Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association.

Purpose- Much has transpired since the last scientific statement on pediatric stroke was published 10 years ago. Although stroke has long been recognized as an adult health problem causing substantial morbidity and mortality, it is also an important cause of acquired brain injury in young patients, occurring most commonly in the neonate and throughout childhood. This scientific statement represents a synthesis of data and a consensus of the leading experts in childhood cardiovascular disease and stroke. Methods- Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association's Manuscript Oversight Committee and were chosen to reflect the expertise of the subject matter. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. This scientific statement is based on expert consensus considerations for clinical practice. Results- Annualized pediatric stroke incidence rates, including both neonatal and later childhood stroke and both ischemic and hemorrhagic stroke, range from 3 to 25 per 100 000 children in developed countries. Newborns have the highest risk ratio: 1 in 4000 live births. Stroke is a clinical syndrome. Delays in diagnosis are common in both perinatal and childhood stroke but for different reasons. To develop new strategies for prevention and treatment, disease processes and risk factors that lead to pediatric stroke are discussed here to aid the clinician in rapid diagnosis and treatment. The many important differences that affect the pathophysiology and treatment of childhood stroke are discussed in each section. Conclusions- Here we provide updates on perinatal and childhood stroke with a focus on the subtypes, including arterial ischemic, venous thrombotic, and hemorrhagic stroke, and updates in regard to areas of childhood stroke that have not received close attention such as sickle cell disease. Each section is highlighted with considerations for clinical practice, attendant controversies, and knowledge gaps. This statement provides the practicing provider with much-needed updated information in this field.

Thrombophilia risk is not increased in children after perinatal stroke.

Perinatal stroke causes cerebral palsy and lifelong disability. Specific diseases are definable, but mechanisms are poorly understood. Evidence suggests possible associations between arterial perinatal stroke and prothrombotic disorders, but population-based, controlled, disease-specific studies are limited. Understanding thrombophilia in perinatal stroke informs pathogenesis models and clinical management. We conducted a population-based, prospective, case-control study to determine the association of specific perinatal stroke diseases with known thrombophilias. Children with idiopathic magnetic resonance imaging-classified neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), or fetal periventricular venous infarction (PVI) were recruited. Standardized thrombophilia evaluations were performed after 12 months of age on stroke cases and controls, including quantified proteins C and S, antithrombin, factors VIII/IX/XI, fibrinogen, lipoprotein(a), homocysteine, lupus anticoagulant, anticardiolipin antibodies and genotyping of factor V Leiden (FVL), factor II G20210A (FII), and methylenetetrahydrofolate reductase C677T. A total of 212 children were studied: 46 with NAIS, 34 with APPIS, 55 with PVI, and 77 controls (male, 53%; median age, 4.8 years). Of 14 parameters, no differences were observed in 12, including all common thrombophilias. Mean prothrombin time was shorter in arterial strokes (P < .001). Rates of antiphospholipid antibodies were low, comparable to those in controls, and resolved on repeat testing. FVL and FII rates were comparable to population norms. Total number of possible abnormalities did not differ between cases and controls. Our prospective, population-based, controlled, disease-specific study suggests minimal association between perinatal stroke and thrombophilia. This does not exclude the possibility of disordered coagulation at the time of stroke but suggests testing in childhood is not indicated.

Berlin Heart EXCOR Pediatric ventricular assist device Investigational Device Exemption study: study design and rationale.

