During hyperammonemic crises (HAC), generally defined as ammonia >100 µmol/L and requiring hospitalization or emergency visits (F.6121), numerous studies including 2019 updated European UCD management guidelines, case studies, and reviews support the initial removal of all protein from the diet for 24-48 hours to reduce ammonia production (F.6452, F.6480, F.7664, F.7801, F.7802). Some studies specify limiting total protein removal to 12-24 hours only (F.7963, F.7594, F.7597) or removing only intact protein (F.4756), as many individuals are nutritionally compromised at hospital admission. For example, low concentrations of branched chain amino acids (BCAA) and essential amino acids (EAA) and a negative correlation between glutamine and the phenylalanine-to-tyrosine ratio (marker for protein turnover and whole body protein balance) were found in 14 individuals with UCDs at the time of hospitalization (96 admissions), supporting that individuals with UCDs often have suboptimal plasma EAA at the time of admission (F.7967). Thus, early introduction of EAA-based medical foods, which contain a higher proportion of BCAA compared to intact proteins, within the first 24 hours of admission (e.g., 0.5 g EAA protein equivalent/kg/day) can promote anabolism without providing excessive nitrogen (F.4756, F.7594).

In mild UCD cases or mild hyperammonemia (<150 µmol/L), a recent review (2022) suggested total removal of protein is not always necessary and may instead be reduced (F.4594).

Delphi 1 Results

Across all Delphi 1 respondents there was strong consensus (96%) that protein should be removed for a maximum of 24 hours from the time of the individual's last intake. One respondent commented that protein may be reduced rather than removed in individuals who present after long periods of over-restriction. Another noted preference to remove protein for 12 hours only and never hold for more than 24 hours.

During HAC, energy intake is targeted at approximately 100-125% of estimated needs to reduce catabolism and promote anabolism (F.4756, F.7664, F.7963). A 2022 retrospective review highlighted the use of "hypercaloric parenteral nutrition" in all inborn errors of metabolism (IEM) patients requiring dialysis, including eight with UCDs (F.4567). Clinical strategies have employed high-energy regimens, such as 90-100 kcal/kg/day via intravenous (IV) glucose and lipids for CPS (F.4975), 100 kcal/kg/day using protein-free parenteral nutrition or enteral feeds in CPS and ASA (F.7596), and 112 kcal/kg/day for a neonate with CIT-I and severe hyperammonemia (F.7802). For adolescents and adults, regimens have included 40 kcal/kg/day to stabilize ammonia in a 16-year-old with CPS (F.5709) and a high-calorie diet of 1800 kcal/day post-hemodialysis in a 69-year-old late-onset male with OTC (F.5509). Studies addressing energy intake during HAC emphasize the use of "non-protein hypercaloric solutions" during the initial 24-48 hours of treatment (F.7802), with a 2018 review supporting a "reasonable" goal of 80-120 kcal/kg/day for neonates (F.7594).

Delphi 1 Results

There was strong agreement (96%) to provide energy meeting 100-120% of estimated energy needs during HAC.

IV dextrose infusion is critical for preventing or reversing catabolic states during HAC, as supported by case studies (n=15 individuals) and management reviews and guidelines (2018-2022). IV fluids containing at least 10% dextrose are typically administered, which can be given peripherally at rates of approximately 1.5 times maintenance fluid needs (F.4663, F.4816, F.7664, F.7802, F.7969). However, clinical factors such as intracranial hemorrhage and/or concurrent medications can restrict fluid volume, necessitating the use of concentrated dextrose solutions to meet the target glucose infusion rate (GIR) (F.6838, F.7969). Furthermore, 10% dextrose at 1.5 times maintenance provides only 51 kcal/kg/day and is insufficient to meet calorie needs (F.4663). For individuals requiring parenteral nutrition for more than 48 hours, a more concentrated dextrose solution (12-30%) is used to ensure sufficient caloric intake (F.4663, F.7802).

