REVIEW J Neurocrit Care 2016;9(2):63-70 eissn 2508-1349 급성간부전에서의두개내압상승의병태생리와치료 장세영 1 장준영 2 경북대학교의과대학ㆍ의학전문대학원내과학교실소화기내과 1, 창원경상대학교병원신경과 2 Pathophysiology and Treatment of Cerebral Edema in Acute Liver Failure Se Young Jang, MD, PhD 1 and Jun Young Chang, MD 2 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, 2 Department of Neurology, Gyeongsang National University Changwon Hospital, Changwon, Korea Early diagnosis and management of cerebral edema in acute liver failure is important to reduce neurological complication and mortality. Ammonia-induced astrocyte swelling and increased blood brain barrier permeability via transmembrane dysfunction are major mechanisms of cerebral edema in acute liver failure. Conventional therapy can be used to lower intracranial pressure. In addition, various treatment options are available to reduce serum ammonia level. Herein, we described the pathophysiology, monitoring, and management of cerebral edema in acute liver failure. J Neurocrit Care 2016;9(2):63-70 Key words: Liver failure, Acute; Brain edema; Physiopathology; Therapy Received October 31, 2016 Revised November 11, 2016 Accepted November 21, 2016 Corresponding Author: Jun Young Chang Department of Neurology, Gyeongsang National University Changwon Hospital, 11 Samjeongja-ro, Seongsan-gu, Changwon 51472, Korea Tel: +82-55-214-3813 Fax: +82-55-214-2638 E-mail: kjychang@gmail.com Copyright 2016 The Korean Neurocritical Care Society 서론 두개골이라는한정된공간에뇌척수액 (10%, 140 ml), 혈액 (10%, 140 ml) 및뇌실질 (80%, 1,120 ml) 이포함되어있으며각각의구성성분이조화를이루어두개내압을일정하게유지한다. 1 여러가지원인으로인해보상기전과균형이깨어지게되면두개내압이상승하게되는데, 세가지구성요소중가장많은비중을차지하고있는뇌실질의부종이가장흔한두개내압상승의원인이다. 2 뇌부종에의한두개내압상승은뇌질환이외에도급성간부전으로인한간성뇌병증, 콩팥기능저하로인한투석환자에서의투석불균형증후군, 고혈압성뇌병증등의전신질환과동반되어서도나타날수있으며조기에진단해서치료하는것이중요하다. 본논문에서는뇌부종을초래할 수있는전신질환중간질환으로인한뇌부종의원인및병태생리와치료방침에관해알아보고자한다. 본론 1. 급성간부전과간성뇌병증급성간부전 (acute liver failure) 은기저간질환이없는환자에서갑자기발생하는심한간세포의소실로인한임상증후군으로사망률이 80% 에달하며이러한사망원인중일부는심한뇌부종으로인한두개내압상승과뇌탈출에기인한다. 급성간부전의발생원인으로아세트아미노펜과비아세트아미노펜에의한약물유발간독성이 50% 이상을차지하며그외 B형간염 cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. www.e-jnc.org 63
