Current strategies for the management of neonatal
`urea cycle disorders
`
`Marshall Summar, MD
`
`
`
`The treatment of newborns with urea cycle disorders has evolved over the
`years into a complex multidisciplinary effort. The complexity derives from
`the numberofissues that must be addressed simultaneously. At the Urea
`Cycle Disorders Consensus Meeting held in Washington, D.C., a panel of
`physicians and other professionals with extensive experience in this field
`was assembled to bring some systematizationto this task. This manuscript
`is a condensation of the collective opinion and experience of that group. The
`outcomeof untreated or poorly treated patients with urea cycle disordersis
`universally bad. Although a favorable outcomeis not alwaysfeasible, even
`with the best therapy, the methods outlined here should help treat such a
`patient by drawing on the experience of others who havetreated patients
`with urea cycle disorders. This article does not purport to bethe final word
`in treating children with these disorders. However,by establishing some
`commonground, new methodscan be tried and compared with existing
`ones. In a future that holds the prospect of gene therapy “cures” for these
`diseases, striving for the best possible outcomein the critical newborn peri-
`od is a worthy goal. (J Pediatr 2001;138:S30-S39)
`
`Neonatal hyperammonemiais a med-
`ical emergency requiring advanced
`planning, sophisticated facilities, and
`multidisciplinary teamwork. Urea
`cycle disorders are the primary cause
`of hyperammonemia during the vul-
`nerable newborn period. Genetic de-
`fects in any ofthe first 4 enzymes of
`the pathway (carbamyl] phosphate syn-
`thetase I, ornithine transcarbamylase,
`argininosuccinic
`acid
`synthetase,
`argininosuccinic acid lyase), or a co-
`factor producer (N-acetyl glutamate
`
`synthase) result in accumulations of
`precursor metabolites including am-
`monia (Fig 1). Because thereis no ef-
`fective secondary clearance system for
`ammonia, disruption of this pathway
`has a rapid clinical course. The catabo-
`lism normally present in the newborn
`period together with the immaturity of
`the liver combine to accentuate defects
`in these enzymes. This rapid accumu-
`lation of ammonia and other precursor
`metabolites results in acute cerebral
`edema with severe neurologic compro-
`
`Fromthe Division ofAledical Genetics, Department of Pediatrics and Molecular Physiology & Biophysics, Vander-
`bilt University Medical Center, Nashville, Tennesee.
`Reprint Requests: Marshall Summar, MD, Division of Medical Genetics, Department of Pedi-
`atrics, Vanderbilt University Medical Center, DD 2205 MCN, Nashville, TN 37232-2578.
`Copyright © 2001 by Mosby,Inc.
`0022-3476/2001/$35.00 +0 9/0/111834
`
`doi:10.1067/mpd.2001.111834
`
`$30
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`mise.!> Thus fast and effective treat-
`ment is key to improvingthe patient’s
`outcome.
`
`A clear, concise protocol is required
`to treat neonates with severe hyperam-
`monemia caused by UCDs.In review-
`ing the experience of a numberofclin-
`iclans who have cared for
`these
`patients, several stages of treatment
`become apparent. These include (1)
`recognition and supportive treatment,
`(2) bulk ammonia removal and phar-
`macologic scavenging, (3) stabilization
`and catabolic reversal, and (4) transi-
`tion to home management. These steps
`are undertaken to accomplish specific
`therapeutic goals and include rapidly
`clearing ammonia from the neonate’s
`bloodstream, blocking the production
`of additional ammonia, removing ex-
`cess nitrogen, and protecting the neu-
`rologic integrity of the baby. All of
`these goals should be pursued with
`thoughtful expediency in the context
`of the patient's clinical situation.
