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`CRITICAL CARE
`
`CLINICS
`
`Presentation and Management
`
`of Urea Cycle Disorders Outside
`
`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
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`0 Number 48
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`This material may be protected by Copyright law (Title 17 U.S. Code)
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`LSEVIE
`SAUNDERS
`
`Crit Care Clin 21 (2005) S27—S35
`
`CRITICAL
`
`CARE
`
`CLINICS
`
`Nutritional Management of Urea Cycle Disorders
`
`Rani H. Singh, PhD, RD”, William J. Rhead, MD, PhDb, Wendy Smith, MD°’d,
`Brendan Lee, MD, PhDe, Lisa Snidemian King, MScf, Marshall Summar, MDg
`
`“Depuirnienr 0fHi/mu/i Genetics, E/naiji Ul1ll’(’I'Slf_)'SCl100lQ/‘lVl€(ll(’lI7€, Atlanta, GA 30032, USA
`bDepm‘Imen/ Q/"Perlir/tries and Palliologv, Me(l1'eul Callege of Wisconsin, Mar/ison, WI, USA
`CD€[)(ll‘lI)l€llf
`0fGeueIi'cs, Tlie BlIl‘l7[Il‘(I Bus/i Clii/dre/i.'s' Hospi/(il, Maine Merlical Ce/ilel; P0l‘ll(Ill£l, ME, USA
`"Dep(u'1‘nieiit 0fPe(li'm‘rics, Dl\'lSl0lI 0‘/'G€lI€ll('S, Maine Pediur/'ie Specialty Group, Porllrl/id, ME, USA
`°Depci/‘I/ue/it 0./'M0leeul(u' and Human Genetics, Baylor College aflvlerlicine, Hons/mi, TX, USA
`|D€p[lI‘lIl1€lIf
`0fPe(lia/i'i'Cs, Dirison of Ge/relics and DEl'€l0pIlI€I1/,
`University 0fl’V(l.S'l1llIgl0l1, Seu/rle,
`IVA, USA
`gCe/ile/jfbi‘ Himimi Genetic Researeli l!l1llDl\’l.S‘l0lI Q/"ll/lerlicul Ge/ie/res, Depmmielil of'Pe(liufries, Vanrle/'lu'lI U/i1'vei'Sii‘_i'Medical Ce/iler, Nus/iiii//e, TN, USA
`
`(UCD)
`A cardinal principle of urea cycle disorder
`management is the restriction of protein intake to minimize
`the flux of nitrogen through the urea cycle. However, the
`calculation of tolerated protein intake is neither simple nor
`static. Tissue protein is constantly being synthesized and
`catabolized, and ammonia detoxification needs vaiy accord-
`ing to enzyme deficiency, growth rate, activity level, and the
`patient”s developmental and health status. During growth,
`increased protein intake is necessaiy to prevent catabolism.
`Careful protein management is also essential during hospital
`treatment when a patient may receive only parenteral nutri-
`tion and is subjected to long intervals of bed rest, which can
`contribute to breakdown of tissue protein. Administration of
`essential and other amino acids must also be considered in
`
`the nutritional equation, as should the appropriate titration
`of nitrogen-scavenging medications, energy intake, and vi-
`tamin and mineral supplements.
`In addition,
`the patient’s
`own eating behaviors,
`lifestyle, and life events may often
`confound even the most carefully balanced prescription.
`In both acute and loiig-terin situations, close monitoring
`and calibration of the relevant factors are critical
`to pre-
`venting metabolic decompensation. This, in tum, is essential
`to maintaining existing neurologic status and providing the
`patient (and patient’s family) with a reasonable quality of
`life. This paper presents two case histories and a series of
`recommendations outlining the nutrition management of
`
`Dr. Suniinar acknowledges the support of NIH grants MOl—RR—0O95
`and U54—RR—0l9453.
`
`Complete financial disclosure information for each author is provided
`in the frontmatter of this supplement on page iii.
`* Corresponding author. Department of I-Iiiman Genetics, Emory
`University School of Medicine, Atlanta, GA 30032.
