~
`~.
`theclinics.com
`
`CRITICAL CARE
`CLINICS
`
`Presentation and Management
`of Urea Cycle Disorders Outside
`the Newborn Period
`
`EBLING LIBRARY
`UNIVERSITY OF WISCONSIN
`NOV 17 2005
`iahland Avenue
`70OEWL53705
`
`GUEST EDITOR
`Marshall L. Summar, MD
`
`Proceedings of a symposium conducted in Toronto,
`October 25 and 26, 2004. Supported by an unrestricted
`educational grant from Ucyclyd Pharma, a division of
`Medicis Pharmaceutical Corporation, Scottsdale, Arizona.
`
`October 2005 © Volume 21
`
`© Number 45S
`
`SAUNDERS
`
`An Imprint of Elsevier, Inc.
`PHILADELPHIA LONDON TORONTO MONTREAL SYDNEY TOKYO
`
`Page 1 of 11
`
`Horizon Exhibit 2004
`Horizon Exhibit 2004
`Par v. Horizon
`Parv. Horizon
`IPR2017-01769
`IPR2017-01769
`
`Page 1 of 11
`
`

`

`W.B. SAUNDERS COMPANY
`
`ADivision of Elsevier Inc.
`
`Elsevier Inc. ¢ 1600 John F. Kennedy Blvd., Suite 1800 ¢ Philadelphia, Pennsylvania 19103-2899
`
`http: //www.theclinics.com
`
`CRITICAL CARE CLINICS
`October 2005
`Editor: Joe Rusko
`
`Volume 21, Number 45
`ISSN 0749-0704
`
`Copyright © 2005 ElsevierInc. All rights reserved. Nopartof this publication may be reproducedor transmitted in any form or by any means,
`electronic or mechanical, including photocopy, recording, or any informationretrieval system, without written permission fromthe publisher.
`
`Single photocopiesofsingle articles may be made for personaluse as allowedbynational copyright laws. Permission of the publisher and pay-
`mentofa fee is required forall other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes,
`resale, and all forms of documentdelivery. Special rates are available for educational institutions that wish to make photocopies for non-profit
`educational classroomuse. Permissions may be soughtdirectly from Elsevier’s Rights Departmentin Philadelphia, PA, USA; phone: (+1) 215
`239 3804, fax: (+1) 215 239 3805, e-mail: healthpermissions@elsevier.com. Requests may also be completed on-line via the Elsevier homepage
`(http:// www.elsevier.com/locate/permissions). You may also contact Rights & Permissions directly through Elsevier’s homepage (http://
`wwwelsevier.com), selecting first ‘Customer Support’, then ‘General Information’, then ‘Permission Query Form’. In the USA, users mayclear
`permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone (978)
`750-8400, fax: (978) 750-4744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court
`Road, London W1P OLP, UK; phone: (+44) 171 436 5931; fax: (+44) 171 436 3986. Other countries may havea local reprographic rights agency
`for payments.
`
`Reprints. For copies of 100 or more,ofarticles in this publication, please contact the Commercial Reprints Department, Elsevier Inc., 360 Park
`Avenue South, New York, NewYork 10010-1710. Phone: (212) 633-3813; Fax: (212) 462-1935; I!-mail: reprints@elsevier.com
`
`The ideas and opinions expressed in Critical Care Clinics do not necessarily reflect those of the Publisher. The Publisher does not assume any
`responsibility for any injury and/or damage to persons orpropertyarising outof orrelated to anyuse of the material contained inthis perio-
`dical, The readeris advised to check the appropriate medicalliterature and the product information currently provided by the manufacturer of
`each drug to be administeredto verify the dosage, the method and duration of administration, or contraindications.It is the responsibility of
`the treating physician orother health care professional, relying on independent experience and knowledge of the patient, to determine drug
`dosages and the besttreatmentfor the patient. Mentionof any productinthis issue should not be construedas endorsementby the contributors,
`editors, or the Publisherof the product or manufacturers’ claims.
`
`Critical Care Clinics (ISSN 0749-0704) is published quarterly by W.B. Saunders Company. Corporate and editorial offices: Elsevier Inc., 1600 John
`F. KennedyBlvd., Philadelphia, PA 19103-2899. Accounting and circulation offices: 6277 Sea Harbor Drive, Orlando, FL 32887-4800. Periodicals
`postage paid at Orlando, FL 32862, and additional mailing offices. Subscription prices are $170.00 per yearfor US individuals, $280.00 per year
`for USinstitution, $85.00 peryearfor US students andresidents, $210.00 per year for Canadianindividuals, $340.00 per year for Canadianinsti-
`tutions, $230.00 per yearforinternational individuals, $340.00 per yearfor internationalinstitutions and $115.00 peryear for Canadian andforeign
`students/residents. To receive student/residentrate, orders must be accompanied by nameofaffiliated institution, date of term, and the sig-
`nature of program/residency coordinator on institution letterhead. Orders will be billed at individual rate until proofof status is received.
