Organ-specific oxidative events under restrictive versus full reperfusion following hemorrhagic traumatic shock in rats

Dissertation - Veterinärmedizinische Universität Wien - 2022 Aus rechtlichen Gründen sind nicht alle Teile dieser Arbeit frei zugänglich. Der Zugriff auf den elektronischen Volltext ist auf Angehörige der Veterinärmedizinischen Universität Wien beschränkt. Bitte einloggen!Einleitung und Fragestellung: Die Letalität nach hämorrhagisch-traumatischem Schock (HTS) ist direkt mit der einhergehenden Minderdurchblutung des Gewebes und der darauffolgenden Unterversorgung mit Sauerstoff verbunden. Obwohl die erneute Versorgung des Gewebes mit Sauerstoff im Rahmen der Reperfusion überlebensnotwendig ist, wird sie auch mit einer erhöhten Sauerstoffradikal-(ROS)-bildung in Zusammenhang gebracht. Das Ziel dieser Studie war es, die Auswirkungen von zwei unterschiedlichen Reperfusionsstrategien - einer beschränkten, restriktiven Reperfusion (RR) im Vergleich zu einer unbeschränkten, vollen Reperfusion (FR) - auf die ROS-bildung und damit einhergehende Organschäden nach HTS zu untersuchen. Material und Methoden: Das klinisch relevante und standardisierte HTS Modell in der Ratte beinhaltet eine Laparotomie, Blutentzug (Blutdrucksenkung auf 35-40 mmHg, 30 % Blutverlust) bis zur reversiblen Dekompensation mit anschließender Volumentherapie mit Ringerlösung. Anschließend wurden die Tiere randomisiert einer Reperfusionsgruppe zugeordnet. Die RR-Gruppe ist charakterisiert durch eine initiale 40 minütige inadäquate Reperfusionsphase (30 mL/kg/h), bei der der Blutdruck nicht höher als 50-55 mmHg ansteigt (prähospitale Phase). Darauf folgt eine volle Reperfusionsphase (75 mL/kg/h), die eine hospitale, adäquate Volumentherapie darstellt. Die Tiere, die der FR-Gruppe zugeordnet wurden, bekamen gleich zu Reperfusionsbeginn eine adäquate Flüssigkeitszufuhr über 60 Minuten (75 mL/kg/h) mit anschließender 40 minütiger Verabreichung von 30 mL/kg/h. Über den ganzen Reperfusionszeitraum wurde der ROS-fänger 1-hydroxy-3-carboxy-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (CP-H) infundiert um die zell- und organspezifischen ROS-Konzentrationen am Versuchende zu messen. Diese wurden direkt proportional mittels Elektronen-Paramagnetischer-Resonanzspektroskopie (EPR) bestimmt. Zusätzliche wurden thiobarbituric acid substances (TBARS), Peroxiredoxin-4 (Prx-4) und verschiedene Zell- und Organfunktionsparameter gemessen. Der Versuch wurde nach 100 Minuten Reperfusiontherapie terminiert. Eine Sham-operierte Gruppe (kein HTS und Reperfusion) diente als Kontrolle. Ergebnisse: Der mittlere arterielle Blutdruck (MAP) war zu Beginn der Reperfusion in der FR-Gruppe höher. Die ROS-Bildung zeigte keinen signifikanten Unterschied zwischen den 26 beiden Reperfusionsgruppen, jedoch konnten erhöhte ROS-Werte in den Erythrozyten und in der Leber der RR-Gruppe nachgewiesen werden im Vergleich zur Kontrollgruppe. Die im Plasma gemessene Prx-4-Konzentration und die Organschäden in Leber, Niere und Lunge waren in der RR-Gruppe signifikant erhöht zur FR-Gruppe. Schlussfolgerungen: Beide Reperfusionsstrategien beeinflussen die HTS-induzierten Zell und Organschäden nachhaltig. Jedoch geht eine RR mit einer erhöhten ROS-Bildung in Erythrozyten und Leber sowie einer erhöhten Prx-4-Konzentration im Plasma einher.Dissertation - University of Veterinary Medicine Vienna - 2022 The full text is only available to university members. Please log in!Background aim: Complications after hemorrhagic-traumatic shock (HTS) and reperfusion are partially related to the formation of reactive oxygen species (ROS) during reoxygenation. The aim of our study was to compare the effects of an adequate full reperfusion (FR) with an inadequate restrictive reperfusion (RR) approach on ROS formation. Materials and methods: Male rats were exposed to HTS and randomized to receive a FR (75 ml/kg/h) or RR (30 ml/kg/h to uphold a mean arterial blood pressure (MAP) of 50-55 mmHg for 40 minutes followed by 75 ml/kg/h) with Ringer’s solution. ROS distribution of organs and blood was directly determined by infusion of ROS scavenger 1-hydroxy-3-carboxy-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (CP-H) during reperfusion followed by electron paramagnetic resonance (EPR) spectroscopy. Measurement of thiobarbituric acid reactive substances (TBARS) and peroxiredoxin-4 (Prx-4) were performed for indirect ROS determination. Cell and organ injury were assessed by various blood chemistry parameters, myeloperoxidase activity and wet/dry ratio of the lungs. Sham operated rats functioned as controls (n=8). The trial ended 100 minutes post-shock. Results: MAP was significantly higher in the FR compared to the RR group during reperfusion (66±2 vs 49±2 mmHg). RR animals only showed higher concentrations of ROS in erythrocytes (1951±420 vs 724±75 AU) and liver (474±57 vs 261±21 AU) compared to sham. Animals in the RR group showed significantly higher values of the antioxidant-enzyme Prx-4 in plasma when compared to the FR group (20±2 vs 14±0.5 RLU). This was accompanied by elevated alanine aminotransferase (ALT) and creatinine (CREA) levels (p<0.05). However, TBARS were significantly elevated only in the kidney in the FR group (p<0.05). Conclusion: Both reperfusion strategies have a lasting effect on cell and organ damage. A RR is related to an enhanced ROS formation in erythrocytes and liver in comparison to controls. Moreover, the RR was accompanied with an increased release of the antioxidant-enzyme Prx-4 into plasma, and a distinct injury to kidney and liver when compared to a FR

