家犬实验性脑出血后MRI、ICP及脑组织间液微透析监测研究
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摘要
背景和目的:脑出血(intracerebral hemorrhage,ICH)预后不良,存在较高发病率和死残率,但ICH后继发脑损伤的机制目前并不清楚。本研究旨在将磁共振(magneticresonance imaging,MRI)、颅内压(intracranial pressure,ICP)及脑组织间液微透析(microdialysis)监测等运用于家犬实验性ICH模型,观察实验性ICH的MRI表现、ICP变化、血肿周围脑组织间液微透析监测结果,并结合病理学,进一步研究ICH后继发脑损伤演变过程和机制。
方法:(1)选择雄性成年家犬12只,随机分为ICH组和生理盐水注入对照组,每组6只:(2)运用Medtronic神经影像导航系统校正额叶注血部位及角度,推注非抗凝自体动脉血3 ml(按比例计算相当于人60ml ICH)建立家犬额叶ICH动物模型,对照组动物在相同部位注入等量生理盐水;(3)行血糖、血气分析、脑温监测,判断ICH组与生理盐水注入对照组是否存在可比性;(4)分别观察两组家犬模型制备前1 hr和模型制备后2 hr、6 hr、24 hr、3 d、7 d、14 d各时相点动物行为学,动态MRI观察,各时相点ICP,以及实验结束时的病理学,确定模型建立的可靠性,并研究ICP与血肿周围脑损伤之间的相互关系及趋势;(5)行脑组织间液微透析监测,了解血肿周围脑组织及对侧相应脑区脑组织间液葡萄糖浓度、乳酸浓度、丙酮酸浓度、甘油浓度和谷氨酸浓度,计算乳酸/丙酮酸比值,并与生理盐水注入对照组进行比较。
结果:(1)本实验两组均选择雄性家犬,排除雌激素对ICH周围脑组织的保护作用,监测血糖、血气分析、脑温等基础理化指标,两组差异不显著(P＜0.05),监测结果存在可比性;(2)与生理盐水注入对照组,ICH组动物行为学注血后呼吸浅快、后肢强直状态等症状更明显,戊巴比妥钠维持时间和动物苏醒时间均延长,实验动物存在反应迟钝,行动迟缓,对外界刺激反应力降低,不思饮食等表现更突出,并出现不同程度恐惧、防御状态、凶残等精神症状。(3)MRI检查发现生理盐水注入对照组仅存在穿刺道和沿额叶走行的囊腔,周围无脑水肿形成,7d穿刺道消失,囊腔略扩张,而ICH组在注血后2hr即出现血肿周围长T1长T2信号带,3d范围达到最大,14d血肿周围仍然存在长T1长T2信号带,但范围缩小且信号减弱,同时3d血肿出现红细胞分解特征性短T1短T2信号环,7d较为明显,14d血肿少量残留;(4)ICP监测发现两组均存在ICH模型制备后2hr出现ICP高峰,之后逐渐下降,生理盐水注入对照组3d即恢复正常,而ICH组至14d实验结束仍存在ICP明显高于基线数值(P＜0.05)和生理盐水注入对照组(P＜0.01);(5)病理学结果可见ICH组额叶血肿腔沿脑叶走行,血肿少量残留,占位效应不明显,血肿周围可见水肿带,部分可见患侧丘脑散在点状出血,而生理盐水注入对照组额叶囊腔沿脑叶走行,囊腔内清洁。HE、尼氏染色和透射电镜均发现ICH组血肿周围脑水肿和神经元损伤较生理盐水注入对照组明显;(6)血肿周围脑组织间液微透析分析发现血肿周围脑组织间液葡萄糖浓度实验期间无显著变化,乳酸浓度24hr和3d升高(P＜0.05),丙酮酸浓度在6hr、24hr和3d升高(P＜0.05),甘油浓度在24hr升高(P＜0.05),谷氨酸浓度注血后即升高,3d达到高峰,至14d仍明显高于对照组和基线数值(P＜0.05)。
结论:(1)本实验采用的额叶注射非抗凝自体动脉血制备ICH模型,模型成功率高,动物存活率高,便于护理,可以较好地模拟临床ICH演变过程。(2)家犬头颅MRI显示实验性ICH后2 hr即出现血肿周围长T1长T2信号带,3 d范围达到最大,14 d血肿周围仍然存在长T1长T2信号带,但范围缩小且信号减弱,而生理盐水注入对照组囊腔周围脑组织MRI未见明显异常信号,提示ICH组注血后早期即出现血肿周围脑损伤,3d达到高峰,14 d血肿周围脑损伤仍然存在,血肿周围脑损伤程度远较生理盐水注入对照组严重。(3)ICH后早期ICP升高是血肿占位与血肿周围继发脑损伤共同效应所致,而晚期ICP升高则与ICH后血肿周围脑组织能量代谢紊乱和兴奋性氨基酸毒性所致继发脑损伤有关。(4)ICH周围脑组织间液微透析监测结果支持血肿周围存在“生化半暗带(biochemical penumbra)”区域,结合家犬MRI T2WI像和病理结果,血肿周围脑组织能量代谢紊乱和兴奋性氨基酸毒性可能是血肿周围脑水肿及继发脑损伤形成机制之一。
Background and Purposes:
Intracerebral hemorrhage(ICH) leads bad prognosis and high rate of morbility and mortality to patients,but the mechanisms of secondary brain injury after ICH are still not well known.In order to study how the ICH do harm to the brain,characteristics of MRI, ICP and in vivo microdialysis of experimental intracerebral hemorrhage in mongrel canines were investigated.
Materials and methods:
