Percutaneous Cavopulmonary Assist: From Design to 96 Hour Survival in Lethal Cavopulmonary Failure Sheep.

We are developing a clinically practical percutaneous double lumen cannula (DLC)-based cavopulmonary assist (CPA) system to support failing Fontan patients. In this study, our CPA DLC was redesigned for even blood flow, minimal recirculation, and easy insertion/deployment. After bench testing, this new CPA system was evaluated for 4 hours (n = 10) and 96 hours (n = 5) in our clinically relevant lethal cavopulmonary failure (CPF) sheep model for ease of cannulation/deployment, reversal of CPF hemodynamics/end-organ hypoperfusion, and durability/biocompatibility. Cavopulmonary failure was achieved in all sheep. All DLCs were successfully inserted/deployed into Fontan anatomy. Cavopulmonary assist reversed CPF with normalized central venous pressure and cardiac output. All survival sheep were ambulatory with normal eating/drinking. One sheep was euthanized after 6 hours from cannula kinking, and one sheep died of hypokalemia after 8 hours. Three sheep survived 96 hours with normal hemodynamics. Free hemoglobin was only 3.7 ± 1.2 mg/dl at 96 hours, indicating negligible hemolysis. Creatinine, blood urea nitrogen, and lactate increased from hypoperfusion but normalized by 72 hours CPA. Necropsy showed only a small, immobilized thrombus ring at umbrella attachment to DLC. Our DLC-based system provided total ambulatory CPA in a lethal CPF sheep model with 96 hour survival and complete reversal of hemodynamics and end-organ hypoperfusion.

Failing Fontan cardiovascular support: Review.

BACKGROUND: Although all congenital heart defects (CHD) present unique challenges, univentricular CHD are especially challenging given the difficulty of passively perfusing pulmonary blood flow. Three surgical procedures are required within the first years of life, with the final completing a Fontan circulation in which the inferior vena cava is connected to the pulmonary artery and previously connected superior vena cava. This allows passive venous return to the pulmonary circulation then flow into the single ventricle for systemic circulation. METHODS: Although a Fontan provides successful palliation for two to three decades, many complications can arise as pulmonary resistance must remain low to allow adequate forward flow. Eventually, the failing Fontan circulation requires temporary support as the patient awaits a heart transplant. We reviewed PubMed, Google Scholar, and U. Kentucky library for different techniques evaluated to support a failing Fontan circulation. RESULTS: Multiple technologies have been developed as a bridge to transplant to decrease morbidity. Innovative types of extracorporeal membrane oxygenation, ventricular assist devices, and total artificial hearts have been attempted in laboratory settings as well as in Fontan patients with varying degrees of success. This article emphasizes the strengths and weaknesses of each technology in the context of Fontan physiology. CONCLUSION: The end game for these patients remains a heart transplant. Without easy access to donors, each of the options discussed is a potential bridge to limit morbidity and mortality until a suitable donor heart becomes available.

AvalonElite Double Lumen Cannula for Total Cavopulmonary Assist in Failing Fontan Sheep Model with Valved Extracardiac Conduit.

The AvalonElite double lumen cannula (DLC) provides total cavopulmonary assist (CPA) in failing Fontan sheep, but recirculation limits reliability. To improve CPA performance, a two-valve extracardiac conduit (ECC) was used to bracket infusion blood toward pulmonary artery (PA). A total cavopulmonary connection with failing Fontan circulation adult sheep model was created with valved ECC (n = 6). The valved ECC was connected to superior/inferior venae cavae (SVC/IVC) and right PA. The AvalonElite DLC was inserted from right jugular vein with infusion opening between the ECC valves. The DLC drainage lumen withdrew blood from SVC/IVC, and the infusion lumen returned blood to ECC. A failing Fontan sheep model with valved ECC was successfully created. Central venous pressure increased from 9 ± 1 to 17 ± 1 mm Hg, systolic arterial pressure decreased from 103 ± 9 to 51 ± 13 mm Hg, and cardiac output decreased from 3.6 ± 0.3 to 1.4 ± 0.2 L/min. Serum lactate significantly increased, indicating poor tissue perfusion. At 4 L/min pumping flow, the AvalonElite DLC returned hemodynamics/lactate to baseline levels throughout 6 hour CPA. Necropsy revealed intact/well-functioning ECC valves and well-positioned DLC with no visible thrombosis. The AvalonElite DLC provides reliable CPA performance in failing Fontan sheep with valved ECC.

