Effect of Automated Real-Time Feedback on Early-Sepsis Care: A Pragmatic Clinical Trial.

OBJECTIVES: To determine if a real-time monitoring system with automated clinician alerts improves 3-hour sepsis bundle adherence. DESIGN: Prospective, pragmatic clinical trial. Allocation alternated every 7 days. SETTING: Quaternary hospital from December 1, 2020 to November 30, 2021. PATIENTS: Adult emergency department or inpatients meeting objective sepsis criteria triggered an electronic medical record (EMR)-embedded best practice advisory. Enrollment occurred when clinicians acknowledged the advisory indicating they felt sepsis was likely. INTERVENTION: Real-time automated EMR monitoring identified suspected sepsis patients with incomplete bundle measures within 1-hour of completion deadlines and generated reminder pages. Clinicians responsible for intervention group patients received reminder pages; no pages were sent for controls. The primary analysis cohort was the subset of enrolled patients at risk of bundle nonadherent care that had reminder pages generated. MEASUREMENTS AND MAIN RESULTS: The primary outcome was orders for all 3-hour bundle elements within guideline time limits. Secondary outcomes included guideline-adherent delivery of all 3-hour bundle elements, 28-day mortality, antibiotic discontinuation within 48-hours, and pathogen recovery from any culture within 7 days of time-zero. Among 3,269 enrolled patients, 1,377 had reminder pages generated and were included in the primary analysis. There were 670 (48.7%) at-risk patients randomized to paging alerts and 707 (51.3%) to control. Bundle-adherent orders were placed for 198 intervention patients (29.6%) versus 149 (21.1%) controls (difference: 8.5%; 95% CI, 3.9-13.1%; p = 0.0003). Bundle-adherent care was delivered for 152 (22.7%) intervention versus 121 (17.1%) control patients (difference: 5.6%; 95% CI, 1.4-9.8%; p = 0.0095). Mortality was similar between groups (8.4% vs 8.3%), as were early antibiotic discontinuation (35.1% vs 33.4%) and pan-culture negativity (69.0% vs 68.2%). CONCLUSIONS: Real-time monitoring and paging alerts significantly increased orders for and delivery of guideline-adherent care for suspected sepsis patients at risk of 3-hour bundle nonadherence. The trial was underpowered to determine whether adherence affected mortality. Despite enrolling patients with clinically suspected sepsis, early antibiotic discontinuation and pan-culture negativity were common, highlighting challenges in identifying appropriate patients for sepsis bundle application.

Circulating N-lactoyl-amino acids and N-formyl-methionine reflect mitochondrial dysfunction and predict mortality in septic shock.

INTRODUCTION: Sepsis is a highly morbid condition characterized by multi-organ dysfunction resulting from dysregulated inflammation in response to acute infection. Mitochondrial dysfunction may contribute to sepsis pathogenesis, but quantifying mitochondrial dysfunction remains challenging. OBJECTIVE: To assess the extent to which circulating markers of mitochondrial dysfunction are increased in septic shock, and their relationship to severity and mortality. METHODS: We performed both full-scan and targeted (known markers of genetic mitochondrial disease) metabolomics on plasma to determine markers of mitochondrial dysfunction which distinguish subjects with septic shock (n = 42) from cardiogenic shock without infection (n = 19), bacteremia without sepsis (n = 18), and ambulatory controls (n = 19) - the latter three being conditions in which mitochondrial function, proxied by peripheral oxygen consumption, is presumed intact. RESULTS: Nine metabolites were significantly increased in septic shock compared to all three comparator groups. This list includes N-formyl-L-methionine (f-Met), a marker of dysregulated mitochondrial protein translation, and N-lactoyl-phenylalanine (lac-Phe), representative of the N-lactoyl-amino acids (lac-AAs), which are elevated in plasma of patients with monogenic mitochondrial disease. Compared to lactate, the clinical biomarker used to define septic shock, there was greater separation between survivors and non-survivors of septic shock for both f-Met and the lac-AAs measured within 24 h of ICU admission. Additionally, tryptophan was the one metabolite significantly decreased in septic shock compared to all other groups, while its breakdown product kynurenate was one of the 9 significantly increased. CONCLUSION: Future studies which validate the measurement of lac-AAs and f-Met in conjunction with lactate could define a sepsis subtype characterized by mitochondrial dysfunction.

Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker.

BACKGROUND: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. METHODS: We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2Qtotal) and its components in the vertical (CV2Qvgrad) and cranio-caudal (CV2Qzgrad) directions, and the residual heterogeneity (CV2Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics. RESULTS: O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2Qvgrad was significantly higher in controls than in PAH (0.08 (0.055-0.10) vs. 6.7 × 10-3 (2 × 10-4-0.02), p < 0.001) with a considerable gap between groups. Qvgrad and CV2Qtotal showed smaller differences: - 7.3 vs. - 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV2Qvgrad had the largest effect size among the primary parameters during O2 + iNO. CV2Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. CONCLUSIONS: Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.

Plasma Soluble Suppression of Tumorigenicity-2 Associates with Ventilator Liberation in Acute Hypoxemic Respiratory Failure.

Rationale: Standard physiologic assessments of extubation readiness in patients with acute hypoxemic respiratory failure (AHRF) may not reflect lung injury resolution and could adversely affect clinical decision-making and patient outcomes. Objectives: We hypothesized that elevations in inflammatory plasma biomarkers sST2 (soluble suppression of tumorigenicity-2) and IL-6 indicate ongoing lung injury in AHRF and better inform patient outcomes compared with standard clinical assessments. Methods: We measured daily plasma biomarkers and physiologic variables in 200 patients with AHRF for up to 9 days after intubation. We tested the associations of baseline values with the primary outcome of unassisted breathing at Day 29. We analyzed the ability of serial biomarker measurements to inform successful ventilator liberation. Measurements and Main Results: Baseline sST2 concentrations were higher in patients dead or mechanically ventilated versus breathing unassisted at Day 29 (491.7 ng/ml [interquartile range (IQR), 294.5-670.1 ng/ml] vs. 314.4 ng/ml [IQR, 127.5-550.1 ng/ml]; P = 0.0003). Higher sST2 concentrations over time were associated with a decreased probability of ventilator liberation (hazard ratio, 0.80 per log-unit increase; 95% confidence interval [CI], 0.75-0.83; P = 0.03). Patients with higher sST2 concentrations on the day of liberation were more likely to fail liberation compared with patients who remained successfully liberated (320.9 ng/ml [IQR, 181.1- 495.6 ng/ml] vs. 161.6 ng/ml [IQR, 95.8-292.5 ng/ml]; P = 0.002). Elevated sST2 concentrations on the day of liberation decreased the odds of successful liberation when adjusted for standard physiologic parameters (odds ratio, 0.325; 95% CI, 0.119-0.885; P = 0.03). IL-6 concentrations did not associate with outcomes. Conclusions: Using sST2 concentrations to guide ventilator management may more accurately reflect underlying lung injury and outperform traditional measures of readiness for ventilator liberation.

Filter clotting with continuous renal replacement therapy in COVID-19.

Coronavirus disease 2019 (COVID-19) appears to be associated with increased arterial and venous thromboembolic disease. These presumed abnormalities in hemostasis have been associated with filter clotting during continuous renal replacement therapy (CRRT). We aimed to characterize the burden of CRRT filter clotting in COVID-19 infection and to describe a CRRT anticoagulation protocol that used anti-factor Xa levels for systemic heparin dosing. Multi-center study of consecutive patients with COVID-19 receiving CRRT. Primary outcome was CRRT filter loss. Sixty-five patients were analyzed, including 17 using an anti-factor Xa protocol to guide systemic heparin dosing. Fifty-four out of 65 patients (83%) lost at least one filter. Median first filter survival time was 6.5 [2.5, 33.5] h. There was no difference in first or second filter loss between the anti-Xa protocol and standard of care anticoagulation groups, however fewer patients lost their third filter in the protocolized group (55% vs. 93%) resulting in a longer median third filter survival time (24 [15.1, 54.2] vs. 17.3 [9.5, 35.1] h, p = 0.04). The rate of CRRT filter loss is high in COVID-19 infection. An anticoagulation protocol using systemic unfractionated heparin, dosed by anti-factor Xa levels is reasonable approach to anticoagulation in this population.

