Clifford S. Deutschman, MS, MD

Clifford Deutschman, MS, MD, is a graduate of Trinity College (BS), Northwestern University (MS) and New York Medical College (MD). After flirtations with surgery and neurosurgery, he completed training in surgical critical care (University of Minnesota) and Anesthesiology (Johns Hopkins University). He was on the faculty at Johns Hopkins from 1988 to 1993 and the University of Pennsylvania from 1993 to 2014 as an anesthesiologist, specializing in critical intensive care medicine. As a member of Penn’s Department of Anesthesiology and Critical Care, he directed the Fellowship in Critical Care Medicine, the NIH-funded Research Fellowship (T32) and the Stavropoulos Sepsis Research Program. In 2004, he received the Leonard Berwick Teaching Award, which recognizes educators who best synthesize basic science into the clinical curriculum. In 2014, Dr. Deutschman joined Northwell Health as vice chair of research in the Department of Pediatrics at Cohen Children’s Medical Center. 

Dr. Deutschman served as president of the Society of Critical Care Medicine in 2012 and the American Society of Critical Care Anesthesiologists from 2002 to 2004. He has been a permanent member of the NIH Surgery, Anesthesia and Trauma Study Section, and has also reviewed grant proposals for the VA Merit system, Wellcome Trust in the UK, Health Research Board of Ireland and Research Foundation-Flanders. He is scientific editor of the journal Critical Care Medicine and serves on the editorial boards of a number of other journals. He has been the recipient of a number of awards and honors, including the Lifetime Achievement Award from the Society of Critical Care Anesthesiologists. Dr. Deutschman is one of approximately 100 individuals worldwide who have been awarded the designation “Master of Critical Care Medicine (MCCM)” by the American College of Critical Care Medicine. 

Dr. Deutschman has co-authored more than 160 peer-reviewed publications, and over 90 book chapters and editorials. He is the co-editor of the textbook, "Evidence-Based Practice of Critical Care", the third edition, which was released in January 2020.

Dr. Deutschman’s research focuses on sepsis, a common, life-threatening disorder that arises when the body’s response to infection injures its own tissues and organs—and a topic of which he has achieved international recognition. He is the co-first and corresponding author of the report of an international task force to re-examine and refine the definitions of sepsis, also known as Sepsis-3, published in JAMA in 2016 (as of February 2021, this paper has been cited 6,200 times). 

His experimental work on sepsis pathobiology is supported in part by the NIH and focuses on 1) how changes in the endocrine and neural systems alter function in the heart, lung, liver and kidneys, and 2) cellular and sub-cellular abnormalities, specifically in biological signal transduction and on mitochondrial function. 

They are developing rat/mouse models of pneumonia that lead to organ dysfunction, the sine qua non of sepsis. Advantages are numerous and include the ability to modulate the strength of the infectious stimulus to produced either simple infection or infection and organ dysfunction, and to vary the infecting organism (eg, gram +, gram -, anaerobic bacteria, viruses, fungi). The new platform also provides the opportunity to test therapeutic interventions and compile large sets of data that will allow them to identify “sepsis phenotypes,” or different patterns of gene expression, inflammation, organ dysfunction, etc., that may have both diagnostic and therapeutic implications. 

CNS regulation of inflammation and sepsis 

Collaborators: Valentin Pavlov, PhD; Matthew Taylor, MD; Mabel Abraham, PhD; Sandra Resnik, PhD (St. John’s University) 

Our work has shown that CLP dramatically reduces activity in a system of hypothalamic neurons that secrete the neurotransmitter orexin. The orexinergic system is a key modulator of many basic functions —respiration, cardiodynamics, temperature, appetite and arousal—and of the secretion of pituitary hormones such as TSH, ACTH, GH, etc. Restoration of orexinergic activity restores sepsis-induced alterations in HR, RR, T, motor activity and pituitary hormone release. Work by Dr. Tracey and Dr. Pavlov has established that another key component of sepsis, white cell activation, is also subject to CNS control, a process controlled by impulses carried to the abdominal viscera by the vagus nerve. Control of this “inflammatory reflex” is modulated by the central cholinergic system. The inflammatory reflex is impaired in sepsis. Finally, delirium is a well-described component of acute sepsis in humans, while cognitive dysfunction is prevalent in long-term survivors. Our investigations involve several components: 

