Two Hours of In Vivo Lung Perfusion Improves Lung Function in Sepsis-Induced Acute Respiratory Distress Syndrome.

Sepsis is the leading cause of acute respiratory distress syndrome (ARDS) in adults and carries a high mortality. Utilizing a previously validated porcine model of sepsis-induced ARDS, we sought to refine our novel therapeutic technique of in vivo lung perfusion (IVLP). We hypothesized that 2 hours of IVLP would provide non-inferior lung rehabilitation compared to 4 hours of treatment. Adult swine (n = 8) received lipopolysaccharide to develop ARDS and were placed on central venoarterial extracorporeal membrane oxygenation. Animals were randomized to 2 vs 4 hours of IVLP. The left pulmonary vessels were cannulated to IVLP using antegrade Steen solution. After IVLP treatment, the left lung was decannulated and reperfused for 4 hours. Total lung compliance and pulmonary venous gases from the right lung (control) and left lung (treatment) were sampled hourly. Biochemical analysis of tissue and bronchioalveolar lavage was performed along with tissue histologic assessment. Throughout IVLP and reperfusion, treated left lung PaO2/FiO2 ratio was significantly higher than the right lung control in the 2-hour group (332.2 ± 58.9 vs 264.4 ± 46.5, P = 0.01). In the 4-hour group, there was no difference between treatment and control lung PaO2/FiO2 ratio (258.5 ± 72.4 vs 253.2 ± 90.3, P = 0.58). Wet-to-dry weight ratios demonstrated reduced edema in the treated left lungs of the 2-hour group (6.23 ± 0.73 vs 7.28 ± 0.61, P = 0.03). Total lung compliance was also significantly improved in the 2-hour group. Two hours of IVLP demonstrated superior lung function in this preclinical model of sepsis-induced ARDS. Clinical translation of IVLP may shorten duration of mechanical support and improve outcomes.

Secondary Burn Progression Mitigated by an Adenosine 2A Receptor Agonist.

Current burn therapy is largely supportive with limited therapies to curb secondary burn progression. Adenosine 2A receptor (A2AR) agonists have anti-inflammatory effects with decreased inflammatory cell infiltrate and release of proinflammatory mediators. Using a porcine comb burn model, we examined whether A2AR agonists could mitigate burn progression. Eight full-thickness comb burns (four prongs with three spaces per comb) per pig were generated with the following specifications: temperature 115°C, 3-kg force, and 30-second application time. In a randomized fashion, animals (four per group) were then treated with A2AR agonist (ATL-1223, 3 ng/kg/min, intravenous infusion over 6 hours) or vehicle control. Necrotic interspace development was the primary outcome and additional histologic assessments were conducted. Analysis of unburned interspaces (72 per group) revealed that ATL-1223 treatment decreased the rate of necrotic interspace development over the first 4 days following injury (p < .05). Treatment significantly decreased dermal neutrophil infiltration at 48 hours following burn (14.63 ± 4.30 vs 29.71 ± 10.76 neutrophils/high-power field, p = .029). Additionally, ATL-1223 treatment was associated with fewer interspaces with evidence of microvascular thrombi through postburn day 4 (18.8% vs 56.3%, p = .002). Two weeks following insult, the depth of injury at distinct burn sites (adjacent to interspaces) was significantly reduced by ATL-1223 treatment (2.91 ± 0.47 vs 3.28 ± 0.58 mm, p = .038). This work demonstrates the ability of an A2AR agonist to mitigate burn progression through dampening local inflammatory processes. Extended dosing strategies may yield additional benefit and improve cosmetic outcome in those with severe injury.

Isolated Lung Perfusion in the Management of Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality, and current management has a dramatic impact on healthcare resource utilization. While our understanding of this disease has improved, the majority of treatment strategies remain supportive in nature and are associated with continued poor outcomes. There is a dramatic need for the development and breakthrough of new methods for the treatment of ARDS. Isolated machine lung perfusion is a promising surgical platform that has been associated with the rehabilitation of injured lungs and the induction of molecular and cellular changes in the lung, including upregulation of anti-inflammatory and regenerative pathways. Initially implemented in an ex vivo fashion to evaluate marginal donor lungs prior to transplantation, recent investigations of isolated lung perfusion have shifted in vivo and are focused on the management of ARDS. This review presents current tenants of ARDS management and isolated lung perfusion, with a focus on how ex vivo lung perfusion (EVLP) has paved the way for current investigations utilizing in vivo lung perfusion (IVLP) in the treatment of severe ARDS.

Hospital Variability Drives Inconsistency in Antiplatelet Use After Coronary Bypass.

