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]     

Advanced neuromonitoring including cerebral tissue oxygenation and outcome after traumatic brain injury.

For 51 patients suffering from traumatic brain injury (GCS < 9), we compared the prognostic value of critical parameters derived from neuromonitoring of intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygenation (PiO2) during different time periods after trauma (< or = 12, < or = 24, < or = 48, < or = 72 and < or = 96 h). For patients with good outcome (GOS = 4-5, n = 30) the proportion of critical ICP values (> 40 mmHg) was about 0.2% during all time periods. The corresponding proportions for patients with bad outcome (GOS = 1-3, n = 21) rose from 0.2% to 4.7% during increasing time periods. The frequency of critical ICP values was significantly related to outcome (p < 0.001) for time periods > 48 h after trauma. Differences of critical CPP (< or = 50 mmHg) and hypoxic PiO2 (< or = 5 mmHg) between both outcome groups were less pronounced and for both parameters significant relations to outcome were only obtained for the longest time period (< or = 96 h, p < or = 0.05). Higher thresholds for CPP (< or = 60 mmHg, < or = 70 mmHg) did not reveal any relation to outcome. For all neuromonitoring parameters significant relations between the frequency of critical values and outcome could be determined. Critical ICP values provide the earliest and highest prognostic power, while critical CPP and hypoxic PiO2 only showed prognostic power in later time periods.     

Impact of pyrexia on neurochemistry and cerebral oxygenation after acute brain injury

BACKGROUND: Postischaemic pyrexia exacerbates neuronal damage. Hyperthermia related cerebral changes have still not been well investigated in humans. OBJECTIVE: To study how pyrexia affects neurochemistry and cerebral oxygenation after acute brain injury. METHODS: 18 acutely brain injured patients were studied at the onset and resolution of febrile episodes (brain temperature > or = 38.7 degrees C). Intracranial pressure (ICP), brain tissue oxygen tension (PbrO2), and brain tissue temperature (Tbr) were recorded continuously; jugular venous blood was sampled intermittently. Microdialysis probes were inserted in the cerebral cortex and in subcutaneous tissue. Glucose, lactate, pyruvate, and glutamate were measured hourly. The lactate to pyruvate ratio was calculated. RESULTS: Mean (SD) Tbr rose from 38 (0.5) to 39.3 (0.3) degrees C. Arteriojugular oxygen content difference (AJD(O2)) fell from 4.2 (0.7) to 3.8 (0.5) vol% (p < 0.05) and PbrO2 rose from 32 (21) to 37 (22) mm Hg (p < 0.05). ICP increased slightly and no significant neurochemical alterations occurred. Opposite changes were recorded when brain temperature returned towards baseline. CONCLUSIONS: As long as substrate and oxygen delivery remain adequate, hyperthermia on its own does not seem to induce any further significant neurochemical alterations. Changes in cerebral blood volume may, however, affect intracranial pressure.     

亚低温治疗颅脑创伤患者颅内生化代谢动态研究

目的应用微透析技术研究了24例颅脑创伤患者脑细胞间液中葡萄糖(Glu)、乳酸(Lac)、丙酮酸(Pyru)、甘油(Gly)、乳酸/葡萄糖比值(L/G)和乳酸/丙酮酸比值(L/P)的变化规律以及亚低温治疗的影响。方法将微透析导管分别插入患者脑创伤病灶半暗带区、相对正常脑组织区和腹部皮下组织,收集微透析液,灌流速度为0.3μl/min。1管透析液/h。平均收集时间为67.37±21.20h;收集的透析液用生化分析仪测定Glu、Lac、Pyru和Gly。结果(1)亚低温治疗较常温治疗可明显降低患者脑创伤病灶半暗带区GLY,明显升高L/P比值, 而Glu、Lac、Pyru、L/G与常温组无显著性差异;(2)亚低温治疗较常温治疗能显著降低相对正常的脑组织Glu、Lac含量和L/P比值,但对Pyru、L/G、Gly较常温组无显著性差异;(3)亚低温治疗较常温治疗可显著提高Glu含量,降低腹部组织Lac、Gly含量和L/G、L/P的比值,但对Pyru含量无明显调节作用。结论微透析技术提供了一种实时监测颅脑创伤患者脑和皮下组织细胞间液生化指标的手段,亚低温治疗能预防患者近损伤区细胞膜的进一步降解,对未受伤的脑组织和腹部组织具有更好的保护作用,从而防止继发性损害。     

