RESUMO
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.
Assuntos
Custos Hospitalares , Transplante de Fígado , Humanos , Transplante de Fígado/economia , Transplante de Fígado/estatística & dados numéricos , Transplante de Fígado/efeitos adversos , Criança , Masculino , Pré-Escolar , Feminino , Lactente , Adolescente , Custos Hospitalares/estatística & dados numéricos , Estados Unidos , Complicações Pós-Operatórias/economia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Estudos Retrospectivos , Doença Hepática Terminal/cirurgia , Doença Hepática Terminal/economia , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/diagnóstico , Índice de Gravidade de Doença , Tempo de Internação/estatística & dados numéricos , Tempo de Internação/economia , Adulto Jovem , Custos de Cuidados de Saúde/estatística & dados numéricos , Recém-NascidoRESUMO
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.
Assuntos
Terapia de Substituição Renal Contínua , Transplante de Fígado , Adulto , Humanos , Criança , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Terapia de Substituição RenalRESUMO
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.
Assuntos
Insuficiência Hepática Crônica Agudizada , Atresia Biliar , Transplante de Fígado , Lactente , Humanos , Criança , Feminino , Adolescente , Masculino , Insuficiência Hepática Crônica Agudizada/complicações , Insuficiência Hepática Crônica Agudizada/diagnóstico , Estudos Retrospectivos , Atresia Biliar/complicações , Atresia Biliar/cirurgia , Taxa de Sobrevida , Cirrose Hepática/complicações , Cirrose Hepática/cirurgia , PrognósticoRESUMO
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.
Assuntos
Transplante de Fígado , Respiração Artificial , Lactente , Humanos , Criança , Estudos Retrospectivos , Transplante de Fígado/efeitos adversos , Fatores de Risco , Cirrose Hepática/etiologiaRESUMO
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.
Assuntos
Infecções por Adenovirus Humanos , Gastroenterite , Falência Hepática Aguda , Transplante de Fígado , Criança , Humanos , Transplante de Fígado/efeitos adversos , Adenoviridae , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/cirurgiaRESUMO
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.
Assuntos
Bacteriemia , Infecções Bacterianas , Sepse , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Deleção de Genes , Fígado , Citocinas/genética , Bacteriemia/complicações , Bacteriemia/genética , Nucleotídeos , Arginina , Receptores Purinérgicos , Aminoácidos , Camundongos Endogâmicos C57BL , Receptores Purinérgicos P2Y2/genética , Camundongos KnockoutRESUMO
Myocardial dysfunction in end stage cirrhotic liver disease, termed cirrhotic cardiomyopathy, is a long known, but little understood comorbidity seen in â¼50% 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.
Assuntos
Cardiomiopatias , Hemodinâmica , Cirrose Hepática , Transplante de Fígado , Fígado , Miocárdio/metabolismo , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Humanos , Fígado/metabolismo , Fígado/fisiopatologia , Fígado/cirurgia , Cirrose Hepática/complicações , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Cirrose Hepática/cirurgiaRESUMO
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.
Assuntos
Hepatopatias , Transplante de Fígado , Trombose , Trombose Venosa , Anticoagulantes/uso terapêutico , Catéteres/efeitos adversos , Criança , Sobrevivência de Enxerto , Artéria Hepática/cirurgia , Humanos , Hepatopatias/complicações , Transplante de Fígado/efeitos adversos , Veia Porta/cirurgia , Estudos Retrospectivos , Trombose/etiologia , Trombose/cirurgia , Resultado do Tratamento , Trombose Venosa/etiologia , Trombose Venosa/cirurgiaRESUMO
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.
Assuntos
Cuidados Críticos/métodos , Doença Hepática Terminal/cirurgia , Transplante de Fígado , Insuficiência de Múltiplos Órgãos/cirurgia , Assistência Perioperatória/métodos , Traqueostomia , Adolescente , Criança , Pré-Escolar , Estado Terminal , Doença Hepática Terminal/complicações , Doença Hepática Terminal/mortalidade , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Insuficiência de Múltiplos Órgãos/complicações , Insuficiência de Múltiplos Órgãos/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
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.
