Revisiting optimal static lung preservation techniques in an era when machine perfusion is transforming organ recovery: thermoregulation is still an important concept

Introduction

In 2022, multiple aspects of the clinical practice of organ transplantation were transformed by a highly impactful National Academies of Sciences, Engineering, and Medicine (NASEM) report, requested by the United States Congress and sponsored by the National Institutes of Health (NIH) (1). Together with the admirable efforts by the Donation after Circulatory Death Lung Transplant Collaborative team launched by the Organ Procurement and Transplantation Network (OPTN), these initiatives led to an outstanding increase in lung procurement and utilization employing donation after circulatory death (DCD) (2). Lungs from DCD donors undergo a period of warm ischemia between circulatory arrest and organ procurement, potentially leading to more damage as compared with lungs from donation after brain death (DBD) donors. Historically, concerns of ischemia-reperfusion injury and associated complications, including primary graft dysfunction, have been raised regarding lung graft quality after DCD. Whereas this shift challenging traditional limitations to donor resources is encouraging, outcomes after lung transplantation, particularly after DCD lung transplantation, have lagged behind the notable success seen for transplantation of abdominal organs such as kidneys and livers.

Additionally, the evolving role of machine perfusion (MP) has changed the face of organ recovery practices during abdominal organ transplantation, leading to increased success in both transplant volume and outcomes (3-7). However, in lung transplantation, improvements through the use of MP have not been as clearly appreciated or consistently demonstrated (8-10). The lungs are uniquely sensitive to perfusion, as compared with kidneys and livers, due to their distinct organ biology. Thus, refining static organ-preservation techniques without perfusion may be more successful in improving outcomes than trying to replicate the success of continuous MP in abdominal organ procurement by modifying a variety of ex vivo lung perfusion (EVLP) protocols (11). Focusing on optimizing temperature-based protocols for lung procurement may be particularly helpful.

In this review, we posit that temperature-based refinement is necessary to optimize static lung preservation techniques and that precise thermoregulation may lead to better outcomes after lung transplantation, especially with DCD lungs. This novel thermoregulation concept is based on previously published basic science studies on organ bio-physiology inherent to lungs and key differences between the lungs and other organs.

Key point 1: differences between organ preservation at 4 and organ preservation on ice—ice is not 4 ℃

Static lung preservation at temperatures around 4 ℃ has been the standard for decades and has proven effective, particularly when optimizing the balance between mitochondrial protection and reduced metabolic activity (12). However, historically lungs have been stored on ice after procurement, which brings the temperature to close to 0 ℃, rather than the often-cited 4 ℃. Both recent studies and published older work have incorrectly assumed that “on ice” translates to a temperature of 4 ℃, which has indeed led to ongoing confusion in the lung transplant field (13,14).

This temperature difference, 4 ℃ versus 0 ℃, is not trivial but rather has significant implications for cellular function, metabolism, and injury during preservation (13). At 0 ℃, cellular processes slow down to a minimum, providing a form of metabolic “stasis” that helps mitigate ischemia-reperfusion injury (15). However, when lungs are stored at 4 ℃, even a slight increase in temperature can cause cellular metabolism to remain active enough to lead to a buildup of metabolic waste, oxidative stress, and early signs of cell injury (12). This difference has affected the interpretation of outcomes in research studies and, more importantly, in clinical practice.A few of my colleagues have also advocated for clarity in temperature reporting to ensure that researchers and clinicians understand the metabolic state of the organs being preserved (15). Revisiting the standard for lung-preservation temperature and more accurately reporting preservation temperatures in published studies could correct this longstanding discrepancy and contribute to more consistent post-transplant findings.

Key point 2: the importance of studying thermal dynamics during static lung preservation—temperature-dependent ischemic tolerance

The majority of lung preservation studies have not examined the effects of temperature on lung preservation in a finely tuned manner (i.e., at 1 ℃ intervals), and typically have only compared broader ranges, such as 0 ℃, 4 ℃, or room temperature (12). This leaves a gap in our understanding of the nuanced impact of temperature variations on lung preservation. Even a difference of only a few degrees can dramatically influence cellular metabolism, enzyme activity, and ischemia-reperfusion injury responses in the lungs (12,16).

Due to the large alveolar surface and high vascularization of the lungs, maintaining cellular integrity when oxygen supply and perfusion are compromised is uniquely challenging (17). Therefore, a deeper understanding of thermal dynamics and metabolic thermoregulation becomes central. As the temperature drops, cellular metabolism slows; insufficiently low temperatures may not fully arrest metabolic functions, but excessively low temperatures (close to freezing) could risk cell membrane injury and osmotic imbalances (15).

Because the lungs are highly sensitive to small temperature changes, analyzing the effects of 1 ℃ intervals, or at a minimum more granularly than has been attempted previously, could provide a much clearer picture of the optimal temperature range for preservation. This could reveal an “inflection point” at which cellular processes are sufficiently slowed to reduce damage without triggering additional injury from extreme cold exposure (12). Advocating for further studies to optimize this ‘thermoregulation window’ could encourage researchers to examine the impact of temperature changes of 1 ℃ or smaller, moving toward a lung preservation protocol that reduces ischemic injury and potentially improves post-transplant outcomes.

Such granular studies would be logistically challenging but valuable. They would likely involve controlled preservation set-ups with lungs precisely maintained at incremental temperatures—an approach that modern preservation technologies could feasibly support. With these insights, we could potentially shift from general estimates toward an evidence-backed standard temperature that maximizes lung viability and refine storage protocols while ensuring the protocols are both safe and standardized across centers. This degree of rigor in temperature control could become particularly relevant in light of recent innovations like the LungGuard (Paragonix Technologies) and the X°Port (Traferox), which are designed to allow for highly accurate and steady-state temperature management (12,16).

Table 1 details publications that support the statements above regarding the effects of small changes in temperature on lung preservation.

Key point 3: the optimal temperature for static lung preservation: 4 ℃ versus 8 ℃ versus 10 ℃—more evidence is needed

Some recent studies have suggested that 8–10 ℃ is more favorable for static lung preservation than the traditional 4 ℃ (16,19); however, these studies have shortcomings which must be considered. The protocols tested used an ice cooler followed by an incubator. Neither organ temperature nor preservation solution temperature was measured. A target setting was mentioned, but this was not a measured temperature. The lungs warm unevenly when exposed to room temperature air, and thermal imaging to assess surface temperature has not been sufficiently reproducible. Therefore, solution temperature is considered the most accurate proxy for organ temperature among currently available assessment tools; however, it was not applied in these studies.

This lack of direct temperature control may have resulted in unintended fluctuations. Targeting 8–10 ℃ preservation could still allow for temperature drops or spikes due to handling or external factors. This variability might explain inconsistent findings and would mean the benefits reported for organ preservation at higher temperatures could be influenced by unintentional deviations rather than true physiological responses to 8–10 ℃ preservation. More importantly, the lack of continuous monitoring in many studies poses a major limitation and may impact the validity of these reports.

A robust validation of 8–10 ℃ preservation will require strict temperature monitoring (23), in line with the critical role of thermoregulation within the unique lung bio-physiology as delineated above.

Key point 4: synergistic benefits of controlled hypothermic preservation and MP are seen in kidney and liver but not in lungs—different strategies should be pursued

Lastly, there are several points that should be borne in mind when aiming to develop optimal lung preservation techniques in combination with MP, especially with regards to the role of thermoregulation in the broader context of lung preservation protocols.

The benefits of MP in abdominal organ preservation have been observed not only in DCD, where normothermic regional perfusion (NRP) is common, but also in DBD (24). MP plays a vital role by actively supplying oxygen and nutrients to organs at a carefully controlled temperature, bridging the gap between static cold storage and transplant surgery. In abdominal organs, such as kidneys and livers, the combination of moderate hypothermic temperatures (8–10 ℃) and MP has synergistic effects, resulting in excellent clinical outcomes (25). In lung procurement, however, the situation is different.

The lack of a continuous perfusion system equivalent to abdominal organ MP for use in the lungs has been a limiting factor in optimizing MP during lung transplantation. While EVLP has been a successful platform for evaluating and reconditioning lungs before transplantation (26), it is not routinely or widely used in extended lung preservation. In the absence of a proven MP protocol for the lungs and in light of the critical role of thermoregulation in lung preservation, as discussed above, we should not minimize the distinct differences between lungs and abdominal organs or attempt to simply replicate protocols for abdominal organs by adopting 8–10 ℃ as a preservation strategy in lung transplantation.

Conclusions

Thermoregulation is a key concept in static lung preservation, is based on organ bio-physiology inherent to lungs, and is a pillar of successful lung transplantation. The standard of 4 ℃ remains the preservation temperature most strongly supported by the evidence currently available. This temperature (4 ℃) minimizes metabolic demand while preserving cellular structure and function reasonably well, as shown in multiple lung preservation studies (12,16). Recent investigations are, indeed, exploring temperatures in the 8–10 ℃ range, which could potentially mitigate ischemic damage more effectively by allowing some metabolic processes to continue at a minimal level, and theoretically supporting a more gradual cellular shutdown. However, until these moderate hypothermic approaches demonstrate consistent, superior outcomes in large, multi-center studies, lung transplant programs are likely to adhere to the established 4 ℃ protocol.

Precise investigations of thermoregulation during procurement and preservation should lead to better posttransplant outcomes, especially when transplanting DCD lungs. As innovative technologies, such as controlled thermal management devices, allow us to refine our understanding of optimal preservation temperatures, clinical practices should and will undoubtably shift.

Acknowledgments

The authors gratefully acknowledge the assistance of Krista Paplaczyk, Kalyna Sconzert, and Mary Jacoski of Paragonix, a Getinge Company, for editorial support in the review of this manuscript. We thank Shannon Wyszomierski, PhD for further assistance polishing the language in the manuscript.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1606/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1606/coif). N.S. serves as an unpaid editorial board member of Journal of Thoracic Disease from September 2025 to June 2027. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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