Kelly L. Koch

Development of an Artificial Placenta IV: 24-Hour Venovenous Extracorporeal Life Support in Premature Lambs

An extracorporeal artificial placenta would change the paradigm of treating extremely premature infants. We hypothesized that a venovenous extracorporeal life support (VV-ECLS) artificial placenta would maintain fetal circulation, hemodynamic stability, and adequate gas exchange for 24 hours. A near-term neonatal lamb model (130 days; term = 145 days) was used (n = 9). The right jugular vein was cannulated for VV-ECLS outflow, and an umbilical vein was used for inflow. The circuit included a peristaltic roller pump and a 0.5 m2 hollow fiber oxygenator. Lambs were maintained on VV-ECLS in an “amniotic bath” for up to 24 hours. Five of nine fetuses survived for 24 hours. In the survivors, average mean arterial pressure was 69 ± 10 mm Hg for the first 4 hours and 36 ± 8 mm Hg for the remaining 20 hours. The mean fetal heart rate was 202 ± 30. Mean VV-ECLS flow was 94 ± 20 ml/kg/min. Using a gas mixture of 50% O2/3% CO2 and sweep flow of 1–2 L/min, the mean pH was 7.27 ± 0.09, with Po2 of 35 ± 12 mm Hg and Pco2 of 48 ± 12 mm Hg. Necropsy revealed a patent ductus arteriosus in all cases, and there was no gross or microscopic intracranial hemorrhage. Complications in failed attempts included technically difficult cannulation and multisystem organ failure. Future studies will enhance stability and address the factors necessary for long-term support.

Development of an artificial placenta V: 70 h veno-venous extracorporeal life support after ventilatory failure in premature lambs

PURPOSE An artificial placenta would change the paradigm of treating extremely premature infants. We hypothesized that using a veno-venous extracorporeal life support (VV-ECLS) artificial placenta after ventilatory failure would stabilize premature lambs and maintain normal fetal physiologic parameters for 70 h. METHODS A near-term neonatal lamb model (130 days; term=145) was used. The right jugular vein (drainage) and umbilical vein (reinfusion) were cannulated with 10-12 Fr cannulas. Lambs were then transitioned to an infant ventilator. After respiratory failure, the endotracheal tube was filled with amniotic fluid, and VV-ECLS total artificial placenta support (TAPS) was initiated. Lambs were maintained on TAPS for 70 h. RESULTS Six of seven lambs survived for 70 h. Mean ventilation time was 57 ± 22 min. During ventilation, mean MAP was 51 ± 14 mmHg, compared to 44 ± 14 mmHg during TAPS (p=0.001). Mean pH and lactate during ventilation were 7.06 ± 0.15 and 5.7 ± 2.3 mmol/L, compared to 7.33 ± 0.07 and 2.0 ± 1.8 mmol/L during TAPS (p<0.001 for both). pO(2) and pCO(2) remained within normal fetal parameters during TAPS, and mean carotid blood flow was 25 ± 7.5 mL/kg/min. Necropsy showed a patent ductus arteriosus and no intracranial hemorrhage in all animals. CONCLUSIONS The artificial placenta stabilized premature lambs after ventilatory failure and maintained fetal circulation, hemodynamic stability, gas exchange, and cerebral perfusion for 70 h.

A Low Mortality Model of Chronic Pulmonary Hypertension in Sheep

BACKGROUND Pulmonary hypertension and right ventricular failure are major contributors to morbidity and mortality in chronic lung disease. Therefore, large animal models of pulmonary hypertension and right ventricular hypertrophy are needed to study underlying disease mechanisms and test new treatment modalities. The objective of this study was to create a low-mortality model of chronic pulmonary hypertension and right ventricular hypertrophy in sheep. METHODS The vena cavae of nine sheep weighing 62 ± 2 (SEM) kg were injected with 0.375 g of dextran beads (sephadex) every day for 60 d. Pulmonary hemodynamics were assessed via pulmonary artery catheterization prior to the first injection and again on d 14, 28, 35, 42, 49, and 56. At the end of the experiment, the heart was removed, dissected, and weighed to determine the ratio of right ventricular mass to left ventricle plus septal mass (RV:LV+S). RESULTS All sheep survived to 60 d. The average pulmonary artery pressure rose from 17 ± 1 mmHg at baseline to 35 ± 3 mmHg on d 56 with no significant change in cardiac output (8.7 ± 0.7 to 9.8 ± 0.7 L/min, P = 0.89). The RV:LV+S was significantly higher (0.42 ± 0.01, P < 0.001) than a historic group of untreated normal animals (0.35 ± 0.01, n = 13). CONCLUSION This study provides a low-mortality large animal model of moderate chronic pulmonary hypertension and right ventricular hypertrophy.

