`
`Supplement to
`
`
`THEJOURNAL OF
`EDIATRICS
`
`Volume 138
`
`Number I
`
`January 2001
`
`Consensus statement from a Conference for the
`
`
`
`With Urea Cycle Disorders
`
`Management of Patients
`The Urea Cycle Diforderd Conference Group�
`
`
`DIAGNOSIS A ND
`TREATMENT OF A
`UREA CYCLE
`DISORDER
`
`Reco1nm.e1idalion
`can be a finding in many other dis­
`
`
`All neonates with symptomatic hyp er­
`eases. These symptoms progress
`quickly to lethargy and coma unless
`ammonemia should be transferred as
`hyp erammonemia
`
`is recognized and
`
`quickly as possible to a level III neona­
`tal unit with hemodialysis facilities.
`therapy initiated.
`
`NEONATAL
`PRESENTATION
`
`The recommendations made in this
`
`Recom.1ne1ulation
`
`CPS Carbamyl phosphate synthetase
`I
`
`
`consensus statement reflect the opin­
`The plasma ammonia level should be
`OTC Omithine transcarbamylase
`measured at the time of any sepsis
`
`ions and experience of the conference
`UCO Urea cycle disorder
`
`
`participants. The participants are
`
`workup in a patient without an obvi­
`ous infection.
`
`aware that some of the recommenda­
`
`tions have not been scienti6cally stud­
`RATIONALE. With no effective clear­
`
`
`ance system for ammonia, levels in­
`RATIONALE. Almost all neonates with a
`
`ied and thus cannot be regarded as ev­
`
`
`
`crease rapidly, resulting in cerebral
`
`idence-based medicine.
`
`U CD are initially thought to be septic.
`
`edema with severe neurologic compro­
`
`mise. Dialysis is the only means of rapid
`Recom.1ne1ulation
`removal of ammonia from blood in acute
`
`
`Respiratory alkalosis is an important
`
`neonatal hyp erammonemia, and he­
`
`
`initial clue for the diagnosis of a UCO.
`
`
`modialysis is preferred over peritoneal
`Recomm.e,ulation
`the diag nosis of an
`
`dialysis because it is much more effec­
`Always consider
`
`
`
`RATIONALE. Respiratory alkalosis is
`not usually seen in sepsis or in other
`
`inborn error of metabolism, including
`
`
`tive. lf hemodialysis is not available, he­
`
`mo6ltration can be used, although am­
`
`causes of severe illness in the neonate.
`
`urea cycle disorder, in a sick neonate.
`monia removal may be slower.
`
`
`The alkalosis results from stimulation
`
`of the respiratory center by hyperam­
`RATIONALE. The initial symptoms of a
`
`
`
`neonate with hyperammonemia are
`
`monemia and is a frequent but often
`Reco1nm.e1idalion
`
`If time permits, and without delaying
`subtle occurrence.
`
`
`
`failure to feed and somnolence, which
`
`
`the transport of the patient, samples
`should be sent for plasma amino acid
`lflMbington Unive1>1ity Scbool of Mdicu,e.
`
`From Cbi!dret1:, National Mdical Center, WaJbu,gton, DC, Tiu George
`
`
`
`
`analysis and for urinary amino acid,
`
`
`
`
`
`
`Reprint requests: Mendel Tuchman MD, Children's National Medical Center, 111 Michigan
`organic acid, and orotic acid determi­
`Ave, NW, Washington, DC20010.
`
`0See page S5 for the list of conference group members.
`nation. Plasma and urine should be
`frozen for future testing.
`
`J Pediatr 2001;138:Sl-S5.
`
`Copyright© 2001 by Mosby, Inc.
`
`0022-3476/2001/$35.00 + 0 9/0/111830
`doi:I0.1067/mpd.2001.111830
`
`Page 1 of 5
`
`RATIONALE. These tests will help iden­
`
`tify the cause of the hype rammonemia.
`
`Horizon Exhibit 2025
`SI
`Lupin v. Horizon
`IPR2017-01159
`
`

`

`UCD CONFERENCE GROUP
`
`Recommendation
`Administration of intravenous glu-
`cose and fluids should be started be-
`fore transport. Tracheal intubation and
`placement of an umbilical venous
`catheter are recommended; however,
`transport should not be delayed if cen-
`tral venous access is not available.
`
`RATIONALE. Many neonates are dehy-
`drated at presentation. Intravenous ac-
`cess permits rapid rehydration and al-
`lows for administration of drugs and
`fluids during transport. Intubation and a
`central venous catheter are useful in case
`of circulatory collapse during transport.
