Benefit of Hypothermic Perfusion

TransMedics’ Organ Care System (OCS) is the current leader in normothermic machine perfusion (NMP) for the preservation of multiple organs and carries the only FDA-approved device for the preservation of hearts recovered from donors after circulatory death (DCD) (2). XVIVO, a Swedish-based leader in organ preservation, was an early pioneer in lung preservation with its novel perfusion solution and device (3). Today, XVIVO offers a range of devices for the preservation of major solid organs, utilizing both normothermic and hypothermic technologies. Several of these devices are approved for use internationally, while in the U.S., the kidney and lung preservation devices have received regulatory approval, and the heart preservation device is currently in clinical trials (4). Organ Recovery Systems’ LifePort® devices are widely used in clinical practice, with the LifePort® Kidney Transporter becoming the standard of care for kidney preservation in many European countries, particularly France5. Paragonix KidneyVault™, recently debuted, provides hypothermic perfusion without oxygenation.  Many other companies, in addition to those listed in Table 1, offer perfusion devices designed for organ preservation at the transplant hospital but not for transportation. While these devices play a critical role in organ transplantation, they will not be discussed further in this paper. 

Case for Normothermic Machine Perfusion (NMP) 

NMP preserves organs at body temperature (37˚C) with blood based oxygenated perfusate, simulating near-physiological conditions. This technique allows for real-time physiological evaluation, enabling the assessment of organ function before transplantation (1). By maintaining physiological temperature, NMP minimizes ischemia-reperfusion injury and supports cellular homeostasis. Compared to static cold storage (SCS), NMP can prolong preservation while keeping the organ viable, potentially expanding the donor pool (6,7). It is particularly beneficial for high-risk or marginal organs that might otherwise be discarded (8). In addition, advances in NMP have made DCD organs a more viable option by reviving the organ following the initial ischemic/hypoxic stress.  The donor heart pool has increased by around 25% with the more recent acceptance of DCD heart utilization with this technology. 

Case Against NMP 

Despite its advantages, NMP presents several drawbacks. Current organ perfusion preservation systems that utilize NMP are large, heavy, and expensive. The equipment and consumables required for NMP are costly, increasing the overall expense of transplantation (9). Due to their significant energy demands of heating elements and motor driven pumps, these systems require both battery and wall power capabilities. They are housed in enclosures roughly the size of a small refrigerator and can weigh over 150 pounds. Consequentially, transporting these devices typically requires several technicians and longer trips often necessitate chartered aircraft. Because the system operates at 37°C, oxygen carrying capacity in the form of blood products, often from the donor, are needed to meet oxygen demand by the organ further complicating the use of the device. The system also requires continuous monitoring by trained personnel, adding operational challenges (8).  

Furthermore, system failures pose a significant risk; a mechanical or operational failure can result in immediate organ loss. Some studies indicate that for certain organs, NMP does not significantly improve transplant success rates compared to static cold storage (10). Furthermore, the metabolic activity of the organ during NMP can lead to the accumulation of metabolic toxins if not properly managed, necessitating careful perfusate regulation (11,12). NMP systems also tend to be heavy and bulky requiring chartered air transport services to move the organ from recovery to transplant facilities. 

Case for Hypothermic Machine Perfusion (HMP) 

HMP preserves organs at low temperatures using crystalloid perfusates,  typically between 4 and 10°C to reduce metabolic demands, with some devices providing controlled oxygenation (1,13). By lowering metabolic activity, HMP decreases the accumulation of metabolic toxins, minimizing the potential of cellular damage. Some HMP systems that oxygenate the perfusate can support some minimal metabolic activity, further mitigating ischemic-reperfusion injury, and post-transplant complications (14,15). HMP is significantly more cost-effective and requires less specialized equipment and training for implementation. Unlike NMP, an HMP device failure does not immediately compromise organ viability, as the organ remains in a stable cold environment, making it a lower risk alternative (16). 

Case Against HMP 

While HMP offers protective benefits, it has limitations. Unlike NMP, HMP does not allow for real-time functional evaluation of the organ before transplantation, increasing the risk of post-transplant complications (7). Temperature sensitivity is also a concern; improper management leading to a warmer environment may result in inadequate metabolic suppression, potentially leading to cellular damage (17,18), while too cold of an environment can also cause tissue injury. Newer, oxygenated HMP methods are being explored to address some of these limitations. 

Kidney-Specific Considerations 

Kidneys were among the first organs to benefit from HMP, with early studies demonstrating its efficacy in reducing delayed graft function (DGF) compared to SCS (19). Technological advancements and shifting donor demographics have renewed interest in HMP, particularly for high-risk donor kidneys, such as those from extended criteria donors (ECD) and donation after circulatory death (DCD) (20). Randomized control trials and meta-analyses confirm that HMP significantly lowers the risk of DGF, shortens its duration, and improves early graft survival compared to SCS (14,21). 

NMP, however, offers real-time functional assessments, though studies in porcine models and human trials suggest its benefits over HMP remain variable (19-22). Some findings indicate that NMP may minimize certain ischemic injuries but may also lead to greater structural alterations, such as tubular damage (23). Given that kidneys traditionally tolerate hypothermic conditions well, HMP continues to be widely accepted as the gold standard for preservation. Future research should clarify whether NMP’s viability assessment and therapeutic potential could further refine kidney preservation. 

Liver-Specific Considerations 

Liver transplantation presents unique challenges in organ preservation, making the choice between NMP and HMP particularly important. The liver is also the only organ with significant historical data for both HMP and NMP, as the OCS™ Liver device (NMP), the metra® device (NMP), and the ORS LifePort® Liver Transporter (HMP) have been in the US market for several years. 

Studies indicate that HMP can significantly reduce ischemia-reperfusion injury by providing continuous oxygenation and metabolic support (24). This technique has been associated with lower incidences of biliary complications and better graft survival compared to static cold storage (10). Furthermore, HMP has demonstrated benefits in preserving extended-criteria donor (ECD) livers, reducing early allograft dysfunction (EAD), and improving overall transplant outcomes. 

In contrast, NMP allows for real-time viability assessment, which is particularly advantageous for marginal livers that might otherwise be discarded (6). This capability enables surgeons to make informed decisions regarding organ suitability before implantation. However, NMP is associated with higher operational costs and a greater requirement for technical expertise. While NMP may improve immediate graft function, its long-term benefits over HMP remain inconclusive (10,25). Future research should aim to clarify whether a combination of both techniques, such as sequential HMP followed by NMP, can further optimize liver transplantation outcomes. 

Heart-Specific Considerations 

While NMP has demonstrated benefits in heart transplantation, particularly for DCD cases, its application presents unique challenges. Among the most significant limitations are the constraints posed by heart size and the financial burden associated with device failure. 

One of the inherent challenges of NMP is its compatibility with donor hearts of varying sizes. The perfusion circuits and chambers of currently available NMP systems are typically designed for average-sized adult hearts (16). This presents difficulties when attempting to perfuse smaller hearts, such as those from pediatric or undersized donors. These hearts may be subject to inappropriate physiological flows and pressures within the system’s standard operating parameters leading to irreparable damage rendering the heart unusable for transplantation (26). Additionally, the OCS heart system requires a liter of donor blood creating an additional challenge with these smaller donors (26,27). This limitation may reduce the effective donor pool, as hearts falling outside the optimal size range may not be successfully preserved or assessed using NMP (28). 

Another major concern with NMP is the financial implications associated with machine perfusion failure. Unlike HMP, where failure defaults to the standard of care, SCS, an NMP failure, whether due to mechanical malfunction, user error, or unexpected perfusion complications, can result in the immediate loss of the organ (9). Given that the machine perfuses a beating heart, any disruption in the perfusion process can rapidly lead to irreversible myocardial damage, leaving little margin for error. The financial burden of NMP extends beyond device failures. The technology itself is considerably more expensive than SCS or HMP, requiring specialized equipment, transport logistics, and trained personnel to operate the system effectively (8). In some cases, as seen in clinical trials, donor hearts have been deemed unsuitable for transplantation after perfusion in an NMP system, further compounding the cost without a successful transplant outcome (9,29)​. Additionally, centers implementing NMP must allocate resources for system maintenance, disposable perfusion kits, and real-time monitoring, further increasing the total cost of heart transplantation programs. 

While NMP offers potential advantages in preserving and assessing donor hearts, particularly from ECD or DCD donors (30), its limitations must be carefully weighed. The challenges related to heart size and the high costs associated with machine failures highlight the need for continued refinement of perfusion systems and cost-effectiveness analyses. 

HMP for heart allografts is an emerging alternative that may address some of these limitations. Unlike NMP, which maintains the heart in a beating state, HMP preserves the organ in a metabolically reduced condition, with most heart preservation devices also providing continuous oxygenation. Early studies suggest that HMP may offer superior protection against ischemia-reperfusion injury, reduce the metabolic demands of the heart during preservation, and potentially extend the preservation window (​31,32). Additionally, HMP may mitigate some of the risks associated with NMP failures, as the heart is not actively beating during transport, reducing its vulnerability to abrupt perfusion disruptions. 

The introduction of HMP to heart preservation could lead to impactful changes in DCD heart transplantation by improving organ viability, increasing the number of usable donor hearts, and potentially reducing costs associated with machine perfusion. By offering a more stable and cost-effective preservation method, HMP has the potential to complement or even replace NMP in certain scenarios, broadening the scope of heart transplantation and improving long-term outcomes for recipients. Future research should focus on optimizing HMP protocols, comparing its efficacy directly against NMP, and determining the best clinical scenarios for its implementation in heart transplantation. 

Lung-Specific Considerations 

Lung transplantation presents unique preservation challenges due to the organ’s high susceptibility to ischemia-reperfusion injury. The development of both HMP and NMP has significantly influenced lung transplantation outcomes by extending preservation times and improving organ viability (33). 

HMP has demonstrated benefits in reducing metabolic activity, minimizing inflammatory cytokine release, and mitigating ischemic injury (34). Studies have shown that hypothermic preservation effectively slows lung deterioration by limiting cellular metabolism and down regulating apoptotic pathways. Furthermore, the combination of cold storage with periods of oxygenation in some HMP protocols has been associated with improved lung function post-transplantation (35,36). A study performed by Arni et al. further complicates the temperature discussion by suggesting that sub-normothermic preservation improves many physiological parameters in the donor lung (37).   

In contrast, NMP allows for continuous organ evaluation and reconditioning. This technique has been particularly useful for high-risk donor lungs that might otherwise be discarded. NMP provides an opportunity for real-time physiological assessment, improving the likelihood of successful transplantation (38). However, it presents logistical and financial challenges, requiring complex perfusion circuits and trained personnel. Some studies suggest that while NMP improves early graft function, its long-term benefits compared to HMP remain inconclusive​. 

Recent research has explored hybrid approaches, such as sequential NMP followed by HMP, to optimize lung preservation39. By leveraging the advantages of both strategies, these techniques aim to extend preservation time while maintaining organ viability. Continued investigation into temperature modulation, perfusion duration, and metabolic support will further refine lung preservation strategies and improve transplant outcomes​.

Conclusions and Future Considerations 

Determining the most effective perfusion strategy requires a comprehensive analysis of multiple factors. In terms of cost per organ, NMP generally incurs significantly higher outlays due to equipment and personnel requirements, whereas HMP remains a more affordable alternative. Studies indicate that organ viability and failure rates vary, with some findings suggesting similar long-term outcomes and others highlighting organ-specific advantages for each technique. When assessing post-transplant health outcomes, NMP may provide improved immediate graft function in some cases, while HMP's metabolic protection contributes comparable long-term success rates. Overall, while NMP allows for easier organ viability evaluation, HMP offers a lower-risk, cost-effective solution with significant preservation benefits for most organs. 

The next generation of organ preservation devices must prioritize affordability, portability, and ease of use while remaining adaptable across multiple organ types. An ideal system should be compact enough to easily travel on most commercial airlines, lightweight (weighing no more than 50 pounds) to allow for single-person transport, and cost-effective, with a target price below $75,000. Additionally, it should feature access ports for biomarker sampling and a display interface for real-time monitoring of perfusion pressure, temperature, perfusate flow, and vascular resistance. Given the energy constraints and the size of current normothermic technologies, a practical device of this nature would likely operate at temperatures between 4–10°C. 

A universal, organ-agnostic preservation device would drive substantial cost savings across the transplant field. By standardizing preservation methods for all organs, the high volume of kidney transplants would help offset costs, thereby reducing the per-unit expense for less frequently transplanted organs, such as hearts. This economic advantage extends from manufacturing to clinical implementation, making organ transplantation more accessible and cost-effective. 

Technological advancements are accelerating the development of compact and portable preservation devices, easing transportation challenges. At the same time, real-time monitoring systems are enhancing organ viability assessment, while machine learning algorithms are being integrated to optimize perfusion parameters dynamically. As research progresses, oxygenated HMP is emerging as a pivotal technology, promising improved transplant outcomes and increased organ availability. Future iterations of these devices could incorporate advanced biosensors and AI-driven analytics to fine-tune perfusion conditions while minimizing energy consumption. 

Given recent scientific advancements and clinical outcomes, oxygenated HMP is positioned to become the preferred method of organ preservation. Studies have demonstrated its effectiveness in reducing delayed graft function, improving long-term graft survival, mitigating ischemia-reperfusion injury, and preserving mitochondrial function. These benefits further support the potential expansion of the donor pool, particularly for marginal organs such as those recovered from DCD donors. As ongoing research and clinical data continue to shape transplant practices, the widespread adoption of oxygenated HMP will likely redefine organ preservation, improving both access to and success rates of transplantation worldwide.