In 408 patients in whom hemostasis was achieved, mixed effects Poisson regression with robust error variance and modified Bonferroni corrections found that every 15-minute decrease in time to hemostasis was associated with decreased 30-day mortality (RR 0.97, 95% confidence interval [CI], 0.94–0.99, p < 0.001) and decreased incidence of AKI (RR 0.97, 95% CI 0.96–0.98, p < 0.001), ARDS (RR 0.98, 95% CI 0.97–0.99, p < 0.01), MOF (RR 0.94, 95% CI 0.91–0.97, p < 0.001), and sepsis (RR 0.98, 95% CI 0.96–0.99, p < 0.001), but not 24-hour mortality (RR 1.14, 95% CI 0.98–1.32, p = 0.13) or VTE (RR 0.99, 95% CI 0.96–1.03, p = 0.73). Results before and after adjustment for age, ISS, treatment arm, injury mechanism, time to OR/IR, and admission base excess are summarized in Figure 4.
Diagnostic studies were performed (supplemental digital content, Figures 1–14, http://links.lww.com/TA/B330). In terms of global goodness-of-fit, chi-squared tests of the deviance statistic were not significant (p > 0.05). Visual inspection of deviance residuals versus predicted values revealed no outliers in three models and 1% outliers in four models (defined as deviance residual < −2 or > +2). Due to the dichotomous outcome, the residuals were not expected to be normally distributed. Instead, we used our models to generate simulated data; visual comparison of actual versus simulated residuals revealed moderate deviations in the sepsis model and no deviations in other models.
Patients who did not achieve hemostasis had undefined time to hemostasis and were excluded from the primary analysis, likely leading to survival bias. Therefore, two sensitivity analyses were performed including the 60 patients who exsanguinated before hemostasis was achieved. First, these patients were assigned time to hemostasis of 315 minutes, which was at the 95th percentile for time to hemostasis. After modified Bonferroni correction, decreased time to hemostasis was significantly associated with decreased risk of mortality at 24 hours (RR, 0.93; 95% CI, 0.91–0.95) and 30 days (RR 0.95, 95% CI 0.93–0.96), as well as decreased risk of AKI (RR 0.97, 95% CI 0.96–0.99) and MOF (RR 0.94, 95% CI 0.91–0.97), but not ARDS (RR 1.00, 95% CI 0.96–1.03), sepsis (RR 0.99, 95% CI 0.97–1.03), or VTE (RR 1.02, 95% CI 0.97–1.07). Another sensitivity analysis was performed in which group assignment (Table 1) was substituted for time to hemostasis. After modified Bonferroni correction, decreasing group number was significantly associated with decreased mortality at 24 hours and 30 days, as well as decreased risk of MOF, but not AKI, ARDS, sepsis, or VTE.
We performed a prespecified secondary analysis of the PROPPR study and found no significant differences in rate of hemostasis between sites, but there was significant variability in time to hemostasis between sites. We also found significant variability in use of IR between sites and increased time to emergent IR compared to emergent OR, consistent with a previous report.16 Decreased time to hemostasis was independently associated with decreased incidence of 30-day mortality, AKI, ARDS, MOF, and sepsis, but not 24-hour mortality or VTE.
Components of hemostasis acquisition include recognition of significant hemorrhage, transport to the OR/IR suite, and the hemorrhage control procedure itself. Studies have reported improved outcomes with earlier time to operative7,8 or IR intervention9 in bleeding trauma patients. Several scoring methods have also been reported to rapidly identify bleeding patients in the trauma bay,17–19 and catheter-based interventions in conjunction with hybrid operating suites may further reduce delays in initiating appropriate therapy.20 However, clinical benefit is ultimately achieved by acquiring earlier definitive hemorrhage control (i.e., hemostasis). Determinants of time to hemostasis after arrival to OR/IR include factors which are nonmodifiable (e.g., pattern of injury), modifiable (e.g., surgeons' skill level and judgment including decision for damage control vs. definitive therapy), and potentially modifiable (e.g., availability of hybrid operating capability). Previous studies have used time to OR/IR as a surrogate for time to hemostasis, which does not take into account the actual time required to perform definitive hemorrhage control maneuvers. In the present study, we found that time from OR/IR to hemostasis accounted for most of the overall time to hemostasis (Fig. 2).
Hemorrhagic death occurs rapidly with a median time to death of 2 hours to 3 hours after hospital arrival.4,5 Oyeniyi et al.21 performed a single-center retrospective study at a Level I center and found that trauma mortality from hemorrhage significantly decreased after implementation of significant changes in control of bleeding and early resuscitation procedures as part of a hemorrhage control bundle. These included earlier transfusion of plasma and platelets, earlier and increased use of temporizing hemorrhage control devices (extremity and junctional tourniquets, pelvic binders, hemostatic dressings, and resuscitative endovascular balloon occlusion of the aorta), and decreased time to OR/IR.6,22,23 We have previously argued that outcomes of clinical studies should be consistent with the disease process being investigated, and have proposed using an outcome of all-cause mortality at 6 hours for future hemorrhage studies.24 Given that purposeful action to effect earlier time to hemostasis will improve patient outcomes after trauma, the results of the current study support the use of time to hemostasis as a clinically significant endpoint for future hemorrhage studies. The overall complication rate was level until about 75 minutes, then steadily increased as time to hemostasis increased (Fig. 2). Time to hemostasis may serve as a quality metric for trauma centers, but further studies are needed to identify modifiable and potentially modifiable determinants of time to hemostasis as well as an optimal benchmark.