• The contribution of orexinergic dysregulation to the development of CLP-induced dysfunction in specific organ systems. We use biochemical, molecular, cellular, histologic and functional techniques to demonstrate the presence of and the mechanisms underlying CLP-induced abnormalities in the lung, liver, heart, kidney and brain. We are currently determining the role of the orexinergic nervous system in the development of these abnormalities and how manipulation of the orexinergic system affects organ dysfunction. These studies involve unique methods, developed in conjunction with researchers at St. John's University, of delivering orexin into the CNS. 
• Exploration of the effects of CLP on neural pathways conducting impulses between the orexinergic centers in the lateral hypothalamus and the cholinergic nuclei in the medial septum and the lateral tegmentum. We are using pharmacologic, genetic and electrophysiologic approaches to explore the extent to which the interactions between these systems are altered following CLP. 
• We are investigating how long-term survival from CLP impairs memory, learning and homeostasis, how interactions between the cholinergic and orexinergic systems contribute and if reversal of the known defects in these systems improves abnormalities. 

Sepsis-induced alterations in oxidative metabolisms and mitochondrial function 

Collaborators: Scott Weiss MD; Todd Kilbaugh MD (CHOP); Luke O’Neill PhD (Trinity College, Dublin, IE); Rick Levy, MD (Columbia); Mervyn Singer, MD (University College London, UK); Lance Becker, MD 

Sepsis is known to impair oxidative phosphorylation, resulting in enhanced glycolysis despite adequate oxygen availability (aerobic glycolysis). We have shown that CLP depresses the activity of mitochondrial electron transport chain Complexes II and IV. However, recent work by Luke O’Neill at Trinity College in Dublin, Ireland, has shown that, in inflammatory states, the Krebs cycle in macrophages and lymphocytes is “broken,” that is, several key reactions are impaired. This change results in an increased reliance on glycolysis for energy production and in stimulation of both pro- and anti-inflammatory pathways. Substrate that would normally enter the electron transport chain is thus limited. For example, the activity of succinate dehydrogenase, which catalyzes the conversion of succinate to fumarate, is impaired, allowing succinate to function as a pro-inflammatory stimulus. To support inflammation, electron transport may actually be “reversed”—electrons that would normally contribute to the formation of water from molecular oxygen by Complex IV are instead diverted to enhance succinate production. Whether or not these changes are present in sepsis or CLP, which represent aberrant inflammatory states, is unknown. 

• We are examining samples from solid organs to determine if similar changes in the Krebs cycle are present following CLP. 
• Our prior work has shown impairment of complex II, which is an enzyme in both the Krebs cycle and the electron transport chain. Our work revealed that the activity of succinate dehydrogenase, the component that is part of the Krebs cycle, is normal. However, the activity of the electron transport component, CoQ reductase, is impaired. This finding suggests that a block in this enzyme component pathologically reverses electron transport and inappropriately activates inflammation. We are exploring mechanisms that might lead to the CoQ reductase block, the upstream and downstream consequences of these aberrations, and potential strategies to reverse the changes. 
• In a project directed by Scott Weiss, MD, at CHOP, we are examining white cell mitochondrial function in samples obtained from septic children. 

Sepsis-induced alterations in renal tubular function 

Collaborators: Daniel Leisman (Mass General Hospital); Christine Sethna, MD; Matt Taylor, MD; Christine Capone, MD; Rinaldo Bellomo, MD (University of Melbourne/Monash University, Melbourne, AU); La Jolla Pharmaceuticals Inc (San Diego, CA) 

We have recently demonstrated that CLP induced renal dysfunction despite maintained or increased renal blood flow. These changes were associated with down regulation of the type 1 angiotensin 2 (AngII) receptor (ATR1). Treatment with AngII, (Giapreza, kindly provided by La Jolla Pharmaceuticals) reversed some of these abnormalities. We are currently exploring the effects of CLP on the type 2 AngII receptor, (ATR2), the renal type 2 angiotensin converting enzyme (ACE2) and its product, Ang 1-7, which, in contrast to AngII, is a vasodilator. We are also examining renin levels. We are comparing these results with findings in the human sepsis, both from established datasets and from Northwell patients. 

