Mortality Benefit From the Passive Leg Raise Maneuver in Guiding Resuscitation of Septic Shock Patients: A Systematic Review and Meta-Analysis of Randomized Trials.

BACKGROUND: Fluid therapy plays a major role in the management of critically ill patients. Yet assessment of intravascular volume in these patients is challenging. Different invasive and non-invasive methods have been used with variable results. The passive leg raise (PLR) maneuver has been recommended by international guidelines as a means to determine appropriate fluid resuscitation. We performed this systematic review and meta-analysis to determine if using this method of volume assessment has an impact on mortality outcome in patients with septic shock. METHODS: This study is a systematic review and meta-analysis. We searched available data in the MEDLINE, CINAHL, EMBASE, and CENTRAL databases from inception until October 2020 for prospective, randomized, controlled trials that compared PLR-guided fluid resuscitation to standard care in adult patients with septic shock. Our primary outcome was mortality at the longest duration of follow-up. RESULTS: We screened 1,425 article titles and abstracts. Of the 23 full-text articles reviewed, 5 studies with 462 patients met our eligibility criteria. Odds ratios (ORs) and associated 95% confidence intervals (CIs) for mortality at the longest reported time interval were calculated for each study. Using random effects modeling, the pooled OR (95% CI) for mortality with a PLR-guided resuscitation strategy was 0.82 (0.52 -1.30). The included studies were not blinded and they ranged from having low to high risk of bias using the Cochrane Risk of Bias Tool. CONCLUSION: Our analysis showed there was no statistically significant difference in mortality among septic shock patients treated with PLR-guided resuscitation vs. those with standard care.

AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19.

BACKGROUND: AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT). METHODS: We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients. RESULTS: A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission. CONCLUSIONS: AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission.

Use of Biomarkers to Identify Acute Kidney Injury to Help Detect Sepsis in Patients With Infection.

OBJECTIVES: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care. DESIGN: Retrospective, international, Sapphire study. SETTING: Academic Medical Center. PATIENTS: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We stratified patients enrolled in the Sapphire study into three groups-those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2-3 acute kidney injury within the first 3 days compared with 14% without stage 2-3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53-11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2-3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8-34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury. CONCLUSIONS: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria.

Mechanistic study of the cause of decreased blood 1,25-Dihydroxyvitamin D in sepsis.

BACKGROUND: Vitamin D deficiency, determined by blood levels of 25-hydroxyvitamin D [25(OH) D, i.e. the major vitamin D form in blood], has been shown to associate with all-cause mortalities. We recently demonstrated that blood levels of 1,25-dihydroxyvitamin D [1,25(OH)2D, i.e. the active vitamin D] were significantly lower in non-survivors compared to survivors among sepsis patients. Unexpectedly, despite the well documented roles of 1,25(OH)2D in multiple biological functions such as regulation of immune responses, stimulation of antimicrobials, and maintenance of barrier function, 1,25(OH)2D supplementation failed to improve disease outcomes. These previous findings suggest that, in addition to 1,25(OH)2D deficiency, disorders leading to the 1,25(OH)2D deficiency also contribute to mortality among sepsis patients. Therefore, this study investigated the mechanisms leading to sepsis-associated 1,25(OH)2D deficiency. METHODS: We studied mechanisms known to regulate kidney 25-hydroxylvitamin D 1α-hydroxylase which physiologically catalyzes the conversion of 25(OH) D into 1,25(OH)2D. Such mechanisms included parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 23 (FGF-23), and kidney function. RESULTS: We demonstrated in both human subjects and mice that sepsis-associated 1,25(OH)2D deficiency could not be overcome by increased production of PTH which stimulates 1α-hydroxylase. Further studies showed that this failure of PTH to maintain blood 1,25(OH)2D levels was associated with decreased blood levels of IGF-1, increased blood levels of FGF-23, and kidney failure. Since the increase in blood levels of FGF-23 is known to associate with kidney failure, we further investigated the mechanisms leading to sepsis-induced decrease in blood levels of IGF-1. Our data showed that blood levels of growth hormone, which stimulates IGF-1 production in liver, were increased but could not overcome the IGF-1 deficiency. Additionally, we found that the inability of growth hormone to restore the IGF-1 deficiency was associated with suppressed expression and signaling of growth hormone receptor in liver. CONCLUSIONS: Because FGF-23 and IGF-1 have multiple biological functions besides their role in regulating kidney 1α-hydroxylase, our data suggest that FGF-23 and IGF-1 are warranted for further investigation as potential agents for the correction of 1,25(OH)2D deficiency and for the improvement of survival among sepsis patients.

