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

Quantitative MRI of physiological brain tissue deformation in humans

The objective of the work presented in this thesis was to develop non-invasive imaging techniques of brain pulsations in response to the beating heart and respiration, in order to pave the way to non-invasive, in-vivo assessment of the impact of disease and physiological stressors on the properties of the brain tissue and microvasculature. Physiological brain tissue deformation is driven, among others, by variations in blood pressure induced by cardiac and respiratory cycles. The pulsations of brain tissue form a valuable source of information. The tissue deformation is not only driven by variations in blood volume from the microvasculature, but also reflects differences in tissue properties like stiffness. In this work, we started from two MRI motion mapping methods that provide these motion field maps. These MRI methods deploy the MRI phase signal to encode the respective velocity or displacement into the MRI signal. In Chapter 2 we compared the performance of PC-MRI with DENSE through computer simulations and found that DENSE outperforms PC-MRI for small deformations in the human brain tissue, such as induced by the heartbeat. Cardiac and respiration-induced contributions to brain tissue deformation were disentangled in Chapter 3. Yet, the single-shot approach limited the acquired volume to 2D images only. We acquired two orthogonal slices and performed a 3D analysis of tissue strain along the intersection line. Here we observed, for the first time, the Poisson effect reflected in the tissue deformation, where longitudinal tissue stretch was accompanied by transverse shrinkage of tissue. Furthermore, the results showed that cardiac-induced tissue deformation is dominating respiration contributions by approximately a factor of five. In Chapter 4, we extended the single-shot DENSE method by combining the approach with a simultaneous multi-slice (SMS) acquisition. The work was the first to report the full cardiac-induced strain tensor of brain tissue deformation with complete brain coverage, for which we found well-defined strain patterns that are consistent between subjects. We called this novel approach Strain Tensor Imaging (STI). The potential of the STI technique to detect abnormalities in disease, was explored in a case study patient that was treated with a craniectomy. At the time of the MRI acquisitions, the cranial opening – 12 cm in diameter – had not yet been closed by a reconstructed skull part. We compared the strain maps from the patient with the strain maps obtained in healthy subjects, and showed distinct differences between these maps in Chapter 5. This ‘Angelo Mosso experiment in modern days’ shows that the MRI technique is sensitive enough to detect abnormalities in brain tissue deformation. The DENSE sequence can simultaneously provide both strain data and diffusion data in the brain. We used this property in Chapter 6 to investigate to what extent observed ADC variations in the brain over the cardiac cycle can be explained by measurement errors induced by variations in tissue strain. We found that observed ADC variations are at least a factor of 2 larger than could be explained by variations in the tissue strain

Cardiac and respiration-induced brain deformations in humans quantified with high-field MRI

Microvascular blood volume pulsations due to the cardiac and respiratory cycles induce brain tissue deformation and, as such, are considered to drive the brain's waste clearance system. We have developed a high-field magnetic resonance imaging (MRI) technique to quantify both cardiac and respiration-induced tissue deformations, which could not be assessed noninvasively before. The technique acquires motion encoded snapshot images in which various forms of motion and confounders are entangled. First, we optimized the motion sensitivity for application in the human brain. Next, we isolated the heartbeat and respiration-related deformations, by introducing a linear model that fits the snapshot series to the recorded physiological information. As a result, we obtained maps of the physiological tissue deformation with 3 mm isotropic spatial resolution. Heartbeat- and respiration induced volumetric strain were significantly different from zero in the basal ganglia (median (25-75% interquartile range): 0.85·10-3 (0.39·10-3-1.05·10-3), p = 0.0008 and -0.28·10-3 (-0.41·10-3-0.06·10-3), p = 0.047, respectively). Smaller volumetric strains were observed in the white matter of the centrum semi ovale (0.28·10-3 (0-0.59·10-3) and -0.06·10-3 (-0.17·10-3-0.20·10-3)), which was only significant for the heart beat (p = 0.02 and p = 0.7, respectively). Furthermore, heartbeat induced volumetric strain was about three times larger than respiration induced volumetric strain. This technique opens a window on the driving forces of the human brain clearance system

Cardiac and respiration-induced brain deformations in humans quantified with high-field MRI

Microvascular blood volume pulsations due to the cardiac and respiratory cycles induce brain tissue deformation and, as such, are considered to drive the brain's waste clearance system. We have developed a high-field magnetic resonance imaging (MRI) technique to quantify both cardiac and respiration-induced tissue deformations, which could not be assessed noninvasively before. The technique acquires motion encoded snapshot images in which various forms of motion and confounders are entangled. First, we optimized the motion sensitivity for application in the human brain. Next, we isolated the heartbeat and respiration-related deformations, by introducing a linear model that fits the snapshot series to the recorded physiological information. As a result, we obtained maps of the physiological tissue deformation with 3 mm isotropic spatial resolution. Heartbeat- and respiration induced volumetric strain were significantly different from zero in the basal ganglia (median (25-75% interquartile range): 0.85·10-3 (0.39·10-3-1.05·10-3), p = 0.0008 and -0.28·10-3 (-0.41·10-3-0.06·10-3), p = 0.047, respectively). Smaller volumetric strains were observed in the white matter of the centrum semi ovale (0.28·10-3 (0-0.59·10-3) and -0.06·10-3 (-0.17·10-3-0.20·10-3)), which was only significant for the heart beat (p = 0.02 and p = 0.7, respectively). Furthermore, heartbeat induced volumetric strain was about three times larger than respiration induced volumetric strain. This technique opens a window on the driving forces of the human brain clearance system

Strain Tensor Imaging: Cardiac-induced brain tissue deformation in humans quantified with high-field MRI

The cardiac cycle induces blood volume pulsations in the cerebral microvasculature that cause subtle deformation of the surrounding tissue. These tissue deformations are highly relevant as a potential source of information on the brain's microvasculature as well as of tissue condition. Besides, cyclic brain tissue deformations may be a driving force in clearance of brain waste products. We have developed a high-field magnetic resonance imaging (MRI) technique to capture these tissue deformations with full brain coverage and sufficient signal-to-noise to derive the cardiac-induced strain tensor on a voxel by voxel basis, that could not be assessed non-invasively before. We acquired the strain tensor with 3 mm isotropic resolution in 9 subjects with repeated measurements for 8 subjects. The strain tensor yielded both positive and negative eigenvalues (principle strains), reflecting the Poison effect in tissue. The principle strain associated with expansion followed the known funnel shaped brain motion pattern pointing towards the foramen magnum. Furthermore, we evaluate two scalar quantities from the strain tensor: the volumetric strain and octahedral shear strain. These quantities showed consistent patterns between subjects, and yielded repeatable results: the peak systolic volumetric strain (relative to end-diastolic strain) was 4.19⋅10−4 ± 0.78⋅10−4 and 3.98⋅10−4 ± 0.44⋅10−4 (mean ± standard deviation for first and second measurement, respectively), and the peak octahedral shear strain was 2.16⋅10−3 ± 0.31⋅10−3 and 2.31⋅10−3 ± 0.38⋅10−3, for the first and second measurement, respectively. The volumetric strain was typically highest in the cortex and lowest in the periventricular white matter, while anisotropy was highest in the subcortical white matter and basal ganglia. This technique thus reveals new, regional information on the brain's cardiac-induced deformation characteristics, and has the potential to advance our understanding of the role of microvascular pulsations in health and disease

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc

Long-term (180-Day) outcomes in critically Ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months