Design and Implementation of a Real-time Monitoring Platform for Optimal Sepsis Care in an Emergency Department: Observational Cohort Study.

BACKGROUND: Sepsis is the leading cause of death in US hospitals. Compliance with bundled care, specifically serial lactates, blood cultures, and antibiotics, improves outcomes but is often delayed or missed altogether in a busy practice environment. OBJECTIVE: This study aims to design, implement, and validate a novel monitoring and alerting platform that provides real-time feedback to frontline emergency department (ED) providers regarding adherence to bundled care. METHODS: This single-center, prospective, observational study was conducted in three phases: the design and technical development phase to build an initial version of the platform; the pilot phase to test and refine the platform in the clinical setting; and the postpilot rollout phase to fully implement the study intervention. RESULTS: During the design and technical development, study team members and stakeholders identified the criteria for patient inclusion, selected bundle measures from the Center for Medicare and Medicaid Sepsis Core Measure for alerting, and defined alert thresholds, message content, delivery mechanisms, and recipients. Additional refinements were made based on 70 provider survey results during the pilot phase, including removing alerts for vasopressor initiation and modifying text in the pages to facilitate patient identification. During the 48 days of the postpilot rollout phase, 15,770 ED encounters were tracked and 711 patient encounters were included in the active monitoring cohort. In total, 634 pages were sent at a rate of 0.98 per attending physician shift. Overall, 38.3% (272/711) patients had at least one page. The missing bundle elements that triggered alerts included: antibiotics 41.6% (136/327), repeat lactate 32.4% (106/327), blood cultures 20.8% (68/327), and initial lactate 5.2% (17/327). Of the missing Sepsis Core Measures elements for which a page was sent, 38.2% (125/327) were successfully completed on time. CONCLUSIONS: A real-time sepsis care monitoring and alerting platform was created for the ED environment. The high proportion of patients with at least one alert suggested the significant potential for such a platform to improve care, whereas the overall number of alerts per clinician suggested a low risk of alarm fatigue. The study intervention warrants a more rigorous evaluation to ensure that the added alerts lead to better outcomes for patients with sepsis.

Veno-venous Extracorporeal Membrane Oxygenation for Respiratory Failure in COVID-19 Patients: Early Experience From a Major Academic Medical Center in North America.

AND BACKGROUND DATA: VV ECMO can be utilized as an advanced therapy in select patients with COVID-19 respiratory failure refractory to traditional critical care management and optimal mechanical ventilation. Anticipating a need for such therapies during the pandemic, our center created a targeted protocol for ECMO therapy in COVID-19 patients that allows us to provide this life-saving therapy to our sickest patients without overburdening already stretched resources or excessively exposing healthcare staff to infection risk. METHODS: As a major regional referral program, we used the framework of our well-established ECMO service-line to outline specific team structures, modified patient eligibility criteria, cannulation strategies, and management protocols for the COVID-19 ECMO program. RESULTS: During the first month of the COVID-19 outbreak in Massachusetts, 6 patients were placed on VV ECMO for refractory hypoxemic respiratory failure. The median (interquartile range) age was 47 years (43-53) with most patients being male (83%) and obese (67%). All cannulations were performed at the bedside in the intensive care unit in patients who had undergone a trial of rescue therapies for acute respiratory distress syndrome including lung protective ventilation, paralysis, prone positioning, and inhaled nitric oxide. At the time of this report, 83% (5/6) of the patients are still alive with 1 death on ECMO, attributed to hemorrhagic stroke. 67% of patients (4/6) have been successfully decannulated, including 2 that have been successfully extubated and one who was discharged from the hospital. The median duration of VV ECMO therapy for patients who have been decannulated is 12 days (4-18 days). CONCLUSIONS: This is 1 the first case series describing VV ECMO outcomes in COVID-19 patients. Our initial data suggest that VV ECMO can be successfully utilized in appropriately selected COVID-19 patients with advanced respiratory failure.

