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(B) Enlarged image. (C) and (D) Histopathology of the chest wall lesion. The papillomas comprise finger-like projections with a central fibrovascular nucleus and stratified pavimentous epithelium. 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[ "nombre" => "Carlos Miguel" "apellidos" => "Chiesa Estomba" ] 1 => array:2 [ "nombre" => "Jose Angel" "apellidos" => "González García" ] 2 => array:2 [ "nombre" => "Jon Alexander" "apellidos" => "Sistiaga Suarez" ] 3 => array:2 [ "nombre" => "Izaskun Thomas" "apellidos" => "Arrizabalaga" ] 4 => array:2 [ "nombre" => "Ekhiñe" "apellidos" => "Larruscain Sarasola" ] 5 => array:2 [ "nombre" => "Xabier" "apellidos" => "Altuna Mariezcurrena" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001651917301590" "doi" => "10.1016/j.otorri.2017.06.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001651917301590?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S217357351830019X?idApp=UINPBA00004N" "url" => "/21735735/0000006900000002/v1_201803220938/S217357351830019X/v1_201803220938/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review article</span>" "titulo" => "Cochleotoxicity monitoring protocol" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "105" "paginaFinal" => "109" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "José Ferreira Penêda, Nuno Barros Lima, Leandro Ribeiro, Diamantino Helena, Bruno Domingues, Artur Condé" "autores" => array:6 [ 0 => array:4 [ "nombre" => "José" "apellidos" => "Ferreira Penêda" "email" => array:1 [ 0 => "jfpeneda@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Nuno" "apellidos" => "Barros Lima" ] 2 => array:2 [ "nombre" => "Leandro" "apellidos" => "Ribeiro" ] 3 => array:2 [ "nombre" => "Diamantino" "apellidos" => "Helena" ] 4 => array:2 [ "nombre" => "Bruno" "apellidos" => "Domingues" ] 5 => array:2 [ "nombre" => "Artur" "apellidos" => "Condé" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Otorhinolaryngology, Centro-Hospitalar Vila Nova de Gaia-Espinho, Vila Nova de Gaia, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Protocolo de monitorización de cocleototoxicidad" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">According to the American Academy of Otolaryngology Position Statement (<span class="elsevierStyleItalic">American Academy of Otolaryngology–Head and Neck Surgery, revised in 26/09/2015</span>), ototoxicity may be defined as inner ear damage as a consequence of drug or chemical administration. Despite being a concept known for centuries, it was first scientifically described in 1945 by Hinshaw and Feldman on their work with streptomycin.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">1,2</span></a> Since then, more than 200 medications were labelled as potential ototoxic.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> Aminoglycosides antibiotics (AG) and platinum based chemotherapeutic agents are the most studied ones since they cause cochlear damage in a frequent and permanent manner.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Since its discovery in 1940s by Waksman and his team, streptomycin and the more recent aminoglycosides have been widely used for several gram negative bacteria and <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> infections.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2,4</span></a> They inhibit protein synthesis by binding to the bacterial 30S ribosomal subunit<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">5,6</span></a> and are largely used mainly due to low price, broad-spectrum efficacy, low incidence of allergic reactions and wide accessibility.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> Due to this reasons, in the developing countries, ototoxicity due to aminoglycosides antibiotics is a major public health issue.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Despite being known since the 19th century as <span class="elsevierStyleItalic">Peyrone's salt</span>, cisplatin (CP) antineoplastic action was only discovered in the following century by Rosenberg and his team.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> Since then cisplatin have been used to treat several malignancies such as head and neck primary and metastatic cancer.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2,4</span></a> Cancer cell uptakes cisplatin that binds covalently to DNA, further initiating down-stream apoptotic pathways.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">5,6</span></a> Carboplatin and oxaplatin, although less ototoxic than cisplatin, seem to be less effective than cisplatin against some cancers.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The molecular pathways of ototoxicity are complex and incompletely understood; several necrotic and apoptotic pathways may be involved<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> but its description is beyond the scope of this article. The common feature of AG and CP ototoxicity is the production of Reactive Oxidative Species (ROS) and their effects on hair cell death.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">5,6,8,9</span></a> Besides that, there is a tonotopic pattern of cochlear hair cell loss present both in AG and CP ototoxicity – it affects initially the outer hair cells of basal part of the cochlea (high frequencies) further progressing not only from base-to-apex (lower frequencies) but also from outer-to-inner cells.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2,4,5,8,9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The increased susceptibility of basal hair cells may be due to less effective calcium-handling mechanisms and consequently calcium overload, like in noise-induced hearing loss. In fact, the relative lack of otorfelin on basal outer cells, a calcium sensing protein involved in hair cell survival, support this theory.