Association Between Time to Source Control in Sepsis and 90-Day Mortality.

Importance: Rapid source control is recommended to improve patient outcomes in sepsis. Yet there are few data to guide how rapidly source control is required. Objective: To determine the association between time to source control and patient outcomes in community-acquired sepsis. Design, Setting, and Particpants: Multihospital integrated health care system cohort study of hospitalized adults (January 1, 2013, to December 31, 2017) with community-acquired sepsis as defined by Sepsis-3 who underwent source control procedures. Follow-up continued through January 1, 2019, and data analyses were completed March 17, 2022. Exposures: Early (<6 hours) compared with late (6-36 hours) source control as well as each hour of source control delay (1-36 hours) from sepsis onset. Main Outcomes and Measures: Multivariable models were clustered at the level of hospital with adjustment for patient factors, sepsis severity, resource availability, and the physiologic stress of procedures generating adjusted odds ratios (aOR) and 95% CI. Results: Of 4962 patients with sepsis (mean [SD] age, 62 [16] years; 52% male; 85% White; mean [SD] Sequential Organ Failure Assessment score, 3.8 [2.5]), source control occurred at a median (IQR) of 15.4 hours (5.5-21.7) after sepsis onset, with 1315 patients (27%) undergoing source control within 6 hours. The crude 90-day mortality was similar for early and late source control (n = 177 [14%] vs n = 529 [15%]; P = .35). In multivariable models, early source control was associated with decreased risk-adjusted odds of 90-day mortality (aOR, 0.71; 95% CI, 0.63-0.80). This association was greater among gastrointestinal and abdominal (aOR, 0.56; 95% CI, 0.43-0.80) and soft tissue interventions (aOR, 0.72; 95% CI, 0.55-0.95) compared with orthopedic and cranial interventions (aOR, 1.33; 95% CI, 0.96-1.83; P < .001 for interaction). Conclusions and Relevance: Source control within 6 hours of community-acquired sepsis onset was associated with a reduced risk-adjusted odds of 90-day mortality. Prioritizing the rapid identification of septic foci and initiation of source control interventions can reduce the number of avoidable deaths among patients with sepsis.

Enhancing Implementation of Complex Critical Care Interventions through Interprofessional Education.

Background: Many critical care interventions that require teamwork are adopted slowly and variably despite strong evidence supporting their use. We hypothesize that educational interventions that target the entire interprofessional team (rather than professions in isolation) are one effective way to enhance implementation of complex interventions in the intensive care unit (ICU). Objective: As a first step toward testing this hypothesis, we sought to qualitatively solicit opinions about team dynamics, evidence translation, and interprofessional education as well as current knowledge, attitudes, and practices surrounding the use of one example of a team-based practice in the ICU-preventive postextubation noninvasive ventilation (NIV). Methods: We conducted a qualitative evaluation using semistructured interviews and focus groups with nurses, respiratory therapists, and physicians working in four ICUs in four hospitals within an integrated health system. ICUs were selected based on variation in academic versus community status. We iteratively analyzed transcripts using a thematic content analysis approach. Results: From December 2018 to January 2019, we conducted 32 interviews (34 people) and 3 focus groups (20 people). Participants included 31 nurses, 15 respiratory therapists, and 8 physicians. Participants had favorable views of how their teams work together but discussed ways team dynamics (e.g., leader inclusiveness) impact care coordination. Participants viewed interprofessional education favorably and shared suggestions regarding preferred content and delivery (e.g., include both profession-specific and team-oriented content). Though participants reported frequently using NIV as a treatment, they described rarely using NIV as a preventive strategy, and nurses and respiratory therapists described challenges to use such as perceived patient discomfort. There were ICU-specific differences in management of patients at a high risk for respiratory failure after extubation, with some preferring to delay extubation. Conclusion: Participants reported optimism that interprofessional education can be an acceptable and effective way to improve translation of evidence into practice. Participants also detailed patient-specific and ICU-wide barriers to the implementation of preventive postextubation NIV. This information about teamwork in the ICU, suggestions for interprofessional education, and barriers and facilitators to use of a target evidence-based practice can inform the development of novel educational strategies in ways that increase acceptability, appropriateness, and feasibility of the intervention.

Treatment Patterns and Clinical Outcomes After the Introduction of the Medicare Sepsis Performance Measure (SEP-1).

