Effectiveness of High-Volume Therapeutic Plasma Exchange for Acute and Acute-on-Chronic Liver Failure in Korean Pediatric Patients

Acute liver failure (ALF) is a rare disease with a very high mortality rate even with appropriate treatment [1, 2]. There are two categories of ALF in children: ALF, which occurs without any underlying disease; and acute-on-chronic liver failure (ACLF), which shows acute exacerbation in children with underlying diseases [3]. Both are rare, but when they occur, synthetic and metabolic functions of the liver deteriorate, and toxins and immune substances accumulate in the body, which can lead to multiorgan failure [3, 4].

Standard medical therapy (SMT) is commonly used in patients who develop ALF and ACLF [3, 4]. The purpose of SMT is to treat ALF and ACLF by providing sufficient time for liver regeneration. However, in some cases, SMT has limited effectiveness, and liver transplantation (LT) is eventually required to treat the patient. Among the extracorporeal liver support used in adults, high-volume therapeutic plasma exchange (HV-TPE) has proven to be effective for LT-free survival [5]. In 2019, the American Society for Apheresis recommended HV-TPE as category 1 (accepted as first-line therapy) and grade 1A (strong recommendation, high-quality evidence) in patients with ALF [6]. TPE is also recommended in the European ALF treatment guidelines [3]. Although the use of HV-TPE in adults is recommended, there are limited proven examples of its efficacy in children. Several studies have reported that HV-TPE is effective in children who develop ALF due to Wilson’s disease [7, 8].

Since 2017, our institution has been conducting HV-TPE on children waiting for LT using a prismaflex machine and the TPE-2000 kit. Before LT, we applied HV-TPE to stabilize the condition of the patients. In this study, we aimed to evaluate the effectiveness of HV-TPE in pediatric patients with ALF and ACLF. To the best of our knowledge, this is the first study to evaluate the efficacy of HV-TPE in Korean children with ALF or ACLF.

We reviewed the records of children waiting for LT at Severance Hospital who underwent HV-TPE between January 2017 and August 2021. The timing of LT was determined according to King’s College Criteria (KCC) for non-acetaminophen-related ALF and pediatric end-stage liver disease (PELD) score [9, 10]. All patients underwent SMT, which includes maintaining vital signs, appropriate volume status, and the balance of electrolytes and glucose, and managing intracranial pressure (ICP) in cases of hepatic encephalopathy (HE). Lactulose was used to control hyperammonemia and mannitol was used for ICP management. Renal replacement treatment and ventilation were not administered to all patients and were used only when necessary. Laboratory data was collected for the analysis of liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin (TB and DB), gamma-glutamyl transferase (GGT), ammonia, and coagulation parameter-international normalized ratio (INR), before and after HV-TPE. For statistical analysis, the Wilcoxon signed-rank test and Mann–Whitney U-test were performed using IBM SPSS Statistics for Windows, version 26.0 (IBM Co., Armonk, NY, USA). The statistical significance was set at p<0.05. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Severance Children’s Hospital (IRB number: 4-2022-0233). The requirement for informed consent was waived because of the retrospective nature of the study.

According to numerous guidelines and published papers, in adults, it is helpful to use extracorporeal liver supports, such as molecular adsorbent recycling systems or TPE, when the liver condition rapidly deteriorates, and it helps to increase LT-free survival [5, 6]. To the best of our knowledge, this is the first study to evaluate the efficacy of HV-TPE in Korean children with ALF or ACLF. In our institution, there are limitations when only SMT is used on patients with ALF and ACLF; accordingly, LT is considered a curative treatment. Owing to these limitations, we attempted to determine whether HV-TPE is effective in pediatric patients. In a comparison of toxic substances, liver function tests, and coagulatory profiles before and after the first HV-TPE application, a significant decrease was observed in the values of AST, ALT, TB, DB, GGT, and INR. Based on these results, we suggest that HV-TPE filters toxins from the body and improves coagulation factors to enhance the patient’s condition and prepare for LT in a more stable state.

