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 Acids in the Preterm Infant During the First Week of Life BAPEN Leeds, November 27, 2007 Patti Thureen, MD, Professor of Pediatrics University of Colorado Health Sciences Center and the Children s Hospital of Denver patti.thureen@uchsc.edu Financial Disclosures: No relevant financial relationships with any commercial interests
Objectives Discuss the arguments for and against early amino acid nutrition in preterm infants Review the safety and efficacy of Early Aggressive Parenteral Amino Acid Nutrition Discuss new data on benefits of early amino acids Present controversies and unresolved issues with early parenteral amino acid administration in preterm infants
Why Not Give Early Aggressive Parenteral Nutrition? i Persistent concerns regarding protein intolerance and toxicity Potential adverse outcomes with early amino acids delivery to preterm infants (e.g. cholestasis) Until very recently, few data to indicate that this strategy has long-term benefit on growth or developmental outcomes
Why Give Early Aggressive Parenteral Amino Acid Nutrition? Cost Effective? Minimal nutritional reserves in preterms Nationally and internationally we are producing postnatal growth retardation that t is not reversed by the time of hospital discharge
What Should be the Goals of Early Parenteral Nutrition? Maximize growth and developmental outcome Define minimal acceptable intakes Clarify maximal acceptable intakes: avoid nutrient t toxicity it Wean off parenteral amino acids to enteral nutrition as soon as possible
Our Approach to Early Aggressive Parenteral Nutrition The Very Preterm Newborn: A NUTRITIONAL EMERGENCY Glucose stores of only 200 kcal Catabolic: net protein loss With IV glucose alone, lose 1% body protein/day 10% loss of protein stores = protein malnutrition
Protein Losses In Infants Receiving Glucose Without Amino Acids Gestational Age (g/kg/d) Protein Loss Term 0.7 32 weeks 1.1 26 weeks 15 1.5 Denne, JCI 1996; Clark, Pediatr Res 1997; Poindexter, Am J Physiol 1997
Our Primary Nutrition Goal in Very Preterm Infants is Protein Accretion There is increasing evidence that the amount of protein intake early in life correlates with improved developmental outcome Protein gain is the best indicator of real growth Greatest rate of relative protein gain throughout life occurs prior to birth
Highest rate of protein gain/kg/d occurs prior to 32 weeks gestation Nutritional needs of Micheliet et al,,in ŅNutritional needs of the preterm infant, Tsang, 1993
*Protein Accretion Protein deposition depends on: 1) Protein quantity and quality 2) Energy intake 3) Underlying disease state (sepsis) 4) Medications (steroids, narcotics)
Protein Quantity is the Primary Determinant of Protein Accretion Minimum Parenteral Amino Acid Intake Zero Balance (i.e. not catabolic) Can be achieved with 1.0-1.5 g/kg/d protein Initial goal of limiting catabolism and preserving endogenous protein stores can be easily accomplished if parenteral AAs are initiated on the first day of life in ELBW infants, even if caloric intake is low
Protein Quantity is the Primary Determinant of Protein Accretion Maximal Parenteral Intake Yet to be defined, limited by concerns of toxicity If goal is to achieve fetal delivery rates (Ziegler): 24-25 weeks 3.75-4.0 g/kg/d 27-28 weeks 3.5 g/kg/d 32 weeks 3.2 g/kg/d Term infants 2.8-3.0 g/kg/d
How Much Protein and How Quickly? Are Early High Amino Acid Intakes Safe? Current markers used to determine parenteral amino acid intolerance: Metabolic acidosis High ammonia concentration Elevated blood urea nitrogen (BUN) Abnormal plasma amino acid levels *Reliable and sensitive markers of amino acid intolerance still need to be defined
How Much Protein and How Quickly? Low vs High Amino Acid Intake Study Hypothesis: Thureen et al, Pediatr Res 53, 2003 In ELBW infants in the first 48 hours of life receiving Low (1 g/kg/d) versus High (3 g/kg/d) IV amino acid intake, the High intake would be: 1) More efficacious (improved protein accretion) 2) Safe : no significant acidosis, elevated BUN, abnormal amino acid concentrations
