Prevention of secondary stroke and resolution of transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy

PREVENTION OF SECONDARY STROKE AND RESOLUTION OF TRANSFUSIONAL IRON OVERLOAD IN CHILDREN WITH SICKLE CELL ANEMIA USING HYDROXYUREA AND PHLEBOTOMY RUSSELL E. WARE, MD, PHD, SHERRI A. ZIMMERMAN, MD, PAMELA B. SYLVESTRE, MD, NICOLE A. MORTIER, MHS, PA-C, JACQUELINE S. DAVIS, RN, MPH, WILLIAM R. TREEM, MD, AND WILLIAM H. SCHULTZ, MHS, PA-C

Objective Transfusions prevent secondary stroke in children with sickle cell anemia (SCA) but also cause iron overload. Alternatives for stroke prophylaxis with effective therapy to reduce iron burden are needed. Study design For 35 children with SCA and stroke, transfusions were prospectively discontinued. Hydroxyurea was prescribed for stroke prophylaxis, and phlebotomy removed excess iron. Initial patients discontinued transfusions before hydroxyurea therapy, but later patients overlapped transfusions with hydroxyurea until tolerating full-dose therapy. Results Children received hydroxyurea for 42 ± 30 months (range, 3-104 months). Hydroxyurea (26.7 ± 4.8 mg/kg per day) led to mild neutropenia (3.9 ± 2.3 3 109/L) with significant increases in hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin. Stroke recurrence rate was 5.7 events per 100 patient-years, but children receiving overlapping hydroxyurea therapy had only 3.6 events per 100 patient-years. For 26 children with >6 months of phlebotomy, 14,311 ± 12,459 mL blood (315 ± 214 mL/kg) was removed, with serum ferritin decreasing from a median of 2722 to 298 ng/mL. Among patients completing phlebotomy, liver biopsy documented normal histology and no excess iron deposition. Conclusions For children with SCA and stroke, hydroxyurea effectively prevents secondary stroke and serial phlebotomy leads to complete resolution of transfusional iron overload. (J Pediatr 2004;145:346-52)

trokes in children with sickle cell anemia (SCA) are typically infarcts involving the large intracranial arteries.1,2 Histologically, there is extensive intimal hyperplasia that leads to erythrocyte adhesion, intraluminal thrombosis, vessel stenosis, and ultimately acute interruption of cerebral blood flow.2-4 Many children with stroke are left with substantial motor, cognitive, and neuropsychological deficits. The frequency of stroke in children with SCA ranges from 5% to 10%.5-9 The incidence of stroke is 0.7 events per 100 patient-years,9,10 with a cumulative incidence of 7.8% by age 14 years in Jamaica9 and 11% by age 20 years in the Cooperative Study of Sickle Cell Disease.10 Since about 50,000 persons in the United States have SCA and another 2000 affected babies are born each year,11 the development of stroke in patients with SCA has major implications for health care and financial resources. Without specific intervention, recurrent (secondary) stroke occurs in 47% to 93% of children with SCA and stroke.5,6,9,12,13 Current medical treatment includes erythrocyte transfusions to suppress sickle erythropoiesis and reduce the fraction of sickle hemoglobin.6,8,10,13-15 Chronic transfusions are efficacious but not fully protective in this setting, since 10% to 20% of patients will have another stroke despite transfusion prophylaxis, with a secondary stroke rate of 2.2 to 6.4 events per 100 patient-years.16,17 Moreover, transfusions can transmit infections,18 induce erythrocyte alloantibody and autoantibody formation,19-21 and lead to iron accumulation.22,23

S

ANC HbF MTD

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Absolute neutrophil count Fetal hemoglobin Maximum tolerated dose

