BACKGROUND AND PURPOSE:The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. METHODS:Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively. RESULTS:Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a-3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. CONCLUSIONS:Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors.Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760.Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers.Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia.

Background Autologous peripheral blood stem-cell collection (PBSCC) in children has become an integral part of contemporary treatment protocols, but the procedure is often complicated due to technical issues related to vascular access. Central line placement is often implemented to surmount this problem, but is associated with complications such as bleeding, thrombosis and pneumothorax. As an alternative we have introduced the use of radial arterial lines for PBSCC in children. Procedure Data from autologous stem cell collections performed from October 2002 to December 2011 using a radial arterial line were collected. Results A total of 372 PBSCC procedures were performed during the study period; an arterial line was used in 311 PBSCC's in 208 children. The average patient age and weight were 7.9 years (SD 5.4) and 28.3kg (SD 20.4), respectively. The smallest patient was 9 months old and weighed 7kg. The mean total volume processed was 8,593cm3 (SD 4,854), and the mean number of blood volumes processed was 4.3. Mean collection time for a single blood volume was 55minutes (SD 15.5). The mean number of CD34+ cells collected per donation was 5.8x106/kg. Ninety-seven patients (46%) required more than one collection to meet the requested CD34+ cell target. No serious adverse effects associated with vascular access occurred in this cohort. Conclusion Percutaneous placement of radial artery catheters can be rapidly and safely performed in very small infants and in children with difficult venous access. This technique provides a reliable platform for efficient PBSCC. Pediatr Blood Cancer 2013; 60: 946948. (c) 2012 Wiley Periodicals, Inc.

Myocarditis among pediatric patients varies in severity from mild disease to a fulminant course with overwhelming refractory shock and a high risk of death. Because the disease is potentially reversible, it is reasonable to deploy extracorporeal membranous oxygenation (ECMO) to bridge patients until recovery or transplantation. This study aimed to review the course and outcome of children with acute fulminant myocarditis diagnosed by clinical and echocardiographic data only who were managed by ECMO because of refractory circulatory collapse. A chart review of a single center identified 12 children hospitalized over an 8-year period who met the study criteria. Data were collected on demographics, diagnosis, disease course, and outcome. The patients ranged in age from 20 days to 8 years (25.5 ± 29.6 months). Echocardiography showed a severe global biventricular decrease in myocardial function, with a shortening fraction of 12% or less. Ten children (83.3%) were weaned off extracorporeal support after 100–408 h (mean, 209.9 ± 82.4 h) and discharged home. Two patients died: one due to multiorgan failure and one due to sustained refractory heart failure. During a long-term follow-up period, all survivors showed normal function in daily activities and normal myocardial function. The study showed that ECMO can be safely and successfully used for children with acute fulminant myocarditis diagnosed solely on clinical and radiographic grounds who need mechanical support. These patients usually have a favorable outcome, regaining normal or near normal heart function without a need for heart transplantation.

Abstract Introduction Anomalous origin of one pulmonary artery from the ascending aorta is a rare cardiac anomaly in which the pulmonary artery abnormally arises from the ascending aorta. Physiologically, most patients develop signs of cardiac failure due to high flow to both lungs, with systemic or supra-systemic pressures in the normally connected lung. The purpose of this study is to present our experience with this rare anomaly, in which early anatomic repair lead to rapid physiologic correction. Materials and methods Retrospective case review of all patients with anomalous origin of one pulmonary artery from the ascending aorta at Schneider Chidren’s Medical center of Israel between 1986 and 2007. All clinical operative and echocardiographic charts were analysed. Results Twelve patients were diagnosed as anomalous origin of one pulmonary artery from the ascending aorta. In 10 patients, the right pulmonary artery rose from the ascending aorta, while in two an anomalous origin of the left pulmonary artery was associated with a right aortic arch. Initial diagnoses was made with two-dimensional echocardiography in all patients. In six patients, diagnostic cardiac catheterisation was performed in order to confirm the diagnosis. Age at diagnosis ranged from 5 to 180 days with a median of 15 days, and patient weight ranged from 780 grams to 5 kilograms, with a median of 3 kilograms. Initial echocardiographic evaluation showed systemic (four patients) or supra-systemic (seven patients) pressures in the right ventricle and normally connected lung. All underwent surgical repair. There was no operatrive mortality. All reconstructed patients achieved normal right ventricular pressures within days after surgery. The flow pattern in both pulmonary arteries was normalised. Conclusions Early surgical repair of anomalous origin of one pulmonary artery from the ascending aorta is feasible and safe even in newborn and premature babies with complete resolution of the pulmonary hypertension and normalisation of pulmonary vascular resistance.

SummaryBackground : Postoperative bleeding and blood product requirements can be substantial in children undergoing open‐heart surgery, and reexploration is required in 1% of cases. Recombinant activated factor VII (rFVIIa, NovoSeven®, NovoNordisk, Denmark) is a hemostatic agent approved for the treatment of hemophilic patients with inhibitors to factor VIII or factor IX. It has also been used with success in other conditions. We present our experience with rFVIIa treatment for uncontrolled bleeding after open‐heart surgery in five pediatric patients.Methods : The study group consisted of five patients after open‐heart surgery with excessive blood loss. The patients were treated with rFVIIa after failure of conventional treatment to control the bleeding. Blood loss, blood product consumption, and coagulation test results were recorded before and after rFVIIa administration.Results : In all cases, blood loss decreased considerably after rFVIIa administration (mean 7.8 ml·kg−1·h−1), almost eliminating the need for additional blood products, and the prolonged prothrombin time normalized. In two patients with thrombocytopathy, rFVIIa helped to discriminate surgical bleeding from bleeding caused by a defect in hemostasis. No side effects of rFVIIa treatment were noted.Conclusions : These cases support the impression that RFVIIa is efficient and safe in correcting hemostasis in children after cardiopulmonary bypass when other means fail. However, the data are still limited, and more extensive research is needed.

OBJECTIVE:To evaluate the safety of a propofol-ketamine mixture to induce and maintain anesthesia in spontaneously breathing pediatric patents during cardiac catheterization.DESIGN:Prospective clinical study.SETTING:Departments of Cardiothoracic Surgery, Anesthesiology, and Pediatric Anesthesiology in a university hospital.PARTICIPANTS:Forty-five children aged 6 months to 16 years with ASA grade II to III undergoing cardiac catheterization.INTERVENTIONS:Continuous intravenous infusion of a mixture of propofol (4 mg/mL) and ketamine (2 mg/mL) with spontaneous ventilation. The infusion rate was changed and additional boluses of propofol or/and ketamine were given as needed. Hemodynamic, respiratory, and other variables were recorded during the procedure and recovery.RESULTS:Mean dose of ketamine was 26 +/- 8.3 microg/kg/min and of propofol, 68.3 +/- 21.7 microg/kg/min. Changes in heart rate and mean arterial pressure of more than 20% from baseline were observed in 4 and 5 patients, respectively. A transient reduction in oxygen saturation because of hypoventilation was observed in 3 patients and responded to oxygen administration and manual assisted ventilation. No other complications were observed.CONCLUSIONS:The propofol-ketamine mixture is a safe, practical alternative for general anesthesia in pediatric patients undergoing cardiac catheterization.