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Research at Mass General
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Research efforts have led to significant historical contributions in the development of opioid anesthesia, as well as the study of blood conservation, protamine reactions, pulmonary vasoreactivity, right ventricular dysfunction and treatment and response to acute anemia by hemodilution.
Current research activities involve several topics in basic science, investigator-initiated clinical studies and industry-supported trials. These research initiatives include studying:
Edwin G. Avery, MD Current research projects in the Avery Laboratory include the CHOOSE trial, a multicenter study with the goal to demonstrate that the direct thrombin inhibitor bivalirudin is a safe and effective alternative to heparin anticoagulation for patients requiring heart surgery with the use of the heart-lung machine. The laboratory is also involved in an ongoing clinical trial, KALAHARI, involving the study of the drug ecallantide, which is being tested and developed to help reduce bleeding and blood product transfusions in heart surgery patients. Another ongoing clinical trial is the study of a novel renal biomarker in cardiac surgical patients (EVOLVE).
Fumito Ichinose, MD, PhD Research in the Ichinose Laboratory at the Massachusetts General Hospital Heart Center focuses on elucidating molecular mechanisms responsible for the depressed cardiomyocyte function in severe sepsis and other critical illness including cardiac arrest and cardiopulmonary resuscitation and ischemia and reperfusion injury.
Marcos F. Vidal Melo, MD, PhD Research interests in the Vidal Melo Laboratory at the Massachusetts General Hospital Heart Center are in the development and application of imaging and bioengineering techniques to investigate the cardiopulmonary system in different disease states and the study of functional changes during cardiac surgery. This laboratory conducts the investigations as translational studies in the Laboratory of Applied Biofluids (LAB)/DACC/MGH and clinical investigations in the cardiac operating rooms.
Massachusetts General Hospital led the enrollment nationally in a multicenter study with the goal to demonstrate that the direct thrombin inhibitor bivalirudin is a safe and effective alternative to heparin anticoagulation for patients requiring heart surgery with the use of the heart-lung machine. For well over fifty years, heart surgery has been performed using only heparin to anticoagulate the blood while patients are on the heart-ling machine. When patients are allergic to heparin there was previously no safe or effective alternative for clinicians to use until now. The CHOOSE Trial demonstrated that bivalirudin can be used safely and effectively as an alternative anticoagulant method in patients who are allergic to heparin that require cardiac surgery involving the use of CPB.
Another recently completed clinical trial included the largest multicenter study (ECLIPSE) of an intravenous antihypertensive agent ever performed in cardiac surgical patients. Mass General Hospital contributed greatly to this study in terms of patient enrollment and authoring manuscripts that will ultimately teach several other clinicians from many cardiac focused disciplines within medicine the utility of the novel, ultra-short acting antihypertensive agent, clevidipine.
An ongoing clinical trial, KALAHARI, involves the study of the drug ecallantide, which is being tested and developed to help reduce bleeding and blood product transfusions in heart surgery patients. Blood product transfusions in cardiac surgery have been demonstrated to be associated with detrimental effects on clinical outcomes in cardiac surgery patients. Throughout the course of this multicenter clinical trial, Mass General Hospital has been the study wide leader in patient enrollment and is hopeful that these efforts will yield an FDA-approved drug that further improves the safety profile of cardiac surgery.
Another ongoing clinical trial is the study of a novel renal biomarker in cardiac surgical patients (EVOLVE). Mass General Hospital is part of a national multicenter clinical trial of the biomarker NGAL (neutrophil gelatinase associated lipocalin) which has the goal of demonstrating that this blood test will reveal the potential threat of kidney damage several days earlier than the currently available blood test. Kidney damage at the time of heart surgery is a serious problem because its presence is known to be associated with a much higher rate of death within the first month after this type of surgery.
Research in the Ichinose Laboratory at the Massachusetts General Hospital Heart Center focuses on elucidating molecular mechanisms responsible for the depressed cardiomyocyte function in severe sepsis and other critical illness including cardiac arrest and cardiopulmonary resuscitation and ischemia and reperfusion injury.
Of particular interests are the modulatory roles of nitric oxide (NO) or hydrogen sulfide (H2S)-dependent signals on cellular functions including mitochondrial respiration and calcium handling. Researchers have recently reported previously unrecognized protective impact of nitric oxide synthase 3 (NOS3) on sepsis-induced myocardial dysfunction. These results led to further investigation of the role of cGMP-dependent and independent effects of NO in cardiomyocyte function in critical illness. Several studies are underway to elucidate the role of soluble guanylate cyclase and protein S-nitrosylation on cardiomyocyte function.
Another area of strong interest is in the effects of H2S on cellular metabolism and organ function. Recently, research groups have reported cardiovascular and metabolic effects of H2S inhalation in mice. A follow-up study is underway to examine the effects of H2S donor on systemic ischemia-reperfusion injury. This research is supported by Gas-Enabled Medical Innovation Fund.
In collaboration with a multidisciplinary team of mechanical, systems and biomedical engineers, anesthesiologists and pulmonary/critical care physicians, researchers use mathematical modeling and tracer kinetics analysis of positron emission tomography (PET) images to study lung structure (density), function (ventilation and perfusion) and inflammation. The area represents an innovative approach to the investigation of lung function through non-invasive three-dimensional high-resolution imaging. These techniques reveal in great detail at the regional level the mechanisms involved in the derangements of gas exchange and inflammation during lung disease and allow for the study of strategies to manage lung dysfunction.
Researchers have developed methods to calculate regional ventilation-perfusion (V/Q) ratios using intravenous injection of the insoluble tracer 13NN. The team has also enhanced the analysis and interpretation of the data by combining the PET derived V/Q distributions with compartmental models of gas exchange. Application of the methods to different models of lung diseases provided new insights into their pathophysiology. In studies during methacholine induced bronchoconstriction, researchers explored the ability to accurately estimate V/Q heterogeneities at the regional level to reveal that the topographic distribution of the V/Q heterogeneity involves a significant contribution from lung regions under 2.2 cm3. Furthermore, the team showed that those regions are essential to explain the existence of the bimodal distribution of V/Q ratios observed in bronchoconstricted animals and asthmatic humans. Such results contributed to the development of a mathematical model to explain the development of large areas of air trapping in asthmatic humans.
Addressing pulmonary embolism, researchers developed an experimental model of acute thrombotic embolism in sheep and showed that a significant drop in regional ventilation occurs in embolized lung areas immediately following embolism. Investigating acute lung injury, researchers modeled arterial 13NN kinetics to show that the fraction of available alveolar gas volume effectively participating in gas exchange is reduced in the supine position in contrast to the prone position by an amount much larger than that expected from the sole reduction in lung volume.
More recently, laboratory researchers expanded their interest to the quantification of regional lung metabolic activity using the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) to investigate regional lung inflammation. The combination of this method with the above mentioned 13NN methods provided a valuable set of tools to study non-invasively lung structure-function-inflammation relationships. With them, researchers have shown that in conditions such as ventilator induced lung injury (VILI) and smoke inhalation injury, inflammatory changes may precede and determine functional and structural changes.
In the clinical area, researchers have participated in several multicenter industry initiated studies as well as conducted investigator initiated research on lung function during cardiac surgery, echocardiography and ventricular assist devices, and perioperative neurocognitive dysfunction. Researchers are currently conducting a study on inflammatory mediators of respiratory dysfunction during cardiopulmonary bypass.
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