Modifications to therapeutic plasma exchange to achieve rapid exchange on cardiopulmonary bypass prior to pediatric cardiac transplant.

BACKGROUND: Cardiac transplants increasingly occur following placement of ventricular assist devices (VADs). A strong association exists between human leukocyte antigen (HLA) sensitization and VAD placement; however, desensitization protocols that utilize therapeutic plasma exchange (TPE) are fraught with technical challenges and are at increased risk of adverse events. In response to increased VAD utilization in our pre-transplant population, we developed a new institutional standard for TPE in the operating room. METHODS: Through a multidisciplinary effort, we developed an institutional protocol for intraoperative TPE immediately prior to cardiac transplantation after cannulation onto cardiopulmonary bypass (CPB). All procedures used the standard TPE protocol on the Terumo Optia (Terumo BCT, Lakewood, CO, USA), but incorporated multiple modifications to limit patients' bypass times, and to coordinate with the surgical teams. These modifications included deliberate misidentification of replacement fluid and maximization of the citrate infusion rate. RESULTS: These adjustments allowed the machine to run at maximal inlet speeds, minimizing duration of TPE. To date, 11 patients have been treated with this protocol. All survived their cardiac transplantation operation. Hypocalcemia and hypotension were noted; however, none of these adverse events appeared to have clinical impact. Technical complications included unexpected fibrin deposition in the TPE circuit and air in the inlet line due to surgical manipulation of the CPB cannula. No thromboembolic complications occurred in any patient. CONCLUSION: We feel that this procedure can be rapidly and safely performed in HLA sensitized pediatric patients on CPB to limit the risk of antibody mediated rejection of their heart transplant.

Strain Echocardiography and Myocardial Dysfunction in Critically Ill Children With Multisystem Inflammatory Syndrome Unrecognized by Conventional Echocardiography: A Retrospective Cohort Analysis.

OBJECTIVES: Multisystem inflammatory syndrome in children is a newly defined complication of severe acute respiratory syndrome coronavirus 2 infection that can result in cardiogenic shock in the pediatric population. Early detection of cardiac dysfunction is imperative in directing therapy and identifying patients at highest risk for deterioration. This study compares the strengths of conventional and strain echocardiography in identifying cardiac dysfunction in critically ill children with multisystem inflammatory syndrome in children and their association with ICU therapeutic needs and clinical outcomes. DESIGN: Retrospective, observational cohort study. SETTING: A large, quaternary care PICU. PATIENTS: Sixty-five pediatric patients admitted to the PICU with the diagnosis of multisystem inflammatory syndrome in children from March 2020 to March 2021. INTERVENTIONS: Global longitudinal strain four chamber was measured retrospectively by strain echocardiography and compared with conventional echocardiography. Cardiac dysfunction was defined by left ventricular ejection fraction less than 55% and global longitudinal strain four chamber greater than or equal to -17.2%. Clinical variables examined included cardiac biomarkers, immune therapies, and ICU interventions and outcomes. MEASUREMENTS AND MAIN RESULTS: Twenty-four patients (37%) had abnormal left ventricular ejection fraction and 56 (86%) had abnormal global longitudinal strain four chamber. Between patients with normal and abnormal left ventricular ejection fraction, we failed to identify a difference in cardiac biomarker levels, vasoactive use, respiratory support needs, or ICU length of stay. Global longitudinal strain four chamber was associated with maximum cardiac biomarker levels. Abnormal global longitudinal strain four chamber was associated with greater odds of any vasoactive use (odds ratio, 5.8; 95% CI, 1.3-25.3; z-statistic, 2.3; p = 0.021). The number of days of vasoactive infusion was correlated with global longitudinal strain four chamber (r = 0.400; 95% CI, 2.4-3.9; p < 0.001). Children with abnormal strain had longer ICU length of stay (4.5 d vs 2 d; p = 0.014). CONCLUSIONS: Our findings suggest strain echocardiography can detect abnormalities in cardiac function in multisystem inflammatory syndrome in children patients unrecognized by conventional echocardiography. These abnormalities are associated with increased use of intensive care therapies. Evaluation of these patients with strain echocardiography may better identify those with myocardial dysfunction and need for more intensive therapy.

Cardiac echocardiogram findings of severe acute respiratory syndrome coronavirus-2-associated multi-system inflammatory syndrome in children.

