Septic shock treatment

Inhibitors of NOS, while widely used in experimental research, are still in under investigation for clinical application. As mentioned above, the release of endogenous NO may be pathologically enhanced in septicaemia, leading to septic shock. Treatment with NOS inhibitors has been suggested as early as ten years ago but is still in the experimental stage. Inhibitors of iNOS are also of interest (and at the... 

A recombinant, soluble fusion protein that is a dimer of an extracellular portion of the human TNF receptor and the Fc portion of IgGl (TNFR Fc) binds and neutralizes TNFa and prevents death in animal models of bacteremia and endotoxemia. In patients with septic shock, treatment with the TNFR Fc fusion protein does not reduce mortality, and higher doses appear to be associated with increased mortality. 

Rivers E, Nguyen B, Havstad S, et al. Early Goal-directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001 345 1368-1377. 

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

An important overall approach for treatment of sepsis is goal-directed therapy. Mortality can be reduced by early placement and use of a central venous catheter, increased fluid volume administration, dobutamine therapy if needed, and red blood cell transfusion, to achieve specific physiologic goals in the first 6 hours. Evidence-based treatment recommendations for sepsis and septic shock from the Surviving Sepsis campaign are presented in Table 45-3. 

Evidence-Based Treatment Recommendations for Sepsis and Septic Shock... 

Less labile metal ions can be used to control the levels of biologically active ligands in the body. Thus Fe(III) in sodium nitroprusside delivers NO to tissues and is used for the treatment of hypertension and control of blood pressure. The possibility arises of utilizing Ru(III) to scavenge NO in the treatment of septic shock. 

Complex 101 has been shown to reverse the poor response of the artery to vasoconstrictor drugs (508), which is a major clinical problem in the treatment of patients with septic shock. The excessive production of NO appears to be a major contributory factor not only in... 

Dopamine is used in the treatment of shock owing to inadequate cardiac output (cardiogenic shock), which may be due to myocardial infarction or congestive heart failure. It is also used in the treatment of septic shock, since renal circulation is frequently compromised in this condition. An advantage of using dopamine in the treatment of shock is that its inotropic action increases cardiac output while dilating renal blood vessels and thereby increasing renal blood flow. 

Even though nitric oxide is the physiological mediator of a variety of responses, excess nitric oxide is toxic to many cells as a result of its role in the production of per-oxynitrite and resultant lipid oxidation. Inhibitors of the NOS enzyme are in clinical trials for the treatment of hypotension associated with septic shock. Administration of low concentrations of nitric oxide through respiratory ventilators has been implemented to treat persistent pulmonary hypertension of the newborn. 

Prompt intensive treatment with corticosteroids may be lifesaving when an excessive inflammatory reaction has resulted in septic shock. A massive infusion of corticosteroids can restore cardiac output and reverse hypotension by sensitizing the response of adrenoceptors in the heart and blood vessels to the stimulating action of catecholamines. This protective role of steroids may be due to a direct effect on vascular smooth muscle. The combination of glucocorticoids and dopamine therapy preserves renal blood flow during shock. 

A bactericidal permeability increasing protein found inside human neutrophils has been investigated as a potent endotoxin neutralizing agent in the treatment of septic shock. It has also been shown to enhance the activity of antibiotics, suggesting a potential use in treating antibiotic-resistant infections (28). 

ONO-1714 has reached phase II clinical trials for the treatment of hypotension and septic shock. The compound is a very potent and competitive inhibitor of the human iNOS with no selectivity over the neuronal form and 10-fold selectivity over eNOS. The compound is very active in vivo, reducing LPS-stimulated NO production in a mouse model with an ID5o value of 0.1 mg/kg s.c.. In 2000, the analgesic activity of ONO-1714 was filed by Ono Pharmaceuticals (Naka and Kobayashi). 

Abraham, E., Glauser, M. P., Butler, T., Garbino.J., Gelmont, D., Laterre, P. F. etal. (1997). P55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. JAMA 277, 1531-1538. 

Ziegler, E.J., Fisher, C.J.Jr, Sprung, C. L. etal. (1991). Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin A randomized, double-blind, placebo-controlled trial. N. Eng.]. Med. 324, 429-436. 

McCloskey, R. V., Straube, R. C., Sanders, C., Smith, S. M., and Smith, C. R. (1994). CHESS Trial Study Group. Treatment of septic shock with human monoclonal antibody HA-1A. Ann. Intern. Med. 121, 1-5. 

Tosyliminothiochromone-2-carboxylates 585 are inhibitors of interleukin-1 and are thus useful for the treatment of rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis and septic shock <1995WO9514670>, and thiochromones possessing a sulfamoyloxy side chain at either C-6 or C-7 behave as steroid sulfatase inhibitors < 1999W O9952890>. 

Dinarello, C.A. The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J Infect Dis 163 (1991) 1177-1184. 

Nakamura, T., Ebihara, I., Shoji, H., Ushiyama, C., Suzuki, S., Koide, H. Treatment with polymyxin B-immobilized fiber reduces platelet activation in septic shock patients decrease in plasma levels of soluble P-selectin, platelet factor 4 and beta-thromboglobulin. Inflamm Res 48 (1999) 171-175. 

Calandra, T., Glauser, M.P., Schellekens, J., Verhoef, J. Swiss Dutch, J5 Immunoglobulin Study Group, Treatment of Gram-negative septic shock with human IgG antibody to Escherichia coli J5 A prospective, double-blind, randomized trial, JInfectDis 158 (1988) 312-319. 

Fomsgaard, A., Baek, L., Fomsgaard, J.S., Engquist, A. Preliminary study on treatment of septic shock patients with antilipopolysaccharide IgG from blood donors. Scand J Infect Dis 21 (1989) 697-708. 

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