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.

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.

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.

Effects of Timing of Invasive Mechanical Ventilation in Patients with Shock. An Analysis of the Multicenter Prospective Observational VOLUME-CHASERS Cohort.

Objectives: Describe the variation in practice and identify predictors of invasive mechanical ventilation (IMV) use in shock. Explore the association between the timing of IMV initiation ("Early" vs. "Delayed") on shock duration. Design: Multicenter, prospective, observational cohort study between September 2017 and February 2018 Setting: 34 hospitals in the United States and Jordan. Patients: Consecutive, adult, critically ill patients with shock, defined as a systolic blood pressure less than or equal to 90mm Hg, mean arterial pressure less than or equal to 65mm Hg, or need for a vasopressor medication. Interventions: None. Measurements and Main Results: "Early" IMV was defined as starting IMV 0-6 hours of shock onset and "Delayed" IMV was defined as starting IMV between 6 and 48 hours of shock onset. The primary outcome was shock-free days, defined as the number of days without shock after the first 48 hours of shock onset. Variation and predictors of IMV use were examined within the whole cohort as well as the subgroup of those intubated within 0-48 hours of shock onset. Mixed effects modeling with hospital site as a random effect showed that there was 7% variation by site in the use and timing of IMV in this shock cohort. In a propensity-matched model for the timing of IMV, "Early" IMV after shock onset was associated with more shock-free days when compared to "Delayed" IMV in those intubated within 0-48 hours of shock onset (Beta coefficient 0.65 days, 95% CI 0.14-1.16 days). Conclusions: Timing of IMV initiation for patients in shock has potentially important implications for patient outcomes and merits further study.

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.

Any Role of High-Dose Vitamin C for Septic Shock in 2021?

While the use of vitamin C as a therapeutic agent has been investigated since the 1950s, there has been substantial recent interest in the role of vitamin C supplementation in critical illness and particularly, sepsis and septic shock. Humans cannot synthesize vitamin C and rely on exogenous intake to maintain a plasma concentration of approximately 70 to 80 µmol/L. Vitamin C, in healthy humans, is involved with antioxidant function, wound healing, endothelial function, and catecholamine synthesis. Its function in the human body informs the theoretical basis for why vitamin C supplementation may be beneficial in sepsis/septic shock.Critically ill patients can be vitamin C deficient due to low dietary intake, increased metabolic demands, inefficient recycling of vitamin C metabolites, and loss due to renal replacement therapy. Intravenous supplementation is required to achieve supraphysiologic serum levels of vitamin C. While some clinical studies of intravenous vitamin C supplementation in sepsis have shown improvements in secondary outcome measures, none of the randomized clinical trials have shown differences between vitamin C supplementation and standard of care and/or placebo in the primary outcome measures of the trials. There are some ongoing studies of high-dose vitamin C administration in patients with sepsis and coronavirus disease 2019; the majority of evidence so far does not support the routine supplementation of vitamin C in patients with sepsis or septic shock.

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. Design, Setting, and Participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. Main Outcomes and Measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. Conclusions and Relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Variation in Fluid and Vasopressor Use in Shock With and Without Physiologic Assessment: A Multicenter Observational Study.

OBJECTIVES: To characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality. DESIGN: Multicenter prospective cohort study between September 2017 and February 2018. SETTINGS: Thirty-four hospitals in the United States and Jordan. PATIENTS: Consecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Of 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, -0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45-2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19-0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27-2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63-1.18). CONCLUSIONS: The use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration.

Evaluation of Vasopressor Exposure and Mortality in Patients With Septic Shock.

OBJECTIVES: The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. DESIGN: Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. SETTING: Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1). PATIENTS: Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851-5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 µg/min norepinephrine equivalents (3.4-18.1 µg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 µg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16-1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. CONCLUSIONS: Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.

Association between hospital mortality and inspiratory airway pressures in mechanically ventilated patients without acute respiratory distress syndrome: a prospective cohort study.

