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Anesthesia induced neurotoxicity and organ protection

In the 1950s, concerns regarding the debilitating effect of general anesthesia on neurologic function initially reported which was related with personality changes, those were observed especially in younger children following exposure to cyclopropane.1) Several decades later, potentially deleterious effects of anesthetics on young children is ignited initially, first, in a study observing neuronal degeneration following repeated N-methyl-D-aspartate (NMDA) antagonist exposure in neonatal rat pubs.2) The neurotoxic effects observed in animals include apoptotic neuronal cell death, diminished neuronal density, decreased neurogenesis, alterations in dendritic architecture, diminution of neurotrophic factors, mitochondrial degeneration, cytoskeletal destabilization, learning and memory impairment. Because it is impossible to examine brain tissue in infant or children, human studies have relied on observe any prospective data and are obviously interfered by inability to randomize young children to undergo painful procedures without anesthesia and analgesia. Furthermore, exposure to anesthetic agent or sedative, analgesics cannot be justified without a surgery or diagnostic procedure and it is difficult to distinguish the respective contributions of the underlying condition, surgical procedure on the postoperative neurologic outcome. Therefore, to the recently, available human data rely all on postoperative behavioral studies, epidemiologic analysis. Comparisons of long-term neurologic outcomes in children suffering from illness requiring the administration of anesthetics and sedatives during surgery or intensive care hampered gathering meaningful solution. Until proven today, it can be recommended to keep anesthesia and surgery as short as possible, to use short acting agents and/or multimodal therapy to reduce the overall drug dosage.

What we already knew,

1. In the developing brain, the major excitatory neurotrans-mitter, glutamate, transmitters play a central role in brain morphogenesis, including synapse formation, proliferation, mi gration, differentiation and survival of neurons.3)

2. Although gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in adults, it acts as an excitatory trans-mitter in the developing CNS.4)

3. The excess cells are eliminated by an inherent cell death

program, termed apoptosis. In later stages of normal brain development (i.e. synaptogenesis), neuronal elimination is a very tightly controlled phenomenon during which a very small number of neurons are destined to die.5)

4. In humans, synaptogenesis starts during the third trimester and rapid brain growth occurs in different brain regions at different ages. By age 2 to 3 years, rapid brain growth in nearly all brain regions is mostly complete.6)

5. All anesthetics and sedatives used in infants and children including inhaled agents, benzodiazepines, barbiturates, keta-mine, propofol, and etomidate are believed to block NMDA receptors and/or enhance GABA-A receptors to varying degrees.7)

6. Several studies report that anesthesia in infants and young children is associated with an increased risk of learning disabilities (with multiple anesthesia exposures, but not single), developmental and behavioral abnormalities, impa-ired language and abstract reasoning (with both single and multiple anesthetic exposures), and poor academic performance. Other studies do not find any association between anesthesia during early childhood and poor school academic performance or abnormal behavior later in life.8-10)

What studies in animals or humans in progress are?

1. In preclinical research, in vivo imaging of rodent and non-human primate models by positron emission tomography (microPET) allows for an objective and quantitative assessment of functional and molecular targets in a longitudinal manner. PET offers a unique bridging approach allowing insight into “structure and function” issues that are not accessible via other methods.11)

2. The use of stem cell-derived models, especially human embryonic stem cells (in vitro) with their capacity for proli-feration and potential for differentiation, have a great advantage for detecting potential anesthetic-induced neurotoxicity.12)

3. FDA launches SAFEKIDS Initiative with Academic and Clinical Partners.The Safety of Key Inhaled and Intravenous

마취제의 뇌독성과 장기보호 효과

Anesthesia induced neurotoxicity in developing brain

Il-Ok Lee

Department of Anesthesiology and Pain Medicine, Korea University

2015 대한마취통증의학회 제92차 종합학술대회12

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Bedside to Evidence, Evidence to Bedside

Drugs in Pediatrics (SAFEKIDS) Initiative is a multi-year project designed to address major gaps in scientific information about the safe use of anesthetics and sedatives received by millions of children each year.• The International Anesthesia Research Society (Cleveland, Ohio): leading the administrative oversight and the over-arching framework

• Children's Hospital - Harvard University (Boston): regional or general anesthesia as neonates or infants.

•Arkansas Children's Hospital Research Institute (Little Rock, Ark.): pharmacokinetics, pharmacodynamics, and neurotoxic effects of an anesthetic agent

• Columbia University (New York): neurocognitive, emotional and behavioral outcomes

•MASK (Mayo Safety in Kids) (Rochester, Minn.): long-term cognitive development

•GAS study (National Institute of Health): general anesthesia and spinal

• PANDA (Pediatric Anesthesia and Neurodevelopment Assessment): multicenter neurodevelopment and cognitive function, NEPSY-II

Summary

Currently, the available evidence does not support a change in clinical practice. However, it is unwise to ignore several epidemiologic human studies have observed an association between anesthesia exposure in younger 3 years and subsequent neurologic sequelae. Practically, it will be recommended that parents must talk to their pediatrician about the risks and benefits of procedures requiring anesthetics and weigh them against the known health risks of not treat ing certain conditions. The SmartTots website (www.smarttots.org) remains resources for up-to-date informations.

References

1. Eckenhoff JE. Relationship of anesthesia to postoperative per-

sonality changes in children. AMA Am J Dis Child. 1953 Nov; 86(5):587-91.

2. Ikonomidou C(1), Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999 Jan 1;283(5398):70-4.

3. Lujan R, Shigemoto R, Lopez-Bendito G. Glutamate and GABA receptor signaling in the developing brain. Neuroscience 2005;130:567-80.

4. Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL. GABAA, NMDA and AMPA receptors: a developmentally regulated 'menage a trois'. Trends Neurosci 1997;20:523-9.

5. Blaschke AJ, Weiner JA, Chun J. Programmed cell death is a universal feature of embryonic and postnatal neuroproliferative regions throughout the central nervous system. J Comp Neurol 1998;396:39-50.

6. Huttenlocher, P.R. and A.S. Dabholkar, Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997;387:167-78.

7. Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003;348:2110-24.

8. DiMaggio, C., L.S. Sun, and G. Li, Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg 2011;113:1143-51.

9. Ing, C., et al., Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia. Pediatrics 2012;130:e476-85.

10. Block, R.I., et al., Are Anesthesia and Surgery during Infancy Associated with Altered Academic Performance during Childhood? Anesthesiology 2012;117:494-503.

11. Zhang, X., et al., MicroPET imaging of ketamine-induced neuronal apoptosis with radiolabeled DFNSH. J Neural Transm 2011;118:203-11.

12. Trujillo, C.A., Schwindt, T.T., Martins, A.H., Alves, J.M., Mello, L.E. & Ulrich, H. Novel perspectives of neural stem cell differentiation: from neurotransmitters to therapeutics. Cytometry A 2009;75:38-53.

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서론

노인들은 전 신체 기관에 걸쳐 기능적 예비력(functional reserve)이 점진적으로 감소하는데, 뇌를 포함한 중추신경계도 예외가 아니다. 노화에 따라 각 장기의 기능적 예비력이 감소함에 따라 마취 및 수술과 같은 스트레스에 대한 대응능력이 떨어지게 되고, 그에 따른 합병증이 발생하기 쉽다. 또한 각 장기에서 노화에 따라 그 병태 생리가 발현되는 특유의 질환들이 존재한다. 노인에서 특히 잘 발생하는 수술 후 인지기능 장애(postoperative cognitive dysfunction, POCD)나 섬망(delirium), 혹은 치매(dementia)는 노화와 관련된 대표적인 뇌기능 이상이나 질환이다.

전신마취제는 주 작용부위가 중추신경계이고 그 작용의 결과 대상자의 인지 상태(cognitive state)를 변화시키는데, 일반적으로 이러한 작용은 지속시간이 짧고 가역적으로 인식되고 있다. 하지만 마취 및 수술 후 상당기간 지속되는 인지기능 변화 내지는 장애는 이미 오래 전부터 감지되고 있었다[1,2]. 특히 노인에서는 마취제의 작용으로 인해 직접적으로 인지기능을 손상시키는 것인지 혹은 치매와 같은 인지기능을 저해하는 질환을 발병시키거나 악화시키는 것인지가 최근에 주요 관심사가 되고 있다. 따라서 많은 연구자들이 마취제의 작용에 의해 POCD나 dementia의 발생이나 중증도가 달라지는지를 탐구하고 있다. 본 강의에서는 마취제가 마취 후까지 지속적으로 이러한 인지 장애를 유발할 수 있는 기저 기전(underlying mechanism)을 소개하고 이를 바탕으로 임상적인 의의를 고찰해 보기로 한다.

마취제의 뇌 독성 작용 - 실험적 증거들

임상연구에서는 마취에는 수술이 반드시 동반되기 때문에 마취 자체로 인해 인지 기능 이상이 발생하는지를 연구하기에는 한계가 있다. 따라서 이러한 연구는 세포 배양이나 동물 실험을 통해 그 가능성을 연구하는 것이 일반적이다. 이와 관련된 최초의 연구는 Culley 등이 시행한 실험으로 노령의 쥐를 대상으로 isoflurane과 N

2O에 노출시킨 결과, 적어도 3주 이상 지속되는 기

억 및 학습 장애가 나타났다[3]. 이 후 이어지는 연구들을 통해 마취제는 다음에 기술하는 기전들을 통해 잠재적으로 뇌신경 독성을 가질 있다는 사실을 주지하게 되었다.

