Hypoperfusion in the acute phase of subarachnoid hemorrhage.

PURPOSE: Acute disruption of cerebral perfusion and metabolism is a well-established hallmark of the immediate phase after subarachnoid hemorrhage (SAH). It is thought to contribute significantly to acute brain injury, but despite its prognostic importance, the exact mechanism and time course is largely unknown and remains to be characterized. METHODS: We investigated changes in cerebral perfusion after SAH in both an experimental and clinical setting. Using an animal model of massive, experimental SAH (n=91), we employed Laser-Doppler flowmetry (LDF), parenchymal microdialysis (MD; n=61), Diffusion-weighted imaging (DWI) and MR spectroscopy (MRS; n=30) to characterize the first hours after SAH in greater detail. The effect of prophylactic treatment with hypothermia (HT; 32°C) and an endothelin-A (ET-A) receptor antagonist (Clazosentan) was also studied. In a group of patients presenting with acute SAH (n=17) we were able to determine cerebral blood flow (CBF) via Xenon-enhanced computed tomography (XeCT) within 12 h after the ictus. RESULTS: The acute phase after SAH is characterized both experimentally and clinically by profound and prolonged hypoperfusion independent from current intracranial pressure (ICP), indicating acute vasospasm. Experimentally, when treated with hypothermia or a ET-A receptor antagonist prophylactically, acute hypoperfusion improved rapidly. DWI showed a generalized, significant decline of the apparent diffusion coefficient (ADC) after SAH, indicating cytotoxic edema which was not present under hypothermia. SAH causes a highly significant reduction in glucose, as well as accumulation of lactate, glutmate and aspartate (MD and MRS). HT significantly ameliorated these metabolic disturbances. CONCLUSION: Acute vasospasm, cytotoxic edema and a general metabolic stress response occur immediately after experimental SAH. Prophylactic treatment with hypothermia or ET-A antagonists can correct these disturbances in the experimental setting. Clinically, prolonged and ICP-independent hypoperfusion was also confirmed. As the initial phase is of particular importance regarding the neurological outcome and is amenable to beneficial intervention, the acute stage after SAH demands further investigation and warrants the exploration of measures to improve the immediate management of SAH patients.

Changes in cortical and subcortical energy metabolism after repetitive and single controlled cortical impact injury in the mouse.

In the present investigation we examined regional ATP, glucose, and lactate content in the cortical and subcortical region, in a mouse model of controlled cortcal impact (CCI) injury. In serial tissue sections, bioluminescence imaging of ATP, glucose, and lactate was performed 1 h after a single CCI injury or sham surgery and 15 min, 1, 24, and 48 h after the induction of a second CCI injury 24 h later or sham surgery. Bioluminescence images were analyzed by computer-assisted densitometry at the lesion site, at the contralateral site, and in a subcortical region. After repetitive CCI injury, the cortical ATP content decreased bilaterally at 15 min and 1 h, and reached a significant minimum at 24 h, as compared with sham. At 48 h the ATP content bilaterally reached base level again. No significant changes in ATP were found in the subcortical region. After repetitive CCI injury, the lactate content increased bilaterally, reached a significant level at 15 min at the trauma site, and bilaterally reached a significant maximum at 1 h. Thereafter, lactate content decreased below base level without reaching significance and reached baseline again at 48 h. In the ipsilateral subcortical region, lactate content increased transiently above the baseline at 1 h and decreased to a significant minimum at 24 and 48 h. No significant changes were found in the contralateral subcortical area. No significant differences between glucose content in sham animals and the cortical and subcortical area could be measured over time; the subcortical glucose content was bilaterally lower than cortical content at all time points and reached a significant minimum bilaterally at 48 h after repetitive CCI injury compared with cortical glucose content. Single CCI injury did not affect ATP, glucose, and lactate contents at any time point. Repetitive CCI injury caused a more severe depression in cerebral metabolism at early time points after trauma compared with a single CCI injury and indicates that lactate might be an early indicator of post-traumatic metabolic disruption.

Regional energy metabolism following short-term neural stem cell transplantation into the injured spinal cord.

Stem cells have been shown to partly restore central nervous system (CNS) function after transplantation into the injured CNS. However, little is known about their influence on acute energy metabolism after spinal cord injury. The present study was designed to analyze regional changes in energy metabolites. Young adult mice were subjected to laminectomy with subsequent hemisection at the L2/3 vertebral level. Immediately thereafter a stable clone of murine neural stem cells (NSCs) was injected into the lesion site. After 4 and 24 h, spinal cords were removed and ATP, glucose, and lactate were analyzed by a bioluminescence approach in serial sections and compared to a laminectomized (intact control), hemisected-only or hemisected vehicle-injected control group. At both time points, ATP content of the hemisected group in the tissue segments adjacent to the lesion was increased when compared to the laminectomized control. At the lesion site ATP content decreased significantly at 24 h in the cell-transplanted group when compared to the laminectomized control group. Glucose content decreased at the lesion site and in segments adjacent to the lesion at both time points and in all experimental groups when compared to the laminectomized control group. Lactate content decreased significantly at 4 h in the caudal segments of the vehicle-injected group and in both adjacent segments of the transplanted group when compared to the laminectomized control. At the lesion site, lactate content decreased significantly at 4 and 24 h in the cell-transplanted group, when compared to the laminectomized control. The area of ATP decline at the lesion site 24 h postinjury was significantly lower in the vehicle control group as compared to the hemisected or transplanted group. The decrease in glucose combined with an increase in ATP in the lesion-adjacent segments may indicate that the tissue responds with an increased use of glucose to support itself with sufficient ATP. The significant decrease in glucose, lactate, and ATP in the cell-transplanted group at 24 h may indicate a high metabolic need of the stem cells. The lower area of ATP decline 24 h after vehicle administration suggests that the vehicle solution washes out toxic mediators, thus ameliorating hemisection-dependent secondary tissue damage.

