Lim SY et al. Treatment and prevention of acute exacerbation of COPD 급성악화의예방과적절한치료는 COPD에서무엇보다도중요한것으로사료되며, 2018년도개정된국내 COPD 진료지침을중심으로급성악화의치료와예방에관련된내용을

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1 FOCUSED ISSUE OF THIS MONTH J Korean Med Assoc 2018 September; 61(9): pissn / eissn 만성폐쇄성폐질환급성악화의치료와예방 임성용 1 김현정 2 나승원 3 이지현 4 김태형 5 1 성균관대학교의과대학강북삼성병원, 2 계명대학교동산의료원, 3 울산대학교의과대학울산대병원, 4 차의과학대학교분당차병원, 5 한양대학교의과대학구리병원호흡기내과 Treatment and prevention of acute exacerbation of chronic obstructive pulmonary disease Seong Yong Lim, MD 1 Hyun Jung Kim, MD 2 Seung Won Ra, MD 3 Ji-Hyun Lee, MD 4 Tae-Hyung Kim, MD 5 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul; Department of Internal Medicine, 2 Keimyung University Dongsan Hospital, Daegu, 3 Ulsan University Hospital, Ulsan University College of Medicine, Ulsan, 4 CHA Bundang Medical Center, CHA University, Seongnam; 5 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea Acute exacerbation of chronic obstructive pulmonary disease (COPD) is defined as an acute aggravation of the patient s respiratory symptoms, particularly cough, sputum production, and dyspnea, which requires a change of medication. COPD exacerbation leads to an accelerated decline in lung function, poorer health status, and is the main cause of hospital admission and death in patients with COPD. A majority of COPD exacerbations are triggered by respiratory infection. The Management of acute exacerbation of COPD consists of systemic corticosteroids, antibiotics, and inhaled short-acting bronchodilators. Oxygen supplementation is an essential component of treatment to improve hypoxemia. Noninvasive or invasive ventilator support is necessary for COPD patients with severe exacerbation, particularly associated with hypercapnic respiratory failure. The Korean clinical practice guideline for COPD was revised in 2018 by the members of the Korean Academy of Tuberculosis and Respiratory Diseases as well as participating members of the Health Insurance Review and Assessment Service. The purpose of this review is to provide an overview of the treatment and prevention strategies recommended in the 2018 Korean Academy of Tuberculosis and Respiratory Diseases for patient with acute exacerbation of COPD. Key Words: Pulmonary disease, chronic obstructive; Acute exacerbation; Therapeutics; Prevention & control 서론 의질을저하시키며, 병원입원과사망률을증가시킨다 [1]. 국 내 COPD 환자들의급성악화빈도를보면 EPOCH (Epide- 만성폐쇄성폐질환 (chronic obstructive pulmonary disease, COPD) 의급성악화는환자의폐기능을감소시키고, 삶 Received: August 13, 2018 Accepted: August 20, 2018 Corresponding author: Seong Yong Lim mdlimsy@skku.edu Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. miologic review and Prospective Observation of COPD and Health) 연구에서는전체의 35.5%[2], KOCOSS (The Korea Chronic Obstructive Pulmonary Disorders Subgroup Study) 연구에서는전체의 26.5% 의환자가등록전 1년동안한번이상의급성악화를경험한것으로보고되고있으며 [3], 폐기능이나쁘거나증상이심할수록, 급성악화과거력이있는경우급성악화의빈도가증가함을보고하였다. 552 대한의사협회지

