Extracorporeal Perfusion System Research Articles

Increasing Utilization of Extended Criteria Donor Hearts for Transplantation: The OCS Heart EXPAND Trial

BackgroundExtended criteria donor (ECD) hearts available with donation after brain death (DBD) are underutilized for transplantation due to limitations of cold storage. ObjectivesThis study evaluated use of an extracorporeal perfusion system on donor heart utilization and post-transplant outcomes in ECD DBD hearts. MethodsIn this prospective, single-arm, multicenter study, adult heart transplant recipients received ECD hearts using an extracorporeal perfusion system if hearts met study criteria. The primary outcome was a composite of 30-day survival and absence of severe primary graft dysfunction (PGD). Secondary outcomes were donor heart utilization rate, 30-day survival, and incidence of severe PGD. The safety outcome was the mean number of heart graft–related serious adverse events within 30 days. Additional outcomes included survival through 2 years benchmarked to concurrent nonrandomized control subjects. ResultsA total of 173 ECD DBD hearts were perfused; 150 (87%) were successfully transplanted; 23 (13%) did not meet study transplantation criteria. At 30 days, 92% of patients had survived and had no severe PGD. The 30-day survival was 97%, and the incidence of severe PGD was 6.7%. The mean number of heart graft–related serious adverse events within 30 days was 0.17 (95% CI: 0.11-0.23). Patient survival was 93%, 89%, and 86% at 6, 12, and 24 months, respectively, and was comparable with concurrent nonrandomized control subjects. ConclusionsUse of an extracorporeal perfusion system resulted in successfully transplanting 87% of donor hearts with excellent patient survival to 2 years post-transplant and low rates of severe PGD. The ability to safely use ECD DBD hearts could substantially increase the number of heart transplants and expand access to patients in need. (International EXPAND Heart Pivotal Trial [EXPANDHeart]; NCT02323321; Heart EXPAND Continued Access Protocol; NCT03835754)

Extracorporeal Perfusion of Vascularized Composite Tissues: The Bridging Role of an Emerging Technology in Reconstructive Microsurgery.

Complex defects with exposed critical structures after trauma or tumor resections are routinely reconstructed with free flaps. In the current practice of reconstructive microsurgery, the success rate at high-volume centers is above 95%. However, despite high success rates, free tissue transfer is not without challenges and limitations. The high degree of technical skill and resources needed to perform these lengthy procedures are not fulfilled at every institution globally. In some cases, the availability of recipient vessels can be limited due to vascular disease or prior treatments. Additionally, perioperative patient decompensation could affect outcomes, especially in complex multitrauma patients. Therefore, an improved approach is still needed to ensure reliable flap transfer even in the presence of unanticipated events and compromised recipient vasculature. Considering the major advancements over the past few decades, further improvement at this point requires a paradigm shifting approach. Machine perfusion, classically used in the preservation of solid organs, offers a wide variety of implications for vascularized composite tissues. An extracorporeal perfusion system (EPS), similar to that used during cardiopulmonary bypass, can be used to isolate the tissue via cannulation of the primary artery and vein and provide temporary support. The research on this topic1 can be furthered to enable clinical use of such technology in three distinct purposes (Fig. 1).Fig. 1.: Conceptual schematic of the potential clinical needs that an extracorporeal perfusion system could address. Machine perfusion support could serve three distinct purposes in reconstructive microsurgery: (1) bridge-to-anastomosis, (2) bridge-to-neovascularization for traditional flaps, and (3) bridge-to-neovascularization for bioengineered flaps. Even the uses for purposes 1 and 2 might be rarer occurrences; once the technology is established for purpose 3, its indications will continually expand to cover purposes 1 and 2. Created with BioRender.com.●Bridge-to-anastomosis: An EPS could be used to maintain support of the tissue until transplantation and successful anastomosis to mitigate ischemia/reperfusion injury. This purpose could support the tissues during delays between harvesting and anastomosis such as transportation of composite allografts, temporizing replants, or stabilization of decompensating patients.2,3 ●Bridge-to-neovascularization for traditional flaps: A portable/wearable EPS could be maintained following inset of the tissue over a wound bed and obviate the need to isolate and connect to recipient vessels. Extracorporeal support would continue until sufficient vessel ingrowth and tissue integration has occurred and can be weaned once the neovascularized network itself can provide full tissue support. The basic feasibility of the bridge-to-neovascularization approach in a vessel depleted wound was demonstrated in a small case series and showed that less than 2 weeks of external perfusion could allow sufficient neovascularization.4 ●Bridge-to-neovascularization for bioengineered flaps: The third application has the broadest implications for clinical impact and the field of bioengineered vascularized composite tissues. Currently, although there are limited studies, a major obstacle in engineered vascular networks is thrombosis.5 An EPS would be crucial to ensure successful transfer of engineered constructs with the benefit of closed-system isolated drug delivery (eg, heparin, vasodilatory agents) and conditioned perfusate (eg, platelet depletion) to prevent intravascular thrombosis. Similarly, this closed circuit could be used for delivery of growth factors to induce angiogenesis and facilitate integration of the transferred tissue. In summary, an EPS would address immediate and future problems in complex soft-tissue reconstruction. Recent advancements in the machine perfusion field and its integration with reconstructive microsurgery could open doors for a novel subspecialty. The challenging scenario of extensive tissue loss could be managed without the need for microsurgery using a compact perfusion system. DISCLOSURE The authors have no financial interest to declare in relation to the content of this article.

