Christian Dohna-Schwake

Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism

BACKGROUND Newborns with inborn errors of metabolism often present with hyperammonaemic coma, requiring prompt diagnosis and specific medical therapy, nutritional support and efficient toxin removal. Little information regarding the efficacy and safety of continuous venovenous haemodialysis (CVVHD) as an option for extracorporal ammonia detoxification in children is available. METHODS Twenty-one patients with hyperammonaemia [19 neonates (mean age 4.1 +/- 2.4 days) and two children 1 and 7 years of age, respectively] were admitted to our hospital for dialysis between 1996 and 2008. Seventeen children (15 neonates), received CVVHD. Four neonates received continuous peritoneal dialysis (CPD). All started medical treatment with sodium benzoate, l-arginine hydrochloride and carnitine as well as protein-restricted parenteral diets with high caloric intake before dialysis. RESULTS Plasma ammonia levels (range 464-7267 microg/dl before dialysis and 27-3317 microg/dl after dialysis) were significantly reduced by 50% within 4.7 +/- 2.5 h with CVVHD compared with 13.5 +/- 6.2 h with CPD (P < 0.0001). Plasma ammonia levels <200 microg/dl critical range were achieved within 22.4 +/- 18.1 h in CVVHD patients compared with 35.0 +/- 24.1 h with CPD. Depending on the weight and blood pressure stability of the patients, mean blood flow velocities of 9.8 +/- 3.4 ml/kg/min and mean dialysate flow rates of 3925 +/- 2398 ml/min/1.73 m(2) were employed. Blood and dialysate flows significantly correlated with ammonia clearance and decay of ammonia in vivo. Because of the severe underlying disease, 18% of CVVHD patients died compared with 50% undergoing CPD. In total, 82% of CVVHD patients survived the first 6 months after dialysis. Among these, 43% were without sequelae, 43% developed moderate mental retardation, and two (14%) developed severe mental retardation. CONCLUSION CVVHD effectively and quickly eliminates plasma ammonia. To optimize long-term mental outcome, rapid identification and appropriate treatment of the underlying disease as well as starting dialysis early are of enormous therapeutic value.

Severe H1N1 infection in a pediatric liver transplant recipient treated with intravenous zanamivir: efficiency and complications.

