Effects of the "ICU Support" team meeting concept on patient-centered and staff-centered outcomes: study protocol for a randomized controlled multicenter study.

BACKGROUND: Providing optimal care for critically ill patients is an extremely important but also highly demanding task, both emotionally and physically. The "ICU Support" team meeting concept aims to support intensive care unit (ICU) teams by promoting interprofessional communication, peer support, and patient safety by providing a structure for daily team meetings. This protocol describes a study to explore the effectiveness of "ICU Support" for patient- and staff-centered outcomes. METHODS: ICU Support will be implemented at nine university hospitals located in Germany, following a two-arm randomized parallel group design with an intervention and a control condition and three data collection periods. In the intervention arm, leading ICU personnel (physicians and nurses) will be trained in ICU Support and implement the ICU Support elements into the daily work routine of their units upon completion of data collection period T0 (baseline). In the control arm, ICU Support will not be implemented until the completion of the data collection period T1 (1 month after study start). Until then, the regular daily schedule of the ICU teams will be maintained. The final data collection period (T2) will take place 4 months after the start of the study. Primary outcomes include the number of intensive care complications per patient during their ICU stay during T1 and the sick-related absence of ICU staff during T1. Secondary outcomes include, among others, the average severity of intensive care complications per patient and employee self-reported data regarding their teamwork and patient safety behaviors. DISCUSSION: The need for healthy and well-trained ICU staff is omnipresent; thus, structured and evidence-based interventions aimed at supporting ICU teams and facilitating patient safety are required. This multicenter study aims to explore the effectiveness of ICU Support for patient- and staff-centered outcomes. The insights derived from this study have the potential to significantly improve ICU patient safety, staff communication, and connectedness and decrease sickness-related expenses and social costs associated with high work demands among ICU staff. TRIAL REGISTRATION: German Clinical Trials Register DRKS00028642 . Registered on 4 April 2022.

Pain management after robot-assisted minimally invasive esophagectomy.

Background: Adequate pain control after open esophagectomy is associated with reduced complications, earlier recovery and higher patient satisfaction. While further developing surgical procedures like robot-assisted minimally invasive esophagectomy (RAMIE) it is relevant to adapt postoperative pain management. The primary question of this observational survey was whether one of the two standard treatments, thoracic epidural analgesia (TEA) or intravenous patient-controlled analgesia (PCA), is superior for pain control after RAMIE as the optimal pain management for these patients still remains unclear. Use of additional analgesics, changes in forced expiratory volume in 1 s (FEV1), postoperative complications and duration of intensive care and hospital stay were also analyzed. Methods: This prospective observational pilot study analyzed 50 patients undergoing RAMIE (postoperative PCA with piritramide or TEA using bupivacaine; each n = 25). Patient reported pain using the numeric rating scale score and differences in FEV1 using a micro spirometer were measured at postoperative day 1, 3 and 7. Additional data of secondary endpoints were collected from patient charts. Results: Key demographics, comorbidity, clinical and operative variables were equivalently distributed. Patients receiving TEA had lower pain scores and a longer-lasting pain relief. Moreover, TEA was an independent predictive variable for reduced length of hospital stay (HR -3.560 (95% CI: -6.838 to -0.282), p = 0.034). Conclusions: Although RAMIE leads to reduced surgical trauma, a less invasive pain therapy with PCA appears to be inferior compared to TEA in case of sufficient postoperative analgesia and length of hospital stay. According to the results of this observational pilot study analgesia with TEA provided better and longer-lasting pain relief compared to PCA. Further randomized controlled trials should be conducted to evaluate the optimal postoperative analgesic treatment for RAMIE.

Current hemoglobin thresholds in pediatric anesthesia - guidelines and studies.

PURPOSE OF REVIEW: The use of restrictive transfusion triggers to avoid unnecessary transfusions is one important pillar of Patient Blood Management (PBM). For the safe application of this principle in pediatric patients, anesthesiologists need evidence-based guidelines for hemoglobin (Hb) transfusions thresholds in this specially vulnerable age-group. RECENT FINDINGS: This review outlines recent prospective and observational studies examining transfusion thresholds in pediatrics. Recommendations to use transfusion triggers in the perioperative or intensive care setting are summarized. SUMMARY: Two high-quality studies confirmed that the use of restrictive transfusion triggers in preterm infants in the intensive care unit (ICU) is reasonable and feasible. Unfortunately, no recent prospective study could be found investigating intraoperative transfusion triggers. Some observational studies showed wide variability in Hb levels before transfusion, a tendency toward restrictive transfusion practices in preterm infants, and liberal transfusion practices in older infants. Although there are comprehensive and useful guidelines for clinical practice in pediatric transfusion, most of them do not cover the intraoperative period in particular because of a lack of high-quality studies. This lack of prospective randomized trials focusing on intraoperative transfusion management remains a major problem for the application of pediatric PBM.

