Abdominal ultrasound with scintigraphic and clinical correlates in infants with sickle cell anemia: baseline data from the BABY HUG trial.

OBJECTIVE: The purpose of this study is to perform and evaluate baseline abdominal ultrasound in infants with sickle cell anemia who participated in the BABY HUG multiinstitutional randomized placebo-controlled trial of hydroxyurea therapy and to examine the potential relationships among ultrasound results and clinical, nuclear medicine, and laboratory data. SUBJECTS AND METHODS: After local institutional review board approval and with informed guardian consent, 116 girls and 87 boys (age range, 7.5-18 months) with sickle cell anemia underwent standardized abdominal sonography at 14 institutions. Imaging was centrally reviewed by one radiologist who assessed and measured the spleen, kidneys, gallbladder, and common bile duct. Baseline physical assessment of spleen size, serum alanine aminotransferase and bilirubin levels, (99m)Tc sulfur colloid liver-spleen scans, and (99m)Tc diethylenetriaminepentaacetic acid clearance glomerular filtration rates (GFRs) were obtained. Analysis of variance and the Student test were performed to compare sonographic findings to published results in healthy children and to clinical and laboratory findings. RESULTS: The mean (± SD) spleen volume (108 ± 47 mL) was significantly greater than published normal control values (30 ± 14 mL; p < 0.0001). There was no correlation between spleen volume and function assessed by liver-spleen scan. The mean GFR (125 ± 34 mL/min/1.73 m(2)) was elevated compared with control GFRs (92 ± 18 mL/min/1.73 m(2)). Renal volumes (right kidney, 29 ± 8 mL; left kidney, 31 ± 9 mL) were significantly greater than control volumes (right kidney, 27 ± 3 mL; left kidney, 27 ± 3 mL; p < 0.0001) and were positively correlated with GFR (p = 0.0009). Five percent of patients had sonographic biliary abnormalities (sludge, n = 6; dilated common bile duct, n = 2; and cholelithiasis and thickened gallbladder wall, n = 1 each). There was no correlation between biliary sonographic findings and laboratory results. CONCLUSION: In infants with sickle cell anemia, sonographic spleen volume does not reflect function, but increased renal volume correlates with GFR and is consistent with hyperfiltration. Sonographic biliary abnormalities can occur early in life, while remaining clinically silent.

Renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial.

OBJECTIVES: To examine the feasibility and accuracy of glomerular filtration rate (GFR) measurements in infants with sickle cell anemia (SCA). STUDY DESIGN: The NHLBI/NICHD-sponsored Phase III randomized double-blinded placebo-controlled trial (BABY HUG) tests the hypothesis that hydroxyurea can prevent chronic organ damage in SCA. GFR elevation is a coprimary endpoint, measured quantitatively by technetium 99m-labeled diethylenetriaminepentaacetic acid (DTPA) plasma clearance and estimated by the Schwartz equation with height and creatinine. RESULTS: Baseline DTPA GFR measurement was attempted in 191 infants; 176 of 184 completed studies (96%) were interpretable. Average age (mean +/- 1SD) was 13.7 +/- 2.6 months. Average DTPA GFR was 125.2 +/- 34.4 (range 40.2-300.9, normal 91.5 +/- 17.8 mL/min/1.73m(2)), while Schwartz estimates were higher at 184.4 +/- 55.5 mL/min/1.73m(2). DTPA GFR was correlated with Schwartz GFR (r(2) = 0.0658, P = .0012); also with age, weight, height, and kidney volume (all P < .002); but not with hemoglobin, HbF, white blood cell count, reticulocytes, medical events, or splenic function. CONCLUSIONS: Quantitative GFR measurement is feasible but variable among infants with SCA. Schwartz GFR estimates are not highly correlated with quantitative DTPA GFR values. Baseline GFR measurements suggest that renal dysfunction in SCA, evidenced by glomerular hyperfiltration, begins during infancy.

Urine concentrating ability in infants with sickle cell disease: baseline data from the phase III trial of hydroxyurea (BABY HUG).

BACKGROUND: A urine concentrating defect is quite common in sickle cell anemia, has its onset in early childhood, and may be reversible with transfusion. The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) is a double-blind, placebo-controlled trial to assess efficacy of hydroxyurea in preventing organ damage in young children with sickle cell anemia. PROCEDURES: Enrolled infants were subjected to parent-supervised fluid deprivation, and urine and serum osmolality were determined. RESULTS: Of 185 infants age 7.5-17.9 months (mean 13.0 +/- 2.7) and fluid-deprived 7.4 +/- 2.4 hr (range 4-13), 178 had concurrent determinations of urine and serum osmolality. Mean serum osmolality was 286 +/- 6 mOsm/kg H(2)O (range 275-312) and independent of age, height, weight, or duration of fluid deprivation. Urine osmolality (mean 407 +/- 151, range 58-794 mOsm/kg H(2)O) was greater than serum (P < 0.0001) and correlated with duration of fluid deprivation (P = 0.001). Of 142 (77.2%) who concentrated urine, 54 (29.4%) had urine osmolality >500 mOsm/kg H(2)O. Urine osmolality correlated with (99m)Tc-DTPA clearance (P = 0.02) and serum urea nitrogen (P < 0.0001), but not with serum osmolality, gender, age, height, weight, or serum creatinine. Infants able to produce urine with osmolality >500 mOsm/kg H(2)O had higher mean fetal hemoglobin concentrations than did those who could not (P = 0.014). CONCLUSIONS: Even with often limited fluid deprivation, 77.2% of young infants with sickle cell anemia were able to concentrate urine. Preservation of concentrating ability was associated with higher fetal hemoglobin concentration. Assessment will be repeated after 2 years of hydroxyurea or placebo treatment (ClinicalTrials.gov number, NCT00006400).

Adherence to study medication and visits: data from the BABY HUG trial.

BACKGROUND: Subject retention and adherence are essential to maintain the power and validity of the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). We designed a study to assess adherence with study medication administration and study visits and to evaluate socioeconomic factors (SES) that may influence these measurements of adherence. These data are important for assessing impact of adherence on BABY HUG trial outcome and defining impact of SES on adherence. METHODS: Each subject's median study medication (MedAd) and mean visit adherence (VAd) were evaluated. We examined associations of adherence with SES of participating families. RESULTS: MedAd data were available on 153 of the 191 subjects who started randomized study medication. MedAd was 101.7% of volume prescribed, with 88.9% of subjects taking at least 80% of doses. VAd data were available on 185 of the 191 subjects who started randomized study medication. VAd was 97.3%, with 82.2% of subjects having no missed visits. During dose titration, subjects had on average 12.9% higher medication adherence than subjects who were on a stable dose and had less frequent study visits. MedAd and VAd were not significantly associated with SES. CONCLUSION: Subjects in the BABY HUG trial have had excellent adherence. SES was not associated with adherence, suggesting that SES should not be used as a criterion for enrolment in clinical trials. Additional efforts are needed to maintain medication adherence, particularly when the interval between scheduled visits increases. (ClinicalTrials.gov number, NCT00006400).

Transcranial doppler ultrasonography (TCD) in infants with sickle cell anemia: baseline data from the BABY HUG trial.

BACKGROUND: Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years. PROCEDURE: TCD was performed on infants with SCA enrolled in the BABY HUG trial. Subjects were 7-17 months of age (mean 12.6 months). TCD examinations were successfully performed in 94% of subjects (n = 192). RESULTS: No patient had an abnormal TCD as defined in the older child (time averaged maximum mean TAMM velocity > or =200 cm/sec) and only four subjects (2%) had velocities in the conditional range (170-199 cm/sec). TCD velocities were inversely related to hemoglobin (Hb) concentration and directly related to increasing age. CONCLUSION: Determination of whether the TCD values in this very young cohort of infants with SCA can be used to predict stroke risk later in childhood will require analysis of exit TCD's and long-term follow-up, which is ongoing (ClinicalTrials.gov number, NCT00006400).

The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design.

Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9-17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400).

MRI abnormalities of the brain in one-year-old children with sickle cell anemia.

BACKGROUND: Sickle cell anemia (SCA) frequently results in damage to the central nervous system (CNS), but the age of onset of these effects is uncertain. We performed MRI examinations of the brain in infants with SCA, who were evaluated as part of the multicenter randomized double-blinded Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). METHODS: Determination of eligibility for enrollment in the trial originally required baseline MRI and magnetic resonance angiography (MRA) of the brain. A standardized imaging protocol was utilized across eight clinical centers. MRI/MRA exams were reviewed by a panel of three neurology/neuroradiology readers and interpretations reported to the coordinating center. Results were correlated with patient age, gender, history, WBC count, platelet count, hemoglobin (Hb), HbF level, score on the Bayley Scales of Infant Development, and velocity on transcranial Doppler ultrasonography (TCD). RESULTS: Twenty-three subjects with HbSS were examined at average age 13.7 months (range 10-18 months); 13 were male. Three (13%, CI: 3-34%) had silent infarcts on MRI, two in the right frontal area and one bilaterally. None had MRA abnormalities. The lesions were correlated with increased right-sided TCD velocity and low HbF level, but not with age, history, Hb level, developmental score, or left-sided velocity. CONCLUSIONS: Silent brain infarcts occur in a small but significant number of infants with SCA as early as a year of age. This finding indicates a need for thorough evaluation of the CNS very early in life in children with SCA in order to develop timely intervention strategies.

Highly precise eye length measurements in children aged 3 through 12 years.

OBJECTIVE: To determine the feasibility, reliability, and validity of using partial coherence interferometry, a noncontact method that detects interference patterns from various layers of the eye, to measure axial length in young children. METHODS: The right eye of 64 subjects (mean age, 8.4 y; age range, 3.4-12.9 y; best-corrected visual acuity >or=20/30) was measured. Subjects fixated monocularly on the collimated light pattern from a laser diode (the alignment beam) and the operator used a video monitor to align the corneal reflection in the optical path. Axial length was measured during an 0.8-second scan using interference patterns from a collimated short coherence superluminescence diode aligned coaxially with the laser diode. Five series of 16 readings each were obtained. The average axial length for each of the 5 series of readings was calculated. Main Outcome Measure Axial length. RESULTS: Within-subject precision of axial length measurements was high, with an overall SE of measurement of 8 micro m for individual subjects across the 5 sessions (95% confidence interval, +/-16 micro m). Subgroup analysis showed that sex, age, spherical equivalent, and refractive error exerted statistically significant effects on precision, but all of the differences among subgroups were 3 micro m or less and likely to be insignificant clinically. Axial length measured by partial coherence interferometry varied systematically, with factors known to influence eye length (ie, age and refractive error), further validating the measurement method. CONCLUSION: The partial coherence interferometry technique provides reproducible, extraordinarily precise eye length measurements in young children and should enable novel approaches to study eye growth and refractive development.