Current strategies for the management of neonatal
`urea cycle disorders
`
`[Hardball Sum/mu; MD
`
`The treatment of newborns with urea cycle disorders has evolved over the
`
`years into a complex multidisciplinary effort. The complexity derives from
`the number of issues 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 systematization to this task. This manuscript
`is a condensation of the collective opinion and experience of that group. The
`outcome of untreated or poorly treated patients with urea cycle disorders is
`universally bad. Although a favorable outcome is not always feasible, even
`with the best therapy, the methods outlined here should help treat such a
`patient by drawing on the experience of others who have treated patients
`with urea cycle disorders. This article does not purport to be the final word
`in treating children with these disorders. However, by establishing some
`common ground, new methods can be tried and compared with existing
`ones. In a future that holds the prospect of gene therapy I'cures" for these
`diseases, striving for the best possible outcome in the critical newborn peri-
`od is a worthy goal. (J Pediatr 2001;158:850-559)
`
`Neonatal hyperammonemia is 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 of the first 4 enzymes of
`the pathway (carbamyl phosphate syn-
`thetase I, ornithine transcarbamylase,
`argininosuccinic
`acid
`synthetase,
`argininosuccinic acid Iyase), or a co-
`factor producer (N-acetyl glutamate
`
`synthase) result in accumulations of
`precursor metabolites including am-
`monia (Fig 1). Because there is 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-
`
`1"/wn I/h‘ Div/«hm if/IIMM'H/ Gruehlw, Drymrhnmf 13f PIJIIIIN‘I'L‘J ambllu/rcu/m‘ P/Jyulh/uyy 0’ BIin/Iymlv, Vander-
`IIi/l (”Him/wry.M'r’mz/ Calm; Min/wills, Trmwnrg.
`Reprint Requests: Marshall Summar, MD, Division of Medical Genetics, Department of Pedi-
`atrics, Vanderbilt University Medical Center, DD 2205 MCN, Nashville, TN 57252-2578.
`Copyright © 2001 by Mosby, Inc.
`0022-5476/2001/$55.00 + 0
`9/0/111854
`
`doi:10.1067/mpd.2001.111854
`
`530
`
`1 of 10
`
`mise.1'5 Thus fast and effective treat-
`
`ment is key to improving the patient's
`outcome.
`
`A clear, concise protocol is required
`to treat neonates with severe hyperam-
`monemia caused by UCDs. In review-
`ing the experience ofa number of clin-
`icians 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, (5) 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 patients 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
`Urea cycle disorder
`
`NAGS
`NG
`NJ
`OTC
`UCD
`
`During each stage of management
`there are a number of critical elements
`
`to consider, including what is being
`done, what are 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
`|PR2018-00459
`
`1 of 10
`
`

`

`THEJOURNALOFPEDMTNCS
`VOLUMEl38,NUMBERl
`
`SUMMAR
`
`Benzoale
`
`NH"4
`ot-Ketoglutarnte
`Glycine .‘_____.. NH"!I _\-pGlutamate $+Glutamine Phenylacetate 4—Phenylbutyrate
`Y Hco3
`
`ATP
`
`CPS
`
`
`
`Phenylacetylglutmnine
`
`Carbamyl p wsplime
`
`
`
`Omithinc
`
`Citrulline
`
`Aspartatc
`
`AS
`
`I|
`
`Ii
`
`I
`III
`F
`
`I!tII
`
`Argininosuccinate
`
`Argimse
`
`AL
`
`Arginine
`
`”xv
`
`Fumumle
`
`Supplemented — - "'
`arginine
`
`Fly 1. Urea cycle and intermediate components.
`
`specifics of treating a patient with
`neonatal hyperammonemia.
`
`RECOGNITION AND
`
`SUPPORTIVE
`
`TREATMENT
`
`Once neonatal hyperammonemia is
`recognized, the necessary organization
`and supportive care are initiated to re-
`verse it as soon as possible.
`
`CLbukallewwnhahbn
`
`In the immediate newborn period,
`infants with UCDs will typically look
`normal. The problems that may have
`been observed while the child was still
`
`in hospital are often not seen until the
`child is at home because of 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 and care is
`sought later when the child’s illness has
`progressed to become more severe.
`The progression of symptoms moves
`from somnolence, through lethargy,
`and on to coma. There is 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 on the brain stem.4'5 Seizures
`are seen in approximately 50% of se—
`verely hyperammonemic neonates.
`Hyperventilation caused by cerebral
`edema causes a respiratory alkalosis
`that is also a common symptom in the
`early stages of the hyperammonemic
`attack. This progresses to hypoventila-
`tion and respiratory arrest as pressure
`increases on the brain stem.6'7
`
`The algorithm in Fig 2 may assist
`with the evaluation ofa hyperammone-
`mic newborn, but outside factors can
`
`influence the differential diagnosis.
`Factors such as the overall health of
`
`the duration of hyperam-
`the liver,
`monemia, and pharmacologic agents
`already given to the patient should be
`factored into the interpretation ofthe
`clinical observations.
`
`S3l
`
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`
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`
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`

