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Biomedical subjects

Thomas M Egan

Publications and source records attributed to Thomas M Egan.

At least 19 recordsLinked to original sources
PubMed2006

Ex vivo evaluation of human lungs for transplant suitability.

BACKGROUND: If lungs could be retrieved from non-heart-beating donors, the critical shortage of lungs for transplant could be alleviated. An obstacle to this approach is the inability to predict these lungs' suitability for transplant. We used human lungs deemed unsuitable for transplant to develop a method to perfuse and ventilate human lungs ex vivo to assess gas exchange and vascular resistance, and to perform bronchoscopic inspection and radiographic evaluation. METHODS: Lungs were retrieved from six brain-dead organ donors after cold Perfadex (Vitrolife, Kungsbacka, Sweden) flush, stored cold for 6 to 13 hours (mean, 8.7 hours) then perfused and rewarmed in a modified cardiopulmonary bypass circuit. Circuit perfusate was buffered colloid-crystalloid containing type-specific leukocyte-filtered blood (hematocrit of 10%-12%), circulated through a membrane oxygenator ventilated with CO2 and nitrogen to deoxygenate it. Lungs were ventilated with fraction of inspired oxygen (Fio2) 0.5 when 32 degrees C was reached. Gas exchange and vascular resistance was assessed at 5 L/minute flow at 37 degrees C, Fio2 0.5 and 1.0. Bronchoscopy, plain radiographs, and spiral computed tomographic (CT) scans were performed. Lung biopsies were obtained pre- and post-reperfusion. RESULTS: Ex vivo perfusion did not cause increased wet to dry ratio, or major abnormalities by microscopy but was associated with elevated tissue levels of conjugated dienes. The alveolar-arterial difference in partial pressure of oxygen (Pao2)/Fio2 ratio in the ex vivo circuit was generally higher than in the six donors. Ex vivo radiographs and CT scans were abnormal in all lungs, confirming unsuitability of these lungs for transplant. CONCLUSIONS: Ex vivo evaluation of human lungs is feasible and may be useful to evaluate transplant suitability of lungs retrieved after circulatory arrest from non-heart-beating donors.

Adolescent↗
PubMed2006

Ex-vivo perfusion and ventilation of rat lungs from non-heart-beating donors before transplant.

BACKGROUND: We developed an ex-vivo circuit to evaluate human lungs retrieved from non-heart-beating donors. We assessed the effect of a similar circuit on the function of transplanted rat lungs retrieved from non-heart-beating donors. METHODS: One hour after death, Sprague-Dawley rat heart-lung blocks were flushed with 20 mL of cold Perfadex, stored cold for 1 hour, then warmed to 37 degrees C in a circuit perfused with Earle's crystalloid solution with or without washed porcine erythrocytes (hematocrit 12% to 15%). At 37 degrees C, lungs were ventilated for 15 minutes with alveolar gas, perfusion-cooled to 20 degrees C, flushed again with cold Perfadex, and then stored cold for 2.5 hours. The left lung was transplanted using a modified cuff technique with flow probes on the main and left pulmonary arteries. After 1 hour of reperfusion, arterial blood gases from the left pulmonary vein and wet/dry weight ratio (W/D) of both donor lungs were determined. Lungs transplanted after retrieval from heart-beating or non-heart-beating donors served as controls (n = 6 per group). RESULTS: Lungs gained weight in the circuit but W/D and PO2 were similar after transplantation for all groups. After transplantation, vascular resistance was higher and dynamic compliance was lower for lungs perfused in the circuit. Myeloperoxidase and conjugated diene levels were modestly elevated in lungs transplanted from non-heart-beating donors irrespective of perfusion in the circuit. CONCLUSIONS: Rat lungs are suitable for transplant after ex-vivo perfusion and ventilation. This model closely mimics methods used to evaluate the function of lungs retrieved from human non-heart-beating donors and can economically evaluate ex-vivo therapies for lungs retrieved from non-heart-beating donors.

Animals↗
PubMed2006

Nitroglycerin reperfusion reduces ischemia-reperfusion injury in non-heart-beating donor lungs.