`Foreign air speed deliveryis included inall Clinics subscription prices. All prices are subject to change without notice. POSTMASTER: Send
`address changes to Critical Care Clinics, W.B. Saunders Company, Periodicals Fulfillment, Orlando, FL 32887-4800. Customer Service: 1-800-654-
`2452 (US). From outside of the US, call 1-407-345-1000. E-mail: hhspces@harcourt.com
`
`Critical Care Clinics is also published in Spanish by Editorial Inter-Medica, Junin 917, 1°" A, 1113, Buenos Aires, Argentina.
`
`Crilical Care Clinics is covered in Index Medicus, EMBASE/Excerpta Medica, Current Concepts/Clinical Medicine, ISI/BIOMED, and Chemical
`Abstracts.
`
`Printed in the United States of America.
`
`Page 2 of 11
`
`Page 2 of 11
`
`

`

`Page 3 of 11
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`828
`
`SINGH ET AL
`
`that becomes conditionally essential because of the de-
`creased rate of synthesis by the urea cycle(in all urea cycle
`disorders except L-arginase deficiency). This prescription
`offered 112 keals/kg/d and 0 g/kg/d of protein. Nitrogen
`scavenging was provided by sodium phenylacetate and so-
`dium benzoate (Ammonul) 500 mg/kg/d. Within 24 hours,
`the plasma ammonia concentration had decreased to
`80umol/L.
`On the ninth day of life (day 4 of treatment), the pa-
`tient began transitioning to oral feeds and hyperalimenta-
`tion fluids and intravenous medications were decreased.
`Starting with a hyperalimentation regimen of dextrose
`25% in water 18 mL/hr, insulin 0.02 u/kg/d, essential and
`nonessential amino acid mixture (TrophAmine ) 0.5 g/kg,
`fat emulsion (Intralipid) 20% 1g/kg/d, and L-arginine
`IICL 10% 500 mg/kg/d, she was gradually advanced to
`full oral
`feeds,
`including amino acid modified medical
`food with iron (Cyclinex-1) 25 g, protein-free diet pow-
`der with iron (ProPhree)
`3 g, L-arginine base 27 mL
`(66.6 mg/mL)(after intravenous arginine wasdiscontinued),
`and the oral nitrogen scavenger sodium phenylbutyrate
`(Buphenyl) 500 mg/kg/d.
`Although her plasma citrulline concentration did not
`change significantly (Table 1), the patient showed gencral
`improvement
`in other important parameters. The plasma
`glutamine concentration decreased substantially and fell
`below the lower limit of the reference range. The other
`plasma essential amino acids, which include the branched
`chain amino acids, were in the reference ranges, although
`both leucine and isoleucine were near the lower end of
`the range. The patient was discharged when she was
`12 days old.
`
`Table 1
`
`Plasma amino acid concentrations (jumol/L)
`Patient at
`Patient after
`Patient at
`Reference
`
`Aminoacid
`diagnosis
`treatment
`discharge
`range
`Taurine
`124
`200
`175
`38-227
`Aspartic acid
`15
`9
`5
`0-28
`Threonine
`83
`75
`299
`50-248
`Serine
`127
`53]
`95
`90-209
`Glutamic acid
`209 J
`67
`52
`10-189
`Glutamine
`2079 T
`811
`172|
`246-984
`Proline
`349
`54]
`106
`88-417
`Glycine
`253
`16
`265
`125.497
`Alanine
`578 1
`197
`262
`124-573
`Citrulline
`2694 f
`1856 7
`2260 T
`6-52
`Valine
`195
`97
`153
`67-299
`Cystine
`42
`7
`40
`4-65
`Methionine
`160 7
`26
`49
`7-49
`Isoleucine
`40
`20
`35
`20-96
`Leucine
`108
`47
`63
`29-15]
`Tyrosine
`11
`8l
`71
`24-129
`Phenylalanine
`63
`60
`71
`37-86
`Ornithine
`32
`168
`1831
`19-173
`Lysine
`464 7
`77
`224
`43-243
`Histidine
`152T
`63
`68
`38-145
`
`Arginine 20-149 26 258 16
`
`
`
`
`Discharge regimen
`It was imperative in the weeks and months following
`discharge that the infant ingest sufficient protein, cnergy,
`and other essential nutrients to ensure growth, but not so
`much protein that elevated ammonia levels or vomiting
`would result. With the advent of nitrogen scavenging
`medications, protein intake did not needto be as restricted
`as in the past. Care required a carefully calibrated diet,
`written instructions for ongoing management and dietary
`modifications during illness, and rigorous education of the
`parents regarding the necessity to adhere to the diet,
`the value of nasogastric feeds as needed, and the need for
`a rapid response to any signs of decompensation.
