Pediatric acute liver failure (PALF) is a rare but life-threatening condition which can lead to multisystem organ failure (MSOF) and death. Liver transplantation (LT) is considered the definitive treatment for patients with acute liver failure (ALF) but, timely, advanced medical therapy has led to survival without it through spontaneous regeneration of the liver. This is particularly important as access to LT remains limited in many parts of the world. Therefore, therapies that bridge patients with PALF and MSOF to liver regeneration form the mainstay of management. The Pediatric Health Information System database in the United States reported an increase in the rate of hepatic spontaneous regeneration from 56% (1999–2004) to 74% (2008–2012) (1).

To understand the rationale of these therapies, it is important to understand the pathophysiology of MSOF in PALF. Hyperammonemia leading to cerebral edema and intracranial hypertension, as well as sepsis with MSOF, are the leading causes of death in children with PALF. Our understanding of systemic inflammation during MOSF has completely revolutionized our approach to managing PALF. In addition to other nontransplant measures (such as early diagnosis and treatment of the underlying etiology, neuromonitoring and neuroprotection, supportive therapies including rationale use of blood products), extracorporeal therapies now have a major role in these patients (2,3). Although strictly not an extracorporeal liver assist device, continuous renal replacement therapy (CRRT) is used as a first-line extracorporeal system to treat hyperammonemia, fluid overload, and acute kidney injury (AKI) associated with PALF. For example, small water-soluble toxins such as ammonia can be removed by CRRT. However, larger protein-bound toxins and pro-inflammatory molecules that lead to hepatic encephalopathy, cardiovascular instability, and MSOF require an extracorporeal device with large pore sized membrane and immune modulatory properties. Therapeutic plasma exchange is one such extracorporeal modality which can perform detoxification, as well as synthetic- and immune-modulating functions of the liver (4).

Since Larsen et al (5) published the first open randomized controlled trial (RCT) of plasma exchange in patients with ALF in 2016, high-volume plasma exchange (HVPE) has been added to the therapies used in adult patients. HVPE is included in the European Association for the Study in Liver Disease guidelines as a level I, grade 1 recommendation in management of ALF (6). Similarly, the American Society for Apheresis recommends HVPE for use in ALF (7).

In this issue of Pediatric Critical Care Medicine, Vo et al (8) from Vietnam describe their experience of use of total plasma exchange combined with CRRT in children with dengue-associated ALF. Dengue-associated ALF is a common cause of infection-associated ALF in South-East Asia and India (9). Vo et al (8) have carried out a before-versus-after comparison of outcomes referenced to their practice of using CRRT alone before 2018, versus their current practice of combining total plasma exchange with CRRT. The recent practice of a combination intervention was associated with improvement in hepatic encephalopathy, liver transaminases, coagulation profiles, blood lactate, and serum ammonia levels. Of note, ALF in dengue fever and shock syndrome is mediated by immune and inflammatory responses that lead to a cytokine storm. This new study shows adds to the evidence that plasma exchange during PALF seems to bridge patients to recovery without the need for LT. Hence, in a resource-limited country where access to LT is limited, the combination of CRRT and total plasma exchange in dengue-associated PALF could be an attractive option. The rationale being that the combination therapy reduces hyperammonemia and damage-associated molecular patterns (DAMPs), which together cause activation of the innate immune system. Therefore, the new report sets the stage for use of combined CRRT and total plasma exchange in patients with other causes of PALF.

Despite this optimistic note there are, however, some important additional considerations. First, use of total plasma exchange in PALF is subject to a few limitations, for example, center-based availability of resources, patient severity of illness, underlying cause of PALF, and physician preference. At present, experience with total plasma exchange in PALF is limited to case series (10,11). Most clinicians use total plasma exchange in immune-mediated ALF, Wilson’s disease, and resistant coagulopathy. In contrast, Vo et al (8) have used total plasma exchange in conjunction with CRRT in those patients who had grade III/IV hepatic encephalopathy, hyperammonemia, and high lactate.

