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- 1. P é rdida de la Audición Inducida por Ruido (PAIR): Prevención Soha N. Ghossaini, MD Comite de Esfuerzos Humanitarios de la Academia Americana de Otolaryngologia / Cirugia de Cabeza y Cuello
- 24. Adaptado de: Lynch ED &Kil J, 2005 Clase Compuesto ROA Comentarios Antioxidante GSH pro droga Allopurinol i.p. Reduccion TTS ALCAR i.p. Reduccion PTS; estudios limitados Edavarona local Reduccion PTS Acido lipoico i.p., p.o. Reduccion PTS y TTS Resveratrol p.o. Reduccion PTS y TTS; estudios limitados; pretratamiento extenso R-PIA local Reduccion PTS; estudios limitados α -tocoferol i.p. Reduccion PTS y TTS Metionina 200 mg/kg i.p. Reduccion PTS Monoetilester 50–150 mM local Reduccion PTS NAC 325 mg/kg i.p. Reduccion PTS y TTS; Ph-III PAIR completa OTC 735 mg/kg i.p. proteccion PTS limitada Antioxidant enzymes GPx Ebselen/SPI p.o. Reduccion PTS y TTS; accidentes vasculares agudos interrumpidos; PAIR Ph I/II proximo SOD SOD–PEG i.m. Estudios limitados; Reduccion PTS; potencial para SOD paradox
- 26. NAC Adaptado de: Kopke RD et al. 2007
- 27. NAC. Datos pre clinicos From: Kopke RD et al. 2007 Modelo Dosis y administracion Efecto auditivo y en las celulas peludas Referencias Ruido en estado regular, chinchilla 325 mg/kg inyeccion intraperitoneal Reduccion de las celulas peludas y perdida auditiva Kopke et al. (2000) Ruido en estado regular, cobayo 500 mg/kg inyeccion intraperitoneal Reduccion de las celulas peludas y perdida auditiva Ohinata et al.(2003) Impulsos de ruido, rat 350 mg/kg inyeccion intraperitoneal Reduccion de las celulas peludas y perdida auditiva Duan et al. (2004) Impulsos de ruido, chinchilla 325 mg/kg inyeccion intraperitoneal Reduccion de las celulas peludas y perdida auditiva Kopke et al. (2005) Impulsos de ruido, chinchilla Dosis respusta 50, 100, 325 mg/kg inyeccion intraperitoneal Perdida auditiva reducida en cada dosis Kopke et al. (2004) Ruido en estado regular, chinchilla 325 mg/kg by gavage Perdida auditiva reducida Bielefeld et al. (in press) Ruido kurtotic, chinchilla 325 mg/kg inyeccion intraperitoneal Perdida auditiva reducida Bielefeld et al. (in press)
- 35. Adaptado de: Lynch ED &Kil J, 2005 Clase Compuesto ROA Coments Inhibidores Calcineurina Ciclosporin A local Reduccion PTS y TTS; estudios limitados FK506 local Reduccion PTS y TTS; estudios limitados Diureticos Manitol i.p. Reduccion PTS; estudios limitados Glucocorticoides Dexametasone local Reduccion PTS en forma de U; estudios limitados Factores de crecimiento aFGF local Reduccion PTS; estudios limitados GDNF 100 local Reduccion PTS ; altas dosis fueron ototoxicas Queladores de hierro Deferoxamina s.c. Reduccion PTS; estudios limitados; se observo ototoxicidad clinicamente Inhibidores JNK CEP-1347 s.c. Reduccion PTS; estudios limitados estudios de la enfermedad de Parkinson interrumpidos D-JNKI-1 local Reduccion PTS y TTS Magnesio Mg 4 g en humanos p.o. Reduccion PTS y TTS; eficacia se correlaciona con la deficiencia de magnesio versus el tratamiento Antagonistas NMDA Carbamatos i.p. Reduccion PTS; estudios limitados Caroverine local Reduccion PTS; bloqueo transitorio de la transduccion del sonido MK-801 i.p. Reduccion PTS; estudios limitados PD 174494 i.p. Proteccion PTS limitado Inhibidores NOS L-NAME i.p. Estudios limitados; alguna ototoxicidad vista en altas frecuencia
Notas del editor
- El ruido es una causa común de perdida de la audición a nivel mundial. En esta presentación expondremos la prevalencia de este problema, su impacto y las formas en las cuales puede ser prevenido.