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> Alternatively, basal outer cell vulnerability may be explained by the higher presence of transient receptor potential vanilloid 1 and 4 (the cell entry route of aminoglycosides) or by lower expression of the anti-oxidant glutathione.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Cochleotoxicity seems to be underestimated due to audiometric testing and pharmacologic variability (no relation among toxicity and drug dosage, plasma level or crossed renal toxicity).<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,10</span></a> Its prevalence is probably underestimated considering the absence of clinical signs in early ototoxicity due to the tonotopic pattern described elsewhere.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11,12</span></a> The reported prevalence varies widely due to the reason explained above: AG ototoxicity may range from 0 to 63%, although in long-term treatments (6m–1yr) virtually all patients are affected; CP ototoxicity reports range from 3% to 100%.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,5,12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Several risk factors for AG and CP ototoxicity were identified: poor diet and low nutritional state (anaemia and hypoalbuminemia), kidney failure, previous hearing loss, acoustic trauma and HIV infection. Simultaneous treatment with loop diuretics (furosemide, ethacrynic acid) or antineoplastic drugs (vincristine, ifosfamide) may potentiate AG or CP toxicity, respectively. Young and old age as well as genetic polymorphisms (mutation in the 12S ribosomal RNA for AG and glutathione s-transferase polymorphisms for CP) may also be implied. Therapeutic details such as quick intravenous bolus and coexistent cranial radiotherapy also play a role in CP ototoxicity potentiation.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2,7,13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">There is still no universally accepted monitoring protocol for cochleototoxicity.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,10</span></a> Our aim was to review the available literature and elaborate a monitoring protocol adapted to Portuguese reality and to the resources available on our centre.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0045" class="elsevierStylePara elsevierViewall">Articles relative to ototoxicity monitoring were searched in PubMed® database. Mesh terms “hearing loss”, “aminoglycosides” and “cisplatin” were used. Articles in English or Portuguese published in the last ten years were included (17). 3 articles fit the aim of this work; quoted articles considered relevant for the issue were also included, as well as position statement from worldwide societies and, when available, guidelines on ototoxicity monitorization.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results and discussion</span><p id="par0050" class="elsevierStylePara elsevierViewall">A monitoring protocol for ototoxicity aims to detect hearing loss as early as possible.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,4</span></a> Since vestibular toxicity monitoring remains arbitrary,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> only cochleotoxicity is approached in this work. Some medications are more prone to cause hearing loss what makes patients taking those drugs obvious candidates for monitorization.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,5,10</span></a> Among these patients, the ones with comorbidities witch render them more susceptible for ototoxicity (anaemia, kidney failure, HIV infection, old age) and those taking other cochleotoxic medications (loop diuretics, vincristine) deserve special attention.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2,11</span></a> There is consensus in adapting monitoring tests to patients cooperation level.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,10</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">There are no standard criteria universally used to define cochleototoxicity.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,14</span></a> ASHA criteria (1994) remain the most widely used, defining a significant hearing loss as: (a) ≥20<span class="elsevierStyleHsp" style=""></span>dB decrease at any tested frequency, (b) ≥10<span class="elsevierStyleHsp" style=""></span>dB decrease at any two adjacent frequencies, or (c) loss of response at three consecutive frequencies where positive responses were previously given.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Initial assessment aims to document baseline hearing and should be as complete as possible, including all the test needed in subsequent evaluations.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,11</span></a> Ideally performed before any drug administration, when taking AG it may be delayed to 72<span class="elsevierStyleHsp" style=""></span>h after initial dosage since no cochlear damage has been histologically shown before that; since CP may cause cochlear damage only 24<span class="elsevierStyleHsp" style=""></span>h after initial dosage, initial evaluation when taking platinum compounds should not be deferred further.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,10,11</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Cochleotoxicity monitoring protocol (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>)</span><p id="par0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Baseline evaluation</span> must comprise a detailed medical history focusing on medical comorbidities, medications taken and other risk factors (e.g.: noise or radiation exposure).<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> Otoscopy and immittance tests (tympanometry and acoustic reflex testing) are vital to assure middle ear and conduction system integrity.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10,11</span></a> Full audiometric evaluation in conventional frequencies – pure-tone air and bone thresholds, speech recognition thresholds and discrimination testing – represents the patients hearing acuity before treatment.