Analysis of clinical prognosis in patients with non-hepatic hyperammonemia.

ABSTRACT: The aim of this study was to evaluate the association of non-hepatic hyperammonemia (NHH) with the prognosis of critically ill patients with NHH.According to the serum ammonia level, the patients with NHH (n = 498) were retrieved by us. The risk factors of the mortality with NHH patients were investigated by conducting univariate and multivariate logistic regression analyses. A nomogram to predict the risk of hospital mortality was constructed. Receiver operating characteristic curve (ROC) analysis was conducted to compare nomogram (ammonia into a prognostic model, P1) with the simplified acute physiology II (SAPSII) and quick sequential organ failure assessment (qSOFA).Five independent factors for the mortality in patients with NHH were identified, including age, platelets, bun, hemoglobin, and ammonia. Models P1 using ammonia showed good prediction power. The AUROC of P1 (AUROC, 0.755 [95% CI, 0.713-0.796]) was higher than that of qSOFA (AUROC, 0.500 [95% CI, 0.449-0.551]), and SAPS II (AUROC, 0.703[95% CI, 0.658-0.748]).Ammonia was an independent prognostic predictor of mortality for NHH patients. We developed a nomogram that can predict hospital mortality with patients. Nomogram had superior discriminative power to qSOFA and SAPS II, indicating that the nomogram may have clinical utility.

Prognosis of Patients with Sepsis and Non-Hepatic Hyperammonemia: A Cohort Study.

BACKGROUND Hyperammonemia has been reported in some critically ill patients with sepsis who do not have hepatic failure. A significant proportion of patients with non-hepatic hyperammonemia have underlying sepsis, but the association between non-hepatic hyperammonemia and prognosis is unclear. MATERIAL AND METHODS Information about patients with sepsis and non-hepatic hyperammonemia was retrieved from the Medical Information Mart for Intensive Care-III database. Survival rates were analyzed using the Kaplan-Meier method. Multivariate logistic regression models were employed to identify prognostic factors. Receiver operating characteristic (ROC) curve analysis was used to measure the predictive ability of ammonia in terms of patient mortality. RESULTS A total of 265 patients with sepsis were enrolled in this study. Compared with the non-hyperammonemia group, the patients with hyperammonemia had significantly higher rates of hospital (59.8% vs. 43.0%, P=0.007), 30-day (47.7% vs. 34.8%, P=0.036), 90-day (61.7% vs. 43.7%, P=0.004), and 1-year mortality (67.3% vs. 49.4%, P=0.004). In the survival analysis, hyperammonemia was associated with these outcomes. Serum ammonia level was an independent predictor of hospital mortality. The area under the ROC curve for the ammonia levels had poor discriminative capacity. The hyperammonemia group also had significantly lower Glasgow Coma Scale scores (P=0.020) and higher incidences of delirium (15.9% vs. 8.2%, P=0.034) and encephalopathy (37.4% vs. 19.6%, P=0.001). Intestinal infection and urinary tract infection with organisms such as Escherichia coli may be risk factors for hyperammonemia in patients who have sepsis. CONCLUSIONS Higher ammonia levels are associated with poorer prognosis in patients with sepsis. Ammonia also may be associated with sepsis-associated encephalopathy. Therefore, we recommend that serum ammonia levels be measured in patients who are suspected of having sepsis.

A retrospective review of outcomes in the treatment of hyperammonemia with renal replacement therapy due to inborn errors of metabolism.

BACKGROUND: Outcomes for severe hyperammonemia treated with renal replacement therapy (RRT) reported in the literature vary widely. This has created differing recommendations regarding when RRT is beneficial for hyperammonemic patients. METHODS: To evaluate our institution's experience with RRT in pediatric patients with inborn errors of metabolism (IEMs) and potential prognostic indicators of a better or worse outcome, we performed a retrospective chart review of patients who received RRT for hyperammonemia. Our cohort included 19 patients with confirmed IEMs who received RRT between 2000 and 2017. Descriptive statistics are presented as medians with interquartile ranges with appropriate statistical testing assuming unequal variance. RESULTS: There were 16 males (84%) and 3 females (16%) identified for inclusion in this study. There were 9 survivors (47%) and 10 non-survivors (53%). The average age of survivors was 67 months (age range from 3 days to 15.6 years). The average age of non-survivors was 1.8 months (age range from 2 days to 18.7 months). Peak ammonia, ammonia on admission, and at RRT initiation were higher in non-survivors compared with survivors. Higher ammonia levels and no change in ammonia between admission and RRT initiation were associated with an increased risk of mortality. CONCLUSIONS: Hyperammonemia affects two distinct patient populations; neonates with markedly elevated ammonia levels on presentation and older children who often have established IEM diagnoses and require RRT after failing nitrogen-scavenging therapy. Our experience demonstrates no significant change in mortality associated with neonatal hyperammonemia, which remains high despite improvements in RRT and intensive care.

