Yale University and Yale New Haven Medical Center are among the premier research and training institutions in the country. As part of this rich tradition, the areas of research interest in the department of Anesthesiology encompass both “traditional” areas of anesthesia research, and new areas of science and medicine. Expanding and enhancing the research mission in the department is one of the top priorities in Anesthesia at Yale.
Clinical research in Yale Anesthesia includes topics such as anesthesia patient safety and outcomes research. In addition, clinical studies of several novel agents that are active in the cardiovascular and coagulation systems are underway in the operating rooms and intensive care units. Furthermore, studies of peri-operative and post-operative outcomes and the impact of preoperative beta blockade, amongst other interventions, are being quantified and understood. Lastly, the impact of old age on anesthetic dosing requirements, intra-operatiave stability and peri-operative outcomes are being evaluated in the clinical setting.
Among topics being actively pursued by our faculty, we have basic research in the areas of basic neurobiology, as pertain to perception of pain, touch and itch. Research in these topics spans the gamut from whole animal studies (including human), to fundamental molecular approaches looking at the gene expression patterns of single neurons that are involved in sensation. This research program complements a variety of other research programs in Neurobiology at Yale having to do with the central nervous system.
Other faculty members study topics in vascular biology, as it pertains to peri-operative outcomes and sepsis, as well as stroke and the regeneration of blood vessels that are damaged by injury or disease. All of this work dovetails with various investigators in the Vascular Biology program at Yale. In addition, we are working on pioneering new strategies for regeneration of entire segments of functional lung, for the treatment of end-stage lung diseases such as emphysema and cystic fibrosis.
Looking at the practice of Anesthesia holistically, faculty members are studying the environmental impact of disposable items and exhausted gasses that are used in anesthetic practice, with a goal of mitigating environmental effects of these agents. These exciting areas of research, in addition to many others, are part of the Yale training and clinical experience. Working together, we’re breaking new ground and forging new links in science and medicine.
Dr. Burg has for over 25 years conducted a federally funded program of research on the pathways by which stress and emotional factors contribute to risk for hypertension and cardiovascular disease, and contribute to prognosis after acute cardiac events. In the context of clinical trials, he has also investigated how best to address this risk, using new models of care delivery. His current interests extend to post-traumatic stress in Veterans returning from conflicts in Iraq and Afghanistan, and early surveillance for cardiovascular disease risk associated with this disorder.
Individuals of all ages now use social media. Print media such as The New York Times and The Wall Street Journal have embraced social media. However, medical journals have not followed suit. Many anesthesiologists do not stay current with the medical literature once they leave their residency. My research is designed to examine techniques that allow physicians to stay up to date with medical research.
Dr. Schonberger's NIH funded research investigates ways of integrating perioperative encounters into long-term cardiovascular risk-factor reduction. Present studies have examined predictive models for identifying poorly controlled hypertension and the effectiveness of patient interventions. Dr. Schonberger's other research includes informatics work, health services research, and ways to improve extra-corporeal membrane oxygenation.
Kirk Shelley & Aymen Awad Alian
Our lab is dedicated to the investigation of cardiopulmonary and autonomic physiology through the use of non-invasive monitors. This is accomplished through carefully documented clinical observations during surgical procedures (e.g. scoliosis, craniofacial, laparoscopic and shoulder surgery). We also perform normal volunteer studies under a wide variety conditions (e.g. lower body negative pressure, blood withdrawal & replacement, positioning & respiratory maneuvers).
In recent years our focus has been on the pulse oximeter and peripheral venous pressure waveforms. The collected waveforms are then analyzed using digital signal processing. The primary goal is a better understanding of the underlying physiology. The secondary goal is the use of this understanding to develop new methods of patient monitoring. This work so far has generated over 100 research abstracts, 40 peer reviewed papers, and numerous patents.