Normothermic liver machine perfusion as a dynamic platform for regenerative purposes: What does the future have in store for us?

Liver transplantation has become an immense success; nevertheless, far more recipients are registered on waiting lists than there are available donor livers for transplantation. High-risk, extended criteria donor livers are increasingly used to reduce the discrepancy between organ demand and supply. Especially for high-risk livers, dynamic preservation using machine perfusion can decrease post-transplantation complications and may increase donor liver utilisation by improving graft quality and enabling viability testing before transplantation. To further increase the availability of donor livers suitable for transplantation, new strategies are required that make it possible to use organs that are initially too damaged to be transplanted. With the current progress in experimental liver transplantation research, (long-term) normothermic machine perfusion may be used in the future as a dynamic platform for regenerative medicine approaches, enabling repair and regeneration of injured donor livers. Currently explored therapeutics such as defatting cocktails, RNA interference, senolytics, and stem cell therapy may assist in the repair and/or regeneration of injured livers before transplantation. This review will provide a forecast of the future utility of normothermic machine perfusion in decreasing the imbalance between donor liver demand and supply by enabling the repair and regeneration of damaged donor livers.

50. Isolated Support With an Extracorporeal Perfusion System Deters Ischemia-related Metabolic Derangement of a Rat Fasciocutaneous Free Flap

50. Isolated Support With an Extracorporeal Perfusion System Deters Ischemia-related Metabolic Derangement of a Rat Fasciocutaneous Free Flap

Ex Vivo Thrombolysis to Salvage Free Flaps Using Machine Perfusion: A Pilot Study in a Porcine Model

Mechanical evacuation of capillary thrombi in free flaps is difficult, and often requires thrombolytic therapy. Utilizing machine perfusion systems, the possibility rises to salvage free flaps ex vivo by administering high doses of thrombolytic agents. The primary aim of this pilot study in a porcine model is to investigate the feasibility of ex vivo thrombolysis using an extracorporeal perfusion machine. A model of stasis-induced thrombosis was used in 12 free rectus abdominis flaps harvested from six Dutch Landrace pigs. Compromised flaps were ex vivo perfused with University of Wisconsin preservation solution and treated according to the following study groups: (1) 1 mg of tissue plasminogen activator (t-PA) as additive, (2) 3 mg of t-PA as an additive, and (3) no thrombolytic additive. Microcirculation was assessed using near-infrared fluorescence angiography. Pedicled abdominal flaps were created and thrombus formation was successfully induced. Eleven abdominal flaps were perfused using the modified heart-lung machine setup. Near-infrared fluorescence angiography showed delayed or no filling was noted in the control group. In comparison, the flaps which were perfused with 1 mg t-PA or 3 mg t-PA as additive showed increased fluorescence intensity curves. This pilot study in a porcine model presents a reliable and reproductive stasis-induced thrombosis model in free flaps. By adding t-PA to a custom-made extracorporeal perfusion system, the indocyanine green fluorescence intensity curves increased of all flaps that were perfused with different dosages of t-PA as additives, indicating restoration of capillary pressure and microcirculatory inflow.

