Poor physical fitness and functional status compromise postoperative functional recovery and lead to adverse postoperative outcomes, including complications, prolonged length of in-hospital stay, and mortality (1).

In current practice, patients who undergo (major) abdominal surgery are postoperatively supported by physical therapists and dieticians as part of the Enhanced Recovery After Surgery (ERAS^®) program to accelerate postoperative recovery by enhancing perioperative health and reducing the impact of hospitalization and surgical stress (2,3). In addition, preoperative physical fitness measured by cardiopulmonary exercise tests has shown to be an independent predictor for postoperative morbidity and mortality after major abdominal surgery (4). Therefore, in the recent years, an increasing amount of scientific evidence focusses on preoperative “rehabilitation,” known as prehabilitation (5,6). Prehabilitation is aimed at strengthening the “psychophysiological reserve” and mitigating the postoperative surgical stress response to improve postoperative outcomes by enhancing preoperative general health and reducing individual risk factors (6).

Previous studies showed that prehabilitation programs are feasible, safe, and effective in patients scheduled for major abdominal surgery (7-9). However, the evidence regarding the beneficial effects of prehabilitation in patients awaiting orthotopic liver transplantation (OLT), a generally physically ‘frail’ patient population, is limited. OLT candidates not only exhibit key premorbid components of frailty, such as diminished functional capacity, sarcopenia, and decreased aerobic capacity, but may also suffer from cirrhosis-induced complications, such as ascites, hepatic encephalopathy, or variceal bleeding (10,11), which raises questions concerning their trainability. However, the waiting period for this procedure, on average 28 weeks in the Netherlands, 13–17 weeks in the United Kingdom, and 24 weeks in the United States of America, might be used to optimize physical condition by training prior to OLT (12-14).

Moreover, previous research in OLT candidates predicted a higher survival after OLT in patients with a higher anaerobic threshold (a submaximal exercise parameter of cardiorespiratory reserve) (15). Therefore, prehabilitation could possibly benefit patients in reducing morbidity and mortality during the waiting period or after OLT.

The primary objective of this systematic review is to evaluate the observed effects of preoperative training on physical and functional capacity, and to evaluate the effect of prehabilitation on postoperative surgical outcomes after OLT. The secondary objective is to determine the feasibility and safety of prehabilitation programs in patients awaiting OLT. In addition to the primary and secondary objectives, we aim to provide an overview of the studied prehabilitation programs, including their content and potential for success (16,17).

The aim of this systematic review was to evaluate the effect of prehabilitation on physical capacity and surgical outcome in patients actively waiting for OLT. Six out of eight studies demonstrated significant improvements in aerobic or physical capacity (23-28). Adherence to the training programs was 69% or higher, and none of the included studies reported any serious adverse events. Therefore, these findings imply that prehabilitation programs are safe, feasible, and, potentially, effective for OLT-candidates.

In the past, one other review and one meta-analysis have been conducted in patients with chronic liver disease to assess the effect of training on their physical capacity (31,32). And although this current review shows resemblance to these previously conducted reviews, the majority of their included studies excluded potential OLT candidates and patients with MELD score ≥12, while this current review solely focussed on patients with ESLD awaiting OLT (31,32). For example, in the review conducted by Williams et al., the authors concluded that moderate‐to-high intensity exercise can improve the physical components of frailty and QoL in patients with chronic liver disease, but that it remained to be elucidated whether this also applies to patients with Child Pugh B/C decompensated cirrhosis (33-39). In the review of Brustia et al., where not solely patients awaiting OLT were included, no adverse events were caused by the training, but neither an improvement in physical capacity was observed (32).

