Symposium 3

“Fl id d N t iti S t f th“Fluid and Nutrition Support of the Pre-term Infant in the First Week

of Life”

Guidelines for the Provision of Amino Guidelines for the Provision of Amino f ff fAcids in the Preterm Infant During the Acids in the Preterm Infant During the

First Week of LifeFirst Week of LifeBAPENBAPENBAPENBAPEN

Leeds, November 27, 2007Leeds, November 27, 2007

Patti Patti ThureenThureen, MD, Professor of Pediatrics, MD, Professor of PediatricsUniversity of Colorado Health Sciences Center University of Colorado Health Sciences Center University of Colorado Health Sciences Center University of Colorado Health Sciences Center

and the Children’s Hospital of Denverand the Children’s Hospital of Denver

patti.thureen@uchsc.edupatti.thureen@uchsc.edupatti.thureen@uchsc.edupatti.thureen@uchsc.edu

Financial Disclosures: No relevant financial relationships with any commercial Financial Disclosures: No relevant financial relationships with any commercial Financial Disclosures: No relevant financial relationships with any commercial Financial Disclosures: No relevant financial relationships with any commercial interestsinterests

ObjectivesObjectivesjj

•• Discuss the arguments for and against early Discuss the arguments for and against early i id t iti i t i f ti id t iti i t i f tamino acid nutrition in preterm infantsamino acid nutrition in preterm infants

•• Review the safety and efficacy of “Early Review the safety and efficacy of “Early Aggressive Parenteral Amino Acid Nutrition”Aggressive Parenteral Amino Acid Nutrition”

•• Discuss new data on benefits of early amino acidsDiscuss new data on benefits of early amino acidsDiscuss new data on benefits of early amino acidsDiscuss new data on benefits of early amino acids•• Present controversies and unresolved issues with Present controversies and unresolved issues with

l l d dl l d dearly parenteral amino acid administration in early parenteral amino acid administration in preterm infantspreterm infants

Why Why NotNot Give Early “Aggressive” Give Early “Aggressive” P l i i ?P l i i ?Parenteral Nutrition?Parenteral Nutrition?

•• Persistent concerns regarding protein Persistent concerns regarding protein intolerance and toxicityintolerance and toxicity

•• Potential adverse outcomes with early amino Potential adverse outcomes with early amino •• Potential adverse outcomes with early amino Potential adverse outcomes with early amino acids delivery to preterm infants (e.g. acids delivery to preterm infants (e.g. cholestasischolestasis) )

•• Until very recently few data to indicate that Until very recently few data to indicate that •• Until very recently, few data to indicate that Until very recently, few data to indicate that this strategy has longthis strategy has long--term benefit on growth term benefit on growth or developmental outcomesor developmental outcomes

Why Give Early “Aggressive” Why Give Early “Aggressive” Parenteral Amino Acid Nutrition?Parenteral Amino Acid Nutrition?

•• Cost Effective?Cost Effective?•• Minimal nutritional reserves in pretermsMinimal nutritional reserves in preterms•• Nationally and internationally we are Nationally and internationally we are •• Nationally and internationally we are Nationally and internationally we are

producing “producing “postnatalpostnatal growth retardationgrowth retardation” ” th t i t d b th ti f h it l th t i t d b th ti f h it l that is not reversed by the time of hospital that is not reversed by the time of hospital dischargedischarge

What Should be the Goals of What Should be the Goals of Early Parenteral Nutrition?Early Parenteral Nutrition?

•• Maximize growth and developmental Maximize growth and developmental outcomeoutcome

•• Define Define minimalminimal acceptable intakesacceptable intakesDefine Define minimalminimal acceptable intakesacceptable intakes•• Clarify Clarify maximalmaximal acceptable intakes: avoid acceptable intakes: avoid

t i t t i itt i t t i itnutrient toxicitynutrient toxicity•• Wean off parenteral amino acids to enteral Wean off parenteral amino acids to enteral

nutrition as soon as possiblenutrition as soon as possible

Our Approach to Early Our Approach to Early pp ypp yAggressive Parenteral NutritionAggressive Parenteral Nutrition

•• The Very Preterm Newborn:The Very Preterm Newborn:

A NUTRITIONAL EMERGENCYA NUTRITIONAL EMERGENCY•• A NUTRITIONAL EMERGENCYA NUTRITIONAL EMERGENCY•• Glucose stores of only 200 kcalGlucose stores of only 200 kcalGlucose stores of only 200 kcalGlucose stores of only 200 kcal•• CatabolicCatabolic: : net protein lossnet protein loss

••With IV glucose alone, lose 1% With IV glucose alone, lose 1% body protein/daybody protein/daybody protein/daybody protein/day

••10% loss of protein stores = 10% loss of protein stores = t i l t itit i l t itiprotein malnutritionprotein malnutrition

Protein Losses In Infants Receiving Protein Losses In Infants Receiving ggGlucose Without Amino AcidsGlucose Without Amino Acids

Gestational AgeGestational Age Protein Loss Protein Loss gg(g/kg/d)(g/kg/d)

