Red blood cell alloimmunization in sickle cell disease: prevalence in 2010.

BACKGROUND: Transfusion of red blood cells (RBCs) is frequently required for care of individuals with sickle cell disease (SCD). Alloimmunization rates are high and may be reduced by matching for RBC antigens that can cause alloimmunization. STUDY DESIGN AND METHODS: During the PROACTIVE Feasibility Study, patients with SCD age 2 years or older admitted for pain without acute chest syndrome were enrolled for possible randomization to preventive blood transfusion or standard care. Transfusion and antibody histories were obtained at each site, and antibody screening was done, to assess transfusion burden and alloimmunization prevalence. Participating sites were surveyed regarding antigen matching practice. RESULTS: A total of 237 patients (169 SS, 42 SC, 15 Sß(0) -thalassemia, 11 Sß(+) -thalassemia), 118 males and 119 females, were enrolled. Mean age was 19.3 years (range, 2.0-68.0); there were 122 children and 115 adults. A total of 75.8% had received at least a single transfusion of RBCs before the study. Thirty-four patients (14.4%) had a history of at least one alloantibody and 17 of these had more than one. When surveyed, 19 sites (83% of responders) reported antigen matching to at least include C, E, and K for transfusion of all patients with SCD. CONCLUSION: Though antigen typing before transfusion of people with SCD and providing antigen-negative units is now widely employed by sickle cell centers, the alloimmunization rate remains quite high in contemporary sickle cell populations and may be due in large part to transfusions received at institutions not providing extended matching.

Factors impacting echocardiographic imaging after the Fontan procedure: a report from the pediatric heart network fontan cross-sectional study.

Echocardiographic image quality in Fontan survivors may be limited by a variety of factors. We sought to describe echocardiographic quality and factors associated with study quality in subjects participating in the Pediatric Heart Network Fontan Cross-Sectional Study. Echocardiograms were obtained at 7 clinical sites using a standard protocol. Quality grading and analysis were performed by a core laboratory. Univariate and multivariable modeling were performed to assess factors associated with quality and ability to obtain images sufficient for prespecified quantitative analysis. A total of 543 echocardiograms were obtained. The quality of echocardiograms improved over the duration of the study. The great arteries, systemic veins, and pulmonary veins were less likely to be adequately imaged than other cardiac structures. Quantitative analysis of ventricular volume was possible in 76% overall, but only 41% of those with mixed ventricular morphology. Factors independently associated with better quality included younger age, levocardia, acquisition of the echocardiogram at a longer time since the beginning of enrollment, absence of a pulmonary artery stent, and clinical site. Patient and center-specific factors are associated with echocardiographic quality after the Fontan procedure. Increased familiarity and experience with a standard imaging protocol is likely to result in improved quality.

Inpatient management of sickle cell pain: a 'snapshot' of current practice.

The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. While PROACTIVE was not designed to assess pain management and was terminated early due to inadequate patient accrual, collection of clinical data allowed a "snapshot" of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient-controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain.

Practice variability and outcomes of coil embolization of aortopulmonary collaterals before Fontan completion: a report from the Pediatric Heart Network Fontan Cross-Sectional Study.

BACKGROUND: The practice of coiling aortopulmonary collaterals (APCs) before Fontan completion is controversial, and published data are limited. We sought to compare outcomes in subjects with and without pre-Fontan coil embolization of APCs using the Pediatric Heart Network Fontan Cross-Sectional Study database which enrolled survivors of prior Fontan palliation. METHODS: We compared hospital length of stay after Fontan in 80 subjects who underwent APC coiling with 459 subjects who did not. Secondary outcomes included post-Fontan complications and assessment of health status and ventricular performance at cross-sectional evaluation (mean 8.6 ± 3.4 years after Fontan). RESULTS: Centers varied markedly in frequency of pre-Fontan APC coiling (range 0%-30% of subjects, P < .001). The coil group was older at Fontan (P = .004) and more likely to have single right ventricular morphology (P = .054) and pre-Fontan atrioventricular valve regurgitation (P = .03). The coil group underwent Fontan surgery more recently (P < .001), was more likely to have a prior superior cavopulmonary anastomosis (P < .001), and more likely to undergo extracardiac Fontan connection (P < .001) and surgical fenestration (P < .001). In multivariable analyses, APC coiling was not associated with length of stay (hazard ratio for remaining in-hospital 0.91, 95% CI 0.70-1.18, P = .48) or postoperative complications, except more post-Fontan catheter interventions (hazard ratio 1.74, 95% CI 1.04-2.91, P = .03), primarily additional APC coils. The groups had similar outcomes at cross-sectional evaluation. CONCLUSION: Management of APCs before Fontan shows marked practice variation. We did not find an association between pre-Fontan coiling of APCs and shorter postoperative hospital stay or with better late outcomes. Prospective studies of this practice are needed.

