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Therapeutic plasma exchange and continuous renal replacement therapy in pediatric dengue-associated acute liver failure: A case series from Vietnam

Open AccessPublished:November 28, 2022DOI:https://doi.org/10.1016/j.transci.2022.103617

      Highlights

      • Paediatric dengue-associated acute liver failure (PALF) is a rare and fatal complication.
      • Pediatric mortality risk score improved significantly in patients treated with CRRT+TPE.
      • Substantial improvements in liver transaminases levels, coagulation profiles, and metabolic biomarkers and clinical hepatoencephalopathy.
      • Nine in twelve patients (75 %) survived, and alive patients completely recovered with normal neurological functions.
      • A proposal of indication for commencing the combined TPE and CRRT interventions in children with dengue-associated PALF.

      Abstract

      Background and objectives

      Paediatric dengue-associated acute liver failure (PALF) is a rare and fatal complication. To date, clinical data regarding the combination of therapeutic plasma exchange (TPE) and continuous renal replacement therapy (CRRT) for the treatment of dengue-associated PALF are limited.

      Methods

      We conducted a single-center, retrospective study of all children with dengue-associated PALF admitted to the paediatric intensive care unit of Children Hospital No.2, Vietnam, who were treated with TPE+CRRT between January 2021 and March 2022. The main study outcomes were in-hospital survival, normalisation of hepatic function, and hepatic encephalopathy improvement.

      Results

      Twelve patients aged from 06 to 12 years underwent TPE+CRRT procedures. Among them, three (25 %) patients died of severe sepsis and septic shock confirmed by Enterobacteriaceae spp. haemocultures (stable on maintenance treatment of COVID-19-associated MIS-C with low dose of oral steroids on hospital admission), acute respiratory distress syndrome (ARDS), and clinically apparent intracranial haemorrhage. Nine patients (75 %) survived. The paediatric mortality risk score improved significantly at discharge compared with PICU admission (P < 0.01). Markedly, all twelve patients were diagnosed with hepatoencephalopathy of grades III and IV on PICU admission. After the combined TPE+CRRT interventions, there were substantial improvements in liver transaminases levels, coagulation profiles, and metabolic biomarkers. Normal neurological functions were observed in nine alive patients at hospital discharge. Only one patient experienced an adverse event of slightly low blood pressure, which rapidly self-resolved.

      Interpretation and conclusions

      Combined TPE+CRRT significantly improved survival outcome, neurological status, and rapid normalisation of liver functions in dengue-associated PALF.

      Abbreviations:

      PALF (paediatric acute liver failure), TPE (therapeutic plasma exchange), CRRT (continuous renal replacement therapy), PRISM (Paediatric Risk of Mortality), pSOFA (Pediatric Sequential Organ Failure Assessment), AST (aspartate aminotransferase), ALT (alanine aminotransferase), INR (international normalised ratio)

