Background: Although tissue plasminogen activator (tPA) has revolutionized the treatment of acute ischemic stroke in adults, no thrombolysis trials in childhood stroke have been conducted. Experience in adults cannot be applied to children due to fundamental age-related differences in coagulation systems, stroke pathophysiology and neuropharmacology. Obstacles to acute treatment trials in childhood stroke include delays in diagnosis and minimizing risk in a vulnerable population. Study Design: Thrombolysis in Pediatric Stroke (TIPS) is an international multicenter study to assess the safety of intravenous tPA within 0–3 h and intra-arterial tPA within 3–6 h of onset of arterial ischemic stroke in childhood. Through the International Pediatric Stroke Study, 30 international centers will enroll a total of 48 patients: 24 will be treated with intravenous tPA (0.6, 0.75, 0.9, and 1.0 mg/kg) using the classical dose-finding method, and 24 will be treated with intra-arterial tPA (maximum 0.2, 0.3, 0.4, and 0.5 mg/kg) using a Bayesian dose-finding method. Conclusion: The TIPS trial will be the first clinical trial exploring the safety and feasibility of systemic and local thrombolytic therapy in childhood stroke and the obstacles in conducting such a trial.
© 2009 S. Karger AG, Basel
- Acute childhood stroke
- Tissue plasminogen activator
- Marler JR, Tilley BC, Lu M, Brott TG, Lyden PC, Grotta JC, Broderick JP, Levine SR, Frankel MP, Horowitz SH, Haley EC Jr, Lewandowski CA, Kwiatkowski TP: Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology 2000;55:1649–1655.
- McGlennan C, Ganesan V: Delays in investigation and management of acute arterial ischaemic stroke in children. Dev Med Child Neurol 2008;50:537–540.
- Rafay MF, Pontigon AM, Chiang J, Adams M, Jarvis DA, Silver F, MacGregor D, deVeber GA: Delay to Diagnosis in Acute Pediatric Arterial Ischemic Stroke. Stroke, E-pub ahead of print.
- Amlie-Lefond C, Benedict S, Bernard T, Carpenter J, Chan A, et al, and the International Paediatric Stroke Study Investigators: Thrombolysis in children with arterial ischemic stroke: initial results from the International Paediatric Stroke Study. Stroke 2007;38:485.
- Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L: Maturation of the hemostatic system during childhood. Blood 1992;80:1998–2005.
- Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, De RL, Hamilton S, Ragg P, Robinson S, Auldist A, Crock C, Roy N, Rowlands S: Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006;95:362–372.
- International Paediatric Stroke Study: Establishing a multinational research network in paediatric stroke: the International Paediatric Stroke Study. Ann Neurol 2006;60 (suppl 10):149.
- Golomb M, Fullerton HJ, Nowak-Gottl U, deVeber G: Male predominance in childhood ischemic stroke: findings from the International Pediatric Stroke Study. Stroke, E-pub ahead of print.
- Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–1587.
- Ichord RN, Smith SE, Garg BP, Garcia-Espana FJ, Licht DJ, O’Tool E, Clancy RC: Pediatric adaptation of NIH stroke scale predicts outcome after arterial ischemic stroke in children. Stroke 2005;36:480-481.
- Lewandowski CA, Frankel M, Tomsick TA, Broderick J, Frey J, Clark W, Starkman S, Grotta J, Spilker J, Khoury J, Brott T: Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke 1999;30:2598–2605.
- Kirton A, deVeber GA, Yeboah O, Ichord R, Rafay MF, MacGregor D, Curtis R, Friefeld S: Pediatric NIHSS as a predictor of neurological outcome in childhood stroke. Stroke 2006;37:640.
- Bladin CF, Alexandrov AV, Bellavance A, Bornstein N, Chambers B, Cote R, Lebrun L, Pirisi A, Norris JW: Seizures after stroke: a prospective multicenter study. Arch Neurol 2000;57:1617–1622.
- Yang JS, Park YD, Hartlage PL: Seizures associated with stroke in childhood. Pediatr Neurol 1995;12:136–138.
- Coolman M, de Groot CJ, Steegers EA, Geurts-Moespot A, Thomas CM, Steegers-Theunissen RP, Sweep FC: Concentrations of plasminogen activators and their inhibitors in blood preconceptionally, during and after pregnancy. Eur J Obstet Gynecol Reprod Biol 2006;128:22–28.
- Adams H Jr, del ZG, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF: Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke 2007;38:1655–1711.
- Adams RJ, Ohene-Frempong K, Wang W: Sickle cell and the brain. Hematology Am Soc Hematol Educ Program 2001;31–46.
- Shellhaas RA, Smith SE, O’Tool E, Licht DJ, Ichord RN: Mimics of childhood stroke: characteristics of a prospective cohort. Pediatrics 2006;118:704–709.