Effect of Assertive Community Treatment for Patients with Substance Use Disorder: A Systematic Review

Purpose: Substance use disorders (SUD) are an important health issue internationally. Traditional outpatient programmes often do not adequately address the substantial medical and social needs and in addition many patients have difficulties accessing the care needed. The assertive community treatment (ACT) model was originally developed for patients with a severe mental illness but has been adapted for patients with SUD by integrating specific SUD treatments into the traditional ACT model. This paper aims to assess the effectiveness of ACT for patients with SUD on a number of measures. Methods: We performed a systematic review of ACT interventions for patients with SUD by analyzing randomized controlled studies published before June 2017 found on the electronic databases PsychINFO, MEDLINE, PsychARTICLES. Eleven publications using 5 datasets were included in the analysis. Quality of studies was analyzed using the JADAD scale or Oxford quality scoring system. Outcome measures used were substance use, treatment engagement, hospitalization rates, quality of life, housing status, medication compliance and legal problems. Patients included in the studies had a diagnosis of SUD. Two datasets included homeless patients and 2 datasets included patients with high service use. Results and Conclusions: The results of the very few existing randomized control studies are mixed. Treatment engagement was higher for ACT in 4 datasets. One dataset reported higher service contact rates for the ACT group than for controls. In 2 datasets a positive effect on hospitalization rates was found. Higher fidelity to the ACT model appears to improve outcomes. Substance use reduced only in half of the datasets, of which only one showed a significant reduction in the ACT group. Overall, ACT is a promising approach that may be useful for promoting treatment engagement for patients with SUD. According to earlier studies on patients with severe mental illness, patients with high inpatient service use benefit most from this assertive approach. We hypothesize that a similar high need user group among patients with SUD might benefit most from ACT. Further research is needed to examine which types of clinical interventions might help difficult-to-engage patients with addictions.</p

