WI
`.
`K.
`theclmlcs.com
`
`CRITICAL CARE
`
`CLINICS
`
`Presentation and Management
`
`of Urea Cycle Disorders Outside
`
`EBLING LIBRARY
`UNIVERSITY OF WISCONSIN
`NOV 1'1 2005
`
`750 Highlan Avenue
`
`the Newborn Period
`
`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 0 Volume 2T
`
`0 Number 48
`
`SAUNDERS
`
`An Imprinl oI EIsevier, Inc,
`PHILADELPHIA LONDON TORONTO MONTREAL SYDNEY TOKYO
`
`Page 1 of 11
`
`Horizon Exhibit 2004
`
`Horizon Exhibit 2004
`Lupin v. Horizon
`Lupin v. Horizon
`IPR2017-01159
`IPR2017-01159
`
`Page 1 of 11
`
`

`

`W.B. SAUNDERS COMPANY
`
`A Division of Elsciiici' Inc.
`
`Elsevrer Inc. ' 1600 John P. Keiuiedy Blvd, Suite l800 ' Philadelphia, Pennsylvania 1910372899
`
`http: // www.theclinicscom
`
`CRITICAL CARE CLINICS
`October 2005
`Editor: Joe Rusko
`
`Volume 21, Number 45
`ISSN 0749—0704
`
`Copyright © 2005 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means,
`electronic or mechanical, including photocopy, recording, or any information retrieval system, without written permission from the publisher.
`
`Single photocopies of single articles may be made for personal Lise as allowed by national copyright laws. Permission of the publisher and pay—
`ment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes,
`resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non—profit
`educational classroom use. Permissions may be sought directly from Elscvicr’s Rights Department in Philadelphia, PA, USA; phone: (+1) 215
`239 3804, fax: (+1) 215 239 3805, e-mail: healthperrnlssions@elsevier.com. Requests may also be completed on—line via the Elsevier homepage
`(http://w\ivwelseviercom/locate/permissions). You may also contact Rights & Permissions directly through Elsevier’s homepage (http://
`wwwelseviercom), selecting first ’Customer Support’, then ‘General Information’, then ’Permission Query Porm’. In the USA, users may Clear
`permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone (978)
`7511—84-00, fax: (978) 75047414, 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 4% 3986. Other countries may have a local reprographic rights agency
`for payments.
`
`Reprints. For copies of 100 or more, of articles in this publication, please contact the Commercial Reprints Department, Elsevier Inc, 360 Park
`Avenue South, New York, New York 10010-1710. Phone: (212) 633-3813; Fax: (212) 462-19715; til-mail: reprints@elsevier.com
`
`The ideas and opinions expressed in Critical Care Clinic: do not necessarily reflect those of the Publisher. The Publisher does not assume any
`responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this perio-
`dical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of
`each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of
`the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug
`dosages and the best treatment for the patient. Mention of any product in this issue should not be construed as endorsement by the contributors,
`editors, or the Publisher of the product or manufacturers’ claims.
`
`C ritirnl Carr Clinics (ISSN 0749—0704) is published quarterly by W.B. Saunders Company. Corporate and editorial offices: Elsevier Inc, 1600 John
`F, Kennedy Blvd, Philadelphia, PA 19103-2899. Accotuiting and circulation offices: 6277 Sea Harbor Drive, Orlando, FL 323874800. Periodicals
`postage paid at Orlando, lr'L. 32862, and additional mailing offices. Subscription prices are $170.00 per year for US individuals, $280.00 per year
`for US institution, $85.00 per year for US students and residents, $210.00 per year for Canadian individuals, 5340.00 per year for Canadian instr
`tutions, $230.00 per year for international individuals, $340.00 per year for international institutions and $115.00 per year for Canadian and foreign
`students /residents, To receive student/ resident rate, orders must be accompanied by name of alliliated institution, date of term, and the Sig?
`mill/11’ of program/residency coordinator on institution letterhead. Orders will be billed at individual rate until proof of status is received.
`Foreign air speed delivery is included in all Clinics subscription prices. All prices are subject to change without notice. l’OS‘l‘MASTER: Send
`address changes to Critical Care Clinics, W13. Saunders Company, Periodicals Fulfillment, Orlando, FL 328877 4800. Customer Service: 1—800-654-
`2452 (US). From outside of the US, call 1—407-345-1000. E—mail: hlispcs@harcourt.com
`
`Critical Carr Clinics is also published in Spanish by Editorial IntereMedica, lunin 917, 1er A, 1113, 31161105 Ait'e'S, Argentina-
`
`Crilicnl Carr Clinics is covered in Iiirli’x Mediczis, EMBASE/Exccrptii Mn‘licn, 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)
`
`

