Carbamyl phosphate synthetase (CPS) and ornithine transcarbamylase (OTC) are located in the mitochondria. Arginase, argininosuccinate synthetase (ASS) and argininosuccinic acid lyase (ASL), also known as argininosuccinase, are cytosolic in location. The major site of complete urea cycle activity is the hepatocyte. Citrullinemia is autosomal recessive in inheritance; males and females are equally affected.

Unlike fats and carbohydrates, the body does not store protein. Excess protein is catabolized, releasing liberated nitrogen as ammonia (NH3). This additional NH3 cannot be metabolized by a defective urea cycle and so accumulates. In general, protein overload comes from either dietary protein intake beyond bodily requirements or secondary to catabolic processes, e.g. stresses of the newborn period, infection, dehydration etc...

Raised ammonia levels appear to be extremely toxic to the central nervous system, causing cerebral edema. It is not clear whether this is a primary effect and/or secondary to elevated glutamine (GLN) which, containing two nitrogenous moieties, functions as a temporary "repository" for ammonia. GLN thus accumulates in excessive quantities in affected untreated individuals, as does alanine (ALA) in the plasma. Amino acid abnormalities may precede hyperammonemia and the onset of symptoms.

PRESENTATION 

PRESENTATION
· Lethargy
· Irritability
· Vomiting
· Ataxia
· Protein avoidance
· Developmental delay
· Failure to thrive
· Hyperammonemia
· Seizures
· Hepatomegaly
· Coma

Apart from arginase deficiency, which usually presents neurologically rather than as a hyperammonemic syndrome, the other urea cycle defects often present in the newborn period with catastrophic hyperammonemia, hepatomegaly, seizures and coma secondary to cerebral edema. Typically OTC and CPS have the most severe presentation but citrullinemia and argininosuccinic acidemia may also present with severe illness. However, all the UCD disorders may present later in life with a severe acute onset or a more chronic course.

DIAGNOSIS 

Assess for cardiorespiratory instability, dehydration, fever, infection or any other physical stressor (e.g. surgery), as a potential precipitant for metabolic decompensation. Assess hepatic and neurological status.

· Blood glucose
· Electrolytes, CO2 and blood gas
· Ammonia (1.5 ml blood in sodium-heparin tube sent STAT to lab on ice)
· Plasma amino acids
· LFTs (AST,ALT,AlkPO4, bilirubin)

Plasma ammonia is a direct index of toxicity, important for acute management. A level greater than 250 mg/dl (150 µmol/L), typically with the absence of metabolic acidosis (though may occur secondary to a primary respiratory alkalosis).

Plasma amino acids should be drawn first thing in the morning , calling the metabolic lab in advance for urgent samples. Glutamine acts as an ammonia buffer and reflects the direction of control of hyperammonemia. It is therefore essential that amino acids are checked daily in the acutely sick child with hyperammonemia secondary to a urea cycle defect.

THERAPY 

An infant/child at risk from a urea cycle disorder should be treated prospectively. The rationale of treatment includes -

1. Minimize protein intake.
2. Reverse or minimize catabolism.
3. Promote waste nitrogen excretion.

1. MINIMIZE/OPTIMIZE PROTEIN INTAKE

DIET SHOULD BE PLANNED IN CONJUNCTION WITH A METABOLIC DIETICIAN

In citrullinemia,
the infant can start with 0.6 grams/kg/day on day 1, using a regular formula. The administered protein is gradually increased to a maximum of 1.5-2.0 grams/kg/day. Supplemental calories are provided as Mead- Johnson 80056 formula or equivalent.

Enteral feeds should be started as soon as practical, may even occur concomitant with IV via NG or NJ tube if necessary. Essential amino acids should not be withheld > 24 hours, to avoid catabolic breakdown of endogenous proteins. To avoid excess amino acid load aim for 1.0 - 1.5g protein/kg body weight (50% as essential amino acids). Contact the metabolic nutritionist (and discuss with the parent) before starting oral diet such as Mead Johnson 80056 or Ross ProPhree. Once patient stabilized, feedings established and the ammonia not fluctuating may switch to oral UCD medications.

2. REVERSE OR MINIMIZE CATABOLISM

The caloric intake for these infants should run at least 120-130 kcal/g/day. Accurate records of intake and output should be kept to monitor hydration. Infection as a potential but severe catabolic stressor should be considered early (when clinical signs are apparent) and managed vigorously. Avoid valproic acid, as it decreases urea cycle function and accentuates hyperammonemia.

3. PROMOTE WASTE NITROGEN EXCRETION

To help facilitate the excretion of waste nitrogen, the following medications are employed.

(i) Sodium benzoate - conjugates with glycine to form hippuric acid which bypasses the urea cycle
    and is excreted in urine.
(ii) Sodium phenylacetate - conjugates with glutamine to form phenylacetylglutamine which bypasses
     the urea cycle and is excreted in the urine.
(iii) Arginine - to prevent ARG deficiency and prime any residual OTC activity but must NOT BE used in
     arginase deficiency where there is already an excess of arginine.

Avoid carnitine as it has not been shown to be helpful. Although UCD infants are often low in carnitine, it is known to conjugate with sodium benzoate. Also avoid citrulline as it will will further exacerbate citrullinemia and ASA in which there already is an excess of citrulline

If an IV is required, that solution should NOT contain sodium as plenty will be provided by the sodium benzoate and sodium phenylacetate.

