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.

     

A virtual environment for surgical image guidance in intraoperative MRI.

Intraoperative MRI has recently entered the operating room as a new imaging modality. Customized visualization systems might further facilitate the use of this imaging technology. A visualization system for use in the interventional MRI has been developed, providing a virtual environment for surgical navigation using real-time images and for controlling the scanner. The visualization system has customized features for certain clinical applications. A training and testing facility has also been established. The introduction of the visualization system in the interventional MRI overcame several ambiguities and inconsistencies that were previously present, and resulted in a more transparent man-machine interface approach. A pilot study using the software to place cryoprobes in an animal liver showed promising results. Augmentation of real-time MR images with 3D rendering and customized navigation features opens new possibilities in intraoperative MRI. The described system can also be extended to other intraoperative imaging modalities.     

Short-term patient-reported outcomes after different exercise-based cardiac rehabilitation programmes.

BACKGROUND: An objective of exercise-based cardiac rehabilitation is improvement in patient-reported outcomes such as health-related quality of life as well as anxiety and depressive symptoms. There are no direct comparisons of the effectiveness of inpatient and outpatient exercise-based cardiac rehabilitation programmes on patient-reported outcomes. METHODS: In this non-randomized study we collected patient-reported outcomes data with the MacNew Heart Disease health-related quality of life questionnaire and the Hospital Anxiety and Depression Scale at baseline, 1 month and again 3 months after admission to exercise-based cardiac rehabilitation in a cohort of 216 consecutive patients enrolled either in a 4-week inpatient exercise-based cardiac rehabilitation (n=62) or a 3-month outpatient exercise-based cardiac rehabilitation (n=87) and in a usual care group (n=67) to document the natural course in patient-reported outcome variables without exercise-based cardiac rehabilitation. RESULTS: Although MacNew health-related quality of life scores improved more with inpatient than outpatient exercise-based cardiac rehabilitation by month 1, the improvement was still significant in both groups at month 3 and also in the usual care group when compared to baseline. The health-related quality of life scores in the inpatient group, however, decreased between month 1 and 3 whereas they continued to improve in the outpatient group. The significant reduction in both anxiety and depressive symptoms in both exercise-based cardiac rehabilitation groups by month 1 was maintained at month 3 only with outpatient exercise-based cardiac rehabilitation. No significant changes over the 3 months were observed in the usual care group. CONCLUSION: Significant improvements of 1-month patient-reported outcomes are achieved in patients attending inpatient as well as outpatient exercise-based cardiac rehabilitation when compared with no exercise-based cardiac rehabilitation. In contrast to inpatient exercise-based cardiac rehabilitation, however, outpatient exercise-based cardiac rehabilitation leads to a further improvement of patient-reported outcomes. These results suggest that, if patients have to be admitted for inpatient exercise-based cardiac rehabilitation, this programme should be followed by an outpatient exercise-based cardiac rehabilitation to further improve and stabilize these patient-reported outcome variables.     

Diabetes mellitus, hypertension and medial temporal lobe atrophy: the LADIS study.

HYPOTHESIS: Based on recent findings on the association between vascular risk factors and hippocampal atrophy, we hypothesized that hypertension and diabetes mellitus (DM) are associated with medial temporal lobe atrophy (MTA) in subjects without disability, independent of the severity of white matter hyperintensities. METHODS: In the Leukoaraiosis And DISability in the elderly (LADIS) study, we investigated the relationships between DM, hypertension, blood pressure and MTA in 582 subjects, stratified by white matter hyperintensity severity, using multinomial logistic regression. MTA was visually scored for the left and right medial temporal lobe (score 0-4), and meaned. RESULTS: Mean age was 73.5 years (sd 5.1), 54% was female. Of the subjects, 15% had DM, and 70% had a history of hypertension. The likelihood of having MTA score 3 was significantly higher in subjects with DM (OR 2.9; 95% CI: 1.1-7.8) compared with an MTA score of 0 (no atrophy). The odds ratio for MTA score 2 was not significantly increased (OR 1.8; CI: 0.9-4). Systolic and diastolic blood pressure and a history of hypertension were not associated with MTA. There was no interaction between DM and hypertension. Stratification on white matter hyperintensities (WMH) did not alter the associations. CONCLUSION: Our study strengthens the observation that MTA is associated with DM, independently of the amount of small vessel disease as reflected by WMH.     

Is the political system really related to health?

We analyze whether the political system and its stability are related to cross-country differences in health. We apply factor analysis on various national health indicators for a large sample of countries over the period 2000–2005 and use the outcomes of the factor analysis to construct two new health measures, i.e., the health of individuals and the quality of the health care sector. Using a cross-country structural equation model with various economic and demographic control variables, we examine the relationship between the type of regime and political stability on the one hand and health on the other. The political variables and the control variables are measured as averages over the period 1980–1999. Our results suggest that democracy has a positive relationship with the health of individuals, while regime instability has a negative relationship with the health of individuals. Government instability is negatively related to individual health via its link with the quality of the health care sector, while democracy is positively related with individual health through its link with income. Our main findings are confirmed by the results of a panel model and various sensitivity tests.     

In vivo effects of hypothermia on the microcirculation during extracorporeal circulation.

