대한응급의학회지제 24 권제 2 호 Volume 24, Number 2, April, 2013 원 저 병원밖심정지환자에서뇌출혈유무에따른특징및예후차이분석 : 후향적분석 가천대학교길병원응급의학교실 장연식 임용수 조진성 김진주 현성열 양혁준 이 @ 근 The Effect of Brain Hemorrhage on the Prognosis of Out-of-Hospital Cardiac Arrest: a Retrospective Study Yeon Sik Jang, M.D., Yong Su Lim, M.D., Jin Seong Cho, M,D., Jin Joo Kim, M.D., Sung Youl Hyun, M.D., Hyuk Jun Yang, M.D., Gun Lee, M.D. (p=0.026), and S-100 (p=0.047) showed significant results. Conclusion: The prognosis of ICH patients in OHCA is poor; further studies are needed to improve the prognosis of ICH patients after ROSC in OHCA. Key Words: Out-of-Hospital Cardiac arrest, Intracranial hemorrhage, Brain Computed Tomography Purpose: Spontaneous intracranial hemorrhage (ICH) is not an uncommon cause of cardiac arrest. The purpose of this study was to identify the prognosis of patients with ICH for Out-of-Hospital Cardiac arrest (OHCA). Methods: From January 2008 to December 2010, a total of 214 patients were checked brain computed tomography (CT) in OHCA. The majority of patients were male (136, 63.8%), and the median age was 55.0 (±16.7). We included all patients who were checked through brain CT for nontraumatic OHCA. Data were collected from electronic medical records and pre-hospital records. Demographic, clinical and laboratory data were compared between the ICH and non-ich group. Results: The detection of ICH by clinical manifestations and laboratory data was difficult. Out of 214 patients, 21 (9.8%) patients were positive for ICH and 193(90.2%) patients had a normal brain CT. In demographic and clinical data, the neurological outcome (CPC score, p=0.009) and 30-day survival rate (p<0.001) were statistically different between the two groups. Using the Cox proportional hazards model, the ICH group had a 3.54 hazard ratio compared with non-ich group. In addition, ph (p=0.033), lactate (p=0.023) in ABGA, potassium (p=0.008), glucose 책임저자 : 임용수인천광역시남동구구월동가천대학교길병원응급의학교실 Tel: 032) 460-3015, Fax: 032) 460-3019 E-mail: yongem@gilhospital.com 접수일 : 2013년 1월 24일, 1차교정일 : 2013년 2월 16일게재승인일 : 2013년 2월 28일 142 Department of Emergency Medicine, Gachon University Gil Medical Center, Incheon, Korea 서 심정지의원인은다양하다. 연구에따라차이가있지만심장성심장지가약 70% 정도로가장흔한원인으로꼽힌다 1). 일부전향적코호트연구에서는비심장성심정지의원인으로폐색전, 뇌출혈등을보고하였고사망환자의부검으로사망원인을분석한연구에서약 10% 에서지주막하출혈이있음을발표하였다 1-3). 또심정지후자발순환이회복된환자에서두부전산화단층촬영 (computed tomography, CT) 시 16.2% 에서지주막하출혈이있음을보고하였다 4). 뇌출혈에의해심정지가발생한경우에심정지전에두통을호소하는비율이약 30~50% 정도였으며, 사망율은 90% 이상으로불량하다언급하였다 4-7). 최근발표된 2010년미국심장협회에서발표한심정지후증후군환자관리지침에서는자발순환회복뒤의두부 CT 촬영의필요성이새롭게제기되었다 8). 본연구에서는외상환자를제외한병원밖심정지환자를대상으로하여자발순환회복뒤두부 CT를실시한환자들에대해임상적, 혈액학적특징및예후에대해조사하였으며, 또한뇌출혈이존재하는군과없는군을분류하여두군을비교하였고임상적, 혈액학적결과가뇌출혈이있는환자에서신경학적예후및사망율에어떻게영향을미치는지분석하였다. 론
