Cellular host response sepsis test for risk stratification of patients in the emergency department: A pooled analysis.

OBJECTIVES: Sepsis is one of the most common, costly, and misdiagnosed conditions in U.S. emergency departments (EDs). ED providers often treat on nonspecific signs, subjective suspicion, or presumption of infection, resulting in over- and undertreatment. An increased understanding of host response has opened a new direction for sepsis diagnostics. The IntelliSep test is a U.S. Food and Drug Administration-cleared cellular host response diagnostic that could help distinguish sepsis in ED settings. Our objective was to evaluate the potential of the cellular host response test to expedite appropriate care for patients who present with signs of infection. METHODS: We performed a pooled analysis of five adult (≥18 years) cohorts enrolled at seven geographically diverse U.S. sites in separate studies. Structured blinded adjudication was used to classify presence or absence of sepsis, and only patients with high confidence in the adjudicated label were included (n = 1002), defined as patients for whom there was consensus in the determination of sepsis per the Sepsis-3 and severe sepsis per the Sepsis-2 definitions between both the independent adjudication panel and the site-level physician. RESULTS: Among patients with signs or suspicion of infection, the test achieved similar or better performance compared to other indicators in identifying patients at high risk for sepsis (specificity > 83%) and significantly superior performance in identifying those at low risk (sensitivity > 92%; 0% sepsis-associated mortality). The test also stratified severity of illness, as shown by 30-day in-hospital mortality (p < 0.001), hospital length of stay (p < 0.01), and use of hospital resources (p < 0.001). CONCLUSIONS: Our data suggest that the cellular host response test provides clinically actionable results for patients at both high and low risk for sepsis and provides a rapid, objective means for risk stratification of patients with signs of infection. If integrated into standard of care, the test may help improve outcomes and reduce unnecessary antibiotic use.

Validation of a Novel, Rapid Sepsis Diagnostic for Emergency Department Use.

OBJECTIVES: To assess the in vitro IntelliSep test, a microfluidic assay that quantifies the state of immune activation by evaluating the biophysical properties of leukocytes, as a rapid diagnostic for sepsis. DESIGN: Prospective cohort study. SETTING: Five emergency departments (EDs) in Louisiana, Missouri, North Carolina, and Washington. PATIENTS: Adult patients presenting to the ED with signs (two of four Systemic Inflammatory Response Syndrome criteria, where one must be temperature or WBC count) or suspicion (provider-ordered culture) of infection. INTERVENTIONS: All patients underwent testing with the IntelliSep using ethylene diamine tetraacetic acid-anticoagulated whole blood followed by retrospective adjudication for sepsis by sepsis-3 criteria by a blinded panel of physicians. MEASUREMENTS AND MAIN RESULTS: Of 599 patients enrolled, 572 patients were included in the final analysis. The result of the IntelliSep test is reported as the IntelliSep Index (ISI), ranging from 0.1 to 10.0, divided into three interpretation bands for the risk of sepsis: band 1 (low) to band 3 (high). The median turnaround time for ISI results was 7.2 minutes. The ISI resulted band 1 in 252 (44.1%), band 2 in 160 (28.0%), and band 3 in 160 (28.0%). Sepsis occurred in 26.6% (152 of 572 patients). Sepsis prevalence was 11.1% (95% CI, 7.5-15.7%) in band 1, 28.1% (95% CI, 21.3-35.8%) in band 2, and 49.4% (95% CI, 41.4-57.4%) in band 3. The Positive Percent Agreement of band 1 was 81.6% and the Negative Percent Agreement of band 3 was 80.7%, with an area under the receiver operating characteristic curve of 0.74. Compared with band 1, band 3 correlated with adverse clinical outcomes, including mortality, and resource utilization. CONCLUSIONS: Increasing ISI interpretation band is associated with increasing probability of sepsis in patients presenting to the ED with suspected infection.

Variability in Provider Assessment of Sepsis and Potential of Host Response Technology to Address this Dilemma-Results of an Online Delphi Study.

