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Intraventricular fibrinolysis with tissue plasminogen activator is associated with transient cerebrospinal fluid inflammation: a randomized controlled trial. - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Locally administered tissue plasminogen activator (TPA) accelerates clearance of intraventricular hemorrhage (IVH), but its impact on neurologic outcomes remains unclear and preclinical research suggests it may have pro-inflammatory effects. We randomly allocated patients with ruptured cerebral aneurysms and IVH, treated with endovascular coiling and ventricular drainage, to receive either 2-mg intraventricular TPA or placebo every 12 hours. Cerebrospinal fluid (CSF) and serum cytokine and white blood cell (WBC) concentrations were measured before drug administration and daily for 72 hours. Cerebrospinal fluid D-dimer levels were assessed 6 and 12 hours after administration to quantify fibrinolysis. Six patients were randomized to each group. Patients treated with TPA developed higher CSF cytokine concentrations compared with placebo-treated patients (P<0.05 for tumor necrosis factor-Î±, interferon-Î³, interleukin (IL)-1Î±, IL-1Î², IL-2, IL-4, and IL-6), as well as higher CSF WBC counts (P=0.03). Differences were greatest after 24 hours and decreased over 48 to 72 hours. The magnitude of the inflammatory response was significantly associated with peak CSF D-dimer concentration and extent of IVH clearance. We conclude that intraventricular TPA administration produces a transient local inflammatory response, the severity of which is strongly associated with the degree of fibrinolysis, suggesting it may be induced by release of hematoma breakdown products, rather than the drug itself.
Pharmacokinetics and Pharmacodynamics of Tissue Plasminogen Activator Administered Through an External Ventricular Drain. - Neurocritical care
Intraventricular hemorrhage (IVH) frequently complicates spontaneous intracerebral or subarachnoid hemorrhage (SAH). Administration of intraventricular tissue plasminogen activator (TPA) accelerates blood clearance, but optimal dosing has not been clarified. Using a standardized TPA dose, we assessed peak cerebrospinal fluid (CSF) TPA concentrations, the rate at which TPA clears, and the relationship between TPA concentration and biological activity.Twelve patients with aneurysmal SAH and IVH, treated with endovascular coiling and ventricular drainage, were randomized to receive either 2Â mg intraventricular TPA or placebo every 12Â h (five doses). CT scans were performed 12, 48, and 72Â h after initial administration, and blood was quantified using the SAH Sum and IVH Scores. CSF TPA and fibrin degradation product (D-dimer) concentrations were measured at baseline and 1, 6, and 12Â h after the first dose using ELISA assays.Median CSF TPA concentrations in seven TPA-treated patients were 525 (IQR 352-2129), 323 (233-413), and 47 (29-283) ng/ml, respectively, at 1, 6, and 12Â h after drug administration. Peak concentrations varied markedly (401-8398Â ng/ml). Two patients still had slightly elevated levels (283-285Â ng/ml) when the second dose was due after 12Â h. There was no significant correlation between the magnitude of CSF TPA elevation and the rate of blood clearance or degree of D-dimer elevation. D-dimer peaked at 6Â h, had declined by 12Â h, and correlated strongly with radiographic IVH clearance (rÂ =Â 0.82, pÂ =Â 0.02).The pharmacokinetics of intraventricular TPA administration varies between individual patients. TPA dose does not need to exceed 2Â mg. The optimal administration interval is every 8-12Â h.
Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex. - Frontiers in behavioral neuroscience
Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1) and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs) which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET) and wild-type (WT) mice using [(3)H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV) and the dentate gyrus (DG) of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL) subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However, in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex.
Intraventricular tissue plasminogen activator in subarachnoid hemorrhage patients: a prospective, randomized, placebo-controlled pilot trial. - Neurocritical care
The quantity of subarachnoid (SAH) and intraventricular hemorrhage (IVH) occurring in the setting of a ruptured cerebral aneurysm is strongly associated with subsequent complications and poor outcomes.We randomly allocated aneurysmal SAH patients with a modified Fisher score of 4, who had been treated with endovascular coil embolization and ventricular drainage, to receive either 2 mg intraventricular tissue plasminogen activator (TPA) every 12 h (maximum 10 mg) or placebo. Computed tomography scans were performed 12, 48, and 72 h after administration. Primary outcomes included feasibility (enrollment and consent rates), safety (assessed by prospectively screening for complications), and rate of intracranial blood clearance (measured using sequential IVH, modified Graeb, and SAH sum scores). Secondary outcomes included angiographic vasospasm, delayed cerebral ischemia, need for ventriculoperitoneal shunting, and 6-month neurological outcomes.Seventy-seven patients were screened, 17 were eligible, and 12 were randomized. The consent rate was 87 %. There were no cases of new intracranial hemorrhage complicating use of TPA. Models fit using generalized estimating equations demonstrated more rapid reduction in IVH volume (p = 0.009), modified Graeb score (p < 0.001), and SAH sum score (p < 0.001) among patients treated with TPA. SAH clearance at 48 h was enhanced by earlier drug administration (p = 0.02). There were no differences in secondary outcomes.Intraventricular TPA accelerates clearance of SAH and IVH, especially when administered early. A larger-scale clinical trial of intraventricular TPA is feasible, will need to be conducted at multiple centers, and is required to determine whether this practice reduces complications and improves outcomes.
