Cardiovascular risk assessment of the liver transplant candidate

Liver transplantation (LT) candidates today are increasingly older, have greater medical acuity, and have more cardiovascular comorbidities than ever before. Steadily rising model for end-stage liver disease (MELD) scores at the time of transplant, resulting from high organ demand, reflect the escalating risk profiles of LT candidates. In addition to advanced age and the presence of comorbidities, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Patients with cirrhosis requiring LT usually demonstrate increased cardiac output and a compromised ventricular response to stress, a condition termed cirrhotic cardiomyopathy. These cardiac disturbances are likely mediated by decreased beta-agonist transduction, increased circulating inflammatory mediators with cardiodepressant properties, and repolarization changes. Low systemic vascular resistance and bradycardia are also commonly seen in cirrhosis and can be aggravated by beta-blocker use. These physiologic changes all contribute to the potential for cardiovascular complications, particularly with the altered hemodynamic stresses that LT patients face in the immediate post-operative period. Post-transplant reperfusion may result in cardiac death due to a multitude of causes, including arrhythmia, acute heart failure, and myocardial infarction. Recognizing the hemodynamic challenges encountered by LT patients in the perioperative period and how these responses can be exacerbated by underlying cardiac pathology is critical in developing recommendations for the pre-operative risk assessment and management of these patients. The following provides a review of the cardiovascular challenges in LT candidates, as well as evidence-based recommendations for their evaluation and management.     

Poor survival of patients with idiopathic cardiomyopathy considered too well for transplantation

Although the success of cardiac transplantation has encouraged earlier referral of potential candidates, those with mild symptoms of heart failure are frequently considered "too well" for transplantation. Outcome was investigated for 28 patients with non-ischemic dilated cardiomyopathy and ejection fraction of 25 percent or less who were denied transplantation due to lack of severe symptoms. One-year survival without transplantation was 46 percent. Low stroke volume and history of ventricular arrhythmias were independent predictors of early mortality. High risk, defined as either stroke volume of 40 ml or less or history of ventricular arrhythmia, identified 13 of 14 patients who did not survive one year and only one of 12 one-year survivors (p less than 0.001). Low stroke volume predicted hemodynamic failure (p less than 0.05) whereas arrhythmic history predicted sudden death (p less than 0.001). Clinical status improved in only six patients, all of whom had symptom duration of seven or less months at initial evaluation (p less than 0.001). Thus, patients referred to transplantation for dilated cardiomyopathy with an ejection fraction of 25 percent or less have a poor prognosis even if symptoms are mild. Patients with high hemodynamic risk may require early transplantation, whereas those with high arrhythmia risk may require other aggressive therapy in order to avoid transplantation until symptoms become severe.     

Dissociation between peak exercise oxygen consumption and hemodynamic dysfunction in potential heart transplant candidates

Objectives. The purpose of this study was to determine how often peak exercise oxygen consumption (Vo₂) misclassifies the severity of cardiac dysfunction in potential heart transplant candidates.Background. Cardiopulmonary exercise testing is being used to help select heart transplant candidates on the basis of the assumption that a low peak exercise Vo₂indicates severe hemodynamic dysfunction and a poor prognosis. However, noncardiac factors, such as muscle deconditioning, can also influence exercise capacity. Therefore, peak exercise Vo₂may overestimate the severity of cardiac dysfunction in some patients.Methods. Hemodynamic and respiratory responses to maximal treadmill exercise were measured in 64 sequential patientsundergoing evaluation for heart transplantation, all of whom had an ejection fraction <35% and reduced peak exercise Vo₂levels (mean [±SD] 13.3 ± 2.7 ml/min per kg).Results. Twenty-eight (44%) of 64 patients exhibited a reduced cardiac output response to exercise and pulmonary wedge pressure >20 mm Hg at peak exercise, consistent with severe hemodynamic dysfunction. Twenty-three patients (36%) exhibited a normal cardiac output response to exercise but a wedge pressure >20 mm Hg at peak exercise, suggesting moderate hemodynamic dysfunction. Thirteen patients (20%) exhibited a normal cardiac output and wedge pressure <20 mm Hg at peak exercise, suggesting mild hemodynamic dysfunction. Despite these markedly different hemodynamic responses, all three groups exhibited similar peak exercise Vo₂levels (mild dysfunction 14.2 ± 3.5 ml/min per kg, moderate dysfunction 13.9 ± 2.7 ml/min per kg, severe dysfunction 12.4 ± 2.1 ml/min per kg). A peak exercise Vo₂level <14 ml/min per kg, considered to reflect severe hemodynamic dysfunction, was observed in 18 of the patients with a normal cardiac output response to exercise, whereas 7 patients with severe hemodynamic dysfunction had a peak Vo₂level >14 ml/min per kg.Conclusions. More than 50% of potential heart transplant candidates with a reduced peak exercise Vo₂level exhibit only mild or moderate hemodynamic dysfunction during exercise. Hemodynamic responses to exercise should be directly measured in potential transplant candidates to confirm severe circulatory dysfunction.     

