Filip Rega

Proof of concept: hemodynamic response to long-term partial ventricular support with the synergy pocket micro-pump

OBJECTIVES The purpose of this study was to test the hemodynamic effects of partial ventricular support in patients with advanced heart failure. BACKGROUND The use of current left ventricular assist devices (VADs) that provide full circulatory support is restricted to critically ill patients because of associated risks. Smaller, less-invasive devices could expand VAD use to a larger pool of less-sick patients but would pump less blood, providing only partial support. METHODS The Synergy Pocket Micro-pump device (CircuLite, Inc., Saddle Brook, New Jersey) pumps approximately 3.0 l/min, is implanted (off pump) via a mini-thoracotomy, and is positioned in a right subclavicular subcutaneous pocket (like a pacemaker). The inflow cannula inserts into the left atrium; the outflow graft connects to the right subclavian artery. RESULTS A total of 17 patients (14 men), age 53 +/- 9 years with ejection fraction 21 +/- 6%, mean arterial pressure 73 +/- 7 mm Hg, pulmonary capillary wedge pressure 29 +/- 6 mm Hg, and cardiac index 1.9 +/- 0.4 l/min/m(2) received an implant. Duration of support ranged from 6 to 213 (median 81) days. In addition to demonstration of significant acute hemodynamic improvements in the first day of support, 9 patients underwent follow-up right heart catheterization at 10.6 +/- 6 weeks. These patients showed significant increases in arterial pressure (67 +/- 8 mm Hg vs. 80 +/- 9 mm Hg, p = 0.01) and cardiac index (2.0 +/- 0.4 l/min/m(2) vs. 2.8 +/- 0.6 l/min/m(2), p = 0.01) with large reductions in pulmonary capillary wedge pressure (30 +/- 5 mm Hg vs. 18 +/- 5 mm Hg, p = 0.001). CONCLUSIONS Partial support appears to interrupt the progressive hemodynamic deterioration typical of late-stage heart failure. If proven safe and durable, this device could be used in a relatively large population of patients with severe heart failure who are not sick enough to justify use of currently available full support VADs. (Safety and Performance Evaluation of CircuLite Synergy; NCT00878527).

Machine perfusion in organ transplantation: a tool for ex-vivo graft conditioning with mesenchymal stem cells?

Purpose of reviewMachine perfusion has emerged as a tool to evaluate pretransplant graft function more objectively during preservation. Machine perfusion also offers the possibility to recondition questionable organs and to ‘immunomodulate’ allografts ex vivo. This article aims to review the current knowledge on machine perfusion of the various solid thoracic and abdominal organs, and to discuss the new possibility of conditioning and treating grafts with mesenchymal stem cells (MSCs) during machine perfusion. Recent findingsDifferent methods of machine perfusion have been described varying among organs in temperature and composition of perfusate. Commercial devices have recently become available for machine perfusion of all organs, with the largest clinical experience acquired in kidney and lung transplantation. Clinical studies are ongoing for liver, heart, and pancreas. MSC therapy in organ transplantation is now emerging with clinical studies set up to investigate its potential to attenuate ischemia/reperfusion injury (innate immunity) and to downregulate the alloimmune response (adaptive immunity) and promote engraftment after transplantation. We hypothesize that delivery of MSCs directly into the machine perfusion circuit may provide a unique opportunity to treat and immunomodulate organs prior to transplantation. To our knowledge, no study on ex-vivo delivery of MSCs during machine perfusion has been reported. SummaryMachine perfusion of solid organs has regained much attention during the last decade. It provides a new promising tool that may allow pretransplant ex-vivo assessment, preservation, repair, and conditioning of grafts. Experimental research and clinical trials testing the administration of MSCs during machine perfusion are warranted to explore the potential benefit and mechanisms of this approach.

Transapical left ventricular access for difficult to reach interventional targets in the left heart

