Sean P. McCully

The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients

BACKGROUND The international normalized ratio (INR) was developed to assess adequacy of Coumadin dosing. Its use has been generalized to guide fresh frozen plasma (FFP) therapy in stable patients. Thrombelastography (TEG) is a whole-blood assay measuring the viscoelastic properties of the clot in near real time. This study hypothesized that INR does not reflect coagulopathy and should not be used to guide FFP therapy in stable trauma and surgical patients. METHODS Prospective observational data were collected from stable trauma and surgical patients (n = 106) who received FFP transfusions. Pretransfusion and posttransfusion blood samples were obtained to assess complete blood count, standard coagulation parameters (INR, partial thromboplastin time, fibrinogen and D-dimer), soluble clotting factors (II, V, VII, VIII, IX, X, XI, XII, proteins C and S) and TEG. Data were analyzed using a Mann-Whitney U-test. Significance was defined as p < 0.05. RESULTS A total of 262 U of FFP were transfused, with 78% of 106 patients receiving two or more units. Despite a reduction in INR, median TEG values remained within normal limits, while clotting factor levels retained adequate function to produce normal clotting before and following FFP transfusion. CONCLUSION The use of FFP in this population did not affect coagulation status in a clinically relevant manner based on TEG values and coagulation factor function. INR is not a predictor of coagulopathy and should not be used to guide coagulation factor replacement in stable trauma and surgical patients. LEVEL OF EVIDENCE Diagnostic study, level III.

Traumatic brain injury is not associated with coagulopathy out of proportion to injury in other body regions.

BACKGROUND Coagulopathy following trauma is associated with poor outcomes. Traumatic brain injury has been associated with coagulopathy out of proportion to other body regions. We hypothesized that injury severity and shock determine coagulopathy independent of body region injured. METHODS We performed a prospective, multicenter observational study at three Level 1 trauma centers. Conventional coagulation tests (CCTs) and rapid thrombelastography (r-TEG) were used. Admission vital signs, base deficit (BD), CCTs, and r-TEG data were collected. The Abbreviated Injury Scale (AIS) score and Injury Severity Score (ISS) were obtained. Severe injury was defined as AIS score greater than or equal to 3 for each body region. Patients were grouped according to their dominant AIS region of injury. Dominant region of injury was defined as the single region with the highest AIS score. Patients with two or more regions with the same greatest AIS score and patients without a region with an AIS score greater than or equal to 3 were excluded. Coagulation parameters were compared between the dominant AIS region. Significant hypoperfusion was defined as BD greater than or equal to 6. RESULTS Of the 795 patients enrolled, 462 met criteria for grouping by dominant AIS region. Patients were predominantly white (59%), were male (75%), experienced blunt trauma (71%), and had a median ISS of 25 (interquartile range, 14–29). Patients with BD greater than or equal to 6 (n = 110) were hypocoagulable by CCT and r-TEG compared with patients with BD less than 6 (n = 223). Patients grouped by dominant AIS region showed no significant differences for any r-TEG or CCT parameter. Patients with BD greater than or equal to 6 demonstrated no difference in any r-TEG or CCT parameter between dominant AIS regions. CONCLUSION Coagulopathy results from a combination of tissue injury and shock independent of the dominant region of injury. With the use of AIS as a measure of injury severity, traumatic brain injury was not independently associated with more profound coagulopathy. LEVEL OF EVIDENCE Epidemiologic study, level III.

Traumatic brain injury and its effect on coagulopathy.

Polytraumatic injury results in tissue factor (TF) release from damaged cells. The acute coagulopathy of trauma (ACT) occurs early and results from significant tissue injury and tissue hypoperfusion. ACT is augmented by therapies resulting in acidemia, hypothermia, and hemodilution contributing to trauma-induced coagulopathy. Coagulopathy associated with traumatic brain injury (TBI) results from the interplay of numerous variables. Because of the high concentration of TF in brain tissue, TBI has been believed to be associated with a greater degree of coagulopathy compared with injury in other body systems. TBI has also recently been shown to cause platelet dysfunction. Platelet receptor inhibition prevents cellular initiation and amplification of the clotting cascade, limiting thrombin incorporation, and stabilization of clot to stop hemorrhage. Therefore, head injury in the presence of polytrauma does appear to augment ACT and warrants close monitoring and appropriate intervention.

Comparison of the hemostatic efficacy of low-volume lyophilized plasma reconstituted using sterile water, lactated Ringer's, normal saline, and Hextend solutions.

BACKGROUND Low-volume ascorbic acid–buffered reconstituted lyophilized plasma (LP) provides logistic advantages, reduces the risks for large-volume resuscitation, modulates inflammation, and is equally effective for hemostatic resuscitation as full-volume LP. We compared the physiologic effects of resuscitation using LP reconstituted with sterile water (LP-SW), lactated Ringer’s solution (LP-LR), normal saline (LP-NS), and Hextend (LP-Hx). METHODS Plasma was collected from swine, lyophilized, and then reconstituted into four test solutions: LP-SW, LP-LR, LP-NS, or LP-Hx. Forty swine were anesthetized and subjected to a validated model of polytrauma and hemorrhagic shock (including a Grade V liver injury), then randomized to receive one of the four test solutions. Physiologic parameters, blood loss, lactate, and hematocrit were followed up. Coagulation status was evaluated using thrombelastography. Inflammatory mediator expression was evaluated by multiplex serum assay. RESULTS Forty animals were included in the study (10 animals per group). One animal died following LP-Hx resuscitation. There was less blood loss in the LP-SW and LP-LR groups compared with the LP-NS and LP-Hx groups (p < 0.05). The LP-SW group exhibited less early coagulopathic changes by thrombelastography, and the LP-Hx group had persistently elevated international normalized ratios at the end of the study period (p < 0.05). Serum interleukin 6 was lower after 4 hours in the LP-SW group compared with LP-NS (p < 0.05). CONCLUSION Resuscitation using low-volume LP-SW and LP-LR buffered with ascorbic acid confers an anti-inflammatory benefit and results in less blood loss. Sterile water is a safe, cost-effective, and universally available fluid for creating a low-volume hemostatic LP resuscitation solution.

Effect of ascorbic acid concentrations on hemodynamics and inflammation following lyophilized plasma transfusion.

BACKGROUND Compared with lyophilized plasma (LP) buffered with other acids, LP with ascorbic acid (AA) attenuates systemic inflammation and DNA damage in a combat relevant polytrauma swine model. We hypothesize that increasing concentrations of AA in transfused LP will be safe, will be hemodynamically well tolerated, and will attenuate systemic inflammation following polytraumatic injury and hemorrhage in swine. METHODS This prospective, randomized, blinded study involved 52 female swine. Forty animals were subjected to our validated polytrauma model and resuscitated with LP. Baseline control sham (n = 6), operative control sham (n = 6), low-AA (n = 10), medium-AA (n = 10), high-AA (n = 10) groups, and a hydrochloric acid control (HCL, n = 10) were randomized. Hemodynamics, thrombelastography, and blood chemistries were assessed. Inflammatory cytokines (tumor necrosis factor &agr;, interleukin 6 [IL-6], C-reactive protein, and IL-10) and DNA damage were measured at baseline, 2 hours, and 4 hours after liver injury. Significance was set at p < 0.05, with a Bonferroni correction for multiple comparisons. RESULTS Hemodynamics, shock, and blood loss were similar between groups. All animals had robust procoagulant activity 2 hours following liver injury. Inflammation was similar between groups at baseline, and AA groups remained similar to HCL following liver injury. IL-6 and tumor necrosis factor &agr; were increased at 2 hours and 4 hours compared with baseline within all groups (p < 0.008). DNA damage increased at 2 hours compared with baseline in all groups (p < 0.017) and further increased at 4 hours compared with baseline in HCL, low-, and high-AA groups (p < 0.005). C-reactive protein was similar between and within groups. IL-10 increased at 2 hours compared with baseline in low- and high-AA groups and remained elevated at 4 hours compared with baseline in the low-AA group (all, p < 0.017). CONCLUSION Concentrations of AA were well tolerated and did not diminish the procoagulant activity of LP. Within our tested range of concentrations, AA can safely be used to buffer LP.

Diet-induced obesity prevents the development of acute traumatic coagulopathy.

BACKGROUND Obesity and hemorrhagic shock following trauma are predictors of mortality but have conflicting effects on coagulation. Following hemorrhage, tissue injury and hypoperfusion lead to acute traumatic coagulopathy (ATC), producing a hypocoagulable state. Inversely, obesity promotes clotting and impairs fibrinolysis to yield a hypercoagulable state. High rates of venous thromboembolism, organ failure, and early mortality may be caused by hypercoagulability in obese patients. We hypothesize that obesity prevents the development of ATC following injury-induced hemorrhagic shock. METHODS Male Sprague-Dawley rats (250–275 g) were fed a high-fat diet (32%kcal from fat) for 4 weeks to 6 weeks and diverged into obesity-resistant (OR, n = 9) and obesity-prone (OP, n = 9) groups. Age-matched control (CON) rats were fed normal diet (10% kcal from fat, n = 9). Anesthetized rats were subjected to an uncontrolled hemorrhage by a Grade V splenic injury to a mean arterial pressure (MAP) of 40 mm Hg. Hypotension (MAP, 30–40 mm Hg) was maintained for 30 minutes to induce shock. MAP, heart rate, lactate, base excess, cytokines, blood loss, and thrombelastography (TEG) parameters were measured before and after hemorrhagic shock. RESULTS At baseline, OP rats exhibited a shorter time to 20-mm clot (K), and higher rate of clot formation (&agr; angle), clot strength (maximal amplitude), and coagulation index, compared with the CON rats (p < 0.05), indicating enhanced coagulation. Physiologic parameters following shock were similar between groups. In the CON and OR rats, shock prolonged the time to clot initiation (R) and K and decreased &agr; angle and coagulation index (all p < 0.05 vs. baseline). In contrast, shock had no effect on these TEG parameters in the OP rats. Maximal amplitude was the only TEG parameter affected by shock in the OP rats, which was decreased in all groups. CONCLUSION Obesity prevents the development of ATC following hemorrhage shock. Complications associated with obesity following hemorrhagic shock may be attributed to the preserved hypercoagulable state.

