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)

Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Context Infection is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. However, relatively little information is available about the global epidemiology of such infections. Objective To provide an up-to-date, international picture of the extent and patterns of infection in ICUs. Design, Setting, and Patients The Extended Prevalence of Infection in Intensive Care (EPIC II) study, a 1-day, prospective, point prevalence study with follow-up conducted on May 8, 2007. Demographic, physiological, bacteriological, therapeutic, and outcome data were collected for 14 414 patients in 1265 participating ICUs from 75 countries on the study day. Analyses focused on the data from the 13 796 adult (>18 years) patients. Results On the day of the study, 7087 of 13 796 patients (51%) were considered infected; 9084 (71%) were receiving antibiotics. The infection was of respiratory origin in 4503 (64%), and microbiological culture results were positive in 4947 (70%) of the infected patients; 62% of the positive isolates were gram-negative organisms, 47% were gram-positive, and 19% were fungi. Patients who had longer ICU stays prior to the study day had higher rates of infection, especially infections due to resistant staphylococci, Acinetobacter, Pseudomonas species, and Candida species. The ICU mortality rate of infected patients was more than twice that of noninfected patients (25% [1688/6659] vs 11% [ 682/6352], respectively; P  Conclusions Infections are common in patients in contemporary ICUs, and risk of infection increases with duration of ICU stay. In this large cohort, infection was independently associated with an increased risk of hospital death.

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International Study of the Prevalence and Outcomes of Infection in Intensive Care Units

Objective:To better define the incidence of sepsis and the characteristics of critically ill patients in European intensive care units.Design:Cohort, multiple-center, observational study.Setting:One hundred and ninety-eight intensive care units in 24 European countries.Patients:All new adult admissi

Sepsis in European intensive care units: results of the SOAP study.

Objective: The aim was to formulate clinical practice guidelines for pheochromocytoma and paraganglioma (PPGL). Participants: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), seven experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, European Society of Endocrinology, and Americal Association for Clinical Chemistry reviewed drafts of the guidelines. Conclusions: The Task Force recommends that initial biochemical testing for PPGLs shou...

/pdf/pheochromocytoma-and-paraganglioma-an-endocrine-society-4ij7m1t7fo.pdf

Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline

Van Beest et al. [1] performed a post hoc analysis of 53 patients with severe sepsis or septic shock to investigate the interchangeability of mixed and central venous-to-arterial carbon dioxide (CO2) differences (mvaCO2gap and cvaCO2gap, respectively) and the relation between the cvaCO2gap (“pCO2gap” or the “gap”), cardiac index (CI), and outcome. The authors observed a strong agreement between pCO2 measured from either mixed venous or central venous sites with relatively small limits of agreement. The authors claim that combining ScvO2 values, as easily obtained from a central venous catheter, as a surrogate for global tissue hypoxia, and pCO2gap as a surrogate for CI, obtained from the same central venous catheter, may be useful in assessing cardiovascular state during resuscitation in critically ill patients. We cannot agree more and propose thereafter a tentative “ScvO2-cvaCO2gap-guided protocol” (Fig. 1). Cuschieri et al. [2] previously demonstrated in a mixed population of critically ill patients that the relationships between the mvaCO2gap or the cvaCO2gap and the CI were equivalent. Since central venous blood is readily available from a central venous catheter, whereas mixed venous blood requires a pulmonary artery catheter, the cvaCO2gap, as an easily available clinical monitoring tool, is attractive. At ICU admission, 24 patients in the van Beest et al. study had a pCO2gap greater than 0.8 kPa (or 6 mmHg). Persistence of such a large pCO2gap after 24 h of treatment was predictive of higher mortality.



