Impact of a Transplantation Critical Care Model on Short-Term Outcomes Following Liver Transplantation in High Acuity Patients: A Single-Center Experience.

BACKGROUND: Orthotopic liver transplantation (OLT) is the definitive treatment for end-stage liver disease (ESLD). Patients with high acuity ESLD are frequently denied life-saving OLT by transplant centers due to reported inferior outcomes. We sought to analyze the impact of a specialized transplant critical care model (TCCM) on patient access to OLT and survival outcomes in high acuity patients. METHODS: From January 2009 to December 2016, 122 adults were wait-listed at our transplant center with laboratory Model for ESLD ≥35 or Status I. Outcomes in Era I (prior to TCCM) were compared to Era II (TCCM established October 1, 2012). RESULTS: Era II (TCCM) led to a significant increase in patients' access to OLT. Frequency and need to seek OLT at another center dropped 4-fold in Era II. Compared to Era I, the majority of patients in Era II required intensive care unit management (22% vs 83%, P < .01) and renal replacement therapy (11% vs 70%, P < .01) prior to OLT. Despite a higher acuity of illness in Era II, 1-year patient survival was comparable (89% Era I, 80% Era II, P = .35). CONCLUSION: Implementation of a specialized TCCM expanded OLT access to high acuity patients, reduced the need to seek higher level of care elsewhere, and achieved excellent short-term post-transplant survival outcomes.

Transabdominal Intrapericardial Approach in Liver Transplantation for Unresectable Primary Hepatic Functioning Paraganglioma With Invasion Into Hepatic Veins and Suprahepatic Vena Cava: A Surgical and Anesthesia Management Challenge.

Primary hepatic functional paraganglioma is a rare form of extra-adrenal catecholamine-secreting tumor. Definitive treatment of functioning paraganglioma is challenging because of the critical location of the tumor frequently in close proximity to vital structures and risk of excessive catecholamine release during operative manipulation. We report the multidisciplinary management approach for a case of unresectable primary hepatic functional paraganglioma with invasion into the hepatic veins and suprahepatic vena cava. To our knowledge, this is the first report showing that orthotopic liver transplantation is curative for patients with unresectable primary hepatic paraganglioma. For locally advanced unresectable hepatic paraganglioma that involves the intrapericardial vena cava, a meticulous pre- and intraoperative medical management and transabdominal intrapericardial vascular control of the suprahepatic vena cava during orthotopic liver transplantation allows for complete extirpation of the tumor and achieves optimal outcome.

Emerging Innovations in Liver Preservation and Resuscitation.

The availability of marginal liver grafts represents a potential resource of orthotopic liver transplantation (OLT) in the era of organ shortage. However, an increased susceptibility to ischemia-reperfusion injury results in the increased risk for primary nonfunction and biliary complications. Novel methods of organ preservation and resuscitation are under investigation to improve outcomes of OLT with the use of marginal grafts. Machine perfusion (MP) in OLT is categorized based on the temperature setting. Hypothermic MP minimizes oxygen demand and uses single- or dual-vessel infusion with or without oxygenation. Normothermic MP increases the metabolic rate to the physiologic level, and requires dual-vessel infusion with a higher blood flow rate with oxygenation typically by blood as an oxygen carrier. Midthermic or subnormothermic MP uses medium temperature settings to allow metabolic activity to maintain cellular integrity as well as decrease oxygen demand. Since 2010, a total of 9 clinical trials have investigated the safety and feasibility of hypothermic and normothermic MP. The results suggest that the incidence of primary nonfunction was minimal even when marginal grafts were used. Organ preservation time could be reasonably increased. MP offers an opportunity to assess the viability and time to apply therapeutic interventions. This review highlights the history of MP, mechanisms of different temperature settings in MP, and recent large animal studies and clinical trials in OLT.

A Specialized Transplantation Critical Care Model: Expanding Liver Transplantation Access to High-Acuity Patients.

The current organ crisis has led to prolonged waiting times for liver transplantation, the progression of liver disease, and the subsequent increase in severity of illness. High acuity patients in need of orthotopic liver transplantation (OLT) maybe denied access to life-saving transplantation due to perceived poor outcomes after OLT and severe comorbid conditions. Recent studies demonstrated the highest survival benefit and acceptable post-OLT outcomes in high-acuity patients. This article provides an overview of a transplantation critical care model to increase liver transplantation access and optimize post-OLT outcomes in high-acuity patients.