Stress-resistant neural stem cells positively influence regional energy metabolism after spinal cord injury in mice.

The importance of stem cells to ameliorate the devastating consequences of traumatic injuries in the adult mammalian central nervous system calls for improvements in the capacity of these cells to cope, in particular, with the host response to the injury. We have previously shown, however, that in the acutely traumatized spinal cord local energy metabolism led to decreased ATP levels after neural stem cell (NSC) transplantation. As this might counteract NSC-mediated regenerative processes, we investigated if NSC selected for increased oxidative stress resistance are better suited to preserve local energy content. For this purpose, we exposed wild-type (WT) NSC to hydrogen peroxide prior to transplantation. We demonstrate here that transplantation of WT-NSC into a complete spinal cord compression injury model even lowers the ATP content beyond the level detected in spinal cord injury-control animals. Compared to WT-NSC, stress-resistant (SR) NSC did not lead to a further decrease in ATP content. These differences between WT- and SR-NSC were observed 4 h after the lesion with subsequent transplantation. At 24 h after lesioning, these differences were no more as obvious. Thus, in contrast to native NSC, transplantation of NSC selected for oxidative stress resistance can positively influence local energy metabolism in the first hours after spinal cord compression. The functional relevance of this observation has to be tested in further experiments.

Delayed cerebral ischemia and spreading depolarization in absence of angiographic vasospasm after subarachnoid hemorrhage.

It has been hypothesized that vasospasm is the prime mechanism of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Recently, it was found that clusters of spreading depolarizations (SDs) are associated with DCI. Surgical placement of nicardipine prolonged-release implants (NPRIs) was shown to strongly attenuate vasospasm. In the present study, we tested whether SDs and DCI are abolished when vasospasm is reduced or abolished by NPRIs. After aneurysm clipping, 10 NPRIs were placed next to the proximal intracranial vessels. The SDs were recorded using a subdural electrode strip. Proximal vasospasm was assessed by digital subtraction angiography (DSA). 534 SDs were recorded in 10 of 13 patients (77%). Digital subtraction angiography revealed no vasospasm in 8 of 13 patients (62%) and only mild or moderate vasospasm in the remaining. Five patients developed DCI associated with clusters of SD despite the absence of angiographic vasospasm in three of those patients. The number of SDs correlated significantly with the development of DCI. This may explain why reduction of angiographic vasospasm alone has not been sufficient to improve outcome in some clinical studies.

Acute hypoperfusion immediately after subarachnoid hemorrhage: a xenon contrast-enhanced CT study.

The acute neurological deficit present immediately after subarachnoid hemorrhage (SAH) correlates with overall outcome. Only limited data are available to quantify changes in cerebral perfusion in this acute phase, and this study sought to characterize those changes within the first 12 h post-SAH. Xenon contrast-enhanced CT scanning was performed in 17 patients (Hunt and Hess grade [HH] 1-3, n = 9; HH 4-5, n = 8) within 12 h after SAH. Cerebral blood flow (CBF) was analyzed in all cortical and central vascular regions of interest (ROI), as well as infratentorial ROI. Hemodynamic stress distribution (central/cortical ROI) was also calculated. Asymptomatic patients without perfusion deficits served as controls (n = 5), and Glasgow Outcome Scale score (GOS) was determined 3 months after the event. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were within normal limits in all patients. CBF was significantly reduced in all patients with SAH (34 mL/100 g x min) compared to controls (67 mL/100 g x min; p < 0.001). Patients in better clinical condition (HH 1-3) presented with significantly less reduction of CBF (41 mL/100 g x min) compared to patients with more severe hemorrhage (HH 4-5: 24 mL/100 g x min; p < 0.001), and had better outcomes. Changes in perfusion were more pronounced in supratentorial than in infratentorial ROI. Hemodynamic stress distribution was most pronounced in patients with higher HH grade (p < 0.05). The first 12 h after SAH are characterized by persistent, severe reduction of CBF, which in turn correlates with HH grade, but is independent of ICP or CPP. Acute peripheral vasospasm of the microvasculature, not detectable by conventional angiography, may account for this early phase of prolonged hypoperfusion.