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Surgery_Schwartz. reaction. The first sign of a transfusion reaction may be diffuse bleeding. The pathogenesis of this bleed-ing is thought to be related to the release of ADP from hemolyzed red blood cells, resulting in diffuse platelet aggregation, after which the platelet clumps are removed out of the circulation.Transfusion purpura occurs when the donor platelets are of the uncommon HPA-1 group. This is an uncommon cause of thrombocytopenia and associated bleeding after transfusion. The platelets sensitize the recipient, who makes antibody to the foreign platelet antigen. The foreign platelet antigen does not completely disappear from the recipient circulation but attaches to the recipient’s own platelets. The antibody then destroys the recipient’s own platelets. The resultant thrombocytopenia and bleeding may continue for several weeks. This uncommon cause of thrombocytopenia should be considered if bleeding follows transfusion by 5 or 6 days. Platelet transfusions are of little help in the


Surgery_Schwartz

Surgery_Schwartz. bleeding may continue for several weeks. This uncommon cause of thrombocytopenia should be considered if bleeding follows transfusion by 5 or 6 days. Platelet transfusions are of little help in the management of this syndrome because the new donor platelets usually are subject to the binding of antigen and dam-age from the antibody. Corticosteroids may be of some help in reducing the bleeding tendency. Posttransfusion purpura is self-limited, and the passage of several weeks inevitably leads to subsidence of the problem.DIC is characterized by systemic activation of the coagu-lation system, which results in the deposition of fibrin clots and microvascular ischemia and may contribute to the development CoagulationLYFibrinolysisRMAKAngleFigure 4-7. Illustration of a thromboelastogram (TEG) tracing. K = clot kinetics; LY = lysis.Brunicardi_Ch04_p0103-p0130.indd 12429/01/19 11:05 AM 125HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4of multiorgan failure. Consumption and


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Surgery_Schwartz. tracing. K = clot kinetics; LY = lysis.Brunicardi_Ch04_p0103-p0130.indd 12429/01/19 11:05 AM 125HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4of multiorgan failure. Consumption and subsequent exhaustion of coagulation proteins and platelets due to the ongoing acti-vation of the coagulation system may induce severe bleeding complications.Lastly, severe hemorrhagic disorders due to thrombo-cytopenia have occurred as a result of gram-negative sepsis. Defibrination and hemostatic failure also may occur with meningococcemia, Clostridium perfringens sepsis, and staph-ylococcal sepsis. Hemolysis appears to be one mechanism in sepsis leading to defibrination.REFERENCESEntries highlighted in bright blue are key references. 1. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007;13:680-685. 2. Kulkarani R. Comprehensive care of the patient with haemo-philia and inhibitors undergoing surgery: practical


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Surgery_Schwartz. of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007;13:680-685. 2. Kulkarani R. Comprehensive care of the patient with haemo-philia and inhibitors undergoing surgery: practical aspects. Hemophilia. 2013;19(1):2-10. 3. Federicini AB, Mannucci PM. Management of inherited von Willebrand disease in 2007. Ann Med. 2007;39:(5):346-358. 4. Girolami A, de Marinis GB, Bonamigo E, Lombardi AM. Recombinant FVIIa concentrate-associated thrombotic events in congenital bleeding disorders other than hemophil-ias. Hematology. 2012;17(6):346-349. 5. Peyvandi F, Bolton-Maggs PHB, Batorova A, De Moerloose P. Rare bleeding disorders. Haemophilia. 2012;18(Suppl 4): 148-153. 6. Peyvandi F, Mannucci PM. Rare coagulation disorders. Thromb Haemost. 1999;82(4):1207-1214. 7. Anwar R, Miloszewski KJ. Factor XIII deficiency. Br J Hae-matol. 1999;107(3):468-484. 8. Anwar R, Minford A, Gallivan L, Trinh CH, Markham AF. Delayed umbilical bleeding—a presenting feature for factor XIII


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Surgery_Schwartz. Miloszewski KJ. Factor XIII deficiency. Br J Hae-matol. 1999;107(3):468-484. 8. Anwar R, Minford A, Gallivan L, Trinh CH, Markham AF. Delayed umbilical bleeding—a presenting feature for factor XIII deficiency: clinical features, genetics, and management. Pediatrics. 2002;109(2):E32. 9. George JN, Caen JP, Nurden AT. Glanzmann’s throm-basthenia: the spectrum of clinical disease. Blood. 1990;75(7):1383-1395. 10. Stasi R, Evangelista ML, Stipa E, et al. Idiopathic thrombo-cytopenic purpura: current concepts in pathophysiology and management. Thromb Haemost. 2008;99:4-13. 11. George JN. Sequence of treatments for adults with primary immune thrombocytopenia. Am J Hematol. 2012;87:S12-S15. 12. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA; American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. 13. Provan D, Stasi R, Newland AC, et al. International consen-sus


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Surgery_Schwartz. American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. 13. Provan D, Stasi R, Newland AC, et al. International consen-sus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168-186. 14. Baldwin ZK, Spitzer AL, Ng VL, Harkin AH. Contemporary standards for the diagnosis and treatment of heparin-induced thrombocytopenia (HIT). Surgery. 2008;143:305-312. 15. Amiral J, Peynaud-Debayle E, Wolf M, et al. Generation of antibodies to heparin-PF4 complexes without thrombocyto-penia in patients treated with unfractionated or low-molecular weight heparin. Am J Hematol. 1996;52:90-95. 16. Lo GK, Juhl D, Warkentin T, et al. Evaluation of pretest clini-cal score (4 Ts) for the diagnosis of heparin-induced throm-bocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765. 17. Greinacher A. Heparin-induced thrombocytopenia. N Engl J Med. 2015;373(3):252-261. This is


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Surgery_Schwartz. of heparin-induced throm-bocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765. 17. Greinacher A. Heparin-induced thrombocytopenia. N Engl J Med. 2015;373(3):252-261. This is an excellent review of the diagnosis and treatment of heparin-induced thrombocytopenia. 18. Linkins LA, Dans AL, Moores LK, et al; American College of Chest Physicians. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and pre-vention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e495S-e530S. 19. Zimrin AB, Hess JR. Thrombocytopenic purpura: going against the evidence. Crit Care Med. 2006;34:2247-2248. 20. Kremer Hovinga JA, Meyer SC. Current management of thrombotic thrombocytopenic purpura. Curr Opin Hematol. 2008;15(5):445-450. 21. Mariotte E, Veyradier A. Thrombotic thrombocytopenic purpura: from diagnosis to therapy. Curr Opin Crit Care. 2015;21(6):593-601. 22. Brown LM,


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Surgery_Schwartz. purpura. Curr Opin Hematol. 2008;15(5):445-450. 21. Mariotte E, Veyradier A. Thrombotic thrombocytopenic purpura: from diagnosis to therapy. Curr Opin Crit Care. 2015;21(6):593-601. 22. Brown LM, Call MS, Knudson M, et al. A normal platelet count may not be enough: the impact of admission platelet count on mortality and transfusion in severely injured trauma patients. J Trauma. 2011;71(2 Suppl 3):S337-S342. 23. Holcomb JB, Zarzabal LA, Michalek JE, et al. Increased platelet: RBC ratios are associated with improved survival after massive transfusion. J Trauma. 2011;71(2 Suppl 3): S318-S328. 24. Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141 (2 Suppl):e89S-e119S. 25. Sarode R. How do I transfuse platelets (PLTs) to reverse anti-PLT drug effect? Transfusion. 2012;52:695-701. 26. Lavelle WF, Lavell EA,


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Surgery_Schwartz. practice guidelines. Chest. 2012;141 (2 Suppl):e89S-e119S. 25. Sarode R. How do I transfuse platelets (PLTs) to reverse anti-PLT drug effect? Transfusion. 2012;52:695-701. 26. Lavelle WF, Lavell EA, Uhl R. Operative delay for orthope-dic patients on clopidogrel (Plavix): a complete lack of con-sensus. J Trauma. 2008;64:996. 27. Hess JR, Lawson JH. The coagulopathy of trauma ver-sus disseminated intravascular coagulation. J Trauma. 2006;60:S12-S19. 28. Taylor FB, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327-1330. 29. Dhainaut JF, Yan SB, Joyce DE, et al. Treatment effects of drotrecogin alfa (activated) in patients with or without overt disseminated intravascular coagulation. J Thromb Haemost. 2004;2:1924-1933. 30. Angstwurm MW, Dempfle CE, Spannagl M. New dissemi-nated intravascular coagulation score: a useful tool to predict mortality in comparison


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Surgery_Schwartz. coagulation. J Thromb Haemost. 2004;2:1924-1933. 30. Angstwurm MW, Dempfle CE, Spannagl M. New dissemi-nated intravascular coagulation score: a useful tool to predict mortality in comparison with Acute Physiology and Chronic Health Evaluation II and Logistic Organ Dysfunction scores. Crit Care Med. 2006;34:314-320. 31. Wada H, Thachil J, Di Nisio M, et al. Guidance for diag-nosis and treatment of DIC from harmonization of the rec-ommendations from three guidelines. J Thromb Haemost. 2013;11:761-767. 32. Tefferi A. Polycythemia vera and essential thrombocythemia: 2012 update on diagnosis, risk stratification, and manage-ment. Am J Hematol. 2012;87(3):285-293. 33. Feistauer SM, Penner E, Mayr WR, et al. Target platelet anti-gen of autoantibodies in patients with primary biliary cirrho-sis. Hepatology. 1997;25:1343. 34. Lisman T, Bongers TN, Adelmeijer J, et al. Elevated lev-els of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity.


