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Published Online: 5 December 2018

Patterns of Death in Patients with Sepsis and the Use of Hydrocortisone, Ascorbic Acid, and Thiamine to Prevent These Deaths

Publication: Surgical Infections
Volume 19, Issue Number 8

Abstract

Background: In general, patients with sepsis die from the host response to the infecting pathogen rather than from the infecting pathogen itself. Four patterns of death have been identified in sepsis, namely vasoplegic shock, single-organ respiratory failure (acute respiratory distress syndrome [ARDS]), multi-system organ failure (MSOF), and persistent MSOF with ongoing inflammation and immunosuppression with recurrent infections (persistent inflammation-immunosuppression and catabolism syndrome [PICS]). To improve the outcome of sepsis adjunctive therapies that modulate the immune system have been tested; these therapies that have targeted specific molecules or pathways have universally failed.
Conclusion: We propose that the combination of hydrocortisone, intravenous ascorbic acid, and thiamine (HAT therapy), which synergistically targets multiple pathways, restores the dysregulated immune system and organ injury, and reduces the risk of death and organ failure following sepsis.

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References

1. Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 2016;193:259–272.
2. Gaieski DF, Edwards JM, Kallan MJ, et al. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 2013;41:1167–1174.
3. Stevenson EK, Rubenstein AR, Radin GT, et al. Two decadesof mortality trends among patients with severe sepsis: A comparative meta-analysis. Crit Care Med 2014;42:625–631.
4. Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 2014;311:1308–1316.
5. Torio CM, Moore B1J. National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013: Statistical Brief #240. Healthcare Costs and Utilization Project (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research and Quality. 2016.
6. Tenhunen JJ. In death, truth lies: Why do patients with sepsis die? Anesth Analg 2009;108:1731–1733.
7. Vincent JL, Nelson DR, Williams MD. Is worsening multiple organ fialure the cuase of death in patients with severe sepsis? Crit Care Med 2011;39:1050–1055.
8. Sweeney TE, Azad TJ, Donato M, et al. Unsupervised analysis of transcriptomics in bacterial sepsis across multiple datasets reveals three robust clusters. Crit Care Med 2018;46:915–992.
9. Villar J, Martinez D, Mosteiro F, et al. Is overall mortality the right composite endpoint in clinical trials of acute respiratory distress syndrome. Crit Care Med 2018; 46:892–899.
10. Landry DW, Oliver JA. Pathogenesis of vasodilatory shock. N Engl J Med 2001;345:588–595.
11. Jentzer JC, Vallabhajosyula S, Khanna AK, et al. Management of refractory vasodilatory shock. Chest 2018;S0012-3692:30072-2.
12. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334–1349.
13. Mac Sweeney R, McAuley DF. Acute respiratory distress syndrome. Lancet 2016;388:2416–2430.
14. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707–710.
15. Mira JC, Gentile LF, Mathias BJ, et al. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit Care Med 2017;45:253–262.
16. Torgersen C, Moser P, Luckner G, et al. Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis. Anesth Analg 2009;108:1841–1847.
17. Frencken JF, van Vught LA, Peelen LM, et al. An unbalanced inflammatory cytokine response is not associated with mortality following sepsis: A prospective cohort study. Crit Care Med 2017;45:e493–e499.
18. Weiss SL, Balamuth F, Hensley J, et al. The epidemiology of hospital death following severe sepsis: When, why, and how children with sepsis die. Pediatr Crit Care Med 2017;18:823–830.
19. Calvano SE, Xiao W, Richards DR, et al. A network-based analysis of systemic inflammation in humans. Nature 2005;437:1032–1037.
20. Tang BM, Huang SJ, McLean AS. Genome-wide transcription profiling of human sepsis: A systematic review. Crit Care 2010;14:R237.
21. Carcamo JM, Pedraza A, Borquez-Ojeda O, et al. Vitamin C suppresses TNF-alpha induced NFkB activation by inhibiting IkB-alpha phosphorylation. Biochem 2002;41:12995–3002.
22. Kim SR, Kim YM, Park EJ, et al. Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals. Biochem Pharmacol 2015;95:279–289.
23. Hattori M, Yamazaki M, Ohashi W, et al. Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis. Intensive Care Med Exp 2016;4:36.
24. Hagel AF, Layritz CM, Hagel WH, et al. Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases. Naunyn-Schmiedebergs Arch Pharmacol 2013;386:789–793.
25. May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal 2013;19:2068–2083.
26. Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care 2014;18:460.