The appropriate GIR varies by age and clinical condition. For neonates and young children, a GIR of 8-10 mg/kg/min is supported by clinical studies and standard practices (F.4594, F.4726, F.5416, F.6580, F.6702, F.7664, F.7891, F.7963). For older children and adults, lower GIRs of approximately 6-7 mg/kg/min are used to meet metabolic demands while adjusting for tolerance (F.5118, F.7963).

During acute hyperammonemia, insulin may be used to promote anabolism, particularly when blood glucose concentrations rise above 150-200 mg/dL, with expert opinions and reviews (2001-2022) recommending adding insulin rather than reducing glucose infusion rates to maintain anabolism (F.4594, F.4663, F.5652, F.7597, F.7664). Insulin should be used cautiously to avoid hypoglycemia (F.4861), including hourly blood glucose monitoring in individuals receiving insulin infusion to prevent hypoglycemia and large fluctuations in glucose (F.7597, F.7963).

Delphi 1 Results

There was strong agreement (96% and 92%, respectively) to provide IV fluid with 10% dextrose at 1.5 to 2 times maintenance (or equivalent glucose infusion if fluid restricted) and to administer insulin, as needed, to allow sufficient glucose infusion for anabolism.

Thirteen studies, primarily case reports, retrospective reviews, and management review articles, addressed use of intravenous lipid emulsion (ILE). ILE is frequently combined with IV dextrose to provide sufficient non-protein energy during HAC. Standard ILE dosing typically ranges from 1-3 g/kg/day, with most starting at 2 g/kg/day (F.4567, F.5405, F.6702, F.7664, F.7802, F.7899, F.7963). Higher doses up to 4 g/kg/day may be used for newborns (F.7969), and doses as high as 3-5 g/kg/day may be appropriate for individuals without suspected fatty acid oxidation defects (F.4663).

In contrast, a 2013 Urea Cycle Disorders Consortium (UCDC) Longitudinal Study report on 128 individuals with UCDs found that while 79% received intravenous dextrose during HAC events, only 33% were given ILE (F.6121). Furthermore, a 2016 study using a simulated model of an adult male with a UCD demonstrated that dextrose alone (20% dextrose at 1.5 times maintenance = 2800 kcal/day) was more effective than a combination of dextrose and ILE (10% dextrose at 1.5 times maintenance + 2 g ILE/kg/day = 2800 kcal/day) in minimizing nitrogen loss and restoring nitrogen balance under scenarios of dietary nonadherence and infection (F.5752).

Delphi I Results

There was strong agreement (96%) to provide 20% IV lipid emulsion at 1-3 g/kg/day to help meet estimated energy needs.

Enteral nutrition (EN) should be reinitiated as soon as possible during the management of HAC according to 2019 European UCD management guidelines (F.7963). For critically ill children, published guidelines further emphasize initiating enteral feeding within 24 hours of admission unless contraindicated (L.454).

EN is often combined with parenteral nutrition (PN) to ensure adequate energy and nutrient intake during transitional phases (F.7802). In cases where gastrointestinal function is partially intact, peripheral nutrition with lipids and dextrose can initially prevent catabolism, followed by nasogastric (NG) tube insertion to provide a slow, continuous drip of EAA (F.7801). One review specifically recommended NG tube placement in the early phases of HAC (F.7597), and several case studies have reported successful use of NG feeding to mitigate catabolism when oral intake is insufficient (F.4603, F.4824, F.5497, F.6302).

Early protein reintroduction through EN is particularly beneficial, as it supports the role of the splanchnic system (stomach, intestines, liver, spleen, pancreas) in protein retention and metabolism, which may be more advantageous than intravenous supplementation in these cases (F.7967). Practical considerations, such as antiemetics, may further support successful transitions to enteral feeding (F.7802). Overall, early initiation and appropriate use of EN, tailored to individual tolerance and clinical status, are critical components of managing HAC.

Delphi 1 Results

There was unanimous agreement to reintroduce enteral feeds (total or partial) as soon as possible, and strong agreement (96%) that protein can be reintroduced in either parenteral or enteral feeds.

