DOI: 10.4046/trd.2009.66.4.267 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2009;66:267-273 CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 수면호흡장애의내과적치료 Review 가톨릭대학교의과대학내과학교실 문화식 Medical Treatment of Sleep Disordered Breathing Hwa Sik Moon, M.D. Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea 서 론 폐쇄성수면무호흡의치료 수면호흡장애 (sleep disordered breathing) 에는다양한형태가있으나주로수면무호흡 (sleep apnea) 의치료에대하여간략히기술한다. 정확한진단은효과적인치료를위해필수적이며, 진단된환자에서치료의필요성여부를결정하고적절한치료방법을선택하기위해서는중증도판정및발병요인에대한고려가필요하다. 수면호흡장애, 특히수면무호흡은모든사람에서발생할수있으며일정범위를초과하지않는경우에는임상적으로문제가되지않는다. 수면무호흡증후군의진단기준은연구기관에따라다소차이가있으며, 최근미국수면의학회 (American Academy of Sleep Medicine) 는 Table 1과같은진단기준을제시한바있다 1,2. 중증도판정에는무호흡-저호흡지수, 저산소증의정도, 고탄산증의발생여부, 주간졸음증의정도, 심혈관계질환의동반여부등이종합적으로고려되어야할것으로생각되고있다. 그러나현재까지세계적으로공인된중증도판정기준은없는실정이다. 미국수면의학회는무호흡-저호흡지수 (AHI) 를기준으로다음과같은중증도판정기준을제시한바있다 1,2. 경증 (mild), 5 AHI 15; 중등도 (moderate), 15<AHI 30; 중증 (severe), AHI>30. Address for correspondence: Hwa Sik Moon, M.D. Department of Internal Medicine, St. Paul's Hospital, The Catholic University of Korea College of Medicine, 620-56, Jeonnong 2-dong, Dongdaemun-gu, Seoul 130-709, Korea Phone: 82-2-958-2463, Fax: 82-2-968-7250 E-mail: hsmoon@catholic.ac.kr Received: Nov. 13, 2008 Accepted: Dec. 11, 2008 연구보고에의하면중등도이상의환자에서수면무호흡을적절히치료하지않을경우에는정상인에비해장기사망률이현저히증가하나, 단순코골음혹은경증환자의경우에는정상인과비교하여장기사망률이큰차이가없는것으로알려져있다 3. 따라서치료방침을결정할경우에는중등도이상의환자와경증환자를구분하여야한다. 환자의임상적문제점은대부분무호흡에의한빈번한각성, 저산소증혹은고탄산증에의해발생하므로중등도이상의환자는진단즉시무호흡자체가발생되지않도록하는적극적인치료법을검토하여야한다. 반면에경증환자의경우에는행동요법과더불어수면무호흡의발생요인에대한치료를먼저고려하고 (Table 2), 치료효과가불확실하지만약물요법도시도해볼수있다 4,5. 그러나경증인경우에도주간졸음증이심하여일상생활이어렵거나심혈관계질환이동반된환자에서는적극적인치료를고려하여야한다 (Table 3) 4,5. 1. 행동요법 (behavioral therapy) 진단된모든환자는치료개시시점부터체중감량, 금주, 코의개통성 (nasal patency) 을개선시키고, 수면무호흡을유발하거나악화시킬수있는약제의투약을금지하며, 잠을잘때는특정체위를유지하도록하는등의행동요법을시행하도록한다 6. 수면무호흡환자는비만인경우가많으며비만자체가수면무호흡의위험요인으로작용하기도한다 7. 경증환자의경우에는체중감량만으로도코골음과수면무호흡이현저히호전된다. 체중감량을위해식이요법, 운동, 식욕억제제투여, 최면요법및수술적방법등이다양하게 267
HS Moon: Medical treatment of sleep disordered breathing Table 1. Diagnostic criteria of sleep apnea syndrome Obstructive sleep apnea syndrome Central sleep apnea syndrome *RERAs: respiratory effort related arousals. Table 2. Risk factors of sleep apnea syndrome A, B, and D or C and D satisfy the criteria A. At least one of the following applies i. The patient complains of unintentional sleep episodes during wakefulness, daytime sleepiness, unrefreshing sleep, fatigue, or insomnia. ii. The patient wakes with breath holding, gasping, or choking. iii. The bed partner reports loud snoring, breathing interruptions, or both during the patient