Low-Volume Plasma Exchange to Treat Children with Acute Liver Failure

In severe cases with acute liver disease extrahepatic manifestations such as hepatic encephalopathy (HE) and renal failure may evolve. The clinical manifestation with HE defines acute liver failure (ALF) and refers to adult patients. In children, ALF is defined by biochemical evidence of acute liver injury with an international normalized ratio (INR) > 1.5 in the presence of HE or to an INR >2 regardless of the presence or absence of clinical HE. In any case, the prognosis of these children and adolescents is gloomy with a transplant-free survival of only 10–40% and the condition accounts for approximately 11% of liver transplantations done in children.1Squires Jr., R.H. Shneider B.L. Bucuvalas J. et al.Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.J Pediatr. 2006; 148: 652-658Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar,2Kulkarni S.S. Goss C.W. Khan A.S. et al.Outcomes analyses of pediatric acute liver failure subjects listed for liver transplantation.J Pediatr Gastroenterol Nutr. 2022; 74: 750-756Crossref PubMed Scopus (3) Google Scholar In Europe and the USA, paracetamol poisoning is a frequent etiological cause, while acute viral hepatitis seems to be a bigger problem in other parts of the world.3Bernal W. Wendon J. Acute liver failure.N Engl J Med. 2013 Dec 26; 369 (PMID:24369077): 2525-2534https://doi.org/10.1056/NEJMra1208937Crossref PubMed Scopus (784) Google Scholar In India, yet another etiological challenge has evolved namely poisoning with rat exterminators for suicidal intent and is now the most frequent cause of acute liver failure in India.4Reddy M.S. Rajakumar A. Mathew J.S. et al.Liver transplantation society of India guidelines for the management of acute liver injury secondary to yellow phosphorus-containing rodenticide poisoning using the modified delphi technique of consensus development.J Clin Exp Hepatol. 2021 Jul-Aug; 11 (Epub 2020 Oct 6. PMID: 34276154; PMCID: PMC8267358): 475-483https://doi.org/10.1016/j.jceh.2020.09.011Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The extrahepatic manifestations of liver failure with the development of HE and multiorgan failure are often complicated by the development of brain edema, which has previously been the most frequent cause of death especially in younger patients.3Bernal W. Wendon J. Acute liver failure.N Engl J Med. 2013 Dec 26; 369 (PMID:24369077): 2525-2534https://doi.org/10.1056/NEJMra1208937Crossref PubMed Scopus (784) Google Scholar The pathophysiological sequence of events behind this clinical deterioration really comes down to two profound consequences of the failing and necrotic liver. The first is the development of hyperammonemia, as the liver can no longer produce urea. The consequence is that the splanchnic system instead of remove nitrogen becomes a major ammonia-producing organ system.5Clemmesen J.O. Larsen F.S. Kondrup J. Hansen B.A. Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.Hepatology. 1999 Mar; 29 (PMID:10051463): 648-653https://doi.org/10.1002/hep.510290309Crossref PubMed Scopus (539) Google Scholar,6Clemmesen J.O. Kondrup J. Nielsen L.B. Larsen F.S. Ott P. Effects of high-volume plasmapheresis on ammonia, urea, and amino acids in patients with acute liver failure.Am J Gastroenterol. 2001 Apr; 96 (PMID:11316173): 1217-1223https://doi.org/10.1111/j.1572-0241.2001.03706.xCrossref PubMed Google Scholar The second complication is caused by the dying/necrotic liver cells that release large fragments of degrading proteins, that is, damage associated molecular patterns (DAMPs) such as high-mobility group box, DNA and RNA fragments, S100 proteins, hyaluronan fragments, and purine metabolites. This tissue decay not only causes pro-inflammatory activation of intrahepatic macrophages with the release of inflammatory cytokines, but also result in an overflow of DAMPs molecules into the systemic circulation. This overflow of DAMPs also activates monocytes and macrophages in the systemic circulation with further release of pro-inflammatory cytokines.7Larsen F.S. Schmidt L.E. Bernsmeier C. et al.High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.J Hepatol. 2016 Jan; 64 (Epub 2015 Aug 29. PMID: 26325537): 69-78https://doi.org/10.1016/j.jhep.2015.08.018Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar The overflow of DAMPs consists of both lipophilic and hydrophilic molecules and quickly translates into a clinical picture that resembles septic shock, a condition that is further complicated by severe encephalopathy and brain edema.3Bernal W. Wendon J. Acute liver failure.N Engl J Med. 2013 Dec 26; 369 (PMID:24369077): 2525-2534https://doi.org/10.1056/NEJMra1208937Crossref PubMed Scopus (784) Google Scholar In this fragile medical situation, it would be highly desirable to have a procedure that ensures rapid purification of the blood for both hydrophilic and lipophilic substances to reverse the critical condition or prolong survival until liver transplantation can be performed. Before the pathophysiological importance of hyperammonemia and DAMPs was realized, it was assumed that the toxic molecules responsible for the development of multiorgan failure were distributed throughout the extracellular volume, that is, almost 20% of body weight using bilirubin as a toxin marker.8Tygstrup N. Larsen F.S. Hansen B.A. Treatment of acute liver failure by high-volume plasmapheresis.in: Lee WL and Williams R. Acute Liver Failure. Cambridge University Press, 1997: 267-278Google Scholar The idea was to replace “toxic” plasma from the patient with fresh frozen plasma to such an extent that it would replace some of the failing liver's capacity to remove toxic substances. This approach was called high-volume plasmapheresis and was tested during the 1990s and was for pragmatic reasons modified to replace only about 130–140 ml/kg body weight.5Clemmesen J.O. Larsen F.S. Kondrup J. Hansen B.A. Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.Hepatology. 1999 Mar; 29 (PMID:10051463): 648-653https://doi.org/10.1002/hep.510290309Crossref PubMed Scopus (539) Google Scholar,6Clemmesen J.O. Kondrup J. Nielsen L.B. Larsen F.S. Ott P. Effects of high-volume plasmapheresis on ammonia, urea, and amino acids in patients with acute liver failure.Am J Gastroenterol. 2001 Apr; 96 (PMID:11316173): 1217-1223https://doi.org/10.1111/j.1572-0241.2001.03706.xCrossref PubMed Google Scholar,8Tygstrup N. Larsen F.S. Hansen B.A. Treatment of acute liver failure by high-volume plasmapheresis.in: Lee WL and Williams R. Acute Liver Failure. Cambridge University Press, 1997: 267-278Google Scholar,9Clemmesen J.O. Gerbes A.L. Gülberg V. et al.Hepatic blood flow and splanchnic oxygen consumption in patients with liver failure. Effect of high-volume plasmapheresis.Hepatology. 1999 Feb; 29 (PMID:9918909): 347-355https://doi.org/10.1002/hep.510290206Crossref PubMed Scopus (67) Google Scholar In a subsequent randomized, controlled clinical study of 182 adult patients with ALF, high-volume plasma exchange for 3 days was compared to standard medical treatment.7Larsen F.S. Schmidt L.E. Bernsmeier C. et al.High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.J Hepatol. 2016 Jan; 64 (Epub 2015 Aug 29. PMID: 26325537): 69-78https://doi.org/10.1016/j.jhep.2015.08.018Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar The study demonstrated an improvement in overall hospital survival (58.7% vs. 47.8%; HR 0.56; 95% CI 0.36–0.86; p = 0.008). High-volume plasmapheresis before transplantation did not improve survival compared with patients who received standard medical therapy alone (CI 0.37–3.98; p = 0.75). The survival of those patients who fulfilled poor prognostic criteria but were not listed for transplantation due to contraindications (such as severe psychiatric disease or medical comorbidity) was significantly higher in those who received high-volume plasmapheresis as compared to those in receipt of standard medical therapy alone.7Larsen F.S. Schmidt L.E. Bernsmeier C. et al.High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.J Hepatol. 2016 Jan; 64 (Epub 2015 Aug 29. PMID: 26325537): 69-78https://doi.org/10.1016/j.jhep.2015.08.018Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar To explain the beneficial effect of plasma exchange, mechanistic studies were undertaken, and it was shown that it was due to both removal of DAMPs molecules and a reduction of circulating ammonia. In a subsequent interesting study by Maiwall et al. using standard volume, they confirmed that plasma exchange improves survival in adult patients with ALF by modulating the innate immune system.10Maiwall R. Bajpai M. Singh A. et al.Standard-volume plasma exchange improves outcomes in patients with acute liver failure: a randomized controlled trial.Clin Gastroenterol Hepatol. 2022 Apr; 20 (Epub 2021 Jan 29. PMID: 33524593): e831-e854https://doi.org/10.1016/j.cgh.2021.01.036Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar In children, the experience with plasma exchange is spares. Jorgensen et al.11Jørgensen M.H. Rasmussen A. Christensen V.B. et al.Safety of high-volume plasmapheresis in children with acute liver failure.J Pediatr Gastroenterol Nutr. 2021 Jun 1; 72 (PMID: 33633079): 815-819https://doi.org/10.1097/MPG.0000000000003108Crossref PubMed Scopus (10) Google Scholar demonstrated that in children with ALF, high-volume plasma exchange is feasibility and safe. However, it remained an open question whether high-volume plasma exchange in children with ALF also results in an improved survival as seen in adults. It is of great importance that Dr. Uday Zachariah and his colleagues from the Christian Medical College, Vellore in India in this issue of J Exp Clin Hepatol12Thomas L. Chandran J. Goel A. et al.Improving transplant-free survival with low-volume plasma exchange to treat children with rodenticide induced hepatotoxicity.J Clin Exp Hepatol. 2023; 13: 252-258Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar for the first time provide data that show that the chance of survival in children with ALF is statistically significantly improves if supporting extracorporeal therapy by plasma exchange on top of stand medical therapy is performed. Interestingly, the authors used only 50% of the estimated plasma volume and replaced it with fresh frozen plasma for 3 days (or more) in children with ALF caused by intake of rodenticide containing yellow phosphorus. Their results12Thomas L. Chandran J. Goel A. et al.Improving transplant-free survival with low-volume plasma exchange to treat children with rodenticide induced hepatotoxicity.J Clin Exp Hepatol. 