BACKGROUND: Currently, there are no Food and Drug Administration-approved devices available that can provide long-term mechanical circulatory support to smaller children with severe heart failure as a bridge to heart transplant (HT). In recent years, the Berlin Heart EXCOR Pediatric ventricular assist device (VAD) has emerged as a potential treatment option. Systematic data on the safety and efficacy of the EXCOR are limited. METHODS: The Investigational Device Exemption (IDE) clinical study is designed to evaluate the safety and probable benefit of the EXCOR to support regulatory review of the device under the Humanitarian Device Exemption regulation. The study design and rationale are reviewed in light of the well-described challenges inherent in small population studies. RESULTS: The Berlin Heart EXCOR IDE clinical study is a prospective, multicenter, single-arm, clinical cohort study. Children aged 0 to 16 years with severe heart failure (Interagency Registry for Mechanically Assisted Circulatory Support profile 1 or 2) due to 2-ventricle heart disease and actively listed for HT comprise the primary study cohort. The control population is a propensity-matched retrospective cohort of children supported with extracorporeal membrane oxygenation, the only bridge device available to smaller children before the EXCOR. The primary efficacy end point is survival to heart transplantation or recovery. The primary safety end point is the incidence of serious adverse events as defined by pediatric Interagency Registry for Mechanically Assisted Circulatory Support criteria. The study will enroll a total of 48 subjects in 2 cohorts based on body surface area (cohort 1 <0.7 m(2), cohort 2 0.7-1.5 m(2)) and is powered to show safety superiority to a prespecified performance goal of 0.25 serious adverse events per day of support. Children ineligible for the primary cohort will still have access to the device in a third compassionate-use cohort where adverse event data will be collected for additional safety characterization of the device. CONCLUSION: The Berlin Heart IDE clinical study will be the first bridge-to-HT VAD study designed exclusively for children. It is anticipated that the study will provide important information on the safety and efficacy of the Berlin Heart EXCOR Pediatric in children while providing valuable lessons into the design and conduct of future VAD studies in children.

Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This chapter about antithrombotic therapy in neonates and children is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs, and Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading, see Guyatt et al in this supplement, pages 123S-131S). In this chapter, many recommendations are based on extrapolation of adult data, and the reader is referred to the appropriate chapters relating to guidelines for adult populations. Within this chapter, the majority of recommendations are separate for neonates and children, reflecting the significant differences in epidemiology of thrombosis and safety and efficacy of therapy in these two populations. Among the key recommendations in this chapter are the following: In children with first episode of venous thromboembolism (VTE), we recommend anticoagulant therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1B]. Dosing of IV UFH should prolong the activated partial thromboplastin time (aPTT) to a range that corresponds to an anti-factor Xa assay (anti-FXa) level of 0.35 to 0.7 U/mL, whereas LMWH should achieve an anti-FXa level of 0.5 to 1.0 U/mL 4 h after an injection for twice-daily dosing. In neonates with first VTE, we suggest either anticoagulation or supportive care with radiologic monitoring and subsequent anticoagulation if extension of the thrombosis occurs during supportive care (Grade 2C). We recommend against the use of routine systemic thromboprophylaxis for children with central venous lines (Grade 1B). For children with cerebral sinovenous thrombosis (CSVT) without significant intracranial hemorrhage (ICH), we recommend anticoagulation initially with UFH, or LMWH and subsequently with LMWH or vitamin K antagonists (VKAs) for a minimum of 3 months (Grade 1B). For children with non-sickle-cell disease-related acute arterial ischemic stroke (AIS), we recommend UFH or LMWH or aspirin (1 to 5 mg/kg/d) as initial therapy until dissection and embolic causes have been excluded (Grade 1B). For neonates with a first AIS, in the absence of a documented ongoing cardioembolic source, we recommend against anticoagulation or aspirin therapy (Grade 1B).

A clinically significant incidence of bleeding in critically ill children receiving therapeutic doses of unfractionated heparin: a prospective cohort study.

Unfractionated heparin (UFH) is frequently prescribed for children for the prevention and treatment of thrombosis; however, its safety and efficacy have not been assessed. The aim of this single center, prospective cohort study was to determine the incidence of major bleeding and recurrent thrombosis in children receiving UFH. Major bleeding was defined a priori as: central nervous system or retroperitoneal bleeding, bleeding resulting in UFH being stopped or overt bleeding causing a drop in hemoglobin >20 g/dL in less than 24 h. Major bleeding events occurred in 9/38 children (24%, 95% CI 11-40%) and 2/38 (5%, 95% CI 0-18%) developed thrombosis. In conclusion, there is clinically significant bleeding in children receiving UFH.

Lack of correlation between heparin dose and standard clinical monitoring tests in treatment with unfractionated heparin in critically ill children.

UNLABELLED: The activated partial thromboplastin time (aPTT) and anti-Xa activity are used for monitoring unfractionated heparin (UFH) therapy in children and may not be optimal. OBJECTIVE: Determine correlations of aPTT, anti-Xa and UFH dose in children. Single centre prospective cohort study in children receiving UFH. The aPTT and anti-Xa results from routine coagulation monitoring were collected. Thirty-nine children (median age 18 days) were enrolled. There was no relationship between aPTT and UFH dose (r2=0.12) or anti-Xa and UFH dose (r2=0.03) or aPTT and anti-Xa (r2=0.22). aPTT and anti-Xa do not accurately monitor UFH therapy in children.

