Stephan Schwarz

Background: Perioperative stroke is a cerebrovascular event occurring during or after surgery that can result in devastating and often unrecoverable outcomes. The primary objective of this thesis project was to identify independent predictors of 30-day mortality, adverse discharge, and length of hospital stay (LOS) in both noncardiac and cardiac surgery patients. The secondary objective was to examine temporal trends in poor outcome throughout the study period.Methods: This retrospective cohort study included noncardiac and cardiac surgical patients who experienced a perioperative stroke in the American College of Surgeons National Surgical Quality Improvement Program database between 2005 and 2020. The data included patient demographics, comorbidities, stroke as well as surgical and anesthetic variables. Least absolute shrinkage and selection operator (LASSO) was used to examine variables associated with 30-day mortality (primary outcome), adverse discharge (death or a non-home facility, only available after 2010), and LOS in multivariable logistic models. Results: We identified 14,386 noncardiac and 906 cardiac surgical patients who experienced a perioperative stroke meeting our inclusion criteria. Mortality rates were 24.6% and 14.8% for noncardiac and cardiac stroke patients, respectively. Median [interquartile range] LOS was 9 [4–21] days for noncardiac patients and 13 [9–21] days for cardiac patients. Independent predictors associated with increased risk of mortality after stroke in both cohorts included increasing age, postoperative comorbidities, perioperative transfusion, and fewer days from operation to stroke. Operation year was associated with decreased LOS in both noncardiac and cardiac stroke populations, but not mortality or adverse discharge. Conclusion: We identified several independent predictors of poor outcome following perioperative stroke in noncardiac and cardiac surgical patients, including potentially modifiable risk factors such as perioperative transfusion and concurrent postoperative complications. These findings are novel and warrant further investigation to identify mechanisms and possible interventions to improve outcomes after perioperative stroke.

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Poorly managed acute pain, particularly postoperative pain, reduces quality of life, delays recovery, and increases financial burden. Current therapeutic regimens focus on nonsteroidal anti-inflammatory drugs and systemic opioids. Unfortunately, these analgesics are associated with notable and potentially life-threatening adverse events. Thus, there is a great need for analgesic alternatives.Local anesthetics are among the most effective non-opioid analgesic options for acute pain. However, conventional agents are limited by their short duration as well as local and systemic toxicity. Previous research at the UBC Hugill Anesthesia Research Centre, showed that the quaternary lidocaine derivative, QX-314, produces long-lasting local anesthesia in animals. However, QX-314 was found to be more toxic compared to its parent compound. The quaternary lidocaine derivatives, QX-572 and QX-222, have not been studied systematically to compare their duration and toxicity. In this thesis, I tested the primary hypothesis that perineural injection of QX-572 and QX-222, similar to QX-314, will produce long-lasting local anesthesia. I assessed nerve blockade in mice and found that QX-572 concentration-dependently produced long-lasting sensory and motor blockade. In contrast, QX-222 produced long-lasting sensory blockade but did not produce extended motor blockade. I determined the order of potency among quaternary lidocaine derivatives to be: QX-572 > QX-314 > QX-222. Additionally, I tested the secondary hypothesis that QX-572 and QX-222 have more favorable local and systemic toxicity profiles relative to QX-314. I found that QX-314 and QX-222 induced myofibre degeneration whereas QX-572 induced ischemic necrosis of the mouse tail. Adverse reactions were observed that manifested as death. To investigate the possibility of systemic toxicity, I developed a novel liquid chromatography tandem mass spectrometry method to measure plasma concentrations of quaternary derivatives. I found that QX-314 and QX-222 were absorbed more readily than QX-572 or lidocaine. The results from this thesis suggest that differences in therapeutic and toxic local anesthetic effects are mediated by structural differences. Overall, the present findings do not unreservedly support the transition of QX-314, QX-572, or QX-222 into human studies for the treatment of acute postoperative pain, however, they illustrate a potentially promising pharmacological avenue for further research and provide insight into quaternary anesthetic pharmacology.

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