Abstract
BACKGROUND: Massive transfusion protocols to treat postinjury hemorrhage are based on predefined blood product transfusion ratios followed by goal-directed transfusion based on patient's clinical evolution. However, it remains unclear how these transfusion ratios impact patient outcomes over time from injury. METHODS: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) is a phase 3, randomized controlled trial, across 12 Level I trauma centers in North America. From 2012 to 2013, 680 severely injured patients required massive transfusion. We used semiparametric machine learning techniques and causal inference methods to augment the intent-to-treat analysis of PROPPR, estimating the dynamic relationship between transfusion ratios and outcomes: mortality and hemostasis at different timepoints during the first 24 hours after admission. RESULTS: In the intention-to-treat analysis, the 1:1:1 group tended to have decreased mortality, but with no statistical significance. For patients in whom hemostasis took longer than 2 hours, the 1:1:1 ratio was associated with a higher probability of hemostasis, statistically significant from the 4th hour on. In the per-protocol, actual-transfusion-ratios-received analysis, during four successive time intervals, no significant association was found between the actual ratios and mortality. When comparing patient groups who received both high plasma/PRBC and high platelet/PRBC ratios to the group of low ratios in both, the relative risk of achieving hemostasis was 2.49 (95% confidence interval, 1.19-5.22) during the third hour after admission, suggesting a significant beneficial impact of higher transfusion ratios of plasma and platelets on hemostasis. CONCLUSION: Our results suggest that the impact of transfusion ratios on hemostasis is dynamic. Overall, the transfusion ratios had no significant impact on mortality over time. However, receiving higher ratios of platelets and plasma relative to red blood cells hastens hemostasis in subjects who have yet to achieve hemostasis within 3 hours after hospital admission.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 505-513 |
| Number of pages | 9 |
| Journal | Journal of Trauma and Acute Care Surgery |
| Volume | 89 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 1 2020 |
Keywords
- Blood transfusion
- Hemorrhage
- Postinjury hemostasis
- Trauma
ASJC Scopus subject areas
- Surgery
- Critical Care and Intensive Care Medicine
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In: Journal of Trauma and Acute Care Surgery, Vol. 89, No. 3, 01.09.2020, p. 505-513.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Dynamic impact of transfusion ratios on outcomes in severely injured patients
T2 - Targeted machine learning analysis of the pragmatic, randomized optimal platelet and plasma ratios randomized clinical trial
AU - Nguyen, Minh
AU - Pirracchio, Romain
AU - Kornblith, Lucy Z.
AU - Callcut, Rachael
AU - Fox, Erin E.
AU - Wade, Charles E.
AU - Schreiber, Martin
AU - Holcomb, John B.
AU - Coyle, Jeremy
AU - Cohen, Mitchell
AU - Hubbard, Alan
N1 - Funding Information: Group Acknowledgments: The PROPPR Study Group: Clinical Coordinating Center, University of Texas Health Science Center, Houston: John B. Holcomb, MD, Charles E. Wade, PhD, Deborah J. del Junco, PhD, Erin E. Fox, PhD, Nena Matijevic, PhD (laboratory committee co-chair), Jeanette M. Podbielski, RN, Angela M. Beeler, BS. Data Coordinating Center, University of Texas Health Science Center, Houston: Barbara C. Tilley, PhD, Sarah Baraniuk, PhD, Stacia M. DeSantis, PhD, Hongjian Zhu, PhD, Joshua Nixon, MS, Roann Seay, MS, Savitri N. Appana, MS, Hui Yang, MS, Michael O. Gonzalez, MS. Core Laboratory, University of