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  1. Remifentanil and the brain Acta Anaesthesiologica Scandinavica 2008; 52: 319-26 마취통증의학과 4년차 전주연

  2. Introduction • Remifentanil-based anesthesia • Most desirable features of a neuroanesthetic regime • Rapid anesthetic emergence • Delayed and recurring respiratory depression has not been reported • Low incidence of N/V (esp. the addition of propofol) • Up-to-date information on the effects of remifentanil on the CNS

  3. Cerebral metabolism • Opioids • Little or no effect on cerebral metabolism. • Remifentanil • Favorable effects on cerebral metabolism • Decreasing the cerebral metabolic rate of oxygen (CMRO2) • Cf) Large dose remifentanil • Increase CMRO2 in the temporal lobe from 6.29 to 7.68mg/100g/min

  4. Electroencephalogram (EEG) and electrocorticography (EcoG) • Very stable EEG during noxious stimulations. • Effect on BIS –controversial • Use of narcotic agents – confound measurements of depth of sedation or anesthesia • Sevoflurane-remifentanil – strongly synergistic for clinical sedation • BIS and A-line autoregressive index(AAI) are insensitive • Remifentanil to propofol affects BIS • only when a painful stimulus • Attenuated or abolished increases in EEG, BIS, auditory-evoked potentials and MAP during noxious stimulations

  5. Electroencephalogram (EEG) and electrocorticography (EcoG) • Effects of remi on the quality of intraop. EcoG • Sedative doses of this opioid • Minimal effects on EcoG spike activity • Continuous infusion of 0.1 μg/kg /min • Non-significant decrease in spike frequency with slowed background EcoG activity • Remifentanil enhances epileptiform activity • Facilitating localization of the epileptogenic zone and minimizing resection of nonepileptogenic eloquent brain tissue. • Opioid administration • Generalized tonic-clonic seizure like activity • So-called ‘opioid-seizure syndrome’

  6. Motor-evoked potentials (MEPs) • MEPs • Useful in preventing permanent neurological deficits during cranial and spinal procedures • Quality of MEPs • Depend on the stimulation pattern and technique of anesthesia. • Opioids, propofol and thiopental • Supress myogenic, but not neurogenic • Remifentanil • the least suppressive effects • Remifentanil with propofol • Enhances the quality of intraop. MEPs and allows recoding of myogenic potential

  7. Regional cerebral blood flow (rCBF) • rCBF changes • Dose-dependent manner in areas involved in pain processing • Low doses(0.05 μg/kg /min) • Increase in rCBF-lat.prefrontal cortices inf. Parietal cortices, and supplementary motor area • rCBF decreases in the basal mediofrontal cortex, cerebellum, sup. temporal lobe and midbrain gray matter. • Moderate doses(0.15 μg/kg /min) • rCBF increase in mediofrontal and ant. cingulate cortices, occipital lobe transition and caudal periventricular gray matter • Decrease in the inf. Parietal lobes

  8. Arterial hypotension and hypertension • Cerebral vascular system – admirable autoregulation • In neuroanesthesia – controlled hypotension, damaged brain may fail to compensation the reduction of MAP, with a subsequent risk of ischemia. • Remifentanil • increased incidence of hypotensive episodes(in comparison with other opioids) • ABP decreases by about 30% - more evident in aged, hypovolemic and obese patients • > 65yr – drug dosage must be reduced by 50% • Obese pt. – dose must be calcuated on the basis of ideal wt. and not on the actual wt. • Undergoing neurosurgery and receiving osmotic diuretics, simulating a hypovolemic-like clinical effect in the pt. – reduction of the dasage.

  9. Arterial hypotension and hypertension • Increased clinical experience • Patients are hemodynamically more stable • Decreased incidence of opioid-related adverse events. • TIVA c propofol-remifentanil ( compared with balanced anesthesia c sevo.-fentanyl) • Increased incidence of arterial hypertension requiring antihypertensive medication to maintain the MAP within 20% of the baseline.

