Whole-exome sequencing reveals a monogenic cause in 56% of individuals with laterality disorders and associated congenital heart defects.

BACKGROUND: The molecular basis of heterotaxy and congenital heart malformations associated with disruption of left-right asymmetry is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far. OBJECTIVE: We sought to elucidate the molecular basis of laterality disorders and associated congenital heart defects in a cohort of 30 unrelated probands of Arab-Muslim descent, using next-generation sequencing techniques. METHODS: Detailed clinical phenotyping followed by whole-exome sequencing (WES) was pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families. RESULTS: Using WES, we reached a molecular diagnosis for 17 of the 30 probands (56.7%). Genes known to be associated with heterotaxy and/or primary ciliary dyskinesia, in which homozygous pathogenic or likely pathogenic variants were detected, included CFAP53 (CCDC11), CFAP298 (C21orf59), CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40, PKD1L1 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy in humans. Three additional probands were found to harbour variants of uncertain significance. These included variants in DNAH6, HYDIN, CELSR1 and CFAP46. CONCLUSIONS: Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next-generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families.

Congenital Aortic Vascular Ring: In-Utero Sonographic Assessment of Tracheal Patency and Postnatal Outcome.

OBJECTIVE: Congenital aortic vascular ring may present after birth with variable degrees of respiratory distress due to tracheal compression. The aim of this study was to prospectively evaluate in utero tracheal patency in correlation with postnatal outcome. METHODS: During an eight-year period, fetuses with aortic arch abnormality encircling the trachea and forming a complete ring were recruited for the study. Tracheal patency was classified as: no compression, partial compression, or complete compression. Postnatal MRI/CTangio studies were performed and outcome data was retrospectively analyzed from the medical records. RESULTS: Among the 46 fetuses recruited to the study, 38 had right aortic arch (RAA), and 8 presented with double aortic arch (DAA). In the RAA group 35 (92.1 %) of the fetuses presented no compression and 34 (97.1 %) of them were asymptomatic in the long-term follow-up. Three fetuses (7.9 %) in this group presented in utero compression: one was terminated at 16 weeks of gestation due to associated ominous findings, and the other two had mild respiratory symptoms around 12 months of age and underwent surgery with a good outcome. In the DAA group, all fetuses presented in utero with tracheal compression. Seven showed partial and one complete compression. Among the seven with partial compression, six were symptomatic and underwent surgery. The case with severe airway occlusion had emergency tube insertion in the delivery room and underwent surgery at 7 days but died from severe respiratory complications. CONCLUSION: This is the first study to evaluate in utero tracheal patency in cases with vascular ring. It allows better prenatal and postnatal workup and follow-up including potentially life-threatening respiratory failure.

Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.

Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome.

Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.

A founder truncating variant in GDF1 causes autosomal-recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds.

The genetic basis of congenital heart malformations associated with disruption of left-right (L-R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left-right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab-Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left-right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.

The added value of f-TAPSE in the surveillance of pregnancies complicated by fetal and placental tumors.

INTRODUCTION: Fetal and placental tumors are associated with high prevalence of obstetrical complications and poor fetal outcome. The aim of our study was to assess the added value of serial fetal Tricuspid Annular Plane Systolic Excursion (f-TAPSE) measurements for monitoring cardiac function in cases of fetal and placental tumors. METHODS: Serial measurements of f-TAPSE were performed prospectively in fetuses referred for fetal and placental tumors. The patients were followed longitudinally every 2 weeks. In each visit, tumor measurements, Doppler flow indices, fetal cardiothoracic index and measurements of f-TAPSE were performed. RESULTS: During the study period, 11 fetuses were followed prospectively: seven chorioangiomas and four fetal tumors. In eight cases, the f-TAPSE was measured in the upper range for gestational age. In three cases of small or poorly vascularized tumors, the measurements were within the 50th percentile for gestational age. In two cases who presented with elevated f-TAPSE, a regression in the f-TAPSE percentile was observed: in the first case, the tumor regressed; however, in the second case, the f-TAPSE pseudo normalized and was followed by cardiac decompensation. CONCLUSIONS: f-TAPSE may serve as a complementary tool for assessing tumors associated hyper-dynamic state and early diagnosis of cardiac decompensation. © 2017 John Wiley & Sons, Ltd.

