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.

     

Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants

Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half-lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post-transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r = 0.93 and r = 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half-life and a remarkably improved bioavailability. Received: 29 November 1996 Received after revision: 10 April 1997 Accepted: 15 May 1997     

Blood pressure and excretion of sodium, potassium, calcium and magnesium in 8- and 9-year old boys from 19 European centres

We have measured systolic and diastolic blood pressure and excretions of sodium, potassium, calcium and magnesium in groups of about 50 8- and 9-year-old boys from 19 European centres using standardized methods for the measurement of blood pressure and collection of urine, and by carrying out all analyses in one laboratory. Weight, height, pulse rate and environmental temperature were also studied. Mean systolic blood pressure ranged from 91 to 105 mm Hg and diastolic blood pressure from 51 to 66 mm Hg. Mean 24-h excretion of sodium was between 91 and 146 mmol/d, that of potassium between 29 and 60 mmol/d, that of calcium between 1.5 and 2.6 mmol/d and that of magnesium between 2.7 and 4.2 mmol/d. Mean sodium excretion tended to be lower and potassium excretion tended to be higher in the boys from the north-western parts of Europe. Relations between either systolic or diastolic blood pressure and electrolyte excretions were generally weak or absent. Most remarkable is that only the association between mean diastolic blood pressure and 24-h magnesium excretion (partial regression coefficient (b +/- s.e., -5.04 +/- 2.08 mm Hg/mmol/d) was statistically significant after adjusting for differences in creatinine excretion and environmental temperature. Mean systolic blood pressure was not significantly related with any of the variables measured. The partial regression coefficient (b +/- s.e.) for diastolic blood pressure on weight was 0.186 +/- 0.062 mm Hg/kg, on height 0.165 +/- 0.056 mm Hg/cm, on pulse rate 0.364 +/- 0.100 mm Hg/beats per min and on outside temperature -0.25 +/- 0.07 mm Hg/degrees C.     

Season of birth and risk of atopic disease among children and adolescents.

BACKGROUND: Season of birth (SOB) has been regarded as a risk factor for atopy. The aim of this study was to explore the relationship between season of birth (SOB) and later development of atopic disease in children and adolescents. METHODS: A total of 1,007 randomly selected subjects, 7 to 17 years of age, who were living in urban Copenhagen, Denmark were studied. All participants were interviewed about respiratory symptoms and possible risk factors for atopic disease. Skin test reactivity, serum total immunoglobulin E (IgE), and airway responsiveness were measured using standard techniques. RESULTS: The overall risk of atopy, as judged by skin test reactivity and serum total IgE, was the same regardless of SOB. On the contrary, asthma was more common in subjects born in the autumn compared with subjects born during the remaining part of the year (12.4% vs. 5.6%), OR = 2.40, 95% CI (1.56-3.94), p < 0.001. This was observed both for atopic asthma OR = 2.41, 95% CI (1.25-4.64), p = 0.007, non-atopic asthma, OR = 2.35, 95% CI (1.14-4.83), p = 0.02, and house dust mite (HDM) sensitive airway hyperresponsiveness, OR = 3.00, 95% CI (1.44-6.24), p = 0.002. Rhinitis and pollen allergy were not significantly related to SOB. CONCLUSIONS: Atopy itself is independent of season of birth, whereas asthma is more prevalent among subjects born during the autumn. Regarding asthma, these results suggest that the first months of life enclose a period of particular vulnerability towards environmental risk factors, especially exposure to aeroallergens like HDM.     

Antioxidant defence during cardiopulmonary bypass surgery.

OBJECTIVE: Cardiac surgery may lead to severe oxidative stress due to formation of oxidation products generated during ischemia and reperfusion. We investigated to which extent oxidative stress influences a number of endogenous antioxidants and markers of cellular activation. METHODS: At six time points blood was withdrawn from patients undergoing coronary artery bypass grafting, using the on-pump procedure. RESULTS: Both glutathione peroxidase and superoxide dismutase show a gradual and strong increase in activity during surgery (40 and 30%, respectively), returning to baseline values 24 h after surgery. The total antioxidant capacity has a maximum increase of 60%. Markers of cellular activation, such as eosinophil cationic protein and tryptase also increase during the procedure. CONCLUSION: Cardiac surgery results in systemic inflammation accompanied or caused by severe oxidative stress. The human body has a strong innate oxidative defence screen, which is probably not sufficient to fully compensate for the total amount of oxidative damage.     