Table 1. Severity of hepatic encephalopathy (West Haven criteria) Grades Level of consciousness Cognitive function Psychiatric symptoms Neuromuscular function 1 Trivial lack of awareness, sleep disorder 2 Lethargy, forgetfulness Disorientation to time, amnesia of recent events 3 Somnolence (sleepiness) to stupor 4 Coma (unresponsive to verbal, noxious stimuli) Shortened attention span Euphoria, depression Tremor, in-coordination with or without asterixis Confusion, gross disorientation Inability to comply with testing Inappropriate behavior, anxiety Bizarre behavior Inability to comply with testing Slurred speech, hyperactive reflexes Babinski reflex, rigidity Inability to comply with testing (7%), 다른바이러스에의한간염 (3%), 자가면역간염 (5%), 허혈성간염 (4%) 등이있다. 3 간성뇌병증은황달의발생에서부터뇌병증이발생하는기간에따라 1주일이내의초급성기, 8일에서 28일사이의급성기, 5-12주사이의아급성기로분류하기도하며초급성으로빠르게뇌병증으로진행하는경우에뇌부종이발생할위험성이가장높다. 4,5 간성뇌병증의경우의식수준및인지기능정도에따라단계를구분하게되며침상에서도평가가가능한 West Haven criteria를많이사용한다 (Table 1). 6,7 3단계환자의 25-35%, 4 단계환자의 65~75% 에서급성간부전으로인한뇌부종이발생하며암모니아의배출장애로인한축적이중요한원인으로알려져있다. 8,9 별아교세포 (astrocyte) 의팽윤으로인한세포독성부종과혈액뇌장벽의손상으로인한혈관성부종두가지기전이모두급성간부전환자에서의뇌부종발생에영향을미친다. 2. 별아교세포의팽윤으로인한세포독성부종지속적으로세포내로유입되는나트륨, 칼슘과같은양이온및글루탐산염 (glutamate) 과같은신경전달물질을세포막에존재하는아데노신삼인산염 (adenosine triphosphate, ATP) 의존성 Na + /K + 이온통로를포함한여러이온채널들이세포밖으로배출하여세포내외의이온균형을유지하게된다. 허혈이나저산소손상등다양한원인에의해뇌세포가손상을받게되면세포의기능을유지하게위해필수적인 ATP의생성이줄어들게된다. ATP가부족하게되면나트륨, 칼슘등의양이온이세포밖으로배출되지못한채지속적으로내부에축적되고, 이온균형을맞추기위해염소이온과같은음이온이유입되어세포내부의삼투압이증가하게된다. 10,11 증가된세포내부의삼투압으로인해 Aquaporin 통로를통해수분이유입되어세포내의부피가증가하고수포형태의표면변화가발생하면서부풀어오르다사멸하는것이세포독성부종이다. 11,12 급성간부전에서는세포독성부종의발생에암모니아가주 NH 4 + Glutamate Oxidative stress Mitochondria NH 4 + + Glutamine Glutamine Glutamine transporter Figure 1. Cytotoxic astrocyte swelling due to oxidative stress in the mitochondria. The excess glutamine transported into mitochondria and degraded into ammonia and glutamate by phosphate-activated glutaminase (PAG). Ammonia and glutamate accumulated inside the mitochondria produce reactive oxygen species, resulting in astrocyte swelling. 된역할을하고글루탐산염, 염증성사이토카인, 젖산, 괴사된 간으로부터유리되는물질, 고온, 저나트륨혈증등이추가적인 상승효과를를일으키는것으로알려져있다. 13-15 특히이러한 세포독성부종은뇌전체부피의 1/3 을차지하며회색질에분 포하고있는별아교세포의발돌기 (foot process) 에주로발생한 다. 16 암모니아는소장에있는글루탐산분해효소 (glutaminase) 에의해글루타민이글루탐산염과암모니아로분해되면서생성 되며이러한암모니아의대부분이간의요소회로 (urea cycle) 을통해대사된다. 