Time to treatment and mortality for clinical sepsis subtypes.

BACKGROUND: Sepsis is common, deadly, and heterogenous. Prior analyses of patients with sepsis and septic shock in New York State showed a risk-adjusted association between more rapid antibiotic administration and bundled care completion, but not an intravenous fluid bolus, with reduced in-hospital mortality. However, it is unknown if clinically identifiable sepsis subtypes modify these associations. METHODS: Secondary analysis of patients with sepsis and septic shock enrolled in the New York State Department of Health cohort from January 1, 2015 to December 31, 2016. Patients were classified as clinical sepsis subtypes (α, ß, γ, δ-types) using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Exposure variables included time to 3-h sepsis bundle completion, antibiotic administration, and intravenous fluid bolus completion. Then logistic regression models evaluated the interaction between exposures, clinical sepsis subtypes, and in-hospital mortality. RESULTS: 55,169 hospitalizations from 155 hospitals were included (34% α, 30% ß, 19% γ, 17% δ). The α-subtype had the lowest (N = 1,905, 10%) and δ-subtype had the highest (N = 3,776, 41%) in-hospital mortality. Each hour to completion of the 3-h bundle (aOR, 1.04 [95%CI, 1.02-1.05]) and antibiotic initiation (aOR, 1.03 [95%CI, 1.02-1.04]) was associated with increased risk-adjusted in-hospital mortality. The association differed across subtypes (p-interactions < 0.05). For example, the outcome association for the time to completion of the 3-h bundle was greater in the δ-subtype (aOR, 1.07 [95%CI, 1.05-1.10]) compared to α-subtype (aOR, 1.02 [95%CI, 0.99-1.04]). Time to intravenous fluid bolus completion was not associated with risk-adjusted in-hospital mortality (aOR, 0.99 [95%CI, 0.97-1.01]) and did not differ among subtypes (p-interaction = 0.41). CONCLUSION: Timely completion of a 3-h sepsis bundle and antibiotic initiation was associated with reduced risk-adjusted in-hospital mortality, an association modified by clinically identifiable sepsis subtype.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

Respiratory Variation in Carotid Artery Peak Systolic Velocity Is Unable to Predict Fluid Responsiveness in Spontaneously Breathing Critically Ill Patients When Assessed by Novice Physician Sonologists.

BACKGROUND: Respiratory variation in carotid artery peak systolic velocity (ΔVpeak) assessed by point-of-care ultrasound (POCUS) has been proposed as a noninvasive means to predict fluid responsiveness. We aimed to evaluate the ability of carotid ΔVpeak as assessed by novice physician sonologists to predict fluid responsiveness. METHODS: This study was conducted in 2 intensive care units. Spontaneously breathing, nonintubated patients with signs of volume depletion were included. Patients with atrial fibrillation/flutter, cardiogenic, obstructive or neurogenic shock, or those for whom further intravenous (IV) fluid administration would be harmful were excluded. Three novice physician sonologists were trained in POCUS assessment of carotid ΔVpeak. They assessed the carotid ΔVpeak in study participants prior to the administration of a 500 mL IV fluid bolus. Fluid responsiveness was defined as a ≥10% increase in cardiac index as measured using bioreactance. RESULTS: Eighty-six participants were enrolled, 50 (58.1%) were fluid responders. Carotid ΔVpeak performed poorly at predicting fluid responsiveness. Test characteristics for the optimum carotid ΔVpeak of 8.0% were: area under the receiver operating curve = 0.61 (95% CI: 0.48-0.73), sensitivity = 72.0% (95% CI: 58.3-82.56), specificity = 50.0% (95% CI: 34.5-65.5). CONCLUSIONS: Novice physician sonologists using POCUS are unable to predict fluid responsiveness using carotid ΔVpeak. Until further research identifies key limiting factors, clinicians should use caution directing IV fluid resuscitation using carotid ΔVpeak.

Development of a Deep Learning Network to Classify Inferior Vena Cava Collapse to Predict Fluid Responsiveness.

