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.

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.

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.

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.

Sepsis and burn complicated by sepsis alter cardiac transporter expression.

UNLABELLED: Sepsis alone and burn complicated by sepsis produce significant cardiac dysfunction. Since calcium handling by the cardiomyocyte is essential for cardiac function, one mechanism for cardiac abnormalities may be calcium dyshomeostasis. We hypothesized that sepsis and burn plus sepsis alter cardiac calcium transporter expression. Sprague-Dawley rats were divided into: (1) control, (2) sepsis (intratracheal S. Pneumoniae, 4x10(6) CFU), and (3) burn (40% TBSA) plus sepsis. Myocyte [Ca(2+)](i) and [Na(+)](i) were quantified with Fura-2 AM and SBFI, respectively. Western blot analysis of rat hearts used antibodies against the sarcoplasmic reticular Ca(2+) ATPase (SERCA), the L-type calcium channel, the Na(+)/Ca(2+) exchanger or the Na(+)/K(+) ATPase. RESULTS: Sepsis in the presence and absence of burn trauma increased [Ca(2+)](i) and [Na(+)](i). SERCA expression was decreased in the sepsis and burn plus sepsis groups while calcium channel expression was transiently increased in these sepsis groups. Na(+)/Ca(2+) exchanger expression exhibited a biphasic pattern of altered expression. Sepsis and burn plus sepsis reduced Na(+)/K(+) ATPase protein levels. These data suggest that altered transporter expression produce cardiomyocyte calcium and sodium loading and may contribute to sepsis-mediated cardiac contractile dysfunction.

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.

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.

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.

Rho-associated kinase modulates myocardial inflammatory cytokine responses.

Rho, a Ser-Thr kinase identified as a member of the RAS GTPase super family, is highly expressed in the heart, and has been implicated in the development of heart failure. GTPase Rho is located downstream of Gq, and Rho and the associated kinase (Rho kinase) regulate myofibril organization, apoptosis, and myofibrillar sensitivity to calcium. Myocardial injury and dysfunction occur after major burn injury, and this phenomenon has been linked to cardiac myocyte synthesis and the secretion of proinflammatory cytokines. Whether Rho-associated kinase modulates any aspect of cardiomyocyte synthesis of inflammatory mediators, contributing to myocardial dysfunction, has not been studied and was the focus of this study. Hearts were collected at several times postburn to determine if an acute injury such as thermal trauma altered myocardial Rho kinase expression. In addition, cardiomyocytes were isolated (collagenase digestion) from adult control Sprague Dawley rats, plated (5 x 10 cells/microtiter well), incubated with medium alone or in the presence of burn serum (collected 24 h after burn over 40% total body surface area in rats) in a CO2 incubator at 37 degrees C in the presence/absence of specific Rho-kinase inhibitors (HA1077, 10 microM or Y27632, 10 microM). After 18 h, supernatants were collected to measure secreted cytokines (enzyme-linked immunoabsorbant assay), cells were loaded with Fura-2AM (2 microg) or sodium-binding benzofuran isophthalate (2 microg) for 45 min at 37 degrees C, and fluorescence was measured with an InCyt IM2 fluorescence imaging system to measure myocyte calcium and sodium. In parallel studies, cells were examined to determine if burn serum challenge increased Rho kinase in this cell population. In vivo burn injury or in vitro burn serum challenge of isolated myocytes increased Rho-kinase expression and promoted cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin 1beta, and interleukin 6, and increased cardiomyocyte calcium and sodium levels compared with values measured when myocytes were incubated in medium alone (P < 0.05). Pretreating cardiomyocytes with Rho-kinase inhibitor (HA1077 or Y27632) prevented burn serum-related upregulation of Rho-kinase and attenuated the associated inflammatory cytokine responses, and attenuated myocyte calcium and sodium loading. Our data suggest that the Rho-kinase pathway is one potential upstream regulator of cardiac inflammatory response to burn injury.

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.

Activation of stress-responsive pathways by the sympathetic nervous system in burn trauma.

