Jennifer S. Li

Neurodevelopmental Outcomes in Children With Congenital Heart Disease: Evaluation and Management A Scientific Statement From the American Heart Association

Background— The goal of this statement was to review the available literature on surveillance, screening, evaluation, and management strategies and put forward a scientific statement that would comprehensively review the literature and create recommendations to optimize neurodevelopmental outcome in the pediatric congenital heart disease (CHD) population. Methods and Results— A writing group appointed by the American Heart Association and American Academy of Pediatrics reviewed the available literature addressing developmental disorder and disability and developmental delay in the CHD population, with specific attention given to surveillance, screening, evaluation, and management strategies. MEDLINE and Google Scholar database searches from 1966 to 2011 were performed for English-language articles cross-referencing CHD with pertinent search terms. The reference lists of identified articles were also searched. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. A management algorithm was devised that stratified children with CHD on the basis of established risk factors. For those deemed to be at high risk for developmental disorder or disabilities or for developmental delay, formal, periodic developmental and medical evaluations are recommended. A CHD algorithm for surveillance, screening, evaluation, reevaluation, and management of developmental disorder or disability has been constructed to serve as a supplement to the 2006 American Academy of Pediatrics statement on developmental surveillance and screening. The proposed algorithm is designed to be carried out within the context of the medical home. This scientific statement is meant for medical providers within the medical home who care for patients with CHD. Conclusions— Children with CHD are at increased risk of developmental disorder or disabilities or developmental delay. Periodic developmental surveillance, screening, evaluation, and reevaluation throughout childhood may enhance identification of significant deficits, allowing for appropriate therapies and education to enhance later academic, behavioral, psychosocial, and adaptive functioning.

Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients.

OBJECTIVES The purpose of this prospective study was to examine the role of echocardiography in patients with Staphylococcus aureus bacteremia (SAB). BACKGROUND The reported incidence of infective endocarditis (IE) among patients with SAB varies widely. Distinguishing patients with uncomplicated bacteremia from those with IE is therapeutically and prognostically important, but often difficult. METHODS One hundred-three consecutive patients undergoing both transthoracic (TTE) echocardiography and transesophageal (TEE) echocardiography were prospectively evaluated. All patients presented with fever and > or = 1 positive blood culture and were followed up for 12 weeks. RESULTS Although predisposing heart disease was present in 42 patients (41%), clinical evidence of infective endocarditis (IE) was rare (7%). TTE revealed anatomic abnormalities in 33 patients, but vegetations in only 7 (7%), and was considered indeterminate in 19 (18%). TEE identified vegetations in 22 patients (aortic valve in 5, mitral valve in 9, tricuspid valve in 4, catheter in 2 and pacemaker in 2, abscesses in 2, valve perforation in 1 and new severe regurgitation in 1; 26 total [25%]). Using Duke criteria for the diagnosis of IE, definite IE was present in 26 patients (25%). Clinical findings and predisposing heart disease did not distinguish between patients with and without IE. The sensitivity of TTE for detecting IE was 32%, and the specificity was 100%. The addition of TEE increased the sensitivity to 100%, but resulted in one false positive result (specificity 99%). TEE detected evidence of IE in 19% of patients with a negative TTE and 21% of patients with an indeterminate TTE. At follow-up, cure of staphylococcal infection occurred in a similar percentage of patients with and without IE (77% and 75%, respectively). However, death due to sepsis was significantly more likely among patients with IE (4 of 26 [15%]) than among those without IE (2 of 77 [3%]) (p = 0.03). CONCLUSIONS Our results suggest that IE is common among patients admitted to the hospital with SAB and is associated with an increased risk of death due to sepsis. TEE is essential to establish the diagnosis and to detect associated complications. Therefore, the test should be considered part of the early evaluation of patients with SAB.

