Coagulopathy after a liver resection: is it over diagnosed and over treated?

BACKGROUND: Prothrombin time-international normalized ratio (PT-INR) is widely utilized to guide plasma therapy and initiation of thromboprophylaxis after a hepatectomy. Thrombelastography (TEG) monitors shear elasticity, which is sensitive to cellular and plasma components in blood, allowing for functional assessment of the life of the clot. The objective of this study was to prospectively compare PT-INR and TEG in liver resection patients. METHODS: Forty patients were enrolled before undergoing an elective hepatectomy. Patients underwent a liver resection utilizing a low central venous pressure (CVP) anaesthetic technique and intermittent Pringle manoeuver. PT-INR and TEG were drawn prior to incision, post-operatively, and post-operative days 1, 3 and 5. RESULTS: All post-operative PT-INR values increased significantly when compared with pre-operative PT-INR (P < 0.01). The time of onset to clot (R-value) decreased significantly at the post-operative time point (P = 0.04), consistent with a relative hypercoagulability. Subsequent R-values were not different compared with the pre-operative R-value. The strength of the clot (maximum amplitude, MA) was unchanged when comparing pre- and post-operative time points. DISCUSSION: In spite of an elevation in PT-INR, patients undergoing a liver resection demonstrated a brief hypercoagulable state, followed by normal coagulation function based on TEG. These data call into question the practice of utilizing PT-INR to guide plasma transfusion and timing of prophylactic anticoagulation after a liver resection.

Advanced hemostatic dressings are not superior to gauze for care under fire scenarios.

BACKGROUND: Advanced hemostatic dressings perform superior to standard gauze (SG) in animal hemorrhage models but require 2 minutes to 5 minutes application time, which is not feasible on the battlefield. METHODS: Twenty-four swine received a femoral artery injury, 30 seconds uncontrolled hemorrhage and randomization to packing with SG, Combat Gauze (CG), or Celox Gauze (XG) without external pressure. Animals were resuscitated to baseline mean arterial pressures with lactated Ringers and monitored for 120 minutes. Physiologic and coagulation parameters were collected throughout. Dressing failure was defined as overt bleeding outside the wound cavity. Tissues were collected for histologic and ultrastructural studies. RESULTS: All animals survived to study end. There were no differences in baseline physiologic or coagulation parameters or in dressing success rate (SG: 8/8, CG: 4/8, XG: 6/8) or blood loss between groups (SG: 260 mL, CG: 374 mL, XG: 204 mL; p > 0.3). SG (40 seconds ± 0.9 seconds) packed significantly faster than either the CG (52 ± 2.0) or XG (59 ± 1.9). At 120 minutes, all groups had a significantly shorter time to clot formation compared with baseline (p < 0.01). At 30 minutes, the XG animals had shorter time to clot compared with SG and CG animals (p < 0.05). All histology sections had mild intimal and medial edema. No inflammation, necrosis, or deposition of dressing particles in vessel walls was observed. No histologic or ultrastructural differences were found between the study dressings. CONCLUSIONS: Advanced hemostatic dressings do not perform better than conventional gauze in an injury and application model similar to a care under fire scenario.

Hextend and 7.5% hypertonic saline with Dextran are equivalent to Lactated Ringer's in a swine model of initial resuscitation of uncontrolled hemorrhagic shock.

BACKGROUND: The optimal fluid strategy for the early treatment of trauma patients remains highly debated. Our objective was to determine the efficacy of an initial bolus of resuscitative fluids used in military and civilian settings on the physiologic response to uncontrolled hemorrhagic shock in a prospective, randomized, blinded animal study. METHODS: Fifty anesthetized swine underwent central venous and arterial catheterization followed by celiotomy. Grade V liver injury was performed, followed by 30 minutes of uncontrolled hemorrhage. Then, liver packing was completed, and fluid resuscitation was initiated over 12 minutes with 2 L normal saline (NS), 2 L Lactated Ringer's (LR), 250 mL 7.5% hypertonic saline with 3% Dextran (HTS), 500 mL Hextend (HEX), or no fluid (NF). Animals were monitored for 2 hours postinjury. Blood loss after initial hemorrhage, mean arterial pressure (MAP), tissue oxygen saturation (StO2), hematocrit, pH, base excess, and lactate were measured at baseline, 1 hour, and 2 hours. RESULTS: NF group had less post-treatment blood loss compared with other groups. MAP and StO2 for HEX, HTS, and LR at 1 hour and 2 hours were similar and higher than NF. MAP and StO2 did not differ between NS and NF, but NS resulted in decreased pH and base excess. CONCLUSIONS: Withholding resuscitative fluid results in the least amount of posttreatment blood loss. In clinically used volumes, HEX and HTS are equivalent to LR with regard to physiologic outcomes and superior to NF. NS did not provide a measurable improvement in outcome compared with NF and resulted in increased acidosis.