- Benedict SL, Ni OK, Schloesser P, White KS, Bale JF Jr: Intra-arterial thrombolysis in a 2-year-old with cardioembolic stroke. J Child Neurol 2007;22:225–227.
- Cannon BC, Kertesz NJ, Friedman RA, Fenrich AL: Use of tissue plasminogen activator in a stroke after radiofrequency ablation of a left-sided accessory pathway. J Cardiovasc Electrophysiol 2001;12:723–725.
- Carlson MD, Leber S, Deveikis J, Silverstein FS: Successful use of rt-PA in pediatric stroke. Neurology 2001;57:157–158.
- Golomb MR, Rafay M, Armstrong D, Massicotte P, Curtis R, Hune S, deVeber GA: Intra-arterial tissue plasminogen activator for thrombosis complicating cerebral angiography in a 17-year-old girl. J Child Neurol 2003;18:420–423.
- Gruber A, Nasel C, Lang W, Kitzmuller E, Bavinzski G, Czech T: Intra-arterial thrombolysis for the treatment of perioperative childhood cardioembolic stroke. Neurology 2000;54:1684–1686.
- Jain SV, Morton LD: Ischemic stroke and excellent recovery after administration of intravenous tissue plasminogen activator. Pediatr Neurol 2008;38:126–129.
- Kirton A, Wong JH, Mah J, Ross BC, Kennedy J, Bell K, Hill MD: Successful endovascular therapy for acute basilar thrombosis in an adolescent. Pediatrics 2003;112:248–251.
- Losurdo G, Giacchino R, Castagnola E, Gattorno M, Costabel S, Rossi A, Amato S, Di PP, Molinari AC: Cerebrovascular disease and varicella in children. Brain Dev 2006;28:366–370.
- Noser EA, Felberg RA, Alexandrov AV: Thrombolytic therapy in an adolescent ischemic stroke. J Child Neurol 2001;16:286–288.
- Ortiz GA, Koch S, Wallace DM, Lopez-Alberola R: Successful intravenous thrombolysis for acute stroke in a child. J Child Neurol 2007;22:749–752.
- Shuayto MI, Lopez JI, Greiner F: Administration of intravenous tissue plasminogen activator in a pediatric patient with acute ischemic stroke. J Child Neurol 2006;21:604–606.
- Thirumalai SS, Shubin RA: Successful treatment for stroke in a child using recombinant tissue plasminogen activator. J Child Neurol 2000;15:558.
- Amlie-Lefond C, Benedict S, Bernard T, Carpenter J, Chan A, et al, and the International Paediatric Stroke Study Investigators: tPA in children with arterial ischemic stroke: cases from the IPSS compared with the literature-based cases. J Thromb Haemost 2007;5 (suppl 2):579.
- Ichord RN, Smith SE., Agner S Licht D: Eligibility for thrombolysis in children with arterial ischemic stroke: a prospective cohort study. Stroke 2007;38:581.
- Rafay MF, Pontigan AM, Chiang J, Adams J, Jarvis A, Silver F, deVeber G: Diagnostic delays in acute pediatric arterial ischemic stroke. Neuropediatrics 2006;37(suppl 1):s83.
- Khatri P, Khoury JC, Alwell K, Woo D, Kissela MB, Moomaw CJ, et al: Potential rtPA eligibility in children: a population based study. Stroke 2006;37:641.
- Del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M: PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke 1998;29:4–11.
- Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F: Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999;282:2003–2011.
- deVeber GA, and the Canadian Pediatric Ischemic Stroke Study Group: Canadian Pediatric Ischemic Stroke Registry: analysis of children with arterial ischemic stroke. Ann Neurol 2000;48:526.
- Parmar N, Albisetti M, Berry LR, Chan AK: The fibrinolytic system in newborns and children. Clin Lab 2006;52:115–124.
- Burger IM, Murphy KJ, Jordan LC, Tamargo RJ, Gailloud P: Safety of cerebral digital subtraction angiography in children: complication rate analysis in 241 consecutive diagnostic angiograms. Stroke 2006;37:2535–2539.
- Bourekas EC, Slivka AP, Casavant MJ: Intra-arterial thrombolysis of a distal internal carotid artery occlusion in an adolescent. Neurocrit Care 2005;2:179–182.
- Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke 2004;35:904–911.
- Tomsick T: TIMI, TIBI, TICI: I came, I saw, I got confused. AJNR Am J Neuroradiol 2007;28:382–384.
- Crowley J, Ankerst DP: Handbook of Statistics in Clinical Oncology, ed 2. Boca Raton, Chapman & Hall/CRC, 2006.
- Berger C, Fiorelli M, Steiner T, Schabitz WR, Bozzao L, Bluhmki E, Hacke W, von KR: Hemorrhagic transformation of ischemic brain tissue: asymptomatic or symptomatic? Stroke 2001;32:1330–1335.
- Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke 1997;28:2109–2118.
- Brott TG, Haley EC Jr, Levy DE, Barsan W, Broderick J, Sheppard GL, Spilker J, Kongable GL, Massey S, Reed R: Urgent therapy for stroke. 1. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992;23:632–640.
- Haley EC Jr, Levy DE, Brott TG, Sheppard GL, Wong MC, Kongable GL, Torner JC, Marler JR: Urgent therapy for stroke. 2. Pilot study of tissue plasminogen activator administered 91–180 minutes from onset. Stroke 1992;23:641–645.
- Wang M, Hays T, Balasa V, Bagatell R, Gruppo R, Grabowski EF, Valentino LA, Tsao-Wu G, Manco-Johnson MJ: Low-dose tissue plasminogen activator thrombolysis in children. J Pediatr Hematol Oncol 2003;25:379–386.
- Mori E, Tabuchi M, Yoshida T, Yamadori A: Intracarotid urokinase with thromboembolic occlusion of the middle cerebral artery. Stroke 1988;19:802–812.
- Sasaki O, Takeuchi S, Koike T, Koizumi T, Tanaka R: Fibrinolytic therapy for acute embolic stroke: intravenous, intracarotid, and intra-arterial local approaches. Neurosurgery 1995;36:246–252.
- Derex L, Nighoghossian N, Hermier M, Adeleine P, Froment JC, Trouillas P: Early detection of cerebral arterial occlusion on magnetic resonance angiography: predictive value of the baseline NIHSS score and impact on neurological outcome. Cerebrovasc Dis 2002;13:225–229.
- Whelan HT, Cook JD, Amlie-Lefond CM, Hovinga CA, Chan AK, Ichord RN, deVeber GA, Thall PF: Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children. Stroke 2008;39:2627–2636.
- Sloan MA, Alexandrov AV, Tegeler CH, Spencer MP, Caplan LR, Feldmann E, Wechsler LR, Newell DW, Gomez CR, Babikian VL, Lefkowitz D, Goldman RS, Armon C, Hsu CY, Goodin DS: Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2004;62:1468–1481.
- Qureshi AI, Siddiqui AM, Kim SH, Hanel RA, Xavier AR, Kirmani JF, Suri MF, Boulos AS, Hopkins LN: Reocclusion of recanalized arteries during intra-arterial thrombolysis for acute ischemic stroke. AJNR Am J Neuroradiol 2004;25:322–328.
- Wunderlich MT, Goertler M, Postert T, Schmitt E, Seidel G, Gahn G, Samii C, Stolz E: Recanalization after intravenous thrombolysis: does a recanalization time window exist? Neurology 2007;68:1364–1368.
- Thall PF, Russell KE: A strategy for dose-finding and safety monitoring based on efficacy and adverse outcomes in phase I/II clinical trials. Biometrics 1998;54:251–264.
- Thall PF, Cook JD, Estey EH: Adaptive dose selection using efficacy-toxicity trade-offs: illustrations and practical considerations. J Biopharm Stat 2006;16:623–638.
- Eckert B, Kucinski T, Neumaier-Probst E, Fiehler J, Rother J, Zeumer H: Local intra-arterial fibrinolysis in acute hemispheric stroke: effect of occlusion type and fibrinolytic agent on recanalization success and neurological outcome. Cerebrovasc Dis 2003;15:258–263.
- The IMS II Trial Investigators: The Interventional Management of Stroke (IMS) II Study. Stroke 2007;38:2127–2135.
- Molina CA, Alexandrov AV, Demchuk AM, Saqqur M, Uchino K, Alvarez-Sabin J, for the CLOTBUST Investigators: Improving the predictive accuracy of recanalization on stroke outcome in patients treated with tissue plasminogen activator. Stroke 2004;35:151–156.
- Hill MD, Demchuk AM, Frayne R: Noninvasive imaging is improving but digital subtraction angiography remains the gold standard. Neurology 2007;68:2057–2058.
- The IMS Study Investigators: Hemorrhage in the Interventional Management of Stroke study. Stroke 2006;37:847–851.
Catherine Amlie-Lefond, MD
Medical College of Wisconsin, Department of Neurology
9200 W Wisconsin Ave
Milwaukee, WI 53226 (USA)
Tel. +1 414 266 7545, Fax +1 414 266 3466, E-Mail Klefond@mcw.edu
Received: October 15, 2008
Accepted after revision: December 8, 2008
Published online: February 18, 2009
Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 0, Number of References : 62
Vol. 32, No. 4, Year 2009 (Cover Date: April 2009)
Journal Editor: Feigin V.L. (Auckland)
ISSN: 0251-5350 (Print), eISSN: 1423-0208 (Online)
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