Postoperative vasoplegia in lung transplantation: incidence and relation to outcome in a single-centre retrospective study.

BACKGROUND: The incidence and clinical importance of vasoplegia after lung transplantation remains poorly studied. We describe the incidence of vasoplegia and its association with complications after lung transplantation. METHODS: Perioperative data of 279 lung transplant recipients operated on from 2015 to 2020 in a UK hospital were analysed retrospectively. RESULTS: Vasoplegia occurred in 41.6% of patients after lung transplantation (mild, 31.0%; moderate, 55.2%; severe, 13.8%). Compared with non-vasoplegic patients, vasoplegic patients had a higher incidence of any acute kidney injury, defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria (78.5% vs 65%, P=0.015), renal replacement therapy (47.4% vs 24.5%, P<0.001), and delayed chest closure (18.4% vs 9.2%, P=0.025); were ventilated longer (70 [32-368] vs 34 [19-105] h, P<0.001); and stayed longer in the ICU (12.9 [5-30] vs 6.8 [3-20] days, P<0.001). Mortality at 30 days and 1 yr was higher in patients with vasoplegia (11.2% vs 5.5% and 20.7% vs 11.7%, P=0.039, respectively). Severe vasoplegia represented a predictor of longer-term mortality (hazard ratio=1.65, P=0.008). Underlying infectious disease, increased BMI, higher preoperative pulmonary artery systolic pressure and bilirubin levels, lower glomerular filtration rate, and increased fresh frozen plasma transfusion were predictors of vasoplegia severity. Neutrophilia, leucocytosis, and increased C-reactive protein were associated with vasoplegia, but release of the neutrophil activation markers myeloperoxidase and heparin-binding protein was similar between groups. CONCLUSIONS: Influenced by preoperative status as well as procedural factors and inflammatory response, vasoplegia is a common and critical condition after lung transplantation with worse short-term outcomes and long-term survival.

Antifungal stewardship in solid-organ transplantation: What is needed?

BACKGROUND: Antifungal stewardship (AFS) lags behind antimicrobial stewardship (AMS) in terms of implementation, evidence base, and workforce experience. Solid-organ transplantation (SOT) carries a significant risk of invasive fungal infection, with high associated mortality, and is therefore associated with significant opportunities to optimize antifungal use. METHODS: A literature search for the terms "antifungal stewardship" and "solid-organ transplant" revealed a small evidence base to support AFS programs in this patient group. RESULTS: There is significant overlap in the methodology used in AMS and AFS programs, with notable differences in diagnostics, which are discussed in detail. The primary AFS interventions tested in SOT recipients are implementation of clinical guidelines and care bundles, digital enablers of AFS, and post-prescription review/audit and feedback. CONCLUSION: There is an urgent need for further research to support effective AFS strategies in this highly susceptible population.

Hemithioindigo-Based Visible Light-Activated Molecular Machines Kill Bacteria by Oxidative Damage.

Antibiotic resistance is a growing health threat. There is an urgent and critical need to develop new antimicrobial modalities and therapies. Here, a set of hemithioindigo (HTI)-based molecular machines capable of specifically killing Gram-positive bacteria within minutes of activation with visible light (455 nm at 65 mW cm-2 ) that are safe for mammalian cells is described. Importantly, repeated exposure of bacteria to HTI does not result in detectable development of resistance. Visible light-activated HTI kill both exponentially growing bacterial cells and antibiotic-tolerant persister cells of various Gram-positive strains, including methicillin-resistant S. aureus (MRSA). Visible light-activated HTI also eliminate biofilms of S. aureus and B. subtilis in as little as 1 h after light activation. Quantification of reactive oxygen species (ROS) formation and protein carbonyls, as well as assays with various ROS scavengers, identifies oxidative damage as the underlying mechanism for the antibacterial activity of HTI. In addition to their direct antibacterial properties, HTI synergize with conventional antibiotics in vitro and in vivo, reducing the bacterial load and mortality associated with MRSA infection in an invertebrate burn wound model. To the best of the authors' knowledge, this is the first report on the antimicrobial activity of HTI-based molecular machines.

Light-activated molecular machines are fast-acting broad-spectrum antibacterials that target the membrane.

