L-arginine infusion during resuscitation for hemorrhagic shock: impact and mechanism.

Trauma is the leading cause of death in the first four decades of life, and the fifth leading cause overall.1 In the early phase of hospital treatment, most of these patients die, succumb to neurologic injury, or hemorrhage.2 The insult of blood loss results in an inability for the oxygen supply to meet the demands of the body. Trauma and hypovolemia trigger multiple compensatory mechanisms, which include activation of the sympathetic nervous system, cardiac adjustments, hormonal changes, renal volume, and electrolyte alterations that act to preserve oxygenation and tissue blood flow. Some microcirculatory beds are rerouted to sustain flow to essential organs. In the hospital setting, hemorrhage is controlled and trauma-hemorrhage victims are resuscitated with intravenous crystalloid fluids to restore oxygen delivery. Despite these salvage mechanisms, victims may develop irretrievable loss of capillary bed perfusion (the no-reflow phenomenon), immune suppression, and systemic inflammation.2 After resuscitation, there may be ischemia-reperfusion injury that may precipitate further tissue damage, immunosuppression, sepsis, multiple organ failure, and death.3 Injury and blood loss manifest clinically with tachycardia, tachypnea, hypoxia, and hypotension. Persistent hypovolemia causes hypoperfused tissues and cellular hypoxia resulting in increased anaerobic cellular activity and increased levels of lactate.3,4 The endpoints of resuscitation are determined by a combination of clinical, laboratory, and invasive monitoring. Blood pressure, heart rate, and urine output, base deficit, and lactate are all used to monitor the extent of hemorrhagic shock.5 The role of the L-Arginine (L-Arg)-nitric oxide (NO) pathway in the regulation of tissue perfusion and modulation of the inflammatory response continues to evolve. L-Arg is an amino acid that may have antioxidant and immunomodulatory activity.6 NO is a downstream product of L-Arg oxidation formed by NO synthetase (NOS). The enzyme exists in an inducible form, which is activated by immunologic and inflammatory responses and a constitutive form that continuously produces low levels of NO, mainly in the vascular endothelium.7,8 Some studies have suggested that the augmentation of the L-Arg-NO pathway by the infusion of L-Arg can restore the depressed cardiac output and improve tissue hypoperfusion seen after trauma and hemorrhage.9–11 Other studies suggest that augmenting this pathway by providing L-Arg or NO donors may attenuate systemic and regional inflammation and improve outcomes after shock with or without the preceding trauma.12–14 Our previous study demonstrated increased survival of swine receiving L-Arg before lethal hemorrhagic shock, trauma, and resuscitation (unpublished data). The mechanism of these salutary effects of L-Arg have yet to be systematically demonstrated. The major aim of this study was to demonstrate that the beneficial effects seen after L-Arg administration in the setting of hemorrhagic shock are due to metabolism through the NO pathway.