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Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. Knowledge of the pathophysiology of organ failure in sepsis is crucial for optimizing the management and treatment of patients and for the development of potential new therapies. In clinical practice, six major organ systems — the cardiovascular (including the microcirculation), respiratory, renal, neurological, haematological and hepatic systems — can be assessed and monitored, whereas others, such as the gut, are less accessible. Over the past 2 decades, considerable amounts of new data have helped improve our understanding of sepsis pathophysiology, including the regulation of inflammatory pathways and the role played by immune suppression during sepsis. The effects of impaired cellular function, including mitochondrial dysfunction and altered cell death mechanisms, on the development of organ dysfunction are also being unravelled. Insights have been gained into interactions between key organs (such as the kidneys and the gut) and organ–organ crosstalk during sepsis. The important role of the microcirculation in sepsis is increasingly apparent, and new techniques have been developed that make it possible to visualize the microcirculation at the bedside, although these techniques are only research tools at present.

C-reactive protein; PCT: procalcitonin. http://dx.doi.org/10.1371/journal.pmed.1002022.g001 However, not all these elements are always present: for example, an immunosuppressed patient may not develop fever, and a source of infection is sometimes impossible to identify. [...]while many critically ill patients have some degree of hyperthermia, this does not necessarily imply the presence of an infection [10,11]; also, some patients, particularly the elderly, may have hypothermia, and this is associated with worse outcomes [12]. [...]tachycardia and tachypnea are common in critically ill patients, and the white blood cell count, even with differential, is of little interest in the acutely ill, as changes may be due to any form of stress. [...]leukopenia can be observed in severe cases when leukocytes are activated in mass and trapped in the periphery.

Introduction Sepsis biomarkers can have important diagnostic, therapeutic, and prognostic functions. In a previous review, we identified 3370 references reporting on 178 different biomarkers related to sepsis. In the present review, we evaluate the progress in the research of sepsis biomarkers. Methods Using the same methodology as in our previous review, we searched the PubMed database from 2009 until September 2019 using the terms “Biomarker” AND “Sepsis.” There were no restrictions by age or language, and all studies, clinical and experimental, were included. Results We retrieved a total of 5367 new references since our previous review. We identified 258 biomarkers, 80 of which were new compared to our previous list. The majority of biomarkers have been evaluated in fewer than 5 studies, with 81 (31%) being assessed in just a single study. Apart from studies of C-reactive protein (CRP) or procalcitonin (PCT), only 26 biomarkers have been assessed in clinical studies with more than 300 participants. Forty biomarkers have been compared to PCT and/or CRP for their diagnostic value; 9 were shown to have a better diagnostic value for sepsis than either or both of these biomarkers. Forty-four biomarkers have been evaluated for a role in answering a specific clinical question rather than for their general diagnostic or prognostic properties in sepsis. Conclusions The number of biomarkers being identified is still increasing although at a slower rate than in the past. Most of the biomarkers have not been well-studied; in particular, the clinical role of these biomarkers needs to be better evaluated.

Circulatory shock is present when physical signs and changes in laboratory values suggest tissue hypoperfusion. This article in the Critical Care Medicine series reviews the diagnosis and treatment of various forms of shock. Shock is the clinical expression of circulatory failure that results in inadequate cellular oxygen utilization. Shock is a common condition in critical care, affecting about one third of patients in the intensive care unit (ICU). 1 A diagnosis of shock is based on clinical, hemodynamic, and biochemical signs, which can broadly be summarized into three components. First, systemic arterial hypotension is usually present, but the magnitude of the hypotension may be only moderate, especially in patients with chronic hypertension. Typically, in adults, the systolic arterial pressure is less than 90 mm Hg or the mean arterial pressure is less than 70 . . .

Background Septic shock is the most severe form of sepsis, in which profound underlying abnormalities in circulatory and cellular/metabolic parameters lead to substantially increased mortality. A clear understanding and up-to-date assessment of the burden and epidemiology of septic shock are needed to help guide resource allocation and thus ultimately improve patient care. The aim of this systematic review and meta-analysis was therefore to provide a recent evaluation of the frequency of septic shock in intensive care units (ICUs) and associated ICU and hospital mortality. Methods We searched MEDLINE, Embase, and the Cochrane Library from 1 January 2005 to 20 February 2018 for observational studies that reported on the frequency and mortality of septic shock. Four reviewers independently selected studies and extracted data. Disagreements were resolved via consensus. Random effects meta-analyses were performed to estimate pooled frequency of septic shock diagnosed at admission and during the ICU stay and to estimate septic shock mortality in the ICU, hospital, and at 28 or 30 days. Results The literature search identified 6291 records of which 71 articles met the inclusion criteria. The frequency of septic shock was estimated at 10.4% (95% CI 5.9 to 16.1%) in studies reporting values for patients diagnosed at ICU admission and at 8.3% (95% CI 6.1 to 10.7%) in studies reporting values for patients diagnosed at any time during the ICU stay. ICU mortality was 37.3% (95% CI 31.5 to 43.5%), hospital mortality 39.0% (95% CI 34.4 to 43.9%), and 28-/30-day mortality 36.7% (95% CI 32.8 to 40.8%). Significant between-study heterogeneity was observed. Conclusions Our literature review reaffirms the continued common occurrence of septic shock and estimates a high mortality of around 38%. The high level of heterogeneity observed in this review may be driven by variability in defining and applying the diagnostic criteria, as well as differences in treatment and care across settings and countries.

