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We are working on optimizing damage control resuscitation following severe traumatic hemorrhage to improve trauma care, including using pharmaceutical cytoprotective agents to improve coagulation function and survival.

This study investigated changes in plasma fibrinogen metabolism and changes in coagulation in severely burned adults. Ten patients (27 ± 3 years; 91 ± 6 kg) with 51 ± 3% TBSA were consented and enrolled into an institutional review board-approved prospective study. On the study day, stable isotope infusion of 1-13C-phenylalanine and d5-phenylalanine was performed to quantify fibrinogen production and consumption. During the infusion, vital signs were recorded and blood samples were drawn every hour. Coagulation was measured by thromboelastograph (TEG). Ten normal healthy volunteers (37 ± 7 years; 74 ± 4 kg) were included as the control group. Burned adults had elevated heart rates (120 ± 2 vs 73 ± 5 [control] beats/minute), respiration rates (23 ± 2 vs 15 ± 1 breaths/minute), plasma glucose (127 ± 10 vs 89 ± 2 mg/dl), and fibrinogen levels (613 ± 35 vs 239 ± 17 mg/dl); and decreased albumin (1.3 ± 0.2 vs 3.7 ± 0.1 g/dl) and total protein (4.4 ± 0.2 vs 6.8 ± 0.1 g/dl, all P < .05). Fibrinogen breakdown was elevated in the burn group (2.3 ± 0.4 vs. 1.0 ± 0.3 µmol/kg/minute); and fibrinogen synthesis was further enhanced in the burn group (4.4 ± 0.7 vs 0.7 ± 0.2 µmol/kg/minute, both P < .05). Clotting speed (TEG-alpha) and clot strength (TEG-MA) were increased in the burn group (62 ± 4 vs 50 ± 4°, and 76 ± 2 vs 56 ± 2 mm, respectively, both P < .05). Fibrinolysis of TEG-LY60 was accelerated in the burn group (16 ± 6 vs 3 ± 1) and so was the increase in D-dimer level in the burn group (4.5 ± 0.4 vs 1.9 ± 0.3 mg/l, both P < .05). The hypercoagulable state postburn is in part a result of increased fibrinogen synthesis, over and above increased fibrinogen breakdown.

The aim of this study was to determine whether visceral protein levels increase under positive nitrogen balance during times of decrease in acute-phase reactant levels in patients with burn injury. This was a post hoc analysis of a prospective, interventional study approved by the local institutional review board. A total of 10 subjects between the ages of 18 and 72 with =20% total body surface area burn were enrolled over a 14-month period. Data were collected for five subjects (average age of 28 ± 8 years and total body surface area burn of 69 ± 15%) who met the inclusion criteria. Changes in visceral protein levels were examined along with nitrogen balance and acute-phase reactants when the subjects were on enteral nutrition, and the proteins were not examined during times of acute kidney injury. Descriptive statistics were performed, and linear regression was used to analyze the association of visceral proteins and nitrogen balance during times that acute-phase reactant levels were decreasing. The subjects received an average of 3044 ± 1613 kcal/day (39 ± 20 kcal/kg), meeting 72% of caloric goals and achieving positive nitrogen balance during 68% of the 40 weekly measurements, with 174 ± 85 g of protein intake per day (2.2 ± 1.1 g/kg). There was a weak relationship between nitrogen balance and changes in visceral protein levels during times that the acute-phase reactant levels were decreasing (P> .05). Visceral proteins were found to be poor markers of nutritional status. This study is unique because the subjects were able to achieve positive nitrogen balance despite severe burns.

Acetaminophen (Ace) and meloxicam (Mel) are the two types of analgesic and antipyretic medications. This study investigated the dose responses of acetaminophen and meloxicam on platelet aggregation and coagulation function in human blood samples. Blood samples were collected from six healthy humans and processed to make platelet-adjusted (100 × 103 cells/μl) blood samples. Acetaminophen (Tylenol, Q-PAP, 100 mg/ml) was added at the doses of 0 μg/ml (control), 214 μg/ml (the standard dose, 1×), 4×, 8×, 10×, 12×, 16×, and 20×. Similarly, meloxicam (Metacam, 5 mg/ml) was added at doses of 0 μg/ml (control), 2.85 μg/ml (the standard dose, 1×), 4×, 8×, 10×, 12×, 16×, and 20×. Fifteen minutes after the addition of acetaminophen and/or meloxicam, platelet aggregation was stimulated with collagen (2 μg/ml) or arachidonic acid (0.5 mmol/l) and assessed using a Chrono-Log 700 aggregometer. Coagulation function was assessed by prothrombin time (PT), activated partial thromboplastin time (aPTT), and using Rotem thrombelastogram. A robust inhibition by acetaminophen and/or meloxicam was observed in arachidonic acid-stimulated platelet aggregation starting at 1× dose. Collagen-stimulated platelet aggregation was inhibited by ACE starting at 1× (78 ± 10% of control), and by meloxicam starting at 4× (72 ± 5% of control, both P < 0.05). The inhibitions by acetaminophen and meloxicam combined were similar to those by acetaminophen or meloxicam. aPTT was prolonged by meloxicam starting at 4×. No changes were observed in PT or any of Rotem measurements by acetaminophen and/or meloxicam. Acetaminophen and meloxicam compromised platelet aggregation and aPTT. Further effort is warranted to characterize the effects of acetaminophen and meloxicam on bleeding in vivo.

