ABSTRACT
Systemic complement activation has been noted in a variety of shock states, and there is growing evidence that, in addition to being proinflammatory effectors, products of complement activation contribute directly to generalized manifestations of shock, such as hypotension and acidosis. To study the effects of complement activation, we examined responses in rats to systemic activation of complement with cobra venom factor (CVF), including blood pressure, metabolic acidosis, changes in vascular permeability, and lung function. High doses of CVF produced circulatory collapse (mean arterial pressure = 110 +/- 16 and 35 +/- 9 mmHg in control and with CVF, respectively, P < 0.05), metabolic acidosis (HCO concentration = 27.8 +/- 1.7 and 9.6 +/- 3.4 meq/l in control and with CVF, respectively, P < 0.05), extravasation of albumin into the lung and gut, and modest arterial hypoxemia (PO2 = 486 +/- 51 and 201 +/- 36 Torr in control and during 100% O2 breathing, respectively, P < 0.05). Prior depletion of complement protected against these abnormalities. Other interventions, including neutrophil depletion and cyclooxygenase inhibition, prevented lung injury but had much less effect on systemic hemodynamics or gut permeability, suggesting that complement activation products induce injury by neutrophil- and cyclooxygenase-dependent pathways in the lung but not in the gut. These studies underscore the significant systemic abnormalities developing after systemic activation of complement.
Subject(s)
Complement Activation/physiology , Hemodynamics/physiology , Lung/physiology , Acidosis/metabolism , Animals , Blood Pressure/physiology , Capillary Permeability/drug effects , Complement Inactivator Proteins/pharmacology , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Elapid Venoms/pharmacology , Enzyme Inhibitors/pharmacology , Hemodynamics/drug effects , Intestine, Small/pathology , Isoenzymes/metabolism , Lung/pathology , Lysine Carboxypeptidase/antagonists & inhibitors , Myocardium/pathology , Neutrophils/physiology , Oxygen/blood , Phospholipases A/antagonists & inhibitors , Prostaglandin-Endoperoxide Synthases/metabolism , Rats , Respiratory Function TestsABSTRACT
The complement system has been implicated in early inflammatory events and a variety of shock states. In rats, we measured complement activation after hemorrhage and examined the hemodynamic and metabolic effects of complement depletion before injury and worsening of complement activation after hemorrhage and resuscitation [with a carboxypeptidase N inhibitor (CPNI), which blocks the clearance of C5a]. Rats were bled to a mean arterial pressure of 30 mmHg for 50 min and were then resuscitated for 2 h. Shock resulted in significant evidence of complement consumption, with serum hemolytic activity being reduced by 33% (P < 0.05). Complement depletion before injury did not affect hemorrhage volume (complement depleted = 28 +/- 1 ml/kg, complement intact = 29 +/- 1 ml/kg, P = 0.74) but improved postresuscitation mean arterial pressure by 37 mmHg (P < 0.05) and serum bicarbonate levels (complement depleted = 22 +/- 3 meq/ml, complement intact = 13 +/- 8 meq/ml, P < 0.05). Pretreatment with CPNI was lethal in 80% of treated animals vs. the untreated hemorrhaged group in which no deaths occurred (P < 0.05). In this model of hemorrhagic shock, complement activation appeared to contribute to progressive hypotension and metabolic acidosis seen after resuscitation. The lethality of CPNI during acute blood loss suggests that the anaphylatoxins are important in the pathophysiological events involved in hemorrhagic shock.
Subject(s)
Complement Activation , Shock, Hemorrhagic/immunology , Acidosis/metabolism , Acidosis/physiopathology , Animals , Blood Pressure , Complement Activation/drug effects , Complement Inactivator Proteins/pharmacology , Elapid Venoms/pharmacology , Lysine Carboxypeptidase/antagonists & inhibitors , Male , Myocardial Ischemia/physiopathology , Myocardial Reperfusion , Rats , Rats, Sprague-Dawley , Resuscitation , Shock, Hemorrhagic/metabolism , Shock, Hemorrhagic/physiopathology , Survival RateABSTRACT
OBJECTIVE: To determine whether epinephrine in combination with high flow worsens left ventricular (LV) myocardial high-energy phosphate stores during reperfusion of ischemic ventricular fibrillation (VF). DESIGN: Blinded, prospective block randomized, placebo controlled study. SETTING: University medical center research laboratory. SUBJECTS: A total of 22 mixed breed swine weighing 22.0+/-3.3 kg (SD). INTERVENTIONS: Open-chest swine, anesthetized with alpha-chloralose, underwent 10 mins of nonperfused VF followed by reperfusion with cardiopulmonary bypass for 90 mins and then defibrillation. Animals were block randomized to four groups for reperfusion: Group 1 (n = 5), high flow (100 mL/kg/min) and epinephrine (2.5 microg/kg/min); Group 2 (n = 5), high flow and placebo; Group 3 (n = 6), low flow (30 mL/kg/min) and epinephrine; and Group 4 (n = 6), low flow and placebo. MEASUREMENTS AND MAIN RESULTS: In vivo LV creatine phosphate (CP) and adenosine triphosphate (ATP) were determined using whole wall and spatially localized 31P NMR spectroscopy at 4.7 Tesla. During perfusion of the fibrillating myocardium, epinephrine significantly increased aortic pressure (p < .05) and improved defibrillation rates (p < .01). ATP levels during reperfusion were significantly decreased within all groups compared with baseline. There were no differences in ATP levels between groups. High flow, independent of epinephrine, was associated with increased preservation of ATP (p < .05), increased CP/ATP ratios (p < .02) in all layers of the LV wall, and decreased aortic and cardiac vein lactates (p < .001). CONCLUSIONS: Epinephrine, in combination with flow higher than standard cardiopulmonary resuscitation flows, increased perfusion pressure and defibrillation rates, but did not significantly alter myocardial ATP during VF reperfusion in the in vivo heart Reperfusion flow, independent of epinephrine, is a critical determinant of myocardial ATP preservation.
