Faculty Bibliography

OBJECTIVE:Famotidine is a commonly used agent in pediatric intensive care units. There is no data regarding the safety of undiluted intravenous push (IVP) administration in pediatrics; however, there are historical concerns for hemodynamic instability in the adult population. This study assesses the safety of famotidine administered undiluted IVP for doses ≥ 5 mg in pediatric patients. METHODS:We performed a retrospective, observational, medication use evaluation in pediatric patients (≤ 18 years) who received famotidine undiluted IVP from February to July 2022. Patients with arterial lines and continuous cardiac telemetry were included. Patients requiring extracorporeal membrane oxygenation, receiving famotidine doses < 5 mg, or who had a change in vasoactive medication doses within 1 hour prior to famotidine IVP administration were excluded. The primary outcome was the incidence of hypotension and bradycardia within 45 minutes of undiluted famotidine IVP administration. RESULTS:A total of 59 patients were included. There were 8 patients (13.6%) with hypotension and 1 patient (1.7%) with bradycardia after famotidine administration in the full cohort. Of these 9 patients, 7 had hypotension and bradycardia at baseline. Two patients (3.4%) required adjustment of their vasoactive medication within 45 minutes after receiving famotidine, although these patients were also postoperative day zero from cardiac surgery. None of the patients required a fluid bolus for hypotension following famotidine administration. The percent change in hemodynamics from baseline were minimal across the various time intervals. CONCLUSION/CONCLUSIONS:Famotidine administered undiluted IVP produced no clinically significant hemodynamic -adverse effects in critically ill pediatric patients.

Precision-based percutaneous coronary intervention (PCI) integrates contemporary strategies across the pre-, intra-, and post-procedural phases to improve outcomes and minimize complications. Emerging evidence underscores the value of these strategies in reducing adverse events and improving procedural efficiency. While artificial intelligence and pharmacogenomics hold long-term promise for enhancing personalization, their clinical utility in PCI remains in the early stages of development.

Tacrolimus is highly effective at preventing allograft rejection and prolonging survival after lung transplantation. However, erratic pharmacokinetics may limit efficacy and predispose to greater adverse effects. We conducted a prospective, open-label trial of lung transplant recipients who underwent early conversion (within 30 days) to LCP tacrolimus (LCPT, n = 40) and compared first-year outcomes to an historical control of patients who remained on immediate-release tacrolimus (IRT, n = 24). Subjects were converted 1:1 from IRT to LCPT. The first dose of LCPT overlapped with the last morning dose of IRT. Conversion to LCPT occurred at a median of 17.5 [IQR 12-25] days. The conversion dose ratio was 1.0 mg:mg [IQR 0.75-1.50] at 14 days. At 1 year, there were no differences between LCPT and IRT in the incidence of biopsy-proven (12.5% vs. 25.0%, p = 0.30) or clinically treated (20.0% vs. 25.0%, p = 0.64) acute cellular rejection. However, the severity of any biopsy-proven rejection was significantly higher in the IRT cohort (27.5% vs. 54.2%, p = 0.03). Although not achieving statistical significance, de novo donor-specific antibodies were more commonly observed in the LCPT group (20.0% vs. 4.2%, p = 0.14). Despite this, the incidence of antibody-mediated rejection (7.5% vs. 0.0%, p = 0.29) and early-onset chronic lung allograft dysfunction (7.5% vs. 9.1%, p = 1.00) were similar. The incidence of chronic kidney disease stage 4 or greater at 1-year was similar (7.5% vs. 12.5%, p = 0.66). In conclusion, early conversion to LCPT was feasible and similarly efficacious to IRT in a cohort of lung transplant recipients. Trial Registration: ClinicalTrials.gov identifier: NCT04420195.

