Identifying drivers of cost in pediatric liver transplantation.

Understanding the economics of pediatric liver transplantation (LT) is central to high-value care initiatives. We examined cost and resource utilization in pediatric LT nationally to identify drivers of cost and hospital factors associated with greater total cost of care. We reviewed 3295 children (<21 y) receiving an LT from 2010 to 2020 in the Pediatric Health Information System to study cost, both per LT and service line, and associated mortality, complications, and resource utilization. To facilitate comparisons, patients were stratified into high-cost, intermediate-cost, or low-cost tertiles based on LT cost. The median cost per LT was $150,836 [IQR $104,481-$250,129], with marked variance in cost within and between hospital tertiles. High-cost hospitals (HCHs) cared for more patients with the highest severity of illness and mortality risk levels (67% and 29%, respectively), compared to intermediate-cost (60%, 21%; p <0.001) and low-cost (51%, 16%; p <0.001) hospitals. Patients at HCHs experienced a higher prevalence of mechanical ventilation, total parental nutrition use, renal comorbidities, and surgical complications than other tertiles. Clinical (27.5%), laboratory (15.1%), and pharmacy (11.9%) service lines contributed most to the total cost. Renal comorbidities ($69,563) and total parental nutrition use ($33,192) were large, independent contributors to total cost, irrespective of the cost tertile ( p <0.001). There exists a significant variation in pediatric LT cost, with HCHs caring for more patients with higher illness acuity and resource needs. Studies are needed to examine drivers of cost and associated outcomes more granularly, with the goal of defining value and standardizing care. Such efforts may uniquely benefit the sicker patients requiring the strategic resources located within HCHs to achieve the best outcomes.

Intraoperative renal replacement therapy during liver transplantation in children: Safety, efficacy and impact on survival.

BACKGROUND: Intraoperative Continuous Renal Replacement Therapy (iCRRT) can prevent life-threatening complications, facilitate fluid management, and maintain metabolic homeostasis during liver transplantation (LT) in adults. There is a paucity of data in pediatric LT. We evaluated the safety, efficacy, and impact on survival of iCRRT in pediatric LT. METHODS: We conducted a retrospective cohort study of all children requiring CRRT pre-OLT at a quaternary children's hospital from 2014 to 2022. Demographic characteristics, intraoperative events, and post-LT outcomes were compared between those who received iCRRT and those who did not. RESULTS: Out of 306 patients who received LT, 30 (10%) were supported with CRRT at least 24 h prior to LT, of which 11 (36%) received iCRRT. The two cohorts were similar in demographics, diagnosis of liver disease, and severity of illness. The iCRRT patients experienced massive blood loss and increased transfusion requirements. There was no difference in intraoperative metabolic balance. One-year post-LT mortality rates were similar. CONCLUSION: ICRRT is safe in critically ill children with pre-LT renal dysfunction. It optimizes fluid and blood product resuscitation while maintaining metabolic homeostasis. Candidates need to be carefully chosen for this highly resource-intensive therapy to benefit this fragile population.

Postoperative outcomes of acute-on-chronic liver failure in infants and children with biliary atresia.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is associated with increased mortality and morbidity in patients with biliary atresia (BA). Data on impact of ACLF on postoperative outcomes, however, are sparse. METHOD: We performed a retrospective analysis of patients with BA aged <18 years who underwent LT between 2011 and 2021 at our institution. ACLF was defined using the pediatric ACLF criteria: ≥1 extra-hepatic organ failure in children with decompensated cirrhosis. RESULTS: Of 107 patients (65% female; median age 14 [9-31] months) who received a LT, 13 (12%) had ACLF during the index admission prior to LT. Two (15%) had Grade 1; 4 (30%) had Grade 2; and 7 (55%) had Grade ≥3 ACLF. ACLF cohort was younger at time of listing (5 [4-8] vs. 9 [6-24] months; p < .001) and at LT (8 [8-11] vs. 16 [10-40] months, p < .001) compared to no-ACLF group. Intraoperatively, ACLF patients had higher blood loss (40 [20-53] vs. 10 [6-19] mL/kg; p < .001) and blood transfusion requirements (33 [21-69] vs. 18 [7-25] mL/kg; p = .004). Postoperatively, they needed higher vasopressor support (31% vs. 10.6%; p = .04) and had higher total hospital length of stay (106 [45-151] vs. 13 [7-30] days; p = .023). Rate of return to the operating room, hospital readmission rates, and 1-year post-LT survival rates were comparable between the groups. CONCLUSION: Despite higher perioperative complications, survival outcomes for ACLF in BA after LT are favorable and comparable to those without ACLF. These encouraging data reiterate prioritization during organ allocation of these critically ill children for LT.

