880 S troke is an important acute neurological condition in chil- dren with an annual incidence ranging from 2.3 to 13 per 100 000 children. 1–3 Although most children who experience stroke do not die of the acute disorder, the consequences of the brain injury are amortized during the lengthy life span that follows. 4–8 The reduction potential in lifelong morbidity by timely and effective intervention with a thrombolytic agent, such as tissue-type plasminogen activator (tPA), in children with acute arterial ischemic stroke (AIS) constituted the core rationale for the study of tPA treatment of acute AIS in chil- dren. The perceived high potential for benefit after treatment justified assumption of risk for intracranial hemorrhage (ICH) after its use. 9 Because in adults, the risk of hemorrhage after tPA use was thought to be related to infarct volume; this prin- ciple was assumed for children. The known developmental trajectory of the fibrinolytic system includes lower levels of endogenous tPA and higher levels of plasminogen activator inhibitor-1 in young children than are found in adults and war- ranted a dose-finding study beginning at doses lower than that used in adults with incremental increase through the currently used adult dose of 0.9 mg/kg and careful assessment of tPA pharmacokinetics. 10 Currently, information on children treated with tPA con- sists of case reports, small case series, and hospital database documentation. Best practice for the treatment of children with acute stroke has received little rigorous study. Clinical approach varies widely among centers and reflects a dearth of research on which to base treatment protocols. Although tPA is not approved for use in childhood stroke, ≤2% of children with acute stroke are reported to have been treated with tPA in the United States, despite lack of safety and efficacy data. 11–14 In 2010, the National Institute of Neurological Disorders and Stroke (NINDS) funded the first prospective treatment trial in acute pediatric stroke, the Thrombolysis in Pediatric Stroke (TIPS) trial (National Institutes of Health [NIH] grant R01NS065848). TIPS reflected a multi-institutional, multidis- ciplinary design to determine safety, best dose, and feasibility of treatment with intravenous (IV) tPA of children who pres- ent with AIS. Secondary aims comprise the determination of the pharmacokinetics of tPA in children and assessment of the 90-day clinical outcome among treated patients. TIPS was closed by the NIH in December 2013 for lack of accrual. Herein, we summarize the lessons learned during the development and initial execution of the TIPS trial, the protocol synopsis, and the results of the challenges in implementation of the study. The occurrence of symptomatic ICH after the use of tPA in children with acute ischemic stroke constitutes a principal concern. When administered to adults according to NINDS guidelines, IV tPA therapy for AIS is associated with symp- tomatic ICH in 6.4%. 15 This risk may be lower in younger patients because none of the 48 young adults (16–49 years of age) treated with IV tPA for AIS developed symptomatic ICH. 16 In adults with acute stroke, increasing hemorrhagic volume after IV tPA treatment correlated with increasingly poor neurological outcome. 17 During childhood, the fibrinolytic system is not yet mature. 10,18–20 Baseline-free tPA concentration is decreased and plasminogen activator inhibitor-1 concentration, an inhibitor of tPA, is increased in children compared with that in adults. 20,21 In addition, children have an increased volume of distribu- tion 22,23 and more rapid hepatic clearance, suggesting that they will clear tPA more quickly. 24 This raises the possibility that a Michael J. Rivkin, MD; Gabrielle deVeber, MD, MHSc; Rebecca N. Ichord, MD; Adam Kirton, MD, MSc; Anthony K. Chan, MBBS; Collin A. Hovinga, PharmD, MS; Joan Cox Gill, MD; Aniko Szabo, PhD; Michael D. Hill, MD; Kelley Scholz, MSW; Catherine Amlie-Lefond, MD Received December 22, 2014; final revision received December 22, 2014; accepted December 30, 2014. From the Departments of Neurology, Psychiatry and Radiology, Boston Children’s Hospital, and Department of Neurology, Harvard Medical School, Boston, MA (M.J.R.); Division of Neurology, Department of Pediatrics, Hospital for Sick Children Toronto, Ontario, Canada (G.d.V.); The Children’s Hospital of Philadelphia, Departments of Neurology and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.N.I.); Department of Neurology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada Alberta Children’s Hospital (A.K.) and Department of Clinical Neurosciences and Hotchkiss Brain Institute (M.D.H.), University of Calgary, Alberta, Canada; Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada (A.C.); Dell Children's Medical Center and University of Texas at Austin College of Pharmacy (C.A.H.); BloodCenter of Wisconsin and Department of Pediatrics (J.C.G.) and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee; Center for Integrated Brain Research, Seattle Children’s Research Institute, WA (K.S.); and Seattle Children's Hospital, Department of Neurology, University of Washington, Seattle (C.A.-L.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 114.008210/-/DC1. Correspondence to Catherine Amlie-Lefond, MD, Department of Neurology, Seattle Children’s Hospital/University of Washington, M/S B5552, 4800 Sand Point Way NE, Seattle, WA 98105. E-mail calefond@uw.edu (Stroke. 2015;46:880-885. DOI: 10.1161/STROKEAHA.114.008210.) © 2015 American Heart Association, Inc. 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