Tinen L. Iles

Prolonged EVLP Using OCS Lung: Cellular and Acellular Perfusates.

Background We report the ability to extend lung preservation up to 24 hours (24H) by using autologous whole donor blood circulating within an ex vivo lung perfusion (EVLP) system. This approach facilitates donor lung reconditioning in a model of extended normothermic EVLP. We analyzed comparative responses to cellular and acellular perfusates to identify these benefits. Methods Twelve pairs of swine lungs were retrieved after cardiac arrest and studied for 24H on the Organ Care System (OCS) Lung EVLP platform. Three groups (n = 4 each) were differentiated by perfusate: (1) isolated red blood cells (RBCs) (current clinical standard for OCS); (2) whole blood (WB); and (3) acellular buffered dextran-albumin solution (analogous to STEEN solution). Results Only the RBC and WB groups met clinical standards for transplantation at 8 hours; our primary analysis at 24H focused on perfusion with WB versus RBC. The WB perfusate was superior (vs RBC) for maintaining stability of all monitored parameters, including the following mean 24H measures: pulmonary artery pressure (6.8 vs 9.0 mm Hg), reservoir volume replacement (85 vs 1607 mL), and PaO2:FiO2 ratio (541 vs 223). Acellular perfusion was limited to 6 hours on the OCS system due to prohibitively high vascular resistance, edema, and worsening compliance. Conclusions The use of an autologous whole donor blood perfusate allowed 24H of preservation without functional deterioration and was superior to both RBC and buffered dextran-albumin solution for extended lung preservation in a swine model using OCS Lung. This finding represents a potentially significant advance in donor lung preservation and reconditioning.

An Experimental Study of the Recovery of Injured Porcine Lungs with Prolonged Normothermic Cellular Ex Vivo Lung Perfusion Following Donation after Circulatory Death

Donation after circulatory death (DCD) is an underused source of donor lungs. Normothermic cellular ex vivo lung perfusion (EVLP) is effective in preserving standard donor lungs but may also be useful in the preservation and assessment of DCD lungs. Using a model of DCD and prolonged EVLP, the effects of donor warm ischemia and postmortem ventilation on graft recovery were evaluated. Adult male swine underwent general anesthesia and heparinization. In the control group (n = 4), cardioplegic arrest was induced and the lungs were procured immediately. In the four treatment groups, a period of agonal hypoxia was followed by either 1 h of warm ischemia with (n = 4) or without (n = 4) ventilation or 2 h of warm ischemia with (n = 4) or without (n = 4) ventilation. All lungs were studied on an EVLP platform for 24 h. Hemodynamic measures, compliance, and oxygenation on EVLP were worse in all DCD lungs compared with controls. Hemodynamics and compliance normalized in all lungs after 24 h of EVLP, but DCD lungs demonstrated impaired oxygenation. Normothermic cellular EVLP is effective in preserving and monitoring of DCD lungs. Early donor postmortem ventilation and timely procurement lead to improved graft function.

Investigating the physiological effects of 10.5 Tesla static field exposure on anesthetized swine

In this work, we investigated the relative effects of static magnetic field exposure (10.5 Tesla [T]) on two physiological parameters; blood pressure (BP) and heart rate (HR).

Blood clotting behavior is innately modulated in Ursus Americanus during early and late denning relative to summer months.

ABSTRACT Remarkably, American black bears (Ursus americanus) are capable of varying their heart rates to coincide with their breathing, creating pauses of 30 s or more, yet they do not appear to suffer from embolic events. We evaluated some features of the clotting cascade of black bears, providing novel insights into the underlying mechanisms they evoke for embolic protection during hibernation. We measured activated clotting time, prothrombin time and activated partial thromboplastin time during early denning (December), late denning (March) and summer (August). Activated clotting time during early hibernation was ∼3 times longer than that observed among non-hibernating animals. Clotting time was reduced later in hibernation, when bears were within ∼1 month of emerging from dens. Prothrombin time was similar for each seasonal time point, whereas activated partial thromboplastin time was highest during early denning and decreased during late denning and summer. We also examined D-dimer concentration to assess whether the bears were likely to have experienced embolic events. None of the non-parturient bears exceeded a D-dimer concentration of 250 ng ml−1 (considered the clinical threshold for embolism in mammals). Our findings suggest there is unique expression of the clotting cascade in American black bears during hibernation, in which extrinsic pathways are maintained but intrinsic pathways are suppressed. This was evaluated by a significant difference between the activated clotting time and activated partial thromboplastin time during the denning and non-denning periods. These changes are likely adaptive, to avoid clotting events during states of immobilization and/or periods of asystole. However, an intact extrinsic pathway allows for healing of external injuries and/or foreign body responses. Summary: Features of the blood clotting cascade of black bears provide novel insights into the underlying mechanisms they evoke for embolic protection during hibernation.

