Analysis of Perioperative Factors Leading to Postoperative Pulmonary Complications, Graft Injury and Increased Postoperative Mortality in Lung Transplantation.

OBJECTIVES: Postoperative complications such as postoperative pulmonary complications (PPCs) and other organ complications are associated with increased morbidity and mortality after successful lung transplantation and have a detrimental effect on patient recovery. The aim of this study was to investigate perioperative risk factors for in-hospital mortality and postoperative complications with a focus on PPC and graft injury in patients undergoing lung transplantation DESIGN: Single-center retrospective cohort study of 173 patients undergoing lung transplantation SETTING: University Hospital, Medical Center Freiburg. MAIN RESULTS: In the stepwise multivariate regression analysis, donor age >60 years (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.27-2.81), intraoperative extracorporeal membrane oxygenation (OR, 2.4; 95% CI, 1.7-3.3), transfusion of >4 red blood cell concentrates (OR, 3.1; 95% CI, 1.82-5.1), mean pulmonary artery pressure of >30 mmHg at the end of surgery (OR, 3.5; 95% CI, 2-6.3), the occurrence of postoperative graft injury (OR, 4.1; 95% CI, 2.8-5.9), PPCs (OR, 2.1; 95% CI, 1.7-2.6), sepsis (OR, 4.5; 95% CI, 2.8-7.3), and Kidney disease Improving Outcome grading system stage 3 acute renal failure (OR, 4.3; 95% CI, 2.4-7.7) were associated with increased in hospital mortality, whereas patients with chronic obstructive pulmonary disease had a lower in-hospital mortality (OR, 1.6; 95% CI, 1.4-1.9). The frequency and number of PPCs correlated with postoperative mortality. CONCLUSIONS: Clinical management and risk stratification focusing on the underlying identified factors that could help to improve patient outcomes.

Criteria for continuous neuraxial analgesia associated with reduced mortality in patients undergoing thoracotomy.

INTRODUCTION: Both thoracic epidural analgesia and thoracic paravertebral analgesia are effective techniques to control pain and minimize the stress response following thoracic surgery. We hypothesized that continuous neuraxial techniques may be associated with a decrease in the incidence of postoperative mortality after thoracotomy. Additionally, we aimed to identify subgroup populations that may benefit more from neuraxial anesthesia. METHOD: 1620 patients who underwent open thoracotomy were included in this retrospective study from the German Thoracic Registry database at four university hospitals. All-cause inpatient mortality was determined for patients who had and did not have neuraxial anesthesia. Logistic regression was used to adjust for and explore various covariates. RESULTS: Continuous neuraxial analgesia was associated with a lower overall mortality in the postoperative period (2.9%, 23/796 vs 5.3%, 44/824, p=0.02) only after the univariate analysis but not the multivariable analysis (OR 0.49, 95 % CI 0.237 to 1.12, p=0.15). In patients with epidural or paravertebral catheters, mortality was significantly lower in the following subgroups: age >75 (5/113 vs 18/77, OR 0.1, 95% CI 0.02 to 0.67, p=0.02), American Society of Anesthesiologists Performance Score >III (11//97 vs 33/155, OR 0.32, 95% CI 0.11 to 0.89, p=0.03), chronic kidney disease (5/83 vs 16/77, OR 0.16, 95% CI 0.03 to 0.82, p=0.03), and postoperative sepsis (9/21 vs 17/25, OR 0.13, 95% CI 0.07 to 0.44, p<0.01). CONCLUSIONS: Neuraxial analgesic techniques are associated with reductions in postoperative mortality after open thoracic surgery in selected patients.

Increased Donor Organ Size and Age is Associated with Reduced Survival in Female Lung Transplant Recipients.

BACKGROUND: Organ selection in lung transplantation (LTx) is still controversial. We here analyze the impact of mismatches in size, age, and gender on early and long-term outcome after LTx. METHODS: Retrospective analysis of donor and recipient characteristics of patients who underwent double LTx between March 2003 and December 2021. Statistical analysis was performed using SPSS and GraphPad software. RESULTS: Two hundred three patients were included (94 women and 109 men). In the whole cohort, oversizing donor organs 10% to 20% compared to the recipients' predicted total lung capacity led to a decreased incidence of severe Primary Graft Dysfunction grades 2 and 3 (2/3; 15% vs 41%, P = .03), and further oversizing > 20% was associated with reduced long-term survival (hazard ratio, 2.33, P = .011). Analyzing donor and recipient age, we found that increased donor age correlated with reduced long-term survival (P = .013). In this cohort, female recipients received older organs (median 57 vs 46 years, P = .0003) and had a higher incidence of > 20% oversizing (13% vs 4%, P = .019) of donor lungs, which resulted in a significantly reduced long-term survival (P = .02) compared with male recipients. Median Lung Allocation Scores were similar in both groups. CONCLUSION: Mismatch of donor age and size can be important for organ function and survival in LTx recipients. Particularly female recipients seem to have a higher risk for unfavorable long-term outcome when transplanting organs of increased size and age. Multicenter studies are warranted to further address this question. TRIAL REGISTRATION NUMBER: (DKRS): 00033312.

