The current management guidelines for acute liver failure and liver failure superimposed on chronic liver disease are predominantly supportive in nature and aimed at treating the precipitating cause and managing potential complications.1 In the pretransplant era, the short-term survival of patients with fulminant liver failure was as low as 18%.2 With the advent of liver transplantation, survival has markedly improved.3 However, relative paucity and delayed availability of organ donors influence outcomes.3 In the United States, each year, an estimated 1,800 patients awaiting a potential donor fail to survive transplantation.4 Acute decompensation of chronic liver disease has a high mortality as well, with cirrhosis being recently reported as the 12th leading cause of death in the United States.5 This highlights the importance of seeking better supportive therapy in such patients.
Since the 1960s, a number of artificial liver support systems have been conceived with the intention to support patients either until resolution of hepatic function, while the underlying precipitant is dealt with, or as a bridge to transplantation.6 They have ranged from early attempts at hemofiltration and plasma exchange to more recent sophisticated hepatocyte and membrane-based systems.6 One recently introduced support system, extracorporeal albumin dialysis (ECAD), uses a combination of albumin dialysis to remove albumin-bound substances and conventional hemodialysis to remove water-soluble substances. This system has been studied extensively with recent studies revealing mixed results regarding its impact on survival without significant adverse effects.7,8
Our aim was to perform a systematic review and meta-analysis of the current literature to assess the clinical efficacy and safety of ECAD therapy in patients with acute and acute-on-chronic liver failure using the most widely used method, the Molecular Adsorbants Recirculation System (MARS; Gambro, Lund, Sweden). The impact of MARS on survival and West-Haven grade of hepatic encephalopathy in such patients would help us evaluate its potential therapeutic value, whereas the change in total bilirubin levels would enable us to assess its ability to clear albumin-bound substances.9,10
Materials and Methods
We included all randomized controlled trials (RCTs) and nonrandomized controlled studies that enrolled patients with acute, acute-on-chronic, and hyperacute liver failure and compared ECAD using MARS versus standard medical therapy. We included studies that reported on all-cause mortality, net change in total bilirubin levels, and improvement (as defined in individual studies) in the West-Haven grade of hepatic encephalopathy (criteria for grading of mental state in patients with liver failure).11–13 If authors published more than one article on the same study, data from the most inclusive report were used.
We searched MEDLINE, EMBASE, and the Cochrane Registry of Controlled Trials database (1966 to May 2010), using the following Medical Subject Headings (MeSH) database search terms: “Liver, Artificial,” “Liver Failure,” “Liver Diseases,” “Bilirubin,” “Hepatic Encephalopathy,” “Survival,” and “Mortality” (Appendix). The search strategy was limited to human studies with no language restrictions. We also searched ClinicalTrials.gov for completed trials using similar search terms, reviewed abstracts from recent annual scientific meetings (2009–2010) of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the American Gastroenterology Association (Digestive Diseases Week), and the American College of Gastroenterology, and performed a manual search of references in narrative reviews and previously published systematic reviews on ECAD.
Study Selection and Data Abstraction
Two independent reviewers (A.V. and H.C.) screened the titles and abstracts of all electronic citations. The full-text articles were retrieved for comprehensive review and rescreened. The same reviewers independently extracted in duplicate the following data from full-text articles: country of origin, year of publication, period of study, study design, population setting (acute, acute-on-chronic, and hyperacute liver failure), patient summary characteristics (including sex, mean age, etiology of liver failure, and mean Child-Turcotte-Pugh [CTP] score), summary characteristics of the MARS device used (including duration of treatment, percentage of albumin dialysate used, blood flow rate, and anticoagulation use), duration of follow-up, and efficacy data including improvement in hepatic encephalopathy, mean total bilirubin levels, and survival. Safety end-points were also extracted including data on hemodynamic instability, thrombocytopenia, transfusion requirement, and other serious adverse events. Disagreements were resolved through consensus. Two authors were contacted by e-mail (up to two attempts per author) for additional information.8,14
Both reviewers (A.V. and H.C.) assessed the quality of the studies using the Jadad scale,15,16 which is based on the adequacy of randomization, double blinding, attrition rate, allocation concealment, and the use of an intention-to-treat analysis. This 0–5 scale, with a score of 5 corresponding to “best” quality, was used as a surrogate for overall quality assessment.
We performed meta-analyses of the odds ratio (OR) for improvement in West-Haven grade of hepatic encephalopathy and death in patients with liver failure treated with MARS relative to those treated with standard medical therapy. Because of the low number of events in some studies (zero in two study groups), we used the Peto fixed-effect model for our primary analysis.17,18 As a sensitivity analysis, we also performed a random-effects model meta-analysis.19 We calculated the I2 index and the chi-squared p value to assess for heterogeneity among studies.
