【作者】 王其平；

【导师】 张世明；

【作者基本信息】 苏州大学 ， 外科学（专业学位）， 2013， 博士

【摘要】 目前重型脑损伤(severe traumatic brain injury, sTBI)是死致残的主要原因，直到现在，尚无有效治疗药物，治疗的重点是识别和控制继发性脑损伤,颅内压(intracranial pressure，ICP)监测是最常用的监测指标,只能反应颅内容积的平衡，不能反映脑血流与脑代谢。局部脑组织氧分压(partial pressure of brain tissue oxygen, PbtO2)监测是目前脑氧代谢最直接、可靠的方法，最新的TBI指南就包含了PbtO2监测，但没有说明如何处理PbtO2，采用哪些治疗措施能够升高PbtO2。甘露醇是目前渗透治疗的首选药物，也存在许多副作用，新近研究表明，高渗盐水（hypertonicsaline，HTS）具有优异的降颅压效果，副作用少，渗透治疗对PbtO2的影响如何？PbtO2能否为甘露醇的替代药物提供选择的依据？sTBI患者常有贫血，需要输注红细胞(red blood cell transfusion，RBCT)，血红蛋白（hemoglobin,Hgb）在什么水平需要输血仍然没有确立，输血对PbtO2的影响能否为sTBI患者提供更合理的输血策略？sTBI常常伴随合并多发伤，容易发生缺氧和低血压，加重了继发性损伤，影响了患者预后，目前合并的多发伤对于sTBI脑缺氧的影响到底如何，尚不明确。综上所述，本研究分为以下三个部分内容：第一部分：脑组织氧分压联合颅内压监测在治疗重型颅脑损伤中的作用目的探讨脑组织氧分压联合颅内压监测对重型颅脑损伤治疗的指导意义，以提高脑氧为目标干预治疗的效果。方法对江阴市人民医院神经外科2010年6月至2012年6月收治收治46例重型颅脑损伤患者，随机分成两组，每组23例，即：应用脑组织氧分压联合颅内压监测的患者（Pbt02组）与单独进行颅内压监测的患者（ICP组），两组患者的治疗目标维持颅内压＜20mmHg，脑灌注压≥60mmHg，对脑组织氧分压监测患者，将脑组织氧分压目标控制≥20mmHg，伤后六月比较两组死亡率及格拉斯哥预后评分。结果两组平均每天的颅内压、脑灌注压水平相似的，ICP组患者死亡率21.7%（5例），预后良好47.8%（11例），而Pbt02组死亡率8.7%（2例），预后良好65.2%（15例），两组比较（P＜0.05）。Pbt02监测共发现236次脑缺氧（PbtO2＜20mm Hg），通过对病因处理，使65%的脑缺氧得以纠正（PbtO2≥20mm Hg），增加吸入氧浓度，镇静，血管升压药物使用，是纠正PbtO2降低最常用的措施。在PbtO2组中，生存者中对PbtO2治疗有效率为72%，而死亡者为35%（P＜0.05）；预后良好者中对PbtO2治疗有效率为81%，而预后不良者为44%（P＜0.05）。结论与单独ICP监测相比，PbtO2联合ICP监测并依据PbtO2进行指导治疗能够改善PbtO2，能够降低重型颅脑损伤患者的死亡率，改善预后。第二部分治疗因素对重型颅脑损伤患者脑组织氧分压的影响一、3%高渗盐水与20%甘露醇治疗重型颅脑损伤对脑组织氧分压的影响目的研究3%高渗盐水与20%甘露醇治疗重型颅脑损伤颅内高压的同时能否升高脑组织氧分压。方法对江阴市人民医院神经外科2010年6月-2012年6月收治收治40例重型颅脑损伤患者，随机分成两组：3%高渗盐水组和20%甘露醇组，采取前瞻性研究，通过颅内压降阶梯治疗，当颅内压大于20mm Hg时，依据随机化分组情况，接受3%高渗盐水或者20%甘露醇进行渗透性治疗，同时连续进行多参数监测，观察治疗后30min、60min、120min、180min脑组织氧分压、颅内压、平均动脉压、脑灌注压、中心静脉压变化。结果40例重型颅脑损伤患者中，18例接受3%高渗盐水治疗，而17例接受20%甘露醇治疗，5例患者颅内压小于20mmHg没有接受渗透治疗。两种药物均在治疗后30min降低颅内压，增加脑灌注压(p<0.05)，60min时最明显，持续至180min，与20%甘露醇相比，3%高渗盐水治疗后60min至180min，伴随着平均动脉压的升高、脑灌注压增加效果更加明显，而且同时能够升高脑组织氧分压(p<0.05)，而20%甘露醇在各时间点对脑组织氧分压无明显影响(p＞0.05)。结论与20%甘露醇相比，3%高渗盐水在降低颅内压、增加脑灌注压的同时能够升高脑组织氧分压，还能够降低重型颅脑损伤患者的死亡率，改善患者预后。二、输注晶体红细胞对重型颅脑损伤患者早期脑组织氧分压的影响目的研究输注晶体红细胞对重型颅脑损伤患者早期脑组织氧分压影响。方法对江阴市人民医院神经外科ICU2010年6月-2012年6月收治收治18例血红蛋白介于70-90g/L、PbtO2＜20mmHg接受输注晶体红细胞（2单位）的重型颅脑损伤患者（GCS<8），采取前瞻性研究，观察输血治疗前和输血治疗后1-4h脑组织氧分压、颅内压、脑灌注压、动脉血氧饱和度、血红蛋白浓度的变化。结果对18例重型颅脑损伤患者20次的输血进行分析，输血治疗后4h内，脑组织氧分压升高5.3±2.4mm Hg(p＜0.05)，血红蛋白浓度升高11±6g/L(p＜0.05)，颅内压、脑灌注压、动脉血氧饱和度、CPP变化无统计学意义(P＞0.05)。65%(n=13)的患者脑组织氧分压升高，35%(n=7)的患者不变化或降低。多重逐步回归分析显示血红蛋白浓度与脑组织氧分压呈正相关（偏回归系数0.12，95%的可信区间为0.04-0.22，P＜0.05）。结论：输注浓缩晶体红细胞早期能够升高脑组织氧分压。第三部分：PbtO2联合ICP多参数监测在急性重型颅脑损伤合并多发伤治疗中的作用目的探讨脑组织氧分压（PbtO2）联合颅内压（ICP）、平均动脉（MAP）压、中心静脉压（CVP）多参数监测对重型颅脑损伤合并多发伤治疗的指导意义和以PbtO2为目标干预治疗的效果。方法对江阴市人民医院神经外科2010年6月-2012年6月收治收治20例单纯的重型颅脑损伤患者(GCS＜8, ISS＜16)与20例重型颅脑损伤合并多发伤患者(GCS＜8，ISS＞16)应用PbtO2、ICP、MAP、CVP多参数监测，进行前瞻性研究，治疗目标为控制ICP＜20mm Hg，维持脑灌注压（CPP）≥60mmHg，PbtO2≥20mmHg。比较两组继发性损伤的发生情况，比较两组伤后六月死亡率及GOS评分。结果在治疗后2h、24h、48h、72h重型颅脑损伤合并多发伤组与单纯重型颅脑损伤组之间ICP、CPP结果差异无统计学意义（P＞0.05）。PbtO2监测结果显示，重型颅脑损伤合并多发伤组在监测后2h、24h、48h PbtO2数值低于单纯重型颅脑损伤组，PbtO2＜20mmHg次数多于单纯重型颅脑损伤组（P＜0.05），而至72h差异无统计学意义（P＞0.05）。单纯重型颅脑损伤组患者死亡率35%（7例），预后良好率45%（9例），重型颅脑损伤合并多发伤组死亡率是40%（8例），预后良好占40%（8例）（P＞0.05）。单纯重型颅脑损伤的患者中有65%的脑缺氧得以纠正（PbtO2≥20mm Hg），重型颅脑损伤合并多发伤的患者中有78%的脑缺氧得以纠正（PbtO2≥20mmHg）（P＜0.05）。结论PbtO2联合ICP、MAP、CVP多参数监测能够有效发现重型颅脑损伤合并多发伤继发性损伤患者脑缺氧，多发伤加重了重型颅脑损伤脑缺氧，依据PbtO2为目标的治疗能够纠正脑缺氧，降低重型颅脑损伤合并多发伤患者的死亡率，改善预后。更多还原