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<.001). In the group without tricuspid insufficiency, all sheep died beginning at the 70% shunt condition, whereas all animals with tricuspid insufficiency survived the entire experiment. Normal arterial blood gases were maintained under all conditions. 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.

Hemodynamic design requirements for in-series thoracic artificial lung attachment in a model of pulmonary hypertension.

Recent thoracic artificial lung (TAL) prototypes have impedances lower than the natural lung. With these devices, proximal pulmonary artery (PA) to distal PA TAL attachment may be possible in patients without right ventricular dysfunction. This study examined the relationship between pulmonary system impedance and cardiac output (CO) to create TAL design constraints. A circuit with adjustable resistance and compliance (C) was attached in a PA–PA fashion with the pulmonary circulation of seven sheep with chronic pulmonary hypertension. The pulmonary system zeroth harmonic impedance modulus (Z0) was increased by 1, 2.5, and 4 mmHg/(L/min) above baseline. At each Z0, C was set to 0, 0.34, and 2.1 ml/mmHg. The change in pulmonary system zeroth and first harmonic impedance moduli (&Dgr;Z0 and &Dgr;Z1), the percent change in CO (%&Dgr;CO), and the inlet and outlet anastomoses resistances were calculated for each situation. Results indicate that &Dgr;Z0 (p < 0.001) but not &Dgr;Z1 (p = 0.5) had a significant effect on %&Dgr;CO and that %&Dgr;CO = −7.45*&Dgr;Z0 (R2 = 0.57). Inlet and outlet anastomoses resistances averaged 0.77 ± 0.16 and 0.10 ± 0.19 mmHg/(L/min), respectively, and the relationship between %&Dgr;CO and TAL resistance, RT, in mmHg/(L/min) was determined to be %&Dgr;CO = −(7.45f)×(RT + 0.87), in which f = the fraction of CO through the TAL. Thus, newer TAL designs can limit %&Dgr;CO to less than 10% if f < 0.75.

Fourteen Day In Vivo Testing of a Compliant Thoracic Artificial Lung

The compliant thoracic artificial lung (cTAL) has been studied in acute in vivo and in vitro experiments. The cTAL’s long-term function and potential use as a bridge to lung transplantation are assessed presently. The cTAL without anticoagulant coatings was attached to sheep (n = 5) via the pulmonary artery and left atrium for 14 days. Systemic heparin anticoagulation was used. Compliant thoracic artificial lung resistance, cTAL gas exchange, hematologic parameters, and organ function were recorded. Two sheep were euthanized for nondevice-related issues. The cTAL’s resistance averaged 1.04 ± 0.05 mmHg/(L/min) with no statistically significant increases. The cTAL transferred 180 ± 8 ml/min of oxygen with 3.18 ± 0.05 L/min of blood flow. Except for transient surgical effects, organ function markers were largely unchanged. Necropsies revealed pulmonary edema and atelectasis but no other derangements. Hemoglobin levels dropped with device attachment but remained steady at 9.0 ± 0.1 g/dl thereafter. In a 14 day experiment, the cTAL without anticoagulant coatings exhibited minimal clot formation. Sheep physiology was largely unchanged except for device attachment-related hemodilution. This suggests that patients treated with the cTAL should not require multiple blood transfusions. Once tested with anticoagulant coatings and plasma resistant gas exchange fiber, the cTAL could serve as a bridge to transplantation.

Preliminary in vivo Testing of a Novel Pump for Short-Term Extracorporeal Life Support

BACKGROUND Blood pumps used for temporary circulatory support have limitations. We propose a novel device designed for short-term extracorporeal support that is intrinsically volume responsive, afterload insensitive, and incapable of cavitation or excessive hemolysis. After in vitro testing, we performed the initial in vivo implantations and assessments. METHODS The BioVAD prototype (MC3, Inc, Ann Arbor, MI) was implanted in 6 adult male sheep (60.2±2.8 kg) through the left ventricular apex and descending thoracic aorta. Arterial, left and right atrial, and pump inlet and outlet pressures and BioVAD flow were measured and recorded. The animals were volume loaded to assess volume responsiveness, and the inlet lines were abruptly clamped during maximum support to observe for cavitation. An acute heart failure model was created with rapid ventricular pacing, and the animals were supported for 4 hours. RESULTS Peak flow was 3.19±0.56 L/min and increased to 3.71±0.53 L/min with 20 mm Hg vacuum-assisted drainage. Without manual changes in pump settings, pump flow increased 17.5% with volume loading. During acute venous line occlusion, there was no evidence of cavitation, and inlet suction was minimal. Hemodynamics were maintained for 4 hours during acute heart failure. CONCLUSIONS The BioVAD provided adequate flow in an acute in vivo model. Its design may be superior for short-term extracorporeal support.

