Clifford S Deutschman

Hofstra North Shore-LIJ School of Medicine, Feinstein Institute for Medical Research · Pediatrics

IMPORTANCE Pediatric acute kidney injury (AKI) is a prevalent and morbid complication of shock. Its pathogenesis and early identification remain elusive. OBJECTIVES We aim to determine whether renal blood flow (RBF) measurements by point-of-care ultrasound (POCUS) and renin-angiotensin-aldosterone system (RAAS) hormones in pediatric shock associat...

Background Individual T cell responses vary significantly based on the microenvironment present at the time of immune response and on prior induced T cell memory. While the cecal ligation and puncture (CLP) model is the most commonly used murine sepsis model, the contribution of diverse T cell responses has not been explored. We defined T cell subs...

Background The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1 muscarinic acetylcholine (ACh) receptor (M1AChR) attenuated this endotoxin-mediated cha...

OBJECTIVES To identify research priorities in the management, epidemiology, outcome, and pathophysiology of sepsis and septic shock. DESIGN Shortly after publication of the most recent Surviving Sepsis Campaign Guidelines, the Surviving Sepsis Research Committee, a multiprofessional group of 16 international experts representing the European Socie...

Background: The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1/M4 muscarinic acetylcholine (ACh) receptor (M1/M4AChR) attenuated this endotoxin-media...

Background Sepsis is characterized as an insulin resistant state. However, the effects of sepsis on insulin’s signal transduction pathway are unknown. The molecular activity driving insulin signaling is controlled by tyrosine phosphorylation of the insulin receptor β-subunit (IRβ) and of insulin receptor substrate molecules (IRS) -1 and IRS-2. Hyp...

Sepsis, defined as organ dysfunction caused by a dysregulated host-response to infection, is characterized by immunosuppression. The vasopressor norepinephrine is widely used to treat low blood pressure in sepsis but exacerbates immunosuppression. An alternative vasopressor is angiotensin-II, a peptide hormone of the renin-angiotensin system (RAS),...

LPS challenge is used to model inflammation‐induced organ dysfunction. The effects of T cell activation on LPS‐mediated organ dysfunction and immune responses are unknown. We studied these interactions through in vivo administration of anti‐CD3ε (CD3) T cell activating antibody and LPS. Mortality in response to high‐dose LPS (LPSHi; 600 μg) was 60%...

Introduction: Peripheral blood mononuclear cells (PBMCs) are commonly used to compare mitochondrial function in patients with versus without sepsis, but how these measurements in this mixed cell population vary by composition of immune cell subtypes is not known, especially in children. We determined the effect of changing immune cell composition...

Objective To identify priorities for administrative, epidemiologic and diagnostic research in sepsis. Design As a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addr...

Objectives: To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients. Design: The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care...

Objectives: Expound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data sources: Original paper, search of the literature. Study selection: This study is selected by several members of the o...

The role of T cell memory in sepsis is poorly understood. Recent work has demonstrated that mice exposed to frequent antigenic stimulation, in contrast to laboratory mice, better recapitulate the human T cell repertoire. This difference may profoundly alter responses to inflammatory insults. We induced isolated T cell memory by inoculating C57Bl/6...

The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we repo...

Objectives: To assess the early physiologic response to angiotensin-II treatment in patients with coronavirus disease 2019-induced respiratory failure and distributive shock. Design: Retrospective consecutive-sample cohort study. Setting: Three medical ICUs in New York during the coronavirus disease 2019 outbreak. Patients: All patients were...

Recent studies have demonstrated that induction of a diverse repertoire of memory T cells (“immune education”) affects responses to murine cecal ligation and puncture (CLP), the most widely – used animal model of sepsis. Among the documented effects of immune education on CLP are changes in T cell, macrophage and neutrophil activity, more pronounce...

Objectives: Expound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Data sources: Original paper, search of the literature. Study selection: By several members of the original task force with...

In sepsis-induced acute kidney injury, kidney blood flow may increase despite decreased glomerular filtration. Normally, angiotensin-II reduces kidney blood flow to maintain filtration. We hypothesized that sepsis reduces angiotensin type-1 receptor (AT1R) expression to account for this observation and tested this hypothesis in a patient case-contr...

Recent studies have demonstrated that laboratory mice lack a robust repertoire of memory T cell. Administration of an anti‐CD3ε activating antibody (clone 145‐2C11) induces persistent CD4 and CD8 T cell memory in both lymphatic and solid organs while maintaining T cell responses and without increased anergy or altering innate immunity.

Hyperglycemia is a characteristic finding in sepsis, and its presence worsens outcome (1). Patients with sepsis need larger doses of insulin to reduce glucose levels. This abnormality has been termed “insulin resistance” but the molecular mechanism by which sepsis attenuates the insulin signaling pathway is unknown. Previous work has shown impairme...

Sepsis is a syndrome that affects millions of patients worldwide. Despite this burden, the pathobiology of the disorder is poorly understood. Over the past three decades, three separate expert task forces have attempted to define sepsis. The final approach, Sepsis-3, is unique because it differentiates the definition from clinical criteria that mig...