1. Amyloid-β

Amyloid-β (Aβ)는 synapse부위 membrane에 존재하는 amy-loid precursor protein (APP)가 분해되어 형성된 작은 조각 펩타이드(small fragment peptide)로 알츠하이머병(Alzheimer’s disease, AD)의 병인에 중요한 역할을 하는 것으로 알려져 있다. 모든 유전성 AD에는 APP나 그와 관계하는 인자들의 유전적 돌연변이(mutation)가 있다. Aβ monomer가 세포 밖(extracellular)에 과도하게 축적되면 oligomer를 형성하기 시작하며 궁극적으로는 plaque가 된다. 현재까지 밝혀진 바에 따르면 amyloid plaque 비해 oligomer들이 직접적인 신경 독성을 나타내거나 뇌 신경계의 주 면역세포인 microglia와의 작용으로 인한 염증반응을 일으키는 것으로 알려져 있다. 이러한 직접적인 뇌신경 독성 내지는 연관된 염증반응으로 인해 점차적으로 신경세포(neuron)와 신경접합부(synapse)를 소실시켜 그 손상이 일정 한계를 넘으면 인지 기능 장애가 나타난다. Aβ가 과도하게 생성되는 유전자 이식 쥐 모델(Tg2576 mice)에서 halothane 투여가 amyloid plaque 형성을 유의하게 증가시킨다는 보고[4] 이후, 흡입 마취제가 β-amyloid cleaving enzyme을 증가시켜 Aβ 유리를 증가시키고[5,6], Aβ monomers의 polymerization를 증가시켜 oligomers 형성을 촉진하며[7], 또한 수주 동안Aβ 청소에 관여하는 몇몇 단백질의 수준을 감소시켜 Aβ를 뇌에서 제거하는 기전에 문제를 일으킬 수 있다는 연구가 이어졌다[8]. 반면에 propofol은 흡입마취제에 의한 Aβ oligomerization을 차단할 수 있다는 보고들도 있다[9]. 이와 같은 보고들은 마취제가 AD의 주요 병인으로 간주되는 Aβ의 뇌내 농도 및 oligomer를 증가시켜 AD 발병이나 악화에 영향을 미칠 수도 있고 궁극적으로 인지기능의 장애를 일으킬 가능성이 있음을 시사한다. 하지만, 젊은 유전자 이식쥐에서 동등한 수준의 마취제를 투여하였을 때 Aβ의 수준에 변화가 없고 학습이나 기억의 장애가 발생하지 않는 점을 고려하면[10], 마취제 단독으로 AD나 인지기능 이상을 일으키지는 않는다는 것을 알 수 있다.

2. Tau (τ)

AD형 치매의 또 다른 특징적 병변은 인산화(phosphorylated)된 τ단백질이 결집하여 형성된 neurofibrillary tangle이다. τ단백질은 원래 microtubule의 안정성과 활동성을 조절하는 역할을 한다. 하지만 τ단백질이 인산화 되면 micorotubule에서 분리되고, 특히 과도한 양이 유리되면 집합체(aggregation)를 형성하여 결국은 원섬유(fibril)가 되어 세포 독성을 띠게 된다. 마취와 관련해


노인에서 마취제의 뇌 독성작용

이재훈

연세대학교 의과대학 세브란스병원 마취통증의학과


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서는 마취제 자체와 마취에 따른 부수적 작용으로 인해 호발하는 저체온 모두가 τ단백질 인산화와 관계가 있다. τ단백질의 탈인산화(dephosphorylation)를 담당하는 효소(phosphatases)는 온도에 민감해서 온도가 2-3oC만 낮아져도 인산화된 τ단백질이 증가하게 된다. 따라서 마취 상태에서 저체온이 발생하면 역시 τ단백질 인산화가 증가하게 된다[11]. 하지만 정상체온에서도 흡입 마취제 및 propofol이 τ 인산화를 증가시킬 수도 있다[12,13]. 하지만 마취제가 τ인산화를 촉진시키는 결과를 얻기 위해서는 일회성 투여가 아닌 반복 투여가 필요한 것으로 보인다[10,12]. 이와 같은 연구들에 따르면, AD의 2번째 특징인 taunopathy는 전신 마취제나 전신마취와 동반하는 생리적 상태에 영향을 받기 때문에, 마취와 AD 병인과의 상호 작용이 수술 후 인지기능 감퇴의 원인이 될 수도 있다는 근거를 제공한다.

3. Mitochondrial dysfunction

Mitochondria는 세포 내의 작은 organelle로 세포의 에너지 공급원으로, 대부분의 세포 기능과 밀접한 연관관계가 있다. 이 mitochondria는 나이가 듦에 따라 또 AD에서 기능이상이 나타나는 경향이 있다. 신경 세포를 이용한 실험들에서 흡입 마취제 isoflurane은 reactive oxygen species (ROS)를 증가시켜 mitochondrial membrane에 손상을 일으키고, 이에 따라 cytochrome C, calcium, 그리고 더욱 많은 ROS가 mirochondria로 부터 유출된다. 유출된 cytochrome C에 의해 caspase-9 및 caspase-3가 활성화되어 apoptosis가 유도된다. 아울러 isoflurane은 mitochondrial permeability transition pore (mPTP)를 개방하여 caspase-3 활성화에 따른 apoptosis를 유발할 수 있다(하지만 desflurane은 mPTP를 개방하지 않는다) [14,15]. 또한 유출된 calcium은 다음에 기술할 excitotoxic injury를 가중시킬 수 있다.

4. Excitotoxic neuronal injury

Aβ는 직접적인 신경 독성 및 염증 유발 작용 이외에도 신경 세포내 calcium 항상성을 교란시켜 신경 세포를 excitotoxic injury에 취약하게 만든다[16]. 이러한 현상은 특히 endoplasmic reticulum (ER)에서 calcium을 방출시키는 ryanodine receptor channel과 inositol 1,4,5-triphosphate (IP3) receptor channel들과 관련되며, 이 또한 알츠하이머 병인으로 간주된다. 한편 흡입마취제는 악성고열증(malignant hyperthermia)과 관련된 기전으로서 근육 세포에서 ryanodine receptor를 활성화시킴으로써 세포내 calcium을 증가시키는 것으로 알려져 있다. 또한 흡입마취제는 voltage-gated calcium channel들의 활성화를 차단함으로써 IP3-gated calcium channel들을 활성화 시킨다. 이들에서 유추해 볼 수 있는 결과로서, 1 MAC 이상의 흡입마취제는 신경세포의 세포 내 calcium 농도를 높일 수 있고, 결과적으로 Aβ와 상승적으로 작용하여 excytotoxic neuronal injury를 일으킬 수 있다[17]. 또한 세포 내 calcium 농도 상승은 mitochondria에 작용하여 apoptosis를 유발할 수 있다. 반면, propofol은 ER에 대한 이러한 작용이 현저하게 적은 것으로 알려져 있다.

5. Surgery/Neuro-inflammation

실제 임상에서 마취와 필연적으로 연계되는 수술은 대부분 말초의 염증반응을 유발한다. 이러한 말초 염증 반응은 proinflammatory cytokine (interleukin-1β 혹은 TNF-α)이나 구심성 미주 신경(vagal afferents)을 통해 중추 신경계로 전달될 수 있다. 신경 염증이 인지기능 저해를 일으킬 수 있다는 사실은 잘 알려져 있고, 말초에서 전달된 신경염증이 상당한 수준의 인지기능 장애을 일으킬 수 있다는 것이 실험적으로 증명되었다[18-20]. 이러한 기전에 따른 인지기능 장애는 POCD의 이론적 기반으로 간주되고 있다. 동시에 신경염증은 AD형 치매의 주요 병인으로도 여겨진다[21]. 치매, 특히 AD 형에서 Aβ에 의해 microglia들이 활성화되어 있고, proinflammatory cytokine들이 상향 조절되고 있으며, 말초의 monocyte들이 뇌신경계로 침투해 있다[22]. 이와 같이 신경염증이 인지기능을 저해할 수 있다는 것은 명확하지만, 마취제가 염증 반응을 조절할 수 있는지는 확실치 않다. 흡입마취제의 경우 항염증작용이 없는 것으로 간주되고 있고, propofol의 경우 특유의 radical scavenging 효과로 인해 항염증작용이 다소 있는 것으로 평가되고 있다. 결론적으로 전신마취 하에 수술을 진행한 경우, 이후 발생하는 인지기능 장애는 마취제가 유발한 장애라기 보다는 수술 자체에 의한 뇌신경 염증에 인한 것일 가능성을 충분히 고려해야 한다.

마취제의 뇌 독성 작용 - 임상적 고찰

많은 연구들을 통해 마취 및 수술이 인지기능에 장기적인 영향을 미칠 수 있다는 것이 증명되었다. 특히 심장 수술 후에 관찰된다고 보고되었던 인지기능장애가 비심장수술 후에도 비슷한 중증도로 나타날 수 있다는 보고가 이어지고 있다. 이러한 수술 후 인지 기능 저하는 다양한 시점에서 서로 다른 신경정신검사 내지는 진단 기준에 따라 정량화되어, POCD 혹은 delirium으로 분류되고 있다. 뿐만 아니라 앞서 언급한 내용처럼 마취 및 수술은 AD를 유발하거나 악화시킬 가능성도 있으므로 이로 인한 인지 기능 쇠퇴도 고려해야 한다. 이들 POCD, delirium, 그리고 AD는 서로 교차되는 부분이 있는 것으로 보여진다. AD를 앓는 환자들은 입원 중 delirium의 발생 위험이 높고[23], AD의 preclinical sign을 가진 환자들은 마취 및 수술 후 POCD 발생 위험 역시 높다[24]. 반복되는 내용이지만 마취 및 수술에 따른 병태생리적 변화는 AD 병인과 밀접한 관련이 있다.

