Clinical And Experimental Research For Cellular Energy Crisis During The Resuscitation Of Sepsis

Objective:To investigate the performance for combining PI and P(v-a)CO2/C(a-v)O2 ratio to identify poor lactate clearance and incoherence during the resuscitation of critically ill patients with sepsis.And,to study the effect of panx-1 mediated release ATP from the cell on the cellular energy crisis in the sepsis rabbit model.Methods:1.clincal investigation:the patients with sepsis were prospectively observed,who admitted to critically care medicine department of PUMCH from Nov 2013-Feb,2014.The hemodynamic parameters,simultaneous arterial and central venous blood gas analysis and PI were obtained at the enrollment(TO)and 8hours(T8)during resuscitation.The patients were divided into two groups according to lactate clearance at T8 after resuscitation:an LC group with LC>10%and a Non-LC group with LC?10%.Additionally,the patients also divided into three sub-groups according to the PI value at T8:the normalized PI group with PI>1.4,the mild impaired PI with 1.4<PI<0.6 and severe impaired PI with PI<0.6.2.Experimental investigation:24 anesthetized and ventilated rabbits were randomly assigned to receive one of four treatments:infusion LPS without probenecid(LPS group),infusion LPS with probenecid(PLS+ Pro group),sham of operation without probenecid(control group)and sham of operation with probenecid(control+ Pro group).The inflammatory factors,serum ATP level,expression of Panx-1 in sketel muscle tissue,and the content of APT and ADP in muscle tissue,pathological damage in the skeletal muscle,cardiac tissue,renal tissue were measured and compared between groups.Result 1.clincal investigation:a total of 84 patients were enrolled in this study,and 168 pairs venous-arterial gas analysis were obtained.?.8h-lactate clearance rate were significantly negative correlated with the P(v-a)CO2 gap(r=-0.226,P=0.039),P(v-a)CO2/C(a-v)O2(r=-0.218,P=0.046)and significantly positive correlated to the PI(r=0.266,P=0.014).However,the 8h-lactate clearance rate was not related to ScvO2,MAP and CVP.?.The LC group had a significantly lower P(v-a)CO2,P(v-a)CO2/C(a-v)O2 ratio and higher PI at T8 after resuscitation than the Non-LC group.? The areas under the ROC curves of the P(v-a)CO2/C(a-v)O2 ratio for predicting the LC>10%was significantly better than the ScvO2.There were 65 patients with a normalized ScvO2(?70%)at T8 after resuscitation.A cutoff 1.23 of P(v-a)CO2/C(a-v)O2 ratio to predict LC>10%with a 91.7%sensitivity and 53.7%specificity,and the area of ROC was 0.769.?.There was a higher LC percentage in the normalized PI group than the severely impaired PI group after resuscitation(71%vs 37%,?2 = 6.591,P =0.01).Moreover,the non-LC patients(13/32)still had a higher P(v-a)CO2/C(a-v)O2 ratio than the LC patients in the subgroup with normalized PI.However,there is no significant difference in PI?ScvO2?MAP?P(v-a)CO2 between Non-LC patients and LC patients who had been normalized the PI.Furthermore,multivariate analysis showed P(v-a)CO2/C(a-v)O2 ratio(Exp(B)2.235,95%CI 1.232-4.055,P=0.008)was an independent risk factor of Non-LC.2.Experimental investigation:?.The PLS group had a significantly higher serum ATP,TNF-a,IL-6,IL-1?,lower skeletal muscle ATP level,a lower ratio of muscle ATP/ADP and worse pathological damage of muscle,cardiac and renal tissue than the control group.? The LSP group has a significantly higher expression of Panx-1 in the skeletal muscle tissue than the control group.Moreover,there was a significantly higher expression of Panx-1 of blood cell between baseline and T1 after the LPS.And,the serum ATP level was significantly positive correlated to the TNF-a,IL-6 and IL-1? level in all the measurements.?.The LPS+Pro had a significantly lower inflammatory factors level,serum ATP level,the ATP content and ATP/ADP ratio in skeletal muscle tissue,histopathological damage in skeletal muscle,cardiac and renal tissue.Conclusions:Both of high P(v-a)CO2/C(a-v)O2 ratio and impaired PI were related to non-lactate clearance after resuscitation in sepsis,and the combination of Ratio and PI could be helpful to determine the incoherence of resuscitation and provide information to optimize the lactate clearance.The P(v-a)CO2/C(a-v)O2 ratio still work as a marker to assess the cellular oxygen metabolism when the ScvO2 or PI has been normalized after resuscitation,and it might be a potential target of resuscitation for cellular energy.A high expression of Panx-1 mediated release ATP from cell plays an important role in the energy crisis and organs injury in the sepsis.Inhibiting Panx-1 mediated release ATP from cell decrease the inflammation response and restore skeletal muscle tissue energy metabolism,and attenuates skeletal muscle,cardiac,renal injury induced by sepsis...