ISHLT Consensus Statement on adult and pediatric airway complications after lung transplantation: Definitions, grading system, and therapeutics.

Airway complications remain a major cause of morbidity and mortality after cardiothoracic transplantation. The reported incidence of airway ischemic complications varies widely, contributed to by the lack of a universally accepted grading system and standardized definitions. Furthermore, the majority of the existing classification systems fail to integrate the wide range of possible bronchial complications that may develop after lung transplant. Hence, a Working Group was created by the International Society for Heart and Lung Transplantation with the aim of elaborating a universal definition of adult and pediatric airway complications and grading system. One such area of focus is to understand the problem in the context of a more standardized consensus of classifying airway ischemia. This consensus definition will have major clinical, therapeutics, and research implications.

"Age" in lung transplantation: factors related to outcomes and other considerations.

The age of lung transplant recipients is steadily increasing. Older donors are more frequently considered. The risk factors associated with advanced age in lung transplantation warrant discussion to ensure optimal outcomes in this complex endeavor. This report provides a summary of the pertinent topics and available evidence.

Comprehensive genetic testing identifies targetable genomic alterations in most patients with non-small cell lung cancer, specifically adenocarcinoma, single institute investigation.

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular Intelligence, and Response Genetics Inc. For the entire adenocarcinoma cohort, 25% of patients were African Americans; 90% of KRAS mutations were detected in smokers, including current and former smokers; 46% of EGFR and 61% of ALK alterations were detected in never smokers. 99.4% of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor subtypes. However, mutations were not mutually exclusive. NGS in this study identified potentially targetable genetic alterations in the majority of patients tested, detected concurrent alterations and provided information on variants of unknown significance at this time but potentially targetable in the future.

Educational affairs at the International Society for Heart and Lung Transplantation: Perspective and governance of post-graduate learning dimensions.

The purpose of this contribution is to review the development and scope of postgraduate training and educational affairs of the International Society of Heart and Lung Transplantation.

Association of body mass index and outcomes after major lung resection.

OBJECTIVES: Obesity has been thought to predispose patients to excess morbidity after lung resection because of decreased diaphragm excursion, reduced lung volumes and relative immobility. We assessed the relationship of body mass index (BMI) to acute outcomes after major lung resection. METHODS: Information from our database of lung resections was evaluated for the period 1980-2011. Univariate analysis for adverse events (pulmonary, cardiovascular, other and overall) was used to select variables for inclusion in multivariate logistic regression analyses. Missing values were imputed. BMI was categorized as underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), obese (30-34.9) and very obese (≥ 35). RESULTS: Among 1369 patients, there were 703 males (51%) and the mean age was 62 ± 11 years. Complications included the following: pulmonary 12%, cardiovascular 15%, other 16%, mortality 5% and any 29%. The incidence of complications decreased during each decade of study (40, 30, 26, 20%; P < 0.0001) and the incidence of obese/very obese increased during the same intervals (11, 22, 30, 25%; P = 0.0007). Adjusting for age, performance status, coronary artery disease, smoking status, diffusing capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and operation year, being overweight/obese/very obese did not increase the risk of postoperative complications in any category. In fact, patients in this group showed a lower rate of cardiovascular complications than those with BMI ≤ 25 (odds ratio (OR): 0.72; 95% confidence interval (CI): 0.51-1.00; P = 0.048). However, being underweight was importantly associated with an increased risk of pulmonary complications (OR: 2.5; 95% CI: 1.3-4.9; P = 0.0087) and of operative mortality (OR: 2.96; 95% CI: 1.28-6.86; P = 0.011). CONCLUSION: Being overweight or obese does not increase the risk of complications after major lung resection. In contrast, patients who are underweight are at significantly increased risk of pulmonary complications and mortality. Knowledge of the relationship of BMI to perioperative risk for major lung resection is essential in proper risk stratification.

Clinical neurology in lung transplantation.