장연식외 : 병원밖심정지환자에서뇌출혈유무에따른특징및예후차이분석 : 후향적분석 / 143 대상과방법 2008년 1월부터 2010년 12월까지일개 3차대학병원에병원밖심정지로내원한환자중외상의병력이없는환자들을연구대상으로하였다. 외부충격에의한사고및약물과용, 입수등외부적인요인의증거가뚜렷한환자와의무기록이불충분한환자는연구대상에서제외하였다. 병원전단계의처치에대해서는구급기록을참고하였고구급차를타고병원에내원한경우가아니면목격자의진술을토대로기록하였으며, 응급실에서의처치는병원전자의무기록을이용하여확인하였다. 심폐소생술은 2005년및 2010년미국심장협회가권고한진료지침대로시행하였다. 자발순환회복후두부 CT 시행은자발순환회복후 20분이상수축기혈압이 90 mmhg 이상인환자를대상으로하였으며, 20분이상의자발순환이확인된시점에서 20 분안에촬영하였다. Siemens Somatom sensation 16 (Siemens Ltd, Germany) 기계를이용하여두부 CT를촬영하였으며, 결과는영상의학과의사가판독하였다. 과거병력, 항응고제복용에대해서는의무기록을참조하였으며, 의무기록에확인되지않은경우결손데이터로분 류하였다. 내원시최초심전도는응급실내원직후확인한심전도를이용하였다. 뇌출혈이있는군과뇌출혈이없는군사이의생존율의차이를주결과변수 (primary outcome) 로삼았으며, 그외임상적, 혈액학적차이및신경학적예후의차이를이차결과변수 (secondary outcome) 로삼았다. 통계분석시연속형자료는중앙값과 25%, 75% 범위값을이용하였으며, 범주형자료는퍼센트값으로기술하였다. 연속형자료는 Mann-Whitney U test를, 범주형자료는 Chi-square test 혹은 Fisher s exact test를이용하여비교하였다. 또한 Cox 비례위험모형 (Cox proportional hazard model) 을이용해뇌출혈군과뇌출혈이없는군사이의사망율차이를분석하였다. STATA 11.0 (Stata Corp LP, Texas, USA) 을이용하였고 p value가 0.05이하로확인된값을통계적으로유의하다고보았다. 결과 3년간의조사기간중총 1,280명의환자가심정지로내원하였다. 심폐소생술을시행하지않은환자, 외상병력이 Fig. 1. This diagram shos study design. OHCA: out of hospital cardiac arrest, ROSC: resuscitation of spontaneous circulation, CT: computed tomography, ICH: intracranial hemorrhage
144 / 대한응급의학회지 : 제 24 권제 2 호 2013 있거나외상의증거가확실하지않은환자, 자발순환회복후자발순환유지시간이 20분이내인환자를제외한 287 명의환자가연구에포함되었고, 이중두부 CT를실시한사람은 214명이었다. 이환자들중총 21명 (9.8%) 에서뇌출혈을확인하였다 (Fig. 1). 총 21명의뇌출혈환자중지주막하출혈은 15명이었고뇌실질내출혈은 6명이었다. 남성은 11명이었고, 나이의중앙값은 52.3세였다. 4명이고혈압, 1명이당뇨병병력을가지고있었으며심질환의병력및뇌출혈병력을가진자는없었다. 한명의환자가아스피린등의항응고제제의약물을복용하고있었다. 퇴원시 CPC (Cerebral Performance Category) 점수를이용한신경학적예후를확인한결과 4점이 2명이었고나 머지 19명이 5점이었다. 30일내사망여부를조사한결과뇌출혈이있는모든환자가 30일내사망하였으며평균사망일수는 4.1일이었다 (Table1, 2). Cox 비례위험모형을통하여뇌출혈이있는군과뇌출혈이없는군사이의내원후 30일내사망율을분석한결과나이, 성별, 과거병력, 초기심전도, 목격자의여부, 심정지에서심폐소생술시작까지의시간에대한변수를보정하여다변수분석시두군사이의 hazard ratio가 3.54였다 (Table 3). 또한 Kaplan-Meier 생존분석결과뇌출혈이있는군과뇌출혈이없는군사이에유의한생존율의차이가있었다 (Fig. 2). 