`An age-appropriate diet was prescribed. The diet con-
`sisted of medical foods and infant formula which provided
`1.9 g/kg/d of protein (54% protein from medical foods and
`46% from Enfamil [Mcad Johnson & Company, Evansville,
`Indiana]), 123 kcal/kg/d of energy, and 500 mg/kg/d of
`L-arginine base. This regimen supplied about 24 kcal/fluid
`ounce, Additional water (100 to 150 mL/d) wasto be offered.
`Parents were instructed how to insert a nasogastric tube
`in the event of a poor suck. In this case, formula was to be
`given every 3 hours, and sodium phenylbutyrate was to be
`administered every 6 hours. The parents were also provided
`witha letter at discharge that detailed the regimento be used
`to prevent decompensation during periods of metabolic
`stress associated with infections and fevers. Symptoms they
`were instructed to look for included refusal to suck, labored
`breathing,
`lethargy, and excess sleepiness. Should the
`child appearill, they were told to temporarily decrease or
`eliminate protein intake from food and substitute a special
`metabolic formula that would provide increased calories
`from non-protein sources, as well as necessary vitamins and
`minerals. They were also instructed to continue sodium
`phenylbutyrate, and to administer antiemetic medication and
`nasogastric feeding, if required. In the event that feeding
`was disrupted, the child was to be taken to the emergency
`room (ER) where the staff should be given a copy of the
`“emergency letter.”
`At age 2, a gastrostomy tube (g-lube) was placed to
`overcomethe child’s mild anorexia.
`
`
`
`Outcome data
`With sodium phenylbutyrate and diet management,
`plasma ammonia concentrations have been maintained in
`treatmentrange. Asreflected in Table 2, the patient’s protein
`and energy intake have been within the recommended
`guidelines throughout herlife. Because a reduction in whole
`dietary protcin alone does not usually offer adequate nu-
`trients for growth, her diet has consistently provided
`about 50% ofprotein through supplementation with medical
`foods. This has not only provided higher concentrations
`of essential amino acids to take advantage of their lower
`nitrogen density, but also provided a source of vitamins
`and minerals, and additional calories from fats and carbo-
`hydrates. Such high essential amino acid protein sources
`
`Page 4 of 11
`
`Page 4 of 11
`
`

`

`NUTRITIONAL MANAGEMENT
`
`$29
`
`Table 2
`
`Recommended daily nutrient intake in urea cycle disorders
`Nutrient
`
`
`
`
`60-130
`60-130
`30-120
`(mL/day)
`945-1890
`365-2445
`730-3465
`
`575-3150
`260-3150
`875-2625
`
`Patient protein
`Patient energy
`Fluid
`
`Age
`intake* (g/kg)
`Protein (g/kg)
`intake* (kcal/kg)
`Energy (kcal/kg)
`(mL/kg)
`Infants
`0 to <3 mo
`3 to <6 mo
`9 to<12m
`Girls and boys
`1
`to <4 yr
`4 to <7 yr
`7 to <1 yr
`Women
`11 to <15 yr
`15 to <19 yr
`>19 yr
`Men
`2100-3885
`2100-3885
`20-23
`11 to <15 yr
`2200-4095
`2200-4095
`21-24
`15 to <19 yr
`
`>19 yr 2625-3465 23-32 2625-3465
`
`
`* Data are for Case | patient.
`Modified from Acosta PB, Yannicelli S. Nutrition support protocols. Columbus, OH: Ross Products Division, Abbott Laboratories; 2001; with permission.