Utilization of a multidisciplinary emergency department sepsis huddle to reduce time to antibiotics and improve SEP-1 compliance.

Sepsis is a significant public health crisis in the United States, contributing to 50% of inpatient hospital deaths. Given its dramatic health effects and implications in the setting of new CMS care guidelines, ED leaders have renewed focus on appropriate and timely sepsis care, including timely administration of antibiotics in patients at risk for sepsis. Modeling the success of multidisciplinary bedside huddles in improving compliance with appropriate care in other healthcare settings, a Sepsis Huddle was implemented in a large, academic ED, with the goal of driving compliance with standardized sepsis care as described in the CMS SEP-1 measure. A retrospective cohort analysis was performed, with the primary finding that utilization of the Sepsis Huddle resulted in antibiotics being administered on average 41 min sooner than when the Sepsis Huddle was not performed. Given that literature suggests that early administration of appropriate antibiotic therapy is a major driver of mortality reduction in patients with sepsis, this study represents a proof of concept that utilization of a Sepsis Huddle may serve to improve outcomes among ED patients at risk for sepsis.

Hypoxic Pulmonary Vasoconstriction Does Not Explain All Regional Perfusion Redistribution in Asthma.

RATIONALE: Regional hypoventilation in bronchoconstricted patients with asthma is spatially associated with reduced perfusion, which is proposed to result from hypoxic pulmonary vasoconstriction (HPV). OBJECTIVES: To determine the role of HPV in the regional perfusion redistribution in bronchoconstricted patients with asthma. METHODS: Eight patients with asthma completed positron emission tomographic/computed tomographic lung imaging at baseline and after bronchoconstriction, breathing either room air or 80% oxygen (80% O2) on separate days. Relative perfusion, specific ventilation (sV), and gas fraction (Fgas) in the 25% of the lung with the lowest specific ventilation (sVlow) and the remaining lung (sVhigh) were quantified and compared. MEASUREMENTS AND MAIN RESULTS: In the sVlow region, bronchoconstriction caused a significant decrease in sV under both room air and 80% O2 conditions (baseline vs. bronchoconstriction, mean ± SD, 1.02 ± 0.20 vs. 0.35 ± 0.19 and 1.03 ± 0.20 vs. 0.32 ± 0.16, respectively; P < 0.05). In the sVlow region, relative perfusion decreased after bronchoconstriction under room air conditions and also, to a lesser degree, under 80% O2 conditions (1.02 ± 0.19 vs. 0.72 ± 0.08 [P < 0.001] and 1.08 ± 0.19 vs. 0.91 ± 0.12 [P < 0.05], respectively). The Fgas increased after bronchoconstriction under room air conditions only (0.99 ± 0.04 vs. 1.00 ± 0.02; P < 0.05). The sVlow subregion analysis indicated that some of the reduction in relative perfusion after bronchoconstriction under 80% O2 conditions occurred as a result of the presence of regional hypoxia. However, relative perfusion was also significantly reduced in sVlow subregions that were hyperoxic under 80% O2 conditions. CONCLUSIONS: HPV is not the only mechanism that contributes to perfusion redistribution in bronchoconstricted patients with asthma, suggesting that another nonhypoxia mechanism also contributes. We propose that this nonhypoxia mechanism may be either direct mechanical interactions and/or unidentified intercellular signaling between constricted airways, the parenchyma, and the surrounding vasculature.

High-flow oxygen therapy and other inhaled therapies in intensive care units.