Potentially septic patients have a huge clinical and economic impact on hospitals and often present to the emergency department (ED) with undifferentiated symptoms. The triage of these patients is complex and has historically relied heavily upon provider judgment. This study aims to evaluate the consistency of provider judgment and the potential of a new host response sepsis test to aid in the triage process. A modified Delphi study involving 26 participants from multiple specialties was conducted to evaluate provider agreement about sepsis risk and to test proposed actions based on the results of a sepsis test. The participants considered case vignettes of potentially septic patients designed to represent diagnostic dilemmas. Provider assessment of sepsis risk in these cases ranged from 10% to 90% and agreement was poor. Agreement about clinical actions to take in response to testing improved when participants considered their own hypothetical borderline cases. New host response testing for sepsis may have the potential to improve sepsis diagnosis and care and should be applied in a protocolized fashion to ensure consistency of results.

Costs and Consequences of a Novel Emergency Department Sepsis Diagnostic Test: The IntelliSep Index.

Sepsis causes 270,000 deaths and costs $38 billion annually in the United States. Most cases of sepsis present in the emergency department (ED), where rapid diagnosis remains challenging. The IntelliSep Index (ISI) is a novel diagnostic test that analyzes characteristics of WBC structure and provides a reliable early signal for sepsis. This study performs a cost-consequence analysis of the ISI relative to procalcitonin for early sepsis diagnosis in the ED. PERSPECTIVE: U.S. healthcare system. SETTING: Community hospital ED. METHODS: A decision tree analysis was performed comparing ISI with procalcitonin. Model parameters included prevalence of sepsis, sensitivity and specificity of diagnostic tests (both ISI and procalcitonin), costs of hospitalization, and mortality rate stratified by diagnostic test result. Mortality and prevalence of sepsis were estimated from best available literature. Costs were estimated based on an analysis of a large, national discharge dataset, and adjusted to 2018 U.S. dollars. Outcomes included expected costs and survival. RESULTS: Assuming a confirmed sepsis prevalence of 16.9% (adjudicated to Sepsis-3), the ISI strategy had an expected cost per patient of $3,849 and expected survival rate of 95.08%, whereas the procalcitonin strategy had an expected cost of $4,656 per patient and an expected survival of 94.98%. ISI was both less costly and more effective than procalcitonin, primarily because of fewer false-negative results. These results were robust in sensitivity analyses. CONCLUSIONS: ISI was both less costly and more effective in preventing mortality than procalcitonin, primarily because of fewer false-negative results. The ISI may provide health systems with a higher-value diagnostic test in ED sepsis evaluation. Additional work is needed to validate these results in clinical practice.

Efficacy and safety of MAS825 (anti-IL-1ß/IL-18) in COVID-19 patients with pneumonia and impaired respiratory function.

MAS825, a bispecific IL-1ß/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 ± 1.87 and 13.5 ± 1.8 in the MAS825 and placebo groups, respectively (P = 0.33). MAS825 + SoC led to 33% relative reduction in intensive care unit (ICU) admissions, ~1 day reduction in ICU stay, reduction in mean duration of oxygen support (13.5 versus 14.3 days), and earlier clearance of virus on Day 15 versus placebo + SoC group. On Day 15, compared with placebo group, patients treated with MAS825 + SoC showed a 51% decrease in CRP levels, 42% lower IL-6 levels, 19% decrease in neutrophil levels, and 16% lower interferon-γ levels, indicative of IL-1ß and IL-18 pathway engagement. MAS825 + SoC did not improve APACHE II score in hospitalized patients with severe COVID-19 pneumonia; however, it inhibited relevant clinical and inflammatory pathway biomarkers and resulted in faster virus clearance versus placebo + SoC. MAS825 used in conjunction with SoC was well tolerated. None of the adverse events (AEs) or serious AEs were treatment-related.

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.

Biophysical Changes of Leukocyte Activation (and NETosis) in the Cellular Host Response to Sepsis.

Sepsis, the leading cause of mortality in hospitals, currently lacks effective early diagnostics. A new cellular host response test, the IntelliSep test, may provide an indicator of the immune dysregulation characterizing sepsis. The objective of this study was to examine the correlation between the measurements performed using this test and biological markers and processes associated with sepsis. Phorbol myristate acetate (PMA), an agonist of neutrophils known to induce neutrophil extracellular trap (NET) formation, was added to whole blood of healthy volunteers at concentrations of 0, 200, and 400 nM and then evaluated using the IntelliSep test. Separately, plasma from a cohort of subjects was segregated into Control and Diseased populations and tested for levels of NET components (citrullinated histone (cit-H3) DNA and neutrophil elastase (NE) DNA) using customized ELISA assays and correlated with ISI scores from the same patient samples. Significant increases in IntelliSep Index (ISI) scores were observed with increasing concentrations of PMA in healthy blood (0 and 200: p < 10-10; 0 and 400: p < 10-10). Linear correlation was observed between the ISI and quantities of NE DNA and Cit-H3 DNA in patient samples. Together these experiments demonstrate that the IntelliSep test is associated with the biological processes of leukocyte activation and NETosis and may indicate changes consistent with sepsis.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

Assessment of a cellular host response test to risk-stratify suspected COVID-19 patients in the Emergency Department setting.

