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Anne Kuebart,1,* Verena Wollborn,1,* Ragnar Huhn,1 Henning Hermanns,2 Robert Werdehausen,3 Timo Brandenburger1 1Department of Anesthesiology, University Hospital Düsseldorf, Medical Faculty, Düsseldorf 40225, Germany; 2Department of Anesthesiology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; 3Department of Anesthesiology and Intensive Care, University of Leipzig, Medical Faculty, Leipzig 04103, Germany*These authors contributed equally to this workCorrespondence: Timo BrandenburgerDepartment of Anesthesiology, University Hospital Düsseldorf, Moorenstr. 5, Düsseldorf 40225, GermanyEmail timo.brandenburger@med.uni-duesseldorf.deRobert WerdehausenDepartment of Anesthesiology and Intensive Care, University of Leipzig, Medical Faculty, Leipzig 04103, GermanyEmail robert.werdehausen@medizin.uni-leipzig.deBackground: Alterations of the expression of microRNAs (miRNAs) in chronic pain models seem to play a crucial role in the development of neuropathic pain, with microRNA-1 (miR-1) being of particular interest. Recently, we were able to show that decreased miR-1 levels were associated with increased expression of brain-derived neurotrophic factor (BDNF) and Connexin 43 (Cx43). We hypothesized that miR-1 mimetic nucleotides could alleviate neuropathic pain caused by chronic constriction injury in rats.Methods: MiR-1 mimetic nucleotides were evaluated for effectiveness, functionality, and intracellular stability by transfecting human glioblastoma cells (U-87 MG). In vivo transfection with miR-1 mimics and corresponding scrambled miRNAs serving as control was performed by repetitive injection (days 0, 3, and 7) into the sciatic nerve following chronic constriction injury (CCI) in rats. Quantitative PCR was used to measure miR-1 content. Cx43 expression was determined by Western blot analysis. Effects on neuropathic pain were assessed by detecting paw withdrawal thresholds using an automated filament application.Results: Transfection of miR-1 mimics was confirmed in U-87 MG cells, with miR-1 content being increased significantly after 48 h and after 96 h (p< 0.05). Effective downregulation of Cx43 expression was observed 48 and 96 h after transfection (− 44 ± 0.07% and − 40 ± 0.11%; p< 0.05). In vivo, repetitive transfection with miR-1 mimetic nucleotides led to a 17.9-fold (± 14.2) increase of miR-1 in the sciatic nerve. However, the protein expression of Cx43 in sciatic nerves as well as paw withdrawal thresholds for mechanical stimulation was not significantly increased 10 days after chronic constriction injury.Conclusion: While transfection with miR-1 mimics effective reduces Cx43 expression in vitro and restores miR-1 after CCI, we did neither observe altered levels of Cx43 protein level in nerves nor a beneficial effect on mechanical allodynia in vivo, most likely caused by insufficient Cx43 suppression.Keywords: chronic pain, neuropathic pain, microRNAs, peripheral nerve

Background and Purpose: The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV 1.7 mutation in vitro.Experimental Approach: Human wild-type and L858F-mutated NaV 1.7 channels were expressed in HEK293A cells. Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties.Key Results: While the concentration-dependent tonic block of peak currents by mexiletine was similar in wild-type and L858F channels, phasic block was more pronounced in cells transfected with the L858F mutation. Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858F-mutated channels towards wild-type values and the voltage-dependence of steady-state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents.Conclusion and Implications: Mexiletine has a normalizing effect on the pathological gating properties of the L858F gain-of-function mutation in NaV 1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders. [ABSTRACT FROM AUTHOR]

Background and Purpose The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L858 F primary erythromelalgia NaV1.7 mutation in vitro. Experimental Approach Human wild-type and L858 F-mutated NaV1.7 channels were expressed in HEK293A cells. Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties. Key Results While the concentration-dependent tonic block of peak currents by mexiletine was similar in wild-type and L858 F channels, phasic block was more pronounced in cells transfected with the L858 F mutation. Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858 F-mutated channels towards wild-type values and the voltage-dependence of steady-state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents. Conclusion and Implications Mexiletine has a normalizing effect on the pathological gating properties of the L858 F gain-of-function mutation in NaV1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders. [ABSTRACT FROM AUTHOR]