The increasing occurrence of antibiotic-resistant bacteria and the dwindling antibiotic research and development pipeline have created a pressing global health crisis. Here, we report the discovery of a distinctive antibacterial therapy that uses visible (405 nanometers) light-activated synthetic molecular machines (MMs) to kill Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, in minutes, vastly outpacing conventional antibiotics. MMs also rapidly eliminate persister cells and established bacterial biofilms. The antibacterial mode of action of MMs involves physical disruption of the membrane. In addition, by permeabilizing the membrane, MMs at sublethal doses potentiate the action of conventional antibiotics. Repeated exposure to antibacterial MMs is not accompanied by resistance development. Finally, therapeutic doses of MMs mitigate mortality associated with bacterial infection in an in vivo model of burn wound infection. Visible light-activated MMs represent an unconventional antibacterial mode of action by mechanical disruption at the molecular scale, not existent in nature and to which resistance development is unlikely.

Volatile organic compound profiling to explore primary graft dysfunction after lung transplantation.

Primary graft dysfunction (PGD) is a major determinant of morbidity and mortality following lung transplantation. Delineating basic mechanisms and molecular signatures of PGD remain a fundamental challenge. This pilot study examines if the pulmonary volatile organic compound (VOC) spectrum relate to PGD and postoperative outcomes. The VOC profiles of 58 bronchoalveolar lavage fluid (BALF) and blind bronchial aspirate samples from 35 transplant patients were extracted using solid-phase-microextraction and analyzed with comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry. The support vector machine algorithm was used to identify VOCs that could differentiate patients with severe from lower grade PGD. Using 20 statistically significant VOCs from the sample headspace collected immediately after transplantation (< 6 h), severe PGD was differentiable from low PGD with an AUROC of 0.90 and an accuracy of 0.83 on test set samples. The model was somewhat effective for later time points with an AUROC of 0.80. Three major chemical classes in the model were dominated by alkylated hydrocarbons, linear hydrocarbons, and aldehydes in severe PGD samples. These VOCs may have important clinical and mechanistic implications, therefore large-scale study and potential translation to breath analysis is recommended.

Lung transplantation for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis. Lung transplantation is the only intervention shown to increase life expectancy for patients with IPF, but it is associated with disease-specific challenges. In this Review, we discuss the importance of a proactive approach to the management of IPF comorbidities, including gastro-oesophageal reflux, pulmonary hypertension, coronary artery disease, and malignancy. With a donor pool too small to meet demand and unacceptably high mortality on transplant waiting lists, we discuss different systems used internationally to facilitate organ allocation. We explore the rapidly evolving landscape of transplantation for patients with IPF with regards to antifibrotic therapy, technological advances in extracorporeal life support, advances in understanding of the genetics of the disease, and the importance of a holistic multidisciplinary approach to care. Finally, we consider potential advances over the next decade that are envisaged to improve transplantation outcomes in patients with advanced IPF.

Mechanical ventilation after lung transplantation.

INTRODUCTION: To explore the hypothesis that early ventilation strategies influence clinical outcomes in lung transplantation, we have examined our routine ventilation practices in terms of tidal volumes (Vt) and inflation pressures. METHODS: A total of 124 bilateral lung transplants between 2010 and 2013 were retrospectively assigned to low (<6 mL/kg), medium (6-8 mL/kg), and high (>8 mL/kg) Vt groups based on ventilation characteristics during the first 6 hours after surgery. Those same 124 patients were also stratified to low-pressure (<25 cm H2O) and high-pressure (≥25 cm H2O) groups. RESULTS: Eighty percent of patients were ventilated using pressure control mode. Low, medium, and high Vt were applied to 10%, 43%, and 47% of patients, respectively. After correcting for patients requiring extracorporeal support, there was no difference in short-term to midterm outcomes among the different Vt groups. Low inflation pressures were applied to 61% of patients, who had a shorter length of intensive care unit stay (5 vs 12 days; P = .012), higher forced expiratory volume in 1 second at 3 months (77.8% vs 60.3%; P < .001), and increased 6-month survival rate (95% vs 77%; P = .008). CONCLUSION: Low Vt ventilation has not been fully adopted in our practice. Ventilation with higher inflation pressures, but not Vt, was significantly associated with poorer outcomes after lung transplantation.