Perioperative diagnosis and impact of acquired von Willebrand syndrome in infants with congenital heart disease.

Acquired von Willebrand syndrome (aVWS) has been reported in patients with congenital heart diseases 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 with multimer analysis as diagnostic criterion standard and aimed to clarify the role of aVWS in intraoperative hemorrhage. A total of 65 newborns and infants aged 0 to 12 months scheduled for cardiac surgery at our tertiary referral center from March 2018 to July 2019 were included in the analysis. The glycoprotein Ib M assay (GPIbM)/von Willebrand factor antigen (VWF:Ag) ratio provided the best predictability of aVWS (area under the receiver operating characteristic curve [AUC], 0.81 [95% CI, 0.75-0.86]), followed by VWF collagen binding assay/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 ratios were inversely correlated with cardiopulmonary bypass (CPB) time (r = -0.57) and aortic cross-clamp time (r = -0.54). Patients with intraoperative aVWS received significantly more fresh frozen plasma (P = .016) and fibrinogen concentrate (P = .011) than 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.

Cerebral venous sinus thrombosis and thrombocytopenia due to heparin-independent anti-PF4 antibodies after adenovirus infection.

Not available.

Cerebral Oxygen Metabolism Before and After RBC Transfusion in Infants Following Major Surgical Procedures.

OBJECTIVE: Although infants following major surgery frequently require RBC transfusions, there is still controversy concerning the best definition for requirement of transfusion in the individual patient. The aim of this study was to determine the impact of RBC transfusion on cerebral oxygen metabolism in noncardiac and cardiac postsurgical infants. DESIGN: Prospective observational cohort study. SETTING: Pediatric critical care unit of a tertiary referral center. PATIENTS: Fifty-eight infants (15 after pediatric surgery and 43 after cardiac surgery) with anemia requiring RBC transfusion were included. INTERVENTIONS: RBC transfusion. MEASUREMENTS AND MAIN RESULTS: We measured noninvasively regional cerebral oxygen saturation and microperfusion (relative cerebral blood flow) using tissue spectrometry and laser Doppler flowmetry before and after RBC transfusion. Cerebral fractional tissue oxygen extraction and approximated cerebral metabolic rate of oxygen were calculated. Fifty-eight RBC transfusions in 58 patients were monitored (15 after general surgery, 24 after cardiac surgery resulting in acyanotic biventricular physiology and 19 in functionally univentricular hearts including hypoplastic left heart following neonatal palliation). The posttransfusion hemoglobin concentrations increased significantly (9.7 g/dL vs 12.8 g/dL; 9.7 g/dL vs 13.8 g/dL; 13.1 g/dL vs 15.6 g/dL; p < 0.001, respectively). Posttransfusion cerebral oxygen saturation was significantly higher than pretransfusion (61% [51-78] vs 72% [59-89]; p < 0.001; 58% [35-77] vs 71% [57-88]; p < 0.001; 51% [37-61] vs 58% [42-73]; p = 0.007). Cerebral fractional tissue oxygen extraction decreased posttransfusion significantly 0.37 (0.16-0.47) and 0.27 (0.07-039), p = 0.002; 0.40 (0.2-0.62) vs 0.26 (0.11-0.57), p = 0.001; 0.42 (0.23-0.52) vs 0.32 (0.1-0.42), p = 0.017. Cerebral blood flow and approximated cerebral metabolic rate of oxygen showed no significant change during the observation period. The increase in cerebral oxygen saturation and the decrease in cerebral fractional tissue oxygen extraction were most pronounced in patients after cardiac surgery with a pretransfusion cerebral fractional tissue oxygen extraction greater than or equal to 0.4. CONCLUSION: 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.

Nurse-driven analgesia and sedation in pediatric patients with univentricular hearts requiring extracorporeal life support after first-stage palliation surgery: A pilot study.

