REVIEW J Neurocrit Care 2016;9(1):1-6 http://dx.doi.org/10.18700/jnc.2016.9.1.1 eissn: 2508-1349 뇌전증지속상태의치료 부산대학교의학전문대학원신경과학교실, 부산대학교병원의생명연구원 이가현 정대수 Treatment of Status Epilepticus Gha-Hyun Lee, MD, and Dae Soo Jung, MD, PhD Department of Neurology, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Busan, Korea Status epilepticus is a severe neurological disease associated with substantial mortality and health-care cost. Treatment of status epilepticus should proceed without delay even in the pre-hospital setting because prolonged generalized convulsive seizures may lead to neuronal injury, pharmacoresistance, and poor prognosis. These concepts have led to the establishment of an updated treatment algorithm emphasizing a more rapid escalation to third-line therapy for refractory convulsive status epilepticus. This article reviews the guidelines and current evidence for the management of status epilepticus. J Neurocrit Care 2016;9(1):1-6 Key Words: Status epilepticus; Anticonvulsants; Benzodiazepines; Anesthesia 서 론 본 론 뇌전증지속상태는심한후유증이발생할수도있는응급질 환으로환자상태에대한빠른판단과처치가필요하다. 초기 의빠른경련조절이환자의예후에큰영향을미치기때문에 내원전처치에대한중요성이대두되고있으며, 내원후에도 경련이조절되지않으면 60 분이내에삼차약제까지약물치 료가시작되어야한다. 이러한치료경향은최근발표된미국 뇌전증협회의경련성뇌전증지속상태치료지침에도반영되 었다. 1 본논문에서는현재까지발표된뇌전증지속상태의치 료지침에대해알아보고, 최근바뀌고있는치료동향에대해 살펴보도록한다. Received: May 24, 2016 / Revised: May 27, 2016 Accepted: May 27, 2016 Address for correspondence: Gha-Hyun Lee, MD Department of Neurology, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea Tel: +82-51-240-7317, Fax: +82-51-245-2783 E-mail: ka-hyun-ii@hanmail.net 뇌전증지속상태의내원전처치 (Pre-hospital management of status epilepticus) 뇌전증지속상태는경련시간이길어질수록약물저항성이높아지고신경손상이발생하기때문에빨리치료를시작할수록치료효과가좋으며예후도개선된다. 2,3 뇌전증지속상태로확인되면지체없이치료를시작해야하며, 이러한이유로내원전처치의중요성이대두되고있다. 4,5 소아난치성뇌전증환자에서경련이길게지속될경우보호자나간병인이직접병원내원하기전직장내로 diazepam을투여하여경련을멈추도록하는치료가효과가있음이이미 1970년대에보고되었다. 6,7 뇌전증지속상태환자에서병원내원전 benzodiazepines (lorazepam, diazepam) 투여의효과와안전성에대한무작위대조시험이있었으며, 병원전정맥내 benzodiazepines 투여는뇌전증지속상태치료효과가위약보다우수했으며, 병원도착후기관내삽관율을감소시켰다. 8 내원전처치가뇌전증지속상태치료에우수하다는것이연구를통해밝혀지면서비의료인이시행할수있는내원전처치 Copyright 2016 The Korean Neurocritical Care Society 1
