Tadayoshi Nakagomi

Blood Pressure Management in Acute Intracerebral Hemorrhage Relationship Between Elevated Blood Pressure and Hematoma Enlargement

Background and Purpose— The association between elevated blood pressure (BP) and hematoma enlargement in acute intracerebral hemorrhage (ICH) has not been clarified. We investigated the association between maximum systolic BP (SBP) and hematoma enlargement, measuring SBP between a baseline and a second CT scan in patients with hypertensive ICH. Methods— We assessed 76 consecutive patients with hypertensive ICH retrospectively. We usually attempted to lower SBP below targets of 140, 150, or 160 mm Hg. Recordings of serial BP from admission until the second CT scan were assessed. A neuroradiologist, who was not informed of the aim of this study, reviewed CT films. Hematoma enlargement was defined as an increase in volume of ≥140% or 12.5 cm3. Results— Hematoma enlargement occurred in 16 patients. Maximum SBP was significantly associated with hematoma enlargement (P = 0.0074). A logistic regression model for predicting hematoma enlargement was constructed with the use of maximum SBP, hematoma volume, and Glasgow Coma Scale score at admission. After adjustment for these factors, maximum SBP was independently associated with hematoma enlargement (odds ratio per mm Hg, 1.04; 95% CI, 1.01 to 1.07). Target SBPs of ≥160 mm Hg were significantly associated with hematoma enlargement compared with those of ≤150 mm Hg (P = 0.025). Conclusions— Our findings suggest that elevated BP increases the risk of hematoma enlargement. Efforts to lower SBP below 150 mm Hg may prevent this risk.

Early recovery of protein synthesis following ischemia in hippocampal neurons with induced tolerance in the gerbil.

SummaryFollowing brief cerebral ischemia, tolerance to subsequent ischemia is induced in the hippocampal neurons. In this experiment, recovery of protein synthesis was investigated autoradiographically in gerbils with induced tolerance. The animals were subjected to single forebrain ischemia for 5 min (5-min ischemia group) or 2 min (2-min ischemia group). To observe the effect of tolerance acquisition, double forebrain ischemia (double ischemia group), 2-min ischemia followed by 5-min ischema was induced 2 days later. At various recircultion periods (90 min, 6 h, 1 day, and 4 days following ischemia), animals received a single dose of Lxxx-[2,3-3H]valine. In the 5-min ischemia group, protein synthesis in the CA1 sector was severely suppressed during the period from 90 min to 1 day of recirculation and never returned to the normal level even at 4 day of recirculation. In the 2-min ischemia group, protein synthesis recovered gradually and returned to near normal at 4 days of recirculation. On the other hand, in the double ischemia group, recovery of protein synthesis in the CA1 sector was rapid. At 1 day of recirculation, protein synthesis returned to near normal. Protein synthesis in the CA2 sector was inhibited during the 4 days of recirculation in this group. The present study revealed an early recovery of protein synthesis in the hippocampal CA1 neurons in the gerbil with induced tolerance. We suggest that recovery of protein synthesis is essential for the survival of neurons exposed to transient ischemia.

Long-term spatial cognitive impairment following middle cerebral artery occlusion in rats. A behavioral study.

Behavioral changes in the chronic phase of permanent occlusion of the right middle cerebral artery (MCA) in rats were investigated. One month after MCA occlusion, 23 rats were unable and 7 rats were able to solve a radial 8-arm maze task during a 1-month period. Three months after occlusion, 19 MCA-occluded rats failed to solve the task successfully again during at least a 1-month period (the cognitively impaired rats), and 11 MCA-occluded rats were able to solve it (the cognitively unimpaired rats). When a delay of 60 min was imposed for this task, five cognitively unimpaired rats failed to solve it. The locomotor activity of the cognitively impaired rats increased significantly 2 months after occlusion, and this increase showed good correlation with spatial cognitive deficit. However, the mean time a rat spent at each arm remained unchanged among the cognitively impaired, unimpaired, and sham-operated rats. There was no significant difference in the ratio between the cognitively impaired and unimpaired rats for disturbed motor coordination. These results suggest that MCA occlusion is capable of producing long-term spatial cognitive disturbance in rats. In addition, this spatial cognitive deficit does not seem to be primarily due to hypermotility or a disturbance in motor coordination.