BACKGROUND: Few data are available regarding requirements of sedation and analgesia in children during extracorporeal life support. AIMS: The aim of this study was to evaluate if children with functionally univentricular hearts on extracorporeal life support after first-stage palliation surgery have higher requirement of analgesics and sedatives compared with children without extracorporeal life support using a goal-directed nurse-driven analgesia and sedation protocol. METHODS: This prospective observational matched case-control pilot study was conducted at a cardiac pediatric intensive care unit of a tertiary referral center. Seventeen patients with functionally univentricular hearts including hypoplastic left heart syndrome who were on extracorporeal life support after first-stage palliation surgery were enrolled from July 2012 to January 2017. Seventeen matched patients served as controls. Doses of morphine, midazolam, clonidine, and muscle relaxants as well as sedation scores (COMFORT behavior scale and the nurse interpretation of sedation scale) were assessed according to a nurse-driven protocol every 8 hours up to 120 hours after first-stage palliation surgery. RESULTS: Sedation scores were equal in the extracorporeal life support group and in the control group at most points in time. There was no significant difference in cumulative doses of morphine and midazolam. However, children of the extracorporeal life support group received higher doses of midazolam and morphine at some points in time. CONCLUSION: 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.

Long-Term Pulmonal Therapy of Cystic Fibrosis-Patients with Amitriptyline.

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.

Successful thrombolysis following enoxaparin therapy in two pediatric patients with congenital heart disease presenting with intracardiac and cerebral thrombosis.

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.

Therapy of CF-patients with amitriptyline and placebo--a randomised, double-blind, placebo-controlled phase IIb multicenter, cohort-study.

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.

Left Atrioventricular Transvalvular Pressure Gradients Derived from Intraoperative and Postoperative Echocardiograms following Atrioventricular Septal Defect Repair.

BACKGROUND: Left atrioventricular valve (LAVV) stenosis following an atrioventricular septal defect (AVSD) repair is a rare but potentially life-threatening complication. While echocardiographic quantification of diastolic transvalvular pressure gradients is paramount in the evaluation of a newly corrected valve function, it is hypothesized that these measured gradients are overestimated immediately following a cardiopulmonary bypass (CPB) due to the altered hemodynamics when compared to postoperative valve assessments using awake transthoracic echocardiography (TTE) upon recovery after surgery. METHODS: Out of the 72 patients screened for inclusion at a tertiary center, 39 patients undergoing an AVSD repair with both intraoperative transesophageal echocardiograms (TEE, performed immediately after a CPB) and an awake TTE (performed prior to hospital discharge) were retrospectively selected. The mean (MPGs) and peak pressure gradients (PPGs) were quantified using a Doppler echocardiography and other measures of interest were recorded (e.g., a non-invasive surrogate of the cardiac output and index (CI), left ventricular ejection fraction, blood pressures and airway pressures). The variables were analyzed using the paired Student's t-tests and Spearman's correlation coefficients. RESULTS: The MPGs were significantly higher in the intraoperative measurements when compared to the awake TTE (3.0 ± 1.2 vs. 2.3 ± 1.1 mmHg; p < 0.01); however, the PPGs did not significantly differ (6.6 ± 2.7 vs. 5.7 ± 2.8 mmHg; p = 0.06). Although the assessed intraoperative heart rates (HRs) were also higher (132 ± 17 vs. 114 ± 21 bpm; p < 0.001), there was no correlation found between the MPG and the HR, or any other parameter of interest, at either time-point. In a further analysis, a moderate to strong correlation was observed in the linear relationship between the CI and the MPG (r = 0.60; p < 0.001). During the in-hospital follow-up period, no patients died or required an intervention due to LAVV stenosis. CONCLUSIONS: The Doppler-based quantification of diastolic transvalvular LAVV mean pressure gradients using intraoperative transesophageal echocardiography seems to be prone to overestimation due to altered hemodynamics immediately after an AVSD repair. Thus, the current hemodynamic state should be taken into consideration during the intraoperative interpretation of these gradients.

Acquired von Willebrand syndrome is common in infants with systemic-to-pulmonary shunts: Retrospective case-series.