Near-infrared spectroscopy--not useful to monitor cerebral oxygenation after severe brain injury

Since its development more than twenty years ago, non-invasive near-infrared-spectroscopy (NIRS) has been widely used to monitor cerebral oxygenation. Despite of its growing number of users, the diagnostic value of near-infrared spectroscopy still remains unclear, especially in case of acute brain injury and long-term neuromonitoring, necessary during intensive care therapy. To evaluate quality and sensitivity of NIRS measurements compared to invasive ICP-, CPP- and regional brain tissue--pO2 (p(ti)O2) monitoring, 31 patients, suffering from severe brain injury due to subarachnoid hemorrhage or severe head injury, were studied. NIRS measurements were only possible in 80% (using the INVOS oximeter) and in 46% (using the CRITIKON monitor), while good data quality was obtained in 100% from ICP, CPP and p(ti)O2. Major reasons for the failure of NIRS measurements were: (1) a wet chamber between sensor and skin, (2) galea hematoma or (3) subdural air after craniotomy. Different tests were performed to compare the sensitivity of regular oxygen saturation (NIRS) with the sensitivity of invasively determined p(ti)O2. Only induced hyperoxia (FiO2 = 1.0) revealed a significant correlation between both parameters (r = 0.67, p < 0.01). Lower or no correlation was found after changing paCO2 and administration of mannitol. The high failure rate and the limited sensitivity does not make the clinical use of near-infrared spectroscopy suitable as a part of neuromonitoring after acute brain injury at the present time.     

Alterations in cerebral oxygen metabolism after traumatic brain injury in children

Traumatic brain injury (TBI) is the most common cause of acquired disability in children. Metabolic defects, and in particular mitochondrial dysfunction, are important contributors to brain injury after TBI. Studies of metabolic dysfunction are limited, but magnetic resonance methods suitable for use in children are overcoming this limitation. We performed noninvasive measurements of cerebral blood flow and oxygen metabolic index (OMI) to assess metabolic dysfunction in children with severe TBI. Cerebral blood flow is variable after TBI but hypoperfusion and low OMI are predominant, supporting metabolic dysfunction. This finding is consistent with preclinical and adult clinical studies of brain metabolism and mitochondrial dysfunction after TBI.     

Temporal changes in cerebral tissue oxygenation with cerebrovascular pressure reactivity in severe traumatic brain injury

Objective

To investigate the temporal relationship between cerebrovascular pressure reactivity and brain tissue oxygenation in patients with severe head injury.

Methods

In 40 patients, brain tissue oxygenation and intracranial pressure were monitored. Time‐averaged values for intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion pressure (CPP) and brain tissue oxygenation (PtiO₂) were computed. The pressure reactivity index (PRx) was calculated. The mean values of the variables were obtained at the 6‐h and 72‐h post‐injury time points, and the difference between the two time points for each of the variables was denoted as delta (δ).

Results

Of the 40 patients, 32 were survivors and 8 were non‐survivors. Statistically significant differences were present between these two groups with regard to δMAP (p = 0.013), ICP at 6 h (p = 0.027), CPP at 72 h (p = 0.018), δCPP (p = 0.033), PRx at 6 h (p = 0.029), PRx at 72 h (p = 0.002), PtiO₂ at 72 h (p<0.0005) and δPtiO₂ (p = 0.023) values, reflecting an improvement with time in survivors and a deterioration with time in non‐survivors. In non‐survivors, the magnitude of change in PtiO₂ and CPP with time correlated in a negative linear fashion (p = 0.042 and 0.029, respectively) with the change in PRx with time, whereas no such relationship was seen in survivors.

