INVITED REVIEW online ML Comm J Neurocrit Care 2009;2 Suppl 1:S10-S15 ISSN 2005-0348 심정지후증후군 : 치료와예후 국립의료원신경과학교실 고임석 Management and Prognosis of Post-Cardiac Arrest Syndrome Im Seok Koh, MD Department of Neurology, National Medical Center, Seoul, Korea The pathology caused by complete ischemia and reperfusion after cardiac arrest was unique in that it had a definite cause, time course, and pathologic process, this state called a new term: post-cardiac arrest syndrome. Post-cardiac arrest syndrome is a complex combination of pathological processes and symptoms, which include 1) post-cardiac arrest brain injury (hypoxic-ischemic brain injury), 2) post-cardiac arrest myocardial dysfunction, 3) systemic ischemia/reperfusion response, and 4) underlying process caused the cardiac arrest. Advances in cardiopulmonary resuscitation enable progress in management of post-cardiac arrest syndrome, but the overall prognosis after cardiac arrest has not improved. The managements include the effective monitoring, early hemodynamic optimization, oxygenation, ventilation, circulatory support, acute coronary syndrome treatment, therapeutic hypothermia, proper sedation and neuromuscular blockade, seizure control and prevention, aggressive fever and glucose control, treatment of adrenal dysfunction, renal function, and infection. J Neurocrit Care 2009;2 Suppl 1:S10-S15 KEY WORDS: Post-cardiac arrest syndrome Hypoxic-ischemic brain injury. 서 론 다양한원인에의해발생한심정지 (cardiac arrest) 는적극적인심폐소생술 (cardiopulmonary resuscitation, CPR) 에의해순환이회복된경우에도치명적인병태생리학적반응을일으킨다. 1972 년 Vladimir Negovsky 는심정지후살아난환자에서다른질환에서는볼수없는일련의병리적과정으로신체전반에걸쳐허혈및재관류 (reperfusion) 손상과이에따른다양한증상이발생함을기술하면서이를 postresuscitation disease 라고지칭하였다. 1 그러나최근에는소생 (resuscitation) 이라는단어를대신해서순환회복이이루어진후나타나는다양한증상과징후를포괄적으로표현한심정지후증후군 ( post-cardiac arrest syndrome ) 이라는용어가사용되고있다. 2 심정지시여 Address for correspondence: Im Seok Koh, MD Department of Neurology, National Medical Center, 18-79 Eulgiro 6-ga, Jung-gu, Seoul 100-799, Korea Tel: +82-2-2260-7290, Fax: +82-2-2273-7144 E-mail: neukoh@naver.com 러장기에발생하는허혈손상및혈액순환이회복된후나타나는재관류손상은매우복합적인병리기전과증상을유발하는데중요장기손상을중심으로보면 1) 심정지후뇌손상 (post-cardiac arrest brain injury) 인저산소허혈뇌손상 (hypoxic-ischemic brain injury), 2) 심정지후심근부전 (post-cardiac myocardial dysfunction), 3) 신체전반에걸친허혈및재관류손상 (systemic ischemic/reperfusion response) 등으로분류할수있으며각각손상부위와정도에따라적절한진단과치료를시행해야하며반드시최초심정지를일으킨근본적인유발원인에대한정확한평가와치료가이루어져야한다. 