OBJECTIVE: Assess the IntelliSep Index (ISI) for risk stratification of patients presenting to the Emergency Department (ED) with respiratory symptoms suspected of COVID-19 during the pandemic. METHODS: An observational single-center study of prospective cohort of patients presenting to the ED during the early COVID-19 pandemic with respiratory symptoms and a CBC drawn within 4.5 hours of initial vital signs. A sample of this blood was aliquoted for performance of the ISI, and patients were followed for clinical outcomes. The study required no patient-centered activity beyond standard of care and treating clinicians were unaware of study enrollment and ISI test results. MAIN FINDINGS: 282 patients were included. The ISI ranges 0.1 to 10.0, with three interpretation bands indicating risk of adverse outcome: low (green), 0.1-4.9; intermediate (yellow), 5.0-6.2; and high (red), 6.3-10.0. Of 193 (68.4%) tested for SARS-CoV-2, 96 (49.7%) were positive. The ISI resulted in 182 (64.5%) green, 54 (18.1%) yellow, and 46 (15.6%) red band patients. Green band patients had a 1.1% (n = 2) 3-day mortality, while yellow and red band had 3.7% (n = 2, p > .05) and 10.9% (n = 5, p < .05) 3-day mortalities, respectively. Fewer green band patients required admission (96 [52.7%]) vs yellow (44 [81.5%]) and red (43 [93.5%]). Green band patients had more hospital free days (median 23 (Q1-Q3 20-25) than yellow (median 22 [Q1-Q3 0-23], p < 0.05) and red (median 21 [Q1-Q3 0-24], p < 0.01). SOFA increased with interpretation band: green (2, [Q1-Q3 0-4]) vs yellow (4, [Q1-Q3 2-5], p < 0.001) and red (5, [Q1-Q3 3-6]) p < 0.001). CONCLUSIONS: The ISI rapidly risk-stratifies patients presenting to the ED during the early COVID-19 pandemic with signs or suspicion of respiratory infection.

Retrospective identification of infection in the emergency department: A significant challenge in sepsis clinical trials.

BACKGROUND: This study examined three methods for retrospectively identifying infection in emergency department (ED) patients: modified objective definitions of infection (MODI) from the CDC/NHSN, physician adjudication determination of infection, and ED treating physician behavior. METHODS: This study used a subset of data from a prospective sepsis trial. We used Fleiss's Kappa to compare agreement between two physicians retrospectively adjudicating infection based on the patient's medical record, modified infection definition from the CDC/NHSN, and ED treating physician behavior. RESULTS: Overall, there was similar agreement between physician adjudication of infection and MODI criteria (Kappa=0.59) compared to having two physicians independently identify infection through retrospective chart review (Kappa=0.58). ED treating physician behavior was a poorer proxy for infection when compared to the MODI criteria (0.41) and physician adjudication (Kappa = 0.50). CONCLUSIONS: Retrospective identification of infection poses a significant challenge in sepsis clinical trials. Using modified definitions of infection provides a standardized, less time consuming, and equally effective means of identifying infection compared to having multiple physicians adjudicate a patient's chart.

Reduced turnaround times through multi-sectoral community collaboration during the first surge of SARS-CoV-2 and associated effect on patient care and hospital operations.

BACKGROUND: In March 2020, an influx of admissions in COVID-19 positive patients threatened to overwhelm healthcare facilities in East Baton Rouge Parish, Louisiana. Exacerbating this problem was an overall shortage of diagnostic testing capability at that time, resulting in a delay in time-to-result return. An improvement in diagnostic testing availability and timeliness was necessary to improve the allocation of resources and ultimate throughput of patients. The management of a COVID-19 positive patient or patient under investigation requires infection control measures that can quickly consume personal protective equipment (PPE) stores and personnel available to treat these patients. Critical shortages of both PPE and personnel also negatively impact care in patients admitted with non-COVID-19 illnesses. METHODS: A multisectoral partnership of healthcare providers, facilities and academicians created a molecular diagnostic lab within an academic research facility dedicated to testing inpatients and healthcare personnel for SARS-CoV-2. The purpose of the laboratory was to provide a temporary solution to the East Baton Rouge Parish healthcare community until individual facilities were self-sustaining in testing capabilities. We describe the partnership and the impacts of this endeavor by developing a model derived from a combination of data sources, including electronic health records, hospital operations, and state and local resources. FINDINGS: Our model demonstrates two important principles: the impact of reduced turnaround times (TAT) on potential differences in inpatient population numbers for COVID-19 and savings in PPE attributed to the more rapid TAT.

