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Surgery_Schwartz. by downregulating the immune response.226 The Inflammation and the Host Response to Injury trial was a prospective, multicenter, federally funded study that aimed to define specific genetic pathways that differ in the response to both burns and traumatic injury.227 Blood and tissue samples from a strictly defined patient population were analyzed using gene arrays to determine whether differential expression in cer-tain genetic pathways affects clinical outcomes.228 Although data from this study are still being analyzed, some interesting findings suggest that sepsis, trauma, and burn patients share common gene expression patterns, starting early after injury.229 These genes can upregulate proinflammatory pathways as well as disrupt antigen presentation pathways. A better understand-ing of these common genomic responses may allow for the tar-geted treatment of immunologic and signal pathways to help improve patient survival from burn injuries.Another area of increasing interest includes


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Surgery_Schwartz. common genomic responses may allow for the tar-geted treatment of immunologic and signal pathways to help improve patient survival from burn injuries.Another area of increasing interest includes integration of technology to burn size estimation and resuscitation. These include the use of smart device applications to assist with esti-mation of burn size and resuscitation recommendations.230-232 Further investigation is needed to determine the applicability of these models to burn estimation and resuscitation. However, as these models can include hourly updates and recommendations, they nudge clinicians to frequently reconsider fluid parameters during the critical stages of resuscitation.With the dramatic progress in improving survival follow-ing a major burn injury during the twentieth century, under-standing and addressing functional and psychological outcomes is critical to the well-being of burn survivors. Since 1993, the National Institute of Disability and Rehabilitation Research


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Surgery_Schwartz. under-standing and addressing functional and psychological outcomes is critical to the well-being of burn survivors. Since 1993, the National Institute of Disability and Rehabilitation Research has funded four burn model systems to identify long-term sequelae of burn injuries and to develop ways to improve outcomes for survivors. Ongoing outcome studies are crucial for dismantling barriers that our patients face in returning to their communities and to the workplace or to school.REFERENCESEntries highlighted in bright blue are key references. 1. Baxter CR, Shires T. Physiological response to crystal-loid resuscitation of severe burns. Ann N Y Acad Sci. 1968;150(3):874-894. doi:10.1111/j.1749-6632.1968.tb14738.xBrunicardi_Ch08_p0251-p0270.indd 26228/12/18 11:51 AM 263BURNSCHAPTER 8 2. Janzekovic Z. A new concept in the early excision and imme-diate grafting of burns. J Trauma. 1970;10(12):1103-1108. Available at: http://www.ncbi.nlm.nih.gov/pubmed/4921723. Accessed May 7,


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Surgery_Schwartz. 8 2. Janzekovic Z. A new concept in the early excision and imme-diate grafting of burns. J Trauma. 1970;10(12):1103-1108. Available at: http://www.ncbi.nlm.nih.gov/pubmed/4921723. Accessed May 7, 2018. 3. Taylor S, Curri T, Lawless M, Sen S, Greenhalgh DG, Palm-ieri TL. Predicting resource utilization in burn treatment. J Burn Care Res. 2014;35(Suppl 2):S235-S246. doi:10.1097/BCR.0000000000000076 4. Gibran NS; Committee on Organization and Delivery of Burn Care ABA. Practice guidelines for burn care, 2006. J Burn Care Res. 27(4):437-438. doi:10.1097/01.BCR.0000226084.26680.56 5. Supple KG, Fiala SM, Gamelli RL. Preparation for burn cen-ter verification. J Burn Care Rehabil. 1997;18(1 Pt 1):58-60. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9063789. Accessed May 7, 2018. 6. Klein MB, Kramer CB, Nelson J, Rivara FP, Gibran NS, Con-cannon T. Geographic access to burn center hospitals. JAMA. 2009;302(16):1774-1781. doi:10.1001/jama.2009.1548 7. Klein MB, Nathens AB, Emerson D,


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Surgery_Schwartz. MB, Kramer CB, Nelson J, Rivara FP, Gibran NS, Con-cannon T. Geographic access to burn center hospitals. JAMA. 2009;302(16):1774-1781. doi:10.1001/jama.2009.1548 7. Klein MB, Nathens AB, Emerson D, Heimbach DM, Gibran NS. An analysis of the long-distance transport of burn patients to a regional burn center. J Burn Care Res. 2007;28(1):49-55. doi:10.1097/BCR.0B013E31802C894B 8. Stewart BT, Gyedu A, Agbenorku P, Amankwa R, Kushner AL, Gibran N. Routine systemic antibiotic prophylaxis for burn injuries in developing countries: a best evidence topic (BET). Int J Surg. 2015;21:168-172. doi:10.1016/j.ijsu.2015.08.002 9. Kolodny A, Courtwright DT, Hwang CS, et al. The prescrip-tion opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu Rev Public Health. 2015;36: 559-574. doi:10.1146/annurev-publhealth-031914-122957 10. Agarwal V, O’Neill PJ, Cotton BA, et al. Prevalence and risk factors for development of delirium in burn intensive care unit patients. J Burn


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Surgery_Schwartz. 559-574. doi:10.1146/annurev-publhealth-031914-122957 10. Agarwal V, O’Neill PJ, Cotton BA, et al. Prevalence and risk factors for development of delirium in burn intensive care unit patients. J Burn Care Res. 31(5):706-715. doi:10.1097/BCR.0b013e3181eebee9 11. Freiburg C, Igneri P, Sartorelli K, Rogers F. Effects of differ-ences in percent total body surface area estimation on fluid resuscitation of transferred burn patients. J Burn Care Res. 2007;28(1):42-48. doi:10.1097/BCR.0B013E31802C88B2 12. Burn incidence and treatment in the US: 2016 fact sheet. Available at: http://ameriburn.org/who-we-are/media/ burn-incidence-fact-sheet/. Accessed October 29, 2017. 13. Ramati A, Pliskin NH, Keedy S, et al. Alteration in func-tional brain systems after electrical injury. J Neurotrauma. 2009;26(10):1815-1822. doi:10.1089/neu.2008.0867 14. Saffle JR, Crandall A, Warden GD. Cataracts: a long-term complication of electrical injury. J Trauma. 1985;25(1):17-21. Available at:


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Surgery_Schwartz. Neurotrauma. 2009;26(10):1815-1822. doi:10.1089/neu.2008.0867 14. Saffle JR, Crandall A, Warden GD. Cataracts: a long-term complication of electrical injury. J Trauma. 1985;25(1):17-21. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3965734. Accessed May 7, 2018. 15. Arnoldo B, Klein M, Gibran NS. Practice guidelines for the management of electrical injuries. J Burn Care Res. 27(4): 439-447. doi:10.1097/01.BCR.0000226250.26567.4C 16. Gupta P. Fundamentals of Toxicology 1st Edition Essential Con-cepts and Applications. 1st ed. New York: Academic Press; 2016. 17. Steven W. Salyer. Essential Emergency Medicine: For the Healthcare Practitioner. 1st ed. Philadelphia: Saunders; 2007. 18. Chick LR, Borah G. Calcium carbonate gel therapy for hydrofluoric acid burns of the hand. Plast Reconstr Surg. 1990;86(5):935-940. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2236319. Accessed May 7, 2018. 19. Hatzifotis M, Williams A, Muller M, Pegg S. Hydroflu-oric acid burns. Burns.