`

`S28
`
`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 kcals/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.
`0n 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 hyperalirnentation regimen of dextrose
`25% in water 18 mL/hr, insulin 0.02 u/kg/d, essential and
`nonessential amino acid mixture (Tropermine ) 0.5 g/kg,
`fat emulsion (Intralipid) 20% lg/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—l) 25 g, protein-free diet pow—
`der with iron (ProPhree)
`3 g, L—arginine base 27 mL
`(66.6 mg/mL) (after intravenous arginine was discontinued),
`and the oral nitrogen scavenger sodium phenylbutyrate
`(Buphenyl) 500 mg/kg/d.
`Although her plasma citrulline concentration did not
`change significantly (Table l), the patient showed general
`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 (lunol/l.)
`Patient at
`Patient after
`Patient at
`Reference
`
`Amino acid
`diagnosis
`treatment
`discharge
`range
`Taurine
`124
`200
`175
`384227
`Aspartic acid
`15
`9
`5
`0—28
`Threonine
`83
`75
`299
`507248
`Serine
`127
`53L
`95
`90—209
`Glutamic acid
`209 T
`67
`52
`107189
`Glutamine
`207‘) T
`811
`1721
`246—984
`Proline
`349
`541
`106
`8841] 7
`Glycine
`253
`16
`265
`125 497
`Alanine
`578 l
`197
`262
`1247573
`C‘itrulline
`2694 t
`1856 t
`2360 T
`6452
`Valine
`195
`97
`153
`677299
`Cystine
`42
`7
`40
`4—65
`Methionine
`160 l
`26
`49
`749
`Isoleucine
`40
`20
`35
`20796
`Leticine
`108
`47
`63
`29—1 51
`Tyrosine
`l
`l 1
`81
`71
`24—1 2‘)
`Phenylalanine
`63
`60
`7]
`37486
`Ornithine
`32
`168
`183 1
`197173
`Lysine
`464 i
`77
`224
`437243
`Histidine
`152T
`63
`68
`384145
`
`Argininc 204149 26 258 16
`
`
`
`
`Disc/rrllge regimen
`It was imperative in the weeks and months following
`discharge that the infant ingest sufficient protein, energy,
`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 need to 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 corr-
`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 [Mead 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) was to be offered.
`Parents were instnrcted how to insert a nasogastric tube
`in the event of a poor suck. In this case, formula was to ac
`given every 3 hours, and sodium phenylbutyrate was to De
`administered every 6 hours. The parents were also provided
`with a letter at discharge that detailed the regimen to be used
`to prevent decompensation during periods of metabo iC
`stress associated with infections and fevers. Symptoms they
`were instructed to look for included refusal to suck, labored
`breathing,
`lethargy, and excess sleepiness. Should tie
`child appear ill, they were told to temporarily decrease or
`eliminate protein intake from food and substitute a spec'al
`metabolic formula that would provide increased calories
`from non—protein sources, as well as necessary vitamins a rd
`minerals. They were also instructed to continue soditm
`phenylbutyrate, and to administer antiemetic medication a 1d
`nasogastric feeding, if required. In the event that feedi 1g
`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—tube) was placed to
`overcome the child’s mild anorexia.
`
`
`
`Outcome data
`
`With sodium phenylbutyrate and diet management,
`plasma ammonia concentrations have been maintained in
`treatment range. As reflected in Table 2. the patient’s protein
`and energy intake have been within the recommended
`guidelines throughout her life. Because a reduction in whole
`dietary protein alone does not usually offer adequate nu-
`trients for growth, her diet has consistently provided
`about 50% of protein 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 arnino acid protein sources
`
`Page 4 of 11
`
`Page 4 of 11
`
`