Coronary Artery Pattern and Outcome of Arterial Switch Operation for Transposition of the Great Arteries A Meta-Analysis

Background—Prior studies of coronary pattern and outcome after arterial switch operation (ASO) for transposition of the great arteries (TGA) have been hindered by limited statistical power. This meta-analysis assesses the effect of coronary anatomy on post-ASO mortality, both overall and adjusted for time. Methods and Results—A literature search revealed 9 independent series that reported post-ASO mortality by coronary pattern in a total of 1942 patients. Odds ratios comparing all-cause mortality in patients with usual versus variant coronary patterns were calculated and combined by use of an empirical Bayesian model. Single coronary patterns, both of which loop around the great vessels, were associated with significant mortality (OR 2.9, 95% CI 1.3 to 6.8), whereas looping patterns that arose from 2 separate ostia were not (OR 1.2, 95% CI 0.8 to 1.9). This latter group includes patients with the most common variant, circumflex from right coronary artery. Patients with an intramural coronary artery had the greatest mortality (OR 6.5, 95% CI 2.9 to 14.2). Overall, patients with any variant coronary pattern had nearly twice the mortality seen in those with the usual pattern (OR 1.7, 95% CI 1.3 to 2.4). Single ostium patterns and intramural coronary arteries remained associated with significant added mortality after adjustment for time-trend effects. Conclusions—Over the past 2 decades, patients with common coronary variants have undergone ASO without added mortality compared with those with the usual coronary pattern. Those with intramural or single coronary arteries have significant added mortality that has persisted over time.

Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants

Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were 6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc(4). Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM-positive patients were deceased or invasively ventilated (p<0.0001). By age 27.1 months, all CRIM-negative patients and 4/21 (19.0%) CRIM-positive patients were deceased or invasively ventilated. Cardiac function and gross motor development improved significantly more in the CRIM-positive group. IgG antibodies to rhGAA developed earlier and serotiters were higher and more sustained in the CRIM-negative group. CRIM-negative status predicted reduced overall survival and invasive ventilator-free survival and poorer clinical outcomes in infants with Pompe disease treated with rhGAA. The effect of CRIM status on outcome appears to be mediated by antibody responses to the exogenous protein.

A Cross-Sectional Study of Exercise Performance During the First 2 Decades of Life After the Fontan Operation

OBJECTIVES The aim of this study was to describe exercise performance during the first 2 decades of life in Fontan survivors by a cross-sectional study and to identify factors that influence exercise performance. BACKGROUND Exercise performance after the Fontan procedure is reduced relative to performance in healthy subjects. Data on pre-adolescents are limited, and the patterns of exercise performance in different ages are unexplored. METHODS Ramp cycle ergometry was performed with expired gas. Data were analyzed for the entire study population and for subpopulations that did and did not achieve a maximal aerobic capacity. RESULTS Of 411 subjects tested (12.4 +/- 3.2 years of age), 166 achieved a maximal aerobic capacity. Peak oxygen consumption (VO(2)) was 26.3 ml/kg/min (65% of predicted for age and gender [% predicted]) for the entire population and was lower in the submaximal capacity subgroup compared with the maximal capacity subgroup (63% predicted and 67% predicted, respectively; p = 0.02). Oxygen consumption at ventilatory anaerobic threshold (VAT) was better preserved (78% predicted for the total population) than peak VO(2). Higher % predicted O(2) pulse at peak exercise was associated with greater % predicted peak VO(2), work rate, and VAT. Adolescence and male gender were associated with decreased % predicted peak VO(2). The relationship between echocardiographic indexes of ventricular function and exercise function was surprisingly weak. CONCLUSIONS In Fontan patients, maximal aerobic capacity is reduced compared with healthy subjects, with better preservation of submaximal performance. Higher O(2) pulse is associated with better exercise performance, whereas adolescence and male gender are associated with decreased performance compared with healthy subjects.

Coronary Artery Involvement in Children With Kawasaki Disease Risk Factors From Analysis of Serial Normalized Measurements

Background— Most studies of coronary artery involvement and associated risk factors in Kawasaki disease have used the Japanese Ministry of Health dichotomous criteria. Analysis of serial normalized artery measurements may reveal a broader continuous spectrum of involvement and different risk factors. Methods and Results— Clinical, laboratory, and echocardiographic measurements obtained at baseline and 1 week and 5 weeks after presentation were examined in 190 Kawasaki disease patients as part of a clinical trial of primary therapy with pulse steroids in addition to standard intravenous immunoglobulin. Maximum coronary artery z score normalized to body surface area was significantly greater than normal at all time points, decreasing significantly over time from baseline. A maximal z score ≥2.5 at any time was noted in 26% of patients. Japanese Ministry of Health dimensional criteria were met by 23% of patients. Significant independent factors associated with greater z score at any time included younger patient age, longer interval from disease onset to treatment with intravenous immunoglobulin, lower serum IgM level at baseline, and lower minimum serum albumin level. z Scores of the proximal right coronary artery were higher than those in the left anterior descending branch. Conclusions— Analyses of serial normalized coronary artery measurements in optimally treated Kawasaki disease patients demonstrated that for most patients, measurements are greatest at baseline and subsequently diminish; baseline measurements appear to be good predictors of involvement during early follow-up. When a more precise assessment is used, risk factors for coronary artery involvement are similar to those defined with arbitrary dichotomous criteria.

