Ethical considerations in xenotransplantation of thoracic organs - a call for a debate on value based decisions.

Xenotransplant covers a broad ethical territory and there are several ethical questions that have arisen in parallel with the technological advances that have allowed the first porcine transplants to occur. This brief communication highlights ethical considerations regarding heart and lung xenotransplantation, with an emphasis on unresolved value-based concerns in the field. The aim of this text is therefore to encourage the readers to consider the vast potential of this emerging technique to do good, but also the risk of doing harm, and to participate in a discussion. The list of questions presented here is not exhaustive but hopefully represents some of the questions that appear to be most pressing as the field advances. The focus is on the value-based, or ethical questions, not the questions related to the practical medical procedures.

Should Antimicrobial Resistance Limit Access to an Organ Transplant?

Burkholderia cenocepacia (B cenocepacia) is a gram-negative bacteria associated with significant morbidity and mortality following lung transplantation. Most US transplant programs consider B cenocepacia colonization to be an absolute contraindication to transplantation. This article argues that, if clinicians have good clinical reasons to expect poor outcomes for patients with B cenocepacia, then offering transplantation anyway is an abrogation of clinicians' fiduciary duties. This article also discusses other fiduciary obligations transplant programs might have to patients with B cenocepacia, such as referring to another transplant center, considering novel treatment options, and investigating how the infection's virulence factors stratify that patient's risk for poor transplant outcomes.

Percutaneous Venopulmonary Extracorporeal Membrane Oxygenation as Bridge to Lung Transplantation.

Mechanical circulatory support (MCS) as a bridge to lung transplant is an infrequent but accepted pathway in patients who have refractory end-stage pulmonary failure. The American Association of Thoracic Surgeons Expert Consensus Guidelines, published in 2023, recommends venovenous (VV) extracorporeal membrane oxygenation (ECMO) as the initial configuration for those patients who have failed conventional medical therapy, including mechanical ventilation, while waiting for lung transplantation and needing MCS. Alternatively, venoarterial (VA) ECMO can be used in patients with acute right ventricular failure, hemodynamic instability, or refractory respiratory failure. With the advancement in percutaneous venopulmonary (VP) ECMO cannulation techniques, this option is becoming an attractive configuration as bridge to lung transplantation. This configuration enhances stability of the right ventricle, prevents recirculation with direct introduction of pulmonary artery oxygenation, and promotes hemodynamic stability during mobility, rehabilitation, and sedation-weaning trials before lung transplantation. Here, we present a case series of eight percutaneous VP ECMO as bridge to lung transplant with all patients mobilized, awake, and successfully transplanted with survival to hospital discharge.

The impact of high volumes of COVID-related lung transplant on waitlist mortality for non-COVID candidates in the United States.

Some patients with coronavirus disease 19 (COVID) develop serious, irreversible lung disease, including acute respiratory distress syndrome or pulmonary fibrosis. For select candidates, lung transplant is the only option to improve quality and length of life. Because of the severity of end-stage COVID-related lung disease, these candidates receive high allocation priority in the United States, including higher priority than many patients without COVID-related lung disease. This study assessed whether transplant centers with a large volume of COVID-related lung transplants experienced an increase in waitlist mortality for non-COVID transplant candidates. Nineteen centers were included as high-volume programs, defined as being in the top third of centers who transplanted COVID patients. Of the 2867 non-COVID patients waitlisted at these centers, there was no significant difference in waitlist mortalities of non-COVID transplant candidates between the pre-COVID transplant era (January 2018-February 2020) and during the period of high COVID transplant volume (March 2020-October 2022) (subhazard ratio: .92 [95% CI = .81-1.05], p = .22). Among high volume centers, the decision to transplant and to prioritize patients with COVID-related lung disease did not significantly impact the waitlist mortality of other candidates.

Lung transplant outcomes after acute respiratory distress syndrome requiring extracorporeal life support: Lessons from the COVID-19 pandemic.

