Management Of Hyperammonemia Research Articles

Hyperammonemia in the Pediatric Emergency Department.

Hyperammonemia is a serious clinical condition associated with significant morbidity and mortality. In the pediatric population, this is often caused by urea cycle disorders, acute liver failure, or other less common underlying etiologies. Children and teens with hyperammonemia can have a broad range of clinical findings, including vomiting, respiratory distress, and changes in mental status. As ammonia levels worsen, this presentation can progress to respiratory failure, encephalopathy, cerebral edema, seizures, and death. Given the risk of neurologic damage, timely identification and management of hyperammonemia is critical and includes initial resuscitation, early consultation with subspecialists, and initiation of appropriate therapies. It is important for pediatric emergency medicine providers to understand the clinical findings, causes, diagnosis, and management of hyperammonemia because they play a key role in the provision of effective, multidisciplinary care of these patients.

The management and clinical outcomes of pregnancies in women with urea cycle disorders: A review of the literature and results of an international survey.

An increasing number of women with urea cycle disorders (UCDs) are reaching child-bearing age and becoming pregnant. Improved diagnostics and increased awareness of inherited metabolic diseases has also led to more previously undetected women being diagnosed with a UCD during or shortly after pregnancy. Pregnancy increases the risk of acute metabolic decompensation with hyperammonemia-which can occur in any trimester, and/or the postpartum period, and may lead to encephalopathy, psychosis, coma, and even death, if not diagnosed promptly and treated appropriately. There are also (theoretical) concerns that a maternal UCD, or its treatment, may cause potential risks for the unborn child. Currently evidence on management and outcome of pregnancies in UCDs is limited to case reports and there are no clear guidelines. In order to inform management and investigate outcomes of pregnancies in women with a UCD, we performed a retrospective review of published cases and analyzed data collected from an international online survey. We conclude that, although risk during the intra- and postpartum period exists, multidisciplinary management by an experienced team and a prospective plan usually result in successful pregnancy, labor, delivery, and postpartum period. No deaths were reported in mothers managed accordingly. With the exception of male neonates with Ornithine Transcarbamylase deficiency, the clinical outcome of children born to mothers with UCDs appears positive, although follow-up is limited. The outcome for women presenting with a first acute metabolic decompensation during pregnancy or postpartum is less favorable. Deaths were associated with diagnostic delay/late management of hyperammonemia in previously undiagnosed women.

Diagnosis and Management of Hyperammonemia in Newborns: Is It Still a Challenge?

Background: Hyperammonaemia is a serious cause of mortality and morbidity duringin the neonatal period, regardless of the aetiology. Quickly differentiatingon between inherited metabolic diseases (IMDs) and other causes is important in terms of for treatment and prognosis. We This study aimed to determine the diagnostic and prognostic differences between IMD- and non-IMD-related causes with based on a literature review. Methods: Clinical and laboratory data of newborns treated for hyperammonaemia between 2016 and 2019 were evaluated retrospectively. Results: Hyperammonaemia was detected in 60 out of 1963 (3%) patients, and 25% of these patients were diagnosed with IMD. The most common non-IMD etiologies were sepsis (31.6%) and prematurity (31.6%). Significant differences were detected between the two groups inregarding gestational age (P=0.001) and birth weight (P=0.005)were detected (p=0.001 and p=0.005, respectively). Moreover, another significant difference was observed between the two groups in terms of glutamine (P=0.004), alanine (P=0.004), and citrulline (P=0.001) levels and as well as the proportions of glutamine to arginine (G/A)P=0.001), citrulline (G/CP=0.0001), ornithine (G/OP=0.003), and alanine (G/A) (P=0.003). Conclusion: Metabolic screening tests should be performed to rapidly diagnose hyperammonaemia. In addition to the diagnosing diagnosis of IMDs, it can promptly differentiate non-metabolic causes.

Hyperammonemia in azotemic cats.

