Craig M. Coopersmith

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

IMPORTANCEnDefinitions 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.nnnOBJECTIVEnTo evaluate and, as needed, update definitions for sepsis and septic shock.nnnPROCESSnA task force (nu2009=u200919) 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).nnnKEY FINDINGS FROM EVIDENCE SYNTHESISnLimitations 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.nnnRECOMMENDATIONSnSepsis 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.nnnCONCLUSIONS AND RELEVANCEnThese 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.

Redefining the gut as the motor of critical illness

The gut is hypothesized to play a central role in the progression of sepsis and multiple organ dysfunction syndrome. Critical illness alters gut integrity by increasing epithelial apoptosis and permeability and by decreasing epithelial proliferation and mucus integrity. Additionally, toxic gut-derived lymph induces distant organ injury. Although the endogenous microflora ordinarily exist in a symbiotic relationship with the gut epithelium, severe physiological insults alter this relationship, leading to induction of virulence factors in the microbiome, which, in turn, can perpetuate or worsen critical illness. This review highlights newly discovered ways in which the gut acts as the motor that perpetuates the systemic inflammatory response in critical illness.

A comparison of critical care research funding and the financial burden of critical illness in the United States

Objectives:To estimate federal dollars spent on critical care research, the cost of providing critical care, and to determine whether the percentage of federal research dollars spent on critical care research is commensurate with the financial burden of critical care. Design and Data Sources:The National Institutes of Health Computer Retrieval of Information on Scientific Projects database was queried to identify funded grants whose title or abstract contained a key word potentially related to critical care. Each grant identified was analyzed by two reviewers (three if the analysis was discordant) to subjectively determine whether it was definitely, possibly, or definitely not related to critical care. Hospital and total costs of critical care were estimated from the Premier Database, state discharge data, and Medicare data. To estimate healthcare expenditures associated with caring for critically ill patients, total costs were calculated as the combination of hospitalization costs that included critical illness as well as additional costs in the year after hospital discharge. Measurements and Main Results:Of 19,257 grants funded by the National Institutes of Health, 332 (1.7%) were definitely related to critical care and a maximum of 1212 (6.3%) grants were possibly related to critical care. Between 17.4% and 39.0% of total hospital costs were spent on critical care, and a total of between

The Accreditation Council for Graduate Medical Education resident duty hour new standards: history, changes, and impact on staffing of intensive care units.

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The Gut as the Motor of Multiple Organ Dysfunction in Critical Illness

263 billion was estimated to be spent on patients who required intensive care. This represents 5.2% to 11.2%, respectively, of total U.S. healthcare spending. Conclusions:The proportion of research dollars spent on critical care is lower than the percentage of healthcare expenditures related to critical illness. (Crit Care Med 2012; 40:–1079)

Chronic Alcohol Ingestion Increases Mortality and Organ Injury in a Murine Model of Septic Peritonitis

Objectives:The Accreditation Council for Graduate Medical Education recently released new standards for supervision and duty hours for residency programs. These new standards, which will affect over 100,000 residents, take effect in July 2011. In response to these new guidelines, the Society of Critical Care Medicine convened a task force to develop a white paper on the impact of changes in resident duty hours on the critical care workforce and staffing of intensive care units. Participants:A multidisciplinary group of professionals with expertise in critical care education and clinical practice. Data Sources and Synthesis:Relevant medical literature was accessed through a systematic MEDLINE search and by requesting references from all task force members. Material published by the Accreditation Council for Graduate Medical Education and other specialty organizations was also reviewed. Collaboratively and iteratively, the task force corresponded by electronic mail and held several conference calls to finalize this report. Main Results:The new rules mandate that all first-year residents work no more than 16 hrs continuously, preserving the 80-hr limit on the resident workweek and 10-hr period between duty periods. More senior trainees may work a maximum of 24 hrs continuously, with an additional 4 hrs permitted for handoffs. Strategic napping is strongly suggested for trainees working longer shifts. Conclusions:Compliance with the new Accreditation Council for Graduate Medical Education duty-hour standards will compel workflow restructuring in intensive care units, which depend on residents to provide a substantial portion of care. Potential solutions include expanded utilization of nurse practitioners and physician assistants, telemedicine, offering critical care training positions to emergency medicine residents, and partnerships with hospitalists. Additional research will be necessary to evaluate the impact of the new standards on patient safety, continuity of care, resident learning, and staffing in the intensive care unit.

A Framework for the Development and Interpretation of Different Sepsis Definitions and Clinical Criteria

All elements of the gut - the epithelium, the immune system, and the microbiome - are impacted by critical illness and can, in turn, propagate a pathologic host response leading to multiple organ dysfunction syndrome. Preclinical studies have demonstrated that this can occur by release of toxic gut-derived substances into the mesenteric lymph where they can cause distant damage. Further, intestinal integrity is compromised in critical illness with increases in apoptosis and permeability. There is also increasing recognition that microbes alter their behavior and can become virulent based upon host environmental cues. Gut failure is common in critically ill patients; however, therapeutics targeting the gut have proven to be challenging to implement at the bedside. Numerous strategies to manipulate the microbiome have recently been used with varying success in the ICU.