Background: Lidocaine exerts antinociceptive effects when applied systemically. The mechanisms are not fully understood but glycinergic mechanisms might be involved. The synaptic glycine concentration is controlled by glycine transporters. Whereas neurons express two types of glycine transporters, astrocytes specifically express glycine transporter 1 (GlyT1). This study focuses on effects of lidocaine and its major metabolites on GlyT1 function.Methods: The effects of lidocaine and its metabolites monoethylglycinexylidide (MEGX), glycinexylidide, and N-ethylglycine on GlyT1 function were investigated in uptake experiments with [¹⁴C]-labeled glycine in primary rat astrocytes. Furthermore, the effect of lidocaine and its metabolites on glycine-induced currents were investigated in GlyT1-expressing Xenopus laevis oocytes.Results: Lidocaine reduced glycine uptake only at toxic concentrations. The metabolites MEGX, glycinexylidide, and N-ethylglycine, however, significantly reduced glycine uptake (P < 0.05). Inhibition of glycine uptake by a combination of lidocaine with its metabolites at a clinically relevant concentration was diminished with increasing extracellular glycine concentrations. Detailed analysis revealed that MEGX inhibits GlyT1 function (P < 0.05), whereas N-ethylglycine was identified as an alternative GlyT1 substrate (EC₅₀ = 55 μM).Conclusions: Although lidocaine does not function directly on GlyT1, its metabolites MEGX and N-ethylglycine [corrected] were shown to inhibit GlyT1-mediated glycine uptake by at least two different mechanisms. Whereas N-ethylglycine [corrected] was demonstrated to be an alternative GlyT1 substrate, MEGX was shown to inhibit GlyT1 activity in both primary astrocytes and in GlyT1-expressing Xenopuslaevis oocytes at clinically relevant concentrations. These findings provide new insights into the possible mechanisms for the antinociceptive effect of systemic lidocaine. [ABSTRACT FROM AUTHOR]

Background: The significance of computed tomography (CT)-based volume measurement of the inferior vena cava (IVC) in the treatment and prognosis of trauma patients is not yet fully understood. The conflicting results that have been reported may be attributable to differences in injury severity and the use of different measurement methods, including IVC index and volumetry. The purpose of this study was to determine the relationship between IVC volume and red blood cell (RBC) transfusion and mortality in intubated trauma patients who were stable enough for initial CT imaging., Methods: A retrospective analysis was conducted on all consecutive trauma patients who underwent emergency tracheal intubation and mechanical ventilation before initial whole-body CT imaging at a level-1 trauma center over a 12-year period (2008-2019). The IVC volume was determined on initial trauma CT and included in multivariable models with demographic and diagnostic data. Associations of overall RBC transfusion, massive transfusion, 24-h mortality, and 30-day mortality were assessed using logistic regression analyses and Cox proportional hazard models., Results: A total of 438 patients (75.3% male) with a median age of 50 years, and a median injury severity score (ISS) of 26 points were included in the analysis. Most of the patients (97.5%) had suffered from blunt trauma mechanisms. Median IVC volume was 36.25 cm 3 , and RBC transfusion and massive transfusion were performed in 197 and 90 patients, respectively. The 24-h and 30-day mortality rates were 7.3% and 23.3%, respectively. VCI volume was found to be independently associated with the necessity of RBC transfusion and 24-h mortality (OR 0.98, 95% CI 0.96-0.99, p = 0.01 and HR 0.96, 95% CI 0.93-0.99, p = 0.025, respectively), while associations with massive transfusion and 30-day mortality were not statistically significant in multivariable analyses., Conclusion: Initial IVC volume may serve as a predictor of patients at risk for overall RBC transfusion requirements and 24-h mortality, suggesting the possibility of its diagnostic efficacy in short-term outcomes. Further studies are needed to confirm these findings., (© 2024. The Author(s).)

