The Effect of dialysis rate on continuous renal replacement therapy for neonatal hyperammonemia

The Effect of dialysis rate on continuous renal replacement therapy for neonatal hyperammonemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effect of dialysis rate on continuous renal replacement therapy for neonatal hyperammonemia Xiaoyun Chu, Yifan Sun, Wenchao Hong, Xiaohui Gong, Cheng Cai This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2045798/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background CRRT has attracted more and more attention in the treatment of acute neonatal hyperammonemia. Methods We retrospectively analyzed the clinical data of hyperammonemic neonates treated with CRRT in the neonatal intensive care unit (NICU) of Shanghai Children's Hospital from August 2016 to September 2021, and further explored the relationship between the rate of decrease of blood ammonia and dialysis rate. Results A total of 6 cases of neonatal hyperammonemia were included, their primary diseases were 3 cases of ornithine transcarbamyltransferase deficiency (OTCD), 1 case of carbamoyl phosphate synthetase 1 deficiency (CPS1D), 1 case of methylmalonic acidemia (MMA) with homocysteinemia (combined MMA) and 1 case of transient hyperammonemia. All infants developed impaired consciousness, convulsions and severe hyperammonemia, so CRRT was superimposed on diet control and medication, and the mode of continuous venovenous hemodiafiltration (CVVHDF) was used in all cases. The gestational age at birth was (37.98 ± 1.12) weeks, the age at onset was (1.91 ± 0.91) d, and the weight at CRRT was (3157.50 ± 605.95) g. The dialysis rate was (880–3937) ml/h/1.73m 2 , the decrease rate of blood ammonia was (15.79–33.33) µmol/h, and the duration of CRRT diversion was 44–110 h. The decrease rate of blood ammonia increased with the increase in dialysis rate, without an increase in the incidence of serious complications. Conclusions CRRT can alleviate the metabolic crisis of hyperammonemic neonates, and increasing the dialysis rate of CRRT can safely and more effectively reduce blood ammonia levels in critically hyperammonemic neonates. continuous renal replacement therapy dialysis rate hyperammonemia neonates Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Hyperammonemia is a rare, critical and life-threatening condition for neonates [1]. Based on the etiology, it can be classified as congenital hereditary, acquired and transient hyperammonemia, among which congenital hereditary hyperammonemia caused by urea cycle disorders and organic acidemia is the common cause of neonatal hyperammonemia [2]. The clinical symptoms of hyperammonemia are mainly due to neurotoxicity caused by rapidly elevated blood ammonia levels [3]. In neonates, sepsis-like manifestations such as poor circulation, shortness of breath and lethargy may occur within hours to days after birth and progress rapidly to respiratory failure and coma, with a high mortality rate [4,5]. In surviving neonates, repeated and frequent episodes of hyperammonemia can lead to growth and mental retardation [6], causing a huge economic and psychological burden to the family and society. Therefore, early diagnosis and rapid normalisation of blood ammonia levels is essential to avoid neurological damage and associated complications [7]. At present, in addition to restriction of protein intake and administration of ammonia scavengers, blood purification techniques (including peritoneal dialysis, hemodialysis, and CRRT) have attracted more and more attention in the treatment of acute neonatal hyperammonemia. Of these, CRRT has become an important treatment for neonatal hyperammonemia because it causes fewer cardiovascular complications and has a lower risk of rebound hyperammonemia [8,9]. However, in neonates, CRRT is difficult to perform due to a large circuit volume and establishment of vascular access. Therefore, there is still a lack of large-scale multi-center data on CRRT in the treatment of neonatal hyperammonemia. This retrospective study was designed to evaluate the safety and efficacy of CRRT with different dialysis rates for the treatment of hyperammonemic neonates during episodes of metabolic dysregulation. At the same time, we further investigated the relationship between the dialysis rate of CRRT and the rate of decrease in blood ammonia. Methods Study population This was a single center, retrospective, observational cohort study, which was approved by the Institutional Review Board (IRB) of Shanghai Children's Hospital (IRB number：2020R064-E02). All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects and their legal guardians. Neonates who received CRRT for hyperammonemia in the NICU of Shanghai Children’s Hospital from August 2016 to September 2021 were enrolled in this study. Inclusion criteria were age at CRRT 500 µmol/L. We excluded any neonates who had CRRT for reasons other than ammonia clearance. Hyperammonemia is defined as blood ammonia above 150 μmol/L in premature neonates, above 100 μmol/L in term neonates, above 40 μmol/L in infants and children, and above 32 μmol/L in adults [10]. Non-renal replacement therapy In the initial management of acute hyperammonaemia, the patient's vital signs should be stabilized immediately. Oxygen can be administered in cases of respiratory distress and, if necessary, tracheal intubation. For neonates in shock, apply fluid resuscitation and, if necessary, vasoactive drugs. Sedation and antispasmodic for convulsions; mannitol to lower cranial pressure for cerebral edema; rehydration and stabilization of internal environment for acid-base imbalance and electrolyte disturbance. The first-line treatment for hyperammonemia includes stopping protein intake for 24-48 h and initiating intravenous glucose and lipids to prevent catabolism. The continuous glucose infusion could be 8-10 mg/(kg.min) and lipids could be 1-2 g/(kg.d) to reach 130-150 kcal/(kg.d) caloric. Intravenous l-arginine hydrochloride 200 mg/kg in patients with urea cycle disorder to improve the flow through the urea cycle. L-carnitine was administered at a dose of 100 mg/(kg.d) to prevent secondary carnitine deficiency. Cobalamin (vitamin B12 1mg) was administered as an injection for patients with combined MMA. CRRT treatment The equipment was Plasauto iQ21, and a 5F double-lumen central venous line was left in the right internal jugular or femoral vein, all in CVVHDF mode. (1) Pre-filling: the filter was pre-filled with heparin saline first, and then the filter was pre-filled with red blood cell suspension. (2) Anticoagulation: conventional plain heparin anticoagulation at a dose of 10-30 U/kg/h to maintain the activated partial thromboplastin time at 1.5-2.0 times the normal value. (3) Parameter settings: blood flow rate of blood pump was 