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1 대한내과학회전공의연수강좌 -COPD 의급성악화 - 고신의대호흡기내과 정만홍

2 증례 COPD로규칙적으로외래치료를받고있던 68세의남자흡연자가이틀전부터점차심해지는호흡곤란과가래의색깔이진해지고양도증가되어서응급실로내원하였다. 내원당시흉부 X-선사진 : Hyperinflation, no acute infiltrates AGBA 소견 (room air): ph: 7.27, Pao 2 : 50 mmhg, Paco 2 60 mmhg

3 고려사항 이환자는중환자실아니면일반병실로? 어떤치료를시작해야할까? 입원기간동안에사망할가능성은? 인공호흡기를사용해야할까? 퇴원후 6개월내에재입원할가능성은?

4 The Clinical Problems COPD의새로운정의및진단 GOLD guidelines 급성악화 (acute exacerbation) 란? 급성악화가발생했을경우에치료는? 기관지확장제의선택은? 스테로이드의사용은? 항생제의사용및종류는? Mechanical ventilators는언제, 어떤것을사용? 재발방지를위한대책은?

5 G O lobal Initiative for Chronic bstructive L D ung isease

6 COPD 의정의 (GOLD guideline) A disease state characterized by airflow limitation (post-bd FEV 1 /FVC 70% >, FEV 1 < 80% predicted) that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

7 Diagnosis of COPD SYMPTOMS cough sputum dyspnea EXPOSURE TO RISK FACTORS tobacco occupation indoor/outdoor pollution SPIROMETRY

8 최대호기류량곡선 (MEFV curve)

9 FEV /FVC < 70%, 1 FEV > 80% 1 predicted(post-bd) With or without chronic symptoms (cough, sputum production)

10 Classification by Severity Stage Characteristics 0: At risk Normal spirometry Chronic symptoms (cough, sputum) I: Mild FEV 1 /FVC < 70%; FEV 1 80% predicted With or without symptoms (cough, sputum) II: Moderate FEV 1 /FVC < 70%; 30% FEV 1 < 80% predicted (IIA: 50% FEV 1 < 80% predicted; IIB: 30% FEV 1 < 50% predicted) With or without chronic symptoms (cough, sputum, dyspnea) III: Severe FEV 1 /FVC < 70%; FEV 1 < 30% predicted or FEV 1 or respiratory failure or clinical signs of right heart failure

11 Pathogenesis of COPD NOXIOUS AGENT (tobacco smoke, pollutants, occupational agent) Genetic factors Respiratory infection Other COPD

12 Chronic airway inflammation in COPD 1. Inflammatory cells and mediators 2. Protease-antiprotease imbalance 3. Oxidative stress 4. Systemic effects 5. Amplifying mechanisms

13 INFLAMMATION Small airway disease Airway inflammation Airway remodeling Parenchymal destruction Loss of alveolar attachments Decrease of elastic recoil AIRFLOW LIMITATION

14 Noxious particles and gases Anti-oxidants Lung inflammation Host factors Anti-proteinases Oxidative stress Proteinases Repair mechanisms COPD pathology

17 COPD 의특징적인병력 약 20 pack-year 의흡연력이있다. 40대에가래를동반한기침이생기고폐감염으로입원하기도한다 대가되면서운동시호흡곤란을느끼기시작하고객담, 천명음, 발열등이동반되기도한다. 병이진행되면서그빈도가증가하고심해지면폐성심으로진행한다.

18 Risk Factors for COPD Host Factors deficiency) Exposure Genes (e.g. alpha1-antitrypsin Hyperresponsiveness Lung growth Tobacco smoke Occupational dusts and chemicals Infections Socioeconomic status

19 발생빈도 흡연인구의증가, 인구의고령화등으로계속증가될것으로생각되며, 미국의경우성인인구의약 5% 에서 COPD 환자일것으로추정된다. 우리나라의경우도유사할것으로생각된다. WHO 연구에의하면전세계적으로 2020 년에는발생빈도 5 위, 사망원인 3 위가될것으로추정된다. (1990 년발생빈도 12 위, 사망원인 6 위 )

20 Percent Change in Age- Adjusted Death Rates, U.S., Proportion of 1965 Rate Coronary Heart Disease Stroke Other CVD COPD All Other Causes % 64% 35% +163% 7%

21 COPD 의병리학적변화 기도폐쇄의시작은호흡세기관지의 mononuclear cell inflammation으로시작한다. 만성기관지염에서는그후 mucosal glands와 goblet cell이증가하고 smooth muscle이비후하여기도폐쇄가진행하게된다. 폐기종에서는세기관지주위의폐포의파괴가생기고그결과로기도의 patency를유지하지못하여기도폐쇄가생긴다. 폐기종은그형태에따라서 centriacinar, panacinar, distal acinar type로나눈다.

