Early pathophysiology-driven airway pressure release ventilation versus low tidal volume ventilation strategy for patients with moderate-severe ARDS: study protocol for a randomized, multicenter, controlled trial.

BACKGROUND: Conventional Mechanical ventilation modes used for individuals suffering from acute respiratory distress syndrome have the potential to exacerbate lung injury through regional alveolar overinflation and/or repetitive alveolar collapse with shearing, known as atelectrauma. Animal studies have demonstrated that airway pressure release ventilation (APRV) offers distinct advantages over conventional mechanical ventilation modes. However, the methodologies for implementing APRV vary widely, and the findings from clinical studies remain controversial. This study (APRVplus trial), aims to assess the impact of an early pathophysiology-driven APRV ventilation approach compared to a low tidal volume ventilation (LTV) strategy on the prognosis of patients with moderate to severe ARDS. METHODS: The APRVplus trial is a prospective, multicenter, randomized clinical trial, building upon our prior single-center study, to enroll 840 patients from at least 35 hospitals in China. This investigation plans to compare the early pathophysiology-driven APRV ventilation approach with the control intervention of LTV lung-protective ventilation. The primary outcome measure will be all-cause mortality at 28 days after randomization in the intensive care units (ICU). Secondary outcome measures will include assessments of oxygenation, and physiology parameters at baseline, as well as on days 1, 2, and 3. Additionally, clinical outcomes such as ventilator-free days at 28 days, duration of ICU and hospital stay, ICU and hospital mortality, and the occurrence of adverse events will be evaluated. TRIAL ETHICS AND DISSEMINATION: The research project has obtained approval from the Ethics Committee of West China Hospital of Sichuan University (2019-337). Informed consent is required. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences. TRIAL REGISTRATION: The study was registered at Clinical Trials.gov (NCT03549910) on June 8, 2018.

Sequential use of midazolam and dexmedetomidine for long-term sedation may reduce weaning time in selected critically ill, mechanically ventilated patients: a randomized controlled study.

BACKGROUND: Current sedatives have different side effects in long-term sedation. The sequential use of midazolam and dexmedetomidine for prolonged sedation may have distinct advantages. We aimed to evaluate the efficacy and safety of the sequential use of midazolam and either dexmedetomidine or propofol, and the use of midazolam alone in selected critically ill, mechanically ventilated patients. METHODS: This single-center, randomized controlled study was conducted in medical and surgical ICUs in a tertiary, academic medical center. Patients enrolled in this study were critically ill, mechanically ventilated adult patients receiving midazolam, with anticipated mechanical ventilation for ≥ 72 h. They passed the spontaneous breathing trial (SBT) safety screen, underwent a 30-min-SBT without indication for extubation and continued to require sedation. Patients were randomized into group M-D (midazolam was switched to dexmedetomidine), group M-P (midazolam was switched to propofol), and group M (sedation with midazolam alone), and sedatives were titrated to achieve the targeted sedation range (RASS - 2 to 0). RESULTS: Total 252 patients were enrolled. Patients in group M-D had an earlier recovery, faster extubation, and more percentage of time at the target sedation level than those in group M-P and group M (all P < 0.001). They also experienced less weaning time (25.0 h vs. 49.0 h; HR1.47, 95% CI 1.05 to 2.06; P = 0.025), and a lower incidence of delirium (19.5% vs. 43.8%, P = 0.002) than patients in group M. Recovery (P < 0.001), extubation (P < 0.001), and weaning time (P = 0.048) in group M-P were shorter than in group M, while the acquisition cost of sedative drug was more expensive than other groups (both P < 0.001). There was no significant difference in adverse events among these groups (all P > 0.05). CONCLUSIONS: The sequential use of midazolam and dexmedetomidine was an effective and safe sedation strategy for long-term sedation and could provide clinically relevant benefits for selected critically ill, mechanically ventilated patients. TRIAL REGISTRATION: NCT02528513 . Registered August 19, 2015.

Electrical stimulation of the substantia nigra pars reticulata (SNr) suppresses chemically induced neocortical seizures in rats.

Deep brain stimulation is an alternate treatment strategy for intractable epilepsy. The effects of low- and high-frequency electrical stimulation to the substantia nigra pars reticulata (SNr) of different sides on chemically induced neocortical seizure were investigated in the present study. After neocortical seizure was induced by ferric chloride injection into the left sensorimotor cortex, SNr was stimulated ipsilaterally, contralaterally, or bilaterally at frequencies of 130 or 20 Hz in rats. Unilateral and bilateral stimulation at 130 Hz reduced significantly the number of seizures but not their duration. Ipsilateral, contralateral as well as bilateral stimulations at 130 Hz were all equally effective, producing reductions in seizures of 63.62, 77.84, and 68.74% compared with the control group, respectively. Electrical stimulation at 20 Hz did not reduce the number or duration of seizures regardless of the side stimulated. Both unilateral and bilateral stimulations of SNr at 130 Hz can suppress ictogenesis in the cortex, but electrical stimulation at 130 or 20 Hz does not reduce the severity of individual seizures. The frequency of stimulation is paramount in suppressing neocortical seizures in which DBS at least targets SNr.

Oxidative parameters in the rat brain of chronic mild stress model for depression: relation to anhedonia-like responses.