Lyophilized plasma with ascorbic acid decreases inflammation in hemorrhagic shock.

BACKGROUND: Delivery of a high ratio of plasma to packed red blood cells to patients who require massive transfusion is associated with improved survival. Hemorrhagic shock causes increased production of pro-inflammatory cytokines. These are associated with late morbidity and mortality. The use of fresh frozen plasma makes high ratio resuscitation logistically difficult and does not address dysfunctional inflammation. Lyophilized plasma (LP) is a stable powdered form of plasma that is both safe and easily reconstituted. Previous work demonstrated that LP reconstituted with ascorbic acid (AA) decreased inflammation. Whether the reduction of inflammation was associated with LP or the AA is unknown. METHODS: Thirty female swine were anesthetized and subjected to a multisystem combat relevant model consisting of femur fracture, controlled hemorrhage, and hypothermia. A standardized grade V liver injury was made and the animals were randomly assigned to receive LP reconstituted with AA, citric acid (CA), or hydrochloric acid (HCl). Blood was drawn at baseline and at 2 hours and 4 hours for interleukin (IL)-6, IL-8, and tumor necrosis factor-α serum concentrations measured by enzyme-linked immunosorbent assay. Lung tissue was harvested and processed for gene expression before euthanizing the animals. RESULTS: No differences were observed in mortality, baseline cytokine serum concentration, or gene expression. Enzyme-linked immunosorbent assay demonstrated that IL-6 concentration increased over time for all groups (p < 0.05), but less so at 2 hours in the AA group compared with CA and HCl. CONCLUSION: In this animal model of trauma, hemorrhage and resuscitation, AA decreases IL-6 expression relative to CA and HCl. These findings confirm previous work from our laboratory and suggest that AA is responsible for suppression of dysfunctional inflammation in this model.

Lyophilized plasma reconstituted with ascorbic acid suppresses inflammation and oxidative DNA damage.

BACKGROUND: Lyophilized plasma (LP) has been shown to be as effective as fresh frozen plasma (FFP) for resuscitation in polytrauma and hemorrhagic shock. LP reconstituted with ascorbic acid is associated with suppression of cytokines when compared with fresh frozen plasma. We aimed to determine the effect of using alternate LP reconstitution acids on physiologic parameters, blood loss, coagulation, oxidative DNA damage, and proinflammatory cytokines in a polytrauma and hemorrhagic shock model. METHODS: Thirty swine were anesthetized, subjected to polytrauma, hemorrhagic shock, and randomized to resuscitation with LP-ascorbic acid (AA), LP-citric acid (CA), or LP-hydrochloric acid (HCL). Physiologic data were continuously monitored, blood loss measured, and serum collected at baseline, 2 hours, and 4 hours for enzyme-linked immunosorbent assays. Measured 8-OH-2'-deoxyguanosine (8-OHdG) was a biomarker of oxidative DNA damage. RESULTS: No differences were observed in physiologic measures, blood loss, or coagulation parameters. Interleukin-6 increased over time for all groups, but at 2 hours, the concentration in AA (median [minimum, maximum]: 113 ng/mL [0, 244]) was lower compared with CA (181 ng/mL [69, 314], p = 0.01) and HCL (192 ng/mL [41, 310], p = 0.03). Comparing 4 hours to baseline, a significant increase in oxidative DNA damage was observed in CA (22.9 ng/mL [16.3, 34.3] vs. 15.6 ng/mL [13.6, 26.7], p = 0.03) and HCL (19.6 ng/mL [15.7, 56.7] vs. 15.8 ng/mL [11.6, 21.4], p = 0.01) but not in AA (17.9 ng/mL [12.6, 26.9] vs. 17.1 ng/mL [11.8, 18.4], p = 0.24). CONCLUSIONS: Resuscitation with AA results in decreased interleukin-6 expression and oxidative DNA damage compared with CA and HCL.

Red blood cells accelerate the onset of clot formation in polytrauma and hemorrhagic shock.

