Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis
01 Mar 2013-American Journal of Respiratory and Critical Care Medicine (American Thoracic Society)-Vol. 187, Iss: 5, pp 509-517
TL;DR: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs, and the degree of cell injury and death does not account for severity of sepsi-induced organ dysfunction.
Abstract: Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined.Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death.Methods: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study.Measurements and Main Results: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (<1–2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P < 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens...
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University College London1, The Feinstein Institute for Medical Research2, University of Pittsburgh3, Guy's and St Thomas' NHS Foundation Trust4, Monash University5, Vanderbilt University6, Emory University7, Washington University in St. Louis8, Brown University9, University of Toronto10, Sunnybrook Health Sciences Centre11
TL;DR: The task force concluded the term severe sepsis was redundant and updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsi or at risk of developing sepsic shock.
Abstract: 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 needed, update definitions for sepsis and septic shock. Process A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). Key Findings From Evidence Synthesis Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. Recommendations Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. Conclusions and Relevance These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.
14,699 citations
King's College London1, Guy's and St Thomas' NHS Foundation Trust2, Ohio State University3, Rhode Island Hospital4, University of Pittsburgh5, Kaiser Permanente6, The Feinstein Institute for Medical Research7, Hofstra University8, Sunnybrook Health Sciences Centre9, University of Toronto10, University College London11
TL;DR: A consensus process using results from a systematic review, surveys, and cohort studies found that adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.
Abstract: 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 Participants The Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; n = 28 150), University of Pittsburgh Medical Center (UPMC) (2010-2012; n = 1 309 025), and Kaiser Permanente Northern California (KPNC) (2009-2013; n = 1 847 165) electronic health record (EHR) data sets. Main Outcomes and Measures Evidence for and agreement on septic shock definitions and criteria. Results The systematic review identified 44 studies reporting septic shock outcomes (total of 166 479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock–associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity ( I 2 = 99.5%; τ 2 = 182.5; P Conclusions and Relevance Based on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.
1,531 citations
TL;DR: Outcomes in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in supportive care for critically ill patients.
Abstract: Sepsis, severe sepsis, and septic shock represent increasingly severe systemic inflammatory responses to infection. Sepsis is common in the aging population, and it disproportionately affects patients with cancer and underlying immunosuppression. In its most severe form, sepsis causes multiple organ dysfunction that can produce a state of chronic critical illness characterized by severe immune dysfunction and catabolism. Much has been learnt about the pathogenesis of sepsis at the molecular, cell, and intact organ level. Despite uncertainties in hemodynamic management and several treatments that have failed in clinical trials, investigational therapies increasingly target sepsis induced organ and immune dysfunction. Outcomes in sepsis have greatly improved overall, probably because of an enhanced focus on early diagnosis and fluid resuscitation, the rapid delivery of effective antibiotics, and other improvements in supportive care for critically ill patients. These improvements include lung protective ventilation, more judicious use of blood products, and strategies to reduce nosocomial infections.
663 citations
TL;DR: More mechanistic studies are needed to better understand the convoluted pathophysiology of S-AKI and to translate these findings into potential treatment strategies and add to the promising pharmacologic approaches being developed and tested in clinical trials.
524 citations
University of Melbourne1, University of Pittsburgh2, St. Michael's Hospital3, University of Toronto4, Karolinska Institutet5, Geelong Football Club6, Royal Adelaide Hospital7, University of Alberta8, Monash University9, Austin Hospital10, Florey Institute of Neuroscience and Mental Health11, University of Helsinki12, University Hospital of Lausanne13
TL;DR: In this paper, the optimal intensity of renal replacement therapy has been established, while the timing of when to commence RRT is now a focus of investigation, as well as when to start RRT in patients with septic AKI.
Abstract: Acute kidney injury (AKI) and sepsis carry consensus definitions. The simultaneous presence of both identifies septic AKI. Septic AKI is the most common AKI syndrome in ICU and accounts for approximately half of all such AKI. Its pathophysiology remains poorly understood, but animal models and lack of histological changes suggest that, at least initially, septic AKI may be a functional phenomenon with combined microvascular shunting and tubular cell stress. The diagnosis remains based on clinical assessment and measurement of urinary output and serum creatinine. However, multiple biomarkers and especially cell cycle arrest biomarkers are gaining acceptance. Prevention of septic AKI remains based on the treatment of sepsis and on early resuscitation. Such resuscitation relies on the judicious use of both fluids and vasoactive drugs. In particular, there is strong evidence that starch-containing fluids are nephrotoxic and decrease renal function and suggestive evidence that chloride-rich fluid may also adversely affect renal function. Vasoactive drugs have variable effects on renal function in septic AKI. At this time, norepinephrine is the dominant agent, but vasopressin may also have a role. Despite supportive therapies, renal function may be temporarily or completely lost. In such patients, renal replacement therapy (RRT) becomes necessary. The optimal intensity of this therapy has been established, while the timing of when to commence RRT is now a focus of investigation. If sepsis resolves, the majority of patients recover renal function. Yet, even a single episode of septic AKI is associated with increased subsequent risk of chronic kidney disease.