Characteristics and outcomes of critically ill patients with severe hyperammonemia.

PURPOSE: To determine the etiology and outcomes of critically ill patients with severe hyperammonemia. MATERIALS AND METHODS: Retrospective observational study of adults (18 years or older) admitted to a MICU from 2007 to 2016 who had a serum ammonia level >180 µmol/L (3 times the upper limit of normal). RESULTS: The 78 patients (45 male, 32 female) had a median age of 52 (interquartile range [IQR] 46-58) years. Hyperammonemia occurred most often with acute-on-chronic liver failure (ACLF) (49 %) or decompensated cirrhosis (27 %) and less often as a consequence of prior gastric bypass (9%), acute hepatic failure (6%), or valproic acid (3%). Median serum ammonia level was 201 µmol/L (IQR 126-265, range 18-736) on admission, with peak value of 245 µmol/L (IQR 205-336, range 185-842). Fifty (64%) patients died during the hospitalization. Cerebral edema was documented in 8 (10%) patients, only one of whom survived. Six of the 8 patients with cerebral edema had hyperammonemia related to ACLF, giving an incidence of 14% in this subset of patients. Neither mortality nor cerebral edema was associated with peak ammonia level. CONCLUSIONS: Critically ill patients with severe hyperammonemia have a high mortality rate and are at risk of developing cerebral edema.

A constitutive knockout of murine carbamoyl phosphate synthetase 1 results in death with marked hyperglutaminemia and hyperammonemia.

The enzyme carbamoyl phosphate synthetase 1 (CPS1; EC 6.3.4.16) forms carbamoyl phosphate from bicarbonate, ammonia, and adenosine triphosphate (ATP) and is activated allosterically by N-acetylglutamate. The neonatal presentation of bi-allelic mutations of CPS1 results in hyperammonemia with reduced citrulline and is reported as the most challenging nitrogen metabolism disorder to treat. As therapeutic interventions are limited, patients often develop neurological injury or die from hyperammonemia. Survivors remain vulnerable to nitrogen overload, being at risk for repetitive neurological injury. With transgenic technology, our lab developed a constitutive Cps1 mutant mouse and reports its characterization herein. Within 24 hours of birth, all Cps1 -/- mice developed hyperammonemia and expired. No CPS1 protein by Western blot or immunostaining was detected in livers nor was Cps1 mRNA present. CPS1 enzymatic activity was markedly decreased in knockout livers and reduced in Cps1+/- mice. Plasma analysis found markedly reduced citrulline and arginine and markedly increased glutamine and alanine, both intermolecular carriers of nitrogen, along with elevated ammonia, taurine, and lysine. Derangements in multiple other amino acids were also detected. While hepatic amino acids also demonstrated markedly reduced citrulline, arginine, while decreased, was not statistically significant; alanine and lysine were markedly increased while glutamine was trending towards significance. In conclusion we have determined that this constitutive neonatal mouse model of CPS1 deficiency replicates the neonatal human phenotype and demonstrates the key biochemical features of the disorder. These mice will be integral for addressing the challenges of developing new therapeutic approaches for this, at present, poorly treated disorder.

Follow-up of fatty acid ß-oxidation disorders in expanded newborn screening era.

