Academic literature on the topic 'Circulatory death'

Cardiac transplantation is the treatment of choice for eligible patients with advanced heart failure; however, it is limited by a critical shortage of suitable organs from traditional brain-dead donors. Organs donated following circulatory death (DCD) have been used to successfully expand the pool of organs available for kidney, liver, and lung transplantation; however, concerns regarding the severity of injury sustained by the heart following withdrawal of life sustaining therapy have deterred the clinical transplantation of DCD hearts. Investigations aiming to optimize the resuscitation, preservation, and evaluation of DCD hearts may facilitate the development of an evidence based protocol for DCD heart transplantation that can be translated to the clinical area and expand the donor pool. Therefore, the objectives of this thesis are to develop a clinically relevant large animal model of DCD and gain a greater understanding regarding the physiologic impact of donor extubation on the DCD heart, demonstrate as a ‘proof-of-concept’ that utilizing an approach to donor heart resuscitation, preservation, and evaluation that is tailored to the DCD context can facilitate successful transplantation, and finally to investigate ways to optimize the resuscitation, preservation, and evaluation of DCD hearts for transplantation. The results of this thesis may then be used to inform the development of an evidence-based protocol for DCD heart transplantation that can be translated to the clinical area. The clinical adoption of such a protocol has the potential to expand the donor pool and improve outcomes for patients with end-stage heart failure.
May 2017

Donor organ shortage is a major barrier to the progress of liver transplantation; options to widen the donor pool include use of marginal donor grafts and those from donors after circulatory death (DCD), despite risks of early graft failure. This thesis studies the key metabolic feature differences between DCD and from donors after brain death (DBD), using combination of microdialysis for tissue fluid sampling, and colourimetry, Coularray and Fourier Transform ion Cyclotron Resistance - mass spectrometry(FTICR-MS) as analytical platforms. The initial study proved feasibility of above methods to identify metabolic changes through cold storage to reperfusion, and the involvement of energy and amino acid metabolism pathways. Comparison of DCD and DBD grafts by microdialysis combined with colourimetry proved energy depletion, and increased lactate/pyruvate ratio in DCD grafts. Metabolomic studies consolidated the findings of primary impact on energy metabolism pathways during cold storage. Both CEAD and FTICR-MS identified key biomarker differences and the effect on tryptophan and kynurenine pathway, and this finding was reproduced in all three metabolomic studies conducted. Over expression of these metabolites in DCD grafts and failed allografts may be related to energy metabolism, and tryptophan and kynurenine could potentially be developed as biomarkers predicting liver graft function.

There is a chronic lack of donor hearts to meet the need for heart transplant both in the US and worldwide. Further, the use of available hearts is limited by the short period between collection and implantation during which the heart can be safely preserved ex vivo. Using mid-thermic Langendorff machine perfusion, we have been able to preserve the metabolic function of a healthy heart for up to 8 hours, twice the limit for current static cold storage. We have also been able to preserve the metabolic function of a damaged DCD Heart collected 30 minutes after cardiac arrest for a period of 8 hours. We further investigated whether it was possible to improve the preservation of DCD heart using treatment with 10 μM Triiodothyronine to stimulate the tissue metabolism and we did find a reduction in damage markers in the treated DCD hearts as compared to the untreated group.