`

`NUTRITIONAL MANAGFMFNT
`
`$29
`
`Table 2
`
`Recommended daily nutrient intake in urea cycle disorders
`Nutrient
`
`
`Patient protein
`Patient energy
`:luid
`
`Age
`intake* (g/ltg)
`Protein (glkg)
`intake“ (keal/kg)
`Energy (keallkg)
`(mL/kg)
`Infants
`0 0 <3 mo
`3 0 <6 mo
`9 o <12 in
`Girls and boys
`1
`0 <4 yr
`4 0 <7 yr
`7 o <11 yr
`Women
`11 to <15 yr
`15 to <19 yr
`2 9 yr
`Men
`210073885
`210073885
`20723
`11 to <15 yr
`220041095
`22004095
`21724
`15 to <19 yr
`
`3 L) yr 2625—3465 23732 2625—3465
`
`
`* Data are for Case 1 patient.
`ll/ltitli‘lier/jium Acosta PB, Yannicelli S. Nutrition support protocols. Columbus, OH: Ross Products Division, Abbott Laboratories; 2001; with permission.
`
`2.14.4
`1.54.2
`1.2 1.1
`(g/day)
`18.6—12.5
`2107190
`22.07240
`
`
`
`ISU—Hll
`100780
`80—75
`(keal/day)
`800 1040
`1196714135
`119971693
`
`2.20—1.25
`1004.15
`1.607090
`(g/day)
`8712
`12715
`14—17
`
`20723
`20—23
`2725
`
`l50—l25
`1407120
`1207110
`(kcal/day)
`94571890
`1365 2415
`1730 3465
`
`1575<3150
`1260—3150
`178572625
`
`
`
`607130
`60—130
`307120
`(mL/day)
`945—1890
`36572445
`73073465
`
`57573150
`260—3150
`87572625
`
`have helped meet all essential amino acid requirements. At
`10 years of age.
`the child’s growth continues to be sat-
`isfactory: height 25m percentile and weight 50Lh percentile.
`
`Case 2
`
`Onset of l7_ip€r(mmronemia
`
`Medical histole
`A 10-year-old African—American female 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 330tunol/L. A presumptive diagnosis of a urea
`cycle disorder was made and she was treated with intra-
`venous sodium benzoate and sodium phenylaeetate (Amino-
`nul), L—"trginine, and substantial IV and enteral carbohydrate
`intake. The plasma ammonia concentration dropped some
`
`IIl.
`Ammonia
`
`100 tunol/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 protein restriction at 1.0 g/kg/d, sodium
`phenylbutyrate (Buphenyl) 308 tnglkg/d (20 g/d), and
`citrulline 108 mg/kg/d (7 g/d),
`the latter two dose levels
`represent the usttal maximum adult dosage for her weight of
`65 kg. She was later identified as a symptomatic carrier for
`omithine 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
`eonsciottsness.
`l-ler initial plasma ammonia concentration
`was between 200 and 225 trmol/L (Fig, 1). It was reduced to
`a normal concentration within 24 hours following admin-
`istration of IV sodium benozoate and sodium phenylacetate
`(Ammonul) and L—arginine as before; the patient was then
`
`asp—f:-
`soc-E2507:
`
`507E
`
`Af
`a“.
`
`.
`5,
`it
`
`
`i 200E
`
`1150 ‘
`a
`=
`100E
`
` 26 Mon
`27 Tue
`28 Wed 29 Thu
`30 Fri
`31 Sat
`20 Tue
`21 Wed 22 Thu
`23 Fri
`24 Sat
`25 Sun
`Jul 2004
`
`
`
`Fig. 1. Plasma ammonia concentrations following admission for disorientation.
`
`Page 5 of 11
`
`Page 5 of 11
`
`

