A multifaceted educational intervention improved anti-infectious measures but had no effect on mortality in patients with severe sepsis.

Sepsis is a major reason for preventable hospital deaths. A cluster-randomized controlled trial on an educational intervention did not show improvements of sepsis management or outcome. We now aimed to test an improved implementation strategy in a second intervention phase in which new intervention hospitals (former controls) received a multifaceted educational intervention, while controls (former intervention hospitals) only received feedback of quality indicators. Changes in outcomes from the first to the second intervention phase were compared between groups using hierarchical generalized linear models controlling for possible confounders. During the two phases, 19 control hospitals included 4050 patients with sepsis and 21 intervention hospitals included 2526 patients. 28-day mortality did not show significant changes between study phases in both groups. The proportion of patients receiving antimicrobial therapy within one hour increased in intervention hospitals, but not in control hospitals. Taking at least two sets of blood cultures increased significantly in both groups. During phase 2, intervention hospitals showed higher proportion of adequate initial antimicrobial therapy and de-escalation within 5 days. A survey among involved clinicians indicated lacking resources for quality improvement. Therefore, quality improvement programs should include all elements of sepsis guidelines and provide hospitals with sufficient resources for quality improvement.Trial registration: ClinicalTrials.gov, NCT01187134. Registered 23 August 2010, https://www.clinicaltrials.gov/ct2/show/study/NCT01187134 .

Adverse effects of delayed antimicrobial treatment and surgical source control in adults with sepsis: results of a planned secondary analysis of a cluster-randomized controlled trial.

BACKGROUND: Timely antimicrobial treatment and source control are strongly recommended by sepsis guidelines, however, their impact on clinical outcomes is uncertain. METHODS: We performed a planned secondary analysis of a cluster-randomized trial conducted from July 2011 to May 2015 including forty German hospitals. All adult patients with sepsis treated in the participating ICUs were included. Primary exposures were timing of antimicrobial therapy and delay of surgical source control during the first 48 h after sepsis onset. Primary endpoint was 28-day mortality. Mixed models were used to investigate the effects of timing while adjusting for confounders. The linearity of the effect was investigated by fractional polynomials and by categorizing of timing. RESULTS: Analyses were based on 4792 patients receiving antimicrobial treatment and 1595 patients undergoing surgical source control. Fractional polynomial analysis identified a linear effect of timing of antimicrobials on 28-day mortality, which increased by 0.42% per hour delay (OR with 95% CI 1.019 [1.01, 1.028], p ≤ 0.001). This effect was significant in patients with and without shock (OR = 1.018 [1.008, 1.029] and 1.026 [1.01, 1.043], respectively). Using a categorized timing variable, there were no significant differences comparing treatment within 1 h versus 1-3 h, or 1 h versus 3-6 h. Delays of more than 6 h significantly increased mortality (OR = 1.41 [1.17, 1.69]). Delay in antimicrobials also increased risk of progression from severe sepsis to septic shock (OR per hour: 1.051 [1.022, 1.081], p ≤ 0.001). Time to surgical source control was significantly associated with decreased odds of successful source control (OR = 0.982 [0.971, 0.994], p = 0.003) and increased odds of death (OR = 1.011 [1.001, 1.021]; p = 0.03) in unadjusted analysis, but not when adjusted for confounders (OR = 0.991 [0.978, 1.005] and OR = 1.008 [0.997, 1.02], respectively). Only, among patients with septic shock delay of source control was significantly related to risk-of death (adjusted OR = 1.013 [1.001, 1.026], p = 0.04). CONCLUSIONS: Our findings suggest that management of sepsis is time critical both for antimicrobial therapy and source control. Also patients, who are not yet in septic shock, profit from early anti-infective treatment since it can prevent further deterioration. Trial registration ClinicalTrials.gov ( NCT01187134 ). Registered 23 August 2010, NCT01187134.

Fever and hypothermia represent two populations of sepsis patients and are associated with outside temperature.