Big data: Airway management at a university hospital over 16 years; a retrospective analysis.

PURPOSE: Little is known about the current practice of airway management in Germany and its development over the last decades. The present study was, therefore, designed to answer the following questions. Which airway management procedures have been performed over the last 16 years and how has the frequency of these procedures changed over time? Is there a relationship between patient characteristics or surgical specialisation and the type of airway management performed? METHODS: In the present study, we used our in-house data acquisition and accounting system to retrospectively analyse airway management data for all patients who underwent a surgical or medical procedure with anaesthesiological care at our tertiary care facility over the past 16 years. 340,748 airway management procedures were analysed by type of procedure, medical/surgical specialty, and type of device used. Logistic regression was used to identify trends over time. RESULTS: Oral intubation was the most common technique over 16 years (65.7%), followed by supraglottic airway devices (18.1%), nasal intubation (7.5%), mask ventilation (1.6%), tracheal cannula (1.3%), double lumen tube (0.7%), and jet ventilation (0.6%). On average, the odds ratio of using supraglottic airway devices increased by 17.0% per year (OR per year = 1.072, 95% CI = 1.071-1.088) while oral intubation rates decreased. In 2005, supraglottic airway devices were used in about 10% of all airway management procedures. Until 2020, this proportion steadily increased by 27%. Frequency of oral intubation on the other hand decreased and was about 75% in 2005 and 53% in 2020. Over time, second-generation supraglottic airway devices were used more frequently than first-generation supraglottic airway devices. While second-generation devices made up about 9% of all supraglottic airway devices in 2010, in 2020 they represented a proportion of 82%. The use of fibreoptic intubation increased over time in otorhinolaryngology and dental, oral, and maxillofacial surgery, but showed no significant trends over the entire 16-year period. CONCLUSION: Our data represent the first large-scale evaluation of airway management procedures over a long time. There was a significant upward trend in the use of supraglottic airway devices, with an increase in the use of second-generation masks while a decrease in oral intubations was observed.

Influence of intraoperative fluid replacement on ampicillin serum levels and surgical site infections.

BACKGROUND: Surgical site infections (SSI) occur despite antimicrobial prophylaxis and increase postoperative morbidity and mortality. This could be caused by an intraoperative decrease in antibiotic serum concentrations such as ampicillin after major abdominal surgery due to blood loss and fluid therapy, which possibly promotes SSI. This hypothesis was tested in the present study. METHODS: This pilot study was performed as a prospective observational trial between March 2018 and May 2019. Ampicillin/sulbactam was administered intravenously during anesthesia induction. Fluid replacement was guided based on hemodynamic variables, including analysis of pulse pressure variation. The primary outcome was ampicillin serum level (ASL), measured after administration and hourly within 4 hours. The incidence of SSI at hospital discharge was the secondary outcome. Linear mixed and logistic regression models were used for statistical analyses. RESULTS: After screening of 133 adult patients, 129 were enrolled, and 102 completed the study protocol. No correlation was found between the volume of intraoperative fluids and ASL, nor was any association found between ASL and SSI. Based on 5 SSI cases, SSI were associated with higher intraoperative fluid volume. ASL was sufficient to provide intraoperative coverage for all potential bacterial strains. CONCLUSION: Intraoperative fluid replacement had no effect on ASL up to 4 hours after ampicillin/sulbactam administration. SSI were within an acceptable range, indicating adequate antimicrobial prophylaxis, so intraoperative control of ASL does not seem necessary. In conclusion, contrary to our initial hypothesis, ASL is not influenced by volume turnover or blood loss during major surgery and therefore does not affect SSI.

Improving competence and safety in pain medicine: a practical clinical teaching strategy for students combining simulation and bedside teaching.