Hybrid Extracorporeal Membrane Oxygenation Using Avalon Elite Double Lumen Cannula Ensures Adequate Heart/Brain Oxygen Supply.

BACKGROUND: Differential hypoxia exists in peripheral venoarterial (VA) extracorporeal membrane oxygenation (ECMO) patients with compromised lungs, causing hypoxic damage to heart or brain. We proposed an Avalon Elite (Maquet, Rastatt, Germany) double lumen cannula-based hybrid ECMO to add a venovenous (VV) blood flow into the pulmonary circulation onto the existing VA ECMO circuit to increase oxygen saturation in the left ventricle and ascending aorta, mitigating heart/brain hypoxia. METHODS: This hybrid ECMO circuit consists of two cannulas (27F Avalon Elite double lumen cannula from the inferior vena cava to the superior vena cava to right atrium to inferior vena cava; 17F infusion cannula in femoral artery), a blood pump, and a gas exchanger. This hybrid ECMO circuit was tested in 7 adult sheep with simulated lung failure. Total ECMO blood flow (2.8 to 3.3 L/min) was split between VV and VA blood flow. The VV blood flow was adjusted from 0% to 50% of total ECMO flow by approximately 10% increments. RESULTS: In VA ECMO, simulated respiratory failure resulted in differential hypoxia (low oxygen level in left ventricle and high oxygen level in abdominal aorta). In hybrid ECMO, adding VV blood flow (10% to 50% of total ECMO flow) to the VA ECMO circuit progressively increased left ventricle blood oxygen saturation from 70% ± 8% at zero VV blood flow (pure VA ECMO) to 82% ± 6% at 300 mL/min VV blood flow, and 96% ± 6% at 1,700 mL/min VV blood flow. CONCLUSIONS: The Avalon Elite double-lumen cannula-based hybrid ECMO circuit is a simple circuit that provides efficient performance and flexible VA/VV blood distribution. In this hybrid ECMO circuit, incremental VV blood flow (10% to 50%) progressively increased left ventricular blood oxygen level, ensuring adequate heart and brain oxygen supply.

A Numerical Simulation Comparing a Cavopulmonary Assist Device and VA ECMO for Failing Fontan Support.

A cavopulmonary assist device (CPAD) has been developed for failing Fontan support. This CPAD pumps blood from superior/inferior vena cavae (SVC/IVC) to pulmonary artery. In this study, we compared failing Fontan support with CPAD versus veno-arterial extracorporeal membrane oxygenation (VA ECMO) in silico. A numerical lumped-parameter circulatory system model was used to simulate Fontan circulation. Failing Fontan was simulated by increased pulmonary resistance. Central venous pressure (CVP), mean pulmonary arterial pressure (mPAP), left atrial pressure (LAP), and univentricular outflow (CO) were simulated and compared with published clinical data. The CPAD and VA ECMO were simulated using 1-5 L/min pump flows. In agreement with published clinical data, the simulated failing Fontan condition had increased CVP (19 mmHg) and mPAP (18 mmHg) with decreased LAP (7 mmHg) and cardiac output (3 L/min) compared with functional Fontan condition. The CPAD achieved total Fontan assistance with pump flows higher than original CO. Veno-arterial extracorporeal membrane oxygenation provided partial Fontan assistance with low pump flows. Blood went through pulmonary circulation with CPAD whereas VA ECMO bypassed pulmonary circulation and diminished univentricular blood flow (0.8 L/min). This in silico study demonstrated that CPAD preserved heart/lung function whereas VA ECMO had very low univentricular flow, potentially leading to thrombosis or univentricular atrophy.

A transapical-to-aorta double lumen cannula-based neonate left ventricular assist device efficiently unloads the left ventricle in neonate lambs.

