A systematic review of the evidence supporting post-operative antithrombotic use following cardiopulmonary bypass in children with CHD

Objectives: To determine the optimal antithrombotic agent choice, timing of initiation, dosing and duration of therapy for paediatric patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: We used PubMed and EMBASE to systematically review the existing literature of clinical trials involving antithrombotics following cardiac surgery from 2000 to 2020 in children 0–18 years. Studies were assessed by two reviewers to ensure they met eligibility criteria. Results: We identified 10 studies in 1929 children across three medications classes: vitamin K antagonists, cyclooxygenase inhibitors and indirect thrombin inhibitors. Four studies were retrospective, five were prospective observational cohorts (one of which used historical controls) and one was a prospective, randomised, placebo-controlled, double-blind trial. All included were single-centre studies. Eight studies used surrogate biomarkers and two used clinical endpoints as the primary endpoint. There was substantive variability in response to antithrombotics in the immediate post-operative period. Studies of warfarin and aspirin showed that laboratory monitoring levels were frequently out of therapeutic range (variably defined), and findings were mixed on the association of these derangements with bleeding or thrombotic events. Heparin was found to be safe at low doses, but breakthrough thromboembolic events were common. Conclusion: There are few paediatric prospective randomised clinical trials evaluating antithrombotic therapeutics post-cardiac surgery; most studies have been observational and seldom employed clinical endpoints. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal drug, timing of initiation, dosing and duration to improve outcomes by limiting post-operative morbidity and mortality related to bleeding or thrombotic events.

Rectal Acetaminophen Improves Shunt Volume and Reduces Patent Ductus Arteriosus Ligation in Extremely Preterm Infants

Objective An alternative therapy for preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) is needed when cyclooxygenase inhibitors fail or where treatment is contraindicated due to coexisting renal failure, necrotizing enterocolitis, and/or intestinal perforation. No studies have evaluated the efficacy of per rectum (PR) acetaminophen. The study aimed to evaluate the efficacy of PR acetaminophen in modulating the risk of PDA ligation. Study Design A retrospective matched case–control study was conducted to compare neonates born <29 weeks' gestation with evidence of hsDA, in an era when rescue rectal acetaminophen was used (January 2014–March 2018) as a treatment strategy, versus historical controls (July 2006–August 2012). All patients underwent comprehensive echocardiography assessment of ductal shunt volume according to a standardized protocol. Acetaminophen treated neonates were matched according to demographics, gestation, preintervention echocardiography features, and comorbidities. Control patients were selected when an echocardiography was performed at an equivalent postnatal age. Infants with a genetic syndrome, severe congenital malformation, or major forms of congenital heart disease excluding small atrial septal defect or ventricular septal defect, PDA, or patent formale ovale were excluded. The primary outcome was surgical ligation of the PDA. Secondary outcomes included echocardiography indices of hemodynamic significance, the composite of death, or severe BPD (defined by ventilator dependence at 36 weeks postmenstrual age). Descriptive statistics and univariate (t-tests, Fisher's exact test, and Mann–Whitney U test) analyses were used to evaluate clinical and echocardiography characteristics of the groups and compare outcomes. Results Forty infants (20 cases and 20 controls), with similar demographic and echocardiography features, were compared. Cases received 6.8 ± 0.7 days (60 mg/kg/day) of PR acetaminophen. Responders (n = 12, 60%) had echocardiography evidence of reduced ductal diameter (2.2 mm [1.9–2.6] to 1.1 mm [0–1.7], p = 0.002), left ventricular output (363 ± 108–249 ± 61 mL/min/kg; p = 0.002) and left atrium to aortic root ratio (1.7 ± 0.3–1.3 ± 0.2; p = 0.002) following treatment. The rate of PDA ligation was 50% lower (p = 0.02) and composite outcome of death or severe bronchopulmonary dysplasia was reduced (p = 0.04) in the acetaminophen group. Conclusion Rectal acetaminophen was associated with improvement in echocardiography indices of PDA shunt volume, a 50% reduction in PDA ligation rates and a reduction in the composite outcome of death or severe BPD. Pharmacologic and further prospective clinical studies are needed. Key Points

In Vitro and In Silico Evaluation of New 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone as Promising Cyclooxygenase Inhibitors

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4-d]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX‑2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions.

Persisting patency of the ductus arteriosus in the preterm infant

By 1769, it was known to Morgagni that the ductus arteriosus may persist until adulthood. In 1835, Jörg linked delayed postnatal closure with disturbed respiration, a discovery that afterwards was forgotten for a century. When blood gas analysis became available, the association between persisting patency and diminished oxygenation resurfaced. When it became known that prostaglandins played a role in maintaining ductal patency, the development of pharmacologic intervention with cyclooxygenase inhibitors immediately followed. This rapid progress was due to the interaction between basic science, paediatric cardiology, and neonatology disciplines at the Cardiovascular Research Institute in San Francisco, coordinated by Julius Comroe, as well as President Kennedy’s foundation of the National Institute of Child Health and Development. This series of events exemplifies how clinical research became an integrated managed multidisciplinary endeavour in the 20th century.

Efficacy of the Addition of Celecoxib to Selective Serotonin Reuptake Inhibitors in Treating Obsessive–Compulsive Disorder: A Double-Blind Clinical Trial Study

Purpose of the Study: Inflammatory processes in the brain play an important role in etiopathogenesis of Obsessive-Compulsive Disorder (OCD). Cyclooxygenase inhibitors such as celecoxib reduce the production of proinflammatory cytokines. This triple-blind study aimed to investigate the efficacy of the addition of Celecoxib to selective serotonin reuptake inhibitors in treating Obsessive–Compulsive Disorder (OCD) Ther Methods: Sixty patients who met the diagnostic and statistical manual of mental disorders criteria –fourth edition (DSM-IV) were recruited in the study for OCD screening by two psychiatrists to participate in the trial. The participants included 23 patients who received SSRIs and celecoxib (400 mg twice daily) and 22 patients in the control group that received SSRIs and placebo. At the beginning of the study, in weeks four, eight and 12, the patients were assessed by a psychiatrist using the Yale-Brown Obsessive Compulsive Scale (Y-BCOS). The Results: A significant difference was observed in the change of scores on the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) in week 12 compared with the onset of the study in two groups (t:-8.976, df:38, P:0.001). There was a significant difference between two groups in obsession (F:49.19, df:1, P≤0.001) and compulsion (F:13.78, df:1, P:0.001), and in obsessive compulsive disorder (F:57.25, df:1, P≤0.001) which was higher in Celecoxib group. The Conclusion: This study showed that adjuvant treatment with celecoxib can treat symptoms of OCD under treatment with SSRIs.