Brain & NeuroRehabilitation Vol. 7, No. 1, March, 2014 http://dx.doi.org/10.12786/bn.2014.7.1.5 저산소 - 허혈성뇌병증환자의신경학적회복예측 연세대학교의과대학재활의학교실및재활의학연구소 윤서연ㆍ김제경ㆍ김용욱 Prediction of Neurological Recovery in Patients with Hypoxic-ischemic Encephalopathy Seo Yeon Yoon, M.D., Je Kyung Kim, M.D. and Yong Wook Kim, M.D., Ph.D. Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine The incidence of hypoxic-ischemic encephalopathy (HIE) is not well known, however, the common causes of hypoxic-ischemic encephalopathy are sudden cardiac arrest, acute respiratory failure and carbon monoxide poisoning. Due to high metabolic demand, the brain is very susceptible to damage from deprivation of blood supply and oxygen delivery. When patients recover from comatose after HIE, there are various spectrums of neurological outcomes, ranging from vegetative state to good recovery. Various methods including neurologic examination, neurophysiologic and biochemical tools, neuroimaging technique have been proposed for the prognostic evaluation of HIE. This article reviews the pathophysiology of HIE and predictive methods for neurological recovery after HIE. (Brain & NeuroRehabilitation 2014; 7: 5-9) Key Words: hypoxic-ischemic encephalopathy, neurological recovery, prediction 서론 저산소-허혈성뇌병증 (hypoxic-ischemic encephalopathy) 은의식장애또는인지장애등의심한신경학적후유증을유발하는뇌질환으로, 유병률은아직정확히알려진바가없으나가장흔한원인으로는급성심정지, 급성호흡부전, 일산화탄소중독등이알려져있다. 1 뇌조직은높은대사요구량때문에혈액공급량손실이나산소공급의부족, 독성물질등의다양한원인에의하여손상을받게되며, 발병기전에따라허혈성, 핍혈성 (oligemic), 무산소성, 저산소성, 조직독성, 빈혈성으로분류된다 (Table 1). 2 저산소- 허혈성뇌병증은발병후식물상태 (vegetative state) 또는최소의식상태 (minimally conscious state) 등의의식장애에서시작하여신경학적회복이많이일어난경우일상생활로의복귀까지다양한임상적경과를보이나, 3 예후에대한예측은매우어렵다. 최근에는급성심정 Correspondence to: Yong Wook Kim, Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel: 02-2228-7316, Fax: 02-363-2795 E-mail: ywkim1@yuhs.ac This work was supported by a faculty research grant of Yonsei University College of Medicine for 2010 (6-2010-0034), Seoul, Republic of Korea. 지후심폐소생술로소생된환자들에게저체온요법을시도하면서신경학적호전을보였고이와함께의식의회복비율도높아지게되었다. 따라서저산소- 허혈성뇌병증환자에서의예후예측은더중요하게되었으며, 이는정확한예후를예측함으로써보호자들에게명확한설명을할수있고이를통하여불필요하게들게되는의료비용을절감할수있으며, 기계에의존한삶을지속할것인지결정을하는법적인측면에서역시중요하다고할수있겠다. 현재까지알려진저산소-허혈성뇌병증예후예측인자는신경학적검사를포함한임상적소견, 신경생리학적소 Table 1. Classification of Hypoxic-Ischemic Encephalopathy Type Mechanism Example Ischemic Total cessation of blood supply to the brain Cardiac arrest Oligemic Impaired blood supply to the brain Hypotension Anoxic Total absence of oxygen delivery Respiratory failure Hypoxic Reduction in arterial oxygen delivery Chronic pulomnary disease Histotoxic Poisoning of celluar oxidative CO intoxification mechanism Anemic Insufficient hemoglobin to carry available O 2 5
