Adherence to protective mechanical ventilation in COVID-19 versus non-COVID-19-associated acute respiratory distress syndrome: Comparison between two prospective cohorts / Adhesión a la ventilación mecánica protectora en el síndrome de dificultad respiratoria aguda asociado a COVID-19 o asociado a otras etiologias: comparación entre dos cohortes prospectivas

Objective To compare adherence to protective mechanical ventilation (MV) parametersin patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 with patients with ARDS from other etiologies. Design Multiple prospective cohort study. Setting: Two Brazilian cohorts of ARDS patients were evaluated. One with COVID-19 patients admitted to two Brazilian intensive care units (ICUs) in 2020 and 2021 (C-ARDS, n=282), the other with ARDS-patients from other etiologies admitted to 37 Brazilian ICUs in 2016 (NC-ARDS, n=120). Patients: ARDS patients under MV. Interventions: None. Main variables of interest: Adherence to protective MV (tidal volume ≤8mL/kg PBW; plateau pressure ≤30cmH2O; and driving pressure ≤15cmH2O), adherence to each individual component of the protective MV, and the association between protective MV and mortality. Results Adherence to protective MV was higher in C-ARDS than in NC-ARDS patients (65.8% vs. 50.0%, p=0.005), mainly due to a higher adherence to driving pressure ≤15cmH2O (75.0% vs. 62.4%, p=0.02). Multivariable logistic regression showed that the C-ARDS cohort was independently associated with adherence to protective MV. Among the components of the protective MV, only limiting driving pressure was independently associated with lower ICU mortality. Conclusions Higher adherence to protective MV in patients with C-ARDS was secondary to higher adherence to limiting driving pressure. Additionally, lower driving pressure was independently associated with lower ICU mortality, which suggests that limiting exposure to driving pressure may improve survival in these patients (AU)

Objetivo Comparar la adhesión a la ventilación mecánica (VM) protectora en pacientes con síndrome de dificultad respiratoria aguda (SDRA) causada por COVID-19 con pacientes con SDRA de otras etiologías. Diseño Estudio de cohorte prospectivo. Âmbito: Se evaluaron dos cohortes de pacientes con SDRA: 1.pacientes con COVID-19 ingresados en dos unidades de cuidados intensivos (UCI) brasileñas en 2020 y 2021 (C-ARDS, n=282); 2.pacientes con SDRA de otras etiologías ingresados en 37 UCI brasileñas en 2016 (NC-ARDS, n=120). Pacientes: Pacientes con SDRA bajo VM invasiva. Intervenciones: No. Variables de interés principals: Adhesión a la VM protectora (volumen tidal ≤8mL/kg; presión de meseta ≤30cmH2O; y presión de distensión [PD] ≤15cmH2O), adhesión a cada componente individual de la VM protectora, y la asociación entre la VM protectora y la mortalidad. Resultados La adhesión a la VM protectora fue mayor en la cohorte C-ARDS que en la NC-ARDS (65,8% vs. 50,0%, p=0,005), principalmente debido a mayor adhesión a la PD≤15cmH2O (75,0% vs. 62,4%, p=0,02). La regresión logística multivariable mostró que la cohorte C-ARDS se asoció de forma independiente con la adhesión a la VM protectora. Entre los componentes de la VM protectora, sólo la limitación de la PD se asoció de forma independiente con menor mortalidad en la UCI. Conclusión La mayor adhesión a la VM protectora en los pacientes con C-ARDS fue secundaria a la mayor adhesión a limitación da PD. Además, una menor PD se asoció de forma independiente a menor mortalidad en la UCI, lo que sugiere que limitar la exposición a altas PD puede mejorar la supervivencia en estos pacientes (AU)

Adherence to protective mechanical ventilation in COVID-19 versus non-COVID-19-associated acute respiratory distress syndrome: Comparison between two prospective cohorts.

OBJECTIVE: To compare adherence to protective mechanical ventilation (MV) parameters in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 with patients with ARDS from other etiologies. DESIGN: Multiple prospective cohort study. SETTING: Two Brazilian cohorts of ARDS patients were evaluated. One with COVID-19 patients admitted to two Brazilian intensive care units (ICUs) in 2020 and 2021 (C-ARDS, n=282), the other with ARDS-patients from other etiologies admitted to 37 Brazilian ICUs in 2016 (NC-ARDS, n=120). PATIENTS: ARDS patients under MV. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Adherence to protective MV (tidal volume ≤8mL/kg PBW; plateau pressure ≤30cmH2O; and driving pressure ≤15cmH2O), adherence to each individual component of the protective MV, and the association between protective MV and mortality. RESULTS: Adherence to protective MV was higher in C-ARDS than in NC-ARDS patients (65.8% vs. 50.0%, p=0.005), mainly due to a higher adherence to driving pressure ≤15cmH2O (75.0% vs. 62.4%, p=0.02). Multivariable logistic regression showed that the C-ARDS cohort was independently associated with adherence to protective MV. Among the components of the protective MV, only limiting driving pressure was independently associated with lower ICU mortality. CONCLUSIONS: Higher adherence to protective MV in patients with C-ARDS was secondary to higher adherence to limiting driving pressure. Additionally, lower driving pressure was independently associated with lower ICU mortality, which suggests that limiting exposure to driving pressure may improve survival in these patients.

Functional improvements associated with cranioplasty after stroke and traumatic brain injury: a cohort study.

OBJECTIVE: Decompressive craniectomy is part of the acute management of several neurosurgical illnesses, and is commonly followed by cranioplasty. Data are still scarce on the functional and cognitive outcomes following cranioplasty. We aim to evaluate these outcomes in patients who underwent cranioplasty following traumatic brain injury (TBI) or stroke. METHODS: In this prospective cohort, we assessed 1-month and 6-month neuropsychological and functional outcomes in TBI and stroke patients who underwent cranioplasty at a Brazilian tertiary center. The primary outcome was the change in the Digits Test at 1 and 6 months after cranioplasty. Repeated measures general linear models were employed to assess the patients' evolution and interactions with baseline characteristics. Effect size was estimated by the partial η2. RESULTS: A total of 20 TBI and 14 stroke patients were included (mean age 42 ± 14 years; 52.9% male; average schooling 9.5 ± 3.8 years; 91.2% right-handed). We found significant improvements in the Digits Tests up to 6 months after cranioplasty (p = 0.004, partial η2 = 0.183), as well as in attention, episodic memory, verbal fluency, working memory, inhibitory control, visuoconstructive and visuospatial abilities (partial η2 0.106-0.305). We found no interaction between the cranioplasty effect and age, sex or schooling. Patients submitted to cranioplasty earlier (<1 year) after injury had better outcomes. CONCLUSION: Cognitive and functional outcomes improved after cranioplasty following decompressive craniectomy for stroke or TBI. This effect was consistent regardless of age, sex, or education level and persisted after 6 months. Some degree of spontaneous improvement might have contributed to the results.

Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials.

Machine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.

Acute Appendicitis after Liver Transplantation: A Case Report and Review of the Literature.

Acute appendicitis is one of the most common etiologies for acute abdomen. However, fewer than 30 cases of acute appendicitis after liver transplantation have so far been reported in the literature. Previous case studies have concluded that acute appendicitis after liver transplantation may present differently than in non-immunosuppressed patients and thus may lead to more complications. Herein, we describe the fourth case of laparoscopic appendectomy in a 40-year-old female presenting with an acute abdomen, 10 years after orthotopic liver transplantation for autoimmune hepatitis. Additionally, we review the literature, and emphasize the importance for laparoscopic, rather than open appendectomy after liver transplantation. Overall, despite the small number of reported cases of appendicitis after orthotopic liver transplantation, we found the incidence and clinical presentation are similar to patients without liver transplantation. The etiologies for appendicitis in patients after liver transplantation may be different than in those not chronically immunosuppressed, with significantly less lymphoid hyperplasia and increased fecalith and cytomegaloviral infections. Preliminary results showed that laparoscopic appendectomy after liver transplantation results in decreased hospital stays and fewer complications.

Pilot Study Evaluating Regulatory T Cell-Promoting Immunosuppression and Nonimmunogenic Donor Antigen Delivery in a Nonhuman Primate Islet Allotransplantation Model.