We also performed a random-effects model meta-analysis to assess the net change in total bilirubin levels in patients with MARS relative to those treated with standard medical therapy. When necessary, the standard error of the net change was estimated from the reported standard deviations of baseline and final total bilirubin values. When necessary, we converted reported median and ranges to the estimates of means and standard errors.20
To evaluate the heterogeneity, we performed subgroup analyses using the Peto fixed-effect model based on a priori selected characteristics, including mean age (<50 vs. $50 years), number of MARS sessions (#3 vs. >3), percentage of albumin dialysate used in MARS (20% vs. <20%), and study quality (defined by Jadad score). The Student’s t-test was used to compare subgroups. The meta-analyses were performed using MetaAnalyst beta version 3.1 (Tufts University, Boston, MA)21 and the metan command (version 9) in Stata version 11 (Stata Corporation, College Station, TX).22
A total of 1,529 potentially relevant citations were identified and screened, of which 515 originated from MEDLINE (Pubmed), 998 from EMBASE, and 15 from the Cochrane Registry of Controlled Trials database. In addition, one abstract originated from an annual scientific meeting. Of these, 454 articles were identified, which specifically dealt with MARS or other similar ECAD systems and 102 relevant articles were retrieved for detailed evaluation. Of these, 10 fulfilled eligibility criteria (Figure 1). Nine studies were RCTs8,14,23–29 and three were nonrandomized comparative studies.7
Characteristics of the individual studies are presented in Table 1. The studies were all carried out within the last 10 years and varied in sample size from 13 to 189 patients. All but two studies24,28 had a predominance of men. Mean ages ranged from 42 to 63 years. Where reported, the mean CTP score ranged from 11.6 to 12.9 (CTP class C) implying that most patients enrolled had advanced liver failure. The mean baseline serum albumin levels ranged from 2.4 to 3.3 g/dl with mean prothrombin time values ranging from 20.4 to 51 seconds and mean baseline total bilirubin levels ranging from 8.5 to 29.5 mg/dl, where reported. The etiology of liver disease in most patients was alcohol ingestion or viral hepatitis, with one study by design recruiting patients exclusively with acute liver failure secondary to cardiogenic shock,26 another including patients with liver failure secondary to acetaminophen toxicity,28 and a third including patients with liver graft dysfunction.7 Most studies enrolled patients with acute-on-chronic liver failure30 (however, the inclusion criteria defining liver failure differed as described in Table 2) with the etiology not reported in two studies.7,8 One study included patients with hyperacute liver failure28 (<1 week from the onset of jaundice)31 exclusively and another two studies included patients with acute liver failure7,26 (<26 weeks from the onset of liver disease).1 One study included patients exclusively with type 1 hepatorenal syndrome as a component of the acute-on-chronic liver failure.24
All the studies used the ECAD system MARS in their intervention arm with some differences, as described in Table 3. The mean number of MARS sessions per patient ranged from 1 to 10 sessions with durations of 6 to 8 hours per session, where reported. The strength of albumin dialysate used ranged from 10% to 20% where reported. Five studies reported the use of anticoagulation during the MARS sessions,7,14,24,26,29 with the use of minimal or no anticoagulation in 2 studies,27,28 one of which decreased the body temperature to 36°C in an attempt to minimize clotting.28
Death was ascertained in-hospital in two studies,7,26 at 28 days in one study,8 at 30 days in two studies,24,27 at 180 days in one study,25 and at 1 year in one study.32 The duration of follow-up was not documented in one study.28 The net change in total bilirubin levels was ascertained from six studies where bilirubin levels were documented7,14,24,26,28,29 with durations of follow-up ranging from 1 to 30 days. The improvement in West-Haven grade of hepatic encephalopathy was documented in four studies8,14,25,27 with durations of follow-up ranging from 5 to 30 days.
Overall, the quality of the study was poor (arbitrarily defined as 0–1 on the Jadad scale) to fair (2–3). Because no RCT was blinded as a result of the nature of the intervention, no study could be rated as good (4–5) by the Jadad quality score. In brief, randomization was adequate in five trials14,24,25,27,29 of the six studies that documented the procedure14,24–27,29 with attrition rates of 8%27 and 16%25 in two of them and no attrition in the rest. One of these studies described a crossover arm purely for ethical purposes.26 One study was randomized with no description of the procedure8 and three other studies were not adequately randomized.7,28,32 The concealment of allocation was only reported in two studies.24,25 Among the six studies that provided an optimal documentation of their analysis,8,14,24,25,27,29 five used an intention-to-treat analysis.14,24,25,27,29
Data Synthesis and Analysis
Effect of MARS on total bilirubin levels. The six studies that reported a change in total bilirubin levels analyzed 128 patients (Figure 2). By meta-analysis, the use of MARS resulted in a significant decrease in total bilirubin levels (net change−7.0 mg/dl; 95% CI−10.4,−3.7 mg/dl; p < 0.001). The studies included differed considerably in their sizes and quality scores; however, there was no evidence of statistical heterogeneity of effects (I14;2 = 0%; p = 0.85).
