A Phase 3 Trial of l-Glutamine in Sickle Cell Disease.

BACKGROUND: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain. METHODS: In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle ß0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period. RESULTS: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group. CONCLUSIONS: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).

Nonsurgical Management of Acute Appendicitis in Sickle Cell Disease.

A 9-year-old child with sickle cell disease (sickle beta zero thalassemia) was diagnosed to have acute appendicitis during a hospitalization for pain, acute chest syndrome, and exacerbation of asthma. Because of his high surgical risk, his appendicitis was treated nonsurgically, successfully deferring his appendectomy. He remains well after 1 year. This approach should be considered at least in other sickle cell patients with appendicitis, and perhaps other high-risk populations, if not all children with appendicitis.

Massive Splenic Infarction in a Child With Sickle Cell Disease on Chronic Transfusion Therapy.

Massive splenic infarction (MSI) is a rare complication of sickle cell disease, as the spleen generally atrophies within the first few years of life. We report a case of MSI in a 12-year-old boy with homozygous sickle cell anemia (Hb SS) whose chronic transfusion therapy resulted in hypersplenism. The occurrence of a complicated MSI in our patient should perhaps further encourage elective splenectomy in such patients, despite known potential perioperative complications and postsplenectomy risks of infection and thrombosis.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.

Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial.

The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging/magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ≥Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85%/79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities, which were associated with worse stenoses (incidence risk ratio [IRR] = 5.1, P ≤ .0001 and IRR = 4.1, P < .0001) than normal velocities; only 2% to 12% had any conditional/abnormal velocity. Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard/8 alternative arm subjects) had substantial parenchymal injury/vessel stenosis. At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis. SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980.

Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload.

Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (-8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.

Unexpected Anemia and Reticulocytopenia in an Adolescent With Sickle Cell Anemia Receiving Chronic Transfusion Therapy.

In a patient with sickle cell disease receiving chronic transfusion, exacerbation of anemia with reticulocytopenia must prompt consideration of a delayed hemolytic transfusion reaction with hyperhemolysis, as further transfusion may worsen this condition; definitive diagnosis is sometimes difficult. Anemia evolving during parvovirus B19-induced erythroid hypoplasia (transient aplastic crisis) should be attenuated in chronic transfusion patients due to superior survival of transfused over endogenous red blood cells. A 16-year-old with sickle cell disease receiving chronic transfusion of modified intensity (goal to maintain hemoglobin S<50%) who developed symptomatic anemia with reticulocytopenia was later shown to have had transient aplastic crisis.

Impact of hydroxyurea on clinical events in the BABY HUG trial.

The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov).

How I treat acute chest syndrome in children with sickle cell disease.

Acute chest syndrome describes new respiratory symptoms and findings, often severe and progressive, in a child with sickle cell disease and a new pulmonary infiltrate. It may be community-acquired or arise in children hospitalized for pain or other complications. Recognized etiologies include infection, most commonly with atypical bacteria, and pulmonary fat embolism (PFE); the cause is often obscure and may be multifactorial. Initiation of therapy should be based on clinical findings. Management includes macrolide antibiotics, supplemental oxygen, modest hydration and often simple transfusion. Partial exchange transfusion should be reserved for children with only mild anemia (Hb > 9 g/dL) but deteriorating respiratory status. Therapy with corticosteroids may be of value; safety, efficacy and optimal dosing strategy need prospective appraisal in a clinical trial. On recovery, treatment with hydroxyurea should be discussed to reduce the likelihood of recurrent episodes.

Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial.

