Daniel T Redford

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Journals/Publications

• Jones, A. R., Patel, R. P., Marques, M. B., Donnelly, J. P., Griffin, R. L., Pittet, J. F., Kerby, J. D., Stephens, S. W., DeSantis, S. M., Hess, J. R., Wang, H. E., & , P. S. (2018). Older Blood Is Associated With Increased Mortality and Adverse Events in Massively Transfused Trauma Patients: Secondary Analysis of the PROPPR Trial. Annals of emergency medicine.
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  The transfusion of older packed RBCs may be harmful in critically ill patients. We seek to determine the association between packed RBC age and mortality among trauma patients requiring massive packed RBC transfusion.
• Wei, S., Gonzalez Rodriguez, E., Chang, R., Holcomb, J. B., Kao, L. S., Wade, C. E., & , P. S. (2018). Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial. Journal of the American College of Surgeons, 227(6), 587-595.
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  Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis.
• McCully, B. H., Connelly, C. R., Fair, K. A., Holcomb, J. B., Fox, E. E., Wade, C. E., Bulger, E. M., Schreiber, M. A., & , P. S. (2017). Onset of Coagulation Function Recovery Is Delayed in Severely Injured Trauma Patients with Venous Thromboembolism. Journal of the American College of Surgeons, 225(1), 42-51.
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  Altered coagulation function after trauma can contribute to development of venous thromboembolism (VTE). Severe trauma impairs coagulation function, but the trajectory for recovery is not known. We hypothesized that enhanced, early recovery of coagulation function increases VTE risk in severely injured trauma patients.
• Nielsen, V. G., Redford, D. T., & Boyle, P. K. (2017). Effect of iron and carbon monoxide on fibrinogenase-like degradation of plasmatic coagulation by venoms of four Crotalus species. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.
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  Annually, thousands suffer poisonous snake bite, often from defibrinogenating species. Iron and carbon monoxide (CO) improve coagulation kinetics by modulation of fibrinogen as demonstrated in various Agkistrodon species and Crotalus atrox. Thus, we sought to determine whether pretreatment of plasma with iron and CO could attenuate venom-mediated catalysis of fibrinogen obtained from four common Crotalus species with known fibrinogenase activity. Human plasma was pretreated with ferric chloride (0-10 μmol/l) and CO-releasing molecule-2 (0-100 μmol/l) prior to exposure to venom from a Northern Pacific rattlesnake, Arizona black rattlesnake, prairie rattlesnake, or red diamond rattlesnake. The concentration of venom used decreased coagulation function of one or more kinetic parameters by at least 50% of normal values. Coagulation kinetics were determined with thrombelastography.Three snake venoms significantly degraded plasmatic coagulation kinetics, prolonging the onset to clot formation, diminishing velocity of clot growth and decreasing clot strength. However, red diamond rattlesnake venom exposure resulted in mixed coagulation kinetics, significantly decreasing the time to onset of coagulation without decreasing the velocity of clot growth. Iron and CO attenuated these coagulation kinetic changes in a species-specific manner. Further in vitro investigation of other fibrinogenolytic venoms is indicated to determine if iron and CO can attenuate venom compromised coagulation.
• Nielsen, V. G., Sánchez, E. E., & Redford, D. T. (2018). Characterization of the Rabbit as an In Vitro and In Vivo Model to Assess the Effects of Fibrinogenolytic Activity of Snake Venom on Coagulation. Basic & clinical pharmacology & toxicology. doi:10.1111/bcpt.12848
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  Several in vitro investigations have demonstrated that anticoagulant effects of fibrinogenolytic snake venom metalloproteinases have been abrogated in human plasma by modifying fibrinogen with iron (Fe) and carbon monoxide (CO) to prevent catalysis or by directly inhibiting these enzymes with CO. To translate these findings, we chose to assess the rabbit as a model of envenomation with Crotalus atrox venom. It was determined with thrombelastography that 15 times the concentration of venom noted to compromise coagulation in plasma in vitro was required to cause coagulopathy in vivo, likely secondary to venom binding to blood cells and being cleared from the circulation rapidly. Unlike human plasma, rabbit plasma pre-treated with Fe/CO was not protected from fibrinogenolysis by venom. Consequently, the administration of purified human fibrinogen (with or without Fe/CO) would be required before venom administration to rabbits. Of greater interest, venom exposed to CO had complete loss of fibrinogenolytic effect in rabbit plasma and partial loss of activity in whole blood, indicative of unbinding of CO from venom and binding to haemoglobin. Thus, venom exposed to CO could remain partially or completely inhibited in whole blood long enough for clearance from the circulation, allowing rabbits to be a useful model to test the efficacy of regional CO administration to the bite site. Future investigations are planned to test these novel approaches to attenuate venom-mediated coagulopathy in the rabbit.