OBJECTIVE: We are developing a transapical-to-aorta double lumen cannula (TAA DLC) for a less-invasive/more dependable neonatal left ventricular assist device. METHODS: The 18-Fr TAA DLC prototypes were bench tested and evaluated for 6 hours in neonate lambs (n = 6, 7.7-10 kg). The cardiac apex was exposed through a left anterolateral thoracotomy through the sixth intercostal space. The TAA DLC was inserted through a mattress stitch on apex, passing LV-aortic valve, into the ascending aorta with insertion/deployment guided by pressure waveform. The DLC was connected to blood pump. Cardiac output and aortic root blood flow were measured with perivascular flow sensors. Activated clotting time was maintained at 180-250 seconds. RESULTS: The DLC pumped up to 1.8 L/min flow against 63 mm Hg drainage pressure and 145 mm Hg infusion pressure in bench testing. In all lambs, the DLC was inserted/deployed properly within 1 minute on the first attempt. Pumping flow was maintained at 1.2-1.3 L/min. Systolic arterial pressure decreased and diastolic arterial pressure/mean arterial pressure increased, indicating decreased afterload and increased perfusion pressure. Left ventricular end-diastolic pressure decreased from 13 ± 1 mm Hg to 6 ± 2 mm Hg, indicating decreased preload. Aortic root backward flow was 2.4% ± 0.6% without DLC and 3.5% ± 0.8% of cardiac output with DLC, indicating no significant DLC-induced aortic valve regurgitation. After 6 hours, free hemoglobin was <5 mg/dL with hemoglobin/platelets unchanged. No significant thrombus was found in pumps/DLCs. No trauma was found in LV, aortic valve, and aorta. CONCLUSIONS: Our TAA DLC-based neonate left ventricular assist device efficiently unloaded the LV in lambs.

Percutaneous Double Lumen Cannula for Right Ventricle Assist Device System: A Computational Fluid Dynamics Study.

OBJECTIVES: Our goal is to develop a double lumen cannula (DLC) for a percutaneous right ventricular assist device (pRVAD) in order to eliminate two open chest surgeries for RVAD installation and removal. The objective of this study was to evaluate the performance, flow pattern, blood hemolysis, and thrombosis potential of the pRVAD DLC. METHODS: Computational fluid dynamics (CFD), using the finite volume method, was performed on the pRVAD DLC. For Reynolds numbers <4000, the laminar model was used to describe the blood flow behavior, while shear-stress transport k-ω model was used for Reynolds numbers >4000. Bench testing with a 27 Fr prototype was performed to validate the CFD calculations. RESULTS: There was <1.3% difference between the CFD and experimental pressure drop results. The Lagrangian approach revealed a low index of hemolysis (0.012% in drainage lumen and 0.0073% in infusion lumen) at 5 l/min flow rate. Blood stagnancy and recirculation regions were found in the CFD analysis, indicating a potential risk for thrombosis. CONCLUSIONS: The pRVAD DLC can handle up to 5 l/min flow with limited potential hemolysis. Further modification of the pRVAD DLC is needed to address blood stagnancy and recirculation.

Development of a Double-Lumen Cannula for a Percutaneous RVAD.

The objectives were to design/fabricate a double-lumen cannula (DLC) for a percutaneous right ventricular assist device (pRVAD) and to test the feasibility/performance of this pRVAD system. A 27 Fr DLC prototype was made and tested in six adult sheep. The pRVAD DLC was inserted into the right jugular vein; advanced through the superior vena cava, the right atrium (RA), the right ventricle (RV); ending in the pulmonary artery (PA). A CentriMag pump and optional gas exchanger were connected to the DLC. Blood was withdrawn from RA, pumped through gas exchanger, and perfused PA. Maximal pumping flow was maintained for 2 hours. The pRVAD DLC was successfully deployed in all six sheep. In first three sheep, maximal average pumping flow was less than 3 L/min because the DLC was advanced too far with drainage opening against RA side wall. In last three sheep with well-positioned DLC, average maximal flow was more than 3.5 L/min. The gas exchanger provided up to 230 ml/min CO2 removal and 174 ml/min O2 transfer. Our DLC-based pRVAD system is feasible for percutaneous right heart and respiratory assistance through a single cannulation. The pRVAD DLC can be easily placed prophylactically during left ventricular assist device implantation and removed as needed without additional open chest procedures.

