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

KAPS (kinematic assessment of passive stretch): a tool to assess elbow flexor and extensor spasticity after stroke using a robotic exoskeleton

Abstract Background Spasticity is a common sequela of stroke. Traditional assessment methods include relatively coarse scales that may not capture all characteristics of elevated muscle tone. Thus, the aim of this study was to develop a tool to quantitatively assess post-stroke spasticity in the upper extremity. Methods Ninety-six healthy individuals and 46 individuals with stroke participated in this study. The kinematic assessment of passive stretch (KAPS) protocol consisted of passive elbow stretch in flexion and extension across an 80° range in 5 movement durations. Seven parameters were identified and assessed to characterize spasticity (peak velocity, final angle, creep (or release), between-arm peak velocity difference, between-arm final angle, between-arm creep, and between-arm catch angle). Results The fastest movement duration (600 ms) was most effective at identifying impairment in each parameter associated with spasticity. A decrease in peak velocity during passive stretch between the affected and unaffected limb was most effective at identifying individuals as impaired. Spasticity was also associated with a decreased passive range (final angle) and a classic ‘catch and release’ as seen through between-arm catch and creep metrics. Conclusions The KAPS protocol and robotic technology can provide a sensitive and quantitative assessment of post-stroke elbow spasticity not currently attainable through traditional measures

A postural unloading task to assess fast corrective responses in the upper limb following stroke

Abstract Background Robotic technologies to measure human behavior are emerging as a new approach to assess brain function. Recently, we developed a robot-based postural Load Task to assess corrective responses to mechanical disturbances to the arm and found impairments in many participants with stroke compared to a healthy cohort (Bourke et al, J NeuroEngineering Rehabil 12: 7, 2015). However, a striking feature was the large range and skewed distribution of healthy performance. This likely reflects the use of different strategies across the healthy control sample, making it difficult to identify impairments. Here, we developed an intuitive “Unload Task”. We hypothesized this task would reduce healthy performance variability and improve the detection of impairment following stroke. Methods Performance on the Load and Unload Task in the KINARM exoskeleton robot was directly compared for healthy control (n = 107) and stroke (n = 31) participants. The goal was to keep a cursor representing the hand inside a virtual target and return “quickly and accurately” if the robot applied (or removed) an unexpected load to the arm (0.5–1.5 Nm). Several kinematic parameters quantified performance. Impairment was defined as performance outside the 95% of controls (corrected for age, sex and handedness). Task Scores were calculated using standardized parameter scores reflecting overall task performance. Results The distribution of healthy control performance was smaller and less skewed for the Unload Task compared to the Load Task. Fewer task outliers (outside 99.9 percentile for controls) were removed from the Unload Task (3.7%) compared to the Load Task (7.4%) when developing normative models of performance. Critically, more participants with stroke failed the Unload Task based on Task Score with their affected arm (68%) compared to the Load Task (23%). More impairments were found at the parameter level for the Unload (median = 52%) compared to Load Task (median = 29%). Conclusions The Unload Task provides an improved approach to assess fast corrective responses of the arm. We found that corrective responses are impaired in persons living with stroke, often equally in both arms. Impairments in generating rapid motor corrections may place individuals at greater risk of falls when they move and interact in the environment

Robotic tests for position sense and movement discrimination in the upper limb reveal that they each are highly reproducible but not correlated in healthy individuals

Abstract Background Robotic technologies for neurological assessment provide sensitive, objective measures of behavioural impairments associated with injuries or disease such as stroke. Previous robotic tasks to assess proprioception typically involve single limbs or in some cases both limbs. The challenge with these approaches is that they often rely on intact motor function and/or working memory to remember/reproduce limb position, both of which can be impaired following stroke. Here, we examine the feasibility of a single-arm Movement Discrimination Threshold (MDT) task to assess proprioception by quantifying thresholds for sensing passive limb movement without vision. We use a staircase method to adjust movement magnitude based on subject performance throughout the task in order to reduce assessment time. We compare MDT task performance to our previously-designed Arm Position Matching (APM) task. Critically, we determine test-retest reliability of each task in the same population of healthy controls. Method Healthy participants (N = 21, age = 18–22 years) completed both tasks in the End-Point Kinarm robot. In the MDT task the robot moved the dominant arm left or right and participants indicated the direction moved. Movement displacement was systematically adjusted (decreased after correct answers, increased after incorrect) until the Discrimination Threshold was found. In the APM task, the robot moved the dominant arm and participants “mirror-matched” with the non-dominant arm. Results Discrimination Threshold for direction of arm displacement in the MDT task ranged from 0.1–1.3 cm. Displacement Variability ranged from 0.11–0.71 cm. Test-retest reliability of Discrimination Threshold based on ICC confidence intervals was moderate to excellent (range, ICC = 0.78 [0.52–0.90]). Interestingly, ICC values for Discrimination Threshold increased to 0.90 [0.77–0.96] (good to excellent) when the number of trials was reduced to the first 50. Most APM parameters had ICC’s above 0.80, (range, ICC = [0.86–0.88]) with the exception of variability (ICC = 0.30). Importantly, no parameters were significantly correlated across tasks as Spearman rank correlations across parameter-pairings ranged from − 0.27 to 0.30. Conclusions The MDT task is a feasible and reliable task, assessing movement discrimination threshold in ~ 17 min. Lack of correlation between the MDT and a position-matching task (APM) indicates that these tasks assess unique aspects of proprioception that are not strongly related in young, healthy individuals