SARS-CoV-2 environmental contamination from hospitalised patients with COVID-19 receiving aerosol-generating procedures.

BACKGROUND: Continuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are considered 'aerosol-generating procedures' in the treatment of COVID-19. OBJECTIVE: To measure air and surface environmental contamination with SARS-CoV-2 virus when CPAP and HFNO are used, compared with supplemental oxygen, to investigate the potential risks of viral transmission to healthcare workers and patients. METHODS: 30 hospitalised patients with COVID-19 requiring supplemental oxygen, with a fraction of inspired oxygen ≥0.4 to maintain oxygen saturation ≥94%, were prospectively enrolled into an observational environmental sampling study. Participants received either supplemental oxygen, CPAP or HFNO (n=10 in each group). A nasopharyngeal swab, three air and three surface samples were collected from each participant and the clinical environment. Real-time quantitative polymerase chain reaction analyses were performed for viral and human RNA, and positive/suspected-positive samples were cultured for the presence of biologically viable virus. RESULTS: Overall 21/30 (70%) participants tested positive for SARS-CoV-2 RNA in the nasopharynx. In contrast, only 4/90 (4%) and 6/90 (7%) of all air and surface samples tested positive (positive for E and ORF1a) for viral RNA respectively, although there were an additional 10 suspected-positive samples in both air and surfaces samples (positive for E or ORF1a). CPAP/HFNO use or coughing was not associated with significantly more environmental contamination than supplemental oxygen use. Only one nasopharyngeal sample was culture positive. CONCLUSIONS: The use of CPAP and HFNO to treat moderate/severe COVID-19 did not appear to be associated with substantially higher levels of air or surface viral contamination in the immediate care environment, compared with the use of supplemental oxygen.

Untargeted Molecular Analysis of Exhaled Breath as a Diagnostic Test for Ventilator-Associated Lower Respiratory Tract Infections (BreathDx).

Patients suspected of ventilator-associated lower respiratory tract infections (VA-LRTIs) commonly receive broad-spectrum antimicrobial therapy unnecessarily. We tested whether exhaled breath analysis can discriminate between patients suspected of VA-LRTI with confirmed infection, from patients with negative cultures. Breath from 108 patients suspected of VA-LRTI was analysed by gas chromatography-mass spectrometry. The breath test had a sensitivity of 98% at a specificity of 49%, confirmed with a second analytical method. The breath test had a negative predictive value of 96% and excluded pneumonia in half of the patients with negative cultures. Trial registration number: UKCRN ID number 19086, registered May 2015.

RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic.

BACKGROUND: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. METHODS: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again. RESULTS: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease. CONCLUSION: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.

Surveillance for lower airway pathogens in mechanically ventilated patients by metabolomic analysis of exhaled breath: a case-control study.

BACKGROUND: Healthcare associated infections, including ventilator associated pneumonia, are difficult to diagnose and treat, and are associated with significant morbidity, mortality and cost. We aimed to demonstrate proof of concept that breath volatile profiles were associated with the presence of clinically relevant pathogens in the lower respiratory tract. METHODS: Patients with sterile brain injury requiring intubation and ventilation on the intensive care unit were eligible for inclusion. Serial clinical and breath data were obtained three times a week, from admission up to a maximum of 10 days. Bronchial lavage for semiquantitative culture was collected immediately prior to breath sampling. Breath samples were collected in triplicate for off-line analysis by thermal-desorption/gas chromatography/time-of-flight mass spectrometry. Breath data were recorded as retention time/mass ion pairs, and analysed (pathogen present vs absent) by ANOVA-mean centre principal component analysis. RESULTS: Samples were collected from 46 patients (mean (SD) age 49 (19) years; 27 male). The dominant factors affecting breath sample analysis were the individual breath profile and duration of intubation. When these were taken into account, clear separation was seen between breath profiles at each time point by the presence/absence of pathogens. Loadings plots identified consistent metabolite peaks contributing to this separation at each time point. CONCLUSIONS: Breath volatile analysis is able to classify breath profiles of patients with and without significant pathogen load in the lower respiratory tract. If validated in independent cohorts, these findings could lead to development of rapid non-invasive point-of-care surveillance systems and diagnostics for lower respiratory tract infection in the intensive care unit.