Brain& NeuroRehabilitation:2014; 7: 5~9 견, 생화학적검사결과및뇌영상학적소견들이제시되고있다. 이에본논문에서는저산소-허혈성뇌병증의발병기전및신경학적예후를결정하는것으로알려져있는인자에대해알아보고자한다. 본론 1) 발병기전저산소- 허혈성뇌병증의가장흔한원인은급성심정지다. 1 심정지로인한허혈성뇌병증 (ischemic encephalopathy) 의기전은여러동물실험을통하여연구된결과, 신경학적손상및회복은심정지후소생술이시작된시간과관련이있다고보고되었고, 심정지후일정시간내재관류되는경우뇌세포괴사를줄일수있는데이기간을 재생기간 (revival period) 이라고한다. 4 심정지발생후심폐소생술이시도되지않고 15분이경과하면뇌조직에전반적인경색이유발되면서 90% 이상의뇌손상을유발한다. 5 전신적순환이회복되더라도뇌손상이일정기간지속될수있는데, 순환회복직후 15분간혈류가정상수준의 2 3 배까지증가되는허혈후충혈현상이일어나며, 이후 6 24시간까지정상혈류수준의 30 50% 까지감소하는저관류상태가된다. 6,7 이러한변화외에도혈액점도의증가, 5 혈관경련에의한뇌관류- 전신순환부조화등이생겨뇌손상을유발할수있다. 8 손상부위는해마, 소뇌, 신피질 (neocortex), 시상, 선조체, 혈관의분기지역 (vascular watershed zone) 과같이신진대사가활발히일어나거나산소요구량이높은뇌영역에서더흔하게관찰된다. 9-13 기도폐쇄, 기도손상, 약물중독등의원인에의하여급성호흡부전이발생하는경우에는저산소성뇌병증 (hypoxic encephalopathy) 을초래하게된다. 발생기전중저산소성손상만있는경우에는전신순환이보존되어있는한저산소기간이길더라도심한뇌손상을유발하지는않지만저산소성손상과함께심정지가유발된경우의식장애를동반하는심한뇌손상을유발한다. 저산소상태만발생한경우신경세포의사멸보다는기능적변화만유발하기때문에심정지환자에서보다더많은신경학적회복을더기대할수있다. 14 또한환자들의연령대역시심정지와같은허혈성손상에비하여젊은편이어서, 심 뇌혈관계자가조절기능이더보존되어있어뇌혈관의확장과뇌혈류의증가를유도할수있다. 15 손상부위는피질하백질, 혈관의분기지역을주로침범하며, 신경접합부수준 (synaptic level) 에손상이생기면근 간대경련, 가바성결핍 (GABA-ergic deficit) 에의한경련을유발할수있다. 14 일산화탄소중독과같은조직독성뇌병증 (histotoxic encephalopathy) 은산소가혈색소에붙는것이제한됨으로써뇌혈관확장, 질산분비, 자유라디칼형성, 심근허혈등의증상을일으킨다. 14 신진대사가활발히일어나거나산소요구량이높은뇌부위에손상이많이생기며, 기저핵에손상이발생하면파킨슨증상을유발할수있고, 해마와백질에손상이생기면인지저하를초래할수있다. 16 2) 예후예측인자 (1) 신경학적검사저산소-허혈성뇌병증의예후를예측하기위해서는신경생리학적검사, 생화학적검사등많은요소들을확인해야하는데, 침상에서시행하는신경학적검사를통해서도어느정도예측이가능하다. 수상 72시간에외부자극에의미있는반응이없는경우, 즉대광반사, 각막반사, 통증자극에운동반응이없는경우나쁜예후를예측할수있다. 17-21 대광반사가없는경우지속적인혼수상태를예측할수있으며, 17,18 통증자극에운동반응이없는경우는나쁜예후에대한독립적인예측인자라고제시되었던바있고, 19 각막반사가없는경우나쁜예후에대한위양성확률이거의없다고보고된바있다. 20,21 이렇게외부자극에대한반응이없는경우들은대뇌피질과뇌간을포함한광범위한뇌손상이있음을의미한다. 이외에온도ㆍ안진검사 (caloric test) 도예후예측인자로제시가된바있으나, 마취제등의약물을사용하는상황에서는결과를정확히얻을수없다는제한점이있다. 21 수상후 24시간에근간대성간질지속상태 (myoclonic status epilepticus) 가관찰되는경우는나쁜예후예측인자로사지, 체간및안면부위에양측성으로동시에일어나는경련반응 (bilateral synchronous twitches of limb, trunk, face) 을의미하며, 국소다발적비동시성간대성근경련 (multifocal asynchronus myoclonus) 인전신성강직성간대경련 (generalized tonic clonic seizure) 과감별을해야한다. 21,22 발병초기글라스고우혼수척도 (Glasgow coma scale, GCS) 로도예후를예측할수가있는데, 발병초기글라스고우혼수척도가 6점이상이고, 수상 6일째글라스고우혼수척도가 9점이상인경우좋은예후를시사한다고보고된바있고, 23 발병 72시간경의글라스고우혼수척도가 3점이하인경우나쁜예후를시사한다고보고되었다. 19 이와같이글라스고우혼수척도를이용한예후예측은연구자들에따라결과에다소차이가있어민감도가낮다고판단되며예후를예측할때다른결과들과종합하여판단할필요가있겠다. 24 (2) 신경 생리학적요소체성감각유발전위검사 (Somatosensory evoked potential), 6
