만성폐쇄성폐질환의급성악화로입원했던환자에서장기간사망의예측인자 이화여자대학교의과대학내과학교실정해선, 이진화, 천은미, 문진욱, 장중현 Predictors of Long-term Mortality after Hospitalization for Acute Exacerbation of COPD Hae-Sun Jung, M.D., Jin Hwa Lee, M.D., Eun Mi Chun, M.D., Jin Wook Moon, M.D. and Jung Hyun Chang, M.D. Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea Background : Acute exacerbations form a major component of the socioeconomic burden of COPD. As yet, little information is available about the long-term outcome of patients who have been hospitalized with acute exacerbations, although high mortality rates have been reported. The aim of this study was to determine predictors of long-term mortality after hospitalization for acute exacerbation of COPD. Methods : We performed a retrospective cohort study of consecutive patients admitted to the hospital for COPD exacerbation between 2000 through 2004. Patients who had died in hospital or within 6-months after discharge, had tuberculosis scar, pleural thickening or bronchiectasis by chest radiography or had been diagnosed with malignancy during follow-up periods were excluded. Results : Mean age of patients was 69.5 years, mean follow-up duration was 49 months, and mean FEV 1 was 1.00L (46% of predicted). Mortality was 35% (17/48). In the multivariate Cox regression analysis, heart rate of 100/min or more (p=0.003; relative risk [RR], 11.99; 95% confidence interval [CI], 2.34-61.44) and right ventricular systolic pressure (RVSP) of 35mmHg or more (p=0.019; RR, 6.85; 95% CI, 1.38-34.02) were independent predictors of mortality. Conclusion : Heart rate and RVSP in stable state may be useful in predicting long-term mortality for COPD patients admitted to hospital with acute exacerbation. (Tuberc Respir Dis 2006; 60: 205-214) Key words : COPD, Mortality determinants, Heart rate, Right ventricular systolic pressure 서 만성폐쇄성폐질환 (chronic obstructive pulmonary disease, COPD) 은점진적으로진행하고폐의비정상적인염증상태를수반하며완전히가역적이지않은기류제한을특징으로하는질병상태를말한다. 미국에서는사망원인중 4위를차지할만큼사망률이높은질환의하나이며, 2020년에는세계적으로공중보건에서 5위의질병부담이될것으로예측하는중요한문제이다 1. 론 Address for correspondence : Jin Hwa Lee, M.D. Department of Internal Medicine, Ewha Womans University, College of Medicine 911-1 Mokdong Yancheon-gu, Seoul 158-710 Korea Phone : +82-2-2650-6007, Fax : +82-2-2655-2076, E-mail : jinhwalee@ewha.ac.kr Received : Nov. 22. 2005 Accepted : Feb. 1. 2006 만성폐쇄성폐질환환자는 1년중 1-3회급성악화를일으키며, 이들중 3-16% 는병원입원이필요하다 2. 만성폐쇄성폐질환환자의병원내사망률은 4-30% 에이르고, 급성악화로인한호흡부전이사망의중요한원인으로알려져있다 3. 지금까지연구결과나이 3-9, 동반질환 3,4,10, 질환의중증도 11-13, 폐기능 5,7,9,11, 고탄산혈증의정도 11,14, 부정맥 14 등이만성폐쇄성폐질환환자에서사망의예측인자로보고되었다. 만성폐쇄성폐질환환자에서사망관련위험인자를아는것은치료과정에서중점적으로고려하여정기적으로추적관찰하여야하는점이무엇인지알수있게해주며, 이를통해예후를추정할수있기때문에중요하다. 본연구는만성폐쇄성폐질환의급성악화로 1회이상입원했던환자를대상으로생존자군과사망자군으로구분하여장기추적관찰시사망관련위험인자를찾아보고자하였다. 205