Texas Health Science Center, Houston: Lisa Baer, MS, Yao-Wei Willa Wang, MD, Brittany S. Hula, MS, Elena Espino, BS, An Nguyen, BS, Nicholas Pawelczyk, BS, Kisha D. Arora-Nutall, BS, Rishika Sharma, MD, Jessica C. Cardenas, PhD, Elaheh Rahbar, PhD, Tyrone Burnett Jr, BS, David Clark, BS. Resuscitation Outcomes Consortium, University of Washington: Gerald van Belle, PhD, Susanne May, PhD, Brian Leroux, PhD, David Hoyt, MD, Judy Powell, BSN, RN, Kellie Sheehan, BSN. Systems Biology Committee, University of California, Berkeley: Alan Hubbard, PhD (co-chair), Adam P. Arkin, PhD. Transfusion Committee: John R. Hess, MD, MPH (co-chair, University of Washington), Jeannie L. Callum, MD (co-chair, Sunnybrook Health Sciences Centre). Anesthesiology Committee: Jean-Francois Pittet, MD (chair, University of Alabama, Birmingham). Emergency Medicine Committee: Christopher N. Miller, MD (chair, University of Cincinnati). PROPPR Clinical Sites (listed in order of number of patients enrolled): University of Texas Health Science Center, Houston: Bryan A. Cotton, MD, MPH, Laura Vincent, BSN, RN, CCRP, Timothy Welch, Tiffany Poole, DC, Evan G. Pivalizza, MD, Sam D. Gumbert, MD, Yu Bai, MD, PhD, James J. McCarthy, MD, Amy Noland, MD, Rhonda Hobbs, MT(ASCP)SBB. University of Washington: Eileen M. Bulger, MD, Patricia Klotz, RN, Lindsay Cattin, BA, Keir J. Warner, BS, Angela Wilson, BA, David Boman, BA, Nathan White, MD, MS, Andreas Grabinsky, MD, Jennifer A. Daniel-Johnson, MBBS. University of California, San Francisco: Mitchell Jay Cohen, MD (systems biology and laboratory committee co-chair), Rachael A. Callcut, MD, MSPH, Mary Nelson, RN, MPA, Brittney Redick, BA, Amanda Conroy, BA, Marc P. Steurer, MD, DESA, Preston C. Maxim, MD, Eberhard Fiebig, MD, Joanne Moore, Eireen Mallari, MT. University of Cincinnati: Peter Muskat, MD, Jay A. Johannigman, MD, Bryce R. H. Robinson, MD, Richard D. Branson, MSc, RRT, Dina Gomaa, BS, RRT, Christopher Barczak, BS, MT (ASCP), Suzanne Bennett, MD, Patricia M. Carey, MD, Helen Hancock, BS, MT(ASCP), Carolina Rodriguez, BA. University of Southern California: Kenji Inaba, MD, Jay G. Zhu, MD, Monica D. Wong, MS, Michael Menchine, MD, MPH, Kelly Katzberg, MD, FACEP, Sean O. Henderson, MD, Rodney McKeever, MD, Ira A. Shulman, MD, Janice M. Nelson, MD, Christopher W. Tuma, BA, MT(ASCP), SBB, Cheryl Y. Matsushita, BS, MT(ASCP). Shock, Trauma and Anesthesiology Research-Organized Research Center, R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center: Thomas M. Scalea, MD, Deborah M. Stein, MD, MPH, Cynthia K. Shaffer, MS, MBA, Christine Wade, BA, Anthony V. Herrera, MS, Seeta Kallam, MBBS, Sarah E. Wade, BS, Samuel M. Galvagno Jr, DO, PhD, Magali J. Fontaine, MD, PhD, Janice M. Hunt, BS, MT(ASCP) SBB, Rhonda K. Cooke, MD. University of Tennessee Health Science Center, Memphis: Timothy C. Fabian, MD, Jordan A. Weinberg, MD, Martin A. Croce, MD, Suzanne Wilson, RN, Stephanie Panzer-Baggett, RN, Lynda WaddleSmith, BSN, Sherri Flax, MD. Medical College of Wisconsin: Karen J. Brasel, MD, MPH, Pamela Walsh, AS, CCRC, David Milia, MD, Allia Nelson, BS, BA, Olga Kaslow, MD, PhD, Tom P. Aufderheide, MD, MS, Jerome L. Gottschall, MD, Erica Carpenter, MLS (ASCP). University of Arizona: Terence O'Keeffe, MBChB, MSPH, Laurel L. Rokowski, RN, BSN, MKT, Kurt R. Denninghoff, MD, Daniel T. Redford, MD, Deborah J. Novak, MD, Susan Knoll, MS, MT(ASCP)SBB. University of Alabama, Birmingham: Jeffrey D. Kerby, MD, PhD, Patrick L. Bosarge, MD, Albert T. Pierce, MD, Carolyn R. Williams, RN, BSN, BSME, Shannon W. Stephens, EMTP, Henry E. Wang, MD, MS, Marisa B. Marques, MD. Oregon Health & Science University: Martin A. Schreiber, MD, Jennifer M. Watters, MD, Samantha