Modern resuscitation of hemorrhagic shock: what is on the horizon?

European Journal of Trauma and Emergency Surgery

Volumn 40, Issue 6, 2014, Pages 641-656

  Martin, D T ^a,b   Schreiber, M A ^a,b  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

FFP; Glycocalyx; Hemorrhagic shock; Resuscitation; Trauma; Trauma induced coagulopathy

Indexed keywords

EID: 84912527519     PISSN: 18639933     EISSN: 16153146     Source Type: Journal    
DOI: 10.1007/s00068-014-0416-5     Document Type: Review

References (120)

1. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, et al. Epidemiology of trauma deaths: a reassessment. J Trauma-Injury Infect Crit Care. 1995;38(2):185–93.
2. Evans JA, van Wessem KJ, McDougall D, Lee KA, Lyons T, Balogh ZJ. Epidemiology of traumatic deaths: comprehensive population-based assessment. World J Surg. 2010;34(1):158–63.
3. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, Oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454(3):345–59.
4. Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng. 2007;9:121–67.
5. Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc Res. 2010;87(2):300–10.
6. Levick JR. Capillary filtration-absorption balance reconsidered in light of dynamic extravascular factors. Exp Physiol. 1991;76(6):825–57.
7. Weinbaum S. 1997 whitaker distinguished lecture: Models to solve mysteries in biomechanics at the cellular level; a new view of fiber matrix layers. Ann Biomed Eng. 1998;26(4):627–43.
8. Michel CC. Starling: the formulation of his hypothesis of microvascular fluid exchange and its significance after 100 years. Exp Physiol. 1997;82(1):1–30.
9. Adamson RH, Lenz JF, Zhang X, Adamson GN, Weinbaum S, Curry FE. Oncotic pressures opposing filtration across non-fenestrated rat microvessels. J Physiol. 2004;557(Pt 3):889–907.
10. Hu X, Weinbaum S. A new view of starling’s hypothesis at the microstructural level. Microvasc Res. 1999;58(3):281–304.
11. Lipowsky HH. The endothelial glycocalyx as a barrier to leukocyte adhesion and its mediation by extracellular proteases. Ann Biomed Eng. 2012;40(4):840–8.
12. Torres FI, Torres LN, Sondeen JL, Polykratis IA, Dubick MA. In vivo evaluation of venular glycocalyx during hemorrhagic shock in rats using intravital microscopy. Microvasc Res. 2013;85:128–33.
13. Chappell D, Jacob M, Hofmann-Kiefer K, Bruegger D, Rehm M, Conzen P, et al. Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx. Anesthesiology. 2007;107(5):776–84.
14. Chappell D, Hofmann-Kiefer K, Jacob M, Rehm M, Briegel J, Welsch U, et al. TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol. 2009;104(1):78–89.
15. Chappell D, Jacob M, Hofmann-Kiefer K, Rehm M, Welsch U, Conzen P, et al. Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion. Cardiovasc Res. 2009;83(2):388–96.
16. Sillesen M, Rasmussen LS, Jin G, Jepsen CH, Imam A, Hwabejire JO, et al. Assessment of coagulopathy, endothelial injury, and inflammation after traumatic brain injury and hemorrhage in a porcine model. J Trauma Acute Care Surg. 2014;76(1):12–20.
17. Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation. 2007;116(17):1896–906.
18. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, degradation is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg. 2011;254(2):194–200.
19. Haywood-Watson RJ, Holcomb JB, Gonzalez EA, Peng Z, Pati S, Park PW, et al. Modulation of syndecan-1 shedding after hemorrhagic shock and resuscitation. PLoS One. 2011;6(8):e23530.
20. Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289–95.
21. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007;13(6):680–5.
22. Maegele M, Lefering R, Yucel N, Tjardes T, Rixen D, Paffrath T, et al. Early coagulopathy in multiple injury: an analysis from the german trauma registry on 8724 patients. Injury. 2007;38(3):298–304.
23. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54(6):1127–30.
24. Floccard B, Rugeri L, Faure A, Saint Denis M, Boyle EM, Peguet O, et al. Early coagulopathy in trauma patients: An on-scene and hospital admission study. Injury. 2012;43(1):26–32.
25. Noel P, Cashen S, Patel B. Trauma-induced coagulopathy: from biology to therapy. Semin Hematol. 2013;50(3):259–69.
26. Johansson PI, Ostrowski SR. Acute coagulopathy of trauma: balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation. Med Hypotheses. 2010;75(6):564–7.
27. Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway? Ann Surg. 2007;245(5):812–8.