OBJECTIVE: Lung transplant for acute respiratory distress syndrome in patients supported with extracorporeal membrane oxygenation was rare before 2020, but was rapidly adopted to rescue patients with COVID-19 with lung failure. This study aims to compare the outcomes of patients who underwent lung transplant for COVID-associated acute respiratory distress syndrome and non-COVID acute respiratory distress syndrome, and to assess the impact of type and duration of extracorporeal membrane oxygenation support on survival. METHODS: Using the United Network for Organ Sharing database, we identified 311 patients with acute respiratory distress syndrome who underwent lung transplant from 2007 to 2022 and performed a retrospective analysis of the patients who required extracorporeal membrane oxygenation preoperatively, stratified by COVID-associated acute respiratory distress syndrome and non-COVID acute respiratory distress syndrome listing diagnoses. The primary outcome was 1-year survival. Secondary outcomes included the effect of type and duration of extracorporeal membrane oxygenation on survival. RESULTS: During the study period, 236 patients with acute respiratory distress syndrome and preoperative extracorporeal membrane oxygenation underwent lung transplant; 181 patients had a listing diagnosis of COVID-associated acute respiratory distress syndrome (77%), and 55 patients had a listing diagnosis of non-COVID acute respiratory distress syndrome (23%). Patients with COVID-associated acute respiratory distress syndrome were older, were more likely to be female, had higher body mass index, and spent longer on the waitlist (all P < .02) than patients with non-COVID acute respiratory distress syndrome. The 2 groups had similar 1-year survival (85.8% vs 81.1%, P = .2) with no differences in postoperative complications. Patients with COVID-associated acute respiratory distress syndrome required longer times on extracorporeal membrane oxygenation pretransplant (P = .02), but duration of extracorporeal membrane oxygenation support was not a predictor of 1-year survival (P = .2). CONCLUSIONS: Despite prolonged periods of pretransplant extracorporeal membrane oxygenation support, selected patients with acute respiratory distress syndrome can undergo lung transplant safely with acceptable short-term outcomes. Appropriate selection criteria and long-term implications require further analysis.

The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Lung transplantation for COVID-2019 respiratory failure in the United States: Outcomes 1-year posttransplant and the impact of preoperative extracorporeal membrane oxygenation support.

OBJECTIVE: Patients with end-stage respiratory failure after severe coronavirus disease 2019 (COVID-19) infection may benefit from lung transplant; however, data on transplant outcomes and the impact of prolonged circulatory support before transplant in these patients are limited. METHODS: We assessed survival, postoperative complications, and the impact of pretransplant extracorporeal membrane oxygenation (ECMO) in patients undergoing lung transplant in the United States from August 2020 through March 2022 using records validated by United Network for Organ Sharing experts and extracted from the United Network for Organ Sharing database. RESULTS: In 305 patients with COVID-19-related respiratory failure and validated data, survival for up to 1-year posttransplant did not differ between 188 patients with COVID-19-related acute respiratory distress syndrome and 117 patients with post-COVID-19 pulmonary fibrosis (P = .8). Pretransplant ECMO support (median 66 days) was required in 191 patients (63%), and venovenous ECMO was used in 91.2% of patients. One-, 6-, and 12-month survival was not significantly different between patients requiring ECMO and patients without ECMO (95.8% vs 99.1%, 93.1% vs 96.4%, 84.8% vs 90.9%, P = .2) In addition, 1-year survival was similar in recipients requiring ECMO for COVID-19 lung failure and recipients requiring ECMO for non-COVID-19 restrictive lung failure (84.8% vs 78.0%, P = .1). CONCLUSIONS: These findings suggest that lung transplant in patients with COVID-19 respiratory failure yields acceptable 1-year outcomes. Despite an often more complex postoperative course, prolonged ECMO pretransplant in well-selected patients was associated with adequate clinical and functional status.

Reevaluating Rehabilitation Practice for Patients Who Were Critically Ill After COVID-19 Infection: An Administrative Case Report.

