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).

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.

The Year in Cardiothoracic Transplant Anesthesia: Selected Highlights From 2020 Part I - Lung Transplantation.

This special article focuses on the highlights in cardiothoracic transplantation literature in the year 2020. Part I encompasses the recent literature on lung transplantation, including the advances in preoperative assessment and optimization, donor management, including the use of ex-vivo lung perfusion, recipient management, including those who have been infected with coronavirus disease 2019, updates on the perioperative management, including the use of extracorporeal membrane oxygenation, and long-term outcomes.

Experience with a Revised Hospital Policy on Not Offering Cardiopulmonary Resuscitation.

Critical care society guidelines recommend that ethics committees mediate intractable conflict over potentially inappropriate treatment, including Do Not Resuscitate (DNR) status. There are, however, limited data on cases and circumstances in which ethics consultants recommend not offering cardiopulmonary resuscitation (CPR) despite patient or surrogate requests and whether physicians follow these recommendations. This was a retrospective cohort of all adult patients at a large academic medical center for whom an ethics consult was requested for disagreement over DNR status. Patient demographic predictors of ethics consult outcomes were analyzed. In 42 of the 116 cases (36.2%), the patient or surrogate agreed to the clinician recommended DNR order following ethics consultation. In 72 of 74 (97.3%) of the remaining cases, ethics consultants recommended not offering CPR. Physicians went on to write a DNR order without patient/surrogate consent in 57 (79.2%) of those cases. There were no significant differences in age, race/ethnicity, country of origin, or functional status between patients where a DNR order was and was not placed without consent. Physicians were more likely to place a DNR order for patients believed to be imminently dying (p = 0.007). The median time from DNR order to death was 4 days with a 90-day mortality of 88.2%. In this single-center cohort study, there was no evidence that patient demographic factors affected ethics consultants' recommendation to withhold CPR despite patient/surrogate requests. Physicians were most likely to place a DNR order without consent for imminently dying patients.

Mobile health technology to improve emergent frailty after lung transplantation.

We evaluated the feasibility, safety, and efficacy of a mHealth-supported physical rehabilitation intervention to treat frailty in a pilot study of 18 lung transplant recipients. Frail recipients were defined by a short physical performance battery (SPPB score ≤7). The primary intervention modality was Aidcube, a customizable rehabilitation mHealth platform. Our primary aims included tolerability, feasibility, and acceptability of use of the platform, and secondary outcomes were changes in SPPB and in scores of physical activity, and disability measured using the Duke Activity Status Index (DASI) and Lung Transplant-Value Life Activities (LT-VLA). Notably, no adverse events were reported. Subjects reported the app was easy to use, usability improved over time, and the app enhanced motivation to engage in rehabilitation. Comments highlighted the complexities of immediate post-transplant rehabilitation, including functional decline, pain, tremor, and fatigue. At the end of the intervention, SPPB scores improved a median of 5 points from a baseline of 4. Physical activity and patient-reported disability also improved. The DASI improved from 4.5 to 19.8 and LT-VLA score improved from 2 to 0.59 at closeout. Overall, utilization of a mHealth rehabilitation platform was safe and well received. Remote rehabilitation was associated with improvements in frailty, physical activity and disability. Future studies should evaluate mHealth treatment modalities in larger-scale randomized trials of lung transplant recipients.

Lung transplantation outcomes after crossing low-level donor specific antibodies without planned augmented immunosuppression.