Venovenous perfusion-induced systemic hyperthermia: five-day sheep survival studies.

OBJECTIVE: Since hyperthermia selectively kills lung cancer cells, we developed a venovenous perfusion-induced systemic hyperthermia system for advanced lung cancer therapy. Our objective was to test the safety and accuracy of our venovenous perfusion-induced systemic hyperthermia system in 5-day sheep survival studies, following Good Laboratory Practice standards. METHODS: Our venovenous perfusion-induced systemic hyperthermia system, which included a double-lumen cannula (Avalon Elite, Rancho Dominguez, Calif), a centrifugal pump (Bio-Pump 560; Medtronic Inc, Minneapolis, Minn), a heat exchanger (BIOtherm; Medtronic Perfusion Systems, Brooklyn Park, Minn), and a heater/cooler (modified Blanketrol IIIl Cincinnati Subzero, Cincinnati, Ohio), was tested in healthy adult sheep (n=5). The perfusion circuit was primed with prewarmed Plasma-Lyte A (Baxter Healthcare Corp, Deerfield, Ill) and de-aired. Calibrated temperature probes were placed in the right and left sides of the nasopharynx, bladder, and blood in/out tubing in the animal. The double-lumen cannula was inserted through the jugular vein into the superior vena cava, with the tip in the inferior vena cava. RESULTS: Therapeutic core temperature (42°C-42.5°C), calculated from the right and left sides of the nasopharynx and bladder temperatures, was achieved in all sheep. Heating time was 21±5 minutes. Therapeutic core temperature was maintained for 120 minutes followed by a cooling phase (35±6 minutes) to reach baseline temperature. All sheep recovered from anesthesia with spontaneous breathing within 4 hours. Arterial, pulmonary, and central venous pressures were stable. Transient increases in heart rate, cardiac output, and blood glucose occurred during hyperthermia but returned to normal range after venovenous perfusion-induced systemic hyperthermia termination. Electrolytes, complete blood counts, and metabolism enzymes were within normal to near normal range throughout the study. No significant venovenous perfusion-induced systemic hyperthermia-related hemolysis was observed. Neurologic assessment showed normal brain function all 5 days. CONCLUSIONS: Our venovenous perfusion-induced systemic hyperthermia system safely delivered the hyperthermia dose with no significant hyperthermia-related complications.

A paired membrane umbrella double-lumen cannula ensures consistent cavopulmonary assistance in a Fontan sheep model.

OBJECTIVES: The Avalon Elite (Macquet, Rastatt, Germany) double-lumen cannula can provide effective cavopulmonary assistance in a Fontan (total cavopulmonary connection) sheep model, but it requires strict alignment. The objective was to fabricate and test a newly designed paired umbrella double-lumen cannula without alignment requirement. METHODS: The paired membrane umbrellas were designed on the double-lumen cannula to bracket infusion blood flow toward the pulmonary artery. Two umbrellas were attached, one 4 cm above and one 4 cm below the infusion opening. Umbrellas were temporarily wrapped and glued to the double-lumen cannula body to facilitate insertion. A total cavopulmonary connection mock loop was used to test cavopulmonary assistance performance and reliability with double-lumen cannula rotation and displacement. The paired umbrella double-lumen cannula also was tested in a total cavopulmonary connection adult sheep model (n = 6). RESULTS: The bench test showed up to 4.5 L/min pumping flow and approximately 90% pumping flow efficiency at 360° rotation and 8-cm displacement of double-lumen cannula. The total cavopulmonary connection model with compromised hemodynamics was successfully created in all 6 sheep. The cavopulmonary assistance double-lumen cannula with paired umbrellas was smoothly inserted into the superior vena cava and extracardiac conduit in all sheep. At 3.5 to 4.0 L/min pump flow, the systolic arterial blood pressure and central venous pressure returned to normal baseline and remained stable throughout the 90-minute experiment, demonstrating effective cavopulmonary assistance support. Double-lumen cannula rotation and displacement did not affect performance. Autopsy revealed well-opened and positioned paired umbrellas, and double-lumen cannulas were easily removed from the right jugular vein. CONCLUSIONS: Our double-lumen cannula with paired umbrellas is easy to insert and remove. The paired umbrellas eliminated the strict alignment requirement and ensured consistent cavopulmonary assistance performance.