`SUMMAR
`
`THEJOURNALOFPEDMINCS
`JANUARYZOOI
`
`Diagnostic Considerations
`
`Symptomatic: lethargy, coma. etc.
`Lab: blood ammonia
`
`
`
`Elevaled
`
`
`>approx. loouMoi/L
`Lab: anion gap. glucose, blood and urine kelones
`
`
`
`
`I
`Other Metabolic Disorders
`Anlon gap >20 and/or hypoglycemia, and/or kelones
`Lab: organic acids. amino acids, carnlllne elc.
`
`
`
`|
`Primary Urea Cycle Delecl
`
`
`
`Anion gap <20. glucose normal, low kelones
`Lab: plasma/urine amino and urine organic acids
`
`
`
`THAN or NAGS. CPS or OTC Deliciency
`
`Normal or Low Cilrulline
`
`ASD
`ALD
`
`THAN or NAGS or CPSD
`OTC Deliciency
`Absent Argininosuccinate
`Elevated Argininosuccinale
`
`Elevated Orolale
`
`
`Low or Normal Orolele
`Lab: libroblasl
`Lab: libroblast or red
`Lab: biopsy or DNA
`Lab: biopsy or DNA
`enzyme ass av
`cell an: me assay
`
`
`
`ASD or ALD
`Elevated Citrulline
`
`F1312. Algorithm for encephalopathic newborns.
`
`Table I. Diagnostic laboratory tests
`
`Table II. Laboratory measurements in acutely ill infants without UCD
`
`Ammonia
`
`pH and CO2
`Plasma quantitative amino acids
`Anion gap
`Glucose
`
`Urine organic acids and orotic acid
`Specific enzymatic or DNA analysis
`
`Laboratory data useful in the diagno-
`sis of UCDs include plasma ammonia
`
`levels, pH, C02, the anion gap, plasma
`amino acids, and urine organic acid
`analyses. Table 1 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, and that later
`stages of treatment should be tailored
`to the specific disorder (Table I).
`An elevated plasma ammonia level of
`150 umol/L or higher, associated with
`a normal anion gap and a normal blood
`glucose level, is a strong indication for
`the presence ofa UCD. Quantitative
`amino acid analysis can be used to
`evaluate these patients and arrive at a
`tentative diagnosis. The amino acids in
`sick newborns are often quite different
`from those in children and adults, and
`
`....Earamst9r...............................................Average............................................$9..............................
`
`Ammonia
`Glutamine
`Glycine
`Alanine
`Citrulline
`Arginine
`
`47 ilmol/L
`581
`502
`519
`10.5
`38.5
`
`(15.5)
`(182)
`(100)
`(252)
`(7)
`(18.4)
`
`Averaged results from 25 babies admitted to the neonatal intensive care unit.
`All babies were 55 weeks' gestation with respiratory problems (birth asphyxia, respiratory dis-
`tress, or meconium aspiration syndrome).
`
`Table 11 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 more detail else-
`
`where in 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 other features 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 for transport 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 of the patient's
`condition and to the probable long-
`term outcome. Patients who have been
`
`in a hyperammonemic coma for sever-
`al days have an extremely poor neuro-
`logic outcome. Although the patient
`may be successfully "detoxified" and
`stabilized, the damage to the central
`nervous system is likely to be devastat-
`ing and permanent. Thus the option of
`withdrawal of support should be dis-
`
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`
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`
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`

