http://dx.doi.org/10.4046/trd.2012.72.2.149 ISSN: 1738-3536(Print)/2005-6184(Online) Tuberc Respir Dis 2012;72:149-155 CopyrightC2012. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 기계환기가요구된중증지역사회획득폐렴에서전신스테로이드의투여가예후와합병증의발생에미치는영향 경상대학교의학전문대학원 1 내과학교실, 2 건강과학연구원, 3 예방의학교실이승준 1, 이승훈 1, 김유은 1, 조유지 1,2, 정이영 1,2, 김호철 1,2, 이종덕 1,2, 김장락 2,3, 황영실 1,2 Original Article Systemic Corticosteroid Treatment in Severe Community-Acquired Pneumonia Requiring Mechanical Ventilation: Impact on Outcomes and Complications Seung Jun Lee, M.D. 1, Seung Hun Lee, M.D. 1, You Eun Kim, M.D. 1, Yu Ji Cho, M.D. 1,2, Yi Yeong Jeong, M.D. 1,2, Ho Cheol Kim, M.D. 1,2, Jong Deog Lee, M.D. 1,2, Jang Rak Kim, M.D. 2,3, Young Sil Hwang, M.D. 1,2 1 Department of Internal Medicine, 2 Gyeongsang Institute of Health Sciences, 3 Department of Preventive Medicine, Gyeongsang National University College of Medicine, Jinju, Korea Background: This study is to evaluate the effect of systemic corticosteroid on the clinical outcomes and the occurrence of complications in mechanical ventilated patients with severe community-acquired pneumonia (CAP). Methods: We retrospectively assessed the clinical outcomes and complications in patients with severe CAP admitted to ICU between March 1, 2003 and July 28, 2009. Outcomes were measured by hospital mortality after ICU admission, duration of mechanical ventilation (MV), ICU, and hospital stay. Complications such as ventilator associated pneumonia (VAP), catheter related-blood stream infection (CR-BSI), and upper gastrointestinal (UGI) bleeding during ICU stay were assessed. Results: Of the 93 patients, 36 patients received corticosteroids over 7 days while 57 patients did not receive corticosteroids. Age, underlying disease, APACHE II, PSI score, and use of vasopressor were not different between two groups. In-hospital mortality was 30.5% in the steroid group and 36.8% in the non-steroid group (p>0.05). The major complications such as VAP, CR-BSI and UGI bleeding was significantly higher in the steroid group than in the non-steroid group (19.4% vs. 7%, p<0.05). The use of steroids and the duration of ICU stay were significantly associated with the development of major complications during ones ICU stay (p<0.05). Conclusion: Systemic corticosteroid in patients with severe CAP requiring mechanical ventilation may have no beneficial effect on clinical outcomes like duration of ICU