OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis.

OBJECTIVE: Sepsis is life-threatening organ dysfunction due to dysregulated host responses to infection. Current knowledge of human B-cell alterations in sepsis is sparse. We tested the hypothesis that B-cell loss in sepsis involves distinct subpopulations of B cells and investigated mechanisms of B-cell depletion. DESIGN: Prospective cohort study. SETTING: Critical care units. PATIENTS: Adult sepsis patients without any documented immune comorbidity. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: B-cell subsets were quantified by flow cytometry; annexin-V status identified apoptotic cells and phosphorylation of intracellular kinases identified activation status of B-cell subsets. B cell-specific survival ligand concentrations were measured. Gene expression in purified B cells was measured by microarray. Differences in messenger RNA abundance between sepsis and healthy controls were compared. Lymphopenia present in 74.2% of patients on admission day was associated with lower absolute B-cell counts (median [interquartile range], 0.133 [0.093-0.277] 10 cells/L) and selective depletion of memory B cells despite normal B cell survival ligand concentrations. Greater apoptotic depletion of class-switched and IgM memory cells was associated with phosphorylation of extracellular signal-regulated kinases, implying externally driven lymphocyte stress and activation-associated cell death. This inference is supported by gene expression profiles highlighting mitochondrial dysfunction and cell death pathways, with enriched intrinsic and extrinsic pathway apoptosis genes. CONCLUSIONS: Depletion of the memory B-cell compartment contributes to the immunosuppression induced by sepsis. Therapies targeted at reversing this immune memory depletion warrant further investigation.

Short-term and medium-term survival of critically ill patients with solid tumours admitted to the intensive care unit: a retrospective analysis.

OBJECTIVES: Patients with cancer frequently require unplanned admission to the intensive care unit (ICU). Our objectives were to assess hospital and 180-day mortality in patients with a non-haematological malignancy and unplanned ICU admission and to identify which factors present on admission were the best predictors of mortality. DESIGN: Retrospective review of all patients with a diagnosis of solid tumours following unplanned admission to the ICU between 1 August 2008 and 31 July 2012. SETTING: Single centre tertiary care hospital in London (UK). PARTICIPANTS: 300 adult patients with non-haematological solid tumours requiring unplanned admission to the ICU. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOMES: Hospital and 180-day survival. RESULTS: 300 patients were admitted to the ICU (median age 66.5 years; 61.7% men). Survival to hospital discharge and 180 days were 69% and 47.8%, respectively. Greater number of failed organ systems on admission was associated with significantly worse hospital survival (p<0.001) but not with 180-day survival (p=0.24). In multivariate analysis, predictors of hospital mortality were the presence of metastases (OR 1.97, 95% CI 1.08 to 3.59), Acute Physiology and Chronic Health Evaluation II (APACHE II) Score (OR 1.07, 95% CI 1.01 to 1.13) and a Glasgow Coma Scale Score <7 on admission to ICU (OR 5.21, 95% CI 1.65 to 16.43). Predictors of worse 180-day survival were the presence of metastases (OR 2.82, 95% CI 1.57 to 5.06), APACHE II Score (OR 1.07, 95% CI 1.01 to 1.13) and sepsis (OR 1.92, 95% CI 1.09 to 3.38). CONCLUSIONS: Short-term and medium-term survival in patients with solid tumours admitted to ICU is better than previously reported, suggesting that the presence of cancer alone should not be a barrier to ICU admission.

The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a multicenter, multinational, 14-day inception cohort study.

PURPOSE: In this prospective, multicenter, 14-day inception cohort study, we investigated the epidemiology, patterns of infections, and outcome in patients admitted to the intensive care unit (ICU) as a result of severe acute respiratory infections (SARIs). METHODS: All patients admitted to one of 206 participating ICUs during two study weeks, one in November 2013 and the other in January 2014, were screened. SARI was defined as possible, probable, or microbiologically confirmed respiratory tract infection with recent onset dyspnea and/or fever. The primary outcome parameter was in-hospital mortality within 60 days of admission to the ICU. RESULTS: Among the 5550 patients admitted during the study periods, 663 (11.9 %) had SARI. On admission to the ICU, Gram-positive and Gram-negative bacteria were found in 29.6 and 26.2 % of SARI patients but rarely atypical bacteria (1.0 %); viruses were present in 7.7 % of patients. Organ failure occurred in 74.7 % of patients in the ICU, mostly respiratory (53.8 %), cardiovascular (44.5 %), and renal (44.6 %). ICU and in-hospital mortality rates in patients with SARI were 20.2 and 27.2 %, respectively. In multivariable analysis, older age, greater severity scores at ICU admission, and hematologic malignancy or liver disease were independently associated with an increased risk of in-hospital death, whereas influenza vaccination prior to ICU admission and adequate antibiotic administration on ICU admission were associated with a lower risk. CONCLUSIONS: Admission to the ICU for SARI is common and associated with high morbidity and mortality rates. We identified several risk factors for in-hospital death that may be useful for risk stratification in these patients.