      Keywords

      1. Introduction

      Dengue infection affects vast regions across the globe, particularly Southeast Asia and the Indian subcontinent [
      • Bhatt S.
      • Gething P.W.
      • Brady O.J.
      • Messina J.P.
      • Farlow A.W.
      • Moyes C.L.
      • et al.
      The global distribution and burden of dengue.
      ]. The disease causes substantial burden, with an estimated 390 million dengue infections per year, and the case fatality rate was reported to be approximately 25 % among children admitted to the paediatric intensive care unit (PICU) [
      • Bhatt S.
      • Gething P.W.
      • Brady O.J.
      • Messina J.P.
      • Farlow A.W.
      • Moyes C.L.
      • et al.
      The global distribution and burden of dengue.
      ,
      • Sachdev A.
      • Pathak D.
      • Gupta N.
      • Simalti A.
      • Gupta D.
      • Gupta S.
      • et al.
      Early predictors of mortality in children with severe dengue fever: a prospective study.
      ]. Paediatric acute liver failure (PALF) is a rare and fatal complication in children with severe dengue infection due to the detrimentally dysregulated cytokine cascade resulting from sophisticated interactions between dengue viruses and host factors [
      • Teerasarntipan T.
      • Chaiteerakij R.
      • Komolmit P.
      • Tangkijvanich P.
      • Treeprasertsuk S.
      Acute liver failure and death predictors in patients with dengue-induced severe hepatitis.
      ,
      • Bhatt P.
      • Sabeena S.P.
      • Varma M.
      • Arunkumar G.
      Current understanding of the pathogenesis of dengue virus infection.
      ]. Excessive pro-inflammatory cytokine levels and liver-associated toxicities are significantly associated with a high mortality rate in patients with acute liver failure [
      • Stravitz R.T.
      • Sanyal A.J.
      • Reisch J.
      • Bajaj J.S.
      • Mirshahi F.
      • Cheng J.
      • et al.
      Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure: potential mechanism of improvement in transplant-free survival.
      ,
      • Antoniades C.G.
      • Berry P.A.
      • Wendon J.A.
      • Vergani D.
      The importance of immune dysfunction in determining outcome in acute liver failure.
      ]. Moreover, massive dengue-induced hepatocyte necrosis results in acute liver failure which further exacerbates multiorgan failure and hepatic encephalopathy [
      • Bernal W.
      • Wendon J.
      Acute liver failure.
      ]. Most significantly, multi-organ dysfunction, multiple vasopressor requirements, and higher blood lactate levels were identified as significant predictors of mortality in critically ill Dengue-infected children [
      • Sachdev A.
      • Pathak D.
      • Gupta N.
      • Simalti A.
      • Gupta D.
      • Gupta S.
      • et al.
      Early predictors of mortality in children with severe dengue fever: a prospective study.
      ]. Therefore, the elimination of liver-associated toxicities and harmful cytokines is critical for normalising hepatic function and mitigating multiorgan failure. Consequently, the survival outcomes of patients with dengue-associated ALF will improve [
      • Stravitz R.T.
      • Sanyal A.J.
      • Reisch J.
      • Bajaj J.S.
      • Mirshahi F.
      • Cheng J.
      • et al.
      Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure: potential mechanism of improvement in transplant-free survival.
      ,
      • Antoniades C.G.
      • Berry P.A.
      • Wendon J.A.
      • Vergani D.
      The importance of immune dysfunction in determining outcome in acute liver failure.
      ].
      Therapeutic plasma exchange (TPE) has been shown to be beneficial for patients with acute liver failure by removing hepatic toxins and detrimental cytokines, and replenishing coagulation proteins. TPE ameliorates multi-organ dysfunction and hepatic encephalopathy and increases the liver transplant-free survival of patients [
      • Bernal W.
      • Wendon J.
      Acute liver failure.
      ,
      • Chris-Olaiya A.
      • Kapoor A.
      • Ricci K.S.
      • Lindenmeyer C.C.
      Therapeutic plasma exchange in liver failure.
      ,
      • Larsen F.S.
      • Schmidt L.E.
      • Bernsmeier C.
      • Rasmussen A.
      • Isoniemi H.
      • Patel V.C.
      • et al.
      High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.
      ,
      • Sriphongphankul H.
      • Liabsuetrakul T.
      • Osatakul S.
      Clinical outcomes of children diagnosed dengue-associated acute liver failure with or without N-acetylcysteine treatment: a retrospective cohort study.
      ]. A recent study has shown the beneficial effects of TPE in treating patients with dengue-associated ALF complicated by hyperferritinaemia syndrome and hepatic encephalopathy [
      • Arunpriyandan V.
      • Sundaresan K.T.
      Fulminant hepatic failure in dengue fever without plasma leakage: a case report.
      ]. In addition, continuous renal replacement therapy (CRRT) can eliminate toxic chemicals, balance water, electrolytes, acids, and bases, and downregulate excessive cytokine levels [
      • Ankawi G.
      • Neri M.
      • Zhang J.
      • Breglia A.
      • Ricci Z.
      • Ronco C.
      Extracorporeal techniques for the treatment of critically ill patients with sepsis beyond conventional blood purification therapy: the promises and the pitfalls.
      ]. Acute kidney injury (AKI), high serum lactate acidosis, and ammonia levels are frequently observed in patients with acute liver failure [
      • Stahl K.
      • Hadem J.
      • Schneider A.
      • Manns M.P.
      • Wiesner O.
      • Schmidt B.M.W.
      • et al.
      Therapeutic plasma exchange in acute liver failure.
      ,
      • Cardoso F.S.
      • Gottfried M.
      • Tujios S.
      • Olson J.C.
      • Karvellas C.J.
      • US Acute Liver Failure Study Group
      Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure.
      ]. Thus, CRRT plays a critical role in improving AKI and removing metabolic substances, which significantly enhances the therapeutic effect of TPE in various clinical scenarios of ALF [
      • Trepatchayakorn S.
      • Chaijitraruch N.
      • Chongsrisawat V.
      • Chanakul A.
      • Kongkiattikul L.
      • Samransamruajkit R.
      Therapeutic plasma exchange with continuous renal replacement therapy for pediatric acute liver failure: a case series from Thailand.
      ,
      • Ide K.
      • Muguruma T.
      • Shinohara M.
      • Toida C.
      • Enomoto Y.
      • Matsumoto S.
      • et al.
      Continuous veno-venous hemodiafiltration and plasma exchange in infantile acute liver failure.
      ,
      • Deep A.
      • Stewart C.E.
      • Dhawan A.
      • Douiri A.
      Effect of continuous renal replacement therapy on outcome in pediatric acute liver failure.
      ]. However, clinical data on combined TPE+CRRT treatment in children with dengue-associated acute liver failure are extremely limited [
      • Arunpriyandan V.
      • Sundaresan K.T.
      Fulminant hepatic failure in dengue fever without plasma leakage: a case report.
      ]. Therefore, we conducted this study to examine the combination therapeutic effect of plasma exhange and continuous renal replacement therapy in improving patient’s survival, hepatoencephalopathy and normalisation of hepatic functions. Additionally, we also proposed an indication for commencing the combined TPE and CRRT in children with the dengue-associated PALF in clinical practice.

      2. Material and methods

      2.1 Ethics statements

      This study was approved by the Institutional Review Board of Children Hospital No.2, Ho Chi Minh City, Vietnam. The approval number was 391/QĐ-BVND92, which was signed on 22nd March, 2022. The study data were anonymised to ensure patient confidentiality. This study was conducted in compliance with the principles of good clinical practice and the Declaration of Helsinki.

      2.2 Study design and participants

      This was a single-center, retrospective study conducted at the Children Hospital No.2, Ho Chi Minh City, Vietnam, which is one of the three largest tertiary referral paediatric hospitals in the south of Vietnam, with the capacity to receive approximately 1400 in-hospital beds. We screened all critically ill Dengue-infected children with acute liver failure who were admitted to the paediatric intensive care unit between January 2021 and March 2022 and were managed with combined treatments of TPE and CRRT. Eligibility criteria included age < 18 years, laboratory-confirmed dengue infection, and paediatric acute liver failure, regardless of concomitant aetiologies of liver injury in patients with dengue infection [

      European Association for the Study of the Liver. Electronic address: [email protected]; Clinical practice guidelines panel, Wendon, J; Panel members, Cordoba J, Dhawan A, Larsen FS, Manns M, Samuel D, Simpson KJ, Yaron I; EASL Governing Board representative, Bernardi M. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047–1081. https:// doi: 〈10.1016/j.jhep.2016.12.003〉.