그외변수에서뇌출혈이있는군과뇌출혈이없는군사 Table 1. Comparing between non-intracranial hemorrhage and intracranial hemorrhage patients, N (%). ICH (+) ICH (-) n (%) n (%) p value Total (N=214) 21 193 Male 11 (52) 125 (65)0,,0.379 Age (Year, median [IQR]) 52 (43-63) 56 (46-68),,0.881 Hypertension history 04 (19) 78 (41),,0.061 Diabetes mellitus history 1 (5) 44 (23),,0.086 Cardiac disease history 0 (0) 33 (17),,0.050 Brain hemorrhage history 0 (0) 3 (2),,1.000 Initial rhythm (VF, pulseless VT) 03 (14) 39 (20),,0.510 CPC score (CPC 1-2) 0 (0) 44 (23),,0.009 30 days survival 0 (0) 77 (40) <0.001 Anticoagulation medication 1 (5) 16 (8)0,,0.198 Bystander CPR 1 (5) 19 (10),,0.700 Place of cardiac arrest,,0.943 Home 14 (67) 108 (57)0 Workplace 1 (5) 5 (3) Public place 02 (10) 25 (13) Street 1 (5) 15 (8)0 Ambulance 1 (5) 11 (6)0 Hospital 1 (5) 8 (4) Etc 1 (5) 19 (10) Witness,,0.813 Family 10 (48) 77 (41) Bystander 06 (29) 51 (27) EMT 0 (0) 10 (5)0 Doctor 1 (5) 4 (2) Etc 0 (0) 5 (3) None 04 (19) 43 (23) Arrest-BLS (min, Median [IQR]) 9.0 (5.5-12.0) 6.0 (4.0-10.0),,0.077 Arrest-ACLS (min, Median [IQR]) 21.0 (18.0-24.0) 18.5 (14.0-24.0),,0.172 Arrest-1 st ROSC (min, Median [IQR]) 30.0 (22.0-39.0) 29.0 (20.3-37.8),,0.888 Arrest-Last ROSC (min, Median [IQR]) 33.0 (24.8-49.3) 32.0 (21.0-45.0),,0.723 ACLS-1 st ROSC (min, Median [IQR]) 6.0 (4.0-12.5) 8.0 (6.0-14.0),,0.062 ACLS-Last ROSC (min, Median [IQR]) 11.0 (4.3-19.8)0 10.0 (6.0-27.0),,0.487 ICH: Intracranial hemorrhage, SD: standard deviation, VF: ventricular fibrillation, CPC: cerebral performance categories, EMT: emergency medical technician, BLS: basic life support, ACLS: advanced cardiac life support, ROSC: restoration of spontaneous circulation, IQR: interqurtile range, VT: Ventricular tachycardia, CPR: Cardiopulmonary resuscitation, Etc: et cetera
장연식외 : 병원밖심정지환자에서뇌출혈유무에따른특징및예후차이분석 : 후향적분석 / 145 이에통계적으로의미있는차이가확인된변수는 CPC 점수 (p value=0.009) 와초기혈액검사의칼륨 (p value= 0.019), 혈당 (p value=0.008), S-100(p value=0.047) 이었다. 고찰심정지환자중뇌출혈이있는군은뇌출혈이없는군에내원후 30일내사망률의위험이높았으며, 두군은 CPC 점수, 칼륨, S-100수치에서의미있는차이가있었다. 심정지의가장큰원인으로급성관상동맥증후군등의심장문 제가있고심장문제를제외한원인으로는외상, 중독, 폐색전, 뇌출혈등이있다 1-3). 사망환자에대한부검이활발하지않은한국의특성상심정지환자중정확히몇퍼센트가뇌출혈을동반하고있었는지확인할수는없었지만, 이번연구에서자발순환이회복된환자에서뇌출혈의빈도를확인하였을때약 10% 정도가있었고, 지주막하출혈로국한시에는 7% 정도가있었다. 이결과는심정지환자에서두부 CT 촬영후지주막하출혈의빈도를확인한 Inamasu 등 4) 이나 Sim 등 5) 이발표한이전의논문들과비교하여낮 은값이다. 