115 results on '"Martini, Wenjun Z."'
Search Results
2. Valproic acid during hypotensive resuscitation in pigs with trauma and hemorrhagic shock does not improve survival
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Martini, Wenjun Z., Xia, Hui, Ryan, Kathy L., Bynum, James, and Cap, Andrew P.
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- 2022
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- View/download PDF
3. Autoresuscitation of Poloxamer 188 in Pigs with Traumatic Severe Hemorrhage
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Martini, Wenjun Z., Xia, Hui, Terrazas, Irasema, and Dubick, Michael A.
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- 2021
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4. Efficacy of resuscitation with fibrinogen concentrate and platelets in traumatic hemorrhage swine model
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Martini, Wenjun Z., Rodriguez, Cassandra M., Cap, Andrew P., and Dubick, Michael A.
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- 2020
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5. Fibrinogen Availability and Coagulation Function after Hemorrhage and Resuscitation in Pigs
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Martini, Wenjun Z
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- 2011
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6. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs
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Martini, Wenjun Z., Chinkes, David L., Pusateri, Anthony E., Holcomb, John B., Yu, Yong-Ming, Zhang, Xiao-Jun, and Wolfe, Robert R.
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Coagulation -- Research ,Hemorrhage -- Research ,Hemorrhage -- Physiological aspects ,Swine -- Research ,Swine -- Physiological aspects ,Biological sciences - Abstract
Hemorrhagic coagulopathy is involved in the morbidity and mortality of trauma patients. Nonetheless, many aspects of the mechanisms underlying this disorder are poorly understood. We have therefore investigated changes in fibrinogen metabolism and coagulation function after a moderate hemorrhagic shock, using a new stable isotope approach. Twelve pigs were randomly divided into the control (C) and hemorrhage (H) groups. Hemorrhage was induced by bleeding 35% total blood volume over a 30-min period. A primed constant infusion of [1-[sup.13]C]phenylalanine (Phe), [d.sub.5]-phenylalanine, and [alpha]-[1-[sup.13]C]ketoisocaproate (KIC) was given to quantify fibrinogen synthesis and breakdown, together with measurements of circulating liver enzyme activities and coagulation function. Mean arterial pressure was decreased by hemorrhage from 89 [+ or -] 4 mmHg in C to 47 [+ or -] 4 mmHg in H (P < 0.05), followed by a rebound to 68 [+ or -] 5 mmHg afterward. Fibrinogen fractional synthesis rate increased from 2.7 [+ or -] 0.2%/h in C to 4.2 [+ or -] 0.4%/h in H by Phe (P < 0.05) and from 3.1 [+ or -] 0.4%/h in C to 4.4 [+ or -] 0.5%/h in H by KIC (P < 0.05). Fibrinogen fractional breakdown rate increased from 3.6 _+ 1.0%/h in C to 12.9 [+ or -] 1.8%/h in H (P < 0.05). The absolute breakdown rate accelerated from 3.0 [+ or -] 0.4 mg x [kg.sup.-1] x [h.sup.-1] in C to 5.4 [+ or -] 0.6 mg x [kg.sup.-1] x [h.sup.-1] in H (P < 0.05), but the absolute synthesis rate remained unchanged. These metabolic changes were accompanied by a reduction in blood clotting time to 92.7 [+ or -] 1.6% of the baseline value by hemorrhage (P < 0.05). No changes were found in liver enzyme activities. We conclude that the observed changes in coagulation after hemorrhagic shock are mechanistically related to the acute acceleration of fibrinogen degradation. stable isotopes; fibrinogen metabolism; hemorrhage; coagulation
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- 2005
7. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation
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Chandler, Margaret P., Kerner, Janos, Huang, Hazel, Vazquez, Edwin, Reszko, Aneta, Martini, Wenjun Z., Hoppel, Charles L., Imai, Makoto, Rastogi, Sharad, Sabbah, Hani N., and Stanley, William C.
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Heart failure -- Research ,Biological sciences - Abstract
Moderate severity heart failure does not involve a down-regulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol 287: H1538-H1543. 2004. First published June 10, 2004; 10.1152/ajpheart.00281.2004.--Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by downregulation of tree fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs (n = 8) and in dogs with microembolization-induced HF (n = 18, ejection fraction = 28%) by infusing three isotopic tracers ([9,[10-.sup.3]H]oteate, [[U-.sup.14]C]glucose, and [[1-.sup.13]C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl-CoA between groups; however, malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Michaelis-Menten constant and maximal velocity tot malonyl-CoA decarboxylase because neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF and that the downregulation of fatty acid oxidation enzymes and the switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomemon. cardiac: metabolism; malonyl CoA
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- 2004
8. Fractional synthesis rates of DNA and protein in rabbit skin are not correlated
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Zhang, Xiao-jun, Chinkes, David L., Wu, Zhanpin, Martini, Wenjun Z., and Wolfe, Robert R.
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DNA -- Influence ,Rabbits -- Diet therapy ,Food/cooking/nutrition - Abstract
We developed a method for measurement of skin DNA synthesis, reflecting cell division, in conscious rabbits by infusing e-[U-[sup.13][C.sub.6]]glucose and L-[[sup.15]N] glycine. Cutaneous protein synthesis was simultaneously measured by infusion of L-[ring-[sup.2][H.sub.5]] phenylalanine. Rabbits were fitted with jugular venous and carotid arterial catheters, and were studied during the infusion of an amino acid solution (10% Travasol). The fractional synthetic rate (FSR) of DNA from the de novo nucleotide synthesis pathway, a reflection of total cell division, was 3.26 [+ or -] 0.59%/d in whole skin and 3.08 [+ or -] 1.86%/d in dermis (P = 0.38). The de novo base synthesis pathway accounted for 76 and 60% of the total DNA FSR in whole skin and dermis, respectively; the contribution from the base salvage pathway was 24% in whole skin and 40% in dermis. The FSR of protein in whole skin was 5.35 [+ or -] 4.42%/d, which was greater (P < 0.05) than that in dermis (2.91 [+ or -] 2.52%/d). The FSRs of DNA and protein were not correlated (P = 0.33), indicating that cell division and protein synthesis are likely regulated by different mechanisms. This new approach enables investigations of metabolic disorders of skin diseases and regulation of skin wound healing by distinguishing the 2 principal components of skin metabolism, which are cell division and protein synthesis. KEY WORDS: * stable isotopes * mass spectrometer * fractional synthetic rate * rabbits
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- 2004
9. The intracellular free amino acid pool represents tracer precursor enrichment for calculation of protein synthesis in cultured fibroblasts and myocytes
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Martini, Wenjun Z., Chinkes, David L., and Wolfe, Robert R.