      ].

      2.3 Study outcomes

      The main study outcomes were in-hospital survival, normalisation of hepatic function, and hepatic encephalopathy improvement.

      2.4 Study definitions

      Pediatric acute liver failure was defined by the as an acute episode of severe hepatic dysfunction with biochemical evidence of liver injury in children without pre-existing chronic liver diseases, liver-induced coagulopathy not corrected by vitamin K supplementation, an International Normalized Ratio (INR) > 1.5 if the patient has encephalopathy or INR >2.0 if the patient does not [

      European Association for the Study of the Liver. Electronic address: [email protected]; Clinical practice guidelines panel, Wendon, J; Panel members, Cordoba J, Dhawan A, Larsen FS, Manns M, Samuel D, Simpson KJ, Yaron I; EASL Governing Board representative, Bernardi M. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047–1081. https:// doi: 〈10.1016/j.jhep.2016.12.003〉.

      ].
      Dengue infection was defined according to the WHO criteria (2009) with laboratory confirmation by the Dengue-IgM antibody test or non-structural 1 (NS1) antigen test [
      • Horstick O.
      • Martinez E.
      • Guzman M.G.
      • Martin J.L.
      • Ranzinger S.R.
      WHO dengue case classification 2009 and its usefulness in practice: an expert consensus in the Americas.
      ].
      Hepatic encephalopathy was defined as a reversible syndrome of cerebral function impairment caused by critical complications of acute or chronic liver dysfunction. Clinical hepatoencephalopathy manifests as significant changes in personality, consciousness, temporal and spatial disorientation, motor dysfunction, somnolence, stupor, and eventually, coma [
      • Ferenci P.
      Hepatic encephalopathy.
      ].

      3. Study interventions

      3.1 Therapeutic plasma exchange procedure

      Plasma exchange was performed using a Gambro Prismaflex® system (Baxter, USA). A dialysis catheter (Balton®) was inserted into the right internal jugular or femoral vein using a sterile procedure at the bedside. The TPE-1000 filter membrane was used for small children weighing 9–20 kg, and the TPE-2000 apparatus was used for children weighing over 20 kg [
      • Wong E.C.
      • Balogun R.A.
      Therapeutic apheresis in pediatrics: technique adjustments, indications and nonindications, a plasma exchange focus.
      ,
      • Hunt E.A.
      • Jain N.G.
      • Somers M.J.
      Apheresis therapy in children: an overview of key technical aspects and a review of experience in pediatric renal disease.
      ]. Owing to coagulation disorder and low platelet count caused by severe dengue infection, unfractionated heparin infusions with doses ranging from 10 to 20 IU/kg per hour were restrictively administered to patients. The speed of withdrawing the patient’s blood was set at 04–06 ml/kg/min. The estimated amount of plasma was calculated using the formula, 0.07 x weight (kg) x (1-haematocrit). The TPE solution was fresh frozen plasma, and the standard TPE was set at 1.5 folds the patient’s total plasma volume. In children weighing < 9 kg, we performed extracorporeal priming with red blood cells mixed with normal saline 0.9 % to obtain a haematocrit of 45 % (equivalent to 90 ml) [
      • Wong E.C.
      • Balogun R.A.
      Therapeutic apheresis in pediatrics: technique adjustments, indications and nonindications, a plasma exchange focus.
      ,
      • Hunt E.A.
      • Jain N.G.
      • Somers M.J.
      Apheresis therapy in children: an overview of key technical aspects and a review of experience in pediatric renal disease.
      ]. Vital signs were closely monitored during the TPE procedures. All patients were administered 10 % intravenous calcium chloride to prevent the potential risk of hypocalcaemia. In addition, diphenhydramine and methylprednisolone were prophylactically administered to the patients to prevent anaphylaxis.

      3.2 Continuous renal replacement therapy

      The CRRT procedure was conducted using a Gambro Prismaflex® haemofiltration system (Baxter, USA) and a polymembrane (AN69) filter (29). For AN69 filter membranes, HF20 was used for children weighing < 10 kg, M60 for those weighing 10–15 kg, and M100 for those weighing >15 kg [
      • Walters S.
      • Porter C.
      • Brophy P.D.
      Dialysis and pediatric acute kidney injury: choice of renal support modality.
      ,
      • Sanderson K.R.
      • Harshman L.A.
      Renal replacement therapies for infants and children in the ICU.
      ]. The filtration mode of the CVVHDF combined with convection and dialysis methods was applied. The CRRT dose was adjusted from 60 to 90 ml/kg/h depending on the ammonia (NH3) levels. The dialysis solution used was Prismasol B0® (Bieffe Medital S.p.A.Italy). If the extracorporeal circulatory volume was >15 % of the blood volume, the priming procedure was performed by mixing red blood cells with normal saline 0.9 % to obtain a haematocrit of 45 % [
      • Walters S.
      • Porter C.
      • Brophy P.D.
      Dialysis and pediatric acute kidney injury: choice of renal support modality.
      ,
      • Sanderson K.R.
      • Harshman L.A.
      Renal replacement therapies for infants and children in the ICU.
      ].

      3.3 Sequence of TPE and CRRT interventions

      The CRRT procedure was initially commenced and continued until there was no indication for CRRT. Then TPE performance was followed on the average of 03 cycles (a maximum of 05 cycles) for each patient. Importantly, the CRRT was used in combination with TPE, regarding high prevalences of acute kidney injury, serum lactate acidosis and ammonia elevations in dengue-infected children with acute liver failure [
      • Stahl K.
      • Hadem J.
      • Schneider A.
      • Manns M.P.
      • Wiesner O.
      • Schmidt B.M.W.
      • et al.
      Therapeutic plasma exchange in acute liver failure.
      ,
      • Cardoso F.S.
      • Gottfried M.
      • Tujios S.
      • Olson J.C.
      • Karvellas C.J.
      • US Acute Liver Failure Study Group
      Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure.
      ].