Fig. 1

The ScvO2-cvaCO2gap-guided protocol. ScvO 2 venous central O2 saturation, cvCO 2 gap central venous-to-arterial pCO2 difference, SaO 2 arterial O2 saturation, CI cardiac index, SVV stroke volume variability, PPV pulse pressure variability



These data are in line with results of Vallee et al. [3] who prospectively tested this hypothesis in 56 septic shock patients resuscitated to an ScvO2 greater than 70 % (according to the Rivers’ study results [4]). They found that patients who still had altered tissue perfusion (assessed by serum lactate levels greater than 2 mmol L−1) in spite of a normalized ScvO2 displayed a large cvaCO2gap (greater than 6 mmHg). CO2 is the end product of aerobic metabolism and its concentration in the venous blood reflects the global tissue blood flow relative to metabolic demand. Since CO2 is about 20 times more soluble than O2 the likelihood of it diffusing out of ischemic tissues and into the venous effluent is great, making it a very sensitive marker of hypoperfusion. Thus, in situations where an O2 diffusion barrier exists (resulting from non-functional and obliterated capillaries), “masking” poor O2 extraction (O2ER) and increased tissue O2 debt, CO2 still diffuses to the venous effluent, “unmasking” the low perfusion state for the clinician when venous-to-arterial CO2 difference is evaluated. Consistently Vallee et al. [3] evidenced that patients with high cvaCO2gap values had lower lactate clearance and CI values, and presented a significant lower decrease in Sepsis-related Organ Failure Assessment score than patients with a low cvaCO2gap. Thus, the cvaCO2gap represents a useful complementary tool to identify patients who remain inadequately resuscitated when the 70 % ScvO2 threshold value has been reached.

The obvious limitation of ScvO2 is therefore that normal/high values cannot discriminate whether delivery is adequate or in excess to demand. High ScvO2 profiles have even been shown to be related to elevated blood lactate concentration and poor survival rates [5]. Although ScvO2 may thus not miss any global oxygen delivery (DO2) disorder, it may remain “blind” to local perfusion disorders, which abound in sepsis because of impaired microcirculation. Under conditions where O2 uptake (VO2) does not meet O2 demand, tissue dysoxia occurs, leading to organ failure and death. The crucial point here is that these tissues might remain however accessible to conventional therapeutic hemodynamic management (inotropes and fluid infusion).

Whether the resultant effect on pCO2 gap depends in principle on the flow state or anaerobic CO2 production was tested by Vallet et al. [6] in an experimental model of isolated limb in which ischemic hypoxia (IH) and hypoxic hypoxia (HH) were compared. The authors demonstrated that when DO2 was reduced beyond its critical threshold in IH (dysoxia), this was associated with an increased limb venous-to-arterial pCO2gap [6]. Conversely, in HH, pCO2gap did not increase in spite of a marked VO2 and VCO2 reduction, clearly evidencing the gap as a marker of adequacy of venous blood flow to remove CO2 produced rather than a marker of tissue hypoxia or dysoxia.

In conclusion, determining the gap during resuscitation of critically ill patients is useful when deciding when to stop resuscitation despite persistent evidence of organ ischemia and an ScvO2 of greater than 70 % (see Fig. 1, Table 1). All forms of circulatory stress are potentially associated with hyperlactatemia, but hyperlactatemia is not a discriminatory factor in defining the cause of that stress. A goal of a gap lower than 6 could be a useful complementary tool to evaluate the adequacy of blood flow to global metabolic demand. In this regard it can help to titrate inotropes in order to adapt DO2 to VCO2, or to choose between hemoglobin correction or fluid/inotrope infusion. Whatever way you use it or like it, from mixed or central venous, in patients with septic shock, please “mind the gap”!



Table 1

Lactate-ScvO2-cvaCO2gap as shock diagnostic tools

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Resuscitation of patients with septic shock: please “mind the gap”!

The usefulness of parameters measured using the pulmonary artery catheter has been challenged because no benefit in patient outcome has been observed in clinical trials. However, technological advances have been made, including continuous measurement of cardiac output (CO), mixed venous saturation (SvO2), and right ventricle end-diastolic volume (CEDV) have been made. Pulmonary artery occlusion pressure (PAOP), CEDV and right atrial pressure (RAP) are not good predictors of fluid load responsiveness except when very low. Despite this methodological limitation, variation of these parameters during fluid loading remains a good indicator of fluid challenge tolerance. Accuracy of continuous thermodilution and SvO2 measurement has been demonstrated in vitro and at bedside. A decrease in SvO2 is a global index of an inadequate oxygen delivery (DO2)/oxygen requirement relationship. In this setting, a therapeutic decision to improve determinants of SvO2 should be considered with the help of all other PAC parameters. Technological improvement transforms PAC in a real time integrated physiological device and allows one to observe the impact of therapeutic intervention. What we need now is a clinical trial with a PAC-guided treatment algorithm taking into account the above integrated PAC parameters.