`
`ASL
`ASS
`CPS
`ECMO
`
`Argininosuccinic acid lyase
`Argininosuccinic acid synthetase
`Carbamyl phosphate synthetase|
`Extracorporeal membrane
`oxygenation
`ECMO/HD Extracorporeal membrane
`oxygenation driving a
`hemodialysis machine
`N-acetyl! glutamate synthase
`Nasogastric
`Nasojejunal
`Ornithine transcarbamylase
`Ureacycle disorder
`
`NAGS
`NG
`NJ
`OTC
`UCD
`
`During each stage of management
`there are a numberofcritical elements
`to consider, including what is being
`done, whatare the results, and what
`remains to be done. This article is an
`attempt to provide guidance on the
`Horizon Exhibit 2005
`Horizon Exhibit 2005
`Lupin v. Horizon
`Lupin v. Horizon
`IPR2018-00459
`IPR2018-00459
`
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`THE JOURNAL OF PEDIATRICS
`VoLUME 138, NuMBER|
`
`SUMMAR
`
`a-Ketoglutarate
`NH*,
`Glycine «——_________» NH", LyGlutamate ALyGlutamine Phenylacetate «q—Phenylbutyrate
`Benzoate
`No HCO,
`ATP
`
`
`
`Phenylacetylglutamine
`
`CPS
`
`*aeeoo
`
`Urine
`
`Carbamy] phosphate
`
`
`
`xcretion
`
`Ornithine
`
`Citrulline
`
`Aspartate
`
`AS
`
`i;
`/
`
`‘
`if
`,
`
`iéé’
`
`Argininosuccinate
`
`Arginase
`
`AL
`
`Arginine
`
`ww
`
`Fumarate
`
`Supplemented ---7~~
`arginine
`
`Fig 1. Urea cycle and intermediate components.
`
`specifics of treating a patient with
`neonatal hyperammonemia.
`
`RECOGNITION AND
`SUPPORTIVE
`‘TREATMENT
`
`Once neonatal hyperammonemiais
`recognized, the necessary organization
`and supportivecare areinitiated to re-
`verse it as soonas possible.
`
`Clinical Presentation
`In the immediate newborn period,
`infants with UCDswill typically look
`normal. The problems that may have
`been observed while the child wasstill
`in hospital are often not seen until the
`child is at home becauseof the current
`
`practice of discharging the mother and
`newborn baby early. This places much
`of the burden of recognition on the
`family and the pediatrician or primary
`care physician. The typical
`initial
`symptoms of a child with hyperam-
`monemia,failure to feed, and somno-
`lence may not be recognized by new
`parents. As a result, advice andcareis
`soughtlater when the child’s illness has
`progressed to become moresevere.
`The progression of symptoms moves
`from somnolence, through lethargy,
`and on to coma. Thereis a loss of ther-
`moregulation with a low core tempera-
`ture and feeding disruption that corre-
`lates with the somnolence.
`Abnormal posturing and encepha-
`lopathy are often related to the degree
`of central nervous system swelling and
`
`pressure onthe brain stem.*> Seizures
`are seen in approximately 50%ofse-
`verely hyperammonemic neonates.
`Hyperventilation caused by cerebral
`edema causesa respiratory alkalosis
`that is also a common symptomin the
`early stages of the hyperammonemic
`attack, This progresses to hypoventila-
`tion and respiratory arrest as pressure
`increases on the brain stem.°”
`The algorithm in Fig 2 may assist
`with the evaluation of a hyperammone-
`mic newborn, but outside factors can
`influence the differential diagnosis.
`Factors such as the overall health of
`the liver,
`the duration of hyperam-
`monemia, and pharmacologic agents
`already given to the patient should be
`factored into the interpretation of the
`clinical observations.
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`THE JOURNAL OF PEDIATRICS
`JANUARY 2001
`
`Symptomatic: lethargy, coma, etc.
`Lab: blood ammonia
`
`Diagnostic Considerations
`
`
`Elevated
`
`papprox. 100,Mol/L
`
`Lab: anion gap, glucose, blood and urine ketones
`
`
`
`
`]
`Other Metabolic Disorders
`
`
`
`
`Primary Urea Cycle Defect
`Anion gap >20 and/or hypoglycemla, and/or ketones
`Anion gap <20, glucose normal, low ketones
`Lab: organic acids, amino acids, carnitine etc.
`Lab: plasma/urine amino andurine organic acids
`
`THAN or NAGS, CPS or OTC Deficiency
`Normalor Low Citrulline
`
`
`
`
`ASD
`ALD
`THAN or NAGSor CPSD
`OTC Deficiency
`
`
`AbsentArgininosuccinate
`Elevated Argininosuccinate
`Elevated Orotate
`Low or Normal Orotate
`Lab:fibroblast
`Lab; fibroblast or red
`
`Lab: biopsy or DNA
`Lab: biopsy or DNA
`enzyme assay
`cell enzyme assay
`
`
`
`ASD or ALD
`Elevated Citrulline
`
`Fig 2. Algorithm for encephalopathic newborns.