Estimating risk of prolonged mechanical ventilation after liver transplantation in children: PROVE-ALT score.

BACKGROUND: Children at high risk for prolonged mechanical ventilation (PMV) after liver transplantation (LT) need to be identified early to optimize pulmonary support, allocate resources, and improve surgical outcomes. We aimed to develop and validate a metric that can estimate risk for Prolonged Ventilation After LT (PROVE-ALT). METHODS: We identified preoperative risk factors for PMV by univariable analysis in a retrospective cohort of pediatric LT recipients between 2011 and 2017 (n = 205; derivation cohort). We created the PROVE-ALT score by mapping multivariable logistic regression coefficients as integers, with cutoff values using the Youden Index. We validated the score by C-statistic in a retrospectively collected separate cohort of pediatric LT recipients between 2018 and 2021 (n = 133, validation cohort). RESULTS: Among total 338 patients, 21% (n = 72) were infants; 49% (n = 167) had cirrhosis; 8% (n = 27) required continuous renal replacement therapy (CRRT); and 32% (n = 111) required management in hospital (MIH) before LT. Incidence of PMV post-LT was 20% (n = 69) and 3% (n = 12) required tracheostomy. Independent risk factors (OR [95% CI]) for PMV were cirrhosis (3.8 [1-14], p = .04); age <1-year (8.2 [2-30], p = .001); need for preoperative CRRT (6.3 [1.2-32], p = .02); and MIH before LT (12.4 [2.1-71], p = .004). PROVE-ALT score ≥8 [Range = 0-21] accurately predicted PMV in the validation cohort with 73% sensitivity and 80% specificity (AUC: 0.81; 95% CI: 0.71-0.91). CONCLUSION: PROVE-ALT can predict PMV after pediatric LT with a high degree of sensitivity and specificity. Once externally validated in other centers, PROVE-ALT will empower clinicians to plan patient-specific ventilation strategies, provide parental anticipatory guidance, and optimize hospital resources.

Acute liver failure and unique challenges of pediatric liver transplantation amidst a worldwide cluster of adenovirus-associated hepatitis.

Investigation into a recent cluster of acute hepatitis in children from the southeastern United States identified human adenovirus (HAdV) DNAemia in all 9 cases. Molecular genotyping in 5 of 9 (56%) children identified HAdV type 41 in all cases (100%). Importantly, 2 children from this cluster progressed rapidly to pediatric acute liver failure (PALF) and required liver transplantation. HAdV type 41, a known cause of self-limited gastroenteritis, has not previously been associated with severe cholestatic hepatitis and liver failure in healthy children. Adenovirus polymerase chain reaction assay and sequencing of amplicons performed on DNA extracted from formalin-fixed, paraffin-embedded liver tissue also identified adenovirus species F (HAdV type 40 or 41) in these 2 children with PALF. Transplant considerations and successful liver transplantation in such situations remain scarce. In this report, we describe the clinical course, laboratory results, liver pathology, and treatment of 2 children with PALF associated with HAdV type 41, one of whom developed secondary hemophagocytic lymphohistiocytosis. Their successful posttransplant outcomes demonstrate the importance of early multidisciplinary medical management and the feasibility of liver transplantation in some children with PALF and HAdV DNAemia.

P2Y2 purinergic receptor gene deletion protects mice from bacterial endotoxin and sepsis-associated liver injury and mortality.