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,4,10</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Despite its importance in defining pre-treatment hearing acuity in speech frequencies and speech recognition, conventional frequency audiometry lacks sensitivity in detecting early cochleototoxicity.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> As described elsewhere, early cochleotoxic lesion affects the basal cochlea and high-frequency hearing<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2,5,8</span></a>; thus, High-Frequency Audiometry (HFA) – 8–20<span class="elsevierStyleHsp" style=""></span>kHz – is universally accepted as the most sensitive and specific test for detecting early cochleotoxicity.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,10,11,15</span></a> Despite this, HFA is limited in patients with previous hearing loss (such as most elderly patients suffering from presbyacusis)<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> and depends on patients response and cooperation.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> Besides, HFA still lacks universal criteria for normality<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a>; however, a recent study conducted in a Spanish population aimed to find standard values for HFA thresholds according to patients age<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a>; cut-offs of 18<span class="elsevierStyleHsp" style=""></span>kHz for patients younger than 40 years old, 14<span class="elsevierStyleHsp" style=""></span>kHz for the 40–49 years old group and 11.2<span class="elsevierStyleHsp" style=""></span>kHz for patients older than 50 years old were found and seem reproducible in our population.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In non-cooperative patients (neurologic deficit, young age), objective hearing testing is needed since conventional and high-frequency audiometry may not be feasible.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,10</span></a> Otoacoustic emissions (OAE) objectively evaluate outer hair cells integrity and detect cochleotoxicity earlier than conventional audiometry.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,12</span></a> When choosing between transient-evoked and Distortion Products Otoacoustic Emissions (DP-OAE), the last show several advantages: allow evaluation of higher frequencies (above 4<span class="elsevierStyleHsp" style=""></span>kHz) thus detecting cochleotoxicity earlier, are more sensitive because are present in patients with more severe sensorineural loss, and are also more frequency-specific since are elicited using two tones – for this reasons, they tend to be preferred.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,11,12</span></a> DP-OAE are particularly useful for non-cooperative patients due to time-efficiency, portability and test–retest reliability.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11,12</span></a> However, commercially available equipment does not allow DP-OAE testing through ultra-higher frequencies (>6–12<span class="elsevierStyleHsp" style=""></span>kHz) and there are still no universally accepted criteria for DP-OAE interpretation.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,4,11</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Treatment monitorization</span>: patients taking AG should be evaluated every 2–3 days<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> but for practical reasons weekly or biweekly assessments seem acceptable.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,11</span></a> For CP treatments, there is consensus in evaluating patients 24<span class="elsevierStyleHsp" style=""></span>h before every dosage.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,7,11</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Medical evaluation begins by asking the patient about newly developed symptoms such as hearing impairment, tinnitus or vertigo, and synergistic factors such as noise exposure or other ototoxic drugs.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> In cooperative patients this is followed by otoscopy, conventional frequency and high frequency pure-tone audiometry.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> Since most changes in hearing are observed within one octave of the highest audible frequency for each patient,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> a series of shortened protocol for HFA application have been proposed and shown viable.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,11</span></a> If hearing loss is suspected further testing is required: immittance measures to exclude middle ear pathology,<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10,11</span></a> speech audiometry to guide counselling and rehabilitation process,<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> DP-OAE or Brainstem-Evoked Response Audiometry (BERA) to confirm cochlear damage as the source of hearing loss.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> The patients are retested in the 24<span class="elsevierStyleHsp" style=""></span>h to confirm hearing loss and is assessed weekly till stabilization.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,11</span></a> When ototoxicity is confirmed, treatment modification (drug withdrawal or dosage change) must be pondered; strategies to block ROS production and prevent inner ear damage are being studied and represent a logical step in cochleotoxicity prevention.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">6,9</span></a> Intratympanic drug administration is another field of research with promising results.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">16–19</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In non-cooperative patients behavioural tests are not possible and thus a shortened protocol consisting of otoscopy, immittance tests and DP-OAE is used.