We evaluated spleen function in 193 children with sickle cell anemia 8 to 18 months of age by (99m)Tc sulfur-colloid liver-spleen scan and correlated results with clinical and laboratory parameters, including 2 splenic biomarkers: pitted cell counts (PIT) and quantitative Howell-Jolly bodies (HJB) enumerated by flow cytometry. Loss of splenic function began before 12 months of age in 86% of infants in association with lower total or fetal hemoglobin and higher white blood cell or reticulocyte counts, reinforcing the need for early diagnosis and diligent preventive care. PIT and HJB correlated well with each other and liver-spleen scan results. Previously described biomarker threshold values did define patients with abnormal splenic function, but our data suggest that normal spleen function is better predicted by PIT of ≤1.2% or HJB ≤55/10(6) red blood cells and absent function by PIT ≥4.5% or HJB ≥665/10(6). HJB is methodologically advantageous compared with PIT, but both are valid biomarkers of splenic function. This trial was registered at www.clinicaltrials.gov as #NCT00006400.

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.

Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial.

To compare the non-neurological events in children with sickle cell anemia (SCA) and previous stroke enrolled in SWiTCH. The NHLBI-sponsored Phase III multicenter randomized clinical trial stroke with transfusions changing to hydroxyurea (SWiTCH) (ClinicalTrials.gov NCT00122980) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload. All randomized children were included in the analysis (intention to treat). The Fisher's Exact test was used to compare the frequency of subjects who experienced at least one SCA-related adverse event (AE) or serious adverse event (SAE) in each arm and to compare event rates. One hundred and thirty three subjects, mean age 13 ± 3.9 years (range 5.2-19.0 years) and mean time of 7 years on chronic transfusion at study entry, were randomized and treated. Numbers of subjects experiencing non-neurological AEs were similar in the two treatment arms, including SCA-related events, SCA pain events, and low rates of acute chest syndrome and infection. However, fewer children continuing transfusion/chelation experienced SAEs (P = 0.012), SCA-related SAEs (P = 0.003), and SCA pain SAEs (P = 0.016) as compared to children on the hydroxyurea/phlebotomy arm. The timing of phlebotomy did not influence SAEs. Older age at baseline predicted having at least 1 SCA pain event. Patients with recurrent neurological events during SWiTCH were not more likely to experience pain. In children with SCA and prior stroke, monthly transfusions and daily iron chelation provided superior protection against acute vaso-occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy.

IMPROVE trial: a randomized controlled trial of patient-controlled analgesia for sickle cell painful episodes: rationale, design challenges, initial experience, and recommendations for future studies.

BACKGROUND: The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease. PURPOSE: The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies. METHODS: The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint. RESULTS: Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation. LIMITATIONS: While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers. LESSONS LEARNED: Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size. CONCLUSIONS: A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials.

Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE).

Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.

Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).

BACKGROUND: Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects. METHODS: This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sß(0)thalassaemia, were aged 9-18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2-4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400. FINDINGS: 96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m(2), p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia. INTERPRETATION: On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia. FUNDING: The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.

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.

Massive accidental overdose of hydroxyurea in a young child with sickle cell anemia.

The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) confirmed safety and efficacy of hydroxyurea therapy for infants with sickle cell anemia. Treatment was associated with reduction in rates of pain, acute chest syndrome, hospitalizations, and blood transfusions; improved hematologic values; and, perhaps, preservation of organ function. During the study, a 2-year-old ingested at one time an entire 35-day supply of hydroxyurea (612 mg/kg body weight). Despite a serum level of 7,756 µM 4 hours post-ingestion, the only toxicity was transient mild myelosuppression. With wider usage of hydroxyurea anticipated, conservative management of future overdoses seems reasonable (ClinicalTrials.gov NCT00006400).

Influence of severity of anemia on clinical findings in infants with sickle cell anemia: analyses from the BABY HUG study.

