
==== Front
Crit Care Med
Crit Care Med
CCM
Critical Care Medicine
0090-3493
1530-0293
Lippincott Williams & Wilkins Hagerstown, MD

38832833
CCMED-D-23-01086
00012
10.1097/CCM.0000000000006346
3
Review Articles
Quality Evaluation of Guidelines for the Diagnosis and Treatment of Liver Failure
Wang Xia MM 1
Zheng Meng-Yao MM 1
He Hai-Yu MM 1
Zhu Hui-Ling MM 1
Zhao Ya-Fang MM 1
Chen Yu-Hang MM 1
Xu Zhi-Yuan MM 1
Yang Jin-Hui MM 1
Sun Da-Li MD 2
1 Department of Gastroenterology, Second Affiliated Hospital of Kunming Medical University, Kunming, China.
2 Department of Gastrointestinal Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming, China.
For information regarding this article, E-mail: yangjinhui@kmmu.edu.cn, sundali2018@126.com
04 6 2024
10 2024
52 10 16241632
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

OBJECTIVES:

This study aimed to systematically assess the methodological quality and key recommendations of the guidelines for the diagnosis and treatment of liver failure (LF), furnishing constructive insights for guideline developers and equipping clinicians with evidence-based information to facilitate informed decision-making.

DATA SOURCES:

Electronic databases and manual searches from January 2011 to August 2023.

STUDY SELECTION:

Two reviewers independently screened titles and abstracts, then full texts for eligibility. Fourteen guidelines were included.

DATA EXTRACTION AND SYNTHESIS:

Two reviewers extracted data and checked by two others. Methodological quality of the guidelines was appraised using the Appraisal of Guidelines for Research and Evaluation II tool. Of the 14 guidelines, only the guidelines established by the Society of Critical Care Medicine and the American College of Gastroenterology (2023) achieved an aggregate quality score exceeding 60%, thereby meriting clinical recommendations. It emerged that there remains ample room for enhancement in the quality of the guidelines, particularly within the domains of stakeholder engagement, rigor, and applicability. Furthermore, an in-depth scrutiny of common recommendations and supporting evidence drawn from the 10 adult LF guidelines unveiled several key issues: controversy exists in the recommendation, the absence of supporting evidence and confusing use of evidence for recommendations, and a preference in evidence selection.

CONCLUSIONS:

There are high differences in methodological quality and recommendations among LF guidelines. Improving these existing problems and controversies will benefit existing clinical practice and will be an effective way for developers to upgrade the guidelines.

guidelines
liver failure
management
quality assessment
National Natural Science Foundation of China 10.13039/501100001809 82160106 Jin-Hui YangScholarship for Academic Leader of Yunnan Province 10.13039/501100015287 202105AC160049 Da-Li SunOPEN-ACCESSTRUE
SDCT
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pmcKEY POINTS

Question: What is the methodological quality and key recommendations of the guidelines for the diagnosis and treatment of liver failure?

Findings: A total of 14 guidelines were identified. Only two guidelines achieved an aggregate quality score exceeding 60%, thereby meriting clinical recommendations. The key recommendations have been apparently inconsistent.

Meaning: The problems found in the current research will help the developers to upgrade the guideline, and provide reference for the clinicians to select high-quality guidelines and appropriate recommendations.

Liver failure (LF) constitutes a cluster of clinical syndromes resulting from multiple etiological factors. These include coagulation disorders, jaundice, hepatic encephalopathy, ascites, etc. LF may present as acute or subacute (in the absence of prior liver disease), acute-on-chronic liver failure (ACLF, an acute worsening of preexisting chronic liver disease), or as a further deterioration of end-stage liver disease (1).