The Role of Heat Shock Protein 70 in Mediating Age-Dependent Mortality in Sepsis

Background Patients admitted to the intensive care unit with alcohol use disorders have increased morbidity and mortality. The purpose of this study was to determine how chronic alcohol ingestion alters the host response to sepsis in mice. Methods Mice were randomized to receive either alcohol or water for 12 weeks and then subjected to cecal ligation and puncture. Mice were sacrificed 24 hours post-operatively or followed seven days for survival. Results Septic alcohol-fed mice had a significantly higher mortality than septic water-fed mice (74% vs. 41%, pu200a=u200a0.01). This was associated with worsened gut integrity in alcohol-fed mice with elevated intestinal epithelial apoptosis, decreased crypt proliferation and shortened villus length. Further, alcohol-fed mice had higher intestinal permeability with decreased ZO-1 and occludin protein expression in the intestinal tight junction. The frequency of splenic and bone marrow CD4+ T cells was similar between groups; however, splenic CD4+ T cells in septic alcohol-fed mice had a marked increase in both TNF and IFN-γ production following ex vivo stimulation. Neither the frequency nor function of CD8+ T cells differed between alcohol-fed and water-fed septic mice. NK cells were decreased in both the spleen and bone marrow of alcohol-fed septic mice. Pulmonary myeloperoxidase levels and BAL levels of G-CSF and TFG-β were higher in alcohol-fed mice. Pancreatic metabolomics demonstrated increased acetate, adenosine, xanthine, acetoacetate, 3-hydroxybutyrate and betaine in alcohol-fed mice and decreased cytidine, uracil, fumarate, creatine phosphate, creatine, and choline. Serum and peritoneal cytokines were generally similar between alcohol-fed and water-fed mice, and there were no differences in bacteremia, lung wet to dry weight, or pulmonary, liver or splenic histology. Conclusions When subjected to the same septic insult, mice with chronic alcohol ingestion have increased mortality. Alterations in intestinal integrity, the host immune response, and pancreatic metabolomics may help explain this differential response.

Epidermal growth factor improves survival and prevents intestinal injury in a murine model of pseudomonas aeruginosa pneumonia.

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 important, and the tendency of most potential criteria to be distributed in at-risk populations in such a way as to hinder separation into discrete sets of patients. We propose that the development and evaluation of any definition or diagnostic criteria should follow four steps: 1) define the epistemologic underpinning, 2) agree on all relevant terms used to frame the exercise, 3) state the intended purpose for any proposed set of criteria, and 4) adopt a scientific approach to inform on their usefulness with regard to the intended purpose. Usefulness can be measured across six domains: 1) reliability (stability of criteria during retesting, between raters, over time, and across settings), 2) content validity (similar to face validity), 3) construct validity (whether criteria measure what they purport to measure), 4) criterion validity (how new criteria fare compared to standards), 5) measurement burden (cost, safety, and complexity), and 6) timeliness (whether criteria are available concurrent with care decisions). The relative importance of these domains of usefulness depends on the intended purpose, of which there are four broad categories: 1) clinical care, 2) research, 3) surveillance, and 4) quality improvement and audit. This proposed methodologic framework is intended to aid understanding of the strengths and weaknesses of different approaches, provide a mechanism for explaining differences in epidemiologic estimates generated by different approaches, and guide the development of future definitions and diagnostic criteria.

The turn team: a novel strategy for reducing pressure ulcers in the surgical intensive care unit.

Sepsis is primarily a disease of the aged, with increased incidence and mortality occurring in aged hosts. Heat shock protein (HSP) 70 plays an important role in both healthy aging and the stress response to injury. The purpose of this study was to determine the role of HSP70 in mediating mortality and the host inflammatory response in aged septic hosts. Sepsis was induced in both young (6- to 12-wk-old) and aged (16- to 17-mo-old) HSP70−/− and wild-type (WT) mice to determine whether HSP70 modulated outcome in an age-dependent fashion. Young HSP70−/− and WT mice subjected to cecal ligation and puncture, Pseudomonas aeruginosa pneumonia, or Streptococcus pneumoniae pneumonia had no differences in mortality, suggesting HSP70 does not mediate survival in young septic hosts. In contrast, mortality was higher in aged HSP70−/− mice than aged WT mice subjected to cecal ligation and puncture (p = 0.01), suggesting HSP70 mediates mortality in sepsis in an age-dependent fashion. Compared with WT mice, aged septic HSP70−/− mice had increased gut epithelial apoptosis and pulmonary inflammation. In addition, HSP70−/− mice had increased systemic levels of TNF-α, IL-6, IL-10, and IL-1β compared with WT mice. These data demonstrate that HSP70 is a key determinant of mortality in aged, but not young hosts in sepsis. HSP70 may play a protective role in an age-dependent response to sepsis by preventing excessive gut apoptosis and both pulmonary and systemic inflammation.