Long-term outcomes of pulmonary embolism in children and adolescents.

ABSTRACT: Knowledge regarding the long-term consequences of pulmonary embolism (PE) in children is limited. This cohort study describes the long-term outcomes of PE in children who were followed-up at a single-center institution using a local protocol that included clinical evaluation, chest imaging, echocardiography, pulmonary function tests, and cardiopulmonary exercise tests at follow-up, starting 3 to 6 months after acute PE. Children objectively diagnosed with PE at age 0 to 18 years, who had ≥6 months of follow-up were included. Study outcomes consisted of PE resolution, PE recurrence, death, and functional outcomes (dyspnea, impaired pulmonary or cardiac function, impaired aerobic capacity, and post-PE syndrome). The frequency of outcomes was compared between patients with/without underlying conditions. In total, 150 patients were included; median age at PE was 16 years (25th-75th percentile, 14-17 years); 61% had underlying conditions. PE did not resolve in 29%, recurrence happened in 9%, and death in 5%. One-third of patients had at least 1 documented abnormal functional finding at follow-up (ventilatory impairments, 31%; impaired aerobic capacity, 31%; dyspnea, 26%; and abnormal diffusing capacity of the lungs to carbon monoxide, 22%). Most abnormalities were transient. When alternative explanations for the impairments were considered, the frequency of post-PE syndrome was lower, ranging between 0.7% and 8.5%. Patients with underlying conditions had significantly higher recurrence, more pulmonary function and ventilatory impairments, and poorer exercise capacity. Exercise intolerance was, in turn, most frequently because of deconditioning than to respiratory or cardiac limitation, highlighting the importance of physical activity promotion in children with PE.

Anticoagulant Medications: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the medications used for anticoagulation for pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE (PEACE). DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Included studies assessed anticoagulation used in pediatric ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third reviewer adjudicating any conflicts. Eighteen references were used for data extraction as well as for creation of recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements, or good practice statements for anticoagulation during pediatric ECMO. A web-based modified Delphi process was used to build consensus via the Research and Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. Two recommendations, two consensus statements, and one good practice statement were developed, and, in all, agreement greater than 80% was reached. CONCLUSIONS: There is insufficient evidence to formulate optimal anticoagulation therapy during pediatric ECMO. Additional high-quality research is needed to inform evidence-based practice for anticoagulation during pediatric ECMO.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

Quick, Effective Screening Tasks Identify Children With Medical Conditions or Disabilities Needing Physical Literacy Support.

PURPOSE: This study evaluated screening tasks able to identify children with medical conditions or disabilities who may benefit from physical literacy. METHOD: Children completed ≤20 screening tasks during their clinic visit and then the Canadian Assessment of Physical Literacy (2nd edition) at a separate visit. Total Canadian Assessment of Physical Literacy scores <30th percentile were categorized as potentially needing physical literacy support. Receiver operator characteristic curves identified assessment cut points with 80% sensitivity and 40% specificity relative to total physical literacy scores. RESULTS: 223 children (97 girls; 10.1 [2.6] y) participated. Physical activity adequacy, predilection, and physical competence achieved ≥80% sensitivity and ≥40% specificity in both data sets. Adequacy ≤ 6.5 had 86% to 100% sensitivity and 48% to 49% specificity. Daily screen time >4.9 hours combined with Adequacy ≤6.15 had 88% to 10% sensitivity and 53% to 56% specificity. CONCLUSIONS: Activity adequacy, alone or with screen time, most effectively identified children likely to benefit from physical literacy support. Adequacy and screen time questionnaires are suitable for clinical use. Similar results regardless of diagnosis suggest physical competence deficits are not primary determinants of active lifestyles. Research to enhance screening specificity is required.

Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis.