Hyperammonemia occurs in cats with hepatobiliary and nutritional (cobalamin and arginine deficiency) disorders, and has also been documented in four cats with renal azotemia. We hypothesized that in cats with renal azotemia, fasting hyperammonemia would correlate with indices of worsening kidney function, and would be independent of cobalamin, potassium, systemic inflammation or urinary tract infection (UTI) with urease-producing bacteria. A fasted blood sample was prospectively collected for ammonia and cobalamin analysis from 18 client-owned cats with renal azotemia (creatinine [Cr] ⩾1.6 mg/dl, urine specific gravity <1.030 or documentation of historical chronic kidney disease [CKD]). Correlations between blood ammonia and selected biochemical parameters were analyzed using Pearson's correlation coefficient. Seven castrated males and 11 spayed females with a median age of 12 years (range 4-19 years) were enrolled. Ten of 18 (56%) cats presented for acute kidney injury (AKI) or acute on chronic kidney disease (AoCKD), and 8/18 (44%) presented for progressive CKD. The median Cr was 5.9 mg/dl (range 1.9-24.7 mg/dl). Hyperammonemia was documented in 4/18 (22%) cats, with a median of 95 µmol/dl (range 85-98 µmol/dl), and all four of these cats were classified as AKI/AoCKD. Blood ammonia concentrations had a significant moderate positive correlation between blood urea nitrogen (BUN) (r = 0.645, P = 0.003), Cr (r = 0.578, P = 0.012) and serum phosphorus (r = 0.714, P = 0.0009) but not with cobalamin, potassium or white blood cell count. No cats had UTIs with urease-producing bacteria. A correlation exists between blood ammonia and BUN, Cr and phosphorus in cats with renal azotemia. Future studies are warranted in a larger population of cats to determine the true prevalence, etiology and potential therapeutic effect of medical management of hyperammonemia on long-term prognosis in cats with kidney disease.

S3271 Blame It on the Alcohol...or Not?

INTRODUCTION: Hyperammonemia (HA) can cause cerebral edema and brain herniation leading to coma or death, making it a common cause to be considered in patients who present with altered mental status (AMS). However, the etiology of hyperammonemia must be determined to guide treatment. While alcohol-related liver disease is one of the most common causes of liver cirrhosis, there are many other causes of cirrhosis that can also lead to hyperammonemia. We aim to study whether the etiology of cirrhosis plays a role in the severity of hyperammonemia in patients who present with AMS. METHODS: We performed a retrospective chart review of 190 patients seen at community hospital between July to August 2019 with an ICD-10 code of altered mental status (R41.82), hepatic failure without coma (K72.90) and cirrhosis of liver (K74.60). Data points included history/etiology of cirrhosis, history of alcohol abuse, AMS, and ammonia level on presentation. HA was defined as an ammonia level > 45 µmol/L. Patients were separated by the etiology of cirrhosis with alcohol in one group and other etiologies, including autoimmune hepatitis, non-alcoholic steatohepatitis (NASH), and viral hepatitis leading malignancy, and unknown etiology, in another group. We compared the average ammonia level for each group. RESULTS: Out of a total 190 patients who met criteria, 143 presented with ammonia levels >45 µmol/L. Out of this cohort, 52% had cirrhosis due to alcohol, and 48% had cirrhosis due to other causes. The average ammonia level for patients who presented with hyperammonemia with a history of alcoholic cirrhosis and cirrhosis due to other etiologies were 139µmol/L and 110 µmol/L, respectively. CONCLUSION: Alcohol-related liver disease is one of the most common causes of liver cirrhosis, but there are many other etiologies for liver cirrhosis. Hyperammonemia is known to be associated with increasing severity of liver cirrhosis. Whether the etiology of liver cirrhosis plays a role in the level of hyperammonemia that a patient presents with is unknown. This study found that patients with cirrhosis due to alcohol-related liver disease presented with a higher level of hyperammonemia on average compared to those with other etiologies of cirrhosis. However, the significance of determining the etiology of liver cirrhosis and its relation to diagnosing and management of hyperammonemia is yet to be determined. Limitations included the exclusion of other causes of hyperammonemia and being a single-center retrospective study.

Point-of-Care Analysis of Blood Ammonia with a Gas-Phase Sensor.

Elevated blood ammonia (hyperammonemia) may cause delirium, brain damage, and even death. Effective treatments exist, but preventing permanent neurological sequelae requires rapid, accurate, and serial measurements of blood ammonia. Standard methods require volumes of 1 to 3 mL, centrifugation to isolate plasma, and a turn-around time of 2 h. Collection, handling, and processing requirements mean that community clinics, particularly those in low resource settings, cannot provide reliable measurements. We describe a method to measure ammonia from small-volume whole blood samples in 2 min. The method alkalizes blood to release gas-phase ammonia for detection by a fuel cell. When an inexpensive first-generation instrument designed for 100 μL of blood was tested on adults and children in a clinical study, the method showed a strong correlation (R2 = 0.97) with an academic clinical laboratory for plasma ammonia concentrations up to 500 μM (16 times higher than the upper limit of normal). A second-generation hand-held instrument designed for 10-20 μL of blood showed a near-perfect correlation (R2 = 0.99) with healthy donor blood samples containing known amounts of added ammonium chloride up to 1000 μM. Our method can enable rapid and inexpensive measurement of blood ammonia, transforming diagnosis and management of hyperammonemia.