Lung transplantation is the only established therapeutic option for several end-stage respiratory diseases. Limited mostly by lack of suitable allografts, the results have measurably improved over the last decade. Numerous surgical and pharmaceutical improvements have had positive impact on outcomes. The potential for critical care issues and the need for interdisciplinary management remains paramount. Cardiac, renal, and metabolic complications are frequently encountered in the acute postoperative phase. Allograft rejection and infectious diseases as well as problems related to immunosuppressive regimen are seen later after lung transplantation. Neurologic manifestations with a range of etiologies are discussed here in this context.

Role of innate immunity in primary graft dysfunction after lung transplantation.

PURPOSE OF REVIEW: Primary graft dysfunction (PGD), a form of acute lung injury after lung transplantation, has a significant impact on clinical outcomes after lung transplantation. This potentially reversible graft impairment occurs after ischemia-reperfusion injury. This review describes the expanding body of literature evaluating the central role of innate immune activation, nonadaptive responses and dysregulation in the development of PGD after lung transplant. RECENT FINDINGS: The innate immune system, highlighted by Toll-like receptor pathways and neutrophil migration and influx, plays an important role in the initiation and propagation of ischemia-reperfusion injury. Recent plasma biomarker and gene association studies have identified several genes and proteins composing innate immune pathways to be associated with PGDs. Long pentraxin-3 and Toll-like receptors, as well as inflammasomes and Toll-interacting protein, are associated with the development of PGD after lung transplantation. SUMMARY: Innate immune pathways are involved in the development of PGD and may provide attractive targets for therapies. It may be possible to prevent or treat PGD, as well as to allow pre-transplant PGD risk stratification. To improve understanding of the mechanisms behind clinical risk factors for PGD will require further in-depth correlation of donor-specific and recipient-related triggers of nonadaptive immune responses.

Donation after cardiac death lung transplantation outcomes.

PURPOSE OF REVIEW: Lung transplantation is now a well established treatment option for several end-stage respiratory diseases. Survival after lung transplantation has significantly improved over the last decade. The primary limitation to increased utilization of lung transplantation remains donor scarcity. Suitable allografts have been procured from donors after determination of neurologic death and from donors after determination of cardiac death (DDCD or DCD). Historically, the first human lung transplantation performed, utilized an allograft procured after cardiovascular death, also referred to as nonheart-beating donor.The experience at University of Wisconsin in 1993 reintroduced DCD lung transplantation with the first successful clinical case. RECENT FINDINGS: A potential additional lung allograft source, DCD lung transplantation has been established with very acceptable outcomes observed by several centers. We provide the relevant background for the rationale of donor allograft expansion to include DCD lungs from controlled (Maastricht category III donors). SUMMARY: This review considers the available evidence for DCD lung transplantation and compares reported primary graft dysfunction rates and current survival data available.

Treatment of the brain-dead lung donor with aprotinin and nitric oxide.

BACKGROUND: It has been previously shown that donor treatment with aprotinin or inhaled nitric oxide reduces reperfusion injury after lung transplantation in animals. These studies used living donors with normal lungs. However, the main source of lungs for transplantation is brain-dead donors. Brain death causes systemic inflammatory response and lung injury, rendering the organ susceptible to reperfusion injury after transplantation. We hypothesized that treatment with aprotinin or inhaled nitric oxide after brain death would improve the donor inflammatory response and reduce lung reperfusion injury after transplantation. METHODS: Brain death was induced in 24 rats by intracranial balloon inflation. Subsequently, the animals received intravenous aprotinin (n = 8), inhaled nitric oxide (n = 7), or no treatment (n = 9) for 5 hours. The lungs were retrieved and reperfused for 2 hours using recipient rats. RESULTS: After brain death, oxygenation deteriorated earlier and significantly more in rats that received treatment, especially with nitric oxide. Treatment did not reduce the donor systemic inflammatory response as assessed by serum levels of proinflammatory cytokines. Oxygenation, airway pressure, pulmonary vascular resistance, lung water index and bronchoalveolar lavage cytokine levels were similar after reperfusion of grafts from all three groups of donors. CONCLUSIONS: Donor treatment with aprotinin or inhaled nitric oxide does not improve lungs that have been injured by brain death.