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Proteins -- Research ,Amino acids -- Nutritional aspects ,Amino acids -- Research ,Food/cooking/nutrition - Abstract
We assessed the approach of using intracellular free amino acid enrichment as precursor enrichment for calculating the fractional synthetic rate of using the stable isotope tracer incorporation technique. We assumed that the true rate of protein synthesis was reflected by the rate of tracer incorporation over time divided by the plateau enrichment in protein. Isolated human fibroblasts and myocytes were cultured in medium supplemented with [[sup.15]N]glycine, [[sup.15]N]proline, and [[d.sub.5]]phenylalanine. Culture medium and cells were collected daily from d 1 to 5. A portion of cells harvested on d 5 was subcultured for an additional 3 passages to d 20. Protein enrichments in both cell types reached a plateau after 20 d of cell culture. In fibroblasts, the true protein synthesis rates were 0.74, 0.85, and 0.86%/h, using protein plateau enrichments of [[sup.15]N]]glycine, [[sup.15]N]]proline, and [[d.sub.5]phenylalanine as precursor enrichments, respectively. When the corresponding intracellular free amino acid enrichments were used, protein synthesis rates were 0.76, 0.79, and 0.76%/h, respectively. Similarly, in myocytes, the true protein synthesis rates were 0.98 and 1.14%/h by protein plateau enrichments of [[sup.15]N]glycine and [[d.sub.5]]phenylalanine, respectively. The synthesis rates were 0.94 and 1.01 %/h by the corresponding intracellular enrichments, respectively. Extracellular amino acid enrichments resulted in underestimation of protein synthesis by a variable amount. We conclude that the intracellular free amino acid enrichment is an optimal surrogate for precursor enrichment to quantify protein synthesis. KEY WORDS: * protein synthesis * stable isotopes * precursor enrichment * GC-MS * plateau enrichment
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- 2004
10. Quantitative assessment of anaplerosis from propionate in pig heart in vivo
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Martini, Wenjun Z., Stanley, William C., Huang, Hazel, Des Rosiers, Christine, Hoppel, Charles L., and Brunengraber, Henri
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Propionates -- Physiological aspects ,Mass spectrometry -- Physiological aspects ,Swine -- Measurement ,Biological sciences - Abstract
Normal cardiac metabolism requires continuous replenishment (anaplerosis) of catalytic intermediates of the citric acid cycle. Little is known about the quantitative aspects of propionate as a substrate of in vivo anaplerosis; therefore, we measured the rate of propionate entry into the citric acid cycle in hearts of anesthetized pigs. [U-[sup.13][C.sub.3]]propionate (0.25 mM) was infused in a coronary artery branch for I h via an extracorporeal perfusion circuit, and cardiac biopsies were analyzed for the mass isotopomer distribution of citric acid cycle intermediates. Infusion of propionate did not affect myocardial oxygen consumption, heart rate, or contractile function. In the infused territory, propionate infusion did not affect uptake of glucose and lactate but decreased free fatty acid uptake by one-half (P < 0.05). Propionate extraction and uptake were 57.4 [+ or -] 3.3% and 0.078 [+ or -] 0.009 [micro]mol * [min.sup.-1] * [g.sup.-1]. Anaplerosis from propionate, calculated from the mass isotopomer distribution of succinate, accounted for 8.9 [+ or -] 1.3% of the citric acid cycle flux. Propioylcarnitine release accounted for only 0.033 [+ or -] 0.002% of propionate uptake. Methylcitrate did not accumulate. Thus administration of a low concentration of propionate appears to be a convenient and safe way to boost anaplerosis in the heart. tricarboxylic acid cycle; cataplerosis; mass isotopomer analysis; mass spectrometry
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- 2003
11. Autoresuscitation of Poloxamer 188 in Pigs With Traumatic Severe Hemorrhage.
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Martini, Wenjun Z., Xia, Hui, Terrazas, Irasema, and Dubick, Michael A.
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- 2022
- Full Text
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12. Hypothermia Induced Impairment of Platelets: Assessment With Multiplate vs. ROTEM—An In Vitro Study.
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Wallner, Bernd, Schenk, Bettina, Paal, Peter, Falk, Markus, Strapazzon, Giacomo, Martini, Wenjun Z., Brugger, Hermann, and Fries, Dietmar
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INDUCED hypothermia ,BLOOD platelets ,ADENOSINE diphosphate ,ARACHIDONIC acid ,BLOOD coagulation - Abstract
Introduction: This experimental in vitro study aimed to identify and characterize hypothermia-associated coagulopathy and to compare changes in mild to severe hypothermia with the quantitative measurement of rotational thromboelastometry (ROTEM) and multiple-electrode aggregometry (MULTIPLATE). Methods: Whole blood samples from 18 healthy volunteers were analyzed at the target temperatures of 37, 32, 24, 18, and 13.7°C with ROTEM (ExTEM, InTEM and FibTEM) and MULTIPLATE using the arachidonic acid 0.5 mM (ASPI), thrombin receptor-activating peptide-6 32 µM (TRAP) and adenosine diphosphate 6.4 µM (ADP) tests at the corresponding incubating temperatures for coagulation assessment. Results: Compared to baseline (37°C) values ROTEM measurements of clotting time (CT) was prolonged by 98% (at 18°C), clot formation time (CFT) was prolonged by 205% and the alpha angle dropped to 76% at 13.7°C (p < 0.001). At 24.0°C CT was prolonged by 56% and CFT by 53%. Maximum clot firmness was only slightly reduced by ≤2% at 13.7°C. Platelet function measured by MULTIPLATE was reduced with decreasing temperature (p < 0.001): AUC at 13.7°C −96% (ADP), −92% (ASPI) and −91% (TRAP). Conclusion: Hypothermia impairs coagulation by prolonging coagulation clotting time and by decreasing the velocity of clot formation in ROTEM measurements. MULTIPLATE testing confirms a linear decrease in platelet function with decreasing temperatures, but ROTEM fails to adequately detect hypothermia induced impairment of platelets. [ABSTRACT FROM AUTHOR]
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- 2022
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13. Changes in Intermediary Metabolism in Severe Surgical Illness
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Wolfe, Robert R. and Martini, Wenjun Z.
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- 2000
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14. Lung surfactant kinetics in conscious pigs
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Martini, Wenjun Z., Chinkes, David L., Barrow, Robert E., Murphey, E.D., and Wolfe, Robert R.
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Pulmonary surfactant -- Physiological aspects ,Fatty acids -- Physiological aspects ,Lecithin -- Physiological aspects ,Swine -- Physiological aspects ,Biological sciences - Abstract
The role of plasma free fatty acids and de novo synthesized fatty acids in the synthesis of lung surfactant phosphatidylcholine (PC) has been studied. A new stable isotope tracer model was used in infusing (1,2-13C2)acetate and uniformly labeled (U-13C16)palmitate in nine overnight fasted pigs. Surfactant kinetics were measured during the basal state and during low-dose glucose infusion. Results indicate glucose does not affect PC synthesis. Plasma is also the main contributor of fatty acids for surfactant PC synthesis.
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- 1999
15. The Intracellular Free Amino Acid Pool Represents Tracer Precursor Enrichment for Calculation of Protein Synthesis in Cultured Fibroblasts and Myocytes
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Chinkes, David L., Wolfe, Robert R., and Martini, Wenjun Z.
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- 2004
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16. Muscle deteriorations become prominent within 24 hours after admission in severely burned adults.
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Martini, Wenjun Z., Yong-Ming Yu, Chung, Kevin K., Dubick, Michael A., and Yu, Yong-Ming
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- 2021
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17. Alteration of Hepatic Fatty Acid Metabolism After Burn Injury in Pigs
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Martini, Wenjun Z., Irtun, Oivind, Chinkes, David L., Rasmussen, Blake, Traber, Daniel L., and Wolfe, Robert R.
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- 2001
18. Assay of the Concentration and 13C Isotopic Enrichment of Propionyl-CoA, Methylmalonyl-CoA, and Succinyl-CoA by Gas Chromatography–Mass Spectrometry
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Kasumov, Takhar, Martini, Wenjun Z., Reszko, Aneta E., Bian, Fang, Pierce, Bradley A., David, France, Roe, Charles R., and Brunengraber, Henri
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- 2002
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19. Dietary fat composition alters pulmonary function in pigs
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Wolfe, Robert R, Martini, Wenjun Z, Irtun, Oivind, Hawkins, Hal K, and Barrow, Robert E
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- 2002
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20. Hypothermia-Associated Coagulopathy: A Comparison of Viscoelastic Monitoring, Platelet Function, and Real Time Live Confocal Microscopy at Low Blood Temperatures, an in vitro Experimental Study.