OBJECTIVE: The goal of this case report is to describe the process, challenges, and opportunities of implementing rehabilitation for individuals who were critically ill and required both mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) support following a coronavirus 2019 (COVID-19) infection in an academic medical center. METHODS: This administrative case report is set in a heart and vascular intensive care unit, a 35-bed critical care unit that provides services for patients with various complex cardiovascular surgical interventions, including transplantation. Patients were admitted to the heart and vascular intensive care unit with either COVID-19 acute respiratory distress syndrome or pulmonary fibrosis for consideration of bilateral orthotropic lung transplantation. The authors describe the process of establishing rehabilitation criteria for patients who, by previously established guidelines, would be considered too ill to engage in rehabilitation. RESULTS: The rehabilitation team, in coordination with an interprofessional team of critical care providers including physicians, respiratory care providers, perfusionists, and registered nurses, collaborated to implement a rehabilitation program for patients with critical COVID-19 being considered for bilateral orthotropic lung transplantation. This was accomplished by (1) reviewing previously published guidelines and practices; (2) developing an interdisciplinary framework for the consideration of rehabilitation treatment; and (3) implementing the framework for patients in our heart and vascular intensive care unit. CONCLUSION: In response to the growing volume of patients admitted with critical COVID-19, the team initiated and developed an interprofessional framework and successfully provided rehabilitation services to patients who were critically ill. While resource-intensive, the process demonstrates that rehabilitation can be implemented on a case-by-case basis for select patients receiving extracorporeal membrane oxygenation and MV, who would previously have been considered too critically ill for rehabilitation services. IMPACT: Rehabilitating patients with end-stage pulmonary disease on extracorporeal membrane oxygenation and MV support is challenging but feasible with appropriate interprofessional collaboration and knowledge sharing.

Magnetic Resonance Guided Focused Ultrasound Thalamotomy for Treatment of Severe Essential Tremor in a Lung Transplant Recipient-A Case Report.

Calcineurin inhibitor-related tremors occur in up to 50% of solid organ transplant recipients and are disabling in severe cases. We describe a bilateral lung transplant recipient with essential tremors that significantly worsened after tacrolimus initiation. She did not have improvement with the change to extended-release tacrolimus, the use of everolimus as a calcineurin inhibitor-sparing agent, or the addition of primidone, clonazepam, or propranolol. She underwent magnetic resonance-guided focused ultrasound thalamotomy with significant improvement in her tremor and activities of daily living.

Declining to Provide or Continue Requested Life-Sustaining Treatment: Experience With a Hospital Resolving Conflict Policy.

In 2015, the major critical care societies issued guidelines outlining a procedural approach to resolving intractable conflict between healthcare professionals and surrogates over life-sustaining treatments (LST). We report our experience with a resolving conflict procedure. This was a retrospective, single-centre cohort study of ethics consultations involving intractable conflict over LST. The resolving conflict process was initiated eleven times for ten patients over 2,015 ethics consultations from 2000 to 2020. In all cases, the ethics committee recommended withdrawal of the contested LST. In seven cases, the patient died or was transferred or a legal injunction was obtained before completion of the process. In the four cases in which LST was withdrawn, the time from ethics consultation to withdrawal of LST was 24.8 ± 12.2 days. Healthcare provider and surrogate were often distressed during the process, sometimes resulting in escalation of conflict and legal action. In some cases, however, surrogates appeared relieved that they did not have to make the final decision regarding LST. Challenges regarding implementation included the time needed for process completion and limited usefulness in emergent situations. Although it is feasible to implement a due process approach to conflict over LST, there are factors that limit the procedure's usefulness.

Infectious complications associated with bronchial anastomotic dehiscence in lung transplant recipients.