Bakgrund: Organdonation kan rädda människors liv när all annan möjlig behandling redan testats. Behovet av organ i Sverige överskrider idag tillgången, vilket resulterar i att människor avlider i väntan på ett organ. Förutom att möjliggöra en människas överlevnad är transplantation mer kostnadseffektivt än kontinuerlig behandling. I nuläget finns inga nationella riktlinjer i Sverige för utbildning inom organdonation för intensivvårdssjuksköterskor. Forskning har visat att intensivvårdssjuksköterskans arbete är av stor vikt för donationsprocessen. Syfte: Syftet med studien är att belysa behovet av utbildning hos intensivvårdssjuksköterskor som vårdar potentiella avlidna donatorer. Metod: Studien har utförts genom en litteraturstudie med systematisk datainsamling. Integrativ metod med en kvalitativ innehållsanalys har använts då artiklar med både kvalitativ och kvantitativ ansats analyserats för att besvara syftet för studien. Resultat: En stor del intensivvårdssjuksköterskor upplevde sig vara obekväma med att vårda organdonatorer. Vårdandet av en donator kan medföra att mycket känslor uppstår hos intensivvårdssjuksköterskan och upplevdes som mentalt påfrestande. Utbildning inom organdonation kan hjälpa intensivvårdssjuksköterskan att hantera dessa känslor. Utbildning kan även leda till att fler potentiella donatorer identifieras. Utbildning behöver ges regelbundet och intensivvårdssjuksköterskan behöver specifikt utbildning om donationsprocessen, bemötande och kommunikation av de närstående samt skillnader i hjärt- och hjärndöda patienter. Slutsats: Intensivvårdssjuksköterskan behöver få en djupare förståelse av vården kring organdonation och få en ökad kunskap och utbildning för att stärka sin professionella roll. Utbildning kan även förbättra donationsprocessen och möjliggöra för fler donatorer. Vidare forskning inom området anses behövas för att utveckla vården kring donatorer och närstående.
Background: Organ donation can save lives when all other treatment options have been exhausted. Today, the demand for organs in Sweden exceeds supply, resulting in people dying in wait for an available organ for transplantation. In addition to saving a person’s life, transplantations are more cost-effective than continuous treatment. Currently, there are no national guidelines for the provision of training in the area of organ donations for intensive care nurses. Research has shown that the efforts of intensive care nurses play a major role in the donation process. Aim: The aim of this study is to shed light on the need for training of intensive care nurses caring for potential deceased donors. Methodology: The study was conducted through a literature review with systematic data collection. An integrative method with qualitative content analysis was employed, as articles with both qualitative and quantitative approaches were analysed to shed light on the aim of the study. Findings: A large proportion of intensive care nurses felt uncomfortable caring for organ donors. Caring for a donor can be a very emotional and mentally trying experience for intensive care nurses. Organ donation training can help intensive care nurses cope with these feelings. Training can also result in the identification of more potential donors. Regular training is necessary, and intensive care nurses require specific training on the donation process, treatment and communication with next of kin as well as differences between donation after cardiac death patients and donation after brain death patients. Conclusion: The intensive care nurses needs to gain a deeper understanding of the care surrounding organ donation. To increase the professional role of the nurse there is a need to strengthen the knowledge and education. The donation process could be improved by education, which can lead to more organ donations. Further research within this area of expertise needs to be done to be able to develop the care for the donors and their families.

Bakgrund: Över hela världen råder det brist på organ. 1 januari 2019 stod 807 personer på väntelistan för att få ett nytt organ i Sverige. Efterfrågan på organ är större än tillgången. Efterfrågan skulle kunna tillmötesgå bättre om DCD (eng. Donation after Circulatory Death) kan implementeras som ett komplement till DBD (eng. Donation after Brain Death). Det har pågått ett pilotprojekt på sex olika sjukhus i Sverige.Måletmed projektet var att utreda om DCD i framtiden kan vara ett komplement till den idag etablerade donationsprocessen DBD vilket leder till att sjukvården kan möta allmänhetens donationsvilja samt öka antalet organ för transplantation. Då DCD inte är nationellt implementerat och genom att intensivvårdssjuksköterskor har ansvaret för att vårda potentiella organdonatorer är det viktigt med forskning som belyser intensivvårdssjuksköterskorsresonemang och föreställningar kring DCD.Syfte:Syftet var att beskriva intensivvårdssjuksköterskors resonemang och föreställningar om donation vid kontrollerad DCD.Metod:Kvalitativ intervjustudie med ändamålsenligt urval genomfördes. Data analyserades med kvalitativ innehållsanalys.Resultat:Analysen resulterade i fyra kategorier; Att påbörja något nytt inom området donation, Att erhålla kunskap minskar farhågor och oro, Att införa donation efter cirkulationsstillestånd ger möjlighet att möta en hög donationsvilja och att informera och ge tröst till anhöriga.Slutsats: Denna studie visar att engagemanget är stort hos intensivvårdssjuksköterskor och att tilltron tillett införande av DCD är hög. Genom att införa DCD som ett komplement till DBD så skulle fler donationer kunna genomföras och på sikt kunna matcha efterfrågan på organ. Mer forskning samt utbildning behövs för att öka kunskapen utifrån de krav som kommer att ställas på intensivvårdssjuksköterskor vid en eventuell implementering av DCD.