23 COPD 의검사실소견 흉부방사선사진소견폐기종이많이진행된경우나폐고혈압이동반된경우에이상소견을관찰할수있다. 다른폐질환과감별진단할때절대필요하다. Computed tomograph High resolution CT 가보급되면서폐기종의진단에널리사용되며수술을하거나합병된기관지확장증을진단하는데도움이된다.

25 COPD 의폐기능검사 COPD의진단과기도폐쇄의심한정도를평가하는데절대필요한검사이다. FEV1이가장널리이용되는검사이다. 만성기관지염과폐기종을감별하는특별한폐기능검사는없다. 동맥혈가스분석에서저산소혈증과고탄산혈증이생길수있는데특히 FEV1이 1.0 L 이하인경우에서흔하다.

26 폐기종에서폐용적의측정시기능적잔기량, 잔기량및전폐량이증가되고, 폐확산능은감소되지만특이적인검사는아니다. 기관지확장제사용전후의환기기능검사 의측정은기도폐쇄의가역성여부를 평가하는데도움이되는데 COPD 환자의약 30% 에서 FEV1 이 15% 이상증가되며초기에는반응이없어도경과중에반응을보이는경우도있다.

27 폐기종이있는 67 세남자환자의 환기기능검사 ( 흡연자 )

28 폐기종이있는 67 세남자환자의 환기기능검사 ( 흡연자 )

29 COPD 의자연경과 비흡연자도 35세가지나면매년 ml씩 FEV1 이감소한다. 흡연자는흡연량, 나이에따라서그정도가더커지며, 같은흡연량에서도일부에서는더욱더저명하다 ( 약 15% 에서 ). 금연을한경우에는감소정도가비흡연자와유사하게된다.

31 GOLD Workshop Report Four Components of COPD Management Assess and monitor disease Reduce risk factors Manage stable COPD Education Pharmacologic Non-pharmacologic Manage exacerbations

32 The Goals of Effective COPD Management Prevent disease progression Relieve symptoms Improve exercise tolerance Improve health status Prevent and treat complications Prevent and treat exacerbations Reduce mortality

33 Management of COPD Stage 0: At Risk Characteristics Recommended Treatment Chronic symptoms - cough - sputum No spirometric abnormalities

34 Management of COPD: All stages Avoidance of noxious agents - smoking cessation - reduction of indoor pollution - reduction of occupational exposure Influenza vaccination

35 COPD 의예방및치료의시작은 절대금연으로부터

37 STRATEGIES TO HELP THE PATIENT WILLING TO QUIT SMOKING ASK: Systematically identify all tobacco users at every visit. Implement an office-wide system that ensures that, for every patient at every clinic visit, tobacco-use status is queried and documented. 2. ADVISE: Strongly urge all tobacco users to quit. In a clear, strong, and personalized manner, urge every tobacco user to quit. 3. ASSESS: Determine willingness to make a quit attempt. Ask every tobacco user if he or she is willing to make a quit attempt at this time (e.g., within the next 30 d).

38 4. ASSIST: Aid the patient in quitting. Help the patient with a quit plan; provide practical counseling; provide intratreatment social support; help the patient obtain extratreatment social support; recommend use of approved pharmacotherapy except in special circumstances; provide supplementary materials. 5. ARRANGE: Schedule follow-up contact. Schedule follow-up contact, either in person or via telephone.

41 Manage Stable COPD None of the existing medications for COPD has been shown to modify the long-term decline in lung function that is the hallmark of this disease (Evidence A). Therefore, pharmacotherapy for COPD is used to decrease symptoms and/or complications. Bronchodilator medications are central to the symptomatic management of COPD (Evidence A).

42 Management of COPD Stage I: Mild COPD Characteristics Recommended Treatment FEV 1 /FVC < 70 % FEV 1 > 80 % predicted With or without symptoms Short-acting bronchodilator as needed

43 BRONCHODILATORS IN STABLE COPD Bronchodilator medications are central to symptom management in COPD. 2. Inhaled therapy is preferred. 3. The choice between 2-agonist, anticholinergic, theophylline, or combination therapy depends on availability and individual response in terms of symptom relief and side effects.

44 BRONCHODILATORS IN STABLE COPD 4. Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms. 5. Long-acting inhaled bronchodilators are more convenient. 6. Combining bronchodilators may improve efficacy and decrease the risk of side effects compared with increasing the dose of a single bronchodilator.

45 COMMONLY USED BRONCHODILATORS Drug* MDI (μg) Nebulizer (mg) Oral (mg) Duration (h) ß2-agonists Fenoterol Salbutamol Terbutaline Formoterol Salmeterol Anticholinergics Ipratropium bromide Oxitropium bromide Methylxanthines Aminophylline (SR) Variable, up to 24 Theophylline (SR) Variable, up to 24 * Not all products are available in all countries. Doses: ß2-agonists refer to average dose given up to 4 times daily for short-acting and 2 times daily for long-acting preparations; anticholinergics are usually given 3-4 times daily. Name in parentheses refers to North American generic term. Methylxanthines require dose titration depending on side effects and plasma theophylline levels.