3-5ml/kg/min, the flow rate of replacement fluid was 15-30ml/kg/h, dialysis fluid 880-3937ml/h/1.73m 2 . Dewatering capacity depending on liquid overload, with uninterrupted diversion. (4) Dialysis fluid and replacement fluid: both used modified Ports formula, Ringer’s solution 3000 ml, 5% glucose solution 100 ml, 10% calcium chloride solution 7.5 ml, 50% magnesium sulfate solution 1.6 ml and 5% sodium bicarbonate solution 200 ml. The ion concentrations of this formula were: Na + 130.0 mmol/L, K + 4.0 mmol/L, HCO3 - 28.0 mmol/L, Ca 2+ 1.5 mmol/L, Mg 2+ 3.2 mmol/L, Cl - 109.0 mmol/L. The ion concentrations were adjusted according to electrolyte monitoring. Observation item Summarize the clinical information of the neonates including gestational age, age at onset of disease, weight at CRRT, primary disease, initial blood ammonia concentration, CRRT dialysis rate, treatment duration, blood ammonia decline rate, blood ammonia after treatment and clinical outcome. Evaluation of curative effect We evaluated the efficacy by analyzing changes of blood ammonia, blood electrolytes and the recovery of consciousness levels before and after CRRT, and further explore the relationship between the rate of decrease in blood ammonia and the rate of dialysis. Evaluation of safety We assessed the presence of related complications by monitoring temperature, blood pressure, white blood cells, platelets and CRP before and after treatment. Statistical analysis Statistical analysis of data was performed using SPSS 17.0 statistical software. The measurement data conforming to normal distribution were expressed as`x±s. The t-test was used for comparison between groups. The relationship between dialysis rate and the rate of blood ammonia decrease was analyzed by Pearson correlation, P <0.05 was considered statistically significant. Results Patient's general information A total of 6 neonates with hyperammonemia were included, with 3 cases of OTCD, 1 case of CPS1D, 1 case of combined MMA and 1 case of transient hyperammonemia. The gestational age (GA) were (37.98 ± 1.12) weeks, the age at onset of disease was (1.91 ± 0.91) d, and the weight at CRRT was (3157.50 ± 605.95) g. The blood ammonia levels of all six children decreased significantly after treatment, of which two survived and four died after abandoning treatment (Table 1). Table 1. Clinical profile of 6 neonates with hyperammonemia treated with CRRT Characteristics Study cohort (n = 6) Gestational age (week) 37.98±1.12 Sex, male/female 3/3 Age at onset of disease (d) 1.91±0.91 Weight at CRRT (g) 3157.50±605.95 Primary disease OTCD/CPSID/combined MMA Prognosis, discharged/ Died 2/4 Observation of the efficacy of different CRRT dialysis rates The initial blood ammonia concentration of the 6 neonates was >700 μmol/L, and all of them had different degrees of disturbance of consciousness and convulsions during the course of the disease. Therefore, CRRT was superimposed on the diet and medication, and the mode of CVVHDF was chosen for all of them. The dialysis rate was 880-3937 ml/h/1.73/m 2 , the rate of decrease of blood ammonia was 15.79-33.33 μmol/h, and the duration of CRRT diversion was 44-110 h. After CRRT, the infants blood ammonia concentration decreased to 137.33±70.32 μmol/L (Table 2), and their consciousness gradually recovered (Fig. 1). Moreover, there was a significant positive correlation between the dialysis rate and the decrease rate of blood ammonia (Fig. 2). Table 2. Various indicators in patients with different CRRT dialysis rates Characteristics Study cohort (n = 6) Initial blood ammonia (μmol/L) ＞700 Dialysis rate (ml/h/1.73m 2 ) 880-3937 Rate of decrease in blood ammonia (μmol/h) 15.79-33.33 Duration of the diversion (h) 44-110 Post-treatment blood ammonia (μmol/L) 137.33±70.32 The safety of CRRT The body temperature and blood pressure of all 6 neonates were maintained within the normal range before and after treatment (Fig. 3). Four neonates had hypocalcemia before CRRT, which returned to normal after CRRT, and the rest of electrolytes were normal (Fig. 4). The leukocyte and CRP of all 6 neonates were monitored normally, the platelets of 4 neonates dropped after CRRT and returned to normal after platelet transfusions (Fig. 5). One neonate developed circuit clotting during CRRT. Discussion Neonatal hyperammonemia is a critical illness with clinical manifestations of acute metabolic decompensated encephalopathy. A dramatic increase in blood ammonia levels can cross the brain barrier causing elevated extracellular potassium and increased glutamine synthesis in the brain. These changes together lead to increased intracellular osmotic pressure, brain edema, and release of inflammatory cytokines [11,12], resulting in irreversible damage to the brain [13], which can lead to intractable seizures, cognitive and motor deficits, cerebral palsy and even death in neonates [14]. The duration of coma and the degree of hyperammonemia in hyperammonemic neonates are the most critical factors affecting their neurological prognosis [15,16]. Therefore, it is crucial to recognize hyperammonemia in a timely manner and provide aggressive and effective treatment. Based on published case reports and retrospective studies of children aged 1 day to 7 years, the PCRRT Working Group issued a guideline for the treatment of neonatal and pediatric hyperammonemia by non-kidney replacement therapy (NKRT) and kidney replacement therapy (KRT), recommending CKRT specifically high-dose CVVHD as the first-line treatment for acute hyperammonemia [17]. In this study, all 6 neonates had severe hyperammonemia and neurological manifestations such as impaired consciousness and convulsions during the course of their illness. We immediately started CRRT and adopted the CVVHDF mode to remove blood ammonia. A gradual return of consciousness was observed in all 6 neonates and the blood ammonia decreased to 137.33 ± 70.32µmol/L. In addition, by increasing the dialysis rate of CRRT, the rate of decline in blood ammonia was also increased. A pearson correlation analysis revealed a significant positive correlation between the dialysis rate and the rate of decrease in blood ammonia. Spinale corroborated this view [17], using a higher dialysis rate of CRRT (8000 ml/h/1.73m 2 , 4 times higher than the normal dialysate/replacement rate used for acute kidney injury) to efficiently and safely treat 2 neonates with OTCD. In a retrospective study by Markham [18], CRRT at the same dialysis rate was also successful in treating two neonates with hyperammonemia. Therefore, in neonates with severe hyperammonemia, high-clearance CRRT should be used to rapidly reduce blood ammonia levels in the early stages to reduce adverse neurological prognosis. Ammonia is a small molecule with a relative molecular mass of 17 g/mol and, like