비순환기계중환자의예후인자로서 Cardiac Troponin I 의유용성 경상대학교의과대학내과학교실김휘종, 함현석, 조유지, 김호철, 이종덕, 황영실 Usefulness of Cardiac Troponin I as a Prognostic Marker in Non cardiac Critically Ill Patients Hwi Jong Kim, M.D., Hyoun Seok Ham, M.D., Yu Ji Cho, M.D., Ho Cheol Kim, M.D., Jong Deok Lee M.D., Young Sil Hwang M.D. Department of Internal Medicine, College of Medicine, Gyeongsang National University, Jinju Background : Cardiac troponin I (ctni) is a specific marker of myocardial injury. It is known that a higher level of ctni is associated with a poor clinical outcome in patients with acute coronary syndrome. An elevation in ctni is also observed in various noncardiac critical illnesses. This study evaluated whether ctni is useful for predicting the prognosis in noncardiac critically ill patients. Methods : From June 2003 to July 2004 at Gyeongsang National University Hospital, we enrolled 215 patients (male:142, female:73, mean age:63±15 years ) who were admitted for critical illness other than acute coronary syndrome at the medical intensive care unit(icu). The severity score of critical illness (SAPS Ⅱ and SOFA) was determined and serum ctni level was measured within 24 hours after admission to the ICU. The mortality rate was compared between the ctni positive ( 0.1µg/L) and ctni negative (ctni<0.1µg/l) patients at the 10 th and 30 th day after admission to the ICU. The mean ctni value was compared between the survivors and non survivors at the 10 th and 30 th day after admission to the ICU in the ctni positive patients. The correlation between ctni and the severity of the critical illness score (SAPS Ⅱ and SOFA) was also analyzed in ctni positive patients. Results : 1) The number of ctni negative and positive patients were 95(44%) and 120(56%), respectively. 2) The mortality rate at the 10 th and 30 th day after admission to the ICU was significantly higher in the ctni positive patients (29%, 41%) than in the ctni negative patients (12%, 21%)(p<0.01). 3) In the ctni positive patients, the mean value of the ctni at the 10 th and 30 th day after admission to the ICU was significantly higher in the non survivors (4.5 ± 9.2 μg/l, 3.5 ± 7.9 μg/l) than in the survivors( 1.8 ± 3.6 μg/l, 2.0 ± 3.9 μg/l) (p < 0.05). 4) In the ctni positive patients, the ctni level was significantly correlated with the SAPS Ⅱ score (r=0.24, p<0.001) and SOFA score (r=0.30, p<0.001). Conclusion : The ctni may be a useful prognostic marker in noncardiac critically ill patients. (Tuberc Respir Dis 2005; 59: 53-61) Key words : Cardiac troponin I, Prognostic marker, Critically ill, Noncardiac patients 서 중환자실에입원한환자는신속한진단과치료가요구되며, 이를위해서는고가의장비와고급인력의집중투여가요구된다. 