BACKGROUND: A novel paediatric disease, multi-system inflammatory syndrome in children, has emerged during the 2019 coronavirus disease pandemic. OBJECTIVES: To describe the short-term evolution of cardiac complications and associated risk factors in patients with multi-system inflammatory syndrome in children. METHODS: Retrospective single-centre study of confirmed multi-system inflammatory syndrome in children treated from 29 March, 2020 to 1 September, 2020. Cardiac complications during the acute phase were defined as decreased systolic function, coronary artery abnormalities, pericardial effusion, or mitral and/or tricuspid valve regurgitation. Patients with or without cardiac complications were compared with chi-square, Fisher's exact, and Wilcoxon rank sum. RESULTS: Thirty-nine children with median (interquartile range) age 7.8 (3.6-12.7) years were included. Nineteen (49%) patients developed cardiac complications including systolic dysfunction (33%), valvular regurgitation (31%), coronary artery abnormalities (18%), and pericardial effusion (5%). At the time of the most recent follow-up, at a median (interquartile range) of 49 (26-61) days, cardiac complications resolved in 16/19 (84%) patients. Two patients had persistent mild systolic dysfunction and one patient had persistent coronary artery abnormality. Children with cardiac complications were more likely to have higher N-terminal B-type natriuretic peptide (p = 0.01), higher white blood cell count (p = 0.01), higher neutrophil count (p = 0.02), severe lymphopenia (p = 0.05), use of milrinone (p = 0.03), and intensive care requirement (p = 0.04). CONCLUSION: Patients with multi-system inflammatory syndrome in children had a high rate of cardiac complications in the acute phase, with associated inflammatory markers. Although cardiac complications resolved in 84% of patients, further long-term studies are needed to assess if the cardiac abnormalities (transient or persistent) are associated with major cardiac events.

Tricuspid regurgitation velocity and other biomarkers of mortality in children, adolescents and young adults with sickle cell disease in the United States: The PUSH study.

In the US, mortality in sickle cell disease (SCD) increases after age 18-20 years. Biomarkers of mortality risk can identify patients who need intensive follow-up and early or novel interventions. We prospectively enrolled 510 SCD patients aged 3-20 years into an observational study in 2006-2010 and followed 497 patients for a median of 88 months (range 1-105). We hypothesized that elevated pulmonary artery systolic pressure as reflected in tricuspid regurgitation velocity (TRV) would be associated with mortality. Estimated survival to 18 years was 99% and to 25 years, 94%. Causes of death were known in seven of 10 patients: stroke in four (hemorrhagic two, infarctive one, unspecified one), multiorgan failure one, parvovirus B19 infection one, sudden death one. Baseline TRV ≥2.7 m/second (>2 SD above the mean in age-matched and gender-matched non-SCD controls) was observed in 20.0% of patients who died vs 4.6% of those who survived (P = .012 by the log rank test for equality of survival). The baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. Additional biomarkers associated with mortality were ferritin ≥2000 µg/L (observed in 60% of patients who died vs 7.8% of survivors, P < .001), forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80 (71.4% of patients who died vs 18.8% of survivors, P < .001), and neutrophil count ≥10x109 /L (30.0% of patients who died vs 7.9% of survivors, P = .018). In SCD children, adolescents and young adults, steady-state elevations of TRV, ferritin and neutrophils and a low FEV1/FVC ratio may be biomarkers associated with increased risk of death.

Myocardial strain can be measured from first trimester fetal echocardiography using velocity vector imaging.

OBJECTIVES: Alterations in myocardial strain can identify cardiac dysfunction and can be measured in the mid-gestation fetus. This study evaluates feasibility of strain measurements in early fetuses and establishes normal early fetal strain values. METHODS: Normal fetal echocardiograms were reviewed for image adequacy for strain measurements in 12- to 14-week gestation fetuses. Two readers performed independent strain measurements. Values were compared with data from 40 normal second trimester fetuses. RESULTS: Strain evaluation could be attempted in 36 of 53 (68%) of first trimester echocardiograms (mean gestation 13.4 weeks); excessive motion or inadequate imaging planes precluded tracking analysis in the remainder. Strain measurements were feasible in 19 of 53 fetuses (36%, or 53% of those in whom tracking was attempted). Peak systolic global longitudinal left ventricular (RV) and right ventricular (LV) strain were similar (LV = -13.9 ± 5.7%, RV = -14.4 ± 5.5%, p = 0.7). RV strain was higher in first trimester fetuses compared with second trimester normals (p = 0.003). Intraobserver and interobserver agreement were moderate to strong for peak global LV and RV strain but poor for regional basal and mid-septal segments. CONCLUSIONS: Strain measurements were feasible in one-third of retrospectively assessed early fetal echocardiograms. Global longitudinal strain may be higher in earlier than mid-gestation fetuses. © 2016 John Wiley & Sons, Ltd.