460 citations
Cites background from "Mechanisms of Cardiac and Renal Dys..."
...They found more minor tubular lesions, leucocyte infiltration, and apoptosis in septic kidneys [39, 40]....
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...However, in human septic AKI postmortem studies, ATN is uncommon [39, 40]....
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References
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TL;DR: An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae as mentioned in this paper.
12,583 citations
TL;DR: This review examines evolving concepts of sepsis and discusses new and potential therapies, including therapy with activated protein C, stringent control of blood glucose, and early goal-directed therapy to treat cellular oxygen deficit.
Abstract: Sepsis is the leading cause of death in critically ill patients in the United States. Yet the individual host response to septicemia is variable, depending on the patient's immune response, age, nutritional status, and coexisting conditions, as well as on the virulence of the organism and the size of the inoculum. This review examines evolving concepts of sepsis and discusses new and potential therapies. Recent clinical advances include therapy with activated protein C, stringent control of blood glucose, and early goal-directed therapy to treat cellular oxygen deficit. Future therapies may be focused on modulating the immune response in the light of the characteristics of the specific pathogen, the genetic profile of the patient, and the duration of the disease.
3,773 citations
TL;DR: Major changes include the following: rejection with vasculitis is separated from tubulointerstitial rejection; severe rejection requires transmural changes in arteries; "borderline" rejection can only be interpreted in a clinical context; antibody-mediated rejection is further defined, and lesion scoring focuses on most severely involved structures.
2,974 citations
"Mechanisms of Cardiac and Renal Dys..." refers background in this paper
...Arterial intimal fibrosis, arteriolar hyalinosis, interstitial fibrosis, and interstitial inflammation were scored according to established criteria (42)....
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TL;DR: In 2000, it was suggested to me that “Autophagy will be the wave of the future; it will become the new apoptosis,” and this statement turned out to be prophetic, and this process of 'self-eating' rapidly exploded as a research field, as scientists discovered connections to cancer, neurodegeneration and even lifespan extension.
Abstract: In 2000, it was suggested to me that "Autophagy will be the wave of the future; it will become the new apoptosis." Few people would have agreed at the time, but this statement turned out to be prophetic, and this process of 'self-eating' rapidly exploded as a research field, as scientists discovered connections to cancer, neurodegeneration and even lifespan extension. Amazingly, the molecular breakthroughs in autophagy have taken place during only the past decade.
1,827 citations
"Mechanisms of Cardiac and Renal Dys..." refers background in this paper
...In addition to necrosis and apoptosis, autophagic cell death occurs (29, 30)....
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...Methodologic advances have improved our understanding of cell death, providing tools to better define the basis of organ dysfunction in sepsis (29, 30)....
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TL;DR: One of the most frequent and serious problems confronting clinicians is the management of a serious infection and the systemic response to infection, a syndrome termed sepsis, when this syndrome results in hypotension and organ dysfunction, called septic shock.
Abstract: One of the most frequent and serious problems confronting clinicians is the management of a serious infection and the systemic response to infection, a syndrome termed sepsis. When this syndrome results in hypotension and organ dysfunction, it is called septic shock. Septic shock is the most common cause of death in intensive care units,1 and it is the 13th most common cause of death in the United States2. The incidence of the two disorders continues to rise: 400,000 cases of sepsis and 200,000 episodes of septic shock are estimated to occur annually, resulting in more than 100,000 deaths1. . . .
1,618 citations
"Mechanisms of Cardiac and Renal Dys..." refers background in this paper
...Although sepsis-induced myocardial suppression is occasionally lethal, moderate sepsis-induced “hibernation” could be advantageous by preventing stress-induced cardiac injury (1, 18, 49)....
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...Cardiac dysfunction in sepsis is reversible, and the majority of renal failure patients who survive sepsis recover baseline renal function; these observations are consistent with organ “hibernation” (1, 3, 13, 18)....
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