New Therapeutic Measure Of Vascular Hyporeactivity In Septic Shock And Sex And Age Difference Of Vascular Hyporeacitvity

Septic shock is one of severe clinical complication in ICU, The incidence rate is rising gradually,The mortality is still very high although many efforts.Sepsis is a kind of systematic disease,which needs comprehensive treatments.Earlier diagosis and earlier active treatment are the important interventions for improving the prognosis for severe sepsis and septic shock.Among which the early-goal-directed therapy strategy can significantly elevate resuscitation success rate and decrease severe complications.But most severe sepsis and septic shock patients are resistant to fluid resuscitation and vasoactives,Refractory hypotension led by vascular hyporeactivity is a big obstacle for realizing the early treatment goal of sepsis and septic shock.Our previously study showed AVP could improve vascular hyporeactivity in hemorrhagic shock,t Other reports showed AVP can be used in vasodilatory shock,which could elevate MAP.International surviving sepsis campaign suggests AVP is the last selection for those septic shock patients who are resistant to other vasoactives as norepinephrine(NE).SSC also suggests that continous infusion of AVP may be better than bolus input.Another international multi-center randomly double-blinded study for AVP in septic shock found that AVP might be beneficial for patients with low-dose NE treatment,They can shorten the Hospitalization periods,improved the survival.This evidence hinted that continuous infusion of AVP in earlier period may help to realize the early resuscitation goal by improving vascular hyporeacitivity in severe sepsis and septic shock,and decrease the complications.There are two kinds of vasopressin in clinical application:arginine vasopressin(AVP) and terlipressin(TP),The half-time of TP is longer than AVP.The affinity of TP to V1 R is more specific than AVP,So we hypothesized that TP on improving vascular reactivity is more effective than AVP,and has better effect in septic shock to increase the early resuscitation success rate..Based On these issues in the present study,We firstly studied the therapeutical effect and possible mechanism of AVP and TP on septic shock with rabbit endotoxic shock and rat septic shock model comparatively.Then we observed the application value of low-dose of TP in septic shock patients in increasing the early resuscitation success rate of septic shock. Eventually,based on sex difference of host to trauma insult reported by current literatur,we further investigated age and sex difference of vascular reactivity in trauma hemorrhagic shock animals and patients and the role of estrogen.Main Methods:Part 1 Effect of AVP and TP in endotoxic rabbits and septic shock rats.1. Systematic vascular reactivity and resuscitation effect:With LPS-induced endotoxic shock rabbits and CLP-induced septic shock rats model,effect of continous infusion of AVP(0.03u/hr/kg,same as in follow) and TP(2.6μg/kg/h, same as in follow) after enough fluid resuscitation on global vascular reactivity,animal survival time and survival rate were observed.2. Vascular reacitivity in vitro:With endotoxic shock rabbits and septic shock rats,Superior mesenteric artery(SMA) was sampled after AVP and TP administrationfor the measurement of the vascular reactivity to NE..3. Effect of AVP on Rho A/Rho-kinase activity in endotoxic shock rabbits: With endotoxic shock rabbits,SMA was sampled after AVP administration at differe nt time,The activity of Rho A/Rho-kinase was determined to oberve mechanism of AVP in improving vascular reactivity in septic shock animals.Part 2 Effects of low-dose of TP on early resuscitation success rate for septic shock patientsApproved by Ethics Committee of our hospital,according to septic shock diagnosis and treatment criterion of 2008 guideline,32 cases of septic shock patients were recuited and divided into NE treatment group(17 cases) and low-dose of TP group(15 cases).NE usage,vital sign, blood gases,vital organ function,vascular reactivity,some side effects and early resuscitation goal were observed.TP(1.3μg/kg/h) in TP+NE group was given only the hemodynamics can’t be maintained only by NE infusion.Part 3 Age and sex difference of vascular reactivity in normal and traumatic shock victims and effect of estrogen.1. With 177 healthy adults of 21-82 years old,the age and sex difference of vascular reactivity were observed by observing the changes of blood flow of endouasal mucosa.2. The age and sex difference of vascular reactivity of trauma patients to ephedrine, dopamine and phenylephrine were observed in 842 trauma patients by retrospective analysis.3. With different age and sex normal and traumatic shock rats(4 weeks to 1.5 years),The age and sex difference of vascular reactivity and the role of estrogen were observed.Main results:ⅠEffect of AVP and TP in endotoxic rabbits and septic shock rats.1. Global vascular reactivity and resuscitation effect:continous infusion of AVP or TP could significantly increase the MAP, stabilize hemodynamics,and improve the vascular reactivity in endotoxic rabbits.TP+NE was superior to AVP+NE.Further results showed that AVP or TP all could prolong the survival time,and 6-hr and 24-hr survival rate,also TP+NE was better than other groups.Equally,AVP or TP significantly improved MAP and vascular rea ctivity,prolonged the survival time and 24-hr survival rate in septic shock rats.TP or TP+NE also was better than AVP or AVP+NE.2. Beneficial effect on vascular reactivity in vitro:As compared to control group,the vascular reactivity of endotoxic shock rabbits was significantly decreased,the dose-response curve was shifted to right,the maximal tension(Emax) was significantly decreased(P<0.01).AVP or TP could significantly increase the vascular reactivity of endotoxic shock rabbits, the maximal tension( Emax) was increased(P<0.01).As the same as in endotoxic shock rabbits. AVP or TP could significantly increase the vascular reactivity of septic shock rats.TP or TP+NE groups were better than AVP or AVP+NE respectively.3. Effect of AVP on the activity of Rho A/Rho-kinase in endotoxic shock rabbits:The results displayed the activity of Rho-kinase was decreased significantly in endotoxic shock rabbits.Application of AVP could significantly increase the activity of Rho A and Rho-kinase.