The liver plays a significant role in regulating a wide range of metabolic, homeostatic, and host-defense functions. However, the impact of liver injury on the host's ability to control bacteremia and morbidity in sepsis is not well understood. Leukocyte recruitment and activation lead to cytokine and chemokine release, which, in turn, trigger hepatocellular injury and elevate nucleotide levels in the extracellular milieu. P2Y2 purinergic receptors, G protein-coupled and activated by extracellular ATP/UTP, are expressed at the cell surface of hepatocytes and nonparenchymal cells. We sought to determine whether P2Y2 purinergic receptor function is necessary for the maladaptive host response to bacterial infection and endotoxin-mediated inflammatory liver injury and mortality in mice. We report that P2Y2 purinergic receptor knockout mice (P2Y2-/-) had attenuated inflammation and liver injury, with improved survival in response to LPS/galactosamine (LPS/GalN; inflammatory liver injury) and cecal ligation and puncture (CLP; polymicrobial sepsis). P2Y2-/- livers had attenuated c-Jun NH2-terminal kinase activation, matrix metallopeptidase-9 expression, and hepatocyte apoptosis in response to LPS/GalN and attenuated inducible nitric oxide synthase and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 protein expression in response to CLP. Implicating liver injury in the disruption of amino acid homeostasis, CLP led to lower serum arginine and higher bacterial load and morbidity in the WT mice, whereas serum arginine levels were comparable to sham-operated controls in P2Y2-/- mice, which had attenuated bacteremia and improved survival. Collectively, our studies highlight the pathophysiological relevance of P2Y2 purinergic receptor function in inflammatory liver injury and dysregulation of systemic amino acid homeostasis with implications for sepsis-associated immune dysfunction and morbidity in mice.NEW & NOTEWORTHY Our studies provide experimental evidence for P2Y2 purinergic receptor-mediated potentiation of inflammatory liver injury, morbidity, and mortality, in two well-established animal models of inflammatory liver injury. Our findings highlight the potential to target P2Y2 purinergic signaling to attenuate the induction of "cytokine storm" and prevent its deleterious consequences on liver function, systemic amino acid homeostasis, host response to bacterial infection, and sepsis-associated morbidity and mortality.

Mechanistic insights into the pathophysiology of cirrhotic cardiomyopathy.

Myocardial dysfunction in end stage cirrhotic liver disease, termed cirrhotic cardiomyopathy, is a long known, but little understood comorbidity seen in ∼50% of adults and children who present for liver transplantation. Structural, functional, hemodynamic and electrocardiographic aberrations that occur in the heart as a direct consequence of a damaged liver, is associated with multi-organ failure and increased mortality and morbidity in patients undergoing surgical procedures such as porto-systemic shunt placement and liver transplantation. Despite its clinical significance and rapid advances in science and pharmacotherapy, there is yet no specific treatment for this disease. This may be due to a lack of understanding of the pathogenesis and mechanisms behind how a cirrhotic liver causes cardiac pathology. This review will focus specifically on insights into the molecular mechanisms that drive this liver-heart interaction. Deeper understanding of the etio-pathogenesis of cirrhotic cardiomyopathy will allow us to design and test treatments that can be targeted to prevent and/or reverse this co-morbid consequence of liver failure and improve health care delivery and outcomes in patients with cirrhosis.

Our evolution in the treatment of hepatic artery and portal vein thrombosis in pediatric liver transplantation: Success with catheter-directed therapies.

