Value of Animal Models

A great deal of literature exists with regard to canine, swine, and rodent models, but somewhat less information regarding simian or monkey (baboon) models is available. There are some significant interspecies variations in terms of biochemical responses, focus on organ injury, immune response, and neural-element (sympathetic nervous system) involvement. In the canine model there appears to be a significant bowel and splanchnic organ focus of injury, with a combination of endotoxin-like and toxic peptide autodigestive components contributing to the irreversible nature of shock. There is also an early and prominent sympathetic nervous system and adrenal cortical and medullary response. In the canine model splanchnic response to sympathetic nervous system activation and the increase in plasma catecholamines levels is augmentation of the circulating blood volume by autotransfusion from a large splenic reservoir, which does not exist to the same extent in other species.

The appearance of pulmonary injury occurs in a more delayed fashion. Some investigators have preferred the swine model and believe that the hemodynamic responses and cardiovascular reserve capacity more closely relate to the human pathophysiology of hemorrhagic shock. The rodent models provide easier access to large amounts of data, although the technical difficulties of complete cardiovascular monitoring are greater because of the size of the animals and limits to the technology for obtaining certain measurements in small animals. One advantage of the rodent model is the availability of a large number of genetic variants and gene-knockout models, making possible assessment of various tissue mediators, hormones, and neural components of the shock response. The use of simian models has been based on the fact that the animals' anatomy and physiology more closely approximate those of humans and their pathophysiologic responses to hemorrhagic hypotension or shock more closely resemble the human response. The simian models exhibit a more robust response, and the animals usually sustain a more prolonged survival and better outcome with exposure to the same level of hemorrhagic stress to which humans are exposed.

Technical Models

Two principal models of hemorrhagic shock exist: the controlled hemorrhage model and the uncontrolled hemorrhage model. The controlled hemorrhage model uses either bleeding to a predetermined pressure or a predetermined volume as a percentage of blood volume and body weight. In the Wiggers model (Wiggers, 1950), hemorrhage to a mean arterial blood pressure of 40 mm Hg is maintained for a predetermined period of time with measurement of the shed blood volume, various hemodynamic attributes, regional blood flow, biochemical markers of organ function, sympathetic nervous system activity, and the circulating concentrations in plasma of catecholamine and various hormonal indicators of stress such as cortisol. After the predetermined period the animals



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