Fatty acid ß-oxidation (FAO) disorders have a wide variety of symptoms, not usually evident between episodes of acute decompensations. Cardiac involvement is frequent, and severe ventricular arrhythmias are suspected of causing sudden death. Expanded newborn screening (ENS) for these disorders, hopefully, contribute to prevent potentially acute life-threatening events. In order to characterize acute decompensations observed in FAO-deficient cases identified by ENS, a retrospective analysis was performed, covering a period of 9 years. Demographic data, number/type of acute decompensations, treatment, and follow-up were considered. Eighty-three clinical charts, including 66 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 5 carnitine-uptake deficiency (CUD), 3 carnitine palmitoyltransferase I and II (CPT I/II) deficiency, 5 very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), and 4 multiple acyl-CoA dehydrogenase deficiency (MADD) cases were reviewed. Nineteen patients had acute decompensations (1 CPT I, 1 CPT II, 3 MADD, 14 MCADD). Six patients developed symptoms previously to ENS diagnosis. Severe clinical manifestations included multiple organ failure, liver failure, heart failure, and sudden death. Long-chain FAO disorders had the highest number of decompensations per patient.Conclusion: Despite earlier diagnosis by ENS, sudden deaths were not avoided and acute decompensations with severe clinical manifestations still occur as well. What is Known: • Severe ventricular arrhythmias are suspected to cause unexpected death in FAO disorders. • Neonatal screening intends to reduce the incidence of severe metabolic crisis and death. What is New: • Acute severe decompensations occurred in FAO disorders diagnosed through neonatal screening. • Sudden deaths were not avoided by starting treatment precociously.

Continuous venovenous hemofiltration in neonates with hyperammonemia. A case series. / Uso de Hemofiltración veno-venosa continua en neonatos con hiperamonemia. Serie clínica.

INTRODUCTION: Neonatal hyperammonemia secondary due to inborn errors of metabolism is a rare condition with a high rate of neurological sequelae and mortality. Initial medical management is often insufficient to stop the progressive increase of ammonia, with the consequent deterioration of the patient. For this reason, depurative techniques have been implemented, including peritoneal dialysis, intermittent hemodialysis and continuous renal replacement therapy (CRRT). OBJECTIVE: To describe our experience with continuous extracorporeal dialysis in severely ill neonates with hyperammonemia. PATIENTS AND METHODS: Retrospective review of clinical records of neonates with hyperammonemia due to congenital errors of metabolism undergoing CRRT admitted in our institution in the last 6 years. Demographic data, chronological and gestational age, gender, anthropometric and laboratory data (creatininemia, ammonemia), and severity index PIM-II where collected. It was analyzed the CRRT: modality, duration and complications. The stard of therapy depended on the response to medical management in the first 24 hours, progressive neurological involvement, or increased blood ammonia (> 400 qg/dl) at the time of admission. CRRTs were performed using the Prisma Flex system and M100 and/or HF20 filters. RESULTS: 6 neonates, 4 males, half of them with a history of prematurity, all with severe acute neurological involvement and severe ammonemias (> 1,000 qg/dl). The average age and weight at the start of the CRRT were 10 days and 2798 g, respectively, ammonia (median) 1,663 qg/dl (range 1,195 - 3,097). The PIM-II score had a median of 53 (range 13.4 - 87.4). On average, patients were 49.5 hours in continuous therapy. In four neonates, a mixed convective and diffusive technique (hemodiafiltration) was used, and only convective one (hemofiltration) in the 2 remaining. Mortality was 33%, and one of the survivors had permanent moderate neurological damage in clinical follow-up. CONCLUSIONS: The results obtained in this extremely ill group of neonates encourage us to propose this dialytic therapy as an excellent alternative in the management of this type of patients.

Rapid resolution of hyperammonemia in neonates using extracorporeal membrane oxygenation as a platform to drive hemodialysis.

OBJECTIVE: We aimed to clarify the impact of extracorporeal membrane oxygenation (ECMO) as a platform to drive hemodialysis (HD) for ammonia clearance on outcomes of neonates with severe hyperammonemia. STUDY DESIGN: All neonates treated for hyperammonemia at a single children's hospital between 1992 and 2016 were identified. Patient characteristics and outcomes were compared between those receiving medical management or ECMO/HD. RESULT: Twenty-five neonates were treated for hyperammonemia, of which 13 (52%) received ECMO/HD. Peak ammonia levels among neonates treated with ECMO/HD were significantly higher than those medically managed (1041 [IQR 902-1581] µmol/L versus 212 [IQR 110-410] µmol/L; p = 0.009). Serum ammonia levels in the ECMO/HD cohort declined to the median of medically managed within 4.5 (IQR 2.9-7.0) hours and normalized within 7.3 (IQR 3.6-13.5) hours. All neonates survived ECMO/HD, and nine (69.2%) survived to discharge. CONCLUSION: ECMO/HD is an effective adjunct to rapidly clear severe hyperammonemia in newborns, reducing potential neurodevelopmental morbidity.