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Wallner, Bernd, Schenk, Bettina, Hermann, Martin, Paal, Peter, Falk, Markus, Strapazzon, Giacomo, Martini, Wenjun Z., Brugger, Hermann, and Fries, Dietmar
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CRYOMICROSCOPY ,CONFOCAL microscopy ,BLOOD platelets ,BLOOD coagulation factors ,IN vitro studies - Abstract
Introduction: Hypothermia has notable effects on platelets, platelet function, fibrinogen, and coagulation factors. Common laboratory techniques cannot identify those effects, because blood samples are usually warmed to 37°C before analysis and do not fully reflect the in vivo situation. Multiple aspects of the pathophysiological changes in humoral and cellular coagulation remain obscure. This in vitro experimental study aimed to compare the measurements of thromboelastometry (TEM), multiple-electrode aggregometry (MEA) and Real Time Live Confocal Imaging for the purpose of identifying and characterizing hypothermia-associated coagulopathy. Methods: Blood samples were drawn from 18 healthy volunteers and incubated for 30 min before being analyzed at the target temperatures (37, 32, 24, 18, and 13.7°C). At each temperature thromboelastometry and multiple-electrode aggregometry were measured. Real Time Live Confocal Imaging was performed at 4, 24, and 37°C. The images obtained by Real Time Live Confocal Imaging were compared with the functional results of thromboelastometry and multiple-electrode aggregometry. Results: Thromboelastometry standard parameters were impaired at temperatures below baseline 37°C (ANOVA overall effect, p < 0.001): clotting time was prolonged by 27% at 13.7°C and by 60% at 18°C (p < 0.044); clot formation time was prolonged by 157% (p < 0.001). A reduction in platelet function with decreasing temperatures was observed (p < 0.001); the area under the curve at 13.7°C was reduced by 96% (ADP test), 92% (ASPI test), and 91% (TRAP test) of the baseline values. Temperature-associated changes in coagulation were visualized with Real Time Live Confocal Imaging. Molecular changes such as the temperature-associated decrease in the fibrin network are paralleled by cellular effects like the lesser activity of the platelets as a result of decreased temperature. The maximum clot firmness (MCF) in TEM only changed slightly within the temperature range tested. Conclusion: The inhibitory effects of temperature on clot formation were visualized with Real Time Live Confocal Microscopy and compared with standard point-of-care testing. Inhibition of clotting factors and impaired platelet function are probably a result of hypothermia-induced impairment of thrombin. Measurement of MCF in TEM does not fully concur with Real Time Live Confocal Microscopy or MEA in hypothermia. [ABSTRACT FROM AUTHOR]
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- 2020
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21. Hypercoagulation and Hypermetabolism of Fibrinogen in Severely Burned Adults.
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Martini, Wenjun Z, Holcomb, John B, Yu, Yong-Ming, Wolf, Steven E, Cancio, Leopoldo C, Pusateri, Anthony E, and Dubick, Michael A
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FIBRINOGEN ,STABLE isotopes ,HEART beat ,ADULTS ,ALBUMINS ,BURNS & scalds complications ,LENGTH of stay in hospitals ,RESEARCH ,BLOOD coagulation tests ,BURNS & scalds ,RESEARCH methodology ,RESPIRATORY measurements ,BLOOD sugar ,CASE-control method ,MEDICAL cooperation ,EVALUATION research ,SERUM albumin ,COMPARATIVE studies ,BLOOD diseases ,LACTIC acid - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2020
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22. Glucose effects on lung surfactant kinetics in conscious pigs
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MARTINI, WENJUN Z., IRTUN, OIVIND, CHINKES, DAVID L., BARROW, ROBERT E., and WOLFE, ROBERT R.
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Lecithin -- Genetic aspects ,Glycogen -- Synthesis ,Lungs -- Genetic aspects ,Biological sciences - Abstract
Martini, Wenjun Z., Oivind Irtun, David L. Chinkes, Robert E. Barrow, and Robert R. Wolfe. Glucose effects on lung surfactant kinetics in conscious pigs. Am J Physiol Endocrinol Metab 279: E920-E926, 2000.--The primary goal of this study was to investigate the effects of glucose infusion on surfactant phosphatidylcholine (PC) metabolic kinetics in the lungs. A new stable isotope tracer model was used in which [1,2-[sup.13][C.sub.2]]acetate and uniformly labeled [U-[sup.13][C.sub.16]]palmitate were infused in 12 normal overnight-fasted pigs to quantify lung surfactant kinetics with or without glucose infusion (24 mg [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]). With glucose infusion, the rate of surfactant PC incorporation from de novo synthesized palmitate increased from the control value of 2.1 [+ or -] 0.2 to 15.5 [+ or -] 1.9 nmol PC-bound palmitate [multiplied by] [h.sup.-1] [multiplied by] g wet [lung.sup.-1] (P [is less than] 0.05), whereas the incorporation rate from plasma preformed palmitate decreased from the control value of 20.9 [+ or -] 1.9 to 11.6 [+ or -] 1.1 nmol palmitate [multiplied by] [h.sup.-1] [multiplied by] g wet [lung.sup.-1] (P [is less than] 0.05). The palmitate composition in lamellar body surfactant PC increased from the control value of 61.7 [+ or -] 2.1% to 75.9 [+ or -] 0.6% (P [is less than] 0.05). The surfactant PC secretion rate decreased from the control value of 239.0 [+ or -] 26.1 to 81.9 [+ or -] 5.3 nmol PC-bound palmitate [multiplied by] [h.sup.-1] [multiplied by] g wet [lung.sup.-1] (P [is less than] 0.05). We conclude that, whereas surfactant secretion was inhibited by glucose infusion, neither total surfactant PC synthesis nor the surfactant PC pool size was significantly affected due to an increased reliance on de novo synthesized fatty acids. phosphatidylcholine; isotope; synthesis; secretion
- Published
- 2000
23. Stability of Fibrinogen Concentrate in Human Blood Samples: An In Vitro Study.
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Martini, Wenjun Z, Guzman, Rodolfo de, and Dubick, Michael A
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FIBRINOGEN , *BLOOD sampling , *PROTHROMBIN time , *HUMIDITY , *HEMORRHAGE , *BIOCHEMISTRY , *BLOOD coagulation tests , *BLOOD gases analysis , *COMPARATIVE studies , *PHENOMENOLOGY , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *EVALUATION research , *PARTIAL thromboplastin time , *IN vitro studies - Abstract
Objectives: This study was designed to assess the stability and functional activity of fibrinogen concentrates subjected to the changes in temperature and duration observed in field conditions.Methods: Fibrinogen concentrate was stored at -20°C (12 vials), 22°C (12 vials), and 50°C with 80% humidity (12 vials), for up to 6 mo. At each temperature, three vials of fibrinogen concentrate were taken out at 0, 1, 3, and 6 mo and reconstituted. On analysis days, blood samples were taken from a single healthy donor to collect plasma samples. The donor plasma was mixed with commercial fibrinogen-deficient plasma to make fibrinogen-adjusted plasma (FAP). An aliquot of the reconstituted fibrinogen concentrate was used for quantification of stored fibrinogen content (using STA-R) and function (Rotem - Fibtem) in FAP.Results: At 22°C for 0, 1, 3, and 6 mo, there were no significant changes observed in fibrinogen content (1,223 ± 42 mg/vial, 1,286 ± 86 mg/vial, 1,234 ± 76 mg/vial, and 1,178 ± 64 mg/vial), prothrombin time (13.5 ± 0.1 s, 13.7 ± 0.6 s, 13.3 ± 0.4 s, and 13.7 ± 0.2 s), or activated partial thromboplastin time (31.1 ± 0.2 s, 32.0 ± 0.2 s, 31.5 ± 0.2 s, and 32.0 ± 0.8 s), respectively. There were also no significant changes observed in any of the Fibtem measurements. Similarly, no differences were observed in these variables over time at -20°C and 50°C with 80% humidity.Conclusions: Fibrinogen concentrate maintained its content and function when stored at -20°C to 50°C with up to 80% humidity for 6 mo. [ABSTRACT FROM AUTHOR]- Published
- 2018
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24. Physiological Impact of Platelet Apheresis in Pigs: Oxygen Metabolism and Coagulation.