`
`Table I. Diagnostic laboratory tests
`
`Table I. Laboratory measurements in acutelyill infants without UCD
`
`Ammonia
`pH and CO,
`Plasma quantitative amino acids
`Anion gap
`Glucose
`Urine organicacids and orotic acid
`Specific enzymatic or DNAanalysis
`
`Laboratory data useful in the diagno-
`sis of UCDsinclude plasma ammonia
`levels, pH, CO,, the anion gap, plasma
`amino acids, and urine organic acid
`analyses. Table I lists the recommended
`diagnostic tests, and Fig 2 highlights
`their use. The clinician should remem-
`ber that treatment should begin before
`a final diagnosis is made, andthatlater
`stages of treatment should betailored
`to the specific disorder (Table 1).
`Anelevated plasma ammonialevel of
`150 pmol/L or higher, associated with
`a normal anion gap and a normalblood
`glucoselevel, is a strong indication for
`the presence of a UCD. Quantitative
`amino acid analysis can be used to
`evaluate these patients and arrive at a
`tentative diagnosis. The aminoacids in
`sick newbornsare often quite different
`from those in children and adults, and
`
`wihBRAMCEREccccsainssnnniVORscatSsaisaciaicmeinais
`
`Ammonia
`Glutamine
`Glycine
`Alanine
`Citrulline
`Arginine
`
`47 umol/L
`581
`302
`319
`10.3
`38.3
`
`(13.5)
`(182)
`(100)
`(252)
`(7)
`(18.4)
`
`Averaged results from 25 babies admitted to the neonatalintensivecare unit.
`All babies were 35 weeks’ gestation with respiratory problems (birth asphyxia, respiratory dis-
`tress, or meconium aspiration syndrome).
`
`Table I} lists some of our averaged val-
`ues obtained in sick, term newborns
`without UCDs. The required diagnos-
`tic laboratory tests and their interpre-
`tation are discussed in moredetail else-
`wherein this supplement.
`In summary,
`infants with a UCD
`often have an initial normal appear-
`ance that progresses to lethargy and
`coma with the associated features of
`anorexia, hyperventilation, hypother-
`mia, hypoventilation, seizures, neuro-
`logic posturing, and otherfeatures of
`cerebral edema.
`
`Early Supportive Care
`These are the initial treatment steps
`that should be implemented as soon as
`
`the patient is suspected of having a
`urea cycle defect. They can be per-
`formed while the patient is being pre-
`pared fortransport to a metabolic cen-
`ter or being prepared for dialysis or
`pharmacologic management. Before
`care is initiated, some thought should
`be given to the severity ofthe patient's
`condition and to the probable long-
`term outcome. Patients who have been
`in a hyperammonemic comafor sever-
`al days have an extremely poor neuro-
`logic outcome. Although the patient
`may be successfully “detoxified” and
`stabilized, the damage to the central
`nervoussystem islikely to be devastat-
`ing and permanent. Thusthe option of
`withdrawal of support should be dis-
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`SUMMAR
`
`ing it as prophylaxis. A bacterial infec-
`tion in a newborn baby with hyperam-
`monemia could well provefatal.
`There are several other important
`measuresto be taken when caring for
`these infants. Hyperventilation is rec-
`ommended and steroids are to be
`avoided, because they will increase the
`amount of protein turnover and hence
`increase the nitrogen load. Mannitol
`has not been demonstratedto be effec-
`tive in managing cerebral edema
`caused by hyperammonemia.
`The importance of early treatment
`cannot be overstressed. Ultimately the
`neurologic dysfunctionofthe patient is
`related to the duration of cerebral
`edema.”"!9 Most children will have
`cognitive impairment, butearly treat-
`ment to remove ammonia and other
`metabolites from the bloodstream will
`lessen the severity of this impairment.
`
`cussed with parents of patients who
`lism and nitrogen turnover. In addition
`to glucose, Intralipid administration
`have already sustained overwhelming
`can provide additional calories but
`damagetothe brain.
`Intravenous access should be estab-
`should not be
`allowed to delay
`lished as soon as possible. If practical,
`progress toward more ageressive treat-
`ment. Oral feedings should be discon-
`the patient with a UCD should have a
`tinued in patients with severe en-
`deep line placed such as an umbilical
`catheter or a multilumen centralline.
`cephalopathy but restarted as soon as
`practical. Placement of a nasogastric
`The need to resume feedings rapidly
`should influence the selection of line
`tube should be done duringthis early
`type. Stable vascular access will assist
`phase. Feeding ofall protein should be
`halted temporarily andcalories provid-
`with the administration of fluids, med-
`ed as carbohydrate and fat. For pa-
`ications, and the frequent blood sam-
`tients who are able to tolerate oral
`pling. Many patients with UCDsare
`dehydrated at presentation as a result
`feedings, a protein-free formula such
`as Mead Johnson 80056 or Ross For-
`of anorexia and poor oral
`intake.