We have shown previously that bum trauma activates the stress responsive proteins, p38 mitogen-activated protein kinase (MAPK), c-jun NH2-terminal kinase (JNK), and NF-kappaB, and we have shown further that p38 MAPK is an important mediator of cardiomyocyte TNF-alpha secretion and cardiac dysfunction in burn trauma. Since burn trauma causes a rise in circulating catecholamine levels, we hypothesized that this increased sympathetic activity may function as an upstream activator of the p38 MARK pathway in burn trauma. This study determined whether the alpha1-adrenergic receptor ligand phenylephrine could mimic burn trauma activation of p38 MAPK, JNK, and NF-kappaB nuclear translocation; and the effect of the alpha1-adrenergic receptor antagonist prazosin on either phenylephrine or burn-mediated activation of the stress response pathway was examined. Sprague Dawley rats were divided into seven groups: Group 1, controls; Group 2, phenylephrine-treated (2 microg/kg, i.v.) control rats; Group 3, phenylephrine-treated plus prazosin-treated (1 mg/kg, i.v.) control rats; additional rats were given burn over 40% total body surface area (TBSA) and received vehicle (1 mL of 2% sucrose, p.o.) plus fluid resuscitation (Group 4), while in Group 5, burn rats were given prazosin (1 mg/kg, p.o.) plus fluid resuscitation. In Groups 6 and 7, sham-burned rats were given either vehicle (1 mL of 2% sucrose, p.o.) or prazosin (1 mg/kg, p.o.) to provide appropriate controls. Administration of phenylephrine to rats caused a significant activation of cardiac p38 MAPK/JNK activities (Western blot) and cardiac NF-kappaB nuclear translocation (electrophoretic mobility shift assay, EMSA). Prazosin blocked phenylephrine mediated changes in p38 MAPK/JNK activities. Burn trauma activated cardiac p38 MAPK/JNK and NF-kappaB, increased TNF-alpha secretion by cardiomyocytes, and impaired cardiac function. Prazosin treatment in burns interrupted the burn-mediated signaling cascade, decreasing TNF-alpha secretion by cardiomyocytes and preventing post-burn cardiac contractile dysfunction. Thus, burn trauma-related sympathetic activity likely activates the stress-responsive cascade, which regulates myocardial TNF-alpha transcription/translation and culminates in cardiac contraction and relaxation defects.

Burn trauma alters calcium transporter protein expression in the heart.

We have shown previously that burn trauma produces significant cardiac dysfunction, which is first evident 8 h postburn and is maximal 24 h postburn. Because calcium handling by the cardiomyocyte is essential for cardiac function, one mechanism by which burn injury may cause cardiac abnormalities is via calcium dyshomeostasis. We hypothesized that major burn injury alters cardiomyocyte calcium handling through changes in calcium transporter expression. Sprague-Dawley rats were given either burn injury or no burn injury (controls). Cardiomyocyte intracellular calcium and sodium were quantified at various times postburn by fura 2-AM or sodium-binding benzofuran isophthalate fluorescent indicators, respectively. In addition, hearts freeze-clamped at various times postburn (2, 4, 8, and 24 h) were used for Western blot analysis using antibodies against the sarcoplasmic reticulum calcium-ATPase (SERCA), the L-type calcium-channel, the ryanodine receptor, the sodium/calcium exchanger, or the sodium-potassium-ATPase. Intracellular calcium levels were elevated significantly 8-24 h postburn, and intracellular sodium was increased significantly 4 through 24 h postburn. Expression of SERCA was significantly reduced 1-8 h postburn, whereas L-type calcium-channel expression was diminished 1 and 2 h postburn (P < 0.05) but returned toward control levels 4 h postburn. Ryanodine receptor protein was significantly reduced at 1 and 2 h postburn, returning to baseline by 4 h postburn. Sodium/calcium exchanger expression was significantly elevated 2 h postburn but was significantly reduced 24 h postburn. An increase in sodium-potassium-ATPase expression occurred 2-24 h postburn. These data confirm that burn trauma alters calcium transporter expression, likely contributing to cardiomyocyte calcium loading and cardiac contractile dysfunction.

Sympathoadrenal modulation of stress-activated signaling in burn trauma.

Burn injury stimulates stress-responsive components, p38 mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinases (JNK)/nuclear factor (NF)-kappaB. p38 MAPK plays a role in postburn cardiomyocyte tumor necrosis factor-alpha secretion and cardiac dysfunction. Since burn trauma increases circulating catecholamine levels, which in turn modulate inflammatory cytokine production, we hypothesized that increased sympathetic activity after major burn trauma may trigger postburn cardiac p38 MAPK activation via an adrenergic receptor-mediated phenomenon. We examined adrenergic receptor populations involved in burn-activated cardiac stress signaling. Sprague Dawley rats were divided into six groups: 1) control, 2) control plus alpha1-adrenergic agonist phenylephrine (2 microg/kg, intravenous), 3) control plus beta-adrenergic agonist isoproterenol (1 microg/kg, intravenous), 4) burn (fluid resuscitation with lactated Ringer's 4 ml/kg/% burn), 5) burn plus alpha1-adrenergic antagonist prazosin (1 mg/kg, by mouth), and 6) burn plus beta-adrenergic antagonist propranolol (3.3 mg/kg, by mouth). Phenylephrine, but not isoproterenol, increased cardiac p38 MAPK/JNK/NF-kappaB activation. Burn trauma activated p38 MAPK, JNK, and NF-kappaB, and this stress response was blocked by either prazosin or propranolol. Thus, stimulation of the adrenergic pathway may constitute one upstream activator of stress response in burn.

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.

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.

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.

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.

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.