Search Results (470)

Lung transplantation remains the standard of care for end-stage lung disease, yet a persistent gap exists between donor lung availability and growing clinical demand. Expanding the donor pool and optimising donor lung management are therefore critical priorities. However, no universally accepted management protocols are currently in place. This narrative review examines evidence-based strategies to improve lung utilisation across three donor categories: donors after brain death (DBD), controlled donors after circulatory death (cDCD), and uncontrolled donors after circulatory death (uDCD). A systematic literature search was conducted to identify interventions targeting lung preservation and function, including protective ventilation, recruitment manoeuvres, fluid and hormonal management, and ex vivo lung perfusion (EVLP). Distinct pathophysiological mechanisms—sympathetic storm and systemic inflammation in DBD, ischaemia–reperfusion injury in cDCD, and prolonged warm ischaemia in uDCD—necessitate tailored approaches to lung preservation. In DBD donors, early application of protective ventilation, bronchoscopy, and infection surveillance is essential. cDCD donors benefit from optimised pre- and post-withdrawal management to mitigate lung injury. uDCD donor lungs, uniquely vulnerable to ischaemia, require meticulous post-mortem evaluation and preservation using EVLP. Implementing structured, evidence-based lung management strategies can significantly enhance donor lung utilisation and expand the transplantable organ pool. The integration of such practices into clinical protocols is vital to addressing the global shortage of suitable lungs for transplantation. Full article

Fluid resuscitation after thermal injury is paramount to avoid burn shock and restore organ perfusion. Both over- and under-resuscitation can lead to unintended consequences affecting patient outcomes. While many studies have examined systemic effects, limited data exist on how fluid resuscitation impacts burn wound progression in the acute period. Furthermore, the mechanisms underlying burn wound progression remain not fully understood. This study used a swine model to investigate how varying resuscitation levels affect peri-burn wound dynamics. Twenty-seven female Yorkshire pigs were anesthetized, subjected to 40% total body surface area burn and 15% hemorrhage, then randomized (n = 9) to receive decision-support-driven (adequate, 2–4 mL/kg/%TBSA), fluid-withholding (under, <1 mL/kg/%TBSA), or high-constant-rate (over, >>4 mL/kg/%TBSA) resuscitation. Pigs were monitored for 24 h in an intensive care setting prior to necropsy. Laser Doppler Imaging (LDI) was conducted pre-burn and at 2, 6, 12, and 24 h post burn to assess perfusion. Biopsies were taken from burn, peri-burn (within 2 cm), and normal skin. RNA was isolated at 24 h for the qRT-PCR analysis of IL-6, CXCL8, and IFN-γ. At hour 2, LDI revealed increased peri-burn perfusion in over-resuscitated animals vs. under-resuscitated animals (p = 0.0499). At hour 24, IL-6 (p = 0.0220) and IFN-γ (p = 0.0253) were elevated in over-resuscitated peri-burn skin. CXCL8 showed no significant change. TUNEL staining revealed increased apoptosis in over- and under-resuscitated peri-burn skin. Differences in perfusion and cytokine expression based on resuscitation strategy suggest that fluid levels may influence burn wound progression. Full article