27. Beltramo E, Berrone E, Buttiglieri S, et al. Thiamine and benfotiamine prevent increased apoptosis in endothelial cells and pericytes cultured in high glucose. Diabetes Metab Res Rev 2004;20:330–336.
28. de Andrade JA, Gayer CR, Nogueira NP, et al. The effect of thiamine deficiency on inflammation, oxidative stress and cellular migration in an experimental model of sepsis. J Inflamm 2014;11:11.
29. Barabutis N, Khangoora V, Marik PE, et al. Hydrocortisone and ascorbic acid synergistically protect and repair lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Chest 2017;152:954–962.
30. Azari O, Kheirandish R, Azizi S, et al. Protective effects of hydrocortisone, vitamin C and E alone or in combination against renal-ischemia-reperfusion injury rat. Iran J Pathol 2015;10:272–280.
31. Tavasoli M, Azari O, Kheirandish R. Evaluation of combination therapy with hydrocortisone, vitamin C and vitamin E in a rat model of intestine ischemia-reperfusion injury. Comp Clin Pathol 2018;27:439–443.
32. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589–1596.
33. Boyer A, Vargas F, Coste F, et al. Influence of surgical treatment timing on mortality from necrotizing soft tissue infections requiring intensive care management. Intensive Care Med 2009;35:847–853.
34. Marik P, Bellomo R. A rational apprach to fluid therapy in sepsis. Br J Anaesth 2016;116:339–349.
35. Marik PE, Linde-Zwirble WT, Bittner EA, et al. Fluid administration in severe sepsis and septic shock, patterns and outcomes. An analysis of a large national database. Intensive Care Med 2017;43:625–632.
36. Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care 2014;4:21.
37. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008;8:776–787.
38. Parrish WR, Gallowitsch-Puerta M, Czura CJ, et al. Experimental therapeutic strategies for severe sepsis: Mediators and mechanisms. Ann NY Acad Sci 2008;1144:210–236.
39. Tracey KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986;234:470–474.
40. Beutler B, Greenwald D, Hulmes JD, et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 1985;316:552–554.
41. Fischer E, Marano MA, van Zee KJ, et al. Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest 1992;89:1551–1557.
42. Sanfilippo F, Corredor C, Fletcher N, et al. Diastolic dysfunction and mortality in septic patients: A systematic review and meta-analysis. Intensive Care Med 2015;41:1004–1013.
43. Carr AC, Shaw G, Fowler AA, et al. Ascorbate-dependent vasopressor synthesis—A rationale for vitamin C administration in severe sepsis and septic shock? Crit Care 2015;19:418.
44. Armour J. Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat. J Appl Physiol 2001;90:795–803.
45. Wu F, Wilson JX, Tyml K. Ascorbate inhibits iNOS expression and preserves vasoconstrictor responsiveness in skeletal muscle of septic mice. Am J Physiol Regul Integr Comp Physiol 2003;285:R50–R56.
46. Wu F, Wilosn JX, Tymi K. Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression. Free Radic Biol Med 2004;37:1282–1289.
47. Annane D, Bellisant E, Sebille V, et al. Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve. Br J Clin Pharmacol 1998;46:589–597.
48. Chappell D, Jacob M, Hofmann-Kiefer K, et al. Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx. Anesthesiology 2007;107:776–784.
49. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008;36:1937–1949.
50. Wilson JX. Evaluation of vitamin C for adjuvant sepsis therapy. Antioxid Redox Signal 2013;19:2129–2140.
51. Marik PE. “Vitamin S” (steroids) and vitamin C for the treatment of severe sepsis and septic shock! Crit Care Med 2016;44:1228–1229.
52. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study. Chest 2017;151:1229–1238.
53. ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: The Berlin definition. JAMA 2012;307:2526–33.
54. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016;315:788–800.
55. Marik PE, Long A. ARDS complicating pustular psoriasis: Treatment with low-dose corticosteorids, vitamin C and thiamine. BMJ Case Rep 2018. [In press; ].
56. Russell JA. Management of sepsis. N Engl J Med 2006;355:1699–1713.
57. Hawiger J, Veach RA, Zienkiewicz J. New paradigms in sepsis: From prevention to protection of failing microcirculation. J Thromb Haemost 2015;13:1743–1756.
58. Hotchkiss RS, Rust RS, Dence CS, et al. Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole. Am J Physiol 1991;261:R965–R972.
59. Boekstegers P, Weidenhofer S, Pilz G, et al. Peripheral oxygen availability within skeletal muscle in sepsis and septic shock: Comparison to limited infection and cardiogenic shock. Infection 1991;19:317–323.
60. Tran M, Tam D, Bardia A, et al. PGC-1alpha promotes recovery after acute kidney injury during systemic inflammation in mice. J Clin Invest 2011;121:4003–4014.
61. Arulkumaran N, Pollen S, Greco E, et al. Renal tubular cell mitochondrial dysfunction occurs despite preserved renal oxygen delivery in experimental septic acute kidney injury. Crit Care Med 2018;46:e318–e325.
62. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in patients with sepsis. JAMA 1993;269:3024–3029.
63. Marik PE, Bellomo R. Lactate clearance as a target of therapy in sepsis: A flawed paradigm. OA Critical Care 2013;1:3.
64. Garcia-Alvarez M, Marik PE, Bellomo R. Stress hyperlactemia. Lancet Endo Diabetes 2014;2:339–347.
65. Hayes MA, Timmins AC, Yau E, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717–1722.
66. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med 1995;333:1025–1032.
67. Early, Goal-Directed Therapy for Septic shock—A Patient-Level Meta-Analysis, N Engl J Med 2017;376:2223–2234.
68. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock and multiple organ dysfunction. Crit Care Med 1999;27:1230–1251.
69. Takasu O, Gaut JP, Watanabe E, et al. Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med 2013;187:509–517.
70. Pagliarini DJ, Calvo SE, Chang B, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008;134:112–123.
71. Ishikawa K, May CN, Gobe G, et al. Pathophysiology of septic acute kidney injury: A different view of tubular injury. Contrib Nephrol 2010;165:18–27.
72. Graetz TJ, Hotchkiss RS. Preventing organ failure in sepsis: The search continues. Nat Rev Nephrol 2017;13:5–6.
73. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002;360:219–223.
74. Watts JA, Kline JA, Thornton LR, et al. Metabolic dysfunction and depletion of mitochondria in hearts of septic rats. J Mol Cell Cardiol 2004;36:141–150.
75. Gunst J, Derese I, Aertgeerts A, et al. Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness. Crit Care Med 2013;41:177–189.
76. Azevedo LC. Mitochondrial dysfunction during sepsis. Endocr Metab Immune Disord Drug Targets 2010;10:214–23.
77. Clementi E, Brown GC, Feelisch M, et al. Persistent inhibition of cell respiration by nitric oxide: Crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Proc Natl Acad Sci USA 1998;95:7631–7636.
78. Bolanos JP, Heales SJ, Peuchen S, et al. Nitric oxide-mediated mitochondrial damage: A potential neuroprotective role for glutathione. Free Radic Biol Med 1996;21:995–1001.
79. Singer M. Mitochondrial function in sepsis: Acute phase versus multiple organ failure. Crit Care Med 2007;35:S441–S448.
80. Garrabou G, Moren C, Lopez S, et al. The effects of sepsis on mitochondria. J Infect Dis 2012;205:392–400.
81. Langley RJ, Tsalik EL, van Velkinburgh JC, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med 2013;5:195ra195.
82. Langley RJ, Tipper JL, Bruse S, et al. Integrative “omic” analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes. Am J Respir Crit Care Med 2014;190:445–455.
83. Zhang X. Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis. FASEB J 2017;31:4382–4395.
84. Parikh SM, Yang Y, He L, et al. Mitochondrial function and disturbances in the septic kidney. Semin Nephrol 2015;35:108–119.
85. Matkovich SJ, Al Khiami BA, Efimov IR, et al. Widespread down-regulation of cardiac mitochondrial and sarcomeric genes in patients with sepsis. Crit Care Med 2017;45:407–414.
86. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 2014;5:66–72.
87. Schafer ST. Mitochondrial DNA: An endogenous trigger for immune paralysis. Anesthesiol 2016;124:923–933.
88. Fowler AA, Syed AA, Knowlson S, et al. Phase 1 safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 2014;12:32.
89. De Grooth HM, Spoeistra-de Man AM, Oudermans-van Straaten HM. Early plasma vitamin C concentration, organ dysfunction and ICU mortality [Abstract]. Intensive Care Med 2014;40:S199.
90. Borrelli E, Roux-Lombard P, Grau GE, et al. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med 1996;24:392–397.
91. Carr AC, Rosengrave PC, Bayer S, et al. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care 2017;21:300.
92. Fisher BJ, Seropian IM, Masanori Y, et al. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit Care Med 2011;39:1454–1460.
93. Fisher BJ, Kraskauskas D, Martin EJ, et al. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol 2012;303:L20–L32.
94. Fisher BJ, Kraskauskas D, Martin EJ, et al. Attenuation of sepsis-induced organ injury in mice by vitamin C. JPEN 2014;38:825–839.
95. Sagun KC, Carcamo JM, Golde DN. Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J 2005;19:1657–1667.
96. Lowes DA, Webster NR, Galley HF. Dehydroascorbic acid as pre-conditioner: Protection from lipopolysaccharide induced mitochondrial damage. Free Radical Research 2010;44:283–292.
97. Dhar-Mascareno M, Carcamo JM, Golde DW. Hypoxia-reoxygenation-induced mitochondrial damage and apotosis in human endothelial cells inhibited by vitamin C. Free Radic Biol Med 2005;38:1311–1322.
98. Szakmany T. N-acetylcysteine for sepsis and systemic inflammatory response in adults. Cochrane Database Syst Rev 2012;9:CD006616.
99. Molnar Z. N-acetylcysteine as the magic bullet: Too good to be true. Crit Care Med 2008;36:645–646.
