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1 INVITED REVIEW online ML Comm J Neurocrit Care 2008;1 Suppl 1:S32-S36 ISSN 뇌사의진단 : 진단에이용하는검사법 가톨릭대학교의과대학신경과학교실 이광수 The Diagnosis of Brain Death: Diagnostic Tools Kwang-Soo Lee, MD, PhD Department of Neurology, The Catholic University of Korea College of Medicine, Seoul, Korea The physician must understand the clear difference between severe brain damage and brain death, because brain death means that life support is useless. Brain death is the irreversible cessation of function of the brain including the brainstem. The diagnosis of the brain death is primarily based on clinical criteria, usually supported be confirmatory tests such as electrophysiological study, TCD, MRI, SPECT, and angiography. J Neurocrit Care 2008;1 Suppl 1:S32-S36 KEY WORDS: Brain death Clinical criteria of brain death Confirmatory test. 서 뇌사의진단은오랜세월인간의죽음은오로지심장사라는고정관념에서벗어나장기이식의획기적인발전을이루는기초가되었다. 이제대부분국가에서뇌사를법적으로인정하고뇌사자의장기이식을활발하게하여수많은생명을구하고있다. 뇌사의진단은국가별로조금씩다르지만뇌와뇌간의비가역적인상태를확인하는절차가핵심으로임상적인진찰중무호흡검사 (apnea test) 가가장중요한진단법이며그이외에도뇌 SPECT, PET 검사, 경두개초음파검사 (TCD) 등의뇌혈류검사, 뇌혈관촬영, 자기공명영상, CT 혈관촬영등객관적인검사방법등을이용하여뇌사진단에있어객관적이고한치의오차가없도록노력하고있다. 본 뇌사진단기준의발전인공호흡기 (mechanical ventilator) 의발전으로호흡정 Address for correspondence: Kwang-Soo Lee, MD, PhD Department of Neurology, The Catholic University of Korea College of Medicine, 505 Banpo-dong, Seocho-gu, Seoul , Korea Tel: , Fax: ks1007@catholic.ac.kr 지가된말기신경계질환환자의치료경과가변하게되었으며뇌의기능이정지된이후에도신체적인활력징후 (vital sign) 은인공적으로유지가능하게되었다 년 Mollaret 와 Goulon 등이의식소실, 뇌간반사소실, 호흡소실그리고뇌파검사상평탄파 (flat EEG) 를보인 23명의혼수환자를 coma depasse( 비가역적혼수상태 ) 라고처음기술한이후 1968 년하버드의대 ad hoc 위원회에서뇌사의진단기준에대해구체적으로명시하기시작하였다. 1976년영국의학전문위원회에서뇌사란뇌간기능의비가역적소실이다라고정의하고이때부터무호흡검사 (apnea test) 에대한자세한내용을제시하였다 년부터는혼수환자에대한임상관찰을줄이기위한노력으로객관적인확진검사를이용할것을적극추천하였다. 최근시행한 80개국가조사에서 70개국가 (88%) 에서뇌사의진단기준을이용하여뇌사를진단하는것으로보고되어있다. 2 뇌사진단을하는주이유는장기이식이지만아직도선진국에서조차이에대한성적은 27~32% 로미진하여이에대한관심이더필요한실정이다. 3 뇌사의임상진찰법뇌사를진단하는데있어서기본조건으로는심한전해질및산-염기불균형상태, 중심체온이 32 이하인심한저 S32 Copyright c 2008 The Korean Neurocritical Care Society

Diagnosis of Brain Death KS Lee TABLE 1.

of corneal reflexes Absence of caloric responses Absence of gag reflex Absence of coughing in response to tracheal suctioning Absence of sucking and rooting reflexes Absence of respiratory drive at a

hr 18 yr old, interval optional Confirmatory tests Term to 2 mo old, 2 confirmatory tests >2 mo to 1 yr old, 1 confirmatory test >1 yr to <18 yr old, optional 18 yr old, optional *PaCO 2 denotes the

