916 nous intoxication is thought to be the most likely diagnosis at the time of ICU admission Dialysis Equipment Catheter The choice of catheter has to balance between the aim of achieving an adequate[.]
L Barcat et al 916 Ammonia clearance Leucine clearance 35 35 30 30 L/h 25 L/h 20 L/h 15 10 Clearance (ml/min) Clearance (ml/min) L/h L/h 25 20 L/h 15 10 0 10 20 30 40 50 60 Blood flow (ml/min) 10 20 30 40 50 60 Blood flow (ml/min) Fig 47.3 Effect of blood and dialysate flow rate on ammonium and leucine removal by hemodialysis in a neonatal setting (simulation study using Baxter BM25 device and Bellco Spiraflo HFT02 dialyzer) (Modified from Schaefer et al [17]) nous intoxication is thought to be the most likely diagnosis at the time of ICU admission involving two shortened umbilical catheters have been used anecdotally in small neonates Dialysis Equipment Dialyzer Catheter Polysulfone dialyzers should be preferred because of their superior biocompatibility and lower anticoagulation requirements The surface of the dialyzer membrane should approximately match the body surface area of the patient We have had excellent experience with the Fresenius FX paed (FMC, Bad Homburg, Germany) and the Spiraflo HFT02 (Bellco, Mirandola, Italy), which have fill volumes of 18 and 25 mL respectively The choice of catheter has to balance between the aim of achieving an adequate blood flow and the risks of catheter insertion in a newborn Ideally, a blood flow of 150 mL/min/m2 should be attained, that is, 30–35 mL/min in an average neonate This goal can be reached by inserting a 6.5-French double-lumen catheter (e.g., Gambro 6.5 Fr, 3.5 in.) into a femoral vein This catheter provides excellent blood flow rates, but insertion may be difficult in small neonates Alternatively, two 5-French single-lumen catheters (e.g., Medcomp Fr, 3.0 in.) can be inserted [39] Umbilical catheters are less suitable for dialysis because of high flow resistance determined by their length, but special extracorporeal setups Dialysis Machines and Tubing In principle, emergency dialysis in neonates with inborn errors of metabolism can be performed using adjusted tubing systems on standard hemodialysis machines, such as the neonatal tubing 47 Dialytic Therapy of Inborn Errors of Metabolism in Case of Acute Decompensation for the Fresenius 2008 or 4008 devices These tubing sets have a fill volume of 47 mL. Even when used with the smallest neonatal dialyzers available, the total volume of the extracorporeal system exceeds 10% of the estimated blood volume of an average neonate In that case, the circuit can be primed with blood or albumin to have a better hemodynamic tolerance at dialysis start Another disadvantage is that an incorrect blood flow rate is displayed when small-volume neonatal tubes are used Moreover, due to the fixed high dialysate flow rate of at least 500 mL/min with the 2008 device (300 mL/min with the 4008), critical depletions of phosphate and other solutes not present in the dialysis fluid may occur with prolonged use of this technique Machines specifically designed for continuous renal replacement treatment in children are available, such as the BM25 (Baxter) or the PRISMAFLEX device (Gambro) The main advantages of these systems are the small volume of the extracorporeal system, accurate and fine-scaled setting of blood flow even in the low range typical for neonatal dialysis, precise control and variable choice of dialysate flow, and the mobile, reverse osmosis- independent device setup Dialysis Management In order to achieve maximal treatment efficacy, blood flow should be set to the maximal value provided by the machine without alarms, which should be set as wide as possible The dialysate flow rate required to achieve maximal clearance is determined by the blood flow achieved In a neonatal dialysis simulation study, we found a linear relationship between blood flow and ammonium and leucine clearance up to the maximal blood flow rate usually achievable in neonates (i.e., 30 mL/min) with a dialysate flow rate of 5 L/h (Fig. 47.2) As a rule of thumb, extraction of these metabolites is maximal when dialysate flow exceeds blood flow by at least three times This target can easily be achieved by passing bag dialysis fluid along the filter utilizing the 917 filtration/substitution pump system of a pediatric continuous renal replacement machine