07-07김재승

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1 대한응급의학회지제 22 권제 1 호 Volume 22, Number 1, February, 2011 원 저 패혈증쇼크환자에서생존에영향을미치는조기예후인자 서울대학교의과대학응급의학교실 김재승 서길준 권운용 이재혁 김경수 박명희 Early Prognostic Factors of Patients with Septic Shock Jae Seong Kim, M.D., Gil Joon Suh, M.D., Woon Yong Kwon, M.D., Jae Hyuk Lee, M.D., Kyung Su Kim, M.D., Myung Hee Park, M.D. Purpose: To identify prognostic factors during the first 6- hour period of therapy associated with the 28-day survival of patients with septic shock. Methods: We enrolled consecutive patients admitted to the emergency intensive care unit with septic shock. According to the mortality within 28 days, enrolled patients were divided into survivor and non-survivor groups. We compared patients data obtained at 6 hours after therapy between the two groups. Multivariate analysis was performed to find prognostic factors during the first 6 hours of therapy that were associated with the 28-day survival. Results: Among the 138 enrolled patients, 78 survived and 60 died. Amount of fluid which was infused during the first 6 hours of therapy (odds ratio (OR)=1.005; 95% CI, ; p=0.002) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (OR=0.859; 95% CI, ; p=0.005) were independently associated with 28-day survival of patients with septic shock. Area under curve (AUC) of fluid volume for predicting 28-day survival was (95% CI, ) and the optimal cutoff value was 3000 ml. In the survival analysis, patients who received more than 3000 ml of fluid during the first 6 hours of therapy displayed a higher survival rate than patients receiving <3000 ml (p<0.001). 책임저자 : 서길준서울특별시종로구대학로 101 서울대학교의과대학응급의학교실 Tel: 02) , Fax: 02) 접수일 : 2010년 11월 6일, 1차교정일 : 2010년 12월 6일게재승인일 : 2011년 1월 5일 44 Conclusion: The amount of fluid infused during the first 6 hours of therapy was independently associated with 28-day survival in patients with septic shock. Key Words: Patients, Septic Shock, Fluid therapy, Survival Department of Emergency Medicine, Seoul National University College of Medicine 서 패혈증에대한정의는매우다양하게내려지고있으나일반적으로감염에대한개체의복잡하고유해한반응으로정의된다 1). 패혈증으로인한개체의손상은개체의조절능력을넘어서는전신성염증반응증후군 (systemic inflammatory response syndrome, SIRS) 에의하여발생하게된다. 이러한전신성염증반응증후군이감염에의해발생했을때패혈증으로정의할수있으며패혈증으로인한조직관류장애로인해장기부전 (organ dysfunction) 이발생하면중증패혈증으로, 적절한수액공급에반응하지않는저혈압이발생하면패혈증쇼크로정의할수있다 2,3). 