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1.  Cryoprecipitate Use in the Prospective Observational Multicenter Major Trauma Transfusion study (PROMMTT) 
The journal of trauma and acute care surgery  2013;75(1 Suppl 1):S31-S39.
Background
There are few clinical data to guide the use of cryoprecipitate in severely injured trauma patients. Cryoprecipitate is a rich source of fibrinogen, and has been associated with improved survival in animal as well as limited human studies. Our objective was to identify patterns and predictors of cryoprecipitate use and determine whether transfusing cryoprecipitate was associated with improved survival.
Methods
This secondary analysis of 1238 of 1245 PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study patients who had timed transfusion data included 359 (29%) who received cryoprecipitate. For this analysis, one dose of cryoprecipitate was defined as 10 units. Unadjusted predictors of cryoprecipitate use were identified using logistic regression. Multivariable time-dependent Cox models were performed to examine the association of cryoprecipitate on time to in-hospital death.
Results
Cryoprecipitate use varied significantly by center, ranging from 7–82%. Among patients who received cryoprecipitate, the median number of units infused by 24 hours was 10 (IQR: 10–20). The median time from admission to first cryoprecipitate unit was 2.7 hours (IQR: 1.7–4.4 hours). Of those who died a hemorrhagic death within six hours of admission, 72% received no cryoprecipitate. Other unadjusted predictors of cryoprecipitate use included, Injury Severity Score (ISS), initial fibrinogen levels, base deficit, INR, PT/PTT, hemoglobin, damage control surgery and surgical intervention of the chest and abdomen. Cryoprecipitate use was not associated with in-hospital mortality after adjusting for initial pH, initial hemoglobin, ED systolic blood pressure, ED GCS, blood product use, ISS and center.
Conclusions
Ten US Level 1 trauma centers vary greatly in their timing and use of cryoprecipitate in severely injured trauma patients. We could not identify any association of cryoprecipitate use with in-hospital mortality, although most patients did not receive this product. Randomized controlled studies are needed to determine if cryoprecipitate (or fibrinogen concentrates) have a beneficial effect.
Level of Evidence
II
doi:10.1097/TA.0b013e31828fa3ed
PMCID: PMC3736696  PMID: 23936752
PROMMTT; Massive Transfusion; Bleeding; Trauma; Injury; Fibrinogen; Cryoprecipitate
2.  The impact of missing trauma data on predicting massive transfusion 
INTRODUCTION
Missing data are inherent in clinical research and may be especially problematic for trauma studies. This study describes a sensitivity analysis to evaluate the impact of missing data on clinical risk prediction algorithms. Three blood transfusion prediction models were evaluated utilizing an observational trauma dataset with valid missing data.
METHODS
The PRospective Observational Multi-center Major Trauma Transfusion (PROMMTT) study included patients requiring ≥ 1 unit of red blood cells (RBC) at 10 participating U.S. Level I trauma centers from July 2009 – October 2010. Physiologic, laboratory, and treatment data were collected prospectively up to 24h after hospital admission. Subjects who received ≥ 10 RBC units within 24h of admission were classified as massive transfusion (MT) patients. Correct classification percentages for three MT prediction models were evaluated using complete case analysis and multiple imputation. A sensitivity analysis for missing data was conducted to determine the upper and lower bounds for correct classification percentages.
RESULTS
PROMMTT enrolled 1,245 subjects. MT was received by 297 patients (24%). Missing percentage ranged from 2.2% (heart rate) to 45% (respiratory rate). Proportions of complete cases utilized in the MT prediction models ranged from 41% to 88%. All models demonstrated similar correct classification percentages using complete case analysis and multiple imputation. In the sensitivity analysis, correct classification upper-lower bound ranges per model were 4%, 10%, and 12%. Predictive accuracy for all models using PROMMTT data was lower than reported in the original datasets.
CONCLUSIONS
Evaluating the accuracy clinical prediction models with missing data can be misleading, especially with many predictor variables and moderate levels of missingness per variable. The proposed sensitivity analysis describes the influence of missing data on risk prediction algorithms. Reporting upper/lower bounds for percent correct classification may be more informative than multiple imputation, which provided similar results to complete case analysis in this study.
doi:10.1097/TA.0b013e3182914530
PMCID: PMC3736742  PMID: 23936751
PROMMTT; trauma; incomplete data; massive transfusion
3.  Do Not Resuscitate Orders in Trauma Patients May Bias Mortality-Based Effect Estimates: an evaluation utilizing the PROMMTT study 
Background
The impact of do not resuscitate (DNR) orders have not been systematically evaluated in acute trauma research. We determined the frequency, timing and impact on mortality-based effect estimates for patients with DNR orders in the the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study.
Methods
Trauma patients surviving at least 30 minutes and transfused ≥1 RBC unit within 6 hours of admission (n=1245) from ten Level 1 centers were enrolled. We report descriptive statistics and results from survival analysis to compare the association of blood product transfusion ratios with outcome defined as mortality and as a composite, DNR and death.
Results
DNRs were reported for 95 patients (7.6%) with 94 in-hospital deaths. There were 172 deaths without DNRs. Of 90 known DNR order times, the median was 53 hours (IQR=9-186 hours) after admission; the median DNR-to-death time was 10 (2-32) hours. DNRs were for comfort measures only (43%), no CPR (40%), and no intubation or CPR (16%). Compared with the 116 non-DNR deaths that occurred after the earliest DNR order (2-hours), the DNR decedents were significantly older with a less severe base deficit, fewer RBC and plasma transfusions, and a later median time of death: 98 (21-230) vs. 17 (4-91) hours. In multivariable Cox models that accounted for time-varying blood product ratios, the associations were consistent regardless of whether outcome was defined as mortality or the composite.