Objective: Immune dysregulation is a defining feature of sepsis, but the role for mitochondria in the development of immunoparalysis in pediatric sepsis is not known. We sought to determine if mitochondrial dysfunction measured in peripheral blood mononuclear cells (PBMCs) is associated with immunoparalysis and systemic inflammation in children wi...

Outcomes variables for research on sepsis have centered on mortality and changes in the host immune response. However, a recent task force (Sepsis-3) revised the definition of sepsis to "life-threatening organ dysfunction caused by a dysregulated host response to infection". This new definition suggests that human studies should focus on organ dysf...

Objectives: Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis. Design: Prospective obser...

Sepsis can be simulated in animals by perforating the cecum via a surgical procedure termed "cecal ligation and puncture" (CLP), which induces similar inflammatory responses as observed during the clinical course of human sepsis. In addition to anesthetic agents, many Institutional Animal Care and Use Committees (IACUC) often recommend the use of a...

Background: Pre-clinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. Objective: To address this deficit, a Wiggers-Bernard Confere...

Purpose: Pre-clinical animal studies precede the majority of clinical trials. While the clinical sepsis definitions and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on pre-clinical...

The original version of this article unfortunately contained mistakes.

Pre-clinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis...

Abstact: While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review has not been done for pre-clinical models. To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling reviewed the 260 most highly cited papers between 2003 and 2012 using sepsis models to create a seri...

Objective: To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. Design: A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. S...

Abnormalities in higher cerebral function such as delirium and altered cognition are important components of acute sepsis. Sepsis survivors are at high risk for cognitive dysfunction, and this loss of integrative function suggests a persistent, and perhaps progressive, abnormality in the cerebral cortex. Severe dementia is characterized by the accu...

Patients who survive sepsis often suffer from cognitive dysfunction that is life-altering. It is reasonable to propose that this devestating condition is provoked by mechanisms similar to those underlying other disorders that impair memory. The most common of these disorders is Alzheimer’s disease (AD). AD is characterized by hyperphosphorylation a...

Sepsis morbidity and mortality exacts a toll on patients and contributes significantly to healthcare costs. Preclinical models of sepsis have been used to study disease pathogenesis and test new therapies, but divergent outcomes have been observed with the same treatment even when using the same sepsis model. Other disorders such as diabetes, cance...

Objective: To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. Design: A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. S...

Objectives: Interventional trials on glucocorticoids in sepsis have yielded capricious results. Recent studies have identified multiple glucocorticoid receptor isoforms. The relative abundance of these isoforms in septic patients and following murine cecal ligation and puncture is unknown. The objective of this study is to determine the effects of...

Patients who survive sepsis often suffer from cognitive dysfunction that is life-altering. It is reasonable to propose that this devastating condition is provoked by mechanisms similar to those underlying other disorders that impair memory. The most common of these disorders is Alzheimer’s disease (AD). AD is characterized by hyperphosphorylation a...

Abnormalities in higher cerebral function, such as delirium and altered cognition, are important components of acute sepsis. Similarly, sepsis survivors are at high risk for cognitive dysfunction, memory loss, and an inability to perform tasks of daily living. This loss of integrative function suggests a persistent, and perhaps progressive, abnorma...

New definitions of sepsis and septic shock were published in early 2016, updating old definitions that have not been revisited since 2001. These new definitions should profoundly affect sepsis research. In addition, these paper present clinical criteria for identifying infected patients who are highly likely to have or to develop sepsis or septic s...

In Reply The letters from Dr Shrestha, Drs Wira and Swenson, and Drs Burnham and Roman raise valid and important critiques about a process that is inherently complex and imperfect.

In Reply Drs Sprung and Reinhart and Dr Schneider-Lindner and colleagues believe that Sepsis-3 recommends abandoning SIRS. That is not the case. Rather, SIRS may be useful in the presumptive diagnosis of infection. However, SIRS is not specific nor particularly sensitive for infection. As an example, Churpek and colleagues1 reported that 50% of hos...

The current definition of sepsis is life-threatening, acute organ dysfunction secondary to a dysregulated host response to infection. Criteria to operationalize this definition can be judged by six domains of usefulness (reliability, content, construct and criterion validity, measurement burden, and timeliness). The relative importance of these six...

Although sepsis was described more than 2,000 years ago, and clinicians still struggle to define it, there is no "gold standard," and multiple competing approaches and terms exist. Challenges include the ever-changing knowledge base that informs our understanding of sepsis, competing views on which aspects of any potential definition are most impor...

Importance Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.Objective To evaluate and, as...

Importance Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.Objective To develop a new definition and clinical criteria for identifying septic shock in adults.Design, Setting, and Participan...

Importance The Third International Consensus Definitions Task Force defined sepsis as “life-threatening organ dysfunction due to a dysregulated host response to infection.” The performance of clinical criteria for this sepsis definition is unknown.Objective To evaluate the validity of clinical criteria to identify patients with suspected infectio...

IMPORTANCE: The Third International Consensus Definitions Task Force defined sepsis as “life-threatening organ dysfunction due to a dysregulated host response to infection.” The performance of clinical criteria for this sepsis definition is unknown. OBJECTIVE: To evaluate the validity of clinical criteria to identify patients with suspected infecti...

IMPORTANCE: Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition. OBJECTIVE: To develop a new definition and clinical criteria for identifying septic shock in adults. DESIGN, SETTING AND PARTICIPA...

Mitochondria are an essential part of the cellular infrastructure, being the primary site for high-energy adenosine triphosphate production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered, and end organ dysfunction is not only common, but also predictive of long...

Septic shock definitions are being revisited. We assess the feasibility, reliability, and validity characteristics of the current definitions and criteria of septic shock. Septic shock is conceptualised as cardiovascular dysfunction, tissue perfusion and cellular abnormalities caused by infection. Currently, for feasibility, septic shock is identif...

Sepsis, a poorly understood syndrome of disordered inflammation, is the leading cause of death in critically ill patients. Lung injury, in the form of the Acute Respiratory Distress Syndrome (ARDS), is the most common form of organ injury in sepsis. The Heat Shock Response, during which Heat Shock Proteins (HSPs) are expressed, is an endogenous mec...

Of all critical care conditions, sepsis has shaped health policy, dominated the research agenda, and entered the public lexicon with energetic, high profile educational campaigns vowing to reduce the attendant mortality. Yet, when asked to provide a concise definition, even practitioners who treat ‘septic’ patients may struggle. A consensus confere...

Overuse of medical tests and treatments wastes health care resources and leads to unnecessary complications, while underuse results in delayed or missed diagnoses and treatment opportunities. Such problems are well recognized and there have been multiple attempts to correct inappropriate diagnostic testing and treatment over the past several decade...

Mitochondrial dysfunction in peripheral blood mononuclear cells has been linked to immune dysregulation and organ failure in adult sepsis, but pediatric data are limited. We hypothesized that pediatric septic shock patients exhibit mitochondrial dysfunction within peripheral blood mononuclear cells which in turn correlates with global organ injury.

Sepsis, a clinical syndrome occurring in patients following infection or injury, is a leading cause of morbidity and mortality worldwide. Current immunological mechanisms do not explain the basis of cellular dysfunction and organ failure, the ultimate cause of death. Here we review current dogma and argue that it is time to delineate novel immunome...

Oxidative stress has been postulated as a mechanism of organ dysfunction - and thus a potential therapeutic target - in sepsis. Lorente and colleagues report increased serum levels of malondialdehyde, a biomarker of oxidative stress-induced lipid peroxidation, in adults with severe sepsis, particularly in non-survivors. While survivors exhibited a...

Background Infections are a leading cause of death in patients with advanced cirrhosis, but there are relatively few data on the epidemiology of infection in intensive care unit (ICU) patients with cirrhosis. AimsWe used data from the Extended Prevalence of Infection in Intensive Care (EPIC) II one-day point-prevalence study to better define the ch...

Introduction: Mitochondrial dysfunction has been implicated in immune dysregulation and organ failure in sepsis but direct evidence of mitochondrial dysfunction in children with sepsis-related organ failure is limited. Methods: We studied 13 patients <=18 years with septic shock and >=2 organ failures; 9 PICU patients without sepsis or organ failur...

To develop and implement an objective, reliable approach to surveillance for ventilator-associated events in adult patients. The Centers for Disease Control and Prevention (CDC) convened a Ventilator-Associated Pneumonia (VAP) Surveillance Definition Working Group in September 2011. Working Group members included representatives of stakeholder soci...

This article is an executive summary of a report from the Centers for Disease Control and Prevention Ventilator-Associated Pneumonia Surveillance Definition Working Group, entitled “Developing a new, national approach to surveillance for ventilator-associated events” and published in Critical Care Medicine . The full report provides a comprehensive...

Sepsis is a common, lethal poorly understood disorder affecting nearly a million Americans annually. The syndrome is characterized by altered cardiodynamics, respiration, metabolism, pituitary function, arousal, and impaired interaction among organ systems. The immunologic and endocrine systems, which are in part responsible for organ-organ communi...

Although it is recognized that pulmonary hysteresis can influence the effects of positive end-expiratory pressure (PEEP), the extent to which expansion of previously opened (vs. newly opening) peripheral airspaces contribute to increased lung volume is unknown. Following a recruitment maneuver, rats were ventilated with constant tidal volumes and i...

Glucocorticoid use in sepsis is controversial. In contrast to other extracellular signaling molecules, glucocorticoid receptors (GRs) are intra-cytoplasmic. Several GR isoforms have been identified. A study in Critical Care Forum suggests that sepsis alters the abundance of the dominant negative GRβ. Here we discuss GR isoforms and how they may aff...

The Acute Respiratory Distress Syndrome (ARDS) is a major public health problem and a leading source of morbidity in Intensive Care Units (ICUs). Lung tissue in patients with ARDS is characterized by inflammation, with exuberant neutrophil infiltration, activation and degranulation that is thought to initiate tissue injury through the release of pr...