stay and in-hospital mortality but may contribute to the development of ICU acquired complications. Key Words: Pneumonia, Community-Acquired; Adrenal Cortex Hormones; Respiration, Artificial; Mortality; complications 서 론 Address for correspondence: Ho Cheol Kim, M.D. Department of Internal Medicine, Gyeongsang National University College of Medicine, 90, Chiram-dong, Jinju 660-302, Korea Phone: 82-55-750-8684, Fax: 82-55-750-8618 E-mail: hochkim@gnu.ac.kr Received: Sep. 7, 2011 Revised: Oct. 10, 2011 Accepted: Dec. 22, 2011 폐렴은지역사회에서생기는가장흔한감염증중의하나이며질환의중증도에따라다양한임상경과를나타내고예후도많은차이를보인다 1. 대부분의지역사회획득폐렴은적절한항생제의투여로호전되지만기계환기를적용하여중환자실치료가필요한경우에는적절한항생제의투여에도불구하고 30% 이상의높은사망률을보인 149
SJ Lee et al: Steroid in severe community-acquired pneumonia 다 2. 그러므로기계환기가필요한중증지역사회획득폐렴의치료는항생제투여뿐만아니라추가적인보조치료가필요할것으로생각된다 3. 패혈증의예후는전신염증의정도와관련이있다고알려져있고 4 급성호흡곤란증후군이나폐렴에서도폐손상의중등도는체내염증성싸이토카인의정도와관련이있다고알려져있어 5 체내염증을조절하는치료가예후에영향을미칠수있을것으로생각된다. 감염에대한숙주의면역반응을조절하는방법으로전신스테로이드의투여가중증지역사회획득폐렴의예후를개선할수있을것으로생각되어이에대한연구가현재까지진행되어왔다 6-8. 하지만사망률을감소시키는효과에대해서는아직까지이견이있다. 전향적 9 및후향적 10 연구에서중증지역사회획득폐렴에서전신스테로이드의투여가사망률을감소시키고, 사망률의감소와관련된인자로보고되고있지만최근에보고된기계환기를유지하는중증지역사회획득폐렴환자에서는스테로이드의투여가사망률을낮추지못한다고보고되고있다 11,12. 중증지역사회획득폐렴환자에서전신스테로이드의사용이예후에어떠한영향을미치는지에대한연구는많이이루어져있지만합병증의발생에대한보고는상대적으로미비한실정이다. 이에연구자등은중증지역사회획득폐렴으로기계환기를유지하여중환자실에입원한환자를대상으로전신스테로이드사용이예후와합병증의발생에미치는영향을평가하기위해다음과같은연구를시행하였다. 대상및방법 1. 대상환자 2003 년 3월부터 2009 년 7월까지내과중환자실에입원하여기계환기를유지한중증지역사회획득폐렴환자를대상으로하였다. 지역사회획득폐렴의진단은임상적및방사선소견 ( 발열, 기침, 객담, 호흡곤란등의호흡기증상및단순흉부사진또는전산화단층촬영에서폐렴성병변 ) 을기초로하였다. 결핵에의한폐렴환자, 면역결핍바이러스감염자, 면역억제제를복용하고있는환자, 골수또는고형장기이식을받은환자, 혈액종양환자, 기저흉부전산화단층촬영에서심한폐기종을보이는환자및중환자실입실기간이 5일미만인환자는연구대상에서제외하였다. 2. 방법대상환자는전신스테로이드를 7일이상투여한환자와투여하지않은환자로구분하여임상적특성과방사선소견, 예후등을의무기록을통해후향적으로조사하였다. 대상환자들의나이, 성별, 기저질환, 전신스테로이드사용여부및사용기간, 내원시와처음스테로이드를투여한시간간격, 폐렴의원인균, 입원 24시간내 APACHE (Acute Physiology and Chronic Health Evaluation) II 점수, 폐렴중등도점수 (pneumonia severity index, PSI) 13, 저혈압여부, 혈압상승제사용여부를알아보았다. 환자의예후와관련된인자로기계환기적용기간, 중환자실및병원재원기간, 병원내사망여부를조사하였다. 호전되어퇴원한경우는생존한것으로, 호전없이퇴원한경우는사망한것으로판단하였다. 각각의환자에서중환자실입원기간동안발생한합병증을의무기록으로확인하였다. 합병증으로는인공호흡기연관폐렴, 상부위장관출혈, 카테터관련혈행성감염들을확인하였다. 인공호흡기연관폐렴의진단은방사선소견에서새로운폐침윤이생기거나기존의폐침윤이증가하면서임상적으로감염의증거 ( 발열, 객담의증가, 백혈구증가 ) 가있고또한균이동정된경우에진단하였다 14. 카테터관련혈행성감염의진단은혈액배양에서균이동정되고같은균이카테터팁에서배양된경우에진단하였다 15. 상부위장관출혈은내시경에서출혈을확인한경우또는내시경으로확인이안된경우에는비위영양튜브에서출혈이확인되고임상적으로상부위장관출혈의증상및징후가있는경우진단하였다 16. 3. 통계처리자료는평균과표준편차로표시하였다. 양군간의임상적특성은 Student t-test 또는 Mann-Whitney U test를이용하여비교하였고양군간의각특성에따른사망률차이또는합병증의발생빈도, 합병증의발생과관련된인자등의차이는 chi-square test 또는 Fisher's exact test 를이용하였다. 또한사망여부와합병증의발생과관련된위험인자는다변량로지스틱회귀분석으로평가하였다. p값이 0.05 이하인경우의미있는것으로판단하였고 SPSS version 18.0 (SPSS Inc., Chicago, IL, USA) 통계프로그램을이용하였다. 150