`

`S30
`
`SINGII ET AL
`
`is experiencing headache or feeling “off” (about every
`2 months). she has not had airy hyperanrmonemic 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 of urea cycle enzyme deficiencies
`is divided into acute and chronic therapy and depends on the
`specific enzyme defect. The general strategy for acute ther—
`apy is outlined in Box 1 and amplified below.
`
`Immediate wit/idi'mm/ ofpmtein
`During the lryperarnrrronernic episode, external nitrogen
`sources must be eliminated. Thus dietary protein should be
`temporarily withdrawn and adequate energy intake provided
`from nonrprotein sources.
`
`Immediate intervention with non—protein liypé’l‘Cfl/Ol‘iC
`solutions
`Start infusion of dextrose 10% solution and fat emulsion
`
`(lntralipid) 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-
`pr'otein calories (dextrose l2%$0%). Also, sodium and po—
`tassirrrn salts can be added initially or as part of PN to
`meet the body’s salt requirements. Once the vital signs are
`stable, the sensorium is clear, and the ernesis has ceased,
`every effort should be nrade to use nitrogen—free enteral
`feeds made with protein—free formulas. Recommended en—
`ergy intake guidelines are shown iii Table 2. If not tolerated,
`arrtierrretic medication should be administered to transition
`
`take nutrients by
`if the patient cannot
`feeds.
`to enteral
`nouth, institute rrasogastric or g-tube feeds by constant per—
`
`fed orally and given oral sodium plrerrylbutyrate and citrul—
`line. Several days later she showed a nighttime spike in
`plasma ammonia concentration to 350 rrmol/L, followed by
`a fall tolZOunrol/L, and their another spike to 250 rrnrol/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 encephalopatlric; she was clinically well and norme-
`anunonemic every morning. However, she had a regular re-
`elevatiorr 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 irregular dietary pattern:
`she would eat breakfast and then skip food until dinner. it is
`also possible that she was experiencing asymptomatic
`hyperamrrronemic spikes quite frequently at home.
`In this young lady’s case, it is also quite possible that the
`cyclic arrabolism and eatabolisrrr associated with her normal
`menstrual cycles played a role in triggering her hyper-
`amrnonemic episodes, although these potential confounding
`and complicating effects have not been addressed systern—
`atically in the rrrea 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 for the
`premenstrual or menstrual period would seem reasonable.
`
`Discharge regimen
`To minimize hyperammorremic spikes, the patient was
`placed on a regular diet limited to 50—60 g/d of high qual—
`ity natural protein (although her dietary recall suggested
`that she was already self-restricting her protein intake to
`40750 g/d). She was also prescribed 6 tbsp/d amino acid—
`modilied medical food (Cyclirrex—Z) at bedtime to enhance
`essential arrrino acid nutrition, 20 g/d sodium phenylbutyrate
`to promote rrrirrary 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
`hcr noon meal. She was given a standing order to come to
`
`our 3R for an anunonia level at any tirrre if symptomatic in
`any way.
`
`Outcome (iota
`
`The patient is currently 13 years old and postpubertal.
`5 feet 5 inches tall, 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
`
`
`
`Box 1. Acute therapy strategy
`
`
`
`
`° Immediate withdrawal of protein
`- Immediate intervention with non—protein
`hypercaloric solutions (for the first 24—
`48 hours)
`0 Reinstitution of protein and oral nutrition
`- Supplementation of Liarginine or citrulline
`to use alternative pathway
`° Fluid management
`- Nitrogen scavenging medication
`
`Page 6 of 11
`
`