BACKGROUND: Hemorrhage and coagulopathy are major contributors to death after trauma. The contribution of red blood cells (RBCs) in correcting coagulopathy is poorly understood. Current methods of measuring coagulopathy may fail to accurately characterize in vivo clotting. We aimed to determine the effect of RBCs on clotting parameters by comparing resuscitation regimens containing RBCs and plasma with those containing plasma alone. METHODS: Thirty-two Yorkshire swine were anesthetized, subjected to a complex model of polytrauma and hemorrhagic shock, and resuscitated with either fresh frozen plasma, lyophilized plasma (LP), or 1:1 ratios of fresh frozen plasma:packed RBC (PRBC) or LP:PRBC. Activated clotting time, prothrombin time, partial thromboplastin time, and thrombelastography (TEG) were performed at 1 hour, 2 hours, 3 hours, and 4 hours after resuscitation. RESULTS: Animals treated with 1:1 LP:PRBC had less blood loss than the other groups (p < 0.05). The activated clotting time was shorter in the 1:1 groups when compared with the pure plasma groups at all time points (p < 0.05). The 1:1 groups had shorter TEG R times (time to onset of clotting) at 1 hour, 3 hours, and 4 hours compared with pure plasma groups (p < 0.05). Other TEG parameters did not differ between groups. Partial thromboplastin time was shorter in the pure plasma groups than the 1:1 groups at all time points (p < 0.05). CONCLUSIONS: Whole blood assays reveal that RBCs accelerate the onset of clot formation. Coagulation assays using spun plasma underestimate the effect of RBCs on clotting and do not completely characterize clot formation.

Resuscitation of haemorrhagic shock with normal saline vs. lactated Ringer's: effects on oxygenation, extravascular lung water and haemodynamics.

INTRODUCTION: Pulmonary oedema and impairment of oxygenation are reported as common consequences of haemorrhagic shock and resuscitation (HSR). Surprisingly, there is little information in the literature examining differences in crystalloid type during the early phase of HSR regarding the development of pulmonary oedema, the impact on oxygenation and the haemodynamic response. These experiments were designed to determine if differences exist because of crystalloid fluid type in the development of oedema, the impact on oxygenation and the haemodynamic response to fluid administration in early HSR. METHODS: Twenty anaesthetised swine underwent a grade V liver injury and bled without resuscitation for 30 minutes. The animals were randomised to receive, in a blinded fashion, either normal saline (NS; n = 10) or lactated Ringer's solution (LR; n = 10). They were then resuscitated with study fluid to, and maintained at, the preinjury mean arterial pressure (MAP) for 90 minutes. RESULTS: Extravascular lung water index (EVLWI) began to increase immediately with resuscitation with both fluid types, increasing earlier and to a greater degree with NS. A 1 ml/kg increase in EVLWI from baseline occurred after administartion of (mean +/- standard error of the mean) 68.6 +/- 5.2 ml/kg of normal saline and 81.3 +/- 8.7 ml/kg of LR (P = 0.027). After 150 ml/kg of fluid, EVLWI increased from 9.5 +/- 0.3 ml/kg to 11.4 +/- 0.3 ml/kg NS and from 9.3 +/- 0.2 ml/kg to 10.8 +/- 0.3 ml/kg LR (P = 0.035). Despite this, oxygenation was not significantly impacted (Delta partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2)

Use of leukoreduced blood does not reduce infection, organ failure, or mortality following trauma.

BACKGROUND: Leukoreduced (LR) blood has been demonstrated to reduce morbidity and mortality in high-risk surgical patients, but not in trauma patients. The objective of the present study was to determine the effect of LR blood on morbidity and mortality. We hypothesized that the use of LR blood does not improve outcome in trauma patients. METHODS: This study was a retrospective cohort analysis of trauma patients transfused at a level 1 Trauma Center from 2001 to 2004. Between 2002 and 2003, LR blood was transfused. Prior to that time and subsequent to it, non-leukoreduced (NLR) blood was transfused. This created two historical comparison groups. Data collected included patient demographics, units of blood transfused, intensive care unit (ICU) and hospital days, ventilator days, injury severity score (ISS), mortality, presence of acute respiratory distress syndrome (ARDS), and infectious complications. A multiple organ dysfunction syndrome (MODS) score was calculated. RESULTS: The distribution of patients was as follows: 284 patients received only NLR blood, 153 received only LR blood, and 58 received at least one unit of each. The mean ISS was similar (NLR: 26, LR: 24; P > 0.1). No differences were seen between groups in units transfused (6.2 vs. 5.5), number of ICU days (8.2 vs. 9.0), number of hospital days (16.9 vs. 18.6), number of ventilator days (6.1 vs. 5.7), incidence of ARDS (8.3% vs. 8.5%), MODS score (5.5 vs. 5.9), mortality rate (15.1% vs. 15.7%), or infection rate (36% vs. 30%) (P > 0.1). CONCLUSIONS: This study represents the largest series comparing trauma patients who received either LR or standard blood transfusions. The use of LR blood does not improve outcome in trauma patients.

