Louis H. Alarcon

An FFP: PRBC transfusion ratio >/=1:1.5 is associated with a lower risk of mortality after massive transfusion.

OBJECTIVE The detrimental effects of coagulopathy, hypothermia, and acidosis are well described as markers for mortality after traumatic hemorrhage. Recent military experience suggests that a high fresh frozen plasma (FFP):packed red blood cell (PRBC) transfusion ratio improves outcome; however, the appropriate ratio these transfusion products should be given remains to be established in a civilian trauma population. METHODS Data were obtained from a multicenter prospective cohort study evaluating clinical outcomes in blunt injured adults with hemorrhagic shock. Those patients who required >/=8 units PRBCs within the first 12 hours postinjury were analyzed (n = 415). RESULTS Patients who received transfusion products in >/=1:1.50 FFP:PRBC ratio (high F:P ratio, n = 102) versus <1:1.50 FFP:PRBC ratio (low F:P, n = 313) required significantly less blood transfusion at 24 hours (16 +/- 9 units vs. 22 +/- 17 units, p = 0.001). Crude mortality differences between the groups did not reach statistical significance (high F:P 28% vs. low F:P 35%, p = 0.202); however, there was a significant difference in early (24 hour) mortality (high F:P 3.9% vs. low F:P 12.8%, p = 0.012). Cox proportional hazard regression revealed that receiving a high F:P ratio was independently associated with 52% lower risk of mortality after adjusting for important confounders (HR 0.48, p = 0.002, 95% CI 0.3-0.8). A high F:P ratio was not associated with a higher risk of organ failure or nosocomial infection, however, was associated with almost a twofold higher risk of acute respiratory distress syndrome, after controlling for important confounders. CONCLUSIONS In patients requiring >/=8 units of blood after serious blunt injury, an FFP:PRBC transfusion ratio >/=1:1.5 was associated with a significant lower risk of mortality but a higher risk of acute respiratory distress syndrome. The mortality risk reduction was most relevant to mortality within the first 48 hours from the time of injury. These results suggest that the mortality risk associated with an FFP:PRBC ratio <1:1.5 may occur early, possibly secondary to ongoing coagulopathy and hemorrhage. This analysis provides further justification for the prospective trial investigation into the optimal FFP:PRBC ratio required in massive transfusion practice.

Clinical and mechanistic drivers of acute traumatic coagulopathy.

BACKGROUND Acute traumatic coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity, and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma. METHODS Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data. RESULTS There were 1,198 patients with laboratory results, of whom 41.6% were coagulopathic. Using international normalized ratio of 1.3 or greater, 41.6% of patients (448) were coagulopathic, while 20.5% (214) were coagulopathic using partial thromboplastin time of 35 or greater. Coagulopathy was primarily associated with a combination of an Injury Severity Score (ISS) of greater than 15 and a base deficit (BD) of less than −6 (p < 0.05). Regression modeling for international normalized ratio–based coagulopathy shows that prehospital crystalloid (odds ratio [OR], 1.05), ISS (OR, 1.03), Glasgow Coma Scale (GCS) score (OR, 0.93), heart rate (OR, 1.08), systolic blood pressure (OR, 0.96), BD (OR, 0.92), and temperature (OR, 0.84) were significant predictors of coagulopathy (all p < 0.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all p < 0.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p < 0.04). Similar results were found for partial thromboplastin time–defined coagulopathy. CONCLUSION ATC is associated with the depletion of factors I, II, V, VII, VIII, IX, and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of ATC and the effects of resuscitation can guide factor-guided resuscitation and correction of coagulopathy after injury. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level IV.