그리고이러한비용과인력의효율적인사용을위해서여러가지예후의예측인자들이사용되어왔다 1-3. 론 Address for correspondence : Ho Cheol Kim, M.D. Department of Internal Medicine, College of Medicine, Gyeongsang National University. 92 Chilam Dong, Jinju, 660-751, Korea Phone : 055-750-8068 Fax : 055-750-8618 E-mail : hochkim@gshp.gsnu.ac.kr Received : Mar. 21. 2005 Accepted : Jul. 4. 2005 중환자의예후예측지표로현재가장많이쓰이는것으로는중증도평가체계로사용하는 Acute Phy siology And Chronic Health Evaluation (APACHE) 4-6, Simplified Acute Physiology Score (SAPS) 7,8, Mor tality Probability Model (MPM) 9 등이있고장기부전의평가체계로사용하는 Logistic Organ Dysfunction System (LODS) 10, Multi-organ Dysfunction Score (MODS) 11 그리고, Sequential Organ Failure Assess ment (SOFA) 12 등이있다. 그리고최근많이연구되고있는생화학지표로서 C-reactive protein 13, procalci tonin 14, lactate 15, cardiac troponin I 16-18, B-type na triuretic peptide 19 등이있다. 이중에서 Cardiac troponin I (ctni) 는 24-kDa 의 53
HJ Kim et al.: Cardiac troponin I in noncardiac critically ill patients 단백질로서심근의수축작용을억제하는기능이있다. 대개심근손상후 3-4시간이내에혈중에서상승하며 10-24시간에정점을이루고 20 4-10일간증가상태로지속된다 21. 또한심근특수성을가지고있어서급성관상동맥증후군에서진단적인효용성을갖고있고, 예후와도관계가있다 22-24. Guest 등 16 은중환자에서혈청 ctni 에대한연구에서급성심근경색증뿐만아니라심근의허혈증상이없는환자에서도혈청 ctni가증가함을보고하였다. 이후여러연구등에서혈청 ctni 가급성관상동맥증후군뿐만아니라급성폐색전증, 만성폐쇄성폐질환, 패혈증, 만성신부전등과같이비순환기계질환에서도증가되고예후와도관련이있다고보고되고있다 25-28. 그러나이는대상환자가개별적질환만을가진환자들이었으며, 중환자들을대상으로한연구는많지않았고 16,17,29,30, 국내에서는보고된바가없었다. 이에, 저자들은비순환기계중환자에서혈청 ctni 가예후인자로서유용한지를알아보고자하였다. 대상및방법 1. 대상환자 2003년 6월부터 2004년 7월까지경상대학교병원내과계중환자실에입원하여치료한환자를대상으로하였다. 대상환자중에서흉통이있고관상동맥질환이의심되는소견 ( 심전도에서 1 mm이상의 ST분절상승이나하강, Creatine kinase 수치가상한의 2배이상증가중적어도한가지이상 ) 을보이는경우, 최근 21일이내에심장수술을받은경우, 관상동맥질환의과거력이있었던경우는제외하였다. 총 215명 ( 남 : 142 명, 여 : 73명, 평균나이 : 62.9 ± 14.7년 ) 의환자를추적관찰하였다. Ⅱ, SOFA 점수를산출하였다. 혈청 ctni 측정은전혈을채취하여원심분리기로혈장을분리하여, ctni에특정한단일클론항체 2개를이용한 sandwich 면역측정법 (ADVIA Centaur immunoassay system, Bayer Diagnostics, Germany) 을이용하여측정하였다. ctni 의분별한계치를 0.1µg/L로하여 0.1µg/L 이상이면양성군으로 0.1µg/L 미만이면음성군으로분류하였고, 각군에서병일 10일째와 30일째의사망률을구하여비교하였다. 또한 ctni양성군에서병일 10일째와 30 일째의생존군과비생존군에서 ctni 수치를각각비교하였다. ctni의사망에대한민감도, 특이도, 양성예측도, 그리고음성예측도를구하였다. ctni 양성군중에서패혈증, 중증패혈증, 패혈성쇽군으로나누어각군간에 ctni 수치를비교하였다. 그리고중증도평가지표와의관계를알아보기위해 ctni 수치와 SAPS Ⅱ, SOFA 점수간의상관계수를구하였다. 패혈증, 중증패혈증, 패혈성쇽의정의는 ACCP/SCCM consensus conference 31 에서정한기준에따랐다. 3. 자료의분석본연구에쓰인통계분석은윈도우용 SPSS 10.00 version 을이용하였다. 연속성변수에대해서는독립표본 t-검정을사용하였고평균 ± 표준편차로표시하였다. 비연속변수는 chi-square test를이용하였다. ctni와 SAPS Ⅱ, SOFA 점수와의상관관계는이변량상관관계를이용하였다. ctni 양성군과음성군간의누적생존확률곡선은 Kaplan-Meier 방법을이용하였고 log-rank test로비교분석하였다. Receiver operating characteristic (ROC) curve 분석으로 ctni 를이용하여사망률을예측할수있는민감도와특이도및양성예측도와음성예측도를측정하였다. 결과 2. 방법 1. ctni 음성군과양성군의임상적특성 대상환자의중환자실입원 24시간이내중증도와장기부전의정도를평가하기위하여제 1병일 SAPS ctni 음성군은 95명이고 ctni 양성군은 120명이었다. 양군간의연령 (64±1 세, 61±2세 ) 및남 / 여성별빈 54
