Utilization of Paragonix LIVERguard® donor organ transport system for static hypothermic preservation of a multivisceral allograft

Abstract

Background

Intestine transplants are highly sensitive to ischemia-reperfusion injury (IRI). Static cold storage (SCS) is the standard for multivisceral (MVT) allograft preservation but carries known risks. While several devices have been developed for liver, lung, and heart graft preservation, there are no systems validated specifically for MVT grafts. We report the first use of the Paragonix LIVERguard® Donor Liver Transport System for hypothermic static preservation of a donation after brain death (DBD) MVT allograft, transported approximately 1363 miles.

Methods

The Paragonix LIVERguard® was used to preserve a pediatric MVT graft during long-distance transport between the donor and recipient hospitals. We collected donor and recipient characteristics, ischemia intervals, lab markers of IRI, vasopressor duration, intensive care unit (ICU) and hospital length of stay, and time to enteral feeding.

Results

The graft included liver, stomach, pancreas, spleen, small intestine, and colon. Cold ischemia time (CIT) was 6.8 h. The device maintained a mean temperature of 4.5°C (range: 3.8–5.2°C). Endoscopy showed no evidence of rejection. There was rapid normalization of both enzymatic injury markers (AST/ALT) and metabolic markers (lactate). Enteral feeding began on POD 13 and advanced to the goal. She was discharged home on POD 103.

Conclusion

This case represents the first reported use of the Paragonix LIVERguard® for MVT graft preservation and transport. The device maintained a narrow temperature range over a 6.8-hour CIT and more than 1300 miles of travel. Relative to historical institutional experience, the case demonstrated lower peak biochemical markers and faster normalization of graft function. These findings support further investigation into whether preservation strategies that maintain tighter thermal control may influence early graft recovery in MVT.

Introduction

Intestinal failure (IF) is characterized by the inability to maintain nutritional and metabolic balance without parenteral support. When medical management fails or complications of parenteral nutrition arise, intestinal or multivisceral transplantation (MVT) may be indicated [1]. The MVT graft is particularly susceptible to ischemia-reperfusion injury (IRI), and even brief cold ischemia times (CIT) can cause significant epithelial damage and inflammation, leading to poor intestinal function recovery after transplantation [2].

The prevention and treatment of IRI are ongoing areas of focus in the field. One strategy that has garnered increasing attention in recent years is the advancement of organ preservation technology. Presently, static cold storage (SCS) remains the current standard for preservation of MVT allografts. However, SCS has inherent limitations, particularly for large, heterogeneous grafts with high metabolic demand and variable tissue composition. These limitations include passive cooling with potential temperature gradients across the graft, direct contact with ice or slush, and unmonitored temperature fluctuations during transport [3], [4]. In complex grafts such as MVT—comprising liver, pancreas, stomach, intestine, and colon—uneven cooling may disproportionately affect more ischemia-sensitive tissues, including the intestinal mucosa and biliary epithelium, potentially amplifying IRI [5], [6], [7], [8].

Paragonix Technologies developed portable, temperature-controlled transport systems for heart, lung, liver, and pancreas grafts. These preservation devices are FDA-cleared, and are designed to maintain the organ in a sterile, isolated, pressure-controlled canister of cold liquid solution with a proprietary phase-change technology that maintains stable hypothermic temperatures between 4–8 °C. Real-time data monitoring records temperature, location, and case status. By providing controlled, consistent hypothermic preservation, these devices avoid the cellular damage associated with the 0 °C temperature of traditional SCS and prevent direct ice-related tissue injury. Studies from the GUARDIAN registries have reported improved outcomes using these systems, including reduced primary graft dysfunction and improved survival [9].

To date, no device has been validated specifically for MVT transport. We report the first use of the Paragonix LIVERguard® system for preservation and transport of a pediatric MVT graft. We aim to demonstrate feasibility, assess preservation performance during long-distance transport, and discuss implications for broader use.