HS Jung et al. : Predictors of long-term mortality after acute exacerbation of COPD EWUH admission database from 2000 through 2004 N= 158 diagnosed as COPD and performed spirometry n=96 n=61 Subjects included: n=48 Abnormal chest X-ray Malignancy (14) Asthma (4) Anthracofibrosis (1) Bronchiectasis (1) No follow-up of COPD (6) No airflow obstruction (9) follow-up time < 6 months Figure 1. Study design. EWUH, Ewha Womans University Hospital. 1. 대상 대상및방법 2000년부터 2004년까지이대목동병원에만성폐쇄성폐질환의급성악화로입원한환자중폐기능검사를 1회이상시행한적이있는 158명에한하여의무기록을후향적으로조사하였다. 이중흉부 X-선사진을검토하여폐결핵반흔, 흉막비후또는기관지확장증이있는경우를제외하였으며, 추적기간중악성종양으로진단받거나만성폐쇄성폐질환으로진료를받지않은경우를제외하였고, 추적기간이 6개월미만인경우를제외하여, 총 48명이연구대상환자로선정되었다 (Figure 1). 2. 정의 만성폐쇄성폐질환은기침, 가래, 또는호흡곤란이있으면서완전히가역적이지않은기류폐쇄로, 폐기 능검사결과기관지확장제흡입후노력성폐활량 (forced vital capacity, FVC) 에대한 1초간노력성호기량 (forced expiratory volume in 1 second, FEV 1 ) 의비 (FEV 1 /FVC) 가 0.7 미만으로정의하였다 15,16. 만성폐쇄성폐질환의급성악화는화농성객담, 객담양의증가, 그리고호흡곤란의악화중한가지이상이나타날때로정의하였다 16,17. 3. 방법대상환자의나이, 성별, 키, 체중, 체질량지수, 동반질환, 흡연, 추적기간, 생존여부등을조사하였고, 만성폐쇄성폐질환의급성악화로인한입원시혈압, 맥박, 호흡수, 체온, 동맥혈가스분석, 전체혈구계산, creatinine, 혈당, 전해질등을조사하여 Acute Physiology And Chronic Health Evaluation II(APA- CHE II) 점수 10 를계산하였으며, 적혈구침강속도, C- 반응단백, 알부민, 빌리루빈을조사하였다. 추적기간중중환자실입원여부와기계환기치료유무, 경구스테로이드유지여부, 급성악화의빈도와그로인한재입원여부등을조사하였다. 폐기능은안정상태에서 Vmax spectra 22(Sensormedics, USA) 를사용하여미국흉부학회의폐기능검사지침에따라시행하였다 17. 만성폐쇄성폐질환의중증도분류는 Global Initiative for Chronic Obstructive Lung Disease(GOLD) 16 의기준에따라경증을 FEV 1 의정상예측치가 80% 이상으로, 중등증을 50% 이상이면서 80% 미만, 중증을 30% 이상이면서 50% 미만, 최고중증을 30% 미만으로정의하였다. 외래에서추적관찰중이거나퇴원전에환자가안정된상태에서경흉부심초음파검사를 HP 2500(Philips, USA) 으로시행하였다. 심초음파중기록되는심전도에따라심장박동수를기록하였고, 심첨부 four-chamber view에서연속파도플러로수축기동안삼첨판역류속도 (tricuspid regurgitation velocity, TR velocity) 를측정하여 Bernoulli 공식 (4 TR velocity 2 ) 에의해삼첨판에서우심방과우심실의압력차를계산한후우심방압력을 10mmHg의고정된값으로하여우심실수축기압 (right ventricular systolic 206
Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb. 2006 Table 1. Baseline characteristics in survivors and non-survivors with COPD* Variable All patients (n=48) Survivors (n=31) Non-survivors (n=17) p value Male sex (%) 41 (85) 25 (81) 16 (94) NS Height (cm) <166 cm 161.5±8.7 35 (73) 159.4±9.1 26 (84) 165.3±6.3 9 (53) Weight (kg) 51.7±10.2 52.3±10.2 50.7±10.5 NS Body mass index (kg/m 2 ) 19.9±3.8 <21kg/m 2 30 (63) Associated diseases 20.6±3.6 16 (52) 18.6±4.0 14 (82) Hypertension (%) 5 (10) 5 (16) 0 (0) NS Diabetes mellitus (%) 2 (4) 2 (7) 0 (0) NS Liver disease (%) 2 (4) 1 (3) 1 (6) NS Smoking Smoker (%) 42 (88) 26 (84) 16 (94) NS Current smoker (%) 24 (50) 15 (48) 9 (53) NS Ex-smoker (%) 11 (36) 7 (41) 18 (38) NS Never-smoker (%) 6 (13) 5 (16) 1 (6) NS Pack-years 43±29 46±35 37±16 NS NS, not significant. *Data are no. (%) or mean±sd. Data came from ever-smokers. 