LPR 2002 (2)

Laryngopharyngeal reflux 2002: a new paradigm of airway disease. (Introduction).Our purpose in writing this supplement is to provide an overview of laryngopharyngeal reflux (LPR). This supplement is not all-encompassing; some of the material presented is controversial; and we recognize that it does represent the bias of physicians at the Center for Voice Disorders of Wake Forest University. Furthermore, we understand that we raise as many questions as we answer. Still, we hope that this supplement will serve as a useful summary of LPR for clinicians, and that it will stimulate others in the research arena.BackgroundIt is likely that gastroesophageal reflux disease (GERD) was recognized in antiquity.In 1618, Fabricius described the gastroesophageal junction, which he referred to as cardia, a term he attributed to Galen (ca. 200 AD). (1) Galen had coined the term because symptoms arising from the gastroesophageal junction could mimic those arising from the heart. (1) It was not until the 20th century, however, that the relationship between symptoms and gastroesophageal reflux (GER) was established. (2,3)Even though the distally lighted esophagoscope had been invented by Chevalier Jackson in 1890, (1) for the first half of the 20th century he and his contemporaries did not understand GER. For example, they thought that esophageal strictures were caused by inflammatory diseases (e.g., tuberculosis) that arose in the mediastinum or below the diaphragm. In 1935, Winkelstein first described peptic esophagitis in adults.(2) It was not until 1950 that GERD was first described in children. (3)In 1968, laryngopharyngeal reflux (LPR)--that is, GERD that affects the larynx and pharynx--was described in relationship to contact ulcers and granulomas of the larynx. (4,5) However, relatively few reports of LPR/ GERD were published in the otolaryngology literature between 1970 and the mid-1980s. (6-20) GERD patients who did not have heartburn were considered to have atypical GERD, and it was the prevailing belief that laryngopharyngeal symptoms were not the result of actual reflux of gastric contents into the throat, but rather the result of vagally mediated reflexes.To document the presence of acid in the pharynx of presumed LPR patients, Wieneret al used both an esophageal pH probe and a pH probe placed in the pharynx just above the upper esophageal sphincter. (21) Patients actually wore two pH boxes, and the two pH probes were piggy-backed together with small dental rubber bands. Published in 1987, preliminary data from patients with clinical LPR who had undergone ambulatory 24-hour double-probe (simultaneous pharyngeal and esophageal) pH monitoring documented that acid was present in the pharynx of most of these patients. (21)In 1989, Wiener et al reported the results of double-probe pH monitoring in a series of 32 otolaryngology patients with clinical LPR; 78% of them had pH-documented LPR.(22) Analysis of the pH tracings made it apparent that the pattern of reflux in LPR was different from that usually seen in GERD; the LPR patients had predominantly upright (daytime) reflux. (22) This finding was new and surprising, because most patients with GERD had been previously shown to be predominantly supine (nocturnal) refluxers. (1) In addition, fewer than one-third of the LPR patients had esophagitis (by esophagoscopy with biopsy). (22) Thus, it appeared early on that the patterns and mechanisms of LPR might be different from those of classic GERD (figure). But the reason LPR patients were upright refluxers without heartburn or esophagitis was still unknown.Areas of ongoing researchMuch of the subsequent LPR research has been focused on seven areas: (1) associations with other diseases, (2) symptoms and findings, (3) mechanisms, (4) neurophysiologic reflexes, (5) diagnostic tests, (6) treatment outcomes, and (7) cell biology.LPR association data. The goal of this type of research is to show the association between certain medical conditions and the presence of LPR by clinical andreflux-testing criteria. (1,23-49)Defining the symptoms and findings of LPR. Many studies have sought to define the clinical parameters of LPR. (1,50,51)LPR mechanisms. (52-54) Why is LPR different from GERD? Why do LPR patients have upright reflux and not esophagitis or heartburn? How are the mechanisms of LPR different from those of GERD?Neurophysiologic (vagal) reflexes. Using experimental animal models, investigators have begun to examine the neurophysiologic mechanisms and pathophysiology of LPR, reflux-related laryngospasm, asthma, and sudden infant death snydrome. (55-59)New diagnostic tests for LPR. Although double-probe pH testing is an excellent diagnostic test, it has its limitations. Since 1997, our laboratory has been working to develop sensitive immunoassays for human pepsin. Our goal is to develop noninvasive, inexpensive tests for LPR. Other new diagnostic methods (e.g., impedance measurement) are also on the horizon. (60-62)Treatment outcomes. Outcomes data have become increasingly important in clinica l medicine. Outcomes studies have been and still are being conducted in LPR. (51)Cell biology. Investigations of the impact of reflux on a cellular level are beingconducted. In 1998, an international collaborative research network of basic scientists and clinicians was established. Preliminary data suggest that laryngeal epithelium is far more sensitive to reflux-related injury than is esophageal epithelium and that peptic injury can occur at a pH level of 5.0 or more. (63,64)LPR is not GERDDespite discoveries that have yielded a better understanding of LPR and how it differs from GERD, much is still not known. LPR remains controversial, partly because the gastroenterology model of reflux disease (i.e., GERD) does not seem to apply to patients with LPR. The term laryngopharyngeal reflux itself was coined because otolaryngologists wanted a new diagnostic term to designate reflux in otolaryngology patients. The clinical dichotomy of reflux patients who are seen by gastroenterologists and those who are seen by otolaryngologists warrants the use of two different diagnostic designations. Several other terms have been used for LPR in the medical literature (table).The prevalence of GERD and of LPR is unknown, but each has been estimated. Reportedly, 10% of the American population has heartburn on a daily basis, and as many as one-third has it less often. (1) In 1988, we estimated that approximately 10% of patients with laryngeal and voice disorders had LPR. (65) In 2000, a prospective study of 113 patients with laryngeal and voice disorders found that 57 (50%) hadpH-documented reflux. (46)A study to determine the prevalence of LPR symptoms and findings in acommunity-based cohort found that they were common in "normals." (66) The mean age of the 100 volunteers was 60 years, and none of them had a history of reflux disease or took any antireflux medication. However, 35% of these subjects reported one or more LPR symptoms, and 64% had one or more LPR findings on examination.A host of controversies remainsLPR is ubiquitous. If one combines all the clinical and normative data, it would be easy to conclude that at least one-third of the American population older than 40 years has LPR. Although this is speculation, if one combines the potential size of the LPR and GERD populations, as many as 100 million Americans might have reflux. In truth, the epidemiology of LPR and GERD remains to be studied.But who really has LPR? In fact, what is LPR? Is it simply a combination of certain symptoms and findings? How is the diagnosis made? Indeed, there has been controversy about how to diagnose LPR. At our center, we employ a reflux symptom index (RSI) as a clinical tool to compare groups of patients and to compare the symptoms of individual patients during the course of treatment. (50) We have also instituted a standardized method of grading the laryngeal findings of LPR, which wecall the reflux finding score (RFS). (51) This tool has proved to be very useful in the diagnosis and treatment of LPR. The RSI and the RFS are both validated outcomes instruments. Based on data obtained from normals, an RSI of more than 10 and an RFS of more than 5 are abnormal. (66)Why is LPR controversial? Not only are the symptoms and findings of LPR not clearcut, more important is the fact that there is no ideal diagnostic test battery for evaluating LPR. Traditional diagnostic criteria for GERD simply do not apply to LPR. Why is a pH value of less than 4.0 defined as a significant reflux event? Do patients with LPR require esophageal screening for esophagitis and other complications? Why do LPR patients require relatively high-dose (twice-daily) treatment withproton-pump inhibitors for many months? (67) What are the manifestations ofLPR--does it cause laryngeal cancer, subglottic stenosis, laryngospasm, and scarring complications following vocal fold surgery? The controversies surrounding LPR are grounded in uncertainty. The laryngopharyngeal symptoms and findings of LPR are nonspecific. Furthermore, there are no unambiguous diagnostic or treatment outcomes criteria.LPR controversies can be summarized in five categories: (1) symptoms, (2) clinical findings, (3) diagnostic testing, (4) interpretation of findings, and (5) treatment.Symptoms. There is no universal agreement on the symptoms of LPR. When is postnasal drip caused by a nasal or sinus problem, and when is it actually a red herring? Could the presence of too much mucus in the nose and throat be the result of direct irritation from LPR or the result of vagally mediated responses to throat irritation? What happens to patients with sinus symptoms and LPR when the LPR is effectively controlled?Clinical findings. There is no clear consensus about the findings and clinical manifestations of LPR. Although an extremely high incidence of LPR has been reported in patients with subglottic stenosis, (1) the role of LPR in the development of subglottic stenosis remains controversial. (In my opinion, virtually all airway stenosis and complications following intubation are the result of LPR. If it were not for LPR, would mucosal abrasions and ulcers heal uneventfully? Is it not the inflammation of LPR that likely continues the nonhealing process?)Diagnostic testing. Controversy surrounds diagnostic testing for LPR, including pH monitoring. How should it be performed? Should one use a single or double probe? Should manometry be performed first in order to ascertain sphincter location? Which patients should undergo pH monitoring? How is it interpreted? (At our center, we believe that full esophageal manometry of the pharynx and esophageal sphincter is essential in patients with LPR to ensure accurate pH data. (68) Furthermore, we feel that the proximal probe must be located in the pharynx. We perform ambulatory24-hour double-probe simultaneous [esophageal and pharyngeal] pH monitoring, withprobe placement based on manometric measurement. (69)Interpretation of findings. Interpretation of pharyngeal reflux events is controversial. Should we use a pH level of less than 4.0 as the pH threshold for determining reflux in the pharynx? Is laryngeal epithelium more sensitive to acid and peptic injury than is esophageal epithelium? Significant peptic injury to laryngeal epithelium has been reported in patients whose pH level was 5.0. (64) Would it...。