Complications and Their Resolution in Recipients of Deceased and Living Donor Liver Transplants: Findings From the A2ALL Cohort Study.

The purpose of this study was to explore long-term complications in recipients of deceased donor liver transplant (DDLT) and living donor liver transplant (LDLT) in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). We analyzed 471 DDLTs and 565 LDLTs from 1998 to 2010 that were followed up to 10 years for 36 categories of complications. Probabilities of complications and their resolutions were estimated using the Kaplan-Meier method, and predictors were tested in Cox proportional hazards models. Median follow-up for DDLT and LDLT was 4.19 and 4.80 years, respectively. DDLT recipients were more likely to have hepatocellular carcinoma and higher disease severity, including Model for End-Stage Liver Disease score. Complications occurring with higher probability in LDLT included biliary-related complications and hepatic artery thrombosis. In DDLT, ascites, intra-abdominal bleeding, cardiac complications and pulmonary edema were significantly more probable. Development of chronic kidney disease stage 4 or 5 was less likely in LDLT recipients (hazard ratio [HR] 0.41, p = 0.02). DDLT and LDLT had similar risk of grade 4 complications (HR 0.89, p = 0.60), adjusted for other risk factors. Once a complication occurred, the time to resolution did not differ between LDLT and DDLT. Future efforts should be directed toward reducing the occurrence of complications after liver transplantation.

Sirolimus reduces the risk of significant hepatic fibrosis after liver transplantation for hepatitis C virus: a single-center experience.

INTRODUCTION: Hepatitis C virus (HCV) recurrence following orthotopic liver transplantation is an expected outcome in all patients transplanted for a primary diagnosis of HCV. HCV recurrence has been shown to be associated with graft fibrosis and graft loss. Recent studies suggest that sirolimus (SRL) therapy may slow or inhibit hepatic fibrosis following liver transplant in patients positive for HCV at the time of transplant. METHODS: Among 313 patients who underwent orthotopic liver transplantation for HCV between 2000 and 2009, 251 qualified for inclusion in the study. Per protocol liver biopsies were performed on all patients at 1 year following liver transplantation and/or at the time of a clinical diagnosis of HCV recurrence. Biopsies were scored for fibrosis using the Batts-Ludwig staging system (0-4); significant fibrosis was defined as fibrosis ≥ stage 2. RESULTS: Overall, there was no difference in overall survival or graft loss in the SRL compared with the control group. Multivariate analysis revealed SRL therapy to be associated with decreased odds of significant hepatic fibrosis at year 1 postoperatively and over the study duration. CONCLUSIONS: This retrospective, single-center study showed sirolimus-based immunosuppression to be associated with a lower risk of significant graft fibrosis, both at year 1 and throughout the study period, following liver transplantation in HCV-infected recipients.

Biological implications of extracellular adenosine in hepatic ischemia and reperfusion injury.

The purine nucleoside adenosine is clinically employed in the treatment of supraventricular tachycardia. In addition, it has direct coronary vasodilatory effects, and may influence platelet aggregation. Experimental observations mechanistically link extracellular adenosine to cellular adaptation to hypoxia. Adenosine generation has been implicated in several pathophysiologic processes including angiogenesis, tumor defenses and neurodegeneration. In solid organ transplantation, prolonged tissue ischemia and subsequent reperfusion injury may lead to profound graft dysfunction. Importantly, conditions of limited oxygen availability are associated with increased production of extracellular adenosine and subsequent tissue protection. Within the rapidly expanding field of adenosine biology, several enzymatic steps in adenosine production have been characterized and multiple receptor subtypes have been identified. In this review, we briefly examine the biologic steps involved in adenosine generation and chronicle the current state of adenosine signaling in hepatic ischemia and reperfusion injury.

Antiviral prophylaxis and recurrence of hepatocellular carcinoma following liver transplantation in patients with hepatitis B.

BACKGROUND: Orthotopic liver transplantation (OLT) is a viable treatment option for patients with hepatitis B (HBV) and concomitant hepatocellular carcinoma (HCC). However, cancer recurrence following transplantation approaches 20%. This study sought to identify the clinical and pathological factors associated with post-OLT survival. METHODS: Univariate and multivariate analyses considered the following variables: combination viral prophylaxis, HBV recurrence, tumor stage, vascular invasion, distribution, nodularity, pre- and post-OLT tumor size, pre-OLT alpha-fetoprotein (AFP), Milan and UCSF criteria, and Asian race. RESULTS: Cumulatively, HCC recurrence-free survival was 77%, 62%, and 53% at 1, 3, and 5 years, respectively, and was significantly better in patients who were free of viral recurrence post-OLT. Similarly, patients treated with combination prophylaxis had a significantly lower mortality than those who were not. CONCLUSIONS: Multivariate analysis revealed that AFP>500 ng/mL, presence of vascular invasion by explant, HBV recurrence, and combination prophylaxis were independent predictors of HCC recurrence-free survival.