Patient independent representation of the detailed cardiac ventricular anatomy

&NA; Reparameterization of surfaces is a widely used tool in computer graphics known mostly from the remeshing algorithms. Recently, the surface reparameterization techniques started to gain popularity in the field of medical imaging, but mostly for convenient 2D visualization of the information initially represented on 3D surfaces (e.g. continuous bulls‐eye plot). However, by consistently mapping the 3D information to the same 2D domain, surface reparameterization techniques allow us to put into correspondence anatomical shapes of inherently different geometry. In this paper, we propose a method for anatomical parameterization of cardiac ventricular anatomies that include myocardium, trabeculations, tendons and papillary muscles. The proposed method utilizes a quasi‐conformal flattening of the myocardial surfaces of the left and right cardiac ventricles and extending it to cover the interior of the cavities using the local coordinates given by the solution of the Laplaces equation. Subsequently, we define a geometry independent representation for the detailed cardiac left and right ventricular anatomies that can be used for convenient visualization and statistical analysis of the trabeculations in a population. Lastly we show how it can be used for mapping the detailed cardiac anatomy between different hearts, which is of considerable interest for detailed cardiac computational models or shape atlases. HighlightsPatient independent anatomical parametrization of the detailed cardiac ventricular anatomy.Mapping between different cardiac geometries.Parametrization suitable for statistical analysis of the detailed ventricular anatomy.Framework for incorporating detailed anatomy into computational models. Graphical abstract Figure. No caption available.

Medtronic Reveal LINQ™ Devices Provide Better Understanding of Hibernation Physiology in the American Black Bear (Ursus Americanus)

The American black bear (Ursus americanus) has been called a metabolic marvel. In northern Minnesota, where we have conducted long-term physiological and ecological studies of this species, bears may remain in their winter dens for 6 months or more without eating, drinking, urinating or defecating and yet lose very little muscle mass. We also found that hibernating black bears elicit asystolic events of over 30 seconds and experience an exaggerated respiratory sinus arrhythmia. In this previous work we employed Medtronic Reveal XT devices that required us to visit the den and temporarily extract the bear (under anesthesia) to download the stored data. Here we describe Medtronic’s latest generation of Insertable Cardiac Monitor (ICM), the Reveal LINQ, which enables continuous transmission of data via a relay station from the den site. Black bear hibernation physiology remains of high interest because of the multiple potential applications to human medicine. ICMs have been used for nearly two decades by clinicians as a critical diagnostic tool to assess the nature of cardiac arrhythmias in humans. Such devices are primarily implanted subcutaneously to record electrocardiograms. The device size, battery life and transmission capabilities have evolved in recent years. The first devices were relatively large and a programmer was needed to retrieve information during each clinical (or in our case, den visit). These devices were programmed to capture cardiac incidents such as asystolic events, arrhythmias and tachycardias and apply algorithms that ensure proper data collection: e.g. ectopy rejection and p-wave presence algorithms. The new generation Reveal LINQ was made to telemetrically transmit heart data from human patients, but we needed to develop a system to enable transmission from bear dens, which are remote (cannot easily be checked and adjusted) and are subject to extreme winter weather conditions. Besides the advantage of these devices transmitting data automatically, they are considerably smaller and thus less prone to rejection by the extraordinary immune system of the hibernating bear.

Reversible and Irreversible Damage of the Myocardium: Ischemia/Reperfusion Injury and Cardioprotection

Ischemia and reperfusion injuries can lead to major compromises in cardiac function. While the intent of many of the past cardioprotective therapies was to protect the myocardium from ischemic necrosis, it may be that reperfusion injury following ischemia may occur despite such preventative attempts. There are continued efforts to identify improvements in myocardial protective strategies (pre- and postconditioning), and their ultimate goals are to minimize the risk of cellular injuries to all types of patients undergoing cardiovascular therapies, treatments, or surgeries.

Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine

Portable normothermic EVLP has been evaluated in clinical trials using standard and extended‐criteria donor lungs. We describe a swine model of lung transplant following donation after circulatory death using prolonged normothermic EVLP to assess the relationship between EVLP data and acute lung allograft function. Adult swine were anesthetized and heparinized. In the control group (n = 4), lungs were procured, flushed, and transplanted. Treatment swine underwent either standard procurement (n = 3) or agonal hypoxia followed by 1 (n = 4) or 2 hours (H) (n = 4) of ventilated warm ischemia. Lungs were preserved for 24H using normothermic blood‐based EVLP then transplanted. Recipients were monitored for 4 H. After 24H of preservation, mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and dynamic compliance (Cdyn) were improved in all EVLP groups. After transplant, EVLP groups showed similar allograft oxygenation. EVLP PVR, mPAP, and lung block weights had significant negative correlations with post‐transplant allograft oxygenation. EVLP P:F ratio did not correlate with acute post‐transplant allograft function until 24H of preservation. Data measured in the first 8H of EVLP were sufficient for predicting acute post‐transplant allograft function. This study provides a benchmark and platform for evaluation of therapies for donor‐related allograft injury in injured lungs treated with prolonged normothermic EVLP.

Evaluating the roles of detailed endocardial structures on right ventricular haemodynamics by means of CFD simulations

Computational modelling plays an important role in right ventricular (RV) haemodynamic analysis. However, current approaches use smoothed ventricular anatomies. The aim of this study is to characterise RV haemodynamics including detailed endocardial structures like trabeculae, moderator band, and papillary muscles. Four paired detailed and smoothed RV endocardium models (2 male and 2 female) were reconstructed from ex vivo human hearts high-resolution magnetic resonance images. Detailed models include structures with ≥1 mm2 cross-sectional area. Haemodynamic characterisation was done by computational fluid dynamics simulations with steady and transient inflows, using high-performance computing. The differences between the flows in smoothed and detailed models were assessed using Q-criterion for vorticity quantification, the pressure drop between inlet and outlet, and the wall shear stress. Results demonstrated that detailed endocardial structures increase the degree of intra-ventricular pressure drop, decrease the wall shear stress, and disrupt the dominant vortex creating secondary small vortices. Increasingly turbulent blood flow was observed in the detailed RVs. Female RVs were less trabeculated and presented lower pressure drops than the males. In conclusion, neglecting endocardial structures in RV haemodynamic models may lead to inaccurate conclusions about the pressures, stresses, and blood flow behaviour in the cavity.

Left Ventricular Trabeculations Decrease the Wall Shear Stress and Increase the Intra-Ventricular Pressure Drop in CFD Simulations

The aim of the present study is to characterize the hemodynamics of left ventricular (LV) geometries to examine the impact of trabeculae and papillary muscles (PMs) on blood flow using high performance computing (HPC). Five pairs of detailed and smoothed LV endocardium models were reconstructed from high-resolution magnetic resonance images (MRI) of ex-vivo human hearts. The detailed model of one LV pair is characterized only by the PMs and few big trabeculae, to represent state of art level of endocardial detail. The other four detailed models obtained include instead endocardial structures measuring ≥1 mm2 in cross-sectional area. The geometrical characterizations were done using computational fluid dynamics (CFD) simulations with rigid walls and both constant and transient flow inputs on the detailed and smoothed models for comparison. These simulations do not represent a clinical or physiological scenario, but a characterization of the interaction of endocardial structures with blood flow. Steady flow simulations were employed to quantify the pressure drop between the inlet and the outlet of the LVs and the wall shear stress (WSS). Coherent structures were analyzed using the Q-criterion for both constant and transient flow inputs. Our results show that trabeculae and PMs increase the intra-ventricular pressure drop, reduce the WSS and disrupt the dominant single vortex, usually present in the smoothed-endocardium models, generating secondary small vortices. Given that obtaining high resolution anatomical detail is challenging in-vivo, we propose that the effect of trabeculations can be incorporated into smoothed ventricular geometries by adding a porous layer along the LV endocardial wall. Results show that a porous layer of a thickness of 1.2·10−2 m with a porosity of 20 kg/m2 on the smoothed-endocardium ventricle models approximates the pressure drops, vorticities and WSS observed in the detailed models.