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INTRODUCTION: Patients requiring emergent endotracheal intubation are at higher risk of post-intubation hypotension due to altered physiology in critical illness. Post-intubation hypotension increases mortality and hospital length of stay, however, the impact of vasopressors on its incidence and outcomes is not known. This scoping review identified studies reporting hemodynamic data in patients undergoing emergent intubation to provide a literature overview on post-intubation hypotension in cohorts that did and did not receive vasopressors. METHODS: A systematic search of CINAHL, Cochrane, EMBASE and PubMed-Medline was performed from database inception until September 28, 2023. Two independent reviewers completed the title and abstract screen, full text review and data extraction per PRISMA guidelines. Studies including patients < 18 years or intubations during cardiac arrest were excluded. Primary outcome was the presence of hypotension within 30 min of emergent intubation. Secondary outcomes included mortality at 1 h and in-hospital. RESULTS: The systematic search yielded 13,126 articles, with 61 selected for final inclusion. There were 24,547 patients with a mean age of 57.2 years and a slight male predominance (63.8%). Respiratory failure was the most common intubation indication. Across 18 studies reporting on vasopressor use prior to intubation, 1171/7085 patients received vasopressors pre-intubation. Post-intubation hypotension occurred in 22.2% of patients across all studies, and in 34.3% of patients in studies where vasopressor administration pre-intubation was specifically reported. One-hour mortality of patients across all studies and within the vasopressor use studies was 1.2% and 1.6%, respectively. In-hospital mortality across studies was 21.5%, and 13.1% in studies which reported on vasopressor use pre-intubation. CONCLUSION: Patients requiring emergent intubation have a high rate of post-intubation hypotension and in-hospital mortality. While there is an intuitive rationale for the use of vasopressors during emergent intubation, current evidence is limited to support a definitive change in clinical practice at this time.
RéSUMé: INTRODUCTION: Les patients nécessitant une intubation endotrachéale en émergence présentent un risque plus élevé d'hypotension post-intubation en raison de la physiologie altérée de la maladie grave. L'hypotension post-intubation augmente la mortalité et la durée du séjour à l'hôpital, mais on ne connaît pas l'impact des vasopresseurs sur son incidence et ses résultats. Cette revue de la portée a identifié des études qui ont rapporté des données hémodynamiques chez des patients soumis à une intubation d'urgence afin de fournir un aperçu de la littérature sur l'hypotension post-intubation dans les cohortes ayant reçu et n'ayant pas reçu des vasopresseurs. MéTHODES: Une recherche systématique de CINAHL, Cochrane, EMBASE et PubMed-Medline a été effectuée depuis la création de la base de données jusqu'au 28 septembre 2023. Deux examinateurs indépendants ont complété le titre et l'écran des résumés, la révision du texte intégral et l'extraction des données selon les lignes directrices de PRISMA. Les études incluant des patients de moins de 18 ans ou des intubations pendant un arrêt cardiaque ont été exclues. Le principal critère de jugement était la présence d'hypotension dans les 30 minutes suivant l'intubation. Les critères de jugement secondaires comprenaient la mortalité à l'heure et en milieu hospitalier. RéSULTATS: La recherche systématique a donné lieu à 13126 articles, dont 61 ont été sélectionnés pour inclusion finale. On a recensé 24547 patients avec un âge moyen de 57,2 ans et une légère prédominance masculine (63,8 %). L'insuffisance respiratoire était la plus fréquente indication d'intubation. Dans 18 études sur l'utilisation de vasopresseurs avant l'intubation, 1171/7085 patients ont reçu des vasopresseurs avant l'intubation. Une hypotension post-intubation est survenue chez 22,2 % des patients dans toutes les études et chez 34,3 % des patients dans les études où l'administration de vasopresseurs avant l'intubation a été spécifiquement signalée. La mortalité d'une heure des patients dans toutes les études et dans le cadre des études sur l'utilisation de vasopresseurs était respectivement de 1,2 % et 1,6 %. La mortalité en milieu hospitalier dans l'ensemble des études était de 21,5 %, et de 13,1 % dans les études qui ont fait état d'un recours à un vasopresseur avant intubation. CONCLUSION: Les patients nécessitant une intubation d'urgence ont un taux élevé d'hypotension post-intubation et de mortalité en milieu hospitalier. Bien qu'il existe une justification intuitive pour l'utilisation de vasopresseurs pendant l'intubation en phase émergente, les preuves actuelles sont limitées pour soutenir un changement définitif dans la pratique clinique à ce moment-ci.