Lung transplantation: disease-specific considerations for referral

The timing of the referral and listing of patients for lung transplantation remains a difficult decision. Life expectancy and quality of life with and without transplantation are the pivotal issues that need to be considered by physicians and presented to prospective transplant candidates. The recognition of recent advances in the understanding of the various primary diseases, other potential therapies, and the latest posttransplant statistics are essential for a balanced discussion or decision about lung transplantation. This article provides a review of these and other pertinent issues for patients with various forms of advanced lung disease.     

Intravenous therapy for advanced heart failure

Because of the standard use of oral neurohumoral antagonists, the role of intravenous agents for advanced heart failure patients has changed profoundly. Their current use as medical therapy is restricted to two indications: first, as short-term infusion (hours to days) in advanced heart failure patients who decompensate into a symptomatic New York Heart Association class IV condition and who are admitted for rapid hemodynamic support with intravenous vasodilators or inotropes; in these patients after hemodynamic and clinical stabilization, optimization of conventional heart failure therapy has to be reconsidered; second, as long-term application in heart transplantation candidates who are in a similar desperate condition although already receiving maximal oral heart failure therapy.     

Indications, patient selection and timing of referral for lung transplantation.

Lung transplantation (LTx) is now generally accepted as a useful modality of care for patients with severe life-threatening respiratory diseases that are refractory to other medical or surgical therapies. With the huge development of LTx over the last 15 yrs, the disparity between the number of potential recipients and the number of donor organs available has become a major constraint, with many patients dying on the waiting lists. Therefore, it is of primary importance to control and optimise the use of this limited organ resource by weighting the risks and benefits of transplantation in individual patients, and to identify those patients who have a better chance of having a favourable outcome with transplantation. This article discusses the selection process of potential candidates and the currently accepted absolute and relative contraindications, and proposes general and disease-specific recommendations for optimising the timing of referral. Early referral for consideration of lung transplantation is highly desirable as it enhances the patient's chance of surviving to transplant and allows the transplant team to actively manage identified comorbidities during the waiting period.     

Recent updates on alcoholic hepatitis

Alcoholic hepatitis (AH) is a unique clinical syndrome that affects patients with chronic and active harmful alcohol consumption, and is associated with a high mortality of up to 40% at 1 month from presentation. It is important to assess disease severity and prognosis at time of presentation to identify patients at risk for high mortality and potential candidates for specific therapies. The cornerstone therapy for AH is enteral nutrition and abstinence. Steroids remain the only pharmacological option for severe AH however, adverse effects and lack of long-term benefit limit their routine use. Early liver transplantation is a potential salvage therapy for select severe AH patients. This review article comprehensively covers recent advances on the clinical unmet needs in the field including newer therapies and therapeutic targets, role of liver transplantation, and emerging biomarkers throughout the disease process from diagnosis, assessing prognosis and disease severity, and predicting responsiveness to medical therapies for severe AH.     