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Surgery_Schwartz. Reconstr Surg. 1990;86(5):935-940. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2236319. Accessed May 7, 2018. 19. Hatzifotis M, Williams A, Muller M, Pegg S. Hydroflu-oric acid burns. Burns. 2004;30(2):156-159. doi:10.1016/j.burns.2003.09.031 20. Dünser MW, Ohlbauer M, Rieder J, et al. Critical care man-agement of major hydrofluoric acid burns: a case report, review of the literature, and recommendations for therapy. Burns. 2004;30(4):391-398. doi:10.1016/j.burns.2004.01.005 21. Wang X, Zhang Y, Ni L, et al. A review of treatment strat-egies for hydrofluoric acid burns: current status and future prospects. Burns. 2014;40(8):1447-1457. doi:10.1016/j.burns.2014.04.009 22. Dupuytren G DA. Clinical Lectures on Surgery: Delivered at Hotel Dieu. Boston: Carter, Hendee; 1832. 23. Jackson DM. The diagnosis of the depth of burning. Br J Surg. 1953;40(164):588-596. http://www.ncbi.nlm.nih.gov/pubmed/13059343. 24. Watts AM, Tyler MP, Perry ME, Roberts AH, McGrouther DA. Burn depth and its


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Surgery_Schwartz. The diagnosis of the depth of burning. Br J Surg. 1953;40(164):588-596. http://www.ncbi.nlm.nih.gov/pubmed/13059343. 24. Watts AM, Tyler MP, Perry ME, Roberts AH, McGrouther DA. Burn depth and its histological measurement. Burns. 2001;27(2):154-160. http://www.ncbi.nlm.nih.gov/pubmed/11226654. 25. Shin JY, Yi HS. Diagnostic accuracy of laser Doppler imag-ing in burn depth assessment: systematic review and meta-analysis. Burns. 2016;42(7):1369-1376. doi:10.1016/j.burns.2016.03.012 26. Iraniha S, Cinat ME, VanderKam VM, et al. Determination of burn depth with noncontact ultrasonography. J Burn Care Rehabil. 2000;21(4):333-338. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10935815. Accessed May 7, 2018. 27. Zawacki BE, Azen SP, Imbus SH, Chang YT. Multifactorial probit analysis of mortality in burned patients. Ann Surg. 1979;189(1):1-5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/758852. Accessed May 7, 2018. 28. Heng JS, Clancy O, Atkins J, et al. Revised Baux Score and updated


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Surgery_Schwartz. in burned patients. Ann Surg. 1979;189(1):1-5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/758852. Accessed May 7, 2018. 28. Heng JS, Clancy O, Atkins J, et al. Revised Baux Score and updated Charlson comorbidity index are independently asso-ciated with mortality in burns intensive care patients. Burns. 2015;41(7):1420-1427. doi:10.1016/j.burns.2015.06.009 29. Ryan CM, Schoenfeld DA, Thorpe WP, Sheridan RL, Cassem EH, Tompkins RG. Objective estimates of the probability of death from burn injuries. N Engl J Med. 1998;338(6):362-366. doi:10.1056/NEJM199802053380604 30. Moreau AR, Westfall PH, Cancio LC, Mason AD. Develop-ment and validation of an age-risk score for mortality predi-cation after thermal injury. J Trauma. 2005;58(5):967-972. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15920410. Accessed May 7, 2018. 31. Mandell SP, Pham T, Klein MB. Repeat hospitalization and mortality in older adult burn patients. J Burn Care Res. 34(1):e36-41.


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Surgery_Schwartz. burn patients: results of analysis of the nationwide inpatient sample database. J Burn Care Res. 2015; 36(2):258-265. doi:10.1097/BCR.0000000000000064 35. Miller T, Bhattacharya S, Zamula W, et al. Quality-of-life loss of people admitted to burn centers, United States. Qual Life Res. 2013;22(9):2293-2305. doi:10.1007/s11136-012-0321-5 36. Wasiak J, Lee SJ, Paul E, et al. Predictors of health status and health-related quality of life 12 months after severe burn. Burns. 2014;40(4):568-574. doi:10.1016/j.burns.2014.01.021 37. Carrougher GJ, Martinez EM, McMullen KS, et al. Pruritus in adult burn survivors: postburn prevalence and risk factors associated with increased intensity. J Burn Care Res. 2013; 34(1):94-101. doi:10.1097/BCR.0b013e3182644c25 38. Schneider JC, Nadler DL, Herndon DN, et al. Pruritus in pediat-ric burn survivors: defining the clinical course. J Burn Care Res. 2015;36(1):151-158. doi:10.1097/BCR.0000000000000145Brunicardi_Ch08_p0251-p0270.indd 26328/12/18 11:51 AM


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Surgery_Schwartz. al. Pruritus in pediat-ric burn survivors: defining the clinical course. J Burn Care Res. 2015;36(1):151-158. doi:10.1097/BCR.0000000000000145Brunicardi_Ch08_p0251-p0270.indd 26328/12/18 11:51 AM 264BASIC CONSIDERATIONSPART I 39. Mason ST, Esselman P, Fraser R, Schomer K, Truitt A, Johnson K. Return to work after burn injury: a system-atic review. J Burn Care Res. 33(1):101-109. doi:10.1097/BCR.0b013e3182374439 40. Carrougher GJ, Brych SB, Pham TN, Mandell SP, Gibran NS. An intervention bundle to facilitate return to work for burn-injured workers: report from a burn model system investigation. J Burn Care Res. 38(1):e70-e78. doi:10.1097/BCR.0000000000000410 41. Christiansen M, Carrougher GJ, Engrav LH, et al. Time to school re-entry after burn injury is quite short. J Burn Care Res. 2007;28(3):478-481. doi:10.1097/BCR.0B013E318053d2EA 42. American Burn Association. Advanced Burn Life Support Course Provider Manual 2016 Update; 2016. Available at:


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Surgery_Schwartz. is quite short. J Burn Care Res. 2007;28(3):478-481. doi:10.1097/BCR.0B013E318053d2EA 42. American Burn Association. Advanced Burn Life Support Course Provider Manual 2016 Update; 2016. Available at: http://ameriburn.org/education/abls-program/abls-handbook/. Accessed May 7, 2018. 43. Jeng JC, Jablonski K, Bridgeman A, Jordan MH. Serum lac-tate, not base deficit, rapidly predicts survival after major burns. Burns. 2002;28(2):161-166. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11900940. Accessed May 7, 2018. 44. Cochran A, Edelman LS, Saffle JR, Morris SE. The relation-ship of serum lactate and base deficit in burn patients to mor-tality. J Burn Care Res. 2007;28(2):231-240. doi:10.1097/BCR.0B013E318031A1D1 45. Cartotto R, Choi J, Gomez M, Cooper A. A prospective study on the implications of a base deficit during fluid resuscita-tion. J Burn Care Rehabil. 2003;24(2):75-84. doi:10.1097/01.BCR.0000054177.24411.13 46. Andel D, Kamolz L-P, Roka J, et al. Base deficit and lac-tate:


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Surgery_Schwartz. of a base deficit during fluid resuscita-tion. J Burn Care Rehabil. 2003;24(2):75-84. doi:10.1097/01.BCR.0000054177.24411.13 46. Andel D, Kamolz L-P, Roka J, et al. Base deficit and lac-tate: early predictors of morbidity and mortality in patients with burns. Burns. 2007;33(8):973-978. doi:10.1016/j.burns.2007.06.016 47. Venkatesh B, Meacher R, Muller MJ, Morgan TJ, Fraser J. Monitoring tissue oxygenation during resuscitation of major burns. J Trauma. 2001;50(3):485-494. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11265028. Accessed May 7, 2018. 48. Lorente JA, Ezpeleta A, Esteban A, et al. Systemic hemodynam-ics, gastric intramucosal PCO2 changes, and outcome in criti-cally ill burn patients. Crit Care Med. 2000;28(6):1728-1735. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10890610. Accessed May 7, 2018. 49. Holm C, Mayr M, Tegeler J, et al. A clinical randomized study on the effects of invasive monitoring on burn shock resuscitation. Burns. 2004;30(8):798-807.