Objective: Interventional targets may be virtually “excluded” due to vascular access problems or complex previous surgical procedures. This study reviews our experience using transapical ventricular puncture to gain direct access to the systemic ventricle. Patients: Patient 1 (74 years, 2 previous sternotomies), patient 2 (66 years, 5 previous sternotomies), and patient 5 (69 years, 3 previous sternotomies) with prosthetic valves had paravalvular mitral valve leaks. Patient 3 (6.3 years, 2 previous sternotomies) with an extracardiac Fontan conduit, had a significant residual leak after two previous surgical attempts of patch closure of a severely regurgitant right atrioventricular valve. Patient 4 (10 months) had failure of standard ablation of the posteroseptal region of the mitral valve with persistent life‐threatening episodes of ventricular tachycardia. Methods: Procedures were performed under general anesthesia. Entry site was percutaneous in three patients and in two (and one conversion) a mini‐thoracotomy was used. Sheaths were placed (6 F) using standard Seldinger technique, followed by the procedure as required. Direct surgical closure of the puncture site was done in 4 patients and in patient 3, a percutaneous vascular occlusion device was used. Results: Easy and immediate access was obtained in all patients. The paravalvular leaks were crossed within seconds and completely closed with Amplatzer occluders. In patient 3 the valve was crossed using a Brokenbrough needle and a 12‐mm Amplatzer device was placed in the patch leak. Patient 4 was successfully ablated using a 7‐F irrigated catheter endo‐ and epicardially. Complications were in the percutaneous puncture group: in one patient a coronary artery was punctured and in one a hemothorax developed. Conclusion: Direct left ventricular puncture offers a very useful alternative access site in selected patients to reach “inaccessible” targets for certain percutaneous interventions in patients where standard approaches may be impossible or difficult.

Should we ventilate or cool the pulmonary graft inside the non–heart-beating donor? ☆

BACKGROUND The ideal preservation method during the warm ischemic period in the non-heart-beating donor (NHBD) remains unclear. In this study we compare the protective effect of ventilation vs cooling of the non-perfused pulmonary graft. METHODS Domestic pigs (30.8 +/- 0.35 kg) were divided into 3 groups. In Group I, lungs were flushed with cold Perfadex solution, explanted and stored in saline (4 degrees C) for 4 hours (HBD, n = 5). Pigs in the 2 study groups were killed by myocardial fibrillation and left untouched for 1 hour. Lungs in Group II were ventilated (NHBD-V, n = 5) for 3 hours. Lungs in Group III were topically cooled (NHBD-TC, n = 5) in situ for 3 hours with saline (6 degrees C) infused via intra-pleural drains. Thereafter, the left lungs from all groups were prepared for evaluation. In an isolated circuit the left lungs were ventilated and reperfused via the pulmonary artery (PA) with autologous, hemodiluted, deoxygenated blood. Hemodynamic, aerodynamic and oxygenation parameters were measured at 37.5 degrees C and a PA pressure of 20 mm Hg. The wet:dry weight ratio (W/D) was calculated after reperfusion. RESULTS Pulmonary vascular resistance, oxygenation index and W/D weight ratio were significantly worse in NHBD-V (3,774 +/- 629 dyn sec cm(-5), 3.43 +/- 0.5, 6.98 +/- 0.42, respectively) compared with NHBD-TC (1,334 +/- 140 dyn sec cm(-5), 2.47 +/- 0.14, 5.72 +/- 0.24, respectively; p < 0.01, p < 0.05 and p < 0.05, respectively) and HBD (1,130 +/- 91 dyn sec cm(-5), 2.25 +/- 0.09, 5.23 +/- 0.49, respectively; p < 0.01, p < 0.01 and p < 0.05, respectively groups). No significant differences were observed, however, in any of these parameters between NHBD-TC and HBD (p = 0.46, p = 0.35 and p = 0.12, respectively). CONCLUSION These results indicate that cooling of the pulmonary graft inside the cadaver is the preferred method in an NHBD protocol. It is also confirmed that 1 hour of warm ischemia does not diminish graft function upon reperfusion.

Time course of acquired von Willebrand disease associated with two types of continuous-flow left ventricular assist devices: HeartMate II and CircuLite Synergy Pocket Micro-pump

BACKGROUND Bleeding complications are frequent adverse events in patients supported with axial continuous-flow pumps. Previous retrospective studies demonstrated that bleeding events in patients with the HeartMate II (Thoratec Corp, Pleasanton, CA) were attributed to acquired von Willebrand syndrome. We sought to analyze the von Willebrand factor (VWF) profile in patients receiving a HeartMate II or a CircuLite (Saddle Brook, NJ,) device (Synergy Pocket Micro-pump) prospectively. METHODS Prospectively analyzed were 34 patients supported with left ventricular assist device (LVAD; 26 with HeartMate II and 8 with CircuLite). The control group comprised 20 patients who underwent heart transplantation (HTx). Blood samples were taken pre-operatively and at 14 days and 3, 6, 9, and 12 months post-operatively. RESULTS Patients with LVADs had a high incidence of bleeding complications. From the immediate post-operative phase throughout the entire observation, the VWF ristocetin cofactor activity (Rco)/antigen (Ag) ratio of patients with HeartMate II and CircuLite devices was consistently lower compared with HTx patients. No correlation was found between the individual VWF:Rco/Ag ratio and bleeding events or transfusion requirements. The VWF:Rco/Ag ratio normalized immediately in patients who received HTx. CONCLUSIONS Acquired von Willebrand syndrome was confirmed to occur immediately after the implantation of both types of LVAD and persisted up to 12 months. A lower VWF:Rco/Ag ratio was associated with larger transfusion requirements. Acquired von Willebrand syndrome resolves after LVAD explantation.

