Vanderbilt University School of Medicine

Jonathon Wanderer and Jesse Ehrenfeld
Vanderbilt Anesthesiology & Perioperative Informatics Research (VAPIR) Division

The Vanderbilt Anesthesiology & Perioperative Informatics Research (VAPIR) Division is a multi-disciplinary group of physicians, biomedical engineers, software developers, database analysts, and research staff who focus on understanding how the utilization of information technology can improve perioperative, anesthetic, and surgical outcomes. The group, which is a part of the Vanderbilt Department of Anesthesiology, has been recognized as one of the premier anesthesia informatics programs in the world and is led by Jonathan Wanderer, MD, MPhil, an assistant professor in Anesthesiology and Biomedical Informatics, and Medical Director of the Vanderbilt Preoperative Evaluation Center and Jesse M. Ehrenfeld, MD, MPH, an associate professor with appointments in Anesthesiology, Biomedical Informatics, and Surgery.

The Vanderbilt Department of Anesthesiology has been a leader in the area of anesthesia information management systems (AIMS) development since the late 1990s. GasChart, the AIMS component of the Vanderbilt Perioperative Information Management System (VPIMS) is part of an integrated system that covers the entire perioperative process including instrument & supply management, scheduling, and status displays. Because of the extensive effort that has been put toward in-house intraoperative software development, the Vanderbilt Anesthesiology & Perioperative Informatics Research (VAPIR) Division is able to benefit from the availability of thousands of historical intraoperative records, each containing detailed physiologic information.

The group manages a variety of clinical research projects that span many areas including development of real-time point-of-care notification systems, creating predictive models for patient risk-stratification, enhancing patient-provider communication, developing new models for delivery of medical care, and bringing personalized medicine into the operating room. Currently, the group has more than 40 active research projects, with collaborations that extend across Vanderbilt and into a growing number of academic centers across the world. These centers include The University of Michigan, Harvard University, Thomas Jefferson University, and the Norwegian University of Science and Technology.

The Vanderbilt Anesthesiology & Perioperative Informatics Research (VAPIR) Division is dynamic and currently expanding. Qualified candidates are being sought for a variety of full-time analyst positions, and there are also openings for summer interns and research assistants.

Stephen Bruehl Group
Understanding Chronic Pain

The work in Dr. Bruehl’s lab is focused on the general topic of pain, with a current focus on personalized pain medicine. The lab’s recent work has confirmed that responses to opioid analgesics can be predicted by several factors, including endogenous opioid function (assessed using opioid blockade methodology), baseline acute pain sensitivity, and levels of depression, anxiety, anger, and catastrophic cognitions. This work has revealed that endogenous opioid mechanisms contribute to the ability of pain sensitivity and certain psychosocial factors to predict opioid analgesic responses. Currently ongoing work is attempting to manipulate endogenous opioid activity via an aerobic exercise training program to evaluate effects on both chronic low back pain intensity and responses to opioid analgesics. Other work in this area is using an informatics approach to identify novel genetic predictors of opioid-related side effects in a large postoperative clinical sample (using the BioVU and Synthetic Derivative resources at Vanderbilt).

The Bruehl Lab is also exploring mechanisms underlying Complex Regional Pain Syndrome (CRPS). Current work is evaluating genetic, epigenetic, proteomic, metabolomic, and cytokine-related predictors of CRPS in the context of post-traumatic amputation. Genetic correlates of CRPS are also being investigated using an informatics approach in a very large clinical sample (using BioVU and Synthetic Derivative). In addition, the Bruehl lab is also exploring perioperative oxidative stress mechanisms that may predict CRPS in the context of total knee arthroplasty.

The Bruehl lab has published more than 45 peer-reviewed articles since 2010. The overall goal of this research is to better understand the psychophysiological factors contributing to chronic pain and its related health risks, and ultimately, to improve treatment of chronic pain.

Josh Billings Group
Oxidative Stress and Perioperative Organ Injury

My research program aims are to reduce the incidence and severity of postoperative organ injury by testing mechanism-targeted therapies in clinical trials. Primarily, we hope to reduce acute kidney injury (AKI) following cardiac surgery. We are testing the hypothesis that high-dose short-term perioperative atorvastatin reduces the incidence of AKI in an 800 patient, randomized, double-blinded, placebo-controlled clinical trial. Other important clinical outcomes in this trial include postoperative myocardial injury, atrial fibrillation, delirium and cognitive dysfunction. Ischemia reperfusion-induced oxidative stress may contribute to each of these poor outcomes, and within this statin trial we are testing the hypothesis that intraoperative oxidative stress predicts postoperative organ dysfunction and injury. Of particular interest in the lab currently is the role of mitochondria in the generation of reactive oxygen species (ROS). To this end, we are isolating peripheral blood mononuclear cells and measuring mitochondria-derived and cytosol-derived ROS to test the hypothesis that surgery induces mitochondrial dysfunction and mitochondrial dysfunction increases oxidative stress and AKI. Following completion of these mitochondria proof of concept correlative studies, we will initiate a randomized placebo-controlled pilot study to test the hypothesis that a mitochondrial-targeted antioxidant reduces mitochondrial dysfunction and markers of oxidative stress in patients undergoing cardiac surgery.