BACKGROUND: Continuation of dual antiplatelet therapy (DAPT) after coronary artery bypass grafting (CABG) after acute myocardial infarction is recommended by current guidelines. We sought to evaluate guideline adherence over time and factors associated with postoperative DAPT within a regional consortium. METHODS: Isolated CABG patients from 2011 to 2017 who had a myocardial infarction within 21 days prior to surgery were included. Patients were stratified by DAPT prescription at discharge and by time period, early (2011-2014) vs late (2015-2017). Hierarchical regressions were then performed to evaluate factors influencing DAPT use after CABG. RESULTS: A total of 7314 patients were included with an overall rate of DAPT utilization of 31.2% that increased from 29.6% in the early to 33.4% in the late era (P < .01). There was considerable variability in hospital rates of DAPT (range 9.5%-92.1%) and hospital level changes over time (26% increased, 11% decreased, and 63% remained stable). After adjustment for clinical factors, era was not associated with DAPT use but treating hospital remained significantly associated with DAPT use. Other clinical factors associated with increased DAPT utilization included off-pump surgery (odds ratio [OR] 4.48, P < .01) and prior percutaneous coronary intervention (OR 2.02, P < .01), and atrial fibrillation (OR 0.39, P < .01) was associated with decreased utilization. CONCLUSIONS: Dual antiplatelet use has increased between 2011 and 2017, driven primarily by evolving patient demographics. Significant hospital-level variability drives inconsistency in DAPT utilization. Efforts to promote DAPT use for patients treated with CABG after myocardial infarction in concordance with current guidelines should be targeted at the hospital level.

Reduced-flow ex vivo lung perfusion to rehabilitate lungs donated after circulatory death.

BACKGROUND: Current ex vivo lung perfusion (EVLP) protocols aim to achieve perfusion flows of 40% of cardiac output or more. We hypothesized that a lower target flow rate during EVLP would improve graft function and decrease inflammation of donation after circulatory death (DCD) lungs. METHODS: A porcine DCD and EVLP model was utilized. Two groups (n = 4 per group) of DCD lungs were randomized to target EVLP flows of 40% (high-flow) or 20% (low-flow) predicted cardiac output based on 100 ml/min/kg. At the completion of 4 hours of normothermic EVLP using Steen solution, left lung transplantation was performed, and lungs were monitored during 4 hours of reperfusion. RESULTS: After transplant, left lung-specific pulmonary vein partial pressure of oxygen was significantly higher in the low-flow group at 3 and 4 hours of reperfusion (3-hour: 496.0 ± 87.7 mm Hg vs. 252.7 ± 166.0 mm Hg, p = 0.017; 4-hour: 429.7 ± 93.6 mm Hg vs. 231.5 ± 178 mm Hg, p = 0.048). Compliance was significantly improved at 1 hour of reperfusion (20.8 ± 9.4 ml/cm H2O vs. 10.2 ± 3.5 ml/cm H2O, p = 0.022) and throughout all subsequent time points in the low-flow group. After reperfusion, lung wet-to-dry weight ratio (7.1 ± 0.7 vs. 8.8 ± 1.1, p = 0.040) and interleukin-1ß expression (927 ± 300 pg/ng protein vs. 2,070 ± 874 pg/ng protein, p = 0.048) were significantly reduced in the low-flow group. CONCLUSIONS: EVLP of DCD lungs with low-flow targets of 20% predicted cardiac output improves lung function, reduces edema, and attenuates inflammation after transplant. Therefore, EVLP for lung rehabilitation should use reduced flow rates of 20% predicted cardiac output.

Comparison of right ventricle-pulmonary artery shunt position in the Single Ventricle Reconstruction trial.

OBJECTIVE: Placement of a right ventricle-pulmonary artery shunt to the left or right of the neoaorta may influence reinterventions, pulmonary artery development, and survival after the Norwood procedure because of differences in shunt and pulmonary artery geometry and blood flow. METHODS: We analyzed the Pediatric Heart Network Single Ventricle Reconstruction Trial public use dataset. Comparisons were made between patients who received a left- or right-sided right ventricle-pulmonary artery shunt during the Norwood procedure in both the overall (n = 274) and the propensity score-matched (67 pairs) patient cohorts. RESULTS: A left-sided shunt was placed in 168 patients (61%), and a right-sided shunt was placed in 106 patients (39%). At the 12-month follow-up, there were no differences in pulmonary artery measurements, hemodynamic measurements, or pulmonary artery reinterventions between shunt groups. However, the right-sided shunt was associated with fewer surgical shunt revisions in both the overall (8.3 vs 1.9 events per 100 infants, P = .05) and the propensity score-matched (17.9 vs 0 events per 100 infants, P < .001) patient cohorts. In the propensity score-matched cohort only, right-sided shunts were further associated with fewer serious adverse events (84 vs 46 events per 100 infants, P = .01) and improved transplantation-free survival at 3 years follow-up (61% [95% confidence interval, 48-72] vs 80% [95% confidence interval, 69-88], P = .04). CONCLUSIONS: In the Single Ventricle Reconstruction trial, right ventricle-pulmonary artery shunt placement to the right of the neoaorta was associated with fewer shunt revisions and may contribute to improved outcomes in select patients.