Normothermic ex vivo perfusion of the limb allograft depletes donor leukocytes prior to transplantation

The donor immune compartment plays a central role in graft rejection of the vascularised composite allograft (VCA) by contributing to 'direct presentation'. Using our limb ex vivo normothermic machine perfusion (EVNP) protocol designed for prolonged allograft preservation, this study aimed to assess whether donor leukocytes responsible for allograft rejection are mobilised from the donor compartment. Five genetically different pig forelimbs underwent perfusion via the brachial and radial collateral artery for 6h after 2h of cold storage. Oxygenated haemodilute leucocyte-deplete blood was recirculated at normothermia using an extracorporeal perfusion system. Tissue perfusion was evaluated clinically and biochemically via blood perfusate. The temporal kinetics of donor leucocyte extravasation, cytokine secretion and cell-free DNA was characterised in the circulating perfusate. Flow cytometry revealed increasing populations of viable leukocytes over time, reaching 49 billion leukocytes by 6h. T (3.0 × 109 cells) and B cells (3.1 × 108 cells) lymphocytes, monocytes (2.7 × 109 cells), granulocytes (8.1 × 109 cells), NK (6.3 × 108) and γδ (8.1 × 108) cells were all identified. Regulatory T cells comprised a minor population (1.6 × 107 cells). There was a cumulative increase in pro-inflammatory cytokines suggesting that the donor limb has the capacity to elicit significant inflammatory responses that could contribute to leucocyte activation and diapedesis. EVNP not only acts as a preservation tool, but could also be utilized to immunodeplete the VCA allograft prior to transplantation. This has clinical implications to mitigate acute rejection and prevent graft dysfunction and supports the future application of machine perfusion in graft preservation and immune modulation.

Tissue Viability of Free Flaps after Extracorporeal Perfusion Using a Modified Hydroxyethyl Starch Solution.

Background: In free flap surgery, tissue is stored under hypothermic ischemia. Extracorporeal perfusion (EP) has the potential to extend storage time and the tissue’s perspective of survival. In the present study, the aim is to improve a recently established, simplified extracorporeal perfusion system. Methods: Porcine musculus rectus abdominis were stored under different conditions. One group was perfused continuously with a simplified one-way perfusion system for six hours, while the other received only a single flush but no further treatment. A modified hydroxyethyl starch solution was used as a perfusion and flushing solution. Vitality, functionality, and metabolic activity of both groups were analyzed. Results: Perfused muscles, in contrast to the ischemically stored ones, showed no loss of vitality and significantly less functionality loss, confirming the superiority of storage under continuous perfusion over ischemic storage. Furthermore, in comparison to a previous study, the results were improved even further by using a modified hydroxyethyl starch solution. Conclusion: The use of EP has major benefits compared to the clinical standard static storage at room temperature. Continuous perfusion not only maintains the oxygen and nutrient supply but also removes toxic metabolites formed due to inadequate storage conditions.

A drive mechanism for a blood pump integrated in an oxygenator

Abstract The achievement of a low priming volume of the components in an extracorporeal perfusion system for neonatal and pediatric patients is an open research question. This paper presents a concept of a pump-oxygenator in which an oxygenator and a pulsatile blood pump are combined in one housing. For operation of the pump-oxygenator, a special actuating system for the pump process was designed. It consists of a piston pump which is directly coupled with a voice coil actuator (VCA). A servo positioning system was developed to assure the piston motion according to predefined reference trajectories. First experimental results indicate the feasibility of driving this blood pump with a VCA. In an in-vitro study, the pump produced mean flow rates of 60-900 mL/min with stroke frequencies in the range of 60-240 beats per minute.

P.3.b.014 - The association between serum levels of brain-derived neurotrophic factor and cognitive impairment in chronic elderly schizophrenia inpatients

Sickle cell disease (SCD) is a genetic disease caused by mutations in the beta globin gene, and inflammation plays a key role in driving many aspects of disease pathology. Early immune activation is believed to be associated with hemodynamic stresses and thrombus formation as cells traffic through blood vessels. We applied an extracorporeal perfusion system to model these effects ex vivo, and combined this with a phospho-CyTOF workflow to comprehensively evaluate single-cell signatures of early activation across all major circulating immune subsets. These approaches showed immune activation following passage through the perfusion chamber, most notably in monocytes, which exhibited platelet aggregation and significantly elevated expression of multiple phospho-proteins. Overall, these studies outline a robust and broadly applicable workflow to leverage phospho-CyTOF to characterize immune activation in response to ex vivo or in vivo perturbations and may facilitate identification of novel therapeutic targets in SCD and other inflammatory diseases.