A practical and less invasive total cavopulmonary connection sheep model.

Our goal was to develop a less invasive total cavopulmonary connection (TCPC) sheep model for testing total cavopulmonary assist (CPA) devices. Thirteen sheep underwent a right fourth intercostal lateral thoracotomy. In series I (n = 6), a polytetrafluoroethylene (PTFE) extracardiac conduit (ECC) was connected to inferior vena cava (IVC) and superior vena cava (SVC) by end-to-side anastomosis. The SVC/IVC remained connected to right atrium (RA). A PTFE graft bridged ECC to right pulmonary artery (RPA). Clamps between SVC/IVC anastomoses and RA diverted total venous blood to pulmonary circulation. In series II (n = 7), temporary bypasses between SVC/IVC and RA allowed SVC/IVC to be cut off from RA for better RPA exposure. The ECC-SVC/IVC were end-end anastomosed and ECC-RPA side-side anastomosed for total SVC/IVC to pulmonary artery (PA) conversion. In each series, one sheep died of bleeding. In five sheep in series I and six sheep in series II, the TCPC model was successfully created with significantly increased central venous pressure and significantly decreased PA pressure/arterial blood pressure. Our acute TCPC sheep model has a less traumatic right thoracotomy with no cardiopulmonary bypass and less blood loss with no blood transfusion, facilitating future long-term CPA device evaluation.

Resolution of pulmonary hypertension complication during venovenous perfusion-induced systemic hyperthermia application.

We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46°C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42°C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment.

Physiologic response to a simplified venovenous perfusion-induced systemic hyperthermia system.

Our original venovenous perfusion-induced systemic hyperthermia (vv-PISH) system appeared to significantly improve the survival of patients with lung cancer, but was too complex with numerous dialysis problems. We tested a simplified vv-PISH circuit that includes the Avalon Elite (Avalon Laboratories, LLC, Rancho Dominguez, CA) double lumen cannula, a modified heat exchanger, a water heater/cooler, and a centrifugal pump. The purpose of this study was to evaluate this simplified vv-PISH system (without hemodialyzer) and to investigate the physiologic response to whole-body hyperthermia in pigs. We tested our vv-PISH circuit in healthy adult female swine (n = 7, 55-68 kg). The therapeutic core temperature (42°C), calculated as mean of rectal, bladder, and esophageal temperatures, was achieved in six swine. A maximum difference of 0.5°C was observed between the individual temperature sensor readings, indicating homogeneous heat distribution. Heart rate and mean arterial pressure were transiently altered, but were safely managed. A significant elevation in pulmonary artery pressure occurred during the heating phase, resulting in death of one pig. In all other pigs, pulmonary artery pressure returned to physiologic values during the therapeutic phase. Arterial blood electrolytes were maintained without the need of a dialyzer. Major organ function was within normal parameters. The simplified vv-PISH circuit reliably delivered the hyperthermic dose with no need of dialysis.

Long-term support with an ambulatory percutaneous paracorporeal artificial lung.

