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.

https://jamanetwork.com/journals/jama/articlepdf/2492881/jsc160002.pdf

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

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Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008. A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7–9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a Pao
 2/Fio
 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a Pao
 2/Fi
 o
 2 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5–10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven “absolute”’ adrenal insufficiency (2C). Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

/pdf/surviving-sepsis-campaign-international-guidelines-for-229kg8suph.pdf

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012

Prospective Cohort Study

Letter to the EditorReply to: Re: The challenge of Clostridium difficile infection: overview of clinical manifestations, diagnostic tools and therapeutic options

Earlier work within the physical domain showed that acute inflammation changes motivational prioritization and effort allocation rather than physical abilities. It is currently unclear whether a similar motivational framework accounts for the mental fatigue and cognitive symptoms of acute sickness. Accordingly, this study aimed to assess the relationship between fatigue, cytokines and mental effort-based decision making during acute systemic inflammation. Eighty-five participants (41 males; 18-30 years (M=23.0, SD=2.4)) performed a mental effort-based decision-making task before, 2 hours after, and 5 hours after intravenous administration of 1 ng/kg bacterial lipopolysaccharide (LPS) to induce systemic inflammation. Plasma concentrations of cytokines (interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)) and fatigue levels were assessed at similar timepoints. In the task, participants decided whether they wanted to perform (i.e., ‘accepted’) arithmetic calculations of varying difficulty (3 levels: easy, medium, hard) in order to obtain rewards (3 levels: 5, 6 or 7 points). Acceptance rates were analyzed using a binomial generalized estimated equation (GEE) approach with effort, reward and time as independent variables. Arithmetic performance was measured per effort level prior to the decisions and included as a covariate. Associations between acceptance rates, fatigue (self-reported) and cytokine concentrations levels were analyzed using partial correlation analyses. Plasma cytokine concentrations and fatigue were increased at 2 hours post-LPS compared to baseline and 5 hours post-LPS administration. Acceptance rates decreased for medium, but not for easy or hard effort levels at 2 hours post-LPS versus baseline and 5 hours post-LPS administration, irrespective of reward level. This reduction in acceptance rates occurred despite improved accuracy on the arithmetic calculations itself. Reduced acceptance rates for medium effort were associated with increased fatigue, but not with increased cytokines. Fatigue during acute systemic inflammation is associated with alterations in mental effort allocation, similarly as observed previously for physical effort-based choice. Specifically, willingness to exert mental effort depended on effort and not reward information, while task accuracy was preserved. These results extend the motivational account of inflammation to the mental domain and suggest that inflammation may not necessarily affect domain-specific mental abilities, but rather affects domain-general effort-allocation processes. 

Fatigue during acute systemic inflammation is associated with reduced mental effort expenditure while task accuracy is preserved

Do Corticosteroids Influence the Granulocyte Macrophage Colony-Stimulating Factor-mediated Effects on Monocyte Function? Authors' reply

Systemic inflammation (SI) plays a detrimental role in various conditions with high mortality rates1-4. SI manifests an acute hyperinflammation followed by long-lasting immunosuppression, increasing patients risks for secondary infections and impaired clinical outcomes5-7. Due to the extensive heterogeneity in SI etiology, the mechanisms governing these states are incompletely understood. Here, we characterized acute and late effects of lipopolysaccharide (LPS)-induced SI (LPS-SI8) on blood monocytes and bone marrow (BM) cells of healthy volunteers. Like clinical SI, LPS administration elicited a profound but transient acute response. Single-cell transcriptomic analysis of acute LPS-SI unveiled loss of BM monocytes and appearance of an inflammatory monocyte-like (i-Mono's) population, expressing gene programs similar to early-stage sepsis patients9. In the ensuing late phase of LPS-SI, we observed reduced expression of interferon type I (IFN-I) responsive genes in monocytes and profound attenuation of in vivo response to a second LPS challenge. Furthermore, late LPS-SI led to impaired myelopoiesis with a loss of intermediate and non-classical monocytes. In accordance, we show compromised myelopoiesis also occurs in late-stage sepsis. Finally, IFNb; treatment reversed LPS-induced immunosuppression in monocytes. Our results reveal long-lasting effects of SI on myelopoiesis and substantiate the importance of IFN-I in the pathophysiology of SI-induced immunosuppression.

/pdf/systemic-inflammation-impairs-human-myelopoiesis-and-1283eo6s.pdf

Peter Pickkers

Papers

Letter to the EditorReply to: Re: The challenge of Clostridium difficile infection: overview of clinical manifestations, diagnostic tools and therapeutic options

Fatigue during acute systemic inflammation is associated with reduced mental effort expenditure while task accuracy is preserved

Do Corticosteroids Influence the Granulocyte Macrophage Colony-Stimulating Factor-mediated Effects on Monocyte Function? Authors' reply

Systemic inflammation impairs human myelopoiesis and interferon I responses

The "Obesity-Mortality Paradox" Phenomenon in Critically Ill Patients: One Size Does Not Fit All : The authors reply