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.     

Neuromonitoring: Brain oxygenation and microdialysis

Patients with cerebral lesions run a high risk of developing cerebral hypoxic and ischemic damage due to secondary insults. To minimize the risk of secondary cerebral hypoxia and ischemia, new monitoring techniques of cerebral oxygenation and metabolism have been developed and may help to understand the pathophysiology of secondary brain damage for a better treatment and outcome in critical patients. Cerebral microdialysis is a relatively new technique for measuring brain molecules of the extracellular space. The technical aspects, the interpretation of the commonly measured parameters, the use of the two commonly used oxygenation parameters (jugular venous oxygen saturation and monitoring of brain tissue PO₂ and the microdialysis technique to monitor cerebral metabolism in patients with head injury), subarachnoid hemorrhage, and ischemic stroke are considered. Pitfalls of the techniques and their future potential are discussed.     

Cerebral energy metabolism and microdialysis in neurocritical care

It is of obvious clinical importance to monitor cerebral metabolism—in particular, cerebral energy metabolism and indicators of cellular damage—online at the bedside. The technique of cerebral microdialysis provides the opportunity for continuous monitoring of metabolic changes in the tissue before they are reflected in peripheral blood chemistry or in systemic physiological parameters. The basic idea of microdialysis is to mimic the function of a blood capillary by positioning a thin dialysis tube in the tissue and to be used to analyze the chemical composition of the interstitial fluid. The biochemical variables used during routine monitoring were chosen to cover important aspects of cerebral energy metabolism (glucose, pyruvate and lactate), to indicate excessive interstitial levels of excitatory transmitter substance (glutamate) and to give indications of degradation of cellular membranes (glycerol). Furthermore, pharmokinetic studies can be conducted using microdialysis. This article discusses technical and physiological aspects of microdialysis, and its clinical applications in brain injury.     

Brain tissue oxygen tension monitoring in pediatric severe traumatic brain injury Part 1: Relationship with outcome

Introduction  

Intracranial pressure (ICP) monitoring and cerebral perfusion pressure (CPP) management are the current standards to guide care of severe traumatic brain injury (TBI). However, brain hypoxia and secondary brain injury can occur despite optimal ICP and CPP. In this study, we used brain tissue oxygen tension (PbtO₂) monitoring to examine the association between multiple patient factors, including PbtO₂, and outcome in pediatric severe TBI.     

Clinical cerebral microdialysis: Brain metabolism and brain tissue oxygenation after acute brain injury

Abstract

While continuous monitoring of brain tissue oxygenation (p_tiO₂) is known as a practicable, safe and reliable monitoring technology supplementing traditional ICP-CPP-monitoring, the impact of cerebral microdialysis, now available bedside, is not proven extensively. Therefore our studies focused on the practicability, complications and clinical impact of microdialysis during long term monitoring after acute brain injury, especially the analysis of the correlation between changes of local brain oxygenation and metabolism. Advanced neuromonitoring including ICP-CPP-p_tiO₂ was performed in 20 patients suffering from acute brain injury. Analysis of the extracellular fluid metabolites (glucose, lactate, pyruvate, glutamate) were performed bedside hourly. No catheter associated complications, like infection and bleeding, occurred. However, longterm monitoring was limited in 5 out of 20 patients caused by obliteration of the microdialysis catheter after 3-4 days. In the individual patients partly a correlation between increased lactate levels as well as lactate pyruvate ratios and hypoxic brain tissue oxygenation could be found. Analysing the data sets of all patients only a low correlation was detected indicating physiological and increased lactate and lactate/pyruvate ratio during sufficient brain oxygenation. Additionally, concentrations of excitatory amino acid glutamate were found in normal and elevated range during periods of hypoxic oxygenation (p_tiO₂ < 10 mmHg) and intracranial hypertension. Our data strongly suggest partly evidence of correlation between hypoxic oxygenation and metabolic disturbances after brain injury. On the other hand brain metabolism is altered without changes of cerebral oxygenation. Further studies are indicated to improve our pathophysiological knowledge before microdialysis is routinely useful in neurointensive care. [Neurol Res 2001; 23: 801-806]     

Neuronal free Ca(2+)and BBB permeability and ultrastructure in head injury with secondary insult.