Application of phospho-CyTOF to characterize immune activation in patients with sickle cell disease in an ex vivo model of thrombosis

Sickle cell disease (SCD) is a genetic disease caused by mutations in the beta globin gene, and inflammation plays a key role in driving many aspects of disease pathology. Early immune activation is believed to be associated with hemodynamic stresses and thrombus formation as cells traffic through blood vessels. We applied an extracorporeal perfusion system to model these effects ex vivo, and combined this with a phospho-CyTOF workflow to comprehensively evaluate single-cell signatures of early activation across all major circulating immune subsets. These approaches showed immune activation following passage through the perfusion chamber, most notably in monocytes, which exhibited platelet aggregation and significantly elevated expression of multiple phospho-proteins. Overall, these studies outline a robust and broadly applicable workflow to leverage phospho-CyTOF to characterize immune activation in response to ex vivo or in vivo perturbations and may facilitate identification of novel therapeutic targets in SCD and other inflammatory diseases.

Free flap rescue using an extracorporeal perfusion device.

The warm ischaemia time of microvascular free flaps is limited. Incalculable events, such as lack of adequate recipient vessels or intraoperative medical emergencies, can lead to prolonged ischaemia and potentially to flap loss. In this study, critically perfused ischaemic or congested flaps were temporarily perfused with an extracorporeal perfusion system until anastomosis could be commenced. Temporary extracorporeal perfusion was performed in 8 radial forearm flaps for 147±52 (range 77-237) minutes. Flap perfusion was assessed using Indocyanine Green fluorescence angiography and combined laser Doppler flowmetry and remission spectroscopy. Results were compared with those of 30 patients who underwent conventional reconstruction with radial forearm flaps. Flap survival, flap microcirculation, postoperative complications, and hospital stay did not differ between groups. We report successful free flap transfer after short-term extracorporeal perfusion for up to 4h in 8 patient cases. Temporary extracorporeal free flap perfusion reduces the warm ischaemia time in emergency situations and can help to prevent flap failure in critically perfused or congested flaps. The trial is registered with ClinicalTrials.gov, number NCT02449525.

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers.

Donor organ shortages have led to an increased interest in finding new approaches to recover organs from extended criteria donors (ECD). Normothermic extracorporeal liver perfusion (NELP) has been proposed as a superior preservation method to reduce ischemia/reperfusion injury (IRI), precondition suboptimal grafts, and treat ECD livers so that they can be successfully used for transplantation. The aim of this study was to investigate the beneficial effects of a modified NELP circuit on discarded human livers. Seven human livers that were rejected for transplantation were placed on a modified NELP circuit for 8 hours. Perfusate samples and needle core biopsies were obtained at hourly intervals. A defatting solution that contained exendin-4 (50 nM) and L-carnitine (10 mM) was added to the perfusate for 2 steatotic livers. NELP provided normal temperature, electrolytes, and pH and glucose levels in the perfusate along with physiological vascular flows and pressures. Functional, biochemical, and microscopic evaluation revealed no additional injuries to the grafts during NELP with an improved oxygen extraction ratio (>0.5) and stabilized markers of hepatic injury. All livers synthesized adequate amounts of bile and coagulation factors. We also demonstrated a mild reduction (10%) of macroglobular steatosis with the use of the defatting solution. Histology demonstrated normal parenchymal architecture and a minimal to complete lack of IRI at the end of NELP. In conclusion, a modified NELP circuit preserved hepatocyte architecture, recovered synthetic functions, and hepatobiliary parameters of ECD livers without additional injuries to the grafts. This approach has the potential to increase the donor pool for clinical transplantation. Liver Transplantation 22 979-993 2016 AASLD.

Development of an Extracorporeal Perfusion Device for Small Animal Free Flaps.