Tuberculosis and Respiratory Diseases Vol. 72. No. 2, Feb. 2012 결과총 93명의환자가포함되었으며이중 36명이전신스테로이드를 7일이상투여하였고 57명은스테로이드를투여하지않았다. 양군환자들의나이, 성별, 기저질환의유무, 원인균동정빈도, APACHE II, 폐렴중증도점수, 내원시저혈압의유무, 혈압상승제사용빈도등은유의한차이가없었다. 스테로이드를투여한환자군에서내원일과스테로이드사용시작일사이의평균기간은약 1.4±1.5일이었고처음사용한평균용량은 193.3±181.3 mg/day (30 1,000 mg) 이었다 (Table 1). 폐렴의원인균으로가장많은것은 Streptococcus pneumoniae로모두 20예에서동정되었으며이중소변항원양성으로나온경 우가 13예를차지하였다. 균이동정된 40명의환자에서처음사용한항생제가적절했던경우는 32예 (80%), 적절하지않았던경우는 8예 (20%) 이었고이들환자의사망률은각각 31.3%, 37.5% 로유의한차이는없었다 (p>0.05). 스테로이드를투여한군과투여하지않은군사이의중환자실재원기간과기계환기유지기간은스테로이드를투여한군에서유의하게길었으며, 사망률은스테로이드를투여한군이 30.5%, 투여하지않은군이 36.8% 로스테로이드를투여한군이낮았으나통계적인유의성은없었다 (Table 2). 중환자실재원기간동안발생한합병증을보면스테로이드를투여한군은인공호흡기연관폐렴이 3예, 카테터관련혈행성감염 2예, 상부위장관출혈 2예등총 7예의 Table 1. Baseline characteristics of the study population Patients not received corticosteroid (n=57) Patients received corticosteroid (n=36) p-value Age, yr 63.98±15.5 65.19±16.7 0.345 Sex, M:F 42:15 26:10 1.000 Duration of corticosteroid use, day - 11.97±7.3 Interval from admission and corticosteroid received, day 1.41±1.5 Initial dose of corticosteroid used, mg 193.3±181.3 Underlying disease 46 (80.7) 27 (76) 0.607 Causative microorganisms 20 (35.1) 11 (36.1) 1.000 Streptococcus pneumoniae 13 7 Klebsiella pneumoniae 5 3 Staphylococcus aureus 1 2 Acinetobacter baumanii 1 E. coli 1 APACHE II 19.89±5.7 20.06±6.2 0.622 PSI score 108.26±35.5 105.1±33.3 0.884 PSI>class IV V 37 (64.9) 22 (61.1) 0.826 Systolic BP (<90 mm Hg) at admission 14 (25) 11 (29.8) 0.644 Values are presented mean±sd and number (%). Data was calculated with t-test and chi-sqaure test. APACHE: acute physiology and chronic health evaluation; PSI: pneumonia severity index; BP: blood pressure; SD: standard deviation. Table 2. The patients' outcomes Patients not received corticosteroid (n=57) Patients received corticosteroid (n=36) p-value Duration of hospital stay, day 24.3±11.8 29.19±15.5 0.084 Duration of ICU stay, day 14.05±8.7 15.64±11.2 0.016 Duration of MV, day 13.16±9.1 14.11±10.9 0.034 In hospital mortality, n (%) 21/57 (36.8) 11/36 (30.5) 0.655 Values are presented mean±sd unless otherwise indicated. Data was calculated with t-test and chi-square test. MV: mechanical ventilation; ICU: intensive care unit; SD: standard deviation. 151