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,10</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Post-treatment evaluation</span> allows detection of late cochleotoxic effects, and since ototoxic drugs were proven to be present in hair cells 11 months after treatment cessation,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> patients should re-evaluate on treatment completion, 3 and 6 months after.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,11</span></a> Patients who received head and neck radiation should be monitored in the next year or two.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> When hearing loss is detected, weekly evaluation till stabilization is advisable.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Considerations regarding special populations</span>: HFA and DP-OAE are of limited use in elderly people suffering from age related hearing loss.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> In these cases, DP-OAE seem to be more sensitive than HFA.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,12</span></a> However, since in this patients high frequency hearing is already compromised at treatment institution, monitoring should focus on preserving speech frequencies, which is achieved by conventional frequency audiometry.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> Paediatric populations represent a particular challenge since they are in a language developing phase, in which hearing impairment may cause serious limitations on speech comprehension and production.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> Due to behavioural immaturity, cooperation is frequently undermined and objective methods are needed.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,10</span></a> Hence, DP-OAE represent a valid and reproducible method.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,12</span></a> BERA are sometimes considered as an alternative to DP-OAE for ototoxic monitoring on young populations.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,10</span></a> However, the fact that most protocols are limited to 1–4<span class="elsevierStyleHsp" style=""></span>kHz frequencies<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,10</span></a> and the repetitive need of sedation, makes this test unadvisable as a monitoring method.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Tinnitus and vertigo</span> are potential indirect signs of ototoxic damage and its presence should be asked in every consultation.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2,5,11,20</span></a> However, universal guidelines for vestibular toxicity are inexistent<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> and the discussion about the most adequate tests for vestibular monitorization is beyond the scope of this article.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusion</span><p id="par0110" class="elsevierStylePara elsevierViewall">Cochleotoxicity monitoring aims to detect an early hearing loss and ultimately avoid hearing impairment in speech frequencies.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,10</span></a> Comprehensive, serial and prospective evaluations of hearing function remain the only option to do so.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,4,11</span></a> Protocol implementation is dependent on the target population, human and material resources available and the refer network among health professionals.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">4,7,10,11</span></a> From our understanding, there are no published cochleotoxicity monitoring protocols designed for Portuguese population and Portuguese health care facilities. Considering the widespread usage of ototoxic medications and the disability level caused by hearing impairment, implementation of an cochleotoxic monitoring protocol should be regarded as a standard practice. This protocol provides a basis to do so.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Funding</span><p id="par0115" class="elsevierStylePara elsevierViewall">None.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1006674" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec966380" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1006673" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec966381" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results and discussion" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Cochleotoxicity monitoring protocol (Table 1)" ] ] ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusion" ] 8 => array:2 [ "identificador" => "sec0030" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-01-13" "fechaAceptado" => "2017-03-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec966380" "palabras" => array:5 [ 0 => "Aminoglycosides" 1 => "Platinum compounds" 2 => "Hearing loss" 3 => "Audiometry, pure-tone" 4 => "Otoacoustic emissions" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec966381" "palabras" => array:5 [ 0 => "Aminoglucósidos" 1 => "Compuestos de platino" 2 => "Pérdida de la audición" 3 => "Audiometría, tono puro" 4 => "Emisiones otoacústicas." ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cochlear damage is frequent in long-term aminoglycosides therapy or chemotherapeutic treatments with platinum-based agents. Despite its prevalence, it is currently underestimated and underdiagnosed. A monitoring protocol is vital to the early detection of cochleotoxicity and its implementation is widely encouraged in every hospital unit. Our aim was to elaborate a cochleotoxicity monitoring protocol for patients treated with platinum compounds or aminoglycosides antibiotics.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">PubMed® database was searched using terms relevant to drug cochleotoxicity in order to identify the most adequate protocol. Several articles and guidelines influenced our decision.