BACKGROUND: In pediatric liver transplant recipients, hepatic artery thrombosis and portal vein thrombosis are major causes of acute graft failure and mortality within 30 days of transplantation. There is, however, a strong possibility of graft salvage if flow can be re-established to reduce ischemic injury. The current standard treatment is surgical revascularization, and if unsuccessful, retransplantation. Due to our success in treating these complications with catheter-directed therapies, we sought to summarize and publish the outcomes of all patients who experienced hepatic artery thrombosis or portal vein thrombosis within 30 days of liver transplantation. METHODS: We conducted a retrospective cohort analysis of 27 pediatric liver transplant recipients who experienced hepatic artery thrombosis (n = 13), portal vein thrombosis (n = 9), or both (n = 5) between September 2012 and March 2021. We collected and tabulated data on the patients and therapies performed to treat them, including success rates, primary and secondary patency, and clinical outcomes. RESULTS: Among these patients, 6 were managed with anticoagulation and relisting for transplant and 21 had a primary revascularization attempt. Surgical recanalization was attempted in 7 patients of which 3 had successful recanalization (43%) and catheter-directed recanalization was attempted in 14 patients with 100% success in re-establishing blood flow to the graft. Additionally, patency was increased, and mortality was decreased in patients treated with catheter-directed recanalization compared to surgical revascularization or anticoagulation alone. CONCLUSION: This data illustrates the need to further investigate catheter-directed thrombolysis as a potential first-line treatment for postoperative HAT and PVT in pediatric liver transplant recipients.

The use of tracheostomy to support critically ill children receiving orthotopic liver transplantation: a single-center experience.

BACKGROUND: Children with end-stage liver disease and multi-organ failure, previously considered as poor surgical candidates, can now benefit from liver transplantation (LT). They often need prolonged mechanical ventilation (MV) post-LT and may need tracheostomy to advance care. Data on tracheostomy after pediatric LT are lacking. METHOD: Retrospective chart review of children who required tracheostomy in the peri-LT period in a large, freestanding quaternary children's hospital from 2014 to 2019. RESULTS: Out of 205 total orthotopic LTs performed in 200 children, 18 (9%) required tracheostomy in the peri-transplant period: 4 (2%) pre-LT and 14 (7%) post-LT. Among those 14 needing tracheostomy post-LT, median age was 9 months [IQR = 7, 14] at LT and 10 months [9, 17] at tracheostomy. Nine (64%) were infants and 12 (85%) were cirrhotic at the time of LT. Seven (50%) were intubated before LT. Median MV days prior to LT was 23 [7, 36]. Eight (57%) patients received perioperative continuous renal replacement therapy (CRRT). The median MV days from LT to tracheostomy was 46 [33, 56]; total MV days from initial intubation to tracheostomy was 57 [37, 66]. Four (28%) children died, of which 3 (21%) died within 1 year of transplant. Total ICU and hospital length of stay were 92 days [I72, 126] and 177 days [115, 212] respectively. Among survivors, 3/10 (30%) required MV at home and 8/10 (80%) were successfully decannulated at 400 median days [283, 584]. CONCLUSION: Tracheostomy though rare after LT remains a feasible option to support and rehabilitate critically ill children who need prolonged MV in the peri-LT period.

The effect of continuous venovenous hemodiafiltration on amino acid delivery, clearance, and removal in children.

BACKGROUND: In critically ill children with acute kidney injury (AKI), continuous kidney replacement therapy (CKRT) enables nutrition provision. The magnitude of amino acid loss during continuous venovenous hemodiafiltration (CVVHDF) is unknown and needs accurate quantification. We investigated the mass removal and clearance of amino acids in pediatric CVVHDF. METHODS: This is a prospective observational cohort study of patients receiving CVVHDF from August 2014 to January 2016 in the pediatric intensive care unit (PICU) of a tertiary children's hospital. RESULTS: Fifteen patients (40% male, median age 2.0 (IQR 0.7, 8.0) years) were enrolled. Median PICU and hospital lengths of stay were 20 (9, 59) and 36 (22, 132) days, respectively. Overall survival to discharge was 66.7%. Median daily protein prescription was 2.00 (1.25, 2.80) g/kg/day. Median daily amino acid mass removal was 299.0 (174.9, 452.0) mg/kg body weight, and median daily amino acid mass clearance was 18.2 (13.5, 27.9) ml/min/m2, resulting in a median 14.6 (8.3, 26.7) % protein loss. The rate of amino acid loss increased with increasing dialysis dose and blood flow rate. CONCLUSION: CVVHDF prescription and related amino acid loss impact nutrition provision, with 14.6% of the prescribed protein removed. Current recommendations for protein provision for children requiring CVVHDF should be adjusted to compensate for circuit-related loss. A higher resolution version of the Graphical abstract is available as Supplementary information.