0.024 0.021 0.088 0.035 Table 2. Clinical characteristics in survivors and non-survivors with COPD during follow-up period* Variable All patients (n=48) Survivors (n=31) Non-survivors (n=17) p value Follow-up time (months) 49.5±29.8 49.0±27.0 50.3±35.0 NS Maintenance of oral steroid (%) 13 (27) 9 (29) 4 (24) NS Number of acute exacerbation 3.9±3.2 3.5±3.3 4.5±3.2 NS Hospitalization 3.4±3.0 3.1±3.0 3.9±2.8 NS Visit to emergency room 0.1±1.1 0.4±1.0 0.6±1.3 NS ICU admission (%) 24 (50) 12 (39) 12 (71) 0.035 Mechanical ventilation (%) 9 (19) 6 (19) 3 (18) NS Readmission (%) 30 (63) 18 (58) 12 (71) NS Time to readmission 16.3±16.9 19.9±19.1 10.8±11.8 NS NS, not significant. *Data are no. (%) or mean±sd. Discharge after emergency care without admission. Data came from patients who admitted again after discharge. pressure, RVSP) 을다음식과같이계산하였다 18. RVSP (mmhg) = 4 TR velocity 2 + 10 4. 통계분석 며, 이중독립적인사망의예측인자를찾기위해다중 Cox 회귀분석을이용하여생존분석을시행하였다. p 값이 0.05 미만일때통계적으로유의하다고판정하였다. 통계분석은 SPSS 11.0(SPSS Inc, Chicago, IL) 프로그램을이용하였다. 생존한환자와사망한환자사이에연속변수의비교는 Student t-test를, 범주형변수의비교는 χ 2 test를사용하여분석하였다. 두군간에통계적으로유의한차이를보였던변수와만성폐쇄성폐질환의환기장애정도가사망과관련되어있는지를알기위해각각 Cox 회귀분석을시행하였으 결과대상환자는총 48명으로, 평균연령이 69.5세였고, 그중남자가 41명, 여자가 7명이었다. 평균추적기간은 49개월이었고, 평균 FEV 1 은 1.00L로정상예측치의 46% 였다. 사망자가 17명으로사망률은 35% 였다. 생존자군과사망자군으로나누어비교하였을때, 207
HS Jung et al. : Predictors of long-term mortality after acute exacerbation of COPD Table 3. Baseline characteristics in survivors and non-survivors with COPD at admission* Variable All patients (n=48) Survivors (n=31) Non-survivors (n=17) p value Age (years) 69.5±10.2 69.2±9.4 69.9±11.9 NS Systolic blood pressure (mm- Hg) 127±27 124±22 133±35 NS Diastolic blood pressure (mm- Hg) 75±13 73±13 78±14 NS Mean blood pressure (mmhg) 92±16 90±14 96±20 NS Pulse rate (/min) 98±23 97±22 99±25 NS Respiratory rate (/min) 26±7 26±7 25±5 NS Body temperature ( C) 36.9±0.9 36.7±0.8 37.3±1.1 NS Hospital stay (days) 13.6±10.7 13.7±9.5 13.6±13.0 NS APACHE II 10.5±3.9 10.3±3.9 11.0±3.9 NS NS, not significant; APACHE II, acute physiology and chronic health examination II. *Data are mean±sd. Table 4. Laboratory characteristics in survivors and non-survivors with COPD at the admission* Variable All patients (n=48) Survivors (n=31) Non-survivors (n=17) p value Arterial ph 7.42±0.06 7.41±0.06 7.42±0.05 NS PaO 2 (mmhg) 59.2±16.2 61.2±18.0 55.5±11.9 NS PaCO 2 (mmhg) 43.4±13.1 43.5±15.1 43.2±9.0 NS D(A-a)O 2 (mmhg) 95.5±16.4 95.4±18.8 95.7±11.2 NS Hemoglobin (g/dl) 13.2±1.4 13.4±1.3 13.0±1.7 NS Hematocrit (%) 28.8±4.3 39.0±3.9 38.3±5.1 NS WBC counts (x1,000/mm 3 ) 10.2±5.2 10.0±5.2 10.5±5.4 NS Platelet counts (x1,000/mm 3 ) 242±86 248±93 231±73 NS ESR (mm/hr) 32±27 29±25 38±32 NS C-reactive protein (mg/dl) 6.5±6.9 7.0±7.3 5.4±5.9 NS Blood urea nitrogen (mg/dl) 16.2±7.9 15.2±7.0 18.0±9.2 NS Creatinine (mg/dl)<1 mg/dl (%) 0.88±0.25 31 (65) 0.94±0.25 16 (52) 0.79±0.22 15 (88) 0.047 0.011 Glucose (mg/dl) 131±37 137±42 121±24 NS Albumin (g/dl) 3.8±0.6 3.8±0.6 3.8±0.5 NS Total bilirubin (mg/dl) 0.6±0.2 0.6±0.2 0.6±0.2 NS Sodium (mmol/l) 140±5 140±5 140±5 NS Potassium (mmol/l) 4.2±0.6 4.2±0.6 4.1±0.6 NS NS, not significant; D(A-a)O 2, alveolar-arterial oxygen difference; WBC, white blood cell counts; ESR, erythrocyte sedimentation rate. *Data are no. (%) or mean±sd. 