Literature related to Paragonix
The below-listed literature is intended to provide the reader with scientific literature that reviews various aspects of current methods of donor organ storage on ice.
Abstracts and relevant information taken from the published articles highlight the need for:
- temperature control during organ transport
- compliance with the temperature requirements of the currently used organ preservation solutions
- improved donor heart preservation to reduce the incidence of primary graft dysfunction
The First Clinical Use of a Novel Cold Storage System of Donor Hearts
N. Naito, M. Funamoto, R. Pierson, M. Villavicencio, W. Riley, G. Lewis, D. D’Alessandro
The Journal of Heart and Lung Transplantation, Volume 38, Issue 4, S44.
Current cold storage heart preservation technique is associated with wide fluctuation of organ temperature and may result in freeze injury. Paragonix SherpaPak Cardiac Transport System (CTS) (Paragonix Technologies, MA, USA) was recently approved in the United States for clinical use. This single-use disposable device is designed for static hypothermic preservation of a donor heart during transport. We report the first clinical use of the Paragonix SherpaPak CTS.
Since July 2018, the Paragonix SherpaPak CTS has been used in 6, non-consecutive heart transplant procedures at a single institution. All organs were procured from brain dead donors and had normal systolic function. Donor hearts were procured in standard fashion and positioned within the Paragonix SherpaPak CTS per the manufacturer’s instructions. The hearts were removed from the system in the recipient operating room and prepared for implantation in standard fashion.
Six recipients (5 male; mean age 60.3 ± 19.1 years) underwent heart transplantation using donor hearts transported with Paragonix SherpaPak CTS. All donors were categorized as PHS high risk and 5 of them were hepatitis C positive. Donor heart transportation time within the shipper was 24 to 205 (109.67 ± 66.60) min and donor heart total ischemic time was 116 to 312 (225 ± 70) min. Donor hearts were preserved at static hypothermia with a mean temperature of 5.99 ± 0.52℃. Among the patients transplanted there was no observed primary graft failure, and the ICU length of stay ranged from 3 to 21 (8.5 ± 6.3) days. All recipients are alive and well beyond 30 days with normal systolic function at discharge (LVEF 72± 6%).
The Paragonix SherpaPak CTS provides consistent organ temperature regulation throughout the transport observed process. Organs transported using this system demonstrated normal perioperative function even including an organ with more than 5 hours of total ischemic time. This system may decrease cold injury during organ transportation and increase the safe interval of tolerable cold ischemia.
Innovative cold storage of donor organs using the Paragonix SherpaPak™ devices
S.G. Michel, G.M. LaMuraglia II, M.L.L Madariaga, Lisa M. Anderson
Heart, Lung and Vessels. 2015; 7(3): 246-255.
Currently, the gold standard for donor organ preservation in clinical organ transplantation consists of 3 plastic bags and an ice box. The first plastic bag includes the organ itself immersed in preservation solution (e.g. Celsior). This bag is put in a second bag filled with saline, and then these two are put in a third bag filled with saline which is then put in the ice box. The disadvantage of this method is that the organ usually gets too cold. It has been shown that the theoretical perfect temperature for organ preservation is 4°C – 8°C. While higher temperatures lead to hypoxic injury of the organ because the metabolism is not decreased efficiently, lower temperatures than 4°C increase the risk of cold injury with protein denaturation. In the current study, we investigated a device that keeps the organ temperature consistently in the desired range of 4°C – 8°C and can potentially decrease cold injury to donor organs.
Three different ex vivo studies were performed with the Paragonix SherpaPak™ devices: 1) the temperature of the fluid-filled device was measured for up to 30 hours at an outside temperature set at 22°C; 2) the temperature of the fluid-filled device was measured for up to 30 hours at extreme outside temperatures set at -8°C and 31°C; 3) the temperature of a pig heart attached to the device was measured up to 12 hours.
All studies showed that the Paragonix SherpaPak™ can keep the temperature of the heart consistently between 4° and 8°C.
Conclusions: The Paragonix SherpaPak™ device may decrease cold injury of donor organs by maintaining the temperature consistently between 4°C and 8°C and therefore may decrease primary graft failure after organ transplantation.
Improved myocardial preservation at 4 degrees C.
Swanson DK, Dufek JH, Kahn DR.
Ann Thorac Surg. 1980 Dec;30(6):518-26.