Clinical Consequences of Cardiomyopathy in Children With Biliary Atresia Requiring Liver Transplantation.

Cirrhotic cardiomyopathy (CCM), a comorbidity of end-stage cirrhotic liver disease, remains uncharacterized in children, largely because of a lack of an established pediatric definition. The aim of this retrospective cohort analysis is to derive objective two-dimensional echocardiographic (2DE) criteria to define CCM associated with biliary atresia (BA), or BA-CCM, and correlate presence of BA-CCM with liver transplant (LT) outcomes in this population. Using receiver operating characteristic (ROC) curve analysis, optimal cut-off values for left ventricular (LV) geometrical parameters that were highly sensitive and specific for the primary outcomes: A composite of serious adverse events (CSAE) and peritransplant death were determined. These results were used to propose a working definition for BA-CCM: (1) LV mass index (LVMI) ≥95 g/m2.7 or (2) relative wall thickness of LV ≥0.42. Applying these criteria, BA-CCM was found in 34 of 69 (49%) patients with BA listed for LT and was associated with increased multiorgan dysfunction, mechanical and vasopressor support, and longer intensive care unit (ICU) and hospital stays. BA-CCM was present in all 4 waitlist deaths, 7 posttransplant deaths, and 20 patients with a CSAE (P < 0.01). On multivariable regression analysis, BA-CCM remained independently associated with both death and a CSAE (P < 0.01). Utilizing ROC analysis, LVMI was found to be a stronger predictor for adverse outcomes compared with current well-established markers, including Pediatric End-Stage Liver Disease (PELD) score. Conclusion: BA-CCM is highly sensitive and specific for morbidity and mortality in children with BA listed for LT. 2DE screening for BA-CCM may provide pertinent clinical information for prioritization and optimal peritransplant management of these children.

The Safety and Efficacy of Regional Citrate Anticoagulation in Albumin-Assisted Liver Dialysis for Extracorporeal Liver Support in Pediatric Patients.

AIMS: To establish the safety and efficacy of regional citrate anticoagulation (RCA) for pediatric liver failure (LF) patients receiving extracorporeal liver support (ELS) with albumin-assisted dialysis. METHODS: Retrospective review of pediatric LF patients receiving ELS from April 2014 to December 2016 at a tertiary children's hospital pediatric intensive care unit. Demographic and ELS data collected by chart review. Citrate accumulation (CA) was defined as total calcium (mmol/L): ionized calcium (mmol/L) > 2.5 (tCa:iCa). Efficacy was assessed by treatment duration. Safety was assessed by adverse events: bleeding, hemodynamic instability, arrhythmias, unplanned treatment discontinuation. RESULTS: Fifteen patients (median age 3 [interquartile range (IQR) 0.7-8.0]) received 108 ELS treatments (median 5 [IQR 4-7.5]). Sixty-eight episodes of CA were identified. Of those, 6 coincided with intervention and 1 coincided with ELS discontinuation. There were no deaths attributed to ELS or RCA. CONCLUSION: RCA provides safe and effective anticoagulation for pediatric LF patients requiring ELS.

Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart.

Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator-activated receptor-γ coactivator 1α, a key regulator of fatty acid metabolism, and that proliferator-activated receptor-γ coactivator 1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice. CONCLUSIONS: Decreased proliferator-activated receptor-γ coactivator 1α expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart. (Hepatology 2017;65:189-201).

Trends in pediatric liver transplant donors and deceased donor circumstance of death in the United States, 2002-2015.

