Cangrelor PK/PD analysis in post-operative neonatal cardiac patients at risk for thrombosis.

Essentials An optimal therapeutic strategy has yet to be established to prevent early shunt thrombosis. A phase 1 study of cangrelor was performed in neonates after palliation of congenital heart disease. PD endpoint of >90% platelet inhibition in 60% of patients was achieved at 0.5 µg/kg/min dosing. No serious adverse events related to drug administration were observed, including bleeding. ABSTRACT: Background Systemic-to-pulmonary artery shunt thrombosis is a significant cause of early postoperative mortality in neonates after palliation of congenital heart disease. In the context of thromboprophylaxis, an optimal therapeutic strategy has yet to be established before aspirin administration. Cangrelor, a fast-acting, reversible P2Y12 inhibitor, may fill this unmet need. Objectives To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of cangrelor in neonates undergoing stage 1 palliation. Methods This prospective, open-label, single-arm study evaluated two cangrelor dosing cohorts following placement of a systemic-to-pulmonary artery shunt, right ventricle-to-pulmonary artery shunt, or ductal stent. Drug concentrations and platelet reactivity, assessed by light transmission aggregometry and in microfluidic assays (MF), were measured. Results Twenty-two patients were consented and 15 received a 1-hour infusion of cangrelor at either 0.5 µg/kg/min (cohort 1) or 0.25 µg/kg/min (cohort 2). Whereas the primary PD endpoint was achieved at the higher dose (ie, reduction in maximal platelet aggregation by ≥90% in 60% of participants), only 29% of those in cohort 2 attained this goal. Comparable and statistically significant results were obtained in MF assays (P < .0001 vs. baseline). Drug levels during infusion were 3-fold higher in cohort 1 vs. cohort 2 (P < .001). Most participants (70%) had undetectable drug levels by 10 minutes postinfusion with full recovery in platelet function at 1 hour. No drug-related bleeding events occurred. Conclusions Favorable PK/PD properties of cangrelor 0.5 µg/kg/min dosing and safety profile warrant further evaluation in neonates following palliative cardiac procedures.

Determinants of Physician, Sonographer, and Laboratory Productivity: Analysis of the Third Survey from the American Society of Echocardiography Committee on Pediatric Echocardiography Laboratory Productivity.

BACKGROUND: The American Society of Echocardiography Committee on Pediatric Echocardiography Laboratory Productivity was formed in 2011 to study institutional factors that could influence the clinical productivity of physicians and sonographers in academic pediatric echocardiography laboratories. In the previous two surveys, staff clinical productivity remained stable while total echocardiography volumes increased. This third survey was designed to assess how clinical productivity is associated with laboratory infrastructure elements such as training, administrative tasks, quality improvement, research, and use of focused cardiac ultrasound (FCU). METHODS: Survey questions were sent by e-mail to North American laboratories. The aims were to assess (1) educational and training obligations, (2) academic productivity and research, (3) laboratory medical director satisfaction, (4) quality improvement, (5) laboratory leadership roles, and (6) impact and use of FCU. Survey responses were compared with clinical productivity metrics defined in the first two surveys. RESULTS: There were 38 responses. Academic productivity was higher at institutions with more dedicated imaging personnel, personnel with dedicated protected academic time, and advanced imaging fellows. Academic productivity did not correlate with clinical productivity and was not significantly affected by the presence of dedicated research sonographers. The satisfaction level of laboratory medical directors was related to dedicated administrative time and an administrative stipend. The majority of administrative roles were tasked to the laboratory medical director with support of the technical director. FCU was listed as a hospital privilege at four institutions (13%). Twenty-two (58%) were training FCU providers in one or more subspecialties. FCU was not associated with clinical or academic productivity. CONCLUSIONS: This third survey gathered supplemental data to complement the clinical productivity data collected from the first two surveys. Together, the results of these surveys further describe the range of factors that can affect North American academic pediatric echocardiography laboratories.

Determinants of Pediatric Echocardiography Laboratory Productivity: Analysis from the Second Survey of the American Society of Echocardiography Committee on Echocardiography Laboratory Productivity.