OBJECTIVES: To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving a combination of first-line poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) plus androgen receptor axis-targeted agents (ARAT) vs placebo/ARAT. MATERIALS AND METHODS: We conducted a systematic review/meta-analysis of all published Phase III randomised controlled trials using EMBASE, MEDLINE, and Cochrane (inception until 6 June 2023). Published full-text manuscripts and conference abstracts were inclusion eligible. Study selection/data extraction were independently performed by two authors. The Cochrane Risk-of-Bias 2 Tool was used, and certainty of evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Pooled hazard ratios (HRs) and relative risks, with corresponding confidence intervals (CIs), were generated using random-effects models. RESULTS: Three trials were identified: PROpel, MAGNITUDE, and TALAPRO-2. Compared to placebo/ARAT, the PARPi/ARAT combination was associated with a 35% rPFS improvement in the overall cohort (HR 0.65, 95% CI 0.56-0.76), with 68%, 45%, and 26% improvements in the BReast CAncer gene 1/gene 2 (BRCA1/2)-mutated (BRCA1/2m; P < 0.001), homologous recombination repair-mutated (HRRm; P < 0.001), and non-HRRm cohorts (P = 0.003), respectively. OS data maturity ranged from 31% to 48%, with overall cohort OS data unavailable from MAGNITUDE. The PROpel/TALAPRO-2 pooled analysis demonstrated a 16% OS improvement in the overall cohort (HR 0.84, 95 CI 0.72-0.98; P = 0.02). OS in the HRRm (HR 0.76, 95% CI 0.61-0.95) and the BRCA1/2m cohorts (HR 0.53, 95% CI 0.18-1.56) were improved, with a higher effect magnitude compared to the overall cohort. This combination was associated with a 45% relative risk increase in Grade ≥3 TEAEs, including 6.22-fold for Grade ≥3 anaemia (31.9% vs 4.9%). CONCLUSIONS: The addition of PARPi to ARAT in the first-line mCRPC setting is associated with rPFS benefits across subgroups, with the greatest magnitude of benefit in BRCA1/2m patients. OS benefits remain inconsistent irrespective of HRRm status, with significant increases in Grade ≥3 TEAEs, particularly anaemia. Currently, we suggest this combined approach be selectively offered to HRRm patients, preferentially BRCA1/2m.

Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from >3 months to <18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.

Defining vascular anomaly phenotypes in children based on a systematic literature search: A critical step in developing a single severity score for interventional clinical trials.

INTRODUCTION: Genetically targeted drugs in vascular anomalies (VA) are used despite the absence of a validated severity score. The aim of this study was to evaluate the feasibility of grouping phenotypic VA clinical characteristics into a single severity score. METHODS: A systematic literature review including children treated with sirolimus accompanied by a detailed description of phenotype and management was conducted. Demographic data and clinical features were extracted to define distinct categories of phenotypes. RESULTS: Children with VA display two main phenotypes regardless of VA subtype, which may overlap. A systemic phenotype results from direct invasion and compression of vital structures generally leading to hospitalization and aggressive management in infancy. A functional phenotype is associated with chronic pain and disability manifesting mainly during early adolescence and managed in the outpatient setting. CONCLUSION: The two distinct phenotypes described could be the basis for developing a unified scoring system for VA severity assessment.

Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: A report from CYP-C.

There are conflicting data about whether the development of cancer-associated thrombo-embolism (TE) negatively impacts survival in children. The objective was to determine whether TE during treatment was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). We performed a population-based retrospective cohort study using the Cancer in Young People-Canada registry. Children <15 years of age were diagnosed with de novo ALL (2000-2016). The primary exposure variable was radiologically-confirmed thrombo-embolism requiring medical intervention. Multivariable Cox regression models were used to determine the impact of thrombo-embolism on survival, where TE was time-dependent. We included 2006 children (median age: 4 years, 88.5% precursor B-cell ALL). Thrombo-embolism occurred in 113 patients (5.6%), at a median time of 107 days (interquartile range: 35-184 days) after ALL diagnosis. Among standard/low-risk patients, 41/1165 (3.5%) developed TE while among high/very high-risk patients, 72/841 (8.6%) developed TE. Patients with TE had a significantly worse OS (adjusted HR [aHR] of death: 2.61, 95% CI: 1.62-4.22, p < 0.001) and EFS (aHR of an event [death, relapse, second malignancy]: 2.03, 95% CI: 1.35-3.05, p = 0.001), compared with patients without TE. No statistically significant difference was seen in standard/low risk ALL for OS and EFS, but TE was associated with a significantly lower OS and EFS in children with high/very high-risk ALL (aHR of death: 2.90, 95% CI: 1.79-4.72, p < 0.001; aHR of an event: 2.02, 95% CI: 1.30-3.12, p = 0.002). Thus, TE led to a statistically significant reduction in OS and EFS in children with high risk/very high-risk leukemia.