1. 알츠하이머병(Alzheimer’s disease, AD)

AD는 진행성의 노화와 연관된 신경변성 질환(neurodegenerative disease)으로 인지기능의 손상을 초래한다. AD의 병인으로써 다양한 기전들이 밝혀져 있지만, 핵심적인 것은 비정상적인 단백질 구조에 의해 유발되는 산화 스트레스(oxidative stress), 염증 손상(inflammatory damage), 및 시냅스 장애(synaptic dysfunction)이다.

수술적 치료가 꼭 필요한 환자에서 마취 및 수술이 진행되기 때문에, 실제 임상에서 무작위 배정 연구를 할 수가 없고, 따라서 마취 및 수술이 AD 발병 내지는 중증도에 미치는 영향을 직접적

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으로 알아내는데에는 한계가 있다. 기존의 후향적 연구들을 분석한 2011년의 메타분석 연구에서는 분석에 포함된 이전의 연구들로는 마취 및 수술과 AD의 관계를 확실하게 결정하기에 부족하다는 결론을 내렸다[25]. 하지만 그 이후에 나온 대단위 후향적 연구들에서 마취 및 수술 후의 치매의 발생율은 증가한다는 것을 밝혀냈다[26,27]. 여전히 후향적 연구의 한계를 가진 연구지만, 기존에 분석에 포함되지 않았던 많은 인자들을 포함하여 분석한 의미 있는 결과이다.

AD 환자들은 임상적으로 명확한 AD로 진행하기 전에 mild cognitive impairment (MCI) 상태를 거친다. 최근의 한 전향적 무작위 배정 연구에서 sevoflurane 마취 하에 수술을 받은 환자들은 propofol 마취를 받은 수술 환자들이나 수술을 받지 않은 환자들에 비해 MCI의 중증도가 악화되었다고 보고된 바 있다[28]. 이 연구 또한 흡입마취제를 이용한 마취 및 수술이 AD의 병인과 관계하여 AD로 진행시킬 수 있다는 가능성을 보여준다.

마취 및 수술이 AD 병인에 영향을 미치는지 알아볼 수 있는 또 다른 방법은 AD에 대한 biochemical marker를 분석해 보는 것이다. 현재 Aβ42, total τ, 그리고 phospho-τ 같은 cerebrospinal fluid (CSF) biomarker가 AD 진단에 유용하고, 특히 total τ/ Aβ 비는 AD가 발병하기 전에 AD발병을 예측하는 민감하고 특이적인 biomarker로 알려져 있다[29]. 여러 연구에서 마취 및 수술 후에 CSF biomarker들의 변화가 보고 되었었지만[30-32], 일시적인 변화는 장기적인 중요성을 가지지 못하는 것으로 알려져 있다[33]. Off-pump 관상동맥우회술을 받는 환자들을 대상으로 하는 소규모 연구에서 이러한 CSF biomarker들의 변화가 6개월 이상 지속되고 이들 중 일부가 수술 후 6개월에도 인지기능 장애를 보였으나, 소규모 연구임에도 불구하고 대상자 탈락률이 높아 결론을 내릴 수 없었다[30]. CSF biomarker외에도, AD 의 radiologic marker로서 Aβ plaque에 결합하는 radioactive tracer가 있다. 이 tracer를 이용한 PET scan으로 Aβ plaque 수준을 평가할 수 있다[34]. 이 방법은 현재 Aβ plaque 수준이 수술 후 delirium이나 POCD와 연관성이 있는지 알아보는 연구에 이용되고 있다. 또한 τ tracer도 개발 중이다[35]. 이외에도 functional MRI는 어떤 환자가 인지적 작업을 수행하는 동안 활성화되는 뇌 구조에 대한 역동적인 정보를 제공함으로써 AD나 MCI환자와 정상인 간의 신경 활동의 변화를 알려줄 수 있다[36]. 따라서 수술 후 환자의 뇌신경 활동 양식을 분석함으로써 인지 기능 이상을 진단할 수 있을 것이다. 이와 같은 biomarker들을 적극적으로 이용하면 마취 및 수술이 AD 병태생리에 어떠한 영향을 미치는지 밝히는데 도움이 될 것이다.

2. Postoperative cognitive dysfunction (POCD)

POCD는 공식적으로 정의된 질환(disease)나 장애(disorder)가 아니고, 따라서 표준화된 진단 기준 역시 없는 실정이다. 일반적으로 POCD는 수술 전과 수술 후의 신경 심리 검사(neuro-psychologic test) 결과를 비교하여 그 변화 정도를 기반으로 진단되고 있다(신경심리검사는 다양한 인지영역을 평가하는 검사를 말한다). 수술 후 수일 동안 인지기능이 일시적으로 떨어질 수 있다는 사실은 잘 알려져 있고, 이러한 현상은 신경심리학적 평가(neuropsychological assessment)에 의해 쉽게 확인할 수 있으나,

대부분 수술 후 몇 일 정도 지속된 후 수술 전부터 이어지던 인지기능 상태로 되돌아간다. 게다가 이러한 마취 및 수술 후의 일시적인 인지기능장애는 동물 실험과 같은 전임상실험에서 쉽게 재현되며, 마취 자체의 효과라기 보다는 수술적 스트레스에 따른 신경염증 반응과 연관되어 있음이 증명되었다[18-20]. 하지만 실제 임상에서는 수주에서 수개월 이상 지속되는 인지기능 저하가 중요하고, 이러한 POCD는 최근 논란의 중심에 있다. POCD를 보고한 연구들의 일부는 수술을 받지 않은 대조군 혹은 그에 상응하는 적절한 대조군의 설정 없이 마취 및 수술을 받은 환자에서의 인지기능만을 조사 분석하였다[37,38]. 따라서 다양한 병발 질환이나 기저 질환으로 인해 인지기능저하를 가질 수 있는 노인인구에서 수술 후 측정한 인지기능장애가 마취 및 수술과 연관되어 있다는 결론을 내리기 어렵다. 또한 대부분의 연구가 수술 전에 여러 번에 걸쳐 신경심리검사를 시행하지 않았기 때문에, 수술 후 인지기능장애가 나타났다고 하더라도 이것이 수술 전부터 지속적으로 인지기능이 감소되고 있던 것에 연장인지 특별히 마취 및 수술에 의해 악화되었는지 판단할 수가 없다[38]. 하지만 이러한 논란에도 불고하고, 마취 및 수술 후 인지기능이 저하된 환자들이 분명하게 존재하고, 이러한 인지기능 장애가 삶의 질 저하, 생업에서 조기 퇴출, 1년내 사망률 증가 등과 연관된다[39-41]. 따라서 POCD에 대한 예방 및 치료 방안, MCI나 AD 발병이나 경과에 미치는 영향 등에 대한 연구가 지속적으로 필요하다. 아울러 마취 및 수술 후 발생할 수 있는 또 다른 인지기능 관련 합병증으로 delirium이 있는데, 이에 관해서도 같은 방향의 연구가 요구된다.

3. 인지기능저하 위험성을 가진 환자의 주술기 관리

마취 및 수술이 AD의 병인에 기여하거나 실제 임상적으로 중요한 정도의 인지기능장애를 일으킬 수 있느냐에 더하여, 이러한 위험성이 높은 환자들에 대한 바람직한 주술기 관리 방법을 찾는 것 역시 중요하다. 하지만 이에 대한 직접적인 연구는 거의 없는 실정이다. 따라서 관련 연구들을 종합적으로 검토하여 인지기능저하의 위험성이 있는 환자들의 주술기 관리 방법에 관한 힌트를 얻어보기로 한다.

우선 위험성이 있는 환자들을 가려내는 과정이 중요하다. 실제 임상적으로 MCI나 AD를 진단받은 환자뿐 만 아니라, 신경심리검사 상 경미한 인지기능 장애를 가진 환자, AD에 합당한 biomarker나 방사선 소견을 보이는 환자, 그리고 AD에 대한 위험인자들(고혈압, 고지혈증, 당뇨)을 가진 환자 등을 선별하여 인지기능장애에 대한 대비가 필요하다.

AD 환자들은 마취제에 민감하며[42], 수술 후 delirium의 발생 가능성이 높기 때문에[43], 수술 중 마취 깊이를 감시하여 마취 깊이를 적정 수준으로 유지시켜 주면 delirium의 발생 가능성을 줄일 수도 있다[44,45]. 또한 앞서도 언급한 바와 같이 propofol을 이용한 전정맥마취는 seveflurane마취에 비해 MCI의 진행을 막을 수 있다는 보고가 있다[28]. 염증반응을 줄여서 인지기증장애를 개선해보고자 하는 관점에서는 non-steroidal anti-inflammatory drugs (NSAIDs)의 투여가 AD의 위험성을 줄이는가에 관한 연구들이 있다. 관찰연구에서는 NSAIDs의 투여가 효과적으로 보였으나, 전향적 연구에서 그 효과가 입증되지 않았다[21].