The full potential of islet transplantation will only be realized through the development of tolerogenic regimens that obviate the need for maintenance immunosuppression. Here, we report an immunotherapy regimen that combines 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (ECDI)-treated donor lymphoid cell infusion (ECDI-DLI) with thymoglobulin, anti-interleukin-6 receptor antibody and rapamycin to achieve prolonged allogeneic islet graft survival in a nonhuman primate (NHP) model. Prolonged graft survival is associated with Treg expansion, donor-specific T cell hyporesponsiveness and a transient absence of donor-specific alloantibody production during the period of graft survival. This regimen shows promise for clinical translation.

Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation.

To reduce widespread shortages, attempts are made to use more marginal livers for transplantation. Many of these grafts are discarded for fear of inferior survival rates or biliary complications. Recent advances in organ preservation have shown that ex vivo subnormothermic machine perfusion has the potential to improve preservation and recover marginal livers pretransplantation. To determine the feasibility in human livers, we assessed the effect of 3 h of oxygenated subnormothermic machine perfusion (21°C) on seven livers discarded for transplantation. Biochemical and microscopic assessment revealed minimal injury sustained during perfusion. Improved oxygen uptake (1.30 [1.11-1.94] to 6.74 [4.15-8.16] mL O2 /min kg liver), lactate levels (4.04 [3.70-5.99] to 2.29 [1.20-3.43] mmol/L) and adenosine triphosphate content (45.0 [70.6-87.5] pmol/mg preperfusion to 167.5 [151.5-237.2] pmol/mg after perfusion) were observed. Liver function, reflected by urea, albumin and bile production, was seen during perfusion. Bile production increased and the composition of bile (bile salts/phospholipid ratio, pH and bicarbonate concentration) became more favorable. In conclusion, ex vivo subnormothermic machine perfusion effectively maintains liver function with minimal injury and sustains or improves various hepatobiliary parameters postischemia.

Early onset adenovirus infection after simultaneous kidney-pancreas transplant.

Adenoviruses (AdV) are increasingly recognized as important viral pathogens in immunocompromised hosts. The clinical spectrum ranges from asymptomatic viremia to allograft dysfunction, and death. Most of the medical literature is on AdV infection in children and bone marrow transplant recipients. We report a case of AdV in an adult recipient in the first month after simultaneous kidney-pancreas transplant with thymoglobulin induction. This is a rare report of adenovirus infection after multiorgan transplant, and is unique in that it exhibited tissue invasive disease without any localizing signs or allograft dysfunction, while other cases in medical literature had invasive disease of the allograft with allograft dysfunction, failure, or death. In addition, this is the first report of a radiologic presentation of AdV nephritis.

Donor age intensifies the early immune response after transplantation.

Increasing donor age is associated with reduced graft function. We wondered if donor age may not only affect intrinsic function but also alter the immune response of the recipient. Kidneys from young and old F-344 rats (3 vs 18 months) were transplanted into bilaterally nephrectomized young Lewis recipients and compared with age-matched controls (follow-up: 6 months). Renal function and structural changes were assessed serially in both native kidneys and allografts. Host alloreactivity, graft-infiltrating cells, and their inflammatory products were determined at intervals to examine the correlation of immune response and donor age. Functional and structural deterioration had advanced significantly in older allografts compared with age-matched native controls, whereas differences between young allografts and native controls of similar age were only minor. Changes in grafts from elderly rats were associated with a more intense host immune response early post-transplant (up to 1 month) reflected by significantly higher numbers of peripheral T and B cells, increased T-cell alloreactivity and modified cytokine patterns associated with elevated frequencies of intragraft dendritic cells, B cells, and CD31+ cells. By 6 months, recipients of young donor grafts produced comparable or more intense alloantigen-specific immune responses. Older donor grafts elicit a stronger immune response in the early period after transplantation.

Quantification of donor-derived DNA in serum: a new approach of acute rejection diagnosis in a rat kidney transplantation model.

Clinical and laboratory findings of acute rejection (AR) are often late and misleading. Core needle biopsy, the most reliable diagnostic method, is usually performed late in the course of AR and is associated with several complications. Therefore noninvasive approaches to monitor the immune system for detection of early AR is one of the major aims in transplant medicine. In a fully MHC-mismatched renal allograft model in the rat, we quantified donor-derived DNA (ddDNA) in the recipient serum using real-time RT-PCR as an alternative screening procedure for the early diagnosis of acute rejection. We also investigated the influence of different immunosuppressive protocols on the levels of ddDNA. Our results show that donor-derived DNA is present in the serum of kidney allograft recipients prior to acute rejection. Animals that received a syngeneic graft and animals that received a mismatched allograft but were treated with immunosuppressive drugs did not show significant elevations of ddDNA. When steroid therapy failed to avoid acute rejection, the animals showed a delayed peak of ddDNA. In summary, the detection of ddDNA in recipient serum offers a noninvasive diagnostic approach to uncover ongoing rejection processes in the graft.

Grafts from elderly donors elicit a stronger immune response in the early period posttransplantation: a study in a rat model.

With a growing demand for transplants, grafts from older donors are increasingly used. However, altered immune responses associated with increasing donor age may influence graft survival. We dissected the effects of donor age on the immune response in an experimental model. Kidneys from young and old F-344 donors (3 and 18 months) transplanted into young Lewis recipients (3 months) were followed for 6 months. Renal function, structural changes, and immune activation were tested at serial time intervals. Splenocytes and peripheral blood mononuclear cells were examined by flow cytometry; alloantigen-specific intracellular IFN-gamma secretion was evaluated by ELISPOT. Grafts from both young and old donors survived the observation period. The ratio of structural changes (6/1 months) increased twofold in old vs young grafts. In parallel, the ratio of renal function declined by fivefold in recipients of old donor kidneys. Most interestingly, elderly grafts produced a modified immune response: the numbers of T/B cells and alloreactive T cells increased early following the transplantation of old grafts (P < .05). However, by 6 months, the amounts of T and B cells as well as alloantigen-specific immune responses were comparable in recipients of old versus young grafts. Older grafts elicit a stronger immune response during the early period posttransplantation. This process is associated with an increased immunogenicity in older grafts. Clinical immunosuppressive protocols need to consider these effects.

Induction of heme oxygenase-1 in the donor reduces graft immunogenicity.

There is increasing evidence that the induction of the enzyme heme oxygenase-1 (HO-1) improves both graft function and survival. Although it has been shown that HO-1 promotes graft protection, it remains unknown whether it reduces graft immunogenicity by modulating dendritic cells. In the current experiment, we investigated the impact of HO-1 induction on frequencies and trafficking of donor-derived dendritic cells (DCs). Kidneys from DA rats were transplanted into untreated Lewis recipients. Donor animals were treated with cobalt protoporphyrin (CoPP; 5 mg/kg IP) 24 hours prior to organ harvesting to induce HO-1. Controls remained untreated or received zinc protoporphyrin (ZnPP; 20 mg/kg, IP) to block HO-1 induction. Analyses of grafts, spleens, lymph nodes and blood of Lewis recipients were performed at days 1 and 3 posttransplantation. Donor-specific DCs were determined by flow cytometry using haplotype-specific mAb against RT1(ab) and mAb against OX62(+) antigens. Cell markers (CD4/CD8(+) T cells, ED1(+) monocytes, MHC class II(+) CD86(+) DC) were measured by immunohistochemical staining. T-cell alloreactivity of recipient splenocytes was measured by ELISPOT. Induction of HO-1 reduced frequencies of donor-derived DCs in the graft and recipient compartments, which was associated with reduced frequencies of CD4(+) T cells and CD8(+) T cells and alloreactivity. Expression of costimulatory molecule CD86 and MHC class II antigens were also reduced, although not significantly. Thus, induction of HO-1 reduced graft immunogenicity. These mechanisms may explain the protective effects of HO-1 induction.

Induction of carbon monoxide in the donor reduces graft immunogenicity and chronic graft deterioration.

Chronic allograft dysfunction remains the major obstacle for long-term successful transplantation. To date there is no effective treatment. Overexpression of protective genes has provided increased graft function and survival. This mechanism has been implicated in the process of graft accommodation. One of these genes that has been shown to mediate protective effects decodes the enzyme heme oxygenase-1 (HO-1), and an HO-1 downstream product, carbon monoxide (CO). Using an established model of kidney chronic allograft rejection in the rat, we investigated the impact of methylene chloride (MC), a CO donor, as a therapeutic tool to reduce chronic graft deterioration. We showed that donor and long-term recipient treatment with MC improved graft function and reduced histological signs of chronic rejection. Carbon monoxide may be a promising agent to improve graft quality and long-term graft function.