Conclusion
DNR orders were instituted after the 24-hour period of highest mortality risk and more often in older patients not in severe shock. Findings from the primary PROMMTT analyses of the impact of blood product ratios on survival did not materially change when the original mortality outcome was redefined as a composite of DNR or death. DNR orders are potentially an important mediating variable that should be systematically evaluated in trauma research.
doi:10.1097/TA.0b013e31828fa422
PMCID: PMC3744055  PMID: 23778517
survival; resuscitation; withdrawal of care
4.  Increasing time to operation is associated with decreased survival in patients with a positive FAST exam requiring emergent laparotomy 
Introduction
Focused assessment with sonography for trauma (FAST) is commonly used to facilitate the timely diagnosis of life threatening hemorrhage in injured patients. Most patients with positive findings on FAST require laparotomy. Though it is assumed that an increasing time to operation leads to higher mortality, this relationship has not been quantified. This study sought to determine the impact of time to operation (T-OR) on survival in patients with a positive FAST that required emergent laparotomy.
Methods
We retrospectively analyzed patients from the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study that underwent laparotomy within 90 minutes of presentation and had a FAST performed. Cox proportional hazards models including Injury Severity Score (ISS), age, base deficit and hospital site were created to examine the impact of increasing T-OR on in-hospital survival at 24 hours and 30 days. The impact of time from the performance of the FAST exam to operation (TFAST-OR) on in-hospital mortality was also examined using the same model.
Results
One hundred and fifteen patients met study criteria and had complete data. Increasing T-OR was associated with increased in-hospital mortality at 24 hours (hazard ratio [HR] 1.50 for each 10 minute increase in T-OR, confidence interval [CI] 1.14-1.97, p = 0.003) and 30 days (HR 1.41, CI 1.18-2.10, p = 0.002). Increasing TFAST-OR was also associated with higher in-hospital mortality at 24 hours (HR 1.34, CI 1.03-1.72, p = 0.03) and 30 days (HR 1.40, CI 1.06-1.84, p = 0.02).
Conclusion
In patients with a positive FAST who required emergent laparotomy, delay in operation was associated with increased early and late in-hospital mortality. Delays in time to operation in trauma patients with a positive FAST should be minimized.
doi:10.1097/TA.0b013e31828fa54e
PMCID: PMC3744056  PMID: 23778511
time to operation; laparotomy; FAST examination; PROMMTT
5.  Time-Dependent Prediction and Evaluation of Variable Importance Using SuperLearning in High Dimensional Clinical Data 
Background
Prediction of outcome after injury is fraught with uncertainty and statistically beset by misspecified models. Single-time point regression only gives prediction and inference at one time, of dubious value for continuous prediction of ongoing bleeding. New statistical, machine learning techniques such as SuperLearner exist to make superior prediction at iterative time-points while also evaluating the changing relative importance of each measured variable on an outcome. This then can provide continuously changing prediction of outcome and evaluation of which clinical variables likely drive a particular outcome.
Methods
PROMMTT data was evaluated utilizing both naïve (standard stepwise logistic regression) and SuperLearner techniques to develop a time-dependent prediction of future mortality, within discrete time intervals. We avoided both under- and over-fitting using cross-validation to select an optimal combination of predictors among candidate predictors/machine learning algorithms. SuperLearner was also used to produce interval-specific robust measures of variable importance measures (VIM resulting in an ordered list of variables, by time-point) that have the strongest impact on future mortality.
Results
980 patients had complete clinical and outcome data and were included in the analysis. The prediction of ongoing transfusion with SuperLearner was superior to the naïve approach for all time intervals (correlations of cross-validated predictions with the outcome were 0.819, 0.789, 0.792 for time intervals 30–90, 90–180, 180–360, >360 minutes. The estimated VIM of mortality also changed significantly at each time point
Conclusions
The SuperLeaner technique for prediction of outcome from a complex dynamic multivariate dataset is superior at each time interval to standard models. Additionally, the SuperLearner VIM at each time point provides insight into the time-specific drivers of future outcome, patient trajectory and targets for clinical intervention. Thus, this automated approach mimics clinical practice, changing form and content through time to optimize the accuracy of the prognosis based on the evolving trajectory of the patient.
Level of Evidence
Prospective, Level II
doi:10.1097/TA.0b013e3182914553
PMCID: PMC3744063  PMID: 23778512
PROMMTT; Trauma; Injury; Statistical Prediction; Causal Inference
6.  Application of the Berlin definition in PROMMTT patients: the impact of resuscitation on the incidence of hypoxemia 
Introduction
Acute lung injury following trauma resuscitation remains a concern despite recent advances. Utilizing PROMMTT study population, the risk of hypoxemia and potential modifiable risk factors are studied.
Methods
Patients with survival ≥ 24 hours with at least 1 ICU day were included in the analysis. Hypoxemia was categorized utilizing the Berlin definition for ARDS: none (PaO2 to FiO2 ratio (P/F) > 300 mmHg), mild (P/F = 201–300), moderate (P/F = 101–200) or severe (P/F ≤ 100). The cohort was dichotomized into those with none or mild hypoxemia and those with moderate or severe injury. Early resuscitation was defined as that occurring 0–6 hours from arrival, late resuscitation was defined as that occurring 7–24 hours. Multivariate logistic regression models were developed controlling for age, gender, mechanisms of injury, arrival physiology, individual AIS scores, blood transfusions and crystalloid administration.
Results
58.7% (731/1245) met inclusion criteria. Hypoxemia occurred in 69% (mild 24%, moderate 28%, severe 17%). Mortality was highest (24%) in the severe group. During early resuscitation (0–6 h), logistic regression revealed age (OR 1.02, CI 1.00–1.04), chest AIS (OR 1.31, CI 1.10–1.57) and intravenous crystalloid fluids given in 500 mL increments (OR 1.12 CI 1.01–1.25) as predictive of moderate or severe hypoxemia. During late resuscitation, age (OR 1.02, CI 1.00–1.04), chest AIS (OR 1.33, CI 1.11–1.59) and crystalloids given during this period (OR 1.05 CI 1.01–1.10) were also predictive of moderate to severe hypoxemia. RBC, plasma and platelet transfusions (whether received during early or late resuscitation) failed to demonstrate an increased risk of developing moderate/severe hypoxemia.