BACKGROUND: The American Society of Echocardiography Committee on Pediatric Echocardiography Laboratory Productivity aimed to study factors that could influence the clinical productivity of physicians and sonographers and assess longitudinal trends for the same. The first survey results indicated that productivity correlated with the total volume of echocardiograms. METHODS: Survey questions were designed to assess productivity for (1) physician full-time equivalent (FTE) allocated to echocardiography reading (echocardiograms per physician FTE per day), (2) sonographer FTE (echocardiograms per sonographer FTE per year), and (3) machine utilization (echocardiograms per machine per year). Questions were also posed to assess work flow and workforce. RESULTS: For fiscal year 2013 or academic year 2012-2013, the mean number of total echocardiograms-including outreach, transthoracic, fetal, and transesophageal echocardiograms-per physician FTE per day was 14.3 ± 5.9, the mean number of echocardiograms per sonographer FTE per year was 1,056 ± 441, and the mean number of echocardiograms per machine per year was 778 ± 303. Both physician and sonographer productivity was higher at high-volume surgical centers and with echocardiography slots scheduled concordantly with clinic visits. Having an advanced imaging fellow and outpatient sedation correlated negatively with clinical laboratory productivity. Machine utilization was greater in laboratories with higher sonographer and physician productivity and lower for machines obtained before 2009. CONCLUSION: Measures of pediatric echocardiography laboratory staff productivity and machine utilization were shown to correlate positively with surgical volume, total echocardiography volumes, and concordant echocardiography scheduling; the same measures correlated negatively with having an advanced imaging fellow and outpatient sedation. There has been no significant change in staff productivity noted over two Committee on Pediatric Echocardiography Laboratory Productivity survey cycles, suggesting that hiring practices have matched laboratory volume increases.

Cardiac MR imaging and MR angiography for assessment of complex tetralogy of Fallot and pulmonary atresia.

Breath-hold electrocardiographically gated cardiac magnetic resonance (MR) imaging and contrast material-enhanced MR angiography are emerging as ideal techniques for the evaluation of complex congenital heart disease. Tetralogy of Fallot is the most common cause of cyanotic congenital heart disease and, in its classic form, is associated with varying degrees of hypoplasia of the central and peripheral pulmonary arteries, with valvar pulmonary atresia and collateral aortopulmonary vessels occupying the extreme end of the spectrum. Accurate assessment of the size and anatomy of the pulmonary arteries is often difficult with echocardiography and conventional cineangiography. Compared with echocardiography in particular, cardiac MR imaging with three-dimensional reconstruction has distinct advantages for pre- or postoperative assessment of pulmonary anatomy in patients with tetralogy of Fallot and pulmonary atresia. MR imaging enables the clear and complete depiction of anatomy and thus can provide additional information about pulmonary artery abnormalities that are difficult to evaluate with conventional cardiac imaging techniques.

Variations in adult congenital heart disease training in adult and pediatric cardiology fellowship programs.

OBJECTIVES: The purpose of this study was to evaluate adult congenital heart disease (CHD) training among U.S. cardiology fellowship programs. BACKGROUND: Although training recommendations for caring for adults with CHD exist, the educational patterns and numbers of specialists remain unknown. METHODS: We surveyed U.S. directors of 170 adult cardiology and 45 pediatric cardiology (PC) fellowship programs. Adult program surveys contained 1 single-response and 10 multiple-choice questions; pediatric program surveys contained 1 single-response and 13 multiple-choice questions. RESULTS: Ninety-four adult cardiology fellowship directors (55%) and 34 PC directors (76%) responded. Of adult programs, 70% were in university hospitals and 40% were associated with PC groups. Those with PC-affiliation had more adult CHD clinics (p < 0.02) and more adult CHD inpatient (p < 0.02) and outpatient (p < 0.002) visits than those without PC affiliation. Most PC programs were in children's hospitals (38%) or children's hospitals within adult hospitals (50%). Eighty-two percent had associated adult cardiology programs. Pediatric programs followed adult CHD patients in various care settings. Over one-third of adult and pediatric programs had < or = 3 lectures annually regarding adult CHD. Nine adult and 2 pediatric programs offered adult CHD fellowships, and only 31 adult and 11 pediatric fellows pursued advanced CHD training in the last 10 years. CONCLUSIONS: Adult CHD didactic and clinical experiences for cardiology fellows vary widely. Few programs offer advanced CHD training, and the number of specially trained physicians is unlikely to meet projected workforce requirements. Adult cardiology programs with PC affiliation have increased CHD experience and might provide good educational models.

Frequency of aortic root dilation in children with a bicuspid aortic valve.

Bicuspid aortic valve (BAV) is associated with aortic root dilation and dissection in adults, but the age and conditions when dilation begins are unknown. Using echocardiographic data, we compared the aortic root dimensions and valve hemodynamics of 76 children with BAV with valves derived from 41 normal children. The children with BAV had significantly larger aortic roots (p <0.001) regardless of the presence of aortic stenosis or regurgitation.

Transthoracic echocardiographic guidance of transcatheter atrial septal defect closure.