• Nielsen, V. G., Boyer, L. V., Redford, D. T., & Ford, P. (2016). Thrombelastographic characterization of the thrombin-like activity of Crotalus simus and Bothrops asper venoms. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.
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  Annually, thousands suffer venomous snake-bite from Crotalus simus and Bothrops asper vipers in central and South America. The goals of the present study were to generally characterize the thrombin-like effects of venom from these snakes in human plasma with viscoelastic methods. Human plasma was exposed to the venom of three different C. simus subspecies and venoms obtained from B. asper vipers located in three different locations in Mexico. To characterize the factor X-activating and thrombin-like activity of these venoms, plasma (normal or factor XIII deficient) was pretreated with a variety of additives (e.g., heparin) in the absence or presence of calcium prior to exposure to 2.0 μg/ml of each viper's venom. These profiles were compared with plasma without venom that had contact activation of coagulation. Coagulation kinetics were determined with thrombelastography. All venoms had thrombin-like activity, with C. s. simus creating a slow growing, weak clot that was likely mediated by metalloproteinases. In contrast, B. asper venoms had rapid onset of coagulation and a high velocity of thrombus growth. Further, B. asper venom activity was calcium-independent, activated prothrombin, activated factor XIII, and independently polymerized fibrinogen. The viscoelastic methods used were able to differentiate subspecies of C. simus and specimens of B. asper, and provide insight into the mechanisms by which the venoms acted on plasma. These methods may be useful in the profiling of similar venoms and perhaps can assist in the assessment of interventions designed to treat envenomation (e.g., antivenom).
• Redford, D. (2016). In Response. Anesthesia and analgesia, 122(3), 920-1.
• Redford, D., Paidy, S., Steinbrenner, E., & Nielsen, V. (2016). Effects of profound hypoxemia on coagulation & fibrinolysis in normal individuals. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.
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  Hypoxia has been proposed to enhance, diminish, or have no effect on laboratory measures of coagulation or clinical thrombosis. Further, there usually are significant pathological or environmental factors concurrently present with hypoxia. Thus, the goal of the present investigation was to determine whether whole blood or plasmatic coagulation and fibrinolytic kinetics would change in response to progressive hypoxia to a systemic oxygenation (SpO2) of 70%. Healthy, conscious volunteers (n = 9) breathing a hypoxic mixture of gases during an in-vivo validation of noninvasive cerebral oximetry had blood samples collected and assessed with thrombelastography at normoxia and after SpO2 of 70%. A mild release of endogenous heparin-like activity occurred that diminished plasmatic coagulation, and a mild increase in clot lysis time also was noted. Further investigation to determine whether these phenomena occur in more chronic, less hypoxic states as sources of hypocoagulation or thrombophilia is needed.
• Holcomb, J. B., Tilley, B. C., Baraniuk, S., Fox, E. E., Wade, C. E., Podbielski, J. M., del Junco, D. J., Brasel, K. J., Bulger, E. M., Callcut, R. A., Cohen, M. J., Cotton, B. A., Fabian, T. C., Inaba, K., Kerby, J. D., Muskat, P., O'Keeffe, T., Rizoli, S., Robinson, B. R., , Scalea, T. M., et al. (2015). Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA, 313(5), 471-82.
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  Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials.
• Nielsen, V. G., Boyer, L. V., Matika, R. W., Amos, Q., & Redford, D. T. (2015). Iron and carbon monoxide attenuate Crotalus atrox venom-enhanced tissue-type plasminogen activator-initiated fibrinolysis. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.