BACKGROUND: Conventional extracorporeal membrane oxygenation is bulky and non-ambulatory and requires multiple blood transfusions. We hypothesized that a percutaneous, paracorporeal artificial lung (PAL) could be established through a single venous cannulation to provide long-term ambulatory respiratory support. METHODS: Our PAL system was tested in 11 healthy sheep. An Avalon Elite dual-lumen cannula (DLC), inserted through the right jugular vein into the superior vena cava, right atrium, and inferior vena cava, was connected to a CentriMag pump and compact hollow-fiber gas exchanger, forming a short-circuit PAL system. All sheep were moved to intensive care unit and were ambulatory after anesthesia recovery. Hemodynamics and device performance were measured daily. RESULTS: The ambulatory PALs were successfully established in all sheep. The sheep were awake, ate, and moved freely in the metabolic cage, with no need of artificial nutrition or blood transfusion. All sheep had stable hemodynamics, with 2 liters/min of average circuit flow and hemoglobin levels exceeding 9.2 g/dl throughout the experiment. A progressive decrease of oxygen transfer and carbon dioxide removal capacity was observed. Sheep were euthanized between 10 and 24 days for bleeding (n = 2), gas exchanger failure (n = 6), and DLC issues (n = 3). CONCLUSIONS: We successfully established long-term ambulatory PAL for up to 24 days in 11 animals using our patented DLC through a single-site percutaneous venous cannulation. Critical bleeding/thrombosis formation and gas exchanger durability remain two major challenges for long-term-ambulatory PAL.

Complete respiratory support with AVCO2R and CPAP-mimic ventilation for total gas exchange in sheep.

The altered respiratory mechanics in patients with chronic obstructive pulmonary disease (COPD) present unique challenges with regard to treatment during an acute exacerbation that often leads to respiratory support with mechanical ventilation. Alternative therapies are badly needed to reduce morbidity and mortality associated with mechanical ventilator use. We hypothesized that arteriovenous carbon dioxide removal (AVCO(2)R) coupled with continuous positive airway pressure (CPAP) would achieve total gas exchange eliminating the need for intubation/mechanical ventilation, thus reducing baro/volutrauma. This hypothesis was tested in six adult sedated apneic sheep with AVCO(2)R administered through a simple arteriovenous (AV) shunt for CO(2) removal. Because it is impractical to apply a CPAP mask to conscious sheep, the CPAP was mimicked in intubated/sedated sheep by positive end-expiratory pressure (PEEP) of 5-10 mmH(2)O with negligible ventilation. The AVCO(2)R and CPAP-mimic maintained Pa(o)(2) and Pa(co)(2) in the normal physiological ranges. The CO(2) removal was 120-150 ml/min through AVCO(2)R with AV blood flow of 1.1-1.5 L/min. A high fraction of inspired oxygen percentage (Fi(o)(2)) level (89 ± 3%) was required to achieve 40 ± 7% O(2) in the small bronchus. Thus, AVCO(2)R and CPAP-mimic achieved total gas exchange in anesthetized sheep and may be a potential option for acute COPD exacerbation in humans.

Large-animal models of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is characterized by an acute inflammatory response that compromises alveolar-capillary membrane integrity. Clinical symptoms include refractory hypoxemia, noncardiogenic edema, and decreased lung compliance. The purpose of this review is to summarize the different ARDS large-animal models in terms of similarity to the clinical disease and underlying pathophysiology. The repeated lavage, oleic acid, endotoxin, and smoke/burn ARDS models will be discussed in this review. While each model has significant benefits, none is without weaknesses. Thus, the choice of large-animal ARDS model must be carefully considered based upon the study focus and investigative team experience.

Wang-Zwische double-lumen cannula leads to total cavopulmonary support in a failing Fontan sheep model.

BACKGROUND: We are developing a total cavopulmonary support system for failing Fontan physiology using the percutaneous Wang-Zwische double-lumen cannula (DLC). METHODS: We developed a sheep model of failing Fontan physiology through a right thoracotomy in 5 sheep. An extracardiac conduit was anastomosed to the inferior vena cava and superior vena cava, and a graft was applied to connect the conduit and the right pulmonary artery (PA) to create total vena cava-to-PA diversion, excluding the right heart. The DLC (commercialized as AvalonElite, Avalon Laboratories LLC, Rancho Dominguez, CA) was coupled with a CentriMag pump (Levitronix Waltham, MA) to form a cavopulmonary support system. The DLC was inserted through the right jugular vein and the superior vena cava into the extracardiac conduit with the infusion lumen opening aligned with the right PA bridge. Blood was withdrawn from the superior vena cava and the inferior vena cava through the drainage lumen and pumped into the right PA through the infusion lumen, with flow adjusted to 4.0±0.5 L/min. RESULTS: A successful Fontan model was created without cardiopulmonary bypass. After total venous blood diversion from the vena cava to the right PA artery, failing Fontan physiology developed, evidenced by elevated central venous pressure and dropping mean PA pressure and systolic arterial pressure. The DLC was successfully inserted, and hemodynamics were normalized in all 5 sheep for the duration of the 2-hour study. CONCLUSIONS: We created a model of failing Fontan circulation in sheep without cardiopulmonary bypass. The DLC system achieved total cavopulmonary support for 2 hours in our failing Fontan sheep model.

