Early dynamic changes to monocytes following major surgery are associated with subsequent infections.

Background: Post-operative infections are a common cause of morbidity following major surgery. Little is understood about how major surgery perturbs immune function leading to heightened risk of subsequent infection. Through analysis of paired blood samples obtained immediately before and 24 h following surgery, we evaluated changes in circulating immune cell phenotype and function across the first 24 h, to identify early immune changes associated with subsequent infection. Methods: We conducted a prospective observational study of adult patients undergoing major elective gastrointestinal, gynecological, or maxillofacial surgery requiring planned admission to the post-anesthetic care unit. Patients were followed up to hospital discharge or death. Outcome data collected included mortality, length of stay, unplanned intensive care unit admission, and post-operative infections (using the standardized endpoints in perioperative medicine-core outcome measures for perioperative and anesthetic care criteria). Peripheral blood mononuclear cells were isolated prior to and 24 h following surgery from which cellular immune traits including activation and functional status were assessed by multi-parameter flow cytometry and serum immune analytes compared by enzyme-linked immunosorbent assay (ELISA). Results: Forty-eight patients were recruited, 26 (54%) of whom developed a post-operative infection. We observed reduced baseline pre- and post-operative monocyte CXCR4 and CD80 expression (chemokine receptors and co-stimulation markers, respectively) in patients who subsequently developed an infection as well as a profound and selective post-operative increase in CD4+ lymphocyte IL-7 receptor expression in the infection group only. Higher post-operative monocyte count was significantly associated with the development of post-operative infection (false discovery rate < 1%; adjusted p-value = 0.001) with an area under the receiver operating characteristic curve of 0.84 (p < 0.0001). Conclusion: Lower monocyte chemotaxis markers, higher post-operative circulating monocyte counts, and reduced co-stimulatory signals are associated with subsequent post-operative infections. Identifying the underlying mechanisms and therapeutics to reverse defects in immune cell function requires further exploration.

Preoperative N-terminal pro-B-type natriuretic peptide and myocardial injury after stopping or continuing renin-angiotensin system inhibitors in noncardiac surgery: a prespecified analysis of a phase 2 randomised controlled multicentre trial.

BACKGROUND: Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml-1) experience more complications after noncardiac surgery. Individuals prescribed renin-angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations. METHODS: In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L-1 or a ≥5 ng L-1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L-1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml -1) and stopping or continuing RAS inhibitors. RESULTS: Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml -1 (median 339 [160-833] pg ml-1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml-1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml -1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05-5.99); P<0.0001}. For subjects with preoperative NT-proBNP <100 pg ml-1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06-4.65]; P=0.03). For preoperative NT-proBNP >100 pg ml-1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44-2.22]). CONCLUSIONS: Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml -1) increased the likelihood of myocardial injury before noncardiac surgery.

Adult Cerebral Malaria: Acute and Subacute Imaging Findings, Long-term Clinical Consequences.

Cerebral malaria is an important cause of mortality and neurodisability in endemic regions. We show magnetic resonance imaging (MRI) features suggestive of cytotoxic and vasogenic cerebral edema followed by microhemorrhages in 2 adult UK cases, comparing them with an Indian cohort. Long-term follow-up images correlate ongoing changes with residual functional impairment.

UK clinicians' attitudes towards the application of molecular diagnostics to guide antibiotic use in ICU patients with pneumonias: a quantitative study.

BACKGROUND: Molecular diagnostic tests may improve antibiotic prescribing by enabling earlier tailoring of antimicrobial therapy. However, clinicians' trust and acceptance of these tests will determine their application in practice. OBJECTIVES: To examine ICU prescribers' views on the application of molecular diagnostics in patients with suspected hospital-acquired and ventilator-associated pneumonia (HAP/VAP). METHODS: Sixty-three ICU clinicians from five UK hospitals completed a cross-sectional questionnaire between May 2020 and July 2020 assessing attitudes towards using molecular diagnostics to inform initial agent choice and to help stop broad-spectrum antibiotics early. RESULTS: Attitudes towards using molecular diagnostics to inform initial treatment choices and to stop broad-spectrum antibiotics early were nuanced. Most (83%) were positive about molecular diagnostics, agreeing that using results to inform broad-spectrum antibiotic prescribing is good practice. However, many (58%) believed sick patients are often too unstable to risk stopping broad-spectrum antibiotics based on a negative result. CONCLUSIONS: Positive attitudes towards the application of molecular diagnostics to improve antibiotic stewardship were juxtapositioned against the perceived need to initiate and maintain broad-spectrum antibiotics to protect unstable patients.