urea, has a high diffusive removal rate. Blood flow, dialysate flow rate and dialyzer membrane surface area are three important clinical parameters that determine overall ammonia clearance [2]. Intermittent hemodialysis (HD) has a high ammonia clearance rate, which is generally considered the preferred modality for the treatment of acute hyperammonemia [19]. However, the temporary cessation of intermittent HD clearance may lead to a rebound of blood ammonia due to the continuous production of ammonia in the patient's body [20]. In addition, in the setting of cerebral edema, intermittent HD may lose continuous control of ammonia concentration, serum sodium concentration, pH levels, core body temperature, and overall fluid balance [19]. CRRT, provides continuity of treatment, can reduce rebound of blood ammonia and better maintains the body's environmental and haemodynamic stability [17]. In this study, none of the 6 neonates experienced rebound of ammonia during CRRT treatment, which was consistent with previous report [21]. Four neonates had varying degrees of hypocalcaemia during course of the disease, which was considered to be related to the critical state of the child at the time, the exact underlying mechanism of which has not been elucidated, and was corrected after CRRT. All 6 neonates had normal sodium and potassium levels before and after CRRT treatment. This may be due to the fact that CRRT allows electrolyte replacement to be safely mixed in the dialysis/replacement fluid through the pharmacy to maintain normal electrolyte levels [17]. Although CRRT is a life-saving treatment, complications such as circuit clotting, hypothermia, hypotension, anemia, thrombocytopenia and electrolyte disturbances may occur during the treatment [22], with anemia and thrombocytopenia being common complications in neonates [23]. In a single-center retrospective study by Akduman [24], the incidence of thrombocytopenia was 62.5%. In this study, 4 of the 6 hyperammonemic neonates who underwent CRRT developed thrombocytopenia, and the difference was statistically significant, which may be related to the application of anticoagulants and the consumption of blood filters. One neonate had a restricted blood flow and pressure alarm due to inadequate catheter function thus interrupting blood flow and eventually causing circuit clotting. At the same time, there were no significant differences in infection indicators before and after treatment, suggesting that CRRT at high dialysis rates can be safely used in neonates. Conclusions In conclusion, increasing the dialysis rate of CRRT can safely and more effectively reduce blood ammonia levels and alleviate the metabolic crisis in critically hyperammonemic neonates, and CRRT with high dialysis rate is the best choice. However, this study is a single-center retrospective study with a small sample size. Although the dialysis rate of CRRT has been improved according to the actual situation in clinical work, the best choice of dialysis rate needs to be further explored at present. List Of Abbreviations CRRT: continuous renal replacement therapy NICU: neonatal intensive care unit OTCD: ornithine transcarbamyltransferase deficiency CPS1D: carbamoyl phosphate synthetase 1 deficiency MMA: methylmalonic acidemia CVVHDF: continuous venovenous hemodiafiltration IRB: Institutional Review Board Declarations Ethics approval and consent to participate This retrospective review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board (IRB) of Shanghai Children's Hospital (IRB number：2020R064-E02) approved this study. Consent for publication Written informed consent was obtained from patient’s guardian for publication of this paper. Availability of data and materials The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was supported by the special medical innovation research project of Shanghai “scientific and technological innovation action plan” in 2020 (20Y11907000). Authors' contributions C.C. made substantial contributions to conception and design. C.X.Y. and S.Y.F. collected the data. H.W.C. and G.X.H. made analysis and interpretation of data. C.X.Y. drafted the manuscript. C.C. revised the manuscript and gave final approval of the version to be published. Agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript. Acknowledgements The authors thank their hyperammonemic neonates for participating in this study. Special thanks are also due to the NICU nurses who have made this study possible. References Robinson JR, Conroy PC, Hardison D, et al. Rapid resolution of hyperammonemia in neonates using extracorporeal membrane oxygenation as a platform to drive hemodialysis. J Perinatol. 2018;38:665-71. Gupta S, Fenves AZ, Hootkins R. The Role of RRT in Hyperammonemic Patients. Clin J Am Soc Nephrol. 2016;11:1872-8. Ott P, Vilstrup H. Cerebral effects of ammonia in liver disease: current hypotheses. Metab Brain Dis.2014;29:901-11. Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42:1192-230. Häberle J, Chakrapani A, Ah Mew N, et al. Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories. Orphanet J Rare Dis.2018;13:219. Vergano SA, Crossette JM, Cusick FC et al. Improving surveillance for hyperammonemia in the newborn. Mol Genet Metab. 2013;110:102-5. Matoori S, Leroux JC. Recent advances in the treatment of hyperammonemia.Adv Drug Deliv Rev. 2015;90:55-68. Lai YC, Huang HP, Tsai IJ, et al. High-volume continuous venovenous hemofiltration as an effective therapy for acute management of inborn errors of metabolism in young children. Blood Purif. 2007;25:303-8. Hiroma T, Nakamura T, Tamura M, et al. Continuous venovenous hemodiafiltration in neonatal onset hyperammonemia. Am J Perinatol. 2002;19:221-4. Matsumoto S, Häberle J, Kido J, et al. Urea cycle disorders-update. J Hum Genet. 2019;64:833-47. Auron A, Brophy PD. Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol. 2012;27:207-22. Upadhyay R, Bleck TP, Busl KM. Hyperammonemia: What Urea-lly Need to Know: Case Report of Severe Noncirrhotic Hyperammonemic Encephalopathy and Review of the Literature. Case Rep Med. 2016;doi: 10.1155/2016/8512721. Häberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011;170:21-34. Savy N. Acute pediatric hyperammonemia: current diagnosis and management strategies. Hepat Med. 2018;10:105-15. Kido J, Nakamura K, Mitsubuchi H, et al. Long-term outcome and intervention of urea cycle disorders in Japan. J Inherit Metab Dis. 2012;35: 777-85. Picca S, Dionisi-Vici C, Abeni D, et al. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol.2001;16:862-7. Spinale JM, Laskin BL, Sondheimer N, et al. High-dose continuous renal replacement therapy for neonatal hyperammonemia. Pediatr Nephrol. 2013;28: 983-6. Markham C, Williams C, Miller C, et al. Continuous Renal Replacement Therapy for Two Neonates With Hyperammonemia.Front Pediatr. 