`

`NUTRITIONAL MANAGEMENT
`
`S31
`
`fusion. Total volume of the 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. As illustrated in Case I. the latter should be a high—
`energy solution consisting primarily of dextrose 25% in
`water and fat emulsion 20%.
`
`Reinstin/tion of/JI'oteiii and oral nutrition
`As plasma ammonia concentration reverts toward nor—
`mal,
`there is a transitional period of PN plus some oral
`feeds. During this time, protein content is slowly increased.
`After 2448 hours of protein-free energy intervention,
`rcinstitution of protein is begun with approximately 25%—
`50% 0f the prescribed amounts, slowly advancing to toler-
`ance. It is essential to meet protein and energy requirements
`to prevent catabolisrn. Several different amino acid solutions
`are currently available as protein sources to be offered as a
`component of TPN. If a patient is partially tolerant of enteral
`feeds. seine protein may be supplied by carefully measured
`infant formula or human milk obtained by pumping breast
`milk. However on—dernand breast feeding is rarely feasible
`because of uncontrolled volume and protein intake.
`In the recovering younger patient who has been in a
`hyperammonemic coma, it often takes a day or two for the
`'ndividual to awaken sufficiently to feed. Nevertheless, it is
`'mportant to initiate some form of gastric feeding as early as
`possible. For those who have not had placement of a
`iasogastric or nasojejunal tube, introduction of such an aid,
`even while the patient is still on dialysis, allows formula to
`ac dripped into the gut to prepare it for full enteral feeding.
`In the older patient, a potential impediment to recovery from
`an acute hyperammonernic episode is prolonged and fluc-
`uatiiig degrees of obtundation, When coupled with an-
`orexia, common in the recovery phase,
`this situation can
`substantially complicate feeding and reestablislnnent of posi-
`ive nitrogen balance. as well as the transition to orally
`administered ammonia scavenger medication. Prolonged in-
`flammatory effects from a lingering viral infection coupled
`with catabolisrn of muscle mass from bed rest may liker
`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 can also be a confounding factor. Provision ofpositive
`energy balance using total parenteral nutrition or nasogastric
`or g-tube pump feedings is essential until the individual’s
`level of consciousness and appetite permit complete reinsti—
`tution of normal oral feedings and medications.
`
`
`
`Supp/elimination QfL-{ll'gllillte or citrulline to use
`alrarnalive pathway
`is that the urea cycle
`An interesting 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
`
`catabolisrn to produce L-arginine when supplies are low,
`Thus, L—arginine supplementation is a very important con
`cept in nutrition management of these disorders. Admin-
`istration of L—arginine base at 1007500 mg/kg/d enhances
`nitrogen loss by increasing citrulline and argininosuccinic
`acid excretion in ASL and ASS deficiencies [I]. L—ai‘ginine
`can be given in the 1V form if the patient cannot tolerate
`oral feeds. Citnilline 100470 ing/kg/d is used in carbamyl
`phosphate synthetase and OTC deficiencies [I], because
`additional nitrogen is used in the synthesis of L-arginine
`from citrulline.
`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 corr-
`ecm 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 I715 times the normal amount of
`maintenance fluids to meet minimum lluids needs.
`
`Nitrogen scavenging medication
`The pharmacologic management of hyperamrrronemia
`is discussed elsewhere in this supplement by Surnmar and
`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
`compounds the nutrition problem Because dialysis removes
`nutrients, energy and nutrient
`requirements may be in—
`creased by as much as 20%. This in turn may exacerbate
`catabolisrn 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 of intact 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 defect. 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. As illustrated by the case reports, many factors
`may complicate protein requirements. Precise minimum pro—
`
`Page 7 of 11
`
`

