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.

     

Pain and quality of life for patients with venous leg ulcers: proof of concept of the efficacy of Biatain®-Ibu, a new pain reducing wound dressing

Wound pain is a serious problem for elderly patients suffering from chronic leg ulcers, and it may lead to reduced wound healing rates and reduced quality of life. Biatain-Ibu Non-adhesive (Coloplast A/S), a new pain-reducing moist wound healing dressing containing ibuprofen was tested for pain reduction, safety, and efficacy on 10+2 patients in a single-blinded crossover study against Biatain Non-adhesive (Coloplast A/S). Pain was measured with a Numeric Box Scale before, during, and after dressing change. Quality of life was measured using the World Health Organization-5 Well-Being Index. Dressing moist wound healing properties such as absorption capacity and leakage were tested together with assessment of wound exudate and blood plasma content of ibuprofen. Use of the Biatain-Ibu foam dressing correlated with a decrease in pain intensity scores from 7 in the run-in period to approximately 2.5 in the Biatain-Ibu treatment phase. Quality of life measures were improved which together with the reduced pain could contribute to faster wound healing. The moist wound healing properties of Biatain-Ibu were similar to that of the Biatain Non-adhesive and ulcer size was reduced by 24% during the treatment period. Neither side effects nor systemic plasma concentrations of ibuprofen were observed. These data indicate that Biatain-Ibu could reduce persistent and temporary wound pain, increase Quality of life, was found safe to use, and had excellent moist wound healing properties.     

Health-related quality of life assessed before and during chemotherapy predicts for survival in multiple myeloma

Measurement of health-related quality of life was integrated into a randomized trial (NMSG 4/90) comparing melphalan/prednisone to melphalan/prednisone + interferon α-2b in newly diagnosed multiple myeloma. One of the aims of the study was to assess the prognostic significance of quality-of-life scores, using the EORTC QLQ-C30 questionnaire. Univariate analysis showed a highly significant association with survival from the start of therapy for physical functioning as well as role and cognitive functioning, global quality of life, fatigue and pain. In multivariate analysis, physical functioning and W.H.O. performance status were independent prognostic factors ( P values=0.001 for both) when analysed in a Cox regression model with the somatic variables β-2 microglobulin, skeletal disease and age. The best prediction for survival from the start of therapy was obtained by combining the β-2 microglobulin and physical functioning scores in a variable consisting of three risk factor levels with an estimated median survival of 17, 29 and 49 months, respectively. At a 12 months landmark analysis, the relative risk for patients with physical functioning score 0–20 v 80–100 was 5.63 (99% CI 2.76–11.49), whereas the relative risk for patients without an objective response to chemotherapy compared to those with at least a minor response was 2.32 (99% CI 1.44–3.74). Quality-of-life assessment may be an independent and valuable addition to the known prognostic factors in multiple myeloma.     

Eating one's words: Part III. Mentalisation‐based psychotherapy for anorexia nervosa—an outline for a treatment and training manual

This paper presents a new outline for psychotherapy with personsn with anorexia nervosa. ‘Model on mentalisation’ is the intellectual and empirical framework for this contribution. Mentalisation is defined as the ability to understand feelings, cognitions, intentions and meaning in oneself and in others. The capacity to understand oneself and others is a key determinant of self‐organisation and affect regulation, and is acquired in early attachment relationships. Impaired mentalisation is documented and described as a central psychopathological feature in anorexia nervosa. Psychotherapeutic enterprise with individuals with compromised mentalising capacity should be an activity that is specifically focused on the rehabilitation of this function, with special emphasis on how the body is representing mental states. The paper describes psychotherapeutic goals, stances and techniques. It is intended that this outline will be further developed into manuals as a basis for therapy, training and research. Copyright © 2007 John Wiley & Sons, Ltd and Eating Disorders Association.     

