Re-Evaluating Biologic Pharmacotherapies That Target the Host Response during Sepsis
Abstract
:1. Introduction
2. Targeting Cyto/Chemokines
2.1. Anti-Interleukin Therapy
2.2. Anti-TNF⍺ Therapy
3. Targeting the Innate Immune Response
3.1. Alkaline Phosphatase
3.2. Granulocyte-Macrophage Colony Stimulating Factor
3.3. Intravenous Immunoglobulin
4. Targeting the Coagulant Response
4.1. Heparin
4.2. Platelet Activating Factor Acetyl Hydrolase
4.3. Activated Protein C
5. Conclusions/Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
MODS | Multiple organ dysfunction syndrome |
SIRS | Systemic inflammatory response syndrome |
TLR | Toll-like receptor |
IL | Interleukin |
TNF | Tumor necrosis factor |
Fab | Polyclonal antibody fragment |
AP | Alkaline phosphatase |
BIAP | Bovine intestinal alkaline phosphatase |
GM-CSF | Granulocyte-macrophage colony stimulating factor |
APACHE | Acute Physiology, Age, Chronic Health Evaluation |
IVIG | Intravenous immunoglobulin |
UFH | Unfractionated heparin |
PAF | Platelet-activating factor |
rhAPC | Recombinant human activated protein C |
RRR | Relative risk reduction |
ARR | Absolute risk reduction |
RCT | Randomized clinical trial |
References
- Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.D.; Coopersmith, C.M.; et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315, 801–810. [Google Scholar] [CrossRef] [PubMed]
- Rhodes, A.; Evans, L.E.; Alhazzani, W.; Levy, M.M.; Antonelli, M.; Ferrer, R.; Kumar, A.; Sevransky, J.E.; Sprung, C.L.; Nunnally, M.E.; et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017, 43, 304–377. [Google Scholar] [CrossRef] [PubMed]
- Balk, R.A. Systemic inflammatory response syndrome (SIRS): Where did it come from and is it still relevant today? Virulence 2014, 5, 20–26. [Google Scholar] [CrossRef] [PubMed]
- Lagu, T.; Rothberg, M.B.; Shieh, M.S.; Pekow, P.S.; Steingrub, J.S.; Lindenauer, P.K. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit. Care Med. 2012, 40, 754–761. [Google Scholar] [CrossRef] [PubMed]
- Angus, D.C.; Linde-Zwirble, W.T.; Lidicker, J.; Clermont, G.; Carcillo, J.; Pinsky, M.R. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 2001, 29, 1303–1310. [Google Scholar] [CrossRef] [PubMed]
- Kumar, G.; Kumar, N.; Taneja, A.; Kaleekal, T.; Tarima, S.; McGinley, E.; Jimenez, E.; Mohan, A.; Khan, R.A.; Whittle, J.; et al. Nationwide trends of severe sepsis in the 21st century (2000–C2007). Chest 2011, 140, 1223–1231. [Google Scholar] [CrossRef]
- Chousterman, B.G.; Swirski, F.K.; Weber, G.F. Cytokine storm and sepsis disease pathogenesis. Semin. Immunopathol. 2017, 39, 517–528. [Google Scholar] [CrossRef]
- Mera, S.; Tatulescu, D.; Cismaru, C.; Bondor, C.; Slavcovici, A.; Zanc, V.; Carstina, D.; Oltean, M. Multiplex cytokine profiling in patients with sepsis. APMIS 2011, 119, 155–163. [Google Scholar] [CrossRef]
- Gouel-Cheron, A.; Allaouchiche, B.; Guignant, C.; Davin, F.; Floccard, B.; Monneret, G.; AzuRea, G. Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: A powerful association to predict the development of sepsis after major trauma. PLoS ONE 2012, 7, e33095. [Google Scholar] [CrossRef]
- Wu, H.P.; Chen, C.K.; Chung, K.; Tseng, J.C.; Hua, C.C.; Liu, Y.C.; Chuang, D.Y.; Yang, C.H. Serial cytokine levels in patients with severe sepsis. Inflamm. Res. 2009, 58, 385–393. [Google Scholar] [CrossRef]
- Kellum, J.A.; Kong, L.; Fink, M.P.; Weissfeld, L.A.; Yealy, D.M.; Pinsky, M.R.; Fine, J.; Krichevsky, A.; Delude, R.L.; Angus, D.C.; et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch. Intern. Med. 2007, 167, 1655–1663. [Google Scholar] [CrossRef] [PubMed]
