Association of Active Renin Content With Mortality in Critically Ill Patients: A Post hoc Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Trial.

OBJECTIVE: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin-angiotensin system (RAS) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that RAS dysfunction (elevated active renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients. DESIGN: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial. SETTING: Forty-three hospitals across the United States. PATIENTS: Biorepository samples of 103 patients. INTERVENTIONS: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples ( n = 103 and 95, respectively) for assessment of the RAS. The association of RAS values with 30-day mortality was determined using Cox proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use. MEASUREMENTS AND MAIN RESULTS: High baseline active renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10-7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HR Q2 = 2.01 [0.37-11.04], HR Q3 = 3.22 [0.64-16.28], HR Q4 = 5.58 [1.18-26.32], p for linear trend = 0.023). A 1- sd (593.6 pg/mL) increase in renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94-7.22], p < 0.001), and patients whose renin decreased had improved survival compared with those whose renin increased (HR 0.22 [95% CI, 0.08-0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with renin over the median on day 0 who received the VICTAS intervention, but not on day 3 ( p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the RAS from the VICTAS intervention. CONCLUSIONS: Baseline serum active renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating renin from day 0 to day 3 was associated with a higher risk of death.

How Electronic Medical Record Integration Can Support More Efficient Critical Care Clinical Trials.

Large volumes of data are collected on critically ill patients, and using data science to extract information from the electronic medical record (EMR) and to inform the design of clinical trials represents a new opportunity in critical care research. Using improved methods of phenotyping critical illnesses, subject identification and enrollment, and targeted treatment group assignment alongside newer trial designs such as adaptive platform trials can increase efficiency while lowering costs. Some tools such as the EMR to automate data collection are already in use. Refinement of data science approaches in critical illness research will allow for better clinical trials and, ultimately, improved patient outcomes.

Xanthine oxidoreductase gene polymorphisms are associated with high risk of sepsis and organ failure.

BACKGROUND: Sepsis and associated organ failures confer substantial morbidity and mortality. Xanthine oxidoreductase (XOR) is implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders including sepsis and sepsis-associated acute respiratory distress syndrome (ARDS). We examined whether single nucleotide polymorphisms (SNPs) in the XDH gene (encoding XOR) might influence susceptibility to and outcome in patients with sepsis. METHODS: We genotyped 28 tag SNPs in XDH gene in the CELEG cohort, including 621 European American (EA) and 353 African American (AA) sepsis patients. Serum XOR activity was measured in a subset of CELEG subjects. Additionally, we assessed the functional effects of XDH variants utilizing empirical data from different integrated software tools and datasets. RESULTS: Among AA patients, six intronic variants (rs206805, rs513311, rs185925, rs561525, rs2163059, rs13387204), in a region enriched with regulatory elements, were associated with risk of sepsis (P < 0.008-0.049). Two out of six SNPs (rs561525 and rs2163059) were associated with risk of sepsis-associated ARDS in an independent validation cohort (GEN-SEP) of 590 sepsis patients of European descent. Two common SNPs (rs1884725 and rs4952085) in tight linkage disequilibrium (LD) provided strong evidence for association with increased levels of serum creatinine (Padjusted<0.0005 and 0.0006, respectively), suggesting a role in increased risk of renal dysfunction. In contrast, among EA ARDS patients, the missense variant rs17011368 (I703V) was associated with enhanced mortality at 60-days (P < 0.038). We found higher serum XOR activity in 143 sepsis patients (54.5 ± 57.1 mU/mL) compared to 31 controls (20.9 ± 12.4 mU/mL, P = 1.96 × 10- 13). XOR activity was associated with the lead variant rs185925 among AA sepsis patients with ARDS (P < 0.005 and Padjusted<0.01). Multifaceted functions of prioritized XDH variants, as suggested by various functional annotation tools, support their potential causality in sepsis. CONCLUSIONS: Our findings suggest that XOR is a novel combined genetic and biochemical marker for risk and outcome in patients with sepsis and ARDS.

Resuscitation in the First 3 Hours of Sepsis-Induced Hypotension Varies by Patient and Hospital Factors.

Patient and hospital factors affects how we resuscitate patients in the first 3 hours of sepsis-induced hypotension. OBJECTIVES: To evaluate variability in compliance to the 3-hour surviving sepsis campaign (SSC) bundle and explore the association of early compliance with subsequent shock and in-hospital mortality. DESIGN: Retrospective cohort study between September 2017 and February 2018. SETTING: Thirty-four academic medical centers. PARTICIPANTS: A subgroup sepsis-induced hypotensive patients from a larger shock cohort study. MAIN OUTCOMES AND MEASURES: Compliance to SSC bundle that was defined as receiving appropriate antibiotics, 30 mL/kg of crystalloid or initiation of vasopressors, and lactate, obtained in the first 3 hours following sepsis-induced hypotension. RESULTS: We included 977 patients with septic-induced hypotension. Bundle compliance was 43.8%, with the lowest compliance to fluid or vasopressor components (56%). Patients with high Sequential Organ Failure Assessment scores and physiologic assessments were more likely to receive compliant care, as were patients with sepsis-induced hypotension onset in the emergency department (ED) or admitted to mixed medical-surgical ICUs. SSC compliance was not associated with in-hospital mortality (adjusted odds ratio, 0.72; 95% CI, 0.47-1.10). The site-to-site variability contributed to SSC compliance (intraclass correlation coefficient [ICC], 0.15; 95% CI, 0.07-0.3) but not in-hospital mortality (ICC, 0.02; 95% CI, 0.001-0.24). Most patients remained in shock after 3 hours of resuscitation (SSC compliant 81.1% and noncompliant 53.7%). Mortality was higher among patients who were persistently hypotensive after 3 hours of resuscitation for both the SSC compliant (persistent hypotension 37% vs not hypotensive 27.2%; p = 0.094) and noncompliant (30.1% vs 18.2%; p = 0.001, respectively). CONCLUSIONS AND RELEVANCE: Patients with a higher severity of illness and sepsis-induced hypotension identified in the ED were more likely to receive SSC-compliant care. SSC compliance was not associated with in-hospital mortality after adjusting for patient- and hospital-level differences. Higher mortality is seen among those who remain in shock after initial resuscitation, regardless of SSC compliance.

Perceived Hospital Stress, Severe Acute Respiratory Syndrome Coronavirus 2 Activity, and Care Process Temporal Variance During the COVID-19 Pandemic.

OBJECTIVES: The COVID-19 pandemic threatened standard hospital operations. We sought to understand how this stress was perceived and manifested within individual hospitals and in relation to local viral activity. DESIGN: Prospective weekly hospital stress survey, November 2020-June 2022. SETTING: Society of Critical Care Medicine's Discovery Severe Acute Respiratory Infection-Preparedness multicenter cohort study. SUBJECTS: Thirteen hospitals across seven U.S. health systems. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 839 hospital-weeks of data over 85 pandemic weeks and five viral surges. Perceived overall hospital, ICU, and emergency department (ED) stress due to severe acute respiratory infection patients during the pandemic were reported by a mean of 43% ( sd , 36%), 32% (30%), and 14% (22%) of hospitals per week, respectively, and perceived care deviations in a mean of 36% (33%). Overall hospital stress was highly correlated with ICU stress (ρ = 0.82; p < 0.0001) but only moderately correlated with ED stress (ρ = 0.52; p < 0.0001). A county increase in 10 severe acute respiratory syndrome coronavirus 2 cases per 100,000 residents was associated with an increase in the odds of overall hospital, ICU, and ED stress by 9% (95% CI, 5-12%), 7% (3-10%), and 4% (2-6%), respectively. During the Delta variant surge, overall hospital stress persisted for a median of 11.5 weeks (interquartile range, 9-14 wk) after local case peak. ICU stress had a similar pattern of resolution (median 11 wk [6-14 wk] after local case peak; p = 0.59) while the resolution of ED stress (median 6 wk [5-6 wk] after local case peak; p = 0.003) was earlier. There was a similar but attenuated pattern during the Omicron BA.1 subvariant surge. CONCLUSIONS: During the COVID-19 pandemic, perceived care deviations were common and potentially avoidable patient harm was rare. Perceived hospital stress persisted for weeks after surges peaked.

Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial.

Importance: Sepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors. Objective: To describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial. Design, Setting, and Participants: This prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022. Interventions: The intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo. Main Outcomes and Measures: Cognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization. Results: After exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups. Conclusions and Relevance: In survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors. Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity.

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES: To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN SETTING AND PARTICIPANTS: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log2 increase, 1.53; 95% CI, 1.17-2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10-5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

Biological Effects of Intravenous Vitamin C on Neutrophil Extracellular Traps and the Endothelial Glycocalyx in Patients with Sepsis-Induced ARDS.

(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.

Severe Acute Respiratory Infection-Preparedness: Protocol for a Multicenter Prospective Cohort Study of Viral Respiratory Infections.

Respiratory virus infections cause significant morbidity and mortality ranging from mild uncomplicated acute respiratory illness to severe complications, such as acute respiratory distress syndrome, multiple organ failure, and death during epidemics and pandemics. We present a protocol to systematically study patients with severe acute respiratory infection (SARI), including severe acute respiratory syndrome coronavirus 2, due to respiratory viral pathogens to evaluate the natural history, prognostic biomarkers, and characteristics, including hospital stress, associated with clinical outcomes and severity. DESIGN: Prospective cohort study. SETTING: Multicenter cohort of patients admitted to an acute care ward or ICU from at least 15 hospitals representing diverse geographic regions across the United States. PATIENTS: Patients with SARI caused by infection with respiratory viruses that can cause outbreaks, epidemics, and pandemics. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measurements include patient demographics, signs, symptoms, and medications; microbiology, imaging, and associated tests; mechanical ventilation, hospital procedures, and other interventions; and clinical outcomes and hospital stress, with specimens collected on days 0, 3, and 7-14 after enrollment and at discharge. The primary outcome measure is the number of consecutive days alive and free of mechanical ventilation (VFD) in the first 30 days after hospital admission. Important secondary outcomes include organ failure-free days before acute kidney injury, shock, hepatic failure, disseminated intravascular coagulation, 28-day mortality, adaptive immunity, as well as immunologic and microbiologic outcomes. CONCLUSIONS: SARI-Preparedness is a multicenter study under the collaboration of the Society of Critical Care Medicine Discovery, Resilience Intelligence Network, and National Emerging Special Pathogen Training and Education Center, which seeks to improve understanding of prognostic factors associated with worse outcomes and increased resource utilization. This can lead to interventions to mitigate the clinical impact of respiratory virus infections associated with SARI.

SWEAT ICU-An Observational Study of Physician Workload and the Association of Physician Outcomes in Academic ICUs.

The optimal staffing model for physicians in the ICU is unknown. Patient-to-intensivist ratios may offer a simple measure of workload and be associated with patient mortality and physician burnout. To evaluate the association of physician workload, as measured by the patient-to-intensivist ratio, with physician burnout and patient mortality. DESIGN: Cross-sectional observational study. SETTING: Fourteen academic centers in the United States from August 2020 to July 2021. SUBJECTS: We enrolled ICU physicians and collected data on adult ICU patients under the physician's care on the single physician-selected study day for each physician. MEASUREMENTS and MAIN RESULTS: The primary exposure was workload (self-reported number of patients' physician was responsible for) modeled as high (>14 patients) and low (≤14 patients). The primary outcome was burnout, measured by the Well-Being Index. The secondary outcome measure was 28-day patient mortality. We calculated odds ratio for burnout and patient outcomes using a multivariable logistic regression model and a binomial mixed effects model, respectively. We enrolled 122 physicians from 62 ICUs. The median patient-to-intensivist ratio was 12 (interquartile range, 10-14), and the overall prevalence of burnout was 26.4% (n = 32). Intensivist workload was not independently associated with burnout (adjusted odds ratio, 0.74; 95% CI, 0.24-2.23). Of 1,322 patients, 679 (52%) were discharged alive from the hospital, 257 (19%) remained hospitalized, and 347 (26%) were deceased by day 28; 28-day outcomes were unknown for 39 of patients (3%). Intensivist workload was not independently associated with 28-day patient mortality (adjusted odds ratio, 1.33; 95% CI, 0.92-1.91). CONCLUSIONS: In our cohort, approximately one in four physicians experienced burnout on the study day. There was no relationship be- tween workload as measured by patient-to-intensivist ratio and burnout. Factors other than the number of patients may be important drivers of burnout among ICU physicians.

