Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy.

We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9 (i.e., "dead" Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR-transactivator therapy. The dose of rAAV used was 1×1014 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.).

Nurse-Implemented Goal-Directed Strategy to Improve Pain and Sedation Management in a Pediatric Cardiac ICU.

OBJECTIVES: To assess the impact of a nurse-implemented goal-directed sedation strategy on patient care and nursing practice in a pediatric cardiac ICU. DESIGN: Quality improvement project with a pre-post interval measurement plan. SETTING: Thirty-one bed pediatric cardiac ICU in a freestanding tertiary care children's hospital. PATIENTS: Postoperative pediatric cardiac surgery patients. INTERVENTIONS: The implementation of cardiac-Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE), a nurse-implemented goal directed strategy to improve pain and sedation management in a pediatric cardiac ICU which included daily team discussion of the patient's trajectory of illness (acute, titration, or weaning phase), prescription of a sedation target score based on the patient's trajectory of illness, arousal assessments, and opioid and/or sedative titration. Withdrawal Assessment Scores were used to assess and manage iatrogenic withdrawal symptoms. MEASUREMENTS AND MAIN RESULTS: Data related to opioid and sedation use, pain and sedation scores, and the occurrence and management of iatrogenic withdrawal symptoms were reviewed on 1,243 patients during four separate time periods: one pre-implementation and three discontinuous post-implementation time intervals. Patient age and complexity were consistent across the data collection periods. Post-implementation opioids and benzodiazepines use was reduced about 50% without a concomitant increase in the use of other sedative classes. Few post-intervention patients were discharged from the pediatric cardiac ICU or to home on methadone (pediatric cardiac ICU: pre 19% to post 3%; hospital: pre 12% to post 1.3%). Documentation of pain, sedation, and withdrawal scores became more consistent and nurses reported satisfaction with their patient's comfort management. CONCLUSIONS: The implementation of a nurse-driven goal-directed plan such as cardiac-RESTORE to manage pediatric cardiac ICU patient pain and sedation is possible, sustainable, and associated with reduced sedative and methadone use.

Mesenteric near-infrared spectroscopy and risk of gastrointestinal complications in infants undergoing surgery for congenital heart disease.

We hypothesised that lower mesenteric near-infrared spectroscopy values would be associated with a greater incidence of gastrointestinal complications in children weighing <10 kg who were recovering from cardiac surgery. We evaluated mesenteric near-infrared spectroscopy, central venous oxygen saturation, and arterial blood gases for 48 hours post-operatively. Enteral feeding intake, gastrointestinal complications, and markers of organ dysfunction were monitored for 7 days. A total of 50 children, with median age of 16.7 (3.2-31.6) weeks, were studied. On admission, the average mesenteric near-infrared spectroscopy value was 71±18%, and the systemic oxygen saturation was 93±7.5%. Lower admission mesenteric near-infrared spectroscopy correlated with longer time to establish enteral feeds (r=-0.58, p<0.01) and shorter duration of feeds at 7 days (r=0.48, p<0.01). Children with gastrointestinal complications had significantly lower admission mesenteric near-infrared spectroscopy (58±18% versus 73±17%, p=0.01) and higher mesenteric arteriovenous difference of oxygen at admission [39 (23-47) % versus 19 (4-27) %, p=0.02]. Based on multiple logistic regression, admission mesenteric near-infrared spectroscopy was independently associated with gastrointestinal complications (Odds ratio, 0.95; 95% confidence interval, 0.93-0.97; p=0.03). Admission mesenteric near-infrared spectroscopy showed an area under the receiver operating characteristic curve of 0.76 to identify children who developed gastrointestinal complications, with a suggested cut-off value of 72% (78% sensitivity, 68% specificity). In this pilot study, we conclude that admission mesenteric near-infrared spectroscopy is associated with gastrointestinal complications and enteral feeding tolerance in children after cardiac surgery.

Early postoperative outcomes following surgical repair of complete atrioventricular septal defects: is down syndrome a risk factor?

OBJECTIVE: To evaluate the impact of Down syndrome on the early postoperative outcomes of children undergoing complete atrioventricular septal defect repair. DESIGN: Retrospective cohort study. SETTING: Single tertiary pediatric cardiac center. PATIENTS: All children admitted to PICU following biventricular surgical repair of complete atrioventricular septal defect from January 2004 to December 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 107 children, 67 with Down syndrome, were included. Children with Down syndrome were operated earlier: 4 months (interquartile range, 3.5-6.6) versus 5.7 months (3-8.4) for Down syndrome and non-Down syndrome groups, respectively (p < 0.01). There was no early postoperative mortality. There was no significant difference in the prevalence of dysplastic atrioventricular valve between the two groups. Two children (2.9%) from Down syndrome and three children (7.5%) from non-Down syndrome group required early reoperation (p = 0.3). Junctional ectopic tachycardia was the most common arrhythmia, and the prevalence of junctional ectopic tachycardia was similar between the two groups (9% and 10% in Down syndrome and non-Down syndrome, respectively, p = 1). One patient from each group required insertion of permanent pacemaker for complete heart block. Children with Down syndrome had significantly higher prevalence of noncardiac complications, that is, pneumothorax, pleural effusions, and infections (p < 0.01), than children without Down syndrome. There was a trend for longer duration of mechanical ventilation in children with Down syndrome (41 hr [20-61 hr] vs 27.5 hr [15-62 hr], p = 0.2). However, there was no difference in duration of PICU stay between the two groups (2 d [1.3-3 d] vs 2 d [1-3 d], p = 0.9, respectively). CONCLUSIONS: In our study, we found no difference in the prevalence of atrioventricular valve dysplasia between children with and without Down syndrome undergoing complete atrioventricular septal defect repair. This finding contrasts with previously published data, and further confirmatory studies are required. Although clinical outcomes were similar, children with Down syndrome had a significantly higher prevalence of noncardiac complications in the early postoperative period than children without Down syndrome.

