Published online Jan 14, 2020. doi: 10.3748/wjg.v26.i2.219
Peer-review started: October 6, 2019
First decision: November 4, 2019
Revised: December 21, 2019
Accepted: January 1, 2020
Article in press: January 1, 2020
Published online: January 14, 2020
Processing time: 98 Days and 12.9 Hours
Liver failure portends a high mortality without successful liver transplantation. High volume plasma exchange has been included in European guidelines as level I, grade 1 recommendation in management of acute liver failure possibly by removal of plasma cytokines and drivers of systemic inflammatory cascade through plasma exchange. In recent years, there is increasing interest in plasma exchange for the treatment of liver failure, as there is proven improvement in survival in those who do not undergo a liver transplant. Prior to this study, there were several other cohort studies reporting the benefits of plasma exchange in acute liver failure (ALF), however the volume and duration of plasma exchange varies. The evidence for use of high volume plasma (HVP) in acute-on-chronic liver (ACLF) is less robust, but the use of plasmapheresis (not high volume) has been reported in literature.
While there is good evidence to use plasmapheresis in management of acute liver failure especially when there is no liver donor in sight, the optimal volume and duration of plasma exchange is unclear. Donor plasma is a finite resource, and HVP is not without side effects such as hypocalcemia requiring rapid calcium replacement. Several cohort studies showed benefit in standard volume plasmapheresis in management of ALF however no head to head comparisons have been done. Furthermore use of plasma exchange in ACLF, while has been reported to improve survival in literature, has not been widely accepted as standard treatment due to lack of high level evidence.
This study aims to summarize and analyze the current literature for use of plasmapheresis in patients with ACLF and ALF and its effect on mortality particularly in the non-transplanted patients. In addition, the review will summarise the current literature on volume of plasma used during exchange, the duration and frequency of plasma exchange in both ALF and ACLF. It is our hope that this review will serve as a valuable resource by analyzing available literature as well as illustrate the knowledge gaps and unmet needs for future researchers in this field.
This systematic review uses guidance from the PRISMA checklist. Databases MEDLINE via PubMed, and EMBASE were searched and relevant publications up to 30 March, 2019 were assessed. Forty-four studies were shortlisted and included in Tables 2-5. In addition, pooled odds ratios and its corresponding 95% confidence intervals were respectively calculated for 30- and 90-d mortality in ACLF patients using the random effects model. We were unable to do this for ALF group due to paucity of studies and lack of critical information from eligible studies.
There is good evidence for use of high volume plasma exchange in ALF though the optimal duration and volume of plasma exchange at present is uncertain. While high quality randomized control trials are lacking, the use of plasma exchange in ACLF can be considered. Survival in non-transplanted patients was improved in all four studies in patients with ACLF comparing plasma exchange vs standard medical therapy (SMT). Using the aforementioned studies, plasma exchange based therapy in ACLF compared to SMT improved survival in non-transplanted patients at 30 and 90-d with a pooled OR of 0.60 (95%CI: 0.46-0.77, P < 0.01). There remains insufficient evidence to extrapolate the findings which recommend plasma exchange in patients with ACLF. Whether an individualized plasma exchange regime for each patient with liver failure can be personalised based on biomarkers remains unknown. More head to head trials will need to be done.
While there has been good evidence for the use of high volume plasma exchange in acute liver failure to improve survival, due to the paucity of good-quality studies, at present it is unknown if a lower volume or a longer (or shorter) duration (i.e., beyond the first three consecutive days) of plasma exchange will achieve equal or improved survival in ALF. In patients with ACLF, plasma exchange based therapy compared to SMT improves survival at 30 and 90-d in non-transplanted patients. The duration of plasma exchange therapy used in most studies in ACLF was clinical response driven and often intermittent; and not with high volume plasmapheresis. The etiology of ACLF was also mostly HBV related; the definitions of ACLF used are varied and not requiring the diagnosis of more than one organ failure and diagnosis of cirrhosis. At present, there is insufficient evidence to extrapolate the use of high volume plasmapheresis to patients with ACLF.
There are unanswered questions in use of plasma exchange in liver failure: For example, the optimal type, duration, frequency, volume and time to plasma exchange one should use for ALF, and ACLF, if at all. Future randomized control trials studying the use of plasma exchange and or other liver assist devices in liver failure should aim to answer these questions. It is also essential to find out if there is an objective measure of a point of no return whereby plasma exchange or plasma exchange-based ALSS will be futile, whether in ALF or ACLF. Subsequent clinical trials in ACLF or ALF should include study of biomarkers that can predict the success of therapy. This might further shed light on the optimal duration, volume of plasma exchange and or alternative liver support therapy since there is vast heterogeneity in patients with ALF and ACLF and one regime may not fit all. Finally, the definition of ACLF in each study needs to be clearly stated, in order to allow clinicians to assess applicability of study results to their patients.