Diagnostic value of D-dimers for limb deep vein thrombosis in children: A prospective study.

The present study sought to evaluate the discriminative and predictive ability of D-dimer for pediatric limb DVT. Children aged 28 days-18 years requiring imaging to rule out limb DVT, as per the treating clinical team, were enrolled in the study. The outcome was ultrasound proven DVT. The D-dimer levels were obtained around the time of imaging. Receiver operating characteristic (ROC) curves and logistic regression models were used for data analyses. In total, 296 patients were enrolled between 2017-2020; 204 patients were diagnosed with DVT (DVT[+]). Median D-dimer levels were 2.3 µg/ml FEU (25th-75th percentile 0.9-3.9) among DVT(+) and 1.9 µg/ml FEU (25th-75th percentile 0.8-4.0) among DVT(-) patients (p = 0.60). The area under the ROC curve (AUC) was 0.52 (95% confidence interval [CI] 0.45-0.59). The odds ratio for D-dimer levels was 1.00 (95% CI 0.99-1.01), holding confounders constant. In a sub-group exploratory analysis including 23 patients with no underlying conditions or co-morbidities, the AUC curve was 0.90 (95% CI 0.76-1.00). In conclusion, in this prospective cohort study of consecutive children with suspected limb DVT, D-dimer levels had poor discriminative and predictive ability for DVT. However, D-dimer levels showed better discriminative and predictive ability for DVT in an exploratory sample of patients with no underlying conditions or co-morbidities at the time of diagnosis.

CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis.

Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.

Heparin-Induced Thrombocytopenia in a Pediatric Population: Implications for Clinical Probability Scores and Testing.

OBJECTIVES: To determine the applicability of the 4Ts score and the Heparin-Induced Thrombocytopenia (HIT) Expert Probability (HEP) score in children with suspected HIT and to estimate the number of children potentially at risk of HIT. STUDY DESIGN: We retrospectively estimated 4Ts and HEP scores in a cohort of 50 children referred for laboratory screening with enzyme immunoassay. In addition, minor modifications were introduced to the 4Ts score (modified 4Ts score) to adapt it for use in the pediatric setting. All patients with positive enzyme immunoassays were tested with serotonin release assay. We also extracted the number of patients started on heparins in a similar period of time. RESULTS: The median age at the time of testing was 4 years (25th-75th percentile, 8.7 months to 13.5 years); 78% of patients had low and 22% had intermediate risk pretest probability scores using the original 4Ts score; 86% had low risk and 14% had intermediate risk scores using the modified 4Ts score; 54% of children had a HEP score of ≥2. Six patients (12%) had a positive (≥0.40 optical density units) enzyme immunoassay, but none had a positive serotonin release assay. Based on anticoagulation dose, there were 1-2 new daily potentially high-risk exposures to heparinoids at our institution. CONCLUSIONS: The modified 4Ts and original 4Ts scores may be more adequate than the HEP score to determine HIT pretest probability in children. Despite the number of patients potentially at risk, HIT is rare in pediatrics.

Can thrombophilia predict recurrent catheter-related deep vein thrombosis in children?

