Novel Resuscitation Strategies In The Mangement Of Traumatic Hemorrhagic Shock And Their Mechanisms

Treatment of traumatic hemorrhagic shock (THS) involves early control of bleeding and resuscitation as well as organ support and rehabilitation during the late stage. Although much progress has been made in the management of trauma, the treatment of severe trauma confronts substantial methodology issues. In recent years, however, novel resuscitation strategies have been attempted following continuous understanding of trauma. Nonetheless, their influences on patient outcome remain largely unknown which requires to be urgently explored both in the basic and clinic settings. Herein, we studied the effects of short-term therapeutic mild hypothermia (TMH), early target atrial pressure after control of bleeding, and exogenous treatment with atrial natriuretic peptide (ANP) in THS. Our purpose was to explore the roles they played in and the mechanisms underlying the early course of THS. To achieve this, we firstly established a rabbit model of multiple trauma, which incorporates bone fracture, abdominal soft tissue injury, and hemorrhagic shock. Our results showed that the fractures were all closed and comminuted, level of shock was III, and multiple blood parameters met the pathologic changes of hemorrhagic shock. Animals those who were not resuscitated died early, with resuscitation improved their survival time and reduced mortality. Based on this model, we studied two resuscitation strategies, aggressive vs limited fluid resuscitation, with or without short-term TMH on the influence of THS. Our results showed that aggressive fluid resuscitation increased fluid infusion before hemostasis and increased blood loss. TMH improved early survival and cardiac systolic function and reduced lung injury. Moreover, TMH did not influence the changes in electrolytes and acid-base imbalance. Overall, TMH during limited fluid resuscitation resulted in the best outcome compared with the rest studied groups. TMH may improve early outcome through the Bohr effect involving low pH value. Based on these findings, we extended our study scope to explore the ideal target arterial pressure after initial hemostasis, as current clinical guidelines’recommendation does not cover this topic but emphasizes restoration from pathology as quickly as possible, the point of which has never been verified but recently been questioned. Accordingly, our study confirmed, as was previously studied by others using another animal model with lighter injury severity, that in rabbits the ideal target MAP during the initial resuscitation of severe THS after hemostasis was70mmHg. As rabbits in this study received large volume of crystalloid solution, the serum ANP may increase as a result of cardiac stimulus. Thus we measured serum ANP level during volume loading which was found to be increased with the increase of fluid volume. Moreover, correlation analysis revealed that ANP was related to the expression of survival protein (Akt) and correlated negatively with interleukin-10in the bronchoalveolar lavage fluid at7h following trauma. This finding implies that ANP may have a pivotal role in the organ protection and inflammatory response. To confirm this, we established a rat model of THS (injury severity was lighter than the previous model), rats were treated with exogenous ANP for1h (0.025μg/kg/min) during hemorrhagic shock. They were then resuscitated and observed until24h. Data showed that during THS, ANP treatment did not have an influence on hemodynamics but protected hepatorenal function. Moreover, ANP transiently inhibited anti-inflammatory response. But long-term effect was not evident after treatment being ceased. ANP treatment may enhance nonspecific immune response by increasing oxidative stress in multiple organs. The cardiac tissue showed significantly reduced apoptosis after ANP treatment, this was not found in the liver and intestinal tissue. Our study demonstrated that exogenous ANP treatment during the early phase of THS was beneficial. Our series of studies discussed above will help to explore the molecular mechanisms of action of TMH, early target atrial pressure after control of bleeding, and exogenous treatment with ANP in THS. Our findings can serve as theoretical foundation for novel resuscitation stretegies, the ultimate purpose of which is to reduce mortality and improve management in THS.