OBJECTIVE: To study changes in free calcium (Ca(2+)), neuronal and blood-brain barrier (BBB) permeability and ultrastructure in brain after diffuse axonal injury (DAI) with secondary brain insults (SBIs). METHOD: One hundred and twenty Sprague-Dawley (SD) rats were randomised into control, DAI alone and DAI with SBI groups which were sub-divided into 5 groups that were 0.5 h, 2 h, 12 h, 24 h, 48 h post trauma. The animal models of DAI and DAI with SBI have been described before (2). Fluorescence probe Fluo-3/Am was used to measure free Ca(2+)in neurons. Laser scan microscopy was used to detect fluorescence intensity. After the animals were anesthetized, Lanthanum nitrate liquid was used for intracardiac perfusion to assess BBB permeability. Under the transmission electron microscope, changes in cerebral ultrastructure and BBB permeability were observed. RESULTS: The fluorescence intensity was weak in the control. The concentration of free Ca(2+)in neurons was obviously increased at 30 min after brain injury, reached a peak at 12 h-24 h (P< 0.01), and appeared to decrease at 48 h after injury. In the DAI alone group, BBB tight junction opening with particles of Lanthanum nitrate outside the vessels was found at 30 min after injury, and peaked at 24 h. In DAI with SBI, the changes in ultrastructure and BBB permeability were more severe than that in the DAI alone group at the same time interval. The shape of the fluorescence concentration curve was basically the same for both kinds of brain injury. The intensity of fluorescence in DAI with SBI was higher than that in the DAI alone group at the same time interval (P< 0.05). CONCLUSION: In DAI alone and DAI with SBI, Ca(2+)overload and BBB permeability changes interact and both play important roles in the aggravation of brain damage.     

颅脑损伤程度对大鼠脑血流及氧代谢的影响

目的 对颅脑损伤影响脑血流及氧代谢进行前瞻性研究。方法 30只Wistar大白鼠分成3组：颅脑损伤1组（TBI1）、2组（TBI2）及3组（TBI3）各10只,分别为轻、中、重型颅脑损伤。用脑阻抗（REG）测定脑血流量,颈内静脉血氧饱和度（SjVO2)反映全脑氧代谢情况。结果 TBI、TBI2及TBI3组影响脑血流和氧代谢程度依次为TBI3＞TBI2＞TBI1,健侧脑组织含水量各组无明显差异,伤侧脑组织含水量TBI3组最多,其次为TBI2,明显高于TBI1组（P＜0．01）。结论 颅脑损伤后脑血流和氧代谢变化取决于损伤程度,脑血流和氧代谢各参数的监测对正确认识脑组织病理生理变化,指导临床治疗,判断预后有重要价值。     

Endothelial apoptosis does not determine symptom status in carotid artery disease

BACKGROUND: Transcranial Doppler sonography (TCD) has been used widely for long-term monitoring of cerebral blood flow without adverse reports. However, attention has not been adequately paid to the fact that an increase in the time period of TCD insonation causes brain temperature to rise due to ultrasound absorption by tissue and the skull. We measured the actual temperature rise in local brain tissue induced by TCD insonation over a long time period during in vivo animal experiments in order to verify whether or not a pause is required in long-term, continuous TCD monitoring. METHODS: We inserted thermocouples into the skull-brain interface (SBI) of 15 New Zealand White rabbits (10: TCD application group; 5: control group, TCD non-application group). The TCD probe was placed on the parietal bone, and changes in SBI temperature (SBIT) were measured for 90 min. TCD was set at maximum output level (0.2 W, 2 MHz). RESULTS: SBIT in the TCD group increased rapidly to 3.47 degrees C within 25 min and then reached a plateau. The maximum time for safe continuous TCD application is estimated to be 33 min. CONCLUSIONS: Even though there are large differences in factors, such as brain volume and environmental conditions, between rabbits and humans, there is less difference in their cerebral blood flow per brain weight, which is the parameter that is mainly associated with heat reduction. Accordingly, the findings of the present experiment suggest that long-term TCD monitoring in clinical use should include a pause after every 30 min of insonation to avoid thermal damage to the brain surface.     

Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction

Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral ‘mitochondrial dysfunction’ (MD). In patients with TBI and MD, we administered disodium 2,3-¹³C₂ succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered ¹³C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(−12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous ¹³C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.     

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.     

Multimodal brain monitoring in the neurological intensive care unit: where does continuous EEG fit in?

Continuous EEG (cEEG) is a vital component of patient monitoring in the neurologic intensive care unit, allowing the intensivist to diagnose nonconvulsive seizure activity. Though still in its infancy, Fourier-transformed cEEG data are also increasingly being used in ICUs to monitor global cerebral activity and cortical function. In conjunction with other components of multimodality neurologic monitoring, including intracranial pressure, cerebral blood flow, brain tissue oxygen tension monitoring, transcranial Doppler, and microdialysis monitoring, cEEG provides unique data regarding the electrical activity of the brain. The main challenge for clinicians and researchers will be to understand how these different aspects of multimodality monitoring relate to each other, and how physiologic variables such as blood pressure, osmolality, and temperature can be manipulated to optimize cerebral function and tissue survival in the setting of acute injury.     

Multimodality monitoring in severe traumatic brain injury

Traumatic brain injury (TBI) is a major cause of morbidity and mortality with widespread social, personal, and financial implications for those who survive. TBI is caused by four main events: motor vehicle accidents, sporting injuries, falls, and assaults. Similarly to international statistics, annual incidence reports for TBI in Australia are between 100 and 288 per 100,000. Regardless of the cause of TBI, molecular and cellular derangements occur that can lead to neuronal cell death. Axonal transport disruption, ionic disruption, reduced energy formation, glutamate excitotoxicity, and free radical formation all contribute to the complex pathophysiological process of TBI-related neuronal death. Targeted pharmacological therapy has not proved beneficial in improving patient outcome, and monitoring and maintenance of various physiological parameters is the mainstay of current therapy. Parameters monitored include arterial blood pressure, blood gases, intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and direct brain tissue oxygen measurement (ptiO₂). Currently, indirect brain oximetry is used for cerebral oxygenation determination, which provides some information regarding global oxygenation levels. A newly developed oximetry technique, has shown promising results for the early detection of cerebral ischemia. ptiO₂ monitoring provides a safe, easy, and sensitive method of regional brain oximetry, providing a greater understanding of neurophysiological derangements and the potential for correcting abnormal oxygenation earlier, thus improving patient outcome. This article reviews the current status of bedside monitoring for patients with TBI and considers whether ptiO₂ has a role in the modern intensive care setting.     

Neuronal free Caand BBB permeability and ultrastructure in head injury with secondary insult

Objective: To study changes in free calcium (Ca²⁺), neuronal and blood–brain barrier (BBB) permeability and ultrastructure in brain after diffuse axonal injury (DAI) with secondary brain insults (SBIs).Method: One hundred and twenty Sprague-Dawley (SD) rats were randomised into control, DAI alone and DAI with SBI groups which were sub-divided into 5 groups that were 0.5 h, 2 h, 12 h, 24 h, 48 h post trauma. The animal models of DAI and DAI with SBI have been described before (2). Fluorescence probe Fluo-3/Am was used to measure free Ca²⁺in neurons. Laser scan microscopy was used to detect fluorescence intensity. After the animals were anesthetized, Lanthanum nitrate liquid was used for intracardiac perfusion to assess BBB permeability. Under the transmission electron microscope, changes in cerebral ultrastructure and BBB permeability were observed.Results: The fluorescence intensity was weak in the control. The concentration of free Ca²⁺in neurons was obviously increased at 30 min after brain injury, reached a peak at 12 h–24 h (P< 0.01), and appeared to decrease at 48 h after injury. In the DAI alone group, BBB tight junction opening with particles of Lanthanum nitrate outside the vessels was found at 30min after injury, and peaked at 24 h. In DAI with SBI, the changes in ultrastructure and BBB permeability were more severe than that in the DAI alone group at the same time interval. The shape of the fluorescence concentration curve was basically the same for both kinds of brain injury. The intensity of fluorescence in DAI with SBI was higher than that in the DAI alone group at the same time interval (P< 0.05).Conclusion: In DAI alone and DAI with SBI, Ca²⁺overload and BBB permeability changes interact and both play important roles in the aggravation of brain damage.     

