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Your Anaesthetic Should be Apologetic: Anaesthetic Actions That You Don't Want

Your Anaesthetic Should be Apologetic: Anaesthetic Actions That You Don't Want. Jason T Maynes, PhD/MD Departments of Anaesthesia and Molecular Structure and Function “Three things should be considered: problems, theorems and applications.” Gotfrield Leibniz.

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Your Anaesthetic Should be Apologetic: Anaesthetic Actions That You Don't Want

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  1. Your Anaesthetic Should be Apologetic: Anaesthetic Actions That You Don't Want Jason T Maynes, PhD/MD Departments of Anaesthesia and Molecular Structure and Function “Three things should be considered: problems, theorems and applications.” Gotfrield Leibniz

  2. Why do we care about blood pressure? • What happens to the body with no blood pressure? • Loss of oxygen, glucose, removal of waste • Metabolic failure -> loss of energy, cell integrity • Mitochondrial failure • Lack of blood pressure -> mitochondrial failure • Vessel rich group: brain, heart, liver, kidney

  3. Patient Monitoring HR (CO, tissue perfusion) BP (CO, tissue perfusion) PAP (oxygenation) CVP (?Fluid status) SvO2 (metabolic supply/demand) SaO2 (blood oxygenation) CO/CI (tissue oxygenation) EtCO2 (metabolic waste) Neuro: BIS/EEG/rSO2(NIRS)

  4. Low/No Blood Pressure Local Tissue Perfusion Local Nutrient Extraction Drugs/Anaesthesia Pharmacokinetics/dynamics Surgical Stress Mitochondrial Failure Pharmacogenomics Developmental Stage Short term outcomes – Wound infection, hospital Length of stay, recovery times, PICU admission Long term outcomes – ?can my pt still win a Nobel Morbidity and Mortality

  5. Common Anaesthetics (Isoflurane, versed, nitrous) cause widespread neurodegeneration Anaesthesia in the developing brain causes cognitive, behavioral and developmental abN -age < 4 yrs, >1 anaesthetic

  6. Mitochondrial Mechanisms to Produce Lasting Cellular Dysfunction Hepatocyte/Epithelial Culture 1 hr exposure to clinically relevant concentrations of Anaesthetics 0.5,1,1.5 MAC isoflurane 10,25,50 uMPropofol 10,20,50 uMLidocaine Image Mitochondria With dyes – high throughput fluorescent microscopy

  7. Anaesthesia Exposure

  8. Isoflurane Sevoflurane Propofol Lidocaine Etomidate Ketamine Morphine Versed Mitochondrial Morphology Changes Mitochondrial Dysfunction and membrane potential loss Mitochondrial DNA Damage – LASTING CHANGE Mitochondrial DNA Damage in vivo model for neurodegeneration, Dr. G. Stratmann UCSF – anaesthesia, Alzheimer’s, Parkinson’s

  9. Mitigate the Damage Anaesthetic neurotoxicity, post-op recovery times, Sx inflammation, wound healing, POCD Screen small molecule libraries for compounds that may attenuate the damage and identify stress pathways involved (~20 000 molecules) Identify proteins that may be involved, solve their structure by X-ray crystallography and identify activators/inhibitors Express the protein in bacteria/insect cells/mammalian cells, crystallize it, shoot it with a high energy X-ray beam, solve the structure

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