`
`2.1-1.4
`13-12
`1.2--1.1
`(g/day)
`18.6-12.5
`21.0-19.0
`22.0-24.0
`
`
`
`150-101
`100-80
`80-75
`(keal/day)
`800 1040
`1196-1435
`1199-1693
`
`2.20-1.25
`2.00-1.15
`1.60-0.90
`(g/day)
`8-12
`12-15
`14-17
`
`20-23
`20-23
`22-25
`
`150-125
`140-120
`120-110
`(kcal/day)
`945-1890
`1365 2415
`1730-3465
`
`1575-3150
`1260-3150
`1785-2625
`
`have helped meetall essential amino acid requirements. At
`10 years of age,
`the child’s growth continues to be sat-
`isfactory: height 25"percentile and weight 50" percentile.
`
`Case 2
`
`Onset of hyperammonemia
`
`Medical history
`A 10-year-old African-American femalc presented to
`a tertiary care ER with ataxia, disorientation, and mild
`hemiplegia. She had no known prior encephalopathic or
`other unusual episodes. She may have mildly self-restricted
`protein intake. She had reached menarche just 2 months
`before presentation. Her initial plasma ammonia concen-
`tration was 330\umol/L. A presumptive diagnosis of a urea
`cycle disorder was made and she was treated with intra-
`venous sodium benzoate and sodium phenylacetate (Ammo-
`nul), L-arginine, and substantial IV and enteral carbohydrate
`intake. The plasma ammonia concentration dropped some
`
`100 jmol/L in 2 hours, and soon returned to normal.
`However,
`it spiked twice over the next 5 days for no
`apparent reason, eventually tapering to normal. The girl
`suffered no intellectual deficit and was initially discharged
`on a regimen of proteinrestriction at 1.0 g/kg/d, sodium
`phenylbutyrate (Buphenyl) 308 mg/kg/d (20 g/d), and
`citrulline 108 mg/kg/d (7 g/d),
`the latter two dose levels
`represent the usual maximumadult dosage for her weight of
`65 kg. She waslater identified as a symptomatic carrier for
`ornithine transcarbamylase (OTC) deficiency; she had an
`affected male cousin in the maternal line.
`
`Clinical course
`
`Ten months later, the patient became progressively dis-
`oriented over 24 to 48 hours, shortly after her menses
`began. Upon admission, she exhibited a reduced level of
`consciousness. Herinitial plasma ammonia concentration
`was between200 and 225 jumol/L (Fig. 1). It was reduced to
`a normal concentration within 24 hours following admin-
`istration of IV sodium benozoate and sodiumphenylacetate
`(Ammonul) and L-arginine as before; the patient was then
`
`Ammonia
`
`sof
`
`
`
`
`380
`300+
`250+
`ro
`= a ey
`f
`1
`Q
`E 150+
`any
`E
`(a
`100+
`SE
`
`
` 20Tue 21Wed 22Thu 23Frn 24Sat 25 Sun
`26Mon
`27 Tue
`28Wed 29Thu
`30Fri
`31 Sat
`
`
`
`Jul 2004
`
`Fig. 1. Plasma ammonia concentrations following admission for disorientation.
`
`Page 5 of 11
`
`Page 5 of 11
`
`

`

`$30
`
`SINGIT ET AL
`
`fed orally and given oral sodium phenylbutyrate and citrul-
`line. Several days later she showed a nighttime spike in
`plasma ammonia concentration to 350 jumol/L,followed by
`a fall tol20jmol/L, and then anotherspike to 250 jumol/L.
`High-carbohydrate total parenteral nutrition was resumed
`and insulin was administered to block tissue catabolism.
`These measures reduced plasma ammonia concentration and
`were followed by progressive reinitiation of food and oral
`medication. Three more spikes in the patient’s ammonia
`level were seen on three successive nights. Ultimately she
`stabilized and was discharged.
`During the last 4 days of hospitalization, the patient was
`not enccphalopathic; she was clinically well and normo-
`ammonemic every morning. However, she had a regular re-
`elevation of her ammonia level nightly. There was no
`evidence for an infectious etiology. During this period she
`was inactive and confined to bed, which might have led to
`the mobilization of muscle mass, and resulted in significant
`quantities of nitrogen that had to be processed. Moreover,
`the girl was an adolescent with an irregulardietary pattern:
`she wouldeat breakfast and then skip food until dinner. It is
`also possible that she was cxperiencing asymptomatic
`hyperammonemic spikes quite frequently at home.
`In this young lady’s case,it is also quite possible that the
`cyclic anabolism and catabolismassociated with her normal
`menstrual cycles played a role in triggering her hyper-
`ammonemic episodes, althoughthese potential confounding
`and complicating effects have not been addressed system-
`atically in the urea cycle disease literature. Anecdotal evi-
`dence suggests that menstruation may provoke crises in a
`minority of symptomatic OTC females and is presumably
`most problematic in those individuals with marginal hepatic
`urea synthesizing capacity. In females where this pattern is
`pronounced,instituting a “sick day” dietary regimen forthe
`premenstrual or menstrual period would seemreasonable.