Decreasing survival benefit from cardiac transplantation for outpatients as the waiting list lengthens

Many patients are accepted for cardiac transplantation during a period of clinical instability associated with a high risk of death, even though most can be discharged home to await transplantation. As the waiting lists lengthen, priority is awarded solely on the basis of the waiting time of outpatients, who now usually undergo transplantation after they have already survived a major period of jeopardy. To determine the impact of the current waiting times and priority system on the previously expected benefit offered by transplantation, 1-year actuarial survival without transplantation was recalculated after each month without transplantation for 214 potential candidates with an ejection fraction of 0.17 +/- 0.05 discharged on tailored medical therapy after evaluation. These data were compared with the 1-year survival data of 88 outpatients who underwent transplantation. Actuarial survival after 1 year was 67% on tailored therapy compared with 88% after transplantation (p = 0.009). Death without transplantation was sudden in 43 of 51 patients, resulting from hemodynamic decompensation in 8. For outpatients already surviving 6 months without transplantation, actuarial survival over the next 12 months was 83% without transplantation. Thus, the expected improvement in survival after transplantation would be only 5% over the subsequent year for patients waiting 6 months, which is the waiting time for many outpatients. Such patients should be reevaluated to determine whether transplantation remains indicated during the next year.     

Portopulmonary hypertension: state of the art: Concise Review

Portopulmonary hypertension is an uncommon but treatable pulmonary vascular consequence of portal hypertension, which can lead to significant morbidity and mortality. Portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodeling that eventually leads to right-heart failure and death if left untreated. Although pulmonary vascular disease in these patients may be asymptomatic or associated with subtle and nonspecific symptoms (dyspnea, fatigue and lower extremity swelling), it should be looked for especially if patients are potential candidates for liver transplantation. Patients with clinical suspicion of portopulmonary hypertension should undergo screening testing, specifically echocardiography. Right heart catheterization remains the gold standard for the diagnosis. The existence of moderate to severe disease poses higher risks and challenges for liver transplantation. The disease has a substantial impact on survival and requires focused pharmacological therapy. New and evolving medical therapies, such as prostanoids (intravenous, inhaled or oral), endothelin receptors antagonists, phosphodiesterases inhibitors, combination therapy and other experimental drugs might change the natural course of the disease. Case reports and cases series have been published regarding the efficacy and safety of pharmacological therapy, but randomized, controlled multicenter trials are urgently needed. Liver transplantation is not the treatment of choice for portopulmonary hypertension, but after optimal hemodynamic and clinical improvement with medical therapy as a bridge, liver transplant can be considered an option in selected patients.     

Applicability of adult-to-adult living donor liver transplantation

BACKGROUND/AIMS: The applicability of adult-to-adult living donor liver transplantation has not been established yet. We report the first data in a European center of the process leading to this procedure from the first moment the patients were informed about it. METHODS: In phase 1 of the process, 121 adult patients enlisted for cadaveric liver transplantation and their relatives were informed of the technical aspects, advantages and risks of living donor liver transplantation, and the essential criteria for living donation. In phase 2, potential donors identified in phase 1 were evaluated in depth. RESULTS: Twenty-one (17%) patients underwent living donor liver transplantation. This procedure was not performed in 60 patients (50%) for reasons concerning the patients themselves, especially their refusal to receive living donor liver transplantation from a relative (30%). Forty patients (33%) did not undergo living donor liver transplantation for reasons concerning potential donors: donors were not identified (14%), declined the donation (13%), or were refused for technical reasons (6%). The expected waiting time to transplantation was longer in patients who underwent living donor liver transplantation than in those who did not. CONCLUSIONS: The applicability of adult-to-adult living donor liver transplantation is low, mainly because of reasons related to potential recipients.     

Transoesophageal echocardiography during liver transplantation

Liver transplantation (LT) has become the standard of care for patients with end stage liver disease. The allocation of organs, which prioritizes the sickest patients, has made the management of liver transplant candidates more complex both as regards their comorbidities and their higher risk of perioperative complications. Patients undergoing LT frequently display considerable physiological changes during the procedures as a result of both the disease process and the surgery. Transoesophageal echocardiography (TEE), which visualizes dynamic cardiac function and overall contractility, has become essential for perioperative LT management and can optimize the anaesthetic management of these highly complex patients. Moreover, TEE can provide useful information on volume status and the adequacy of therapeutic interventions and can diagnose early intraoperative complications, such as the embolization of large vessels or development of pulmonary hypertension. In this review, directed at clinicians who manage TEE during LT, we show why the procedure merits a place in challenging anaesthetic environment and how it can provide essential information in the perioperative management of compromised patients undergoing this very complex surgical procedure.     