- Noise induced hearing loss (NIHL) is a common and preventable cause of hearing loss in both developed and developing countries, which make is a problem of global concern. In the developed countries, it is estimated that NIHL still accounts for 1/3 of hearing loss despite the wide spread use of Hearing conservation programs . Such a high prevalence calls for more efforts to be put towards its prevention. According to a recent paper by Kopke et al. it is estimated that 50 million people in the US and 600 million people worldwide are exposed to noise hazards occupationally (Kopke RD et al. 2007) .
- NIHLis a sensorineural loss that most commonly affect the 4000 Hz frequency. Loud noise exposure can result in temporary or permanent threshold shifts. The risk for NIHL increases with the increase in the duration of noise exposure. Other medical conditions, smoking and exposure to industrial toxins have all been shown to increase the susceptibility to noise.
- Noise induced hearing loss can result from occupational and/or non- occupational noise exposure. Occupational noise exposure is a common and well recognized cause of hearing loss world wide and is encountered in many industries. Non occupational noise exposure can be the result of “leisure” noise exposure or the result of our daily life exposure to noise.
- For over several decades efforts at defining and limiting occupational hearing loss in the developed counties have been initiated and are still ongoing. Yet NIHL is still one of the most common occupational diseases [NIOSH 2004 mentioned in Bertsche PK 2006] . In the United States alone about 10 million people have NIHL worse than 25 decibels (dB) [USDOL-OSHA, 2002 in Nelson DI et al 2005]. NIHL is common in young workers. It is often missed and is underreported due to its insidious onset that may happen over a period of 10- 15 years [May JJ. 2000]. NIHL is preventable in most instances and continues to be an occupational illness of global concern.
- Studies looking at the global effect of NIHL suffer from the lack of reliable data more so in the developing countries. Depending on the reference, it has been estimated that over 30- 40 million workers in the US are exposed to hazardous noise on their jobs (NIOSH 2004, Kopke RD et al. 2007) . In a survey of European workers, 28% reported that they are exposed to loud noise on their job about one-fourth of the time. Loud noise in this survey was defined as noise loud enough that the workers would have to raise their voices to hold a conversation (corresponds to approximately 85–90 dB) [European Agency for Safety and Health at Work ( EASHW) 2000 mentioned in Nelson DI et al. 2005]. In the developing countries statistics about occupational noise exposure are not available but high occupational noise exposure levels were reported in several studies [Nelson DI et al. 2005]. Despite the prevalence of NIHL in the whole world, WHO and International Labor Organization (ILO) estimate that less than 15% of all workers have access to any kind of occupational health services.
- In an elegant study by Nelson et al the global burden of NIHL was evaluated. In this study they estimated the proportion of the population exposed to occupational noise using noise exposure data from the US National Institute for Occupational Safety and Health (NIOSH) [Nelson DI et al. 2005]. These were adjusted by data on the distribution of the work force by occupational category and economic sector, and economic activity rates in each WHO sub region. They found that worldwide, NIHL accounts for 16% of the disabling hearing loss in adults with a range of 7- 21% depending on the sub region. This has been calculated to be equivalent to over 4 million disability-adjusted life years (DALYs; one DALY is equal to the loss of one healthy life year). They found that the burden of occupational noise exposure to be larger for males than females. They also found that the burden of NIHL is heavier in the younger ages and among certain occupations (e.g., production workers) and economic sectors (e.g., manufacturing, mining, and construction).
- In the same study NIHL was found to have a heavier burden in developing countries than in developed regions of the world. NIHL accounted for over 85% of all adult-onset hearing loss in the developing sub regions versus 15 % in the developed sub region. In addition, in developing countries occupational noise accounted for about 3.8 million years of healthy life lost on an annual basis compared to 0.3 million years in developed countries The difference is mainly due to lack of noise prevention programs and awareness of the consequences of excessive noise exposure.
- Harmful noise levels are frequently encountered in many occupations including construction, mining, agriculture, manufacturing and utilities, transportation, military and many others [Kopke RD et al. , 2007]
- Excessive noise is commonly encountered in non-occupational settings as well. A variety of activities like woodworking, yard care, use of snowmobiles, firearms and music can cause NIHL [Clark W 1991, Schmuzigert N 2006] Duration and level of exposure has an effect on the degree of NIHL. It has been shown that non- occupational noise exposure increases the risk of NIHL in the occupational settings [Mori T, 1985; Abbate C et al. 2005].
- With the popular and common use of personal stereo systems like iPods, portable CD players and MP3s, their effect on hearing has been a concern. NIHL secondary to prolonged use of such personal stereo equipments at high volume setting has been suggested in the literature. In a study by Filgor et al. output measurements were made from multiple headphones with different styles and models using a white noise. The output levels ranged from 91- 121 dBA at maximum volume setting. In order to avoid NIHL from portable electronic devices, it was suggested by this study to limit their use to 1 hour per day at 60%of the maximum gain. [Fligor BJ 2004].
- Noise induced hearing loss doesn’t seem to spare children. According to Third National Health and Nutrition Examination Survey, 12.5 % of US children 6 to 19 years old, (approximately 5.2 million) are estimated to have Noise Induced Threshold Shift in 1 or both ears (defined in the study as a high-frequency audiometric notch in at least one ear). Majority of children had only one ear and only 1 frequency affected [Niskar AS et al. 2001]. This seems to be partly caused by leisure noise exposure to toys and music.
- The impact of NIHL goes well beyond just the hearing loss and or tinnitus. NIHL has a significant impact on the person’s quality of life, safety on the job and economy of the country. Some studies even reported higher morbidity in workers who are exposed to loud noise when compared to controls [Bartosiska M. et al. 2002]
- According to the Hearing Industries association 10 million individuals in the US have NIHL [Hearing Industries Association, 2004]. OSHA estimates that about 17% of production workers or 1.6 million people have at least mild hearing loss resulting from occupational noise exposure. An additional one million or 11% have moderate hearing impairment and nearly half a million or 5% have moderate to severe hearing loss.
- NIHL negatively affects the quality of relationships of affected individuals at home with other family members, at work with other coworkers, and in the community which might result in social isolation.
- The economic impact of NIHL is tremendous with nearly 200 million dollars spent in disability cost annually [NIOSH 2004]. In 2005, veterans hearing disability cost ranged between 60 million to 475 million dollars across different job sectors.
- NIHL may affect the safety of workers in the workplace. Due to their hearing loss workers may have difficulty recognizing and localizing auditory warning signals, thus impairing their ability to act promptly and appropriately. Workers with NIHL were found to have a higher risk of accidents while on the job [Hetu R et al. 1995 in Bertsche PK et al. 2006] .
- NIHL can be prevented by decreasing the amount of noise in the workplace, limiting the amount of time in the exposed area, using protective devices, and monitoring hearing of workers at risk. Occupational noise exposure in the US is regulated by Occupational Safety and Health Administration (OSHA) and National Institute for Occupational Safety and Health (NIOSH).
- According to the standards of OSHA and NIOSH, the recommended exposure limit (REL) for occupational noise is set at 85 decibels, A-weighted, and an 8-hr time-weighted average (85 dBA as an 8-hr TWA). Exposures at and above this level are considered hazardous requiring that workers in such environments use hearing protection devices and get enrolled in hearing conservation programs. In an attempt to reduce amount of time spent in the hazardous noise area, OSHA uses a 5 dB Exchange Rate system where acceptable exposure time is dependent on the intensity of the noise. This indicates that with every 5 dB above 85 dB less and less time is allowed to be spent in such noisy working environments. NIOSH instead adopted the 3 dB exchange rule.
- The use of hearing protection devices is an essential part of every hearing protection program and any other means to prevent NIHL. They however have some limitations. Noise levels can sometimes exceed the protective ability of the device. Inadequate fitting decreases their protective ability as well. The attenuation offered by hearing protection device is frequency dependent. Hearing protection devices can interfere with the workers’ communication ability and safety at times limiting their use. [Kopke et al. 2002]. Compliance with the use of hearing protection devices remains low.
- NIHL remains a very widespread risk to hearing health despite the presence of hearing conservation programs. This speaks for the need for new methods of intervention to prevent and possibly treat NIHL. Pharmacological agents that can be taken either before or after noise exposure would be an appropriate solution and would be used as an adjunct to hearing conservation programs. An ideal drug is one that can be taken orally, is affordable, safe and effective. Before the development of such a pharmacological agent is feasible the knowledge of the pathogenesis of cochlear damage in NIHL is essential.