`mula ProPhreecouldinitially be used.
`Restoration of normal hydration will
`Elemental formulas are not appropri-
`serve to protect renal function (critical
`ate because they contain considerable
`for effective treatment) and ensure ad-
`equate tissue perfusion (to blunt the
`amounts of nitrogen. This complete re-
`striction of protein should be main-
`further catabolic production of nitro-
`tained only for a short period (24 to 48
`gen). Overhydration should be avoid-
`ed because most patients with UCDs
`hours), because depletion of essential
`Organization and Mobilization
`have some degree of cerebral swelling.
`aminoacids will result in further pro-
`Intravenous administration of fluids
`Newborns with UCDs should be
`tein catabolism and nitrogen release.
`The author has found that maximizing
`treated by a team of experienced per-
`with 10% dextrose with one quarter
`caloric intake has a significant impact
`normal saline solution is preferable
`sonnel andin facilities with special re-
`to physiological saline solution, be-
`on patientstabilization after bulk am-
`sources (Table III). The community
`monia removal.
`cause patients treated with ammonia-
`physicians should be aware ofthese fa-
`Evenan infant who is awake andre-
`cilities and how to reach them. A meta-
`scavenging drugs will receive large
`amounts of sodium and chloride ions
`bolic specialist should coordinate the
`sponsive can progress to comaandcar-
`activities of the various team members
`diovascular or respiratory collapse
`as part of their medication regimen.
`and maintain continuity of treatment.
`Other support
`(pressors, buffering
`during transport or preparation for
`dialysis. Therefore it is preferable to
`agents), depending onthe cardiovas-
`As with any team approach,the roles
`cular and acid-balance status of the in-
`perform intubation on infants with
`of the members andthesteps and goals
`borderline clinical condition before
`of treatment should be clear before a
`fant, is also important. Protection of
`transport or before they have respira-
`kidney function is an important aspect
`patient with a UCDpresentsfor treat-
`tory compromise for 2 reasons: (1) if a
`of the early treatment ofthese patients.
`ment.
`In addition to alerting team
`patient is breathing rapidly (respirato-
`Many have depleted intravascular vol-
`members of the impendingarrivalof a
`ry alkalosis driven by cerebral edema),
`umesandgointo shock and have acute
`patient with a UCD,
`the managing
`renal failure. Once the dialysis phase is
`excess calories are burned, contribut-
`physician should also alert the labora-
`ing to catabolism andfurthernitrogen
`complete, the drugs used to scavenge
`tory regarding STATtests. The phar-
`excess ammonia from the bloodstream
`accumulation, and (2) intubation is a
`macy should also be alerted to ensure
`difficult procedure to carry out while
`require normalrenal function. The use
`that the specific medicationsare avail-
`an infant is being transported and can
`of boluses offluid and pressor agents
`able and can be prepared at short no-
`lead to hypoxia.
`should be balanced against the degree
`tice. Human subject permits shouldal-
`It is usual for a lethargic infant to
`of cerebral edemapresentat the time.
`ready be on hand, because treatment
`have undergonea septic workup with
`Oncotic agents such as albumin will
`with intravenous sodium phenylac-
`the initiation of antibiotic treatment.
`etate and sodium benzoateis still con-
`contribute to the overall nitrogen load
`but in selected cases, and onalimited
`With the heavy instrumentation and
`sidered experimental and is under an
`basis, can be used.
`stress patients with UCD undergo,it is
`FDAinvestigational new drug permit
`probably prudent to continue existing
`Caloric supplementation should be
`(contact Ucyclyd Pharmaceuticals for
`maximizedto try and reverse catabo-
`antibiotic coverage or considerinitiat-
`details). We have found that having
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`SUMMAR
`
`Table IT, Treatment team membersand roles and responsibilities
`
`Team member
`
`Metabolic specialist
`Pharmacy
`
`Nephrologist or dialysis team
`Intensive care team
`
`Surgical team
`
`Laboratory staff
`
`Nutritionist
`
`Coordinate treatment and management.
`Formulate ammonia scavenging and
`dialysis agents. Check dosing orders.
`Dialysis
`Assist with physiological support, pain
`management, and ventilator
`management.
`Catheter placement for hemo- and
`peritoneal dialysis. Obtain biopsy
`sample for diagnostictesting.
`Ammonia, aminoacids, and organic
`acids
`
`Establish dietary prescription with
`metabolic foods and supplements.
`Assist with parenteral calorie
`managementandtransition
`to enteral feeding.