J. Underwood, MS, Tahnee Groat, MPH, Craig Newgard, MD, MPH, Matthias Merkel, MD, PhD, Richard M. Scanlan, MD, Beth Miller, MT(ASCP)SBB. Sunnybrook Health Science Center: Sandro Rizoli, MD, PhD, Homer Tien, MD, Barto Nascimento, MD, MSc, CTBS, Sandy Trpcic, Skeeta Sobrian-Couroux, RN, CCRP, BHA, Marciano Reis, Adic Pérez, MD, Susan E. Belo, MD, PhD, Lisa Merkley, BA, MLT, CBTS, Connie Colavecchia, BSc, MLT. This work was supported with grant U01HL077863 from the US National Heart, Lung, and Blood Institute and funding from the US Department of Defense, the Defense Research and Development Canada in partnership with the Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health (grant CRR120612). Role of the Funder/Sponsor: The US National Heart, Lung, and Blood Institute (NHLBI) and the US Department of Defense had a role in the study design but had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: Group Acknowledgments: The PROPPR Study Group: Clinical Coordinating Center, University of Texas Health Science Center, Houston: John B. Holcomb, MD, Charles E. Wade, PhD, Deborah J. del Junco, PhD, Erin E. Fox, PhD, Nena Matijevic, PhD (laboratory committee co-chair), Jeanette M. Podbielski, RN, Angela M. Beeler, BS. Data Coordinating Center, University of Texas Health Science Center, Houston: Barbara C. Tilley, PhD, Sarah Baraniuk, PhD, Stacia M. DeSantis, PhD, Hongjian Zhu, PhD, Joshua Nixon, MS, Roann Seay, MS, Savitri N. Appana, MS, Hui Yang, MS, Michael O. Gonzalez, MS. Core Laboratory, University of Texas Health Science Center, Houston: Lisa Baer, MS, Yao-Wei Willa Wang, MD, Brittany S. Hula, MS, Elena Espino, BS, An Nguyen, BS, Nicholas Pawelczyk, BS, Kisha D. Arora-Nutall, BS, Rishika Sharma, MD, Jessica C. Cardenas, PhD, Elaheh Rahbar, PhD, Tyrone Burnett Jr, BS, David Clark, BS. Resuscitation Outcomes Consortium, University of Washington: Gerald van Belle, PhD, Susanne May, PhD, Brian Leroux, PhD, David Hoyt, MD, Judy Powell, BSN, RN, Kellie Sheehan, BSN. Systems Biology Committee, University of California, Berkeley: Alan Hubbard, PhD (co-chair), Adam P. Arkin, PhD. Transfusion Committee: John R. Hess, MD, MPH (co-chair, University of Washington), Jeannie L. Callum, MD (co-chair, Sunnybrook Health Sciences Centre). Anesthesiology Committee: Jean-Francois Pittet, MD (chair, University of Alabama, Birmingham). Emergency Medicine Committee: Christopher N. Miller, MD (chair, University of Cincinnati). PROPPR Clinical Sites (listed in order of number of patients enrolled): University of Texas Health Science Center, Houston: Bryan A. Cotton, MD, MPH, Laura Vincent, BSN, RN, CCRP, Timothy Welch, Tiffany Poole, DC, Evan G. Pivalizza, MD, Sam D. Gumbert, MD, Yu Bai, MD, PhD, James J. McCarthy, MD, Amy Noland, MD, Rhonda Hobbs, MT(ASCP)SBB. University of Washington: Eileen M. Bulger, MD, Patricia Klotz, RN, Lindsay Cattin, BA, Keir J. Warner, BS, Angela Wilson, BA, David Boman, BA, Nathan White, MD, MS, Andreas Grabinsky, MD, Jennifer A. Daniel-Johnson, MBBS. University of California, San Francisco: Mitchell Jay Cohen, MD (systems biology and laboratory committee co-chair), Rachael A. Callcut, MD, MSPH, Mary Nelson, RN, MPA, Brittney Redick, BA, Amanda Conroy, BA, Marc P. Steurer, MD, DESA, Preston C. Maxim, MD, Eberhard Fiebig, MD, Joanne Moore, Eireen Mallari, MT. University of Cincinnati: Peter Muskat, MD, Jay A. Johannigman, MD, Bryce R. H. Robinson, MD, Richard D. Branson, MSc, RRT, Dina Gomaa, BS, RRT, Christopher Barczak, BS, MT (ASCP), Suzanne Bennett, MD, Patricia M. Carey, MD, Helen Hancock, BS, MT(ASCP), Carolina Rodriguez, BA. University of Southern California: Kenji Inaba, MD, Jay G. Zhu, MD, Monica D. Wong, MS, Michael Menchine, MD, MPH, Kelly Katzberg, MD, FACEP, Sean