Pediatric Dilated Cardiomyopathy Patients Do Not Meet Traditional Cardiac Resynchronization Criteria.

INTRODUCTION: Cardiac resynchronization therapy (CRT) is an effective device-based intervention for adults with heart failure (HF) with specific indications, based on large, multicenter randomized clinical trials. The criteria for CRT in adult HF include significant symptoms, ventricular systolic dysfunction, prolonged QRS duration, and left bundle branch block (LBBB) pattern on electrocardiogram (ECG). Despite having less data, CRT is also being widely utilized in children with HF. The shortage of evidence-based CRT criteria in pediatrics prompted us to review a cohort of children with dilated cardiomyopathy and evaluate their potential eligibility for CRT using the traditional adult criteria. METHODS: Single-center data of all pediatric patients with dilated cardiomyopathy were extracted from the heart failure registry and retrospectively reviewed. Patients who had at least 2 separate visits that included HF scoring, electrocardiogram, and echocardiogram were included. Patients who were ventricular paced were excluded. RESULTS: Data for 52 patients meeting inclusion criteria were analyzed. The mean ejection fraction was 25% on the first clinical evaluation and 27% on the second visit. No patient and 2 patients met the adult criteria for prolonged QRS on the first and second encounters, respectively. No patients had an LBBB pattern on ECG. CONCLUSIONS: None of the pediatric HF patients in our study met the published Class I criteria for CRT device therapy in adults. These findings suggest that extrapolation of adult HF data to pediatrics is not sufficient for CRT criteria. Specific guidelines for device implantation in children must be based on scientific investigation including pediatric clinical trials.

Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia.

Obstructive and restrictive pulmonary changes develop in children with sickle cell disease, but reports conflict as to the type of change that predominates. We prospectively performed spirometry, plethysmography, and lung diffusing capacity in 146 children aged 7 to 20 years with hemoglobin SS or Sß(0)-thalassemia. Nineteen percent of the patients had obstructive physiology as defined according to guidelines of the American Thoracic Society. In addition, 9% had restrictive physiology and 11% had abnormal but not categorized physiology. Increasing age, patient-reported or family-reported history of asthma or wheezing, and higher lactate dehydrogenase concentration were independent predictors of obstruction as reflected in lower forced expiratory volume in the first second/forced vital capacity. In conclusion, abnormal pulmonary function, most often obstructive, is common in children with hemoglobin SS and Sß(0)-thalassemia. Full pulmonary function testing should be performed in children with hemoglobin SS or Sß(0)-thalassemia, especially with history of asthma or wheezing and accentuated elevations in hemolytic markers.

Vosoritide treatment for children with hypochondroplasia: a phase 2 trial.

Background: Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in FGFR3. It presents with disproportionate short stature with a wide range of clinical severity. There are currently no approved medications to treat short stature in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide analog that was recently approved for improving growth in children with achondroplasia. We aimed to evaluate the safety and efficacy of vosoritide in children with hypochondroplasia. Methods: We conducted a single-arm, phase 2, open-label trial at a single centre in the USA and enrolled 26 children with hypochondroplasia. The trial consists of a 6-month observation period to establish a baseline annualized growth velocity followed by a 12-month intervention period during which vosoritide is administered daily via subcutaneous injection at a dose of 15 µg/kg/day. The trial's co-primary endpoints included the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height standardized deviation score (SDS) after 12 months of treatment. This trial is registered with ClinicalTrials.gov (NCT04219007). Findings: Twenty-four participants with a mean age of 5.86 years received vosoritide therapy. The first participant was enrolled on August 4, 2020, and the final participant completed the 18-month trial on September 8, 2023. Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. Hypochondroplasia specific height SDS increased by 0.38 SD. There was a 1.81 cm/year increase in absolute annualized growth velocity. Interpretation: Vosoritide was safe and effective in increasing growth velocity in children with hypochondroplasia. Efficacy was similar to what has been reported in children with achondroplasia. Funding: This study was supported by an investigator-initiated grant from BioMarin Pharmaceutical.

Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease.