Primary Fetal Lung Hypoplasia (PFLH): Imaging and Clinical Characteristics.

Purpose To describe in utero and postnatal imaging and clinical characteristics of primary fetal lung hypoplasia (PFLH). Methods A retrospective review of fetuses and neonates diagnosed in one academic tertiary center during an eleven-year period. Results 12 cases of PFLH were identified. 4 were bilateral and 8 had unilateral involvement. Prenatal sonographic characteristics, postnatal magnetic resonance imaging (MRI), computerized tomographic angiography (CTA), and histologic findings are described. 3 of the 4 bilateral cases were evaluated during fetal live. 2 were terminated and 2 died shortly after delivery. Among the 8 cases with unilateral PFLH, 7 involved the right lung and 1 the left lung. In fetuses with right hypoplasia, 5 showed characteristic features of Scimitar syndrome, while associated gastrointestinal tract (GIT) anomalies were presented in 2 cases. In this group 3 were born alive and the other 5 were terminated. Conclusion Primary PFLH is a rare anomaly that lethal in its bilateral form and with variable prognosis in its unilateral variant. Targeted evaluation of lung vascularity and exclusion of associated anomalies, especially of the GIT, are important prognostic factors.

Micro-RNA-208a, -208b, and -499 as Biomarkers for Myocardial Damage After Cardiac Surgery in Children.

OBJECTIVES: To test the hypothesis that cardiac-enriched micro-RNAs can serve as accurate biomarkers that reflect myocardial injury and to predict the postoperative course following pediatric cardiac surgery. Micro-RNAs have emerged as plasma biomarkers for many pathologic states. We aimed to quantify preoperative and postoperative plasma levels of cardiac-enriched micro-RNA-208a, -208b, and -499 in children undergoing cardiac surgery and to evaluate correlations between their levels, the extent of myocardial damage, and the postoperative clinical course. DESIGN: PICU. PATIENTS: Thirty pediatric patients that underwent open heart surgery for the correction of congenital heart defects between January 2012 to July 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At 12 hours post surgery, the plasma levels of the micro-RNAs increased by 300- to 4,000-fold. At 24 hours, their levels decreased but remained significantly higher than before surgery. Micro-RNA levels were associated with troponin levels, longer cardiopulmonary bypass and aortic crossclamp times, maximal postoperative aspartate aminotransferase levels, and delayed hospital discharge. CONCLUSIONS: Circulating micro-RNA-208a, -208b, and -499 are detectable in the plasma of children undergoing cardiac surgery and may serve as novel biomarkers for monitoring and forecasting postoperative myocardial injury and recovery.

The role of cardiac computed tomography in infants with congenital heart disease.

BACKGROUND: Patients with complex congenital heart disease (CHD) have a high incidence of extracardiac vascular and non-vascular malformations. Those additional abnormalities may have an impact on the precise planning of surgical or non-surgical treatment. OBJECTIVES: To assess the role of electrocardiography-gated CT-angiography (ECG-CTA) in the routine evaluation of CHD in neonates and infants particularly for the assessment of extracardiac findings. METHODS: The study cohort comprised 40 consecutive patients who underwent trans-thoracic echocardiography (TTE) and ECG-CTA. TTE and ECG-gated CTA findings regarding extracardiac vascular structures, coronary arteries and airways were compared with surgical or cardiac catheterization findings. Scans were evaluated for image quality using a subjective visual scale (from 1 to 4). Effective radiation dose was calculated for each scan. RESULTS: Median age was 28 +/- 88 days and mean weight 3.7 +/- 1.5 kg. Diagnostic quality was good or excellent (visual image score 3-4) in 39 of 40 scans (97.5%). ECG-CTA provided important additional information on extracardiac vascular structures and airway anatomy, complementing TTE in 75.6% of scans. Overall sensitivity of ECG-gated CTA for detecting extracardiac findings as compared with operative and cardiac catheterization findings was 97.6%. The calculated mean effective radiation dose was 1.4 +/- 0.07 mSv (range 1.014-2.3 mSv). CONCLUSIONS: ECG-CTA is an accurate modality for demonstrating extracardiac structures in complex CHD. It provides important complementary information to TTE with regard to extracardiac vascular structures and coronary artery anatomy. This modality may obviate the need for invasive cardiac catheterization, thus exposing the patient to a much lower radiation dose.