Pratik Pandharipande Group
Cognitive Impairment and Critical Illness

This is a large and productive research group that focuses on long term outcomes in survivors of critical illness and works to develop interventions to improve cognitive recovery. Specifically, we study the impact of medical conditions and surgical events on the development of conditions such as depression, anxiety, PTSD, and acquired brain injuries. To accomplish these goals, we perform a wide array of clinical testing on patients including assessments of cognitive, mental health, and quality of life related functioning. These assessments are done in the intensive care unit, in patient homes, by telephone, and at the office. We also engage in research on cognitive rehabilitation. The group is funded by several grants from the National Institutes of Health and frequently publishes in high impact journals such as the New England Journal of Medicine, Journal of the American Medical Association and Lancet.

Edward Sherwood Group
Innate and Adaptive Immunity during Sepsis

The lab of Edward Sherwood, MD, PhD, is studying several aspects of sepsis and the systemic inflammatory response syndrome. A major interest is to define mechanisms of sepsis-induced systemic inflammation and organ injury with emphasis on the roles of natural killer (NK) and T lymphocytes. Current studies are being performed to evaluate the mechanisms of NK and T cell activation and chemotaxis during sepsis with emphasis on the chemokine receptor CXCR3 and its ligands, CXCL9 and CXCL10. The Sherwood group showed that CXCR3 activation is crucial for NK cell trafficking during sepsis and that CXCR3 blockade will decrease inflammation and organ injury in experimental models of sepsis. The underlying goal is to further understand the contribution of CXCR3 activation in the pathogenesis of sepsis and develop clinically relevant interventions to block CXCR3 and improve outcome. Additional work is focusing on mechanisms of innate lymphocyte activation with an emphasis on the roles of interleukins 15 and 18 and the importance of inflammasome activation in this process.

The second major interest is in understanding sepsis-induced immune suppression and developing interventions to improve antimicrobial immunity in vulnerable populations. The group is studying the impact of training innate immunity on the host response to infection with an emphasis on understanding the cellular and molecular mechanisms by which toll-like receptor (TLR) ligands reprogram the innate immune response to infection. Studies are focusing on the effect of TLR ligand priming on leukocyte activation and trafficking as well as their effect on the metabolic functions of leukocytes. Drug development projects are underway to take promising TLR ligands into clinical practice. The group also has a strong interest in adaptive immune function during sepsis and has recently launched a prospective randomized clinical trial (RCT) to examine the efficacy of treatment with interleukin-7 in patients with severe sepsis and T lymphocyte dysfunction.

Eric Delpire Group
Understanding Mechanisms of Ion Transport

GABAergic neurotransmission depends upon the transmembrane Cl concentration gradient that exists at the synapse. The intracellular Cl concentration in CNS and PNS neurons is regulated, in part, by cation-chloride cotransport mechanisms such as Na-K-2Cl and K-Cl cotransporters. For example, the inward Na-K-2Cl cotransporter is expressed in immature CNS neurons, resulting in a high intracellular Cl- concentration and GABA depolarizing or excitatory responses. In contrast, mature CNS neurons have low Na-K-2Cl cotransporter and high K-Cl cotransporter leading to low intracellular Cl- and GABA hyperpolarizing or inhibitory responses. This family of ion transporters is also involved in salt reabsorption in kidney and control of blood pressure.

The Delpire Laboratory is creating and studying genetically-modified mouse models of the cotransporters and of proteins that regulate them. The work, involves molecular biology, physiology, electrophysiology and behavior. These studies have significance in pain perception, hyper-excitability and epilepsy, nerve conduction, peripheral neuropathy, paraplegia, as well as salt wasting and blood pressure disorders.

Matt Riess Group
Understanding Organ injury after Cardiac Arrest

Dr. Riess joined the Vanderbilt Department of Anesthesiology in July 2014 from the Medical College of Wisconsin. His team currently focuses on three translational projects:

Genetic mechanisms of protection against myocardial ischemia/reperfusion (IR) injury: While some consomic rat models are very resistant against IR injury and can be additionally protected by ischemic or anesthetic preconditioning, others are highly susceptible to IR injury and cannot be preconditioned. Crossing over genetic information from one into the other strain yields important information on cardioprotective mechanisms. Altered mitochondrial function appears to play a key role in these genetically determined differences.

Protective role of fatty acids against myocardial IR injury: In collaboration with investigators from Duke University and the University of Alaska Fairbanks, Dr. Riess’ team studies the protective role of fatty acids against myocardial IR injury in Arctic Ground Squirrels. Administration of a clinically used fat emulsion, Intralipid, confers nearly complete abrogation of myocardial dysfunction following IR in isolated hearts, challenging the paradigm of glucose being the fuel of choice during oxidative stress.

