Frailty and aging-associated syndromes in lung transplant candidates and recipients.

Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre- and posttransplant mortality, but this risk is not explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age-associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with posttransplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging-associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.

Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation.

RATIONALE: Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation. OBJECTIVES: To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates. METHODS: In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively. MEASUREMENTS AND MAIN RESULTS: Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB. CONCLUSIONS: Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

Management of the Potential Organ Donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement.

This document was developed through the collaborative efforts of the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations. Under the auspices of these societies, a multidisciplinary, multi-institutional task force was convened, incorporating expertise in critical care medicine, organ donor management, and transplantation. Members of the task force were divided into 13 subcommittees, each focused on one of the following general or organ-specific areas: death determination using neurologic criteria, donation after circulatory death determination, authorization process, general contraindications to donation, hemodynamic management, endocrine dysfunction and hormone replacement therapy, pediatric donor management, cardiac donation, lung donation, liver donation, kidney donation, small bowel donation, and pancreas donation. Subcommittees were charged with generating a series of management-related questions related to their topic. For each question, subcommittees provided a summary of relevant literature and specific recommendations. The specific recommendations were approved by all members of the task force and then assembled into a complete document. Because the available literature was overwhelmingly comprised of observational studies and case series, representing low-quality evidence, a decision was made that the document would assume the form of a consensus statement rather than a formally graded guideline. The goal of this document is to provide critical care practitioners with essential information and practical recommendations related to management of the potential organ donor, based on the available literature and expert consensus.

Circulatory death determination in uncontrolled organ donors: a panel viewpoint.

One barrier for implementing programs of uncontrolled organ donation after the circulatory determination of death is the lack of consensus on the precise moment of death. Our panel was convened to study this question after we performed a similar analysis on the moment of death in controlled organ donation after the circulatory determination of death. We concluded that death could be determined by showing the permanent or irreversible cessation of circulation and respiration. Circulatory irreversibility may be presumed when optimal cardiopulmonary resuscitation efforts have failed to restore circulation and at least a 7-minute period has elapsed thereafter during which autoresuscitation to restored circulation could occur. We advise against the use of postmortem organ support technologies that reestablish circulation of warm oxygenated blood because of their risk of retroactively invalidating the required conditions on which death was declared.

An official American Thoracic Society/International Society for Heart and Lung Transplantation/Society of Critical Care Medicine/Association of Organ and Procurement Organizations/United Network of Organ Sharing Statement: ethical and policy considerations in organ donation after circulatory determination of death.

RATIONALE: Donation after circulatory determination of death (DCDD) has the potential to increase the number of organs available for transplantation. Because consent and management of potential donors must occur before death, DCDD raises unique ethical and policy issues. OBJECTIVES: To develop an ethics and health policy statement on adult and pediatric DCDD relevant to critical care and transplantation stakeholders. METHODS: A multidisciplinary panel of stakeholders was convened to develop an ethics and health policy statement. The panel consisted of representatives from the American Thoracic Society, Society of Critical Care Medicine, International Society for Heart and Lung Transplantation, Association of Organ Procurement Organizations, and the United Network of Organ Sharing. The panel reviewed the literature, discussed important ethics and health policy considerations, and developed a guiding framework for decision making by stakeholders. RESULTS: A framework to guide ethics and health policy statement was established, which addressed the consent process, pre- and post mortem interventions, the determination of death, provisions of end-of-life care, and pediatric DCDD. CONCLUSIONS: The information presented in this Statement is based on the current evidence, experience, and clinical rationale. New clinical research and the development and dissemination of new technologies will eventually necessitate an update of this Statement.

Novel Use of Ivabradine for Persistent Sinus Tachycardia in a Patient on Extracorporeal Life Support With Right Ventricular Dysfunction.

Persistent sinus tachycardia (pST) has been associated with adverse cardiovascular events in critically ill patients. Pharmacological control of heart rate with negative inotropic agents has proven to be safe but could be potentially dangerous in patients with concomitant right ventricular (RV) dysfunction. Ivabradine, a medication devoid of negative inotropy, could be a potentially safe solution for this patient population when adequate heart rate control is desired. A 17-year-old male with a history of vaping developed acute respiratory distress syndrome (ARDS) and RV dysfunction, requiring extra corporal life support (ECLS). He suffered from pST. Given his RV dysfunction, a beta-blocker was avoided, and ivabradine was used safely with improvement of his pST. This case demonstrates the efficacy of ivabradine to reduce heart rate and avoid the use of beta-blockers for patients with RV dysfunction, which could be detrimental. Ivabradine was shown to lower the heart rate without altering hemodynamic parameters.

Venovenous ECMO for Acute Chronic Heart Failure after Bilateral Lung Transplantation.

