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Surrogates, In-Vitro, and Clinical Investigations into the Safety and Effectiveness of Anesthesia

Niklewski, Paul J
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383644949

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Anesthesia is an evolving practice that enables painful or invasive procedures. The fundamental question of how anesthetics work remains; Science magazine listed "How do general anesthetics work" as one of the big remaining mysteries in science. This research focuses on four topics pertaining to anesthesia; surrogate endpoints for assessing safety, studying the continuum of anesthesia, neuroprotection from hypoxia/re-oxygenation, and postoperative cognitive dysfunction. The surrogate endpoint study consisted of the review of approximately 200 patient records by 13 anesthesiologists, with risk assigned using a Likert scale. Hypoxia was ranked as one of the most important physiological parameters when assessing sedation risk. A novel index, AUCDesat, was best correlated to the safety assessments, with the constituent components (incidence, depth, and duration) highly correlated, though not as well as AUCDesat. This index may prove to be a valuable measure in assessing risk and quantifying hypoxia when studying outcomes and injury. The study of the continuum of sedation and anesthesia defined by the ASA was a human clinical study of 20 volunteers sedated with increasing concentrations of propofol while maintaining a steady state concentration of fentanyl. The level of sedation was assessed with MOAA/S and BIS scores. The patient was stimulated on the tibial nerve with transcutaneous electrical stimulation. This study reinforced that the anesthetic state is a function of patient stimulus and anesthetic drug concentration, and that anesthesia is a continuum that does not stop at general anesthesia; it has increasingly deeper planes of anesthesia. The research investigated neuroprotection from hypoxia/re-oxygenation of rat hippocampus slices exposed to hypoxia/re-oxygenation episodes. Injury assessment used TTC. Computational modeling and gene expression evaluated potential mechanisms. The study showed hypoxia/re-oxygenation injury is greater when it has multiple exposures, compared to a singular exposure of equal time. Suppression of electrical activity may be sufficient but not necessary to confer neuroprotection. GABA, NMDA, and sodium blockade drugs were neuroprotective by down-regulating CYCS, via MAPK10 and MAPK14. GABA and NMDA drugs also up-regulated BCL2, conferring additional neuroprotection. The last study determined risk factors for cognitive dysfunction after sedation, using a post-hoc analysis of 1,000 sedated patients. LTP was assessed on rat hippocampus slices to understand the risk factors identified in the post-hoc analysis. Risk factors for cognitive dysfunction were drug dosing, recovery time, and desaturation. The effect was short lived, 30 minutes post recovery it was gone. LTP was decreased after hypoxia/re-oxygenation and the addition of an anesthetic did not recover the LTP decrease. This research shows that hypoxia/re-oxygenation on rat hippocampus results in neuronal injury, apoptotic factor up-regulation, and decrease in LTP. Exposure to anesthetics and analgesics affects the degree of injury and gene expression. Using AUCDesat, hypoxic exposure can be quantified, allowing future studies to better understand risks and protective therapies. This research also showed the anesthetic state is a function of stimulus and drug concentration, therefore it is necessary to account for stimulus in future studies. A comprehensive picture of all factors that influence the anesthetic state will improve our understanding, resulting in improved patient outcomes.
Steven Kleene, Ph.D. (Committee Chair)
Steven Lisco, M.D. (Committee Member)
Mark Baccei, Ph.D. (Committee Member)
Kenneth Strauss, Ph.D. (Committee Member)
Hongsheng Wang, Ph.D. (Committee Member)
134 p.
Neurology
anesthesia; hypoxemia; neuroprotection; reoxygenation; cognitive dysfunction; anesthesia continuum

Recommended Citations

Citations

  • Niklewski, P. J. (2013). Surrogates, In-Vitro, and Clinical Investigations into the Safety and Effectiveness of Anesthesia [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383644949

    APA Style (7th edition)

  • Niklewski, Paul. Surrogates, In-Vitro, and Clinical Investigations into the Safety and Effectiveness of Anesthesia. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383644949.

    MLA Style (8th edition)

  • Niklewski, Paul. "Surrogates, In-Vitro, and Clinical Investigations into the Safety and Effectiveness of Anesthesia." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383644949

    Chicago Manual of Style (17th edition)

ucin1383644949
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© 2013, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.