O. Henderson, MD, Rodney McKeever, MD, Ira A. Shulman, MD, Janice M. Nelson, MD, Christopher W. Tuma, BA, MT(ASCP), SBB, Cheryl Y. Matsushita, BS, MT(ASCP). Shock, Trauma and Anesthesiology Research-Organized Research Center, R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center: Thomas M. Scalea, MD, Deborah M. Stein, MD, MPH, Cynthia K. Shaffer, MS, MBA, Christine Wade, BA, Anthony V. Herrera, MS, Seeta Kallam, MBBS, Sarah E. Wade, BS, Samuel M. Galvagno Jr, DO, PhD, Magali J. Fontaine, MD, PhD, Janice M. Hunt, BS, MT(ASCP) SBB, Rhonda K. Cooke, MD. University of Tennessee Health Science Center, Memphis: Timothy C. Fabian, MD, Jordan A. Weinberg, MD, Martin A. Croce, MD, Suzanne Wilson, RN, Stephanie Panzer-Baggett, RN, Lynda WaddleSmith, BSN, Sherri Flax, MD. Medical College of Wisconsin: Karen J. Brasel, MD, MPH, Pamela Walsh, AS, CCRC, David Milia, MD, Allia Nelson, BS, BA, Olga Kaslow, MD, PhD, Tom P. Aufderheide, MD, MS, Jerome L. Gottschall, MD, Erica Carpenter, MLS (ASCP). University of Arizona: Terence O'Keeffe, MBChB, MSPH, Laurel L. Rokowski, RN, BSN, MKT, Kurt R. Denninghoff, MD, Daniel T. Redford, MD, Deborah J. Novak, MD, Susan Knoll, MS, MT(ASCP)SBB. University of Alabama, Birmingham: Jeffrey D. Kerby, MD, PhD, Patrick L. Bosarge, MD, Albert T. Pierce, MD, Carolyn R. Williams, RN, BSN, BSME, Shannon W. Stephens, EMTP, Henry E. Wang, MD, MS, Marisa B. Marques, MD. Oregon Health & Science University: Martin A. Schreiber, MD, Jennifer M. Watters, MD, Samantha J. Underwood, MS, Tahnee Groat, MPH, Craig Newgard, MD, MPH, Matthias Merkel, MD, PhD, Richard M. Scanlan, MD, Beth Miller, MT(ASCP)SBB. Sunnybrook Health Science Center: Sandro Rizoli, MD, PhD, Homer Tien, MD, Barto Nascimento, MD, MSc, CTBS, Sandy Trpcic, Skeeta Sobrian-Couroux, RN, CCRP, BHA, Marciano Reis, Adic Pérez, MD, Susan E. Belo, MD, PhD, Lisa Merkley, BA, MLT, CBTS, Connie Colavecchia, BSc, MLT. (copied from original paper) Disclaimer: The content is the sole responsibility of the authors and should not be construed as official or as reflecting the views of any of the sponsors nor of non-authors in the PROPPR Study Group. Special Acknowledgments: We thank Jonathan Levy, PhD for theoretical and implementation insights; and Robert Talley, MA, for helping with proofreading. Funding/Support: This work was supported with grant U01HL077863 from the US National Heart, Lung, and Blood Institute and funding from the US Department of Defense, the Defense Research and Development Canada in partnership with the Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health (grant CRR120612). Role of the Funder/Sponsor: The US National Heart, Lung, and Blood Institute (NHLBI) and the US Department of Defense had a role in the study design but had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - BACKGROUND: Massive transfusion protocols to treat postinjury hemorrhage are based on predefined blood product transfusion ratios followed by goal-directed transfusion based on patient's clinical evolution. However, it remains unclear how these transfusion ratios impact patient outcomes over time from injury. METHODS: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) is a phase 3, randomized controlled trial, across 12 Level I trauma centers in North America. From 2012 to 2013, 680 severely injured patients required massive transfusion. We used semiparametric machine learning techniques and causal inference methods to augment the intent-to-treat analysis of PROPPR, estimating the dynamic relationship between transfusion ratios and outcomes: mortality and hemostasis at different timepoints during the first 24 hours after admission. RESULTS: In the intention-to-treat analysis, the 1:1:1 group tended