A DNA microarray study of nitric oxide-induced genes in mouse hepatocytes: Implications for hepatic heme oxygenase-1 expression in ischemia/reperfusion

Nitric oxide (NO) can modulate numerous genes directly; however, some genes may be modulated only in the presence of the inflammatory stimuli that increase the expression of the inducible nitric oxide synthase (iNOS). One method by which to examine changes in NO-mediated gene expression is to carry out a gene array analysis on NO-nai;ve cells. Herein, we report a gene array analysis on mRNA from iNOS-null (iNOS(-/-)) mouse hepatocytes harvested from mice exposed to NO by infection with an adenovirus expressing human iNOS (Ad-iNOS). Of the 6500 genes on this array, only approximately 200 were modulated either up or down by the increased iNOS activity according to our criteria for significance. Several clearly defined families of genes were modulated, including genes coding for proinflammatory transcription factors, cytokines, cytokine receptors, proteins associated with cell proliferation and cellular energetics, as well as proteins involved in apoptosis. Our results suggest that iNOS has a generally anti-inflammatory and anti-apoptotic role in hepatocytes but also acts to suppress proliferation and protein synthesis. The expression of iNOS results in increased expression of stress-related proteins, including heme oxygenase-1 (HO-1). We used HO-1 to confirm that a significant change identified by an analysis could be demonstrated as significant in cells and tissues. The elevation of HO-1 was confirmed at the protein level in hepatocytes in vitro. Furthermore, iNOS(-/-) mice experienced greatly increased liver injury subsequent to intestinal ischemia/reperfusion injury, associated with an inability to upregulate HO-1. This is the first study to address the global gene changes induced by iNOS in any cell type, and the findings presented herein may have clinical relevance for conditions such as septic or hemorrhagic shock in which hepatocytes, NO, and HO-1 play a crucial role.

Defining when to initiate massive transfusion: A validation study of individual massive transfusion triggers in PROMMTT patients

BACKGROUND Early predictors of massive transfusion (MT) would prevent undertriage of patients likely to require MT. This study validates triggers using the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. METHODS All enrolled patients in PROMMTT were analyzed. The initial emergency department value for each trigger (international normalized ratio [INR], systolic blood pressure, hemoglobin, base deficit, positive result for Focused Assessment for the Sonography of Trauma examination, heart rate, temperature, and penetrating injury mechanism) was compared for patients receiving MT (≥10 U of packed red blood cells in 24 hours) versus no MT. Adjusted odds ratios (ORs) for MT are reported using multiple logistic regression. If all triggers were known, a Massive Transfusion Score (MTS) was created, with 1 point assigned for each met trigger. RESULTS A total of 1,245 patients were prospectively enrolled with 297 receiving an MT. Data were available for all triggers in 66% of the patients including 67% of the MTs (199 of 297). INR was known in 87% (1,081 of 1,245). All triggers except penetrating injury mechanism and heart rate were valid individual predictors of MT, with INR as the most predictive (adjusted OR, 2.5; 95% confidence interval, 1.7–3.7). For those with all triggers known, a positive INR trigger was seen in 49% receiving MT. Patients with an MTS of less than 2 were unlikely to receive MT (negative predictive value, 89%). If any two triggers were present (MTS ≥ 2), sensitivity for predicting MT was 85%. MT was present in 33% with an MTS of 2 greater compared with 11% of those with MTS of less than 2 (OR, 3.9; 95% confidence interval, 2.6–5.8; p < 0.0005). CONCLUSION Parameters that can be obtained early in the initial emergency department evaluation are valid predictors for determining the likelihood of MT. LEVEL OF EVIDENCE Diagnostic, level II.

Prehospital intravenous fluid is associated with increased survival in trauma patients.