大鼠二次脑损伤后脑内c-fos基因表达和血浆β-内啡肽的变化及意义

目的 探讨脑内c-fos基因表达及血浆β-内啡肽的变化在二次脑损伤（SBI）中的作用。方法 125只雄性SD大鼠随机分为正常对照组、假手术组、脑缺血组、颅脑损伤组和SBI组。分别采用免疫组化及放免分析测定大鼠脑内c-fos蛋白与血浆β-EP的含量，并对脑组织进行病理学观察。结果 SBI组c-fos基因表达分别于伤后3h、24h出现两个高峰．伤后3～48hc-fos基因表达均明显高于颅脑损伤组及脑缺血组（P〈0．05）。SBI组大鼠血浆β-EP水平在伤后1h达高峰，至伤后48h仍未恢复正常（P〈0．05），伤后各时间点均明显高于颅脑损伤组和脑缺血组（P〈0．05）。在伤后12hSBI组脑含水量达高峰；伤后3～48h明显高于颅脑损伤组及脑缺血组（P〈0．05）。伤后648hSBI组神经元损伤数目明显高于颅脑损伤组及脑缺血组（P〈0．05）。结论 伤后大鼠脑内c-fos基因表达增加、血浆β-EP水平明显升高参与了SBI后病理生理过程，提示两者同SBI发展密切相关。     

Continuous Brain Tissue Oxygenation Monitoring in the Management of Pediatric Stroke

Background  

Direct invasive monitoring of brain tissue oxygenation (PbtO₂) has been routinely utilized to predict cerebral ischemia and to prevent secondary injury in patients with traumatic brain injury (TBI) and vasospasm secondary to subarachnoid hemorrhage (SAH). The safety and utility of these devices in the pediatric population have been examined in a few small studies. No studies, however, have examined the use of PbtO₂ monitoring in stroke patients.     

IL-8单抗对颅脑损伤后继发性脑损害的保护作用

目的　观察抗IL 8单抗对兔脑损伤后脑内炎症反应的抑制作用 ,以及对血脑屏障通透性和创伤性脑水肿的影响 ,探讨颅脑损伤后继发性脑损害新的治疗方法。方法　采用自由落体兔脑损伤模型 ,观察家兔抗IL 8单抗治疗前后脑组织中IL 8表达、中性粒细胞 (PMNL)浸润有无变化 ,同时检测脑组织含水量的变化 ,并用胶体金示踪 ,电镜观察抗IL 8单抗使用前后血脑屏障通透性有无改善。结果　抗IL 8单抗治疗组与对照组相比 ,伤后脑组织中IL 8无表达 ,PMNL浸润也明显减少 (P <0 .0 1 ) ,血脑屏障通透性降低 ,脑含水量下降 (P <0 .0 5)。结论　颅脑损伤后早期给予抗IL 8单抗治疗 ,可抑制IL 8的表达 ,抑制IL 8趋化PMNL的作用 ,减少组织中PMNL的浸润 ,减轻脑损伤后脑内炎症反应 ,降低血脑屏障通透性 ,减轻创伤性脑水肿 ,从而改善继发性脑损害。     

Barbiturate therapy for patients with refractory intracranial hypertension following severe traumatic brain injury: its effects on tissue oxygenation, brain temperature and autoregulation.