2 Diagnosis of Brain Death KS Lee TABLE 1. Clinical criteria for brain death in adults and children Coma Absence of motor responses Absence of pupillary responses to light and pupils at midposition with respect to dilatation (4-6 mm) Absence of corneal reflexes Absence of caloric responses Absence of gag reflex Absence of coughing in response to tracheal suctioning Absence of sucking and rooting reflexes Absence of respiratory drive at a PaCO 2 that is 60 mmhg or 20 mmhg above normal base-line values* Interval between two evaluations, according to patient s age Term to 2 mo old, 48 hr >2 mo to 1 yr old, 24 hr >1 yr to <18 yr old, 12 hr 18 yr old, interval optional Confirmatory tests Term to 2 mo old, 2 confirmatory tests >2 mo to 1 yr old, 1 confirmatory test >1 yr to <18 yr old, optional 18 yr old, optional *PaCO 2 denotes the partial pressure of arterial carbon dioxide, See Table 2 for descriptions of the available confirmatory tests. Tests may be required by law outside the United States 체온, 저혈압그리고약물중독과신경근육차단제등의사용근거가없어야한다. CT검사의소견은뇌사진단에매우중요한데뇌부종과덩어리와관련된뇌탈출현상등이일반적이나저산소증이나뇡며등에서는 CT가정상소견을보일수있어이런경우는뇌척수액검사로확인이필수적이다. 자세한혼수환자의평가에는혼수에대한서술, 뇌간반사의소실에대한확인그리고무호흡검사로이루어진다 (Table 1). 4 뇌간반사의진찰법 (Fig. 1) 은중뇌, 뇌줄기, 연수에서반사경로를측정하는것으로혼수상태의정도는운동반응의통증자극에대한반응유무로확인하는데상안와신경, 측두- 하악관절그리고손톱의밑부분등을세게눌러서혼수환자가어떻게반응하는지를관찰한다. 이어서뇌간반사의유무를관찰하는데만일뇌간반사가없다면, 동공이 oval 모양으로정중앙에위치하고 4~6 mm 정도의크기이며빛에반응이없다. 그리고머리를빠르게돌려서 oculocephalic 반사의존재유무를확인해야한다. 만일 oculocephalic 반사가없다하더라도 cold caloric 검사로안구운동유무를확인해야한다. Caloric 검사는머리를 30도정도기울인후얼음물로고막부위를자극하여자극부위쪽으로안구가돌아가지않는지를확인해야한다. 각막반사는각막가장자리부근을적당히자극하여관찰하며기침반사는가래흡입 (suction) 이나기관지튜브를위아래로움직일때 기침반사가일어나는지를확인하는데기관자튜브를움직이는행위는위험성과논란이있어반드시해야하는검사는아니다. 뇌간반사검사가확인된후에는무호흡 (apnea) 검사를해야한다. 이검사는연수부위의호흡중추를최대로자극하는것으로 CO2 60 mmhg 이상혹은기본검사에비해 20 mmhg 이상증가한경우로정의한다. 무호흡검사시인공호흡기에서나타날수있는위양성을배제하기위해인공호흡기를제거해야하며산소를기관지카테터를통해전처치하여체내에남아있는질소를제거하고산소전달이용이하도록준비해야한다. CO2분압상승은일반적으로 biphasic 양상으로상승하며분당 3 mmhg 정도씩증가하게된다. 만일무호흡검사중부정맥이나타나거나혈압이떨어지는경우는미리주는산소전처치가미흡하거나산소공급이원활치못할때나타날수있으므로주의해야한다. 뇌사를판단할때가장논쟁이되는것은자극에대한반응은전혀없는데도불구하고무호흡검사, 뇌사자이동시, 복부절개시점, 그리고기계적호흡당시등에나타날수있는자발적몸의움직임이다. 이들몸의움직임은척수에서기인되는데머리를한쪽으로기울이는모양, 얼굴의 twitching 양상, 지속적으로나타나는바빈스키징후와심부건반사, 복부반사등이알려지고있다. S33

J Neurocrit Care 2008;1 Suppl 1:S32-S36 뇌사와혼동할수있는신경학적질환 Locked-In 증후군, 저체온증, 혹은약물중독등은뇌사라고잘못오인할수있는대표적예이다. Locked-In 증후군은뇌줄기손상으로인하며얼굴이나팔다리를움직일수없고심지어는삼키는기능도없어지게되나자발적눈깜박반사나안구수직운동은가능하고의식은아주명료한상태를말한다.