We tested the ability of various cardiac preservation techniques to preserve left ventricular function of isolated canine hearts using preservation temperatures of 4 degrees or 15 degrees C. The four techniques tested were: (1) topical hypothermia, and hypothermic arrest induced by (2) perfusion of 1 liter of a modified Collins solution, (3) perfusion of 1 liter of a modified extracellular solution (DKS), or (4) perfusion of 500 ml of blood cardioplegia. Following the cold ischemia period, the hearts were reperfused with blood in the working heart preparation and tested for their ability to recover left ventricular function. Hearts preserved 2 hours at 15 degrees C using hypothermia, modified Collins solution, or DKS solution achieved an average of 60, 73, and 95%, respectively, of baseline function. Hearts preserved 3 hours at 4 degrees C using topical hypothermia attained 70% of baseline function, while hearts stored 5 hours at 4 degrees C using modified Collins solution or DKS solution recovered 83 and 92%, respectively, of baseline function. Hearts preserved at 4 degrees C functioned at levels equal to or greater than that of hearts stored at 15 degrees C, even though the hearts preserved at 4 degrees C were stored for longer periods than those preserved at 15 degrees C. Hearts preserved with blood cardioplegia for 2 hours at either 4 degrees or 15 degrees C achieved functions statistically the same as baseline levels during the reperfusion period. These data show no advantage for preservation temperatures of 15 degrees C compared with 4 degrees C. Our data provide a firm experimental basis for the clinical use of myocardial preservation temperatures of 4 degrees C, especially when combined with cardioplegia.
Are temperatures attained by donor hearts during transport too cold?
Hendry PJ1, Walley VM, Koshal A, Masters RG, Keon WJ.
J Thorac Cardiovasc Surg. 1989 Oct;98(4):517-22.
Excessive myocardial cooling may have detrimental effects on donor heart integrity. This study assessed the standard technique for donor myocardial preservation using hearts from seven mongrel dogs (mean weight 192.7 gm), which were arrested, excised, and placed in a cooler containing saline and ice. Temperature probes placed in both the left and right ventricular free walls and the septum revealed that, after cardioplegia, temperatures fell to 10.3 degrees, 7.5 degrees, and 7.6 degrees C, respectively. Temperature decreased to below 1 degree C after 75, 75, and 60 minutes for the left ventricle, right ventricle, and septum, respectively, independent of the size of the heart (range = 104 to 322 gm). After 4 hours of cooling, temperature was below 0 degrees C throughout the myocardium. Examination with an electron microscope showed similar serial changes over 4 hours in all hearts, including moderate-to-severe cytoplasmic and nuclear swelling and mitochondrial calcium deposits. Cell membranes remained intact, which suggests that the damage was not irreversible. We conclude that current donor heart preservation techniques may result in unacceptably low myocardial temperatures that cause reversible myocardial injury.
Accumulation of Crystal Deposits in Abdominal Organs Following Perfusion with Defrosted University of Wisconsin Solutions
Stefan G. Tullius, Alexander Filatenkow, Dietmar Horch, Thomas Mehlitz, Anja Reutzel-Selke, Johann Pratschke, Thomas Steinmüller, Andreas Lun, Hussein Al-Abadi and Peter Neuhaus
American Journal of Transplantation 2002; 2: 627–630
Previous studies reported on both visible and invisible particles in University of Wisconsin (UW) solutions. Those particles originated from components of the bags. In recent clinical observations we noticed macroscopically visible, indissoluble particles in UW bags reaching subzero temperatures during transportation of organs and preservation solutions. In an experimental model we examined whether those particles could be detected following perfusion of abdominal organs with established perfusion solutions. UW-, HTK- or physiological saline solutions reached -3°C to -0.5°C under conditions frequently applied during transportation. UW solutions demonstrated the accumulation of visible, indissoluble crystals and were subsequently used for the perfusion of abdominal organs in LEW rats. After perfusion with UW solutions stored at freezing temperatures, crystals were detected in all abdominal organs localized in and around vessels, bile ducts, glomeruli and in the interstitium of harvested livers, kidneys and pancreas. By spectroscopy, we were able to characterize crystals as adenosine. A 40-mm pore-size filter eliminated crystals from UW solutions. Crystals were absent in organs perfused with HTK- or saline solutions kept at subzero conditions. UW solutions can reach subzero temperatures under commonly used transportation conditions. Under these conditions, visible crystals accumulate and can be detected in abdominal organs of an experimental system.