BACKGROUND: Pain is a devastating sensation and has to be treated immediately. Therefore, we developed a training program to improve the knowledge of medical students in the field of pain medicine. In the present study, the applicability and efficacy of this training program was tested. METHODS: Half of the students attended first a training with simulated patients (SP) followed by bedside teaching (Group 1). Group 2 performed the training programs in reverse order. The evaluation based on standardized questionnaires completed by students (self-assessment) and all students took part in two practical examinations after the learning interventions. RESULTS: This study included 35 students. The quality of the simulation was evaluated by the students with average grade 1.1 (1 = very good, 6 = very bad). The practical work on the ward with patients was rated with grade 1.4 of 6, the whole course with 1.1. Students of Group A were significantly better in the final examination (grade 1.7 vs. grade 2.2, p < 0.05). To rate the improvement of skills (self-assessment) we used a Likert Scale (1 = very certain, 5 = very uncertain). The following skills were similar in both groups and significantly better after the course: taking responsibility, expert knowledge, empathy, relationship building and communication. CONCLUSIONS: Training with simulated patients in combination with small-group teaching at the bedside with real patients achieves a dramatic increase in student competence. Students prefer learning from the simulation before bedside teaching and propose to include simulation into the curricular teaching of pain medicine.

Does the revised intubating laryngeal tube (ILTS-D2) perform better than the intubating laryngeal mask (Fastrach)? - a randomised simulation research study.

BACKGROUND: The intubating laryngeal tube (ILTS-D™) and the intubating laryngeal mask (Fastrach™) are devices that facilitate both extraglottic application and blind tracheal intubation. A revised model of the iLTS-D (for scientific reasons called ILTS-D2) has been designed but not yet evaluated. Therefore, we compared the ILTS-D2 with the established Fastrach under controlled conditions in a prospective randomised controlled simulation research study. METHODS: After ethical approval, we randomised 126 medical students into two groups. Each participant received either Fastrach or ILTS-D2 to perform five consecutive ventilation attempts in a manikin. The primary endpoint was the time to ventilation in the last attempt of using the devices as extraglottic devices. Secondary endpoints were the time to tracheal intubation and the success rates. RESULTS: There was no relevant difference between the two devices in the time to ventilation in the last of five attempts (Fastrach: median 14 s [IQR: 12-15]; ILTS-D2: median 13 s [IQR: 12-15], p = 0.592). Secondary endpoints showed a 2 s faster blind tracheal intubation using the Fastrach than using the ILTS-D2 (Fastrach: median 14 s [IQR: 13-17]; ILTS-D2: median 16 s [IQR: 15-20] p < 0.001). For both devices, the success rates were 100% in the last attempt. CONCLUSIONS: Concerning extraglottic airway management, we could not detect a relevant difference between the revised ILTS-D2 and the Fastrach under laboratory conditions. We advocate for an evaluation of the ILTS-D2 in randomised controlled clinical trials. TRIAL REGISTRATION: Identifier at clinicaltrials.gov: NCT03542747. May 31, 2018.

Impaired Cerebrovascular Autoregulation in Large Vessel Occlusive Stroke after Successful Mechanical Thrombectomy: A Prospective Cohort Study.

INTRODUCTION: Successful thrombectomy improves morbidity and mortality after stroke. The present prospective, observational cohort study investigated a potential correlation between the successful restoration of tissue perfusion by mechanical thrombectomy and intact cerebrovascular autoregulation (CA). OBJECTIVE: Status of CA in patients with large vessel occlusive stroke after thrombectomy. METHODS: After thrombectomy CA was measured using transcranial Doppler ultrasound. For this purpose a moving correlation index (Mxa) based on spontaneous arterial blood pressure fluctuations and corresponding cerebral blood flow velocity changes was calculated. CA impairment was defined by Mxa values more than .3. RESULTS: Twenty patients with an acute occlusion of the middle cerebral artery or distal internal carotid artery were included. A successful recanalization of the occluded vessel via interventional thrombectomy was achieved in 10 of these patients (successful recanalization group), while in 10 patients mechanical recanalization failed or could not be applied (no recanalization group). Mean Mxa at stroke side was .58 ± .21 Table 2a in patients with successful intervention. At the unaffected hemisphere Mxa was .50 ± .20 Table 2a in successful recanalization group and .45 ± .24 Table 2b in no recanalization group without statistically significant differences. Based on the previously defined Mxa cut off more than .3, CA impairment was observable in all successful recanalized patients and in 8 of 10 patients with unsuccessful interventional treatment. CONCLUSIONS: These results suggest that brain perfusion may be affected due to impaired CA even after successful mechanical thrombectomy. Therefore, a tight blood pressure management is of great importance in post-thrombectomy stroke treatment to avoid cerebral hypo- and hyperperfusion.