`
`Discharge regimen
`To minimize hyperammoncmic spikes, the patient was
`placed on a regulardiet limited to 50-60 g/d ofhigh qual-
`ily natural protein (although her dietary recall suggested
`that she was already self-restricting her protein intake to
`40-50 g/d). She was also prescribed 6 tbsp/d amino acid-
`modified medical food (Cyclinex-2) at bedtime to enhance
`essential aminoacid nutrition, 20 g/d sodiumphenylbutyrate
`to promote urinary nitrogen excretion, and 7 g/d citrulline
`to optimize residual urea cycle function. She was strongly
`encouraged to bring a bag lunch to school and not to skip
`her noon meal. She was given a standing order to come to
`
`our ER for an ammonia levelat any time if symptomatic in
`any way.
`
`Outcome data
`The patient is currently 13 years old and postpubertal,
`5 feet 5 inchestall, mildly obese at 82 kg, and exhibits high
`mental development and excellent school performance.
`Although she does get her ammonia checked when she
`
`Page 6 of 11
`
`is experiencing headache or feeling “off (about every
`2 months), she has not had any hyperammonemic episodes
`since the admission described above. The long-term diet
`issues have largely involved reasonable spacing of the
`patient’s food and protein intake throughout the day.
`
`Discussion
`
`Nutrition management: acute therapy
`
`Nutrition management ofurea cycle enzyme deficiencies
`is divided into acute and chronic therapy and dependsonthe
`specific enzyme defect. The general strategy for acute ther-
`apy is outlined in Box | and amplitied below.
`
`Immediate withdrawal ofprotein
`During the hyperammonemic episode, external nitrogen
`sources must be eliminated. Thus dietary protein should be
`temporarily withdrawn and adequate energy intake provided
`from non-protein sources.
`
`Immediate intervention with non-protein hypercaloric
`solutions
`Start infusion of dextrose 10%solution and fat emulsion
`(Intralipid) 20% (beginning at 2 g/kg/d) to be administered
`as peripheral parenteral nutrition. Sufficient energy cannot
`be delivered through this route to meet
`long-term nutri-
`tional needs. Thus, if a patient requires parenteral nutrition
`(PN) for longer than 48 hours, a central venous catheter
`should be placed to provide a higher concentration of non-
`protein calories (dextrose 12%-30%). Also, sodiumand po-
`tassium salts can be added initially or as part of PN to
`meet the body’s salt requirements. Once the vital signs are
`stable, the sensoriumis clear, and the emesis has ceased,
`every effort should be made to use nitrogen-free enteral
`feeds made with protein-free formulas. Recommended en-
`ergy intake guidelines are shownin Table 2. If not tolerated,
`antiemetic medication should be administered to transition
`to enteral
`feeds.
`If the patient cannot
`take nutrients by
`mouth, institute nasogastric or g-tube feeds by constant per-
`
`
`
`
`
`
`Box 1. Acute therapy strategy
`
`° Immediate withdrawal of protein
`e Immediate intervention with non-protein
`hypercaloric solutions (for the first 24-
`48 hours)
`e Reinstitution of protein and oral nutrition
`¢ Supplementation of L-arginine or citrulline
`to use alternative pathway
`e Fluid management
`e Nitrogen scavenging medication
`
`Page 6 of 11
`
`

`

`NUTRITIONAL MANAGEMENT
`
`$31
`
`fusion. Total volume ofthe formula prescribed will depend
`on the intracranial pressure. Should problems arise with
`administering the entire volume enterally, a combination of
`enteral and parenteral
`feedings can be provided, which
`may be advanced to total parenteral nutrition (TPN) if nec-
`essary. Asillustrated in Case 1, the latter should be a high-
`energy solution consisting primarily of dextrose 25% in
`water and fat emulsion 20%.
`
`Reinstitution ofprotein and oral nutrition
`As plasma ammonia concentration reverts toward nor-
`mal,
`there is a transitional period of PN plus some oral
`feeds. Duringthis time, protein content is slowly increased.