Fast proliferating and slowly migrating non-small cell lung cancer cells are vulnerable to decitabine and retinoic acid combinatorial treatment.

Non-small cell lung cancer (NSCLC) patients are often elderly or unfit and thus cannot tolerate standard aggressive therapy regimes. In our study, we test the efficacy of the DNA-hypomethylating agent decitabine (DAC) in combination with all-trans retinoic acid (ATRA), which has been shown to possess little systemic adverse effects. Screening a broad panel of 56 NSCLC cell lines uncovered a decrease in cell viability after the combination treatment in 77% of the cell lines. Transcriptomics, proteomics, proliferation and migration profiling revealed that fast proliferating and slowly migrating cell lines were more sensitive to the drug combination. The comparison of mutational profiles found oncogenic KRAS mutations only in sensitive cells. Additionally, different cell lines showed a heterogeneous gene expression response to the treatment pointing to diverse mechanisms of action. Silencing KRAS, RIG-I or RARB partially reversed the sensitivity of KRAS-mutant NCI-H460 cells. To study resistance, we generated two NCI-H460 cell populations resistant to ATRA and DAC, which migrated faster and proliferated slower than the parental sensitive cells and showed signs of senescence. In summary, this comprehensive dataset uncovers a broad sensitivity of NSCLC cells to the combinatorial treatment with DAC and ATRA and indicates that migration and proliferation capacities correlate with and could thus serve as determinants for drug sensitivity in NSCLC.

Endoscopic Lung Volume Reduction Prior to Lung Transplantation Does Not Increase Postoperative Pulmonary Complications.

INTRODUCTION: Lung transplantation (LTx) remains the only therapeutic option for selected patients with end-stage lung disease. In comparison to surgical lung volume reduction, few data exist on the risks and benefits of pretransplant endoscopic lung volume reduction (eLVR). Here, we investigate the risk of postoperative pulmonary complications (PPCs) after LTx in patients with emphysematous lung disease bridged with eLVR until transplantation. METHODS: Eighty-two patients with emphysematous lung disease who underwent double-LTx (DLTx) were included and retrospectively evaluated. Statistical analysis was performed using SPSS and GraphPad Prism software. RESULTS: 28/82 patients underwent eLVR prior to DLTx. eLVR patients spent comparable time on the waitlist; however, they were older at the time of DLTx (median 60 vs. 58 years, p = 0.02). Both groups showed comparable 90-day (92%) and long-term survival (eLVR 1-/5-/10-year survival: 92/88/77%, vs. control: 89/77/67%, p = 0.5). The odds for PPCs were similar in patients with and without eLVR (OR 0.7; 95% CI: 0.3-1.7), as well as major perioperative surgical and cardiovascular complications. In the entire cohort, we found ≥1 PPC to be a risk factor for death within 90 days (OR 9.7, 95% CI: 1.3-110). Among the PPCs, pneumonia (HR 4.6 95% CI: 1.1-14.9, p = 0.02) and ARDS (HR 11.2 95% CI: 1.6-229.2, p = 0.04) were identified as independent risk factors for reduced long-term survival. CONCLUSIONS: eLVR does not increase the risk for PPCs, surgical complications, or reduced survival after LTx in patients with emphysematous lung disease and can serve as a bridge to LTx.

Risk Factors for Postoperative Pulmonary Complications Leading to Increased Morbidity and Mortality in Patients Undergoing Thoracic Surgery for Pleural Empyema.

OBJECTIVES: Surgery for pleural empyema carries a high burden of morbidity and mortality. The authors investigated the incidence of postoperative pulmonary complications (PPCs) and their effects on perioperative morbidity and mortality. Patient-specific, preoperative, procedural, and postoperative risk factors for PPCs were analyzed. DESIGN: Retrospective observational study. SETTING: A single, large university hospital. PARTICIPANTS: A total of 250 adult patients were included who underwent thoracic surgery for pleural empyema between January 2017 and December 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 250 patients with pleural empyema underwent thoracic surgery by video-assisted thoracoscopic surgery (49%; n = 122) or open thoracotomy (51%; n = 128). A proportion (42% [105]) of patients had ≥1 PPCs; 28% (n = 70) had to undergo resurgery; and 10% (n = 25) were re-admitted unexpectedly to the ICU. Preoperative respiratory failure (odds ratio [OR]: 5.8, 95% CI: 2.4-13.1), general anesthesia without regional analgesia techniques (OR: 2.9, 95% CI: 1.4-5.8), open thoracotomy and subsequent resurgery (OR: 3.9, 95% CI 1.5-9.9), surgery outside the regular working hours (OR: 3.1, 95% CI 1.2-8.2), and postoperative sepsis (OR: 2.6, 95% CI 1.1-6.8) were identified as independent risk factors for PPCs. Postoperative pulmonary complications were independent factors for unplanned intensive care unit admission (OR: 10.5, 95% CI 2.1-51 for >1 PPC), death within 360 days (OR: 4.5, 95% CI 2.2-12.3 for ≥2 PPCs), and death within 30 days for ≥1 PPCs (OR: 1.2, 95% CI 1.1-1.3). CONCLUSIONS: The incidence of PPCs is a significant risk factor for morbidity and mortality after surgery for pleural empyema. Targeting the risk factors identified in this study could improve patient outcomes.

Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis.

Cluster of differentiation 26 (CD26)/dipeptidyl peptidase 4 (DPP4) is an exopeptidase that is expressed as a transmembrane protein in many organs but also present in a circulating soluble form. Beyond its enzymatic and costimulatory activity, CD26/DPP4 is involved in the pathogenesis of chronic fibrotic diseases across many organ types, such as liver cirrhosis, kidney fibrosis and lung fibrosis. Organ fibrosis is associated with a high morbidity and mortality, and there are no causative therapies that can effectively attenuate the progress of the disease. Growing evidence suggests that inhibiting CD26/DPP4 can modulate the profibrotic tissue microenvironment and thus reduce fibrotic changes within affected organs. This review summarizes the role of CD26/DPP4 in fibroproliferative disorders and highlights new opportunities for an antifibrotic treatment by CD26/DPP4 inhibition. As a major advantage, CD26/DPP4 inhibitors have been in safe and routine clinical use in type 2 diabetes for many years and thus qualify for repurposing to repurpose as a promising therapeutic against fibrosis. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.

Independent risk factors for an increased incidence of thromboembolism after lung transplantation.

BACKGROUND: Thromboembolism (TE) after lung transplantation (LTX) is associated with increased morbidity and mortality. The aim of this study is to analyze the incidence and outcome of venous and arterial thromboembolic complications and to identify independent risk factors. PATIENTS AND METHODS: We retrospectively analyzed the medical records of 221 patients who underwent LTX at our institution between 2002 and 2021. Statistical analysis was performed using SPSS and GraphPad software. RESULTS: 74 LTX recipients (33%) developed TE. The 30-days incidence and 12-months incidence were 12% and 23%, respectively. Nearly half of the patients (48%) developed pulmonary embolism, 10% ischemic stroke. Arterial hypertension (p = 0.006), a body mass index (BMI) > 30 (p = 0.006) and diabetes mellitus (p = 0.041) were independent predictors for TE. Moreover, a BMI of > 25 at the time of transplantation was associated with an increased risk for TE (43% vs. 32%, p = 0.035). At the time of LTX, 65% of the patients were older than 55 years. An age > 55 years also correlated with the incidence of TE (p = 0.037) and these patients had reduced overall post-transplant survival when the event occurred within the first postoperative year (59% vs. 72%, p = 0.028). CONCLUSIONS: The incidence of TE after LTX is high, especially in lung transplant recipients with a BMI > 25 and an age > 55 years as well as cardiovascular risk factors closely associated with the metabolic syndrome. As these patients comprise a growing recipient fraction, intensified research should focus on the risks and benefits of regular screening or a prolonged TE prophylaxis in these patients. Trial registration number DKRS: 00021501.

The Impact of Postoperative Pulmonary Complications on Perioperative Outcomes in Patients Undergoing Pneumonectomy: A Multicenter Retrospective Cohort Study of the German Thorax Registry.

Postoperative pulmonary complications have a deleterious impact in regards to thoracic surgery. Pneumonectomy is associated with the highest perioperative risk in elective thoracic surgery. The data from 152 patients undergoing pneumonectomy in this multicenter retrospective study were extracted from the German Thorax Registry database and presented after univariate and multivariate statistical processing. This retrospective study investigated the incidence of postoperative pulmonary complications (PPCs) and their impact on perioperative morbidity and mortality. Patient-specific, preoperative, procedural, and postoperative risk factors for PPCs and in-hospital mortality were analyzed. A total of 32 (21%) patients exhibited one or more PPCs, and 11 (7%) died during the hospital stay. Multivariate stepwise logistic regression identified a preoperative FEV1 < 50% (OR 9.1, 95% CI 1.9-67), the presence of medical complications (OR 7.4, 95% CI 2.7-16.2), and an ICU stay of more than 2 days (OR 14, 95% CI 3.9-59) as independent factors associated with PPCs. PPCs (OR 13, 95% CI 3.2-52), a preoperative FEV1 < 60% in patients with previous pulmonary infection (OR 21, 95% CI 3.2-52), and continued postoperative mechanical ventilation (OR 8.4, 95% CI 2-34) were independent factors for in-hospital mortality. Our data emphasizes that PPCs are a significant risk factor for morbidity and mortality after pneumonectomy. Intensified perioperative care targeting the underlying risk factors and effects of PPCs, postoperative ventilation, and preoperative respiratory infections, especially in patients with reduced pulmonary reserve, could improve patient outcomes.