`THEJOURNALOFPEDMINCS
`VOLUME|38,NUMBER|
`
`cussed with parents of patients who
`have already sustained overwhelming
`damage to the brain.
`Intravenous access should be estab-
`
`lished as soon as possible. If practical,
`the patient with a UCD should have a
`deep line placed such as an umbilical
`catheter or a multilumen central line.
`
`The need to resume feedings rapidly
`should influence the selection of line
`
`type. Stable vascular access will assist
`with the administration of fluids, med-
`
`ications, and the frequent blood sam-
`pling. Many patients with UCDs are
`dehydrated at presentation as a result
`of anorexia and poor oral
`intake.
`Restoration of normal hydration will
`serve to protect renal function (critical
`for effective treatment) and ensure ad-
`
`equate tissue perfusion (to blunt the
`further catabolic production of nitro-
`gen). Overhydration should be avoid-
`ed because most patients with UCDs
`have some degree of cerebral swelling.
`Intravenous administration of fluids
`
`with 10% dextrose with one quarter
`normal saline solution is preferable
`to physiological saline solution, be-
`cause patients treated with ammonia-
`scavenging drugs will receive large
`amounts of sodium and chloride ions
`
`as part of their medication regimen.
`Other support
`(pressors, buffering
`agents), depending on the cardiovas-
`cular and acid-balance status of the in-
`
`fant, is also important. Protection of
`kidney function is an important aspect
`of the early treatment ofthese patients.
`Many have depleted intravascular vol-
`umes and go into shock and have acute
`renal failure. Once the dialysis phase is
`complete, the drugs used to scavenge
`excess ammonia from the bloodstream
`
`require normal renal function. The use
`of boluses of fluid and pressor agents
`should be balanced against the degree
`of cerebral edema present at the time.
`Oncotic agents such as albumin will
`contribute to the overall nitrogen load
`but in selected cases, and on a limited
`basis, can be used.
`
`Caloric supplementation should be
`maximized to try and reverse catabo-
`
`lism and nitrogen turnover. In addition
`to glucose, Intralipid administration
`can provide additional calories but
`should not be
`allowed to delay
`progress toward more aggressive treat-
`ment. Oral feedings should be discon-
`tinued in patients with severe en-
`cephalopathy but restarted as soon as
`practical. Placement of a nasogastric
`tube should be done during this early
`phase. Feeding of all protein should be
`halted temporarily and calories provid-
`ed as carbohydrate and fat. For pa-
`tients who are able to tolerate oral
`
`feedings, a protein-free formula such
`as Mead Johnson 80056 or Ross For-
`
`mula ProPhree could initially be used.
`Elemental formulas are not appropri-
`ate because they contain considerable
`amounts of nitrogen. This complete re-
`striction of protein should be main-
`tained only for a short period (24 to 48
`hours), because depletion of essential
`amino acids will result in further pro—
`tein catabolism and nitrogen release.
`The author has found that maximizing
`caloric intake has a significant impact
`on patient stabilization after bulk am-
`monia removal.
`Even an infant who is awake and re-
`
`sponsive can progress to coma and car-
`diovascular or respiratory collapse
`during transport or preparation for
`dialysis. Therefore it is preferable to
`perform intubation on infants with
`borderline clinical condition before
`
`transport or before they have respira-
`tory compromise for 2 reasons: (I) ifa
`patient is breathing rapidly (respirato-
`ry alkalosis driven by cerebral edema),
`excess calories are burned, contribut-
`
`ing to catabolism and further nitrogen
`accumulation, and (2) intubation is a
`difficult procedure to carry out while
`an infant is being transported and can
`lead to hypoxia.
`It is usual for a lethargic infant to
`have undergone a septic workup with
`the initiation of antibiotic treatment.
`
`SUMMAR
`
`ing it as prophylaxis. A bacterial infec-
`tion in a newborn baby with hyperam-
`monemia could well prove fatal.
`There are several other important
`measures to 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 demonstrated to be effec-
`
`tive in managing cerebral edema
`caused by hyperammonemia.
`The importance of early treatment
`cannot be overstressed. Ultimately the
`neurologic dysfunction of the patient is
`related to the duration of cerebral
`edema.7'10 Most children will have
`
`cognitive impairment, but early treat—
`ment to remove ammonia and other
`metabolites from the bloodstream will
`
`lessen the severity of this impairment.
`
`Organization an? Mobilization
`Newborns with UCDs should be
`
`treated by a team of experienced per—
`sonnel and in facilities with special re-
`sources (Table III). The community
`physicians should be aware ofthese fa-
`cilities and how to reach them. A meta-
`
`bolic specialist should coordinate the
`activities of the various team members
`
`and maintain continuity of treatrrient.
`As with any team approach, the roles
`of the members and the steps and goals
`of treatment should be clear before a
`
`patient with a UCD presents for treat-
`ment.
`In addition to alerting team
`members of the impending arrival of a
`patient with a UCD,
`the managing
`physician should also alert the labora-
`tory regarding STAT tests. The phar-
`macy should also be alerted to ensure
`that the specific medications are avail-
`able and can be prepared at short no—
`tice. Human subject permits should al-
`ready be on hand, because treatment
`with intravenous sodium phenylac-
`etate and sodium benzoate is still con-
`
`With the heavy instrumentation and
`stress patients with UCD undergo, it is
`probably prudent to continue existing
`antibiotic coverage or consider initiat-
`
`sidered experimental and is under an
`FDA investigational new drug permit
`(contact Ucyclyd Pharmaceuticals for
`details). We have found that having
`
`S33
`
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`
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`
`