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Surgery_Schwartz. Hepatology. 1997;25:1343. 34. Lisman T, Bongers TN, Adelmeijer J, et al. Elevated lev-els of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44:53-61. 35. Northup PG, McMahon MM, Ruhl AP, et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006;101:1524.Brunicardi_Ch04_p0103-p0130.indd 12529/01/19 11:05 AM 126BASIC CONSIDERATIONSPART I 36. Gatt A, Riddell A, Calvaruso V, et al. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost. 2010;8:1994. 37. Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med. 2011;365:147. This is a review of the pathophysiologic abnormalities in coagulation associated with chronic liver disease. It challenges the traditional teach-ing that these patients are coagulopathic and presents evi-dence and rational for why they are actually


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Surgery_Schwartz. in coagulation associated with chronic liver disease. It challenges the traditional teach-ing that these patients are coagulopathic and presents evi-dence and rational for why they are actually hypercoaguable. 38. Tripodi A, Primignani M, Lemma L, et al. Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method. Hepatology. 2010;52:249-255. 39. De Pietri L, Bianchini M, Montalti R, et al. Thromboelastog-raphy-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: a randomized, controlled trial. Hepatology. 2016;63(2):566-573. 40. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagu-lopathy. J Trauma. 2003;54(6):1127-1130. 41. Chang R, Cardenas JC, Wade CE, Holcomb JB. Advances in the understanding of trauma-induced coagulopathy. Blood. 2016;128(8):1043-1049. This an up-to-date review of coagu-lation biology as it relates to trauma, emphasizing both the complexity and opportunities for


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Surgery_Schwartz. of trauma-induced coagulopathy. Blood. 2016;128(8):1043-1049. This an up-to-date review of coagu-lation biology as it relates to trauma, emphasizing both the complexity and opportunities for research. 42. Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64:1211-1217. 43. Ostrowski SR, Johansson PI. Endothelial glycocalyx degra-dation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73(1):60-66. 44. Kutcher ME, Redick BJ, McCreery RC, et al. Characteriza-tion of platelet dysfunction after trauma. J Trauma Acute Care Surg. 2012;73(1):13-19. 45. Chapman MP, Moore EE, Moore HB, et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyper-fibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg. 2015;80(1):16-23. 46. Castellino FJ, Chapman MP, Donahue DL, et al. Traumatic


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Surgery_Schwartz. PAI-1 degradation, is responsible for hyper-fibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg. 2015;80(1):16-23. 46. Castellino FJ, Chapman MP, Donahue DL, et al. Traumatic brain injury causes platelet adenosine diphosphate and ara-chidonic acid receptor inhibition independent of hemor-rhagic shock in humans and rats. J Trauma Acute Care Surg. 2014;76(5):1169-1176. 47. Wright AP, Wade CE, Camp E, et al. Pulmonary contusion on admission chest x-ray is associated with coagulopathy and mortality in trauma patients. J Emerg Med Trauma Surg Care. 2015;2:011. 48. Tian Y, Salsbery B, Wang M, et al. Brain-derived micropar-ticles induce systemic coagulation in a murine model of trau-matic brain injury. Blood. 2015;125(13):2151-2159. 49. Moore HB, Moore EE, Gonzalez E, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spec-trum of postinjury fibrinolysis and relevance to antifibrinol-ytic therapy. J Trauma Acute Care Surg.


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Surgery_Schwartz. E, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spec-trum of postinjury fibrinolysis and relevance to antifibrinol-ytic therapy. J Trauma Acute Care Surg. 2014;77(6):811-817. 50. Moore HB, Moore EE, Liras IN, et al. Acute fibrinolysis shutdown following injury occurs frequently and increases mortality: a multicenter evaluation of 2540 severely injured patients. J Am Coll Surg. 2016;222(4):347-355. This large clinical study examined the incidence and outcomes after acute fibrinolysis shutdown, an acute impairment of fibrino-lysis, and demonstrated that it occurs frequently after severe injury and is associated with increased mortality. 51. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic ther-apy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guide-lines. Chest. 2012;141(2 Suppl):e152S-184S. 52. Goldstein JN, Refaai MA, Milling TJ


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Surgery_Schwartz. and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guide-lines. Chest. 2012;141(2 Suppl):e152S-184S. 52. Goldstein JN, Refaai MA, Milling TJ Jr, et al. Fourfactor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385(9982):2077-2087. This is a multicenter phase 3b noninferiority study of patients requiring rapid reversal of vitamin K antagonist-induced anticoagulation for urgent surgical procedures. Four-factor PCC was not just noninferior but in fact superior to plasma for rapid reversal and hemostasis. 53. Milling TJ Jr, Refaai MA, Sarode R, et al. Safety of a four-factor prothrombin complex concentrate versus plasma for vitamin K antagonist reversal: an integrated analysis of two phase IIIb clinical trials. Acad Emerg Med. 2016;23(4): 466-475. 54. Al-Majzoub


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Surgery_Schwartz. prothrombin complex concentrate versus plasma for vitamin K antagonist reversal: an integrated analysis of two phase IIIb clinical trials. Acad Emerg Med. 2016;23(4): 466-475. 54. Al-Majzoub O, Rybak E, Reardon DP, Krause P, Connors JM: Evaluation of warfarin reversal with 4-factor prothrom-bin complex concentrate compared to 3-factor prothrombin complex concentrate at a tertiary academic medical center. J Emerg Med. 2016;50(1):7-13. 55. Voils SA, Baird B. Systematic review: 3-factor versus 4-fac-tor prothrombin complex concentrate for warfarin reversal: does it matter? Thromb Res. 2012;130(6):833-840. 56. Pollack CV Jr, Reilly PA, Bernstein R, et al. Design and ratio-nale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015;114(1):198-205. 57. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511-520. 58. Ghadimi K, Dombrowski KE, Levy JH, Welsby IJ. Andex-anet


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Surgery_Schwartz. in French intensive care unit in Afghanistan. J Trauma. 2011 Dec;71(6):1761-1764. 95. Glassberg E, Nadler R, Gendler S, et al. Freeze-dried plasma at the point of injury: from concept to doctrine. Shock. 2013;40(6):444-450. 96. Pusateri AE, Given MB, Schreiber MA, et al. Dried plasma: state of the science and recent developments. Transfusion. 2016 Apr;56 Suppl 2:S128-139. Due to challenges in using fresh frozen plasma in emergent and austere conditions, a variety of dried plasma products have been and are being developed. The history, state of the science, use of dried products in other coun-tries, and recent developments are reviewed. 97. CRASH-2 Collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haem-orrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32. 98. Morrison JJ, Ross JD, Dubose JJ, et al. Association of cryo-precipitate


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Surgery_Schwartz. with significant haem-orrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32. 98. Morrison JJ, Ross JD, Dubose JJ, et al. Association of cryo-precipitate and tranexamic acid with improved survival fol-lowing wartime injury: findings from the MATTERs II study. JAMA Surg. 2013;148(3):218-225. 99. Cannon JW, Khan MA, Raja AS, et al. Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Associa-tion for the Surgery of Trauma. J Trauma Acute Care Surg. 2017;82(3):605-617. This is a structured analysis of existing trauma transfusion data with practical recommendations for bleeding patients. 100. Gerber DR. Transfusion of packed red blood cells in patients with ischemic heart disease. Crit Care Med. 2008;36:1068-1074. 101. Herbert PC, Wells GW, Blajchman MA, et al. A multi-center, randomized, controlled clinical trial of transfu-sion requirement in critical care. N Engl J Med.


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Surgery_Schwartz. Crit Care Med. 2008;36:1068-1074. 101. Herbert PC, Wells GW, Blajchman MA, et al. A multi-center, randomized, controlled clinical trial of transfu-sion requirement in critical care. N Engl J Med. 1999;340: 409-417. 102. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365(26):2453-2462. 103. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfu-sion. Cochrane Database Syst Rev. 2012;4:CD002042. 104. Carson JL, Guyatt G, Heddle NM, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresh-olds and storage. JAMA. 2016;316(19):2025-2035.Brunicardi_Ch04_p0103-p0130.indd 12729/01/19 11:05 AM 128BASIC CONSIDERATIONSPART I 105. Thorson CM, Van Haren RM, Ryan ML. Admission hema-tocrit and transfusion requirements after trauma. J Am Coll Surg. 2013;216(1):65-73.105a. Holcomb JB, Jenkins D, Rhee P, et al. Damage


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Surgery_Schwartz. CM, Van Haren RM, Ryan ML. Admission hema-tocrit and transfusion requirements after trauma. J Am Coll Surg. 2013;216(1):65-73.105a. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307-310. 106. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 2006;60(6 Suppl):S3. 107. Niles SE, McLaughlin DF, Perkins J, et al. Increased mortal-ity associated with early coagulopathy after trauma in combat casualties. J Trauma. 2008;64:1459-1463. 108. Macleod J, Lynn M, McKenney MG, Jeroukhimov I, Cohn SM. Predictors of mortality in trauma patients. Am Surg. 2004;70:805-810. 109. Moore LJ, Brenner M, Kozar RA, et al. Implementation of resuscitative endovascular balloon occlusion of the aorta as an alternative to resuscitative thoracotomy for noncom-pressible truncal hemorrhage. J Trauma Acute


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Surgery_Schwartz. M, Kozar RA, et al. Implementation of resuscitative endovascular balloon occlusion of the aorta as an alternative to resuscitative thoracotomy for noncom-pressible truncal hemorrhage. J Trauma Acute Care Surg. 2015;79(4):523-532. 110. Savage SA, Sumislawski JJ, Zarzaur BL, Dutton WP, Croce MA, Fabian TC. The new metric to define large-volume hemorrhage: results of a prospective study of the critical administration threshold. J Trauma Acute Care Surg. 2015;78(2):224-229. 111. Cap AP, Spinella PC, Borgman MA, Blackbourne LH, Perkins JG. Timing and location of blood product transfu-sion and outcomes in massively transfused combat casu-alties. J Trauma Acute Care Surg. 2012;73(2 Suppl 1): S89-S94. 112. Carrico CJ, Canizaro PC, Shires GT. Fluid resuscitation fol-lowing injury: rationale for the use of balanced salt solutions. Crit Care Med. 1976;4:46. 113. Harrigan C, Lucas CE, Ledgerwood AM, et al. Serial changes in primary hemostasis after massive transfusion. Surgery.


