Effects Of Hemodynamic Therapy And Inhibition Of Poly(ADP-ribose) Polymerase Over-activation On Tissue Energy Metabolism Disturbances Of Septic Shock

Background: Tissue energy metabolism disturbances induiced cell metabolic failure is the core of the problem of septic shock. The treatment of septic shock is based on hemodynamic therapy to correct tissue hypoxia, increase tissue energy production. But more evidences document that impaired oxygen utilization of cells contributes to tissue energy metabolism disturbance and outcomes of patients. Current hemodynamic therapy strategy using pre-determined goals only has effect on early stage of shock. There is no any effective method for cytopathic hypoxiay therapy. Recent years, Poly(ADP-ribose) Polymerase over-activation is presumed as a central mechanism of cytopathic hypoxia, but limited data are available from septic shock animal models, and the existing results are discordant. So, the treatment of septic shock reasearch should be performed from such two different aspects as developing hemodynamic therapy strategy and improving oxygen utility capacity of cells.Objective: To observe effects of improving hypoperfusive tissue hypoxia by hemodynamic therapy strategy and improving cytopathic hypoxia by inhibition of PARP on tissue energy metabolism disturbances of septic shock.Methods: Use retrospective analysis reviewed patients of refractory septic shock who were placed pulmonary artery catheters during a 5-year sequential period from 2001 to 2006 in intensive care unit of a teaching hospital in Beijing, China. Hemodynamic parameter, lactate concentrations and APACHE II scores were obtained to evaluate the relationship between hemodynamic therapy strategy and outcomes of patients.Animal study used New Zealand White rabbits. Animals were randomize divided into 4 groups: (A) no treatment (control group, n=6); (B) LPS injection without PARP inhibitor (shock group, n=7); (C) LPS injection with PARP inhibitor 3-AB (shock+3-AB group, n=7); and (D) No LPS injection but with PARP inhibitor 3-AB (inhibitor control group, n=6). A single bolus injection of LPS (2mg/kg) through centrol vein was adopted to make endotoxic shock model. PARP inhibitor 3-AB (15mg/kg) was given 10 minites before LPS injection. A pre-determined hemodynamic therapy strategy of achieving CVP at baseline, MAP≥80mmHg, and ScvO2≥70% was performed for shock resuscitation. Immunohistochemical staining for PARP was performed to confirm the activation and inhibition of PARP in liver and skeletal muscle. Energy metabolism of skeletal muscle was detected with high performance liquid Chromatogram (HPLC). Muscle NO concentration, skeletal muscle crude membrane Na⁺-K⁺-ATPase activity, artery blood lactate concentration, buffer excess, pH value, hepatic and renal functions were measured. Results: For refractory septic shock patients, except HR, PAWP were higher in nonsurvivors, other initial PAC derived hemodynamic parameters had no differences between survivors and nonsurvivors. Twenty four hours later, nonsurvivors had lower MAP and higher PAWP than survivors. But survivors had lower initial and 24-hour later blood lactate concentration, APACHEâ…¡scores. Compared different hemodynamic therapy strategies showed that combining CVP≥8mmHg, MAP≥65mmHg and SmvO₂≥65% as goal-directed therapy strategy, at twenty-four hours later patients who achieved the goals had significant lower lactate concentrations and APACHE II scores. Although there existed a decline trend comparing patients who achieved the goals or not, but there had no statistical significance. Patients who achieved the goal of increasing DO₂I more than 10% or patients who achieved the goal of supranormal strategy had no differences in lactate concentrations, APACHEâ…¡scores and fatality rate compared with patients failed achieving the goal. Lactate concentration had good predict value of prognosis. Current hemodynamic therapy strategy has limitation; the fatality rate is still high.PARP immunohistochemical staining confirmed the activation of PARP both in liver and skeletal muscle. Skeletal muscle energy metabolism measurement showed: ATP had no differences at the end of the 4th hour after shock between four groups. Group B had significant higher ADP than control group. PARP inhibition decreased skeletal muscle ADP in shock animals significantly. Skeletal muscle NO and crude membrane Na⁺-K⁺-ATPase activity increased significantly in group B. PARP inhibition decreased it significantly in group C, and had no differences compared with group A and D. Blood lactate concentration increased followed time after shock in group B, and had significant differences at all time points compared with control groups. In group C, blood lactate concentration increased at the end of the 1st hour after shock, and then it dropped to baseline. Except the 1st hour, there had significant differences between group B and C. Metabolic acidosis indices BE values dropped gradually along with observing time in LPS injection groups, and had significant differences at all time points compared with control groups. But group C had higher BE and pH values at the end of 4th hour compared with group B. Hepatic function measurement showed: inhibition of PARP significantly decreased ALT, LDH. Hemodynamic monitoring displayed: at the end of the 1 st and 2nd hour after the LPS injection, MAP of group B and C animalswere lower than group A and D significantly despite fluid resuscitation. But there were nodifferences between group B and C at any time point. HR, ScvO2, PaO2, PaCO2 and Hb hadno differences between all groups. The volume of fluid used to achieve the pre-determinedhemodynamic therapy goals were higher in group B and C than groups A and D, but therewere no differences between group B and C. There were no any difference between group Aand D.Conclusion: The Goal-Directed hemodynamic Therapy strategy can improve tissue energymetabolism disturbances and prognosis indices as a consequence of improving tissuehypoperfusive tissue hypoxia for prolonged septic shock patients. The existence of cytopathichypoxia restricts the effectiveness of hemodynamic therapy of septic shock. Inhibition ofPARP over-activity can further improve tissue energy metabolism disturbances, and organfunctions.