Nutritional considerations for individuals with UCDs receiving dialysis were discussed in twelve studies, primarily case reports. During dialysis, providing non-protein calories through IV dextrose and ILE is essential to meet energy demands (F.4655, F.7332). To further mitigate catabolic stress, nutrient intake may be increased by up to 25-50% (F.4594), and/or amino acids may be added to dialysis fluids (F.4996) to compensate for losses caused by extracorporeal clearance. A 2007 case-control study of 12 neonates with OTC undergoing continuous arteriovenous hemodiafiltration (CAVHDF) showed significantly lower plasma BCAAs, methionine, phenylalanine, and tyrosine when compared to controls (F.5435) further supporting the potential role of EAA provision during dialysis and the importance of monitoring plasma amino acids.

In hemodynamically stable individuals, enteral nutrition can be safely introduced during dialysis to optimize protein and energy intake while preventing catabolism (F.4756). Protein-free enteral nutrition during dialysis has been well tolerated in several case reports (F.4756, F.6794, F.7332), and post-hemodialysis nasogastric feeds have facilitated recovery in pediatric cases (F.7899).

A rebound in ammonia concentrations is commonly observed following the cessation of dialysis and can be prevented by providing adequate energy through parenteral and/or enteral nutrition immediately after dialysis (F.6468). Reintroducing intravenous amino acids or enteral EAA-based medical foods post-dialysis can help stabilize ammonia (F.7969). Additionally, one review reported "more aggressive" reintroduction of protein (removing protein for no longer than 12-24 hours and adding EAA formulations in the first 24 hours) reduced the rebound in ammonia post-dialysis (F.7594).

Given the complexity of dialysis-related nutrient losses and metabolic shifts, close coordination between the metabolic nutrition team and nephrology is essential to optimize nutrition delivery, prevent catabolism, and support metabolic stability during and after dialysis.

Delphi 1 Results

There was unanimous agreement (100%) that hemodialysis should be accompanied by aggressive nutrition support to maximize energy intake (IV dextrose, lipid emulsion, and insulin, if needed). When reintroducing protein in an individual who requires dialysis, start with 50-75% of the Dietary Reference Intake (DRI) or usual intake, and gradually increase up to 25% each day, as tolerated until the protein goal is met (while providing adequate energy) (96% agreement).

Delphi 2 Results

There was unanimous agreement (100%) to provide adequate non-protein energy during dialysis and to consider providing protein during and/or post dialysis to compensate for losses during dialysis.

Nineteen studies included information on protein reintroduction during HAC. These were primarily case studies (n=13 individuals) and management review articles (published in 2000-2021). Protein reintroduction is vital to achieve positive nitrogen balance, as demonstrated in a computational model of an adult male with UCD (F.5752). Protein reintroduction begins once ammonia concentrations normalize or stabilize (F.4662, F.5118, F.6702, F.6838, F.7664) with some guidelines recommending specific ammonia thresholds: <100 µmol/L (F.6373) and <150 µmol/L (F.6756).

Reintroduction of protein is progressive, starting with 25-50% of the individual's protein goal (F.4756, F.6838, F.7801, F.7802), typically starting at 0.5 g/kg/day (F.4662, F.4816, F.6302, F.6345, F.6838, F.7963), depending on the individual's tolerance and clinical status. Protein can be provided through parenteral or enteral/oral feedings, and one group suggested the titration process aims to achieve plasma essential amino acid concentrations in the low-normal range (F.7969).

Case-specific strategies highlight the importance of individualized adjustments. For instance, in a neonate with ASA, an initial attempt to reintroduce protein in four steps (0.25 to 1.5 g/kg) led to lethargy and rising blood ammonia (F.5501). However, subsequent reintroduction at 1 g/kg/day combined with 500 mg/day of arginine hydrochloride was successful, and a gradual increase to 1.5 g/kg/day was well-tolerated with stable ammonia (F.5501). This underscores the need for careful monitoring of ammonia and clinical response throughout the reintroduction process.