The Contegra conduit in the right ventricular outflow tract is an independent risk factor for graft replacement

OBJECTIVE A large spectrum of congenital heart diseases requires valved conduits to establish an anatomical continuity between the right ventricle outflow tract (RVOT) and the pulmonary artery. The aim of the present study was to compare the incidence of graft replacement in patients receiving the Contegra conduit (bovine jugular vein graft) with that in patients receiving a homograft implanted in the RVOT. METHODS We reviewed a total of 347 conduits (Contegra 54; homografts 293) implanted in the RVOT from 1989 to 2003 in 323 patients (median age 12.7 years, range 4 days-69 years). Indications were Tetralogy of Fallot (n = 148), Ross operation (n = 89), truncus arteriosus communis (n = 47), pulmonary valve atresia (n = 30), double-outlet right ventricle (n = 15), transposition of the great arteries (n = 12), and endocarditis (n = 6). Follow-up was 99.4% complete (mean time: 5.9 years; range: 0-14.2 years). RESULTS Freedom from graft replacement at 1, 5, and 10 years of follow-up in the Contegra and homograft groups were 98.1 ± 1.9%, 78.3 ± 5.8%, and 63.5 ± 7.2% and 99.6 ± 0.4%, 94.0 ± 1.6%, and 81.4 ± 3.4%, respectively (log-rank test, p < 0.001). Independent predictors of graft replacement of the whole sample population were: graft size ≤ 20 mm (hazard ratio (HR) 3.6), age ≤ 10.4 years (HR 3.0), the non-anatomical position of the graft (HR 2.9), and the use of the Contegra conduit (HR 2.5). The multivariable analysis carried out on the propensity-score-matched population confirmed three independent predictors of graft replacement: graft size ≤ 20 mm (HR 8.0), the non-anatomical position of the graft (HR 2.3), and the use of the Contegra conduit (HR 3.7). CONCLUSIONS Besides size of the graft, age of the patients, and the non-anatomical position of the graft, the use of the Contegra conduit was found to be an independent risk factor for graft replacement in the RVOT. Patients receiving this conduit were more than twice as likely to undergo re-operation for graft replacement as those receiving a homograft.

How long can we preserve the pulmonary graft inside the nonheart-beating donor?

BACKGROUND The use of lungs from nonheart-beating donors (NHBD) might significantly alleviate the organ shortage. Extending the preharvest interval in NHBD would facilitate distant organ retrieval. We hypothesized that prolonged topical cooling inside NHBD after 60 minutes of initial warm ischemia would not affect the pulmonary graft. METHODS Domestic pigs were anesthetized and divided into three groups (n = 6 in each group). In the control group (HBD), lungs were flushed, explanted, and further stored in low potassium dextran solution (4 degrees C) for 4 hours. In the two study groups pigs were sacrificed by myocardial fibrillation and left untouched for 1 hour. Chest drains were then inserted for topical lung cooling (6 degrees C) for 3 hours (NHBD-TC3) or 6 hours (NHBD-TC6). The left lung in all groups was then prepared for evaluation. In an isolated circuit lungs were ventilated and reperfused through the pulmonary artery. Hemodynamic, aerodynamic, and oxygenation variables were measured 35 minutes after onset of controlled reperfusion. Wet-to-dry weight ratio was calculated. RESULTS No significant differences were observed among the three groups in pulmonary vascular resistance (p = 0.38), mean airway pressure (p = 0.39), oxygenation index (p = 0.62), and wet-to-dry weight ratio (p = 0.09). CONCLUSIONS These data confirm that 1 hour of warm ischemia does not affect the pulmonary graft from NHBD compared with HBD. The preharvest interval can be safely extended up to 7 hours postmortem by additional topical cooling of the graft inside the cadaver. This technique may facilitate distant organ retrieval in NHBD.