Predictors of Unplanned Readmissions Among Patients With Substance Use Disorders

Objective: The objective of this study was to evaluate predictors of unplanned readmission to a specialized hospital addiction unit within less than 30 days, between 30 and 60 days and over 60 days post-discharge among individuals with a diagnosis of substance use disorder. Methods: Cox proportional hazards regressions were used to test the effects of potential risk factors on time-to-onset for unplanned readmissions. The outcome (survival time) was the length of time to hospital readmission and the predictors were age, sex, duration of the first hospital stay, Health of Nation Outcome Scales score and Brief Symptom Check List. Results: Of the 750 readmissions analyzed for the reported period 28.0% took place in less than 30 days, 12.0% between 30 and 60 days and 60.0% after 60 days of discharge. Length of the first hospitalization was a statistically significant predictor of readmission between 30 and 60 days and over 60 days but not for less than 30 days. A 10% increase in length of the first hospitalization, holding all other variables constant, was associated with a 5.0% decrease in unplanned readmissions occurring between 30 and 60 days and a 2.2% decrease in readmissions over 60 days post-discharge. Conclusion: Length of the first hospitalization was found to be a protective factor of readmission between 30 and 60 days and over 60 days but not for less than 30 days post-discharge. The longer the duration of the first hospitalization, the less quickly patients were readmitted to hospital.Objectif: L’objectif de cette étude était d’évaluer les prédicteurs de réadmissions non planifiées dans une unité hospitalière spécialisée en addiction en moins de 30 jours, entre 30 et 60 jours et plus de 60 jours après leur sortie chez les personnes ayant un diagnostic de trouble lié à l’utilisation de substances (TUS). Méthode: Les régressions des risques proportionnels de Cox ont été utilisées pour tester les effets des facteurs de risques potentiels sur le temps reliés aux réadmissions non planifiées. Le pronostic (durée de survie) était la durée jusqu’à la réadmission à l’hôpital et les vérifiables étaient l’âge, le sexe, la durée du premier séjour à l’hôpital, le score des résultats du Health of Nation Outcome Scales (HoNOS-F) et la liste de contrôle des symptômes du Brief Symptom Check List (BSCL). Résultats: Sur les 750 réadmissions analysées pour la période rapportée, 28,0% ont eu lieu en moins de 30 jours, 12,0% entre 30 et 60 jours et 60,0% après 60 jours de congé. La durée de la première hospitalisation était une variable prédictive statistiquement significative pour les réadmissions entre 30 et 60 jours et les plus de 60 jours, mais pas pour les moins de 30 jours. Une augmentation de 10% de la durée de la première hospitalisation, en maintenant toutes les autres variables constantes, a été associée avec une diminution de 5,0% des réadmissions imprévues survenant entre 30 et 60 jours et une diminution de 2,2% des réadmissions plus de 60 jours après la libération. Conclusions: La durée de la première hospitalisation s’est avérée être un facteur de protection contre une réadmission entre 30 et 60 jours et au-delà de 60 jours mais pas pour les moins de 30 jours après la libération. Plus la durée de la première hospitalisation est longue, moins les patients sont réadmis rapidement à l’hôpital.</p

Advance statements to prevent treatment disengagement in substance use disorders

Objectives: Some individuals with substance use disorders find it difficult to engage in outpatient treatment programs. In order to promote clients’ recovery they need to be actively involved in illness management. This implies for both client and health care professional identifying possible signs for treatment disengagement and strategies to regain contact with their service providers. We used advance statements (AS) in order to discuss these signs, strategies, and treatment preferences with service users. This study aims to examine the content of AS developed to prevent treatment disengagement. Methods: Thematic analysis of 62 AS developed by service users with addictive disorders and their care team as part of a substudy of a larger trial on transitional case management for individuals with substance use disorders. The AS used predefined questions and were discussed before hospital discharge. Results: The main reasons for loss of contact were relapse, psychiatric, and more general psychological symptoms, loss of therapeutic alliance, as well as social circumstances. Most service users requested to be contacted by their caregiver. Many participants were able to name specific coping strategies in case of loss of contact. The clients’ networks can play an important role in regaining contact. Conclusion: There is evidence that the AS-related intervention is a feasible and acceptable tool to help service users assess their risk situations and early warning signs for treatment drop-outs. The AS also allow them to plan the interventions or actions they request in case of such situations. Further studies are needed to examine whether AS lead to less treatment disengagement and whether possible loss of contact with caregivers is shorter and with fewer negative consequences.Objectifs: Certaines personnes atteintes de troubles liés aux troubles d’utilisation de substances (TUS) ont du mal à s’engager dans des programmes de traitement ambulatoires. Pour favoriser le rétablissement des clients, ceux-ci doivent participer activement à la gestion de la maladie. Cela implique à la fois pour le client et pour le professionnel de la santé l’identification des signes possibles de désengagement du traitement et des stratégies pour reprendre contact avec leurs fournisseurs de services. Nous avons utilisé les déclarations préalables (DP) pour discuter de ces signes, stratégies et préférences de traitement avec les utilisateurs du service. Cette étude vise à examiner le contenu de DP développées pour prévenir le désengagement du traitement. Méthodes: L’analyse thématique de 62 DP élaborées par des utilisateurs de services avec des TUS et leur équipe de soins dans le cadre d’une sous-étude d’un essai clinique plus vaste sur le case management de transition pour les personnes atteintes de troubles liés aux TUS. Les DP ont utilisé des questions prédéfinies et ont été discutées avant la sortie de l’hôpital. Résultats: Les principales raisons de la perte de contact étaient les rechutes, les symptômes psychiatriques et psychologiques plus généraux, la perte d’alliance thérapeutique et les circonstances sociales. La plupart des utilisateurs du service ont demandé à être contactés par leur fournisseur de soins. De nombreux participants ont pu nommer des stratégies d’adaptations spécifiques en cas de perte de contact. Les réseaux des clients peuvent jouer un rôle important dans la reprise des contacts. Conclusions: Il est prouvé que l’intervention liée au DP est un outil réalisable et acceptable pour aider les utilisateurs de services à évaluer leurs situations de risque et les signes avant-coureurs de l’abandon du traitement. Les DP leur permettent également de planifier les interventions ou actions qu’ils demandent en cas de telles situations. D’autres études sont nécessaires pour déterminer si les DP entraînent moins de désengagement du traitement et si la perte de contact possible avec les soignants est plus courte et entraîne moins de conséquences négatives.</p