2023; 13: 252-258Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar were obtained by randomizing only 40 patients with ALF, and their results give a clear signal that extracorporeal liver support by this simple approach is of great value in alleviating the devastating complications of these patients. In line with previous studies,7Larsen F.S. Schmidt L.E. Bernsmeier C. et al.High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.J Hepatol. 2016 Jan; 64 (Epub 2015 Aug 29. PMID: 26325537): 69-78https://doi.org/10.1016/j.jhep.2015.08.018Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar,10Maiwall R. Bajpai M. Singh A. et al.Standard-volume plasma exchange improves outcomes in patients with acute liver failure: a randomized controlled trial.Clin Gastroenterol Hepatol. 2022 Apr; 20 (Epub 2021 Jan 29. PMID: 33524593): e831-e854https://doi.org/10.1016/j.cgh.2021.01.036Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Dr. Zachariah et al. in this impressive study12Thomas L. Chandran J. Goel A. et al.Improving transplant-free survival with low-volume plasma exchange to treat children with rodenticide induced hepatotoxicity.J Clin Exp Hepatol. 2023; 13: 252-258Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar also shows that plasma exchange primarily works by modulating the innate immune system, that is, by ameliorating the pro-inflammatory state and turn it into a more anti-inflammatory direction. In this study, the beneficial effect was obtained by doing plasmapheresis with replacement of only 50% of plasma volume which is about one fifth of the volume we used in our previous study in adults.7Larsen F.S. Schmidt L.E. Bernsmeier C. et al.High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.J Hepatol. 2016 Jan; 64 (Epub 2015 Aug 29. PMID: 26325537): 69-78https://doi.org/10.1016/j.jhep.2015.08.018Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar This is an important point as it significantly reduces resource consumption for working hours and costs for plasma and utensils. Furthermore, it reduces the potential risk of transmitting infectious diseases to the patient. The study published here12Thomas L. Chandran J. Goel A. et al.Improving transplant-free survival with low-volume plasma exchange to treat children with rodenticide induced hepatotoxicity.J Clin Exp Hepatol. 2023; 13: 252-258Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar contains no systematic data on ammonium and how it changes during low-volume plasmapheresis. Twelve children in this study had grade III-IV HE. Two children developed convulsions, and brain edema was detected by CT of the brain. Eleven out of these 12 patients were treated with low-volume plasmapheresis of which 8 survived. A total of four patients died with HE and brain edema. So, in spite this study emphasizes the value of low-volume plasmapheresis, we must remember that one of the cornerstones in the treatment of patients, especially children and adolescents, with ALF is continuous renal replacement therapy (CRRT) not so much to correct the uremic parameters but just as much to reduce the circulating glutamine and ammonia levels.3Bernal W. Wendon J. Acute liver failure.N Engl J Med. 2013 Dec 26; 369 (PMID:24369077): 2525-2534https://doi.org/10.1056/NEJMra1208937Crossref PubMed Scopus (784) Google Scholar,13Deep A. Stewart C.E. Dhawan A. et al.Effect of continuous renal replacement therapy on outcome in pediatric acute liver failure.Crit Care Med. 2016; 44: 1910-1919Crossref PubMed Scopus (53) Google Scholar In major liver centers, CRRT is often initiated early in the course of the disease, even if kidney function is preserved to reduce lactate and ammonia and to ensure a high sodium level that counteracts the tendency toward water influx to the brain with the formation of cortical edema.3Bernal W. Wendon J. Acute liver failure.N Engl J Med. 2013 Dec 26; 369 (PMID:24369077): 2525-2534https://doi.org/10.1056/NEJMra1208937Crossref PubMed Scopus (784) Google Scholar,5Clemmesen J.O. Larsen F.S. Kondrup J. Hansen B.A. Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration.Hepatology. 1999 Mar; 29 (PMID:10051463): 648-653https://doi.org/10.1002/hep.510290309Crossref PubMed Scopus (539) Google Scholar The combination of CRRT and low-volume plasmapheresis is also attractive from a pathophysiological perspective as it relieves the high circulating level of ammonia and DAMPs molecules at the same time.7Larsen F.S. Schmidt L.E. Bernsmeier C. et al.High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial.J Hepatol. 2016 Jan; 64 (Epub 2015 Aug 29. PMID: 26325537): 69-78https://doi.org/10.1016/j.jhep.2015.08.018Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar Thus, at the present time, when we are approaching 2024,14Bernal W. Lee W.M. Wendon J. Larsen F.S. Williams R. Acute liver failure: a curable disease by 2024?.J Hepatol. 2015; 62: S112-S120Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar significant progress has been made in the treatment of children, adolescents, and adult patients with ALF and is primarily based upon improved pathophysiological understanding of ALF but certainly also comes from the hard work of doing difficult and demanding clinical studies as this one by Dr. Zachariah and his colleagues.