BACKGROUND: Fever and hypothermia have been observed in septic patients. Their influence on prognosis is subject to ongoing debates. METHODS: We did a secondary analysis of a large clinical dataset from a quality improvement trial. A binary logistic regression model was calculated to assess the association of the thermal response with outcome and a multinomial regression model to assess factors associated with fever or hypothermia. RESULTS: With 6542 analyzable cases we observed a bimodal temperature response characterized by fever or hypothermia, normothermia was rare. Hypothermia and high fever were both associated with higher lactate values. Hypothermia was associated with higher mortality, but this association was reduced after adjustment for other risk factors. Age, community-acquired sepsis, lower BMI and lower outside temperatures were associated with hypothermia while bacteremia and higher procalcitonin values were associated with high fever. CONCLUSIONS: Septic patients show either a hypothermic or a fever response. Whether hypothermia is a maladaptive response, as indicated by the higher mortality in hypothermic patients, or an adaptive response in patients with limited metabolic reserves under colder environmental conditions, remains an open question. Trial registration The original trial whose dataset was analyzed was registered at ClinicalTrials.gov (NCT01187134) on August 23, 2010, the first patient was included on July 1, 2011.

[Preoperative fluid fasting : Establishment of a liberal fluid regimen using fasting cards]. / Präoperative Flüssigkeitskarenz : Etablierung eines liberalen Flüssigkeitsregimes mittels Nüchternheitskarten.

BACKGROUND: Preoperative fasting times for clear liquids surpass by far the recommendations of the specialist societies. The aim of this study was to introduce a liberal regimen for preoperative fasting of clear liquids using fasting cards as a training tool and to evaluate the implementation. MATERIAL AND METHODS: We developed a liberalized regimen of preoperative clear fluid fasting times, which allows patients to drink water, apple juice, tea and coffee until being called to the operating theatre. Each patient receives a bed-side fasting card with written information specifying fasting times for solid food and liquids. Patients who are allowed to drink water, apple juice, tea and coffee until the call to the operating theatre receive a blue fasting card. Patients with coexisting diseases or conditions that can affect gastric emptying or who need longer fasting times because of the surgical procedure get a yellow fasting card on which fasting times for fluids and solids can be documented individually. Patients who need to be nil per os (for example patients with ileus or bowel obstruction, emergency care) receive a red fasting card. On the back of the card the information is written in English, Turkish, Russian and Arabic. After a period of 8 months all surgical ward managers were asked to complete a questionnaire to assess the implementation of the new fasting regimen. RESULTS: The response rate of the questionnaire was 100%. Without exception all interviewees would recommend the use of our liberalized fasting regimen. Almost all would also support the implementation of fasting cards. Out of 11 wards 9 found that patients were more relaxed and asked for intravenous fluids less often while waiting for surgery. The multilingual nature of the cards makes it easier to deal with patients who do not speak German. All ward managers consistently approved the new regimen in the event they themselves would need an operation. In order to make the fasting cards also usable in the future for rescue centers and functional units, such as endoscopy, echo or cardiac catheters, the reasons for fasting on the blue and yellow cards have been extended to operation or examination and on the red card to illness, operation or upcoming examination. CONCLUSION: Patients should be allowed to drink water and hypotonic clear fluids until shortly before an operation to avoid complications of overly long fasting times. Fasting cards help to implement this by providing easy to understand information for patients and healthcare workers. This concept should be clearly structured, transparent for everyone, written down and brought to the attention of the patient without a language barrier.

Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock.

Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies in vitro revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.

[Mortality in sepsis and septic shock in Germany. Results of a systematic review and meta-analysis]. / Sterblichkeit bei Sepsis und septischem Schock in Deutschland. Ergebnisse eines systematischen Reviews mit Metaanalyse.