It is unknown whether some donor specific antibodies (DSA) can be crossed at the time of lung transplant without desensitization or augmented induction immunosuppression. This study assessed whether crossing low-level pre-transplant DSA (defined as mean fluorescence intensity [MFI] 1000-6000) without augmented immunosuppression is associated with worse retransplant-free or chronic lung allograft dysfunction (CLAD)-free survival. Of the 458 included recipients, low-level pre-transplant DSA was crossed in 39 (8.6%) patients. The median follow-up time was 2.2 years. There were 15 (38.5%) patients with Class I DSA and 24 (61.5%) with Class II DSA. There was no difference in adjusted overall retransplant-free survival between recipients where pre-transplant DSA was and was not crossed (HR: .98 [95% CI = .49-1.99], P = .96). There was also no difference in CLAD-free survival (HR: .71 [95% CI = .38-1.33], P = .28). There was no difference in Grade 3 PGD at 72 h (OR: 1.13 [95% CI = .52-2.48], P = .75) or definite or probable AMR (HR: 2.22 [95% CI = .64-7.61], P = .21). Lung transplantation in the presence of low-level DSA without planned augmented immunosuppression is not associated with worse overall or CLAD-free survival among recipients with intermediate-term follow-up.

Mortality trends around the one-year survival mark after heart, liver, and lung transplantation in the United States.

INTRODUCTION: One-year post-transplant survival is a significant quality measure for solid organ transplant programs in the United States. It is not known whether the use of this metric is associated with changes in life-sustaining clinical practices that would delay mortality for solid organ recipients until just beyond the one-year time point. METHODS: We compared trends in mortality in the time period immediately preceding the one-year post-transplant mark compared to the period immediately after using second-order Cox proportional hazard regression models. RESULTS: Among recipients of heart, liver, and lung transplantation, mortality did not decrease significantly in the period immediately before day 365 or increase in the 14 days thereafter. There was an increased adjusted hazard of mortality in the 30 days following day 365 among lung transplant recipients (HR 1.33, 95% CI 1.03-1.72, P = .03) with a 0.76% absolute mortality rate (94 deaths) in month 12 following lung transplantation and a 1.14% absolute mortality rate in month 13 (113 deaths). CONCLUSION: Although we did not find evidence that life-sustaining treatment is routinely continued until just beyond the one-year mark in heart and liver transplantation recipients, there was an unexpected increased risk of mortality in the 30 days following day 365 among lung transplant recipients.

Ethics Consultations Related to Opioid Use Disorder.

BACKGROUND: The opioid epidemic has resulted in an increased number of patients with opioid use disorder (OUD) hospitalized for serious medical conditions. The intersection between hospital ethics consultations and the opioid crisis has not received significant attention. OBJECTIVE: The aim of this study was to characterize ethics consult questions among inpatients with OUD at our institution, Massachusetts General Hospital. METHODS: We conducted a single-center retrospective cohort study of ethics consultations from January 1, 1993 to December 31, 2017 at Massachusetts General Hospital. RESULTS: Between 1993 and 2017, OUD played a central role in ethics consultations in 43 of 1061 (4.0%) cases. There was an increase in these requests beginning in 2009, rising from 1.4% to 6.8% of consults by 2017. Compared with other ethics cases, individuals with OUD were significantly younger (P < 0.001), more likely to be uninsured or underinsured (P < 0.001), and more likely to have a comorbid mental health diagnosis (P = 0.001). The most common reason for consultation involved continuation of life-sustaining treatment in the setting of overdose with neurological injury or severe infection. Additional reasons included discharge planning, challenges with pain management and behavior, and the appropriateness of surgical intervention, such as repeat valve replacement or organ transplant. Health care professionals struggled with their ethical obligations to patients with OUD, including when to treat pain with narcotics and how to provide longitudinal care for patients with limited resources outside of the hospital. CONCLUSION: The growing opioid epidemic corresponds with a rise in ethics consultations for patients with OUD. Similar factors associated with OUD itself, including comorbid mental health diagnoses and concerns about relapse, contributed to the ethical complexities of these consults.

In-hospital and subsequent mortality among lung transplant recipients with a prolonged initial hospitalization.