`
`Recommendation
`All feedings containing protein should
`be discontinued. Calories should be pro-
`vided as intravenous glucose and lipid.
`
`RATIONALE. Caloric supplementation
`is needed to reverse catabolism and to
`reduce the protein turnover rate. Pro-
`tein feeds are stopped to prevent an
`additional nitrogen burden but are
`restarted within 48 hours, because de-
`pletion of essential amino acids will re-
`sult in further protein catabolism and
`ammonia formation.
`HOSPITAL
`MANAGEMENT OF
`HYPERAMMONEMIA
`Recommendation
`Measure plasma ammonia level.
`
`RATIONALE. A normal blood ammonia
`level during symptoms of vomiting and
`lethargy eliminates UCD from the dif-
`ferential diagnosis. Note that an elevat-
`ed ammonia level (2 to 3 times normal)
`may be factitious if the sample was not
`properly obtained. In neonatal-onset
`UCD, ammonia levels are usually >300
`µmol/L and are often in the range of
`500 to 1500 µmol/L.
`
`when ammonia elevation causes any
`central nervous system symptoms.
`However, there is no consensus at
`what ammonia level intravenous thera-
`py should be started if no symptoms
`are present. For acute neonatal hyper-
`ammonemic coma, a loading dose of
`600 mg/kg L-arginine-HCL and 250
`mg/kg each of sodium benzoate and
`sodium phenylacetate in 25 to 35
`mL/kg of 10% dextrose solution given
`over a 90-minute period is recom-
`mended. This is followed by a sus-
`tained infusion (250 mg/kg L-arginine-
`HCL and 250 mg/kg each of sodium
`benzoate and sodium phenylacetate
`over a 24-hour period for carbamyl
`phosphate synthetase I and ornithine
`transcarbamylase deficiency; 600 mg/kg
`L-arginine-HCL and 250 mg/kg each
`of sodium benzoate and sodium phenyl-
`acetate over a 24-hour period for cit-
`rullinemia and argininosuccinic acid-
`uria). For argininosuccinic aciduria,
`arginine therapy alone may suffice. If
`locally available, monitoring drug lev-
`els will help reduce the risk of toxicity.
`
`RATIONALE. Hyperammonemia asso-
`ciated with symptoms must be treated
`as soon as possible to avoid further in-
`creases in ammonia and to reduce the
`risk of brain damage.
`
`Recommendation
`Preparation for dialysis should be
`made as soon as possible, even before
`the arrival of the patient. The preferred
`method for ammonia clearance is he-
`modialysis. In centers where hemodial-
`ysis is not available, hemofiltration or
`other forms of dialysis should be used.
`
`RATIONALE. Preparation for hemo-
`dialysis may require several hours.
`Peritoneal dialysis, although helpful,
`may not remove ammonia quickly
`enough to be clinically effective in se-
`vere cases.
`
`Recommendation
`Intravenous therapy with ammonia
`scavenging drugs should be started
`
`Recommendation
`A protocol should be available for
`placement of catheters for hemodialy-
`
`S2
`
`THE JOURNAL OF PEDIATRICS
`JANUARY 2001
`
`sis by a pediatric surgeon. The cathe-
`ters (or a single double-lumen cathe-
`ter) should be placed in large vessels to
`allow the high flows required for effec-
`tive dialysis. If 2 catheters are used,
`one should be placed above and one
`below the diaphragm.
`
`RATIONALE. Effective hemodialysis
`depends on good blood flow, which in
`turn relies on correct placement of ad-
`equate-sized catheters. Placement of
`catheters into different vessels will
`avoid recirculation and ineffective
`dialysis.
`
`Recommendation
`Intravenous therapy with ammonia
`scavenging drugs should be continued
`while dialysis is being performed.
`
`RATIONALE. The use of these medica-
`tions provides a synergistic action for
`ammonia removal, and they are less
`likely to accumulate during dialysis.
`
`Recommendation
`A repeat loading dose of ammonia
`scavenging drugs within 24 hours
`should be given only in neonates with
`severe disorders who are receiving
`dialysis. If drug level monitoring is not
`available, repeated loading in the pre-
`viously described setting should only
`be considered with evaluation of risks
`versus benefits for a particular clinical
`picture. All orders for intravenous
`medications should be carefully check-
`ed for correct dosage.
`
`RATIONALE. Toxicity
`is associated
`with high drug doses (750 mg/kg/d and
`higher). Deaths have been reported
`from accidental overdosing of these
`rarely used medications.
