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Scott C Denne

Regulação da proteólise e ótimo acréscimo de proteína nos recém-nascidos extremamente prematuros ( Regulation of proteolysis and optimal protein accretion in extremely premature newborns). Scott C Denne

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Scott C Denne

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  1. Regulação da proteólise e ótimo acréscimo de proteína nos recém-nascidos extremamente prematuros(Regulation of proteolysis and optimal protein accretion in extremely premature newborns) Scott C Denne The Department of Pediatrics-Neonatology, Indiana University School of Medicine , Indianapolis, IN. Am J Clin Nutr. 2007;85:621S-624S. Apresentação: Daniela Vilela Coordenação: Albaneyde Formiga Unidade de Neonatologia do Hospital Regional da Asa Sul (HRAS)/SES/DF

  2. introdução • Resultados sobre crescimento em pré-termos MMBP(<1000 g) continuam pobres; • National Institutes of Health Neonatal Network -documenta que 90-99% pré-termos MMBP apresentam peso menor que o percentil 10 com 36 semanas de idade gestacional corrigida; • Promover crescimento nos recém-nascidos 9RN) pré-termos de muito muito baixo peso (PTMMBP) requer mais compreensão em limitar a proteólise e favorecer melhor incorporação protéica nesta população.

  3. Proteólise em recém-nascidos pré-termos e termos • A grande característica metabólica do pré-termo extremo é a intensa proteólise (catabolismo intenso); o dobro comparado em adultos saudáveis. • Administração de nutrientes em adultos responde com redução da proteólise total, enquanto que nos prematuros extremos a supressão apresenta mais dificuldade; no adulto a infusão de glicose aumenta a insulina reduzindo a proteólise, resposta que é diferente nos PTMMBP.

  4. Proteólise em recém-nascidos pré-termos e termos • Hertz et al( Intravenous glucose suppresses glucose production but not proteolysis in extremely premature newborns,1993), administrando TIG 6-9 observou altas taxas de insulina e aminoácidos essências fenilalanina e leucina sendo que proteólise não se alterou(Figura-1). • Avaliando a capacidade dos aminoácidos (aa) administrados EV em suprimir a proteólise: RN- termos – aa 1,2g/kg/dia redução 10% aa 2,4g/kg/dia redução 20% RN pré-termos – demonstraram resistência à variação na proteólise (Figura-2).

  5. Mean (±SE) leucine and phenylalanine rates of appearance (Ra) (reflecting proteolysis) and insulin concentrations in extremely preterm infants at 2 different glucose infusion rates: 6 (branco ) and 9 (preto ) mgkg–1min–1. *Significantly different from 6 mgkg–1min–1, P < 0.05. Data are from reference 6. Figura 1

  6. Figura 2 Mean (±SE) endogenous leucine rate of appearance (Ra; reflecting proteolysis) in premature and term infants during the basal state ( ) and during graded infusion of amino acids: 1.2 (branco ) and 2.4 (preto ) gkg–1d–1. *Significantly different from basal, P < 0.05. **Significantly different from 1.2 gkg–1d–1, P < 0.05. Data are from references 7 and 8.

  7. Proteólise em recém-nascidos pré-termos e termos • Administrando aminoácidos, lipídeos e glicose associados equilibradamente em quantidades suficientes para suporte de crescimento o grau de proteólise total em pré-termos (PT) de 26sem e PT de 32sem foi menos afetado.(Figura-3) • Quando se atinge a nutrição parenteral (NP) plena 17% dos RN termo conseguem suprimir a proteólise, mas nos prematuros praticamente não se tem resposta.

  8. Figura 3 Mean (±SE) percentage suppression of proteolysis from basal values in response to full parenteral nutrition in 26-wk gestation (gest) infants, 32-wk gestation infants, and full-term infants. Data are from references 9 and 10.

  9. soluções de aminoácidos e proteólise • Soluções de aminoácidos atuais não contem glutamina, cistina e tirosina; uma potencial explicação para limitação aos efeitos de proteólise nos prematuros. • Estudos com acréscimo destas proteínas estão sendo feitos ; com glutamina mostrou significante redução na proteólise em prematuros, entretanto o efeito não foi visto nos pré-termos extremos.

  10. Administração precoce aminoácidos ev e incorporação protéica • Apesar de limitações nas soluções atuais de aminoácidos em inibir a proteólise nos PTMMBP, está claro que o seu uso precoce resulta em significante aumento de proteína sintética e melhor balanço protéico. • Rivera et al( Effect of intravenous amino acids on protein metabolism of preterm infants during the first three days of life,1993),relata aumento de proteína sintética em 40% nos pré-termos que receberam 1,5 g/kg/ dia aminoácido, tendo um balanço protéico significante melhor(Figura-5).

  11. Figura 4 Top panel: Leucine for protein synthesis and leucine balance in premature infants receiving no amino acids (AA) or 1.5 g AAkg–1d–1. *Significantly different from no AA, P < 0.05. Data are from reference 16. Bottom panel: Leucine for protein synthesis and leucine balance in premature infants receiving amino acids at 1 or and 3 gkg–1d–1. *Significantly different from AA 1, P < 0.005. Data are from reference 18. In both panels, error bars indicate SEs.

  12. Administração precoce aminoácidos ev e incorporação protéica • Thureem et al( Effect of low versus high intravenous amino acids intake on very low birth weight infants in the early neonatal period,2003),examinado efeito 1 g versus 3g aa /kg /dia houve aumento 35 % no grupo que recebeu a maior taxa de aa( o efeito na proteólise não alterou).

  13. Nutrição enteral(NE) e proteólise • NE é muito mais efetiva que NP na diminuição efeito proteólise e aumento a incorporação protéica. • Van der Schoor et al( Lysine kinetics in pretem infants: the importance of enteral feeding,2004); proteólise foi 40% menor durante a NE plena e o balanço protéico total significante maior(Figura-5) • Prematuros extremos não alcançam NE plena por um período de semanas sendo proveitoso combinar NP e NE, podendo assim diminuir proteólise e aumentar incorporação protéica .

  14. Figura 5 Mean (±SE) endogenous lysine rate of appearance (Ra; reflecting proteolysis) and lysine balance during 60% parenteral and 40% enteral nutrition (branco ) and full enteral nutrition (preto ). *Significantly different from parenteral + enteral, P < 0.05. Data are from reference 21.

  15. Proteína via enteral e aumento incorporação protéica • Fazer a transição equilibradamente NP para NE nos pré -termos extremos, a fim de aumentar a incorporação protéica, continua sendo um significante desafio clinico. • Embleton et al (Postnatal malnutricion and growth retardation: an inevitable consequence of current recommendation in pretem infants?,2001); relata a dificuldade de incorporação protéica nos pré-termos < 30 sem recebendo NE plena com formulas padrão para estes, sugerindo ter beneficio aumentar conteúdo protéico nas formulas interais.

  16. Proteína via enteral e aumento incorporação protéica • Zello et al(Minimumproteinintake for thepretermneonatedeterminedbyproteinandaminoacidkinetics,2003); há uma correlação linear entre o balanço protéico ofertando maior proteína -1 -1,5 g/kg/dia. • Cooke et al (Highproteinpre-terminfant formula: effectonnutrient balance, metabolic status andgrowth,2006); estuda um balanço protéico ainda maior administrando proteínas 3,4 -6,2 g /kg /dia. • Estudos com um grupo controle maior, usando formula com alto conteúdo protéico é necessário.

  17. em resumo; • Administrar aminoácidos EV precoce 3 g /kg/dia pode aumentar a incorporação protéica e o crescimento PTMMBP ; • Pré-termos aparentemente tem resistência aos efeitos anti- proteolíticos da NP; estudos examinando uma melhor composição dos aminoácidos na proteólise são promissores ; • Promover uma sistemática investigação sobre os efeitos nutrição enteral(NE) plena e a combinação NP e NE na proteólise aumentando incorporação protéica ; • Priorizar estudos a fim de melhorar formulas atuais para PT, suprindo as necessidades protéicas dos PTMMBP.

  18. ABSTRACT Growth outcomes for extremely premature infants remain poor, and improving growth in this population will require a better understanding of how to limit proteolysis and promote protein accretion. Extremely premature infants exhibit high rates of proteolysis that are unrestrained by physiologic increases in insulin, intravenous amino acids, and full parenteral nutrition. Imbalances in current amino acid solutions may be in part responsible for the inability of parenteral nutrition to reduce proteolysis in preterm infants. However, amino acids in parenteral nutrition are effective for increasing protein synthesis in extremely preterm infants, which leads to improved protein balance. Current evidence suggests that early administration of 3 g amino acidskg–1d–1 to extremely premature infants is safe and effective. Enteral nutrition may be more effective than parenteral nutrition in limiting proteolysis and producing protein accretion in preterm infants, but the protein content of current preterm formulas may be inadequate for supporting optimal growth in this population. Important areas of future research include determining whether altered intravenous amino acid solutions can better effect reductions in proteolysis, investigating the effect of enteral nutrition on proteolysis and protein accretion, and conducting a large randomized controlled trial of formula with a higher protein content.

