Current state of neuroprotective therapy using antibiotics in human traumatic brain injury and animal models.

TBI is a leading cause of death and disability in young people and older adults worldwide. There is no gold standard treatment for TBI besides surgical interventions and symptomatic relief. Post-injury infections, such as lower respiratory tract and surgical site infections or meningitis are frequent complications following TBI. Whether the use of preventive and/or symptomatic antibiotic therapy improves patient mortality and outcome is an ongoing matter of debate. In contrast, results from animal models of TBI suggest translational perspectives and support the hypothesis that antibiotics, independent of their anti-microbial activity, alleviate secondary injury and improve neurological outcomes. These beneficial effects were largely attributed to the inhibition of neuroinflammation and neuronal cell death. In this review, we briefly outline current treatment options, including antibiotic therapy, for patients with TBI. We then summarize the therapeutic effects of the most commonly tested antibiotics in TBI animal models, highlight studies identifying molecular targets of antibiotics, and discuss similarities and differences in their mechanistic modes of action.

Single-Port daVinci Robot-Assisted Cervical Esophagectomy (SP-RACE) - How to Do It.

Minimally invasive esophagectomies, including robot-assisted procedures, have demonstrated superiority over traditional open surgery. Despite the prevalence of transhiatal and transthoracic approaches, cervical access is less common in minimally invasive esophageal surgery. Advancements in robotic systems, such as the daVinci Single-Port (SP), now enable controlled transcervical extrapleural mediastinoscopic access, potentially reducing pulmonary complications and extending surgical options to patients with comorbidities. The daVinci SP Robot-Assisted Cervical Esophagectomy (SP-RACE) employs a single port and laparoscopic approach, demonstrating feasibility with comparable lymphadenectomy and recurrent nerve palsy rates to transthoracic methods. This technique, performed for the first time in Europe at the University Hospital Mainz, involves a transcervical SP-phase that allows for effective mediastinal dissection and esophageal mobilization. Despite technical challenges due to limited space, robotic systems enhance controlled access and eliminate arm collision. The daVinci SP platform's advantages include improved triangulation, fewer interferences, and better control of instruments in confined spaces. This novel approach shows promise for patients with high esophageal tumors and those unsuitable for transthoracic surgery, warranting further investigation into its clinical utility and reproducibility.

Is noninvasive hemoglobin measurement suitable for children undergoing preoperative anesthesia consultation?

Preoperative anemia in children is a significant clinical concern requiring precise diagnosis. Although traditional blood sample collection is effective, it poses challenges because of children's aversion and technical difficulties. Therefore, this study explores the suitability of noninvasive hemoglobin measurements in children during preoperative anesthesia consultation. Noninvasive hemoglobin measurement (SpHb®; Masimo) in children aged ≤ 17 years was performed during preoperative anesthesia consultation and compared with laboratory hemoglobin (labHb) levels. SpHb was measured in 62 children (median age: 6 years, standard deviation [SD] ± 5.3) without adverse effects but was unsuccessful in one child. The bias, limits of agreement, and root mean square error between SpHb and labHb were 0.3, -2.26- +2.8, and 1.3 g/dl, respectively. LabHb demonstrated a significant regression relationship with R2 of 0.359. LabHb was associated with a negative effect on bias [- 0.443 (CI 95: - 0.591- - 0.153, P < 0.001)], i.e., SpHb tends to underestimate labHb for high labHb values. The retest reliability between two consecutive SpHb measurements was 0.727 (P < 0.001). Double measurement of SpHb, age, weight, sex, heart rate, and perfusion index had no significant effects on accuracy. Using SpHb, a specificity of 96.3% (95% confidence interval [CI 95]: 87.3%-99.5%) and a sensitivity of 57.1% (CI 95: 18.4%-90.1%) were observed. Based on adapted cut-off values for SpHb (age-dependent cut-off values plus 0.8 g/dl), a sensitivity of 100% (CI 95: 64.6%-100%) was achieved for the investigated study collective. SpHb measurement in children is a quick procedure. The accuracy of hemoglobin measurement is insufficient for the diagnosis of anemia. Thus, whether the calculated cut-off SpHb values of this study collective can be considered for anemia screening in pediatric patients undergoing preoperative anesthesia consultation should be confirmed. Trial registration number and date of registration: This prospective study was registered at ClinicalTrials.gov (NCT03586141).