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Surgery_Schwartz. King DR. Advanced technologies in trauma critical care management. Surg Clin North Am. 2012;92(4):903-923, viii. doi:10.1016/j.suc.2012.04.001Brunicardi_Ch08_p0251-p0270.indd 26428/12/18 11:51 AM 265BURNSCHAPTER 8 72. Gunst M, Sperry J, Ghaemmaghami V, O’Keeffe T, Friese R, Frankel H. Bedside echocardiographic assessment for trauma/critical care: the BEAT exam. J Am Coll Surg. 2008;207(3):e1-3. doi:10.1016/j.jamcollsurg.2008.05.027 73. Yanagawa Y, Sakamoto T, Okada Y. Hypovolemic shock evaluated by sonographic measurement of the inferior vena cava during resuscitation in trauma patients. J Trauma. 2007;63(6):1245-1248; discussion 1248. doi:10.1097/TA.0b013e318068d72b 74. Yarmus L, Feller-Kopman D. Pneumothorax in the criti-cally ill patient. Chest. 2012;141(4):1098-1105. doi:10.1378/chest.11-1691 75. Liu NT, Salinas J. Machine learning in burn care and research: a systematic review of the literature. Burns. 2015;41(8):1636-1641. doi:10.1016/j.burns.2015.07.001 76. Salinas J, Chung


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Surgery_Schwartz. doi:10.1097/BCR.0b013e31818ba14d 165. Gore DC, Chinkes D, Heggers J, Herndon DN, Wolf SE, Desai M. Association of hyperglycemia with increased mor-tality after severe burn injury. J Trauma. 2001;51(3):540-544. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11535907. Accessed May 7, 2018. 166. van den Berghe G, Wouters P, Weekers F, et al. Inten-sive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. doi:10.1056/NEJMoa011300 167. Thomas SJ, Morimoto K, Herndon DN, et al. The effect of prolonged euglycemic hyperinsulinemia on lean body mass after severe burn. Surgery. 2002;132(2):341-347. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12219032. Accessed May 7, 2018. 168. Jeschke MG, Klein D, Herndon DN. Insulin treatment improves the systemic inflammatory reaction to severe trauma. Ann Surg. 2004;239(4):553-560. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15024317. Accessed May 7, 2018. 169. Gore DC, Wolf SE, Sanford A, Herndon DN, Wolfe RR.


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Surgery_Schwartz. reaction to severe trauma. Ann Surg. 2004;239(4):553-560. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15024317. Accessed May 7, 2018. 169. Gore DC, Wolf SE, Sanford A, Herndon DN, Wolfe RR. Influence of metformin on glucose intolerance and Brunicardi_Ch08_p0251-p0270.indd 26728/12/18 11:51 AM 268BASIC CONSIDERATIONSPART Imuscle catabolism following severe burn injury. Ann Surg. 2005;241(2):334-342. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15650645. Accessed May 7, 2018. 170. Pham TN, Neff MJ, Simmons JM, Gibran NS, Heimbach DM, Klein MB. The clinical pulmonary infection score poorly predicts pneumonia in patients with burns. J Burn Care Res. 28(1):76-79. doi:10.1097/BCR.0b013E31802C88DB 171. Barret JP, Desai MH, Herndon DN. Effects of tracheosto-mies on infection and airway complications in pediatric burn patients. Burns. 2000;26(2):190-193. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10716364. Accessed May 7, 2018. 172. Cochran A, Morris SE, Edelman LS, Saffle


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Surgery_Schwartz. complications in pediatric burn patients. Burns. 2000;26(2):190-193. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10716364. Accessed May 7, 2018. 172. Cochran A, Morris SE, Edelman LS, Saffle JR. Systemic Candida infection in burn patients: a case-control study of management patterns and outcomes. Surg Infect (Larchmt). 2002;3(4):367-374. doi:10.1089/109629602762539580 173. Gravvanis AI, Tsoutsos DA, Iconomou TG, Papadopou-los SG. Percutaneous versus conventional tracheostomy in burned patients with inhalation injury. World J Surg. 2005;29(12):1571-1575. doi:10.1007/s00268-005-7905-y 174. Hershberger RC, Hunt JL, Arnoldo BD, Purdue GF. Abdominal compartment syndrome in the severely burned patient. J Burn Care Res. 2007;28(5):708-714. doi:10.1097/BCR.0b013E318148C988 175. Sullivan SR, Ahmadi AJ, Singh CN, et al. Elevated orbital pressure: another untoward effect of massive resuscitation after burn injury. J Trauma. 2006;60(1):72-76.


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Surgery_Schwartz. SR, Ahmadi AJ, Singh CN, et al. Elevated orbital pressure: another untoward effect of massive resuscitation after burn injury. J Trauma. 2006;60(1):72-76. doi:10.1097/01.ta.0000197657.25382.b2 176. Wibbenmeyer LA, Hoballah JJ, Amelon MJ, et al. The preva-lence of venous thromboembolism of the lower extremity among thermally injured patients determined by duplex sonog-raphy. J Trauma. 2003;55(6):1162-1167. doi:10.1097/01.TA.0000057149.42968.1D 177. Wahl WL, Brandt MM, Ahrns KS, et al. Venous thrombosis incidence in burn patients: preliminary results of a prospective study. J Burn Care Rehabil. 23(2):97-102. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11882798. Accessed May 7, 2018. 178. Ahuja RB, Bansal P, Pradhan GS, Subberwal M. An analysis of deep vein thrombosis in burn patients (part II): a random-ized and controlled study of thrombo-prophylaxis with low molecular weight heparin. Burns. 2016;42(8):1693-1698. doi:10.1016/j.burns.2016.08.007 179. Scott JR, Klein MB, Gernsheimer


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Surgery_Schwartz. II): a random-ized and controlled study of thrombo-prophylaxis with low molecular weight heparin. Burns. 2016;42(8):1693-1698. doi:10.1016/j.burns.2016.08.007 179. Scott JR, Klein MB, Gernsheimer T, Honari S, Gibbons J, Gibran NS. Arterial and venous complications of heparin-induced thrombocytopenia in burn patients. J Burn Care Res. 2007;28(1):71-75. doi:10.1097/BCR.0b013E31802C8929 180. Dudeck MA, Weiner LM, Allen-Bridson K, et al. National Healthcare Safety Network (NHSN) report, data summary for 2012, device-associated module. Am J Infect Control. 2013;41(12):1148-1166. doi:10.1016/j.ajic.2013.09.002 181. O’Mara MS, Reed NL, Palmieri TL, Greenhalgh DG. Central venous catheter infections in burn patients with scheduled cath-eter exchange and replacement. J Surg Res. 2007;142(2):341-350. doi:10.1016/j.jss.2007.03.063 182. Engrav LH, Heimbach DM, Reus JL, Harnar TJ, Marvin JA. Early excision and grafting vs. nonoperative treatment of burns of indeterminant depth: a randomized


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Surgery_Schwartz. doi:10.1016/j.jss.2007.03.063 182. Engrav LH, Heimbach DM, Reus JL, Harnar TJ, Marvin JA. Early excision and grafting vs. nonoperative treatment of burns of indeterminant depth: a randomized prospec-tive study. J Trauma. 1983;23(11):1001-1004. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6355500. Accessed May 7, 2018. 183. Thompson P, Herndon DN, Abston S, Rutan T. Effect of early excision on patients with major thermal injury. J Trauma. 1987;27(2):205-207. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3820353. Accessed May 7, 2018. 184. Saaiq M, Zaib S, Ahmad S. Early excision and grafting versus delayed excision and grafting of deep thermal burns up to 40% total body surface area: a comparison of outcome. Ann Burns Fire Disasters. 2012;25(3):143-147. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23467391. Accessed May 7, 2018. 185. Sheridan RL, Tompkins RG. What’s new in burns and metab-olism. J Am Coll Surg. 2004;198(2):243-263.


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Surgery_Schwartz. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23467391. Accessed May 7, 2018. 185. Sheridan RL, Tompkins RG. What’s new in burns and metab-olism. J Am Coll Surg. 2004;198(2):243-263. doi:10.1016/j.jamcollsurg.2003.11.007 186. Klein MB, Hunter S, Heimbach DM, et al. The Versajet water dissector: a new tool for tangential excision. J Burn Care Rehabil. 2005;26(6):483-487. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16278562. Accessed May 7, 2018. 187. Rode H, Martinez R, Potgieter D, Adams S, Rogers AD. Experience and outcomes of micrografting for major pae-diatric burns. Burns. 2017;43(5):1103-1110. doi:10.1016/j.burns.2017.02.008 188. Nyame TT, Chiang HA, Orgill DP. Clinical applications of skin substitutes. Surg Clin North Am. 2014;94(4):839-850. doi:10.1016/j.suc.2014.05.013 189. Kearney JN. Clinical evaluation of skin substitutes. Burns. 2001;27(5):545-551. 190. Compton CC, Gill JM, Bradford DA, Regauer S, Gallico GG, O’Connor NE. Skin regenerated from cultured epithelial


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Surgery_Schwartz. JN. Clinical evaluation of skin substitutes. Burns. 2001;27(5):545-551. 190. Compton CC, Gill JM, Bradford DA, Regauer S, Gallico GG, O’Connor NE. Skin regenerated from cultured epithelial auto-grafts on full-thickness burn wounds from 6 days to 5 years after grafting. A light, electron microscopic and immunohis-tochemical study. Lab Invest. 1989;60(5):600-612. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2469857. Accessed May 7, 2018. 191. Cirodde A, Leclerc T, Jault P, Duhamel P, Lataillade J-J, Bargues L. Cultured epithelial autografts in massive burns: a single-center retrospective study with 63 patients. Burns. 2011;37(6):964-972. doi:10.1016/j.burns.2011.03.011 192. Tredget EE, Levi B, Donelan MB. Biology and principles of scar management and burn reconstruction. Surg Clin North Am. 2014;94(4):793-815. doi:10.1016/j.suc.2014.05.005 193. Parrett BM, Donelan MB. Pulsed dye laser in burn scars: current concepts and future directions. Burns. 2010;36(4): 443-449.


