Transplant Free Survival in Patients with Acute Liver Failure Treated with Extracorporeal Therapies

Introduction

Acute liver failure (ALF) carries a high mortality.^1,2 Liver transplant is the definitive treatment along with standard medical support. In a country like India, many patients needing liver transplantation do not get one due to the lack of donor organs or financial and social reasons. In the absence of or as a bridge to liver transplant, several assist therapies have been tried; plasmapheresis and continuous renal replacement therapy (CRRT) are two such modalities.

In ALF, the pathophysiology primarily involves a massive inflammatory response triggered by widespread hepatocyte necrosis, leading to a systemic inflammatory response syndrome (SIRS) with cascading effects on other organs.³ This causes dysfunction in multiple systems due to the liver’s inability to clear toxins and maintain homeostasis, ultimately resulting in multi-organ failure.

In recent years, there has been growing interest in plasma exchange as a treatment for liver failure. Since Larsen et al. published the first open randomized control trial (RCT) of plasma exchange in patients with ALF in 2016, plasmapheresis has been added to the treatment armamentarium.⁴ Currently, plasma exchange has been included in European guidelines as a level I, grade 1 recommendation in the management of ALF.⁵ The proposed mechanism is the removal of plasma cytokines and drivers of the systemic inflammatory cascade through plasma exchange.

CRRT removes excess fluids and uremic toxins from the patient’s blood. The process is slow, gentle, and continuous, typically performed over 24 hours or more, enabling fluid homeostasis. CRRT has gained attention for managing patients with combined liver and kidney failure. Hyperammonemia has been associated with intracranial hypertension and mortality in patients with ALF. A study conducted by Cardoso et al. showed that CRRT reduces serum ammonia levels and improves outcomes in ALF.⁶

In this study, we evaluated the utility of therapeutic plasma exchange with CRRT as a bridge to liver transplant or spontaneous recovery of liver functions in patients with ALF. The primary objective was to study the transplant-free survival rate of patients with ALF treated with extracorporeal therapies such as plasmapheresis/CRRT or both. We also ascertained the factors that increased the risk of 30-day mortality in ALF treated with these measures.

Materials and Methods

This is a retrospective cohort study conducted in patients with ALF admitted to the medical intensive care unit who underwent plasmapheresis/CRRT or both. All adult patients with ALF meeting the American Association for Study of Liver Diseases 2005 (AASLD 2005) definition were included. Data were retrieved from electronic medical records. Demographic and biochemical parameters, KCC, Acute Liver Failure-Early Dynamics (ALFED) score, Model for End-Stage Liver Disease (MELD) score, renal function test, liver function test, inotropic requirements, need for mechanical ventilation, sepsis, and need for liver transplantation were recorded. The 30-day mortality rate and transplant-free survival were calculated.

Multifiltrate, Multifiltrate pro (Fresenius), and Prisma flex (Baxter) were used for CRRT. Continuous venovenous hemodiafiltration was used for CRRT. Multibic fluid was used for replacement, and heparin (with or without) was used as the anticoagulant.

Low-volume plasmapheresis (20 mL/kg) was performed; fresh frozen plasma was used for replacement.

ALF was defined as a potentially reversible condition, the consequence of severe liver injury, with the onset of encephalopathy within days to a few weeks of the appearance of the first symptoms (usually jaundice) and in the absence of preexisting liver disease. Patients with chronic liver disease/acute on chronic liver disease, CKD, brain death/irreversible brain injury, sepsis/shock at initial presentation, acute respiratory distress syndrome, and those on inotropic support at hospital admission or multiple organ dysfunction syndrome at admission were excluded.

Results

The total number of patients with ALF over 5 years was 510. Of these, only 79 patients satisfied the inclusion criteria. Twenty-six (32.9%) patients received only plasmapheresis, 16 (20.3%) received only CRRT, and 37 (46.8%) received both treatments. A total of 18 patients from the plasmapheresis group, five from the CRRT group, and 21 from the combined group survived without undergoing transplant. Four patients from the plasmapheresis group, one from the CRRT group, and six from the combined group had to undergo transplantation. Four patients from the plasmapheresis group, 10 patients from the CRRT group, and 10 patients from the combined group died [Figure 1].

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Figure 1:

Patients included in the study. CRRT: Continuous renal replacement therapy.

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The baseline demographic and clinical parameters of the 79 patients included in the study are presented in Table 1. The mean age was 30.75 ± 16.29 years, with a male predominance (62%). AKI was present in 36.7% of patients. The mean INR was 3.63 ± 1.87, and the total serum bilirubin was 12.23 ± 8.58 mg/dL. A majority (81%) underwent plasmapheresis, with a mean of three sessions, and the mean CRRT duration was 58.47 ± 39.71 hours. Inotrope use and mechanical ventilation were required in 60.8% of cases each. The mean MELD score was found to be 37, and the mean ALFED score was 2.