SCA WBC

Sickle cell anemia White blood cell

See editorial, p 287. From the Duke Pediatric Sickle Cell Program, Division of HematologyOncology and Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, and Department of Pathology, Duke University Medical Center, Durham, North Carolina. Submitted for publication Oct 7, 2003; last revision received Feb 18, 2004; accepted Apr 28, 2004. Reprint requests: Russell E. Ware, MD, PhD, St Jude Childrens Research Hospital, 332 N Lauderdale St, Mailstop 310, Memphis, TN 38105. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.04.058

In 1995, we reported two young adults with SCA and stroke who could not continue long-term transfusion prophylaxis.24 Both patients were treated with hydroxyurea to increase fetal hemoglobin (HbF) and received phlebotomy to reduce iron overload and increase endogenous erythropoiesis. During almost 3 years of follow-up, stroke did not recur and serum ferritin decreased in both patients. We then initiated a prospective institutional review board–approved pilot trial to investigate the efficacy of hydroxyurea for prevention of secondary stroke in children with SCA, combined with phlebotomy for reduction of iron overload. Most children safely switched to hydroxyurea, although 3 patients had a recurrent neurologic event 3 to 4 months after abruptly discontinuing transfusions, before the maximal beneficial effects of hydroxyurea therapy were achieved.25 Our protocol was then modified to provide an overlap period between hydroxyurea and transfusions. In the modified protocol, the hydroxyurea dose is escalated over 6 months to the maximum tolerated dose (MTD), and transfusions are discontinued only after full-dose hydroxyurea therapy is tolerated. In this report, we describe the clinical outcome and long-term follow-up for our entire cohort of pediatric patients with SCA receiving hydroxyurea therapy for prevention of secondary stroke.

METHODS Patient Enrollment This prospective trial was approved by the Duke University Medical Center Institutional Review Board. Eligible children included all Duke pediatric patients with SCA and stroke who were receiving chronic erythrocyte transfusions for secondary stroke prevention. The consent form clearly described that standard therapy for secondary stroke prevention was chronic erythrocyte transfusions and that hydroxyurea represented an alternative therapy with a high potential risk of stroke recurrence. At least two healthcare providers from the Duke Pediatric Sickle Cell Program discussed the protocol with the children and their parents or guardians on several occasions, carefully explaining the risks and benefits of treatment with hydroxyurea and phlebotomy. Initially, patients were enrolled if they were unable to continue long-term transfusion therapy for one or more major complications including multiple erythrocyte alloantibodies, erythrocyte autoantibodies, recurrent stroke while receiving transfusions, or a systemic deferrioxamine allergy. Subsequently, children were enrolled for additional reasons including severe iron overload with chelation noncompliance, noncompliance with the transfusion regimen, parental request, or religious objection to blood transfusion.

Hydroxyurea for Secondary Stroke Prevention Initial patients had an abrupt transition from transfusions to hydroxyurea for stroke prophylaxis; the hematologic and clinical results for this cohort were included in an earlier report.25 In these children, transfusions were discontinued and

hydroxyurea commenced 2 weeks later as endogenous erythropoiesis recovered. Hydroxyurea was started at 15 to 20 mg/kg per day as a single daily oral dose and then escalated by 5 mg/kg per day every 8 weeks as tolerated to the MTD (or 30-35 mg/kg per day) as described for children and adults with SCA.26,27 MTD was determined by peripheral blood counts, using a target of mild neutropenia (absolute neutrophil count 2.0-4.0 3 109/L). With this dose escalation, the maximal benefits of hydroxyurea including HbF induction and white blood cell (WBC) reduction were not achieved until at least 6 months of therapy.26,27 However, suppression of endogenous sickle hemoglobin production, and hence protection against recurrent stroke, was lost within 2 to 4 months of stopping transfusions. Subsequent patients had a transition period with overlap between transfusions and hydroxyurea prophylaxis. During this temporary overlap, hydroxyurea therapy was escalated to MTD while monthly transfusions continued, although the transfused volume was reduced slightly (target posttransfusion hemoglobin concentration of 10-11 g/dL) to allow more endogenous erythropoiesis. Transfusions were formally discontinued only after patients tolerated hydroxyurea at MTD. Every attempt was made to ensure compliance with hydroxyurea and to minimize interruptions in therapy for toxicity. Thresholds were established that allowed patients to continue hydroxyurea unless marked myelosuppression occurred. Hematologic toxicity from hydroxyurea therapy was defined as hemoglobin concentration < 6.0 g/dL, absolute neutrophil count (ANC) < 1000 3 106/L, or platelet count < 80 3 109/L. Children with hematologic toxicity had hydroxyurea held temporarily until counts recovered; usually for 1 week. Complete blood counts were performed every 4 weeks; %HbF, renal and hepatic function, and serum ferritin were measured every 8 to 12 weeks.

