Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2)
Patrick Lyden, Thomas Hemmen, James Grotta, Karen Rapp, Karin Ernstrom, Teresa Rzesiewicz, Stephanie Parker, Mauricio Concha, Syed Hussain, Sachin Agarwal, Brett Meyer, Julie Jurf, Irfan Altafullah, Rema Raman, Collaborators, Mary Jane Hess, Anthony Mullin, Mary Jane Hess, Gabriela Muranevici, Bonnie Piantadosi, Gustavo Jimenez-Maggiora, Jia-Shing So, Sonia Jain, Michael Diringer, Colin Derdeyn, Barney Stern, Scott Hamilton, Dalton Dietrich, Kyra Becker, Midori Yenari, Ulrich Dirnagl, Christine Wijman, Ángel Chamorro, Scott Janis, Claudia Moy, Felice Lin, Shlee Song, Konrad Schlick, Pooja Khanolkar, Nancy J Edwards, Ana Roldan, Jeanette Wilson, Amy Little, Pam Lewis, William Neil, Nhu Bruce, Amy Guzik, Ajeet Sohdi, Nabeel Herial, Bruce Ovbiagele, Dawn Meyer, Royya Modir, Ronelyn Chavez, Angela Velazquez, Stephan Mayer, Jan Claassen, Cristina Falo, Gilda Tafreshi, William Neil, Nhu Bruce, Amy Guzik, Royya Modir, Nancy Kelly, Ronelyn Chavez, Bruce Ovbiagele, Erin Shell, Guy Dugan, Elizabeth Kim, Amy Tanner, Patrik Michel, Ashraf Eskandari, Mauro Oddo, Tamarah Suys, Suzette Remillard, Maria Cordier, Robert Brown, Sara Jasak, Louise McCullough, Robert Brautigam, Andrei Alexandrov, April Sisson, Karen Albright, Gregor Broessner, Erich Schmutzhard, Elissanet Escioglou, William Jones, Sharon Poisson, Jennifer Simpson, Qaisar Shah, Karin Jonczak, Patricia Bussinger, Christopher Lewandowski, Shannen Berry, AnneMarie Lundell, Joseph B Miller, Salvador Cruz-Flores, Eve Holzer, Susan Torretta, David Brown, Laura Heim, Carlos Smith, Chip Kelley, David Greer, Evadne G Marcolini, Emily J Gilmore, Neil Rutledge, Del McBee, Anna Khanna, Sonisha Warren, Christina Wilsom, Vishnumurthy Shushrutha Hedna, Christian Rosado, Rosie Kizza, Kristine O'Phelan, Andrea Escobar, Amedeo Merenda, Juan Perez Barcena, Amer Malik, Patrick Lyden, Thomas Hemmen, James Grotta, Karen Rapp, Karin Ernstrom, Teresa Rzesiewicz, Stephanie Parker, Mauricio Concha, Syed Hussain, Sachin Agarwal, Brett Meyer, Julie Jurf, Irfan Altafullah, Rema Raman, Collaborators, Mary Jane Hess, Anthony Mullin, Mary Jane Hess, Gabriela Muranevici, Bonnie Piantadosi, Gustavo Jimenez-Maggiora, Jia-Shing So, Sonia Jain, Michael Diringer, Colin Derdeyn, Barney Stern, Scott Hamilton, Dalton Dietrich, Kyra Becker, Midori Yenari, Ulrich Dirnagl, Christine Wijman, Ángel Chamorro, Scott Janis, Claudia Moy, Felice Lin, Shlee Song, Konrad Schlick, Pooja Khanolkar, Nancy J Edwards, Ana Roldan, Jeanette Wilson, Amy Little, Pam Lewis, William Neil, Nhu Bruce, Amy Guzik, Ajeet Sohdi, Nabeel Herial, Bruce Ovbiagele, Dawn Meyer, Royya Modir, Ronelyn Chavez, Angela Velazquez, Stephan Mayer, Jan Claassen, Cristina Falo, Gilda Tafreshi, William Neil, Nhu Bruce, Amy Guzik, Royya Modir, Nancy Kelly, Ronelyn Chavez, Bruce Ovbiagele, Erin Shell, Guy Dugan, Elizabeth Kim, Amy Tanner, Patrik Michel, Ashraf Eskandari, Mauro Oddo, Tamarah Suys, Suzette Remillard, Maria Cordier, Robert Brown, Sara Jasak, Louise McCullough, Robert Brautigam, Andrei Alexandrov, April Sisson, Karen Albright, Gregor Broessner, Erich Schmutzhard, Elissanet Escioglou, William Jones, Sharon Poisson, Jennifer Simpson, Qaisar Shah, Karin Jonczak, Patricia Bussinger, Christopher Lewandowski, Shannen Berry, AnneMarie Lundell, Joseph B Miller, Salvador Cruz-Flores, Eve Holzer, Susan Torretta, David Brown, Laura Heim, Carlos Smith, Chip Kelley, David Greer, Evadne G Marcolini, Emily J Gilmore, Neil Rutledge, Del McBee, Anna Khanna, Sonisha Warren, Christina Wilsom, Vishnumurthy Shushrutha Hedna, Christian Rosado, Rosie Kizza, Kristine O'Phelan, Andrea Escobar, Amedeo Merenda, Juan Perez Barcena, Amer Malik