such as the Prismaflex Beginning by intermittent hemodialysis, to have a high removal of metabolite first, then continued by continuous hemodialysis to avoid rebound Clearance is at least 35-50 mL/ min/1.73 m2 The major complications to consider when dialyzing neonates or small infants with metabolic crises are clotting of the extracorporeal system, hemodynamic instability, and risk of cerebral edema increase, each of which can cause treatment interruptions and hence hazardous delays in the removal of toxic metabolites In order to prevent clotting, heparin should be administered at a dose sufficient to increase the activated clotting time (ACT) to 120–150 s We use an initial bolus of 1500 IU/m2 followed by continuous infusion of 300–600 IU/ m2/h Anticoagulation should be monitored by hourly ACT measurements Coagulation requirements are inversely related to the blood flow rate However, with the goal to avoid adverse effects due to heparine, a prospective, non-randomized descriptive study on 18 pediatric patients and 119 treatments was published using citrasate (a citrate-based dialysate) with promising results [42] Hemodynamic instability, leading to reduced cerebral perfusion pressure, is common in patients with a prolonged duration of hyperammonemia due to urea cycle disorders Another risk is a quick decrease in osmolarity during dialysis which may lead to intracellular water shift The challenge with both intermittent and continuous techniques is to accomplish rapid removal of ammonia without worsening cerebral edema by inducing hypotension and/or creating osmotic shifts This is achieved by the following measures (1): NaCl 0.9% or albumin 5% infusion before the start of extracorporeal therapy (2), priming the circuit with blood when extracorporeal circuit volume exceeds 10% of the child’s blood volume (80 mL/kg) (3), use of a dialysate fluid of osmolarity equal or greater than patient L Barcat et al 918 osmolarity (4), no ultrafiltration, and (5) if neurologic deterioration is observed during therapy, the toxic clearance should be reduced and mannitol infused CERT seemed to significantly decrease inflammation when compared to intermittent hemodialysis in 22 children [43] This supports the use of CERT in endogenous intoxications, as protein anabolism is one of the main goals of the treatment [43] In 2001, it was suggested in a case report that moderate hypothermia (34 °C) could be considered in order to decrease metabolic activity in severe hyperammonemia [44] This was confirmed later in a short series of seven cases [45] This effect was attributed to a slowing of metabolic ammonia generation Clinical Outcomes Metabolic encephalopathy due to inborn errors of metabolism represented 2% of admissions to a PICU serving a national reference center for metabolic diseases The mortality rate of these patients was 28.6% [6], stable across the years despite an increased use of aggressive treatment [4] In MSUD patients with neonatal onset who were dialyzed, good neurologic development is usually achieved Neonatal onset of urea cycle defects (UCD) and propionic or methylmalonic aciduria (PA/MMA) is characterized by a less favorable outcome than MSUD and late-onset UCD and PA/ MMA. F Deodato et al observed a mortality rate of 27.5% at 2 years and 48% at long-term followup, whereas late-onset patients showed only a 10% mortality rate [46] Similarly, long-term cognitive development worsened in neonatal onset patients but did not deteriorate in late-onset ones Novel therapies are in development for inherited metabolic diseases including enzyme replacement therapy, hepatocyte transplantation followed by liver transplantation, and gene therapy [47–49] For gene therapy the main obstacle to transfer in clinical practice remains the innate inflammatory acute response against the vector capsid protein, a complex and multifactorial phenomenon If such therapies are successful, the main challenge that will remain is to make a rapid diagnosis and initiate efficient treatment at the first onset However, a recent paper highlighted the difficulties of research in that field [50] All these observations emphasize the importance of expeditious diagnosis and prompt referral of infants with suspected inborn errors of metabolism to hospitals with a multidisciplinary team that includes metabolic experts, a skilled pediatric dialysis team, intensivists, laboratory staff, and dieticians [51] References Jouvet P, Rustin P, Taylor DL, Pocock JM, Felderhoff- Mueser U, Mazarakis ND, et al Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease Mol Biol Cell 2000;11(5):1919–32 Ratnakumari L, Qureshi IA, Butterworth RF. Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice Biochem Biophys Res Commun 1992;184(2):746–51 Jouvet P, Touati G, Lesage F, Dupic L, Tucci M, Saudubray JM, et al Impact of inborn errors of metabolism on admission and mortality in a pediatric intensive care unit Eur J Pediatr 2007;166(5):461–5 Meng M, Zhang Y-P. Impact of inborn errors of metabolism on admission in a neonatal intensive care unit: a 4-year report J Pediatr Endocrinol Metab 2013;26(7–8):689–93 Triplett KE, Murray R, Anstey M. Multifactorial non- cirrhotic hyperammonaemic encephalopathy BMJ Case Rep 2018;2018:bcr-2017-223245 Tarasenko TN, McGuire PJ. The liver is a metabolic and immunologic organ: a reconsideration of metabolic decompensation due to infection in inborn errors of metabolism (IEM) Mol Genet Metab 2017;121(4):283–8 Jouvet P, Lortie A, Maranda B, Tasker R. Metabolic encephalopathies in children In: Nichols D, editor Rogers textbook of pediatric intensive care 4th ed Philadelphia: Lippincott, Williams & Wilkins; 2008 p. 973–83 Fernandes J, Saudubray J-M, van den Berghe G, Walter JH, editors Inborn metabolic diseases: diagnosis and treatment [Internet] 4th ed Berlin/ Heidelberg: Springer-Verlag; 2006 [Cited 18 Feb 2019] Available from: https://www.springer.com/la/ book/9783540287858 47 Dialytic Therapy of Inborn Errors of Metabolism in Case of Acute Decompensation Summar M. Current strategies for the management of neonatal urea cycle disorders J Pediatr 2001;138(1):S30–9 10 Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders N Engl J Med 2007;356(22):2282–92 11 Gebhardt B, Dittrich S, Parbel S, Vlaho S, Matsika O, Bohles H. N-Carbamylglutamate protects patients with decompensated propionicaciduria from hyperammonaemia J Inherit Metab Dis 2005;28(2):241–4 12 Picca S, Bartuli A, Dionisi-Vici C. Medical man agement and dialysis therapy for the infant with an inborn error of metabolism Semin Nephrol 2008;28(5):477–80 13 Diane Mok TY, Tseng M-H, Chiang M-C, Lin J-L, Chu SM, Hsu J-F, et al Renal replacement therapy in the neonatal intensive care unit Pediatr Neonatol 2018;59(5):474–80 14 Gupta S, Fenves AZ, Hootkins R. The role of RRT in hyperammonemic patients Clin J Am Soc Nephrol 2016;11(10):1872–8 15 Cho H. Renal replacement therapy in neonates with an inborn error of metabolism Korean J Pediatr 2019;62(2):43–7 16 Semama DS, Huet F, Gouyon JB, Lallemant C, Desgres J. Use of peritoneal dialysis, continuous arteriovenous hemofiltration, and continuous arteriovenous hemodiafiltration for removal of ammonium chloride and glutamine in rabbits J Pediatr 1995;126(5 Pt 1):742–6 17 Schaefer F, Straube E, Oh J, Mehls O, Mayatepek E. Dialysis in neonates with inborn errors of metabolism Nephrol Dial Transplant 1999;14(4):910–8 18 Batshaw ML, Brusilow SW. Treatment of hyperammonemic coma caused by inborn errors of urea synthesis J Pediatr 1980;97(6):893–900 19 Saudubray JM, Ogier H, Charpentier C, Depondt E, Coudé FX, Munnich A, et al Hudson memorial lecture Neonatal management of organic acidurias Clinical update J Inherit Metab Dis 1984;7(Suppl 1):2–9 20 Donn SM, Swartz RD, Thoene JG. Comparison of exchange transfusion, peritoneal dialysis, and hemodialysis for the treatment of hyperammonemia in an anuric newborn infant J Pediatr 1979;95(1):67–70 21 Wiegand C, Thompson T, Bock GH, Mathis RK, Kjellstrand CM, Mauer SM. The management of life-threatening hyperammonemia: a comparison of several therapeutic modalities J Pediatr 1980;96(1):142–4 22 Lettgen B, Bonzel KE, Colombo JP, Fuchs B, Kordass U, Wendel K, et al Therapy of hyperammonemia in carbamyl phosphate synthase deficiency with peritoneal dialysis and venovenous hemofiltration Monatsschr Kinderheilkd 1991;139(9):612–7 23 Gortner L, Leupold D, Pohlandt F, Bartmann P. Peritoneal dialysis in the treatment of metabolic crises caused by inherited disorders of organic 919 and amino acid metabolism Acta Paediatr Scand 1989;78(5):706–11 24 Siegel NJ, Brown RS. Peritoneal clearance of ammonia and creatinine in a neonate J Pediatr 1973;82(6):1044–6 25 Snyderman SE, Sansaricq C, Phansalkar SV, Schacht RC, Norton PM. The therapy