Secondary injuries in Brain trauma : Effects of Hypothermia

1. Secondary injuries in Brain trauma : Effects of Hypothermia J Neurosurg Anesthesiol vol 16 Jan 2004 마취통증의학과 R3 임태완

2. TBI(traumatic brain injury) : pathophysiology 이해에 있어 primary injury, secondary process의 중요성이 강조됨 secondary brain damage– cell injury that is not obviously present immediately after an insult but develops with a delay after the primary impact potentially preventalble, treatable → severe TBI에서 자주 발생, 큰 영향 원인 : 직접적 – self-propagating biochemical & inflam.cascade 간접적 –뇌혈류 감소, vascular distortion, hypoxemia, cerebrovascular narrowing, 뇌대사율 증가 secondary brain damage의 예 early postinjury episodes of hypotension – severe TBI의 1/3 에서 발생. Morbidity, mortality(150%이상) 증가 hypoxemia – outcome의 가장 강력한 predictor

4. Experimental investigations dealing with secondary injury Secondary insult after experimental TBI - exacerbate disturbances in key physiologic variables e.g. hypoperfusion, energy failure, Cb edema, EEG suppression Example of deleterious effect of secondary injury 1. effect of isolated postraumatic hypotension : investigated in pig & cat dealt with the effect of various fluid resuscitation on cerebral & systemic physiology early aggressive fluid Tx → cerebrovascular parameter의 : 임상에서 흔히 시도 최적화 실패, 출혈 증가 → secondary neuronal inj.로서 cerebral contusion 발생

5. 2. effect of posttraumatic hypoxemia : investigated in injury models of rodents group1(TBI + hypoxemia + hypotension ) VS group2(only TBI) → depletion of high-energy phosphates & intracelluar acidosis : group 1에서 pronounced 3. impact-acceleration model in rats Marmarou et al. : severe head inj.에서 흔히 발생하는 brain inj. Pattern pure diffuse axonal inj. induction secondary inj. 없을 경우, neuronal death, Cb edema, intracranial HTN 대부분 발생하지 않음 group1(without secondary insult) VS group2(hypoxemia, hypotension) → 후자에서 extensive neuronal cell loss 발생 biochemical damage & recovery blunting severe systemic hemodynamic impairment 초래

6. 4. acute inflammatory response : TBI발생후 secondary inj. 발생에 주요 인자 investigated in mutant or genetically engineered mice : P-selectin & ICAM-1 deficient → brain edema 감소 (VS wild-type mice group) cerebroprotective pharmacologic therapy TBI후, outcome 개선을 위해 시도중 e.g. free radical scavenger, glutamate antagonist, CaChB : but not show consistent results for cerebroprotection

7. Brain protection by hypothermia in experimental TBI hypothermia – 1950년대 심장수술에 도입 심장수술 이외 영역에선 저체온의 부작용들로 인해 사용하지 않았음 : shivering,arrhythmia,blood.viscosity 증가,rewarming후 출혈 experimental TBI study에서 hypothermia 가치 재인식됨 세포수준에서 hypothermic brain protection 기전 제시되고 있음 spectrum of effect of hypothermia : BBB permeability, edema formation, brain metaboism, brain hemodynamics, excitatory A.A release, inflammation, histopathology, protein induction & degradation, neurologic outcome to a primary insult of TBI → hypothermia는 secondary damage를 초래하는 primary injury에 의한 여러가지 기전들에 영향을 줌 cf) secondary damage e.g. ischemia, Cb swelling, inflamm., neuronal death cascade, excitotoxicity & E failure

8. Posttraumatic hypothermia:controversial results and lack of sufficient data hypothermia –excitatory A.A.의 ischemic induced release 감소시킴 e.g. in focal & global cerebral ischemia state in TBI model – not consistent posttraumatic hypothermia after lateral fluid percussion model in rats : suppression of hydroxyl radical elevation & extracellular Glu release posttraumatic hypothermia after impact-acceleration model in rats : higher cortical level of Glu, Asp, : posttraumatic CBF decrease : similar in normothermia & hypothermia → TBI에서 hypothermic cerebroprotection : interstitial excitatory A.A.의 감소이외의 기전으로 추측 posttraumatic 세포외 A.A. 증가는 CBF 감소와 무관 effect of hypothermia – reduce the lesion vol. without attenuating inj.- induced elevations in interstitial conc. of Glu & Asp 위와 같은 다양한 연구결과 – controversial & confounding

9. Effect of hypothermia on BBB permeability - reduction of permeation of different tracers이 발견 traumatic brain edema에서 BBB opening의 기여 – not known Posttraumatic edema - 아마도 complex cytotoxic events, BBB파괴후 vascular leak와 관련 Beaumont et al – normothermic impact-acceleration model with secondary hypoxemia & hypotension in rats : 뇌부종과 BBB opening은 무관 즉, posttraumatic edema는 by cytotoxic fluid percussion inj. In rats – albumin에 대한 혈관투과도 증가에 에 의해 뇌부종 발생