Abstract
Background and purpose: Therapeutic hypothermia is a potent neuroprotectant approved for cerebral protection after neonatal hypoxia-ischemia and cardiac arrest. Therapeutic hypothermia for acute ischemic stroke is safe and feasible in pilot trials. We designed a study protocol to provide safer, faster therapeutic hypothermia in stroke patients.
Methods: Safety procedures and 4°C saline infusions for faster cooling were added to the ICTuS trial (Intravascular Cooling in the Treatment of Stroke) protocol. A femoral venous intravascular cooling catheter after intravenous recombinant tissue-type plasminogen activator in eligible patients provided 24 hours cooling followed by a 12-hour rewarm. Serial safety assessments and imaging were performed. The primary end point was 3-month modified Rankin score 0,1.
Results: Of the intended 1600 subjects, 120 were enrolled before the study was stopped. Randomly, 63 were to receive hypothermia plus antishivering treatment and 57 normothermia. Compared with previous studies, cooling rates were improved with a cold saline bolus, without fluid overload. The intention-to-treat primary outcome of 90-day modified Rankin Score 0,1 occurred in 33% hypothermia and 38% normothermia subjects, odds ratio (95% confidence interval) of 0.81 (0.36-1.85). Serious adverse events occurred equally. Mortality was 15.9% hypothermia and 8.8% normothermia subjects, odds ratio (95% confidence interval) of 1.95 (0.56-7.79). Pneumonia occurred in 19% hypothermia versus 10.5% in normothermia subjects, odds ratio (95% confidence interval) of 1.99 (0.63-6.98).
Conclusions: Intravascular therapeutic hypothermia was confirmed to be safe and feasible in recombinant tissue-type plasminogen activator-treated acute ischemic stroke patients. Protocol changes designed to reduce pneumonia risk appeared to fail, although the sample is small.
Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01123161.
Keywords: hypothermia; intention to treat analysis; ischemic stroke; neuroprotection; pneumonia; stroke; therapeutics.
© 2016 American Heart Association, Inc.
Figures
![Figure 1. CONSORT flow diagram](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5134910/bin/nihms824615f1.jpg)
![Figure 2. Key Trial Milestones](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5134910/bin/nihms824615f2.jpg)
Figure 3. Vital Signs Throughout the Duration…
Figure 3. Vital Signs Throughout the Duration of Cooling and Rewarming
At each time point…
- Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results.Hemmen TM, Raman R, Guluma KZ, Meyer BC, Gomes JA, Cruz-Flores S, Wijman CA, Rapp KS, Grotta JC, Lyden PD; ICTuS-L Investigators. Hemmen TM, et al. Stroke. 2010 Oct;41(10):2265-70. doi: 10.1161/STROKEAHA.110.592295. Epub 2010 Aug 19. Stroke. 2010. PMID: 20724711 Free PMC article. Clinical Trial.