While much of the discussion regarding expanding the donor pool for pediatric liver transplantation has surrounded the use of technical variant grafts, little attention has been directed toward changes in the deceased donor population. The aim of this study was to investigate trends in the circumstance of the death of deceased donors used for pediatric liver transplantation. All pediatric liver transplant recipients transplanted between 2002 and 2015 were identified in the UNOS database and were categorized based on the donor circumstance of death. There was no significant correlation between year of transplantation and number of pediatric liver transplants performed, pediatric donors, split livers, or living donors. There was a significant downward trend in donors from motor vehicle fatalities and an upward trend in suicide, non-MVA, and death due to natural causes. There was also an upward trend in drowning, one of the most common mechanisms of death among non-MVA in 2015. While the number of donors who died in MVA has fallen, the number of deceased donors who died from suicide, natural causes, and non-MVA, especially drowning, has increased, maintaining the overall number of pediatric deceased donor livers transplanted.

ABO-incompatible deceased donor pediatric liver transplantation: Novel titer-based management protocol and outcomes.

ABO-ILT have re-emerged as an alternate option for select patients awaiting transplant. However, treatment protocols for children undergoing deceased donor ABO-ILT are not standardized. We implemented a novel IS protocol for children undergoing deceased donor ABO-ILT based on pretransplant IH titers. Children with high pretransplant IH titers (≥1:32) underwent an enhanced IS protocol including plasmapheresis, rituximab, IVIG, and mycophenolate, while children with IH titers ≤1:16 received steroids and tacrolimus. We retrospectively assessed our outcomes of ABO-ILT with ABO-compatible recipients of similar age and diagnosis over a 2-year period. Ten children with median age of 8.9 months underwent ABO-ILT, 4 of 10 patients underwent enhanced IS due to high IH titers. Rates of complications (rejection, infections, biliary, and vascular) at both 1 year and up to 3 years post-transplant were comparable between the groups. Patients with ABO-ILT had good graft function with 100% survival at a median follow-up of 3.3 years. In conclusion, IS tailored to pretransplant IH titers in pediatric deceased donor ABO-ILT is feasible and can achieve outcomes similar to ABO-CLT at 1 and 3 years post-transplantation.

Hybrid Extracorporeal Therapies as a Bridge to Pediatric Liver Transplantation.

OBJECTIVES: Standard intensive care treatment is inadequate to keep children with liver failure alive without catastrophic complications to ensure successful transplant, as accumulation of endogenous protein-bound toxins often lead to hepatic encephalopathy, hepatorenal syndrome, cardiovascular instability, and multiple organ failure. Given paucity of proven treatment modalities for liver failure, blood purification using different extracorporeal treatments as a bridge to transplantation is used, but studies evaluating the safety and efficacy of combination of these therapies, especially in pediatric liver failure, are lacking. We describe our experience at a major tertiary children's hospital, where a unique hybrid extracorporeal treatment protocol has been instituted and followed for acute liver failure or acute-on-chronic liver failure as a bridge to transplantation. This protocol combines high-flux continuous renal replacement therapy for hyperammonemia, therapeutic plasma exchange for coagulopathy, and albumin-assisted dialysis (molecular adsorbent recirculating system) for hepatic encephalopathy. DESIGN: Retrospective observational study. SETTING: Freestanding tertiary children's hospital and liver transplant referral center. PATIENTS: All patients with acute liver failure/acute-on-chronic liver failure receiving hybrid extracorporeal therapy over 24 months. INTERVENTION: Hybdrid extracorporeal therapy. MEASUREMENTS AND MAIN RESULTS: Fifteen children (age 3 yr [0.7-9 yr]; 73% male) with acute liver failure/acute-on-chronic liver failure who were either listed or actively considered for listing and met our protocol criteria were treated with hybrid extracorporeal therapy; 93% were ventilated, and 80% were on vasoactive support. Of these, two patients recovered spontaneously, four died prior to transplant, and nine were successfully transplanted; 90-day survival post orthotopic liver transplant was 100%. Overall survival to hospital discharge was 73%. CONCLUSIONS: Hybrid extracorporeal therapies can be effectively implemented in pediatric liver failure as a bridge to transplantation. Overall complexity and heavy resource utilization need to be carefully considered in instituting these therapies in suitable candidates.

Hepatobiliary Dysfunction and Disseminated Intravascular Coagulation Increase Risk of Mortality in Pediatric Hemophagocytic Lymphohistiocytosis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis poses significant challenges due to limited tools to guide clinical decisions in a population at high risk of death. We sought to assess whether disseminated intravascular coagulation and hepatobiliary dysfunction, significant comorbidities seen in critical care settings, would identify hemophagocytic lymphohistiocytosis patients with increased risk of mortality. DESIGN: Retrospective chart review. SETTING: Single-center PICU. PATIENTS: All patients admitted to a tertiary care children's hospital diagnosed with hemophagocytic lymphohistiocytosis from 2005 to 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-three patients were diagnosed with hemophagocytic lymphohistiocytosis with median age of 61 months. The 5-year overall survival was 51% (22/43). Univariate analyses revealed ferritin levels greater than 10,000 (ng/mL), international normalized ratio greater than 1.5, or platelet counts less than 100,000/µL at initiation of dexamethasone were individually associated with mortality. Development of disseminated intravascular coagulation, hepatobiliary dysfunction, or both increased the likelihood of death in hemophagocytic lymphohistiocytosis patients (relative risk; 95% CI) (6; 1.4-34; p < 0.05), (4.1; 1.8-10; p < 0.05), and (7.5; 1.8-42; p < 0.05). Of 12 autopsies performed, 75% had at least one active infection, 66% had chronic lymphopenia, 50% had lymphocyte depletion in the spleen, thymus, or bone marrow, 42% had evidence of microvascular thrombosis, and 92% had evidence of hepatocellular injury. CONCLUSIONS: Hemophagocytic lymphohistiocytosis continues to have high mortality with hemophagocytic lymphohistiocytosis-1994/2004 (dexamethasone/etoposide), the current standard of care for all children with hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis patients who developed disseminated intravascular coagulation, hepatobiliary dysfunction, or both had higher risk of death with mortalities of 60%, 77%, and 77%, respectively. Phenotypic classifications are urgently needed to guide individualized treatment strategies to improve outcomes for children with hemophagocytic lymphohistiocytosis.

Cardiomyopathy reverses with recovery of liver injury, cholestasis and cholanemia in mouse model of biliary fibrosis.

BACKGROUND: Triggers and exacerbants of cirrhotic cardiomyopathy (CC) are poorly understood, limiting treatment options in patients with chronic liver diseases. Liver transplantation alone reverses some features of CC, but the physiology behind this effect has never been studied. AIMS: We aimed to determine whether reversal of liver injury and fibrosis in mouse affects cardiac parameters. The second aim was to determine whether cardiomyopathy can be induced by specifically increasing systemic bile acid (BA) levels. METHODS: 6-8 week old male C57BL6J mice were fed either chow (n = 5) or 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) (n = 10) for 3 weeks. At the end of 3 weeks, half the mice in the DDC fed group were randomized to chow (the reversed [REV] group). Serial ECHOs and electrocardiographic analysis was conducted weekly for 6 weeks followed by liver tissue and serum studies. Hearts were analysed for key components of function and cell signalling. Cardiac physiological and molecular parameters were similarly analysed in Abcb11(-/-) mice (n = 5/grp) fed 0.5% cholic acid supplemented diet for 1 week. RESULTS: Mice in the REV group showed normalization of biochemical markers of liver injury with resolution of electrocardiographic and ECHO aberrations. Catecholamine resistance seen in DDC group resolved in the REV group. Cardiac recovery was accompanied by normalization of cardiac troponin-T2 as well as resolution of cardiac stress response at RNA level. Cardiovascular physiological and molecular parameters correlated with degree of cholanemia. Cardiomyopathy was reproduced in cholanemic BA fed Abcb11(-/-) mice. CONCLUSIONS: Cardiomyopathy resolves with resolution of liver injury, is associated with cholanaemia, and can be induced by BA feeding.

Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXRα variant lacking the DNA-binding domain.