Introduction: Liver transplantation remains the definitive treatment for end-stage liver disease but faces critical challenges including organ shortages and preservation difficulties, particularly with extended criteria donor (ECD) grafts. Hypothermic machine perfusion (HMP) represents a promising alternative to traditional static cold storage (SCS). Methods: This retrospective study analyzed outcomes from 62 liver transplant recipients between 2016 and 2025, comparing 8 grafts preserved by HMP using the Liver Assist^® system and 54 grafts preserved by SCS. Parameters assessed included postoperative complications, hemodynamic stability, ischemia times, and survival outcomes. Results: HMP significantly reduced surgical (0% vs. 75.9%, p = 0.01) and biliary complications (0% vs. 34.4%, p = 0.004), improved hemodynamic stability post-reperfusion (∆MAP%: 1 vs. 21, p = 0.006), and achieved superior one-year survival rates (100% vs. 84.4%). Despite longer ischemia periods, grafts treated with HMP exhibited fewer adverse effects from ischemia-reperfusion injury. Discussion: These findings highlight the substantial benefits of HMP, particularly in improving graft quality from marginal donors and reducing postoperative morbidity. Further adoption of this technology could significantly impact liver transplantation outcomes by expanding the viable donor pool. Conclusions: The study underscores the effectiveness of hypothermic machine perfusion (HMP) as a superior preservation method compared to traditional static cold storage (SCS), HMP appears to be associated with improved short-term outcomes in liver transplantation. By substantially reducing postoperative complications and enhancing graft viability, HMP emerges as a pivotal strategy for maximizing the use of marginal donor organs. Further research and broader clinical implementation are recommended to validate these promising results and to fully harness the potential of HMP in liver transplantation. Full article

The need for organs suitable for transplantation has continued to rise as need outweighs availability. Increased demand has driven innovation in the field. Over the past ten years, donation after circulatory death (DCD) donors have become a greater portion of the donor pool. This method of donation includes a period of warm ischemia time to the organs. Thus, its use is dependent on recovery methods. Historically, extracorporeal membrane oxygenation (ECMO) was one of the first pumping technologies to enhance organ preservation in the potential donor. Subsequently, the adoption of normothermic regional perfusion (NRP) technology has also shown promise in organ transplantation. These technologies have increased utilization of organs and enhanced the pool of donor organs. This review seeks to summarize the literature supporting in situ technologies (ECMO and NRP) utilized in procurement of solid organs from DCD donors. The benefit of in situ perfusion in DCD organ recovery is that these technologies increase the number of organs available for transplantation by reducing ischemic injury. The disadvantages include the added technical aspect, added operating room time, and the increased ethical concerns surrounding these technologies compared to conventional methods of organ recovery. Full article

Background/Objectives: In septic shock, microcirculatory dysfunction contributes to organ failure and mortality. While sidestream dark-field (SDF) imaging is the reference method for assessing microvascular perfusion, its complexity limits routine use. This study evaluates near-infrared spectroscopy (NIRS) with vascular occlusion testing (VOT) as a potential bedside tool for monitoring microcirculatory changes following fluid resuscitation. Methods: Sixty-three fluid-responsive patients with sepsis were randomized to receive either 20% albumin or crystalloid. NIRS-VOT and sublingual SDF measurements were obtained at baseline and 60 min post-resuscitation. The reoxygenation slope (ReOx) derived from NIRS was calculated and compared with clinical severity scores and SDF-derived microcirculatory parameters. Results: ReOx significantly increased from baseline to 60 min in the albumin group (p = 0.025), but not in the crystalloid group. However, between-group differences at 60 min were not statistically significant. ReOx at 60 min was inversely correlated with APACHE II score (ρ = −0.325) and lactate (ρ = −0.277) and showed a weak inverse trend with norepinephrine dose. AUROC for ICU survival based on ReOx was 0.616. NIRS ReOx showed weak correlations with SDF parameters, including the number of crossings (p = 0.03) and the consensus proportion of perfused vessels (CPPV; p = 0.004). Conclusions: NIRS-VOT detected microcirculatory trends after albumin administration but showed limited agreement with SDF imaging. These findings suggest that NIRS and SDF assess different physiological domains. Further studies are warranted to define the clinical utility of NIRS as a microcirculation monitoring tool (Clinicaltrials.gov: NCT05357339). Full article