사망자군의평균키가생존자보다유의하게컸고 (p=0.024), 체질량지수가작았으나통계적으로유의하지않았다 (p=0.088). 체질량지수가 21kg/m 2 을기준으로하였을때, 21kg/m 2 미만인환자가사망자군에서생존자군보다유의하게많았다 (p=0.035). 그외동반질환이나흡연유무에따른차이는없었다 (Table 1). 추적관찰기간에중환자실입원치료를받은경우가사망자군에서생존자군보다유의하게많았으나 (p=0.035), 경구스테로이드사용, 급성악화의빈도, 재입원율과재입원까지의기간등에는차이가없었다 (Table 2). 급성악화로입원시생체징후, 재원기간과 APA- CH II 점수는생존자와사망자사이에차이가없었다 (Table 3). 입원시시행한혈액검사중사망자군의 creatinine 이생존자군보다유의하게낮았지만 (p=0.047), 그외동맥혈가스검사, 혈색소, 염증지표, 혈당, 알부민등은차이가없었다 (Table 4). 안정시시행한폐기능검사결과사망자의평균 FEV 1 과 FVC가생존자군보다작았지만통계적으로 208
Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb. 2006 Table 5. Lung function in survivors and non-survivors with COPD in stable state* Variable All patients (n=48) Survivors (n=31) Non-survivors (n=17) p value FEV 1/FVC (%) 45.4±12.6 45.5±11.0 45.3±15.4 NS FEV 1 (L) 1.00±0.44 1.02±0.42 0.97±0.48 NS FEV 1 % predicted 46.1±23.0 49.3±24.0 40.2±20.4 NS FVC (L) 2.26±.71 2.27±0.73 2.24±0.70 NS FVC % predicted 69.6±21.3 72.6±20.6 64.3±22.0 NS COPD severity NS Mild (%) 5 (10 ) 3 (10) 2 (12) NS Moderate (%) 11 (23) 10 (32) 1 (6) 0.038 Severe (%) 23 (48) 14 (45) 9 (53) NS Very severe (%) 9 (19) 4 (13) 5 (29) NS NS, not significant; FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity. *Data are number (%) or mean±sd. Global initiative for chronic Obstructive Lung Disease (GOLD) criteria as follows: mild, FEV 1 80% of predicted; moderate, 50% FEV 1<80%; severe, 30% FEV 1< 50%; very severe, FEV 1<30% Table 6. Echocardiographic variables in survivors and non-survivors with COPD in stable state* Variable All patients (n=35) Survivors (n=25) Non-survivors (n=10) p value Heart rate (/min) 84±18 79±14 96±23 0.009 <100/min (%) 31 (89) 24 (96) 7 (70%) 0.029 Left atrium (cm) 3.8±0.7 3.8±0.8 3.9±0.6 NS LVEDD (cm) 4.7±0.8 4.8±0.8 4.5±0.7 NS LVESD (cm) 2.8±0.7 2.9±0.7 2.6±0.7 NS %FS 40±8 40±8 43±7 NS Ejection fraction (%) 65±9 64±10 66±8 NS RVSP (mmhg) 36±11 33±7 45±14 0.032 <35mmHg (%) 19 (54) 17 (68) 3 (20) 0.010 E (m/s) 0.66±0.16 0.66±0.17 0.67±0.12 NS A (m/s) 0.93±0.17 0.91±0.18 0.98±0.12 NS Ratio E/A 0.74±0.25 0.76±0.28 0.69±0.12 NS PHT (ms) 78±20 80±21 73±12 NS LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; %FS, LV percent fractional shortening; RVSP, right ventricular systolic pressure; E, peak E velocity; A, peak A velocity; PHT, pressure half time. *Data are number (%) or mean±sd. 유의한차이는없었다. 생존자군과사망자군사이에 GOLD 기준에따른중증도분포를비교하였을때차이가없었으나, 중등도 (50% FEV 1 <80%) 환기장애를가진환자수가생존자군에서사망자군보다더많았다 (p=0.038)(table 5). 