Discussion

In the context of ALF, plasmapheresis may be helpful for the removal of toxic metabolites and the reduction of inflammatory mediators. The activation of the immune system releases pro-inflammatory cytokines and other mediators that worsen liver injury and contribute to multiorgan dysfunction.⁷ Plasmapheresis can remove these inflammatory markers, and thus potentially reduce systemic inflammation. Some studies suggest that plasmapheresis improves survival in certain cases, but results vary depending on the underlying cause of ALF, the stage at which it is initiated, and the presence of other organ dysfunctions.⁸

CRRT is primarily used for managing AKI in critically ill patients, but it also plays a supportive role in patients with ALF. In ALF, renal dysfunction is common, either due to hepatorenal syndrome (HRS) or direct kidney injury.^9-11 CRRT offers slow and continuous dialysis, which can help manage fluid overload, correct electrolyte imbalances, and remove toxins that the liver is unable to clear.^6,12 In cases of ALF with significant renal impairment, CRRT can provide vital support by improving acid-base balance and mitigating electrolyte disturbances, which may be exacerbated by the liver’s inability to metabolize and excrete waste products properly. Some studies have suggested that CRRT, particularly when used in conjunction with liver support techniques like bioartificial liver systems, may improve survival in patients with AKI in the setting of ALF.¹² Compared to intermittent hemodialysis, CRRT is better tolerated in critically ill patients with hypotension or severe hemodynamic instability. CRRT can act as a supportive treatment by maintaining homeostasis while awaiting liver recovery or transplantation.^12,13

The safety and feasibility of the combined therapies were limited to case reports and case series.¹⁴ There are no defined standards for these procedures; tandem procedures connected in series or parallel have been reported in the literature.^15,16 This combination can be particularly useful in patients with severe encephalopathy, marked renal dysfunction, or both.

Amongst the various artificial liver support systems (ALSS) available today, only therapeutic plasma exchange has been shown to improve survival in ALF patients, with encouraging data on survival benefits and provide a successful bridging to transplant.¹⁷ Therapeutic plasma exchange also has immunomodulatory effects on the innate immune system and restores monocyte and neutrophil functionality.¹⁸ The American Society for Apheresis (ASFA) recommends plasmapheresis as the first choice of therapy for acute liver failure.¹⁹ The decision to initiate these therapies requires careful consideration of the patient’s overall prognosis, liver transplant eligibility, and the reversibility of the liver failure.

The Tamil Nadu Chapter of the Indian Society of Gastroenterology (TN-ISG) guidelines are used for managing patients with rodenticide poisoning, particularly those developing hepatotoxicity (liver damage). Presence of deranged LFT and any of the following three after 48 hours of standard medical treatment: (1) INR>4, (2) Worsening INR on serial tests (After 2 doses of vitamin K 4 hours apart and repeat INR) (3) altered behavior/consciousness are indications for initiating Plasmapheresis in patients with ALF with rodenticide poisoning admitted in our institution. We have been using similar guidelines for initiation of these therapies in ALF patients. This guideline focuses on improving survival through supportive care, especially in cases where liver transplantation is not immediately available.²⁰ Serum ammonia > 300 umol/L is an indication for initiating CRRT in ALF.

Among 79 patients with ALF, 44 (55.69%) survived without liver transplantation using plasmapheresis and CRRT as treatment, compared to 22.2% (n=20) who used SMT in the study conducted by Larsen et al.⁴

The 30-day mortality rate in our study was 30.37% (n=24) among 79 patients with ALF who used plasmapheresis/CRRT or both as treatment modalities compared to 52.2% in the SMT group in the study conducted by Larsen et al.⁴ This difference in mortality rate is statistically significant, and the p-value is 0.007.

The transplant-free survival rate is 55.69% (n=44) among 79 patients with ALF who used plasmapheresis/CRRT or both as treatment modalities compared to 22.2% (n=20) in the SMT group(n=90) in the study conducted by Larsen et al.⁴ This difference in transplant-free survival rate is statistically significant, and the p-value is <0.0001. Additionally, 11 patients (13.92%) in this group underwent liver transplantation compared to 35.6% in the study by Larsen et al. where standard medical treatment was given.⁴ Transplant-free survival rate is better with plasmapheresis and CRRT compared to the standard medical group. Hence, plasmapheresis and CRRT can be used as an effective bridge to liver transplant in patients with ALF.

Our study reveals that the requirement of mechanical ventilation, inotrope requirement, presence of AKI are associated with increased risk of mortality. In the study conducted by Urrunaga et al., it was found that AKI was associated with increased mortality in ALF patients.²¹ The requirement for ventilatory supports, need for vasopressors, and presence of AKI are factors that increased mortality in the study conducted by Saluja et al.²²

Alshamsi et al. conducted a systematic review and meta-analysis of RCTs to examine the efficacy and safety of extracorporeal therapies in ALF and found that extracorporeal therapies reduce mortality and improve hepatic encephalopathy in patients.²³

This single-center, retrospective study was conducted in a relatively small group (n=79). Hence, more large-scale, multicenter trials are necessary to define the roles of extracorporeal therapies in the management of ALF. Inability to control confounding variables, selection bias, and potential for missing data are limitations of this study. Our study did not include long-term follow-up beyond 30 days, which is needed to identify long-term outcomes.

To conclude, this cohort of patients, plasmapheresis and/or CRRT achieved a transplant-free survival rate of 55.7%, indicating a clinically meaningful survival benefit in ALF. These findings support the role of extracorporeal therapies as effective bridging or definitive interventions in the management of ALF, particularly in settings where liver transplantation is not immediately available.

The requirement for mechanical ventilation, inotrope requirement, and presence of AKI were found to be the factors associated with increased risk of mortality in patients with ALF treated with extracorporeal therapies.