Most recent efforts have been focused on integrating our research findings into the larger field of functional hemodynamics which combined with early goal directed therapy has been shown to improve patient outcomes. Functional hemodynamics is an exciting approach to the care of patients based upon the principle that the individual patient needs to be optimized to their specific cardiac, pulmonary, and vascular physiology. A key advance has been the recognition that the interactions, between the respiratory, cardiac and autonomic systems, lead to important clues regarding the status of each.
During my 23 years as a researcher and clinician, I have gained expertise and knowledge in the field of cardiovascular medicine as it applies to anesthesiology and critical care. My experience in clinical research also includes leadership responsibilities as Director of Clinical Research at Weill Medical College of Cornell, at Duke University Medical Center, and more recently, at Yale University School of Medicine. A few examples of our research include investigating microthrombotic events and factors that exacerbate perioperative ischemic complication in major vascular surgery, in open-heart surgery, in the setting of ventricular assist device implantation, and in obstetric and pediatric surgery. We are also involved with several multicenter trials in cardiac surgery including: A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Preoperative Antithrombin Supplementation in Patients Undergoing High-Risk Cardiac Surgery with Cardiopulmonary Bypass. Grifols Therapeutics Inc. A Double-Blind, Randomized, Placebo-Controlled Study of Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass. Tenax Therapeutics TRICS-III: Transfusion Requirements in Cardiac Surgery. An International, Multi-Centre, Randomized Controlled Trial to Assess Transfusion Thresholds in Patients Undergoing Cardiac Surgery. Canadian Institutes of Health Research (CIHR) Peer-Reviewed Operating Grant. Lastly, we are both committed and excited about the future of research in the Department of Anesthesiology and are invested in our mission and vision, which is guided by a highly experience group physician-scientist known as the Senior Research Board (Drs. Roberta Hines, Paul Barash, Mathew Burg, Manuel Fontes, Paul Heerdt, Lance Lichtor, Laura Niklason, Albert Perrino, David Silverman, Kirk Shelley).
Basic Science Research
Dr. Niklason is a Professor at Yale University in Biomedical Engineering and Anesthesia, where she has been on faculty since 2006. Dr. Niklason’s research focuses primarily on regenerative strategies for cardiovascular and lung tissues, and the impact of biomechanical and biochemical signals of tissue differentiation and development. For her work in creating engineered arteries, Niklason was named one of only 19 “Innovators for the Next Century” by US News and World Report in 2001. Niklason’s lab was also one of the first to describe the engineering of whole lung tissue that could exchange gas in vivo, and this work was cited in 2010 as one of the top 50 most important inventions of the year by Time Magazine. She was inducted into the National Academy of Inventors in 2014.
Niklason received her PhD in Biophysics from the University of Chicago, and her MD from the University of Michigan. She completed her residency training in anesthesia and intensive care unit medicine at the Massachusetts General Hospital in Boston, and completed post-doctoral scientific training at Massachusetts Institute of Technology. From there she went onto a faculty position at Duke University, where she remained from 1998-2005, before moving to Yale.
Cardiovascular regenerative medicine has taken many avenues over the past three decades. One approach currently in clinical trials does not require any cells from the patient, and is an engineered tissue that is available "off-the-shelf". Our approach to vascular engineering involves seeding allogeneic vascular cells onto a degradable substrate to culture vascular tissues in a biomimetic bioreactor. After a period of 8-10 weeks, engineered tissues are then decellularized to produce an engineered extracellular matrix-based graft. The advantage of using allogeneic cells for graft production is that no biopsy need be harvested from the patient, and no patient-specific culture time is required. The acellular grafts can be stored for 6 months and are available at time of patient need. These grafts are being tested in 3, Phase I clinical trials in Europe and in the US. These tissue engineered vascular grafts have been tested most extensively as hemodialysis access in patients who are not candidates for autogenous arteriovenous fistula creation, with the first patient being implanted in December 2012 in Poland. Since that time, a total of 60 patients have been implanted with engineered, acellular grafts for dialysis access, 40 patients in Europe and 20 in the US. Patients utilize the grafts for dialysis access as soon as 4-8 weeks after graft implantation. This early experience supports the potential utility of this novel tissue engineered vascular graft to provide vascular access for hemodialysis.