1、Twelve adult male mongrel canines with bodyweight 11 to 17 kg were divided randomly into ICH group(n=6) and sodium injecting control group(n=6).ICH model was established by injecting 3 ml unanticoagulated auto-arterial-blood in the right frontal lobe,while animals in the control group were injected 3ml saline in the same site;
2、Some essential biochemistry and physiology conditions such as blood glucose,blood gas analysis and brain temperature were monitored to reduce the deviation of experiment;
3、Animal's behaviors were estimated by Purdy Neurologic Scoring System and intracranial pressures(ICP) were measured at 1 hour pre-ICH and 2~(nd) hour,6~(th) hour,24~(th) hour,3~(rd) day,7~(th) day,14~(th) day post-ICH,and pathological examinations were performed at 14~(th) day post-ICH.
4、MRI was scanned at 1 hour pre-ICH and 2~(nd) hour,6~(th) hour,24~(th) hour,3~(rd) day,7~(th) day, 14~(th) day post-ICH in the ICH group and 6~(th) hour and 7~(th) day post-ICH in the control group.
5、Microdialysis of interstitial fluid of brain in the two groups,including the concentration of glucose,lactate,pyruvate,glutamate were monitored,and the ratio of lactate/pyruvate was calculated.
Results:
1、There were no statistical differences between the two group in sex,blood glucose, blood gas analysis and brain temperature.
2、Some animals appeared tachypnea and spasticity of posterior limb immediately after ICH,Other symptoms including reaction torpidity,dull,anorexia,fear,phylaxis and brutalism.These symptoms were more obviously in the ICH group than those of the control group.
3、MRI of the animals in the ICH group showed there were regions appearing low signal in T1WI and high signal in T2WI around the hematoma,occurred at 2~(nd) hour post-ICH,became greatest on 3~(rd) day,then changed into smaller and weaker gradually,but still existed until 14~(th) day.It's suggested that the edema of the brain around hemorrhage exist in 2 hours and get it's peak on Day 3 and then withdraw gradually,but would not disappear at least 14 days.A low signal T1WI and T2WI ring presented in the outside part of the hematoma at 3~(rd) day post-ICH,became obviously at 7~(th) day,and kept small residual till the 14~(th) day,which indicated the peak of the decomposition of the hematoma is at Day 7 after hemorrhage and release the components of red blood cell to the peri-hematoma region. While in the control group,MRI showed there were only puncture path and capsular space in the right frontal lobe at 6~(th) hour.By Day 7 after saline injection,the capsular space expanded moderately and the puncture path disappeared.