  10. Intracranial pressure (ICP) • Infusion of remifentanil • Decreased ICP with minimal cerebral perfusion pressure(CPP) changes • Excision of supratentorial space-occupying lesions under conditions of a backgroud of isoflurane – no significant effect on ICP at a dose of either 0.5 or 1.0 μg/kg . • Neurosurgical ICU • Remifentanil use has been recommended for ICP control.

  11. Cerebral perfusion pressure (CPP) • Large doses of remifentanil • Reduce cerebral blood flow despite constant perfusion pressure. • Remifentanil (bolus of 0.5 μg/kg , followed by a continuous infusion 0.25 μg/kg /min for 20min) • on-top analgesia in head trauma pts. without adverse effects on cerebrovascular hemodynamics and CPP.

  12. Cerebral autoregulation • Remifentanil with propofol • Induces a dose-dependent low-flow state with preserved cerebral autoregulation • Autoregulatory index increased significantly • Low-flow state and the increase of cerebrovascular reactivity(CVR) – widens the autoregulatory plateau.

  13. Cerebrospinal fluid (CSF) • Rate of CSF formation(Vf) and resistance to reabsorption of CSF(Ra) • Very important as they influence CSF vol., ICP and intracranial elastance. • Independent of remifentanil dosage in rabbits. • Remifentanil dose of 0.1μg/kg /min under normocapnic condition • Systolic CSF peak velocity is not significantly altered in both animals and in healty human volunteers.

  14. Painful stimulation, analgesia and hyperalgesia • Difficult postop. pain management and promotion of hyperalgesia • Large-dose intraop. remifentanil can be associated with the development of hyperalgesia merely increasing sensitivity to noxious stimuli. • Different mechanisms of opioid-induced post-infusion anti-analgesia and secondary hyperalgesia. • Adequate pain therapy after TIVA with short-acting opioid drugs is mandatory.

  15. Neuroprotection • Cerebral ischemia • Excitotoxicity and neuronal death • Neuroprotective role of anesthetic agents. • Barbiturates and volatile agents, ketamine • Significant protective effects against ischemic injury • Endogenous opioid • Both neurodestructive and neuroprotective roles in CNS injury. • μ and k1 receptor – neuroprotective actions • k2 receptors –secondary injury responses • Remifentanil – potent synthetic μ-opioid agonist

  16. Neurotoxicity • Rat • Large dose μ-opioids are reported to produce limbic system hypermetabolism and histopathology. • Remifentanil infusion for 3h of 20-160μg/kg/min, dose-related EEG activation was evident. • In 19 out of 40 remifentanil treated rats, varying degrees of acute neuronal degeneration confined to the limbic system and its associated areas. • Physicians should be aware of these hazardous effects could occur during anesthesia or sedation.

  17. Hypothermia • Hypothermia • In selected patients to improve neuroprotection • Decreases clearance • Increased total remifentanil concentrations. • Elimination clearance decreases by 6.37% for each degree decrease from 37°C • Remifentanil infusion rate is reduced by 30% for each 5° decrease in temperature

  18. Conclusions • Aim of anesthesia • Providing brain relaxation, minimal interference with electrophysiological monitoring, rapid recovery, pt’s cooperation during surgery and neuroprotection • Combination of remifentanil with either an intravenous hypnotic or an inhalation agent – most satisfactory • Cerebral ischemia and neuroprotection • important issues for neurosurgeons, and the potential use of this opioid in neuroanesthesia and neurointensive management has been criticized. • But, Successive data have now emerged supporting and requiring other and more extensive research of remifentanil in the field of neuroprotection

  19. Conclusions • Neurocognitive effect of remifentanil • Disruption of cortical cholinergic NT • post-operative delirium and impaired memory function, increase in patient morbidity, delayed functional recovery and prolonged hospital stays. • Morphine and fentanyl, but not remifentanil, disrupt cholinergic NT. • Remifentanil • perfect titration of the analgesic effects to varying noxious stimulation intensities • rapid recovery • early assessment of postop. neurologic function. • Incidence of collateral effects of remi. –minimal. • Decreased hemodynamic variability, improved recovery profile and decreased incidence of opioid-related adverse events c increasing experience.

  20. Conclusions • Remifentanil - Ideal narcotic agent during neurosurgical procedure.