Organ-Specific Oxidative Events under Restrictive Versus Full Reperfusion Following Hemorrhagic Traumatic Shock in Rats

Background aim: Reperfusion after hemorrhagic traumatic shock (HTS) is often associated with complications that are partly ascribed to the formation of reactive oxygen species (ROS). The aim of our study was to compare the effects of restrictive reperfusion (RR) to rapid full reperfusion (FR) on ROS formation and/or oxidative events. Materials and methods: Anesthetized male rats were randomly subjected to HTS followed by FR (75 mL/kg/h) or RR (30 mL/kg/h for 40 min, followed by 75 mL/kg/h) with Ringer&rsquo;s solution (n = 8/group). Compartment-specific ROS formation was determined by infusion of ROS scavenger 1-hydroxy-3-carboxy-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (CP-H) during resuscitation, followed by electron paramagnetic resonance spectroscopy. Sham-operated animals (n = 8) served as controls. The experiment was terminated 100 min post-shock. Results: Mean arterial pressure was significantly higher in the FR compared to the RR group during early reperfusion. Only RR animals, not FR animals, showed significantly higher ROS concentrations in erythrocytes (1951 &plusmn; 420 vs. 724 &plusmn; 75 AU) and in liver (474 &plusmn; 57 vs. 261 &plusmn; 21 AU) compared to sham controls. This was accompanied by elevated alanine aminotransferase and creatinine levels in RR animals compared to both shams and FR animals, while lipid peroxidation products (thiobarbituric acid reactive substances) were significantly increased only in the kidney in the FR group (p &lt; 0.05). RR animals showed significantly higher plasma peroxiredoxin-4 values when compared to the FR group (20 &plusmn; 2 vs. 14 &plusmn; 0.5 RLU). Conclusion: Restrictive reperfusion after HTS is associated with increased ROS formation in erythrocytes and liver compared to sham controls. Moreover, the restrictive reperfusion is associated with a more pronounced injury to the liver and kidney, which is likely mediated by other than lipid peroxidation process and/or oxidative stress reactions

A novel experimental rat model of peripheral nerve scarring that reliably mimics post-surgical complications and recurring adhesions

Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. These features can reoccur following external neurolysis, currently the most common surgical treatment for peripheral nerve scarring, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients. However, a clinically relevant model combining both histological and functional alterations has not been published to date. We therefore developed a reliable rat model that exhibits the essential pathological processes of peripheral nerve scarring. In our study, we present a novel method for the induction of nerve scarring by applying glutaraldehyde-containing glue that is known to cause nerve injury in humans. After a 3-week contact period with the sciatic nerve in female Sprague Dawley rats, we could demonstrate severe intra- and perineural scarring that resulted in grade 3 adhesions and major impairments in the electrophysiological peak amplitude compared with sham control (P=0.0478). Immunohistochemical analysis of the nerve structure revealed vigorous nerve inflammation and recruitment of T cells and macrophages. Also, distinct nerve degeneration was determined by immunostaining. These pathological alterations were further reflected in significant functional deficiencies, as determined by the analysis of relevant gait parameters as well as the quantification of the sciatic functional index starting at week 1 post-operation (P<0.01). Moreover, with this model we could, for the first time, demonstrate not only the primary formation, but also the recurrence, of severe adhesions 1 week after glue removal, imitating a major clinical challenge. As a comparison, we tested a published model for generating perineural fibrotic adhesions, which did not result in significant pathological changes. Taken together, we established an easily reproducible and reliable rat model for peripheral nerve scarring that allows for the effective testing of new therapeutic strategies