Rosalba Romano

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.

Inhaled nitric oxide in cardiac surgery: Evidence or tradition?

Inhaled nitric oxide (iNO) therapy as a selective pulmonary vasodilator in cardiac surgery has been one of the most significant pharmacological advances in managing pulmonary hemodynamics and life threatening right ventricular dysfunction and failure. However, this remarkable story has experienced a roller-coaster ride with high hopes and nearly universal demonstration of physiological benefits but disappointing translation of these benefits to harder clinical outcomes. Most of our understanding on the iNO field in cardiac surgery stems from small observational or single centre randomised trials and even the very few multicentre trials fail to ascertain strong evidence base. As a consequence, there are only weak clinical practice guidelines on the field and only European expert opinion for the use of iNO in routine and more specialised cardiac surgery such as heart and lung transplantation and left ventricular assist device (LVAD) insertion. In this review the authors from a specialised cardiac centre in the UK with a very high volume of iNO usage provide detailed information on the early observations leading to the European expert recommendations and reflect on the nature and background of these recommendations. We also provide a summary of the progress in each of the cardiac subspecialties for the last decade and initial survey data on the views of senior anaesthetic and intensive care colleagues on these recommendations. We conclude that the combination of high price tag associated with iNO therapy and lack of substantial clinical evidence is not sustainable on the current field and we are risking loosing this promising therapy from our daily practice. Overcoming the status quo will not be easy as there is not much room for controlled trials in heart transplantation or in the current atmosphere of LVAD implantation. However, we call for international cooperation to conduct definite studies to determine the place of iNO therapy in lung transplantation and high risk mitral surgery. This will require new collaboration between the pharmaceutical companies, national grant agencies and the clinical community. Until these trials are realized we should gather multi-institutional experience from large retrospective studies and prospective data from a new international registry. We must step up international efforts if we wish to maintain the iNO modality in the armamentarium of hemodynamic tools for the perioperative management of our high risk cardiac surgical patients.

Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury

Rationale Primary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown. Objective To define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction. Methods Isolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function. Results In mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours. Conclusions These results indicate that lung-marginated intravascular monocytes are retained as a ‘passenger’ leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.

The role of interleukin-1β as a predictive biomarker and potential therapeutic target during clinical ex-vivo lung perfusion

Background Extended criteria donor lungs deemed unsuitable for immediate transplantation can be reconditioned using ex vivo lung perfusion (EVLP). Objective identification of which donor lungs can be successfully reconditioned and will function well post-operatively has not been established. This study assessed the predictive value of markers of inflammation and tissue injury in donor lungs undergoing EVLP as part of the DEVELOP-UK study. Methods Longitudinal samples of perfusate, bronchoalveolar lavage, and tissue from 42 human donor lungs undergoing clinical EVLP assessments were analyzed for markers of inflammation and tissue injury. Levels were compared according to EVLP success and post-transplant outcomes. Neutrophil adhesion to human pulmonary microvascular endothelial cells (HPMECs) conditioned with perfusates from EVLP assessments was investigated on a microfluidic platform. Results The most effective markers to differentiate between in-hospital survival and non-survival post-transplant were perfusate interleukin (IL)-1β (area under the curve = 1.00, p = 0.002) and tumor necrosis factor-α (area under the curve = 0.95, p = 0.006) after 30 minutes of EVLP. IL-1β levels in perfusate correlated with upregulation of intracellular adhesion molecule-1 in donor lung vasculature (R2 = 0.68, p < 0.001) and to a lesser degree upregulation of intracellular adhesion molecule-1 (R2 = 0.30, p = 0.001) and E-selectin (R2 = 0.29, p = 0.001) in conditioned HPMECs and neutrophil adhesion to conditioned HPMECs (R2 = 0.33, p < 0.001). Neutralization of IL-1β in perfusate effectively inhibited neutrophil adhesion to conditioned HPMECs (91% reduction, p = 0.002). Conclusions Donor lungs develop a detectable and discriminatory pro-inflammatory signature in perfusate during EVLP. Blocking the IL-1β pathway during EVLP may reduce endothelial activation and subsequent neutrophil adhesion on reperfusion; this requires further investigation in vivo.

Outcomes of minimally invasive lung transplantation in a single centre: the routine approach for the future or do we still need clamshell incision?

OBJECTIVES Minimally invasive lung transplantation (MILT) via bilateral anterior thoracotomies has emerged as a novel surgical strategy with potential patient benefits when compared with transverse thoracosternotomy (clamshell incision, CS). The aim of this study is to compare MILT with CS by focusing on operative characteristics, postoperative organ function and support and mid-term clinical outcomes at Harefield Hospital. METHODS It was a retrospective observational study evaluating all bilateral sequential lung transplants between April 2010 and November 2013. RESULTS CS was performed in 124 patients and MILT in 70 patients. Skin-to-skin surgical time was less in the MILT group [285 (265, 339) min] compared with CS [380 (306, 565) min] and MILT-cardiopulmonary bypass [426 (360, 478) min]. Ischaemic time was significantly longer (502 ± 116 vs 395 ± 145 min) in the MILT group compared with CS (P < 0.01). Early postoperative physiological variables were similar between groups. Patients in the MILT group required less blood [2 (0, 4) vs 3 (1, 5) units, P = 0.16] and platelet transfusion [0 (0, 1) vs 1 (0, 2) units, P < 0.01]. The median duration of mechanical ventilation was shorter (26 vs 44 h, P < 0.01) and intensive therapy unit stay was 2 days shorter (5 vs 7) in the MILT group. While overall survival was similar, fraction of expired volume in 1 s (FEV1) and forced vital capacity (FVC) were consistently higher in the MILT group compared with CS during mid-term follow-up after transplantation. Specifically, FEV1 and FVC were, respectively, 86 ± 21 and 88 ± 18% predicted in the MILT group compared with 74 ± 21 and 74 ± 19% predicted in the CS group (P < 0.01) at the 6-month follow-up. CONCLUSIONS MILT was successfully introduced at our centre as a novel operative strategy. Despite longer ischaemic times and a more complex operation and management, MILT appears to offer early postoperative and mid-term clinical benefits compared with our traditional approach of clamshell operations. These observations warrant larger definite studies to further evaluate the impact of MILT on physiological, clinical and patient-reported outcomes.