대한내과학회지 : 제73권 부록 2 호 2007 □ 임상강좌 □

Exacerbation of

성균관대학교 의과대학 내과학교실

최 동 철

2007년내과학회임상강좌 2007년내과학회임상강좌 Exacerbation of Asthma Exacerbation of Asthma Key Points

-천식의 악화란 호흡곤란, 기침, 천명,흉부 압박감 등의 증상 중 Inducers 한가지 이상이 나타나는 것을 가리킨다. Respiratory -천식이 악화되면 숨을 내쉬기 어려워 지고 Allergens viral infections Occupational 폐기능검사에서 최대호기유속이나 1초간 노력성 호기량이 감소한다. agents -주요한 치료는 기관지 확장제, 스테로이드 및 산소 투여이다. Asthma flare -치료 목표는 환기 장애와 저산소증을 개선하고 재발을 방지하는 것이다. Aspirin -심한 천식 발작은 응급 상황이며 적절한 시설이 있는 곳에서 치료해야 하고 전문가의 감독이 필요하다. Exercise Irritants Respiratory viral infections -가벼운천식발작(최대호기유속의 감소가 20% 미만)은 지역의료기관에서 치료할 수 있다 Provokers

Trends in Prevalence of Asthma Death Rates for Asthma By Age, U.S., 1985-1996 By Race, Sex, U.S., 1980-1998

80 Rate/1,000 Persons Age (years) Rate/100,000 Persons 70 5 <18 Black Female 60 18-44 4 Black Male 45-64 50 65+ 3 White Female 40 Total (All Ages) 2

30 White Male 1 20 85 86 87 88 89 90 91 92 93 94 95 96 0 1980 Year 1985 1990 1995 2000 Year

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2007년내과학회임상강좌 2007년내과학회임상강좌 Exacerbation of Asthma Histrory (1)

A. Timing of dyspnea Acute onset Insiduous onset anxiety, COPD Q1: 환자의 호흡곤란이천식발작인가 ? asthma, interstitial fibrosis , chest trauma diseases of chest wall (pneumothorax, rib fracture, or diaphragm contusion) spontaneous pneumothorax

2007년내과학회임상강좌 2007년내과학회임상강좌 Exacerbation of Asthma Exacerbation of Asthma Histrory (2) Histrory (3)

B. Relationship to physical activity Nocturnal dyspnea ATS scale Asthma, CHF, GE reflux Grade 0 (none) Not troubled by shortness of breath when hurrying on the level or walking up a slight hill Grade 1 (mild) CHF, massive ascites or pregnancy Troubled by shortness of breath when hurrying on the level or walking up a slight hill Bilateral phrenic nerve paralysis, severe COPD Grade 2 (moderate) (Difficulty in when erect, relieved by lying down) Walks slower than the people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace in the level AV malformation in , interatrial shunt Grade 3 (severe) Trepopnea(dyspnoea in one lateral position) Stops for breath after walking about 100 yards or after a few minutes on the level Heart disease, VQ mismatch Grade 4 (very severe) Too breathlessness to leave the house, or breathless on dressing or undressing

2007년내과학회임상강좌 2007년내과학회임상강좌 Exacerbation of Asthma Exacerbation of Asthma Histrory (4) Physical Exam (1)

High Risk patients - 치료의 시작과 동시에 문진 및 진찰을 실시한다. -기도삽관및인공호흡기사용의병력 - 관찰할 사항: 말을잘하나? - 지난해에 천식 발작으로 응급실을 방문하거나 입원하였던 환자 호흡 및 맥박수, 보조호흡근의 사용, 비정상적인 호흡음 - 최근에 경구 스테로이드를 사용하였거나 사용 중인 환자 - 진찰만으로는 - 흡입 스테로이드를 규칙적으로 사용하지 않는 환자 천식 발작 및 저산소증의 중증도를 객관적으로 평가할 수 없음 -흡입기관지확장제를한달에1개이상사용하는환자 - 폐기능의 측정이 매우 중요 - 천식 치료계획에 순응도가 낮은 환자 - 치료에 지장이 없도록 신속히 폐기능을 측정하고 치료를 시작한다.