The most representative complications, such as thrombocytopenia and hypocalcemia, were not statistically significant in our cases [2]. In one study, 10% calcium gluconate was infused during TPE for proactive correction, with frequent arterial blood gas monitoring for ionized calcium [2]. Since hypocalcemia did not occur in our cases, it was sufficient to check the blood test results and replace calcium, if necessary. The platelet count showed an overall decrease after HV-TPE; however, this was not statistically significant. It is unclear whether such a decrease in platelet count is either due to ALF and ACLF or the implementation of HV-TPE.

It has been reported that HV-TPE is effective in reducing ammonia and is helpful for HE [11, 12]. An overall decrease in ammonia level was observed in our cases, but the decrease was not statistically significant. This can be interpreted in two ways: First, the number of patients was too small to achieve statistical significance. Second, the TPE filter has a structure that is suitable for filtering medium-sized molecules. Ammonia is a small molecule that can pass through the membrane pores of TPE relatively easily compared to other types of molecules. Applying CRRT, which uses a filter with a membrane pore smaller than that of TPE, is more effective in removing ammonia. Five of the eight patients who had CRRT with HV-TPE had a drop in their overall levels of ammonia. In the case of HE, most patients were sedated for ventilator application, CRRT administration, or line insertion. The post-TPE HE status could not be identified.

To confirm the effects of repetitive HV-TPE, the blood test results before and after the first and second HV-TPE procedures were compared. The blood test showed an overall decrease in numbers, with a few showing statistical significance. When repetitive HV-TPE treatments were performed, there was no association between the number of treatments and post-trial blood test results, but the pre-trial test results improved. It can be inferred that the HV-TPE procedure does not affect the patient’s liver function, but it plays a significant role in providing the time for liver regeneration when multiple HV-TPE treatments are performed. Moreover, we compared the initial INR value and TB and albumin levels (components of the PELD score and KCC) of the single-treatment TPE trial group with those of the two-treatment TPE trial group until LT was completed. There was no difference between these variables, which indicates that a simple blood test has limitations in predicting the time to LT.

A limitation of this study was the small sample size. The incidence of ALF and ACLF was low, resulting in statistical limitations. Further studies with larger sample sizes are required. Another limitation is the timing of the application. In the case of HV-TPE, there is no clear indication of its application. For example, in the case of LT, our institution uses the PELD score and KCC to determine whether to perform LT. However, there is no clear standard for the application of HV-TPE; therefore, it can be applied when TB elevation is observed, when organ failure progresses owing to ALF, or when HE progresses. At our institution, HV-TPE was administered to patients who required LT due to ALF or ACLF. A clear indication of the application of HV-TPE must be established to compare its effects. This is consistent with the findings of other studies that have shown that HV-TPE is used to increase the time for liver regeneration [13, 14].

There are several difficulties associated with administering TPE to children. Most children receive a living-donor liver from their parents, due to which transplantation proceeds rapidly. Others require a hemocatheter for TPE, where line insertion becomes another hurdle in pediatric patients. At the onset of TPE, the patient’s PV may be filtered simultaneously, resulting in temporary instability. Vital instability can be adjusted by using transfusions for volume supply and inotropic agents simultaneously with the initiation. As demonstrated in our study, the advantages of TPE include the removal of toxins and improved coagulation. In addition, since living-donor transplants require a donor examination before LT, TPE provides adequate time to perform such examinations. Considering these limitations and benefits, it will be helpful for patients to actively use TPE when necessary.

In the future, it will be necessary to collect and analyze more cases of TPE treatment in children. Accurate indications of how to apply TPE must be established to appropriately apply it to children, if necessary. In addition, to confirm the results of TPE application, research on the relationship between TPE usage and surgical performance, postoperative conditions, and survival is also needed. Also, research is needed to compare the effectiveness of HV-TPE in children with and without LT.

In conclusion, HV-TPE can remove accumulated toxins and improve coagulation. Therefore, we concluded that HV-TPE stabilizes the condition of the patient and can be regarded as a representative bridging therapy before LT.