s sleep. B. Polysomnographic recording shows the following: i. Five or more scoreable respiratory events (i.e., apneas, hypopneas, or RERAs*) per hour of sleep. ii. Evidence of respiratory effort during all or a portion of each respiratory event (In the case of a RERA, this is best seen with the use of esophageal manometry). OR C. Polysomnographic recording shows the following: i. Fifteen or more scoreable respiratory events (i.e., apneas, hypopneas, or RERAs*) per hour of sleep. ii. Evidence of respiratory effort during all or a portion of each respiratory event (In the case of a RERA, this is best seen with the use of esophageal manometry). D. The disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use, or substance use disorder. A. The patient reports at least one of the following: i. Excessive daytime sleepiness. ii. Frequent arousals and awakenings during sleep or insomnia complaints. iii. Awakening short of breath. B. Polysomnography shows five or more central apneas per hour of sleep. C. The disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use, or substance use disorder. Obstructive sleep apnea Obesity Nasal obstruction Nasal septal deviation Nasal polyp Sinusitis Allergic rhinitis Pharyngeal airway stenosis Uvular hypertrophy Adenotonsillar hypertrophy Retrognathia Micrognathia Macroglossia Endocrine disorders Hypothyroidism Acromegaly Drugs Alcohol Sedative, hypnotics, narcotics, anesthetics Sex hormone (progesterone) imbalance Hereditory factors Central sleep apnea Defect of metabolic respiratory control system Central alveolar hypoventilation syndrome Brain stem infarction Encephalitis Defect of respiratory neuromuscular apparatus Muscular dystrophy Spinal atrophy Amyotrophic lateral sclerosis Transient instability of respiratory control system Sleep onset Hypocapnea due to hyperventilation Idiopathic Hypoxia (altitude, pulmonary disease) Cardiovascular disease, pulmonary congestion Central nervous system disease Inhibition of respiratory drive due to upper airway reflux Upper airway collapse Aspiration Gastroesophageal reflux 268
Tuberculosis and Respiratory Diseases Vol. 66. No. 4, Apr. 2009 Table 3. Treatment of obstructive sleep apnea syndrome Category Behavioral therapy Mechenical devices Surgical therapy Drug therapy Strategies Weight reduction Alcohol avoidance Specific position avoidance during sleep Apnea aggravating drug withdrawl :sedative, hypnotics, narcotics, anesthetics CPAP* therapy BiPAP Auto PAP Oral appliances Bypass of upper airway obstructions Tracheostomy Upper airway reconstruction UPPP LAUP Mandibular advancement Hyoid ostotomy Tricyclic antidepressants: protriptyline Medroxyprogesterone Modafinil *continuous positive airway pressure, bilevel positive airway pressure, autotitrating positive airway pressure, uvuloplalatopharyngoplasty, laser-assisted uvuloplasty. 