BACKGROUND: The reported mortality for sepsis and septic shock varies between 15% and 59% in international comparison. For Germany, the number of studies is limited. Previous estimations of mortality in Germany are outdated or based on claims data analyses. Various authors discuss whether lacking quality initiatives and treatment standards in Germany could cause higher mortality for sepsis. This contrasts with the internationally well-recognized performance of the German intensive care infrastructure during the COVID-19 pandemic. OBJECTIVES: The objectives of this systematic review and meta-analysis were to estimate 30-day and 90-day mortality of patients with sepsis and patients with septic shock in Germany and to compare the mortality with that of other industrialized regions (Europe, North America). MATERIAL AND METHODS: A systematic literature search included interventional and observational studies published between 2009 and 2020 in PubMed and the Cochrane Library that analyzed adult patients with sepsis, severe sepsis and septic shock in Europe and North America. Studies with less than 20 patients were excluded. The 30-day and 90-day mortality for sepsis and septic shock were pooled separately for studies conducted in Germany, Europe (excluding Germany) and North America in a meta-analysis using a random effects model. Mortality over time was analyzed in a linear regression model. RESULTS: Overall, 134 studies were included. Of these, 15 studies were identified for the estimation of mortality in Germany, covering 10,434 patients, the number of patients per study ranged from 28 to 4183 patients. The 30-day mortality for sepsis was 26.50% (95% confidence interval, CI: 19.86-33.15%) in Germany, 23.85% (95% CI: 20.49-27.21%) in Europe (excluding Germany) and 19.58% (95% CI: 14.03-25.14%) in North America. The 30-day mortality for septic shock was 30.48% (95% CI: 29.30-31.67%) in Germany, 34.57% (95% CI: 33.51-35.64%) in Europe (excluding Germany) and 33.69% (95% CI: 31.51-35.86%) in North America. The 90-day mortality for septic shock was 38.78% (95% CI: 32.70-44.86%) in Germany, 41.90% (95% CI: 38.88-44.91%) in Europe (excluding Germany) and 34.41% (95% CI: 25.66-43.16%) in North America. A comparable decreasing trend in sepsis 30-day mortality was observed in all considered regions since 2009. CONCLUSION: Our analysis does not support the notion that mortality related to sepsis and septic shock in Germany is higher in international comparison. A higher mortality would not be obvious either, since intensive care, for example also during the COVID-19 pandemic, is regarded as exemplary in Germany and the structural quality, such as the number of intensive care beds per 100,000 inhabitants, is high in international comparison. Nevertheless, deficits could also exist outside intensive care medicine. A comparison of international individual studies should take greater account of the structure of healthcare systems, the severity of disease and the limitations resulting from the data sources used.

Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019- results from a systematic review and meta-analysis.

BACKGROUND: Sepsis and septic shock remain drivers for mortality in critically ill patients. The heterogeneity of the syndrome hinders the generation of reproducible numbers on mortality risks. Consequently, mortality rates range from 15 to 56%. We aimed to update and extend the existing knowledge from meta-analyses and estimate 30- and 90-day mortality rates for sepsis and septic shock separately, stratify rates by region and study type and assess mortality rates across different sequential organ failure assessment (SOFA) scores. METHODS: We performed a systematic review of articles published in PubMed or in the Cochrane Database, between 2009 and 2019 in English language including interventional and observational studies. A meta-analysis of pooled 28/30- and 90-day mortality rated separately for sepsis and septic shock was done using a random-effects model. Time trends were assessed via Joinpoint methodology and for the assessment of mortality rate over different SOFA scores, and linear regression was applied. RESULTS: Four thousand five hundred records were identified. After title/abstract screening, 783 articles were assessed in full text for eligibility. Of those, 170 studies were included. Average 30-day septic shock mortality was 34.7% (95% CI 32.6-36.9%), and 90-day septic shock mortality was 38.5% (95% CI 35.4-41.5%). Average 30-day sepsis mortality was 24.4% (95% CI 21.5-27.2%), and 90-day sepsis mortality was 32.2% (95% CI 27.0-37.5%). Estimated mortality rates from RCTs were below prospective and retrospective cohort studies. Rates varied between regions, with 30-day septic shock mortality being 33.7% (95% CI 31.5-35.9) in North America, 32.5% (95% CI 31.7-33.3) in Europe and 26.4% (95% CI 18.1-34.6) in Australia. A statistically significant decrease of 30-day septic shock mortality rate was found between 2009 and 2011, but not after 2011. Per 1-point increase of the average SOFA score, average mortality increased by 1.8-3.3%. CONCLUSION: Trends of lower sepsis and continuous septic shock mortality rates over time and regional disparities indicate a remaining unmet need for improving sepsis management. Further research is needed to investigate how trends in the burden of disease influence mortality rates in sepsis and septic shock at 30- and 90-day mortality over time.

Recent advances in understanding and managing sepsis.

