Septic Shock

Peter Brouckaert, Molecular Pathophysiology and Experimental Therapy Unit, Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Gent, Belgium

Sepsis is a systemic inflammatory response syndrome resulting from and complicating an infection. The clinical expression is extremely variable, but temperature dysregulation, tachypnea, tachycardia and leukocyte redistribution are common features. When the situation deteriorates, severe sepsis and septic shock may develop, with circulatory insufficiency, inadequate organ perfusion, capillary leak, an imbalance between oxygen demand and supply, and metabolic dysregulation. This may be further complicated by diffuse intravascular coagulation and multiple organ dysfunction syndrome.

The incidence of sepsis is increasing, presumably due to the improved possibilities of medical technology, which allows the survival of patients with important dysfunctions. Although this syndrome and related entities have attracted the attention of numerous (pre)clinical researchers, both from academies and industrial companies, the resulting gain in our understanding of sepsis has so far not been translated into an improved efficacy of treatment. The prognosis of patients with severe sepsis, septic shock and multiple organ dysfunction syndrome remains poor.

The question whether the data collected from (pre)clinical research during the last decades have brought more insight into the relevant pathways leading to lethality is appropriate. The complex pathophysiology of this entity, in which almost all organs and all physiological systems may become involved in a redundant, concerted and interacting way, perhaps leads to a self-sustaining chaotic situation, in which our mechanistic approaches are inadequate. Furthermore, the highly variable clinical expression of these syndromes has led some authors to propose that these syndromes only exist in the mind of clinicians and researchers, and are in fact a variety of disparate pathological processes. Or, in other words, every patient with sepsis has his or her own subtype of the syndrome with a unique pathophysiology. The latter is not only determined by the original provoking challenge, but maybe more importantly by underlying, concomitant disorders and the reactivity of the individual patient. This not only makes it difficult to design an adequate treatment, but also hampers the development of relevant animal models and the design of clinical trials. Perhaps the most devastating concept which inhibited progress was the acceptance of the existence of 'black knights', central mediators of sepsis that would be responsible for the major deleterious, and only for deleterious, events. During the last years, the insight has grown that these presumed central mediators, such as tumor necrosis factor and nitric oxide, are in fact also indispensable to survive major challenges. It is only when the reaction of the body becomes malignant, i.e. uncontrolled, self-sustaining and chaotic, that the deleterious effects become predominant.

Table 1 Definitions

Infection = microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms Bacteremia = the presence of viable bacteria in the blood

Systemic inflammatory response syndrome (SIRS) = the systemic inflammatory response to a variety of severe clinical insults. The response is manifested by two or more of the following conditions: 1) temperature >38°C or <36°C; 2) heart rate >90 beats per minute; 3) respiratory rate >20 breaths per minute or Paco2 <32 mmHg; and 4) white blood cell count >12 000 per cu mm, <4000 cu mm, or >10% immature (band) forms

Sepsis = the systemic response to infection, manifested by two or more of the following conditions as a result of infection: 1) temperature >38°C or <36°C; 2) heart rate >90 beats per minute; 3) respiratory rate >20 breaths per minute or Paco? <32 mmHg; and white blood cell count >12000 per cu mm, <4000 cu mm, or >10% immature (band) forms Severe sepsis = sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status Septic shock = sepsis-induced with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured

Sepsis-induced hypotension = a systolic blood pressure <90 mmHg or a reduction of &40 mmHg from baseline in the absence of other causes for hypotension

Multiple organ dysfunction syndrome (MODS) - presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention

Reproduced with permission from Bone et al (1992).

It may be expected that this cluster of syndromes will remain a major challenge for the biomedical community. The results from such a major effort most likely will also find applications in. less dramatic inflammatory responses.

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