897 and depending on the severity of liver damage, as assessed clinically (duration of encephalopathy) and by liver function tests The criteria to initiate ELS vary consider ably, and recommendations[.]
46 Extracorporeal Liver Support Therapies for Children Table 46.2 Potential indications for extracorporeal liver support Indications HE (≥3°) Unconjugated bilirubin >25 mg/dl Coagulation failure Relative indications Hemodynamic instability Hepatorenal and -pulmonary syndrome Plasma ammonia >200 μmol/l Increased intracranial pressure, HE 2° Legend: No pediatric RCT available RCT in adults comparing ELS for various indications and disease settings suggest reduced encephalopathy and lower mortality with ELS HE hepatic encephalopathy Of note, cut off values for bilirubin and ammonia are based on observational data only and depending on the severity of liver damage, as assessed clinically (duration of encephalopathy) and by liver function tests The criteria to initiate ELS vary considerably, and recommendations have been made almost exclusively based on observational data However, the following criteria should be taken into account in the decision process to start ELS therapy (Table 46.2): presence of hepatic encephalopathy stage or higher, increased cerebral pressure, hepatic cardiomyopathy and cardiocirculatory instability, coagulopathy (INR >1.5– 2.8), presence of hepatorenal failure, high plasma bilirubin concentrations, high plasma ammonium levels >200 μmol/l and high aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (>1500 U/l) All of these factors are dynamic and should be placed into the context of how liver function is changing over time (degree and rapidity of change) The indication for ELS, procedure efficiency, and associated risks and complications should be evaluated prior to and after each treatment by thorough clinical examination, including assessment of coma scale and hepatic encephalopathy score, and by regular measurement of liver and dialysis-related biochemical parameters These include bilirubin, ammonium, complete blood count, international normalized ratio (INR), partial thromboplastin time (PTT), fibrinogen, activated clotting time (ACT), bile acids, albumin, liver enzymes, C-reactive protein, creatinine, urea, electrolytes including phosphate, and acid– 897 base status Factor VII, the coagulation factor with the shortest half-life time (∼4 h), is also a sensitive parameter to assess the capacity of liver synthesis Early ELS therapy initiation appears to be particularly justified in patients with rapid disease progression, although the scientific evidence for an improved outcome with this approach to ELS is still limited The latter is primarily due to the relatively low incidence of ALF precluding large-scale clinical trials (even in adults), the heterogeneity of the underlying diseases and clinical presentations and the still limited availability of advanced technologies Several authors have reported on the removal of water soluble toxins only [7–9] in children with liver failure and dialysis-dependent acute kidney injury Kreuzer et al reviewed data collected over 10 years which revealed better efficacy with continuous venovenous hemofiltration (CVVH) and lower mortality than with peritoneal dialysis (PD) [7] In view of the severity of the often life-threatening conditions associated with ALF, with many proteinbound toxins accumulating and contributing to secondary kidney, lung and heart failure and a bleeding diathesis, selective removal of water soluble toxins should be limited to less severe cases, i.e., those with volume overload, less severe symptoms of intoxication, and sufficient coagulation High sodium CVVH with regional citrate anticoagulation and online dialysate generation was used in 11 adult patients with ALF to precisely titrate serum sodium without undesirable fluctuations in extracellular fluid volume [8] Whether such osmoregulatory effects are beneficial is uncertain Cholestatic Pruritus Another indication of ELS is unbearable cholestatic pruritus that persists despite pharmacological treatment Severe cholestatic pruritus prevents sleep and may result in heavy physical and psychological stress – ultimately resulting in depression and possible suicidal tendencies [10, 11] In adults with intractable pruritus, intermittent MARS has provided good B Schaefer et al 898 results [12–14] In children, MARS treatment every other week to twice weekly resulted in about a 60% reduction in serum bile acids per session and significant improvement of perceived pruritus [10, 15] It should be emphasized that ELS modalities may be modified or discontinued when patients experience severe allergic reactions to components of the extracorporeal circuit, and they should be withheld in patients with circulatory failure and in cases where there is critical progression of the underlying disease or fatal complications precluding a positive outcome The ongoing use of ELS varies globally and is influenced by the availability of resources, the expediency of transplantation, and local expertise The collection of data pertaining to the use of ELS in children therefore becomes challenging – but especially important as best practice recommendations would be beneficial It is without question that the decision to place children on ELS can affect the ability to list a patient for transplantation, and thus knowledge of the available options for ELS remains vital to the pediatric nephrologist, hepatologist, and intensivist Artificial Liver Support Devices The MARS module (Gambro, Lund, Sweden) consists of a proprietary monitor system, which can be combined with conventional hemodialysis machines A high-flux polysulfone dialyzer with a molecular cutoff around 50 kDa allows passage of both protein-bound and water soluble substances into a dialysate circuit, which contains 20% albumin Hydrophilic substances are removed from the albumin circuit via a conventional hemofilter, whereas the albumin-bound substances are adsorbed to a charcoal filter and an anion exchange resin filter placed in series into the albumin circuit (Fig. 46.2) Two different types of MARS filters are available; the adult system filter with 2.1 m2 filter surface area and the MARSmini filter set with 0.6 m2 filter surface area The extracorporeal volumes are 152 and 57 mL, respectively, plus blood lines; the MARSmini system is recommended for patients less than 25 kg body weight The albumin circuits are primed with about 500 (450 mL for MARSmini) of 20% human albumin Urea and vitamin B12 clearances are 195 (34) and 149 Fig 46.2 MARS is a combination of a blood circuit with a polysulfone filter (1, 2) which dialyses against a primary circuit containing 20% albumin (3) and a secondary conventional hemodialysis circuit to remove water soluble toxins (4) While water soluble compounds are removed from the primary dialysate via the second dialysis circuit, the albumin-bound substances adhere to a charcoal filter (5) and an anion exchanger (6) placed in series into the albumin circuit 46 Extracorporeal Liver Support Therapies for Children (25) mL/min with MARS (MARSmini) at 200 and 100 mL/min blood flow rates and 500 and 30 mL/min dialysate flow rates, respectively The molar ratio of bilirubin to albumin in serum is approximately 20-fold higher than the respective dialysate ratio throughout the MARS sessions, giving a rough estimate of the MARS filter clearance capacity [16] Due to its molecular cutoff of around 50 kD, proteins such as albumin, coagulation factors, and immunoglobulins are not removed with MARS The regulation of blood flow depends on multiple factors Included in the determination of targeted blood flow are the metrics of weight, the stability of the patient, the speed and amount of detoxification deemed necessary by the clinical situation, and access The albumin dialysate flow rate should equal the blood flow rate The sum of the secondary dialysate turnover and ultrafiltration rate should not exceed 25% of the blood flow rate The secondary dialysate flow rate should be at least two times the albumin flow rate The efficacy of purification depends on the degree of intoxication and on the amount of toxins filtered and cleared via the albumin circuit MARS dialysis can be performed once daily for about 8 h until the adsorber systems are saturated, or continuously with system exchanges every 8 h, if required [17] The 8 h limit is based upon the treatment time possible prior to saturation of the adsorbent filters; continuation of dialysis with the same system beyond 8 h for clearance of water soluble substances and ultrafiltration is feasible but may be less efficient In addition to the general recommendations given above, MARS may not be applied or should be discontinued in children with active bleeding The coagulation status often deteriorates during MARS therapy The underlying mechanisms for bleeding include progressive failure of hepatic protein synthesis, mechanical platelet sequestration during blood passage through the filter, and membrane-induced immune-mediated coagulation factor consumption [18–20] Hence, it should be emphasized that MARS therapy does not preclude the need for plasma protein supplementation 899 The available data for MARS efficacy in children depend on the endpoints measured In terms of improvement in hepatic encephalopathy (HE) and overall survival (transplant or no transplant), the range of improvement is anywhere from 17% to 100% in HE and 50–100% with respect to patient survival The number of patients accounted for in these studies varies, but remains small compared to larger, adult studies [6, 21–24] OPAL (Hepanet/Albutec GmbH – Hannover, Germany) was recently introduced to further improve ELS efficacy and patient outcome This system incorporates an albumin circuit with a dialysis filter with a large surface area of contact with the charcoal adsorber, thereby potentially improving the regeneration rates and dialysis efficacy by allowing a higher concentration gradient between blood and the albumin dialysate Priming of the circuit may be required in small children To date, very few data are available based on the use of this modality There are no published data on the effectiveness of the OPAL system as compared to the established MARS system, except for the case of a 15-year-old girl with liver transplantation and postoperative bile duct stenosis OPAL was repeatedly compared to MARS and proved to be more effective in bile acid removal and relief of cholestatic pruritus [25] ADVOS (ADVOS multi, Hepa Wash GmbH Munich, Germany) is another new type of albumin dialysis that provides rapid regeneration of toxin-binding albumin by two purification circuits altering the binding capacities of albumin by biochemical (changing of pH) and physical (changing of temperature) modulation of the dialysate ADVOS efficiently eliminated water and protein-bound toxins in 14 patients with ALF [26], although pediatric data are scant The Prometheus device (Fresenius Medical Care, Bad Homburg, Germany) consists of two extracorporeal circuits In the first, plasma is separated from blood via an albumin permeable polysulfone filter The filtrate is purified via two adsorbers in series The neutral resin exchanger retains albumin-bound substances such as bile B Schaefer et al 900 acids, hydrophobic amino acids, and phenolic substances The anion exchanger retains negatively charged toxins such as bilirubin Albumin, hormones, and electrolytes are not bound The purified plasma is reinfused into the blood, which subsequently passes a conventional high-flux polysulfone dialyzer to eliminate water soluble toxins Extracorporeal filter and blood line volumes amount to 340 mL. The volume can be somewhat reduced by exchanging the hemodialysis filter for an appropriate pediatric size high- flux filter The extracorporeal plasma volume is 440 mL. Prometheus is mainly suitable for adolescents and adults Its use in younger patients requires priming of the blood and plasma circuit with packed red blood cells, fresh frozen plasma, and albumin, respectively Treatment time is typically 4–8 h, with a maximal time of 10 h per session Single-pass albumin dialysis (SPAD) is a continuous venovenous hemodialysis procedure against a standard dialysate solution enriched with 20% human albumin to a final concentration of 2–20% The albumin dialysate is discarded after passage through the hemodialysis filter When considering cost–efficacy, a 4–5% dialysate albumin concentration is usually considered adequate The blood flow rate can be adjusted as recommended for standard CVVHD (3–5 mL/min/kg body weight) In adult patients, the albumin dialysate flow rate is often adjusted to 12–25 mL/min (10–20 ml/ kg/h in a 75 kg patient); pediatric centers have used a 20–60 mL/kg/h albumin dialysate flow, which is feasible in small children for whom the absolute amount of human albumin solution is not excessive SPAD can be combined with conventional hemodialysis at high dialysate flow rates (500–800 mL/min) [27] and with hemodiafiltration (Fig. 46.3) Solid efficacy data are lacking Once daily sessions of 6–12 h duration have been reported to attenuate hepatic intoxication Continuous SPAD may be performed to achieve higher clearance rates in children with severe hepatic failure, but at the expense of higher costs Infusion pump Infusion pump Substitute Bubble catcher Substitute pump Substitute High flux Filter Filtrate pump Blood pump Fig 46.3 Scheme of a single-pass albumin hemodiafiltration Albumin solution (usually 4–5%) passes through a high-flux filter, which allows for ultrafiltration replaced Waste by substitution fluid and net ultrafiltration in volume overloaded children 46 Extracorporeal Liver Support Therapies for Children 901 ombined Plasma Exchange C and Hemodialysis Therapies A type of ELS is the use of a hybrid therapy, combining extracorporeal hemodialysis and therapeutic plasma exchange (TPE) As an alternative to MARS and Prometheus, this approach can be performed using conventional hemodialysis machines and filters The filter surface area should roughly equal the patient’s body surface area The standard plasma exchange volume is 150% per session, but can be adapted according to individual needs and should be replaced by fresh frozen plasma Iso-oncotic albumin substitution can be considered only in the rare scenario of ALF with a still intact plasma coagulation status In emergency ALF situations with a need for rapid clearance of both albumin-bound and water soluble toxins such as ammonium, complicated by associated coagulation failure, it is possible to perform simultaneous plasmapheresis and hemodialysis by a single blood circuit passing serially through two dialysis machines encorporating a plasma and a high-flux hemodialysis filter system Toxin elimination and volume- and nitrogen-neutral substitution of plasma proteins can be achieved simultaneously with a reduced workload Total anticoagulation doses are slightly reduced as compared to sequential therapy While dialysis machines have not been approved for such combinations, clinical experience is good [28] (Fig. 46.4) The plasma turnover rate should not exceed 25% of the blood flow rate If a relatively high blood flow rate is achieved, plasmapheresis can be accomplished within 2 h While once daily plasmapheresis is sufficient in the majority of patients, the frequency can be adapted according to clinical needs, especially in the presence of hepatic encephalopathy Limited experience using combined hemodialysis and plasma exchange with fresh frozen plasma has been reported to substantially improve the symptoms of liver failure [6, 28] FFP Plasma Fig 46.4 Plasmapheresis and hemodialysis for liver support therapy can be performed simultaneously with a plasma separator and a conventional high-flux filter configured serially Pressure measurements are placed at indicated positions (crossed circles) Variations may be required when other systems are combined Bioartificial Liver Support Devices As mentioned earlier, a biological approach can be used to treat ALF. The use of therapies such as MARS, TPE, CRRT, and Prometheus is technically nonbiological; however, the promising aim of bioartificial devices is to provide both liver detoxification and supplemental synthetic functions HepatAssist (1) and the extracorporeal liver assist device (ELAD) (2) are the first bioartificial systems which have undergone testing in controlled trials in adult patients HepatAssist contains porcine hepatocytes within the extracapillary compartment of a hollow fiber bioreactor, and ELAD uses human hepatoblastoma cells Besides the safety of the systems [29, 30], one randomized controlled trial recently demonstrated an improvement in transplant-free survival with ELAD plus TPE and hemofiltration versus TPE and hemofitration [31] Pediatric data are lacking At present, bioartificial devices are not ready for routine clinical use in children 902 Implementation of ELS In the absence of the ability to provide clear evidence supporting a certain methodology, familiarity of use (particularly by nursing staff) is vital when deciding on ELS for patients with ALF. To prevent foreign protein exposure, and in children with cholestatic pruritus, albumin dialysis should be utilized Albumin dialysis spans the range of single-pass albumin dialysis to MARS to Prometheus There are no pediatric-specific recommendations on the adequate dose and duration of ELS. At present, ELS is dosed according to clinical and biochemical outcomes, i.e., improvement of hepatic encephalopathy, cardiac and kidney function, lowering of vasopressor requirements, and lowering of blood ammonia and serum bilirubin concentrations In patients treated with ELS for refractory cholestatic pruritus, monitoring of cholestasis markers such as serum bilirubin and bile acids should be performed to demonstrate the efficacy of the treatment A visual analog scale may also be useful for monitoring the perceived improvement and to allow for individual adaptation of the treatment For treatment of hepatic encephalopathy, a careful neurologic exam inclusive of the assessment for hyperreflexia and upper motor neuron function should ideally be performed at least every 2 h Anticoagulation therapy is required in the majority of ALF patients on ELS, even though coagulopathy is a cardinal feature of liver dysfunction, since pro- and anticoagulant factors are imbalanced and rapid clotting of the system may develop Anticoagulation may be started if the endogenous activated clotting time (ACT) is below 160 s In addition to the prevention of system clotting, anticoagulation reduces biofilm formation in the filter and thus preserves dialysis efficacy Regional citrate anticoagulation is feasible in the majority of patients and is indicated when there is coagulation failure [9, 32, 33] A second central intravenous (i.v.) line is usually required for the calcium infusion; otherwise, clotting of the venous dialysis catheter line is likely to occur Hepatic citrate metabolism should be monitored as accumulation of citrate B Schaefer et al leads to metabolic acidosis and the “citrate lock” phenomenon (i.e., dissociation of ionized and total calcium levels) Whether citrate accumulation contributes to a poor outcome or whether the outcome is instead a reflection of the severity of liver failure is unclear Observational studies in children and adults not suggest associated untoward effects of the therapy [32, 33], whereas other factors such as a high lactate and low partial thromboplastin time (PTT) predict a poor outcome [34] The high sodium load (3 sodium per citrate) also requires consideration and dialytic removal of sodium should hypernatremia develop ata for Extracorporeal Liver D Support Individual centers have developed their own policies and techniques for treating children with liver failure by ELS, often based on local availability of resources and appreciation of the limited scientific evidence The available ELS systems have specific advantages and shortcomings (Table 46.3) The major advantage of MARS, Prometheus, and SPAD is the removal of protein-bound substances without administration of exogenous protein Plasmapheresis replaces plasma with fresh frozen plasma or albumin and is thus associated with allergic and infectious risks On the other hand, plasma exchange allows for removal of all plasma protein-bound toxins and for volume and nitrogen neutral correction of liver synthesis failure, in particular coagulation failure Plasma exchange in combination with hemodialysis is an intermittent detoxification treatment, which can be repeated two to three times per day as required, or in severe cases may even be applied continuously Even in infants below year of age with ALF, continuous venovenous hemodiafiltration and plasma exchange have been reported to be well tolerated and has resulted in favorable outcomes [35] Both methods can even be combined in a tandem setup to reduce treatment time and increase cost-effectiveness, which may be advantageous in critically ill patients who require rapid toxin ... Hannover, Germany) was recently introduced to further improve ELS efficacy and patient outcome This system incorporates an albumin circuit with a dialysis filter with a large surface area of... circuit may be required in small children To date, very few data are available based on the use of this modality There are no published data on the effectiveness of the OPAL system as compared to... extracorporeal hemodialysis and therapeutic plasma exchange (TPE) As an alternative to MARS and Prometheus, this approach can be performed using conventional hemodialysis machines and filters The filter surface