Statistical analysis plan for the INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) meta-trial (preprint)

The INHALE-HEP meta-trial is a prospective collaborative individual participant data meta-analysis of randomised controlled trials and early phase studies, to evaluate whether inhaled nebulised UFH in hospitalised patients with COVID-19 who do not require immediate invasive mechanical ventilation, significantly reduces intubation (or death, for patients who died before intubation) at day 28 compared to standard care alone. Objective: In keeping with best practice and with the published protocol, a pre-specified statistical analysis plan has been described and made public before completion of patient recruitment and data collection into the INHALE-HEP meta-trial. Methods: Our statistical analysis plan was designed by the INHALE-HEP executive committee and statisticians and approved by the INHALE-HEP steering committee. We reviewed the data collected as specified in the meta-trial protocol and collected in individual contributing studies. We present information pertaining to data collection, pre-specified subgroups, and study outcomes. Primary and secondary outcomes are defined, and additional subgroup analyses of pre-defined variables are described. Results: We have described our methods for presenting the trial profile and baseline characteristics, as well as our Bayesian approach to monitoring and meta-analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. Conclusion: To minimise analytical bias, we have developed a statistical analysis plan and made this available to the public domain before completion of patient recruitment and data collection into the INHALE-HEP meta-trial.

Risk Factors for 28-Day in-Hospital Mortality in Mechanically Ventilated Patients with COVID-19: An International Cohort Study (preprint)

Background: Risk factors associated with mortality in patients with coronavirus disease 2019 (COVID-19) on mechanical ventilation are still not fully elucidated. Thus, we aimed to identify patient-level factors, readily available at the bedside, associated with the risk of in-hospital mortality within 28 days from commencement of invasive mechanical ventilation (28-day IMV mortality) in patients with COVID-19. Methods: Prospective observational cohort study in 148 intensive care units in the global COVID-19 Critical Care Consortium . Patients with clinically suspected or laboratory confirmed COVID-19 infection admitted to the intensive care unit (ICU) from February 2 nd through December 29th, 2020, requiring IMV. No study-specific interventions were performed. Patient characteristics and clinical data were assessed upon ICU admission, the commencement of IMV and for 28 days thereafter. We primarily aimed to identify time-independent and time-dependent risk factors for 28-day IMV mortality. Results: : A total of 1713 patients were included in the survival analysis, 588 patients died in hospital within 28 days of commencing IMV (34.3%). Cox-regression analysis identified associations between the hazard of 28-day IMV mortality with age (HR 1.27 per 10-year increase in age, 95% CI 1.17 to 1.37, P<0.001), PEEP upon commencement of IMV (HR 0.78 per 5-cmH 2 O increase, 95% CI 0.66-0.93, P=0.005). Time-dependent parameters associated with 28-day IMV mortality were serum creatinine (HR 1.30 per doubling, 95% CI 1.19-1.42, P<0.001), lactate (HR 1.16 per doubling, 95% CI 1.06-1.27 P=0.001), PaCO 2 (HR 1.31 per doubling, 95% CI 1.05-1.64, P=0.015), pH (HR 0.82 per 0.1 increase, 95% CI 0.74-0.91, P<0.001), PaO 2 /FiO 2 (HR 0.56 per doubling, 95% CI 0.50-0.62, P<0.001) and mean arterial pressure (HR 0.92 per 10 mmHg increase, 95% CI 0.88-0.97, P=0.002). Conclusions: : This international study establishes that in mechanically ventilated patients with COVID-19, older age and clinically relevant variables monitored at the bedside are risk factors for 28-day IMV mortality. Further investigation is warranted to validate any causative roles these parameters might play in influencing clinical outcomes.

