Effects of an Early Intensive Blood Pressure-lowering Strategy Using Remifentanil and Dexmedetomidine in Patients with Spontaneous Intracerebral Hemorrhage: A Multicenter, Prospective, Superiority, Randomized Controlled Trial.

BACKGROUND: Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and antisympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage. METHODS: In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) 150 mmHg or greater were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (less than 140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function, and clinical outcomes. RESULTS: A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101 of 161, 62.7% vs. 66 of 166, 39.8%; difference, 23.2%; 95% CI, 12.4 to 34.1%; P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group. CONCLUSIONS: Among intracerebral hemorrhage patients with a SBP 150 mmHg or greater, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management.

Intracranial Pressure Monitoring in the Intensive Care Unit for Patients with Severe Traumatic Brain Injury: Analysis of the CENTER-TBI China Registry.

BACKGROUND: Although the current guidelines recommend the use of intracranial pressure (ICP) monitoring in patients with severe traumatic brain injury (sTBI), the evidence indicating benefit is limited. The present study aims to evaluate the impact of ICP monitoring on patients with sTBI in the intensive care unit (ICU). METHODS: The patient data were obtained from the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury China Registry, a prospective, multicenter, longitudinal, observational, cohort study. Patients with sTBI who were admitted to 52 ICUs across China, managed with ICP monitoring or without, were analyzed in this study. Patients with missing information on discharge survival status, Glasgow Coma Scale score on admission to hospital, and record of ICP monitoring application were excluded from the analysis. Data on demographic characteristics, injury, clinical features, treatments, survival at discharge, discharge destination, and length of stay were collected and assessed. The primary end point was survival state at discharge, and death from any cause was considered the event of interest. RESULTS: A total of 2029 patients with sTBI were admitted to the ICU; 737 patients (36.32%) underwent ICP monitoring, and 1292 (63.68%) were managed without ICP monitoring. There was a difference between management with and without ICP monitoring on in-hospital mortality in the unmatched cohort (18.86% vs. 26.63%, p < 0.001) and the propensity-score-matched cohort (19.82% vs. 26.83%, p = 0.003). Multivariate logistic regressions also indicated that increasing age, higher injury severity score, lower Glasgow Coma Scale score, unilateral and bilateral pupillary abnormalities, systemic hypotension (SBP ≤ 90 mm Hg), hypoxia (SpO2 < 95%) on arrival at the hospital, and management without ICP monitoring were associated with higher in-hospital mortality. However, the patients without ICP monitoring had a lower length of stay in the ICU (11.79 vs. 7.95 days, p < 0.001) and hospital (25.96 vs. 21.71 days, p < 0.001), and a higher proportion of survivors were discharged to the home with better recovery in self-care. CONCLUSIONS: Although ICP monitoring was not widely used by all of the centers participating in this study, patients with sTBI managed with ICP monitoring show a better outcome in overall survival. Nevertheless, the use of ICP monitoring makes the management of sTBI more complex and increases the costs of medical care by prolonging the patient's stay in the ICU or hospital.

Steered migration and changed morphology of human astrocytes by an applied electric field.

Direct current electric field (DC EF) plays a role in influencing the biological behaviors and functions of cells. We hypothesize that human astrocytes (HAs) could also be influenced in EF. Astrocytes, an important type of nerve cells with a high proportion quantitatively, are generally activated and largely decide the brain repair results after brain injury. So far, no electrotaxis study on HAs has been performed. We here obtained HAs derived from brain trauma patients. After purification and identification, HAs were seeded in the EF chamber and recorded in a time-lapse image system. LY294002 and U0126 were then used to probe the role of PI3K or ERK signaling pathway on cellular behaviors. The results showed that HAs could be guided to migrate to the anode in DC EFs, in a voltage-dependent manner. The HAs displayed elongated cell bodies and reoriented perpendicularly to the EF in morphology. When treated with LY294002 or U0126, alternation of parameters such as cellular verticality, track speed, displacement speed, long axis, vertical length and circularity were inhibited partly as expected, while the EF-induced directedness was not terminated even at a high drug dosage which was not consistent with previous electrotaxis studies. In conclusion, applied EFs steered the patient-derived HAs directional migration and changed morphology, in which PI3K and ERK pathways at least partially participate. The characteristics of HAs to EF stimulation may be involved in wound healing and neural regeneration, which could be utilized as a novel treatment strategy in brain injury.

Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.

As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.

The depth of catheter in chronic subdural haematoma: does it matter?

Objective: To investigate the appropriate depth of drainage catheter in the patients with chronic subdural haematoma (CSDH). Methods: We retrospectively analysed the data of 190 patients with CSDH undergoing single parietal burr-hole evacuation and drainage. Results: According to the depth of catheter (DC), 190 patients were divided into three groups: shallow group (DC <4.3 cm), middle group (DC 4.3 ~ 5.4 cm) and deep group (DC > 5.4 cm). During postdischarge 6 months, two, six and nine patients had recurrences in shallow, middle and deep groups, respectively. The recurrence rate in shallow or middle group was significantly lower than that in deep group. No significant difference in preoperative haematoma volume (PHV) was observed in three groups. While the residual subdural space (RSS) in shallow group was significantly smaller than those in the other two groups. The duration of drainage in shallow, middle and deep groups increased successively, and the differences were statistically significant. The total drainage volume (TDV) in shallow group showed no significant difference when compared with the other two groups. Conclusion: The depth of catheter may affect the outcome of CSDH. Inserting drainage catheter shallowly might be a preferred choice in patients with CSDH undergoing burr-hole evacuation and drainage.

Intraventricular intracranial pressure monitoring improves the outcome of older adults with severe traumatic brain injury: an observational, prospective study.

BACKGROUND: Intracranial pressure (ICP) monitoring is widely used in the management of patients with severe traumatic brain injury (TBI). However, there is limited evidence about the efficacy of ICP monitoring in older subjects (aged ≥65 years). This study evaluated the effect of intraventricular ICP monitoring on the outcome of older adults suffering from a severe TBI. METHODS: This prospective, observational study included 166 older TBI patients (aged ≥65 years) with Glasgow Coma scale (GCS) scores lower than 9 at admission. The study cohort was divided into two groups, intraventricular ICP monitoring and non-ICP monitoring. The primary outcome was in-hospital mortality. The secondary outcomes included the Glasgow Outcome Scale (GOS) score 6 months after injury, the ICU and total hospital lengths of stay, and mechanical ventilation days. RESULTS: There were 80 patients in the intraventricular ICP monitoring group and 86 patients in non-ICP monitoring group. There was no statistical difference between groups in demographics and severity of head injury. Patients treated with intraventricular ICP monitoring had lower in-hospital mortality (33.8 % vs 51.2 %, P < 0.05), a higher 6-month GOS score (3.0 ± 1.4 vs 2.5 ± 1.2 P < 0.05), and a lower dosage (514 ± 246 g vs 840 ± 323 g, P < 0.0001) and shorter duration (7.2 ± 3.6 days vs 8.4 ± 4.3 days, P < 0.01) of mannitol use. However, the ICU length of stay (14.3 ± 6.4 days vs 11.6 ± 5.8 days, P < 0.01) and mechanical ventilation days (6.7 ± 3.5 days vs 5.6 ± 2.4 days, P < 0.05) were longer in the ICP monitoring group. The total length of hospital stay did not differ between the two groups (28.5 ± 12.1 days vs 26.1 ± 13.5 days, P = 0.23). CONCLUSIONS: Intraventricular ICP monitoring may have beneficial effects on the decreased in-hospital mortality and improved 6-month outcome of older patients with severe TBI. However, given that this was an observational study conducted in a single institution, further well-designed randomized control trials are needed to evaluate the effect of intraventricular ICP monitoring on the outcome of older severe TBI patients.

Alteration of microRNA expression in cerebrospinal fluid of unconscious patients after traumatic brain injury and a bioinformatic analysis of related single nucleotide polymorphisms.

PURPOSE: It is becoming increasingly clear that genetic factors play a role in traumatic brain injury (TBI), whether in modifying clinical outcome after TBI or determining susceptibility to it. MicroRNAs are small RNA molecules involved in various pathophysiological processes by repressing target genes at the post- transcriptional level, and TBI alters microRNA expression levels in the hippocampus and cortex. This study was designed to detect differentially expressed microRNAs in the cerebrospinal fluid (CSF) of TBI patients remaining unconscious two weeks after initial injury and to explore related single nucleotide polymorphisms (SNPs). METHODS: We used a microarray platform to detect differential microRNA expression levels in CSF samples from patients with post-traumatic coma compared with samples from controls. A bioinformatic scan was performed covering microRNA gene promoter regions to identify potential functional SNPs. RESULTS: Totally 26 coma patients and 21 controls were included in this study, with similar distribution of age and gender between the two groups. Microarray showed that fourteen microRNAs were differentially expressed, ten at higher and four at lower expression levels in CSF of traumatic coma patients compared with controls (p<0.05). One SNP (rs11851174 allele: C/T) was identified in the motif area of the microRNA hsa-miR-431-3P gene promoter region. CONCLUSION: The altered microRNA expression levels in CSF after brain injury together with SNP identified within the microRNA gene promoter area provide a new perspective on the mechanism of impaired consciousness after TBI. Further studies are needed to explore the association between the specific microRNAs and their related SNPs with post-traumatic unconsciousness.

Improved neurite outgrowth on central nervous system myelin substrate by siRNA-mediated knockdown of Nogo receptor.

PURPOSE: To investigate the in vitro effect of short interfering RNAs (siRNAs) against Nogo receptor (NgR) on neurite outgrowth under an inhibitory substrate of central nervous system (CNS) myelin. METHODS: Three siRNA sequences against NgR were designed and transfected into cerebellar granule cells (CGCs) to screen for the most effcient sequence of NgR siRNA by using reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. NgR siRNA sequence 1 was found the most efficient which was then transfected into the CGCs grown on CNS myelin substrate to observe its disinhibition for neurite outgrowth. RESULTS: Compared with the scrambled control sequence of siRNA, the NgR siRNA sequence 1 significantly decreased NgR mRNA level at 24 h and 48 h (p <0.05), which was recovered by 96 h after transfection. NgR immunoreactivity was also markedly reduced at 24 and 48 h after the transfection of siRNA sequence 1 compared with that before transfection (p<0.05). The NgR immunoreactivity was recovered after 72 h post-transfection. Moreover, the neurite outgrowth on the myelin substrate was greatly improved within 72 h after the transfection with siRNA sequence 1 compared with the scrambled sequence-transfected group or non-transfected group (p<0.05). CONCLUSION: siRNA-mediated knockdown of NgR expression contributes to neurite outgrowth in vitro.

Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: a prospective cohort study.

INTRODUCTION: Glial fibrillary acidic protein (GFAP) may serve as a serum marker of traumatic brain injury (TBI) that can be used to monitor biochemical changes in patients and gauge the response to treatment. However, the temporal profile of serum GFAP in the acute period of brain injury and the associated utility for outcome prediction has not been elucidated. METHODS: We conducted a prospective longitudinal cohort study of consecutive severe TBI patients in a local tertiary neurotrauma center in Shanghai, China, between March 2011 and September 2014. All patients were monitored and managed with a standardized protocol with inclusion of hypothermia and other intensive care treatments. Serum specimens were collected on admission and then daily for the first 5 days. GFAP levels were measured using enzyme-linked immunosorbent assay techniques. Patient outcome was assessed at 6 months post injury with the Glasgow Outcome Scale and further grouped into death versus survival and unfavorable versus favorable. RESULTS: A total of 67 patients were enrolled in the study. The mean time from injury to admission was 2.6 hours, and the median admission Glasgow Coma Scale score was 6. Compared with healthy subjects, patients with severe TBI had increased GFAP levels on admission and over the subsequent 5 days post injury. Serum GFAP levels showed a gradual reduction from admission to day 3, and then rebounded on day 4 when hypothermia was discontinued with slow rewarming. GFAP levels were significantly higher in patients who died or had an unfavorable outcome across all time points than in those who were alive or had a favorable outcome. Results of receiver operating characteristic curve analysis indicated that serum GFAP at each time point could predict neurological outcome at 6 months. The areas under the curve for GFAP on admission were 0.761 for death and 0.823 for unfavorable outcome, which were higher than those for clinical variables such as age, Glasgow Coma Scale score, and pupil reactions. CONCLUSIONS: Serum GFAP levels on admission and during the first 5 days of injury were increased in patients with severe TBI and were predictive of neurological outcome at 6 months.

Craniectomy versus craniotomy: What can we do for acute subdural hematoma?

Compared with hematoma evacuation craniotomy, decompressive craniectomy has a higher incidence of intracranial complications and no outcome benefit over craniotomy, which gives surgeons a safer decision-making options during surgery.