TABLE 1.
Clinical studies evaluating anti-inflammation strategies to treat sepsis.
| Intervention | References | Citation in references | Notes |
|---|---|---|---|
| Corticosteroids | 1. 1984/Sprung CL et al., MEJM, vol 311(18), pages 1137,1143, 1984 | Sprung et al. (1984) | |
| 2. 1987/Bone RC et al, NEJM, vol 317(11), pages 653–658, 1987 | Bone et al. (1987) | ||
| 3. 1987/The Veterans Administration Systemic Sepsis Cooperative Study Group, NEJM, vol 317(11), pages 659–665, 1987 | Veterans Administration Systemic Sepsis Cooperative Study Group, (1987) | ||
| 4. 2002/Annane D et al, JAMA, vol vol 288(7), pages 863–871, 2002 | Annane et al. (2002) | ||
| 5. 2007/Cicarelli DD et al, Sao Paulo Medical Journal, vol 25(4), pages 237–241, 2007 | Cicarelli et al. (2007) | ||
| 6. 2008/Sprung CL et al, NEJM, vol 358(2), pages 111–124, 2008 | Sprung et al. (2008) | ||
| 7. 2016/Keh D et al, JAMA, vol 316(17), pages 1775–1785, 2016 | Keh et al. (2016) | ||
| 8. 2016/Gordon AC et al, JAMA vol 316(5), pages 509–518, 2016 | Gordon et al. (2016) | ||
| 9. 2018/Venkatesh B et al, NEJM, vol 378(9), pages 797–808, 2018 | Venkatesh et al. (2018) | ||
| Aspirin | 1. 2016/Kor DJ et al, JAMA, 15 May 2016 (E-pub) | Kor et al. (2016) | Randomized controlled study of aspirin prophylaxis to avert acute respiratory distress syndrome; about 77% of patients with suspected sepsis on enrollment-no mortality. difference with aspirin. |
| Acetaminophen | 1. 2015/Young P et al, NEJM, vol 373(23), pages 2215–2224, 2015 | Young et al. (2015) | |
| Ibuprofen | 1. 1991/Haupt MT et al, Critical Care Medicine, vol 19(11), pages 1339–1347, 1991 | Haupt et al. (1991) | |
| 2. 1997/Bernard GR et al, NEJM, vol 336(13), pages 912–918, 1997 | Bernard et al. (1997) | ||
| Physical Cooling | 1. 2013/Yang Y-L et al, Chinese Medical Journal, vol 126(10), pages 1809–1813, 2013 | Yang et al. (2013) | Water-flow cooling blankets. Increased mortality in experimental group (statistically significant). |
| Neutrophil Elastase Inhibitor | 1. Zeiher BG et al, Critical Care Medicine, vol 32(8), pages 1695–1702, 2004 | Zeiher et al. (2004) | Small molecule inhibitor in patients with acute lung injury, of whom 58.5% were caused by infection. Subgroup with pulmonary infection showed no mortality benefit. |
| Phospholipase A2 inhibition | 1. 2003/Abraham E et al, Critical Care Medicine, vol 31(3), pages 718–728, 2003 | Abraham et al. (2003a) | |
| Anti-endotoxin antibodies | 1. 1991/Ziegler EJ et al, NEJM, vol 324(7), pages 429–438, 1991 | Ziegler et al. (1991) | |
| 2. 1991/Greenman RL et al, JAMA, vol 266(8), pages 1097–1102, 1991 | Greenman et al. (1991) | ||
| 3. 1994/McCloskey RV et al, Annals of Internal Medicine, vol 121(1), pages 1–5, 1994 | McCloskey et al. (1994) | ||
| 4. 1999/Derkx B et al, Clinical Infectious Diseases, vol 28, pages 770–777, 1999 | Derkx et al. (1999) | ||
| TLR4 antagonist (synthetic) | 1. 2010/Rice TW et al, Critical Care Medicine, vol 38(8), pages 1–10, 2010 | Rice et al. (2010) | |
| 2. 2013/Opal SM et al, JAMA, vol 309(11), pages 1154–1162, 2013 | Opal et al. (2013) | ||
| Endotoxin hemofiltration | 1. 2014/Iwagami M et al, Critical Care Medicine, vol 42(5), pages 1187–1193, 2014 | Iwagami et al. (2014) | |
| Polymyxin B hemoperfusion | 1. 2018/Dellinger RP et al, JAMA, vol 320(14), pages 1455–1463, 2018 | Dellinger et al. (2018) | |
| 2. 2015/Payen DM et al, Intensive Care Medicine, vol 41(6), pages 975–984, 2015 | Payen et al. (2015) | ||
| 3. 2009/Cruz DN et al, JAMA, vol 301(23), pages 2445–2452, 2009 | Cruz et al. (2009) | ||
| Bactericidal/Permeability Increasing Protein | 1. 2000/Levin M et al, The Lancet, vol 356(9234), pages 961–967, 2000 | Levin et al. (2000) | Recombinant protein. |
| Continuous veno-venous hemofiltration (low volume) | 1. 2009/Payen D et al, Critical Care medicine, vol 37(3), pages 803–810, 2009 | Payen et al. (2009) | |
