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INTRODUCTION
This protocol is for patients with Arginase deficiency presenting to
the emergency department with illness or hyperammonemia. Arginase is
one of the five enzymes of the urea cycle associated with a known clinical
disorder (collectively known as the Urea Cycle disorders (UCDs).
Though hyperammonemic crises is less common in arginase deficiency than
the other urea cycle defects it does occur in patients ranging from
infancy to adulthood and may be secondary to an intercurrent illness,
possibly subclinical in presentation. Incipient or frank hyperammonemia
may present with anorexia, nausea or vomiting. Lethargy often suggests
progressive accumulation of ammonia. Arginase deficiency has also been
reported in the newborn, and can be devastating despite a less severe
degree of hyperammonemia than seen in other neonatal urea cycle defects.
PATHOPHYSIOLOGY
Arginase
deficiency usually presents with developmental delay and progressive
neurologic features in later childhood. The Arginase isoenzyme associated
with the arginase deficiency phenotype, Arginase A1, is cystolic in
location and is found primarily in hepatocytes (the site of activity)
as well as red blood cells (utilized for diagnostic assay)
Unlike
fats and carbohydrates, the body does not store protein. An excess of
protein leads to an excess of liberated nitrogen from the amino acids
of protein with a consequent excess of ammonia (NH3). This additional
NH3 cannot be metabolized by a defective urea cycle, so the ammonia
accumulates. In general, protein overload comes from two sources ,
1. Dietary protein intake beyond what is needed for tissue
formation and replacement.
2. Any catabolic process, e.g. stresses of the newborn
period, infection, dehydration etc.
.
.Characteristically,
the amino acid glutamine (containing two nitrogenous moieties and therefore
a temporary "repositoryž for ammonia) accumulates in excessive quantities
in affected, untreated individuals. Alanine is also elevated in plasma
sampling. Amino acid abnormalities usually precede hyperammonemia and
the onset of symptoms.
Acute
management of arginase deficiency
Plasma
ammonia levels (direct index of toxicity, important for acute management).
1.5 ml blood in sodium-heparin tube (green top tube).
Plasma amino acids (glutamine, as an ammonia buffer, reflects
direction of control of hyperammonemia, should be checked daily). Require
2 ml blood in green or red top tube.
Urinalysis, assessing ketonuria
Liver function tests (specifically transaminases, bilirubin,
albumin, PT and PTT)
Blood gases, lytes+CO2: Alkalosis (associated
with respiratory stimulation by the hyperammonemia). Alkalosis is more
common than acidosis (as opposed to organic acidemias) but, acidosis
can occur, anion gap typically < 20 (but again not always), normal
glucose, low ketones more indicative of UCD.
BUN: often low but not always, is neither sensitive nor specific
for UCDs.
Newborn screening blood sample. In neonate carry out at 24 hours
of age and call screening lab to track and report results as soon as
possible. Though extremely rare arginase deficiency will be picked up
in the neonatal variant of arginase deficiency.
RISING
BLOOD AMMONIA
Specimens
must be placed immediately on ice and walked to the laboratory. The
most common reason for a (mild) elevation in blood ammonia is a delay
in this process, necessitating the (unfortunate) drawing of another
sample.
PRESENTATION
DIAGNOSIS
THE
DEFINITIVE DIAGNOSIS
If
there is uncertainty about the diagnosis, arginase can be assayed
via red blood cell assay (through the laboratory of Dr. Vivian Shih
at the MGH; tel. 617-726 3884/5.) Differential diagnosis of other metabolic
disorders will be assisted by carrying out the above tests PLUS,
assays in the ACUTELY ill child for
- Urinary organic acids/orotic acid/amino acids/ acylglycines
- Plasma citrulline/carnitine/acyl carnitines/lactate/pyruvate and where
indicated
- CSF Amino acids/ lytes/glucose/lactate/pyruvate
The results of these tests will help to direct the differential diagnosis
THERAPY
A child
with arginase deficiency, either at high risk for metabolically decompensating
(acutely ill), or currently hyperammonemic should be treated aggressively.
The rationale of treatment includes ,
1.
Minimize protein intake.
2. Reverse or minimize catabolism.
3. Promote waste nitrogen excretion.
1.
MINIMIZE PROTEIN INTAKE
The
caloric intake on day 1 is provided by intravenous dextrose and supplemented
with Intralipid to provide 120-130 kcal/kg/day. Protein intake commences
after 24 hours at 0.6 grams/kg/day, administered as essential amino
acids. On day 2, 1.2 grams/kg/day should be supplied, half in the form
of essential amino acids, the other half in the form of a natural protein
source (avoid elemental formulas in infants as they are high in nitrogen
content). Supplemental calories are added from a non-nitrogenous formula
with vitamins and minerals (Mead-Johnson 80056 formula, Ross formula
Prophee or equivalent). Water is then added to dilute to the proper
concentration. Thereafter, the protein intake is increased gradually
in 0.25 , 0.5 gram/kg increments per day to a maximum of 2 grams /kg/day.
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.
Avoid
carnitine, not shown to be helpful. Although UCD infants are often low
in carnitine, it is known to conjugate with sodium benzoate
If
an IV is required, that solution should NOT contain sodium
MANAGEMENT
OF PROGRESSIVE HYPERAMMONEMIA
If
the blood ammonia is > 100 , 125 ug/dl, repeat the level. If
confirmed:
- discontinue oral feedings and oral medications
- administer a 10% (or higher) glucose solution
and Intralipid.
- administer the urea cycle medications as
an IV bolus.
- in neonate insert umbilical lines for potential
dialysis (7Fr or larger)
For ARGINASE DEFICIENCY
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)
In children greater than 20 kg :
Ammonul® 55ml/ square meter (ammonul contains 100mg Sodium benzoate and 100mg Sodium phenylacetate per ml)
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. 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
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 regardless of the amount of 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)
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, under close control by the neonatalogist,
is recommended.
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 µg/dl
Suggest
transfer to PICU with metabolic and hemodialysis facilities and alert
pediatric nephrology team.
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 µg/dl 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)
Adapted from Proceedings of a consensus conference for the management
of patients with Urea Cycle disorders. J Peds. Suppl. Vol. 138 (1),
2001
Any
questions about the patient or this protocol, 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.
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Last Updated: Wednesday, September 6, 2006
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