`After 24-48 hours of protein-free energy intervention,
`reinstitution of protein is begun with approximately 25%—
`50% of the prescribed amounts, slowly advancing totoler-
`ance. It is essential to meet protein and energy requirements
`to prevent catabolism. Scveral different amino acid solutions
`are currently available as protein sources to be offered as a
`component of TPN. Ifa patientis partially tolerant of enteral
`feeds, some protein may be supplied by carefully measured
`infant formula or human milk obtained by pumping breast
`milk. However on-demand breast feeding is rarely feasible
`because ofuncontrolled volume and protein intake.
`In the recovering younger patient who has been in a
`hypcrammonemic coma,it often takes a day or two forthe
`individual to awakensufficiently to feed. Nevertheless, it is
`importantto initiate some formofgastric feeding as early as
`possible. For those who have not had placement of a
`nasogastric or nasojejunal tube, introduction of suchanaid,
`even while the patientis still on dialysis, allows formula to
`be dripped into the gut to prepare it for full cntcral feeding.
`In the olderpatient, a potential impediment to recovery from
`an acute hyperammonemic episode is prolonged and fluc-
`uating degrees of obtundation. When coupled with an-
`orexia, common in the recovery phase,
`this situation can
`substantially complicate feeding and reestablishmentof posi-
`ive nitrogen balance, as well as the transition to orally
`administered ammonia scavenger medication. Prolonged in-
`flammatory cffects from a lingering viral infection coupled
`with catabolism of muscle mass from bed rest may likely
`complicate the recovery period as well. And, although it
`does not seem to have been studied in detail, the timing of
`both protein feeding and administration of ammonia scaven-
`gers canalso be a confoundingfactor. Provision ofpositive
`energy balanceusing total parenteral nutrition or nasogastric
`or g-tube pump feedings is essential until the individual’s
`level of consciousness and appetite permit completereinsti-
`tution of normal oral feedings and medications.
`
`
`
`Supplementation of L-arginine orcitrulline to use
`alternative pathway
`is that the urea cycle
`Aninteresting biochemical fact
`not only makes urea, but also L-arginine. This amino acid
`becomes conditionally essential
`in the absence of a func-
`tioning urea cycle, and,
`in fact,
`the body triggers protein
`
`Page 7 of 11
`
`catabolism to produce L-arginine whensupplics are low.
`Thus, L-arginine supplementation is a very important con-
`cept in nutrition management ofthese disorders. Admin-
`istration of L-arginine base at 100-500 mg/kg/d enhances
`nitrogen loss by increasing citrulline and argininosuccinic
`acid excretion in ASL and ASS deficiencies [1]. L-arginine
`can be given in the IV formif the patient cannot tolerate
`oral feeds. Citrulline 100-170 mg/kg/d is used in carbamyl
`phosphate synthetase and OTC deficiencies [1], because
`additional nitrogen is used in the synthesis of L-arginine
`fromcitrulline.
`Clinicians should bear in mind that excessive amounts
`of L-arginine intake can lead to hyperargininemia and the
`formation of argininosuccinate, and may generate a hepa-
`totoxin [2]. Treatment-induced hyperargininemia is toxic
`and can lead to spasticity. This may be of particular con-
`cern in aberrations in the proximal urea cycle enzymes.
`Treatment must be individualized because all patients
`react differently.
`
`Fluid management
`Adequate hydration is important to promote excretion
`of metabolic waste. Give water to supply a minimum of
`1.5 mL/kcal or give 1—1.5 times the normal amount of
`maintenance fluids to meet minimumfluids needs.
`
`Nitrogen scavenging medication
`-of hyperammonemia
`The pharmacologic management
`is discussed elsewhere in this supplement by Summarand
`coworkers and Smith and colleagues. Management of
`hyperammonemia during acute episodes is best managed
`by aggressive nutrition intervention in conjunction with a
`pharmacologic approach to provide alternative methods
`of waste nitrogen excretion. In the presence of significant
`plasma ammonia elevations, any delays in aggressive nutri-
`tion therapy may result in the need for dialysis, which only
`compoundsthe nutrition problem. Because dialysis removes
`nutrients, energy and nutrient
`requirements may be in-
`creased by as much as 20%. This in turn may exacerbate
`catabolism caused by decreased protein synthesis and in-
`creased proteolysis [3]. Nutrition interruptions should be
`minimized and coordinated with the nutritionist.