BACKGROUND Delivery of intravenous crystalloid fluids (IVF) remains a tradition-based priority during prehospital resuscitation of trauma patients. Hypotensive and targeted resuscitation algorithms have been shown to improve patient outcomes. We hypothesized that receiving any prehospital IVF is associated with increased survival in trauma patients compared with receiving no prehospital IVF. METHODS Prospective data from 10 Level 1 trauma centers were collected. Patient demographics, prehospital IVF volume, prehospital and emergency department vital signs, lifesaving interventions, laboratory values, outcomes, and complications were collected and analyzed. Patients who did or did not receive prehospital IVF were compared. Tests for nonparametric data were used 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 1,245 trauma patients; 45 were excluded owing to incomplete data; 84% (n = 1,009) received prehospital IVF, and 16% (n = 191) did not. There was no difference between the groups with respect to sex, age, and Injury Severity Score (ISS). The on-scene systolic blood pressure was lower in the IVF group (110 mm Hg vs. 100 mm Hg, p < 0.04) and did not change significantly after IVF, measured at emergency department admission (110 mm Hg vs. 105 mm Hg, 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 700 mL (interquartile range, 300–1,300). The Cox regression revealed that prehospital 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). CONCLUSION Prehospital IVF volumes commonly used by PRospective Observational Multicenter Massive Transfusion Study (PROMMTT) investigators do not result in increased systolic blood pressure but are associated with decreased in-hospital mortality in trauma patients compared with patients who did not receive prehospital IVF. LEVEL OF EVIDENCE Therapeutic study, level IV.

Early resuscitation intensity as a surrogate for bleeding severity and early mortality in the PROMMTT study.

BACKGROUND The classic definition of massive transfusion, 10 or more units of 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, and may use, 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 after injury. METHODS Adult patients surviving at least 30 minutes after admission and receiving one or more RBCs within 6 hours of admission from 10 US Level 1 trauma centers were enrolled in the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Total fluid units were calculated as the sum of the number of crystalloid units (1 L = 1 U), colloids (0.5 L = 1 U), and blood products (1 RBC = 1 U, 1 plasma = 1 U, 6 pack platelets = 1 U). 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 (RTS), and Injury Severity Score (ISS). RESULTS A total of 1,096 eligible patients received resuscitative fluids within 30 minutes, including 620 transfused with blood products. Despite varying products used, the total fluid RI was similar across all sites (3.2 ± 2.5 U). Patients who received four or more units of any resuscitative fluid had a 6-hour mortality rate of 14.4% versus 4.5% in patients who received less than 4 U. The adjusted odds ratio of 6-hour mortality for patients receiving 4 U or more within 30 minutes was 2.1 (95% confidence interval, 1.2–3.5). CONCLUSION Resuscitation with four or more 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 Epidemiologic/prognostic study, level III.

Resuscitate early with plasma and platelets or balance blood products gradually: findings from the 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 during the 6 hours following admission, and (2) patients achieving ratios more than 1:2 (relative to ratios <1:2) had significantly decreased 6-hour to 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 multilevel logistic regression to adjust for center effects, we related in-hospital mortality to the early receipt of plasma or platelets within the first three to six transfusion units (including RBCs) and 2.5 hours of admission. We adjusted for the same covariates as in our previous report: Injury Severity Score (ISS), 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 1,245 PROMMTT patients, 619 were eligible for this analysis. Early plasma was associated with decreased 24-hour and 30-day mortality (adjusted odds ratios of 0.47 [p = 0.009] and 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 of 1:2 or greater by Hour 4 was not associated with 30-day mortality (adjusted odds ratios of 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 Therapeutic study, level IV.

Effect of high product ratio massive transfusion on mortality in blunt and penetrating trauma patients.

BACKGROUND Recent data suggest that massively transfused patients have lower mortality rates when high ratios (>1:2) of plasma or platelets to red blood cells (RBCs) are used. Blunt and penetrating trauma patients have different injury patterns and may respond differently to resuscitation. This study was performed to determine whether mortality after high product ratio massive transfusion is different in blunt and penetrating trauma patients. METHODS Patients receiving 10 or more units of RBCs in the first 24 hours after admission to one of 23 Level I trauma centers were analyzed. Baseline physiologic and biochemical data were obtained. Univariate and logistic regression analyses were performed. Adjusted mortality in patients receiving high (≥ 1:2) and low (<1:2) ratios of plasma or platelets to RBCs was calculated for blunt and penetrating trauma patients. RESULTS The cohort contained 703 patients. Blunt injury patients receiving a high ratio of plasma or platelets to RBCs had lower 24-hour mortality (22% vs. 31% for plasma, p = 0.007; 20% vs. 30% for platelets, p = 0.032), but there was no difference in 30-day mortality (40% vs. 44% for plasma, p = 0.085; 37% vs. 44% for platelets, p = 0.063). Patients with penetrating injuries receiving a high plasma:RBC ratio had lower 24-hour mortality (21% vs. 37%, p = 0.005) and 30-day mortality (29% vs. 45%, p = 0.005). High platelet:RBC ratios did not affect mortality in penetrating patients. CONCLUSION Use of high plasma:RBC ratios during massive transfusion may benefit penetrating trauma patients to a greater degree than blunt trauma patients. High platelet:RBC ratios did not benefit either group.