【Abstract】 Traumatic brain injury (TBI) remains the major cause of mortality and morbidity in worldwide.To date, there is no effective drug treatment for TBI. An important goal of neurocritical care isidentifying and managing the secondary brain injury that evolves in the hours and days after TBI.Intracranial pressure (ICP) is the physiological parameter most frequently monitored. ICP monitoringmay be insufficient to detect all episodes of SBI. With the technological developments, PbtO2is likelythe ideal choice in detecting brain hypoxia in neurocritical care patients. The most recent Guidelines forSevere Traumatic Brain Injury include the use of PbtO2monitors but do not provide guidance abouthow PbtO2should be managed and which medical therapies restore normal PbtO2in TBI patients.Furthermore, whether PbtO2-based therapy is associated with improved outcome is unclear.Osmotherapy is frequently used to control elevated ICP. Although mannitol is more frequently usedas a first tier therapy for elevated ICP, some authors have argued that hypertonic saline (HTS) might bea more effective agent. There has been limited study on the effect of different osmotic therapies onPbtO2in brain injured patients.Traumatic brain injury often develop anaemia and may require red blood cell transfusion(RBCT).However, there is little understanding of the effects of transfusion on cerebral oxygenation.There is little understanding of the effects of transfusion on cerebral oxygenation Whether can gainfurther insight into the optimal transfusion strategy in patients with severe TBI needes a prospectiveclinical study.Severe TBI are often accompanied with multiple injuries, especially the thoracic or abdominalinjury, which prone to be hypotension or hypoxia, increasing the risk of secondary injury, worsens theprognosis of the patient. However, few studies have examined the effect of Concomitant Injuries oncerebral oxygenation in patients with severe TBI. As a result, in this study, we divided the content into three parts.Part ⅠThe use of both intracranial pressure and brain tissue PO2monitors and goal directed brain tissue PO2in severe traumatic braininjury patientsObjective To elucidate the effectiveness of brain tissue oxygenation（PbtO2）plusintracranial pressure（ICP）monitoring and targeted therapy in patients of severe traumatic brain injury（TBI）. MethodsAtotal of46patients with severe TB（IGlasgow Coma Scale, GCS scale≤8）admittedat Jiangyin People’s Hospital from June2010to June2012were divided randomly into2groups andevaluated prospectively．Patients undergoing ICP plus PbtO2monitoring were compared with controlswith ICP monitoring alone. Therapies of both patient groups was attempted to maintain an ICP＜20mmHg and a cerebral perfusion pressure (CPP)≥60mm Hg. Among those with PbtO2monitoring,oxygenation was maintained at a level of≥20mm Hg. The scores of Glasgow outcome scale （GOS）were compared between two groups at Month6post-injury.Results The mean daily ICP and CPP levelswere similar in each group.The mortality rate was21.7%in patients with ICP monitoring alone and thefavorable outcome rate was47.8%.However,those receiving combined management had a significantlyreduced mortality rate of8.7%and good outcome rate of65.2%(P<0.05). Two hundred and thirty-sixepisodes of compromised PbtO2were identified from PbtO2monitoring. Medical management used ina“cause-directed”manner successfully reversed65%of the episodes of compromised PbtO2, defined asrestoration of a “normal” PbtO2(≥20mm Hg). Increasing FiO2, sedation, and pressors were the mostfrequent