Donation after cardiac death for lung transplantation: a review of current clinical practice.

PURPOSE OF REVIEW: This review presents a concise update on clinical donation after cardiac death (DCD or DDCD) lung transplantation. Lung allografts have predominantly been procured from donors after determination of neurologic death but will not meet the existing demand. A steadily increasing need for lungs is evident worldwide, especially in an era of improved outcomes for recipients. Other solid organ utilization from donors after determination of cardiac death has markedly increased internationally, but the utilization rate of lungs from such donors is still considerably less. The multifaceted reasons for this discrepancy are considered, and the recent evidence available supporting DCD for lung transplantation in clinical practice is presented in context. The recent experimental research studies are not within the remit of this appraisal. RECENT FINDINGS: The more recent and markedly increased lung recipient cohorts showed very satisfactory survival outcomes for DCD transplantation in several programs. The overall utilization rate, however, remains low. The background and the rationale of lung donor allograft expansion to proactively include DCD allografts from controlled (Maastricht category III donors) is re-emphasized in this review. The feasibility of other DCD categories for lung transplantation is considered. This is particularly prudent with the advent of the ex-vivo lung perfusion modality in pulmonary procurement. SUMMARY: Despite evidence for adequate survival outcomes and reported favorable primary graft dysfunction rates, DCD lung transplantation remains underutilized in most countries. Waiting times could be notably reduced and mortality of lung candidates arguably decreased by a more decided and appropriate implementation of proven DCD lung transplant strategies.

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.

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.

Patient factors associated with lung transplant referral and waitlist for patients with cystic fibrosis and pulmonary fibrosis.

BACKGROUND: Since 2005, the Lung Allocation Score (LAS) has prioritized patient benefit and post-transplant survival, reducing waitlist to transplant time to <200 days and decreasing mortality on the waitlist. A current challenge is the wait for the waitlist-the time between the patient's transplant-eligible diagnosis and waitlist registration. METHODS: We investigated whether sociodemographic (age, sex, race, insurance, marital status, median household income) and clinical (forced expiratory volume in 1 second [FEV1] percent of predicted, body mass index, depression/anxiety, alcohol/substance misuse, absolute/relative contraindications) factors influenced referral and waitlist registration. We conducted a retrospective cohort study through chart review of hospitalized patients on the University of Chicago general medicine service from 2006 to 2014 who met transplant-eligible criteria and ICD-9 billing codes for cystic fibrosis (CF) and pulmonary fibrosis (PF). We analyzed the times from transplant eligibility to referral, work-up and waitlisting using Kaplan-Meier curves and log-rank tests. RESULTS: Overall, the referral rate for transplant-eligible patients was 64%. Of those referred, approximately 36% reach the lung transplant waitlist. Referred CF patients were significantly more likely to reach the transplant waitlist than PF patients (CF 60% vs PF 22%, p < 0.05). In addition, CF patients had a shorter wait from transplant eligibility to waitlist than PF patients (329 vs 2,369 days, respectively [25th percentile], p < 0.05). Patients with PF and CF both faced delays from eligibility to referral and waitlist. CONCLUSIONS: Quality improvement efforts are needed to better identify and refer appropriate patients for lung transplant evaluation. Targeted interventions may facilitate more efficient evaluation completion and waitlist appearance.

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.

"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.

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.

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.

Cellular basis of tissue regeneration by omentum.

The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphoid organs called milky spots. The omentum has been used for its healing potential for over 100 years by transposing the omental pedicle to injured organs (omental transposition), but the mechanism by which omentum helps the healing process of damaged tissues is not well understood. Omental transposition promotes expansion of pancreatic islets, hepatocytes, embryonic kidney, and neurons. Omental cells (OCs) can be activated by foreign bodies in vivo. Once activated, they become a rich source for growth factors and express pluripotent stem cell markers. Moreover, OCs become engrafted in injured tissues suggesting that they might function as stem cells.Omentum consists of a variety of phenotypically and functionally distinctive cells. To understand the mechanism of tissue repair support by the omentum in more detail, we analyzed the cell subsets derived from the omentum on immune and inflammatory responses. Our data demonstrate that the omentum contains at least two groups of cells that support tissue repair, immunomodulatory myeloid derived suppressor cells and omnipotent stem cells that are indistinguishable from mesenchymal stem cells. Based on these data, we propose that the omentum is a designated organ for tissue repair and healing in response to foreign invasion and tissue damage.

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.

Transfer of tolerance to collagen type V suppresses T-helper-cell-17 lymphocyte-mediated acute lung transplant rejection.

BACKGROUND: Rat lung allograft rejection is mediated by collagen type V (col(V)) specific T-helper-cell 17 (Th17) cells. Adoptive transfer of these cells is sufficient to induce rejection pathology in isografts, whereas tolerance to col(V) suppresses allograft rejection. Therefore, we tested whether regulatory T cells from tolerant rats could suppress the Th17-mediated rejection in the syngeneic model of lung transplantation. METHODS: Rats were subjected to syngeneic left lung transplantation, and acute rejection was induced by adoptive transfer of lymph node cells from col(V)-immunized rats. Tolerance was induced by intravenous injection of col(V), and spleen lymphocytes were used for adoptive transfer. CD4+ T cells were depleted using magnetic beads. Lung isografts were analyzed using micro-positron emission tomography imaging and histochemistry. The transvivo delayed type hypersensitivity assay was used to analyze the Th17 response. RESULTS: Adoptive cotransfer of col(V)-specific effector cells with cells from col(V)-tolerized rats suppressed severe vasculitis and bronchiolitis with parenchymal inflammation, and the expression of interleukin (IL)-17 transcripts in mediastinal lymph nodes induced by effector cells alone. Analysis by transvivo delayed type hypersensitivity showed that the reactivity to col(V) was dependent on the presence of tumor necrosis factor-alpha and IL-17 but not interferon-gamma. Depletion of CD4+ T cells from the suppressor cell population abrogated the col(V)-specific protection. CONCLUSION: Th17-mediated acute rejection after lung transplantation is ameliorated by CD4+ col(V)-specific regulatory T cells. The mechanism for this Th17 suppression is consistent with tolerance induction to col(V). The goal of transplantation treatment, therefore, should target Th17 development and not suppression of T-cell activation by suppressing IL-2.

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.

Combined heart-kidney transplantation: the University of Wisconsin experience.

BACKGROUND: Combined heart-kidney transplantation (HKTx) is increasing in frequency, but long-term outcomes are unknown and appropriately comparative analysis is lacking. METHODS: This study was a retrospective review of prospectively collected data for 19 HKTx patients. Patient and graft survival, graft rejection and coronary allograft vasculopathy (CAV) were compared for HKTx vs recipients of a heart (n = 515) or kidney alone (n = 3,188) or both organs at separate time-points (n = 8). RESULTS: Patient and graft survival did not differ for HKTx vs any group. HKTx time to first rejection episode was significantly prolonged for both organs vs single-organ recipients. The incidence of CAV was significantly lower for HKTx. CONCLUSIONS: HKTx provides outcomes similar to those for solitary heart or kidney transplantation. There may be an immunologic advantage to receiving organs in a combined fashion. Such allocation of organs seems medically appropriate; however, more refined strategies are needed to identify optimal recipient populations.

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.