Fetal liver T2* values: defining a standardized scale.

PURPOSE: To define the normal T2* values of liver in the third trimester of pregnancy in normal fetuses. MATERIALS AND METHODS: Multi-echo gradient echo T2* sequence was applied to the fetal abdomen in the axial plane in women undergoing a fetal MRI (1.5 Tesla [T], MRI system). A region of interest, best visualizing in the liver parenchyma was used for measurements. Studies were independently read by two experienced readers to assess intra- and interobserver variability. RESULTS: The study cohort included 46 pregnant women undergoing fetal MRI for any indication other than liver pathology evaluation. Three scans were excluded due to fetal motion. Average maternal and gestational age were 33 ± 4 years and 31.9 ± 3 weeks, respectively. Average T2* values were found to be 19.7 ± 7.4 ms. The intra- and interobserver agreement were very good: 0.93 and 0.8-0.084, respectively. CONCLUSION: T2* MRI allows noninvasive evaluation liver iron content in the third trimester fetus. Measured values at this stage of pregnancy are significantly lower compared with values cited in the literature for adults. This is of major importance in the correct diagnosis of fetal iron overload states. We propose this as the standard reference when evaluating fetal iron overload pathology.

Echocardiographic myocardial deformation evaluation of right ventricular function in comparison with CMRI in repaired tetralogy of Fallot: a cross-sectional and longitudinal validation study.

BACKGROUND: Decreased right ventricular (RV) ejection fraction (EF) increases morbidity in repaired tetralogy of Fallot (rToF). Cardiac magnetic resonance (CMR) is the accepted reference standard for RV EF measurement. There are no established color Doppler tissue imaging (cDTI) values that identify decreased RV EF in rToF. We sought to assess accuracy of cDTI myocardial deformation and velocity indices in predicting CMR-derived RV EF. METHODS: Retrospective evaluation of CMR and echocardiography studies performed on the same day. cDTI-derived peak systolic velocity (pkS), isovolumic acceleration (IVA) of the tricuspid valve annulus, strain (ε) and strain rate (SR) of the RV free wall, adjusted for age, volume and pressure overload were used to compute RV EF. The probability of correctly classifying CMR measured RV EF <45% was estimated by logistic regression analysis. The accuracy of the model was tested on 10 prospective patients. RESULTS: Sixty matched echocardiographic and CMR studies were analyzed. None of the individual cDTI parameters could reliably identify patients with CMR-derived decreased RV EF. However, when adjusted for age in a logistic model: Y = -0.5 - 0.07 × age + 0.016 × Îµ + 0.46 × pkS, where Y is the logit (log odds), patients with RV EF <45% were identified with 86% sensitivity, 93.5% specificity. Prospective application of this model correctly identified all subjects with RV EF <45%. CONCLUSION: The age-adjusted logistic model and not individual parameters, derived from cDTI-derived pkS, and ε can reliably identify patients with decreased RV EF <45%.

Dominant Ventricular Morphology and Early Postoperative Course After the Fontan Procedure.