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Martini, Wenjun Z., Rodriguez, Cassandra M., Richardson, Jonathan, Aden, James K., Cap, Andrew P., and Dubick, Michael A.
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HEMAPHERESIS , *BLOOD coagulation , *HEMODYNAMICS , *PROTHROMBIN time , *PHYSIOLOGICAL transport of oxygen , *ARTERIAL physiology , *BLOOD platelets , *OXYGEN therapy , *OXYGEN metabolism , *ANIMAL experimentation , *ANIMALS , *ARTERIES , *BLOOD pressure , *FIBRINOGEN , *SWINE , *THROMBELASTOGRAPHY , *PARTIAL thromboplastin time , *PHYSIOLOGY - Abstract
Introduction: Platelet apheresis is a routine clinical practice, but the physiological impact on the donors has been incompletely characterized. This study measured the effects of platelet apheresis on hemodynamics, oxygen metabolism, and coagulation in pigs to assess its impact before employing the animals in experimental studies.Methods: Forty pigs (39.8 ± 0.6 kg) were anesthetized and catheterized with an apheresis catheter in the femoral vein. During the platelet apheresis process, blood was withdrawn from the pig to separate platelets, and the remaining red blood cells and plasma returned back to the pigs, using the Haemonetics MCS+9000 system. A total of 12 cycles of blood withdrawn and return were performed during the entire apheresis procedure to reduce platelet counts to a target of 50% of baseline. During the process, hemodynamics was recorded in each cycle. Blood samples were collected before and after apheresis to assess changes in oxygen metabolism and coagulation by prothrombin time, activated partial thromboplastin time (STA-R Evolution Stago), and using Rotem thrombelastometry, and platelet aggregation using a Chrono-Log 700 aggregometer.Results: During each cycle of the apheresis, mean arterial pressure (MAP) was decreased and heart rate was increased by blood withdrawal, but both recovered after blood return. On the completion of the apheresis, platelet count decreased from baseline 345 ± 15 109/L to 141 ± 14 109/L and fibrinogen levels were reduced from 124 ± 5 to 99 ± 4 mg/dL (both p < 0.05). Although oxygen delivery remained unchanged, oxygen consumption was decreased from 4.0 ± 0.2 to 3.2 ± 0.0 mL O2/kg/min (p < 0.05). Rotem alpha (clotting speed) decreased from 79 ± 0 to 69 ± 1° and maximum clot firmness (MCF or clot strength) decreased from 71 ± 1 to 57 ± 1 mm (both p < 0.05). No changes were observed in prothrombin time or activated partial thromboplastin time. Platelet aggregation induced by arachidonic acid or collagen was decreased to 28 ± 6% or 71 ± 3% of baseline values (p < 0.05), respectively.Conclusion: Platelet apheresis caused significant fluctuations in hemodynamics, reduced oxygen consumption, in addition to the compromised platelet aggregation and clotting function expected. The observations warrant consideration in humans undergoing apheresis over extended periods. [ABSTRACT FROM AUTHOR]- Published
- 2017
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25. Coagulation complications following trauma.
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Martini, Wenjun Z.
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- 2016
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26. Dose Responses of Ibuprofen In Vitro on Platelet Aggregation and Coagulation in Human and Pig Blood Samples.
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Martini, Wenjun Z., Rodriguez, Cassandra M., Deguzman, Rodolfo, Guerra, Jessica B., Martin, Angela K., Pusateri, Anthony E., Cap, Andrew P., and Dubick, Michael A.
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IBUPROFEN , *BLOOD platelet aggregation , *BLOOD coagulation , *BLOOD sampling , *COLLAGEN , *ANIMAL experimentation , *BLOOD coagulation tests , *NONSTEROIDAL anti-inflammatory agents , *SWINE , *PHARMACODYNAMICS , *THERAPEUTICS - Abstract
Introduction: Ibuprofen is commonly used by warfighters in the deployed environment. This study investigated its dose effects on in vitro coagulation in human and pig blood.Methods: Blood samples were collected from 6 normal volunteers and 6 healthy pigs and processed to make platelet-adjusted samples (100 × 10(3)/μL, common transfusion trigger in trauma). Ibuprofen was added to the samples at concentrations of 0 μg/mL (control), the concentration from the highest recommended oral dose (163 μg/mL, 1×), and 2×, 4×, 8×, 10×, 12×, 16×, and 20×. Platelet aggregation by Chrono-Log aggregometer and coagulation by rotational thrombelastogram (Rotem) were assessed at 15 minutes after the addition of ibuprofen.Results: A robust inhibition of ibuprofen on arachidonic acid-induced platelet aggregation was observed at all doses tested in human or pig blood. Collagen-stimulated platelet aggregation was inhibited starting at 1× in human blood and 4× in pig blood. Rotem measurements were similarly compromised in pig and human blood starting at 16×, except clot formation time was prolonged at 1× in human blood (all p < 0.05).Conclusion: Ibuprofen inhibited platelet aggregation at recommended doses, and compromised coagulation at higher doses. Human blood was more sensitive to ibuprofen inhibition. Further effort is needed to investigate ibuprofen dose responses on coagulation in vivo. [ABSTRACT FROM AUTHOR]- Published
- 2016
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27. Fibrinogen concentrate administration inhibits endogenous fibrinogen synthesis in pigs after traumatic hemorrhage.
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Martini, Wenjun Z. and Dubick, Michael A.
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- 2015
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28. Are Visceral Proteins Valid Markers for Nutritional Status in the Burn Intensive Care Unit?
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Shields, Beth A., Pidcoke, Heather F., Chung, Kevin K., Wade, Charles E., Martini, Wenjun Z., Renz, Evan M., and Wolf, Steven E.
- Published
- 2015
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29. Effect of Ibuprofen dose on platelet aggregation and coagulation in blood samples from pigs.
