translocation and the release of endotoxin do not appear to be significant mediators of these immune suppressive effects in short-term (up to 1.5-hour) models but may be a factor in longer-term (more severe) models.

Mechanistically, the process by which cell, immune, or organ function is altered appears to be biphasic. The initial early phase is characterized by acute cellular changes (metabolic dyshomeostatis, which consists of a decrease in adenosine triphosphate [ATP] levels and pH, increases in calcium ion [CA2+]I, etc.) associated with systemic proinflammation (an increase in tumor necrosis factor [TNF], interleukin-1 [IL-1], and IL-6 levels, etc.), which accounts for the early depression in the cellular response. This transitions over time to a chronic phase of mediator-induced (an increase in anti-inflammatory cytokine, nitric oxide [NO], and oxygen [O2] levels, etc.) or endocrine system-induced (prolactin, androgens versus estrogens, etc.) sustained immune system or organ dysfunction.

The advantage of mouse models in studying both the pathologic changes that occur during shock and the physiologic responses to acute hemorrhage is that inbred strains of mice have greater uniformity at the species level. Also, transgenic or gene-knockout strains provide animal models that are deficient in various mediators and that therefore add important information that often is not available by traditional pharmacologic approaches.

Swine Models of Combined Hemorrhage and Injury

Research conducted by Proctor (1998) relies on models in which tissue injury is superimposed on hemorrhagic shock, followed by administration of the same type of fluid resuscitation that would be available in the combat or civilian setting. The strength of the model is that injury is always associated with hemorrhage. The addition of tissue injury activates the inflammatory process (neurohumoral factors), which alters the response to hemorrhage.

Trauma and shock produce whole-body ischemia, and resuscitation produces a reperfusion injury. During the traumatic insult, there is decreased blood flow and oxygen delivery and breakdown of ATP to adenosine. Proctor (1998) is investigating in a swine model the roles of increased adenosine levels and altered neutophil activation. The data collected in that research, however, are relevant only to those who survive to the point of first aid. Nonetheless, Proctor has found that there is, in fact, secondary injury caused by the activated white blood cells, which can be affected by altering CD 18 cells or granulocyte colony-stimulating factor (GCSF). The only way that these changes can occur, however, is by administering a secondary insult. These studies have also shown that liquid ventilation is able to produce the same protective effects as positive end expiratory pressure without the negative hemodynamic actions.



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