BACKGROUND & AIMS: Retinoid X Receptor α (RXRα) is the principal heterodimerization partner of class II Nuclear Receptors (NRs), and a major regulator of gene expression of numerous hepatic processes, including bile acid (BA) homeostasis through multiple partners. Specific contributions of hepatic RXRα domains in heterodimer function in response to either BA load or ductular cholestasis are not fully characterized. METHODS: Wild-type (WT) mice and mice expressing a hepatocyte-specific RXRα lacking the DNA-Binding-Domain (hs-RxrαΔex4(-/-)), which retains partial ability to heterodimerize with its partners, were fed a 1% cholic acid (CA) diet for 5 days, a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 3 weeks, or control diet. RESULTS: Serum ALT (6.5-fold; p<0.05), AST (9.3-fold; p=0.06) and BA (2.8-fold; p<0.05) were increased in CA-fed hs-RxαΔex4(-/-) mice compared to CA-fed WT mice, but were equally induced between genotypes by DDC-feeding. CA-feeding elevated total (4.4-fold; p=0.06) and unconjugated (2.2-fold; p<0.02) bilirubin levels in hs-RxrαΔex4(-/-) mice compared to WT mice, but not in DDC-fed hs-RxrαΔex4(-/-) mice. Increased necrosis and inflammation was observed in CA-fed, but not in DDC-fed hs-RxrαΔex4(-/-) mice. Apoptotic markers DR5, CK8, CK18 RNA were increased in CA- and DDC-fed hs-RxrαΔex4(-/-) mice. Cleaved caspase 3, CK18 and p-JNK protein were elevated in CA-fed but not in DDC-fed hs-RxrαΔex4(-/-) mice. Induction of Ostß and Cyp2b10 RNA was impaired in CA-fed and DDC-fed hs-RxrαΔex4(-/-) mice. Surprisingly, DDC-fed hs-RxrαΔex4(-/-) mice showed attenuated fibrosis compared to DDC-fed WT mice. CONCLUSIONS: These two models of cholestasis identify common and injury-specific roles for RXRα heterodimers and the functional relevance of an intact RXRα-DBD in the hepatocytic adaptive cholestatic response.

Catheter-directed thrombolysis for severe pulmonary embolism in pediatric patients.

BACKGROUND: Catheter-directed thrombolytic (CDT) therapies for severe pulmonary embolism (PE) have been shown to be effective and safe when compared with systemic thrombolysis in adults. Pediatric studies assessing efficacy and safety of CDT for PE are lacking. Hence, our aim was to review CDT as a therapy for pediatric PE. METHODS: We retrospectively reviewed charts of patients aged <18 years, who underwent CDT for main or major branch pulmonary artery occlusion associated with hypotension or right ventricular dysfunction secondary to PE during a 3-year period, in our tertiary care academic Pediatric Intensive Care Unit. RESULTS: Six CDT interventions were performed on 5 patients with PE (median age: 16.5 years). All patients presented with chest pain and dyspnea. The predisposing factors for thrombogenesis differed in all patients, and all had multiple risk factors. Five of six procedures (83%) were accompanied by ultrasound agitation with EKOS endowave infusion system (ultrasound-accelerated CDT [UCDT]), whereas 1 had CDT without ultrasound agitation. Complete resolution of PE occurred in 4 instances (67%) at 24 hr, whereas in 2 cases (33%), there was partial resolution. One patient with complete resolution underwent another successful UCDT after 4 months for recurrence. Clinical parameters (heart rate, respiratory rate, blood pressure, and oxygen saturations) and echocardiographic findings improved after treatment in all the patients. Median duration of hospital stay was 9 days with no mortality and treatment-related complications. All patients were discharged with long-term anticoagulation. CONCLUSIONS: Our case series is the first that describes CDT/UCDT as an effective and safe therapy for pediatric patients with severe PE. CDT is known to accelerate fibrinolysis via focused delivery of thrombolytic agent to the thrombus site. For carefully selected patients, CDT/UCDT provides a useful treatment option for severe PE irrespective of the etiology, predisposing conditions, and associated comorbidities.