2021;doi: 10.3389/fped.2021.732354. Warrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver failure: the case for quadruple-H therapy. Anaesth Intensive Care. 2014;42:78-88. Schaefer F, Straube E, Oh J, et al. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant.1999;14:910-8. McBryde KD, Kershaw DB, Bunchman TE, et al. Renal replacement therapy in the treatment of confirmed or suspected inborn errors of metabolism. J Pediatr. 2006;148:770-8. Tandukar S, Palevsky PM. Continuous Renal Replacement Therapy: Who, When, Why, and How. Chest. 2019;155:626-38. Aygun F, Varol F, Aktuglu-Zeybek C, et al. Continuous Renal Replacement Therapy with High Flow Rate Can Effectively, Safely, and Quickly Reduce Plasma Ammonia and Leucine Levels in Children. Children (Basel) . 2019;6: 53. Akduman H, Okulu E, Eminoğlu FT, et al. Continuous venovenous hemodiafiltration in the treatment of newborns with an inborn metabolic disease: a single center experience. Turk J Med Sci. 2020;50:12-7. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2045798","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":136876807,"identity":"7af30f15-d6a2-412c-b6db-32c27de820e0","order_by":0,"name":"Xiaoyun Chu","email":"","orcid":"","institution":"Shanghai Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoyun","middleName":"","lastName":"Chu","suffix":""},{"id":136876809,"identity":"804dd087-6d0d-43e6-ad44-f2822ace19cf","order_by":1,"name":"Yifan Sun","email":"","orcid":"","institution":"Shanghai Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yifan","middleName":"","lastName":"Sun","suffix":""},{"id":136876811,"identity":"999ca8dc-ae0f-4f25-8429-e96930d33e22","order_by":2,"name":"Wenchao Hong","email":"","orcid":"","institution":"Shanghai Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wenchao","middleName":"","lastName":"Hong","suffix":""},{"id":136876813,"identity":"a6b5fdf4-4792-4af4-9642-821529352937","order_by":3,"name":"Xiaohui Gong","email":"","orcid":"","institution":"Shanghai Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaohui","middleName":"","lastName":"Gong","suffix":""},{"id":136876814,"identity":"9ebe9b57-93e9-4e88-bb36-0b52b9f9bc88","order_by":4,"name":"Cheng Cai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYFACxgZmEMXPzNhg8MHAxo54LZLtzQcKZxSkJRNlD1iLwZljCZ95PhxibCCknL/9cOPngoo7dg03cgw32xgcYGZgP3x0Az4tEmcSm6VnnHmW3Dgjx9g4x+AOHwNPWtoNfFoMGBLbmHnbDiczS+SYAbU8Y2aQ4DHDr4X/IVDLv8PJbBI55r8tDA4zNhDUIgGypeGwHQ/PsQRjBmK0SNx42CzNc+xwggR78wHDHoO0ZDZCfuHvT3/4mafmsL090HyDH39s7PjZDx/DqwUGEhtgLDZilIOAPbEKR8EoGAWjYAQCAHu+TJDvmDUWAAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Children's Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Cai","suffix":""}],"badges":[],"createdAt":"2022-09-08 14:44:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2045798/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2045798/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":26583700,"identity":"f1965394-5788-4f26-9def-9d7b40285b86","added_by":"auto","created_at":"2022-09-16 21:10:04","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":194861,"visible":true,"origin":"","legend":"\u003cp\u003eDiagram showed a timeline of the measured ammonia level in 6 neonates, a gradual decrease in blood ammonia can be observed after diet, medication and CRRT treatment during hospitalization.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2045798/v1/50ba545670412a51e322ba8c.jpg"},{"id":26583699,"identity":"dc234478-58c4-44ef-99c8-ea2230e678e5","added_by":"auto","created_at":"2022-09-16 21:10:04","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32600,"visible":true,"origin":"","legend":"\u003cp\u003eWith the increase of dialysis rate, the rate of decrease of blood ammonia also increased, and there was a significant positive correlation between the dialysis rate and the decrease rate of blood ammonia.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2045798/v1/cda0aaffa8c0d0a2311dca2f.jpg"},{"id":26584478,"identity":"dd152c58-2f10-45a8-94f8-69699fafb46f","added_by":"auto","created_at":"2022-09-16 21:15:04","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":46187,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of basic vital signs in 6 neonates before and after CRRT treatment, no statistically significant difference. \u003cstrong\u003eA \u003c/strong\u003eBody temperature, B Mean arterial pressure.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2045798/v1/b156df552f1cf0b8d469ea4a.jpg"},{"id":26583696,"identity":"2822f4e0-9042-45aa-a268-29334b42ed5e","added_by":"auto","created_at":"2022-09-16 21:10:04","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":67243,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of electrolyte levels in 6 neonates before and after CRRT treatment. A statistically significant difference can be seen in blood calcium, with no significant difference in blood potassium and sodium. \u003cstrong\u003eA \u003c/strong\u003eBlood potassium,\u003cstrong\u003e B\u003c/strong\u003e Blood sodium, \u003cstrong\u003eC \u003c/strong\u003eBlood Calcium.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2045798/v1/eb63733b9208624daece893e.jpg"},{"id":26583697,"identity":"e30c0466-44b1-44a9-b3d9-c9ec84e6b6c8","added_by":"auto","created_at":"2022-09-16 21:10:04","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":66301,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of inflammatory indicators in 6 neonates before and after CRRT treatment. A statistically significant difference can be seen in platelets, with no significant difference in leukocytes and C-reactive protein. \u003cstrong\u003eA \u003c/strong\u003eLeukocytes, \u003cstrong\u003eB \u003c/strong\u003ePlatelets, \u003cstrong\u003eC\u003c/strong\u003e C-reactive protein.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2045798/v1/4324377877b618049cbaac00.jpg"},{"id":28256775,"identity":"e1350783-d242-4f7c-a3c3-d849c33ed412","added_by":"auto","created_at":"2022-10-26 03:59:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":508004,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2045798/v1/8e258f29-29d5-4dd3-8637-3a491fcab5b8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of dialysis rate on continuous renal replacement therapy for neonatal hyperammonemia","fulltext":[{"header":"Background","content":"\u003cp\u003eHyperammonemia is a rare, critical and life-threatening condition for neonates [1]. Based on the etiology, it can be classified as congenital hereditary, acquired and transient hyperammonemia, among which congenital hereditary hyperammonemia caused by urea cycle disorders and organic acidemia is the common cause of neonatal hyperammonemia [2]. The clinical symptoms of hyperammonemia are mainly due to neurotoxicity caused by rapidly elevated blood ammonia levels [3]. In neonates, sepsis-like manifestations such as poor circulation, shortness of breath and lethargy may occur within hours to days after birth and progress rapidly to respiratory failure and coma, with a high mortality rate [4,5]. In surviving neonates, repeated and frequent episodes of hyperammonemia can lead to growth and mental retardation [6], causing a huge economic and psychological burden to the family and society. Therefore, early diagnosis and rapid normalisation of blood ammonia levels is essential to avoid neurological damage and associated complications [7]. At present, in addition to restriction of protein intake and administration of ammonia scavengers, blood purification techniques (including peritoneal dialysis, hemodialysis, and CRRT) have attracted more and more attention in the treatment of acute neonatal hyperammonemia. Of these, CRRT has become an important treatment for neonatal hyperammonemia because it causes fewer cardiovascular complications and has a lower risk of rebound hyperammonemia [8,9]. However, in neonates, CRRT is difficult to perform due to a large circuit volume and establishment of vascular access. Therefore, there is still a lack of large-scale multi-center data on CRRT in the treatment of neonatal hyperammonemia. This retrospective study was designed to evaluate the safety and efficacy of CRRT with different dialysis rates for the treatment of hyperammonemic neonates during episodes of metabolic dysregulation. At the same time, we further investigated the relationship between the dialysis rate of CRRT and the rate of decrease in blood ammonia.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a single center, retrospective, observational cohort study, which was approved by the Institutional Review Board (IRB)\u0026nbsp;of Shanghai Children\u0026apos;s Hospital (IRB number：2020R064-E02). All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects and their legal guardians.\u003c/p\u003e\n\u003cp\u003eNeonates who received CRRT for hyperammonemia in the NICU of Shanghai Children\u0026rsquo;s Hospital from August 2016 to September 2021 were enrolled in this study. Inclusion criteria were age at CRRT \u0026lt;28 d and diagnosed hyperammonemia with inadequate clinical response to ammonia scavengers or blood ammonia levels \u0026gt;500 \u0026micro;mol/L. We excluded any neonates who had CRRT for reasons other than ammonia clearance.\u003c/p\u003e\n\u003cp\u003eHyperammonemia is defined as blood ammonia above 150 \u0026mu;mol/L in premature neonates, above 100 \u0026mu;mol/L in term neonates, above 40 \u0026mu;mol/L in infants and children, and above 32 \u0026mu;mol/L in adults\u0026nbsp;[10].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNon-renal replacement therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the initial management of acute hyperammonaemia, the patient\u0026apos;s vital signs should be stabilized immediately. Oxygen can be administered in cases of respiratory distress and, if necessary, tracheal intubation. For neonates in shock, apply fluid resuscitation and, if necessary, vasoactive drugs. Sedation and antispasmodic for convulsions; mannitol to lower cranial pressure for cerebral edema; rehydration and stabilization of internal environment for acid-base imbalance and electrolyte disturbance.\u003c/p\u003e\n\u003cp\u003eThe first-line treatment for hyperammonemia includes stopping protein intake for 24-48 h and initiating intravenous glucose and lipids to prevent catabolism.\u0026nbsp;The continuous glucose infusion could be 8-10 mg/(kg.min) and lipids could be 1-2 g/(kg.d) to reach 130-150 kcal/(kg.d) caloric. Intravenous l-arginine hydrochloride 200\u0026thinsp;mg/kg in patients with\u0026nbsp;urea cycle disorder to improve the flow through the urea cycle. L-carnitine was administered at a dose of 100 mg/(kg.d) to prevent secondary carnitine deficiency. Cobalamin (vitamin B12 1mg) was administered as an injection for patients with combined MMA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRRT treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe equipment was Plasauto iQ21, and a 5F double-lumen central venous line was left in the right internal jugular or femoral vein, all in CVVHDF mode.\u003c/p\u003e\n\u003cp\u003e(1) Pre-filling: the filter was pre-filled with heparin saline first, and then the filter was pre-filled with red blood cell suspension.\u003c/p\u003e\n\u003cp\u003e(2) Anticoagulation: conventional plain heparin anticoagulation at a dose of 10-30 U/kg/h to maintain the activated partial thromboplastin time at 1.5-2.0 times the normal value.\u003c/p\u003e\n\u003cp\u003e(3) Parameter settings: blood flow rate of blood pump was 3-5ml/kg/min, the flow rate of replacement fluid was 15-30ml/kg/h, dialysis fluid 880-3937ml/h/1.73m\u003csup\u003e2\u003c/sup\u003e. Dewatering capacity depending on liquid overload, with uninterrupted diversion.\u003c/p\u003e\n\u003cp\u003e(4) Dialysis fluid and replacement fluid: both used modified Ports formula, Ringer\u0026rsquo;s solution 3000\u0026thinsp;ml, 5% glucose solution 100\u0026thinsp;ml, 10% calcium chloride solution 7.5\u0026thinsp;ml, 50% magnesium sulfate solution 1.6\u0026thinsp;ml and 5% sodium bicarbonate solution 200\u0026thinsp;ml. The ion concentrations of this formula were: Na\u003csup\u003e+\u003c/sup\u003e 130.0 mmol/L, K\u003csup\u003e+\u003c/sup\u003e 4.0 mmol/L, HCO3\u003csup\u003e-\u003c/sup\u003e 28.0 mmol/L, Ca\u003csup\u003e2+\u003c/sup\u003e 1.5 mmol/L, Mg\u003csup\u003e2+\u003c/sup\u003e 3.2 mmol/L, Cl\u003csup\u003e-\u003c/sup\u003e 109.0 mmol/L. The ion concentrations were adjusted according to electrolyte monitoring.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObservation item\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSummarize the clinical information of the neonates including gestational age, age at onset of disease, weight at CRRT, primary disease, initial blood ammonia concentration, CRRT dialysis rate, treatment duration, blood ammonia decline rate, blood ammonia after treatment and clinical outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvaluation of curative effect\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe evaluated the efficacy by analyzing changes of blood ammonia, blood electrolytes and the recovery of consciousness levels before and after CRRT, and further explore the relationship between the rate of decrease in blood ammonia and the rate of dialysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvaluation of safety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe assessed the presence of related complications by monitoring temperature, blood pressure, white blood cells, platelets and CRP before and after treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis of data was performed