TermTerm 0.70.7kk32 weeks32 weeks 1.11.1

26 weeks26 weeks 1 51 526 weeks26 weeks 1.51.5DenneDenne, JCI 1996; , JCI 1996;

ClarkClark PediatrPediatr Res 1997;Res 1997;Clark, Clark, PediatrPediatr Res 1997; Res 1997; Poindexter, Am J Poindexter, Am J PhysiolPhysiol 19971997

Our Primary Nutrition Goal in Very Our Primary Nutrition Goal in Very Preterm Infants is Protein AccretionPreterm Infants is Protein Accretion

•• There is increasing evidence that the amount of There is increasing evidence that the amount of protein intake early in life correlates with protein intake early in life correlates with improved developmental outcomeimproved developmental outcomep pp p

•• Protein gain is the best indicator of “real” Protein gain is the best indicator of “real” ththgrowthgrowth

•• Greatest rate of relative protein gain throughout Greatest rate of relative protein gain throughout p g gp g glife occurs prior to birthlife occurs prior to birth

Highest rate of protein gain/kg/d occurs priorHighest rate of protein gain/kg/d occurs priorto 32 weeks gestationto 32 weeks gestation MicheliMicheliet al,,In et al,,In ŅŅNutritional needs of Nutritional needs of

the preterm infant, Tsang, 1993the preterm infant, Tsang, 1993to 32 weeks gestationto 32 weeks gestation

*Protein Accretion*Protein Accretion*Protein Accretion*Protein Accretion

•• Protein deposition depends on:Protein deposition depends on:•• 1) Protein quantity and quality1) Protein quantity and quality

•• 2) Energy intake2) Energy intake

•• 3) Underlying disease state (sepsis)3) Underlying disease state (sepsis)•• 3) Underlying disease state (sepsis)3) Underlying disease state (sepsis)

•• 4) Medications (steroids, narcotics)4) Medications (steroids, narcotics)4) Medications (steroids, narcotics)4) Medications (steroids, narcotics)

Protein Quantity is the Primary Protein Quantity is the Primary Protein Quantity is the Primary Protein Quantity is the Primary Determinant of Protein AccretionDeterminant of Protein Accretion

•• MinimumMinimum Parenteral Amino Acid IntakeParenteral Amino Acid Intake•• Zero Balance (i.e. not catabolic) Zero Balance (i.e. not catabolic) •• Can be achieved with 1.0 Can be achieved with 1.0 -- 1.5 g/kg/d protein1.5 g/kg/d proteing/ g/ pg/ g/ p•• Initial goal of limiting catabolism and preserving Initial goal of limiting catabolism and preserving

endogenous protein stores can be easily endogenous protein stores can be easily endogenous protein stores can be easily endogenous protein stores can be easily accomplished if parenteral AAs are initiated on the accomplished if parenteral AAs are initiated on the first day of life in ELBW infants even if caloric first day of life in ELBW infants even if caloric first day of life in ELBW infants, even if caloric first day of life in ELBW infants, even if caloric intake is lowintake is low

Protein Quantity is the Primary Protein Quantity is the Primary Determinant of Protein AccretionDeterminant of Protein Accretion

•• MaximalMaximal Parenteral IntakeParenteral Intake•• Yet to be defined, limited by concerns of toxicityYet to be defined, limited by concerns of toxicity, y y, y y•• If goal is to achieve fetal delivery rates (Ziegler):If goal is to achieve fetal delivery rates (Ziegler):

••24 24 -- 25 weeks 25 weeks 3.75 3.75 -- 4.0 4.0 g/kg/d g/kg/d g/kg/d g/kg/d

••27 27 -- 28 weeks 28 weeks 3.5 g/kg/d3.5 g/kg/dg/ g/g/ g/••32 weeks 32 weeks 3.2 g/kg/d3.2 g/kg/d••Term infants Term infants 2.8 2.8 -- 3.0 g/kg/d3.0 g/kg/d

How Much Protein and How Quickly ? How Much Protein and How Quickly ? Are Early High Amino Acid Intakes Safe?Are Early High Amino Acid Intakes Safe?

•• Current markers used to determine parenteral Current markers used to determine parenteral amino acid intolerance:amino acid intolerance:

›› Metabolic acidosisMetabolic acidosis›› High ammonia concentrationHigh ammonia concentration›› Elevated blood urea nitrogen (BUN)Elevated blood urea nitrogen (BUN)›› Elevated blood urea nitrogen (BUN)Elevated blood urea nitrogen (BUN)›› Abnormal plasma amino acid levelsAbnormal plasma amino acid levelspp

•• **Reliable and sensitive markers of amino acid Reliable and sensitive markers of amino acid intolerance still need to be definedintolerance still need to be definedintolerance still need to be definedintolerance still need to be defined

How Much Protein and How Quickly ?How Much Protein and How Quickly ?“Low” “Low” vsvs “High” Amino Acid Intake Study“High” Amino Acid Intake Study