Therapeutic anticoagulation is the mainstay therapy in acute pulmonary embolism (PE), however, select patients benefit from emergent reperfusion to prevent or rescue acute right ventricular failure and haemodynamic collapse. Compared to other leading causes of cardiovascular mortality such as myocardial infarction and stroke, there is a substantial paucity of literature informing on advanced therapies in PE. Recent years have seen significant evolution in the armamentarium available for PE care with the uptake of several endovascular treatment modalities and increased use of mechanical circulatory support. While several ongoing randomised controlled trials may alter the therapeutic landscape and approach to PE management, at present, we are left with multiple selections with limited guidance. In this review, we discuss the latest therapeutic options available for acute PE and offer an approach to their implementation.

INTRODUCTION/BACKGROUND:Data on outcomes between unfractionated heparin and bivalirudin anticoagulation during percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS) remains inconclusive. We aimed to systematically analyze PCI outcomes comparing unfractionated heparin and bivalirudin. METHODS:We systematically searched Ovid MEDLINE, Ovid Embase, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science from database inception in 1966 through January 2024 for studies evaluating PCI outcomes comparing unfractionated heparin and bivalirudin. Two investigators independently reviewed data. Conflicts were resolved through consensus. Random-effects meta-analyses were used. RESULTS:Ten prospective trials were identified that enrolled 42,253 individuals who presented with an acute coronary syndrome. Our analysis found that heparin when compared to bivalirudin was associated with an increased risk of trial-based definition of major bleeding (RR 1.68, 95% CI 1.29-2.20), non-access site complications (RR 4.6, 95% CI 1.75-12.09), TIMI major bleeding (RR 1.70, 95% CI 1.20-2.41), major bleeding risks (RR 1.87, 95% CI 1.49-2.36), cardiovascular disease death (RR 1.26, 95% CI 1.02-1.57), and thrombocytopenia (RR 1.67, 95% CI 1.07-2.62). There were no statistically significant differences between heparin and bivalirudin for all-cause mortality, MACE, stroke, reinfarction, target vessel revascularization, acute or stent thrombosis. CONCLUSIONS:The present meta-analysis demonstrates bivalirudin reduces major bleeding when used for anticoagulation during PCI in patients with acute coronary syndromes and is not associated with an increased risk of stent thrombosis or MACE.

Intravenous (IV) digoxin loading dose recommendations for rate control of atrial arrhythmias in critically ill patients are not well studied. When using digoxin in the setting of atrial fibrillation/atrial flutter (AF/AFL), a loading dose (LD) in either a fixed-dose regimen, weight-based dose, or pharmacokinetic-based calculation to target a serum digoxin concentration (SDC) of 0.8-1.5 ng/mL is recommended. The objective of this study was to assess the safety and effectiveness of digoxin LD used in critically ill patients for rate control of AF/AFL and to assess the SDC achieved. This single center retrospective cohort study included patients who received IV digoxin and had a SDC drawn. The primary endpoint was the median SDC achieved after a digoxin LD. Secondary outcomes included the frequency of SDCs ≥1.5 ng/mL and heart rate (HR) control. A total of 92 patients were included. The median total LD of digoxin for the entire cohort was 11mcg/kg (750 mcg). For 61% of the cohort, the LD was distributed over six-hour intervals. The median SDC after completion of the IV digoxin LD was 1.3 ng/mL (0.9, 1.7). The incidence of supratherapeutic SDC was 36% for the total cohort. A target HR < 110 beats per minute within 24 hours from digoxin LD was achieved in 60% of the cohort. In conclusion, a median total digoxin LD of 750 mcg in critically ill patients with AF/AFL, targeting a SDC < 1.5ng/mL may be considered for acute rate control, taking into account drug-drug interactions in the cardiac intensive care unit. Future studies are necessary to confirm our findings.