Urgent clinical challenges in children with ischemic stroke: analysis of 1065 patients from the 1-800-NOCLOTS pediatric stroke telephone consultation service.

BACKGROUND AND PURPOSE: Clinical trials are lacking in pediatric stroke. As a result, physicians caring for children with stroke face significant challenges. The patient characteristics and specific nature of clinical challenges facing practicing clinicians can inform the design of and priorities for developing relevant clinical trials. METHODS: Physicians consulted the 1-800-NOCLOTS toll-free pediatric stroke telephone consultation service on children (birth to 18 years) with ischemic stroke. Pediatric neurologist or hematologists provided telephone consultation and documented caller and patient characteristics, antithrombotic treatments and callers' questions for entry into a computerized database. Children referred from January 1, 1995 to January 1, 2004, comprised the study cohort. RESULTS: Stroke consults were completed on 1065 children located predominantly in the United States (76%). Children had arterial ischemic stroke (AIS; 679; 64%) or cerebral sinovenous thrombosis (CSVT; 386; 36%) and were 54% male and 16% neonates. Risk factors and antithrombotic agents (none, aspirin, warfarin, and heparins) differed by stroke type. In 60% of patients, callers had not initiated antithrombotic therapy. Callers' questions for both stroke types usually concerned treatment selection (83%), but for AIS, questions more frequently (P<0.0001) concerned the selection and interpretation of etiological investigations. CONCLUSIONS: Research is urgently needed in pediatric stroke to provide direction for management in "real-life" settings. Research efforts should address the unique challenges within different stroke types and include observational studies addressing investigation of the child with AIS. For AIS and CSVT, randomized controlled trials investigating the efficacy of antithrombotic treatment are urgently needed.

Significant association with location of central venous line placement and risk of venous thrombosis in children.

Venous thromboembolic events (VTE) in children are frequently associated with central venous lines (CVL). Identifying risk factors related to CVL management could potentially minimize CVL-related thrombotic complications. The objectives of the study were to assess whether CVL location, type, size, and duration of placement are associated with the incidence of VTE in children. The study was a prospective, multicentre cohort study in a general pediatric population requiring CVL. Data on CVL characteristics were documented prospectively using standardized case report forms. Outcome assessments were by i) clinical monitoring for symptomatic VTE which were confirmed by appropriate objective test, or ii) screening by venography at study exit. Among 158 children, 21 (13%) hadVTE. The incidence of VTE was increased with femoral CVL (32%) and subclavian CVL (27%) compared to brachial CVL (12%) and jugular CVL (8%; p = 0.01). The incidence of VTE was independent of CVL type (peripherally inserted central catheters, untunneled CVL, tunneled exteriorized CVL, subcutaneous ports; p = 0.90), and CVL size (CVL diameter, p = 0.42; number of CVL lumen, p = 0.58). The incidence of VTE did not increase with duration of CVL placement: 0-5 days (17% VTE), 6-20 days (19%), 21-35 days (10%), and 36-50 days (11%, p = 0.68). The incidence of CVL-relatedVTE may be reduced by preferred placement of CVL in brachial or jugular veins. The choice of CVL type and size does not significantly influence the risk of VTE. Short-term CVL are associated with a similar risk of VTE as longer-term CVL.

Systemic thromboembolism in children. Data from the 1-800-NO-CLOTS Consultation Service.

Thromboembolism (TE) has recently been recognized as a clinical entity in children. Determining the clinical characteristics of pediatric TE is an important first step in dealing with this new disorder. The paper summarizes 1776 consecutive children with systemic TE referred to 1-800-NO-CLOTS telephone consultation service. 1-800-NO-CLOTS is a free consultation service for clinicians managing pediatric TE. Patient information was collected immediately using standardized forms. In children with systemic TE, infants under one year of age (47%) including neonates (26%) represented the largest distinct pediatric age group. Age-related differences were seen in TE locations, associated conditions, and risk factors. However, venous TE was the most frequent manifestation (74%). Neonates and children with cardiac disorders were more likely to have an arterial TE than a venous TE Beyond the neonatal period, venous TE associated with a central line is more likely to occur than arterial TE. Children with ALL were 5.7 times more likely to have a venous TE than an arterial TE. TE were infrequent in otherwise healthy children with 90% of children having at least one risk factor. Central catheters were the single most common risk factor associated with TE, present in 2/3 of children. Ultrasound was most frequently employed for diagnosis of TE. Finally, there was marked heterogeneity in treatment of children with TE. In children, neonates form the largest single group with TE. TE usually occur only in the presence of one or more risk factors with catheters being the single most important factor.