La transplantation est la meilleure alternative en cas d'insuffisance rénale terminale. Face à la pénurie de greffons, les équipes de transplantation se sont tournées notamment vers les donneurs décédés par arrêt circulatoire (DDAC) non contrôlés. Ces greffons soumis à une période d'ischémie chaude sont plus fragiles. Des méthodes de reconditionnement chez le donneur par refroidissement in situ (RIS) et circulation régionale normothermique (CRN) se sont développées afin de réduire les lésions d'ischémie-reperfusion. Le choix de la méthode est laissé à l'appréciation de chaque équipe et il existe une grande hétérogénéité des pratiques. Après prélèvement, l'utilisation des machines de perfusion hypothermique (MPH) est généralement recommandée. L'optimisation de ces phases de reconditionnement chez le donneur et de conservation hypothermique apparait comme un enjeu majeur de santé publique. Concernant l'optimisation du mode de reconditionnement, la mise au point d'un modèle préclinique porcin parfaitement reproductible a permis de mettre en évidence une supériorité de la CRN sur le RIS. Une durée de CRN de 4 heures minimum sans dépasser 6 heures paraît optimale. Concernant la conservation hypothermique, les MPH permettent le maintien du niveau d'expression des gènes retrouvé en fin de CRN. L'ajout d'une oxygénation active en MPH ou de curcumine en solution statique améliore le devenir du greffon à court et long termes dans un modèle préclinique d'autogreffe. Ce travail pourrait s'étendre à l'étude d'autres organes, d'autres durées d'ischémie chaude et aux DDAC contrôlés afin d'élargir encore le nombre d'organes éligibles à la transplantation
Transplantation is the best alternative to end-stage renal disease. The shortage of grafts led the transplant teams to consider uncontrolled deceased donors after circulatory death (DCDs). These grafts suffered from a period of warm ischemia and are more vulnerable. Reconditioning methods in the donor by in situ cooling (ISC) and normothermic regional perfusion (NRP) have been developed to reduce the ischemia-reperfusion injuries. Each team has the choice as to the method and there are many different practices. After removal of kidneys, the use of hypothermic perfusion machines (HPM) is generally recommended. The optimization of reconditioning in the donor and hypothermic preservation appears as a major public health challenge. About optimization of the reconditioning method, the development of a high reproducible preclinical porcine model allowed to highlight the superiority of RNP over ISC. NRP duration of 4 hours minimum without exceeding 6 hours seems optimal. About hypothermic preservation, HPM allows to maintain the level of expression of the genes found at the end of RNP. The addition of active oxygenation to HPM or curcumin in static solution improves the graft outcomes in the short and long terms in a preclinical model of auto transplantation. This work could be extended to the study of other organs, other durations of warm ischemia and to controlled DCDs in order to further increase the number of transplantable grafts