- Arend, W.P.; Welgus, H.G.; Thompson, R.C.; Eisenberg, S.P. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J. Clin. Investig. 1990, 85, 1694–1697. [Google Scholar] [CrossRef] [PubMed]
- Hannum, C.H.; Wilcox, C.J.; Arend, W.P.; Joslin, F.G.; Dripps, D.J.; Heimdal, P.L.; Armes, L.G.; Sommer, A.; Eisenberg, S.P.; Thompson, R.C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 1990, 343, 336–340. [Google Scholar] [CrossRef] [PubMed]
- Fisher, C.J., Jr.; Slotman, G.J.; Opal, S.M.; Pribble, J.P.; Bone, R.C.; Emmanuel, G.; Ng, D.; Bloedow, D.C.; Catalano, M.A.; IL-1RA Sepsis Syndrome Study Group. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: A randomized, open-label, placebo-controlled multicenter trial. Crit. Care Med. 1994, 22, 12–21. [Google Scholar]
- Fisher, C.J., Jr.; Dhainaut, J.F.; Opal, S.M.; Pribble, J.P.; Balk, R.A.; Slotman, G.J.; Iberti, T.J.; Rackow, E.C.; Shapiro, M.J.; Greenman, R.L.; et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994, 271, 1836–1843. [Google Scholar] [CrossRef]
- Opal, S.M.; Fisher, C.J., Jr.; Dhainaut, J.F.; Vincent, J.L.; Brase, R.; Lowry, S.F.; Sadoff, J.C.; Slotman, G.J.; Levy, H.; Balk, R.A.; et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit. Care Med. 1997, 25, 1115–1124. [Google Scholar] [CrossRef]
- Nooteboom, A.; Van Der Linden, C.J.; Hendriks, T. Tumor necrosis factor-alpha and interleukin-1beta mediate endothelial permeability induced by lipopolysaccharide-stimulated whole blood. Crit. Care Med. 2002, 30, 2063–2068. [Google Scholar] [CrossRef]
- Ince, C.; Mayeux, P.R.; Nguyen, T.; Gomez, H.; Kellum, J.A.; Ospina-Tascon, G.A.; Hernandez, G.; Murray, P.; De Backer, D.; Workgroup, A.X. The Endothelium in Sepsis. Shock 2016, 45, 259–270. [Google Scholar] [CrossRef]
- Chelazzi, C.; Villa, G.; Mancinelli, P.; De Gaudio, A.R.; Adembri, C. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit. Care. 2015, 19, 26. [Google Scholar] [CrossRef]
- Eichenholz, P.W.; Eichacker, P.Q.; Hoffman, W.D.; Banks, S.M.; Parrillo, J.E.; Danner, R.L.; Natanson, C. Tumor necrosis factor challenges in canines: Patterns of cardiovascular dysfunction. Am. J. Physiol. 1992, 263, H668–H675. [Google Scholar] [CrossRef]
- Natanson, C.; Eichenholz, P.W.; Danner, R.L.; Eichacker, P.Q.; Hoffman, W.D.; Kuo, G.C.; Banks, S.M.; MacVittie, T.J.; Parrillo, J.E. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J. Exp. Med. 1989, 169, 823–832. [Google Scholar] [CrossRef] [PubMed]
- Bozkurt, B.; Kribbs, S.B.; Clubb, F.J., Jr.; Michael, L.H.; Didenko, V.V.; Hornsby, P.J.; Seta, Y.; Oral, H.; Spinale, F.G.; Mann, D.L. Pathophysiologically relevant concentrations of tumor necrosis factor-alpha promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998, 97, 1382–1391. [Google Scholar] [CrossRef]
- Liu, B.; Andrieu-Abadie, N.; Levade, T.; Zhang, P.; Obeid, L.M.; Hannun, Y.A. Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J. Biol. Chem. 1998, 273, 11313–11320. [Google Scholar] [CrossRef] [PubMed]
- Jayadev, S.; Linardic, C.M.; Hannun, Y.A. Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor alpha. J. Biol. Chem. 1994, 269, 5757–5763. [Google Scholar] [PubMed]
- Liu, S.J.; McHowat, J. Stimulation of different phospholipase A2 isoforms by TNF-alpha and IL-1beta in adult rat ventricular myocytes. Am. J. Physiol. 1998, 275, H1462–H1472. [Google Scholar]
- Marshall, J.C. Clinical trials of mediator-directed therapy in sepsis: What have we learned? Intensive Care Med. 2000, 26 (Suppl. 1), S75–S83. [Google Scholar] [CrossRef]