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Surgery_Schwartz. Surg Clin North Am. 2014;94(4):793-815. doi:10.1016/j.suc.2014.05.005 193. Parrett BM, Donelan MB. Pulsed dye laser in burn scars: current concepts and future directions. Burns. 2010;36(4): 443-449. doi:10.1016/j.burns.2009.08.015 194. Cho S Bin, Lee SJ, Chung WS, Kang JM, Kim YK. Treatment of burn scar using a carbon dioxide fractional laser. J Drugs Dermatol. 2010;9(2):173-175. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20214184. Accessed May 7, 2018. 195. Hultman CS, Friedstat JS, Edkins RE, Cairns BA, Meyer AA. Laser resurfacing and remodeling of hypertrophic burn scars: the results of a large, prospective, before-after cohort study, with long-term follow-up. Ann Surg. 2014;260(3):519-29-32. doi:10.1097/SLA.0000000000000893 196. Kwan PO, Tredget EE. Biological principles of scar and contracture. Hand Clin. 2017;33(2):277-292. doi:10.1016/j.hcl.2016.12.004 197. Goverman J, Mathews K, Goldstein R, et al. Adult contrac-tures in burn injury: a burn model system National


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Surgery_Schwartz. of scar and contracture. Hand Clin. 2017;33(2):277-292. doi:10.1016/j.hcl.2016.12.004 197. Goverman J, Mathews K, Goldstein R, et al. Adult contrac-tures in burn injury: a burn model system National Data-base Study. J Burn Care Res. 38(1):e328-e336. doi:10.1097/BCR.0000000000000380 198. Chen H-C, Yang J-Y, Chuang S-S, Huang C-Y, Yang S-Y. Heterotopic ossification in burns: our experience and lit-erature reviews. Burns. 2009;35(6):857-862. doi:10.1016/j.burns.2008.03.002 199. Levi B, Jayakumar P, Giladi A, et al. Risk factors for the devel-opment of heterotopic ossification in seriously burned adults: A National Institute on Disability, Independent Living and Rehabilitation Research burn model system database analysis. J Trauma Acute Care Surg. 2015;79(5):870-876. doi:10.1097/TA.0000000000000838 200. Schneider JC, Simko LC, Goldstein R, et al. Predicting het-erotopic ossification early after burn injuries: a risk scor-ing system. Ann Surg. 2017;266(1):179-184.


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Surgery_Schwartz. doi:10.1097/TA.0000000000000838 200. Schneider JC, Simko LC, Goldstein R, et al. Predicting het-erotopic ossification early after burn injuries: a risk scor-ing system. Ann Surg. 2017;266(1):179-184. doi:10.1097/SLA.0000000000001841 201. Cakir U, Terzi R, Abaci F, Aker T. The prevalence of post-trau-matic stress disorder in patients with burn injuries, and their Brunicardi_Ch08_p0251-p0270.indd 26828/12/18 11:51 AM 269BURNSCHAPTER 8quality of life. Int J Psychiatry Clin Pract. 2015;19(1):56-59. doi:10.3109/13651501.2014.981545 202. Thombs BD, Bresnick MG, Magyar-Russell G. Depression in sur-vivors of burn injury: a systematic review. Gen Hosp Psychiatry. 2006;28(6):494-502. doi:10.1016/j.genhosppsych.2006.08.010 203. Hobbs K. Which factors influence the development of post-traumatic stress disorder in patients with burn injuries? A sys-tematic review of the literature. Burns. 2015;41(3):421-430. doi:10.1016/j.burns.2014.10.018 204. Grant EJ. Burn injuries: prevention, advocacy,


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Surgery_Schwartz. stress disorder in patients with burn injuries? A sys-tematic review of the literature. Burns. 2015;41(3):421-430. doi:10.1016/j.burns.2014.10.018 204. Grant EJ. Burn injuries: prevention, advocacy, and legisla-tion. Clin Plast Surg. 2017;44(3):451-466. doi:10.1016/j.cps.2017.02.005 205. Cox SG, Burahee A, Albertyn R, Makahabane J, Rode H. Parent knowledge on paediatric burn prevention related to the home environment. Burns. 2016;42(8):1854-1860. doi:10.1016/j.burns.2016.05.015 206. Ballesteros MF, Jackson ML, Martin MW. Working toward the elimination of residential fire deaths: the Centers for Dis-ease Control and Prevention’s Smoke Alarm Installation and Fire Safety Education (SAIFE) program. J Burn Care Rehabil. 2005;26(5):434-439. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16151290. Accessed May 7, 2018. 207. DiGuiseppi C, Roberts I, Wade A, et al. Incidence of fires and related injuries after giving out free smoke alarms: cluster ran-domised controlled trial. BMJ.


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Surgery_Schwartz. Accessed May 7, 2018. 207. DiGuiseppi C, Roberts I, Wade A, et al. Incidence of fires and related injuries after giving out free smoke alarms: cluster ran-domised controlled trial. BMJ. 2002;325(7371):995. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12411355. 208. Fallat ME, Rengers SJ. The effect of education and safety devices on scald burn prevention. J Trauma. 1993;34(4): 560-3-4. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 8487342. Accessed May 7, 2018. 209. Cagle KM, Davis JW, Dominic W, Gonzales W. Results of a focused scald-prevention program. J Burn Care Res. 2006; 27(6):859-863. doi:10.1097/01.BCR.0000245423.79531.50 210. Rybarczyk MM, Schafer JM, Elm CM, et al. Prevention of burn injuries in lowand middle-income countries: a sys-tematic review. Burns. 2016;42(6):1183-1192. doi:10.1016/j.burns.2016.04.014 211. Klas KS, Smith SJ, Matherly AF, Dillard BD, Grant EJ, Cusick-Jost J. Multicenter assessment of burn team injury prevention knowledge. J Burn Care Res.


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Surgery_Schwartz. doi:10.1016/j.burns.2016.04.014 211. Klas KS, Smith SJ, Matherly AF, Dillard BD, Grant EJ, Cusick-Jost J. Multicenter assessment of burn team injury prevention knowledge. J Burn Care Res. 2015;36(3):434-439. doi:10.1097/BCR.0000000000000130 212. Conlon KM, Martin S. “Just send them all to a burn centre”: managing burn resources in a mass casualty incident. J Bus Contin Emer Plan. 2011;5(2):150-160. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21835753. Accessed May 7, 2018. 213. Broeze CL, Falder S, Rea S, Wood F. Burn disasters—an audit of the literature. Prehosp Disaster Med. 2010;25(6):555-559. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21181692. Accessed May 7, 2018. 214. ABA Board of Trustees, Committee on Organization and Delivery of Burn Care. Disaster management and the ABA Plan. J Burn Care Rehabil. 2005;26(2):102-106. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15756109. Accessed May 7, 2018. 215. Dai A, Carrougher GJ, Mandell SP, Fudem G, Gibran NS, Pham TN.


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Surgery_Schwartz. ABA Plan. J Burn Care Rehabil. 2005;26(2):102-106. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15756109. Accessed May 7, 2018. 215. Dai A, Carrougher GJ, Mandell SP, Fudem G, Gibran NS, Pham TN. Review of recent large-scale burn disasters world-wide in comparison to preparedness guidelines. J Burn Care Res. 2017;38(1):36-44. doi:10.1097/BCR.0000000000000441 216. Kearns RD, Conlon KM, Valenta AL, et al. Disaster planning: the basics of creating a burn mass casualty disaster plan for a burn center. J Burn Care Res. 2014;35(1):e1-e13. doi:10.1097/BCR.0b013e31829afe25 217. Conlon KM, Ruhren C, Johansen S, et al. Developing and implementing a plan for large-scale burn disaster response in New Jersey. J Burn Care Res. 35(1):e14-20. doi:10.1097/BCR.0b013e3182779b59 218. Wolbarst AB, Wiley AL, Nemhauser JB, Christensen DM, Hen-dee WR. Medical response to a major radiologic emergency: a primer for medical and public health practitioners. Radiology. 2010;254(3):660-677.