Notably, acute liver failure (ALF) and ACLF have received a lot of attention due to their high mortality rates (1–16). ACLF is the most common form of LF, among patients with liver cirrhosis, with a prevalence rate of about 35% and a 90-day mortality rate of around 58% (5). The prevalence rate of ALF is relatively low, typically ranging between 1 and 6 cases per million people annually, whereas the mortality rate exceeds 50% (17). Early identification and management of these conditions are crucial to reduce mortality. In light of this, numerous liver disease organizations have issued clinical practice guidelines (CPGs) (1–17). It has, however, been considered that the inconsistency of these guidelines, especially in the diagnosis and treatment of LF, and the mediocrity of evidence used in their support, have to a great extent reduced the effectiveness of clinical decisions.

Hence, our objective was to assess the methodological quality of these LF-CPGs and analyze recommendations and their supporting evidence for LF diagnosis and treatment looking for consistencies and discrepancies among the guidelines. Our comprehensive review intends to serve as a guide for improving these guidelines, thereby assisting healthcare practitioners in making informed decisions that can ultimately improve patient care.

MATERIALS AND METHODS

Research Design

The implementation of this study complied with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (18). Our evaluation of the methodological quality of LF-CPGs was meticulously conducted using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument (19).

Search Strategy

Two reviewers (X.W., Z.Y.X.) conducted a systematic search across prominent electronic databases including PubMed, Web of Science, Ovid, ScienceDirect, China National Knowledge Infrastructure, and WanFang Data, covering the period from January 2011 to August 2023. We formulated a very sensitive searching strategy (TABLE S1, http://links.lww.com/CCM/H555), which combined the terms “liver failure” with “statement,” “guideline,” “recommendation,” and “consensus.” In parallel, manual scanning of the included guideline references was done with the view of identifying the potentially associated studies. Disagreements were arbitrated through consultation with a third reviewer (M.Y.Z.), and the results were further reviewed by two other reviewers (J.H.Y., D.L.S.).

Guideline Selection and Extraction

The inclusion criteria were defined as follows: 1) guidelines about diagnosing and treating LF, 2) guidelines for the public, and 3) guidelines published in English or Chinese. The exclusion criteria included: 1) guidelines duplicated, 2) guidelines not for adult patients, 3) previous versions of guidelines from the same issuing body, 4) interpretations and translations of the existing guidelines, and 5) expert consensus statements, position articles, reviews, and clinical studies other than guidelines.

Quality Appraisal of the Guidelines

We used the AGREE II User’s Manual for an assessment of the guidelines’ quality (19). Four evaluators (X.W., Y.F.Z., H.L.Z., Y.H.C.) participated to reduce bias, with each one of them having been trained in conducting AGREE II evaluations (APPENDICES 1 and 2, http://links.lww.com/CCM/H555). It is important to note that the AGREE II manual does not provide a specific grading standard (20). To ensure consistency with previous studies using the AGREE II framework and to accommodate the varying levels of evidence in the recommendations of all the included guidelines, we implemented the following protocol (21): a guideline was recommended if it had an overall score of about 60%, whereas that scoring between 30% and 60%, was recommended after an appropriate modification: below 30%, no recommendation was made for that guideline.

Statistical Analysis

For each domain, calculations were performed using a standardized score and descriptive statistics, with results expressed as percentages. Median values and ranges were also provided for each domain. To evaluate the consistency of scores across the four evaluators, a two-way analysis of variance was used to calculate the intragroup correlation coefficients (ICCs). ICC values were interpreted as follows: 0.01–0.20 indicated slight agreement, 0.21–0.40 indicated fair agreement, 0.41–0.60 indicated moderate agreement, 0.61–0.80 indicated substantial agreement, and 0.81–1.00 indicated almost perfect agreement (21). A p value of less than 0.05 was considered statistical significance. The statistical analyses were performed using IBM SPSS Statistics, version 25.0 (IBM Crop., Armonk, NY).