ABSTRACT: Venovenous (VV) ECMO is rarely used during decompensated circulatory states. Although VA ECMO is the routine option, VV ECMO may be an option in selected patients. We present a case of pulmonary edema due to acute heart failure in a patient 4- and 12-year post-lung transplantation who received VV ECMO. Using a thoughtful cannulation strategy, VV ECMO, and aggressive ultrafiltration, the patient was successfully decannulated, extubated, and discharged from the hospital. In cardiogenic pulmonary edema, VV ECMO represents an additional, and likely under-utilized tool, especially in patients who are at high risk for ventilator-associated lung injury. Cannula location and size should be given additional consideration to potentially transition to V-AV ECMO configuration if necessary.

A survey of use of mTOR inhibitors in patients with lymphangioleiomyomatosis listed for lung transplant.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is an uncommon indication for lung transplantation. The use of mechanistic target of rapamycin (mTOR) inhibitors, which are the mainstay of treatment in progressive LAM, in patients awaiting lung transplant is controversial. We sought to examine worldwide practice patterns in use of mTOR inhibitors in LAM patients on the lung transplant waiting list. METHODS: We designed and disseminated an online survey about institution-specific practice patterns, particularly regarding listing LAM patients for lung transplant and use of mTOR inhibitors in those patients on the transplant waitlist. RESULTS: Of the 49 unique respondent programs, 83.6% had previously listed a LAM patient for lung transplant. Thirteen centers allowed patients to continue on mTOR inhibitor until time of lung transplant. None of those centers reported any complications or deaths attributable to mTOR inhibitor adverse effects. CONCLUSION: There exists significant variability in practice patterns concerning the use of mTOR inhibitors in LAM patients on the lung transplant waiting list. Our survey suggests favorable outcomes for those patients that did continue mTOR inhibitor up to time of transplant. Further data regarding the risk of anastomotic complication with use of mTOR inhibitors in the pre-transplant period would help provide clarity in this debate.

Renin Angiotensin Aldosterone System Antagonism in 2019 Novel Coronavirus Acute Lung Injury.

It has been established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocyte pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists in the current pandemic. ACE2 serves as a regulatory enzyme in maintaining homeostasis between proinflammatory angiotensin II and anti-inflammatory angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome. Augmentation of the ACE2/Ang 1,7 axis represents a critical target in the supportive management of coronavirus disease 2019-associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists, requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements.

Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

The circulatory-respiratory determination of death in organ donation.

OBJECTIVE: Death statutes permit physicians to declare death on the basis of irreversible cessation of circulatory-respiratory or brain functions. The growing practice of organ donation after circulatory determination of death now requires physicians to exercise greater specificity in circulatory-respiratory death determination. We studied circulatory-respiratory death determination to clarify its concept, practice, and application to innovative circulatory determination of death protocols. RESULTS: It is ethically and legally appropriate to procure organs when permanent cessation (will not return) of circulation and respiration has occurred but before irreversible cessation (cannot return) has occurred because permanent cessation: 1) is an established medical practice standard for determining death; 2) is the meaning of "irreversible" in the Uniform Determination of Death Act; and 3) does not violate the "Dead Donor Rule." CONCLUSIONS: The use of unmodified extracorporeal membrane oxygenation in the circulatory determination of death donor after death is declared should be abandoned because, by restoring brain circulation, it retroactively negates the previous death determination. Modifications of extracorporeal membrane oxygenation that avoid this problem by excluding brain circulation are contrived, invasive, and, if used, should require consent of surrogates. Heart donation in circulatory determination of death is acceptable if proper standards are followed to declare donor death after establishing the permanent cessation of circulation. Pending additional data on "auto-resuscitation," we recommend that all circulatory determination of death programs should utilize the prevailing standard of 2 to 5 mins of demonstrated mechanical asystole before declaring death.

Underweight Patients With Cystic Fibrosis Have Acceptable Survival Following Lung Transplantation: A United Network for Organ Sharing Registry Study.