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Surgery_Schwartz. AB, Wiley AL, Nemhauser JB, Christensen DM, Hen-dee WR. Medical response to a major radiologic emergency: a primer for medical and public health practitioners. Radiology. 2010;254(3):660-677. doi:10.1148/radiol.09090330 219. Flynn DF, Goans RE. Nuclear terrorism: triage and medical management of radiation and combined-injury casualties. Surg Clin North Am. 2006;86(3):601-636. doi:10.1016/j.suc.2006.03.005 220. DiCarlo AL, Maher C, Hick JL, et al. Radiation injury after a nuclear detonation: medical consequences and the need for scarce resources allocation. Disaster Med Public Health Prep. 2011;5 Suppl 1:S32-S44. doi:10.1001/dmp.2011.17 221. Palmer JL, Deburghgraeve CR, Bird MD, Hauer-Jensen M, Kovacs EJ. Development of a combined radiation and burn injury model. J Burn Care Res. 2011;32(2):317-323. doi:10.1097/BCR.0b013e31820aafa9 222. Barillo DJ, Cancio LC, Goodwin CW. Treatment of white phosphorus and other chemical burn injuries at one burn center over a 51-year period. Burns.


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Surgery_Schwartz. doi:10.1097/BCR.0b013e31820aafa9 222. Barillo DJ, Cancio LC, Goodwin CW. Treatment of white phosphorus and other chemical burn injuries at one burn center over a 51-year period. Burns. 2004;30(5):448-452. doi:10.1016/j.burns.2004.01.032 223. Aviv U, Kornhaber R, Harats M, Haik J. The burning issue of white phosphorus: a case report and review of the literature. Disaster Mil Med. 2017;3:6. doi:10.1186/s40696-017-0034-y 224. Barber RC, Aragaki CC, Chang L-YE, et al. CD14-159 C allele is associated with increased risk of mortality after burn injury. Shock. 2007;27(3):232-237. doi:10.1097/01.shk.0000239770.10528.9a 225. Barber RC, Chang L-YE, Arnoldo BD, et al. Innate immu-nity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res. 2006;4(4):250-255. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17210974. Accessed May 7, 2018. 226. Moore CB, Medina MA, van Deventer HW, et al. Down-regulation of immune signaling genes in patients with large surface burn injury.


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Surgery_Schwartz. Accessed May 7, 2018. 226. Moore CB, Medina MA, van Deventer HW, et al. Down-regulation of immune signaling genes in patients with large surface burn injury. J Burn Care Res. 2007;28(6):879-887. doi:10.1097/BCR.0b013e318159a41e 227. Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13): 2581-2590. doi:10.1084/jem.20111354 228. Klein MB, Silver G, Gamelli RL, et al. Inflammation and the host response to injury: an overview of the multicenter study of the genomic and proteomic response to burn injury. J Burn Care Res. 2006;27(4):448-451. doi:10.1097/01.BCR.0000227477.33877.E6 229. Sood RF, Gibran NS, Arnoldo BD, et al. Early leukocyte gene expression associated with age, burn size, and inhalation injury in severely burned adults. J Trauma Acute Care Surg. 2016;80(2):250-257. doi:10.1097/TA.0000000000000905 230. Godwin Z, Tan J, Bockhold J, Ma J, Tran NK. Development and evaluation of a novel smart device-based application for burn


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Surgery_Schwartz. Acute Care Surg. 2016;80(2):250-257. doi:10.1097/TA.0000000000000905 230. Godwin Z, Tan J, Bockhold J, Ma J, Tran NK. Development and evaluation of a novel smart device-based application for burn assessment and management. Burns. 2015;41(4): 754-760. doi:10.1016/j.burns.2014.10.006 231. Barnes J, Duffy A, Hamnett N, et al. The Mersey Burns App: evolving a model of validation. Emerg Med J. 2015;32(8): 637-641. doi:10.1136/emermed-2013-203416 232. Wurzer P, Parvizi D, Lumenta DB, et al. Smartphone appli-cations in burns. Burns. 2015;41(5):977-989. doi:10.1016/j.burns.2014.11.010Brunicardi_Ch08_p0251-p0270.indd 26928/12/18 11:51 AM


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Surgery_Schwartz. Wound HealingMunier Nazzal, Mohamed F. Osman, Heitham Albeshri, Darren B. Abbas, and Carol A. Angel 9chapterHISTORY OF WOUND HEALINGThe earliest accounts of wound healing date back to about 2000 b.c., when the Sumerians employed two modes of treatment: a spiritual method consisting of incantations, and a physical method of applying poultice-like materials to the wound. The Egyptians were the first to differentiate between infected and diseased wounds compared to noninfected wounds. The 1650 b.c. Edwin Smith Surgical Papyrus, a copy of a much older document, describes at least 48 different types of wounds. A later document (Ebers Papyrus, 1550 b.c.) relates the use of con-coctions containing honey (antibacterial properties), lint (absor-bent properties), and grease (barrier) for treating wounds. These same properties are still considered essential in contemporary daily wound management.The Greeks, equipped with the knowledge bequeathed by the Egyptians, went even further and classified


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Surgery_Schwartz. These same properties are still considered essential in contemporary daily wound management.The Greeks, equipped with the knowledge bequeathed by the Egyptians, went even further and classified wounds as acute or chronic in nature. Galen of Pergamum (120–201 a.d.), appointed as the doctor to the Roman gladiators, had an enormous number of wounds to deal with following gladiato-rial combats. He emphasized the importance of maintaining a moist environment to ensure adequate healing. It took almost 19 centuries for this important concept to be proven scientifi-cally, when it was shown that the epithelialization rate increases by 50% in a moist wound environment when compared to a dry wound environment.1The next major stride in the history of wound heal-ing was the discovery of antiseptics and their importance in reducing wound infections. Ignaz Philipp Semmelweis, a Hungarian obstetrician (1818–1865), noted that the inci-dence of puerperal fever was much lower if medical students,


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Surgery_Schwartz. and their importance in reducing wound infections. Ignaz Philipp Semmelweis, a Hungarian obstetrician (1818–1865), noted that the inci-dence of puerperal fever was much lower if medical students, following cadaver-dissection class and prior to attending child-birth, washed their hands with soap and hypochlorite. Louis Pasteur (1822–1895) was instrumental in dispelling the theory of spontaneous generation of germs and proving that germs existed in and were always introduced from the environment. Joseph Lister probably made one of the most significant con-tributions to wound healing. On a visit to Glasgow, Scotland, Lister noted that some areas of the city’s sewer system were less murky than the rest. He discovered that the water from pipes that were dumping waste containing carbolic acid (phenol) was clear. In 1865, Lister began soaking his surgical instruments in phenol and spraying the operating rooms, reducing the post-operative mortality rates from 50% to 15%. After attending an


Surgery_Schwartz

Surgery_Schwartz. (phenol) was clear. In 1865, Lister began soaking his surgical instruments in phenol and spraying the operating rooms, reducing the post-operative mortality rates from 50% to 15%. After attending an impressive lecture by Lister in 1876, Robert Wood Johnson left the meeting and began 10 years of research that would ulti-mately result in the production of an antiseptic dressing in the form of cotton gauze impregnated with iodoform. Since then, several other materials have been used to impregnate cotton gauze to achieve antisepsis.The 1960s and 1970s led to the development of polymeric dressings. These polymeric dressings can be custom made to specific parameters, such as permeability to gases (occlusive vs. semi-occlusive), varying degrees of absorbency, and different physical forms. Due to the ability to customize, the available range of materials that aid in wound care has grown exponen-tially to include an ever-expanding variety. Currently, the prac-tice of wound healing encompasses