Ovine smoke/burn ARDS model: a new ventilator-controlled smoke delivery system.

BACKGROUND: Our current ovine smoke/burn acute respiratory distress syndrome (ARDS) model utilizes a manual bee smoker. This smoke delivery system lacks standardization and reproducibility, with 20% of sheep failing to meet ARDS criteria. Time to reach ARDS criteria and survival time are also variable. The mild volutrauma (15 mL/kg) applied after smoke/burn injury may also fail to induce ARDS within 24 h. We hypothesized that these inconsistencies were associated with the bee smoker and the mild volutrauma. In the current study, we addressed these problems to improve the consistency of the smoke/burn ARDS model. METHODS: Adult female sheep (n = 10) were given a 40% total body surface area third degree cutaneous burn and 48 breaths (4 × 12) of cotton smoke under general anesthesia. A modified ventilator was then used to deliver a precise and consistent smoke volume (tidal volume) to the sheep. Additional barotrauma was induced by pressure control ventilation (40 cm H(2)0). When ARDS criteria (PaO(2)/FiO(2) < 200) were met, the ARDS Network low tidal volume ventilation protocol (6-8 mL/kg ideal body weight) was used. RESULTS: Carboxyhemoglobin levels were 81.4% ± 5.6% immediately following smoke injury. All sheep met ARDS criteria within 24 h (12.5 ± 4.9 h). Mean survival time post-injury was 62.1 ± 26.4 h. White blood cells and granulocytes were significantly elevated at 24 h post-smoke/burn injury. Lung tissue at necropsy was consistent with ARDS. CONCLUSIONS: The refinements made to the original ovine smoke/burn ARDS model produce a more reliable time to ARDS onset, injury severity, and time of death.

A tetracycline analog improves acute respiratory distress syndrome survival in an ovine model.

BACKGROUND: Acute respiratory distress syndrome (ARDS) mortality remains high with no effective pharmacotherapy available. A chemically modified tetracycline (COL-3) is a potent inhibitor of matrix metalloproteinases. Prophylactic COL-3 administration has been shown to be effective in ARDS treatment. In the present study, the therapeutic effect of COL-3, given shortly after injury, was investigated in an ovine ARDS model. METHODS: The ovine ARDS model was induced by combined 40% body area third-degree burn, smoke inhalation, and barotrauma injuries. The sheep were randomly assigned into two groups: control (10% Solutol, n = 5) or COL-3 (200 mg/m(2), n = 5). Intravenous administration of COL-3 or vehicle was performed 1 hour after the smoke and burn injury. When ARDS criteria were met (arterial partial pressure of oxygen to fraction of inspired oxygen ratio < 200) or no later than 24 hours after injury (if criteria not met), animals underwent the ARDS Network ventilation protocol. At 96 hours after injury or at animal death, lung pathologic processes were assessed. RESULTS: Administration of COL-3 improved hemodynamics and reduced carbon dioxide levels. Administration of COL-3 also significantly delayed ARDS development and prolonged survival time compared with the control group (20.4 + or - 3.8 hours versus 12.9 + or - 3.3 hours; 94.2 + or - 4.0 hours versus 58.6 + or - 26.4 hours; p < 0.05, respectively). Survival analysis showed a higher 96-hour survival from ARDS with COL-3 administration as compared with control (80% versus 20%; p < 0.05). Lung pathologic processes were also improved by COL-3. Plasma matrix metalloproteinase-2 level increased in control but not in COL-3-treated animals. CONCLUSIONS: Our present study suggests that COL-3 may be an effective pharmacotherapy for ARDS treatment.