Assessment of a Cellular Host Response Test as a Sepsis Diagnostic for Those With Suspected Infection in the Emergency Department.

OBJECTIVES: Sepsis is a common cause of morbidity and mortality. A reliable, rapid, and early indicator can help improve efficiency of care and outcomes. To assess the IntelliSep test, a novel in vitro diagnostic that quantifies the state of immune activation by measuring the biophysical properties of leukocytes, as a rapid diagnostic for sepsis and a measure of severity of illness, as defined by Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation-II scores and the need for hospitalization. DESIGN SETTING SUBJECTS: Adult patients presenting to two emergency departments in Baton Rouge, LA, with signs of infection (two of four systemic inflammatory response syndrome criteria, with at least one being aberration of temperature or WBC count) or suspicion of infection (a clinician order for culture of a body fluid), were prospectively enrolled. Sepsis status, per Sepsis-3 criteria, was determined through a 3-tiered retrospective and blinded adjudication process consisting of objective review, site-level clinician review, and final determination by independent physician adjudicators. MEASUREMENTS AND MAIN RESULTS: Of 266 patients in the final analysis, those with sepsis had higher IntelliSep Index (median = 6.9; interquartile range, 6.1-7.6) than those adjudicated as not septic (median = 4.7; interquartile range, 3.7-5.9; p < 0.001), with an area under the receiver operating characteristic curve of 0.89 and 0.83 when compared with unanimous and forced adjudication standards, respectively. Patients with higher IntelliSep Index had higher Sequential Organ Failure Assessment (3 [interquartile range, 1-5] vs 1 [interquartile range, 0-2]; p < 0.001) and Acute Physiology and Chronic Health Evaluation-II (7 [interquartile range, 3.5-11.5] vs 5 [interquartile range, 2-9]; p < 0.05) and were more likely to be admitted to the hospital (83.6% vs 48.3%; p < 0.001) compared with those with lower IntelliSep Index. CONCLUSIONS: In patients presenting to the emergency department with signs or suspicion of infection, the IntelliSep Index is a promising tool for the rapid diagnosis and risk stratification for sepsis.

Development and validation of a cellular host response test as an early diagnostic for sepsis.

Sepsis must be diagnosed quickly to avoid morbidity and mortality. However, the clinical manifestations of sepsis are highly variable and emergency department (ED) clinicians often must make rapid, impactful decisions before laboratory results are known. We previously developed a technique that allows the measurement of the biophysical properties of white blood cells as they are stretched through a microfluidic channel. In this study we describe and validate the resultant output as a model and score-the IntelliSep Index (ISI)-that aids in the diagnosis of sepsis in patients with suspected or confirmed infection from a single blood draw performed at the time of ED presentation. By applying this technique to a high acuity cohort with a 23.5% sepsis incidence (n = 307), we defined specific metrics-the aspect ratio and visco-elastic inertial response-that are more sensitive than cell size or cell count in predicting disease severity. The final model was trained and cross-validated on the high acuity cohort, and the performance and generalizability of the model was evaluated on a separate low acuity cohort with a 6.4% sepsis incidence (n = 94) and healthy donors (n = 72). For easier clinical interpretation, the ISI is divided into three interpretation bands of Green, Yellow, and Red that correspond to increasing disease severity. The ISI agreed with the diagnosis established by retrospective physician adjudication, and accurately identified subjects with severe illness as measured by SOFA, APACHE-II, hospital-free days, and intensive care unit admission. Measured using routinely collected blood samples, with a short run-time and no requirement for patient or laboratory information, the ISI is well suited to aid ED clinicians in rapidly diagnosing sepsis.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

BACKGROUND: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. METHODS: The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. DISCUSSION: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

Background: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods: The Pass ive I mmunity T rial for O ur N ation (PassITON), is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the United States to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial Registration: ClinicalTrials.gov: NCT04362176. Date of trial registration: April 24, 2020, https://clinicaltrials.gov/ct2/show/NCT04362176.

Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis.

BACKGROUND: Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown. METHODS: In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 µg per kilogram of body weight per hour) or propofol (5 to 50 µg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 [unresponsive] to +4 [combative]). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months. RESULTS: Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 µg per kilogram per hour, and 208 received propofol at a median dose of 10.21 µg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups. CONCLUSIONS: Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).

Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): a multicentre cohort study.

BACKGROUND: To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae. METHODS: This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression. FINDINGS: Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation-Sedation Scale score while on invasive mechanical ventilation was -4 (-5 to -3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0·0001). During the 21-day study period, patients were alive without delirium or coma for a median of 5·0 days (0·0 to 14·0). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0·01). 601 (28·8%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU. INTERPRETATION: Acute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19. FUNDING: None. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

Strategies to Optimize ICU Liberation (A to F) Bundle Performance in Critically Ill Adults With Coronavirus Disease 2019.

OBJECTIVES: The severe acute respiratory syndrome coronavirus 2 pandemic has stretched ICU resources in an unprecedented fashion and outstripped personal protective equipment supplies. The combination of a novel disease, resource limitations, and risks to medical personnel health have created new barriers to implementing the ICU Liberation ("A" for Assessment, Prevention, and Manage pain; "B" for Both Spontaneous Awakening Trials and Spontaneous Breathing Trials; "C" for Choice of Analgesia and Sedation; "D" for Delirium Assess, Prevent, and Manage; "E" for Early Mobility and Exercise; and "F" for Family Engagement and Empowerment [ABCDEF]) Bundle, a proven ICU care approach that reduces delirium, shortens mechanical ventilation duration, prevents post-ICU syndrome, and reduces healthcare costs. This narrative review acknowledges barriers and offers strategies to optimize Bundle performance in coronavirus disease 2019 patients requiring mechanical ventilation. DATA SOURCES STUDY SELECTION AND DATA EXTRACTION: The most relevant literature, media reports, and author experiences were assessed for inclusion in this narrative review including PubMed, national newspapers, and critical care/pharmacology textbooks. DATA SYNTHESIS: Uncertainty regarding coronavirus disease 2019 clinical course, shifts in attitude, and changes in routine behavior have hindered Bundle use. A domino effect results from: 1) changes to critical care hierarchy, priorities, and ICU team composition; 2) significant personal protective equipment shortages cause; 3) reduced/restricted physical bedside presence favoring; 4) increased depth of sedation and use of neuromuscular blockade; 5) which exacerbate drug shortages; and 6) which require prolonged use of limited ventilator resources. Other identified barriers include manageable knowledge deficits among non-ICU clinicians unfamiliar with the Bundle or among PICU specialists deploying pediatric-based Bundle approaches who are unfamiliar with adult medicine. Both groups have been enlisted to augment the adult ICU work force to meet demand. Strategies were identified to facilitate Bundle performance to liberate patients from the ICU. CONCLUSIONS: We acknowledge current challenges that interfere with comprehensive management of critically ill patients during the coronavirus disease 2019 pandemic. Rapid response to new circumstances precisely requires established safety mechanisms and protocols like the ABCDEF Bundle to increase ICU and ventilator capacity and help survivors maximize recovery from coronavirus disease 2019 as early as possible.

Ceftaroline-Associated Neutropenia: Case Series and Literature Review of Incidence, Risk Factors, and Outcomes.

Ceftaroline is increasingly prescribed for "off-label" indications involving longer durations and higher doses. There have been postmarketing case reports of neutropenia among patients who have received extended durations of ceftaroline, but limited published data currently exist on its incidence and risk factors. We review a total of 37 published cases of ceftaroline-associated neutropenia including cases (n = 4) identified in our health care system. The median time from ceftaroline initiation to development of neutropenia (range) was 25 (8-125) days, with a median duration of neutropenia (range) of 4 (1-16) days. Agranulocytosis (absolute neutrophil count [ANC] nadir < 100 cells/mm3) developed in 49% of cases (n = 18), and there was an ANC nadir of 0 in 27% (n = 10). The overall incidence of neutropenia among cases receiving ceftaroline for ≥7-14 days (range) was 12% (7%-18% per individual study), higher than for comparator antibiotics in the literature. Risk factors for ceftaroline-associated neutropenia varied among studies and remain poorly defined.