`
`Nutritional management. chronic therapy
`
`therapy usually consists of limited
`Chronic nutritional
`nitrogen intake provided by a mix ofintact dietary protein,
`medical foods made up primarily of essential amino acids or
`non-protein energy, vitamins and minerals, fluids, and the
`oral nitrogen scavenger sodium phenylbutyrate. In addition
`to the specific enzyme detect, appropriate protein intake in
`the chronic setting is generally dependent on growth rate
`and state of health. Recommended ranges of protein that
`may be tolerated by patients of different ages are presented
`in Table 2. Asillustrated by the case reports, many factors
`may complicate protein requirements. Precise minimumpro-
`
`Page 7 of 11
`
`

`

`$32
`
`SINGH ET AL
`
`infants and children are difficult
`tein requirements for
`to calculate because of the large variability in growth. In
`general,
`the most widely accepted recommendations are
`those published by the Food and Agriculture Organization
`and the World Health Organization, which define safe intake
`for mostindividuals. However, the recommendations shown
`in Table 2 are specific for urea cycle disorders based on
`clinical observations. The discussion belowanticipates some
`of the more common management problems and offers a
`guide to minimizing them.
`
`Maintain positive nitrogen halance
`The key to successful nutrition management forpatients
`whohave urea cycle defects is to maintain positive nitrogen
`(N) balance: protein synthesis must be greater than protein
`catabolism. As infant growthslows, usually around 6 months
`of age, protein requirement declines per kg of body weight
`[4]. During the prepubertal growth spurt, protein require-
`ment increases considerably.
`Maximumtolerated protein should be prescribed, with
`approximately 50% to 60% supplied by essential amino
`acids. When ingestion of intact protein is low, essential
`amino acids fail
`to meet recommendations. Thus medical
`foods (amino acids, in eitherliquid or solid form, that yield
`a protein equivalent calculated as grams of N x 6.25) are
`required to help prevent growth failure. When medical food
`supplies 50% to 60%of prescribed protein, it assures that
`
`adequate amounts of minerals, trace minerals, and vitamins
`are provided [5]. As suggested for acute therapy,
`infants
`may obtain the remainderof protein bycarefully measured
`infant formula or human milk obtained by pumping breast
`milk. Again, on-demand breast feeding is rarely feasible
`because of uncontrolled volume and protein intake.
`
`Provide adequate essential amino acids
`Scaglia and coworkers [6] and Lee and coworkers (else-
`where in this issue) suggest that patients with a urea cycle
`enzyme defect who are treated with protein restriction and
`sodium phenylbutyrate may develop low concentrations of
`branched-chain amino acids (BCAAs). Because abnormally
`low concentrations of plasma BCAAscanreducethethresh-
`old for protein catabolism in patients with a UCD, these
`patients may fluctuate between protein insufficiency and
`sufficiency, making them difficult
`to control. Hypotheti-
`cally, increased intake of BCAAs in conjunction with so-
`diumphenylbutyrate could possibly allow greaterrestriction
`of protein for
`improved control and less
`likelihood of
`catabolism. As noted in Table 3, all
`the medical
`foods
`supply greater amounts of BCAAs than human milk,
`whole cow’s milk, or whole egg, and use of medical foods
`in the proportion suggested assures appropriate supplies of
`these nutrients.
`Table 3 compares the protein, essential amino acid, and
`energy content per gramofprotein of milk, egg, and various
`
`Table 3
`
`Comparison of nutrient content of protein sources (per gramof protcin)
`Aminoacid modified medical foods
`Essential
`Whole
`Whole
`Human
`milk
`cow’s milk
`egg
`Cyclinex -1
`Cycelinex -2
`amino acid
`WND-1
`WND-2
`UCD-1
`UCD-2
`
`Nutrient
`(per 98 g)
`(per31g)
`(per8g)
`(per13g)
`(per6.7g)_ mix (per 1.3 g)
`(per 15.4 g)
`(per 12.28)
`(per 1.79 g)
`(per 1.49 g)
`Energy, kcal
`69
`ig
`12
`68
`32
`4
`77
`34
`AS
`4.3
`Protein equiv, g
`1
`1
`|
`1
`1
`1
`1
`I
`1
`Amino acids, mg
`0
`0
`0
`0
`59
`32
`35
`Alanine
`0
`0
`0
`0
`65
`23
`42
`Arginine
`0
`0
`0
`0
`106
`73
`80
`Aspartic Acid
`0
`0
`25
`25
`N/A
`N/A
`N/A
`Carnitine
`0
`55
`40
`40
`22
`5
`19
`Cystine
`0
`0
`0
`0
`134
`201
`165
`Glutamic acid
`0
`0
`0
`0
`34
`23
`25
`Glycine
`54
`55
`48
`48
`25
`23
`23
`Histidine
`133
`136
`170
`170
`54
`51
`55
`Isoleucine
`224
`229
`289
`289
`87
`82
`93
`Leucine
`159
`161
`148
`148
`73
`43
`67
`Lysine
`106
`55
`45
`45
`30
`23
`21
`Methionine
`210
`95
`100
`120
`54
`46
`45
`Phenylalanine
`0
`0
`0
`0
`Al
`106
`80
`Proline
`0
`0
`0
`0
`78
`33
`42
`Serine
`0
`0
`4
`5
`0
`N/A
`N/A
`Taurine
`106
`107
`88
`131
`148
`100
`100
`44
`44
`45
`Threonine
`42
`39
`40
`60
`31
`37
`37
`13
`23
`17
`Tryptophan
`0
`116
`83
`123
`123
`7
`117
`40
`47
`sé
`Tyrosine
`
`
`
`
`
`
`
`
`
`
`62 60 68 190 190 189 52 103 161Valine 159
`Daia from Acosta PB, Yannicelli S. Nutrition support protocols. Columbus, OH: Ross Products Division, Abbott Laboratories; 2001, and U.S. Department of
`Agriculture, Agricultural Research Service. USDA national nutrient database for standard reference, release 17. Available at: http://www.nal.usda.gov/fnic/
`foodcomp. Accessed June 8, 2005.