4、ICP in both groups arrived the top in 2 hours after ICH,in the control group,ICP lowered to normal 3 days later,but in the ICH group,ICP lowered more slowly than the control group(P＜0.05) and was significantly higher than normal(P＜0.01) by 14 days.
5、The pathology at Day 14 showed that,in the ICH group,hemorrhage cave could be found in the right frontal lobe,in which small residual hemorrhage with moderate mass effect could be seen.Punctate hemorrhage was observed in the thalamencephalon.Different to the ICH group,in the control group,there were only capsular spaces in the frontal lobe without hematoma.Peri-hematoma brain edema and neuronal lesions appeared in both groups,but more obviously in the ICH group.
6、The variations of the components in the microdialysis interstitial fluid from the brain in the ICH group were not the same.No changes of glucose were observed after ICH, while lactate production increased at 24~(th) hour and the 3~(rd) day,pyruvate increased at 6~(th) hour, 24~(th) hour and the 3~(rd) day,glyceral increased at 24~(th) hour,the glutamate concentration increased greatly post-ICH,peaking at Day 3,lasted to the 14~(th) day.The difference of the glutamate concentration between the two groups was statistically significant(P＜0.05).
Conclusions:
1、Because of the Characteristics of high survival rate and easy to breed,the ICH model in the experiment prepared by injecting unanticoagulation auto-arterial-blood in the frontal lobe is very useful,and it can imitate the clinical changes of ICH.
2、MRI presentations in this experiment implied that the secondary brain injury existed in the early stage after ICH,and the decomposed components of red blood cell might play an important role in the brain edema and cause the secondary brain injury.
3、At the early stage(in 3 days),mass effect and the secondary brain injury might contribute to the increasing of ICP after ICH,while at the later stage(after 3 days),injuries induced by the energy metabolism disorders and the toxicities from excitatory amino acids might be the main causes of prolonged ICP increasing.
4、The variations of the components in the microdialysis interstitial fluid from the brain support the presence of "biochemical penumbra" around the hematoma after ICH. Combined with the presentations of the MRI and pathology,which suggested disorders of the energy metabolisms and the toxicities of excitatory amino acids probably be two of the important mechanisms of brain edema and secondary brain injuries after ICH.