The last two to three years provided several "big steps" regarding our understanding and management of sepsis. The increasing insight into pathomechanisms of post-infectious defense led to some new models of host response. Besides hyper-, hypo-, and anti-inflammation as the traditional approaches to sepsis pathophysiology, tolerance and resilience were described as natural ways that organisms react to microbes. In parallel, huge data analyses confirmed these research insights with a new way to define sepsis and septic shock (called "Sepsis-3"), which led to discussions within the scientific community. In addition to these advances in understanding and defining the disease, follow-up protocols of the initial "sepsis bundles" from the Surviving Sepsis Campaign were created; some of them were part of quality management studies by clinicians, and some were in the form of mandatory procedures. As a result, new "bundles" were initiated with the goal of enabling standardized management of sepsis and septic shock, especially in the very early phase. This short commentary provides a brief overview of these two major fields as recent hallmarks of sepsis research.

Effect of a combined brief narrative exposure therapy with case management versus treatment as usual in primary care for patients with traumatic stress sequelae following intensive care medicine: study protocol for a multicenter randomized controlled trial (PICTURE).

BACKGROUND: Traumatic events like critical illness and intensive care are threats to life and bodily integrity and pose a risk factor for posttraumatic stress disorder (PTSD). PTSD affects the quality of life and morbidity and may increase health-care costs. Limited access to specialist care results in PTSD patients being treated in primary care settings. Narrative exposure therapy (NET) is based on the principles of cognitive behavioral therapy and has shown positive effects when delivered by health-care professionals other than psychologists. The primary aims of the PICTURE trial (from "PTSD after ICU survival") are to investigate the effectiveness and applicability of NET adapted for primary care with case management in adults diagnosed with PTSD after intensive care. METHODS/DESIGN: This is an investigator-initiated, multi-center, primary care-based, randomized controlled two-arm parallel group, observer-blinded superiority trial conducted throughout Germany. In total, 340 adult patients with a total score of at least 20 points on the posttraumatic diagnostic scale (PDS-5) 3 months after receiving intensive care treatment will be equally randomized to two groups: NET combined with case management and improved treatment as usual (iTAU). All primary care physicians (PCPs) involved will be instructed in the diagnosis and treatment of PTSD according to current German guidelines. PCPs in the iTAU group will deliver usual care during three consultations. In the experimental group, PCPs will additionally be trained to deliver an adapted version of NET (three sessions) supported by phone-based case management by a medical assistant. At 6 and 12 months after randomization, structured blinded telephone interviews will assess patient-reported outcomes. The primary composite endpoint is the absolute change from baseline at month 6 in PTSD symptom severity measured by the PDS-5 total score, which also incorporates the death of any study patients. Secondary outcomes cover the domains depression, anxiety, disability, health-related quality-of-life, and cost-effectiveness. The principal analysis is by intention to treat. DISCUSSION: If the superiority of the experimental intervention over usual care can be demonstrated, the combination of brief NET and case management could be a treatment option to relieve PTSD-related symptoms and to improve primary care after intensive care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03315390 . Registered on 10 October 2017. German Clinical Trials Register, DRKS00012589 . Registered on 17 October 2017.

Effect of a multifaceted educational intervention for anti-infectious measures on sepsis mortality: a cluster randomized trial.

PURPOSE: Guidelines recommend administering antibiotics within 1 h of sepsis recognition but this recommendation remains untested by randomized trials. This trial was set up to investigate whether survival is improved by reducing the time before initiation of antimicrobial therapy by means of a multifaceted intervention in compliance with guideline recommendations. METHODS: The MEDUSA study, a prospective multicenter cluster-randomized trial, was conducted from July 2011 to July 2013 in 40 German hospitals. Hospitals were randomly allocated to receive conventional continuous medical education (CME) measures (control group) or multifaceted interventions including local quality improvement teams, educational outreach, audit, feedback, and reminders. We included 4183 patients with severe sepsis or septic shock in an intention-to-treat analysis comparing the multifaceted intervention (n = 2596) with conventional CME (n = 1587). The primary outcome was 28-day mortality. RESULTS: The 28-day mortality was 35.1% (883 of 2596 patients) in the intervention group and 26.7% (403 of 1587 patients; p = 0.01) in the control group. The intervention was not a risk factor for mortality, since this difference was present from the beginning of the study and remained unaffected by the intervention. Median time to antimicrobial therapy was 1.5 h (interquartile range 0.1-4.9 h) in the intervention group and 2.0 h (0.4-5.9 h; p = 0.41) in the control group. The risk of death increased by 2% per hour delay of antimicrobial therapy and 1% per hour delay of source control, independent of group assignment. CONCLUSIONS: Delay in antimicrobial therapy and source control was associated with increased mortality but the multifaceted approach was unable to change time to antimicrobial therapy in this setting and did not affect survival.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with 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 these critically ill patients with high mortality.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with 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 these critically ill patients with high mortality.

Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial.

Importance: Adjunctive hydrocortisone therapy is suggested by the Surviving Sepsis Campaign in refractory septic shock only. The efficacy of hydrocortisone in patients with severe sepsis without shock remains controversial. Objective: To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted from January 13, 2009, to August 27, 2013, with a follow-up of 180 days until February 23, 2014. The trial was performed in 34 intermediate or intensive care units of university and community hospitals in Germany, and it included 380 adult patients with severe sepsis who were not in septic shock. Interventions: Patients were randomly allocated 1:1 either to receive a continuous infusion of 200 mg of hydrocortisone for 5 days followed by dose tapering until day 11 (n = 190) or to receive placebo (n = 190). Main Outcomes and Measures: The primary outcome was development of septic shock within 14 days. Secondary outcomes were time until septic shock, mortality in the intensive care unit or hospital, survival up to 180 days, and assessment of secondary infections, weaning failure, muscle weakness, and hyperglycemia (blood glucose level >150 mg/dL [to convert to millimoles per liter, multiply by 0.0555]). Results: The intention-to-treat population consisted of 353 patients (64.9% male; mean [SD] age, 65.0 [14.4] years). Septic shock occurred in 36 of 170 patients (21.2%) in the hydrocortisone group and 39 of 170 patients (22.9%) in the placebo group (difference, -1.8%; 95% CI, -10.7% to 7.2%; P = .70). No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days (15 of 171 patients [8.8%] vs 14 of 170 patients [8.2%], respectively; difference, 0.5%; 95% CI, -5.6% to 6.7%; P = .86), 90 days (34 of 171 patients [19.9%] vs 28 of 168 patients [16.7%]; difference, 3.2%; 95% CI, -5.1% to 11.4%; P = .44), and 180 days (45 of 168 patients [26.8%] vs 37 of 167 patients [22.2%], respectively; difference, 4.6%; 95% CI, -4.6% to 13.7%; P = .32). In the hydrocortisone vs placebo groups, 21.5% vs 16.9% had secondary infections, 8.6% vs 8.5% had weaning failure, 30.7% vs 23.8% had muscle weakness, and 90.9% vs 81.5% had hyperglycemia. Conclusions and Relevance: Among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days. These findings do not support the use of hydrocortisone in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT00670254.

Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock: A Randomized Clinical Trial.

IMPORTANCE: High-dose intravenous administration of sodium selenite has been proposed to improve outcome in sepsis by attenuating oxidative stress. Procalcitonin-guided antimicrobial therapy may hasten the diagnosis of sepsis, but effect on outcome is unclear. OBJECTIVE: To determine whether high-dose intravenous sodium selenite treatment and procalcitonin-guided anti-infectious therapy in patients with severe sepsis affect mortality. DESIGN, SETTING, AND PARTICIPANTS: The Placebo-Controlled Trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT), a multicenter, randomized, clinical, 2 × 2 factorial trial performed in 33 intensive care units in Germany, was conducted from November 6, 2009, to June 6, 2013, including a 90-day follow-up period. INTERVENTIONS: Patients were randomly assigned to receive an initial intravenous loading dose of sodium selenite, 1000 µg, followed by a continuous intravenous infusion of sodium selenite, 1000 µg, daily until discharge from the intensive care unit, but not longer than 21 days, or placebo. Patients also were randomized to receive anti-infectious therapy guided by a procalcitonin algorithm or without procalcitonin guidance. MAIN OUTCOMES AND MEASURES: The primary end point was 28-day mortality. Secondary outcomes included 90-day all-cause mortality, intervention-free days, antimicrobial costs, antimicrobial-free days, and secondary infections. RESULTS: Of 8174 eligible patients, 1089 patients (13.3%) with severe sepsis or septic shock were included in an intention-to-treat analysis comparing sodium selenite (543 patients [49.9%]) with placebo (546 [50.1%]) and procalcitonin guidance (552 [50.7%]) vs no procalcitonin guidance (537 [49.3%]). The 28-day mortality rate was 28.3% (95% CI, 24.5%-32.3%) in the sodium selenite group and 25.5% (95% CI, 21.8%-29.4%) (P = .30) in the placebo group. There was no significant difference in 28-day mortality between patients assigned to procalcitonin guidance (25.6% [95% CI, 22.0%-29.5%]) vs no procalcitonin guidance (28.2% [95% CI, 24.4%-32.2%]) (P = .34). Procalcitonin guidance did not affect frequency of diagnostic or therapeutic procedures but did result in a 4.5% reduction of antimicrobial exposure. CONCLUSIONS AND RELEVANCE: Neither high-dose intravenous administration of sodium selenite nor anti-infectious therapy guided by a procalcitonin algorithm was associated with an improved outcome in patients with severe sepsis. These findings do not support administration of high-dose sodium selenite in these patients; the application of a procalcitonin-guided algorithm needs further evaluation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00832039.