Improved diagnosis of SARS-CoV-2 by using Nucleoprotein and Spike protein fragment 2 in quantitative dual ELISA tests (preprint)

SUMMARY The novel Coronavirus, SARS-CoV-2, is the causative agent of the 2020 worldwide coronavirus pandemic. Antibody testing is useful for diagnosing historic infections of a disease in a population. These tests are also a helpful epidemiological tool for predicting how the virus spreads in a community, relating antibody levels to immunity and for assessing herd immunity. In the present study, SARS-CoV-2 viral proteins were recombinantly produced and used to analyse serum from individuals previously exposed, or not, to SARS-CoV-2. The nucleocapsid (Npro) and Spike subunit 2 (S2Frag) proteins were identified as highly immunogenic, although responses to the former were generally greater. These two proteins were used to develop two quantitative ELISA assays that when used in combination resulted in a highly reliable diagnostic test. Npro and S2Frag-ELISAs could detect at least 10% more true positive COVID-19 cases than the commercially available ARCHITECT test (Abbott). Moreover, our quantitative ELISAs also show that specific antibodies to SARS-CoV-2 proteins tend to wane rapidly even in patients that had developed severe disease. As antibody tests complement COVID-19 diagnosis and determine population-level surveillance during this pandemic, the alternative diagnostic we present in this study could play a role in controlling the spread of the virus.

Use of Neuromuscular Blocking Agents in Mechanically Ventilated Patients with COVID-19: A Propensity Score Analysis (preprint)

Background: Neuromuscular blocking agents (NMBA) have been previously used in patients with acute respiratory distress syndrome (ARDS). It is unknown if NMBA are useful in COVID-19 patients who require invasive mechanical ventilation (IMV).Methods: We investigated use of NMBA in COVID-19 patients on IMV from February 1 to November 24, 2020, in 147 hospitals across 6 continents, comprising the COVID-19 Critical Care Consortium. We performed propensity score (PS) matched Cox proportional hazards analysis to appraise the impact of NMBA use for ≥2 days, continuously or discontinuously (treatment), vs. no use of NMBA or only upon commencement of IMV (control) on 28-day intensive care unit (ICU) mortality.Findings: 1548 (72%) patients received any NMBA therapy; 1165 (54%) of patients were stratified in the treatment group, with a median (IQR) time from ICU admission to commencement of NMBA therapy of 0 (0-2) days. The median (IQR) duration of NMBA therapy was 3 (2-6) days (N=1548). Upon commencement of IMV, patients who received NMBA therapy had a lower mean (±SD) PaO2/FiO2 (139±75 vs 157±93; P<0.001). After PS matching, Cox proportional hazard model demonstrated that NMBA therapy was significantly associated with higher 28-day ICU mortality (adjusted HR 2.20, 95% CI 1.67, 2.89, P<0.001). Sensitivity analyses testing various NMBA therapeutic regimens confirmed similar associations with mortality.Interpretation: Use of NMBA is common in COVID-19 patients on IMV and associated with a 2.2-fold increase in risk of 28-day mortality. Until further randomised evidence is available, NMBA should be applied cautiously in routine clinical practice.Funding Statement: University of Queensland, Wesley Medical Research, The Prince Charles Hospital Foundation, The Health Research Board of Ireland; Biomedicine international training research programme for excellent clinician-scientists; European Union’s research and innovation programme (Horizon 2020); la Caixa Foundation. Finally, Carol Hodgson is funded by a National Health and Medical Research Council Grant.Declaration of Interests: Dr. Li Bassi received research support from Fisher & Paykel outside the submitted work. Dr. Dalton has consulting from Innovative ECMO Concepts, Abiomed and Instrumentation Labs , none which affect the current work. Dr. Brodie receives research support from ALung Technologies and he has been on the medical advisory boards for Baxter, Abiomed, Xenios and Hemovent. Dr. Fan reports personal fees from ALung Technologies, Baxter, Fresenius Medical Care, Getinge, and MC3Cardiopulmonary outside the submitted work. Dr. Laffey reports consulting fees from Baxter and Cala Medical, both outside the submitted work. Dr Nichol is supported by a health Research Board of Ireland award (CTN-2014-012). Dr. Fraser receives research support from Fisher & Paykel outside the submitted work. Remaining authors do not have any competing interest to declare. Ethics Approval Statement: Participating hospitals obtained local ethics committee approval and a waiver of informed consent was granted in all cases.De-identified patient data were collected and stored via the REDCap (Vanderbilt/NIH/NCATS UL1 TR000445 v.10.0.23) electronic data capture tool, hosted at the University of Oxford, United Kingdom and University of Queensland.

INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol and Statistical Analysis Plan for an investigator-initiated international meta-trial of randomised studies (preprint)

Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus’ entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anti-coagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. Methods and intervention The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) meta-trial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the meta-trial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes. Analysis We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. Trial registration, ethics and dissemination The meta-trial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board.

Development and assessment of the performance of a shared ventilatory system that uses clinically available components to individualize tidal volumes (preprint)

Objectives To develop and assess the performance of a system for shared ventilation that uses clinically available components to individualize tidal volumes under a variety of clinically relevant conditions. Design Evaluation and in vitro validation study. Setting Ventilator shortage during the SARS-CoV-2 global pandemic. Participants The design and validation team consisted of intensive care physicians, bioengineers, computer programmers, and representatives from the medtech sector. Methods Using standard clinical components, a system of shared ventilation consisting of two ventilatory limbs was assembled and connected to a single ventilator. Individual monitors for each circuit were developed using widely available equipment and open source software. System performance was determined under 2 sets of conditions. First, the effect of altering ventilator settings (Inspiratory Pressure, Respiratory rate, I:E ratio) on the tidal volumes delivered to each lung circuit was determined. Second, the impact of altering the compliance and resistance in one simulated lung circuit on the tidal volumes delivered to that lung and the second lung circuit was determined. All measurements at each setting were repeated three times to determine the variability in the system. Results The system permitted accurate and reproducible titration of tidal volumes to each ‘lung circuit’ over a wide range of ventilator settings and simulated lung conditions. Alteration of ventilator inspiratory pressures stepwise from 4-20cm H 2 O, of respiratory rates from 6-20 breaths/minute and I:E ratio from 1:1 to 1:4 resulted in near identical tidal volumes delivered under each set of conditions to each simulated ‘lung’. Stepwise alteration of compliance and resistance in one ‘test’ lung circuit resulted in reproducible alterations in tidal volume to the ‘test’ lung, with little change to tidal volumes in the ‘control’ lung (a change of only 6% is noted). All tidal volumes delivered were highly reproducible upon repetition. Conclusions We demonstrate the reliability of a simple shared ventilation system assembled using commonly available clinical components that allows individual titration of tidal volumes. This system may be useful as a temporary strategy of last resort where the numbers of patients requiring invasive mechanical ventilation exceeds supply of ventilators. Article Summary Strengths and limitations of this study This solution provides the ability to safely and robustly ventilate two patients simultaneously while allowing differing tidal volumes in each limb. The designed solution uses equipment readily available in most hospitals. Accurate and reproducible titration of tidal volumes to each ‘lung’ was possible over a wide range of ventilator settings. Alteration of one simulated ‘lung’ conditions had minimal impact on the tidal volumes delivered to the unaffected lung The system relies on patients being sedated and paralysed. We have not yet tested this solution in vivo , on COVID-19 patients.