`
`0
`0
`0
`
`21
`0)
`0
`45
`103
`205
`129
`25
`69
`0
`0
`
`0
`0
`0
`
`31
`0
`0
`68
`152
`308
`191
`39
`103
`0
`0
`
`49
`
`49
`135
`210
`172
`49
`74
`
`Page 8 of 11
`
`Page 8 of 11
`
`

`

`NUTRITIONAL MANAGEMENT
`
`$33
`
`medical foods [7,8]. Cyclinex-1, for example, provides con-
`siderably more energy per gram of protein equivalent (N x
`6.25) than other protein sources. Human milk is similar to
`amino acid modified medical food with iron (Cyclinex-1)
`in energy content per gramof protein, but distinctly lowerin
`total protein content than cow’s milk. That is why an infant
`with a mild urea cycle enzyme defect may not present until
`the transition from humanmilk to proprietary infant formula
`or whole cow’s milk. Amino acid modified medical foods
`
`used for older patients (Cyclinex-2, WND-2, UCD-2) pro-
`vide a higher protcin-to-energy ratio.
`To offset restricted protein intake, non-protein energy
`intake must be increased to meet requirements for physical
`activity and growth. If not, energy, the first requirement of
`the body, will be supplied by protein catabolism. Additional
`non-protein energy sources not only help prevent catabolism
`of body protein and decompensation, they maximize use of
`amino acids for protein synthesis, a phenomenoncalled
`“protein sparing effect.” In general, energy intake must
`match resting energy expenditure plus an additional per-
`centage (usually about 25%) to cover these needs. Although
`energy requirement per kilogram of body weight decreases
`with age,
`the total amount of energy required increases
`(Table 2).
`intact protein
`Energy is obtained from medical food,
`(cereals, vegetables, and modified high-protein foods such
`as low-protein cheeses, peanut butter, and other products),
`protein-free energy sources such as the protein-free diet
`powder (Product 80,056; Mead Johnson), protein-free diet
`powderwith iron (ProPhree), and very lowprotein foods
`(a variety of sources including popsicles, juices, and fruits).
`The percentage of energy supplied as medical food orintact
`food varies depending on the extent of each individual’s
`food intake.
`
`
`
`Individuals and families may not always report intake
`accurately, either out of inadvertence or active misrepre-
`sentation. Clinical experience would suggest
`that active
`misrepresentation of dietary protein intake would be more
`prominent
`in older children and adolescents as opposed
`to infants, toddlers and young children. In either case, such
`discrepancies must be taken into account whencalculating
`calorie, protein, and medication prescriptions.
`
`Manage fluids
`Dehydration is often a trigger for hyperammonemia and
`properfluid supplementation is often overlooked by parents
`and caregivers in the chronic setting. Water(fluid) intake by
`the infant should beat least 1.5 mL/kcal. Afterthe first year
`of life through adulthood, fluid requirements decrease to
`about 1.0 mL/kcal.
`
`Titrate the phenylbutyrate dose to maximize protein
`tolerance
`
`Phenylbutyrate dosing up to a maximumof 500 mg/kg/d
`or 20 g/d allows the addition of increased amounts of intact
`protein. The prescription of age-appropriate protein intake
`
`Page 9 of 11
`
`containing as muchin