The role of thrombophilia testing in predicting catheter-related deep vein thrombosis (DVT) after an incident (ie, first) catheter-related DVT in children remains unclear. The present study investigated the association between thrombophilia and recurrent catheter-related DVT. Children with thrombophilia testing, performed according to the clinician's judgment and the family's preference, and a history of objectively confirmed catheter-related DVT were included in the study. Recurrent catheter-related DVT after placement of a new catheter was the main outcome. Thrombophilia was classified as minor, major, or none. Analysis was conducted using mixed effect logistic regression. A total of 245 patients had 1,365 catheters inserted; 941 of these catheters were placed after the incident catheter-related DVT. Anticoagulants as treatment or prophylaxis were administered in 78.1% of inserted catheters for at least 50% of the time they were in place. Minor thrombophilia was found in 12.7% of patients, whereas major thrombophilia was seen in 8.2% of children. The incidence rate of recurrent events was 0.23/100 catheter-days (95% confidence interval, 0.19-0.28 catheter-days); 34.3% (95% confidence interval, 28.6%-40.0%) of patients requiring a new catheter after their incident thrombotic event had at least 1 recurrent event. The incidence proportion of bleeding complications was 4.6/100 patients receiving anticoagulation. Young age of the patient at the time of catheter insertion and lack of administration of treatment or prophylactic doses of anticoagulant were predictive of recurrent events. In contrast, thrombophilia was not predictive of recurrent catheter-related DVT during subsequent catheter insertions among tested patients. Our findings suggest that thrombophilia testing to predict recurrence in these patients may be unnecessary.

Different unfractionated heparin doses for preventing arterial thrombosis in children undergoing cardiac catheterization.

BACKGROUND: The role of cardiac catheterization in pediatrics has progressed significantly over the last two decades, evolving from a primary diagnostic tool to a primary treatment modality in children with congenital heart disease. Vascular complications, particularly arterial thrombosis, are among the most common unwanted post-cardiac catheterization events. In 1974, unfractionated heparin proved to be superior to placebo in decreasing the incidence of arterial thrombosis in pediatric patients. However, the optimal dose of unfractionated heparin to be utilized in this setting remains a matter of controversy. This is an update of the review first published in 2014. OBJECTIVES: To evaluate the use of low-dose (< 100 units/kg) versus high-dose (≥ 100 units/kg) unfractionated heparin administered as an intravenous bolus at the time of initiation of cardiac catheterization (that is, immediately after arterial puncture), with or without subsequent heparin maintenance doses, for the prevention of post-procedural arterial thrombosis in children. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 15 October 2019. We planned to undertake reference checking of identified trials to identify additional studies. No language restrictions were applied. SELECTION CRITERIA: We included randomized or quasi-randomized trials that compared low dose to high dose unfractionated heparin administered prior to cardiac catheterization. We selected studies conducted in children aged 0 to 18 years. DATA COLLECTION AND ANALYSIS: The first screening of potentially eligible studies was conducted by one of the authors (MLA). The second screening, risk of bias assessment and data extraction were independently conducted by two authors (MLA, LRB). Outcomes (thrombotic events, bleeding complications, other complications) were treated as dichotomous variables. The effect measures used were risk ratio (RR), risk difference (RD) and number needed to treat (NNT), with 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: We identified no new studies for inclusion in this review. In total, two studies with a total of 492 participants were included. We had concerns about risk of bias for one of the two studies. The certainty of the evidence for our key outcomes was downgraded to moderate due to risk of bias concerns and imprecision. The confidence interval for the risk of arterial thrombotic events was compatible with benefits of either high or low unfractionated heparin dose regimens (RR low-dose versus high-dose 1.06, 95% CI 0.58 to 1.92). Only one of the studies reported the frequency of bleeding events and found no clear difference in the incidence of major or minor bleeding events between arms (RR low-dose versus high-dose 2.96, 95% CI 0.12 to 71.34 for major bleeding events; RR low-dose versus high-dose 1.38, 95% CI 0.46 to 4.13 for minor bleeding). This study also reported on the incidence of deep vein thrombosis when comparing the high versus low dose of heparin and reported a non-significant difference (RR low-dose versus high-dose 0.34, 95% CI 0.01 to 8.28). The other study lacked information about bleeding. Additional side effects of heparin other than bleeding events were not reported in either of the studies. AUTHORS' CONCLUSIONS: Due to the limitations of the current evidence, small number of included studies, and lack of details reported in one study, we are unable to determine the effects of different dosing regimens of unfractionated heparin for the prevention of vascular thrombosis during cardiac catheterization in children. Further adequately powered, randomized clinical trials are needed.