An Appraisal of Respiratory System Compliance In Mechanically Ventilated Covid-19 Patients (preprint)

Background Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level.Methods We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe the impact of CRS on the ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.Results We enrolled 318 COVID-19 patients enrolled into the study from January 14th through September 31th, 2020 in 19 countries and stratified into two CRS groups. CRS was calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)] and available within 48 h from commencement of MV in 318 patients. Patients were mean ± SD of 58.0 ± 12.2, predominantly from Europe (54%) and males (68%). Median CRS (IQR) was 34.1 mL/cmH2O (26.5–45.5) and PaO2/FiO2 was 119 mmHg (87.1–164) and was not correlated with CRS. Female sex presented lower CRS than in males (95% CI: -13.8 to -8.5 P < 0.001) and higher body mass index (34.7 ± 10.9 vs 29.1 ± 6.0, p < 0.001). Median (IQR) PEEP was 12 cmH2O (10–15), throughout the range of CRS, while median (IQR) driving pressure was 12.3 (10–15) cmH2O and significantly decreased as CRS improved (p < 0.001). No differences were found in comorbidities and clinical management between CRS strata. In addition, 28-day ICU mortality and hospital mortality did not differ between CRS groups.Conclusions This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV – predominantly males or overweight females, in their late 50 s – admitted to ICU during the first international outbreaks. Phenotypes associated with different CRS upon commencement of MV could not be identified. Trial documentation: Available at https://www.covid-critical.com/study.Trial registration ACTRN12620000421932.

INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP): Protocol for an investigator-initiated international meta-trial of randomised studies (preprint)

Introduction: Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential for COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus’ entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anti-coagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. Methods and intervention This meta-trial is a prospective collaborative individual patient data meta-analysis of randomised controlled trials and early phase studies. Individual studies are conducted in multiple countries. Adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, are randomised to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome is intubation (or death, for patients who died before intubation) at day 28, assessed in a time-to-event analysis. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have specific outcome measures in addition to the core set. Ethics and dissemination: The meta-trial is registered at ClinicalTrials.gov, ID NCT04635241. Results of this study will be shared with the WHO, published in scientific journals and presented at scientific meetings.

Sentiment Analysis of User Feedback on the HSE Contact Tracing App (preprint)

Digital Contact Tracing (DCT) is seen as a key tool in reducing the propagation of viruses such as Covid-19, but it requires uptake and participation in the technology across a large proportion of the population to be effective. While we observe the pervasive uptake of mobile device usage across our society, the installation and usage of contact tracing apps developed by governments and health services globally have faced difficulties. These difficulties range across the user-populations’ issues with the installation of the apps, us-ability and comprehension challenges, trust in the efficacy of the technology, performance issues such as the effect on battery life, and concerns about data protection and privacy.  In this work, we present our findings from a comprehensive review of the online user feedback relating to the initial release of the HSE Contact Tracker app, in an effort to inform later iterations and thus help sustain and potentially increase usage of the technology. While this might seem quite tightly scoped to the Irish context only, this app provides the basis for apps in many jurisdictions in the United States and Europe.  Our findings suggest a largely positive sentiment towards the app, and that users thought it handled data protection and transparency aspects well. But feedback also suggested that users would appreciate more targeted feedback,more proactive engagement and also suggested that both the ‘android-battery’ issue and the backward-compatibility issue with iPhones seriously impacted retention/uptake of the app respectively.

In-silico modeling of COVID-19 ARDS: pathophysiological insights and potential management implications (preprint)