Heart transplantation: who should be considered and when?

Heart transplantation is now firmly established as the most effective therapy for selected patients with end‐stage heart disease who have exhausted all other treatment options. The excellent long‐term survival and quality of life achieved by the large majority of heart transplant recipients has led to considerable broadening of the recipient eligibility criteria over the past 24 years of continuous transplant activity in Australia and New Zealand. Although these changes in recipient eligibility criteria have resulted in a marked increase in the potential pool of transplant recipients, heart transplantation remains a relatively rare procedure because of the scarcity of suitable cardiac donors. The primary aim of this review was to provide clinicians with guidelines that enable them to identify patients who are potential candidates for heart transplantation and those who are not. Appropriate timing of referral is also discussed. Apart from their role in the evaluation and management of patients referred for heart transplantation, cardiopulmonary transplant units provide a number of other important services. These include assistance in the diagnostic evaluation and management of patients with primary myocardial diseases and the investigation of novel alternative therapies for patients with end‐stage heart disease.     

Ventilatory and diffusion abnormalities in potential heart transplant recipients

Few data are available concerning pulmonary function in patients with severe chronic congestive heart failure. Of 315 patients evaluated for potential cardiac transplantation at UCLA, 132 underwent pulmonary function tests. The latter patients had severe heart failure with a mean left ventricular ejection fraction of 19 percent and mean cardiac index of 2.1 L/min/m2. Diffusion impairment either alone or combined with restrictive and/or obstructive ventilatory defects occurred in 67 percent of the patients evaluated. Diffusion impairment occurred as the sole abnormality in 31 percent of the patients and in combination with a restrictive ventilatory defect in 21 percent. A reduction in diffusing capacity has not been previously described as a frequent finding in patients with chronic congestive heart failure. In contrast to other studies involving patients with acute heart failure, obstructive ventilatory defects were uncommon. None of the lung function abnormalities was associated with smoking status, prior drug use, chest roentgenographic changes, hemodynamic findings, or clinical features, including duration of congestive heart failure. The mechanism for the diffusion impairment is unclear but could be due to chronic passive congestion with pulmonary fibrosis and/or recurrent pulmonary emboli. Recognition of diffusion impairment as a common finding in patients with severe chronic congestive heart failure who are candidates for heart transplantation is important for proper interpretation of possible post-transplant changes in diffusing capacity due to other causes.     

Impact of psychosocial status on liver transplant process

Liver transplant candidates and recipients are at high risk of psychological distress. Social, psychological and psychiatric patterns seem to influence morbidity and mortality of patients before and after transplant. An accurate organ allocation is mandatory to guarantee an optimal graft and recipient survival. In this context, the pre-transplant social, psychological and psychiatric selection of potential candidates is essential for excluding major psychiatric illness and for estimating the patient compliance. Depression is one of the most studied psychological conditions in the field of organ transplantation. Notably, an ineffectively treated depression in the pre-transplant period has been associated to a worst long-term recipient survival. After transplant, personalized psychological intervention might favor recovery process, improvement of quality of life and immunosuppressant adherence. Active coping strategy represents one of the most encouraging ways to positively influence the clinical course of transplanted patients. In conclusion, multidisciplinary team should act in three directions: prevention of mood distress, early diagnosis and effective treatment. Active coping, social support and multidisciplinary approach might improve the clinical outcome of transplanted patients.     

Echocardiography for Hemodynamic Assessment of Patients With Advanced Heart Failure and Potential Heart Transplant Recipients

Objectives. This study sought to assess the accuracy of Doppler echocardiographic techniques for the determination of right heart catheterization hemodynamic variables in patients with advanced heart failure and in potential heart transplant recipients.

