serve to scavenge or neutralize free radicals, maintaining effective balance between free-radical production and removal (Babbs, 1988).

Oxygen-Derived Free Radicals

The role of free radicals in hemorrhage and shock arises from the fact that volume replacement or reperfusion of previously ischemic tissues has been recognized to produce significant tissue injury and dysfunction. This phenomenon has been described as the "oxygen paradox" and describes the fact that although the restoration of oxygen delivery to ischemic tissue is essential to the maintenance of function and survival, this oxygen may initiate a cascade of deleterious events, producing tissue injury. The free radicals produced during reperfusion or fluid resuscitation from hemorrhagic shock attack multiple components of the cell, including lipids, nucleic acids, and proteins. Therefore, although hypoperfusion itself will produce cellular death with time, the very act of correcting the perfusion deficits introduces significant and greater injury. McCord and Fridovich (1968) proposed that the major source of free radicals during reperfusion was the enzyme xanthine oxidase, an enzyme that is present in the liver and gut.

A decrease in blood flow limits the available oxygen required for adenosine triphosphate (ATP) production. ATP depletion produces a subsequent rise in the level of adenosine monophosphate (AMP), which, in turn, is catabolized to hypoxanthine. With fluid resuscitation and the return of molecular oxygen to previously hypoperfused tissues, hypoxanthine serves as a substrate for xanthine oxidase. A complicated series of reactions converts hypoxanthine to xanthine and finally to uric acid and in the process generates hydrogen peroxide and superoxide, both of which are powerful oxidizing agents. The resulting increased production of superoxide and hydrogen peroxide overwhelms the capacity of endogenous scavengers. Hemorrhagic shock produces "whole-body" ischemia with inadequate perfusion of most tissues. As ATP levels fall dramatically in several tissues, the levels of hypoxanthine in plasma rise. The role of hypoxanthine in hemorrhagic shock was first suggested by Crowell and associates (1969) and was confirmed by others; those studies found that allopurinol provides significant benefits if it is given during blood loss (Bulkley, 1983; Hess et al., 1982; Parks, 1982; Powell and Tortolani, 1992; Rao et al., 1983). Numerous subsequent studies have confirmed the hemodynamic and cardioprotective effects of free-radical scavengers given during either ischemia or shock with hemorrhage (Bernier et al., 1986; Crowell et al., 1969; Cunningham and Keaveny, 1978; Granger et al., 1986; Lee et al., 1987).

Although a major source of oxygen-derived free radicals in hemorrhagic shock is xanthine oxidase, others have shown that adherent and activated neutrophils produce free radicals. Although this serves an important and necessary role in the scavenging of invading bacteria, a burst of neutrophil-produced free radicals may exacerbate the xanthine oxidase activity, producing significant



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