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Martini, Wenjun Z, Deguzman, Rodolfo, Rodriguez, Cassandra M, Guerra, Jessica, Martini, Angela K, Pusateri, Anthony E, and Dubick, Michael A
- Subjects
- *
ANIMAL experimentation , *BIOLOGICAL models , *BLOOD coagulation , *BLOOD coagulation tests , *BLOOD platelet aggregation , *COMPARATIVE studies , *DOSE-effect relationship in pharmacology , *HEMORRHAGIC shock , *RESEARCH methodology , *MEDICAL cooperation , *NONSTEROIDAL anti-inflammatory agents , *RESEARCH , *SWINE , *THROMBELASTOGRAPHY , *IBUPROFEN , *EVALUATION research , *PARTIAL thromboplastin time , *PROTHROMBIN time - Abstract
Introduction: Ibuprofen is commonly used by Soldiers in the deployed environment. This study investigated its dose-effects on in vitro coagulation.Methods: Blood samples were collected from 4 normal healthy pigs and were processed to make platelet-adjusted (100×10(3)/μL) blood samples. Ibuprofen was added to the samples at doses of 0 μg/mL (control), recommended oral dose (163 μg/mL, 1×), 2×, 4×, 8×, 10×, 12×, 16×, and 20×. Arachidonic acid or collagen-stimulated platelet aggregation was assessed at 15 minutes after the addition of ibuprofen. Coagulation was assessed with measurements of prothrombin time (PT) and activated partial thromboplastin time (aPTT), and thrombelastography by Rotem.Results: A robust inhibition of ibuprofen on arachidonic acid-induced platelet aggregation was observed at all doses tested. Collagen-stimulated platelet aggregation was inhibited to 71%±5% and 10%±5% of the control values at ibuprofen doses of 4× and 20×, respectively (both p<0.05). No changes were observed in PT at any dose, but aPTT was prolonged at dose of 16× and 20×. Rotem measurements of coagulation time, clot formation time, maximum clot firmness, and A10 were compromised at dose 16× and 20× (all p<0.05).Conclusion: Ibuprofen inhibited platelet aggregation at recommended doses, but did not compromise aPTT or coagulation profile until at 16 times the recommended doses and higher. Further effort is needed to clarify whether there are different dose-responses between human and pig blood samples in trauma situations. [ABSTRACT FROM AUTHOR]- Published
- 2015
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30. Differential Changes in Hepatic Synthesis of Albumin and Fibrinogen After Severe Hemorrhagic Shock in Pigs.
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Martini, Wenjun Z., Chung, Kevin K., and Dubick, Michael A.
- Published
- 2014
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31. Comparisons of lactated Ringer's and Hextend resuscitation on hemodynamics and coagulation following femur injury and severe hemorrhage in pigs.
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Martini, Wenjun Z., Dubick, Michael A., and Blackbourne, Lorne H.
- Published
- 2013
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32. Comparisons of normal saline and lactated Ringer's resuscitation on hemodynamics, metabolic responses, and coagulation in pigs after severe hemorrhagic shock.
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Martini, Wenjun Z., Cortez, Douglas S., and Dubick, Michael A.
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HEMORRHAGIC shock ,OXYGEN metabolism ,BLOOD coagulation ,RESUSCITATION ,PHYSIOLOGIC salines - Abstract
Background Ongoing improvements in trauma care now recommend earlier use of blood products as part of damage control resuscitation, but generally these products are not available at far forward battlefield locations. For the military, questions continue to arise regarding efficacy of normal saline (NS) vs. lactated Ringer's (LR). Thus, this study compared the effects of LR and NS after severe hemorrhage in pigs. Methods 20 anesthetized pigs were randomized into control (n = 6), LR (n = 7), and NS (n = 7) groups. Hemorrhage of 60 % estimated total blood volume was induced in LR and NS groups by removing blood from the left femoral artery using a computer-controlled pump. Afterwards, the pigs were resuscitated with either LR at 3 times the bled volume or the volume of NS to reach the same mean arterial pressure (MAP) as in LR group. Hemodynamics were measured hourly and blood samples were taken at baseline (BL), 15 min, 3 h and 6 h after resuscitation to measure changes in coagulation using thrombelastography®. Results MAP was decreased by hemorrhage but returned to BL within 1 h after resuscitation with LR (119 ± 7 ml/kg) or NS (183 ± 9 ml/kg, p < 0.05). Base excess (BE) was decreased by hemorrhage; resuscitation with LR recovered BE but not with NS. Total peripheral resistance was decreased with NS and LR, with a larger drop shown in NS. Serum potassium was increased with NS, but not affected with LR. Coagulation changes were similar between LR and NS. Conclusions NS may be inferior to LR in resuscitation due to its vasodilator effects and the risks of metabolic acidosis and hyperkalemia. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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33. Different recovery profiles of coagulation factors, thrombin generation, and coagulation function after hemorrhagic shock in pigs.
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Martini, Wenjun Z., Cortez, Douglas S., Dubick, Michael A., and Blackbourne, Lome H.
- Published
- 2012
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34. Daily Profiles of Fibrinogen Metabolism for 5 Days Following Hemorrhage and Lactated Ringer’s Resuscitation in Pigs.
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Martini, Wenjun Z., Chung, Kevin K., Dubick, Michael A., and Blackbourne, Lorne H.
- Published
- 2012
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35. Coagulation Changes to Systemic Acidosis and Bicarbonate Correction in Swine.
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Darlington, Daniel N., Kheirabadi, Bijan S., Delgado, Angel V., Scherer, Michael R., Martini, Wenjun Z., and Dubick, Michael A.
- Published
- 2011
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36. ENHANCED ALBUMIN SYNTHESIS IN SEVERELY BURNED ADULTS.
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Martini, Wenjun Z., Wolf, Steven E., Chinkes, David L., Chung, Kevin K., Dubick, Michael A., Blackbourne, Lorne, and Yu, Yong-Ming
- Published
- 2010
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37. EFFECTS OF HEMORRHAGE AND LACTATED RINGER'S RESUSCITATION ON COAGULATION AND FIBRINOGEN METABOLISM IN SWINE.
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Martini, Wenjun Z., Chinkes, David L., Sondeen, Jill, and Dubick, Michael A.
- Published
- 2006
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38. Fractional Synthesis Rates of DNA and Protein in Rabbit Skin Are Not Correlated.
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Xiao-Jun Zhang, Chinkes, David L., Zhanpin Wu, Martini, Wenjun Z., and Wolfe, Robert R.
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DNA synthesis ,PROTEIN synthesis ,GLUCOSE ,AMINO acids ,CELL division ,DERMIS ,SKIN ,LABORATORY rabbits - Abstract
We developed a method for measurement of skin DNA synthesis, reflecting cell division, in conscious rabbits by infusing D-[U-
13 C6 ]glucose and L-[15 N]glycine. Cutaneous protein synthesis was simultaneously measured by infusion of L-[ring-²H5 ]phenylalanine. Rabbits were fitted with jugular venous and carotid arterial catheters, and were studied during the infusion of an amino acid solution (10% Travasol). The fractional synthetic rate (FSR) of DNA from the de novo nucleotide synthesis pathway, a reflection of total cell division, was 3.26 ± 0.59%/d in whole skin and 3.08 ± 1.86%/d in dermis (P = 0.38). The de novo base synthesis pathway accounted for 76 and 60% of the total DNA FSR in whole skin and dermis, respectively; the contribution from the base salvage pathway was 24% in whole skin and 40% in dermis. The FSR of protein in whole skin was 5.35 ± 4.42%/d, which was greater (P < 0.05) than that in dermis (2.91 ± 2.52%/d). The FSRs of DNA and protein were not correlated (P = 0.33), indicating that cell division and protein synthesis are likely regulated by different mechanisms. This new approach enables investigations of metabolic disorders of skin diseases and regulation of skin wound healing by distinguishing the 2 principal components of skin metabolism, which are cell division and protein synthesis. [ABSTRACT FROM AUTHOR]- Published
- 2004
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39. Assay of the Concentration and 13C Isotopic Enrichment of Propionyl-CoA, Methylmalonyl-CoA, and Succinyl-CoA by Gas Chromatography–Mass Spectrometry
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Kasumov, Takhar, Martini, Wenjun Z., Reszko, Aneta E., Bian, Fang, Pierce, Bradley A., David, France, Roe, Charles R., and Brunengraber, Henri
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- *
COENZYMES , *GAS chromatography/Mass spectrometry (GC-MS) - Abstract
We developed gas chromatography–mass spectrometry assays for the concentration and mass isotopomer distribution of propionyl-CoA, methylmalonyl-CoA, and succinyl-CoA in tissues. The assays involves perchloric acid extraction of the tissue, spiking the extract with [2H5]propionyl-CoA and [2H4]succinyl-CoA internal standards, and isolation of short-chain acyl-CoA fraction on an oligonucleotide purification cartridge. Propionyl-CoA is reacted with sarcosine and the formed N-propionylsarcosine is assayed as its pentafluorobenzyl derivative. Methylmalonyl-CoA and succinyl-CoA are hydrolyzed and the corresponding acids assayed as tert-butyl dimethylsilyl derivatives. The assay was applied to a study of [U-13C3]propionate metabolism in perfused rat livers. While propionyl-CoA is only M3 labeled, succinyl-CoA is M3, M2, and M1 labeled because of isotopic exchanges in the citric acid cycle. Methylmalonyl-CoA is M3 and M2 labeled, reflecting reversal of S-methylmalonyl-CoA mutase. Thus, our assays allow measuring the turnover of the coenzyme A derivatives involved in anaplerosis of the citric acid cycle via precursors of propionyl-CoA, i.e., propionate, odd-chain fatty acids, isoleucine, threonine, and valine. [Copyright &y& Elsevier]
- Published
- 2002
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40. Coagulation and fluid resuscitation by HyperHES in severe hemorrhage.
