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

2. TBI(traumatic brain injury) : pathophysiology primary injury, secondary process 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 TBI, : – self-propagating biochemical & inflam.cascade –, vascular distortion, hypoxemia, cerebrovascular narrowing, secondary brain damage early postinjury episodes of hypotension – severe TBI 1/3. Morbidity, mortality(150% ) hypoxemia – outcome 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 parameter :, secondary neuronal inj. cerebral contusion

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 1 pronounced 3. impact-acceleration model in rats Marmarou et al. : severe head inj. brain inj. Pattern pure diffuse axonal inj. induction secondary inj., neuronal death, Cb edema, intracranial HTN group1(without secondary insult) VS group2(hypoxemia, hypotension) extensive neuronal cell loss biochemical damage & recovery blunting severe systemic hemodynamic impairment

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

7. Brain protection by hypothermia in experimental TBI hypothermia – 1950 : shivering,arrhythmia,blood.viscosity,rewarming experimental TBI study hypothermia hypothermic brain protection 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 hypothermia secondary damage primary injury 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. ischemic induced release 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 TBI hypothermic cerebroprotection : interstitial excitatory A.A. posttraumatic A.A. CBF effect of hypothermia – reduce the lesion vol. without attenuating inj.- induced elevations in interstitial conc. of Glu & Asp – controversial & confounding

9. Effect of hypothermia on BBB permeability - reduction of permeation of different tracers traumatic brain edema BBB opening – not known Posttraumatic edema - complex cytotoxic events, BBB vascular leak Beaumont et al – normothermic impact-acceleration model with secondary hypoxemia & hypotension in rats : BBB opening, posttraumatic edema by cytotoxic fluid percussion inj. In rats – albumin

10. Brain edema hypothermia - not clearly understood injury, albumin immunoreactivity injury, acute SDH model injury 60, BBB 25% VS normothermic hypotension TBI cerebral blood flow cerebral metabolism uncoupling : CBF, ischemia Schmoker et al – normothermic hemorrhagic hypotension after TBI CMRO2, Cerebral O2 delivery RICP, cortical water content (VS TBI without hypotension) systemic O2 delivery, cerebral ischemia systemic hemodynamic cf), O2, ICP, brain water content

11. TBI and hypothermia : Are inflammation, histopathology, and neurobehavioral data less conflicting? acute inflammation – TBI secondary brain damage. TBI inflam. classic hallmark - edema formation, swelling, resident immune cell, blood-borne immunocompetent cell cerebral infiltration hypothermia : secondary brain damage (may) trauma 4hr hypothermia (32 ) – IL-1beta, PMN cascade e.g. posttraumatic hypothermia(32 ) for 3 hrs in rat - motor & cognitive recovery

12. hypothermia - experimental TBI, neurologic deficit (may) e.g. hypothermia(30C) after fluid percussion inj. In rat : less beam-walking & beam-balancing deficit cf) functional improvement, cortex necrotic tissue volume, cf) Kline et al – CA3 hippocampal neuronal cell survival Hypothermia histopathologic outcome study - hypothermia benefit TBI model histopathologic protection effect e.g.injury 5 hypothermia 30 C necrotic cortical neuron, contusion vol. in a rat fluid percussion inj. Model posttraumatic cooled model(32C, 4hr) injured axon early or delayed posttraumatic hypothermia(32C) axon damage in impact-acceleration model

13. Bramlett et al – moderate(30C) posttraumatic hypothermia chronic histopatholgic outcome : lat.ventricle enlargement in normothermic TBI lat. Ventricle enlarge attenuation in hypothermia chronic neuroprotection cf). TBI study in piglet combined with hemorrhagic hypotension : traumatic axon inj. protection : ischemic & traumatic brain inj. hypothermia neuroprotective effect

14. Conditions for hypothermia application in TBI Posttraumatic hypothermia main goal : maximize the benefits for the damaged brain & minimize the risk of side effects Trauma 60 protective effect as to edema formation & neurologic outcome in controlled cortical impact model reducing diffuse axonal damage in impact-acceleration model Trauma 90 no effect on edema formation & behavioral outcome : hypothermia brief therapeutic window (metabolic store 1 glutamate release TBI & ischemia 60-90 ) cf) delayed hypothemia – refractory RICP neurological outcome

15. delayed hypothermia - secondary brain damage inflammation, apoptosis (may) e.g. transient global & focal ischemia 6 hypothermia, ischemic cell damage, brain edema, infarct vol. Hypothermia detrimental effect – reperfusion, prot.kinase activity, lipid peroxidation, hydroxyl radical production, cellular repair prot. reperfusion – rewarming hypothermia neuroprotection, intracranial HTN rebound slow rewarming - cerebral microcirculation free radical scavenging effect normal arteriolar vascular response normal CO2 reactivity rapid rewarming – altered cerebrovascular response even under nonpathologic condition

16. Hypothermia in clinical trials and perspectives Hypothermia after TBI : cerebroprotective effect. Not always consistent hypothermia after TBI asso c uncontrollable RICP : ICP, CPP, survival VS normothermia group introop. hypothermia With SAH undergoing craniotomy for An repair : hypothermia group better neurologic outcome VS normothermia out-of-hospital cardiac arrest : mild hypothermia, 6,

17. hypothermia infection, cardiac arrhythmia, coagulopathy, pancreatic enz.elevation, electro imbalance temperature dependent hypothermia duration dependent

19. Conclusion 1. hypothermia 2.rewarming (hypothermia neuroprotection effect ) 3.small temperature reduction (for prevention of side effects)