Split liver transplantation.

Seventy-five thousand Americans develop organ failure each year. Fifteen percent of those on the list for transplantation die while waiting. Several possible mechanisms to expand the organ pool are being pursued including the use of extended criteria donors, living donation, and split deceased donor transplants. Cadaveric organ splitting results from improved understanding of the surgical anatomy of the liver derived from Couinaud. Early efforts focused on reduced-liver transplantation (RLT) reported by both Bismuth and Broelsch in the mid-1980s. These techniques were soon modified to create both a left lateral segment graft appropriate for a pediatric recipient and a right trisegment for an appropriately sized adult. Techniques of split liver transplantation (SLT) were also modified to create living donor liver transplantation. Pichlmayr and Bismuth reported successful split liver transplantation in 1989 and Emond reported a larger series of nine split procedures in 1990. Broelsch and Busuttil described a technical modification in which the split was performed in situ at the donor institution with surgical division completed in the heart beating cadaveric donor. In situ splitting reduces cold ischemia, simplifies identification of biliary and vascular structures, and reduces reperfusion hemorrhage. However, in situ splits require specialized skills, prolonged operating room time, and increased logistical coordination at the donor institution. At UCLA over 120 in situ splits have been performed and this technique is the default when an optimal donor is available. Split liver transplantation now accounts for 10% of adult transplantations at UCLA and 40% of pediatric transplantations.

Surgical applications of organ preconditioning.

In 1986, Murry et al. reported that brief periods of antecedent ischemia in dogs paradoxically reduced (rather than exacerbated) the size of myocardial infarcts created by subsequent prolonged ischemia. This fortuitous discovery, now termed "preconditioning", stimulated further investigation of the inherent adaptive mechanisms present in a variety of tissues and organs. In addition to ischemia, it is now recognized that a protective response can be initiated by multiple means including lipopolysaccharide, heat stress, exercise, adrenergic drugs and even noise. Furthermore, preconditioning protects not only against cell death but also against postischemic contractile dysfunction, stunning and arrhythmias. Despite the preponderance of animal studies demonstrating the benefits of preconditioning, its clinical application has been hampered by clinicians' hesitancy to intentionally subject patients to a noxious stress prior to a planned intervention. However, many of the intracellular signals responsible for the protective effect of preconditioning have been delineated, and pharmacologic manipulation of these signals can accomplish the same benefits. The existence of preconditioning in humans has been demonstrated in vitro and in small clinical trials, and targeted strategies that exploit this endogenous protective mechanism promise to broaden the therapeutic potential of organ preconditioning.

Organ preconditioning.

The initial discovery of cardiac preconditioning has evolved into an exciting series of practical surgical applications. An enormous amount of evidence demonstrating both the safety and efficacy of ischemic preconditioning is available from animal studies. The challenging premise of intentionally subjecting patients and their organs to transient ischemia has acted as a formidable psychological and ethical impediment to the widespread clinical application of organ preconditioning. A more palatable alternative to ischemic preconditioning now involves approved medications designed to manipulate the cellular machinery mediating ischemic preconditioning. Pharmacologically induced preconditioning seems to confer equal organ protection. The relatively brief (but surgically relevant) window of protection provided by strategies such as ischemic preconditioning or adenosine agonists and potassium-adenosine triphosphate channel openers may, in the future, be extended. We have developed and reported the feasibility of liposomal delivery of heat shock protein to cardiac myocytes with subsequent protection against sepsis-induced dysfunction. Targeted strategies will ultimately broaden the therapeutic potential of organ preconditioning.

Psychosocial outcomes of urban African American adolescents born to teenage mothers.

This is a study of psychosocial outcomes of adolescents born to teenage mothers. Adolescents'problem behaviors, psychological well-being, social support, school variables, and sexual behaviors are compared across three groups- those born to mothers 17 or younger, mothers 18-19 years old, and mothers 20 or older. Analyses from two samples of African American adolescents from Maryland (n = 205) and Michigan (n = 570) are reported. The results from both samples indicate that mother's age at birth is unrelated to adolescents' psychosocial outcomes. These two studies add to the limited number of analyses that examine adolescent outcomes for children of teen mothers. The results suggest that efforts to understand social structural determinants of healthy and problematic adolescent development may be more informative than examining the effects of mother's age. They also suggest that teen pregnancy prevention programs may be more effective if they are part of a larger prevention strategy that incorporates social structural change efforts and not only a focus on individual level change.

