Treatment according to target(s)
| Therapies that target the host-pathogen interaction | Reference no. | ||
| Antibiotics* | 221 | ||
| Anti-endotoxin antibodies† | 16, 17, 222, 223 | ||
| Toll-like receptor or CD14 antagonists | 224 | ||
| Mediator-specific therapies that target inflammation | |||
| Anti–tumor necrosis factor antibodies† | 225, 226 | ||
| Platelet-activating factor acetylhydrolase | 227 | ||
| Bradykinin antagonists† | 228, 229 | ||
| Anti–factor XII antibodies‡ | 230 | ||
| Prostaglandin antagonists† | 228, 231, 232 | ||
| Anti–high mobility group 1 antibodies | 233-235 | ||
| Anti-C5a antibodies | 236, 237 | ||
| Granulocyte-macrophage colony-stimulating factor inhibition | 238, 239 | ||
| Macrophage inhibitory factor inhibition | 240, 241 | ||
| Anti-inflammatory agents (eg, interleukin 10) | 242-244 | ||
| Receptor antagonists | |||
| Interleukin-1r antagonist† | 12, 245 | ||
| Soluble tumor necrosis factor receptor† | 13 | ||
| Platelet-activating factor receptor antagonist† | 246, 247 | ||
| C5a receptor antagonists | 248 | ||
| Protease-activated receptor antagonists | 249, 250 | ||
| Mediator nonspecific therapies that target inflammation | |||
| CI-esterase inhibitor | 49, 251, 252 | ||
| Antioxidants | 253, 254 | ||
| Glucocorticoids1-153 | 148, 255-257 | ||
| Activated protein C1-153 | 10, 11 | ||
| Tissue factor pathway inhibitor† | 161, 258, 290 | ||
| Antithrombin III† | 145, 259 | ||
| Therapies that target cell-cell interactions | |||
| Antiplatelet agents | 260-262 | ||
| Antiadhesion strategies | 153, 263 | ||
| Therapies that target coagulation | |||
| Antithrombin agents | |||
| Heparin | 157 | ||
| Hirudin | 45 | ||
| Antithrombin III† | 145, 259 | ||
| Inhibition of extrinsic pathway | |||
| Anti–tissue factor antibodies | 264 | ||
| Factor VII inhibition | 162, 265 | ||
| Tissue factor pathway inhibitor† | 161, 258, 290 | ||
| Inhibition of cofactor activity | |||
| Activated protein C1-153 | 10, 11 | ||
| Enhanced fibrinolysis | |||
| Tissue plasminogen activator | 266 | ||
| Activated protein C1-153 | 10, 11 | ||
| Miscellaneous targets, amenable to inhibition | |||
| Apoptosis | 139 | ||
| Transcription factors (eg, NF-κB) | 188, 267 | ||
| Ubiquitin-proteasome pathway | 189 | ||
| Mechanical stretch, barotrauma1-153 | 147, 268 | ||
| Fever | 269 | ||
| Hyperglycemia1-153 | 149, 270 | ||
| Elastase | 271, 272 | ||
| Poly (ADP-ribose) synthetase (PARS) | 273 | ||
| Poly (ADP-ribose) polymerase 1 | 274, 275 | ||
| Nitric oxide | 209, 210, 213 | ||
| P38 MAPK | 196, 198 | ||
| PKCδ, ζ | 199, 276 | ||
| Miscellaneous targets, amenable to enhancement | |||
| Oxygenation | 173, 277-280 | ||
| Blood flow and hemodynamic forces1-153 | 150, 281-284 | ||
| Phospholipid oxidation products | 142 | ||
| Soluble lectin-like domain of TM | 285 | ||
| VEGF/Angiopoietin balance | 286 |
| Therapies that target the host-pathogen interaction | Reference no. | ||
| Antibiotics* | 221 | ||
| Anti-endotoxin antibodies† | 16, 17, 222, 223 | ||
| Toll-like receptor or CD14 antagonists | 224 | ||
| Mediator-specific therapies that target inflammation | |||
| Anti–tumor necrosis factor antibodies† | 225, 226 | ||
| Platelet-activating factor acetylhydrolase | 227 | ||
| Bradykinin antagonists† | 228, 229 | ||