BackgroundExtracorporeal perfusion (ECP) might prolong the vital storage capabilities of composite free flaps, potentially opening a wide range of clinical applications. Aim of the study was the development a validated low-cost extracorporeal perfusion model for further research in small animal free flaps.MethodsAfter establishing optimal perfusion settings, a specially designed extracorporeal perfusion system was evaluated during 8-hour perfusion of rat epigastric flaps followed by microvascular free flap transfer. Controls comprised sham-operation, ischemia and in vivo perfusion. Flaps and perfusate (diluted blood) were closely monitored by blood gas analysis, combined laser Doppler flowmetry and remission spectroscopy and Indocyanine-Green angiography. Evaluations were complemented by assessment of necrotic area and light microscopy at day 7.ResultsECP was established and maintained for 8 hours with constant potassium and pH levels. Subsequent flap transfer was successful. Notably, the rate of necrosis of extracorporeally perfused flaps (27%) was even lower than after in vivo perfusion (49%), although not statistically significant (P = 0,083). After sham-operation, only 6% of the total flap area became necrotic, while 8-hour ischemia led to total flap loss (98%). Angiographic and histological findings confirmed these observations.ConclusionsVital storage capabilities of microvascular flaps can be prolonged by temporary ECP. Our study provides important insights on the pathophysiological processes during extracorporeal tissue perfusion and provides a validated small animal perfusion model for further studies.

58. In vivo preconditioning: An advanced donation algorithm for cryopreservation of organs for transplantation

Improved cryopreservation techniques could potentially achieve long-term organ storage and therefore solve the problem of worldwide organ shortage for transplantation. Current experimental approaches mostly rely on complex ex vivo machine perfusion protocols for organ preconditioning after explantation. These machines deliver cocktails of cryoprotectants, nanoparticles and other agents through the vasculature of organs and into the cells in order to overcome major hurdles regarding the cooling and thawing processes. However, many of the commonly used agents are toxic and the procedures are technically challenging, and introduce prolonged times that can decrease organ quality. While research efforts are focusing on even more complex attempts to address the aforementioned problems ex vivo, beating heart donor organ transplantation offers an extensive time frame for manipulation in vivo. In current practice, the donor is “only” maintained and monitored during this period. In the future, the period of time when the brain-dead donor has a beating heart could be used to apply several approaches where the donor becomes a production and delivery platform in order to improve organ quality for the purpose of cryopreservation. In nature, animals provide multiple examples of how in vivo preconditioning induces freeze tolerance to prepare for hibernation. Utilizing the normothermic circulation in a physiological environment provided by the donor, the production of beneficial proteins could be induced. This strategy would not only involve drug application such as microRNA transfection for protein synthesis regulation, but also the application of physical triggers, using the donor’s physiological responses. For example, the production of heat shock proteins that have recently been demonstrated to have a potential protective effect against chilling injury can be induced systemically within the donor by local external heat application. If these strategies are applied shortly after consent for donation, there is time to induce protein production and for the proteins to take effect. Going forward, suitable animal models should be developed to assess the effectiveness of externally induced in vivo preconditioning. An ethical debate is needed to address whether the extra physical and chemical stress that the beating heart donors will have to undergo is justifiable. In conclusion, under the current algorithm for organ donation, valuable time and treatment opportunities for organ preconditioning are unutilized during the period of time while beating heart donors are awaiting organ procurement. The physiological environment in heart beating donors enables treatment options that cannot be provided by extracorporeal perfusion systems after explantation. Therefore, utilizing the donor body for preconditioning of the organs may enable new protocols that are less toxic and reduce the duration of ex vivo preconditioning to ultimately facilitate success in cryopreservation.

Isolated limb infusion chemotherapy with or without hemofiltration for recurrent limb melanoma.

To better define the efficacy and the safety of intra-arterial infusion performed with or without hemofiltration for recurrent limb melanoma. Patients with the following characteristics were included in the study: recurrent limb melanoma not indicated for surgical resection, measurable disease in the extremity, > 18 years, performances status (Eastern Cooperative Oncology Group ) was 0-1 and life expectancy of at least 6 mo. Twenty nine consecutive patients were enrolled in the study. Patients underwent fluoroscopic placement of angiographic arterial and venous catheters to infuse the drug in the artery [isolated limb infusion (ILI)], and to stop the out flow (venous). Melphalan was rapidly infused into the isolated limb via the arterial catheter after the inflation of venous balloon catheter. Then the circulation of the limb was completely blocked with a pneumatic cuff at the root of the limb. Haemofiltration (HF) was available only in the main center, and was performed with an extracorporeal perfusion system, in order to reduce high systemic toxic peaks of drug. Thirty seven ILI were done in 29 cases (31 ILI-HF and 6 ILI) between 2001 and 2014 at Ancona and Pesaro Hospitals, Italy. Clinical outcomes were monitored 30 d after treatment. Eleven patients (38%) received infusion of melphalan alone, 7 (24%) melphalan associated to mitomicin C and 7 (24%) melphalan associated to cisplatin, the remaining 4 were treated with cisplatin, melphalan and epirubicin or cisplatin and mitomicin C. The overall response rate was 66%, in particular, 3 patients (10%) were complete responders and 16 (56%) were partial responders; whereas 7 patients (24%) had stable disease, and 3 (10%) showed progressive disease. Limb toxicity was assessed adopting Wieberdink scale, with evidence of 90% of low grade (I and II) toxicity. ILI-HF and ILI are effective and safe treatments for recurrent non-resectable limb melanoma. They present evidence of favorable clinical benefit and is effective in delaying progression.