  19. Referências do artigo Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. Pediatrics [serial online] 2001;107:e1. Internet: http://pediatrics.aappublications.org/cgi/content/full/107/1/e1 (accessed 16 December 2006). Dusick AM, Poindexter BB, Ehrenkranz RA, Lemons JA. Growth failure in the preterm infant: can we catch up? Semin Perinatol 2003;27:302–10.[Medline] Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 2003;111:986–90.[Abstract/Free Full Text] Denne S, Liechty E, Liu Y, Brechtel G, Baron A. Proteolysis in skeletal muscle and whole body in response to euglycemic hyperinsulinemia in normal adults. Am J Physiol 1991;261:E809–14. Robert JJ, Bier DM, Zhao XH, Matthews DE, Young VR. Glucose and insulin effects on the novo amino acid synthesis in young men: studies with stable isotope labeled alanine, glycine, leucine, and lysine. Metabolism 1982;31:1210–8.[Medline]

  20. Hertz DE, Karn CA, Liu YM, Liechty EA, Denne SC. Intravenous glucose suppresses glucose production but not proteolysis in extremely premature newborns. J Clin Invest 1993;92:1752–8.[Medline] Poindexter BB, Karn CA, Ahlrichs JA, et al. Amino acids suppress proteolysis independent of insulin throughout the neonatal period. Am J Physiol 1997;272:E592–9. Poindexter BB, Karn CA, Leitch CA, Liechty EA, Denne SC. Amino acids do not suppress proteolysis in premature neonates. Am J Physiol Endocrinol Metab 2001;281:E472–8.[Abstract/Free Full Text] Denne SC, Karn CA, Ahlrichs JA, Dorotheo AR, Wang J, Liechty EA. Proteolysis and phenylalanine hydroxylation in response to parenteral nutrition in extremely premature and normal newborns. J Clin Invest 1996;97:746–54.[Medline] Clark SE, Karn CA, Ahlrichs JA, et al. Acute changes in leucine and phenylalanine kinetics produced by parenteral nutrition in premature infants. Pediatr Res 1997;41:568–74.[Medline] Poindexter BB, Karn CA, Denne SC. Exogenous insulin reduces proteolysis and protein synthesis in extremely low birth weight infants. J Pediatr 1998;132:948–53.[Medline]

  21. Christensen M, Helms R, Veal D, Boehm K, Storm M. Clearance of N-acetyl-L-tyrosine in infants receiving a pediatric amino acid solution. Clin Pharmacol 1993;12:606–9.[Medline] Kalhan SC, Parimi PS, Gruca LL, Hanson RW. Glutamine supplement with parenteral nutrition decreases whole body proteolysis in low birth weight infants. J Pediatr 2005;146:642–7.[Medline] Poindexter BB, Ehrenkranz RA, Stoll BJ, et al. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics 2004;113:1209–15.[Abstract/Free Full Text] Poindexter B, Wright-Coltart S, Denne SC. The effect of N-acetyl tyrosine and cysteine in parenteral nutrition on protein metabolism in extremely low birth weight neonates. Pediatr Res 2000;47:294A. Rivera A, Bell EF, Bier DM. Effect of intravenous amino acids on protein metabolism of preterm infants during the first three days of life. Pediatr Res 1993;33:106–11.[Medline] Van Goudoever JB, Colen T, Wattimena JLD, Huijmans JGM, Carnielli VP, Sauer PJJ. Immediate commencement of amino acid supplementation in preterm infants: effect on serum amino acid concentrations and protein kinetics on the first day of life. J Pediatr 1995;127:458–65.[Medline]

  22. Thureen PJ, Melara D, Fennessey PV, Hay WW Jr. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003;53:24–32.[Medline] Poindexter BB, Langer JC, Dusick AM, Ehrenkranz RA. Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcome. J Pediatr 2006;148:300–5.[Medline] Yu YM, Burke JF, Vogt JA, Chambers L, Young VR. Splanchnic and whole body L-[1-13C,15N]leucine kinetics in relation to enteral and parenteral amino acid supply. Am J Physiol Endocrinol Metab 1992;262:E687–94.[Abstract/Free Full Text] van der Schoor SR, Reeds PJ, Stellaard F, et al. Lysine kinetics in preterm infants: the importance of enteral feeding. Gut 2004;53:38–43.[Abstract/Free Full Text] Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107:270–3.[Abstract/Free Full Text] Zello GA, Menendez CE, Rafii M, et al. Minimum protein intake for the preterm neonate determined by protein and amino acid kinetics. Pediatr Res 2003;53:338–44.[Medline] Cooke R, Embleton N, Rigo J, Carrie A, Haschke F, Ziegler E. High protein pre-term infant formula: effect on nutrient balance, metabolic status and growth. Pediatr Res 2006;59:265–70.[Medline]

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