패혈증쇼크의병태생리및치료에관한수십년간의연구에도불구하고패혈증쇼크환자의사망률은뚜렷한감소를보이지않으며비심혈관계중환자실의가장흔한사망원인으로보고되고있다 4-6). 패혈증진단후최초 6시간내에일정범위의중심정맥압 (8~12 mmhg), 평균동맥압 (65~90 mmhg), 및중심정맥산소포화도 (> 70%) 의달성을목표로하는조기목표지향적치료 (early goal-directed therapy, EGDT) 는현재까지보고된패혈증에대한치료방법중중증패혈증및패혈증쇼크환자의생존을향상시킬수있는효과적인방법으로알려져있다 7,8). 그러나, 국내외에서시행된조기목표지향적치료의효과를평가하고자하는연구들에서패혈증쇼크환자들에게조기목표지향적치료를적용하였을때조기목표달성여부외에도초기수액투여량의증가, 적극적인수혈등의조기목표달성을위한실제적인치료의변화, 패혈증쇼크 론

2 김재승외 : 패혈증쇼크환자에서생존에영향을미치는조기예후인자 / 45 진단후항생제투여까지의시간의감소등의이차적인효과들이생존향상에영향을미칠수있음이보고되고있다 9-14). 이에저자들은본연구를통해응급센터에서패혈증쇼크로진단받은후응급중환자실로입원한환자들의 28일생존향상과관련된최초 6시간동안의예후인자를찾아보고자하였다. 대상과방법 1. 연구대상본연구는 2006년 1월부터 2007년 12월까지본원응급센터를통해응급중환자실에입원한패혈증쇼크환자들을대상으로하였다. 감염으로인하여전신성염증반응증후군이발생한환자들중초기 30분간 20 ml/kg의생리식염수를정주한후에도수축기혈압이 90 mmhg 이상으로유지되지않을경우패혈증쇼크환자로정의하였다 1). 18 세이하의소아, 패혈증쇼크진단 24시간이내에사망한환자, 집중치료거부에대한사전의료지시서가작성된환자는본연구에서제외하였다. 2. 패혈증쇼크치료지침본원응급센터및응급중환자실에서의패혈증쇼크환자에대한조기목표지향적치료는 2006년 7월부터지침개발및시범적용을시행하였으며 8개월간의적응기간을거친후 2007년 3월부터본격적으로시행하였다. 조기목표지향적치료지침이도입되기전에는표준화된치료지침없이담당의사의주관적인경험에따라치료가시행되었다. 조기목표지향적치료지침이도입된후에는다음과같은치료가시행되었다. 패혈증쇼크의심환자가응급센터에발생하면즉시 30분간의 20 ml/kg의생리식염수정맥투여를시작하였으며동시에응급의학과전문의 3인, 전공의 2인으로구성된응급중환자실진료팀에게인계되었다. 생리식염수정맥투여에도불구하고수축기혈압이 90 mmhg 이상으로유지되지않으면중심정맥카테터삽입을시행하여조기목표지향적치료를시작하면서즉시응급중환자실로입원하였다. 균배양검사시행후가능한빨리광범위항생제를투여하였으며중심정맥압, 평균동맥압, 중심정맥산소포화도를일정간격으로감시하며조기목표달성을위해수액투여, 승압제 (norepinephrine/ dopamine) 투여, 수혈, 강심제 (dobutamine) 투여를최초 6시간동안시행하였다. 6시간이후에는 2004년발표된중증패혈증및패혈증쇼크환자를위한패혈증생존캠페인의국제치료지침에따른표준화된치료를시행하였다 15). 3. 자료수집및분석대상환자의성별, 연령, 감염병소, 인공호흡기적용여부, 초기 24시간동안의중증도지수 (Acute Physiology and Chronic Health Evaluation II score, APACHE II score) 를수집하였으며조기목표지향적치료의적용여부, 조기목표달성여부, 패혈증쇼크진단후항생제투여까지의시간, 최초 6시간동안의수액투여량, 적혈구수혈량및체중당소변량을기록하였다. 치료결과로 28일생존여부를확인하여대상환자들을 28일사망군및 28일생존군으로분류하여비교분석하였다. 이외에도인공호흡기적용기간, 중환자실체류기간, 병원입원기간을추가로분석하였다. 조기목표의항목들을측정하지못한환자들은조기목표를달성하지않은것으로간주하였다. 4. 통계검정두군간의비교를위한통계검정은연속형변수들은평균값 ± 표준편차의형태로기술하였으며 student s t-test 를사용하여분석하였다. 비연속형변수들은빈도수 (%) 로기술하였으며 Pearson s chi-square test 또는 Fisher s exact test를사용하여분석하였다. 패혈증환자들의 28 일생존과관련된독립적예후인자를찾아내기위하여로지스틱회귀분석을통한다변량분석을시행하였다. 또한 receiver operating characteristic (ROC) 곡선을통해위에서확인된예후인자의 28일생존예측력을평가하였으며 Kaplan-Meier 생존분석및로그순위검정을시행하여예후인자에따른 28일동안의생존율의차이를비교하였다. 모든통계검정은 SPSS version 17.0 for Windows (SPSS, Chicago, IL, USA) 를이용하여시행하였으며 p값이 0.05 미만인경우를통계적으로유의한것으로간주하였다. 결과총 138명의환자중사망군은 60명 (43.5%), 생존군은 78명 (56.5%) 이었다 (Fig. 1). 두군을비교하였을때, 평균연령과성별, 패혈증쇼크를유발한감염병소에서유의미한차이는없었다. 인공호흡기사용환자비율 (76.7 vs. 47.4%, p=0.001) 과중증도지수 (APACHE II score 32.83±8.23 vs ±7.71, p<0.001) 는사망군에서생존군에비해유의하게높았다 (Table 1). 조기목표지향적치료를적용한환자의비율, 조기목표 ( 중심정맥압, 평균동맥압, 중심정맥산소포화도 ) 의달성여부와최초 6시간동안의체중당소변량및수혈량은두군간에통계적으로의미있는차이가없었다 (Table 1). 패혈증쇼크진단후