The aim of this study was to explore the effects of barbiturate coma on cerebral tissue oxygen tension and cerebrovascular pressure reactivity (PRx), as an index of cerebral autoregulation in severe head injury patients. This was a prospective observational clinical study of 12 patients with severe traumatic brain injury, carried out at a tertiary-level neurosurgical intensive care unit between April 2002 and May 2005. All patients received standard neurosurgical intensive care and monitoring. Probes for intracranial pressure (ICP), brain temperature (BT) and brain tissue oxygenation (PTiO2) were inserted into (noncontused) normal-looking white matter. Cerebrovascular PRx was measured as a moving correlation between ICP and arterial blood pressure. Barbiturate coma was instituted when ICP became refractory (ICP>20 mmHg). All data from the multimodal monitoring were digitally extracted and statistically analysed. The mean ICP decreased with barbiturate coma in eight of the 12 patients (75% of the patients), but only four achieved a value below 20 mmHg. Of eight patients with prebarbiturate PTiO2 levels above 10 mmHg, six had a further improvement in oxygenation. Thus, concordant favourable changes in ICP, PRx and PTiO2 with barbiturate coma were seen in those who survived. Effective response to barbiturates can be detected by improved PTiO2 and autoregulation (PRx) in severe head injury patients.     

Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model

Neurosurgical procedures result in surgically induced brain injury (SBI) that causes postoperative complications including brain edema and neuronal apoptosis in the surrounding brain tissue. SBI leads to the release of cytokines that indirectly cause the stimulation of kynurenine 3-monooxygenase (KMO) and the release of neurotoxic quinolinic acid (QUIN). This study tested a KMO inhibitor, RO 61-8048, to prevent postoperative brain edema and consequent neuronal apoptosis in an in vivo model of SBI. A rodent model of SBI was utilized which involves partial resection of the right frontal lobe. A total of 127 Sprague-Dawley male rats (weight 275–325 g) were randomly divided into the following groups: Sham surgical group, SBI, SBI + DMSO, SBI + RO 61-8048 (10 mg/kg), SBI + RO 61-8048 (40 mg/kg), and SBI + RO 61-8048 (40 mg/kg) + KAT II inhibitor PF-04859989 (5 mg/kg). RO 61-8048 was administered by intraperitoneal injection after SBI. Postoperative assessment at different time points included brain water content (brain edema), neurological scoring, and western blot. SBI increased brain water content (ipsilateral frontal lobe), decreased neurological function, and increased apoptotic markers compared with sham animals. Treatment with RO 61-8048 (40 mg/kg) reduced brain water content and improved long-term neurological function after SBI. RO 61-8048 increased the expression of kynurenic acid while reducing QUIN and apoptotic markers in the surrounding brain tissue after SBI. These neuroprotective effects were reversed by PF-04859989. This study suggests KMO inhibition via RO 61-8048 as a potential postoperative therapy following neurosurgical procedures.     

川芎嗪对大鼠重型颅脑损伤后神经细胞凋亡及Bcl-2、Bax表达的影响

目的探讨川芎嗪对大鼠重型颅脑损伤后神经细胞凋亡及相关基因Bcl-2、Bax表达的影响和对脑神经的保护作用。方法120只SD健康大鼠随机分为假手术组、模型组、治疗组,其中模型组和治疗组采用Feeney自由落体撞击装置制作大鼠重型颅脑损伤模型,治疗组给予盐酸川芎嗪,用TUNEL及免疫组化法检测三组间细胞凋亡及Bcl-2、Bax蛋白的表达情况。结果大鼠脑组织中细胞凋亡率及Bcl-2、Bax表达水平在治疗组和模型明屁高于假手术组（P〈0．05）。在伤后72h、168h,治疗组的细胞凋亡率及Bax表达水平明显低于模型组,而Bcl-2的表达水平则明显高于模型组（P〈0．05）。结论川芎嗪可能通过抑制Bax的表达,上调Bcl-2的表达,减少神经细胞凋亡,减轻重型颅脑损伤后继发脑损害,从而发挥脑神经保护作用。