28. Cohen MJ, Kutcher M, Redick B, Nelson M, Call M, Knudson MM, et al. Clinical and mechanistic drivers of acute traumatic coagulopathy. J Trauma Acute Care Surg. 2013;75(1 Suppl 1):S40–7.
29. Johansson PI, Sørensen AM, Perner A, Welling KL, Wanscher M, Larsen CF, et al. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study. Crit Care. 2011;15(6):R272.
30. Ostrowski SR, Johansson PI. Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73(1):60–6.
31. Rourke C, Curry N, Khan S, Taylor R, Raza I, Davenport R, et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10(7):1342–51.
32. Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M, Barnett C, et al. Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg. 2010;252(3):434–44.
33. Schochl H, Voelckel W, Maegele M, Solomon C. Trauma-associated hyperfibrinolysis. Hamostaseologie. 2012;32(1):22–7.
34. Tauber H, Innerhofer P, Breitkopf R, Westermann I, Beer R, El Attal R, et al. Prevalence and impact of abnormal ROTEM(R) assays in severe blunt trauma: results of the ‘diagnosis and treatment of trauma-induced coagulopathy (DIA-TRE-TIC) study’. Br J Anaesth. 2011;107(3):378–87.
35. Barros JM, do Nascimento PJ, Marinello JL, Braz LG, Carvalho LR, Vane LA, et al. The effects of 6 % hydroxyethyl starch-hypertonic saline in resuscitation of dogs with hemorrhagic shock. Anesth Analg. 2011;112(2):395–404.
36. Zaar M, Lauritzen B, Secher NH, Krantz T, Nielsen HB, Madsen PL, et al. Initial administration of hydroxyethyl starch vs lactated ringer after liver trauma in the pig. Br J Anaesth. 2009;102(2):221–6.
37. Ogilvie MP, Pereira BM, McKenney MG, McMahon PJ, Manning RJ, Namias N, et al. First report on safety and efficacy of hetastarch solution for initial fluid resuscitation at a level 1 trauma center. J Am Coll Surg. 2010;210(5):870–82.
38. James MF, Michell WL, Joubert IA, Nicol AJ, Navsaria PH, Gillespie RS. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (fluids in resuscitation of Severe Trauma). Br J Anaesth. 2011;107(5):693–702.
39. Mutter TC, Ruth CA, Dart AB. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev. 2013;7:CD007594.
40. Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clin Pharmacokinet. 2012;51(4):225–36.
41. Sirtl C, Laubenthal H, Zumtobel V, Kraft D, Jurecka W. Tissue deposits of hydroxyethyl starch (HES): dose-dependent and time-related. Br J Anaesth. 1999;82(4):510–5.
42. Rizoli SB, Kapus A, Fan J, Li YH, Marshall JC, Rotstein OD. Immunomodulatory effects of hypertonic resuscitation on the development of lung inflammation following hemorrhagic shock. J Immunol. 1998;161(11):6288–96.
43. Vassar MJ, Perry CA, Gannaway WL, Holcroft JW. 7.5 % sodium chloride/dextran for resuscitation of trauma patients undergoing helicopter transport. Arch Surg. 1991;126(9):1065–72.
44. Bulger EM, May S, Kerby JD, Emerson S, Stiell IG, Schreiber MA, et al. Out-of-hospital hypertonic resuscitation after traumatic hypovolemic shock: a randomized, placebo controlled trial. Ann Surg. 2011;253(3):431–41.
45. Bulger EM, May S, Brasel KJ, Schreiber M, Kerby JD, Tisherman SA, et al. Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. JAMA. 2010;304(13):1455–64.
46. CRASH-2 trial c, Shakur H, Roberts R, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23–32.
47. CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: An exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096–101 1101.e1-2.
48. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg. 2012;147(2):113–9.
49. Bickell WH, Wall MJ Jr, Pepe PE, Martin RR, Ginger VF, Allen MK, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994;331(17):1105–9.
50. Dutton RP, Mackenzie CF, Scalea TM. Hypotensive resuscitation during active hemorrhage: impact on in-hospital mortality. J Trauma. 2002;52(6):1141–6.
51. Morrison CA, Carrick MM, Norman MA, Scott BG, Welsh FJ, Tsai P, et al. Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial. J Trauma. 2011;70(3):652–63.
52. Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D, Wade CE, Holcomb JB. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma-Injury Infect Crit Care. 2007;63(4):805–13.
53. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal LA, Schreiber MA, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248(3):447–58.
54. Sperry JL, Ochoa JB, Gunn SR, Alarcon LH, Minei JP, Cuschieri J, et al. An FFP:PRBC transfusion ratio >/=1:1.5 is associated with a lower risk of mortality after massive transfusion. J Trauma-Injury Infect Crit Care. 2008;65(5):986–93.