Lethal forebrain ischemia stimulates sphingomyelin hydrolysis and ceramide generation in the gerbil hippocampus.

Ceramide, a hydrolyzed product of sphingomyelin, is reported to play an important role in apoptosis. In this study, we measured the sphingomyelin and ceramide levels in the hippocampus of the gerbil after transient forebrain ischemia for 5 min (lethal) or 2 min (sublethal). The aim was to examine alterations in the sphingomyelin cycle during delayed neuronal death, which we considered could be due to apoptosis. Sphingolipids were separated on high-performance thin-layer chromatography plates and analyzed by gas-liquid chromatography. At 30 min and 24 h after lethal ischemia, sphingomyelin levels were decreased and ceramide levels were increased compared with control levels. No significant changes were observed after sublethal ischemia. These results suggest that the sphingomyelin cycle may have a role in neuronal death.

Fatty acid composition of the chronic subdural hematoma: with reference to its recurrence

The fatty acid composition of aspirated chronic subdural hematoma (CSDH) was measured by gas liquid chromatography and the relationship between fatty acid and recurrence of the hematoma was assessed. Thirty patients with CSDH were operated on through a single burr-hole; 4 patients developed recurrent hematoma (13%). The lipid composition of CSDH was mainly phosphatidylcholine, sphingomyelin, cholesterol, free fatty acid, triacylglycerol and cholesterol ester. The fatty acid constituents were palmitic, stearic, oleic, linoleic, arachidonic and docosahexanoeic acids. Analysis of the polyunsaturated fatty acids demonstrated that hematoma taken from patients with recurrent CSDH contained more linoleic acid (n-6) than those with non-recurrent CSDH. Linoleic and arachidonic acids are known to induce angiogenesis in cultured aortic endothelial cells. Change in fatty acid composition of recurrent hematoma might be associated with rebleeding from the hematoma capsule.

Differences in the Extent of Primary Ischemic Damage Between Middle Cerebral Artery Coagulation and Intraluminal Occlusion Models

The authors studied the differences between heat-shock/stress protein 70 (hsp70) gene expression and protein synthesis in the unilateral middle cerebral artery (MCA) microsurgical direct occlusion (Tamuras) model and the unilateral intraluminal occlusion model. In Tamuras model, expression of hsp70 mRNA and HSP70 protein and decreased protein synthesis were detected in the ischemic areas, including the ipsilateral cortex and caudate. These phenomena, however, were not observed in the areas outside the MCA territory, including the ipsilateral thalamus, hippocampus, and substantia nigra. These results were consistent among the experimental rats. In the intraluminal occlusion model, however, induction of both hsp70 mRNA and HSP70 protein and impairment of protein synthesis were noted in the areas outside the MCA territory, including the ipsilateral thalamus, hypothalamus, hippocampus, and substantia nigra, as well as in the MCA territory, including the ipsilateral cortex and caudate. These results were not consistent among the experimental rats. These different results might be due to widespread damage resulting from internal carotid artery (ICA) occlusion in the intraluminal occlusion model. Accordingly, the authors suggest that this model be called an ICA occlusion model, rather than a pure MCA occlusion model.

Barrier disruption in the major cerebral arteries during the acute stage after experimental subarachnoid hemorrhage.

The effects of experimental subarachnoid hemorrhage (SAH) on the blood-arterial wall barrier in the basilar arteries were studied during the acute stage after SAH. SAH was induced in rats by injecting fresh autologous blood into the cisterna magna. Horseradish peroxidase (HRP) was given intravenously before killing the animals to assess the integrity of the barrier. In the basilar arteries taken from the animals that were killed 30 minutes after the cisternal injection of either mock cerebrospinal fluid or arterial blood, HRP reaction products were diffusely observed in the subendothelial spaces and smooth muscle layers. At 5 hours after the blood injection, no permeation of HRP into the subendothelial space was observed. Endothelial cell transcytosis seemed to be the important mechanism for HRP permeation into the subendothelial space rather than the opening of interendothelial junctions. The disruption of the blood-arterial wall barrier in the major cerebral arteries after SAH may be involved in the pathogenesis of vasospasm.