Low molecular weight heparin for prevention of central venous catheter-related thrombosis in children.

BACKGROUND: The prevalence of children diagnosed with thrombotic events has been increasing in the last decades. The most common thrombosis risk factor in neonates, infants and children is the placement of a central venous catheter (CVC). It is unknown if anticoagulation prophylaxis with low molecular weight heparin (LMWH) decreases CVC-related thrombosis in children. This is an update of the Cochrane Review published in 2014. OBJECTIVES: To determine the effect of LMWH prophylaxis on the incidence of CVC-related thrombosis and major and minor bleeding complications in children. Further objectives were to determine the effect of LMWH on occlusion of CVCs, number of days of CVC patency, episodes of catheter-related bloodstream infection (CRBSI), other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopaenia and osteoporosis) and mortality during therapy. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 7 May 2019. We undertook reference checking of identified trials to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised trials comparing LMWH to no prophylaxis (placebo or no treatment), or low-dose unfractionated heparin (UFH) either as continuous infusion or flushes (low-dose UFH aims to ensure the patency of the central line but has no systemic anticoagulation activity), given to prevent CVC-related thrombotic events in children. We selected studies conducted in children aged 0 to 18 years. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible studies, which were assessed for study methodology including bias, and extracted unadjusted data where available. In the data analysis step, all outcomes were analysed as binary or dichotomous outcomes. The effects of interventions were summarised with risk ratios (RR) and their respective 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: One additional study was included for this update bringing the total to two included studies (with 1135 participants). Both studies were open-label RCTs comparing LMWH with low-dose UFH to prevent CVC-related thrombosis in children. We identified no studies comparing LMWH with placebo or no treatment. Meta-analysis found insufficient evidence of an effect of LMWH prophylaxis in reducing the incidence of CVC-related thrombosis in children with CVC, compared to low-dose UFH (RR 0.68, 95% CI 0.27 to 1.75; 2 studies; 787 participants; low-certainty evidence). One study (158 participants) reported symptomatic and asymptomatic CVC-related thrombosis separately and detected no evidence of a difference between LMWH and low-dose UFH (RR 1.03, 95% CI 0.21 to 4.93; low-certainty evidence; RR 1.17, 95% CI 0.45 to 3.08; low-certainty evidence; for symptomatic and asymptomatic participants respectively). There was insufficient evidence to determine whether LMWH impacts the risk of major bleeding (RR 0.27, 95% CI 0.05 to 1.67; 2 studies; 813 participants; low-certainty evidence); or minor bleeding. One study reported minor bleeding in 53.3% of participants in the LMWH arm and in 44.7% of participants in the low-dose UFH arm (RR 1.20, 95% CI 0.91 to 1.58; 1 study; 158 participants; very low-certainty evidence), and the other study reported no minor bleeding in either group (RR: not estimable). Mortality during the study period was reported in one study, where two deaths occurred during the study period. Both were unrelated to thrombotic events and occurred in the low-dose UFH arm. The second study did not report mortality during therapy per arm but showed similar 5-year overall survival (low-certainty evidence). No additional adverse effects were reported. Other pre-specified outcomes (including CVC occlusion, patency and CRBSI) were not reported. AUTHORS' CONCLUSIONS: Pooling data from two RCTs did not provide evidence to support the use of prophylactic LWMH for preventing CVC-related thrombosis in children (low-certainty evidence). Evidence was also insufficient to confirm or exclude a difference in the incidence of major and minor bleeding complications in the LMWH prophylaxis group compared to low-dose UFH (low and very low certainty respectively). No evidence of a clear difference in overall mortality was seen. Studies did not report on the outcomes catheter occlusion, days of catheter patency, episodes of CRBSI and other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopaenia and osteoporosis). The certainty of the evidence was downgraded due to risk of bias of the included studies, imprecision and inconsistency, preventing conclusions in regards to the efficacy of LMWH prophylaxis to prevent CVC-related thrombosis in children.