The 2009 emerged pandemic influenza H1N1 is a leading cause for respiratory illness in children. Herein, we report about the first pediatric patient who developed severe bilateral pneumonia with acute respiratory distress syndrome caused by novel influenza H1N1 after liver transplantation. The 2-year-old child received a deceased whole organ liver transplantation because of end-stage Caroli’s disease. Early postoperative course was complicated by portal vein thrombosis, which was successfully treated by thrombectomy 12 hr after transplantation. Immunosuppression was started with cyclosporine A (CSA; 50 mg/m intravenously [IV]; trough blood level 180–230 ng/mL), prednisone (15 mg/ m), and two doses of basiliximab (10 mg on days 0 and 4). Respiratory deterioration occurred 4 days after transplantation. The patient required invasive ventilation and developed adult respiratory distress syndrome (bilateral infiltrates on chest x-ray, PaO2/FiO2 150). Other symptoms were leukopenia and fever. Liver enzymes and function remained stable. Extended bacterial, viral, and fungal diagnostic workup from tracheal secretions revealed positive pandemic H1N1 RNA detected by polymerase chain reaction (PCR). Treatment with oseltamivir (2 30 mg/day) was started immediately after reception of positive H1N1 results at day 3 after the onset of first respiratory symptoms. Because the respiratory situation further deteriorated (PaO2/FiO2 100) and the patient developed gastroparesis, absorption of oseltamivir became questionable. IV zanamivir (2 260 mg/day) was started as “compassionate use” for 5 days from days 10 to 15 after transplantation. Parents gave informed consent, but institutional review board approval could not be achieved because treatment decision was made 2 days before Christmas. The treatment course neither led to negative H1N1 PCR nor to respiratory improvement. CSA was discontinued, and prednisone was reduced to 10 mg/m at day 11 after transplantation. The H1N1 virus tested was susceptible to oseltamivir and zanamivir. Mutations known to be associated with an enhanced pathogenicity were not identified by sequencing analysis. During the treatment with zanamivir, the patient’s liver function worsened as indicated by the increase of serum aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) up to 628 U/L and 193 U/L, respectively. Ultrasound revealed an unexplained retrograde flow of the portal vein but no evidence of portal vein thrombosis. Rejection was ruled out by liver biopsy. Pandemic H1N1 RNA was not detectable in the liver biopsy. To improve the venous outflow of the liver, positive end-expiratory pressure (maximum 16 cm H2O) was gradually reduced without any effect. Portal vein flow normalized 10 days after stopping zanamivir. During zanamivir treatment, serum creatinine level increased from 0.36 mg/dL to a maximum of 0.68 mg/ dL. Kidney function normalized with termination of zanamivir. Oseltamivir was continued for another 10 days. The patient improved slowly and was weaned from mechanical ventilation after 25 days. Pandemic H1N1 RNA in tracheal aspirate became negative 22 days after first detection. Although the majority of cases of pandemic H1N1 infections in children are mild, severe courses have been described, especially in children with comorbidities (1). Until August 2009, 36 deaths had been occurred in children younger than 18 years in the United States (2). Usually treatment of the influenza A virus with the oral preparation oseltamivir is effective to shorten the illness when initiated within 48 hr after first symptoms (3). The neuraminidase inhibitor, zanamivir, developed for IV use is not currently commercially available. In patients with severe illness and a known resistance of pandemic H1N1 to oseltamivir or in patients not tolerating enteral nutrition, this therapy might be an important alternative. Recently, a first case report with successful administration of zanamivir in a child with acute lymphoblastic leukemia has been published (4). In the presented case, zanamivir treatment was initiated as “compassionate use” because of progressive worsening of respiratory symptoms and severe gastroparesis, leading to questionable oseltamivir absorption. However, we were unable to demonstrate any positive effect as neither the symptoms improved nor the PCR became negative. A possible explanation might be the late start of the medication. Conversely, it cannot be excluded that the otherwise unexplained retrograde portal vein flow and kidney injury were caused by the medication. We believe that the coincidence in time of worsening liver function and zanamivir treatment makes a causal relationship at least possible. Duration of treatment with neuraminidase inhibitors was totally 20 days. A prolonged period of treatment is consistent with current published guidelines (5), which recommend treatment in transplant patients until H1N1 PCR becomes negative. Recommendations are based on the fact that viral shedding is prolonged in immunocompromised patients. Conversely, these potential benefits have to outweigh the risk of resistance emergence. Probably, the most important actions for improvement of clinical course in our patient were aggressive ventilatory support and the reduction of immunosuppression, especially the discontinuation of CSA. The presented case also underlines the fact that immunization against pandemic H1N1 should be recommended strongly to the patients on waiting list for organ transplantation (6). Furthermore, vaccination programs for healthcare professionals are emphasized strongly, because our patient was probably infected by a doctor, nurse, or physiotherapist. In conclusion, in other cases, zanamivir has been proven to be effective to shorten pandemic H1N1 influenza illness. If given late in the disease course ( 48 hr after onset of symptoms), caregivers have to balance the reduced efficiency against possible toxic side effects.

Lifesaving liver transplantation for multi-organ failure caused by Bacillus cereus food poisoning.

Bacillus cereus is a spore‐forming, gram‐positive bacterium that causes food poisoning presenting with either emesis or diarrhea. Diarrhea is caused by proteinaceous enterotoxin complexes, mainly hemolysin BL, non‐hemolytic enterotoxin (NHE), and cytotoxin K. In contrast, emesis is caused by the ingestion of the depsipeptide toxin cereulide, which is produced in B. cereus contaminated food, particularly in pasta or rice. In general, the illness is mild and self‐limiting. However, due to cereulide intoxication, nine severe cases with rhabdomyolysis and/or liver failure, five of them lethal, are reported in literature. Here we report the first case of life‐threatening liver failure and severe rhabdomyolysis in this context that could not be survived without emergency hepatectomy and consecutive liver transplantation.

First Case Studies of Successful ABO-Incompatible Living-Related Liver Transplantation in Infants in Germany