OBJECTIVES: We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study. METHODS: Patients with hemoglobin SS (n = 376) and other sickle cell genotypes (n = 127) aged 3-20 yrs were studied at four centers in a cross-sectional manner. A subgroup (n = 293) was followed for a median of 21 months (range 9-35). RESULTS: A patient-reported history of one or more acute pulmonary events, either acute chest syndrome (ACS) or pneumonia, was obtained in 195 hemoglobin SS patients (52%) and 51 patients with other genotypes (40%). By logistic regression, history of acute pulmonary events was independently associated with patient-reported history of asthma (P < 0.0001), older age (P = 0.001), >3 severe pain episodes in the preceding 12 months (P = 0.002), higher tricuspid regurgitation velocity (TRV) (P = 0.028), and higher white blood cell (WBC) count (P = 0.043) among hemoglobin SS patients. History of acute pulmonary events was associated with >3 severe pain episodes (P = 0.009) among patients with other genotypes. During follow-up, 43 patients (15%) had at least one new ACS episode including 11 without a baseline history of acute pulmonary events. History of acute pulmonary events (odds ratio 5.0; P < 0.0001) and younger age (odds ratio 0.9; P = 0.007) were independently associated with developing a new episode during follow-up. CONCLUSIONS: Asthma history, frequent pain, and higher values for TRV and WBC count were independently associated with history of acute pulmonary events in hemoglobin SS patients and frequent pain was associated in those with other genotypes. Measures to reduce pain episodes and control asthma may help to decrease the incidence of acute pulmonary events in SCD.

Risk Factors for Symptomatic Pericardial Effusions Posthematopoietic Stem Cell Transplant.

Background: Pericardial effusions are a known complication posthematopoietic stem cell transplant (HSCT), causing significant morbidity. We aimed to evaluate the risk factors associated with the development of high-grade effusions requiring interventions. Procedure. A retrospective chart review of all HSCT patients over a period of 7 years (2013-2019) in a single institution in the Northeastern United States is conducted. All patients who developed an effusion requiring intervention were included. Patient's clinical characteristics were compared with all others transplanted during the same time period. Echocardiogram findings of the affected patients were compared to a case-control cohort of unaffected patients with similar age and diagnosis. Chi-square and paired t-tests were utilized to ascertain statistical differences between the groups. Results: A total of 15 patients out of 201 (7.5%) transplanted at our institution developed a moderate or large pericardial effusion requiring pericardiocentesis or a pericardial window. Of this cohort, 13 (87%) underwent a myeloablative preparative regimen, 13 (87%) had cyclophosphamide as part of their regimen, 13 (87%) had recent treatment for viral reactivation, 6 (40%) had an underlying hemoglobinopathy diagnosis, and only 4 (27%) had an active diagnosis of GVHD. A myeloablative preparative regimen had a higher rate of effusion requiring intervention, although it was not statistically significant, and concurrent GVHD was not predictive of effusion development. However, exposure to cyclophosphamide, recent treatment for viral reactivation, and a diagnosis of transplant-associated thrombotic microangiopathy (Ta-TMA) were highly associated with effusions. The latter was associated with increased mortality. The duration of pericardial effusion correlated with the pretransplant echocardiogram left ventricle end diastolic diameter z-score and apical 4-chamber left ventricular peak average strain measurement. Conclusions: Potential risk factors for pericardial effusions post-HSCT include a diagnosis of Ta-TMA, active viral infection, exposure to cyclophosphamide, and a higher left ventricle end diastolic diameter z-score. This information may help guide management for these patients, including identifying high-risk subjects, determining the frequency of echocardiograms, and determining specific echocardiogram measures to follow over time.

Clinical outcomes and safety of anakinra in the treatment of multisystem inflammatory syndrome in children: a single center observational study.