Introduction: The vascular architecture of the vocal folds plays a critical role in sustaining the dynamic demands of phonation. Disruptions in this microvascular system are linked to various pathological conditions, including Reinke’s edema, hemorrhage, and laryngeal carcinoma. This review explores the structural and functional components of vocal fold microvascularization, with emphasis on pericytes, endothelial interactions, and neurovascular regulation. Materials and Methods: A systematic review of the literature was conducted using databases such as PubMed, Scopus, Web of Science, and Embase. Keywords included “pericytes”, “Reinke’s edema”, and “vocal fold microvascularization”. Selected studies were peer-reviewed and met criteria for methodological quality and relevance to laryngeal microvascular physiology and pathology. Results: The vocal fold vasculature is organized in a parallel, tree-like pattern with distinct arterioles, capillaries, and venules. Capillaries dominate the superficial lamina propria, while transitional vessels connect to deeper arterioles surrounded by smooth muscle. Pericytes, present from birth, form tight associations with endothelial cells and contribute to capillary stability, vessel remodeling, and mechanical protection during vibration. Their thick cytoplasmic processes suggest a unique adaptation to the biomechanical stress of phonation. Arteriovenous anastomoses regulate perfusion by shunting blood according to functional demand. Furthermore, neurovascular control is mediated by noradrenergic fibers and neuropeptides such as VIP and CGRP, modulating vascular tone and glandular secretion. The limited lymphatic presence in the vocal fold mucosa contributes to edema accumulation while also restricting carcinoma spread, offering both therapeutic challenges and advantages. Conclusions: A deeper understanding of vocal fold microvascularization enhances clinical approaches to voice disorders and laryngeal disease, offering new perspectives for targeted therapies and regenerative strategies. Full article

In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of tissue inflammation through increased endothelial permeability, and ultimately organ damage. As intracellular cyclic AMP (cAMP) levels are known to control intercellular junctions or apoptosis in the endothelium, we investigated here the effect of the Phosphodiesterase 4 inhibitor Roflumilast, a drug increasing cAMP levels, on irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). Using continuous impedance measurements in confluent endothelial cell monolayers, Roflumilast was found to rapidly reinforce the endothelial barrier and to prevent irradiation-induced barrier disruption. In accordance, irradiation-induced alteration in membrane VE-Cadherin-composed adherens junctions was prevented by Roflumilast treatment after irradiation, which was correlated with its protective effect of the actin cytoskeleton. Post-irradiation treatment with Roflumilast also protected HPMECs from irradiation-induced late apoptosis, but was without effect on irradiation-induced ICAM-1 overexpression. Overall, our results indicate that the beneficial effects of Roflumilast after irradiation are linked to the strengthening/protection of the endothelial barrier and reduced apoptosis, suggesting that this medicine may be useful for the treatment of endothelial damages after exposure to a high dose of radiation. Full article

Background and Objectives: Previous studies have shown that a major part of adverse drug reactions (ADRs) are preventable, and they contribute to increased morbidity, mortality, and costs. To our knowledge, no study investigating preventable ADRs has been carried out in Lithuania. Therefore, the aim of this study was to characterize ADRs in the intensive care unit (ICU) of a secondary care Lithuanian hospital as well as to identify drug classes and organ systems most commonly implicated in preventable and nonpreventable ADRs. Materials and Methods: This observational prospective study was conducted in an 18-bed ICU of Kaunas Hospital of the Lithuanian University of Health Sciences from 1 September 2021 to 31 August 2023. All ADRs were assessed for causality, severity, and preventability. The Anatomical Therapeutic and Chemical (ATC) system was used to classify drug classes implicated in ADRs. The organ systems affected were analyzed using the Medical Dictionary for Regulatory Activities (MedDRA). Results: A total of 154 patients with a median age of 78.8 years (range, 18–97) were enrolled into this study. There were 255 ADRs identified; preventable ADRs accounted for 87.5%. Among the preventable ADRs, the top three therapeutic subgroups were antithrombotic agents (26.5%), anti-inflammatory and antirheumatic products (22.0%), and blood substitutes and perfusion solutions (20.2%). Meanwhile, among nonpreventable ADRs, antibacterials for systemic use (62.5%) and antithrombotic agents (46.9%) were the two most common therapeutic subgroups. The gastrointestinal as well as the skin and subcutaneous tissues organ systems were more likely to be affected by nonpreventable ADRs (56.3% vs. 17.5%, p ˂ 0.05 and 12.5% vs. 0.4%, p ˂ 0.05, respectively), while the renal and urinary organ systems were more likely to be affected by preventable ADRs (38.1% vs. 6.3%, p ˂ 0.05). Conclusions: Our study showed a very high incidence of preventable ADRs (87.5%). Drugs affecting blood and blood-forming organs were most frequently implicated in these ADRs. This area deserves special attention and strategies need to be implemented to reduce the incidence of preventable ADRs and their impact on the healthcare system. Moreover, it emphasizes the need for future studies at a national level as, to our knowledge, this is the first study addressing the issues of avoidable harm at the ICU of one Lithuanian hospital. Full article