ThureenThureen et al, et al, PediatrPediatr Res 53, 2003Res 53, 2003

Hypothesis:Hypothesis:In ELBW infants in the first 48 hours of life receiving In ELBW infants in the first 48 hours of life receiving LowLow (1 g/kg/d) versus (1 g/kg/d) versus High High (3 g/kg/d) IV amino acid (3 g/kg/d) IV amino acid intake, the High intake would be:intake, the High intake would be:1) More efficacious (improved protein accretion) 1) More efficacious (improved protein accretion) 2) “Safe”: no significant acidosis, elevated2) “Safe”: no significant acidosis, elevated

BUN, abnormal amino acid concentrationsBUN, abnormal amino acid concentrationsBUN, abnormal amino acid concentrationsBUN, abnormal amino acid concentrations

Subject Demographic and Clinical FeaturesSubject Demographic and Clinical Features

1 g/kg/d1 g/kg/d 3 g/kg/d3 g/kg/d1 g/kg/d1 g/kg/d 3 g/kg/d3 g/kg/dNumber of infants Number of infants 1313 1515

Birth Wt (g)Birth Wt (g) 945 945 ++ 5252 947 947 ++ 6060

Gestational Age (wk)Gestational Age (wk) 27.3 27.3 ++ 0.40.4 27.0 27.0 ++ 0.6 0.6 g ( )g ( )

Birth to start of TPN (h)Birth to start of TPN (h) 22.6 22.6 ++ 3.5 3.5 26.0 26.0 ++ 3.03.0

Time on TPN at study (h)Time on TPN at study (h) 22.8 22.8 ++ 3.43.4 31.6 31.6 ++ 3.43.4

SNAP ScoreSNAP Score 10 3 10 3 ++ 1 01 0 10 4 10 4 ++ 1 31 3SNAP ScoreSNAP Score 10.3 10.3 ++ 1.01.0 10.4 10.4 ++ 1.31.3

NTISS ScoreNTISS Score 24.4 24.4 ++ 0.80.8 26.3 + 0.826.3 + 0.8

mean + sem, no significant differences between groups

2424--hour Nutrient Intake During Experimental Studyhour Nutrient Intake During Experimental Studyg p yg p y

1 g/kg/d1 g/kg/d 3 g/kg/d3 g/kg/d1 g/kg/d1 g/kg/d 3 g/kg/d3 g/kg/d

A i id ( /k /d)A i id ( /k /d) 0 85 0 85 0 080 08 2 65 2 65 0 13*0 13*Amino acids (g/kg/d)cAmino acids (g/kg/d)c 0.85 0.85 ++ 0.080.08 2.65 2.65 ++ 0.13*0.13*

l ( k )l ( k )Glucose (mg/kg/min)Glucose (mg/kg/min) 6.4 6.4 ++ 0.70.7 7.6 7.6 ++ 0.80.8

Lipid (g/kg/d)Lipid (g/kg/d) 2.00 2.00 ++ 0.090.09 1.58 1.58 ++ 0.090.09

NonNon--protein caloric protein caloric intake (kcal/kg/d)intake (kcal/kg/d)

41.5 41.5 ++ 3.73.7 49.1 49.1 ++ 4.34.3

mean + sem; *significant difference between groups. p<0.00001

Protein BalanceProtein BalanceBy Nitrogen Balance

1.5e

0

1

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Protein Balance By Leucine Stable Isotope Method

1.401.60

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Serum BUN

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Essential Amino AcidsEssential Amino Acids

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Study ConclusionsStudy ConclusionsStudy ConclusionsStudy Conclusions

•• Efficacy:Efficacy: ELBW neonates on 3 g/kg/d ELBW neonates on 3 g/kg/d parenteral amino acids immediately after birth parenteral amino acids immediately after birth parenteral amino acids immediately after birth parenteral amino acids immediately after birth have significantly greater rates of protein have significantly greater rates of protein accretion compared to those on 1 g/kg/daccretion compared to those on 1 g/kg/d

•• Safety:Safety: Based on BUN and plasma amino acid Based on BUN and plasma amino acid Safety:Safety: Based on BUN and plasma amino acid Based on BUN and plasma amino acid measurements, 3 g/kg/d amino acid IV amino measurements, 3 g/kg/d amino acid IV amino

id i t k t b t l t d i di t l id i t k t b t l t d i di t l acid intake appears to be tolerated immediately acid intake appears to be tolerated immediately after birth in ELBW neonatesafter birth in ELBW neonates

Benefits of Early Amino Acids Benefits of Early Amino Acids yyAdministration for LBW InfantsAdministration for LBW Infants

STUDYSTUDYAnderson (1979)Anderson (1979)

AA SOLUTIONAA SOLUTIONAminosynAminosyn( )( )

SainiSaini (1989)(1989)van van LingenLingen (1992)(1992)

yyVaminVamin--99AminovenousAminovenous

Rivera (1993)Rivera (1993)KashyapKashyap (1994)(1994)van van GoudoverGoudover (1995)(1995)

AminosynAminosyn--PFPFTrophamineTrophaminePrimenePrimenevan van GoudoverGoudover (1995)(1995)

ThureenThureen (1998)(1998)ThureenThureen (2003)(2003)