Tuberculosis and Respiratory Diseases Vol. 59. No. 1, Jul. 2005 Table 1. Clinical characteristics Variables ctni negative patients(n=95) ctni positive patients(n=120) Age(yrs) 64 ± 1 61 ± 2 Male/Female (n) 80/42 64/32 Serum albumin (g/dl) 2.8 ± 0.6 3.0 ± 0.7 Serum bilirubin (mg/dl) 1.7 ± 3.2 1.9 ± 3.1 C-reactive protein (mg/l) 111 ± 69 102 ± 75 SAPS Ⅱ (points) 35 ± 12 42 ± 19* SOFA (points) 6.03 ± 3.37 7.97 ± 4.98** Underlying disorder (n) Hypertension 4 1 DM 17 19 CRF 4 9 Malignancy 13 10 Liver cirrhosis 4 12 Heart failure 1 2 Others 25 30 *, ** p<0.05 compared with ctni negative patients Data are presented as the mean value ± SD or number of patients. Definition of abbreviations : SAPS Ⅱ = Simplified acute physiology score Ⅱ; SOFA= Sequential organ failure assessment; DM=Diabetes mellitus; CRF=Chronic renal failure. Others include chronic obstructive pulmonary disease and cerebral vascular accident Table 2. Diagnosis upon admission to the IC Diagnosis on admission No. of ctni negative patients (%) No. of ctni positive patients (%) Pneumonia COPD exacerbation ARDS Asthma attack Drug intoxication Acute pancreatitis Acute renal failure Rhabdomyolysis Diabetic ketoacidosis Empyema Septic shock of unknown origin Others 50 ( 23) 10 ( 4) 0 ( 0) 9 ( 4) 1 (0.4) 0 ( 0) 1 (0.4) 0 ( 0) 4 ( 1) 14 ( 6) Definition of abbreviations : COPD = Chronic obstructive pulmonary disease; ARDS = Acute respiratory distress syndrome. 42 (19) 13 ( 6) 2 ( 0.9) 0 ( 0) 24 (11) 6 ( 2) 1 ( 0.4) 5 ( 2) 18 ( 8) 도 (80/42명, 64/32명 ) 는유의한차이가없었다. 그러나 SAPS Ⅱ(35 ± 12, 42 ± 19), SOFA 점수 (6.30 ± 3.37, 7.97 ± 4.98) 는 ctni 양성군이 ctni 음성군에비해유의하게높았다 (Table 1)(p<0.05). 입원당시진단명은폐렴, 만성폐쇄성폐질환의급성악화, 약물중독등의순서로많았다 (Table 2). 와 30일째사망률이 ctni 음성군에비해유의하게높았다 (p<0.01) (Figure 1). 또한 ctni 양성군의누적생존률이 ctni 음성군보다유의하게낮았다 (p<0.001) (Figure 2). 3. ctni 양성군에서생존여부에따른 ctni 수치비교 2. ctni 음성군과양성군에서의사망률비교제 10병일째 ctni 양성군의사망률은 29%, 음성군은 12% 이었고, 제 30병일째 ctni 양성군의사망률은 41%, 음성군은 21% 로 ctni 양성군에서병일 10일째 ctni 양성군에서제10병일째사망군의 ctni 수치 (4.5±9.2μg/L) 가생존군의 ctni 수치 (1.8±3.6μg/L) 보다유의하게높았고 (p<0.05), 제30병일째사망군의 ctni 수치 (3.5±7.9μg/L) 도생존군의 ctni 수치 (2.0± 3.9μg/L) 보다유의하게높았다 (p<0.05) (Figure 3). 55