BACKGROUND: Lung transplantation is severely limited by an inadequate supply of lungs from brain-dead donors. A potential solution is use of lungs from non-heart-beating donors (NHBDs) with retrieval at intervals after circulatory arrest and death. A warm ischemic period with concomitant reperfusion injury is a major limiting factor in the transplantation of lungs retrieved from NHBDs. We hypothesized that the administration of the nitric oxide-donor nitroglycerin to lungs from NHBDs would reduce ischemia-reperfusion injury by activation of guanylate cyclase to form guanosine 3',5'-cyclic monophosphate (cGMP). METHODS: An in situ isolated perfused rat lung model was used. Lungs were retrieved from rats at varying intervals after circulatory arrest and death. Lungs were either ventilated with O(2) in situ or not ventilated. Lungs were reperfused at intervals after death with Earle's solution with or without nitroglycerin (0.1 mg/ml). Lung ischemia-reperfusion injury was assessed by capillary filtration coefficient, wet-to-dry lung weight ratio, and pulmonary hemodynamics. Tissue levels of adenine nucleotides and cGMP concentrations were measured by high-performance liquid chromatography and enzyme immunoassay, respectively. RESULTS: Reperfusion with nitroglycerin decreased capillary filtration coefficient compared with reperfusion without nitroglycerin at all post-mortem ischemic times, irrespective of pre-harvest ventilation. cGMP levels increased significantly with nitroglycerin-reperfusion and attenuated decreases in high-energy adenine nucleotides. CONCLUSIONS: Reperfusion of lungs with nitroglycerin may facilitate safe lung transplantation from NHBDs by reducing capillary leak after reperfusion.

Animals↗
PubMed2006

Inhaled nitric oxide reduces ischemia-reperfusion injury in rat lungs from non-heart-beating donors.

OBJECTIVE: If lungs could be retrieved from non-heart-beating donors, the critical shortage of lungs for transplantation could be alleviated. However, lungs subjected to warm ischemia develop edema when reperfused. We hypothesized that ventilation of rat lungs from non-heart-beating donors with nitric oxide during the period of warm ischemia alone, with reperfusion, or both might reduce ischemia-reperfusion injury. METHODS: An isolated perfused rat lung model measured the filtration coefficient and accumulation of lung water by the wet/dry weight ratio. Donor rats were euthanized, and then lungs were retrieved immediately after death or 2 or 3 hours postmortem. Lungs retrieved postmortem were either not ventilated or ventilated with 100% oxygen alone or 40 ppm nitric oxide in oxygen. In the circuit, lungs were ventilated with alveolar gas with or without 40 ppm nitric oxide. RESULTS: Nitric oxide administration to the non-heart-beating donor or in the perfusion circuit reduced filtration coefficient and wet/dry weight ratio. Lungs retrieved 2 hours postmortem ventilated with nitric oxide or treated with nitric oxide on reperfusion had filtration coefficients and wet/dry weight ratios similar to those of lungs retrieved immediately after death. Nitric oxide was most beneficial when administered both during warm ischemia and at reperfusion in lungs retrieved 3 hours postmortem. Nitric oxide administration in the circuit was associated with increased lung levels of lung cyclic guanosine monophosphate, determined by enzyme-linked immunosorbent assay. CONCLUSIONS: Administration of nitric oxide to non-heart-beating donors during warm ischemia and with reperfusion might facilitate transplantation of lungs from non-heart-beating donors by reducing ischemia-reperfusion injury and capillary leak.

Adenine Nucleotides↗
PubMed2005

Trends in lung pH and PO2 after circulatory arrest: implications for non-heart-beating donors and cell culture models of lung ischemia-reperfusion injury.