Surgery_Schwartz

Surgery_Schwartz. the ability to customize, the available range of materials that aid in wound care has grown exponen-tially to include an ever-expanding variety. Currently, the prac-tice of wound healing encompasses manipulation and/or use of, among others, inflammatory cytokines, growth factors, and bio-engineered tissue. It is the combination of all these modali-ties that enables optimal wound healing. The role of organism in the perpetuation of nonhealing of chronic wounds 1History of Wound Healing 271Phases of Wound Healing 272Hemostasis and Inflammation / 272Proliferation / 273Matrix Synthesis / 274Maturation and Remodeling / 275Epithelialization / 275Role of Growth Factors in Normal Healing / 276Wound Contraction / 276Heritable Diseases of Connective Tissue 276Ehlers-Danlos Syndrome / 276Osteogenesis Imperfecta / 278Epidermolysis Bullosa / 279Acrodermatitis Enteropathica / 279Healing in Specific Tissues 279Gastrointestinal Tract / 279Bone / 280Cartilage / 281Tendon / 281Nerve / 281Fetal Wound


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Surgery_Schwartz. Imperfecta / 278Epidermolysis Bullosa / 279Acrodermatitis Enteropathica / 279Healing in Specific Tissues 279Gastrointestinal Tract / 279Bone / 280Cartilage / 281Tendon / 281Nerve / 281Fetal Wound Healing / 281Classification of Wounds 282Factors Affecting Wound Healing / 283Chronic Wounds / 289Excess Healing 291Treatment of Wounds 294Local Care / 294Antibiotics / 295Dressings / 295Skin Replacements / 296Cellular and Tissue-Based Products in Chronic Wound and Ulcer Management / 297Oxygen Therapy in Wound Healing / 299Biofilm and Chronic Wound Healing / 299Brunicardi_Ch09_p0271-p0304.indd 27101/03/19 4:49 PM 272has been better understood. Although wounds are classified under one entity, it is believed that they behave differently based on the host and organism involved. The future of wound healing is in “precision medicine” in which treatment strategies will be based on the host, the underlying mechanism, and the organisms in the wound bed and tissue.PHASES OF WOUND HEALINGWound


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Surgery_Schwartz. wound healing is in “precision medicine” in which treatment strategies will be based on the host, the underlying mechanism, and the organisms in the wound bed and tissue.PHASES OF WOUND HEALINGWound healing is a complex process of overlapping phases that is initiated by an injury or wound. Normal wound healing is divided into phases defined by characteristic cellular popula-tions and biochemical activities: (a) hemostasis and inflammation, (b) proliferation, and (c) maturation and remodeling. An approximate timeline of these events is depicted in Fig. 9-1. This sequence of events in most circumstances spans the time from injury to resolution of acute wounds. All wounds need to progress through this series of cellular and biochemical events that characterize the phases of healing in order to suc-cessfully reestablish tissue integrity. However, multiple factors can interfere with this sequence and can lead to lengthy healing (chronic wounds) or nonhealing.Hemostasis and


Surgery_Schwartz

Surgery_Schwartz. in order to suc-cessfully reestablish tissue integrity. However, multiple factors can interfere with this sequence and can lead to lengthy healing (chronic wounds) or nonhealing.Hemostasis and InflammationHemostasis precedes and initiates inflammation with the ensuing release of chemotactic factors from the wound site (Fig. 9-2A). Wounding by definition disrupts tissue integrity, leading to divi-sion of blood vessels and direct exposure of extracellular matrix to platelets. Exposure of subendothelial collagen to platelets results in platelet aggregation, degranulation, and activation of the coagulation cascade. Platelet α granules release a number of wound-active substances, such as platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), platelet-activating factor (PAF), fibronectin, and serotonin. In addition to achieving hemostasis, the fibrin clot serves as scaffolding for the migration into the wound of inflammatory cells such as poly-morphonuclear leukocytes


Surgery_Schwartz

Surgery_Schwartz. fibronectin, and serotonin. In addition to achieving hemostasis, the fibrin clot serves as scaffolding for the migration into the wound of inflammatory cells such as poly-morphonuclear leukocytes (PMNs, neutrophils) and monocytes.Cellular infiltration after injury follows a character-istic, predetermined sequence (see Fig. 9-1). PMNs are the 2first infiltrating cells to enter the wound site, peaking at 24 to 48 hours. Increased vascular permeability, local prostaglan-din release, and the presence of chemotactic substances such as complement factors, interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), TGF-β, platelet factor 4, or bacterial prod-ucts all stimulate neutrophil migration.The postulated primary role of neutrophils is phagocytosis of bacteria and tissue debris. PMNs are also a major source of cytokines early during inflammation, especially TNF-α3 which may have a significant influence on subsequent angiogenesis and collagen synthesis (see Fig. 9-2B). PMNs also release


Surgery_Schwartz

Surgery_Schwartz. a major source of cytokines early during inflammation, especially TNF-α3 which may have a significant influence on subsequent angiogenesis and collagen synthesis (see Fig. 9-2B). PMNs also release pro-teases such as collagenases, which participate in matrix and ground substance degradation in the early phase of wound heal-ing. Other than their role in limiting infections, these cells do not appear to play a role in collagen deposition or acquisition of mechanical wound strength. On the contrary, neutrophil fac-tors have been implicated in delaying the epithelial closure of wounds.4The second population of inflammatory cells that invades the wound consists of macrophages, which are recognized as being essential to successful healing.5 Derived from circulat-ing monocytes, macrophages achieve significant numbers in the wound by 48 to 96 hours post injury and remain present until wound healing is complete.Macrophages, like neutrophils, participate in wound debridement via phagocytosis and


Surgery_Schwartz

Surgery_Schwartz. significant numbers in the wound by 48 to 96 hours post injury and remain present until wound healing is complete.Macrophages, like neutrophils, participate in wound debridement via phagocytosis and contribute to microbial stasis via oxygen radical and nitric oxide synthesis (see Fig. 9-2B,C). The macrophage’s central function is activation and recruitment of other cells via mediators such as cytokines and growth fac-tors, as well as directly by cell-cell interaction and intercellular adhesion molecules (ICAM). By releasing such mediators as TGF-β, vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), epithelial growth factor (EGF), and lac-tate, macrophages regulate cell proliferation, matrix synthesis, and angiogenesis.6,7 Macrophages also play a significant role in regulating angiogenesis and matrix deposition and remodeling (Table 9-1).T lymphocytes comprise another population of inflam-matory/immune cells that routinely invades the wound. Less Key


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Surgery_Schwartz. role in regulating angiogenesis and matrix deposition and remodeling (Table 9-1).T lymphocytes comprise another population of inflam-matory/immune cells that routinely invades the wound. Less Key Points1 Wound healing is a complex cellular and biochemical cascade that leads to restitution of integrity and function.2 All tissues heal by similar mechanisms, and the process undergoes phases of inflammation, cellular migration, pro-liferation, matrix deposition, and remodeling.3 Factors that impede normal healing include local, systemic, and technical conditions that the surgeon must take into account.4 Clinically, excess healing can be as significant a problem as impaired healing; genetic, technical, and local factors play a major role.5 Optimal outcome of acute wounds relies on complete eval-uation of the patient and of the wound and application of best practices and techniques.6 Antibiotics should be used only in the presence of infec-tion; colonization and contamination does not mean


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Surgery_Schwartz. of the patient and of the wound and application of best practices and techniques.6 Antibiotics should be used only in the presence of infec-tion; colonization and contamination does not mean there is infection.7 Dressing should facilitate the major changes taking place during healing to produce an optimally healed wound and take into consideration the comorbid conditions associated with chronic wounds.8 Cellular and tissue-based products are additional mea-sures, and these products might accelerate the rate of heal-ing but will not replace basic wound care.9 Chronic wounds have a decrease in oxygen supply to the wound, which contributes to delayed healing; oxygen therapy might aid in the healing of certain types of wounds.10 Biofilm is the term used for the bacterial growth on a chronic wound that is encapsulated by a protective layer made up of the host and bacterial proteins; this layer makes it difficult to heal chronic wounds and control infection.Brunicardi_Ch09_p0271-p0304.indd


