The authors' objective with this narrative review is to explore the impact of rehabilitative interventions at each stage of liver disease. TYPE: Narrative review.

Literature search conducted in Medline, Embase, and Google Scholar databases.

Articles were included if they were identified in one of the three database, written in English, peer-reviewed, and involved human participants without any restrictions on the publication date. Reference lists of these publications were also scrutinized for other articles that might be relevant. Elibigle articles were reviewed to determine whether they met inclusion crtieria.

Authors synthesized findings in the eligible articles to create a narrative summary.

Chronic liver disease is a major cause of morbidity and mortality across the globe. Cirrhosis causes alterations in metabolic and circulatory functions that negatively affect nutritional status and exercise capacity. Frailty is identified in nearly half of patients with advanced liver disease and bears a poor prognosis. Exercise and nutritional interventions improve key components of physical frailty and quality of life in chronic liver disease and after liver transplantation. Early mobility is generally recommended following liver transplantation and deemed to be safe and feasible. Inpatient rehabilitation may be considered in patients who require ongoing daily medical management by a physician, demonstrate a significant functional decline from their baseline, tolerate intensive rehabilitation, and have functional goals that can be addressed by at least two skilled therapies. Rehabilitation is safe and improves outcomes at every stage of liver disease from cirrhosis to following transplantation. This literature review explores the impact of rehabilitative interventions at each stage of liver disease from cirrhosis to transplantation and beyond.

Cirrhosis is a prevalent disease and ranks among the leading causes of death worldwide. Sarcopenia is believed to be associated with a poorer prognosis in patients with cirrhosis.

To evaluate the impact of sarcopenia on the prognosis of patients hospitalized for acute decompensation of cirrhosis, with or without acute-on-chronic liver failure.

This prospective cohort study evaluated patients hospitalized for acute decompensation of cirrhosis, with or without acute-on-chronic liver failure. Sarcopenia was assessed according to the European Working Group on Sarcopenia in Older People, using skeletal muscle mass analysis by bioelectrical impedance and handgrip strength testing. The data was collected between March-2019 and April-2020. Qualitative variables were presented as frequencies and percentages, and quantitative variables as means and standard deviations when symmetrical, or medians and 25th and 75th percentiles when asymmetrical. The association of sarcopenia and mortality with quantitative variables was tested using Student's t-test or the Mann-Whitney test, while associations with qualitative variables were tested using the Chi-square test or Fisher's Exact test. For significant associations, crude and adjusted (multivariate analysis) relative risk estimates with a 95% confidence interval were calculated using Poisson regression analysis. Results with P<0.05 were considered significant.

Fifty patients were included, with a mean age of 60.5 years (±10.4) and a slight predominance of men (56%). The main causes of cirrhosis were alcohol use disorder (28%) and hepatitis C (24%). The median Child-Pugh score was 8 points (7-10), and the median Model for End-stage Liver Disease score was 15 points (12.5-21). Ten patients were diagnosed with acute-on-chronic liver failure. Sarcopenia was present in 50% of the sample. Sarcopenia was present in 70.0% of patients with acute-on-chronic liver failure and in 43.2% of those without acute-on-chronic liver failure (P=0.168). Overall mortality was 48% in patients with sarcopenia and 44% in those without sarcopenia (P=1.000). In multivariate analysis, overall mortality was associated only with leukocyte count (relative risk=1.01, 95% confidence interval=1.01-1.01) and Model for End-stage Liver Disease score (relative risk=1.07, 95% confidence interval =1.03-1.10).

In this study, sarcopenia was not associated with mortality in patients hospitalized for acute decompensation of cirrhosis, with or without acute-on-chronic liver failure. There was a non-significant trend towards a higher prevalence of sarcopenia among individuals with acute-on-chronic liver failure.

Prehabilitation, defined as preparing the body physically and psychologically for upcoming surgery is of increasing prominence in presurgical care. The aim of this review is to discuss the evidence base around prehabilitation in solid organ transplantation, the use of digital health as a tool to deliver these interventions, and consider future directions.

Prehabilitation is of increasing interest as an adjunct to pretransplant care for individuals working up for solid organ transplantation. To date, research has shown that prehabilitation is acceptable and feasible; however, the literature base remains small. The majority of research has been delivered using in-person rehabilitation programmes, and the evidence base utilizing digital health as a means to deliver prehabilitation is limited.

To date, the research evidence base in prehabilitation for solid organ transplantation is limited. Evidence in other surgical populations has demonstrated promising results, particularly in aerobic capacity, physical function and postoperative complications. Further high-quality randomized controlled clinical trials are required to strengthen the evidence base, understand how digital health can be harnessed and utilized to deliver multimodal prehabilitation with an aim to see how this may form part of routine care in the solid organ transplantation pathway.

Frailty, a measure of physiological aging and reserve, has been validated as a prognostic indicator of mortality in patients with cirrhosis. However, large-scale analyses of the independent association of frailty with clinical and financial outcomes following liver transplantation (LT) are lacking.

Adults (≥18 years) undergoing LT were identified in the 2016-2020 National Readmissions Database. Frailty was defined using the binary Johns Hopkins Adjusted Clinical Groups frailty indicator. Multivariable linear and logistic regression models were developed to evaluate the independent association of frailty with in-hospital mortality, perioperative complications, and costs.

Of an estimated 34 442 patients undergoing LT, 8265 (24%) were frail. After adjustment, frailty was associated with greater odds of mortality (adjusted odds ratio [AOR] 1.80; 95% Confidence Interval [CI]: 1.49-1.18), postoperative length of stay (β + 11 days; 95% CI: +10, +12), and hospitalization costs (+$86 880; 95% CI: +75 660, +98 100), as well as a two-fold increase in relative risk of nonhome discharge (AOR 2.17, 95% CI: 1.90-2.49).

Frailty is associated with an increased risk of in-hospital mortality, complications, and resource utilization among LT recipients. As the proportion of frail LT patients continues to rise, our findings underscore the need for novel risk-stratification and individualized care protocols for such vulnerable patients.

Frailty and sarcopenia are associated with an increased risk of hospitalization and mortality in patients with end-stage liver disease. The ability to identify frail patients at risk of adverse outcomes could help optimize liver transplant (LT) evaluations and pre-transplant care. This study compared sarcopenia, via L3-psoas muscle index (L3-PMI), to frailty, via liver frailty index (LFI) and analyzed associated outcomes after liver transplantation (LT).

A retrospective review of consecutive LT-recipients with cross-sectional abdominal/pelvic imaging were reviewed over 5 years at a single transplant center.

Four hundred and twenty-six patients underwent transplant during this study interval; 31% of patients were sarcopenic. Two hundred eight patients underwent LFI evaluation: 25% were frail, 59% were prefrail, and 16% were robust. Sarcopenic patients had higher LFI scores indicating greater frailty (p = 0.02). Both sarcopenia and LFI-frailty were associated with significantly higher MELD-Na scores. Length of post-LT hospital stay was increased in sarcopenic (mean 14 vs. nonsarcopenic 11 days, p = 0.02) and LFI-frail patients (mean 13 vs. 10 prefrail, 8 robust, p = 0.04). As a categorical variable, neither LFI-frailty nor sarcopenia were significantly associated with reduced survival at 1-year (robust 100%, prefrail 93.5%, frail 91.1%, p = 0.31) (nonsarcopenic 94.4%, sarcopenic 91.4%, p = 0.30). However, LFI score was significantly associated with mortality at 1-year (OR 2.133, p = 0.047).

Radiographic sarcopenia is a suitable proxy for in-person frailty assessment as both L3-PMI and LFI capture frail patients' pre-LT. However, physical assessment with frailty better predicts 1-year mortality post-LT than the measurement of muscle mass.

The goal of the Spanish Society for Liver Transplantation (Sociedad Española de Trasplante Hepático) is to promote and create consensus documents about current topics in liver transplantation with a multidisciplinary approach. To this end, in November 2022, the 10th Consensus Document Meeting was held, with the participation of experts from the 26 authorized Spanish liver transplantation programs. This edition discusses enhanced recovery after liver transplantation, dividing needed actions into 3periods: preoperative, intraoperative and postoperative. The evaluated evidence and the consensus conclusions for each of these topics are described.