Objectives: Patients with COVID-19 Acute Respiratory Distress Syndrome (CARDS) appear to present with at least two distinct phenotypes: severe hypoxemia with relatively well-preserved lung compliance and lung gas volumes (Type 1) and a more conventional ARDS phenotype displaying the typical characteristics of the baby lung (Type 2). We aimed to test plausible hypotheses regarding the pathophysiological mechanisms underlying CARDS, and to evaluate the resulting implications for ventilatory management. Design: We adapted a high-fidelity computational simulator, previously validated in several studies of ARDS, to (a) develop quantitative insights into the key pathophysiologic differences between CARDS and conventional ARDS, and (b) assess the impact of different PEEP, FiO2 and tidal volume settings. Setting: Interdisciplinary Collaboration in Systems Medicine Research Network. Subjects: The simulator was calibrated to represent CARDS patients with both normal and elevated body mass indices undergoing invasive mechanical ventilation. Measurements and Main Results: An ARDS model implementing disruption of hypoxic pulmonary vasoconstriction and vasodilation leading to hyperperfusion of collapsed lung regions failed to replicate clinical data on Type 1 CARDS patients. Adding mechanisms to reflect disruption of alveolar gas-exchange due to the effects of pneumonitis, and heightened vascular resistance due to the emergence of microthrombi, produced levels of V/Q mismatch and hypoxemia consistent with data from Type 1 CARDS patients, while preserving close to normal lung compliance and gas volumes. Atypical responses to PEEP increments between 5 and 15 cmH2O were observed for this Type 1 CARDS model across a range of measures: increasing PEEP resulted in reduced lung compliance and no improvement in oxygenation, while Mechanical Power, Driving Pressure and Plateau Pressure all increased. FiO2 settings based on ARDSnet protocols at different PEEP levels were insufficient to achieve adequate oxygenation. Incrementing tidal volumes from 5 to 10 ml/kg produced similar increases in multiple indicators of ventilator induced lung injury in the Type 1 CARDS model to those seen in a conventional ARDS model. Conclusions: Our model suggests that use of standard PEEP/ FiO2 tables, higher PEEP strategies, and higher tidal volumes, may all be potentially deleterious in Type 1 CARDS patients, and that a highly personalized approach to treatment is advisable.

A National Survey of attitudes to COVID-19 Digital Contact Tracing in the Republic of Ireland (preprint)

Background: Contact tracing remains a critical part of controlling the spread of COVID-19. Many countries have developed novel software applications (Apps) in an effort to augment traditional contact tracing methods. Aim: To conduct a national survey of the Irish population to examine barriers and levers to the use of a contact tracing App.Methods: Adult participants were invited to respond via an online survey weblink sent via email and messaging Apps and posted on our university website and on popular social media platforms. Results: A total of 8,088 responses were received, with all 26 counties of the Republic of Ireland represented. 54% of respondents said they would definitely download a contact tracing App, while 30% said they would probably download a contact tracing App. 95% of respondents identified at least one reason for them to download the App, with the most common reasons being the potential for the App to help family members and friends and a sense of responsibility to the wider community. 59% identified at least one reason not to download the App, with the most common reasons being fear that technology companies or the government might use the App technology for greater surveillance after the pandemic.Conclusion: Irish citizens surveyed express high levels of willingness to download a public health-backed App to augment contact tracing. Concerns raised regarding privacy and data security will be critical if the App is to achieve the large-scale adoption and ongoing use required for its effective operation.

Can Nebulised Heparin Reduce Time to Extubation in SARS CoV 2 The CHARTER Study Protocol (preprint)

Introduction: COVID 19 is associated with the development of ARDS displaying the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. The anticoagulant actions of nebulised heparin limit fibrin deposition and progression of lung injury. Serendipitously, unfractionated heparin also inactivates the SARS CoV 2 virus and prevents its entry into mammalian cells. Nebulisation of heparin may therefore limit both fibrin mediated lung injury and inhibit pulmonary infection by SARS CoV 2. For these reasons we have initiated a multicentre international trial of nebulised heparin in patients with COVID 19. Methods and intervention: Mechanically ventilated patients with confirmed or strongly suspected SARS CoV 2 infection, hypoxaemia and an acute pulmonary opacity in at least one lung quadrant on chest Xray, will be randomised to nebulised heparin 25,000 Units every 6 hours or standard care for up to 10 days while mechanically ventilated. The primary outcome is the time to separation from invasive ventilation to day 28, where non survivors to day 28 are treated as though not separated from invasive ventilation. Ethics and dissemination: The study protocol has been submitted to the human research and ethics committee of St Vincents Hospital, Melbourne, Australia. Submission is pending in other jurisdictions. Results of this study will be published in scientific journals and presented at scientific meetings.