많은 AD나 MCI를 동반한 환자들이 중추신경계에 작용하는


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acetylcholinesterase inhibitor를 복용하고 있다. 하지만 이 약제의 작용은 말초에도 나타나서 plasma cholinesterase의 작용도 약화시키고, 따라서 이 약제를 복용하는 환자들은 succinylcholine을 투여 받았을 때 phase II block이 발생할 위험성이 있다[46]. 또한 비탈분극성 근이완제의 작용이나 neostigmine같은 reversal agents의 작용에 영향을 미칠 수 있다[47]. 하지만 주술기에 acetylcholinesterase inhibitor의 복용을 중단시키는 것은 이미 delirium의 위험성이 높은 상태에서인지 관련 합병증이 높이는 결과를 초래할 수 있다. 따라서 acetylcholinesterase inhibitor를 복용하는 환자에서는 탈분극성 근이완제는 사용하지 않는 것이 바람직하며, 지속시간이 짧은 비탈분극성 근이완제를 사용하고 reversal agents 없이 자연 회복을 시키는 것이 추천된다.

마취제가 AD 병인에 미칠 수 있는 잠재적 영향이나 benzo-diazepine이나 opioids가 delirium을 유발시킬 수 있다는 점을 고려해 볼 때, 부위 마취가 수술 후 인지 관련 합병증을 줄일 수 있을 것으로 생각되었지만, 메타 분석 결과 부위 마취는 전신마취에 비해 POCD나 delirium의 발생률을 줄이지 못했다[48]. 이는 대부분의 부위마취가 마취제를 이용한 진정을 동반해서일 수도 있고, 혹은 마취 보다 수술 자체에 의한 스트레스가 인지관련 합병증의 발생에 더 큰 영향을 미치는 것이라 추측할 수도 있겠다.

결론

전임상 단계의 많은 실험 연구들은 마취제 자체가 다양한 기전을 통해 직접적으로 인지 기능을 저하시킬 수 있는 가능성을 보여 주고 있지만, 실제 임상에서 마취제 단독으로 수술 후 인지 기능 관련 합병증을 발생시킨다고 판단할 근거는 거의 없다. 실제 수술을 받는 환자들에서는 수술 자체의 스트레스, 환자의 연령이나 동반 질환과 관련된 변화 역시 수술 후 인지 기능에 큰 영향을 미치기 때문이다. 하지만 이러한 수술 후의 인지 기능 관련 합병증은 환자의 실제 예후를 크게 변화시킬 수 있기 때문에, 수술이나 환자의 기질적인 위험인자뿐 아니라 마취제의 잠재적인 위험성까지 포함하여 병태 생리, 예방 및 치료 방법에 대하여 포괄적이고 지속적인 연구가 필요한 실정이다.

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7. Eckenhoff RG, et al. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology 2004;101:703-9.

8. Liu Y, et al. Sevoflurane alters the expression of receptors and enzymes involved in Abeta clearance in rats. Acta Anaesthesiol Scand 2013;57:903-10.

9. Zhang Y, et al. Anesthetic propofol attenuates the isoflurane-induced caspase-3 activation and aβ oligomerization. PloS One 2011;6:e27019.

10. Tang JX, et al. Anesthesia in presymptomatic Alzheimer’s disease: a study using the triple-transgenic mouse model. Alzheimers Dement 2011;7:521-31.

11. Planel E, et al. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci 2007;27:3090-7.

12. Le Freche H, et al. Tau phosphorylation and sevoflurane anesthesia: An association to post-operative cognitive impair-ment. Anesthesiology 2012;116:779-87.

13. Whittington RA, et al. Propofol directly increases tau phos-phorylation. PloS one 2011;6:e16648.

14. Zhang Y, et al. The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J Biol Chem 2010;285:4025-37.

15. Zhang Y, et al. Anesthetics isoflurane and deflurane differentially affect mitochondrial function, learning, and memory. Ann Neurol 2012;71:687-98.

16. Mattson MP, et al. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992;12:376-89.

17. Xu Z, et al. The potential dual effects of anesthetic isoflurane on ABeta-induced apoptosis. Curr Alzheimer Res 2011;8:741-52.

18. Cibelli M, et al. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 2010;68:360-8.

19. Wan Y, et al. Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in hippocampus. Anesthesiology 2007;106:436-44.

20. Terrando N, et al. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol 2011;70:986-95.

21. Wyss-Coray T, et al. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Col Spring Harb Perspect Med 2012;2:a006346.

22. Perry VH. Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol 2010;120:277-86.

23. Gross AL, et al. Delirium and long-term cognitive trajectory among persons with dementia. Arch Intern Med 2012;172: 1324-3.

24. Xie Z, et al. Cerebrospinal fluid aβ to tau ratio and postoperative cognitive change. Ann Surg 2013;258:364-9.

25. Seitz DP, et al. Exposure to general anesthesia and risk of Alzheimer’s disease: A systemic review and meta-analysis.

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BMC Geriatr 2011;11:83.26. Chen CW, et al. Increased risk of dementia in people with

previous exposure to general anesthesia: A nationwide popul-ation-based case-control study. Alzheimers Dement 2013;10: 196-204.

27. Chen PL, et al. Risk of dementia after anaesthesia and surgery. Br J Psychiatry 2013;204:323.

28. Liu Y, et al. Inhaled sevoflurane may promote progression of amnestic mild cognitive impairment: A prospective rand-omized parallel-group study. Am J Med Sci 2013;345:355-60.

29. Shaw LM, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 2009;65:403-13.

30. Palotas A, et al. Coronary artery bypass surgery provokes Alzheimer’s disease-like changes in the cerebrospinal fluid. J Alzheimers Dis 2010;21:1153-64.

31. Reinsfelt B, et al. Open heart surgery increases cerebrospinal levels of Alzheimer-associated amyloid beta. Acta Anaesthesiol Scand 2013;57:82-8.

32. Tang XJ, et al. Human Alzheimer and inflammation biomarkers after anesthesia and surgery. Anesthesiology 2011;115:727-32.

33. Kang JE, et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 2009;326:1005-7.

34. Wong DF, et al. In vivo imaging of amyloid deposition in Alzheimer’s disease using the radioligand 18F-AV-45. J Nucl Med 2010;51:913-20.

35. Zhang W, et al. A highly selective and specific PET tracer for imaging of tau pathologies. J Alzheimers Dis 2012;31:601-12.

36. Dhanjal NS, et al. Auditory cortical function during verbal episodic memory encoding in Alzheimer’s disease. Ann Neurol 2013;73:294-302.

37. McDonagh DL, et al. Cognitive function after major noncardiac surgery, apolipoprotein E4 genotype, and biomarkers of brain

injury. Anesthesiology 2010;112:852-9.38. Avidan MS, et al. Review of clinical evidence for persistent

cognitive decline or incident dementia attributable to surgery or general anesthesia. J Alzheimers Dis 2011;24:201-16.

39. Phillips-Bute B, et al. Association of neurocognitive function and quality of life 1 year after coronary bypass graft (CABG) surgery. Psychosom Med 2006;68:369-75.

40. Steinmetz J, et al. Long term consequences of postoperative cognitive dysfunction. Anesthesiology 2009;110:1306-16.

41. Monk TG, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008;108:18-30.

42. Erdogan MA, et al. The effects of cognitive impairment on anaesthetic requirement in the elderly. Eur J Anaesthesiol 2012; 29:326-31.

43. Gross AL, et al. Delirium and long-term cognitive trajectory among persons with dementia. Arch Intern Med 2012;172: 1324-31.

44. Sieber FE, et al. Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clin Proc 2010;85:18-26.

45. Chan MT, et al. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol 2013; 25:33-42.

46. Sprung J, et al. The effects of donepezil and neostigmine in a patient with unusual pseudocholinesterase activity. Anesth Analg 1998;87:1203-5.

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48. Mason SE, et al. The impact of general and regional anesthesia on the incidence of post-operative cognitive dysfunction and post-operative delirium: a systemic review with meta-analysis. J Alzheimers Dis 2010;22(S):67-79.


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Introduction

Ischemia-reperfusion (IR) injury can be resulted from many factors such as the release of free oxygen radicals and con-secutive lipid peroxidation, cell death by apoptosis or necrosis, inflammatory cytokines, and damage to the microvasculature [1, 2]. Reactive oxygen species (ROS) that appear with reperfusion injury damage cellular structures through the process of the lipid peroxidation of cellular membranes and yield toxic metabolites such as malondialdehyde (MDA), that is, used as a sensitive marker of IR injury. The mechanism of organ damage after IRI include production of ROS, release of proinflammatory cytokines and chemokines, and activation of immune cells to promote inflammation and tissue damage [3]. There are three time frames in which protection against ischemia-reperfusion injury can be induced: before ischemia occurs, during ischemia, and after the ischemia at the onset of reperfusion. A variety of investigations using experimental animals have shown that volatile or intravenous anesthetics have a protective effect against IR injury.

Volatile anesthetics

1. Brain

- Cerebral IR injury is encountered from various neurological, vascular, and cardiovascular procedures. This typically causes a disorder of water homeostasis and has been associated with oxidative stress, inflammatory response, lipid peroxidation, and apoptosis [4-7].

- Isoflurane neuroprotection has been demonstrated in a variety of experimental models of ischemia, including hemispheric [8], focal [9] and near complete ischemia [10]. Similarly, the available data suggest that both sevoflurane [11,12] and desflurane [13,14] can reduce ischemic cerebral injury.

- Multiple mechanisms have been proposed for the neuro-protection induced by volatile anesthetics [15,16]. Volatile ane-sthetics reduce metabolic rate of the brain. This effect should prolong the ischemic time that can be tolerated by the brain

tissues and, therefore, should contribute to the anesthetics-induced neuroprotection. Volatile anesthetics reduce glutamate neurotoxicity due to their inhibition on glutamate receptors [17]. Since glutamate-induced over-excitation and the subsequent cell injury in the brain are a major mechanism for ischemic brain injury [18], anesthetics may provide neuroprotection through their inhibition of glutamate neurotoxicity. Also, increased intracellular calcium plays a critical role in ischemic brain injury [18]. Volatile anesthetics can regulate intracellular calcium concentrations [19], which may contribute to their neuroprotective effects.