| Anti–factor XII antibodies‡ | 230 | ||
| Prostaglandin antagonists† | 228, 231, 232 | ||
| Anti–high mobility group 1 antibodies | 233-235 | ||
| Anti-C5a antibodies | 236, 237 | ||
| Granulocyte-macrophage colony-stimulating factor inhibition | 238, 239 | ||
| Macrophage inhibitory factor inhibition | 240, 241 | ||
| Anti-inflammatory agents (eg, interleukin 10) | 242-244 | ||
| Receptor antagonists | |||
| Interleukin-1r antagonist† | 12, 245 | ||
| Soluble tumor necrosis factor receptor† | 13 | ||
| Platelet-activating factor receptor antagonist† | 246, 247 | ||
| C5a receptor antagonists | 248 | ||
| Protease-activated receptor antagonists | 249, 250 | ||
| Mediator nonspecific therapies that target inflammation | |||
| CI-esterase inhibitor | 49, 251, 252 | ||
| Antioxidants | 253, 254 | ||
| Glucocorticoids1-153 | 148, 255-257 | ||
| Activated protein C1-153 | 10, 11 | ||
| Tissue factor pathway inhibitor† | 161, 258, 290 | ||
| Antithrombin III† | 145, 259 | ||
| Therapies that target cell-cell interactions | |||
| Antiplatelet agents | 260-262 | ||
| Antiadhesion strategies | 153, 263 | ||
| Therapies that target coagulation | |||
| Antithrombin agents | |||
| Heparin | 157 | ||
| Hirudin | 45 | ||
| Antithrombin III† | 145, 259 | ||
| Inhibition of extrinsic pathway | |||
| Anti–tissue factor antibodies | 264 | ||
| Factor VII inhibition | 162, 265 | ||
| Tissue factor pathway inhibitor† | 161, 258, 290 | ||
| Inhibition of cofactor activity | |||
| Activated protein C1-153 | 10, 11 | ||
| Enhanced fibrinolysis | |||
| Tissue plasminogen activator | 266 | ||
| Activated protein C1-153 | 10, 11 | ||
| Miscellaneous targets, amenable to inhibition | |||
| Apoptosis | 139 | ||
| Transcription factors (eg, NF-κB) | 188, 267 | ||
| Ubiquitin-proteasome pathway | 189 | ||
| Mechanical stretch, barotrauma1-153 | 147, 268 | ||
| Fever | 269 | ||
| Hyperglycemia1-153 | 149, 270 | ||
| Elastase | 271, 272 | ||
| Poly (ADP-ribose) synthetase (PARS) | 273 | ||
| Poly (ADP-ribose) polymerase 1 | 274, 275 | ||
| Nitric oxide | 209, 210, 213 | ||
| P38 MAPK | 196, 198 | ||
| PKCδ, ζ | 199, 276 | ||
| Miscellaneous targets, amenable to enhancement | |||
| Oxygenation | 173, 277-280 | ||
| Blood flow and hemodynamic forces1-153 | 150, 281-284 | ||
| Phospholipid oxidation products | 142 | ||
| Soluble lectin-like domain of TM | 285 | ||
| VEGF/Angiopoietin balance | 286 |
References are not all-inclusive, but rather draw on a selection of basic, preclinical, early clinical and/or phase 3 clinical studies, as well as selected reviews.
Rapid institution of appropriate antibiotic therapy remains a mainstay in therapy of patients with severe sepsis.
Phase 3 clinical trials have been conducted and demonstrated no survival benefit.
The major physiologic role of Factor XII is not to mediate coagulation activation, but rather to increase the rate and extent of prekallikrein activation, resulting in generation of bradykinin, increased profibrinolytic activity and inhibition of thrombin-mediated platelet activation.287-289
Phase 3 clinical trials have been conducted and shown to improve survival. The degree to which treatment-related attenuation of endothelial cell activation contributed to overall benefit is unknown.