이러한결과등을바탕으로하여미국심장협회는 2010년발표한심정지후증후군관리지침을통해심정지환자에서높은빈도를차지하는뇌출혈및기타뇌병 Table 2. Comparing lab finding between non-cerebral hemorrhage and cerebral hemorrhage patients (N=214). ICH (+) ICH (-) p value ABGA ph 7.12 (6.98-7.25) 7.02 (6.88-7.19) 0.033 ABGA pco 2 (mmhg) 61.5 (35.5-72.5) 63.0 (41.3-85.0) 0.335 ABGA HCO 3- (mmhg) 17.9 (14.3-21.4) 17.2 (13.9-20.5) 0.711 ABGA lactate (mmol/l) 8.2 (4.7-9.6) 9.3 (7.0-12.4) 0.023 Serum Na (meq/l) 138.0 (134.5-141.5) 139.0 (137.0-142.0) 0.256 Serum K (meq/l) 4.1 (3.6-5.0) 5.0 (4.0-5.9) 0.008 Serum Cl (meq/l) 105.0 (100.5-107.5) 105.0 (101.0-108.0) 0.955 Serum Ca (mg/dl) 8.3 (8.1-8.8) 8.7 (7.9-9.2) 0.123 Serum P (mg/dl) 6.9 (5.4-9.3) 6.8 (5.3-8.6) 0.763 Serum Glucose (mg/dl) 284.0 (178.0-330.5) 209.5 (149-282.8) 0.026 Serum BUN (mg/dl) 16.8 (12.0-20.1) 15.8 (11.8-23.1) 0.774 Serum Cr (mg/dl) 1.1 (1.0-1.3) 1.2 (1.0-1.5) 0.295 Serum CPK (U/L) 143.0 (109.0v203.0) 158.0 (89.0-341.0) 0.692 Serum CK-MB (ng/ml) 1.0 (1.0-3.4) 1.0 (1.0-3.7) 0.929 Serum Troponin I (ng/ml) 0.1 (0.1-0.1) 0.1 (0.1-0.1) 0.555 Serum S-100 (μg/l) 4.8 (1.3-8.0) 1.3 (0.4-3.6) 0.047 ICH: Intracranial hemorrhage, IQR: interqurtile range, ABGA: arterial blood gas analysis, BUN: blood urea nitrogen, CPK: creatine phosphokinase, CK: Creatinine Kinase All data are expressed as median (interquartile range). Table 3. Univariate and multivariable analysis about factors related to death ratio. Unadjusted Hazard ratio Adjusted Hazard ratio Hazard ratio 95% CI Hazard ratio 95% CI ICH 3.79 2.30-6.25 3.54 2.00-6.26 Age 1.01 1.00-1.02 1.00 1.00-1.02 Sex 1.18 0.82-1.69 HTN 0.92 0.64-1.32 1.06 0.69-1.62 DM 1.13 0.75-1.71 1.13 0.70-1.84 CVA 0.51 0.12-2.09 V.fib or pulseless VT 0.40 0.23-0.69 0.39 0.21-0.73 Witness 0.75 0.40-1.39 0.67 0.45-1.00 Arrest to BLS 1.03 0.99-1.06 1.02 0.99-1.05 ICH: Intracranial hemorrhage, HTN: Hypertension, DM: Diabetes mellitus, CVA: Cerebrovascular attack, V.fib: Ventricular fibrillation, VT: Ventricular tachycardia, BLS: Basic life support, CI: confidence interval
146 / 대한응급의학회지 : 제 24 권제 2 호 2013 변을확인하기위해자발순환회복후뇌 CT 촬영의필요성을언급하였다 8). 또한기존의논문들은심정지환자중지주막하출혈이있는환자는대부분신경학적예후가나쁘고사망율이높다는결과를발표하였다 4,5). 저자들은이에더해사망율에영향을미칠수있는변수를다양화하였고, 뇌출혈을제외한변수들을보정하여심정지환자에서뇌출혈의유무가사망율에어느정도영향을미치는지다변수분석을시행하였다. 본연구에서는병원밖심정지환자중뇌출혈이있는환자군은뇌출혈이없는환자군에비해통계적으로유의한 30일내사망율을보였다. 뇌출혈이있는 21명의환자모두가 30일내사망하였으나뇌출혈이없는군의환자는 117명 (60%) 이사망하였다 (p<0.001). 또한다변수분석을통한두군간의사망위험도분석결과뇌출혈이있는경우의 hazard ratio가 3.54였다. 뇌출혈이있는환자의경우대부분신경학적예후도불량하였는데 21명의환자중두명의환자만이 CPC 점수 4점으로확인되었고그외모든환자는 CPC 점수 5점으로본원에서사망하였다. 심정지환자중뇌출혈이있는군과뇌출혈이없는두군간사망율과신경학적예후에통계적으로유의한차이가있는것은병원밖심정지환자중뇌출혈이있는환자의특성에대해연구한이전의논문들과비슷한결과이다 4,5). 