Conclusion
Severe chest injury, increasing age and crystalloid-based resuscitation, but not blood transfusions, were associated with increased risk of developing moderate to severe hypoxemia following injury.
Level of Evidence
I
doi:10.1097/TA.0b013e31828fa408
PMCID: PMC3744064  PMID: 23778513
PROMMTT; resuscitation; hypoxemia; lung injury; trauma
7.  Resuscitate early with plasma and platelets or balance blood products gradually: Findings from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study 
Background
The trauma transfusion literature has yet to resolve which is more important for hemorrhaging patients: transfusing plasma and platelets along with red blood cells (RBCs) early in resuscitation or gradually balancing blood product ratios. In a previous report of PROMMTT results, we found 1) plasma and platelet:RBC ratios increased gradually over the 6 hours following admission, and 2) patients achieving ratios >1:2 (relative to ratios <1:2) had significantly decreased 6–24 hour mortality adjusting for baseline and time-varying covariates. To differentiate the association of in-hospital mortality with early plasma or platelet transfusion from that with delayed but gradually balanced ratios, we developed a separate analytic approach.
Methods
Using PROMMTT data and multi-level logistic regression to adjust for center effects, we related in-hospital mortality to the early receipt of plasma or platelets within the first 3–6 transfusion units (including RBCs) and 2.5 hours of admission. We adjusted for the same covariates as in our previous report: injury severity score, age, time and total number of blood product transfusions upon entry to the analysis cohort, and bleeding from the head, chest or limb.
Results
Of 1245 PROMMTT patients, 619 were eligible for this analysis. Early plasma was associated with decreased 24 hour and 30 day mortality (adjusted odds ratios, ORs=0.47, p=0.009; 0.44, p=0.002 respectively). Too few patients (24) received platelets early for meaningful assessment. In the subgroup of 222 patients receiving no early plasma but continuing transfusions beyond hour 2.5, achieving gradually balanced plasma and platelet:RBC ratios ≥1:2 by hour 4 was not associated with 30 day mortality (adjusted ORs=0.9 and 1.1 respectively). There were no significant center effects.
Conclusion
Plasma transfusion early in resuscitation had a protective association with mortality whereas delayed but gradually balanced transfusion ratios did not. Further research will require considerably larger numbers of patients receiving platelets early.
Level of Evidence
Prospective, Level II
doi:10.1097/TA.0b013e31828fa3b9
PMCID: PMC3744122  PMID: 23778507
PROMMTT; Massive transfusion; trauma; plasma; platelets
8.  Waiver of consent in non-interventional, observational emergency research: the PROMMTT experience 
Background
In the PRospective Observational Multi-center Major Trauma Transfusion (PROMMTT) study, waiver of consent was utilized because previous literature reported low response rates and subsequent bias. The goal of this manuscript is to examine the rationale and tradeoffs of using waiver of consent in PROMMTT.
Methods
PROMMTT enrolled trauma patients receiving at least one unit of red blood cells within 6 hours after admission at ten US Level 1 Trauma Centers. Local Institutional Review Boards (IRBs) from all sites approved the study. Site 8 was required by their IRB to attempt consent, but was allowed to retain data on patients unable to be consented.
Results
Of 121 subjects enrolled at Site 8, 55 consents were obtained (46%) and no patient or legally-authorized representative refused to give consent. Thirty-six (30%) patients died and 6 (5%) were discharged before consent could be attempted. Consent was attempted but not possible among 24 patients (20%). Of the 10 clinical sites, six of the local IRBs approved collection of residual blood samples, one had prior approval to collect timed blood samples under a separate protocol, and three reported that their local IRBs would not approve collection of residual blood under a waiver of consent.
Conclusions
Waiver of consent was used in PROMMTT because of the potential adverse impact of consent refusals; however, there were no refusals. If Site 8’s IRB had required withdrawal of patients unable to consent and destruction of their data, a serious bias would likely have been introduced. Other tradeoffs included a reduction in sites participating in residual blood collection, and a smaller than expected amount of residual blood collected among sites operating under a waiver of consent. Non-interventional emergency research studies should consider these potential tradeoffs carefully before deciding whether waiver of consent would best achieve the goals of a study.
Level of Evidence
Prospective, Level II
doi:10.1097/TA.0b013e31828fa3a0
PMCID: PMC3744180  PMID: 23778508
PROMMTT; Massive transfusion; trauma; waiver of consent
9.  A latent class model for defining severe hemorrhage: Experience from the PRospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study 
Background
Several predictive models have been developed to identify trauma patients who have had severe hemorrhage (SH) and may need a massive transfusion protocol (MTP). However, almost all these models define SH as the transfusion of ≥10 units of red blood cells (RBCs) within 24 hours of ED admission (aka massive transfusion, MT). This definition excludes some patients with SH, especially those who die before a 10th unit of RBCs could be transfused, which calls the validity of these prediction models into question. We show how a latent class model could improve the accuracy of identifying the SH patients.
Methods
Modeling SH classification as a latent variable, we estimate the posterior probability of a patient in SH based on ED admission variables (SBP, HR, pH, Hemoglobin), the 24-hour blood product utilization (plasma:RBCs and platelets: RBCs ratios), and 24-hour survival status. We define the SH subgroup as those having a posterior probability of ≥0.5. We compare our new classification of SH with that of the traditional MT using data from PROMMTT study.
Results
Of 1245 patients, 913 had complete data which were used in the latent class model. About 25.3% of patients were classified as SH. The overall agreement between the MT and SH classifications was 83.8%. However, among 49 patients who died before receiving the 10th unit of RBCs 41 (84%) were classified as SH. Seven of the remaining 8 (87.5%) who were not classified as SH had head injury.
Conclusion
Our definition of SH based on the aforementioned latent class model has an advantage of improving on the traditional MT definition by identifying SH patients who die before receiving the 10th unit of RBCs. We recommend further improvements to more accurately classify SH patients that could replace the traditional definition of MT for use in developing prediction algorithms.