Non-invasive assessment of Pulse Wave Transit Time (PWTT) is a poor predictor for intraoperative fluid responsiveness: a prospective observational trial (best-PWTT study).

BACKGROUND: Aim of this study is to test the predictive value of Pulse Wave Transit Time (PWTT) for fluid responsiveness in comparison to the established fluid responsiveness parameters pulse pressure (ΔPP) and corrected flow time (FTc) during major abdominal surgery. METHODS: Forty patients undergoing major abdominal surgery were enrolled with continuous monitoring of PWTT (LifeScope® Modell J BSM-9101 Nihon Kohden Europe GmbH, Rosbach, Germany) and stroke volume (Esophageal Doppler Monitoring CardioQ-ODM®, Deltex Medical Ltd, Chichester, UK). In case of hypovolemia (difference in pulse pressure [∆PP] ≥ 9%, corrected flow time [FTc] ≤ 350 ms) a fluid bolus of 7 ml/kg ideal body weight was administered. Receiver operating characteristics (ROC) curves and corresponding areas under the curve (AUCs) were used to compare different methods of determining PWTT. A Wilcoxon test was used to discriminate fluid responders (increase in stroke volume of ≥ 10%) from non-responders. The predictive value of PWTT for fluid responsiveness was compared by testing for differences between ROC curves of PWTT, ΔPP and FTc using the methods by DeLong. RESULTS: AUCs (area under the ROC-curve) to predict fluid responsiveness for PWTT-parameters were 0.61 (raw c finger Q), 0.61 (raw c finger R), 0.57 (raw c ear Q), 0.53 (raw c ear R), 0.54 (raw non-c finger Q), 0.52 (raw non-c finger R), 0.50 (raw non-c ear Q), 0.55 (raw non-c ear R), 0.63 (∆ c finger Q), 0.61 (∆ c finger R), 0.64 (∆ c ear Q), 0.66 (∆ c ear R), 0.59 (∆ non-c finger Q), 0.57 (∆ non-c finger R), 0.57 (∆ non-c ear Q), 0.61 (∆ non-c ear R) [raw measurements vs. ∆ = respiratory variation; c = corrected measurements according to Bazett's formula vs. non-c = uncorrected measurements; Q vs. R = start of PWTT-measurements with Q- or R-wave in ECG; finger vs. ear = pulse oximetry probe location]. Hence, the highest AUC to predict fluid responsiveness by PWTT was achieved by calculating its respiratory variation (∆PWTT), with a pulse oximeter attached to the earlobe, using the R-wave in ECG, and correction by Bazett's formula (AUC best-PWTT 0.66, 95% CI 0.54-0.79). ∆PWTT was sufficient to discriminate fluid responders from non-responders (p = 0.029). No difference in predicting fluid responsiveness was found between best-PWTT and ∆PP (AUC 0.65, 95% CI 0.51-0.79; p = 0.88), or best-PWTT and FTc (AUC 0.62, 95% CI 0.49-0.75; p = 0.68). CONCLUSION: ΔPWTT shows poor ability to predict fluid responsiveness intraoperatively. Moreover, established alternatives ΔPP and FTc did not perform better. TRIAL REGISTRATION: Prior to enrolement on clinicaltrials.gov (NC T03280953; date of registration 13/09/2017).

Intraoperative transfusion practice in burned children in a university hospital over four years: a retrospective analysis.