Cardiac surgery in infants with low birth weight is associated with increased mortality: Analysis of the Society of Thoracic Surgeons Congenital Heart Database

OBJECTIVE The evaluation of operative mortality risk for cardiac surgery in infants with low weight is limited. To determine whether low weight is a risk factor for increased mortality, we reviewed the experience within the Society of Thoracic Surgeons Congenital Heart Surgery Database of infants who have undergone surgical correction or palliation for congenital heart disease. METHODS We analyzed mortality in 3022 infants ages 0 to 90 days weighing 1 to 2.5 kg (n = 517) and greater than 2.5 to 4 kg (n = 2505) who underwent cardiac surgery from 2002 through 2004 at 32 participating centers. Patients were grouped according to the primary procedure performed and analyzed according to their weight at the time of surgical intervention. Patients were also analyzed according to Risk Adjustment for Congenital Heart Surgery-1 and Aristotle Basic Complexity scores. RESULTS Compared with infants weighing 2.5 to 4 kg, infants weighing less than 2.5 kg had a significantly higher mortality for the following operations: repair of coarctation of the aorta, total anomalous pulmonary venous connection repair, arterial switch procedure, systemic to pulmonary artery shunt, and the Norwood procedure. Lower infant weight remained strongly associated with mortality risk after stratifying the population by Risk Adjustment for Congenital Heart Surgery-1 levels 2 through 6 and Aristotle Basic Complexity levels 2 through 4. CONCLUSIONS Low weight at the time of surgical intervention is associated with increased mortality in patients undergoing several types of cardiovascular procedures. These data do not allow assessment of specific risks or benefits of any particular treatment strategy. However, they do support the need for prospective analysis of specific treatment strategies for these high-risk patients.

Cost-effectiveness of transesophageal echocardiography to determine the duration of therapy for intravascular catheter-associated Staphylococcus aureus bacteremia