The limitations of this study are as follows. Importantly, we could not control for several factors impacting time to hemostasis. Some injury patterns, such as retrohepatic caval injuries, result in substantial and difficult-to-control hemorrhage, and such injury patterns are not recapitulated by ISS. Other factors affecting time to hemostasis include the surgeons' technical skill and judgment, including the decision to perform damage control versus definitive therapy and knowing when to ask for help. Although hemostasis was defined a priori in the PROPPR study as no bleeding requiring intervention in the surgical field or resolution of contrast blush in IR, it is to some degree subjective and consequently subject to bias, possibly accounting for some of the between-study site variability in time to hemostasis. Study sites also had significant differences in rates of blunt versus penetrating injury, which may have also contributed to variation in time to hemostasis. However, we believe that our method of mixed-effects regression (using study site as a random effect) accounts for this in our statistical models. Additionally, the ultimate goal of achieving early hemostasis is to reduce blood loss due to hemorrhage, but accurately measuring the volume of blood loss after trauma is prohibitively difficult. We have shown that time to hemostasis more accurately reflects the degree of blood loss compared with time to OR/IR, but time to hemostasis is nevertheless still a surrogate for volume of blood loss. Direct correlation between time to hemostasis and actual volume of blood loss is obfuscated by several factors including rate of hemorrhage. Interestingly, among all 680 patients in the PROPPR trial, the 1:1:1 group had increased proportion of hemostasis (86% vs. 78%, p < 0.01), but similar time to hemostasis (median, 144 minutes vs. 131 minutes; p = 0.17) compared with the 1:1:2 group,5 suggesting that higher plasma:RBC and platelet:RBC reduced the rate of hemorrhage instead of allowing clinicians to achieve hemostasis more rapidly. We used time to hemostasis as a continuous variable in our multivariable models, which necessarily excluded 60 (15%) patients who exsanguinated before hemostasis could be achieved, resulting in survivor bias. Sensitivity analyses which included these 60 patients still found significant associations between time to hemostasis versus mortality, MOF, and possibly AKI. In the primary analysis of 408 patients who achieved hemostasis, we demonstrated that increased time to hemostasis was associated with increased incidence of several posttraumatic complications which was further correlated with increased 30-day mortality. Given that it takes time for these complications to manifest, it makes sense that there was no correlation with 24-hour mortality. These limitations are counterbalanced by the strengths of this study, which include our method of mixed-effects analysis, correction for multiple comparisons, and transparency in reporting diagnostics of our statistical tests.
In conclusion, time to hemostasis, but not rate of hemostasis, varied significantly between study sites in the PROPPR trial. Despite previous focus on time from hospital arrival to OR/IR, time from OR/IR to hemostasis accounts for the majority of overall time to hemostasis. Decreased time to hemostasis was independently associated with decreased 30-day mortality as well as incidence of AKI, ARDS, sepsis, and MOF. We find it biologically plausible that delayed hemostasis would result in increased blood loss, greater end organ ischemia, greater organ dysfunction, and increased late mortality. Time to hemostasis should be considered as an endpoint in future hemorrhage studies, and further studies investigating its use as a potential quality metric for trauma centers are warranted.
Study inception and design by RC, JDK, GVB, EEF, BAC, MJC, MAS, KB, EMB, KI, SR, JMP, CEW, and JBH. Data acquisition by JDK, GVB, EEF, BAC, MJC, MAS, KB, EMB, KI, SR, JMP, CEW, JBH, and PROPPR Study Group. Data analysis by RC, JDK, KJK, GVB, EEF, CEW, and JBH. All authors participated in manuscript preparation and critical appraisal.
PROPPR Study Group:
Clinical Coordinating Center, University of Texas Health Science Center at 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 at 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 at 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 at 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 at 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 Committees 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 (STAR-ORC), 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 Waddle-Smith, 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 at 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 and 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 Sciences Centre: Sandro Rizoli, MD, PhD; Homer Tien, MD; Barto Nascimento, MD, MSc, CTBS; Sandy Trpcic; Skeeta Sobrian-Couroux, RN, CCRP, BHA; Marciano Reis; Adic Pe'rez, MD; Susan E. Belo, MD, PhD; Lisa Merkley, BA, MLT, CBTS; Connie Colavecchia, BSc, MLT.
B.A.C. is a paid consultant to Haemonetics Corp. S.R. reported receiving grant funding from TEM International and CSL Behring. Otherwise, authors report no conflicts of interest.
The Pragmatic Randomized Optimal Platelet and Plasma Ratio (PROPPR) trial was sponsored by the U.S. National Heart, Lung, and Blood Institute (U01HL077863) and the U.S. Department of Defense. RC is supported by a T32 fellowship (grant 5T32GM008792) from the National Institute of General Medical Sciences.
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