Level of Evidence
II, Prospective
doi:10.1097/TA.0b013e31828fa3d3
PMCID: PMC3744183  PMID: 23778516
PROMMTT; Massive Transfusion; Hemorrhage; Trauma; Latent Class Analysis
10.  Purposeful Variable Selection and Stratification to Impute Missing FAST Data in Trauma Research 
Background
The Focused Assessment with Sonography for Trauma (FAST) exam is an important variable in many retrospective trauma studies. The purpose of this study was to devise an imputation method to overcome missing data for the FAST exam. Due to variability in patients’ injuries and trauma care, these data are unlikely to be missing completely at random (MCAR), raising concern for validity when analyses exclude patients with missing values.
Methods
Imputation was conducted under a less restrictive, more plausible missing at random (MAR) assumption. Patients with missing FAST exams had available data on alternate, clinically relevant elements that were strongly associated with FAST results in complete cases, especially when considered jointly. Subjects with missing data (32.7%) were divided into eight mutually exclusive groups based on selected variables that both described the injury and were associated with missing FAST values. Additional variables were selected within each group to classify missing FAST values as positive or negative, and correct FAST exam classification based on these variables was determined for patients with non-missing FAST values.
Results
Severe head/neck injury (odds ratio, OR=2.04), severe extremity injury (OR=4.03), severe abdominal injury (OR=1.94), no injury (OR=1.94), other abdominal injury (OR=0.47), other head/neck injury (OR=0.57) and other extremity injury (OR=0.45) groups had significant ORs for missing data; the other group odds ratio was not significant (OR=0.84). All 407 missing FAST values were imputed, with 109 classified as positive. Correct classification of non-missing FAST results using the alternate variables was 87.2%.
Conclusions
Purposeful imputation for missing FAST exams based on interactions among selected variables assessed by simple stratification may be a useful adjunct to sensitivity analysis in the evaluation of imputation strategies under different missing data mechanisms. This approach has the potential for widespread application in clinical and translational research and validation is warranted.
Level of Evidence
Level II Prognostic or Epidemiological
doi:10.1097/TA.0b013e31828fa51c
PMCID: PMC3744188  PMID: 23778515
FAST exam; imputation; MCAR; MAR
11.  Pre-Hospital Intravenous Fluid is Associated with Increased Survival in Trauma Patients 
Background
Delivery of intravenous crystalloid fluids (IVF) remains a tradition-based priority during pre-hospital resuscitation of trauma patients. Hypotensive and targeted resuscitation algorithms have been shown to improve patient outcomes. We hypothesized that receiving any pre-hospital IVF is associated with increased survival in trauma patients compared to receiving no pre-hospital IVF.
Methods
Prospective data from ten Level 1 trauma centers were collected. Patient demographics, pre-hospital IVF volume, pre-hospital and Emergency Department vital signs, life-saving interventions, laboratory values, outcomes and complications were collected and analyzed. Patients who did or did not receive pre-hospital IVF were compared. Tests for non-parametric data were utilized to assess significant differences between groups (p ≤ 0.05). Cox regression analyses were performed to determine the independent influence of IVF on outcome and complications.
Results
The study population consisted of 1245 trauma patients; 45 were removed due to incomplete data; 84% (n=1009) received pre-hospital IVF, and 16% (n=191) did not. There was no difference between the groups with respect to gender, age, and Injury Severity Score. The on-scene systolic blood pressure (SBP) was lower in the IVF group (110 vs. 100 mmHg, p<0.04) and did not change significantly after IVF, measured at ED admission (110 vs. 105 mmHg, p=0.05). Hematocrit/hemoglobin, fibrinogen, and platelets were lower (p<0.05), and Prothrombin Time/International Normalized Ratio and Partial Thromboplastin Time were higher (p<0.001) in the IVF group. The IVF group received a median fluid volume of 700ml (IQR: 300-1300). The Cox regression revealed that pre-hospital fluid administration was associated with increased survival, Hazard Ratio: 0.84 (95% Confidence Interval: 0.72, 0.98; p=0.03). Site differences in ISS and fluid volumes were demonstrated (p<0.001).
Conclusions
Pre-hospital IVF volumes commonly used by PROMMTT investigators do not result in increased SBP but are associated with decreased in-hospital mortality in trauma patients compared to patients who did not receive pre-hospital IVF.
Level of Evidence
II, Prospective
doi:10.1097/TA.0b013e318290cd52
PMCID: PMC3744192  PMID: 23778518
pre-hospital; resuscitation; clinical parameters; PROMMTT
12.  Early resuscitation intensity as a surrogate for bleeding severity and early mortality in the PRospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study 
Background
The classic definition of MT, ≥10 units red blood cells (RBCs) in 24 hours, has never been demonstrated as a valid surrogate for severe hemorrhage and can introduce survival bias. In addition, the definition fails to capture other products that the clinician may have immediately available during the initial resuscitation. Assuming that units of resuscitative fluids reflect patient illness, our objective was to identify a rate of resuscitation intensity (RI) that could serve as an early surrogate of sickness for patients with substantial bleeding post-injury.
Methods
Adult patients surviving at least 30 minutes post-admission and receiving ≥1 RBC within 6 hours of admission from ten US Level 1 trauma centers were enrolled in the PRospective Observational Multicenter Major Trauma Transfusion study. Total fluid units were calculated as the sum of the number of crystalloid units (1 L=1 unit), colloids (0.5 L=1 unit) and blood products (1 RBC=1 unit, 1 plasma=1 unit, 6 pack platelets=1 unit). Univariable and multivariable logistic regressions were used to evaluate associations between RI and 6-hour mortality, adjusting for age, center, penetrating injury, weighted Revised Trauma Score, and Injury Severity Score.
Results
1096 eligible patients received resuscitative fluids within 30 minutes, including 620 transfused with blood products. Despite varying products utilized, the total fluid RI was similar across all sites (3.2±2.5 units). Patients who received ≥4 units of any resuscitative fluid had a 6-hour mortality rate of 14.4% vs. 4.5% in patients who received <4 units. The adjusted odds ratio of 6-hour mortality for patients receiving ≥4 units within 30 minutes was 2.1 (95% Confidence Interval: 1.2–3.5).