2 Lim SY et al. Treatment and prevention of acute exacerbation of COPD 급성악화의예방과적절한치료는 COPD에서무엇보다도중요한것으로사료되며, 2018년도개정된국내 COPD 진료지침을중심으로급성악화의치료와예방에관련된내용을소개하고자한다. COPD 급성악화의정의및중요성 2-4시간마다환자의증상호전여부반응에따라투여하게한다. 급성악화에서안정시치료에많이쓰이는지속성기관지확장제의치료효과는명확히증명된바없다. 적절한흡입이가능한경우급성악화동안에도안정시치료약제를지속하거나퇴원이전가능한한빨리재개하는것을권고한다. 테오필린을비롯한메틸잔틴계기관지확장제의정맥투여는유의한부작용을이유로급성악화에서권고하지않는다 [16]. 급성악화는 COPD 환자의기본적인호흡기증상이매일매일의변동범위를넘어서치료약제의추가가필요할정도로급격히악화된상태로정의할수있으며, 경증, 중등증, 중증악화로분류할수있다 [4]. 경증악화는속효성기관지확장제치료만필요한경우, 중등증악화는속효성기관지확장제와항생제또는경구스테로이드치료가필요한경우, 중증악화는응급실방문이나입원이필요한악화로급성호흡부전을동반할수있다. 급성악화는삶의질악화 [5,6], 증상과폐기능악화 [7], 폐기능감소의가속화 [8,9], 사망률의유의한증가 [10,11], 사회경제적비용의증가와 [12] 같은악영향을줄수있기때문에급성악화의예방과악화초기의적절한치료가 COPD에의한부담을줄이는데중요하다 [13]. 급성악화로입원한경우 3년사망률이약 49% 에이르는등예후가매우좋지않은것으로보고되고있다 [10]. 우리나라통계는아직발표된것이없으나우리나라의유병률이외국과크게다르지않음을고려하면사망률도큰차이가나지않을것으로추정된다. 약물치료 1. 기관지확장제속효성항콜린제와동시혹은단독으로속효성베타작용제를 COPD의급성악화의치료에서가장먼저사용할수있다 [14]. 속효성기관지확장제투여시네불라이저또는정량식흡입기를사용할수있는데, 투여방법간에치료효과의차이는없다 [15]. 정량식흡입기는한시간마다한번씩 2-3번흡입한후 2. 스테로이드제급성악화시전신스테로이드는회복기간과재원기간을줄이고, 폐기능과동맥혈산소분압을개선시킬뿐아니라이후의악화를줄이는효과가있다 [17]. 치료용량은프레드니솔론기준으로하루 mg을 10-14일간사용하는것을권고하나, 최근프레드니솔론 40 mg을 5일간사용하는단기치료도치료효과및부작용면에서대등하다는연구결과도있으며 [18], 경구스테로이드제투여는주사투여에비해치료효과가떨어지지않는다 [19]. 또한, 네불라이저로부데소나이드를흡입할경우경구스테로이드제를대체할수있다는연구결과도있다 [20]. 최근의몇몇연구들은급성악화에서전신스테로이드의효과가혈중호산구수치가낮은환자의경우높은환자들에비해전신스테로이드의효과가작을수있음을시사하였다 [21]. 3. 항생제급성악화환자에서호흡곤란악화, 객담량, 객담화농성증가라는 3가지주요증상을모두만족시키는경우또는객담화농성증가를포함한 2가지주요증상을만족하는경우또는기계호흡이필요한경우에서항생제를처방하여야하며, 5-7일간의투여를권고한다 [22]. 이때, 항생제의선택은각지역세균의항생제내성패턴에근거해야하며, 초기경험적치료에는 aminopenicillin-clavulanic acid, 2, 3세대 cephalosporin, 또는차세대 macrolide 를사용할수있다. 특히, 65세이상, 1초간강제호기량 50% 미만, 잦은악화, 심장질환동반등의위험인자를갖고있는경우에는 fluoroquinolone (levofloxacin, moxifloxacin, zabofloxacin 등 ), Pseudomonas 감염의위험인자가있는 만성폐쇄성폐질환급성악화의치료와예방 553

3 J Korean Med Assoc 2018 September; 61(9): Table 1. Indication for NIV in acute exacer-bation of chronic obstructive pulmonary disease 경우에는 anti-pseudomonal antibiotics (ciprofloxacin, anti-pseudomonal cephalosporin 등 ) 을초기치료부터고 려할수있다 [23]. 호흡보조요법 Potential indications for NIV At least one of the following Respiratory acidosis (ph 7.35 or PaCO 2 45 mmhg) Severe dyspnea with clinical signs of respiratory muscle fatigue, increased work of breathing or both Persistent hypoxemia despite supplementary oxygen therapy NIV, noninvasive mechanical ventilation. 적기계환기법을선택적으로고려해볼수있다 [25]. 중증 COPD 환자에게침습적기계환기를적용할경우환자의회복가능성, 치료에대한의지, 그리고중환자실가용성등을고려하여야하며, 가능하다면환자가나빠지기전에미리치료에대한의지가있는지확인해두는것이필요하다. COPD 환자에서기계환기에대한의존성이생길수있어기계환기이탈은매우어렵고, 이탈후호흡일과호흡근능력사이에불균형이기계환기이탈실패의주요원인이되기도한다 [26]. 기계환기이탈은매우어렵고장기간시간이소요될수있으며, 비침습적기계환기는기계환기이탈에실패한 COPD 환자에게도움이되고, 재삽관을예방하며사망률을감소시킨다 [27]. 1. 산소요법산소는 COPD 급성악화시치료의핵심적인요소이며, 산소요법의목표는환자의산소포화도를 88-92% 정도로유지하는것이다 [24]. 산소요법을시작하면 30-60분후에동맥혈가스검사를시행하여이산화탄소의축적없이적절한산소농도에도달했는지점검한다. COPD 환자의경우고농도산소를투여하면과탄산혈증이발생할수있으므로투여하는산소농도가너무높지않도록주의하여야한다. 2. 비침습적기계환기 COPD 급성악화로입원한급성호흡부전환자의초기치료로는침습적기계환기보다비침습적기계환기치료가선호된다. 비침습적기계환기는호흡산증개선, 합병증감소, 입원기간단축효과뿐만아니라기도삽관율및사망률을감소시킨다고알려지고있다. 비침습적기계환기의기준은 Table 1과같다 [4]. 3. 침습적기계환기최근비침습적기계환기법에대한치료경험이증가함에따라침습적기계환기의적응증에해당되던상황도비침습적기계환기법으로치료에성공하는경우가많아지고있어서침습적기계환기의적응증에해당되는경우도비침습 급성악화의예방 COPD 급성악화입원후에는추가악화를예방하기위한적절한조치가시작되어야한다. 속효성기관지확장제를처방중급성악화를경험한경우는흡입지속성기관지확장제를사용하여야하며, 한가지흡입지속성기관지확장제를사용했던경우는병합요법을고려하고, 병합요법을사용하는경우는흡입스테로이드와의 3제병합요법을고려해야한다. 병합요법에도불구하고연 2회이상급성악화병력이있고만성기관지염을수반한경우에는 PDE4억제제를사용하여추가로발생하는급성악화를예방하는조치를취하여야한다. 약물요법이외에도금연과적절한흡입기사용및질병악화시대처법등에대한환자교육을통한위험요소제거, 호흡재활, 기관지내시경폐용적축소술, 예방접종과같은비약물요법도급성악화예방에도움이되므로이를통한적극적관리가매우중요하다. 급성악화의예방을위하여사용할수있는약물또는비약물적방법들은 Table 2와같다 [4,28,29]. 결론 COPD 급성악화는증상의변동으로치료약제의추가가필 554 대한의사협회지