BACKGROUND AND OBJECTIVE: Evidence for the treatment of multisystem inflammatory syndrome in children (MIS-C) is lacking. Anakinra, which targets IL-1-mediated inflammation, is reserved for refractory cases of MIS-C; however, its use in the treatment of MIS-C is not clearly established. PATIENTS AND METHODS: To examine a role for anakinra in MIS-C, we performed a single center observational cohort study of all MIS-C patients diagnosed at our children's hospital from May 15 to November 15, 2020. Demographics, clinical features, diagnostic testing, and cardiac function parameters were compared between MIS-C patients treated with intravenous immunoglobulin (IVIG) monotherapy and IVIG with anakinra (IVIG + anakinra). RESULTS: Among 46 patients with confirmed MIS-C, 32 (70%) were in the IVIG + anakinra group, of which 9 (28%) were also given corticosteroids (CS). No patients were treated with anakinra alone. MIS-C patients in the IVIG + anakinra group were enriched in a CV shock phenotype (p = 0.02), and those with CV shock were treated with higher doses of anakinra for a longer duration. Furthermore, MIS-C patients in the IVIG + anakinra group exhibited improvements in fever and cardiac function with or without CS. No significant adverse events were observed, and no differences in IL-1ß levels were found among MIS-C patients in the IVIG + anakinra group. CONCLUSIONS: Anakinra treatment, which was co-administered with IVIG primarily in patients with severe MIS-C, was associated with improvements in fever and cardiac function, and demonstrated a favorable side-effect profile. These findings suggest a role for adjunctive anakinra in the treatment of severe MIS-C.

Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia.

OBJECTIVE: To identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of patients with sickle cell anemia (SCA) enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease. STUDY DESIGN: Clinical and laboratory characteristics of children with SCA who had ≥3 severe pain crises requiring health care in the preceding year were compared with those of subjects with <3 such episodes. RESULTS: Seventy-five children (20%) reported ≥3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR, 1.2; 95% CI, 1.1-1.3; P < .0001), α-thalassemia trait (OR 3.5; 1.6-6.7; P = .002), higher median hemoglobin (OR 1.7; 95% CI: 1.2-2.4; P < .003), and lower lactate dehydrogenase concentration (OR 1.82; 95% CI: 1.07-3.11; P = .027). Children with high pain frequency also had an increased iron burden (serum ferritin, 480 vs 198 µg/L; P = .006) and higher median tricuspid regurgitation jet velocity (2.41 vs 2.31 m/s; P = .001). Neither hydroxyurea use nor fetal hemoglobin levels were significantly different according to severe pain history. CONCLUSIONS: In our cohort of children with SCA, increasing age was associated with higher frequency of severe pain episodes as were α-thalassemia, iron overload, higher hemoglobin and lower lactate dehydrogenase concentration, and higher tricuspid regurgitation velocity.

Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia).

BACKGROUND: Patients with Chuvash polycythemia, (homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL)), have elevated levels of hypoxia inducible factors HIF-1 and HIF-2, often become iron-deficient secondary to phlebotomy, and have elevated estimated pulmonary artery pressure by echocardiography. The objectives of this study were to provide a comprehensive echocardiographic assessment of cardiovascular physiology and to identify clinical, hematologic and cardiovascular risk factors for elevation of tricuspid regurgitation velocity in children and adults with Chuvash polycythemia. DESIGN AND METHODS: This cross-sectional observational study of 120 adult and pediatric VHL(R200W) homozygotes and 31 controls at outpatient facilities in Chuvashia, Russian Federation included echocardiography assessment of pulmonary artery pressure (tricuspid regurgitation velocity), cardiac volume, and systolic and diastolic function, as well as hematologic and clinical parameters. We determined the prevalence and risk factors for elevation of tricuspid regurgitation velocity in this population and its relationship to phlebotomy. RESULTS: The age-adjusted mean ± SE tricuspid regurgitation velocity was higher in VHL(R200W) homozygotes than controls with normal VHL alleles (2.5±0.03 vs. 2.3±0.05 m/sec, P=0.005). The age-adjusted left ventricular diastolic diameter (4.8±0.05 vs. 4.5±0.09 cm, P=0.005) and left atrial diameter (3.4±0.04 vs. 3.2±0.08 cm, P=0.011) were also greater in the VHL(R200W) homozygotes, consistent with increased blood volume, but the elevation in tricuspid regurgitation velocity persisted after adjustment for these variables. Among VHL(R200W) homozygotes, phlebotomy therapy was associated with lower serum ferritin concentration, and low ferritin independently predicted higher tricuspid regurgitation velocity (standardized beta=0.29; P=0.009). CONCLUSIONS: Children and adults with Chuvash polycythemia have higher estimated right ventricular systolic pressure, even after adjustment for echocardiography estimates of blood volume. Lower ferritin concentration, which is associated with phlebotomy, independently predicts higher tricuspid regurgitation velocity (www.clinicaltrials.gov identifier NCT00495638).

Relationship of erythropoietin, fetal hemoglobin, and hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease.

