Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

The effect of activated protein C on plasma cytokine levels in a porcine model of acute endotoxemia

Objective To assess the anti-inflammatory effects of recombinant human activated protein C (rhAPC) in a porcine model of acute endotoxemia. Design and setting Animal randomized controlled study at the Laboratory of Clinical Institute, Aarhus University Hospital. Subjects Eighteen female landrace pigs (30 kg). Interventions By pairwise randomization, pigs were given either LPS or LPS and rhAPC. Both groups received a stepwise increasing LPS infusion for 30 min; whereafter the infusion continued at a lower rate (300 min LPS in both groups). The LPS+rhAPC group received rhAPC (100 μg/kg per hour) 15 min before the LPS infusion began and throughout the trial period. Results While rhAPC showed no modifying effects on peak plasma levels of pro- or anti-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-10), TNF-α and IL-10 peaked significantly later in the rhAPC-treated animals. The profibrinolytic effects of rhAPC were confirmed by decreased plasminogen activator inhibitor 1 levels, while no differences were found in other coagulation markers, hemodynamic, metabolic, or leukocyte data between the two groups. Conclusions We found no significant effect of rhAPC on plasma levels of either pro- or anti-inflammatory cytokines in this porcine model of acute endotoxemia. However, TNF-α and IL-10 peaked significantly later in the rhAPC-treated animals.     

Improved interobserver variation after training of doctors in the Neer system. A randomised trial

We investigated whether training doctors to classify proximal fractures of the humerus according to the Neer system could improve interobserver agreement. Fourteen doctors were randomised to two training sessions, or to no training, and asked to categorise 42 unselected pairs of plain radiographs of fractures of the proximal humerus according to the Neer system. The mean kappa difference between the training and control groups was 0.30 (95% CI 0.10 to 0.50, p = 0.006). In the training group the mean kappa value for interobserver variation improved from 0.27 (95% CI 0.24 to 0.31) to 0.62 (95% CI 0.57 to 0.67). The improvement was particularly notable for specialists in whom kappa increased from 0.30 (95% CI 0.23 to 0.37) to 0.79 (95% CI 0.70 to 0.88). These results suggest that formal training in the Neer system is a prerequisite for its use in clinical practice and research.     

Low agreement among 24 doctors using the Neer-classification; only moderate agreement on displacement,even between specialists

Twenty-four orthopaedic surgeons classified 42 pairs of radiographs according to the Neer system for proximal humeral fractures. Mean kappa value for inter-observer agreement was 0.27 (95% CI 0.26-0.28) with no clinically significant difference between orthopaedic residents ( n=9), fellows ( n=6) and specialists ( n=9). Mean kappa for agreement of displacement versus non-displacement was 0.41 (95% CI 0.39-0.43) overall, and 0.50 (95% CI 0.45-0.56) within the specialist group. The agreement found in our study is unsatisfactory from a clinical perspective.     

A web-based therapeutic workplace for the treatment of drug addiction and chronic unemployment

This article describes a Web-based therapeutic workplace intervention designed to promote heroin and cocaine abstinence and train and employ participants as data entry operators. Patients are paid to participate in training and then to perform data entry jobs in a therapeutic workplace business. Salary is linked to abstinence by requiring patients to provide drug-free urine samples to gain access to the workplace. Prior data show that a prototype of the intervention could promote drug abstinence. Preliminary data on the Web-based intervention suggest that it should be able to teach adults with histories of chronic unemployment and drug addiction to become skilled data entry operators in about 3 to 6 months. Early experience in the business provides preliminary evidence that it might become financially successful. The therapeutic workplace intervention may serve as an effective and practical long-term treatment for chronic unemployment and heroin and cocaine addiction.     

Genotoxicity of acrylic bone cements.

The genotoxicity of conventional polymethylmethacrylate (PMMA) and a new formulation of bone cement: methylmethacrylate/n-decylmethacrylate/isobornylmethacrylate (MMA/DMA/IBMA) were tested by micronucleus test and reverse mutation assays of Salmonella typhimurium (Ames test). In extracts from cement pellets (37 degrees, 72 hr) with water and water/ethanol the concentration of MMA was reduced by 13-19 times with the new formulation and the concentrations of accelerators were reduced by 4-5 times. New chemical constituents (DMA, IBMA, dihydroxy-propyl-p-toluidine) were found in negligible concentrations. In the micronucleus test all three cement brands were found non-mutagenic and in the Ames test scattered increased revertant ratios were found without differences between the three brands. The new formulation does not possess any increased risk of genotoxicity.     

Genotoxicity of Acrylic Bone Cements

Abstract: The genotoxicity of conventional polymethylmethacrylate (PMMA) and a new formulation of bone cement: methylmethacrylate/n-decylmethacrylate/isobornylmethacrylate (MMA/DMA/IBMA) were tested by micronucleus test and reverse mutation assays of Salmonella typhimurium (Ames test). In extracts from cement pellets (37°, 72 hr) with water and water/ethanol the concentration of MMA was reduced by 13–1. times with the new formulation and the concentrations of accelerators were reduced by 4-5 times. New chemical constituents (DMA, IBMA, dihydroxy- propyl-p-toluidine) were found in negligible concentrations. In the micronucleus test all three cement brands were found non-mutagenic and in the Ames test scattered increased revertant ratios were found without differences between the three brands. The new formulation does not possess any increased risk of genotoxicity.     

Similar clinical outcome after unicompartmental knee arthroplasty using a conventional or accelerated care program: A randomized, controlled study of 40 patients

Background and purpose Over the last 5 years, there has been increasing interest in reducing length of hospitalization (LOS) through accelerated programs. We examined the clinical outcome of patients undergoing a unicompartmental knee replacement (UKR) in an accelerated care program (A group) compared to a conventional care program (C group).Methods 40 patients randomized into 2 groups were included (A group: 17 patients; C group: 23 patients). Nausea, micturition problems, lower limb dysfunction, pain (VAS), opiate consumption, Knee Society score (KSS), day of discharge, rehospitalization within 3 months, contact with a general physician or nurse, and level of satisfaction were registered. Patients in the A group attended an information meeting. An intraarticular infiltration with Marcaine and adrenaline was used peroperatively. Patients in the C group had an epidural pump for 2 or 3 days. Patients in the A program were treated with NSAID and paracetamol postoperatively. Opiates were used in both groups in the case of breakthrough pain. The patients were considered ready for discharge when they were able to climb stairs to the second floor within 5 min.Results The median length of stay was 1 (1–3) day in the A group and 6 (4–7) days in the C group. The median pain score (VAS) at day 0 was 1 (0–3) in the A group and 5 (0–8) in the C group (p < 0.001). 11/23 of the patients in the C group had weakness of the lower limbs on day 1 due to the epidural; all patients in the A group were exercising on the day of the operation. Micturition problems necessitating intermediate catherization were more frequent in patients in the C program (19/23) than in patients in the A programme (3/17) (p = 0.001). There were no statistically significant differences between the two groups concerning nausea, average pain on days 1 and 2, use of opioids (during the first week postoperatively), KSS, contact with primary sector, level of satisfaction, or level of confidence.Interpretation We achieved a reduction in LOS of 5 days without affecting the clinical outcome.     

Lauryl ether sulphate dermatitis in Denmark

Lauryl ether sulphate (LES), a synthetic detergent, may sometimes contain an allergenic impurity, which has given rise to several outbreaks of contact dermatitis. Such an outbreak occurred in Denmark in 1971. All cases diagnosed were confined to one household, while other cases may have passed unnoticed.