Laryngopharyngeal reflux 2002: a new paradigm of airway disease. (Introduction).AbstractOur purpose in writing this supplement is to provide an overview of laryngopharyngeal reflux This supplement is not all-encompassing; some of the material presented is controversial; and we recognize that it does represent the bias of physicians at the Center for Voice Disorders of Wake Forest University. Furthermore, we understand that we raise as many questions as we answer. Still, we hope that this supplement will serve as a useful summary of LPR for clinicians, and that it will stimulate others in the research arena.Background) was recognized in antiquity. In 1618, Fabricius described the gastroesophagealjunction, which he referred to as cardia(1) Galen had coined the term because symptoms arising from the gastroesophageal junction could mimic those arising from the heart. (1) It was not until the 20th century, however, that the relationship between symptoms and gastroesophageal refluxAds by Google Questions on Lung DiseaseFind Instant Answers to All Your Lung Disease Questions on Bing ™. Ask a Feline Vet Online8 Veterinarians Are Online! Ask a Question, Get an Answer ASAP. /Cat/Felinein 1890, (1) for the first half of the 20th century he and his contemporaries did not understand GER. For example, they thought that esophageal strictures were caused by inflammatory diseases (e.g., tuberculosis) that arose in thechildren. (3)In 1968, laryngopharyngeal reflux (LPR)--that is, GERD that affects the larynx and pharynx--was described in relationship to contact ulcers and granulomas of the larynx. (4,5) However, relatively few reports of LPR/ GERD were published in the otolaryngology literature between 1970 and the mid-1980s. (6-20) GERD patients who did not have heartburnthe prevailing belief that laryngopharyngeal symptoms were not the result of actual reflux of gastric contents into the throat, but rather the result of vagally mediated reflexes.LPR patients, Wiener et al used both an esophageal pH probe and a pH probe placed in thepiggy-backed together with small dental rubber bands. Published in 1987, preliminary data from patients with clinical LPR who had undergone ambulatory 24-hour double-probedocumented that acid was present in the pharynx of most of these patients. (21)In 1989, Wiener et al reported the results of double-probe pH monitoring in a series of 32 otolaryngology patients with clinical LPR; 78% of them had pH-documented LPR. (22) Analysis of the pH tracings made it apparent that the pattern of reflux in LPR was different from that usually seen in GERD; the LPR patients had predominantly upright (daytime) reflux. (22) This finding was new and surprising, because most patients with GERD had been previously shown to be predominantly supine (nocturnal) refluxers. (1) In addition,appeared early on that the patterns and mechanisms of LPR might be different from those of classic GERD (figure). But the reason LPR patients were upright refluxers without heartburn or esophagitis was still unknown.Areas of ongoing researchMuch of the subsequent LPR research has been focused on seven areas: (1) associationswith other diseases, (2) symptoms and findings, (3) mechanisms, (4) neurophysiologic reflexes, (5) diagnostic tests, (6) treatment outcomes, and (7) cell biology.LPR association data. The goal of this type of research is to show the association between certain medical conditions and the presence of LPR by clinical and reflux-testing criteria. (1,23-49)Defining the symptoms and findings of LPR. Many studies have sought to define the clinical parameters of LPR. (1,50,51)LPR mechanisms. (52-54) Why is LPR different from GERD? Why do LPR patients have upright reflux and not esophagitis or heartburn? How are the mechanisms of LPR different from those of GERD?have begun to examine the neurophysiologic mechanisms and pathophysiologyNew diagnostic tests for LPR. Although double-probe pH testing is an excellent diagnostictest, it has its limitations. Since 1997, our laboratory has been working to develop sensitiveOur goal is to develop noninvasive, inexpensive tests for LPR. Other new diagnostic methods (e.g., impedance measurement) are also on the horizon. (60-62)Treatment outcomes. Outcomes data have become increasingly important in clinical medicine. Outcomes studies have been and still are being conducted in LPR. (51)Cell biology. Investigations of the impact of reflux on a cellular level are being conducted. In 1998, an international collaborative research network of basic scientists and clinicians wasinjury than is esophageal epithelium and that peptic injury can occur at a pH level of 5.0 or more. (63,64)LPR is not GERDDespite discoveries that have yielded a better understanding of LPR and how it differs from GERD, much is still not known. LPR remains controversial, partly because the gastroenterology model of reflux disease (i.e., GERD) does not seem to apply to patients with LPR. The term laryngopharyngeal reflux itself was coined because otolaryngologists wanted a new diagnostic term to designate reflux in otolaryngology patients. The clinical dichotomy of reflux patients who are seen by gastroenterologists and those who are seen by otolaryngologists warrants the use of two different diagnostic designations. Several other terms have been used for LPR in the medical literature (table).The prevalence of GERD and of LPR is unknown, but each has been estimated. Reportedly, 10% of the American population has heartburn on a daily basis, and as many as one-third has it less often. (1) In 1988, we estimated that approximately 10% of patients with laryngealand voice disorders had LPR. (65) In 2000, a prospective study of 113 patients with laryngeal and voice disorders found that 57 (50%) had pH-documented reflux. (46)A study to determine the prevalence of LPR symptoms and findings in a community-based cohort found that they were common in "normals." (66) The mean age of the 100 volunteers was 60 years, and none of them had a history of reflux disease or took any antireflux medication. However, 35% of these subjects reported one or more LPR symptoms, and 64% had one or more LPR findings on examination.A host of controversies remainsLPR is ubiquitous. If one combines all the clinical and normative data, it would be easy to conclude that at least one-third of the American population older than 40 years has LPR. Although this is speculation, if one combines the potential size of the LPR and GERD populations, as many as 100 million Americans might have reflux. In truth, the epidemiology of LPR and GERD remains to be studied.But who really has LPR? In fact, what is LPR? Is it simply a combination of certain symptoms and findings? How is the diagnosis made? Indeed, there has been controversy about how to diagnose LPR. At our center, we employ a reflux symptom index (RSIas a clinical tool to compare groups of patients and to compare the symptoms of individual patients during the course of treatment. (50) We have also instituted a standardized method of grading the laryngeal findings of LPR, which we call the reflux finding score (RFSLPR. The RSI and the RFS are both validated outcomes instruments. Based on data obtained from normals, an RSI of more than 10 and an RFS of more than 5 are abnormal. (66)Why is LPR controversial? Not only are the symptoms and findings of LPR not clearcut, more important is the fact that there is no ideal diagnostic test battery for evaluating LPR. Traditional diagnostic criteria for GERD simply do not apply to LPR. Why is a pH value of less than 4.0 defined as a significant reflux event? Do patients with LPR require esophageal screening for esophagitis and other complications? Why do LPR patients require relatively high-dose (twice-daily) treatment with proton-pump inhibitors for many months? (67) WhatThe laryngopharyngeal symptoms and findings of LPR are nonspecificLPR controversies can be summarized in five categories: (1) symptoms, (2) clinical findings,Symptoms. There is no universal agreement on the symptoms of LPR. When is postnasalactually a red herring? Could the presence of too much mucus in the nose and throat be the result of direct irritation from LPR or the result of vagally mediated responses to throat irritation? What happens to patients with sinus symptoms and LPR when the LPR is effectively controlled?Clinical findings. There is no clear consensus about the findings and clinical manifestations of LPR. Although an extremely high incidence of LPR has been reported in patients with subglottic stenosis, (1) the role of LPR in the development of subglottic stenosis remains controversial. (In my opinion, virtually all airway stenosis and complications followingabrasions and ulcers heal uneventfully? Is it not the inflammation of LPR that likely continues the nonhealing process?)Diagnostic testing. Controversy surrounds diagnostic testing for LPR, including pH monitoring. How should it be performed? Should one use a single or double probe? Shouldshould undergo pH monitoring? How is it interpreted? (At our center, we believe that full esophageal manometry of the pharynx and esophageal sphincter is essential in patients with LPR to ensure accurate pH data. (68) Furthermore, we feel that the proximal probe must be located in the pharynx. We perform ambulatory 24-hour double-probe simultaneous [esophageal and pharyngeal] pH monitoring, with probe placement based on manometric measurement. (69)Interpretation of findings. Interpretation of pharyngeal reflux events is controversial. Should we use a pH level of less than 4.0 as the pH threshold for determining reflux in the pharynx?Is laryngeal epithelium more sensitive to acid and peptic injury than is esophageal epithelium? Significant peptic injury to laryngeal epithelium has been reported in patients whose pH level was 5.0. (64) Would it be appropriate to use a pH level of less than 5.0 as the threshold for determining/measuring pharyngeal reflux? How many reflux events in the pharynx should be considered normal? Does a single positive pharyngeal reflux event not prove the existence of LPR?Treatment. It is interesting that many experienced clinicians have long recognized that treatment of LPR must be more intense and prolonged than is treatment for GERD. Indeed, the recently published position statement by the American Academy of Otolaryngology--Head and Neck Surgery on LPR was in part commissioned to provide a patient advocacy position--that is, to support the use of twice-daily proton-pump inhibitor medications in LPR, often for extended periods. (67)Considerations for future researchI personally believe that LPR research will someday present us with a new paradigm of airway disease. Reflux will be shown to dominate the internal environment and thus influence nearly all airway diseases (but obviously not all airway diseases in all patients). Tasker et al recently used a pepsin assay to demonstrate high levels of pepsin in the middleFuture research might show that reflux (of activated pepsin) is an inflammatory catalyst for many airway diseases, including cancers of the larynx, lung, esophagus, and pharynx.Table.Synonyms for 'laryngopharyngeal reflux'Atypical refluxExtraesophagela refluxGastropharyngeal refluxLaryngeal refluxPharyngoesophageal refluxReflux laryngitisSupraesophageal refluxReferences(1.) Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): A clinical investigation of 225 patients using ambulatory 25-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 1991;101 (Suppl 53):1-78.(3.) Berenberg W, Neuhauser EB. Cardio-esophageal relaxation (achalasia(4.) Cherry J, Margulies SI. Contact ulcer of the larynx. Laryngoscope 1968;78:1937-40.(5.) Delahunty JE, Cherry J. Experimentally produced vocal cord granulomas. Laryngoscope1968;78:1941-7.(7.) Chodosh PL. Gastro-esophago-pharyngeal reflux. Laryngoscope 1977;87:1418-27.202.(9.) Ward PH, Zwitman D, Hanson D, Berci G. Contact ulcers and granulomas of the larynx: New insights into their etiology as a basis for more rational treatment. Otolaryngol Head Neck Surg 1980;88:262-9.(10.) Ward PH, Berci G. Observations on the pathogenesis of chronic non-specificLaryngoscope 1982; 92:1377-82.(11.) Orenstein SR, Orenstein DM, Whitington PF. Gastroesophageal reflux causing stridor(12.) Bain WM, Harrington JW, Thomas LE, Schaefer SD. Head and neck manifestations of gastroesophageal reflux. Laryngoscope 1983;93:175-9.(13.) Ohman L, Olofsson J, Tibbling L, Ericsson G. Esophageal dysfunction in patients with contact ulcer of the larynx. Ann Otol Rhinol Laryngol 1983;92:228-30.(14.) Olson NR. Effects of stomach acid on the larynx. Proc Am Laryngol Assoc1983;104:108-12.(15.) Belmont JR. Grundfast K. Congenital laryngeal stridor (laryngomalacia): Etiologic factors and associated disorders. Ann Otol Rhinol Laryngol 1984:93:430-7.(16.) Feder RJ, Michell MJ. Hyperfunctional, hyperacidic, and intubation granulomas. Arch Otolaryngol 1984;110:582-4.(18.) Little FB, Koufman JA, Kohut RI, Marshall RB. Effect of gastric acid on the pathogenesis of subglottic stenosis. Ann Otol Rhinol Laryngol 1985;94:516-9.(19.) Menon AP, Schefft GL, Thach BT. Apnea associated with regurgitation(20.) Olson NR. The problem of gastroesophageal reflux. Otolaryngol Clin North Am 1986;19:119-33.(21.) Wiener GJ, Koufman JA, Wu WC, et al. The pharyngo-esophageal dual ambulatory pH probe for evaluation of atypical manifestations of gastroesophageal reflux (GER) [abstract]. Gastroenterology 1987;92:1694.(22.) Wiener GJ, Koufman JA, Wu WC, et al. Chronic hoarseness secondary togastroesophageal reflux disease: Documentation with 24-h ambulatory pH monitoring. Am J Gastroenterol 1989; 84:1503-8.(23.) Svensson G, Schalen L, Fex S. Pathogenesis of idiopathic contact granuloma of the larynx. Results of a prospective clinical study. Acta Otolaryngol Suppl 1988;449:123-5.factor of carcinoma of the laryngopharynx1988;99:370-3.(26.) Andze GO, Brandt ML, St. Vil D, et al. Diagnosis and treatment of gastroesophageal reflux in 500 children with respiratory symptoms: The value of pH monitoring. J Pediatr Surg 199l;26:295-300.(27.) Burton DM, Pransky SM, Katz RM, et al. Pediatric airway manifestations of gastroesophageal reflux. Ann Otol Rhinol Laryngol 1992;101:742-9.(28.) Koufman JA. Contact ulcer and granuloma of the larynx. In: Gates GA, ed. Current Therapy in Otolaryngology--Head and Neck Surgery. 5th ed. St. Louis: Mosby, 1994:456-9.(29.) Jindal JR, Milbrath MM, Shaker R, et al. Gastroesophageal reflux disease as a likely cause of "idiopathic" subglottic stenosis. Ann Otol Rhinol Laryngol 1994;103:186-91.(30.) Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: Acidparoxysmal (per´ksiz´m l),Laryngoscope 1996;106:1502-5.(32.) Parsons DS. Chronic sinusitis: A medical or surgical disease? Otolaryngol Clin North Am 1996;29:1-9.(33.) Koufman JA, Burke AJ. The etiology and pathogenesis of laryngeal carcinoma. Otolaryngol Clin North Am 1997;30:1-19.(34.) Little JP, Matthews BL, Glock MS. et al. Extraesophageal pediatric reflux: 24-hourdouble-probepH monitoring in 222 children. Ann Otol Rhinol Laryngol Suppl1997;169:1-16.(35.) Walner DL, Holinger LD. Supraglottic stenosis in infants and children. A preliminary report. Arch Otolaryngol Head Neck Surg 1997; 123:337-41.(36.) Toohill RJ, Kuhn JC. Role of refluxed acid in pathogenesis of laryngeal disorders. Am J Med 1997;103(5A):100S-106S.(37.) Toohill RJ, Ulualp SO, Shaker R. Evaluation of gastroesophageal reflux in patients with laryngotracheal stenosis. Ann Otol Rhinol Laryngol 1998;107:l0l0-4.(38.) Ross JA, Noordzji JP, Woo P. Voice disorders in patients with suspected laryngo-pharyngeal reflux disease. J Voice 1998;12: 84-8.(40.) Kuhn J, Toohill RJ, Ulualp SO, et al. Pharyngeal acid reflux events in patients with(41.) Gumpert L, Kalach N, Dupont C, Contencin P. Hoarseness and gastroesophageal reflux in children. J Laryngol Otol 1998;112: 49-54.(42.) Halstead LA. Role of gastroesophageal reflux in pediatric upper airway disorders. Otolaryngol Head Neck Surg 1999;120:208-14.(43.) Al-Sabbagh G, Wo JM. Supraesophageal manifestations of gastroesophageal reflux disease. Semin Gastrointest Dis 1999;10: 113-9.(44.) Hanson DG, Jiang JJ. Diagnosis and management of chronic laryngitis associated with reflux. Am J Med 2000;108(Suppl 4a):112S-119S.(45.) Grontved AM, West F. pH monitoring in patients with benign voice disorders. Acta Otolaryngol Suppl 2000;543:229-31.(46.) Koufman JA, Amin MR, Panetti M. Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg 2000;123:385-8.(47.) Poelmans J, Tack J, Feenstra L. Chronic middle ear disease and gastroesophageal reflux disease: A causal relation? Otol Neurotol 2001;22:447-50.(48.) Tasker A, Dettmar PW, Panetti M, et al. Reflux of gastric juice and glue ear in children [letter]. Lancet 2002;359:493.(49.) Loehrl TA, Smith TL, Darling RJ, et al. Autonomic dysfunction, vasomotor rhinitis, and extraesophageal manifestations of gastroesophageal reflux. Otolaryngol Head Neck Surg 2002;126: 382-7.(50.) Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice 2002;16:274-7.(51.) Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope 2001;1l1: 1313-7.(52.) Aviv JE, Liu H, Parides M, et al. Laryngopharyngeal sensory deficits in patients with(53.) Postma GN, Tomek MS. Belafsky PC, Koufman JA. Esophageal motor function in laryngopharyngeal reflux is superior to that in classic gastroesophageal reflux disease. Ann Otol Rhinol Laryngol 2001;ll0:1114-6.(54.) Koufman JA, Belafsky PC, Daniel E, et al. Prevalence of esophagitis in patients with pH-documented laryngopharyngeal reflux. Laryngoscope 2002;112:1606-9.(55.) Loughlin CJ, Koufman JA, Averill DB, et al. Acid-induced laryngospasm in a canine model. Laryngoscope 1996;106:1506-9.(56.) Duke SG, Postma GN, McGuirt WF, Jr., et al. Laryngospasm and diaphragmatic arrestin immature dogs after laryngeal acid exposure: A possible model for sudden infant death(57.) Sekizawa S, Ishikawa T, Sant'Ambrogio FB, Sant' Ambrogio G. Vagal esophageal(58.) Ishikawa T, Sekizawa SI, Sant' Ambrogio FB, Sant' Ambrogio G. Larynx vs. esophagus as reflexogenic sites for acid-induced bronchoconstriction in dogs. J Appl Physiol1999;86:1226-30.(59.) Sant' Ambrogio FB, Sant' Ambrogio G, Chung K. Effects of HCI-pepsin laryngeal instillations on upper airway patency-maintaining mechanisms. J Appl Physiol1998;84:1299-304.evolving technique to measure type and proximal extent of gastroesophageal reflux. Am J Med 2001; 111(Suppl 8A):157S-159S.(61.) Srinivasan R, Vela MF, Katz PO, et al. Esophageal function testing using multichannel intraluminal impedance. Am J Physiol Gastrointest Liver Physiol 2001;280:G457-62.Cardiovasc Surg 2001;13:255-64.(63.) Axford SE, Sharp N, Ross PE, et al. Cell biology of laryngeal epithelial defenses in health and disease: Preliminary studies. Ann Otol Rhinol Laryngol 2001;110:1099-1108.(64.) Johnson N, Bulmer D, Gill G, et al. Cell biology of laryngeal epithelial defenses in health and disease: Preliminary studies (Part II). Submitted for publication.(65.) Koufman JA, Wiener GJ, Wu WC, Castell DO. Reflux laryngitis and its sequelae(66.) Reulbach TR, Belafsky PC, Blalock PD, et al. Occult laryngeal pathology in a community-based cohort. Otolaryngol Head Neck Surg 2001;124:448-50.(67.) Koufman JA, Aviv JE, Casiano RR, Shaw GY. Laryngopharyngeal reflux: Position statement of the committee on speech, voice, and swallowing disorders of the American Academy of Otolaryngology--Head and Neck Surgery. Otolaryngol Head Neck Surg2002;127:32-5.(68.) Johnson PE, Koufman JA, Nowak LJ, et al. Ambulatory 24-hour double-probe pH monitoring: The importance of manometry. Laryngoscope 2001;111:1970-5.(69.) Johnson PE, Amin MA, Postma GN, et al. pH monitoring in patients with laryngopharyngeal reflux (LPR): Why the pharyngeal probe is essential. Submitted for publication.。