The decellularization approach has also allowed us to generate scaffolds to support whole lung regeneration. Using rat, porcine and human sources of organs, lungs have been subjected to a range of decellularization procedures, with the goal of removing a maximal amount of cellular material while retaining matrix constituents. Next-generation proteomics approaches have shown that gentle decellularization protocols result in near-native retention of key matrix molecules involved in cell adhesion, including proteoglycans and glycoproteins. Repopulation of the acellular lung matrix with mixed populations of neonatal lung epithelial cells results in regio-specific epithelial seeding in correct anatomic locations. Survival and differentiation of lung epithelium is enhanced by culture in a biomimetic bioreactor that is designed to mimic some aspects of the fetal lung environment, including vascular perfusion and liquid ventilation. Current challenges involve the production of a uniformly recellularized scaffold within the vasculature, in order to shield blood elements from the collagenous matrix which can stimulate clot formation. In addition, we have developed methods to quantify barrier function of acellular and repopulated matrix, in order to predict functional gas exchange in vivo.
The environmental impact of perioperative services is among the largest in all of medicine. Inhaled anesthetics account for 5% of hospital emissions, and 33% of hospital solid waste is generated in the ORs. Anesthesiologists have a unique opportunity and responsibility to improve the pollution profile of our specialty, however little is presently known where to target our efforts. The central goal of Dr. Jodi Sherman research in the Yale University Department of Anesthesiology is to quantify the environmental and public health effects of common drugs and devices for entire anesthetic pathways, so these results may aid in targeted waste reduction and pollution prevention strategies where choices exist, as they often do in clinical practice. Dr. Sherman collaborates with Dr. Julie Zimmerman, Ph.D. and other environmental engineers from the Yale School of Forestry and Environmental Sciences, applying Life Cycle Assessment (LCA) scientific modeling to questions in anesthetic practice, quantifying energy, greenhouse gas emissions, human health impacts, and economic densities of therapeutic drugs, OR devices, and perioperative behaviors to help guide clinical decision making toward more ecologically sustainable practices. Dr. Sherman also serves on the Environmental Task Force of the American Society of Anesthesiologists.
Dr. LaMotte's laboratory investigates the peripheral and central neural mechanisms of pain, itch and touch.
- Experiments on pain examine the functional properties of dorsal root ganglion (DRG) neurons in the rodent. We are currently interested in how electrophysiological and neurochemical changes in these properties, occurring after a chronic compression of the DRG (CCD model), lead to behavioral signs of neuropathic pain.
- Experiments on itch use psychophysical methods in humans to measure the pruritic and nociceptive sensations and altered sensory states produced by the application of pruritic substances to the skin. As part of a collaborative effort with two other laboratories, our psychophysical findings will be compared with electrophysiologically recorded responses of peripheral nerve fibers and of spinothalamic neurons to the same pruritic stimuli.
- Experiments on touch have investigated the peripheral neural coding of object texture, shape and softness.
Dr. Xu’s lab is interested in understanding molecular mechanisms that underlie mammalian aging process; and thus, in the long run, developing therapeutic intervention(s) for aging and age-associated diseases. Currently, our research is focused on:
- To study the impact of epigenetically regulated mechanism on cell and tissue aging. Aging is a major risk factor for many chronic diseases, including cancer, cardiovascular diseases and neurodegenerative disorders. Epigenetics has recently emerged as a possible mechanism controlling gene expression and a potential causative factor for cell/ tissue aging and age-associated abnormalities. Epigenetic regulation is primarily mediated by DNA methylation, posttranslational modify of nucleosomal histones, and non-coding RNAs. To achieve our goal, the cutting-edge technologies such as next-generation sequencing (DNA methyl-seq, RNA-seq, and ChIP-seq), conditional cell/tissue specific transgenic and knock-out mouse models, and phenotype characterization are applied to address our research interest.