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Surgery_Schwartz. rationale for the use of balanced salt solutions. Crit Care Med. 1976;4:46. 113. Harrigan C, Lucas CE, Ledgerwood AM, et al. Serial changes in primary hemostasis after massive transfusion. Surgery. 1985;98:836. 114. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63(4):805-813. 115. Holcomb JB, Wade CE, Michalek JE, 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):447-458. 116. Mitra B, Mori A, Cameron PA, et al. Fresh frozen plasma (FFP) use during massive blood transfusion in trauma resus-citation. Injury. 2010;41(1):35-39. 117. Peiniger S, Nienaber U, Lefering R, et al. Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury. Crit Care. 2011;15(1):R68. 118. Cotton BA, Reddy N, Hatch QM, et al. Damage


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Surgery_Schwartz. Nienaber U, Lefering R, et al. Balanced massive transfusion ratios in multiple injury patients with traumatic brain injury. Crit Care. 2011;15(1):R68. 118. Cotton BA, Reddy N, Hatch QM, et al. Damage control resuscitation is associated with a reduction in resuscitation volumes and improvement in survival in 390 damage control laparotomy patients. Ann Surg. 2011;254(4):598-605. 119. Holcomb JB, del Junco DJ, Fox EE, et al. The prospective, obser-vational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148:127-136. 120. Holcomb JB, Tilley BC, Baraniuk S, et al. 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. 2015;313:471-482. This is a prospective randomized study at 12 level 1 trauma centers of massively bleeding trauma patients, com-paring two balanced transfusion


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Surgery_Schwartz. randomized clinical trial. JAMA. 2015;313:471-482. This is a prospective randomized study at 12 level 1 trauma centers of massively bleeding trauma patients, com-paring two balanced transfusion groups. Fewer patients bled to death in the 1:1:1 group. 121. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg. 2011;112(6):1289-1295. 122. Potter DR, Baimukanova G, Keating SM, et al. Fresh frozen plasma and spray-dried plasma mitigate pulmonary vascu-lar permeability and inflammation in hemorrhagic shock. J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S7-S17. 123. Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012;108(3):384-394. 124. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial gly-cocalyx degradation,


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Surgery_Schwartz. fluid therapy. Br J Anaesth. 2012;108(3):384-394. 124. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial gly-cocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg. 2011;254(2):194-200. 125. Ostrowski SR, Johansson PI. Endothelial glycocalyx degra-dation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg. 2012;73(1):60-66. 126. Rahbar E, Cardenas JC, Baimukanova G, et al. Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients. J Transl Med. 2015;13:117. 127. Johansson PI, Stensballe J, Oliveri R, Wade CE, Ostrowski SR, Holcomb JB. How I treat patients with massive hemor-rhage. Blood. 2014;124(20):3052-3058. 128. McLaughlin DF, Niles SE, Salinas J, et al. A predictive model for massive transfusion in combat casualty patients.


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Surgery_Schwartz. How I treat patients with massive hemor-rhage. Blood. 2014;124(20):3052-3058. 128. McLaughlin DF, Niles SE, Salinas J, et al. A predictive model for massive transfusion in combat casualty patients. J Trauma. 2008;64(2 Suppl):S57. 129. Yücel N, Lefering R, Maegele M, et al. Trauma-Associated Severe Hemorrhage (TASH) score: probability of mass trans-fusion as surrogate for life threatening hemorrhage after mul-tiple trauma. J Trauma. 2006;60:1228. 130. Moore FA, Nelson T, McKinley BA, et al. Massive transfu-sion in trauma patients: tissue hemoglobin oxygen saturation predicts poor outcome. J Trauma. 2008;64:1010. 131. Schreiber MA, Perkins J, Kiraly L, et al. Early predictors of massive transfusion in combat casualties. J Am Coll Surg. 2007;205:541. 132. Cotton BA, Dossett LA, Haut ER, et al. Multicenter valida-tion of a simplified score to predict massive transfusion in trauma. J Trauma. 2010;69(Suppl 1):S33-S39. 133. Radwan ZA, Bai Y, Matijevic N, et al. An emergency depart-ment


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Surgery_Schwartz. et al. Multicenter valida-tion of a simplified score to predict massive transfusion in trauma. J Trauma. 2010;69(Suppl 1):S33-S39. 133. Radwan ZA, Bai Y, Matijevic N, et al. An emergency depart-ment thawed plasma protocol for severely injured patients. JAMA Surg. 2013;148(2):170-175. 134. Holcomb JB, Donathan DP, Cotton BA, et al. Prehospital transfusion of plasma and red blood cells in trauma patients. Prehosp Emerg Care. 2015;19(1):1-9. 135. Brown JB, Sperry JL, Fombona A, Billiar TR, Peitzman AB, Guyette FX. Pre-trauma center red blood cell transfusion is associated with improved early outcomes in air medical trauma patients. J Am Coll Surg. 2015;220(5):797-808. 136. O’Reilly DJ, Morrison JJ, Jansen JO, Apodaca AN, Rasmus-sen TE, Midwinter MJ. Prehospital blood transfusion in the en route management of severe combat trauma: a matched cohort study. J Trauma Acute Care Surg. 2014;77(3 Suppl 2):S114-S120. 137. Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB. Warm fresh


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Surgery_Schwartz. management of severe combat trauma: a matched cohort study. J Trauma Acute Care Surg. 2014;77(3 Suppl 2):S114-S120. 137. Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB. Warm fresh whole blood is independently asso-ciated with improved survival for patients with combat-related traumatic injuries. J Trauma. 2009;66(4 Suppl):S69-S76. 138. Nessen SC, Eastridge BJ, Cronk D, 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-113S. 139. Neel S. Chapter 9: The military blood program. In: Medical Support of the U.S. Army in Vietnam. Washington D.C.: Office Brunicardi_Ch04_p0103-p0130.indd 12829/01/19 11:05 AM 129HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4of the Surgeon General, Department of the Army; 1991; 114-126. Available at: http://history.amedd.army.mil/books-docs/vietnam/medicalsupport/chapter9.html. Accessed June 28,


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Surgery_Schwartz. AND TRANSFUSIONCHAPTER 4of the Surgeon General, Department of the Army; 1991; 114-126. Available at: http://history.amedd.army.mil/books-docs/vietnam/medicalsupport/chapter9.html. Accessed June 28, 2016. 140. Strandenes G, Austlid I, Apelseth TO, et al. Coagulation function of stored whole blood is preserved for 14 days in austere conditions: A ROTEM feasibility study during a Norwegian antipiracy mission and comparison to equal ratio reconstituted blood. J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S31-38. 141. Cotton BA, Podbielski J, Camp E, et al. A randomized con-trolled pilot trial of modified whole blood versus component therapy in severely injured patients requiring large volume transfusions. Ann Surg. 2013;258(4):527-532. This is the first randomized study of whole blood in trauma patients. This small pilot study showed feasibility and suggested benefit. 142. Yazer MH, Jackson B, Sperry JL, et al. Initial safety and fea-sibility of cold-stored uncrossmatched whole blood


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Surgery_Schwartz. trauma patients. This small pilot study showed feasibility and suggested benefit. 142. Yazer MH, Jackson B, Sperry JL, et al. Initial safety and fea-sibility of cold-stored uncrossmatched whole blood transfu-sion in civilian trauma patients. J Trauma Acute Care Surg. 2016;81(1):21-26. 143. Stubbs JR, Zielinski MD, Jenkins D. The state of the science of whole blood: lessons learned at Mayo Clinic. Transfusion. 2016;56(Suppl 2):S173-181. 144. Rourke C, Curry N, Khan S, et al. Fibrinogen levels dur-ing trauma hemorrhage response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10(7):1342-1351. 145. Inaba K, Karamanos E, Lustenberger T, et al. Impact of fibrin-ogen levels on outcomes after injury in patients requiring a massive transfusion. J Am Coll Surg. 2013;216(2):290-297. 146. Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012;43(1):26-32. 147. Levy JH, Welsby I,


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Surgery_Schwartz. 2013;216(2):290-297. 146. Floccard B, Rugeri L, Faure A, et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012;43(1):26-32. 147. Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeu-tic target for bleeding: a review of critical levels and replace-ment therapy. Transfusion. 2014 May;54(5):1389-1405. 148. Curry N, Rourke C, Davenport R, et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth. 2015;115(1):76-83. 149. www.clinical trials.gov. Fibrinogen concentrate in trauma patients presumed to bleed; NCT01475344. Accessed December 28, 2016.149a. Meyer DE, Reynolds JW, Hobbs R, et al. The Incidence of Transfusion-Related Acute Lung Injury at a Large, Urban Tertiary Medical Center: A Decade’s Experience. Anesth Analg. 2018;127(2):444-449. 150. Pandey S, Vyas GN. Adverse-effects of plasma transfusion. Transfusion. 2012;52:65S-79S. 151. Goodnough LT, Brecher ME, Kanter MH.


