Changes Of Vagal Activity After Trauma And Its Effects On Systemic Inflammation

Severe trauma is the most frequent cause of death in people below the age of 40 years. Immediate and early trauma deaths are determined by severe primary brain injuries or significant blood loss.Late mortality is caused by secondary brain injuries,sepsis,and multiple organs failure(MOF).An overwhelming pro-inflammatory response leads to the clinical manifestation of systemic inflammatory response syndrome(SIRS) and finally to multiple organs dysfunction syndrome(MODS).Overload of pro-inflammatory cytokines mediates secondary tissue injuries.Increased tumor necrosis factor(TNF)-α,interleukin(IL)-1βor IL-8 serum levels are observed in patients with systemic inflammation,as well as in bronchoalveolar lavage fluids of patients with thoracic trauma,or acute respiratory distress syndrome.In addition,IL-6 serum levels correlate with the injury severity score(ISS),the incidence of MODS,acute respiratory distress syndrome(ARDS),or sepsis and with outcome.Except pro-inflammatory cytokines, anti-inflammatory mediators are also produced after injury to avoid secondary tissue damage.But an overwhelming anti-inflammatory response seems to be responsible for post-traumatic immunosuppression,with a high susceptibility to infections and septic complications.This immunological status is defined as compensatory anti-inflammatory response syndrome(CARS).An imbalance of these dual immune responses seems to be responsible for organ dysfunction and increased susceptibility to infections.So restraining cytokine release would help host to strike a fine balance between SIRS and CARS,and thereby avoids excessive inflammation with secondary tissue damage and susceptibility to infections.Clinical research implicates a significant correlation between depressed vagus nerve activity and increased morbidity and mortality in sepsis,rheumatoid arthritis,inflammatory bowel diseases and other diseases.It is well known that inflammatory cytokines play an important role in the process of these diseases,so we conjecture that overexpression cytokines after trauma also correlate with decreased vagus activity,which might facilitate the inflammatory responses underlying and worsening injury.Increasing vagus activity might be benefit to trauma patients.Theory of the cholinergic anti-inflammatory pathway is a major supporting point of our hypothesis.The production of sera TNF-αcould be regulated by neural signals through vagus nerve releasing acetylcholine which bands theα7 subunit of the nicotinic acetylcholine receptor(α7-nAChR)on macrophages and other cells.Vagus nerve stimulation,or administration ofα7-nAChR agonists can inhibit TNF-αrelease and thereby prevent inflammatory damage;Mice exposed to endotoxin realize an unbalanced,excessive cytokine response characterized by exaggerated TNF levels if they are deficient in either theα7-nAChR subunit or vagus nerve activity.Moreover,vagus nerve stimulation inα7-nAChR-knockout animals fails to suppress cytokine synthesis whereas it significantly inhibits cytokine release in wild-type littermates.Ligand-receptor interaction on cytokine-expressing cells would decrease nuclear translocation of nuclear factor(NF)-κB. This make the cholinergic anti-inflammatory pathway possibily have broad spectrum effects of anti-inflammation,and actually,activiting the cholinergic anti-inflammatory pathway which inhibits not only TNF but also IL-1,IL-6,IL-8,and high mobility group box 1(HMGB 1).Increasing vagus nerve activity may be an effective style to inhibit excessive inflammatory response after trauma.Many studies indicated that acupuncture at special acupoint could regulate the activity of automatic nervous system(ANS),such as accelerating gastrointestinal motility,increasing gastric acidity,decreasing heart rate,and attenuating the LPS-induced fever.Since acupuncture can elicit measurable increases in vagus nerve activity,so it is at least theoretically possible that this stimulation can modulate the cytokine response via the cholinergic anti-inflammatory pathway.The aim of this study is to determine the changes of ANS after trauma,especially the vagal function,and whether stimulation vagus nerver by acupuncture could active the cholinergic antiinflammatory pathway via heart rate variability(HRV) analysis and serum TNF-αand IL-6 levels monitoring in severe trauma patients.The experiment concluded two main steps:1.We observed the change of the autonomic nervous system activity in multiple trauma patients by heart rate variability.Patients were divided into three groups according ISS:slight injury group(ISS≤16),serious injury group(16＜ISS≤25),and very serious injury group(ISS＞25).Electrocardiogram(ECG) data were collected at 1,7,14d post injury during 8am to 10am.Then power spectral analysis was used to evaluate short time(5 minutes) heart rate variability(HRV).We found low-frequency(LF) power and high-frequency(HF) power of HRV decreased significantly in trauma patients while LF to HF power ratio(LF/HF) increased markedly,and these changes correlated with ISS.The decreased of LF and HF and the increased of LF/HF indicated attenuated parasympathetic drive,and descent level was related to the severity of injury.During the convalescence,HF and LF increased and LF/HF decreased gradually,the balance of sympathetic and parasympathetic activities recovered.Clinical research implicates correlation between high ISS score and increased sera pro-inflammatory cytokine and increase morbidity in SIRS and MODS.So the results indicant depressed vagus nerve activity is an important reason of excessive inflammation in severe trauma patients.Increasing vagus nerve activity might be effective to atteneue inflammatory responses and benefit to trauma patients.2.We observed the effects of acupuncture on vagal activity by HRV analyzing and sera TNF-αand IL-6 concentrations via enzyme linked immunosorbent assay(ELISA) to determine the impact of acupuncture on the cholinergic anti-inflammatory pathway.Severe multiple trauma patients were randomly divided into 3 groups.Acupunctures were applied to the bilateral ST-36(Zusanli) and PC-6(Neiguan) acupoints in the acupuncture group, and such stimulations were applied to non-acupuncture points in the shame acupuncture group.Only standard resuscitation techniques were performed in the control group.ECG was collected before and after acupuncture stimulation for transient HRV analysis to evaluate vagal activity.Serial blood samples were obtained before and after stimulation to determine the serum TNF-αand IL-6 concentrations in each group.Then we found acupuncture at ST-36 and PC-6 significantly increased the normalized units of high frequency component(HFnu) and decreased the ratio of low frequency and high frequency component(LF/HF),which indicated an increased vagal activity and a tilt of the sympathovagal balance.Sera TNF-αand IL-6 concentrations were decreased significantly after stimulation at ST-36 and PC-6,but remained unchanged following stimulation at the non-acupoint area.During the whole study period,much lower concentrations of TNF-αand IL-6 were detected in patients of acupuncture group than in patients of other groups.So we confirmed that increasing vagal activity by acupuncture at PC-6 and ST-36 significantly decreases serum TNF-αand IL-6 concentrations in severe multiple trauma patients.In short,we evaluated ANS function in trauma patient and observed the effects of acupuncture on systemic inflammation via HRV analysis and ELISA.We found vagal activity was decreased and this change was correlated with the severity of trauma.We also found acupuncture was effective to increase vagal activity and decrease sera pro-inflammatory cytokine level.These findings indicate that the decrease of vagul activity is an important alteration which might facilitate the inflammatory responses,and increasing vagus activity is effective to inhibit pro-inflammatory cytokine synthesis.It also indicated that acupuncture is an effective stimulation pattern of activiting the cholinergic anti-inflammatory pathway.Acupuncture might be a novelty management to control inflammatory response in server trauma patients.