AIM A series study mainly from Asia suggests that ABO-incompatible (ABOi) living-related liver transplantation (LRLT) for pediatric recipients is associated with excellent short- and long-term graft and patient survival. Until now, ABOi LRLT has been rarely performed in Europe. The aim of this study was to analyze the safety and early results of an ABOi LRLT in a German high-volume pediatric liver transplant center. METHODS Six consecutive pediatric patients (four males and two females) were included in this prospective study from January, 2010 to January, 2013 with a median age of 13 months (range, 6-30 months) receiving ABOi LRLT and were matched with six patients receiving ABO-compatible LRLT in the same period. In the ABOi group, titers of IgG and IgM isoagglutinins against the donors blood group were determined at day 14 before the transplantation and from day 1 to 14 after the transplantation, and then twice a week for another 8 weeks. The titer results were determined as the reciprocal number of the highest serum dilution that caused macroscopical reaction. RESULTS The patients receiving ABOi and those receiving ABO-compatible LRLT were comparable regarding the recipients preoperative pediatric end-stage liver disease (PELD), age, gender, and technical aspects of transplantation. The median follow-up was 2.6 years (range, 1-4.5 years). At the time of operation, the mean body weight was 7.7 kg (range, 5.7-16 kg) in ABO-compatible LRLT recipients and 8.8 kg (range, 5.5-18 kg) in ABOi LRLT recipients. In each group, the median PELD score was 28 (range, 28-35), respectively. All recipients received tacrolimus plus mycophenolate mofetil-based standard immunosuppression and four ABOi transplanted patients received intravenous immunoglobulins at days 1, 3, and 5 after liver transplantation. Patient and graft survival in this group was 83%. One female patient died within 24 hours due to fulminant gram-negative sepsis. Another patient developed acute cellular rejection at the 8th postoperative day, which responded to steroid treatment. No further complications occurred. In the ABO-compatible group, patient survival was 100% and graft survival was 83%; one patient in this group received retransplantation after 4 days. During follow-up, two patients of the ABOi group had maximum alloantibody titers of four against the donors blood group; all other patients had titers below four. CONCLUSION ABOi LRLT seems to be safe without an escalation of immunosuppression and should be considered as an additional option to timely facilitate the transplantation.

Undue Elevation of Procalcitonin in Pediatric Paracetamol Intoxication isNot Explained by Liver Cell Injury Alone

INTRODUCTION AND AIM Procalcitonin is widely used as a biomarker to distinguish bacterial infections from other etiologies of systemic inflammation. Little is known about its value in acute liver injury resulting from intoxication with paracetamol. MATERIAL AND METHODS We performed a single-center retrospective analysis of the procalcitonin level, liver synthesis, liver cell damage and renal function of patients admitted with paracetamol-induced liver injury to a tertiary care childrens hospital. Children with acute liver failure due to other reasons without a bacterial or fungal infection served as the control group. Twelve patients with acute paracetamol intoxication and acute liver injury were compared with 29 patients with acute liver failure. RESULTS The procalcitonin levels were higher in children with paracetamol intoxication than in patients with acute liver failure without paracetamol intoxication (median 24.8 (0.01-55.57) ng/mL vs. 1.36 (0.1-44.18) ng/mL; p < 0.005), although their liver and kidney functions were better and the liver cell injury was similar in both groups. Outcome analysis showed a trend towards better survival without transplantation in patients with paracetamol intoxication (10/12 vs. 15/29). Within each group, procalcitonin was significantly correlated with alanine aminotransferase and aspartate aminotransferase but was not correlated with the International Normalized Ratio or paracetamol blood levels in the paracetamol group. In conclusion, paracetamol intoxication leads to a marked increase in procalcitonin serum levels, which are significantly higher than those seen in acute liver failure. CONCLUSION The underlying mechanism is neither caused by infection nor fully explained by liver cell death alone and remains to be determined.INTRODUCTION AND AIM Procalcitonin is widely used as a biomarker to distinguish bacterial infections from other etiologies of systemic inflammation. Little is known about its value in acute liver injury resulting from intoxication with paracetamol. MATERIAL AND METHODS We performed a single-center retrospective analysis of the procalcitonin level, liver synthesis, liver cell damage and renal function of patients admitted with paracetamol-induced liver injury to a tertiary care childrens hospital. Children with acute liver failure due to other reasons without a bacterial or fungal infection served as the control group. Twelve patients with acute paracetamol intoxication and acute liver injury were compared with 29 patients with acute liver failure. RESULTS The procalcitonin levels were higher in children with paracetamol intoxication than in patients with acute liver failure without paracetamol intoxication (median 24.8 (0.01-55.57) ng/mL vs. 1.36 (0.1-44.18) ng/mL; p < 0.005), although their liver and kidney functions were better and the liver cell injury was similar in both groups. Outcome analysis showed a trend towards better survival without transplantation in patients with paracetamol intoxication (10/12 vs. 15/29). Within each group, procalcitonin was significantly correlated with alanine aminotransferase and aspartate aminotransferase but was not correlated with the International Normalized Ratio or paracetamol blood levels in the paracetamol group. In conclusion, paracetamol intoxication leads to a marked increase in procalcitonin serum levels, which are significantly higher than those seen in acute liver failure. CONCLUSION The underlying mechanism is neither caused by infection nor fully explained by liver cell death alone and remains to be determined.