Conclusions
Resuscitation with ≥4 units of any fluid was significantly associated with 6-hour mortality. This study suggests that early RI regardless of fluid type can be used as a surrogate for sickness and mortality in severely bleeding patients.
Level of Evidence
PROMMTT is a prospective observational study, Level II.
doi:10.1097/TA.0b013e31828fa535
PMCID: PMC3744217  PMID: 23778506
rate of transfusion; mortality; plasma; crystalloid; colloid
13.  INCREASE IN ACTIVATED PROTEIN C MEDIATES ACUTE TRAUMATIC COAGULOPATHY IN MICE 
Shock (Augusta, Ga.)  2009;32(6):659-665.
In severely injured and hypoperfused trauma patients, endogenous acute coagulopathy (EAC) is associated with an increased morbidity and mortality. Recent human data correlate this coagulopathy with activation of the protein C pathway. To examine the mechanistic role of protein C in the development of EAC, we used a mouse model of trauma and hemorrhagic shock, characterized by the combination of tissue injury and severe metabolic acidosis. Mice were subjected to one of four treatment groups: 1) C, control; 2) T, trauma (laparotomy); 3) H, hemorrhage (MAP, 35 mmHg × 60 min); 4) TH, trauma + hemorrhage. After 60 min, blood was drawn for analysis. Compared with C mice, the TH mice had a significantly elevated activated partial thromboplastin time (23.3 vs. 34.5 s) and significantly increased levels of activated protein C (aPC; 2.30 vs. 13.58 ng/mL). In contrast, T and H mice did not develop an elevated activated partial thromboplastin time or increased aPC. Selective inhibition of the anticoagulant property of aPC prevented the coagulopathy seen in response to trauma/hemorrhage (23.5 vs. 38.6 s [inhibitory vs. control monoclonal antibody]) with no impact on survival during the shock period. However, complete blockade of both the anticoagulant and cytoprotective functions of aPC caused 100% mortality within 45 min of shock, with histopathology evidence of pulmonary thrombosis and perivascular hemorrhage. These results indicate that our unique mouse model of T/H shock mimics our previous observations in trauma patients and demonstrates that EAC is mediated by the activation of the protein C pathway. In addition, the cytoprotective effect of protein C activation seems to be necessary for survival of the initial shock injury.
doi:10.1097/SHK.0b013e3181a5a632
PMCID: PMC3574570  PMID: 19333141
Trauma; shock; hemorrhage; hypoperfusion; coagulation; survival
14.  Goal Directed Resuscitation in the Prehospital Setting: A Propensity Adjusted Analysis 
Background
The scope of prehospital (PH) interventions has expanded recently; not always with clear benefit. PH crystalloid resuscitation has been challenged, particularly in penetrating trauma. Optimal PH crystalloid resuscitation strategies remain unclear in blunt trauma as does the influence of PH hypotension. The objective was to characterize outcomes for PH crystalloid volume in patients with and without PH hypotension.
Methods
Data were obtained from a multicenter prospective study of blunt injured adults transported from the scene with ISS > 15. Subjects were divided into HIGH (>500cc) and LOW (≤500cc) PH crystalloid groups. Propensity adjusted regression determined the association of PH crystalloid group with mortality and acute coagulopathy (admission INR>1.5) in subjects with and without PH hypotension (SBP<90mmHg) after controlling for confounders.
Results
Of 1,216 subjects, 822 (68%) received HIGH PH crystalloid and 616 (51%) had PH hypotension. Initial base deficit and ISS were similar between HIGH and LOW crystalloid groups in subjects with and without PH hypotension. In subjects without PH hypotension, HIGH crystalloid was associated with an increase in the risk of mortality (HR 2.5; 95%CI 1.3 – 4.9, p<0.01) and acute coagulopathy (OR 2.2; 95%CI 1.01–4.9, p=0.04) but not in subjects with PH hypotension. HIGH crystalloid was associated with correction of PH hypotension on ED arrival (OR 2.02; 1.06–3.88, p=0.03). The mean corrected SBP in the ED was 104mmHg. Each 1mmHg increase in ED systolic blood pressure was associated with a 2% increase in survival in subjects with PH hypotension (OR 1.02; 1.01–1.03, p<0.01).
Conclusions
In severely injured blunt trauma patients, PH crystalloid >500cc was associated with worse outcome in patients without PH hypotension but not with PH hypotension. HIGH crystalloid was associated with corrected PH hypotension. This suggests PH resuscitation should be goal directed based on the presence or absence of PH hypotension.
Level of Evidence
II, Therapeutic Study
doi:10.1097/TA.0b013e31828c44fd
PMCID: PMC3634596  PMID: 23609269
Prehospital; Crystalloid; Resuscitation; Blunt trauma; Outcome
15.  A principal component analysis of coagulation after trauma 
Background
Clotting factor abnormalities underlying acute traumatic coagulopathy are poorly understood, with application of traditional regression techniques confounded by collinearity. We hypothesized that principal components analysis (PCA), a pattern-finding and data reduction technique, would identify clinically predictive patterns in the complex clotting factor milieu after trauma.
Methods
Plasma was prospectively collected from 163 critically-injured trauma patients. Prothrombin, Factors V, VII, VIII, IX, X, D-dimer, activated and native Protein C, and antithrombin III levels were assayed, and subjected to non-linear PCA to identify principal components (PCs).
Results
Of 163 patients, 19.0% were coagulopathic on admission. PCA identified 3 significant PCs, accounting for 67.5% of overall variance. PC1 identified global clotting factor depletion; PC2 the activation of Protein C and fibrinolysis; and PC3 Factor VII elevation and VIII depletion. PC1 score correlated with penetrating injury and injury severity, predicting coagulopathy (OR 4.67, p<0.001) and mortality (OR 1.47, p=0.032). PC2 score correlated with injury severity, acidosis, and shock, and significantly predicted ventilator-associated pneumonia (OR 1.59, p=0.008), acute lung injury (OR 2.24, p<0.001), multiorgan failure (OR 1.83, p=0.002), and mortality (OR 1.62, p=0.006), but was not associated with INR- or PTT-based coagulopathy (p>0.200). PC3 did not significantly predict outcomes.