INTRODUCTION: Bronchial anastomotic dehiscence (AD) is an uncommon complication following lung transplantation that carries significant morbidity and mortality. The objective of this study was to characterize fungal and bacterial infections in ADs, including whether infections following AD were associated with progression to bronchial stenosis. METHODS: This was a single-center study of 615 lung transplant recipients between 6/1/2015 and 12/31/2021. Airway complications were defined according to ISHLT consensus guidelines. RESULTS: 22 of the 615 recipients (3.6%) developed an AD. Bronchial ischemia or necrosis was common prior to dehiscence (68.1%). Fourteen (63.6%) recipients had bacterial airway infections, most commonly with Gram-negative rods, prior to dehiscence. Thirteen (59.1%) recipients had an associated pleural infection, most commonly with Candida species (30.8%). Post-dehiscence Aspergillus species were isolated in 4 recipients, 3 of which were de novo infections. Eleven had bacterial infections prior to dehiscence resolution, most commonly with Pseudomonas aeruginosa. Eleven recipients developed airway stenosis requiring dilation and/or stenting. Development of secondary infection prior to AD resolution was not associated with progression to stenosis (OR = .41, 95% CI = .05-3.30, p = .41). CONCLUSIONS: Gram-negative bacterial infections are common before and after AD. Pleural infection should be suspected in most cases. Infections prior to healing were not associated with subsequent development of airway stenosis.

Rehabilitation Characteristics and Outcomes for Lung Transplantation for COVID-19: A Case Series.

OBJECTIVE: Severe coronavirus disease 2019 (COVID-19) can result in irreversible lung damage, with some individuals requiring lung transplantation. The purpose of this case series is to describe the initial experience with the rehabilitation and functional outcomes of 9 patients receiving a lung transplant for COVID-19. METHODS: Nine individuals, ranging in age from 37 to 68 years, received bilateral orthotopic lung transplantation (BOLT) for COVID-19 between December 2020 and July 2021. Rehabilitation was provided before and after the transplant, including in-hospital rehabilitation, postacute care inpatient rehabilitation, and outpatient rehabilitation. RESULTS: Progress with mobility was limited in the pretransplant phase despite rehabilitation efforts. Following transplantation, 2 individuals expired before resuming rehabilitation, and 2 others had complications that delayed their progress. The remaining 5 experienced clinically important improvements in mobility and walking capacities. CONCLUSION: Considerable rehabilitation resources are required to care for individuals both before and after BOLT for COVID-19. Rehabilitation can have a profound impact on both functional and clinical outcomes for this unique patient population. IMPACT: There is limited literature on the rehabilitation efforts and outcomes for patients who received BOLT for COVID-19. Occupational therapists and physical therapists play an important role during the pretransplant and posttransplant recovery process for this novel patient population. LAY SUMMARY: Patients with a bilateral orthotopic lung transplant due to COVID-19 require a unique rehabilitation process. They have significant difficulties with activities of daily living and functional mobility across the pretransplant and posttransplant continuum of care, but progressive gains in functional performance may be possible with a comprehensive multidisciplinary rehabilitation program.

Anti-fibrotic therapy and lung transplant outcomes in patients with idiopathic pulmonary fibrosis.

BACKGROUND: It is unclear whether continuing anti-fibrotic therapy until the time of lung transplant increases the risk of complications in patients with idiopathic pulmonary fibrosis. OBJECTIVES: To investigate whether the time between discontinuation of anti-fibrotic therapy and lung transplant in patients with idiopathic pulmonary fibrosis affects the risk of complications. METHODS: We assessed intra-operative and post-transplant complications among patients with idiopathic pulmonary fibrosis who underwent lung transplant and had been treated with nintedanib or pirfenidone continuously for ⩾ 90 days at listing. Patients were grouped according to whether they had a shorter (⩽ 5 medication half-lives) or longer (> 5 medication half-lives) time between discontinuation of anti-fibrotic medication and transplant. Five half-lives corresponded to 2 days for nintedanib and 1 day for pirfenidone. RESULTS: Among patients taking nintedanib (n = 107) or pirfenidone (n = 190), 211 (71.0%) had discontinued anti-fibrotic therapy ⩽ 5 medication half-lives before transplant. Anastomotic and sternal dehiscence occurred only in this group (anastomotic: 11 patients [5.2%], p = 0.031 vs patients with longer time between discontinuation of anti-fibrotic medication and transplant; sternal: 12 patients [5.7%], p = 0.024). No differences were observed in surgical wound dehiscence, length of hospital stay, or survival to discharge between groups with a shorter versus longer time between discontinuation of anti-fibrotic therapy and transplant. CONCLUSION: Anastomotic and sternal dehiscence only occurred in patients with idiopathic pulmonary fibrosis who discontinued anti-fibrotic therapy < 5 medication half-lives before transplant. The frequency of other intra-operative and post-transplant complications did not appear to differ depending on when anti-fibrotic therapy was discontinued. REGISTRATION: clinicaltrials.gov NCT04316780: https://clinicaltrials.gov/ct2/show/NCT04316780.