Changes of plasma albumin and fibrinogen after various insults have been described as acute phase responses. This study investigated the acute changes of hepatic synthesis of albumin and fibrinogen after hemorrhage and resuscitation with lactated Ringer’s (LR) solution or normal saline (NS) in pigs.

This study compared coagulation function after resuscitation with Hextend and lactated Ringer’s (LR) solution in pigs with tissue injury and hemorrhagic shock.

Hemorrhagic shock contributes to coagulopathy after trauma. We investigated daily changes of coagulation components and coagulation function for 5 days in hemorrhaged and resuscitated pigs.

This study’s objective was to investigate the daily dynamics of fibrinogen metabolism and coagulation function for 5 days after hemorrhagic shock in pigs. Sixteen pigs were randomized into the control (C) and the hemorrhage (H) groups. On day 1, hemorrhage was induced in H by bleeding 35 of the estimated total blood volume, followed by resuscitation with lactated Ringer’s solution at three times the bled volume. Then, a primed constant infusion of stable isotopes was performed in both groups daily for 5 days to measure changes in fibrinogen metabolism, together with changes in hemodynamics and coagulation function. Hemorrhage caused a decrease in mean arterial pressure and an increase in heart rate. Fluid resuscitation corrected these changes. Compared with baseline day 1, fibrinogen levels in H were decreased to 76 ± 6 by hemorrhage and resuscitation on day 1, increased to 217 ± 16 on day 2, and remained elevated afterward; clot strength in H was decreased by hemorrhage on day 1 and returned to baseline values on day 2 and afterward. Compared with day 1 control value (1.3 ± 0.1 mgkg per hour), fibrinogen synthesis in H was increased to 3.6 ± 0.1, 5.1 ± 0.5, 2.6 ± 0.4, 2.7 ± 0.5, and 2.3 ± 0.3 mgkg per hour on days 1 through 5 (all P< 0.05); fibrinogen breakdown in H was elevated on days 1 and 2 but returned to control values afterward. Hemorrhage caused acute decreases in fibrinogen concentration and clot strength, followed by an increase in fibrinogen concentration and recovery of clot strength. The increase in fibrinogen appeared primarily due to a sustained increase in fibrinogen synthesis.

As part of our overall interest in the mechanisms and treatment related to the development of the lethal triad of hypothermia, acidosis, and coagulopathy seen in trauma patients, the purpose of this study was to determine whether acidosis, inducible either by HCl infusion or hemorrhage/hypoventilation, leads to coagulopathy, and if correction of the acidosis will alleviate this coagulopathy.

Albumin plays an important role in maintaining physiological homeostasis. Although decreased albumin concentration has been well described as an acute-phase response following injury, it is unclear whether the decrease is due to compromised synthesis of albumin, dilution, or imbalance between synthesis and breakdown rates, particularly after injury. We investigated changes in albumin synthesis in severely burned patients using stable isotope infusion techniques. Five patients (29 ± 3 years; 80 ± 7 kg) with burn of 48% ± 4% total body surface area (TBSA) were enrolled and studied in the ICU at the Burn Unit of the US Army Institute of Surgical Research. Five age- and sex-matched healthy volunteers (33 ± 5 years; 81 ± 6 kg) were included as controls. On the study day (13 ± 3 days after burn), a primed constant infusion (4 h) of stable isotope d5-phenlylalanine and d3-ketoisocaproic acid was given. Hourly arterial blood samples were drawn during the infusion to determine albumin synthesis rates, using gas chromatography-mass spectrometry analysis. Burned patients had higher heart and respiration rates. Plasma total protein in burn patients (4.5 ± 0.3 g · dL−1) was lower compared with controls (6.8 ± 0.2 g · dL−1). Plasma albumin concentration in burn patients (1.1 ± 0.1 g · dL−1) was also lower compared with controls (3.8 ± 0.1 g · dL−1; both P< 0.05). Albumin synthesis rate in burn patients (4.6 ± 0.2 mg · kg−1· h−1) was enhanced compared with controls (2.2 ± 0.2 mg · kg−1· h−1; P< 0.05). Despite the decrease in albumin concentration, albumin synthesis was enhanced in severely burned patients during the flow phase.

To investigate the hemostatic status of critically ill, nonbleeding trauma patients. We hypothesized that a hypercoagulable state exists in patients early after severe injury and that the pattern of clotting and fibrinolysis are similar between burned and nonburn trauma patients.

Hypothermia and hemorrhagic shock contribute to coagulopathy after trauma. In this study, we investigated the independent and combined effects of hypothermia and hemorrhage with resuscitation on coagulation in swine and evaluated clinically relevant tests of coagulation.