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Vico, Sylvain, Dubost, Clément, Mérat, Stéphane, Martini, Wenjun Z., and Dubick, Michael A.
- Published
- 2013
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41. Re: Coagulation and fluid resuscitation by HyperHES in severe hemorrhage.
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Martini, Wenjun Z and Dubick, Michael A
- Published
- 2013
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42. Acetaminophen and meloxicam inhibit platelet aggregation and coagulation in blood samples from humans.
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Martini AK, Rodriguez CM, Cap AP, Martini WZ, and Dubick MA
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- Arachidonic Acid antagonists & inhibitors, Arachidonic Acid pharmacology, Blood Cells drug effects, Blood Specimen Collection, Cells, Cultured, Collagen antagonists & inhibitors, Collagen pharmacology, Dose-Response Relationship, Drug, Humans, Meloxicam, Partial Thromboplastin Time, Prothrombin Time, Thrombelastography, Acetaminophen pharmacology, Blood Coagulation drug effects, Platelet Aggregation drug effects, Thiazines pharmacology, Thiazoles pharmacology
- Abstract
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 × 10 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.
- Published
- 2014
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43. Acidosis and correction of acidosis does not affect rFVIIa function in swine.
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Darlington DN, Kheirabadi BS, Scherer MR, Martini WZ, and Dubick MA
- Abstract
Background: Hemorrhagic shock and trauma are associated with acidosis and altered coagulation. A fall in pH has been reported to attenuate the activity of recombinant activated Factor VII (rFVIIa) in vitro. However, it is not known if acidosis induced by hemorrhagic shock or infusion of HCl attenuates FVIIa activity in vivo. The purpose of this study was to determine if acidosis, induced by two methods, affects recombinant FVIIa (rFVIIa) activity in swine, and if correction of the pH restores rFVIIa activity to normal., Methods: Acidosis was induce in anesthetized swine in two separate models: 1) HCl infusion (n=10) and 2) hemorrhage/hypoventilation (n=8). Three groups per model were used: Control (pH7.4), Acidosis (arterial pH7.1) and Acidosis-Corrected (bicarbonate infusion to return pH from 7.1 to 7.4). Pigs were then injected with rFVIIa (90 μg/kg) or vehicle (saline) at target pH and arterial blood samples were taken for measurement of coagulation function, including Thromboelastography -TEG, Thrombin Generation, Activated Clotting Time, Prothrombin Time, activated Partial Thromboplastin Time, Fibrinogen Concentration and Platelet count before and 5min after injection of rFVIIa., Results: Acidosis led to a hypocoagulation as measured by almost all coagulation parameters in both models. Furthermore, the change in coagulation function produced after infusion of rFVIIa was not different between control, acidosis and acidosis-corrected groups for all coagulation parameters measured., Conclusion: Acidosis associated with hemorrhagic shock or HCl infusion led to a hypocoagulation that was not corrected with bicarbonate infusion. Furthermore, acidosis did not affect rFVIIa function, and correction of the acidosis with bicarbonate had no effect on rFVIIa function in these models. This suggests that in vivo acidosis did not diminish rFVIIa function.
- Published
- 2012
44. Thromboelastography as a better indicator of hypercoagulable state after injury than prothrombin time or activated partial thromboplastin time.
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Park MS, Martini WZ, Dubick MA, Salinas J, Butenas S, Kheirabadi BS, Pusateri AE, Vos JA, Guymon CH, Wolf SE, Mann KG, and Holcomb JB
- Subjects
- Adult, Antithrombin III analysis, Case-Control Studies, Factor XIa analysis, Female, Humans, Intensive Care Units, Male, Middle Aged, Partial Thromboplastin Time, Protein C analysis, Prothrombin Time, Pulmonary Embolism diagnosis, Pulmonary Embolism etiology, Venous Thromboembolism diagnosis, Venous Thromboembolism etiology, Thrombelastography, Thrombophilia diagnosis, Thrombophilia etiology, Wounds and Injuries complications
- Abstract
Objectives: 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., Materials: Patients admitted to the surgical or burn intensive care unit within 24 hours after injury were enrolled. Blood samples were drawn on days 0 through 7. Laboratory tests included prothrombin time (PT), activated partial thromboplastin time (aPTT), levels of activated factor XI, D-dimer, protein C percent activity, antithrombin III percent activity, and thromboelastography (TEG)., Results: Study subjects were enrolled from April 1, 2004, to May 31, 2005, and included nonburn trauma patients (n = 33), burned patients (n = 25), and healthy (control) subjects (n = 20). Despite aggressive thromboprophylaxis, three subjects (2 burned and 1 nonburn trauma patients [6%]) had pulmonary embolism during hospitalization. Compared with controls, all patients had prolonged PT and aPTT (p < 0.05). The rate of clot formation (alpha angle) and maximal clot strength were higher for patients compared with those of controls (p < 0.05), indicating a hypercoagulable state. Injured patients also had lower protein C and antithrombin III percent activities and higher fibrinogen levels (p < 0.05 for all). Activated factor XI was elevated in 38% of patients (control subjects had undetectable levels)., Discussion: Thromboelastography analysis of whole blood showed that patients were in a hypercoagulable state; this was not detected by plasma PT or aPTT. The high incidence of pulmonary embolism indicated that our current prophylaxis regimen could be improved.
- Published
- 2009
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45. Thrombelastography is better than PT, aPTT, and activated clotting time in detecting clinically relevant clotting abnormalities after hypothermia, hemorrhagic shock and resuscitation in pigs.