`
`BLOOD SAMPLING AND
`LABORATORY TESTING
`Recommendation
`Sodium, potassium, lithium heparin,
`or tubes containing EDTA should be
`used. Serum is not adequate for ammo-
`
`Page 2 of 5
`
`

`

`THE JOURNAL OF PEDIATRICS
`VOLUME 138, NUMBER 1
`
`nia determination. Blood for ammonia
`determination should be collected in a
`prechilled, ammonia-free tube on ice
`and delivered to the laboratory imme-
`diately. Samples should be kept on ice,
`and plasma should be separated within
`15 minutes of collection. If the assay is
`not run immediately, plasma should be
`stored frozen at –70oC.
`
`RATIONALE. Hemolysis, delay in sam-
`ple processing, and exposure to room
`temperature all factitiously increase
`the plasma ammonia level. Correct
`handling
`is more
`important than
`whether arterial or venous blood is col-
`lected.
`
`Recommendation
`Capillary blood is not suitable for the
`accurate measurement of ammonia
`level.
`
`RATIONALE. The great variability in
`mode of collection and tissue damage
`frequently causes factitious elevation
`of ammonia.
`
`Recommendation
`Assay of liver enzyme activity is the
`standard for confirmation of N-acetyl
`glutamate synthase, CPS, and OTC
`deficiencies. Plasma and urine amino
`acid analyses are the laboratory stan-
`dards for confirmation of citrullinemia
`(argininosuccinate synthetase deficien-
`cy) and argininosuccinic aciduria
`(argininosuccinate lyase deficiency).
`Arginase deficiency is confirmed
`with red blood cell enzyme analysis.
`
`RATIONALE. There is a perception that
`DNA diagnosis for UCD can be per-
`formed on a routine basis. This may be
`available in the future. Currently, rou-
`tine DNA analysis is available only for
`OTC deficiency where a mutation can
`be identified in most patients.
`
`Recommendation
`The following Web sites list laborato-
`ries offering tests for UCD diagnosis:
`• Gene Tests (www.genetests.org)
`
`• University of California at San
`Diego (www.biochemgen.ucsd.
`edu)
`
`INTERPRETATION OF
`RESULTS
`Recommendation
`Both the plasma ammonia level and
`the clinical picture should be consid-
`ered when choosing therapy (dialysis
`vs intravenous pharmacologic therapy
`vs management at home with diet and
`medications).
`
`RATIONALE. There may be lack of
`concordance between the ammonia
`level and the clinical condition of the
`patient. This is especially true for am-
`monia levels <200 µmol/L.
`
`Observation
`There is no consensus on whether an
`elevated plasma ammonia level (> 3 ×
`normal) in a patient with chronic
`asymptomatic disease indicates a re-
`quirement for intravenous therapy
`with pharmacologic ammonia scaveng-
`ing drugs.
`
`RATIONALE. Ammonia levels change
`rapidly. An elevated ammonia level
`during a clinic visit in a patient with-
`out symptoms, however, does require
`adjustment of therapy or better com-
`pliance with the recommended treat-
`ment regimen.
`
`CHRONIC (LONG-TERM)
`MANAGEMENT
`Recommendation
`Plasma glutamine level is a useful
`marker for effective therapy. Most par-
`ticipants agreed that the plasma gluta-
`mine level should be maintained at <1000
`µmol/L. Glutamine levels are obtained
`by quantitative plasma amino acid analy-
`sis, preferably in a preprandial state.
`
`RATIONALE. Glutamine appears to be
`a better marker than ammonia for
`chronic management, but scientific ev-
`
`UCD CONFERENCE GROUP
`
`idence to support a threshold value is
`lacking.
`
`Recommendation
`Protein intake should be reduced
`temporarily (for 24 to 48 hours) dur-
`ing an infection. Use of ibuprofen for
`fever relief is preferred over aceta-
`minophen. Extreme caution should be
`exercised in the use of antiemetics.
`
`RATIONALE. Protein-free diets are nu-
`tritionally inadequate. Acetaminophen
`in high doses is potentially toxic to the
`liver. Antiemetics may mask signs of
`hyperammonemia.
`
`Recommendation
`Parents should be trained in the
`placement of nasogastric tubes, and in
`selected cases consideration should be
`given to the placement of gastric tubes
`or buttons to facilitate treatment of pa-
`tients with severe disorders.
`
`RATIONALE. This practice could reduce
`the number of times a child has to be
`admitted to hospital, by permitting di-
`etary and pharmacologic therapy to be
`continued if oral intake is compromised.
`
`NUTRITIONAL
`MANAGEMENT
`Recommendation
`A reduced protein intake is an im-
`portant part of therapy.