- Our knowledge about the pathogenesis of cochlear damage in NIHL has increased tremendously in the last few decades. In the past NIHL was thought to be caused purely by mechanical or physical damage. Now we know that the damage is metabolically induced. [Lim et al. 1971; Lim and Dunn, 1979; Slepecky, 1986 from Kopke RD et al. 2007]. Loud noise exposure leads to a chain of reactions including: ischemic reperfusion; excessive glutamate release; Reactive Oxygen and Nitrogen Species overproduction, injury to the mitochondria; lipid peroxidation; glutathione depletion ; programmed cell death and necrosis , eventually leading to loss of hair cells and neurons. Therefore theoretically speaking blocking any reaction in this cascade would protect the ear from noise induced damage.
- Glutathione has received a lot of attention in the potential prevention of NIHL. Glutathione is thought to be the primary cellular antioxidant system of the body and the primary endogenous defense of the inner ear in response to loud noise exposure. Glutathione levels have shown to increase temporarily in the inner ear in response to loud noise exposure [from Kopke RD et al. 2007]. Glutathione pro drugs supplementation has a protective effect on the inner ear after noise exposure and Glutathione depletion increases the inner ear’s susceptibility to noise [from Kopke RD et al. 2007].
- Drugs that eventually cause an increase in the level of Glutathione have been extensively used in research and found to have variable protective effect on the inner ear in response to noise exposure. This table lists most drugs that have been tried so far in animal and few human studies for the prevention and possible treatment of noise induced hearing loss. This table has been modified from a paper by Lynch ED & Kil J [Lynch ED &Kil J, 2005]. The route of administration (ROA) of these agents included intra peritoneal (i.p.), local to the round window membrane, intramuscular (i.m.), oral (p.o.) and subcutaneous (s.c.). Their effect varied between temporary threshold shift (TTS) reduction and / or permanent threshold shift (PTS) reduction. GSH= glutathione ALCAR= acetyl-L carnitine R-PIA= R-phenylisopropyladenosine NAC= N-acetylcysteine OTC= 2-oxothiazolidine-4-carboxylate GPx = glutathione peroxidase Ebselen/SPI SOD = superoxide dismutase
- NAC is an antioxidant and a substrate for glutathione synthesis that has been studied extensively in NIHL. It acts as a free radical scavenger and has been shown to decrease permanent hearing loss due to loud noise exposure. NAC is FDA approved as an antidote to acetaminophen overdose and as a mucolytic agent. Few side effects are experienced at 100 g orally over 72 hours.
- NAC has been shown to act at several levels of the pathologic mechanism involved in cochlear injury in response to loud noise exposure. It acts as a free radical scavenger, replenishes glutathione, decreases the effect of glutamate excitotoxicity and protects cochlear mitochondria, and from injury eventually resulting in the inhibition of cell death pathways and necrosis. ROS: Reactive oxygen species RNS: reactive nitrogen species 4-HNE 4-hydroxynonenal GSH: Glutathione MAPK/JNK = mitogen-activated protein (MAPK) kinase/(C-Jun kinase) JNK is a stress kinase system Src/ Ptk= Src protein tyrosine kinase (Src PTK) signaling cascade
- NAC has been effective in reducing PTS in noise-exposed guinea pigs and chinchillas, with no effect on TTS in man or rodents [Kopke RD et al. 2007].
- NAC has undergone limited clinical testing. In a study by Kramer et al. NAC demonstrated no beneficial effect over placebo on temporary threshold shifts in discotheque attendees when taken 1 hour prior to 2 hours of noise exposure. This correlates with animal studies showing less beneficial effect of NAC on TTS [Kramer S. et al. 2006].
- In a prospective, randomized, double blinded, placebo controlled study of NAC (900 mg t.i.d) versus placebo was found safe and effective in reducing auditory threshold shifts in 566 military subjects undergoing routine weapons training for 2 weeks. (Kopke RD et al. in preparation as mentioned in Kopke RD et al 2007).
- An ongoing a prospective, randomized, double blinded placebo controlled study is looking at the effect of NAC given shortly after acute acoustic trauma on permanent threshold shifts in military subjects [Kopke RD et al. 2007].
- D- Methionine is an essential amino acid and pro drug to glutathione. It is FDA-approved to acidify urine and is tolerated orally at 500–1000 mg per day when administered orally. It was found to reduce PTS when administered prior to noise exposure. [Kopke RD et al. 2005]
- Ebselen is a mimic of glutathione peroxidase. Glutathione peroxidase catalyzes glutathione function as an antioxidant. It s activity is decreased in response loud noise exposure. It reduces oxidative stress levels in different cells. [Lynch and Kill 2005]
- Ebselen has been found to reduce TTS as well as PTS when tested in guinea pigs and rats with oral administration. Since Ebselen acts as catalyst, low doses might be enough [Lynch and Kill 2005].