The goal of the Spanish Society for Liver Transplantation (La Sociedad Española de Trasplante Hepático) is to promote and create consensus documents about current topics in liver transplantation with a multidisciplinary approach. To this end, in November 2022, the 10th Consensus Document Meeting was held, with the participation of experts from the 26 authorized Spanish liver transplantation programs. This edition discusses Enhanced Recovery After Liver Transplantation, dividing needed actions into three periods: preoperative, intraoperative and postoperative. The evaluated evidence and the consensus conclusions for each of these topics are described.

Frailty and sarcopenia are frequently observed in patients with end-stage liver disease. Frailty is a complex condition that arises from deteriorations across various physiological systems, including the musculoskeletal, cardiovascular, and immune systems, resulting in a reduced ability of the body to withstand stressors. This condition is associated with declined resilience and increased vulnerability to negative outcomes, including disability, hospitalization, and mortality. In cirrhotic patients, frailty is influenced by multiple factors, such as hyperammonemia, hormonal imbalance, malnutrition, ascites, hepatic encephalopathy, and alcohol intake. Assessing frailty is crucial in predicting morbidity and mortality in cirrhotic patients. It can aid in making critical decisions regarding patients' eligibility for critical care and transplantation. This, in turn, can guide the development of an individualized treatment plan for each patient with cirrhosis, with a focus on prioritizing exercise, proper nutrition, and appropriate treatment of hepatic complications as the primary lines of treatment. In this review, we aim to explore the topic of frailty in liver diseases, with a particular emphasis on pathophysiology, clinical assessment, and discuss strategies for preventing frailty through effective treatment of hepatic complications. Furthermore, we explore novel assessment and management strategies that have emerged in recent years, including the use of wearable technology and telemedicine.

Hepatic resection (HR) is an excellent option for patients with hepatocellular carcinoma (HCC). For patients meeting the Milan criteria, a liver transplant (LT) is also a viable option for patients with HCC, especially those with end-stage liver disease. With increasing rates of LTs amongst the elderly, we sought to determine long-term outcomes in patients who underwent HR compared to LTs in this patient population.

We queried the national cancer database for elderly patients (≥70 years) diagnosed with HCC between 2004 and 2020. The primary outcome was overall survival (OS) computed using the Kaplan-Meier method and Cox proportional hazard regression. One-to-one propensity score matching was conducted on the basis of clinicodemographic features to account for baseline differences between patients undergoing each procedure.

Of the 5090 patients included, 4674 (91.8%) and 416 (8.2%) patients underwent HR and LT, respectively. Compared with HR patients, patients receiving LT had better OS (p < 0.001) and greater median survival time (65.6 months HR vs. 97.9 months LT, p < 0.001). On multivariable analysis, a LT was independently associated with improved survival (adjusted hazard ratio: 0.61, 95% confidence interval: 0.50-0.76, p < 0.001).

LT is associated with improved survival for well-selected elderly patients with HCC. Age alone should not be used as the sole parameter for the candidacy of LT in elderly patients.

The existing literature suggests that exercise for cirrhotic patients is safe and favours significant improvement to their physical capacity. However, exercise training for this population and how to deliver activities, especially in severe stages of the disease and while waiting for a liver transplant (LT), remain undefined.

To review the existing exercise prescriptions for cirrhotic patients on the waiting list for LT, their results for frailty evolution and their effect on clinical outcomes.

A systematic review was performed following the Preferred Reporting Review and Meta-Analysis guidelines and searching the PubMed, MEDLINE, and Scopus databases. The keyword "liver transplant" was used in combination with the free terms "frailty" and "exercise" for the literature review. Clinical studies that evaluated the effect of a regular training program, independent of supervision or the duration or intensity of physical exercise, in cirrhotic patients on the waiting list for LT were reviewed. The data on safe physical activity prescriptions following Frequency, Intensity, Time, and Type recommendations were extracted and summarised.

Nine articles met the inclusion criteria for this review. Various instruments for frailty assessment were used, frequently in combination. Five studies prescribed physical activity for patients, one in-person and four to be performed remotely and unsupervised. The remaining four studies only used a self-report instrument to assess the level of physical activity. None reported adverse events related to exercise training. The exercise frequency mainly varied from daily to a minimum of twice per week. The intensity depended on frailty and included increasing levels of activity. The type of exercise was predominantly a combination of aerobic and resistance training. The duration of exercise varied from 4 to 12 wk. Three articles evaluated the effect of the exercise program on clinical outcomes, reporting a reduction in 90-d readmission rates post-transplant and improved frailty scores, as well as improved survival of cirrhotic patients waiting for LT.

