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.

Plasma follistatin is elevated in patients with type 2 diabetes: relationship to hyperglycemia, hyperinsulinemia, and systemic low-grade inflammation.

BACKGROUND: Plasma follistatin is elevated in patients with low-grade inflammation and insulin resistance as observed with polycystic ovary syndrome. In the present study, we evaluated plasma follistatin in patients with type 2 diabetes characterised by low-grade inflammation and assessed the acute effects of hyperglycemia, hyperinsulinemia and LPS on plasma follistatin. METHODS: Baseline plasma follistatin and inflammatory biomarkers were measured in a cross-sectional study that involved 95 patients with type 2 diabetes and 103 matched controls. To determine the acute effect of hyperglycemia and hyperinsulinemia on follistatin, hyperglycemic and hyperinsulinemic-euglycemic clamps were performed in five healthy males. Furthermore, 15 patients with type 2 diabetes and 22 healthy controls were challenged with low-dose LPS to determine the effect on follistatin. RESULTS: Patients with type 2 diabetes have higher HOMA2-IR values mean [95% CI] 1.64 [1.40-1.93] versus mean 0.86 [0.75-0.99], p < 0.001 and inflammatory markers compared with controls. Baseline plasma follistatin is elevated in patients with type 2 diabetes compared with controls mean 1564 [1456-1680] versus mean 1328 [1225-1440] ng/L, p = 0.003 and correlates with fasting glucose levels (r = 0.44, p < 0.0001), 2 h glucose (r = 0.48, p < 0.0001), HbA1c (r = 0.41, p < 0.0001), triacylglycerol (r = 0.28, p = 0.008) and total cholesterol (r = 0.33, p = 0.004) in patients but not in controls. No correlation exists between plasma follistatin and inflammatory biomarkers in either of the groups. Neither hyperglycemia, hyperinsulinemia nor LPS increase plasma follistatin. CONCLUSIONS: Plasma follistatin is moderately elevated in patients with type 2 diabetes. Our findings suggest that this is not likely caused by hyperglycemia, hyperinsulinemia or systemic low-grade inflammation.

Human endotoxemia as a model of systemic inflammation.

Systemic inflammation is a pathogenetic component in a vast number of acute and chronic diseases such as sepsis, trauma, type 2 diabetes, atherosclerosis, and Alzheimer's disease, all of which are associated with a substantial morbidity and mortality. However, the molecular mechanisms and physiological significance of the systemic inflammatory response are still not fully understood. The human endotoxin model, an in vivo model of systemic inflammation in which lipopolysaccharide is injected or infused intravenously in healthy volunteers, may be helpful in unravelling these issues. The present review addresses the basic changes that occur in this model. The activation of inflammatory cascades as well as organ-specific haemodynamic and functional changes after lipopolysaccharide are described, and the limitations of human-experimental models for the study of clinical disease are discussed. Finally, we outline the ethical considerations that apply to the use of human endotoxin model.

Autologous transfusion of shed mediastinal blood after coronary artery bypass grafting and bacterial contamination.

BACKGROUND: Autologous transfusion of shed mediastinal blood is often used after coronary artery bypass grafting (CABG). Shed blood has in a few studies been cultured during the first postoperative hours. However, autologous transfusion might in some cases be continued for several hours and no study has yet examined the bacterial contamination of shed blood later than 6 hours postoperatively. METHODS: Seventy-five patients undergoing electively performed CABG were included. Cultures of shed blood were taken at initiation of the autologous transfusion and the following morning. Infection variables were measured preoperatively and postoperatively. Infectious complications during the first postoperative week were registered. RESULTS: The frequency of patients with bacterial growth in the first culture was 0.22 (95% confidence interval: 0.12 to 0.31) compared with 0.04 (95% confidence interval: -0.044 to 0.087) in the second culture (p < 0.002). We found no significant difference in infection variables between patients with or without bacterial growth in the cultures. No patients suffered from early postoperative infectious complications. CONCLUSIONS: There is no further contamination of the shed blood during the period between initiating the autologous transfusion and the following morning.