      4. Data collection

      All patient data were anonymised to ensure compliance with good clinical practice. Patients with dengue-associated PALF were searched and sorted out from the hospital electronic database by using ICD-10-CM code numbers for severe dengue (A97.2) and paediatric acute liver failure (K72.0). Then, case report forms were used to collect data from paper-based medical records for study analysis. Clinical and laboratory variables of interest were collected at various times after hospitalisation, including at PICU admission, initiation and 24 h after the final TPE and CRRT sessions, and PICU discharge. Data of all 12 study participants were fully collected at PICU admission (baseline); however, data for comparisons between before the first CRRT-TPE procedure and 24 h after the last CRRT-TPE performance were only available for 10 patients because two patients died soon after completing the first session of TPE and CRRT interventions. Hence, post-TPE and CRRT laboratory tests could not be performed in those two patients. In addition, the paediatric risk of mortality score (PRISM) and paediatric sequential organ failure assessment (pSOFA) scores were calculated using online tools [
      • Pollack M.M.
      • Ruttimann U.E.
      • Getson P.R.
      Pediatric risk of mortality (PRISM) score.
      ,
      • Mohamed El-Mashad G.
      • Said El-Mekkawy M.
      • Helmy Zayan M.
      La escala pediátrica de evaluación del fallo multiorgánico secuencial (pSOFA): una nueva escala de predicción de la mortalidad en la unidad de cuidados intensivos pediátricos [Paediatric sequential organ failure assessment (pSOFA) score: a new mortality prediction score in the paediatric intensive care unit].
      ].

      5. Statistical analyses

      Continuous variables were summarised as medians and interquartile ranges (IQRs). Categorical variables are presented as numbers (n) and percentages (%). Two-sided paired t-tests and Mann-Whitney U tests were used to compare continuous variables. Statistical significance was set at P values <0.05. The R statistical software (version 4.1.3, Boston, MA, USA) was used for all analyses.

      6. Results

      Twelve dengue patients with ALF underwent TPE and CRRT. Among them, three (25 %) patients died of sepsis and septic shock confirmed by Enterobacteriaceae cloacae haemoculture result (ongoingly stable on maintenance treatments of COVID-19-associated MIS-C with low dose of oral steroids on hospital admission), acute respiratory distress syndrome (ARDS), and clinically apparent intracranial haemorrhage without validated radiological evidence, regardless of normalised liver function tests. Nine (75 %) patients with dengue-associated PALF survived with fully normalised neurological function after combined TPE+CRRT interventions. The clinical and laboratory characteristics of all participants at PICU admission are shown in Table 1. The median patient age was 10 years (IQR, 06–11 years). Three-quarters of the participants were male and one-quarter were female. The median body mass index was 22 kg/m2. All participants experienced prolonged dengue shock, accompanied by clinical presentations of hepatoencephalopathy (grades III and IV) and required mechanical ventilation. The renal, hepatic, neurological and respiratory failures were commonly observed. Most patients (83.3 %) had at least three-organ failures. The haemodynamic and respiratory parameters were stably managed on PICU admission. The median vasopressor inotrope score (VIS) was 23 (IQR, 0–60). Cell blood counts revealed a slight increase in total white blood cell counts and a marked decrease in platelet cell counts. Notably, there were substantial elevations in transaminase levels, heavy coagulation disorders, and metabolic parameters (serum bicarbonate, lactate, and ammonia), indicating critical hepatic dysfunction. Most patients underwent from 02 to 03 TPE sessions combined with CRRT (a median of roughly 03 cycles of TPE per patient) to manage fatal acute liver failure. TPE was performed with a 1.5 fold patient’s total plasma volume, and blood flow was well adjusted, ranging from 100 to 150 ml per minute. In terms of complications associated with TPE and CRRT interventions, only one patient experienced a minor drop in blood pressure at the first TPE session, which was frequently associated with extracorporeal red cell priming and spontaneously resolved in the next TPE procedure. No further complication was observed in any of the remaining patients. In addition, most patients required platelet transfusions. Most importantly, there was a significant improvement in the paediatric risk of mortality score at PICU discharge compared with admission (P < 0.01, paired t-test) (Fig. 1A). Paediatric sequential organ failure assessment improved dramatically at PICU discharge in comparison to within-6-hour PICU admission (P = 0.02, paired t-test) (Fig. 1B).
      Table 1Clinical and laboratory characteristics of participants at PICU admission (N = 12).
      Patient characteristicsStatistics*
      Age (years)10 (06–11)
      Gender, male09 (75)
      BMI (kg/m2)21.5 (19.6–23.7)
      Organ failures (no.%)
      Kidney failure

       Liver failure

       Neurological failure

       Respiratory failure
      08 (66.7)

      12 (100)

      12 (100)

      06 (50)
      Number of organ failures (no.%)
      02

      03

      04
      02 (16.7)

      06 (50)

      04 (33.3)
      Hepatic encephalopathy grade (no.%)**
      HE grade III

       HE grade IV
      05 (41.7)

      07 (58.3)
      Respiratory rate (breaths per minute)20 (20–25)
      MAP (mmHg)82 (79–90)
      Shock index (bpm/mmHg)0.96 (0.90–1.22)
      White blood cell counts (x 109/L)16.2 (11.6–19.3)
      Hemoglobin (g/dL)12.1 (7.3–14.3)
      Haematocrit (%)38 (23–44)
      Platelet count (x109/L)37 (14–76)
      INR06 (3.1–10.6)
      PT (s)70 (39–124)
      aPTT (s)115 (56–180)
      AST (IU/L)8757 (5225–13,777)
      ALT (IU/L)1964 (978–2712)
      Total bilirubin (µmol/L)48 (24–67)
      Serum creatinin (µmol/L)89 (72–133)
      Serum lactate (mmol/L)10.5 (6.6–13.3)
      Serum bicarbonate (mmol/L)12 (8.4–15)
      CRP (mg/L)10 (5.8–14.5)
      PCT (ng/ml)2.34 (1.5–2.18)
      Ferritinemia (x103 ng/ml)40 (40–40)
      Troponin T (ng/ml)0.67 (0.32–1.18)
      Fluid balance (ml)54 (31–102)
      Total fluid volume given (ml/kg/day)187 (120–303)
      Platelet transfusion (no.%)10 (83.3)
      VIS23 (0–60)
      Median TPE sessions per patient2.5 (02–03)
      TPE sessions (no.%)

      1x

      2x

      3x
      01 (8.3)

      05 (41.7)

      06 (50)
      Blood flow (ml/min)

       100

       120

       140

       150
      02 (16.7)

      08 (66.7)

      01(8.3)

      01 (8.3)
      Hypotension associated with TPE (no.%)01 (8.3)
      pSOFA score within 6 h on PICU admission17 (15–18)
      pSOFA score at PICU discharge11 (10–15)
      PRISM score within 6 h on PICU admission21 (19–23)
      PRISM score at PICU discharge17 (14–19)
      Notes. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRRT, continuous renal replacement therapy; HE, hepatic encephalopathy; IBW, ideal body weight; INR, international normalized ratio; PT, prothrombin time; aPTT, activated partial thromboplastin time; MAP, mean arterial pressure, PICU, pediatric intensive care unit; PRISM, pediatric risk of mortality score; pSOFA, pediatric sequential organ failure assessment, TPE, therapeutic plasma exchange; VIS, vasopressor inotrope score
      * Summary statistic is median (interquartile range, IQR) for continuous variables and frequency (%) for categorical variables.
      ** West Haven score to assess patient’s hepatic encephalopathy status
      Fig. 1
      Fig. 1Significant improvement in pediatric risk of mortality score (PRISM) (A) and pediatric sequential organ failure assessment (pSOFA) (B) at discharge compared with admission to PICU.
      The clinical outcomes of patients are presented in Table 2. Combined TPE+CRRT significantly improved the survival rate (75 %) of patients with PALF. The median length of hospital and PICU stays were 28 days and 18 days, respectively and with those of mechanical ventilation and vasopressor support were 10 days and 03 days. Haemodynamic parameters, hepatic function tests, and other laboratory values before and after the TPE+CRRT procedures are shown in Table 3. There were no differences in haemodynamics, white blood cell counts, total bilirubin, serum creatinine, troponin T, ferritinemia, and oxygenation index. Nevertheless, there were significant improvements in liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), coagulation profile (international normalised ratio [INR]), and metabolic biomarkers (serum lactate and ammonia), as illustrated in Fig. 2.
      Table 2Clinical outcomes of patients managed with combined TPE and CRRT Treatments (N = 12).
      OutcomesStatistics
      Summary statistic is median (IQR) for continuous variables and frequency (%) for categorical variables.
      In-hospital mortality (no.%)03 (25)
      Length of hospital stay (days)28 (07–40)
      Length of PICU stay (days)18 (08–32)
      Duration of mechanical ventilation (days)10 (07–17)
      Duration of vasopressor support (days)03 (02–07)
      * Summary statistic is median (IQR) for continuous variables and frequency (%) for categorical variables.
      Table 3Comparisons of clinical and laboratory data before and after TPE+CRRT procedures (N = 10).
      VariablesBefore TPE+CRRTAfter TPE+CRRTP-value
      Hemodynamic parameters
      MAP (mmHg)80 (73–88)86 (73–95)0.95
      Shock index (bpm/mmHg)1.1 (1.0–1.2)0.9 (0.7–1.0)0.08
      Laboratory values
      WBC counts (x 109/L)10.8 (8.1–13.9)14.6 (12.6–21.9)0.06
      Platelet count (x 109/L)18 (15–38)69 (28–101)0.04
      AST (IU/L)4350 (1956–8397)1015 (379–1981)0.03
      ALT (IU/L)853 (529–2350)327 (211–532)0.02
      INR3.4 (2.3–8.7)1.7 (1.3–1.9)<0.01
      Total bilirubin (µmol/L)74 (29–114)50 (27–71)0.41
      Serum lactate (mmol/L)8.1 (5.5–11.8)3.1 (2.0–6.7)<0.01
      Serum bicarbonate (mmol/L)13.7 (9.2–14.5)20.5 (16–23.4)<0.001
      Ammonia level (µg/dL)146 (126–198)97 (52–114)0.04
      Serum creatinin (µmol/L)81 (58–126)74 (57–122)0.59
      Troponin T (ng/ml)0.32 (0.16–0.45)0.31 (0.04–0.92)0.56
      Oxygenation index8.7 (7.5–12.1)7.8 (6.5–12.9)0.31
      Ferritinemia (x 103 ng/ml)36.7 (21.2–40)22.1 (8.7–40)0.51*
      Notes. ALT, alanine aminotransferase; AST, aspartate aminotransferase; HE, hepatic encephalopathy; IBW, ideal body weight; INR, international normalized ratio; MAP, mean arterial pressure; TPE, therapeutic plasma exchange; WBC, white blood cell counts
      Statistics are median (IQR) for continuous variables and frequency (%) for categorical variables.
      P values withdrawn from paired t-tests, except for ferritinemia (*) Mann-Whitney U test due to non-normally distributed variable
      Fig. 2
      Fig. 2The dynamic variations in liver transaminases, coagulation and metabolic biomarkers in patients (n = 10) managed with combined TPE+CRRT treatments at various time points, indicated by triangle symbols: T0, PICU admission; T1, TPE+CRRT initiation (indicated by dash lines); T2, TPE+CRRT termination;T3, PICU discharge. The blue line indicates mean values with 95 % confidence interval of parameters. A statistically significant reductions were observed in the post-TPE+CRRT procedure values (AST, ALT, INR, serum lactate and ammonia).

      7. Discussion

      In this single-center, retrospective study, we present a small case series of dengue children with critical acute liver failure which is rarely observed, in contrast to the high mortality rate reported. We aimed to examine the combined therapeutic effects of TPE and CCRT on survival outcome, normalisation of hepatic function, biochemical parameters, and clinical hepatoencephalopathy in children with dengue-associated PALF.
      TPE and high-volume CRRT treatments have previously been demonstrated to be effective therapies for children with acute fulminant liver failure [
      • Larsen F.S.
      • Schmidt L.E.
      • Bernsmeier C.
      • Rasmussen A.
      • Isoniemi H.
      • Patel V.C.
      • et al.
      High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.
      ,
      • Stahl K.
      • Hadem J.
      • Schneider A.
      • Manns M.P.
      • Wiesner O.
      • Schmidt B.M.W.
      • et al.
      Therapeutic plasma exchange in acute liver failure.
      ,
      • Trepatchayakorn S.
      • Chaijitraruch N.
      • Chongsrisawat V.
      • Chanakul A.
      • Kongkiattikul L.
      • Samransamruajkit R.
      Therapeutic plasma exchange with continuous renal replacement therapy for pediatric acute liver failure: a case series from Thailand.
      ,
      • Deep A.
      • Stewart C.E.
      • Dhawan A.
      • Douiri A.
      Effect of continuous renal replacement therapy on outcome in pediatric acute liver failure.
      ]. Single therapy with CRRT resulted in a survival rate of approximately 60 % for paediatric ALF [
      • Deep A.
      • Stewart C.E.
      • Dhawan A.
      • Douiri A.
      Effect of continuous renal replacement therapy on outcome in pediatric acute liver failure.
      ], while single treatment with TPE had an in-hospital survival rate of 65 % [
      • Stahl K.
      • Hadem J.
      • Schneider A.
      • Manns M.P.
      • Wiesner O.
      • Schmidt B.M.W.
      • et al.
      Therapeutic plasma exchange in acute liver failure.
      ]. Dengue-associated ALF is rarely seen, but is associated with a high mortality rate of 20 % up to 68 % [
      • Leowattana W.
      • Leowattana T.
      Dengue hemorrhagic fever and the liver.
      ]. However, clinical data on TPE and CRRT therapies for managing critical dengue-associated PALF are substantially restrictive [
      • Arunpriyandan V.
      • Sundaresan K.T.
      Fulminant hepatic failure in dengue fever without plasma leakage: a case report.
      ]. Therefore, we conducted this study to shed light on this gap. Most significantly, our report clearly showed that TPE+CRRT treatment was highly effective in improving the survival outcome of 9/12 (75 %) patients with paediatric dengue-associated PALF. Remarkably, the paediatric risk of mortality scores of our study participants were substantially improved at PICU discharge compared with PICU admission. The main causes of death in the remaining three patients were the severe sepsis and septic shock confirmed by Enterobacteriaceae spp. haemoculture (ongoingly stable on maintenance treatments of COVID-19-associated MISC with low dose of oral steroids on hospital admission), acute respiratory distress syndrome, and another with a clinical diagnosis of intracranial haemorrhage without cerebral imaging confirmation. The survival data for dengue-associated PALF in our study are consistent with previous reports that combined TPE+CRRT treatments increased survival outcomes by up to 75 % for acute liver failure due to severe sepsis, septic shock, toxicities, and Wilson’s disease [
      • Stahl K.
      • Hadem J.
      • Schneider A.
      • Manns M.P.
      • Wiesner O.
      • Schmidt B.M.W.
      • et al.
      Therapeutic plasma exchange in acute liver failure.
      ,
      • Trepatchayakorn S.
      • Chaijitraruch N.
      • Chongsrisawat V.
      • Chanakul A.
      • Kongkiattikul L.
      • Samransamruajkit R.
      Therapeutic plasma exchange with continuous renal replacement therapy for pediatric acute liver failure: a case series from Thailand.
      ,
      • Aygün F.
      • Varol F.
      • Durak C.
      • Talip Petmezci M.
      • Kacar A.
      • Dursun H.
      • et al.
      Evaluation of continuous renal replacement therapy and therapeutic plasma exchange, in severe sepsis or septic shock in critically Ill children.
      ]. In addition, although Sriphongphankul et al. has recently reported a case series of dengue-associated paediatric ALF with a mortality rate of 42 % (14/33 patients died), there were several major study limitations [
      • Sriphongphankul H.
      • Liabsuetrakul T.
      • Osatakul S.
      Clinical outcomes of children diagnosed dengue-associated acute liver failure with or without N-acetylcysteine treatment: a retrospective cohort study.
      ]. First, the heterogeneity of the PALF population by dengue haemorrhagic fever (DHF) encompassed a vast array of disease severities, ranging from DHF grades I and II (21 %) and DHF grades III and IV (79 %). Second, DHF patients with PALF were diagnosed using the previous version of the WHO dengue guidelines in 1997 [
      • Sriphongphankul H.
      • Liabsuetrakul T.
      • Osatakul S.
      Clinical outcomes of children diagnosed dengue-associated acute liver failure with or without N-acetylcysteine treatment: a retrospective cohort study.
      ]. Notably, dynamic changes in liver transaminases, coagulation profiles, and metabolic biomarkers (serum lactate and ammonia) had not been shown. In contrast, our study clearly showed promising results in improving the survival of patients with dengue-associated PALF. However, this finding should be cautiously taken into account because of the small sample size of our case series; hence, further studies with larger sample sizes are needed to make a more robust conclusion. In terms of safety, the TPE+CRRT treatments were well tolerated. In particular, the commonly reported complications of TPE and CRRT are bleeding, haemodynamic instability and infection, which were not observed in our study, except for one patient with slightly low blood pressure commonly associated with extracorporeal red cell priming, self-resolved soon [
      • Larsen F.S.
      • Schmidt L.E.
      • Bernsmeier C.
      • Rasmussen A.
      • Isoniemi H.
      • Patel V.C.
      • et al.
      High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.
      ,
      • Stahl K.
      • Hadem J.
      • Schneider A.
      • Manns M.P.
      • Wiesner O.
      • Schmidt B.M.W.
      • et al.
      Therapeutic plasma exchange in acute liver failure.
      ,
      • Trepatchayakorn S.
      • Chaijitraruch N.
      • Chongsrisawat V.
      • Chanakul A.
      • Kongkiattikul L.
      • Samransamruajkit R.
      Therapeutic plasma exchange with continuous renal replacement therapy for pediatric acute liver failure: a case series from Thailand.
      ]. Nevertheless, highly skilled physicians and nurses are required to minimise complications associated with TPE and CRRT procedures.
      The combined TPE+CRRT treatment substantially reduced elevated transaminase levels, coagulation, and biochemical parameters which reversed severe coagulopathy and hepatic encephalopathy. Transaminases and coagulation dysfunctions were critically adjusted, as evidenced by dramatic reductions in AST and ALT levels and significant improvements in INR and platelet counts after TPE and CRRT procedures. Nonetheless, our study data revealed that serum bilirubin levels in patients took an average of three weeks to decrease gradually. Most importantly, TPE was shown to enhance normalisation of hepatic dysfunction which can greatly contribute to improving the survival outcomes of patients with dengue-associated PALF [
      • Maheshwari A.
      • Bajpai M.
      • Patidar G.K.
      Effects of therapeutic plasma exchange on liver function test and coagulation parameters in acute liver failure patients.
      ]. Hepatic encephalopathy, a severe neuropsychiatric syndrome, is a commonly observed complication of hepatic failure [
      • Bosoi C.R.
      • Rose C.F.
      Elevated cerebral lactate: Implications in the pathogenesis of hepatic encephalopathy.
      ]. High blood lactate concentrations lead to elevated cerebral lactate levels, which results in brain oedema and hepatic encephalopathy [
      • Bosoi C.R.
      • Rose C.F.
      Elevated cerebral lactate: Implications in the pathogenesis of hepatic encephalopathy.
      ]. The survival rate has been reported to increase by 50 %, corresponding to every 10 % reduction in blood ammonia concentration by CRRT from baseline within 48 h [
      • Deep A.
      • Stewart C.E.
      • Dhawan A.
      • Douiri A.
      Effect of continuous renal replacement therapy on outcome in pediatric acute liver failure.
      ]. Importantly, high-volume CRRT was shown to significantly improve hepatic encephalopathy status in paediatric acute liver failure [
      • Chevret L.
      • Durand P.
      • Lambert J.
      • Essouri S.
      • Balu L.
      • Devictor D.
      • et al.
      High-volume hemofiltration in children with acute liver failure.
      ]. Our patients showed substantial decreases in blood lactate and ammonia levels after the TPE and CRRT procedures. As a result, hepatic encephalopathy improved markedly, as observed in nine patients recovering with fully normalised neurological functions at hospital discharge.
      To date, there has been no specific guideline for cut-off parameters of dengue-associated PALF concomitant with dengue shock to initiate the TPE+CRRT interventions. Akdogan M et al. demonstrated that delayed treatment led to poor outcomes of patients [
      • Akdogan M.
      • Camci C.
      • Gurakar A.
      • Gilcher R.
      • Alamian S.
      • Wright H.
      • et al.
      The effect of total plasma exchange on fulminant hepatic failure.
      ]. In particular, despite TPE administration, patients with hepatoencephalopathy grades of III and IV had the mortality rates of 42 % and 100 %, respectively [
      • Akdogan M.
      • Camci C.
      • Gurakar A.
      • Gilcher R.
      • Alamian S.
      • Wright H.
      • et al.
      The effect of total plasma exchange on fulminant hepatic failure.
      ]. In addition, patients with INR values ranging from 1.5 to 5, who were performed TPE had the fatality rate of 36 %, and those with INR >5 corresponding to the mortality rate of 82 % [
      • Akdogan M.
      • Camci C.
      • Gurakar A.
      • Gilcher R.
      • Alamian S.
      • Wright H.
      • et al.
      The effect of total plasma exchange on fulminant hepatic failure.
      ]. The King's College Criteria [
      • O'Grady J.G.
      • Alexander G.J.
      • Hayllar K.M.
      • Williams R.
      Early indicators of prognosis in fulminant hepatic failure.
      ] and Clichy-Villejuif Criteria [
      • Bernuau J.
      • Goudeau A.
      • Poynard T.
      • Dubois F.
      • Lesage G.
      • Yvonnet B.
      • et al.
      Multivariate analysis of prognostic factors in fulminant hepatitis B.
      ] favored an early intervention before patients presented the death predictors of acute liver failure, including hepatic encephalopathy grades of III and IV, INR >3.5 and bilirubin level >300 µmol/L. Likewise, blood lactate levels >3.5 mmol/L on admission or 12 h after resuscitation were significant predictors of death in patients with PALF [
      • Bernal W.
      • Donaldson N.
      • Wyncoll D.
      • Wendon J.
      Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study.
      ]. Thus, we support an early TPE performance when there is a marked increase in blood lactate level despite receiving intensive treatments. In addition, serum ammonia concentration > 100 µmol/L on admission was an independent predictor of developing high-grade hepatoencephalopathy [
      • Bernal W.
      • Hall C.
      • Karvellas C.J.
      • Auzinger G.
      • Sizer E.
      • Wendon J.
      Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure.
      ], and ammonia level > 200 µmol/L was reported to be associated with brain herniation [
      • Clemmesen 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.
      ]. The ammonia cut-off values of 100 µmol/L, 150 µmol/L and 200 µmol/L were associated with the 21-day mortality with fairly high values of both sensitivity (77 %, 58 % and 42 %, respectively) and specificity (55 %, 76 % and 87 %), and an area under the curve (AUC) of 0.72 [
      • Cardoso F.S.
      • Gottfried M.
      • Tujios S.
      • Olson J.C.
      • Karvellas C.J.
      • US Acute Liver Failure Study Group
      Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure.
      ]. In addition, the Pediatric Acute Liver Failure Study Group demonstrated that bilirubin level > 85.5 µmol/L (or 5 mg/dL) and INR ≥ 2.55 on hospital admission predicted risk of death and/or liver transplant [
      • Squires Jr, R.H.
      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      ]. Significantly, Stravitz et al. showed a minimal change in bilirubin in patients with acetaminophen toxicity and reduced blood perfusion [
      • Stravitz R.T.
      • Lee W.M.
      Acute liver failure.
      ]. Our study participants were children with dengue shock syndrome, and acute liver failure was associated with prolonged shock and blood hypoperfusion. We observed minimal variation in bilirubin in our patients. The administration of colloid fluids in dengue-infected patients as well as fresh frozen plasma infusion markedly affected coagulation profile, particularly INR values [
      • Kozek-Langenecker S.A.
      Fluids and coagulation.
      ]. Therefore, an indication for TPE only based on bilirubin and INR levels can protract timely and appropriate interventions for patients with dengue-associated acute liver failure.
      On this basis, we propose an indication for TPE+CRRT procedures in paediatric patients with dengue-associated PALF. We immediately perform the combined CRRT and TPE interventions in children who meet the definition of pediatric acute liver failure [

      European Association for the Study of the Liver. Electronic address: [email protected]; Clinical practice guidelines panel, Wendon, J; Panel members, Cordoba J, Dhawan A, Larsen FS, Manns M, Samuel D, Simpson KJ, Yaron I; EASL Governing Board representative, Bernardi M. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047–1081. https:// doi: 〈10.1016/j.jhep.2016.12.003〉.

      ], plus either one of these criteria: (i) Hepatoencephalopathy grades I and II, poor treatment response within 12–24 h of intensive care, or (ii) Hepatoencephalopathy grades III and IV at any time during hospital admission, (iii) ammonia level more than 150 μmol/L, poor therapeutic response within 6–8 h of treatments or ammonia concentration ≥ 200 μmol/L at any time during hospitalisation and (iv) a marked increase in serum lactate with poor treatment response. Furthermore, we also recommend the combination TPE and CRRT treatments as the first-line therapy for children with dengue-associated acute liver failure, and it should be classified as category I, according to the 2019 American Society for Apheresis (ASFA) guidelines [
      • Padmanabhan A.
      • Connelly-Smith L.
      • Aqui N.
      • Balogun R.A.
      • Klingel R.
      • Meyer E.
      • et al.
      Guidelines on the use of therapeutic apheresis in clinical practice - evidence-based approach from the Writing Committee of the American Society for Apheresis: the eighth special issue.
      ].

      8. Limitations of the study

      Our study had several limitations inherent to its retrospective nature and small sample size. Other restrictions were placed on the unstandardised collection of clinical and laboratory data, and various TPE sessions were performed. Inflammatory biomarkers, particularly serum ferritin levels and cytokine profiles, were lacking; hence, comparisons could not be performed.

      9. Conclusions

      Our study results showed that combined TPE and CRRT treatments significantly improved the in-hospital survival outcome, normalisation of liver transaminases, coagulation profiles, and metabolic biomarkers in critical paediatric dengue-associated PALF. These findings call for larger studies to determine the combined effect of TPE and CRRT on the clinical outcomes of children with dengue-associated paediatric acute liver failure.

      CRediT authorship contribution statement

      Conceptualized and designed the study: Luan VT, Thanh NT, Clinical data collection: Luan VT, Phuong NTM, Dat NT, Thinh TN, Thanh MTH, Bao NT, Son PT, Investigation: Thanh NT, Luan VT, Phuong NTM, Dat NT, Thinh TN, Thanh MTH, Bao NT, Son PT, Formal data analysis: Thanh NT, Luan VT, Writing the original manuscript: Thanh NT, Luan VT, Critically reviewed manuscript: Luan VT, Thanh NT, Thien V, Son PT, Viet DC, Tung TH, All authors approved the final manuscript.

      Conflicts of interest

      We declare that there is no conflict of interest.

      Acknowledgement

      We thank the administration and study staff (particularly Mr. Tuan Anh Tran) for their assistance in medical data retrieval.

      Financial support and sponsorship

      This study was self-funded.

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