Uso de Hemofiltración veno-venosa continua en neonatos con hiperamonemia. Serie clínica / Continuous venovenous hemofiltration in neonates with hyperammonemia. A case series

Resumen: Introducción: La hiperamonemia neonatal secundaria a errores congénitos del metabolismo es una entidad poco frecuente pero con una alta tasa de secuelas neurológicas y mortalidad. El manejo médico inicial es en muchas ocasiones insuficiente para detener el progresivo aumento de la amonemia, con el consecuente deterioro del paciente. Por esta razón se han implementado técnicas depurativas entre las que se cuenta la diálisis peritoneal, la hemodiálisis intermitente y las terapias de reemplazo renal continuo (TRRC). Objetivo: Describir nuestra experiencia en diálisis extracorpórea continua en pacientes con hiperamonemia neonatal gravemente enfermos. Pacientes y Método: Revisión retrospectiva de fichas clínicas de neonatos con hiperamonemias secundarias a errores congénitos del metabolismo sometidos a TRRC, admitidos en nuestra institución en los últimos 6 años. Se obtuvieron datos demográficos, edad cronológica y gestacional, género; datos antropométricos y de laboratorio (creatininemia, amonemia) e índice de gravedad por PIM-II. Se analizó la TRRC utilizada: modalidad, duración y complicaciones. El inicio de la terapia dependió de la respuesta al manejo médico en las primeras 24 horas, compromiso neurológico progresivo, o cifras de amonio sanguíneo elevados (> 400 μg/dl) al momento del ingreso. Las TRRC fueron realizadas con la máquina Prisma Flex, usando filtros M100 y/o HF20. Resultados: 6 neonatos, 4 varones, la mitad con antecedentes de prematurez, todos con compromiso neurológico agudo severo y amonemias en rango grave (> 1.000 μg/dl). La edad y peso promedio al iniciar la TRRC fueron de 10 días y 2.798 g respectivamente, amonemia (mediana) 1.663 μg/dl (rango 1.195-3.097). El puntaje PIM-II tuvo una mediana de 53 (rango 13,4-87,4). En promedio, los pacientes estuvieron 49,5 h en la terapia continua. En cuatro neonatos se usó una técnica dialítica mixta convectiva y difusiva (hemodiafiltración), y solo convectiva (hemofiltración) en las 2 restantes. La mortalidad fue de 33%, y uno de los sobrevivientes quedó con daño neurológico moderado permanente en seguimiento clínico. Conclusiones: Los resultados obtenidos en este grupo de neonatos extremadamente graves nos incentivan a proponer esta terapia dialítica como una excelente alternativa en el manejo de este tipo de pacientes.

Abstract: Introduction: Neonatal hyperammonemia secondary due to inborn errors of metabolism is a rare condition with a high rate of neurological sequelae and mortality. Initial medical management is often insufficient to stop the progressive increase of ammonia, with the consequent deterioration of the patient. For this reason, depurative techniques have been implemented, including peritoneal dialysis, intermittent hemodialysis and continuous renal replacement therapy (CRRT). Objective: To describe our experience with continuous extracorporeal dialysis in severely ill neonates with hyperammonemia. Patients and Methods: Retrospective review of clinical records of neonates with hyperammonemia due to congenital errors of metabolism undergoing CRRT admitted in our institution in the last 6 years. Demographic data, chronological and gestational age, gender, anthropometric and laboratory data (creatininemia, ammonemia), and severity index PIM-II where collected. It was analyzed the CRRT: modality, duration and complications. The stard of therapy depended on the response to medical management in the first 24 hours, progressive neurological involvement, or increased blood ammonia (> 400 qg/dl) at the time of admission. CRRTs were performed using the Prisma Flex system and M100 and/or HF20 filters. Results: 6 neonates, 4 males, half of them with a history of prematurity, all with severe acute neurological involvement and severe ammonemias (> 1,000 qg/dl). The average age and weight at the start of the CRRT were 10 days and 2798 g, respectively, ammonia (median) 1,663 qg/dl (range 1,195 - 3,097). The PIM-II score had a median of 53 (range 13.4 - 87.4). On average, patients were 49.5 hours in continuous therapy. In four neonates, a mixed convective and diffusive technique (hemodiafiltration) was used, and only convective one (hemofiltration) in the 2 remaining. Mortality was 33%, and one of the survivors had permanent moderate neurological damage in clinical follow-up. Conclusions: The results obtained in this extremely ill group of neonates encourage us to propose this dialytic therapy as an excellent alternative in the management of this type of patients.

Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study.

Hepatic encephalopathy (HE) influences short-term and long-term prognoses. Recently, glycerol phenylbutyrate (PB), that lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion, has shown that it was effective in preventing the occurrence of HE in RCT. The aim was to assess the benefits of sodium PB in cirrhotic patients admitted to ICU for overt HE, in terms of ammonia levels decrease, neurological improvement, and survival. Cirrhotic patients who presented with overt HE, ammonia levels >100 µmol/L, and did not display any contra-indication were included. Sodium PB was administered at 200 mg/kg/day. Control group included historical controls treated by standard therapy, matched for age, sex, MELD score, and severity of HE. Eighteen patients were included and treated with sodium PB (age: 59 [45-68], male gender: 15 [83%], Child-Pugh B: 8 [44%], Child-Pugh C: 10 [56%], and MELD score: 16 [13-23]). Ammonia levels significantly decreased in the PB as compared to the control group from inclusion to 12 h and from inclusion to 48 h (P = 0.0201 and P = 0.0230, respectively). The proportion of patients displaying neurological improvement was only higher in the PB-treated group as compared to controls at ICU discharge (15 [83%] vs. 9 [50%], P = 0.0339). ICU discharge survival was significantly higher in patients treated with PB (17 [94%] vs. 9 [50%], P = 0.0017). In cirrhotic patients with overt HE, sodium PB could be effective in reducing ammonia levels and might be effective in improving neurological status and ICU discharge survival. More extensive data, especially a RCT, are mandatory.

Clinical course of 63 patients with neonatal onset urea cycle disorders in the years 2001-2013.

BACKGROUND: Urea cycle disorders (UCDs) are rare inherited metabolic defects of ammonia detoxification. In about half of patients presenting with a UCD, the first symptoms appear within a few days after birth. These neonatal onset patients generally have a severe defect of urea cycle function and their survival and outcome prognoses are often limited. To understand better the current situation of neonatal onset in UCDs, we have performed a multicentre, retrospective, non-interventional case series study focussing on the most severe UCDs, namely defects of carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (ASS). METHODS AND RESULTS: Data of 63 patients were collected (27 patients with ASS deficiency, 23 patients with OTC deficiency, and 12 patients with CPS1 deficiency, one patient definite diagnosis not documented). The majority of patients (43/63, 68 %) had an initial ammonia concentration exceeding 500 µmol/L (normal < 100), of which most (26/43, 60.5 %) were also encephalopathic and were treated with hemodialysis. In patients surviving the initial crisis, recurrence of hyperammonemic events within the first 1.5 years of life occurred frequently (mean 3.6 events, range 0-20). Of all patients, 16 (25.4 %) died during or immediately after the neonatal period. CONCLUSION: We observed in this cohort of neonatal onset UCD patients a high rate of initial life-threatening hyperammonemia and a high risk of recurrence of severe hyperammonemic crises. These corresponded to a high mortality rate during the entire study period (30.2 %) despite the fact that patients were treated in leading European metabolic centers. This underlines the need to critically re-evaluate the current treatment strategies in these patients.

Hyperammonemia Syndrome After Lung Transplantation: A Single Center Experience.

BACKGROUND: Hyperammonemia is a rare, often fatal complication after transplantation. The etiology is unknown, but recognition and rapid treatment may help to improve the survival of this unusual syndrome. We present the largest case series to date of hyperammonemia after lung transplantation (LTx) and discuss a treatment protocol that has been developed at our institution. METHODS: We conducted a retrospective cohort series of patients who underwent LTx between January 1, 2000, and December 31, 2013. Patients who developed hyperammonemia syndrome in the posttransplantation period, which was defined as symptoms of encephalopathy and plasma ammonia level exceeding 200 µmol/L on at least 1 occasion, were included. Data including demographics, antimicrobial and immunosuppression regimens, ammonia levels and other pertinent laboratory data, treatments administered, and outcomes were recorded. RESULTS: Eight of 807 lung transplant recipients developed hyperammonemia syndrome postoperatively during this time period. Median time to onset was 9.0 days, and median peak ammonia level was 370 µmol/L. All 8 patients were treated with hemodialysis, 7 of 8 patients were treated with bowel decontamination, and 5 of 8 patients were treated with nitrogen scavenging agents. Six of the 8 patients died. CONCLUSIONS: The incidence of hyperammonemia syndrome in LTx patients was approximately 1%. Future research is needed to determine the efficacy of treatment, including hemodialysis, bowel decontamination, antibiotics, and the use of nitrogen scavenging agents in lung recipients with hyperammonemia.