方法:(1)选择雄性成年家犬12只,随机分为ICH组和生理盐水注入对照组,每组6只:(2)运用Medtronic神经影像导航系统校正额叶注血部位及角度,推注非抗凝自体动脉血3 ml(按比例计算相当于人60ml ICH)建立家犬额叶ICH动物模型,对照组动物在相同部位注入等量生理盐水;(3)行血糖、血气分析、脑温监测,判断ICH组与生理盐水注入对照组是否存在可比性;(4)分别观察两组家犬模型制备前1 hr和模型制备后2 hr、6 hr、24 hr、3 d、7 d、14 d各时相点动物行为学,动态MRI观察,各时相点ICP,以及实验结束时的病理学,确定模型建立的可靠性,并研究ICP与血肿周围脑损伤之间的相互关系及趋势;(5)行脑组织间液微透析监测,了解血肿周围脑组织及对侧相应脑区脑组织间液葡萄糖浓度、乳酸浓度、丙酮酸浓度、甘油浓度和谷氨酸浓度,计算乳酸/丙酮酸比值,并与生理盐水注入对照组进行比较。
结果:(1)本实验两组均选择雄性家犬,排除雌激素对ICH周围脑组织的保护作用,监测血糖、血气分析、脑温等基础理化指标,两组差异不显著(P＜0.05),监测结果存在可比性;(2)与生理盐水注入对照组,ICH组动物行为学注血后呼吸浅快、后肢强直状态等症状更明显,戊巴比妥钠维持时间和动物苏醒时间均延长,实验动物存在反应迟钝,行动迟缓,对外界刺激反应力降低,不思饮食等表现更突出,并出现不同程度恐惧、防御状态、凶残等精神症状。(3)MRI检查发现生理盐水注入对照组仅存在穿刺道和沿额叶走行的囊腔,周围无脑水肿形成,7d穿刺道消失,囊腔略扩张,而ICH组在注血后2hr即出现血肿周围长T1长T2信号带,3d范围达到最大,14d血肿周围仍然存在长T1长T2信号带,但范围缩小且信号减弱,同时3d血肿出现红细胞分解特征性短T1短T2信号环,7d较为明显,14d血肿少量残留;(4)ICP监测发现两组均存在ICH模型制备后2hr出现ICP高峰,之后逐渐下降,生理盐水注入对照组3d即恢复正常,而ICH组至14d实验结束仍存在ICP明显高于基线数值(P＜0.05)和生理盐水注入对照组(P＜0.01);(5)病理学结果可见ICH组额叶血肿腔沿脑叶走行,血肿少量残留,占位效应不明显,血肿周围可见水肿带,部分可见患侧丘脑散在点状出血,而生理盐水注入对照组额叶囊腔沿脑叶走行,囊腔内清洁。HE、尼氏染色和透射电镜均发现ICH组血肿周围脑水肿和神经元损伤较生理盐水注入对照组明显;(6)血肿周围脑组织间液微透析分析发现血肿周围脑组织间液葡萄糖浓度实验期间无显著变化,乳酸浓度24hr和3d升高(P＜0.05),丙酮酸浓度在6hr、24hr和3d升高(P＜0.05),甘油浓度在24hr升高(P＜0.05),谷氨酸浓度注血后即升高,3d达到高峰,至14d仍明显高于对照组和基线数值(P＜0.05)。
结论:(1)本实验采用的额叶注射非抗凝自体动脉血制备ICH模型,模型成功率高,动物存活率高,便于护理,可以较好地模拟临床ICH演变过程。(2)家犬头颅MRI显示实验性ICH后2 hr即出现血肿周围长T1长T2信号带,3 d范围达到最大,14 d血肿周围仍然存在长T1长T2信号带,但范围缩小且信号减弱,而生理盐水注入对照组囊腔周围脑组织MRI未见明显异常信号,提示ICH组注血后早期即出现血肿周围脑损伤,3d达到高峰,14 d血肿周围脑损伤仍然存在,血肿周围脑损伤程度远较生理盐水注入对照组严重。(3)ICH后早期ICP升高是血肿占位与血肿周围继发脑损伤共同效应所致,而晚期ICP升高则与ICH后血肿周围脑组织能量代谢紊乱和兴奋性氨基酸毒性所致继发脑损伤有关。(4)ICH周围脑组织间液微透析监测结果支持血肿周围存在“生化半暗带(biochemical penumbra)”区域,结合家犬MRI T2WI像和病理结果,血肿周围脑组织能量代谢紊乱和兴奋性氨基酸毒性可能是血肿周围脑水肿及继发脑损伤形成机制之一。
Background and Purposes:
Intracerebral hemorrhage(ICH) leads bad prognosis and high rate of morbility and mortality to patients,but the mechanisms of secondary brain injury after ICH are still not well known.In order to study how the ICH do harm to the brain,characteristics of MRI, ICP and in vivo microdialysis of experimental intracerebral hemorrhage in mongrel canines were investigated.
Materials and methods:
1、Twelve adult male mongrel canines with bodyweight 11 to 17 kg were divided randomly into ICH group(n=6) and sodium injecting control group(n=6).ICH model was established by injecting 3 ml unanticoagulated auto-arterial-blood in the right frontal lobe,while animals in the control group were injected 3ml saline in the same site;
2、Some essential biochemistry and physiology conditions such as blood glucose,blood gas analysis and brain temperature were monitored to reduce the deviation of experiment;
3、Animal's behaviors were estimated by Purdy Neurologic Scoring System and intracranial pressures(ICP) were measured at 1 hour pre-ICH and 2~(nd) hour,6~(th) hour,24~(th) hour,3~(rd) day,7~(th) day,14~(th) day post-ICH,and pathological examinations were performed at 14~(th) day post-ICH.
4、MRI was scanned at 1 hour pre-ICH and 2~(nd) hour,6~(th) hour,24~(th) hour,3~(rd) day,7~(th) day, 14~(th) day post-ICH in the ICH group and 6~(th) hour and 7~(th) day post-ICH in the control group.
5、Microdialysis of interstitial fluid of brain in the two groups,including the concentration of glucose,lactate,pyruvate,glutamate were monitored,and the ratio of lactate/pyruvate was calculated.
Results:
1、There were no statistical differences between the two group in sex,blood glucose, blood gas analysis and brain temperature.
2、Some animals appeared tachypnea and spasticity of posterior limb immediately after ICH,Other symptoms including reaction torpidity,dull,anorexia,fear,phylaxis and brutalism.These symptoms were more obviously in the ICH group than those of the control group.
3、MRI of the animals in the ICH group showed there were regions appearing low signal in T1WI and high signal in T2WI around the hematoma,occurred at 2~(nd) hour post-ICH,became greatest on 3~(rd) day,then changed into smaller and weaker gradually,but still existed until 14~(th) day.It's suggested that the edema of the brain around hemorrhage exist in 2 hours and get it's peak on Day 3 and then withdraw gradually,but would not disappear at least 14 days.A low signal T1WI and T2WI ring presented in the outside part of the hematoma at 3~(rd) day post-ICH,became obviously at 7~(th) day,and kept small residual till the 14~(th) day,which indicated the peak of the decomposition of the hematoma is at Day 7 after hemorrhage and release the components of red blood cell to the peri-hematoma region. While in the control group,MRI showed there were only puncture path and capsular space in the right frontal lobe at 6~(th) hour.By Day 7 after saline injection,the capsular space expanded moderately and the puncture path disappeared.
4、ICP in both groups arrived the top in 2 hours after ICH,in the control group,ICP lowered to normal 3 days later,but in the ICH group,ICP lowered more slowly than the control group(P＜0.05) and was significantly higher than normal(P＜0.01) by 14 days.
5、The pathology at Day 14 showed that,in the ICH group,hemorrhage cave could be found in the right frontal lobe,in which small residual hemorrhage with moderate mass effect could be seen.Punctate hemorrhage was observed in the thalamencephalon.Different to the ICH group,in the control group,there were only capsular spaces in the frontal lobe without hematoma.Peri-hematoma brain edema and neuronal lesions appeared in both groups,but more obviously in the ICH group.
6、The variations of the components in the microdialysis interstitial fluid from the brain in the ICH group were not the same.No changes of glucose were observed after ICH, while lactate production increased at 24~(th) hour and the 3~(rd) day,pyruvate increased at 6~(th) hour, 24~(th) hour and the 3~(rd) day,glyceral increased at 24~(th) hour,the glutamate concentration increased greatly post-ICH,peaking at Day 3,lasted to the 14~(th) day.The difference of the glutamate concentration between the two groups was statistically significant(P＜0.05).
Conclusions:
1、Because of the Characteristics of high survival rate and easy to breed,the ICH model in the experiment prepared by injecting unanticoagulation auto-arterial-blood in the frontal lobe is very useful,and it can imitate the clinical changes of ICH.
2、MRI presentations in this experiment implied that the secondary brain injury existed in the early stage after ICH,and the decomposed components of red blood cell might play an important role in the brain edema and cause the secondary brain injury.
3、At the early stage(in 3 days),mass effect and the secondary brain injury might contribute to the increasing of ICP after ICH,while at the later stage(after 3 days),injuries induced by the energy metabolism disorders and the toxicities from excitatory amino acids might be the main causes of prolonged ICP increasing.
4、The variations of the components in the microdialysis interstitial fluid from the brain support the presence of "biochemical penumbra" around the hematoma after ICH. Combined with the presentations of the MRI and pathology,which suggested disorders of the energy metabolisms and the toxicities of excitatory amino acids probably be two of the important mechanisms of brain edema and secondary brain injuries after ICH.
引文
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