Nitric Oxide-Independent Soluble Guanylate Cyclase Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease.

Sickle cell disease (SCD) is associated with intravascular hemolysis and oxidative inhibition of nitric oxide (NO) signaling. BAY 54-6544 is a small-molecule activator of oxidized soluble guanylate cyclase (sGC), which, unlike endogenous NO and the sGC stimulator, BAY 41-8543, preferentially binds and activates heme-free, NO-insensitive sGC to restore enzymatic cGMP production. We tested orally delivered sGC activator, BAY 54-6544 (17 mg/kg/d), sGC stimulator, BAY 41-8543, sildenafil, and placebo for 4-12 weeks in the Berkeley transgenic mouse model of SCD (BERK-SCD) and their hemizygous (Hemi) littermate controls (BERK-Hemi). Right ventricular (RV) maximum systolic pressure (RVmaxSP) was measured using micro right-heart catheterization. RV hypertrophy (RVH) was determined using Fulton's index and RV corrected weight (ratio of RV to tibia). Pulmonary artery vasoreactivity was tested for endothelium-dependent and -independent vessel relaxation. Right-heart catheterization revealed higher RVmaxSP and RVH in BERK-SCD versus BERK-Hemi, which worsened with age. Treatment with the sGC activator more effectively lowered RVmaxSP and RVH, with 90-day treatment delivering superior results, when compared with other treatments and placebo groups. In myography experiments, acetylcholine-induced (endothelium-dependent) and sodium-nitroprusside-induced (endothelium-independent NO donor) relaxation of the pulmonary artery harvested from placebo-treated BERK-SCD was impaired relative to BERK-Hemi but improved after therapy with sGC activator. By contrast, no significant effect for sGC stimulator or sildenafil was observed in BERK-SCD. These findings suggest that sGC is oxidized in the pulmonary arteries of transgenic SCD mice, leading to blunted responses to NO, and that the sGC activator, BAY 54-6544, may represent a novel therapy for SCD-associated pulmonary arterial hypertension and cardiac remodeling.

Characterizing Delirium and Associated Risk Factors Using the Cornell Assessment of Pediatric Delirium Score in Pediatric Burn Patients.

Delirium is a syndrome of acute brain dysfunction with disturbance in consciousness and cognition that is increasingly recognized in critically ill pediatric patients. The Cornell Assessment of Pediatric Delirium (CAPD) tool is used to detect delirium in children of all ages and developmental stages in various hospital settings. To date, the incidence of delirium in the pediatric burn population has been poorly defined. In order to describe the incidence as well as risk factors for delirium in this patient population, we retrospectively reviewed patients <18 years of age admitted to our American Burn Association-verified pediatric burn center from March 2018 to May 2021 who underwent delirium screening using the CAPD tool. Patient demographics, burn characteristics, hospitalization details, and date of first positive delirium screening were collected, and χ2, Fisher's exact test, univariate, and multivariate analyses were performed. Delirium was identified in 42 (10.8%) of 389 patients meeting inclusion criteria. Patients screening positive for delirium were older (4 years [IQR: 2, 11] vs 2 years [IQR: 1, 6], P < .0005) and had larger TBSA burns (21.63% [IQR: 9, 42] vs 3.5% [IQR: 1.75, 6], P < .0001) than delirium-negative patients. Delirium-positive patients required a longer duration of mechanical ventilation (OR 4.23; 95% CI [1.16-15.39], P = .0289) and had higher TBSA burns (OR 1.12; 95% CI [1.06-1.17], P < .0001). Delirium-positive patients had 1.6 day longer length-of-stay adjusted for TBSA burned (95% CI [0.81-2.41], P < .0001). Compared to delirium-negative patients, delirium-positive patients had a 5.4-day longer PICU admission (95% CI [2.93-10.3]; P < .0001). Screening pediatric burn patients with risk factors known to be associated with delirium by using the CAPD score could improve delirium prevention and allow for early intervention.