using SPSS 17.0 statistical software. The measurement data conforming to normal distribution were expressed as`x\u0026plusmn;s. The t-test was used for comparison between groups. The relationship between dialysis rate and the rate of blood ammonia decrease was analyzed by Pearson correlation, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient\u0026apos;s general information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 6 neonates with hyperammonemia were included, with 3 cases of OTCD, 1 case of CPS1D, 1 case of combined MMA and 1 case of\u0026nbsp;transient hyperammonemia. The gestational age (GA) were (37.98 \u0026plusmn; 1.12) weeks, the age at onset\u0026nbsp;of disease\u0026nbsp;was (1.91 \u0026plusmn; 0.91) d, and the weight at CRRT was (3157.50 \u0026plusmn; 605.95) g. The blood ammonia levels of all six children decreased significantly after treatment, of which two survived and four died after abandoning treatment (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Clinical profile of 6 neonates with hyperammonemia treated with CRRT\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"47.863247863247864%\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"52.136752136752136%\"\u003e\n \u003cp\u003eStudy cohort (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"47.863247863247864%\"\u003e\n \u003cp\u003eGestational age (week)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"52.136752136752136%\"\u003e\n \u003cp\u003e37.98\u0026plusmn;1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"47.863247863247864%\"\u003e\n \u003cp\u003eSex, male/female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"52.136752136752136%\"\u003e\n \u003cp\u003e3/3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"47.863247863247864%\"\u003e\n \u003cp\u003eAge at onset of disease (d)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"52.136752136752136%\"\u003e\n \u003cp\u003e1.91\u0026plusmn;0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"47.863247863247864%\"\u003e\n \u003cp\u003eWeight at CRRT (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"52.136752136752136%\"\u003e\n \u003cp\u003e3157.50\u0026plusmn;605.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"47.863247863247864%\"\u003e\n \u003cp\u003ePrimary disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"52.136752136752136%\"\u003e\n \u003cp\u003eOTCD/CPSID/combined MMA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"47.863247863247864%\"\u003e\n \u003cp\u003ePrognosis, discharged/\u0026nbsp;Died\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"52.136752136752136%\"\u003e\n \u003cp\u003e2/4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObservation of the efficacy of different CRRT dialysis rates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe initial blood ammonia concentration of the 6 neonates was \u0026gt;700 \u0026mu;mol/L, and all of them had different degrees of disturbance of consciousness and convulsions during the course of the disease. Therefore, CRRT was superimposed on the diet and medication, and the mode of CVVHDF was chosen for all of them. The dialysis rate was 880-3937 ml/h/1.73/m\u003csup\u003e2\u003c/sup\u003e, the rate of decrease of blood ammonia was 15.79-33.33 \u0026mu;mol/h, and the duration of CRRT diversion was 44-110 h. After CRRT, the infants blood ammonia concentration decreased to 137.33\u0026plusmn;70.32 \u0026mu;mol/L\u0026nbsp;(Table 2),\u0026nbsp;and their consciousness gradually recovered\u0026nbsp;(Fig. 1). Moreover, there was a significant positive correlation between the dialysis rate and the decrease rate of blood ammonia (Fig. 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Various indicators in patients with different CRRT dialysis rates\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"65.79476861167002%\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"34.20523138832998%\"\u003e\n \u003cp\u003eStudy cohort (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"65.79476861167002%\"\u003e\n \u003cp\u003eInitial blood ammonia (\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"34.20523138832998%\"\u003e\n \u003cp\u003e＞700\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"65.79476861167002%\"\u003e\n \u003cp\u003eDialysis rate (ml/h/1.73m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"34.20523138832998%\"\u003e\n \u003cp\u003e880-3937\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"65.79476861167002%\"\u003e\n \u003cp\u003eRate of decrease in blood ammonia (\u0026mu;mol/h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"34.20523138832998%\"\u003e\n \u003cp\u003e15.79-33.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"65.79476861167002%\"\u003e\n \u003cp\u003eDuration of the diversion (h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"34.20523138832998%\"\u003e\n \u003cp\u003e44-110\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"65.79476861167002%\"\u003e\n \u003cp\u003ePost-treatment blood ammonia (\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"34.20523138832998%\"\u003e\n \u003cp\u003e137.33\u0026plusmn;70.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe safety of CRRT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe body temperature and blood pressure of all 6 neonates were maintained within the normal range before and after treatment (Fig. 3). Four neonates had hypocalcemia before CRRT, which returned to normal after CRRT, and the rest of electrolytes were normal (Fig. 4). The leukocyte and CRP of all 6 neonates were monitored normally, the platelets of 4 neonates dropped after CRRT and returned to normal after platelet transfusions (Fig. 5). One neonate developed circuit clotting during CRRT.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNeonatal hyperammonemia is a critical illness with clinical manifestations of acute metabolic decompensated encephalopathy. A dramatic increase in blood ammonia levels can cross the brain barrier causing elevated extracellular potassium and increased glutamine synthesis in the brain. These changes together lead to increased intracellular osmotic pressure, brain edema, and release of inflammatory cytokines [11,12], resulting in irreversible damage to the brain [13], which can lead to intractable seizures, cognitive and motor deficits, cerebral palsy and even death in neonates [14]. The duration of coma and the degree of hyperammonemia in hyperammonemic neonates are the most critical factors affecting their neurological prognosis [15,16]. Therefore, it is crucial to recognize hyperammonemia in a timely manner and provide aggressive and effective treatment.