Subject Demographic and Clinical Features 1 g/kg/d 3 g/kg/d Number of infants 13 15 Birth Wt (g) 945 + 52 947 + 60 Gestational Age (wk) 27.3 + 0.4 27.0 + 0.6 Birth to start of TPN (h) 22.6 + 3.5 26.0 + 3.0 Time on TPN at study (h) 22.8 + 3.4 31.6 + 3.4 SNAP Score 10.3 + 10 1.0 10.4 + 13 1.3 NTISS Score 24.4 + 0.8 26.3 + 0.8 mean + sem, no significant differences between groups
24-hour Nutrient Intake During Experimental Study 1 g/kg/d 3 g/kg/d Amino acids (g/kg/d)c /d) 0.85 + 008 0.08 2.65 + 0.13* Glucose (mg/kg/min) 6.4 + 0.7 7.6 + 0.8 Lipid (g/kg/d) 2.00 + 0.09 1.58 + 0.09 Non-protein caloric intake (kcal/kg/d) 41.5 + 3.7 49.1 + 4.3 mean + sem; *significant difference between groups. p<0.00001
Protein Balance By Nitrogen Balance 1.5 alance d) gen Ba g/kg/d Nitrog (g 1 0.5 0-0.5 p=0.010 010 1 1 gm/kg/d 3 gm/kg/d -1 AA Intake
Protein Balance By Leucine 1.60 Stable Isotope Method Protei n Bal ance (gm m/kg/d d) 1.40 1.20 100 1.00 0.80 060 0.60 0.40 0.20 p=0.007 007 1.0 gm/kg/d 3.0 gm/kg/d 0.00 1 AA Intake
Serum BUN 40.0 0 UN mg/d l 30.0 20.0 p=0 0.232 1 1 1g/kg/d 3g/kg/d B 10.0 0 0 0.0 1 AA Intake
Essential Amino Acids ** 1 g/kg/d amino acid intake 3 g/kg/d amino acid intake id Conce entration n (umol/m ml) Am mino Ac 200 100 ** ns ** ** ** ns * * p<0.05 ** p<0.005 0 VAL LEU ILEU THR PHE MET LYS HIS
Essential Amino Acids Amino Ac cid Conce entration n (umol/l L) 400 ELBW, 3 g/kg/d AA Cetin et al, Fetal 2nd Trimester Cetin et al, Fetal 3rd Trimester 300 200 100 0 VAL LEU ILEU THR PHE MET LYS HIS
Study Conclusions Efficacy: ELBW neonates on 3 g/kg/d parenteral amino acids immediately after birth have significantly greater rates of protein accretion compared to those on 1 g/kg/d Safety: Based on BUN and plasma amino acid measurements, 3 g/kg/d amino acid IV amino acid intake appears to be tolerated t immediately after birth in ELBW neonates
Benefits of Early Amino Acids Administration for LBW Infants STUDY Anderson (1979) Saini (1989) van Lingen (1992) Rivera (1993) Kashyap (1994) van Goudover (1995) Thureen (1998) Thureen (2003) Ibrahim (2004) te Braake (2005) AA SOLUTION Aminosyn Vamin-9 Aminovenous Aminosyn-PF Trophamine Primene Trophamine Trophamine Trophamine Primene
Outcomes with Early Amino Acids The majority of reported positive outcomes are from studies showing 1) short-term term increase in nitrogen balance 2) evidence of growth Poindexter et al, J Pediatr 2006, Dinerstein i et al, J Perinatol, 2006 Retrospective and prospective studies: 1) shorter time to regain birth weight 2) suggestion of lower incidence of BPD with early amino acids Ho MY et al, Nutrition, 2003; Porcelli,JPGN,, 2002
Outcomes with Early Amino Acids NICHD Studies Early Provision of Parenteral Amino Acids in ELBW Infants: Relationship to Growth and Neurodevelopmental Outcome at 18 Months Corrected Age Initially suggested improved neurodevelopmental outcomes, but not borne out in final analyses Poindexter, J Pediatr 2006
Parenteral AA Intake over the first 20 days of life 3.5 Pare enteral AA Intake (g/ /kg/d) Grams per kilo per day 3.03 2.5 2.02 1.5 1.01 1 Early A A Late AA 0.5 0.00 5 10 0 2 4 6 8 10 12 14 16 18 20 20 A ge (days) Days of life From: Poindexter, J Pediatr 2006
Growth at 36 weeks CA in ELBW Infants Stratified by Early or Late AAs Early (n=182) Late (n=836) p-value or OR Weight (g) 1958 1958 ± 383 Wt <10th 127 (82%) 383 1819 ± 320 p<0.0001 127 (82%) 681 (95%) OR 4.2 Length(cm) 41.7 ± 2.7 41.0 ±2.3 p= 0.0108 HC (cm) 30.9 ± 1.8 30.3 ±1.6 p<0.0001 From: Poindexter, J Pediatr 2006
Growth at 18-22 months CA in ELBW Infants Stratified by Early or Late AAs Early (n=182) Late (n=836) p-value or OR (95% CI) Weight (kg) 10.7 ±1.5 10.5 ±1.5 NS Wt <10th 70 (47%) 311 (44%) 0.9 (0.6-1.4) Length(cm) 81.0 ±3.9 80.8 ±3.9 NS HC (cm) 47.1 ±1.9 46.8 ±2.0 NS HC < 5th 15 (10%) 124 (17%) 22(1 2.2 (1.2-4.1) 41) At 18 months CA there were no differences in weight, length or neurodevelopment. However, males in the late group were twice as likely to have head circumference <10th %. Poindexter, J Pediatr 2006
Effect of Amino Acid Intake on Hyperglycemia In our 1 vs 3 g/kg/d amino acid intake study, insulin concentrations correlated with amino acid intake. Our incidence of neonatal hyperglycemia has dramatically decreased since starting early parenteral amino acids. Though correlation of decreased incidence of hyperglycemia with increased amino acid intake has been noted, the only publication regarding this was reported by Micheli et al, 1994.