Effect of MARS on hepatic encephalopathy. The four studies that reported an improvement in West-Haven grade of hepatic encephalopathy analyzed 268 patients (Figure 3). By meta-analysis, the use of MARS resulted in a threefold higher odds of improvement in hepatic encephalopathy (OR 3.0; 95% CI 1.9, 5.0; p < 0.001). The studies differed considerably in their sizes and quality scores, and the study findings were statistically heterogeneous (I14;2 = 79%; p = 0.02).
Effect of MARS on mortality. The eight studies that reported mortality analyzed 497 patients (Figure 4). By meta-analysis, the use of MARS was associated with an overall statistically nonsignificant 9% reduction in mortality (OR 0.91; 95% CI 0.64, 1.31; p = 0.62). Only one study reported a statistically significant reduction in mortality (OR 0.14; 95% CI 0.03, 0.81).27 The studies differed considerably with respect to a number of variables, including their size, quality, and MARS delivery, and the study findings were heterogeneous (I14;2 = 47%; p = 0.07).
Sensitivity analyses and subgroup analysis. To explore the robustness of our findings in the Peto fixed-effects model meta-analyses, we repeated the meta-analyses using the random-effects model. As shown in Figures 2–4, the random-effects models displayed similar effect estimates.
We performed subgroup analyses to explore possible explanations for the heterogeneity of effects (Figure 5). In brief, the subgroup analyses revealed that mean age within the studies (#50 vs. >50 years) and the number of MARS sessions (#3 vs. >3 sessions/patient) did not significantly influence the net change in total bilirubin levels or the reduction in mortality. The strength of albumin dialysate (<20% vs. 20%) and the quality of studies (Jadad score 0 vs. 3) did not significantly influence the reduction in mortality either. Because of the small number of studies in each group, these variables could not be analyzed with regard to a net change in bilirubin levels or hepatic encephalopathy. Although not significant, there were trends to suggest a larger reduction in total bilirubin levels (p = 0.27) and mortality (p = 0.16) in patients undergoing a higher number of MARS sessions (>3 sessions) and a higher mortality reduction among older patients (>50 years) (p = 0.37).
Safety analysis of MARS. Adverse events related to the use of MARS were not commented on in four studies8,14,26,32 and were absent in two other studies.7,28 Two studies reported thrombocytopenia related to the use of the device with no transfusion requirements or serious consequences.24,29 One study reported serious adverse events in nine of 39 patients, which might have been related to the use of MARS.25 These included hemodynamic instability, thrombocytopenia, and acute renal failure. None of them resulted in death. One final study reported 17 possible adverse events related to the use of MARS among 12 patients, with only one death when compared with six deaths among 12 patients undergoing standard medical therapy.27 These events included bleeding, coagulopathy, anemia, and catheter-related sepsis. Because of lack of consistency of reporting, these safety data could not be meta-analyzed.
Extracorporeal albumin dialysis, in particular MARS, has attracted significant attention since its development. However, until recently, controlled trials have been few and far between because of limitations imposed by design. The present meta-analysis, of all reported controlled studies, suggests that the use of MARS in patients with acute, acute-on-chronic, and hyperacute liver failure is associated with a significant reduction in total bilirubin levels and marked improvement in hepatic encephalopathy but has no significant impact on all-cause mortality.
Although prior meta-analyses have examined the impact of MARS on survival, the number of studies included (and hence the number of patients) have been small with results that were either inconclusive or included studies of various designs.33,34 In addition, none of these meta-analyses specifically examined improvement in hepatic encephalopathy, bilirubin clearance, and the impact of specific characteristics of the albumin dialysis system on outcomes.
Our data synthesis has several strengths. It includes the largest number of patients analyzed to date and despite the heterogeneity among studies, the results persisted in almost every subgroup analysis. One possible argument against this meta-analysis is the diverse nature of the patient population with regard to the severity and etiology of liver failure.35 However, although the etiology and definition of liver failure differed among the patients included in this review, the majority of them had advanced liver failure with similar mean CTP scores (11.6–12.9; class C) reducing diversity. Moreover, our results are in agreement with those observed in the largest study to date.8
There are however several important limitations to consider. Significant heterogeneity among studies limited our analysis of the impact of MARS on mortality and improvement in hepatic encephalopathy. The study periods, as well as the periods of follow-up in particular, differed considerably. Another shortcoming is the use of differing definitions for liver failure as inclusion criteria among the trials (Table 2). We can only speculate whether including patients with similar etiologies of liver disease or similar biochemical parameters would have yielded different results. The number of patients analyzed, though the largest of any such analysis to date, is still relatively small. The small number of studies included for the impact of MARS on hepatic encephalopathy in particular precluded a subgroup analysis among this cohort.