In this Series paper, we review the current evidence for the use of high-flow oxygen therapy, inhaled gases, and aerosols in the care of critically ill patients. The available evidence supports the use of high-flow nasal cannulae for selected patients with acute hypoxaemic respiratory failure. Heliox might prevent intubation or improve gas flow in mechanically ventilated patients with severe asthma. Additionally, it might improve the delivery of aerosolised bronchodilators in obstructive lung disease in general. Inhaled nitric oxide might improve outcomes in a subset of patients with postoperative pulmonary hypertension who had cardiac surgery; however, it has not been shown to provide long-term benefit in patients with acute respiratory distress syndrome (ARDS). Inhaled prostacyclins, similar to inhaled nitric oxide, are not recommended for routine use in patients with ARDS, but can be used to improve oxygenation in patients who are not adequately stabilised with traditional therapies. Aerosolised bronchodilators are useful in mechanically ventilated patients with asthma and chronic obstructive pulmonary disease, but are not recommended for those with ARDS. Use of aerosolised antibiotics for ventilator-associated pneumonia and ventilator-associated tracheobronchitis shows promise, but the delivered dose can be highly variable if proper attention is not paid to the delivery method.

Plasma Concentrations of Soluble Suppression of Tumorigenicity-2 and Interleukin-6 Are Predictive of Successful Liberation From Mechanical Ventilation in Patients With the Acute Respiratory Distress Syndrome.

OBJECTIVES: Soluble suppression of tumorigenicity-2 and interleukin-6 concentrations have been associated with the inflammatory cascade of acute respiratory distress syndrome. We determined whether soluble suppression of tumorigenicity-2 and interleukin-6 levels can be used as prognostic biomarkers to guide weaning from mechanical ventilation and predict the need for reintubation. DESIGN, SETTING, AND PATIENTS: We assayed plasma soluble suppression of tumorigenicity-2 (n = 826) concentrations and interleukin-6 (n = 755) concentrations in the Fluid and Catheter Treatment Trial, a multicenter randomized controlled trial of conservative fluid management in acute respiratory distress syndrome. We tested whether soluble suppression of tumorigenicity-2 and interleukin-6 levels were associated with duration of mechanical ventilation, the probability of passing a weaning assessment, and the need for reintubation. MEASUREMENTS AND MAIN RESULTS: In models adjusted for Acute Physiology and Chronic Health Evaluation score and other relevant variables, patients with higher day 0 and day 3 median soluble suppression of tumorigenicity-2 and interleukin-6 concentrations had decreased probability of extubation over time (day 0 soluble suppression of tumorigenicity-2: hazard ratio, 0.85; 95% CI, 0.72-1.00; p = 0.05; day 0 interleukin-6: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; day 3 soluble suppression of tumorigenicity-2: hazard ratio, 0.64; 95% CI, 0.54-0.75; p < 0.0001; and day 3 interleukin-6: hazard ratio, 0.73; 95% CI, 0.62-0.85; p = 0.0001). Higher biomarker concentrations were also predictive of decreased odds of passing day 3 weaning assessments (soluble suppression of tumorigenicity-2: odds ratio, 0.62: 95% CI, 0.44-0.87; p = 0.006 and interleukin-6: odds ratio, 0.61; 95% CI, 0.43-0.85; p = 0.004) and decreased odds of passing a spontaneous breathing trial (soluble suppression of tumorigenicity-2: odds ratio, 0.45; 95% CI, 0.28-0.71; p = 0.0007 and interleukin-6 univariate analysis only: odds ratio, 0.55; 95% CI, 0.36-0.83; p = 0.005). Finally, higher biomarker levels were significant predictors of the need for reintubation for soluble suppression of tumorigenicity-2 (odds ratio, 3.23; 95% CI, 1.04-10.07; p = 0.04) and for interleukin-6 (odds ratio, 2.58; 95% CI, 1.14-5.84; p = 0.02). CONCLUSIONS: Higher soluble suppression of tumorigenicity-2 and interleukin-6 concentrations are each associated with worse outcomes during weaning of mechanical ventilation and increased need for reintubation in patients with acute respiratory distress syndrome. Biomarker-directed ventilator management may lead to improved outcomes in weaning of mechanical ventilation in patients with acute respiratory distress syndrome.