Extraction and Analysis of Recommendations

We meticulously extracted and analyzed the recommendations from various guidelines, while organizing them according to the highest levels of supporting evidence and the strength of the recommendations. The evidence and recommendations within these guidelines were graded following the Grading of Recommendations Assessment Development and Evaluation system (TABLE S2, http://links.lww.com/CCM/H555) (22). Two reviewers (X.W., Z.Y.X.) performed data extraction, which was then verified by another two reviewers (H.Y.H., M.Y.Z.).

RESULTS

Guideline Characteristics

A total of 175 articles were initially obtained, from which 14 LF-CPGs were ultimately included (1–16) (Fig. 1). The majority of these guidelines were from China (1, 13–16) and the United States (2, 3, 6, 8, 11). Six guidelines focused on ACLF (4, 5, 8, 13, 15, 16), whereas four addressed ALF (6, 7, 9–11). Additionally, two guidelines (2, 3, 12) addressed both ALF and ACLF, and two guidelines (1, 14) did not specify the LF type. Additional characteristics are shown in TABLE S3 (http://links.lww.com/CCM/H555).

Figure 1. Flowchart of study selection.

Quality Assessment of Guidelines

The methodological quality of all included guidelines was evaluated using the AGREE II tool, with outcomes detailed in TABLE S4 (http://links.lww.com/CCM/H555) (scoring details provided in TABLE S5, http://links.lww.com/CCM/H555). The domain of scope and purpose achieved the highest median values at 89.6% (range, 47.2–98.6%). Clarity of presentation and editorial independence garnered scores of 77.8% (range, 25.0–7.2%) and 50.0% (range, 0–100%), respectively. However, stakeholder involvement, rigor of development, and applicability displayed lower median values at 34.7% (range, 8.3–66.7%), 39.1% (range, 10.4–72.9%), and 37.0% (range, 0–68.8%), respectively.

The comprehensive scores for each guideline are listed in TABLE S4 (http://links.lww.com/CCM/H555). Two guidelines (2, 3, 8) received an overall rating exceeding 60%, justifying a recommendation. Twelve guidelines (1, 4–7, 9–16) obtained overall scores between 30% and 60%, indicating they are recommended but require improvement. The ICCs for AGREE II evaluations conducted by the four assessors exceeded 0.8, indicating strong agreement.

The Level of Evidence and Recommendation Strength of the Common Recommendations

In the review of 14 adult LF guidelines, 2 guidelines did not include explicit recommendations (1, 13, 14), and 1 guideline primarily focused on the application of traditional Chinese medicine (16). Consequently, our analysis was confined to 10 LF guidelines addressing ALF and ACLF (2–12, 15), as detailed in Figure 2. From these guidelines, we extracted detailed recommendations for the diagnosis and treatment of ALF and ACLF, mentioned in at least three guidelines. Furthermore, we evaluated the strength of these recommendations and identified the highest level of evidence supporting them, as illustrated in Figures 3 and 4.

Figure 2. Recommendations for diagnosis and management of liver failure are in the included guidelines. AC = American College of Gastroenterology, ACG = American College of Gastroenterology, ACLF = acute-on-chronic liver failure, AG = American Gastroenterological Association, ALF = acute liver failure, AP = Asian Pacific association for the study of the liver, EA = European Association for the Study of the Liver, ID = Infectious Disease Committee, Chinese Association of the Integration Medicine, IN = Indian National Association for Study of the Liver, PB = Paugam-Burtz C et al, SC = Society of Critical Care Medicine.

Figure 3. The highest level of evidence and strength for key recommendations in the guidelines for acute liver failure (ALF). AC = American College of Gastroenterology, AG = American Gastroenterological Association, ARDS = acute respiratory distress syndrome, CRRT = continuous renal replacement therapy. GRADE = Grading of Recommendations Assess m ent Development and Evaluation system, EA = European Association for the Study of the Liver, IN = Indian National Association for Study of the Liver, KCC = King’s College Criteria, MELD = Model for End-Stage Liver Disease, NAC = N-acetylcysteine, PB = Paugam-Burtz C et al, PEEP = positive end-expiratory pressure, RCT = randomized control trials, SC = Society of Critical Care Medicine.