Discontinuation vs. continuation of renin-angiotensin system inhibition before non-cardiac surgery: the SPACE trial.

BACKGROUND AND AIMS: Haemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin-angiotensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear. METHODS: From 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin-angiotensin system inhibitors were withheld for different durations (2-3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 mmHg) and hypotension requiring vasoactive therapy. RESULTS: Two hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45-1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16-1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)]. CONCLUSIONS: Discontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies.

A randomized controlled trial of nebulized surfactant for the treatment of severe COVID-19 in adults (COVSurf trial).

SARS-CoV-2 directly targets alveolar epithelial cells and can lead to surfactant deficiency. Early reports suggested surfactant replacement may be effective in improving outcomes. The aim of the study to assess the feasibility and efficacy of nebulized surfactant in mechanically ventilated COVID-19 patients. Patients were randomly assigned to receive open-labelled bovine nebulized surfactant or control (ratio 3-surfactant: 2-control). This was an exploratory dose-response study starting with 1080 mg of surfactant delivered at 3 time points (0, 8 and 24 h). After completion of 10 patients, the dose was reduced to 540 mg, and the frequency of nebulization was increased to 5/6 time points (0, 12, 24, 36, 48, and an optional 72 h) on the advice of the Trial Steering Committee. The co-primary outcomes were improvement in oxygenation (change in PaO2/FiO2 ratio) and ventilation index at 48 h. 20 patients were recruited (12 surfactant and 8 controls). Demographic and clinical characteristics were similar between groups at presentation. Nebulized surfactant administration was feasible. There was no significant improvement in oxygenation at 48 h overall. There were also no differences in secondary outcomes or adverse events. Nebulized surfactant administration is feasible in mechanically ventilated patients with COVID-19 but did not improve measures of oxygenation or ventilation.

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial): A Multicenter, Randomized, Controlled Clinical Trial.

Rationale: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in coronavirus disease (COVID-19)-related acute respiratory distress syndrome (ARDS). Objectives: We investigated the safety and efficacy of ORBCEL-C (CD362 [cluster of differentiation 362]-enriched, umbilical cord-derived MSCs) in COVID-19-related ARDS. Methods: In this multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial (NCT03042143), patients with moderate to severe COVID-19-related ARDS were randomized to receive ORBCEL-C (400 million cells) or placebo (Plasma-Lyte 148). The primary safety and efficacy outcomes were the incidence of serious adverse events and oxygenation index at Day 7, respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2:FiO2 ratio, and Sequential Organ Failure Assessment score. Clinical outcomes relating to duration of ventilation, lengths of ICU and hospital stays, and mortality were collected. Long-term follow-up included diagnosis of interstitial lung disease at 1 year and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at Days 0, 4, and 7. Measurements and Main Results: Sixty participants were recruited (final analysis: n = 30 received ORBCEL-C, n = 29 received placebo; 1 participant in the placebo group withdrew consent). Six serious adverse events occurred in the ORBCEL-C group and three in the placebo group (risk ratio, 2.9 [95% confidence interval, 0.6-13.2]; P = 0.25). Day 7 mean (SD) oxygenation index did not differ (ORBCEL-C, 98.3 [57.2] cm H2O/kPa; placebo, 96.6 [67.3] cm H2O/kPa). There were no differences in secondary surrogate outcomes or in mortality at Day 28, Day 90, 1 year, or 2 years. There was no difference in the prevalence of interstitial lung disease at 1 year or significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. Conclusion: ORBCEL-C MSCs were safe in subjects with moderate to severe COVID-19-related ARDS but did not improve surrogates of pulmonary organ dysfunction.

Embedded point of care randomisation for evaluating comparative effectiveness questions: PROSPECTOR-critical care feasibility study protocol.