BACKGROUND: Single ventricle heart disease comprises a wide variety of critical heart defects that lead to the provision of systemic cardiac output by one dominant ventricle. It requires staged surgical palliation that culminates in Fontan circulation. Dominant ventricular morphology in single ventricle patients reportedly has an impact on postoperative morbidity and mortality with varying results. The objectives of this study were to examine the association between ventricular morphology and the early postoperative course after the Fontan procedure. METHODS: A retrospective cohort study in a tertiary referral pediatric medical center that included 98 consecutive patients who underwent Fontan procedure between October 2009 and May 2016. Postoperative outcomes were compared between patients with left ventricular morphology and those with right ventricular morphology (crude effect and regression analysis). RESULTS: Patients with right ventricular morphology had longer postoperative hospitalizations compared to patients with left ventricular morphology (26.5 days vs 18.2 days, respectively, P = .028), higher postoperative maximal vasoactive-inotropic scores (25.6 vs 12.4, P = .02), higher serum lactate levels (7.7 mmol/L vs 6.4 mmol/L, P = .03), higher proportions of ventilation throughout 24 h or more (16 patients [38%] vs 8 patients [14%], P = .009), higher proportions of ventricular dysfunction (12 patients [29%] vs 5 patients [9%], P = .0001), and lower blood oxygen saturation levels at discharge (87% vs 92%, P = .03). CONCLUSIONS: The Fontan procedure in patients with right ventricular morphology is associated with longer postoperative hospitalization and worse early postoperative characteristics (ventricular dysfunction and atrioventricular valve regurgitation) as well as higher rates of early, transient signs of sub-optimal postoperative hemodynamics compared to those with left ventricular morphology.

Prenatal diagnosis of major aortopulmonary collateral arteries (MAPCA) in fetuses with pulmonary atresia with ventricular septal defect and agenesis of ductus arteriosus.

OBJECTIVE: The aim of this study was to describe the prenatal diagnosis of Major Aortopulmonary Collateral Arteries (MAPCAs), and to present a systematic ultrasound method for evaluating lung vascularity in fetuses with pulmonary atresia with ventricular septal defect (PAVSD) and agenesis of ductus arteriosus (DA). METHOD: This retrospective study evaluated fetuses diagnosed with PAVSD with agenesis of DA, for the presence of the MAPCAs anomaly. Fetal pulmonary vasculature was investigated by 2D and 4D Spatio Temporal Image Correlation (STIC) technology using High Definition Color Doppler. RESULTS: Over a 10 year period, six fetuses were diagnosed with MAPCAs. Prenatal diagnosis was made between 17 w 6 d and 28 w 4 d in five fetuses, with the sixth diagnosed at 37 w 6 d. All six had PAVSD with agenesis DA, four exhibited pulmonic atresia without any arterial outflow, while two fetuses presented with absent left pulmonary artery, and a miniscule right pulmonary artery. In five cases, the parents elected to terminate the pregnancy and the last, although born alive, did not survive an attempt at restorative surgery and died at the age of 5 months. Postnatal CT angiography imaging of this case revealed the subclavian origin of the MAPCAs. Chromosomal micro array analysis of the amniotic fluid revealed that five of the six fetuses were normal and one was lost to follow up. CONCLUSION: MAPCAs should be investigated in cases of PAVSD with agenesis DA. A meticulous ultrasound evaluation using 2D and 4D STIC can permit the prenatal diagnosis of this anomaly and provide the parents with the opportunity for prenatal consultation.

Proof of concept: Comparative accuracy of semiautomated VR modeling for volumetric analysis of the heart ventricles.