BACKGROUND: Patient blood management programs should be applied to the pediatric population, but little is known about the current transfusion practice of pediatric burn injury patients. This retrospective study was performed to evaluate the practice of red blood cell (RBC) transfusion in children with burn injury, their predictive factors, and adherence to the German transfusion guideline. METHODS: We reviewed the RBC transfusion practice of all children younger than 8 years with burn injury who were operated during a four-year period in a German university medical center. We analyzed the data associated with transfusion and guideline conformity of transfusion triggers for RBCs from the beginning to the end of hospital stay using logistic regression. RESULTS: During the four-year period, 138 children (median age 21 months, minimum-maximum 9-101 months) with burn injury needed surgery, 31 children were transfused with RBCs. During their hospital stay, the median hemoglobin concentrations (Hb) of transfused and non-transfused children were 8 g/dL (6.3-11.3 g/dL) and 10.7 (7-13.8 g/dL), respectively. Total body surface area burned (TBSA) (OR = 1.17 per % TBSA, 95% CI = [1.05; 1.30], p = 0.0056), length of surgery (OR = 1.016 per minute, 95% CI = [1.003; 1.028], p = 0.0150), and Hb (OR = 0.48 per 1 g/dl in Hb, 95% CI = [0.24; 0.95], p = 0.0343) were associated with transfusion while other factors (age, gender, ASA, and catecholamines) did not show notable association. Length of stay was mainly influenced by TSBA (+ 1.38 days per %, p <  0.0001), age (+ 0.21 days per month, p = 0.0206), and administering of catecholamines (+ 14.3 days, p = 0.0118), but not by RBC transfusion. The decision to transfuse was in 23% too restrictive and in 74% too liberal according to the German guidelines. CONCLUSIONS: Amount of TBSA, length of surgery, and Hb influenced the RBC transfusion rate in burned children. However, age and length of stay were not affected by transfusion of RBCs. In clinical practice of burned children, physicians follow a more liberal transfusion strategy than the proposed in guidelines.

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.

Depletion of regulatory T cells increases T cell brain infiltration, reactive astrogliosis, and interferon-γ gene expression in acute experimental traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. T cells were shown to infiltrate the brain during the first days after injury and to exacerbate tissue damage. The objective of this study was to investigate the hitherto unresolved role of immunosuppressive, regulatory T cells (Tregs) in experimental TBI. METHODS: "Depletion of regulatory T cell" (DEREG) and wild type (WT) C57Bl/6 mice, treated with diphtheria toxin (DTx) to deplete Tregs or to serve as control, were subjected to the controlled cortical impact (CCI) model of TBI. Neurological and motor deficits were examined until 5 days post-injury (dpi). At the 5 dpi endpoint, (immuno-) histological, protein, and gene expression analyses were carried out to evaluate the consequences of Tregs depletion. Comparison of parametric or non-parametric data between two groups was done using Student's t test or the Mann-Whitney U test. For multiple comparisons, p values were calculated by one-way or two-way ANOVA followed by specific post hoc tests. RESULTS: The overall neurological outcome at 5 dpi was not different between DEREG and WT mice but more severe motor deficits occurred transiently at 1 dpi in DEREG mice. DEREG and WT mice did not differ in the extent of brain damage, blood-brain barrier (BBB) disruption, or neuronal excitotoxicity, as examined by lesion volumetry, immunoglobulin G (IgG) extravasation, or calpain-generated αII-spectrin breakdown products (SBDPs), respectively. In contrast, increased protein levels of glial fibrillary acidic protein (GFAP) and GFAP+ astrocytes in the ipsilesional brain tissue indicated exaggerated reactive astrogliosis in DEREG mice. T cell counts following anti-CD3 immunohistochemistry and gene expression analyses of Cd247 (CD3 subunit zeta) and Cd8a (CD8a) further indicated an increased number of T cells infiltrating the brain injury sites of DEREG mice compared to WT. These changes coincided with increased gene expression of pro-inflammatory interferon-γ (Ifng) in DEREG mice compared to WT in the injured brain. CONCLUSIONS: The results show that the depletion of Tregs attenuates T cell brain infiltration, reactive astrogliosis, interferon-γ gene expression, and transiently motor deficits in murine acute traumatic brain injury.

Correction to: Depletion of regulatory T cells increases T cell brain infiltration, reactive astrogliosis, and interferon-γ gene expression in acute experimental traumatic brain injury.

Following publication of the original article [1], the authors opted to correct the following mistakes. According to the title and our results, the conclusions in the abstract and at the end of the discussion the term "attenuates" must be corrected to read as "increases".

Analgesic treatment limits surrogate parameters for early stress and pain response after experimental subarachnoid hemorrhage.