Routine frailty assessment is essential for this population. Although more robust evidence is required, the prescription of exercise is safe and can improve patients' functional capacity, improving pre- and post-LT outcomes.

In recent years, various physical exercise interventions have been developed with a view to reducing comorbidity and morbidity rates among patients with chronic diseases. Regular physical exercise has been shown to reduce hypertension and mortality in patients with type 2 diabetes. Diabetes and obesity are often associated with the development of nonalcoholic fatty liver disease, which can lead to liver fibrosis and then (in some cases) nonalcoholic steatohepatitis cirrhosis. We searched the literature for publications on personalized physical exercise programs in cirrhotic patients before and after liver transplantation. Eleven studies in cirrhotic patients and one study in liver transplant recipients were included in the systematic review, the results of which were reported in compliance with the preferred reporting items for systematic reviews and meta-analyses guidelines. The personalized physical exercise programs lasted for 6 to 16 weeks. Our review evidenced improvements in peak oxygen consumption and six-minute walk test performance and a reduction in the hepatic venous pressure gradient. In cirrhotic patients, personalized physical exercise programs improve quality of life, are not associated with adverse effects, and (for transplant recipients) might reduce the 90-day hospital readmission rate. However, none of the literature data evidenced reductions in the mortality rates before and after transplantation. Further prospective studies are needed to evaluate the benefit of long-term physical exercise programs in cirrhotic patients before and after liver transplantation.

Well-selected patients with kidney disease and diabetes mellitus who undergo simultaneous kidney-pancreas transplantation often experience dramatic improvements in quality of life and long-term survival compared to those who remain on medical therapy. Over the past several years the importance of frailty in the pancreas transplant candidate and recipient populations has grown. More patients with advanced age have entered the waitlist, and complications from prolonged diabetes, even in younger patients, have created increased evidence of risk for frailty. Given these concerns, and the broad challenges facing pancreas transplantation volumes overall, we generated this review to help establish the impact and implications. We summarize the interplay of immunological factors, aging, environmental factors, diabetes mellitus, and chronic kidney disease that put these patients at risk for frailty. We discuss its measurement and recommend a combination of two instruments (both well-validated and one entirely objective). We describe the outcomes for patients before and after pancreas transplantation who may have frailty, and what interventions can be taken to mitigate its effects. Broader investigation into frailty in the pancreas transplant population is needed to better understand how to select patients for pancreas transplantation and to how manage its consequences thereafter.

To highlight the importance of biological age in the context of prehabilitation and to present relevant research regarding prehabilitation prior to solid organ transplantation.

Studies on the effect of prehabilitation have been performed in kidney-, lung-, liver-, and heart transplant patient populations. Prior to kidney transplantation, exercise interventions have been shown to improve cardiopulmonary- and physical fitness and result in a decreased length of hospital stay postoperatively. Among lung transplant candidates, various methods of prehabilitation have been studied including home-based, outpatient and in-patient programs, consisting of physical training, psychological support, education, and nutritional interventions. Overall, prehabilitation seems to improve or maintain quality of life and exercise capacity in this patient population. Patients undergoing liver transplantation seem to benefit from prehabilitation as well. Not only does it seem safe and feasible, but significant improvements in aerobic and functional capacity have also been found. Regarding heart transplant candidates, both inpatient and outpatient, supervised prehabilitation programs show promising results with improvements in exercise capacities and quality of life.

Prehabilitation is an effective and safe intervention for improving functional outcomes of solid organ transplant patients. Future studies should evaluate whether prehabilitation translates into improved pre- and post-transplant clinical outcomes.

The pleiotropic effects of statin therapy on inflammation and coagulation may reduce the risk of venous thromboembolism. This study evaluated whether statin therapy is associated with decreased venous thromboembolic (VTE) events following kidney transplantation.

We performed a retrospective analysis of all primary kidney transplants performed between January 2014 and December 2019 at Mayo Clinic Arizona. Patients were divided into two groups depending on sustained statin therapy during the first year following transplantation. Recipient and donor clinical and demographic data were collected. The primary outcome was admission for symptomatic VTE events (deep vein thrombosis [DVT] or pulmonary embolism [PE]).