This study aimed to characterize the time-dependent effects of methane (CH₄) inhalation, initiated at defined intervals following sepsis onset, on organ function, systemic oxygen utilization, and mitochondrial respiration in a rodent model. Adult rats were subjected to abdominal sepsis or sham operation. Septic animals were assigned to groups receiving 2.2% CH₄ in normoxic air at specific post-insult phases (early: 3–6 h; intermediate: 16–19 h; late: 19–22 h), while a control group remained untreated. At 24 h, organ function was evaluated using a Rat-Specific Organ Failure Assessment (ROFA) score, along with measurements of plasma myeloperoxidase (MPO) activity, Complex I–II-linked oxidative phosphorylation in renal and cerebellar tissues, systemic oxygen extraction, and global tissue perfusion (pCO₂-gap). Sepsis induced significant organ dysfunction, impaired hemodynamics, reduced oxygen utilization, and decreased mitochondrial respiration. CH₄ inhalation improved survival when administered early, restored cerebellar mitochondrial respiration during the intermediate phase, and in the late phase reduced ROFA scores and MPO levels, while attenuating mitochondrial dysfunction in renal and cerebellar tissues. All CH₄-treated groups demonstrated improved renal function and enhanced tissue oxygenation. Targeted CH₄ inhalation during sepsis confers protective effects by preserving mitochondrial function, reducing inflammation, and improving oxygen dynamics, suggesting promising therapeutic potential. Full article

Background/Objectives: Challenges in normothermic machine perfusion (NMP) remain, particularly concerning the duration for which individual organs can be safely preserved. We hypothesize that optimal preservation can be achieved by perfusing organs together in a multivisceral block. Therefore, our aim was to establish a platform for ex situ multivisceral organ perfusion. Methods: Multivisceral grafts containing the liver, kidneys, pancreas, spleen, and intestine were obtained from Yorkshire pigs. Three generation (gen) set-ups were tested during the iterative design process, and minor changes were made throughout. Gen 1 (n = 4) used a custom-designed single perfusion circuit. Gen 2 (n = 3) employed a dual perfusion circuit. Gen 3 (n = 4) featured a single perfusion circuit with an optimized basin and reservoir. Grafts underwent NMP using an autologous blood-based perfusate, while hemostatic parameters and function were assessed. Results: Comparing Gen 1 versus Gen 3, the mean aortic flow improved (1.018 vs. 2.089 L), resistance decreased (0.224 vs. 0.038), urine output increased (51.90 vs. 271.3 mL), oxygen consumption rose (43.56 vs. 49.52 mL O₂/min), perfusate lactate levels dropped (10.44 vs. 3.10 mmol/L), and the pH became more physiological (7.27 vs. 7.30). Cellular injury trended lower in Gen 3. Histological evaluation demonstrated minimal differences in Gens 2 and 3. Conclusions: We demonstrate the feasibility of abdominal multivisceral NMP for up to 8 h. Adequate arterial flow, stable perfusate pH, and high oxygen consumption in setup 3 indicated organ viability. Multivisceral perfusion may serve as a plat-form for long-term NMP. Full article