Conclusion

The severity of brain tissue oxygenation derangement correlates with increasing cerebrovascular dysautoregulation in patients succumbing to severe head injury, supporting the utility of PRx as a monitoring variable and the rationale for a target‐driven approach to head injury management.Cerebral ischaemia is a critical contributory factor to secondary brain injury after trauma. In the presence of an unstable cerebral perfusion pressure (CPP), the autoregulatory cerebrovascular reactivity attempts to maintain an adequate cerebral blood flow. Increasing CPP may result in raised or lowered intracranial pressure (ICP), depending on whether cerebral autoregulation is preserved. Rosner et al¹ have described how increases in CPP within the autoregulatory range lead to compensatory vasoconstriction to maintain a stable cerebral blood flow. In so doing, cerebral blood volume and thus ICP levels fall. However, outside of these autoregulatory limits, a pressure‐passive scenario exists where increases in CPP lead to vasodilatation and a rise in ICP. Investigators have defined an index comparing arterial blood pressure (ABP) and ICP to quantify this relationship between CPP and ICP, known as the pressure reactivity index (PRx).^2,3 If a rise in ABP (and hence CPP) leads to a parallel increase in ICP, a good correlation exists, and the PRx is positive. However, in the face of intact cerebral autoregulatory capacity, vasoconstriction in the face of rising CPP leads to a drop in ICP, and hence PRx approaches zero or takes a negative value. Measurement of PRx could thus form the basis for target‐driven management, as ABP can be manipulated.Clinical studies on patients with head injury have shown the feasibility of continuous monitoring of local brain tissue oxygenation (PtiO₂) as a variable for cerebral oxygenation.^4,5,6 Despite the limitations of such a local method of measurement, PtiO₂ indicates global cerebral oxygenation when the monitoring is carried out in a relatively uninjured part of the brain.⁶ The presence of autoregulation disturbance could conceivably lead to disturbance in oxygen tension in the tissue of interest by virtue of blood flow metabolism uncoupling as PtiO₂ reflects the net balance between oxygen supply and demand at the tissue level.⁷We hypothesised that a worsening PRx indicative of increasing dysautoregulation during the temporal course of monitoring is related to mortality, and this may arise from specific patterns of change in various physiological variables including PtiO₂.     

外伤后急性半球脑肿胀的手术治疗

目的 探讨外伤后急性大脑半球肿胀（ACHS）的治疗效果以及影响疗效的主要因素.方法 对38例外伤后急性半球脑肿胀病人的资料进行回顾性分析.所有患者均接受了去骨瓣减压手术.结果 大骨瓣减压术后,CT影像显示脑中线结构无明显移位、环池结构清晰.术后6个月按GOS评分标准评估：良好14例（占36.8%）、中残9例（占23.7%）、重残5例（占13.2%）、植物生存4例（占10.5%）、死亡6例（占15.8%）.结论 早期去骨瓣减压手术可改善患者预后,而脑肿胀合并急性硬膜下血肿、手术后出血性脑挫伤处血肿量明显增加以及出现创伤后大面积脑梗死的患者预后较差.     

Improvement in cerebral metabolism in chronic brain injury after hyperbaric oxygen therapy

While no research study has yet demonstrated convincing evidence for the efficacy of Hyperbaric Oxygen Therapy (HBOT) in patients with chronic neurological disorders (CND), anecdotal studies have been supportive of its use in improving healing of the damaged brain. The current study hypothesized that (1) individuals with CND show increases in cerebral blood flow and metabolism as measured by Single Positron Emission Computed Tomography (SPECT) in the cerebral hemispheres, but not on measures of cerebellar and pons blood flow; and (2) younger patients show more improvement than older patients. The study used archival data to compare 25 older and 25 younger subjects who were given SPECT scans pretherapy, midtherapy, and posttherapy. ANOVAs using the SPECT scans as a within subjects variable and age as a between subjects variable confirmed the hypothesis that the cerebral measures all changed but that the cerebellar and pons measures did not. Post-hoc t-tests confirmed that there was improvement in blood flow from the beginning to the end of the study. An age effect was found on only two of the five measures; however, there were no interactions. Analysis by post-hoc t-tests showed that the younger group had higher blood flows, but not more improvement than the older group. The results provided the first statistical research data to show the effectiveness of HBOT in improving blood flow in CND. These results indicate that HBOT can be an effective part of the treatment for such clients. The implications of these findings and future research directions were discussed.     

Fluorometric assay of nitrite and nitrate in brain tissue after traumatic brain injury and cerebral ischemia

Nitric oxide synthase (NOS) is distributed within the brain, and nitric oxide (NO) is felt to be involved in the pathophysiology of deterioration after head injury and cerebral ischemia. This study determined the levels of the stable end products of NOS (NO_x=nitrite+nitrate) after traumatic brain injury (TBI) and transient cerebral ischemia. A fluorometric assay using nitrate reductase and the NADPH regenerating system was used to quantitate NO_x in ultrafiltered (10-kDa cutoff) cortical and hippocampal extracts after reduction of nitrate. In TBI rats, both the plasma and tissue showed a sharp increase in NO_x levels 5 min after injury. Plasma NO_x returned to control levels by 2 h after injury. Ipsilateral-cortex NO_x levels returned to control levels 6 h after injury and remained constant from 6–24 h. Contralateral-cortex returned near to control levels after 1 h. Hippocampus also followed a similar trend. In gerbils, there was a significant elevation in tissue NO_x levels immediately after 10 min transient cerebral ischemia, which gradually returned to control levels over 24 h reperfusion. This striking burst of NO synthesis immediately after injury is clearly evident whether the injury is head trauma or ischemia, or whether the measurements were performed on tissue or plasma. It is unknown whether endothelial NOS, neuronal NOS, or both caused the elevation of the NO end products seen after the CNS insults.     

