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      Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy

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          Abstract

          Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.

          Abstract

          This expert Consensus Statement from the Pediatric Continuous Renal Replacement Therapy (PCRRT) workgroup presents recommendations for the management of hyperammonaemia requiring kidney replacement therapy in paediatric populations. Additional studies are needed to strengthen these recommendations, which will be reviewed every 2 years.

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          Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods.

          Hypothermia is being used with increasing frequency to prevent or mitigate various types of neurologic injury. In addition, symptomatic fever control is becoming an increasingly accepted goal of therapy in patients with neurocritical illness. However, effectively controlling fever and inducing hypothermia poses special challenges to the intensive care unit team and others involved in the care of critically ill patients. To discuss practical aspects and pitfalls of therapeutic temperature management in critically ill patients, and to review the currently available cooling methods. Review article. None. Cooling can be divided into three distinct phases: induction, maintenance, and rewarming. Each has its own risks and management problems. A number of cooling devices that have reached the market in recent years enable reliable maintenance and slow and controlled rewarming. In the induction phase, rapid cooling rates can be achieved by combining cold fluid infusion (1500-3000 mL 4 degrees C saline or Ringer's lactate) with an invasive or surface cooling device. Rapid induction decreases the risks and consequences of short-term side effects, such as shivering and metabolic disorders. Cardiovascular effects include bradycardia and a rise in blood pressure. Hypothermia's effect on myocardial contractility is variable (depending on heart rate and filling pressure); in most patients myocardial contractility will increase, although mild diastolic dysfunction can develop in some patients. A risk of clinically significant arrhythmias occurs only if core temperature decreases below 30 degrees C. The most important long-term side effects of hypothermia are infections (usually of the respiratory tract or wounds) and bedsores. Temperature management and hypothermia induction are gaining importance in critical care medicine. Intensive care unit physicians, critical care nurses, and others (emergency physicians, neurologists, and cardiologists) should be familiar with the physiologic effects, current indications, techniques, complications and practical issues of temperature management, and induced hypothermia. In experienced hands the technique is safe and highly effective.
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            Glutamine: a Trojan horse in ammonia neurotoxicity.

            Mechanisms involved in hepatic encephalopathy still remain to be defined. Nonetheless, it is well recognized that ammonia is a major factor in its pathogenesis, and that the astrocyte represents a major target of its CNS toxicity. In vivo and in vitro studies have shown that ammonia evokes oxidative/nitrosative stress, mitochondrial abnormalities (the mitochondrial permeability transition, MPT) and astrocyte swelling, a major component of the brain edema associated with fulminant hepatic failure. How ammonia brings about these changes in astrocytes is not well understood. It has long been accepted that the conversion of glutamate to glutamine, catalyzed by glutamine synthetase, a cytoplasmic enzyme largely localized to astrocytes in brain, represented the principal means of cerebral ammonia detoxification. Yet, the "benign" aspect of glutamine synthesis has been questioned. This article highlights evidence that, at elevated levels, glutamine is indeed a noxious agent. We also propose a mechanism by which glutamine executes its toxic effects in astrocytes, the "Trojan horse" hypothesis. Much of the newly synthesized glutamine is subsequently metabolized in mitochondria by phosphate-activated glutaminase, yielding glutamate and ammonia. In this manner, glutamine (the Trojan horse) is transported in excess from the cytoplasm to mitochondria serving as a carrier of ammonia. We propose that it is the glutamine-derived ammonia within mitochondria that interferes with mitochondrial function giving rise to excessive production of free radicals and induction of the MPT, two phenomena known to bring about astrocyte dysfunction, including cell swelling. Future therapeutic approaches might include controlling excessive transport of newly synthesized glutamine to mitochondria and its subsequent hydrolysis.
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              Hyperammonemia in review: pathophysiology, diagnosis, and treatment.