Current Perspectives and Concerns Facing Hospital Evacuation: The Results of a Pilot Study and Literature Review.

OBJECTIVE: To analyze the evacuation preparedness of hospitals within the European Union (EU). METHOD: This study consisted of 2 steps. In the first step, a systematic review of the subject matter, according to the PRISMA flow diagram, was performed. Using Scopus (Elsevier, Amsterdam, Netherlands), PubMed (National Library of Medicine, Bethesda, MD), and Gothenburg University´s search engine, 11 questions were extracted from the review and were sent to representatives from 15 European Union (EU)- and non-EU countries. RESULTS: The findings indicate that there is neither a full preparedness nor a standard guideline for evacuation within the EU or other non-EU countries in this study. A major shortcoming revealed by this study is the lack of awareness of the untoward consequences of medical decision-making during an evacuation. Some countries did not respond to the questions due to the lack of relevant guidelines, instructions, or time. CONCLUSION: Hospitals are exposed to internal and external incidents and require an adequate evacuation plan. Despite many publications, reports, and conclusions on successful and unsuccessful evacuation, there is still no common guide for evacuation, and many hospitals lack the proper preparedness. There is a need for a multinational collaboration, specifically within the EU, to establish such an evacuation planning or guideline to be used mutually within the union and the international community.

Developing a roadmap to improve trial delivery for under-served groups: results from a UK multi-stakeholder process.

BACKGROUND: Participants in clinical research studies often do not reflect the populations for which healthcare interventions are needed or will be used. Enhancing representation of under-served groups in clinical research is important to ensure that research findings are widely applicable. We describe a multicomponent workstream project to improve representation of under-served groups in clinical trials. METHODS: The project comprised three main strands: (1) a targeted scoping review of literature to identify previous work characterising under-served groups and barriers to inclusion, (2) surveys of professional stakeholders and participant representative groups involved in research delivery to refine these initial findings and identify examples of innovation and good practice and (3) a series of workshops bringing together key stakeholders from funding, design, delivery and participant groups to reach consensus on definitions, barriers and a strategic roadmap for future work. The work was commissioned by the UK National Institute for Health Research Clinical Research Network. Output from these strands was integrated by a steering committee to generate a series of goals, workstream plans and a strategic roadmap for future development work in this area. RESULTS: 'Under-served groups' was identified and agreed by the stakeholder group as the preferred term. Three-quarters of stakeholders felt that a clear definition of under-served groups did not currently exist; definition was challenging and context-specific, but exemplar groups (e.g. those with language barriers or mental illness) were identified as under-served. Barriers to successful inclusion of under-served groups could be clustered into communication between research teams and participant groups; how trials are designed and delivered, differing agendas of research teams and participant groups; and lack of trust in the research process. Four key goals for future work were identified: building long-term relationships with under-served groups, developing training resources to improve design and delivery of trials for under-served groups, developing infrastructure and systems to support this work and working with funders, regulators and other stakeholders to remove barriers to inclusion. CONCLUSIONS: The work of the INCLUDE group over the next 12 months will build on these findings by generating resources customised for different under-served groups to improve the representativeness of trial populations.

Ensuring that COVID-19 research is inclusive: guidance from the NIHR INCLUDE project.