Introduction Intravenous fluid administration is an essential component of sepsis management, but a positive fluid balance has been associated with worse prognosis. We analyzed whether a positive fluid balance and its persistence over time was an independent prognostic factor in septic patients. Methods We prospectively studied fluid intake and output for 7 days in 173 consecutive adult patients treated for sepsis in our Department of Intensive Care. Results Of the 173 patients, 59 died (34 %). Mean daily fluid intake was higher in non-survivors than in survivors (59 ± 24 ml/kg vs. 48 ± 23 ml/kg, p = 0.03), but output volumes were similar. As a result, the daily fluid balance was more than twice as large in the non-survivors as in the survivors (29 ± 22 vs. 13 ± 19 ml/kg, p <0.001). Persistence of a positive fluid balance over time was associated with increased mortality. Using a multivariable time-dependent Cox model, a positive fluid balance was independently associated with higher mortality (adjusted hazard ratio 1.014 [1.007–1.022] per ml/kg increase, p <0.001). Conclusions Persistence of a positive daily fluid balance over time was quite strongly associated with a higher mortality rate in septic patients.

The central venous pressure (CVP) is the most frequently used variable to guide fluid resuscitation in critically ill patients, although its use has been challenged. In this viewpoint, we use a question and answer format to highlight the potential advantages and limitations of using CVP measurements to guide fluid resuscitation.

Until relatively recently, critical illness was considered as a separate entity and the intensive care unit (ICU), often a little cut-off from other areas of the hospital, was in many cases used as a last resort for patients so severely ill that it was no longer possible to care for them on the general ward. However, we are increasingly realizing that critical illness should be seen as just one part of the patient’s disease trajectory and how the patient is managed before and after ICU admission has an important role to play in optimizing outcomes. Identifying critical illness early, before it reaches a stage where it is life-threatening, is a challenge and requires a combination of improved and more frequent or continuous monitoring of at-risk patients, staff training to recognize when a patient is deteriorating, a system to “call for help,” and an effective response to that call. Critical care doctors are now widely available 24 h a day for consultation, and many hospitals have rapid response or medical emergency teams composed of staff trained in intensive care and with resuscitation skills who can attend patients on the ward who have been identified to be deteriorating, assess them to determine the need for ICU admission, and initiate further tests and/or initial therapy. Early intensivist input may also be important for patients undergoing interventions that are likely to result in ICU admission, e.g., transplantation or cardiac surgery. The patient’s continuum after ICU discharge must also be taken into account during their ICU stay, with attempts made to limit the longer-term physical and psychological consequences of critical illness as much as possible. Minimal sedation, good communication, and early mobilization are three factors that can help patients survive their ICU stay with minimal sequelae.

Background Severe traumatic injury continues to present challenges to healthcare systems around the world, and post-traumatic bleeding remains a leading cause of potentially preventable death among injured patients. Now in its fifth edition, this document aims to provide guidance on the management of major bleeding and coagulopathy following traumatic injury and encourages adaptation of the guiding principles described here to individual institutional circumstances and resources. Methods The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004, and the current author group included representatives of six relevant European professional societies. The group applied a structured, evidence-based consensus approach to address scientific queries that served as the basis for each recommendation and supporting rationale. Expert opinion and current clinical practice were also considered, particularly in areas in which randomised clinical trials have not or cannot be performed. Existing recommendations were re-examined and revised based on scientific evidence that has emerged since the previous edition and observed shifts in clinical practice. New recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated. Results Advances in our understanding of the pathophysiology of post-traumatic coagulopathy have supported improved management strategies, including evidence that early, individualised goal-directed treatment improves the outcome of severely injured patients. The overall organisation of the current guideline has been designed to reflect the clinical decision-making process along the patient pathway in an approximate temporal sequence. Recommendations are grouped behind the rationale for key decision points, which are patient- or problem-oriented rather than related to specific treatment modalities. While these recommendations provide guidance for the diagnosis and treatment of major bleeding and coagulopathy, emerging evidence supports the author group’s belief that the greatest outcome improvement can be achieved through education and the establishment of and adherence to local clinical management algorithms. Conclusions A multidisciplinary approach and adherence to evidence-based guidance are key to improving patient outcomes. If incorporated into local practice, these clinical practice guidelines have the potential to ensure a uniform standard of care across Europe and beyond and better outcomes for the severely bleeding trauma patient.

Targeted temperature management (TTM) is a complex intervention used with the aim of minimizing post-anoxic injury and improving neurological outcome after cardiac arrest. There is large variability in the devices used to achieve cooling and in protocols (e.g., for induction, target temperature, maintenance, rewarming, sedation, management of post-TTM fever). This variability can explain the limited benefits of TTM that have sometimes been reported. We therefore propose the concept of “high-quality TTM” as a way to increase the effectiveness of TTM and standardize its use in future interventional studies.