J Neurocrit Care 2016;9(1):1-6 의중요성이대두되었으며정맥내투여외에비의료인이쉽게시행할수있는다른투여방법에대한연구가진행되었다. 내원전경련조절에있어서구강내 midazolam 투여가직장내 diazepam 투여와효과가비슷하거나더좋으며, 호흡저하의빈도도증가하지않았다. 9,10 Rapid Anticonvulsant Medications Prior to Arrival Trial (RAMPART) 연구는무작위대조시험으로, 내원전정맥내 lorazepam 투여와 midazolam의근육내주사를비교한연구로, 근육내 midazolam 투여가정맥내 lorazepam 투여에비해합병증및치료효과에서비슷한결과를보였다. 11 이러한내원전치료의노력들은, 가족을포함한환자의주보호자및응급구조사가빠른처치를할수있게하여합병증및신경손상을감소시킬수있다. 뇌전증지속상태의내원후처치 (Hospital management of status epilepticus) (Fig. 1) 경련성뇌전증지속상태는응급질환으로, 다른의식저하가동반된응급질환의처치와마찬가지로기도확보및정맥로확보가빨리이루어져야한다. 12,13 대부분의환자는기도확보만되어있으면경련도중에도호흡이가능하나, 전신근간대성경련은무호흡, 청색증, 대사성산증을일으킬수있기때문에코삽입관이나안면마스크등으로산소공급을해야하며임상적으로호흡부전이관찰될경우에는기관내삽관을시도해야한다. 만약기관내삽관이필요한경우는근육경련을잠시멈추기위해단기작용근육이완제를사용해야한다. 응급실에환자가내원하였을경우에는혈당검사가필수적이며포도당투여시에는베 Figure 1. Treatment algorithm for convulsive status epilepticus. EEG, Electroencephalography. 2
Treatment of Status Epilepticus Lee GH, et al. 르니케뇌병증을예방하기위해포도당투여와함께티아민정주가필요하다. 14 혈당검사외에전해질이상이있는지확인해야하며경련유발약물이나독극물을사용하고있으면끊도록한다. 고열이있는경우빠르게교정한다. 15 환자의활력징후가안정화된이후에는경련이오래지속될수록신경손상및약물저항성이커져서예후가나빠질수있기때문에경련을빨리멈추기위한처치가즉각적으로필요하다. 4,5 현재까지뇌전증지속상태의일차약제는 benzodiazepine으로그중에서도 lorazepam을정맥내투여한다. 3,8,16 이전 RAM- PART 연구에서 midazolam 근육주사와 lorazepam의정맥주사가비슷한효과를보였지만이연구는병원내원전처치에대한연구로, 병원내에서정맥확보만빨리된다면 lorazepam 정맥내주사부터실시해야한다. 11 경련성뇌전증지속상태에서 1998 년도에발표된이중맹검무작위대조연구에의하면, lorazepam 단독투여, phenobarbital 단독투여, diazepam과 phenytoin 동시투여, phenytoin 단독투여로네가지치료법을비교하였을때 lorazepam 투여가 phenytoin 단독투여보다효과적이였으며, phenobarbital 단독투여및 diazepam과 phenytoin 동시투여와경련조절효과면에서는비슷한결과를보였으나, lorazepam의정맥내주입이신속하고편리하며경제적인이유로가장선호된다. 3 2 mg 에서 4 mg을투여할수있으며경련이신속하게멈추지않는경우한번더투여할수있다. Lorazepam 투여이후에는경련이조절되던조절되지않던이차약제를투여한다. 경련이조절되었다하더라도, benzodiazepines의효과가떨어지면경련이다시발생하는것을막아야하기때문이다. 이차약제는정맥내투여가가능하고치료효과농도로빨리부하투여가가능한 phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital 등을고려한다. 이전까지지침은 phenytoin/fosphenytoin을투여후호전되지않는경우 valproic acid, phenobarbital, levetiracetam, lacosamide 등의이차약제를사용하는것이나, 처음부터 phenytoin 대신에다른약물을사용해도효과가비슷한결과를보인소규모연구들이많이발표되어현재대규모연구가진행중이다. 17 36명을대상으로 diazepam과 phenytoin을동시투여한그룹과 phenobarbital 단독투여그룹을비교한무작위비맹검임상연구에서두그룹의경련감소효과는비슷하였으며, phenobarbital 투여가 phenytoin 투여에비해신속하고편리하였다. Valproic acid 과 phenytoin의비교는비교적연구가많이되었으며대부분의연구에서 valproic acid가 phenytoin과효과가비슷하였으며, 18-20 valproic acid의치료효과가 phenytoin에비해우수하게나타난연구도있었다. 21 따라서, lorazepam 투여후이차약제의선택은 phenytoin/fosphenytoin으로고정하지않고, 뇌전증지속상태의원인과동반질환을고려해결정해야한다. 특발성전신 뇌전증환자에서약물금단증상으로뇌전증지속상태가발생하였을때는 valproic acid나 levetiracetam을사용하고 phenytoin/ fosphenytoin은사용하면안된다. 또한심장전도지연이있는환자에서는심장전도지연을악화시킬수있는 phenytoin은피하는것이좋다. 간부전, 혈소판감소증등이있는환자에서는간독성및혈액응고장애를일으킬수있는 valproic acid는지양해야하며, phenobarbital은진정효과가길게지속되는등의부작용으로최근에는잘사용하지않는추세이다. 