This study examines the safety and efficacy of transthoracic echocardiographic (TTE) guidance of atrial septal defect (ASD) device closure. We evaluated 74 patients for TTE-guided ASD closure. Fifty-six patients had successful device implantation using TTE guidance. Twelve patients were referred for surgical ASD closure on the basis of TTE evaluation. Five patients with multiple ASDs or poor transthoracic acoustic windows had ASD device closure guided by transesophageal echocardiography (TEE).

Myocardial perfusion and viability by positron emission tomography in infants and children with coronary abnormalities: correlation with echocardiography, coronary angiography, and histopathology.

OBJECTIVES: This study was designed to assess the feasibility and accuracy of positron emission tomography (PET) imaging in infants and children. BACKGROUND: Positron emission tomography is employed in adults for the evaluation of myocardial perfusion and the detection of myocardial viability. METHODS: Perfusion and metabolism findings on PET in infants and children with suspected coronary abnormalities (age 14 days to 12 years old, mean 3.3 +/- 4.0 years) were correlated with findings on coronary angiography, echocardiography, and myocardial histopathology. The segmental myocardial uptake of the flow tracer (13)N-ammonia and of the glucose tracer (18)F-deoxyglucose ((18)FDG) was graded on a five-point scale and compared with the angiographic perfusion score, with regional wall motion, and the presence of fibrosis. RESULTS: There was an agreement of r = 0.72 (p < 0.05) between regional myocardial perfusion and angiography. The correlation of histopathologic changes with normal, moderately, and severely reduced segmental (13)N-ammonia uptake was 87%, 60%, and 75%, respectively. Segmental myocardial (18)FDG uptake and histopathologic findings were concordant in 48 (79%) of 64 segments without fibrosis; absence of viability by perfusion and metabolism imaging correlated with the presence of fibrosis in 21 (84%) of 25 segments. CONCLUSIONS: The observed agreements between the findings on PET perfusion and metabolism imaging with those on coronary angiography, echocardiography, and histopathology support the utility and accuracy of PET for characterizing myocardial perfusion abnormalities and viability in pediatric patients.

Noninvasive measurement of myocardial activity concentrations and perfusion defect sizes in rats with a new small-animal positron emission tomograph.

BACKGROUND: We explored the feasibility of measuring regional tracer activity concentrations and flow defects in myocardium of rats with a high spatial resolution small-animal PET system (microPET). METHODS AND RESULTS: Myocardial images were obtained after intravenous (18)F-fluorodeoxyglucose (18FDG) in 11 normal rats (group 1) and assembled into polar maps. Regional 18F activity concentrations were measured in 9 regions of interest and compared with tissue activity concentrations measured by well counting. In another 9 rats (group 2), myocardial perfusion images were acquired with 13N-ammonia at baseline and during coronary occlusion. On the polar maps recorded during coronary occlusion, the size of perfusion defects was measured as the myocardium with <50% of maximum activity and expressed as percent total myocardium and was correlated with the area at risk defined by postmortem staining. The diagnostic quality of 18FDG and 13N-ammonia microPET images was good to excellent; the images were easily assembled into polar maps. In group 1, regional (18)F concentrations by microPET and postmortem were correlated linearly (r=0.99; P<0.01 for average and r=0.97; P<0.01 for regional concentrations). In group 2, perfusion defect sizes by microPET and postmortem were correlated linearly (P<0.01; r=0.93). CONCLUSIONS: The findings indicate the feasibility of noninvasive studies of the myocardium in rats with a dedicated small-animal PET-imaging device.

Midazolam as an effective intravenous adjuvant to prolonged ketamine sedation in young rhesus (Macaca mulatta) and Vervet (Cercopithecus aethiops sabaeus) monkeys: A preliminary report.

The present study investigated a recently developed benzodiazepine, midazolam, as an intravenous adjuvant to ketamine in infant monkeys undergoing prolonged sedation during positron emission tomography of the brain and heart. Subjects were two rhesus macaque (Macaca mulatta) and ten vervet monkeys (Cercopithecus aethiops sabaeus) ranging in age from 26 to 260 days. Midazolam was an effective intravenous adjuvant to ketamine. This treatment regime resulted in complete immobilization of the animals. Ketamine infusion rates did not vary significantly with age for either species. Sensitivity to midazolam appeared to be age-dependent in vervets because significantly lower dose rates were sufficient to maintain anesthesia in older animals. For rhesus monkeys, midazolam dose rates decreased until approximately 4 months of age, and increased gradually thereafter. © 1993 Wiley-Liss, Inc.