INTRODUCTION: Many routinely administered treatments lack evidence as to their effectiveness. When treatments lack evidence, patients receive varying care based on the preferences of clinicians. Standard randomised controlled trials are unsuited to comparisons of different routine treatment strategies, and there remains little economic incentive for change.Integrating clinical trial infrastructure into electronic health record systems offers the potential for routine treatment comparisons at scale, through reduced trial costs. To date, embedded trials have automated data collection, participant identification and eligibility screening, but randomisation and consent remain manual and therefore costly tasks.This study will investigate the feasibility of using computer prompts to allow flexible randomisation at the point of clinical decision making. It will compare the effectiveness of two prompt designs through the lens of a candidate research question-comparing liberal or restrictive magnesium supplementation practices for critical care patients. It will also explore the acceptability of two consent models for conducting comparative effectiveness research. METHODS AND ANALYSIS: We will conduct a single centre, mixed-methods feasibility study, aiming to recruit 50 patients undergoing elective surgery requiring postoperative critical care admission. Participants will be randomised to either 'Nudge' or 'Preference' designs of electronic point-of-care randomisation prompt, and liberal or restrictive magnesium supplementation.We will judge feasibility through a combination of study outcomes. The primary outcome will be the proportion of prompts displayed resulting in successful randomisation events (compliance with the allocated magnesium strategy). Secondary outcomes will evaluate the acceptability of both prompt designs to clinicians and ascertain the acceptability of pre-emptive and opt-out consent models to patients. ETHICS AND DISSEMINATION: This study was approved by Riverside Research Ethics Committee (Ref: 21/LO/0785) and will be published on completion. TRIAL REGISTRATION NUMBER: NCT05149820.

Presymptomatic diagnosis of postoperative infection and sepsis using gene expression signatures.

PURPOSE: Early accurate diagnosis of infection ± organ dysfunction (sepsis) remains a major challenge in clinical practice. Utilizing effective biomarkers to identify infection and impending organ dysfunction before the onset of clinical signs and symptoms would enable earlier investigation and intervention. To our knowledge, no prior study has specifically examined the possibility of pre-symptomatic detection of sepsis. METHODS: Blood samples and clinical/laboratory data were collected daily from 4385 patients undergoing elective surgery. An adjudication panel identified 154 patients with definite postoperative infection, of whom 98 developed sepsis. Transcriptomic profiling and subsequent RT-qPCR were undertaken on sequential blood samples taken postoperatively from these patients in the three days prior to the onset of symptoms. Comparison was made against postoperative day-, age-, sex- and procedure- matched patients who had an uncomplicated recovery (n =151) or postoperative inflammation without infection (n =148). RESULTS: Specific gene signatures optimized to predict infection or sepsis in the three days prior to clinical presentation were identified in initial discovery cohorts. Subsequent classification using machine learning with cross-validation with separate patient cohorts and their matched controls gave high Area Under the Receiver Operator Curve (AUC) values. These allowed discrimination of infection from uncomplicated recovery (AUC 0.871), infectious from non-infectious systemic inflammation (0.897), sepsis from other postoperative presentations (0.843), and sepsis from uncomplicated infection (0.703). CONCLUSION: Host biomarker signatures may be able to identify postoperative infection or sepsis up to three days in advance of clinical recognition. If validated in future studies, these signatures offer potential diagnostic utility for postoperative management of deteriorating or high-risk surgical patients and, potentially, other patient populations.

Beneficial ex vivo immunomodulatory and clinical effects of clarithromycin in COVID-19.