윤서연외 2 인 : 저산소 - 허혈성뇌병증환자의신경학적회복예측 뇌파검사가저산소-허혈성뇌병증의예후를예측하는데사용된다. 저산소-허혈성뇌병증환자들은수상초기에기관삽관과호흡기를사용하는경우가많으며여러약물들을함께사용하게된다. 체성감각유발전위검사는뇌파검사에비하여검사결과가약물에의하여영향을덜받기때문에유용하며, 여러연구결과들에서가장정확한예측인자로제시되고있다. 24 주로 N20의잠시를측정하는데, 양측정중신경의잠시가측정되지않을때나쁜예측인자로알려져있다. 21,25 검사시기에대하여는아직논란이많으나발병 1 3일경에검사하는것이의미있는결과를보인다고보고된바있는데, 3 특히수상 24시간내에는잠시의변화가계속생기기때문에 24시간이후에검사할것을추천하고있다. 26 일부환자들에서는 N20이수상 1 일째정상소견을보이다가 3일째소실되는경우가있는데, 한번소실되면다시측정되는경우는관찰하기어렵고이는나쁜예후인자로제시되고있다. 25 이외에체성감각유발전위검사에서경척수전도시간 (Cervicomedullary conduction time) 이 N20과비슷한양상으로변화하기때문에이를측정하는것이예후예측에도움이된다고보고된바있다. 26 뇌파검사역시예후예측을위하여많이시행되는검사이다. 저산소- 허혈성뇌병증발생직후많은수의환자에서시행한뇌파검사결과피질반응이나타나지않기때문에수상직후에시행한검사로는예후를예측할수없어, 수상후 24시간은경과한후검사를진행해야한다. 18,27 수상 1일째 20μV미만의 generalized suppression, generalized epileptic form activity를동반한돌발파억제 (burst suppression), flat background의 generalized periodic complexes 가측정되는경우는나쁜예후를시사하며, 28 수상 1주일동안돌발파억제가보이는경우는지속적인혼수상태또는식물인간상태를시사한다. 17 (3) 생화학적검사저산소-허혈성뇌병증의예후예측인자로가장많이제시되고있는생화학적검사로는 Neuron specific endolase (NSE) 를들수있다. 수상 1 3일경측정한혈청 NSE수치가 33μg/L 이상인경우는나쁜예후를시사하고, 3,21 좋은예후를예측할수있는최적의 NSE수치는수상후 48 시간경에측정한 NSE수치가 58.3μg/L미만인경우로제시된바있다. 29 그러나현재까지신경학적회복을예측할수있는 NSE의정확한수치와측정시기에대하여는아직여러연구들에서각각다르게제시되고있다. 신경교단백질 (glial protein) 인 S100 단백질은수상후 24시간경에혈청최고치를이루고, 이후 48시간동안점차감소하는경향을보인다. 수상 1 3일경 NSE와 S100 protein 수치가같이상승되어있는경우는나쁜예후를시사한다. 27 이외에혈청과뇌척수액에서의 creatinine kinase (BB fraction), 신경미세섬유단백질 (neufofilament protein) 의측정도예측인자로제시되고있으나나쁜예후에대한특이도가크지않다. 3 위에설명한바와같이여러생화학적검사들이예후예측을위하여연구되었지만측정시기와예측가능한수치에대한결과가연구마다차이가있어실제사용에는제한적인실정이다. (4) 뇌 신경영상학적검사뇌 신경영상학적검사는전산화단층촬영, 자기공명영상촬영, 기능적뇌영상검사등을시행하여예후예측을시도할수있다. 뇌전산화단층촬영은저산소-허혈성뇌손상직후에는정상소견을보이는경우가많으나, 수상 3일째의뇌부종소견, 백질-회백질의음영의반전은나쁜예측인자로제시되며, 27 회백질 / 백질의비율이 1.18미만인경우에예후가나쁘다고보고되었다. 30,31 뇌자기공명영상촬영은뇌손상후 49 108시간내에시행하는것이예후예측에가장도움이되며, 확산강조영상 (diffusion weighted imaging) 과겉보기확산계수 (apparent diffusion coefficient) 를주의해서봐야한다. 32,33 측두엽, 후두엽, 롤란딕영역주변부 (peri-rolandic area) 등의피질조직과조가비핵 (putamen) 에서이상소견이발견된경우는예후가나쁘며, 대부분수상 1.5일째에주로발견되며수상 3 5일경에가장심해진다고보고되었다. 34,35 또한, 혼수상태로부터회복될수있는좋은예측인자로는뇌손상후뇌자기공명영상검사에서측두엽, 후두엽, 해마, 부챗살관 (corona radiata) 의손상이적은경우로알려져있다. 34 기능적뇌영상검사는뇌자기공명영상검사, 뇌양전자방출단층촬영등의방법으로시행되며, 대부분의연구에서식물상태또는최소의식상태의뇌기능을측정하여회복가능여부를예측하고있으나아직까지많은연구가이루어지고있지않다. 