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Surfactant protein B (SP-B) deficiency is a rare genetic disease that causes fatal respiratory failure within the first year of life. Currently, the only corrective treatment is lung transplantation. Here, we co-transduced the murine lung with adeno-associated virus 6.2FF (AAV6.2FF) vectors encoding a SaCas9-guide RNA nuclease or donor template to mediate insertion of promoterless reporter genes or the (murine) Sftpb gene in frame with the endogenous surfactant protein C (SP-C) gene, without disrupting SP-C expression. Intranasal administration of 3 × 1011 vg donor template and 1 × 1011 vg nuclease consistently edited approximately 6% of lung epithelial cells. Frequency of gene insertion increased in a dose-dependent manner, reaching 20%-25% editing efficiency with the highest donor template and nuclease doses tested. We next evaluated whether this promoterless gene editing platform could extend survival in the conditional SP-B knockout mouse model. Administration of 1 × 1012 vg SP-B-donor template and 5 × 1011 vg nuclease significantly extended median survival (p = 0.0034) from 5 days in the untreated off doxycycline group to 16 days in the donor AAV and nuclease group, with one gene-edited mouse living 243 days off doxycycline. This AAV6.2FF-based gene editing platform has the potential to correct SP-B deficiency, as well as other disorders of alveolar type II cells.
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Doxiciclina , Edición Génica , Ratones , Animales , Dependovirus/genética , Vectores Genéticos/genética , ARN Guía de Sistemas CRISPR-Cas , Pulmón/metabolismo , Tensoactivos/metabolismo , Sistemas CRISPR-CasRESUMEN
Wide-complex, monomorphic tachycardias represent a range of tachyarrhythmias. Such patients can present asymptomatically and hemodynamically stable, while others are in shock. The etiology of the rhythm can be difficult to determine in the emergency department, and although electrocardiogram findings may be helpful, a workup after stabilization may be necessary to determine the cause. Treatment is therefore dependent on hemodynamic status and follows a stepwise approach, as initial therapies may be ineffective. We present the case of a three-year-old girl with wide-complex tachycardia which was exceedingly refractory to preliminary treatments and required trials of multiple treatment approaches to achieve conversion to normal sinus rhythm.
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Gene therapy is the delivery of a therapeutic gene for endogenous cellular expression with the goal of rescuing a disease phenotype. It has been used to treat an increasing number of human diseases with many strategies proving safe and efficacious in clinical trials. Gene delivery may be viral or non-viral, performed in vivo or ex vivo, and relies on gene integration or transient expression; all of these techniques have been applied to the treatment of Fabry disease. Fabry disease is a genetic disorder of the α-galactosidase A gene, GLA, that causes an accumulation of glycosphingolipids in cells leading to cardiac, renal and cerebrovascular damage and eventually death. Currently, there are no curative treatments available, and the therapies that are used have significant drawbacks. These treatment concerns have led to the advent of gene therapies for Fabry disease. The first Fabry patients to receive gene therapy were treated with recombinant lentivirus targeting their hematopoietic stem/progenitor cells. Adeno-associated virus treatments have also begun. Alternatively, the field of gene-editing is a new and rapidly growing field. Gene-editing has been used to repair disease-causing mutations or insert genes into cellular DNA. These techniques have the potential to be applied to the treatment of Fabry disease provided the concerns of gene-editing technology, such as safety and efficiency, were addressed. This review focuses on the current state of gene therapy as it is being developed for Fabry disease, including progresses and challenges as well as an overview of gene-editing and how it may be applied to correct Fabry disease-causing mutations in the future.