SJ Lee et al: Steroid in severe community-acquired pneumonia Table 3. The development of complications in the ICU Patients not received corticosteroid (n=57) Patients received corticosteroid (n=36) p-value Ventilator associated pneumonia 2 (3.5) 3 (8.3) 0.372 Catheter-related blood stream infection 0 2 (5.5) 0.147 Gastrointestinal bleeding 1 (1.7) 2 (5.5) 0.557 Total, n (%) 3 (7) 7 (19.4) 0.042 Values are presented as number (%). Data was calculated with chi-square test. ICU: intensive care unit. Table 4. Factors associated with increased hospital mortality by using multivariate analysis Factors OR 95% CI p-value Age, >65 7.07 1.00 49.64 0.049 Sex 1.98 0.57 6.87 0.28 APACHE II 0.86 0.77 0.98 0.018 PSI score 0.99 0.97 1.01 0.539 Underlying disease 2.54 0.61 10.54 0.199 Hypotension 0.97 0.29 3.16 0.961 Bactermia 0.52 0.06 4.26 0.54 Bilateral or multi-lobar involvement 0.55 0.16 2.38 0.42 Use of corticosteroid 1.88 0.79 7.58 0.248 Data was calculated with multivariate logistic regression analysis. OR: odds ratio; CI: confidence interval; APACHE: acute physiology and chronic health evaluation; PSI: pneumonia severity index; ICU: intensive care unit. 합병증이발생하였고, 스테로이드를투여하지않은군에서는인공호흡기연관폐렴 2예, 상부위장관출혈 1예등총 3예에서합병증이발생하여스테로이드를투여한환자군이유의하게전체합병증의빈도가높았다 (Table 3). 폐렴의원인균은 methicillin-resistant staphylococcus aureus (MRSA) 가 2예, Acinetobacter baumani 와 Pseudomonas auroginosa 가각각 1예이었고 1예는임상적으로폐렴이의심되었지만균이동정되지않았다. 스테로이드를사용한군에서합병증의발생여부에따른최초사용스테로이드의평균용량은각각 171.4±80.7 mg, 195.2±190.4 mg으로차이가없었지만, 합병증이발생환환자에서스테로이드사용은평균기간이 16.6±12.8 일로합병증이발생하지않은환자의 10.9±5.1 일보다유의하게길었다 (p <0.05). 다변량분석으로확인한사망과관련된위험인자중에서스테로이드사용여부는사망률과관련이없었으며임상양상에서 APACHE II 점수와 65세이상의고령이사망률과의미있게관련이있었다 (Table 4). 중환자실재원기 Table 5. Factors associated with the development of major complications in ICU stay by using multivariate analysis Factors OR 95% CI p-value Age, >65 0.125 0.01 1.09 0.06 APACHE II 0.15 0.05 1.25 0.227 PSI score 1.00 0.98 1.07 0.294 Hypotension 0.48 0.07 8.7 0.784 Use of corticosteroid 5.04 1.11 99.12 0.04 Duration of ICU stay 2.39 1.01 1.73 0.04 Duration of MV 0.52 0.68 1.1 0.235 Data was calculated with multivariate logistic regression analysis. OR: odds ratio; CI: confidence interval; APACHE: acute physiology and chronic health evaluation; PSI: pneumonia severity index; ICU: intensive care unit; MV: mechanical ventilation. 간동안합병증의발생과관련된위험인자로스테로이드사용여부와중환자실재원기간이의미있는인자였다 (Table 5). 152