1) Neuroprotection induced by application of volatile

anesthetics before brain ischemia

The concept “ischemic preconditioning” was introduced into the literature in 1986 [20]. Ischemic preconditioning describes a phenomenon in which episode(s) of short ischemia applied before a prolonged episode of ischemia reduce cell injury caused by the prolonged ischemia. This protection has two effective time phases. The acute phase starts minutes after the preconditioning stimulus and lasts for a few hours. The delayed phase starts hours after preconditioning stimulus and can last for many days [21]. These time windows relate when the prolonged episode of ischemia occurs for the protective effects to be present. Subsequently, various stimuli including volatile anesthetics have been found to induce a preconditioning effect in many organs [21,22].

Previous studies have found that volatile anesthetics induce preconditioning effects in the brain (volatile anesthetic precondi-tioning-induced neuroprotection) [23-25]. We showed that the acute phase of this protection is anesthetic concentration-de-pendent. In case of isoflurane, this protection was maximized by the exposure to 2% isoflurane for 20 min [24]. Numerous studies have shown volatile anesthetic preconditioning induced protection in the brain and spinal cord [26]. This protection appears to improve long-term neurological outcome in neonatal or adult rats [27,28]. Multiple molecules including signaling molecules, such as free radicals [29], intracellular Ca++ [30], calcium/calmodulin-dependent protein kinase II [31], mitogen-activated protein kinase [23], protein kinase B/Akt [30], hypoxiainducible factor-1a [32],


Anesthesia-induced protection-experiment: the effect of anesthetics on ischemic-reperfusion injury of brain, liver and kidney

So Yeon Kim, Bon-Nyeo Koo

Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea

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and inducible nitric oxide synthase [25,33], have been implicated in the volatile anesthetic preconditioning-induced neuroprotection.

Bedirli et al. [34] carried out a study to examine the effects of sevoflurane or isoflurane preconditioning on cerebral IR induced inflammation, oxidative stress, and lipid peroxidation and test the hypothesis that the underlining mechanism of the protective effect of preconditioning involves changes in the apoptotic gene expression profiles in an experimental model of middle cerebral artery occlusion (MCAO) in rats. In consequence of their study they

found that sevoflurane and isoflurane preconditioning ameliorates inflammation, cerebral lipid peroxidation, and histologic injury. They also concluded that downregulation of proapoptotic molecules and upregulation of antiapoptotic molecules may be associated with this effect.


anesthetics after brain ischemia

The phrase “ischemic postconditioning” was first used in the


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literature in 2003 [35]. It describes the protection induced by introducing short episodes of ischemia during the early phase of reperfusion after a prolonged episode of ischemia. Since this protection does not require the prediction on when the detrimental ischemia will occur, postconditioning-induced protection is considered to be more applicable in the clinical practice. In fact, post-treatment/postconditioning has been a common practice to provide medical care because most patients seek medical attention only after a disease/injury has occurred.

Application of isoflurane at the onset of reperfusion improves neurological outcome after a 90-min MCAO [36]. There are so far 6 published studies showing volatile anesthetic post-treatment-/postconditioning-induced neuroprotection [31,35-40]. This pro-tection requires the application of volatile anesthetics within 1 h after the onset of reperfusion. Isoflurane, sevoflurane and de-sflurane at clinically relevant concentrations with the exposure times of 30-60 min have been shown to induce this protection. This protection can be induced in primary rat neuronal cultures, human neuron-like cell cultures, adult rats after transient focal brain ischemia, neonatal rats after brain hypoxia-ischemia injury or mice after an intracerebral hemorrhagic stroke. Various signaling molecules including glycogen synthase kinase 3b, Akt and mitochondrial KATP channels have been implicated in this neuroprotection. However, there is no clinical study yet to determine whether volatile anesthetic can induce a postconditioning effect in the human CNS.


anesthetics during brain ischemia

It was realized in 1990s that ischemic cell death is a dynamic process that can last for at least 2 weeks after brain ischemia in rodents [41]. To evaluate the long-term neuroprotective effects of volatile anesthetics when applied during brain ischemia, an early study subjected adult rats to MCAO for 70 min in the presence or absence of 1.5 minimum alveolar concentrations (MAC) of isoflurane. Animals with isoflurane exposure during brain ischemia had smaller infarct volumes than those without isoflurane exposure at 2 days, but not at 14 days, after brain ischemia [42]. This result suggests that neuroprotective effects of isoflurane may not be long-lasting. However, a recent study showed that adult rats had smaller brain infarct volumes and better neurological outcomes evaluated at 14 or 28 days after brain ischemia if 1.8% isoflurane (~1.4 MACs) was applied during a 50-min or 80-min MCAO [43]. These findings strongly suggest that isoflurane provides long-lasting neuroprotection. One important difference between these two studies is that the early study permanently ligated the ipsilateral common carotid artery, which could cause chronic hypoperfusion to the brain regions including the previously ischemic brain tissues. The second study only temporarily occluded the common carotid artery during MCAO. This difference in creating MCAO may have resulted in

the different conclusions regarding whether isoflurane-induced neuroprotection is long-lasting.

Ishiyama et al. [44] compared the effects of sevoflurane with propofol on cerebral pial arteriolar and venular diameters during global brain ischemia and reperfusion. Twenty rabbits were anesthetized with sevoflurane or propofol and then global brain ischemia was induced by clamping the brachiocephalic, left common carotid, and left subclavian arteries. They observed pial microcirculation microscopically through closed cranial windows and measured using a digital video analyzer. They found that pial arterioles and venules did not dilate immediately after reperfusion and subsequently constricted throughout the reperfusion period in propofol group. In contrast, pial arterioles and venules dilated temporarily and returned to baseline in sevoflurane group. Adverse effects in sevoflurane group (pulmonary edema and acute brain swelling) were higher than propofol group. In addition, blood pressure, heart rate, and plasma glucose were stable in sevoflurane group.

2. Liver

- Ischemic liver injury occurs in a variety of clinical set-tings such as trauma, shock, and liver surgery [45,46]. Isch-emia and subsequent reperfusion injury rapidly evolves to sinusoid endothelial cell damage, activation of Kupffer cells, inflammation, hepatocyte necrosis and finally liver dysfunction [47].

- The hepatoprotective effects of volatile anaesthetics have been observed in experimental studies [48,49]. However, there are conflicting results regarding the superiority of sevoflurane in preventing liver IR injury when compared to isoflurane. Imai et al. [50] reported that isoflurane and sevoflurane exerted protective effects of similar magnitude in rats after IR injury. Another study [51] using pigs did not show any difference in the extent of hepatic IR injury between isoflurane and sevoflurane. However, sevoflurane (2%) given before, during, and after hepatic ischemia, but not isoflurane (1.5%), provided significant protection against IR injury, and this effect was apparent even in the early postischemic period in rats [52]. When sevoflurane and isoflurane were tested in experimental model simulating liver transplantation, sevoflurane anesthesia seems to have superior protective and antioxidant effects to isoflurane anesthesia [53].

3. Kideny

- Renal IR injury is a leading cause of perioperative acute kidney injury (AKI) and frequently complicates major vascular, transplant, cardiac, and liver surgeries. The cellular mechanisms of ischemic AKI are briefly summarized in Figure 1 and proposed renal protection mechanisms of volatile anesthetics in Figure 2 [54].

- Clinically relevant concentrations (1 MAC) of volatile anes-

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thetics given both during and after renal ischemia (3 h of reperfusion) protect against renal IR injury in rats by dramatically reducing tubular necrosis typically observed after renal IR injury. In addition, volatile anesthetics showed differential protection from renal IR injury in that desflurane was less effective and showed less antiinflammatory effects compared with isoflurane, sevoflurane, or halothane [55]. Obal et al. [56] reported post-conditioning by a short (15 min) administration of 1 MAC desflurane (6.7 vol%) at the beginning of reperfusion reduces IR injury in the kidney. This effect was more pronounced after 30 min than after 45 min of renal artery occlusion [57].

Intravenous anesthetics

1. Propofol

1) Brain

Propofol, at clinically relevant concentrations, is neuroprotective in models of cerebral ischemia in vitro and in vivo and that it may act by preventing the increase in neuronal mitochondrial swelling [58] Anti-apoptotic effect of propofol in cerebral ischemia-reperfusion rats is involved in regulation the expression of apoptosis related genes, B-cell leukemia-2 (Bcl-2) and Bcl-2-associated X protein (Bax) [59]. Propofol post-treatment after focal cerebral IR injury

Figure 1. Cellular mechanisms of ischemic AKI. Prolonged renal ischemia causes significant depletion of ATP, leading to various cellular changes (e.g., bleb formation and loss of renal tubular polarity). Adhesion molecules and neutrophil chemoattractants expressed on the endothelial cells cause migration of neutrophils. Cytokines and chemokines produced by renal tubular epithelial cells further cause renal tubular and endothelial inflammation. Breakdown of the endothelial basement membrane causes vascular leakage and neutrophil migration into the interstitial space. Orchestration of dendritic cells, neutrophils, and T lymphocytes further promotes epithelial and endothelial injury by inducing inflammation and cytokine/chemokine generation.On the other hand, a subset of the T-cell population, called regulatory T cells, plays an important role in protecting the kidney fromIR injury by suppressing inflammation and by facilitating recovery. Volatile anesthetics via release of multiple cytoprotective and anti-inflammatory molecules can target many of the pathways involved in renal tubular, endothelial, and interstitial inflammation and injury.