- Mild hypothermia after intravenous thrombolysis in patients with acute stroke: a randomized controlled trial.Piironen K, Tiainen M, Mustanoja S, Kaukonen KM, Meretoja A, Tatlisumak T, Kaste M. Piironen K, et al. Stroke. 2014 Feb;45(2):486-91. doi: 10.1161/STROKEAHA.113.003180. Epub 2014 Jan 16. Stroke. 2014. PMID: 24436240 Clinical Trial.
- Endovascular therapeutic hypothermia for acute ischemic stroke: ICTuS 2/3 protocol.Lyden PD, Hemmen TM, Grotta J, Rapp K, Raman R. Lyden PD, et al. Int J Stroke. 2014 Jan;9(1):117-25. doi: 10.1111/ijs.12151. Epub 2013 Nov 10. Int J Stroke. 2014. PMID: 24206528 Free PMC article. Clinical Trial.
- Combination therapy with hypothermia for treatment of cerebral ischemia.Tang XN, Liu L, Yenari MA. Tang XN, et al. J Neurotrauma. 2009 Mar;26(3):325-31. doi: 10.1089/neu.2008.0594. J Neurotrauma. 2009. PMID: 19216635 Free PMC article. Review.
- Therapeutic hypothermia for acute ischemic stroke.Froehler MT, Ovbiagele B. Froehler MT, et al. Expert Rev Cardiovasc Ther. 2010 Apr;8(4):593-603. doi: 10.1586/erc.09.129. Expert Rev Cardiovasc Ther. 2010. PMID: 20397832 Review.
- Editorial: Selective brain and heart hypothermia - A path toward targeted organ resuscitation and protection.Choi JH, Pile-Spellman J, Weinberger J, Poli S. Choi JH, et al. Front Neurol. 2023 Mar 14;14:1162865. doi: 10.3389/fneur.2023.1162865. eCollection 2023. Front Neurol. 2023. PMID: 36998777 Free PMC article. No abstract available.
- Embracing Heterogeneity in The Multicenter Stroke Preclinical Assessment Network (SPAN) Trial.Morais A, Locascio JJ, Sansing LH, Lamb J, Nagarkatti K, Imai T, van Leyen K, Aronowski J, Koenig JI, Bosetti F, Lyden P, Ayata C; SPAN Investigators. Morais A, et al. Stroke. 2023 Feb;54(2):620-631. doi: 10.1161/STROKEAHA.122.040638. Epub 2023 Jan 5. Stroke. 2023. PMID: 36601951 Review.
- Therapeutic hypothermia for stroke: Unique challenges at the bedside.You JS, Kim JY, Yenari MA. You JS, et al. Front Neurol. 2022 Oct 3;13:951586. doi: 10.3389/fneur.2022.951586. eCollection 2022. Front Neurol. 2022. PMID: 36262833 Free PMC article. Review.
- Expedited brain cooling: Persistent temperature management from first aid to interhospital treatment.Xu S, Ji X, Li M, Wu D. Xu S, et al. J Cereb Blood Flow Metab. 2023 Feb;43(2):319-321. doi: 10.1177/0271678X221127088. Epub 2022 Sep 20. J Cereb Blood Flow Metab. 2023. PMID: 36127836
- Non-invasive Brain Temperature Measurement in Acute Ischemic Stroke.Horn M, Diprose WK, Pichardo S, Demchuk A, Almekhlafi M. Horn M, et al. Front Neurol. 2022 Aug 5;13:889214. doi: 10.3389/fneur.2022.889214. eCollection 2022. Front Neurol. 2022. PMID: 35989905 Free PMC article. Review.
- Multicenter Study
- Randomized Controlled Trial
- Aged
- Aged, 80 and over
- Female
- Follow-Up Studies
- Humans
- Hypothermia, Induced / adverse effects
- Hypothermia, Induced / instrumentation
- Hypothermia, Induced / methods*
- Hypothermia, Induced / standards
- Male
- Middle Aged
- Outcome Assessment, Health Care*
- Single-Blind Method
- Stroke / therapy*
- ClinicalTrials.gov/NCT01123161
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 3. Vital Signs Throughout the Duration…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5134910/bin/nihms824615f3.jpg)
Source: PubMed