- Ebselen In an upcoming double-blind placebo-controlled Phase II study of oral ebselen, 60 young, healthy US Army recruits will receive doses of ebselen twice daily for two continuous weeks during weapons training. They will be assessed within six hours to determine TTS and subsequently at two and four weeks post-noise to determine PTS [Lynch and Kill 2005].
- Several other compounds have been tried as well and are summarized in this table adapted from Lynch ED & Kil J, 2005 JNK = c-Jun N-terminal kinase NOS= nitric oxide synthase aFGF: acidic fibroblast growth factor GDNF: Glial derived neurotrophic factor
- So far studies have proved the protective effect of antioxidants and other agents in the prophylactic protection against NIHL. However loud noise exposure with resultant NIHL can be unpredictable and therefore for treatment to be effective it has to be administered post noise exposure. Few studies have looked at the effectiveness of post exposure pharmacological treatment with variable results. NAC and salicylate when administered immediately following noise exposure showed to have a small but significant reduction in NIHL [Kopke RD et al 2000]. In an another study Salicylate and Trolox ( water-soluble analog of vitamin E) were administered prior to noise exposure, days 1, 3 or 5 post-noise exposure with resultant protective effect when d elivered up to 3 days after noise exposure [ Yamashita D et al., 2005]. Allupurinol has been found to have a protective effect when used post noise exposure [Seidman MD 1993]. In an another study by Franze’ et al it was found to only reduce the TTS after intense noise exposure and not the PTS [Franze’ A et al . 2003]. In a recent study by Campbell et al. D- methionine was found to provide complete protection from permanent NIHL when administered within 1 hour after noise exposure [Campbell KC et al. 2007].
- Although animal research and few clinical studies have demonstrated the effectiveness of certain pharmacological agents in inner ear protection against loud noise exposure, pharmacological treatment or pharmacological prevention of NIHL is still not available for clinical use. To date the most effective method of minimizing or treating NIHL is by its prevention. Prevention of NIHL starts by increasing the awareness of the effect of loud noise exposure on hearing among the general public as well as health care professionals. Another important method is to reinforce the need for the use of hearing protection devices in noisy environments. This can best be accomplished by combining the efforts of health care providers, educators and employers in parallel to those of regulatory agencies.
- Increasing the awareness of NIHL can be accomplished by educating primary care physicians, other health care providers and the general public about NIHL through seminars and health fares. Health care providers in turn can screen patients for signs and symptoms of NIHL, identify patients at risk, advise them to use hearing protection devices in addition to educating them about the consequences of loud noise exposure.
- In the developed countries hearing conservation programs are mandated by regulatory agencies. Employers on the other hand should ensure that the guidelines are properly followed and invest in engineering methods to minimize noise levels in the working environment. The use of hearing protection devices in hazardous environments is also mandated by regulatory agencies however compliance rate is low. Employers should periodically educate workers about the benefits of hearing protection devices in an attempt to increase compliance. Early education of students in school about NIHL can potentially help to increase the awareness of NIHL among students and thus decrease NIHL in this population.
- The above mentioned strategies are harder to implement in the developing countries mainly due to the lack of regulatory agencies and hearing conservation programs. In the absence of regulation, perhaps the best strategy to help prevent NIHL is similar to that recommended by WHO-PDH Informal Consultation, Geneva, 28-30 October 1997. Some of their recommendations were as follow: Promoting data collection and research in the developing countries to determine the social and economic consequences of NIHL; collaborating with concerned non-governmental organizations and other interested parties to support prevention at the community level; increasing the awareness of consequences of loud noise exposure among general public and legislators.
- In conclusion, Noise Induced Hearing Loss (NIHL) is common in both industrial and poorly developed countries and is preventable. Chemical exposure may potentate the effects of noise. As noise exposure is often unregulated in developing countries, workers in these countries may be at higher risk. Adequate prevention of noise induced hearing loss requires improved measuring of noise in risky environments, monitoring for hearing loss in the workplace, alteration of the work place to reduce noise and exposure time, and the development of noise protection programs that workers will use. All governments should recognize and take steps to reduce noise induced hearing loss.