424 Pharmacologic Management of Hyperammonemia with Sodium Phenylacetate/Sodium Benzoate with or without Dialysis: A Case Study

424 Pharmacologic Management of Hyperammonemia with Sodium Phenylacetate/Sodium Benzoate with or without Dialysis: A Case Study

Efficacy and Safety of Sodium Benzoate in The Management of Hyperammonemia in Decompensated Chronic Liver Disease of the Childhood-A Double-blind Randomized Controlled Trial.

The objective was to evaluate the efficacy and safety of sodium benzoate in the management of hyperammonemia and hepatic encephalopathy (HE) in decompensated chronic liver disease. It was a prospective, interventional, double-blinded randomized controlled trial conducted from August 2017 to December 2018. Children with decompensated chronic liver disease and hyperammonemia were included in the study. Those with ammonia >400 μg/dL, already receiving sodium benzoate or with grade III ascites were excluded. Group A received sodium benzoate (400 mg/kg loading dose followed by 200 mg · kg · daymaintenance for 5 days) along with the standard medical therapy. Group B received standard medical therapy with placebo. A total of 108 episodes of hyperammonemia occurred in 86 patients of whom 16 were excluded. The final analysis included 46 episodes in each group. The median decrease in ammonia from baseline to day 5 was 52 μg/dL in group A versus 42 μg/dL in group B (P = 0.321). There was a significant decrease in ammonia on days 1 and 2 in group A as compared to group B, but not on subsequent days. There was no significant difference in the resolution of HE (57.1% vs 50%; P = 1), but there was higher, albeit insignificant increase in ascites in group A (15.9% vs 4.5%). Addition of sodium benzoate significantly reduced the ammonia levels on the first 2 days of therapy but the effect was not sustained till day 5. The effect of sodium benzoate would probably be more sustained, if higher dosage (400 mg · kg · day) could be used under monitoring of benzoate levels. There was no effect on resolution of HE. Sodium benzoate caused an increasing trend of adverse events with no effect on short-term survival.

Efficacy and Safety of Sodium Benzoate in the Management of Hyperammonemia in Infants, Children and Adolescent With Chronic Liver Disease.

Efficacy and Safety of Sodium Benzoate in the Management of Hyperammonemia in Infants, Children and Adolescent With Chronic Liver Disease.

The Role of Supportive Treatment in the Management of Hyperammonemia in Neonates and Infants

Background: The objective of this study is to investigate the efficacy of continuous renal replacement therapy (CRRT), mainly continuous venovenous hemodiafiltration (CVVHDF), and evaluate vasoactive requirements in hyperammonemic neonates and infants. Methods: Patients who underwent CRRT for hyperammonemia were retrospectively analyzed. Measurements and Main Results: Patients in 7 of the encounters were treated solely by CVVHDF. During 3 encounters, patients who received continuous venovenous hemodialysis (CVVHD) were transitioned to CVVHDF. CVVHD was used in 3 encounters. The median 50% reduction time for ammonia was 8 h (range 3–15 h). The median duration of CRRT treatment was 40 h (range 24–89 h). Survival to hospital discharge occurred in 12 encounters (92.3%). Eleven encounters (84.6%) were treated with different vasoactive agents. In those encounters, the median vasoactive medications’ start time was the 6th hours (range 2–60 h) of CRRT. There was no association between the vasoactive index score and pre-dialysis ammonia concentration. Conclusions: CRRT achieves timely control of hypeammonemic states. Hemodynamic instability necessitating intervention with vasoactive medications is a common finding in patients with hyperammonemia.

