二次脑创伤后大鼠皮层脑血流及前列腺素变化及血红蛋白液的作用

目的：探讨二次脑创伤后大鼠皮层脑血流（ＣｏＣＢＦ）与前列腺素变化及双阿斯匹林联偶血红蛋白液（ＤＣＬＨｂ）的作用。方法：在一种新的大鼠加速性弥漫性脑损伤模型基础上，采用抽血及颈动脉结扎造成低血压及脑缺血、缺氧，观察大鼠ＣｏＣＢＦ与血栓素Ａ２（ＴＸＡ２）、前列环素（ＰＧＩ２）含量变化以及ＤＣＬＨｂ治疗作用。３２只ＳＤ大鼠随机分为假手术对照、单纯脑损伤、脑损伤并二次脑创伤及治疗四组。所有动物均气管内插管并实施同步生理监护。结果：伤后４小时，与假手术组对比，合并二次脑创伤组ＣｏＣＢＦ显著降低，ＴＸＡ２含量增高（Ｐ＜０．０５）；ＤＣＬＨｂ治疗组无ＣｏＣＢＦ降低，但ＴＸＡ２及ＰＧＩ２含量均有增高。结论：合并二次脑创伤组有ＣｏＣＢＦ降低及ＴＸＡ２含量增高，提示在其病理过程中存在脑血管痉挛及微血栓形成，导致脑缺血、缺氧。ＤＣＬＨｂ则可能通过增加ＰＧＩ２合成发挥脑保护作用。     

二次脑创伤的基础与临床研究

低血压或高热等是引起脑外伤病人二次脑创伤常见因素。本研究首先在大鼠弥漫性脑损伤模型基础上，造成大鼠低血压及高热，观察大鼠脑皮层脑血流（ＣｏＣＢＦ）变化。１６只ＳＤ大鼠随机分为假手术对照、脑损伤并二次脑创伤两组。结果表明，伤后４ｈ与假手术组对比，合并二次脑创伤组ＣｏＣＢＦ显著降低。随后对１６５例重型颅脑损伤病人进行回顾研究，探讨二次脑创伤因素如高热、低血压对颅脑损伤预后的影响。表明合并二次脑创伤因素者预后差。基础与临床研究提示，二次脑创伤者预后差的原因可能是其导致脑血管痉挛，脑血流下降，直接影响正常脑代谢     

实验性脑缺血急性期大鼠脑甲状腺激素受体初步研究

运用４血管闭塞法制造ＳＤ大鼠全脑缺血动物模型，并经受体放射分析法测定大鼠脑甲状腺激素受体（Ｔ３Ｒ）的最大结合容量和亲和力的变化。结果显示：与假手术组相比较，缺血５ｍｉｎ脑Ｔ３Ｒ即开始上升，缺血１５ｍｉｎＴ３Ｒ含量明显增高（Ｐ＜０．０１），受体亲和力无改变。大鼠脑缺血急性期脑甲状腺激素受体向上调节为机体的重要代偿反应。     

大鼠局部脑缺血再灌流的实验研究

采用大鼠局部脑缺血再灌流模型，研究了大鼠脑缺血６ｈ、９ｈ和缺血６ｈ再灌流３ｈ脑梗塞体积，脑含水量，能量代谢，丙二醛（ＭＤＡ）和超氧化物歧化酶（ＳＯＤ）的变化。结果：脑缺血６ｈ、９ｈ可以造成严重的脑梗塞和脑水肿，ＡＴＰ含量和ＳＯＤ活性显著降低，乳酸和ＭＤＡ含量显著增加，和对照组相比均有显著差异（Ｐ＜０．０５或Ｐ＜０．００１）。再灌组和缺血两组比较，脑梗塞体积，脑水肿无明显差别（Ｐ＞０．０５），ＡＴＰ、乳酸、ＳＯＤ和ＭＤＡ均有不程度的改善。提示，大鼠局部脑缺血超过６ｈ可造成严重的脑损伤，并随缺血时间的再延长，脑损伤变化趋于平缓。再灌后，脑损伤未见明显加重。     