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Surgery_Schwartz. that is encapsulated by a protective layer made up of the host and bacterial proteins; this layer makes it difficult to heal chronic wounds and control infection.Brunicardi_Ch09_p0271-p0304.indd 27201/03/19 4:49 PM 273WOUND HEALINGCHAPTER 9numerous than macrophages, T-lymphocyte numbers peak at about 1 week post injury and truly bridge the transition from the inflammatory to the proliferative phase of healing. Though known to be essential to wound healing, the role of lymphocytes in wound healing is not fully defined.8 A significant body of data supports the hypothesis that T lymphocytes play an active role in the modulation of the wound environment. Depletion of most wound T lymphocytes decreases wound strength and col-lagen content,9 while selective depletion of the CD8+ suppressor subset of T lymphocytes enhances wound healing. However, depletion of the CD4+ helper subset has no effect.10 Lympho-cytes also exert a downregulating effect on fibroblast collagen synthesis by


Surgery_Schwartz

Surgery_Schwartz. subset of T lymphocytes enhances wound healing. However, depletion of the CD4+ helper subset has no effect.10 Lympho-cytes also exert a downregulating effect on fibroblast collagen synthesis by cell-associated interferon IFN-γ, TNF-α, and IL-1. This effect is lost if the cells are physically separated, suggest-ing that extracellular matrix synthesis is regulated not only via soluble factors but also by direct cell-cell contact between lym-phocytes and fibroblasts.11ProliferationThe proliferative phase is the second phase of wound healing and roughly spans days 4 through 12 (see Fig. 9-2C). It is dur-ing this phase that tissue continuity is reestablished. Fibroblasts and endothelial cells are the last cell populations to infiltrate the healing wound, and the strongest chemotactic factor for fibroblasts is PDGF.12,13 Upon entering the wound environment, recruited fibroblasts first need to proliferate, and then become activated, to carry out their primary function of matrix synthesis


Surgery_Schwartz

Surgery_Schwartz. for fibroblasts is PDGF.12,13 Upon entering the wound environment, recruited fibroblasts first need to proliferate, and then become activated, to carry out their primary function of matrix synthesis remodeling. This activation is mediated mainly by the cytokines and growth factors released from wound macrophages.Fibroblasts isolated from wounds synthesize more colla-gen than nonwound fibroblasts, they proliferate less, and they actively carry out matrix contraction. Although it is clear that the cytokine-rich wound environment plays a significant role in this phenotypic alteration and activation, the exact mediators are only partially characterized.14,15 Additionally, lactate, which accumulates in significant amounts in the wound environment over time (∼10 mmol), is a potent regulator of collagen syn-thesis through a mechanism involving adenosine diphosphate (ADP)-ribosylation.16,17Endothelial cells also proliferate extensively during this phase of healing. These cells participate in


Surgery_Schwartz

Surgery_Schwartz. collagen syn-thesis through a mechanism involving adenosine diphosphate (ADP)-ribosylation.16,17Endothelial cells also proliferate extensively during this phase of healing. These cells participate in the formation of new capillaries (angiogenesis), a process essential to successful wound healing. Endothelial cells migrate from intact venules close to the wound. Their migration, replication, and new capil-lary tubule formation is under the influence of such cytokines and growth factors as TNF-α, TGF-β, and VEGF. Although Figure 9-1. The cellular, biochemical, and mechanical phases of wound healing.Phases of healing0246810121416MaturationProliferationInflammationmonths0246810121416Relative number of cellsNeutrophilsMacrophagesFibroblastsLymphocytes0246810121416Relative amount ofmatrix synthesisDays postwoundingCollagen ICollagen IIIWound-breakingstrengthFibronectinBrunicardi_Ch09_p0271-p0304.indd 27301/03/19 4:50 PM 274BASIC CONSIDERATIONSPART Imany cells produce VEGF, macrophages


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Surgery_Schwartz. postwoundingCollagen ICollagen IIIWound-breakingstrengthFibronectinBrunicardi_Ch09_p0271-p0304.indd 27301/03/19 4:50 PM 274BASIC CONSIDERATIONSPART Imany cells produce VEGF, macrophages represent a major source in the healing wound, and VEGF receptors are located specifically on endothelial cells.18,19Matrix SynthesisBiochemistry of Collagen. Collagen, the most abundant pro-tein in the body, plays a critical role in the successful comple-tion of adult wound healing. Its deposition, maturation, and subsequent remodeling are essential to the functional integrity of the wound.Although there are at least 18 types of collagen described, the main ones of interest to wound repair are types I and III. Type I collagen is the major component of extracellular matrix in skin. Type III, which is also normally present in skin, becomes more prominent and important during the repair process.Biochemically, each chain of collagen is composed of a glycine residue in every third position. The second


Surgery_Schwartz

Surgery_Schwartz. normally present in skin, becomes more prominent and important during the repair process.Biochemically, each chain of collagen is composed of a glycine residue in every third position. The second position in the triplet is made up of proline or lysine during the translation process. The polypeptide chain that is translated from mRNA contains approximately 1000 amino acid residues and is called protocollagen. Release of protocollagen into the endoplasmic reticulum results in the hydroxylation of proline and lysine by specific hydroxylases (Fig. 9-3). Prolyl hydroxylase requires oxygen and iron as cofactors, α-ketoglutarate as co-substrate, and ascorbic acid (vitamin C) as an electron donor. In the endo-plasmic reticulum, the protocollagen chain is also glycosylated by the linking of galactose and glucose at specific hydroxyly-sine residues. These steps of hydroxylation and glycosylation alter the hydrogen bonding forces within the chain, imposing steric changes that force the


Surgery_Schwartz

Surgery_Schwartz. of galactose and glucose at specific hydroxyly-sine residues. These steps of hydroxylation and glycosylation alter the hydrogen bonding forces within the chain, imposing steric changes that force the protocollagen chain to assume an α-helical configuration. Three α-helical chains entwine to form a right-handed superhelical structure called procollagen. At both ends, this structure contains nonhelical peptide domains called registration peptides. Although initially joined by weak, ionic bonds, the procollagen molecule becomes much stronger by the covalent cross-linking of lysine residues.Extracellularly, the nonhelical registration peptides are cleaved by a procollagen peptidase, and the procollagen strands undergo further polymerization and cross-linking. The resulting collagen monomer is further polymerized and cross-linked by the formation of intraand intermolecular covalent bonds.Collagen synthesis, as well as posttranslational modifica-tions, are highly dependent on systemic


Surgery_Schwartz

Surgery_Schwartz. is further polymerized and cross-linked by the formation of intraand intermolecular covalent bonds.Collagen synthesis, as well as posttranslational modifica-tions, are highly dependent on systemic factors such as an adequate oxygen supply; the presence of sufficient nutrients (amino acids and carbohydrates) and cofactors (vitamins and trace metals); and the local wound environment (vascular supply and lack of infection). Addressing these factors and reversing nutritional defi-ciencies can optimize collagen synthesis and deposition.Proteoglycan Synthesis. Glycosaminoglycans comprise a large portion of the “ground substance” that makes up granula-tion tissue. Rarely found free, they couple with proteins to form proteoglycans. The polysaccharide chain is made up of repeat-ing disaccharide units composed of glucuronic or iduronic acid and a hexosamine, which is usually sulfated. The disaccharide


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Surgery_Schwartz. to form proteoglycans. The polysaccharide chain is made up of repeat-ing disaccharide units composed of glucuronic or iduronic acid and a hexosamine, which is usually sulfated. The disaccharide EpidermisFibrinPlateletsClotNeutrophilsLymphocytesScabCollagenMacrophageEndothelialbudsDisruptedblood vesselRed bloodcellsDermisABCEpidermisDermisEpidermisDermisFibroblastFigure 9-2. The phases of wound healing viewed histologically. A. The hemostatic/inflammatory phase. B. Latter inflammatory phases reflecting infiltration by mononuclear cells and lympho-cytes. C. The proliferative phase, with associated angiogenesis and collagen synthesis.Table 9-1Macrophage activities during wound healingACTIVITYMEDIATORSPhagocytosisReactive oxygen speciesNitric oxideDebridementCollagenase, elastaseCell recruitment and activationGrowth factors: PDGF, TGF-β, EGF, IGFCytokines: TNF-α, IL-1, IL-6FibronectinMatrix synthesisGrowth factors: TGF-β, EGF, PDGFCytokines: TNF-α, IL-1, IFN-γEnzymes: arginase,