Figure 4. The highest level of evidence and strength for key recommendations in the guidelines for the acute-on-chronic liver (ACLF). ACG = American College of Gastroenterology, AP = Asian Pacific association for the study of the liver, CRRT = continuous renal replacement therapy. ES = European Association for the Study of the Liver, HBV = hepatitis B virus, ID = Infectious Disease Committee, Chinese Association of the Integration Medicine, PB = Paugam-Burtz C et al, SC = Society of Critical Care Medicine.

DISCUSSIONS

Quality Evaluation of Guidelines by AGREE II

Our search covered LF-CPGs over the past decade. Despite a rise in the quantity of these guidelines, visible enhancements in their quality remained elusive. This shortfall was primarily evident in several key areas.

Rigor is essential for assessing their credibility and appropriateness for user implementation. In this investigation, the median total rigor score across the domain was notably low, at 39.1%. A number of the guidelines demonstrated weak performance in the rigor of guideline development. This was largely due to the absence of clear descriptions regarding the use of systematic methods for evidence retrieval and the criteria for evidence selection in some guidelines (1, 4, 6, 7, 9, 10, 12, 14–16). Additionally, there was no mention of whether any of the guidelines had been subjected to external expert review before their publication. Only one guideline (4) outlined the procedure for updates, despite the fact that three guidelines (1, 4, 14) were, in fact, updates of previous versions.

The development of guidelines mandates collaborative endeavors and inputs from various specialized medical teams. Equally crucial is the integration of intentions and preferences from all stakeholders, including patients, underscoring their indispensable role in the guideline formulation process. In our study, the median total score for stakeholder involvement was notably modest, recorded at 34.7%. This modest score can be largely attributed to the exclusion of perspectives from the intended target population in the guidelines. Furthermore, a substantial number of the guidelines fail to adequately detail the roles and responsibilities of the individuals participating in the guideline development process (1, 4–7, 12, 14, 15).

In this study, the domain of applicability was found to be relatively limited, with a score of 37.0%. This can be primarily attributed to the guidelines’ predominant focus on academic considerations, with only a few addressing factors that influence the dissemination of guidelines (1–3, 8) or additional resource investment for implementing recommended recommendations (2, 3, 5).

To explore the prevalence of the concerns within guidelines, we performed an analysis of limitations on 115 articles that systematically assessed guidelines using the AGREE II instrument over the last 10 years (FIGURE S1, http://links.lww.com/CCM/H555). The domains of applicability, editorial independence, and rigor of development exhibited substantial potential for improvement, with 61.74%, 36.52%, and 29.57% of the articles, respectively, indicating deficiencies. Our analysis reveals considerable heterogeneity in the methodological quality of guidelines across different diseases, underscoring the critical importance of evaluating guidelines for various disease diagnoses and treatments.

Analysis of Consistency and Variability in the Key Recommendations

Management of ALF

Six guidelines (2, 3, 6, 7, 9–12) address the management of ALF, offering consistent recommendations for liver biopsy, respiratory, nervous, renal, gastrointestinal, hematologic, metabolic systems, and infections management (Fig. 3). However, discrepancies exist in certain recommendations.

Etiological screening

Asian guidelines (4, 9, 10, 15) primarily recommend viral hepatitis screening, whereas European and American guidelines (6, 7, 12) focus on screening for drug-induced acute LF, especially acetaminophen toxicity. Although the emphasis on regional factors in the etiology of LF is logical, it is notable that not all guidelines, including those from the European Association for the Study of the Liver (EASL) (7), American Gastroenterological Association (AGA) (6), and the French (12), address globally prevalent causes like drug-induced liver injury, viral hepatitis, Wilson disease, and autoimmune hepatitis. Given the rapid evolution in the epidemiology of ALF and ACLF over the past decade, it is imperative that future guidelines accord greater attention to these universal etiological factors.

