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.

     

Intracranial pressure increase and changes in cerebrovascular circulation, associated with brain death, studied by transcranial Doppler sonography

Blood flow velocity of 24 patients in state of the brain death were examined by transcranial Doppler sonography. Authors expound the characteristic velocity-pulse graphs recorded in progressively increasing intracranial pressure and their chronology as well. The different forms of the oscillating flow and their successive development are described. The oscillating flow, the systolic spikes and the so called "zero Flow" are the transcranial Doppler signs of the ceased cerebral blood flow, and these signs can be used as one of the evidence of the brain death.     

The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial: rationale and design of a multicenter, randomized, placebo-controlled, clinical trial of metoprolol for patients with diabetes mellitus who are undergoing major noncardiac surgery

Background

Recent trials suggest that perioperative β-blockade reduces the risk of cardiac events in patients with a risk of myocardial ischemia who are undergoing noncardiac surgery. Patients with diabetes mellitus are at a high-risk for postoperative cardiac morbidity and mortality. They may, therefore, benefit from perioperative β-blockade.

Methods

The Diabetic Postoperative Mortality and Morbidity (DIPOM) trial is an investigator-initiated and -controlled, centrally randomized, double-blind, placebo-controlled, multicenter trial. We compared the effect of metoprolol with placebo on mortality and cardiovascular morbidity rates in patients with diabetes mellitus who were β-blocker naive, ≥40 years old, and undergoing noncardiac surgery. The study drug was given during hospitalization for a maximum of 7 days beginning the evening before surgery. The primary outcome measure is the composite of all-cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure leading to hospitalization or discovered or aggravated during hospitalization. Follow-up involves re-examination of patients at 6 months and collection of mortality and morbidity data via linkage to public databases. The study was powered on the basis of an estimated 30% 1-year event rate in the placebo arm and a 33% relative risk reduction in the metoprolol arm. The median follow-up period was 18 months.

Results

Enrollment started in July 2000 and ended in June 2002. A total of 921 patients were randomized, and 54% of these patients had known cardiac disease, hypertension, or both.

Conclusion

The results of this study may have implications for reduction of perioperative and postoperative risk in patients with diabetes mellitus who are undergoing major noncardiac surgery.     

Mitochondrial oxygen monitoring with COMET: verification of calibration in man and comparison with vascular occlusion tests in healthy volunteers

Mitochondria are the primary consumers of oxygen and therefore an important location for oxygen availability and consumption measurement. A technique has been developed for mitochondrial oxygen tension (mitoPO₂) measurement, incorporated in the COMET. In contrast to most textbooks, relatively high average mitoPO₂ values have been reported. The first aim of this study was to verify the validity of the COMET calibration for mitoPO₂ measurements in human skin. The second aim was to compare the dynamics of mitoPO₂ to several other techniques assessing tissue oxygenation. Firstly, we performed a two-point calibration. Mitochondrial oxygen depletion was achieved with vascular occlusion. A high mitoPO₂ was reached by local application of cyanide. MitoPO₂ was compared to the arterial oxygen partial pressure (PaO₂). Secondly, for deoxygenation kinetics we compared COMET variables with the LEA O2C, SenTec OxiVenT? and Medtronic INVOS? parameters during a vascular occlusion test. 20 healthy volunteers were recruited and resulted in 18 datasets (2 times 9 subjects). The lowest measured mitoPO₂ value per subject had a median [IQR] of 3.0 [1.0–4.0] mmHg, n?=?9. After cyanide application the mitoPO₂ was 94.1 mmHg [87.2–110.9] and did not differ significantly (n?=?9, p?=?0.5) from the PaO₂ of 101.0 [98.0–106.0] mmHg. In contrast to O2C, OxiVenT? and INVOS parameters, mitoPO₂ declined within seconds with pressure on the probe. The kinetics from this decline are used to mitochondrial oxygen consumption (mitoVO₂). This study validates the calibration of the COMET device in humans. For mitoVO₂ measurements not only blood flow cessation but application of local pressure is of great importance to clear the measurement site of oxygen-carrying erythrocytes.

     

Comprehensive proteomic analysis of human dentin

Proteomic analysis of the human body is a significant recent scientific endeavour. In this study, we investigated the proteomic profile of human dentin using modern analytical and mass spectrometric techniques. Five healthy permanent human molars from five adults were cut, pulverized, denaturated with guanidine buffer, and demineralized with EDTA buffer. The extracted proteins were analysed by gel electrophoresis (SDS-PAGE and two-dimensional gel electrophoresis), digested with trypsin, and separated by liquid chromatography/high-resolution tandem mass spectrometry. We identified 289 proteins with high confidence, 90 of which had not been previously detected in human dentin. Nine (currently hypothetical) proteins were identified for the first time in an actual human sample. The proteins have a variety of functions, including calcium-ion binding, formation of the extracellular matrix, formation of the cytoskeleton, cytoskeletal protein binding, immune response, and transport. In conclusion, this is the first use of two-dimensional electrophoresis for investigating human dentin.     

Systematic review of cardiac output measurements by echocardiography vs. thermodilution: the techniques are not interchangeable

Purpose

Echocardiography is frequently used in the hemodynamic evaluation of critically ill patients, but inaccurate measurements may lead to wrong clinical decisions. The aim of our systematic review was to investigate the interchangeability of echocardiography with thermodilution technique in measuring cardiac output and its changes.

Methods

In August 2015 we systematically searched electronic databases and included studies investigating the echocardiographic measurement of cardiac output compared with thermodilution technique using the Bland–Altman method. Two authors independently reviewed the studies and extracted data on type of measurements, clinical setting and characteristics, and those of the Bland–Altman and trending ability analyses.

Results

We identified 13,834 citations and included 24 studies in the final analysis. The median number of participants was 32 (range 8–65). Most of the studies assessed left-sided heart structures and the majority had small bias, wide limits of agreement, and high percentage error between echocardiography and thermodilution. In only two of the 24 studies the precision of each technique (echocardiography and thermodilution) was assessed before comparing them. In the single study evaluating trending ability using valid methodology, agreement was observed between echocardiography and thermodilution in detecting the directional changes in cardiac output, but the magnitude of changes varied considerably.

Conclusions

The majority of studies comparing echocardiography with thermodilution were difficult to interpret, but current evidence does not support interchangeability between these techniques in measuring cardiac output. The techniques may be interchangeable in tracking directional changes in cardiac output, but this has to be confirmed in large high-quality studies.