- Author
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Martini WZ, Cortez DS, Dubick MA, Park MS, and Holcomb JB
- Subjects
- Animals, Blood Coagulation Factors metabolism, Disease Models, Animal, Hypothermia etiology, Platelet Count, Predictive Value of Tests, Resuscitation, Shock, Hemorrhagic etiology, Swine, Thrombelastography, Wounds and Injuries complications, Wounds and Injuries therapy, Blood Coagulation physiology, Hypothermia blood, Hypothermia therapy, Shock, Hemorrhagic blood, Shock, Hemorrhagic therapy, Wounds and Injuries blood
- Abstract
Background: 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., Methods: Pigs (n = 24) were randomized into four groups of six animals each: sham control, hypothermia, hemorrhage with resuscitation, and hypothermia, hemorrhage with resuscitation combined. Hypothermia to 32 degrees C was induced with a cold blanket. Hemorrhage was induced by bleeding 35% of total blood volume followed by resuscitation with lactated Ringer's solution. Coagulation was assessed by thrombin generation, prothrombin time (PT), activated partial thromboplastin time (aPTT), activated clotting time (ACT), and thrombelastography (TEG) from blood samples taken at baseline and 4 hour after hypothermia and/or hemorrhage with resuscitation. Data were compared with analysis of variance., Results: Baseline values were similar among groups. There were no changes in any measurements in the control group. Compared with baseline values, hemorrhage with resuscitation increased lactate to 140% +/- 15% (p < 0.05). Hypothermia decreased platelets to 73% +/- 3% (p < 0.05) with no effect on fibrinogen. Hemorrhage with resuscitation reduced platelets to 72% +/- 4% and fibrinogen to 71% +/- 3% (both p < 0.05), with similar decreases in platelets and fibrinogen observed in the combined group. Thrombin generation was decreased to 75% +/- 4% in hypothermia, 67% +/- 6% in hemorrhage with resuscitation, and 75% +/- 10% in the combined group (all p < 0.05). There were no significant changes in PT or aPTT by hemorrhage or hypothermia. ACT was prolonged to 122% +/- 1% in hypothermia, 111% +/- 4% in hemorrhage with resuscitation, and 127% +/- 3% in the combined group (all p < 0.05). Hypothermia prolonged the initial clotting time (R) and clot formation time (K), and decreased clotting rapidity (alpha) (all p < 0.05). Hemorrhage with resuscitation only decreased clot strength (maximum amplitude [MA], p < 0.05). TEG parameters in the combined group reflected the abnormal R, K, MA, and alpha observed in the other groups., Conclusion: Hypothermia inhibited clotting times and clotting rate, whereas hemorrhage impaired clot strength. Combining hypothermia with hemorrhage impaired all these clotting parameters. PT, aPTT were not sensitive whereas ACT was not specific in detecting these coagulation defects. Only TEG differentiated mechanism related to clotting abnormalities, and thus may allow focused treatment of clotting alterations associated with hypothermia and hemorrhagic shock.
- Published
- 2008
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46. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital.
- Author
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Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas J, Martini WZ, Hess JR, Dubick MA, Simon CD, Beekley AC, Wolf SE, Wade CE, and Holcomb JB
- Subjects
- Cohort Studies, Erythrocyte Count, Hospitals, Military, Humans, Injury Severity Score, ROC Curve, Retrospective Studies, Survival Rate, United States, Wounds and Injuries therapy, Erythrocyte Transfusion, Fibrinogen metabolism, Iraq War, 2003-2011, Wounds and Injuries blood, Wounds and Injuries mortality
- Abstract
Background: To treat the coagulopathy of trauma, some have suggested early and aggressive use of cryoprecipitate as a source of fibrinogen. Our objective was to determine whether increased ratios of fibrinogen to red blood cells (RBCs) decreased mortality in combat casualties requiring massive transfusion., Methods: We performed a retrospective chart review of 252 patients at a U.S. Army combat support hospital who received a massive transfusion (>or=10 units of RBCs in 24 hours). The typical amount of fibrinogen within each blood product was used to calculate the fibrinogen-to-RBC (F:R) ratio transfused for each patient. Two groups of patients who received either a low (<0.2 g fibrinogen/RBC Unit) or high (>or=0.2 g fibrinogen/RBC Unit) F:R ratio were identified. Mortality rates and the cause of death were compared between these groups, and logistic regression was used to determine if the F:R ratio was independently associated with survival., Results: Two-hundred and fifty-two patients who received a massive transfusion with a mean (SD) ISS of 21 (+/-10) and an overall mortality of 75 of 252 (30%) were included. The mean (SD) F:R ratios transfused for the low and high groups were 0.1 grams/Unit (+/-0.06), and 0.48 grams/Unit (+/-0.2), respectively (p < 0.001). Mortality was 27 of 52 (52%) and 48 of 200 (24%) in the low and high F:R ratio groups respectively (p < 0.001). Additional variables associated with survival were admission temperature, systolic blood pressure, hemoglobin, International Normalized Ratio (INR), base deficit, platelet concentration and Combined Injury Severity Score (ISS). Upon logistic regression, the F:R ratio was independently associated with mortality (odds ratio 0.37, 95% confidence interval 0.171-0.812, p = 0.013). The incidence of death from hemorrhage was higher in the low F:R group, 23/27 (85%), compared to the high F:R group, 21/48 (44%) (p < 0.001)., Conclusions: In patients with combat-related trauma requiring massive transfusion, the transfusion of an increased fibrinogen: RBC ratio was independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage. Prospective studies are needed to evaluate the best source of fibrinogen and the optimal empiric ratio of fibrinogen to RBCs in patients requiring massive transfusion.
- Published
- 2008
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47. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs.
- Author
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Martini WZ and Holcomb JB
- Subjects
- Animals, Blood Coagulation Tests, Disease Models, Animal, Hematocrit, Platelet Count, Swine, Time Factors, Acidosis blood, Blood Coagulation physiology, Fibrinogen metabolism
- Abstract
Objective: Uncontrolled bleeding from coagulopathy signals imminent death in severely injured patients. Acidosis is an important predictor of coagulopathy, but the underlying contributing mechanisms are unclear. This study was designed to investigate the effects of acidosis on fibrinogen metabolism and coagulation function in a swine model., Methods: Twelve pigs were randomly divided into the control (n = 6) and acid (n = 6) groups. Acidosis of pH 7.1 was induced by infusion of 0.2 M HCl in lactated Ringer solution in the acid group. Afterward, an infusion of stable isotope 1-13C-phenylalanine (6 hours) and d5-phenylalanine (4 hours) was performed. Blood samples were withdrawn hourly to quantify fibrinogen synthesis and degradation rates using gas chromatograph and mass spectrometry analysis. To correlate changes in fibrinogen metabolism, coagulation changes were assessed by prolonged prothrombin time, partial activated thromboplastin time, activated clotting time, and thrombelastograph (TEG)., Results: Acidosis caused decreases in mean arterial pressure, arterial bicarbonate concentration, base excess, fibrinogen concentration, and platelet counts. Acidosis increased fibrinogen degradation rate from the control value of 4.3 +/- 1.0 mg/kg/h to 11.8 +/- 1.4 mg/kg/h (P < 0.05), with no effect on fibrinogen synthesis. Prolonged prothrombin time, partial activated thromboplastin time, activated clotting time were consistently prolonged by acidosis (all P < 0.05). Clotting rapidity (angle alpha in TEG) was decreased from a baseline value of 73.3 +/- 1.1 degree to 63.0 +/- 2.4 degree (P < 0.05). Clot strength (maximum amplitude in TEG) was decreased from a baseline value of 72.2 +/- 1.4 mm to 56.2 +/- 3.1 mm (P < 0.05)., Conclusions: Acidosis compromised the clotting process and accelerated fibrinogen consumption with no effect on fibrinogen production, resulting in a deficit in fibrinogen availability.
- Published
- 2007
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48. Evaluation of tris-hydroxymethylaminomethane on reversing coagulation abnormalities caused by acidosis in pigs.