The chronic mild stress (CMS) protocol is widely used to evoke depression-like behaviors in the laboratory. Some animals exposed to CMS are resistant to the development of anhedonia, whereas the remaining are responsive, CMS-resilient and CMS-sensitive, respectively. The aim of this study was to examine the effects of chronic stress on oxidative parameters in the rat brain. The consumption of sweet food, protein and lipid oxidation levels and superoxide dismutase and catalase activities in the rat hippocampus, cortex and cerebellum were assessed. We found a significant increase in protein peroxidation (hippocampus and cortex), a significant increase in catalase activity (cortex, hippocampus and cerebellum) and a decrease in superoxide dismutase activity (cortex, hippocampus and cerebellum) in the CMS-sensitive group compared to the CMS-resilient group and normal controls as well as an increase in lipid peroxidation (cerebellum) in the CMS-sensitive and CMS-resilient groups compared to normal controls. However, there was no significant difference in protein peroxidation (cerebellum) and lipid peroxidation (cortex and hippocampus) among the three groups. In conclusion, our results indicate that the segregation into CMS-sensitive and -resilient groups based on sucrose intake is paralleled by significant differences in oxidative parameters. CMS induces oxidative damage and alterations in the activity of antioxidants which may lead to increased oxidative damage, irrespective of the anhedonia-like status of the stressed animals.

Responsive electrical stimulation suppresses epileptic seizures in rats.

BACKGROUND: A responsive electrical stimulation pattern based on our recently developed novel seizure prediction method was designed to suppress the penicillin-induced epileptic seizures. METHODOLOGY: Seizures were induced by Penicillin injection at rat cortex. A responsive electrical stimulation system was triggered prior to seizures predicted with phase synchronisation. Rats with induced seizures were stimulated by the electrical pulses at a responsive or 1 Hz periodic pattern of an open system. The effectiveness of stimulation on seizures suppression was assessed by measuring the average number and duration of seizures per hour. RESULTS: The prediction algorithm reliably identified seizures in real time and triggered the responsive stimulation. This type of electrical stimulation dramatically suppressed seizure activity and the performance was better than the open stimulation system with fewer and shorter seizures. CONCLUSIONS: A responsive electrical stimulation system triggered by the phase synchronisation prediction is able to significantly suppress seizures. SIGNIFICANCE: Responsive electrical stimulation could achieve superior treatment performance and reduce power consumption and side effects.

Temporal lobe seizure prediction based on a complex Gaussian wavelet.

OBJECTIVE: Abnormal synchronisation change is closely associated with the process of seizure generation. The immediate and accurate detection of the changes in synchronisation may offer advantages in seizure prediction. Thus, we develop a phase synchronisation detection method for this purpose. METHODS: An analysis of phase synchronisation based on the complex Gaussian wavelet transform (PSW) was conducted to detect synchronised phases of long-lasting scalp electroencephalograph (EEG) recordings from eight epilepsy patients with intractable temporal lobe epilepsy. Four assessment indicators, namely sensitivity, maximum false prediction rate, seizure occurrence period and seizure prediction horizon were used to assess and compare PSW with the analysis of phase synchronisation, based on the Hilbert transform (PSH) and a random predictor Poisson process. RESULTS: An obvious decrease was found upon phase synchronisation prior to visual detection of electroencephalograph seizure onset, which was consistent with the EEG mechanism in the ictal events. The results suggest that PSW is the most effective among the three prediction methods. CONCLUSIONS: The results confirm that the analysis of phase synchronisation based on the complex Gaussian wavelet transform can be used for seizure prediction. SIGNIFICANCE: Phase synchronisation analysis may be a useful algorithm for clinical application in epileptic prediction.

Increased expression of urokinase-type plasminogen activator receptor in the frontal cortex of patients with intractable frontal lobe epilepsy.

Urokinase-type plasminogen activator receptor (uPAR) is a glycosyl phosphatidylinositol-anchored protein involved in cell adhesion, proliferation, differentiation, migration, invasion, and tissue repair and remodeling. Our aim was to investigate uPAR expression in the frontal cortex of patients with intractable frontal lobe epilepsy and to explore the possible role of uPAR in intractable epilepsy. Tissue samples were obtained from the frontal cortex of 25 patients who had undergone surgery for intractable epilepsy and 15 histologically normal frontal cortex tissues from patients with orbital frontal lobe severe contusion (the control group). The frontal cortex expression of uPAR was studied by Western blot and immnohistochemistry. Double immunofluorescence was used to determine the expression of uPAR in astrocytes, microglia, and neurons. The normal frontal cortex uPAR protein level was shown to be low. In the brain tissue of patients with intractable epilepsy, the expression of uPAR protein increased dramatically. Based on the results of double immunofluorescence, many uPAR-positive cells are colocalized with the cell soma of NeuN-positive neurons, whereas only a few GFAP- and CD11b-positive cells colocalized with uPAR staining. These findings provide new information pertaining to the epileptogenesis of intractable epilepsy and suggest that increased expression of uPAR in human brain may be associated with human intractable epilepsy.

Low- and high-frequency electric cortical stimulation suppress the ferric chloride-induced seizures in rats.

The clinic treatment of epilepsy with epileptic foci overlapped with eloquent cortex is not satisfactory. In this study we investigated the direct effects of low- and high-frequency electric cortical stimulation (ECS) on ferric chloride-induced seizures in the experimental rats. Results showed that spontaneous seizures were observed in all rats during the EEG recording after the intracortical injection of ferric chloride solution into left sensorimotor cortex. One-hertz or 100-Hz ECS with 0.3 ms duration and 0.1 mA amplitude square pulses in 1h on the cortical lesioned area significantly decreased the number of seizures compared with that of the non-stimulation control group. The mean duration time of seizures in 1-Hz or 100-Hz groups was apparently shorter than that in the control group. In brief, this study showed that both low- and high-frequency ECS suppressed the seizures induced by ferric chloride in rats, indicating their potential treatment effects on epilepsy in clinic.