Quantification of thermal spread and burst pressure after endoscopic vessel harvesting: A comparison of 2 commercially available devices

OBJECTIVE Endoscopic vein harvesting systems have grown in popularity and are becoming the gold standard for coronary artery bypass grafting. Although a consensus is present that endoscopic vessel harvesting minimizes wound complications, long-term graft patency remains a concern. It has been proposed that endoscopic vessel harvesting affects graft patency because of irreversible trauma to the endothelium. This study was performed to examine the extent of thermal injury caused by 2 commercially available endoscopic vessel harvesting systems in a porcine model. METHODS Superficial epigastric veins and saphenous arteries were exposed in 10 anesthetized swine. All vessel samples (conduits) were harvested randomly with either a VirtuoSaph (Terumo Cardiovascular, Ann Arbor, Mich) or VASOVIEW 6 (MAQUET, Inc, Wayne, NJ) endoscopic vessel harvesting system. Conduits were harvested and saved for either histologic analysis or burst-pressure test. Statistical differences were analyzed by using a Wilcoxon rank sum test in SAS 9.2 software (SAS Institute, Inc, Cary, NC) for thermal spread and a 2-tailed t test with equal variance for burst pressure. RESULTS The average thermal spreads for saphenous artery and superficial epigastric vein conduits were significantly shorter in the VirtuoSaph group (0.42 ± 0.08 and 0.49 ± 0.05 mm, respectively) than in the VASOVIEW 6 group (1.05 ± .04 and 0.94 ± 0.19 mm, respectively). No significant differences were observed in burst pressure. CONCLUSIONS The length of thermal spread is short in arterial and venous conduits (0.4-1.1 mm) and depends on the endoscopic vessel harvesting system. Clinical protocols should include a minimal length of the cauterized branch to ensure that thermal spread does not reach the main vessel. The results of this study suggest that at least 1 mm is sufficient.

In-parallel attachment of a low-resistance compliant thoracic artificial lung under rest and simulated exercise.

BACKGROUND Previous thoracic artificial lungs (TALs) had blood flow impedance greater than that of the natural lungs, which could cause abnormal pulmonary hemodynamics. New compliant TALs (cTALs), however, have an impedance lower than that of the natural lung. METHODS In this study, a cTAL of new design was attached between the pulmonary artery (PA) and the left atrium (LA) in 5 sheep (60.2 ± 1.9 kg). A distal PA band was placed to control the percentage of cardiac output (CO) routed to the cTAL. Rest and exercise conditions were simulated using a continuous dobutamine infusion of 0 and 5 μg/kg/min, respectively. At each dose, a hemodynamic data set was acquired at baseline (no flow to the cTAL), and 60%, 75%, and 90% of CO was shunted to the cTAL. RESULTS Device resistance did not vary with blood flow rate, averaging 0.51 ± 0.03 mm Hg/(L/min). Under all conditions, CO was not significantly different from baseline. Pulmonary system impedance increased above baseline only with 5 μg/kg/min of dobutamine and 90% of CO diverted to the cTAL. CONCLUSIONS Results indicated minimal changes in pulmonary hemodynamics during PA-LA cTAL attachment for high device flows under rest and exercise conditions.

Comparing the Effectiveness of an Axial and a Centrifugal Left Ventricular Assist Device in Ventricular Unloading

Centrifugal (CFG) and axial flow (AX) left ventricular assist devices have different hydrodynamic properties that may impact the effectiveness of left ventricular unloading. We sought to determine whether patients implanted with the HeartWare HVAD (CFG) and HeartMate II (AX) had a similar degree of hemodynamic support by comparing parameters measured using echocardiography and right heart catheterization. Using our prospectively collected database, we identified 268 patients implanted with the AX and 93 with the CFG. Demographic characteristics were similar between groups. AX patients had a significantly lower INTERMACS score. Baseline ventricular dimension, mitral regurgitation, right ventricular systolic pressure, right atrial pressure, mean pulmonary artery pressure, cardiac output, and pulmonary vascular resistance were similar. Wedge pressure was higher, and left ventricular ejection fraction was lower at baseline in the AX. After implantation, there was a greater reduction of right atrial pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure, and left ventricular internal diameter during diastole in the AX cohort. After implantation, cardiac output by Fick calculation showed a greater improvement in the AX group. These results demonstrate that both AX and CFG devices resulted in left ventricular unloading; however, AX devices may offer advantages in the magnitude of left ventricular unloading, which could have implications in myocardial recovery or reduction in pulmonary vascular resistance before transplantation.