Characterization of Post-Thrombotic Syndrome in Children with Cardiac Disease.

OBJECTIVE: To assess the validity of existing clinical scales assessing the presence of physical and functional abnormalities for diagnosing post-thrombotic syndrome (PTS) in children, including specific evaluation of use in children with congenital heart disease (CHD). STUDY DESIGN: One hundred children aged >2 years (average age, 6 years), including 33 with CHD and previously proven extremity deep vein thrombosis (DVT), 37 with CHD and no previous DVT, and 30 healthy siblings, were blindly assessed for PTS using the modified Villalta Scale (MVS). All patients aged <6 years underwent neurodevelopmental testing and an age-appropriate quality of life assessment. RESULTS: The MVS identified mild PTS in 20 children and moderate PTS in 1 child (including 14 of 33 [42%] in the CHD/DVT group, 5 of 37 [14%] in the CHD/no DVT group, and 2 of 30 controls [7%]). The diagnosis of PTS was confirmed clinically in 14 patients, all of whom had previous thrombosis and 1 of whom was MVS-negative. MVS had an accuracy of 91% and performed reasonably well as a screening tool but poorly as a diagnostic tool. MVS reliability was acceptable. Children with PTS had similar quality of life as those without PTS but had higher rates of neurodevelopmental delays in gross motor skills (70% vs 24%; P = .02) and problem-solving indicators (60% vs 15%; P = .008). CONCLUSIONS: Using the MVS scale for PTS screening in children with CHD is feasible and reliable, and the scale has good correlation with a clinical diagnosis of PTS despite a high prevalence of false-positive findings. Further research is needed to determine the clinical relevance of PTS in this population.

Clinical Impact of Chronic Venous Changes Induced by Central Lines in Children: A Cohort with Abnormal Venograms.

PURPOSE: To explore the hypothesis that central venous stenosis/obstructions (CVS/O) in children are influenced by prior central venous access devices (CVADs) and are associated with future risk for thromboses. MATERIAL AND METHODS: A convenience sample of 100 patients with abnormal venography (stenosis, collaterals, occlusions) documented during peripherally inserted central catheter (PICC) placements were identified from consecutive PICC placements (January 2008 to November 2012). The patients (41 males, 59 females, median age 2.7 years, median weight 11 kg) were categorized based on venographic presence (Group A, n = 53) or absence (Group B, n = 47) of visible connection to the superior vena cava. Each patient's CVAD history, before and after venography, was analyzed (until October 2016). RESULTS: Before venogram, Group B patients were associated with a higher number of previous CVADs, larger diameter devices, greater incidence of malposition, and more use of polyurethane catheters than Group A patients (P < .001). An ipsilateral PICC was successfully placed in 98% of Group A, compared to 32% of Group B (P < .001). After venogram, significantly more Doppler ultrasounds (DUS) were performed and thromboses diagnosed in Group B (57% and 36%) compared to Group A (21% and 8%) (P < .003; P = .001), respectively. CONCLUSIONS: Previous catheter characteristics influenced the severity of venographic changes of CVS/O (Group B). Group B was associated with more subsequent symptomatic thromboses. This information may assist parents and referring physicians to anticipate potential adverse sequelae from CVS/O on the child's venous health.

Postthrombotic syndrome and other outcomes of lower extremity deep vein thrombosis in children.