안정상태에서시행한심초음파결과, 사망자군의심장박동수가생존자군보다유의하게빨랐고 (p= 0.009), 우심실수축기압이높았다 (p=0.032). 그외좌심실박출율등다른지표에서는차이가없었다 (Table 6). 사망의예측인자를분석하기위해생존자군과사망자군사이에차이를보였던변수에대해 Cox 회귀 분석을시행한결과, 만성폐쇄성폐질환환자에서사망률은중환자실에입원한경력이있을수록 ( 상대위험도 : 3.181, p=0.047), 심장박동수가분당 100회이상일때 ( 상대위험도 : 7.746, p=0.009), 그리고우심실수축기압이 35mmHg 이상일때 ( 상대위험도 : 5.150, p=0.039) 유의하게증가하였다 (Table 7). 다중 Cox 회귀분석을시행하여다른변수의영향을보정한결과, 분당 100회이상의심장박동수와 ( 상대위험도 : 11.988, 95% 신뢰구간 : 2.339-61.442, p=0.0 03) 35mmHg 이상의우심실수축기압이 ( 상대위험도 : 6.852, 95% 신뢰구간 : 1.380-34.021, p=0.019) 만성폐쇄성폐질환환자에서사망에영향을주는유의한독 209
HS Jung et al. : Predictors of long-term mortality after acute exacerbation of COPD Table 7. Predictors of long-term mortality in patients with COPD: univariate analysis Variables Relative risk 95% confidence interval p value Height (cm) <166 1 166 1.459 0.543-3.917 0.454 BMI (kg/m 2 ) <21 1 21 0.362 0.103-1.272 0.113 ICU admission No 1 Yes 3.181 1.017-9.946 0.047 Creatinine (mg/dl) <1 1 1 0.328 0.073-1.467 0.145 FEV 1 % predicted 80 1 50 to <80 1.688 0.301-9.479 0.552 30 to <50 0.403 0.045-3.590 0.416 <30 0.959 0.318-2.897 0.941 Heart rate (/min) <100 1 100 7.746 1.680-35.714 0.009 RVSP (mmhg) <35 1 35 5.150 1.087-24.389 0.039 BMI, body mass index; ICU, intensive care unit; FEV 1, forced expiratory volume in 1 second; RVSP, right ventricular systolic pressure. Table 8. Multivariate analysis based on Cox regression model for predictors of long-term mortality in patients with COPD Variables Relative risk 95% confidence interval p value Heart rate (/min) <100 1 100 11.988 2.339-61.442 0.003 RVSP (mmhg) <35 1 35 6.852 1.380-34.021 0.019 RVSP, right ventricular systolic pressure. 1.0 1.0.8.8.6.6.4.4.2 Heart rate.2 RVSP 100/min 35mmHg 0.0 0 30 60 90 120 <100/min 0.0 0 30 60 90 120 <35mmHg Follow-up (months) Figure 2. Survival curve during follow-up for the presence or absence of tachycardia in stable state of COPD. Follow-up (months) Figure 3. Survival curve during follow-up for different levels of right ventricular systolic pressure (RVSP) measured using echocardiography. 210
Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb. 2006 립변수였다 (Table 8, Figure 2 and 3). 고찰만성폐쇄성폐질환은환자의삶의질을저하시키고사회경제적부담을증가시키는질환으로, 급성악화로인한잦은입원과이와연관된높은사망률이잘알려져있다. 본연구는 5년동안만성폐쇄성폐질환의급성악화로입원한적이있는환자를대상으로한후향적코호트연구로, 퇴원후 6개월까지사망하지않고추적관찰이가능한환자에대하여사망률이 35% 로비교적높은사망률을보였다. 상대적으로대상수가적으며개개환자마다추적기간이달라서다른연구와정확한비교가어렵지만, 다른연구도이질환의급성악화와관련하여높은사망률을보고하였다. 지금까지연구중만성폐쇄성폐질환의급성악화로입원한환자의사망률에대한가장대규모연구는 Conner 등 6 에의한전향적코호트연구로, 5개병원에서 1,016명의입원중사망률이 11%, 1년후사망률이 43%, 2년후사망률이 49% 이었다. Seneff 등 19 은만성폐쇄성폐질환의급성악화로인한호흡부전으로기계환기를받은환자의사망률이 24% 이고, 이중 65세이상환자의사망률이 30%, 퇴원 1년후사망률이 59% 라고보고하였다. 본연구에서만성폐쇄성폐질환의급성악화로입원했던환자에서장기추적관찰시사망과관련된독립적인예측인자로, 가장유의한변수는안정시측정된심장박동수였다. 빈맥은이완기에좌심실의충만기를짧게하여조기충만이충분히이루어지기전에심방의수축을가져온다. 