OBJECTIVE: To provide guidance to researchers, funders, regulators and study delivery teams to ensure that research on COVID-19 is inclusive, particularly of groups disproportionately affected by COVID-19 and who may have been historically under-served by research. SUMMARY OF KEY POINTS: Groups who are disproportionately affected by COVID-19 include (but are not limited to) older people, people with multiple long-term conditions, people with disabilities, people from Black, Asian and Ethnic minority groups, people living with obesity, people who are socioeconomically deprived and people living in care homes. All these groups are under-served by clinical research, and there is an urgent need to rectify this if COVID-19 research is to deliver relevant evidence for these groups who are most in need. We provide a framework and checklists for addressing key issues when designing and delivering inclusive COVID-19 research, based on the National Institute for Health Research INnovations in CLinical trial design and delivery for the UnDEr-served project roadmap. Strong community engagement, codevelopment and prioritisation of research questions and interventions are essential. Under-served groups should be represented on funding panels and ethics committees, who should insist on the removal of barriers to participation. Exclusion criteria should be kept to a minimum; intervention delivery and outcome measurement should be simple, flexible and tailored to the needs of different groups, and local advice on the best way to reach and engage with under-served communities should be taken by study delivery teams. Data on characteristics that allow identification of under-served groups must be collected, analyses should include these data to enable subgroup comparisons and results should be shared with under-served groups at an early stage. CONCLUSION: Inclusive COVID-19 research is a necessity, not a luxury, if research is to benefit all the communities it seeks to serve. It requires close engagement with under-served groups and attention to aspects of study topic, design, delivery, analysis and dissemination across the research life cycle.

Bench-to-bedside review: the promise of rapid infection diagnosis during sepsis using polymerase chain reaction-based pathogen detection.

Early infection diagnosis as the cause of a patient's systemic inflammatory syndrome is an important facet of sepsis care bundles aimed at saving lives. Microbiological culture provides the main route for infection diagnosis but by its nature cannot provide time-critical results that can impact on early management. Consequently, broad-spectrum and high-potency antibiotics are essential during the immediate management of suspected sepsis in critical care but are associated with the development of drug-resistant organisms and superinfections. Established molecular laboratory techniques based on polymerase chain reaction (PCR) technology can detect pathogen DNA rapidly and have been developed for translation into a clinical diagnostic setting. In the setting of sepsis in critical care, emerging commercial systems are now available for the analysis of whole blood within hours, with the presumed aim of adoption into the current care bundles. In this review, we consider the importance of early infection diagnosis in sepsis, how this is limited by culture approaches and how the emerging PCR methods are showing promise in early clinical observational studies. The strengths and weaknesses of culture and PCR pathogen detection in whole-blood samples will be highlighted and recommendations made for urgent appropriately powered diagnostic validation studies in advance of clinical effectiveness trials before these emerging PCR pathogen detection techniques can be considered for adoption in clinical practice.

Biomarker-guided antibiotic cessation in sepsis: evidence and future challenges.

Sepsis is a medical emergency, which requires the initiation of broad-spectrum antimicrobial agents as early as possible. In the absence of positive microbiological cultures providing targeted antimicrobial advice, broad-spectrum antibiotics are commonly continued until there is clinical evidence of infection resolution. With an absence of robust evidence to inform when it is safe to stop antimicrobial agents in sepsis, the duration of antimicrobial courses may be longer than is required. Prolonged courses of potent broad-spectrum antimicrobials increase the risk of adverse drug events and contribute to the growing emergence of multidrug resistant pathogens, which is a global public health emergency. The protocolised use of protein biomarkers to guide clinical decision making can be used to help combat excessive durations of antimicrobials in patients with sepsis. This article reviews the current evidence for biomarker-guided antimicrobial discontinuation protocols in sepsis, identifies related evidence gaps and examines future innovation challenges in this field.

Removal of Contaminant DNA by Combined UV-EMA Treatment Allows Low Copy Number Detection of Clinically Relevant Bacteria Using Pan-Bacterial Real-Time PCR.

BACKGROUND: More than two decades after its discovery, contaminant microbial DNA in PCR reagents continues to impact the sensitivity and integrity of broad-range PCR diagnostic techniques. This is particularly relevant to their use in the setting of human sepsis, where a successful diagnostic on blood samples needs to combine universal bacterial detection with sensitivity to 1-2 genome copies, because low levels of a broad range of bacteria are implicated. RESULTS: We investigated the efficacy of ethidium monoazide (EMA) and propidium monoazide (PMA) treatment as emerging methods for the decontamination of PCR reagents. Both treatments were able to inactivate contaminating microbial DNA but only at concentrations that considerably affected assay sensitivity. Increasing amplicon length improved EMA/PMA decontamination efficiency but at the cost of assay sensitivity. The same was true for UV exposure as an alternative decontamination strategy, likely due to damage sustained by oligonucleotide primers which were a significant source of contamination. However, a simple combination strategy with UV-treated PCR reagents paired with EMA-treated primers produced an assay capable of two genome copy detection and a <5% contamination rate. This decontamination strategy could have important utility in developing improved pan-bacterial assays for rapid diagnosis of low pathogen burden conditions such as in the blood of patients with suspected blood stream infection.