Background: Body composition parameters provide relevant prognostic significance in critical care cohorts and cancer populations. Published results regarding polytrauma patients are inconclusive to date. The goal of this study was to analyse the role of body composition parameters in severely injured trauma patients., Methods: All consecutive patients requiring emergency tracheal intubation and mechanical ventilation before initial computed tomography (CT) at a level-1 trauma centre over a 12-year period (2008-2019) were reanalysed. The analysis included CT-derived body composition parameters based upon whole-body trauma CT as prognostic variables for 30-day mortality, intensive care unit length of stay (ICU LOS) and mechanical ventilation duration., Results: Four hundred seventy-two patients (75% male) with a median age of 49 years, median injury severity score of 26 and 30-day mortality rate of 22% (104 patients) met the inclusion criteria and were analysed. Regarding body composition parameters, 231 patients (49%) had visceral obesity, 75 patients had sarcopenia (16%) and 35 patients had sarcopenic obesity (7.4%). After adjustment for statistically significant univariable predictors age, body mass index, sarcopenic obesity, visceral obesity, American Society of Anesthesiologists classification ≥3, injury severity score and Glasgow Coma Scale ≤ 8 points, the Cox proportional hazard model identified sarcopenia as significant prognostic factor of 30-day mortality (hazard ratio 2.84; 95% confidence interval 1.38-5.85; P = 0.004), which was confirmed in Kaplan-Meier survival analysis (log-rank P = 0.006). In a subanalysis of 363 survivors, linear multivariable regression analysis revealed no significant associations of body composition parameters with ICU LOS and duration of mechanical ventilation., Conclusions: In a multivariable analysis of mechanically ventilated trauma patients, CT-defined sarcopenia was significantly associated with 30-day mortality whereas no associations of body composition parameters with ICU LOS and duration of mechanical ventilation were observed., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Objectives: Coronary artery calcifications detected by computed tomography (CT) provide prognostic relevance for vascular disorders and coronary heart disease, whereas their prognostic relevance in severely injured trauma patients remains unclear., Material and Methods: All consecutive trauma patients requiring emergency tracheal intubation before initial CT at a level-1 trauma center and admission to the intensive care unit (ICU) over a 12-year period (2008-2019) were reanalyzed. The Weston score, a semiquantitative method to quantify coronary calcifications, was evaluated as a prognostic variable based upon whole-body trauma CT analysis., Results: Four hundred fifty-eight patients (74.6% male) with a median age of 49 years, median injury severity score of 26 points, 24-h mortality rate of 7.6%, and 30-day mortality rate of 22.1% met the inclusion criteria and were analyzed. Coronary artery calcification was present in 214 patients (46.7%). After adjustment for confounding factors, the Weston score was an independent predictor for 24-h mortality (hazard ratio, HR 1.19, 95% confidence interval, CI 1.06-1.32, p = .002) and 30-day mortality (HR 1.09, 95% CI 1.01-1.17, p = .027). In a subanalysis of 357 survivors, the Weston score was significantly associated with ICU length of stay (LOS) (beta weight 0.89, 95% CI 0.3-1.47, p = .003) but not with mechanical ventilation duration (beta weight 0.05, 95% CI -0.2-0.63, p = .304)., Conclusion: CT-detected coronary calcification was a significant prognostic factor for 24-h- and 30-day-mortality in severely injured trauma patients requiring tracheal intubation, and influenced ICU LOS in survivors., (© 2024. The Author(s).)

Purpose: Epicardial adipose tissue (EAT) detected by computed tomography (CT) is associated with morbidity and mortality in patients with COVID-19 and other critical care patient cohorts, whereas their prognostic relevance in trauma patients remains unclear. The present study explored associations with four potential short-term outcomes in trauma patients., Methods: All consecutive trauma patients requiring emergency tracheal intubation and mechanical ventilation before initial whole-body CT imaging at a level-1 trauma center over a 12-year period (2008-2019) were reanalyzed for this study. EAT was measured semiquantitatively in initial CT and analyzed regarding associations with 24-hour and 30-day mortality using Cox proportional hazard models. In survivors, associations of EAT with intensive care unit length of stay (ICU LOS) and mechanical ventilation duration were analyzed using linear regression analyses., Results: Four hundred fifty-five patients (74.7% male) with a median age of 49 years, and a median injury severity score (ISS) of 26 points were analyzed. In univariable analysis, EAT index was significantly associated with 24-hour and 30-day mortality (p = 0.007, and p = 0.013, respectively). After adjustment for significant predictors age, body mass index, and ISS, no significant associations were confirmed (p = 0.622, and p = 0.903, respectively). In a subanalysis of 353 survivors, EAT index was significantly associated with ICU LOS and mechanical ventilation duration in univariable analyses (p = 0.031, and p = 0.014, respectively), but not in multivariable analyses (p = 0.81 and p = 0.46, respectively)., Conclusion: EAT index was associated with short-term outcomes in severely injured trauma patients, which not remained significant in multivariable analysis, suggesting that its prognostic capability is limited., (© 2024. The Author(s).)