Hyperammonemic syndrome after Roux-en-Y gastric bypass.

OBJECTIVE: Hyperammonemic encephalopathy is an uncommon but severe complication of the Roux-en-Y gastric bypass surgery for obesity. Mechanisms underlying this complication are incompletely understood, resulting in delayed recognition and management. This study evaluated common laboratory findings and possible etiology of hyperammonemic encephalopathy after successful Roux-en-Y gastric bypass surgery. METHODS: A retrospective review of 20 patients identified through our own clinical practice was conducted, with the addition of similar cases from other institutions identified through the review of literature. RESULTS: Patients presenting with hyperammonemic encephalopathy after Roux-en-Y gastric bypass surgery presented with overlapping clinical and laboratory findings. Common features included: (1) weight loss following successful Roux-en-Y gastric bypass for obesity; (2) hyperammonemic encephalopathy accompanied by elevated plasma glutamine levels; (3) absence of cirrhosis; (4) hypoalbuminemia; and (5) low plasma zinc levels. The mortality rate was 50%. Ninety-five percent of patients were women. Three patients were diagnosed with proximal urea cycle disorders. One patient experienced improvement in the hyperammonemia after surgical correction of spontaneous splenorenal shunt. CONCLUSIONS: Hyperammonemic encephalopathy after Roux-en-Y gastric bypass surgery is a newly recognized, potentially fatal syndrome with diverse pathophysiologic mechanisms encompassing genetic and nongenetic causes.

A liver-specific defect of Acyl-CoA degradation produces hyperammonemia, hypoglycemia and a distinct hepatic Acyl-CoA pattern.

Most conditions detected by expanded newborn screening result from deficiency of one of the enzymes that degrade acyl-coenzyme A (CoA) esters in mitochondria. The role of acyl-CoAs in the pathophysiology of these disorders is poorly understood, in part because CoA esters are intracellular and samples are not generally available from human patients. We created a mouse model of one such condition, deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HL), in liver (HLLKO mice). HL catalyses a reaction of ketone body synthesis and of leucine degradation. Chronic HL deficiency and acute crises each produced distinct abnormal liver acyl-CoA patterns, which would not be predictable from levels of urine organic acids and plasma acylcarnitines. In HLLKO hepatocytes, ketogenesis was undetectable. Carboxylation of [2-(14)C] pyruvate diminished following incubation of HLLKO hepatocytes with the leucine metabolite 2-ketoisocaproate (KIC). HLLKO mice also had suppression of the normal hyperglycemic response to a systemic pyruvate load, a measure of gluconeogenesis. Hyperammonemia and hypoglycemia, cardinal features of many inborn errors of acyl-CoA metabolism, occurred spontaneously in some HLLKO mice and were inducible by administering KIC. KIC loading also increased levels of several leucine-related acyl-CoAs and reduced acetyl-CoA levels. Ultrastructurally, hepatocyte mitochondria of KIC-treated HLLKO mice show marked swelling. KIC-induced hyperammonemia improved following administration of carglumate (N-carbamyl-L-glutamic acid), which substitutes for the product of an acetyl-CoA-dependent reaction essential for urea cycle function, demonstrating an acyl-CoA-related mechanism for this complication.

Aggravation of cyclophosphamide-induced acute neurological disorders under conditions of artificial acidification of chyme in rats.