15 Phenytoin/fosphenytoin은뇌전증지속상태의이차치료약제로현재까지가장많이사용하는약물로, 비용이다소비싸더라도 fosphenytoin을사용하는것이바람직하다. Fosphenytoin 은 phenytoin의수용성전구물질로, fosphenytoin을 phenytoin 비해빨리투여하더라도부정맥및저혈압의발생빈도가낮으며, 혈관외유출시발생하는 purple glove syndrome도줄일수있다. 22 인산염이부하되면서 50% 환자에서가려움증을일으킬수있으나, 알레르기반응이아니며주입속도를늦추면증상이호전된다. Phenytoin은 20 mg/kg를 50 mg/min 속도로정주해야하며 fosphenytoin은 20 mgpe (phenytoin equivalents)/kg 를 150 mg/min 속도로투여할수있어세배빨리투여할수있다. 그래도경련이멈추지않을경우 5-10 mg/kg 를추가로투여하여약물농도를치료범위이상으로유지한다. 3 Valproic acid를사용하는경우에는통상용량보다고용량을사용하는것이추천되며 (~40 mg/kg), 최대 6 mg/kg/min 속도로정맥주사할수있다. 13,23 진정및심폐기능에영향을거의주지않는장점이있으나, 간독성및혈소판감소증등이발생할수있으므로유의한다. 18,21 Levetiracetam은새로운항경련제중에서정맥주사가가능하며, 상대적으로부작용이적고다른약물과상호작용이없어많이사용되고있는추세이다. 하지만뇌전증지속상태치료효과에대한 valproic acid 와의비교연구에서는 valproic acid에비해효과가떨어지는것으로발표되었다. 20 난치성뇌전증지속상태 (Refractory status epilepticus) (Fig. 1) 난치성뇌전증지속상태는 benzodiazepines에의한일차약제나, phenytoin, valproic acid, levetiracetam 같은이차약제에경련이멈추지않는경우를말한다. 24 난치성뇌전증지속상태는약물투여후에도임상적으로경련이관찰되거나, 임상적으로경련이관찰되지않더라도뇌파검사상무증상경련이지속되는경우이다. 전체뇌전증지속상태환자에서대략 30-40% 환자가난치성뇌전증지속상태로나타나고, 난치성뇌전증지속상태의사망률은 17% 에서 39% 로비난치성뇌전증지속상태에비해현저하게높다. 24-28 동물실험에서연구된바에따르면, 뇌전증지속상태의급성기에는 GABA (γ-aminobutyric acid) 작용제가효과가좋으나, 경 3
J Neurocrit Care 2016;9(1):1-6 련발생 5분이지나가면서 GABA 수용체가세포내로이동하면서 GABA 작용제의효과는점차떨어진다. 29-31 이로인해 GABA receptor에주로작용하는 benzodiazepines의효과는점차감소할수밖에없으며, 이차약제에도반응하지않는경우에는빠른경련중지가환자의예후에중요한요인으로인식되면서경련발생후 60분이내에삼차약제를시작하는것이바람직한것으로인식되고있다. 32 뇌전증지속상태에서가장많이사용되는삼차약제로는 midazolam, propofol, pentobarbital 이다. 삼차약제모두부하용량을정맥내대량주입후일정농도로유지한다. 33 세가지약물중에더효과적이거나사망률을낮추는약물은현재까지연구로밝혀져있지않다. 27,34 Midazolam은처음에는반감기가짧지만, 사용하는기간이길어질수록반감기도길어진다. 35 Midazolam 같은 benzodiazepines은사용할수록경련에내성이생기는단점이있으며 pentobarbital에비해치료도중돌발경련이발생할가능성이높아경련조절시약물농도의조절이지속적으로필요하다. Propofol은 GABA A 수용체활동성을증가시키고, 나트륨통로차단제로작용한다. 짧은반감기를가지고있으나, propofol 사용시에는 propofol 정맥주입증후군을유의하여야한다. Propofol 정맥주입증후군은드물게발생하지만, propofol을용량을높게 (5 mg/kg/h 이상 ), 길게 (48시간이상 ) 사용할수록, 환자가젊은나이거나, 급성신경학적질환이있는경우자주발생하며, 횡문근융해, 대산성산증, 고칼륨혈증, 신부전, 심부전등을일으켜사망에이르게하는치명적인질환이다. 36 Pentobarbital은지방조직에침착하는성질이있어앞의두약제에비해반감기가훨씬길다. 일반적으로 pentobarbital은 midazolam과 propofol에비해경련억제효과는좋으나저혈압, 폐렴등의합병증은더빈번하게발생한다. 34-38 난치성뇌전증지속상태의치료에서는겉으로나타나는임상적경련없이뇌파상경련만지속될수있기때문에적절한약물치료를위하여지속적인뇌파감시가필수적이다. 돌발파억제가어느정도여야하는지, 치료기간이얼마여야하는지에대한정확한지침및뒷받침하는연구는없으나, 대개 1-2초의돌발파사이에는 10초정도의뇌파억제가필요하다. 치료도중돌발경련이발생할경우에는추가용량을일시적으로주사하거나, 유지용량을증량한다. 경련발생없이돌발파억제가하루에서이틀간잘유지되면항경련제는유지또는증량하면서삼차약제의감량을고려해볼수있다. 