Number of infants < 1000 g 60 with hyperglycemia Š hyperkalemia 50 41% 34% 43% 5% 7% 0% 40 30 20 10 0 1988 1989 1990 1991 1992 1993 simple glucose infusion amino acids + glucose Micheli et al, Seminars in Neonatal Nutrition and Metabolism, 1994
Controversies and Unresolved Issues with Early Amino Acids in Preterm Infants TPN Issues Current and ideal amino acid solutions Conditionally essential amino acids Markers of Amino Acid Toxicity i TPN complications Role of TPN in Cholestasis
Quality of Parenteral AA Intake to Maximize Protein growth Maximal protein accretion depends on providing the perfect balance of amino acids The optimal ratio of all amino acids in parenteral nutrition of the preterm infant is unknown In theory, deficiency of one essential amino acid will limit overall protein synthesis, and all other amino acids will be in relative excess and will be preferentially oxidized (used for energy)
Essential Amino Acids Amino Acid Co oncentrat tion (umo ol/l) 400 ELBW, 3 g/kg/d g AA Cetin et al, Fetal 2nd Trimester Cetin et al, Fetal 3rd Trimester 300 200 100 0 VAL LEU ILEU THR PHE MET LYS HIS
Neonatal Amino Acid Solutions Three generations of development: 1) Casein hydrolysates 2) Crystalline amino acid mixtures (Aminosyn, FreAmine III, Travasol) 3) Special pediatric preparations of the crystalline amino acids (Aminosyn PF, Trophamine, Primene, Neopham) *None of the above specifically designed for the ELBW infant
Neonatal Amino Acid Solutions Trophamine (Premasol identical in composition) originally formulated to produce plasma amino acid concentrations of healthy, term, breast-fed infants Aminosyn Aminosyn-PF designed to produce AA levels within a normal range of concentrations from breast-fed + parenterally-fed infants Primene derived d from fetal and neonatal cord blood amino acid concentrations
Essential or Indispensable AA Cannot be synthesized by humans so must be added Aminosyn-PF (Abbott) Trophamine (B. Braun) Primene (Baxter) Valine 673 780 760 Leucine 1200 1400 1000 Isoleucine 760 820 670 Threonine 512 420 370 Phenylalanine 427 480 420 Methionine 180 340 240 Lysine 677 820 1100 Histidine 312 480 380 Tryptophan 312 480 380 AA conc. in mg/dl; AA mixtures shown are 10% solutions
Non-Essential AA Can be synthesized from other amino acids or from other precursors Aminosyn- PF Trophamin e Primene Serine 495 380 400 Glycine 385 360 400 Alanine 698 540 800 Tyrosine 44 240* 45 Glutamine 820 500 1000 Glutamic acid Aspartic acid - - - 527 320 320 Asparagine - - AA conc. in mg/dl; AA mixtures shown are 10% solutions
Conditionally Essential or Semi-Essential AA These are non-essential AAs that become essential under certain circumstances (e.g.sepsis) These amino acids can be synthesized from other AAs Aminosyn-PF Trophamine Primene Glycine 385 360 400 *Proline 812 680 300 *Arginine 1227 1200 840 Tyrosine 44 240* 45 Cysteine - <16 189?Taurine 70 25 60 *Some debate exists about the conditional essentiality of arginine and proline AA conc. in mg/dl; AA mixtures shown are 10% solutions
Stock or Starter Amino Acid (AA) Solutions Parenteral AA and Dextrose Solution Once prepared it is stable for up to two weeks if refrigerated and with no vitamins, minerals or lipids added We use as initial intravenous fluid after birth
Example Stock or Starter Amino Acid (AA) Solutions 2% AA in D10W at 60 ml//kg/d 1.2 g/kg/d AA 2% AA in D10W at 80 ml//kg/d 1.6 g/kg/d AA 5% AA in D7.5W at 60 ml//kg/d 3.0 g/kg/d AA If you start with 5% AA you can t increase the fluid rate! Additional fluids can be co-infused if glucose and/or electrolyte requirements change
Complications of Parenteral Nutrition: Parenteral Nutrition Associated Cholestasis (PNAC) Etiology of PNAC is unknown and likely to be multifactorial Risk Factors: Younger gestational ti age» Significantly increased if infants <1000g at birth Duration of TPN Perhaps earlier initiation of TPN Absence of enteral feeding Sepsis, cholangitis, bacterial translocation