뇌손상후의식장애를보이는환자에서기능적뇌자기공명영상검사를이용하여연구한결과, 고수준연합피질 (high-level associative cortex) 에비정형적인활성이측정된경우는식물상태로부터회복될가능성이있으며, 저수준일차감각피질 (low-level primary sensory cortex) 이활성화되거나뇌피질의활성화가관찰되지않는경우에는회복을예측하기어렵다고보고되었다. 36 저산소 -허혈성뇌손상식물상태를보이는환자를대상으로뇌양전자방출단층검사를시행한결과, 식물상태의경우의식조절뇌신경망을구성하는전두-두정엽, 쐐기앞소엽 (precuneus), 후띠이랑 (posterior cingulated gyrus) 의뇌대사량이저하되어있다고보고된바있다. 37 이외에뇌분광촬영술 (Brain MR spectography) 을이용한연구들도시행되고 7
Brain& NeuroRehabilitation:2014; 7: 5~9 있으나아직까지보다많은연구가필요한실정이다. 결론 저산소- 허혈성뇌병증은심정지, 호흡부전, 일산화탄소중독등의다양한원인에의하여발생하며, 뇌손상이광범위하게일어나기때문에대부분에서의식장애를동반한다. 손상후기능회복은식물상태로부터정상생활가능수준까지다양하게일어나지만기능회복을예측하는방법은아직확립되어있지않다. 현재까지예후예측을위한방법은신경학적검사, 신경생리학적검사, 생화학적검사, 뇌신경영상학적검사들이이용되고있으나한가지방법으로예측하는것은어려움있어여러가지방법을복합적으로적용하여판단하여야하겠다. 참고문헌 1) Callans DJ. Out-of-hospital cardiac arrest-the solution is shocking. N Engl J Med. 2004;351:632-634 2) Brierly JB, Graham DI. Hypoxia and vascular disorders of the central nervous system. In: Adams JH, Corsellis JAN, Duchan LW, eds. Greenfield s Neuropathology. 4th ed. London: Arnold; 1984:125-207 3) Wijdicks EFM, Hijdra A, Young GB, Bassetti CL, Wiebe S. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidencebased review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;67:203-10 4) Hossmann KA, Reperfusion of the brain after global ischemia:hemodynamic disturbances. Shock. 1997;8(2):95-103 5) Ames A 3 rd, Wright RL, Kowada M, Thurston JM, Majno G. Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol. 1968;52(2):437-453 6) Crumrine RC, LaManna JC. Regional cerebral metabolites, blood flow, plasma volume, and mean transit time in total cerebral ischemia in the rat. J Cereb Blood Flow Metab. 1991;11(2):272-282 7) LaManna JC, Crumrine RC, Jackson DL. No correlation between cerebral blood flow and neurologic recovery after reversible total cerebral ischemia in the dog. Exp Neurol. 1988;101(2):234-247 8) Ginsberg MD, Myers RE. The topography of impairedmicrovascular perfusion in the primate brain following total circulatory arrest. Neurology. 1972;22(10):998-1011 9) Cervos-Navarro J, Diemer NH. Selective vulnerability in brain hypoxia. Crit Rev Neurobiol. 1991;6(3):149-182 10) Petito CK, Feldmann E, Pulsinelli WA, Plum F. Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology. 1987;37(8):1281-1286 11) Kawai K, Nitecka L, Ruetzler CA, Nagashima G, Joó F, Mies G, Nowak TS Jr, Saito N, Lohr JM, Klatzo I. Global cerebral ischemia associated with cardiac arrest in the rat: I. Dynamics of early neuronal changes. J Cereb Blood Flow Metab. 