Percutaneous hepatic melphalan perfusion (chemosaturation) in patients with liver metastases is known to be associated with procedure-related hemodynamic depression and coagulation impairment, which may cause bleeding complications and/or a prolonged intensive care unit length of stay (ICU LOS). We retrospectively analyzed possible predictive factors for bleeding complications and an ICU LOS > 1 d in a cohort of 31 patients undergoing 90 chemosaturation procedures. Using a multivariable mixed-model approach, we identified the amount of perioperative fluid volume (OR 12.0, 95% CI 2.3-60.0, p = 0.003) and protamine (OR 0.065, 95% CI 0.007-0.55, p = 0.012) to be associated with bleeding complications. Furthermore, the amount of perioperative fluid volume was associated with an ICU LOS > 1 d (OR 5.2, 95% CI 1.4-19.0, p = 0.011). Heparin dosage, melphalan dosage, extracorporeal circulation time, and noradrenaline dosage had no significant effects on outcomes. Protamine use was not associated with anaphylactic or thromboembolic complications. Despite the limited sample size, these results suggest a restrictive perioperative fluid regime to be beneficial, and support the use of protamine for heparin reversal after chemosaturation procedures. Further prospective randomized trials are needed to confirm these findings.

Percutaneous hepatic melphalan perfusion (PHMP) is a last-line treatment of inoperable primary or secondary liver tumors. Selective perfusion and saturation (chemosaturation) of the liver with the chemotherapeutic agent melphalan is performed via catheterization of the hepatic artery without affecting the rest of the body with its cytotoxic properties. Using an extracorporeal circulation and balloon occlusion of the inferior vena cava, the venous hepatic blood is filtered and returned using a bypass procedure. During the procedure, considerable circulatory depression and coagulopathy are frequent. The purpose of this article is to review the anesthesiological and postprocedural management of patients undergoing PHMP with consideration of the pitfalls and special circumstances., (© 2022. The Author(s).)

Background: The field of pain medicine was established as an obligatory subject area of medical schools in Germany in 2016. No prior study has evaluated the effects of this curricular change on students' competences in the field of pain medicine., Objective: The aim of this study was to find out to what extent the introduction of the additional subject "pain medicine" positively influenced the students' acquisition of competences measured via a self-assessment., Material and Methods: A longitudinal and interdisciplinary curriculum for pain medicine was developed according to the current recommendations for curriculum development for medical education. In parallel, a questionnaire was created for the students' self-assessment of their own level of knowledge and the importance of pain medicine teaching content on a 5-stage Likert scale. The surveys were conducted before the implementation of the curriculum (2014), directly after the first cohort finished (2016) and 5 years after the implementation (2019) and compared by Kruskal-Wallis test., Results: The implementation of the curriculum has led to significant improvement in relevant aspects. For example, students now feel better prepared overall for the treatment of pain patients (2.67 in 2014 vs. 3.18 in 2019). Individual sub-aspects such as taking a pain history (3.63 vs. 4.10) or drawing up an analgesia scheme (3.56 vs. 4.14) are now also subjectively better mastered., Conclusion: Even though the results are encouraging, there is further potential for improvement in some sub-areas. For example, the students' rating regarding the question about their preparation for treating patients in pain is not yet satisfactory. Therefore, the curriculum should be developed further with a focus on competence orientation. Digital teaching formats can be integrated as well as interprofessional units and simulated patients. Additionally, the examination formats should be further developed towards standardized practical examinations., (© 2022. The Author(s).)