Life after sepsis: an international survey of survivors to understand the post-sepsis syndrome.

OBJECTIVE: In this study, we aim to describe the post-sepsis syndrome from the perspective of the sepsis survivors. DESIGN AND SETTING: The study is a prospective, observational online international survey. PARTICIPANTS: Sepsis survivors enrolled via social media from 13 September 2014 to 13 September 2016. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Physiologic, physical and psychological function post-sepsis; and patient satisfaction with sepsis-centered care. RESULTS: 1731 completed surveys from 41 countries were analyzed, with 79.9% female respondents, age 47.6 ± 14.4 years. The majority of respondents (47.8%) had sepsis within the last year. Survivors reported an increase in sensory, integumentary, digestive, breathing, chest pain, kidney and musculoskeletal problems after sepsis (all P-value <0.0001). Physical functions such as daily chores, running errands, spelling, reading and reduced libido posed increased difficulty (all P-value <0.0001). Within 7 days prior to completing the survey, the survivors reported varying degrees of anxiety, depression, fatigue and sleep disturbance. Sepsis survivors reported dissatisfaction with a number of hospital support services, with up to 29.3% of respondents stating no social services support was provided for their condition. CONCLUSIONS: Sepsis survivors suffer from a myriad of physiologic, physical and psychological challenges. Survivors overall reveal dissatisfaction with sepsis-related care, suggesting areas for improvement both in-hospital and post-discharge.

Patient-Centered Structured Interdisciplinary Bedside Rounds in the Medical ICU.

OBJECTIVES: We examined the effects of introducing patient-centered structured interdisciplinary bedside rounds in the medical ICU with respect to rounding efficiency, provider satisfaction, and patient/family satisfaction. DESIGN: A prospective, nonblinded, nonrandomized, parallel group study from June 21, 2016, to August 15, 2016. SETTING: The medical ICU at a tertiary care academic medical center. SUBJECTS: A consecutive sample of adult patients, family members, and healthcare providers. The patients and healthcare providers were arbitrarily assigned to either the patient-centered structured interdisciplinary bedside rounds or nonstructured interdisciplinary bedside round care team. INTERVENTIONS: Healthcare providers on the patient-centered structured interdisciplinary bedside rounds team were educated about their respective roles and the information they were expected to discuss on rounds each day. Rounds completion data and satisfaction questionnaires from healthcare providers, patients, and family members were obtained from both patient-centered structured interdisciplinary bedside rounds and nonstructured interdisciplinary bedside round teams. MEASUREMENTS AND MAIN RESULTS: Data were obtained from 367 patient-centered structured interdisciplinary bedside rounds and 298 nonstructured interdisciplinary bedside round patient encounters. Family members were present during 31.1% rounding encounters on the patient-centered structured interdisciplinary bedside rounds team and 10.1% encounters on the nonstructured interdisciplinary bedside round team (p < 0.01). Total rounding and interruption times were significantly shorter on patient-centered structured interdisciplinary bedside rounds compared with nonstructured interdisciplinary bedside round patients, 16.9 ± 10.0 versus 22.4 ± 14.9 and 2.0 ± 2.2 versus 3.9 ± 5.5 minutes, respectively (both p < 0.01). Mechanical ventilation, patient-centered structured interdisciplinary bedside rounds, and attending style independently contributed to the earlier completion of rounds (all p < 0.01). Surveys of 338 healthcare provider encounters on the patient-centered structured interdisciplinary bedside rounds team compared with 301 nonstructured interdisciplinary bedside round encounters showed perceptions of improved communication of patient management plans, increased input from the entire team, and clarity on task assignments (all p < 0.05). The attending physicians provided teaching points on 51.2% of patient-centered structured interdisciplinary bedside rounds compared with 33.9% of nonstructured interdisciplinary bedside round patient encounters (p < 0.01). For the patients and family members surveyed, 38 patient-centered structured interdisciplinary bedside rounds, and 30 nonstructured interdisciplinary bedside round, there were no differences in measures of satisfaction. CONCLUSIONS: Patient-centered structured interdisciplinary bedside rounds provide a venue for increased rounding efficiency, provider satisfaction, and consistent teaching, without impacting patient/family perception.