3 46 / 대한응급의학회지 : 제 22 권제 1 호 2011 항생제투여까지의시간은사망군보다생존군에서짧았으며 (115.90±49.90 vs ±19.50 분, p<0.001) 최 Fig. 1. Enrolled patients. EICU, emergency intensive care unit 초 6시간동안의수액투여량 ( ± vs ± ml, p<0.001) 은사망군보다생존군에서많았다 (Table 1). 인공호흡기적용일수, 중환자실재실일수, 병원재원일수에서두군간에통계적으로유의한차이는관찰되지않았다. 28일생존향상에대한다변량분석을시행하였을때, 중증도지수 (APACHE II score) (Odds ratio [OR]=0.859, 95% Confidence intervals [CI], , p=0.005) 와최초 6시간동안의수액투여량 (OR=1.005, 95% CI, , p=0.002) 이독립적으로관련이있었다 (Table 2). ROC curve를통해최초 6시간동안의수액투여량의 28일생존예측력을평가하였을때, area under curve (AUC) 가 0.940(95% CI, ) 로나타나높은예측력을보이고있었다 (Fig. 2). 적정 cutoff value를 3000 ml로선택하였을때민감도는 79.5%, 특이도는 86.0% 로나타났다. 대상환자들을최초 6시간동안투여한수액량이 3000 ml 이상인환자군과 3000 ml 이하인 Table 1. Univariate analysis Non-surv (n=60) Surv (n=78) p-value Patients characteristics Age (years) ± ±12.95 <0.984 Male gender, n (%) 40 (66.7) 49 (62.8) <0.640 Infection source, n (%) <0.332 Pulmonary, n (%) 28 (46.7) 28 (35.9) Gastrointestinal 08 (13.3) 09 (11.5) Genitourinary 05 (08.3) 14 (17.9) Hepatobiliary 08 (13.3) 17 (21.8) Others 08 (13.3) 06 (07.7) Unknown 03 (05.0) 04 (05.1) MV use 46 (76.7) 37 (47.4) <0.001 APACHE II score 32.83± ±7.71 <0.001 EGDT protocol application 19 (31.7) 31 (39.7) <0.328 Goal achievement at 6 hours CVP (mmhg) achieved 28 (46.7) 47 (60.3) <0.124 MAP (mmhg) achieved 54 (90.0) 74 (94.9) <0.331 ScvO 2 (%) achieved 24 (40.0) 35 (44.9) <0.566 Time to antibiotics use (min)* ± ±19.50 <0.001 Fluid volume for 6 hours (ml)* ± ± <0.001 Urine output for 6 hours (ml/kg) 03.96± ±1.45 <0.837 Packed RBC for 6 hours (pack) 00.69± ±1.40 <0.216 Outcomes Duration of MV use (days) 04.36± ±6.19 <0.704 ICU length of stay (days) 06.57± ±6.55 <0.311 Hospital length of stay (days) ± ±21.34 <0.104 Non-surv: non survivors on day 28, Surv: survivors on day 28, MV: mechanical ventilator, APACHE II score: the Acute Physiology and Chronic Health Evaluation II score, EGDT: early goal-directed therapy, CVP: central venous pressure, MAP: mean arterial pressure, ScvO 2: central venous oxygen saturation, RBC: red blood cells, ICU: intensive care unit. * Significantly different between the non-survivors and survivors.