고혈압은뇌출혈의가장중요한위험인자이다 11). 본연구에서는뇌출혈이확인된환자중 4명 (19%) 만이고혈압을과거병력으로가지고있었다. 이는뇌출혈이확인되지않은환자중고혈압을가지고있던환자 78명 (41%) 에비해낮은빈도이나통계적으로는두군간에의미가없는것으로확인되었다 (p value=0.277). 또한뇌출혈의중요한요인으로항응고제복용여부가있다. Hart 등 12) 은항응고제가뇌출혈을일으키는데유의한인자임을기술하였고그외 Berwaerts 등 13) 및 Cervera 등 14) 도같은결과를발표하였다. 하지만본연구에서는환자중뇌출혈이확인된환자중 1명 (5%) 만이아스피린을복용하고있는것으로확인되어두군사이에직접적인통계비교는불가할것으로사료된다. 뇌출혈시부정맥이발생하는것은많은논문에서알려진사실이다 15). 하지만이에관한정확한기전은밝혀지지않은상태인데 Opheheimer 등 16) 은뇌출혈과부정맥간의관계를연구한논문에서뇌출혈시급격하게분비되는카테콜라민에의해교감신경의작용과그로인한심근의구조적, 생리적변화에주목하였다. 본논문에서는뇌출혈이있는 21명의환자중 3명 (14%) 에서심실세동및무맥성심실빈맥이초기에확인되었는데이는뇌출혈이없는환자에서확인된 20% 에비해낮은수치이나통계적으로는의미는없었다. 저자들은뇌출혈환자와비뇌출혈환자군사이서확인된혈액학점검사의차이점에도주목하였다. 특히 S-100의경우뇌병변이있는환자에서의미있게상승된다는결과가많이보고되었다 17-20). 본연구결과에서는뇌출혈환자와뇌출혈이없는환자군사이에통계적으로의미있는 S- 100의결과차이가있었다. 또한 glucose가두군사이에서의미있게차이가잇는것으로확인되었는데 Lindsberg 등 21) 은급성뇌졸중에서코티솔의분비및인슐린의상대적부족이혈액내혈당상승을일으킨다고보고하였다. 하지만혈액학적검사의결과에차이가나는원인을밝혀내기위해서는앞으로좀더많은연구가필요하다. Fig. 2. This figure appears analysis of 30 days survival between non-cerebral hemorrhage and cerebral hemorrhage patients by Kaplan-Meier survival estimates. ICH: intracranial hemorrhage
장연식외 : 병원밖심정지환자에서뇌출혈유무에따른특징및예후차이분석 : 후향적분석 / 147 본연구에는몇가지제한점이존재한다. 먼저구조대원 이도착하기전환자의상태에대한사실관계를보호자의진술에의존하여조사했다. 이는환자의병력조사에대한정확도를떨어뜨려결과에영향을미칠수있다. 또한두부 CT를자발순환이회복된환자만을상대로촬영하였기때문에실제사망인구중어느정도의비율에서뇌출혈이있었는지는밝혀내지못하였다. 다만, 사망후부검을시행한일본의논문에서전체사망환자중부검후지주막하출혈이확인된경우가 10% 라고밝힌것으로보아한국의그것과크게차이가나지않을것이라추측할수있다 3). 마지막으로본연구에서는자발순환이회복된환자중혈압이안정화된일부의환자에서만두부 CT를실시하였기때문에나타나는선택오차 (selection bias) 를추측해볼수있다. 이에대한결과를간접적으로확인하기위해자발순환이회복된군에서두부 CT를실시한군과 CT를실시하지않은군사이의나이, 성별, 목격자여부, 병원전심폐소생술시행여부, 심정지부터기본심폐소생술까지걸린시간, 고혈압및당뇨병과거력, 초기심전도를비교하였고나이를제외한요소에서큰의미가없음을확인하였다. 결 본연구를통해병원밖비외상성심정지환자중두부 CT 촬영시 9.8% 에서뇌출혈을확인하였다. 또한뇌출혈이있는군과없는군사이에 CPC 점수와 S-100 등에서통계적으로유의한차이가있었고, 심정지후자발순환이회복된환자에서뇌출혈이발견된경우사망률이높음을확인하였다 론 참고문헌 01. Zheng ZJ, Janet BC, Wayne HG, George AM. Sudden cardiac death in the United States, 1989 to 1998. Circulation. 2001;104:2158-63. 02. Kuisma M, Alaspää A. Out-of-hospital cardiac arrests of non-cardiac origin. Epidemiology and outcome. Eur Heart J. 1997;18:1122-8. 03. Kitahara T, Masuda T, Soma K. The etiology of sudden cardiopulmonary arrest in subarachnoid hemorrhage. No Shinkei Geka. 1993;21:781-6. 04. Inamasu J, Miyatake S, Tomioka H, Suzuki M, Nakatsukasa M, Maeda N, et al. Subarachnoid haemorrhage as a cause of out-of-hospital cardiac arrest: a prospective computed tomography study. Resuscitation. 2009;80:977-80. 