The relationships between air exposure, negative pressure, and hemolysis.

The purpose of this study was to describe the hemolytic effects of both negative pressure and an air-blood interface independently and in combination in an in vitro static blood model. Samples of fresh ovine or human blood (5 ml) were subjected to a bubbling air interface (0-100 ml/min) or negative pressure (0-600 mm Hg) separately, or in combination, for controlled periods of time and analyzed for hemolysis. Neither negative pressure nor an air interface alone increased hemolysis. However, when air and negative pressure were combined, hemolysis increased as a function of negative pressure, the air interface, and time. Moreover, when blood samples were exposed to air before initiating the test, hemolysis was four to five times greater than samples not preexposed to air. When these experiments were repeated using freshly drawn human blood, the same phenomena were observed, but the hemolysis was significantly higher than that observed in sheep blood. In this model, hemolysis is caused by combined air and negative pressure and is unrelated to either factor alone.</p

Timing of heparin and perfusion temperature during procurement of organs with extracorporeal support in donors after circulatory determination of death.

Despite successful resuscitation of donors after circulatory determination of death (DCD) with extracorporeal support (ECS), the technique is limited by ethical concerns about donor management (heparinization) and the complexity to operate the ECS circuit. This work studies different timing of heparin administration and the effects of ECS-perfusion temperature. Cardiac arrest (CA) was induced in swine. Heparin studies, three groups: 1) PRE5, heparin 5 minutes before CA; 2) POST5, heparin 5 minutes after CA, plus 2 minutes external chest compressions; and 3) POST30, heparin with the initiation of ECS after 30 minutes CA. Perfusion temperature study, two groups: 1) normothermic, ECS-38.5°C after 30 minutes CA and 2) room temperature, ECS-25.5°C for the first 90 minutes, followed by ECS-38.5°C. Heparin studies: ECS target flows (>50 ml/kg/min) were not achieved in the POST30 group, affecting local organ perfusion as observed with poor bile (/min) and urine output (/min), when compared with the other groups (normal values). Temperature study: In both groups, ECS target flows were reached, and urine/bile output was restored. Heparinization 5 minutes after CA is equivalent to premortem heparinization in this ECS-DCD model. Heparinization after CA could reduce ethical concerns. Donors after circulatory determination of death were successfully resuscitated at both temperatures, suggesting that the heat exchanger/water heater can be removed to simplify the ECS circuit.</p

Use of venovenous extracorporeal membrane oxygenation and an atrial septostomy for pulmonary and right ventricular failure.

BACKGROUND: Right ventricular failure is a major contributor to morbidity and mortality on the lung transplant waiting list. This study was designed to evaluate the effectiveness of an atrial septostomy with venovenous extracorporeal membrane oxygenation (VV-ECMO) as a novel potential bridge to transplantation. METHODS: Adult sheep (58±3 kg; n=12) underwent a clamshell thoracotomy and instrumentation to measure all relevant pressures and cardiac output (CO). Sheep with tricuspid insufficiency (TI [n=5]) and without tricuspid insufficiency (ØTI [n=7]) were examined. After creation of a 1-cm atrial septal defect and initiating VV-ECMO, the pulmonary artery (PA) was banded to allow progressive reduction of pulmonary blood flow, and data were collected. RESULTS: The CO in both groups remained unchanged from baseline at all pulmonary blood flow conditions. With TI, the CO was 5.1±1.2 L/min at baseline versus 5.1±1.2 L/min with a fully occluded PA (p=0.99). For ØTI, the CO was 4.5±1.4 L/min at baseline versus 4.5±1.2 L/min with no pulmonary blood flow (p=0.99). Furthermore, CO was not affected by the presence of TI (p=0.76). Mean right ventricular pressures were significantly lower in the TI group (TI=20.2±11 mm Hg versus ØTI=29.9±8.9 mm Hg; p0.5). Lastly, VV-ECMO maintained normal blood gases, with mean O2 saturations of 99% ± 4.1% in both groups. CONCLUSIONS: Right to left atrial shunting of oxygenated blood with VV-ECMO is capable of maintaining normal systemic hemodynamics and normal arterial blood gases during high right ventricular afterload dysfunction.</p

Veno-venous extracorporeal membrane oxygenation with interatrial shunting: a novel approach to lung transplantation for patients in right ventricular failure.