`
`RATIONALE. The Recommended Daily
`Allowance for dietary protein is higher
`than the minimum needed for normal
`growth. Most patients with a UCD can
`receive less than the Recommended
`Daily Allowance of protein and still
`maintain adequate growth patterns.
`
`Recommendation
`Patients with severe disorders may
`need essential amino acids as part of
`their protein intake (25% to 50%).
`
`RATIONALE. This recommendation is
`based only on theoretical considera-
`
`S3
`
`Page 3 of 5
`
`

`

`UCD CONFERENCE GROUP
`
`tions and anecdotal experience. It has
`not been carefully studied.
`
`Recommendation
`Restricted diets should be supple-
`mented with minerals, vitamins, and
`trace elements.
`
`RATIONALE. Although
`commercial
`formulas are nutritionally complete,
`there may be a requirement for supple-
`mentation when the restricted dietary
`intake comes largely from natural food.
`
`Recommendation
`Monitoring of linear growth, appear-
`ance of hair, skin and nails, and the
`biochemical tests for essential amino
`acids, glutamine, hemoglobin, albu-
`min, pre-albumin, and transferrin pro-
`vide useful criteria to assess the nutri-
`tional status of the patient.
`
`RATIONALE. These are all useful mark-
`ers of nutritional status.
`
`PHARMACOLOGIC
`MANAGEMENT
`Recommendation
`The labeling for intravenous sodium
`benzoate and sodium phenylacetate
`should be modified to include a new in-
`dication for the treatment of patients
`with argininosuccinic aciduria.
`
`RATIONALE. Clinical experience indi-
`cates that these drugs are helpful in re-
`ducing ammonia in this condition, act-
`ing by a mechanism different from that
`of arginine.
`
`Recommendation
`High-dose arginine is very effective in
`reducing plasma levels of ammonia in
`patients with citrullinemia and arginino-
`succinic aciduria. Arginine-HCL should
`preferably be given through a central
`line and may require simultaneous ad-
`ministration of sodium bicarbonate.
`
`the amino acids citrulline and argini-
`nosuccinate, providing an alternative
`pathway for waste nitrogen excretion.
`High-dose arginine-HCL may cause
`metabolic acidosis, and it can cause tis-
`sue necrosis if extravasation occurs.
`
`Recommendation
`L-citrulline, given by nasogastric tube
`during the initial phase of intravenous
`therapy, may be useful in the treatment
`of CPS and OTC deficiency.
`
`RATIONALE. This recommendation is
`based on consensus clinical experi-
`ence. Citrulline is not available in in-
`travenous form. Given (orally) in CPS
`and OTC deficiency, it has the advan-
`tage of removing one nitrogen atom
`while being converted to arginine.
`
`Recommendation
`Written orders for pharmacologic
`scavenging agents should be double-
`checked to avoid overdosing.
`
`RATIONALE. Used in higher than rec-
`ommended doses, these compounds can
`be highly toxic. Accidental overdosing
`has resulted in deaths. The clinical pic-
`ture of toxicity is similar to that seen
`with salicylate poisoning (ketoacidosis).
`
`Recommendation
`Where available, plasma levels of
`ammonia scavenging drugs should be
`monitored to avoid toxicity.
`
`RATIONALE. Variable drug excretion
`may cause toxicity. In the absence of
`drug levels, a serum anion gap of >15
`mEq/L and an anion gap that has risen
`>6 mEq/L could indicate drug accumu-
`lation and increased risk for toxicity.
`
`Recommendation
`Intravenous arginine-HCL and sodi-
`um benzoate/sodium phenylacetate
`should be available in hospitals where
`patients with UCD are treated.
`
`RATIONALE. In these disorders arginine
`promotes incorporation of ammonia into
`
`RATIONALE. These medications are
`not routinely available and may be re-
`
`S4
`
`THE JOURNAL OF PEDIATRICS
`JANUARY 2001
`
`quired on an emergency basis to treat
`patients with acute hyperammonemia.
`
`Recommendation
`Patients should have a written treat-
`ment protocol with them. This should
`outline the steps in acute management
`and define the specific dosage of med-
`ications to be used. The protocol
`should be updated as the child grows.
`
`RATIONALE. The availability of such a
`protocol at the time the patient comes
`to an emergency room because of
`hyperammonemia can hasten effective
`treatment and potentially avoid incor-
`rect dosage.
`
`Recommendation
`To avoid hyperammonemic crises dur-
`ing intercurrent illness, a “sick day” regi-
`men should be established. This may in-
`volve decreasing protein intake, increasing
`non-protein calories, and adjusting med-
`ication dosage. Parents should become
`knowledgeable about this regimen.