2023年中级经济师之中级经济师金融专业题库练习试卷B卷附答案单选题（共30题）1、一个国家在一定时期内，国际收支如果是顺差，则增加外汇储备，中央银行增加基础货币投资，货币供应量（）。

A.等额扩张B.数倍扩张C.等额收缩D.数倍收缩【答案】 B2、早在2003年9月，我国对金融控股集团的监管就采取()制度。

A.中央银行监管B.主监管C.统一监管D.集体监管【答案】 B3、某股票的每股预期股息收入为每年2元，如果市场年利率为5%，则该股票的每股市场价格应为()元。

A.20B.30C.40D.50【答案】 C4、投资银行财务顾问业务的服务对象通常是()。

A.机构投资者B.个人投资者C.公司或者政府机构等融资者D.金融中介机构【答案】 C5、设某地区某时流通中的通货为1500亿元，中央银行的法定存款准备金率为7％，商业银行的存款准备金为500亿元，存款货币总量为4000亿元。

根据以上材料回答下列问题。

若中央银行将法定准备金率上调为8％，则该地区当时的货币供应量将()。

A.减少B.不变C.不确定D.增加【答案】 A6、受外部环境及内部经营等因素的影响，2020年以来，某信托公司的发展出现困难，相关风控指标趋于恶化。

资料显示，2020 年第一季度末，该公司的风险资本为3亿元(人民币，下同)，净资本为2.2亿元，净资产为6亿元。

同期，该公司还因违规将信托财产挪用于非信托目的的用途，推介部分信托计划未充分揭示风险以及未真实、准确、完整披露信息等原因而多次受到处罚。

为规范经营行为，化解经营风险，维护市场稳定，监管部门对该公司实施了“贴身监管”，要求该公司尽快进行整改。

A.操作风险B.市场风险C.信用风险D.合规风险【答案】 D7、以下（）是直接融资工具。

A.商业票据B.银行本票C.保险单D.银行债券【答案】 A8、由某一集团公司控制或收购若干家银行，但是，被控制或收购的银行仍然具有独立法人地立，这种业银行组织制度属于()制度。

LPR对利率市场化改革影响的文献综述作者：刘开饮来源：《商业经济》 2021年第8期[作者简介] 刘开饮(1986-)，安徽阜阳人，助教，金融学硕士，研究方向：商业银行、金融科技。