－ S 738 － －최동철 : Exacerbation of Asthma －

2007년내과학회임상강좌 2007년내과학회임상강좌 Physical Exam (2) Physical Exam (3) Inspection, , Palpation Mechanism of production of wheezing

- Vital signs including respiration rate

- Body habitus: obese or cachectic 1. Normal airway - Position: leaning foward in COPD - Expansion of chest wall: symmetricity

- Use of accessory muscles: ICS or suprclavicular fossa 2. Slight narrowing retraction - or clubbing alternation of 2 & 3 produces continuous sound - Extended jugular vein or hepatojugular reflux 3. Greater narrowing - Unilateral vs bilateral L/E edema

2007년내과학회임상강좌 2007년내과학회임상강좌 Labaratory test (1) Labaratory test (2) Screening tests in dypnea (1) Screening tests in dypnea (2)

General Principle A. Plain chest radiography " The labaratory test is occasionally of help in the diagnosis of - diagnosis: pneumothorax, , pneumonia, TB, dyspnea" emphysema, lung cancer, interstitial lung disease (Stulbarg MS, Adams L: Dyspnea. In Textbook of respiartory diseases p521) - helpful: cardiomegaly, chest wall deformity, pulmonary vascular abnormality Screening tests to be performed - In asthma: hyperinflation, pneumothorax Most helpful : Chest PA, ECG, Spirometry, ABGA B. 12 lead ECG Occasionally helpful: CBC, TFT* - does not establish diagnosis directly - provides indirect evidence for causative diseases of dyspnea * variable depending on authors (arrhythmia, myocardial ischemia, chamber enlargement etc)

2007년내과학회임상강좌 2007년내과학회임상강좌 Labaratory test (3) Labaratory test (4) Screening tests in dypnea (3) Screening tests in dypnea (4) D. Arterial Blood Gas Analysis (ABGA)

C. Pulmonary function test - measures amount of dissolved O2 & CO2 in arterial blood

A. Spirometry cf. Oximetry: measures fraction of O2 carried in hemoglobin Peak Expiratory Flow Rate (PEFR) - provides best measure for delivery of oxygen from atmosphere Forced Vital Capacity (FVC) to blood - minor change in ventilation affect Forced expiratory volune in 1 second (FEV1) PaCO2 level more significantly than PaO2 level * Changes of spirometry in pulmonary disease - Normal value in adult: 80-103 mmHg at room air FEV1 FVC FEV1/FVC PEFR PaO2 = 5 x FiO2 Obstructive lung disease - In any patient with dyspnea, Restrictive lung disease presence of is worrisome.

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2007년내과학회임상강좌 2007년내과학회임상강좌 Labaratory test (5) Screening tests in dypnea (5) " Cross Over " in severe asthma

pH PaCO A-a DO2 (Alveolar arterial oxygen tension difference) 2 Formula 1 7.50 60

A-a DO2 = PAO2 -PaO2 50 = PIO2 - (PaCO2 x 1.2) - PaO2

= (760 - PB) x FiO2 -(PaCO2 x 1.2) - PaO2 7.40 40 PaO2 without O2 Formula 2

Normal A-a DO2 : 4 + age/4 30

7.30 20 - In patients with dyspnea, calculation of A-a DO2 may give additional diagnostic clue. Day 1 Day 2 Day 3 Day 4 Day 5 (modified from Weiss EB, Stein M: Bronchial asthma, 3rd ed, 1993) - If A-a DO2 <20, little possibility for parenchymal lung disease

2007년내과학회임상강좌 2007년내과학회임상강좌

Five major causes of hypoxemia

Causes A-a DO2 Examples Comments

Alveolar O2 High altitude, CO poisoning tension

Ventilation CNS disorders(IICP), drugs, PaCO2 compensation for metabolic alkalosis, Q2: 얼마나심한천식발작인가? COPD or severe asthma Diffusion Interstital lung disease rare resting hypoxema V/Q mismatch Pneumonia, pneumothorax, improves

CHF, ARDS, pulmonary embolism with O2 asthma, COPD Shunt ASD, VSD, AV malformation does no improve with 100% O2

2007년내과학회임상강좌 2007년내과학회임상강좌

2006 Severity of Asthma Exacerbations (1) Severity of Asthma Exacerbations (2)

－ S 740 － －최동철 : Exacerbation of Asthma －

2007년내과학회임상강좌 2007년내과학회임상강좌 Management of Asthma Exacerbations Community settings

- 최대호기유속의 감소가 20 % 미만인 가벼운 천식 발작은 Q3: 어디서 치료하나 ? 지역의료기관에서 치료 가능 - 속효성 기관지확장제를 몇 차례 흡입 후 1시간이내에 상태가 호전되면 굳이 응급실로 보낼 필요 없음

- 호전될 때 까지 전신 스테로이드의 처방을 고려

2007년내과학회임상강좌

Q4: 어떤 치료제를 사용하나 ?