OBJECTIVES: To create a deep learning algorithm capable of video classification, using a long short-term memory (LSTM) network, to analyze collapsibility of the inferior vena cava (IVC) to predict fluid responsiveness in critically ill patients. METHODS: We used a data set of IVC ultrasound (US) videos to train the LSTM network. The data set was created from IVC US videos of spontaneously breathing critically ill patients undergoing intravenous fluid resuscitation as part of 2 prior prospective studies. We randomly selected 90% of the IVC videos to train the LSTM network and 10% of the videos to test the LSTM network's ability to predict fluid responsiveness. Fluid responsiveness was defined as a greater than 10% increase in the cardiac index after a 500-mL fluid bolus, as measured by bioreactance. RESULTS: We analyzed 211 videos from 175 critically ill patients: 191 to train the LSTM network and 20 to test it. Using standard data augmentation techniques, we increased our sample size from 191 to 3820 videos. Of the 175 patients, 91 (52%) were fluid responders. The LSTM network was able to predict fluid responsiveness moderately well, with an area under the receiver operating characteristic curve of 0.70 (95% confidence interval [CI], 0.43-1.00), a positive likelihood ratio of infinity, and a negative likelihood ratio of 0.3 (95% CI, 0.12-0.77). In comparison, point-of-care US experts using video review offline and manual diameter measurement via software caliper tools achieved an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.83-0.99). CONCLUSIONS: We demonstrated that an LSTM network can be trained by using videos of IVC US to classify IVC collapse to predict fluid responsiveness. Our LSTM network performed moderately well given the small training cohort but worse than point-of-care US experts. Further training and testing of the LSTM network with a larger data sets is warranted.

Time to Treatment and Mortality during Mandated Emergency Care for Sepsis.

BACKGROUND: In 2013, New York began requiring hospitals to follow protocols for the early identification and treatment of sepsis. However, there is controversy about whether more rapid treatment of sepsis improves outcomes in patients. METHODS: We studied data from patients with sepsis and septic shock that were reported to the New York State Department of Health from April 1, 2014, to June 30, 2016. Patients had a sepsis protocol initiated within 6 hours after arrival in the emergency department and had all items in a 3-hour bundle of care for patients with sepsis (i.e., blood cultures, broad-spectrum antibiotic agents, and lactate measurement) completed within 12 hours. Multilevel models were used to assess the associations between the time until completion of the 3-hour bundle and risk-adjusted mortality. We also examined the times to the administration of antibiotics and to the completion of an initial bolus of intravenous fluid. RESULTS: Among 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3-hour bundle completed within 3 hours. The median time to completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P<0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P<0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P=0.21). CONCLUSIONS: More rapid completion of a 3-hour bundle of sepsis care and rapid administration of antibiotics, but not rapid completion of an initial bolus of intravenous fluids, were associated with lower risk-adjusted in-hospital mortality. (Funded by the National Institutes of Health and others.).

Effect of Best Practice Advisories on Sedation Protocol Compliance and Drug-Related Hazardous Condition Mitigation Among Critical Care Patients.

OBJECTIVES: To determine whether best practice advisories improved sedation protocol compliance and could mitigate potential propofol-related hazardous conditions. DESIGN: Retrospective observational cohort study. SETTING: Two adult ICUs at two academic medical centers that share the same sedation protocol. PATIENTS: Adults 18 years old or older admitted to the ICU between January 1, 2016, and January 31, 2018, who received a continuous infusion of propofol. INTERVENTIONS: Two concurrent best practice advisories built in the electronic health record as a clinical decision support tool to enforce protocol compliance with triglyceride and lipase level monitoring and mitigate propofol-related hazardous conditions. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were baseline and day 3 compliance with triglyceride and lipase laboratory monitoring per protocol and time to discontinuation of propofol in the setting of triglyceride and/or lipase levels exceeding protocol cutoffs. A total of 1,394 patients were included in the study cohort (n = 700 in the pre-best practice advisory group; n = 694 in the post-best practice advisory group). In inverse probability weighted regression analyses, implementing the best practice advisory was associated with a 56.6% (95% CI, 52.6-60.9) absolute increase and a 173% relative increase (risk ratio, 2.73; 95% CI, 2.45-3.04) in baseline laboratory monitoring. The best practice advisory was associated with a 34.0% (95% CI, 20.9-47.1) absolute increase and a 74% (95% CI, 1.39-2.19) relative increase in day 3 laboratory monitoring after inverse probability weighted analyses. Among patients with laboratory values exceeding protocol cutoffs, implementation of the best practice advisory resulted in providers discontinuing propofol an average of 16.6 hours (95% CI, 4.8-28.3) sooner than pre-best practice advisory. Findings from alternate analyses using interrupted time series were consistent with the inverse probability weighted analyses. CONCLUSIONS: Best practice advisories can be effectively used in ICUs to improve sedation protocol compliance and may mitigate potential propofol-related hazardous conditions. Best practice advisories should undergo continuous quality assurance and optimizations to maximize clinical utility and minimize alert fatigue.

Delay in Antibiotic Administration Is Associated With Mortality Among Septic Shock Patients With Staphylococcus aureus Bacteremia.

OBJECTIVES: The relationship between the timing of antibiotics and mortality among septic shock patients has not been examined among patients specifically with Staphylococcus aureus bacteremia. DESIGN: Retrospective analysis of a Veterans Affairs S. aureus bacteremia database. SETTING: One-hundred twenty-two hospitals in the Veterans Affairs Health System. PATIENTS: Patients with septic shock and S. aureus bacteremia admitted directly from the emergency department to the ICU from January 1, 2003, to October 1, 2015, were evaluated. INTERVENTIONS: Time to appropriate antibiotic administration and 30-day mortality. MEASUREMENTS AND MAIN RESULTS: A total of 506 patients with S. aureus bacteremia and septic shock were included in the analysis. Thirty-day mortality was 78.1% for the entire cohort and was similar for those participants with methicillin-resistant S. aureus and methicillin-sensitive S. aureus bacteremia. Our multivariate analysis revealed that, as compared with those who received appropriate antibiotics within 1 hour after emergency department presentation, each additional hour that passed before appropriate antibiotics were administered produced an odds ratio of 1.11 (95% CI, 1.02-1.21) of mortality within 30 days. This odds increase equates to an average adjusted mortality increase of 1.3% (95% CI, 0.4-2.2%) for every hour that passes before antibiotics are administered. CONCLUSIONS: The results of this study further support the importance of prompt appropriate antibiotic administration for patients with septic shock. Physicians should consider acting quickly to administer antibiotics with S. aureus coverage to any patient suspected of having septic shock.

Family Care Rituals in the ICU to Reduce Symptoms of Post-Traumatic Stress Disorder in Family Members-A Multicenter, Multinational, Before-and-After Intervention Trial.

OBJECTIVES: To assess the feasibility and efficacy of implementing "Family Care Rituals" as a means of engaging family members in the care of patients admitted to the ICU with a high risk of ICU mortality on outcomes including stress-related symptoms in family members. DESIGN: Prospective, before-and-after intervention evaluation. SETTING: Two U.S. academic medical ICU's, and one Italian academic medical/surgical ICU. SUBJECTS: Family members of patients who had an attending predicted ICU mortality of greater than 30% within the first 24 hours of admission. INTERVENTIONS: A novel intervention titled "Family Care Rituals" during which, following a baseline observation period, family members enrolled in the intervention phase were given an informational booklet outlining opportunities for engagement in care of the patient during their ICU stay. MEASUREMENTS AND MAIN RESULTS: Primary outcome was symptoms of post-traumatic stress disorder in family members 90 days after patient death or ICU discharge. Secondary outcomes included symptoms of depression, anxiety, and family satisfaction. At 90-day follow-up, 131 of 226 family members (58.0%) responded preintervention and 129 of 226 family members (57.1%) responded postintervention. Symptoms of post-traumatic stress disorder were significantly higher preintervention than postintervention (39.2% vs 27.1%; unadjusted odds ratio, 0.58; p = 0.046). There was no significant difference in symptoms of depression (26.5% vs 25.2%; unadjusted odds ratio, 0.93; p = 0.818), anxiety (41.0% vs 45.5%; unadjusted odds ratio, 1.20; p = 0.234), or mean satisfaction scores (85.1 vs 89.0; unadjusted odds ratio, 3.85; p = 0.052) preintervention versus postintervention 90 days after patient death or ICU discharge. CONCLUSIONS: Offering opportunities such as family care rituals for family members to be involved with providing care for family members in the ICU was associated with reduced symptoms of post-traumatic stress disorder. This intervention may lessen the burden of stress-related symptoms in family members of ICU patients.

Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19).

BACKGROUND: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed. METHODS: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations. RESULTS: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy. CONCLUSION: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.

Performance of a 25% Inferior Vena Cava Collapsibility in Detecting Fluid Responsiveness When Assessed by Novice Versus Expert Physician Sonologists.

OBJECTIVES: Inferior vena cava collapsibility (cIVC) measured by point-of-care ultrasound (POCUS) has been proposed as a noninvasive means of assessing fluid responsiveness. We aimed to prospectively evaluate the performance of a 25% cIVC cutoff value to detect fluid responsiveness among spontaneously breathing intensive care unit (ICU) patients when assessed with POCUS by novice versus expert physician sonologists. METHODS: Prospective observational study of spontaneously breathing ICU patients. Fluid responsiveness was defined as a >10% increase in cardiac index following a 500 mL fluid bolus, measured by bioreactance. Novice sonologist measured cIVC with POCUS. Their measurements were later compared to an expert physician sonologist who independently reviewed the POCUS images and assessed cIVCs. RESULTS: Of the 85 participants, 44 (52%) were fluid responders. A 25% cIVC cutoff value performed better when assessed by expert sonologists than novice physician sonologists (receiver-operator characteristic curve, ROC = 0.82 [0.74-0.88] vs ROC = 0.69 [0.60-0.77]). CONCLUSIONS: A 25% cIVC cutoff value measured by POCUS detects fluid responsiveness. However, the experience of the physician sonologist affects test performance and should be considered when interpreting and clinically using cIVC to direct intravenous fluid resuscitation.

Effect of Dexmedetomidine on duration of mechanical ventilation in septic patients: a systematic review and meta-analysis.

BACKGROUND: Because of its analgesic and light sedative properties, the highly selective alpha-2 adrenergic receptor agonist dexmedetomidine (DEX) has been suggested for the treatment of septic patients, but its effect on the duration of mechanical ventilation remains unclear. The present study was conducted to review the extant literature in DEX and determine its influence on ventilation time in adult septic patients. METHODS: Databases of PubMed, Cochrane, and EMBASE were applied till 20th January 2019 without language restriction. The searching strategy as following: sepsis OR septic AND mechanical ventilation AND dexmedetomidine. Two authors screened titles, abstracts, and even articles to meet the including criterion independently. In addition, references of related articles or reviews were also referred. Data was recorded in a table and analyzed using the software of Review Manager 5.0. RESULTS: Four studies with a total of 349 patients were included. Three trials with 267 patients revealed the effect of DEX on duration of mechanical ventilation, two trials with 264 patients on ventilator-free days and four trials with 334 patients on 28-day mortality. The analyzed results indicated that DEX was not associated with significantly different durations of mechanical ventilation (MD 0.65, 95% CI, - 0.13 to 1.42, P = 0.10). However, there were significant differences in ventilator-free days (MD 3.57, 95% CI, 0.26 to 6.89, P = 0.03) and 28-day mortality (RR 0.61, 95% CI, 0.49 to 0.94, P = 0.02) in the septic patients. CONCLUSION: Administration of DEX for sedation in septic patients was not associated with the duration of mechanical ventilation, but it increased the ventilator-free days and reduced 28-day mortality.

Validation of END-of-life ScorING-system to identify the dying patient: a prospective analysis.

BACKGROUND: The "END-of-Life ScorING-System" (ENDING-S) was previously developed to identify patients at high-risk of dying in the ICU and to facilitate a practical integration between palliative and intensive care. The aim of this study is to prospectively validate ENDING-S in a cohort of long-term critical care patients. MATERIALS AND METHODS: Adult long-term ICU patients (with a length-of-stay> 4 days) were considered for this prospective multicenter observational study. ENDING-S and SOFA score were calculated daily and evaluated against the patient's ICU outcome. The predictive properties were evaluated through a receiver operating characteristic (ROC) analysis. RESULTS: Two hundred twenty patients were enrolled for this study. Among these, 21.46% died during the ICU stay. ENDING-S correctly predicted the ICU outcome in 71.4% of patients. Sensitivity, specificity, positive and negative predictive values associated with the previously identified ENDING-S cut-off of 11.5 were 68.1, 72.3, 60 and 89.3%, respectively. ROC-AUC for outcome prediction was 0.79 for ENDING-S and 0.88 for SOFA in this cohort. CONCLUSIONS: ENDING-S, while not as accurately as in the pilot study, demonstrated acceptable discrimination properties in identifying long-term ICU patients at very high-risk of dying. ENDING-S may be a useful tool aimed at facilitating a practical integration between palliative, end-of-life and intensive care. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02875912; First registration August 4, 2016.

Sepsis and septic shock.

Sepsis is a common condition that is associated with unacceptably high mortality and, for many of those who survive, long-term morbidity. Increased awareness of the condition resulting from ongoing campaigns and the evidence arising from research in the past 10 years have increased understanding of this problem among clinicians and lay people, and have led to improved outcomes. The World Health Assembly and WHO made sepsis a global health priority in 2017 and have adopted a resolution to improve the prevention, diagnosis, and management of sepsis. In 2016, a new definition of sepsis (Sepsis-3) was developed. Sepsis is now defined as infection with organ dysfunction. This definition codifies organ dysfunction using the Sequential Organ Failure Assessment score. Ongoing research aims to improve definition of patient populations to allow for individualised management strategies matched to a patient's molecular and biochemical profile. The search continues for improved diagnostic techniques that can facilitate this aim, and for a pharmacological agent that can improve outcomes by modifying the disease process. While waiting for this goal to be achieved, improved basic care driven by education and quality-improvement programmes offers the best hope of increasing favourable outcomes.

The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study.

OBJECTIVES: It is unclear if a low- or high-volume IV fluid resuscitation strategy is better for patients with severe sepsis and septic shock. DESIGN: Prospective randomized controlled trial. SETTING: Two adult acute care hospitals within a single academic system. PATIENTS: Patients with severe sepsis and septic shock admitted from the emergency department to the ICU from November 2016 to February 2018. INTERVENTIONS: Patients were randomly assigned to a restrictive IV fluid resuscitation strategy (≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care. MEASUREMENTS AND MAIN RESULTS: We enrolled 109 patients, of whom 55 were assigned to the restrictive resuscitation group and 54 to the usual care group. The restrictive group received significantly less resuscitative IV fluid than the usual care group (47.1 vs 61.1 mL/kg; p = 0.01) over 72 hours. By 30 days, there were 12 deaths (21.8%) in the restrictive group and 12 deaths (22.2%) in the usual care group (odds ratio, 1.02; 95% CI, 0.41-2.53). There were no differences between groups in the rate of new organ failure, hospital or ICU length of stay, or serious adverse events. CONCLUSIONS: This pilot study demonstrates that a restrictive resuscitation strategy can successfully reduce the amount of IV fluid administered to patients with severe sepsis and septic shock compared with usual care. Although limited by the sample size, we observed no increase in mortality, organ failure, or adverse events. These findings further support that a restrictive IV fluid strategy should be explored in a larger multicenter trial.

The SOFA score-development, utility and challenges of accurate assessment in clinical trials.

The Sequential Organ Failure Assessment or SOFA score was developed to assess the acute morbidity of critical illness at a population level and has been widely validated as a tool for this purpose across a range of healthcare settings and environments.In recent years, the SOFA score has become extensively used in a range of other applications. A change in the SOFA score of 2 or more is now a defining characteristic of the sepsis syndrome, and the European Medicines Agency has accepted that a change in the SOFA score is an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis. The requirement to detect modest serial changes in a patients' SOFA score therefore means that increased clarity on how the score should be assessed in different circumstances is required.This review explores the development of the SOFA score, its applications and the challenges associated with measurement. In addition, it proposes guidance designed to facilitate the consistent and valid assessment of the score in multicentre sepsis trials involving novel therapeutic agents or interventions.ConclusionThe SOFA score is an increasingly important tool in defining both the clinical condition of the individual patient and the response to therapies in the context of clinical trials. Standardisation between different assessors in widespread centres is key to detecting response to treatment if the SOFA score is to be used as an outcome in sepsis clinical trials.

Mortality Changes Associated with Mandated Public Reporting for Sepsis. The Results of the New York State Initiative.