Delphi 1 Results

There was strong agreement (92%) to reintroduce protein after 24 hours of a protein-free diet and/or once ammonia concentrations are less than 100 μmol/L, whichever comes first.

There was strong agreement (96%) that protein can be reintroduced in either parenteral or enteral feeds.

Delphi 2 Results

There was strong agreement (92%) that, for individuals who do NOT require dialysis, to reintroduce protein starting with 25-50% of typical intake and increasing up to 25-50% each day, as tolerated.

For individuals who can tolerate enteral nutrition during hyperammonemia, management review articles published between 2000 and 2021 indicate that EAAs are typically used as the initial protein source to minimize nitrogen load while restoring plasma EAA concentrations (F.4662, F.7594, F.7801, F.7969). EAA-based medical foods are particularly recommended during the first 24 hours of admission (F.7594) and may temporarily serve as the sole protein source, even when most caloric support is provided parenterally (F.7969). Case studies and reviews reported initial dosing of EAA-based medical foods was often 0.5 g protein/kg/day (F.4816, F.6302), with total protein gradually increased to approximately 1.0-1.5 g/kg/day depending on individual tolerance (F.4816, F.5501, F.6302, F.6568, F.6739, F.6789, F.7596, F.7969).

During protein reintroduction, several reports describe the use of mixed protein sources. For example, nasogastric feeds providing 0.75 g/kg/day of total protein from equal contributions of intact protein and EAA-based medical foods (0.4 g/kg/day each) were successfully used in neonates with CPS deficiency (F.6302). Similar strategies combining intact protein and EAA-based medical foods have also been reported in older individuals, including a 14-year-old with ARG (F.6452). In neonates with CPS and ASA, protein reintroduction has been described using a combination of human milk and EAA-based medical food (F.6933, F.5419, F.4603), and a recent systematic review noted that expressed human milk (vs. on demand breastfeeding) was commonly used following acute management of infants with UCDs (L.465). However, EAA-based medical food may not be necessary for all individuals, particularly those who do not require EAAs at baseline and who respond quickly to medical management.

Overall, the selected protein source(s) should aim to replete and maintain plasma EAA concentrations to support anabolism (F.7969).

Delphi 1 Results

There was unanimous agreement that, in a neonate, it is appropriate to reintroduce protein with human milk (if available).

Delphi 2 Results

There was strong agreement (92%) to consider including EAA-based medical food, alone or in combination with intact protein, when reintroducing protein, particularly in neonates with severe presentation and individuals consuming EAA-based medical food at baseline.

Ideally, clinicians should prioritize PN formulations with higher concentrations of EAAs, particularly BCAAs, to maintain therapeutic amino acid concentrations and promote nitrogen excretion (F.7801, F.7969). Amino acid dosing should be carefully titrated based on tolerance, with one case report showing that doses of 0.4 g/kg/day were well-tolerated during prolonged dialysis without increasing ammonia (F.7265).

Delphi 2 Results

There was no consensus (71%) to examine available PN mixtures and select one with the highest BCAA content when reintroducing protein via PN. While no respondents disagreed with the statement, 7 of the 25 respondents neither agreed nor disagreed.

Nitrogen scavenging medications, such as sodium benzoate and sodium phenylbutyrate, are a cornerstone of HAC management. Published case reports and retrospective reviews consistently describe the use of intravenous and/or oral nitrogen scavengers during acute decompensation (F.4610, F.4677, F.5177, F.5235, F.5414, F.5416, F.5519, F.5757, F.6302, F.6481, F.6580, F.6933, F.7416). In acute crises, IV formulations containing sodium benzoate and sodium phenylacetate are typically administered as a loading dose followed by maintenance infusions to rapidly reduce plasma ammonia concentrations (F.5071, F.7594, F.7801, F.7963, F.7969). Once individuals are stabilized, therapy is transitioned to oral maintenance regimens and adjusted based on dietary protein intake (F.5641, F.7594). These medications are most effective when combined with high-energy, protein-free nutrition to minimize catabolism (F.7594, F.7801). Proper dosing and monitoring are essential to avoid complications like metabolic acidosis (F.6498, F.7416).