Ascending Aortic Extension for Right Pulmonary Artery Stenosis Associated With Ventricular-to-Pulmonary Artery Conduit Replacement

A bstract Background : Ventricular-to-pulmonary artery conduits in growing patients with congenital heart disease will require replacement from time to time due to somatic growth, neointimal hyperplasia, and pulmonary artery stenosis. The purpose of this article is to review our experience with ascending aortic extension for significant long-segment pulmonary artery stenosis in patients undergoing reoperation for right ventricular-to-pulmonary artery conduit replacement. Methods : From 1989 to 1997, 8 patients had aortic transection, right pulmonary artery augmentation arterioplasty, and aortic interposition graft (Hemashield in 7 and Gore-tex in 1) in association with right ventricular-to-pulmonary artery conduit replacement in 7 patients and completion Fontan operation in 1 patient. Aortic cross-clamp time was 90 ± 34 minutes, and the cardiopulmonary bypass time was 205 ± 37 minutes. Results : All patients survived. In those 7 patients who had conduit replacement, the RV/LV ratio declined from 0.78 ± 0.15 to 0.45 ±; 0.05 postoperatively (P < 0.05). Average length of stay was 8.9 ± 7.2 days. Follow-up range is 18 months to 8 years (mean 4 years). Two complications included cardiac transplantation for pre-existing poor left ventricular function and accelerated conduit stenosis leading to conduit re-replacement. Conclusion : Ascending aortic extension facilitates long-segment pulmonary artery augmentation arterioplasty and enlarges the retroaortic space, preventing future compression restenosis.     

Very old people’s use of the pedestrian environment: functional limitations, frequency of activity and environmental demands

Due to decreased functional capacity as well as high environmental demands there is a risk of diminishing activity outside home in very old age (age 80+). In order to explore differences according to functional limitations (FL) among very old people with respect to frequency of activity, perceived health, overall perception of neighbourhood environment, and perceived problems in the pedestrian environment, data derived from a postal questionnaire survey to very old people living in an urban area in Sweden were used. This explorative study is based on the sub-sample of people aged 80+ who reported outdoor activities (n = 97). Four groups of respondents with different types of FL were identified: with no FL (n = 23), with only movement-related FL (n = 26), with only perception/cognition-related FL (n = 16), and with both movement- and perception/ cognition-related FL (n = 32). The majority of the respondents reported rather high frequency of activity outside home. When examining differences between the four groups, the analysis indicated how the complexity of FL and perceived problems in the pedestrian environment impacted on their activity performance. Persons with both movement- and perception/cognition-related FL were less satisfied with their frequency of activity, experienced their health more negatively and experienced more problems in the pedestrian environment than in the other groups. The findings from this study indicate the importance of considering combinations of FL in creating supportive environments for activity and health.     

Development of Lung Function in Relation to Increased Degree of Bronchial Responsiveness

To study the relationship between development of lung function and bronchial responsiveness, we examined 106 subjects recruited from a random sample of 527 subjects, aged 8-18 years, from Copenhagen. Lung function and bronchial responsiveness to inhaled histamine were measured at two occasions, in 1986 and 1988. The participating subjects (n = 106) were divided into three groups: (a) 20 asthmatics with bronchial hyperresponsiveness (BHR), (b) 42 nonasthmatic subjects with BHR in 1986, and (c) 44 controls without BHR. In 1986, FEV₁ expressed as percentage of predicted value, was found to be similar in the three groups (91%, 94%, and 99%, respectively). The increase in height during the observation period was found to be 5, 6, and 6 cm, respectively, in the three groups. However, at the second examination, in 1988, FEV₁ was found to be significantly reduced in both asthmatics (87%) and nonasthmatic subjects (85%) compared with the controls (103%). In 1988, 16 asthmatics (80%) and 24 (57%) nonasthmatic subjects were found to have BHR, whereas none of the controls were found to have BHR. A multiple regression analysis was used to determine the correlation between change in FEV₁ and potential factors of importance. The change in FEV₁ was highly correlated with the presence of BHR in 1986, however, no correlation was found between change in FEV₁ and change in bronchial responsiveness. In conclusion, nonasthmatic subjects with former BHR showed signs of airflow obstruction and less increase in lung function during growth irrespective of the change in level of bronchial responsiveness, which may suggest a risk for subsequent development of obstructive lung disease.