BACKGROUND: Higher inspiratory airway pressures are associated with worse outcomes in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). This relationship, however, has not been well investigated in patients without ARDS. We hypothesized that higher driving pressures (ΔP) and plateau pressures (Pplat) are associated with worse patient-centered outcomes in mechanically ventilated patients without ARDS as well as those with ARDS. METHODS: Using data collected during a prospective, observational cohort study of 6179 critically ill participants enrolled in 59 ICUs across the USA, we used multivariable logistic regression to determine whether ΔP and Pplat at enrollment were associated with hospital mortality among 1132 mechanically ventilated participants. We stratified analyses by ARDS status. RESULTS: Participants without ARDS (n = 822) had lower average severity of illness scores and lower hospital mortality (27.3% vs. 38.7%; p <  0.001) than those with ARDS (n = 310). Average Pplat (20.6 vs. 23.9 cm H2O; p <  0.001), ΔP (14.3 vs. 16.0 cm H2O; p <  0.001), and positive end-expiratory pressure (6.3 vs. 7.9 cm H2O; p <  0.001) were lower in participants without ARDS, whereas average tidal volumes (7.2 vs. 6.8 mL/kg PBW; p <  0.001) were higher. Among those without ARDS, higher ΔP (adjusted OR = 1.36 per 7 cm H2O, 95% CI 1.14-1.62) and Pplat (adjusted OR = 1.42 per 8 cm H2O, 95% CI 1.17-1.73) were associated with higher mortality. We found similar relationships with mortality among those participants with ARDS. CONCLUSIONS: Higher ΔP and Pplat are associated with increased mortality for participants without ARDS. ΔP may be a viable target for lung-protective ventilation in all mechanically ventilated patients.

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial.

Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 µg/mL; difference, 7.94 µg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

A Case for Change in Adult Critical Care Training for Physicians in the United States: A White Paper Developed by the Critical Care as a Specialty Task Force of the Society of Critical Care Medicine.

OBJECTIVES: In the United States, physician training in Critical Care Medicine has developed as a subspecialty of different primary boards, despite significant commonality in knowledge and skills. The Society of Critical Care Medicine appointed a multidisciplinary Task Force to examine alternative approaches for future training. DESIGN: The Task Force reviewed the literature and conducted informal discussions with key stakeholders. Specific topics reviewed included the history of critical care training, commonalities among subspecialties, developments since a similar review in 2004, international experience, quality patient care, and financial and workforce issues. MAIN RESULTS: The Task Force believes that options for future training include establishment of a 1) primary specialty of critical care; 2) unified fellowship and certification process; or 3) unified certification process with separate fellowship programs within the current specialties versus 4) maintaining multiple specialty-based fellowship programs and certification processes. CONCLUSIONS: 1) Changing the current Critical Care Medicine training paradigms may benefit trainees and patient care. 2) Multiple pathways into critical care training for all interested trainees are desirable for meeting future intensivist workforce demands. 3) The current subspecialties within separate boards are not "distinct and well-defined field[s] of medical practice" per the American Board of Medical Specialties. Recommendations for first steps are as follows: 1) as the society representing multidisciplinary critical care, the Society of Critical Care Medicine has an opportunity to organize a meeting of all stakeholders to discuss the issues regarding Critical Care Medicine training and consider cooperative approaches for the future. 2) A common Critical Care Medicine examination, possibly with a small percentage of base-specialty-specific questions, should be considered. 3) Institutions with multiple Critical Care Medicine fellowship programs should consider developing joint, multidisciplinary training curricula. 4) The boards that offer Critical Care Medicine examinations, along with national critical care societies, should consider ways to shorten training time.

Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review and meta-analysis addresses the efficacy and safety of corticosteroids in critically ill patients with sepsis. DATA SOURCES: We updated a comprehensive search of MEDLINE, EMBASE, CENTRAL, and LILACS, and unpublished sources for randomized controlled trials that compared any corticosteroid to placebo or no corticosteroid in critically ill children and adults with sepsis. STUDY SELECTION: Reviewers conducted duplicate screening of citations, data abstraction, and, using a modified Cochrane risk of bias tool, individual study risk of bias assessment. DATA EXTRACTION: A parallel guideline committee provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. We assessed overall certainty in evidence using Grading of Recommendations Assessment, Development and Evaluation methodology and performed all analyses using random-effect models. For subgroup analyses, we performed metaregression and considered p value less than 0.05 as significant. DATA SYNTHESIS: Forty-two randomized controlled trials including 10,194 patients proved eligible. Based on low certainty, corticosteroids may achieve a small reduction or no reduction in the relative risk of dying in the short-term (28-31 d) (relative risk, 0.93; 95% CI, 0.84-1.03; 1.8% absolute risk reduction; 95% CI, 4.1% reduction to 0.8% increase), and possibly achieve a small effect on long-term mortality (60 d to 1 yr) based on moderate certainty (relative risk, 0.94; 95% CI, 0.89-1.00; 2.2% absolute risk reduction; 95% CI, 4.1% reduction to no effect). Corticosteroids probably result in small reductions in length of stay in ICU (mean difference, -0.73 d; 95% CI, -1.78 to 0.31) and hospital (mean difference, -0.73 d; 95% CI, -2.06 to 0.60) (moderate certainty). Corticosteroids result in higher rates of shock reversal at day 7 (relative risk, 1.26; 95% CI, 1.12-1.42) and lower Sequential Organ Failure Assessment scores at day 7 (mean difference, -1.39; 95% CI, -1.88 to -0.89) (high certainty). Corticosteroids likely increase the risk of hypernatremia (relative risk, 1.64; 95% CI, 1.32-2.03) and hyperglycemia (relative risk, 1.16; 95% CI, 1.08-1.24) (moderate certainty), may increase the risk of neuromuscular weakness (relative risk, 1.21; 95% CI, 1.01-1.52) (low certainty), and appear to have no other adverse effects (low or very low certainty). Subgroup analysis did not demonstrate a credible subgroup effect on any of the outcomes of interest (p > 0.05 for all). CONCLUSIONS: In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness.

Evaluation of RBC Transfusion Practice in Adult ICUs and the Effect of Restrictive Transfusion Protocols on Routine Care.

OBJECTIVE: Research supports the efficacy and safety of restrictive transfusion protocols to reduce avoidable RBC transfusions, but evidence of their effectiveness in practice is limited. This study assessed whether admission to an ICU with an restrictive transfusion protocol reduces the likelihood of transfusion for adult patients. DESIGN: Observational study using data from the multicenter, cohort Critical Illness Outcomes Study. Patient-level analyses were conducted with RBC transfusion on day of enrollment as the outcome and admission to an ICU with a restrictive transfusion protocol as the exposure of interest. Covariates included demographics, hospital course (e.g., lowest hematocrit, blood loss), severity of illness (e.g., Sequential Organ Failure Assessment score), interventions (e.g., sedation/analgesia), and ICU characteristics (e.g., size). Multivariable logistic regression modeling assessed the independent effects of restrictive transfusion protocols on transfusions. SETTING: Fifty-nine U.S. ICUs. PATIENTS: A total of 6,027 adult ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 59 study ICUs, 24 had an restrictive transfusion protocol; 2,510 patients (41.6%) were in an ICU with an restrictive transfusion protocol. The frequency of RBC transfusion among patients with severe (hematocrit, < 21%), moderate (hematocrit, 21-30%), and mild (hematocrit, > 30%) anemia in restrictive transfusion protocol ICUs was 67%, 19%, and 4%, respectively, compared with 60%, 14%, and 2% for those in ICUs without an restrictive transfusion protocol. Only 27% of transfusions were associated with a hematocrit less than 21%. Adjusting for confounding factors, restrictive transfusion protocols independently reduced the odds of transfusion in moderate anemia with an odds ratio of 0.59 (95% CI, 0.36-0.96) while demonstrating no effect in mild (p = 0.93) or severe (p = 0.52) anemia. CONCLUSIONS: In this sample of ICU patients, transfusions often occurred outside evidence-based guidelines, but admission to an ICU with an restrictive transfusion protocol did reduce the risk of transfusion in moderately anemic patients controlling for patient and ICU factors. This study supports the effectiveness of restrictive transfusion protocols for influencing transfusions in clinical practice.