Phlebotomy Regimen After discontinuing transfusions, patients with iron overload (serum ferritin >1000 ng/mL) had phlebotomy performed by outpatient pediatric hematology/oncology nurses. At least 5 mL/kg, and usually 10 mL/kg of venous blood, was removed over a period of 20 to 40 minutes through a peripheral intravenous catheter, followed by immediate equal volume replacement with normal saline. Vital signs were obtained before phlebotomy and every 10 minutes until the procedure was completed. A blood count was obtained at the time of catheter placement, and phlebotomy was performed only if the hemoglobin concentration was >7.0 g/dL. Phlebotomy was performed every 2 to 4 weeks, according to each family’s schedule. Seven children who tolerated phlebotomy well, with hemoglobin concentrations consistently >8.5 g/dL, had a portion of their phlebotomy procedures performed by home health pediatric nurses. Using a written protocol provided by our healthcare team, these nurses established intravenous access, performed phlebotomy, and provided intravenous fluid replacement at the patient’s home.

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Assessment of End-Organ Damage and Iron Overload The phlebotomy regimen was discontinued once the serum ferritin was < 200 ng/mL on 2 separate measurements. Percutaneous liver biopsy was then offered for histologic analysis and quantification of iron stores. Each patient received overnight intravenous hydration followed by conscious sedation (fentanyl and midazolam) for the biopsy; one biopsy core was sent for histology and iron staining and the other was shipped to Mayo Medical Laboratories (Rochester, Minn) for liver iron quantification. Echocardiography was performed to quantify left ventricular shortening fraction.

Statistical Analyses Laboratory and clinical data were recorded with the use of Microsoft Access and Microsoft Excel (Redmond, Wash). Descriptive statistics, t test, and comparison of proportions were performed with the use of Primer of Biostatistics (McGraw-Hill, New York, NY). For comparison of blood counts and serial ferritin measurements before and after phlebotomy, the Wilcoxon signed rank test (Statview, SAS Institute, Cary, NC) was used.

RESULTS Characteristics of the Patients Among 37 eligible African-American children with SCA and stroke receiving care in the Duke Pediatric Sickle Cell Program, 35 (23 boys and 12 girls) were enrolled in this protocol. One family chose to continue receiving chronic transfusions; the only patient with an unaffected HLAmatched sibling received bone marrow transplantation. Of the 35 children who enrolled, 33 had a diagnosis of HbSS; one boy had HbS/bo-thalassemia and another had HbS/OArab. The average age at primary stroke was 7.7 ± 3.7 years (range, 1.1-17.3). Each stroke was infarctive, with right and left sides affected almost equally. At enrollment, all patients were receiving chronic erythrocyte transfusions; all had previously received simple transfusions but 15 were currently receiving erythrocytapheresis.28 The average duration of previous transfusion prophylaxis was 50 ± 33 months (range, 7-130). The mean age at enrollment was 11.9 ± 4.0 years (range, 3.0-19.9). Reasons to discontinue transfusions varied, and some children had more than one reason, including erythrocyte autoantibodies (n = 6) or multiple alloantibodies (n = 6); noncompliance with prescribed transfusions (n = 5) or deferrioxamine chelation (n = 12); parental preference for transfusion alternatives (n = 8) including two with religious objection; progression of neurologic disease with worsening brain MRI or MRA (n = 3) or overt secondary stroke on transfusions (n = 2); and systemic deferrioxamine allergy (n = 2). Most patients (n = 33) also had transfusional iron overload with ferritin >1000 ng/mL. 348