              Ammonia is an important source of nitrogen and is required for amino acid synthesis. It is also necessary for normal acid-base balance. When present in high concentrations, ammonia is toxic. Endogenous ammonia intoxication can occur when there is impaired capacity of the body to excrete nitrogenous waste, as seen with congenital enzymatic deficiencies. A variety of environmental causes and medications may also lead to ammonia toxicity. Hyperammonemia refers to a clinical condition associated with elevated ammonia levels manifested by a variety of symptoms and signs, including significant central nervous system (CNS) abnormalities. Appropriate and timely management requires a solid understanding of the fundamental pathophysiology, differential diagnosis, and treatment approaches available. The following review discusses the etiology, pathogenesis, differential diagnosis, and treatment of hyperammonemia.
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                Author and article information

                Contributors
                rraina@akronchildrens.org
                Journal
                Nat Rev Nephrol
                Nat Rev Nephrol
                Nature Reviews. Nephrology
                Nature Publishing Group UK (London )
                1759-5061
                1759-507X
                8 April 2020
                8 April 2020
                2020
                : 16
                : 8
                : 471-482
                Affiliations
                [1 ]ISNI 0000 0000 9013 1194, GRID grid.413473.6, Department of Nephrology, , Akron Children’s Hospital, ; Akron, OH USA
                [2 ]Akron Nephrology Associates/Cleveland Clinic Akron General, Akron, OH USA
                [3 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Center for Human Genetics, , University Hospitals Cleveland Medical Center and Department of Genetics and Genome Sciences, Case Western Reserve University, ; Cleveland, OH USA
                [4 ]ISNI 0000 0000 9753 0008, GRID grid.239553.b, Division of Medical Genetics, , UPMC Children’s Hospital of Pittsburgh, ; Pittsburgh, PA USA
                [5 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Department of Paediatrics, Sainte-Justine Hospital, , University of Montreal, ; Montreal, Quebec Canada
                [6 ]ISNI 0000 0001 0727 6809, GRID grid.414125.7, Division of Nephrology and Dialysis, Department of Paediatrics, , Bambino Gesù Children’s Hospital and Research Institute, ; Rome, Italy
                [7 ]ISNI 0000 0004 1936 9510, GRID grid.253615.6, Children’s National Rare Disease Institute, , The George Washington University, ; Washington, DC USA
                [8 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Department of Emergency Medicine, , University of São Paulo School of Medicine, ; São Paulo, Brazil
                [9 ]GRID grid.415629.d, Department of Pediatrics, , Rainbow Babies and Children’s Hospital, ; Cleveland, OH USA
                [10 ]ISNI 0000 0000 9144 1055, GRID grid.414154.1, Department of Pediatric Nephrology, , Children’s Hospital of Michigan, ; Detroit, MI USA
                [11 ]ISNI 0000 0004 0458 8737, GRID grid.224260.0, Pediatric Nephrology & Transplantation, Children’s Hospital of Richmond, , Virginia Commonwealth University, ; Richmond, VA USA
                [12 ]ISNI 0000 0004 1764 4857, GRID grid.429252.a, Paediatric Nephrology & Paediatric Kidney Transplantation, Kidney and Urology Institute, Medanta, The Medicity Hospital, ; Gurgaon, India
                [13 ]ISNI 0000 0004 0459 7529, GRID grid.261103.7, Northeast Ohio Medical University, ; Rootstown, OH USA
                [14 ]ISNI 0000 0004 1937 1151, GRID grid.7836.a, Red Cross War Memorial Children’s Hospital, , University of Cape Town, ; Cape Town, South Africa
                [15 ]ISNI 0000 0004 1773 5396, GRID grid.56302.32, Department of Paediatrics, , King Saud University, College of Medicine, ; Riyadh, Saudi Arabia
                [16 ]ISNI 0000 0004 1767 6103, GRID grid.413618.9, Division of Paediatric Nephrology, , All India Institute of Medical Sciences, ; New Delhi, India
                [17 ]ISNI 0000 0004 0371 6071, GRID grid.428158.2, Department of Pediatric Critical Care Medicine, , Children’s Healthcare of Atlanta, ; Atlanta, GA USA
                [18 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Division of Paediatric Nephrology, , University Children’s Hospital Heidelberg, ; Heidelberg, Germany
                [19 ]ISNI 0000 0004 1936 8884, GRID grid.39381.30, Division of Paediatric Nephrology, Department of Paediatrics, , Western University, ; London, Ontario Canada
                [20 ]ISNI 0000 0004 0415 5050, GRID grid.239559.1, Division of Nephrology, , University of Missouri–Kansas City School of Medicine, Children’s Mercy, ; Kansas City, MO USA
                Author information
                http://orcid.org/0000-0003-1891-6765
                Article
                267
                10.1038/s41581-020-0267-8
                7366888
                32269302
                604ffc35-9113-4fcf-b5ad-4b32f05f965a
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 March 2020
                Categories
                Consensus Statement
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                © Springer Nature Limited 2020

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