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Surgery_Schwartz. recruitment and activationGrowth factors: PDGF, TGF-β, EGF, IGFCytokines: TNF-α, IL-1, IL-6FibronectinMatrix synthesisGrowth factors: TGF-β, EGF, PDGFCytokines: TNF-α, IL-1, IFN-γEnzymes: arginase, collagenaseProstaglandinsNitric oxideAngiogenesisGrowth factors: FGF, VEGFCytokines: TNF-αNitric oxideEGF = epithelial growth factor; FGF = fibroblast growth factor; IGF = insulin-like growth factor; IFN-γ = interferon-γ; IL = interleukin; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.Brunicardi_Ch09_p0271-p0304.indd 27401/03/19 4:50 PM 275WOUND HEALINGCHAPTER 9composition of proteoglycans varies from about 10 units in the case of heparin sulfate to as much as 2000 units in the case of hyaluronic acid.The major glycosaminoglycans present in wounds are dermatan and chondroitin sulfate. Fibroblasts synthesize these compounds, increasing their concentration greatly during the first 3


Surgery_Schwartz

Surgery_Schwartz. hyaluronic acid.The major glycosaminoglycans present in wounds are dermatan and chondroitin sulfate. Fibroblasts synthesize these compounds, increasing their concentration greatly during the first 3 weeks of healing. The interaction between collagen and proteoglycans is being actively studied. It is thought that the assembly of collagen subunits into fibrils and fibers is depen-dent upon the lattice provided by the sulfated proteoglycans. Furthermore, it appears that the extent of sulfation is critical in determining the configuration of the collagen fibrils. As scar collagen is deposited, the proteoglycans are incorporated into the collagen scaffolding. However, with scar maturation and collagen remodeling, the content of proteoglycans gradually diminishes.Maturation and RemodelingThe maturation and remodeling of the scar begins during the fibroplastic phase and is characterized by a reorganization of previously synthesized collagen. Collagen is broken down by matrix


Surgery_Schwartz

Surgery_Schwartz. RemodelingThe maturation and remodeling of the scar begins during the fibroplastic phase and is characterized by a reorganization of previously synthesized collagen. Collagen is broken down by matrix metalloproteinases (MMPs), and the net wound collagen content is the result of a balance between collagenolysis and collagen synthesis. There is a net shift toward collagen synthesis and eventually the reestablishment of extracellular matrix com-posed of a relatively acellular collagen-rich scar.Wound strength and mechanical integrity in the fresh wound are determined by both the quantity and quality of the newly deposited collagen. The deposition of matrix at the wound site follows a characteristic pattern: fibronectin and collagen type III constitute the early matrix scaffolding; glycosamino-glycans and proteoglycans represent the next significant matrix components; and collagen type I is the final matrix. By several weeks post injury, the amount of collagen in the wound reaches a


Surgery_Schwartz

Surgery_Schwartz. and proteoglycans represent the next significant matrix components; and collagen type I is the final matrix. By several weeks post injury, the amount of collagen in the wound reaches a plateau, but the tensile strength continues to increase for sev-eral more months.20 Fibril formation and fibril cross-linking result in decreased collagen solubility, increased strength, and increased resistance to enzymatic degradation of the collagen matrix. Fibrillin, a glycoprotein secreted by fibroblasts, is essen-tial for the formation of elastic fibers found in connective tis-sue. Scar remodeling continues for many (6 to 12) months post injury, gradually resulting in a mature, avascular, and acellular scar. The mechanical strength of the scar never achieves that of the uninjured tissue.There is a constant turnover of collagen in the extracellular matrix, both in the healing wound as well as during normal tissue homeostasis. Collagenolysis is the result of collagenase activity, a class of MMPs


Surgery_Schwartz

Surgery_Schwartz. constant turnover of collagen in the extracellular matrix, both in the healing wound as well as during normal tissue homeostasis. Collagenolysis is the result of collagenase activity, a class of MMPs that require activation. Both collagen synthesis and lysis are strictly controlled by cytokines and growth factors. Some factors affect both aspects of collagen remodeling. For example, TGF-β increases new collagen transcription and also decreases collagen breakdown by stimulating synthesis of tis-sue inhibitors of metalloproteinase.21 This balance of collagen deposition and degradation is the ultimate determinant of wound strength and integrity.EpithelializationEpithelialization is the final step in establishing tissue integrity. This process is characterized primarily by proliferation and migration of epithelial cells adjacent to the wound (Fig. 9-4). The process begins within 1 day of injury and is seen as thicken-ing of the epidermis at the wound edge. Marginal basal cells at the edge


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Surgery_Schwartz. of epithelial cells adjacent to the wound (Fig. 9-4). The process begins within 1 day of injury and is seen as thicken-ing of the epidermis at the wound edge. Marginal basal cells at the edge of the wound lose their firm attachment to the underly-ing dermis, enlarge, and begin to migrate across the surface of the provisional matrix. Fixed basal cells in a zone near the cut edge undergo a series of rapid mitotic divisions, and these cells appear to migrate by moving over one another in a leapfrog fashion until the defect is covered.22 Once the defect is bridged, the migrating epithelial cells lose their flattened appearance, become more columnar in shape, and increase their mitotic activity. Layering of the epithelium is reestablished, and the surface layer eventually keratinizes.23LysyloxidaseALDOL condensationCollagen genesPre-mRNAmRNA transcriptionmRNA processingmRNA translationOHOHTriple helix formationRibosomeon roughendoplasmicreticulumGolgiSecretory vesicleCell membraneProline


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Surgery_Schwartz. condensationCollagen genesPre-mRNAmRNA transcriptionmRNA processingmRNA translationOHOHTriple helix formationRibosomeon roughendoplasmicreticulumGolgiSecretory vesicleCell membraneProline and Lysine hydroxylationCollagen mRNASyndesineAldimineCH OCH OH OH OHOHOProcollagen peptidaseExtracellular space˜-1˜-1˜-2NonenzymaticNH2CCCCFigure 9-3. The steps of collagen synthesis. mRNA = messenger RNA.Brunicardi_Ch09_p0271-p0304.indd 27501/03/19 4:50 PM 276BASIC CONSIDERATIONSPART IReepithelialization is complete in less than 48 hours in the case of approximated incised wounds but may take sub-stantially longer in the case of larger wounds, where there is a significant epidermal/dermal defect. If only the epithelium and superficial dermis are damaged, such as occurs in split-thickness skin graft donor sites or in superficial second-degree burns, then repair consists primarily of reepithelialization with minimal or no fibroplasia and granulation tissue formation. The


Surgery_Schwartz

Surgery_Schwartz. skin graft donor sites or in superficial second-degree burns, then repair consists primarily of reepithelialization with minimal or no fibroplasia and granulation tissue formation. The stimuli for reepithelialization remain incompletely defined; however, it appears that the process is mediated by a combination of a loss of contact inhibition; exposure to constituents of the extracel-lular matrix, particularly fibronectin; and cytokines produced by immune mononuclear cells.24,25 In particular EGF, TGF-β, basic fibroblast growth factor (bFGF), PDGF, and IGF-1 have been shown to promote epithelialization.Role of Growth Factors in Normal HealingGrowth factors and cytokines are polypeptides produced in nor-mal and wounded tissue that stimulate cellular migration, pro-liferation, and function. They often are named for the cells from which they were first derived (e.g., platelet-derived growth fac-tor, PDGF) or for their initially identified function (e.g., fibro-blast growth factor, FGF).


Surgery_Schwartz

Surgery_Schwartz. They often are named for the cells from which they were first derived (e.g., platelet-derived growth fac-tor, PDGF) or for their initially identified function (e.g., fibro-blast growth factor, FGF). These names are often misleading because growth factors have been demonstrated to have mul-tiple functions. Most growth factors are extremely potent and produce significant effects in nanomolar concentrations.They may act in an autocrine manner (where the growth factor acts on the cell producing it), a paracrine manner (by release into the extracellular environment, where it acts on the immediately neighboring cells), or in an endocrine manner (where the effect of the substance is distant to the site of release, and the substance is carried to the effector site through the blood stream). In addition to the concentration of the growth factor, the timing of release is as important to determine their effective-ness. As these growth factors exert their effects by cell-surface receptor binding,