4 김재승외 : 패혈증쇼크환자에서생존에영향을미치는조기예후인자 / 47 환자군으로다시구분하여 28일동안의생존율의변화를비교하였을때, 최초 6시간동안 3000 ml 이상의수액을투여받은환자군의생존율이유의하게높았다 (p<0.039) (Fig. 3). 고찰연구결과중증도지수와함께최초 6시간의수액투여량이패혈증쇼크환자들의 28일생존과독립적으로연관이있었다. 또한, ROC curve를통해최초 6시간의수액투여량이생존을예측하는데유용하게사용될수있음을확인하였으며, 6시간동안 3000 ml 이상의수액을투여받은환자들의생존율이유의하게높게관찰되었다. 패혈증쇼크및중증외상환자를대상으로한많은기존연구에서도승압제의투여등다른처치이전에초기에다량의수액을투여할경우사망을감소시킬수있음이보고되고있다 8,11,16,17). 투여모델을통한연구에서적절한수액투여는염증성매개물질인 tumor necrosis factor-α(tnf-α), interleukin-1β(il-1β), IL-8의혈중농도를감소시킴과동시에항염증물질인 IL-10의농도를증가시킴이보고되었다 18). 적절한수액처치는혈액의점도를감소시킴으로써미세순환을향상시킬수있으며염증반응의진행에중요한역할을하는안지오텐신 II 및카테콜아민의활성화를억제할수있다. 이와같은수액처치의항염증효과는내독소투여로인한증상의발현과발열을억제하며동반되는혈역학적지표의안정에도도움이되며패혈증발생 1 시간후부터 6시간에가장잘나타나는것으로보고되었다 18,19). 다른연구에서는적절한수액처치를통해승압제, 스테로이드, 침습적모니터링의필요도함께감소한다고보고하고있다 20). 본연구에서는생존군과사망군사이의최초 6시간동안의수액투여량은의미있는차이를보였으나체내혈장량을 적절한초기수액처치는패혈증쇼크환자의초기염증반응의진행을억제하는것으로알려져있다. 인간내독소 Fig. 2. Receiver operating characteristic (ROC) curve of 6- hour fluid volume for 28-day survival. AUC: area under curve. Fig. 3. Survival at 28 days after the diagnosis of septic shock. The Kaplan-Meier survival curve shows that the fluid volume (>3000 ml) for initial 6 hours improves 28-day survival of patients with septic shock. *p=0.039 vs. the patients with fluid volume for 6 hours < 3000 ml. Table 2. Multivariate analysis for 28-day survival Odds ratio 95% Confidence interval p-value MV use APACHE II score* Time to antibiotics use (min) Fluid volume for 6 hours (ml)* MV, mechanical ventilation; APACHE II, Acute physiology and chronic health evaluation II * Independently associated with 28-day survival of patients with septic shock

5 48 / 대한응급의학회지 : 제 22 권제 1 호 2011 반영하기위해목표로설정된중심정맥압의달성여부는통계적으로유의한차이를보이지않았다. 이는위에서언급한바와같이혈장량의증가이외의수액처치의독립적인항염증효과또는중증패혈증쇼크환자의체내혈장량의증가를중심정맥압이적절히반영하지못하기때문으로사료된다. 중심정맥압은조기목표지향적치료프로토콜에서체내혈장량의적절성을판단하는데사용하고있으나다음과같은문제가있다. 신체자세, 흉곽압의변화, 호기말양압의존재, 호흡주기에따라크게변하며, 좌심실전부하를정확하게반영하지못한다 21-23). 양극단의값을가지는경우를제외하고대부분의경우에중심정맥압은좌심실전부하의이상여부를감별하지못하며, 수액투여에의한중심정맥압의변화역시체내혈장량의증가를통한심박출량의변화를반영하지못하는것으로알려져있다 24). 중심정맥압의이러한제한점들을극복하기위해여러연구에서비침습적인심박출량측정방법들을적용한조기목표지향적치료가제안되고있다 25). 조기목표지향적치료효과를평가한많은기존연구들에서조기목표지향적치료를시행할경우초기의수액투여량이증가함이보고되고있다. 본연구에서도 138명의대상환자들중 50명 (36.2%) 에서조기목표지향적치료가적용되었다. 조기목표지향적치료가적용된환자의중증도지수 (APACHE II score) 는미적용된환자에비해유의하게높았다 (29.06±9.10 vs 25.53±9.57, p= 0.034). 조기목표지향적치료가적용된 50명의환자들중중심정맥압 40명 (80.8%), 평균동맥압 50명 (100%), 중심정맥산소포화도 39명 (78.0%) 에서조기목표의달성이이루어졌다. 그러나조기목표지향적치료적용의영향을분석하였을때초기의수액투여량외에조기목표의달성여부가통계적으로환자의생존향상과직접적인관련을보이지는못했다. 이는조기목표의달성여부및최초 6시간동안이루어지는실제적인치료의변화중적극적인수액처치가패혈증쇼크환자의생존향상을위한가장중요한예후인자임을시사한다. 또한조기목표지향적치료를적용할경우최초 6시간동안의다량의수액투여가다른무엇보다도선행되어야함을시사하고있다. 다만패혈증쇼크환자들은그개인마다가지고있는생리적능력이다르고패혈증의정도도차이가있을수있으며초기치료중필요한수액투여량은환자의상태에매우다양하게요구될수있으므로이를예측및평가하는데있어서는조기목표를지표로활용하는것이도움이될수있을것이다. 본연구는다음과같은제한점을지닌다. 첫째, 1개의응급센터및응급중환자실에서시행된후향적연구이며대상환자수가적어연구결과를일반화시키기어렵다. 둘째, 자료수집의한계로인해조기목표지향적치료를적용한패혈증쇼크환자들의 28일생존에영향을미치는예후인자로써승압제와강심제의사용을같이분석하지못하였 다. 셋째, 조기목표지향적치료를적용하지않은환자들도포함되어있어상당수의환자들에서표준화된방법으로중심정맥압과중심정맥산소포화도를측정하지못하여정량적인조기목표의수치를비교할수없었다. 결 최초 6시간동안의수액주입량이응급센터에서패혈증쇼크로진단받은후응급중환자실로입원한환자들의 28 일생존향상과독립적으로관련이있었다. 론 참고문헌 01. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit care med 2003;31: Bone RC, Sprung CL, Sibbald WJ. Definitions for sepsis and organ failure. Crit Care Med 1992;20: Matot I, Sprung CL. Definition of sepsis. Intensive Care Med 2001;27 Suppl 1:S Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to Crit Care Med 2007;35: Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29: Strehlow MC, Emond SD, Shapiro NI, Pelletier AJ, Camargo CA, Jr. National study of emergency department visits for sepsis, 1992 to Ann Emerg Med 2006; 48: Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: Crit Care Med 2008;36: Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345: Cho TJ, Kim H. The effect of early goal-directed therapy protocol implementation on the prognosis of patients with severe sepsis and septic shock in the emergency department. J Korean Soc Emerg Med 2009;20: Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy proto-

6 김재승외 : 패혈증쇼크환자에서생존에영향을미치는조기예후인자 / 49 col for severe sepsis and septic shock. Chest 2007; 132: Puskarich MA, Marchick MR, Kline JA, Steuerwald MT, Jones AE. One year mortality of patients treated with an emergency department based early goal directed therapy protocol for severe sepsis and septic shock: a before and after study. Crit Care 2009;13:R Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A, et al. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med 2009;180: Murphy CV, Schramm GE, Doherty JA, Reichley RM, Gajic O, Afessa B, et al. The importance of fluid management in acute lung injury secondary to septic shock. Chest 2009;136: Hébert PC, Tinmouth A, Corwin HL. Controversies in RBC transfusion in the critically ill. Chest 2007;131: Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32: Sperry JL, Minei JP, Frankel HL, West MA, Harbrecht BG, Moore EE, et al. Early use of vasopressors after injury: caution before constriction. J Trauma 2008;64: Permpikul C, Tongyoo S, Ratanarat R, Wilachone W, Poompichet A. Impact of septic shock hemodynamic resuscitation guidelines on rapid early volume replacement and reduced mortality. J Med Assoc Thai 2010;93 Suppl 1:S Dorresteijn MJ, van Eijk LT, Netea MG, Smits P, van der Hoeven JG, Pickkers P. Iso-osmolar prehydration shifts the cytokine response towards a more anti-inflammatory balance in human endotoxemia. J Endotoxin Res 2005;11: Rivers EP, Jaehne AK, Eichhorn-Wharry L, Brown S, Amponsah D. Fluid therapy in septic shock. Curr Opin Crit Care 2010;16: Rivers EP, Kruse JA, Jacobsen G, Shah K, Loomba M, Otero R, et al. The influence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shock. Crit Care Med 2007;35: Kee LL, Simonson JS, Stotts NA, Skov P, Schiller NB. Echocardiographic determination of valid zero reference levels in supine and lateral positions. Am J Crit Care 1993;2: Schmitt EA, Brantigan CO. Common artifacts of pulmonary artery and pulmonary artery wedge pressures: recognition and interpretation. J Clin Monit 1986;2: Gödje O, Peyerl M, Seebauer T, Lamm P, Mair H, Reichart B. Central venous pressure, pulmonary capillary wedge pressure and intrathoracic blood volumes as preload indicators in cardiac surgery patients. Eur J Cardiothorac Surg 1998;13: Lichtwarck-Aschoff M, Zeravik J, Pfeiffer UJ. Intrathoracic blood volume accurately reflects circulatory volume status in critically ill patients with mechanical ventilation. Intensive Care Med 1992;18: Ahrens T. Hemodynamics in sepsis. AACN Adv Crit Care 2006;17:

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