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

Jason T Maynes, PhD/MDDepartments of Anaesthesia and Molecular Structure and Function

“Three things should be considered: problems, theorems and applications.”

Gotfrield Leibniz

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

Patient MonitoringHR (CO,

tissue perfusion)

BP (CO, tissue perfusion)

PAP (oxygenation)

CVP (?Fluid status)

EtCO2 (metabolic waste)

CO/CI (tissue oxygenation)

SaO2 (blood oxygenation)

SvO2 (metabolic supply/demand)

Neuro: BIS/EEG/rSO2(NIRS)

Low/No Blood Pressure

Mitochondrial Failure

Morbidity and Mortality

Local Tissue Perfusion Local Nutrient Extraction

Surgical StressDrugs/AnaesthesiaPharmacokinetics/dynamics

PharmacogenomicsDevelopmental Stage

Long term outcomes – ?can my pt still win a Nobel

Short term outcomes – Wound infection, hospital Length of stay, recovery times, PICU admission

Common Anaesthetics (Isoflurane, versed, nitrous) cause

widespread neurodegeneration

Anaesthesia in the developing brain causes cognitive, behavioral

and developmental abN-age < 4 yrs, >1 anaesthetic

Mitochondrial Mechanisms to Produce Lasting Cellular Dysfunction

Hepatocyte/Epithelial Culture

1 hr exposure to clinically relevant concentrations of Anaesthetics0.5,1,1.5 MAC isoflurane10,25,50 uM Propofol10,20,50 uM Lidocaine

Image Mitochondria With dyes – high throughput fluorescent microscopy

Anaesthesia Exposure

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

Anaesthetic neurotoxicity, post-op recovery times, Sx inflammation,wound healing, POCD

Mitigate the Damage

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-raycrystallography 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