Transfusion of aged packed red blood cells results in decreased tissue oxygenation in critically injured trauma patients.

BACKGROUND: Blood transfusion is a common event in the treatment of injured patients. The effect of red blood cell transfusion on tissue oxygenation is unclear. The transfusion of older blood has been shown to be detrimental in retrospective studies. This study aims to study the effect of the age of the blood transfused on the tissue oxygenation using near infrared spectroscopy. METHODS: Thirty-two critically injured trauma patients for whom a blood transfusion had been ordered were recruited. Each patient had a transcutaneous probe placed on the thenar eminence. The probe was placed 1 hour before the transfusion and left in place until 4 hours after transfusion. Tissue oxygen saturation (Sto2) was recorded every 2 minutes. The Sto2 area under the curve (AUC) over time periods was calculated. A control group (n = 16), not transfused, was recruited. The transfusion group was divided into two groups by blood age. One group received blood less than 21 days old, (new blood, n = 15) and the other received blood 21 days old or greater (old blood, n = 17). The data were analyzed for significance with Kendall's W and Wilcoxon's signed rank test (p < 0.05). RESULTS: Baseline characteristics such were not significantly different between groups. The baseline AUC did not differ between groups. The old blood group demonstrated a significant decline in Sto2 comparing its baseline period to its transfusion period (p < 0.05). There was no similar decline in the control group or the new blood group. The posttransfusion period AUC for the old blood group was also lower versus baseline (p = 0.06). There was a moderate correlation between increasing age of blood and decrease in oxygenation (r = 0.5). CONCLUSIONS: There was a decrease in peripheral tissue oxygenation in patients receiving older red blood cells. There was no oxygenation decrease in patients receiving blood less than 21 days. This indicates that factors in stored blood may influence the peripheral vasculature and oxygen delivery.

A novel highly porous silica and chitosan-based hemostatic dressing is superior to HemCon and gauze sponges.

BACKGROUND: Hemostatic dressings have become increasingly popular as the optimal initial treatment for severe hemorrhage. The purpose of this study was to compare the hemostatic properties of a novel highly porous silica and chitosan-based dressing (TraumaStat) to HemCon, and gauze dressing in a severe groin injury model in swine. METHODS: Thirty swine were blindly randomized to receive TraumaStat, HemCon, or standard gauze dressing for hemostatic control. A complex groin injury involving complete transaction of the femoral artery and vein was made. After 30 seconds of uncontrolled hemorrhage, the randomized dressing was applied and pressure was held for 5 minutes. Fluid resuscitation was initiated to achieve and maintain the baseline mean arterial pressure and the wound was inspected for bleeding. Failure of hemostasis was defined as pooling of blood outside of the wound. Animals were then monitored for 120 minutes and surviving animals were euthanized. RESULTS: Blood loss before treatment was similar between groups (p > 0.1). TraumaStat had one failure, compared with five for gauze, and eight for HemCon (p = 0.005, TraumaStat vs. HemCon). TraumaStat significantly reduced median blood loss when compared with both HemCon and gauze (117 vs. 774 and 268 mL respectively, p < 0.05). At study conclusion, TraumaStat animals had a greater median hematocrit than both HemCon (24 vs. 19, p = 0.033), and gauze (24 vs. 19, p = 0.049) animals. Median volume of fluid resuscitation and mortality were not different between groups (p > 0.1). CONCLUSIONS: TraumaStat was superior to HemCon and gauze dressings in controlling bleeding from a severe groin injury. TraumaStat may be a better hemostatic dressing for control of active hemorrhage than current standards of care.

Ketamine-based total intravenous anesthesia versus isoflurane anesthesia in a swine model of hemorrhagic shock.