HJ Kim et al.: Cardiac troponin I in noncardiac critically ill patients 50 * ** 40 41 Mortality rate(%) 30 20 10 12 29 21 0 ICU 10th day ctni-negative patients ICU 30th day ctni-positive patients Figure 1. Comparison of the mortality rate between the ctni positive and negative patients at the 10 th and 30 th day after admission to the ICU. *, ** p < 0.01 50 * ** 40 41 Mortality rate(%) 30 20 10 12 29 21 Figure 3. Comparison of the ctni level between the survivors and non-survivors at 10 th and 30 th day after admission of to the ICU in the ctni-positive patients. *,** p < 0.05 5. ctni 수치와질환의중증지수와의상관관계 0 ICU 10th day ctni-negative patients ICU 30th day ctni-positive patients Figure 2. Comparison of the Kaplan - Meier survival cu rves between the ctni-negative and ctni-positive patients. 4. ctni의중환자실 30일째사망에대한민감도와특이도및양성예측도와음성예측도 ctni 수치와질환의중증지수인 SAPS Ⅱ(r=0.25, p<0.001), SOFA (r=0.30, p<0.001) 와는유의한상관관계를보였다 (Figure 5). 6. ctni 양성군에서패혈증의중증도에따른 ctni 수치비교및패혈성쇽과패혈증간의 ctni 양성율비교 중환자실사망과 ctni 사이의 receiver operating characteristics(roc) curve에서 area under the curve (AUC) 는 0.612였고, ctni가 0.75 μg/l 일때, 민감도 55.1%, 특이도 59.2%, 양성예측도 48.2%, 음성예측도 73.6% 로사망률을예측할수있었다 (Figure 4). ctni 양성군에서패혈증, 중증패혈증, 패혈성쇽군간에 ctni 수치는각각 1.20 ± 1.03 μg/l, 2.48 ± 3.55 μg/l, 4.29 ± 9.13 μg/l로패혈성쇽군이패혈증및중증패혈증군에비해높은경향을보였으나통계적으로유의하지는않았다 (p>0.05) (Figure 6). 그러 56
Tuberculosis and Respiratory Diseases Vol. 59. No. 1, Jul. 2005 1.00.75.50 SENSITIVITY.25 0.00 SAPS II ctn I 0.00.25.50.75 1.00 1 - SPECIFICITY Figure 4. ROC curve of ctni and SAPS II for the ICU mortality. ROC curve: receiver operating characteristic curve SAPS II: simplified acute physiology score II ctni: cardiac troponin I Figure 6. Comparison of the ctni level according to the severity of sepsis. *, **, p > 0.05 150 * ctni positive patients (%) 100 50 79 41 0 Septic shock(n=51) Sepsis (n=71) Figure 7. Proportion of ctni positive patients in septic shock and sepsis. * p<0.001 나패혈성쇽환자 51명중 ctni 양성환자는 40명 (78.4%) 이었고, 패혈증및중증패혈증환자 71명중 ctni 양성환자는 29명 (40.8%) 으로패혈성쇽환자에서 ctni 양성율이유의하게높았다 (p<0.001) (Figure 7). 고 찰 ctni는심근손상의매우특이한표지자로서, 심근경색이나불안정성협심증같은급성관상동맥증후 Figure 5. Correlation between the ctni level and the SAPS Ⅱ(A) and SOFA score(b) in the ctni positive patient, p<0.001 군환자에서매우민감하게증가한다. 또한예후와도관련이있다는것은그동안의연구에서잘알려진사실이다 22-24. 57