돌연사의중요한원인인심정지는제세동기사용을비롯한심폐소생술의발달로인해과거에비해사망하지않고순환회복이재개되는환자가증가하고있고순환이복귀된후의생존율증가및기능회복을위한다양한치료들이개발되고시도되고있다. 그러나, 심정지후순환이재개된환자들의예후를조사한최근의연구들을살펴보면실망스럽게도수십년전의조사결과와큰차이가없는것으 S10 Copyright c 2009 The Korean Neurocritical Care Society
Management and Prognosis of Post-Cardiac Arrest Syndrome IS Koh 로발표되고있다. 최초의대규모조사인 1953 년도 672 명의성인과소아를대상으로시행한연구결과심정지후순환이회복한환자에서단기간내사망률이 50% 이상으로보고된바있고, 3 2006년 19,819 명의성인과 524명의소아에서시행된연구 (the National Registry of Cardiopulmonary Resuscitation) 의사망률은각각 67%, 55%, 4 24,132 명의심정지후증후군환자를대상으로시행된최근의조사에서도 71% 의사망률을보여 50년전의결과가차이가없는것으로나타났다. 5 물론, 이와같은결과들은심정지가발생한장소 ( 병원외 vs. 병원내 ), 심정지지속시간, 심정지의기준과원인등에따른많은변수가있어과거연구와의정확한비교는불가능하나, 다른분야에서이루어진의학적발전과성과를고려할때심정지후증후군환자의치료에대해서는아직도많은연구와개선이필요하다. 심정지후증후군환자에서치료이외에확인해야될중요한측면으로는정확한예후평가가있으며최근까지심정지지속시간과원인, 심폐소생술의시작및지속시간등으로예후를추정해왔다. 일반적으로 3일이후에도의식회복이없을때예후가나쁠것으로간주하며 6 3일이전의조기예후평가는매우어려워현재순환회복후의신경학적이학상태, 각종검사소견및생화학적표시인자등을분석함으로써정확한예후를예측하는연구들이진행되고있다. 또한최근비교적좋은성과를보여주고있는저온치료등의시도에따라과거와는다른예후가나타나고있으므로예후평가에대한새로운접근이필요할것으로보인다. 여기에서는최근보고되고있는심정지후증후군의전반적인치료와예후평가에대해그간발표된연구문헌등을통해정리해보고자한다. 치료 Oxygenation, Ventilation, Circulation, Hemodynamic Support 순환이재개된후가장중요한것은허혈손상을받은장기의요구량에따라혈액과산소를적절하게공급하고유지하는것이다. 혈량의부족은치명적인결과를초래하므로즉각적으로교정해야되며, 뇌부종을막기위해서저장성수액 (hypotonic fluid) 은가급적사용하지않는다. 7 아직대규모의무작위연구는시행된바없으나기존에추천되고있는도달해야될급성기목표지표로는중심정맥압 (central venous pressure) 8~12 mmhg, 평균동맥압 (mean arterial blood pressure, MAP) 65~90 mmhg, 연속적중심정맥산소포화도 (Scvo 2 )>70%, 적혈구용적률 (hematocrit) >30% 또는혈색소 (hemoglobin)>8 g/dl, 유산염 (lactate)<2 mmol/l(18mg/dl), 소변량 (urine output)>0.5 ml/ Kg/h, 산소운반량 >600 ml/min/m 2 등이있다. 특히대뇌는자기조절작용 (cerebral autoregulation) 에의해평균동맥혈압 (mean arterial pressure, MAP) 50 mmhg에서 150 mm Hg까지는일정한뇌혈류가유지되나저산소-허혈손상을받은뇌의경우자기조절작용이손상됨에따라대부분환자에서전적으로뇌관류압 (cerebral perfusion pressure) 이혈압에의존하므로적극적인평균동맥압의조절이필수적이다. 심정후후증후군환자에서나타날수있는 noreflow 현상은혈액순환이재개될당시순간적인뇌혈류량증가후감소가나타나는것으로 8 이와같은현상과뇌의자기조절능력상실을고려해서다소높은평균동맥압의유지가바람직하다는주장도제기되고있다. 