Treatment of severe sepsis: where next? Current and future treatment approaches after the introduction of drotrecogin alfa.
Severely septic patients continue to experience excessive morbidity and mortality despite recent advances in critical care. Although significant resources have been invested in new treatments, almost all have failed to improve outcomes. An improved understanding of sepsis pathophysiology, including the complex interactions between inflammatory, coagulation, and fibrinolytic systems, has accelerated the development of novel treatments. Recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated) (DAA), is currently the only US Food and Drug Administration (FDA)-approved medicine for the treatment of severe sepsis, and only in patients with a high risk of death. This review will discuss the treatment of severe sepsis, focusing on recent discoveries and unresolved questions about DAA's optimal use. Increasing pharmacological experience has generated enthusiasm for investigating medicines already approved for other indications as treatments for severe sepsis. Replacement doses of hydrocortisone and vasopressin may reduce mortality and improve hypotension, respectively, in a subgroup of patients with catecholamine-refractory septic shock. In addition to discussing these new indications, this review will detail the provocative preliminary data from four promising treatments, including two novel modalities: antagonizing high mobility group box protein and inhibiting tissue factor (TF). Observational data from the uncontrolled administration of heparin or statins in septic patients will also be reviewed.
Rice
Todd W
TW
Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville,TN 37232-2650, USA. todd.rice@vanderbilt.edu
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000925:Anticoagulants / Q000627:therapeutic use; D050034:Antidiuretic Agents / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004358:Drug Therapy / Q000639:trends; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D018579:Patient Selection; D011486:Protein C / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D012720:Severity of Illness Index; D013925:Thromboplastin / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D014667:Vasopressins / Q000627:therapeutic use
D000305:Adrenal Cortex Hormones; D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D050034:Antidiuretic Agents; D024243:HMGB1 Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011486:Protein C; D011994:Recombinant Proteins; D014667:Vasopressins; D006493:Heparin; D013925:Thromboplastin; C421124:drotrecogin alfa activated