`

`SUMMAR
`
`Table III. Treatment team members and 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 diagnostic testing.
`Ammonia, amino acids, and organic
`acids
`
`Establish dietary prescription with
`metabolic foods and supplements.
`Assist with parenteral calorie
`management and transition
`to enteral feeding.
`
`the medications from the pharmacy
`ahead of time and having blood hand-
`delivered to the chemistry laboratory
`saves considerable critical time. Delays
`in treatment or response to changing
`status may affect the eventual outcome
`(Table III).
`
`Bulk Ammonia Removal an?
`
`P/zarmacologic Ammonia
`Scaveuging
`
`The best way to remove ammonia
`rapidly is by dialysis.7'll‘15 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. Exchange transfusion is in-
`effective in removing ammonia, and
`dialysis is the treatment of choice for
`rapid removal of this toxin.7'11'13
`
`Preparation for Diaiydid
`Dialysis is the primary means by
`which ammonia is removed from the
`
`immediately. If dialysis is not immedi-
`ately available, it is appropriate to use a
`loading dose of drugs to induce the re-
`moval of ammonia. However, in the pa-
`tient with severe hyperammonemia,
`pharmacologic agents are not sufficient
`to remove ammonia quickly.
`The method of dialysis chosen de-
`pends on the available expertise and
`equipment. The fastest removal system
`uses an extracorporeal membrane oxy-
`genation pump system to drive a he-
`modialysis machine.l2'l‘l‘15 ECMO has
`become more Widely available because
`ofits use in infant lung disease and car-
`diac surgery. Other methods include
`hemoflltration (both arteriovenous and
`venovenous), standard dialysis, peri-
`toneal
`dialysis,
`and
`continuous-
`drainage peritoneal dialysis. Each
`method has its own advantages and
`drawbacks.l2'l4'18 Because ammonia
`
`crosses the dialysis membrane rapidly,
`the faster the flow rate, the higher the
`clearance. In critically ill newborns it
`is difficult to perform standard dialysis
`for more than a few hours and main-
`
`patient's body during the early manage-
`ment period. Ideally, the surgical and
`dialysis teams should be waiting for the
`patient to arrive and initiate treatment
`
`tain homeostasis. Peritoneal dialysis
`clears ammonia at a low rate of 5 to 5
`mL/min, and if it is the sole means of
`
`ammonia removal, it may take several
`
`534
`
`5 of 10
`
`THEJOURNALOFPEDMTNCS
`JANUARYZOOI
`
`days to reduce a significant ammonia
`burden.12 Peritoneal dialysis also com-
`plicates attempts at early refeeding and
`increases the 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 of peritoneal dialysis
`with continuous inflow and outflow is
`
`effective but requires extremely close
`monitoring. Hemofiltration produces
`clearance rates of 10 to 50 mL/min,
`and clearance rates with ECMO/HD
`are on the order of 170 to 200
`
`mL/min.12 With the advent of percuta-
`neous catheter placement for ECMO
`and the increased pump rates avail-
`able,
`the advantages of this method
`may outweigh the risk of blood vessel
`damage. Another advantage to the use
`of an ECMO pump is that a hemofilter
`can be placed in the circuit to continue
`removal of ammonia between dialysis
`runs. We have demonstrated reduc-
`
`tions of blood ammonia levels by >1000
`umol/L in a period of I to 2 hours with
`ECMO/I-ID.12 Osmotic shifts have not
`
`been observed with this rapid dialysis,
`and recovery of neurologic activity is
`faster. For patients with less severe hy-
`perammonemia, a hemofiltration pump
`may suffice for bulk ammonia removal.
`
`A review of the literature suggests that
`approximately 50% of the neonates re-
`quiring dialysis for any reason under-
`go dialysis with a pressure-supported
`system. The extensive amount of in-
`strumentation arising from the use of
`any of these methods increases the 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 umol/L and can be dis-
`continued. Once dialysis is stopped,
`and while the patient is still in the acute
`phase, there may be a rebound of sever-
`al hundred umol in the ammonia level.
`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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`
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`