Background. Doppler echocardiographic techniques permit the noninvasive acquisition of hemodynamic variables traditionally used for the assessment of patients with advanced heart failure and potential heart transplant candidates. However, the accuracy of these techniques has not been sufficiently well documented for clinical application in individual patients.

Methods. Echocardiographic data required for estimation of mean right atrial, pulmonary artery and mean left atrial pressures and cardiac output were obtained. Right heart catheterization was performed immediately after Doppler echocardiographic data were acquired, before any intervention that might have altered the subject’s hemodynamic status.

Results. A complete Doppler echocardiographic hemodynamic data set was acquired in 21 (84%) of 25 subjects. For all variables, invasive and noninvasive hemodynamic values were highly correlated (p < 0.001), with minimal bias and narrow 95% confidence limits. An algorithm constructed from the noninvasive hemodynamic variable values identified all patients with adverse pulmonary vascular hemodynamic variables (i.e., transpulmonary gradient ≥12 mm Hg, pulmonary vascular resistance ≥3 Wood units or pulmonary vascular resistance index ≥6 Wood units × m²). This algorithm identified 12 (71%) of 19 patients for whom right heart catheterization was unnecessary.

Conclusions. Doppler echocardiographic estimates of hemodynamic variables in patients with advanced heart failure are accurate and reproducible. This noninvasive methodology may assist with monitoring and optimization of medical therapy in patients with advanced heart failure and may obviate the need for routine right heart catheterization in potential heart transplant candidates.     

Indications and selection criteria for cardiac transplantation

Assessment of indications for cardiac transplantation is a complex process including first a comparison of expected survival of a patient with end-stage heart disease, mostly ischemic or dilative cardiomyopathy, allocated either to conventional medical or surgical therapy or to cardiac transplantation, second the expected increase in exercise tolerance and quality of life after transplantation. Furthermore the exclusion of contraindications is required: severe irreversible secondary organ damage (especially of kidneys and liver), malignant tumors and systemic malignancies, severe pulmonary hypertension, florid infections, unstable psychosocial conditions of the patient and his surrounding. Although a considerable number of clinical, electrocardiographic, echocardiographic and hemodynamic factors have been defined as indicating very poor prognosis, there exists no prognostic index combining all these factors into a precise prediction of survival of an individual patient with end-stage cardiac failure. Whereas high survival rates have been concordantly documented for the first years after transplantation, the long-term prognosis cannot be estimated as yet with equally sufficient certainty, due to increasing observation of vasculopathies and of progressive myocardial (mostly diastolic) dysfunction of transplanted hearts. These problems suggest to continue with very careful selection of candidates for transplantation. Even in the case of cardiac decompensation and poor prognostic factors, usually a single examination of the patient is not sufficient, but rather a thorough observation of the patient over a period of time including an evaluation of the rate of clinical and hemodynamic decline and of the response to medical therapy.     

Approaching the sensitized lung patient: risk assessment for donor acceptance

The presence of HLA antibodies is widely recognized as a barrier to solid organ transplantation, and for lung transplant candidates, it has a significant negative impact on both waiting time and waiting list mortality. Although HLA antibodies have been associated with a broad spectrum of allograft damage, precise characterization of these antibodies in allosensitized candidates may enhance their accessibility to transplant. The introduction of Luminex-based single antigen bead (SAB) assays has significantly improved antibody detection sensitivity and specificity, but SAB alone is not sufficient for risk-stratification. Functional characterization of donor-specific antibodies (DSA) is paramount to increase donor accessibility for allosensitized lung candidates. We describe here our approach to evaluate sensitized lung transplant candidates. By employing state-of-the-art technologies to assess histocompatibility and determine physiological properties of circulating HLA antibodies, we can provide our Clinical Team a better risk assessment for lung transplant candidates and facilitate a “road map” to transplant. The cases presented in this paper illustrate the “individualized steps” taken to determine calculated panel reactive antibodies (cPRA), titer and complement-fixing properties of each HLA antibody present in circulation. When a donor is considered, we can better predict the risk associated with potentially crossing HLA antibodies, thereby allowing the Clinical Team to approach allosensitized lung patients with an individualized medicine approach. To facilitate safe access of sensitized lung transplant candidates to potential donors, a synergy between the histocompatibility laboratory and the Clinical Team is essential. Ultimately, donor acceptance is a decision based on several parameters, leading to a risk-stratification unique for each patient.     