This topic was not included in the Delphi consensus process.

For CPS and OTC, typical doses of intravenous L-arginine hydrochloride (10% solution) range from 100-250 mg/kg/day (F.4663, F.5650, F.5910, F.7265, F.7593, F.7594, F.7664, F.7963). In adults with late-onset OTCD, doses of 210 mg/kg/day (F.6838) or up to 380 mg/kg/day (F.6345) have been shown to improve outcomes. Administration is typically initiated as a bolus over 90-120 minutes, followed by continuous or divided maintenance doses (F.4662, F.4663, F.6915). Dosing of IV L-arginine hydrochloride should be adjusted to maintain plasma concentrations between 80 and 150 μmol/L (F.7664).

For CIT-I and ASA, reported intravenous L-arginine hydrochloride (10% solution) dosing includes 200-400 mg/kg/day as cited in the 2019 European UCD guidelines (F.7963). Doses described in expert opinion and case reports from 2002-2018 range from 100-500 mg/kg/day (F.7802) to approximately 600 mg/kg/day (F.7593, F.7594, G.179, G.182), including regimens specifying 600 mg/kg/day for individuals <20 kg and 12 g/day for those >20 kg (F.7664), or up to 700 mg/kg/day (F.5650). An isolated case report described dosing as high as 1000 mg/kg/day during peritoneal dialysis (F.7444).

Delphi 1 Results

Regarding IV L-arginine hydrochloride supplementation, there was agreement (88%) to provide IV L-arginine hydrochloride (approximately 200-400 mg/kg/day) to individuals with CPS, OTC, ASA, and CIT-I until able to resume oral supplements. Some dietitians do not recommend IV L-arginine hydrochloride doses in their facilities, and indicated they neither agree nor disagree with this statement.

There was unanimous agreement to provide L-citrulline in individuals with CPS and OTC once tolerating oral/enteral feeds.

Blood ammonia concentrations should be closely monitored to guide treatment and assess metabolic stability. In acutely ill infants and children, management review articles (published in 2000-2022) indicate ammonia is typically monitored every 2-4 hours (F.4594, F.7664, F.7963), while case studies describe monitoring intervals for adults that range from every 4-8 hours to once every 24 hours, depending on clinical status (F.4594, F.4662, F.7265). More frequent monitoring, every 1-2 hours, is advised during continuous renal replacement therapy (CRRT) or high-flow dialysis until ammonia concentrations decrease and stabilize to approximately <200 µmol/L, after which testing can be spaced out to every few hours (F.7597, F.7898).

Given the challenges in obtaining accurate ammonia readings, laboratory teams should collaborate closely with metabolic specialists when hyperammonemia is detected to ensure precise assessment and interpretation (F.6452). Additionally, one case report suggested repeating plasma ammonia testing if initial concentrations exceed 120 µmol/L or three times the normal range, reinforcing the need for careful verification of critical ammonia elevations (F.5422).

Delphi 1 Results

When asked which laboratory results impact decisions about changes to an individual's diet prescription during illness, respondents indicated ammonia (100%), glutamine (96%), arginine (88%), citrulline (88%), electrolytes (100%), blood glucose (92%), and trends in ammonia, plasma amino acids, and clinical status (100%).

Overall, there was agreement for the following schedule for ammonia monitoring, though two respondents disagreed with each: monitor every 2-6 hours until concentrations decrease to a clinically acceptable level (92%), every 3-12 hours while introducing protein (92%), and every 8-24 hours until tolerating home feeds and medications (92%).

Delphi 2 Results

There was strong consensus (96%) to monitor blood ammonia every 2-4 hours to assess treatment response and guide urgent clinical decisions.