RATIONALE/BACKGROUND:Lower airway enrichment with oral commensals has been previously associated with grade 3 severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades, including milder forms, and whether it is associated with a distinct host inflammatory endotype. METHODS:Lower airway samples from 96 LT recipients with varying degrees of PGD were used to evaluate the lung allograft microbiota via 16S rRNA gene sequencing. Bronchoalveolar lavage (BAL) cytokine concentrations and cell differential percentages were compared across PGD grades. In a subset of samples, we evaluated the lower airway host transcriptome using RNA sequencing methods. RESULTS:Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in both moderate and severe PGD. Dirichlet Multinomial Mixtures (DMM) modeling identified two distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD were identified within the dysbiotic cluster (C-SPT) than within the no PGD group (48 and 29%, respectively) though this difference did not reach statistical significance (p=0.06). PGD severity associated with increased BAL neutrophil concentration (p=0.03) and correlated with BAL concentrations of MCP-1/CCL2, IP-10/CXCL10, IL-10, and TNF-α (p<0.05). Furthermore, microbial signatures of dysbiosis correlated with neutrophils, MCP-1/CCL-2, IL-10, and TNF-α (p<0.05). C-SPT exhibited differential expression of TNF, SERPINE1 (PAI-1), MPO, and MMP1 genes and upregulation of MAPK pathways, suggesting that dysbiosis regulates host signaling to promote neutrophilic inflammation. CONCLUSIONS:Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD pathogenesis. This data highlights a putative role for lower airway microbial dysbiosis in the pathogenesis of this syndrome.

OBJECTIVE/UNASSIGNED:Anticoagulation monitoring in patients supported on extracorporeal membrane oxygenation is challenging given the risks of both bleeding and thrombotic complications. Based on our early clinical experience, we revised our heparin protocol by reducing our target anti-factor Xa assay from 0.3 to 0.7 U/mL to 0.15 to 0.5 U/mL, while instituting a partial thromboplastin time cutoff of 70 seconds. We evaluated the impact of this change on bleeding/thrombotic complications. METHODS/UNASSIGNED:A single-center retrospective study of adult patients on extracorporeal membrane oxygenation support was conducted from January 2015 to August 2022. Patients were stratified into groups based on protocol revision: Pre-Revision (2015-2018) or Post-Revision (2019-2022). Our primary end point was the incidence of bleeding/thrombotic complications. Time in therapeutic range was calculated to determine protocol adherence. Poisson regression was performed to correlate time in therapeutic range with the likelihood of complication. RESULTS/UNASSIGNED:008). CONCLUSIONS/UNASSIGNED:A modified heparin monitoring protocol defined by a lower therapeutic anti-factor Xa assay target and a set partial thromboplastin time cutoff correlated with decreases in bleeding/thrombotic complications in patients on extracorporeal membrane oxygenation.

The clinical effect of drug-drug interactions (DDIs) between antiplatelets and antiretrovirals (ART) on bleeding, thrombosis, and other major adverse cardiovascular events (MACE) is unknown. The objective of this retrospective study was to assess the incidence of DDI at P2Y12 inhibitor (P2Y12inh) initiation and the effect of DDI on patient outcomes. Adult people living with human immunodeficiency virus (PLWH; HIV) receiving ART newly initiated on an oral P2Y12inh were included. The primary outcome was the incidence of DDI between ART and P2Y12inh at P2Y12inh initiation. Secondary outcomes included bleeding events, MACE, and switches in P2Y12inh. There were 149 PLWH included, of these, 119 (80%) were initiated on clopidogrel, 23 (15%) on ticagrelor, and 7 (5%) on prasugrel. 93 PLWH (60%) had a DDI at time of P2Y12inh initiation, with highest incidence in the clopidogrel group (n=84, 71%), followed by ticagrelor (n=9, 39%) and none with prasugrel. Within 1 year, MACE occurred in 12 PLWH, with DDI present at the time of 4 events. There were 29 bleeding events occurring within 1 year, including 17 events with DDI at time of event. However, 88% of DDI in patients with bleeding events were expected to decrease the efficacy of P2Y12inh. Though we observed high incidence of DDI between P2Y12inh and ART in PLWH, MACE and bleeding events at 1 year did not correlate with DDI. It remains unknown if DDI presence at P2Y12inh initiation with ART causes clinical outcomes of concern, or if underlying platelet reactivity in PLWH is associated with these events.