The effect of artificial acidification of the intestinal content on neurological manifestations of acute severe cyclophosphamide intoxication was studied in rats. The animals were gavaged with 20 ml/kg sulfuric (0.05 M), hydrochloric, boric, or lactic acids (0.1 M) 3 h before intraperitoneal injections of the cytostatic in doses of 0, 200, 600, or 1000 mg/kg. The decrease in pH (by.0) and ammonia-producing activity of the cecal chyme developed within 3 h after administration of acids. Cyclophosphamide caused hyperammonemia; glutamine/ammonia and urea/ammonia ratios in the blood decreased. These changes augmented after administration of acids (boric acid produced maximum and lactic acid minimum effects). Acid treatment resulted in greatest elevation of ammonia level in the portal venous blood and a lesser elevation in the vena cava posterior blood. Acid treatment promoted manifestation of cyclophosphamide neurotoxic effect and animal death. Hence, acidification of the chyme inhibited the formation of ammonia in it, while ammonia release from the gastrointestinal tract into the blood increased; the treatment augmented hyperammonemia and aggravated the neurological manifestations of cyclophosphamide intoxication.

A novel biochemically salvageable animal model of hyperammonemia devoid of N-acetylglutamate synthase.

All knockout mouse models of urea cycle disorders die in the neonatal period or shortly thereafter. Since N-acetylglutamate synthase (NAGS) deficiency in humans can be effectively treated with N-carbamyl-l-glutamate (NCG), we sought to develop a mouse model of this disorder that could be rescued by biochemical intervention, reared to adulthood, reproduce, and become a novel animal model for hyperammonemia. Founder NAGS knockout heterozygous mice were obtained from the trans-NIH Knock-Out Mouse Project. Genotyping of the mice was performed by PCR and confirmed by Western blotting of liver and intestine. NCG and L-citrulline (Cit) were used to rescue the NAGS knockout homozygous (Nags(-/-)) pups and the rescued animals were characterized. We observed an 85% survival rate of Nags(-/-) mice when they were given intraperitoneal injections with NCG and Cit during the newborn period until weaning and supplemented subsequently with both compounds in their drinking water. This regimen has allowed for normal development, apparent health, and reproduction. Interruption of this rescue intervention resulted in the development of severe hyperammonemia and death within 48 h. In addition to hyperammonemia, interruption of rescue supplementation was associated with elevated plasma glutamine, glutamate, and lysine, and reduced citrulline, arginine, ornithine and proline levels. We conclude that NAGS deprived mouse model has been developed which can be rescued by NCG and Cit and reared to reproduction and beyond. This biochemically salvageable mouse model recapitulates the clinical phenotype of proximal urea cycle disorders and can be used as a reliable model of induced hyperammonemia by manipulating the administration of the rescue compounds.

Persistent hyperammonemia is associated with complications and poor outcomes in patients with acute liver failure.

BACKGROUND & AIMS: Patients admitted to the hospital with acute liver failure (ALF) and high arterial levels of ammonia are more likely to have complications and poor outcomes than patients with lower levels of ammonia. ALF is a dynamic process; ammonia levels can change over time. We investigated whether early changes (first 3 days after admission) in arterial levels of ammonia were associated with complications and outcomes and identified factors associated with persistent hyperammonemia. METHODS: We performed a prospective observational study that measured arterial ammonia levels each day for 5 days in 295 consecutive patients with ALF. We analyzed associations of changes in ammonia levels during the first 3 days with complications and outcomes. RESULTS: Patients with persistent arterial hyperammonemia (≥122 µmol/L for 3 consecutive days), compared with those with decreasing levels, had lower rates of survival (23% vs 72%; P < .001) and higher percentages of cerebral edema (71% vs 37%; P < .001), infection (67% vs 28%; P = .003), and seizures (41% vs 7.7%; P < .001). Patients with persistent hyperammonemia had greater mortality, with an odds ratio (OR) of 10.7, compared with patients with baseline levels of ammonia ≥122 µmol/L (OR, 2.4). Patients with persistent hyperammonemia were more likely to progress to and maintain advanced hepatic encephalopathy than those with decreasing levels. Patients with persistent, mild hyperammonemia (≥85 µmol/L for 3 days) were also more likely to have complications or die (P < .001) than patients with serial ammonia levels <85 µmol/L. Infections (OR, 4.17), renal failure (OR, 2.20), and decreased arterial pH (OR, 0.003) were independent predictors of persistent hyperammonemia. CONCLUSIONS: Patients with ALF and persistent arterial hyperammonemia for 3 days after admission are more likely to develop complications and have greater mortality than patients with decreasing levels or high baseline levels. Infection, renal failure, and decreased arterial pH are independent predictors of persistent hyperammonemia.

Threshold for toxicity from hyperammonemia in critically ill children.