55. Holcomb JB, Del Junco DJ, Fox EE, Wade CE, Cohen MJ, Schreiber MA, et al. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. Arch Surg. 2012;15:1–10.
56. Holcomb JB, del Junco DJ, Fox EE, Wade CE, Cohen MJ, Schreiber MA, et al. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148(2):127–36.
57. del Junco DJ, Holcomb JB, Fox EE, Brasel KJ, Phelan HA, Bulger EM, et al. Resuscitate early with plasma and platelets or balance blood products gradually: findings from the PROMMTT study. J Trauma Acute Care Surg. 2013;75(1 Suppl 1):S24–30.
58. Kim BD, Zielinski MD, Jenkins DH, Schiller HJ, Berns KS, Zietlow SP. The effects of prehospital plasma on patients with injury: a prehospital plasma resuscitation. J Trauma Acute Care Surg. 2012;73(2 Suppl 1):S49–53.
59. Inaba K, Branco BC, Rhee P, Blackbourne LH, Holcomb JB, Teixeira PG, et al. Impact of plasma transfusion in trauma patients who do not require massive transfusion. J Am Coll Surg. 2010;210(6):957–65.
60. Moore EE, Chin TL, Chapman MC, Gonzalez E, Moore HB, Silliman CC, et al. Plasma first in the field for postinjury hemorrhagic shock. Shock. 2014;41(Suppl 1):35–8.
61. Sapsford W, Watts S, Cooper G, Kirkman E. Recombinant activated factor VII increases survival time in a model of incompressible arterial hemorrhage in the anesthetized pig. J Trauma. 2007;62(4):868–79.
62. Hauser CJ, Boffard K, Dutton R, Bernard GR, Croce MA, Holcomb JB, et al. Results of the CONTROL trial: efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage. J Trauma. 2010;69(3):489–500.
63. Wade CE, Eastridge BJ, Jones JA, West SA, Spinella PC, Perkins JG, et al. Use of recombinant factor VIIa in US military casualties for a five-year period. J Trauma. 2010;69(2):353–9.
64. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013;17(2):R76.
65. Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas JM, Wenjun Z, Hess JR, et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma-Injury Infect Crit Care. 2008;64((2) (Supplement)):S79–85 Advances in Combat Casualty Care: Clinical Outcomes from the War.
66. Bruce D, Nokes TJ. Prothrombin complex concentrate (beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care. 2008;12(4):R105.
67. Toth P, Van Veen JJ, Robinson K, Maclean RM, Hampton KK, Laidlaw S, et al. Real world usage of PCC to “rapidly” correct warfarin induced coagulopathy. Blood Transfus. 2013;11(4):500–5.
68. Grottke O, Braunschweig T, Spronk HM, Esch S, Rieg AD, van Oerle R, et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood. 2011;118(7):1943–51.
69. Schöchl H, Nienaber U, Maegele M, Hochleitner G, Primavesi F, Steitz B, et al. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care. 2011;15(2):R83.
70. Innerhofer P, Westermann I, Tauber H, Breitkopf R, Fries D, Kastenberger T, et al. The exclusive use of coagulation factor concentrates enables reversal of coagulopathy and decreases transfusion rates in patients with major blunt trauma. Injury. 2013;44(2):209–16.
71. Lelkens CC, Koning JG, de Kort B, Floot IB, Noorman F. Experiences with frozen blood products in the Netherlands military. Transfus Apher Sci. 2006;34(3):289–98.
72. Pati S, Matijevic N, Doursout MF, Ko T, Cao Y, Deng X, et al. Protective effects of fresh frozen plasma on vascular endothelial permeability, coagulation, and resuscitation after hemorrhagic shock are time dependent and diminish between days 0 and 5 after thaw. J Trauma-Injury Infect Crit Care. 2010;69(Suppl 1):S55–63.
73. Glassberg E, Nadler R, Gendler S, Abramovich A, Spinella PC, Gerhardt RT, et al. Freeze-dried plasma at the point of injury: from concept to doctrine. Shock. 2013;40(6):444–50.
74. Lee TH, Van PY, Spoerke NJ, Hamilton GJ, Cho SD, Watson K, et al. The use of lyophilized plasma in a severe multi-injury pig model. Transfusion. 2013;53(Suppl 1):72S–9S.
75. Wataha K, Menge T, Deng X, Shah A, Bode A, Holcomb JB, et al. Spray-dried plasma and fresh frozen plasma modulate permeability and inflammation in vitro in vascular endothelial cells. Transfusion. 2013;53(Suppl 1):80S–90S.