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  In addition to degrading fibrinogen as a source of consumptive coagulopathy, rattlesnake venom has also been demonstrated to enhance fibrinolysis and degrade alpha-2-antiplasmin. The goals of this investigation was to characterize the kinetic fibrinolytic profile of Crotalus atrox venom in the absence and presence of tissue-type plasminogen activator (tPA), and to also ascertain if iron and carbon monoxide (CO, a positive modulator of alpha-2-antiplasmin) could attenuate venom-enhanced fibrinolysis. Utilizing thrombelastographic methods, the coagulation and fibrinolytic kinetic profiles of human plasma exposed to C. atrox venom (0-2 μg/ml) were determined in the absence or presence of tPA (0-100 IU/ml). Then, either separately or in combination, plasma was exposed to iron (ferric chloride, 10 μmol/l) or CO (carbon monoxide-releasing molecule-2, 100 μmol/l) prior to incubation with venom; the plasma sample was subsequently subjected to thrombelastographic analysis with addition of tPA. Venom exposure in the absence of tPA did not result in detectable fibrinolysis. In the presence of tPA, venom markedly enhanced fibrinolysis. Iron and CO, markedly attenuated venom enhancement of fibrinolysis. C. atrox venom enhances tPA-mediated fibrinolysis, and interventions that enhance/protect alpha-2-antiplasmin activity significantly attenuate venom-enhanced fibrinolysis. Future preclinical investigation is required to determine if iron and CO can attenuate venom-mediated degradation of alpha-2-antiplasmin-dependent fibrinolytic resistance.
• Nielsen, V. G., Redford, D. T., & Boyle, P. K. (2015). Effect of Iron and Carbon Monoxide on Fibrinogenase-like Degradation of Plasmatic Coagulation by Venoms of Six Agkistrodon Species. Basic & clinical pharmacology & toxicology.
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  Annually, thousands suffer poisonous snake bite, often from defibrinogenating species. It has been demonstrated that iron and carbon monoxide change the ultrastructure of plasma thrombi and improve coagulation kinetics. Thus, the present investigation sought to determine if pre-treatment of plasma with iron and carbon monoxide could attenuate venom-mediated catalysis of fibrinogen obtained from Agkistrodon species with fibrinogenase activity. Human plasma was pre-treated with ferric chloride (0-10 μM) and carbon monoxide releasing molecule-2 (CORM-2, 0-100 μM) prior to exposure to 0.5-11 μg/ml of six different Agkistrodon species' venom. The amount of venom used for experimentation needed to decrease coagulation function of one or more kinetic parameters by at least 50% of normal values for (e.g., half the normal speed of clot formation). Coagulation kinetics were determined with thrombelastography. All six snake venoms degraded plasmatic coagulation kinetics to a significant extent, especially prolonging the onset to clot formation and diminishing the speed of clot growth. Pre-treatment of plasma with iron and carbon monoxide attenuated these venom-mediated coagulation kinetic changes in a species-specific manner, with some venom effects markedly abrogated while others were only mildly decreased. Further in vitro investigation of other pit viper venoms that possess fibrinogenolytic activity is indicated to identify species amenable to or resistant to iron and carbon monoxide-mediated attenuation of venom-mediated catalysis of fibrinogen. Lastly, future preclinical investigation with animal models (e.g., rabbit ear bleed model) is planned to determine if iron and carbon monoxide can be used therapeutically after envenomation. This article is protected by copyright. All rights reserved.
• Novak, D. J., Bai, Y., Cooke, R. K., Marques, M. B., Fontaine, M. J., Gottschall, J. L., Carey, P. M., Scanlan, R. M., Fiebig, E. W., Shulman, I. A., Nelson, J. M., Flax, S., Duncan, V., Daniel-Johnson, J. A., Callum, J. L., Holcomb, J. B., Fox, E. E., Baraniuk, S., Tilley, B. C., , Schreiber, M. A., et al. (2015). Making thawed universal donor plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. Transfusion, 55(6), 1331-9.
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  The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial was a randomized clinical trial comparing survival after transfusion of two different blood component ratios for emergency resuscitation of traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of request.
• Redford, D. T. (2015). In Response. Anesthesia and analgesia, 121(2), 576-7.
• Typpo, K. V., Larmonier, C. B., Deschenes, J., Redford, D., Kiela, P. R., & Ghishan, F. K. (2015). Clinical characteristics associated with postoperative intestinal epithelial barrier dysfunction in children with congenital heart disease. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, 16(1), 37-44.
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  Children with congenital heart disease have loss of intestinal epithelial barrier function, which increases their risk for postoperative sepsis and organ dysfunction. We do not understand how postoperative cardiopulmonary support or the inflammatory response to cardiopulmonary bypass might alter intestinal epithelial barrier function. We examined variation in a panel of plasma biomarkers to reflect intestinal epithelial barrier function (cellular and paracellular) after cardiopulmonary bypass and in response to routine ICU care.