4 Lim SY et al. Treatment and prevention of acute exacerbation of COPD Table 2. Pharmacologic or non-pharmacologic treatments that reduce chronicobstructive pulmonary disease exacerbations Bronchodilators 요할정도로악화된상태로기관지확장제, 스테로이드, 항 생제가치료에사용되며, 중증악화로인한호흡부전이있 는경우산소요법, 비침습적또는침습적기계환기가호흡 보조요법으로사용된다. 급성악화가발생하면삶의질과폐 기능이악화되고, 사망률이증가되므로초기에적절한치료 를시행하여야하며, 추가악화를예방하기위한약물과비 약물적치료를병행하여급성악화위험과빈도를줄이도록 노력하여야한다. 찾아보기말 : 만성폐쇄성폐질환 ; 급성악화 ; 치료 ; 예방 ORCID Intervention class Corticosteroid-containing drugs Seong Yong Lim, Hyun Jung Kim, Seung Won Ra, Ji-Hyun Lee, Tae-Hyung Kim, REFERENCES LABAs LAMAs LABA + LAMA Intervention LABA + ICS LABA + LAMA + ICS Anti-inflammatory (non-steroid) Roflumilast [28] Anti-infectives Mucoregulators Others Vaccines Long-term macrolides N-acetylcysteine Carbocysteine Smoking cessation Rehabilitation [29] Lung volume reduction LABA, long-acting beta2-agonist; LAMA, long-acting anti-muscarinic; ICS, inhaled corticosteroid. 1. Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. Eur Respir J 2007;29: Hwang YI, Lee SH, Yoo JH, Jung BH, Yoo KH, Na MJ, Lee JD, Park MJ, Jung CY, Shim JJ, Kim KC, Kim YJ, Choi HS, Choi IS, Lee CT, Lee SD, Kim DJ, Uh ST, Lee HS, Kim YS, Lee KH, Ra SW, Kim HR, Choi SJ, Park IW, Park YB, Park SY, Lee J, Jung KS. History of pneumonia is a strong risk factor for chronic obstructive pulmonary disease (COPD) exacerbation in South Korea: the Epidemiologic review and Prospective Observation of COPD and Health in Korea (EPOCH) study. J Thorac Dis 2015;7: Lee JY, Chon GR, Rhee CK, Kim DK, Yoon HK, Lee JH, Yoo KH, Lee SH, Lee SY, Kim TE, Kim TH, Park YB, Hwang YI, Kim YS, Jung KS. Characteristics of patients with chronic obstructive pulmonary disease at the first visit to a pulmonary medical center in Korea: The KOrea COpd Subgroup Study Team Cohort. J Korean Med Sci 2016;31: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 [Internet]. [place unknown]: Global Initiative for Chronic Obstructive Lung Disease; 2017 [cited 2018 Aug 29]. Available from: 5. Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J 2004;23: Kessler R, Ståhl E, Vogelmeier C, Haughney J, Trudeau E, Löfdahl CG, Partridge MR. Patient understanding, detection, and experience of COPD exacerbations: an observational, interview-based study. Chest 2006;130: Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161: Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57: Kanner RE, Anthonisen NR, Connett JE; Lung Health Study Research Group. Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med 2001;164: Gunen H, Hacievliyagil SS, Kosar F, Mutlu LC, Gulbas G, Pehlivan E, Sahin I, Kizkin O. Factors affecting survival of hospitalised patients with COPD. Eur Respir J 2005;26: Soler-Cataluna JJ, Martínez-García MA, Roman Sanchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60: Wouters EF. The burden of COPD in The Netherlands: results from the Confronting COPD survey. Respir Med 2003;97 Suppl C:S51-S Wilkinson TM, Donaldson GC, Hurst JR, Seemungal TA, Wedzicha JA. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;169: Celli BR, MacNee W; ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23: 만성폐쇄성폐질환급성악화의치료와예방 555