BACKGROUND: Medicare requires that hospitals report on their adherence to the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1). OBJECTIVE: To evaluate the effect of SEP-1 on treatment patterns and patient outcomes. DESIGN: Longitudinal study of hospitals using repeated cross-sectional cohorts of patients. SETTING: 11 hospitals within an integrated health system. PATIENTS: 54 225 encounters between January 2013 and December 2017 for adults with sepsis who were hospitalized through the emergency department. INTERVENTION: Onset of the SEP-1 reporting requirement in October 2015. MEASUREMENTS: Changes in SEP-1-targeted processes, including antibiotic administration, lactate measurement, and fluid administration at 3 hours from sepsis onset; repeated lactate and vasopressor administration for hypotension within 6 hours of sepsis onset; and sepsis outcomes, including risk-adjusted intensive care unit (ICU) admission, in-hospital mortality, and home discharge among survivors. RESULTS: Two years after its implementation, SEP-1 was associated with variable changes in process measures, with the greatest effect being an increase in lactate measurement within 3 hours of sepsis onset (absolute increase, 23.7 percentage points [95% CI, 20.7 to 26.7 percentage points]; P < 0.001). There were small increases in antibiotic administration (absolute increase, 4.7 percentage points [CI, 1.9 to 7.6 percentage points]; P = 0.001) and fluid administration of 30 mL/kg of body weight within 3 hours of sepsis onset (absolute increase, 3.4 percentage points [CI, 1.5 to 5.2 percentage points]; P < 0.001). There was no change in vasopressor administration. There was a small increase in ICU admissions (absolute increase, 2.0 percentage points [CI, 0 to 4.0 percentage points]; P = 0.055) and no changes in mortality (absolute change, 0.1 percentage points [CI, -0.9 to 1.1 percentage points]; P = 0.87) or discharge to home. LIMITATION: Data are from a single health system. CONCLUSION: Implementation of the SEP-1 mandatory reporting program was associated with variable changes in process measures, without improvements in clinical outcomes. Revising the measure may optimize its future effect. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Blue Light Enhances Bacterial Clearance and Reduces Organ Injury During Sepsis.

OBJECTIVES: The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis. DESIGN: Laboratory animal research, pilot human feasibility trial. SETTING: University basic science laboratory and tertiary care hospital. SUBJECTS: Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis. INTERVENTIONS: Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light. MEASUREMENTS AND MAIN RESULTS: Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERBα and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations. CONCLUSIONS: Modifying the spectrum of light may offer therapeutic utility in sepsis.

Omega-3 supplementation in patients with sepsis: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Nutritional supplementation of omega-3 fatty acids has been proposed to modulate the balance of pro- and anti-inflammatory mediators in sepsis. If proved to improve clinical outcomes in critically ill patients with sepsis, this intervention would be easy to implement. However, the cumulative evidence from several randomized clinical trials (RCTs) remains unclear. METHODS: We searched the Cochrane Library, MEDLINE, and EMBASE through December 2016 for RCTs on parenteral or enteral omega-3 supplementation in adult critically ill patients diagnosed with sepsis or septic shock. We analysed the included studies for mortality, intensive care unit (ICU) length of stay, and duration of mechanical ventilation, and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the quality of the evidence for each outcome. RESULTS: A total of 17 RCTs enrolling 1239 patients met our inclusion criteria. Omega-3 supplementation compared to no supplementation or placebo had no significant effect on mortality [relative risk (RR) 0.85; 95% confidence interval (CI) 0.71, 1.03; P = 0.10; I 2 = 0%; moderate quality], but significantly reduced ICU length of stay [mean difference (MD) -3.79 days; 95% CI -5.49, -2.09; P < 0.0001, I 2 = 82%; very low quality] and duration of mechanical ventilation (MD -2.27 days; 95% CI -4.27, -0.27; P = 0.03, I 2 = 60%; very low quality). However, sensitivity analyses challenged the robustness of these results. CONCLUSION: Omega-3 nutritional supplementation may reduce ICU length of stay and duration of mechanical ventilation without significantly affecting mortality, but the very low quality of overall evidence is insufficient to justify the routine use of omega-3 fatty acids in the management of sepsis.

Blue light reduces organ injury from ischemia and reperfusion.

Evidence suggests that light and circadian rhythms profoundly influence the physiologic capacity with which an organism responds to stress. However, the ramifications of light spectrum on the course of critical illness remain to be determined. Here, we show that acute exposure to bright blue spectrum light reduces organ injury by comparison with bright red spectrum or ambient white fluorescent light in two murine models of sterile insult: warm liver ischemia/reperfusion (I/R) and unilateral renal I/R. Exposure to bright blue light before I/R reduced hepatocellular injury and necrosis and reduced acute kidney injury and necrosis. In both models, blue light reduced neutrophil influx, as evidenced by reduced myeloperoxidase (MPO) within each organ, and reduced the release of high-mobility group box 1 (HMGB1), a neutrophil chemotactant and key mediator in the pathogenesis of I/R injury. The protective mechanism appeared to involve an optic pathway and was mediated, in part, by a sympathetic (ß3 adrenergic) pathway that functioned independent of significant alterations in melatonin or corticosterone concentrations to regulate neutrophil recruitment. These data suggest that modifying the spectrum of light may offer therapeutic utility in sterile forms of cellular injury.

Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria.

The current definition of sepsis is life-threatening, acute organ dysfunction secondary to a dysregulated host response to infection. Criteria to operationalize this definition can be judged by six domains of usefulness (reliability, content, construct and criterion validity, measurement burden, and timeliness). The relative importance of these six domains depends on the intended purpose for the criteria (clinical care, basic and clinical research, surveillance, or quality improvement [QI] and audit). For example, criteria for clinical care should have high content and construct validity, timeliness, and low measurement burden to facilitate prompt care. Criteria for surveillance or QI/audit place greater emphasis on reliability across individuals and sites and lower emphasis on timeliness. Criteria for clinical trials require timeliness to ensure prompt enrollment and reasonable reliability but can tolerate high measurement burden. Basic research also tolerates high measurement burden and may not need stability over time. In an illustrative case study, we compared examples of criteria designed for clinical care, surveillance and QI/audit among 396,241 patients admitted to 12 academic and community hospitals in an integrated health system. Case rates differed four-fold and mortality three-fold. Predictably, clinical care criteria, which emphasized timeliness and low burden and therefore used vital signs and routine laboratory tests, had the greater case identification with lowest mortality. QI/audit criteria, which emphasized reliability and criterion validity, used discharge information and had the lowest case identification with highest mortality. Using this framework to identify the purpose and apply domains of usefulness can help with the evaluation of existing sepsis diagnostic criteria and provide a roadmap for future work.

The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.

OBJECTIVE: The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies. DATA SOURCES: We selected the major clinical studies that investigated interventional trials with novel therapies to treat sepsis over the last 30 years. STUDY SELECTION: Phase II and phase III trials investigating new treatments for sepsis and editorials and critiques of these studies. DATA EXTRACTION: Selected manuscripts and clinical study reports were analyzed from sepsis trials. Specific shortcomings and potential pit falls in preclinical evaluation and clinical study design and analysis were reviewed and synthesized. DATA SYNTHESIS: After review and discussion, a series of 12 recommendations were generated with suggestions to guide future studies with new treatments for sepsis. CONCLUSIONS: We need to improve our ability to define appropriate molecular targets for preclinical development and develop better methods to determine the clinical value of novel sepsis agents. Clinical trials must have realistic sample sizes and meaningful endpoints. Biomarker-driven studies should be considered to categorize specific "at risk" populations most likely to benefit from a new treatment. Innovations in clinical trial design such as parallel crossover design, alternative endpoints, or adaptive trials should be pursued to improve the outlook for future interventional trials in sepsis.

Calcium supplementation during sepsis exacerbates organ failure and mortality via calcium/calmodulin-dependent protein kinase kinase signaling.

BACKGROUND: Calcium plays an essential role in nearly all cellular processes. As such, cellular and systemic calcium concentrations are tightly regulated. During sepsis, derangements in such tight regulation frequently occur, and treating hypocalcemia with parenteral calcium administration remains the current practice guideline. OBJECTIVE: We investigated whether calcium administration worsens mortality and organ dysfunction using an experimental murine model of sepsis and explored the mechanistic role of the family of calcium/calmodulin-dependent protein kinases in mediating these physiological effects. To highlight the biological relevance of these observations, we conducted a translational study of the association between calcium administration, organ dysfunction, and mortality among a cohort of critically ill septic ICU patients. DESIGN: Prospective, randomized controlled experimental murine study and observational clinical cohort analysis. SETTING: University research laboratory and eight ICUs at a tertiary care center. PATIENTS: A cohort of 870 septic ICU patients. SUBJECTS: C57Bl/6 and CaMKK mice. INTERVENTIONS: Mice underwent cecal ligation and puncture polymicrobial sepsis and were administered with calcium chloride (0.25 or 0.25 mg/kg) or normal saline. MEASUREMENTS AND MAIN RESULTS: Administering calcium chloride to septic C57Bl/6 mice heightened systemic inflammation and vascular leak, exacerbated hepatic and renal dysfunction, and increased mortality. These events were significantly attenuated in CaMKK mice. In a risk-adjusted analysis of septic patients, calcium administration was associated with an increased risk of death, odds ratio 1.92 (95% CI, 1.00-3.68; p = 0.049), a significant increase in the risk of renal dysfunction, odds ratio 4.74 (95% CI, 2.48-9.08; p < 0.001), and a significant reduction in ventilator-free days, mean decrease 3.29 days (0.50-6.08 days; p = 0.02). CONCLUSIONS: Derangements in calcium homeostasis occur during sepsis that is sensitive to calcium administration. This altered calcium signaling, transduced by the calmodulin-dependent protein kinase kinase cascade, mediates heightened inflammation and vascular leak that culminates in elevated organ dysfunction and mortality. In the clinical management of septic patients, calcium supplementation provides no benefit and may impose harm.

Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial.

OBJECTIVE: To assess the survival benefit and safety profile of low-dose (850 mg/kg) and high-dose (1350 mg/kg) phospholipid emulsion vs. placebo administered as a continuous 3-day infusion in patients with confirmed or suspected Gram-negative severe sepsis. Preclinical and ex vivo studies show that lipoproteins bind and neutralize endotoxin, and experimental animal studies demonstrate protection from septic death when lipoproteins are administered. Endotoxin neutralization correlates with the amount of phospholipid in the lipoprotein particles. DESIGN: A three-arm, randomized, blinded, placebo-controlled trial. SETTING: Conducted at 235 centers worldwide between September 2004 and April 2006. PATIENTS: A total of 1379 patients participated in the study, 598 patients received low-dose phospholipid emulsion, and 599 patients received placebo. The high-dose phospholipid emulsion arm was stopped, on the recommendation of the Independent Data Monitoring Committee, due to an increase in life-threatening serious adverse events at the fourth interim analysis and included 182 patients. MEASUREMENTS AND MAIN RESULTS: A 28-day all-cause mortality and new-onset organ failure. There was no significant treatment benefit for low- or high-dose phospholipid emulsion vs. placebo for 28-day all-cause mortality, with rates of 25.8% (p = .329), 31.3% (p = .879), and 26.9%, respectively. The rate of new-onset organ failure was not statistically different among groups at 26.3%, 31.3%, 20.4% with low- and high-dose phospholipid emulsion, and placebo, respectively (one-sided p = .992, low vs. placebo; p = .999, high vs. placebo). Of the subjects treated, 45% had microbiologically confirmed Gram-negative infections. Maximal changes in mean hemoglobin levels were reached on day 10 (-1.04 g/dL) and day 5 (-1.36 g/dL) with low- and high-dose phospholipid emulsion, respectively, and on day 14 (-0.82 g/dL) with placebo. CONCLUSIONS: Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.

Parenteral calcium for intensive care unit patients.

BACKGROUND: Hypocalcemia is prevalent among critically ill patients requiring intensive care. Several epidemiological studies highlight a direct association between hypocalcemia and mortality. These data provide the impetus for current guidelines recommending parenteral calcium administration to normalize serum calcium. However, in light of the considerable variation in the threshold for calcium replacement, the lack of evidence to support a causal role of hypocalcemia in mortality, and animal studies illustrating that calcium supplementation may worsen outcomes, a systematic review is essential to evaluate whether or not the practice of calcium supplementation for intensive care unit (ICU) patients provides any benefit. OBJECTIVES: To assess the effects of parenteral calcium administration in ICU patients on the following outcomes: mortality, multiple organ dysfunction, ICU and hospital length of stay, costs, serum ionized calcium concentration, and complications of parenteral calcium administration. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, Current Controlled Trials, and the National Research Register. We hand-searched conference abstracts from the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, the American Thoracic Surgery, the American College of Surgeons, the American College of Chest Physicians, the American College of Physicians, and the International Consensus Conference in Intensive Care Medicine. We checked references of publications and attempted to contact authors to identify additional published or unpublished data. SELECTION CRITERIA: Randomised controlled and controlled clinical trials of ICU patients comparing parenteral calcium chloride or calcium gluconate administration with no treatment or placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied eligibility criteria to trial reports for inclusion and extracted data. MAIN RESULTS: There are no identifiable studies that have evaluated the association between parenteral calcium supplementation in critically ill ICU patients and the following outcomes: mortality, multiple organ dysfunction, ICU and hospital length of stay, costs, and complications of calcium administration. Serum ionized calcium concentration was reported in 5 studies (12 trial arms, 159 participants). These trials showed a small but significant increase in serum ionized calcium concentration after calcium administration. These trials showed considerable statistical heterogeneity and differed extensively in the population studied (adult versus neonate), the indication (hypocalcemia versus prophylaxis) and threshold of hypocalcemia for which parenteral calcium was administered, and the timing of subsequent measurement of serum ionized calcium concentration to the extent that we consider a pooled estimate almost inappropriate. AUTHORS' CONCLUSIONS: There is no clear evidence that parenteral calcium supplementation impacts the outcome of critically ill patients.