反复性脑缺血大脑皮质LTC_4、cAMP和OFR的代谢变化

目的：研究反复脑缺血大脑皮质白三烯（ＬＴＣ４）、环腺苷酸（ｃＡＭＰ）和氧自由基（ＯＦＲ）的代谢变化与神经元损伤的关系。方法：对比观察大鼠反复性与单次性脑缺血大脑皮质ＬＴＣ４、ｃＡＭＰ、超氧化物歧化酶（ＳＯＤ）和丙二醛（ＭＤＡ）的含量变化及相应的病理改变。结果：反复缺血及再灌流早期ＬＴＣ１、ｃＡＭＰ的含量明显升高,ＳＯＤ活性显著降低,ＭＤＡ延迟性持续显著增高,皮质神经元损害显著重于单次缺血组。结论：ＬＴＣ４、ｃＡＭＰ和 ＯＦＲ均参与了反复缺血性脑损害的病理机制,可能与 Ｃａ＋＋介导的花生四烯酸（ＡＡ）瀑布效应有关。     

沙土鼠脑缺血后脑组织匀浆及血浆中SOD,MDA的含量改变及其意义

１１２只沙土鼠分为正常组、假手术组、手术组，成功地建立了沙土鼠脑缺血模型，并测定了脑组织匀浆及血浆中超氧化物歧化酶（ＳＯＤ）、丙二醛（ＭＤＡ）的含量，结果示：缺血右半球ＭＤＡ值较同体左半球ＭＤＡ值有明显增高（Ｐ＜０．０５），说明脑缺血后脑组织内确曾发生明显的脂质过氧化反应，提示自由基对缺血性脑损害的形成有一定作用。缺血右半球ＳＯＤ活力较同体左半球下降（Ｐ＜０．０５）。整个实验中，脑缺血后血浆ＳＯＤ、ＭＤＡ均无明显变化。     

聚合牛血红蛋白对缺血再灌注脑组织氧自由基和SOD的影响

目的探讨聚合牛血红蛋白（ＰＢＨｂ）在缺血再灌注后脑损伤的治疗作用。方法采用大鼠全脑缺血再灌注损伤模型，观察缺血前后应用ＰＢＨｂ对脑组织氧自由基和超氧化物歧化酶（ＳＯＤ）含量的影响。结果与缺血再灌注组相比，脑保护及复苏ＰＢＨｂ组均能有效减少氧自由基产生，其中脑复苏ＰＢＨｂ组比白蛋白对照组作用更强。同时，ＳＯＤ含量相应降低，尤以脑复苏ＰＢＨｂ组显著。结论ＰＢＨｂ能有效地抑制氧自由基产生而表现出良好的脑保护及复苏作用，这种作用不是通过增强ＳＯＤ活力产生的。     

实验性超负荷血糖大鼠脑缺血后脑毛细血管内皮细胞ICAM-1表达的研究

目的　了解超负荷血糖条件下，脑缺血后，脑毛细血管内皮细胞细胞间粘附分子１（ＩＣＡＭ－１）表达的情况。方法　采用ＳＤ大鼠尾静脉注射链脲霉素，建立超负荷血糖模型。用免疫组化方法动态观察大鼠超负荷血糖１ 月条件下以尼龙线栓堵大鼠大脑中动脉造成持续性局灶性脑缺血后不同时间，脑毛细血管内皮细胞ＩＣＡＭ－１ 的表达。结果　超负荷血糖１月脑缺血０．５ 小时ＩＣＡＭ－１ 的表达明显升高；１小时达高峰，表达范围弥漫整个缺血半球；缺血３～１２ 小时， ＩＣＡＭ－１表达仍很明显，但主要集中在颞、顶叶缺血区；缺血２４ 小时表达不明显；假手术组大鼠脑组织毛细血管内皮细胞ＩＣＡＭ－１只有较少的表达；正常血糖对照组及阴性对照者脑毛细血管内皮细胞均未见ＩＣＡＭ－１ 表达。结论　与正常血糖ＳＤ大鼠脑缺血相比，超负荷血糖大鼠脑缺血后， ＩＣＡＭ－１ 在脑毛细血管内皮细胞上表达出现的早而明显，提示对加重脑缺血后的病理损伤起到了重要作用。     