PrimenePrimeneTrophamineTrophamineTrophamineTrophamine

Ibrahim (2004)Ibrahim (2004)tete BraakeBraake (2005)(2005)

ppTrophamineTrophaminePrimenePrimene

Outcomes with EarlyOutcomes with Early Amino AcidsAmino Acidsyy

•• The majority of reported positive outcomes are The majority of reported positive outcomes are from studies showing from studies showing gg

1) short1) short--term increase in nitrogen term increase in nitrogen balance balance balance balance 2) evidence of growth2) evidence of growth

P i d t t l J P di t 2006 Di t i t l J P i t l 2006P i d t t l J P di t 2006 Di t i t l J P i t l 2006Poindexter et al, J Pediatr 2006, Dinerstein et al, J Perinatol, 2006Poindexter et al, J Pediatr 2006, Dinerstein et al, J Perinatol, 2006

•• Retrospective and prospective studies: Retrospective and prospective studies: ›› 1) shorter time to regain birth weight 1) shorter time to regain birth weight ›› 1) shorter time to regain birth weight 1) shorter time to regain birth weight ›› 2) suggestion of lower incidence of BPD with early 2) suggestion of lower incidence of BPD with early

amino acidsamino acids Ho MY et al, Nutrition, 2003; Porcelli,JPGN, 2002Ho MY et al, Nutrition, 2003; Porcelli,JPGN, 2002, , ; , ,, , ; , ,

Outcomes with EarlyOutcomes with Early Amino AcidsAmino AcidsOutcomes with EarlyOutcomes with Early Amino AcidsAmino AcidsNICHD StudiesNICHD Studies

•• “Early Provision of Parenteral Amino Acids “Early Provision of Parenteral Amino Acids Early Provision of Parenteral Amino Acids Early Provision of Parenteral Amino Acids in ELBW Infants: Relationship to Growth in ELBW Infants: Relationship to Growth and Neurodevelopmental Outcome at 18 and Neurodevelopmental Outcome at 18 ppMonths Corrected Age” Months Corrected Age”

•• Initially suggested improved Initially suggested improved y gg py gg pneurodevelopmental outcomes, but not neurodevelopmental outcomes, but not borne out in final analysesborne out in final analyses

•• Poindexter, J Pediatr 2006Poindexter, J Pediatr 2006

Parenteral AA Intakeover the first 20 days of life3 5

over the first 20 days of life

33.0

3.5

/kg/

d)pe

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0 5 10 200.0

0 2 4 6 8 10 12 14 16 18 20A ge (days)

From: Poindexter, J Pediatr From: Poindexter, J Pediatr 20062006

Growth at 36 weeks CA in ELBW Growth at 36 weeks CA in ELBW Infants Stratified by Early or Late AAsInfants Stratified by Early or Late AAs

EarlyEarly( 182)( 182)

LateLate( 836)( 836)

pp--value orvalue orOROR(n=182)(n=182) (n=836)(n=836) OROR

Weight (g)Weight (g) 1958 1958 ±± 383383 1819 1819 ±± 320320 p<0.0001p<0.0001Weight (g)Weight (g) 1958 1958 ±± 383383 1819 1819 ±± 320320 p<0.0001p<0.0001

Wt <10thWt <10th 127 (82%)127 (82%) 681 (95%)681 (95%) OR 4.2OR 4.2( )( ) 681 (95%)681 (95%)

Length(cm)Length(cm) 41.7 41.7 ±± 2.72.7 41.0 41.0 ±± 2.32.3 p= 0.0108p= 0.0108

HC (cm)HC (cm) 30.9 30.9 ±± 1.81.8 30.3 30.3 ±± 1.61.6 p<0.0001p<0.0001

From: Poindexter, J From: Poindexter, J PediatrPediatr 20062006

Growth at 18Growth at 18--22 months CA in ELBW 22 months CA in ELBW Infants Stratified by Early or Late AAsInfants Stratified by Early or Late AAs

EarlyEarly(n=182)(n=182)

LateLate(n=836)(n=836)

pp--value orvalue orOR (95% CI)OR (95% CI)(n=182)(n=182) (n=836)(n=836) OR (95% CI)OR (95% CI)

Weight (kg)Weight (kg) 10.7 10.7 ±± 1.51.5 10.5 10.5 ±± 1.51.5 NSNSg ( g)g ( g)Wt <10thWt <10th 70 (47%)70 (47%) 311 (44%)311 (44%) 0.9 (0.60.9 (0.6--1.4)1.4)Length(cm)Length(cm) 81.0 81.0 ±± 3.93.9 80.8 80.8 ±± 3.93.9 NSNS

HC (cm)HC (cm) 47.1 47.1 ±± 1.91.9 46.8 46.8 ±± 2.02.0 NSNSHC < 5thHC < 5th 15 (10%)15 (10%) 124 (17%)124 (17%) 2 22 2 (1 2(1 2 4 1)4 1)HC < 5thHC < 5th 15 (10%)15 (10%) 124 (17%)124 (17%) 2.22.2 (1.2(1.2--4.1)4.1)

At 18 months CA there were no differences in weight, length or neurodevelopment.At 18 months CA there were no differences in weight, length or neurodevelopment.