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Enfermedad de Fabry/genética , Enfermedad de Fabry/terapia , Edición Génica/métodos , Edición Génica/normas , Terapia Genética/métodos , Humanos , Mutación , Fenotipo , alfa-Galactosidasa/genéticaRESUMEN
Empyema necessitans (EN) is a rare but dangerous complication of a lower respiratory tract infection. The diagnosis can be difficult to make and therefore delayed. We describe a case of a child with an atypical presentation of EN. He was afebrile and without chest pain and presented with a palpable chest wall mass after a history of recent respiratory infection. The threshold of suspicion for EN should be low, and it must be suspected in all children with a chest wall mass and recent history of respiratory infection.
L'empyème de nécessité (Empyema necessitans) est une complication rare, mais dangereuse, d'une infection respiratoire inférieure. Il peut être difficile de parvenir au diagnostic, qui est souvent tardif, et s'associe à une hospitalisation prolongée et à une augmentation du taux de mortalité. Les auteurs décrivent le cas d'un garçon ayant des symptômes atypiques d'empyème de nécessité. Il n'avait pas de fièvre ni de douleurs thoraciques, mais avait une masse palpable de la paroi thoracique et avait récemment souffert d'une infection respiratoire. Le seuil d'évocation de l'empyème de nécessité doit être faible et s'appliquer à tous les cas d'enfants ayant une masse thoracique et une histoire récente d'infection respiratoire.
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Surfactant protein B (SP-B) deficiency is an autosomal recessive disorder that impairs surfactant homeostasis and manifests as lethal respiratory distress. A compelling argument exists for gene therapy to treat this disease, as de novo protein synthesis of SP-B in alveolar type 2 epithelial cells is required for proper surfactant production. Here we report a rationally designed adeno-associated virus (AAV) 6 capsid that demonstrates efficiency in lung epithelial cell transduction based on imaging and flow cytometry analysis. Intratracheal administration of this vector delivering murine or human proSFTPB cDNA into SP-B deficient mice restores surfactant homeostasis, prevents lung injury, and improves lung physiology. Untreated SP-B deficient mice develop fatal respiratory distress within two days. Gene therapy results in an improvement in median survival to greater than 200 days. This vector also transduces human lung tissue, demonstrating its potential for clinical translation against this lethal disease.
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Terapia Genética/métodos , Vectores Genéticos , Parvovirinae/genética , Proteinosis Alveolar Pulmonar/congénito , Proteína B Asociada a Surfactante Pulmonar/deficiencia , Animales , Animales Recién Nacidos , Línea Celular , Dependovirus , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Células HEK293 , Humanos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Transgénicos , Precursores de Proteínas/genética , Proteolípidos/genética , Proteinosis Alveolar Pulmonar/genética , Proteinosis Alveolar Pulmonar/metabolismo , Proteinosis Alveolar Pulmonar/terapia , Proteína B Asociada a Surfactante Pulmonar/genética , Proteína B Asociada a Surfactante Pulmonar/metabolismo , Proteínas Asociadas a Surfactante Pulmonar/genética , Transducción GenéticaRESUMEN
Lung gene therapy requires efficient transduction of slow-replicating epithelia and stable expression of delivered transgenes in the respiratory tract. Lentiviral (LV) vectors have the ideal coding, expression, and transducing capacity required for gene therapy. A modified envelope glycoprotein from the Jaagsiekte Sheep Retrovirus, termed Jenv, is well suited for LV-mediated lung gene therapy due to its inherent lung tropism. Here, two novel Jenv-pseudotyped LVs that effectively transduce lung tissue and yield titers similar to the gold standard, vesicular stomatitis virus glycoprotein (VSVg)-pseudotyped LVs, were generated. As the concentration efficiency of LVs was found to depend on envelope pseudotype, a large-scale production method tailored for Jenv-pseudotyped LVs was developed and the most appropriate method of concentration was determined. In contrast to VSVg and Ebola virus glycoprotein-pseudotyped LVs, ultracentrifugation through a sucrose cushion drastically reduced the yield of Jenv LVs, whereas polyethylene glycol precipitation and tangential flow filtration (TFF) proved to be more suitable methods for concentrating Jenv LVs. Importantly, pressure during TFF was found to be crucial for increasing LV recovery. Finally, a unique mouse model was developed to test the suitability of these novel Jenv-pseudotyped LVs for use in lung gene therapy applications.