Pediatric lower extremity deep vein thrombosis (LE-DVT) can lead to postthrombotic syndrome (PTS) and other adverse events. We investigated the outcomes of LE-DVT in children. Three groups were compared: non-line-related (Non-LR) DVT, LR DVT in neonates (LRneonates), and LR DVT in non-neonates (LRnon-neonates). A total of 339 children were included (Non-LR, n = 56; LRneonates, n = 95; and LRnon-neonates, n = 188). We found a statistically significant difference in the frequency of PTS (P = .04; 62.5%, 40.0%, and 46.3% in Non-LR, LRneonates, and LRnon-neonates, respectively), of recurrent LE-DVT (P = .001; 10.7% and 2.0% in Non-LR and LRnon-neonates, respectively), and pulmonary embolism (PE) (P < .001; 19.6% and 3.2% in Non-LR and LRnon-neonates, respectively) among groups. There was no difference in DVT resolution (P = .41). Multivariable analysis showed that DVT resolution, triggering event, and sex predicted Modified Villalta Scale (MVS; for pediatric PTS) scores >1; there was an interaction between DVT triggering event and sex. The time to reach an MVS >1 was significantly different when comparing groups (log-rank test, P < .001). Moreover, we found a significant difference in baseline MVS scores among groups, but the difference did not appear to change over time. In conclusion, LR LE-DVT had more benign outcomes than Non-LR DVT. Sex, DVT triggering event, and DVT resolution predicted LE-PTS in our cohort.

Vascular anomaly cases for the pediatric hematologist oncologists-An interdisciplinary review.

Vascular anomalies (VAs) are classified as tumors or malformations depending on their clinical characteristics, pathological diagnosis, and genomic information. Diagnosis can be challenging because of the heterogeneity of clinical presentation; thus, the best diagnosis and care are provided by an interdisciplinary team of specialists. Over the past 10 years, an increasing number of pediatric hematologist/oncologists are caring for patients with VAs secondary to new medical therapy options and clinical trials. This paper focuses on complicated VA issues often seen by the pediatric hematologist/oncologist. The paper reviews clinical pearls on diagnosis, histology, radiology, and treatment options.

Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study.

BACKGROUND: The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults. METHODS: This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5-18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5-2 years, 2-6 years, 6-12 years and 12-18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows. RESULTS: Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments. The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study. CONCLUSIONS: Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01145859.

Increased risk of symptomatic upper-extremity venous thrombosis with multiple peripherally inserted central catheter insertions in pediatric patients.

BACKGROUND: Peripherally inserted central catheters (PICCs) are associated with superficial and deep venous thrombosis of the arm. OBJECTIVE: The purpose of this study was to analyze the sequelae of repeated upper limb PICC insertions in children, in terms of the frequency of upper limb thrombosis in this patient group. MATERIALS AND METHODS: The study population included all children who underwent their first successful arm PICC insertion between January 2010 and December 2015. We included subsequent ipsilateral arm PICCs in the analysis. Patients were followed until March 2016 or until any alternative central venous line insertion. For each PICC insertion, we collected demographic variables and line characteristics. We correlated all symptomatic deep and superficial thromboses of the arm with the PICC database. RESULTS: Applying inclusion and exclusion criteria, 2,180 PICCs remained for analysis. We identified first, second, third and fourth PICC insertions in the same arm in 1,955, 181, 38 and 6 patients, respectively. In total there were 57 upper body deep symptomatic thrombotic events. An increasing odds ratio was seen with higher numbers of PICC insertions, which was significant when comparing the first with the third and fourth PICC insertions in the same arm (odds ratio [OR] 6.00, 95% confidence interval [CI] 2.25-16.04, P=0.0004). Double-lumen PICCs were associated with a significantly higher risk of thrombosis than single lumen (OR 2.77, 95% CI 1.72-4.47, P=0.0003). CONCLUSION: Repetitive PICC insertions in the same arm are associated with an increased risk of symptomatic thrombosis. Double-lumen PICCs are associated with a higher risk of thrombosis compared to single-lumen lines.