`THE JOURNAL OF PEDIATRICS
`VOLUME I38. NUMBER I
`
`enging medications to take effect. The
`use of hemofiltration can blunt or pre-
`vent this rebound. It is recommended
`
`that the catheters be removed only after
`the plasma ammonia level has been sta-
`ble for at least a day. However, this
`should be balanced by the risk of main-
`taining the patient in an anticoagulated
`state. Some patients may require more
`than one session of dialysis to bring the
`ammonia level under control. In summa-
`
`ry, it is recommended that patients with
`severe hyperammonemia be treated
`initially with pump-driven dialysis
`(ECMO/I—ID) followed by continuous
`hemofiltration with the same pump
`system. In patients who are hemody-
`namically unstable, this procedure offers
`pressure support and better control over
`dialysis flow rates. A further advantage
`is that enteral feeding through an NG or
`nasojejunal tube can be started.
`
`lermaeologic Management
`RATIONALE. The second line of the
`
`treatment for acute hyperammonemia
`involves the use of compounds that re—
`move nitrogen by alternative path-
`ways. Phenylacetate combines with
`glutamine to produce phenylacetylglu-
`tamine, a compound that is excreted in
`the urine.8'19 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
`more direct beneficial effectw‘25 Ben-
`
`zoate combines with glycine to pro-
`duce hippurate, which is also rapidly
`cleared by the kidneys.24'25 The
`glycine is replaced by synthesis, thus
`removing more waste nitrogen from
`the pool. While the precursor nitrogen
`is removed from circulation, attention
`
`must also be paid to replacing the defi-
`cient product(s) of the urea cycle (Fig
`l). 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
`
`6of10
`
`SUMMAR
`
`tration packaging for intravenous sodi-
`um benzoate/sodium phenylacetate
`and the protocols developed by Dr.
`Saul Brusilow.6'7'11 They are summa-
`rized in Table IV.
`
`Loaaing Dode
`The current protocol for the acute
`management of hyperammonemia in-
`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 55 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-
`nine is believed to have a significant im-
`pact on patients with ASS and ASL
`deficiency and be relatively safe for pa-
`tients with OTC, CPS, and NAGS de-
`
`ficiency. Caution should be exercised if
`additional doses of sodium benzoate
`
`and sodium phenylacetate are given
`within 24 hours of the 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 (I loading
`dose + maintenance infusion). At 750
`mg/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 severe disorders or those
`
`who are undergoing dialysis and, based
`on the results 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).
`
`block in ASS prevents the condensa-
`tion of aspartate with citrulline, which
`accounts for 50% of the 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.26'27
`
`Even in ASS and ASL deficiency,
`where there is 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
`endogenous protein.26'27 In ASS and
`ASL deficiency it
`is used in larger
`amounts to "prime" the cycle to pro-
`duce
`citrulline
`or
`argininosucci-
`nate.24'28 This has the advantage ofin-
`corporating a substantial amount of
`nitrogen in compounds having a lower
`toxicity and higher renal excretion. In
`ASS (citrullinemia), 1 mol of nitrogen
`can be removed for every mole of argi-
`nine metabolized through the cycle, and
`this doubles in ASL to 2 mol.
`L—
`
`citrulline may serve as a better supple-
`ment for patients with OTC and CPS
`than arginine, because it is converted to
`arginine while promoting the incorpo-
`ration of one waste nitrogen; however,
`an intravenous formulation of citrulline
`
`is not currently available. A note of cau-
`tion concerning arginine. Arginine is a
`precursor of nitric oxide, a potent va-
`sodilator. Anecdotal evidence and the
`
`author's own experience suggest that
`in CPS and OTC deficiencies,
`large
`amounts of excess arginine may accu-
`mulate, resulting in overproduction of
`nitric oxide and leading to extreme
`vasodilation and hypotension.12 Reduc-
`tion in arginine administration corre-
`sponded with restored venous tone in 2
`patients cared for in our institution.
`
`Aaminidtration Protocol
`These dose recommendations are
`
`Maintenance Infwion
`Once the loading dose is given, the pa-
`tient should be switched to the mainte-
`
`based on the Food and Drug Adminis-
`
`nance infusion. The doses differ only in
`
`535
`
`6 of 10
`
`