Staphylococcus aureus bacteremia is an increasingly common and potentially catastrophic complication of intravascular catheters (1-3). After S. aureus bacteremia develops, it can be difficult to distinguish uncomplicated bacteremia from occult endocarditis (4-7). For this reason, controversy exists about the appropriate duration of therapy. Prolonged courses (4 to 6 weeks) of parenteral antibiotics have traditionally been recommended because of the high rates of endocarditis found in early studies (8). However, this approach is expensive and may result in complications of therapy. Noting the decreased rates of endocarditis in patients with infection secondary to intravascular devices (2, 5, 9-16), some investigators recommend treating patients with catheter removal and abbreviated ( 14 days) courses of therapy (2, 13, 14, 17, 18). Although 4 to 6 weeks of therapy may be unnecessary for most patients with catheter-associated S. aureus bacteremia, short-course therapy will fail in a subset of patients because of inadequately treated occult endocarditis (19). Transesophageal echocardiography (TEE) has been suggested as a technique with which to prospectively identify patients with endocarditis; this technique would allow more appropriate assignment to short or long courses of therapy (20). Because of its high sensitivity (21-31) and specificity (21, 25, 27, 28) for endocarditis on native cardiac valves, TEE allows improved diagnosis and therapeutic regimens that target specific patients. However, TEE is an invasive and expensive procedure, and it is unclear whether its benefits justify its costs. The purpose of our investigation was to determine the cost-effectiveness of TEE for stratifying patients with catheter-associated S. aureus bacteremia to a specific duration of therapy. Methods Decision Model Following standard cost-effectiveness methods (32), we used decision analysis (33) to model the clinical and cost consequences of alternate management strategies in patients with catheter-associated S. aureus bacteremia. The model (Figure 1)compared three approaches to management of catheter-related S. aureus bacteremia in patients with no indwelling prosthetic devices who appeared to have a clinically uncomplicated disease course (that is, prompt defervescence, no clinical evidence of metastatic sites of infection, and rapid resolution of bacteremia); the catheter had been removed from all patients (15, 18, 34). The first approach (the TEE strategy) used TEE at the time of initial diagnosis to stratify patients to short-course or long-course intravenous antibiotic therapy. Patients who showed evidence of endocarditis on TEE were treated with intravenous antibiotics for 4 weeks. If there was no evidence of endocarditis, patients were treated with intravenous antibiotics for 2 weeks. The second approach (the long-course strategy) called for all patients to receive a 4-week course of parenteral antibiotics. With the third approach (the short-course strategy), all patients were treated with a 2-week course of intravenous antibiotics. This model is not applicable to patients at increased risk for complications (that is, immunosuppressed patients, patients who have used intravenous drugs, or patients with indwelling prosthetic devices). Figure 1. Figure 1. Decision model for the treatment of catheter-associated Staphylococcus aureus bacteremia. Assumptions of the Model We modeled the most serious complications of infective endocarditis: stroke, valvular insufficiency necessitating surgical replacement, and death. We assumed that valve replacement, if required, would be done during the initial hospitalization. Furthermore, we assumed that patients who experienced a relapse had the same probability of adverse events as they did during their initial disease episode. This assumption biased the model in favor of short-course therapy because patients who have relapse are likely to have more serious infections. In accordance with previous studies (14, 19), we assumed that relapses of S. aureus bacteremia were caused by inadequately treated occult endocarditis. For the base-case analysis, we assumed that cases of occult endocarditis treated with short-course therapy would not be cured. This assumption biased the model in favor of long-course therapy and was tested extensively in sensitivity analyses. We assumed that patients could have relapse only once. Patients who had relapse were hospitalized again with presumed endocarditis and were re-treated with long-course therapy. On the basis of evidence from previous work (35-37), we assumed that endocarditis could be adequately treated on an outpatient basis. Therefore, parenteral antibiotic treatment was initiated in the hospital and completed on an outpatient basis. Likelihood of Events The natural history of catheter-associated S. aureus bacteremia was estimated from our institutional data and data from the literature. The clinical data involved 60 consecutive patients with S. aureus endocarditis and 196 consecutive patients with uncomplicated catheter-associated S. aureus bacteremia who were included in an institutional registry maintained since September 1994. Using MEDLINE (1966 to February 1998) and bibliographical review of relevant articles, we searched the literature for studies on the natural history of catheter-associated S. aureus bacteremia and S. aureus endocarditis. We reviewed endocarditis case series for data specifically pertaining to S. aureus regardless of catheter involvement. We also reviewed reports on endocarditis from any causal microorganism for mortality rates associated with strokes and valve replacement operations. Studies that dealt primarily with pediatric patients, immunocompromised patients, patients who used intravenous drugs, patients with prosthetic valve endocarditis, or patients with methicillin-resistant S. aureus were excluded. When studies reported data for patients with native and prosthetic valves, we excluded data for patients with prosthetic valves if the data were reported separately. When outcomes could not be separated, we excluded studies in which more than 20% of the reported data were from patients with prosthetic valves and studies in which more than 40% of the reported data were from patients who used intravenous drugs. The probabilities used in the decision model are presented in Table 1. We derived the natural history of endocarditis and the mortality rate in uncomplicated bacteremia by pooling data from the literature and clinical data. Event probabilities for patients with bacteremia uncomplicated by endocarditis were derived by using data specific to patients with catheter-associated S. aureus bacteremia. Because of the paucity of data on catheter-related endocarditis, we derived event probabilities for patients who developed endocarditis from studies of patients with S. aureus endocarditis from any cause. When the pooled sample size was fewer than 100 S. aureus-infected patients, literature sources were expanded to include studies reporting event rates for endocarditis caused by any infectious microorganism. Derivation of these estimates is available from the authors in a technical report (www.dcri.duke.edu). Table 1. Probabilities for Decision Model The reported prevalence of endocarditis in patients with catheter-associated S. aureus bacteremia ranged from 0% to 38% (2, 5, 9-16) across heterogeneous patient groups. Because of this wide range among different patient populations, we did not use a pooled estimate for endocarditis prevalence. Rather, we worked backward from an accepted short-course relapse rate to derive an estimate of prevalence. The short-course relapse rate was adopted from a meta-analysis by Jernigan and Farr (19), which found a late complication rate of 6.1% in patients receiving short-course therapy for catheter-associated S. aureus bacteremia. Using this rate of relapse (cases attributed to occult endocarditis) and our assumption that short-course therapy would not cure any cases of endocarditis, we assigned an endocarditis prevalence rate of 6.1%. These estimates were tested extensively in sensitivity analyses. For patients with endocarditis, the relapse rate after long-course therapy was set at 2.6% (19). Published estimates of the sensitivity of TEE for vegetations or other intracardiac complications of endocarditis on native valves (including valve dehiscence and intracardiac abscess) range from 87% to 100% (21-31). Reported specificities range from 89% to 100% (21, 25, 27, 28). For the base-case analysis, we used a sensitivity of 96% from a study by Mugge and colleagues (22) in which surgical and autopsy findings were the gold standard for comparison. A value of 95% was used for the specificity because it falls in the mid-range of reported values. The morbidity (0.18%) and mortality (0.01%) rates associated with TEE were obtained from an analysis of more than 10 200 patients (80). One complication of intravenous antimicrobial therapy, phlebitis necessitating line removal with subsequent reinsertion for therapy completion, was also considered in this analysis. Catheter-survival rates were obtained from the literature (81). Because this complication is expressed as a per catheter-day rate, it was applied to all patients according to the number of days of antibiotic therapy received at home. The inclusion of only one complication of antimicrobial therapy biased the model in favor of long-course therapy. Costs The model took the societal perspective and included direct medical costs, direct nonmedical costs, and productivity costs (costs associated with lost ability to work because of illness or death) but excluded the intangible costs of pain and suffering. All medical costs were standardized to 1997 U.S. dollars by using the medical care component of the Consumer Price Index (87). All other costs were standardized by using the Consumer Price Index for All Urban Consumers (87). All costs are summari