`
`the medications from the pharmacy
`ahead oftime and having blood hand-
`delivered to the chemistry laboratory
`saves considerablecritical time. Delays
`in treatment or response to changing
`status may affect the eventual outcome
`(Table ITI).
`
`Bulk Ammonia Removal and
`Pharmacologic Ammonia
`Scavenging
`The best way to remove ammonia
`rapidly is by dialysis.”!!-!5 Keeping
`ammonia
`from reaccumulating is
`achieved through the use of nitrogen
`scavenger drugs, discussed in detail
`elsewhere in this supplement. Loading
`with scavenger drugs should be done
`as soon as possible if urine output is
`adequate. Exchangetransfusionis in-
`effective in removing ammonia, and
`dialysis is the treatment of choice for
`rapid removalofthis toxin,”!1-15
`
`Preparation for Dialysis
`Dialysis is the primary means by
`which ammonia is removed from the
`patient’s body during the early manage-
`ment period, Ideally, the surgical and
`dialysis teams should be waiting for the
`patient to arrive andinitiate treatment
`
`immediately. If dialysis is not immedi-
`ately available, it is appropriate to use a
`loading dose of drugs to induce there-
`moval of ammonia. However,in the pa-
`tient with severe hyperammonemia,
`pharmacologic agents are not sufficient
`to remove ammonia quickly.
`The method ofdialysis chosen de-
`pends onthe available expertise and
`equipment. The fastest removal system
`uses an extracorporeal membrane oxy-
`genation pumpsystem to drive a he-
`modialysis machine.!#14.15 ECMO has
`become more widely available because
`ofits use in infant lung disease and car-
`diac surgery. Other methods include
`hemofiltration (both arteriovenous and
`venovenous), standard dialysis, peri-
`toneal
`dialysis,
`and
` continuous-
`drainage peritoneal dialysis. Each
`method has its own advantages and
`drawbacks.!?:!4-18 Because ammonia
`crosses the dialysis membranerapidly,
`the faster the flow rate, the higher the
`clearance. In critically ill newbornsit
`is difficult to perform standarddialysis
`for more than a few hours and main-
`tain homeostasis. Peritoneal dialysis
`clears ammonia at a low rate of 3 to 5
`mL/min, and if it is the sole means of
`ammonia removal, it may take several
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`days to reduce a significant ammonia
`burden.!? Peritoneal dialysis also com-
`plicates attempts at early refeeding and
`increasesthe risk of infection. Howev-
`er, peritoneal dialysis may be the most
`widely available form of toxin removal
`and does not require an entire dialysis
`team. A variation ofperitoneal dialysis
`with continuous inflow and outflow is
`effective but requires extremely close
`monitoring. Hemofiltration produces
`clearance rates of 10 to 30 mL/min,
`and clearance rates with ECMO/HD
`are on the order of 170 to 200
`mL/min.!? With the advent of percuta-
`neouscatheter placement for ECMO
`and the increased pumprates avail-
`able,
`the advantages of this method
`may outweighthe risk of blood vessel
`damage. Another advantage to the use
`of an ECMOpumpisthat a hemofilter
`can beplacedin the circuit to continue
`removal of ammonia betweendialysis
`runs. We have demonstrated reduc-
`tions of blood ammonialevels by >1000
`mol/L in a period of 1 to 2 hours with
`ECMO/HD.!? Osmoticshifts have not
`been observed withthis rapid dialysis,
`and recovery of neurologic activity is
`faster. For patients with less severe hy-
`perammonemia, a hemofiltration pump
`maysuffice for bulk ammonia removal.
`A review ofthe literature suggests that
`approximately 50% of the neonatesre-
`quiring dialysis for any reason under-
`go dialysis with a pressure-supported
`system. The extensive amountofin-
`strumentation arising from the use of
`any of these methodsincreasesthe risk
`of infection, and prophylactic antibiot-
`ic coverage should be considered for
`all patients.
`Dialysis seems to become less effec-
`tive when the plasma ammonia level
`falls below 200 mol/L and canbedis-
`continued. Once dialysis is stopped,
`and while the patientisstill in the acute
`phase, there may be a reboundofsever-
`al hundred [mol in the ammonialevel.
`This reflects both the continued cata-
`bolic state of the patient with the conse-
`quent production of waste nitrogen and
`the time required for the nitrogen scav-
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`enging medicationsto take effect. The
`use of hemofiltration can bluntor pre-
`vent this rebound. It is recommended
`that the catheters be removedonly after
`the plasma ammonialevel has beensta-
`ble for at least a day. However, this
`should be balanced by the risk of main-
`taining thepatient in an anticoagulated
`state. Some patients may require more
`than onesession ofdialysis to bring the
`ammonia level under control. In summa-
`ry, it is recommendedthat patients with
`severe hyperammonemia be treated
`initially with pump-driven dialysis
`(ECMO/HD)followed by continuous
`hemofiltration with the same pump
`system. In patients who are hemody-
`namically unstable, this procedureoffers
`pressure supportandbetter control over
`dialysis flow rates. A further advantage
`is that enteral feeding through an NG or
`nasojejunal tube can bestarted.
`
`Pharmacologic Management
`RATIONALE. The second line of the
`treatment for acute hyperammonemia
`involves the use of compoundsthatre-
`move nitrogen by alternative path-
`ways. Phenylacetate combines with
`glutamine to produce phenylacetylglu-
`tamine, a compoundthatis excreted in
`the urine.®:!9 The scavenged glutamine
`is replaced by synthesis in muscle and
`liver, thus reducing the nitrogen load.
`In addition, glutamine has been impli-
`cated in the neurotoxicity of UCDs;
`therefore its elimination may have a
`moredirect beneficialeffect.2°?3 Ben-
`zoate combines with glycine to pro-
`duce hippurate, which is also rapidly
`cleared by the kidneys.24?5 The
`glycine is replaced by synthesis, thus
`removing more waste nitrogen from
`the pool. While the precursor nitrogen
`is removed from circulation, attention
`mustalso be paid to replacing the defi-
`cient product(s) of the urea cycle (Fig
`1). CPS, NAGS, and OTC defects
`prevent
`the formation of citrulline
`from ornithine and carbamyl phos-
`phate. This in turn decreases the syn-
`thesis of arginine, resulting in it be-
`coming an essential amino acid. A
`
`block in ASS prevents the condensa-
`tion of aspartate withcitrulline, which
`accounts for 50%ofthe nitrogen incor-
`porated into the pathway. ASL defi-
`ciency blocks conversion of argini-
`nosuccinate to arginine. Therefore
`arginine is also an essential amino acid
`in ASS and ASL deficiencies.2&?7
`Even in ASS and ASL deficiency,
`wherethereis a partially intact urea
`cycle,
`the body rapidly depletes its
`pool of urea cycle intermediates into
`which it normally incorporates nitro-
`gen. Therefore arginine serves as a
`therapeutic agent in UCD. In CPS,
`NAGS, OTC, ASS, and ASL deficien-
`cy; arginine is used to restore its blood
`levels and prevent the breakdown of
`endogenousprotein.2°?7 In ASS and
`ASL deficiency it
`is used in larger
`amounts to “prime” the cycle to pro-
`duce
`citrulline
`or
`argininosucci-
`nate.?48 This has the advantageofin-
`corporating a substantial amount of
`nitrogen in compoundshaving a lower
`toxicity and higher renal excretion. In
`ASS(citrullinemia), 1 mol of nitrogen
`can be removed for every moleof argi-
`nine metabolized throughthe cycle, and
`this doubles in ASL to 2 mol. L-
`citrulline may serve as a better supple-
`mentfor patients with OTC and CPS
`than arginine, becauseit is converted to
`arginine while promoting the incorpo-
`ration of one waste nitrogen; however,
`an intravenous formulationof citrulline
`is not currently available. A note of cau-
`tion concerning arginine. Arginineis a
`precursorofnitric oxide, a potent va-
`sodilator. Anecdotal evidence and the
`author’s own experience suggest that
`in CPS and OTCdeficiencies, large
`amounts of excess arginine may accu-
`mulate, resulting in overproduction of
`nitric oxide and leading to extreme
`vasodilation and hypotension.!? Reduc-
`tion in arginine administration corre-
`sponded with restored venoustone in 2
`patients caredfor in ourinstitution.
`
`Administration Protocol
`These dose recommendations are
`based on the Food and Drug Adminis-
`
`SUMMAR
`
`tration packaging for intravenoussodi-
`um benzoate/sodium phenylacetate
`and the protocols developed by Dr.
`Saul Brusilow.©”:!! They are summa-
`rized in Table IV.