刘开饮（安徽工商职业学院经济贸易学院，安徽合肥230000）[摘要] 利率市场化是经济社会发展的必然方向，利率市场化有助于资源的合理配置，降低融资成本，当前我国处在利率市场化改革的深水区，正确认识和对待LPR存在的意义以及研究分析对经济活动产生的影响为我国经济的更好发展提供指导意义。

基于利率市场化以及LPR的基本原理的分析，综述现有文献中LPR对经济生产产生的影响以及各界对利率市场化的认识，试图找到我国利率市场化发展的思路和方向。

[关键词] LPR；利率市场化；文献综述[中图分类号] F832.4 [文献标识码] A [文章编号] 1009-6043（2021）08-0179-03利率市场化改革是我国继续深化社会主义市场经济制度的必然选择，自1996年我国开始实行利率市场化改革以来取得很大进步，2003年3月央行发布的《2002年中国货币政策执行报告》中已经明确我国利率市场化改革的基本思路：先外币、后本币；先贷款、后存款；先长期、大额，后短期、小额。

2013年我国全面放开贷款利率浮动限制，2015年我国又放开了存款利息上浮限制，此时已基本完成利率市场化；2018年4月11日，中国人民银行行长易纲认为“中国正继续推进利率市场化改革，仍存在利率的‘双轨制’，一方面是因为存贷款方面仍有基准利率，另一方面货币市场利率还完全由市场决定的。

”为进一步促进利率市场化改革，优化利率传导效率，有效降低实体经济融资成本，2019年中国人民银行发布第15号公告，不断优化贷款市场报价利率(LPR)形成机制，更好地促进利率市场化。

一、LPR理论综述LPR，即Loan Prime Rate的简称，又称为贷款市场报价利率，起源于20世纪30年代的美国大萧条时期，为了应对恶性竞争、避免银行破产倒闭提供资金，美国率先开发了区域利率市场化的应用工具。

浅析利率市场化改革对于我国商业银行的影响【摘要】自1993年起，我国便开始进行利率市场化改革。

近年来，随着金融改革的全面推进，利率市场化改革也迈入深水区，而这一系列改革对商业银行产生了巨大的影响。

本文通过对我国利率市场化进程的回顾，以及对于一些发达国家商业银行面对利率市场化进程应对方案的梳理，分析了利率市场化可能给我国商业银行带来的影响，并针对这些影响提出了相应的建议和应对措施，以期我国商业银行能成功面对利率市场化带来的挑战。

【关键词】利率市场化、商业银行一、引言我国作为一个银行主导型的金融体系，商业银行在经济运行的作用十分重要。

近几年，我国金融改革全面推进，利率市场化作为金融改革的重要一环逐渐加快。

2019年，央行推出了一系列政策推进利率市场化进程加快，同时，据有关政策文件显示，2020年利率市场化改革将涉足深水区，改革进程的加速推进必然会对各个经济主体产生巨大的影响。

本文将试图探讨，作为利率传导过程中的重要一环，商业银行将会受到怎样的影响以及应该采取什么样的措施去面对这种影响。

二、我国利率市场化进程回顾及展望总体来讲，我国利率市场化借鉴了国外的经验，主要路径是“先外币、后本币；先贷款、后存款；先长期、大额，后短期、小额”的思路，主要分为为三个阶段。

（一）、货币市场利率改革（1993—1999年）在利率市场化进程之中，首先要为市场利率寻找一个参考的均衡点，即人们常说的“锚”。

而货币市场作为流动性最强的金融市场，其利率能够及时、充分地反映资金的供求关系，因此货币市场利率是各国市场化利率的重要的参考指标，我国的利率市场化改革也从此开始。

1996年，取消银行同业拆借利率限制；一年后，放开银行间债券回购利率。

1998年，国开行首次用市场化的方式在银行间债券市场发债，随后，国债也开始进行市场招标。

自此，我国银行间市场利率、国债和政策性金融债发行利率市场化逐渐完成，货币市场均衡利率逐渐形成。

（二）、贷款利率放开管制，存款利率浮动加大（1999—2013年）在第一阶段货币市场利率的改革过程中，我国便同时尝试着扩大了贷款利率浮动区间。

云南财经大学学报 2010年第4期(总第144期)理论探讨收稿日期:2010-04-09基金项目:中国国家留学基金(CSSF2007U 01162),韩国国际交流财团(G S08134)作者简介:马相东(1976 ),男,湖南永兴人,北京大学经济学院国际经济研究所研究员,日本京都大学经济学部博士后研究员,经济学博士,研究方向为世界经济、国际贸易理论与政策;杨丽花(1977 ),女,山西原平人,中国政法大学商学院讲师,经济学博士,研究方向为美国经济、国际贸易理论与政策。

感谢上述基金的研究资助,感谢北京大学王跃生教授,P rof H iroshi O hn i sh i at K yoto U n i versity ,P rof R ose m ary R ossiter and D r Bo long Cao a t Oh i o U n i versity 富有建设性的修改意见,文责自负。

瑞典皇家科学院于2008年10月13日宣布,将该年度诺贝尔经济学奖授予美国普林斯顿大学保罗 克鲁格曼(P au lK rugm an)教授,以表彰 他对贸易模式和经济活动的区位的研究 ,这是自1969年首届诺贝尔经济学奖以来第二次授予国际贸易研究的经济学家。

第一次于1977年授予瑞典经济学家俄林和英国经济学家米德,以表彰他们对国际贸易理论(俄林)和国际资本流动(米德)所做的开创性研究。

详情参见http ://nobe -l pr i ze org /nobe l _prizes /econo m ics/lau reates /。

贸易模式、企业异质性与国际贸易:研究述评与展望马相东1,2,杨丽花3(1 北京大学经济学院,北京100871;2 日本京都大学经济学部,日本京都;3 中国政法大学商学院,北京102249)摘 要:贸易模式一直是国际贸易研究的重要领域之一。

迄今为止,国际贸易研究仅有的两位诺贝尔经济学奖得主俄林和克鲁格曼获奖的主要原因都与其对贸易模式开创性研究有关。

央行历次降息一览表央行降息2019央行一共降息几次央行历次降息一览表央行降息降息时间表降准时间表央行历次降息一览表央行降息年期贷款基准利率下调0.25个百分点至4.6%;一年期存款基准利率下调0.25个百分点至1.75%。

自2015年9月6日起，下调金融机构人民币存款准备金率0.5个百分点，以保持银行体系流动性合理充裕，引导货币信贷平稳适度增长。

2015年6月28日，下调金融机构人民币贷款和存款基准利率。

其中，金融机构一年期贷款基准利率下调0.25个百分点至4.85%;一年期存款基准利率下调0.25个百分点至2%;其他各档次贷款及存款基准利率、个人住房公积金存贷款利率相应调整。

2015年5月10日, 一年期贷款基准利率下调0.25个百分点至5.1%;一年期存款基准利率下调0.25个百分点至2.25%，同时结合推进利率市场化改革，将金融机构存款利率浮动区间的上限由存款基准利率的1.3倍调整为1.5倍;2015年3月1日, 一年期贷款基准利率下调0.25个百分点至5.35%;一年期存款基准利率下调0.25个百分点至2.5%，同时结合推进利率市场化改革，将金融机构存款利率浮动区间的上限由存款基准利率的1.2倍调整为1.3倍;2014年11月22日, 一年期贷款基准利率下调0.4个百分点至5.6%;一年期存款基准利率下调0.25个百分点至2.75%，同时结合推进利率市场化改革，将金融机构存款利率浮动区间的上限由存款基准利率的1.1倍调整为1.2倍;2012年7月6日，一年期存款和贷款基准利率分别下调0.25个百分点和0.31个百分点,其他各档次存贷款基准利率及个人住房公积金存贷款利率相应调整;2012年6月8日，一年期存贷款基准利率分别下调0.25个百分点2011年7月6日，一年期存贷款基准利率分别上调0.25个百分点2011年4月5日，一年期存贷款基准利率分别上调0.25个百分点2011年2月8日，一年期存、贷款基准利率上调0.25个百分点2010年12月25日，一年期存贷款基准利率分别上调0.25个百分点2010年10月19日，一年期存贷款基准利率上调0.25个百分点2008年12月22日，一年期存贷款基准利率下调0.27个百分点2008年11月26日，一年期存贷款基准利率下调1.08个百分点2008年10月30日，一年期存贷款基准利率下调0.27个百分点2008年10月9日，一年期存贷款基准利率下调0.27个百分点2008年9月16日，一年期贷款基准利率下调0.27个百分点2007年12月20日，一年期存款基准利率上0.27个百分点;一年期贷款基准利率上调0.18个百分点2007年09月15日，一年期存款基准利率上调0.27个百分点;一年期贷款基准利率上调0.27个百分2007年08月22日，一年期存款基准利率上调0.27个百分点;一年期贷款基准利率上调0.18个百分点2007年07月20日，上调金融机构人民币存贷款基准利率0.27个百分点2007年5月19日上调金融机构人民币存贷款基准利率。