Inhibition of bleomycin-induced pulmonary fibrosis through pre-treatment with collagen type V.

BACKGROUND: Tolerance to collagen structures has been shown to inhibit the progression of autoimmune scleroderma and rheumatoid arthritis. More recently, tolerance induction to collagen type V (colV) in experimental models of lung transplantation was shown to ameliorate the complex pathology known as "chronic rejection." The link between colV autoimmunity and progressive graft dysfunction and subsequent development of bronchiolitis obliterans syndrome (BOS) has been established in human lung transplant recipients. We hypothesized that intravenous injection of colV inhibits development of lung fibrosis in a bleomycin-induced lung injury mouse model. METHODS: Experimental animals were injected intravenously with saline or colV 10 days before intratracheal instillation of bleomycin. Pulmonary inflammation was monitored and quantified for the presence of cells in the bronchoalveolar lavage (BAL) fluid by flow cytometry and histology of lung tissue. RESULTS: ColV-pre-treated animals showed a significant reduction in lung inflammation compared with non-treated animals, according to histology and morphometry. The number of inflammatory cells in the BAL fluid was significantly reduced and associated with a lower proportion of gammadelta T cells and CD4(+) T cells in the colV-pre-treated group. Matrix metalloproteinase-2 and -9 (MMP-2 and -9; also known as gelatinase A and gelatinase B, respectively) levels in the BAL fluid were significantly reduced in colV-pre-treated mice compared with the non-treated mice. In addition, intravenous injection of colV was associated with a significant reduction in the relative expression of interleukin (IL)-6, IL-17 and IL-22 in cells present in BAL fluid at 7 and 14 days after bleomycin instillation. CONCLUSIONS: Pre-treatment by intravenous injection of colV inhibits bleomycin-induced pulmonary fibrosis by inhibiting IL-6 and IL-17 production. Fibrosis treatment in this context therefore should target induction of colV tolerance and Th17 development.

Interventional bronchoscopy for benign tracheobronchial diseases under cardiopulmonary bypass support: case reports and literature review.

The use of cardiopulmonary bypass as an adjunct to airway surgery for non-malignant diseases in adults is not well established in the UK. We are reporting two cases which demonstrate the additional benefits of using cardiopulmonary bypass during difficult bronchoscopy and complex airway stenting. The first case presents an emergency indication for cardiopulmonary bypass in a life-threatening but benign condition. The second case presented, utilises cardiopulmonary bypass standby as adjunct to a potentially life threatening procedure. A review of the literature is also provided.

Early institution of extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation improves outcome.

BACKGROUND: Primary graft dysfunction (PGD) after lung transplantation (LTx) carries a significant mortality and clinical management is controversial. Extracorporeal membrane oxygenation (ECMO) has been used infrequently for recovery from acute lung injury (ALI) in this setting. We reviewed our experience with ECMO after primary LTx. METHODS: The present study is a retrospective analysis of all LTx patients between 1991 and 2004. Twenty-two patients sustained severe PGD with subsequent placement on ECMO. We analyzed indications and 30-day, 1-year and 3-year mortality. Complications and incidence of multiple-organ failure (MOF) were determined. Critical appraisal of the evidence available to date was performed. RESULTS: A total of 297 LTxs were performed during the study period, with 97.5%, 88.6% and 73.8% survival at 30 days, 1 year and 3 years, respectively. Twenty-two patients (7.9%) had severe allograft dysfunction leading to ECMO support. Twelve patients received single-lung (SLTx), 8 double-lung (BLTx), 1 single-lung/kidney (SLKTx) and 1 heart/lung (HLTx) transplantation. Thirty-day, 1-year and 3-year survival of LTx recipients with ECMO support post-operatively were 74.6%, 54% and 36%, respectively. MOF was the predominant cause of death (58.3%) in patients on ECMO support for PGD. CONCLUSIONS: Our data suggest that, in addition to prolonged ventilation and pharmacologic support, ECMO should be considered as a bridge to recovery from PGD in lung transplantation. Early institution of ECMO may lead to diminished mortality in the setting of ALI despite the high incidence of MOF. Late institution of ECMO was associated with 100% mortality in this investigation.