Saline is as effective as nitrogen scavengers for treatment of hyperammonemia

Urea cycle enzyme deficiency (UCED) patients with hyperammonemia are treated with sodium benzoate (SB) and sodium phenylacetate (SPA) to induce alternative pathways of nitrogen excretion. The suggested guidelines supporting their use in the management of hyperammonemia are primarily based on non-analytic studies such as case reports and case series. Canine congenital portosystemic shunting (CPSS) is a naturally occurring model for hyperammonemia. Here, we performed cross-over, randomized, placebo-controlled studies in healthy dogs to assess safety and pharmacokinetics of SB and SPA (phase I). As follow-up safety and efficacy of SB was evaluated in CPSS-dogs with hyperammonemia (phase II). Pharmacokinetics of SB and SPA were comparable to those reported in humans. Treatment with SB and SPA was safe and both nitrogen scavengers were converted into their respective metabolites hippuric acid and phenylacetylglutamine or phenylacetylglycine, with a preference for phenylacetylglycine. In CPSS-dogs, treatment with SB resulted in the same effect on plasma ammonia as the control treatment (i.e. saline infusion) suggesting that the decrease is a result of volume expansion and/or forced diuresis rather than increased production of nitrogenous waste. Consequentially, treatment of hyperammonemia justifies additional/placebo-controlled trials in human medicine.

Early treatment of a child with NAGS deficiency using N-carbamyl glutamate results in a normal neurological outcome

Acute hyperammonemia has a variety of etiologies and clinical manifestations. If not treated early in neonates, it leads to irreversible brain damage or death. We present a 7-day-old female patient who was brought to the emergency department with drownsiness and vomiting. Metabolic work-up revealed a blood ammonia level of 290 μmol/L (normal <100 μmol/L in neonates) with a compensated respiratory alkalosis, normal glycaemia and lactate and absence of urinary ketones. Oral feeding was stopped, an infusion of 20 % glucose was started, and sodium benzoate and arginine hydrochloride were given. After a drop of ammonemia within 12 h of treatment, it started rising again. N-carbamylglutamate (NCG) was added resulting in a rapid normalisation of ammonemia. Feedings were progressively reintroduced, the ammonia levels remained low. The results of the metabolic work-up were compatible with carbamyl phosphate synthase 1 (CPS1) or N-acetyl glutamate synthase (NAGS) deficiency. Genetic analysis confirmed the latter diagnosis with a homozygous mutation c. 1450T > C (p.W484R) in exon 6 of the NAGS gene in the patient and a carrier state in both parents. At the age of 9 months, the child is growing well with normal neurological development, under treatment with NCG 100 mg/kg/day and a normal diet. Conclusion: This case highlights the importance of keeping a high index of suspicion and early testing for ammonia levels in neonates/children with unexplained encephalopathy. In neonates with congenital hyperammonemia, NCG should always be started together with the standard management of hyperammonemia until all laboratory investigations are complete or indicate another disease.

CONTINUOUS ARTERIOVENOUS HEMODIAFILTRATION IN THE ACUTE TREATMENT OF HYPERAMMONAEMIA DUE TO ORNITHINE TRANSCARBAMYLASE DEFICIENCY

Background. Acute hyperammonemia caused by urea cycle disorder is a medical emergency for which immediate managements should be taken to minimize permanent brain damage. Among different enzyme defects, ornithine transcarbamylase deficiency (OTC) is one of the most common enzyme defect in urea cycle disorders. We utilized continuous renal replacement therapy techniques in the acute treatment of hyperammonemia due to ornithine transcarbamylase deficiency.Patients and methods. Three male neonates with elevated serum ammonia levels were shown, based on urine organic acid analysis and serum amino acid studies, to have OTC deficiency. Administration of sodium benzoate and sodium phenylacetate for activating alternative nitrogen waste pathway were used associated with protein restriction. Other modalities, including blood exchange transfusion, peritoneal dialysis, continuous renal replacement therapy were utilized in an attempt to lower serum ammonia concentration.Results. We report the successful use of continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), continuous arteriovenous hemodiafiltration (CAVHDF) in the acute management of hyperammonemia due to OTC deficiency. We also compared the ammonia clearance between peritoneal dialysis, exchange transfusion, CAVH, CAVHD and CAVHDF. It demonstrated the evidence that CAVHDF provides the best ammonia clearance.Conclusion. Continuous renal replacement therapy including CAVH, CAVHD, and CAVHDF may be the alternative techniques for acute management of hyperammonemia in inborn error of metabolism when dialysis machine is not available. Our data suggests CAVHDF provides the best ammonia clearance.