㊃专题㊃通信作者:马建刚,E m a i l :m j ge n t 79@163.c o m 反流性咽喉炎的诊断与治疗马建刚,段乃超,贾晓菲(河北医科大学第二医院耳鼻咽喉二科,河北石家庄050000) 摘 要:在耳鼻咽喉科临床中,咽喉反流(L P R )的诊断及治疗得到了越来越多的重视㊂然而,对L P R 引起的症状还多依赖于经验性治疗,但有时患者症状无明显改善㊂本文针对L P R 发病㊁临床诊断及治疗进行总结,目的在于增加对L P R 疾病的认识㊂关键词:咽炎;食管炎,消化性;诊断;治疗中图分类号:R 766 文献标志码:A 文章编号:1004-583X (2017)01-0046-05d o i :10.3969/j.i s s n .1004-583X.2017.01.011D i a g n o s i s a n d t r e a t m e n t o f l a r y n g o p h a r y n ge a l r ef l u x M a J i a ng a n g,D u a nN a i c h a o ,J i aX i a o f e i D e p a r t m e n t o f O t o r h i n o l a r y n g o l o g y ,t h eS e c o n d H o s p i t a l o f H e b e iM e d i c a lU n i v e r s i t y ,S h i j i a z h u a n g 050000,C h i n a C o r r e s p o n d i n g a u t h o r :M aJ i a n g a n g ,E m a i l :m j ge n t 79@163.c o m A B S T R A C T :I no t o l a r y n g o l o g yp r a c t i c e ,t h e r e i sar i s i n g c o n c e r nw i t ht h ec u r r e n td i a g n o s i sa n d m a n a ge m e n t of l a r y ng o ph a r y n g e a l r e f l u x (L P R ).M a n y c o mm o n h e a d a n d n e c k s y m p t o m si nL P Rd e p e n d o n e m p i r i c t h e r a p y,b u t t h e r e a r em a n yp a t i e n t sw h os h o w n oo v e r a l l i m p r o v e m e n t i nt h es y m p t o m s .T h i sa r t i c l er e v i e w st h eo t o l a r y n g o l o g i s t s a p p r o a c h t oL P R ,t h e v a r i o u sw a y s i n t h e d i a g n o s i s ,a n d t h e g u i d e l i n e s i no t o l a r y n g o l o g y m a n a ge m e n t o fL P R.K E Y W O R D S :p h a r y n g i t i s ;e s o p h a g i t i s ,p e p t i c ;d i a gn o s i s ;t r e a t m e nt 马建刚,男,医学博士,河北医科大学第二医院耳鼻咽喉二科主任,主任医师,教授,硕士研究生导师,中华医学会耳鼻咽喉-头颈外科学会会员,中国医疗保健国际交流促进会睡眠医学分会委员,河北省医学会耳鼻咽喉科学分会秘书,河北省抗癌协会委员,河北省医疗事故鉴定委员会专家组成员,河北省中西医结合学会会员,河北省中西医结合学会变态反应专业委员会常务委员,石家庄市医学会耳鼻咽喉科学会秘书㊂曾在在德国波恩大学耳鼻咽喉头颈外科中心和海德堡大学曼海姆医学睡眠中心及意大利锡耶纳大学医院耳鼻咽喉-头颈外科及睡眠鼾症中心访问学习㊂在国家级核心期刊上发表第一作者论文20余篇,主持省级科研课题2项;主编专业著作1部,副主编专业著作1部,参编卫生部医学视听教材1部,卫生厅乡村医生医学知识与技能培训教材1部;获河北省科技厅科技进步三等奖1项,获河北省卫生厅医学科技一等奖和二等奖各1项,河北省科技厅科技成果2项㊂咽喉反流(L P R )在耳鼻咽喉科临床中已经成为了一个重要的诊断㊂目前耳鼻咽喉科多称为 咽喉反流 ,而消化科则称为 食管外反流性疾病 ,两种诊断均指胃内容物自食管反流入咽腔及喉腔㊂L P R可引起多种头颈部常见症状,包括发声困难,咳嗽,吞咽困难,以及咽部异物感㊂并且考虑其可能与鼻炎㊁鼻窦炎㊁中耳炎等相关[1]㊂尽管L P R 可引起多种耳鼻咽喉科相关临床症状,但目前还没有诊断的金标准㊂由于L P R 症状复杂多变㊁体征轻重不一,而且无特异性,临床工作中很难实现客观诊断及病情分级,临床上存在过度诊断㊁过度治疗以及误诊误治㊂本文对L P R 的流行病学㊁多种诊断的途径以及治疗进行概述㊂1 流行病学在过去的20年中,L P R 引起了人们广泛的重视㊂K o u f m a n 等[2]对656例研究对象的胃食管反流病(G E R D )以及L P R 的发病率进行了统计,发现40%的受试者存在反流现象,其中22%的受试者有典型的反流症状而18%有L P R 的症状㊂C o n n o r等[3]的调查表明:26%的人有咽喉部症状,考虑为L P R ㊂研究显示将近10%的耳鼻咽喉科门诊患者及超过50%的声嘶患者存在L P R ㊂且随着国人生活水平的提高及饮食习惯的改变,可以预见L P R 疾病的发病率将会增加,同时由于L P R 治疗上建议使用质子泵抑制剂(P P I )用量为每日2次,连用超过2个月,因此为患者带来了很大的经济负担[4-5]㊂2 L P R 诊断既然L P R 可以不并发G E R D ,可疑的L P R 患者㊃64㊃‘临床荟萃“ 2017年1月5日第32卷第1期 C l i n i c a l F o c u s ,J a n u a r y 5,2017,V o l 32,N o .1Copyright ©博看网. All Rights Reserved.症状一般比较模糊,而且P P I治疗效果欠佳,那么如何精确诊断L P R呢对于耳鼻咽喉科医师来说,虽然没有诊断的金标准,仍有一些手段可以协助诊断L P R,即病史,查体(包括喉部查体),经验用药,p H 监测以及胃蛋白酶化验㊂2.1 L P R病史2002年,美国耳鼻咽喉头颈外科学会定义了L P R㊂K o u f m a n等[4]定义了L P R的最常见症状:声嘶,咽部异物感,发声困难,咳嗽,慢性清嗓以及咽痛㊂对于耳鼻咽喉科医师,这些临床症状在最初病史采集时即可提示存在L P R㊂单独存在的症状经常存在非反流性的因素,因此无法将症状与反流一对一的对应起来:例如,声嘶可能由反流引起,但也有可能存在声带新生物,声带创伤或者声带麻痹㊂因此,L P R的以症状为基础的诊断需要综合多种不同的症状来创建一个 复合 的评分,从而更好地反映反流的有无㊂B e l a f s k y等[6]在2001年首次提出了用反流症状指数(r e f l u xs y m p t o mi n d e x, R S I)来评估L P R的症状,认为若R S I>13分,可诊断为疑似L P R,在此之后有很多研究证实了这个量表对L P R的诊断价值㊂K o u f m a n最初提出的症状经过了严格的随访研究,提示为L P R非特异性㊂病史采集并不是精确诊断L P R的可靠方法㊂咳嗽㊁咽部异物感㊁清嗓以及声嘶可由其他咽喉部的刺激或炎症引发[7-8]㊂多种症状的存在也并不能排除非反流性因素导致㊂研究表明R S I与p H检测之间基本没有明确的关联,而且应用R S I来评价治疗效果对于临床上也没有太大帮助[9]㊂因此,病史采集能够提示存在L P R,但不能单凭病史来确诊㊂2.2体格检查/喉镜另一个诊断反流的手段是依据咽喉部的表现来判断病理性反流的有无㊂并不是单一的水肿或红肿的表现,而是对喉腔内多个部位可能炎症表现的系统评分,这就是反流体征评分(R F S)㊂当R F S>11提示存在L P R㊂与R S I一样,该评分及其阈值已经过了食管p H测定的验证[10]㊂然而,R F S也不能精确诊断反流[5,11]㊂R F S评分中的声带水肿,杓间区增生以及杓状软骨红肿也存在于非反流性疾病中[7]㊂此外,喉镜检查使用的仪器可能对检查结果产生偏倚㊂对于同一个患者的检查,相比于硬性喉镜,纤维喉镜能够更轻易的发现杓状软骨炎症,室带肥厚以及声带沟[8]㊂与R