OBJECTIVE: Induced hypothermia has been shown to be protective during cardiac surgery, but also in traumatic, ischemic, burn, and neurological injury. In previous in vivo animal experiments, we documented increased leukocyte/endothelial (L/E) cell interaction following normothermic extracorporeal blood circulation (ECC). This study was carried out to investigate whether reduced core temperature during ECC affects the damage to the microcirculation as evidenced by leukocyte adherence and edema formation. METHODS: Intravital fluorescence microscopy was used on the dorsal skinfold chamber preparation in Syrian golden hamsters. ECC was introduced via a micro-rollerpump (1 ml/min) and a 60 cm silicon tube (1mm inner diameter) shunted between the carotid artery and the jugular vein after application of 300IE Heparin/kg per body weight. Experiments were performed in chronically instrumented, awake animals (age 10-14 weeks, weight 65-75 g). Animals of the experimental group were cooled to 18 degrees C body temperature while ECC, followed by a rewarming period (n=7), controls experienced ECC under normothermia (37 degrees C, n=7). RESULTS: 30 min ECC at 18 degrees C resulted in a decrease of rolling and adherent leucocytes (stickers) in postcapillary venules after 1, 4 and 8h compared with the control group (119+/-46 vs. 274+/-113 n/mm2, P<0.05, mean+/-SD; n=7 in each group). Functional capillary density was significantly reduced during hypothermia (80+/-16 vs. 148+/-16 cm/cm2, P<0.05), but restored after rewarming. In contrast, edema formation was markedly increased during hypothermia. CONCLUSIONS: Hypothermia during ECC significantly reduced L/E cell interaction in the early post-ECC period. Hypothermia markedly reduced microvascular perfusion, but was completely restored upon rewarming. Despite a reduced number of adherent leukocytes, no protection of endothelial barrier function was seen as a consequence of induced hypothermia.     

Risk stratification with cardiac troponin I in patients undergoing elective coronary artery bypass surgery.

OBJECTIVE: Cardiac troponin I (cTnI) is a highly sensitive and specific marker for postoperative prediction of patients outcome after coronary artery bypass surgery (CABG). Whether preoperatively elevated cTnI levels similarly predict the outcome in patients scheduled for elective CABG is currently unknown. METHODS: Therefore, a possible correlation between preoperative cTnI levels and perioperative major adverse events and in-hospital mortality after CABG was investigated. CTnI was measured within 24h before surgery in 1405 out of 3124 consecutive elective CABG patients. Out of these patients, 1178 had a preoperative cTnI level below 0.1ng/ml (group 1), 163 patients had a cTnI level between 0.11 and 1.5ng/ml (group 2), and 64 patients had a cTnI level above 1.5ng/ml (group 3). CTnI levels, electrocardiograms, clinical data, adverse events and in-hospital mortality were recorded prospectively. Patients with ST-elevation myocardial infarction less than 7 days before surgery were excluded from the study. RESULTS: Perioperative myocardial infarction (PMI) occurred in 69/1178 patients (5.9%) in group 1, 14/163 patients (8.6%; odds ratio (OR) 1.5, 95% confidence interval (CI): 0.8-2.8) in group 2, and 11/64 patients (17.2%; OR 3.3, CI: 1.6-7.0) in group 3 (overall: P<0.001, Cochran-Armitage trend test). Low cardiac output syndrome (LCOS) occurred in 19/1178 patients (1.6%), 9/163 (5.5%; OR 3.6, CI: 1.5-8.5), and 7/64 patients (10.9%; OR 7.5, CI: 2.7-19.8) (overall: P<0.001, group 1 vs. group 2: P<0.002), respectively. In-hospital mortality was 1.7% in group 1 and 3.1% in group 2, but 6.3% (OR 3.9, CI: 1.1-12.5) in group 3 (overall: P<0.01, group 1 vs. group 2: P=NS). Intensive care and hospital stay were significantly longer in group 3 compared to groups 1 and 2. Univariate and multivariate logistic regression analysis confirmed the statistically significant relationship between cTnI and PMI, LCOS and in-hospital mortality, respectively (P<0.001). CONCLUSIONS: Risk stratification by measurement of cTnI levels within 24h before elective CABG clearly identifies a subgroup of patients with increased risk for postoperative adverse outcome and in-hospital mortality.     

Sequential intramedullary nailing of open tibial shaft fractures after external fixation

We reviewed 32 tibial shaft fractures in 31 patients treated with sequential intramedullary nailing after primary external fixation. There were 30 open fractures and 2 closed injuries with severe blunt trauma requiring fasciotomy. Fifty per cent of the fractures were classified as Gustilo type III A and B injuries [13]. The mean external fixation treatment averaged 6.6 weeks, and secondary intramedullary nailing was done on average 7.4 weeks after injury. In 50% of the fractures, secondary nailing was done at the same procedure as removal of the external fixation. Overall, the incidence of osteomyelitis and nonunion was 3.1% each and of malunion 19%. The time to full weight-bearing averaged 31.2 weeks. The results were separately analyzed according to Gustilo types and subtypes. In the Gustilo type III B injuries, the incidence of osteomyelitis and non-union was 11 %, while malunion occurred in 33%. The time to full weight-bearing averaged 53 weeks. These results support the conclusion that this treatment modality is a valid alternative to other treatment options. However, previous pintract infections should be regarded as a contraindication for secondary nailing.Beispiel: Presented at the 15th Annual Meeting on Mycorrhizae, Chicago, 1992