그밖에많은진정제나마취제들이뇌사와유사한효과를보일수있는데대부분이런약제들사용한경우에는동공반사는유지하며뇌간반사도일부소실되는경우를보여 완전한뇌사자와혼동은피할수있으나바비츄레이트나 TCA 항우울제는감별이매우힘든것으로보고되고있다. 만일혈액검사로농도측정을할수있는경우에는치료적절농도이하로나온경우에만임상적뇌사진단을할것을권고하고있다.

3 J Neurocrit Care 2008;1 Suppl 1:S32-S36 뇌사와혼동할수있는신경학적질환 Locked-In 증후군, 저체온증, 혹은약물중독등은뇌사라고잘못오인할수있는대표적예이다. Locked-In 증후군은뇌줄기손상으로인하며얼굴이나팔다리를움직일수없고심지어는삼키는기능도없어지게되나자발적눈깜박반사나안구수직운동은가능하고의식은아주명료한상태를말한다. 또수일내에진행하여얼굴신경과말초신경마비를초래하는길랑-바레증후군과장기간환경노출로인한사고성저체온증도조심해야할경우이다. 중심체온이 28~32 에서는동공반사가없어지며 28 이하에서는뇌간반사가없어진다. 이들반사들은대부분체온이회복되면가역적으로돌아오는것으로알려져있다. 그밖에많은진정제나마취제들이뇌사와유사한효과를보일수있는데대부분이런약제들사용한경우에는동공반사는유지하며뇌간반사도일부소실되는경우를보여 완전한뇌사자와혼동은피할수있으나바비츄레이트나 TCA 항우울제는감별이매우힘든것으로보고되고있다. 만일혈액검사로농도측정을할수있는경우에는치료적절농도이하로나온경우에만임상적뇌사진단을할것을권고하고있다. 따라서약제와관련이있다고판단되는경우에는두가지로나누어판단하는데 (1) 약제의종류는 FIGURE 2. EEG shows an isoelectric electroencephalogram in which the only pulse is artifactual. Shown is a bipolar montage with the electrodes placed according to 10/20 configuration. TABLE 2. Confirmatory testing for a determination of brain death Cerebral angiography The contrast medium should be injected under high pressure in both anterior and posterior circulation. No intracerebral filling should be detected at the level of entry of the carotid or vertebral artery to the skull. The external carotid circulation should be patent. The filling of the superior longitudinal sinus may be delayed. Eletroencephalography A minimum of eight scalp enectrodes should be used. Interelectrode impedance should be between 100 and 10,000 Ω. The integrity of the entire recording system should be tested. The distance between electrodes should be at least 10 cm. The sensitivity should be increased to at least 2 μv for 30 minutes with inclusion of appropriate calibrations. The high-frequency filter setting should not be set below 30 Hz, and the low-frequency setting should not be above 1 Hz. Electroencephalography should demonstrate a lack of reactivity to intense somatosensory or audiovisual stimuli. Transcranial Doppler ultrasonography The should be bilateral insonation. The probe should be placed at the temporal bone above the zygomatic arch or the vertebrobasilar arteries through the suboccipital transcranial window. The abnormalities should include a lack of diastolic or reverberating flow and documentation of small systolic peaks in early systole. A finding of a complete absence of flow may not be reliable owing to inadequate transtemporal windows for insonation. Cerebral scintigraphy (technetium Tc 99 m hexametazime) The isotope should be injected within 30 minutes after its reconstitution. A static image of 500,000 counts should be obtained at several time points: immediately, between 30 and 60 minutes later, and at 2 hours. A correct intravenous injection may be confirmed with additional images of the liver demonstrating uptake (optional). S34 FIGURE 3. Transcranial Doppler sonogram show reverberating flow and small systolic peaks, both of which are patterns seen in patients with massively increased intracranial pressure that can also be seen when brain death has occurred.