Low Systemic Oxygen Delivery and BP and Risk of Progression of Early AKI.

BACKGROUND AND OBJECTIVES: The optimal hemodynamic management of patients with early AKI is unknown. This study aimed to investigate the association between hemodynamic parameters in early AKI and progression to severe AKI and hospital mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study retrospectively analyzed the data of all patients admitted to the adult intensive care unit in a tertiary care center between July 2007 and June 2009 and identified those with stage 1 AKI (AKI I) per the AKI Network classification. In patients in whom hemodynamic monitoring was performed within 12 hours of AKI I, hemodynamic parameters in the first 12 hours of AKI I and on the day of AKI III (if AKI III developed) or 72 hours after AKI I (if AKI III did not develop) were recorded. Risk factors for AKI III and mortality were identified using univariate and multivariate logistic regression analyses. RESULTS: Among 790 patients with AKI I, 210 (median age 70 years; 138 men) had hemodynamic monitoring within 12 hours of AKI I; 85 patients (41.5%) progressed to AKI III and 91 (43%) died in the hospital. AKI progressors had a significantly higher Sequential Organ Failure Assessment score (8.0 versus 9.6; P<0.001), lower indexed systemic oxygen delivery (DO2I) (median 325 versus 405 ml/min per m(2); P<0.001), higher central venous pressure (16 versus 13; P=0.02), and lower mean arterial blood pressure (MAP) (median 71 versus 74 mmHg; P=0.01) in the first 12 hours of AKI I compared with nonprogressors. Multivariate analysis confirmed that raised lactate, central venous pressure, and Sequential Organ Failure Assessment score as well as mechanical ventilation were independently associated with progression to AKI III; higher DO2I and MAP were independently associated with a lower risk of AKI III but not survival. The associations were independent of sepsis, heart disease, recent cardiac surgery, or chronic hypertension. CONCLUSIONS: Higher DO2I and MAP in early AKI were independently associated with a lower risk of progression.

The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study.

BACKGROUND: Pulmonary vascular leakage occurs early in acute respiratory distress syndrome (ARDS). Mortality is high (35-45%), but no effective pharmacotherapy exists. Production of anti-inflammatory adenosine by ecto-5'-nucleotidase (CD73) helps maintain endothelial barrier function. We tested whether interferon-beta-1a (IFN-beta-1a), which increases CD73 synthesis, can reduce vascular leakage and mortality in patients with ARDS. METHODS: In ex-vivo studies, we first established that IFN-beta-1a induced CD73 up-regulation in cultured human lung tissue samples. We then tested the safety, tolerability, and efficacy of intravenous human recombinant IFN-beta-1a (FP-1201) in patients with ARDS in an open-label study (comprising dose-escalation and expansion phases). We recruited patients from eight intensive care units in the UK. Eligible patients were aged 18 years or older, had ARDS, and were being treated with assisted ventilation. We established an optimal tolerated dose (OTD) in the first, dose-escalation phase. Once established, we gave all subsequently enrolled patients the OTD of intravenous FP-1201 for 6 days. We assessed 28-day mortality (our primary endpoint) in all patients receiving the OTD versus 28-day mortality in a group of patients who did not receive treatment (this control group comprised patients in the study but who did not receive treatment because they were screened during the safety windows after dose escalation). This trial is registered with ClinicalTrials.gov, number NCT00789685, and the EU Clinical Trials Register EudraCT, number 2008-000140-13. FINDINGS: IFN-beta-1a increased the number of CD73-positive vessels in lung culture by four times on day 1 (p=0·04) and by 14·3 times by day 4 (p=0·004). For the clinical trial, between Feb 23, 2009, and April 7, 2011, we identified 150 patients, of whom 37 were enrolled into the trial and given treatment. The control group consisted of 59 patients who were recruited to take part in the study, but who did not receive treatment. Demographic characteristics and severity of illness did not differ between treatment and control groups. The optimal tolerated FP-1201 dose was 10 µg per day for 6 days. By day 28, 3 (8%) of 37 patients in the treatment cohort and 19 (32%) of 59 patients in the control cohort had died-thus, treatment with FP-1201 was associated with an 81% reduction in odds of 28-day mortality (odds ratio 0·19 [95% CI 0·03-0·72]; p=0·01). INTERPRETATION: FP-1201 up-regulates human lung CD73 expression, and is associated with a reduction in 28-day mortality in patients with ARDS. Our findings need to be substantiated in large, prospective randomised trials, but suggest that FP-1201 could be the first effective, mechanistically targeted, disease-specific pharmacotherapy for patients with ARDS.