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improved neurobehavioral manifestations and attenuated cerebral edema, in association with reduced expression of aquaporins (AQPs), matrix metalloproteinases (MMPs) such as AQP-1, AQP-4, MMP-2, and MMP-9 [60,61]. The neuroprotective effect of propofol also is associated with the attenuation of inflammatory reaction and the inhibition of inflammatory genes such as Nuclear factor-kappa B (NF-κB), Cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α) [62].

2) Liver

Propofol was shown to protect suspensions of isolated rat hepatocytes from an oxidant insult [63]. Moreover, Lee et al. [64] found that propofol, but not pentobarbital, exerts a protective effect on hepatocytes exposed to H

2O

2 oxidant stress in vitro. Ling et al.

[65] showed propofol infusion was shown to attenuate hepatic IR injury in vivo in rabbits. However the duration of propofol infusion before the ischemic insult did not influence its hepatoprotective effects or the extent of hepatic injury. Intravenous infusion of

Figure 2. Proposed renal protection mechanisms of volatile anesthetics. Volatile anesthetics interact with the plasma membrane lipid bilayer in renal tubular cells and induce phosphatidylserine externalization and TGF-b1 generation. Volatile anesthetics also increase the formation of caveolae/caveolin lipid rafts in the buoyant fractions of the renal tubular plasma membranes and facilitate caveolae sequestration of several cytoprotective signaling intermediates (e.g., SK-1, TGF-b1 receptors, and S1P). TGF-b1 generated by volatile anesthetics binds to the TGF-b1 receptor, leading to translocation of SMAD-3 to the nucleus to increase the expression of renal tubular CD73. Increased CD73 expression subsequently increases renal tubular adenosine generation. Activation of renal tubular and perhaps endothelial ARs increases SK-1 protein expression via induction of HIF-1a transcription factor. In addition, activation of A1 ARs increases renal tubular IL -11 synthesis via ERK-MAPK activation. Finally, IL-11 also induces SK-1 generation via the HIF-1a pathway. CD, cluster of differentiation; ERK-MAPK: extracellular signal-regulated kinase mitogen-activated protein kinase; Gi/o, inhibitory regulative G protein; IL-11R, IL-11 receptor; S1PR, S1P receptor.

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propofol, at a dose of 10 or 20 mg/kg/h starting 30 min before ischemia and continued until reperfusion, was effective in reducing hepatic IR injury and decreasing associated cellular apoptosis, with no observed dose-dependent effects [66]. Propofol protects liver from IR injury by sustaining the mitochondrial function, which is possibly involved with the modulation of mitochondrial permeability transition pore and Glycogen synthase kinase 3 beta (GSK-3β) [67]. Propofol could regulate the expression of IR injury-related proteins and inhibit the attack of free radical to liver, having a remarkable advantage in preventing liver IR injury and controlling the development of IR injury [68].

3) Kidney

Propofol reduces renal oxidative injury and facilitates repair following renal IR injury by a reduction in pro-inflammatory cytokine generation and a concomitant increase in bone mor-phogenetic protein 2 (BMP2) expression [69]. Propofol and iso-flurane showed the same level of protection against renal IR injury [70]. Propofol has a direct effect in tubular cells, attenuating IR-induced cell necrosis and apoptosis in an established cellular model of renal IR, and that this direct protection is related to the activation of adenosine triphosphate-sensitive potassium (KATP) channels [71]. Luo et al. [72] have conducted a series of in vitro and in vivo studies and demonstrated that connexin32 (Cx32) plays a critical role in autologous orthotopic liver transplantation-induced AKI and that inhibition of Cx32 function may represent major mechanism whereby propofol reduces oxidative stress and subsequently attenuates post-orthotopic liver transplantation AKI. Propofol also conveyed significant renoprotective effect against renal IR injury in the presence of hyperglycemia by preservation of antioxidant ability, attenuation neutrophil infiltration, pro-inflammatory cytokine and inducible nitric oxide synthase (iNOS) production, and downregulation of the phosphorylation of inhibitor of NF-κB (I-κB) and NF-κB [73].

2. Opioid

1) Brain

The inhibitory effects of remifentanil preconditioning on the brain IR injury are achieved through blocking the activation of TNF-α/tumor necrosis factor receptor 1 (TNFR1), JNK signal transduction pathways, which implies that remifentanil preconditioning may be a potential and effective way for prevention of IR injury through the suppression extrinsic apoptotic signal pathway induced by TNF-α/TNFR1, Jun N-terminal Kinase (JNK) signal pathways [74]. Remifentanil postconditioning exhibits neuroprotective effects against global cerebral IR injury in rats, and its mechanisms might involve inhibition of neuronal apoptosis through the phosphatidylinositol-3-kinase (PI3K) pathway [75]. Remifentanil infusion which was started 10 minutes before MCAO and continued until reperfusion reduced infarct volume, possibly

through the activation of δ-opioid receptors and attenuation of ERK 1/2 activity and TNF-α production, in the rat brain [76].

2) Liver

Pretreatment with remifentanil can attenuate liver injury both in vivo and in vitro [77]. Inducible NOS but not opioid receptors partly mediate this effect by exhausting reactive oxygen species and attenuating the inflammatory response [77]. Remifentanil preconditioning significantly reduced IR-induced hepatocyte apoptosis. In addition, remifentanil protected against IR-induced mitochondrial swelling and loss of membrane potential and inhibited IR-induced increases in TNF-α, intercellular adhesion molecule 1, and NF-κB p65 levels in liver tissues. Remifentanil preconditioning also inhibited the loss in superoxide dismutase and rise in MDA levels in liver tissues going through IR injury [78]. Morphine pretreatment, by either intravenous or intrathecal routes, offered protection against hepatic IR injury both in normal and cirrhotic liver. This involves opioid receptors, PI3K, and Akt [79].

3) Kidney

Subcutaneous administration of morphine 30 min before left renal artery occlusion improved renal function after IR by decreasing serum creatinine and BUN levels and on other hand preserved renal histology [80]. Morphine dependence protects the kidney against IR injury via opioid receptor-dependent pathways [81]. Ischemic preconditioning showed no protective effect in renal IR injury with isoflurane anesthesia, however, ischemic preconditioning demonstrated beneficial effect on the kidney under isoflurane and remifentanil anesthesia [82].

3. Dexmedetomidine

1) Brain

In a rat model of asphyxial cardiac arrest-induced global cerebral ischemic injury, dexmedetomidine preconditioning was effective in protecting against cardiac arrest-induced cerebral ischemia injury by upregulation of hypoxia-inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) expression [83]. Administration of dexmedetomidine immediately after the onset of MCAO reduced cerebral injury, and this was mediated by the activation of the PI3K/Akt and ERK1/2 pathways as well the phosphorylation of downstream GSK-3β [84].

2) Liver

Dexmedetomidine protect liver against IR injury in the experi-mental rat model by reducing the MDA level while increasing the superoxide dismutase (SOD), catalase, glutathione, and gluta-thione peroxidase activities [85]. Dexmedetomidine when given before induction of ischemia, reduced total oxidative activity and oxidative stress index, while increased total antioxidant capacity


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and paraoxonase in hepatic IR injury [86].

3) Kidney

In this experimental study, 10 mg/kg and 100 mg/kg doses of dexmedetomidine have a protective effect in the

kidney IR damages by reducing MDA level while increasing SOD activity [87]. Dexmedetomidine reduced hypoxia/reoxygenation induced apoptosis in rat kidney proximal tubular cells through the inhibition of gap junction activity by reducing Cx32 protein levels [88]. Dexmedetomidine protects kidney against IR injury through its inhibitory effects on injury-induced activation of kinase and signal transducer and activator of transcription (JAK/STAT) signaling pathway [89]. Gonullu et al. [90] re-ported that dexmedetomidine used both before ischemia and after reperfusion reduced the effects of renal IR injury at the 24th hour histomorphologically. Although no histomorphologic significant difference was determined between the two methods, administration of dexmedetomidine in the reperfusion period was considered more effective due to the decrease in BUN levels and increase in urinary output.

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서론

본 강좌에서는 마취제가 장기에 미치는 영향 중에서 주로 뇌와 관련된 효과에 대하여 논의하고자 한다. 수술후 뇌혀혈은 일반적으로 발생빈도가 높지 않으나 심장수술의 경우는 2-6%로 더 많이 발생하는 것으로 보고되어 왔다. 또한 carotid endarterectomy나 뇌동맥류 또는 뇌 동정맥 기형 수술을 시행하는 경우에도 뇌허혈의 위험도가 크다. 더불어 수술후 신경학적 인식기능의 저하로 나타나는 신경퇴행(neurodegeneration)도 뇌보호에 포함되어 다루어지고 있다.

마취약은 수십 년 동안 뇌보호 효과가 있는 것으로 알려져 왔다. 그 기전으로는 비가역적인 신경학적 사망을 유발하는 생화학적 연속과정의 속도를 낮추거나 차단함으로써 뇌보호 효과를 나타낸다고 한다. 그러나 불행하게도 실험의 결과로 밝혀진 마취제의 뇌보호 효과를 임상에서 밝혀내는 데는 거의 모두 실패로 끝났다. 이런 맥락에서 기초 및 임상 관점 모두에서 마취약제의 장기보호 효과에 대한 전반적인 검토와 재정비가 필요하다. 여기에서는 뇌허혈에 따른 뇌손상의 병태생리, 마취제의 뇌보호 효과에 대한 임상연구, 실험연구에서 임상으로의 전이(translation) 실패, 앞으로의 연구방향에 대하여 알아보고자 한다.