76. Martinaud C, Ausset S, Deshayes AV, Cauet A, Demazeau N, Sailliol A. Use of freeze-dried plasma in french intensive care unit in Afghanistan. J Trauma. 2011;71(6):1761–4 discussion 1764–5.
77. Spoerke N, Zink K, Cho SD, Differding J, Muller P, Karahan A, et al. Lyophilized plasma for resuscitation in a swine model of severe injury. Arch Surg. 2009;144(9):829–34.
78. Sailliol A, Martinaud C, Cap AP, Civadier C, Clavier B, Deshayes AV, et al. The evolving role of lyophilized plasma in remote damage control resuscitation in the French armed forces health service. Transfusion. 2013;53(Suppl 1):65S–71S.
79. Kauvar DS, Holcomb JB, Norris GC, Hess JR. Fresh whole blood transfusion: a controversial military practice. J Trauma. 2006;61(1):181–4.
80. Nessen SC, Eastridge BJ, Cronk D, Craig RM, Berseus O, Ellison R, et al. Fresh whole blood use by forward surgical teams in Afghanistan is associated with improved survival compared to component therapy without platelets. Transfusion. 2013;53(Suppl 1):107S–13S.
81. Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB. Warm fresh whole blood is independently associated with improved survival for patients with combat-related traumatic injuries. J Trauma-Injury Infect Crit Care. 2009;66(4 Suppl):S69–76.
82. Perkins JG, Cap AP, Spinella PC, Shorr AF, Beekley AC, Grathwohl KW, et al. Comparison of platelet transfusion as fresh whole blood versus apheresis platelets for massively transfused combat trauma patients (CME). Transfusion. 2011;51(2):242–52.
83. Cotton BA, Podbielski J, Camp E, Welch T, del Junco D, Bai Y, et al. A randomized controlled pilot trial of modified whole blood versus component therapy in severely injured patients requiring large volume transfusions. Ann Surg. 2013;258(4):527–32 discussion 532–3.
84. Strandenes G, Berseus O, Cap AP, Hervig T, Reade M, Prat N, et al. Low titer group O whole blood in emergency situations. Shock. 2014;41(Suppl 1):70–5.
85. Snyder EL, Whitley P, Kingsbury T, Miripol J, Tormey CA. In vitro and in vivo evaluation of a whole blood platelet-sparing leukoreduction filtration system. Transfusion. 2010;50(10):2145–51.
86. Murdock AD, Berseus O, Hervig T, Strandenes G, Lunde TH. Whole blood: the future of traumatic hemorrhagic shock resuscitation. Shock. 2014;41:62–9.
87. Holmes CL, Landry DW, Granton JT. Science review: vasopressin and the cardiovascular system part 1—receptor physiology. Crit Care. 2003;7(6):427–34.
88. Holmes CL, Landry DW, Granton JT. Science review: vasopressin and the cardiovascular system part 2—clinical physiology. Crit Care. 2004;8(1):15–23.
89. Anand T, Skinner R. Arginine vasopressin: the future of pressure-support resuscitation in hemorrhagic shock. J Surg Res. 2012;178(1):321–9.
90. Cohn SM, DeRosa M, McCarthy J, Song J, White C, Louden C, et al. Characterizing vasopressin and other vasoactive mediators released during resuscitation of trauma patients. J Trauma Acute Care Surg. 2013;75(4):620–8.
91. Westermann I, Dünser MW, Haas T, Jochberger S, Luckner G, Mayr VD, et al. Endogenous vasopressin and copeptin response in multiple trauma patients. Shock. 2007;28(6):644–9.
92. Morales D, Madigan J, Cullinane S, Chen J, Heath M, Oz M, et al. Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock. Circulation. 1999;100(3):226–9.
93. Stadlbauer KH, Wagner-Berger HG, Krismer AC, Voelckel WG, Konigsrainer A, Lindner KH, et al. Vasopressin improves survival in a porcine model of abdominal vascular injury. Crit Care. 2007;11(4):R81.
94. Voelckel WG, Raedler C, Wenzel V, Lindner KH, Krismer AC, Schmittinger CA, et al. Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med. 2003;31(4):1160–5.
95. Stadlbauer K, Wagner-Berger HG, Raedler C, Voelckel WG, Wenzel V, Krismer AC, et al. Vasopressin, but not fluid resuscitation, enhances survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs. Anesthesiology. 2003;98(3):699–704.
96. Johnson KB, Pearce FJ, Jeffreys N, McJames SW, Cluff M. Impact of vasopressin on hemodynamic and metabolic function in the decompensatory phase of hemorrhagic shock. J Cardiothorac Vasc Anesth. 2006;20(2):167–72.