颅内压及脑灌注压监护对重型颅脑损伤诊治的意义

研究颅内压（ＩＣＰ）和脑灌注压（ＣＰＰ）在重型颅脑损伤中的临床应用价值。方法对５０例重型颅脑损伤病人（ＧＣＳ３～８分）进行ＩＣＰ与ＣＰＰ连续监测并与５０例伤情基本相似的非监护组病人对比研究。结果监护组能根据ＩＣＰ和ＣＰＰ变化及时行正确治疗，非监护组仅按常规治疗，两组病死率分别为１４％和２８％（Ｐ＜０．０１），痊愈和生活自理者分别占７４％和５０％（Ｐ＜０．０１）。结论重型颅脑损伤病人行连续ＩＣＰ与ＣＰＰ监护是早期诊断和治疗的重要保证。     

脑缺血对大鼠循环铁的影响

目的 探讨脑缺血对大鼠循环铁的影响。方法 雄性Wistar大鼠随机分为脑缺血1、3、7、28d和假手术组；脑缺血组结扎双侧颈总动脉造成大鼠脑缺血，假手术组仅分离出双侧颈总动脉但不结扎；采用比色法测定大鼠血清铁含量；用放射免疫法测定血清铁蛋白含量。结果脑缺血1d大鼠血清铁含量低于假手术组（P〈0．05）；缺血3d血清铁含量虽低于假手术组，但无统计学意义（P〉0．05）；之后随着缺血时间的延长血清铁含量呈增高趋势，缺血28d时显著高于假手术组（P〈0．01）。脑缺血1d大鼠血清铁蛋白含量与假手术组比较无明显差别（P〉0．05）；缺血3d组低于假手术组（P〈0．05）；之后随着缺血时间的延长血清铁蛋白含量呈增高趋势，在缺血7、28d时均高于假手术组（P〈0．05）。结论脑缺血早期引起大鼠循环铁降低，晚期升高；循环铁的改变可能参与了脑铁含量升高和神经元铁沉积过程。     

Brain TXA2 and PGI2 levels related to diffuse brain injury with secondary insults

Secondary insults such as hypotension and hypoxia with head injury are associated with increased mortality and morbidity in comparison with head injury alone. In the present study the changes of brain thromboxane A₂ (TXA₂) and prostacyclin (PGI₂) levels in a Marmarou's rodent model of diffuse brain injury with hypotension and hypoxia were observed and the effect of diaspirin cross linked haemoglobin solution (DCLHb) were also investigated. Thirty-two male Sprague—Dawley (SD) rats were randomized into four groups: sham; head injury alone; head injury with secondary insults; and injury with insults followed by DCLHb administration. The results showed that there were no changes in TXB₂ and 6-keto-PFG_1a (metabolites of TXA₂ and PGI₂) levels in the injury alone group, while TXB₂ levels in the secondary insults group were elevated significantly; both TXB₂ and 6-keto-PGF_1a levels in the injury with insults followed by DCLHb administration group were augmented significantly in comparison with the corresponding value of sham at 4 postimpact. The only increase in TXA₂ levels in the secondary insults rats suggests that an imbalance in TXA₂-PGI₂ production contributes to the traumatic secondary processes, which include ischaemia and oedema. It is hypothesized that DCLHb may exert its protective properties through increasing PGI₂ production in injured brain by improving blood supply to injured blood vessels.     