BACKGROUND & AIMS: Hyperammonemia results from reduction of hepatocyte function or enzyme of urea cycle deficiency. Hyperammonemia contributes to cerebral edema that may lead to cerebral herniation. The threshold of toxicity of ammonemia is unknown. METHODS: We conducted a retrospective observational study in our pediatric intensive care unit. All children who developed hyperammonemia from January 2000 to April 2009 were included. Clinical and laboratory data at admission, specific treatments implemented, and ammonemias the first 7 days after inclusion were collected. The outcome assessed was 28 day mortality. Risk of mortality was estimated by a logistic regression model. RESULTS: Ninety patients with liver failure (63.3%) and primary or secondary urea cycle defect (23.3%) were included. Patients with urea cycle defects were more likely to receive ammonia scavengers than patients with liver failure (47.6% versus 3.5%). The 28 day mortality rate was 31.1%. Risk of mortality increased according to the ammonemia within 48 h: odds ratio 1.5, 1.9, 3.3, 2.4 for ammonemia above 100, 150, 200, and 300 µmol/L, respectively. Peak ammonemia ≥200 µmol/L within the first 48 h was an independent risk factor for mortality, with greater risk found in liver failure than in urea cycle defect. CONCLUSIONS: Our study identifies a threshold of exposure to ammonia (≥200 µmol/L) above which mortality increases significantly, especially in liver failure. Specific treatments of hyperammonemia are rarely used in liver failure when compared with urea cycle defect even though use of ammonia scavengers may help to decrease ammonemia.

Continuous hemofiltration in the control of neonatal hyperammonemia: a 10-year experience.

In a 10-year review of the utilization of continuous veno-venous hemofiltration (CVVH) for the treatment of neonatal hyperammonemia, 14 patients were identified with hyperammonemia due to either a urea cycle defect or an organic acidemia. Intensive care survival was 64%. The pretreatment level of serum ammonia and the rapidity of ammonia clearance did not differ between survivors and non-survivors (p = 0.16 and p = 0.93, respectively). Likewise, the duration of CVVH therapy did not differ between survivors and non-survivors (p = 0.1). Indicators of pretreatment physiological stress showed either a correlation with non-survival [Pediatric Risk of Mortality (PRISM) score, p = 0.006, cardioactive drug requirement, p = 0.003], or demonstrated a trend to such a correlation (serum lactate, p = 0.06). Complications associated with the CVVH technique were infrequent. Hypotension was seen in seven patients, but in only one patient did it arise de novo following the initiation of CVVH. In conclusion, neither the severity of the hyperammonemic state nor the efficacy of ammonia removal correlated with patient outcome. The pre-CVVH PRISM score and requirement for cardio-active medication were significantly greater in those patients who did not survive their acute illness. The pre-CVVH physiological condition of the neonates in this cohort was the main determinant of outcome.

Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications.

Acute liver failure (ALF) may lead to rapid death unless the patients receive a liver for transplantation. However, the number of livers available is not enough and a number of patients die before a suitable liver is available for transplantation. The liver has a high capacity for regeneration which may allow complete recovery even in patients with severe liver failure. It would be therefore very useful to have procedures to prevent or delay the mechanisms by which ALF leads to death. These mechanisms are no well understood. Progression of ALF leads to multi-organ failure, systemic inflammatory response, hepatic encephalopathy, cerebral oedema and increased intracranial pressure, which seem the most important immediate causes of mortality in patients with ALF. A main contributor to these events is hyperammonemia, due to impaired ammonia detoxification in the liver. Acute hyperammonemia per se leads to death, which is mediated by activation of the NMDA type of glutamate receptors in brain and may be prevented by antagonists blocking these receptors. Acute liver failure also leads to hyperammonemia and excessive activation of NMDA receptors in brain which contributes to ALF-induced death. Sustained blocking of NMDA receptors by continuous administration of the antagonists MK-801 or memantine increases about twice the survival time of rats with severe ALF due to injection of 2.5g/kg of galactosamine. In rats with milder ALF due to injection of 1.5g/kg of galactosamine, blocking NMDA receptors increases the percentage of surviving rats from 23% to 62% and increases about twice the survival time of the rats which die. These data strongly support that blocking NMDA receptors would improve survival of patients with ALF, either by allowing more time for liver regeneration or to get a liver suitable for transplantation.