Survival data and predictors of functional outcome an average of 15 years after the Fontan procedure: the pediatric heart network Fontan cohort.

OBJECTIVE: Multicenter longitudinal outcome data for Fontan patients surviving into adulthood are lacking. The aim of this study was to better understand contemporary outcomes in Fontan survivors by collecting follow-up data in a previously well-characterized cohort. DESIGN: Baseline data from the Fontan Cross-Sectional Study (Fontan 1) were previously obtained in 546 Fontan survivors aged 11.9 ± 3.4 years. We assessed current transplant-free survival status in all subjects 6.8 ± 0.4 years after the Fontan 1 study. Anatomic, clinical, and surgical data were collected along with socioeconomic status and access to health care. RESULTS: Thirty subjects (5%) died or underwent transplantation since Fontan 1. Subjects with both an elevated (>21 pg/mL) brain natriuretic peptide and a low Child Health Questionnaire physical summary score (<44) measured at Fontan 1 were significantly more likely to die or undergo transplant than the remainder, with a hazard ratio of 6.2 (2.9-13.5). Among 516 Fontan survivors, 427 (83%) enrolled in this follow-up study (Fontan 2) at 18.4 ± 3.4 years of age. Although mean scores on functional health status questionnaires were lower than the general population, individual scores were within the normal range in 78% and 88% of subjects for the Child Health Questionnaire physical and psychosocial summary score, and 97% and 91% for the SF-36 physical and mental aggregate score, respectively. Since Fontan surgery, 119 (28%) had additional cardiac surgery; 55% of these (n = 66) in the interim between Fontan 1 and Fontan 2. A catheter intervention occurred in 242 (57%); 32% of these (n = 78) after Fontan 1. Arrhythmia requiring treatment developed in 118 (28%) after Fontan surgery; 58% of these (n = 68) since Fontan 1. CONCLUSIONS: We found 95% interim transplant-free survival for Fontan survivors over an average of 7 years of follow-up. Continued longitudinal investigation into adulthood is necessary to better understand the determinants of long-term outcomes and to improve functional health status.

Reliability of Tanner stage assessments in a multi-center study.

Tanner stage indices have been frequently used in research studies to characterize the level of sexual maturation among adolescents. The Cooperative Study of Sickle Cell Disease (CSSCD) is a large multi-center study in which the assessment of Tanner stage indices has been performed to describe delays in sexual maturation and correlates of delays. Rigorous training, however, in rating Tanner stages was not provided for the clinicians in the study. Data from the CSSCD were analyzed to characterize the reliability of the assessment of sexual maturation in this study, and demonstrate the potential for increasing the reliability by more careful training. In lieu of a gold standard, a maximum likelihood algorithm was employed to examine the longitudinal consistency of Tanner stage assessments. Based on the assumption that the underlying process of sexual maturation is progressive, models were developed that allowed one to estimate jointly the incidence distribution for the attainment of Tanner stages and the error rates of assessment. Estimated false-positive rates for assessing the attainment of Tanner stages from the CSSCD ranged from 2% to 19%. Estimated false-negative rates ranged from 1% to 18%. The occurrence of these errors was found not to vary markedly with the subject's age. Error rates of this magnitude can introduce considerable bias to the estimation of the distribution of Tanner stages and result in serious losses in relative efficiency. While the validity of Tanner stage indices can be demonstrated from study data, the loss in statistical efficiency and power associated with the study error rates was severe. This underscores the utility of careful training in pubertal rating for research studies.

The ventricular volume variability study of the Pediatric Heart Network: study design and impact of beat averaging and variable type on the reproducibility of echocardiographic measurements in children with chronic dilated cardiomyopathy.

BACKGROUND: Clinical trials often rely on echocardiographic measures of left ventricular size and function as surrogate end points. However, the quantitative impact of factors that affect the reproducibility of these measures is unknown. To address this issue, the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network designed a longitudinal observational study of children with known or suspected dilated cardiomyopathy aged 0 to 22 years from eight pediatric clinical centers. METHODS: Clinical data were collected together with 150 echocardiographic indices of left ventricular size and function. Separate observers performed duplicate echocardiographic imaging. Multiple observers performed measurements from three cardiac cycles to enable assessment of intraobserver and interobserver variability. The impacts of beat averaging (BA), observer type (local vs core), and variable type (areas, calculations, dimensions, slopes, time intervals, and velocities) on measurement reproducibility were studied. The outcome measure was percentage error (100 × difference/mean). RESULTS: Of 173 enrolled subjects, 131 met criteria for dilated cardiomyopathy. BA, variable type and observer type all influenced percentage error (P < .0001). Core interobserver percentage error (medians, 11.4%, 10.2%, and 9.3% for BA using one, two, and three beats, respectively) was approximately twice the intraobserver percentage error (medians, 6.3%, 4.9%, and 4.2% for BA using one, two, and three beats, respectively). Slopes and calculated variables exhibited high percentage error despite BA. Chamber dimensions, areas, velocities, and time intervals exhibited low percentage error. CONCLUSIONS: This comprehensive evaluation of quantitative echocardiographic methods will provide a valuable resource for the design of future pediatric studies. BA and a single core lab observer improve the reproducibility of echocardiographic measurements in children with dilated cardiomyopathy. Certain measurements are highly reproducible, while others, despite BA, are poorly reproducible.