INTRODUCTION: Macrolide antibiotics have immunomodulatory properties which may be beneficial in viral infections. However, the precise effects of macrolides on T cell responses to COVID, differences between different macrolides, and synergistic effects with other antibiotics have not been explored. METHODS: We investigated the effect of antibiotics (amoxicillin, azithromycin, clarithromycin, and combined amoxicillin with clarithromycin) on lymphocyte intracellular cytokine levels and monocyte phagocytosis in healthy volunteer PBMCs stimulated ex vivo with SARS-CoV-2 S1+2 spike protein. A retrospective cohort study was performed on intensive care COVID-19 patients. RESULTS: Co-incubation of clarithromycin with spike protein-stimulated healthy volunteer PBMCs ex vivo resulted in an increase in CD8+ (p = 0.004) and CD4+ (p = 0.007) IL-2, with a decrease in CD8+ (p = 0.032) and CD4+ (p = 0.007) IL-10. The addition of amoxicillin to clarithromycin resulted in an increase in CD8+ IL-6 (p = 0.010), decrease in CD8+ (p = 0.014) and CD4+ (p = 0.022) TNF-alpha, and decrease in CD8+ IFN-alpha (p = 0.038). Amoxicillin alone had no effect on CD4+ or CD8+ cytokines. Co-incubation of azithromycin resulted in increased CD8+ (p = 0.007) and CD4+ (p = 0.011) IL-2. There were no effects on monocyte phagocytosis. 102 COVID-19 ICU patients received antibiotics on hospital admission; 62 (61%) received clarithromycin. Clarithromycin use was associated with reduction in mortality on univariate analysis (p = 0.023), but not following adjustment for confounders (HR = 0.540; p = 0.076). CONCLUSIONS: Clarithromycin has immunomodulatory properties over and above azithromycin. Amoxicillin in addition to clarithromycin is associated with synergistic ex vivo immunomodulatory properties. The potential benefit of clarithromycin in critically ill patients with COVID-19 and other viral pneumonitis merits further exploration.

Understanding decisions about antibiotic prescribing in ICU: an application of the Necessity Concerns Framework.

BACKGROUND: Antibiotics are extensively prescribed in intensive care units (ICUs), yet little is known about how antibiotic-related decisions are made in this setting. We explored how beliefs, perceptions and contextual factors influenced ICU clinicians' antibiotic prescribing. METHODS: We conducted 4 focus groups and 34 semistructured interviews with clinicians involved in antibiotic prescribing in four English ICUs. Focus groups explored factors influencing prescribing, whereas interviews examined decision-making processes using two clinical vignettes. Data were analysed using thematic analysis, applying the Necessity Concerns Framework. RESULTS: Clinicians' antibiotic decisions were influenced by their judgement of the necessity for prescribing/not prescribing, relative to their concerns about potential adverse consequences. Antibiotic necessity perceptions were strongly influenced by beliefs that antibiotics would protect patients from deterioration and themselves from the ethical and legal consequences of undertreatment. Clinicians also reported concerns about prescribing antibiotics. These generally centred on antimicrobial resistance; however, protecting the individual patient was prioritised over these societal concerns. Few participants identified antibiotic toxicity concerns as a key influencer. Clinical uncertainty often complicated balancing antibiotic necessity against concerns. Decisions to start or continue antibiotics often represented 'erring on the side of caution' as a protective response in uncertainty. This approach was reinforced by previous experiences of negative consequences ('being burnt') which motivated prescribing 'just in case' of an infection. Prescribing decisions were also context-dependent, exemplified by a lower perceived threshold to prescribe antibiotics out-of-hours, input from external team members and local prescribing norms. CONCLUSION: Efforts to improve antibiotic stewardship should consider clinicians' desire to protect with a prescription. Rapid molecular microbiology, with appropriate communication, may diminish clinicians' fears of not prescribing or of using narrower-spectrum antibiotics.

INHALE: the impact of using FilmArray Pneumonia Panel molecular diagnostics for hospital-acquired and ventilator-associated pneumonia on antimicrobial stewardship and patient outcomes in UK Critical Care-study protocol for a multicentre randomised controlled trial.

