The Daily Dose • Friday, May 14, 2021

From Bench to Bedside: How Anesthesiologists are Changing the Future of Medicine

Mark Arcario, MD, PhD

Continuing the excellent showing from day one of the AUA 2021 Annual Meeting, many attendees were excited to hear more about innovative advances in anesthesiology that the physician-scientists presenting on day two had to offer. The session “Scientific Advisory Board Oral Session II,” on May 14, provided a wide range of thought-provoking research displayed throughout the meeting. With topics ranging from molecular science to clinical outcomes research, there was something for every interest.

Kicking off the session was Timothy Walsh, MD, a pediatric anesthesiology fellow at Boston Children’s Hospital and recipient of the Fellow Research Award for his abstract on “Over-Transfusion in Pediatric Patients Intra-operatively. A Retrospective Observational Study at a Tertiary Pediatric Hospital.” He presented an excellent study on risk factors for perioperative overtransfusion. With growing interest in and data supporting restrictive transfusion goals, he aimed to investigate how a single-center had responded to the paradigm shift. In a retrospective, observational trial, he described that approximately three-quarters of patients who received an intraoperative transfusion had been overtransfused (with overtransfusion being defined as a hemoglobin concentration of 9.5 g/dL at 24 hours postoperatively), with this being more common in younger populations. In fact, almost 93% of neonates who had received intraoperative transfusion were seen to be overtransfused and approximately 55% showed extreme overtransfusion (hemoglobin concentration >12 g/dL). The evidence was quite convincing that this is a common occurrence.

He then set out to identify risk factors for overtransfusion across all populations. In their analysis, surgical duration, weight, emergent status, and preoperative anemia were all independently associated with increased risk of overtransfusion. Analyzing outcomes showed increased hospital length of stay, increased time of mechanical ventilation, increased risk of pulmonary infection, and increased risk of acute heart failure. This thought-provoking work helps us reflect on how we are doing as a community with restrictive transfusion goals and the possible outcomes for our patients of overtransfusion.

Following this was an invigorating presentation on novel therapeutics for chronic pain by Yan Xu, PhD of the University of Pittsburgh School of Medicine, recipient of the Best of Meeting Research Award for his research on “Preclinical Evaluation of A Novel Glycinergic Analgesic for Treatment of Chronic Pain in Rodents.” Previous studies from Dr. Yu, using both computational and electrophysiological methods, had described a novel transmembrane binding pocket in glycine receptor as well as potential therapeutics directed at this channel. His presentation today focused on testing the identified therapeutic agents in a murine neuropathic pain model. After design of an ingenious thermal plate experiment, Dr. Yu was able to show that three of the “top hit” compounds were able to alleviate the chronic neuropathic pain.

He also tested the top candidate, named MJPY1, in thermal and mechanical pain models. The drug candidate faired equally well in these tests. As a way to show that this drug candidate, MJPY1, was not acting through opioid receptors, naloxone was coadministered with the drug and the experiments repeated. These results showed no changes, suggesting that MJPY1 is working through another mechanism. Following these results, behavioral studies to examine side effects and abuse potential were conducted. These showed that MJPY1 had no significant effect on behavior of the mice and the abuse potential was nonexistent, especially compared to morphine, the positive control in this scenario. Overall, this report represents a novel approach to chronic pain therapeutics and an exciting new direction in treatment of these patients.

Continuing the session, Dianna E. Willis, PhD, from Burke Neurological Institute at Weill Cornell Medicine and recipient of the Top Oral Abstract, presented on “A Hindered HCN1-selective inhibitor is Antihyperalgesic in a Rat Spares Nerve Injury Neuropathic Pain Model,” discussing her recent work centered on developing novel therapeutic agents targeting HCN1 channels in neuropathic pain. As a target, HCN1 has been shown to be upregulated in chronic neuropathic pain animal models and would make a good target for multimodal analgesia. While designing a target for the channel, the goal was to develop a molecule that would block peripheral HCN1 channels without affecting the same channels located in the central nervous system. Using a clever maneuver of tethering the active molecule to a fatty group, she was able to anchor the active molecule to the plasma membrane, allowing the peripheral channels to be blocked without the molecule crossing into the central nervous system. Interestingly, she presented data with different tether lengths and anchor groups that showed differences in efficacy with the main conclusion being that the anchor selection and tether length are critical in ensuring the active molecule is able to properly access the site of action. Lastly, she presented some data on the safety profile, which showed no changes in motor activity and no significant abuse potential. Overall, this represents a thoughtful and creative way to address the ongoing chronic pain epidemic.

Rounding out the session was Mengwen Zhu, BS, of the University of Wisconsin – Madison, recipient of the Top Oral Abstract for her research, “Hippocampal Engrams Recapitulate Contextual Memory Formation, Its Suppression by Etomidate, and Its Persistence in Mice Lacking a5-GABAA Receptors in Interneurons,” on understanding how anesthetics induce amnesia in a murine model. First, Dr. Zhu described how hippocampal “place” cells display specific firing patterns when the animals return to a familiar environment and the combination of firing activity from these cells leads to memory encodement. It is hypothesized that drugs, as well as genetic alterations, lead to a remapping of these cells and altered firing patterns. Using a spatial learning environment model, Dr. Zhu exposed the mice to either saline or etomidate. Using a calcium fluorescence assay, he was able to show that the mice in the etomidate group showed decreased formation of hippocampal place cells compared to control. Moreover, when re-exposed to the same environment at a later time, the place cells that did form in the experimental group misfired. These results demonstrate that etomidate is disrupting the fundamental role of place cells in memory formation. Lastly, in GABA receptor knock-out mice, the effect of etomidate on place cells was nullified, suggesting that GABA receptor is imperative for the amnesia associated with anesthetics. This exciting work provides some additional insight into the neuronal landscape induced by the anesthetics we provide to patients daily and a possible way forward to reducing the side effects associated with these medications.

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