Background: In observational studies, a high body temperature has been associated with unfavorable outcome. In in vitro studies, the fibrinolytic activity of alteplase decreased 5% per degree Celsius reduction in temperature. The modifying effect of body temperature on treatment with alteplase in patients with acute ischemic stroke is unclear. We assessed the influence of baseline body temperature on the effect of alteplase on functional outcome in patients with acute ischemic stroke, included in the Paracetamol (Acetaminophen) in Stroke (PAIS) trial. Methods: PAIS was a randomized, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke. For this study, we selected all patients with ischemic stroke and randomization within 6 h of symptom onset. We estimated the effect of treatment with alteplase on the modified Rankin Scale score at 3 months with ordinal logistic regression, stratified by baseline body temperature. We made adjustments for confounding factors and expressed associations as adjusted odds ratios (aOR) with 95% confidence intervals (CI). We also tested for interaction between treatment with alteplase and body temperature. Results: We included 647 of the 1,400 patients in PAIS in our study. Treatment with alteplase was associated with improved functional outcome at 3 months (aOR 1.51, 95% CI 1.09–2.08). In the 286 patients (44%) with a baseline body temperature of 37.0°C or higher, alteplase was associated with a larger effect (aOR 2.13, 95% CI 1.28–3.45) than in patients with a temperature below 37.0°C (aOR 1.11, 95% CI 0.71–1.69). A test for interaction between body temperature and alteplase did not reach statistical significance (p = 0.18). Conclusion: Patients with ischemic stroke and a high body temperature may have a larger benefit of treatment with alteplase than patients with lower body temperatures. These findings are in line with those from in vitro studies, in which lowering temperature decreased the fibrinolytic activity of the enzyme alteplase. This interaction should be explored further in randomized clinical trials of thrombolytic therapy or modification of body temperature. Trials of therapeutic hypothermia should be controlled for treatment with thrombolytics, and trials of thrombolytic treatment should consider body temperature as a potential effect modifier.

Keywords:
Ischemic stroke, Thrombolysis, Body temperature, Alteplase
1.
Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, et al: The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the Third International Stroke Trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352–2363.
2.
den Hertog HM, van der Worp HB, van Gemert HMA, Dippel DWJ: Therapeutic hypothermia in acute ischemic stroke. Expert Rev Neurother 2007;7:155–164.
3.
Kallmunzer B, Kollmar R: Temperature management in stroke – an unsolved, but important topic. Cerebrovasc Dis 2011;31:532–543.
4.
van der Worp HB, Macleod MR, Kollmar R: Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab 2010;30:1079–1093.
5.
Naess H, Idicula T, Lagallo N, Brogger J, Waje-Andreassen U, Thomassen L: Inverse relationship of baseline body temperature and outcome between ischemic stroke patients treated and not treated with thrombolysis: the Bergen stroke study. Acta Neurol Scand 2010;122:414–417.
6.
Lees JS, Mishra NK, Saini M, Lyden PD, Shuaib A: Low body temperature does not compromise the treatment effect of alteplase. Stroke 2011;42:2618–2621.
7.
den Hertog HM, van der Worp HB, van Gemert HMA, Algra A, Kappelle LJ, van Gijn J, et al: The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial. Lancet Neurol 2009;8:434–440.
8.
Rijken DC, Lijnen HR: New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 2009;7:4–13.
9.
de Ridder IR, de Jong FJ, den Hertog HM, Lingsma HF, van Gemert HMA, Schreuder AHCML, Ruitenberg A, Maasland E, Saxena R, Oomes P, van Tuijl J, Koudstaal PJ, Kappelle LJ, Algra A, van der Worp HB, Dippel DWJ: Paracetamol (Acetaminophen) in Stroke 2 (PAIS 2). Protocol for a randomized, placebo-controlled, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke and a body temperature of 36.5°C or above. Int J Stroke 2012, E-pub ahead of print.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.