to have decreased mortality, but with no statistical significance. For patients in whom hemostasis took longer than 2 hours, the 1:1:1 ratio was associated with a higher probability of hemostasis, statistically significant from the 4th hour on. In the per-protocol, actual-transfusion-ratios-received analysis, during four successive time intervals, no significant association was found between the actual ratios and mortality. When comparing patient groups who received both high plasma/PRBC and high platelet/PRBC ratios to the group of low ratios in both, the relative risk of achieving hemostasis was 2.49 (95% confidence interval, 1.19-5.22) during the third hour after admission, suggesting a significant beneficial impact of higher transfusion ratios of plasma and platelets on hemostasis. CONCLUSION: Our results suggest that the impact of transfusion ratios on hemostasis is dynamic. Overall, the transfusion ratios had no significant impact on mortality over time. However, receiving higher ratios of platelets and plasma relative to red blood cells hastens hemostasis in subjects who have yet to achieve hemostasis within 3 hours after hospital admission.
AB - BACKGROUND: Massive transfusion protocols to treat postinjury hemorrhage are based on predefined blood product transfusion ratios followed by goal-directed transfusion based on patient's clinical evolution. However, it remains unclear how these transfusion ratios impact patient outcomes over time from injury. METHODS: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) is a phase 3, randomized controlled trial, across 12 Level I trauma centers in North America. From 2012 to 2013, 680 severely injured patients required massive transfusion. We used semiparametric machine learning techniques and causal inference methods to augment the intent-to-treat analysis of PROPPR, estimating the dynamic relationship between transfusion ratios and outcomes: mortality and hemostasis at different timepoints during the first 24 hours after admission. RESULTS: In the intention-to-treat analysis, the 1:1:1 group tended to have decreased mortality, but with no statistical significance. For patients in whom hemostasis took longer than 2 hours, the 1:1:1 ratio was associated with a higher probability of hemostasis, statistically significant from the 4th hour on. In the per-protocol, actual-transfusion-ratios-received analysis, during four successive time intervals, no significant association was found between the actual ratios and mortality. When comparing patient groups who received both high plasma/PRBC and high platelet/PRBC ratios to the group of low ratios in both, the relative risk of achieving hemostasis was 2.49 (95% confidence interval, 1.19-5.22) during the third hour after admission, suggesting a significant beneficial impact of higher transfusion ratios of plasma and platelets on hemostasis. CONCLUSION: Our results suggest that the impact of transfusion ratios on hemostasis is dynamic. Overall, the transfusion ratios had no significant impact on mortality over time. However, receiving higher ratios of platelets and plasma relative to red blood cells hastens hemostasis in subjects who have yet to achieve hemostasis within 3 hours after hospital admission.
KW - Blood transfusion
KW - Hemorrhage
KW - Postinjury hemostasis
KW - Trauma
UR - http://www.scopus.com/inward/record.url?scp=85089806781&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089806781&partnerID=8YFLogxK
U2 - 10.1097/TA.0000000000002819
DO - 10.1097/TA.0000000000002819
M3 - Article
C2 - 32520897
AN - SCOPUS:85089806781
SN - 2163-0755
VL - 89
SP - 505
EP - 513
JO - Journal of Trauma and Acute Care Surgery
JF - Journal of Trauma and Acute Care Surgery
IS - 3
ER -