Assuntos
Injúria Renal Aguda , Terapia de Substituição Renal Contínua , Hemodiafiltração , Aminoácidos , Criança , Pré-Escolar , Estado Terminal/terapia , Feminino , Hemodiafiltração/efeitos adversos , Hemodiafiltração/métodos , Humanos , Masculino , Estudos Prospectivos , Diálise RenalRESUMO
OBJECTIVES: Acute-on-chronic liver failure (ACLF), whereas increasingly well-defined in adults, has been poorly characterized in pediatric patients other than having a poor prognosis. This study aimed to identify ACLF and evaluate prognosis in the American pediatric population. METHODS: Modified ACLF definitions (p-CLIF) were applied to 11,300 children listed for liver transplantation from March 2002 through 2017 in the Organ Procurement and Transplantation Network (OPTN) database. RESULTS: Pediatric ACLF patients have greater mortality within 90 days from listing (46.6% by p-CLIF) than other types of failure (<30%), including acute liver failure, as well as greater mortality within the first 30 and 90 days after transplantation than all other types of liver failure, but do not have increased mortality rates relative to other groups between 90 and 365 days from transplant. Although some ACLF listings also received 1B status, ACLF mortality at 90 days was greater than the general 1B population (50 vs 29.4%). Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease scores of ACLF patients are lower than 1B listings, and do not predict waitlist or posttransplant death. Greater number of organ failures does correlate with increased mortality. Biliary atresia is the leading etiology of pediatric chronic liver disease, accounting for over 30% of chronic and 45% of ACLF listings, yet is protective against mortality (hazard ratio [HR]â=â0.142 for ACLF). Receiving exception approval is independently but similarly protective in ACLF (HRâ=â0.145). CONCLUSIONS: These findings pose a challenge for allocation decisions but indicate greater attention to ACLF is needed, as scoring systems may not capture these children's risk of early death, which appears to currently be mitigated by exceptions. Multicenter, clinical, preferably prospective study of ACLF is necessary to determine how to prioritize ACLF relative to other liver failure types to address its relatively higher early mortality.
Assuntos
Insuficiência Hepática Crônica Agudizada , Doença Hepática Terminal , Adulto , Criança , Doença Hepática Terminal/cirurgia , Humanos , Cirrose Hepática , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Listas de EsperaRESUMO
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.
Assuntos
Atresia Biliar/complicações , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico por imagem , Cirrose Hepática/complicações , Cirrose Hepática/cirurgia , Transplante de Fígado , Pré-Escolar , Estudos de Coortes , Ecocardiografia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
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.
Assuntos
Anticoagulantes/administração & dosagem , Ácido Cítrico/administração & dosagem , Hemofiltração/métodos , Unidades de Terapia Intensiva , Falência Hepática/terapia , Albumina Sérica Humana/administração & dosagem , Anticoagulantes/efeitos adversos , Criança , Pré-Escolar , Ácido Cítrico/efeitos adversos , Feminino , Humanos , Lactente , Falência Hepática/sangue , Masculino , Estudos Retrospectivos , Albumina Sérica Humana/efeitos adversosRESUMO
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).
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Ácidos e Sais Biliares/fisiologia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Animais , Ácidos e Sais Biliares/sangue , Cardiomiopatias/sangue , Cardiomiopatias/fisiopatologia , Ácidos Graxos/metabolismo , Masculino , Camundongos , Camundongos KnockoutRESUMO
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.
Assuntos
Causas de Morte/tendências , Transplante de Fígado , Doadores de Tecidos/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Masculino , Estados UnidosRESUMO
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.
Assuntos
Sistema ABO de Grupos Sanguíneos , Incompatibilidade de Grupos Sanguíneos , Transplante de Fígado/normas , Criança , Pré-Escolar , Protocolos Clínicos , Quimioterapia Combinada , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/uso terapêutico , Lactente , Transplante de Fígado/métodos , Transplante de Fígado/mortalidade , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Resultado do TratamentoRESUMO
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.
Assuntos
Insuficiência Hepática Crônica Agudizada/terapia , Circulação Extracorpórea/métodos , Transplante de Fígado/métodos , Troca Plasmática/métodos , Terapia de Substituição Renal/métodos , Criança , Pré-Escolar , Terapia Combinada , Humanos , Lactente , Período Pré-Operatório , Estudos RetrospectivosRESUMO
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.
Assuntos
Doenças Biliares/epidemiologia , Coagulação Intravascular Disseminada/epidemiologia , Hepatopatias/epidemiologia , Linfo-Histiocitose Hemofagocítica/mortalidade , Adolescente , Estudos de Casos e Controles , Causas de Morte , Criança , Pré-Escolar , Progressão da Doença , Feminino , Ferritinas/sangue , Humanos , Lactente , Hepatopatias/patologia , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
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.
Assuntos
Cardiomiopatias/etiologia , Colestase/tratamento farmacológico , Ácido Cólico/sangue , Cirrose Hepática Biliar/tratamento farmacológico , Fígado/efeitos dos fármacos , Piridinas/farmacologia , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/genética , Agonistas Adrenérgicos beta/farmacologia , Animais , Biomarcadores/sangue , Cardiomiopatias/sangue , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Colestase/sangue , Colestase/etiologia , Colestase/patologia , Ácido Cólico/administração & dosagem , Modelos Animais de Doenças , Resistência a Medicamentos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Recuperação de Função Fisiológica , Transdução de Sinais , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
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.