5 J Korean Med Assoc 2018 September; 61(9): Turner MO, Patel A, Ginsburg S, FitzGerald JM. Bronchodilator delivery in acute airflow obstruction. A meta-analysis. Arch Intern Med 1997;157: Barr RG, Rowe BH, Camargo CA Jr. Methylxanthines for exacerbations of chronic obstructive pulmonary disease: meta-analysis of randomised trials. BMJ 2003;327: Alia I, de la Cal MA, Esteban A, Abella A, Ferrer R, Molina FJ, Torres A, Gordo F, Elizalde JJ, de Pablo R, Huete A, Anzueto A. Efficacy of corticosteroid therapy in patients with an acute exacerbation of chronic obstructive pulmonary disease receiving ventilatory support. Arch Intern Med 2011;171: Leuppi JD, Schuetz P, Bingisser R, Bodmer M, Briel M, Drescher T, Duerring U, Henzen C, Leibbrandt Y, Maier S, Miedinger D, Müller B, Scherr A, Schindler C, Stoeckli R, Viatte S, von Garnier C, Tamm M, Rutishauser J. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 2013;309: de Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA, van den Berg JW. Oral or IV prednisolone in the treatment of COPD exacerbations: a randomized, controlled, double-blind study. Chest 2007;132: Gunen H, Hacievliyagil SS, Yetkin O, Gulbas G, Mutlu LC, In E. The role of nebulised budesonide in the treatment of exacerbations of COPD. Eur Respir J 2007;29: Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2012;186: Masterton RG, Burley CJ. Randomized, double-blind study comparing 5- and 7-day regimens of oral levofloxacin in patients with acute exacerbation of chronic bronchitis. Int J Antimicrob Agents 2001;18: Siddiqi A, Sethi S. Optimizing antibiotic selection in treating COPD exacerbations. Int J Chron Obstruct Pulmon Dis 2008; 3: Austin MA, Wills KE, Blizzard L, Walters EH, Wood-Baker R. Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ 2010;341:c Conti G, Antonelli M, Navalesi P, Rocco M, Bufi M, Spadetta G, Meduri GU. Noninvasive vs. conventional mechanical ventilation in patients with chronic obstructive pulmonary disease after failure of medical treatment in the ward: a randomized trial. Intensive Care Med 2002;28: Purro A, Appendini L, De Gaetano A, Gudjonsdottir M, Donner CF, Rossi A. Physiologic determinants of ventilator dependence in long-term mechanically ventilated patients. Am J Respir Crit Care Med 2000;161: Ferrer M, Sellares J, Valencia M, Carrillo A, Gonzalez G, Badia JR, Nicolas JM, Torres A. Non-invasive ventilation after extubation in hypercapnic patients with chronic respiratory disorders: randomised controlled trial. Lancet 2009;374: Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374: Puhan MA, Gimeno-Santos E, Scharplatz M, Troosters T, Walters EH, Steurer J. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011;(10):CD Peer Reviewers Commentary 이논문은 2018 년대한결핵및호흡기학회에서개정발표한만 성폐쇄성폐질환 (COPD) 진료지침중급성악화의치료와예방 에대한내용을소개하고있다. 국내에서시행된연구에따르면, 전체 COPD 환자의 26.5% 가일년동안 1 회이상의급성악화를 경험하는것으로보고되고있다. COPD 환자의급성악화는삶의 질악화, 증상과폐기능악화, 폐기능감소의가속화, 사망률의유 의한증가, 사회 - 경제적비용의증가와같은악영향을줄수있 으므로급성악화의예방과악화초기의적절한치료가 COPD 에 의한부담을줄이는데중요하다. 이논문은국내현실에맞게개 정된 COPD 진료지침을바탕으로, 급성악화환자에서기관지확 장제, 스테로이드, 항생제, 산소요법, 및비침습적또는침습적기 계환기등의사용원칙을제시하고있으므로일선진료현장에서 적용할가능성이클것으로판단된다. [ 정리 : 편집위원회 ] 556 대한의사협회지

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon