三檢驗 Diagnostic evaluation of pediatric acute liver failure (PALF) Evaluation Population Studies Biochemical All patients to assess severity of liver

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1 急性肝衰竭 Acute liver failure 一定義 1. Biochemical evidence of liver injury in a child without evidence of chronic liver disease. 2. Coagulopathy not corrected by vitamin K administration. 3. INR greater than 1.5 if the patient has encephalopathy or greater than 2.0 if encephalopathy is absent. Reference: [2] 二鑑別診斷 Etiology Neonates Infectious (13.4%) Metabolic (18.1%) Ischemic Older children Infectious (4.5%) Drugs (19.5%) Disease Herpesviruses Echovirus Adenovirus Hepatitis B Galactosemia Tyrosinemia Neonatal hemochromatosis Mitochondrial disease Congenital heart disease or cardiac surgery Myocarditis Asphyxia Hepatitis A Hepatitis B Indeterminate hepatitis Herpesviruses Sepsis Valproate (Depakine) Isoniazid Acetaminophen Carbamazepine (Tegretol) Halothane Toxins Amanita phalloides ( 毒鵝膏 ) Carbon tetrachloride ( 四氯化碳 ) Metabolic (7.4%) Wilson s disease (rare before 3 years of age) Hereditary fructose intolerance Autoimmune (8.7%) Hepatitis (types 1 and 2) Ischemic Congenital heart disease or surgery Asphyxia Budd-Chiari syndrome Reference: [1,2]

2 三檢驗 Diagnostic evaluation of pediatric acute liver failure (PALF) Evaluation Population Studies Biochemical All patients to assess severity of liver injury Coagulation profile: PT(INR), aptt, fibrinogen Liver function test: AST, ALT, GGT, alkaline phosphatase, bilirubin-t/d, albumin, total protein Coagulation factors: V, VII, VIII Metabolic panel: Electrolytes (Na, K, Cl, Ca, P, Mg), BUN, creatinine, blood glucose Blood gas CBC/DC Viral studies Drugs/Toxin Metabolic studies As clinical indicated. Viral infections are one of the most common known etiologies of ALF in children <7 months of age; herpes simplex virus is the most common infectious agent. Acetaminophen overdose was the most common cause of drug-induced ALF Metabolic diseases are the one of the most common known etiologies of ALF in children below one year of age. Wilson s disease usually presents after age of three years. Immune function Autoimmune hepatitis typically affects adolescent patients; however it can be seen in all age group. Ammonia Viral hepatitis serology: Anti-HAV IgM, HBsAg, Anti-HBc IgM and IgG, Anti-HCV, Anti-HEV Viral studies: EBV, CMV, Enterovirus, Adenovirus, HHV6, HSV 1/2, Parvovirus Urine toxin screen Serum acetaminophen level Lactate, Pyruvate Serum amino acid profile Urine amino acids/organic acids Urine succinylacetone (tyrosinemia type 1) Ferritin, Iron, TIBC Carnitine level and acyl carnitine profile Ceruloplasmin, 24 hour urine copper (Wilson s disease) Autoimmune hepatitis serology: Anti-nuclear antibody, Smooth muscle antibody, Liverkidney-microsomal antibody NK cell function, perforin, granzyme B, sil-2, triglycerides (HLH) Liver biopsy Bone marrow biopsy Histology/Tissue As clinically indicated studies Imaging studies As clinically indicated Ultrasound liver with Doppler exam CT/MRI head (if indicated) Reference: [2]

3 四找出可以治療的 ALF Etiology specific treatment of PALF Etiology Diagnosis Treatment Acetaminophen Confirmed of suspected history of acetaminophen ingestion. Elevated acetaminophen level 4 hours post ingestion Suspect in high aminotransferases and low bilirubin. N-acetylcysteine, should be started as soon as possible after ingestion N-acetylcysteine used in any case of ALF in which acetaminophen overdose is suspected as possible cause 劑量見下表 Hepatitis B Hepatitis B virus surface Ag/e Ag Hepatitis B PCR Entecavir/Tenofovir/Lamivudine Limited experience with Entecavir and Tenofovir IV Acyclovir HSV 1,2 Viral culture/pcr from vesicles, oropharynx, conjunctiva, blood, CSF Autoimmune Positive autoimmune hepatitis hepatitis serology Elevated IgG level Liver biopsy response to steroids Wilson s disease Low serum ceruloplasmin Copper chelation High 24 hours urinary copper Plasmapheresis Elevated liver copper Kayser-Fleischer rings present in about 50% of patient with ALF High alkaline phosphatase/bilirubin ratio (>4) Evidence of hemolysis Tyrosinemia Marked elevation of α-fetoprotein NTBC type 1 Elevated urine succinylacetaone Gene or enzyme testing for fumarylacetate hydrolase Galactosemia Urine positive for non-glucose Lactose free formula reducing substance on lactose containing feeds Galactose-1 phosphatase uridyl transferase enzyme assay Gestational High serum ferritin alloimmune liver Lip/salivary gland biopsy disease/neonatal MRI liver/brain/pancreas with hemochromatosis characteristic findings HLH High serum triglyceride Low fibrinogen Cytopenia High serum ferritin Elevated soluble IL-2 receptor Low/absent NK cell activity Genetic testing Bone marrow biopsy Amanita toxicity History of mushroom Amanita Silibinin IV Methylprednisolone Evaluation for liver transplantation should not be delayed while awaiting High dose IVIG Possible exchange transfusion Corticosteroids Chemotherapy Bone marrow transplantation

4 palloides and Amanita virosa ingestion Often present with vomiting/diarrhea High dose penicillin G Low survival without transplantation Budd Chiari syndrome Imaging studies showing hepatic venous thrombosis TIPS (rarely possible) Transplantation may be necessary NTBC: 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexandion HLH: hemophagocytic lymphohistiocytosis Reference: [2] N-acetylcysteine (NAC) for acetaminophen overdose Patient 20 kg ( 在 21 小時內, 由靜脈輸注 NAC 300 mg/kg) Loading dose 150 mg/kg in 3 ml per kg of diluent given IV over 60 minutes Second dose 50 mg/kg in 7 ml per kg of diluent given IV over 4 hours (12.5 mg/kg NAC per hour) Third dose 100 mg/kg in 14 ml per kg of diluent given IV over 16 hours (6.25 mg/kg NAC per hour) Patients >20 and 40 kg Loading dose 150 mg/kg in 100 ml of diluent given IV over 60 minutes Second dose 50 mg/kg in 250 ml of diluent given IV over 4 hours (12.5 mg/kg NAC per hour) Third dose 100 mg/kg in 500 ml of diluent administered over 16 hours (6.25 mg/kg NAC per hour) Patient >40 kg as adult (Simplified 20 hour IV protocol, less non-allergic anaphylactic reactions) Loading dose administer a 4 hour infusion at 50 mg/kg/hr IV (200 mg/kg over 4 hours) Second dose administer a 16 hour infusion at 6.25 mg/kg/hr IV (100 mg/kg over 16 hours) 須注意可能出現過敏或噁心嘔吐症狀, 小心 fluid overload! Reference: [3]

5 五併發症與處置 Common Management Issues and Condition-Specific Elements of Care in ALF Organ system and common Assessment Specific elements of care conditions Cardiovascular system Hypotension Invasive monitoring for all Intravascular volume depletion conditions; echocardiography for Correct volume depletion Vasodilatation low cardiac output and right Vasopressors (Norepinephrine) Low cardiac output and right ventricular failure Inotropic support ventricular failure Hepatic system Evolving hepatic dysfunction Serial biochemical and Intravenous N-acetylcysteine coagulation testing A Plasma exchange therapy B Respiratory system Risk of aspiration pneumonitis due to HE Neurologic observation to monitor level of consciousness Early tracheal intubation for depressed level of consciousness Respiratory dysfunction secondary to sepsis, volume overload, pulmonary hemorrhage, or ARDS Mechanical ventilation strategies for pediatric ARDS: low tidal volume (5-8 ml/kg predicted BW) and moderately elevated levels of PEEP titrated to maintain normal oxygenation and hemodynamic response Metabolic and renal system Hypoglycemia Serial biochemical testing and monitor U/O Maintain normoglycemia (GIR mg/kg/min) to keep euglycemia Electrolytes disturbance Active fluid management (hypo-na/k/ca/p/mg) Prompt correction of abnormalities Acute kidney injury (AKI), lactic acidosis, Minimizing intravenous contrast or nephrotoxic drugs hyperammonemia Avoiding over diuresis Effective restoration of appropriate intravascular volume and maintaining renal perfusion Renal-replacement therapy (RRT) Impaired drug metabolism Review drug administration Central nervous system Hepatic encephalopathy (HE) C Keep minimal stimulation Brain edema/intracranial hypertension Neurologic observation (GCS level, pupil size/light reflex, muscle power, reflexes, asterixis) Monitoring of serum ammonia level Transcranial ultrasonography Consideration of ICP monitoring Bed elevated Treat hyperammonemia (lactulose, neomycin) D Endotracheal intubation for airway protection and controlled ventilation (keep SpO2 >95% and Paco2 of mmhg) Fluid restriction 75-80% maintenance Keep diastolic pressure >50 mmhg (except infants) Target for serum sodium mmol/l Osmolar therapy (hypertonic saline and mannitol) E