Hepatocellular carcinoma: Advances in diagnosis,management, and long term outcome

Hepatocellular carcinoma (HCC) remains a common and lethal malignancy worldwide and arises in the setting of a host of diseases. The incidence continues to increase despite multiple vaccines and therapies for viruses such as the hepatitis B and C viruses. In addition, due to the growing incidence of obesity in Western society, there is anticipation that there will be a growing population with HCC due to non-alcoholic fatty liver disease. Due to the growing frequency of this disease, screening is recommended using ultrasound with further imaging using magnetic resonance imaging and multi-detector computed tomography used for further characterization of masses. Great advances have been made to help with the early diagnosis of small lesions leading to potential curative resection or transplantation. Resection and transplantation maybe used in a variety of patients that are carefully selected based on underlying liver disease. Using certain guidelines and clinical acumen patients may have good outcomes with either resection or transplantation however many patients are inoperable at time of presentation. Fortunately, the use of new locoregional therapies has made down staging patients a potential option making them potential surgical candidates. Despite a growing population with HCC, new advances in viral therapies, chemotherapeutics, and an expanding population of surgical and transplant candidates might all contribute to improved long-term survival of these patients.     

Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group.

Patients with pulmonary hypertension are at risk of developing fatal right heart failure after heart transplantation. To evaluate this risk potential, candidates for heart transplantation are screened by measuring rest right heart pressures and the response to nitroprusside. To test the validity of this approach, the influence of pretransplantation right heart catheterization data on outcome after transplantation was analyzed in 293 of 301 consecutive patients. Patients with a pulmonary vascular resistance greater than 2.5 Wood units measured at baseline study had a 3-month mortality rate of 17.9% compared with 6.9% in patients with resistance less than or equal to 2.5 units (p less than 0.02). Patients with a pulmonary vascular resistance greater than 2.5 units at baseline study could be differentiated further according to their hemodynamic response to nitroprusside; those whose resistance could be reduced to less than or equal to 2.5 units with a stable systemic systolic pressure greater than or equal to 85 mm Hg had a 3-month mortality rate of only 3.8%. In contrast, patients whose pulmonary vascular resistance could not be reduced to less than 2.5 units, and those whose resistance could be reduced to less than or equal to 2.5 units but only at the expense of systemic hypotension (systolic pressure less than or equal to 85 mm Hg) had a 3-month mortality rate of 40.6% and 27.5%, respectively. Furthermore, all 10 patients who died of right heart failure belonged to the latter two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intraoperative support during lung transplantation

The role of intraoperative mechanical support during lung transplantation (LTx) is essential to provide a safe hemodynamic and ventilatory status during critical intraoperative events. This hemodynamic and ventilatory stability is vital to minimize the odds of suboptimal outcomes, especially considering that, due to the scarcity of donors and the fact that more and more patients with significant comorbidities are being considered for this therapy, a more aggressive approach is often needed by the transplant centers. Hence, the attenuation of any potential injury that can happen during this complex event is paramount. While a thorough assessment of the donor and optimization of postoperative care is pursued, certainly protective intraoperative management would also contribute to better outcomes. Understanding each patient’s underlying anatomy and cardiopulmonary physiology, associated with awareness of critical events during a complicated procedure like LTx, is essential for a precise indication and safe use of support. Cardiopulmonary bypass (CPB) and veno-arterial extracorporeal membrane oxygenation (VA ECMO) have been the most common approaches used, with the latter gaining popularity more recently and we have used VA ECMO exclusively for the last decade. New technologies certainly contributed to more liberal use of VA ECMO intraoperatively, enabling a protecting and physiologic environment for the newly implanted grafts. In this setting, potential prophylactic use for lung protection during a critical period is also considered.