46 Management of COPD Stage IIA: Moderate COPD Characteristics Recommended Treatment FEV 1 /FVC < 70% 50% < FEV 1 < 80% predicted With or without symptoms Regular treatment with one or more bronchodilators Rehabilitation Inhaled glucocorticosteroids if significant symptoms and lung function response

47 Manage Stable COPD Regular treatment with inhaled glucocorticosteroids should only be prescribed for symptomatic COPD patients with a documented spirometric response to glucocorticosteroids or in those with an FEV 1 < 50% predicted and repeated exacerbations requiring treatment with antibiotics and/or oral glucocorticosteroids (Evidence B).

48 Management of COPD Stage IIB: Moderate COPD Characteristics Recommended Treatment FEV 1 /FVC < 70% 30% < FEV 1 < 50% predicted With or without symptoms Regular treatment with one or more bronchodilators Rehabilitation Inhaled glucocorticosteroids if significant symptoms and lung function response or if repeated exacerbations

49 Manage Stable COPD Chronic treatment with systemic glucocorticosteroids should be avoided because of an unfavorable benefit-to-risk ratio (Evidence A). All COPD-patients benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue (Evidence A). The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory failure has been shown to increase survival (Evidence A).

50 Management of COPD Stage III: Severe COPD Characteristics Recommended Treatment FEV 1 /FVC < 70% FEV 1 < 30% predicted or presence of respiratory failure or right heart failure Regular treatment with one or more bronchodilators Inhaled glucocorticosteroids if significant symptoms and lung function response or if repeated exacerbations Treatment of complications Rehabilitation Long-term oxygen therapy if respiratory failure Consider surgical options

52 Diagnosis of Acute Exacerbation Increased breathlessness: main symptom Wheezing, chest tightness, fever Increased cough and sputum, change of the color or tenacity of sputum Suggest bacterial cause of AE A number of non-specific complaints Malaise, insomnia, sleepiness, fatigue, depression, and confusion

53 Key Points of Acute Exacerbation(AE) of COPD The most common causes of AE are infection of the tracheobronchial tree and air pollution (1/3: unknown) Inhaled BD, theophlline, and systemic glucocorticoids (preferably oral) are effective Pt with clinical signs of airway infection (increased volume and change of color of sputum, or fever) may benefit from antibiotics NIPPV improves blood gases and ph, reduces hospital mortality, decreases the need for invasive MV, intubation, and the length of hospital stay

54 AECB: Etiology Infectious, 80% Bacterial pathogens, 40% 50% S. pneumoniae, H. influenzae, M. catarrhalis Viruses, 30% 40% Rhinovirus, RSV, corona virus, influenza virus Atypical bacteria, 5% 10% Noninfectious, 20% Environmental factors air pollution, temperature Noncompliance with medical therapy About 2-3 exacerbations/ year in moderate or severe COPD patients Sethi S. Chest. 2000;117(suppl):380S. Sethi S et al. N Engla J Med 2002;347:

55 Viral AECB: Clinical Presentation AECB manifestations Increased dyspnea, 76% Increased sputum volume, 62% Increased sputum purulence, 39% Anthonisen type Type 1 (all 3 of above symptoms), 20% Type 2 (2 of above symptoms), 46% Type 3 (1 of above symptoms), 34% 64% of AECB associated with prior cold (18 days) Seemungal T et al. Am J Respir Crit Care Med. 2001;164:1618.

56 RV-Induced Airway Inflammation Plasma leakage Mucus hypersecretion Inflammatory cell recruitment and activation Virus-infected epithelium Airway Hyperresponsiveness Neural activation Adapted from Gern JE, Busse WW. J Allergy Clin Immunol. 2000;106:201.

57 FEV 1 <50% predicted Viral AECB: Medical Resource Utilization 52 hospitalizations in 12 patients 82% acute exacerbations, 22% pneumonia 5 of 6 deaths were COPD related % VRI 100 Office ER Hospital ER=emergency room. Data from Greenberg SB et al. Am J Respir Crit Care Med. 2000;162: Control FEV 1 50% predicted FEV 1 <50% predicted

58 Assessment of Severity Is based on the patient s medical history before the AE, Sx, P/Ex and laboratory tests. PFT PEF < 100 L/min or FEV1 < 1.0 L indicates a severe exacerbation ABGA Pao 2 < 60 mmhg, Sao 2 < 90% (room air) indicate respiratory failure Pao 2 < 50 mmhg, Paco 2 > 70 mmhg, and ph < 7.30 point toward a life-threatening episode ICU Chest X-ray and ECG - in DDx with other diseases Other tests: the whole blood count, a sputum culture and an antibiogram( not responding to the initial AB), and other biochemical tests