Contemporary outcomes after the Fontan procedure: a Pediatric Heart Network multicenter study.

OBJECTIVES: We characterized a large cohort of children who had a Fontan procedure, with measures of functional health status, ventricular size and function, exercise capacity, heart rhythm, and brain natriuretic peptide (BNP). BACKGROUND: The characteristics of contemporary Fontan survivors are not well described. METHODS: We enrolled 546 children (age 6 to 18 years, mean 11.9 years) and compared them within pre-specified anatomic and procedure subgroups. History and outcome measures were obtained within a 3-month period. RESULTS: Predominant ventricular morphology was 49% left ventricular (LV), 34% right ventricular (RV), and 19% mixed. Ejection fraction (EF) was normal for 73% of subjects; diastolic function grade was normal for 28%. Child Health Questionnaire mean summary scores were lower than for control subjects; however, over 80% of subjects were in the normal range. Brain natriuretic peptide concentration ranged from <4 to 652 pg/ml (median 13 pg/ml). Mean percent predicted peak O2 consumption was 65% and decreased with age. Ejection fraction and EF Z score were lowest, and semilunar and atrioventricular (AV) valve regurgitation were more prevalent in the RV subgroup. Older age at Fontan was associated with more severe AV valve regurgitation. Most outcomes were not associated with a superior cavopulmonary connection before Fontan. CONCLUSIONS: Measures of ventricular systolic function and functional health status, although lower on average in the cohort compared with control subjects, were in the majority of subjects within 2 standard deviations of the mean for control subjects. Right ventricular morphology was associated with poorer ventricular and valvular function. Effective strategies to preserve ventricular and valvular function, particularly for patients with RV morphology, are needed.

Can peak systolic velocities be used for prediction of stroke in sickle cell anemia?

BACKGROUND AND PURPOSE: Ischemic stroke occurs in at least 11% of patients with homozygous sickle cell anemia (SCD) by the time they turn 20 years old. High risk associated with distal intracranial internal carotid (ICA) and proximal middle cerebral artery (MCA) stenosis can be detected by transcranial Doppler (TCD). TCD screening offers the possibility of reducing the risk of first stroke significantly based on a paradigm tested and proven to be effective in a stroke prevention trial in sickle cell anemia (STOP). Children with high flow velocity in the ICA and MCA of 200 cm/s time average mean of the maximum (TAMM) or higher had a 10% per year risk of first stroke that was reduced to <1% with regular red cell transfusion (reduction of hemoglobin S <30%). The clinical application of the STOP results could be enhanced if criteria for treatment could be found that are based on peak systolic velocity (PSV), the measure more commonly used in vascular ultrasound practice. OBJECTIVE: To compare PSV and end diastolic velocity (EDV) with TAMM for prediction of stroke and to derive PSV cutpoints for STOP protocol definitions of conditional and abnormal TCD. Using the STOP TCD and stroke outcome data to compare PSV and TAMM in terms of stroke prediction, PSV cutpoints comparable to those based on TAMM and used in STOP were derived. Because of their familiarity to the vascular ultrasound community, PSV cutpoints should be an important alternative to TAMM and may increase availability of screening and risk stratification for children with this disease. MATERIALS AND METHODS: Data from 1,937 baseline TCD studies from STOP were correlated with stroke outcome in those not treated with transfusion. Stroke prediction was assessed with survival analysis using TAMM, PSV and EDV as continuous variables individually and then pair-wise in the same model, which contained 53 stroke events. RESULTS: PSV and EDV were highly correlated to the TAMM velocity (r=0.94). The multivariate model for prediction indicated that TAMM velocity was a better predictor than EDV, and PSV and TAMM were approximately equivalent. PSV cutpoints defining the two relevant STOP risk categories--"conditional," which should lead to increased TCD surveillance, and "abnormal," which should lead to strong consideration for treatment according to STOP--were derived taking into consideration known differences in measurements between the dedicated Doppler systems (TCD) used in STOP and the transcranial Doppler imaging (TCDI) systems commonly used in clinical practice. The recommended PSV cutpoint for conditional TCD is 200 cm/s, and for abnormal TCD triggering consideration for treatment is 250 cm/s. CONCLUSION: Assuming TCDI equipment is used and the STOP protocol is applied, a PSV cutpoint of 200 cm/s is recommended as the threshold for increased TCD surveillance (comparable to a TCD TAMM of 170 cm/s in STOP); a PSV of 250 cm/s is recommended as the cutpoint at which, if confirmed in a second examination, chronic transfusion should be considered. Assuming the STOP scanning protocol is used, PSV is at least as good as TAMM and can be used to select children with SCD for treatment or increased surveillance to prevent first stroke.