Prenatal screening for major congenital heart disease: assessing performance by combining national cardiac audit with maternity data.

OBJECTIVE: Determine maternity hospital and lesion-specific prenatal detection rates of major congenital heart disease (mCHD) for hospitals referring prenatally and postnatally to one Congenital Cardiac Centre, and assess interhospital relative performance (relative risk, RR). METHODS: We manually linked maternity data (3 hospitals prospectively and another 16 retrospectively) with admissions, fetal diagnostic and surgical cardiac data from one Congenital Cardiac Centre. This Centre submits verified information to National Institute for Cardiovascular Outcomes Research (NICOR-Congenital), which publishes aggregate antenatal diagnosis data from infant surgical procedures. We included 120 198 unselected women screened prospectively over 11 years in 3 maternity hospitals (A, B, C). Hospital A: colocated with fetal medicine, proactive superintendent, on-site training, case-review and audit, hospital B: on-site training, proactive superintendent, monthly telemedicine clinics, and hospital C: sonographers supported by local obstetrician. We then studied 321 infants undergoing surgery for complete transposition (transposition of the great arteries (TGA), n=157) and isolated aortic coarctation (CoA, n=164) screened in hospitals A, B, C prospectively, and 16 hospitals retrospectively. RESULTS: 385 mCHD recorded prospectively from 120 198 (3.2/1000) screened women in 3 hospitals. Interhospital relative performance (RR) in Hospital A:1.68 (1.4 to 2.0), B:0.70 (0.54 to 0.91), C:0.65 (0.5 to 0.8). Standardised prenatal detection rates (funnel plots) demonstrating inter-hospital variation across 19 hospitals for TGA (37%, 0.00 to 0.81) and CoA (34%, 0.00 to 1.06). CONCLUSIONS: Manually linking data sources produced hospital-specific and lesion-specific prenatal mCHD detection rates. More granular, rather than aggregate, data provides meaningful feedback to improve screening performance. Automatic maternal and infant record linkage on a national scale, requires verified, prospective maternity audit and integration of health information systems.

Risky business: human factors in critical care.

Remarkable achievements have occurred in pediatric cardiac critical care over the past two decades. The specialty has become well defined and extremely resource intense. A great deal of focus has been centered on optimizing patient outcomes, particularly mortality and early morbidity, and this has been achieved through a focused and multidisciplinary approach to management. Delivering high-quality and safe care is our goal, and during the Risky Business symposium and simulation sessions at the Eighth International Conference of the Pediatric Cardiac Intensive Care Society in Miami, December 2010, human factors, systems analysis, team training, and lessons learned from malpractice claims were presented.

Databases for assessing the outcomes of the treatment of patients with congenital and paediatric cardiac disease--the perspective of critical care.

The development of databases to track the outcomes of children with cardiovascular disease has been ongoing for much of the last two decades, paralleled by the rise of databases in the intensive care unit. While the breadth of data available in national, regional and local databases has grown exponentially, the ability to identify meaningful measurements of outcomes for patients with cardiovascular disease is still in its early stages. In the United States of America, the Virtual Pediatric Intensive Care Unit Performance System (VPS) is a clinically based database system for the paediatric intensive care unit that provides standardized high quality, comparative data to its participants [https://portal.myvps.org/]. All participants collect information on multiple parameters: (1) patients and their stay in the hospital, (2) diagnoses, (3) interventions, (4) discharge, (5) various measures of outcome, (6) organ donation, and (7) paediatric severity of illness scores. Because of the standards of quality within the database, through customizable interfaces, the database can also be used for several applications: (1) administrative purposes, such as assessing the utilization of resources and strategic planning, (2) multi-institutional research studies, and (3) additional internal projects of quality improvement or research.In the United Kingdom, The Paediatric Intensive Care Audit Network is a database established in 2002 to record details of the treatment of all critically ill children in paediatric intensive care units of the National Health Service in England, Wales and Scotland. The Paediatric Intensive Care Audit Network was designed to develop and maintain a secure and confidential high quality clinical database of pediatric intensive care activity in order to meet the following objectives: (1) identify best clinical practice, (2) monitor supply and demand, (3) monitor and review outcomes of treatment episodes, (4) facilitate strategic healthcare planning, (5) quantify resource requirements, and (6) study the epidemiology of critical illness in children.Two distinct physiologic risk adjustment methodologies are the Pediatric Risk of Mortality Scoring System (PRISM), and the Paediatric Index of Mortality Scoring System 2 (PIM 2). Both Pediatric Risk of Mortality (PRISM 2) and Pediatric Risk of Mortality (PRISM 3) are comprised of clinical variables that include physiological and laboratory measurements that are weighted on a logistic scale. The raw Pediatric Risk of Mortality (PRISM) score provides quantitative measures of severity of illness. The Pediatric Risk of Mortality (PRISM) score when used in a logistic regression model provides a probability of the predicted risk of mortality. This predicted risk of mortality can then be used along with the rates of observed mortality to provide a quantitative measurement of the Standardized Mortality Ratio (SMR). Similar to the Pediatric Risk of Mortality (PRISM) scoring system, the Paediatric Index of Mortality (PIM) score is comprised of physiological and laboratory values and provides a quantitative measurement to estimate the probability of death using a logistic regression model.The primary use of national and international databases of patients with congenital cardiac disease should be to improve the quality of care for these patients. The utilization of common nomenclature and datasets by the various regional subspecialty databases will facilitate the eventual linking of these databases and the creation of a comprehensive database that spans conventional geographic and subspecialty boundaries.