BACKGROUND: Clinical complications of sickle cell anemia begin in infancy. BABY HUG (ClinicalTrials.gov, NCT00006400) was a NHLBI-NICHD supported randomized phase III placebo-controlled trial of hydroxyurea (HU) in infants (recruited at 9-18 months) unselected for clinical severity with sickle cell anemia. This secondary analysis of data from BABY HUG examines the influence of anemia on the incidence of sickle cell related complications, and the impact of hydroxyurea therapy in altering these events by comparing children with lower (<25th percentile) and higher (>75th percentile) hemoglobin concentrations at study entry. PROCEDURE: Infants were categorized by: (1) age-adjusted hemoglobin quartiles as determined by higher (Hi) and lower (Lo) hemoglobin concentrations at study entry (9-12 months old: <8.0 and >10.0 gm/dL; 12-18 months old: <8.1 and >9.9 gm/dL) and (2) treatment arm (hydroxyurea or placebo). Four subgroups were created: placebo (PL) LoHb (n = 25), PL HiHb (n = 27), hydroxyurea (HU) LoHb (n = 21), and HU HiHb (n = 18). The primary and secondary endpoints of BABY HUG were analyzed by subgroup. RESULTS: Infants with lower hemoglobin at baseline were more likely to have a higher incidence of clinical events (acute chest syndrome, pain crisis, fever) as well as higher TCD velocities and lower neuropsychological scores at study exit. Hydroxyurea reduced the incidence of these findings. CONCLUSION: Infants with more severe anemia are at risk for increased clinical events that may be prevented by early initiation of hydroxyurea.

Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia.

BACKGROUND: Children with sickle cell anemia (SCA) often develop hyposthenuria and renal hyperfiltration at an early age, possibly contributing to the glomerular injury and renal insufficiency commonly seen later in life. The Phase III randomized double-blinded Clinical Trial of Hydroxyurea in Infants with SCA (BABY HUG) tested the hypothesis that hydroxyurea can prevent kidney dysfunction by reducing hyperfiltration. PROCEDURE: 193 infants with SCA (mean age 13.8 months) received hydroxyurea 20 mg/kg/day or placebo for 24 months. (99m) Tc diethylenetriaminepentaacetic acid (DTPA) clearance, serum creatinine, serum cystatin C, urinalysis, serum and urine osmolality after parent-supervised fluid deprivation, and renal ultrasonography were obtained at baseline and at exit to measure treatment effects on renal function. RESULTS: At exit children treated with hydroxyurea had significantly higher urine osmolality (mean 495 mOsm/kg H(2) O compared to 452 in the placebo group, P = 0.007) and a larger percentage of subjects taking hydroxyurea achieved urine osmolality >500 mOsm/kg H(2) O. Moreover, children treated with hydroxyurea had smaller renal volumes (P = 0.007). DTPA-derived glomerular filtration rate (GFR) was not significantly different between the two treatment groups, but was significantly higher than published norms. GFR estimated by the Chronic Kidney Disease in Children (CKiD) Schwartz formula was the best non-invasive method to estimate GFR in these children, as it was the closest to the DTPA-derived GFR. CONCLUSION: Treatment with hydroxyurea for 24 months did not influence GFR in young children with SCA. However, hydroxyurea was associated with better urine concentrating ability and less renal enlargement, suggesting some benefit to renal function.

Rehabilitation and Return to Sport After Arthroscopic Treatment of Femoroacetabular Impingement: A Review of the Recent Literature and Discussion of Advanced Rehabilitation Techniques for Athletes.

The purpose of the article is to present an updated literature review, as well as describe our approach to rehabilitation and return to sports following hip arthroscopy for femoroacetabular impingement (FAI) with labral repair. A literature review was performed to identify articles published within the last 10 years that were focused on this topic. Relevant articles were reviewed, and reference lists were searched to identify additional articles. Findings were summarized for rehabilitation phases and return-to-sports assessment. Additionally, advanced rehabilitation topics are reviewed. Several systematic reviews and individual case series were identified. There is relative uniformity concerning the use of a four-phase approach for rehabilitation. However, there is inconsistency in terms of timing and criteria for ultimate return to sport. Advanced rehabilitation topics were reviewed, and description of their relevance at various rehabilitation phases was provided. A four-phase approach to rehabilitation following hip arthroscopy for FAI is widely used with general uniformity, although the timing and level of detail concerning assessment and readiness for return to sport are variable. Advanced rehabilitation techniques may be used in select patients returning to high-level activities.