Sustained statin therapy in the first year following transplant was observed in 16.1% (n = 223) of 1384 kidney transplants. The overall incidence of VTE events in the year following kidney transplant was 3.8%. VTE occurred in 4.1% of recipients treated with statins and 3.8% of the controls - (hazard ratio [HR] .92, 95% confidence interval [95% CI] .39, 2.21, p = .86). However, there were significant differences between the groups in terms of age, sex, race/ethnicity, body mass index, indication for transplant, diagnosis of diabetes and discharge antiplatelet or anticoagulant therapy. Following sensitivity analysis in which cohort matching was performed to account for these differences, there was no difference in VTE event-free survival (HR .89, 95% CI .41, 1.96, p = .78) or overall survival (HR .54, 95% CI .15, 1.94, p = .35) between patients treated with statins compared to controls.

Statin therapy in the year following successful kidney transplant was not associated with a reduction in risk of VTE.

Liver transplantation is the most important therapeutic intervention for end-stage liver disease (ELD). The prioritization of these patients is based on the model for end-stage liver disease (MELD), which can successfully predict short-term mortality. However, despite its great validity and value, it cannot fully incor porate several comorbidities of liver disease, such as sarcopenia and physical frailty, variables that can sufficiently influence the survival of such patients. Subsequently, there is growing interest in the importance of physical frailty in regard to mortality in liver transplant candidates and recipients, as well as its role in improving their survival rates.

To evaluate the effects of an active lifestyle on physical frailty on liver transplant candidates.

An observational study was performed within the facilities of the Department of Transplant Surgery of Aristotle University of Thessaloniki. Twenty liver tran splant candidate patients from the waiting list of the department were included in the study. Patients that were bedridden, had recent cardiovascular incidents, or had required inpatient treatment for more than 5 d in the last 6 mo were excluded from the study. The following variables were evaluated: Activity level via the International Physical Activity Questionnaire (IPAQ); functional capacity via the 6-min walking test (6MWT) and cardiopulmonary exercise testing; and physical frailty via the Liver Frailty Index (LFI).

According to their responses in the IPAQ, patients were divided into the following two groups based on their activity level: Active group (A, 10 patients); and sedentary group (S, 10 patients). Comparing mean values of the recorded variables showed the following results: MELD (A: 12.05 ± 5.63 vs S: 13.99 ± 3.60; P > 0.05); peak oxygen uptake (A: 29.78 ± 6.07 mL/kg/min vs S: 18.11 ± 3.39 mL/kg/min; P < 0.001); anaerobic threshold (A: 16.71 ± 2.17 mL/kg/min vs S: 13.96 ± 1.45 mL/kg/min; P < 0.01); 6MWT (A: 458.2 ± 57.5 m vs S: 324.7 ± 55.8 m; P < 0.001); and LFI (A: 3.75 ± 0.31 vs S: 4.42 ± 0.32; P < 0.001).

An active lifestyle can be associated with better musculoskeletal and functional capacity, while simultaneously preventing the evolution of physical frailty in liver transplant candidates. This effect appears to be independent of the liver disease severity.

Prehabilitation programs as part of ERAS protocols are being increasingly used in multiple surgeries, improving postoperative outcomes. Data regarding prehabilitation programs in patients awaiting liver transplantation and their outcomes is scarce.

To identify whether prehabilitation programs based on exercise training conducted prior to liver transplantation improve short-term postoperative outcomes, and to provide expert panel recommendations.

Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central.

Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. Studies included those evaluating postoperative outcomes, as well as those evaluating functional outcomes.

CRD42021236305.

Of the 170 studies screened, only one assessed the primary objective. Most studies focus on the preoperative impact of exercise training on aerobic capacity, muscle mass and/or strength, showing positive effects and no significant adverse events, but are underpowered and with heterogenous designs and interventions. The non-randomized observational study which assessed relevant postoperative outcomes, showed a non-significant trend towards reduced 90-day readmission rate and shorter length of stay in the prehabilitation group.

Prehabilitation prior to liver transplantation is unlikely to be harmful, and likely to have short term benefits on functional status. We cautiously recommend prehabilitation on the basis of absence of harm and possibility of benefit (Quality of Evidence; Very Low | Grade of Recommendation; Low).