`
`RATIONALE. This approach may pre-
`vent hospitalizations during self-limit-
`ed illnesses. However, any clinical
`symptom of hyperammonemia should
`prompt a visit to the hospital.
`
`CHRONIC THERAPY
`Recommendation
`Three-times-daily dosing of ammo-
`nia scavenging drugs is the minimum,
`with 4 times daily recommended. Ad-
`ministration of the drugs should be
`linked to meals to maximize the effect
`of ammonia removal.
`
`RATIONALE. The half-lives of these
`drugs are approximately 2 to 4 hours.
`Dosing adjustment to the timing of ex-
`cessive ammonia production (ie, after
`a protein load) may be needed.
`
`Recommendation
`Risk/benefit for the use of these drugs
`in patients who may become, or are,
`pregnant should be carefully considered.
`
`Page 4 of 5
`
`

`

`UCD CONFERENCE GROUP
`
`Robert Barsotti, Thomas Jefferson
`University, Philadelphia, PA; Mark
`Batshaw, Children’s National Medical
`Center, Washington, DC; Gerard
`Berry, Children’s Hospital of Philadel-
`phia, Philadelphia, PA; Stephen Ceder-
`baum, Mental Retardation Research
`Center, UCLA, Los Angeles, CA;
`Michael Jopling, St. Ann’s Hospital,
`Columbus, OH; Brendan Lee, Baylor
`College of Medicine, Houston, TX;
`Cynthia LeMons, NUCDF, La Cana-
`da, CA; James Leonard, Institute of
`Child Health, London, UK; Dorothy
`Markowitz, Fairview University Med-
`ical Center, Minneapolis, MN; Robert
`McArthur, Columbia University, New
`York, NY; Shideh Mofidi, New York,
`NY; Mindy Rosen, NUCDF, Cherry
`Hill, NJ; Rani Singh, Emory Univer-
`sity, Atlanta, GA; Robert Steiner,
`Oregon Health Sciences University,
`Portland, OR; Marshall Summar, Van-
`derbilt University Medical Center,
`Nashville, TN; Mendel Tuchman,
`Children’s National Medical Center,
`Washington, DC; Sharon Vonachen,
`Fairview University Medical Center,
`Minneapolis, MN.
`
`THE JOURNAL OF PEDIATRICS
`VOLUME 138, NUMBER 1
`
`RATIONALE. The safety of these drugs
`in pregnancy has not been determined.
`
`LONG-TERM
`CORRECTION
`Recommendation
`Liver transplantation should be con-
`sidered for patients with severe CPS or
`OTC deficiency, for patients with
`argininosuccinic aciduria and liver cir-
`rhosis, and for any patient who has re-
`current symptomatic hyperammone-
`mic episodes despite optimal medical
`management.
`
`RATIONALE. The 5-year post-trans-
`plantation survival rate for patients
`with UCD is now approximately 80%.
`Liver transplantation cures the hyper-
`ammonemia but does not correct the
`arginine deficiency, for which arginine
`supplements may be required.
`
`Recommendation
`Families should not delay treatment
`decisions (including liver transplanta-
`tion) based on the possibility of gene
`therapy in the near future.
`
`RATIONALE. It remains to be deter-
`mined whether long-term correction
`with gene therapy is feasible and safe.
`
`PSYCHOSOCIAL ISSUES
`Recommendation
`Health care practitioners must be
`aware of the psychosocial needs to sup-
`port patient and family. All families
`
`should be assessed by a social worker,
`and approved support programs should
`be developed.
`
`RATIONALE. This is rarely mentioned
`in the medical literature but has a pro-
`found impact on outcome. All families
`experience great stress and endure a
`period of adjustment to the disorder
`and its complications.
`
`Recommendation
`All families in which a member has
`been diagnosed with a UCD should re-
`ceive genetic counseling.
`
`RATIONALE. These are genetic disor-
`ders with a risk of recurrence. Avail-
`ability of carrier testing and prenatal
`diagnosis provides a number of repro-
`ductive options.
`
`Recommendation
`Provide assistance to ensure that sta-
`ble financing of care is in place.
`
`RATIONALE. Support for the intensive,
`long-term and outpatient care, and the
`relatively unknown medicines is diffi-
`cult to organize and is an important
`problem faced by families.
`
`UREA CYCLES
`DISORDERS
`CONFERENCE GROUP
`
`Mary Ahrens, Fairview University
`Medical Center, Minneapolis, MN;
`
`S5
`
`Page 5 of 5
`
`