`E—muil (/(l(l/'es.s'.' rsingli@genetics.emoiy.edu (R.H. Singh).
`
`0749-0704/05/$ — see front matter © 2005 Elsevier Inc, All rights reserved.
`doi:10. 1016/_i.c'5é=l§6o§.8§.l)li3
`
`urea cycle disorders. It also identifies difficulties that arise
`in the course of treatment, and suggests practical solutions
`for overcoming them.
`
`Case 1
`
`Inducing aiiabolisni
`
`Medical liistoijv
`After an uneventful birth and successful breastfeeding
`for the first 2 days of life, a 3-day—old white girl exhibited
`lethargy and refusal to suck. Enzyme values reflecting liver
`function were mildly increased and her plasma ammonia
`concentration at 5 days of life was significantly elevated
`at > 500 nmol/L.
`Further findings included abnormal urine lactic and py-
`ruvic acids caused by shock and poor perfusion; elevated
`plasma amino acid concentrations, specifically citiulline
`(2694 ).LlTlOl/L), glutainic acid, glutamine, alanine, methio-
`nine, lysine, and histidine; and excessive urine orotic acid.
`A diagnosis of citiullinemia (argiiiinosuccinate synthetase
`[ASS] deficiency) was made.
`
`Ti'e(u‘mem‘
`
`Treatment was started on day 5 at which time the pa-
`tient’s plasma ammonia concentration was 5l8iimol/L. To
`maximize caloric intake, the child received hyperalimenta-
`tion via umbilical artery catheter. The regimen included
`dextrose 25% in water at 18 ITIL/ht‘, fat emulsion (Intralipid)
`20% at 0.75 mL/hr (1 g/kg/d) as an energy source, and
`insulin 0.05 u/kg/d to promote nutrient use. In addition, she
`was given L—arginine HCL lO% 500 mg/kg/d, an amino acid
`
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`S28
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`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 rng/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% lg/kg/d, and L—arginine
`HCL 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 rnL
`(66.6 rng/rnL) (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 1), the patient showed general
`improvement
`in other important parameters. The plasma
`glutarnirre 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 (nmol/L)
`Patient at
`Patient after
`treatrrrent
`
`Amino acid
`
`200
`9
`75
`531
`67
`811
`541
`16
`197
`18561
`
`diagnosis
`124
`15
`83
`127
`209 1
`2079 1
`349
`253
`578 1
`26941
`195
`42
`160 1
`40
`108
`111
`63
`33
`
`Taurine
`Aspartic acid
`Threonine
`Serine
`Glutamic acid
`Glutarnine
`Proline
`Glycine
`Alanine
`Citrulline
`Valine
`Cystinc
`1\/Iethionine
`lsoleucine
`Leucine
`Tyrosine
`Phenylalanine
`Ornithine
`
`Lysine
`1-listidine
`
`Arginine
`
`464 7
`1521
`
`P539374 of 11
`
`Patient at
`
`Reference
`
`discharge
`175
`5
`299
`95
`52
`1721
`106
`265
`262
`22601
`153
`40
`49
`35
`63
`71
`71
`
`range
`38—227
`0-28
`50-248
`90-209
`10—l89
`246-984
`884117
`125497
`l24—573
`652
`67—299
`4-65
`1749
`20,96
`29-151
`24-139
`37,86
`19-173
`
`43-243
`33-145
`
`20-149
`
`Disc/mrge 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 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 [Mead Johnson & Company, Evansville,
`1ndia1ra]), 123 kcal/kg/d of energy, and 500 rng/kg/d of
`L—arginine base. This regimen supplied about 24 kcal/fluid
`ounce. Additional water (100 to 150 1nL/d) was to 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
`with a letter at discharge that detailed the regimen to 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
`
`lethargy, and excess sleepiness. Should the
`breathing,
`child appear ill, 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 antiernetic 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-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 arrajwaeagigl gmpfein sources
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`
`NUTRITIONAL MANAGEMENT
`
`Table 2
`
`Recommended daily nutrient intake in urea cycle disorders
`Nutrient
`
`Age
`Infants
`0 to <3 mo
`3 to <6 mo