Regular monitoring of plasma amino acids (PAA) is essential for guiding nutritional and metabolic management during HAC. One review suggested PAA concentrations should be assessed daily in acute settings (F.7597). Monitoring PAA during dialysis is particularly important, as one study showed significantly lower amino acid concentrations in neonates with OTC deficiency compared to controls, highlighting the need for targeted nutritional interventions (F.5435). Additionally, a retrospective review of 14 individuals with OTC deficiency revealed low plasma arginine concentrations, raising concerns about potential nitric oxide deficiency and its impact on endothelial function, further supporting the need for PAA monitoring during HAC (F.6465). Other studies emphasize the necessity of routine PAA monitoring to assess essential and conditional amino acid deficiencies and guide nutritional strategies, though specific frequency of monitoring was not described (F.4677, F.5416, F.6373, F.7664). One review suggested that PAA should be measured no earlier than 24 hours after modifying a nutritional intervention to allow for accurate assessment of nutritional changes (F.7696).

Delphi 1 Results

When asked which laboratory results impact decisions about changes to an individual's diet prescription during illness, respondents indicated ammonia (100%), glutamine (96%), arginine (88%), citrulline (88%), electrolytes (100%), blood glucose (92%), and trends in ammonia, plasma amino acids, and clinical status (100%).

There was no consensus regarding monitoring plasma amino acids at least every other day while making dietary changes in the hospital.

Delphi 2 Results

There was strong consensus (92%) to monitor plasma amino acids regularly, up to once daily, and no sooner than 24 hours after changing dietary treatment.

Hepatic dysfunction and/or liver failure have been reported during HAC with liver failure being reported more often in those with severe OTC (F.5137, F.6122, F.7594). In two cases of citrullinemia (neonate and toddler), hepatic dysfunction and liver failure resolved after HAC treatment (F.5137). Both studies suggest monitoring liver function tests (LFTs) during HAC but the desired frequency of testing is not reported.

Frequent monitoring of electrolytes, acid-base balance, and/or glucose is commonly done based on case reports and management review articles (F.4594, F.4677, F.5416, F.6373, F.7594, F.7597, F.7664, F.7898). When insulin is administered, glucose is monitored frequently, beginning 30 minutes after insulin and subsequently every hour (F.6373). Other laboratory assessments include measuring blood gases and ion concentrations at the same frequency as ammonia (F.4594), and monitoring triglycerides if receiving ILE (F.7969). BUN monitoring was noted in two case studies of late-onset OTC (F.4655, F.4677).

Delphi 2 Results

There was strong consensus (96%) to monitor blood glucose and electrolytes frequently, with glucose checks up to every hour if insulin is administered to prevent hypoglycemia.

A sick-day plan aims to mitigate hyperammonemia during stressors such as intercurrent illness, with strategies including dietary adjustments, emergency medication management, and enhanced caregiver preparedness (F.7802).

During mild illness, dietary management typically includes a temporary reduction in protein intake, typically by 50% and up to 100% for 24-48 hours (F.7802, G.187) or for no more than 2-3 days (G.189), alongside an increase in non-protein calories of approximately 20% (G.187), 20-25% (G.189), or 25-50% above maintenance (F.7802). Frequent small meals may help ensure adequate caloric intake (F.4594), and fluid intake is generally increased to 1-1.5 times maintenance levels (F.7802). For individuals unable to meet needs orally, enteral feeding via a feeding tube may be considered (F.6480).

Emergency medications include the use of nitrogen scavengers prescribed for use only during illness in individuals with mild UCDs (F.5641, F.6119), as well as anti-emetics to reduce metabolic instability (F.7802).