- Panacek, E.A.; Marshall, J.C.; Albertson, T.E.; Johnson, D.H.; Johnson, S.; MacArthur, R.D.; Miller, M.; Barchuk, W.T.; Fischkoff, S.; Kaul, M.; et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab’)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit. Care Med. 2004, 32, 2173–2182. [Google Scholar] [CrossRef]
- Reinhart, K.; Wiegand-Lohnert, C.; Grimminger, F.; Kaul, M.; Withington, S.; Treacher, D.; Eckart, J.; Willatts, S.; Bouza, C.; Krausch, D.; et al. Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: A multicenter, randomized, placebo-controlled, dose-ranging study. Crit. Care Med. 1996, 24, 733–742. [Google Scholar] [CrossRef]
- Gallagher, J.; Fisher, C.; Sherman, B.; Munger, M.; Meyers, B.; Ellison, T.; Fischkoff, S.; Barchuk, W.T.; Teoh, L.; Velagapudi, R. A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome. Intensive Care Med. 2001, 27, 1169–1178. [Google Scholar] [CrossRef]
- Morris, P.E.; Zeno, B.; Bernard, A.C.; Huang, X.; Das, S.; Edeki, T.; Simonson, S.G.; Bernard, G.R. A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock. Crit. Care 2012, 16, R31. [Google Scholar] [CrossRef]
- Bernard, G.R.; Francois, B.; Mira, J.P.; Vincent, J.L.; Dellinger, R.P.; Russell, J.A.; Larosa, S.P.; Laterre, P.F.; Levy, M.M.; Dankner, W.; et al. Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-alpha fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: Randomized, double-blind, placebo-controlled phase IIb study*. Crit. Care Med. 2014, 42, 504–511. [Google Scholar] [CrossRef] [PubMed]
- Sharma, U.; Pal, D.; Prasad, R. Alkaline phosphatase: An overview. Indian J. Clin. Biochem. 2014, 29, 269–278. [Google Scholar] [CrossRef] [PubMed]
- Malo, M.S.; Biswas, S.; Abedrapo, M.A.; Yeh, L.; Chen, A.; Hodin, R.A. The pro-inflammatory cytokines, IL-1beta and TNF-alpha, inhibit intestinal alkaline phosphatase gene expression. DNA Cell Biol. 2006, 25, 684–695. [Google Scholar] [CrossRef] [PubMed]
- Heemskerk, S.; Masereeuw, R.; Moesker, O.; Bouw, M.P.; van der Hoeven, J.G.; Peters, W.H.; Russel, F.G.; Pickkers, P.; Group, A.S. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit. Care Med. 2009, 37, 417–423.e1. [Google Scholar] [CrossRef]
- Nierhaus, A.; Montag, B.; Timmler, N.; Frings, D.P.; Gutensohn, K.; Jung, R.; Schneider, C.G.; Pothmann, W.; Brassel, A.K.; Schulte Am Esch, J. Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med. 2003, 29, 646–651. [Google Scholar] [CrossRef]
- Wu, J.F.; Ma, J.; Chen, J.; Ou-Yang, B.; Chen, M.Y.; Li, L.F.; Liu, Y.J.; Lin, A.H.; Guan, X.D. Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Crit. Care 2011, 15, R220. [Google Scholar] [CrossRef] [Green Version]
- Meisel, C.; Schefold, J.C.; Pschowski, R.; Baumann, T.; Hetzger, K.; Gregor, J.; Weber-Carstens, S.; Hasper, D.; Keh, D.; Zuckermann, H.; et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: A double-blind, randomized, placebo-controlled multicenter trial. Am. J. Respir. Crit. Care Med. 2009, 180, 640–648. [Google Scholar] [CrossRef]
- Jolles, S.; Sewell, W.A.; Misbah, S.A. Clinical uses of intravenous immunoglobulin. Clin. Exp. Immunol 2005, 142, 1–11. [Google Scholar] [CrossRef]
- Shankar-Hari, M.; Spencer, J.; Sewell, W.A.; Rowan, K.M.; Singer, M. Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective. Crit. Care 2012, 16, 206. [Google Scholar] [CrossRef] [Green Version]
- Alejandria, M.M.; Lansang, M.A.; Dans, L.F.; Mantaring, J.B., 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013. [Google Scholar] [CrossRef]
- Laupland, K.B.; Kirkpatrick, A.W.; Delaney, A. Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: A systematic review and meta-analysis. Crit. Care Med. 2007, 35, 2686–2692. [Google Scholar] [PubMed]
