氢化可的松、维生素 C 和维生素 B1 联合治疗脓毒症研究进展_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

刘琼 ,  王金荣 , 崔朝勃

哈励逊国际和平医院重症医学科（河北衡水 053000）;

Corresponding author：

王金荣, Email: iamwjr306@163.com

Keywords：

DOI：

10.7507/1671-6205.201812008

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Citation： 刘琼, 王金荣, 崔朝勃. 氢化可的松、维生素 C 和维生素 B1 联合治疗脓毒症研究进展. Chinese Journal of Respiratory and Critical Care Medicine, 2021, 20(5): 366-371. doi: 10.7507/1671-6205.201812008 Copy

1.	Fleischmann C, Scherag A, Adhikari N, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med, 2016, 193(3): 259-272.
2.	Karlsson S, Ruokonen E, Varpula T, et al. Long-term outcome and quality-adjusted life years after severe sepsis. Crit Care Med, 2009, 37(4): 1268-1274.
3.	Yende S, Austin S, Rhodes A, et al. Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit Care Med, 2016, 44(8): 1461-1467.
4.	Ou SM, Chu H, Chao PW, et al. Long-term mortality and major adverse cardiovascular events in sepsis survivors. A nationwide population-based study. Am J Respir Crit Care Med, 2016, 194(2): 209-217.
5.	Prescott HC, Langa KM, Liu V, et al. Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med, 2014, 190(1): 62-69.
6.	Liu V, Lei X, Prescott HC, et al. Hospital readmission and healthcare utilization following sepsis in community settings. J Hosp Med, 2014, 9(8): 502-507.
7.	Shah FA, Pike F, Alvarez K, et al. Bidirectional relationship between cognitive function and pneumonia. Am J Respir Crit Care Med, 2013, 188(5): 586-592.
8.	Prescott HC, Angus DC. Enhancing recovery from sepsis: a review. JAMA, 2018, 319(1): 62-75.
9.	Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med, 2001, 345(8): 588-595.
10.	Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med, 2010, 363(7): 689-691.
11.	May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal, 2013, 19(17): 2068-2083.
12.	Prauchner CA. Oxidative stress in sepsis: Pathophysiological implications justifying antioxidant co-therapy. Burns, 2017, 43(3): 471-485.
13.	Artenstein AW, Higgins TL, Opal SM. Sepsis and scientific revolutions. Crit Care Med, 2013, 41(12): 2770-2772.
14.	Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood, 2003, 101(10): 3765-3777.
15.	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(6): 1229-1238.
16.	Galon J, Franchimont D, Hiroi N, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J, 2002, 16(1): 61-71.
17.	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(4): 512-520.
18.	Rygård SL, Butler E, Granholm A, et al. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med, 2018, 44(7): 1003-1016.
19.	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(5): 1167-1174.
20.	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(13): 1308-1316.
21.	Minneci PC, Deans KJ, Eichacker PQ, et al. The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis. Clin Microbiol Infect, 2009, 15(4): 308-318.
22.	Volbeda M, Wetterslev J, Gluud C, et al. Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med, 2015, 41(7): 1220-1234.
23.	Kalil AC, Sun J. Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies. Intensive Care Med, 2011, 37(3): 420-429.
24.	Lv QQ, Gu XH, Chen QH, et al. Early initiation of low-dose hydrocortisone treatment for septic shock in adults: a randomized clinical trial. Am J Emerg Med, 2017, 35(12): 1810-1814.
25.	Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med, 2018, 378(9): 797-808.
26.	Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med, 2018, 378(9): 809-818.
27.	Hyvernat H, Barel R, Gentilhomme A, et al. Effects of increasing hydrocortisone to 300?mg Per day in the treatment of septic shock: a pilot study. Shock, 2016, 46(5): 498-505.
28.	Nazer L, AlNajjar T, Al-Shaer M, et al. Evaluating the effectiveness and safety of hydrocortisone therapy in cancer patients with septic shock. J Oncol Pharm Pract, 2015, 21(4): 274-279.
29.	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(17): 1775-1785.
30.	Galley HF, Davies MJ, Webster NR. Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading. Free Radic Biol Med, 1996, 20(1): 139-143.
31.	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(3): 392-397.
32.	Evans-Olders R, Eintracht S, Hoffer LJ. Metabolic origin of hypovitaminosis C in acutely hospitalized patients. Nutrition, 2010, 26(11-12): 1070-1074.
33.	Rojas C, Cadenas S, Herrero A, et al. Endotoxin depletes ascorbate in the guinea pig heart. Protective effects of vitamins C and E against oxidative stress. Life Sci, 1996, 59(8): 649-657.
34.	Armour J, Tyml K, Lidington D, et al. Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat. J Appl Physiol (1985), 2001, 90(3): 795-803.