뇌허혈의 병태 생리

뇌산소 소모량은 3.5-4.0 ml/100 gm/min으로 뇌의 대사가 매우 활발하며 신경원에 소모되는 총 에너지의 50%는 전기적 활성을 유지하는데 50%는 기본적인 세포의 항상성을 유지하기 위해서 사용된다. 뇌혈류는 정상시에는 50 ml/100 gm/kg로 유지되는데 뇌혈류가 10 ml/100 g/min 이하로 감소하여 뇌허헐에 이르면 5분내로 ATP가 감소하게 되고 항상성이 깨지게 되면서 허혈성 신경손상이 일어나기 시작한다.

허혈성 신경 손상은 크게 excitotoxicity에 의한 조기 손상과 apoptosis에 의한 지연 손상으로 특징지어진다. 허혈 후에 ATP와 같은 에너지원이 고갈되면 신경원은 탈분극이 되어서 신경원 말단(neuron terminal)에서 glutamate가 대량 유리가 되고 이에 따라 post-synaptic receptor에 있는 AMPA 수용체나 NMDA 수용체를 자극되어 세포 내로 Na+과 Ca2+ 이온의 유입이 일어나게 된다. 세포내로 과량 유입된 Ca2+은 protease, lipase, endonuclease등을 분비하면서 세포내 lipid, DNA의 손상, free radical의 생산, membrane lipid의 파괴 및 proteolysis를 일으켜서 짧은 시간에 neuron의 사망을 유발한다(excitotoxicity). 뇌의 허혈 손상

은 역동적이어서 허혈 후 14일까지도 신경의 손상이 계속해서 진행되어 일어나는데 이 과정은 주로 apoptosis에 의한다고 한다. 뇌허혈 후에 증가된 reactive oxygen radical, glutamate, Ca2+

이 apoptosis를 유발하며 다음의 세가지 과정을 거치게 된다; intrinsic (mitochondria-mediated), extrinsic (receptor-mediated), caspase-independent pathway. Caspase-dependent pathway는 procaspase 8과 procaspase 9에서 만들어진 caspase 3가 활성화되면서 apoptosis를 유발하고, caspase-independent pathway는 caspase와 무관하게 apoptosis-inducing factor에 의해서 apoptosis가 유발된다. 뇌허혈은 오랜 시간 동안 뇌손상이 진행되어서 길게는 6-8개월까지도 신경원 소실이 이루어진다.

임상에서 마취제의 뇌보호 효과에 대한 연구

다음은 임상에서 많이 사용되고 있는 마취제에 대한 대표적인 임상연구들을 표로 요약하여 정리하였다. 마취제가 뇌보호 효과를 나타낸 연구는 저자의 이름에 ‘**’로 표시하였고, 마취제들 간에 유사한 뇌보호 효과를 보인 경우에는 저자의 이름에 ‘*’로 표시하였다. 마취제의 뇌보호 효과가 실험에 의해 그 기전에 대한 많은 연구 결과가 보고되었으나, 임상에서 밝혀진 마취제의 뇌보호 효과에 대한 결과는 비교적 미미하다.

Bioltta 등은 2013년까지 보고된 약물의 뇌보호 작용에 관한 임상연구(마취약제; thiopental; 2 case, lidocaine; 4 case, propofol; 2 case, ketamine; 2 case, xenon; 1 case)를 모아서 (1) 술후 새로운 신경학적 결함, (2) 술후 인지장애, (3) 사망을 검토하여 발표를 하였다. 수술후 신경학적 결함의 경우는 thiopental은 연구에 따라 상반된 결과를 보였으나 다른 나머지 약제에서는 유의한 차이가 없었으며, 수술 후 인지장애는 lidocaine과 ketamine의 일부 연구에서는 뇌신경 보호효과가 있는 것으로 보고 되었으며, 사망은 조사된 모든 약제에서 유의한 차이가 없었다. 임상연구에 있어서 다양한 결과는 실험에 사용된 마취약제의 용량, 주입시간, 환자군의 다양성 등에 기인하는 것으로 여겨진다. 또한 연구방법에 있어서 불일치, 임상연구에 포함된 환자의 뇌손상의 이질성, 적은 환자의 수 등으로 인해서 타당한 결과를 얻지 못한 것으로 생각된다.

실험연구에서 임상연구로의 전이 실패

실험적으로 검증된 마취제의 뇌보호 효과를 임상적으로 전이(translation)하는데 있어서 많은 실패를 경험하게 되면서 이 문제


마취제의 장기보호효과 - 임상

신혜원

고려대학교 의과대학 마취통증의학과

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점에 대한 많은 보고들이 있어왔다(Table). 뇌보호에 대한 임상연구에 있어서 이전 실패(translational failure)는 많은 연구들이 대표성이 없는 임상전 모델을 사용하여 타당성이 없는 가정을 제시하였고 생리학적인 변수(뇌의 온도, 혈장 당 농도, PaCO

2, pH, 혈

압 등)를 적절하게 조절하는데 실패하였으며 더불어 실험상에서 고려되어야 할 많은 것들이 제시되었다.

결론

수 십년 동안 허혈에 의한 신경학적 손상의 병리학적인 기전은 특징지어져 왔다. 이와 더불어 마취약의 뇌보호 효과 및 뇌보호 기전에 대한 많은 실험과 연구가 있어왔다. 그러나 마취

제에 의한 뇌보호 효과에 대하여 실험에서의 유효한 결과를 얻었으나 이를 임상에서 적용해서 유사한 효과를 기대하는 이전(translation)을 수없이 시도하였으나 거의 모든 연구에서 실패하였다. 이는 실험, 임상 연구의 디자인 결함, 다양성에 기인한다. 실험의 유효한 결과를 임상에 이전시키려는 관점에서 실험에서 연구의 질을 철저하게 관리하기 위해서 Stroke Therapy Academic and Industry Roundtable (STAIR)에서 만든 실험연구에 대한 guideline에 기초하여 시행되고 있다. 뇌보호는 뇌허혈에 있어서 충격의 다양성(focal vs global ischemia, hemorrhage, trauma), 허혈 손상의 복합성, 허혈 손상부위의 다양성으로 인해 단일 약물학적 치료보다는 다양한 약물의 사용 및 다양한 생리학적 변수의 조절 등으로 다방면에서 이루어져야 한다.

(1) 흡입마취제

Study Surgery Dose of drug The purpose of studyPostoperative

follow-upClinical outcomes

Schoen2011

Cardiac surgery Sevoflurane vs. propofol

Regional cerebral oxygen saturation (ScO

2 < 50%:

desaturation), Cognitive test(mental test, stroop test, trail-making test, word lists, mood-assessment tests were performed before, 2, 4, and 6 days after cardiac surgery

At postop. 2, 4, 6 days.

Better short-term postoperative cognitive performance in sevoflurane compared with propofol.

Kadoi2007

CABG sevoflurane vs. propofol

Cognitive test (Mini mental state examination, Rey auditory verbal learning test, trail-making test, digit span forward, and the grooved pegboard), Neurological defect.

At postop. 1 day, 6 month.

No significant differences on the postoperative cognitive dysfunction (p=0.94; 22% with sevo vs. 23% without sevo).

Michenfeld-er

1987

Carotid endarterectomy

isoflurane, enflurane, and halothane

critical CBF measurement (EEG ischemic change within 3 min of carotid occlusion)

Critical CBF (isoflurane: 10 ml/100g/min, enflurane 15 ml/100g/min, halothane 20 ml/100g/min)

EEG ischemic changes was less in isoflurane (18%) than enflurane (26%) or halothane (25%) anesthesia.

* Isoflurane was neuroprotective than the other volatile anesthetics.

Hoffman 1998

Aneurysm clipping, MCA occlusion for >15 min

Up to burst suppression etomidate vs. desflurane

brain tissue (PO2, PCO

2, pH) Up to 40 min

after drug injection

Greater reduction in brain tissue PO

2 and increase of

brain tissue PCO2, pH than

that of desflurane.*Not neuroprotective.

Nehls* 1987

(Primates)

MCAO 6 h (focal ischemia model)

Up to burst suppression, isoflurane vs. thiopental.

cerebral protective effect (neurological status, infarct volume)

No difference in neuroprotecitve effect btw isoflurlane and thiopental.

Milde* 1988

(Primates)

MCAO 5 h (focal ischemia model)

Up to burst suppression, isoflurane, thiopental.

Neurological function for 8 days. Infarct volume

No difference in neurological outcome and neurological deficit.


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(2) Thiopental



Zaidan 1991

CABG To create burst suppression

Neurological outcomes At 2, 5 postop. days

postop.stroke (P>0.05; 1.3% control vs. 3.3% thio),

* Did not reduce the neurological sequelae after CABG.

Eisenberg** 1988

Head injury with IICP

10 mg/kg over 30 min loading, 5 mg/kg/hr maintenance

ICP control Up to postop. 30 min

*Effective for ICP control in severe head injury.

The pts with hypotension before thiopental provided no benefit of thiopental infusion.

Nussmeier**1986

CABG 50-100 mg until EEG became isolelectric

Neuropsychiatric complications

At 5, 10 postop. days

Neuropsychiatric complications; at postop. 1day (p>0.05; 8.6% control vs. 5.6% thio), at postop. 10 day (p<0.025; 7.5% vs. 0%).

*Cerebral protection by thiopental.