Diagnosis of Brain Death KS Lee 알수있으나약제의양을가늠하지못하는경우에는, 약제의제거반감기의최소 4배에해당되는시간동안관찰해야하며 (2) 약제의종류를알수없으나의심이되는경우에는뇌간반사에어떠한영향을주는지를 48시간동안관찰하고어떤변화가일어나지않는다면확진을위한검사를해야한다. FIGURE 4.

뇌사를확진하기위한객관적검사법 (Table 2) 성인의경우뇌사를판단할때확진검사는선택적으로이용될수있으나 1세이상어린이에서는반드시시행할것을권유하고있다. 일부유럽국가, 남미, 아시아일부국가에서는이러한확진검사를법으로요구하고있으며스웨덴등일부국가에서는뇌혈관촬영을반드시해야한다.

뇌파검사 (EEG) 는수많은국가에서이용하는검사로확진을위한객관적검사중의하나로인정받고있다. 뇌파기록은최소 30분이상 16~18 채널이상의뇌파기계로시행해야하며 2 uv/mm(sensitivity) 로검사시 2uV 이상의 electrical activity 가없어야한다 (Fig. 2).

테크네슘을이용한핵의학검사에서는 tracer 의두개내흡수유무로판단하게된다. 일반적인뇌혈관촬영과비교연구에서아주유용성이높은검사이며 (Fig. 4), 6 코부근에만혈류공급이원활하고두개내는혈류가차단되어코부위의모양이강조되는 hot nose sign (Fig. 5) 이특징적이다.

4 Diagnosis of Brain Death KS Lee 알수있으나약제의양을가늠하지못하는경우에는, 약제의제거반감기의최소 4배에해당되는시간동안관찰해야하며 (2) 약제의종류를알수없으나의심이되는경우에는뇌간반사에어떠한영향을주는지를 48시간동안관찰하고어떤변화가일어나지않는다면확진을위한검사를해야한다. FIGURE 4. A dynamic nuclear scan shows no intracranial filling - the so-called hollow-skull sign. FIGURE 5. Tc-99m HMPAO shows accumulation much more posterior to the nose. 뇌사를확진하기위한객관적검사법 (Table 2) 성인의경우뇌사를판단할때확진검사는선택적으로이용될수있으나 1세이상어린이에서는반드시시행할것을권유하고있다. 일부유럽국가, 남미, 아시아일부국가에서는이러한확진검사를법으로요구하고있으며스웨덴등일부국가에서는뇌혈관촬영을반드시해야한다. 뇌혈관촬영은 anterior, posterior 순환상태를확인하기위하여대동맥궁부위에주사를해야하며 posterior 순환상태는 foramen magnum 부위에서뇌혈관이보이지않고 anterior 순환상태는목동맥 petrosal 부위이상에서뇌혈관이보이지않게된다. MRA검사에서도유사한소견이보인다. 뇌파검사 (EEG) 는수많은국가에서이용하는검사로확진을위한객관적검사중의하나로인정받고있다. 뇌파기록은최소 30분이상 16~18 채널이상의뇌파기계로시행해야하며 2 uv/mm(sensitivity) 로검사시 2uV 이상의 electrical activity 가없어야한다 (Fig. 2). 경두개초음파 (Transcranial Doppler, TCD) 검사는민감도 77~87%, 특이도 100% 를보이는아주유용한검사법이다. 5 뇌사자의전형적인검사양상은뇌혈관의확장기파가보이지않거나 reverberating 혈류파가나타나는것이다. 보통저항계수가매우높게나타난다 (Fig. 3). 테크네슘을이용한핵의학검사에서는 tracer 의두개내흡수유무로판단하게된다. 일반적인뇌혈관촬영과비교연구에서아주유용성이높은검사이며 (Fig. 4), 6 코부근에만혈류공급이원활하고두개내는혈류가차단되어코부위의모양이강조되는 hot nose sign (Fig. 5) 이특징적이다. 7 그밖에최근확진검사로 MR diffusion/adc/ MRI검사가빠른뇌사를진단할수있다는연구 (Fig. 6) 8 와 CT-angiography 에대한연구가있다 (Fig. 7). 9 FIGURE 6. Diffusion-weighted MR and axial T2-weighted slice. Both hemispheres are hyperintense, corresponding to a drop in the ADC and showing diffuse hyperintensity in the left sided cortex as well as in the medial right-sided temporal lobe. A prepontine mass that is also hyperintense is shown as well. S35