9 심정지후증후군환자대부분에서인공호흡기가사용되며이때저산소증과과이산화탄소증은피해야하며일부연구에서초기산소분압 (PaO 2 ) 을 100 mmhg 이상유지할것으로추천하고있다. 7 심정지후발생할수있는뇌부종과뇌압상승은초기치료에서반드시고려해야할대상이나예상보다흔치않고뇌압저하를위해무조건적인과호흡시도는혈관수축을유발하고허혈손상을악화시키므로피해야한다. Management of myocardial dysfunction 갑작스러운심정지의경우심근경색과같은관상동맥질환에의해발생하는경우가가장흔하므로기존의질환을반드시확인하고이에대해중재적치료를포함한적극적치료가필요하다. 또한기존특정한심장질환이없었던환자에서도심정지후순환회복이재개될당시부터심근기능부전이나타나는경우가흔하며원인은명확하지않으나. 대개 24~48 시간지속된후호전되는데매우불안정한심박수및혈압이관찰되므로각별한주의를요한다. 심폐소생술당시사용되는약제들 (epinephrine, atropine) 등이작용으로혈압상승이나빈맥도나타나지만주로혈압저하가나타나는데원인으로는허혈손상에의한심장및부신등의기타장기의기능부전, 면역학적이상, 혈액응고체계의활성화및패혈증을비롯한각종감염, 심정지를일으킨기존질환의악화등이있으며이로인한추가적인혈압저하가허혈손상을받은장기를더욱악화시키는결과를초래하므로이에대한적극적인대처가필요하다. S11
J Neurocrit Care 2009;2 Suppl 1:S10-S15 Aggressive fever and glucose control 발열은심정지후뇌손상을악화시키므로해열제사용을포함해서적극적으로열을떨어뜨려야한다. 예방목적을위해무조건적으로광범위항생제를사용하는것은바람직하지않으나발열시반드시원인을찾아치료하여야하며, 우선적으로폐렴, 비뇨기계감염, 패혈증등을고려하여적절한항생제를사용한다. 2 심정지후증후군에서흔히관찰되는소견으로고혈당이있으며혈당상승의이유는명확하지않으나인체내스트레스호르몬이주된작용을하는것으로보여지고심폐소생술시흔히사용되는 epinephrine과최근에적용되고있는저온요법도인슐린의분비능및민감도를저하시켜혈당을올리는것으로생각된다. 저혈당과고혈당은모두저산소- 허혈뇌손상을악화시킬수있으므로지속적인혈당검사를통한적극적조절이필요하며, 고혈당발생시인슐린을사용할수있으나정상적인식사와영양공급이어려운경우가많으므로지속형인슐린사용시는저혈당에대한주의가필요하다. 이상적인혈당에관해서는아직밝혀져있지않으며현재대규모임상연구가진행중이다. Sedation and seizure control 심정지후뇌손상을막기위한또다른방편으로뇌대사요구량을줄여주는약물의사용이시도되고있는데현재까지무작위대규모연구를통해유의한결과가확인된바는없으며, 부작용과신경학적검사가불가능하다는점등을고려하여불응성뇌압증가와같은특수한상황에서만시도해볼수있다. 비교적많은경우에서다양한양상의발작 (seizure), 근육간대경련 (myoclonus) 이발생하며발작은뇌대사요구량및뇌압을증가시키고의식회복을방해하므로필요시항전간제를사용하여치료한다. 그러나경련이발생하기전항전간제의예방적사용은근거가불충분하며경련이없는환자에서도의식회복이지연되는경우는뇌파검사를시행해야한다. Therapeutic hypothermia 심정지후증후군환자에서저온요법은뇌대사요구량을줄여주는효과가있으며이미표준화된치료로인식되고있다. 몇개의소규모연구를거쳐성인에서시행된무작위연구와메타분석이발표된바있는데모든연구에서 33 또는 32~34 정도로약한저온치료가 12~24 시간정도시행된바있으며대조군에비해유의한효과가있는것으로나타났다. 하지만아직가장좋은목표온도, 지속 시간, 정상체온으로돌려주는속도등의기술적인부분에있어서는확실하게밝혀져있지않아추후지속적인연구가필요할것으로보인다. 10 예후 예후에대한평가를하기전에우선먼저고려해야될문제는 어떤환자를예측할것인가? 하는것이다. 즉의식을회복할수있는환자를예측할것인가? 아니면절대회복하지못할환자를예측할것인가? 아니면회복된후심각한결손이동반될환자를예측할것인가? 어떤경우이던가장중요한것은 false pessimistic prediction ( 비관적으로예측을했는데환자가회복될경우 ) 을피하는것이다. 즉시간이 3일이상경과된후에도회복되는경우가있으므로섣부른비관적예측으로보호자들이환자를포기하도록만들게하면안되며, 이와같은이유로예후를평가시는높은특이도 (specificity) 와양성예측률 (positive prediction value) 이민감도 (sensitivity) 보다우선적으로요구된다. Circumstances surrounding CPR 순환회복이이루어진후의이학적, 신경학적상태등을배제한채심정지가발생할당시의상황만을분석하여예후를예측하기위한많은연구들이시도되어왔다. 