Comparative Effectiveness of Second Vasoactive Agents in Septic Shock Refractory to Norepinephrine.

OBJECTIVE: We aim to identify the appropriate vasoactive agent in patients with septic shock who are refractory to optimal doses of norepinephrine. METHODS: In this retrospective observational cohort study over a 4-year period, patients who received norepinephrine within 24 hours of ICU admission and a second agent within 48 hours were enrolled. RESULTS: Among 2640 patients screened, 234 patients were enrolled, aged 60.8 ± 17.8 years, Acute Physiology and Chronic Health Evaluation IV 98.3 ± 27.5, 81.6% mechanically ventilated, and 65.8% in-hospital mortality. Within 96 hours, 2.8 ± 1.0 vasoactive agents were administered. Fifty, 50, 66, and 68 patients received dobutamine, dopamine, phenylephrine, and vasopressin as the second agent, with crude in-hospital mortality 40.0%, 66.0%, 74.2%, and 76.5%, respectively, P < .001. Survival analysis showed a statistically significant difference in survival time by second vasoactive agent, P < .001. After adjusting for confounding variables, dobutamine showed significant decreased odds ratio (OR) for mortality compared to vasopressin: OR 0.34 (95% confidence interval 0.14-0.84, P = .04). The relative risk of dying was 55.8% lower in patients receiving dobutamine versus vasopressin, P < .01. CONCLUSION: Dobutamine is associated with decreased mortality compared to other second vasoactive agents in septic shock when norepinephrine is not sufficient. A prospective randomized trial examining the outcome impact of the second vasoactive agent is needed.

Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor-Binding Protein 7 for Risk Stratification of Acute Kidney Injury in Patients With Sepsis.

OBJECTIVES: To examine the performance of the urinary biomarker panel tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 in patients with sepsis at ICU admission. To investigate the effect of nonrenal organ dysfunction on tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 in this population. METHOD: In this ancillary analysis, we included patients with sepsis who were enrolled in either of two trials including 39 ICUs across Europe and North America. The primary endpoint was moderate-severe acute kidney injury (equivalent to Kidney Disease Improving Global Outcome stage 2-3) within 12 hours of enrollment. We assessed biomarker performance by calculating the area under the receiver operating characteristic curve, sensitivity, specificity, and negative and positive predictive values at three cutoffs: 0.3, 1.0, and 2.0 (ng/mL)/1,000. We also calculated nonrenal Sequential Organ Failure Assessment scores for each patient on enrollment and compared tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 results in patients with and without acute kidney injury and across nonrenal Sequential Organ Failure Assessment scores. Finally, we constructed a clinical model for acute kidney injury in this population and compared the performance of the model with and without tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7. RESULTS: We included 232 patients in the analysis and 40 (17%) developed acute kidney injury. We observed significantly higher urine tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 in patients with acute kidney injury than without acute kidney injury in both patients with low and high nonrenal Sequential Organ Failure Assessment scores (p < 0.001). The area under the receiver operating characteristic curve (95% CI) of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 was 0.84 (0.73-0.92) and 0.85 (0.76-0.94), in low and high nonrenal Sequential Organ Failure Assessment score subgroups. Performance of the tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 test was not modified by nonrenal Sequential Organ Failure Assessment (p = 0.70). In multivariate analysis, the addition of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 significantly improved the performance of a clinical model for predicting acute kidney injury (p = 0.015). CONCLUSION: Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 accurately predicts acute kidney injury in septic patients with or without other organ failures.

Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE.