Methods

Paragonix LIVERguard® was used to preserve a pediatric MVT graft during long-distance transport. Variables on donor/recipient characteristics, ischemia time, laboratory markers, vasopressor duration, intensive care unit (ICU) and hospital length of stay, and time to enteral feeding were recorded. All analyses were performed in R (Version 4.3.3).

Results

Recipient characteristics

The recipient was a 3-year-old female with megacystis microcolon intestinal hypoperistalsis syndrome. She was dependent on total parenteral nutrition since infancy. She experienced multiple complications of IF, including liver dysfunction, bacteremia, and coagulopathy. She weighed 15 kg and measured 89 cm. Pretransplant PELD was 35. At the time of transplant, she was listed as status 1B with a bilirubin of 13.6 mg/dL, INR of 1.9, and platelet count of 89,000.

Donor characteristics

The donor was a 21-month-old male, declared brain dead after a seizure-related anoxic event. The patient weighed 12.7 kg and measured 83.8 cm. The patient had no known medical problems. The downtime was unknown, but the patient had been hospitalized for 6 days. There were no periods of acidosis. All lab values remained within normal range, except for AST/ALT, which remained elevated during the hospitalization course (average 380 U/L and 207 U/L, respectively). The patient required vasopressors, including norepinephrine for a total duration of 3 h and 48 min, and epinephrine for 31 h and 22 min.

Donor operation

The donor operation was performed by the recipient team. The donor operation proceeded in the usual fashion as previously described by Yersiz et al. [10], and the multivisceral graft was procured en bloc, including the liver, stomach, duodenum, pancreas, spleen, small intestine, and large intestine. The graft was flushed with Servator B™ University of Wisconsin (UW) solution. The time from donor cross clamp to MVT graft procurement was 18 min. The time from incision to procurement was 87 min. The time from procurement to placement of the graft into the LIVERguard® preservation system was 9 min. The total ischemia time (TIT) accrued by the graft was 7.5 h, which consisted of 27 min of donor warm ischemia time (WIT), 6.8 h CIT, and 16 min of recipient WIT. The graft remained in the Paragonix LIVERguard® system for a total of 4.5 h. Temperature was maintained between 3.8 and 5.2 °C, with an average temperature of 4.5 °C.

Recipient operation

A two-stage MVT proceeded in the standard fashion [11]. Stage I consisted of an en bloc resection of the native liver, stomach, spleen, pancreas, jejuno-ileum, and colon with an en bloc MVT including the donor liver, stomach, duodenum, pancreas, spleen, jejuno-ileum, and colon. A supra-celiac aortic conduit using the donor thoracic aorta was placed for arterial inflow. A bicaval implantation was used for the liver portion of the allograft. Stage II took place 24 h later, and consisted of the restoration of gastrointestinal continuity between the remnant native gastric pouch and the transplanted stomach. An end transplant colostomy was performed. Abdominal wall closure was completed on POD 6.

Recipient post-operative course

Immunosuppression

The patient received induction immunotherapy with basiliximab (Simulect®, Novartis, McKesson, Irving, TX, USA), pulse and maintenance methylprednisolone, mycophenolate mofetil (MMF/Cellcept®, Hoffmann-La Roche Inc., Switzerland) and tacrolimus (Prograf®, Astellas Pharma, Deerfield, IL, USA) to target trough levels of 10 ng/mL for the first 30 days post-transplant.

Clinical course

The patient returned to the operating room on POD 1 for a bile leak from the cystic duct stump following cholecystectomy, which was ligated and repaired, and simultaneous stage II transplant completion with fashioning of a gastro-gastrostomy between the remnant native gastric pouch and the transplanted stomach. She underwent abdominal wall closure with AlloDerm™ inlay mesh on POD 6. Vasopressors were weaned by POD 2. She was extubated on POD 12. Enteral feeding began on POD 13 and ultimately advanced to goal. She developed sepsis on POD 22 and was treated with antibiotics. Simultaneously, she was noted to have bleeding from the colostomy, concerning for rejection, and was treated empirically with a steroid pulse from POD 22–28. Endoscopic biopsies of the transplanted small bowel and colon on POD 26 showed no features of rejection or PTLD, or infectious organisms (negative immunoperoxidase stain for adenovirus). She was found positive for adenovirus in stool and serology on POD 25, and started on Cidofovir. Throughout her postoperative course, she was never found to have positive blood cultures. She developed a pleural empyema on POD 37 which resolved after antibiotics and drainage. She was discharged home on POD 103.