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Hydroxyurea Therapy to Prevent Secondary Stroke The average hydroxyurea dose was 26.7 ± 4.8 mg/kg per day (range, 17.0-34.8, Table). Overall, the children tolerated hydroxyurea extremely well, with few interruptions for toxicity. Hydroxyurea compliance was assessed by several criteria, including frequency of missed clinic appointments, discussions with patients and families, and serial monitoring of blood counts and %HbF. The peripheral blood smear was examined at each clinic visit for the presence of macrocytes and reduced numbers of sickled erythrocytes. On the basis of these assessments, 5 patients (14%) had poor or questionable long-term compliance with hydroxyurea therapy. Mean duration of hydroxyurea therapy was 42 ± 30 months (range, 3-104; Table). Hydroxyurea therapy led to expected increases in mean corpuscular volume and %HbF, along with slight reductions in the leukocyte count, ANC, reticulocyte count, and platelet count. The 20 patients who received transfusions and hydroxyurea together had an average overlap of 6 ± 3 months (range, 3-15). These children had a shorter duration of hydroxyurea therapy compared with those with transfusions discontinued abruptly but had no significant differences in their laboratory responses to hydroxyurea (Table). Transfusions were formally discontinued only after full-dose hydroxyurea was tolerated with clinical and laboratory evidence of compliance. The overlap period was shortened (#4 months) for 3 patients with brisk hematologic responses to hydroxyurea whose elevated hemoglobin concentrations precluded further transfusions. The overlap period was extended (12 and 15 months) for 2 patients with poor compliance with the hydroxyurea treatment regimen.

Phlebotomy Regimen to Reduce Iron Overload Serial phlebotomy ($6 months) was performed on 26 children for an average duration of 30 ± 18 months (range, 774 months; Table). Most patients received phlebotomy every 4 weeks; shorter intervals were well tolerated but less convenient. During phlebotomy, no child had weakness or other symptoms suggestive of recurrent stroke. On rare occasions ( < 5% of procedures) a child became light-headed or dizzy; these symptoms resolved after lying flat with prompt intravenous fluid replacement. The average total volume of blood removed was 14,311 ± 12,459 mL ([315 ± 214 mL/kg]; range, 1810-50,376 mL [49-814 mL/kg]). Before phlebotomy, the average serum ferritin for these 26 children was 3134 ± 1788 ng/mL (median, 2722 ng/mL; range, 1025-8830). Latest values document an average serum ferritin of 617 ± 685 ng/mL (median value, 298 ng/mL; range, 69-2313). Fourteen children discontinued phlebotomy after their serum ferritin was < 200 ng/mL on two measurements.

Recurrent Neurologic Events on Hydroxyurea Therapy Seven children had new neurologic events (all infarctive CVA events, no transient ischemic attacks or seizures), for an The Journal of Pediatrics  September 2004

Table. Effects of hydroxyurea therapy in pediatric patients with SCA to prevent secondary stroke, with phlebotomy to reduce iron overload Abrupt discontinuation