Thrombophilia and pregnancy complications.

The implications of currently available data on the association of gestational vascular complications with thrombophilia are presented in this consensus report. Screening is recommended for women with the following previous complications: fetal loss including three or more first trimester loss, two or more second trimester loss, or any stillbirth; early, severe or recurrent preeclampsia and severe intrauterine growth restriction. Maternal antithrombotic therapy is currently evaluated in women with thrombophilia and previous complications.

An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial.

OBJECTIVE(S): Venous thromboembolic events (VTE) are serious complications in children and for which the standard of care, unfractionated heparin followed by oral anticoagulation (UFH/OA), is problematic. The objective of REVIVE was to compare the efficacy and safety of a low molecular weight heparin (reviparin-sodium) to UFH/OA for the treatment of VTE in children. STUDY DESIGN: This multicenter, open-label study, with blinded central outcome adjudication, randomized patients with objectively confirmed VTE to receive either reviparin-sodium or UFH/OA. Dose adjustments were made using nomograms. The efficacy outcome was based on recurrent VTE and death due to VTE during the 3-month treatment period. The safety outcomes were major bleeding, minor bleeding and death. Due to slow patient accrual, REVIVE was closed prematurely. RESULTS: At 3 months, with reviparin-sodium, 2/36 patients (5.6%) had recurrent VTE or death compared to 4/40 patients (10.0%) receiving UFH/OA (odds ratio=0.53; 95% CI=(0.05, 4.00); Fisher's exact test: 2P=0.677). There were 7 major bleeds, 2/36 (5.6%) in the reviparin-sodium group and 5/40 (12.5%) in UFH/OA group (odds ratio=0.41; 95% confidence interval 0.04, 2.76); Fisher's exact test: P=0.435). There were 5 deaths during the study period, 1 (2.8%) in the reviparin-sodium group and 4 (10.0%) in the UFH/OA group. All five deaths were unrelated to VTE but one was due to an intracranial hemorrhage in the UFH/OA group. CONCLUSIONS: Although limited by small sample size, REVIVE provides valuable information on the incidence of recurrent VTE, major bleeding and problematic issues associated with therapy of VTE in children.

A cross-sectional study evaluating post-thrombotic syndrome in children.

BACKGROUND: Post-thrombotic syndrome (PTS) in adults, characterized by swelling, skin pigmentation, pain, and ulceration of the limb, is secondary to deep vein thrombosis (DVT). In contrast to the extensive documentation on PTS in adults, little is known about the risk of PTS in children. OBJECTIVE: To determine the incidence, clinical characteristics, and predictors of PTS in children. METHODS: A cross-sectional study in 153 nonselected children with objectively confirmed DVT. All children were assessed for PTS using a standardized score. As per the PTS score, severity was classified as: absent, mild, moderate, or severe. RESULTS: Post-thrombotic syndrome was present in 96/153 children (63%), in which 80 (83%) were mild and 16 (17%) were moderate. Swelling was the most frequently recorded subjective symptom (43%) while increased limb circumference (71%) and presence of collateral circulation (53%) were the most frequently recorded objective symptoms. Risk factors for development of PTS were: lack of resolution of the DVT by radiographic assessment (OR 3.96, 95% CI 1.68-9.30), number of vessels involved in the initial DVT (OR 2.05, 95% CI 1.52-2.77), and length of follow-up (OR 1.22, 95% CI 1.08-1.39). CONCLUSIONS: These findings demonstrate that PTS is a clinically significant disease in children with previous DVT.

Dose-finding and pharmacokinetic profiles of prophylactic doses of a low molecular weight heparin (reviparin-sodium) in pediatric patients.