Association between the cerebral inflammatory and matrix metalloproteinase responses after severe traumatic brain injury in humans. - Journal of neurotrauma
An increasing number of preclinical investigations have suggested that the degree of expression of the matrix metalloproteinase (MMP) family of endopeptidases may explain some of the variability in neurological damage after traumatic brain injury (TBI). As cytokines are a prominent stimulus for MMP expression in animals, we conducted a prospective multimodal monitoring study and determined their association with temporal MMP expression after severe TBI in eight critically ill adults. High cutoff, cerebral microdialysis (n=8); external ventricular drainage (n=3); and arterial and jugular venous bulb catheters were used to measure the concentration of nine cytokines and eight MMPs in microdialysate, cerebrospinal fluid (CSF), and plasma over 6 days. Severe TBI was associated with a robust central inflammatory response, which was largely similar between microdialysate and CSF. At all time points after injury, this response was predominated by the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8. Use of univariate generalized estimating equations suggested that the concentration of several MMPs varied with cytokine levels in microdialysate. The largest of these changes included increases in microdialysate concentrations of MMP-8 and MMP-9 with increases in the levels of IL-1Î± and -2 and IL-1Î± and -2 and TNF-Î±, respectively. In contrast, the microdialysate level of MMP-7 decreased with increases in microdialysate concentrations of IL-1Î², -2, and -6. These findings support the observations of animal studies that cross-talk exists between the neuroinflammatory and MMP responses after acute brain injury. Further study is needed to determine whether this link between cerebral inflammation and MMP expression may have clinical relevance to the care of patients with TBI.
A prospective evaluation of the temporal matrix metalloproteinase response after severe traumatic brain injury in humans. - Journal of neurotrauma
Abstract Accumulating pre-clinical data suggests that matrix metalloproteinase (MMP) expression plays a critical role in the pathophysiology of secondary brain injury. We conducted a prospective multimodal monitoring study in order to characterize the temporal MMP response after severe traumatic brain injury (TBI) in eight critically ill humans and its relationship with outcomes. High-cutoff, cerebral microdialysis (n=8); external ventricular drainage (n=3); and arterial and jugular venous bulb catheters were used to collect microdialysate, cerebrospinal fluid, and arterial and jugular bulb blood over 6 days. Levels of MMP-8 and -9 were initially high in microdialysate and then gradually declined over time. After these MMPs decreased, a spike in the microdialysate levels of MMP-2 and -3 occurred, followed by a gradual rise in the microdialysate concentration of MMP-7. Use of generalized estimating equations suggested that MMP-8 concentration in microdialysate was associated with mortality (p=0.019) and neurological outcome at hospital discharge (p=0.013). Moreover, the mean microdialysate concentration of MMP-8 was 2.4-fold higher among those who died after severe TBI than in those who survived. Mean microdialysate levels of MMP-8 also rose with increasing intracranial pressure (ICP), whereas those of MMP-7 decreased with increasing cerebral perfusion pressure (CPP). Significant changes in the mean microdialysate concentrations of MMP-1, -2, -3, and -9 and MMP-1, -2, -3, -7, and -9 also occurred with increases in microdialysate glucose and the lactate/pyruvate ratio, respectively. These results imply that monitoring of MMPs following severe TBI in humans is feasible, and that their expression may be associated with clinical outcomes, ICP, CPP, and cerebral metabolism.
Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study. - CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne
Severe traumatic brain injury often leads to death from withdrawal of life-sustaining therapy, although prognosis is difficult to determine.To evaluate variation in mortality following the withdrawal of life-sustaining therapy and hospital mortality in patients with critical illness and severe traumatic brain injury, we conducted a two-year multicentre retrospective cohort study in six Canadian level-one trauma centres. The effect of centre on hospital mortality and withdrawal of life-sustaining therapy was evaluated using multivariable logistic regression adjusted for baseline patient-level covariates (sex, age, pupillary reactivity and score on the Glasgow coma scale).We randomly selected 720 patients with traumatic brain injury for our study. The overall hospital mortality among these patients was 228/720 (31.7%, 95% confidence interval [CI] 28.4%-35.2%) and ranged from 10.8% to 44.2% across centres (Ï‡(2) test for overall difference, p < 0.001). Most deaths (70.2% [160/228], 95% CI 63.9%-75.7%) were associated with withdrawal of life-sustaining therapy, ranging from 45.0% (18/40) to 86.8% (46/53) (Ï‡(2) test for overall difference, p < 0.001) across centres. Adjusted odd ratios (ORs) for the effect of centre on hospital mortality ranged from 0.61 to 1.55 (p < 0.001). The incidence of withdrawal of life-sustaining therapy varied by centre, with ORs ranging from 0.42 to 2.40 (p = 0.001). About one half of deaths that occurred following the withdrawal of life-sustaining therapies happened within the first three days of care.We observed significant variation in mortality across centres. This may be explained in part by regional variations in physician, family or community approaches to the withdrawal of life-sustaining therapy. Considering the high proportion of early deaths associated with the withdrawal of life-sustaining therapy and the limited accuracy of current prognostic indicators, caution should be used regarding early withdrawal of life-sustaining therapy following severe traumatic brain injury.
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