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Surgery_Schwartz. A Decade’s Experience. Anesth Analg. 2018;127(2):444-449. 150. Pandey S, Vyas GN. Adverse-effects of plasma transfusion. Transfusion. 2012;52:65S-79S. 151. Goodnough LT, Brecher ME, Kanter MH. Transfusion medi-cine: blood transfusion. N Engl J Med. 1999;340:438. 152. Looney MR, Gropper MA, Matthay MA. Transfusion-related acute lung injury. Chest. 2004;126:249. 153. Toy P, Gajic O, Bacchetti P, et al. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012;119(7):1757-1767. 154. Zou S, Stramer SL, Dodd RY. Donor testing and risk: cur-rent prevalence, incidence, and residual risk of transfusion-transmissible agents in US allogeneic donations. Transfusion Med Rev. 2012;26(2):119-128. 155. Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill. 2014;19(14). 156. Jimenez A, Shaz BH, Bloch EM. Zika Virus and the blood sup-ply:


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Surgery_Schwartz. blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill. 2014;19(14). 156. Jimenez A, Shaz BH, Bloch EM. Zika Virus and the blood sup-ply: what do we know? Transfus Med Rev. 2017;31(1):1-10. 157. Bierlaire D, Mauguin S, Broult J, Musso D. Zika virus and blood transfusion: the experience of French Polynesia. Trans-fusion. 2017;57(3pt2):729-733. 158. Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21:1-11. 159. Mallet SV, Cox DJA. Thromboelastography: a review article. Br J Anaesth. 1992;69:307. 160. Jackson GN, Ashpole KJ, Yentis SM. The TEG vs the ROTEM thromboelastography/ thromboelastometry systems. Anaesthe-sia. 2009;64(2):212-215. 161. Cotton BA, Radwan ZA, Matijevic N, et al. Admission rapid thromboelastography (rTEG) predicts development of pulmonary embolism in trauma patients. J Trauma. 2012;72(6):1470-1477. 162. Cotton BA, Faz G, Hatch Q, et al. Rapid


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Surgery_Schwartz. N, et al. Admission rapid thromboelastography (rTEG) predicts development of pulmonary embolism in trauma patients. J Trauma. 2012;72(6):1470-1477. 162. Cotton BA, Faz G, Hatch Q, et al. Rapid thromboelastogra-phy (r-TEG) delivers real-time results that predict transfusion within one hour of admission. J Trauma. 2011;71(2):407-417. 163. Schöchl H, Cotton BA, Inaba K, et al. FIBTEM provides early prediction of massive transfusion in trauma. Crit Care. 2011;15:R265-R271. 164. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinoly-sis on admission is an uncommon but highly lethal event associated with shock and pre-hospital fluid administration. J Trauma. 2012;72(2):365-370. 165. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thromboelastography (r-TEG) can replace conventional coag-ulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg. 2012;256(3): 476-486.Brunicardi_Ch04_p0103-p0130.indd 12929/01/19 11:05 AM


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Surgery_Schwartz. ShockBrian S. Zuckerbraun, Andrew B. Peitzman, and Timothy R. Billiar 5chapter“Shock is the manifestation of the rude unhinging of the machinery of life.”1—Samuel V. Gross, 1872EVOLUTION IN UNDERSTANDING SHOCKOverviewShock, at its most rudimentary definition and regardless of its etiology, is the failure to meet the metabolic needs of the cell and the consequences that ensue. The initial cellular injury that occurs is reversible; however, the injury will become irre-versible if tissue perfusion is prolonged or severe enough such that, at the cellular level, compensation is no longer pos-sible. Our understanding of shock and the disease processes that result in shock made its most significant advances throughout the 20th century as our appreciation for the physiology and pathophysiology of shock matured. Most notably, our compre-hension of the sympathetic and neuroendocrine stress responses on the cardiovascular system has flourished. The clinical mani-festations of these physiologic


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Surgery_Schwartz. shock matured. Most notably, our compre-hension of the sympathetic and neuroendocrine stress responses on the cardiovascular system has flourished. The clinical mani-festations of these physiologic responses are most often what lead practitioners to the diagnosis of shock as well as guide the management of patients in shock. However, hemodynamic parameters such as blood pressure and heart rate are relatively insensitive measures of shock, and additional considerations must be used to help aid in early diagnosis and treatment of patients in shock. The general approach to the management of patients in shock has been empiric: assuring a secure airway with adequate ventilation, control of hemorrhage in the bleeding patient, and restoration of vascular volume and tissue perfusion.Historical BackgroundIntegral to our understanding of shock is the appreciation that our bodies attempt to maintain a state of homeostasis. Claude Bernard suggested in the mid-19th century that the organism


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Surgery_Schwartz. BackgroundIntegral to our understanding of shock is the appreciation that our bodies attempt to maintain a state of homeostasis. Claude Bernard suggested in the mid-19th century that the organism attempts to maintain constancy in the internal environment against external 1forces that attempt to disrupt the milieu interieur.2 Walter B. Cannon carried Bernard’s observations further and introduced the term homeostasis, emphasizing that an organism’s ability to survive was related to maintenance of homeostasis.3 The failure of physiologic systems to buffer the organism against external forces results in organ and cellular dysfunction, what is clini-cally recognized as shock. He first described the “fight or flight response,” generated by elevated levels of catecholamines in the bloodstream. Cannon’s observations on the battlefields of World War I led him to propose that the initiation of shock was due to a disturbance of the nervous system that resulted in vasodilation and hypotension. He


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Surgery_Schwartz. observations on the battlefields of World War I led him to propose that the initiation of shock was due to a disturbance of the nervous system that resulted in vasodilation and hypotension. He proposed that secondary shock, with its attendant capillary permeability leak, was caused by a “toxic factor” released from the tissues.In a series of critical experiments, Alfred Blalock docu-mented that the shock state in hemorrhage was associated with reduced cardiac output due to volume loss, not a “toxic factor.”4 In 1934, Blalock proposed four categories of shock: hypovole-mic, vasogenic, cardiogenic, and neurogenic. Hypovolemic shock, the most common type, results from loss of circulating blood volume. This may result from loss of whole blood (hemorrhagic shock), plasma, interstitial fluid (bowel obstruction), or a combi-nation. Vasogenic shock results from decreased resistance within capacitance vessels, usually seen in sepsis. Neurogenic shock is a form of vasogenic shock in which


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Surgery_Schwartz. (bowel obstruction), or a combi-nation. Vasogenic shock results from decreased resistance within capacitance vessels, usually seen in sepsis. Neurogenic shock is a form of vasogenic shock in which spinal cord injury or spinal anesthesia causes vasodilation due to acute loss of sympathetic vascular tone. Cardiogenic shock results from failure of the heart as a pump, as in arrhythmias or acute myocardial infarction (MI).This categorization of shock based on etiology persists today (Table 5-1). In recent clinical practice, further classifi-cation has described six types of shock: hypovolemic, septic (vasodilatory), neurogenic, cardiogenic, obstructive, and trau-matic shock. Obstructive shock is a form of cardiogenic shock that results from mechanical impediment to circulation leading to depressed cardiac output rather than primary cardiac failure. Evolution in Understanding Shock 131Overview / 131Historical Background / 131Current Definitions and Challenges/ 133Pathophysiology of


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Surgery_Schwartz. depressed cardiac output rather than primary cardiac failure. Evolution in Understanding Shock 131Overview / 131Historical Background / 131Current Definitions and Challenges/ 133Pathophysiology of Shock 133Neuroendocrine and Organ-Specific Responses to Hemorrhage/ 134Afferent Signals / 134Efferent Signals / 135Circulatory Homeostasis / 136Metabolic Effects 136Cellular Hypoperfusion / 137Immune and Inflammatory Responses 137Cytokines/Chemokines / 138Complement / 140Neutrophils / 140Cell Signaling / 140Forms of Shock 141Hypovolemic/Hemorrhagic / 141Traumatic Shock / 145Septic Shock (Vasodilatory Shock) / 145Cardiogenic Shock / 148Obstructive Shock / 150Neurogenic Shock / 151Endpoints in Resuscitation 152Assessment of Endpoints in Resuscitation / 152Brunicardi_Ch05_p0131-p0156.indd 13129/01/19 11:06 AM 132Table 5-1Classification of shockHypovolemicCardiogenicSeptic (vasogenic)NeurogenicTraumaticObstructiveKey Points1 Shock is defined as a failure to meet the metabolic demands of


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Surgery_Schwartz. 11:06 AM 132Table 5-1Classification of shockHypovolemicCardiogenicSeptic (vasogenic)NeurogenicTraumaticObstructiveKey Points1 Shock is defined as a failure to meet the metabolic demands of cells and tissues and the consequences that ensue.2 A central component of shock is decreased tissue perfusion. This may be a direct consequence of the etiology of shock, such as in hypovolemic/hemorrhagic, cardiogenic, or neuro-genic etiologies, or may be secondary to elaborated or released molecules or cellular products that result in endothelial/ cellular activation, such as in septic shock or traumatic shock.3 Physiologic responses to shock are based upon a series of affer-ent (sensing) signals and efferent responses that include neu-roendocrine, metabolic, and immune/inflammatory signaling.4 The mainstay of treatment of hemorrhagic/hypovolemic shock includes volume resuscitation with blood products. In the case of hemorrhagic shock, timely control of bleeding is essential and influences


Surgery_Schwartz

Surgery_Schwartz. mainstay of treatment of hemorrhagic/hypovolemic shock includes volume resuscitation with blood products. In the case of hemorrhagic shock, timely control of bleeding is essential and influences outcome.5 Prevention of hypothermia, acidemia, and coagulopathy are essential in the management of patients in hemorrhagic shock.6 The mainstay of treatment of septic shock is fluid resuscita-tion, initiation of appropriate antibiotic therapy, and control of the source of infection. This includes drainage of infected fluid collections, removal of infected foreign bodies, and debridement of devitalized tissues.7 A combination of physiologic parameters and markers of organ perfusion/tissue oxygenation are used to determine if patients are in shock and to follow the efficacy of resuscitation.This includes etiologies such as pulmonary embolism or tension pneumothorax. In traumatic shock, soft tissue and bony injury lead to the activation of inflammatory cells and the release of circulating