이런빈맥은저산소증이나베타2-작용제, 테오필린등의약제뿐아니라정맥으로의순환감소나저혈량등에의한좌심실의전부하감소에의해서도일어날수있다 23. 지금까지의연구중만성폐쇄성폐질환환자에서사망의예측인자로심장박동수에대한연구는드물다. 최근 Lacasse 등 24 이만성폐쇄성폐질환환자 147명과건강한대조군 25명을대상으로운동부하검사를시행하여, 안정시심장박동수, 운동시최고심장박동수및운동후심장박동 수의회복정도 ( 운동시최고심장박동수와운동중단 1분후심장박동수의차이 ) 와사망률의관계를조사하였다. 연구결과만성폐쇄성폐질환환자의안정시심장박동수가대조군보다빠르고, 운동후심장박동수회복이느렸다. 또만성폐쇄성폐질환환자중안정시심장박동수는사망자군에서생존자군보다유의하게높았고, 사망의상대위험도가 1.03배였다. 특히다중회귀분석결과 FEV 1 과함께운동후심장박동수의회복정도가독립적인사망의예측인자로, 운동후심장박동수의회복이느릴수록사망의위험이증가하였다. Burrows 등 25 이만성폐쇄성폐질환환자 200명을대상으로한연구에서도, 안정시심장박동수가생존의주요한예측인자임을보고한바있다. Anthonisen 등 5 은저산소증이없는만성폐쇄성폐질환환자 985명을 3년동안추적관찰한결과, 사망률이 23% 였고 FEV 1 이가장중요한사망의예측인자였는데, FEV 1 과나이를보정하였을때안정시의심장박동수가사망과관련되어있음을보고하였다. 위에언급한연구와다르게본연구에서 FEV 1 은사망과관련된인자가아니었는데, 대상환자의차이에기인할수도있지만, FEV 1 단독으로예후를예측하는데제한적임이이미제시된바있다 26,27. 본연구에서또다른사망의독립적인예측인자는우심실수축기압으로, 35mmHg 이상상승되었을때사망위험이유의하게증가하였다. 심초음파에서우심실수축기압은폐동맥압을대변하는지표로, 그정확성에대해서는논란이있으나비침습적이라는장점때문에널리사용되어왔다. 이전의많은연구에서폐동맥고혈압은만성폐쇄성폐질환에서독립적인사망의예측인자로알려졌다. Dallari 등 20 이장기간산소치료를받고있는만성폐쇄성폐질환환자 166명을 4개월동안추적관찰하여사망의예측인자를조사한결과, 평균우심실수축기압이생존자군에서 30mmHg, 사망자군에서 42mmHg 로사망자군에서유의하게높았고, 우심실수축기압이 35mmHg 이상인군에서사망률이높음을보고하였다. Skwarski 등 21 은장기산소치료를받고있는만성폐쇄성폐질환환자에서우심실수축기압이 29mmHg 이상이었을때예후가불량함을보고하였고, Wuertemberger 등 22 도우심실 211
HS Jung et al. : Predictors of long-term mortality after acute exacerbation of COPD 수축기압이 30mmHg 이상을사망의예측인자로보고하였다. 그밖에도본연구에서사망자군의평균키가생존자군에비해유의하게크고, 체질량지수가작았다. 특히체질량지수를 21kg/m 2 을기준으로하였을때 15, 21kg/m 2 미만인환자가사망자군에서더많았는데, 생존분석결과사망의예측인자는아니었다. 이는이전에발표된연구와다른결과로, 대상환자의특성이나숫자, 추적기간이다르기때문일것이다. 이전의연구에서체질량지수는만성폐쇄성폐질환환자의영양상태를판단하는기준으로사용되었고, 낮은체질량지수가사망의예측인자로나타났다. Chailleux 등 28 은장기간산소치료를받고있는만성폐쇄성폐질환환자 4,088명에서체질량지수에따른 5년생존율을조사하였는데, 체질량지수가 20kg/m 2 이하인군에서 24%, 20-25kg/m 2 에서 34%, 25-30kg/m 2 에서 44%, 30kg/m 2 이상에서 59% 로, 낮은체질량지수가사망을예측할수있는독립적인지표라고하였다. Landbo 등 26 은 Copenhagen City Heart Study 코호트로부터 2,132명의만성폐쇄성폐질환환자를전향적으로 17년간추적관찰하여, 체질량지수가낮은환자를정상인환자와비교한결과남성에서는 1.64배, 여성에서는 1.42배로사망위험이증가했다고보고하였다. Celli 등 27 은만성폐쇄성폐질환환자에서체질량지수 (Body mass index), FEV 1 으로측정한기도폐쇄의정도 (airway Obstruction), 호흡곤란 (Dyspnea) 및운동능력 (Exercise capacity index) 을합친 BODE 점수를계산하여점수가높을수록사망위험과호흡계통의원인으로사망할위험이각각증가한다고보고하였고, BODE 점수가 FEV 1 단독보다더나은사망의예측인자라고발표하였다. 본연구에서사망자군에서혈청 creatinine이유의하게낮았는데, creatinine이골격근육량을반영하는지표임을고려할때사망자군에서생존자군에비해상대적으로골격근육량이작다고추측할수있다. Fuld 등 29 은만성폐쇄성폐질환환자 38명을두군으로나누어각각속임약과 creatine을투여하였더니, creatine 보충이 fat-free mass, 말초근육의강도와내구성을향상시킴을확인한바있다. 그외다른연구에서사망의예측인자로알려졌던나이 3,7, 남성 3, 경구스테로이드 7,30, PaCO 7,12 2, 동반질환 3,4, 재입원 4, APACHE II 점수 12 는본연구결과사망의예측인자가아니었다. 본연구의제한점으로는, 첫째, 후향적인연구로사망의예측인자로서예비변수선정이제한되어주관적인호흡곤란이나운동능력등을포함하지못한점, 둘째, 개개인에따라추적기간이다르다는점, 셋째, 결핵유병률이높은우리나라에서폐결핵반흔이있는환자를제외하면서대상환자수가적어졌다는점, 넷째, 사망의원인을분석하지못하였다는점이있다. 17명의사망자중 5명에서사망원인이밝혀졌는데, 각각패혈쇼크, 급성심근경색, 다기관부전, 급성호흡부전, 기흉이었다. 본연구를통해만성폐쇄성폐질환의급성악화로입원했던환자에서장기간추적관찰시안정상태의빈맥과폐동맥고혈압이사망을예측하는독립적인위험인자임을확인하였다. 따라서, 만성폐쇄성폐질환의급성악화로치료받고퇴원한환자를추적관찰할때, 정기적인심장박동수측정과심초음파검사를통한우심실수축기압측정이예후측정에도움이될것이다. 앞으로만성폐쇄성폐질환환자에서사망의예측인자에대한전향적인대규모연구가필요하다. 요약배경 : 만성폐쇄성폐질환의급성악화는주요한사회경제적부담이다. 이질환의높은사망률이잘알려져있지만, 아직까지급성악화로입원했던환자의장기예후에대해서는잘알려져있지않다. 본연구의목적은만성폐쇄성폐질환의급성악화로입원했던환자에서장기간사망의예측인자를알아보기위함이다. 방법 : 2000년부터 2004년사이에만성폐쇄성폐질환의급성악화로입원한환자를대상으로후향적으로조사하였다. 입원중또는퇴원후 6개월이내에사망하거나흉부 X-선촬영에서결핵반흔, 흉막비후나기관지확장증이동반된경우, 추적기간중악성종양을진단 212