Overlapping hydroxyurea

39 ± 32

15 7.8 ± 5.1 13.1 ± 4.9 None 55 ± 35

20 7.7 ± 2.5 11.1 ± 2.9 6±3 27 ± 23

26.7 ± 4.8 42 ± 30

26.0 ± 4.3 54 ± 34

27.2 ± 5.1 33 ± 24

9.2 ± 112 ± 18.6 ± 7.3 ± 3855 ± 186 ± 349 ±

9.3 113 15.4 7.1 3693 210 381

All patients No. of patients Age at primary stroke (y) Age at enrollment (y) Overlap with transfusions (mo) Duration off transfusions (mo) Hydroxyurea therapy Average dose (mg/kg/d) Duration of therapy (mo) Hematologic effects Hemoglobin concentration (g/dL) Mean corpuscular volume (fL) Fetal hemoglobin (%) White blood cell count (3109/L) Absolute neutrophil count (3106/L) Reticulocyte count (3109/L) Platelet count (3109/L) Phlebotomy $6 mo No. of patients Duration (mo) Volume blood removed (mL) Volume of blood removed (mL/kg) Initial ferritin (ng/mL) Latest ferritin (ng/mL) Phlebotomy discontinued (%) Recurrent neurologic events No. of patients (%) Recurrence rate (per 100 pt-years)

35 7.7 ± 3.7 11.9 ± 4.0

1.4 9 6.6 2.5 2288 116 131

26 30 ± 18 14,311 ± 12,459 315 ± 214 3134 ± 1788 617 ± 685 54

41 22,386 472 3952 372

7 (20) 5.7

± 1.3 ±9 ± 4.4 ± 2.2 ± 2055 ± 125 ± 164

9.1 ± 112 ± 20.3 ± 7.4 ± 3977 ± 169 ± 325 ±

10 ± 21 ± 14,540 ± 229 ± 2570 ± 687 90

16 22 ± 12 9263 ± 7825 217 ± 135 2622 ± 800 770 ± 659 31

5 (33) 7.4

1.6 8 6.9 2.7 2495 109 98

2 (10) 3.6

Enrollment and treatment characteristics are shown for all patients, followed by patients with abrupt discontinuation of transfusions and those with temporary overlap with hydroxyurea before discontinuation of transfusions.

overall stroke recurrence rate of 20% or 5.7 events per 100 patient-years. Four of these events occurred #4 months after initiating hydroxyurea, before achieving maximal hematologic effects, whereas another occurred after 15 months coincident with a febrile illness. This overall stroke recurrence rate for all 35 patients compares favorably with the published stroke recurrence rates for children with SCA receiving transfusion prophylaxis against secondary stroke (Figure, A). However, only 2 of the 20 children who temporarily overlapped hydroxyurea therapy with transfusions have had a second event, for a stroke recurrence rate of 10% or 3.6 events per 100 patient-years (Figure, B). Two patients had late recurrent neurologic events, both after discontinuing hydroxyurea therapy against medical advice. Upon reaching age 21 years, the original Duke patient24 stopped hydroxyurea after 56 months and had a fatal stroke 4 months later. A second patient discontinued hydroxyurea after 17 months, on reaching age 22 years, and had a recurrent hemiplegic stroke 4 months later. Overall, 4 of the 7 patients with stroke recurrence were noncompliant with

hydroxyurea therapy, and 3 were previously noncompliant with transfusions.

Assessment of End-Organ Damage and Iron Overload After discontinuation of their phlebotomy program, 14 patients were offered a percutaneous liver biopsy to assess hepatic histology and iron content. To date, 11 children have undergone this procedure, 2 families have moved away, and 1 family declined. Histologic review of the liver (n = 11) revealed minimal periportal fibrosis except for 1 patient with mild bridging fibrosis; no patient had evidence of cirrhosis. No or small amounts of iron (0 to 1+) were identified in the portal tracts, with minimal iron around the central vein. Quantitative iron measurement revealed a median of 1.61 mg iron (range, 0.77 to 4.59 mg; normal, 1.0 to 2.4 mg) per gram of dry weight liver. Cardiac function was assessed by echocardiography (n = 9) to measure left ventricular shortening fraction. Each child had a normal shortening fraction (median, 38%; range, 33% to 44%; normal value >30%).