When elaborating on the physical effects of prehabilitation in OLT candidates, previous literature has shown that preoperative VO2 peak and MELD score are independent prognostic factors of mortality and duration of hospitalization during both the pre- and post-transplantation periods (15,40-42). Hence, it can be hypothesized that increased VO2 peak due to training, could improve surgical outcome for the OLT candidate. The ability to increase this physical capacity with training was shown by several studies included in this review (23-27). The studies of Debette-Gratien, Morkane and Williams et al. all found a significant improvement in aerobic capacity after training (23,25,26). Their results, however, differed from the study by Chen et al., who found no difference in VO2 peak after training (27). This difference in results might be explained by the differences in design of the training programs of the three studies: Debette-Gratien and Morkane et al. provided specified supervised aerobic training with a cycle ergometer, Williams et al. used video guided exercises and non-supervised walking training, and Chen et al. solely implemented non-supervised walking training (23,25-27). Thereby, only three out of eight studies outlined the aerobic intensity of the exercises (23,25,26). Debette-Gratien et al. and Morkane et al. based their patient-adjusted aerobic training protocol on VO₂ peak and on the anaerobic threshold which was objectified by CPET (23,26). Williams et al. used a subjective scale where patients were asked to achieve a work rate of 12–14 on the Borg scale (25). To speculate, these results should be interpreted with caution, but suggest that supervised aerobic cycling training by use of a patient-adjusted protocol could be more beneficial than unsupervised walking training. The hypothesis that physical training improves postoperative recovery was only described in three out of the eight included studies (11,25,26), and seems to be consistent with the findings of Lin et al., who found a significant correlation between survival advantage with improvement of the LFI score (28), and Morkane et al., who found a significant median difference of 17 days in the length of in-hospital stay between the intervention and control groups (26). However, in contrast with Morkane et al.’s finding, Al-Judaibi et al. found no difference in the length of in-hospital stay or 90-day readmission rate (11). The differences between the studies of Morkane and Al-Judaibi et al. may be explained by the studies’ population sizes (n = 17 vs. n = 458, respectively) and the significantly older population with more comorbidities in the training group compared to the control group in the study of Al-Judaibi et al. (11), while in the study of Morkane et al. no significant differences in baseline demographics of the two groups were reported (26).

Debette-Gratien et al. were able to include 100% of eligible candidates in their study (23), while Chen et al. only included 7% of eligible candidates. This discrepancy between eligible and eventually included patients could be caused by tight inclusion criteria, but results in a questionable feasibility of the study and could increase the risk of potential attrition bias. However, when evaluating feasibility of the training programs, all studies that mentioned adherence to the program reported a 38–90% adherence in unsupervised exercise training (24,25,28) and 94% or higher adherence to supervised exercise training (24,26), suggesting a high feasibility of prehabilitation programs in OLT candidates. These findings are somewhat surprising since the psychological burden on the OLT candidate is high (43), and the long waiting time and presence of symptoms related to liver cirrhosis possibly corrode compliance and motivation (34). Nonetheless, the dropout rate was low in all studies, and the most common reason for dropout was because patients were transplanted before the end of the study period.

This review has several limitations. First of all, this review was not pre-registered on the PROSPERO database, which could have caused reduced transparency of the applied search strategy of this review. Secondly, there are certain limitations regarding the studied evidence: most included studies consisted of small patient populations, and focused on different primary outcomes, which made the comparison and analysis of the studies challenging. In addition, most of the studies were non-randomized, which leads to a reduction in the analysis strength of this review. Finally, as the values of the baseline and post-training outcomes are not independent of each other, and correlations were not reported by the individual studies, meta-analyses were not possible (44). The high heterogeneity and lack of high-quality trials make it difficult to draw conclusions on the true effect of prehabilitation, when taking infrastructural differences, waiting time and clinical status as prognostic factors of success of the training programs in account. However, by strictly including only studies with patients having ESLD who are actively waitlisted for OLT, a bias of representing a “healthier” study group is prevented. Therefore, the strength of this review is, therefore, to represent the “most physically frail” patients, namely the OLT candidates with ESLD.

In our opinion, home-based training, which is supervised by a dedicated physical therapist and is combined with nutritional and educational support by a dietician, could be suitable for preoperative optimization until OLT. Patients might make some progress during these weeks of training, but, most importantly, deterioration of aerobic capacity could be prevented (27) and the number of hospital admissions due to decompensated liver disease during the waiting period could be reduced (45). To the best of our knowledge, the economic burden of the implementation of a prehabilitation program in this patient population has not been studied yet. One can imagine that the supervision and provision of a personalized training program for this frail population requires professional health-care workers as physiotherapists and dieticians. However, since previous studies showed cost-effectiveness for prehabilitation in patients undergoing abdominal surgery (46), we think that investing in personalized training programs for this specifically frail population could be beneficial. However, the effects of physical training in this patient population are still not decisive, and objectively measured effects of structured training programs on days of hospitalization, presence of complications and functional evolution after transplantation are scarce. Therefore, this review emphasizes the need for large (multicentre) longitudinal trials that not only study the physical effects, but also focus on possible improvement of surgical outcomes after a longer duration of training during the waiting period prior to OLT. Randomizing between training and no training is, in our opinion, not ethically justifiable, because various studies (45,47,48) have shown the benefits of improved physical capacity, activity, and muscle status with surgical outcome.

In conclusion, this systematic review found that prehabilitation in patients actively listed for OLT may improve aerobic and functional capacity, and, more importantly, that deterioration in aerobic and functional capacity could be countered by prehabilitation. Thereby, since no serious adverse events were reported and adherence to the training programs was high, we conclude that prehabilitation is safe and feasible in the OLT candidate. Thus, from our point of view, all patients awaiting OLT, especially the most physically frail ones, should be enrolled in predefined prehabilitation programs.