급성간기능손상으로인해혈중암모니아 가분해되지못하고축적되게되면확산을통해혈액뇌장벽을 통과한후별아교세포내로유입되어세포부종을초래하게된 다. 기존에는암모니아가별아교세포내부에서글루타민으로 재합성되어축적된글루타민이삼투물질로작용하여세포부 종을초래하는것으로알고있었으나글루타민의농도와세포 부종의정도및시간적선후관계가잘맞지않는다는보고가 있어, 17,18 최근에는별아교세포내부에서재합성된글루타민이 미토콘드리아로유입되면서 phosphate-activated glutaminase PAG Astrocyte 64
Se Young Jang, et al. Pathophysiology and Treatment of Cerebral Edema in Acute Liver Failure (PAG) 에의해암모니아와글루탐산염으로다시분해되고이로인한산화스트레스가세포부종을유발한다는설명이유력하다 (Trojan Horse hypothesis, Fig. 1). 19-21 3. 혈관뇌장벽의손상으로인한혈관성부종과거연구에서는급성간부전으로인한뇌부종의경우혈액뇌장벽의구조에는큰변화가없어주로세포독성부종에의한현상으로파악하였으나, 최근연구에서는치밀이음부 (tight junction) 를구성하는단백질의미세한기능변화와전신염증성사이토카인의영향으로인한혈액뇌장벽투과도의변화로인해혈관성부종이함께발생하는것으로밝혀졌다. 혈액뇌장벽은모세혈관내피세포및치밀이음부, 혈관주위세포 (pericyte), 별아교세포의발돌기로이루어져있으며이중내피세포와치밀이음부가장벽으로서의기능을하는데중요한역할을한다. 특히내피세포간치밀이음부에존재하는 occludin, claudin-5, junctional adhesion molecule (JAM), cadherin과같은여러가지의막경유단백들이세포주변통로 (paracellular path) 를통한물질의이동에관여한다. 급성간부전을유도한쥐의혈액뇌장벽을전자현미경으로관찰하였을때치밀이음부의구조적인변화는명확하지않으나여러다양한염색물질들의투과도는증가하는현상을관찰하였고이는구조적인변화보다는치밀이음부에존재하는막경유단백질의기능변화로인한현상으로판단하고있다. 특히급성간부전시에괴사한간세포로부터혈관내로유리되는 tumor necrosis factor alpha, interleukin-1, interleukin-6 등염증성사이토카인이 Toll-like receptor 4/NF-kB 경로를활성화시켜치밀이음부단백의발현을억제하고 Matrix metalloproteinase-9 (MMP-9) 이치밀이음부에존재하는 occludin, claudin-5와같은단백질을분해함으로써혈액뇌장벽의투과도를증가시킨다. 22-24 또한암모니아가 MMP-9의활성및활성산소 (reactive oxygen species), 산화질소 (nitric oxide) 의생성을증가시켜혈액뇌장벽의투과도를증가시키기도한다. 25 4. 뇌부종발생유무에대한평가및모니터급성간부전환자에서뇌부종발생을예측하는위험인자로는 3단계이상의간성뇌병증이발생한경우, 혈중암모니아수치가 100 umol/l를초과하는경우, 초급성으로간성뇌병증이발생하는경우, 전신성염증반응증후군 (sysmetic inflammatory response syndrome) 이동반된경우, 신대치요법이나승압제가필요한경우등이있다. 19,26 급성간부전으로인한간성뇌병증환자에서두통, 구토, 의식상태악화등과같은임상증상만으로는뇌부종발생여부를조기에진단하기에불충분하다. 혈압이갑자기상승하면서서맥및불규칙한호흡을보이는쿠싱반사, 동공반사및전정안구반사 (oculovestibular reflex) 의이상, 대뇌제거자세 (decerebrate posture) 역시뇌부종이진행된상태에서나타나므로조기진단에활용하기에는적절하지않다. 고위험환자에서시기적절한뇌부종의진단과치료를위해뇌컴퓨터단층촬영 (CT), 뇌자기공명영상 (MRI), 뇌혈류초음파 (TCD) 와같은뇌영상검사가필요하다. 뇌 CT를통해혈액응고장애로인해발생할수있는뇌출혈을배제할수있고뇌고랑소실, 뇌백질과회색질의경계소실, 뇌바닥수조의압박, 수두증을관찰함으로써뇌부종발생유무를평가할수있다. 