- To further investigate the functions and mechanisms of our newly identified longevity genes, Pch-2/TRIP13 and Bmk-1/KIF-11. Testing the hypothesis that loss of function (expression) of certain genes in tissues is a driven force for aging, Dr. Niklason and I examined genome-wide gene expression changes in both age-sensitive cells/tissues and age-resistant cells/tissues of mouse and human. We essentially identified a small number of candidate longevity genes. The C. elegans worm and human cell culture have been employed to test if any of those candidates are indeed having impact on lifespan/health-span regulation.
The Yale Center for Medical Informatics
Professor Perry Miller is Director of the Yale Center for Medical Informatics (YCMI) and of Yale's Biomedical Informatics research training program. Biomedical Informatics is a discipline at the intersection of biomedicine and the computing and information sciences. The field focuses on the creative application of computers in clinical medicine, biomedical research, and medical education. In clinical medicine, the growing use of computers in patient care, education, and research makes the field increasingly important. In biomedical research, informatics is rapidly becoming a critical component of virtually all bioscience fields.
Projects at the YCMI include major initiatives in clinical, neuro-, and genome informatics. In these projects, the YCMI collaborates with faculty and staff from many departments at Yale. Additional information is available at the YCMI web site.
- Biomedical informatics research training. Since 1985, Dr. Miller has been Director of Yale's Biomedical Informatics Research Training Program, supported in part by the National Library of Medicine. This program currently supports trainees whose activities are roughly equally divided between clinical informatics and bioscience informatics.
- Genomic and genetic informatics. Over the past 15 years, the YCMI has been involved in a number of projects involving genomics and genetics. An early project involved exploring the use of parallel computation in biological sequence analysis, genetic linkage analysis, and molecular dynamics, in collaboration with Prof. David Gelernter (Computer Science) and his colleagues. Another project provided Internet-based informatics support for a collaborative Genome Center involving the Albert Einstein College of Medicine and Yale to map human chromosome 12. Current projects include 1) developing and maintaining a variety of databases that are used actively within the laboratory of Dr. Kenneth Kidd (Genetics), 2) working with Dr. Michael Snyder to develop and refine databases for a) yeast gene expression data and b) yeast proteome chip data, and tools to help analyze that data, and 3) working with several groups to provide University-wide informatics support for microarray experiments. Dr. Kei Cheung (Assistant Professor, YCMI) plays a central role in many of these activities.
- Neuroinformatics. Dr. Miller directs the informatics components of a collaborative Program Project involving Drs. Gordon Shepherd (Neurobiology), Michael Hines (Computer Science), and Prakash Nadkarni (YCMI), supported as part of the national Human Brain Project. The project is developing informatics support for neuroscience research and computer-based neural simulation using the olfactory system as a model system.
- Informatics in support of clinical research. Since 1996, the YCMI has had a major project to develop, refine, and use Trial/DB, a client-server, Web-accessible database designed to support clinical research projects. Trial/DB is currently being used for a growing number of clinical trials and clinical research projects at Yale. It is also supported by two cooperative grants to Dr. Prakash Nadkarni (Associate Professor, YCMI): a) to serve as the special studies database for the NCI's multisite Cancer Genetics Network, and b) to help support the NIH's multisite Pharmacogenetics Network. Dr. Cynthia Brandt (Assistant Professor, YCMI) also plays a central role in many phases of this project.
- The PathMaster cell image database. Dr. Miller directs a collaborative research contract from the National Library of Medicine to build a database of cell images indexed by computationally-derived descriptors, implemented using parallel computation, as a testbed to explore desirable Next Generation Internet capabilities.
- Clinical informatics activities. The YCMI is also involved in a number of collaborative clinical informatics activities. A longstanding research activity has involved the development of programs which bring computer-based advice to the practicing clinician. One current project directed by Dr. Richard Shiffman (Associate Director, YCMI) involves developing GEM (Guideline Elements Model), an XML-based standard to help organize the creation and use of clinical practice guidelines. Another recent clinical informatics project involves Personal Digital Assistants (PDAs) which offer a lightweight, mobile platform that can be used at the point-of-care.