Poindexter, J Pediatr 2006Poindexter, J Pediatr 2006

g gg gHowever, males in the late group were twice as likely to have head circumference <10th %.However, males in the late group were twice as likely to have head circumference <10th %.

Effect of Amino Acid Intake on Effect of Amino Acid Intake on HyperglycemiaHyperglycemia

•• In our 1 In our 1 vsvs 3 g/kg/d amino acid intake study, insulin 3 g/kg/d amino acid intake study, insulin concentrations correlated with amino acid intake.concentrations correlated with amino acid intake.

•• Our incidence of neonatal hyperglycemia has Our incidence of neonatal hyperglycemia has dramatically decreased since starting early parenteral dramatically decreased since starting early parenteral dramatically decreased since starting early parenteral dramatically decreased since starting early parenteral amino acids.amino acids.

•• Though correlation of decreased incidence of Though correlation of decreased incidence of •• Though correlation of decreased incidence of Though correlation of decreased incidence of hyperglycemia with increased amino acid intake has hyperglycemia with increased amino acid intake has been noted the only publication regarding this was been noted the only publication regarding this was been noted, the only publication regarding this was been noted, the only publication regarding this was reported by reported by MicheliMicheli et al, 1994.et al, 1994.

Number of infants < 1000 g

50

60with hyperglycemia Š hyperkalemia

41% 34% 43% 5% 7% 0%

40

50 41% 34% 43% 5% 7% 0%

20

30

10

20

01988 1989 1990 1991 1992 1993

simple glucose infusion amino acids + glucosep g g

Micheli et al, Seminars in Neonatal Nutrition and Metabolism, 1994

Controversies and Unresolved Issues with Controversies and Unresolved Issues with Early Amino Acids in Preterm InfantsEarly Amino Acids in Preterm Infants

•• TPN IssuesTPN Issues

d d l dd d l d›› Current and ideal amino acid Current and ideal amino acid solutionssolutions

›› Conditionally essential amino acidsConditionally essential amino acidsM k f A i A id T i iM k f A i A id T i i•• Markers of Amino Acid ToxicityMarkers of Amino Acid Toxicity

•• TPN complicationsTPN complicationspp

›› Role of TPN in CholestasisRole of TPN in Cholestasis

Quality of Parenteral AA Intake Quality of Parenteral AA Intake yyto Maximize Protein growthto Maximize Protein growth

••Maximal protein accretion depends on providing the Maximal protein accretion depends on providing the “ f t b l ” f i id“ f t b l ” f i id“perfect balance” of amino acids“perfect balance” of amino acids••The optimal ratio of all amino acids in parenteral The optimal ratio of all amino acids in parenteral

t iti f th t i f t i kt iti f th t i f t i knutrition of the preterm infant is unknownnutrition of the preterm infant is unknown••In theory, deficiency of one essential amino acid willIn theory, deficiency of one essential amino acid will

•• limit overall protein synthesis, andlimit overall protein synthesis, and•• all other amino acids will be in relative excess and all other amino acids will be in relative excess and will be preferentially oxidized (used for energy)will be preferentially oxidized (used for energy)

Essential Amino Acids

400 ELBW, 3 g/kg/d AA, g gCetin et al, Fetal 2nd TrimesterCetin et al, Fetal 3rd Trimester

ol/L

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300

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Neonatal Amino Acid SolutionsNeonatal Amino Acid SolutionsNeonatal Amino Acid SolutionsNeonatal Amino Acid Solutions

Three “generations” of development:Three “generations” of development:g pg p1)1) Casein Casein hydrolysateshydrolysates2)2) C t lli i id i t C t lli i id i t 2)2) Crystalline amino acid mixtures Crystalline amino acid mixtures

((AminosynAminosyn, , FreAmineFreAmine III, III, TravasolTravasol))3)3) Special pediatric preparations of the Special pediatric preparations of the

crystalline amino acids (crystalline amino acids (AminosynAminosynPF, PF, TrophamineTrophamine, , PrimenePrimene, , NeophamNeopham))

**None of the above specifically designed for the None of the above specifically designed for the p y gp y gELBW infantELBW infant

Neonatal Amino Acid SolutionsNeonatal Amino Acid SolutionsNeonatal Amino Acid SolutionsNeonatal Amino Acid Solutions

••TrophamineTrophamine ((PremasolPremasol identical in composition)identical in composition)

••originally formulated to produce plasma amino acid originally formulated to produce plasma amino acid ••originally formulated to produce plasma amino acid originally formulated to produce plasma amino acid concentrations of healthy, term, breastconcentrations of healthy, term, breast--fed infantsfed infants

••AminosynAminosyn PFPF••AminosynAminosyn--PFPF••designed to produce AA levels within a normal range of designed to produce AA levels within a normal range of concentrations from breastconcentrations from breast fed + fed + parenterallyparenterally fed infantsfed infantsconcentrations from breastconcentrations from breast--fed + fed + parenterallyparenterally--fed infantsfed infants

••PrimenePrimened i d f f t l d t l d bl d i id d i d f f t l d t l d bl d i id ••derived from fetal and neonatal cord blood amino acid derived from fetal and neonatal cord blood amino acid

concentrationsconcentrations

Essential or “Indispensable” AACannot be synthesized by humans so must be addedCannot be synthesized by humans so must be added