`
`Loading Dose
`The current protocol for the acute
`management of hyperammonemiain-
`cludes arginine hydrochloride (600
`mg/kg in a 10% solution), and a combi-
`nation of sodium benzoate and sodium
`phenylacetate (250 mg/kg of each
`drug), all infused in 25 to 35 mL/kg of
`10% dextrose in water over a 90-
`minute period. The blood pH should be
`monitored and buffer added to coun-
`teract the acidity of the arginine hy-
`drochloride. The dose of arginine has
`been increased from previous proto-
`cols, because a rapid infusion of argi-
`nineis believed to have a significant im-
`pact on patients with ASS and ASL
`deficiency and berelatively safe for pa-
`tients with OTC, CPS, and NAGSde-
`ficiency. Caution should be exercised if
`additional doses of sodium benzoate
`and sodium phenylacetate are given
`within 24 hours ofthe original dose,
`but experience suggests that 500 mg/kg
`each of sodium benzoate and sodium
`phenylacetate during the first 24 hours
`is an acceptable regimen (1 loading
`dose + maintenance infusion). At 750
`me/kg/24 h,
`there is some toxicity
`(vomiting, lethargy), and at >750 mg/
`kg/24 h, the toxicity is essentially in-
`variable and can be life-threatening.
`Reloading (repeating the initial regi-
`men) should be contemplated only in
`neonates with severedisorders or those
`whoare undergoing dialysis and, based
`on theresults of pharmacokinetic stud-
`ies, should be spaced at least 6 hours
`apart (refer to Dr. Batshaw’s article
`elsewhere in this supplement for more
`extensive information on the pharma-
`cologic management of UCDs).
`
`Maintenance Infusion
`Oncethe loading doseis given, the pa-
`tient should be switched to the mainte-
`nanceinfusion. The dosesdiffer only in
`
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`

`SUMMAR
`
`THE JOURNAL OF PEDIATRICS
`JANUARY 2001
`
`Table IV. Recommended doses of pharmacologic agents to be used during dialysis periods
`
`Sodium benzoate/phenylacetate dosage and administration
`sieNaaNaeatuCsRNSENESUM,CANE.ussnsnsnnnnnnnsninsinnnnnnnnnnnsnnesnns
`
`Patientpopulation
`
`a.omponentsofinfusionsolution
`
`soon.dosageprovided
`
`SB/SA
`
`Arginine HCl
`
`Dextrose
`
`Sodium
`
`Sodium
`benzoate
`
`Neonates/Infants/Young children:
`Prospective treatment pending definitive diagnosis of urea cycle enzyme deficiency
`6.0 mL/kg
`~ 25 mL/kg
`250 mg/kg
`250 mg/kg
`2.5 mL/kg
`6.0 mL/kg
`~ 25 mL/kg
`250 mg/kg
`250 mg/kg
`2.5 mL/kg
`CPS or OTC Deficiency
`2.0 mL/kg
`~ 25 mL/kg
`2.0 mL/kg
`~ 25 mL/kg
`ASSor ASL deficiency
`6.0 mL/kg
`~ 25 mL/kg
`6.0 mL/kg
`~ 25 mL/kg
`
`Loading dose
`Maintenancedose
`
`Loading dose
`Maintenancedose
`
`2.5 mL/kg
`2.5 mL/kg
`
`Loading dose
`Maintenance dose
`Olderchildren and adults:
`
`2.5 mL/kg
`2.5 mL/kg
`
`250mg/kg
`250 mg/kg
`
`250 mg/kg
`250 mg/kg
`
`250 mg/kg
`250 mg/kg
`
`250 me/kg
`250 mg/kg
`
`600 mg/kg
`600 mg/kg
`
`200 mg/kg
`200 mg/kg
`
`600 mg/kg
`600 mg/kg
`
`200 mg/kg
`200 me/kg
`
`600 mg/kg
`600 mg/kg”
`
`Loading dose
`Maintenance dose
`
`Loading dose
`Maintenance dose
`
`55 mL/m?
`55 mL/m2
`
`55 mL/m2
`55 mL/m?
`
`SB, Sodium benzoate; SA, sodium phenylacetate.
`
`CPSor OTCdeficiency
`2.0 mL/kg
`~ 25 mL/kg
`2.0 mL/kg
`~ 25 mL/kg
`ASSor ASLdeficiency
`6.0 mL/kg
`~ 25 mL/kg
`6.0 mL/kg
`~ 25 mL/kg
`
`5.5 g/m?
`5.5 g/m?
`
`5.5 g/m?
`5.5 g/m?
`
`5.5 g/m?
`5.5 g/m?
`
`5.5 g/m?
`5.5 g/m?
`
`the amountofarginine hydrochloride
`given and are dependenton the diagno-
`sis. The 24-hourdose of the combination
`of sodium benzoate/sodium phenylac-
`etate is 250 mg/kg/24 h of each drug.