Tuberculosis and Respiratory Diseases Vol. 72. No. 2, Feb. 2012 고찰본연구는기계환기가요구되는중증의지역사회획득폐렴환자에서보조치료로서스테로이드의투여가사망률의감소를가져오지못하고오히려중환자실재원기간동안주요합병증의발생을증가시킬수있다는것을보여준다. 중증지역사회획득폐렴에서스테로이드의사용이환자의예후에미치는영향에대해서는현재까지많은임상연구가이루어졌으며사망률을감소시키는효과에대해서는이견이있다. Confalonieri 등 9 이보고한전향적다기관연구에서는 7일간의하이드로코티손 (240 mg/day) 의정맥투여가의미있는사망률의감소를보인다고보고하였고, 308명의중증환자를대상으로한후향적연구에서도스테로이드의투여가사망률의감소와관련된독립인자로주장하고있다 10. 그러나전자의연구는대상환자가 46명으로많지않고, 하이드로코티손을투여한 23명의환자중에서 7명만이침습적기계환기를적용하였으며, 후자의연구도대상환자중에서 11명만이중환자실에입원하였고 30% 이상이만성폐쇄성폐질환환자였다. 이외다른연구들을통해중증의지역사회획득폐렴에서전신스테로이드의효과가어느정도입증되었지만전체대상환자수와기계환기를유지한비율이적다는문제점을가지고있다 17,18. 본연구에포함된환자는모두침습적기계환기를유지하였으며흉부전산화단층촬영이나폐기능검사에서만성폐쇄성폐질환이나심한폐기종을보이는환자는대상에서제외하였다. 만성폐쇄성폐질환의급성악화시에는전신스테로이드의사용이기계환기적용가능성과중환자실재원기간을줄이고동시에사망률을감소 19 시키는것으로알려져있기때문에기저폐질환이없는지역사회획득폐렴환자에서스테로이드의효과를평가하기위해서만성폐쇄성폐질환환자는대상에서제외하였다. 본연구에서는스테로이드의투여가사망률의감소를보여주지못하였는데최근발표된후향적연구들에서도비슷한연구결과를보여주고있다. 각각 97명 11, 110명 12 의침습적기계환기가요구된중증지역사회획득폐렴환자에서스테로이드의투여가사망률을감소시키는효과는없는것으로연구되었다. 최근보고된전향적무작위이중맹법연구에서도 40 mg 프레드니졸론을 7일간투여한지역사회획득폐렴환자는완치율증가나사망률의감소, 재원기간단축등의효과는없었으며오히려임상적으로호전되다가다시악화를보이는후기치료실패율이높은 것으로보고되었다 20. 스테로이드사용량과임상적효과의관점에서는이견이있을것으로생각된다. 효과를입증한몇몇임상연구에서사용한스테로이드의용량은하루 40 mg에서 240 mg 정도로다양하며 6 효과가입증되지않은임상연구의경우에도사용한용량은비슷한것으로나와있다 11,12,20. 하지만중증의급성호흡곤란증후군환자에서스테로이드투여로임상적호전을보인연구에서는하루사용량은 240 mg 정도로비슷하지만약 4주간의기간을사용한특징이있다 21. 장기간의전신스테로이드사용은 2차감염, 상부위장관출혈, 혈당증가, 근위축, 백내장등의다양한합병증발생을유발할수있다 22. 중환자실에서기계환기를유지하는환자는다양한감염에노출될가능성이많으며이런환자에서일정기간의스테로이드사용은감염과관련된합병증의발생을증가시킬수있을것으로생각된다. 본연구에서는스테로이드를사용한환자군에서인공호흡기연관폐렴과카테터관련혈행성감염과같은감염합병증의빈도가높은경향을보였고상부위장관출혈과같은주요합병증의발생도높은경향을보였다. 전신스테로이드의투여가지역사회획득폐렴환자에서합병증의발생을증가시키는지에대해서는이견이있다. Confalonieri 등 9 은지역사회획득폐렴환자에서스테로이드의투여는인공호흡기연관폐렴, 신부전, 상부위장관출혈등의주요합병증의발생을유의하게감소시킨다고보고하였고, 당내성또는전해질이상등의합병증발생에도유의한영향이없다고보고하고있다 18. 최근의전향적연구에서는 2차감염의빈도가각각 2.1%, 1.9% 로의미있는차이는없는것으로보고하였지만 20, 기계환기가요구된환자중에서중환자실획득감염의빈도가각각 38%, 26% 로스테로이드를사용한환자에서높은경향을보인것으로보고하고있다 11. 기계환기를유지하는환자에서는인공호흡기연관폐렴의위험도가상당히증가하기때문에기계환기를유지하는중증의폐렴환자에서스테로이드의사용이감염의발생을증가시키는지는향후더연구가필요할것으로생각된다. 본연구에서스테로이드를투여한환자군이투여하지않은환자군에비해중환자실재원기간과기계환기유지기간이유의하게길었다. 이것은스테로이드를사용한환자에서합병증의발생이증가하였으므로그에따른재원일수의증가에의한것으로생각할수있으며또한치료를받지않은환자에서조기사망에따른재원기간과기계호흡기유지기간의단축에기인할수있다. 다른측면으로 153