Cerebral metabolic adaptation and ketone metabolism after brain injury.

The developing central nervous system has the capacity to metabolize ketone bodies. It was once accepted that on weaning, the 'post-weaned/adult' brain was limited solely to glucose metabolism. However, increasing evidence from conditions of inadequate glucose availability or increased energy demands has shown that the adult brain is not static in its fuel options. The objective of this review is to summarize the body of literature specifically regarding cerebral ketone metabolism at different ages, under conditions of starvation and after various pathologic conditions. The evidence presented supports the following findings: (1) there is an inverse relationship between age and the brain's capacity for ketone metabolism that continues well after weaning; (2) neuroprotective potentials of ketone administration have been shown for neurodegenerative conditions, epilepsy, hypoxia/ischemia, and traumatic brain injury; and (3) there is an age-related therapeutic potential for ketone as an alternative substrate. The concept of cerebral metabolic adaptation under various physiologic and pathologic conditions is not new, but it has taken the contribution of numerous studies over many years to break the previously accepted dogma of cerebral metabolism. Our emerging understanding of cerebral metabolism is far more complex than could have been imagined. It is clear that in addition to glucose, other substrates must be considered along with fuel interactions, metabolic challenges, and cerebral maturation.     

Simultaneous assessment of brain tissue oxygenation and cerebral perfusion during orthostatic stress

Simultaneous registration of cerebral tissue oxygenation parameters obtained by near infrared spectroscopy (NIRS), intracranial blood flow velocity (CBFV) measured by transcranial Doppler sonography (TCD) and basic cardiovascular parameters was carried out during a passive 80 degrees head-up tilt table test in 15 patients with a history of orthostatic syncope and 20 control subjects. In normals, the cardiovascular parameters showed a specific course after changing to a vertical position: the heart rate increased, the mean arterial blood pressure remained unchanged, and the CBFV decreased. The NIRS measurements showed an increase in deoxyhemoglobin (HHb) and a decline in oxyhemoglobin (O(2)Hb) and the regional oxygen saturation (RSAT). Patients had a significantly more prominent decline in arterial blood pressure (p < 0.001), CBFV (p < 0.001) and RSAT (p = 0.04). Five patients experienced symptoms of (pre)syncope during the experiment, which were associated with a further sudden and marked (>10%) drop of O(2)Hb. The results indicate that the combination of TCD and NIRS increases the understanding of hemodynamic and metabolic changes during orthostatic stress, which may lead to individually suited therapeutic procedures.     

大鼠急性颅脑损伤后早期脑微血管改变的形态学研究

报道大鼠实验性脑损伤后早期，１０分钟至２４小时，大脑皮层微血管减少，并有“微无血管区”，微血管内可见微血栓形成，血脑屏障通透性增加，出现脑水肿，提示微循环障碍缺血是产生外伤性脑水肿的重要病因因素，救治重型颅脑损伤要重视防治脑微循环障碍，纠正脑缺氧。     

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 oxygenation and systemic trauma related factors determining neurological outcome after brain injury.