| Continuous veno-venous hemofiltration (high volume) | 1. 2013/Joannes-Boyau O et al, Intensive Care Medicine, vol 39(9), pages 1535–1546, 2013 | Joannes-Boyau et al. (2013) | Meta-analysis of randomized controlled studies in N = 5 studies (N = 241 subjects) showing no differences between high volume hemofiltration vs low volume hemofiltration in Sepsis. Since above study showed no beneficial effect of low volume hemofiltration it is implied high-volume hemofiltration is likewise ineffective vs sepsis. |
| 2. 2020/Yin F et al, Annals of Translational Medicine, vol 8(7), pages 1–10, 2020 | Yin et al. (2020) | ||
| Plasma exchange | 1. 2014/Rimmer E et al, Critical Care, vol 18(6), pages 1–8, 2014 | Rimmer et al. (2014) | Systematic review and meta-analysis identified 4 randomized controlled trials in pateints with sepsis or septic shock. Overall, no benefit but found benefit if analysis restricted to adult patients (N = 128) but not in children (N = 66). |
| CytoSorbⓇ Extracorporeal Cytokine Hemadsorption | 1. 2017/Schädler D et al, Plos One, vol 12(10), pages 1–18, 2017 | Schadler et al. (2017) | Randomized controlled open-label study (N = 100, mortality = secondary outcome). |
| Coupled plasma filtration adsorption | 1. 2014/Livigni S et al, BMJ Open, vol January 8, 4(1), pages 1–10, 2014 | Livigni et al. (2014) | |
| Phospholipid emulsion | 1. 2009/Dellinger RP et al, Critical Care Medicine, vol 37(11), pages 2029–2038, 2009 | Dellinger et al. (2009) | |
| Nitric oxide inhibition | 1. 2004/Lopez A et al, Critical Care Medicine, vol 32(1), pages 21–30, 2004 | Lopez et al. (2004) | Increased mortality in experimental group (statistically significant). |
| Bradykinin antagonist (synthetic) | 1. 1997/Fein AM et al, JAMA, vol 277(6), pages 482–487, 1997 | Fein et al. (1997) | |
| Antithrombin-3 (natural) | 1. 2001/Warren BL et al, JAMA, vol 286(15), pages 1868–1878, 2001 | Warren et al. (2001) | |
| 2. 2013/Gando S et al, Critical Care, vol 17(6) R297, pages 1–10, 2013 | Gando et al. (2013) | ||
| Tissue factor pathway inhibitor (recombinant) | 1. 2001/Abraham E et al, Critical Care Medicine, vol 29(11), pages 2081–2088, 2001 | Abraham et al. (2001) | |
| 2. 2003/Abraham E et al, JAMA, vol 290(2), pages 238–247, 2003 | Abraham et al. (2003b) | ||
| Soluble human thrombomodulin (human recombinant) | 1. 2013/Vincent J-L et al, Critical Care Medicine, vol 41(9), pages 2069–2079, 2013 | Vincent et al. (2013) | Review and meta-analysis of drug approved for DIC therapy in Japan; included 3 randomized controlled trials (N = 838) showing no 28–30 days mortality benefit in adult DIC patients with sepsis or severe sepsis. |
| 2. 2014/Yamakawa K et al, Journal of Thrombosis and Hemostasis, vol 13 (4), pages 508–519, 2014 | Yamakawa et al. (2015) | ||
| 3. 2019/Vincent J-L et al, JAMA, vol 321(20), pages 1993–2002, 2019 | Vincent et al. (2019) | ||
| Heparin (Heparin possesses anti-inflammatory properties) | 1. 2007/Levi M et al, American Journal of Respiratory and Critical Care Medicine, vol 176, pages 483–490, 2007 | Levi et al. (2007) | Randomized assignment to heparin in patients given activated protein C. Systematic review and meta-analysis (9 randomized controlled trials with 2,637 patients). |
| 2. 2009/Jaimes F et al, Critical Care Medicine, vol 37(4), pages 1185–1196), 2009 | Jaimes et al. (2009) | ||
| 3. 2015/Zarychanski R et al, Critical Care Medicine, vol 43(3), pages 511–518, 2015 | Zarychanski et al. (2015) | ||
| Activated Protein C (recombinant) | 1. 2001/Bernard GR et al, NEJM, vol 344(10), pages 699–709, 2001 | Bernard et al. (2001) | Positive study- could not be replicated. |
| 2. 2005/Abraham E et al, NEJM, vol 353(13), pages 1332–1341, 2005 | Abraham et al. (2005) | ||
| 3. 2007/Nadel et al, LANCET, vol 369, pages 836–843, 2007 | Nadel et al. (2007) | ||
| 4. 2012/Ranieri VM et al, NEJM, vol 366(2), pages 2055–2064, 2012 | Ranieri et al. (2012) | ||
| IL-1 receptor antagonist (recombinant) | 1. 1994/Fisher CJ et al, Critical Care Medicine, vol 22(1), pages 12–21, 1994 | Fisher et al. (1994b) | Remarkable open label randomized placebo-controlled study showing dose-response mortality reduction. |
| 2. 1994/Fisher CJ et al, JAMA, vol 271(23), pages 1836–1843, 1994 | Fisher et al. (1994a) | ||