10. Brain edema형성에의 hypothermia의 효과 - not clearly understood 저체온은 injury전에 적용시, albumin immunoreactivity 크게 감소시킴 저체온을 injury후에 적용시, acute SDH model에서 뇌수분함량감소 저체온을 injury후 60분에 적용시, BBB 투과도 25% 감소 VS normothermic hypotension TBI후 cerebral blood flow와 cerebral metabolism의 uncoupling : CBF 감소, 뇌대사 증가 → ischemia에 기여 Schmoker et al – normothermic hemorrhagic hypotension after TBI → CMRO2 감소 , Cerebral O2 delivery 감소 발견 RICP, cortical water content 증가 (VS TBI without hypotension) systemic O2 delivery 조기 복구에도 불구, 발생하며 cerebral ischemia는 systemic hemodynamic복구와 무관하게 진행됨 cf) 이 연구에 저체온 적용시, 뇌의 O2이용도 증가, ICP 감소, brain water content 감소시킬 것으로 추정

11. TBI and hypothermia : Are inflammation, histopathology, and neurobehavioral data less conflicting? acute inflammation – TBI후 secondary brain damage에 기여할 수. TBI때 inflam.의 classic hallmark - edema formation, swelling, resident immune cell의 활성화, blood-borne immunocompetent cell의 cerebral infiltration →이때hypothermia 적용 : secondary brain damage 감소(may) trauma직후 4hr동안 hypothermia 적용(32도) – IL-1beta, PMN 감소 → 염증 cascade 감소에 효과적 e.g. posttraumatic hypothermia(32도) for 3 hrs in rat - motor & cognitive recovery 에 항염증제 투여보다효과적

12. hypothermia - experimental TBI후, neurologic deficit 감소시킴(may) e.g. hypothermia(30C) after fluid percussion inj. In rat : less beam-walking & beam-balancing deficit cf) 하지만 다른 연구에서 functional improvement에도 불구, cortex의 necrotic tissue의 volume,은 유의미한 차이 없었음 cf) Kline et al – CA3 hippocampal neuronal cell survival 증가 Hypothermia의 histopathologic outcome study - 대부분의 연구에서 hypothermia로부터 benefit 없었음 몇몇 TBI model에선 histopathologic protection effect e.g.injury후 5분내 시작한 hypothermia 30 C → necrotic cortical neuron, contusion vol. 감소 in a rat fluid percussion inj. Model posttraumatic cooled model(32C, 4hr)에서 → injured axon 유의미한 감소 early or delayed posttraumatic hypothermia(32C) → axon damage 감소 in impact-acceleration model

13. Bramlett et al – moderate(30C) posttraumatic hypothermia 적용 chronic histopatholgic outcome 연구 결과 : lat.ventricle enlargement in normothermic TBI lat. Ventricle enlarge attenuation in hypothermia → chronic neuroprotection 으로 간주 cf) 다른 연구에선 효과없는 것으로 나오기도. TBI study in piglet combined with hemorrhagic hypotension : traumatic axon inj.로부터 protection 안됨 결론 : ischemic & traumatic brain inj.에 대해 hypothermia의 neuroprotective effect는 있는 것으로 보이나 실험조건에 따라 일관되지 않은 결과를 보임

14. Conditions for hypothermia application in TBI Posttraumatic hypothermia사용의 main goal : maximize the benefits for the damaged brain & minimize the risk of side effects Trauma후 60분이내 적용 protective effect as to edema formation & neurologic outcome in controlled cortical impact model reducing diffuse axonal damage in impact-acceleration model Trauma후 90분에 적용 no effect on edema formation & behavioral outcome : hypothermia 적용시 brief therapeutic window때문 (metabolic store가 1시간내 고갈되고 glutamate release가 TBI & ischemia 발생 60-90분내에 일어나기 때문) cf) delayed hypothemia – refractory RICP조절엔 효과있으나 neurological outcome에는 효과 없음

15. delayed hypothermia - secondary brain damage가 있을 경우에는 inflammation, apoptosis감소에 효과가 있음(may) e.g. transient global & focal ischemia후 6시간이내에hypothermia 를 적용할 경우, ischemic cell damage, brain edema, infarct vol. 감소 Hypothermia에 의해 영향받는 detrimental effect – reperfusion, prot.kinase activity, lipid peroxidation, hydroxyl radical production, cellular repair prot.재합성 reperfusion – rewarming때 hypothermia의 neuroprotection방해 체온 급상승시, intracranial HTN rebound 발생 slow rewarming - cerebral microcirculation에 free radical scavenging effect 제공 normal arteriolar vascular response 유지 normal CO2 reactivity 유지 rapid rewarming – altered cerebrovascular response even under nonpathologic condition

16. Hypothermia in clinical trials and perspectives Hypothermia after TBI : cerebroprotective effect. Not always consistent < Benefit > hypothermia after TBI asso c uncontrollable RICP : ICP 감소, CPP개선, survival개선 VS normothermia group introop. hypothermia With SAH undergoing craniotomy for An repair : hypothermia group이 better neurologic outcome VS normothermia out-of-hospital cardiac arrest : mild hypothermia적용시, 6개월 사망률 감소, 신경학적 호전율 증가

17. < controversy > hypothermia적용시 infection증가, cardiac arrhythmia, coagulopathy, pancreatic enz.elevation, electro imbalance 이런 부작용들은 temperature dependent hypothermia duration dependent

19. Conclusion 1.hypothermia를 가능한 빨리 적용개시할 것 2.rewarming은 천천히 할 것(hypothermia의 neuroprotection effect 보존) 3.small temperature reduction이 좋은 것 같음 (for prevention of side effects)