`

`S32
`
`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 most individuals. However, the recommendations shown
`in Table 2 are specific for urea cycle disorders based on
`clinical observations. The discussion below anticipates some
`of the more common management problems and offers a
`guide to minimizing them.
`
`Maintain positive nitrogen balance
`The key to successful nutrition management for patients
`who have urea cycle defects is to maintain positive nitrogen
`(N) balance: protein synthesis must be greater than protein
`catabolisrn. As infant growth slows, 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.
`Maximum tolerated protein should be prescribed, with
`approximately 50% to 60% supplied by csscntial amino
`acids. When ingestion of intact protein is low, essential
`amino acids fail
`to meet recommendations. Thus medical
`
`foods (amino acids, in either liquid 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 remainder of protein by carefully 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 cyclc
`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 BCAAs can reduce the thresl —
`old for protein catabolisrn 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—
`dium phenylbutyrate could possibly allow greater restriction
`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 ofmcdical foods
`in the proportion suggested assures appropriate supplies of
`these nutrients.
`
`Table 3 compares the protein, essential amino acid, and
`energy content per gram of protein of milk, egg. and various
`
`Table 3
`
`Comparison of nutrient content of protein sources (per gram of protein)
`Amino acid modified medical foods
`Essential
`Whole
`Whole
`Human
`milk
`cow's milk
`egg
`Cyclinex —1 Cyclinex —2
`amino acid
`WND—l
`WND—2
`UCD-l
`UCD—2
`
`Nutrient
`(per 98 g)
`(per 31 g)
`(per 8 g)
`(per 13 g)
`(per 6.7 g) mix (per 1.3 g)
`(per 15.4 g)
`(per 12.2 g)
`(per 1.79 g)
`(per 1.49 g)
`Energy, kcal
`69
`19
`12
`(78
`32
`4
`77
`34
`4.5
`4.3
`Protein equiv, g
`1
`1
`l
`l
`l
`l
`l
`l
`1
`1
`Amino acids. mg
`0
`0
`0
`0
`59
`32
`35
`Alanine
`0
`O
`0
`0
`65
`23
`42
`Arginine
`0
`0
`0
`O
`106
`73
`80
`Aspartic Acid
`0
`0
`25
`25
`N/A
`NtA
`N/A
`Carnitine
`0
`55
`40
`40
`22
`5
`19
`Cystine
`0
`0
`0
`0
`134
`201
`165
`Glulauiic acid
`0
`0
`0
`0
`34
`23
`25
`Glycine
`54
`55
`48
`48
`25
`23
`23
`Histidine
`133
`136
`170
`170
`54
`51
`55
`lsoleucine
`224
`229
`28‘)
`289
`87
`82
`93
`Leucine
`159
`161
`148
`148
`73
`43
`67
`Lysine
`106
`55
`45
`45
`30
`23
`21
`Methionine
`210
`95
`100
`[20
`54
`46
`45
`Phenylalanine
`0
`0
`0
`0
`41
`106
`80
`Proline
`0
`O
`0
`0
`78
`33
`42
`Serine
`()
`O
`4
`5
`0
`N/A
`N/A
`Taurinc
`106
`107
`88
`131
`148
`100
`100
`44
`44
`45
`Threoninc
`42
`39
`4-0
`(30
`31
`37
`37
`13
`23
`17
`Tiyptophan
`0
`116
`83
`123
`123
`117
`t 17
`40
`47
`52
`Tyrosine
`
`
`
`
`
`
`
`
`
`
`62 60 68 190 190 189 152 103 161Valine 159
`Datafi‘mn Acosta Pl}, Yannicelli S. Nutrition support protocols. Columbus, OH: Ross Products Division, Abbott Laboratories: 21101, and US. Department 01“
`Agriculture, Agricultural Research Service USDA national nutrient database for standard reference, release 17. Available at: http://www.iial.usdagov/firic/
`foorlcomp. Accessed .lune 8, 2005.
`
`O
`O
`O
`
`21
`t)
`0
`45
`103
`205
`129
`25
`69
`0
`0
`
`0
`0
`O
`
`31
`0
`(l
`68
`152
`308
`191
`39
`103
`0
`O
`
`49
`
`49
`135
`210
`172
`49
`74
`
`Page 8 of 11
`
`Page 8 of 11
`
`

`

`NUTRITIONAL MANAGEMENT
`
`S3?
`
`medical foods [7,8]. Cyclinex-l, 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—l)
`in energy content per gram of protein, but distinctly lower in
`total protein content than cow’s milk. That is wiry an infant
`with a mild urca cycle enzyme defect may not present until
`the transition from human milk to proprietary infant formula
`or whole cow’s milk. Arrrino acid modified medical foods
`
`used for older patients (Cyclinex-Z, WND-Z, UCD-2) pro—
`vide a higher protein-to-energy ratio
`To offset restricted protein intake, non—protein energy
`intake rrrust be increased to meet requirements for physical
`activity and growth. If not, energy, the first requirement of
`the body, will be supplied by protein catabolisrn. Additional
`non—protein energy sources not only help prevent catabolisrn
`of body protein and decompensation, they maximize use of
`amino acids for protein synthesis, a phenomenon called
`“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
`witi age,
`the total amount of energy required increases
`(Taole 2).
`intact protein
`Energy is obtained from medical food,
`(cereals, vegetables, and modified high-protein foods such
`as lowaprotein 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
`powder with iron (ProPhree), and very low protein foods
`(a variety of sources including popsicles, juices. and fruits).
`The percentage of energy supplied as medical food or intact
`food varies depending on the extent of each individualis
`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 when calculating
`calorie, protein, and medication prescriptions.
`
`ll/Ianage fluids
`Dehydration is often a trigger for hyperarnrnonemia and
`proper fluid supplementation is often overlooked by parents
`and caregivers in the chronic setting. Water (fluid) intake by
`the infant should be at least 1.5 mL/keal. After the first y