Infective Endocarditis Due to Staphylococcus aureus: 59 Prospectively Identified Cases with Follow-up

Fifty-nine consecutive patients with definite Staphylococcus aureus infective endocarditis (IE) by the Duke criteria were prospectively identified at our hospital over a 3-year period. Twenty-seven (45.8%) of the 59 patients had hospital-acquired S. aureus bacteremia. The presumed source of infection was an intravascular device in 50.8% of patients. Transthoracic echocardiography (TTE) revealed evidence of IE in 20 patients (33.9%), whereas transesophageal echocardiography (TEE) revealed evidence of IE in 48 patients (81.4%). The outcome for patients was strongly associated with echocardiographic findings: 13 (68.4%) of 19 patients with vegetations visualized by TTE had an embolic event or died of their infection vs. five (16.7%) of 30 patients whose vegetations were visualized only by TEE (P < .01). Most patients with S. aureus IE developed their infection as a consequence of a nosocomial or intravascular device-related infection. TEE established the diagnosis of S. aureus IE in many instances when TTE was nondiagnostic. Visualization of vegetations by TTE may provide prognostic information for patients with S. aureus IE.

Evaluation of Kawasaki Disease Risk-Scoring Systems for Intravenous Immunoglobulin Resistance

OBJECTIVES To assess the performance of 3 risk scores from Japan that were developed to predict, in children with Kawasaki disease, resistance to intravenous immunoglobulin (IVIG) treatment. STUDY DESIGN We used data from a randomized trial of pulsed steroids for primary treatment of Kawasaki disease to assess operating characteristics of the 3 risk scores, and we examined whether steroid therapy lowers the risk of coronary artery abnormalities in patients prospectively classified as IVIG resistant. RESULTS For comparability with published cohorts, we analyzed the data of 99 patients who were not treated with steroids (16% IVIG-retreated) and identified male sex, lower albumin level, and higher aspartate aminotransferase level as independent risk factors for IVIG resistance. The Kobayashi score was similar in IVIG-resistant and -responsive patients, yielding a sensitivity of 33% and specificity of 87%. There was no interaction of high-risk versus low-risk status by treatment received (steroid versus placebo) with any of the 3 risk score algorithms. CONCLUSION Risk-scoring systems from Japan have good specificity but low sensitivity for predicting IVIG resistance in a North American cohort. Primary steroid therapy did not improve coronary outcomes in patients prospectively classified as being at high-risk for IVIG resistance.