• Baraniuk, S., Tilley, B. C., del Junco, D. J., Fox, E. E., van Belle, G., Wade, C. E., Podbielski, J. M., Beeler, A. M., Hess, J. R., Bulger, E. M., Schreiber, M. A., Inaba, K., Fabian, T. C., Kerby, J. D., Cohen, M. J., Miller, C. N., Rizoli, S., Scalea, T. M., O'Keeffe, T., , Brasel, K. J., et al. (2014). Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial: design, rationale and implementation. Injury, 45(9), 1287-95.
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  Forty percent of in-hospital deaths among injured patients involve massive truncal haemorrhage. These deaths may be prevented with rapid haemorrhage control and improved resuscitation techniques. The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial was designed to determine if there is a difference in mortality between subjects who received different ratios of FDA approved blood products. This report describes the design and implementation of PROPPR.
• Redford, D. T., Thompson, J. L., McCulloch, J. C., & Nielsen, V. G. (2014). Left atrial myxoma presenting as pulmonary embolism: potential role of heme oxygenase-1. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 25(6), 621-4.
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  We present the case of a patient with left atrial myxoma that presented with pulmonary embolism. The patient did not have any intracardiac communication between right and left sides of the heart. Using thrombelastography, the patient was determined to have an abnormally large velocity of plasma thrombus growth and strength with reduced vulnerability to lysis. Critically, increased carboxyhemoglobin concentrations were present, likely secondary to hemolysis from the tumor and engagement of systemic heme oxygenase-1. It was determined that the patient's plasmatic hypercoagulability was in part due to carboxyhemefibrinogen formation via a thrombelastographic method. In addition to circulating hypercoagulability, the patient also had an area of chronic venous stasis in his left ankle that had not changed for over a decade prior to this thrombophilic episode. In conclusion, we present the first case of paradoxical pulmonary embolism in the presence of a left atrial myxoma, potentially secondary to a combination of hemolysis, heme oxygenase-1 up-regulation, systemic hypercoagulability/hypofibrinolysis, and regional venous stasis.
• Redford, D., Paidy, S., & Kashif, F. (2014). Absolute and trend accuracy of a new regional oximeter in healthy volunteers during controlled hypoxia. Anesthesia and analgesia, 119(6), 1315-9.
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  Traditional patient monitoring may not detect cerebral tissue hypoxia, and typical interventions may not improve tissue oxygenation. Therefore, monitoring cerebral tissue oxygen status with regional oximetry is being increasingly used by anesthesiologists and perfusionists during surgery. In this study, we evaluated absolute and trend accuracy of a new regional oximetry technology in healthy volunteers.
• Swyers, T., Redford, D., & Larson, D. F. (2014). Volatile anesthetic-induced preconditioning. Perfusion, 29(1), 10-5.
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  The myocardium has an innate ability to protect itself from ischemic events. This protection occurs when the myocardium is exposed to a brief ischemic period prior to a more extreme ischemic event. This is termed ischemic preconditioning. Ischemic preconditioning induces a series of molecular pathways that protect the cardiac myocyte; first, for a period of 1-6 hours (early preconditioning) and, also, for a second period from 24-72 hours (delayed phase). The early preconditioning is mediated by the release of adenosine which induces a protective signal that is related to the mitochondrial KATP channel activation and activation of the δ-opioid and bradykinin receptors. The delayed phase is related to the induction of inducible nitric oxide synthase, superoxide dismutase and heat-shock proteins. Indirect evidence indicates that O2-derived free radicals are involved in the delayed phase, as noted in the early preconditioning phase. Applying ischemic preconditioning to clinical practice can be dangerous and difficult to implement in a controlled fashion. However, recent studies have shown that the use of volatile anesthetics, such as sevoflurane, isoflurane and desflurane, can mimic the early phase of ischemic preconditioning through a multi-pathway signaling of mitochondrial KATP channels. This important finding can easily be applied to clinical practice for patients undergoing surgery. It can also be significantly important for patients undergoing off-pump cardiac bypass surgery or cardiac bypass surgery where there is no cross-clamp or cardioplegia used where the probability of myocardial ischemia is greatly increased. This report will, therefore, discuss the mechanism, safety and efficacy of volatile anesthetics as inducers of cardiac preconditioning.

Presentations

• Redford, D. T. (2015, September). What the Anesthesiologist Wants the Blood Bank to Know. American Society of Clinical Pathologists. Long Beach, CA.

Poster Presentations

• Redford, D., & Smith, D. (2015, May). Anesthetic Considerations for Removal of Large Intravascular Uterine Leiomyoma. Western Anesthesia Resident's Conference.