutions [12]. While Nader et al. found no difference in ABR from baseline after a 5 min exposure of 3% hydrogen peroxide to the middle ear of chinchillas, Perez et al. found the majority of sand rats tested had an increase in threshold from an average of 55 dB to 108 dB after 5 applications of 3% hydrogen peroxide [12,13].

Discussion
In this review, we identified 13 studies showing the ototoxicity of povidone-iodine, chlorhexidine gluconate, ethanol/ ethyl alcohol and hydrogen peroxide in controlled non-trauma settings. All studies were animal studies and no direct human correlation can be drawn given the differences in anatomy of the middle ear space, dosing of antiseptic preparations and in some cases the duration of exposure being in the order of several weeks. However, some solutions showed high ototoxicity in relatively low concentrations and short exposure times. This includes povidone-iodine scrub which contains detergent, povidone-iodine in 70% alcohol, and chlorhexidine gluconate in 70% alcohol [5][6][7]14]. However for other solutions there is no consensus from the studies identified. (Tables 1, 2 and 3).
There are several limitations of this current review. The methods and objective measures are inconsistent.
All the studies identified in this review were animal studies so we are cautious about drawing conclusions from different species using different methods on the potential of the solutions to cause damage in human subjects. In studies conducted on guinea pigs and chinchillas the main hypothesized method of inner ear penetration for solutions is through the round window. The Chinchilla round window membrane is 1/6 of the thickness of that of humans therefore this model is likely over estimating ototoxicity in humans [15].
There are also several challenges differentiating conductive hearing loss from sensorineural hearing loss in animal subjects. The time period over which animals were assessed may not have been adequate [7].

Conclusion
Given the findings of this review, the evidence of human ototoxicity of currently used antiseptic preparations is not strong. Iodine based, non-alcoholic, non-detergent solutions may be the least ototoxic but all should be used with caution.