El daño miocárdico por isquemia-reperfusión es una de las principales causas de morbilidad y mortalidad. La reperfusión es el tratamiento de elección en pacientes con infarto de miocardio. Sin embargo, ésta ocasiona un daño adicional por mecanismos provocados por la restauración del flujo, que puede ser prevenido, al menos en parte y en el escenario experimental, por sustancias aplicadas en el momento de la reperfusión. Una de las posibles dianas terapéuticas es la conexina 43 (Cx43) y los canales que forma (canales de gap junctions (GJ)). La Cx43 es la principal proteína que forma GJ en ventrículo miocárdico, donde es esencial permitiendo el acoplamiento químico y eléctrico entre cardiomiocitos. Sin embargo, se ha sugerido que las GJ participarían en la propagación del daño celular durante la reperfusión, y que la Cx43 estaría implicada en la señalización endógena de cardioprotección durante el precondicionamiento isquémico (IPC). No obstante, la mayoría de los estudios previos se han realizado usando agentes desacoplantes de GJ con baja especificidad y muchos efectos secundarios. Por ello, se han desarrollado modelos de ratones transgénicos deficientes de Cx43. Los objetivos de esta tesis fueron investigar los efectos de la deficiencia en Cx43 en el metabolismo energético del miocardio, en la tolerancia a la isquemia-reperfusión y en la susceptibilidad al precondicionamiento isquémico y farmacológico, así como en la incidencia de arritmias ventriculares. Se usaron dos modelos transgénicos de ratones: el knock-in, en el que la Cx43 es reemplazada por Cx32, una isoforma con una conductancia y permeabilidad más baja; y el knock-out condicional para Cx43 (Cx43Cre-ER(T)/fl). En este modelo, los corazones de ratones Cx43Cre/fl expresan, en condiciones normales, la mitad del contenido de Cx43 observado en los correspondientes controles genéticos (Cx43fl/fl). Sin embargo, 14 días después de iniciar el tratamiento con tamoxifeno, los corazones de estos animales expresan solo un contenido residual de Cx43, inferior al 5%. Se observó que ambas estrategias genéticas de deficiencia de Cx43 alteran el metabolismo energético del miocardio, ya que mostraron niveles de ATP inferiores a los de los correspondientes controles genéticos. Experimentos en corazones aislados, perfundidos en un sistema Langenforff, demostraron una mayor tolerancia a la isquemia-reperfusión en corazones de ratones knock-in HOM y Cx43Cre/fl tratados con tamoxifeno, debido a una disminución del tamaño del infarto y una menor liberación de LDH. Este efecto pareció ser más dependiente de la comunicación por GJ en el modelo Cx43Cre-ER(T)/fl. Además, la protección por IPC, y especialmente la del diazóxido, desapareció en ambos modelos de deficiencia de Cx43. Se demostró que estos efectos fueron independientes de una activación diferente de las cascadas de señalización citosólicas RISK y SAFE, sugiriendo que la activación de estas vías durante el IPC es anterior a los efectos de la deficiencia de Cx43. Finalmente, se observó que ambos modelos de deficiencia de Cx43, simulando una reducción de la conductancia unitaria de las GJ y del número de canales GJ, respectivamente, están asociados a un aumento de la incidencia de taquiarritmias ventriculares, tanto espontáneas como inducidas, durante la isquemia-reperfusión. Este hecho hace que la posibilidad de translación de estas estrategias terapéuticas a la clínica requiera que sean aplicadas de manera muy localizada en el área en riesgo. Como conclusion, esta tesis demuestra un importante, y previamente desconocido, papel de la Cx43 en el metabolismo energético del miocardio, en la tolerancia al daño por isquemia-reperfusión y en la cardioprotección endógena. La Cx43 y las GJ pueden llegar a ser interesantes dianas terapéuticas para aumentar la supervivencia de los pacientes con cardiopatía isquémica, aunque la traslación debe esperar a que se resuelvan los efectos pro-arrítmicos de estos tratamientos.
Myocardial ischemia-reperfusion injury is one of the main causes of morbidity and mortality worldwide every year. Reperfusion is the treatment of choice in patients undergoing myocardial infarction in order to prevent cardiomyocyte death and improve patient’s survival and prognosis. However, reperfusion causes an additional injury, through mechanisms triggered by flow restoration, that can be prevented, at least in part and in the experimental setting, by drugs applied at the time of reperfusion. This fact has led to an intense research in order to identify therapeutic strategies able to limit myocardial infarction when applied at the time of reperfusion. One of the candidate targets is Connexin 43 (Cx43), and the channels that it forms (i.e, gap junction (GJ) channels). Cx43 is the main protein forming GJ in the ventricular myocardium, where it plays an essential role in electrical and chemical coupling between cardiomyocytes. However, previous studies have suggested that GJ play also a role in spreading of cell death during reperfusion, and that Cx43 may be involved in endogenous cardioprotective signaling during ischemic preconditioning (IPC). However, most of these studies have been conducted using GJ uncouplers having low specificity and lots of side effects. This made necessary to find new strategies to study the role of Cx43 in cell death during myocardial infarction and cardioprotection, including the use of transgenic mice models. Thus, the aims of this thesis were to assess the effects of Cx43 deficiency in isolated hearts from transgenic models on cardiac energetic metabolism, tolerance to ischemia-reperfusion injury, susceptibility to ischemic and pharmacological preconditioning, and on the incidence of ventricular arrhythmias. We used a knock-in mice model, in which Cx43 is replaced by Cx32, a connexin with lower conductivity and permeability, and a conditional knock-out model of Cx43 deficiency (Cx43Cre-ER(T)/fl). In this last model, isolated hearts from Cx43Cre/fl animals express, under normal conditions, half of the Cx43 content seen in their corresponding genetic controls (Cx43fl/fl). However, 14 days after tamoxifen treatment, hearts from these animals have only a residual Cx43 content, lower than 5%. We found that both genetic strategies alter myocardial energetic metabolism, with hearts from these mice having reduced ATP levels as compared with hearts from the corresponding genetic controls. Furthermore, isolated, Langendorff-perfused, hearts from homozygous (HOM) knock-in mice and from Cx43Cre/fl animals treated with tamoxifen, depicted an increased tolerance to ischemia-reperfusion injury, as denoted by a reduction in infarct size and in LDH release. In Cx43Cre/fl animals treated with tamoxifen, this effect seems to be more dependent on GJ communication than in HOM knock-in mice. Moreover, susceptibility to IPC and especially to diazoxide protection was abolished in both models of Cx43 deficiency. Furthermore, we have demonstrated that these effects were independent of a differential activation of cytosolic signaling cascades, including the RISK and SAFE pathways, which is suggestive that activation of these pathways during IPC is upstream of Cx43 deficiency. Finally, we have demonstrated that both models of Cx43 deficiency, mimicking a reduction in unitary GJ conductance and in the number of GJ channels, respectively, are associated with an increased incidence of both spontaneous and induced ventricular tachyarrhythmias. This finding indicates that the possibility of translation of these therapeutic strategies to the clinical arena requires that they could be applied locally at the area at risk. In conclusion, this thesis demonstrates an important, and previously unknown, specific role of Cx43 in myocardial energetic metabolism, tolerance to ischemia-reperfusion injury and in endogenous cardioprotection. GJ and Cx43 can become interesting pharmacological targets to improve the clinical outcome in patients with ischemic heart disease. However, translation should wait until the proarrhythmic effects of these treatments are solved.