35.	Victor VM, Guayerbas N, Puerto M, et al. Changes in the ascorbic acid levels of peritoneal lymphocytes and macrophages of mice with endotoxin-induced oxidative stress. Free Radic Res, 2001, 35(6): 907-916.
36.	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(1): R50-6.
37.	Tyml K, Li F, Wilson JX. Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med, 2005, 33(8): 1823-1828.
38.	Fowler AA 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med, 2014, 12: 32.
39.	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(1): 300.
40.	de Grooth HJ, Manubulu-Choo WP, Zandvliet AS, et al. Vitamin C pharmacokinetics in critically ill patients: A Randomized Trial of Four IV Regimens. Chest, 2018, 153(6): 1368-1377.
41.	Wilson JX. Evaluation of vitamin C for adjuvant sepsis therapy. Antioxid Redox Signal, 2013, 19(17): 2129-2140.
42.	Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care, 2014, 18(4): 460.
43.	Marik PE. Hydrocortisone, ascorbic acid and thiamine (HAT Therapy) for the treatment of sepsis. Focus on ascorbic acid. Nutrients, 2018, 10(11): 1762.
44.	Seo MY, Lee SM. Protective effect of low dose of ascorbic acid on hepatobiliary function in hepatic ischemia/reperfusion in rats. J Hepatol, 2002, 36(1): 72-77.
45.	Manzella JP, Roberts NJ Jr. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J Immunol, 1979, 123(5): 1940-1944.
46.	Siegel BV. Enhancement of interferon production by poly(rI)-poly(rC) in mouse cell cultures by ascorbic acid. Nature, 1975, 254(5500): 531-532.
47.	Motl J, Radhakrishnan J, Ayoub IM, et al. Vitamin C compromises cardiac resuscitability in a rat model of ventricular fibrillation. Am J Ther, 2014, 21(5): 352-357.
48.	Kuck JL, Bastarache JA, Shaver CM, et al. Ascorbic acid attenuates endothelial permeability triggered by cell-free hemoglobin. Biochem Biophys Res Commun, 2018, 495(1): 433-437.
49.	Spoelstra-de Man AME, Elbers PWG, Oudemans-van Straaten HM. Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury. Crit Care, 2018, 22(1): 70.
50.	Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A, 2007, 104(21): 8749-8754.
51.	Chen Q, Espey MG, Krishna MC, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A, 2005, 102(38): 13604-13609.
52.	Chen Q, Espey MG, Sun AY, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A, 2008, 105(32): 11105-11109.
53.	Levine M, Padayatty SJ, Espey MG. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr, 2011, 2(2): 78-88.
54.	Mühlhöfer A, Mrosek S, Schlegel B, et al. High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers. Eur J Clin Nutr, 2004, 58(8): 1151-1158.
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1. Fleischmann C, Scherag A, Adhikari N, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med, 2016, 193(3): 259-272.
2. Karlsson S, Ruokonen E, Varpula T, et al. Long-term outcome and quality-adjusted life years after severe sepsis. Crit Care Med, 2009, 37(4): 1268-1274.
3. Yende S, Austin S, Rhodes A, et al. Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit Care Med, 2016, 44(8): 1461-1467.
4. Ou SM, Chu H, Chao PW, et al. Long-term mortality and major adverse cardiovascular events in sepsis survivors. A nationwide population-based study. Am J Respir Crit Care Med, 2016, 194(2): 209-217.
5. Prescott HC, Langa KM, Liu V, et al. Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med, 2014, 190(1): 62-69.
6. Liu V, Lei X, Prescott HC, et al. Hospital readmission and healthcare utilization following sepsis in community settings. J Hosp Med, 2014, 9(8): 502-507.
7. Shah FA, Pike F, Alvarez K, et al. Bidirectional relationship between cognitive function and pneumonia. Am J Respir Crit Care Med, 2013, 188(5): 586-592.
8. Prescott HC, Angus DC. Enhancing recovery from sepsis: a review. JAMA, 2018, 319(1): 62-75.
9. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med, 2001, 345(8): 588-595.
10. Lee WL, Slutsky AS. Sepsis and endothelial permeability. N Engl J Med, 2010, 363(7): 689-691.
11. May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal, 2013, 19(17): 2068-2083.
12. Prauchner CA. Oxidative stress in sepsis: Pathophysiological implications justifying antioxidant co-therapy. Burns, 2017, 43(3): 471-485.
13. Artenstein AW, Higgins TL, Opal SM. Sepsis and scientific revolutions. Crit Care Med, 2013, 41(12): 2770-2772.
14. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood, 2003, 101(10): 3765-3777.
15. 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(6): 1229-1238.