AminosynAminosyn--PFPF(Abbott)(Abbott)

Trophamine Trophamine (B Braun)(B Braun)

PrimenePrimene(Baxter)(Baxter)(Abbott)(Abbott) (B. Braun)(B. Braun) (Baxter)(Baxter)

ValineValine 673673 780780 760760L iL i 12001200 14001400 10001000LeucineLeucine 12001200 14001400 10001000IsoleucineIsoleucine 760760 820820 670670ThreonineThreonine 512512 420420 370370PhenylalaninePhenylalanine 427427 480480 420420MethionineMethionine 180180 340340 240240LysineLysine 677677 820820 11001100HistidineHistidine 312312 480480 380380TryptophanTryptophan 312312 480480 380380yptop ayptop a 33 8080 380380

AA conc. in mg/dL; AA mixtures shown are 10% solutions

NonNon--Essential AAEssential AACan be synthesized from other amino acidsCan be synthesized from other amino acidsCan be synthesized from other amino acids Can be synthesized from other amino acids

or from other precursorsor from other precursors

AminosynAminosyn--PFPF

TrophaminTrophaminee

PrimenePrimene

SerineSerine 495495 380380 400400

GlycineGlycine 385385 360360 400400

AlanineAlanine 698698 540540 800800

TyrosineTyrosine 4444 240*240* 4545

GlutamineGlutamine 820820 500500 10001000

Glutamic Glutamic idid

-- -- --acidacidAspartic Aspartic acidacid

527527 320320 320320

AsparagineAsparagine -- --AA conc. in mg/dL; AA mixtures shown are 10% solutions

Conditionally Essential or “SemiConditionally Essential or “Semi--Essential” AAEssential” AAyyThese are nonThese are non--essential AAs that become essential AAs that become

essential under certain circumstances (essential under certain circumstances (e.g.sepsise.g.sepsis))These amino acids can be synthesized from other AAsThese amino acids can be synthesized from other AAsThese amino acids can be synthesized from other AAsThese amino acids can be synthesized from other AAs

AminosynAminosyn--PFPF TrophamineTrophamine PrimenePrimeneAminosynAminosyn PFPF TrophamineTrophamine PrimenePrimeneGlycineGlycine 385385 360360 400400

*Proline*Proline 812812 680680 300300ProlineProline 812812 680680 300300

**ArginineArginine 12271227 12001200 840840

TyrosineTyrosine 4444 240*240* 4545TyrosineTyrosine 4444 240240 4545

CysteineCysteine -- <16<16 189189

?T i?T i 7070 2525 6060?Taurine?Taurine 7070 2525 6060

*Some debate exists about the conditional essentiality of*Some debate exists about the conditional essentiality of argininearginine andand prolineprolineAA conc. in mg/dL; AA mixtures shown are 10% solutions

Some debate exists about the conditional essentiality of Some debate exists about the conditional essentiality of argininearginine and and prolineproline

“Stock” or “Starter” “Stock” or “Starter” Amino Acid (AA) SolutionsAmino Acid (AA) Solutions

••ParenteralParenteral AA and Dextrose SolutionAA and Dextrose Solution••Once prepared it is stable for up to two Once prepared it is stable for up to two

weeks if refrigerated and with no vitamins, weeks if refrigerated and with no vitamins,

minerals or lipids addedminerals or lipids addedminerals or lipids addedminerals or lipids added

••We use as initial intravenous fluid after birthWe use as initial intravenous fluid after birthWe use as initial intravenous fluid after birthWe use as initial intravenous fluid after birth

Example “Stock” or “Starter” Example “Stock” or “Starter” Amino Acid (AA) SolutionsAmino Acid (AA) Solutions

2% AA in D10W at 60 2% AA in D10W at 60 mLmL//kg/d //kg/d ⇒⇒ 1.2 g/kg/d 1.2 g/kg/d AA AA

2% AA in D10W at 80 2% AA in D10W at 80 mLmL//kg/d //kg/d ⇒⇒ 1.6 g/kg/d 1.6 g/kg/d AA AA

5% AA in D7 5W at 60 5% AA in D7 5W at 60 mLmL//kg/d //kg/d ⇒⇒ 3 0 g/kg/d 3 0 g/kg/d 5% AA in D7.5W at 60 5% AA in D7.5W at 60 mLmL//kg/d //kg/d ⇒⇒ 3.0 g/kg/d 3.0 g/kg/d AAAA••If you start with 5% AA you can’t increase the fluid If you start with 5% AA you can’t increase the fluid rate!rate!••Additional fluids can be coAdditional fluids can be co--infused if glucose infused if glucose and/or electrolyte requirements changeand/or electrolyte requirements changeand/or electrolyte requirements changeand/or electrolyte requirements change

Complications of Parenteral Nutrition:Complications of Parenteral Nutrition:ppParenteral Nutrition Associated Parenteral Nutrition Associated CholestasisCholestasis (PNAC)(PNAC)

•• Etiology of PNAC is unknown and likely to be Etiology of PNAC is unknown and likely to be multifactorialmultifactorialmultifactorialmultifactorial