100. Cruickshank AM, Telfer AB, Shenkin A. Thiamine deficiency in the critically ill. Intensive Care Med 1988;14:384–387.
101. Corcoran T, O'Neil M, Webb SA. Prevalence of vitamin deficiencies on admission: relationship to hospital mortality in critically ill patients. Anaesthesia & Intensive Care 2009;37:254–260.
102. Holmberg MJ, Moskowitz A, Patel PV, et al. Thiamine in septic shock patients with alcohol use disorders: An observational pilot study. J Crit Care 2018;43:61–64.
103. Donnino MW, Carney E, Cocchi MN, et al. Thiamine deficiency in critically ill patients with sepsis. J Crit Care 2010;25:567–581.
104. Costa NA, Gut AL, de Souza Dorna M, et al. Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock. J Crit Care 2014;29:249–252.
105. Donnino MW, Andersen LW, Chase M, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: A pilot study. Crit Care Med 2016;44:360–367.
106. Moskowitz A, Anderson LW, Cocchi MN, et al. Thiamine as a renal protective agent in septic shock: A secondary analysis of a randomized, double-blind, placebo-controlled trial. Ann Am Thorac Soc 2017;14:737–741.
107. Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002;236:814–822.
108. Gentile LF, Cuenca AG, Effron PA, et al. Persistent inflammation and immunosuppression: A common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg 2012;72:1491–1501.
109. Klenner FR. The treatment of poliomyelitis and other virus diseases with vitamin C. South Med Surg 1949;111:209–214.
110. Pauling L. Ascorbic acid and the common cold. Am J Clin Nutr 1971;24:1294.
111. Hemila H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2013;1:CD000980.
112. Furuya A, Uozaki M, Yamasaki H, et al. Antiviral effects of ascorbic and dehydroascorbic acids in vitro. Int J Mol Med 2008;22:541–45.
113. Madhusudana SN. In vitro inactivation of the rabies virus by ascorbic acid. Int J Infect Dis 2004;8:21–25.
114. Anderson R. Vitamin C and cellular immune functions. Protection against hypochlorous acid-mediated inactivation of glyceraldehyde-3-phosphate dehydrogenase and ATP generation in human leukocytes as a possible mechanism of ascorbate-mediated immunostimulation. Ann NY Acad Sci 1990;587:34–48.
115. Manzella JP, Roberts NJ. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J Immunol 1979;123:1940–1944.
116. Siegel BV. Enhancement of interferon production by poly(rI)-poly(rC) in mouse cell cultures by ascorbic acid. Nature 1975;254:531–532.
117. Jeong YJ, Kim JH, Hong JM, et al. Vitamin C treatment of mouse bone marrow-derived dendritic cells enhanced CD8(+) memory T cell production capacity of these cells in vivo. Immunobiology 2014;219:554–564.
118. Mohammed BM, Fisher BJ, Kraskauskas D, et al. Vitamin C: a novel regulator of neutrophil extracellular trap formation. Nutrients 2013;5:3131–3151.
119. Huijskens MJ, Walczak M, Sarkar S, et al. Ascorbic acid propmotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy 2015;17:613–620.
120. Manning J, Mitchell B, Appadurai DA, et al. Vitamin C promotes maturation of T-cells. Antioxid Redox Signal 2013;19:2054–2067.
121. Gao YL, Lu B, Zhai JH, et al. The parenteral vitamin C improves sepsis and sepsis-induced multiple organ dysfunction syndrome via preventing cellular immunosuppression. Mediators Inflamm 2017;2017:4024672.
122. Keh D, Boehnke T, Weber-Cartens S, et al. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: A double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 2003;167:512–520.
123. Roquilly A, Mahe PJ, Seguin P, et al. Hydrocortisone therapy for corticosteroid insufficiency related to trauma. The HYPOLYT study. JAMA 2011;305:1201–1209.
124. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018;378:797–808.
125. Annane D, Renault A, Brub-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 2018;378:809–818.
126. Keh D, Trips E, Marx G, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis. The HYPRESS Randomized Clinical Trial. JAMA 2016;316:1755–1785.

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cover image Surgical Infections
Surgical Infections
Volume 19Issue Number 8November/December 2018
Pages: 812 - 820
PubMed: 30040533

History

Published online: 5 December 2018
Published in print: November/December 2018
Published ahead of print: 24 July 2018

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Paul E. Marik [email protected]
Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, Virginia.

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Address for correspondence: Dr. Paul E. Marik, Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 410, Norfolk, VA 23517 [email protected]

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The author has no real or potential conflicts of interest concerning this manuscript.

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