Hydroxyurea and higher hemoglobin F improve the clinical course and survival in sickle cell disease, but their roles in protecting from pulmonary hypertension are not clear. We studied 399 children and adolescents with sickle cell disease at steady state; 38% were being treated with hydroxyurea. Patients on hydroxyurea had higher hemoglobin concentration and lower values for a hemolytic component derived from 4 markers of hemolysis (P < or = .002) but no difference in tricuspid regurgitation velocity compared with those not receiving hydroxyurea; they also had higher hemoglobin F (P < .001) and erythropoietin (P = .012) levels. Hemoglobin F correlated positively with erythropoietin even after adjustment for hemoglobin concentration (P < .001). Greater hemoglobin F and erythropoietin each independently predicted higher regurgitation velocity in addition to the hemolytic component (P < or = .023). In conclusion, increase in hemoglobin F in sickle cell disease may be associated with relatively lower tissue oxygen delivery as reflected in higher erythropoietin concentration. Greater levels of erythropoietin or hemoglobin F were independently associated with higher tricuspid regurgitation velocity after adjustment for degree of hemolysis, suggesting an independent relationship of hypoxia with higher systolic pulmonary artery pressure. The hemolysis-lowering and hemoglobin F-augmenting effects of hydroxyurea may exert countervailing influences on pulmonary blood pressure in sickle cell disease.

Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia.

BACKGROUND: While in adults with sickle cell disease an elevation of tricuspid regurgitation velocity is associated with increased mortality, the importance of this finding in children has not been established. The role of intravascular hemolysis in the development of this complication is controversial. DESIGN AND METHODS: We conducted a prospective, longitudinal, multi-center study of 160 individuals aged 3-20 years with hemoglobin SS, performing baseline and follow-up determinations of clinical markers, six-minute walk distance less than tricuspid regurgitation velocity and E/Etdi ratio by echocardiography. RESULTS: At baseline, 14.1% had tricuspid regurgitation velocity of 2.60 m/sec or over, which suggests elevated systolic pulmonary artery pressure, and 7.7% had increased E/Etdi, which suggests elevated left ventricular filling pressure. Over a median of 22 months, baseline elevation in tricuspid regurgitation velocity was associated with an estimated 4.4-fold increase in the odds of a 10% or more decline in age-standardized six-minute-walk distance (P = 0.015). During this interval, baseline values above the median for a hemolytic component derived from four markers of hemolysis were associated with a 9.0-fold increase in the odds of the new onset of elevated tricuspid regurgitation velocity (P = 0.008) and baseline E/Etdi elevation was associated with an estimated 6.1-fold increase in the odds (P = 0.039). In pathway analysis, higher baseline hemolytic component and E/Etdi predicted elevated tricuspid regurgitation velocity at both baseline and follow up, and these elevations in turn predicted decline in six-minute-walk distance. CONCLUSIONS: Further studies should define the long-term risks of elevated tricuspid regurgitation velocity in childhood and identify potential interventions to prevent increased pulmonary artery pressure and preserve function.

Predictors of osteoclast activity in patients with sickle cell disease.

BACKGROUND: Bone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. DESIGN AND METHODS: We examined tartrate-resistant acid phosphatase 5b concentrations in patients with sickle cell disease and normal controls of similar age and sex distribution at steady state. Serum tartrate-resistant acid phosphatase 5b concentration was measured using an immunocapture enzyme assay and plasma concentrations of other cytokines were assayed using the Bio-Plex suspension array system. Tricuspid regurgitation velocity, an indirect measure of systolic pulmonary artery pressure, was determined by echocardiography. RESULTS: Tartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively; P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=-0.28, P=0.031) concentrations, but not with serum ferritin concentration. Frequent blood transfusions (>10 units in life time) were not associated with higher tartrate-resistant acid phosphatase 5b levels in multivariate analysis. There were strong correlations among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). CONCLUSIONS: Patients with sickle cell disease have increased osteoclast activity as reflected by serum tartrate-resistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease.

Cardiac changes in pediatric cancer survivors.