interventions. Successful medical treatment of brain hypoxia was associated with decreasedmortality. Survivors (n=21) had a72%rate of response to treatment and non-survivors (n=2) had a35%rate of response （P＜0.05）. The Glasgow Outcome Scale score at6months in patients treatedwith PbtO2demonstrated patients with good outcome (n=15) had a81%rate of response to treatmentand those with poor outcome (n=8) had a44%rate of response （P＜0.05）. Conclusions Thecombined use of both ICP and PbtO2may be associated with reduced patient mortality and improvedpatient outcome with severe TBI. Medical interventions other than those to treat ICP and CPP canimprove PbtO2. PartⅡ The influence of therapeutics measures（hypertonic saline andpacked red blood cell transfusion）on brain tissue PO2in severe traumaticbrain injury patientsFacor1. Effect of3%hypertonic saline and20%mannitol on cerebraloxygenation inpatients with severe traumatic brain injury and intracranial hypertensionObject To explore if3%hypertonic saline（HTS）and20%mannitol treatment of raisedintracranial pressure（ICP）will result in an improvement in brain tissue PO2(PbtO2) in severe traumaticbrain injury patients. Methods40patients with severe TBI（Glasgow Coma Scale,GCS scale<8）admitted at Jiangyin People’s Hospital NICU from June2010to June2012were divided into twogroups:3%HTS group and20%mannitol group randomly and evaluated prospectively. Step-wisetherapy under ICP monitoring，if ICP＞20mmHg，patients were received osmotic therapies：either3%HTS or20%mannitol according randomized groups at a defined infusion rate, PbtO2, ICP, mean arterialpressure (MAP), cerebral perfusion pressure (CPP), central venous pressure (CVP)，harte rate （HR），were monitored continuously and the time point30min、60min、120min、180min data was recorded.Results Of the40patients,18patients received3%HTS and17received20%mannitol therapy. Infive patients,ICP did not exceed20mm Hg so osmotic treatment was not necessary.3%HTS and20%mannitol were both associated with a significant ICP reduction from30min to180min after the end ofinfusion (p <0.05).The maximum decrease in ICP and increase in CPP occurred in both groups after60min after the end of infusion (p <0.05). Compared with mannitol,3%HTS was associated with lowerICP and higher MAP and CPP from60min to180min after treatment (p <0.05). HTS treatment wasalso associated with an increase in PbtO2，while20%mannitol did not affect PbtO2at all times analysed(p＞0.05). Conclusions3%HTS and20%mannitol are both effective in reducing ICP and increasingCPP in the treatment of increased ICP. Compared with20%mannitol,3%HTS therapy is associatedwith a significant increase in brain oxygenation and with reduced patient mortality and improved patientoutcome with severe TBI. Facor2. The ealy effect of packed red blood cell transfusion on brain tissue oxygenation withsevere traumatic brain injuryObject To examine the ealy effect of packed red blood cell transfusion on cerebraloxygenation in patients with sTBI. Methods18patients with STBI（Glasgow Coma Scale,GCSscale<8） admitted at Jiangyin People’s Hospital NICU from June2010to June2012, which receiving2unit packed red blood cell transfusion (RBCT) when hemoglobin concentration70-90g/L and PbtO2＜20mmHg, were studied prospectively. To analyze the changes of the following physiologic variablesbefore and2hrs after RBCT: PbtO2, intracranial