Surgery_Schwartz

Surgery_Schwartz. includes etiologies such as pulmonary embolism or tension pneumothorax. In traumatic shock, soft tissue and bony injury lead to the activation of inflammatory cells and the release of circulating factors, such as cytokines and intracellular molecules that modulate the immune response. Recent investigations have revealed that the inflammatory mediators released in response to tissue injury (damage-associated molecular patterns [DAMPs]) are recognized by many of the same cellular receptors (pattern recognition receptors [PRRs]) and activate similar signaling pathways as do bacterial products elaborated in sepsis (pathogen-associated molecular patterns), such as lipopolysaccharide.5 These effects of tissue injury are combined with the effects of hemorrhage, creating a more complex and amplified deviation from homeostasis.In the midto later 20th century, further development of experimental models contributed significantly to the under-standing of the pathophysiology of shock. In 1947,


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Surgery_Schwartz. deviation from homeostasis.In the midto later 20th century, further development of experimental models contributed significantly to the under-standing of the pathophysiology of shock. In 1947, Wiggers developed a sustainable, irreversible model of hemorrhagic shock based on uptake of shed blood into a reservoir to maintain a set level of hypotension.6 G. Tom Shires added further under-standing of hemorrhagic shock with a series of clinical stud-ies demonstrating that a large extracellular fluid deficit, greater than could be attributed to vascular refilling alone, occurred in severe hemorrhagic shock.7,8 The phenomenon of fluid redistri-bution after major trauma involving blood loss was termed third spacing and described the translocation of intravascular volume into the peritoneum, bowel, burned tissues, or crush injury sites. These seminal studies form the scientific basis for the current treatment of hemorrhagic shock with red blood cells and lac-tated Ringer’s solution or isotonic


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Surgery_Schwartz. burned tissues, or crush injury sites. These seminal studies form the scientific basis for the current treatment of hemorrhagic shock with red blood cells and lac-tated Ringer’s solution or isotonic saline.As resuscitation strategies evolved and patients survived the initial consequences of hemorrhage, new challenges of sustained shock became apparent. During the Vietnam War, aggressive fluid resuscitation with red blood cells and crystal-loid solution or plasma resulted in survival of patients who pre-viously would have succumbed to hemorrhagic shock. Renal failure became a less frequent clinical problem; however, a new disease process, acute fulminant pulmonary failure, appeared as an early cause of death after seemingly successful surgery to control hemorrhage. Initially called DaNang lung or shock lung, the clinical problem became recognized as acute respiratory dis-tress syndrome (ARDS). This led to new methods of prolonged mechanical ventilation. Our current concept of ARDS is a


Surgery_Schwartz

Surgery_Schwartz. or shock lung, the clinical problem became recognized as acute respiratory dis-tress syndrome (ARDS). This led to new methods of prolonged mechanical ventilation. Our current concept of ARDS is a com-ponent in the spectrum of multiple organ system failure.Studies and clinical observations over the past two decades have extended the early observations of Canon, that “restoration of blood pressure prior to control of active bleeding may result in loss of blood that is sorely needed,” and challenged the appro-priate endpoints in resuscitation of uncontrolled hemorrhage.9 Core principles in the management of patients in hemorrhagic shock include: (a) control of active hemorrhage must occur promptly (delay in control of bleeding increases mortality and recent battlefield data would suggest that in the young and otherwise healthy population commonly injured in combat, that control of bleeding is the paramount priority); (b) volume resuscitation with blood products (red blood cells, plasma,


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Surgery_Schwartz. in the young and otherwise healthy population commonly injured in combat, that control of bleeding is the paramount priority); (b) volume resuscitation with blood products (red blood cells, plasma, and platelets) with limited volume of crystalloid must occur while operative control of bleeding is achieved; (c) unrecognized or inadequately corrected hypoperfusion increases morbidity and mortality (i.e., inadequate resuscitation results in avoidable early deaths from shock); and (d) excessive fluid resuscitation may exacerbate bleeding (i.e., uncontrolled resuscitation is harmful). Thus, both inadequate or unrestrained volume resus-citation are harmful.Likewise, observations in the management of septic shock have led to consensus statements and evolving guideline based management.10 Core principles in the management of patients in septic shock include: (a) septic shock is an emergency, and treatment/resuscitation should begin as early as possible; (b) specific anatomic diagnosis of


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Surgery_Schwartz. principles in the management of patients in septic shock include: (a) septic shock is an emergency, and treatment/resuscitation should begin as early as possible; (b) specific anatomic diagnosis of infection requiring emergent source control be identified or excluded as rapidly as possible and that any required source control intervention be imple-mented as soon as medically and logistically practical; (c) ini-tiation of broad spectrum antibiotics within 1 hour of diagnosis; (d) in the resuscitation from sepsis-induced hypoperfusion, at Brunicardi_Ch05_p0131-p0156.indd 13229/01/19 11:06 AM 133SHOCKCHAPTER 5least 30 mL/kg of intravenous crystalloid fluid be given within the first 3 hours, and additional fluids be guided by frequent reassessment of hemodynamic status; (e) vasopressors (norepi-nephrine) should be added to achieve a mean arterial pressure of 65 mmHg if fluid resuscitation is inadequate.Current Definitions and ChallengesA modern definition and approach to shock


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Surgery_Schwartz. (norepi-nephrine) should be added to achieve a mean arterial pressure of 65 mmHg if fluid resuscitation is inadequate.Current Definitions and ChallengesA modern definition and approach to shock acknowledges that shock consists of inadequate tissue perfusion marked by decreased delivery of required metabolic substrates and inade-quate removal of cellular waste products. This involves failure of oxidative metabolism that can involve defects of oxygen (O2) delivery, transport, and/or utilization. Current challenges include moving beyond fluid resuscitation based upon endpoints of tissue oxygenation and using therapeutic strategies at the cellular and molecular level. This approach will help to identify compensated patients or patients early in the course of their disease, initiate appropriate treatment, and allow for con-tinued evaluation for the efficacy of resuscitation and adjuncts.Current investigations focus on determining the cellular events that often occur in parallel to result


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Surgery_Schwartz. treatment, and allow for con-tinued evaluation for the efficacy of resuscitation and adjuncts.Current investigations focus on determining the cellular events that often occur in parallel to result in organ dysfunc-tion, shock irreversibility, and death. This chapter will review our current understanding of the pathophysiology and cellular responses of shock states. Current and experimental diagnostic and therapeutic modalities for the different categories of shock are reviewed, with a focus on hemorrhagic/hypovolemic shock and septic shock.PATHOPHYSIOLOGY OF SHOCKRegardless of etiology, the initial physiologic responses in shock are driven by tissue hypoperfusion and the developing cellular energy deficit. This imbalance between cellular supply and demand leads to neuroendocrine and inflammatory responses, the magnitude of which is usually proportional to the degree and duration of shock. The specific responses will differ based on the etiology of shock, as certain physiologic


Surgery_Schwartz

Surgery_Schwartz. inflammatory responses, the magnitude of which is usually proportional to the degree and duration of shock. The specific responses will differ based on the etiology of shock, as certain physiologic responses may be limited by the inciting pathology. For exam-ple, the cardiovascular response driven by the sympathetic ner-vous system is markedly blunted in neurogenic or septic shock. Additionally, decreased perfusion may occur as a consequence of cellular activation and dysfunction, such as in septic shock and to a lesser extent traumatic shock (Fig. 5-1). Many of the organ-specific responses are aimed at maintaining perfusion in the cerebral and coronary circulation. These are regulated at multiple levels including (a) stretch receptors and baroreceptors in the heart and vasculature (carotid sinus and aortic arch), (b) chemoreceptors, (c) cerebral ischemia responses, (d) release of endogenous vasoconstrictors, (e) shifting of fluid into the intra-vascular space, and (f) renal


Surgery_Schwartz

Surgery_Schwartz. (carotid sinus and aortic arch), (b) chemoreceptors, (c) cerebral ischemia responses, (d) release of endogenous vasoconstrictors, (e) shifting of fluid into the intra-vascular space, and (f) renal reabsorption and conservation of salt and water.Furthermore, the pathophysiologic responses vary with time and in response to resuscitation. In hemorrhagic shock, the body can compensate for the initial loss of blood volume primar-ily through the neuroendocrine response to maintain hemody-namics. This represents the compensated phase of shock. With continued hypoperfusion, which may be unrecognized, cellular death and injury are ongoing, and the decompensation phase of shock ensues. Microcirculatory dysfunction, parenchymal tissue damage, and inflammatory cell activation can perpetuate hypo-perfusion. Ischemia/reperfusion injury will often exacerbate the initial insult. These effects at the cellular level, if untreated, will lead to compromise of function at the organ system level, thus


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Surgery_Schwartz. Ischemia/reperfusion injury will often exacerbate the initial insult. These effects at the cellular level, if untreated, will lead to compromise of function at the organ system level, thus leading to the “vicious cycle” of shock (Fig. 5-2). Persis-tent hypoperfusion results in further hemodynamic derange-ments and cardiovascular collapse. This has been termed the irreversible phase of shock and can develop quite insidiously and may only be obvious in retrospect. At this point, there has occurred extensive enough parenchymal and microvascular injury such that volume resuscitation fails to reverse the pro-cess, leading to death of the patient. In experimental animal models of hemorrhagic shock (modified Wiggers model), this is 23Figure 5-1. Pathways leading to decreased tissue perfusion and shock. Decreased tissue perfusion can result directly from hemorrhage/hypovolemia, cardiac failure, or neurologic injury. Decreased tissue perfusion and cellu-lar injury can then result in immune


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Surgery_Schwartz. and shock. Decreased tissue perfusion can result directly from hemorrhage/hypovolemia, cardiac failure, or neurologic injury. Decreased tissue perfusion and cellu-lar injury can then result in immune and inflammatory responses. Alternatively, elaboration of microbial products during infection or release of endogenous cellular products from tissue injury can result in cellular activation to subsequently influ-ence tissue perfusion and the develop-ment of shock. HMGB1 = high mobility group box 1; LPS = lipopolysaccharide; RAGE = receptor for advanced glycation end products.Bacterial products(i.e., LPS)Direct effectPattern recognition receptor activation(Toll-like receptors, RAGE)TissueinjuryDamage associatedmolecular patterns(i.e., HMGB1, heparan sulfate)Released/elaboratedmediators ofinflammationCellular activationDecreased tissue perfusionCellular hypoxia/ischemiaShockDisruptionhost-microbeequilibriumAcute heart failureNeurogenicHemorrhageTraumaCellular