BACKGROUND: Hospital-acquired and ventilator-associated pneumonias (HAP and VAP) are common in critical care and can be life-threatening. Rapid microbiological diagnostics, linked to an algorithm to translate their results into antibiotic choices, could simultaneously improve patient outcomes and antimicrobial stewardship. METHODS: The INHALE Randomised Controlled Trial is a multi-centre, parallel study exploring the potential of the BioFire FilmArray molecular diagnostic to guide antibiotic treatment of HAP/VAP in intensive care units (ICU); it identifies pathogens and key antibiotic resistance in around 90 min. The comparator is standard care whereby the patient receives empirical antibiotics until microbiological culture results become available, typically after 48-72 h. Adult and paediatric ICU patients are eligible if they are about to receive antibiotics for a suspected lower respiratory infection (including HAP/VAP) for the first time or a change in antibiotic because of a deteriorating clinical condition. Breathing spontaneously or intubated, they must have been hospitalised for 48 h or more. Patients are randomised 1:1 to receive either antibiotics guided by the FilmArray molecular diagnostic and its trial-based prescribing algorithm or standard care, meaning empirical antibiotics based on local policy, adapted subsequently based upon local microbiology culture results. Co-primary outcomes are (i) non-inferiority in clinical cure of pneumonia at 14 days post-randomisation and (ii) superiority in antimicrobial stewardship at 24 h post-randomisation (defined as % of patients on active and proportionate antibiotics). Secondary outcomes include further stewardship reviews; length of ICU stay; co-morbidity indicators, including septic shock, change in sequential organ failure assessment scores, and secondary pneumonias; ventilator-free days; adverse events over 21 days; all-cause mortality; and total antibiotic usage. Both cost-effectiveness of the molecular diagnostic-guided therapy and behavioural aspects determining antibiotic prescribing are being explored. A sample size of 552 will be required to detect clinically significant results with 90% power and 5% significance for the co-primary outcomes. DISCUSSION: This trial will test whether the potential merits of rapid molecular diagnostics for pathogen and resistance detection in HAP/VAP are realised in patient outcomes and/or improved antibiotic stewardship. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16483855 . Retrospectively registered on 15 July 2019.

Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort.

OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-ß, interferon-γ, interleukin-1ß, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-ß, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. CONCLUSIONS: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.

Descriptors of Sepsis Using the Sepsis-3 Criteria: A Cohort Study in Critical Care Units Within the U.K. National Institute for Health Research Critical Care Health Informatics Collaborative.

OBJECTIVES: To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records. DESIGN: Retrospective cohort study using electronic health records. SETTING: Ten ICUs from four U.K. National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative. PATIENTS: A total of 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical). MEASUREMENTS AND MAIN RESULTS: Twenty-nine thousand three hundred forty-three episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. A total of 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate greater than 2.0 mmol/L, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%; 95% CI, 21.9-25.6%), followed by hospital-acquired sepsis (18.6%; 95% CI, 17.5-19.9%), and community-acquired sepsis (12.9%; 95% CI, 12.1-13.6%) (p for comparison less than 0.0001). CONCLUSIONS: We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding.

Intensivists' beliefs about rapid multiplex molecular diagnostic testing and its potential role in improving prescribing decisions and antimicrobial stewardship: a qualitative study.

BACKGROUND: Rapid molecular diagnostic tests to investigate the microbial aetiology of pneumonias may improve treatment and antimicrobial stewardship in intensive care units (ICUs). Clinicians' endorsement and uptake of these tests is crucial to maximise engagement; however, adoption may be impeded if users harbour unaddressed concerns or if device usage is incompatible with local practice. Accordingly, we strove to identify ICU clinicians' beliefs about molecular diagnostic tests for pneumonias before implementation at the point-of-care. METHODS: We conducted semi-structured interviews with 35 critical care doctors working in four ICUs in the United Kingdom. A clinical vignette depicting a fictitious patient with signs of pneumonia was used to explore clinicians' beliefs about the importance of molecular diagnostics and their concerns. Data were analysed thematically. RESULTS: Clinicians' beliefs about molecular tests could be grouped into two categories: perceived potential of molecular diagnostics to improve antibiotic prescribing (Molecular Diagnostic Necessity) and concerns about how the test results could be implemented into practice (Molecular Diagnostic Concerns). Molecular Diagnostic Necessity stemmed from beliefs that positive results would facilitate targeted antimicrobial therapy; that negative results would signal the absence of a pathogen, and consequently that having the molecular diagnostic results would bolster clinicians' prescribing confidence. Molecular Diagnostic Concerns included unfamiliarity with the device's capabilities, worry that it would detect non-pathogenic bacteria, uncertainty whether it would fail to detect pathogens, and discomfort with withholding antibiotics until receiving molecular test results. CONCLUSIONS: Clinicians believed rapid molecular diagnostics for pneumonias were potentially important and were open to using them; however, they harboured concerns about the tests' capabilities and integration into clinical practice. Implementation strategies should bolster users' necessity beliefs while reducing their concerns; this can be accomplished by publicising the tests' purpose and benefits, identifying and addressing clinicians' misconceptions, establishing a trial period for first-hand familiarisation, and emphasising that, with a swift (e.g., 60-90 min) test, antibiotics can be started and refined after molecular diagnostic results become available.