“Although the manufacturers of UW solutions state that the solutions should be stored at 2–8.C, in the clinical situation preservation solutions and organ bags are frequently surrounded by frozen saline bags during transportation. Under these conditions, subzero temperatures occur, and macroscopically visible and indissoluble particles have been observed in UW solutions.”
“In summary, our results demonstrate for the first time the accumulation of intravascular and interstitial crystal deposits in intra-abdominal organs following perfusion with UW solutions reaching subzero temperatures under frequently applied clinical transporting conditions. Adequate storage temperatures of both grafts and perfusion solutions, in addition to the utilization of filter systems, seem of major importance in avoiding potential graft injuries.”
Organ Transport Temperature Box: Multicenter Study on Transport Temperature of Organs
D.F. Horch, T. Mehlitz, O. Laurich, A. Abel, S. Reuter, H. Pratschke, P. Neuhaus, and C. Wesslau
Transplantation Proceedings, 34, 2320 (2002)
An important factor for successful organ transplantation is cold ischemia, which begins with immediate perfusion and cooling of the organ, followed by transportation, and finishing with reperfusion. Manufacturer’s instructions call for a storage and transportation temperature of between 2°C and 8°C for preservation solution. New technical approaches for improving quality management have led to a more precise consideration of previous procedures.
Temperature sensors such as the SpyT, allow direct measurement of organ temperature processes during transportation as well as complete documentation and statistical evaluation. We tested the usual packing procedure following the ET transaction guidelines. Surprisingly, organ temperature was maintained at below _0°C in all packing procedures.
A multicenter trial including the DSO areas of Bavaria and Berlin/Brandenburg was initiated. A measurement of the ice machines used in all German DSO areas at the beginning of the study showed a homogeneous crushed-ice temperature of -0.5°C.
The average organ temperature during transportation (n = 186) was below 2°C, and after 6 hours below 0°C, as previously verified experimentally.”
Organ reperfusion and preservation
Russell W. Jamieson, Peter J. Friend
Frontiers in Bioscience 13, 221-235, January 1, 2008
Organ transplantation is one of the medical success stories of the 20th century. Transplantation is, however, a victim of its own success with demand for organs far exceeding supply. The ischemia/reperfusion injury associated with organ transplantation is complex with interlinking cellular pathways and cascades. With increasing use of marginal organs and better understanding of the consequences of ischemia/reperfusion, enhanced organ preservation is required. Traditional static cold preservation cannot prevent ischemia/reperfusion injury, the low temperature itself is damaging and viability testing is limited. Donor preconditioning techniques to enhance organ preservation in advance of retrieval are starting to show convergence on several key pathways (HO-1 and cell apoptosis). Microdialysis and bioimpedence techniques may allow viability assessment during cold storage. Hypothermic machine perfusion has a role to play, particularly in preservation of kidneys from non-heart-beating donors although results of clinical trials are awaited. Normothermic preservation offers benefits over cold storage (at least experimentally) by avoiding damage induced by low temperature, minimising ischemia/reperfusion injury and allowing resuscitation of damaged organs. Normothermic preservation is likely to increase as the average quality of donor organs declines and clinical trials are needed. In the long term, normothermic preservation may be used, not just to resuscitate organs, but facilitate organ immunomodulation.
Organ Preservation: Current Concepts and New Strategies for the Next Decade
Edgardo E. Guiberta, Alexander Y. Petrenko Cecilia L. Balabana Alexander Y. Somov, Joaquín V. Rodrigueza, Barry J. Fullerc
Transfus Med Hemother 2011;38:125–142
This manuscript reviews organ preservation strategies for all solid organs. For donor heart preservation, the authors note:
“Cold storage of the heart is one of the most challenging fields for organ preservation because of the high sensitivity of cardiac muscle to hypoxic injury and the serious perioperative consequences of inadequate preservation, leading to poor early graft function with associated high morbidities and mortalities. Careful selection of donor hearts is mandated.”