13 Table 1. Treatment of super-refractory status epilepticus Other anesthetic drug Ketamine Immune therapies Methylpredinosolone IV immunoglobulin Plasmapheresis Nonpharmacologic therapies Electroconvulsive therapy Hypothermia Resective surgery Ketogenic diet 은환자에서뇌염에의한뇌전증지속상태가발생한경우에많 으며난치성뇌전증지속상태에서 20% 정도를차지한다. 24,39 이러한경우에는다른삼차약제로바꿔서사용하거나, 두가 지이상의삼차약제를함께사용하기도하며, N-methyl-Daspartate 수용체에작용하는 ketamine 을추가로투여해볼수 있다. 현재까지기술한약물들을제외하고, 스테로이드나면역 글로불린등의면역요법을고려할수있으며, 케톤식이, 저체 온요법, 신경외과적수술및전기경련요법등을시도해볼수 있다 (Table 1). 23,40,41 비경련성뇌전증지속상태 (Non-convulsive status epilepticus) 비경련성뇌전증지속상태의치료에대해서는연구보고가 별로없고특별한지침도마련되어있지않다. 경련성뇌전증 지속상태와다르게생명을위협하는전신기능이상을동반하 지않아경련성뇌전증지속상태에비해서는비응급성질환이 다. 하지만비경련성뇌전증지속상태에서도경련이오래지속 되면, 신경손상이나타나기때문에빨리진단하여치료해야한 다. 42,43 초기치료는경련성뇌전증지속상태와마찬가지로 benzodiazepines 을사용하며, benzodiazepines 에반응이없는경우 추가로이차약제를사용한다. 44 이차항경련제에반응이없는 경우경련성뇌전증지속상태와는달리삼차약제치료를시작 하는것이아니라다른항경련제추가를고려하는데, 이는마 취제사용에의한합병증이환자의예후에더나쁜영향을끼 칠수있기때문이다. 44,45 Loading: 1.5 mg/kg IV Maintenance 1.2-7.5 mg/kg/h 1 g/day during 3 days 0.4 g/kg/day for 5 days 1 session every other day for 7 days 1 session daily for 3-8 days 30-35, 24-60 hrs 악성 / 초난치성뇌전증지속상태 (Malignant/super-refractory status epilepticus) 삼차약제사용에도경련이조절되지않는경우, 악성 39 또는초난치성 40 뇌전증지속상태라고일컫는경우가있으며주로젊 심정지후발생한뇌전증지속상태 (Status epilepticus after cardiac arrest) 저산소성뇌병증이후에발생한뇌전증지속상태는예후가나쁜것으로알려져있고특히전신의지속적인근간대발작이동 4
Treatment of Status Epilepticus Lee GH, et al. 반된경우, 회복할가능성이 10% 미만으로매우불량한것으로 알려져있다. 46 하지만저체온법치료를많이적용하기시작하 면서, 심정지후전신근간대발작이지속적이라하더라도, 저체 온요법이후에비교적양호한예후를보이는경우가있으며, 특 히배경뇌파가통증등에대해변화가있을경우좋은예후를보 일가능성이높기때문에적극적인치료가필요하다. 47 결 론 뇌전증지속상태는높은사망률을보이고큰후유증을남기 는심각한질환으로즉각적인치료가필요하다. 경련을빨리치 료할수록병의난치성을방지하고예후가호전되기때문에최 대한빨리경련을조절하는것에집중하여야하며, 병원도착하 기전에비의료인에의한항경련제투여가이루어질수있도록 사회적노력이필요하다. 난치성뇌전증지속상태및비경련성 뇌전증지속상태에대한적절한치료지침에대해서는추가연구 가필요하다. REFERENCES 1. Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: Report of the guideline committee of the american epilepsy society. Epilepsy Curr 2016;16:48-61. 2. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality. Neurology 1996;47:83-9. 3. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans affairs status epilepticus cooperative study group. N Engl J Med 1998;339:792-8. 4. Kapur J, Macdonald RL. Rapid seizure-induced reduction of benzodiazepine and Zn 2+ sensitivity of hippocampal dentate granule cell gabaa receptors. J Neurosci 1997;17:7532-40. 5. Jones DM, Esmaeil N, Maren S, Macdonald RL. Characterization of pharmacoresistance to benzodiazepines in the rat Li-pilocarpine model of status epilepticus. Epilepsy Res 2002;50:301-12. 