人工肝支持系统在肝功能衰竭中的应用

肝功能衰竭是多种因素引起的严重肝脏损害,在儿科病因更为复杂且病情凶险,传统的内科综合治疗效果欠佳,病死率高.人工肝支持系统也常称为人工肝,是一种能够替代或模拟正常肝脏的部分或全部功能的体外装置,可以使因肝功能衰竭所产生的各种有害物质得以清除,并替代肝脏的部分代谢功能,以维持患者生命.人工肝应用至今已逾50年,其血液净化方式包括血液透析、血浆置换、血液灌流、吸附、全血或血浆滤过以及应用肝组织或细胞研制的有生物效应的治疗方法等.由于肝脏有强大的再生能力,人工肝可为病变肝脏自身再生恢复或接受肝移植尽可能争取时间.随着人工肝支持系统相关技术的不断完善,非生物型人工肝治疗已在临床广泛应用,并取得很好的疗效,成为各种重症肝功能衰竭的重要治疗手段之一.人工肝在儿科临床也有应用报道,但资料有限,仍需要进一步研究和实践.

Abstract：

Despite a combination of all available treatment, the mortality of liver failure is very high,especially in children patients. Artificial liver support methods have been tested for over 50 years. Standard techniques of blood purification like hemodialysis, adsorption, hemo or plasma filtration as well as bioreactorbased approaches using liver cells or tissues have been used. It' s believed that the damaged liver has the ability to return to normal. Artificial liver support systems are expected to be useful for temporary support of liver function. If the liver does not regenerate to normal functions, an artificial liver support system may be useful as a bridge to liver transplantation. In conclusion, artificial liver support method appears to be a reliable therapy for advanced liver diseases and has significantly decreased the mortality of liver failure. Artificial liver support system has been used in children patients as well, but it still needs more researches.     

体外生命支持模式及临床应用

危重患儿常合并多器官功能障碍.体外生命支持治疗利用体外设备代替体内脏器功能,从而达到维持生命的目的.体外设备可以支持多脏器功能障碍患儿的心、肺、肝、肾功能.与成人不同,多脏器衰竭患儿的基础疾病可能逆转,因此体外生命支持更为有效.本文概括介绍不同的体外脏器支持模式,包括体外膜肺、连续性肾脏替代治疗、人工肝、血液灌流和血浆置换治疗.

Abstract：

Multiple organ dysfunction(MODS) can be seen in critically ill children.Modality of extracorporeal life support (ECLS) is the use of mechanical devices to support life when the native organ failure occurs.Extracorporeal devices can effectively support heart,lung,liver,and kidney function of the sick children with MODS.Unlike the adult experience,ECLS is an effective therapy in children with MODS,because the underlying disease possibly is reversible.This article focuses on the different modalities of ECLS which involve extracorporeal membrane oxygenation,continuous renal replacement therapy,artificial liver support system,hemoperfusion and plasma exchange.     

应用儿童终末期肝病模型评分预测Kasai术后联合激素治疗胆道闭锁的短期预后

Objective To assess the effects of steroid therapy on the biliary atresia patients after Kasai portoenterostomy using pediatric of end-stage liver disease (PELD) scoring system. Methods Eighty patients with biliary atresia were enrolled in this study. The patients were randomly grouped into Kasai surgery group and combined therapy group. The patients of Kasai surgery group were performed Kasai portoenterostomy. The patients in combined therapy group underwent Kasai portoenterostomy and steroid therapy after surgery. Each patient's PELD score was calculated. Biochemical parameters,mortality,and PELD scores of two groups were compared. Results In the patients with a PELD less than 16, the levels of total bilirubin (TBIL), prothrombin time-international normalized ratio (INR) and PELD score of combined therapy patients were 23. 3 ± 1. 1 mg/L,2. 31 ± 0. 24,and 10. 6 ± 2.3, respectively; which were significantly lower than these parameters of the Kasai surgery group patients (TBIL,28. 9 ± 2. 1 mg/dL; INR,2. 63 ± 0. 18; PELD, 13. 2 ± 2.7). The combined therapy patients' albumin was also significantly higher than that of Kasai surgery group patients (P＜0. 05). The same results were also seen among the patients with a PELD between 16 and 28. Among the patients with a PELD higher than 28,only the difference of TBIL between the Kasai surgery group and combined therapy group was found. The mortality of the combined therapy patients was significantly lower than that of Kasai surgery group patients among the patients whose PELD ＜28. However, in the patients with a PELD≥28,no difference of the mortality was found between the two groups. Conclusions In the BA patients with PELD less than 27, Kasai portoenterostomy plus postoperative steroid therapy can improve the outcomes and prognosis.     

危重病肾上腺功能障碍的研究进展

There is high incidence of relative adrenal insufficiency (RAI) in critical children. The causes of adrenal insufficiency in patients with severe sepsis and septic shock are the mechanical injury of the hypothalamic-pituitary-adrenal axis, cytokines and other mediators of inflammatory or hormone resistance. There are many symptoms associated with adrenal insufficiency. Diagnosis is often suspected when these patients have hypotension refractory to fluid therapy and to vasoactive drugs. The corticotropin stimulation test is widely used as a method to identify adrenocortical hyporesponsiveness, but controversy exists as to the corticotropin dose to be used. The 250 μg dose is the standard dose. Low doses of corticotropin (1 μg) have recenfly been proposed,suggesting that they may have higher sensitivity and the characteristics of safe and effective.     

重症肠道病毒71型感染患儿胃肠功能损害的诊治

危重手足口病患儿可出现脑干脑炎、脑脊髓炎、肺水肿/肺出血和心血管功能衰竭等严重合并症.部分患儿合并严重胃肠功能损害,表现为腹胀、肠麻痹、便血、呕血等胃肠动力学障碍或消化道出血等症状."儿茶酚胺风暴"和病毒性炎症反应可能是胃肠功能障碍的主要原因,应重视对胃肠损害的监测.胃肠功能障碍的防治以预防为主,并应注意避免医源性损害.

Abstract：

Severe hand, foot and mouth disease (HFMD) may lead to the high mortality due to brainstem encephalitis, encephalomyelitis, pulmonary edema/pulmonary hemorrhage and cardiopulmonary failure in children. Some patients are complicated with severe gastrointestinal dysfunction, manifested as abdominal distension, intestinal paralysis, bleedy stool, haematemesis. "Catecholamine storm" and viral systemic inflammatory response syndrome may be the main mechanisms for gastrointestinal dysfunction. It is important to focus on the monitoring of gastrointestinal dysfunction of severe HFMD. Preventing and avoiding iatrogenic damage of gastrointestinal dysfunction are main treatment strategies.     

Notch配体、受体在小儿胆道畸形肝组织中的表达及意义

Objective To investigate the expressions of Notch ligands and its receptors in the liver tissues of the pediatric patients with bile duct malformations. Methods Twenty three patients including 12 patients with biliary atresia and 11 with choledochal cyst were enrolled in this study. The patients' liver specimens were harvested during surgery. Immunohistochemistry and real-time fluorescent quantitative RT-PCR were performed to examine the expression of Notch ligands and its receptors in the liver tissues. Nine health liver tissues served as controls. The clinical data of these patients were also collected and analyzed. Results The expression of Jag1 significantly increased in the proliferating ductules of the patients with biliary atresia. Jag2 was negative in the portal area of all patients. The mRNA of Jag1 of the patients with bile duct malformations was higher than that of controls (P＜0. 01). No difference of the mRNA of Jag2 was found between the bile duct malformation patients and the controls (P＞0. 05). The expression of Notch 1 and Notch 2 was mostly found in hepatocytes and bile ductules of the controls' and the choledochal cyst patients' liver tissues. No Notch 1 and Notch 2 expression was found in proliferating ductules of the biliary atresia patients. Notch 3 was expressed in the neovascularization and mesenchyme of the biliary atresia patients. There was no significant difference of Notch1 and Notch 2 mRNA between the biliary atresia patients, choledochal cyst patients and controls (P＞0. 05). Notch 3 mRNA of biliary atresia patients was higher than that of the controls (P＜0. 01). Notch 4 expression was undetectable in all patients. Conclusions The expression patterns of Notch ligands and its receptors are changed in the patients with biliary atresia, which may contribute to the pathogenesis of biliary atresia.     

Infliximab therapy and outcomes in patients with polyarticular juvenile idiopathic arthritis:a single-center study in China

Background Juvenile idiopathic arthritis(JIA)is a chronic inflammatory disease that includes seven heterogeneous subgroups with different prognoses.In particular,polyarticular JIA(pJIA)has a longer period of active disease and a poorer prognosis.Tumor necrosis factor(TNF)-alpha inhibitors are effective in patients with pJIA,but the therapeutic regimen remains controversial.Here,we performed a single-center study to determine the potential correlation between TNF-alpha inhibitor(infliximab)therapy and outcomes in these patients.Methods Clinical data of 40 pJIA patients were collected at our center from January 1,2010 to January 1,2018,and patients were grouped according to the timing of infliximab therapy.The erythrocyte sedimentation rate(ESR),the number of joints with active disease,and the 27-point juvenile arthritis disease activity score(JADAS-27)were analyzed.Results The ESR,the active joint count,and the JADAS-27 decreased significantly in all groups after 3 months(P=0.041/0.415/0.008,0.022/0.030/<0.001,and 0.05/0.012/<0.001,respectively)and 6 months(P=0.036/0.045/0.041,0.076/0.037/<0.001,and 0.096/0.006/<0.001,respectively)of infliximab treatment,although the rates of change of these parameters were similar.However,after 12 months,only patients treated with infliximab within 3 months of disease onset had a stable ESR,active joint count,and JADAS-27,while these parameters increased sharply when infliximab was administered 3 months and especially 1 year after disease onset.Conclusions TNF-alpha is a pleiotropic pro-inflammatory cytokine of crucial importance in the pathogenesis of JIA.Infliximab can improve the outcomes of patients with pJIA significantly,and should be introduced early during the clinical course.     

血浆置换与血液灌流在体外生命支持中的地位和应用

近年来,体外生命支持技术取得迅猛发展,尤其表现在体外膜肺氧合技术在心肺支持上的广泛应用.近20年来,在血液透析基础上发展而来的血液净化技术进入了一个持续快速发展的新时期.血液净化治疗包括血液透析、血液滤过、免疫吸附、连续性血液净化及腹膜透析等,作为其重要组成部分的血浆置换和血液灌流,在许多器官系统疾病的治疗中发挥重要作用,治疗范畴已涉及肾脏疾病、神经系统疾病、肝脏疾病、代谢性疾病、结缔组织疾病以及感染性疾病、药物中毒等.

Abstract：

The progress and development of extracorporeal life support (ECLS) is suprising and on-going,especially extracorporeal membrane oxygenation (ECMO) has become an accepted therapeutic modality for patients who have failed conventional therapy with respiratory and/or cardiac support.Blood purification developed from hemodialysis is designed to remove substances from the circulation and now includes hemodialysis,hemofiltration,immunoadsorption,continous blood purification and peritoneal dialysis.Plasma exchange and hemoperfusion play an important role in critically system diseases,i.e.,some kidney diseases,neurologic diseases,liver failure,metabolic diseases,connective tissue disease,infection diseases,intoxication and so on.     

体外生命支持系统在小儿急重症的应用

体外生命支持可以维持心、肺、肝、肾功能以及增加脑供血、降低颅内压,对儿童急重症合并多脏器功能衰竭有不可替代的作用,为原发病治疗赢得时间,能降低儿童急危重症病死率和后遗症的发生率.本文介绍了体外生命支持在儿科急重症中的适应证、病理生理机制及时机.

Abstract：

Extracorporeal life support system (ELSS) can maintain the heart,lung,liver,kidney function and increased cerebral blood supply and reduce intracranial pressure.In addition,for children with emergency and serious disease combined multiple organ failure (MOF),ECLS has an irreplaceable role in gaining time for the treatment of protopathy,which can ultimately reduce mortality and sequelae for children with emergency and serious disease.This review briefly summarizes the indication,pathophysiology and timing of ECLS in pediatric emergency and serious disease.     

Plasma Levels of Nitrate in Congenital Heart Disease: Comparison with Healthy Children

Nitric oxide (NO) is an endothelium- derived relaxing factor, and plasma nitrate is the stable end product of NO production. The aim of this study was to investigate the change in levels of plasma nitrate according to age and to elucidate the effect of pulmonary hypertension (PH) associated with congenital heart disease on NO production. We measured plasma levels of nitrate in 48 healthy children aged 5 days to 12 years to establish the normal range. Forty-six preoperative patients aged 4 months to 12 years with congenital heart disease were studied by cardiac catheterization. Plasma nitrate in healthy children decreased with age, from 1 month to 1 year, and then remained almost constant until the age of 12 years. Plasma nitrate was significantly increased in 22 preoperative patients with PH (mean pulmonary arterial pressure >?25 mmHg) compared with age-matched normal controls: (mean 56.9 vs 33.5 μmol/L, p<0.05) and was significantly correlated with pulmonary to systemic pressure ratio (r= 0.83, p < 0.0001). There was no significant difference between plasma nitrate levels in 24 preoperative patients without PH and those in the age-matched normal control (mean 25.6 vs 24.9 μmol/L). In 10 patients with preoperative PH who were examined before and after surgery, plasma nitrate levels remained high in the cases with residual PH but decreased to the normal range in the cases without residual PH. Plasma nitrate level is useful for evaluating PH both before and after operation in patients more than 4 months of age, and it is important to note differences in normal plasma nitrate levels according to age.     

Novel protocol including liver biopsy to identify and treat CD8+ T‐cell predominant acute hepatitis and liver failure

In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune‐mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T‐cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue‐based approach to diagnosis and treatment that may improve transplant‐free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.     

Orthotopic liver transplantation for acute liver failure secondary to autoimmune hepatitis in a child with autoimmune polyglandular syndrome type 1

Autoimmune polyglandular syndrome type 1 (APS-1) is an autosomal-recessive condition characterized by hypoparathyroidism, autoimmune Addison's disease, and chronic mucocutaneous candidiasis. Autoimmune hepatitis develops in 10-20% of affected patients and has a variable course ranging from asymptomatic chronic liver disease to lethal fulminant hepatic failure. Liver transplantation has been documented previously in only two patients. We report a 14-yr-old boy with APS-1 who developed acute liver failure secondary to associated autoimmune hepatitis. He did not respond to corticosteroid therapy and was successfully treated with an orthotopic liver transplant.     

Medical and surgical treatment of neonatal hemochromatosis: single center experience

NH is a rare disorder of iron storage in newborns resulting in rapid liver failure. Outcomes are dismal with 20-30% survival. We report our experience in eight children with NH. Assessment of liver function included admission PT and serum levels of FV and FVII. Medical treatment (antioxidant cocktail) was started in all patients, with chelation therapy in six. Of these six, three survived with medical treatment alone. The other three underwent liver transplant. One died 158 days after transplant to sepsis: two are well more than five yr after transplant. The two neonates who did not receive chelation therapy, died to multi-organ failure and sepsis. In summary, five children (62.5%) survived long-term. In the three transplanted, one- and five-yr-survival was 66%. Older children with compromised synthetic liver function (FVII levels < or = 15%) required liver replacement for survival. Early referral to a tertiary care center is essential to increase survival of these children with a rare and otherwise fatal disease. Single center experience of children with NH is here presented. Potentials for survival improvement with of medical and surgical treatment are examined.     

Neonatal liver failure

Liver failure in the neonatal period is challenging to diagnose and manage, and still carries a high mortality. With ongoing developments in the field of metabolic disorders and antiviral therapy, and the ability to offer liver transplantation to small babies, an overall survival of 40% has been achieved. Early recognition of liver failure, good supportive care and prompt referral to a paediatric liver transplant centre are essential elements in improving the outcome for these babies. Decisions about contra-indications to and timing of transplantation are complex as many of the disease processes are still evolving in the neonatal period, and extrahepatic disease, which cannot be corrected by a transplant, may appear later.     

Early liver transplantation is indicated for tyrosinemia type I

Liver transplantation is now accepted as the treatment of choice for tyrosinemia type I (hereditary tyrosinemia). In an effort to determine whether any factors in these patients would aid in predicting optimal timing of the transplant procedure, we evaluated several clinical, biochemical, and radiographic parameters in five successive patients undergoing liver transplant for tyrosinemia type I at the University of Minnesota. All five patients evidenced prolonged periods of clinical and metabolic stability with dietary therapy and four of five remained stable at the time of evaluation for transplantation. Nevertheless, all five suffered significant and unexpected complications of tyrosinemia prior to the time of liver transplant. Four developed renal stones, two were in liver failure, and one developed a neurologic crisis that left him completely paralyzed. Hepatocellular carcinoma was found in one of the five at transplant. We could identify no clinical, biochemical, or radiographic study that was predictive of the likelihood of significant complications of the disorder. Survival from the transplant procedure itself was 100%. The inability to predict or prevent significant complications of tyrosinemia and the favorable outcome from transplantation lead us to recommend liver transplant for all patients with tyrosinemia type I by 12 months of age.     

Acute liver failure in children: A regional experience

OBJECTIVE: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia. METHODOLOGY: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia. RESULTS: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long-term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function. CONCLUSIONS: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.     

Acute liver failure

Acute liver failure (ALF) is a rare condition in the pediatric population. Patients who present with severe failure of liver synthetic function have a high mortality with medical therapy alone. The main causes of death are cerebral edema, hemorrahge, renal failure and sepsis. The etiology of ALF is age specific, with a significant number due to inborn errors of metabolism especially in neonates and infants. Treatment of children with ALF is supportive, aimed at preventing and managing associated complications until the native liver recovers or liver transplantation. Sedation should not be administered unless a decision for artificial ventilation has been made. As all children are potential transplant candidates, transfer to and management in a liver transplant centre is recommended. Prognostic criteria for mortality are less well defined compared to the adult population, although a significantly elevated INR≥4 carries a high chance of death, and liver transplantation should be considered at this stage. Auxiliary transplantation is an attractive option in selected individuals and provides the chance to stop immunosuppression should sufficient hepatic regeneration occur. The use of various liver assist devices and hepatocyte transplantation as a bridge to liver transplantation show promise, although when used in isolation, they do not have an impact on overall patient survival.     

Liver transplantation from a deceased donor with β‐thalassemia intermedia is not contraindicated: A case report

The use of extended criteria donors who might have previously been deemed unsuitable is an option to increase the organ supply for transplantation. This report presents a pediatric case of a successful liver transplantation from a donor with β‐thalassemia intermedia. A patient, 6‐year‐old female, with a diagnosis of cryptogenic liver cirrhosis underwent deceased donor liver transplantation from a thalassemic donor. Extreme hyperferritinemia was detected shortly after transplantation. The most probable cause of hyperferritinemia was iron overload secondary to transplantation of a hemosiderotic liver. Hepatocellular injury due to acute graft rejection might have contributed to elevated ferritin levels by causing release of stored iron from the hemosiderotic liver graft. Iron chelation and phlebotomy therapies were started simultaneously in the early postoperative period to avoid iron‐related organ toxicity and transplant failure. Follow‐up with monthly phlebotomies after discharge yielded a favorable outcome with normal transplant functions. Thalassemia intermedia patients can be candidates of liver donors to decrease pretransplant waitlist mortality. After transplantation of a hemosiderotic liver, it is important to monitor the recipient in terms of iron overload and toxicity. Early attempts to lower iron burden including chelation therapy and/or phlebotomy should be considered to avoid organ toxicity and transplant failure.     

Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation

Parenteral nutrition represents standard therapy for children with short bowel syndrome and other causes of intestinal failure. Most infants with short bowel syndrome eventually wean from parenteral nutrition, and most of those who do not wean tolerate parenteral nutrition for protracted periods. However, a subset of children with intestinal failure remaining dependent on parenteral nutrition will develop life-threatening complications arising from therapy. Intestinal transplantation (Tx) can now be recommended for this select group. Life-threatening complications warranting consideration of intestinal Tx include parenteral nutrition-associated liver disease, recurrent sepsis, and threatened loss of central venous access. Because a critical shortage of donor organs exists, waiting times for intestinal Tx are prolonged. Therefore, it is essential that children with life-threatening complications of intestinal failure and parenteral nutrition therapy be identified comparatively early, i.e. in time to receive suitable donor organs before they become critically ill. Children with liver dysfunction should be considered for isolated intestinal Tx before irreversible, advanced bridging fibrosis or cirrhosis supervenes, for which a combined liver and intestinal transplant is necessary. Irreversible liver disease is suggested by hyperbilirubinemia persisting beyond 3-4 months of age combined with features of portal hypertension such as splenomegaly, thrombocytopenia, or prominent superficial abdominal veins; esophageal varices, ascites, and impaired synthetic function are not always present. Death resulting from complications of liver failure is especially common during the wait for a combined liver and intestinal transplant, and survival following combined liver and intestinal Tx is probably lower than following an isolated intestinal transplant. The incidence of morbidity and mortality following intestinal Tx is greater than that following liver or kidney Tx, but long-term survival following intestinal Tx is now at least 50-60%. It is probable that outcomes shall improve in the future with continued refinements in operative technique and post-operative management, including immunosuppression.     

The use of everolimus in pediatric liver transplant recipients: first experience in a single center

The role of mTOR inhibitors, such as EVL, has not been established for pediatric liver transplant recipients up to now, although data from adult solid organ graft transplantation are very promising. Major complications following pediatric liver transplantation in the long-term course include chronic graft rejection and CNI-derived nephrotoxicity. The purpose of our study was to report first results using EVL as a rescue therapy in pediatric liver transplant recipients for the following indications: chronic graft dysfunction n=12, suspected CNI toxicity n=3, hepatoblastoma n=2, and recurrence of primary sclerosing cholangitis post-Ltx n=1. Four patients with chronic graft dysfunction developed completely normal liver function tests using EVL, six patients showed partial improvement, and two patients did not respond at all. One patient with CNI-induced nephropathy showed a slightly improved GFR. Both patients with hepatoblastoma did not develop any metastasis post-Ltx. First experience with EVL in pediatric liver transplant recipients shows promising results in patients with chronic graft failure when standard immunosuppression has failed. The future role of EVL in immunosuppressive protocols for children post-Ltx has to be proven by controlled clinical trials.