`

`SUMMAR
`
`THEJOURNALOFPEDMINCS
`JANUARYZOOI
`
`TableIV. Recommended doses of pharmacologic agents to be used during dialysis periods
`
`Sodium benzoate/phenylacetate dosage and administration
`...............................................................................................................Summarytable
`
`....E§§i§.n§.299.9!a£i9.n.
`
`.........§.9_m29!19n.t§..9f.infusisn.salaries................
`
`................l29§ags.2r9yi9s§...........................
`
`SB/SA
`
`Arginine HCI
`
`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/lcg
`2.5 mL/kg
`2.5 mL/kg
`6.0 mL/kg
`~ 25' mL/kg
`250 mg/kg
`250 mg/kg
`CPS or OTC Deficiency
`2.0 mL/kg
`~ 25 mL/kg
`2.0 mL/kg
`~ 25 mL/kg
`ASS or ASL deficiency
`6.0 mL/kg
`~ 25 mL/kg
`6.0 mL/kg
`~ 25 mL/kg
`
`Loading dose
`Maintenance dose
`
`Loading dose
`Maintenance dose
`
`2.5 mL/kg
`2.5 mL/kg
`
`Loading dose
`Maintenance dose
`Older children and adults:
`
`2.5 mL/kg
`2.5 mL/kg
`
`250' mg/kg
`250 mg/kg
`
`250 mg/kg
`250 mg/kg
`
`250 mg/kg
`250 mg/kg
`
`250 mg/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 mg/kg
`
`600 mg/kg
`600 mg/ltg°
`
`Loading dose
`Maintenance dose
`
`Loading dose
`Maintenance close
`
`55 mL/m2
`55 mL/m2
`
`55 mL/m2
`55 mL/m2
`
`SB, Sodium benzoate; SA, sodium phenylacetate.
`
`CPS or OTC deficiency
`2.0 mL/kg
`~ 25 mL/kg
`2.0 mL/kg
`~ 25 mL/kg
`ASS or ASL deficiency
`6.0 mL/kg
`~ 25 mL/kg
`6.0 mL/kg
`~ 25 mL/kg
`
`5.5 g/m2
`5.5 g/m2
`
`5.5 g/m2
`5.5 g/m2
`
`5.5 g/m2
`5.5 g/m2
`
`5.5 g/m2
`5.5 g/m2
`
`the amount of arginine hydrochloride
`given and are dependent on the diagno-
`sis. The 24 -hour dose 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 of arginine
`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
`
`sodium
`because
`potassium added,
`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 whether treat-
`ment should be discontinued.
`
`Laboratory Monitoring
`Our center measures ammonia plas-
`ma levels every hour during high-flow
`rate dialysis. These samples should be
`handled expeditiously to get the fastest
`possible turnaround. Once the ammo-
`nia plasma level has stabilized to <200
`to 300 umol/L,
`the monitoring fre-
`quency can be reduced to once every
`few hours. When the patient is 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 amount of
`blood removed should be monitored
`and transfusion used to avoid iatro-
`
`genic anemia.
`
`Other Acute Treatment [muted
`
`Opinion is divided among experts
`on the use of glucose and insulin in
`these patients. Glucose and insulin can
`serve as suppressors of catabolism, 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 glucose levels 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.
`
`535
`
`7 of 10
`
`7 of 10
`
`

`

`THE JOURNAL OF PEDIATRICS
`VOLUME I38, 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 and chloride ions.
`The use of carnitine in neonates
`
`being treated with sodium benzoate is
`not believed to be beneficial. There
`have been no documented cases of car-
`
`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
`known to decrease urea cycle function
`and will aggravate the hyperammone-
`mia.29'31
`Enteral citrulline is used in some
`centers for neonates with UCD and
`
`CPS or OTC deficiencies, the rationale
`
`being that pulling aspartate into the
`pathway may increase nitrogen clear-
`ance. The dose of 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 who al-
`ready have excessive amounts of this
`amino acid.
`
`Staéilization an? Catabolic
`Reveraal
`
`This phase overlaps with the second
`phase to some extent. One of the keys
`to successful treatment of a patient
`with a UCD is to reverse the catabolic
`This
`process.
`decreases nitrogen
`turnover and