Conclusions
PCA identifies distinct patterns of coagulopathy: depletion coagulopathy predicts mortality and INR/PTT elevation, while fibrinolytic coagulopathy predicts infection, end-organ failure, and mortality, without detectable differences in INR or PTT. While depletion coagulopathy is intuitive, fibrinolytic coagulopathy may be a distinct but often overlapping entity with differential effects on outcomes.
Level of evidence
Prognostic study, Level III
doi:10.1097/TA.0b013e31828b7fa1
PMCID: PMC3638007  PMID: 23609271
Coagulopathy; principal components analysis; fibrinolysis
16.  Comparing Clinical Predictors of Deep Venous Thrombosis vs. Pulmonary Embolus After Severe Injury: A New Paradigm for Post-Traumatic Venous Thromboembolism? 
Background
The traditional paradigm is that deep venous thrombosis (DVT) and pulmonary embolus (PE) are different temporal phases of a single disease process, most often labeled as the composite endpoint venous thromboembolism (VTE). However, we theorize that after severe blunt injury, DVT and PE may represent independent thrombotic entities rather than different stages of a single pathophysiologic process and therefore exhibit different clinical risk factor profiles.
Methods
We examined a large, multi-center prospective cohort of severely injured blunt trauma patients to compare clinical risk factors for DVT and PE, including indicators of injury severity, shock, resuscitation parameters, comorbidities and VTE prophylaxis. Independent risk factors for each outcome were determined by cross-validated logistic regression modeling using advanced exhaustive model search procedures.
Results
The study cohort consisted of 1,822 severely injured blunt trauma patients (median ISS = 33, median base deficit = −9.5). Incidence of DVT and PE were 5.1% and 3.9% respectively. Only 9 of 73 (5.7%) patients with a PE were also diagnosed with DVT. Independent risk factors associated with DVT include prophylaxis initiation within 48 hours (OR 0.57, 95% CI 0.36–0.90) and thoracic AIS ≥ 3 (OR 1.82, 95% CI 1.12–2.95), while independent risk factors for PE were serum lactate >5 (OR 2.33, 95% CI 1.43–3.79) and male gender (OR 2.12, 95% CI 1.17–3.84). Both DVT and PE exhibited differing risk factor profiles from the classic composite endpoint of VTE.
Conclusion
Deep venous thrombosis and pulmonary embolus exhibit differing risk factor profiles following severe injury. Clinical risk factors for diagnosis of DVT after severe blunt trauma include the inability to initiate prompt pharmacologic prophylaxis and severe thoracic injury, which may represent overall injury burden. In contrast, risk factors for PE are male gender and physiologic evidence of severe shock. We hypothesize that post-injury DVT and PE may represent a broad spectrum of pathologic thrombotic processes as opposed to the current conventional wisdom of peripheral thrombosis and subsequent embolus.
Level of Evidence
Prognostic study, Level III
doi:10.1097/TA.0b013e31828cc9a0
PMCID: PMC3716365  PMID: 23609272
Venous thromboembolism; Deep venous thrombosis; Pulmonary embolus; Trauma; Injury
17.  The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-varying Treatment with Competing Risks 
JAMA surgery  2013;148(2):127-136.
Context
Hemorrhagic shock is the leading potentially preventable cause of death after injury. Transfusion of early and increased ratios of plasma and platelets to red blood cells (RBCs) has been associated with decreased mortality; however conflicting reports and the time-varying nature of transfusions and hemorrhagic death raise concern for the validity of the clinical conclusions drawn from the retrospective data.
Objective
To relate in-hospital mortality to: 1) early transfusion of plasma and/or platelets and 2) time-varying plasma:RBC and platelet:RBC ratios.
Design
Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models.
Setting
Ten US Level 1 trauma centers.
Patients
Adult trauma patients surviving for 30 minutes after admission, transfused at least 1 unit RBC within 6 hours of admission (n=1245, the original study group) and at least 3 total units (of RBC, plasma or platelets) within 24 hours (n=905, the analysis group).
Main outcome measure
In-hospital mortality
Results
Plasma:RBC and platelet:RBC ratios were not constant over the first 24 hours (p<.001 for both). In a multivariable time-dependent Cox model, increased ratios of plasma:RBC (adjusted hazard ratio, HR=0.31, 95% CI=0.16–0.58) and platelets:RBC (adjusted HR=0.55, 95% CI=0.31–0.98) were independently associated with decreased 6-hour mortality, when hemorrhagic death predominated. In the first 6 hours, patients with ratios < 1:2 were 3–4 times more likely to die than patients with ratios ≥1:1. After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from non-hemorrhagic causes prevailed.
Conclusions
Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients transfused at least three units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.
doi:10.1001/2013.jamasurg.387
PMCID: PMC3740072  PMID: 23560283
19.  CHARACTERIZATION OF ACUTE COAGULOPATHY AND THE GENDER DIMORPHISM POST-INJURY: FEMALES AND COAGULOPATHY JUST DON’T MIX 
Background
Acute traumatic coagulopathy (ATC) predicts poor outcome following injury. Females have been demonstrated to be hypercoagulable early in the post trauma period. It remains unclear whether presence of ATC alters gender based outcomes post-injury. This study objective was to characterize the gender dimorphism following severe injury in the presence and absence of ATC.
Methods
Data were obtained from a multicenter prospective cohort study of blunt trauma patients with hemorrhagic shock. ATC was defined as arrival INR >1.5. Cox regression was utilized to determine the independent risks of mortality and multiple organ failure (MOF) associated with gender in subjects with ATC and without (NON-ATC) while controlling for important confounders. The gender mortality differences were characterized over time to determine at what point post-injury any differential risks diverge.