6 Hematologic system Coagulopathy F Laboratory coagulation testing (Prolongation of PT(INR) and thrombocytopenia Temperature control (active normothermia C) Seizure control (EEG and phenytoin) No routine correction of coagulation abnormalities, only for invasive procedures (including platelets and fibrinogen) Immunologic system High risk of sepsis Clinical evaluation Antibiotic prophylaxis Reference: [1,2,4] A. 每天抽血 :CBC/DC PT(INR)/aPTT Na/K/Cl/Ca/P, BUN/Cre AST/ALT Bil-T/D ammonia albumin glucose blood gas [ 可依臨床狀況調整監測頻率 ] B. 血漿置換術 (plasma exchange therapy) 醫囑 1. 簽署同意書 2. On double lumen catheter (12.5 or 13 Fr) 3. 照會腎臟科, 並與洗腎室約時間 ( 一般先洗 QOD)[ 修訂中 ] 4. 備血置換血漿容積 =70 BW(kg) (1-Hct) (1.5-2) 備 FFP ( 欲置換血漿容積的量 ) PRBC (2U) 5. 進行血漿置換術前, 抽血 CBC/DC PT/aPTT Na/K/Cl/Ca/P AST/ALT BUN/Cre 6. 維持 Plt >50000/mm 3,Hb >10 7. 填寫血液分離術申請單 8. 進行血漿置換術時, 每 15 分鐘量一次血壓, 並監測是否出現低血液容積過敏低血鈣 ( 出血傾向或周邊肢體感覺麻木 ) 等症狀 ; 結束後, 每 30 分鐘量一次血壓直到 3 小時或病人穩定為止 9. 可定時在血漿置換術進行到一半或病人出現低血鈣症狀時, 靜脈注射 CaCl2 補充鈣離子 10. 在血漿置換術結束後 3 小時, 抽血 CBC PT/aPTT Na/K/Cl/Ca/P 11. 若有凝血功能異常, 優先補充鈣離子來矯正

7 C. 肝性腦病變 (Hepatic encephalopathy) 分期 Classification of hepatic encephalopathy Grade Clinical manifestations Asterixis/Reflexes Neurologic signs EEG changes Subclinical None Absent/normal Abnormalities on psychometric testing and proton magnetic spectroscopy in older patients Grade 1 Grade 2 Grade 3 Grade 4 Confused, mood changes, altered sleep habits, loss of spatial orientation, forgetfulness Drowsy, inappropriate behavior, decreased inhibitions Child is stuporous but obeys simple commands; infant is sleeping but arousable Child is comatose but arousable by painful stimuli (IVa) or does not respond to stimuli (IVb) Absent/normal Tremor, apraxia, impaired handwriting Usually absent May be absent or diffuse, slowing to theta rhythm, triphasic waves Present/hyperreflexive Dysarthria, ataxia Abnormal, generalized slowing, triphasic waves Present/hyperreflexive with positive Babinski sign Absent Muscle rigidity Decerebrate or decorticate Abnormal, generalized slowing, triphasic waves Abnormal, very slow delta activity D. 高氨血症 (hyperammonemia) 治療 Reference: [3] 1. Lactulose: 嬰兒 :1.7 to 6.7 g/day (2.5 to 10 ml/day) in divided doses; 孩童與青少年 :26.7 to 60 g/day (40 to 90 ml/day) in divided doses; 以每天解 2-3 次軟便為目標調整劑量 2. Neomycin: mg/kg/day PO Q6H (maximum dose 12g/day) for a maximum of 7 days; 具有耳毒性與腎毒性 3. 低蛋白質飲食 :1 g/kg/day E. 腦水腫 (cerebral edema) 治療 Reference: [5] 1. Hypertonic saline (3%): 先給 bolus (2-6 ml/kg), 接著 continuous infusion (0.1 to 1 ml/kg/hr), 控制血鈉在 meq/l 血清滲透壓在 mosm/l 副作用 : 腦出血靜脈栓塞高血氯代謝性酸血症凝血功能異常 2. Mannitol: g/kg IV bolus Q6-8H, 維持血清滲透壓在 mosm/l 可於出現 uncal herniation 症狀 ( 瞳孔放大沒有光反射心跳變慢高血壓 ) 時, 用作急救副作用 : 高滲透壓體液過多電解質異常急性腎衰竭 F. 凝血功能異常 (coagulopathy) Reference: [2] 1. 雖然抽血可見 PT(INR) 延長與血小板低下, 但臨床上出現嚴重出血的機率 <5%, 出現自發性腦出血的機率 <1% 對於急性肝衰竭的病人而言, 驗 PT(INR) 來預測出血傾向反而不及評估肝臟製造功能有沒有恢 Reference: [1]

8 復來得重要 2. 可施打一劑 Vit K 評估對異常 PT(INR)/aPTT 的矯正效果 : 新生兒 1-2 mg/day; 孩童與青少年 0.2 mg/kg/d0se, max 10 mg/d0se 若沒有效果就不須天天施打 3. 除非活動性出血或者預計做侵入性手術治療, 否則應避免常規輸注 FFP 或 recombinant Factor VIIa 以積極矯正 PT(INR) 4. 輸注血小板也僅限於血小板 < 或有活動性出血且血小板 < 者六其他 supportive care 1. 營養 Reference [2,6] 急性肝衰竭時身體處於分解大於合成的 catabolic stage 成人 data 建議增加 20% 熱量攝取需給予適量的蛋白質 (1 g/kg/day) 特殊 branched-chain amino acid 配方可改善肝性腦病變, 但對於死亡率並無影響本院品項有 Aminoleban Aminopoly-H Aminosteril N-Hepa 8%, 依年度招標而定若需靜脈給予脂肪乳劑, 宜選用含 MCT 的脂肪乳劑本院品項有 Lipofundin Venolipid, 依年度招標而定 2. 止痛鎮靜神經肌肉阻斷適當的止痛與鎮靜有助於腦壓的控制, 但有可能會影響神經功能的評估, 且 BZD 與 propofol 都會增加 GABA 神經傳導而惡化肝性腦病變, 所以要謹慎使用, 並盡量選擇短效的不經肝臟代謝的藥物為佳止痛 :Fentanyl 鎮靜 :Propofol 神經肌肉阻斷 :Cisatracurium 七預後 Reference: [7] 1. Children with acetaminophen induced liver failure had the best survival (94%). 2. The patients with indeterminate causes and those with nonacetaminophen induced liver failure had the worst outcome with a survival rate of 43% and 41% respectively. 3. 常用於預測的指標包括 serum bilirubin, prothrombin time, blood ammonia, white blood cell count, and onset of hepatic encephalopathy.

9 八 Reference 1. Pediatric Gastrointestinal and Liver Disease, ed5 2. Lutfi R, Abulebda K, Nitu ME, Molleston JP, Bozic MA, Subbarao G. Intensive Care Management of Pediatric Acute Liver Failure. J Pediatr Gastroenterol Nutr Oct UpToDate 4. Bernal W, et al. Acute liver failure. N Engl J Med. 26;369(26): Dec Huh JW, Raghupathi R. New concepts in treatment of pediatric traumatic brain injury. Anesthesiol Clin. 27(2): Jun Schütz T, Bechstein WO, Neuhaus P, Lochs H, Plauth M. Clinical practice of nutrition in acute liver failure--a European survey. Clin Nutr. 23(5): Oct Lu BR, Zhang S, Narkewicz MR, Belle SH, Squires RH, Sokol RJ; Pediatric Acute Liver Failure Study Group. Evaluation of the liver injury unit scoring system to predict survival in a multinational study of pediatric acute liver failure. J Pediatr. 162(5): May Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology. 41(5): May 2005.

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三 檢驗 Diagnostic evaluation of pediatric acute liver failure (PALF) Evaluation Population Studies Biochemical All patients to assess severity of liver

三檢驗 Diagnostic evaluation of pediatric acute liver failure (PALF) Evaluation Population Studies Biochemical All patients to assess severity of liver