N-acetylcysteine (NAC) may be advantageous for nonacetaminophen-induced acute liver failure

Four guidelines (7, 9–12) strongly support its use, presenting grade B as the highest level of evidence. Conversely, one guideline (6) recommends its application solely within clinical trials, albeit without providing evidence grading or references.

Transplantation selection criteria

Two guidelines (6, 9, 10) advocate for the use of the Model for End-Stage Liver Disease (MELD) Scores to assess the need for liver transplantation in ALF patients, in preference to the King’s College Criteria (KCC), citing grade B evidence from a cohort study (23). On the other hand, the EASL guideline (7) advises considering transplantation for patients who meet the Clichy or KCC criteria, supported by grade C evidence from a meta-analysis (24). Additionally, the American College of Gastroenterology guideline (11) suggests a moderate recommendation for using either KCC criteria or MELD score, citing grade D evidence and referencing the same meta-analysis (24). Given the existence of over 10 prognostic scoring systems for predicting the prognosis of ALF (6), further research into diagnostic tests is needed to identify the most appropriate prognostic model.

Initial fluid resuscitation

Two guidelines (7, 9, 10) consistently recommend crystalloids as the initial choice, supported by grade B evidence. Meanwhile, the SCCM guideline (2, 3) conditionally recommends using albumin for resuscitating patients with ALF or ACLF when serum albumin levels are low (< 3 mg/dL), based on grade D evidence. This recommendation is due to albumin’s role in maintaining oncotic pressure, which is crucial given its hepatic synthesis. Despite a general consensus on the necessity for adequate fluid therapy, the optimal fluid resuscitation strategy remains uncertain (25, 26), underscoring the need for well-designed, large-scale randomized controlled trials to evaluate fluid choices in LF patients amid currently limited, low-quality evidence.

Management of intracranial hypertension

Four guidelines (2, 3, 7, 9–11) unanimously recommend the use of hypertonic saline or mannitol to alleviate intracranial pressure (ICP) during episodes of ICP fluctuations with the highest level of evidence at A, based on randomized control trials (RCTs) (27). One guideline (6) suggests against the empiric use of treatments to reduce ICP, based on five RCTs (no references are provided), these studies showed that there was no effect overall of treatment of ICP on mortality.

Management of ACLF

In the management of ACLF, key recommendations regarding antiviral therapy, anti-infective treatment, coagulation function monitoring, renal management, and early liver transplantation exhibit general consistency across various guidelines (2–5, 8, 12, 15) (Fig. 4). However, the following areas remain contentious:

The definition of chronic liver disease

The APASL guideline (4) excludes patients with chronic liver disease who have experienced decompensated cirrhosis previously, assigning the highest level of evidence at A, based on multiple cohort studies (4, 28, 29). Conversely, the EASL guidelines (5) include patients with either compensated or decompensated cirrhosis, excluding those without cirrhosis, based on a large-scale multinational cohort study (30). The Chinese guidelines (15) encompass all patients based on expert consensus (1). This variance may reflect regional differences (31). An international collaboration among leading liver disease centers is anticipated to facilitate larger-scale clinical studies, aiming to refine the definition.

Plasma exchange

Two guidelines (4, 15) support the use of plasma exchange as a promising treatment for ACLF patients awaiting liver transplants or experiencing spontaneous regeneration, backed by strong evidence (level A). However, the EASL guideline (5) advises against routine use of plasma exchange for ACLF outside of research trials, also supported by level A evidence. We reviewed additional meta-analyses (32, 33) which suggest that plasma exchange may benefit patients with HBV-related ACLF, but further research is needed to confirm its clinical utility.