16. Galon J, Franchimont D, Hiroi N, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J, 2002, 16(1): 61-71.
17. 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(4): 512-520.
18. Rygård SL, Butler E, Granholm A, et al. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med, 2018, 44(7): 1003-1016.
19. 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(5): 1167-1174.
20. 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(13): 1308-1316.
21. Minneci PC, Deans KJ, Eichacker PQ, et al. The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis. Clin Microbiol Infect, 2009, 15(4): 308-318.
22. Volbeda M, Wetterslev J, Gluud C, et al. Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med, 2015, 41(7): 1220-1234.
23. Kalil AC, Sun J. Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies. Intensive Care Med, 2011, 37(3): 420-429.
24. Lv QQ, Gu XH, Chen QH, et al. Early initiation of low-dose hydrocortisone treatment for septic shock in adults: a randomized clinical trial. Am J Emerg Med, 2017, 35(12): 1810-1814.
25. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med, 2018, 378(9): 797-808.
26. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med, 2018, 378(9): 809-818.
27. Hyvernat H, Barel R, Gentilhomme A, et al. Effects of increasing hydrocortisone to 300?mg Per day in the treatment of septic shock: a pilot study. Shock, 2016, 46(5): 498-505.
28. Nazer L, AlNajjar T, Al-Shaer M, et al. Evaluating the effectiveness and safety of hydrocortisone therapy in cancer patients with septic shock. J Oncol Pharm Pract, 2015, 21(4): 274-279.
29. 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(17): 1775-1785.
30. Galley HF, Davies MJ, Webster NR. Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading. Free Radic Biol Med, 1996, 20(1): 139-143.
31. 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(3): 392-397.
32. Evans-Olders R, Eintracht S, Hoffer LJ. Metabolic origin of hypovitaminosis C in acutely hospitalized patients. Nutrition, 2010, 26(11-12): 1070-1074.
33. Rojas C, Cadenas S, Herrero A, et al. Endotoxin depletes ascorbate in the guinea pig heart. Protective effects of vitamins C and E against oxidative stress. Life Sci, 1996, 59(8): 649-657.
34. Armour J, Tyml K, Lidington D, et al. Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat. J Appl Physiol (1985), 2001, 90(3): 795-803.
35. Victor VM, Guayerbas N, Puerto M, et al. Changes in the ascorbic acid levels of peritoneal lymphocytes and macrophages of mice with endotoxin-induced oxidative stress. Free Radic Res, 2001, 35(6): 907-916.
36. 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(1): R50-6.
37. Tyml K, Li F, Wilson JX. Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med, 2005, 33(8): 1823-1828.
38. Fowler AA 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med, 2014, 12: 32.
39. 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(1): 300.
40. de Grooth HJ, Manubulu-Choo WP, Zandvliet AS, et al. Vitamin C pharmacokinetics in critically ill patients: A Randomized Trial of Four IV Regimens. Chest, 2018, 153(6): 1368-1377.
41. Wilson JX. Evaluation of vitamin C for adjuvant sepsis therapy. Antioxid Redox Signal, 2013, 19(17): 2129-2140.
42. Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care, 2014, 18(4): 460.
43. Marik PE. Hydrocortisone, ascorbic acid and thiamine (HAT Therapy) for the treatment of sepsis. Focus on ascorbic acid. Nutrients, 2018, 10(11): 1762.
44. Seo MY, Lee SM. Protective effect of low dose of ascorbic acid on hepatobiliary function in hepatic ischemia/reperfusion in rats. J Hepatol, 2002, 36(1): 72-77.
45. Manzella JP, Roberts NJ Jr. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J Immunol, 1979, 123(5): 1940-1944.
46. Siegel BV. Enhancement of interferon production by poly(rI)-poly(rC) in mouse cell cultures by ascorbic acid. Nature, 1975, 254(5500): 531-532.
47. Motl J, Radhakrishnan J, Ayoub IM, et al. Vitamin C compromises cardiac resuscitability in a rat model of ventricular fibrillation. Am J Ther, 2014, 21(5): 352-357.
48. Kuck JL, Bastarache JA, Shaver CM, et al. Ascorbic acid attenuates endothelial permeability triggered by cell-free hemoglobin. Biochem Biophys Res Commun, 2018, 495(1): 433-437.
49. Spoelstra-de Man AME, Elbers PWG, Oudemans-van Straaten HM. Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury. Crit Care, 2018, 22(1): 70.
50. Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A, 2007, 104(21): 8749-8754.
51. Chen Q, Espey MG, Krishna MC, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A, 2005, 102(38): 13604-13609.
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