The validity of trans-esophageal Doppler ultrasonography as a measure of cardiac output in critically ill adults.

OBJECTIVE: To determine the validity of the esophageal Doppler monitor (EDM) and echo-esophageal Doppler (Echo-ED) in measuring cardiac output in the critically ill. DESIGN: Systematic search of relevant international literature and data synthesis. SEARCH STRATEGY: Literature search (1989-2003) using Ovid interface to Medline, Embase and Cochrane databases aimed at finding studies comparing EDM or Echo-ED cardiac output with that derived from simultaneous pulmonary artery thermodilution (PAC(TD)) with Bland Altman measures of validity. PATIENTS: Critically ill adults in operating departments or intensive care units. DATA SYNTHESIS: Summary validity measures synthesized from Bland Altman analyses included pooled median bias and the median percentage of clinical agreement (PCA) derived from the limits of agreement. MAIN RESULTS: Eleven validation papers for EDM (21 studies) involving 314 patients and 2,400 paired measurements. The pooled median bias for PAC(TD) versus EDM was 0.19 l/min (range -0.69 to 2.00 l/min) for cardiac output (16 studies), and 0.6% (range 0-2.3%) for changes in cardiac output (5 studies). The pooled median percentage of clinical agreement for PAC(TD) versus EDM was 52% (interquartile range 42-69%) for cardiac output and 86% (interquartile range 55-93%) for changes in cardiac output. These differences in PCA were significant ( p=0.03 Mann-Whitney) for bolus PAC(TD) as the clinical "gold standard". We found an insufficient number of studies (2 papers) to assess the validity of Echo-ED. CONCLUSIONS: The esophageal Doppler monitor has high validity (no bias and high clinical agreement with pulmonary artery thermodilution) for monitoring changes in cardiac output.

Organ-specific effects of oxygen and carbogen gas inhalation on tissue longitudinal relaxation times.

Molecular oxygen has been previously shown to shorten longitudinal relaxation time (T1) in the spleen and renal cortex, but not in the liver or fat. In this study, the magnitude and temporal evolution of this effect were investigated. Medical air, oxygen, and carbogen (95% oxygen/5% CO2) were administered sequentially in 16 healthy volunteers. T1 maps were acquired using spoiled gradient echo sequences (TR=3.5 ms, TE=0.9 ms, alpha=2 degrees/8 degrees/17 degrees) with six acquisitions on air, 12 on oxygen, 12 on carbogen, and six to 12 back on air. Mean T1 values and change in relaxation rate were compared between each phase of gas inhalation in the liver, spleen, skeletal muscle, renal cortex, and fat by one-way analysis of variance. Oxygen-induced T1-shortening occurred in the liver in fasted subjects (P<0.001) but not in non-fasted subjects (P=0.244). T1-shortening in spleen and renal cortex (both P<0.001) were greater than previously reported. Carbogen induced conflicting responses in different organs, suggesting a complex relationship with organ vasculature. Shortening of tissue T1 by oxygen is more pronounced and more complex than previously recognized. The effect may be useful as a biomarker of arterial flow and oxygen delivery to vascular beds.

Estimation of errors in determining intrathoracic blood volume using the single transpulmonary thermal dilution technique in hypovolemic shock.