OBJECTIVE: This study evaluated the effectiveness of an atrial septostomy with veno-venous extracorporeal membrane oxygenation in alleviating high afterload right ventricular dysfunction while providing respiratory support. This technique could be applied as a bridge to lung transplantation. METHODS: Sheep (56±3 kg) underwent a clamshell thoracotomy and hemodynamic instrumentation, including right ventricular pressure and cardiac output. Sheep with and without tricuspid insufficiency (n=5 each) were examined. While sheep were on extracorporeal membrane oxygenation, right ventricular failure was established by banding the pulmonary artery until cardiac output was 40% to 60% of baseline. An extracardiac atrial shunt was created with modified vascular grafts to examine the effect of shunt flow on hemodynamics. Hemodynamic data were thus collected at baseline, during right ventricular failure, and for 1 hour at 100% (fully open), 70%, 50%, and 30% of baseline shunt flow. RESULTS: Cardiac output was returned to baseline values (tricuspid insufficiency: 5.2±0.2 L/min, without tricuspid insufficiency: 5.3±1.2 L/min) with 100% shunt flow (tricuspid insufficiency: 4.8±1.1 L/min, without tricuspid insufficiency: 4.8±1.0 L/min; P=.15) but remained significantly lower than baseline at 70% to 30% shunt flow. At 100% shunt flow, tricuspid insufficiency shunt flow was 1.4±0.8 L/min and without tricuspid insufficiency shunt flow was 1.7±0.2 L/min. Right ventricular pressure was significantly elevated over baseline values at all shunt flows (P CONCLUSIONS: An atrial septostomy accompanied by veno-venous extracorporeal membrane oxygenation is capable of eliminating right ventricular failure while maintaining normal arterial blood gases if sufficient shunt flows are achieved. The presence of tricuspid insufficiency improves the efficacy of the shunt.</p

Organ donation after cardiac determination of death (DCD): a swine model.

Donors after Cardiac Death (DCD) may reduce the organ scarcity; however, their use is limited because of warm ischemia time. Fortunately, this is less important in a subclass of DCD called expected (e-DCD), those with irreversible but incomplete brain injury. This study analyzed hemodynamic/pulmonary data to establish a clinically relevant model of cardiac death that would simulate an e-DCD setting. Hemodynamics, pulmonary artery flows, arterial blood gasses, and left atrial pressure were recorded q 5 minutes in anesthetized swine. After baseline data collection, the ventilator was discontinued and heparin was administered. Cardiac death was defined: as asystole, or mean arterial presusure < or = 25 mm Hg with a pulse pressure < or = 20 mm Hg. The time to death was approximately 14.8 minutes. Within 5 minutes of removal of the ventilator, there was a hyperdynamic period. Blood gases throughout the apneic time showed a rapid hypercapnia and acidosis. The hyperdynamic reflex response was followed by hypotension, bradycardia, and finally asystole or ventricular fibrillation. The protocol of withdrawal of ventilation, systemic anticoagulation, determination of death was developed to closely resemble the clinical e-DCD scenario. The physiologic changes that happen before death in DCD were described. An e-DCD model that can be used in studies related to organ transplantation was established.</p

Improved <i>in Vivo</i> Performance of Amperometric Oxygen (<i>P</i>O₂) Sensing Catheters via Electrochemical Nitric Oxide Generation/Release

A novel electrochemically controlled release method for nitric oxide (NO) (based on electrochemical reduction of nitrite ions) is combined with an amperometric oxygen sensor within a dual lumen catheter configuration for the continuous <i>in vivo</i> sensing of the partial pressure of oxygen (<i>P</i>O₂) in blood. The on-demand electrochemical NO generation/release method is shown to be fully compatible with amperometric <i>P</i>O₂ sensing. The performance of the sensors is evaluated in rabbit veins and pig arteries for 7 and 21 h, respectively. Overall, the NO releasing sensors measure both venous and arterial <i>P</i>O₂ values more accurately with an average deviation of −2 ± 11% and good correlation (<i>R</i>² = 0.97) with <i>in vitro</i> blood measurements, whereas the corresponding control sensors without NO release show an average deviation of −31 ± 28% and poor correlation (<i>R</i>² = 0.43) at time points >4 h after implantation in veins and >6 h in arteries. The NO releasing sensors induce less thrombus formation on the catheter surface in both veins and arteries (<i>p</i> < 0.05). This electrochemical NO generation/release method could offer a new and attractive means to improve the biocompatibility and performance of implantable chemical sensors

In-parallel artificial lung attachment at high flows in normal and pulmonary hypertension models.