BACKGROUND: A better understanding of lung tissue environment after circulatory arrest would allow more accurate cell culture models to study ischemia-reperfusion lung injury and facilitate retrieval of lungs from non-heart-beating donors. METHODS: To establish the time course of changes in pH and PO2 in lung tissue after circulatory arrest, 12 Sprague-Dawley rats were sacrificed. After sternotomy, pH and PO2 microelectrodes were inserted into the lungs and sealed by application of Focal Seal. Rats were maintained at normothermia (37 degrees C). Two groups of rats (n = 6 atelectatic, n = 6 room air-inflated) were followed for 4 hours after arrest, when lung tissue adenine nucleotide levels were measured by chromatography and cell death was quantified by trypan blue exclusion. Human umbilical vein endothelial cells underwent simulated ischemia and 6 hours of cold storage by replacement of culture medium with cold Perfadex. Interleukin (IL)-6 and IL-8 were measured in medium 21 hours later by enzyme-linked immunosorbent assay (ELISA). RESULTS: In both groups of rats, lung [H+] increased linearly with time. In atelectatic lungs, PO2 fell precipitously, but in inflated lungs, PO2 decreased linearly for 60 to 75 minutes post-mortem and then became stable. After 4 hours at 37 degrees C, most parenchymal lung cells were dead in both groups. IL-6 and IL-8 levels increased significantly in medium of cultured endothelial cells subjected to cold storage without hypoxia. CONCLUSIONS: In room-air-inflated lungs maintained at 37 degrees C, oxygen consumption continues for at least 1 hour after circulatory arrest. Warm atelectasis is poorly tolerated. Hypothermic storage can induce elaboration of cytokines by endothelial cells in the absence of hypoxia.

Animals↗
PubMed2005

Lung transplantation: opportunities for research and clinical advancement.

Lung transplantation is the only definitive therapy for many forms of end-stage lung diseases. However, the success of lung transplantation is limited by many factors: (1) Too few lungs available for transplantation due to limited donors or injury to the donor lung; (2) current methods of preservation of excised lungs do not allow extended periods of time between procurement and implantation; (3) acute graft failure is more common with lungs than other solid organs, thus contributing to poorer short-term survival after lung transplant compared with that for recipients of other organs; (4) lung transplant recipients are particularly vulnerable to pulmonary infections; and (5) chronic allograft dysfunction, manifest by bronchiolitis obliterans syndrome, is frequent and limits long-term survival. Scientific advances may provide significant improvements in the outcome of lung transplantation. The National Heart, Lung, and Blood Institute convened a working group of investigators on June 14-15, 2004, in Bethesda, Maryland, to identify opportunities for scientific advancement in lung transplantation, including basic and clinical research. This workshop provides a framework to identify critical issues related to clinical lung transplantation, and to delineate important areas for productive scientific investigation.

Acute Disease↗
PubMed2005

Isoproterenol reduces ischemia-reperfusion lung injury despite beta-blockade.

BACKGROUND: If lungs could be retrieved from non-heart-beating donors (NHBDs), the shortage of lungs for transplantation could be alleviated. The use of lungs from NHBDs is associated with a mandatory warm ischemic interval, which results in ischemia-reperfusion injury upon reperfusion. In an earlier study, rat lungs retrieved 2-h postmortem from NHBDs had reduced capillary leak measured by filtration coefficient (Kfc) when reperfused with isoproterenol (iso), associated with an increase in lung tissue levels of cyclic AMP (cAMP). The objective was to determine if this decrease in Kfc was because of beta-stimulation, or would persist despite beta-blockade. MATERIALS AND METHODS: Donor rats were treated intraperitoneally with beta-blockade (propranolol or pindolol) or carrier, sacrificed, and lungs were retrieved immediately or 2 h postmortem. The lungs were reperfused with or without iso and the beta-blockers in the reperfusate. Outcome measures were Kfc, wet:dry weight ratio (W/D), lung levels of adenine nucleotides and cAMP. RESULTS: Lungs retrieved immediately after death had normal Kfc and W/D. After 2 h of ischemia, Kfc and W/D were markedly elevated in controls (no drug) and lungs reperfused with beta-blockers alone. Isoproterenol-reperfusion decreased Kfc and W/D significantly (P < 0.01) even in the presence of beta-blockade. Lung cAMP levels were increased only with iso in the absence of beta-blockade. CONCLUSIONS: The attenuation of ischemia-reperfusion injury because of iso occurs even in the presence of beta-blockade, and may not be a result of beta-stimulated increased cAMP.

Adrenergic beta-Antagonists↗
PubMed2005

Assessment of real-time 3D visualization for cardiothoracic diagnostic evaluation and surgery planning.

RATIONALE AND OBJECTIVES: Three-dimensional (3D) real-time volume rendering has demonstrated improvements in clinical care for several areas of radiological imaging. We test whether advanced real-time rendering techniques combined with an effective user interface will allow radiologists and surgeons to improve their performance for cardiothoracic surgery planning and diagnostic evaluation. MATERIAL AND METHODS: An interactive combination 3D and 2D visualization system developed at the University of North Carolina at Chapel Hill was compared against standard tiled 2D slice presentation on a viewbox. The system was evaluated for 23 complex cardiothoracic computed tomographic (CT) cases including heart-lung and lung transplantation, tumor resection, airway stent placement, repair of congenital heart defects, aortic aneurysm repair, and resection of pulmonary arteriovenous malformation. Radiologists and surgeons recorded their impressions with and without the use of the interactive visualization system. RESULTS: The cardiothoracic surgeons reported positive benefits to using the 3D visualizations. The addition of the 3D visualization changed the surgical plan (65% of cases), increased the surgeon's confidence (on average 40% per case), and correlated well with the anatomy found at surgery (95% of cases). The radiologists reported fewer and less major changes than the surgeons in their understanding of the case due to the 3D visualization. They found new findings or additional information about existing findings in 66% of the cases; however, they changed their radiology report in only 14% of the cases. CONCLUSION: With the appropriate choice of 3D real-time volume rendering and a well-designed user interface, both surgeons and radiologists benefit from viewing an interactive 3D visualization in addition to 2D images for surgery planning and diagnostic evaluation of complex cardiothoracic cases. This study finds that 3D visualization is especially helpful to the surgeon in understanding the case, and in communicating and planning the surgery. These results suggest that including real-time 3D visualization would be of clinical benefit for complex cardiothoracic CT cases.

Confidence Intervals↗
PubMed2004

Trigger for intercellular adhesion molecule-1 expression in rat lungs transplanted from non-heart-beating donors.

BACKGROUND: Lung transplantation from non-heart-beating donors causes ischemia-reperfusion injury. We sought to determine the trigger for expression of intercellular adhesion molecule-1 (ICAM-1) caused by ischemia-reperfusion injury. METHODS: Thirty-six Sprague-Dawley rats underwent left lung transplant (six groups of 6). Lungs were transplanted immediately after arrest, or from non-heart-beating donors after 2 hours of oxygen-ventilation or no ventilation. Recipients were reperfused for 4 or 6 hours, then lungs were stained with a mouse anti-rat ICAM-1 monoclonal antibody, developed with avidin-biotin peroxidase to a biotinylated anti-mouse immunoglobin G antibody. Intercellular adhesion molecule-1 expression was graded by two masked observers as 0 = absent, 1 = weak, or 2 = strong in alveoli, arterioles, and venules. Explanted recipient left lungs served as negative controls, and positive controls were generated 6 hours after intraperitoneal injection of endotoxin. Intercellular adhesion molecule-1 expression above baseline among groups was compared by Fisher's exact test. RESULTS: Constitutive expression of ICAM-1 was present in rat lung alveoli, with 24 of 35 controls staining weakly and 4 of 35 strongly positive in alveolar areas. Intercellular adhesion molecule-1 expression was not increased in transplanted lungs evaluated after 4 hours of reperfusion, even lungs retrieved from non-heart-beating donors. But when non-heart-beating donor lungs were assessed 6 hours after onset of reperfusion, ICAM-1 expression was significantly more apparent in alveolar and arteriolar areas, compared with controls and lungs transplanted immediately after arrest. CONCLUSIONS: Lungs transplanted immediately after circulatory arrest do not sustain sufficient ischemia-reperfusion injury to upregulate ICAM-1. Onset of reperfusion is the signal for ICAM-1 expression, not the onset of ischemia or the total duration of ischemic and reperfusion time together. Strategies at reperfusion may minimize ICAM-1 expression.