Chronic liver disease and liver transplantation are risk factors for poor physical health and quality of life. This meta-analysis aimed to examine whether supervised exercise improves the physical health and quality of life in patients with chronic liver disease and liver transplant. Articles were searched in four databases (MEDLINE, Cochrane, Embase, and the Web of Science) from 1 January 1990 to 6 July 2021. Studies that assessed the change in aerobic capacity and quality of life following supervised exercise in patients with chronic liver disease or in those who had undergone liver transplantation were included in this meta-analysis. The two independent reviewers extracted data and the methodological quality of the included studies was assessed by the Cochrane Handbook for Systematic Reviews of Interventions. The extracted data were statistically analyzed using review management software (RevMan 5.3). The meta-analysis included 11 studies, comprising 159 patients. We observed that aerobic capacity measured as VO2 peak and 6-min walking test improved in patients with chronic liver disease and liver transplant after supervised exercise. Among the parameters of Short-form-36 (SF-36) used for measuring the quality of life, only physical functioning improved after supervised exercise. The other parameters of SF-36 including role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health were not significantly improved after supervised exercise. Supervised exercise seems essential for patients with chronic liver disease and liver transplant. It was found to be helpful in enhancing the aerobic capacity and physical function in these patients.

Frailty and sarcopenia associate with increased mortality in patients with liver cirrhosis on the transplant waitlist. We conducted a systematic review on the impact of pretransplant frailty and sarcopenia on post-transplant outcomes in adult patients with liver cirrhosis.

We performed a search in Medline, Embase and Cochrane Central. Of the 12276 references initially recovered, 34 were included.

Frailty and sarcopenia presented a negative impact on post-transplant outcomes and seemed to associate with an overall two-fold reduction in early and 50% reduction in late survival, for severe conditions, according to the largest cohorts. These patients required longer ICU and hospitalization time, had higher rates of sepsis and respiratory complications and lower graft-survival. The reversibility of frailty depended on the severity of functional impairment and on the co-morbidities contributing to frailty. Reversibility of sarcopenia occurred in only a minority of patients, in unbiased studies.

Frailty and sarcopenia are double-edged swords: patients with frailty/sarcopenia should be prioritized for liver transplantation due to increased mortality on the waitlist; however, severe frailty/sarcopenia may justify delisting because it associates with dismal prognosis post-liver transplantation. Patients presenting mild to moderate frailty/sarcopenia, should be submitted to liver transplantation before those conditions worsen to a level that significantly impacts post-liver transplantation outcomes.

Reduction in muscle mass is a highly prevalent phenomenon in cirrhosis and is now well-documented to be associated with significant morbidity and mortality. Research into muscle loss in cirrhosis remains limited by an ongoing poor understanding of its relationship with muscle function, physical activity, and aerobic capacity. Alterations in exercise physiology have been documented in studies of individuals with cirrhosis that provide important information on physical function that is not captured by simple quantification of muscle mass. Despite expert consensus recommending regular exercise in end-stage liver disease to maintain muscle mass and function, there is little evidence guiding clinicians as to which form of exercise or delivery mechanism is most effective. It also remains unproven whether any specific intervention can alter clinically relevant outcomes. This review article summarizes the available literature regarding the changes in exercise physiology observed in cirrhosis, the associated impact on physical capacity, and the results of existing trials that examine the potential benefits of exercise delivery in patients with cirrhosis, particularly pertaining to their impact on exercise physiology.

Acute-on-chronic liver failure (ACLF) is a syndrome in which acute liver failure with extrahepatic organ failure occurs on chronic liver disease. Recently, liver transplantation is the only effective treatment for ACLF. There is still room for discussion on the optimal surgery timing for ACLF, perioperative infection prevention and control, and maintenance of nutrition and organ function. The Transplantation Immunology Committee of Branch of Organ Transplantation Physician of Chinese Medical Doctor Association and Enhanced Recovery of Liver Transplantation Group of Enhanced Recovery after Surgery Committee of Chinese Research Hospital Association invited relevant experts to discuss the perioperative management of ACLF liver transplantation in areas including surgery timing, organ protection, nutritional support, infection prevention and control, rehabilitation exercises, regulation of the internal environment, etc. An expert consensus was developed as reference for clinicians.