\u003c/p\u003e \u003cp\u003e Based on published case reports and retrospective studies of children aged 1 day to 7 years, the PCRRT Working Group issued a guideline for the treatment of neonatal and pediatric hyperammonemia by non-kidney replacement therapy (NKRT) and kidney replacement therapy (KRT), recommending CKRT specifically high-dose CVVHD as the first-line treatment for acute hyperammonemia [17]. In this study, all 6 neonates had severe hyperammonemia and neurological manifestations such as impaired consciousness and convulsions during the course of their illness. We immediately started CRRT and adopted the CVVHDF mode to remove blood ammonia. A gradual return of consciousness was observed in all 6 neonates and the blood ammonia decreased to 137.33\u0026thinsp;\u0026plusmn;\u0026thinsp;70.32\u0026micro;mol/L. In addition, by increasing the dialysis rate of CRRT, the rate of decline in blood ammonia was also increased. A pearson correlation analysis revealed a significant positive correlation between the dialysis rate and the rate of decrease in blood ammonia. Spinale corroborated this view [17], using a higher dialysis rate of CRRT (8000 ml/h/1.73m\u003csup\u003e2\u003c/sup\u003e, 4 times higher than the normal dialysate/replacement rate used for acute kidney injury) to efficiently and safely treat 2 neonates with OTCD. In a retrospective study by Markham [18], CRRT at the same dialysis rate was also successful in treating two neonates with hyperammonemia. Therefore, in neonates with severe hyperammonemia, high-clearance CRRT should be used to rapidly reduce blood ammonia levels in the early stages to reduce adverse neurological prognosis.\u003c/p\u003e \u003cp\u003eAmmonia is a small molecule with a relative molecular mass of 17 g/mol and, like urea, has a high diffusive removal rate. Blood flow, dialysate flow rate and dialyzer membrane surface area are three important clinical parameters that determine overall ammonia clearance [2]. Intermittent hemodialysis (HD) has a high ammonia clearance rate, which is generally considered the preferred modality for the treatment of acute hyperammonemia [19]. However, the temporary cessation of intermittent HD clearance may lead to a rebound of blood ammonia due to the continuous production of ammonia in the patient's body [20]. In addition, in the setting of cerebral edema, intermittent HD may lose continuous control of ammonia concentration, serum sodium concentration, pH levels, core body temperature, and overall fluid balance [19]. CRRT, provides continuity of treatment, can reduce rebound of blood ammonia and better maintains the body's environmental and haemodynamic stability [17]. In this study, none of the 6 neonates experienced rebound of ammonia during CRRT treatment, which was consistent with previous report [21]. Four neonates had varying degrees of hypocalcaemia during course of the disease, which was considered to be related to the critical state of the child at the time, the exact underlying mechanism of which has not been elucidated, and was corrected after CRRT. All 6 neonates had normal sodium and potassium levels before and after CRRT treatment. This may be due to the fact that CRRT allows electrolyte replacement to be safely mixed in the dialysis/replacement fluid through the pharmacy to maintain normal electrolyte levels [17].\u003c/p\u003e \u003cp\u003eAlthough CRRT is a life-saving treatment, complications such as circuit clotting, hypothermia, hypotension, anemia, thrombocytopenia and electrolyte disturbances may occur during the treatment [22], with anemia and thrombocytopenia being common complications in neonates [23]. In a single-center retrospective study by Akduman [24], the incidence of thrombocytopenia was 62.5%. In this study, 4 of the 6 hyperammonemic neonates who underwent CRRT developed thrombocytopenia, and the difference was statistically significant, which may be related to the application of anticoagulants and the consumption of blood filters. One neonate had a restricted blood flow and pressure alarm due to inadequate catheter function thus interrupting blood flow and eventually causing circuit clotting. At the same time, there were no significant differences in infection indicators before and after treatment, suggesting that CRRT at high dialysis rates can be safely used in neonates.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, increasing the dialysis rate of CRRT can safely and more effectively reduce blood ammonia levels and alleviate the metabolic crisis in critically hyperammonemic neonates, and CRRT with high dialysis rate is the best choice. However, this study is a single-center retrospective study with a small sample size. Although the dialysis rate of CRRT has been improved according to the actual situation in clinical work, the best choice of dialysis rate needs to be further explored at present.\u003c/p\u003e"},{"header":"List Of Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eCRRT:\u003c/strong\u003e continuous renal replacement therapy\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNICU:\u0026nbsp;\u003c/strong\u003eneonatal intensive care unit\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOTCD:\u003c/strong\u003e ornithine transcarbamyltransferase deficiency\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCPS1D:\u003c/strong\u003e carbamoyl phosphate synthetase 1 deficiency\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMMA:\u003c/strong\u003e methylmalonic acidemia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCVVHDF:\u003c/strong\u003e continuous venovenous hemodiafiltration\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIRB:\u0026nbsp;\u003c/strong\u003eInstitutional Review Board\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board (IRB) of Shanghai Children\u0026apos;s Hospital (IRB number：2020R064-E02) approved this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from patient\u0026rsquo;s guardian for publication of this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the special medical innovation research project of Shanghai \u0026ldquo;scientific and technological innovation action plan\u0026rdquo; in 2020 (20Y11907000).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC.C. made substantial contributions to conception and design. C.X.Y. and S.Y.F. collected the data. H.W.C. and G.X.H. made analysis and interpretation of data. C.X.Y. drafted the manuscript. C.C. revised the manuscript and gave final approval of the version to be published. Agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank their hyperammonemic neonates for participating in this study. Special thanks are also due to the NICU nurses who have made this study possible.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRobinson JR, Conroy PC, Hardison D, et al. Rapid resolution of hyperammonemia in neonates using extracorporeal membrane oxygenation as a platform to drive hemodialysis. J Perinatol. 2018;38:665-71.