Ward 1985

Severe head injury

5-10 mg/kg until EEG became

isoelectric

Clinical follow-up (ICP, temperature, complication: pneumonia, ARDS, sepsis, SIADH, CNS infection, GI bleeding, hypotension)

Up to discharge

No difference in outcomes (IICP incidence, duration of IICP, response to IICP to treatment. More reduction in BP and temperature (p<0.05).

*No recommendation of pentobarbital use in pts with severe head injury.

Schwartz 1984

Intracranial hematoma removal operation

pentobarbital vs. mannitol

ICP control, mortality not obtained Mortality: IICP without hematoma removal (p<0.05; 77% mann vs. 41% pento), IICP with hematoma removal (P>0.05; 40% vs. 43%).

*No benefits in mortality or ICP control for pts with intracranial hematoma.

(3) Propofol



Schlunzen2012

Volunteers propofol Regional cerebral blood flow (rCBF), regional glucose metabolism rate (rGMR) using PET

　 Total CBF and GMR decreased during anesthesia with 47% and 54%, respectively. Marked metabolic and vascular responsiveness in some cortical areas and thalamus.

Kanbak*2004

CABG propofol vs. isoflurane

neurological outcome(S-100 beta), neuropsychologic test (MMSET, VADST)

Up to postop. 1, 3, 6 days

MMSET: no change, VADST: decreased, S-100 beta: increased, no differences btw groups. * Propofol appeared to offer no advantage over isoflurane for cerebral protection.

Kelly* 1999

Severe head injury

propofol vs. morphine

ICP control, CPP, 6 month GOS(Glasgow outcome scale)

Up to 6 month

At 3 day, lower ICP in propofol (p<0.05), At 6 month, similar outcome and mortality.

Favorable GOS in high-dose propofol (p<0.05; 70% high propofol vs. 38.5% low propofol).

* Propofol-based ICP control is safe alternative to opioid-based regimen.

Roach* 1999

Open heart valve surgery

Sufentanil (S) vs. sufentanil+propofol (SP), Up to create burst suppression.

Neurologic test (NIH stroke scale, Western neurologic scale), Neuroospychologic test(Wechsler adult intelligence scale, Wechsler memory scale, etc)

At postop. 1, 6, 60 days.

No differences in neurologic deficit at postop. 1 day (p=0.06; 40% S vs. 25% SP), 6 day (p=0.07; 18% S vs. 8% SP), 60 day (p=0.8; 6% S vs. 6% SP) days. No differences in neuropsychologic deficit at postop. 6 day (p=0.73; 91% S vs. 92% SP), 60 day (p=0.58; 52% S vs. 47% SP).

* No neurologic or neuropsychologic benefit from using propofol-EEG burst suppression.

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(4) Lidocaine



Mathew 2009

Cardiac surgery

1 mg/kg bolus; 2 mg/min for 2 h; 1 mg/min for 10 h, (anesthesia with midazolam, fentanyl, isoflurane.)

Cognitive test (Randt memory test, Wechsler intelligence scale-revised test, trail making test, etc)

At postop. 6 week

No differences in cognitive deficit (p=0.97; 45.5% lidocaine vs. 45.7% placebo).

* Lidocaine did not reduce POCD.

Mitchell2009

Cardiac surgery

1 mg/kg in bolus; 4 mg/min for 1 h; 2 mg/min for 2 h; 1 mg/min for 46 h.

(anesthesia with midazolam, isoflurane.)

Cognitive test (Auditory-verbal learning test, Wechsler intelligence scale-revised test, Thurstone word fluency, etc), Stay in ICUand hospital.

At postop. 10 weeks, 25 weeks.

No differences in cognitive deficits at 10 weeks (p=0.57; 45.8% lidocaine vs. 40.7% placebo), 25 weeks (p=0.71; 35.2% lidocaine vs. 37.7% placebo). No differences in stay in ICU and hospital.

* Lidocaine was not neuroprotective.

Wang** 2002

CABG 1.5 mg/kg in bolus; 4 mg/min until end of operation,

(anesthesia with midazolam, fentanyl, isoflurane)

9 cognitive test (mental control and digit span, Wechsler intelligence scale-revised test, Halsted-Reitan trail making test, Grooved pegboard test, etc). Postop. Variables(duration of ICU stay and ventilation, IABP, transfusion)

At postop. 9 day

Reduced POCD (p=0.028; 18.6% lidocaine vs. 40.0% placebo), No differences in postoperative variables.

* Lidocaine infusion reduced the POCD in early postoperative period.

Mitchell** 1999

Open heart valve surgery

1 mg/kg in bolus; 4 mg/min for 1 h; 2 mg/min for 48 h. (anesthesia with benzodiazepine, fentanyl, isoflurane.)

11 cognitive test (performance tests, self-rating inventory test, Control test for depression, etc), Postop. Variables (duration of ICU stay and ventilation, Inotropes required, IABP, renal dysfunction, new atrial fibrillation, hospital stay)

at postop. 10 day, 10 weeks, 6 months

less sequential decrease of cognitive test at 10 days, 10 weeks, 6 months (p<0.05 for inspection time, Trails B, AVLT distraction test, SDMT (symbol digit modality test; oral, written), memory assessment, and clinics self-report inventory). No differences in postoperative variables except ICU stay (p<0.05; 24.7 h lidocaine vs. 29.4 h placebo).

* Lidocaine was neuroprotective.

(5) Ketamine



Hudetz **2009

Cardiac surgery

saline or ketamine 0.5 m/kg bolus, anesthesia with isoflurane with fentanyl

Cognitive test(nonverbal memory, Verbal memory, Executive function), CRP

up to 1 week Less cognitive dysfunction (p<0.001; 7 pts ketamine vs. 21 pts saline), low level of CRP (p<0.01).

* Ketamine attenuates POCD by the anti-inflammatory effect.

Nagels 2004

Open heart surgery

propofol with remifentanil or ketamine (2.5 mg/kg bolus, 125 mg/kg/min)

Cognitive test (trail making, symbol digit modalities test, Rey auditory verbal learning test, visual reaction time, etc), Postoperative variables (stay in ICU, duration of intubation, hospital stay).

at postop. 1, 10 weeks

No difference in cognitive deficit (p=0.54; 20% ketamine vs. 25% control), No differences in postop. variable.

* Ketamine offers no neuroprotective effect.


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참고 문헌

1. Kawaguchi M, Furuya H, Patel PM.Neuroprotective effects of anesthetic agents. J Anesth 2005;19:150-6.

2. Head BP, Patel P. Anesthetics and brain protection. Curr Opin Anaesthesiol 2007;20:395-9.

3. Zuo Z. Are volatile anesthetics neuroprotective or neurotoxic? Med Gas Res 2012;2:10.

4. Werner C. Anesthetic drugs and sustained neuroprotection in acute cerebral ischemia: can we alter clinical outcomes? Can J

Anaesth 2009;56:883-8. 5. Bilotta F, Gelb AW, Stazi E, Titi L, Paoloni FP, Rosa G.

Pharmacological perioperative brain neuroprotection: a quali-tative review of randomized clinical trials. Br J Anaesth 2013; 110:Suppl 1:i113-20.

6. Sutherland BA, Minnerup J, Balami JS, Arba F, Buchan AM, Kleinschnitz C. Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke 2012; 7:407-18.

(6) Xenon



Hocker* 2009

elderly pts with major non-cardiac surgery (abdominal or urologic surgery >2 h)

propfol with sufentanil vs. Xenon with sufentanil

Postop. Neuropsychological assessment(MMSS, depression inventroy score, memory, attention, motor skills etc)

At postop. 1, 6, 30 days

No differences in postop. cognitive dysfunction at postop. 1day (44% Xenon vs. 50% pro), 6 day (1% Xenon vs. 18% pro), 30 day (6% Xenon vs. 12% pro) days. No difference in hospitalization btw groups.

* No differences btw groups.

Cobum*2007

Elective surgery (>2 h)

Xenon vs. desflurane

Neurocongnitive test (Attentional Performance with alertness, civided Attention, working memory), Recovery profiles (time to open eyes, to react on demand, to extubation, to orientation), Modified Aldrete score.

At postop. 16-12 h, 66-72 h

No differences in postop. cognitive dysfunction. More rapid recovery profiles, higher recovery score in Xenon.

(7) Etomidate



Hoffman 1998

Aneurysm clipping, MCA occlusion for >15 min

up to burst suppression etomidate vs. desflurane

brain tissue (PO2, PCO

2, pH) Up to 40 min

after drug injection

Greater reduction in brain tissue PO

2 and increase of brain tissue

PCO2, pH than that of desflurane.

*Not neuroprotective.

Table. Reasons for translational failure of anesthetic neuroprotection from laboratory studies to clinical studies.

Laboratory studies Clinical studies

1. Highly controlled, homogeneous population 2. Younger animals 3. Limited comorbidities 4. Induced onset of stroke Uniform etiology 5. Ischemic territory usually from MCA 6. Control over therapeutic time window (usually early treatment) 7. Controlled occlusion duration 8. Adequate sample size 9. Wide scope for dose optimization 10. Multiple routes of administration 11. Rapid availability of drugs to target area 12 Infarct volume as outcome

1. Variable, heterogeneous population 2. Older patients 3. Numerous comorbidities 4. Spontaneous onset of stroke 5. Variable etiologies 6. Less control over therapeutic time window (usually delayed treatment) 7. Variable occlusion duration 8. Inadequate sample size 9. Reduced scope for dose optimization10. Limited routes of administration11. Slow availability of drugs to target area12. Function as outcome