Of interest is the fact that our analysis revealed a statistically significant reduction in total bilirubin levels among patients with liver failure with the use of MARS indicating effective clearance of albumin-bound substances. In vitro and animal studies have shown bile acids and bilirubin to be toxic to nephrons and hepatocytes.36,37 However, our analysis could not display a significant mortality benefit with the use of MARS in such patients. Adverse events related to the use of MARS could not be summarized because of the inconsistent reporting of such events.
Although the number of studies was small, we also observed a statistically significant improvement in hepatic encephalopathy suggesting a clinical benefit with the use of MARS among patients with liver failure.
The studies included in our review also differed in certain characteristics of the albumin dialysis system (MARS) used (Table 3). We looked at the impact of the number of MARS sessions per patient on mortality and total bilirubin levels. Although not statistically significant, there was a trend to suggest a larger reduction in total bilirubin levels and mortality in the group undergoing a higher number of MARS sessions (>3 sessions). An in vitro study has suggested that a higher concentration of albumin dialysate used in the MARS system would result in increased clearance of albumin-bound substances.38 Because of the lack of variation in strength of albumin dialysate use among the studies looking at a change in bilirubin levels, we could not assess the impact of this variable; however, we were able to analyze its impact on mortality. Not surprisingly, there was no change in survival with alterations in the strength of albumin dialysate used.
Data from large RCTs examining the impact of MARS on survival (with up to 110 patients in the FULMAR trial and 189 patients in the RELIEF [Recompensation of Exacerbated Liver Insufficiency With Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure] trial8 included in this analysis) are still in the process of being analyzed.
In conclusion, in the present meta-analysis, the use of MARS among patients with acute, acute-on-chronic, and hyperacute liver failure appears to successfully reduce total bilirubin levels and clinically improve hepatic encephalopathy; however, an impact on all-cause mortality was difficult to assess. Hence, the clinical utility of this device in the critical care setting for symptomatic benefit may be implied, with inconclusive evidence of an impact on short- or long-term survival. The heterogeneity of the studies included variable follow-up periods and variable definitions of liver failure that preclude definitive conclusions.
Although further larger, adequately powered and more homogeneous studies are required to provide more definitive conclusions, this analysis does provide food for thought on the benefits of MARS in patients with liver failure awaiting spontaneous resolution or as a bridge to transplantation.
Search terms used the following:
- 1.Medline (Pubmed):
“Liver, Artificial”[Mesh] AND (“Liver Failure”[Mesh] OR “Bilirubin”[Mesh] OR “Hepatic Encephalopathy”[Mesh] OR “Survival”[Mesh] OR “Liver Diseases”[Mesh] OR “Mortality”[Mesh] OR “mortality “[Subheading] OR “Survival Rate”[Mesh] OR “Liver Failure, Acute”[Mesh] OR “Disease-Free Survival”[Mesh] OR “Liver Diseases, Alcoholic”[Mesh])
- a.exp liver failure/ and exp albumin dialysis/(180)
- b.exp liver failure/ and artificial liver.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] (510)
- c.exp liver failure/ and exp liver support/(274)
- d.exp liver failure/ and MARS.tw. (211)
- e.exp liver failure/(17975)
- f.molecular adsorbent recirculating system.tw. (129)
- g.5 and 6 (99)
- h.1 or 2 or 3 or 4 or 7 (796)
- i.extracorporeal liver support.tw. (119)
- j.exp albumin dialysis/ (271)
- k.exp bilirubin/ (17996)
- l.artificial liver.mp. (1057)
- m.exp survival/ (253640)
- n.11 and 12 (88)
- o.11 and 6 (56)
- p.11 and 9 (26)
- q.11 and 10 (69)
- r.13 and 12 (147)
- s.13 and 6 (42)
- t.13 and 9 (23)
- u.13 and 10 (70)
- v.8 or 9 or 10 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 (998)
- 3.COCHRANE Registry of Controlled Trials: “Liver, Artificial”[Mesh] AND (“Liver Failure”[Mesh] OR “Bilirubin”[Mesh] OR “Hepatic Encephalopathy”[Mesh] OR “Survival”[Mesh] OR “Liver Diseases”[Mesh] OR “Mortality”[Mesh] OR “mortality “[Subheading] OR “Survival Rate”[Mesh] OR “Liver Failure, Acute”[Mesh] OR “Disease-Free Survival”[Mesh] OR “Liver Diseases, Alcoholic”[Mesh])
Supported by Grant Number UL1 RR025752 from the National Center for Research Resources (NCRR). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR. This work would not have been possible without the assistance of Ms. Cathy Guarcello, librarian at the Medical Library, St. Elizabeth’s Medical Center, Boston, MA.
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