Parenteral Nutrition Associated Cholestasis (PNAC) Risk Factors: Could lipid infusion be a risk for parenteral nutrition-associated i t cholestasis in LBW infants? Eur J Pediatr, 2007 Significant correlation with duration of TPN, duration of fasting, days of antibiotic use, positive C-reative protein, total t amino acid intake, and total lipid intake Prenatal desamethasone was a significant protective factor for PNAC
PNAC Potential Predisposing Factors/Causes Immaturity of the neonatal liver and GI tract Reduced total bile salt pool in preterm neonates Decreased hepatic uptake tk and synthesis of bile salts Reduced enterohepatic circulation Deficient sulfation (important step in the solubilization of toxic bile salts)
PNAC Toxicity of TPN components Animal studies: Decreased bile flow with glucose infusions Cholestatic effect of amino acid infusions (esp. methionine, sulfur containing amino acids) Choline dfii deficiency causes steatosis t in rats Human studies Hepatic dysfunction with infusion of excessive calories Cholestatic effect of amino acid infusions (tryptophan, methionine, excess homocystine) Impaired bilirubin excretion in adults receiving high dose intravenous lipids Free radical production is increased by administration of TPN in infants
PNAC Potential Therapies in Neonates Parenteral taurine supplementation in specific subgroups of neonatal patients: JPEN, 2005 Significantly reduced PNAC in neonates with NEC Demonstrated a trend to decreased incidence of PNAC in preterm infants versus those without taurine supplementation Conclusions: Infants with NEC or severe prematurity are most likely to benefit from taurine supplementation
PNAC Potential Therapies Avoid glucose overload Early detection ti and treatment t t of infections Oral refeeding as soon as possible Ursodeoxycholic Acid (UDCA) Chen, et al Pediatr 2004;317 Prevent free radical production (cover lipid and TPN to avoid photo-oxidation) oxidation) Increase anti-oxidant capacities of TPN solutions
Toxicity of Early Amino Acids Is BUN an Appropriate Marker for Determining i Protein Intolerance? Blood urea nitrogen (BUN) may increase when administered protein is not completely utilized. This may be accompanied by hyperammonemia (? Bad BUN ) However, urea production may also be a by- product of amino acid oxidation (i.e. amino acids are used as an energy source) (? Good BUN )
Fetal Amino Acid (AA) Metabolism Fetal AA uptake from the placenta greatly exceeds protein accretion requirements Excess fetal AA can be used as an energy source (oxidation) It is estimated that 25-50% 50% of energy in the fetal sheep comes from oxidation of AA Animal and human studies show that the normal fetus produces BUN at a high level
Human Neonatal Amino Acid (AA) Metabolism In our studies, there is evidence that ELBW neonates who do not tolerate glucose and lipid (i.e., high serum glucose and triglyceride levels at low glucose and lipid id intakes) may use amino acids as an energy source In this case, elevated BUN may reflect a beneficial utilization of AA for energy and not intolerance of protein intake
Predictors of Increased BUN Ridout E, Thureen P et al, Journal of Perinatology, December, 2004 Retrospective p review of 4 studies of BUN concentrations in parenterally fed neonates in the first 3 days of life: 122 neonates, 137 BUN values Mean GA: 27.8 + 1.8 weeks Mean BWt: 982 + 247 g
Effect of Amino Acid Intake on BUN 45 40 /d) mg/kg/ BUN (m 35 30 25 20 15 10 5 0 BUN = 21 + 1.1AA Intake = r 2 P value NS = 0.01 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Amino Acid Intake (g/kg/d) Adapted from: Ridout, et al. Journal of Perinatology 25:130, 2005
Conclusions Early yp parenteral amino acid nutrition in very preterm neonates is associated with both desirable and adverse outcomes There are still many unanswered questions regarding the amount, duration and ideal composition of parenteral amino acid solutions in very preterm neonates