Intra-individual variation in blood flow velocities in cerebral arteries of children with sickle cell disease

BACKGROUND: Children with sickle cell disease (SCD) are at elevated risk of stroke. Risk increases with blood flow velocity in selected cerebral arteries, as measured by transcranial Doppler (TCD) ultrasound, and use of TCD to screen these patients is widely recommended. Interpretation of TCD results should be based on knowledge of intra-individual variation in blood flow velocity, information not currently available for sickle cell patients. PROCEDURES: Between 1995 and 2002, 4,141 subjects, 2-16 years old, with homozygous SCD or Sbeta0-thalasemmia and no history of stroke were screened with TCD, including 2,018 subjects screened in one clinical trial (STOP), 1,816 screened in another (STOP 2), and 307 screened in an interim ancillary prospective study. The 812 subjects with >or=2 examinations<6 months apart were selected for analysis, including 242 (29.8%) subjects with normal average velocities (i.e., <170 cm/sec), 350 (43.1%) subjects with conditional velocities (i.e., 170-199 cm/sec), and 220 (27.1%) subjects with abnormal velocities (i.e., >or=200 cm/sec). The intra-subject standard deviation of TCD velocity was estimated from the difference between velocities at the first two interpretable examinations on each subject. RESULTS: An intra-subject standard deviation of 14.9 cm/sec was obtained. Seven (0.9%) subjects had unusually large and unexplained differences between velocities at the two examinations (range of absolute differences: 69-112 cm/sec). CONCLUSIONS: While stroke risk is well demonstrated to increase with increasingly abnormal TCD velocity, given the relatively large intra-subject variability, one TCD examination is generally not sufficient to characterize stroke risk in this patient population.     

Hydroxyurea therapy in UK children with sickle cell anaemia: A single‐centre experience

1 Introduction

Despite the demonstrated efficacy of hydroxyurea therapy, children with sickle cell anaemia in the UK are preferentially managed with supportive care or transfusion. Hydroxyurea is reserved for children with severe disease phenotype. This is in contrast to North America and other countries where hydroxyurea is widely used for children of all clinical phenotypes. The conservative UK practice may in part be due to concerns about toxicity, in particular marrow suppression with high doses, and growth in children.

2 Methods and results

We monitored 37 paediatric patients with sickle cell anaemia who were treated with hydroxyurea at a single UK treatment centre. Therapy was well tolerated and mild transient cytopenias were the only toxicity observed. Comparative analysis of patients receiving ≥26 mg/kg/day versus <26 mg/kg/day demonstrates increasing dose has a significant positive effect on foetal haemoglobin (Hb; 29.2% vs. 20.4%, P = 0.0151), mean cell volume (94.4 vs. 86.5, P = 0.0183) and reticulocyte count (99.66 × 10⁹/l vs. 164.3 × 10⁹/l, P = 0.0059). Marrow suppression was not a clinical problem with high‐dose treatment, Hb 92.25 g/l versus 91.81 g/l (ns), neutrophil count 3.3 × 10⁹/l versus 4.8 × 10⁹/l (ns) and platelet count 232.4 × 10⁹/l versus 302.2 × 10⁹/l (ns). Normal growth rates were maintained in all children. Good adherence to therapy was a significant factor in reducing hospitalisations.

3 Conclusion

This study demonstrates the effectiveness and safety in practice of high‐dose hydroxyurea as a disease‐modifying therapy, which we advocate for all children with sickle cell anaemia.     

Hydroxyurea use among children with sickle cell anemia

This study describes hydroxyurea use among children ages 1 to 17 with sickle cell anemia (SCA) enrolled in at least one year of Medicaid in six states from 2005 to 2012. Administrative claims were used to summarize the number of days’ supply of hydroxyurea dispensed by state and year. A total of 7963 children with SCA contributed 22 424 person‐years. Among person‐years with greater than 30 days of hydroxyurea, only 18% received at least 300 days of hydroxyurea, which varied by state. Following updated recommendations for all children with SCA to be offered hydroxyurea, strategies to increase hydroxyurea adherence among this population are needed.     

Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, toxicity, and management in children

Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children.     

Hydroxyurea treatment of children with hemoglobin SC disease

The efficacy of hydroxyurea in hemoglobin SC (HbSC) patients is not well documented. We describe the long‐term response to hydroxyurea in children with clinically severe HbSC. In 15 patients, hydroxyurea resulted in a significant increase in mean corpuscular volume (MCV) and fetal hemoglobin (HbF) and a significant decrease in episodes of acute chest syndrome and hospitalization for pain; there was no effect on hemoglobin level. The most significant side effect was thrombocytopenia, which led to discontinuation of treatment in one patient. This study suggests that hydroxyurea has efficacy and is safe for long‐term therapy in patients with HbSC. Pediatr Blood Cancer 2013;60:323–325. © 2012 Wiley Periodicals, Inc.     

Secondary benefit of maintaining normal transcranial Doppler velocities when using hydroxyurea for prevention of severe sickle cell anemia

In a retrospective cohort study, we tested the hypothesis that when prescribing hydroxyurea (HU) to children with sickle cell anemia (SCA) to prevent vaso‐occlusive events, there will be a secondary benefit of maintaining low transcranial Doppler (TCD) velocity, measured by imaging technique (TCDi). HU was prescribed for 90.9% (110 of 120) of children with SCA ≥5 years of age and followed for a median of 4.4 years, with 70% (n = 77) receiving at least one TCDi evaluation after starting HU. No child prescribed HU had a conditional or abnormal TCDi measurement. HU initiation for disease severity prevention decreases the prevalence of abnormal TCDi velocities.