97. Sperry JL, Minei JP, Frankel HL, West MA, Harbrecht BG, Moore EE, et al. Early use of vasopressors after injury: caution before constriction. J Trauma. 2008;64(1):9–14.
98. Plurad DS, Talving P, Lam L, Inaba K, Green D, Demetriades D. Early vasopressor use in critical injury is associated with mortality independent from volume status. J Trauma. 2011;71(3):565–70.
99. Cohn SM, McCarthy J, Stewart RM, Jonas RB, Dent D, Michalek JE. Impact of low-dose vasopressin on trauma outcome: prospective randomized study. World J Surg. 2011;35(2):430–9.
100. Marti-Carvajal AJ, Sola I, Gluud C, Lathyris D, Cardona AF. Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst Rev. 2012;12:CD004388.
101. Wilson JX, Wu F. Vitamin C in sepsis. Subcell Biochem. 2012;56:67–83.
102. Schorah CJ, Downing C, Piripitsi A, Gallivan L, Al-Hazaa AH, Sanderson MJ, et al. Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. Am J Clin Nutr. 1996;63(5):760–5.
103. Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg. 2000;135(3):326–31.
104. Collier BR, Giladi A, Dossett LA, Dyer L, Fleming SB, Cotton BA. Impact of high-dose antioxidants on outcomes in acutely injured patients. JPEN J Parenter Enteral Nutr. 2008;32(4):384–8.
105. Giladi AM, Dossett LA, Fleming SB, Abumrad NN, Cotton BA. High-dose antioxidant administration is associated with a reduction in post-injury complications in critically ill trauma patients. Injury. 2011;42(1):78–82.
106. Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002;236(6):814–22.
107. Van PY, Hamilton GJ, Kremenevskiy IV, Sambasivan C, Spoerke NJ, Differding JA, et al. Lyophilized plasma reconstituted with ascorbic acid suppresses inflammation and oxidative DNA damage. J Trauma. 2011;71(1):20–4 discussion 24–5.
108. Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Gao H, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–90.
109. Cuenca AG, Gentile LF, Lopez MC, Ungaro R, Liu H, Xiao W, et al. Development of a genomic metric that can be rapidly used to predict clinical outcome in severely injured trauma patients. Crit Care Med. 2013;41(5):1175–85.
110. Granger A, Abdullah I, Huebner F, Stout A, Wang T, Huebner T, et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J. 2008;22(10):3549–60.
111. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10(1):32–42.
112. Li Y, Alam HB. Modulation of acetylation: creating a pro-survival and anti-inflammatory phenotype in lethal hemorrhagic and septic shock. J Biomed Biotechnol. 2011;2011:523481.
113. Shults C, Sailhamer EA, Li Y, Liu B, Tabbara M, Butt MU, et al. Surviving blood loss without fluid resuscitation. J Trauma. 2008;64(3):629–38 discussion 638–40.
114. Hwabejire JO, Lu J, Liu B, Li Y, Halaweish I, Alam HB. Valproic acid for the treatment of hemorrhagic shock: a dose-optimization study. J Surg Res. 2014;186(1):363–70.
115. Alam HB, Shuja F, Butt MU, Duggan M, Li Y, Zacharias N, et al. Surviving blood loss without blood transfusion in a swine poly-trauma model. Surgery. 2009;146(2):325–33.
116. Causey MW, Miller S, Hoffer Z, Hempel J, Stallings JD, Jin G, et al. Beneficial effects of histone deacetylase inhibition with severe hemorrhage andischemia-reperfusion injury. J Surg Res. 2013;184(1):533–40.
117. Causey MW, Salgar S, Singh N, Martin M, Stallings JD. Valproic acid reversed pathologic endothelial cell gene expression profile associated with ischemia-reperfusion injury in a swine hemorrhagic shock model. J Vasc Surg. 2012;55(4):1096.e51–1103.e51.
118. Jin G, Duggan M, Imam A, Demoya MA, Sillesen M, Hwabejire J, et al. Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury. J Trauma Acute Care Surg. 2012;73(6):1461–70.
119. Imam AM, Jin G, Duggan M, Sillesen M, Hwabejire JO, Jepsen CH, et al. Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury and hemorrhagic shock. Surgery. 2013;154(2):388–96.
120. Nelson DW, Porta CR, McVay DP, Salgar SK, Martin MJ. Effects of histone deacetylase inhibition on 24-hour survival and end-organ injury in a porcine trauma model: a prospective, randomized trial. J Trauma Acute Care Surg. 2013;75(6):1031–9.