Emergency planning emphasizes providing caregivers with a written sick-day plan outlining when and how to contact the metabolic team or seek emergency care (F.6373, F.7594, F.7802), carrying an emergency letter, card, or bracelet for use by emergency personnel (F.7594), and keeping protein-free formula or foods at home (F.7801). Some sources also recommend urine ketone strips to monitor for catabolism, as elevated ketones reflect metabolic stress (F.7801). Families are advised to act promptly if symptoms persist beyond 24-48 hours despite implementation of the sick-day plan, contacting the on-call metabolic team or seeking emergency care using the provided documentation (F.7802, G.193). Professional support includes ongoing monitoring of plasma ammonia concentrations (F.6119), consideration of hospitalization if ammonia concentrations reach three times the upper limit of normal (F.4662), coordination with local physicians as needed (F.6119), and ensuring access to hospitals with metabolic expertise, particularly during travel (F.7594).

Consensus based on clinical practice – Delphi 1 Results

Regarding recommendations to include in a home sick-day plan for mild illness, there was strong agreement to

1. Increase energy intake by 10-20% of usual intake using carbohydrates and fats (100%),
2. Increase fluids by 10-20% of usual intake (96%),
3. Promote intake of energy and fluids by providing small, frequent feedings (100%),
4. Provide the family/individual information about monitoring for clinical signs and symptoms of decompensation (100%),
5. Advise family/caretaker to contact metabolic clinic when illness occurs and to seek medical assistance if unable to tolerate oral/enteral feeds and fluids (100%),
6. Provide an individualized "emergency letter" to be used in the event of an emergency department visit (100%).

There was no consensus about the degree of protein restriction, though two respondents commented that they would reduce typical protein intake by 50%.

One respondent commented they also advise families to contact their metabolic specialist even if they present to the hospital with an emergency letter.

Delphi 2 Results

There was unanimous agreement that, as part of a sick day feeding protocol for mild illness, it is appropriate to reduce protein intake up to 50%, generally for 24 hours and no more than 48 hours, based on clinical status. One respondent commented that sick-day management should be guided by the individual clinical situation rather than an arbitrary 48-hour cutoff, noting that an additional day with adequate caloric support may be beneficial in some cases.

HAC are often triggered by factors that increase nitrogen turnover or nitrogen load. Infection is the most common precipitant, accounting for 58% of HAC events in a study of 562 individuals (F.6121), and also supported by findings in an open-label study of 260 individuals with UCDs (F.7590). Adherence to dietary and medication regimens is also critical, as non-compliance has been associated with approximately 15% of HAC events (F.7590). Other key triggers include non-adherence with dietary and medication regimens (15% and 10%, respectively), as well as stressors such as surgery, trauma, and pregnancy (10%) (F.7590). Decreased energy intake has also been associated with HAC, as seen in cases of hypercatabolic states and rapid weight loss (F.4543, F.5708, F.7593), particularly in undiagnosed individuals when paired with protein supplementation (F.5423) or malnutrition and weight loss (F.6424). Psychological stress, such as bullying at school (F.5065), and non-compliance with nitrogen scavengers or amino acid supplements are additional contributing factors (F.6999). Excessive protein intake beyond one's tolerance can precipitate HAC (F. F.5177, F.5546), particularly in undiagnosed or late-onset cases, though some studies suggest that low energy and/or protein intake is a more frequent trigger (F.4952, F.4756).

Medications that affect protein metabolism, such as sodium valproate, systemic corticosteroids, and other drugs like topiramate or carbamazepine, are known to precipitate HAC (F.5708, F.5873, F.6114, F.6289, F.7593, F.7802) and require careful management with enhanced nutritional support and monitoring (F.5873, F.7802).

Prevention strategies include prompt treatment of infections and illnesses (F.6121), supporting adherence to prescribed diets and nitrogen-scavenging medications (F.7590), and ensuring emergency preparedness with sick-day plans (F.7594, F.7802) and medical identification (e.g., emergency letter, medical alert bracelet) (F.7594, F.7801). Preemptive care and mental health support are also crucial, particularly for individuals facing physical (F.7590, F.7963) or psychological stressors (F.5065). Implementing these proactive strategies can help mitigate HAC risk.

Delphi 1 Results

There was strong agreement (96%) to provide families with a contingency management plan in the event of interruptions in access to prescribed UCD medications, supplements, and/or EAA-based medical foods.