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OBJECTIVE: Standardized pain assessment and interventions are recommended for youth hospitalized for pain. This quality improvement (QI) project integrated into a pediatric psychology service aimed to increase the standardized assessment of pain-related functional ability for youth with sickle cell disease (SCD) hospitalized for pain. METHODS: Children and adolescents (n=102) with SCD referred for psychology consultation for poor coping in response to pain during hospitalization completed a validated self-report of functional ability in addition to pain intensity during inpatient psychology visits. At the time of the quality initiative, routine and standardized assessment of pain-related functional ability was not integrated into standard clinical care. Plan, Do, Study, Act (PDSA) cycles determined the feasibility and addressed common barriers of routine assessment and documentation of pain-related functional ability among youth with SCD during inpatient psychology visits with the primary goal to increase assessment of functional ability to at least 85% among patients with SCD referred for pediatric psychology consultation to address pain management within 1 year. RESULTS: Through iterative PDSA cycles, routine assessment of pain-related functional ability during psychology visits increased to an average of 93% over the course of 12 months. Routine, standardized assessment of functional ability was considered feasible within a pediatric psychology service. CONCLUSIONS/LESSONS LEARNED: This project supported the feasibility of integrating standardized assessment of functional ability to enhance pain assessment for youth hospitalized for SCD pain as part of routine clinical care in a multidisciplinary setting regardless of psychology referral.

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 increa...

BACKGROUND Although red blood cell (RBC) transfusion represents an integral component of sickle cell disease (SCD) care, transfusion support for some patients can result in alloimmunization to RBC antigens. Alloimmunized patients with SCD appear to experience worse survival compared to nonalloimmunized patients. While this difference in mortality may in part be due to underlying immunologic differences related to disease severity, it may also reflect direct clinical consequences of RBC alloimmunization. Alloimmunized patients have an increased risk of serious hemolytic transfusion reactions (HTRs) and may not receive adequate RBC transfusion support due to lack of compatible RBC units. CASE REPORT This study reports on five RBC alloimmunized patients with SCD who died, to illustrate the concept that RBC alloimmunization itself contributes to premature death. RESULTS The clinical course for each of the reported patients provides insight into the direct and indirect consequences of RBC alloimmunization, where patients experienced delayed HTRs or did not receive needed RBC transfusions. CONCLUSION Future work examining the clinical impact of RBC alloimmunization should not only consider HTRs but should also address the potential consequences associated with difficulties in obtaining compatible blood.

Physical function and functional recovery are important aspects of the acute pain experience in children and adolescents in hospitalized settings. Measures of function related to pediatric acute pain do not exist currently, limiting understanding of recovery in youth undergoing acute and procedural pain. To address this gap, we developed and assessed the clinical utility and preliminary validity of the Youth Acute Pain Functional Ability Questionnaire (YAPFAQ). We evaluated psychometric properties of this measure in 159 patients with sickle cell disease, ages 7 to 21 years, who were hospitalized for vaso-occlusive episodes at 4 urban children's hospitals. The YAPFAQ demonstrated strong internal reliability and test-retest reliability. An exploratory factor analysis was conducted to examine the preliminary factor structure and to help reduce the number of items for the final scale. Evidence for moderate construct validity was demonstrated among validated measures of pain burden, motor function, functional ability, and quality of life. The YAPFAQ is a new measure of youth functional ability in the acute pain setting. Further evaluation of this measure in additional pediatric populations is needed to understand applicability across a spectrum of youth experiencing acute pain related to illness, trauma, and medical/surgical procedures. Perspective Measures of function in response to acute pain are needed in order to more comprehensively evaluate acute pain interventions in pediatrics; however, no specific measures are available. Our preliminary psychometric evaluation of an acute pain functional ability measure for youth indicates that it may be a promising tool for further refinement in additional pediatric acute pain populations.

Children’s Healthcare of Atlanta, Atlanta, Georgia and Emory UniversityTransitioning from pediatric to adult care is a challenging process for adolescents withsickle cell disease (SCD). There is a critical need for well-designed and practicallyadaptable SCD transition programs that are compatible within the social and culturalcontext of the individual. The purpose of this article is to outline the design of atheoretically informed intervention to facilitate successful transition for adolescents andyoung adults (AYAs) diagnosed with SCD. The authors propose and describe the useof a developmental–ecological framework in creating and implementing the Sickle CellDisease–Age Based Curriculum for Transition (SCD-ABC). The SCD-ABC Transitionprogram’s framework begins at birth with the parent–caregiver and spans throughouta child’s development into young adulthood. This program involves a multidisciplinaryteam approach with collaboration from pediatric and adult medical providers, familyand peers, social services, the community, and adult mentors living with SCD. The goalof this program was to foster increased disease knowledge and self-efficacy for AYAs

Although elevated tricuspid regurgitant velocity (TRV), an echocardiographic marker for pulmonary hypertension, has previously been tied to mortality in adult patients with sickle cell disease, recent data demonstrated that it correlates poorly with catheterization findings. We describe the largest echocardiographic evaluation of pediatric patients with sickle cell disease to date, specifically the results of a protocol whereby a TRV≥250 cm/s prompted further evaluation. We investigated if elevated TRV would independently identify patients at risk for increased morbidity. A clinical echocardiographic database containing 630 patients with sickle cell disease was retrospectively reviewed; 120 patients (19%) met inclusion criteria and were compared 1:1 to randomly selected age-matched controls from the same database. By multivariate analysis, the elevated TRV cohort did not differ from controls in likelihood of acute chest episodes, hospitalization, or stroke. The study cohort's mean TRV in fact decreased to 242±33 cm/s at follow-up without a discernible and comprehensive intervention to explain the improvement. Three patients had catheterization-proven pulmonary hypertension. In conclusion, elevated TRV in children with sickle cell disease is less prevalent than previously thought and is not independently associated with increased short-term morbidity.

Background Prolonged hospitalizations for sickle cell disease painful episodes are not uncommon, as analgesic options are often suboptimal. Observations Seven patients (15.4 ± 3.7 y, 6 females) were treated with epidural analgesia for refractory pain. The median duration of epidural catheter placement was 4 days (interquartile range, 3 to 6 d). Mean pain scores changed from 6.8 ± 2.7 to 4.8 ± 2.2, whereas mean daily parenteral opioid requirements changed from 79.7 ± 100.4 to 13.0 ± 13.1 mg of morphine equivalents. Conclusion Continuous epidural analgesia is an alternative to continuing intravenous opioids in sickle cell disease patients with refractory pain, and may reduce opioid-related side effects and facilitate transition to oral analgesics.

The purpose of this study was to develop and validate a brief, clinically relevant, multidimensional interview to assess pain burden among children and adolescents with sickle cell disease (SCD). The Sickle Cell Disease Pain Burden Interview–Youth (SCPBI-Y) was developed using a panel of experts, patients, and caregivers. Validation was undertaken with children and youth with SCD, ages 7 to 21 years (N = 129), recruited from 4 urban children's hospitals. Participants were recruited from inpatient (n = 62) and outpatient (n = 67) settings. The SCPBI-Y demonstrated strong internal consistency reliability, cross-informant concordance (child-caregiver), and test-retest reliability (outpatient setting). Moderate construct validity was found with validated measures of functional ability, pain, and quality of life. The SCPBI-Y demonstrated construct validity using a contrasted group approach between youth in inpatient versus outpatient settings and by severity of SCD symptoms, suggesting that youth in inpatient settings and with higher disease severity exhibited greater pain burden. Discriminant validity was found between SCPBI-Y and mood. Our preliminary findings suggest that the SCPBI-Y is a valid and reliable multidimensional interview that can be used in different clinical settings to evaluate pain burden among children and adolescents with SCD. Perspective Multifaceted pain assessments are salient in providing optimal care to children and adolescents with SCD; however, current evaluations are lengthy and cumbersome to administer clinically. The current study introduces and validates a brief, clinically useful multidimensional interview to evaluate pain burden specific to youth with SCD.

Sickle cell disease, the most common hemo-globinopathy in the world, affects patient lives from early childhood. Effective care of sickle cell disease requires frequent medical monitoring, such as tracking the frequency, severity, and duration of painful events. Conventional monitoring includes paper- or web-based reporting diaries. These systems require that patients carry forms, which are easily lost, or laptop computers, which are impractical to scale to large populations. Both are prone to sporadic use by older adolescents due to lack of reminders. In this paper, we design and prototype a Sickle cell disease REporting and MOnitoring TElemedicine system (SickleREMOTE), aiming to resolve limitations of conventional monitoring diaries. This monitoring system is configured as automated short message service text (SMS-text) messages that arrive at a mobile phone anywhere on a cellular network. The messages may be reminders to encourage treatment adherence or questionnaires to collect self-assessed clinical data relating to treatment adjustments. Patients respond to the messages using pre-determined templates and a cloud database parses and stores messages automatically. Providers use a web-based interface to view, analyze, and download collected data. SickleREMOTE is developed by Georgia Institute of Technology in conjunction with Children's Healthcare of Atlanta (CHOA). System effectiveness will be evaluated using a trial of 30 adolescents with sickle cell disease and measured by response rate, time to response, error rate, and correspondence with data collected by telephone calls.

