The Journal of antimicrobial chemotherapy
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Complement provides a critical and multifaceted defence system against infection. Following activation, complement can clear invading microorganisms by lysis or by opsonization, which promotes recognition by complement receptors on phagocytes. ⋯ The host has developed regulatory mechanisms for controlling complement activation and for protecting its own cells against complement attack. Some microorganisms have also evolved ways to avoid the opsonic and lytic action of complement.
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Cardiovascular alterations in sepsis include a decrease in vascular tone and an impairment in myocardial contractility, and occur largely as the result of the release and action of mediators of the sepsis cascade. Many mediators are involved including cytokines, particularly tumour necrosis factor and interleukin-1, and secondary mediators such as nitric oxide and oxygen free radicals. The degree of reduced vascular tone and myocardial depression have both been related to the severity of sepsis. In this article we will review current knowledge on the factors involved in the cardiovascular alterations of sepsis, the clinical implications of these alterations, and the possibilities for future treatments.
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J. Antimicrob. Chemother. · Jan 1998
ReviewExperimental therapies for sepsis directed against tumour necrosis factor.
Tumour necrosis factor (TNF) has been identified as an important mediator involved in the generation of sepsis syndrome. Two major strategies have evolved for counteracting the effects of TNF in patients with severe manifestations of sepsis: neutralization by anti-TNF antibodies and competitive antagonism of TNF with synthetic soluble TNF receptors. ⋯ Trials of a 55 kDa soluble TNF receptor are continuing and this drug is apparently safe. Drugs that modify TNF in vivo may be a useful component of future management of sepsis, either as monotherapy or as part of a combined strategy of immunomodulation.
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Nitric oxide (NO) is one of many vasoactive substances released, from a variety of cells, under conditions of endotoxaemia and sepsis. Under physiological conditions it is produced by two constitutive calcium-dependent enzymes (nitric oxide synthase; NOS) in neurones (nNOS) and endothelial cells (eNOS) and has functions ranging from neurotransmission and vasodilatation to inhibition of platelet adhesion and aggregation. Following bacterial infection, especially with Gram-negative organisms, its formation from L-arginine is enhanced due to the cytokine-mediated induction of a NOS enzyme (iNOS) in cells (e.g. cardiac myocytes, vascular smooth muscle) that do not normally have the ability to synthesize NO. ⋯ Because some of these detrimental effects are due to inhibition of eNOS, attempts have been made to examine the effects of substances with a higher selectivity for the induced form of the enzyme. In experimental animals, one of these (L-canavanine) protects endothelial cells from damage, increases survival time and restores vascular responsiveness without increasing blood pressure or peripheral vascular resistance. However, whether even this approach will be of benefit to patients with sepsis remains in doubt since studies in iNOS knock-out mice do not support the concept that eliminating this particular source of NO improves ultimate survival.
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The pathophysiology of sepsis has been studied intensively in recent years and a variety of opportunities for therapeutic intervention have been identified. A number of biological products including endotoxin antibodies, cytokine inhibitors and receptor antagonists have been evaluated after the failure of pharmacological doses of steroids to influence survival in septic shock. Despite a number of large, international multi-centre studies, the therapeutic promise of these various interventions remains unfulfilled. ⋯ Factors such as the appropriateness of antibiotic therapy, the adequacy of medical and surgical management, and the issue of withdrawal or withholding of life support are discussed in relation to these studies. Furthermore the role of an independent scientific extramural review committee is stressed, particularly in relation to the impact of confounding events of an unforeseen nature. The potential for improving the quality of the analyses of clinical trials of sepsis is illustrated by a recently completed study of the efficacy of a murine monoclonal antibody to human tumour necrosis factor-alpha.