BACKGROUND: In animal research, authorities require a classification of anticipated pain levels and a perioperative analgesia protocol prior to approval of the experiments. However, data on this topic is rare and so is the reported use of analgesics. We determined surrogate parameters of pain and general well-being after subarachnoid hemorrhage (SAH), as well as the potential for improvement by different systemic analgesia paradigms. Brain injury was induced by filament perforation to mimic SAH. Sham-operated mice were included as surgical control groups with either neck or no-neck preparation. Mice with controlled cortical impact (CCI) injury were included as a control group with traumatic brain injury (TBI), but without neck preparation. Mice were randomized to buprenorphine, carprofen, meloxicam, or vehicle treatment. 24 h after SAH, CCI or sham surgery, pain and stress levels were assessed with a visual assessment score and the amount of food intake was recorded. RESULTS: Neck preparation, which is required to expose the surgical field for SAH induction, already increased pain/stress levels and sham surgeries for both CCI and SAH reduced food intake. Pain/stress levels were higher and food intake was lower after SAH compared with CCI. Pain/stress levels after CCI without analgesic treatment were similar to levels after SAH sham surgery. Pain treatment with buprenorphine was effective to reduce pain after SAH, whereas lower pain/stress intensity levels after CCI were not improved. CONCLUSION: This study emphasizes the importance of pain and stress assessment after surgeries and the efficacy of buprenorphine to improve pain and comfort levels after experimental SAH.

Favour the best in case of emergency cricothyroidotomy-a randomized cross-over trial on manikin focused training and simulation of common devices.

Background: Performing an emergency cricothyroidotomy (EC) is extremely challenging, the devices used should be easy to handle and the selected technique reliable. However, there is still an ongoing debate concerning the most superior technique. Methods: Three different techniques were compared using a standardized, simulated scenario regarding handling, performing, training and decision making: The scalpel-bougie technique (SBT), the surgical anatomical preparation technique (SAPT) and the Seldinger technique (ST). First, anaesthesia residents and trainees, paramedics and medical students (each group n = 50) performed a cricothyroidotomy randomly assigned with each of the three devices on a simulator manikin. The time needed for successful cricothyroidotomy was the primary endpoint. Secondary endpoints included first-attempt success rate, number of attempts and user-satisfaction. The second part of the study investigated the impact of prior hands-on training on both material selection for EC and on time to decision-making in a simulated "cannot intubate cannot ventilate" situation. Results: The simulated scenario revealed that SBT and SAPT were significantly faster than percutaneous EC with ST (p < 0.0001). Success rate was 100% for the first attempt with SBT and SAPT. Significant differences were found with regard to user-satisfaction between individual techniques (p < 0.0001). In terms of user-friendliness, SBT was predominantly assessed as easy (87%). Prior training had a large impact regarding choice of devises (p < 0.05), and time to decision making (p = 0.05; 180 s vs. 233 s). Conclusion: This study supports the use of a surgical technique for EC and also a regular training to create familiarity with the materials and the process itself.The trial was registered before study start on 11.11.2018 at ClinicalTrials.gov (NCT: 2018-13819) with Nicole Didion as the principal investigator.

A novel non-invasive nociceptive monitoring approach fit for intracerebral surgery: a retrospective analysis.

Background: Measuring depth of anesthesia during intracerebral surgery is an important task to guarantee patient safety, especially while the patient is fixated in a Mayfield-clamp. Processed electro-encephalography measurements have been established to monitor deep sedation. However, visualizing nociception has not been possible until recently and has not been evaluated for the neurosurgical setting. In this single-center, retrospective observational analysis, we routinely collected the nociceptive data via a nociception level monitor (NOL®) of 40 patients undergoing intracerebral tumor resection and aimed to determine if this monitoring technique is feasible and delivers relevant values to potentially base therapeutic decisions on. Methods: Forty patients (age 56 ± 18 years) received total intravenous anesthesia and were non-invasively connected to the NOL® via a finger clip as well as a bispectral-index monitoring (BIS®) to confirm deep sedation. The measured nociception levels were retrospectively evaluated at specific time points of nociceptive stress (intubation, Mayfield-positioning, incision, extubation) and compared to standard vital signs. Results: Nociceptive measurements were successfully performed in 35 patients. The largest increase in nociceptive stimulation occurred during intubation (NOL® 40 ± 16) followed by Mayfield positioning (NOL® 39 ± 16) and incision (NOL® 26 ± 12). Correlation with BIS measurements confirmed a sufficiently deep sedation during all analyzed time points (BIS 45 ± 13). Overall, patients showed an intraoperative NOL® score of 10 or less in 56% of total intervention time. Conclusions: Nociceptive monitoring using the NOL® system during intracerebral surgery is feasible and might yield helpful information to support therapeutic decisions. This could help to reduce hyperanalgesia, facilitating shorter emergence periods and less postoperative complications. Prospective clinical studies are needed to further examine the potential benefits of this monitoring approach in a neurosurgical context. Trial registration: German trial registry, registration number DRKS00029120.