Rationale and study design of ViPS - variable pressure support for weaning from mechanical ventilation: study protocol for an international multicenter randomized controlled open trial.

BACKGROUND: In pressure support ventilation (PSV), a non-variable level of pressure support is delivered by the ventilator when triggered by the patient. In contrast, variable PSV delivers a level of pressure support that varies in a random fashion, introducing more physiological variability to the respiratory pattern. Experimental studies show that variable PSV improves gas exchange, reduces lung inflammation and the mean pressure support, compared to non-variable PSV. Thus, it can theoretically shorten weaning from the mechanical ventilator. METHODS/DESIGN: The ViPS (variable pressure support) trial is an international investigator-initiated multicenter randomized controlled open trial comparing variable vs. non-variable PSV. Adult patients on controlled mechanical ventilation for more than 24 hours who are ready to be weaned are eligible for the study. The randomization sequence is blocked per center and performed using a web-based platform. Patients are randomly assigned to one of the two groups: variable PSV or non-variable PSV. In non-variable PSV, breath-by-breath pressure support is kept constant and targeted to achieve a tidal volume of 6 to 8 ml/kg. In variable PSV, the mean pressure support level over a specific time period is targeted at the same mean tidal volume as non-variable PSV, but individual levels vary randomly breath-by-breath. The primary endpoint of the trial is the time to successful weaning, defined as the time from randomization to successful extubation. DISCUSSION: ViPS is the first randomized controlled trial investigating whether variable, compared to non-variable PSV, shortens the duration of weaning from mechanical ventilation in a mixed population of critically ill patients. This trial aims to determine the role of variable PSV in the intensive care unit. TRIAL REGISTRATION: clinicaltrials.gov NCT01769053.

Standing up the National Ignition Facility radiation protection program.

Operation of the NIF requires a large and varied number of routine and infrequent activities involving contaminated and radioactive systems, both in servicing online equipment and offline refurbishment of components. Routine radiological operations include up to several dozen entries into contaminated systems per day, multiple laboratories refurbishing radiologically impacted parts, handling of tens of curies of tritium, and (eventually) tens of workers spending most of their day working in radiation areas and handling moderately activated parts. Prior to the introduction of radioactive materials and neutron producing experiments (capable of causing activation), very few of the operating staff had any radiological qualifications or experience. To support the full NIF operating program, over 600 radiological workers needed to be trained, and a functional and large-scale radiological protection program needed to be put in place. It quickly became evident that there was a need to supplement the LLNL site radiological protection staff with additional radiological controls technicians and a radiological protection staff within NIF operations to manage day-to-day activities. This paper discusses the approach taken to stand up the radiological protection program and some lessons learned.

Retrospective analysis of outcome of women with breast or gynaecological cancer in the intensive care unit.

OBJECTIVES: Advances in oncological care have led to improved short and long-term outcomes of female patients with breast and gynecological cancer but little is known about their prognosis when admitted to the intensive care unit (ICU). Our aim was to describe the epidemiology of patients with women's cancer in ICU. DESIGN: Retrospective analysis of data of patients with breast and gynecological cancer in ICU between February 2004 and July 2008. SETTING: ICU in a tertiary referral centre in London. PARTICIPANTS: Nineteen critically ill women with breast or gynaecological cancer. MAIN OUTCOME MEASURES: ICU and six-month outcome. RESULTS: Eleven women had breast cancer and eight patients had gynaecological cancer. Twelve patients were known to have metastatic disease. The main reasons for admission to ICU were sepsis (94.7%), respiratory failure (36.8%) and need for vasoactive support (26.3%). ICU mortality was 31.6%. There was no difference in age and Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) score on admission to ICU between ICU survivors and non-survivors. During their stay in ICU, non-survivors had significantly more organ failure. Six-month mortality was 68.4%. Four patients had >1 admission to ICU. CONCLUSIONS: ICU outcome of critically ill women with breast or gynaecological cancer was similar to that of other non-cancer patient cohorts but six-month mortality was significantly higher. The decision to admit patients with women's cancer to the ICU should depend on the severity of the acute illness rather than factors related to the underlying malignancy. More research is needed to explore the outcome of patients with women's cancer after discharge from ICU.

