The Daily Dose • Thursday, May 13, 2021

Examining Advances in Anesthesiology and Anticipating the Future

Mark Arcario, MD, PhD

As the AUA 2021 Annual Meeting began on May 13, attendees anticipated hearing from the world’s foremost experts about advances in all fields of anesthesiology and what to expect from research in the upcoming year. The session, “Scientific Advisory Board Oral Session I,” featuring junior faculty, resident researchers and AUA awards winners, was no exception. These presenters covered research ranging from personalized medicine to gut microbiome to microvascular biology and outcomes in stroke patients.

Dr. Senthil Packiasabapathy, from Indiana University School of Medicine, recipient of the AUA Junior Faculty Pediatric Medicine Research Award for his research, “CYP2B6 and POR Polymorphisms Influence Metabolism Influence Metabolism and Clinical,” discussed his investigations into genetic polymorphisms on the clinical effects of methadone in a pediatric perioperative population. In addition to the mu-opioid agonism, methadone has many attractive properties as part of a multimodal analgesia plan, including NMDA receptor antagonism, fast onset (within minutes), and long half-life (generally hours). There is significant variability in its clinical effect, however. Genetic polymorphisms in cytochrome P450 2B6 and P450 oxidoreductase have been shown to affect metabolism of methadone in maintenance therapy, but no definitive role in perioperative outcomes has been shown. Utilizing whole genome sequencing, high-precision liquid chromatography, and mass spectrometry, Dr. Packiasabapathy has been able to identify specific genetic polymorphisms associated with poor and rapid metabolism of methadone. This is not the whole story, however. Combining this data with clinical outcomes, such as pain scores, postoperative opioid use, and incidence of postoperative nausea, Dr. Packiasabapathy has associated specific CYP 2B6 polymorphisms with increased postoperative pain scores and incidence of postoperative nausea. In this age of increasing personalized medicine, this data will prove to be invaluable in developing individualized multimodal analgesia plans.

Following Dr. Packiasabapathy, Dr. Mara Serbanescu, from the Johns Hopkins University School of Medicine, recipient of the Junior Faculty Perioperative Medicine Research Award, discussed the influence of the perioperative events on the gut microbiome in her presentation, “Anesthesia and Gut Microbiome: Exploring the Effects of Isoflurane, Propofol, and Supplemental Oxygen in a Murine Model of General Anesthesia.” In October 2019, Dr. Serbanescu and colleagues had published a report, “General Anesthesia Alters the Diversity and Composition of the Intestinal Microbiota in Mice,” in Anesthesia & Analgesia, documenting a reduction in gut microbiome diversity in a mouse model receiving isoflurane, specifically the Clostridiales family. This research suggested that the volatile agents used daily could cause dysbiosis and a host of downstream, immune-mediated complications. Following this fantastic and forward-thinking work, Dr. Serbanescu was left with a lingering question, however. Could the original reduction in biodiversity seen in her experimental arm (i.e., those mice receiving isoflurane) be more correctly attributed to the hyperoxia the mice were also experiencing? She began investigating this question by exposing her murine model to either 100% oxygen or 100% oxygen plus 1.5% isoflurane in a murine model. Using 16s RNA sequencing and metabolomic analysis, she was able to show that while hyperoxia did contribute somewhat to the gut microbiome diversity reduction, there was still some effect from isoflurane. This reduction in diversity also led to alterations in key metabolic pathways that include molecular signals in inflammatory pathways.

Dr. Matthew Barajas, from Vanderbilt University Medical Center, recipient of the Junior Faculty Research Award for “Comparison of Intravenous Waveform Analysis to Current Markers for Detection of Hemmorhage in a Rat Model,” detailed his research into an improved intravascular volume status marker utilizing intravenous waveform analysis. First, he detailed how current markers of volume status, such as heart rate, mean arterial pressure,  and pulse pressure variation, have limitations and drawbacks in many situations, including in the setting of rapid volume changes seen in the perioperative environment. Underutilization of intravascular waveforms prompted Dr. Barajas to investigate whether intravenous waveforms could be utilized in acute fluid shift settings. Applying fast Fourier transform to intravenous waves, he was able to determine the fundamental frequency in the intravenous waveform, termed F1. In a rat hemorrhage model, this was compared to other currently used markers of intravascular depletion, including cardiac output, central venous pressure, mean arterial pressure, and pulse pressure variation. In this hemorrhage model, F1 was shown to be most sensitive to change in intravascular loss, fairing slightly better than cardiac output, and could detect when intravascular volume had decreased by only 2%, translating to about 100 mL of blood in an adult human. This paves the way for further research into methods to determine change in intravascular status, especially for patients in which small changes can be quite deleterious.

Dr. Yifan Xu, from Oregon Health Sciences University, recipient of the Margaret Wood Resident Research Award for her research, “Modulation of Microvascular Blood Flow and Stroke Outcome via GPR39 in Mice,” rounded out the session, presenting a very thought-provoking presentation on microvascular biology and outcomes in stroke patients. She astutely pointed out that, although we often see patients with similar initial insults, we can see wide-ranging recovery trajectories, ranging from full recovery to very little residual function, even following intervention in the microvasculature. Therefore, it would seem that the microvascular environment would have a large role in determining natural history of stroke. Her hypothesis was that GPR39, a receptor that senses the extracellular eicosanoid balance, may play a large role in setting microvascular tone and would have direct effect on outcomes of stroke patients. Using a combination of histologic and optical imaging techniques in a transient occlusive murine stroke model, she was able to show that GPR39 knock-out mice had larger infarct territories compared to wild-type and that this was likely secondary to changes in microvascular flow. These results help promote the next steps of her research agenda, which include looking at the behavioral consequences of GPR39 knock-out, exploring differential expression of GPR39 before and after stroke, and considering pharmacologic means to exploit the role of GPR39.

To learn more about these research projects, check out the presenters ePosters here.