Evaluation of dynamic cerebrovascular autoregulation during liver transplantation.

BACKGROUND: Cerebrovascular autoregulation in patients with acute and chronic liver failure is often impaired, yet an intact autoregulation is essential for the demand-driven supply of oxygenated blood to the brain. It is unclear, whether there is a connection between cerebrovascular autoregulation during liver transplantation (LTX) and the underlying disease, and if perioperative anesthesiologic consequences can result from this. METHODS: In this prospective observational pilot study, data of twenty patients (35% female) undergoing LTX were analyzed. Cerebral blood velocity was measured using transcranial doppler sonography and was correlated with arterial blood pressure. The integrity of dynamic cerebrovascular autoregulation (dCA) was evaluated in the frequency domain through transfer function analysis (TFA). Standard clinical parameters were recorded. Mixed one-way ANOVA and generalized estimating equations were fitted to data involving repeated measurements on the same patient. For all other correlation analyses, Spearman's rank correlation coefficient (Spearman's-Rho) was used. RESULTS: Indications of impaired dCA are seen in frequency domain during different phases of LTX. No correlation was found between various parameter of dCA and primary disease, delirium, laboratory values, length of ICU or hospital stay, mortality or surgical technique. CONCLUSIONS: Although in most cases the dCA has been impaired during LTX, the heterogeneity of the underlying diseases seems to be too diverse to draw valid conclusions from this observational pilot study.

Analysis of the Effects of Epidural Anesthesia on the Nociception Level Index (NOL®) during Abdominal Surgery.

Background: The NOL® system (PMD-200™ Nociception Level Monitor; Medasense Ltd., Ramat Gan, Israel) is used for the real-time detection of physiological nociception in anesthetized patients by assessing the parameters indicative of sympathetic activity, such as photoplethysmography, skin conductance, peripheral temperature, and accelerometry, which are quantified into the NOL®-Index. This index is more sensitive than traditional clinical parameters in estimating pain and stress responses. While its effectiveness in general anesthesia is well documented, its efficacy in epidural anesthesia needs further investigation. Methods: This retrospective study analyzed NOL®-Index dynamics compared to conventional parameters after epidural administration of bupivacaine. Following ethics committee approval, 119 NOL® measurements were retrospectively analyzed after thoracic epidural catheter administration in 40 patients undergoing abdominal and urological surgery. The NOL-Index® was assessed at 0, 1, 3, and 5 min post application and compared to heart rate, blood pressure, and bispectral index dynamics. Results: This study showed a significant decrease in the NOL®-Index post-local-anesthetic administration with better sensitivity than classical clinical parameters (0 min = 38 ± 11; 1 min = 22 ± 13*; 3 min = 17 ± 11*; 5 min = 12 ± 10*). Higher doses of local anesthetics led to a significant, dose-dependent decrease in NOL®-Index (low dose, 5 min = 15 ± 10*; high dose, 5 min = 8 ± 8*). Conclusions: This study is the first to demonstrate the effectiveness of the NOL®-Index in measuring nociceptive effects following epidural administration, highlighting its potential superiority over conventional parameters and its sensitivity to dose variations.

Changes of pulse wave transit time after haemodynamic manoeuvres in healthy adults: a prospective randomised observational trial (PWTT volunteer study).