•• Risk Factors:Risk Factors:Y t ti l Y t ti l ›› Younger gestational ageYounger gestational age

»» Significantly increased if infants <1000g at birthSignificantly increased if infants <1000g at birth›› Duration of TPN Duration of TPN ›› Duration of TPN Duration of TPN ›› Perhaps earlier initiation of TPNPerhaps earlier initiation of TPN

Absence of enteral feedingAbsence of enteral feeding›› Absence of enteral feedingAbsence of enteral feeding›› Sepsis, cholangitis, bacterial translocationSepsis, cholangitis, bacterial translocation

Parenteral Nutrition Associated Parenteral Nutrition Associated CholestasisCholestasis(PNAC)(PNAC)

•• Risk Factors: “Could lipid infusion be a risk Risk Factors: “Could lipid infusion be a risk f t l t itif t l t iti i t d h l t i i t d h l t i for parenteral nutritionfor parenteral nutrition--associated cholestasis associated cholestasis in LBW infants?”in LBW infants?” Eur J Pediatr, 2007Eur J Pediatr, 2007•• Significant correlation with duration of TPN, Significant correlation with duration of TPN,

duration of fasting, days of antibiotic use, duration of fasting, days of antibiotic use, iti Citi C ti t i t t l i id i t k ti t i t t l i id i t k positive Cpositive C--reative protein, total amino acid intake, reative protein, total amino acid intake,

and total lipid intakeand total lipid intake•• Prenatal desamethasone was a significant Prenatal desamethasone was a significant •• Prenatal desamethasone was a significant Prenatal desamethasone was a significant

protective factor for PNACprotective factor for PNAC

PNACPNACPotential Predisposing Factors/CausesPotential Predisposing Factors/Causes

•• Immaturity of the neonatal liver and GI Immaturity of the neonatal liver and GI tracttracttracttract•• Reduced total bile salt pool in preterm neonatesReduced total bile salt pool in preterm neonates•• D d h ti t k d th i f bil D d h ti t k d th i f bil •• Decreased hepatic uptake and synthesis of bile Decreased hepatic uptake and synthesis of bile

saltssalts•• Reduced enterohepatic circulationReduced enterohepatic circulation•• Reduced enterohepatic circulationReduced enterohepatic circulation•• Deficient sulfation (important step in the Deficient sulfation (important step in the

solubilization of toxic bile salts)solubilization of toxic bile salts)solubilization of toxic bile salts)solubilization of toxic bile salts)

PNACPNACToxicity of TPN componentsToxicity of TPN components

•• Animal studies:Animal studies:•• Decreased bile flow with glucose infusionsDecreased bile flow with glucose infusions•• CholestaticCholestatic effect of amino acid infusions (esp. effect of amino acid infusions (esp.

methioninemethionine, sulfur containing amino acids), sulfur containing amino acids)•• Ch liCh li d fi i d fi i t t it t i i ti t•• CholineCholine deficiency causes deficiency causes steatosissteatosis in ratsin rats

•• Human studiesHuman studies•• Hepatic dysfunction with infusion of excessive caloriesHepatic dysfunction with infusion of excessive calories•• Hepatic dysfunction with infusion of excessive caloriesHepatic dysfunction with infusion of excessive calories•• CholestaticCholestatic effect of amino acid infusions (tryptophan, effect of amino acid infusions (tryptophan,

methioninemethionine, excess , excess homocystinehomocystine) ) ,, yy ))•• Impaired bilirubin excretion in adults receiving high dose Impaired bilirubin excretion in adults receiving high dose

intravenous lipidsintravenous lipids•• Free radical production is increased by administration of Free radical production is increased by administration of

TPN in infantsTPN in infants

PNACPNACPotential Therapies in NeonatesPotential Therapies in Neonates

•• Parenteral taurine supplementation in specific Parenteral taurine supplementation in specific subgroups of neonatal patientssubgroups of neonatal patients:: JPEN 2005JPEN 2005subgroups of neonatal patientssubgroups of neonatal patients:: JPEN, 2005JPEN, 2005

•• Significantly reduced PNAC in neonates with NECSignificantly reduced PNAC in neonates with NEC•• Demonstrated a trend to decreased incidence of Demonstrated a trend to decreased incidence of •• Demonstrated a trend to decreased incidence of Demonstrated a trend to decreased incidence of

PNAC in preterm infants versus those without PNAC in preterm infants versus those without taurine supplementationtaurine supplementationpppp

•• Conclusions: Infants with NEC or severe Conclusions: Infants with NEC or severe prematurity are most likely to benefit from taurine prematurity are most likely to benefit from taurine supplementationsupplementation

PNACPNACPotential TherapiesPotential Therapies

•• Avoid glucose overloadAvoid glucose overload•• E l d t ti d t t t f i f tiE l d t ti d t t t f i f ti•• Early detection and treatment of infectionsEarly detection and treatment of infections•• Oral refeeding as soon as possibleOral refeeding as soon as possible•• Ursodeoxycholic Acid (UDCA)Ursodeoxycholic Acid (UDCA) Chen, et al Pediatr Chen, et al Pediatr

2004;3172004;317

•• Prevent free radical production (cover lipid and Prevent free radical production (cover lipid and TPN to avoid photoTPN to avoid photo--oxidation)oxidation)pp ))

•• Increase antiIncrease anti--oxidant capacities of TPN oxidant capacities of TPN solutionssolutionssolutionssolutions

Toxicity of Early Amino Acids Toxicity of Early Amino Acids I BUN A i t M k f D t i i I BUN A i t M k f D t i i Is BUN an Appropriate Marker for Determining Is BUN an Appropriate Marker for Determining

Protein Intolerance?Protein Intolerance?