`9 to <12 in
`Girls and boys
`1
`to <4 yr
`4 to <7 yr
`7 to <11 yr
`Women
`11 to <15 yr
`15 to <19 yr
`219 yr
`Men
`11 to <15 yr
`15 to <19 yr
`319 yr
`
`Patient protein
`intake* (g/kg)
`
`Protein (g/kg)
`
`Patient energy
`intake"‘ (kcal/kg)
`
`Energy (kcal/kg)
`
`2.1-1.4
`1.5-1.2
`1.2-1.1
`(g/day)
`18.6-12.5
`21.0-19.0
`22.0-24.0
`
`2.20-1.25
`2.00-1.15
`1.60-0.90
`(g/day)
`8-12
`12-15
`14-17
`1
`
`Lu
`
`lQl‘J|\J 1'1”‘.3° tu|\Jl\>DJL/vb.-I
`l\.)l\.)1\.)W“TO DJ101\J[U-5
`
`150-101
`100-80
`80-75
`(kcal/day)
`800-1040
`1196-1435
`1199-1693
`
`150-125
`140-120
`120-1 10
`(kcal/day)
`945-1890
`1365-2415
`1730-3465
`
`1575-3150
`1260-3150
`1785-2625
`
`Fluid
`(mL/kg)
`
`160-130
`160-130
`130-120
`(mL/day)
`945-1890
`1365-2445
`1730-3465
`
`1575-3150
`1260-3150
`1875-2625
`
`‘-”‘ Data are for Case 1 patient.
`/1//or/ifietlf/"0n1 Acosta PB, Yannicelli S. Nutrition support protocols. Columbus, OH: Ross Products Division, Abbott Laboratories; 2001; with permission.
`
`have helped meet all 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
`
`012581‘ of /zypercmznzonemia
`
`Medical /71's1‘0I'y
`A 10-year-old African—American female presented to
`a teitiaiy 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 330umol/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
`
`1]
`
`100 umol/L in 2 hours, and soon returned to nonnal.
`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 mg/kg/d (20 g/d), and
`citrulline 108 mg/kg/d (7 g/d),
`the latter two dose levels
`represent the usual 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, shoitly after her menses
`began. Upon admission, she exhibited a reduced level of
`consciousness. Her initial plasma ammonia concentration
`was between 200 and 225 umol/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
`
`20 Tue
`
`21 Wed 22 Thu
`
`23 Fri
`
`24 Sat
`
`25 Sun
`
`26 Mon
`
`27 Tue
`
`28 Wed 29 Thu
`
`30 Fri
`
`31 Sat
`
`Jul 2004
`
`Page 5of11
`
`Fig. 1. Plasma ammonia concentrations following admission for disorientation.
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`S30
`
`SINGH 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 umol/L, followed by
`a fall tol20|,rmol/L, and then another spike to 250 umol/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 encephalopathic; she was clinically well and nor‘mo-
`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 irregular dietary pattern:
`she would eat breakfast and then skip food until dinner. It is
`also possible that she was experiencing asymptomatic
`hyperammonemic spikes quite frequently at home.
`In this young lady’s case, it is also quite possible that the
`cyclic anabolism and catabolism associated with her normal
`menstrual cycles played a role in triggering her hyper-
`amrnonernic episodes, although these potential confounding
`and complicating effects have not been addressed systern-
`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 for the
`premenstrual or menstrual period would seem reasonable.
`
`Disc/rarge regimen
`To minimize hyperammonemic 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
`40-50 g/d). She was also prescribed 6 tbsp/d amino acid-
`rnodifred medical food (Cyclinex-2) at bedtime to enhance
`essential amino acid nutrition, 20 g/d sodium phenylbutyrate
`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 level at any time if symptomatic in
`any way.
`
`Outcome (lam
`
`The patient is currently l3 years old and postpubertal,
`5 feet 5 inches tall, mildly obese at 82 kg, and exhibits high
`mental development and excellent school performance.
`Although slhageleesf get her ammonia checked when she
`
`is experiencing headache or feeling “of ” (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 nzmzagemenr: acute I/rerapy
`
`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 wir‘/IdI'(1w(1/ 0_fpI'0leI'n
`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.