Organ shortage is a major challenge in transplantation, prompting the use of extended criteria donor grafts. These require improved preservation techniques and reliable methods to assess graft function. This study aimed to evaluate changes in the kidney metabolome following three preservation methods: normothermic ex vivo kidney perfusion (NEVKP), hypothermic machine perfusion (HMP) and static cold storage (SCS) in porcine autotransplant models. A chemical biopsy allowed minimally invasive sampling of metabolites, which were analyzed using liquid chromatography coupled with high-resolution mass spectrometry. The results highlighted metabolites affected by ischemia and oxidative stress in donor kidneys, as well as changes specific to each preservation method. Differences were observed immediately after transplantation and reperfusion and several days post-surgery. NEVKP was associated with the activation of physiological anti-oxidative and anti-inflammatory mechanisms, suggesting potential protective effects. However, some metabolites had dual roles, which may influence future graft treatment designs. HMP and SCS, while reducing energy demand in cells, also limit physiological repair mechanisms. These findings provide a basis for improving graft assessment and organ preservation, with chemical biopsy serving as both a tool for discovery and a potential diagnostic method for monitoring graft quality. Full article

Background: PP-007 (SANGUINATE^®, PEGylated carboxyhemoglobin, bovine) is under development to treat conditions of ischemia/hypoxia. Hemorrhagic/hypovolemic shock (H/HVS) becomes a life-threatening comorbidity due in part to hypotension and hypoxia. Blood transfusions are indicated, but supply and compatibility issues may limit subject access or when blood is not an option due to religious restriction or concern for clinical complications. PP-007 is universally compatible with an effective hydrodynamic radius and colloidal osmotic pressure facilitating perfusion without promoting extravasation. Methods: A review of previous clinical trials was performed and revealed an Open-Label Phase 1 safety study of acute severe anemia (hemoglobin ≤ 5 g/dL) in adult (≥18 y) patients unable to receive red blood cell transfusion (NCT02754999). Primary outcomes included safety events with secondary efficacy measures of organ function and survival at 1, 14, and 28 days. Additionally, a retrospective review of published, peer-reviewed case reports was performed, evaluating the administration of Sanguinate for Expanded Access in those patient populations where blood was not an option over the past 12 years. Results: A total of 103 subjects were enrolled in the Phase I safety study with significant co-morbidities that most commonly included hypertension (n = 43), acute and chronic kidney disease (n = 38), diabetes mellitus (n = 29), gastrointestinal bleeds (n = 18), and sickle cell disease (n = 13). Enrollment characteristics included decreased hemoglobin and severe anemia (mean baseline hemoglobin of 4.2 g/dL). Treatments included an average of three infusions [range 1–17]. Secondary efficacy measures were mean Hb levels, respiratory support, and vasopressor requirements, all demonstrating clinically relevant improvements. Fourteen additional cases were identified in the literature. Though one patient died due to pre-treatment conditions, all patients but one were discharged home in stable condition. Conclusion: Collectively, these observations are encouraging and provide support for the continued evaluation of PP-007 in advanced clinical trials in severe anemia including H/HVS. The review of published case reports underscored the potential of Sanguinate to reduce early mortality. Adverse effects included transient hypertension, lethargy, dizziness, and troponin elevation. These findings highlight the need for continued research and funding of blood alternatives to improve outcomes when standard blood transfusions are unavailable or contraindicated. Full article

Ex situ machine perfusion has emerged as a pivotal technique for organ preservation and pre-transplant viability assessment, where the real-time monitoring of mitochondrial biomarkers—flavin mononucleotide (FMN) and nicotinamide adenine dinucleotide (NADH)—could significantly mitigate ischemia-reperfusion injury risks. This study develops a non-invasive optical method combining fluorescence and UV-visible spectrophotometry to quantify FMN and NADH in hypothermic oxygenated perfusion media. Calibration curves revealed linear responses for both biomarkers in absorption and fluorescence (FMN: λ_ex = 445 nm, λ_em = 530–540 nm; NADH: λ_ex = 340 nm, λ_em = 465 nm) at concentrations < 100 μg mL⁻¹. However, NADH exhibited nonlinear fluorescence above 100 μg mL⁻¹, requiring shifted excitation to 365 nm for reliable detection. Spectroscopic analysis further demonstrated how perfusion solution composition alters FMN/NADH fluorescence properties, with consistent reproducibility across media. The method’s robustness was validated through comparative studies in clinically relevant solutions, proposing a strategy for precise biomarker quantification without invasive sampling. These findings establish a foundation for real-time, optical biosensor development to enhance organ perfusion monitoring. By bridging spectroscopic principles with clinical needs, this work advances translational sensor technologies for transplant medicine, offering a template for future device integration. Full article

As the population of adults with congenital heart disease (ACHD) continues to grow, a significant and often underrecognized complication is the development of cardiorenal syndrome (CRS)—a complex, bidirectional interaction between cardiac and renal dysfunction. While CRS has been extensively studied in acquired heart failure, its manifestations and implications in ACHD remain insufficiently understood. Emerging data suggest that renal dysfunction is highly prevalent in ACHD, with significant associations to adverse outcomes regardless of cardiac lesion type or functional status. This review explores CRS within three key physiologic categories in ACHD: patients with a systemic right ventricle, those with a subpulmonary right ventricle, and those with Fontan circulation. Each subgroup presents unique hemodynamic challenges that affect renal perfusion, filtration pressure, and systemic congestion, contributing to both acute and chronic renal impairment. The utility of renal biomarkers such as albuminuria, cystatin C, and estimated glomerular filtration rate (eGFR) is emphasized, alongside the importance of early detection and multidisciplinary management. Heart failure therapy tailored to congenital anatomy, neurohormonal modulation, and careful volume control remain the cornerstones of treatment, while transplantation strategies must consider the potential for irreversible end-organ damage. Given the profound implications of CRS on quality of life and survival, a comprehensive understanding of its pathophysiology and management in ACHD is critical to optimizing long-term outcomes in this increasingly complex patient population. Full article

Perfusable microvasculature is critical for advancing in vitro tissue models, particularly for neural applications where limited diffusion impairs organoid growth and fails to replicate neurovascular function. This study presents a versatile fabrication platform that integrates mesh-driven design, two-photon lithography (TPL), and modular interfacing to create multi-material, perfusable 3D microvasculatures. Various 2D and 3D capillary paths were test-printed using both polygonal and lattice support strategies. A double-layered capillary scaffold based on the Hilbert curve was used for comparative materials testing. Methods for printing rigid (OrmoComp), moderately stiff hydrogel (polyethylene glycol diacrylate, PEGDA 700), and soft elastomeric (photocurable polydimethylsiloxane, PDMS) materials were developed and evaluated. Cone support structures enabled high-fidelity printing of the softer materials. A compact heat-shrink tubing interface provided leak-free perfusion without bulky fittings. Physiologically relevant flow velocities and Dextran diffusion through the scaffold were successfully demonstrated. Cytocompatibility assays confirmed that all TPL-printed scaffold materials supported human neural stem cell viability. Among peripheral components, lids fabricated via fused deposition modeling designed to hold microfluidic needle adapters exhibited good biocompatibility, while those made using liquid crystal display-based photopolymerization showed significant cytotoxicity despite indirect exposure. Overall, this platform enables creation of multi-material microvascular systems facilitated by TPL technology for complex, 3D neurovascular modeling, blood–brain barrier studies, and integration into vascularized organ-on-chip applications. Full article