Vascular cell adhesion molecule--1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction.

BACKGROUND: Sepsis-induced cardiac dysfunction occurs commonly in critically ill patients and is associated with high mortality rates. Neutrophils play a central role in sepsis-induced lung and liver injury; however, the mechanism of sepsis-induced cardiac dysfunction remains unclear. Vascular cell adhesion molecule-1 (VCAM-1) has been implicated in neutrophil-mediated liver injury during endotoxemia and is also expressed in myocardium. The purposes of this study were to examine the temporal relationship of myocardial VCAM-1 expression with neutrophil accumulation during endotoxemia and to determine whether VCAM-1 mediates neutrophil accumulation and cardiac dysfunction during endotoxemia. METHODS: Mice were subjected to lipopolysaccharide (LPS; 0.5 mg/kg, intraperitoneally). Myocardial VCAM-1 expression and neutrophil accumulation were determined by immunofluorescence staining. Cardiac performance with or without VCAM-1 blocking antibody (5 mg/kg, intravenously) was determined by the Langendorff technique. RESULTS: LPS caused a time-dependent increase in both myocardial VCAM-1 expression and neutrophil accumulation. At 6 hours after LPS, the immunofluorescent intensity for VCAM-1 increased from 2.5 +/- 0.6 x 10(6) in saline solution controls to 19.9 +/- 3.5 x 10(6) (P <.05, analysis of variance), and neutrophil count increased from 2.4 +/- 1.7/mm(2) in saline solution controls to 13.0 +/- 2.5/mm(2) (P <.05). Left ventricular developed pressure was decreased maximally at 6 hours after LPS compared with saline solution controls (29.1 +/- 1.1 mm Hg vs 53.1 +/- 3.9 mm Hg; P <.05). Treatment with VCAM-1 monoclonal antibody abrogated both myocardial neutrophil accumulation and cardiac dysfunction during endotoxemia. CONCLUSIONS: LPS-induced myocardial dysfunction is associated with increased expression of VCAM-1 and with neutrophil accumulation. Blockade of VCAM-1 abrogates myocardial neutrophil accumulation and preserves cardiac function during endotoxemia, which supports a role for VCAM-1 as a therapeutic target for myocardial protection during sepsis.

Children's understanding of psychogenic bodily reactions.

One hundred twenty-eight children in preschool through fifth grade (range = 4,3-11,4) and 76 adults serving as a comparison group participated in two studies that examined how children reason about psychogenic bodily reactions, that is, ailments or nonconscious physiological responses with origins in the mind (e.g., stress-induced headache). Psychogenic bodily reactions provide an opportunity to study how children integrate knowledge between the domains of bodily response and psychology. In Study 1, participants were asked whether various familiar psychogenic bodily reactions were possible (e.g., can someone get a tummyache from worrying?). In Study 2, participants were presented with a novel domain (hypothetical "aliens" from outer space) and were asked whether various unfamiliar bodily conditions (e.g., toes swelling) could arise from various physical or psychological causes. As predicted, adults typically reported that psychogenic bodily reactions were possible, and that unfamiliar bodily conditions could result from either psychological or physical causes. In contrast, young children typically denied that psychogenic bodily reactions could occur and predicted that unfamiliar bodily conditions resulted from physical causes only. The results support a developmental path: younger children view psychogenic bodily responses as wholly physical, but with age, view them as both physical and psychological phenomena.

The case for beta-adrenergic blockade as prophylaxis against perioperative cardiovascular morbidity and mortality.

Perioperative morbidity and mortality are frequently cardiac in origin. Many studies have prospectively attempted to define risk factors for cardiac ischemic events. Although we can now identify high-risk patients, optimal cardioprotective management strategies remain unclear. Treatment with beta-adrenergic antagonists decreases myocardial oxygen consumption and is generally well tolerated. This article reviews the physiologic and clinical basis for using these agents as prophylaxis against cardiovascular events in high-risk surgical patients.

Clinical applications of cardiovascular angiogenesis.