무호흡시간, 심폐소생술지속시간, 심정지의원인 ( 심장탓 vs 비심장탓 ), 심정지발생시의부정맥유형등이환자의예후와관련이있을것이라고예상했었으나실제로아직까지는이와같은인자들과예후와는유의한연관이있음은증명된바없다. 11 Hyperthermia 체온이높은경우예후가불량한것으로알려지고있으며이는저온치료를통해뇌손상을줄여보고자하는연구들을시도하게된계기이기도하다. 일부연구에따르면심정지후첫 48시간이내에고막체온 (tympanic temperature) 를측정하여 37 이상인경우에는사망률및 6개월이후식물상태 (vegetative state) 일위험이 2.26배로보고되었지만, 다른관련인자가많아높은체온이불량한예후와연관되는독립적인인자인지는확인이되지않고있다. 12 Features of the neurologic examination Glasgow 혼수척도 (Glasgow coma scale; GCS), Glasgow 혼수척도 -운동영역(GCS-Motor part), 뇌간반사 (brainstem reflex: 동공반사, 각막만사, 자발안구운동 ) 와 S12
Management and Prognosis of Post-Cardiac Arrest Syndrome IS Koh 같은신경학적이학검사소견과근육간대경련간질지속증등의신경학적증상을통한예후예측을보면, 심정지 72 시간이후의결과를확인시 Glasgow 혼수척도운동영역점수가 2점이하이거나뇌간반사가소실된경우불량한예후에대한위양성 (false positive rate) 0이었다는보고가있었다. 11,13,14 Glasgow 혼수척도는대부분의환자들이기관지삽관상태로언어영역검사가불가능하고안구검사의경우도예측평가도구로서의의미가적어운동영역만으로평가하는경우가전체척도를평가하는경우보다더우월하다고한다. 10 경련특히근육간대경련지속증이발생시예후가나쁜것은잘알려져있었으나근육간대경련의아형에따라예후가달라지는것으로보인다. 심정지후증후군에서나타나는근육간대경련은크게무산소후근육간대경련 (postanoxic myoclonus, Lance-Adams syndrome), 근육간대경련지속증 (status myoclonus, more than 30 minutes of myoclonic activity), 근육간대경련성간질지속증 (myoclonic status epilepticus, myoclonic jerks merging with tonic-clonic seizures and lasting over 30 minutes) 등으로구분하는데 15 일반적으로무산소후근육간대경련이불량한예후와관계가있다고한다. 특히근육간대경련지속증은심장자체에서기인한심정지증후군시동반될수있고, 뇌파검사상돌발파억제 (burst suppression) 가나타나는데이는아주불량한예측인자로약물치료에잘반응하지않는다. 16 반면단순경련이나국소적인근육간대경련은예후예측인자로서의미가없는것으로보여지며, 근육간대경련지속증경우초기에만존재하거나혹은관찰되지않을수있어서실제보다유병율이낮다고보고된바있다. 14,17,18 이와같은연구결과들을종합해서분석해보면심정지환자에서첫 24시간내에근육간대경련간질지속증이발생하거나심정지후 3일내에동공반사또는각막반사의소실, 3일후에 GCS- 운동영역 2점이하시예후가불량할것으로보여진다. Clinical prediction scales 일반적으로혼수환자의예후예측을위해 Longstreth Awakening Score, Grubb Prognostic score, Glasgow 혼수척도등여러진단방법들이제시되어왔다. Glasgow 혼수척도는현재까지가장흔히사용되나기관삽관을하고있는경우모든항목을평가할수없으며뇌간반사등을평가할수없다는한계를가지고있다. 이의보완을위해 FOUR Scale 등의다양한척도들이제시되어왔으며최근까지도 Glasgow 혼수척도를대체할수있는진단방법을찾기위한연구가계속되고있다. 19,20 Electrophysiologic studies 뇌파및기타전기생리검사를이용한예후평가연구들이꾸준히시도되고있는데일반적으로심한뇌손상을의미하는특징적인일부뇌의전기적활동의변화들이불량한예후와관련을있을것으로간주되나, 이러한뇌파소견은검사를시행하는시기와혈역학적, 대사적인자들과약물등의다른교란변수 (confounding factor) 들의영향을받는다. 즉뇌파검사만으로환자의예후를예측시 false pessimistic prediction 의위험이크다는단점이있으므로단독사용은피해야하며주로다른예후인자들과조합하여사용한다. 