The relevance of ice crystal formation for the cryopreservation of tissues and organs
David E. Pegg
This paper discusses the role of ice crystal formation in causing or contributing to the difficulties that have been encountered in attempts to develop effective methods for the cryopreservation of some tissues and all organs. It is shown that extracellular ice can be severely damaging but also that cells in situ in tissues can behave quite differently from similar cells in a suspension with respect to intracellular freezing.
It is concluded that techniques that avoid the formation of ice altogether are most likely to yield effective methods for the cryopreservation of recalcitrant tissues and vascularised organs.
Primary Graft Failure after Heart Transplantation
Arjun Iyer, Gayathri Kumarasinghe, Mark Hicks, Alasdair Watson, Ling Gao, Aoife Doyle, Anne Keogh, Eugene Kotlyar, Christopher Hayward, Kumud Dhital, Emily Granger, Paul Jansz, Roger Pye, Phillip Spratt, and Peter Simon Macdonald
Journal of Transplantation
Volume 2011, Article ID 175768, 9 pages
Primary graft failure (PGF) is a devastating complication that occurs in the immediate postoperative period following heart transplantation. It manifests as severe ventricular dysfunction of the donor graft and carries significant mortality and morbidity. In the last decade, advances in pharmacological treatment and mechanical circulatory support have improved the outlook for heart transplant recipients who develop this complication. Despite these advances in treatment, PGF is still the leading cause of death in the first 30 days after transplantation. In today’s climate of significant organ shortages and growing waiting lists, transplant units worldwide have increasingly utilised “marginal donors” to try and bridge the gap between “supply and demand.” One of the costs of this strategy has been an increased incidence of PGF. As the threat of PGF increases, the challenges of predicting and preventing its occurrence, as well as the identification of more effective treatment modalities, are vital areas of active research and development.
“There is a clear need to develop more effective preservation strategies—either by bolstering the cardioprotective efficacy of the storage solution or through use of oxygenated ex vivo perfusion systems.”
“The period of heart storage and transport is the second period that offers an opportunity to intervene.”
Predictive risk factors for primary graft failure requiring temporary extra-corporeal membrane oxygenation support after cardiac transplantation in adults
Cosimo D’Alessandro, Jean-Louis Golmard, Eleodoro Barreda, Mojgan Laali, Ralouka Makris, Charles-Edouard Luyt, Pascal Leprince, Alain Pavie
European Journal of Cardio-Thoracic Surgery, Volume 40, Issue 4, 1 October 2011, Pages 962–970
Primary graft failure (PGF) is a major risk factor for death after heart transplantation. We investigated the predictive risk factors for severe PGF that require extra-corporeal membrane oxygenation (ECMO) circulatory support after cardiac transplantation.
Between January 2003 and December 2008, 402 adult patients underwent isolated cardiac transplantation at our institution. PGF was defined as the need for ECMO support in the immediate postoperative period. Thirty-three recipient and 37 donor variables were analyzed for the risk of PGF occurrence. Results: PGF occurred in 91 (23%) patients. Predictive risk factors for PGF occurrence were, in the recipient, being aged >60 years (odds ratio (OR) 2.11, p = 0.01) and preoperative mechanical circulatory support (MCS) (OR 2.65, p = 0.01); in the donor, they were mean norepinephrine dose (OR 2.02, p < 0.01), trauma as the cause of death (OR 2.45, p < 0.01), left-ventricle ejection fraction (LVEF) <55% (OR 2.72, p = 0.02), and the ischemic time (OR 1.01, p < 0.01). Weaning and discharge rates after ECMO support for PGF were, respectively, 60% (55/91 patients) and 46% (42/91 patients). The absence of PGF was correlated with improved long-term survival: 78% at 1 year and 71% at 5 years without PGF versus 39% at 1 year and 34% at 5 years with PGF (p < 0.01). Surviving patients treated with ECMO for PGF have similar conditional 1-year survival rates as non-PGF patients: 93% at 3 years and 91% at 5 years without PGF versus 93% at 3 years and 84% at 5 years with PGF (p = 0.46, NS).
Occurrence of PGF is a multifactorial event that depends on both donor and recipient profiles. ECMO support is a reliable treatment for severe PGF; furthermore, surviving patients treated with ECMO have the same 1-year conditional survival rates as patients not having suffered a PGF.