Hemorrhagic coagulopathy is a significant complication after traumatic injury, and much of the underlying mechanism remains unclear. We investigated the changes in fibrinogen metabolism and coagulation after a moderate hemorrhage and resuscitation. Pigs of either sex (weight, 40.9 ± 0.8 kg) were anesthetized and instrumented with arterial and venous catheters and a thermodilution cardiac output catheter. Pigs were randomized into control (C; n = 6), hemorrhage (H; n = 6), and hemorrhage and resuscitation (H-LR; n = 6) groups. Hemorrhage was induced by bleeding 35% of total blood volume for 30 min in H and H-LR groups. Resuscitation in H-LR group was performed using lactated Ringer's solution (LR) at 3 times the bled volume for 30 min. Fibrinogen metabolism was quantified using a primed constant infusion of 1-13C-phenylalanine (6 h) and d5-phenylalanine (4 h) and subsequent analysis by gas chromatograph-mass spectrometry, together with measurements of hemodynamics (hourly) and coagulation by thromboelastography (at baseline and 4 h after hemorrhage and resuscitation). Hemorrhage caused decreases in arterial pH and base excess, and an increase in arterial lactate content. Fluid resuscitation corrected these changes toward normal levels. Fibrinogen level was unchanged in C and decreased to 76% ± 4% in H and to 73% ± 3% in H-LR (both P< 0.05, compared with baseline) after hemorrhage and resuscitation. Fibrinogen breakdown was increased from 3.0 ± 0.4 mg kg−1h−1in C to 5.4 ± 0.6 mg kg−1h−1in H and to 5.6 ± 0.5 mg kg−1h−1in H-LR (both P< 0.05, compared with control), but synthesis was unchanged. The clotting reaction time was unchanged in C and shortened to 93% ± 3% in H and to 91% ± 1% in H-LR (both P< 0.05, compared with baseline). We conclude that hemorrhagic shock caused accelerated fibrinogen breakdown and coagulation. The LR resuscitation reduced tissue hypoxia indexes but did not affect the changes in fibrinogen metabolism and coagulation from hemorrhage. Thus, effective treatment of hemorrhage should include combining standard-of-care resuscitation with interventions to correct alterations in coagulation.

Coagulopathy is an important contributor to morbidity and mortality in trauma patients. Acidosis contributes to coagulopathy. Acidosis can be neutralized with intravascular bicarbonate, but it is unclear if the coagulation defect is rapidly reversed. The effects of acidosis and bicarbonate neutralization on coagulation function were investigated in vivo.

Under normal circumstances there is a reciprocal relation between the availability of free fatty acids (FFAs) and glucose in plasma. In the fasted state, FFAs predominate in both availability and the relative contribution to energy production, whereas the same is true for glucose in the fed state. The extent of glucose oxidation is directly determined by its availability, whereas FFAs are normally available well in excess of their rate of oxidation. The rate of FFA oxidation is determined by the rate of transfer into the mitochondria via the carnitine palmitoyltransferase (CPT) enzyme system, which in turn is regulated by the metabolism of glucose. With critical illness the stress response involves mobilization of both plasma glucose and FFAs simultaneously in both the fed and fasted states. In the situation of excess availability of substrates, the metabolism of glucose limits the oxidation of FFAs, thereby channeling those fatty acids into triglyceride (TG) stores in the muscle and the liver. The high FFA concentrations and increased tissue TG stores can limit glucose clearance from the blood, thereby contributing to the development of hyperglycemia. Also, the excessive metabolism of glucose can result in lacticacidemia and can contribute to the depletion of muscle glutamine. The nutritional treatment of such patients must account for these underlying metabolic responses to avoid amplifying potentially detrimental responses to the excess availability of substrates already present in the fasting state.

Under normal circumstances there is a reciprocal relation between the availability of free fatty acids (FFAs) and glucose in plasma. In the fasted state, FFAs predominate in both availability and the relative contribution to energy production, whereas the same is true for glucose in the fed state. The extent of glucose oxidation is directly determined by its availability, whereas FFAs are normally available well in excess of their rate of oxidation. The rate of FFA oxidation is determined by the rate of transfer into the mitochondria via the carnitine palmitoyltransferase (CPT) enzyme system, which in turn is regulated by the metabolism of glucose. With critical illness the stress response involves mobilization of both plasma glucose and FFAs simultaneously in both the fed and fasted states. In the situation of excess availability of substrates, the metabolism of glucose limits the oxidation of FFAs, thereby channeling those fatty acids into triglyceride (TG) stores in the muscle and the liver. The high FFA concentrations and increased tissue TG stores can limit glucose clearance from the blood, thereby contributing to the development of hyperglycemia. Also, the excessive metabolism of glucose can result in lacticacidemia and can contribute to the depletion of muscle glutamine. The nutritional treatment of such patients must account for these underlying metabolic responses to avoid amplifying potentially detrimental responses to the excess availability of substrates already present in the fasting state.