Adoptive ex vivo transfer of EBNA-1-specific T cells is a feasible and well-tolerated therapeutic option, representing a fast and efficient procedure to achieve reconstitution of antiviral T-cell immunity after SCT.

Background/Aims: Several recent studies revealed an accumulation of ceramide in bronchial, tracheal and intestinal epithelial cells of mice and patients with cystic fibrosis (CF). Normalization of ceramide concentrations in lungs of CF mice employing the functional acid sphingomyelinase inhibitor amitriptyline also normalized mucociliary clearance, chronic inflammation and infection susceptibility to pulmonary P. aeruginosa in these mice. Methods: To test for a beneficial effect of amitriptyline in vivo, we performed a phase IIb randomised, double-blind, placebo-controlled study. Twenty-one CF patients were treated with 25 mg/d amitriptyline twice daily for 28 days. The placebo consisted of 19 patients and was also treated twice per day. The primary endpoint was the change in lung function in the intention-to-treat (ITT) population. Secondary endpoints were ceramide levels in epithelial cells and safety. Results: After treatment, forced expiratory volume in 1 sec predicted (FEV₁) increased 6.3±11.5% (p=0.08) in the ITT population (36 of 40 CF patients) and 8.5±10% (p=0.013) in the per protocol (PP) population (29 of 40 patients). Ceramide levels decreased in nasal epithelial cells after amitriptyline treatment. Amitriptyline had no severe and only mild and mostly transient adverse effects, i.e. xerostomia and tiredness. Conclusion: Amitriptyline is safe in CF-patients, increases FEV₁ and reduces ceramide in lung cells of CF patients.

A nurse-driven protocol for analgesia and sedation of children with extracorporeal life support is feasible. Patients with extracorporeal life support do not need deeper sedation levels and have not higher cumulative sedation requirements than children without extracorporeal life support.

Following RBC transfusion, cerebral oxygen saturation increases and cerebral fractional tissue oxygen extraction decreases. The data suggest that cerebral oxygenation in postoperative infants with cerebral fractional tissue oxygen extraction greater than or equal to 0.4 may be at risk in instable hemodynamic or respiratory situations.

Background/Aims: Several recent clinical studies revealed an accumulation of ceramide in bronchial epithelial cells of patients with cystic fibrosis (CF). Degradation of ceramide concentrations in lungs of CF patients employing the functional acid sphingomyelinase inhibitor amitriptyline revealed a benefit in lung function, weight and exacerbation rates. Methods: To test for a beneficial effect of amitriptyline in vivo, we performed two phase II randomised, double-blind, placebo-controlled studies. CF patients were treated with 25 mg amitriptyline twice daily, i.e. a total dose of 50 mg/d. After those two studies part of the patients used amitriptyline in an off-lable-use for routine treatment. These patients were observed after one, two and three years after continuous use of amitriptyline and were matched with those patients who were not treated. These patients were used as a control group. Results: After one year of treatment, forced expiratory volume in 1 sec predicted (FEV₁) increased significantly by 7.6±7.0%, p=<0.001, and weight increased by 2.1±2.3kg, p=<0.001 in the amitriptyline population (n=20), whereas FEV₁ decreased significantly in the control group by 1.8±3.3%, p=0.010, and weight increased by 1.1±2.7kg, p=0.010 (n=14). After two years of treatment, FEV₁ increased significantly by 5.6±10.3%, p=0.009, and weight increased by 3.6±2.9kg, p=<0.001 in the amitriptyline population (n=12). In contrast, FEV₁ decreased in the control group by 2.1±3.7%, p=0.051 and weight increased by only 0.4±2.9kg, p=0.31 (n=10). After three years of treatment, FEV₁ increased significantly by 7.7±8%, p=0.050, and weight increased by 7.3±3.8kg, p=0.016, in the amitriptyline population (n=5), whereas FEV₁ decreased in the control group by 1.0±1.3%, p=0.075 and weight increased by 0.4±1.5kg, p=0.29 (n=5). Conclusion: Amitriptyline significantly increases FEV₁, reduces ceramide in lung cells and increases weight of CF patients.

