Changes And Mechanisms Of Hemodynamics And Cardiovascular Reactivity On Multiple Trauma Rats Headed By SCI During Acute Stage

With the development of industry and transportation, the cause of spinal cord injury (SCI) are always associated with high energy incidents such as traffic accident, aloft fall, crush or crash by heavy objects. Multiple traumas occur quaque, and the traumatic conditions always are complex and critical. After system literature retrieval, little researches were found about multiple trauma in which SCI was leading cause of trauma. In our formal study, this kind of trauma were named of"multiple trauma headed by SCI"firstly and be defined as"a kind of serious multiple trauma (ISS>17) in which SCI was the main trauma (AIS≥4, ISS≥16)". At the same time, we found that hemodynamic disorder always occur during acute stage and have great influence on the curative results. Stabilizing hemodynamics is the main goal during emergency medical treatment. But little was known about the change mode of hemodynamics of multiple trauma headed by SCI. This kind of multiple trauma always lead to severe shock whose basic clinical remedy rules are"supplement blood volume and use vaso-excitor drugs early". Therefore, cardiovascular reactivity to vaso-excitor (cardiovascular reactivity) is crucial to therapeutic result. However, cardiovascular reactivity is still unknown in emergency treatment during acute stage about this kind of trauma. For the above reasons, the hemodynamic and cardiovascular reactivity researches about multiple trauma headed by SCI are needed urgently to improve clinical therapeutic results and decline the mortality and invalidity rate.Methods: Firstly, as it is hard to collect cases and to make experiment on those patients for the crisis pathogenetic conditions, a new rat model of experimental multiple trauma headed by SCI had been established according to the main cause factors of this kind of trauma: high level SCI (T1-C7), fracture (lateral tibia) and bleeding. Secondly, the change patterns of hemodynamics were observed by hemodynamic monitor system on this model during acute stage. Catecholamine and neuropeptide Y (NPY) in blood, the main sympathesis vasoconstrictor neurotransmitter, were measured by ELSA or RIA. Organs regional blood flow (RBF) were monitored consecutively by color-labeled microspheres technique in vivo, and total peripheral resistance (TPR) rise and cardiac output (CO) were calculated simultaneously. Thirdly, to investigate cardiovascular reactivity, total cardiovascular reactivity was measured by the pressor effect of norepinephrine (NE) at different time after trauma. Then the vascular reactivity was measured separately by microcirculation monitor system in vivo and by vascular ring tension system in vitro. The cardia reactivity was measured by monitor the heart function after injected NE (3ug/kg) in vivo. The main receptors of NE are beta (β) - and alfa1 (α1)-adenoreceptor (AR) in heart and link to AR-adenylate cyclase (AC)-cAMP signal system. Any changes of reaction to NE of heart must original to this signal system. For this reason, we checked the numbers and affinity ofβ-AR andα1-AR by radioligand binding assay (RBA) of receptors and AC activity by unlabeled substrate assay.Results:①This animal model exhibited typical characters of multiple trauma headed by SCI that are include abnormal of hemodynamics, blood gases in early period and high mortality even after resuscitation.②MAP of multiple trauma headed by SCI rats in 1-6 h, HR in 0, 0.5, 4, 5, 6 h, LVSP in 3-6 h,±dp/dtmax , CO and TPR in 0.5-6 h drop dramatically compared with other groups (P<0.05 or 0.01).③The concentration of epinephrine (EPI) in 0.5, 1, 2, 3, 5 h, NE in 2, 3, 6 h rise slightly compared with sham (P<0.05). The concentration of NPY exhibited two peaks compare with normal: the first rise emerges between 0.5-2 h and the second between 5-6 h after trauma (compared with normal, P<0.05). The concentrations of NE, EPI, NPY are far lower than trauma-hemorrhage rats (P<0.05).④Organ RBF drop significantly and simultaneously which did not have significant difference with other organs (P>0.05).⑤The pressor effect of NE in this rats model was significantly higher than sham and trauma-hemorrhage rats at all the time point (P<0.01). The vascular reactivity of SMA to NE was increase significantly 1-3 h after trauma as compared with sham: the Emax and pD2 were significantly increased (P<0.01), the cumulative dose-response curves were shift to the left. The aboved indexes decrease significantly at 4-6 h after trauma and the cumulative dose-response curve were shift to the right.⑥The cardia function indexes of multiple trauma rats rise significantly after i.v. NE in vivo whereas decreased in trauma-hemorrhage rats during 1-6h after trauma(P<0.01).⑦ Bothα1- andβ- AR density reach the summit 1h after trauma (P<0.01) and decrease gradually as the time went on.β-AR density increase more significantly thanα1-AR or sham(P<0.01). It still keep higher level until 6h after trauma. No significant difference in the equilibrium dissociation constants (Kd) for both receptors was observed during 1-3 h and rise simultaneously 6h after trauma. Both basal AC activity and the concentration of cAMP in membrane preparations drop dramatically after trauma and their relationship was significant correlation (r=0.9392,P<0.05). AC activity stimulated by isoproterenol increased during 1-6 h after trauma and the highest rise at 1 h after trauma (by 2.5 times higher over the sham). It implies hyper-reactivity ofβ-AR-G protein-AC-cAMP signal transduction system which persisted 6h after trauma. No significant statistic difference was observed on AC activity stimulated by forskolin. It implies that there are no change on AC catalytic subunit protein itself. AC activity stimulated by NaF showed little increase during 1 h after trauma and a dramatic decreasing appeared during 3-6 h after trauma (P<0.01). It implies uncoupling of G protein and AC catalytic subunit during this period of time.Conclusions:①This animal model with trauma of stable degree can be repeated easily and fit for the needs of early pathophysiological study of multiple trauma headed by SCI.②Appearance early, long duration, serious degree and compensation handicap are the characters of hemodynamics and heart function disorder of multiple trauma rats headed by SCI. Organ RBF drop too and did not exhibit redistribution unlike trauma-hemorrhage rats. The deterioration of hemodynamics is positive correlation with the degree of trauma. The concentration of sympathesis vasoconstrictor neurotransmitter show relative deficiency.③The total cardiovascular reactivity rise (hypereactivity) and the vascualar reactivity exhibited biphasic change during 1-6 h after trauma. But the cardia reactivity exhibited hyper-reactive during 1-6 h. With reference to the change time points, tendency and degree, the increased cardia reactivity could be one of the main reasons for the cardiovascular hypereactivity but vascular reactivity.④Multiple trauma rats headed by SCI exhibited high reactivity of AR-AC-cAMP signal transduction system that mainly due to increased density of AR after trauma during acute stage. That could be one of the important compensation mechanisms of cardia hypersensitivity after trauma. At the same time, some changes, such as relative deficency of sympathesis vasoconstrictor neurotransmitter, low activity of basal AC activity and the concentration of cAMP in myocardium, uncoupling G protein and AC catalytic subunit, also occur and could be one of the main reasons of aggravation of heart function and hemodynamics after trauma.