William J. Schirmer

Complement-mediated hemodynamic depression in the early postburn period.

This study examines the influence of complement on systemic hemodynamics following severe thermal injury in rats. Animals were injected intraperitoneally at t = -36 and t = -24 hours with either cobra venom factor (20 units/kg/dose; n = 56) to delete circulating complement or with saline alone (n = 64). Rats within each subset were then subjected to either a 50% TBSA full-thickness scald burn or sham burn. Cardiac output (CO), mean arterial pressure (MAP), heart rate, systemic vascular resistance (SVR), stroke volume, and cardiac power as well as hematocrit and the change in per cent complement activity were determined at various time periods between 15 minutes and 25 hours after the burn. In normocomplementemic animals the burn produced a marked early (t = 3-6 hours) depression in CO and MAP with a rise in SVR. Over time the hemodynamics returned to normal (t = 12 hours) and eventually approached a hyperdynamic response (t = 24 hours). Serum hemolytic complement activity fell immediately and progressively after the burn, indicating significant complement activation. Complement depletion attenuated the early decline in CO and sharply lowered the rise in SVR in the early postburn period. In addition, complement depletion improved heart rate and stroke volume and appeared to preserve/enhance late (t = 24 hours) cardiac function. This study suggests that complement activation contributes to the depression in cardiac output in the early postburn period.

Contribution of toxic oxygen intermediates to complement-induced reductions in effective hepatic blood flow

This study examines the effects of complement activation and of complement-induced oxygen radical production on the principal determinant of hepatic function, i.e., effective hepatic blood flow (EHBF). Female Sprague-Dawley rats received cobra venom factor, 40 units/kg, in two divided doses at 30-minute intervals. At t = 2 hours, thermodilution cardiac output, mean arterial pressure, heart rate, hematocrit, and EHBF by galactose clearance were determined. Complement activation produced a significant depression in EHBF independent of changes in systemic perfusion. To determine whether oxygen radicals participated in the insult, additional animals were pretreated with superoxide dismutase, 6 mg/kg, plus catalase, 15 mg/kg, immediately before complement activation. Concomitant treatment with the oxygen radical scavengers attenuated the degree of complement-induced hepatic ischemia, again independent of effects on systemic perfusion. This study suggests that the reduction in hepatic blood flow that accompanies animal models of trauma and sepsis may result, in part, from the sequelae of complement activation with oxygen radicals as secondary mediators.

Flow redistribution in a hyperdynamic small animal burn: comparison to patterns in sepsis.

Visceral hypoperfusion with local accumulation of lactate in the ischemic tissues has been reported in a septic rat model despite a hyperdynamic systemic circulation. This visceral ischemia is felt to contribute to the multiple system organ failure (MSOF) syndrome associated with sepsis. The purpose of this study was to determine whether a similar redistribution of blood flow existed in rats after a severe thermal injury as it too is associated with MSOF. Twenty-four hours after animals were subjected to either a resuscitated 50% scald burn (BURN) or sham treatment (SHAM), thermodilution cardiac output (CO), effective hepatic blood flow (EHBF) by galactose clearance at low concentrations, effective renal plasma flow (ERPF) by para-aminohippurate clearance, and blood, liver, and skeletal muscle pyruvate (P), and lactate (L) concentrations were determined. CO increased 52% in BURN (46.5 +/- 2.8 ml/min/100 g, n = 21) versus SHAM (30.7 +/- 1.0 ml/min/100 g, n = 22; P less than 0.001) while EHBF increased only 18% (BURN: 6.81 +/- 0.36 ml/min/100 g, n = 8 vs SHAM: 5.77 +/- 0.29 ml/min/100 g, n = 8; P less than 0.025) and ERPF showed an insignificant 24% increase (BURN: 2.98 +/- 0.32 ml/min/100 g, n = 6 vs SHAM: 2.40 +/- 0.40 ml/min/100 g, n = 6; P less than 0.10), demonstrating a redistribution of flow. There was no local accumulation of lactate in blood, liver, or skeletal muscle and no derangement in P/L ratios. This study when compared to previous observations in sepsis suggests that (1) the flow redistribution of sepsis has features differentiating it from solely a stress response.(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol and lodoxamide in complement-induced hepatic ischemia☆

Intravascular complement activation with either zymosan or cobra venom factor (CVF) impairs hepatic blood flow. Oxygen radical scavengers given at the time of complement activation attenuate the resulting hepatic ischemia. It is not clear whether complement-stimulated phagocytes or transiently ischemic then reperfused endothelial and parenchymal cells generated the toxic oxygen radicals. In this study, a group of rats were given allopurinol (50 mg/kg/day postoperatively X 3 days plus 100 mg/kg iv at t = 0), a specific inhibitor of xanthine oxidase, prior to complement activation with CVF (20 units/kg iv at t = 30 and 60 min) to determine whether xanthine oxidase-derived oxygen radicals contributed significantly to the hepatic perfusion abnormalities. Additional rats received lodoxamide tromethamine (10 mg/kg iv bolus at t = 0 followed by 20 mg/kg/hr iv infusion), a novel and potent inhibitor of mast cell release and inhibitor of xanthine oxidase, prior to the same CVF challenge to determine whether mast cell mediators were involved in the flow disturbance. Thermodilution cardiac output, mean arterial pressure, heart rate, hematocrit, and effective hepatic blood flow (EHBF) by galactose clearance were determined at t = 2 hr. The percentage change in total hemolytic complement activity (% delta CH50) was determined between serum obtained prior to sacrifice and at t = 0. Systemic hemodynamics and HCT were for the most part unaffected regardless of pretreatment group or challenge with CVF or saline. CVF challenge produced a 25% reduction (P less than 0.05) in EHBF in vehicle-pretreated rats compared to saline challenge. Neither allopurinol nor lodoxamide tromethamine significantly improved EHBF when given prior to CVF challenge.(ABSTRACT TRUNCATED AT 250 WORDS)