Prior to 2001 there was no standard for early management of severe sepsis and septic shock in the emergency department. In the presence of standard or usual care, the prevailing mortality was over 40-50 %. In response, a systems-based approach, similar to that in acute myocardial infarction, stroke and trauma, called early goal-directed therapy was compared to standard care and this clinical trial resulted in a significant mortality reduction. Since the publication of that trial, similar outcome benefits have been reported in over 70 observational and randomized controlled studies comprising over 70,000 patients. As a result, early goal-directed therapy was largely incorporated into the first 6 hours of sepsis management (resuscitation bundle) adopted by the Surviving Sepsis Campaign and disseminated internationally as the standard of care for early sepsis management. Recently a trio of trials (ProCESS, ARISE, and ProMISe), while reporting an all-time low sepsis mortality, question the continued need for all of the elements of early goal-directed therapy or the need for protocolized care for patients with severe and septic shock. A review of the early hemodynamic pathogenesis, historical development, and definition of early goal-directed therapy, comparing trial conduction methodology and the changing landscape of sepsis mortality, are essential for an appropriate interpretation of these trials and their conclusions.

Variations in organism-specific severe sepsis mortality in the United States: 1999-2008.

OBJECTIVE: Recent studies have reported decreased overall severe sepsis mortality, but associations with organism trends have not yet been investigated. This study explored organism-specific severe sepsis mortality trends from 1999 to 2008 in a large hospital-based administrative database. DESIGN: Secondary data analysis using the Nationwide Inpatient Sample. SETTING: United States hospitals sampled in the Nationwide Inpatient Sample dataset. PATIENTS: This sample approximates a stratified 20% sample of all nonfederal, short-term, general, and specialty hospitals serving adults in the United States. Severe sepsis hospitalizations and organism-specific causes were identified using predetermined International Classification of Diseases, 9th Revision, Clinical Modification codes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analysis was conducted using descriptive Cox proportional hazards and linear regression trend analysis. Adjustments were made for the influence of demographics, comorbidities, number of organisms, and number of organ failures on hospital mortality. The data for 5,033,257 severe sepsis hospitalizations were examined and revealed decreased in-hospital mortality from 40.0% to 27.8% during the study period. The leading cause of severe sepsis was 51.5% Gram-negative bacteria, followed by 45.6% Gram-positive, 1.7% anaerobic, and 1.2% fungal species. The most common Gram-negative organisms were 39.9% Escherichia coli and 17.6% Pseudomonas. Staphylococcus species (62.2% methicillin-sensitive Staphylococcus aureus and 22.6% Streptococcus) were the most commonly reported Gram-positive organisms. Crude mortality estimates were higher for anaerobic and fungal organisms, 34.5% and 31.4%, respectively. Among Gram-positive bacteria, mortality was highest for methicillin-sensitive S. aureus, 30.9%, whereas Pseudomonas was associated with the highest mortality for Gram-negative septicemia cases, 29.5%. After adjusting for covariates, anaerobes were associated with the highest mortality hazard of 1.31 (95% CI, 1.23-1.40). Methicillin-resistant S. aureus had the highest mortality hazard of 1.38 (1.33-1.44) for Gram-positive organisms, whereas all Gram-negative bacteria had decreased mortality hazards. CONCLUSIONS: We not only confirmed an overall decline in severe sepsis mortality from 1999 to 2008 but also identified previously unreported variations in organism-specific severe sepsis mortality. Gram-negative organisms predominate, whereas anaerobes and methicillin-resistant S. aureus are significant predictors of mortality. Future clinical trials exploring new treatments in severe sepsis should incorporate individual organism trends to elucidate potential effect on mortality.

Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.

RATIONALE: We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. OBJECTIVES: We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. METHODS: We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. MEASUREMENTS AND MAIN RESULTS: Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). CONCLUSIONS: Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

Real-time sonographically guided percutaneous dilatational tracheostomy using a long-axis approach compared to the landmark technique.