6. Knudsen FU. Rectal administration of diazepam in solution in the acute treatment of convulsions in infants and children. Arch Dis Child 1979;54:855-7. 7. Hoppu K, Santavuori P. Diazepam rectal solution for home treatment of acute seizures in children. Acta Paediatr Scand 1981;70:369-72. 8. Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-7. 9. Scott RC, Besag FM, Neville BG. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: A randomised trial. Lancet 1999;353:623-6. 10. McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP, Phillips B, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: A randomised controlled trial. Lancet 2005;366:205-10. 11. Silbergleit R, Durkalski V, Lowenstein D, Conwit R, Pancioli A, Palesch Y, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591-600. 12. Meierkord H, Boon P, Engelsen B, Gocke K, Shorvon S, Tinuper P, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2010;17:348-55. 13. Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3-23. 14. Sechi G, Serra A. Wernicke s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol. 2007;6:442-55. 15. Lawrence JH, Gaspard N. Status epilepticus. Continuum (Minneap Minn) 2013;19:767-94. 16. Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay RE, Patrick B. Double-blind study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452-4. 17. Cock HR, Group E. Established status epilepticus treatment trial (ESETT). Epilepsia 2011;52 Suppl 8:50-2. 18. Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, Garg N. Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure 2007;16:527-32. 19. Gilad R, Izkovitz N, Dabby R, Rapoport A, Sadeh M, Weller B, et al. Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin. Acta Neurol Scand 2008;118:296-300. 20. Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011;52:1292-6. 21. Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology 2006;67:340-2. 22. Browne TR, Kugler AR, Eldon MA. Pharmacology and pharmacokinetics of fosphenytoin. Neurology 1996;46(6 Suppl 1):S3-7. 23. Foreman B, Hirsch LJ. Epilepsy emergencies: diagnosis and management. Neurol Clin 2012;30:11-41, vii. 24. Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59:205-10. 25. Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005;76:534-9. 5
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