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

Postoperative course of body weight.

<p>Points represent average relative body weight, in relation to the weight prior to operation, for the control group (□) and the groups receiving tacrolimus: T0.5 (◼), T2 (Δ) and T5 (●).</p

Wound breaking strength.

<p>Data represent mean and SEM in the control groups (white bars) and the T0.5 (black & white bars), T2 (grey bars) and T5 (black bars) tacrolimus groups. A= ileum anastomoses, B= colon anastomoses, C = fascia.</p

Wound hydroxyproline content.

<p>Data are expressed as hydroxyproline content per 5 mm tissue length and represent mean and SEM for the controls (white bars) and the T2 (grey bars) and T5 (black bars) tacrolimus groups. A= ileum, B= colon, C = fascia. *: p<0.05 vs T2 group; #: p<0.05 vs control group.</p

MMP activity in intestinal anastomoses.

<p>Columns represent mean values + SEM for controls (white bars) and the T2 (grey bars) and T5 (black bars) tacrolimus groups. Data represent total activities, in arbitrary units, per 5-mm segment for proMMP-9 (A), MMP-9 (B), proMMP-2 (C), and MMP-2 (D). *: p<0.05 vs control group.</p

Paracetamol does not compromise early wound repair in the intestine or abdominal wall in the rat

Item does not contain fulltextBACKGROUND: Paracetamol is a cornerstone for perioperative pain relief. Its mechanism of action may include a local anti-inflammatory effect with inhibition of cyclooxygenase isoenzymes. The scarce literature available on its effects on wound healing consists of preclinical studies into the effect of paracetamol on healing of the musculoskeletal system. Although the drug is used abundantly for pain relief after surgery of the gastrointestinal tract, there are no published data on the influence of paracetamol on anastomotic and abdominal healing. This also holds for the crucial, early inflammatory phase of repair. The recovery of wound strength could therefore conceivably be affected by paracetamol. METHODS: In 78 male Wistar rats, we constructed an anastomosis in colon and ileum. The rats received either low- or high-dose (50 or 200 mg/kg/d, divided over 2 doses) paracetamol or vehicle (controls) until they were killed on day 3 or 7 after surgery (n = 13 each). In anastomoses, the main outcome variables were 2 independent measures for wound strength, bursting pressure, and breaking strength, the latter being the primary outcome variable. In addition, collagen levels were measured and histology was performed. In fascia, breaking strength was analyzed. RESULTS: No significant differences were found between control and paracetamol-treated groups at any time point for any of the variables. Wound strength increased significantly from day 3 to day 7 in all groups. In the colon anastomosis, the breaking strength increased from 130 +/- 9 g (mean +/- SEM) at day 3 to 232 +/- 17 g at day 7 in the control group, from 144 +/- 10 to 224 +/- 9 g in the low-dose group, and from 130 +/- 12 to 263 +/- 28 g in the high-dose group. The lower limit for the 95% confidence interval was -11 for the difference between control and low-dose groups at day 3 and -25 for the difference between control and high-dose groups. No differences in collagen levels were found between the high-dose and control groups. Histology did not indicate the presence of gross differences between groups. CONCLUSIONS: Perioperative use of paracetamol in a rat model of intestinal surgery does not significantly impede wound repair in the early postoperative period