Endoscopic evaluation

Endoscopies were performed throughout the post-transplant period following the standard of care [12]. During endoscopic evaluations, biopsies are taken of the transplanted small bowel and colon. The first endoscopic evaluation was performed on POD 11. Endoscopies performed on POD 26, 45, 55, 65, 78, and 93 all showed no features of rejection.

Laboratory evaluation

There was rapid normalization of both enzymatic injury markers (AST/ALT) and metabolic markers (lactate).(Fig. 1) In this case, the maximal AST was 563 U/L, and the maximal ALT was 261 U/L on POD 1; both values normalized by POD 3. The maximal total bilirubin was 2.5 mg/dL on POD 1, and normalized to 1.3 on POD 2. Lactate was normal from POD 1–3, then peaked moderately to 32 mg/dL on POD 5, but quickly cleared again to 13 on POD 7. Initial INR on POD 1 was elevated at 1.3, but decreased to 1.1 by POD 2 and reached a stable range of 1.0–1.1 by POD 3. Throughout the remainder of the 30-day postoperative period, INR remained within or near the normal range (≤1.2), without evidence of secondary elevation.

Fig. 1.

Trends in serum biochemical parameters (POD 1–30). (A) AST and ALT (reference range: AST 13–62 U/L, ALT 8–90 U/L), (B) total and conjugated bilirubin (reference range: total bilirubin 0.1–1.2 mg/dL, conjugated bilirubin < 0.3 mg/dL), (C) Lactate (reference range: 5–18 mg/dL), and (D) INR (reference range: 0.8–1.2). Values shown as measured; missing points indicate days without laboratory sampling.

Discussion

This case represents the first reported use of the Paragonix LIVERguard® for MVT graft preservation and transport. The device maintained a narrow temperature range over a 6.8-hour CIT and more than 1300 miles of travel. There was rapid normalization of both enzymatic injury markers (AST/ALT) and metabolic markers (lactate). Endoscopic surveillance showed no rejection, suggesting effective graft protection.

Despite several significant postoperative complications, these events appear unrelated to graft preservation quality or CIT. The bile leak on POD 6, while requiring reoperation, is a known technical complication and does not necessarily reflect graft viability or ischemic injury. The suspected rejection on POD 22 was treated empirically with steroids; however, endoscopic biopsies showed no histologic evidence of acute rejection, further supporting the robustness of the graft. The bilateral pleural empyema on POD 37 was attributed to systemic infection rather than graft-related pathology, and it resolved with antibiotics and drainage. Notably, rapid normalization of both enzymatic injury markers (AST/ALT) and metabolic markers (lactate) suggests good early graft function. The early normalization of these markers, along with consistently normal endoscopic surveillance, supports that the Paragonix LIVERguard® system provided adequate preservation, and the complications encountered were largely unrelated to IRI or CIT and are within the spectrum of expected morbidity in high-risk pediatric MVT recipients.

Between November 1991 and December 2020, 132 patients received 155 transplants (38 isolated intestine, 78 liver/intestine, 28 MVT, 11 modified MVT) at our center [11]. Of those 28 receiving MVT grafts, mean CIT was 6.7 + /- 2.0 h (median 6.3 h) and mean WIT was 0.7 + /- 0.3 h (median 0.6 h), for a mean total ischemia time of 7.4 + /1.9 h (median 7.0 h) – similar to the case presented herein. Historic median maximum values and time to normalization of key biochemical markers differ from the case presented herein: historic AST/ALT were 359 and 184 and normalized by POD 7 (compared to 563 and 261, normalized by POD 3), total bilirubin/conjugated bilirubin were 4.75 and 2.6 and normalized after POD 30 (compared to 2.5 and 2, normalized by POD 1), lactate was 24 and normalized by POD 7 (compared to 9 on POD 1), and INR was 1.6 and normalized on POD 7 (compared to 1.3, normalized by POD 2). When contextualized against historical MVT cases at our center preserved with conventional SCS, this case was characterized by lower peak biochemical markers of IRI and more rapid normalization of graft function. Although such comparisons are inherently limited by differences in patient and procedural factors, the observed biochemical trajectory is consistent with attenuated early ischemic injury and supports further investigation into whether preservation strategies that maintain tighter thermal control may influence early graft recovery in MVT.

