Design

This systematic review will be conducted according to the Cochrane Handbook [25] and in accordance with the guidelines of the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) declaration [26]. This proposed systematic review will be written according to PRISMA-P statement (Additional file 1) and is registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021290618).

Eligibility criteriaTypes of studies

All peer-reviewed randomised controlled trials (RCTs), including cluster RCTs, controlled (non-controlled) clinical trials (CCTs) or cluster trials, cohort, observational studies that addresses the research questions. Individual case reports, review papers, editorials and conference abstracts with no subsequent peer reviewed full-text paper will be excluded. We will exclude any paper that is not written in English, unless provided with a translated manuscript by the authors.

Participants

The review will consider all studies that include adult patients (\(\ge\) 18 years old) with cirrhosis and waiting for liver transplantation. No limitations will be placed on programme duration, delivery method, intensity, geographical location, gender, ethnicity, duration of illness and nationality.

Interventions

This review will consider cirrhosis prehabilitation programmes including exercise as the major component. Prehabilitation is defined as the practice of strengthening a patient’s functional capacity before surgery with the goal of improved postoperative outcomes [27]. Exercise is a type of physical activity that is planned, structured and repetitive with the enhancement or maintenance of physical fitness as its ultimate or intermediate goal. Various training modalities, including Yoga, Qigong and Tai chi, as well as resistance, aerobic and flexibility training, can be used as part of an exercise intervention during a prehabilitation programme. There will be no restrictions on the environment (land-based or aquatic training), materials used, and type of exercise.

Comparators

We will include comparator interventions defined as preoperative exercise also named preoperative rehabilitation. We defined preoperative exercise as a regimen of physical activity, which can include individualised, home-based, or supervised physical exercise training programmes.

Outcomes

We will include studies that report on primary health outcomes and secondary outcomes. The primary outcomes include physical and functional capacity, muscle strength, aerobic function, sarcopenia, frailty and health-related quality of life. The secondary outcomes include body composition (weight, waist circumference, body mass index, body fat % and thigh circumference), lipids profile (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and/or triglycerides), waist circumference and blood pressure.

Search strategy

The search strategy will aim to locate both published and unpublished studies. We will conduct a systematic search following Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions [25]. An initial limited search will be conducted in PubMed using the keywords “cirrhosis,” “prehabilitation,” “preoperative exercise” and “liver transplantation” and their synonyms. The text words in the titles and abstracts used in the retrieved articles as well as the index terms used to describe the articles will be used to develop a full search strategy (Table 1). The search strategy will be adapted for each included database. The databases to be searched include PubMed, MEDLINE via EBSCO, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL and Scopus via Elsevier. The search for unpublished studies and grey literature will include Scopus and the ProQuest Dissertations and Theses Global database. An electronic database search will be performed by searching titles, abstracts, keywords and subheadings for articles published up to 2023.

Study selection

Titles and abstracts of the studies identified will be screened by two independent reviewers (EN and DP) for assessment against the inclusion criteria for the review. Potentially relevant studies will be retrieved in full, and their citation details imported into the JBI System for the Unified Management, Assessment, and Review of Information (JBI SUMARI; JBI, Adelaide, Australia). The full text of selected citations will be assessed in detail against the inclusion criteria by two independent reviewers. Disagreement will be solved by the application of criteria, discussion and consensus. Where no consensus can be reached a third reviewer (DC) will be consulted. The results of the search will be reported in full in the final systematic review and presented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart (Fig. 1).

Fig. 1

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Data extraction

Two reviewers (EN and DP) will independently extract the data from the selected studies into a standardised form in Microsoft Excel Spreadsheet. Data extracted will include the following: population interventions, comparators, outcomes, setting and study design (Table 2). This tool will be modified and revised as necessary during the process of extracting data from each included paper. Modifications will be detailed in the full systematic review. In the case of missing, incomplete or ambiguous data, the authors of the study will be contacted for clarification. If additional data or clarification is required, the authors of the papers will be contacted. Disagreements will be resolved by reaching a consensus.

Table 2 Data extraction instrumentRisk of bias assessment

Two reviewers (EN and DP) will independently use the Cochrane “Risk of bias” tool described in the Cochrane Handbook for Systematic Reviews Interventions [25] to assess the risk of bias. The risk of bias will judge them as either low risk of bias, some concerns or high risk of bias. The following domain will be assessed: allocation, outcome assessors, incomplete outcome data, baseline outcome measurements, knowledge of allocated intervention (blinding), selective outcome reporting and randomisation procedures.

Data synthesis

The extracted data will be presented in tabular, diagrammatic or figure form in a manner that aligns with the objective of this systematic review and will be supported by narrative descriptions of the data. A meta-analysis will be carried out using Review Manager (RevMan) V.5.3 (Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Effect sizes will be expressed as a standardised mean difference, and their 95% confidence intervals will be calculated and presented as a forest plot. The standard χ2 and I2 tests will be used to test heterogeneity. If the chi-square test is significant below p = 0.05, we will quantify the amount of heterogeneity using I2 statistics. We will consider I2 above 50% as indicative of substantial heterogeneity. If data cannot be meta-analysed, we will summarise the articles ad conclude on high-quality studies. Subgroup analysis will be conducted by splitting the participant data into subgroups to make comparisons between them.

Publication bias

Publication of bias will be examined using Egger’s linear regression test for funnel plot asymmetry [28]. Duval and Tweedie’s trim and fill will be conducted if there is evident publication bias.

Grading of evidence

Overall quality of the evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool [29] by two independent reviewers. The evidence will then be classified as high, moderate, low or very low.

Discussion and implications of the review

Prehabilitation in patients awaiting liver transplantation may enhance aerobic and functional ability, and more crucially, prehabilitation may prevent the decline in aerobic and functional capacity. In patients preparing for abdominal surgery, prehabilitation may facilitate improvements in physical function, cardiorespiratory fitness and muscle strength in the preoperative period. Prehabilitation is associated with a low incidence of postoperative complications and a shorter length of hospital stay following liver transplantation. Exercise therapists could provide various prehabilitation programmes to patients who are waiting for liver transplantation. The review will provide known evidence of prehabilitation for patients awaiting liver transplantation in the identified primary and secondary outcomes. It will also identify the gaps in this area of research and inform future research.