Up-regulation of c-myc gene expression following focal ischemia in the rat brain

Changes in gene expression including that of c-fos occur following cerebral ischemia. Proto-oncogenes c-myc and s-myc and oncosuppressor gene p53 are known to induce apoptosis in some types of cells, whereas proto-oncogene bcl-2 inhibits apoptosis. Possible induction of mRNAs for c-myc, N-myc, s-myc, c-fos, p53 and bcl-2 was examined following focal ischemia in the rat anterior cortex, hippocampus, thalamus and cerebellum by Northern blot analysis. Animals were decapitated 1, 2, 6, 12, and 24 hours following the left middle cerebral artery (MCA) occlusion. In sham-operated control rats, the mRNAs for c-myc, N-myc, c-fos and p53 were present in the anterior cortex, hippocampus, thalamus on both sides, and in the cerebellum, whereas those for s-myc and bcl-2 were not. The c-myc gene expression was rapidly and markedly induced by the MCA occlusion in the ipsilateral anterior cortex, hippocampus and thalamus in a time-dependent manner. In these regions, the c-fos gene expression was also induced as early as 1 hour after the MCA occlusion. The p-53 mRNA was induced in the ipsilateral hippocampus at 24 hours after MCA occlusion. In contrast, mRNAs for N-myc, s-myc and bcl-2 were not induced following MCA occlusion. These results indicate a possibility that high-level expression of the c-myc gene may be involved in the ischemic cellular events including apoptosis.

Relationship between shunt-dependent hydrocephalus after subarachnoid haemorrhage and duration of cerebrospinal fluid drainage

Subarachnoid haemorrhage (SAH) patients in Fisher group 3 have a high risk of vasospasm and chronic hydrocephalus. We have provided cisternal irrigation combined with a head-shaking method for preventing vasospasm in SAH patients. We investigated 76 SAH patients in Fisher group 3 who received cisternal irrigation with head-shaking to evaluate the relationship between the occurrence of hydrocephalus and various clinical factors, including duration of cerebrospinal fluid (CSF) drainage. Chronic hydrocephalus occurred in 25 patients (33%). The occurrence of hydrocephalus was associated with longer duration of CSF drainage (median, 13 days versus 9 days). By logistic regression analysis using significant factors, including age, preoperative neurological grade and Glasgow Outcome Scale, only the duration of drainage was independently associated with the occurrence of hydrocephalus (Odds ratio = 1.18 per day; 95% confidence interval, 1.02 – 1.36). These results indicate that long duration of CSF drainage for preventing vasospasm may increase the occurrence of hydrocephalus.

Preconditioning In Vivo Ischemia Inhibits Anoxic Long-Term Potentiation and Functionally Protects CA1 Neurons in the Gerbil

Preconditioning with sublethal ischemia induces tolerance to subsequent lethal ischemia in neurons. We investigated electrophysiologic aspects of the ischemic tolerance phenomenon in the gerbil hippocampus. Gerbils were subjected to 2 minutes of forebrain ischemia (preconditioning ischemia). Some of them were subjected to a subsequent 5 minutes of forebrain ischemia 2 to 3 days after the preconditioning ischemia (double ischemia). Hippocampal slices were prepared from these gerbils subjected to the preconditioning or double ischemia, and field excitatory postsynaptic potentials were recorded from CA1 pyramidal neurons. Capacity for long-term potentiation triggered by tetanic stimulation (tetanic LTP) was transiently inhibited 1 to 2 days after the double ischemia but then recovered. Latency of anoxic depolarization was not significantly different between slices from preconditioned gerbils and those from sham-operated gerbils when these slices were subjected to in vitro anoxia. Postanoxic potentiation of N-methyl-D-aspartate (NMDA) receptor-mediated transmission (anoxic LTP) was inhibited in slices from gerbils 2 to 3 days after the preconditioning ischemia, whereas it was observed in slices from sham-operated gerbils and gerbils 9 days after the preconditioning ischemia. These results suggest that protection by induced tolerance is (1) not only morphologic but also functional, and (2) expressed in inhibiting postischemic overactivation of NMDA receptor-mediated synaptic responses.