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

Aging impairs heat loss, but when does it matter?

Aging is associated with an attenuated physiological ability to dissipate heat. However, it remains unclear if age-related impairments in heat dissipation only occur above a certain level of heat stress and whether this response is altered by aerobic fitness. Therefore, we examined changes in whole body evaporative heat loss (HE) as determined using whole body direct calorimetry in young (n = 10; 21 +/- 1 yr), untrained middle-aged (n = 10; 48 +/- 5 yr), and older (n = 10; 65 +/- 3 yr) males matched for body surface area. We also studied a group of trained middle-aged males (n = 10; 49 +/- 5 yr) matched for body surface area with all groups and for aerobic fitness with the young group. Participants performed intermittent aerobic exercise (30-min exercise bouts separated by 15-min rest) in the heat (40 degrees C and 15% relative humidity) at progressively greater fixed rates of heat production equal to 300 (Ex1), 400 (Ex2), and 500 (Ex3) W. Results showed that HE was significantly lower in middle-aged untrained (Ex2: 426 +/- 34; and Ex3: 497 +/- 17 W) and older (Ex2: 424 +/- 38; and Ex3: 485 +/- 44 W) compared with young (Ex2: 472 +/- 42; and Ex3: 558 +/- 51 W) and middle-aged trained (474 +/- 21; Ex3: 552 +/- 23 W) males at the end of Ex2 and Ex3 (P = 400 W when performed in a hot environment. These impairments in untrained middle-aged males can be minimized through regular aerobic exercise training

Esophageal, visceral and mean skin temperature responses during each exercise (Ex)/recovery (Rec) cycle and onset thresholds, thermosensitivities, time constants and amplitudes of evaporative heat loss for each exercise bout.

<p>Values are mean ± standard deviation.</p><p>T_es, esophageal temperature.</p><p>T_visc, visceral temperature.</p><p>T_Sk, mean skin temperature.</p><p>τ, time constant. Mean body temperature was used to calculated the onset threshold and thermosensitivity.</p><p>*Significant difference from young females.</p><p>†Significant difference from Ex1/Rec1.</p><p>‡Significant difference from Ex2/Rec2.</p><p>Esophageal, visceral and mean skin temperature responses during each exercise (Ex)/recovery (Rec) cycle and onset thresholds, thermosensitivities, time constants and amplitudes of evaporative heat loss for each exercise bout.</p

Local heat loss and heart rate responses during each exercise (Ex)/recovery (Rec) cycle.

<p>Values are mean ± standard deviation.</p><p>LSR, local sweat rate.</p><p>SkBF, skin blood flow.</p><p>HR, heart rate. % of max, percentage of individual’s maximum.</p><p>†Significant difference from Ex1/Rec1.</p><p>‡Significant difference from Ex2/Rec2.</p><p>Local heat loss and heart rate responses during each exercise (Ex)/recovery (Rec) cycle.</p

Mean ± standard deviation rates of evaporative heat loss (circles) and the required amount of evaporation for heat balance (E_req, squares) measured at baseline and over three 30-min exercise bouts (Ex 1, Ex 2 and Ex 3) and three 15-min recovery bouts (Rec 1, Rec 2 and Rec 3) in a hot, dry (40°C, 15% RH) environment in young (grey) and older (white) females.

<p>There were no differences in the required amount of evaporation for heat balance between groups. Significant difference (p≤0.05) in evaporative heat loss from young is denoted by an asterisk (*). Significant difference from Ex1/Rec1 is denoted by a cross (†). Significant difference from Ex2/Rec2 is denoted by a double cross (‡).</p

Mean ± standard deviation values for changes in body heat storage during each exercise/recovery cycle as well as the total change in body heat storage over the exercise protocols in a hot, dry (40°C, 15% RH) environment.

<p>The solid bars represent changes in body heat storage during exercise and the striped bars represent changes in body heat storage during recovery. The grey bars/stripes represent the young group and the white bars/black stripes represent the older group. Significantly different (p≤0.05) from young is denoted by an asterisk (*). Significant difference from Ex1/Rec1 is denoted by a cross (†). Significant difference from Ex2/Rec2 is denoted by a double cross (‡).</p