시도되고있다. 체중을 10% 감량하면 AHI 가 26% 감소하고, 1% 의체중변화는 3% 의 AHI 변화를유발한다는연구결과가보고된바있다 8. 수면중의체위특히앙와위 (supine position) 에서는중력에의해턱, 혀, 구개수 (uvula) 및연구개 (soft palate) 가후방으로이동하여상기도내경을감소시키기때문에코골음과수면무호흡이악화될수있다 9. 따라서측와위 (lateral decubitus position) 혹은반입위 (semiupright posture) 상태로잠자는것이좋으며 10, 앙와위를방지하기위해특별히고안된베개를사용하거나잠옷의등쪽에공을넣은주머니를부착하기도한다 11. 그러나체위에큰영향을받지않는수면무호흡의경우체위변경을통한치료는제한점이있다. 음주 12, 진정제 13, 수면제 14, 마약 15, 마취제, 베타차단제와같은항고혈압제, 남성호르몬 16 등은수면중호흡중추를억제하거나상기도근육긴장도를저하시킬수있으므로이들약제의복용을금해야한다. 특히취침전음주는반드시금하여야한다. 음주는중추성호흡중추의자극을억제하고인두근육의활동성을저해하여상기도저항을증가시켜저산소증을악화시키고무호흡의빈도및지속시간을증가시킨다. 수면무호흡증후군환자혹은선 단거대증 (acromegaly) 과같이수면무호흡발생가능성이높은환자를수술하는경우에는수술전에진정제혹은마약의사용을가급적금하는것이좋고, 수술후발관 (extubation) 시에는수술후에도지속될수있는마취제나근육이완제의작용으로수면무호흡이악화될수있으므로주의를요한다. 2. CPAP치료폐쇄성수면무호흡발생을가장완벽하게예방할수있는치료법은폐쇄부위를우회하는기관절개술 (tracheostomy) 이며극히위중한환자에서만드물게시행된다. 기관절개술다음으로효과가입증된치료법은지속적기도양압 (continuous positive airway pressure, CPAP) 치료로서, 코마스크를통해상기도에지속적으로양압을공급함으로써상기도폐쇄를예방하며, 이치료법을흔히 nasal CPAP 이라고한다 17. CPAP 치료는특히허혈성심질환혹은울혈성심부전이동반된환자에서는가장탁월한치료법이라는사실이연구결과밝혀져있으며 18, 상기도저항증후군의치료에도매우효과적이다. CPAP 치료는주로중등도이상의환자에서시행되지만, 경증의경우에도고혈압, 뇌졸중, 과도한주간졸음증, 허혈성심질환, 불면증, 우울증등이있는경우에시행될수있다 19. CPAP 치료를적용하고자할경우에는수면다원검사를다시시행하면서 CPAP 치료를시도하여적정압력을결정해야한다. 적정압력이란모든수면단계에서코골음, 무호흡, 저호흡, 저산소증및각성을방지할수있는최소압력을의미한다. 또한검사를시행하면서환자에게어떤마스크가가장적합한지를결정하고 20, 마스크의안면접촉면에서공기가새는지 (air leak) 여부를관찰한다 21. 적정압력이결정되면 CPAP 기계에압력을고정시키고매일전체수면기간동안지속적으로사용하도록한다. CPAP 치료의필요성, 예측되는문제점과대처방안, 마스크착용법등을충분히교육시키고처방후적절히시행하는지여부를지속적으로관찰함으로써 CPAP 치료에대한불안감을줄이고향후치료순응도를높일수있다 22. CPAP 치료를실시하면처음에는렘수면이증가하지만약 1주일이경과하면대부분의환자가정상수면구조를보인다. CPAP치료시행중에는비충혈, 비점막의건조감이나자극증상이나타날수있으며이러한경우에는습도조절장치를 CPAP기계에부착하거나비충혈완화제, 항히스타민제혹은부신피질호르몬제의국소적사용으로치료가가능하다. 마스크주변으로공기가새어눈을자극 269
HS Moon: Medical treatment of sleep disordered breathing 할수있으나최근에는마스크소재가새로이개발되어이러한부작용이많이감소하였다. 또한이비인후과와의협진을통해상기도의합병증을조절할수있다 23. CPAP 치료의적용에도불구하고주간졸음증이호전되지않는경우에는수면무호흡증후군진단이정확히이루어진것인지, CPAP 치료가적절히시행되었는지혹은다른수면장애가있는지여부를살펴볼필요가있다. 일반적인 CPAP 치료에잘적응하지못하는환자의경우에는흡기압과호기압을보다유연성있게조정할수있는장비 (bilevel positive airway pressure, BiPAP) 혹은기도저항의변화에따라압력이변동되도록고안된장비 (autotitrating positive airway pressure, Auto PAP) 가시도될수있다. BiPAP 은높은압력으로인해 CPAP 치료를견디지못하는환자 24, 제한성폐질환이나저환기증후군환자에서이용될수있다 16. Auto PAP의경우에는음주, 수면제복용, 체위변동등에따라자동적으로압력을변화시켜 CPAP 치료보다낮은평균압력을유지할수있다 25. 그러나마스크로부터공기가새는경우 (air leak) 와같은압력변화에도민감하게반응하여필요이상으로압력을높일수있다. 