BACKGROUND: Reduced BMI is an absolute contraindication for lung transplantation (LTx) at most centers in the United States. The objective of this study was to quantify post-LTx survival of moderate to severely underweight patients with cystic fibrosis (CF) (BMI < 17 kg/m2) in the United States relative to normal-weight recipients with CF and other frequently transplanted patient cohorts. METHODS: Using United Network for Organ Sharing Registry data (undergoing transplant from June 2005-November 2015), Kaplan-Meier estimates of median posttransplant survival were calculated for all patients with CF, COPD, and idiopathic pulmonary fibrosis (IPF), as well as low and normal weight CF subgroups. Cox regression modeling stratified according to transplant center assessed risk of posttransplant mortality in recipients with CF and a BMI < 17 kg/m2 compared with recipients with COPD (reference). RESULTS: Median posttransplant survival (95% CI) for CF, COPD, and IPF was 7.9 (7.2-8.6), 5.9 (5.6-6.2), and 5.5 (5.2-5.8) years, respectively. Although an absolute decrease was noted in posttransplant survival for recipients with CF and a BMI < 17 kg/m2, compared with those with CF and a BMI ≥ 17 kg/m2 (7.0 years [4.5-7.9] vs 8.2 years [7.3-9.0]), Cox modeling found no increased mortality risk (adjusted hazard ratio, 1.09; 95% CI, 0.90-1.32; P = .38). There was no difference in posttransplant mortality between patients with CF and a BMI < 17 kg/m2 and recipients with COPD and all BMIs (adjusted hazard ratio, 1.04; 95% CI, 0.86-1.25; P = .71). CONCLUSIONS: Transplant recipients with CF and a BMI < 17 kg/m2 had posttransplant survival rates comparable to those of other groups frequently undergoing transplantation. BMI < 17 kg/m2 as a single risk factor in the CF population should not be treated as an absolute contraindication to LTx.

Family member satisfaction with end-of-life decision making in the ICU.

RATIONALE: Families of ICU patients may be at risk for increased psychological morbidity due to end-of-life decision making. The identification of chart-based quality indicators of palliative care that predict family satisfaction with decision making may help to guide interventions to improve decision making and family outcomes. OBJECTIVE: To determine patient and family characteristics and chart the documentation of processes of care that are associated with increased family satisfaction with end-of-life decision making for ICU patients. METHODS: We conducted a cohort study of ICU patients dying in 10 medical centers in the Seattle-Tacoma area. MEASUREMENT: Outcomes from family surveys included summary scores for family satisfaction with decision making and a single-item score that indicated feeling supported during decision making. Predictor variables were obtained from surveys and chart abstraction. MAIN RESULTS: The survey response rate was 41% (442 of 1,074 families responded). Analyses were conducted of 356 families with questionnaire and chart abstraction data. Family satisfaction with decision making was associated with the withdrawal of life support, and chart documentation of physician recommendations to withdraw life support, discussions of patients' wishes, and discussions of families' spiritual needs. Feeling supported during decision making was associated with the withdrawal of life support, spiritual care involvement, and chart documentation of physician recommendations to withdraw life support, expressions of families' wishes to withdraw life support, and discussions of families' spiritual needs. CONCLUSIONS: Increased family satisfaction with decision making is associated with withdrawing life support and the documentation of palliative care indicators including the following: physician recommendations to withdraw life support; expressions of patients' wishes; and discussions of families' spiritual needs. These findings provide direction for future studies to investigate approaches to improving family satisfaction in end-of-life decision making. In addition, because there were few nonwhites in this study, these results may not be generalizable to more diverse populations. Future studies should target diverse populations in order to test whether similar factors are similarly important for end-of-life decision making.

Posttraumatic stress disorder following critical illness.

Posttraumatic stress disorder (PTSD) is a common psychiatric condition that can occur after a traumatic event. Individuals exposed to traumatic events are at risk for PTSD and other psychologic morbidity, such as depression, panic disorder, generalized anxiety disorder, and substance abuse. The burden of PTSD can be high, with inability to work or return to prior levels of functioning. Emerging literature suggests a significantly increased risk for symptoms of PTSD among survivors of critical illness and the families of patients who survive or die after critical illness. This review summarizes these studies and provides suggestions for current clinical implications and for future research.

Lung allocation score for lung transplantation: impact on disease severity and survival.

BACKGROUND: Prior to implementation of the lung allocation score (LAS) system, allocation of donor lungs was based on accrued time on the waiting list and was potentially influenced by center-specific thresholds for listing. The impact of LAS implementation on patient characteristics and survival is unknown. METHODS: United Network of Organ Sharing data were obtained on all lung transplant candidates listed and all patients undergoing transplantation in region 6 between May 4, 2003, and May 4, 2006. Each data set was divided into two cohorts: 2 years before LAS implementation, and 1 year after LAS implementation. LAS was calculated and compared by cohort. Pre-LAS and post-LAS differences in patient characteristics were examined. Waiting list and posttransplant survival rates for each cohort were examined using Kaplan-Meier estimates and Cox regression. RESULTS: After LAS implementation, the distribution of diagnoses in patients undergoing transplantation significantly changed (p = 0.02), while the distribution of diagnoses in those listed did not (p = 0.17). Characteristics of patients on the waiting list were similar, except that a higher proportion of nonwhite patients were listed (p = 0.04) and lower FVC (p < 0.001) was observed after LAS implementation. Similarly, characteristics of patients undergoing transplantation did not change, except that posttransplant hospital length of stay was shorter (p = 0.01) after LAS implementation. Calculated LAS was higher after LAS implementation (p = 0.006). After controlling for age and diagnosis, neither waiting list nor transplant survival was significantly different (p = 0.93 and p = 0.81, respectively). CONCLUSIONS: After LAS implementation, the distribution of diagnoses in lung transplant recipients was significantly changed, while that of candidates was not. Posttransplant and waiting list survival were not affected by the LAS system, but power was limited. Larger and long-term survival studies are needed to determine if the LAS system improves overall allocation and survival for patients interested in lung transplantation.