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Analysis of Patients Who Failed Hydroxyurea Prophylaxis for Secondary Stroke Prevention The 7 children with secondary stroke on hydroxyurea therapy were older at enrollment than the 28 children without recurrent stroke (15.2 ± 4.0 vs 11.1 ± 3.6 years, P = .013). There were no statistically significant differences, however, in the prevalence of severe vessel stenosis or moya-moya vasculopathy (not shown). Concomitant medical illness at the time of primary stroke, which was recently suggested to portend a reduced secondary stroke rate,17 also was not significantly different between children who had a recurrent stroke on hydroxyurea therapy and those who did not. However, patients with secondary stroke had laboratory evidence of reduced hydroxyurea efficacy, from either inadequate duration of therapy or poor compliance. Specifically, these 7 children with a recurrent stroke on hydroxyurea therapy had less marrow suppression, including a significantly higher treatment ANC (P = .010), as well as trends toward a higher WBC count (P = .087) and a lower treatment %HbF (P = .11).

DISCUSSION Since initial reports of success 25 years ago,14,15 erythrocyte transfusions have been used to prevent secondary stroke in children with SCA. Because prospective studies have documented a high stroke recurrence rate after discontinuation of transfusions,29,30 most pediatric hematologists transfuse indefinitely in this setting.31 However, transfusional iron overload is increasingly recognized as a serious consequence of chronic erythrocyte transfusions in SCA, leading to hepatic fibrosis, cardiomyopathy, and death.22,32 Deferrioxamine (Desferal) chelation has numerous side effects and inconvenient subcutaneous administration; noncompliance is common.33 Indefinite erythrocyte transfusions without adequate chelation should not be considered acceptable long-term therapy for secondary stroke prevention in SCA. An alternative therapy to prevent stroke recurrence is needed, specifically one that also improves the treatment of iron overload. Hydroxyurea has proven hematologic efficacy for children and adults with SCA26,27 as well as clinical efficacy for reducing the frequency of acute vaso-occlusive events.34 Its efficacy for patients with cerebrovascular disease remains unproven, but hydroxyurea has hematologic effects that are theoretically advantageous for secondary stroke prevention. Hydroxyurea therapy leads to HbF induction, which inhibits intracellular HbS polymerization and improves erythrocyte rheology.35 Myelosuppression from hydroxyurea may also be important, since elevated WBC correlates with an increased risk of primary stroke in SCA.10 Short-term toxicities of hydroxyurea are minimal, and early concerns that hydroxyurea might increase stroke risk in SCA36,37 are not supported by large, prospective studies involving pediatric and adult patients with SCA.27,34,38,39 Our previous experience with abrupt discontinuation of transfusions suggested that hydroxyurea could help prevent 350

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Figure. Secondary stroke rates for children with SCA who switched from transfusions to hydroxyurea prophylaxis for prevention of recurrent stroke. Tick marks indicate the position of individual patients. A, Secondary stroke rate for all 35 children who switched from transfusions to hydroxyurea therapy is shown by long dashes, juxtaposed against published data for stroke recurrence on transfusion prophylaxis by Pegelow et al16 (short dashes) and Scothorn et al17 (solid line). B, Secondary stroke rates for the 35 children are illustrated according to transfusion overlap. Fifteen children had transfusions abruptly discontinued before initiation of hydroxyurea therapy, illustrated by the lower curve with short dashes; 20 patients continued transfusions with overlap until they tolerated full-dose hydroxyurea therapy, as illustrated in the top curve with long dashes. The recurrent stroke rate for the entire cohort of 35 pediatric patients is illustrated in the middle curve by the solid line.

secondary stroke in most children with SCA, but recurrent events could occur before the maximal effects of hydroxyurea therapy.25 The current data suggest that a defined overlap period with hydroxyurea escalation to MTD before discontinuing transfusions is more effective, although these two regimens were not compared in a randomized fashion. This overlap period allows maximal HbF induction and WBC The Journal of Pediatrics  September 2004