59 Differential Diagnosis of A.E. Pneumonia Congestive heart failure Pneumothorax Pleural effusion Pulmonary embolism Spiral CT and angiography and perhaps specific D-dimer assays are the best tools, but V/P scanning is of no value in DDx with COPD A low systolic BP and an inability to increase the Pao 2 about 60 mmhg with O 2 therapy Arrythmia

60 Indications for Hospital Assessment or Admission for Acute Exacerbations 1. Marked increase in intensity of symptoms (e.g. sudden development of resting dyspnea ) 2. Severe background COPD 3. Onset of new physical signs (e.g. cyanosis, peripheral edema) 4. Failure of exacerbation to respond to initial medical management 5. Significant co-morbidities 6. Newly occurring arrhythmias 7. Diagnostic uncertainty 8. Older age 9. Insufficient home support

61 INDICATIONS FOR ICU ADMISSION OF PATIENTS WITH ACUTE EXACERBATIONS OF COPD* Severe dyspnea that responds inadequately to initial emergency therapy 2. Confusion, lethargy, coma 3. Persistent or worsening hypoxemia (PaO2 < 6.7 kpa, 50 mm Hg), or severe/ worsening hypercapnia (PaCO2 > 9.3 kpa, 70 mm Hg) or severe/worsening respiratory acidosis (ph < 7.30) despite supplemental oxygen and NIPPV * Local resources need to be considered.

62 Management of Severe but Not Life- Threatening Exacerbations of COPD in the ER or the Hospital 1. Assess severity of symptoms, ABGA, chest PA. 2. Administer controlled oxygen therapy and repeat ABGA after 30 min. Pao 2 > 60 mmhg, Sao 2 > 90% 3. Bronchodilators: Increase dose or frequency. Combine ß 2 -agonists and anticholinergics. Use spacers or air-driven nebulizers. Consider adding IV aminophylline, if needed.

63 4. Add corticosteroids (oral > IV) shorten recovery time and help to restore lung function more quickly. Should be considered in addition to BD if pt s baseline FEV 1 is < 50% predicted. A dose of (30)-40 mg prednisolone/day for10 days with tapering is recommended. 5. Consider antibiotics when signs of bacterial infection, oral or occasionally IV. (5-10 days course of narrow spectrum antibiotics) 6. Consider noninvasive mechanical ventilation. 7. At all times: Monitor fluid balance and nutrition. Consider subcutaneous heparin. Identify and treat associated conditions (e.g., heart failure, arrhythmias). Closely monitor condition of the patient.

65 Selection Criteria for NIPPV (at least two should be present) Moderate to severe dyspnea with use of accessory muscles and paradoxical abdominal motion Moderate to severe acidosis (ph ) and hypercapnia (PaCO kpa, mmhg) Respiratory frequency > 25 breaths/min From Kramer and coworkers, Am J Respir Crit Care Med 1995;151:

66 Exclusion Criteria for NIPPV (any may be present) Respiratory arrest Cardiovascular instability (hypotension, arrythmias, myocardial infarction) Somnolence, impaired mental status, uncooperative patients High aspiration risks; viscous or copious secretions Recent facial or gastroesophageal surgery Craniofacial trauma, fixed nasopharyngeal abnormalities Extreme obesity From Kramer and coworkers, Am J Respir Crit Care Med 1995;151:

67 Discharge Criteria for Patients with Acute Exacerbations Inhaled BD therapy, no more than every 4 hours Patient is able to do self-care Clinically stable for hours ABGA has been stable for hours Patient, family, and physician are confident patient can manage successfully

68 Follow-up Assessment 4-6 Weeks after Discharge 1. Ability to cope in usual environment 2. Measurement of FEV 1 3. Reassessment of inhaler technique 4. Understanding of recommended treatment regimen 5. Need for long-term therapy or home nebulizer (for patients with severe COPD)

69 고려사항 이환자는중환자실아니면일반병실로? 먼저일반병실로입원 : acidosis 어떤치료를시작해야할까? Administration of a combination of BD A limited-spectrum antibiotics Intravenous corticosteroids

70 고려사항 입원기간동안에사망할가능성은? 10 15% 인공호흡기를사용해야할까? Rapid reversal of acidemia 가없으면 bilevel noninvasive positive pressure ventilation 퇴원후 6 개월내에재입원할가능성은? It depends on the cooperation of Pt. and Dr.

71 Thank U!

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ÀÇÇÐ°�ÁÂc00Ì»óÀÏ˘ Common Allergic Diseases in Children Sang - Il Lee, M.D. Department of pediatrics Sungkyunkwan University School of Medicine, Samsung Medical Center E - mail : silee@smc.samsung.co.kr Abstract Allergy