OBJECTIVES: Sonographic evaluation of neck anatomy before performing percutaneous dilatational tracheostomy (PDT) has been shown to predict PDT success. In this study, we compared the real-time, long-axis, in-plane approach to the traditional bronchoscopically guided landmark technique. METHODS: Data were analyzed from a prospectively maintained PDT database at a university tertiary care medical intensive care unit. A convenience sample of adult patients requiring PDT for prolonged mechanical ventilation dependence was enrolled. Critical care fellows, under direct supervision of an attending intensivist, performed all PDTs. Tracheostomy performance from the sonographically guided and landmark techniques was compared. RESULTS: Twenty-three patients were enrolled: 11 in the sonography group and 12 in the landmark group. Initial midline introducer needle puncture was achieved in 72.7% in the sonography group compared to 8.3% in the landmark group (P< .001). The mean number of introducer needle punctures ± SD was significantly lower in the sonography group compared to the landmark group (1.4 ± 0.7 versus 2.6 ± 0.9; P < .001). The total tracheostomy time was 11.4 ± 4.2 minutes in the sonography group versus 15.3 ± 6.8 minutes in the landmark group (P = .12). Sonography accurately predicted tracheal ring space insertion in 90.9% of patients. Procedural complications did not differ significantly between the groups. CONCLUSIONS: Percutaneous dilatational tracheostomy under real-time sonographic guidance using a long-axis approach may increase the rate of midline punctures and decrease the number of needle punctures when compared to the landmark technique. Sonographic guidance can also help guide accurate and efficient placement of a tracheostomy tube into the desired tracheal ring space.

Rapid identification of sepsis in the emergency department.

Objectives: Recent research has helped define the complex pathways in sepsis, affording new opportunities for advancing diagnostics tests. Given significant advances in the field, a group of academic investigators from emergency medicine, intensive care, pathology, and pharmacology assembled to develop consensus around key gaps and potential future use for emerging rapid host response diagnostics assays in the emergency department (ED) setting. Methods: A modified Delphi study was conducted that included 26 panelists (expert consensus panel) from multiple specialties. A smaller steering committee first defined a list of Delphi statements related to the need for and future potential use of a hypothetical sepsis diagnostic test in the ED. Likert scoring was used to assess panelists agreement or disagreement with statements. Two successive rounds of surveys were conducted and consensus for statements was operationally defined as achieving agreement or disagreement of 75% or greater. Results: Significant gaps were identified related to current tools for assessing risk of sepsis in the ED. Strong consensus indicated the need for a test providing an indication of the severity of dysregulated host immune response, which would be helpful even if it did not identify the specific pathogen. Although there was a relatively high degree of uncertainty regarding which patients would most benefit from the test, the panel agreed that an ideal host response sepsis test should aim to be integrated into ED triage and thus should produce results in less than 30 minutes. The panel also agreed that such a test would be most valuable for improving sepsis outcomes and reducing rates of unnecessary antibiotic use. Conclusion: The expert consensus panel expressed strong consensus regarding gaps in sepsis diagnostics in the ED and the potential for new rapid host response tests to help fill these gaps. These finding provide a baseline framework for assessing key attributes of evolving host response diagnostic tests for sepsis in the ED.

Patient and hospital characteristics associated with inpatient severe sepsis mortality in California, 2005-2010.

OBJECTIVES: The primary objective of this study was to identify which patient demographic, patient health, and hospital characteristics were associated with in-hospital mortality. A secondary objective was to determine the relative influence of these characteristics on mortality. DESIGN AND SETTING: Public-use data for 2005-2010 were used in this retrospective, cross-sectional analysis of discharges from nonfederal, general acute hospitals in California. A staged logistic regression approach was used to examine the relative influence of variables associated with in-hospital mortality. PATIENTS: A total of 1,213,219 patient discharges for adults (aged ≥18 yrs) having International Classification of Diseases-9 diagnosis and procedure codes indicating severe sepsis. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Patient demographics (age, gender, race, ethnicity, and payer category), patient health status (acute transfer, Charlson-Deyo comorbidity index, and organ failures), and hospital characteristics (ownership type, teaching status, bed size, annual patient days, acute discharges, emergency department visits, inpatient surgeries, severe sepsis as a percentage of all discharges, and year) were obtained from the California Office of Statewide Health Planning and Development. Overall, in-hospital mortality was 17.8%. There was a steady annual increase in the number of sepsis discharges, but a decrease in mortality throughout the study period. Mortality increased with age and was associated with white race, and Medicaid (Medi-Cal) and private insurance. Patient health status additionally explained inpatient mortality. Hospital volume measures were statistically significant in regression analysis, whereas static structural measures were not. There were modest associations between measures of annual treatment volume and likelihood of inpatient mortality, notably decreasing likelihood with more acute discharges and with greater severe sepsis volume. CONCLUSIONS: Although patient demographics and health status are the most important predictors of in-hospital mortality of patients with severe sepsis, hospital characteristics do play a substantial role. Findings regarding hospital volume can be used to improve processes and improve patient outcomes.