\u003c/li\u003e\n\u003cli\u003eGupta S, Fenves AZ, Hootkins R. The Role of RRT in Hyperammonemic Patients. Clin J Am Soc Nephrol. 2016;11:1872-8.\u003c/li\u003e\n\u003cli\u003eOtt P, Vilstrup H. Cerebral effects of ammonia in liver disease: current hypotheses. Metab Brain Dis.2014;29:901-11.\u003c/li\u003e\n\u003cli\u003eH\u0026auml;berle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42:1192-230.\u003c/li\u003e\n\u003cli\u003eH\u0026auml;berle J, Chakrapani A, Ah Mew N, et al. Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories. Orphanet J Rare Dis.2018;13:219.\u003c/li\u003e\n\u003cli\u003eVergano SA, Crossette JM, Cusick FC et al. Improving surveillance for hyperammonemia in the newborn. Mol Genet Metab. 2013;110:102-5.\u003c/li\u003e\n\u003cli\u003eMatoori S, Leroux JC. Recent advances in the treatment of hyperammonemia.Adv Drug Deliv Rev. 2015;90:55-68.\u003c/li\u003e\n\u003cli\u003eLai YC, Huang HP, Tsai IJ, et al. High-volume continuous venovenous hemofiltration as an effective therapy for acute management of inborn errors of metabolism in young children. Blood Purif. 2007;25:303-8.\u003c/li\u003e\n\u003cli\u003eHiroma T, Nakamura T, Tamura M, et al. Continuous venovenous hemodiafiltration in neonatal onset hyperammonemia. Am J Perinatol. 2002;19:221-4.\u003c/li\u003e\n\u003cli\u003eMatsumoto S, H\u0026auml;berle J, Kido J, et al. Urea cycle disorders-update. J Hum Genet. 2019;64:833-47.\u003c/li\u003e\n\u003cli\u003eAuron A, Brophy PD. Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol. 2012;27:207-22.\u003c/li\u003e\n\u003cli\u003eUpadhyay R, Bleck TP, Busl KM. Hyperammonemia: What Urea-lly Need to Know: Case Report of Severe Noncirrhotic Hyperammonemic Encephalopathy and Review of the Literature. Case Rep Med. 2016;doi: 10.1155/2016/8512721.\u003c/li\u003e\n\u003cli\u003eH\u0026auml;berle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011;170:21-34.\u003c/li\u003e\n\u003cli\u003eSavy N. Acute pediatric hyperammonemia: current diagnosis and management strategies. Hepat Med. 2018;10:105-15.\u003c/li\u003e\n\u003cli\u003eKido J, Nakamura K, Mitsubuchi H, et al. Long-term outcome and intervention of urea cycle disorders in Japan. J Inherit Metab Dis. 2012;35: 777-85.\u003c/li\u003e\n\u003cli\u003ePicca S, Dionisi-Vici C, Abeni D, et al. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol.2001;16:862-7.\u003c/li\u003e\n\u003cli\u003eSpinale JM, Laskin BL, Sondheimer N, et al. High-dose continuous renal replacement therapy for neonatal hyperammonemia. Pediatr Nephrol. 2013;28: 983-6.\u003c/li\u003e\n\u003cli\u003eMarkham C, Williams C, Miller C, et al. Continuous Renal Replacement Therapy for Two Neonates With Hyperammonemia.Front Pediatr. 2021;doi: 10.3389/fped.2021.732354.\u003c/li\u003e\n\u003cli\u003eWarrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver failure: the case for quadruple-H therapy. Anaesth Intensive Care. 2014;42:78-88.\u003c/li\u003e\n\u003cli\u003eSchaefer F, Straube E, Oh J, et al. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant.1999;14:910-8.\u003c/li\u003e\n\u003cli\u003eMcBryde KD, Kershaw DB, Bunchman TE, et al. Renal replacement therapy in the treatment of confirmed or suspected inborn errors of metabolism. J Pediatr. 2006;148:770-8.\u003c/li\u003e\n\u003cli\u003eTandukar S, Palevsky PM. Continuous Renal Replacement Therapy: Who, When, Why, and How. Chest. 2019;155:626-38.\u003c/li\u003e\n\u003cli\u003eAygun F, Varol F, Aktuglu-Zeybek C, et al. Continuous Renal Replacement Therapy with High Flow Rate Can Effectively, Safely, and Quickly Reduce Plasma Ammonia and Leucine Levels in Children. Children (Basel)\u003cem\u003e.\u003c/em\u003e 2019;6: 53.\u003c/li\u003e\n\u003cli\u003eAkduman H, Okulu E, Eminoğlu FT, et al. Continuous venovenous hemodiafiltration in the treatment of newborns with an inborn metabolic disease: a single center experience. Turk J Med Sci. 2020;50:12-7.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"continuous renal replacement therapy, dialysis rate, hyperammonemia, neonates","lastPublishedDoi":"10.21203/rs.3.rs-2045798/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2045798/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCRRT has attracted more and more attention in the treatment of acute neonatal hyperammonemia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We retrospectively analyzed the clinical data of hyperammonemic neonates treated with CRRT in the neonatal intensive care unit (NICU) of Shanghai Children's Hospital from August 2016 to September 2021, and further explored the relationship between the rate of decrease of blood ammonia and dialysis rate.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 6 cases of neonatal hyperammonemia were included, their primary diseases were 3 cases of ornithine transcarbamyltransferase deficiency (OTCD), 1 case of carbamoyl phosphate synthetase 1 deficiency (CPS1D), 1 case of methylmalonic acidemia (MMA) with homocysteinemia (combined MMA) and 1 case of transient hyperammonemia. All infants developed impaired consciousness, convulsions and severe hyperammonemia, so CRRT was superimposed on diet control and medication, and the mode of continuous venovenous hemodiafiltration (CVVHDF) was used in all cases. The gestational age at birth was (37.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12) weeks, the age at onset was (1.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91) d, and the weight at CRRT was (3157.50\u0026thinsp;\u0026plusmn;\u0026thinsp;605.95) g. The dialysis rate was (880\u0026ndash;3937) ml/h/1.73m\u003csup\u003e2\u003c/sup\u003e, the decrease rate of blood ammonia was (15.79\u0026ndash;33.33) \u0026micro;mol/h, and the duration of CRRT diversion was 44\u0026ndash;110 h. The decrease rate of blood ammonia increased with the increase in dialysis rate, without an increase in the incidence of serious complications.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCRRT can alleviate the metabolic crisis of hyperammonemic neonates, and increasing the dialysis rate of CRRT can safely and more effectively reduce blood ammonia levels in critically hyperammonemic neonates.\u003c/p\u003e","manuscriptTitle":"The Effect of dialysis rate on continuous renal replacement therapy for neonatal hyperammonemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-16 21:10:02","doi":"10.21203/rs.3.rs-2045798/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6fb20663-65df-44b6-927d-b01fbcdbbdd5","owner":[],"postedDate":"September 16th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-10-26T03:59:22+00:00","versionOfRecord":[],"versionCreatedAt":"2022-09-16 21:10:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2045798","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2045798","identity":"rs-2045798","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}