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The Noninvasive ICP (Intracranial Pressure) Monitoring System NIP-200/210 has been used in several hospitals with more than 2000 patients since March 2002. It is based on the N2 wave response to flash visual evoked potentials (FVEP). According to our data, the mean latency period for the FVEP-induced N2 wave in healthy controls was 126.61 ± 14.64 ms, in which that of females was shorter than that of males (123.95 ± 10.345 ms vs. 130.75 ± 14.632 ms; <0.05). There was no significant difference between the left or right side response (126.71 ± 14.91 ms vs. 124.468 ± 15.043 ms, >0.05). No significant difference in latency was found across age groups in our patient pool. In general, the N2 wave was stable and easily identified in most of the patients or healthy controls. When the data obtained with the NIP-200/210 Noninvasive ICP Monitoring System was compared with that from invasive techniques, the results were quite consistent (correlation index 0.651–0.97, standard error 8–15%). From our clinical trial results, we conclude that the latency periods for the FVEP-induced N2 wave reflected ICP values. However this technique is not suitable in patients with bifrontal hematoma, retinal concussion, or contusion of the optical nerve, because an FVEP value cannot be measured accurately in these cases. In our clinical trials, we used the FVEP technique to determine the effectiveness of mannitol in decreasing the ICP. The data revealed that ICP values decreased significantly within 20 minutes after a mannitol injection, and reached a minimum level at 40 minutes. For a single bolus of mannitol, the duration of the ICP decrease ranged from 30–210 minutes. Elevated ICP is one of the most important clinical issues in neurosurgery and neurology. The present noninvasive technique is safe and easy to perform, with a minimal risk of complications.

A new absolute ICP (aICP) measurement method was designed which does not need calibration. In this study we compared a new method with invasive aICP method in ICU on the patients with closed severe traumatic brain injury.

A new method is based on two-depth TCD technique for aICP and external absolute pressure aPe comparison using the eye artery (EA) as natural “balance”. The intracranial segment of EA is compressed by aICP and the extracranial segment is compressed by aPe applied to the tissues surrounding the eye. The blood flow parameters in both EA segments are approximately the same when aPe=aICP. Two-depth TCD device is used as an indicator of balance aPe=aICP when the pulsatility index of blood flow velocity waveform in intracranial and extracranial segments are the same.

Fifty seven simultaneous invasive and non-invasive aICP measurements were performed in aICP range from 3.0 to 37.0 mmHg. Bland Altman plot of the differences between simultaneous invasive and non-invasive aICP measurements shows the negligible mean difference (mean=0.94 mmHg) with a standard deviation of 6.18 mmHg.

This validation study shows that it is possible to measure aICP non-invasively without calibration of the system with 95% confidence interval of 12 mmHg.

Ultrasonic “time-of-flight” monitor (Vittamed) was used for continuous monitoring of intracranial blood volume (IBV) pulse, respiratory, slow waves and cerebrovascular autoregulation (CA). The objectives are to compare of invasively and non-invasively monitored slow intracranial waves and CA of ICU patients and to evaluate the phase shift between ABP and IBV respiratory waves as a possible estimator of CA.

CA monitoring has been performed in 13 patients with severe TBI (age mean/range 30.5/(18–64)). Data were collected from 87 one-hour sessions of simultaneous invasive and non-invasive wave monitoring and from 53 one-hour sessions of invasive and non-invasive CA monitoring.

High correlation (R>0.9) has been obtained between invasively and non-invasively recorded intracranial slow waves. Bland Altman difference between invasively and non-invasively recorded intracranial slow waves is clinically not significant (mean=−0.07, SD=0.089, α=0.05). Agreement has been confirmed between invasive and non-invasive CA monitoring data in a wide range of R = [−0.85; +0.96].

Hypothesis of the coincidence of invasive and non-invasive CA assessment is accepted (p<0.05).

Phase shift monitoring of permanent respiratory ABP waves and IBV waves permit continuous non-invasive CA estimation without unnatural physical or pharmacological stimulations of CA system.

There is a bi-directional communication between the immune and central nervous system. In this context, it is known that patients with traumatic brain injury suffered from systemic immunodepression and an increased risk to develop infectious complications. We investigated the role of an increased intracranial pressure (ICP) and sympathetic activation on systemic immune changes. A sustained increase in ICP was achieved by inflation of a subdural balloon. At different time points, plasma levels of the anti-inflammatory cytokine, interleukin (IL)-10, were measured. Furthermore, the effect of a sympathetic blockade by co-administration of the β-adreoreceptor antagonist, propranolol, was evaluated. Finally, we examined the impact of epinephrine infusion on blood IL-10 levels. We showed that an increase in ICP with activation of the sympathetic nervous system was able to induce systemic release of IL-10. This effect was blocked by administration of the β-adreoreceptor antagonist. Furthermore, epinephrine infusion directly induced systemic release of IL-10. Our data suggested that sympathetic activation with release of epinephrine may induce systemic immunodepression with risk of infectious complications in brain-injured patients.