Ischaemia‐related cell damage in extracorporeal preserved tissue – new findings with a novel perfusion model

Tissue undergoing free transfer in transplant or reconstructive surgery always is at high risk of ischaemia-related cell damage. This study aims at assessing different procedures using an extracorporeal perfusion and oxygenation system to investigate the expression of hypoxia inducible factor (HIF)-1-α as marker for hypoxia and of the pro-apoptotic protein Caspase-3 in skeletal muscle to elucidate potential improvements in tissue conservation. Twenty-four porcine rectus abdominis muscles were assigned to five different groups and examined after they had been extracorporeally preserved for 60 min. time. Group I was left untreated (control), group II was perfused with a cardioplegic solution, group III was flushed with 10 ml of a cardioplegic solution and then left untreated. Group IV and V were perfused and oxygenated with either an isotone crystalloid solution or a cardioplegic solution. Among others, immunohistochemistry (Caspase-3 and HIF-1-α) of muscle samples was performed. Furthermore, oxygen partial pressure in the perfusate at the arterial and venous branch was measured. Expression of Caspase-3 after 60 min. was reduced in all groups compared to the control group. Furthermore, all groups (except group III) expressed less HIF-1-α than the control group. Oxygenation leads to higher oxygen levels at the venous branch compared to groups without oxygenation. Using an extracorporeal perfusion and oxygenation system cell damage could be reduced as indicated by stabilized expressions of Caspase-3 and HIF-1-α for 60 min. of tissue preservation. Complete depletion of oxygen at the venous branch can be prevented by oxygenation of the perfusate with ambient air.

Extracorporeal Liver Perfusion System for Artificial Liver Support Across a Membrane

An extracorporeal porcine liver perfusion (ECPLP) system circumvents the limitations of hepatocyte based bio-artificial liver, but its clinical application has been limited so far due to the potential risk of transmission of porcine endogenous retroviruses. The aim of this study was to develop an ECPLP model that can provide artificial hepatic support across a semi-permeable membrane, which has the potential to block porcine viruses due to its pore size. Livers from white landrace pigs were perfused with normothermic oxygenated blood using Medtronic BP560 centrifugal pump (Medtronic, Inc., Minneapolis. MN). This ECPLP system was used to support a "surrogate" patient across the filter Evaclio-EC4A. Function of liver was measured by indocyanine green retention at 15 min (ICGR15). Clearance of galactose, ammonia, and para-aminobenzoic acid infused into the "surrogate" patient circulation was calculated to assess liver support across the membrane. The study was designed as test (n = 15) versus control (n = 5), with control experiments having no liver in the circuit. For the test experiments, we perfused 15 livers with mean hepatic artery pressure of 87 mm Hg and flows of 1.2 L/min. ICGR15 in test experiments was 11%. Ammonia clearance was 945 mg/min/kg, galactose metabolic rate was 111.7 mg/min/Kg, and the hippurate ratio was 91% in the test. In contrast, the control experiments did not show any significant change in the concentration of any of these compounds. Our ECPLP model was able to provide hepatic support in an experimental setting across a hollow fiber filter. Further work on an anhepatic animal is needed prior to application in human trials.