The care of lung transplant recipients with prolonged index hospitalizations can be ethically complex, with conflicts arising over whether the expected outcomes justify ongoing intensive interventions. There are limited data to guide these conversations. The objective of this study was to evaluate survival to discharge for lung transplant recipients based on length of stay (LOS). This was a retrospective cohort study of adult lung transplant recipients in the Scientific Registry of Transplant Recipients. For each day of the index hospitalization the mortality rate among patients who survived to that length of stay or longer was calculated. Post-discharge survival was compared in those with and without a prolonged hospitalization (defined as the 97th percentile [>90 days]). Among the 19 250 included recipients, the index hospitalization mortality was 5.4%. Posttransplant stroke and need for dialysis were the strongest predictors of index hospitalization mortality. No individual or combination of available risk factors, however, was associated with inpatient mortality consistently above 50%. Recipients with >90 day index hospitalization had a 28.8% subsequent inpatient mortality. Their 1, 3 and 5 year survival following discharge was 53%, 26%, and 16%. These data provide additional context to goals of care conversations for transplant recipients with prolonged index hospitalizations.

Early clinical experience of bacteriophage therapy in 3 lung transplant recipients.

Bacteriophage therapy (BT) uses bacteriophages to treat pathogenic bacteria and is an emerging strategy against multidrug-resistant (MDR) infections. Experience in solid organ transplant is limited. We describe BT in 3 lung transplant recipients (LTR) with life-threatening MDR infections caused by Pseudomonas aeruginosa (n = 2) and Burkholderia dolosa (n = 1). For each patient, lytic bacteriophages were selected against their bacterial isolates. BT was administered for variable durations under emergency Investigational New Drug applications and with patient informed consent. Safety was assessed using clinical/laboratory parameters and observed clinical improvements described, as appropriate. All patients received concurrent antibiotics. Two ventilator-dependent LTR with large airway complications and refractory MDR P. aeruginosa pneumonia received BT. Both responded clinically and were discharged from the hospital off ventilator support. A third patient had recurrent B. dolosa infection following transplant. Following BT initiation, consolidative opacities improved and ventilator weaning was begun. However, infection relapsed on BT and the patient died. No BT-related adverse events were identified in the 3 cases. BT was well tolerated and associated with clinical improvement in LTRs with MDR bacterial infection not responsive to antibiotics alone. BT may be a viable adjunct to antibiotics for patients with MDR infections.

Discharge frailty following lung transplantation.

INTRODUCTION: Frailty at listing for lung transplant has been associated with waitlist and post-transplant mortality. Frailty trajectories following transplant, however, have been less well characterized, including whether recipient frailty improves. The objective of this study was to identify prevalence and risk factors for frailty at discharge and to evaluate changes in frail recipients enrolled in an outpatient physical therapy program. METHODS: This was a single-center prospective cohort study of lung transplant recipients. Enrollees completed a short physical performance battery (SPPB) to assess frailty at listing and at initial hospital discharge. RESULTS: Of the 111 enrolled recipients, none were frail at listing and 18 (16.2%) were prefrail. At discharge, however, 60 (54.1%) patients were frail. Discharge frailty was associated with prefrailty at listing, acute kidney injury post-transplant, and longer intensive care unit stay. Among the 35 patients who were frail at discharge and who were enrolled in an outpatient PT program, the median improvement in SPPB was 6 points (IQR = 5-7 points), and 85.7% became not frail over a median of 6 weeks. CONCLUSION: Discharge frailty is common following lung transplantation. In most frail patients, an intensive outpatient physical therapy program is associated with improvement in frailty, as assessed by the SPPB.

Complications related to totally implantable venous access devices in children and adults following lung transplantation.

INTRODUCTION: Totally implantable venous access devices (TIVADs) are the preferred devices for patients with advanced lung disease who require long-term venous access. The primary purpose of this study was to describe the natural history of TIVADs left in place at the time of transplant. METHODS: This multicenter retrospective cohort study evaluated pediatric and adult lung transplant recipients from 5/5/2005 to 12/31/17 with pretransplant TIVAD. Incident rates (IR) for infectious and mechanical complications were calculated. Poisson regression models were used to identify TIVAD characteristics associated with complications. RESULTS: Of 1253 transplant recipients, 82 (6.5%) had pretransplant TIVAD. Five (6.1%) TIVADs were removed at transplantation. Fifty-five (67.1%) TIVADs were eventually removed, most commonly because they were no longer required (50.9%) or because of infection (25.5%). Overall incident rates (IR) of infectious or mechanical complications were 0.33 and 0.14, respectively. The IR of infection was highest within one year of transplant, particularly during the index hospitalization (IR = 1.67). Youngest tertile (<22 years) had the lowest incident rate ratio of TIVAD infections (IRR = 0.22). CONCLUSION: Although TIVAD complication rates in lung transplant recipients are similar to non-transplant and other immunocompromised patients, TIVAD removal at transplant or within the first post-transplant year may minimize the risk of TIVAD infections.