BACKGROUND: Inhalational anesthetics can cause profound hemodynamic effects including decreases in systemic vascular resistance and cardiac inotropy. Although widely used in uncontrolled hemorrhagic shock (UHS), their consequences compared with other anesthetic regimens are not well-studied. Ketamine-based total intravenous anesthesia (TIVA) may produce less profound cardiovascular depression, and has been used during elective surgery but rarely during traumatic shock. The purpose of this study was to compare the effects of isoflurane (ISO) and TIVA regimens in a swine grade V liver injury model. We hypothesized that TIVA would result in less hypotension and dysfunctional inflammation than ISO. METHODS: Twenty swine were randomized blindly to receive either 1% to 3% ISO, or intravenous ketamine, midazolam, and buprenorphine for maintenance anesthesia. Six animals acted as controls. After sedation and intubation, randomized anesthesia was initiated and monitored by an independent animal technician. Invasive lines were placed followed by celiotomy and splenectomy. Baseline mean arterial pressure (MAP) was documented and a grade V liver injury created. After 30 minutes of UHS, animals were resuscitated with 8 mL of Ringer's lactate per milliliter blood loss at 165 mL/min. MAP and tissue oxygen saturation (StO2) were continuously recorded. The animals were sacrificed 120 minutes after injury and lung tissue was harvested. Serum cytokines (interleukin-6 [IL-6], IL-8, and tumor necrosis factor-alpha [TNF-alpha]) were quantified with enzyme-linked immunosorbent assay. Lung cytokine mRNA levels were quantified with real time reverse transcriptase polymerase chain reaction. RESULTS: Animal weight, liver injury pattern, and blood loss were similar (p > 0.1). The ISO group had a lower MAP at baseline (p = 0.02), at injury (p = 0.004), and study completion (p = 0.001). After resuscitation, MAP decreased in the ISO group but remained stable in the TIVA group. StO2 was significantly higher in the TIVA group immediately after injury (p = 0.004), but similar between groups throughout the remainder of the study. Animals who received TIVA trended toward higher levels of lactate and lower pH throughout the study, reaching significance at 30 minutes postinjury (p = 0.037 and 0.043). Inflammatory cytokine (IL-6, IL-8, and TNF-alpha) production did not differ between groups, however TNF-alpha mRNA production was significantly lower in the TIVA group (p = 0.04). CONCLUSION: Although a TIVA regimen produced less pronounced hypotension in a swine model of UHS than did ISO, end-organ perfusion with TIVA appeared to be equivalent or inferior to ISO. In circumstances of limited resources, such as those experienced by forward Army surgical teams, a ketamine-based TIVA regimen may be an option for use in UHS.

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.

Thromboelastogram-guided enoxaparin dosing does not confer protection from deep venous thrombosis: a randomized controlled pilot trial.

BACKGROUND: The incidence of deep venous thrombosis (DVT) remains high in general surgery and trauma patients despite widespread prophylaxis with enoxaparin. A recent study demonstrated decreased incidence of DVT if patients on enoxaparin had a change in R time (ΔR) of greater than 1 minute when heparinase-activated thromboelastography (TEG) was compared with normal TEG. We hypothesized that using ΔR-guided dosing would result in decreased DVT rates. METHODS: A prospective, randomized controlled trial was performed at a Level 1 trauma center. Both trauma and general surgery patients were included. Upon enrollment, demographic data including age, sex, body mass index, and Acute Physiology and Chronic Health Evaluation II score were obtained. Enrolled patients were randomized to standard (30 mg twice a day) or TEG-guided dosing. Dose-adjusted patients underwent daily enoxaparin titration to achieve an ΔR of 1 minute to 2 minutes. Venous thromboembolism screening was performed per institutional protocol. Antithrombin III (AT-III) and anti-Xa levels were drawn at peak enoxaparin concentrations. RESULTS: A total of 87 patients were enrolled. There was no difference in demographic data between the groups. No pulmonary emboli were identified. The control group had a DVT rate of 16%, while the experimental group had a rate of 14% (p = nonsignificant). The experimental group's median enoxaparin dosage, 50 mg twice a day, was significantly higher than that of the control (p < 0.01). TEG ΔR was not different between the control and experimental groups. Beginning at Day 3, anti-Xa levels were higher in the experimental group (p < 0.05). There was no difference in AT-III activity between the two groups; 67% of the patients demonstrated AT-III deficiency. CONCLUSION: TEG adjusted enoxaparin dosing led to significant increases in anti-Xa activity, which did not correlate with a decreased DVT rate. Failure to reduce the DVT rate and increase ΔR despite increased dosing and increased anti-Xa activity is consistent with the high rate of AT-III deficiency detected in this study cohort. These data suggest that the future of DVT prevention may not lie in the optimization of low molecular weight heparin therapy but rather in compounds that increase antithrombin directly or operate independently of the AT-III pathway. LEVEL OF EVIDENCE: Therapeutic study, level III.