Increased jugular bulb saturation is associated with poor outcome in traumatic brain injury

The objective was to compare secondary insults, particularly decreases in jugular bulb oxyhaemoglobin saturation (SjO(2)), during intensive care in patients with "poor" and "good" outcomes 12 months after traumatic brain injury. A prospective observational study of patients' physiological data collected each minute from multimodality monitoring was carried out. Patients had duration of physiological insults quantified as a percentage of their validated monitoring time (once invalid data due to technical reasons were removed). Treatment protocols were designed to minimise secondary insults by maintaining intracranial pressure (ICP) less than 20 mm Hg, and cerebral perfusion pressure (CPP) greater than 70 mm Hg, with prompt correction of hypoxia and pyrexia. Twelve months after injury patients' neurological function was assessed using the Glasgow outcome scale (GOS). A poor outcome was defined as GOS 1 to 3 (group 1) and a good outcome as GOS 4 and 5 (group 2). Seventy five patients (64 male), median age of 34 years (range 15 to 70), were studied. At 12 months 33 patients had a poor outcome (group 1), and 42 a good outcome (group 2). Group 1 spent proportionately more time with SjO(2) greater than 75% compared with group 2 (p<0.05), and more time with SjO(2) below 54% (p<0.04). Group 1 patients also spent proportionately more time with CPP less than 70 mm Hg than group 2 (p<0.04). Patients in group 1 were older (p<0.04) and had a lower postresuscitation Glasgow coma score (p<0.002). There was no difference between the groups for ICP, injury severity score, peripheral pulse saturation, and pyrexia. This study confirms that secondary insults, including an increased SjO(2), occur significantly more in patients with poor outcomes. More research into strategies to reduce the impact of secondary insults, including management of increased SjO(2), is required.     

Critical thresholds of intracranial pressure and cerebral perfusion pressure related to age in paediatric head injury

BACKGROUND: The principal strategy for managing head injury is to reduce the frequency and severity of secondary brain insults from intracranial pressure (ICP) and cerebral perfusion pressure (CPP), and hence improve outcome. Precise critical threshold levels have not been determined in head injured children. OBJECTIVE: To create a novel pressure-time index (PTI) measuring both duration and amplitude of insult, and then employ it to determine critical insult thresholds of ICP and CPP in children. METHODS: Prospective, observational, physiologically based study from Edinburgh and Newcastle, using patient monitored blood pressure, ICP, and CPP time series data. The PTI for ICP and CPP for 81 children, using theoretical values derived from physiological norms, was varied systematically to derive critical insult thresholds which delineate Glasgow outcome scale categories. RESULTS: The PTI for CPP had a very high predictive value for outcome (receiver operating characteristic analyses: area under curve = 0.957 and 0.890 for mortality and favourable outcome, respectively) and was more predictive than for ICP. Initial physiological values most accurately predicted favourable outcome. The CPP critical threshold values determined for children aged 2-6, 7-10, and 11-15 years were 48, 54, and 58 mm Hg. respectively. CONCLUSIONS: The PTI is the first substantive paediatric index of total ICP and CPP following head injury. The insult thresholds generated are identical to age related physiological values. Management guidelines for paediatric head injuries should take account of these CPP thresholds to titrate appropriate pressor therapy.     

The effect of hypoxia on traumatic head injury in rats: alterations in neurologic function, brain edema, and cerebral blood flow

We evaluated the effects of early posttraumatic hypoxia on neurologic function, magnetic resonance images (MRI), brain tissue specific gravities, and cerebral blood flow (CBF) in head-injured rats. By itself, an hypoxic insult (PaO2 40 mm Hg for 30 min) had little effect on any measure of cerebral function. After temporal fluid-percussion impact injury, however, hypoxia significantly increased morbidity. Of rats subjected to impact (4.9 +/- 0.3 atm) plus hypoxia, 71% had motor weakness contralateral to the impact side 24 h after injury, while only 29% of rats subjected to impact alone had demonstrable weakness (p less than 0.05). Lesions observed on MR images 24 h after injury were restricted to the impact site in rats with impact injury alone, but extensive areas with longer T1 relaxation times were observed throughout the ipsilateral cortex in rats with impact injury and hypoxic insult. Brain tissue specific gravity measurements indicated that much more widespread and severe edema developed in rats with impact injury and hypoxia. [14C]Iodoantipyrine autoradiography performed 24 h after injury showed that there was extensive hypoperfusion of the entire ipsilateral cortex in rats with impact injury and hypoxia. These results show that large areas of impact-injured brain are extremely vulnerable to secondary insults that can irreparably damage neural tissue, and provide experimental evidence for the observed adverse effects of hypoxia on outcome after human head injury.     