Extravascular lung water in acute respiratory distress syndrome: potential clinical value, assumptions and limitations.

Extravascular lung water has been proposed as a marker of disease severity, response to treatment and mortality in patients with acute respiratory distress syndrome. Here, we discuss its potential value and limitations in clinical practice.

Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients.

PURPOSE: Colloids are administered to more patients than crystalloids, although recent evidence suggests that colloids may possibly be harmful in some patients. The European Society of Intensive Care Medicine therefore assembled a task force to compile consensus recommendations based on the current best evidence for the safety and efficacy of the currently most frequently used colloids--hydroxyethyl starches (HES), gelatins and human albumin. METHODS: Meta-analyses, systematic reviews and clinical studies of colloid use were evaluated for the treatment of volume depletion in mixed intensive care unit (ICU), cardiac surgery, head injury, sepsis and organ donor patients. Clinical endpoints included mortality, kidney function and bleeding. The relevance of concentration and dosage was also assessed. Publications from 1960 until May 2011 were included. The quality of available evidence and strength of recommendations were based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RECOMMENDATIONS AND CONCLUSIONS: We recommend not to use HES with molecular weight ≥ 200 kDa and/or degree of substitution >0.4 in patients with severe sepsis or risk of acute kidney injury and suggest not to use 6% HES 130/0.4 or gelatin in these populations. We recommend not to use colloids in patients with head injury and not to administer gelatins and HES in organ donors. We suggest not to use hyperoncotic solutions for fluid resuscitation. We conclude and recommend that any new colloid should be introduced into clinical practice only after its patient-important safety parameters are established.

Management of the critically ill patient with severe acute pancreatitis.

OBJECTIVE: Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course requiring only brief hospitalization to a rapidly progressive, fulminant illness resulting in the multiple organ dysfunction syndrome (MODS), with or without accompanying sepsis. The goal of this consensus statement is to provide recommendations regarding the management of the critically ill patient with severe acute pancreatitis (SAP). DATA SOURCES AND METHODS: An international consensus conference was held in April 2004 to develop recommendations for the management of the critically ill patient with SAP. Evidence-based recommendations were developed by a jury of ten persons representing surgery, internal medicine, and critical care after conferring with experts and reviewing the pertinent literature to address specific questions concerning the management of patients with severe acute pancreatitis. DATA SYNTHESIS: There were a total of 23 recommendations developed to provide guidance to critical care clinicians caring for the patient with SAP. Topics addressed were as follows. 1) When should the patient admitted with acute pancreatitis be monitored in an ICU or stepdown unit? 2) Should patients with severe acute pancreatitis receive prophylactic antibiotics? 3) What is the optimal mode and timing of nutritional support for the patient with SAP? 4) What are the indications for surgery in acute pancreatitis, what is the optimal timing for intervention, and what are the roles for less invasive approaches including percutaneous drainage and laparoscopy? 5) Under what circumstances should patients with gallstone pancreatitis undergo interventions for clearance of the bile duct? 6) Is there a role for therapy targeting the inflammatory response in the patient with SAP? Some of the recommendations included a recommendation against the routine use of prophylactic systemic antibacterial or antifungal agents in patients with necrotizing pancreatitis. The jury also recommended against pancreatic debridement or drainage for sterile necrosis, limiting debridement or drainage to those with infected pancreatic necrosis and/or abscess confirmed by radiologic evidence of gas or results or fine needle aspirate. Furthermore, the jury recommended that whenever possible, operative necrosectomy and/or drainage be delayed at least 2-3 wk to allow for demarcation of the necrotic pancreas. CONCLUSIONS: This consensus statement provides 23 different recommendations concerning the management of patients with SAP. These recommendations differ in several ways from previous recommendations because of the release of recent data concerning the management of these patients and also because of the focus on the critically ill patient. There are a number of important questions that could not be answered using an evidence-based approach, and areas in need of further research were identified.