Effect of respiratory training with a mouth-nose-mask in tetraplegics

Ten tetraplegics, 8 males and 2 females, with a median age of 32 years participated in a scheduled 6 weeks training programme with a respiratory muscle training mouth-nose-mask (RMT-mask) with a fixed expiratory and an increasing inspiratory resistance set by the tetraplegic in accordance to his/her increasing ability during the training period. During the 6 weeks the tetraplegics required to use the RMT-mask for 15 minutes three times a day. Before and after each training session they measured peak flow (PEF). Lung volumes, ventilatory and diffusion capacity were measured before and after the 6 weeks training period. The training resulted only in a significant change in the PEF, which increased with 11% from 371 l/min before to 412 l/min in average after the 6 weeks of training (p less than 0.025). This statistically significant increase was confirmed by the measurements of PEF performed by the tetraplegics themselves during the training period. In addition there was an increase in PEF from before to immediately after each 15 minutes training session, this trend reached statistically significance (p less than 0.025) in the third '2 weeks period'. These results might indicate a possibility of improving the tetraplegics ability to cough by use of a simple RMT-mask, which in turn might prevent certain lung complications including pneumonia, and atelectasia.     

Exercise rapidly increases eukaryotic elongation factor 2 phosphorylation in skeletal muscle of men

Protein synthesis in skeletal muscle is known to decrease during contractions but the underlying regulatory mechanisms are unknown. Here, the effect of exercise on skeletal muscle eukaryotic elongation factor 2 (eEF2) phosphorylation, a key component in protein translation machinery, was examined. Eight healthy men exercised on a cycle ergometer at a workload eliciting ∼67% peak pulmonary oxygen consumption     with skeletal muscle biopsies taken from the vastus lateralis muscle at rest as well as after 1, 10, 30, 60 and 90 min of exercise. In response to exercise, there was a rapid (i.e. < 1 min) 5- to 7-fold increase in eEF2 phosphorylation at Thr56 that was sustained for 90 min of continuous exercise. The in vitro activity of skeletal muscle eEF2 kinase was not altered by exercise indicating that the increased activity of eEF2 kinase to eEF2 is not mediated by covalent mechanisms. In support of this, the increase in AMPK activity was temporally unrelated to eEF2 phosphorylation. However, skeletal muscle eEF2 kinase was potently activated by Ca²⁺–calmodulin in vitro , suggesting that the higher eEF2 phosphorylation in working skeletal muscle is mediated by allosteric activation of eEF2 kinase by Ca²⁺ signalling via calmodulin. Given that eEF2 phosphorylation inhibits eEF2 activity and mRNA translation, these findings suggest that the inhibition of protein synthesis in contracting skeletal muscle is due to the Ca²⁺-induced stimulation of eEF2 kinase.     

BIOCHEMICAL CORRECTION IN THE SYNDROME OF HYPERTENSION AND HYPERKALAEMIA BY SEVERE DIETARY SALT RESTRICTION SUGGESTS RENIN-ALDOSTERONE SUPPRESSION CRITICAL IN PATHOPHYSIOLOGY

1. Plasma potassium and chloride concentrations were raised and plasma renin activity, aldosterone, bicarbonate and arterial pH were reduced in two brothers with the syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate (Gordon's syndrome), on unrestricted or moderately restricted sodium diets. 2. These abnormalities were corrected in both patients within 10 days of severe sodium restriction. 3. Pressor sensitivity to cold and angiotensin II decreased on low sodium diet, associated with a fall in blood pressure. 4. Increasing distal tubular sodium delivery by infusion of normal saline increased fractional excretion of potassium when aldosterone had been stimulated by severely restricted sodium diet, but not when aldosterone levels were low on unrestricted sodium diet. 5. These findings are consistent with excessive sodium reabsorption as the primary renal lesion in Gordon's syndrome, leading to volume expansion and suppression of renin and aldosterone. Severe dietary sodium restriction leading to volume contraction, by stimulating renin and aldosterone and promoting kaliuresis, corrects the abnormalities.