We examined the relationship between clinical and radiological findings, cerebral oxygenation patterns during intensive care management, presence of systemic trauma related injuries and severity of illness in 50 patients (age: 32.3 +/- 12 years, GCS: 8 +/- 4) who were rescued from the accident scene within a 30 min period after trauma. Presence of systemic injuries was quantified using the Injury Severity Score (ISS) and severity of illness was scored using the Acute Physiology and Chronic Health Evaluation (APACHE II). Cerebral oxygenation parameters included continuous monitoring of jugular bulb oxygen saturation (SjvO(2)) for 12 840 h, and 2323 periodical blood sampling for measurement of arteriovenous differences in oxygen content (AVDO(2)), arteriovenous difference of lactate (AVDL) and lactate oxygen index (LOI). Fifteen patients (30%) presented with anisocoria or non-reacting pupils. Diffuse lesions on computed tomography (CT) were found in 34% of the patients and in 66% a mass lesion was removed. The mean ISS was 28 +/- 15.3 and 34 patients (68%) had an APACHE II score between 20 and 29 (mean 24 +/- 15). No statistically significant association between age (P = 0.45), gender (P = 0.83), initial Glasgow Coma Score (GCS) (P = 0.43), episodes of cerebral perfusion pressure (CPP) < 70 mm Hg (P = 0.8), ISS (P = 0.28), pupillary abnormalities (P = 0.57), initial CT findings (P = 0.74), APACHE II scores (P = 0. 36) and outcome could be demonstrated. The number of SjvO(2)desaturations (< 60%) was the only statistically significant factor associated with outcome (P = 0.05). The percentage of patients with poor neurological outcomes (GOS 1-3) was 38% in patients with no or one desaturation episode, and 57.6% in those with multiple desaturations. In conclusion, in patients who are resuscitated early and quickly transferred to the hospital, the number of SjvO(2)desaturations during intensive care management might be associated with outcome more strongly than other clinical and radiological features.     

Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study.

Brain trauma is accompanied by regional alterations of brain metabolism, reduction in metabolic rates and possible energy crisis. We hypothesize that microdialysis markers of energy crisis are present during the critical period of intensive care despite the absence of brain ischemia. In all, 19 brain injury patients (mean GCS 6) underwent combined positron emission tomography (PET) for metabolism of glucose (CMRglu) and oxygen (CMRO(2)) and cerebral microdialysis (MD) at a mean time of 36 h after injury. Microdialysis values were compared with the regional mean PET values adjacent to the probe. Longitudinal MD data revealed a 25% incidence rate of metabolic crisis (elevated lactate/pyruvate ratio (LPR) > 40) but only a 2.4% incidence rate of ischemia. Positron emission tomography imaging revealed a 1% incidence of ischemia across all voxels as measured by oxygen extraction fraction (OEF) and cerebral venous oxygen content (CvO(2)). In the region of the MD probe, PET imaging revealed ischemia in a single patient despite increased LPR in other patients. Lactate/pyruvate ratio correlated negatively with CMRO(2) (P < 0.001), but not with OEF or CvO(2). Traumatic brain injury leads to a state of persistent metabolic crisis as reflected by abnormal cerebral microdialysis LPR that is not related to ischemia.     

大鼠急性脑损伤后脑局部代谢磁共振波谱分析

目的：本实验研究鼠急性颅脑损伤局部脑组织代谢的情况，以找出颅脑损伤与恢复过程中局部脑组织各种代谢成分变化的规律。方法：采用自由落体致鼠脑损伤模型，伤后３０分钟、３、２４、１６８小时取材，用核磁共振波谱法分析颅脑损伤局部脑组织代谢的变化。各组间采用ｔ检验。结果：颅脑损伤后伤区脑组织乳酸含量于伤后３小时已显著增高（Ｐ＜０．０１），伤后２４小时仍然明显高于正常。胆碱于伤后３小时已有明显升高，２４小时达高峰（Ｐ＜０．０１）。Ｎ－乙酰门冬氨酸含量自伤后３小时明显降低，伤后２４～１６８小时仍然显著低于正常（Ｐ＜０．０１）。谷氨酸自伤后３０分钟开始明显降低，３小时降到最低水平（Ｐ＜０．０１）。结论：实验表明颅脑损伤后３小时伤区脑组织已显著呈缺血性改变，伤后２４小时达高峰。     

Alternative brain organization after prenatal cerebral injury: convergent fMRI and cognitive data.

The current study presents both longitudinal behavioral data and functional activation data documenting the effects of early focal brain injury on the development of spatial analytic processing in two children, one with prenatal left hemisphere (LH) injury and one with right hemisphere (RH) injury. A substantial body of evidence has shown that adults and children with early, lateralized brain injury show evidence of spatial analytic deficits. LH injury compromises the ability to encode the parts of a spatial pattern, while RH injury impairs pattern integration. The two children described in this report show patterns of deficit consistent with the site of their injury. In the current study, their longitudinal behavioral data spanning the age range from preschool to adolescence are presented in conjunction with data from a functional magnetic resonance imaging (fMRI) study of spatial processing. The activation results provide evidence that alternative profiles of neural organization can arise following early focal brain injury, and document where in the brain spatial functions are carried out when regions that normally mediate them are damaged. In addition, the coupling of the activation with the behavioral data allows us to go beyond the simple mapping of functional sites, to ask questions about how those sites may have come to mediate the spatial functions.