/pdf/clinical-relevance-of-data-from-the-pulmonary-artery-j3l2ng8stq.pdf

Clinical relevance of data from the pulmonary artery catheter.

Physiologic transfusion triggers.

ObjectiveTo investigate the effects of AZ-1, a murine monoclonal antiglycoprotein-IIb/IIIa antibody, on endothelium and on hemostasis in a rabbit endotoxic shock model.DesignProspective laboratory study.SettingUniversity laboratory.SubjectsThirty-five male New-Zealand rabbits.InterventionsIn vitro v

Beneficial effect of glycoprotein IIb/IIIa inhibitor (AZ-1) on endothelium in Escherichia coli endotoxin-induced shock.

Adequate volume expansion (VE) in patients with evidence of hypoperfusion should be aimed not only at achieving an increase in stroke volume (SV) and cardiac index (CI) but also at improved tissue perfusion and oxygenation. Our aim in this study was to assess the dynamic changes in muscle tissue oxygen saturation (StO2) during hypovolaemia and in response to VE. We conducted a prospective study of 42 fluid challenges in patients undergoing major abdominal surgery with evidence of hypovolaemia, defined as pulse pressure variation (PPV) >13% and SV variation (SVV) >12%. CI, SV, SVV (FloTrac/Vigileo) and PPV were measured before and after VE. Fluid responsiveness was defined as an increase of SV >15% after a 500-mL colloid infusion over 15 minutes. In all patients, the muscle StO2 and its changes during a standardised vascular occlusion test were analysed using a near-infrared spectroscopy device after anaesthesia induction (which defined the baseline state) and before and after each VE. No patients were preload-responsive after anaesthesia induction. Twenty-nine of forty-two fluid challenges (69%) were positive for VE, with a statistically significant (P < 0.001) difference in SV changes between positive and negative responses to VE. There was a statistically significant difference in PPV and SVV values before VE in the positive and negative fluid responses [PPV: 16% (15% to 18%) vs. 14% (13% to 15%), P = 0.001; and SVV: 14% (13% to 16%) vs. 16% (15% to 16%), P = 0.03 or positive and negative fluid responses, respectively]. Data are presented as medians and 25th and 75th percentiles Before VE there was no significant difference in StO2 values relative to baseline [86% (78% to 88%) vs. 84% (77% to 91%), P = 0.83], without a significant difference (P = 0.36) between positive and negative fluid challenges. Hypovolaemia was associated with a significant reduction (P = 0.004) in StO2 recovery slope, with a significant difference (P = 0.02) between positive and negative fluid challenges. The VE-induced increase in the StO2 recovery slope was 62 ± 49% (P < 0.001) for positive fluid challenges and 26 ± 34% (P = 0.04) for negative fluid challenges. Hypovolaemia significantly affects the muscle StO2 recovery slope. Restoring effective intravascular volume with fluid loading significantly improves the StO2 recovery slope, despite apparently ineffective changes in systemic haemodynamics.

/pdf/use-of-near-infrared-spectroscopy-during-a-vascular-42sjm3vha0.pdf

Benoit Vallet

Papers

Resuscitation of patients with septic shock: please “mind the gap”!

Clinical relevance of data from the pulmonary artery catheter.

Physiologic transfusion triggers.

Beneficial effect of glycoprotein IIb/IIIa inhibitor (AZ-1) on endothelium in Escherichia coli endotoxin-induced shock.

Use of near-infrared spectroscopy during a vascular occlusion test to assess the microcirculatory response during fluid challenge.