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.

     

Long-term course of epilepsy in a large cohort of intellectually disabled patients.

This study was designed to describe the course of epilepsy (in terms of seizure frequency) and to assess the variables (antiepileptic therapy regimens and others) correlated to improvement. Seizure frequency (categories: seizure free, more than one seizure/year, monthly seizures, weekly seizures and daily seizures) and antiepileptic medication were retrospectively compared between 1992 and 2002 in a large cohort of 550 inpatients with chronic epilepsy and different degrees of intellectual disability or multiple handicaps. RESULTS: Seizure frequency decreased significantly (p<0.001). 218 of the 394 patients (55.3%) not seizure free in 1992 improved (changed into a better frequency category). The improvement rate was marginally higher in patients who had undergone a medication change (p=0.08). A high seizure frequency in 1992 (p=0.016) and older age (p=0.006), but not epilepsy syndrome or degree of intellectual disability, were predictors for improvement (stepwise logistic regression analysis). 56.4% of the improved patients were on combinations of two AEDs (17.4%, monotherapy; 20.2%, triple therapy). The most frequent therapy regimens in the improved patients were lamotrigine/valproate (48 patients), carbamazepine/phenobarbital (21) and carbamazepine only (19). Lamotrigine/valproate was effective in all kinds of epileptic syndromes. Most patients on lamotrigine had serum concentrations above 10microg/ml, approximately one half had dosages above 200mg/day. The rate of seizure freedom increased from 28.4 to 37.6%. The 84% of the patients seizure free in 1992 remained seizure free. Predictors for seizure freedom in 2002 were higher age (stepwise logistic regression, p<0.0005) and seizure freedom in 1992 (p<0.0005). CONCLUSIONS: Substantial improvement can be achieved even in intellectually disabled patients with chronic epilepsy. Although the rate of seizure freedom is reduced in comparison with a non-ID population, once seizure freedom has been achieved it is most likely to continue. For a majority of this patient population, monotherapy may not be sufficient. Lamotrigine/valproate appears to be a major therapeutic innovation.     

Situation analysis of quality of abortion care in the main maternity hospital in Hai Phòng, Viet Nam

Six months after a Comprehensive Abortion Care project was implemented in Phu-San Hospital, the main maternity hospital in Hai Phòng, northern Viet Nam, a study of quality of abortion services was carried out. The study explored the interaction between providers and women seeking abortion and how cultural values influenced quality of care. A quantitative and qualitative approach was employed: a three-part structured survey with 748 women before and after they had an abortion, 20 in-depth interviews with women just after abortion, seven informal interviews with health care staff and 100 participant observations. Both the women and the staff equated quality of care mainly with improved technical performance of abortion. Insufficient knowledge and skills had a negative impact on provision of information and good quality counselling in relation to understanding and uptake of contraception, treating reproductive tract infection and preventing post-abortion infection. To further improve abortion care in hospitals such as Phu-San, training programmes are needed that integrate counselling and clinical skills and address the cultural factors that hinder health staff and women from interacting in an equitable manner. A supportive supervisory system that holds health staff accountable for conducting high quality information and counselling sessions should also be established.     

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.     

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.     

Severe Neurological Complications after Central Neuraxial Blockades in Sweden 1990-1999

Background: Central neuraxial blockades find widespread applications. Severe complications are believed to be extremely rare, but the incidence is probably underestimated.

Methods: A retrospective study of severe neurologic complications after central neuraxial blockades in Sweden 1990-1999 was performed. Information was obtained from a postal survey and administrative files in the health care system. During the study period approximately 1,260,000 spinal blockades and 450,000 epidural blockades were administered, including 200,000 epidural blockades for pain relief in labor.

Results: The 127 complications found included spinal hematoma (33), cauda equina syndrome (32), meningitis (29), epidural abscess (13), and miscellaneous (20). Permanent neurologic damage was observed in 85 patients. Incidence of complications after spinal blockade was within 1:20-30,000 in all patient groups. Incidence after obstetric epidural blockade was 1:25,000; in the remaining patients it was 1:3600 (P < 0.0001). Spinal hematoma after obstetric epidural blockade carried the incidence 1:200,000, significantly lower than the incidence 1:3,600 females subject to knee arthroplasty (P < 0.0001).     

Does the nature of the solvent affect the anti-inflammatory capacity of triclosan? An experimental study

Abstract The anti-inflammatory properties of triclosan have been revealed in several recent studies, including an effect on histamine-induced inflammation. In other studies, the nature of the solvent has been shown to be of importance for the plaque inhibiting as well as the antibacterial potential of triclosan. This study was aimed at examining whether the nature of the solvent also may influence the anti-inflammatory capacity of triclosan and further to study a possible dose/response relationship. The study was performed as 3 separate, double-blind experiments, comprising 10, 11 and 12 healthy females. In all 3 experiments, 5 sites on the lower part of the back of the volunteers were intradermally exposed to one drop of 1% histamine dihydrochloride for 15 min. The size of the resulting wheals was recorded before and after 40 min of triclosan treatment. In experiment I. 4 different concentrations of triclosan in 2-fold dilutions in absolute alcohol (0.125%-1%) were applied on the histamine-induced wheals. In experiments 2 and 3, 4 different solutions containing 0.5% triclosan and a saline solution as negative control were used. The solvents in experiment 2 were as follows: (1) absolute alcohol (positive control). (2) propylene glycol (PG), (3) polyethylene glycol (PEG). (4) olive oil, and in experiment 3: (1) absolute alcohol (positive control). (2) Tween 80. (3) sodium carbonate, (4) soy oil. The results showed a dose/ response effect of triclosan and further that the solvent may be of importance for its anti-inflammatory potential.