27 뇌 MRI의확산강조영상을통해뇌부종의발생위치와정도를좀더민감하게확인할수있고겉보기확산계수 (apparent diffusion coefficient) 영상을통해세포독성부종과혈관성부종을감별할수있으나검사에시간이오래걸 Velocity, cm/s * Velocity, cm/s Time, second Time, second Figure 2. Transcranial doppler waveform of middle cerebral artery from a patient with acute liver failure. Under normal circumstances, the first peak is related to myocardial contractility and the second peak is produced by the distensibility of the arterial wall (asterisk indicates diastolic vascular recoil). As intracranial pressure increases, peak systolic velocity increases and wave becomes sharpened due to external compression of the artery. The second peak becomes reduced due to the reduced compliance of the artery and finally disappeared (loss of Windkessel effect). 65
리고장시간바로누운자세를유지해야하는위험이있다. 3 뇌혈류초음파는뇌혈관의자동조절능력이손상된상황에서는뇌혈류량이뇌압과비례한다는사실을근거로뇌혈류속도를측정해서간접적으로뇌압의변화양상을비침습적으로모니터할수있다. 뇌부종이발생하게되면가장먼저중대뇌동맥의수축기혈류속도가증가하다가점차뇌압이상승하면서혈류속도는감소하게되고박동지수 (pulsatility index) 는증가하게된다. 최대수축기혈류파형이날카로워지고뇌내혈관의탄성도가감소하면서혈관의탄성반동 (elastic recoil) 이소실됨으로인해수축기때의혈류파형이변화하게된다 (loss of the Windkessel notch, Fig. 2). 28 간이식이필요한 3, 4단계간성뇌병증환자및아세트아미노펜에의한급성간부전과같이간이식의적응증은아니나추후회복될여지가있는환자군에서는정확한두개내압측정과변동양상에대한빠른평가를위해두개내압측정카테터를이용한모니터가필요하며뇌실질내에직접삽입하는방법이가장정확하다. 29 응고병증이동반되어있는경우 INR 1.5 미만을유지하기위해신선냉동혈장 (fresh frozen plasma) 을먼저투여하고이후에도교정이되지않을경우에는재조합활성제 8인자 (recombinant factor VIIIa) 의투여를고려해보아야한다. 30 혈소판감소증이동반되어경우혈소판수를 100,000/μL 이상유지하기위해예방적인혈소판수혈후에시술을고려해야출혈의위험성을줄일수있다. 31 혈청내피브리노겐 (fibrinogen) 이 100 mg/dl 미만인경우에는동결침전제제 (cryoprecipitate) 를투여한이후에시술을고려해볼수있다. 목정맥팽대카테터를이용한정맥내산소포화도측정 (jugular bulb oximetry, SjvO 2 >80% indicates hyperemia, SjvO 2 <50% indicates insufficient oxygen supply), Licox 카테터를이용한뇌조직산소농도측정 (Pbto 2 <10 mmhg indicates tissue hypoxia), microdialysis를이용한뇌조직내에너지대사측정 (lactate/pyruvate ratio >40 indicates metabolic crisis) 이두개내압상승환자를집중관리하는데도움이될수있으나대부분의연구가외상성뇌손상환자를대상으로되어있어간부전에의한뇌부종환자에게적용하는데에는근거가부족한상태이다. 27 5. 급성간부전환자의내과적치료급성간부전환자에게는여러장기손상이동반될수가있는데심장기능및부신기능저하로인한혈역학적불안정및조직저관류, 폐기능저하로인한저산소혈증, 콩팥기능저하로인한복강내부종및위장관벽의부종, 면역기능저하로인한 감염증, 응고장애로인한출혈등이발생할수있다. 32 따라서급성간부전환자의치료는환자의대사와혈역학적안정을유지하여간의재생을돕고합병증을최소화하는것이근간이되겠다. 급성간부전에서는저혈당이호발하므로당을혈액내로주입하는것이필요하지만저나트륨혈증과뇌부종을악화시킬수있어저장성용액을대량주입하는것은피해야한다. 또한, 급성간부전상태에서는에너지가다량소모되고단백질이화작용 (protein catabolism) 이되므로적절한영양을공급하여환자의근육양과면역기능이유지되도록해야한다. 