pressure, cerebral perfusion pressure, hemoglobinoxygen saturation (SaO2), FIO2, hemoglobin, and hematocrit. Results Twenty blood transfusions in18patients were evaluated. The mean (SD) increase in PbtO2for all patients was（5.3±2.4mm Hg）(p＜0.05), Improvement in PbtO2was associated with a significant mean increase in hemoglobin afterRBCT（11±6g/L）(p＜0.05). ICP，Cerebral perfusion pressure, SaO2did not change significantlyafter RBCT.65%of (n=13) patients experienced an increase in PbtO2during the course of the study,whereas in35%of patients, PbtO2either did not change or decreased. the multivariant correlation andregression analysis revealed change in hemoglobin concentration to significantly and positivelyassociated with change in PbtO2（partial regression coefficient was0.12，95%confidence interval0.04-0.22，P＜0.05. Conclusions Transfusion of packed red blood cells ealy results in improved braintissue oxygen with sTBI. Part Ⅲ The use of both intracranial pressure and brain tissue PO2monitors and goal directed brain tissue PO2in severe traumatic braininjury patients whith multiple injuriesObject To elucidate the effectiveness of brain tissue PO2combined intracranial pressure （ICP）、mean arterial pressure (MAP)、central venous pressure(CVP）multiple monitors and therapy directed at brain tissue PO2in severe traumatic brain injury whith multiple injuries patients. Methods20isolatedsevere TBI patients（Glasgow Coma Scale,GCS <8）and20severe TBI patients with associatedextracranial injuries（GCS <8，Injury Severity Score，ISS＞16)）admitted at Jiangyin People’s HospitalNICU from June2010to June2012were evaluated prospectively．All the patients treated with braintissue PO2combined intracranial pressure、mean arterial pressure、central venous pressure multiplemonitors. Therapy in both patient groups was aimed at maintaining an ICP less than20mmHg, acerebral perfusion pressure (CPP) greater than60mmHg and oxygenation was maintained at levelsgreater than20mm Hg. The occurrence of secondary brain injuries (ICP>20mm Hg, CPP <60mm Hg,PbtO2<20mm Hg) was comparable in patients with sTBI and those sTBI patients with associatedmultiple injuries. The secondary insults and the scores of Glasgow outcome scale （GOS）were alsocompared between two groups at Month6post-injury. Results The ICP and CPP levels and occurrenceof ICP>20mm Hg, CPP <60mm Hg were similar between the two groups after treated2h，24h，48hand72h（P＞0.05）. The brain tissue PO2levels and occurrence of PbtO2<20mm Hg in sTBI patientswith associated multiple injuries were lower those in isolated severe TBI patients after treated2h，24hand48h（P＜0.05）, however, this difference couldn’t be found after treated72h（P＞0.05）.Themortality rate was35%and the favorable outcome rate was45%in isolated severe TBI patients.Patients with associated multiple injuries had a40%mortality rate and40%good outcome rate （P＞0.05）. Medical management used in a “cause-directed” manner successfully reversed65%of theepisodes of compromised PbtO2in isolated severe TBI patients and78%of episodes of compromisedbrain oxygen were corrected in sTBI patients with associated multiple injuries. Conclusions Thecombined use of brain tissue PO2monitors and multimodality monitoring can detected brainproxia.Therapy directed at brain tissue PO2, is associated with decreased disability rate and mortalityfollowing sTBI patients with associated multiple injuries.更多还原