Introduction: Simpson's rule is generally used to estimate cardiac volumes. By contrast, modern methods such as Virtual Reality (VR) utilize mesh modeling to present the object's surface spatial structure, thus enabling intricate volumetric calculations. In this study, two types of semiautomated VR models for cardiac volumetric analysis were compared to the standard Philips dedicated cardiac imaging platform (PDP) which is based on Simpson's rule calculations. Methods: This retrospective report examined the cardiac computed tomography angiography (CCTA) of twenty patients with atrial fibrillation obtained prior to a left atrial appendage occlusion procedure. We employed two VR models to evaluate each CCTA and compared them to the PDP: a VR model with Philips-similar segmentations (VR-PS) that included the trabeculae and the papillary muscles within the luminal volume, and a VR model that only included the inner blood pool (VR-IBP). Results: Comparison of the VR-PS and the PDP left ventricle (LV) volumes demonstrated excellent correlation with a ρ c of 0.983 (95% CI 0.96, 0.99), and a small mean difference and range. The calculated volumes of the right ventricle (RV) had a somewhat lower correlation of 0.89 (95% CI 0.781, 0.95), a small mean difference, and a broader range. The VR-IBP chamber size estimations were significantly smaller than the estimates based on the PDP. Discussion: Simpson's rule and polygon summation algorithms produce similar results in normal morphological LVs. However, this correlation failed to emerge when applied to RVs and irregular chambers. Conclusions: The findings suggest that the polygon summation method is preferable for RV and irregular LV volume and function calculations.

Repeatability of cardiac-MRI-measured right ventricular size and function in congenital heart disease.

BACKGROUND: The measurement error for right ventricular (RV) size and function assessed by cardiac MRI (CMRI) in congenital heart disease has not been fully characterized. As CMRI parameters are being increasingly utilized to make clinical decisions, defining error in the clinical setting is critical. OBJECTIVE: This investigation examines the repeatability of CMRI for RV size and function. MATERIALS AND METHODS: Forty consecutive people with congenital heart disease involving the RV were retrospectively identified. Contouring of RV volumes was performed by two expert CMRI clinicians. The coefficient of variability and repeatability coefficients were calculated. Repeatability coefficients were multiplied by the mean value for each group studied to define a threshold beyond which measurement error was unlikely to be responsible. RESULTS: The variability for indexed RV end-diastolic volume = 3.2% and 3.3% for intra- and interobserver comparisons, respectively. The repeatability coefficients were 13.2% and 14.9% for intra- and interobserver comparisons, which yielded threshold values of 15.1 ml/m^2 and 20.2 ml/m^2, respectively. For RV ejection fraction (EF), the repeatability coefficients for intra- and interobserver comparisons were 5.0% and 6.0%, which resulted in threshold values of 2.6 EF% and 3.0 EF%. CONCLUSION: The threshold values generated can be used during serial assessment of RV size and function.

The "No ARSA" Sign: A Novel Method of Prenatal Screening for Aberrant Right Subclavian Artery.

An aberrant right subclavian artery (ARSA) can be overlooked by the conventional method as described by Chaoui et al., due to acoustic shadowing. The aim of this study was to evaluate the feasibility and accuracy of a novel screening method for ARSA by demonstrating the brachiocephalic artery bifurcation, referred to as the "No ARSA" sign. A prospective study conducted at a tertiary care center between 2018 and 2019 included unselected pregnant patients at a median gestational age of 15.1 (14.2-22.1; IQR (inter-quartile range)) weeks, who had been referred for a routine or targeted anomaly scan. All participants were scanned for the presence or absence of ARSA using both the conventional and the novel "No ARSA" methods for validation purposes. A total of 226 unselected patients were enrolled in the study. The "No ARSA" sign was visualized in 218 fetuses (96.5%). In the remaining 8 cases (3.5%), the "No ARSA" sign was not demonstrated. In these fetuses, an ARSA was visualized by the conventional method. The new method exhibited 100% feasibility and was in complete agreement with the conventional method. Intra- and inter-observer agreement was excellent (κ = 1). The results of the study suggest that the "No ARSA" sign is an efficient and reliable screening tool for ARSA.

Cardiac failure in very long chain acyl-CoA dehydrogenase deficiency requiring extracorporeal membrane oxygenation (ECMO) treatment: A case report and review of the literature.

Fatty acid oxidation (FAO) defects often present with multi-system involvement, including several life-threatening cardiac manifestations, such as cardiomyopathy, pericardial effusion and arrhythmias. We report herein a fatal case of cardiac dysfunction and rapid-onset tamponade following an acute illness in a neonate with molecularly proven very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (harboring the known del799_802 mutation), requiring 15 days of extracorporeal membrane oxygenation (ECMO) treatment. As data regarding the use of ECMO in FAO defects in general, and VLCAD in particular, are scarce, we review the literature and discuss insights from in vitro models and several successful reported cases.