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Surgery_Schwartz. ofinflammationCellular activationDecreased tissue perfusionCellular hypoxia/ischemiaShockDisruptionhost-microbeequilibriumAcute heart failureNeurogenicHemorrhageTraumaCellular effectBrunicardi_Ch05_p0131-p0156.indd 13329/01/19 11:06 AM 134BASIC CONSIDERATIONSPART Irepresented by the “uptake phase” or “compensation endpoint” when shed blood must be returned to the animal to sustain the hypotension at the set level to prevent further hypotension and death.11 If shed blood volume is slowly returned to maintain the set level of hypotension, eventually the injury progresses to irreversible shock, where further volume will not reverse the process and the animal dies (Fig. 5-3).Neuroendocrine and Organ-Specific Responses to HemorrhageThe goal of the neuroendocrine response to hemorrhage is to maintain perfusion to the heart and the brain, even at the expense of other organ systems. Peripheral vasoconstriction occurs, and fluid excretion is inhibited. The mechanisms include autonomic


Surgery_Schwartz

Surgery_Schwartz. is to maintain perfusion to the heart and the brain, even at the expense of other organ systems. Peripheral vasoconstriction occurs, and fluid excretion is inhibited. The mechanisms include autonomic control of peripheral vascular tone and cardiac contractility, hormonal response to stress and volume depletion, and local microcirculatory mechanisms that are organ specific and regu-late regional blood flow. The initial stimulus is loss of circulat-ing blood volume in hemorrhagic shock. The magnitude of the neuroendocrine response is based on both the volume of blood lost and the rate at which it is lost.Afferent SignalsAfferent impulses transmitted from the periphery are processed within the central nervous system (CNS) and activate the reflexive effector responses or efferent impulses. These effec-tor responses are designed to expand plasma volume, maintain peripheral perfusion and tissue O2 delivery, and restore homeo-stasis. The afferent impulses that initiate the body’s intrinsic


Surgery_Schwartz

Surgery_Schwartz. effec-tor responses are designed to expand plasma volume, maintain peripheral perfusion and tissue O2 delivery, and restore homeo-stasis. The afferent impulses that initiate the body’s intrinsic adaptive responses and converge in the CNS originate from a variety of sources. The initial inciting event usually is loss of circulating blood volume. Other stimuli that can produce the neuroendocrine response include pain, hypoxemia, hypercarbia, acidosis, infection, change in temperature, emotional arousal, or hypoglycemia. The sensation of pain from injured tissue is trans-mitted via the spinothalamic tracts, resulting in activation of the hypothalamic-pituitary-adrenal axis, as well as activation of the autonomic nervous system (ANS) to induce direct sympathetic stimulation of the adrenal medulla to release catecholamines.Baroreceptors also are an important afferent pathway in initiation of adaptive responses to shock. Volume receptors, sensitive to changes in both chamber pressure and


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Surgery_Schwartz. to release catecholamines.Baroreceptors also are an important afferent pathway in initiation of adaptive responses to shock. Volume receptors, sensitive to changes in both chamber pressure and wall stretch, are present within the atria of the heart. They become activated with low volume hemorrhage or mild reductions in right atrial pressure. Receptors in the aortic arch and carotid bodies respond to alterations in pressure or stretch of the arterial wall, respond-ing to larger reductions in intravascular volume or pressure. These receptors normally inhibit induction of the ANS. When activated, these baroreceptors diminish their output, thus dis-inhibiting the effect of the ANS. The ANS then increases its output, principally via sympathetic activation at the vasomotor centers of the brain stem, producing centrally mediated constric-tion of peripheral vessels.Chemoreceptors in the aorta and carotid bodies are sensi-tive to changes in O2 tension, H+ ion concentration, and car-bon dioxide


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Surgery_Schwartz. producing centrally mediated constric-tion of peripheral vessels.Chemoreceptors in the aorta and carotid bodies are sensi-tive to changes in O2 tension, H+ ion concentration, and car-bon dioxide (CO2) levels. Stimulation of the chemoreceptors results in vasodilation of the coronary arteries, slowing of the heart rate, and vasoconstriction of the splanchnic and skeletal circulation. In addition, a variety of protein and nonprotein mediators are produced at the site of injury as part of the inflam-matory response, and they act as afferent impulses to induce a host response. These mediators include histamine, cytokines, Decreased cardiac outputDecreased tissue perfusion˜ Venousreturn˜ CoronaryperfusionMetabolicacidosisCellularhypoxiaParenchymal cell injuryEndothelial activation/microcirculatory damageCellularaggregationIntracellularfluid lossFigure 5-2. The “vicious cycle of shock.” Regardless of the etiol-ogy, decreased tissue perfusion and shock results in a feed-forward loop that can


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Surgery_Schwartz. damageCellularaggregationIntracellularfluid lossFigure 5-2. The “vicious cycle of shock.” Regardless of the etiol-ogy, decreased tissue perfusion and shock results in a feed-forward loop that can exacerbate cellular injury and tissue dysfunction.Figure 5-3. Rat model of hemorrhagic shock through the phases of compensa-tion, decompensation, and irreversibility. The percentages shown above the curve represent survival rates. (Reproduced with permission from Shah NS, Kelly E, Billiar TR, et al. Utility of clinical param-eters of tissue oxygenation in a quantita-tive model of irreversible hemorrhagic shock, Shock. 1998 Nov;10(5):343-346.)Rat hemorrhagic shock model24-hour survival following resuscitationMean arterial pressureCompensatedDecompensatedIrreversible% Shedblood returnTransition to acute irreversible shockTransition to subacute lethal shockABDeath100%90%50%30%10%0%10%20%30%40%50%0%Compensation endpoint8040ABBrunicardi_Ch05_p0131-p0156.indd 13429/01/19 11:06 AM


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Surgery_Schwartz. to acute irreversible shockTransition to subacute lethal shockABDeath100%90%50%30%10%0%10%20%30%40%50%0%Compensation endpoint8040ABBrunicardi_Ch05_p0131-p0156.indd 13429/01/19 11:06 AM 135SHOCKCHAPTER 5eicosanoids, and endothelins, among others that are discussed in greater detail later in this chapter in the “Immune and Inflam-matory Responses” section.Efferent SignalsCardiovascular Response. Changes in cardiovascular func-tion are a result of the neuroendocrine response and ANS response to shock, and they constitute a prominent feature of both the body’s adaptive response mechanism and the clinical signs and symptoms of the patient in shock. Hemorrhage results in diminished venous return to the heart and decreased cardiac output. This is compensated by increased cardiac heart rate and contractility, as well as venous and arterial vasoconstriction. Stimulation of sympathetic fibers innervating the heart leads to activation of β1-adrenergic receptors that increase heart rate and


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Surgery_Schwartz. contractility, as well as venous and arterial vasoconstriction. Stimulation of sympathetic fibers innervating the heart leads to activation of β1-adrenergic receptors that increase heart rate and contractility in this attempt to increase cardiac output. Increased myocardial O2 consumption occurs as a result of the increased workload; thus, myocardial O2 supply must be maintained, or myocardial dysfunction will develop. The car-diovascular response in hemorrhage/hypovolemia differs from the responses elicited with the other etiologies of shock. These are compared in Table 5-2.Direct sympathetic stimulation of the peripheral circula-tion via the activation of α1-adrenergic receptors on arterioles induces vasoconstriction and causes a compensatory increase in systemic vascular resistance and blood pressure. The arte-rial vasoconstriction is not uniform; marked redistribution of blood flow results. Selective perfusion to tissues occurs due to regional variations in arteriolar resistance,


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Surgery_Schwartz. blood pressure. The arte-rial vasoconstriction is not uniform; marked redistribution of blood flow results. Selective perfusion to tissues occurs due to regional variations in arteriolar resistance, with blood shunted away from less essential organ beds such as the intestine, kidney, and skin. In contrast, the brain and heart have autoreg-ulatory mechanisms that attempt to preserve their blood flow despite a global decrease in cardiac output. Direct sympathetic stimulation also induces constriction of venous vessels, decreas-ing the capacitance of the circulatory system and accelerating blood return to the central circulation.Increased sympathetic output induces catecholamine release from the adrenal medulla. Catecholamine levels peak within 24 to 48 hours of injury and then return to baseline. Persis-tent elevation of catecholamine levels beyond this time suggests ongoing noxious afferent stimuli. The majority of the circulating epinephrine is produced by the adrenal medulla, while


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Surgery_Schwartz. Persis-tent elevation of catecholamine levels beyond this time suggests ongoing noxious afferent stimuli. The majority of the circulating epinephrine is produced by the adrenal medulla, while norepi-nephrine is derived from synapses of the sympathetic nervous system. Catecholamine effects on peripheral tissues include stimulation of hepatic glycogenolysis and gluconeogenesis to increase circulating glucose availability to peripheral tissues, an increase in skeletal muscle glycogenolysis, suppression of insulin release, and increased glucagon release.Hormonal Response. The stress response includes activation of the ANS as discussed previously in the “Afferent Signals” section, as well as activation of the hypothalamic-pituitary-adrenal axis. Shock stimulates the hypothalamus to release corticotropin-releasing hormone, which results in the release of adrenocorticotropic hormone (ACTH) by the pituitary. ACTH subsequently stimulates the adrenal cortex to release cortisol. Cortisol acts