Impact of cardiopulmonary resuscitation on a cannot intubate, cannot oxygenate condition: a randomised crossover simulation research study of the interaction between two algorithms.

OBJECTIVES: During a 'cannot intubate, cannot oxygenate' situation, asphyxia can lead to cardiac arrest. In this stressful situation, two complex algorithms facilitate decision-making to save a patient's life: difficult airway management and cardiopulmonary resuscitation. However, the extent to which competition between the two algorithms causes conflicts in the execution of pivotal treatment remains unknown. Due to the rare incidence of this situation and the very low feasibility of such an evaluation in clinical reality, we decided to perform a randomised crossover simulation research study. We propose that even experienced healthcare providers delay cricothyrotomy, a lifesaving approach, due to concurrent cardiopulmonary resuscitation in a 'cannot intubate, cannot oxygenate' situation. DESIGN: Due to the rare incidence and dynamics of such a situation, we conducted a randomised crossover simulation research study. SETTING: We collected data in our institutional simulation centre between November 2016 and November 2017. PARTICIPANTS: We included 40 experienced staff anaesthesiologists at our tertiary university hospital centre. INTERVENTION: The participants treated two simulated patients, both requiring cricothyrotomy: one patient required cardiopulmonary resuscitation due to asphyxia, and one patient did not require cardiopulmonary resuscitation. Cardiopulmonary resuscitation was the intervention. Participants were evaluated by video records. PRIMARY OUTCOME MEASURES: The difference in 'time to ventilation through cricothyrotomy' between the two situations was the primary outcome measure. RESULTS: The results of 40 participants were analysed. No carry-over effects were detected in the crossover design. During cardiopulmonary resuscitation, the median time to ventilation was 22 s (IQR 3-40.5) longer than that without cardiopulmonary resuscitation (p=0.028), including the decision-making time. CONCLUSION: Cricothyrotomy, which is the most crucial treatment for cardiac arrest in a 'cannot intubate, cannot oxygenate' situation, was delayed by concurrent cardiopulmonary resuscitation. If cardiopulmonary resuscitation delays cricothyrotomy, it should be interrupted to first focus on cricothyrotomy.

Proteasome and Autophagy-Mediated Impairment of Late Long-Term Potentiation (l-LTP) after Traumatic Brain Injury in the Somatosensory Cortex of Mice.

Traumatic brain injury (TBI) can lead to impaired cognition and memory consolidation. The acute phase (24-48 h) after TBI is often characterized by neural dysfunction in the vicinity of the lesion, but also in remote areas like the contralateral hemisphere. Protein homeostasis is crucial for synaptic long-term plasticity including the protein degradation systems, proteasome and autophagy. Still, little is known about the acute effects of TBI on synaptic long-term plasticity and protein degradation. Thus, we investigated TBI in a controlled cortical impact (CCI) model in the motor and somatosensory cortex of mice ex vivo-in vitro. Late long-term potentiation (l-LTP) was induced by theta-burst stimulation in acute brain slices after survival times of 1-2 days. Protein levels for the plasticity related protein calcium/calmodulin-dependent protein kinase II (CaMKII) was quantified by Western blots, and the protein degradation activity by enzymatical assays. We observed missing maintenance of l-LTP in the ipsilateral hemisphere, however not in the contralateral hemisphere after TBI. Protein levels of CaMKII were not changed but, interestingly, the protein degradation revealed bidirectional changes with a reduced proteasome activity and an increased autophagic flux in the ipsilateral hemisphere. Finally, LTP recordings in the presence of pharmacologically modified protein degradation systems also led to an impaired synaptic plasticity: bath-applied MG132, a proteasome inhibitor, or rapamycin, an activator of autophagy, both administered during theta burst stimulation, blocked the induction of LTP. These data indicate that alterations in protein degradation pathways likely contribute to cognitive deficits in the acute phase after TBI, which could be interesting for future approaches towards neuroprotective treatments early after traumatic brain injury.

