Feasibility and Safety of Peripheral Intravenous Administration of Vasopressor Agents in Resource-limited Settings

Vasopressors are conventionally administered through a central venous catheter (CVC) and not through a peripheral venous catheter (PVC) since the latter is believed to be associated with increased risk of extravasation. Placement of a CVC requires suitably trained personnel to be on hand, and in resource-limited settings, this requirement may delay placement. Because of this and in cases where suitably trained personnel are not immediately available, some clinicians may be prompted to utilise a PVC for infusing vasopressors. The objective of this study is to assess the feasibility and safety of vasopressors administered through a PVC

Intelligent Sensors for Integrated Health Management Systems

This paper describes work being conducted on the development of intelligent sensors with learning capabilities as part of an integrated systems approach. The integrated systems approach treats the sensor as a complete system with its own sensing hardware (the traditional sensor), A/D converter, processing and storage capabilities, software drivers, self-assessment algorithms, communication protocols and evolutionary methodologies that allow the system to learn its own behavior. The immediate application is the monitoring of rocket test stands, but the technology should be generally applicable to the Integrated Systems Health Monitoring (ISHM) vision. This paper outlines progress made in the development of intelligent sensors by describing the work done till date on Physical Intelligent Sensors (PIS) and Virtual Intelligent Sensors (VIS). The PIS as discussed here consists of a thermocouple used to read temperature in an analog form which is then converted into digital values. A microprocessor collects the sensor readings and runs numerous embedded event detection routines on the digital data. If any event, i.e. spike, drift, noise, is detected, it is reported, stored and sent to a remote system through an Ethernet connection. Hence the output of the PIS is data coupled with a confidence factor in the reliability of the data. The VIS discussed here is a virtual implantation of the PIS in the G2 software environment. The VIS is designed to mirror the operations of the PIS; however, the VIS works on a computer at which digital data is provided as the input. This work lays the foundation for the next generation of smart devices that have embedded intelligence for distributed decision making capabilities

Physical and Virtual Intelligent Sensors for Integrated Health Management Systems

This paper describes the development of intelligent sensors as part of an integrated systems approach. The integrated systems approach treats the sensor as a complete system with its own sensing hardware (the traditional sensor), A/D converter, processing and storage capabilities, software drivers, self-assessment algorithms and communication protocols. The immediate application is the monitoring of rocket test stands, but the technology should be generally applicable to the Integrated Systems Health Monitoring (ISHM) vision. This paper outlines progress made in the development of intelligent sensors by describing the work done to date on Physical Intelligent Sensors (PIS) and Virtual Intelligent Sensors (VIS). The PIS as discussed here consists of a thermocouple used to read temperature in an analog form which is then converted into digital values. A microprocessor collects the sensor readings and runs numerous embedded event detection routines on the digital data. If any event, i.e. spike, drift, noise, is detected, it is reported, stored and sent to a remote system through an Ethernet connection. Hence the output of the PIS is data coupled with a confidence factor in the reliability of the data. The VIS discussed here is a virtual implantation of the PIS in C++. The VIS is designed to mirror the operations of the PIS; however, the VIS works on a computer at which digital data is provided as the input and is thus portable to any sensor system. This work lays the foundation for the next generation of smart devices that have embedded intelligence for distributed decision making capabilities

Higher vs. Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: protocol and statistical analysis plan.

BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society

Higher vs lower doses of dexamethasone in patients with COVID‐19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan

BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial.

PURPOSE We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. METHODS We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. RESULTS The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. CONCLUSION We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25

Long-term outcomes of dexamethasone 12 mg versus 6 mg in patients with COVID-19 and severe hypoxaemia.

PURPOSE We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. RESULTS We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). CONCLUSION Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose