Zhenzhou Lin

Glibenclamide Improves Survival and Neurologic Outcome After Cardiac Arrest in Rats.

Objectives:Glibenclamide confers neuroprotection in animal models as well as in retrospective clinical studies. This study determines whether glibenclamide improves outcome after cardiac arrest in rats. Design:Prospective randomized laboratory study. Setting:University research laboratory. Subjects:Male Sprague-Dawley rats (n = 126). Interventions:Rats successfully resuscitated from 8-minute asphyxial cardiac arrest were randomized to glibenclamide or vehicle group. Rats in the glibenclamide group were intraperitoneally administered glibenclamide with a loading dose of 10 &mgr;g/kg at 10 minutes and a maintenance dose of 1.2 &mgr;g at 6, 12, 18, and 24 hours after return of spontaneous circulation, whereas rats in the vehicle group received equivalent volume of vehicle solution. Measurements and Main Results:Survival was recorded every day, and neurologic deficit scores were assessed at 24, 48, and 72 hours and 7 days after return of spontaneous circulation (n = 22 in each group). Results showed that glibenclamide treatment increased 7-day survival rate, reduced neurologic deficit scores, and prevented neuronal loss in the hippocampal cornu ammonis 1 region. To investigate the neuroprotective effects of glibenclamide in acute phase, we observed neuronal injury at 24 hours after return of spontaneous circulation and found that glibenclamide significantly decreased the rate of neuronal necrosis and apoptosis. In addition, glibenclamide reduced the messenger RNA expression of tumor necrosis factor-&agr; and monocyte chemoattractant protein-1 in the cortex after return of spontaneous circulation. Furthermore, the sulfonylurea receptor 1 and transient receptor potential M4 heteromers, the putative therapeutic targets of glibenclamide, were up-regulated after cardiac arrest and cardiopulmonary resuscitation, indicating that they might be involved in neuroprotective effect of glibenclamide. Conclusions:Glibenclamide treatment substantially improved survival and neurologic outcome throughout a 7-day period after return of spontaneous circulation. The salutary effects of glibenclamide were associated with suppression of neuronal necrosis and apoptosis, as well as inflammation in the brain.

Predictors of Extubation Failure in Neurocritical Patients Identified by a Systematic Review and Meta-Analysis

Background Prediction of extubation failure, particularly in neurocritical patients, is unique and controversial. We conducted a systematic review and meta-analysis to identify the risk factors for extubation failure in these patients. Methods A literature search of databases (MEDLINE, EMBASE, the Cochrane Library, and Web of Science) was performed up to August of 2013 to identify trials that evaluated extubation failure predictors. Included trials were either prospective or retrospective cohort studies. Results Nine studies involving 928 participants were included. The systematic review and meta-analysis revealed that the following were predictive for extubation failure: pneumonia, atelectasis, mechanical ventilation of >24 h, a low Glasgow Coma Scale score (7–9T) (OR = 4.96, 95% CI = 1.61–15.26, P = 0.005), the inability to follow commands (OR = 2.07, 95% CI = 1.15–3.71, P = 0.02), especially the command to close the eyes, thick secretion, and no intact gag reflex. Meanwhile, the following were not predictive for extubation failure: sex, secretion volume, coughing upon suctioning, and the inability to follow one command among showing two fingers, wiggling the toes, or coughing on command. Additionally, some traditional weaning parameters were shown to poorly predict extubation failure in neurocritical patients. Conclusions Besides pneumonia, atelectasis, and the duration of mechanical ventilation, other factors that should be taken into consideration in the prediction of extubation failure when neurocritical patients are weaned from tracheal intubation include neurologic abilities (Glasgow Coma Scale score and following commands), the secretion texture, and the presence of a gag reflex.

The prediction of 30-day mortality in patients with primary pontine hemorrhage: a scoring system comparison

Owing to its low morbidity but high mortality, no accurate scoring system focuses on primary pontine hemorrhage (PPH) has been established. We aim to compare the performances of the Acute Physiology and Chronic Health Evaluation (APACHE) II and the Simplified Acute Physiology Score (SAPS) II with the ICH score in predicting the 30‐day mortality in patients with PPH.

Glibenclamide Is Comparable to Target Temperature Management in Improving Survival and Neurological Outcome After Asphyxial Cardiac Arrest in Rats

Background We previously have shown that glibenclamide (GBC), a sulfonylurea receptor 1–transient receptor potential M4 (SUR1‐TRPM4) channel inhibitor, improves survival and neurological outcome after asphyxial cardiac arrest and cardiopulmonary resuscitation (ACA/CPR). Here, we further compare the efficacy of GBC with target temperature management (TTM) and determine whether the efficacy of GBC is affected by TTM. Methods and Results Male Sprague‐Dawley rats (n=213) subjected to 10‐minute ACA/CPR were randomized to 4 groups after return of spontaneous circulation (ROSC): normothermia control (NT); GBC; TTM; and TTM+GBC. Survival, neurodeficit scores, histological injury, as well as the expressions of SUR1 and TRPM4 were evaluated. The 7‐day survival rate was 34.4% (11 of 32) in the NT group, 65% (13 of 20) in the GBC group, 50% (10 of 20) in the TTM group, and 70% (14 of 20) in the TTM+GBC group. Rats that received either GBC, TTM alone, or in combination showed less neurological deficit than NT control at 24, 48, and 72 hours and 7 days after ROSC. Moreover, TTM or GBC ameliorated neuronal degeneration and glial activation in the hippocampal CA1 region with similar efficacy, whereas the combination of them had a trend toward better effect. The subunits of SUR1‐TRPM4 heterodimers were both strongly upregulated after ACA/CPR and expressed in multiple types of brain cells, but partly suppressed by TTM. Conclusions GBC is comparable to TTM in improving survival and neurological outcome after ACA/CPR. When GBC is given along with TTM, less histological injury tended to be achieved.

Glibenclamide enhances the effects of delayed hypothermia after experimental stroke in rats

In order to evaluate whether glibenclamide can extend the therapeutic window during which induced hypothermia can protect against stroke, we subjected adult male Sprague-Dawley rats to middle cerebral artery occlusion (MCAO). We first verified the protective effects of hypothermia induced at 0, 2, 4 or 6h after MCAO onset, and then we assessed the effects of the combination of glibenclamide and hypothermia at 6, 8 or 10h after MCAO onset. At 24h after MCAO, we assessed brain edema, infarct volume, modified neurological severity score, Evans Blue leakage and expression of Sulfonylurea receptor 1 (SUR1) protein and pro-inflammatory factors. No protective effects were observed when hypothermia was induced too long after MCAO. At 6h after MCAO onset, hypothermia alone failed to decrease cerebral edema and infarct volume, but the combination of glibenclamide and hypothermia decreased both. The combination also improved neurological outcome, ameliorated blood-brain barrier damage and decreased levels of COX-2, TNF-α and IL-1β. These results suggest that glibenclamide enhances and extends the therapeutic effects of delayed hypothermia against ischemia stroke, potentially by ameliorating blood-brain barrier damage and declining levels of pro-inflammatory factors.

Development and Validation of a Grading Scale for Primary Pontine Hemorrhage.

Background and Purpose— We aimed to develop and validate a grading scale for predicting 30-day mortality and 90-day functional outcome in patients with primary pontine hemorrhage (PPH). Methods— We retrospectively reviewed records of consecutive patients with first-ever pontine hemorrhage from 3 teaching hospitals between 2005 and 2012. Independent factors associated with 30-day mortality were identified by logistic regression to establish a risk stratification scale, named the new PPH score. For validation of the new PPH score, we prospectively recruited subjects from 10 units between December 2014 and November 2015. The performance of the new PPH score was presented as discrimination and calibration, measured by area under the curve of the receiver operating characteristic and Hosmer–Lemeshow goodness-of-fit, respectively. Results— Data of 171 patients were available for scale development. The new PPH score consisted of 2 independent factors with individual points assigned as follows: Glasgow Coma Scale score 3 to 4 (=2 points), 5 to 7 (=1 point), and 8 to 15 (=0 point); PPH volume >10 mL (=2 points), 5 to 10 mL (=1 point), and <5 mL (=0 point). An independent cohort of 98 patients was applied as an external validation of the new PPH score. Results showed that the new PPH score was discriminative in predicting both 30-day mortality (area under the curve, 0.902) and 90-day good outcome (area under the curve, 0.927). Furthermore, the new PPH score revealed a good calibration (&khgr;2=1.387; P=0.846) in 30-day mortality prediction. Conclusions— The new PPH score is simple and reliable in predicting short-term and long-term outcome for PPH patients. Clinical Trial Registration— URL: http://www.chictr.org.cn. Unique identifier: ChiCTR-OOC-14005533.

Glibenclamide ameliorates cerebral edema and improves outcomes in a rat model of status epilepticus

Abstract Glibenclamide (GBC), a sulfonylurea receptor 1 blocker, emerges recently as a promising neuron protectant in various neurological disorders. This study aimed to determine whether GBC improves survival and neurological outcome of status epilepticus (SE). Male Sprague‐Dawley rats successfully undergoing SE for 2.5 h (n = 134) were randomly assigned to GBC or vehicle group. Rats in the GBC group received a loading dose of 10 &mgr;g/kg of GBC, followed by 1.2 &mgr;g/6 h for 3 days, while same dose of vehicle was used as control. The 28‐day survival rate in the GBC group (11/23) was significantly higher than that in the vehicle group (8/36). In addition, the frequency and duration of spontaneous recurrent seizures in SE rats were profoundly reduced by GBC but not by vehicle treatment. Moreover, cognitive impairment was observed in the SE rats at day 28, which was reversed by GBC treatment. Meanwhile, cerebral edema, as well as neuronal loss, was decreased in several brain areas in the GBC group. Additionally, on the molecular basis, the subunits of sulfonylurea receptor 1/transient receptor potential M4 (SUR1‐TRPM4) heterodimer were both strongly upregulated after SE but partly suppressed by GBC treatment. Furthermore, gene knockdown of Trpm4 in SE rats reduced BBB disruption and neuronal loss, similar to the inhibitory effects with GBC treatment. Taken together, GBC treatment markedly improved survival and neurologic outcomes after SE. The salutary effects of GBC were correlated to the alleviation of cerebral edema and reduction in neurological injury via down‐regulation of SUR1‐TRPM4 channel. HighlightsGBC improved survival and alleviated cerebral edema after SE.GBC ameliorated neuronal loss of SE rats.GBC improved neurological outcomes of SE rats.GBC inhibited the upregulations of SUR1 and TRPM4 induced by SE.TRPM4 knockdown reduced BBB disruption and neuronal loss of SE rats.

Hyperchloremia Is Associated With Poorer Outcome in Critically Ill Stroke Patients

Background and Purpose: This study aims to explore the cause and predictive value of hyperchloremia in critically ill stroke patients. Materials and Methods: We conducted a retrospective study of a prospectively collected database of adult patients with first-ever acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) admitted to the neurointensive care unit (NICU) of a university-affiliated hospital, between January 2013 and December 2016. Patients were excluded if admitted beyond 72 h from onset, if they required neurocritical care for less than 72 h, and were treated with hypertonic saline within 72 h or had creatinine clearance less than 15 mL/min. Results: Of 405 eligible patients, the prevalence of hyperchloremia ([Cl−] ≥ 110 mmol/L) was 8.6% at NICU admission ([Cl−]0) and 17.0% within 72 h ([Cl−]max). Thirty-eight (9.4%) patients had new-onset hyperchloremia and 110 (27.1%) had moderate increase in chloride (Δ[Cl−] ≥ 5 mmol/L; Δ[Cl−] = [Cl−]max − [Cl−]0) in the first 72 h after admission, which were found to be determined by the sequential organ failure assessment score in multivariate logistic regression analysis. Neither total fluid input nor cumulative fluid balance had significant association with such chloride disturbance. New-onset hyperchloremia and every 5 mmol/L increment in Δ[Cl−] were both associated with increased odds of 30-day mortality and 6-month poor outcome, although no independent significance was found in multivariate models. Conclusion: Hyperchloremia tends to occur in patients more severely affected by AIS and ICH. Although no independent association was found, new-onset hyperchloremia and every 5 mmol/L increment in Δ[Cl−] were related to poorer outcome in critically ill AIS and ICH patients. Subject terms: clinical studies, intracranial hemorrhage, ischemic stroke, mortality/survival, quality and outcomes.