`For patients with CPS, OTC, or NAGS
`deficiency,
`the dose of arginine hy-
`drochloride is 200 mg/kg/24 h. For ASS
`and ASL deficiency the dose ofarginine
`is 600 mg/kg/24 h. For patients awaiting
`diagnosis, the 200 mg/kg/24 h dose of
`arginine should be used in conjunction
`with sodium benzoate and sodium
`phenylacetate. Attention should be paid
`to the potassium level of the patient, and
`the maintenance fluids should have
`potassium added,
`because
`sodium
`phenylacetate may cause potassium de-
`pletion. The maintenance infusion is
`continued until a conversion to oral
`medication is made. Cerebral blood flow
`or electroencephalography analysis may
`be required to determine whethertreat-
`ment should be discontinued.
`
`Laboratory Monitoring
`Our center measures ammoniaplas-
`malevels every hour during high-flow
`rate dialysis. These samples should be
`handled expeditiously to get the fastest
`possible turnaround. Once the ammo-
`nia plasmalevelhasstabilized to <200
`to 300 pmol/L,
`the monitoring fre-
`quency can be reduced to once every
`few hours. When the patientis receiv-
`ing a stable drug regimen and no
`longer requires dialysis, the frequency
`can be further reduced to every 12
`hours and to once-daily before dis-
`charge. During the acute phase, elec-
`trolytes and acid-base balance should
`be
`carefully monitored (every 4
`hours). Glucose should be monitored
`hourly in patients receiving a glucose/
`insulin infusion to avoid wide swings
`in glucose levels. Amino acids should
`be monitored on a daily basis to assess
`nutritional status and the effectiveness
`of glutamine removal and citrulline/
`
`arginine replacement. The amountof
`blood removed should be monitored
`and transfusion used to avoid iatro-
`genic anemia.
`
`Other Acute Treatment Issued
`Opinion is divided among experts
`on the use of glucose and insulin in
`these patients. Glucose and insulin can
`serve as suppressorsofcatabolism, but
`their use requires care. The consensus
`opinion at this meeting was to admin-
`ister 6 to 8 mg/kg/min of glucose (ad-
`ministered as 10% dextrose in water)
`and to use insulin sparingly to main-
`tain the serum glucose level <170
`mg/dL. The presence of glycosuria is
`an indication for continued adminis-
`tration of intravenous regular insulin
`at a rate that keeps glucoselevels be-
`tween 120 and 170 mg/dL. Wide swings
`in glucose levels can change the osmo-
`lality of the brain and therefore should
`be avoided.
`
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`THE JOURNAL OF PEDIATRICS
`VoLUME 138, NUMBER|
`
`The use of normal saline solution
`
`should also be avoided, because the
`pharmacologic agents used in ammo-
`nia removal contain large amounts of
`sodium andchlorideions.
`The use of carnitine in neonates
`being treated with sodium benzoateis
`not believed to be beneficial. There
`have been no documentedcasesofcar-
`nitine deficiency, even though carni-
`tine levels are low in these neonates,
`and carnitine is known to conjugate
`with sodium benzoate.
`Valproic acid should be avoided in
`any patient who has seizures. It is
`knownto decrease urea cycle function
`and will aggravate the hyperammone-
`mia.29-5!
`Enteral citrulline is used in some
`centers for neonates with UCD and
`
`CPSor OTCdeficiencies, the rationale
`being that pulling aspartate into the
`pathway may increase nitrogenclear-
`ance. The doseof citrulline used is 150
`to 200 mg/kg/24 h. A clear diagnosis
`should be made before citrulline is
`used to avoid providing citrulline to
`patients with ASS and ASL whoal-
`ready have excessive amounts ofthis
`amino acid.
`
`Stabilization and Catabolic
`Reversal
`
`This phase overlaps with the second
`phase to some extent. Oneofthe keys
`to successful treatment of a patient
`with a UCDisto reverse the catabolic
`This
`process.
`decreases nitrogen
`turnover and reduces the amount of
`ammonia that must be detoxified. Dur-
`ing this stage there may be fluctuations
`in the ammonia plasma levels, and
`often the bulk ammonia removal pro-
`tocol will have to be repeated. Some
`form of low-level dialysis (hemofiltra-
`tion) may be continued during the
`early parts of this phase while the pa-
`tient’s nitrogen production exceeds re-
`moval.
`
`Caloric Management
`The author recommendsthat the pa-
`tient be started on some form ofenteral
`
`feed as soon as is practical. This may
`occur while the patientis still undergo-
`ing cannulation. The pla