`
`Immedic/r‘e intervenf1'0/7 wit/I 11011-protein /ryperea/oric
`so/L/r‘i01r.s'
`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, sodium and 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 sensorium is 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 shown in Table 2. If not tolerated,
`antiernetic medication should be administered to transition
`
`take nutrients by
`feeds. If the patient cannot
`to enteral
`mouth, institute nasogastric or g-tube feeds by constant per-
`
`Box 1. Acute therapy strategy
`
`- Immediate withdrawal of protein
`- Immediate intervention with non—protein
`hypercaloric solutions (for the first 24-
`48 hours)
`
`- Reinstitution of protein and oral nutrition
`- Supplementation of L-arginine or citrulline
`to use alternative pathway
`0 Fluid management
`- Nitrogen scavenging medication
` 4?m
`Lupin v. H-orizon
`IPRZO16-00829
`
`Page 6 of 11
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`IPR2016-00829
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`
`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%.
`
`Reilrsrifr/tiolt ofproteilr and oral mil/'i2‘I'0n
`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,
`reinstitution of protein is begun with approximately 25%-
`50% of the prescribed amounts, slowly advancing to toler-
`ance. It is essential to meet protein and energy requirements
`to prevent catabolism. 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, some protein may be supplied by carefully measured
`infant fomrula 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
`hyperarnmonernic coma, it often takes a day or two for the
`individual to awaken sufficiently to feed. Nevertheless, it is
`important to initiate some form of gastric feeding as early as
`possible. For those who have not had placement of a
`nasogastric or nasojejunal tube, introduction of such an aid,
`even while the patient is still on dialysis, allows formula to
`be dripped into the gut to prepare it for full enteral feeding.
`In the older patient, a potential impediment to recovery from
`an acute hyperamrnonemic episode is prolonged and fluc-
`tuating degrees of obtundation. When coupled with an-
`orexia, common in the recovery phase,
`this situation can
`substantially complicate feeding and reestablishment of posi-
`tive nitrogen balance, as well as the transition to orally
`administered ammonia scavenger medication. Prolonged in-
`flammatory effects 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 strrdied in detail, the timing of
`
`both protein feeding and administration of ammonia scaven-
`gers can also be a confounding factor. Provision of positive
`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.
`
`Szlpp/emenfafion 0fL-arginme or cirru//1'/re to use
`alternative pm/rway
`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 rrr'eBag§!C7l©f11nd,
`in fact,
`the body triggers protein
`
`catabolism 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 I00-500 rng/kg/d enhances
`nitrogen loss by increasing citrulline and argininosuccinic
`acid excretion in ASL and ASS deficiencies [I]. L-arginine
`can be given in the IV form if the patient cannot tolerate
`oral feeds. Citrulline I00-170 rng/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 lryperarginirrernia 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 ma/1(/gemem‘
`Adequate hydration is important to promote excretion
`of metabolic waste. Give water to supply a minimum of
`1.5 1nL/kcal or give I-1.5 times the normal amount of
`maintenance fluids to meet minimum fluids needs.
`
`Nifrogelr scrzve/rgi/1g medic(m'0n
`The pharmacologic management of hyperamrnonemia
`is discussed elsewhere in this supplement by Summar 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
`catabolism caused by decreased protein synthesis and in-
`creased proteolysis [3]. Nutrition intenuptions should be
`minimized and coordinated with the nutritionist.
`
`Nurritiozml mcmagemenr: C/ironic 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 1‘eqr1ir‘errr5Wfi,efir::§cggomirrirrrrrrrr pro-
`Lupin v. Horizon
`|PR2016-00829
`
`Page 7 of 11
`
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`IPR2016-00829
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`

`
`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 recornrrrendations 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.
`
`Maim‘ai/1 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
`catabolism. 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 essential 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
`
`Table 3
`
`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, orr-dernand 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 ofplasrna BCAAS can reduce the thresh-
`old for protein catabolisrn in patients with a UCD, these
`patients may fluctuate between protein insufficie