BACKGROUND: End-stage lung disease patients who require a thoracic artificial lung (TAL) must be extubated and rehabilitated prior to lung transplantation. The purpose of this study is to evaluate hemodynamics and TAL function under simulated rest and exercise conditions in normal and pulmonary hypertension sheep models. METHODS: The TAL, the MC3 Biolung (MC3, Inc, Ann Arbor, MI), was attached between the pulmonary artery and left atrium in nine normal sheep and eight sheep with chronic pulmonary hypertension. An adjustable band was placed around the distal pulmonary artery to control the percentage of cardiac output (CO) diverted to the TAL. Pulmonary system hemodynamics and TAL function were assessed at baseline (no flow to the TAL) and with approximately 60%, 75%, and 90% of CO diverted to the TAL. Intravenous dobutamine (0, 2, and 5 mcg . kg(-1). min(-1)) was used to simulate rest and exercise conditions. RESULTS: At 0 and 2 mcg . kg(-1). min(-1), CO did not change significantly with flow diversion to the TAL for both models. At 5 mcg . kg(-1). min(-1), CO decreased with increasing TAL flow up to 28% +/- 5% in normal sheep and 23% +/- 5% in pulmonary hypertension sheep at 90% flow diversion to the artificial lung. In normal sheep, the pulmonary system zeroth harmonic impedance modulus, Z(0), increased with increasing flow diversion. In hypertensive sheep, Z(0) decreased at 60% and 75% flow diversion and returned to baseline levels at 90%. The TAL outlet blood oxygen saturation was 95% or greater under all conditions. CONCLUSIONS: Pulmonary artery to left atrial TAL use will not decrease CO during rest or mild exercise but may not allow more vigorous exercise.</p

Fabrication and in vivo thrombogenicity testing of nitric oxide generating artificial lungs.

<p>Hollow fiber artificial lungs are increasingly being used for long-term applications. However, clot formation limits their use to 1-2 weeks. This study investigated the effect of nitric oxide generating (NOgen) hollow fibers on artificial lung thrombogenicity. Silicone hollow fibers were fabricated to incorporate 50 nm copper particles as a catalyst for NO generation from the blood. Fibers with and without (control) these particles were incorporated into artificial lungs with a 0.1 m(2) surface area and inserted in circuits coated tip-to-tip with the NOgen material. Circuits (N = 5/each) were attached to rabbits in a pumpless, arterio-venous configuration and run for 4 h at an activated clotting time of 350-400 s. Three control circuits clotted completely, while none of the NOgen circuits failed. Accordingly, blood flows were significantly higher in the NOgen group (95.9 ± 11.7, p < 0.01) compared to the controls (35.2 ± 19.7; mL/min), and resistance was significantly higher in the control group after 4 h (15.38 ± 9.65, p < 0.001) than in NOgen (0.09 ± 0.03; mmHg/mL/min). On the other hand, platelet counts and plasma fibrinogen concentration expressed as percent of baseline in control group (63.7 ± 5.7%, 77.2 ± 5.6%; p < 0.05) were greater than those in the NOgen group (60.4 ± 5.1%, 63.2 ± 3.7%). Plasma copper levels in the NOgen group were 2.8 times baseline at 4 h (132.8 ± 4.5 μg/dL) and unchanged in the controls. This study demonstrates that NO generating gas exchange fibers could be a potentially effective way to control coagulation inside artificial lungs.</p

Long-term animal model of venovenous extracorporeal membrane oxygenation with atrial septal defect as a bridge to lung transplantation.

<p>This study evaluated the effectiveness of an atrial septal defect (ASD) with venovenous extracorporeal membrane oxygenation (vv-ECMO) as a bridge to transplantation. Sheep (56 ± 3 kg; n = 7) underwent a right-sided thoracotomy to create the ASD (diameter = 1 cm) and place instrumentation and a pulmonary artery (PA) occluder. After recovery, animals were placed on ECMO, and the PA was constricted to generate a twofold rise in right ventricular (RV) systolic pressure. Sheep were then maintained for 60 hours on ECMO, and data were collected hourly. Five sheep survived 60 hours. One sheep died because of a circuit clot extending into the RV, and another died presumably because of an arrhythmia. Mean right ventricular pressure (mRVP) was 19 ± 3 mm Hg at baseline, averaged 27 ± 7 mm Hg over the experiment, but was not statistically significant (p = 0.27) due to one sheep without an increase. Cardiac output was 6.8 ± 1.2 L/min at baseline, averaged 6.0 ± 1.0 L/min during the experiment, and was statistically unchanged (p = 0.34). Average arterial oxygen saturation and PCO2 over the experiment were 96.8 ± 1.4% and 31.8 ± 3.4 mm Hg, respectively. In conclusion, an ASD combined with vv-ECMO maintains normal systemic hemodynamics and arterial blood gases during a long-term increase in RV afterload.</p

Origin of Long-Term Storage Stability and Nitric Oxide Release Behavior of CarboSil Polymer Doped with <i>S</i>‑Nitroso‑<i>N</i>‑acetyl‑d‑penicillamine

The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of <i>S</i>-nitroso-<i>N</i>-acetyl-d-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 days) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC–MS. Raman spectroscopy and powder X-ray diffraction characterization of SNAP-doped CarboSil films demonstrate that a polymer–crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4–4.0 wt %). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of <i>Staphylococcus aureus</i> biofilm (a leading cause of nosocomial bloodstream infections) (<i>in vitro</i>) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility