Waiting for a well-rested team: facilitating semi-elective lung transplantation

Historically, lung allografts have been limited to less than 6 hours of total ischemic times (1-3). However, this practice to minimize the ischemic period often necessitates that lung transplants be performed at night. Although exceptions to ischemic time limitations now commonly occur (3), approximately 50% of current lung transplants are still performed between 7 p.m. and 7 a.m. (4). A recent prospective, single-center study by Deitz et al. suggests lung transplants that historically would be performed at night can be safely postponed until the following morning (5). In their study, lung transplants that were postponed from the nighttime until the following morning demonstrated non-inferior survival and primary graft dysfunction (PGD) grade 3 outcomes compared to lung transplants that proceeded according to the conventional time course. Indeed, this study adds to a growing body of evidence that demonstrates the potential feasibility of semi-elective lung transplantation.

Previous studies demonstrated that lung transplants performed at night have worse outcomes compared to daytime transplants. Although nighttime lung transplants demonstrate similar short-term survival to those performed in the daytime (4), overnight cases were found to have worse overall 5-year and bronchiolitis obliterans syndrome-free survivals (6), higher rates of PGD, and longer lengths of hospital stay (7). Recently, Choi et al. observed that lung transplant cases with donor cross-clamp times between 8 a.m. and 1 p.m. along with allograft reperfusion times between 1 p.m. and 6 p.m. had superior 90-day survivals (8). Additionally, lung transplants performed overnight were associated with more frequent postoperative adverse events, which included delayed chest closure, unexpected return to the operating room, pneumonia, airway complications, bronchopleural fistula, pulmonary embolus, tracheostomy, reintubation, and PGD grade 3 (PGD-3) at 72 hours (6). Inferior outcomes have similarly been reported with heart (9), liver (10), and kidney (11) transplants that are performed at night. It has been suggested that, in general, inferior nighttime surgical outcomes may be attributed to surgeon and staff fatigue, less availability of experienced personnel, and less access to specialized equipment at night (12,13). Patlin et al. further suggest that an allograft’s quality may also be affected by the donor’s intrinsic circadian rhythms and the immune/biochemical fluctuations that occur throughout the day (14), although this phenomenon has not been widely investigated.

Notably, the historically-cited ischemic time limit was determined for lung allografts that were traditionally stored and transported on ice. However, new technological developments now allow more uniform regulation of allograft temperature that was not possible with traditional ice storage, and this has greatly extended the viable period of allograft storage beyond the historical 6-hour limit. While storage in ice is assumed to maintain the allograft at approximately 4 ℃, recent canine experiments suggests that donor lungs may be more optimally stored at 10 ℃ and that storage at this temperature may extend lung viability to as long as 36 hours (15). Indeed, prolonged storage of donor lungs at 10 ℃ has been found to be safe for up to 24 hours and does not adversely affect lung transplant outcomes (16). Moreover, storage on ice can also result in heterogenous cooling of the allograft and can cause freezing injury in areas of the allograft that are in close contact with the ice (17,18). The potential advantages and/or disadvantages of controlled allograft storage temperatures between 4 and 10 ℃, inclusively, are unknown and will require head-to-head comparisons to elucidate more clearly.

A number of new devices have been developed to facilitate donor lung transport. The LUNGguard (Paragonix Technologies, Waltham, MA, USA) is a novel lung storage device that cools the allograft uniformly to 4–8 ℃. Compared to ice storage, donor lung transport in the LUNGguard resulted in lower PGD-3 rates and improved 1-year survival following transplantation (19). Additionally, evidence suggests that the LUNGguard can safely extend lung allograft ischemic times to >15 hours (20). A second-generation device, the BAROguard (Paragonix Technologies), also regulates airway pressure at 12–15 cmH₂O in addition to regulating temperature, and preliminary results have suggested benefits of this combination (21). The X°Port Lung Transport Device (Traferox Technologies Inc., Mississauga, Canada) is another portable temperature-management system that stores lung allografts at 10 ℃ and is currently being investigated in a clinical trial (https://clinicaltrials.gov/study/NCT05898776) (22). The VITALPACK EVO (E3 Cortex, Plailly, France) is used to store and transport donor organs at 2–8 ℃, but no data has yet been reported for its use in lung preservation (22). Some groups have reportedly used other generic commercial coolers with temperature regulation systems analogous to those found on medical organ transport devices. Notably, however, these generic coolers were not specifically intended for medical use and the safety implications of using them for allograft transport have not been thoroughly investigated.

In addition to new methods for cold static storage, machine lung perfusion—namely, ex vivo lung perfusion (EVLP)—has emerged as another modality for extending allograft storage times (18). A single-center study retrospectively examined lung transplant cases in which EVLP extended the total preservation times (the sum of pre-EVLP cold ischemic time, EVLP time, and post-EVLP cold ischemic time) to greater than 12 hours (23). Extending graft preservation time greater than 12 hours using EVLP did not adversely affect hospital or intensive care unit (ICU) lengths of stay, PGD rates, or survival when compared to cases that had preservation times less than 12 hours.

These new storage methods have introduced the possibility of performing semi-elective lung transplantation during normal working hours and obviating the need to perform these surgeries overnight. This practice, referred to as “time-shifting”, involves overnight storage of allografts that were recovered at night and delaying their implantation until the following morning. This strategy can potentially avoid the clinical and financial disadvantages associated with performing nighttime transplants. In addition, time-shifting can improve surgeons’ work-life balance. An American College of Surgeons survey of 14 surgical specialties indicated that transplant surgeons reported the highest incidence of depression, the most hours worked and number of nights on-call per week, and a low quality of life (24). Another study showed that high work-related demands contribute to a high burnout rate among transplant surgeons (25). Time-shifting would not only prevent surgeon burnout but could also mitigate the shortage of transplant surgeons by eliminating a barrier that discourages many surgeons from choosing the field as a career.

Although time-shifting in lung transplantation is not yet widely practiced, several studies have examined its feasibility and outcomes. To date, only methods of static cold allograft storage have been examined in time-shifting lung transplant cases. While EVLP has been shown to safely extend donor lung preservation time (23), there have not yet been any studies that used EVLP for the specific purpose of postponing nighttime lung transplants until the following morning.

Following an encouraging pilot study from the University of Toronto that demonstrated prolonged organ preservation and acceptable post-transplant outcomes with 10 ℃ allograft storage (15), a prospective, multicenter, nonrandomized clinical trial was performed to further examine time-shifting’s clinical potential (26). In this trial, lung transplant cases involving donors that were cross-clamped overnight between 6 p.m. and 4 a.m. were time-shifted, such that the donor lungs were transported on ice to the transplant center, stored in a 10 ℃ incubator, and then transplanted into the recipient the following morning. Seventy cases in this time-shifted group were compared to 140 matched controls drawn from a contemporaneous cohort of recipients who were transplanted with donor lungs that were preserved in ice and implanted in the standard time course. Compared to the control group, the median cold ischemic time was longer in the time-shifted group for both the first [control vs. time-shifted: 365 vs. 673 min; standard mean difference (SMD) 2.1] and second (102 vs. 829 min; SMD 1.7) implanted lungs. There was no significant difference in the primary outcome—PGD-3 rates at 72 hours [control vs. time-shifted: 9.3% vs. 5.7%; difference: −3.6%; 95% confidence interval (CI): −10.5% to 5.3%]—between the two groups, nor was there any significant differences in the secondary outcomes examined, which included post-operative ventilator times, ICU and hospital lengths of stays, post-transplant extracorporeal membrane oxygenation (ECMO) use, and 30-day survival. Additionally, the 1-year survival of 94% in the time-shifted group was not significantly different from the 87% survival in the control group [hazard ratio (HR) =0.65; 95% CI: 0.26–1.6].

The recent study by Deitz et al. was a prospective, single-center study that examined time-shifting for cases in which the donor was cross-clamped after 6 p.m. (5). Allografts in the 18 time-shifted (“semi-elective”) cases were stored overnight using the LUNGguard device and were implanted into recipients the following morning. Outcomes for the semi-elective cases were compared to those from a cohort of 64 recipients from the preceding 15 months who were transplanted in a standard time course. The median ischemic times in the semi-elective group was more than double those of the standard group [standard vs. semi-elective: 6.8 (6.1–7.4) vs. 13.9 (12.5–15.6) h; P<0.001]. The primary outcomes in this study included 30-day, 90-day, and 6-month survival as well as PGD-3 at 72 hours and ECMO within 24 hours postoperatively. There were no significant differences in postoperative survival between the two groups with 6-month survival being 91% in the standard group and 94% in the semi-elective group (P>0.99). PGD-3 rates (standard vs. semi-elective: 20% vs. 17%; P>0.99) and postoperative ECMO utilization (standard vs. semi-elective: 22% vs. 22%; P>0.99) were also similar between the two groups. Other secondary postoperative outcome comparisons—including dialysis, stroke, bowel ischemia, hepatic dysfunction, delayed chest closure, hemothorax, ICU length of stay, hospital length of stay, ventilator duration, pneumonia, ischemia-reperfusion grade, and discharge destination—did not significantly differ between the two groups. Additional analysis was performed to compare outcomes between the semi-elective group and 29 overnight lung transplants that were performed during the study period, and no differences in primary or secondary outcomes were noted between these two cohorts.

In addition to the aforementioned studies, a couple of published abstracts also support time-shifting’s feasibility. A prospective, single-center study by Ragalie et al. demonstrated no significant differences with in-hospital or 30-day survival, 1-year survival, PGD-3 rates, or hospital length of stay between 27 time-shifted lung transplants and a contemporary cohort of 27 matched control cases, despite the time-shifted group having a significantly longer ischemic time (27). Botros et al. reported using the LUNGguard in time-shifting 10 lung transplant cases; the time-shifted cases had no PGD and demonstrated a shorter liberation from oxygen, ICU length of stay, and hospital length of stay compared to 3 cases that were not time-shifted during the study period (28).

Although the evidence for time-shifting has been encouraging to date, there are several practical limitations and challenges that may be encountered with regards to the practice. There may be reluctance among individual surgeons, institutions, and the broader transplant community to implement time-shifting, since it deviates from the long-standing practices. There are also additional supply expenses associated with using a 10 ℃ incubator, LUNGguard, or BAROguard for overnight organ storage. This additional cost, however, may be offset by the savings incurred by device reusability as well as from avoiding expenses associated with staff overtime and increased postoperative complications. At Johns Hopkins Hospital, we use either the LUNGguard or BAROguard to both transport the donor lungs and store them overnight for time-shifted cases. Currently, approximately 54% of donor lung allografts are transported in a LUNGguard or BAROguard (personal communication with Paragonix Technologies). We have found that their commercial availability and ease of use makes these devices a practical choice for our time-shifted cases. Finally, a time-shifting strategy may provoke scheduling conflicts between these semi-elective transplants and the cases that were previously scheduled for that day. As such, operating room availability may be more limited during the daytime compared to the night. For this reason, the time-shifting strategy may be easier to accommodate at larger hospitals that have dedicated operating rooms for their lung transplants.

The concept of time-shifting represents a significant paradigm shift in clinical practice. Since immediate implantation of the allografts has, until recently, been the tradition throughout the history of lung transplantation, this practice may arouse some discomfort among practitioners and institutional leadership. Nevertheless, new technological advances have markedly prolonged organ preservation following retrieval, and recent studies suggest that these new methods can alleviate some of the urgency to implant the allograft. If future studies continue to support the efficacy and safety of time-shifting, then eventual widespread adaptation of a semi-elective approach may drastically alter the lung transplant workflow and mitigate many of the challenges that are currently associated with lung transplantation.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Current Challenge of Thoracic Surgery. The article has undergone external peer review.

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-9/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-9/coif). E.L.B. has received consulting fees as an educational consultant for Medtronic Cardiovascular. 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.

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