Results
Of 2,007 enrolled subjects, 1,877 had an arrival INR with 439 (23%) having ATC. There was no difference in incidence of ATC across gender (24% vs. 23%, p=0.95). In the ATC group, no difference in ISS, arrival INR, base deficit, temperature or 24 hour blood requirements were found across gender. Cox hazard regression revealed gender was not associated with mortality in NON-ATC patients (HR 0.94, 95%CI 0.6–1.5). Female gender was independently associated with mortality only in the ATC group (HR 2.04, 95%CI 1.1–3.9, p=0.03). These mortality risk differences across gender diverged within the first 24 hours post-injury.
Conclusions
An exaggerated gender dimorphism exists in patients with ATC, with females demonstrating a 2-fold higher independent risk of mortality. These differential mortality risks across gender diverge early post-injury suggesting they may be due to ongoing hemorrhage. Females that present with ATC on admission have a significantly greater risk of poor outcome. Further studies are warranted to explore the mechanisms responsible for gender dimorphism in the setting of ATC.
doi:10.1097/TA.0b013e31825b9f05
PMCID: PMC3540988  PMID: 23064602
20.  Comparison of the predictive performance of the BIG, TRISS, and PS09 score in an adult trauma population derived from multiple international trauma registries 
Critical Care  2013;17(4):R134.
Background
The BIG score (Admission base deficit (B), International normalized ratio (I), and Glasgow Coma Scale (G)) has been shown to predict mortality on admission in pediatric trauma patients. The objective of this study was to assess its performance in predicting mortality in an adult trauma population, and to compare it with the existing Trauma and Injury Severity Score (TRISS) and probability of survival (PS09) score.
Materials and methods
A retrospective analysis using data collected between 2005 and 2010 from seven trauma centers and registries in Europe and the United States of America was performed. We compared the BIG score with TRISS and PS09 scores in a population of blunt and penetrating trauma patients. We then assessed the discrimination ability of all scores via receiver operating characteristic (ROC) curves and compared the expected mortality rate (precision) of all scores with the observed mortality rate.
Results
In total, 12,206 datasets were retrieved to validate the BIG score. The mean ISS was 15 ± 11, and the mean 30-day mortality rate was 4.8%. With an AUROC of 0.892 (95% confidence interval (CI): 0.879 to 0.906), the BIG score performed well in an adult population. TRISS had an area under ROC (AUROC) of 0.922 (0.913 to 0.932) and the PS09 score of 0.825 (0.915 to 0.934). On a penetrating-trauma population, the BIG score had an AUROC result of 0.920 (0.898 to 0.942) compared with the PS09 score (AUROC of 0.921; 0.902 to 0.939) and TRISS (0.929; 0.912 to 0.947).
Conclusions
The BIG score is a good predictor of mortality in the adult trauma population. It performed well compared with TRISS and the PS09 score, although it has significantly less discriminative ability. In a penetrating-trauma population, the BIG score performed better than in a population with blunt trauma. The BIG score has the advantage of being available shortly after admission and may be used to predict clinical prognosis or as a research tool to risk stratify trauma patients into clinical trials.
doi:10.1186/cc12813
PMCID: PMC4057174  PMID: 23844754
21.  Altering physiological networks using drugs: steps towards personalized physiology 
BMC Medical Genomics  2013;6(Suppl 2):S7.
Background
The rise of personalized medicine has reminded us that each patient must be treated as an individual. One factor in making treatment decisions is the physiological state of each patient, but definitions of relevant states and methods to visualize state-related physiologic changes are scarce. We constructed correlation networks from physiologic data to demonstrate changes associated with pressor use in the intensive care unit.
Methods
We collected 29 physiological variables at one-minute intervals from nineteen trauma patients in the intensive care unit of an academic hospital and grouped each minute of data as receiving or not receiving pressors. For each group we constructed Spearman correlation networks of pairs of physiologic variables. To visualize drug-associated changes we split the networks into three components: an unchanging network, a network of connections with changing correlation sign, and a network of connections only present in one group.
Results
Out of a possible 406 connections between the 29 physiological measures, 64, 39, and 48 were present in each of the three component networks. The static network confirms expected physiological relationships while the network of associations with changed correlation sign suggests putative changes due to the drugs. The network of associations present only with pressors suggests new relationships that could be worthy of study.
Conclusions
We demonstrated that visualizing physiological relationships using correlation networks provides insight into underlying physiologic states while also showing that many of these relationships change when the state is defined by the presence of drugs. This method applied to targeted experiments could change the way critical care patients are monitored and treated.
doi:10.1186/1755-8794-6-S2-S7
PMCID: PMC3654899  PMID: 23819503
22.  Coordination and management of multicenter clinical studies in trauma: Experience from the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) Study 
Resuscitation  2011;83(4):459-464.
Aim
Early death due to hemorrhage is a major consequence of traumatic injury. Transfusion practices differ among hospitals and it is unknown which transfusion practices improve survival. This report describes the experience of the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) Study Data Coordination Center in designing and coordinating a study to examine transfusion practices at ten Level 1 trauma centers in the U.S.
Methods
PROMMTT was a multisite prospective observational study of severely injured transfused trauma patients. The clinical sites collected real-time information on the timing and amounts of blood product infusions as well as colloids and crystalloids, vital signs, initial diagnostic and clinical laboratory tests, life saving interventions and other clinical care data.
Results
Between July 2009 and October 2010, PROMMTT screened 12,561 trauma admissions and enrolled 1,245 patients who received one or more blood transfusions within 6 hours of ED admission. A total of 297 massive transfusions were observed over the course of the study at a combined rate of 5.0 massive transfusion patients/week.
Conclusion
PROMMTT is the first multisite study to collect real-time prospective data on trauma patients requiring transfusion. Support from the Department of Defense and collaborative expertise from the ten participating centers helped to demonstrate the feasibility of prospective trauma transfusion studies. The observational data collected from this study will be an invaluable resource for research in trauma surgery and it will guide the design and conduct of future randomized trials.
doi:10.1016/j.resuscitation.2011.09.019
PMCID: PMC3303947  PMID: 22001613
23.  The Changing Pattern and Implications of Multiple Organ Failure (MOF) After Blunt Injury With Hemorrhagic Shock 
Critical Care Medicine  2012;40(4):1129-1135.
Objective
To describe the incidence of post-injury multiple organ failure (MOF) and its relationship to nosocomial infection and mortality in trauma centers employing evidence-based standard operating procedures (SOPs).
Design
Prospective cohort study wherein SOPs were developed and implemented to optimize post-injury care.
Setting
Seven U.S. Level I trauma centers.
Patients
Severely injured patients (> 16 years old) with a blunt mechanism, systolic hypotension (< 90 mmHg) and/or base deficit (> 6 meq/L), need for blood transfusion within the first 12 hrs, and an abbreviated injury score (AIS) ≥ two excluding brain injury were eligible for inclusion.
Measurements and Main Results
1,002 patients were enrolled and 916 met inclusion criteria. Daily markers of organ dysfunction were prospectively recorded for all patients while receiving intensive care. Overall, 29% of patients developed MOF. Development of MOF was early (median time of two days), short - lived, and predicted an increased incidence of NI, whereas, persistence of MOF predicted mortality. However, surprisingly, NI did not increase subsequent MOF and there was no evidence of a “second-hit” induced late onset MOF.
Conclusions
MOF remains common after severe injury. Contrary to current paradigms, the onset is only early, and not bimodal, nor is it associated with a “second-hit” induced late onset. MOF is associated with subsequent NI and increased mortality. SOP-driven interventions may be associated with a decrease in late MOF and morbidity.
doi:10.1097/CCM.0b013e3182376e9f
PMCID: PMC3343366  PMID: 22020243
trauma; injury; standards of care; infection; multiple organ failure; mortality
24.  Crystalloid to Packed Red Blood Cell Transfusion Ratio in the Massively Transfused Patient: When A Little Goes Along Way 
Objective
Massive transfusion protocols have emphasized the importance of ratio-based transfusion of plasma and platelets relative to packed red blood cells (PRBCs), however the risks attributable to crystalloid resuscitation in patients requiring massive transfusion remain largely unexplored. We hypothesized that an increased crystalloid:PRBC (C:PRBC) ratio would be associated with increased morbidity and poor outcome following massive transfusion.
Methods
Data were obtained from a multi-center prospective cohort study evaluating outcomes in blunt injured adults with hemorrhagic shock. Patients requiring massive transfusion (≥10u PRBCs in first 24hrs) were analyzed. The C:PRBC ratio was computed by the ratio of crystalloid infused in liters (L) to the units of PRBCs transfused in the first 24hrs post-injury. Logistic regression modeling was used to characterize the independent risks associated with the 24hr C:PRBC ratio, after controlling for important confounders and other blood component transfusion requirements.
Results
Logistic regression revealed that the 24hr C:PRBC ratio was significantly associated with a greater independent risk of MOF, acute respiratory distress syndrome (ARDS) and abdominal compartment syndrome (ACS). No association with mortality or nosocomial infection was found. A dose response analysis revealed patients with a C:PRBC ratio >1.5:1, had over a 70% higher independent risk of MOF, and over a 2-fold higher risk of ARDS and ACS.
Conclusion
In patients requiring massive transfusion, crystalloid resuscitation in a ratio greater than 1.5:1 per unit of PRBCs transfused was independently associated with a higher risk of MOF, ARDS, and ACS. These results suggest overly aggressive crystalloid resuscitation should be minimized in these severely injured patients. Further research is required to determine if incorporation of the C:PRBC ratio into massive transfusion protocols improves outcome.
doi:10.1097/TA.0b013e31823d84a7
PMCID: PMC3347772  PMID: 22491601
25.  Changes in Massive Transfusion Over Time: An Early Shift In The Right Direction? 
Objective
Increasing evidence suggests that high fresh frozen plasma:packed red blood cell (FFP:PRBC) and platelet:packed red blood cell (PLT:PRBC) transfusion ratios may prevent or reduce the morbidity associated with early coagulopathy which complicates massive transfusion (MT). We sought to characterize changes in resuscitation which have occurred over time in a cohort severely injured patients requiring MT.
Methods
Data were obtained from a multicenter prospective cohort study evaluating outcomes in blunt injured adults with hemorrhagic shock. MT was defined as requiring ≥ 10u PRBCs within 24hrs post-injury. Mean PRBC, FFP and PLT requirements (per unit, 6hr, 12hrs and 24hrs) were determined over time (2004–2009). SUB-MT, those patients just below the threshold for MT, were defined as requiring ≥ 7 and < 10u PRBC’s in the initial 24hrs. The % of resuscitation given at 6hrs relative to 24hrs total (6/24%) was determined and compared across EARLY (admission until 12/07) and RECENT (after 12/07) periods for each component.
Results
Over the study time period (2004–09) for the MT group (n=526), initial base deficit and presenting INR were unchanged, while ISS was significantly higher. The % of patients who required MT overall significantly decreased over time. No significant differences were found over time for 6hr, 12hr or 24hr FFP:PRBC and PLT:PRBC transfusion ratios in MT patients. SUB-MT patients (n=344) had significantly higher 6hr FFP:PRBC ratios and significantly higher 6hr, 12hr and 24hr PLT:PRBC ratios in the RECENT time period. The 6HR/24HR% total for FFP and PLT transfusion was significantly greater in the RECENT time period. (FFP 54% vs. 70%, p=0.004, PLT 46% vs. 61%, p=0.048)
Conclusion
In a severely injured cohort requiring MT, FFP:PRBC and PLT:PRBC ratios have not changed over time, while the rate of MT overall has significantly decreased. During the RECENT time period (after 12/7) significantly higher transfusion ratios and a greater % of 6hr/24hr FFP and PLT were found in the SUB-MT group, those patients just below the PRBC transfusion 1 threshold definition of MT. This data suggests early, more aggressive attainment of high transfusions ratios may reduce the requirement for MT, may shift overall blood requirements below those which currently define MT. Further prospective evidence is required to verify these findings.
doi:10.1097/TA.0b013e3182410a3c
PMCID: PMC3276234  PMID: 22310123

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