| 3. 1997/Opal SM et al, Critical Care Medicine, vol 25(7), pages 1115–1124, 1997 | Opal et al. (1997) | ||
| TNF Antagonists | 1. 1993/Fisher CJ et al, Critical Care Medicine, vol 21(3), pages 318–327, 1993 | Fisher et al. (1993) | |
| 2. 1995/Abraham E et al, JAMA, vol 273(12), pages 934–941, 1995 | Abraham et al. (1995) | ||
| 3. 1996/Fisher CJ et al, NEJM, vol 334(26), pages 1697–1702, 1996 | Fisher et al. (1996) | Used etanercept (Enbrel®). Increased mortality in experimental group (statistically significant). | |
| 4. 1996/Cohen J and Carlet J, Critical Care Medicine, vol 24(9), pages 1431–1440, 1996 | Cohen and Carlet, (1996) | ||
| 5. 1996/Reinhart K et al, Critical Care Medicine, vol 24(5), pages 733–742, 1996 | Reinhart et al. (1996) | ||
| 6. 1998/Abraham E, Lancet, vol 351(9107), pages 929–933, 1998 | Abraham et al. (1998) | ||
| 7. 2001/Reinhart K et al, Critical Care Medicine, vol 29(4), pages 765–769, 2001 | Reinhart et al. (2001) | ||
| 8. 2004/Panacek EA et al, Critical Care Medicine, vol 32(11), pages 2173–2182, 2004 | Panacek et al. (2004) | Reported as positive study, but restricted to subgroup with IL-6>1,000 and using post-study logistic regression to balance data (both elements established prospectively). | |
| 9. 2006/Rice TW et al, Critical Care Medicine, vol 34(9), pages 2271–2281, 2006 | Rice et al. (2006) | ||
| Platelet Activating factor receptor antagonist | 1. 1994/Dhainaut JF et al, Critical Care Medicine, vol 22(11), pages 1720–1728, 1994 | Dhainaut et al. (1994) | |
| 2. 1998/Dhainaut JF et al, Critical Care Medicine, vol 26(12)), pages 1963–1971, 1998 | Dhainaut et al. (1998) | ||
| 3. 2000/Suputtamongkol Y et al, Antimicrobial Agents and Chemotherapy, vol 44(3), pages 693–696, 2000 | Suputtamongkol et al. (2000) | ||
| 4. 2000/Vincent JL et al, Critical Care Medicine, vol 28(3), pages 638–642, 2000 | Vincent et al. (2000) | ||
| 5. 2000/Poeze M et al, Shock, vol 14(4), pages 421–428, 2000 | Poeze et al. (2000) | ||
| 6. 2004/Opal S et al, Critical Care Medicine, vol 32(2), pages 332–341, 2004 | Opal et al. (2004) | ||
| Statins | 1. 2013/Kruger P et al, American Journal of Respiratory and Critical Care Medicine, Vol 187(7), pages 743–750, 2013 | Kruger et al. (2013) | Meta-analysis (4 randomized controlled studies, 1818 adult patients with severe sepsis). Systematic review and meta-analysis (7 randomized controlled studies, 1720 adult patients with sepsis). Systematic review of 8 randomized controlled studies (N = 2,275 adults with sepsis). |
| 2. 2014/McAuley DF et al, New England Journal of Medline, vol 371(18), pages 1695–1703, 2014 | McAuley et al. (2014) | ||
| 3. 2015/Thomas G et al, Minerva Anestesiologica, vol 81(8), pages 921–930, 2015 | Thomas et al. (2015) | ||
| 4. 2015/Deshpande, A. et al, American Journal of Medicine, vol 128, pages 410–417, 2015 | Deshpande et al. (2015) | ||
| 5. 2016/Quinn M et al., Indian Journal of Critical Care Medicine, vol 20(9), pages 534–541, 2016 | Quinn et al. (2016) | ||
| Vitamin C + Hydrocortisone + Thiamine | 1. 2016/Marik PE et al, Chest, vol 151(6), pages 1229–1238, 2016. | Marik et al. (2017) | Substantial reduced mortality in non-contemporaneous controls (hospital mortality = 8.5% vs 40.4% = 79% relative mortality reduction). Septic shock in adults in prospective, randomized, controlled (hydrocortisone alone) trial that was OPEN LABEL; no effect for outcome of alive and vasopressor-free duration. Subgroups showed no mortality benefit for combination therapy at days 28, 90, or in ICU (in fact, mortality slightly increased for intervention for all mortality assessments). Another study with non-contemporaneous controls propensity-score matched showed no mortality benefit (mortality in ICU or 28 days or 60 days). No change in SOFA score over first 3 days. Intervention showed reduced length of stay in ICU or in hospital. |
| 2. 2020/Fujii T et al, JAMA vol 324(5), pages 423–431, 2020 | Fujii et al. (2020) | ||
| 3. 2020/Mitchell AB et al, American Journal of Medicine, vol 133(5), pages 635–638, 2020 | Mitchell et al. (2020) |