Ⅱ Effects of low-dose of TP on early resuscitation success rate for septic shock patients1. Low dose of TP helped realize the early resuscitation goal of septic shock patients:Results displayed low-dose of TP could help NE elevate MAP,increased the success rate early resuscitation goal for septic shock patients.Which was increased from 47% in control group to 73.3% in TP group.MAP could be maintained around 80 mm Hg,SPO2 was near to 95%,central venous oxygen saturation exceeded 70%,and 75% of patients had urine volume exceeding 0.5ml/kg/hr after low dose of TP given..2. TP could decrease the side effects:The results displayed that low dose of TP not only improved the hemodynamics but also reduced the dose of NE for septic shock patients, Meanwhile The incidence rate of anuria was significantly decreased after TP administration,The side effects that AVP commonly had did not appear after TP application such as the decrease of blood platelet count,the damage to liver and renal function,and water-sodium retention.Also there were no coagulation dysfunction and cutaneous necrosis lesions appeared after TP administration.3. Effect of TP on vascular reactivity:Results obtained from small vessels ultrasound displayed that the caliber of radial artery was significantly contracted,its blood flow velocity was significantly accelerated after TP administration.As compared with NE group alone,the vascular reactivity of septic shock patients was greatly improved in TP+NE group.Ⅲ Age and sex difference of vascular reactivity in normal and traumatic shock victims and effect of estrogen.1. Age and sex difference of vascular reactivity in health adults and trauma patients(1)Vascular reactivity of females was better than age-matched males in health adults.Along with aging,especially after 40 years old,The vascular reactivity was gradually decreased,The decrease degree in females was lower than males,but there was no sex difference in vascular reactivity after 60 years old.(2)There was significant age and sex difference of vascular reactivity in severe trauma patients.The results of 842 patients in our study displayed that the pressure response in middle-aged(45-59 years) and youth(21-44 years) patients to vasoactives such as ephedrine,dopamine and phenylephrine was better than aged trauma patients(≥60 years).Equally,The pressor response to vasoactives was better in females than in age-matched males,also there wasn’t sex difference after 60 years old.2. Age and sex difference of vascular reactivity in health and traumatic hemorrhagic shock rats as well as the effect of estrogen(1)In health rats:vascular reactivity in female rats were better than age-matched male rats during the period of reproductive(8-24 weeks),As age increase,the sex difference was gradually reduced,there was no sex difference in old rats.(2)In trauma shock rats:There was significant age and sex difference in vascular reactivity in trauma shock rats.The vascular reactivity in male rats decreased more obviously than the same as female rats after traumatic hemorrhagic shock.The loss rate of vascular reactivity after shock was not different between males and females in 1-1.5 years old rats.(3)Role of estrogen:Supplementation of estrogen(17-βestradiol 0.1mg/kg,iv) for one week could significantly improved the vascular reactivity in both female and male rats in reproductive period.But there was no effect on vascalar reactivity in 1.5 years old rats. Further study found that estrogen(17-βestradiol 0.1mg/kg,iv) could also significantly improve the vascular reactivity of traumatic hemorrhagic shock rats,improved the survival rate and survival time of shock animals.Conclusion:1. Animal experiments displayed there was significant vascalar hyporeactivity in septic shock rats and rabbits, which showed obvious resistance or no response to enough fluid resuscitation and vasoactives.Low-dose of AVP or TP with or without NE could improve the vascular reactivity and increase the animal survival of septic shock.TP or TP+NE were better than that in AVP or AVP+NE.2. Clinical trial showed TP could help NE to increase the early resuscitation goal success rate in septic shock patients who were resistant to NE.decreased the incidence of long-term complications,and prolonged the survival time of septic shock patients. Furthermore, TP can reduce NE dose,lessen the side effects that AVP had.It may be a good first-aid measure for realizing early resuscitation goal in septic shock patients.3. AVP could greatly increase the activity of Rho A/Rho-kinase in vascular smooth muscle cell,suggesting that AVP and TP possessed the beneficial effect on septic shock via influencing the activity of Rho A/Rho-kinase and then improved the vascular reactivity.4. Vascular reactivity has age and sex differences both in normal and shock state.estrogen had protection effect on vascular reactivity,especially to trauma hemorrhagic shock victims. These findings suggested that estrogen might be one of effective adjunctive measures to clinical critical illness such as traumatic shock and septic shock.