- Author
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Martini WZ, Dubick MA, Wade CE, and Holcomb JB
- Subjects
- Acidosis blood, Acidosis complications, Animals, Blood Coagulation Disorders etiology, Blood Coagulation Tests, Buffers, Fibrinogen metabolism, Hydrogen-Ion Concentration, Partial Thromboplastin Time, Platelet Count, Prothrombin Time, Random Allocation, Swine, Thrombin biosynthesis, Acidosis drug therapy, Blood Coagulation Disorders prevention & control, Tromethamine therapeutic use
- Abstract
Objective: To investigate the effect of tris-hydroxymethylaminomethane (THAM) pH neutralization on reversing coagulation abnormalities caused by acidosis., Design: Random and controlled study., Setting: Animal research facility and laboratory., Subjects: Yorkshire swine (n = 18)., Interventions: Acidosis was induced in 12 pigs by infusing 0.2 M hydrochloric acid (HCl). When the target pH of 7.1 was achieved, the pigs were infused with either 0.3 M THAM to achieve pH of 7.4 (intervention group) or an equal volume of lactated Ringer's solution (acid control group)., Measurements and Main Results: Blood samples were taken at baseline, 15 mins after reaching pH of 7.1, and 15 mins after THAM pH neutralization. Coagulation function was assessed by thrombin generation, prothrombin time, activated partial thromboplastin time, activated clotting time, and thromboelastography (maximum clot formation time [R+K], clotting rapidity [alpha], and clot strength [maximum amplitude]). An additional six pigs (sham group) were infused with THAM, and an equal volume of fluid as the 12 coagulopathic pigs was given to assess effects of THAM and hemodilution. Comparisons were made using a mixed model analysis of variance. No change in any indexes of coagulation was observed in sham pigs. Compared with baseline, acidosis of pH 7.1 decreased base excess from 6.6 +/- 0.5 mM to -12.4 +/- 0.5 mM; reduced fibrinogen levels to 72% +/- 2%, platelet counts to 53% +/- 3%, thrombin generation to 58% +/- 4%, alpha to 84% +/- 2%, and maximum amplitude to 75% +/- 3%; and prolonged prothrombin time to 113% +/- 2%, partial thromboplastin time to 122% +/- 4%, activated clotting time to 124% +/- 3%, and R + K to 119% +/- 3% (all p < .05). THAM infusion corrected pH to 7.40 +/- 0.02 and base excess to 2.6 +/- 0.9 mM (p < .05). However, there were no differences in thrombin generation, prothrombin time, partial thromboplastin time, activated clotting time, R+K, alpha, or maximum amplitude between the groups with or without pH correction., Conclusions: Acidosis impaired coagulation by depleting clotting factors, inhibiting thrombin generation, and affecting clot strength and stability. THAM corrected acid-base deficit but did not acutely reverse the coagulation abnormalities in the model.
- Published
- 2007
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49. Does bicarbonate correct coagulation function impaired by acidosis in swine?
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Martini WZ, Dubick MA, Pusateri AE, Park MS, Ryan KL, and Holcomb JB
- Subjects
- Acidosis complications, Analysis of Variance, Animals, Blood Coagulation Disorders etiology, Blood Coagulation Disorders physiopathology, Blood Coagulation Tests, Swine, Acidosis therapy, Bicarbonates therapeutic use, Blood Coagulation Disorders therapy
- Abstract
Background: 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., Methods: Acidosis was induced in 12 pigs by infusing 0.2 mol/L HCl to pH 7.1. Pigs were then infused with either LR to maintain a pH of 7.1 (A-LR, n = 6) or 0.3 mol/L bicarbonate to a pH of 7.4 (A-Bi, n = 6). Blood samples were taken at baseline, 15 minutes after acidosis induction, and 15 minutes after bicarbonate neutralization. Coagulation function was assessed by prothrombin time (PT), partial thromboplastin time (PTT), thrombin generation, initial clot formation time (R), clotting rapidity (alpha), and clot strength (MA)., Results: Compared with baseline values, acidosis reduced fibrinogen concentration to 66% +/- 2% in A-LR and to 71% +/- 3% in A-Bi, and decreased platelet counts to 49% +/- 4% in A-LR and to 53% +/- 4% in A-Bi. Thrombin generation decreased to 60% +/- 4% in A-LR and to 53% +/- 7% in A-Bi. Acidosis prolonged PT and PTT about 20% and decreased alpha and MA. After pH neutralization, fibrinogen and platelet levels remained depleted and no reversal of acidosis-induced changes in thrombin generation, PT, PTT, alpha, and MA were observed., Conclusion: Acidosis impaired coagulation by depleting fibrinogen and platelets and by inhibiting clotting kinetics. The deficit associated with acidosis was not reversed with bicarbonate pH neutralization.
- Published
- 2006
- Full Text
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50. Independent contributions of hypothermia and acidosis to coagulopathy in swine.
- Author
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Martini WZ, Pusateri AE, Uscilowicz JM, Delgado AV, and Holcomb JB
- Subjects
- Acidosis physiopathology, Animals, Blood Coagulation Disorders physiopathology, Blood Pressure, Disease Models, Animal, Fibrinogen analysis, Heart Rate, Hypothermia physiopathology, Platelet Count, Reference Values, Swine, Thrombin metabolism, Whole Blood Coagulation Time, Acidosis blood, Acidosis complications, Blood Coagulation Disorders blood, Blood Coagulation Disorders etiology, Hypothermia blood, Hypothermia complications
- Abstract
Background: Clinical coagulopathy occurs frequently in the presence of acidosis and hypothermia. The purpose of this study was to determine the relative contributions of acidosis and hypothermia to coagulopathy, as measured by current standard bedside and clinical laboratory analyses (i.e., bleeding time and prothrombin time). In addition, we investigated possible mechanisms of these effects using a modified prothrombin time test, thromboelastography, and thrombin kinetics analyses. An improved understanding of coagulopathy should facilitate hemorrhage control., Methods: Twenty-four pigs were randomly allocated into normal (pH, 7.4; 39 degrees C), acidotic (pH, 7.1; 39 degrees C), hypothermic (pH, 7.4; 32 degrees C), and acidotic and hypothermic (pH, 7.1; 32 degrees C) combined groups. Acidosis was induced by the infusion of 0.2N hydrochloric acid in lactated Ringer's solution. Hypothermia was induced by using a blanket with circulating water at 4 degrees C. Development of a clinical coagulopathy was defined as a significant increase in splenic bleeding time. Measurements were compared before (pre) and 10 minutes after (post) the target condition was achieved., Results: Acidosis, hypothermia, or both caused the development of coagulopathy, as indicated by 47%, 57%, and 72% increases in splenic bleeding time (p < 0.05, pre vs. post). Plasma fibrinogen concentration was decreased by 18% and 17% in the acidotic and combined groups, respectively, but not in the hypothermic group. Hypothermia caused a delay in the onset of thrombin generation, whereas acidosis primarily caused a decrease in thrombin generation rates. At 4 minutes' quench time, thrombin generation in the acidotic, hypothermic, and combined groups were 47.0%, 12.5%, and 5.7%, respectively, of the value in the control group. There were no changes in serum tumor necrosis factor-alpha and interleukin-6 in any group during the study., Conclusion: Acidosis and hypothermia cause a clinical coagulopathy with different thrombin generation kinetics. These results confirm the need to prevent or correct hypothermia and acidosis and indicate the need for improved techniques to monitor coagulopathy in the trauma population.
- Published
- 2005
- Full Text
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