The Highly Sensitized Recipient: Pretransplant and Posttransplant Considerations.

Highly sensitized patients, who are often black and Hispanic women, are less likely to be listed for lung transplant and are at higher risk for prolonged waitlist time and waitlist death. In this review, the authors discuss strategies for improving access to transplant in this population, including risk stratification of crossing pretransplant donor-specific antibodies, based on antibody characteristics. The authors also review institutional protocols, such as perioperative desensitization, for tailoring transplant immunosuppression in the highly sensitized population. The authors conclude with suggestions for future research, including development of novel donor-specific antibody-directed therapeutics.

Mismatch identified in symptom burden profiles in lung transplantation.

BACKGROUND: There is considerable heterogeneity in symptom burden among lung transplant candidates that may not be explained by objective measures of illness severity. OBJECTIVES: This study aimed to characterize symptom burden, identify distinct profiles based on symptom burden and illness severity, and determine whether observed profiles are defined by differences in social determinates of health (SDOH). METHODS: This was a prospective study of adult lung transplant candidates. Symptoms were assessed within 3 months of transplant with the Memorial Symptom Assessment Scale (MSAS). MSAS subscale (physical and psychological) scores range 0-4 (higher=more symptom burden). The lung allocation score (LAS) (range 0-100) was our proxy measure of illness severity. The MSAS subscales and LAS were used as continuous indicators in a latent profile analysis to identify distinct symptom-illness severity profiles. Comparative statistics were used to identify SDOH differences among observed profiles. RESULTS: Among 93 candidates, 3 distinct symptom-illness severity profiles were identified: 71% had a mild profile in which mild symptoms (MSAS physical 0.49; MSAS psychological 0.57) paired with mild illness severity (LAS 38.59). Of the 29% mismatched participants, 9% had moderate symptoms (MSAS physical 0.88; MSAS psychological 1.47) but severe illness severity (LAS 88.02) and 20% had severe symptoms (MSAS physical 1.30; MSAS psychological 1.94) but mild illness severity (LAS 42.13). The two mismatch profiles were younger, more racially diverse, and had higher psychosocial risk scores. CONCLUSION: Symptom burden is heterogenous, does not always reflect objective measures of illness severity, and may be linked to SDOH.

Clinical Ethics Consultation During the First COVID-19 Pandemic Surge at an Academic Medical Center: A Mixed Methods Analysis.

While a significant literature has appeared discussing theoretical ethical concerns regarding COVID-19, particularly regarding resource prioritization, as well as a number of personal reflections on providing patient care during the early stages of the pandemic, systematic analysis of the actual ethical issues involving patient care during this time is limited. This single-center retrospective cohort mixed methods study of ethics consultations during the first surge of the COVID 19 pandemic in Massachusetts between March 15, 2020 through June 15, 2020 aim to fill this gap. Results indicate that there was no significant difference in the median number of monthly consultation cases during the first COVID-19 surge compared to the same period the year prior and that the characteristics of the ethics consults during the COVID-19 surge and same period the year prior were also similar. Through inductive analysis, we identified four themes related to ethics consults during the first COVID-19 surge including (1) prognostic difficulty for COVID-19 positive patients, (2) challenges related to visitor restrictions, (3) end of life scenarios, and (4) family members who were also positive for COVID-19. Cases were complex and often aligned with multiple themes. These patient case-related sources of ethical issues were managed against the backdrop of intense systemic ethical issues and a near lockdown of daily life. Healthcare ethics consultants can learn from this experience to enhance training to be ready for future disasters.