Report from a consensus conference on primary graft dysfunction after cardiac transplantation
Jon Kobashigawa, MD, Andreas Zuckermann, MD, Peter Macdonald, MD, PhD, Pascal Leprince, MD, PhD, Fardad Esmailian, MD, Minh Luu, MBBS, Donna Mancini, MD, Jignesh Patel, MD, PhD, Rabia Razi, MD, MPH, Hermann Reichenspurner, MD, PhD, Stuart Russell, MD, Javier Segovia, MD, PhD, Nicolas Smedira, MD, Josef Stehlik, MD, MPH, Florian Wagner, MD, PhD and on behalf of the Consensus Conference participants
The Journal of Heart and Lung Transplantation, Vol 33, No 4, April 2014
The authors of this international consensus paper note in Table 1 the results of an online survey on the prevention of primary graft dysfunction after cardiac transplantation.
“Precautions against PGD: (descending order of importance)
1. Cooling of the heart during implantation (by using devices such as cooling jackets, ice, cooling via vent into left atrium/ventricle)
2. Controlled reperfusion
3. Special cardioplegic solution protocol during surgery
4. Temperature control during transport”
Frostbite of the liver: An unrecognized cause of primary non‐function?
Kristina Potanos, Heung Bae Kim
“Appropriate hypothermic packaging techniques are an essential part of organ procurement. We present a case in which deviation from standard packaging practice may have caused sub‐zero storage temperatures during transport, resulting in a clinical picture resembling PNF. An 18‐month‐old male with alpha‐1‐antitrypsin deficiency underwent liver transplant from a size‐matched pediatric donor. Upon arrival at the recipient hospital, ice crystals were noted in the UW solution. The transplant proceeded uneventfully with short ischemia times. Surprisingly, transaminases, INR, and total bilirubin were markedly elevated in the postoperative period but returned to near normal by discharge. Follow‐up of over five yr has demonstrated normal liver function. Upon review, it was discovered that organ packaging during recovery included storage in the first bag with only 400 mL of UW solution, and pure ice in the second bag instead of slush. This suggests that the postoperative delayed graft function was related to sub‐zero storage of the graft during transport. This is the first report of sub‐zero cold injury, or frostbite, following inappropriate packaging of an otherwise healthy donor liver. The clinical picture closely resembled PNF, perhaps implicating this mechanism in other unexpected cases of graft non‐function.”
Cost Implications of Mechanical Circulatory Support for Primary Graft Dysfunction Following Heart Transplantation
A. A. Ali, M. Schechter, K. Southerland, L. Harling, J. Schroder, C. Milano.
The Journal of Heart and Lung Transplantation, Vol 34, No 4S, April 2015
Primary graft dysfunction (PGD) following heart transplantation often necessitates institution of mechanical circulatory support (MCS). Mild to moderate PGD can be supported with intra-aortic balloon pump (IABP) counterpulsation, whereas severe PGD requires ventricular assist device (VAD) insertion. Our aim was to analyze the costs associated with MCS for PGD following heart transplantation.
Demographic, operative, clinical and cost data were obtained retrospectively through review of electronic records. Only hospital costs were analyzed with professional fees excluded from the cost analysis. Patients were classified according to whether or not they required MCS following transplantation.
From January 1st, 2011 to December 31st, 2013, 142 patients underwent cardiac transplantation at Duke University Medical Center. Twenty-three patients (16.1%) required MCS for PGD. Six (4.2%) patients required biventricular (BIVAD) support with the remaining 17 (11.9%) requiring only right ventricular assist device (RVAD) support. Thirty-day mortality in patients requiring MCS was 13.1%. Total average cost was significantly greater in patients who required post-transplant MCS (MCS $324,226+/-140,751 vs. No MCS $156,793+/-47,359; P<0.001). The cost of BIVAD support was not significantly different from that of RVAD support. The total cost encountered for patients requiring MCS over this period was $7,132,980 which accounted for 25.5% of the total expenditure for heart transplantation at our institution ($27,986,506).
The costs associated with MCS for PGD following heart transplantation are substantially greater than those for patients who do not require support. Our previous analysis identified total ischemic time as the only independent predictor of the need for post-transplant MCS. Devices for continuous normothermic blood perfusion of the donor organ, as an alternative to cold storage, may reduce the incidence of PGD. The cost of these devices has limited their routine use. However, if avoidance of cold storage reduces the incidence of severe PGD, a cost benefit of organ perfusion devices may become apparent.