Tuberculosis and Respiratory Diseases Vol. 60. No. 2, Feb. 2006 받은환자는제외하였다. 결과 : 평균연령은 69.5세였고, 추적기간은 49개월이었으며, 평균 FEV 1 은 1.00L( 예측치의 46%) 였다. 사망률은 35%(17/48) 였다. 다중 Cox 회귀분석결과분당 100회이상의빈맥과 (p=0.003; 상대위험도, 11.99; 9 5% 신뢰구간, 2.34-61.44) 35mmHg이상의우심실수축기압이 (p=0.019; 상대위험도, 6.85; 95% 신뢰구간, 1.38-34.02) 사망위험을높이는독립적인예측인자였다. 결론 : 만성폐쇄성폐질환의급성악화로입원했던환자의장기간사망위험을예측하는데안정시심장박동수와우심실수축기압이유용할것이다. 참고문헌 1. Mannino DM. COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest 2002;121(Suppl):121S-6S. 2. Yun SH. Acute exacerbation of chronic obstructive pulmonary disease. Korean J Crit Care Med 2003; 18:1-6. 3. Patil SP, Krishnan JA, Lechtzin N, Diette GB. In-hospital mortality following acute exacerbations of chronic obstructive pulmonary disease. Arch Intern Med 2003;163:1180-6. 4. Almagro P, Calbo E, Ochoa de Echaguen A, Barreiro B, Quintana S, Heredia JL, et al. Mortality after hospitalization for COPD. Chest 2002;121:1441-8. 5. Anthonisen NR, Wright EC, Hodgkin JE. Prognosis in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986;133:14-20. 6. Connors AF Jr, Dawson NV, Thomas C, Harrell FE Jr, Desbiens N, Fulkerson WJ, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease: the SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med 1996;154:959-67. 7. Groenewegen KH, Schols AM, Wouters EF. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest 2003;124:459-67. 8. Hansen EF, Phanareth K, Laursen LC, Kok-Jensen A, Dirksen A. Reversible and irreversible airflow obstruction as predictors of overall mortality in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:1267-71. 9.Traver GA, Cline MG, Burrows B. Predictors of mortality in chronic obstructive pulmonary disease: a 15-year follow-up study. Am Rev Respir Dis 1979; 119:895-902. 10. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACH II: a severity of disease classification system. Crit Care Med 1985;13:818-29. 11. Ai-Ping C, Lee KH, Lim TK. In-hospital and 5-year mortality of patients treated in the ICU for acute exacerbation of COPD: a retrospective study. Chest 2005;128:518-24. 12.Goel A, Pinckney RG, Littenberg B. APACHE II predicts long-term survival in COPD patients admitted to a general medical ward. J Gen Intern Med 2003;18:824-30. 13. Nevins ML, Epstein SK. Predictors of outcome for patients with COPD requiring invasive mechanical ventilation. Chest 2001;119:1840-9. 14. Fuso L, Incalzi RA, Pistelli R, Muzzolon R, Valente S, Pagliari G, et al. Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease. Am J Med 1995;98:272-7. 15. American Thoracic Society/European Respiratory Society Task Force. Standards for the diagnosis and management of patients with COPD [Internet]. Version 1.2. New York: American Thoracic Society; 2004 [updated 2005 September 8]. Available from: http:// www.thoracic.org/copd/. 16. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163: 1256-76. 17. American Thoracic Society. Standardization of spirometry: 1994 update. Am J Respir Crit Care Med 1995;152:1107-36. 18.Feigenbaum H, Armstrong WF, Ryan T. Feigenbaum's echocardiography. 6th ed. London: Lippincott Williams & Wilkins ;2005. 19. Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus WA. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JA- MA 1995;274:1852-7. 20. Dallari R, Barozzi G, Pinelli G, Meright V, Grandi P, Manzotti M, et al. Predictors of survival in subjects with chronic obstructive pulmonary disease treated with long-term oxygen therapy. Respiration 1994;61: 8-13. 213
HS Jung et al. : Predictors of long-term mortality after acute exacerbation of COPD 21. Skwarski K, MacNee W, Wraith PK, Silwinski P, Zielinski J. Predictors of survival in patients with chronic obstructive pulmonary disease treated with long-term oxygen therapy. Chest 1991;100:1522-7. 22. Wuertemberger G, Zielinsky J, Sliwinsky P,Auw- Haedrich C, Matthys H. Survival in chronic obstructive pulmonary disease after diagnosis of pulmonary hypertension related to long-term oxygen therapy. Lung 1990;168:762-9. 23. Boussuges A, Pinet C, Molenat F, Burnet H, Ambrosi P, Badier M, et al.. Left atrial and ventricular filling in chronic obstructive pulmonary disease: an echocardiography and doppler study. Am J Respir Crit Care Med 2000;162:670-5. 24. Lacasse M, Maltais F, Poirier P, Lacasse Y, Marquis K, Jobin J, et al. Post-exercise heart rate recovery and mortality in chronic obstructive pulmonary disease. Respir Med 2005;99:877-86. 25. Burrows B, Earle RH. Prediction of survival in patients with chronic airway obstruction. Am Rev Respir Dis 1969;99:865-71. 26. Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1856-61. 27. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005-12. 28. Chailleux E, Laaban JP, Veale D. Prognostic value of nutritional depletion in patients with COPD treated by long-term oxygen therapy: data from the ANT- ADIR observatory. Chest 2003;123:1460-6. 29. Fuld JP, Kilduff LP, Neder JA, Pitsiladis Y, Lean ME, Ward SA, et al. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax 2005;60:531-7. 30. Schols AM, Wesseling G, Kester AD, de Vries G, Mostert R, Slangen J, et al. Dose dependent increased mortality risk in COPD patients treated with oral glucocorticoids. Eur Respir J 2001;17:33 7-42. 214