The international normalized ratio overestimates coagulopathy in patients after major hepatectomy.

BACKGROUND: The International Normalized Ratio (INR) is commonly used to guide therapy after hepatectomy. We hypothesized that the use of thrombelastography (TEG) would demonstrate a decreased incidence of hypocoagulability in this patient population. METHODS: Seventy-eight patients were prospectively enrolled before undergoing hepatectomy. INR, TEG, and coagulation factors were drawn before incision, postoperatively, and on postoperative days 1, 3, and 5. RESULTS: Patients demonstrated an elevated INR at all postoperative time points. However, TEG demonstrated a decreased R value postoperatively, with subsequent normalization. Other TEG measurements were equivalent to preoperative values. All procoagulant factors save factor VIII decreased postoperatively, with a simultaneous decrease in protein C. CONCLUSIONS: TEG demonstrated a brief hypercoagulable state after major hepatectomy, with coagulation subsequently normalizing. The INR significantly overestimates hypocoagulability after hepatectomy and these data call into question current practices using the INR to guide therapy in this patient population.

Chitosan based advanced hemostatic dressing is associated with decreased blood loss in a swine uncontrolled hemorrhage model.

BACKGROUND: The purpose of this study was to compare standard gauze (SG) and advanced hemostatic dressings in use by military personnel in a no-hold model. METHODS: A randomized, controlled trial was conducted using 36 swine. Animals underwent femoral arteriotomy, followed by 60 seconds of uncontrolled hemorrhage. After hemorrhage, packing with 1 of 3 dressings-SG, Combat Gauze (CG), or Celox Rapid gauze (XG)-and a 500-mL bolus of Hextend were initiated. Pressure was not held after packing, and animals were followed for 120 minutes. Physiologic parameters were monitored continuously, and electrolyte and hematologic laboratory assessments were performed before injury and 30 and 120 minutes after injury. Dressing failure was determined if bleeding occurred outside the wound. RESULTS: All animals survived to study end. Baseline characteristics were similar between groups. No statistical difference was seen in initial blood loss or dressing success rate (SG, 10 of 12; CG, 10 of 12; and XG, 12 of 12). Secondary blood loss was significantly less with XG (median, 12.8 mL; interquartile range, 8.8 to 39.7 mL) compared with SG (median, 44.7 mL; interquartile range, 17.8 to 85.3 mL; P = .02) and CG (median, 31.9 mL; interquartile range, 18.6 to 69.1 mL; P = .05). Packing time was significantly shorter with XG (mean, 37.1 ± 6.2 seconds) compared with SG (mean, 45.2 ± 6.0 seconds; P < .01) and CG (mean, 43.5 ± 5.6 seconds; P = .01). CONCLUSIONS: XG demonstrated shorter application time and decreased secondary blood loss in comparison with both SG and CG. These differences may be of potential benefit in a care-under-fire scenario.

Uncontrolled hemorrhagic shock results in a hypercoagulable state modulated by initial fluid resuscitation regimens.