Background: Pulse wave transit time (PWTT) shows promise for monitoring intravascular fluid status intraoperatively. Presently, it is unknown how PWTT mirrors haemodynamic variables representing preload, inotropy, or afterload. Methods: PWTT was measured continuously in 24 adult volunteers. Stroke volume was assessed by transthoracic echocardiography. Volunteers underwent four randomly assigned manoeuvres: 'Stand-up' (decrease in preload), passive leg raise (increase in preload), a 'step-test' (adrenergic stimulation), and a 'Valsalva manoeuvre' (increase in intrathoracic pressure). Haemodynamic measurements were performed before and 1 and 5 min after completion of each manoeuvre. Correlations between PWTT and stroke volume were analysed using the Pearson correlation coefficient. Results: 'Stand-up' caused an immediate increase in PWTT (mean change +55.9 ms, P-value <0.0001, 95% confidence interval 46.0-65.7) along with an increase in mean arterial pressure and heart rate and a drop in stroke volume (P-values <0.0001). Passive leg raise caused an immediate drop in PWTT (mean change -15.4 ms, P-value=0.0024, 95% confidence interval -25.2 to -5.5) along with a decrease in mean arterial pressure (P-value=0.0052) and an increase in stroke volume (P-value=0.001). After 1 min, a 'step-test' caused no significant change in PWTT measurements (P-value=0.5716) but an increase in mean arterial pressure and heart rate (P-values <0.0001), without changes in stroke volume (P-value=0.1770). After 5 min, however, PWTT had increased significantly (P-value <0.0001). Measurements after the Valsalva manoeuvre caused heterogeneous results. Conclusion: Noninvasive assessment of PWTT shows promise to register immediate preload changes in healthy adults. The clinical usefulness of PWTT may be hampered by late changes because of reasons different from fluid shifts. Clinical trial registration: German clinical trial register (DRKS, ID: DRKS00031978, https://www.drks.de/DRKS00031978).

A multidisciplinary pulmonary embolism response team (PERT): first experience from a single center in Germany.

BACKGROUND: Over the last few years, the concept of multidisciplinary pulmonary embolism response teams (PERTs) has emerged to encounter the increasing variety and complexity in managing acute pulmonary embolism (PE). PURPOSE: To investigate PERT's composition and added clinical value in a university center in Germany. METHODS: Over 4 years (01/2019-11/2022), patients with confirmed PE were enrolled in a prospective single-center cohort study (PERT Mainz). We investigated the composition of PERT and compared, after propensity score matching, patients with acute PE before and after the initiation of PERT at our Medical University Centre. The primary outcome was in-hospital PE-related mortality. RESULTS: From 2019 to 2022, 88 patients with acute PE with a PERT decision were registered. Of those, 13 (14.8%) patients died during the in-hospital stay. Patients evaluated by a PERT had a median age of 68; 48.9% were females, and 21.7% suffered from malignancy. Right ventricular dysfunction was present in 76.1% of all patients. In total, 42.0% were classified as intermediate-high-risk PE and 11.4% as high-risk PE. First PERT contact mainly originated from emergency departments (33.3%) and intensive care units (30.0%), followed by chest pain units (21.3%) and regular wards (12.0%). The participation rate of medical specialties demonstrated that cardiologists (100%) or cardiac/vascular surgeons (98.6%) were included in almost all PERT consultations, followed by radiologists (95.9%) and anesthesiologists (87.8%). Compared to the PERT era, more patients in the pre-PERT era were classified as simplified pulmonary embolism severity index (sPESI) ≥ 1 (78.4% vs 71.6%) and as high-risk PE according to ESC 2019 guidelines (18.2% vs. 11.4%). In the pre-PERT era, low- and intermediate-low patients with PE received more frequently advanced reperfusion therapies such as systemic thrombolysis or surgical embolectomy compared to the PERT era (10.7% vs. 2.5%). Patients in the pre-PERT were found to have a considerably higher all-cause mortality and PE-related mortality rate (31.8% vs. 14.8%) compared to patients in the PERT era (22.7% vs. 13.6%). After propensity matching (1:1) by including parameters as age, sex, sPESI, and ESC risk classes, univariate regression analyses demonstrated that the PE management based on a PERT decision was associated with lower risk of all-cause mortality (OR, 0.37 [95%CI 0.18-0.77]; p = 0.009). For PE-related mortality, a tendency for reduction was observed (OR, 0.54 [95%CI 0.24-1.18]; p = 0.121). CONCLUSION: PERT implementation was associated with a lower risk of all-cause mortality rate in patients with acute PE. Large prospective studies are needed further to explore the impact of PERTs on clinical outcomes.

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.

AT2 activation does not influence brain damage in the early phase after experimental traumatic brain injury in male mice.