SJ Lee et al: Steroid in severe community-acquired pneumonia 는중증폐렴에서스테로이드의투여가조기사망률을감소시키는효과도있다고판단할수있다. 본연구는몇가지제한점이있는것으로생각된다. 첫번째는중환자실에서발생한합병증을후향적으로평가하여정확한진단에문제가있었을것으로생각된다. 인공호흡기연관폐렴의경우에는폐렴이발생하기전에대부분항생제를사용하므로원인균이증명이되지않고임상적으로진단되는경우가많은데본연구에서는대부분균이동정된폐렴환자만을포함하여대상환자수가적게측정되었을가능성이있다. 두번째는각환자마다스테로이드를사용한기간이나용량, 처음사용한시점등이일정하지않다는것이다. 스테로이드의사용은감염증에서숙주의면역반응을억제하는역할을하지만폐렴의발생시기가각각다르고염증반응의정도차이가있으므로그에따른적절한용량과기간, 시작시점에대한정해진기준이필요할것으로생각된다. 일반적으로스테로이드투여는염증반응이심한질병의초기보다는그이후에사용하는문제점이있다. 세번째로대상환자의상당수에서내원시저혈압이동반되었지만부신기능을평가하지않았다. 패혈증이나패혈증쇼크환자에서상대적부신기능저하는약 30% 의환자에서있는현상으로상대적부신기능의저하가있는환자에서는스테로이드투여가사망률의감소를가져오는것으로연구되어있다 23. 마지막으로가장흔하게발생하는합병증으로고혈당이나근위축과같은합병증에대한언급이부족하다는것이다. 마지막으로스테로이드의투여에대해정해진기준이없이담당의의주관적판단에따라결정하였다는것이다. 이것은환자의상태가좋지않은경우에보조요법으로스테로이드를투여하는경향이있으므로환자의처음상태가예후와합병증의발생에영향을미쳤을가능성이있다는것이다. 하지만본연구에서스테로이드를투여한환자와투여하지않은환자의질환의중등도는차이가없었으며스테로이드를투여한시점이대부분내원후 3일이내였다. 결론적으로본연구에서는기계환기가필요한중증지역사회획득폐렴환자에서스테로이드의투여는환자의사망률감소를가져오지못하고중환자실재원기간동안합병증의발생을증가시키는문제가있을것으로생각된다. 하지만스테로이드의사용과합병증의발생에대해서는전향적인대규모연구가필요할것으로생각된다. 참고문헌 1. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730-54. 2. Woodhead M, Welch CA, Harrison DA, Bellingan G, Ayres JG. Community-acquired pneumonia on the intensive care unit: secondary analysis of 17,869 cases in the ICNARC Case Mix Programme Database. Crit Care 2006;10 Suppl 2:S1. 3. Siempos II, Vardakas KZ, Kopterides P, Falagas ME. Adjunctive therapies for community-acquired pneumonia: a systematic review. J Antimicrob Chemother 2008; 62:661-8. 4. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Proversus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 2000;181:176-80. 5. Bauer TT, Montón C, Torres A, Cabello H, Fillela X, Maldonado A, et al. Comparison of systemic cytokine levels in patients with acute respiratory distress syndrome, severe pneumonia, and controls. Thorax 2000; 55:46-52. 6. Salluh JI, Póvoa P, Soares M, Castro-Faria-Neto HC, Bozza FA, Bozza PT. The role of corticosteroids in severe community-acquired pneumonia: a systematic review. Crit Care 2008;12:R76. 7. Annane D, Meduri GU. Corticosteroids for community-acquired pneumonia: time to act! Crit Care 2008;12: 166. 8. Sibila O, Agustí C, Torres A. Corticosteroids in severe pneumonia. Eur Respir J 2008;32:259-64. 9. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005;171: 242-8. 10. Garcia-Vidal C, Calbo E, Pascual V, Ferrer C, Quintana S, Garau J. Effects of systemic steroids in patients with severe community-acquired pneumonia. Eur Respir J 2007;30:951-6. 11. Salluh JI, Soares M, Coelho LM, Bozza FA, Verdeal JC, Castro-Faria-Neto HC, et al. Impact of systemic corticosteroids on the clinical course and outcomes of patients with severe community-acquired pneumonia: a cohort study. J Crit Care 2011;26:193-200. 154
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