J Neurocrit Care 2008;1 Suppl 1:S32-S36 로운생명을주게된다. 논리적인임상적진단과필요시확진검사를통하여뇌사진단을정확히해야하며더많은뇌사자가장기를기증할수있도록국가적, 사회적계몽이필요하다. FIGURE 7.

No intracranial vessels could be identified, and only bilateral external carotid artery branches were observed (arrow). Based on the results of this examination, brain death was considered.

Practice parameters for determining brain death in adults. Neurology 1995;45:1012-4. 2. McCarthy M. Study survey brain death guidelines in 80 nations. Lancet 2002;359:139. 3. Viltala S, Palo J.

Kuo JR, Chen CF, Choi CC, Chang CH, Wang CC, Yang CM, et al. Time dependent validity in the diagnosis of brain death using transcranial Doppler sonography.

5 J Neurocrit Care 2008;1 Suppl 1:S32-S36 로운생명을주게된다. 논리적인임상적진단과필요시확진검사를통하여뇌사진단을정확히해야하며더많은뇌사자가장기를기증할수있도록국가적, 사회적계몽이필요하다. FIGURE 7. CT angiography performed after the cessation of brainstem reflex and spontaneous breathing. No intracranial vessels could be identified, and only bilateral external carotid artery branches were observed (arrow). Based on the results of this examination, brain death was considered. 결 뇌사의진단은이제장기이식의아주중요한첫단계가되었다. 뇌사의빠르고정확한진단으로의학발전에이바지할뿐아니라장기이식이필요한수많은환자들에겐새 REFERENCES 1. The Quality standards subcommittee of the American academy of neurology. Practice parameters for determining brain death in adults. Neurology 1995;45: McCarthy M. Study survey brain death guidelines in 80 nations. Lancet 2002;359: Viltala S, Palo J. Diagnosis and frequency of brain death. Lancet 1999;354: Wijdicks Eelco FM. The diagnosis of brain death. New Eng J Med 2001;344: Kuo JR, Chen CF, Choi CC, Chang CH, Wang CC, Yang CM, et al. Time dependent validity in the diagnosis of brain death using transcranial Doppler sonography. J Neurol Neurosurg Psychiatry 2006; 77: Munari M, Zucchetta P, Carollo C, Gallo F, Nardin MD, Marzola MC, et al. Confirmatory tests in the diagnosis of brain death: Comparison between SPECT and contrast angiography. Crit Care Med 2005;33: Applet EA, Song WS, Phillips WT, Metter DF, Salman UA, Blumhardt R. The Hot Nose sign on brain death nuclear scintigraphy; where does the flow really go? Clin Nucl Med 2008;33: Lovblad KO, Basssetti C. Diffusion weighted magnetic resonance imaging in brain death. Stroke 2000;31: Yu SL, Lo YK, Lin SL, Lai PH, Huang WC. Computed tomographic angiography for determination of brain death. J Comput Assist Tomogr 2005;29: S36

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