An Ethical Framework for the Care of Patients with Prolonged Hospitalization Following Lung Transplantation.

The lung allocation score system in the United States and several European countries gives more weight to risk of death without transplantation than to survival following transplantation. As a result, centers transplant sicker patients, leading to increased length of initial hospitalization. The care of patients who have accumulated functional deficits or additional organ dysfunction during their prolonged stay can be ethically complex. Disagreement occurs between the transplant team, patients and families, and non-transplant health care professionals over the burdens of ongoing intensive intervention. These cases highlight important ethical issues in organ transplantation, including the nature and requirements of transplant informed consent, the limits of physician prognostication, patient autonomy and decision-making capacity following transplant, obligations to organ donors and to other potential recipients, and the impact of program metrics on individualized recipient care. We outline general ethical principles for the care of lung transplant recipients with prolonged hospitalization and give regulatory, research, and patient-centered recommendations for these cases.

Predictors and outcomes of unplanned early rehospitalization in the first year following lung transplantation.

Unplanned early rehospitalization (UER), defined as an unscheduled admission within 30 days of a hospital discharge, is associated with graft loss and recipient mortality in some solid organ transplants but has not been investigated in lung transplant. In this retrospective study, we collected socio-demographic and clinical factors to determine predictors and outcomes of UER in the first year following lung transplantation. There were 193 patients who underwent lung transplantation and survived to discharge during the 7.9-year study period. There were 116 (60.1%) patients with at least one UER. Infections (32.8%) and post-surgical complications (11.8%) were the most common reasons for UER. On multivariate analysis, the strongest predictor of having an UER was discharge to a long-term acute care facility (odds ratio: 3.01, 95% confidence interval [CI] 1.46-6.20; P=.003). Patients with any UER in the first year following transplantation had worse adjusted survival (hazard ratio: 1.89, 95% CI 1.02-3.50; P=.04). It is unclear, however, to what extent UERs reflect preventable outcomes. Further large-scale, prospective research is needed to identify the extent to which certain types of UER are modifiable and to define patients at high-risk for preventable UER.

The Effect of Pretransplant Depression and Anxiety on Survival Following Lung Transplant: A Meta-analysis.

BACKGROUND: Current lung transplant allocation guidelines recommend considering psychological function when assessing candidacy despite limited data on whether patients with conditions, such as anxiety and depression, have reduced benefit from transplant because of decreased survival after transplant. OBJECTIVE: The aim of this article was to determine whether pretransplant depression and anxiety are associated with worse posttransplant survival. METHODS: We searched Medline, Journal Storage, and Embase for original articles that assessed the effect of pretransplant depression and anxiety on survival following lung transplant published up to November 2015. We calculated a summary estimate of hazard ratios for death using a random effects model. RESULTS: In total, 6 prospective longitudinal cohort studies were included in the meta-analysis, 4 of which used continuous scores on validated instruments to measure anxiety and depression. There were 711 patients of whom 345 (48.5%) died during the available follow-up time (mean = 7.8 years). Pretransplant anxiety and depression were not associated with posttransplant survival (hazard ratio = 1.009; 95% CI: 0.998-1.019). Heterogeneity was not detected (I(2) = 0.00%, Q = 5.87, p = 0.66) and the results did not differ whether anxiety or depression was treated as the exposure of interest. CONCLUSIONS: There is sufficient evidence to conclude that scores on indices of depression and anxiety pretransplant are not associated with worse survival following lung transplant.

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.