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2007년내과학회임상강좌 2007년내과학회임상강좌 GINA 2006 update GINA 2006 update Management of asthma exacerbations Management of asthma exacerbations in acute care setting in acute care setting

2005 update 2006 revision Treatment for Moderate Episode Treatment for Moderate Episode 2005 update 2006 revision Initial Treatment Initial Treatment Oxygen Inhaled β2-agonist and inhaled Inhaled β2-agonist and inhaled Inhaled rapid-acting β2-agonist, usually by Inhaled rapid-acting β2-agonist continuously for anticholinergic every 60 minutes anticholinergic every 60 min nebulization, one dose every 20 minutes for one one hour. Consider glucocorticosteroids Oral glucocorticosteroids hour. Continue treatment 1-3 hours, provided Continue treatment for 1-3 hours, provided there is improvement there is improvement

GINA 2006 update 2007년내과학회임상강좌 2007년내과학회임상강좌 Drugs in Emergency Tx (1) Management of asthma exacerbations Sympathomimetic agents in acute care setting

2005 update 2006 revision - Mechanism: activation of adenyl cyclase on airway smooth muscle Criteria for Severe Episode Criteria for Severe Episode - Do not inhibit late asthmatic reactions

• Hx: high-risk patient • History of risk factors for near fatal asthma - Beta-2 selective agents preferred • PEF < 60% predicted/personal best • PEF < 60% predicted/personal best - MDI with spacer or Nebulizer vs Oral or IV,SQ route • Physical exam: severe symptoms at rest, • Physical exam: severe symptoms at rest, chest retraction chest retraction - Advantage: Rapid onset of action • No improvement after initial treatment • No improvement after initial treatment Good patient acceptance Treatment: Treatment: Effective bronchodilation with little tachycardia •Oxygen • Oxygen Wide therapeutic range • Inhaled β2-agonist and inhaled • Inhaled β2-agonist and inhaled anticholinergic anticholinergic - Proper technique is required for maximal effect • Systemic glucocorticosteroid • Systemic glucocorticosteroids • Consider intravenous magnesium • Intravenous magnesium Open vs Closed mouth technique • Consider subcutaneous, intramuscular, or MDI with spacer vs Nebulizer intravenous β 2-agonist • Consider intravenous methylxanthines

2007년내과학회임상강좌 2007년내과학회임상강좌 Bronchodilatory effect of β-agonist & anticholinergics β2-adrenergic agonist 800 salbutamol

Dosages for inhaled β2-adrenergic agonist for acute asthma in adults 600 ipratropium Drug available form dosage comments 400 salbutamol MDI:100 µg/puff 2-4 puffs or 0.5~1ml safe for Pt without (=ventolin) solution: 5mg/ml every 20min x 3, cardiovascular disease

200 then every hour

Increase terbutaline DPI:500µg/puff no MDI in Korea UDV: 5mg/vial 0.5-1ml 0 0 30 60 90 120 180 240 300 360 420 480 fenoterol MDI:400µg/puff ? not FDA approved Time(min) ( NIH Guidelines for the diagnosis and management of asthma, 1991) Responses to 25 asthmatics after inhalation of either 200µg of salbutamol or 40µg of ipratropium (Ruffin et al. J Allergy Clin Immunol 59:136,1977)

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2007년내과학회임상강좌 Drugs in Emergency Tx (2) Drugs in Emergency Tx (2) Anticholinergics Methylxathines (1) ” β2-교감신경 자극제와 같이 투여하면 더 효과적인가 ?" 그렇다 - Mechanism: not clear - 급성 천식 발작시 β-agonist 나항콜린제제의단독투여보다병용 phosphodiesterase inhibition 투여가 효과적이다 (Rebuck et al. Am J Med 82:59,1987) Stimulation of catecholamine release - 흡입 β-agonist 투여 후에도 반응이 불완전한 환자들에게 Prostagladin antagonism 항콜린제제를 투여하였더니 폐기능이 호전되었다. Inhibit release of proteolytic enzymes or O2 metabolites (Bryant et al. Chest 102:742,1992) - Narrow therapeutic range with severe side effects 아니다 - Tight dose adjustment required - 오히려 paradoxical brochospasm 을 유발하였다 - Linear relationship between (Conolly et al.,1982; Mann et al.,1984;Rafferty et al.,1988) Bronchodilatory effect and Log(serum level) - 만성 천식 치료에서 항콜린제제의 효과는 아직 입증되지 않았다. - Ideal serum concentration: 10-12µg/ml (Int'l consensus report on Diagnosis and Management of Asthma) - Additive effect with oral or inhaled beta2 agonist ?

2007년내과학회임상강좌 2007년내과학회임상강좌 Drugs in Emergency Tx Algorithm for IV aminophylline Methylxanthines (2) for acute asthma

Increase in FEV1 ObtainObtain HxHx of of theophyllinetheophylline Mx Mx in in previousprevious 24hr24hr

checkcheck levellevel oror 2.5mg/kg2.5mg/kg loadingloading LoadingLoading 5mg/Kg5mg/Kg

40 StartStart continuouscontinuous IV IV viavia infusion infusion pump pump 30 child>9yrschild>9yrs && smoker: smoker: 0.6mg/kg/hr 0.6mg/kg/hr nonnon smoker smoker withoutwithout CHF CHF or or CLD:CLD: 0.4mg/kg/hr0.4mg/kg/hr CHFCHF or or Liver Liver dysfunction:0.2-0,3mg/kg/hr dysfunction:0.2-0,3mg/kg/hr 20

Check serum level 4-6hrs after IV infusion(TDM) 10 Check serum level 4-6hrs after IV infusion(TDM)

1 5 >20microgram/ml>20microgram/ml <10<10 10-2010-20 StopStop infusion infusion AdditionalAdditional Loadig Loadig 1mg/kg 1mg/kg Theophylline Blood level(µg/ml) ContinueContinue IVIV infusioninfusion decreasedecrease rate rate by by 20% 20% increaseincrease rate rate by by 20% 20%

2007년내과학회임상강좌 2007년내과학회임상강좌 Drugs in Emergency Tx (3) Corticosteroid Drugs in Emergency Tx (4) IV magnesium sulphate 전신 스테로이드(systemic corticosteroid)

- 가벼운 천식 발작에서는 사용할 필요 없지만 중등증 이상의 천식 발작에 사용하면 천식 증상의 호전이 빠르다. -모든 천식 발작에 권장되지는 않음 - 경구로 투여해도 효과가 있으나 최소한 4시간은 있어야 효과가 나타난다. -내원 당시 1초간 노력성 호기량이 예측치의 25-30% 정도이고 - 만약 경구 투여가 불가능하면 주사로 투여한다. 치료 1시간 후에도 예측치의 60% 미만인 환자에 투여하면 - 경구 투여시 하루에 methylprednisolone 60-80mg 상당의 스테로이드를 1번투여 효과적이라는 보고가 있음 - 주사투여시 -2g을 20분에 걸쳐 1회 정맥 투여한다. hydrocortisone 300-400 mg 상당을수회에걸쳐투여한다. - 급성 발작의 치료를 위해서 대부분의 성인 환자는 1주일, 소아 환자는 3-5 일 정도면 충분하다.

－ S 743 － － 대한내과학회지 : 제73권 부록 2 호 2007 －

2007년내과학회임상강좌 2007년내과학회임상강좌 Drugs in Emergency Tx (5) Status Asthmaticus (1) Other Treatment used in Asthma Tx (Bronchial Asthma,E.Weiss et al,1993) (NIH Guidelines for asthma, 1991) Definition: No specific Criteria Antibiotics: purulent ,fever,leukocytosis Severe,Life threatening airflow obstruction which is Hydration: In adult, aggressive hydration does not refractory to Initial bronchodilator therapy play a role in Tx of severe asthma Incidence: No precise statistics Children>Adult, Female>Male Chest Physical Therapy: may be beneficial Underlyng Pathology: Hyperinflated Mucolytics: Intra-bronchial Tx is contraindicated Airway Occlusion by Mucus Sedation: Anxiolytics&Hypnotics should be strictly Goblet cell Meta&Hyperplasia avoided in severe adult & child patients Bronchial muscle hyperplasia BM thickening

2007년내과학회임상강좌 Status asthmaticus (2) Ventilator Therapy in Bronchial Asthma(1) (Bronchial Asthma,E.Weiss et al,1993) (Bronchial Asthma,E.Weiss et al,1993)