Thalidomide has previously been shown to have anti-angiogenic properties. More recently, clinical efficacy of this agent has been demonstrated in multiple myeloma and prostate cancer. Neuroblastoma is the most frequent solid tumor of the abdomen of childhood, yet children with this disease frequently have metastases at presentation. Such patients have a very poor prognosis with current therapies. Thus, new approaches are needed. We have previously shown that VEGF antagonists can inhibit neoangiogenesis and tumor growth in experimental neuroblastoma. In this study, we investigated the anti-angiogenic and anti-tumor properties of thalidomide in a xenograft model of human neuroblastoma. Tumors were induced in athymic mice using the human neuroblastoma cell line NGP. Intraperitoneal thalidomide (100 mg/kg/dose) or vehicle was administered beginning one week after implantation, and animals euthanized at six weeks. Thalidomide treatment did not significantly alter tumor growth as compared with controls. However, thalidomide suppressed angiogenesis, as demonstrated both by fluorescein angiography and immunohistochemical staining, and induced apoptosis of endothelial cells in neuroblastoma xenografts. Quantification of microvessel density demonstrated a significant reduction of vasculature in treated tumors (p

Vascular endothelial growth factor (VEGF) is a critical promoter of blood vessel growth during embryonic development and tumorigenesis. To date, studies of VEGF antagonists have primarily focused on halting progression in models of minimal residual cancer. Consistent with this focus, recent clinical trials suggest that blockade of VEGF may impede cancer progression, presumably by preventing neoangiogenesis. However, VEGF is also a key mediator of endothelial–vascular mural cell interactions, a role that may contribute to the integrity of mature vessels in advanced tumors. Here, we report that high-affinity blockade of VEGF, using the recently described VEGF-Trap, abolishes mature, preexisting vasculature in established xenografts. Eradication of vasculature is followed by marked tumor regression, including regression of lung micrometastases. Thus, the contribution of relatively low levels of VEGF to vessel integrity may be critical to maintenance of even very small tumor masses. Potent blockade of VEGF may provide a new therapeutic option for patients with bulky, metastatic cancers.

Hepatoblastoma is the most common primary hepatic malignancy of childhood, frequently presenting as advanced disease. Vascular endothelial growth factor (VEGF) is an endothelial mitogen and survival factor critical to growth and angiogenesis in many human cancers. Inhibition of VEGF effectively suppresses tumorigenesis in multiple experimental models. The authors hypothesized that anti-VEGF antibody would alter vascular architecture and impede tumor growth in experimental hepatoblastoma.The Institutional Animal Care and Use Committee of Columbia University approved all protocols. Xenografts were established in athymic mice by intrarenal injection of cultured human hepatoblastoma cells. Anti-VEGF antibody (100 microg/dose) or vehicle was administered intraperitoneally 2 times per week for 5 weeks. At week 6, 10 control/treated mice were killed and remaining animals maintained without treatment until week 8. Tumor weights were compared by Kruskal-Wallis analysis, and vascular alterations ascertained by fluorescein angiography and specific immunostaining.Anti-VEGF antibody significantly inhibited tumor growth at 6 weeks (1.85 g +/- 0.60 control, 0.05 +/- 0.03 antibody, P.0003). In comparison with controls, treated xenografts showed decreased vascularity and dilated surviving vessels with prominent vascular smooth muscle elements.Specific anti-VEGF therapy inhibits neoangiogenesis and significantly suppresses tumor growth in experimental hepatoblastoma. Surviving vasculature displays dilation and increased vascular smooth muscle. Anti-VEGF agents may represent new therapeutic alternatives for children with advanced disease.

Vascular endothelial growth factor (VEGF) plays a key role in human tumor angiogenesis. We compared the effects of inhibitors of VEGF with different specificities in a xenograft model of neuroblastoma. Cultured human neuroblastoma NGP-GFP cells were implanted intrarenally in nude mice. Three anti-VEGF agents were tested: an anti-human VEGF 165 RNA-based fluoropyrimidine aptamer; a monoclonal anti-human VEGF antibody; and VEGF-Trap, a composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to an Fc segment of IgG1. A wide range of efficacy was observed, with high-dose VEGF-Trap causing the greatest inhibition of tumor growth (81% compared with controls). We examined tumor angiogenesis and found that early in tumor formation, cooption of host vasculature occurs. We postulate that this coopted vasculature serves as a source of blood supply during the initial phase of tumor growth. Subsequently, control tumors undergo vigorous growth and remodeling of vascular networks, which results in disappearance of the coopted vessels. However, if VEGF function is blocked, cooption of host vessels may persist. Persistent cooption, therefore, may represent a novel mechanism by which neuroblastoma can partly evade antiangiogenic therapy and may explain why experimental neuroblastoma is less susceptible to VEGF blockade than a parallel model of Wilms tumor. However, more effective VEGF blockade, as achieved by high doses of VEGF-Trap, can lead to regression of coopted vascular structures. These results demonstrate that cooption of host vasculature is an early event in tumor formation, and that persistence of this effect is related to the degree of blockade of VEGF activity.