HJ Kim et al.: Cardiac troponin I in noncardiac critically ill patients 중환자에서심장의기능이상은독립적인예후인자로알려져있다 30. 따라서심근손상의특이지표인 ctni는중환자의초기예후인자로유용할가능성이있다. 본연구에서 215명의비순환기계중환자중 120 명 (55.8%) 에서혈청 ctni가증가하였고, ctni 양성군의사망률이 ctni 음성군보다높았다. 그리고, 혈청 ctni의수치는중증도점수와양의상관관계가있었다. 이는cTnI 가비순환기계중환자의예후인자로사용할수있음을시사하는결과라할수있겠다. 최근여러연구에서 ctni는급성관상동맥증후군뿐만아니라패혈증, 급성폐색전증, 만성폐쇄성폐질환, 만성신부전등과같이비순환기계환자에서도증가한다고보고되고있다 32,33. Guest 등 16 은비순환기계환자 209명의환자중에서 15% 인 32명이 ctni가증가하였고 (ctni > 3.6ng/ml), Ammann등 17 은 58명의비순환기계중환자중에서 55% 인 32명의환자에서 ctni가증가함을보고하였다 (ctni > 0.1ng/mL). 본연구에서는 215명의비순환기계중환자중 56% 인 120명의환자들이 ctni 증가를보여비교적높은 ctni 양성률을보였다. ctni의양성률은연구마다차이가있는데, 이는 ctni의측정체계가아직표준화되어있지않아 ctni 의분별한계수치가연구마다다르기때문이다. 본연구에서는 ctni의분별한계수치를 0.1ng/ ml로하여 Ammann등 17 의연구결과에서보이는 ctni 양성률과비슷한결과를보였다. 패혈증의경우, 본연구에서 122명의환자중 57% 인 69명이혈청 ctni 의증가를보였다. 지금까지여러연구에서패혈증환자의 31%-80% 정도가혈청 ctni 가증가한다고보고되고있는데 16,34,35, 패혈증환자에서혈청 ctni의증가원인은아직정확하게알려지지않고있다. 다만가능하다고생각되는기전으로는 Tumor necrosis factor-α 17,36 나활성산소 (reactive oxygen species) 와같은매개체들에의해유발되는심근독성, 박테리아의내독소에의한심근손상, 미세순환장애에의한심근의허혈과재관류손상등이있다 37. 만성폐쇄성폐질환의경우, 215명의대상환자중 23명이만성폐쇄성폐질환의급성악화로입원하였으며이중에서 13 명 (57%) 에서 ctni 이증가하였다. Baillard 등 26 은 71명의만성폐쇄성폐질환의급성악화를보인 환자의 18% 에서 ctni 증가를보였다고보고하였고그기전으로급성악화에의한호흡일과산소소비의증가, 흉곽내압력의감소로인한좌심실후부하의증가, 폐고혈압의악화, 그리고저산소증과고탄산혈증등이심근손상을유발할것으로추측하였다. 이처럼혈청 ctni는관상동맥질환이아닌비순환기계질환에서도증가한다는것을볼수있다. 본연구에서는 ctni가 0.75 ng/ml 일때민감도가 55.1%, 특이도가 59.1% 로, 비록높지는않았다. 그러나본연구에서 ctni 양성군이음성군에비해제10병일째와제30병일째모두사망률이높았으며, 제10병일째와제30병일째사망군의혈청 ctni 수치가생존군보다높았다. 그리고혈청 ctni와제1병일째 SAPS Ⅱ, SOFA 점수와유의한상관관계가있었다. 이는 ctni 가유용한예후예측인자로사용할수있다는것을시사하는소견이다. Wright 등 18 과 Mehta 등 38 은 ctni가독립적인예후인자로작용한다고보고하였고, 그동안의여러연구에서 ctni는중환자예후와관련이있다고보고되고있다. 하지만 Gunnerwiek 등 29 은 34명의중환자에서 ctni 음성군과양성군간에사망률의차이를찾지못하였다고보고하였지만이연구는조사대상의환자수가적은제한점이있었다. 패혈증환자들에서의 ctni 수치증가여부에관한연구는비교적많이보고가되고있다. 그러나패혈증의중증도에따른 ctni 수치의차이비교에관한연구는거의없다 27. 본연구에서는 ctni 양성군환자에서음성군환자에비해패혈성쇽의비율이유의하게높았다. 패혈증의중증도는사망률과관계가있고 30,39, ctni 수치가질환의중증도및사망률과관계가있으므로 ctni가패혈증에서질환의중증도와예후의지표로사용할수있으리라추측할수있다. 본연구의제한점으로는첫째, 대상환자에서혈청 ctni를연속적으로측정하지않았다는것이다. 심장에서분비되는효소나표지자의측정은시간에따라서기저값과연결되어평가되어야한다 32. 하나의정상혹은비정상의값보다는연속적인값이표지자의농도변화의역동성을반영하고환자의진전되는변화를포착할수있기때문이다 40. 둘째, 대상환자에서급성관상동맥증후군을배제하는데심장초음파나 58
Tuberculosis and Respiratory Diseases Vol. 59. No. 1, Jul. 2005 관상동맥조영술과같이적극적인검사를시행하지않은점이다. 급성관상동맥증후군에는불안정협심증과비 ST분절상승심근경색증이포함되어있기때문에심전도가정상소견이라할지라도상기질환을배제할수없다. 향후상기와같은제한점을고려하여, 독립예후인자로서 ctni 의유용성에대한더많은연구가필요할것으로사료된다. 요약배경 : ctni는심근손상의특이표시자로서급성관상동맥질환에서높은증가는나쁜예후와상관이있다. ctni 의증가는여러가지비심장성중증질환에서도관찰할수있다. 연구자등은비순환기계중환자의예후인자로서 ctni의유용성을조사하였다. 대상및방법 : 2003년 1월부터 2004년 7월까지경상대학교병원내과계중환자실에급성관상동맥증후군이외의중증질환으로입원한 215명의환자 ( 남 :142 명, 여 :73명, 평균나이 :63±2 세 ) 를대상으로하였다. 환자들은중환자실입원 24시간이내에 SAPS Ⅱ와 SOFA점수를산출하였고혈청 ctni를측정하였다. ctni 양성군 ( 0.1µg/L) 과음성군 (<0.1µg/L) 환자의중환자실제 10 병일째와 30병일째사망률을비교하였다. ctni 양성군에서중환자실제 10병일째와 30병일째에혈청 ctni의평균수치를비교하였다. ctni 양성군에서혈청 ctni 수치와 SAPS Ⅱ와 SOFA 점수와의상관관계를조사하였다. 