Advancing the enhanced recovery after surgery paradigm in liver transplantation: evidence-based strategies for a comprehensive care continuum

We read with interest the prospective evaluation by Yuan et al. of an enhanced recovery after surgery (ERAS) protocol in liver-transplant recipients (1). Their study reported 0% in-hospital mortality, 100% early extubation within 6 hours, and 98.5% 1-year survival—outcomes that surpass the 2022 German Institut fur Qualitatssicherung und Transparenz im Gesundheitswesen (IQTIG) benchmarks. This work demonstrates the notable success and feasibility of implementing a comprehensive protocol. We aim to explore how this established pathway could be extended to improve outcomes across the entire transplant journey, from waitlisting to long-term survivorship.

Expanding preoperative optimization through multi-domain prehabilitation

The authors’ comprehensive pre-transplant evaluation provides a platform for prehabilitation. This is highly relevant given the high prevalence of sarcopenia (affecting 18–43% of listed patients) and its established role as an independent predictor of 90-day mortality (2). A recent systematic review demonstrates that structured exercise interventions—incorporating aerobic, resistance, and flexibility routines coupled with protein supplementation—can reduce postoperative complications, shorten hospital stay, and enhance functional recovery by improving cardiorespiratory fitness, muscle strength, and psychological well-being in patients undergoing major surgeries (3). While direct evidence in liver transplantation remains limited, the biological rationale and potential for benefit, particularly in high-risk patients [e.g., model for end-stage liver disease (MELD) ≥20], supports its investigation. Therefore, integrating a multi-domain prehabilitation protocol during the waiting period could yield significant gains in functional capacity for liver transplant recipients. A key next step would be to validate the efficacy of such a structured prehabilitation program within the ERAS framework through a large, multicenter randomized controlled trial.

Enhancing graft preservation with machine perfusion

The significant burden of biliary complications remains a critical challenge. While the 38% donors after circulatory death (DCD) rate in the study by Yuan et al. (1) represents a moderate utilization in a global context—centers in Eurotransplant regions frequently report ≥50% DCD utilization for liver transplantation (4)—DCD donation is a known risk factor for ischemic-type biliary lesions (5). The 13.2% rate of biliary strictures aligns with this risk profile (1). This contextualization is important as centers with higher DCD utilization may face substantially greater biliary morbidity and could derive even more benefit from protective strategies.

A direct, evidence-based solution is the integration of hypothermic machine perfusion (HMP). Current evidence from randomized trials demonstrate that HMP reduces early allograft dysfunction (26% vs. 40%) and decreases the incidence of non-anastomotic biliary strictures (6% vs. 18%) compared with static cold storage (6). This clinical benefit is complemented by economic analyses; a subsequent cost-effectiveness analysis confirmed that Dual Hypothermic Oxygenated Machine Perfusion (DHOPE) reduces total medical costs up to 1 year post-transplant, yielding significant savings in intensive care unit (ICU) (28.4%) and non-surgical intervention costs (24.3%) (7). Furthermore, a recent international validation study demonstrates that measuring mitochondrial biomarkers like flavin mononucleotide (FMN) during hypothermic perfusion can accurately predict graft loss, cholangiopathy, and kidney failure (8). This provides an objective, pre-implantation metric to stratify recipient risk and personalize the postoperative ERAS pathway.

Additionally, normothermic regional perfusion (NRP) represents another emerging strategy with strong evidence. Wall and Testa advocate for implementing NRP as the standard procurement procedure for DCD in the United States (9). In a 2025 study, Croome et al. compared 83 DCD liver transplants receiving sequential NRP ± normothermic machine perfusion (NMP) with 297 static cold storage controls; ischaemic cholangiopathy was 0% in both NRP groups vs. 16.8% with static cold storage (P<0.001), graft survival was significantly higher with NRP (10).

However, widespread implementation faces substantial organizational and systemic barriers. Initial capital investment for equipment, facility modifications, and the establishment of 24-hour trained perfusion teams requires a substantial upfront financial commitment that may be prohibitive for many centers. Quality assurance frameworks are currently underdeveloped, necessitating mandatory competency certification for perfusion teams, annual audits by professional societies, and standardized protocols for perfusate analysis and viability assessment. The optimal implementation pathway likely involves integration within coordinated national ERAS programs that can provide structured support, centralized training and certification, benchmarking, and outcome monitoring. These considerations are particularly relevant for ensuring equity of access across centers with varying transplant volumes and resources.