Indications for Ventilator in Asthma Risk Factors for Status Asthmaticus & Mortality 1) Clinical Demographic: Young age, Non-Caucasian Exhaustion,,Altered Consciousness Historical: Prior life threatening attack,ER visit>3 in last 1yr, Resp.muscle fatigue,Cardiac or Hemodynamic instability Hx of Syncope,Use 3< drugs or steroid,Lung Disease 2) ABGA & Spirometry Psychosocial: Poor compliance,Alcoholism,Smoking,Denial, a. Rising PaCO >40-50mmHg despite aggressive Tx Depression,Delay in seeking medical care 2 Rise in CO >5-10mmHg/hr with respiratory acidosis Physician Related Factors 2 b. PaCO >60mmHg with coexistng acidemia(pH<7.2) Failure to diagnose severity of attack 2 c. Refractory Hypoxia(PaO <50nnHg with FiO 1.0) Underutilization of corticosteroid 2 2 or O induced ventilatory suppression Failure to F/U & monitor using objective measures 2 d. FEV <1.0L or <25% of predicted Inappropriate use of sedatives or narcotics 1 e. PEFR<120L/min or <25% of predicted Failure to Educate patients

2) Pharmacologic Therapy(24) Ventilator Therapy in Bronchial Asthma(2) Ventilator Therapy in Bronchial Asthma(3) (Bronchial Asthma,E.Weiss et al,1993) (Bronchial Asthma,E.Weiss et al,1993) Considerations for Weaning Ventilator Technic Mean duration for Ventilator Tx : 33.7+25.3 hrs - Sedation: Benzodiazepines Narcotic if needed(fentanyl>morphine) Criteria for Weaning from Ventilator - NM blocker if Pt fights or Severe tachycardia/ persist a. A-a PO difference<300-350mmHg at FiO 1.0 Goals of Mechanical Ventilation 2 2 b. Adequate PaO2 at FiO <0.4 a. Limiting PAP<50-55cm H O 2 2 c. VC > 10-15ml/Kg b. Keeping intrinsic PEEP<15cm H2O d. Normal range PaCO2 with VE<10L/min c. O2 saturation>90%(FiO2 set to attain PaO2 60-80mmHg) e. Ability to generate inspiratory Pr>-30cmH2O and d. Normalize PCO2(TV 10-12ml/kg, RR 12-15/min, flow<60L/min) e. adjust I:E ratio f. Clinical Findings support above data - Controlled : To prevent Barotrauma g. Obvious improvement in auscultatory findings Hypercapnea is well tolerated if pH maintained>7.20-7.25 h. Resolution of contributing factors

－ S 744 － －최동철 : Exacerbation of Asthma －

2007년내과학회임상강좌 2007년내과학회임상강좌

증례: 쌕쌕거리고 숨이 차서 응급실로 온 45세여자

Present illness 07.9월초 fever, , dyspnea 발생 07.9.10 숨쉴 때 쌕쌕 소리가 나기 시작. 07.9.15 dyspnea 악화되어 인근 병원 방문 Case RR>30, wheezing on both lung field R/O asthma attack, r/o Pn 로 iv steroid, iv moxi 07.9.20 증상호전 없어서 D 의료원 방문 CBC 15330-14.6-346K

ABGA: pH 7.71, PCO2 12.4, PO2 129 HCO3 -16.3, SpO2 99% 07.9.21 증상 호전 없이 본원 ER로 refer

2007년내과학회임상강좌 2007년내과학회임상강좌

P/E Laboratory finding

V/S 115/72- 93- 46- 36.2 ABGA mental alert pH 7.67, pCO2 17.4, pO2 acute ill looking appearance 116, HCO3 -19.7, SaO2 not anemic conjunctiva, anicteric sclera 99% chest: RHB s m, CBC whole lung field wheezing 15090-14.6-347K Abd: soft and obese CRP 0.05 T/RT(-/-) normoactive bowel sound no organomegaly CVAT(-/-), edema(-)

2007년내과학회임상강좌 2007년내과학회임상강좌

Chest routine CT

Q1: 추가로 필요한 검사는 ?

－ S 745 － － 대한내과학회지 : 제73권 부록 2 호 2007 －

2007년내과학회임상강좌

Flow - volume curves in dyspneic patients

•Bronchoscopy: flow expiration No endobronchial lesion volume

R/O status asthmaticus inspiration Fixed intra or extrathoracic Normal

variable extrathoracic variable intrathoracic

2007년내과학회임상강좌

Final diagnosis

Vocal cord dysfunction R/O Panic disorder Q2: 진단은 ? R/O Conversion disorder ⇒ 입원기간 iv steroid에호전없이asthmatic attack 발생하여 수초내 정상화 되는 양상 반복되었으나, risperidone, alprazolam, diazepam 등의 mood stabilizer 복용하면서 attack 없어져 퇴원함.

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