This report does not establish the inadequacy of SCS nor demonstrate the superiority of the Paragonix LIVERguard® system for preservation of MVT grafts. Rather, it highlights the theoretical and mechanistic advantages of controlled hypothermic preservation that may be particularly relevant for MVT grafts. Temperature-regulated transport systems are designed to maintain a narrow, continuously monitored hypothermic range and eliminate direct ice contact, thereby reducing the risk of both inadvertent freezing and rewarming. In liver transplantation, such systems have been associated with reduced temperature variability, lower rates of early allograft dysfunction, and improved early graft performance, suggesting that thermal stability itself may be a modifiable contributor to IRI [13]. These potential advantages may be especially meaningful in MVT for several reasons. First, the large graft mass and composite anatomy increase susceptibility to uneven cooling with conventional SCS. Second, the intestinal component is highly sensitive to ischemia, and even modest exacerbations of IRI may translate into mucosal barrier dysfunction, systemic inflammation, infection, or early graft dysfunction. Third, MVT frequently involves prolonged procurement, complex implantation, and staged reconstruction, making cumulative ischemic stress an important determinant of early outcomes. In this context, controlled hypothermic preservation may better achieve uniform thermal protection across graft components, mitigate ischemic injury at reperfusion, and preserve early graft function.

In the present case, use of the LIVERguard® system was associated with a tightly controlled temperature profile during long-distance transport and was followed by rapid normalization of biochemical markers of IRI and consistently normal endoscopic surveillance. While these findings cannot be attributed causally to the preservation device, they support the feasibility of controlled hypothermic transport for MVT and suggest that thermal regulation warrants further investigation as a modifiable variable in this high-risk population.

Ultimately, the clinical impact of controlled hypothermic preservation for MVT—whether through reductions in IRI, improved early graft function, or downstream effects on infection, rejection, and recovery—can only be defined through larger, comparative studies. This case should therefore be viewed as hypothesis-generating rather than definitive, providing a rationale for systematic evaluation of temperature-controlled preservation strategies in MVT.

This report is limited by its single-case design and lack of a comparator group. Additionally, patient-specific factors and postoperative events complicate the interpretation of device efficacy. Another major limitation of this report is the absence of reference to intestinal histology before and after reperfusion of the liver and intestine to document IRI, specifically with reference to the Chiu-Park grading scale for the bowel [7]. Nevertheless, this case serves as a proof of concept, supporting the feasibility of controlled hypothermic preservation in MVT.

The Paragonix LIVERguard® system was successfully used for static hypothermic preservation of a pediatric MVT allograft over a long-distance transport. Relative to historical institutional experience, the index case demonstrated lower peak biochemical markers and faster normalization of graft function in the early postoperative period. These findings support further investigation into whether preservation strategies that maintain tighter thermal control may influence early graft recovery in MVT.

Funding

C.P.S. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number T32DK007180. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Ethical Statement

This article does not contain any studies with human participants, and therefore ethical approval and informed consent were not required.

CRediT authorship contribution statement

Jonathan Jou: Conceptualization. Brandon Pearson: Conceptualization. Valeria Ripa: Conceptualization. Caitlin Thornley: Writing – review & editing, Data curation, Conceptualization. Carolyn Smullin: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Farmer Douglas: Writing – review & editing, Investigation, Conceptualization. Samer Ebaid: Conceptualization. Fady Kaldas: Conceptualization. Vatche Agopian: Conceptualization. Venick Robert: Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.