The effects of sepsis on the intracellular insulin pathway 

Collaborators: Phyllis Speiser, MD

Sepsis is known to alter gluconeogenesis. We have demonstrated impaired expression of hepatic genes that encode gluconeogenic enzymes that reflects altered responses to PKA-dependent hormones such as glucagon. However, the effects of sepsis on insulin-mediated control of these genes in unknown. We are therefore examining the effects of sepsis on the insulin pathway. We have demonstrated that CLP reduces phosphorylation, in liver and muscle, of insulin receptor substrates type 1 and 2 (IRS-1/2). We are exploring effects on other phosphorylation events in the insulin signaling pathway. In addition, we are testing the role of CNS control of glucose regulation in sepsis. 

Sepsis-induced alterations in glucocorticoid receptor isoforms 

Collaborators: John Cidlowski, PhD (NIH Campus, Research Triangle, Durham, NC); Phyllis Speiser MD 

Sepsis alters glucocorticoid activity in a manner that often defies explanation. Newly discovered complexities in the glucocorticoid receptor (GR), which has been shown to have a multitude of isoforms, may explain these anomalies. We have shown that CLP decreases expression of GR-alpha, which is active and increases expression of GR-beta, which is a domi9nant negative, in a number of tissues. These differences arise because of slice variants; therefore, we are exploring changes in the activity of the components of the spliceosome. 

Sepsis-induced changes in cytokine signal transduction 

Collaborators: Kevin J. Tracey, MD (Feinstein Institutes) 

Previous work has demonstrated that, while levels of cytokines are increased in sepsis, the signal transduction pathways are impaired. This change primarily reflects an alteration in phosphorylation, one that we believe is linked to mitochondrial dysfunction. 

Unique molecular delivery systems for lung disorders 

Collaborators: Larry Glassman, MD (Thoracic Surgery, Northwell Health); Raphaella Sordella, PhD (Cold Spring Harbor Laboratories); Laurie Kilpatrick, PhD (Pulmonary Medicine, Temple University) 

We have used adenoviral vectors and TAT, a cell-penetrating protein derived from the HIV virus, to deliver biological molecules such as HSP70 and pharmacologic agents, like an inhibitor, to the delta isoform of Protein Kinase C into pulmonary cells. In the past, our efforts have been directed toward lung injury. However, these methods could also be used to delivery other compounds, for example, chemotherapy for lung cancer. We are in the process of initiating a new project, connecting individuals at Feinstein Institutes with clinical thoracic surgery and the cancer biology experts at CSHL. 
 

Mabel Abraham, PhD
Research Scientist, Director, Pediatric Analytic Research Laboratory
Research focus: Glucocorticoid Receptors in sepsis and other disorders
Email: [email protected]

Ariel Brandwein, MD
Instructor in Pediatric Critical Care Medicine
Research focus: Succinate dynamics in CLP and in septic children
Email: [email protected]

Laura Novello, MD
Fellow, Pediatric Endocrinology
Research focus: Tissue distribution of glucocorticoid receptors
Email: [email protected]

Kader Cetin-Gedik, MD
Fellow, Pediatric Rheumatology
Research focus: Behavioral changes induced by anti-TNF antibodies
Email: [email protected]

Johns Hopkins Medical Institutions, Baltimore, MD 
Field of study: Anesthesiology and critical care medicine 
1988 

University of Minnesota Hospitals, Minneapolis-St. Paul, MN 
Field of study: Critical care medicine 
1985 

University of Minnesota Hospitals, Minneapolis-St. Paul MN 
Field of study: Neurosurgery 
1983 

University of Florida Teaching Hospitals, Gainesville, FL 
Field of study: Surgery 
1981 

New York Medical College, Valhalla, NY 
Degree: MD 
Field of study: Medicine 
1980 

Northwestern University, Evanston, IL 
Degree: MS 
Field of study: Chemistry 
1976 

Trinity College, Hartford, CT 
Degree: BS 
Field of study: Chemistry 
1975 

• 2017 Master of Critical Care Medicine, American College of Critical Care Medicine 
• 2014 Lifetime Achievement Award, Society of Critical Care Anesthesiologists, Montreal, Canada 
• 2014 Distinguished Service Award, Society of Critical Care Medicine 
• 2011 Critical Care Teacher of the Year, Critical Care/Trauma Fellows, University of Pennsylvania School of Medicine 
• 2006 Critical Care Teacher of the Year, Critical Care/Trauma Fellows, University of Pennsylvania School of Medicine 
• 2004 Winner, Leonard Berwick Award for the teacher who best combines clinical medicine and basic science, University of Pennsylvania School of Medicine