Redefining critical illness.

Research and practice in critical care medicine have long been defined by syndromes, which, despite being clinically recognizable entities, are, in fact, loose amalgams of heterogeneous states that may respond differently to therapy. Mounting translational evidence-supported by research on respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-suggests that the current syndrome-based framework of critical illness should be reconsidered. Here we discuss recent findings from basic science and clinical research in critical care and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus on the underlying biological changes that underpin critical illness states and that may be amenable to treatment. We hypothesize that such an approach will accelerate critical care research, leading to a richer understanding of the pathobiology of critical illness and of the key determinants of patient outcomes. This, in turn, will support the design of more effective clinical trials and inform a more precise and more effective practice at the bedside.

Implementation of an EMS protocol to improve prehospital sepsis recognition.

PURPOSE: Optimal sepsis outcomes are achieved when sepsis is recognized early. Recognizing sepsis in the prehospital, EMS setting can be challenging and unreliable. The purpose of this study is to evaluate whether implementation of an EMS sepsis screening and prehospital alert protocol called PRESS (PREhospital SepsiS) is associated with improved sepsis recognition by EMS providers. DESIGN: We conducted a 12-month, before-after implementation study of the PRESS protocol in a large, public EMS system. The study intervention was a PRESS training program delivered to EMS providers. EMS patient inclusion criteria included: age ≥ 18 years, EMS systolic blood pressure < 110 mmHg, EMS heart rate > 90 bpm, and EMS respiratory rate > 20 bpm. Study exclusion criteria included the presence of any of following EMS conditions: trauma, cardiac arrest, pregnancy, toxic ingestion, or psychiatric emergency. Retrospective chart review was performed on all eligible EMS encounters during the study period. The primary outcome variable was the proportion of patients with sepsis who were identified by EMS providers. RESULTS: Approximately 300 EMS providers were trained to use PRESS. A total of 498 patient encounters met criteria for study inclusion; 222 were excluded, primarily due to trauma. A total of 276 patient encounters were analyzed. Sepsis recognition by EMS providers increased from 12% pre-PRESS protocol to 59% post-PRESS protocol (p < 0.001). In a post-hoc analysis of the post-PRESS cohort, septic patients who were identified by EMS received antibiotics 24 min faster than septic patients who were not identified by EMS [28 min (IQR 18-48) vs 52 (IQR 27-98), respectively, p = 0.021]. CONCLUSION: Implementation of an EMS sepsis screening and prehospital alert protocol was associated with an increase in sepsis recognition rates by EMS providers and a decrease in time to first antibiotic administration in the emergency department. Further studies are needed to evaluate the impact of this protocol in other populations.

The Future of Critical Care: Optimizing Technologies and a Learning Healthcare System to Potentiate a More Humanistic Approach to Critical Care.

While technological innovations are the invariable crux of speculation about the future of critical care, they cannot replace the clinician at the bedside. This article summarizes the work of the Society of Critical Care Medicine-appointed multiprofessional task for the Future of Critical Care. The Task Force notes that critical care practice will be transformed by novel technologies, integration of artificial intelligence decision support algorithms, and advances in seamless data operationalization across diverse healthcare systems and geographic regions and within federated datasets. Yet, new technologies will be relevant and meaningful only if they improve the very human endeavor of caring for someone who is critically ill.