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">There is no consensus on a universal monitoring protocol. Its formulation and application rely heavily on available resources and personnel. High-frequency audiometry and otoacoustic emissions play an important role on early detection of cochleotoxicity caused by aminoglycoside antibiotics and platinum compounds.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A cochleotoxicity monitoring protocol consisting on an initial evaluation, treatment follow-up and post-treatment evaluation is proposed.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">El daño coclear es frecuente en la terapia de aminoglucósidos a largo plazo, o en tratamientos quimioterapéuticos con agentes a base de platino. A pesar de su prevalencia, actualmente está subestimado y subdiagnosticado. Un protocolo de monitorización es vital para la detección temprana de la ototoxicidad, por lo que se incita a su implementación en todas las unidades hospitalarias. Nuestro objetivo fue elaborar un protocolo de monitorización de la cocleototoxicidad para pacientes tratados con compuestos de platino o antibióticos aminoglucósidos.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se realizaron búsquedas en la base de datos PubMed® utilizando términos relevantes para la cocleototoxicidad de los fármacos con el fin de identificar el protocolo más adecuado. Varios artículos y directrices influyeron en nuestra decisión.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">No hay consenso sobre un protocolo de monitoreo universal. Su formulación y aplicación dependen en gran medida de los recursos y el personal disponibles. La audiometría de alta frecuencia y las emisiones otoacústicas desempeñan un papel importante en la detección temprana de la cocleototoxicidad causada por los antibióticos aminoglucósidos y los compuestos de platino.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusión</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se propone un protocolo de monitorización de la cocleototoxicidad, consistente en una evaluación inicial, seguimiento del tratamiento y evaluación postratamiento.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">We propose a monitoring protocol for chemically-induced hearing loss.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Patient selection</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Patients receiving platinum compounds for head and neck malignancies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Patients receiving AG for pulmonary tuberculosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Baseline evaluation</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>AG: <72<span class="elsevierStyleHsp" style=""></span>h after first dosage \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CP: <24<span class="elsevierStyleHsp" style=""></span>h after first dosage \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cooperative patients: otoscopy, immittance testing, pure-tone and speech audiometry (conventional frequencies), HFA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-cooperative patients: otoscopy, immittance testing, DP-OAE \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Treatment monitorization</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>AG: weekly evaluation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>CP: in 24<span class="elsevierStyleHsp" style=""></span>h before new dosage \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cooperative patients: otoscopy, pure-tone audiometry (conventional frequencies), HFA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-cooperative patients: otoscopy, DP-OAE \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">If loss detected</span></span><span class="elsevierStyleBold">:</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Immittance testing, speech audiometry (if cooperative), DP-OAE/BERA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Repeat in 24<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Weekly evaluation till stabilization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ponder drug withdrawal, dosage modification or treatment completion \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Post-treatment evaluation</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>At treatment completion, 3 and 6 months after \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">If simultaneous head/neck radiation evaluate also at 12 and 24 months</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cooperative patients: pure-tone audiometry (conventional frequencies), HFA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-cooperative patients: DP-OAE \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic"><span class="elsevierStyleBold">If loss detected:</span></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Immittance testing, speech audiometry (if cooperative), DP-OAE/BERA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Repeat in 24<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Weekly evaluation till stabilization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ponder hearing aid \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1704712.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Cochleotoxicity monitoring protocol. AG: aminoglycosides antibiotics; CP: platinum compounds; HFA: high frequency audiometry; DP-OAE: distortion products otoacoustic emissions; BERA: brainstem-evoked response audiometry.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Streptomycin in treatment of clinical tuberculosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H. Hinshaw" 1 => "W. Feldman" 2 => "K. 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Review article
Cochleotoxicity monitoring protocol
Protocolo de monitorización de cocleototoxicidad
José Ferreira Penêda
, Nuno Barros Lima, Leandro Ribeiro, Diamantino Helena, Bruno Domingues, Artur Condé
Autor para correspondencia
Department of Otorhinolaryngology, Centro-Hospitalar Vila Nova de Gaia-Espinho, Vila Nova de Gaia, Portugal