Plasminogen activator inhibitor-1 augments damage by impairing fibrinolysis after traumatic brain injury.

OBJECTIVE: Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma. METHODS: We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1-deficient animals. RESULTS: PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1-deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle. INTERPRETATION: This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667-680.

Is 'anxiety sensitivity' predictive of postoperative nausea and vomiting?: A prospective observational study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is an extremely distressing side effect for patients. Despite PONV prophylaxis guided by well established scoring systems, the incidence of PONV is still high. OBJECTIVE: The aim of the current study was to investigate the predictive value of anxiety sensitivity as an additional independent risk factor for PONV in patients with an increased risk of PONV. DESIGN: A noninterventional, observational study. SETTING: A tertiary care university hospital. PATIENTS: Patients with an increased risk of PONV (i.e. female, nonsmoking) undergoing elective surgery (general, gynaecological, urological, musculoskeletal or neurosurgical) under general anaesthesia. MAIN OUTCOME MEASURES: The number of patients with anxiety sensitivity assessed pre-operatively with the Anxiety Sensitivity Index-3 questionnaire, the number of patients experiencing PONV, predictive value of anxiety sensitivity compared with other established risk factors for PONV. RESULTS: Some 41.5% of the patients experienced PONV within the first 24 h after surgery. In these patients increased anxiety sensitivity (Anxiety Sensitivity Index-3 score higher than seven points) was associated with a five-fold increase in the odds ratio (OR) for PONV. From the regression model, the risk of PONV was increased by lack of PONV prophylaxis (OR, 3.68), the postoperative administration of opioids (OR, 3.60) and patient age (OR, 1.03), but laparoscopic surgery did not increase the risk. CONCLUSION: In addition to the well established risk factors, anxiety sensitivity can help to predict the risk of PONV. It seems justifiable to add psychological factors such as anxiety sensitivity to PONV risk-scores. PONV prophylaxis should be considered when anxiety sensitivity is high. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01875120.

PAI-1 but Not PAI-2 Gene Deficiency Attenuates Ischemic Brain Injury After Experimental Stroke.

After stroke, secondary brain damage is influenced by the extent of fibrin clot formation. This is counteracted by the endogenous fibrinolysis. Of major interest are the key players of the fibrinolytic plasminogen activator system including the urokinase plasminogen activator (uPA), the tissue-type plasminogen activator (tPA), and their endogenous inhibitors plasminogen activator inhibitor 1 (PAI-1) and PAI-2. The role of PAI-1 in brain injury is well established, whereas the importance of PAI-2 is unknown at present. The objectives of the present were twofold: first, to characterize the time-dependent cerebral mRNA expression of the plasminogen activator system (PAS) after brain ischemia and second, to investigate the impact of PAI-1 and PAI-2 on brain infarct volume using gene-deficient mice. Adult C57Bl/6J mice were subjected to unilateral transient middle cerebral artery occlusion (MCAO) followed by reperfusion for 3, 24, 72, or 120 h. Quantitative PCR revealed that brain mRNA expression levels of the PAS components, and particularly of PAI-1 (237-fold) and PAI-2 (19-fold), peaked at 24 h after stroke. Accordingly, PAI-1 plasma activity was strongly increased. Brain infarct volume in TTC (2,3,5-triphenyltetrazolium chloride)-stained brain sections was significantly smaller 24 h after MCAO in PAI-1-deficient mice (- 31%), but not in PAI-2-deficient mice (- 6%). Thus, endogenous upregulation of PAI-1, but not of PAI-2, might contribute to increased brain damage after acute ischemic stroke. The present study therefore shows that PAI-2 is induced by brain ischemia, but does not play an important or relevant role for secondary brain damage after brain injury.

Continuous electroencephalography in a mixed non-neurological intensive care population, an observational study.