1992; 12(2):238-249 12) Plum F, Posner JB, Hain RF. Delayed neurological deterioration after anoxia. Arch Intern Med. 1962;110:18-25 13) Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol. 1928;11(5):491-498 14) Busl KM, Greer DM. Hypoxic-ischemic brain injury: Pathophysiology, neuropathology and mechanism. Neurorehabilitation. 2010;26:5-13 15) Greer DM. Mechanisms of injury in hypoxic-ischemic encephalopathy: implications to therapy. Semin Neurol. 2006;26(4): 373-379 16) Prockop LD, Chichkova RI. Carbon monoxide intoxication:an updated review. J Neurol Sci. 2007;262(1-2):122-130 17) Zandbergen EG, de Haan RJ, Stoutenbeek CP, Koelman JH, Hijdra A. Systemic review of early prediction of poor outcome in anoxic-ischemic coma. Lancet. 1998;352:1808-1812 18) Jørgensen EO, Holm S. Prediction of neurological outcome after cardiopulmonary resuscitation. Resuscitation. 1999;41: 145-152 19) Edgren E, Hedstrand U, Keisey S, Sutton-Tyrrell K, Safar P. Assessment of neurological prognosis in comatose seuvivors of cardiac arrest. BRCT I STUDY Group. Lancet. 1994;343: 1055-1059 20) Berek K, Lechleitner P, Luef G, Felber S, Saltuari L, Schinnerl A, Traweger C, Dienstl F, Aichner F. Early determination of neurological outcome after prehospital cardiopulmonary resuscitation. Stroke. 1995;26(4):543-549 21) Zandbergen EG, Hijdra A, Koelman JH, Hart AA, Vos PE, Verbeek MM, de Haan RJ. Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology. 2006;66(1):62-8 22) Wijdicks EF, Parisi JE, Sharbrough FW. Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol. 1994;35:239-43. 23) Mullie A, Verstringe P, Buylaert W, Houbrechts H, Michem N, Delooz H, Verbruggen H, Van den Broeck L, Corne L, Lauwaert D. Predictive value of Glasgow coma score for awakening after out-of-hospital cardiac arrest. Cerebral Resuscitation Study Group of the Belgian Society for Intensive Care. Lancet. 1988;1:137-40 24) Young GB. Neurologic prognisis after cardiac arrest. N Engl J Med. 2009;361:506-511 25) Young GB, Doig G, Ragazzoni A. Anoxic-ischemic encephalopathy: clinical and electrophysiological associations with outcome. Neurocrit Care. 2005;2:159-64 26) Gendo A, Kramer L, Häfner M, Funk GC, Zauner C, Sterz F, Holzer M, Bauer E, Madl C. Time-dependency of sensory evoked potentials in comatose cardiac arrest survivors. Intensive Care Med. 2001;27(8):1305-11 27) Zingler VC, Krumm B, Bertsch T, Fassbender K, Pohlmann- Eden B. Early prediction of neurological outcome after cardiopulmonary resuscitation: a multimodal approach combining neurochemical and electrophysiological investigations 8