Essentials Bleeding complications during congenital heart disease surgery in neonatal age are very common. We report the perioperative incidence of acquired von Willebrand syndrome (aVWS) in 12 infants. aVWS was detected in 8 out of 12 neonates and infants intraoperatively after cardiopulmonary bypass. Ten patients received von Willebrand factor concentrate intraoperatively and tolerated it well. SUMMARY: Background Cardiac surgery of the newborn and infant with complex congenital heart disease (CHD) is associated with a high rate of intraoperative bleeding complications. CHD-related anatomic features such as valve stenoses or patent arterial ducts can lead to enhanced shear stress in the blood stream and thus cause acquired von Willebrand syndrome (aVWS). Objective To evaluate the intraoperative incidence and impact of aVWS after cardiopulmonary bypass (CPB) in neonates and infants with complex CHD. Patients/Methods We conducted a survey of patients aged < 12 months undergoing complex cardiac surgery in our tertiary referral center. Twelve patients, whose blood samples were analyzed for aVWS before CPB and immediately after discontinuation of CPB on a routine basis, were eligible for the analysis. von Willebrand factor antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo), collagen binding activity (VWF:CB), VWF:multimers and factor VIII activity (FVIII:C) were determined. Results aVWS was diagnosed by VWF multimer analysis in 10 out of 12 patients (83%) prior to surgery and intraoperatively at the end of CPB in 8 out of 12 patients (66%). Ten patients received VWF/FVIII concentrate intraoperatively as individual treatment attempts during uncontrolled bleeding. They tolerated it well without intraoperative thrombotic events. One patient suffered a transient postoperative cerebral sinuous vein thrombosis. Conclusions aVWS is of underestimated incidence in complex CHD surgery. These data may offer a new approach to reduce the risk of severe bleedings and to achieve hemostasis during high-risk pediatric cardiac surgery by tailoring the substitution with von Willebrand factor concentrate.

Enoxaparin displays fibrinolytic activity through stimulation of endothelial release of tissue plasminogen activator. Moreover, enoxaparin increases the release of tissue factor pathway inhibitor, which inhibits coagulation activity. However, there are only few reports regarding the use of enoxaparin for the treatment of children with thrombosis complicating congenital heart disease. We report the clinical findings from two patients, one child with an A. cerebri media infarction and another with a left ventricular thrombus. In both cases successful thrombolysis was obtained by intravenous administration of enoxaparin. The first patient was a 12-year-old girl with an atrioventricular septal defect, who underwent biventricular repair at the age of 8 months. She presented with right-sided middle cerebral artery infarction. Thrombolysis was contraindicated, because she was beyond the therapeutic window recommended by accepted guidelines. Enoxaparin 2.5 mg/kg/d was administered as a continuous intravenous infusion (CII). The MRI 10 days later revealed a reopened middle cerebral artery and she experienced complete remission of the neurological signs. The second patient was a 16-year-old boy who had tetralogy of Fallot corrected in late infancy. He presented with severe heart failure and a mural thrombus in the left ventricular apex. Enoxaparin was administered and resulted in complete disappearance of the thrombus within a week. According to our experience, CII of enoxaparin was safe and well tolerated without secondary bleeding and resulted in complete dissolution of the thrombi without secondary embolization. Therefore, CII of enoxaparin may be a possible alternative for the treatment of thrombotic complications in children with contraindications against conventional thrombolytic therapy.

AVWS (acquired von Willebrand syndrome) has been reported in patients with congenital heart diseases (CHD) associated with shear stress caused by significant blood flow gradients. Its etiology and impact on intraoperative bleeding during pediatric cardiac surgery have not been systematically studied. This single-center, prospective, observational study investigated appropriate diagnostic tools of aVWS compared to multimer analysis as diagnostic gold standard and aimed to clarify the role of aVWS in intraoperative hemorrhage. A total of 65 newborns and infants aged 0-12 months scheduled for cardiac surgery at our tertiary referral center during 03/18 to 07/19 were included in the analysis. The GPIbM/VWF:Ag ratio provided the best predictability of aVWS (area under the curve (AUC) 0.81[0.75-0.86]), followed by VWF:CB/VWF:Ag ratio (AUC 0.70[0.63-0.77]) and peak systolic echocardiographic gradients (AUC 0.69[0.62-0.76]). A cutoff value of 0.83 was proposed for the GPIbM/VWF:Ag ratio. Intraoperative high molecular weight multimer (HMWM) ratios were inversely correlated with cardiopulmonary bypass (CPB) time (r=-0.57) and aortic cross clamp (ACC) time (r=-0.54). Patients with intraoperative aVWS received significantly more fresh frozen plasma (FFP) (p=0.016) and fibrinogen concentrate (FIB) (p=0.011) compared to those without. The amounts of other administered blood components and chest closure times did not differ significantly. CPB appears to trigger aVWS in pediatric cardiac surgery. The GPIbM/VWF:Ag ratio is a reliable test that can be included in routine intraoperative laboratory workup. Our data provide the basis for further studies in larger patient cohorts to achieve definitive clarification of the effects of aVWS and its potential treatment on intraoperative bleeding.