Magnetic resonance angiography in children with sickle cell disease and abnormal transcranial Doppler ultrasonography findings enrolled in the STOP study.

The stroke prevention study in sickle cell disease (STOP) demonstrated a 90% reduction in stroke risk with transfusion among patients with time-averaged mean cerebral blood velocity (TAMV) of 200 cm/s or more as measured by transcranial Doppler (TCD). In STOP, 232 brain magnetic resonance angiograms (MRAs) were performed on 100 patients, 47 in the transfusion arm and 53 in the standard care arm. Baseline MRA findings were interpreted as normal in 75 patients and as indicating mild stenosis in 4 patients and severe stenosis in 21 patients. Among 35 patients who underwent magnetic resonance angiography within 30 days of random assignment, the TAMV was significantly higher in 7 patients with severe stenosis compared with 28 patients with normal MRA findings or mild stenosis (276.7 +/- 34 vs 215 +/- 15.6 cm/s; P<.001). In the standard care arm, 4 of 13 patients with abnormal MRA findings had strokes compared with 5 of 40 patients with normal MRA findings (P=.03). In this arm, TAMV became normal (less than 170 cm/s) or conditional (170-199 cm/s) in 26 of 38 patients with normal or mildly abnormal baseline MRA but remained abnormal in 8 of 10 patients with severely abnormal baseline MRA. These results suggest that TCD often detects flow abnormalities indicative of stroke risk before MRA lesions become evident. Furthermore, patients with abnormal MRA findings and higher TCD velocities are at higher risk for stroke, and their cerebral TAMVs are unlikely to decrease without transfusion.

Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease.

Children with sickle cell anemia (HbSS) are at high risk for neurologically overt cerebral infarcts associated with stroke and neurologically silent cerebral infarcts correlated with neuropsychometric deficit. We used complete magnetic resonance imaging (MRI) histories from 266 HbSS children, aged 6 through 19 years, who were enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) to examine silent infarct prevalence, localization, recurrence, and progression. We report a baseline prevalence of 21.8%, marginally higher than previously reported due to improved imaging technologies. Although we observed no overall sex difference in prevalence, most lesions in girls occurred before age 6, whereas boys remained at risk until age 10. Silent infarcts were significantly smaller and less likely to be found in the frontal or parietal cortex than were infarcts associated with stroke. Children with silent infarct had an increased incidence of new stroke (1.03/100 patient-years) and new or more extensive silent infarct (7.06/100 patient-years) relative to stroke incidence among all children in our cohort (0.54/100 patient-years). Both events were substantially less frequent than the risk of stroke recurrence among children not provided chronic transfusion therapy. Although chronic transfusion is known to decrease occurrence of new silent infarcts and strokes in children with elevated cerebral arterial blood flow velocity, further study is required to determine its risk-benefit ratio in children with silent infarct and normal velocities. Until safe and effective preventive strategies against infarct recurrence are discovered, MRI studies are best reserved for children with neurologic symptoms, neuropsychometric deficits, or elevated cerebral artery velocities.

Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized multicenter controlled trial comparing prophylactic blood transfusion with standard care in sickle cell anemia (SCA) children aged 2 to 16 years selected for high stroke risk by transcranial Doppler (TCD). More than 2000 children were screened with TCD to identify the 130 high-risk children who entered the randomized trial. A total of 5613 TCD studies from 2324 children were evaluated. We also collected information on stroke. We describe the changes in TCD with repeated testing and report the outcome without transfusion in the STOP screened cohort. Risk of stroke was higher with abnormal TCD than with normal or conditional TCD (P <.001) or inadequate TCD (P =.002), and risk with conditional TCD was higher than with normal TCD (P <.001). Repeated TCD in 1215 children showed that the condition of 9.4% of children became abnormal during observation. Younger patients and those with higher initial flow velocities were most likely to convert to abnormal TCDs. Screening in STOP confirmed the predictive value of TCD for stroke. Substantial differences in the probability of conversion to abnormal TCD were observed, with younger children and those with higher velocity more likely to have an abnormal TCD with rescreening.