Novel strategies to improve neurological outcome and survival after cardiac arrest: Together with colleagues at the University of Minnesota, the University of Michigan and the Medical College of Wisconsin, Dr. Riess’ team investigates novel strategies to improve neurological outcome and survival after cardiac arrest and CPR. With a currently only 5 to 7% survival rate after out-of-hospital cardiac arrest, the ground-breaking findings of this inter-institutional and -disciplinary collaboration are highly promising for thousands of patients each year.

Kevin Currie Group
Understanding Adrenal Chromaffin Cell Function

The Currie lab investigates voltage-gated calcium channels and the mechanisms that control neurotransmitter / hormone secretion. A combination of approaches is used, including: transgenic mice, patch-clamp electrophysiology, carbon fiber amperometry, and fluorescent calcium imaging. The main area of focus is catecholamine secretion from adrenal chromaffin cells, the neuroendocrine arm of the sympathetic nervous system. These cells play a key role in the “fight-or-flight” stress response and are also a widely used model that enables detailed analyses of stimulus-secretion coupling.

Efforts in the Currie lab are directed toward understanding the ion channels, G protein coupled receptors (GPCRs), and downstream pathways that orchestrate precise autocrine / paracrine control of calcium entry and catecholamine release. Recently, the lab also identified a novel role for the serotonin transporter (SERT) in chromaffin cell function. SERT is an important target for antidepressants, and ongoing work suggests that chromaffin cells are a previously unrecognized peripheral hub for serotonergic control of the sympathetic nervous system. Another project investigates crosstalk between the immune system and chromaffin cells, and in collaboration with the Sherwood lab will determine how sepsis impacts sympathoadrenal function. A third project focuses on electrical excitability and calcium signaling in dorsal root ganglion neurons and, in collaboration with the Carter lab, how satellite glial cells might modulate itch / pain signaling. The common goal in all these projects is to better understand the pathophysiology of nervous and endocrine system disorders, and to identify novel therapeutic targets for their treatment.

Brad & Carrie Grueter Group
Understanding the Biology of Addiction

This husband and wife team both are doctoral graduates of the Department of Molecular Physiology and Biophysics at Vanderbilt University. The goal of the Grueter lab research program is to advance the current understanding of the nucleus accumbens (NAc), a brain region responsible for integrating information from diverse inputs and modifying complex motivated behaviors, including its involvement in adaptive responses to rewarding and aversive stimuli. Specifically, we strive to elucidate the molecular constituents in the NAc that are necessary and sufficient to drive complex motivated behaviors. As part of the mesolimbic dopamine system, the NAc integrates a complex mix of excitatory, inhibitory and modulatory inputs to optimize adaptive motivated behaviors. Dynamic alterations in synaptic transmission within this circuitry are strongly implicated in the development and expression of many neuropsychiatric disorders. Thus, two broad questions we address are: 1) how does in vivo experience such as cocaine exposure, pain, or high fat diet alter the neurocircuitry of the NAc? 2.) What are the synaptic mechanisms underlying the behavioral adaptations to in vivo experience? The approaches we incorporate allow us to thoroughly characterize the synaptic circuitry of the NAc in basal and pathophysiological conditions using a combination of cutting edge techniques in electrophysiology, molecular biology, metabolic phenotyping, optogenetics and behavior. These studies will provide information on how the NAc circuits integrate environmental stimuli and allow for specific behavioral responses. This enhanced understanding of NAc function may provide a basis for a more individualized approach to the treatment of many psychiatric disorders.

Jerod Denton Group
Molecular pharmacology and physiology of potassium channels in health and disease

Our group is interested in the integrative physiology, molecular pharmacology, and therapeutic potential of inward rectifier potassium (Kir) channels. Kir channels play fundamental roles in kidney, cardiac, neuronal, and endocrine function and may represent novel drug targets for hypertension, pain, diabetes, and some neurological disorders. A critical challenge to studying these problems has been the lack of pharmacological tools for manipulating the activity of specific sub-types of Kir channels in complex tissues/organs and in vivo. To get around this barrier, our group has been using high-throughput screening, medicinal chemistry, and patch clamp electrophysiology to develop some of the first-in-class small-molecule Kir channel probes.

We developed the first two publically disclosed inhibitors of the emerging diuretic target Kir1.1, and are currently evaluating how Kir1.1 inhibition alters kidney function and blood pressure in hypertensive animal models. Our development of the first Kir7.1 inhibitors helped uncover new roles of the channel in regulating uterine tone during pregnancy and melanocortin signaling in the brain. Other projects are exploring the druggability of Kir4.1 in hypertension, the role of Kir4.2 in regulation of blood glucose homeostasis using CRISPR knockout mice, and the mechanism of cardiac ischemic injury protection by a newly discovered KATP channel opener. Our overarching goal is to translate basic science discoveries into novel therapeutics for improving human health.

Jesse Ehrenfeld
Education Research

Dr. Ehrenfeld is the Director of Education Research for the Office of Health Sciences Education (OHSE). OHSE governs the range of educational activities of the Vanderbilt University School of Medicine, including undergraduate medical education/MD program, graduate medical education, and physician continuing professional development, as well as several advanced degree programs in applied medical fields. Areas of focus include educational scholarship, research development, and quality improvement for medical education.