of hyperammonemia due to ornithine transcarbamylase deficiency in a male neonate Pediatrics 1975;56(1):65–73 26 Ring E, Zobel G, Stöckler S. Clearance of toxic metabolites during therapy for inborn errors of metabolism J Pediatr 1990;117(2 Pt 1):349–50 27 Thompson GN, Butt WW, Shann FA, Kirby DM, Henning RD, Howells DW, et al Continuous venovenous hemofiltration in the management of acute decompensation in inborn errors of metabolism J Pediatr 1991;118(6):879–84 28 Falk MC, Knight JF, Roy LP, Wilcken B, Schell DN, O’Connell AJ, et al Continuous venovenous haemofiltration in the acute treatment of inborn errors of metabolism Pediatr Nephrol 1994;8(3):330–3 29 Arbeiter AK, Kranz B, Wingen A-M, Bonzel K-E, Dohna-Schwake C, Hanssler L, et al Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism Nephrol Dial Transplant 2010;25(4):1257–65 30 Rajpoot DK, Gargus JJ. Acute hemodialysis for hyperammonemia in small neonates Pediatr Nephrol 2004;19(4):390–5 31 Sadowski RH, Harmon WE, Jabs K. Acute hemodialysis of infants weighing less than five kilograms Kidney Int 1994;45(3):903–6 32 Rutledge SL, Havens PL, Haymond MW, McLean RH, Kan JS, Brusilow SW. Neonatal hemodialysis: effective therapy for the encephalopathy of inborn errors of metabolism J Pediatr 1990;116(1):125–8 33 Levy HL. Genetic screening Adv Hum Genet 1973;4:1–104 34 Phan V, Clermont M-J, Merouani A, Litalien C, Tucci M, Lambert M, et al Duration of extracorporeal therapy in acute maple syrup urine disease: a kinetic model Pediatr Nephrol 2006;21(5):698–704 35 Wendel U, Becker K, Przyrembel H, Bulla M, Manegold C, Mench-Hoinowski A, et al Peritoneal dialysis in maple-syrup-urine disease: studies on branched-chain amino and keto acids Eur J Pediatr 1980;134(1):57–63 36 Lim VS, Bier DM, Flanigan MJ, Sum-Ping ST. The effect of hemodialysis on protein metabolism A leucine kinetic study J Clin Invest 1993;91(6):2429–36 37 Jouvet P, Jugie M, Rabier D, Desgrès J, Hubert P, Marie Saudubray J, et al Combined nutritional support and continuous extracorporeal removal therapy in the severe acute phase of maple syrup urine disease Intensive Care Med 2001;27(11):1798–806 38 Jouvet P, Hubert P, Saudubray JM, Rabier D, Man NK. Kinetic modeling of plasma leucine levels during continuous venovenous extracorporeal removal 920 therapy in neonates with maple syrup urine disease Pediatr Res 2005;58(2):278–82 39 Köse M, Canda E, Kagnici M, Uỗar SK, ầoker M.A patient with MSUD: acute management with sodium phenylacetate/sodium benzoate and sodium phenylbutyrate [Internet] Case Rep Pediatr 2017 [Cited 13 Feb 2019] Available from: https://www.hindawi com/journals/cripe/2017/1045031/ 40 Mak CM, Lam C, Siu W, Law C, Chan W, Lee HC, et al OPathPaed service model for expanded newborn screening in Hong Kong SAR, China Br J Biomed Sci 2013;70(2):84–8 41 Filippi L, Gozzini E, Fiorini P, Malvagia S, la Marca G, Donati MA. N-carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria Neonatology 2010;97(3):286–90 42 Fajardo C, Sanchez CP, Cutler D, Sahney S, Sheth R. Inpatient citrate-based hemodialysis in pediatric patients Pediatr Nephrol 2016;31(10):1667–72 43 Ağbaş A, Canpolat N, Çalışkan S, Yılmaz A, Ekmekỗi H, Mayes M, etal Hemodiafiltration is associated with reduced inflammation, oxidative stress and improved endothelial risk profile compared to high-flux hemodialysis in children PLoS One 2018;13(6):e0198320 44 Whitelaw A, Bridges S, Leaf A, Evans D. Emergency treatment of neonatal hyperammonaemic coma with mild systemic hypothermia Lancet 2001;358(9275):36–8 45 Lichter-Konecki U, Nadkarni V, Moudgil A, Cook N, Poeschl J, Meyer MT, et al Feasibility of adjunct therapeutic hypothermia treatment for hyperam- L Barcat et al monemia and encephalopathy due to urea cycle disorders and organic acidemias Mol Genet Metab 2013;109(4):354–9 46 Deodato F, Boenzi S, Rizzo C, Abeni D, Caviglia S, Picca S, et al Inborn errors of metabolism: an update on epidemiology and on neonatal-onset hyperammonemia Acta Paediatr Suppl 2004;93(445):18–21 47 Puppi J, Tan N, Mitry RR, Hughes RD, Lehec S, Mieli-Vergani G, et al Hepatocyte transplantation followed by auxiliary liver transplantation a novel treatment for ornithine transcarbamylase deficiency Am J Transplant 2008;8(2):452–7 48 Brunetti-Pierri N, Clarke C, Mane V, Palmer DJ, Lanpher B, Sun Q, et al Phenotypic correction of ornithine transcarbamylase deficiency using low dose helper dependent adenoviral vectors J Gene Med 2008;10(8):890–6 49 Wilhelm M, Chung W. Inborn errors of metabolism In: Nichols D, editor Rogers textbook of pediatric intensive care 4th ed Philadelphia: Lippincott, Williams & Wilkins; 2008 p. 1685–97 50 Talele SS, Xu K, Pariser AR, Braun MM, Farag-El- Massah S, Phillips MI, et al Therapies for inborn errors of metabolism: what has the orphan drug act delivered? Pediatrics 2010;126(1):101–6 51 Echeverri OY, Guevara JM, Espejo-Mojica ÁJ, Ardila A, Pulido N, Reyes M, et al Research, diagnosis and education in inborn errors of metabolism in Colombia: 20 years’ experience from a reference center Orphanet J Rare Dis [Internet] 2018 [Cited 13 Feb 2019];13 Available from: https://www.ncbi.nlm nih.gov/pmc/articles/PMC6097205/ Therapeutic Apheresis in Children 48 Christina Taylan and Scott M. Sutherland Introduction The term “apheresis” is derived from the Greek word “Αφαίρεσης,” which means removal In the most traditional sense, it refers to the large-scale separation or elimination of a blood component For example, plasmapheresis is the removal of plasma and leukapheresis is the removal of white blood cells (WBCs) The technique, in various forms, has been utilized for over a century [1] However, the first use of the technique as we know it today occurred during World War II [2] At that time, Dr Edwin Cohn developed both a technique and a device for isolating the serum albumin fraction of blood plasma Indeed, transfusions of this purified albumin component were responsible for rescuing thousands of soldiers from hypovolemic shock After the war, Cohn worked to develop systems by which every component of donated blood could be used, ensuring that nothing would be wasted The final result was a device with reusable parts capable of sepa- C Taylan Department of Pediatric Nephrology, Children’s and Adolescents’ Hospital, University Hospital of Cologne, Cologne, Germany e-mail: christina.taylan@uk-koeln.de S M Sutherland (*) Department of Pediatrics, Division of Nephrology, Stanford Children’s Health and Lucille Packard Children’s Hospital, Stanford, CA, USA e-mail: suthersm@stanford.edu rating donor plasma “online” during whole blood donation [3] True therapeutic apheresis procedures became feasible after notable trends in the design of instruments improved safety, hygiene, and efficiency For example, lower extracorporeal volumes reduced the risk of hypovolemia and red blood cell (RBC) depletion; monitors and alarms were developed to detect clotting, air accumulation, and dangerous device and access pressures; anticoagulation began to be individualized for patient requirements; the size and weight of the devices decreased, allowing greater portability Therapeutic plasma exchange was first used manually in 1952 to treat a patient with multiple myeloma and hyperviscosity; whole blood was removed from the patient, RBCs were separated gravitationally and returned to the patient, and the plasma component was discarded [4] Several years later, in 1965, the engineer Jodson in collaboration with the physician Freireich created a centrifugal machine capable of removing WBCs from a patient with acute leukemic disease [5] This automated process was initially used to collect white blood cells and platelets; however, it was ultimately modified to be used for plasma exchange in 1970 [6] Today a number of therapeutic apheresis devices are available and the procedure is safe and easy to perform; technical improvements have made procedures quicker, safer, more convenient for instrument operators, and more comfortable for patients [7] © Springer Nature Switzerland AG 2021 B A Warady et al (eds.), Pediatric Dialysis, https://doi.org/10.1007/978-3-030-66861-7_48 921 ... order to decrease metabolic activity in severe hyperammonemia [44] This was confirmed later in a short series of seven cases [45] This effect was attributed to a slowing of metabolic ammonia generation... treatment for ornithine transcarbamylase deficiency Am J Transplant 2008;8(2):452–7 48 Brunetti-Pierri N, Clarke C, Mane V, Palmer DJ, Lanpher B, Sun Q, et al Phenotypic correction of ornithine transcarbamylase... ammonia without worsening cerebral edema by inducing hypotension and/or creating osmotic shifts This is achieved by the following measures (1): NaCl 0.9% or albumin 5% infusion before the start