Position Paper on the Reporting of Norepinephrine Formulations in Critical Care from the Society of Critical Care Medicine and European Society of Intensive Care Medicine Joint Task Force.

OBJECTIVES: To provide guidance on the reporting of norepinephrine formulation labeling, reporting in publications, and use in clinical practice. DESIGN: Review and task force position statements with necessary guidance. SETTING: A series of group conference calls were conducted from August 2023 to October 2023, along with a review of the available evidence and scope of the problem. SUBJECTS: A task force of multinational and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. INTERVENTIONS: The implications of a variation in norepinephrine labeled as conjugated salt (i.e., bitartrate or tartrate) or base drug in terms of effective concentration of norepinephrine were examined, and guidance was provided. MEASUREMENTS AND MAIN RESULTS: There were significant implications for clinical care, dose calculations for enrollment in clinical trials, and results of datasets reporting maximal norepinephrine equivalents. These differences were especially important in the setting of collaborative efforts across countries with reported differences. CONCLUSIONS: A joint task force position statement was created outlining the scope of norepinephrine-dose formulation variations, and implications for research, patient safety, and clinical care. The task force advocated for a uniform norepinephrine-base formulation for global use, and offered advice aimed at appropriate stakeholders.

Awareness with paralysis and symptoms of post-traumatic stress disorder among mechanically ventilated emergency department survivors (ED-AWARENESS-2 Trial): study protocol for a pragmatic, multicenter, stepped wedge cluster randomized trial.

BACKGROUND: Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials have been conducted to prevent AWP in the operating room, where prevalence is 0.1-0.2%. By contrast, AWP in mechanically ventilated emergency department (ED) patients is common, with estimated prevalence of 3.3-7.4% among survivors given NMB. Longer-acting NMB use is a critical risk for AWP, and we have shown an association between ED rocuronium use and increased AWP prevalence. As NMB are given to more than 90% of ED patients during tracheal intubation, this trial provides a platform to test an intervention aimed at reducing AWP. The overall objective is to test the hypothesis that limiting ED rocuronium exposure will significantly reduce the proportion of patients experiencing AWP. METHODS: This is a pragmatic, stepped wedge cluster randomized trial conducted in five academic EDs, and will enroll 3090 patients. Per the design, all sites begin in a control phase, under observational conditions. At 6-month intervals, sites sequentially enter a 2-month transition phase, during which we will implement the multifaceted intervention, which will rely on use of nudges and defaults to change clinician decisions regarding ED NMB use. During the intervention phase, succinylcholine will be the default NMB over rocuronium. The primary outcome is AWP, assessed with the modified Brice questionnaire, adjudicated by three independent, blinded experts. The secondary outcome is the proportion of patients developing clinically significant symptoms of post-traumatic stress disorder at 30 and 180 days after hospital discharge. We will also assess for symptoms of depression and anxiety, and health-related quality of life. A generalized linear model, adjusted for time and cluster interactions, will be used to compare AWP in control versus intervention phases, analyzed by intention-to-treat. DISCUSSION: The ED-AWARENESS-2 Trial will be the first ED-based trial aimed at preventing AWP, a critical threat to patient safety. Results could shape clinical use of NMB in the ED and prevent more than 10,000 annual cases of AWP related to ED care. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05534243 . Registered 06, September 2022.

Nursing Implications of the Updated 2021 Surviving Sepsis Campaign Guidelines.

Sepsis is a life-threatening illness that affects millions of people worldwide. Early recognition and timely treatment are essential for decreasing mortality from sepsis. The Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021, the fifth iteration of the guidelines, was released in October 2021 and includes 93 recommendations for the management of sepsis. The evidence-based guidelines include recommendations and rationales for screening and early treatment, initial resuscitation, mean arterial pressure targets, admission to intensive care, management of infection, hemodynamic monitoring, ventilation, and additional therapies. A new section addresses long-term outcomes and goals of care. This article presents several recommendations, changes, and updates in the 2021 guidelines and highlights the important contributions nurses have in delivering timely and evidence-based care to patients with sepsis. Recommendations may be for or against an intervention, according to the evidence. Although many recommendations are unchanged, several new recommendations directly affect nursing care and may require specialized training (eg, venovenous extracorporeal membrane oxygenation). The newest section, long-term outcomes and goals of care, is aimed at using available resources to provide care that is aligned with the patient and the patient's family through goals-of-care discussions and shared decision-making. Interventions aimed at improving recovery across the continuum of care should include attention to long-term outcomes. Nurses are essential in identifying patients with sepsis, administering and assessing response to treatment, supporting the patient and family, and limiting sequelae from sepsis. This article highlights the 2021 recommendations that influence nursing care for patients with sepsis.

Effects of Compliance With the Early Management Bundle (SEP-1) on Mortality Changes Among Medicare Beneficiaries With Sepsis: A Propensity Score Matched Cohort Study.

BACKGROUND: US hospitals have reported compliance with the SEP-1 quality measure to Medicare since 2015. Finding an association between compliance and outcomes is essential to gauge measure effectiveness. RESEARCH QUESTION: What is the association between compliance with SEP-1 and 30-day mortality among Medicare beneficiaries? STUDY DESIGN AND METHODS: Studying patient-level data reported to Medicare by 3,241 hospitals from October 1, 2015, to March 31, 2017, we used propensity score matching and a hierarchical general linear model (HGLM) to estimate the treatment effects associated with compliance with SEP-1. Compliance was defined as completion of all qualifying SEP-1 elements including lactate measurements, blood culture collection, broad-spectrum antibiotic administration, 30 mL/kg crystalloid fluid administration, application of vasopressors, and patient reassessment. The primary outcome was a change in 30-day mortality. Secondary outcomes included changes in length of stay. RESULTS: We completed two matches to evaluate population-level treatment effects. In standard match, 122,870 patients whose care was compliant were matched with the same number whose care was noncompliant. Compliance was associated with a reduction in 30-day mortality (21.81% vs 27.48%, respectively), yielding an absolute risk reduction (ARR) of 5.67% (95% CI, 5.33-6.00; P < .001). In stringent match, 107,016 patients whose care was compliant were matched with the same number whose care was noncompliant. Compliance was associated with a reduction in 30-day mortality (22.22% vs 26.28%, respectively), yielding an ARR of 4.06% (95% CI, 3.70-4.41; P < .001). At the subject level, our HGLM found compliance associated with lower 30-day risk-adjusted mortality (adjusted conditional OR, 0.829; 95% CI, 0.812-0.846; P < .001). Multiple elements correlated with lower mortality. Median length of stay was shorter among cases whose care was compliant (5 vs 6 days; interquartile range, 3-9 vs 4-10, respectively; P < .001). INTERPRETATION: Compliance with SEP-1 was associated with lower 30-day mortality. Rendering SEP-1 compliant care may reduce the incidence of avoidable deaths.

The Association of Increasing Hospice Use With Decreasing Hospital Mortality: An Analysis of the National Inpatient Sample.

EXECUTIVE SUMMARY: Usage of hospice services for patients facing life-limiting illness has steadily increased. In these services, hospitals discharge patients to various hospice settings, including the inpatient model, where a patient may remain in the discharging hospital to receive hospice services. In this discharge practice, the patient is considered a hospital survivor and subsequent hospice death. The purpose of the study was to determine if the decline of in-hospital mortality for six common high-volume admission diagnoses could be attributed in part to an increase in discharges to a hospice setting for end-of-life care. In this retrospective study using the National Inpatient Sample database from 2007 to 2011, we identified patients ≥18 years for six acute and chronic diagnoses: heart failure, chronic obstructive pulmonary disease, acute myocardial infarction, acute myocardial infarction with cardiogenic shock, septic shock, and lung neoplasm (cancer). We categorized patients according to their hospital discharge disposition as hospice or in-hospital mortality. A total of 10,458,728 patients met our criteria, of which 2.72% were discharged to hospice and 6.38% died. Compared to patients who died in the hospital, hospice patients were older, had a shorter length of stay, and experienced more comorbidities. Hospice use was more common in Medicare patients, in nonteaching hospitals, and in the South. White individuals were more likely to be discharged to hospice compared to nonwhites. Among the six selected diagnoses over the 5-year period, hospice use rose as observed mortality decreased. Our findings suggest that variability among hospitals in hospice use will affect benchmarked hospital mortality comparisons and could inappropriately reward or penalize hospitals in their public reporting.

Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial.

Importance: Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes. Objective: To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity. Design, Setting, and Participants: Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017. Interventions: Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients). Main Outcomes and Measures: The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9. Results: Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, -5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, -10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group). Conclusions and Relevance: Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT01046669.

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.

Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study.

PURPOSE: To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. DESIGN: Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005, through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. SETTING: Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. PATIENTS: Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. METHODS: A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. RESULTS: Overall lower mortality was observed in high (29.0%) versus low (38.6%) resuscitation bundle compliance sites (p < 0.001) and between high (33.4%) and low (32.3%) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7% per site for every three months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4% (95% CI: 1% - 7%; p = 0.012) for every 10% increase in site compliance with the resuscitation bundle. CONCLUSIONS: This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25% relative risk reduction in mortality rate. Every 10% increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock.

Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study.

PURPOSE: To determine the association between compliance with the Surviving Sepsis Campaign (SSC) performance bundles and mortality. DESIGN: Compliance with the SSC performance bundles, which are based on the 2004 SSC guidelines, was measured in 29,470 subjects entered into the SSC database from January 1, 2005 through June 30, 2012. Compliance was defined as evidence that all bundle elements were achieved. SETTING: Two hundred eighteen community, academic, and tertiary care hospitals in the United States, South America, and Europe. PATIENTS: Patients from the emergency department, medical and surgical wards, and ICU who met diagnosis criteria for severe sepsis and septic shock. METHODS: A multifaceted, collaborative change intervention aimed at facilitating adoption of the SSC resuscitation and management bundles was introduced. Compliance with the SSC bundles and associated mortality rate was the primary outcome variable. RESULTS: Overall lower mortality was observed in high (29.0%) versus low (38.6%) resuscitation bundle compliance sites (p < 0.001) and between high (33.4%) and low (32.3%) management bundle compliance sites (p = 0.039). Hospital mortality rates dropped 0.7% per site for every 3 months (quarter) of participation (p < 0.001). Hospital and intensive care unit length of stay decreased 4% (95% CI 1-7%; p = 0.012) for every 10% increase in site compliance with the resuscitation bundle. CONCLUSIONS: This analysis demonstrates that increased compliance with sepsis performance bundles was associated with a 25% relative risk reduction in mortality rate. Every 10% increase in compliance and additional quarter of participation in the SSC initiative was associated with a significant decrease in the odds ratio for hospital mortality. These results demonstrate that performance metrics can drive change in clinical behavior, improve quality of care, and may decrease mortality in patients with severe sepsis and septic shock.

The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial.

BACKGROUND: Septic shock is common and has unacceptably high morbidity, mortality, and associated cost with numerous failed attempts at developing effective therapies. Endotoxin, one of the most potent mediators of sepsis, is found in high levels in approximately 50% of patients with septic shock. Polymyxin B (PMX) hemoperfusion has been shown in numerous studies to successfully remove endotoxin and potentially improve outcomes. EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock) is a theragnostic trial (matching blood measurement to treatment capability) of PMX hemoperfusion in patients with septic shock and confirmed endotoxemia as measured by the endotoxin activity assay (EAA). METHODS: EUPHRATES is a pivotal regulatory trial that is multi-centered, placebo-controlled and blinded. The trial is being conducted in fifty ICUs in the United States and Canada and is powered to enroll 360 patients. Patients with persistent septic shock despite adequate fluid resuscitation on vasopressors for more than 2 and less than 30 hours are eligible for measurement of the EAA. Those with EAA ≥0.60 are eligible to be randomized to treatment with two sessions of PMX hemoperfusion 24 hours apart. The primary endpoint for the trial is 28-day all-cause mortality. DISCUSSION: Unique features of the trial include absence of systemic inflammatory response (SIRS) criteria as a requirement for inclusion, use of the EAA to confirm endotoxemia as a requisite for treatment, and use of a detailed "façade" hemoperfusion event as a blinding mechanism. The outcomes of the second interim analysis included a resizing of the trial to 650 patients and the addition of an exclusion criterion of subjects with multiple organ dysfunction score (MODS) ≤ 9. Results are anticipated in 2016. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01046669. Registered: January 8, 2010.

Sepsis severity score: an internationally derived scoring system from the surviving sepsis campaign database*.

OBJECTIVE: As the Surviving Sepsis Campaign was assessing patient-level data over multiple countries, we sought to evaluate the use of a pragmatic and parsimonious severity-of-illness scoring system for patients with sepsis in an attempt to provide appropriate comparisons with practical application. DESIGN: Prospective, observational evaluation. PATIENTS: Data from 23,438 patients with suspected or confirmed sepsis from 218 hospitals in 18 countries were evaluated. SETTING: This analysis was conducted on prospective data submitted to a database from January 2005 through March 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Maximum likelihood logistic regression was used to estimate model coefficients, and these were then used to develop a Sepsis Severity Score. The probability of hospital mortality was estimated using the Sepsis Severity Score as the sole variable in a logistic regression model. Univariable logistic regression determined which variables were included in the multivariable predictor model. The scale of continuous variables was assessed using fractional polynomials. Two-way interactions between variables were considered for model inclusion if the interaction p value is less than 0.05. The prediction model was developed based on randomly selecting 90% of available patients and was validated on the remaining 10%, as well as by using a bootstrapping technique. The p values for the Hosmer-Lemeshow goodnessof-fit statistic in the developmental and validation datasets were considerably greater than 0.05, suggesting good calibration. Development and validation areas under the receiver operator curve curves were 0.736 and 0.748, respectively. Observed and estimated probabilities of hospital mortality for the total population were both 0.334. The validation and the developmental datasets were gradually compared over deciles of predicted mortality and found to be very similar. CONCLUSION: The 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, which remained consistent over deciles. It functioned well over international geographic regions. This robust, population-specific evaluation of international severe sepsis patients provides an effective and accurate mortality estimate allowing for appropriate quality comparisons with practical clinical and research application.

Targeting sepsis as a performance improvement metric: role of the nurse.

Sepsis is the body's systemic response to infection that can be complicated by acute organ dysfunction and is associated with high mortality rates and adverse outcomes for acute and critically ill patients. The 2012 Surviving Sepsis Campaign guidelines advocated for implementation of evidence-based practice care for sepsis, with a focus on quality improvement. Nurses are directly involved in identification and management of sepsis. Implementing performance improvement strategies aimed at early recognition and targeted treatment can further improve sepsis care and patient outcomes. This article presents an overview of the process of implementing performance improvement initiatives for sepsis care, highlighting the significant contribution of nursing care.

The Surviving Sepsis Campaign: past, present and future.

The Surviving Sepsis Campaign (SSC) was created in 2002 and consists of severe sepsis management guidelines and a sepsis performance improvement program. The second revision of the guidelines, published in 2013, are sponsored by 30 international scientific organizations and contain changes in recommendations for fluids and vasopressor administration. The new 3- and 6-hour sepsis 'bundles' (sets of care elements) include a software program that can be downloaded free from the Surviving Sepsis Campaign website (www.survivingsepsis.org). The traditional intensive care unit and emergency department champion-driven sepsis performance improvement program continues internationally with the kick off of a new grant-funded hospital floor sepsis performance improvement initiative.