간성뇌병증이있는경우에는경구로 1.0-1.5 g/kg/day 가량의단백질을공급하고혈중암모니아수치를모니터링하면서양이과다하지않게조절한다. 33 간이식은급성간부전환자의생존율을개선시킬수있는확실한치료법이긴하나일반적으로환자의병세가매우급격하게진행하고공여간의확보가쉽지않아급성간부전환자의약 10% 에서만이루어진다고알려져있다. 34,35 특히, 뇌사자공여보다는생체부분간이식을시행할수밖에없는경우가많아환자가급성간부전으로진단되는즉시공여자를준비하고환자상태가악화되었을때응급으로간이식을시행할수있도록하는것이필요하다. 이번단락에서는급성간부전환자에서발생할수있는여러합병증중뇌부종과이로인한두개내압상승에대한치료방침에대해서자세히살펴보고자한다. 6. 급성간부전에서발생하는뇌부종의치료 1) 일반적인치료뇌부종조절의일반적인목표는뇌내압 20 mmhg 미만, 뇌관류압 60 mmhg 이상을유지하는것이며다른원인으로인한두개내압상승과비교하여기본적인치료방법에는큰차이가없다. 간성뇌병증과두개내압상승으로인해의식이저하된환자에서조기에빠른기관삽관을하고기계환기를적용하여저산소혈증을예방하고이산화탄소의농도를적절히유지해야한다 (PCO 2 35 40 mmhg). 36 적절한수준의진정 (Ramsay sedation scale 3 5) 과통증조절, 뇌관류압이적절히유지되는범위내에서머리를 30도세워두는자세를유지함으로써두개내압을낮춰줄수있다. 36 그외발열및고혈당조절 ( 목표혈당 140 180 mg/dl), 저나트륨혈증에대한교정, 락툴로즈관장을통해혈중암모니아농도를떨어뜨리는치료가두개내압상승을줄여주는데도움이된다. 27 2) 약물치료삼투압요법으로가장많이쓰이는약물은만니톨과고장식 66
Se Young Jang, et al. Pathophysiology and Treatment of Cerebral Edema in Acute Liver Failure Table 2. The effects of hypothermia on reducing intracranial pressure (ICP) in acute liver failure Target Ammonia Brain osmolarity Brain extracellular space Brain metabolism Cerebrovascular blood flow Inflammation Seizure activity Mechanism of ICP reduction Arterial ammonia level, brain ammonia delivery, bacterial ammonia production from intestinal mucosa, ammonia release by kidney and proteolysis Brain tissue lactate and alanine level Extracellular glutamate and nitric oxide production Brain glucose and oxygen consumption, lactate production Stabilized cerebral blood flow, Cerebral hyperemia, Brain ammonia uptake Arterial concentration and brain influx of inflammatory cytokines (TNF-alpha, IL-1b, IL-6) Seizure activity TNF-alpha, tumor necrosis factor-alpha; IL-1b, interleukin- 1 beta. 염수이다. 만니톨은 0.25 2.0 g/kg의용량으로 6시간간격으로정맥내로투여한다. 기존에알려진혈중삼투압농도 (serum osmolarity) 의절대값보다는삼투압농도차 (osmolar gap <55 mosm/l) 를모니터링하면서투여량과기간을조절하는것이추천되고있고적절한수분공급을통해만니톨투여중에발생할수있는혈량저하증을예방하는것이중요하다. 36-38 고장성식염수는만니톨에비해혈액뇌장벽을비교적덜통과하면서좀더강력한삼투효과를낼수있다는장점이있어최근두개내압을낮추는약물치료로많이사용되고있다. 국내에는 11.7% 염화나트륨주사액 (40 meq/20 ml) 원액 60 ml를중심정맥카테터나말초중심정맥카테터 (peripherally inserted central catheter, PICC) 를통해 20분에걸쳐서서히투여한다. 혈중나트륨농도 145 155 mmol/l를목표로 6시간또는 8시간간격으로투여한다. 고장성식염수는만니톨과달리삼투성이뇨작용이없고혈관내용적을증가시킬수있어간경화나심기능상실환자와같은용적과부하상태에서는조심스럽게투여해야한다. 39 3) 저체온치료체온이낮아지면 1도당 6-10% 가량뇌의대사가감소하면서에너지요구량이줄어들고, 세포막이안정화되면서나트륨이온과칼슘이온의무분별한유입과이로인한뇌세포의부종, 미토콘드리아기능저하, 단백질분해, 자유라디칼의생성으로인한흥분성신경전달물질의무분별한분비가줄어든다. 40,41 또한저체온치료는세포자멸사를억제하고뇌조직으로의다형핵백혈구의유입과염증유발사이토카인의분비를줄여염증반응을감소시킴으로써허혈이나외상에의한뇌질환에서신경보호효과및두개내압감소효과를보여준다. 40 급성간부전으로인한뇌부종과두개내압상승에서저체온치료가생존율향상에도움이된다는전향적연구자료는없다. 3단계이상의간성뇌병증환자들에게저체온치료 (32 35 C) 를시행한 97명의환자를저체온치료를시행하지않은 1,135 명의환자와후향적으로비교한연구에서저체온치료가뇌출혈이나감염증을증가시키지는않았으나 21일생존율에도큰영향을미치지는못하였다. 42 그러나실험을통해저체온치료가급성간부전으로인한뇌부종의개선이도움이된다는보고들이있다. 저체온시에장내세균에의해서암모니아생성이감소되고, 콩팥에서혈중으로유리되는암모니아가감소하면서혈중암모니아농도가떨어지게되고, 동시에뇌혈류감소로인해혈중에서뇌안으로의암모니아흡수가줄어들면서뇌내암모니아농도가감소하게된다. 41,43,44 저체온치료는급성간부전에서간성뇌병증과뇌부종을유발하는것으로알려져있는뇌내알라닌과젖산농도를감소시키고세포외기질에글루탐산염이축적되는것을줄여두개내압을감소시킨다 (Table 2). 45-47 저체온치료시 33 35 C 범위로목표체온을설정하고가능한한조기에목표체온에도달하도록하며평균동맥압 (80 110 mmhg) 과중심정맥압 (8 12 cmh 2 0) 을목표범위로유지하기위한지속적인감시가필요하다. 저체온요법중흔히발생하는떨림은심혈관계합병증발생을증가시키고호흡일량을증가시켜환자의예후를악화시키는요인으로이를방지하기위해체온조절담요를이용해서피부를따뜻하게유지해주는것이중요하다. 체온조절담요로조절되지않는경우여러약제들중간기능이저하된경우에도비교적안전하게사용할수있는 MgSO 4 (4 g 15분간정맥일시투여후 0.5 1.0 g/ hour 지속투여, 혈중농도 3 4 mg/dl 유지 ), dexmedetomidine (0.3 1.5 μg/kg/hour 지속정맥투여 ), cisatracurium(3 μg/kg/ min 정맥일시투여후 0.5 10 μg/kg/min 지속투여 ) 등의약제들을사용해볼수있다. 48 67
4) 실험적인치료법들급성간부전을유발한동물모델에서 minocycline의투여가 oxidative, nitrosative stress를줄임으로써간성혼수와뇌부종이악화되는것을막아주는역할을한다는보고가있으며, 49 N-methyl-D-aspartate (NMDA) 수용체길항제인 memantine 이 NMDA 수용체를통해암모니아독성이발현되는것을억제함으로써뇌부종을줄여주었다는연구결과가있다. 50,51 그외혈장교환술을통해두개내압상승없이뇌관류압과뇌내산소대사율 (cerebral metabolic rate for oxygen, CMRO 2 ) 을증가시켜일부환자의의식상태를개선시켰으며면역시스템과내피세포기능을호전시켜간이식이부적합한환자의생존율을증가시킬수있다는주장도있다. 52 아세트아미노펜을이용해서급성간부전을유도한돼지모델에서내독소 (endotoxin) 를제거하고손상된알부민을대체해주는체외간기능보조기구 (extracorporeal liver support device) 를이용해서암모니아농도및염증성사이토카인의감소, 뇌압감소, 평균동맥압증가를통해생존율을증가시켰다는실험결과도보고된바가있다. 53 결론 급성간부전에서암모니아와글루탐산에의한별아교세포의팽윤과세포독성부종, 혈액뇌장벽의치밀이음부구조단백의미세기능변화로인한혈관성부종이뇌부종유발하여두개내압을상승시킨다. 뇌부종발생유무에대한모니터및치료는뇌의허혈손상이나재관류손상, 외상에의한뇌부종과근본적으로는동일하다. 그러나다른질환에의한뇌부종과달리동반된다발장기부전및감염증에의한혈역학적불안정에대한교정을통해적절한뇌관류압을유지하기위한노력, 두개내압상승에중요한역할을하는뇌내암모니아의농도를낮추기위한치료가중요하다. 또한기계환기시진정을위한약제사용이나저체온치료시떨림부작용을줄이기위한약제사용시간으로대사되는약제선택에제한이있다는점, 고농도의나트륨을이용한삼투압치료시용적과부하상태의악화가능성에대한고려가필요하다는차이점이있다. REFERENCES 1. Mokri B. The Monro-Kellie hypothesis: applications in CSF volume depletion. Neurology 2001;56:1746-8. 