- Kreymann, K.G.; de Heer, G.; Nierhaus, A.; Kluge, S. Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit. Care Med. 2007, 35, 2677–2685. [Google Scholar] [PubMed]
- Capasso, L.; Borrelli, A.; Cerullo, J.; Pisanti, R.; Figliuolo, C.; Izzo, F.; Paccone, M.; Ferrara, T.; Lama, S.; Raimondi, F. Role of immunoglobulins in neonatal sepsis. Transl Med. UniSa 2015, 11, 28–33. [Google Scholar] [PubMed]
- Werdan, K.; Pilz, G.; Bujdoso, O.; Fraunberger, P.; Neeser, G.; Schmieder, R.E.; Viell, B.; Marget, W.; Seewald, M.; Walger, P.; et al. Score-based immunoglobulin G therapy of patients with sepsis: The SBITS study. Crit. Care Med. 2007, 35, 2693–2701. [Google Scholar]
- Li, X.; Ma, X. The role of heparin in sepsis: Much more than just an anticoagulant. Br. J. Haematol 2017, 179, 389–398. [Google Scholar] [CrossRef] [Green Version]
- Jaimes, F.; De La Rosa, G.; Morales, C.; Fortich, F.; Arango, C.; Aguirre, D.; Munoz, A. Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Crit. Care Med. 2009, 37, 1185–1196. [Google Scholar] [CrossRef]
- Palur Ramakrishnan, A.V.; Varghese, T.P.; Vanapalli, S.; Nair, N.K.; Mingate, M.D. Platelet activating factor: A potential biomarker in acute coronary syndrome? Cardiovasc. Ther. 2017, 35, 64–70. [Google Scholar] [CrossRef]
- Graham, R.M.; Stephens, C.J.; Silvester, W.; Leong, L.L.; Sturm, M.J.; Taylor, R.R. Plasma degradation of platelet-activating factor in severely ill patients with clinical sepsis. Crit. Care Med. 1994, 22, 204–212. [Google Scholar] [CrossRef]
- Hofbauer, B.; Saluja, A.K.; Bhatia, M.; Frossard, J.L.; Lee, H.S.; Bhagat, L.; Steer, M.L. Effect of recombinant platelet-activating factor acetylhydrolase on two models of experimental acute pancreatitis. Gastroenterology 1998, 115, 1238–1247. [Google Scholar] [CrossRef]
- Schuster, D.P.; Metzler, M.; Opal, S.; Lowry, S.; Balk, R.; Abraham, E.; Levy, H.; Slotman, G.; Coyne, E.; Souza, S.; et al. Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial. Crit. Care Med. 2003, 31, 1612–1619. [Google Scholar] [CrossRef]
- Opal, S.; Laterre, P.F.; Abraham, E.; Francois, B.; Wittebole, X.; Lowry, S.; Dhainaut, J.F.; Warren, B.; Dugernier, T.; Lopez, A.; et al. Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit. Care Med. 2004, 32, 332–341. [Google Scholar] [CrossRef] [PubMed]
- Bouwens, E.A.; Stavenuiter, F.; Mosnier, L.O. Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J. Thromb. Haemost. 2013, 11 (Suppl. 1), 242–253. [Google Scholar] [CrossRef] [Green Version]
- Mosnier, L.O.; Zlokovic, B.V.; Griffin, J.H. The cytoprotective protein C pathway. Blood 2007, 109, 3161–3172. [Google Scholar] [CrossRef] [PubMed]
- Taylor, F.B., Jr.; Chang, A.; Esmon, C.T.; D’Angelo, A.; Vigano-D’Angelo, S.; Blick, K.E. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J. Clin. Investig. 1987, 79, 918–925. [Google Scholar] [CrossRef] [PubMed]
- Abraham, E.; Laterre, P.F.; Garg, R.; Levy, H.; Talwar, D.; Trzaskoma, B.L.; Francois, B.; Guy, J.S.; Bruckmann, M.; Rea-Neto, A.; et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N. Engl. J. Med. 2005, 353, 1332–1341. [Google Scholar] [CrossRef] [Green Version]
- Dalton, H.J.; Carcillo, J.A.; Woodward, D.B.; Short, M.A.; Williams, M.D. Biomarker response to drotrecogin alfa (activated) in children with severe sepsis: Results from the RESOLVE clinical trial*. Pediatr. Crit. Care Med. 2012, 13, 639–645. [Google Scholar] [CrossRef]