또한울혈성심부전, COPD, 저환기증후군등이동반된환자에서의사용은권장되고있지않다 26. 따라서현재까지는 CPAP 치료가일차적치료로간주되고있다. 일부환자들은안면밀폐공포증혹은마스크착용의불편함을이유로이치료법의적용을거부하기도한다. CPAP 치료를시행한환자들중에서전체수면기간의 70% 이상혹은 4시간이상실제로 CPAP 치료를시행하는환자의비율은보고에따라 46 내지 80% 로큰차이를보이고있으며 27, 장기간지속적으로사용하는비율, 즉유순도 (compliance) 는대략 60 내지 70% 정도를기대할수있는것으로알려져있다 28. CPAP 치료를지속적으로시행할경우에는주간졸음증이호전되어삶의질이향상될뿐만아니라 29 혈압강하및좌심실기능향상에도효과가있으며 30 심혈관질환의빈도를줄여주어중등도이상의환자에서장기사망률이현저히감소하는것으로알려져있다 3. 3. 구강내장치 (oral appliances) 수면중구강내에장착함으로써상기도내강을넓혀주는장치이며, 치과영역에서제작하여사용한다. 다양한형태의구강내장치가개발되어있으며, 혀의후방이동을억제하는장치 (tongue retaining device) 와하악을전방으 로이동시키는장치 (mandibular advancement device) 가가장많이사용되고있다. 연구자료에서는경증및중등도환자의경우약 80%, 중증의경우에도약 60% 의환자에서효과가있는것으로보고하고있다 31. 구강내장치의적응증이되는환자를선별하고, 각각의환자에게가장효과적인장치를선택함으로서효과를높이고부작용을최소화할수있다. 경증혹은중등도폐쇄성수면무호흡증후군환자혹은 CPAP 치료를견디지못하는모든중증도의환자들이적응증이될수있다 32. 치료효과는나이가어릴수록, 비만도 (BMI) 가낮고목둘레가작을수록, AHI 가낮을수록좋다. 수면다원검사를통해치료효과를평가할수있으며, 결과에따라구강내장치를조정할수도있다. 그러나중추성수면무호흡이나저환기증후군의경우에는효과가없고치통이나턱관절의통증, 구강건조나잇몸자극등의부작용이있을수있다 33. 4. 수면무호흡발생요인에대한치료수면무호흡의발생요인은매우다양하며원인을정확히규명하지못하는경우가적지않다 (Table 2) 4,5. 갑상선기능저하증, 선단거대증, 편도비대증등과같이발생요인이명확하고치료가가능한경우에는이를치료한다. 또한수면무호흡발생혹은호흡조절계통에영향을미칠수있는여러가지전신질환을치료한다. 특히비폐쇄 (nasal obstruction) 는무호흡을유발하거나악화시킬수있으므로알레르기성비염, 비중격만곡증, 비용종, 부비동염등과같은이비인후과질환을철저히치료한다. 5. 약물요법여러가지약제에대한연구가진행되었으나치료효과가입증된약제는매우제한적이다. 또한약물요법의효과는환자에따라차이가있기때문에모든환자에게공통적으로적용할수있는약제를제시하기는어려운실정이다. 따라서경증환자의경우에주로시도될수있으며, 약물요법을시행하는경우에는치료효과와장기간약물투여로인한부작용을면밀히관찰하여야한다. 약물투여후효과발현까지는대개수일이경과하여야하며, 1 내지 2주투여후효과가없거나부작용이심한경우에는투약을중지하고다른치료법을고려한다. Protriptyline 은진정작용이없는삼환계항우울제 (tricyclic antidepressant) 로특히렘수면을감소시키는약리작용에의해수면무호흡과저산소증을개선한다. 부작용으로구내건조와변비가생길수있으며특히남자에서는 270
Tuberculosis and Respiratory Diseases Vol. 66. No. 4, Apr. 2009 요축척과발기부전이나타날수있다 34. Protriptyline 이외의다른삼환계항우울제역시유사한효과를나타내는것으로알려져있다. Medroxyprogesterone 은고탄산증에대한중추성환기반응을촉진하고상기도근육긴장도를증가시키는작용이있다. 따라서이산화탄소저류를보이는폐쇄성수면무호흡증후군환자에서특히효과적이며, 비만-저환기증후군 (obesity-hypoventilation syndrome) 환자에서도효과가있다. 부작용으로성기능장애, 유방불쾌감, 혈전색전증등이발생할수있다 35. Modafinil 은각성을촉진하는약제로 CPAP 치료등을시행하였음에도불구하고지속되는주간졸음증의치료에사용될수있는것으로최근 FDA 공인을받았다. 주관적혹은객관적으로주간졸음증이개선되며삶의질이향상되는것으로알려져있다. 그러나수면무호흡자체를치료하는효과가없으므로약제만을단독으로사용하는것은금기이며, 부작용으로두통, 비염, 혈압이나맥박상승등이발생할수있다 36. 6. 상기도근육의전기자극요법상기도의확장근육에직접전기적자극을가함으로써이들근육의활성도를증가시켜폐쇄성수면무호흡을치료하고자하는실험적연구가보고된바있다 37. 그러나신경손상이나심부정맥등의부작용이발생할수있는것으로알려져있어앞으로많은연구가필요하며, 임상영역에서실제적용되지는못하고있다. 중추성수면무호흡의치료일반적으로중추성수면무호흡의치료효과는만족스럽지못하다. 중추성호흡구동의일시적불안정으로인한중추성수면무호흡의치료에는보다어려움이많다. 만성폐포저환기증후군의성격을띠는중추성수면무호흡의치료는다른저환기장애의치료와본질적으로동일하다. 저산소증이동반된환자에서는야간산소투여가좋은반응을보이는경우가있다 38. 일부환자에서는 acetazolamide 투여가좋은반응을보이는데, 이것은산성화 (acidification) 가중추성호흡구동을촉진하기때문이다. 