Angiogenesis is fundamental to both normal physiologic (wound healing) and pathologic (cancer) processes. Manipulation of divergent angiogenic signals promises effective therapy of atherosclerotic cardiovascular disease. Positive proangiogenic strategies promise collateral circulation to ischemic territories, while negative antiangiogenic strategies starve the fibromuscular proliferation within the atherosclerotic lesion. Indeed, recent phase 1 trials suggest that delivering DNA or recombinant protein to the site of vascular occlusion may stimulate physiologically significant collateral circulation in chronically ischemic myocardium. While symptomatic and functional improvement has been documented, toxicity profiles and effects on long-term patient survival are still unclear. The purposes of this article are as follows: (1) to review the pathophysiologic basis for pro- and antiangiogenic strategies in the treatment of cardiovascular disease, (2) to examine the clinical trials of proangiogenic gene or recombinant protein delivery into ischemic beds, and conversely, (3) to explore antiangiogenic strategies in the prevention and treatment of intimal neovascularization and smooth muscle proliferation within the vessel wall.

Forging collaborative partnerships to enhance family health: an assessment of strengths and challenges in conducting community-based research.

Community-based research has emerged as a vital strategy for developing effective, culturally relevant health interventions. This article describes the strengths and challenges of building a collaborative research partnership based on equality between academic researchers, public health practitioners, and representatives from community-based organizations. The model of collaboration adopted for the Fathers and Sons Project is described and examples of model applications are discussed. Lessons learned in the form of strengths/benefits and potential pitfalls in developing a community-based intervention designed to enhance the health behaviors of African American nonresidential fathers and their sons are provided.

Gender differences in HIV-related sexual risk behavior among urban African American youth: a multivariate approach.

Alcohol and other drug (AOD) use during sexual encounters, sexual partner's age, perceived HIV risk and perceived condom effectiveness were studied among 388 sexually active African American youth. Cluster analysis of condom use, number of partners, and frequency of sexual intercourse identified four groups: low risk, monogamy strategy, condom strategy, and high risk. Low-risk youth used condoms consistently and had few partners. High-risk youth used condoms inconsistently with many partners. Monogamy strategy youth used condoms inconsistently but had few partners. Condom strategy youth used condoms consistently with a moderate number of partners. The high-risk group included more males and the monogamy group included more females. High-risk males reported more AOD use during sexual activity than all females, and low-risk or condom strategy males. Females had older partners, rated condoms as less effective and perceived lower HIV/AIDS risk than males. Results suggest differential HIV risk mechanisms by gender. Implications for gender-specific HIV prevention are discussed.

Inhibitory tagging in inhibition of return is affected in schizophrenia: evidence from the stroop task.

L. J. Fuentes, A. B. Vivas, and G. W. Humphreys (1999b) showed that stimulus processing is affected when stimuli are presented to locations subject to inhibition of return. They argued that activated representations of stimuli presented at inhibited locations are disconnected from their associated responses through an "inhibitory tagging" mechanism occurring in inhibition of return. In the present research, the authors asked whether such a mechanism is affected in people with schizophrenia. Healthy adults and patients with schizophrenia performed a Stroop task in an inhibition of return paradigm. Healthy adults showed a reduction in the Stroop interference when stimuli were presented at inhibited locations, a result that agrees with the inhibitory tagging mechanism hypothesis and replicates previous findings. However, patients with schizophrenia did not show such a reduction, a result suggesting that they have a deficit in inhibitory processing occurring in inhibition of return.

Inhibitory processing in visuospatial attention in healthy adults and schizophrenic patients.

This study assessed visuospatial attention in healthy adults and medicated schizophrenic patients. Participants performed a visual orientation task in which a peripheral cue was followed. at different intervals, by a target presented either at valid or invalid locations. When the long stimulus onset asynchrony (SOA) was used, participants were presented with either a single peripheral cue (single-cue condition) or two cues, the peripheral cue followed by a central cue (the double-cue condition). Healthy adults showed marginal facilitation effects with the short SOA and similar inhibition of return effects with the long SOA in both single-cue and double-cue conditions. Schizophrenic individuals showed a big facilitation effect with the short SOA and normal inhibition of return with the long SOA in both cue conditions. Results with the short SOA replicated previous findings (Huey, E.D., Wexler, B.E., 1994. Schizophrenia Research 14, 57-63) but, in contrast, we did not observe blunted inhibition of return with the long SOA. An inspection of the differences in the procedures used in both studies may help both to account for the discrepancies and to reveal what processes involved in visuospatial attention are affected in schizophrenia.