Concerns and Recommendations for Liver Failure Guidelines

Several issues undermine the reliability of the recommendations:

Divergence in recommendations

Conflicting advice exists among various guidelines, particularly due to differences in ethnic and geographical factors that influence the distribution of liver disease etiologies in different regions. This results in discrepancies in recommendations for etiological screening, selection criteria for transplantation, and management of ICP in ALF patients. Additionally, debates surrounding the definition of chronic liver disease and the application of plasma exchange in ACLF patients persist, potentially complicating clinical decision-making.

Inconsistent evidence application

The utilization of evidence to back recommendations is often confusing, with a mix of adult and pediatric study results. For example, one guideline for adults (12) endorses the use of N-acetylcysteine (NAC) for treating nonacetaminophen-related ALF, relying on pediatric studies (34) for evidence. Meanwhile, we have also observed that certain guidelines (1, 6) lack references to support their recommended advice, especially contentious recommendations. Including references would be beneficial for guideline users in selecting the most reliable evidence.

Variability in evidence levels

The evidence supporting the same recommendation exhibits obviously variability across different guidelines. For instance, a notable disparity in the levels of evidence was observed for the recommendation of NAC treatment in acetaminophen-induced ALF, where all five guidelines advocate strongly for it but reference differing levels of evidence. For others, see Figure 3.

Our investigation offers several recommendations for the development of future LF-CPGs: 1) use systematic methodologies for evidence retrieval, referencing internationally recognized tools, such as the Cochrane Handbook (www.thecochranelibrary.com); 2) before developing new guidelines, conduct comprehensive reviews of the current landscape of LF diagnosis and treatment. For recommendations that are controversial or conflicting, convening expert consensus panels is advisable to achieve agreement before finalization; 3) strive to use higher-level evidence and avoid conflating adult and pediatric evidence; 4) provide detailed citations of evidence sources to enhance traceability for guideline users; 5) guideline developers should familiarize themselves with established standards in guideline development, such as the AGREE II framework; 6) the development of clinical guidelines should incorporate the perspectives of the target audience; 7) an external review by experts should be conducted before the guidelines are published; and 8) rigorous assessment of potential conflicts of interest among guideline developers is essential to ensure transparency throughout the development process.

Our study highlights several strengths and limitations. The strengths include: 1) the evaluation of CPGs from diverse fields, enhancing the reliability of our findings. 2) A comprehensive evaluation of the evidence and recommendations of LF-CPGs, identifying some meaningful issues. The limitations manifest as follows: 1) only Chinese and English language CPGs were included in our evaluation, excluding guidelines published in other languages and 2) the AGREE II instrument does not assess the impact of recommendations on current clinical outcomes.

CONCLUSIONS

This study has uncovered substantial disparities in the quality of LF-CPGs, especially in the domains of participant involvement, rigor, and applicability throughout the guideline development process. In these areas, considerable opportunities for improvement have been identified. An in-depth analysis of LF-CPGs revealed several critical concerns pertaining to the recommendations and evidence underpinning the diagnosis and management of LF. Addressing these identified issues during the revision of LF-CPGs by guideline developers will markedly improve their clinical utility and facilitate standardized clinical practice.

Supplementary Material

Drs. Wang, Zheng, and He contributed equally to this work.

Drs. Wang, Sun, Yang, and Zheng designed this study. Drs. Wang, Zheng, Yang, and Sun. designed the inclusion/exclusion criteria and the search strategy. Drs. Wang and Xu searched the literature search and extracted data. Drs. Wang and Xu extracted data. Drs. He and Zheng completed checking. Drs. Wang, Zhu, Zhao, and Chen assessed the quality of each document. Drs. Yang, Sun, and He provided a critical review. Drs. Wang and Zheng drafted the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

This study was supported by the National Natural Science Foundation of China (no. 82160106) to Dr. Yang and Yunnan’s Young Academic and Technical Leaders Reserve Talent Project (no. 202105AC160049) to Dr. Sun. The remaining authors have disclosed that they do not have any potential conflicts of interest
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