A threshold-based classification of cerebral vasospasm needs reference values for intracranial vessel diameters on digital subtraction angiography (DSA). We aimed to generate adjusted reference values for this purpose by retrospectively analyzing angiograms and potential influencing factors on vessel diameters. Angiograms of the anterior circulation were evaluated in 278 patients aged 18−81 years. The vessel diameters of 453 angiograms (175 bilateral) were gathered from nine defined measuring sites. The effect sizes of physical characteristics (i.e., body weight and height, body mass index, gender, age, and cranial side) and anatomical variations were calculated with MANOVA. Segments bearing aneurysms were excluded for the calculation of reference values. Adjusted vessel diameters were calculated via linear regression analysis of the vessel diameter data. Vessel diameters increased with age and body height. Male and right-sided vessels were larger in diameter. Of the anatomical variations, only the hypoplastic/aplastic A1 segment had a significant influence (p < 0.05) on values of the anterior cerebral artery and the internal carotid artery with a small effect size (|ω2| > 0.01) being excluded from the reference values. We provide gender-, age-, and side-adjusted reference values and nomograms of arterial vessel diameters in the anterior circulation., Competing Interests: The authors declare no conflict of interest.

Background: Cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) has been extensively investigated, but the impact of collateralization remains unclear. We investigated the predictive value of collateral activation for delayed cerebral ischemia (DCI)-related infarctions and functional outcome., Methods: Data from 43 patients with CVS (January 2014 to August 2021) were evaluated for the angiographic presence of leptomeningeal and ophthalmic collaterals (anterior falcine artery (AFA), supratrochlear artery (STA), dorsal nasal artery (DNA)) on internal carotid artery angiograms. Vasospasm-related infarction and the modified Rankin Scale (mRS) score after six months were chosen as the endpoints., Results: 77% of the patients suffered from DCI-related infarctions. In 233 angiograms (at hospitalization, before spasmolysis, after six months), positive vessel signs were observed in 31 patients for STA, 35 for DNA, and 31 for AFA. The STA sign had the highest positive (84.6%) and negative (85.7%) predictive value for unfavorable outcome (mRS 4-6) in patients aged ≥50 years. DNA and AFA signs were not meaningful predictors for either endpoint. Leptomeningeal collaterals showed a positive Pearson's correlation with the STA sign in 87.5% ( p = 0.038) without providing any prediction for either endpoint., Conclusions: The STA sign is associated with clinical outcome in patients with CVS after SAH aged ≥50 years, and was correlated with the occurrence of leptomeningeal collaterals.

Background: Cerebral vasospasm (CVS) continues to account for high morbidity and mortality in patients surviving the initial aneurysmal subarachnoid hemorrhage (SAH). Nimodipine is the only drug known to reduce delayed cerebral ischemia (DCI), but it is believed not to affect large vessel CVS. Milrinone has emerged as a promising option. Our retrospective study focused on the effectiveness of the intra-arterial application of both drugs in monotherapy and combined therapy., Methods: We searched for patients with aneurysmal SAH, angiographically confirmed CVS, and at least one intra-arterial pharmacological angioplasty. Ten defined vessel sections on angiograms were assessed before and after vasodilator infusion. The improvement in vessel diameters was compared to the frequency of DCI-related cerebral infarction before hospital discharge and functional outcome reported as the modified Rankin Scale (mRS) score after 6 months., Results: Between 2014 and 2021, 132 intra-arterial interventions (144 vascular territories, 12 bilaterally) in 30 patients were analyzed for this study. The vasodilating effect of nimodipine was superior to milrinone in all intradural segments. There was no significant intergroup difference concerning outcome in mRS ( p = 0.217). Only nimodipine or the combined approach could prevent DCI-related infarction (both 57.1%), not milrinone alone (87.5%). Both drugs induced a doubled vasopressor demand due to blood pressure decrease, but milrinone alone induced tachycardia., Conclusions: The monotherapy with intra-arterial nimodipine was superior to milrinone. Nimodipine and milrinone may be used complementary in an escalation scheme with the administration of nimodipine first, complemented by milrinone in cases of severe CVS. Milrinone monotherapy is not recommended., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jentzsch, Ziganshyna, Lindner, Merkel, Mucha, Schob, Quäschling, Hoffmann, Werdehausen, Halama, Gaber and Richter.)