S I相似, R F S评分可能与食管p H测定或治疗效果关系不大[9]㊂因此,目前认为喉镜检查也不是L P R确诊的精确方式㊂2.3p H监测目前认为诊断L P R的金标准是24小时喉咽部p H监测,早期应用的是喉咽和食管双探头的24小时p H监测,标准是24小时L P R事件ȡ3次就可诊断㊂判定1次L P R事件必须符合下列条件[12]:①喉咽p H<4;②食管p H降低随后发生的喉咽p H降低;③排除进食或吞咽时的p H降低;④快速的p H下降,而不是缓慢的降低㊂单纯p H监测只监测酸反流的情况,而大部分不伴有反酸烧心症状的弱酸反流和碱反流而被漏诊,这部分反流也可引起咽喉部的症状㊂胃蛋白酶在p H4~6仍有活性,仍可损伤咽喉黏膜而引起症状㊂J o h n s t o n等[13]研究认为胃蛋白酶在酸性㊁非酸性和弱酸性环境中均可损伤咽喉黏膜㊂因此,以上监测方法存在假阴性结果㊂为弥补这一不足,学者发明了24小时多通道腔内阻抗-p H监测(m u l t i c h a n n e l i n t r a l u m i n a l i m p e d a n c e-p H,MⅡ-p H),其可以判定所有反流及类型,使检测更准确[14]㊂24小时MⅡ-p H监测酸反流的阳性判断标准为:喉咽部反流次数3ȡ次,或近端食管p H 值<4的总时间ȡ1%㊂亦曾有学者提出24小时内喉咽部反流次数ȡ6.9次或反流面积指数(r e f l u x a r e a i n d e x,R A I)ȡ6.3作为判断L P R的标准[15]㊂除酸反流次数外,可通过24小时MⅡ-p H监测结果分析的资料还包括:①总反流次数和非酸反流次数(p H >4);②酸反流总时间,监测过程中由于反流原因致喉咽部p H值<4的总时间;③最长酸反流时间;④平均酸清除时间,平均每次反流从p H值低于4开始到p H值回到大于4的时间;⑤平均食团清除时间(从阻抗下降到回升至阻抗起始值,且持续时间大于5秒),食团清除时间应少于酸清除时间,这是由于酸清除包括食管蠕动波对食团的清除和唾液对食管黏膜的酸中和㊂综合分析以上资料,p H监测可作为诊断L P R以及判断反流严重程度的重要依据[16]㊂但是最公认L P R的阳性标准还是24小时L P R事件ȡ3次㊂咽部p H监测(D X-p H):D X-p H监测仪是一种气道p H监测系统,可以精确监测咽喉部位的动态p H值,准确测出鼻㊁咽喉㊁气管中反流的微量酸或碱性气体,既可监测液体反流,也可监测气体反流,并能准确反映气道p H值4~6的实时变化情况㊂以R y a n评分反映监测结果[17]㊂国内少数医院已经开展咽部D X-p H监测,但是还没有发表有关临床文献,需要进一步验证其准确性㊂2.4胃蛋白酶化验由于L P R的诊断形式在不断进步,胃蛋白酶化验是一项新兴的可应用于临床的技术[18]㊂从概念上来说,所有出现在上消化道的胃蛋白酶只能是反流导致的,在唾液中找到胃蛋白酶是存在反流的证据㊂在有L P R的症状和体征的患㊃74㊃‘临床荟萃“2017年1月5日第32卷第1期 C l i n i c a l F o c u s,J a n u a r y5,2017,V o l32,N o.1Copyright©博看网. All Rights Reserved.者的呼吸道经常可检测到胃蛋白酶的存在[19]㊂然而,有些反流是生理性的,在正常人体内的上述部位有时也可检查出胃蛋白酶㊂为了将L P R与正常胃蛋白酶的存在量进行区分,人们还需要确定一个胃蛋白酶水平的阈值,并且胃蛋白酶试验还要有能够预测治疗效果的作用㊂临床上这类研究正逐渐被重视起来[20],但是胃蛋白酶试验目前还尚未成熟,无法应用于临床㊂3L P R的治疗目前对于L P R的诊断尚不确定,因此讨论目前存在的L P R治疗手段并寻找 最好的治疗手段 来为临床上食管外反流的诊疗提供参考是有意义的㊂3.1一般治疗对疑似L P R的患者,可给予相应治疗,改变生活方式和饮食习惯尤其重要,包括减肥,戒烟和戒酒;同时尽量避免巧克力,脂肪,咖啡的摄入,避免午夜进食等㊂K o u f m a n等[21]认为低酸饮食治疗同时改变抑郁情绪有助于提高治疗效果㊂因此,在给予相应抑酸治疗时应关注患者的心理状况㊂3.2内科治疗目前经常用于临床的L P R诊断方法为症状体征加4周的试验性治疗[22]㊂而p H监测实际上很少使用㊂抑酸治疗是L P R最常用的内科治疗策略,目前国际上公认的首选药物为P P I,其他药物包括H2受体阻滞剂(H2R A)㊁促胃肠动力剂㊁黏膜保护剂等㊂根据文献报道,对于L P R,推荐的P P I剂量为10~20m g/次,每日2次,早饭和晚饭前30~60分钟服用,持续服用8~12周,症状消失后逐渐减量至停药,以免快速停药造成反跳式胃酸分泌过多[23-25]㊂胃肠动力药通过加速胃排空,增强食管黏膜对反流内容物的清除功能,增强食管下括约肌的静止压力以缓解症状㊂有文献支持促胃肠动力药联合P P I在改善L P R患者症状或体征方面优于单纯应用P P I,可减少L P R症状的反复发作[26-27]㊂但是国际上普遍应用的每日两次P P I治疗L P R并不是据于临床随机对照研究的结果,用药剂量和时间仍有争议[23-24]㊂因此,需要进一步临床随机对照研究,找出合理的用药剂量和时间,规范治疗㊂仅有不到10%的患者停用P P I后症状完全缓解并不再复发,所以常常需要再次应用P P I治疗㊂对P P I疗效不佳者,需要考虑是否为非酸反流㊁或者是较严重的喉咽反流的可能性,也应考虑是否诊断有误,是否为胆汁反流等碱性反流或弱酸,亦或尚存在其他病因如食管咽反流㊁过敏㊁过量烟酒㊁肺部疾患㊁鼻窦病变㊁风湿㊁免疫等因素㊁用嗓过度㊁吸入性刺激物质等因素,可添加组胺受体阻滞剂㊁促胃动力剂等[28-29]㊂中药治疗作为我国的国粹,其在治疗L P R 中的作用不容忽视,吉均祥等[30]证实中药有助于提高P P I治疗L P R的疗效㊂一般来说,人们都认为对于那些存在声嘶㊁清嗓㊁咳嗽或其他症状的患者如果应用P P I有效,则可证明症状是由反流引起的㊂有研究表明许多有类似症状的患者应用P P I后症状得到了改善[31]㊂目前推荐每日2次用药,持续治疗至少2个月,甚至3~4个月[32-33]㊂J i n等[34]特别观察了L P R患者的发声困难症状,并应用振动㊁频闪观察治疗后1~2个月的变化,结论证明患者症状是由L P R引起的㊂然而,另外一些研究则表明使用P P I有效并不能说明是否存在L P R㊂许多随机对照试验表明安慰剂组与P P I治疗组在改善L P R症状方面差异无统计学意义[32,35]㊂与J i n等[34]表明P P I能够改善声音状况的研究相对应的是另外一项由H a m d a n等[35]进行的研究,他们认为P P I对症状改善并不显著㊂一项m e t a分析总结了P P I治疗可疑G E R D相关的慢性喉炎的随机对照研究,结论是P P I组与安慰剂组疗效差异并无统计学意义[36]㊂除此之外,经验性用药试验对于那些疗效欠佳的病例没有任何诊断价值㊂如果应用P P I对患者的咽喉部症状没有明显疗效,有可能是该患者未患L P R,也有可能是存在对所选药物不敏感的难治性L P R㊂经验性试验,即每日两次P P I应用超过2个月,可能存在治疗费用及不良反应的双重问题㊂目前,P P I的不良反应引起了越来越多的重视,长期应用P P I可以减少钙质的吸收,容易引起骨质疏松以及髋部骨折,增加肺炎发生率,对心脏病发作以及肾脏疾病的发生也有影响,还会导致维生素B12吸收障碍[37]㊂因此,经验性应用P P I治疗L P R虽然有效,但其并不宜作为一个理想的诊断方法㊂3.3手术治疗对于有症状的非酸反流(职业用声者中常见)㊁药物及生活方式联合疗效不佳㊁反流严重㊁下食管括约肌功能不良㊁药物不良反应严重㊁年轻患者避免长期用药或经济原因等均可作为手术治疗的适应证㊂最常用和有效的术式是腹腔镜下胃底折叠术,手术目的是恢复食管下括约肌张力,加强抗反流屏障功能以减少L P R事件的发生㊂腹腔镜下胃底折叠术是目前临床最常用和有效的术式[38-41]㊂4结论目前来说,p H监测(未来可能包括胃蛋白酶检测)可以认为是较准确的诊断方法㊂但是,常规进行p H监测并不实际,但是可以作为可疑存在L P R患者进行经验性治疗时可供选择的检查㊂经验性使用抗酸药目前仍是诊断L P R的重要手段[42]㊂㊃84㊃‘临床荟萃“2017年1月5日第32卷第1期 C l i n i c a l F o c u s,J a n u a r y5,2017,V o l32,N o.1Copyright©博看网. All Rights Reserved.