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Técnicas de Transferencia de Gen , Terapia Genética/métodos , Vectores Genéticos , Lentivirus , Pulmón/metabolismo , Animales , Femenino , Glicoproteínas/genética , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ovinos , Transducción Genética/métodos , Transgenes , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismoRESUMEN
Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are small-ruminant betaretroviruses that share high nucleotide and amino acid identity, utilize the same cellular receptor, hyaluronoglucosaminidase 2 (Hyal2) for entry, and transform tissues with their envelope (Env) glycoprotein; yet, they target discrete regions of the respiratory tract-the lung and nose, respectively. This distinct tissue selectivity makes them ideal tools with which to study the pathogenesis of betaretroviruses. To uncover the genetic determinants of tropism, we constructed JSRV-ENTV chimeric viruses and produced lentivectors pseudotyped with the Env proteins from JSRV (Jenv) and ENTV (Eenv). Through the transduction and infection of lung and nasal turbinate tissue slices, we observed that Hyal2 expression levels strongly influence ENTV entry, but that the long terminal repeat (LTR) promoters of these viruses are likely responsible for tissue-specificity. Furthermore, we show evidence of ENTV Env expression in chondrocytes within ENTV-infected nasal turbinate tissue, where Hyal2 is highly expressed. Our work suggests that the unique tissue tropism of JSRV and ENTV stems from the combined effort of the envelope glycoprotein-receptor interactions and the LTR and provides new insight into the pathogenesis of ENTV.
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Productos del Gen env/genética , Retrovirus Ovino Jaagsiekte/fisiología , Virus Oncogénicos/fisiología , Adenomatosis Pulmonar Ovina/virología , Secuencias Repetidas Terminales , Infecciones Tumorales por Virus/virología , Tropismo Viral , Animales , Línea Celular , Orden Génico , Genoma Viral , Especificidad del Huésped , Interacciones Huésped-Patógeno , Humanos , Virus Reordenados/genética , OvinosRESUMEN
Adeno-associated virus (AAV) vectors are an efficient method of gene delivery to various tissues including the lung. Mouse models are often used as a preliminary preclinical model in order to advance AAV lung gene therapy vectors. In this chapter we describe an AAV purification protocol using heparin affinity chromatography as well as an intranasal and intratracheal method of delivering AAV vectors to the lungs of mice.
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Dependovirus/genética , Técnicas de Transferencia de Gen , Vectores Genéticos/genética , Pulmón/metabolismo , Administración Intranasal , Animales , Línea Celular , Cromatografía , Vectores Genéticos/administración & dosificación , Vectores Genéticos/aislamiento & purificación , Humanos , Inyección Intratimpánica , Ratones , Transducción GenéticaRESUMEN
Gene therapy for the treatment of genetic disorders has demonstrated considerable therapeutic success in clinical trials. Among the most effective and commonly used gene delivery vectors are those based on adeno-associated virus (AAV). Despite these advances in clinical gene therapy, further improvements in AAV vector properties such as rapid intracellular processing and transgene expression, targeted transduction of therapeutically relevant cell types, and longevity of transgene expression, will render extension of such successes to many other human diseases. Engineering of AAV capsids continues to evolve the specificity and efficiency of AAV-mediated gene transfer. Here, we describe a triple AAV6 mutant, termed AAV6.2FF, containing F129L, Y445F, and Y731F mutations. AAV6.2FF yielded 10-fold greater transgene expression in lung than AAV6 after 21 days. Additionally, this novel capsid demonstrated 101-fold and 49-fold increased transgene expression in the muscle and lungs, respectively, 24 hr post vector delivery when compared with the parental AAV6. Furthermore, AAV6.2FF retains heparin sulfate binding capacity and displays a 10-fold increase in resistance to pooled immunoglobulin neutralization in vitro. The rapid and potent expression mediated by AAV6.2FF is ideally suited to applications such as vectored immunoprophylaxis, in which rapid transgene expression is vital for use during an outbreak response scenario.