PURPOSE: Continuous electroencephalography (cEEG) improves monitoring of the brain in unconscious patients, but implementation at ICU is difficult. The present investigation shows a way to introduce cEEG at an anesthesiological ICU and discusses the first experiences. MATERIALS AND METHODS: The study analyzed the feasibility of cEEG, assessed the interpretable cEEG time, importance of automatic seizure detection, the incidence of seizures, the predominant background EEG activity, incidence of delirium and mortality. RESULTS: Fifty-three cEEGs of 50 patients with a median interpretable length of 24 hours [IQR 20 to 42 hours] were recorded. One patient had status epilepticus, while 5 patients had non-convulsive seizures. Automated seizure detection recognized the status epilepticus and 3 of 10 non-convulsive seizures, however, detected 42 false positive seizures. Predominant background EEG activity was alpha (9%), theta (17%), delta (26%), burst-suppression (17%), and suppressed background activity (30%). EEG activity correlated neither with dosage of analgo-sedative drugs nor with incidence of delirium or mortality. CONCLUSION: Continuous electroencephalography recording is feasible and manageable. Automatic seizure detection was often false negative/positive; therefore, the interpretation of the cEEG should be supported by EEG-trained neurologists. Background EEG activity was not associated with outcome parameters, which suggests that background activity is a poor outcome predictor.

Noninvasive Hemodynamic Measurements During Neurosurgical Procedures in Sitting Position.

BACKGROUND: Neurosurgical procedures in sitting position need advanced cardiovascular monitoring. Transesophageal echocardiography (TEE) to measure cardiac output (CO)/cardiac index (CI) and stroke volume (SV), and invasive arterial blood pressure measurements for systolic (ABPsys), diastolic (ABPdiast) and mean arterial pressure (MAP) are established monitoring technologies for these kind of procedures. A noninvasive device for continuous monitoring of blood pressure and CO based on a modified Penaz technique (volume-clamp method) was introduced recently. In the present study the noninvasive blood pressure measurements were compared with invasive arterial blood pressure monitoring, and the noninvasive CO monitoring to TEE measurements. METHODS: Measurements of blood pressure and CO were performed in 35 patients before/after giving a fluid bolus and a change from supine to sitting position, start of surgery, and repositioning from sitting to supine at the end of surgery. Data pairs from the noninvasive device (Nexfin HD) versus arterial line measurements (ABPsys, ABPdiast, MAP) and versus TEE (CO, CI, SV) were compared using Bland-Altman analysis and percentage error. RESULTS: All parameters compared (CO, CI, SV, ABPsys, ABPdiast, MAP) showed a large bias and wide limits of agreement. Percentage error was above 30% for all parameters except ABPsys. CONCLUSION: The noninvasive device based on a modified Penaz technique cannot replace arterial blood pressure monitoring or TEE in anesthetized patients undergoing neurosurgery in sitting position.

Sequestosome 1 Deficiency Delays, but Does Not Prevent Brain Damage Formation Following Acute Brain Injury in Adult Mice.

Neuronal degeneration following traumatic brain injury (TBI) leads to intracellular accumulation of dysfunctional proteins and organelles. Autophagy may serve to facilitate degradation to overcome protein debris load and therefore be an important pro-survival factor. On the contrary, clearing may serve as pro-death factor by removal of essential or required proteins involved in pro-survival cascades. Sequestosome 1 (SQSTM1/p62) is a main regulator of the autophagic pathway that directs ubiquinated cargoes to autophagosomes for degradation. We show that SQSTM1 protein levels are suppressed 24 h and by trend 5 days after trauma. In line with these data the expression of Sqstm1 mRNA is reduced by 30% at day 3 after and stays depressed until day 5 after injury, indicating an impaired autophagy post controlled cortical impact (CCI). To determine the potential role of SQSTM1-dependent autophagy after TBI, mice lacking SQSTM1 (SQSTM1-KO) and littermates (WT) were subjected to CCI and brain lesion volume was determined 24 h and 5 days after insult. Lesion volume is 17% smaller at 24 h and immunoblotting reveals a reduction by trend of cell death marker αII-spectrin cleavage. But there is no effect on brain damage and cell death markers 5 days after trauma in SQSTM1-KO compared with WT. In line with these data neurofunctional testing does not reveal any differences. Additionally, gene expression of inflammatory (Tnf-α, iNos, Il-6, and Il-1ß) and protein degradation markers (Bag1 and Bag3) were quantified by real-time PCR. Protein levels of LC3, BAG1, and BAG3 were analyzed by immunoblotting. Real-time PCR reveals minor changes in inflammatory marker gene expression and reduced Bag3 mRNA levels 5 days after trauma. Immunoblotting of autophagy markers LC3, BAG1, and BAG3 does not show any difference between KO and WT 24 h and 5 days after TBI. In conclusion, genetic ablation of SQSTM1-dependent autophagy leads to a delay but shows no persistent effect on post-traumatic brain damage formation. SQSTM1 therefore only plays a minor role for secondary brain damage formation and autophagic clearance of debris after TBI.