BACKGROUND: The transpulmonary thermal dilution technique has been widely adopted for monitoring cardiac preload and extravascular lung water in critically ill patients. This method assumes intrathoracic blood volume (ITBV) to be a fixed proportion of global end-diastolic volume (GEDV). This study determines the relation between GEDV and ITBV under normovolemic and hypovolemic conditions and quantifies the errors in estimating ITBV. METHODS: Nineteen pigs allocated to control (n = 9) and shock (n = 10) groups were studied. Shock was maintained for 60 min followed by volume resuscitation. The dual dye-thermal dilution technique was used to measure GEDV and ITBV (ITBVm) at baseline (time 0), shock phase (30 and 90 min), and after resuscitation (150 min). The regression equations estimated from paired GEDV and ITBVm measurements under normovolemic and hypovolemic conditions were used to estimate ITBV from the corresponding GEDV, and the estimation errors were quantified. A more simplified equation, used in a commercially available clinical monitor (ITBV = 1.25 x GEDV), was then used to estimate ITBV. RESULTS: The regression equation in the control group was ITBVm = 1.21 x GEDV + 99 (r = 0.89, P < 0.0001) and in the shock group at 30 and 90 min was ITBVm = 1.45 x GEDV + 0.6 (r = 0.95, P < 0.0001). The 95% confidence interval for the y-intercept was relatively wide, ranging from 31 to 168 and -47 to 49, respectively, for the two equations. The equation estimated in the control group led to overestimation of ITBV and a significant (P < 0.05) increase in errors in the shock group at 30 and 90 min. Errors in estimating ITBV using the simplified commercial algorithm were less than 15% under normovolemic and hypovolemic conditions. CONCLUSIONS: The linear relation between GEDV and ITBV is maintained in hypovolemic shock. Even though the relation between GEDV and ITBV is influenced by circulatory volume and cardiac output, the mean errors in predicting ITBV were small and within clinically tolerable limits.

Hemodynamic responses to fluid resuscitation after blunt trauma.

OBJECTIVES: To determine the acute circulatory effects of an open fracture and the circulatory effects of different fluid resuscitation strategies after such a fracture. DESIGN: Randomized controlled laboratory study. SETTING: Medical Research Council laboratory, university medical school. SUBJECTS: Four groups of ten immature female Large-White pigs (16.5-27.0 kg): those receiving limited resuscitation, moderate resuscitation, and normal resuscitation, as well as surgical controls. INTERVENTIONS: After induction and intubation with 3% halothane, anesthesia was maintained with intravenous Saffan. Cannulae were placed in the left external jugular vein and both axillary arteries. A pulmonary artery flotation catheter was introduced through the jugular cannula. The left femur was exposed for fracture with a captive bolt. Resuscitation was with 0.9% saline; the moderate resuscitation group received less than the normal resuscitation group (840 +/- 67 mL vs. 1873 +/- 96 mL), whereas the surgical control and limited resuscitation groups received the lowest volumes (466 +/- 10 mL and 452 +/- 19 mL, respectively). MEASUREMENTS AND MAIN RESULTS: Measurements/calculations of global hemodynamics (intravascular pressures, e.g., mean arterial pressure, heart rate, stroke volume index, cardiac output/index, left ventricular stroke work index, and systemic vascular resistance index), metabolism (oxygen delivery index and consumption index, oxygen extraction ratio, plasma lactate, hemoglobin), blood gases, pH, and hematocrit were made before fracture, immediately and 30 mins after fracture, and at 30-min intervals for the next 4 hrs. Hind-limb muscle water content was determined by dessication. Femur fracture led to acute reductions in cardiac output/index, stroke volume index, and oxygen delivery index and increases in systemic vascular resistance index and oxygen extraction ratio. In the absence of fluid resuscitation, these changes persisted and were accompanied by hypotension. Normal resuscitation attenuated the fracture-induced changes such that the only differences during resuscitation between limited resuscitation and normal resuscitation were a reduction in hematocrit in the latter and an increase in oxygen extraction ratio in the former. Water content increased in both injured and uninjured muscle. CONCLUSIONS: The cardiovascular and metabolic changes associated with femur fracture in the anesthetized pig can be reversed or prevented by crystalloids given in a volume equivalent to Advanced Trauma Life Support guidelines.