RATIONALE: In 2013, the New York State Department of Health (NYSDOH) began a mandatory state-wide initiative to improve early recognition and treatment of severe sepsis and septic shock. OBJECTIVES: This study examines protocol initiation, 3-hour and 6-hour sepsis bundle completion, and risk-adjusted hospital mortality among adult patients with severe sepsis and septic shock. METHODS: Cohort analysis included all patients from all 185 hospitals in New York State reported to the NYSDOH from April 1, 2014, to June 30, 2016. A total of 113,380 cases were submitted to NYSDOH, of which 91,357 hospitalizations from 183 hospitals met study inclusion criteria. NYSDOH required all hospitals to submit and follow evidence-informed protocols (including elements of 3-h and 6-h sepsis bundles: lactate measurement, early blood cultures and antibiotic administration, fluids, and vasopressors) for early identification and treatment of severe sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: Compliance with elements of the sepsis bundles and risk-adjusted mortality were studied. Of 91,357 patients, 74,293 (81.3%) had the sepsis protocol initiated. Among these individuals, 3-hour bundle compliance increased from 53.4% to 64.7% during the study period (P < 0.001), whereas among those eligible for the 6-hour bundle (n = 35,307) compliance increased from 23.9% to 30.8% (P < 0.001). Risk-adjusted mortality decreased from 28.8% to 24.4% (P < 0.001) in patients among whom a sepsis protocol was initiated. Greater hospital compliance with 3-hour and 6-hour bundles was associated with shorter length of stay and lower risk and reliability-adjusted mortality. CONCLUSIONS: New York's statewide initiative increased compliance with sepsis-performance measures. Risk-adjusted sepsis mortality decreased during the initiative and was associated with increased hospital-level compliance.

Validation of a Host Response Assay, SeptiCyte LAB, for Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU.

RATIONALE: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. OBJECTIVES: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. METHODS: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands ( www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. MEASUREMENTS AND MAIN RESULTS: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. CONCLUSIONS: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502).

Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness.

BACKGROUND: Critically ill patients with sepsis and acute respiratory distress syndrome have severely altered physiology and immune system modifications. RNA splicing is a basic molecular mechanism influenced by physiologic alterations. Immune checkpoint inhibitors, such as B and T Lymphocyte Attenuator (BTLA) have previously been shown to influence outcomes in critical illness. We hypothesize altered physiology in critical illness results in alternative RNA splicing of the immune checkpoint protein, BTLA, resulting in a soluble form with biologic and clinical significance. METHODS: Samples were collected from critically ill humans and mice. Levels soluble BTLA (sBTLA) were measured. Ex vivo experiments assessing for cellular proliferation and cytokine production were done using splenocytes from critically ill mice cultured with sBTLA. Deep RNA sequencing was done to look for alternative splicing of BTLA. sBTLA levels were fitted to models to predict sepsis diagnosis. RESULTS: sBTLA is increased in the blood of critically ill humans and mice and can predict a sepsis diagnosis on hospital day 0 in humans. Alternative RNA splicing results in a premature stop codon that results in the soluble form. sBTLA has a clinically relevant impact as splenocytes from mice with critical illness cultured with soluble BTLA have increased cellular proliferation. CONCLUSION: sBTLA is produced as a result of alternative RNA splicing. This isoform of BTLA has biological significance through changes in cellular proliferation and can predict the diagnosis of sepsis.

The New York Sepsis Severity Score: Development of a Risk-Adjusted Severity Model for Sepsis.

OBJECTIVES: In accordance with Rory's Regulations, hospitals across New York State developed and implemented protocols for sepsis recognition and treatment to reduce variations in evidence informed care and preventable mortality. The New York Department of Health sought to develop a risk assessment model for accurate and standardized hospital mortality comparisons of adult septic patients across institutions using case-mix adjustment. DESIGN: Retrospective evaluation of prospectively collected data. PATIENTS: Data from 43,204 severe sepsis and septic shock patients from 179 hospitals across New York State were evaluated. SETTINGS: Prospective data were submitted to a database from January 1, 2015, to December 31, 2015. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Maximum likelihood logistic regression was used to estimate model coefficients used in the New York State risk model. The mortality probability was estimated using a logistic regression model. Variables to be included in the model were determined as part of the model-building process. Interactions between variables were included if they made clinical sense and if their p values were less than 0.05. Model development used a random sample of 90% of available patients and was validated using the remaining 10%. Hosmer-Lemeshow goodness of fit p values were considerably greater than 0.05, suggesting good calibration. Areas under the receiver operator curve in the developmental and validation subsets were 0.770 (95% CI, 0.765-0.775) and 0.773 (95% CI, 0.758-0.787), respectively, indicating good discrimination. Development and validation datasets had similar distributions of estimated mortality probabilities. Mortality increased with rising age, comorbidities, and lactate. CONCLUSIONS: The New York Sepsis Severity Score accurately estimated the probability of hospital mortality in severe sepsis and septic shock patients. It performed well with respect to calibration and discrimination. This sepsis-specific model provides an accurate, comprehensive method for standardized mortality comparison of adult patients with severe sepsis and septic shock.