Antagonism of the angiotensin II type 1 receptor (AT1) improves neurological function and reduces brain damage after experimental traumatic brain injury (TBI), which may be partly a result of enhanced indirect angiotensin II type 2 receptor (AT2) stimulation. AT2 stimulation was demonstrated to be neuroprotective via anti-inflammatory, vasodilatory, and neuroregenerative mechanisms in experimental cerebral pathology models. We recently demonstrated an upregulation of AT2 after TBI suggesting a protective mechanism. The present study investigated the effect of post-traumatic (5 days after TBI) AT2 activation via high and low doses of a selective AT2 agonist, compound 21 (C21), compared to vehicle-treated controls. No differences in the extent of the TBI-induced lesions were found between both doses of C21 and the controls. We then tested AT2-knockdown animals for secondary brain damage after experimental TBI. Lesion volume and neurological outcomes in AT2-deficient mice were similar to those in wild-type control mice at both 24 h and 5 days post-trauma. Thus, in contrast to AT1 antagonism, AT2 modulation does not influence the initial pathophysiological mechanisms of TBI in the first 5 days after the insult, indicating that AT2 plays only a minor role in the early phase following trauma-induced brain damage.

Anaesthesia protocol evaluation of the videolaryngoscopy with the McGrath MAC and direct laryngoscopy for tracheal intubation in 1000 patients undergoing rapid sequence induction: the randomised multicentre LARA trial study protocol.

INTRODUCTION: Rapid sequence induction of anaesthesia is indicated in patients with an increased risk of pulmonary aspiration. The main objective of the technique is to reduce the critical time period between loss of airway protective reflexes and rapid inflation of the cuff of the endotracheal tube to minimise the chance of aspiration of gastric contents. The COVID-19 pandemic has reinforced the importance of first-pass intubation success to ensure patient and healthcare worker safety. The aim of this study is to compare the first-pass intubation success rate (FPS) using the videolaryngoscopy compared with conventional direct laryngoscopy in surgical patients with a high risk of pulmonary aspiration. METHODS AND ANALYSIS: The LARA trial is a multicentre, patient-blinded, randomised controlled trial. Consecutive patients requiring tracheal intubation are randomly allocated to either the McGrath MAC videolaryngoscope or direct laryngoscopy using the Macintosh laryngoscope. The expected rate of FPS is 92% in the McGrath group and 82% in the Macintosh group. Each group must include a total of 500 patients to achieve 90% power for detecting a difference at the 5% significance level. Successful intubation with the FPS is the primary endpoint. The secondary endpoints are the time to intubation, the number of intubation attempts, the necessity of airway management alternatives, the visualisation of the glottis using the Cormack and Lehane Score and the Percentage Of Glottic Opening Score and definite adverse events. ETHICS AND DISSEMINATION: The project is approved by the local ethics committee of the Medical Association of the Rhineland Palatine state (registration number: 2020-15502) and medical ethics committee of the University of Freiburg (registration number: 21-1303). The results of this study will be made available in form of manuscripts for publication and presentations at national and international meetings. TRIAL REGISTRATION: NCT04794764.

Deficiency of Plasminogen Activator Inhibitor Type 2 Limits Brain Edema Formation after Traumatic Brain Injury.

Plasminogen activator inhibitor-2 (PAI-2/SerpinB2) inhibits extracellular urokinase plasminogen activator (uPA). Under physiological conditions, PAI-2 is expressed at low levels but is rapidly induced by inflammatory triggers. It is a negative regulator of fibrinolysis and serves to stabilize clots. In the present study, PAI-2 expression is upregulated 25-fold in pericontusional brain tissue at 6 h after traumatic brain injury (TBI), with a maximum increase of 87-fold at 12 h. To investigate a potentially detrimental influence of PAI-2 on secondary post-traumatic processes, male PAI-2-deficient (PAI-2-KO) and wild-type mice (WT) were subjected to TBI by controlled cortical impact injury. Brain lesion volume and cerebral inflammation were not different. Total brain volume was significantly smaller in PAI-2-KO, indicating reduced brain swelling. The brain water content at 24 h post-insult was significantly smaller in PAI-2-KO mice. Markers of vasogenic brain edema showed no difference in blood-brain barrier integrity and expression of blood-brain barrier proteins (claudin-5, zonula occludens-1). In contrast to plasminogen activator inhibitor-1 (PAI-1), PAI-2 plays a limited role for brain lesion formation and does not influence blood-brain barrier integrity. PAI-2 contributes to brain edema formation and could therefore be a promising new target to treat post-traumatic brain edema.

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.