Second, what is the “dose” of the plasma exchange intervention that is needed in PALF? Larsen et al (5) had used HVPE (up to 12 L per session) in adult patients. In children, Pawaria et al (12) studied 37 children with PALF due to Wilson’s disease, half of whom received HVPE plus standard medical therapy, and half received standard medical therapy alone. Transplant free survival at 90 days was present in 47.3% of the HVPE group versus 16.6% of the standard medical therapy group. The study by Vo et al (8) had a small sample size, only included children with Wilson’s disease (which can be classified as acute-on-chronic liver failure rather than ALF), and excluded patients at high-risk of death (i.e., those with sepsis, AKI, and hemodynamic instability). Therefore, it remains an open question whether HVPE in children with PALF also results in improved survival as seen in adults. Large volumes of substituted fresh frozen plasma (FFP) are associated with high cost, more burden for the blood bank, citrate toxicity leading to hypocalcemia and alkalosis, volume overload, and reduced plasma concentrations of prescribed medications. Taking this evidence together, we need to ask whether HVPE has more advantage to standard-volume plasma exchange, 1.5 to 2 times plasma volume? Here, we can draw on experience from a few studies. In an open-label RCT from India, 40 consecutive patients with ALF were randomized 1:1 to standard medical therapy with or without the addition of standard-volume plasma exchange (13). The standard-volume plasma exchange was associated with higher 21-day transplant free-survival. There was also a significant decrease in levels of pro-inflammatory cytokines, and an increase in anti-inflammatory cytokines, along with decreases in endotoxin and DAMPs. In another study, Thomas et al (14) showed survival in PALF caused by rodenticide toxicity if supported by low-volume plasma exchange using only 50% of circulating plasma volume. Vo et al (8) used standard volume (1.5 × plasma volume) plasma exchange and reported significant associations with improved biochemistry. In King’s College Hospital, London, it is our personal practice to use standard volume plasma exchange in patients with immune-mediated ALF, MSOF with rising vasopressor requirements, and grade III/IV hepatic encephalopathy. Similarly, number of total plasma exchange sessions, the interval between sessions, the total duration of treatment, and the type of substitution fluid (FFP or albumin or a combination of FFP and albumin) are important points to be considered.

Third, readers should be aware of technical challenges when combining total plasma exchange with CRRT in children. Some clinicians in our field would pause CRRT for a period of 4–6 hours so that total plasma exchange can be carried out, but this approach is associated with the risks caused by changing multiple circuits or blood loss, increased cost, and rebound hyperammonemia when stopping CRRT. In adult patients, two vascular catheters can be used at two different sites to deliver CRRT and total plasma exchange simultaneously using two different machines. In children, the technical issues of multiple access sites and patient stability means that this approach is not feasible. However, both CRRT and total plasma exchange can be used simultaneously in children via one vascular access site using the tandem therapy in series or in parallel (4,15). This technique requires staff training and expertise. In a series from Tokyo, Ide et al (16) looked at the effect of combined HVPE with CRRT in infants with ALF less than 1 year old. CRRT was continued until LT, while plasma exchange using 100 mL/kg of FFP per treatment was used once daily for 6 to 8 hours until the recovery of coagulopathy. The plasma exchange circuit was attached as a side flow to the CRRT circuit and was removed after each course of plasma exchange.

Last, there is the important question of when to stop total plasma exchange—or put another way, what are the end points of treatment? Most studies continue plasma exchange for a range of unspecified durations, for example, until the patient dies, until a patient improves, or when the patient undergoes LT. An area that triggers the most debate is the effect of total plasma exchange on liver regeneration, since plasma exchange may be removing molecules involved with hepatic regeneration along with molecules causing toxicity (17). Kupffer cells have a major role in the priming stage of hepatocyte regeneration via the secretion of interleukin-6 and tumor necrosis factor-alpha, which are the same molecules that initiate inflammation (18). If we remove these molecules during the inflammatory phase, it will dampen systemic inflammation. However, if we remove them during the regenerative phase, regeneration may be inhibited. Monitoring markers of regeneration (alpha-fetoprotein, international normalized ratio, phosphate, hepatic growth factors) after each session of total plasma exchange would be ideal. In addition, other biomarkers may help to define the stage of hepatic injury in ALF and guide the timing of extracorporeal therapy, including plasma exchange.

In conclusion, the increase in PALF-related “transplant-free” survival over the last few decades (1) has occurred at the same time as reduced occurrence of fulminant cerebral edema and intracranial hypertension, and therapies to control inflammation and immune modulation, such as the combined use of CRRT and total plasma exchange. Significant progress has been made in the treatment of PALF, which is well-demonstrated by the new data from Vo et al (8) in dengue-associated ALF. However, before we embark on widespread application of combining plasma exchange with CRRT in the management of PALF, we need to think more about the indications, when to start and when to stop, therapeutic endpoints, and biomarkers of illness trajectory and treatment unresponsiveness.

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