Background: Pulmonary function is particularly susceptible to acute and chronic injury occurring in patients with sickle cell anemia (SCA). Acute Chest Syndrome (ACS), a common and potentially fatal complication of SCA, can be the cause or the consequence of abnormal pulmonary function (Siddiqui & Ahmed, 2003). Use of hydroxyurea therapy (HU) is increasing for children with recurrent pulmonary complications, following the findings that HU reduces risk of ACS in adults (Charache et al, 1995). How HU may improve pulmonary function in children with SCA is still ill-defined. The purpose of this study was to assess the change observed on serial pulmonary function tests (PFT) for children prescribed HU for abnormal pulmonary function. Methods: Over 240 children with pulmonary complications, such as acute chest syndrome, reactive airway disease, and chronic hypoxia, have been evaluated in the Sickle Cell Pulmonary Clinic at Children’s Healthcare of Atlanta since beginning in July 2000. As part of the Clinic’s standard of care, PFT were routinely attempted on children over the age of 5. A retrospective review of PFT results was done for the children with SCA and prior abnormal PFT. Children were included in the HU cohort (+HU) if repeat PFTs were available following > 3 months on HU therapy and if time on HU did not include frequent RBC transfusions. Children without history of HU therapy (−HU) were selected for comparison. PFTs were performed on a standard plethysmograph. Paired t-test was used to evaluate observed differences. Results: Thirty-one children with prior abnormal PFT had test before and following prescription of HU. Their mean age was 12.6 (range 6–20) years and mean duration of HU was 21 (range 4–47) months at the time of the repeat PFT. Hematologic changes expected on HU occurred for all 31 children. Twenty-four children followed for abnormal PFT had no history of HU (−HU) and matched the +HU group by gender, age (mean 12.3, range 7–19 years), duration followed at time of repeat PFT (mean 19, range 3–66 months; p=0.36), and initial hematologic parameters. Spirometry findings changed for +HU group, and remained stable for −HU group. Mean FVC and FEV1 values improved significantly on HU, when compared to initial (PreHU) PFT and to −HU controls. Conversion to a normal PFT, as interpreted by a pediatric pulmonologist masked to treatment status, occurred in 18 (58%) and 2 (8%) children in the +HU and −HU groups, respectively. Table 1: Serial PFT and hematologic parameters according to HU exposure −HU (n=24) +HU (n=31) Initial Repeat # PreHU Repeat 1 % predicted value for age, sex and height of subject. 2Mean (SD) #No significant changes compared to Initial, p > 0.05. *P value < 0.001 compared to PreHU; ++P value < 0.001 compared to −HU repeat. PFT parameter 1 TLC 88 (13.6)2 85 (11.7) 85 (13.4) 90 (13.5) FVC 78 (9.8) 79 (9.9) 75 (12.6) 90 (13.2)*,++ FEV1 75 (9.6) 74 (12.2) 72 (11.4) 86 (10.2)*,++ FEF 25-75 75 (22) 72 (28.0) 77 (23.4) 79 (26.8) FEV1/FVC (%) 85(6.7) 82 (9.8) 87 (11.8) 86 (11.1) Pulse oximetry (%) 95 (3.1) 96 (2.4) 94 (4.4) 97 (2.8)* WBC (x103/ul) 14 (3.8) 13 (2.9) 13.02 (2.9) 9.0 (2.1) *,++ Hb (g/dl) 8.0 (0.1) 8.0 (0.9) 7.8 (1.1) 9.1 (1.3) *,++ MCV (fl) 84 (9.2) 85 (10.0) 87.3 (8.1) 101.2 (10.1) *,++ HbF (%) 4.3 (1.5) 5.2 (5.2) 6.0 (3.8) 14.0 (7.3) *,++ Conclusions: Serial PFTs showed improved pulmonary function, following initiation of HU therapy in children with prior abnormal PFT. Routine PFT assessments of children prescribed HU may serve as an objective measure of clinical response in children with SCA and pulmonary complications. These results will help in the design of future prospective studies examining the clinical benefits of HU therapy for children at risk for long-term pulmonary complications.