Is extreme obesity a risk factor for cardiac surgery? An analysis of patients with a BMI > or = 40.

BACKGROUND: The increasing prevalence of obesity is a public health concern and perceived as a potential risk factor in open heart surgery. We critically appraised the literature available regarding postoperative complications in obese patients. METHODS: A single-center retrospective evaluation of complication rates (1999-2004) in cardiac surgical patients categorized by body mass index (BMI) was conducted. The overall incidence of complications (CX), renal failure (RF), hemodialysis (HD), atrial fibrillation (AF), cardiac arrest (CA), infections (INF), stroke (CVA and TIA), prolonged ventilation (VENT), and pulmonary embolism (PE) were observed. Patients with normal BMI (20-30) served for comparison, obesity and extreme obesity (ExtOb) were defined as BMI 30-40 and > or =40, respectively. RESULTS: In our institutional review of 1920 patients, 1780 met the inclusion criteria with BMI<20 (n=53), 20-30 (n=1056), 30-40 (n=592), and > or =40 (n=79) based on National Health and Nutrition Examination Survey (NHANES) criteria. Significant increase in complications (STS database guideline definitions) were observed with a BMI> or =40, 58% versus 47% (p=0.04). Extremely obese patients (ExtOb) had increased length of stay (LOS) (11.4 days vs 9.6 days; p< or =0.01), rate of renal failure (14.3% vs 5%; p< or =0.01) and prolonged ventilation (39%; p=0.01) compared to non-obese patients. Extremely obese had no significant increase in hemodialysis (7.3% vs 3.2%; p=0.11) or stroke (5.2% vs 2.9%; p=0.29). Obese patients (Ob) had increased LOS (10 days vs 9.6 days; p=0.04) and prolonged ventilation (28.3% vs 23.5%; p=0.03). CONCLUSIONS: Cardiac surgery can be performed without significant increase in perioperative and 30-day mortality in obese and extremely obese patients. Overall complication rates and LOS in patients with BMI> or =40 is increased and demands attention. We provide evidence that rates of few specific complications increase with extreme obesity. For risk stratification in the setting of an obesity epidemic, we advocate an interdisciplinary approach in obese patients undergoing elective cardiac surgery.

The hemodynamic mechanisms of lung injury and systemic inflammatory response following brain death in the transplant donor.

Brain-dead donors are the major source of lungs for transplantation. Brain death is characterized by two hemodynamic phases. Initially, massive sympathetic discharge results in a hypertensive crisis. This is followed by neurogenic hypotension. Up-regulation of pro-inflammatory mediators occurs in all organs and lung injury develops; this can adversely affect graft function post-transplantation. The mechanisms of the systemic and lung inflammation are unknown. We hypothesized that the hemodynamic changes are responsible for these inflammatory phenomena. Brain death was induced by intra-cranial balloon inflation in rats. This resulted in hypertensive crisis, followed by hypotension. There was a significant increase in blood neutrophil CD11b/CD18 expression and pro-inflammatory cytokine levels in serum and bronchoalveolar lavage, compared with control animals. Rupture of the capillary-alveolar membrane was demonstrated by electron microscopy. Elimination of the hypertensive response by alpha-adrenergic antagonist pre-treatment prevented inflammatory lung injury, reduced the systemic inflammatory markers and preserved capillary-alveolar membrane integrity. Correction of the neurogenic hypotension with noradrenaline ameliorated the systemic inflammatory response and improved oxygenation. We conclude that the sympathetic discharge triggers systemic and lung inflammation, which can be further enhanced by neurogenic hypotension. Management of the brain-dead donor with early anti-inflammatory treatment and vasoconstrictors is warranted.