윤서연외 2 인 : 저산소 - 허혈성뇌병증환자의신경학적회복예측 may provide higher prognostic certainty in patients after cardiac arrest. Eur Neurol. 2003;49:79-84 28) Roest A, van Bets B, Jorens PG, Baar I, Weyler J, Mercelis R. The prognostic value of the EEG in postanoxic coma. Neurocrit Care. 2009;10(3):318-25 29) Bouwes A, Binnekade JM, Kuiper MA, Bosch FH, Zandstra DF, Toornvliet AC, Biemond HS, Kors BM, Koelman JH, Verbeek MM, Weinstein HC, Hijdra A, Horn J. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann Neurol. 2012;71(2):206-2012 30) Torbey MT, Selim M, Knorr J, Bigelow C, Recht L. Quantitative analysis of the loss of distinction between gray and white matter in comatose patients after cardiac arrest. Stroke. 2000;31:2163-2167 31) Torbey MT, Geocadin R, Bhardwaj A. Brain arrest neurological outcome scale (BrANOS): predicting mortality and severe disability following cardiac arrest. Resuscitation. 2004;63:55-63 32) Els T, Kassubek J, Kubalek R, Klisch J. Diffusion-weighted MRI during early global cerebral hypoxia: a predictor for poor clinical outcome? Acta Neurol Scand. 2004;110:361-7 33) Wijman CAC, Mlynash M, Caufield AF, et al. Prognostic value of brain diffusion-weighted imaging after cardiac arrest. Ann Neuro. 2009;65:394-402 34) Mlynash M, Campbell DM, Leproust EM, Fischbein NJ, Bammer R, Eyngorn I, Hsia AW, Moseley M, Wijman CA. Temporal and spatial profile of brain diffusion-weighted MRI after cardiac arrest. Stroke. 2010;41(8):1665-72 35) White ML, Zhang Y, Helvey JT, Omojola MF. Anatomical patterns and correlated MRI findings of non-perinatal hypoxic-ischaemic encephalopathy. Br J Radiol. 2013;86(1021): 20120464 36) Di H, Boly M, Weng X, Ledoux D, Laureys S. Neuroimaging activation studies in the vegetative state: predictors of recovery?. Clin Med. 2008;8(5):502-7 37) Kim YW, Kim HS, An YS. Brain metabolism in patients with vegetative state after post-resuscitated hypoxic-ischemic brain injury: statistical parametric mapping analysis of F-18 fluorodeoxyglucose positron emission tomography. Chin Med J. 2013; 126(5):888-894 9