MANAGEMENT OF PROGRESSIVE HYPERAMMONEMIA

If the blood ammonia is > 100 - 125 ug/dl (60-75 µmol/L), repeat the level. If confirmed:
- discontinue oral feedings and oral medication
- administer a 10% (or higher) glucose solution and Intralipid.
- administer the urea cycle medications as an IV bolus.

Prescribe  medication fluids and separate maintenance fluids as described :

In children less than 20 kg :
Ammonul® 2.5ml/kg (equals Sodium benzoate 250 mg/kg and Sodium phenylacetate 250 mg/kg)
plus 10% Arginine HCl - 600 mg/kg

In children greater than 20 kg :
Ammonul® 55ml/ square meter (ammonul contains 100mg Sodium benzoate and 100mg Sodium phenylacetate per ml) plus 10% Arginine HCl - 600 mg/kg

In each case - Mix each dose together in 25 ml/kg of 10% dextrose (with no sodium or other electrolytes added) and run as a bolus over 90 minutes. This is then followed by the same solution administered as a 24-hour infusion.

IV maintenance fluids (to begin with maintenance dosing of medication fluids): Dextrose 10% + K+ Acetate as indicated. Fluid rate should be determined by the following formula: [1.5x maintenance – 25mL/kg (provided by above doses)/24 hours]. No sodium can be administered since it is present in high doses in the ammonul. Avoid chloride (e.g. KCl) administration as already present in the arginine medication.

These infusions should begin during acute illness regardless of the amount of oral UCD medication already provided. Monitor ammonia levels every 4 hours, amino acids daily. Electrolytes, acid-base status and the anion gap should be monitored regularly. If another IV is required, that solution should not contain sodium.
It is helpful when giving the bolus to also provide an antiemetic such as ondansetron (0.15mg/kg, up to 8 hourly PRN)

For CITRULLINEMIA
Sodium benzoate (250 mg/kg/day or 5.5g/m2)
Sodium phenylacetate (250 mg/kg/day or 5.5g/m2)
10% Arginine HC1 (600 mg/kg/day)

(Surface area for the benzoate and phenylacetate should provide a more accurate dose in adolescents and adults)

Mix this in 35 cc/kg of 10% dextrose (no sodium) and run as a bolus over 90 minutes. This is then followed by the same solution administered as a 24 hour infusion.

· These infusions should begin during acute illness regardless of the amount of oral UCD medication already provided. Monitor ammonia levels every 4 hours, amino acids daily. Electrolytes, acid-base status and the anion gap should be monitored regularly. If another IV is required, that solution should not contain sodium.

· Glucose levels should be kept between 120-170 mg/dl. If necessary for control of hyperglycemia can use insulin (remains controversial) bearing in mind that wide swings in glucose levels affect brain osmolarity.

· Cerebral edema; Oncotic agents such as albumin will increase the overall nitrogen load but may in selected cases be considered. Mannitol has not been found to be helpful for edema secondary to hyperammonemia and steroids should not be used. Hyperventilation is recommended, but only under close appropriate supervision.

Potential side effects of sodium benzoate/phenylacetate regime
Increased incidence of nausea and vomiting with bolus.
Overdoses (3-5x recommended dose) can lead to symptoms reminiscent of hyperammonemia, specifically agitation, confusion and hyperventilation. Death has occurred (associated with cerebral edema, hypotension and cardiovascular collapse)

If the ammonia continues to rise >200-250 mg/dl (120-150 µmol/L)

Suggest transfer to PICU with metabolic and hemodialysis facilities and alert pediatric nephrology team. Remember placement of access lines for dialysis takes time so do not delay. If dialysis is not immediately available, give a loading dose of sodium benzoate/phenylacetate, to slightly retard ammonia rise and in anticipation of dialysis ASAP.

If the ammonia continues to rise >300 mg/dl (175 µmol/L)   CONSIDER DIALYSIS
Dialysis will clear ammonia at :
170-200ml/min for ECMO based dialysis. Osmotic shifts have NOT been observed with this rapid rate of clearance. Additionally a hemofilter in the circuit will continue to remove ammonia between dialysis cycles.
10-30 ml/min hemodialysis
3-5 ml/min peritoneal dialysis (this rate will however take several days to significantly reduce the ammonia load, at a time when brain damage is related to duration of hyperammonemia toxicity)

*note that dialysis itself is associated with significant morbidity/mortality, particularly in the neonate, and decisions to consider using dialysis must balance the risk:benefit ratio for each child.

RECOVERY
As ammonia falls below 125-150mg/dl (60-75mmol/L) and clinical status returns to baseline
Can switch to oral medications and gradual reintroduction of diet in conjunction with the metabolic dietician as described above (in section "therapy"). The use of oral sodium benzoate and sodium phenylbutyrate (the much less odiferous oral form of sodium phenylacetate) is determined, dependent on the patient, either on body weight or body surface area. The dose should be decided in conjunction with a metabolic physician if the patient does not have an up to date regimen.
NOTE that there may be a rebound hyperammonemia initially with the efflux of intracellular ammonia into the 'relatively' ammonia depleted blood. THUS it is important to continue closely monitoring ammonia levels until they remain stable in the normal range.

Adapted from
Proceedings of a consensus conference for the management of patients with Urea Cycle disorders.
J Peds. Suppl. Vol. 138 (1), 2001

This protocol should be used ONLY in conjunction with metabolic consultation. For this please call or have paged the Genetics/Metabolism Fellow-on-call or, failing this, the Metabolic attending on call at your hospital or nearest pediatric tertiary care center (click on "metabolic consultation" at the top of the page to find local contact information [in the New England area] ).

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