Tracheal rupture resulting in life-threatening subcutaneous emphysema.

We present a case of a patient with severe chronic obstructive pulmonary disease who developed dramatic mediastinal and subcutaneous emphysema, without pneumothorax, following a difficult intubation. Misdiagnosis of tracheal rupture as barotrauma from alveolar overdistention initially delayed intervention and caused persistence of subcutaneous emphysema. Despite efforts to minimize tidal volume and airway pressure, the large airway disruption and positive-pressure ventilation resulted in tension subcutaneous emphysema with near-fatal hemodynamic compromise, oliguria, and respiratory acidosis. Decompression with subcutaneous vents immediately reversed the life-threatening circulatory and respiratory compromise and stabilized the patient until surgical correction of the tracheal tear could be accomplished.

Refining Low Physical Activity Measurement Improves Frailty Assessment in Advanced Lung Disease and Survivors of Critical Illness.

RATIONALE: The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and in critical illness survivors. Because respiratory disease and chronic illness can greatly limit physical activity, the measurement of participation in traditional leisure time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients. OBJECTIVES: To test and validate substituting the Duke Activity Status Index (DASI), a simple 12-item questionnaire, for the Minnesota Leisure Time Physical Activity (MLTA) questionnaire, a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype (FFP) instrument. METHODS: In separate multicenter prospective cohort studies of adults with advanced lung disease who were candidates for lung transplant and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated content validity by testing floor effects and construct validity through comparisons with conceptually related factors. We tested the predictive validity of substituting the DASI for the MLTA in the FFP assessment using Cox models to estimate associations between the FFP and delisting/death before transplant in those with advanced lung disease and 6-month mortality in older intensive care unit (ICU) survivors. RESULTS: Among 618 adults with advanced lung disease and 130 older ICU survivors, the MLTA had a substantially greater floor effect than the DASI (42% vs. 1%, and 49% vs. 12%, respectively). The DASI correlated more strongly with strength and function measures than did the MLTA in both cohorts. In models adjusting for age, sex, comorbidities, and illness severity, substitution of the DASI for the MLTA led to stronger associations of the FFP with delisting/death in lung transplant candidates (FFP-MLTA hazard ratio [HR], 1.42; 95% confidence interval [CI], 0.55-3.65; FFP-DASI HR, 2.99; 95% CI, 1.03-8.65) and with mortality in older ICU survivors (FFP-MLTA HR, 2.68; 95% CI, 0.62-11.6; FFP-DASI HR, 5.71; 95% CI, 1.34-24.3). CONCLUSIONS: The DASI improves the construct and predictive validity of frailty assessment in adults with advanced lung disease or recent critical illness. This simple questionnaire should replace the more complex MLTA in assessing the frailty phenotype in these populations.

Pulmonary hypertension is associated with increased post-lung transplant mortality risk in patients with chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary hypertension associated with lung disease (PHLD) has been shown to be a predictor of disease severity and survival in patients awaiting lung transplantation. Little is known about the relationship of PHLD and survival after lung transplantation or how this may vary by disease. This study evaluated the effect of PHLD on 1-year survival after lung transplantation for patients with the 3 most common indications for transplantation: chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF). METHODS: Organ Procurement and Transplantation Network data were obtained for all lung transplant recipients who received an allograft between May 2005 and June 2010. The relationship between PHLD and 1-year survival after lung transplantation for each diagnostic group was examined with Kaplan-Meier estimates and Cox regression. Covariates included in the model were those defined in the current Lung Allocation Score system post-transplant survival model, including age, serum creatinine, percentage predicted forced vital capacity, functional status, and mechanical ventilation use at time of transplant. The estimated relative risk was calculated using Poisson regression with robust error variance and adjustment for covariates. RESULTS: Sample sizes for COPD, IPF, and CF patients were 2,025, 2,304, and 866, respectively. The 1-year post-transplant survival for COPD patients with PHLD was 76.9% vs 86.2% for COPD patients without PHLD (p = 0.001). In multivariate Cox regression analysis COPD patients with PHLD had a 1.74 (95% confidence interval, 1.3-2.3) times higher risk of 1-year post-transplant mortality (p = 0.001). Similar analyses for IPF and CF diagnostic groups showed no significant difference in survival between patients with and without PHLD. CONCLUSIONS: COPD patients with PHLD have increased post-transplant 1-year mortality. No significant difference was seen in patients with IPF or CF. Further studies to evaluate the potential mechanisms for this difference between diagnoses are needed.