2. Mayer SA, Coplin WM, Raps EC. Cerebral edema, intracranial pressure, and herniation syndromes. J Stroke Cerebrovasc Dis 1999;8:183-91. 3. Mohsenin V. Assessment and management of cerebral edema and intracranial hypertension in acute liver failure. J Crit Care 2013;28:783-91. 4. Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010;376:190-201. 5. O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273-5. 6. Montagnese S, Amodio P, Morgan MY. Methods for diagnosing hepatic encephalopathy in patients with cirrhosis: a multidimensional approach. Metab Brain Dis 2004;19:281-312. 7. Cash WJ, McConville P, McDermott E, McCormick PA, Callender ME, McDougall NI. Current concepts in the assessment and treatment of hepatic encephalopathy. QJM 2010;103:9-16. 8. Munoz SJ. Difficult management problems in fulminant hepatic failure. Semin Liver Dis 1993;13:395-413. 9. Shawcross DL, Wendon JA. The neurological manifestations of acute liver failure. Neurochem Int 2012;60:662-71. 10. White BC, Sullivan JM, DeGracia DJ, O'Neil BJ, Neumar RW, Grossman LI, et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 2000;179:1-33. 11. Liang D, Bhatta S, Gerzanich V, Simard JM. Cytotoxic edema: mechanisms of pathological cell swelling. Neurosurg Focus 2007;22:E2. 12. Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci 2003;4:991-1001. 13. Jalan R, Olde Damink SW, Hayes PC, Deutz NE, Lee A. Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J Hepatol 2004;41:613-20. 14. Blei AT, Olafsson S, Therrien G, Butterworth RF. Ammoniainduced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology 1994;19:1437-44. 15. Norenberg MD. Astrocytic-ammonia interactions in hepatic encephalopathy. Semin Liver Dis 1996;16:245-53. 16. Scott TR, Kronsten VT, Hughes RD, Shawcross DL. Pathophysiology of cerebral oedema in acute liver failure. World J Gastroenterol 2013;19:9240-55. 17. Zwingmann C, Chatauret N, Rose C, Leibfritz D, Butterworth RF. Selective alterations of brain osmolytes in acute liver failure: protective effect of mild hypothermia. Brain Res 68
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