Optimizing long-term outcomes through tailored immunosuppressive strategies

While the present study (1) reports effective short-term immunosuppressive management, the leading causes of late mortality following liver transplantation remain cardiovascular disease and renal dysfunction, pathologies strongly linked to long-term calcineurin inhibitor (CNI) exposure (11,12). Systematic CNI-minimization and pharmacogenetic-guided dosing represent two complementary, evidence-based avenues that align with ERAS principles. The current protocol’s use of basiliximab induction and rapid steroid taper provides a framework (1); however, the next frontier in enhancing long-term outcomes lies in systematic management of CNI toxicity.

The HEPHAISTOS trial demonstrates that early initiation of everolimus with reduced-exposure tacrolimus (EVR + rTAC) preserved renal function, providing a statistically significant 8.3 mL/min/1.73 m² improvement in estimate glomerular filtration rate (eGFR) at 12 months compared to standard tacrolimus, with comparable efficacy and safety without increasing rejection risk (11). This evidence is complemented by the CERTITUDE study, which followed patients from the SIMCER trial and demonstrated that an early switch to everolimus with subsequent tacrolimus withdrawal preserved renal function effectively, with 52.3% of patients remaining CNI-free at 24 months and showing significantly better renal function profiles compared to those maintained on tacrolimus (12). Collectively, these approaches align with ERAS principles by systematically addressing the metabolic complications that ultimately govern long-term survival.

This protocol-driven strategy can be refined with precision pharmacology. Pre-emptive CYP3A5 genotyping of both donor and recipient can inform dosing, as expressers demonstrate 76% higher tacrolimus clearance (13.3 vs. 7.56 L/h) than non-expressers, necessitating fundamentally different initial dosing regimens (13). Integrating this pharmacogenetic data enables genotype-stratified starting doses, systematically reducing time to therapeutic range and minimizing early toxicity. The widespread adoption of this precision approach warrants confirmation in broader, more diverse patient cohorts.

Extending the continuum with digital health integration

The established inpatient protocol could be extended into the post-discharge period through digital tools. A randomized controlled trial (single-center, n=100) demonstrated that a telemedicine-based home management program significantly reduced 90-day readmission rates by more than half (28% vs. 58%; P=0.004) and improved quality of life measures in liver transplant recipients (14). Implementing such a “digital safety-net” represents a rational evolution of the ERAS pathway, enabling proactive management during the vulnerable transition to home.

Geographic variability and contextual adaptation

Any discussion of ERAS expansion must acknowledge marked global heterogeneity in transplant practice. Chinese studies, as reflected in the study by Yuan et al. (1), report a high prevalence of hepatitis B virus (HBV)-related cirrhosis (≈78%) and moderate DCD utilization (38%), whereas many Western centers face predominantly hepatitis C virus (HCV)/non-alcoholic fatty liver disease (NAFLD) etiologies and DCD rates often exceeding 50% (4,15). Furthermore, resource-limited regions may lack access to perfusion equipment, widespread CYP3A5 genotyping, or tele-monitoring infrastructure. The modular framework we propose—prehabilitation, graft optimization (HMP or NRP), tailored immunosuppression, and digital follow-up—permits centers to adopt evidence-based components incrementally while awaiting the development of national quality programs and cost-sharing mechanisms that facilitate equitable uptake.

Conclusions

In summary, we propose that the logical evolution of the ERAS pathway in liver transplantation is its extension into a comprehensive, longitudinal care continuum. This evolution integrates four sequential, evidence-based strategies targeting specific challenges across the transplant journey: prehabilitation to optimize the recipient’s physiological reserve pre-operatively; machine perfusion (HMP/NRP) to enhance graft viability and mitigate biliary complications intra-operatively; tailored immunosuppression to mitigate long-term metabolic toxicity post-operatively; and digital health tools to secure recovery during the critical post-discharge transition. As discussed, implementing this framework effectively will require the development of supportive national health policy and implementation programs for training and equitable access. Therefore, the work by Yuan et al. provides a robust foundation for the next critical steps: prospective multi-center trials to validate this synergistic model, coupled with dedicated investment in the necessary health-system infrastructure to ensure its broad and sustainable adoption for improving long-term patient outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-aw-887/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-aw-887/coif). The authors have no conflicts of interest to declare.

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