Perinatal and infant outcomes of prenatal diagnosis of heterotaxy syndrome (asplenia and polysplenia).

Patients with heterotaxy syndrome (HS) have a range of anomalies and outcomes. There are limited data on perinatal outcomes after prenatal diagnosis. To determine the factors influencing perinatal and infant outcomes, we analyzed prenatal and postnatal variables in fetuses with HS from 1995 to 2011. Of 154 fetuses with HS, 61 (40%) had asplenia syndrome (ASP) and 93 (60%) had polysplenia syndrome (PSP). In the ASP group, 22 (36%) patients were elected for termination of pregnancy, 4 (10%) had fetal death, and 35 of 39 (90%) continued pregnancies were live born. In the PSP group, 12 (13%) patients were elected for termination of pregnancy, 5 (6%) had fetal death (4 with bradyarrhythmia), and 76 of 81 (94%) continued pregnancies were live born. Bradyarrhythmia was the only predictor of fetal death. In the live-born ASP group, 43% (15 of 35) died, 7 because of pulmonary vein stenosis, 4 postoperatively, and 4 because of noncardiac causes. In the live-born PSP group, 13% (10 of 76) died, 5 postoperatively, 2 from bradyarrhythmia, 1 from a cardiac event, and 2 from noncardiac causes. Pulmonary vein stenosis and noncardiac anomalies were independent risk factors for postnatal death. Only 8% of ASP patients achieved biventricular circulation, compared with 65% of PSP patients. In the live-born cohort, the 5-year survival rate was 53% for ASP and 86% for PSP. In conclusion, most PSP patients are currently alive with biventricular circulation in contrast with few ASP patients. Bradyarrhythmia was the only predictor of fetal death. Pulmonary vein stenosis and noncardiac anomalies were predictors of postnatal death.

Is propofol safe for procedural sedation in children? A prospective evaluation of propofol versus ketamine in pediatric critical care.

OBJECTIVES: To compare propofol with ketamine sedation delivered by pediatric intensivists during painful procedures in the pediatric critical care department (PCCD). DESIGN: Prospective 15-month study. SETTING: An 18-bed multidisciplinary, university-affiliated PCCD. INTERVENTIONS: All children were randomized to the propofol or ketamine protocol according to prescheduled procedure dates. Propofol was delivered by continuous infusion after a loading bolus dose and a minidose of lidocaine (PL). Ketamine was given as a bolus injection together with midazolam and fentanyl (KMF). Repeated bolus doses of both drugs were given to achieve the desired level of anesthesia. The studied variables included procedures performed, anesthetic drug doses, procedure and recovery durations, and side effect occurrence. The patient's parents, PCCD nurse and resident physician, pediatric intensivist, and the physician performing the procedure graded the adequacy of anesthesia. MEASUREMENTS AND MAIN RESULTS: Of the 105 procedures in 98 children, PL sedation was used in 58 procedures, and KMF was used in 47. Recovery time was 23 mins for PL and 50 mins for KMF, and total PCCD monitoring was 43 mins for PL and 70 mins for KMF. Five children (10.6%) in the KMF group and in none in the PL group experienced discomfort during emergence from sedation. Transient decreases in blood pressure, partial airway obstruction, and apnea were more frequent in the PL than in the KMF sedation. All procedures were successfully completed, and no child recalled undergoing the procedure. The overall sedation adequacy score was 97% for PL and 92% for KMF (p <.05). CONCLUSIONS: Both PL and KMF anesthesia are effective in optimizing comfort in children undergoing painful procedures. PL scored better by all evaluators, recovery from PL anesthesia after procedural sedation was more rapid, total PCCD stay was shorter with PL, and emergence from PL was smoother than with KMF. Because transient respiratory depression and hypotension are associated with PL, it is considered safe only in a monitored environment (e.g., a PCCD).