Animals↗
PubMed2004

Thoracoscopy using a substernal handport for palpation.

BACKGROUND: A substernal handport allows palpation of the lung and thus circumvents one of the major limitations of thoracoscopy. METHODS: This approach has been used in 24 consecutive patients, primarily during planned metastasectomy or when palpation was needed for deeper or smaller lesions that were difficult to find. RESULTS: No long-term complications from this procedure were noted, and the 3 early complications were either minor or unrelated to the procedure. This approach allowed adequate resection to be accomplished by a less invasive approach in 67% of patients, although conversion to an open procedure was necessary in 33% of patients for anatomic and technical reasons. Among the 16 patients who underwent this procedure alone, the median length of stay in the hospital was 3 days. The rate of incomplete resection and of recurrence after metastasectomy was comparable to that for an open approach. CONCLUSIONS: Our experience documents that a substernal handport is safe, does not compromise the ability to perform an adequate metastasectomy, and allows biopsy of lesions that are otherwise not amenable to a minimally invasive approach. This technique should be included in the standard armamentarium of approaches for thoracic surgery.

Adult↗
PubMed2004

Non-heart-beating donors in thoracic transplantation.

Access to lung transplantation is severely limited by a scarcity of suitable donors, resulting in increasing numbers of deaths on the heart and lung transplant waiting lists, and strict selection criteria for recipients. Unlike some other solid organs, the lung may be ideally suited to retrieval for transplant following substantial intervals after circulatory arrest. This may be because lung parenchymal cells do not rely on perfusion for cellular respiration. This review outlines the relevant published experimental data that addresses the concept that lungs might be suitable for transplant even if retrieved from non-heart-beating donors (NHBDs), and the small published clinical experience with NHBDs as lung donors. Aspects of reperfusion injury in this setting are reviewed. The prospect of heart transplant from NHBDs is addressed. The impact of the routine use of NHBDs on lung transplantation is discussed.

Animals↗
PubMed2003

Pulmonary preservation studies: effects on endothelial function and pulmonary adenine nucleotides.

BACKGROUND: Lung transplantation is an effective therapy plagued by a high incidence of early graft dysfunction, in part because of reperfusion injury. The optimal preservation solution for lung transplantation is unknown. We performed experiments using an isolated perfused rat lung model to test the effect of lung preservation with three solutions commonly used in clinical practice. METHODS: Lungs were retrieved from Sprague-Dawley rats and flushed with one of three solutions: modified Euro-Collins (MEC), University of Wisconsin (UW), or low potassium dextran and glucose (LPDG), then stored cold for varying periods before reperfusion with Earle's balanced salt solution using the isolated perfused rat lung model. Outcome measures were capillary filtration coefficient (Kfc), wet-to-dry weight ratio, and lung tissue levels of adenine nucleotides and cyclic AMP. RESULTS: All lungs functioned well after 4 hr of storage. By 6 hr, UW-flushed lungs had a lower Kfc than LPDG-flushed lungs. After 8 hr of storage, only UW-flushed lungs had a measurable Kfc. Adenine nucleotide levels were higher in UW-flushed lungs after prolonged storage. Cyclic AMP levels correlated with Kfc in all groups. CONCLUSIONS: Early changes in endothelial permeability seemed to be better attenuated in lungs flushed with UW compared with LPDG or MEC; this was associated with higher amounts of adenine nucleotides. MEC-flushed lungs failed earlier than LPDG-flushed or UW-flushed lungs. The content of the solution may be more important for lung preservation than whether the ionic composition is intracellular or extracellular.

Adenine Nucleotides↗
PubMed2003

Ethical issues in thoracic organ distribution for transplant.

Demand for thoracic organs for transplant far exceeds supply, resulting in long waiting times and increasing numbers of deaths on the lung and heart transplant lists in the United States. This shortage of donors poses dilemmas for allocation of the limited resource of donated thoracic organs. This article reviews the ethical issues that come into consideration as members of the transplant community grapple with ways to improve the distribution algorithm for thoracic organs for transplant.

Algorithms↗