Cardiac damage from chemotherapy is a known phenomenon leading to significant morbidity and mortality in the cancer surviving population, and identifying high-risk pediatric patients early is challenging. The purpose of this pilot study was to evaluate whether echo strain, cardiac MRI (CMR), and serum biomarkers are more sensitive methods for detecting cardiac toxicity than standard echo and to examine the relationship between biomarkers in patients without decreased systolic function as determined by standard echo. In this pilot study, we prospectively enrolled pediatric subjects after completion of anthracycline inclusive chemotherapy. Each subject underwent a post-treatment echocardiogram (standard with strain), serum biomarkers (N-terminal brain natriuretic peptide (NT-pro-BNP) and interleukin 1 receptor-like 1 protein (ST2)), and CMR (standard and extracellular volumes (ECVs)). We correlated the markers using Pearson correlation. We enrolled 30 subjects, 11F/19M, aged 8-21 years. Cumulative anthracycline dose (CAD) correlated with BNP (p=0.06), CMR ECV 4-chamber (p=0.05) and sagittal (p=0.01), and mitral valve E/A (p=0.02). BNP correlated with CMR ECV 4-chamber (p=0.001) and sagittal (p=0.001) and with echo average longitudinal strain (ALS) (p=0.05). This study demonstrated a significant correlation of CAD with BNP and CMR ECV. There was also a significant correlation of NT-pro-BNP with CMR ECV and ALS. Combining these parameters with standard echo has the potential to identify high-risk patients early. Further studies are needed for long-term follow-up and management in this vulnerable population.

Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients.

Low steady state haemoglobin oxygen saturation in patients with sickle cell anaemia has been associated with the degree of anaemia and haemolysis. How much pulmonary dysfunction contributes to low saturation is not clear. In a prospective study of children and adolescents with sickle cell disease aged 3-20 years at steady state and matched controls, 52% of 391 patients versus 24% of 63 controls had steady state oxygen saturation <99% (P < 0.0001), 9% of patients versus no controls had saturation <95% (P = 0.008) and 8% of patients versus no controls had exercise-induced reduction in saturation > or =3%. Decreasing haemoglobin concentration (P < or = 0.001) and increasing haemolysis (P < or = 0.003) but not pulmonary function tests were independent predictors of both lower steady-state saturation and exercise-induced reduction in saturation. Neither history of stroke nor history of acute chest syndrome was significantly associated with lower steady-state oxygen saturation or exercise-induced reduction in saturation. Tricuspid regurgitation velocity was higher in patients with lower steady state haemoglobin oxygen saturation (P = 0.003) and with greater decline in oxygen saturation during the six-minute walk (P = 0.022). In conclusion, lower haemoglobin oxygen saturation is independently associated with increasing degrees of anaemia and haemolysis but not pulmonary function abnormalities among children and adolescents with sickle cell disease.

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation.

BACKGROUND: Elevation of echocardiography-determined tricuspid regurgitant jet velocity predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell disease. The definition, prevalence and clinical correlates of elevated jet velocity have not been established in pediatric patients. The present study tested the hypotheses that elevated jet velocity affects 10% of pediatric patients, is associated with both hemolysis and hypoxia, and has clinical correlates with acute chest syndrome, stroke, transfusion requirement and abnormal 6-minute walk test results. DESIGN AND METHODS: A prospective multicenter study of 310 patients aged 3-20 years old with sickle cell disease under basal conditions and 54 matched controls was conducted. A hemolytic index was generated by principal component analysis of the levels of lactate dehydrogenase, aspartate aminotransferase and bilirubin and reticulocyte count. RESULTS: Elevated jet velocity (defined as > or =2.60 m/sec based on the mean+/-2 SD in controls) occurred in 32 patients (11.0%) including one child of 3 years old. After adjustment for hemoglobin concentration, systolic blood pressure and left ventricular diastolic function, a 2 SD increase in the hemolytic index was associated with a 4.5-fold increase in the odds of elevated jet velocity (p=0.009) and oxygen saturation < or =98% with a 3.2-fold increase (p=0.028). Two or more episodes of acute chest syndrome had occurred in 28% of children with elevated jet velocity compared to in 13% of other children (p=0.012), more than ten units of blood had been transfused in 39% versus 18% (p=0.017) and stroke had occurred in 19% versus 11% (p=0.2). The distance walked in 6-minute walk tests did not differ significantly, but oxygen saturation declined during the tests in 68% of children with elevated jet velocity compared to in 32% of other children (p=0.0002). CONCLUSIONS: According to a pediatric-specific definition the prevalence of elevated jet velocity in this population of young patients with sickle cell disease was 11%. The study provides evidence for independent associations of elevated jet velocity with hemolysis and oxygen desaturation. Further investigations should address whether elevated jet velocity may indicate future complications and whether early intervention is beneficial.