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Surgery_Schwartz. hormone, which results in the release of adrenocorticotropic hormone (ACTH) by the pituitary. ACTH subsequently stimulates the adrenal cortex to release cortisol. Cortisol acts synergistically with epinephrine and glucagon to induce a catabolic state. Cortisol stimulates gluconeogenesis and insulin resistance, resulting in hyperglycemia as well as muscle cell protein breakdown and lipolysis to provide sub-strates for hepatic gluconeogenesis. Cortisol causes retention of sodium and water by the nephrons of the kidney. In the setting of severe hypovolemia, ACTH secretion occurs independently of cortisol negative feedback inhibition.The renin-angiotensin system is activated in shock. Decreased renal artery perfusion, β-adrenergic stimulation, and increased renal tubular sodium concentration cause the release of renin from the juxtaglomerular cells. Renin catalyzes the conversion of angiotensinogen (produced by the liver) to angiotensin I, which is then converted to angiotensin II by


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Surgery_Schwartz. cause the release of renin from the juxtaglomerular cells. Renin catalyzes the conversion of angiotensinogen (produced by the liver) to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE) produced in the lung. While angiotensin I has no significant functional activity, angiotensin II is a potent vasoconstrictor of both splanchnic and peripheral vascular beds, and also stimulates the secretion of aldosterone, ACTH, and antidiuretic hormone (ADH). Aldo-sterone, a mineralocorticoid, acts on the nephron to promote reabsorption of sodium, and as a consequence, water. Potassium and hydrogen ions are lost in the urine in exchange for sodium.The pituitary also releases vasopressin or ADH in response to hypovolemia, changes in circulating blood volume sensed by baroreceptors and left atrial stretch receptors, and increased plasma osmolality detected by hypothalamic osmo-receptors. Epinephrine, angiotensin II, pain, and hyperglycemia increase


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Surgery_Schwartz. sensed by baroreceptors and left atrial stretch receptors, and increased plasma osmolality detected by hypothalamic osmo-receptors. Epinephrine, angiotensin II, pain, and hyperglycemia increase production of ADH. ADH levels remain elevated for about 1 week after the initial insult, depending on the sever-ity and persistence of the hemodynamic abnormalities. ADH acts on the distal tubule and collecting duct of the nephron to increase water permeability, decrease water and sodium losses, and preserve intravascular volume. Also known as arginine vasopressin, ADH acts as a potent mesenteric vasoconstrictor, shunting circulating blood away from the splanchnic organs during hypovolemia.12 This may contribute to intestinal isch-emia and predispose to intestinal mucosal barrier dysfunction in Table 5-2Hemodynamic responses to different types of shockTYPE OF SHOCKCARDIAC INDEXSVRVENOUS CAPACITANCECVP/PCWPSvo2CELLULAR/METABOLIC


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Surgery_Schwartz. and predispose to intestinal mucosal barrier dysfunction in Table 5-2Hemodynamic responses to different types of shockTYPE OF SHOCKCARDIAC INDEXSVRVENOUS CAPACITANCECVP/PCWPSvo2CELLULAR/METABOLIC EFFECTSHypovolemic↓↑↓↓↓EffectSeptic↑↑↓↑↑↓↑↓CauseCardiogenic↓↓↑↑→↑↓EffectNeurogenic↑↓→↓↓EffectThe hemodynamic responses are indicated by arrows to show an increase (↑), severe increase (↑↑), decrease (↓), severe decrease (↓↓), varied response (↑↓), or little effect →). CVP = central venous pressure; PCWP = pulmonary capillary wedge pressure; Svo2 = mixed venous oxygen saturation; SVR = systemic vascular resistance.Brunicardi_Ch05_p0131-p0156.indd 13529/01/19 11:06 AM 136BASIC CONSIDERATIONSPART Ishock states. Vasopressin also increases hepatic gluconeogen-esis and increases hepatic glycolysis.In septic states, endotoxin directly stimulates arginine vasopressin secretion independently of blood pressure, osmotic, or intravascular volume changes. Proinflammatory cytokines also contribute to


Surgery_Schwartz

Surgery_Schwartz. septic states, endotoxin directly stimulates arginine vasopressin secretion independently of blood pressure, osmotic, or intravascular volume changes. Proinflammatory cytokines also contribute to arginine vasopressin release. Interestingly, patients on chronic therapy with ACE inhibitors are more at risk of developing hypotension and vasodilatory shock with open heart surgery. Low plasma levels of arginine vasopressin were confirmed in these patients.13Circulatory HomeostasisPreload. At rest, the majority of the blood volume is within the venous system. Venous return to the heart generates ventricular end-diastolic wall tension, a major determinant of cardiac out-put. Gravitational shifts in blood volume distribution are quickly corrected by alterations in venous capacity. With decreased arte-riolar inflow, there is active contraction of the venous smooth muscle and passive elastic recoil in the thin-walled systemic veins. This increases venous return to the heart, thus maintain-ing


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Surgery_Schwartz. arte-riolar inflow, there is active contraction of the venous smooth muscle and passive elastic recoil in the thin-walled systemic veins. This increases venous return to the heart, thus maintain-ing ventricular filling.Most alterations in cardiac output in the normal heart are related to changes in preload. Increases in sympathetic tone have a minor effect on skeletal muscle beds but produce a dra-matic reduction in splanchnic blood volume, which normally holds 20% of the blood volume.The normal circulating blood volume is maintained within narrow limits by the kidney’s ability to manage salt and water balance with external losses via systemic and local hemody-namic changes and hormonal effects of renin, angiotensin, and ADH. These relatively slow responses maintain preload by altering circulating blood volume. Acute responses to intravas-cular volume include changes in venous tone, systemic vascular resistance, and intrathoracic pressure, with the slower hormonal changes less


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Surgery_Schwartz. circulating blood volume. Acute responses to intravas-cular volume include changes in venous tone, systemic vascular resistance, and intrathoracic pressure, with the slower hormonal changes less important in the early response to volume loss. Furthermore, the net effect of preload on cardiac output is influ-enced by cardiac determinants of ventricular function, which include coordinated atrial activity and tachycardia.Ventricular Contraction. The Frank-Starling curve describes the force of ventricular contraction as a function of its preload. This relationship is based on force of contraction being deter-mined by initial muscle length. Intrinsic cardiac disease will shift the Frank-Starling curve and alter mechanical performance of the heart. In addition, cardiac dysfunction has been demon-strated experimentally in burns and in hemorrhagic, traumatic, and septic shock.Afterload. Afterload is the force that resists myocardial work during contraction. Arterial pressure is the major


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Surgery_Schwartz. demon-strated experimentally in burns and in hemorrhagic, traumatic, and septic shock.Afterload. Afterload is the force that resists myocardial work during contraction. Arterial pressure is the major component of afterload influencing the ejection fraction. This vascular resistance is determined by precapillary smooth muscle sphinc-ters. Blood viscosity also will increase vascular resistance. As afterload increases in the normal heart, stroke volume can be maintained by increases in preload. In shock, with decreased circulating volume and therefore diminished preload, this com-pensatory mechanism to sustain cardiac output is impeded. The stress response with acute release of catecholamines and sym-pathetic nerve activity in the heart increases contractility and heart rate.Microcirculation. The microvascular circulation plays an integral role in regulating cellular perfusion and is significantly influenced in response to shock. The microvascular bed is innervated by the sympathetic


Surgery_Schwartz

Surgery_Schwartz. microvascular circulation plays an integral role in regulating cellular perfusion and is significantly influenced in response to shock. The microvascular bed is innervated by the sympathetic nervous system and has a pro-found effect on the larger arterioles. Following hemorrhage, larger arterioles vasoconstrict; however, in the setting of sep-sis or neurogenic shock, these vessels vasodilate. Addition-ally, a host of other vasoactive proteins, including vasopressin, angiotensin II, and endothelin-1, also lead to vasoconstriction to limit organ perfusion to organs such as skin, skeletal muscle, kidneys, and the GI tract to preserve perfusion of the myocar-dium and CNS.Flow in the capillary bed is heterogeneous in shock states, which likely is secondary to multiple local mechanisms, including endothelial cell swelling, dysfunction, and activa-tion marked by the recruitment of leukocytes and platelets.14 Together, these mechanisms lead to diminished capillary perfu-sion that may persist


Surgery_Schwartz

Surgery_Schwartz. endothelial cell swelling, dysfunction, and activa-tion marked by the recruitment of leukocytes and platelets.14 Together, these mechanisms lead to diminished capillary perfu-sion that may persist after resuscitation. In hemorrhagic shock, correction of hemodynamic parameters and restoration of O2 delivery generally leads to restoration of tissue O2 consumption and tissue O2 levels. In contrast, regional tissue dysoxia often persists in sepsis, despite similar restoration of hemodynamics and O2 delivery. Whether this defect in O2 extraction in sepsis is the result of heterogeneous impairment of the microcirculation (intraparenchymal shunting) or impaired tissue parenchymal cell oxidative phosphorylation and O2 consumption by the mito-chondria is not resolved.15 Interesting data suggest that in sepsis the response to limit O2 consumption by the tissue parenchymal cells is an adaptive response to the inflammatory signaling and decreased perfusion.16An additional pathophysiologic


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Surgery_Schwartz. that in sepsis the response to limit O2 consumption by the tissue parenchymal cells is an adaptive response to the inflammatory signaling and decreased perfusion.16An additional pathophysiologic response of the microcir-culation to shock is failure of the integrity of the endothelium of the microcirculation and development of capillary leak, intracellular swelling, and the development of an extracellu-lar fluid deficit. Seminal work by Shires helped to define this phenomenon.8,17 There is decreased capillary hydrostatic pres-sure secondary to changes in blood flow and increased cellular uptake of fluid. The result is a loss of extracellular fluid vol-ume. The cause of intracellular swelling is multifactorial, but dysfunction of energy-dependent mechanisms, such as active transport by the sodium-potassium pump contributes to loss of membrane integrity.Capillary dysfunction also occurs secondary to activation of endothelial cells by circulating inflammatory mediators gen-erated in