Adding insult to injury: the prognostic value of early secondary insults for survival after traumatic brain injury

OBJECTIVES—To assessthe prognostic value of summary measures of secondary physiologicalinsult in addition to baseline clinical variables for patients withtraumatic brain injury.
METHODS—A series of110 patients with traumatic brain injury had data on intracranialpressure (ICP), arterial blood pressure (ABP), cerebral perfusionpressure (CPP), arterial O₂ saturation (SaO₂), temperature in °C (Temp), and heart rate in beats/min (HRT) monitored and recorded every minute. Secondary insults were defined according tothe Edinburgh University secondary insult grading system. The prognostic value of summary measures of these secondary insults wasassessed by adding them to a prognostic model for survival at 1 yearafter controlling for baseline clinical variables using a previouslyvalidated model.
RESULTS—Of the eightsecondary insults measured, only ICP added significantly to theprediction of survival in the first 72 hours after injury. Theparticular type of summary measure did not seem to influence theresults. After the addition of ICP to the model, none of the othersecondary insult measures could improve the predictive power of themodel significantly.
CONCLUSIONS—Earlyintracranial hypertension is confirmed as a sign of poor prognosis inpatients with traumatic brain injury, even after controlling forbaseline clinical variables. The value or otherwise of treating suchsecondary insults, however, can only be definitively established in thecontext of prospective randomised controlled trials. The specificpathophysiological evolution of secondary insults is still the subjectof much research, and a clear understanding will be necessary beforethe development of specific treatments is feasible.

     

Influence of cerebral oxygenation following severe head injury on neuropsychological testing

Despite recent advances in the management of severe head injury the mortality and morbidity remains high. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are crucial parameters for the correct management at the intensive care unit, due to their therapeutic and prognostic importance. In addition, regional brain tissue oxygenation (ptiO2) seems to be of importance. While different studies demonstrated the impact of cerebral hypoxia on outcome (mortality), no data are available focusing on morbidity (neuropsychological deficits). Therefore, our study is carried out to demonstrate a possible relationship between amount of cerebral oxygenation during acute stage after severe head injury and neuropsychological outcome. Besides ICP and CPP, ptiO2 was monitored in 40 severely head injured patients during the ICU stay from the day of admission until day 10. Monitoring data were stored and amount of hypoxic episodes were calculated. Besides outcome using the Glasgow Outcome Scale neuropsychological testing was performed 2-3 years after injury. Analysing the quality of brain tissue oxygenation, a relationship to the performance in neuropsychological tests could be found. Patients with low brain tissue oxygenation had a worse outcome in neuropsychological testing, especially concerning intelligence and memory. Associated with these deficits patients showed a reduced performance in their profession. Our data suggest a possible predictive value of brain tissue oxygen on morbidity analysing neurocognitive function after head injury. This may implicate monitoring and treatment of cerebral hypoxia.     

Evaluation of cerebral autoregulation following diffuse brain injury in rats

Abstract

The normal cerebral circulation has the ability to maintain a stable cerebral blood flow over a wide range of cerebral perfusion p(essures and this is known as cerebral autoregulation. This autoregulation may be impaired in the injured brain. Closed head injury was induced in 28 Sprague-Dawley rats weighing 400-450 g. Four groups were studied: control group, head injured rat from meter height using 350 g, 400 g and 450 g respectively. CBF, volume velocity was monitored using laser-Doppler flowmetry together with monitoring of ICP and arterial blood pressure. Correlation to assess the relationship between CBF and CPP was done in each animal every hour. If correlation coefficient was> 0.85 and CPP was within normal range, loss of autoregulation was hypothesized. Chi square test, ANOVA test and unpaired Studen(s t-test were done and significant level of p < 0.05 was established. Mean CBF in injured rats was significantly lower than controls (p = 0.028) at the fifth hour. CBV was lower in the group of 450 g 1 m impact than in controls at 3 h (p = 0.04). Velocity in the group ofall injured rats, was significantly lower than in controls at 3 h (p = 0.032) and at 4 h (p = 0.027). Loss ofautoregulation was seen during first four hours after trauma in all groups of rats who sustained injury. Statistical significant difference (p = 0.041) in loss of autoregulation between injured and control animals was seen. No loss of autoregulation was observed in the control group. In conclusion CBF and CPP provide information about loss of autoregulation in diffuse brain injury. Decrease in CBF and increase of ICP is observed as a result ofloss of cerebral autoregulation. Knowledge of loss of autoregulation could give important information and help in the management of head injured patients. [Neural Res 1997; 19: 393-402]     

Influence of cerebral oxygenation following severe head injury on neuropsychological testing

Abstract

Despite recent advances in the management of severe head injury the mortality and morbidity remains high. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are crucial parameters for the correct management at the intensive care unit, due to their therapeutic and prognostic importance. In addition, regional brain tissue oxygenation (p_tiO₂) seems to be of importance. While different studies demonstrated the impact of cerebral hypoxia on outcome (mortality), no data are available focusing on morbidity (neuropsychological deficits). Therefore, our study is carried out to demonstrate a possible relationship between amount of cerebral oxygenation during acute stage after severe head injury and neuropsychological outcome. Besides ICP and CPP, p_tiO₂ was monitored in 40 severely head injured patients during the ICU stay from the day of admission until day 10. Monitoring data were stored and amount of hypoxic episodes were calculated. Besides outcome using the Glasgow Outcome Scale neuropsychological testing was performed 2–3 years after injury. Analysing the quality of brain tissue oxygenation, a relationship to the performance in neuropsychological tests could be found. Patients with low brain tissue oxygenation had a worse outcome in neuropsychological testing, especially concerning intelligence and memory. Associated with these deficits patients showed a reduced performance in their profession. Our data suggest a possible predictive value of brain tissue oxygen on morbidity analysing neurocognitive function after head injury. This may implicate monitoring and treatment of cerebral hypoxia.     

Brain injury: the pathophysiology of the first hours.'Talk and Die revisited'.

In the 25 years since the 'Talk and Die' paper there have been substantial advances in the management of patients with severe closed head injury. This paper discusses developments in understanding of primary and secondary injury. Current management focuses on preventing secondary brain injury. That this has been successful is illustrated by a fall in mortality in recent decades. Evidence based guidelines have set standards of management but they do not take into account variations between individuals, between regions of the brain and variations with time from injury. Various monitoring techniques such as transcranial doppler, jugular venous oxygen saturation and ICP waveform analysis attempt to set individual therapeutic endpoints and to target therapy appropriately. Primary injury is no longer seen as a single irreversible event occurring at the time of impact, but rather as a process initiated by the impact and evolving over subsequent hours and days. Experimental studies have identified agents which reduce the evolution of brain injury and improve outcome. An experimental model of brain injury developed by the Adelaide He ad Injury Group identifies diffuse axonal injury as a target for therapeutic manipulation. Magnesium has been shown in other studies to improve outcome after diffuse brain injury. This has now been linked with upregulation of beta amyloid precursor prote in. Although this and several other experimental therapies have shown great promise, they have not so far produced benefit in large clinical studies. Avoiding secondary insults will remain the goal of management for the foreseeable future. Halting the evolution of the primary injury remains a highly sought after goal. Although elusive so far, it is likely to be the next major advance in clinical care.