Acute Cortical Transhemispheric Diaschisis after Unilateral Traumatic Brain Injury.

Focal neocortical brain injuries lead to functional alterations, which can spread beyond lesion-neighboring brain areas. The undamaged hemisphere and its associated disturbances after a unilateral lesion, so-called transhemispheric diaschisis, have been progressively disclosed over the last decades; they are strongly involved in the pathophysiology and, potentially, recovery of brain injuries. Understanding the temporal dynamics of these transhemispheric functional changes is crucial to decipher the role of the undamaged cortex in the processes of functional reorganization at different stages post-lesion. In this regard, little is known about the acute-subacute processes after 24-48 h in the brain hemisphere contralateral to injury. In the present study, we performed a controlled cortical impact to produce a unilateral traumatic brain injury (TBI) in the motor and somatosensory cortex of mice. In vitro extracellular multi-unit recordings from large neuronal populations, together with single-cell patch-clamp recordings in the cortical network contralateral to the lesion, revealed a strong, but transient, neuronal hyperactivity as early as 24-48 h post-TBI. This abnormal excitable state in the intact hemisphere was not accompanied by alterations in neuronal intrinsic properties, but it was associated with an impairment of the phasic gamma aminobutyric acid (GABA)ergic transmission and an increased expression of GABAA receptor subunits related to tonic inhibition exclusively in the contralateral hemisphere. These data unravel a series of early transhemispheric functional alterations after diffuse unilateral cortical injury, which may compensate and stabilize the disrupted brain functions. Therefore, our findings support the hypothesis that the undamaged hemisphere could play a significant role in early functional reorganization processes after a TBI.

Lack of NG2 exacerbates neurological outcome and modulates glial responses after traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of death and disability. The underlying pathophysiology is characterized by secondary processes including neuronal death and gliosis. To elucidate the role of the NG2 proteoglycan we investigated the response of NG2-knockout mice (NG2-KO) to TBI. Seven days after TBI behavioral analysis, brain damage volumetry and assessment of blood brain barrier integrity demonstrated an exacerbated response of NG2-KO compared to wild-type (WT) mice. Reactive astrocytes and expression of the reactive astrocyte and neurotoxicity marker Lcn2 (Lipocalin-2) were increased in the perilesional brain tissue of NG2-KO mice. In addition, microglia/macrophages with activated morphology were increased in number and mRNA expression of the M2 marker Arg1 (Arginase 1) was enhanced in NG2-KO mice. While TBI-induced expression of pro-inflammatory cytokine genes was unchanged between genotypes, PCR array screening revealed a marked TBI-induced up-regulation of the C-X-C motif chemokine 13 gene Cxcl13 in NG2-KO mice. CXCL13, known to attract immune cells to the inflamed brain, was expressed by activated perilesional microglia/macrophages seven days after TBI. Thirty days after TBI, NG2-KO mice still exhibited more pronounced neurological deficits than WT mice, up-regulation of Cxcl13, enhanced CD45+ leukocyte infiltration and a relative increase of activated Iba-1+/CD45+ microglia/macrophages. Our study demonstrates that lack of NG2 exacerbates the neurological outcome after TBI and associates with abnormal activation of astrocytes, microglia/macrophages and increased leukocyte recruitment to the injured brain. These findings suggest that NG2 may counteract neurological deficits and adverse glial responses in TBI.

Posttraumatic Propofol Neurotoxicity Is Mediated via the Pro-Brain-Derived Neurotrophic Factor-p75 Neurotrophin Receptor Pathway in Adult Mice.

OBJECTIVES: The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice. DESIGN: Randomized laboratory animal study. SETTING: University research laboratory. SUBJECTS: Adult C57BL/6N and nerve growth factor receptor-deficient mice. INTERVENTIONS: Sedation by IV propofol bolus application delayed after controlled cortical impact injury. MEASUREMENTS AND MAIN RESULTS: Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor. CONCLUSIONS: This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation with propofol and other compounds with GABA receptor activity are frequently used in patients with acute brain pathologies to facilitate sedation or surgical and interventional procedures.