reduction before withdrawing transfusion prophylaxis, thereby lowering the risk of early secondary stroke. The secondary stroke rate on hydroxyurea for our entire cohort of 35 patients is 5.7 events per 100 patient-years, roughly equivalent to the secondary stroke rate on chronic transfusions (Figure, A); our patients with an overlap period had an even lower stroke recurrence rate of 3.6 events per 100 patient-years (Figure, B). Perhaps the greatest advantage of hydroxyurea therapy for secondary stroke prevention is the ability to reduce iron overload through the use of serial phlebotomy. With a hemoglobin concentration averaging 8 to 9 g/dL, removal of 10 mL/kg blood every 4 weeks was well tolerated. Compliance with this phlebotomy regimen was excellent, with normalization of serum ferritin similar to that observed in patients with thalassemia after transplantation.40 Serum ferritin normalized in our patients after serial phlebotomy, and liver biopsy specimens documented mobilization and elimination of hepatic storage iron. After phlebotomy was discontinued, there was no measurable decrease in the elevated %HbF levels, suggesting that phlebotomy does not confer substantial HbF induction beyond the powerful effect of hydroxyurea therapy. Phlebotomy offers an excellent alternative to deferrioxamine iron chelation, which is very expensive and difficult to tolerate. These single institution prospective pilot data suggest that hydroxyurea is an effective therapy for preventing secondary stroke in children with SCA. With an overlap period that allows escalation of hydroxyurea to MTD while still receiving transfusions, most affected children can later successfully discontinue transfusion prophylaxis. Phlebotomy can then reduce transfusional iron overload with biopsyproven resolution of transfusional iron overload. A phase III, multicenter trial is warranted to determine the efficacy and utility of this alternative therapeutic approach for children with SCA and stroke. We thank Shannon F. MacKeigan, MSN, PNP, for her efforts on this protocol, Patricia Palmer, MSN, for assistance with liver biopsies, the Pediatric Hematology/Oncology outpatient nursing staff for tireless phlebotomy, and Pediatric Services of America for home phlebotomy. Special thanks go to Drs Mark Ranalli, David Trauber, Lawrence Frankel, and Larry Herrera for clinical care of patients who moved from Duke, and Rho Inc. for statistical support.

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50 Years Ago in The Journal of Pediatrics NEWER THERAPEUTIC PROCEDURES DESIGNED TO PREVENT ABNORMAL PULMONARY VENTILATION IN THE NEWBORN INFANT

Bloxsom A. J Pediatr 1954;45:373-92 This article is worth digging out of the archives for several reasons. First, from the perspective of our own era where the development of advanced medical technology continues at a dizzying pace, the controversy from 50 years ago around a new, high-technology device is fascinating. The Bloxsom Air Lock was a pressurized incubator for premature infants, and its advocates claimed that application of the device improved outcome for newborns with pulmonary insufficiency. Critics, however, argued that the physiologic concepts on which it was based were flawed and that insufficient evaluation had been performed. Meanwhile, sale of this expensive device to nurseries was proliferating. Sounds like a familiar theme from more recent times. The editorial treatment of Dr Bloxsom’s paper, however, is just as interesting as the device. To help educate the readers without promoting the use of the device, the editor of The Journal sought commentaries from 10 clinicians and scientists, including luminaries of the day such as Clement Smith, Virginia Apgar, and Ashley Weech. Their responses were published as informal narratives, but occupy considerably more journal space than the manuscript itself. The results of a randomized, controlled trial on the efficacy of the Air Lock were published in 1956 and showed no benefit. However, before that time, use of the Air Lock had already precipitously declined due to the demonstrated association of uncontrolled oxygen therapy and retrolental fibroplasias. Interested readers can find a review of this technology in a recent review by Kendig et al.1 Thomas P. Green, MD Department of Pediatrics Children’s Memorial Hospital and Northwestern University Medical School Chicago, IL 60614 YMPD 1055 10.1016/j.jpeds.2004.07.011

REFERENCE 1.

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Kendig JW, Maples PG, Maisels MJ. The Bloxsom Air Lock: a historical perspective. Pediatrics 2001;108:e116:1-4.

Ware et al

The Journal of Pediatrics  September 2004