Reconstitution fluid type does not affect pulmonary inflammation or DNA damage following infusion of lyophilized plasma.

BACKGROUND Dysfunctional inflammation following traumatic hemorrhage can lead to multiple-organ failure and death. In our polytrauma swine model, lyophilized plasma (LP) reconstituted with sterile water and ascorbic acid suppressed systemic inflammation and attenuated DNA damage. However, it remains unknown whether the inflammatory response is affected by the type of fluid used to reconstitute LP. We hypothesized that common resuscitation fluids such as normal saline (LP-NS), lactated Ringer’s solution (LP-LR), Hextend (LP-HX), or sterile water (LP-SW) would yield similar inflammation profiles and DNA damage following LP reconstitution and transfusion. METHODS This was a randomized, prospective, blinded animal study. LP was reconstituted to 50% of original volume with NS, LR, HX, or SW buffered with 15-mM ascorbic acid. Forty swine were subjected to a validated model of polytrauma, hemorrhagic shock, and Grade V liver injury and resuscitated with LP. Serum interleukin 6 (IL-6), IL-10, plasma C-reactive protein, and 8-hydroxy-2-deoxyguanosine concentrations were assessed for systemic inflammation and DNA damage at baseline, 2 hours, and 4 hours following liver injury. Lung inflammation was evaluated by Real Time Polymerize Chain Reaction (RT-PCR). RESULTS Reconstituted LP pH was similar between groups before resuscitation. IL-6 and IL-10 increased at 2 hours and 4 hours compared with baseline in all groups (p < 0.017). DNA damage increased at 2 hours and 4 hours compared with baseline and from 2 hours to 4 hours in the LP-NS, LP-LR, and LP-SW groups (all p < 0.017). Animals resuscitated with LP-HX not only demonstrated increased DNA damage at 4 hours versus baseline but also had the lowest C-reactive protein level at 2 hours and 4-hours (p < 0.017). Overall, differences between groups were similar for DNA damage and lung inflammation. CONCLUSION Reconstitution fluid type does not affect inflammatory cytokine profiles or DNA damage following LP transfusion in this swine polytrauma model. Based on universal availability, these data suggest that sterile water is the most logical choice for LP reconstitution in humans. LEVEL OF EVIDENCE Prognostic, level II.

Positive blood alcohol is associated with reduced DVT in trauma

INTRODUCTION Trauma patients exhibit a complex coagulopathy which is not fully understood and deep venous thrombosis (DVT) rates remain high. The effects of alcohol (EtOH) consumption on coagulopathy in trauma patients have not been studied. We hypothesized that acute EtOH intoxication would produce a relative hypocoagulable state as measured by thrombelastography (TEG) and would be associated with reduced DVT rates. METHODS Data were prospectively collected on 213 trauma patients at a level 1 trauma centre and analyzed in a retrospective secondary analysis. Thrombelastography (TEG), standard laboratory tests and ETOH levels were performed. If the level was positive, patients were grouped as EtOH+ and all patients were screened for DVT using a standard protocol. Statistical significance was p<0.05. RESULTS The EtOH+ group was predominantly male (76%), was younger (p<0.05), had a lower BMI (p<0.05), demonstrated a lower AIS extremity score (p<0.01) and was less likely to have a blunt injury (p<0.01) than the EtOH- group. Gender, ISS and other AIS scores were not significantly different. TEG values in the alcohol group demonstrated a relative hypocoagulable state that was associated with a reduced DVT incidence, 1.4% versus 16.2%, (p<0.01). This difference was not detected with conventional assays. A multivariate logistic regression was performed, controlling for common risk factors for DVT and a positive EtOH level on admission was independently associated with reduced DVT incidence. CONCLUSIONS Alcohol consumption is associated with a relative hypocoagulable state on TEG that is associated with a decreased DVT incidence. This difference is not detected by conventional assays.