Measuring cardiac index with a focused cardiac ultrasound examination in the ED.

OBJECTIVES: Noninvasive technology may assist the emergency department (ED) physician in determining the hemodynamic status in critically ill patients. The objective of our study was to show that ED physicians can accurately measure cardiac index (CI) by performing a bedside focused cardiac ultrasound examination. METHODS: A convenience sample of adult subjects were prospectively enrolled. Cardiac index, left ventricular outflow tract (LVOT) diameter, velocity time integral (VTI), stroke volume index, and heart rate were obtained by trained ED physicians and a certified cardiac sonographer. The primary outcome was percent of optimal LVOT diameter and VTI measurements as verified by an expert cardiologist. RESULTS: One hundred patients were enrolled, with obtainable CI measurements in 97 patients. Cardiac index, LVOT diameter, VTI, stroke volume index, and heart rate measurements by ED physician were 2.42 ± 0.70 L min(-1) m(-2), 2.07 ± 0.22 cm, 18.30 ± 3.71 cm, 32.34 ± 7.92 mL beat(-1) m(-2), and 75.32 ± 13.45 beats/min, respectively. Measurements of LVOT diameter by ED physicians and sonographer were optimal in 90.0% (95% confidence interval, 82.6%-94.5) and 91.3% (73.2%-97.6%) of patients, respectively. Optimal VTI measurements were obtained in 78.4% (69.2%-85.4%) and 78.3% (58.1%-90.3%) of patients, respectively. In 23 patients, the correlation (r) for CI between ED physician and sonographer was 0.82 (0.60-0.92), with bias and limits of agreement of -0.11 (-1.06 to 0.83) L min(-1) m(-2) and percent difference of 12.4% ± 10.1%. CONCLUSIONS: Emergency department ED physicians can accurately measure CI using standard bedside ultrasound. A focused ultrasound cardiac examination to derive CI has potential use in the management of critical ill patients in the ED.

Implementation of early goal-directed therapy and the surviving sepsis campaign resuscitation bundle in Asia.

OBJECTIVE: To examine the impact of implementing sepsis bundle in multiple Asian countries, having 'team' vs. 'non-team' models of patient care. DESIGN: Prospective cohort study. SETTING: Eight urban hospitals, five countries in Asia. PARTICIPANTS: Adult patients with severe sepsis or septic shock. INTERVENTIONS: Implementation was divided into six quartiles: Baseline, Education and four Quality Improvement quartiles. MAIN OUTCOME MEASURES: Quarterly bundle compliance and in-hospital mortality with respect to bundle completion and implementation model. METHODS: In the team model, the implementation was championed by intensivists, where the bundle was completed in the intensive care unit. The non-team model led by emergency physicians completed the bundle in the emergency department as part of standard care. RESULTS: Five hundred and fifty-six patients were enrolled. The overall in-hospital mortality rate was 29.9%, and 67.1% of the patients had septic shock. Compliance to the bundle was 13.3, 26.9, 37.5, 45.9, 48.8 and 54.5% over the six quartiles of implementation (P < 0.01). With team model, compliance increased from 37.5% baseline to 88.2% in the sixth quartile (P < 0.01), whereas hospitals with a non-team model increased compliance from 5.2 to 39.5% (P < 0.01). Crude in-hospital mortality was better in the patients who received the entire bundle (24.5 vs. 32.7%, P = 0.04). Bundle completion was associated with crude in-hospital mortality reduction (odds ratio 0.67, 95% confidence interval 0.45-0.99), but this survival benefit disappeared after adjustment for confounding variables. CONCLUSIONS: Through education and quality improvement efforts, initially low sepsis bundle compliance was improved in Asia. A team model was more effective in achieving bundle compliance compared with a non-team model.

A multinational randomised study comparing didactic lectures with case scenario in a severe sepsis medical simulation course.