•• Blood urea nitrogen (BUN) may increase when Blood urea nitrogen (BUN) may increase when administered protein is not completely utilized. administered protein is not completely utilized. This may be accompanied by hyperammonemia This may be accompanied by hyperammonemia This may be accompanied by hyperammonemia This may be accompanied by hyperammonemia (?“Bad BUN”)(?“Bad BUN”)H d i l b bH d i l b b•• However, urea production may also be a byHowever, urea production may also be a by--product of amino acid oxidation (i.e. amino acids product of amino acid oxidation (i.e. amino acids are used as an energy source) (?“Good BUN”)are used as an energy source) (?“Good BUN”)

Fetal Amino Acid (AA) Fetal Amino Acid (AA) MetabolismMetabolism

•• Fetal AA uptake from the placenta greatly Fetal AA uptake from the placenta greatly exceeds protein accretion requirementsexceeds protein accretion requirementsexceeds protein accretion requirementsexceeds protein accretion requirements

•• Excess fetal AA can be used as an energy source Excess fetal AA can be used as an energy source ( id ti )( id ti )(oxidation)(oxidation)

•• It is estimated that 25It is estimated that 25--50% of energy in the fetal 50% of energy in the fetal gygysheep comes from oxidation of AAsheep comes from oxidation of AA

•• Animal and human studies show that the normal Animal and human studies show that the normal •• Animal and human studies show that the normal Animal and human studies show that the normal fetus produces BUN at a high levelfetus produces BUN at a high level

Human Neonatal Amino Acid Human Neonatal Amino Acid (AA) Metabolism(AA) Metabolism

•• In our studies, there is evidence that ELBW In our studies, there is evidence that ELBW neonates who do not tolerate glucose and lipid neonates who do not tolerate glucose and lipid neonates who do not tolerate glucose and lipid neonates who do not tolerate glucose and lipid (i.e., high serum glucose and triglyceride levels (i.e., high serum glucose and triglyceride levels

t l l d li id i t k ) i t l l d li id i t k ) i at low glucose and lipid intakes) may use amino at low glucose and lipid intakes) may use amino acids as an energy source acids as an energy source

•• In this case, elevated BUN may reflect a In this case, elevated BUN may reflect a beneficial utilization of AA for energy and not beneficial utilization of AA for energy and not gygyintolerance of protein intakeintolerance of protein intake

Predictors of Increased BUNPredictors of Increased BUNPredictors of Increased BUNPredictors of Increased BUNRidoutRidout E, E, ThureenThureen P et al, Journal of P et al, Journal of PerinatologyPerinatology, December, 2004, December, 2004

••Retrospective review of 4 studies of Retrospective review of 4 studies of ppBUN concentrations in parenterally BUN concentrations in parenterally f d t i th fi t 3 d f f d t i th fi t 3 d f fed neonates in the first 3 days of fed neonates in the first 3 days of life:life:life:life:

••122 neonates, 137 BUN values122 neonates, 137 BUN values••Mean GA: 27.8 Mean GA: 27.8 ++ 1.8 weeks1.8 weeks••M BWt 982 M BWt 982 ++ 247 247 ••Mean BWt: 982 Mean BWt: 982 ++ 247 g247 g

Effect of Amino Acid Intake on BUNEffect of Amino Acid Intake on BUN

45

35

40

/d/d))

25

30

mg/

kg/

mg/

kg/

15

20

BUN

(mBU

N (m

5

10

BUN = 21 + 1.1AA Intake2 P value = NSP value = NS

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.00

r2 = 0.01

Amino Acid Intake (g/kg/dAmino Acid Intake (g/kg/d))

P value NSP value NS

Amino Acid Intake (g/kg/dAmino Acid Intake (g/kg/d))Adapted from: Ridout, et al. Journal of Perinatology 25:130, Adapted from: Ridout, et al. Journal of Perinatology 25:130, 20052005

ConclusionsConclusionsConclusionsConclusions

•• Early parenteral amino acid nutrition in very Early parenteral amino acid nutrition in very y p yy p ypreterm neonates is associated with both preterm neonates is associated with both desirable and adverse outcomesdesirable and adverse outcomesdesirable and adverse outcomesdesirable and adverse outcomes

•• There are still many unanswered questions There are still many unanswered questions di th t d ti d id ldi th t d ti d id lregarding the amount, duration and ideal regarding the amount, duration and ideal

composition of parenteral amino acid composition of parenteral amino acid solutions in very preterm neonatessolutions in very preterm neonates