鉴于L P R的诊断和治疗中存在诸多问题,本病属于一个多学科交叉的疾病,其诊断和治疗需要内科㊁外科㊁耳鼻咽喉科㊁儿科等科室的通力合作,也需要咽喉疾病的专家尽快共同制定L P R的诊疗流程或草案,按照统一诊疗流程开展多中心的临床研究,为L P R的诊疗指南的制定奠定研究基础,促使L P R 诊断和治疗的规范化㊂参考文献:[1] B o o k D T,R h e e J S,T o o h i l l R J,e t a l.P e r s p e c t i v e s i nl a r y n g o p h a r y n g e a l r e f l u x:a n i n t e r n a t i o n a l s u r v e y[J].L a r y n g o s c o p e,2002,112(1):1399-1406.[2] K o u f m a n J A,A m i n M R,P a n e t t iM.P r e v a l e n c eo f r e f l u xi n113c o n s e c u t i v e p a t i e n t sw i t h l a r y n g e a l a n d v o i c e d i s o r d e r s[J].O t o l a r y n g o l o g y H e a dN e c kS u r g,2000,123(4):385-388.[3] C o n n o rN P,P a l a z z i-C h u r a sK L P,C o h e nS B,e t a l.S y m p t o m so f e x t r a e s o p h a g e a l r e f l u x i na c o mm u n i t y-d w e l l i n g s a m p l e[J].JV o i c e,2007,21(2):189-202.[4] K o u f m a n J A,A v i v J E,C a s i a n oR R,e t a l.L a r y n g o p h a r y n g e a lr e f l u x:p o s i t i o n s t a t e m e n t o f t h e c o mm i t t e e o ns p e e c h,v o i c e,a n d s w a l l o w i n g d i s o r d e r s o f t h e A m e r i c a n A c a d e m y o fO t o l a r y n g o l o g y-H e a d a n dN e c k S u r g e r y[J].O t o l a r y n g o lH e a dN e c kS u r g,2002,127(1):32-35.[5]S i n g e n d o n k M,P u l l e n sB,V a nH J,e t a l.O P-5i n t e r o b s e r v e rv a l i d i t y o f t h e r e f l u x f i n d i n g s c o r e f o r i n f a n t s i n f l e x i b l e v e r s u sr i g i d l a r y n g o s c o p y[J].JP e d i a t rG a s t r o e n t e r o lN u t r,2015,61(4):510-511.[6] B e l a f s k y P C,P o s t m a G N,K o u f m a n J A.V a l i d i t y a n dr e l i a b i l i t y o f t h er e f l u xs y m p t o mi n d e x(R S I)[J].J V o i c e, 2002,16(2):274-277.[7] H i c k sD M,O u r sTM,A b e l s o nT I,e t a l.T h e p r e v a l e n c eo fh y p o p h a r y n x f i n d i n g sa s s o c i a t e d w i t h g a s t r o e s o p h a g e a l r e f l u xi nn o r m a l v o l u n t e e r s[J].JV o i c e,2003,16(4):564-579.[8] M i l s t e i n C F,C h a r b e lS,H i c k s D M,e ta l.P r e v a l e n c e o fl a r y n g e a l i r r i t a t i o n s i g n s a s s o c i a t e d w i t h r e f l u x i na s y m p t o m a t i c v o l u n t e e r s:i m p a c t o f e n d o s c o p i c t e c h n i q u e(r i g i d v s.f l e x i b l e l a r y n g o s c o p e)[J].L a r y n g o s c o p e,2005,115(12):2256-2261.[9] P o s t m aG N.A m b u l a t o r y p H m o n i t o r i n g m e t h o d o l o g y[J].A n nO t o lR h i n o l L a r y n g o l,2000,184(10):10-14.[10] B e l a f s k y P C,P o s t m a G N,K o u f m a nJ A.T h ev a l i d i t y a n dr e l i a b i l i t y o f t h e r e f l u x f i n d i n g s c o r e(R F S)[J].L a r y n g o s c o p e,2001,111(8):1313-1317.[11] C h a n g B A,M a c n e i l S D,M o r r i s o n M D,e t a l.T h eR e l i a b i l i t yo f t h e r e f l u x f i n d i n g s c o r e a m o n g g e n e r a l o t o l a r y n g o l o g i s t s[J].JV o i c e,2015,29(5):572-577.[12] P o s t m aG N,B e l a f s k y P C,A v i v J E,e t a l.L a r y n g o p h a r y n g e a lr e f l u x t e s t i n g[J].E a rN o s eT h r o a t J,2002,81(2):14-18.[13]J o h n s t o n N,K n i g h t J,D e t t m a r P W,e t a l.P e p s i n a n dc a r b o n i ca n h yd r a s ei s oe n z y m eI I Ia sd i a g n o s t i c m a r k e r sf o rl a r y n g o p h a r y n g e a l r e f l u x d i s e a s e[J].L a r y n g o s c o p e,2004,114(12):2129-2134.[14]王嘉森,李晓雨,李进让.咽喉24h多通道腔内阻抗联合p H监测的临床应用[J].临床耳鼻咽喉头颈外科杂志,2015,(2): 190-193.[15] V i n c e n tD a J r,G a r r e t t J D,R a d i o n o f f S L,e t a l.T h e p r o x i m a lp r o b e i n e s o p h a g e a l p H m o n i t o r i n g:d e v e l o p m e n t o f an o r m a t i v e d a t a b a s e[J].JV o i c e,2000,14(2):247-254. 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