Indocyanine green R15 ratio depends directly on liver perfusion flow rate

Indocyanine green (ICG) is a synthetic dye that is widely used to evaluate liver function in critically ill patients, before liver resection or after liver transplantation. Controversy still exists about the impact exerted on the ICG ratio after 15 min (ICG R15) by differences in liver perfusion rates, hyperdynamic states, or patient cardiac output. We studied the role of different liver perfusion rates on the ICG R15 ratio in a normothermic extracorporeal liver perfusion system under standardized conditions. Livers from landrace pigs (40-50 kg) were perfused with fresh porcine blood. Normal and high perfusion rates were defined as 1 ml and 2 ml/g liver/min, respectively. Perfusate pressure of the hepatic artery and portal vein were within the physiological range in both groups. According to manufacturer's instructions, 0.5 mg of ICG per kg was applied and the ICG R15 was calculated. Calculations were based on fifteen experiments in five liver perfusions. Bile production, liver function and histology were analyzed. All perfusions were characterized by physiological bile production, lack of hepatocellular damage and normal histology. ICG R15 ratio in group I, perfused with 1 ml/g liver, was 18.9 +/- 6%. In group II, perfused with 2 ml/g liver, the ICG R15 ratio was 7.2 +/- 3%. The difference between groups 1 and 2 was statistically significant (p < 0.05). ICG R15 is reliable within one group at defined perfusion rates. Doubled perfusion rates contribute to higher ICG clearance. For clinical application we would like to suggest considering cardiac output of the patient for interpretation of ICG ratios.

Extracorporeal circulatory systems in the interhospital transfer of critically ill patients: experience of a single institution

BACKGROUND AND OBJECTIVES:Critically ill patients with acute circulatory failure cannot be moved to other institutions unless stabilized by mechanical support systems. Extracorporeal heart and lung assist systems are increasingly used as a bridge to end-organ recovery or transplantation, and as an ultimate rescue tool in cardiopulmonary resuscitation.PATIENTS AND METHODS:From July 2001 to April 2008, we had 38 requests for extracorporeal support for interhospital transfer carried out by the air medical service. Respiratory failure was present in 29 patients, who were provided with pumpless extracorporeal lung assist (PECLA) or veno-venous extracorporeal membrane oxygenation (ECMO). Cardiac failure dominated in 9 patients, who underwent implantation of extracorporeal life support (ECLS). Underlying diseases were acute respiratory distress syndrome in 15 patients, pneumonia in 7, prior lung transplant status in 4, cardiogenic shock in 7, and septic shock in 4.RESULTS:All assist systems were connected via peripheral vessels by the Seldinger technique. Transport was uneventful in all cases with no technical failures. On arrival at the specialized care hospital, two patients had leg ischemia and underwent relocation of the arterial cannula. After a mean (SD) support of 5.1 (3.0) days for PECLA, 3.5 (2.9) days for ECLS, and 7.3 (5.8) days for ECMO, 60%, 66%, and 66% of patients, respectively, could be successfully weaned from the systems. Discharge rates were 45% for PECLA, 44% for ECLS, and 56% for ECMO.CONCLUSION:Our experience proves that minimized extracorporeal assist devices allow safe assistance of patients with isolated or combined heart and lung failure in need of interhospital transfer. Critically ill patients get a chance to reach a center of maximum medical care.

Reduced myocardial calcium responsiveness after coronary microembolization

We have recently reported that the myocardial dysfunction observed several hours after coronary microembolization (ME) is related to an oxidative modification of tropomyosin (Canton et al., Eur Heart J 27:875–881, 2006). We have now investigated the impact of ME on calcium responsiveness at a time when myocardial function is reduced, i.e. 6 h after ME. In 10 anesthetized pigs the LAD was cannulated and perfused by an extracorporeal perfusion system. Regional myocardial function was assessed by sonomicrometry. Five pigs received saline as placebo and served as controls. In 5 pigs, ME was induced by injection of microspheres (Ø42 μ; 3000/ml/min coronary inflow) through the perfusion system. Calcium responsiveness was determined by measuring the increase in myocardial work (pressure vs. wall excursion) in response to a graded intracoronary infusion of CaCl2 at baseline and at 6 h after ME or placebo, respectively. Graded CaCl2 increased myocardial work at baseline stepwise. At any CaCl2 myocardial work was attenuated 6 h after ME, whereas it was not different from baseline after 6 h in controls. The absolute concentration of Ca in coronary blood to achieve the half maximal increase in myocardial work remained unchanged in controls (baseline: 189±18 μg/ml, mean±SEM; 6 h: 212±22 μg/ml) and after ME (baseline: 179±8 μg/ml; 6 h: 175±17 μg/ml).