환자에따라서는 CPAP 치료가효과적이라는보고가있다 39. CPAP 치료가중추성수면무호흡을호전시키는기전은아마도호기시기에부가되는기계적부하 (expiratory mechanical load) 로인한소량의동맥혈이산화탄소분압상승과관련이있을것으로추측되고있다 40. 중추성수면무호흡이울혈성심부전으로인해이차적으로발생된환자에서는특히 CPAP 치료가수면의질과심기능을향상시키는효과가있다. 중추성수면무호흡은발생요인을규명하기어려운경우가많으나, 발생요인이명확하고치료가가능한경우에는이에대한치료를병행한다 (Table 2) 4,5. 예를들어상기도허탈에의한상기도반사로인해중추성수면무호흡이발생한경우에는상기도폐쇄요인을치료하거나 CPAP 치료를시행하면효과적이며, 울혈성심부전에기인하는경우에는 CPAP 치료와더불어심질환에대한내과적치료를병행하는것이효과적이다. 결 수면호흡장애의치료에앞서가장중요한것은정확한진단이다. 특히수면무호흡증후군환자의경우다른유형의수면장애와정확한감별진단이필요하며, 수면무호흡과더불어다른수면장애가동반되어있는지여부또한매우중요하다. 수면호흡장애특히수면무호흡증후군으로진단된환자에서행동요법만을권장할것인지혹은보다적극적인치료를시행할것인지여부는환자의임상적문제점및수면무호흡의중증도를고려하여결정한다. 적극적인치료가필요한환자에게실제로적용할효과적인치료법을선택하는것은매우중요하고도어려운문제이며, 이를위해서는여러분야의수면의학전문의와협진이필요하다. 수면무호흡의개선을위해선택할수있는치료방법은현재까지매우제한적이라고저자는생각한다. 특히중추성수면무호흡의치료에는많은어려움이따른다. 앞으로모든환자에게용이하게적용될수있는효과적인치료법이연구개발되기를기대한다. 론 참고문헌 1. Iber C, Ancoli-Israel S, Chesson A, Quan SF. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. 1st ed. Westchester: American Academy of Sleep Medicine; 2007. 2. American Academy of Sleep Medicine. The interna- 271
HS Moon: Medical treatment of sleep disordered breathing tional classification of sleep disorders: diagnostic & coding manual. 2nd ed. Westchester: American Academy of Sleep Medicine; 2005. 3. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046-53. 4. Moon HS. Sleep apnea. In: The Korean Academy of Tuberculosis and Respiratory Disease. Respiratory Disease. 1st ed. Seoul: Koon Ja Publishing, Inc.; 2004. p. 993-1007. 5. Moon HS. Sleep apnea syndrome. In: The Korean Association of Internal Medicine. Prescription guide for the primary care physician (medical part). 2nd ed. Seoul: Korean Institute of Medicine; 2004. p. 779-85. 6. Veasey SC, Guilleminault C, Strohl KP, Sanders MH, Ballard RD, Magalang UJ. Medical therapy for obstructive sleep apnea: a review by the Medical Therapy for obstructive sleep apnea task force of the standards of practice committee of the American Academy of Sleep Medicine. Sleep 2006;29:1036-44. 7. Strohl KP, Redline S. Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 1996;154:279-89. 8. Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000;284:3015-21. 9. George CF, Millar TW, Kryger MH. Sleep apnea and body position during sleep. Sleep 1988;11:90-9. 10. Jokic R, Klimaszewski A, Crossley M, Sridhar G, Fitzpatrick MF. Positional treatment vs continuous positive airway pressure in patients with positional obstructive sleep apnea syndrome. Chest 1999;115:771-81. 11. Skinner MA, Kingshott RN, Filsell S, Taylor DR. Efficacy of the 'tennis ball technique' versus ncpap in the management of position-dependent obstructive sleep apnoea syndrome. Respirology 2008;13:708-15. 12. Taasan VC, Block AJ, Boysen PG, Wynne JW. Alcohol increases sleep apnea and oxygen desaturation in asymptomatic men. Am J Med 1981;71:240-5. 13. Höijer U, Hedner J, Ejnell H, Grunstein R, Odelberg E, Elam M. Nitrazepam in patients with sleep apnoea: a double-blind placebo-controlled study. Eur Respir J 1994;7:2011-5. 14. Lofaso F, Goldenberg F, Thebault C, Janus C, Harf A. Effect of zopiclone on sleep, night-time ventilation, and daytime vigilance in upper airway resistance syndrome. Eur Respir J 1997;10:2573-7. 15. Robinson RW, Zwillich CW, Bixler EO, Cadieux RJ, Kales A, White DP. Effects of oral narcotics on sleepdisordered breathing in healthy adults. Chest 1987;91: 197-203. 16. Liu PY, Yee B, Wishart SM, Jimenez M, Jung DG, Grunstein RR, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab 2003;88:3605-13. 17. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; 1:862-5. 18. Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348:1233-41. 19. Kushida CA, Littner MR, Hirshkowitz M, Morgenthaler TI, Alessi CA, Bailey D, et al. Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders. Sleep 2006;29:375-80. 20. Pépin JL, Leger P, Veale D, Langevin B, Robert D, Lévy P. Side effects of nasal continuous positive airway pressure in sleep apnea syndrome. Study of 193 patients in two French sleep centers. Chest 1995;107:375-81. 21. Massie CA, Hart RW, Peralez K, Richards GN. Effects of humidification on nasal symptoms and compliance in sleep apnea patients using continuous positive airway pressure. Chest 1999;116:403-8. 22. McArdle N, Devereux G, Heidarnejad H, Engleman HM, Mackay TW, Douglas NJ. Long-term use of CPAP therapy for sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999;159:1108-14. 23. Hirshkowitz M, Sharafkhaneh A. Positive airway pressure therapy of OSA. Semin Respir Crit Care Med 2005; 26:68-79. 24. Ballard RD, Gay PC, Strollo PJ. Interventions to improve compliance in sleep apnea patients previously non-compliant with continuous positive airway pressure. J Clin Sleep Med 2007;3:706-12. 25. Ayas NT, Patel SR, Malhotra A, Schulzer M, Malhotra M, Jung D, et al. Auto-titrating versus standard continuous positive airway pressure for the treatment of obstructive sleep apnea: results of a meta-analysis. Sleep 2004;27:249-53. 26. Berry RB, Parish JM, Hartse KM. The use of auto-titrating continuous positive airway pressure for treatment of adult obstructive sleep apnea. An American 272
Tuberculosis and Respiratory Diseases Vol. 66. No. 4, Apr. 2009 Academy of Sleep Medicine review. Sleep 2002;25: 148-73. 27. Kribbs NB, Pack AI, Kline LR, Smith PL, Schwartz AR, Schubert NM, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:887-95. 28. Sin DD, Mayers I, Man GC, Pawluk L. Long-term compliance rates to continuous positive airway pressure in obstructive sleep apnea: a population-based study. Chest 2002;121;430-5. 29. Marshall NS, Barnes M, Travier N, Campbell AJ, Pierce RJ, McEvoy RD, et al. Continuous positive airway pressure reduces daytime sleepiness in mild to moderate obstructive sleep apnoea: a meta-analysis. Thorax 2006;61:430-4. 30. Campos-Rodriguez F, Perez-Ronchel J, Grilo-Reina A, Lima-Alvarez J, Benitez MA, Almeida-Gonzalez C. Long-term effect of continuous positive airway pressure on BP in patients with hypertension and sleep apnea. Chest 2007;132:1847-52. 31. Chan AS, Lee RW, Cistulli PA. Dental appliance treatment for obstructive sleep apnea. Chest 2007;132: 693-9. 32. Kushida CA, Morgenthaler TI, Littner MR, Alessi CA, Bailey D, Coleman J Jr, et al. Practice parameters for the treatment of snoring and Obstructive Sleep Apnea with oral appliances: an update for 2005. Sleep 2006;29:240-3. 33. Gotsopoulos H, Chen C, Qian J, Cistulli PA. Oral appliance therapy improves symptoms in obstructive sleep apnea: a randomized, controlled trial. Am J Respir Crit Care Med 2002;166:743-8. 34. Brownell LG, West P, Sweatman P, Acres JC, Kryger MH. Protriptyline in obstructive sleep apnea: a double-blind trial. N Engl J Med 1982;307:1037-42. 35. Hannhart B, Pickett CK, Moore LG. Effects of estrogen and progesterone on carotid body neural output responsiveness to hypoxia. J Appl Physiol 1990;68:1909-16. 36. Schwartz JR, Hirshkowitz M, Erman MK, Schmidt- Nowara W. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study. Chest 2003;124:2192-9. 37. Oliven A, Tov N, Geitini L, Steinfeld U, Oliven R, Schwartz AR, et al. Effect of genioglossus contraction on pharyngeal lumen and airflow in sleep apnoea patients. Eur Respir J 2007;30:748-58. 38. Staniforth AD, Kinnear WJ, Starling R, Hetmanski DJ, Cowley AJ. Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur Heart J 1998;19:922-8. 39. Okin PM, Devereux RB, Howard BV, Fabsitz RR, Lee ET, Welty TK. Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians: The Strong Heart Study. Circulation 2000;101:61-6. 40. Thomas RJ, Daly RW, Weiss JW. Low-concentration carbon dioxide is an effective adjunct to positive airway pressure in the treatment of refractory mixed central and obstructive sleep-disordered breathing. Sleep 2005; 28;69-77. 273