Agents to reduce cytokine storm.

The increasing insight into pathomechanisms of dysregulated host response in several inflammatory diseases led to the implementation of the term "cytokine storm" in the literature more than 20 years ago. Direct toxic effects as well as indirect immunomodulatory mechanisms during cytokine storm have been described and were the basis for the rationale to use several substances and devices in life-threatening infections and hyperinflammatory states. Clinical trials have been performed, most of them in the form of minor, investigator-initiated protocols; major clinical trials focused mostly on sepsis and septic shock. The following review tries to summarize the background, pathophysiology, and results of clinical investigations that had implications for the development of therapeutic strategies and international guidelines for the management of hyperinflammation during syndromes of cytokine storm in adult patients, predominantly in septic shock.

Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis.

OBJECTIVE: Treatment with inhaled nitric oxide improves oxygenation but not survival in mechanically ventilated patients with acute respiratory distress syndrome, but the effect may depend on the severity of hypoxemia. Our objective was to determine whether nitric oxide reduces hospital mortality in patients with severe acute respiratory distress syndrome (PaO2/FIO2 ≤ 100 mm Hg) but not in patients with mild-moderate acute respiratory distress syndrome (100 < PaO2/FIO2 ≤ 300 mm Hg) at the time of randomization. DATA SOURCES: Data were collected from Medline, Embase, and Cochrane CENTRAL electronic databases (inception to May 2013); proceedings from five conferences (to May 2013); and trial registries (http://www.clinicaltrials.gov and http://www.controlled-trials.com). No language restrictions were applied. STUDY SELECTION: Two authors independently selected parallel-group randomized controlled trials comparing nitric oxide with control (placebo or no gas) in mechanically ventilated adults or postneonatal children with acute respiratory distress syndrome. DATA EXTRACTION: Two authors independently extracted data from included trials. Trial investigators provided subgroup data. Meta-analyses used within-trial subgroups and random-effects models. DATA SYNTHESIS: Nine trials (n = 1,142 patients) met inclusion criteria. Overall methodological quality was good. Nitric oxide did not reduce mortality in patients with severe acute respiratory distress syndrome (risk ratio, 1.01 [95% CI, 0.78-1.32]; p = 0.93; n = 329, six trials) or mild-moderate acute respiratory distress syndrome (risk ratio, 1.12 [95% CI, 0.89-1.42]; p = 0.33; n = 740, seven trials). Risk ratios were similar between subgroups (interaction p = 0.53). There was no between-trial heterogeneity in any analysis (I = 0%). Varying the PaO2/FIO2 threshold between 70 and 200 mm Hg, in increments of 10 mm Hg, did not identify any threshold at which the nitric oxide-treated patients had lower mortality relative to controls. CONCLUSIONS: Nitric oxide does not reduce mortality in adults or children with acute respiratory distress syndrome, regardless of the degree of hypoxemia. Given the lack of related ongoing or recently completed randomized trials, new data addressing the effectiveness of nitric oxide in patients with acute respiratory distress syndrome and severe hypoxemia will not be available for the foreseeable future.