Hyponatremia is a common complication in patients with aneurismal subarachnoid hemorrhage (SAH). Such patient demonstrates excessive natriuresis and an increased risk of symptomatic cerebral vasospasm. However, the precise mechanisms underlying SAH induced hyponatremia remain unclear. In the present study, in order to establish an experimental model of hyponatremia following SAH, we induced SAH in rats, and evaluated the serum sodium (Na) levels, Na excretion and physiological parameters. Twenty-four male Wistar rats were used. SAH was induced by an endovascular puncture method. The mean arterial pressure (MAP), intracranial pressure (ICP), and cerebral blood flow (CBF) were monitored continuously. The urine was collected cumulatively for 12 hours after SAH, and the urine Na concentration was determined with a spectrophotometer. The serum Na levels were measured at 12 hrs, 2 and 4 days following the SAH induction. The mean (± standard deviation) baseline ICP was 3.5 ± 2.6 mmHg, and increased to 67.4 ± 17.6 mmHg immediately following induction of SAH. CBF decreased rapidly, and then gradually recovered to 70–80% of baseline. The urine volume and total Na excretion were significantly increased in comparison to those of the sham (<0.05). The serum Na level was significantly decreased at 4 days following SAH (<0.05). The present results demonstrated for the first time that rats with SAH exhibited excessive natriuresis. The endovascular puncture model is suitable for investigating hyponatremia that occurs concomitantly with natriuresis and diuresis after SAH.

We evaluated the effects of defibrase DF-521 batroxobin on reducing brain edema formation and the expression of ICAM-1, complement C3d and C9 in the perihematomal area after intracerebral hemorrhage (ICH) in rats. A rat ICH model, involving infusion of autologous blood into the right basal ganglia, were used in this study. The animals were sacrificed at 24 and 72 hours after ICH to determine the water content of the brain tissue with wet/dry weight measurement. While the expression of ICAM-1 and complement C3d was detected using immuno-histochemistry, and C9 was detected semi-quantitatively with Western blot analysis in the perihematomal area. Perihematomal brain edema was reduced after intraperitoneally injection of DF-521 batroxobin 24 and 72 hours after intracerebral hemorrhage. Immuno-histochemistry showed that there were less ICAM-1 positive cells were found around the hematoma after intraperitoneally injection of DF-521 batroxobin 24 and 72 hours after ICH. Immuno-histochemistry also showed that C3d deposition reduced significantly, and the Western blot analysis also showed the content of C9 protein declined around the hematoma in DF-521 batroxobin treatment group at 72 hours after ICH. Defibrase DF-521 batroxobin down-regulate ICAM-1 and complement C3d and C9 expression in the perihematomal area, and attenuate brain edema formation in ICH rats.

The present study examined whether thrombin activates the complement cascade in the brain and whether N-acetylheparin, an inhibitor of complement activation, attenuates brain injury induced by thrombin. There were three sets of studies. In the first set, rats had an intracerebral infusion of either five-unit thrombin or a needle insertion. Brains were sampled at 24 hours for Western blot analysis and immuno-histochemistry. In the second set, rats received either five-unit thrombin+saline, five-unit thrombin+25 µg N-acetylheparin or five-unit thrombin+100 µg N-acetylheparin infusion. Brains were sampled 24 hours later for water content measurement. In the third set, rats received either five-unit thrombin+saline or five-unit thrombin+100 µg N-acetylheparin. Behavioral tests sensitive to unilateral striatal damage were carried out for two weeks. Western blotting demonstrated that complement C9 and clusterin levels increase 24 hours after thrombin infusion (<0:01). Both C9 and clusterin positive cells were found around the injection site. High-dose (100-µg) but not low-dose (25-µg) N-acetylheparin attenuated thrombin-induced brain edema (81.5 ± 0.4% vs. 83.7 ± 0.3% in the vehicle, <0:05). Behavior was also significantly improved by N-acetylheparin (<0:05). In conclusion, thrombin-induced edema formation and neurological deficits were both reduced by N-acetylheparin. This suggests that inhibition may be a novel treatment for the thrombin-induced brain injury that occurs in intracerebral hemorrhage.

We determined the role of VEGF-transfected neural stem cells (NSCs) transplantation in rat brain subjected to ischemia.

Fetal NSCs were cultured from E14 days SD rats and transfected with VEGF121 gene by using lipofectamine technique. Temporary middle cerebral artery occlusion (tMCAO) models were established and randomly divided into 1: control group, 2: PBS transplantation group, 3: NSCs transplantation group and 4: VEGF-secreting NSCs transplantation group. Grafts were transplanted into the penumbra zones 3 days after tMCAO model established. Neurological Severity Score (NSS) was checked in all groups 2–12 weeks after transplantation. By using immunofluorescent staining, VEGF expression of transplanted cells, differentiation and migration of transplanted NSCs after transplantation were detected.

VEGF gene-transfected neural stem cells expressed gene products during the first 2 weeks. NSS in this group was significantly lower compared with that in other 3 groups 12 weeks after transplantation. VEGF gene-transfected NSCs migrated and expressed VEGF in hosts’ brains, some of them differentiated to neurons 12 weeks after transplantation.

VEGF-transfected NSCs expressed gene products during the early time after transplantation, which reduce brain injury through protecting the vascular system against ischemic attack.