- Vincent, J.L.; Bernard, G.R.; Beale, R.; Doig, C.; Putensen, C.; Dhainaut, J.F.; Artigas, A.; Fumagalli, R.; Macias, W.; Wright, T.; et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment. Crit. Care Med. 2005, 33, 2266–2277. [Google Scholar] [CrossRef]
- Janssen van Doorn, K.; Spapen, H.; Geers, C.; Diltoer, M.; Shabana, W. Sepsis-related acute kidney injury: A protective effect of drotrecogin alpha (activated) treatment? Acta Anaesthesiol. Scand. 2008, 52, 1259–1264. [Google Scholar] [CrossRef]
- Bernard, G.R.; Vincent, J.L.; Laterre, P.F.; LaRosa, S.P.; Dhainaut, J.F.; Lopez-Rodriguez, A.; Steingrub, J.S.; Garber, G.E.; Helterbrand, J.D.; Ely, E.W.; et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 2001, 344, 699–709. [Google Scholar] [CrossRef]
- Ranieri, V.M.; Thompson, B.T.; Barie, P.S.; Dhainaut, J.F.; Douglas, I.S.; Finfer, S.; Gardlund, B.; Marshall, J.C.; Rhodes, A.; Artigas, A.; et al. Drotrecogin alfa (activated) in adults with septic shock. N. Engl. J. Med. 2012, 366, 2055–2064. [Google Scholar] [CrossRef]
- Shorr, A.F.; Janes, J.M.; Artigas, A.; Tenhunen, J.; Wyncoll, D.L.; Mercier, E.; Francois, B.; Vincent, J.L.; Vangerow, B.; Heiselman, D.; et al. Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated). Crit. Care 2010, 14, R229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nguyen, H.B.; Rivers, E.P.; Knoblich, B.P.; Jacobsen, G.; Muzzin, A.; Ressler, J.A.; Tomlanovich, M.C. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit. Care Med. 2004, 32, 1637–1642. [Google Scholar] [CrossRef] [PubMed]
- Suetrong, B.; Walley, K.R. Lactic Acidosis in Sepsis: It’s Not All Anaerobic: Implications for Diagnosis and Management. Chest 2016, 149, 252–261. [Google Scholar] [CrossRef] [PubMed]
- Derhaschnig, U.; Reiter, R.; Knobl, P.; Baumgartner, M.; Keen, P.; Jilma, B. Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. Blood 2003, 102, 2093–2098. [Google Scholar] [CrossRef] [PubMed]
- Levi, M.; Levy, M.; Williams, M.D.; Douglas, I.; Artigas, A.; Antonelli, M.; Wyncoll, D.; Janes, J.; Booth, F.V.; Wang, D.; et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am. J. Respir. Crit. Care Med. 2007, 176, 483–490. [Google Scholar] [CrossRef] [PubMed]
Biologic Class | Equivocal Outcomes | Beneficial Outcomes | Current Status/Considerations |
---|---|---|---|
rhAPC | [55,56,58,60,64] | [57,59,61] | No clear benefit, discontinued |
Heparins | [46,65] | Potential for LMWH, not UFH | |
hrIL-1a | [14,15,16] | Potential MODS benefit. Need more data in larger trials. More stringent biomarker-guided I/E criteria. | |
Alk Phos | [34] | Need more data in larger trials. | |
anti-TNFα | [31] | [27,30] | Potential benefit with Fabs. More stringent biomarker-guided I/E criteria. |
IVIG | [44] | No clear benefit. | |
GM-CSF | [35,37] | Inconclusive. Need more data in larger trials. | |
rPAF-AH | [51] | Inconclusive. More stringent biomarker-guided I/E criteria. |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Tuttle, K.M.; McDonald, M.D.; Anderson, E.J. Re-Evaluating Biologic Pharmacotherapies That Target the Host Response during Sepsis. Int. J. Mol. Sci. 2019, 20, 6049. https://doi.org/10.3390/ijms20236049
Tuttle KM, McDonald MD, Anderson EJ. Re-Evaluating Biologic Pharmacotherapies That Target the Host Response during Sepsis. International Journal of Molecular Sciences. 2019; 20(23):6049. https://doi.org/10.3390/ijms20236049
Chicago/Turabian StyleTuttle, Kristopher M., Matthew D. McDonald, and Ethan J. Anderson. 2019. "Re-Evaluating Biologic Pharmacotherapies That Target the Host Response during Sepsis" International Journal of Molecular Sciences 20, no. 23: 6049. https://doi.org/10.3390/ijms20236049