BACKGROUND: Previous studies have shown large-volume resuscitation modulates coagulopathy and inflammation. Our objective was to analyze the effects of initial bolus fluids used in military and civilian settings on coagulation and inflammation in a prospective, randomized, blinded trial of resuscitation of uncontrolled hemorrhage. METHODS: Fifty swine were anesthetized, intubated, and ventilated and had monitoring lines placed. A Grade V liver injury was performed followed by 30 minutes of hemorrhage. After 30 minutes, the liver was packed, and randomized fluid resuscitation was initiated during a 12-minute period with 2 L of normal saline, 2 L of lactated Ringer's solution, 250 mL of 7.5% saline with 3% Dextran, 500 mL of Hextend, or no fluid (NF). Animals were monitored for 2 hours after injury. Thrombelastograms (TEGs), prothrombin time (PT), partial thromboplastin time, fibrinogen as well as serum interleukin 6, interleukin 8, and tumor necrosis factor α levels were drawn at baseline and after 1 hour and 2 hours. RESULTS: The NF group had less posttreatment blood loss compared with other groups (p < 0.01). Blood loss was similar in the other groups. TEG R values in each group decreased from baseline at 1 and 2 hours (p < 0.02). The groups receiving 2 L of normal saline, 250 mL of 7.5% saline with 3% Dextran, or 500 mL of Hextend had lower TEG maximum amplitude values compared with NF group (p < 0.02). All fluids except lactated Ringer's solution resulted in significant increases in PT compared with NF, whereas all fluids resulted in significant decreases in fibrinogen compared with NF (p < 0.02). Fluid resuscitation groups as well as NF group demonstrated significant increases in inflammatory cytokines from baseline to 1 hour and baseline to 2 hours. There were no significant differences in inflammatory cytokines between groups at 2 hours. CONCLUSION: Withholding fluid resulted in the least significant change in PT, fibrinogen, and maximum amplitude and in the lowest posttreatment blood loss. Resuscitation with different initial fluid resuscitation strategies did not result in increased proinflammatory mediators compared with animals that did not receive fluid.

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.

Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily.

BACKGROUND: The purpose of this study was to analyze whether 2 standard dosing regimens of enoxaparin (30 mg twice daily vs 40 mg once daily) would result in different deep vein thrombosis (DVT) rates and anti-factor Xa activity (anti-Xa) in surgical patients. METHODS: Patients who required enoxaparin for prophylaxis were followed prospectively. Demographics were recorded. Patients underwent standardized duplex screening. Peak anti-Xa levels were drawn on 4 consecutive days. RESULTS: Sixty-three patients were followed up (28 patients on 30 mg twice daily, 35 patients on 40 mg once daily). There was no significant difference in demographics between groups. Twenty-five percent of patients on 30 mg twice daily developed a DVT, whereas 2.9% of patients on 40 mg once daily developed a DVT. Patients on 30 mg twice daily had significantly lower anti-Xa levels. CONCLUSIONS: The incidence of DVT is increased in surgical patients who receive 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Dosing of 40 mg once daily results in significantly higher peak anti-Xa levels compared with 30 mg twice daily.

Thrombelastography-identified coagulopathy is associated with increased morbidity and mortality after traumatic brain injury.

BACKGROUND: The purpose of this study was to determine the relationship between coagulopathy and outcome after traumatic brain injury. METHODS: Patients admitted with a traumatic brain injury were enrolled prospectively and admission blood samples were obtained for kaolin-activated thrombelastogram and standard coagulation assays. Demographic and clinical data were obtained for analysis. RESULTS: Sixty-nine patients were included in the analysis. A total of 8.7% of subjects showed hypocoagulability based on a prolonged time to clot formation (R time, > 9 min). The mortality rate was significantly higher in subjects with a prolonged R time at admission (50.0% vs 11.7%). Patients with a prolonged R time also had significantly fewer intensive care unit-free days (8 vs 27 d), hospital-free days (5 vs 24 d), and increased incidence of neurosurgical intervention (83.3% vs 34.9%). CONCLUSIONS: Hypocoagulability as shown by thrombelastography after traumatic brain injury is associated with worse outcomes and an increased incidence of neurosurgical intervention.

Trauma induces a hypercoagulable state that is resistant to hypothermia as measured by thrombelastogram.

BACKGROUND: The aim of this study was to test the hypothesis that severely injured trauma patients would be hypercoagulable compared with controls measured by thromboelastography and that this hypercoagulability would persist over a broad range of temperatures. METHODS: A prospective study evaluating the effects of temperature on coagulation in trauma patients with Injury Severity Scores ≥ 15 and controls was completed. Thromboelastography was performed 24 hours after admission at 4 temperatures ranging from 32°C to 38°C. RESULTS: Ninety-two subjects (46 patients) were analyzed. Patients had a median Injury Severity Score of 20 (interquartile range, 16­26). Time to clot formation increased (P < .001) and fibrin cross-linking decreased (P < .01) in both groups as temperature decreased. Between groups, time to clot formation, fibrin cross-linking, and clot strength were significantly different at each temperature (P < .01), with patients being more hypercoagulable. Time to clot formation and fibrin cross-linking were more affected by temperature in controls compared with patients (P < .02). CONCLUSIONS: Severely injured patients are more hypercoagulable than controls throughout a broad range of temperature. Decreasing temperature has a greater effect on coagulation in controls compared with patients.