Institutional protocol improves retrievable inferior vena cava filter recovery rate

BACKGROUND In the trauma population, the use of retrievable inferior vena cava filters (RIVCF) is rapidly gaining acceptance in patients at high risk for venous thromboembolism. This study reports the impact of an institutional protocol on retrieval rates of RIVCF at a level I trauma center. METHODS A review of an institutional Trauma Registry identified 94 consecutive patients who received RIVCF between January 2004 and February 2007 (group I) before the protocol was instituted. Under the protocol, 61 consecutive trauma patients received RIVCF between August 2007 and July 2008 (group II) and were prospectively followed. RESULTS Filter retrieval eligibility criteria were met in 81% (76/94) of patients in group I and in 61% (37/61) of patients in group II. Of those eligible, retrieval-attempt rates were 42% (32/76) in group I versus 95% (35/37) in group II (P < .001). Clinician oversight of the filter accounted for 89% (39/44) of failure of retrieval attempts; patient noncompliance accounted for the rest in group I. In group II, the latter accounted for all such failures. Retrieval was successful in 37% (28/76) and in 84% (31/37) of the eligible patients in groups I and II, respectively (P < .001). No retrieval procedure-related complications occurred. CONCLUSION An institutional protocol for prospective monitoring of RIVCF significantly increases filter retrieval rate.

Preinjury warfarin, but not antiplatelet medications, increases mortality in elderly traumatic brain injury patients

BACKGROUND Previous studies of traumatic brain injury (TBI) outcomes in elderly patients on oral antithrombotic (OAT) therapies have yielded conflicting results. Our objective was to examine the effect of premorbid OAT medications on outcomes among elderly TBI patients with intracranial hemorrhage. METHODS We performed a retrospective analysis of elderly TBI patients (≥65 years) with closed head injury and evidence of brain hemorrhage on computed tomography scan from 2006 to 2010. Patient demographics, injury severity, clinical course, hospital and intensive care unit length of stay, and disposition were collected. Comparison of patients stratified by premorbid OAT use was performed using nonparametric Kruskal-Wallis and Fisher’s exact tests. Multivariable logistic regression was used to compare groups and identify predictors of primary outcomes, including mortality, neurosurgical intervention, hemorrhage progression, complications, and infection. RESULTS A total of 1,552 patients were identified: 543 on aspirin only, 97 on clopidogrel only, 218 on warfarin only, 193 on clopidogrel and aspirin, and 501 on no antithrombotic agent. Blood products were administered to reverse coagulopathy in 77.3% of patients on antithrombotic medications. After adjusting for covariates, including medication reversal, OAT use was associated with increased mortality (p = 0.04). Warfarin use was identified as a key predictor (odds ratio, 2.27; p = 0.05), in contrast to the preinjury use of antiplatelet medications, which was not associated with increased risk of in-hospital death. Rates of neurosurgical intervention differed between groups, with patients on warfarin undergoing intervention more frequently. Survivor subset analysis demonstrated that hemorrhage progression was not associated with preinjury antithrombotic therapy, nor were rates of complication or infection, hospital and intensive care unit lengths of stay, or ventilator days. CONCLUSION Preinjury use of warfarin, but not antiplatelet medications, influences survival and need for neurosurgical intervention in elderly TBI patients with intracranial hemorrhage; hemorrhage progression and morbidity are not affected. The importance of antithrombotic therapy may lie in its impact on initial injury severity. LEVEL OF EVIDENCE Epidemiologic study, level III.