INTRODUCTION: The low molecular weight heparin (LMWH), reviparin-sodium was studied in dose-finding and pharmacokinetic studies in children with central venous lines (CVLs). MATERIALS AND METHODS: The dose-finding study was performed in 24 patients aged 3 days to 16 years. Dose adjustments were made using a nomogram based on anti-factor Xa levels (units (U)/ml) (target of 0.1-0.3 U/ml). The pharmacokinetic study was performed in 19 patients, 9 less than or equal to 5 kg (7 of whom were less than 3 months) and 10 greater than 5 kg (all more than 3 months). RESULTS: The dose-finding study demonstrated that children over 5 kg required 30 International Units (IU)/kilogram (kg), subcutaneous (SC) twice daily (BID), and children less than or equal to 5 kg required 50 IU/kg, SC BID, to achieve target levels. The pharmacokinetic study demonstrated that 80% of anti-factor Xa levels were within the target range with both patient groups having similar peak (average=0.26 U/ml) and trough (average=0.13 U/ml) levels. CONCLUSIONS: Peak anti-factor Xa levels (0.1-0.3 U/ml) using reviparin-sodium are achieved by administering 50 IU/kg in children greater than 3 months of age and 30 U/kg in children less than 3 months of age.

An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial.

OBJECTIVE(S): Central venous lines (CVLs) are major risk factors for venous thromboembolism (VTE) in children. The objective of PROTEKT was to determine if a low molecular weight heparin (reviparin-sodium) safely prevents CVL-related VTE. STUDY DESIGN: This multi-center, open-label study, with blinded central outcome adjudication, randomized patients with new CVLs to twice-daily reviparin-sodium or standard care. The efficacy outcome was based on an exit venogram at Day 30 (+14 days), or earlier in case of CVL removal, or confirmed symptomatic VTE. The safety outcomes were major bleeding and death. Due to slow and restricted patient accrual, PROTEKT was closed prematurely. RESULTS: With reviparin-sodium, 14.1% (11:78) of patients had VTE compared to 12.5% (10:80) of control patients (odds ratio=1.15; 95% confidence interval 0.42, 3.23); 2P=0.82). One patient had a major bleed and there were two deaths, all three events occurring in the standard care group. CONCLUSIONS: The use of reviparin-sodium for short-term prophylaxis of CVL-related VTE in children was safe but its efficacy remains unclear. Although underpowered, PROTEKT provided valuable information on event rates and predictors of CVL-related VTE.

Intra-arterial tissue plasminogen activator for thrombosis complicating cerebral angiography in a 17-year-old girl.

Few reports describe the use of intraarterial recombinant tissue plasminogen activator to treat intracranial thrombosis in children. A 17-year-old girl with a history of prior venous thrombosis developed a left middle cerebral artery thrombus during diagnostic cerebral angiogram. Therapy with intra-arterial tissue plasminogen activator was initiated. An immediate follow-up angiogram demonstrated recanalization, and diffusion-weighted magnetic resonance imaging 9 hours later showed no evidence of infarction. Following the angiogram, femoral artery thrombosis developed. Treatment with supratherapeutic levels of heparin, localized delivery of intra-arterial tissue plasminogen activator, embolectomy, danaparoid, and dipyridamole failed to re-establish perfusion to the lower leg, and below the knee amputation was required. Neurologic examination remained normal 1 year later. Cerebral damage was avoided with the use of emergency intra-arterial tissue plasminogen activator for cerebral artery thrombosis in this child.

Developmental haemostasis: secondary haemostasis.

The haemostatic system is a complex interaction between the vasculature, cellular components and plasma proteins that interact to maintain haemostasis in the healthy body. The haemostatic system can be further defined as primary, secondary and tertiary haemostasis to better define the interdependent mechanisms that combine to maintain haemostasis. The term 'developmental haemostasis' was first introduced by Maureen Andrews in the 1980s to describe the age-related physiological changes of the coagulation system as it develops progressively over time from fetal, neonatal, paediatric to adult and geriatric systems. This paper will focus on developmental changes in secondary haemostasis, that is, the plasma protein changes that occur with age, particularly during the fetal and neonatal period, when the changes are most marked compared to the adult system.

Cerebral venous thrombosis in newborns, infants and children.

Cerebral venous thrombosis is currently thought to be a relatively rare and benign entity in childhood. Recent studies however have shown that cerebral venous thrombosis is more common than previously believed, and carries significant mortality and neurologic morbidity. Neonates are the most commonly affected age group, compared to children >1 month of age. Magnetic resonance imaging venography is the gold standard by which this diagnosis should be made. Clinical trials are currently necessary to determine the most efficacious,safe, and age-specific approach for anticoagulation for this childhood disorder.