Background: Although acquired von Willebrand syndrome (aVWS) has been described in congenital heart disease before, anatomical features leading to aVWS with characteristic reduction or loss of high molecular weight von Willebrand multimers (HMWM) are not well known. This study assesses the prevalence and effects of aVWS in infants with systemic-to-pulmonary shunts (SPS). Methods: This retrospective single-center study analyzes diagnostic data of infants with complex congenital heart defects requiring palliation with SPS. During the study period between 12/15-01/17 fifteen consecutive patients were eligible for analysis. Results of von Willebrand factor antigen (VWF:Ag), collagen binding activity (VWF:CB) and von Willebrand factor multimer analysis were included. Results: In all 15 patients with SPS an aVWS could be found. Blood samples were collected between 5 and 257 days after shunt implantation (median 64 days). None of the patients demonstrated increased bleeding in everyday life. However, 6 out of 15 patients (40%) showed postoperative bleeding complications after SPS implantation. Following shunt excision multimeric pattern normalized in 8 of 10 (80%) patients studied. Conclusions: This study shows that in patients undergoing SPS implantation aVWS might emerge. Pathogenesis can be explained by shear stress resulting from turbulent flow within the shunt. Knowledge of aVWS existence is important for the consideration of replacement therapy with von Willebrand factor containing products and antifibrinolytic treatment in bleeding situations. Implementation of methods for rapid aVWS detection is required to achieve differentiated hemostatic therapy and reduce the risk of complications caused by empiric replacement therapy.

Detection of early incomplete heparin reversal following congenital cardiac surgery: A single-center retrospective observational study.

BACKGROUND: The monitoring of unfractionated heparin (UFH) reversal with protamine plays a crucial role for bleeding management after cardio-pulmonary bypass (CPB) in congenital cardiac surgery. The current standard for the monitoring of UFH and its reversal is the activated clotting time (ACT). While the ACT is affected by other CPB-associated pathologies a bedside technique with more specific heparin-related results would be very helpful. The new point-of-care viscoelastic test Haemonetics TEG® 6s, which is based on small blood samples may fulfill these requirements. This study aimed to compare the new TEG with laboratory assays. METHODS: A retrospective observational study was performed on 40 children with a median age of 130 days (interquartile range 13 to 310 days) undergoing congenital cardiac surgery. After separation of CPB, test results of the TEG® 6s, ACT, anti-Xa for UFH and PTT were compared and correlated with each other. RESULTS: No clinically relevant correlation was found for heparin specific TEG-derived parameters (CK/CKH R-time ratio) with ACT, PTT and anti-Xa measurements. After grouping in dependence to the CK/CKH R-time in patients with and without successful heparin reversal again no significant difference of anti-Xa-UFH-levels, post-/pre-CPB ratio of the PTT and ACT was observed. CONCLUSIONS: In pediatric patients undergoing cardiac surgery using CPB there is no association of conventional coagulation tests and TEG-derived results. While bedside viscoelastic tests deliver rapid results, further studies are needed to compare whether the TEG based management of incomplete heparin reversal is sufficient to monitor heparin reversal and to reduce blood loss.

Adoptive transfer of epstein-barr virus (EBV) nuclear antigen 1-specific t cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation.

PURPOSE: Reactivation of Epstein-Barr virus (EBV) after allogeneic stem-cell transplantation (SCT) can lead to severe life-threatening infections and trigger post-transplantation lymphoproliferative disease (PTLD). Since EBV-specific T cells could prevent PTLD, cellular immunotherapy has been a promising treatment option. However, generation of antigen-specific T-cell populations has been difficult within a short time frame. PATIENTS AND METHODS: To improve availability in urgent clinical conditions, we developed a rapid protocol for isolation of polyclonal EBV nuclear antigen 1 (EBNA-1) -specific T cells by using an interferon gamma (IFN-γ) capture technique. RESULTS: We report on the use of adoptive transfer of EBNA-1-specific T cells in 10 pediatric and adult patients with EBV viremia and/or PTLD after SCT. No acute toxicity or graft-versus-host disease (GVHD) of more than grade 2 occurred as a result of adoptive T-cell transfer. In vivo expansion of transferred EBNA-1-specific T cells was observed in eight of 10 patients after a median of 16 days following adoptive transfer that was associated with clinical and virologic response in seven of them (70%). None of the responders had EBV-associated mortality. Within clinical responders, three patients were disease free by the day of last follow-up (2 to 36 months), three patients died of other infectious complications, and one patient died as a result of relapse of malignancy. EBV-related mortality was observed in two of 10 patients, and another patient had ongoing viremia without clinical symptoms at last follow-up. CONCLUSION: 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.