BACKGROUND: Medical simulation has been used to teach critical illness in a variety of settings. This study examined the effect of didactic lectures compared with simulated case scenario in a medical simulation course on the early management of severe sepsis. METHODS: A prospective multicentre randomised study was performed enrolling resident physicians in emergency medicine from four hospitals in Asia. Participants were randomly assigned to a course that included didactic lectures followed by a skills workshop and simulated case scenario (lecture-first) or to a course that included a skills workshop and simulated case scenario followed by didactic lectures (simulation-first). A pre-test was given to the participants at the beginning of the course, post-test 1 was given after the didactic lectures or simulated case scenario depending on the study group assignment, then a final post-test 2 was given at the end of the course. Performance on the simulated case scenario was evaluated with a performance task checklist. RESULTS: 98 participants were enrolled in the study. Post-test 2 scores were significantly higher than pre-test scores in all participants (80.8 ± 12.0% vs 65.4 ± 12.2%, p<0.01). There was no difference in pre-test scores between the two study groups. The lecture-first group had significantly higher post-test 1 scores than the simulation-first group (78.8 ± 10.6% vs 71.6 ± 12.6%, p<0.01). There was no difference in post-test 2 scores between the two groups. The simulated case scenario task performance completion was 90.8% (95% CI 86.6% to 95.0%) in the lecture-first group compared with 83.8% (95% CI 79.5% to 88.1%) in the simulation-first group (p=0.02). CONCLUSIONS: A medical simulation course can improve resident physician knowledge in the early management of severe sepsis. Such a course should include a comprehensive curriculum that includes didactic lectures followed by simulation experience.

Effectiveness of Angiotensin II for Catecholamine Refractory Septic or Distributive Shock on Mortality: A Propensity Score Weighted Analysis of Real-World Experience in the Medical ICU.

Angiotensin II (ATII) was approved for septic or other distributive shock due to its property of increasing blood pressure within 3 hours. Limited data exist regarding its effectiveness when used in real-world clinical practice. OBJECTIVES: This study examined ATII as a third-line vasopressor based on institutional approval. DESIGN: Retrospective observational cohort study. SETTING AND PARTICIPANTS: Medical ICU at an academic tertiary care medical center. Adult patients requiring 3 or more vasopressor agents for septic shock or other forms of distributed shock from September 1, 2018, to January 31, 2020. MAIN OUTCOMES AND MEASURES: Effect of ATII after norepinephrine and vasopressin on mortality and mean arterial blood pressure response after 3 hours of administration. RESULTS: One-hundred forty-seven patients, 56 receiving ATII and 91 receiving another vasopressor (non-ATII), were enrolled. Patients in the ATII group had higher mortality compared to the non-ATII group, and more required 5 or greater vasopressor agents (p < 0.01). After propensity score weighting, there remains a trend in higher mortality in the ATII compared to non-ATII group, but not statistically significant (86.0% vs 71.0%, p = 0.16). More patients in the ATII group continued to require 5 or greater vasopressor agents compared to the non-ATII group after propensity score weighting (45.9% vs 12.5%, p < 0.01). SOFA score was the only variable associated with mortality (OR = 1.25, 95% CI, 1.05-1.49; p = 0.01). Patients were considered a "responder" if mean arterial pressure greater than 65 mm Hg at 3 hours after the third vasopressor was initiated. Among the ATII group, 37.5% patients were responders compared to 45.1% responders in the non-ATII group (relative risk = 1.07, 95% CI, 0.6-1.93; p = 0.81). CONCLUSIONS AND RELEVANCE: Although previous data support the use of ATII due to its favorable hemodynamic response in patients with distributive shock, there was no observed benefit in mortality or hemodynamic response with ATII as a third-line vasopressor in our study of real-world patients.

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.

Lactate in the critically ill patients: an outcome marker with the times.

Lactic acid was first discovered in human blood in 1843. Since then it has been used as a prognosticator of outcome in critical illness. Regardless of its etiology, lactate's presence and trend over time have been shown to be independently associated with mortality. Two dynamic lactate measures, the time-weighted average lactate and the absolute change in lactate over the first 24 hours in the ICU, were recently shown to be better than static lactate measurements in predicting hospital and ICU deaths.