결과 : 1) ctni 양성군환자는 120명 (56%) 이었고음성군환자는 95명 (44%) 였다. 2) 중환자실제 10병일째와 30 병일째의사망률은 ctni 양성군 (29%, 41%) 이음성군 (12%, 21%) 보다유의하게높았다 (p<0.01). 3) ctni 양성군에서중환자실제 10병일째와 30병일째의 ctni 평균수치는비생존군 (4.5 ± 9.2 μg/l, 3.5 ± 7.9 μg/l) 이생존군 (1.8 ± 3.6 μg/l, 2.0 ± 3.9 μg/l) 보다유의하게높았다 (p<0.05). 4) ctni 양성군에서 ctni 수치는 SAPS Ⅱ 점수 (r=0.24, p<0.001) 와 SOFA 점수 (r=0.30, p<0.001) 와유의한상관관계가있었다. 결론 : 혈청 ctni는비순환기계중환자의유용한예후인자가될수있을것으로사료된다. 참고문헌 1. Keene AR, Cullen DJ. Therapeutic intervention sco ring system: update 1983. Crit Care Med 1983;11: 1-3. 2. Lemeshow S, Teres D, Avrunin JS, Pactides H. A comparison of methods of predict mortality of inten sive care unit patients. Crit Care Med 1987;15:715-22. 3. Bone RC, McElwee NE, Eubanks DH, Gluck EH. Analysis of indication for early discharge from the intensive care unit: clinical efficacy assessment. Chest 1993;104:1812-7. 4. Knaus WA, Draper EA, Lawrence DE, Wagner DP, Zimmerman JE. APACHE acute physiology and chr onic health status evaluation: a physiologically based classification system. Crit Care Med 1981;9:591-7. 5. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE Ⅱ: a severity of disease classification system. Crit Care Med 1985;13:818-29. 6. Knaus WA, Draper EA, Wagner DP, Zimmerman JE, Bergner M, Bastos PG, et al. The APACHE Ⅲ prognostic system: risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991;100: 1619-36. 7. Le Gall JR, Loirat P, Alperovitch A, Glaser P, Gr anthil C, Mathieu D, et al. A simplified acute phy siology score for ICU patients. Crit Care Med 1984; 12:975-7. 8. Le Gall JR, Lemeshow S, Saulnier F. A new sim plified acute physiology score (SAPS Ⅱ) based on Eu ropean/north American multicenter study. JAMA 1993 ;270:2957-63. 9. Lemeshow S, Klar J, Teres D, Avrunin JS, Gehlbach SH, Rapoport J, et al. Mortality probability models for patients in the intensive care unit for 48-72 hours: prospective multicenter study. Crit Care Med 1994;22: 1351-8. 10. Le Gall JR, Klar J, Lemeshow S, Saulnier F, Alberti C, Artigas A, et al. The logistic organ dysfunction system: a new way to assess organ dysfunction in the intensive care unit. JAMA 1996;276:802-10. 11. Weiler T, Baldering HJ, Heinrichs W, Schmitz JE. Qualitatssicherung in der intensivemedizine: ergebnisse einer multicenterstudie in deutschland. Anasthesiol Intensivemed Notfallmed Schmerzther 1997;32:372-5. 59
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