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Surgery_Schwartz. the sodium-potassium pump contributes to loss of membrane integrity.Capillary dysfunction also occurs secondary to activation of endothelial cells by circulating inflammatory mediators gen-erated in septic or traumatic shock. This exacerbates endothelial cell swelling and capillary leak, as well as increases leukocyte adherence. This results in capillary occlusion, which may persist after resuscitation, and is termed no-reflow. Further ischemic injury ensues as well as release of inflammatory cytokines to compound tissue injury. Experimental models have shown that neutrophil depletion in animals subjected to hemorrhagic shock produces fewer capillaries with no-reflow and lower mortality.14METABOLIC EFFECTSCellular metabolism is based primarily on the hydrolysis of adenosine triphosphate (ATP). The splitting of the phosphoan-hydride bond of the terminal or g-phosphate from ATP is the source of energy for most processes within the cell under nor-mal conditions. The majority of ATP is


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Surgery_Schwartz. (ATP). The splitting of the phosphoan-hydride bond of the terminal or g-phosphate from ATP is the source of energy for most processes within the cell under nor-mal conditions. The majority of ATP is generated in our bodies through aerobic metabolism in the process of oxidative phos-phorylation in the mitochondria. This process is dependent on the availability of O2 as a final electron acceptor in the electron transport chain. As O2 tension within a cell decreases, there is a decrease in oxidative phosphorylation, and the generation Brunicardi_Ch05_p0131-p0156.indd 13629/01/19 11:06 AM 137SHOCKCHAPTER 5of ATP slows. When O2 delivery is so severely impaired such that oxidative phosphorylation cannot be sustained, the state is termed dysoxia.18 When oxidative phosphorylation is insuffi-cient, the cells shift to anaerobic metabolism and glycolysis to generate ATP. This occurs via the breakdown of cellular glyco-gen stores to pyruvate. Although glycolysis is a rapid process, it is not


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Surgery_Schwartz. the cells shift to anaerobic metabolism and glycolysis to generate ATP. This occurs via the breakdown of cellular glyco-gen stores to pyruvate. Although glycolysis is a rapid process, it is not efficient, allowing for the production of only 2 mol of ATP from 1 mol of glucose. This is compared to complete oxidation of 1 mol of glucose that produces 38 mol of ATP. Additionally, under hypoxic conditions in anaerobic metabo-lism, pyruvate is converted into lactate, leading to an intracel-lular metabolic acidosis.There are numerous consequences secondary to these met-abolic changes. The depletion of ATP potentially influences all ATP-dependent cellular processes. This includes maintenance of cellular membrane potential, synthesis of enzymes and pro-teins, cell signaling, and DNA repair mechanisms. Decreased intracellular pH also influences vital cellular functions such as normal enzyme activity, cell membrane ion exchange, and cellular metabolic signaling.19 These changes also will lead to


Surgery_Schwartz

Surgery_Schwartz. Decreased intracellular pH also influences vital cellular functions such as normal enzyme activity, cell membrane ion exchange, and cellular metabolic signaling.19 These changes also will lead to changes in gene expression within the cell. Furthermore, acido-sis leads to changes in calcium metabolism and calcium signal-ing. Compounded, these changes may lead to irreversible cell injury and death.Epinephrine and norepinephrine have a profound impact on cellular metabolism. Hepatic glycogenolysis, gluconeogen-esis, ketogenesis, skeletal muscle protein breakdown, and adi-pose tissue lipolysis are increased by catecholamines. Cortisol, glucagon, and ADH also contribute to the catabolism during shock. Epinephrine induces further release of glucagon, while inhibiting the pancreatic β-cell release of insulin. The result is a catabolic state with glucose mobilization, hyperglycemia, pro-tein breakdown, negative nitrogen balance, lipolysis, and insulin resistance during shock and injury. The


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Surgery_Schwartz. of insulin. The result is a catabolic state with glucose mobilization, hyperglycemia, pro-tein breakdown, negative nitrogen balance, lipolysis, and insulin resistance during shock and injury. The relative underuse of glu-cose by peripheral tissues preserves it for the glucose-dependent organs such as the heart and brain.Cellular HypoperfusionHypoperfused cells and tissues experience what has been termed oxygen debt, a concept first proposed by Crowell in 1961.20 The O2 debt is the deficit in tissue oxygenation over time that occurs during shock. When O2 delivery is limited, O2 consumption can be inadequate to match the metabolic needs of cellular respira-tion, creating a deficit in O2 requirements at the cellular level. The measurement of O2 deficit uses calculation of the difference between the estimated O2 demand and the actual value obtained for O2 consumption. Under normal circumstances, cells can “repay” the O2 debt during reperfusion. The magnitude of the O2 debt correlates with


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Surgery_Schwartz. the estimated O2 demand and the actual value obtained for O2 consumption. Under normal circumstances, cells can “repay” the O2 debt during reperfusion. The magnitude of the O2 debt correlates with the severity and duration of hypoperfusion. Surrogate values for measuring O2 debt include base deficit and lactate levels and are discussed later in the “Hypovolemic/ Hemorrhagic” section.In addition to induction of changes in cellular metabolic pathways, shock also induces changes in cellular gene expres-sion. The DNA binding activity of a number of nuclear tran-scription factors is altered by hypoxia and the production of O2 radicals or nitrogen radicals that are produced at the cellular level by shock. Expression of other gene products such as heat shock proteins, vascular endothelial growth factor, inducible nitric oxide synthase (iNOS), heme oxygenase-1, and cytokines also are clearly increased by shock.21 Many of these shock-induced gene products, such as cytokines, have the ability


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Surgery_Schwartz. factor, inducible nitric oxide synthase (iNOS), heme oxygenase-1, and cytokines also are clearly increased by shock.21 Many of these shock-induced gene products, such as cytokines, have the ability to subsequently alter gene expression in specific target cells and tissues. The involvement of multiple pathways emphasizes the complex, integrated, and overlapping nature of the response to shock.IMMUNE AND INFLAMMATORY RESPONSESThe inflammatory and immune responses are a complex set of interactions between circulating soluble factors and cells that can arise in response to trauma, infection, ischemia, toxic, or autoimmune stimuli.21 The processes are well regulated and can be conceptualized as an ongoing surveillance and response sys-tem that undergoes a coordinated escalation following injury to heal disrupted tissue or restore host-microbe equilibrium, as well as active suppression back to baseline levels. Failure to adequately control the activation, escalation, or suppression of the


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Surgery_Schwartz. to heal disrupted tissue or restore host-microbe equilibrium, as well as active suppression back to baseline levels. Failure to adequately control the activation, escalation, or suppression of the inflammatory response can lead to systemic inflammatory response syndrome and potentiate multiple organ failure.Both the innate and adaptive branches of the immune system work in concert to rapidly respond in a specific and effective manner to challenges that threaten an organism’s well-being. Each arm of the immune system has its own set of func-tions, defined primarily by distinct classes of effector cells and their unique cell membrane receptor families. Alterations in the activity of the innate host immune system can be responsible for both the development of shock (i.e., septic shock follow-ing severe infection and traumatic shock following tissue injury with hemorrhage) and the pathophysiologic sequelae of shock such as the proinflammatory changes seen following hypoperfu-sion (see


Surgery_Schwartz

Surgery_Schwartz. severe infection and traumatic shock following tissue injury with hemorrhage) and the pathophysiologic sequelae of shock such as the proinflammatory changes seen following hypoperfu-sion (see Fig. 5-1). When the predominantly paracrine mediators gain access to the systemic circulation, they can induce a variety of metabolic changes that are collectively referred to as the host inflammatory response. Understanding of the intricate, redun-dant, and interrelated pathways that comprise the inflammatory response to shock continues to expand. Despite limited under-standing of how our current therapeutic interventions impact the host response to illness, inappropriate or excessive inflam-mation appears to be an essential event in the development of ARDS, multiple organ dysfunction syndrome (MODS), and posttraumatic immunosuppression that can prolong recovery.22Following direct tissue injury or infection, there are several mechanisms that lead to the activation of the active inflamma-tory and


Surgery_Schwartz

Surgery_Schwartz. and posttraumatic immunosuppression that can prolong recovery.22Following direct tissue injury or infection, there are several mechanisms that lead to the activation of the active inflamma-tory and immune responses. These include release of bioactive peptides by neurons in response to pain and the release of intra-cellular molecules by broken cells, such as heat shock proteins, mitochondrial products, heparan sulfate, high mobility group box 1, and RNA. Only recently has it been realized that the release of intracellular products from damaged and injured cells can have paracrine and endocrine-like effects on distant tissues to activate the inflammatory and immune responses.23 This hypothesis, which was first proposed by Matzinger, is known as danger signaling. Under this novel paradigm of immune function, endogenous molecules are capable of signaling the presence of danger to surrounding cells and tissues. These molecules that are released from cells are known as damage associated


Surgery_Schwartz

Surgery_Schwartz. of immune function, endogenous molecules are capable of signaling the presence of danger to surrounding cells and tissues. These molecules that are released from cells are known as damage associated molecular patterns (DAMPs, Table 5-3). DAMPs are recognized by cell surface receptors to effect intracellular signaling that primes and amplifies the immune response. These receptors are known as pattern recognition receptors (PRRs) and include the Toll-like receptors (TLRs) and the receptor for advanced glycation end products. Interestingly, TLRs and PRRs were first recognized for their role in signaling as part of the immune response to the Brunicardi_Ch05_p0131-p0156.indd 13729/01/19 11:06 AM 138BASIC CONSIDERATIONSPART Ientry of microbes and their secreted products into a normally sterile environment. These bacterial products, including lipo-polysaccharide, are known as pathogen-associated molecular patterns. The salutary consequences of PRR activation most likely relate to the