이와같은뇌파의단점을보완하기위해 Somatosensory evoked potentials(seps), Brain stem auditory evoked potentials(baeps) 등을이용한연구가진행되어왔으며 SEPs 상 short latency cortical response (N20) 가양측에서나오지않을경우예후가나쁘다는보고도있으나 14,21-27 이경우에도다른대사성원인과약물같은교란변수의영향을받는다고하며, 28,29 환자가심정지가발생하기전부터말초신경질환, 척수질환, 대뇌질환등의 SEP pathways 의이상을초래하는질환을가지고있을가능성이있으므로일방적으로적용할수없다는한계가있다. BAEPs 를이용한연구는 SEPs 에비해연구결과가부족하며아직까지는만족스러운결과를보이지못하고있다. 30,31 Biochemical markers 대표적인생화학적표시인자인뇌척수액 (Cerebrospinal fluid: CSF) creatine kinase BB(CK-BB) isoenzyme activity, serum and CSF neuron-specific enolase(nse), CSF-Neurofilament, serum S-100 등의측정을통해예후를예측하고자하는연구들이진행되어왔다. 뇌척수액에서조사된 CK-BB 의경우신경세포 (neurons) 와성상세포 (astrocytes) 에존재하며심정지발생 48~72 시간후에정점에도달하며불량한예후판정에특이도 100% 와민감도 48% 를가진다고한다. 32 민감도가낮은이유는환자가회복되기전에심정지재발등과같은손상으로사망하거나, 측정시점의문제, 또는 0 에서보관되지않을경우의가역적비활성화등이발생하기때문일것으로생각되고있다. 심정지후뇌부종이의심되는경우요추천자시행시의안전성문제는과거시행한연구들을통해요추천자가별다른영향을미치지는않는다고보고된 S13
J Neurocrit Care 2009;2 Suppl 1:S10-S15 바있다. 32,33 Serum NSE는 gamma isomer of enolase 로신경세포및신경외배엽세포 (nuroectodermal cells) 에주로존재하며, CSF NSE 및 CSF-CKBB 와도일치하는것으로알려져요추천자를피할수있다는장점이있다. 심폐소생술 1~3일후 Serum NSE level이 33 μg/l 이상인경우예후가나쁘다는보고가있으며, 13 저온치료가시행된환자군에서 Serum NSE의감소가더흔하며좋은예후와관련이있다는결과가발표되었다. 10 Serum S-100은 Calcium-binding astroglial protein 으로 Serum NSE에비해빠르게정점에도달하므로빠른판정이가능하다는장점이있다. 이러한생화학적표지인자가환자에서예후를예측하는데약물이나다른신경학적질환등에영향을받을수있는 SEP의단점을극복할수있을것으로기대했으나현재까지의결과를분석해보면예후를예측하는데 SEP보다뛰어나지않은것으로나타나고있다. Neuroimaging studies CT, MRI, MRS, PET 등의영상학적분석을통한예후분석연구는계속시도되고있다. CT의경우초기뇌부종을보인환자들에서예후가불량했고이와같은소견은호흡부전에의한심정지후증후군환자에게주로많이보여졌으나호흡부전환자군이상대적으로젊은나이라는점에서독립적인예후인자인지는불분명하며 34 MRI를통한연구에서도유사한결과가나타났다. MRS를이용한연구에서 Lactate positivity 가다른예측인자가없을경우불량한예후를판정하는데유용할수있을것이라고조사되었으나 24 이와같은영상학적분석은소수의환자들에게서만시행이가능하고주로인공호흡기를사용하는급성기에는검사가불가능한경우가많다는한계를가지고있다. Multimodal approach 지금까지언급한다양한예측인자들을복합적으로사용하여예후를분석하는연구들도진행되었는데, 심정지 48 시간후의 GCS 8점이하와 SEP(-, 반응이없는경우 ) 를같이사용하는것이가장의미있는예측을할수있다는연구가발표된바있으며, 35 그외의인자들을종합하여평가한예측연구들도보고되고있다. 36,37 위와같은검사도구를이용한예후분석은다른요인들을배제할수있다는장점이있으나, 이러한예측이환자의치료지침을결정하는데영향을미칠경우결국엔자기실현적예언 (self-fulfilling prophecy) 이될수도있다는점을 인지해야한다. 즉, 환자의치료지침의결정에전혀영향을주지않을경우에는예측인자로써유용하게사용될수있으나, 검사수치를통해나쁜예후가예상된다고할경우적극적인치료가행해지지못함으로써환자의예후가오히려예측에의해결정될위험이있다는모순점이존재하므로이와같은분석도구를사용시각별한주의를요한다. REFERENCES 1. Negovsky VA. The second step in resuscitation: the treatment of the post-resuscitation disease. Resuscitation 1972;1:1-7. 2. Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Bottiger BW, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 2008;118:2452-83. 3. Stephenson HE, Jr., Reid LC, Hinton JW. Some common denominators in 1200 cases of cardiac arrest. Ann Surg 1953;137:731-44. 4. Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, et al. First documented rhythm and clinical outcome from inhospital cardiac arrest among children and adults. JAMA 2006;295: 50-7. 5. Nolan JP, Laver SR, Welch CA, Harrison DA, Gupta V, Rowan K. Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database. Anaesthesia 2007;62:1207-16. 6. Longstreth WT, Jr., Inui TS, Cobb LA, Copass MK. Neurologic recovery after out-of-hospital cardiac arrest. Ann Intern Med 1983;98: 588-92. 7. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support: section 8: postresuscitation care. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000;102:I166-71. 8. Wright WL, Geocadin RG. Postresuscitative intensive care: neuroprotective strategies after cardiac arrest. Semin Neurol 2006;26:396-402. 9. Bell DD, Brindley PG, Forrest D, Al Muslim O, Zygun D. Management following resuscitation from cardiac arrest: recommendations from the 2003 Rocky Mountain Critical Care Conference. Can J Anaesth 2005;52:309-22. 10. Edgren E, Hedstrand U, Kelsey S, Sutton-Tyrrell K, Safar P. Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group. Lancet 1994;343:1055-9. 11. Rogove HJ, Safar P, Sutton-Tyrrell K, Abramson NS. Old age does not negate good cerebral outcome after cardiopulmonary resuscitation: analyses from the brain resuscitation clinical trials. The Brain Resuscitation Clinical Trial I and II Study Groups. Crit Care Med 1995;23: 18-25. 12. Zeiner A, Holzer M, Sterz F, Schorkhuber W, Eisenburger P, Havel C, et al. Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome. Arch Intern Med 2001;161:2007-12. 13. Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F. Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253: 1420-6. S14
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