05. Sim MS, Sung KD, Kang MJ, Na JU, Shin TG, Jo IJ, et al. A retrospective study about characteristics of out-of-hospital cardiac arrest caused by non-traumatic subarachnoid hemorrhage. Korean J Crit Care Med. 2011;26:151-6. 06. Kürkciyan I, Meron G, Sterz F, Domanovits H, Tobler K, Laggner AN, et al. Spontaneous subarachnoid haemorrhage as a cause of out-of-hospital cardiac arrest. Resuscitation. 2001;51:27-32. 07. Noriyuki S, Yoshihiro M, Hiroshi M, Koichi H. Assessing outcome of out-of-hospital cardiac arrest due to subarachnoid hemorrhage using brain CT during or immediately after resuscitation. SIGNA VITAE. 2010;5:21-4. 08. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. Part 9: Post?Cardiac Arrest Care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122:S768-86. 09. Neumar RW, Otto CW, Link MS, Kronick SL, Shuster M, Callaway CW, et al. Part 8: Adult Advanced Cardiovascular Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122:S729-67. 10. Cave DM, Gazmuri RJ, Otto CW, Nadkarni VM, Cheng A, Brooks SC, et al. Part 7: CPR Techniques and Devices: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122:S720-8. 11. Feldmann E, Broderick JP, Kernan WN, Viscoli CM, Brass LM, Brott T, et al. Major risk factors for intracerebral hemorrhage in the young are modifiable. Stroke. 2005;36:1881-5. 12. Hart RG, Boop BS, Anderson DC. Oral Anticoagulants and Intracranial Hemorrhage. Stroke. 1995;26:1471-7. 13. Berwaerts J, Webster J. Analysis of risk factors involved in oral anticoagulant related intracranial haemorrhages. QJM. 2000;93:513-21. 14. Cervera A, Amaro S, Chamorro A. Oral anticoagulantassociated intracerebral hemorrhage. J Neurol. 2012;259: 212-24. 15. Andreoli A, di Pasquale G, Pinelli G, Grazi P, Tognetti F, Testa C. Subarachnoid hemorrhage: frequency and severity of cardiac arrhythmias. A survey of 70 cases studied in the acute phase. Stroke. 1987;18:558-64. 16. Oppenheimer SM. Cerebrogenic cardiac arrhythmias: cortical lateralization and clinical significance. Clin Auton Res. 2006;16:6-11. 17. Delgado P, Alvarez Sabin J, Santamarina E, Molina CA, Quintana M, Rosell A, et al. Plasma S100B level after acute spontaneous intracerebral hemorrhage. Stroke. 2006;37:2837-9. 18. Stranjalis G, Korfias S, Psachoulia C, Kouyialis A, Sakas DE, Mendelow AD. The prognostic value of serum S-
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