Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Towards an improvement in aneurysm assessment: coupling 3D reconstruction tools with engineering know-how

Purpose: Currently, abdominal aortic aneurysms (AAAs), which are a permanent dilation of the aorta, are treated surgically when the maximum transverse diameter surpasses 5.0cm. AAA rupture occurs when the locally acting wall stress exceeds the locally acting wall strength. There is a need to review the current diameter-based criterion, and so it may be clinically useful to develop an additional tool to aid the surgical decision-making process. A Finite Element Analysis Rupture Index (FEARI) was developed. 3D reconstructions were also performed to aid endovascular aneurysm repair (EVAR). Methods: Patient-specific AAAs were reconstructed using Mimics v12 and analysed for use with the FEARI. Previous experimental work on determination of ultimate tensile strengths (UTS) from AAA tissue samples was implemented in this study. By combining peak wall stress along with average regional UTS, a new approach to the estimation of patient-specific rupture risk has been developed. A further 4 AAA cases were reconstructed and analysed in Mimics v12 to determine stent-graft sizes and plan EVAR. Results: A detailed examination of these cases utilising the FEARI analysis suggested that there was a possibility that some of the AAAs may have been less prone to rupture than previously considered. 3D reconstructions as a surgical guidance tool proved to be very effective in accurate device sizing and pre-surgical planning. Conclusions: It is proposed that FEARI, used alongside other rupture risk factors, may improve the current surgical decision-making process. The use of FEARI as an additional tool for rupture prediction may provide a useful adjunct to the diameterbased approach in surgical decision-making. 3D reconstructions aid surgeons in planning EVAR, in particular in the case of extreme cases of aneurismal disease

New approaches to abdominal aortic aneurysm rupture risk assessment - engineering insights with clinical gain

Abdominal aortic aneurysm (AAA) rupture remains a significant cause of death in the developed world. Current treatment approaches rely heavily on the size of the aneurysm to decide on the most appropriate time for clinical intervention and treatment. However, over recent years several alternative rupture-risk indicators have been proposed. This brief review examines some of these new approaches to AAA rupture-risk assessment, from both numerical and experimental aspects and also what the future may hold for AAA rupture-risk. While numerically-predicted wall stress, finite element analysis rupture index (FEARI), rupture potential index (RPI), severity parameter (SP), and geometrical factors such as asymmetry have all been developed and show promise in possibly helping to predict AAA rupture-risk, validation of these tools remains a significant challenge. Validation of biomechanics-based rupture indicators may be feasible by combining in vitro modeling of realistic AAA analogues together with both retrospective and prospective monitoring and modeling of AAA cases. Peak wall stress is arguably the primary result obtained from numerical analyses however, as the majority of ruptures occur in the posterior and posterior-lateral regions, the role of posterior wall stress has also recently been highlighted as potentially significant. It is also known that wall stress alone is not enough to cause rupture as wall strength plays an equal role. Therefore, should a biomechanics-based rupture-risk be implemented? There have been some significant steps, both numerically and experimentally, towards answering this and other questions relating to AAA rupture-risk prediction yet regardless of the efforts underway in several laboratories, the introduction of a numerically-predicted rupture-risk parameter into the clinicians’ decision-making process may still be quite some time away

Factors that affect mass transport from drug eluting stents into the artery wall

Coronary artery disease can be treated by implanting a stent into the blocked region of an artery, thus enabling blood perfusion to distal vessels. Minimally invasive procedures of this nature often result in damage to the arterial tissue culminating in the re-blocking of the vessel. In an effort to alleviate this phenomenon, known as restenosis, drug eluting stents were developed. They are similar in composition to a bare metal stent but encompass a coating with therapeutic agents designed to reduce the overly aggressive healing response that contributes to restenosis. There are many variables that can influence the effectiveness of these therapeutic drugs being transported from the stent coating to and within the artery wall, many of which have been analysed and documented by researchers. However, the physical deformation of the artery substructure due to stent expansion, and its influence on a drugs ability to diffuse evenly within the artery wall have been lacking in published work to date. The paper highlights previous approaches adopted by researchers and proposes the addition of porous artery wall deformation to increase model accuracy

A comparison of modelling techniques for computing wall stress in abdominal aortic aneurysms

BACKGROUND: Aneurysms, in particular abdominal aortic aneurysms (AAA), form a significant portion of cardiovascular related deaths. There is much debate as to the most suitable tool for rupture prediction and interventional surgery of AAAs, and currently maximum diameter is used clinically as the determining factor for surgical intervention. Stress analysis techniques, such as finite element analysis (FEA) to compute the wall stress in patient-specific AAAs, have been regarded by some authors to be more clinically important than the use of a "one-size-fits-all" maximum diameter criterion, since some small AAAs have been shown to have higher wall stress than larger AAAs and have been known to rupture. METHODS: A patient-specific AAA was selected from our AAA database and 3D reconstruction was performed. The AAA was then modelled in this study using three different approaches, namely, AAA(SIMP), AAA(MOD) and AAA(COMP), with each model examined using linear and non-linear material properties. All models were analysed using the finite element method for wall stress distributions. RESULTS: Wall stress results show marked differences in peak wall stress results between the three methods. Peak wall stress was shown to reduce when more realistic parameters were utilised. It was also noted that wall stress was shown to reduce by 59% when modelled using the most accurate non-linear complex approach, compared to the same model without intraluminal thrombus. CONCLUSION: The results here show that using more realistic parameters affect resulting wall stress. The use of simplified computational modelling methods can lead to inaccurate stress distributions. Care should be taken when examining stress results found using simplified techniques, in particular, if the wall stress results are to have clinical importance

A comparison of modelling techniques for computing wall stress in abdominal aortic aneurysms-1

<p><b>Copyright information:</b></p><p>Taken from "A comparison of modelling techniques for computing wall stress in abdominal aortic aneurysms"</p><p>http://www.biomedical-engineering-online.com/content/6/1/38</p><p>BioMedical Engineering OnLine 2007;6():38-38.</p><p>Published online 19 Oct 2007</p><p>PMCID:PMC2169238.</p><p></p> and lumen (yellow) clearly distinguishable. 3D reconstruction of examined AAA is shown on right