Extended Preservation of Ischemic Pulmonary Graft by Postmortem Alveolar Expansion

BACKGROUND If lungs could be retrieved for transplantation from non-heart-beating cadavers, the shortage of donors might be significantly alleviated. METHODS Peak airway pressure, mean pulmonary artery pressure, pulmonary vascular resistance, and wet to dry weight ratio were measured during delayed hypothermic crystalloid flush in rabbit lungs (n = 6) at successive intervals after death comparing cadavers with lungs left deflated (group 1), inflated with room air (group 2) or 100% oxygen (group 4), or ventilated with room air (group 3), or 100% nitrogen (group 5), or 100% oxygen (group 6). RESULTS There was a gradual increase in mean pulmonary artery pressure and pulmonary vascular resistance with longer postmortem intervals in all study groups (p = not significant, group 1 versus group 2 versus group 3). There was also a gradual increase in peak airway pressure and wet-to-dry weight ratio over time in all groups, which reflected edema formation during flush (airway pressure, from 14.5 +/- 1.0 cm H2O to 53.7 +/- 12.2 cm H2O, and wet-to-dry weight ratio, from 3.6 +/- 0.1 to 11.5 +/- 1.2, in group 1 at 0 and 6 hours postmortem, respectively; p < 0.05). Compared with group 1, however, the increase in groups 2 and 3 was much slower (airway pressure, 20.9 +/- 0.5 cm H2O and 18.8 +/- 1.2 cm H2O, and wet-to-dry weight ratio, 5.2 +/- 0.3 and 4.6 +/- 0.4 at 6 hours postmortem, respectively; p < 0.05 versus group 1 and p = not significant, group 2 versus group 3). Airway pressure and wet-to-dry weight ratio did not differ between groups 2 and 4 or between groups 3, 5, and 6. CONCLUSIONS These data suggest that (1) pulmonary edema will develop in atelectatic lungs if hypothermic flush is delayed for 2 hours after death, (2) postmortem inflation is as good as ventilation in prolonging warm ischemic tolerance, (3) inflation with oxygen or ventilation with nitrogen or oxygen is no different from that with room air, and (4) therefore, prevention of alveolar collapse appears to be the critical factor in protecting the lung from warm ischemic damage independent of continued oxygen delivery.

Current preservation technology and future prospects of thoracic organs. Part 2: heart.

Purpose of reviewThe problem of organ shortage continuously emphasizes the importance of proper donor management and selection, organ preservation and recipient selection and treatment. This review summarizes state of the art of cardiac allograft preservation with special regard to recent clinical and experimental findings. Recent findingsOver the past years no major strategy changes have found their way to the clinical setting of cardiac allograft preservation. Static, antegrade, cold, crystalloid flush perfusion is still the commonly used technique to preserve the heart. The importance of electrolyte composition, substrates and ischemia/reperfusion injury inhibiting additives are discussed with special attention to recent findings. Machine perfusion during preservation has regained attention over recent years and has led to the first clinical safety and feasibility trials in Europe and the USA. SummaryNo major changes were introduced in the technique of heart preservation over the past years. Many new ideas based upon experimental data were postulated but still have to find their way to the clinical setting.There is a renewed interest in mechanical perfusion. Everyone is curiously awaiting the first clinical reports.

Delay of adenosine triphosphate depletion and hypoxanthine formation in rabbit lung after death

BACKGROUND If lungs could be retrieved for transplantation from non-heart-beating cadavers, the shortage of donors might be significantly alleviated. METHODS Adenosine triphosphate (ATP) and hypoxanthine levels were measured postmortem in rabbit lungs comparing deflation (group 1), ventilation with room air (group 2), inflation with room air (group 3), ventilation with oxygen (group 4), ventilation with cooled air (group 5), deflation plus cadaver cooling (group 6), and cooling by pulmonary arterial flush (group 7). RESULTS The level of ATP dropped to 25.9% and HYP increased elevenfold at 30 minutes in group 1 but remained constant during 24 hours in group 7. The ATP catabolism beyond 2 hours postmortem appeared less in group 2 compared with group 3 (3.58 +/- 1.24 versus 0.39 +/- 0.08 mumol/g dry weight for ATP and 3.03 +/- 0.49 versus 7.64 +/- 0.94 mumol/g dry weight for hypoxanthine at 24 hours, respectively; p < 0.05). Cadaver cooling significantly slowed ATP catabolism. Changes in ATP level were similar in groups 2, 4, and 5. CONCLUSIONS These data suggest that in the non-heart-beating cadaver (1) cooling, ventilation, and inflation can delay ATP catabolism; (2) postmortem ventilation but not inflation for more than 2 hours will inhibit further ATP breakdown; (3) ventilation with either oxygen or cooled air is not more beneficial than room air ventilation; and (4) cold flush more than cadaver cooling will prevent ATP depletion.