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The effect of oral and intravenous feeding on the plasma amino acid levels of premature infants Lerner, Sarah Ann 1978

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'THE EFFECT OF ORAL AND  INTRAVENOUS FEEDING,  ON THE PLASMA AMINO ACID LEVELS OF PREMATURE INFANTS by  SARAH ANN B. A.,  University  A THESIS SUBMITTED  LERNER of B r i t i s h  Columbia  IN PARTIAL FULFILLMENT OF  THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES The D i v i s i o n of Human N u t r i t i o n School o f Home Economics We accept t h i s t h e s i s as conforming t o the r e q u i r e d  standard  THE UNIVERSITY OF BRITISH COLUMBIA October, 1978. Sarah Ann L e r n e r , 1978  In p r e s e n t i n g t h i s  thesis  in p a r t i a l  fulfilment of  an advanced degree at the U n i v e r s i t y of B r i t i s h the L i b r a r y I  further  for  this  freely  available  for  agree t h a t p e r m i s s i o n f o r e x t e n s i v e  scholarly  by h i s of  s h a l l make i t  the r e q u i r e m e n t s f o r  Columbia,  I agree  r e f e r e n c e and study. copying o f t h i s  thesis  purposes may be granted by the Head o f my Department o r  representatives. thesis for  It  financial  i s understood that gain shall  not  copying o r p u b l i c a t i o n  be allowed without my  written permission.  Department of  \\Or\C (SCONJOMilS  The U n i v e r s i t y o f B r i t i s h 2075 Wesbrook P l a c e V a n c o u v e r , Canada V 6 T 1W5  Date  that  OCToBfcTg fe , l ° n &  Columbia  OF-  HUMAivi M U T E j - r i o/\)  ABSTRACT  The o b j e c t o f t h i s study was t o a s s e s s the adequacy o f the p r o t e i n s o l u t i o n g i v e n t o premature i n f a n t s r e c e i v i n g nutrition.  Plasma aminograms from premature i n f a n t s f e d o r a l l y were  determined and compared w i t h aminograms from premature m a i n t a i n e d on i n t r a v e n o u s n u t r i t i o n . r a t i o , coupled w i t h growth length,  intravenous  infants  The k i l o c a l o r i e : n i t r o g e n  parameters, such as weight g a i n , body  and head c i r c u m f e r e n c e were f u r t h e r used t o e v a l u a t e n u t r i t i o n a l  adequacy. S t a n d a r d i z e d plasma aminograms were o b t a i n e d u s i n g c a p i l l a r y b l o o d samples from a c o n t r o l group o f 16 i n f a n t s 31-36 weeks, mean 3 3 i weeks),  f e d SM^Q  ( g e s t a t i o n a l age  (a commercial  infant formula).  Blood samples were taken between the 7 t h - l 6 t h day a f t e r b i r t h , 1-2 hours a f t e r the f i r s t feed o f t h e day. The study group was comprised o f 11 i n f a n t s between 2^-30 weeks gestation  (mean 28 weeks),  fed intravenously,  using a synthetic  c r y s t a l l i n e L-amino a c i d m i x t u r e (Vamin), running c o n t i n u o u s l y .  Blood  samples from the study group were a l s o taken between the 7th-16th day of  l i f e a t the same time o f the morning as the c o n t r o l  group.  R e s u l t s showed t h a t plasma samples from the study group had lower levels of threonine, asparagine, glutamic a c i d , l y s i n e , c i t r u l l i n e , alanine,  c y s t i n e , methionine,  the c o n t r o l group.  l e u c i n e , o r n i t h i n e , and a r g i n i n e  than  Plasma p h e n y l a l a n i n e l e v e l s were 2-3 times h i g h e r  i n t h e study group than i n the c o n t r o l  group.  i i i  Plasma urea l e v e l s were lower i n the than i n the o r a l l y f e d group. plasma urea and  I t i s l i k e l y t h a t both the  low  low plasma amino a c i d l e v e l s i n d i c a t e e f f i c i e n t  of the i n t r a v e n o u s l y group.  i n t r a v e n o u s l y fed group  i n f u s e d amino  a c i d s by  i n f a n t s i n the  I t i s most p r o b a b l e t h a t the i n f u s e d amino a c i d s are  use  study being  used f o r p r o t e i n s y n t h e s i s r a t h e r than f o r energy purposes. Efficient  use of i n f u s e d amino a c i d s i s f u r t h e r suggested by  the a c t u a l growth i n l e n g t h , head c i r c u m f e r e n c e  and weight g a i n noted  in the i n t r a v e n o u s l y f e d i n f a n t s . F u r t h e r s t u d i e s are needed to e x p l a i n the h i g h e r plasma l e v e l s of p h e n y l a l a n i n e Relatively  seen i n i n f a n t s i n t r a v e n o u s l y  low plasma l e v e l s of m e t h i o n i n e and  v e n o u s l y f e d i n f a n t s seem t o i n d i c a t e t h a t an i n t a k e may  be b e n e f i c i a I.  The  i n f u s e d w i t h Vamin. t y r o s i n e in the increase in t o t a l  t o t a l amount of p h e n y l a l a n i n e  study.  protein  i n Vamin,  in a d d i t i o n to r e l a t i o n s h i p t o the o t h e r amino a c i d s a l s o needs further  intra-  "TABLE OF CONTENTS ABSTRACT TABLE OF CONTENTS LIST OF TABLES LIST OF FIGURES ACKNOWLEDGEMENTS CHAPTER I II  INTRODUCTION LITERATURE SURVEY A. P r o t e i n and Energy Requirements o f the F u l l Term and Premature Infant B. P a r e n t e r a l 1. 2. 3. h.  Nutrition  Hi s t o r y Parenteral n u t r i t i o n and premature i n f a n t s Types of amino a c i d m i x t u r e s a v a i l a b l e Method of a d m i n i s t r a t i o n  C. Amino A c i d M e t a b o l i s m 1. 2. 3.  Normal p h y s i o l o g y Infused amino a c i d m i x t u r e s Plasma aminograms  D. P i t f a l l s  i n S t u d y i n g Plasma Aminograms  E. K i l o c a l o r i e : N i t r o g e n R a t i o — A R e f l e c t i o n S a t i s f y i n g P r o t e i n and Energy Requirements F. Growth Parameters G. Summary III  MATERIALS AND METHODS A. The C o n t r o l  Group  B. The Study Group C. Treatment and A n a l y s i s of Blood Samples D. Other A n a l y s e s E. D e t e r m i n a t i o n of the Ki1 oca l o r i e : N i t r o g e n Ratio F. Growth Parameters G. S t a t i s t i c a l  Analysis  IV V  RESULTS  46  DISCUSSION  71  A. C o n t r o l Values  71  B. Study Values  73  C. Comments on the D i f f e r e n c e s Between C o n t r o l and Study Data D. Recommendations REFERENCES CITED  lk 80 81  APPENDICES A. L e t t e r o f I n t r o d u c t i o n t o P e d i a t r i c i a n s  3k  B. Consent Form C. P a r e n t e r a l N u t r i t i o n Flow Chart  95 96  D.  I n t r a u t e r i n e Growth C h a r t s f o r Each Study Infant  99  V I  LIST OF TABLES TABLE  Page  1.  Amino A c i d Composition of  2.  Study P r o t o c o l - Q u a n t i t i e s of N u t r i e n t s / K g Weight/Day  SMA^Q  and  Breast M i l k Body  35 36  3.  Amino A c i d Composition of Vamin  37  k.  Sex, G e s t a t i o n a l Age and B i r t h Weight of the Premature I n f a n t s i n the C o n t r o l Group  kl  5.  Head C i r c u m f e r e n c e and I n f a n t s i n the C o n t r o l  48  6. 7. 8. 9. 10. 11.  12. 1314.  15-  16.  Length at B i r t h of the Premature Group  Sex, G e s t a t i o n a l Age and B i r t h Weight of Premature I n f a n t s i n the Study Group  49  Head C i r c u m f e r e n c e and Length at B i r t h of Premature I n f a n t s i n the Study Group  50  P r o t e i n Intake For The the Blood Sample Average Amino A c i d Infants  3 Days P r i o r t o the Drawing o f 53  Intake by the C o n t r o l and  Study 5^  I n d i v i d u a l Plasma Amino A c i d Values f o r C o n t r o l Group: Premature I n f a n t s R e c e i v i n g Oral Feeds of SMA^Q  57  I n d i v i d u a l Plasma Amino A c i d V a l u e s f o r the Study Group:Premature I n f a n t s R e c e i v i n g T o t a l P a r e n t e r a l Nutrition  59  Mean Plasma Amino A c i d V a l u e s f o r C o n t r o l and Groups  61  Va1ine:Glycine Ratios f o r Infants Receiving Parenteral N u t r i t i o n  Study  Total 63  L i n e a r R e g r e s s i o n S t a t i s t i c s on G e s t a t i o n a l Age and Plasma Amino A c i d C o n c e n t r a t i o n s , ( G e s t a t i o n a l Age 31-36 wks)  64  L i n e a r R e g r e s s i o n S t a t i s t i c s on G e s t a t i o n a l Age and Plasma Amino A c i d C o n c e n t r a t i o n s , ( G e s t a t i o n a l Age 24-31 wks)  65  L i n e a r R e g r e s s i o n and C o r r e l a t i o n C o e f f i c i e n t of Plasma L e v e l s of Glutamine and A s p a r a g i n e  66  Analysis  S t a t i s t i c a l A n a l y s i s on Data Comparing Amino A c i d C o n c e n t r a t i o n s i n C a p i l l a r y and Venous Samples D u r a t i o n o f T o t a l Intravenous Feeding and Average K i l o c a l o r i e : N i t r o g e n Ratio Attained Comparison of Plasma Amino A c i d s Fu11 Term I n f a n t s  i n Premature and  vi i i  LIST  OF  FIGURES  FIGURE 1.  Page  C h a n g e s in D i s t r i b u t i o n i n M a j o r Body Components the Fetus During the Last T r i m e s t e r of Pregnancy Parenteral  3.  S t a b i l i t y o f G l u t a m i n e and A s p a r a g i n e D u r i n g S t o r a g e o f B l o o d S a m p l e s i n t h e Durrum D-500 Amino A c i d Analyzer Weight, Birth  5-  Weight, Birth  6.  7-  8.  of  of  Length, the  the  Peripheral  and Head C i r c u m f e r e n c e  Control  Length,  Using  6  2.  k.  Nutrition  of  Measurements  43 at 51  Measurements  Group  Growth Data f o r Nutrition  Patient  Relationship Gain  Daily  at 52  A C o m p a r i s o n o f P l a s m a Amino A c i d t h e C o n t r o l and S t u d y G r o u p s  of  17  Group  and Head C i r c u m f e r e n c e  Study  Veins  8 While  Concentrations  of 62  on T o t a l  Parenteral 69  intravenous  Intake With  Weight 70  i x  ACKNOWLEDGEMENTS  I would l i k e to thank Dr. Joseph L e i c h t e r f o r h i s thoughtful d i r e c t i o n and g u i d a n c e t h r o u g h o u t t h e p r e p a r a t i o n of t h i s t h e s i s . S p e c i a l thanks is extended to Dr. Margaret P e n d r a y who a r r a n g e d f o r t h e s e l e c t i o n o f p a t i e n t s and o f f e r e d c l i n i c a l a d v i c e and p e r s o n a l d i r e c t i o n . I am g r e a t l y indebted to Dr. Derek A p p l e g a r t h f o r a r r a n g i n g the specimen a n a l y s e s and f o r t a k i n g t h e t i m e t o t e a c h me how t o i n t e r p r e t t h e f i n d i n g s . I am a l s o g r a t e f u l f o r t h e m o r a l s u p p o r t and e d i t o r i a l assistance o f D r . Nancy S c h w a r t z . I v e r y much a p p r e c i a t e t h e e n t h u s i a s t i c a s s i s t a n c e o f t h e p h y s i c i a n s and n u r s e s a s s o c i a t e d w i t h t h e I n t e n s i v e C a r e N u r s e r i e s o f t h e V a n c o u v e r G e n e r a l and G r a c e H o s p i t a l s . I am e x t r e m e l y t h a n k f u l f o r the help of the t e c h n i c i a n s in the P e d i a t r i c M i c r o c h e m i s t r y L a b o r a t o r i e s o f both h o s p i t a l s . S p e c i a l thanks is extended to the t e c h n i c i a n s of the Biochemical Diseases Laboratory at C h i l d r e n ' s Hospital. F i n a l l y I would l i k e to thank the G r a p h i c s Department a t t h e V a n c o u v e r G e n e r a l H o s p i t a l and M r s . B a r b a r a C a r u k and Vona P r i e s t f o r t h e i r a s s i s t a n c e i n t h e p r e p a r a t i o n o f t h i s thes i s .  1  CHAPTER 1 INTRODUCTION  Parenteral n u t r i t i o n the g a s t r o i n t e s t i n a l  i s a t e c h n i q u e used to feed p a t i e n t s when  route i s i m p o s s i b l e , inadequate or  ill  advised.  Assessment of the adequacy of n u t r i t i o n g i v e n in t h i s manner i s difficult,  especially  intravenous  nutrition  i n the case of  Some i n f a n t s  immediately a f t e r b i r t h .  p e r i o d of v e r y r a p i d growth i t the p r o t e i n  infants.  As t h i s  require  is normally a  i s important to a s s e s s the adequacy of  i n t a k e in these i n f a n t s .  Cerebral  growth i s c r i t i c a l  the p e r i n a t a l p e r i o d and depends in p a r t on o p t i m a l  l e v e l s of  during  circulating  amino a c i d s . A f t e r an o r a l meal the gut e x e r t s h o m e o s t a t i c mechanisms which control  blood l e v e l s of plasma c o n s t i t u e n t s  o u t f l o w of amino a c i d s  i n t o the p o r t a l  such as amino a c i d s .  The  v e i n i s c h a r a c t e r i z e d by a  predominance of a l a n i n e and an absence of g l u t a m a t e and a s p a r t a t e . o c c u r s d e s p i t e the f a c t t h a t g l u t a m a t e and a s p a r t a t e may account 20-30% of the c o n s t i t u e n t amino a c i d s in the i n g e s t e d p r o t e i n . a l s o p l a y s an a c t i v e r o l e  in c o n v e r t i n g  ingested nitrogen  A d m i n i s t e r i n g amino a c i d s v i a the p e r i p h e r a l  for The gut  to a l a n i n e .  c i r c u l a t i o n causes them to  bypass the normal b u f f e r i n g a c t i o n of the g u t . of h o m e o s t a t i c c o n t r o l  This  The absence of t h i s  aspect  a c c e n t u a t e s the need to monitor c a r e f u l l y plasma  ami no a c i d l e v e l s . R e l a t i v e l y g r o s s d i s t u r b a n c e s of plasma amino a c i d s a r e seen in inborn e r r o r s of m e t a b o l i s m . problems  i s not known.  Whether more modest a b n o r m a l i t i e s may cause  Plasma amino a c i d v a l u e s have been shown to v a r y  2 with  both  the  illustrated levels  in  quantity  in  adults  infants  the  amino a c i d  The  establishment  normal  fed  of  in  infants  rapidly  growing This  with  parameters  of  the  dietary  protein  protein  and  affecting possible  is  of  the  determine  synthetic  infants  clinician  digestion,  The  in  1) e s t a b l i s h i n g  premature  infants  of  the  intake  orally  and  the  the  a set  age  of  intake  body  infants.  to  for  to  many  was  to  levels  a g e 31 38 _  patterns  the  adequacy  premature  aminogram v a l u e s  in  parenteral of  2)  using  premature nutrition,  energy  be  growth.  to  weeks,  of  should  Accomplishment of  normal  ratio  It  assess  administered  the  factors  protein.  study  total  head  optimal  optimum  amino a c i d  kilo-  :  When c o m b i n e d  and  for  nutrition.  the  total  used  e s t i m a t e whether  due of  commonly  intake  standard  growth.  of  values  ratio.  Determining  (Vamin)  between  acid  premature  to  length  ratio  this  receiving  relationship  parameters  protein  of  nourished  adequacy,  protein  gestational  plasma  adequately  impossible  parenteral  been  knowledge  comparison with  this  of  has  plasma amino  an a c c u r a t e  and u t i l i z a t i o n  of  as  plasma amino a c i d  gain,  is  mixture  fed,  the  same g e s t a t i o n a l  3) e x a m i n i n g  a diet  fed  nutrition.  links  use  purpose  total  the  kilocalorie:nitrogen  can  a range  amino a c i d  evaluate  of  for  (weight  absorption  required:  to  of  used e f f i c i e n t l y .  primary  m a i n t a i n e d on  standard  the  protein  nutritional  infants,  growth  being  set  parenteral  is  kilocalories  to  group  of  the  requires  important  parameter  consumed.  circumference)  is  total  calories the  a control  of  To e v a l u a t e  a standardized  m a i n t a i n e d on  these  quality  intravenously  Another for  the  and c h i l d r e n .  levels  premature  infants  and  to  this for this  infants and  nitrogen  3 CHAPTER 11  LITERATURE  A.  PROTEIN  AND ENERGY REQUIREMENTS  During nutritional are  intrauterine  requirements  dependent  placenta  on  the  outside  environment  rapidly  result  in  According energy  birth  for  requirement  of  38 and 1 p e r c e n t  of  body  these  and o t h e r  amino a c i d s  cannot  valine,  Histidine  12,15).  was It  These  than  a few  2500  is  to  requirements  grams  all  development  fetus  across  dependent  and  the  on an  i m b a l a n c e s may  term  be s y n t h e s i z e d histidine,  to  Little  the  lysine,  only  the  infants  attention  and  for for  were was  paid  of  (3,9,10,38). (6,7,8,  (4,5). infants.  as w e i g h i n g the  Nine  isoleucine,  premature  to  synthesis  therefore  human i n f a n t  defined  protein  2.2 g  the  and a r e  adults  same f o r  and  tryptophan  the  provides  compounds.  leucine,  is  and an  receive  needed f o r  body  ;  caloric  Human m i l k  important  in  months  35 k c a l / k g  should  are  threonine,  be  six  carbohydrate,  infant  be e s s e n t i a l  may n o t  of  body w e i g h t .  from f a t ,  be e s s e n t i a l  to  recommended  b a s e d on a b a s a l  physiologically  ago p r e m a t u r e  (43).  the  from b i r t h  ( 2 ) . Amino a c i d s  now b e l i e v e d  years  and  ( 2 ) , the  requirement  full  phenylalanine,  thought  is  25 k c a l / k g  These a r e :  methionine,  Standards  figure  average  body w e i g h t / d a y  essential.  reaching  deficiencies  kilocalories  proteins  termed  Until  ( 3 ) . The  growth  becomes t o t a l l y  infants  a growth  10 t o of  term  This  55 k c a l / k g ,  allowance of  protein/kg  infant  supplied with  INFANT  disorders.  full  body w e i g h t .  respectively  the  is  Proper  nutrients  Canadian Dietary  117 k c a l / k g  55,  the mother. of  FULL TERM AND PREMATURE  a fetus  nutritional  growth  requirement  activity  by  where  to  OF THE  existence  quantity  (1). After  SURVEY  duration  less of  4  intrauterine l i f e .  A premature  i n f a n t i s now d e f i n e d  b e f o r e the t h i r t y - s e v e n t h week of g e s t a t i o n  (43).  as an i n f a n t born  Some i n f a n t s have  s u r v i v e d a f t e r o n l y 24 weeks g e s t a t i o n ( 4 4 ) . Premature than f u l l  i n f a n t s o f t e n need more s o p h i s t i c a t e d forms of support  term i n f a n t s .  nutritional  Most i n f a n t s born p r e m a t u r e l y have  needs than normal f u l l  infants f a l l  greater  term i n f a n t s (11,13,14).  Premature  i n t o a c a t e g o r y o f c h i l d r e n who are e s p e c i a l l y s u s c e p t i b l e  to p r o t e i n c a l o r i e m a l n u t r i t i o n from even m i l d l y inadequate n u t r i t i o n a l intakes.  Their s u s c e p t i b i l i t y to p r o t e i n c a l o r i e m a l n u t r i t i o n i s  increased  because they have l i m i t e d f a t and p r o t e i n s t o r e s which a r e  h e a v i l y taxed by e x c e p t i o n a l l y high m e t a b o l i c demands (15,17). In F i g u r e  1-, based on Widdowson's data ( 1 6 ) , H e i r d and W i n t e r s  (11) show the changes  i n body c o m p o s i t i o n o f the f e t u s d u r i n g  t r i m e s t e r of pregnancy. increase  Illustrated  the l a s t  i n t h i s f i g u r e i s the s u b s t a n t i a l  i n f a t and d e c r e a s e i n e x t r a c e l l u l a r water which takes p l a c e  between 24 and 40 weeks of g e s t a t i o n . w e i g h i n g 1000 grams, o n l y is protein  (21).  If a c h i l d  i s born p r e m a t u r e l y ,  1% of i t s body weight i s f a t and almost  I f one assumes a v a i l a b i l i t y o f a l l body f a t and  s t o r e s f o r c a l o r i c needs the t o t a l c a l o r i c r e s e r v e would be 430 body weight ( 1 5 ) .  Without n u t r i t i o n a l  receiving only water, w i l l  s u p p o r t , a small  kcal/kg  body weight/24 hours (15,17).  protein  kcal/kg  premature i n f a n t ,  s u r v i v e a p p r o x i m a t e l y f o u r days  The basal m e t a b o l i c requirement of the premature  8.5%  (.1.5) •  i n f a n t i s 50-60  However, another 50-60 k c a l / k g  body weight/day must be added t o account f o r c o l d s t r e s s , a c t i v i t y , (14,15,17,21). will  growth  A d d i t i o n a l s t r e s s e s , such as s e p s i s or r e s p i r a t o r y d i s t r e s s  f u r t h e r increase  t h e i r c a l o r i c requirement.  By the end of the second  5 week o f l i f e ,  110-150  these i n f a n t s ' d a i l y c a l o r i c requirements reach  k c a l / k g body weight  (18).  The p r o t e i n requirements f o r t h e premature i n f a n t have not y e t been a d e q u a t e l y d e f i n e d .  A g r e a t deal o f c o n t r o v e r s y  has clouded  this  i s s u e s i n c e Gordon ejt a_l_. , (24) found t h a t premature i n f a n t s f e d unmodified cow's m i l k m i x t u r e s mixtures,  however, a l s o c o n t a i n e d  several observers to f l u i d  showed e x c e s s i v e weight g a i n s . more m i n e r a l s  These  than b r e a s t m i l k and  have suggested t h a t t h e i n c r e a s e d weight g a i n was due  r e t e n t i o n (24-28,29).  I t c o u l d be a n t i c i p a t e d t h a t t h e  q u a n t i t a t i v e p r o t e i n requirement o f the premature i n f a n t would be g r e a t e r than t h a t o f a f u l l  term i n f a n t f o r a number o f reasons.  i n c l u d e an impaired  t o d i g e s t and absorb n u t r i e n t s , a r a p i d  ability  r a t e o f growth, and a g r e a t e r of impaired  l o s s o f amino a c i d s  renal tubular reabsorption  coworkers (19,20)  (19).  i n the u r i n e as a r e s u l t  A l t h o u g h Snyderman and  found i n c r e a s e d n i t r o g e n r e t e n t i o n i n i n f a n t s - f e d 9  grams p r o t e i n / k i l o g r a m body w e i g h t / d a y , a p p r e c i a t i o n o f the s t r a i n h i g h s o l u t e loads  These  impose on t h e immature kidney  that  l e d her t o recommend a  more moderate p r o t e i n i n t a k e o f 304 g/kg body weight/day.  These  recommendations a r e based on m o d i f i e d cow's m i l k f o r m u l a s and on t h e assumption o f an i n t a k e o f 140 k c a l / k g body weight/day. More r e c e n t l y , Raiha (23) may be harmful t o the d e v e l o p i n g  f e e l s that since metabolic  c e n t r a l nervous system, c a s e i n - r i c h  high p r o t e i n f o r m u l a s (82:28 casein:1 a c t a 1bumin) should premature i n f a n t s w i t h m e t a b o l i c e_t aj_. , (55) f e e l  imbalances  immaturities.  not be f e d t o  Raiha (23) and G a u l l  t h a t the p r o t e i n i n t a k e should be 2.25 g/kg body  weight/day and t h a t t h i s should  be g i v e n  i n the form o f b r e a s t m i l k o r a  6  Fig. 1 Changes in Distribution in Major Body Components of the Fetus During the Last Trimester of Pregnancy 100 Fat 75 Fat Water  (%) 50  I  Free I  Wet I  Weight  25 Protein 0 1000  lit 1500  Other  2000  2500 gms  from Heird et a l , (11).  3000  3500  7  formula with Other  a similar  researchers  f o r m u l a may n o t in  premature In  tyrosine  life  that  provide  addition  to  the  nine  the  cystine  sources  this  is  an e s s e n t i a l  was due  recently fetal  to  an  however,  liver  Recent rapidly  the  during  developing  that  cystine  and m e t h i o n i n e on d i e t  in  fetal  in  the  life  Low p l a s m a  to  adequate growth  the  for  urine  the  rates  until of  cystine  further  for  week o f  indicated  human i n f a n t  cannot  premature  provide  and  that  The  sufficient  taurine  high the  claim  dietary  They  system. be a c t i v e  that  felt  More i n human  may be e s s e n t i a l  for  S t u r m a n e_t a_j_. , ( 4 1 )  a d e q u a t e amounts o f infant  postnatal  (37,39).  taurine  (411,42).  to  of  suggested  infants.  hydroxylase  gestation  synthesize  precursors.  in  support  (36)  infant.  pathway  later  and D o l i f  and  premature  i n a d e q u a t e amounts from  amino a c i d  has  cystine  biosynthetic  or  levels  ( 1 9 ) and J u r g e n s  eleventh  suggest  dependent  support  enzyme s y s t e m h a s b e e n f o u n d  research  infants  milk-simulated  amino a c i d s ,  immature p h e n y l a l a n i n e  from the  breast  be e s s e n t i a l  be s y n t h e s i z e d  ( 5 6 ) . Snyderman  tyrosine  to  cystathionine  cannot  to  essential  key enzymes  (19,33,3^,35,55,56).  that  milk or  enough p r o t e i n  develop  of  c a s e i n : 1 a c t a 1bumin).  (40:60  (30,31).  one o f  does not  content  breast  are also considered  concentrations  the  feel  infants  Cystathionase, cystine  protein  may t h e n (41,56).  be  taurine entirely  from  8  B.  PARENTERAL NUTRITION  1.  HISTORY Today,  nutrients children  are  parenteral given  and a d u l t s  congenital  recovering  nutrition. colorful  It  three  suggestion the  from major  injections  widely  first  surgical  a challenging  injection  hundred y e a r s of  Sir  of  of  ago,  Christopher the  first  (49).  salts  sustained  in  chronic gut,  the  calories  treatment  bowel  the  therapy  aspect of  (52).  veins  liquid  various  for  and  of  disorders,  burns,  complications  neoplastic disease,  may b e n e f i t  from  human n u t r i t i o n  Wren  b o t h a n i m a l s and man ( 5 2 ) . nutrition  easily  on t h e  parenteral  with  a long  its  use o f  natural  use g l u c o s e is  useful  volume o f  difficult  during  the  and  dextrose.  as  their  only  because i t  isotonic  to develop  occurrence  due t o  in  fluid.  Suitable  to  were  perform  a  of  by many a t t e m p t s  to  blood  of  this  role  century  large  use o f of  (48).  calorie  fat  the  trial not  egg inject  has dextrose  glucose  in  T o d a y some  source.  amount o f  emulsions,  problems of  in  d r a m a t i c but  The e x t e n s i v e  the  upon  injections  half  non-protein  technical  doctors  the c e n t r a l  can s u p p l y  Boyle  place  cholera epidemics  successful  first  stream took  Robert  results  followed  u n d e r s t o o d when o n e c o n s i d e r s  m e t a b o l i s m and  Fat  were  Dr.  for  The s u c c e s s f u l  rabbits  blood  Later,  opportunity  Claude Bernard's  the  by  (48).  into  depended p r i m a r i l y  into  as e x e c u t e d  foods  Parenteral  of  a  the  a small  used  operations  into  regimes  the  undergoing  white  is  t h e method by w h i c h  Patients with  prematurity,  is  is  a b n o r m a l i t i e s of  1820's provided  always  It  is  history.  The over  vein.  alike.  surgical  associated with or  by  nutrition  attaining  energy  however, optimal  in were particle  size  and f i n d i n g  from acute using  and  in  requirements As  producing obtained  size  are  as  and  naturally is  nitrogen  mixture  of  them  effects  was  until these  well  mixture  satisfactory enzymatic  the  after  It  (40) .  amino a c i d of  the  in  was  not  casein  nutrition  centred  of  beef  hydrolysates  occurred.  maintained  on;total  this  days  total  until  not  for  is  now  energy  around  the  rapid  that  showed  nutrition  products  really  was m a i n t a i n e d  of  Elman  an  in  intravenous  meat  (52).  initiated  It  the  n u t r i t i o n (48).  to develop  an  he p r o d u c e d use.  ideal a  It  amino  really was made  by  dialysis. in  the  United  use of  States,  hypertonic  glucose.  dilution  a d v a n c e m e n t was  casein  without  receiving  intravenous by  of  first  hydrolysate  tried  and a n h y d r o u s  intravenous  The  parenteral  available  technique,  while  1 9 ^ that  followed  cava where  A major  e_t aj_. , (53) u s i n g  particle  d e v e l o p e d when  used.  W o r l d War  preparation  parenteral  bution  stable  animals  1913 when a g o a t  19^0's W r e t l i n d  in  vena  in  First  were  superior  emulsion,  a carbohydrate,  into  were  and an e n z y m a t i c  solutions  the  fat  suffered  chylomicrons,  Complications  sixteen  fat  fibrin  patients  made p r e p a r a t i o n s  intravenously  reported  mixtures  early  hydrolysis  As  was  salts  protein  During  into  combined w i t h  (52).  balance for  glucose,  and h a v i n g  occurring  German s c i e n t i s t s  injected  experiment  past,  (50). A safe  as e m u l s i f i e r s  of  the  satisfied.  1889  side  In  reactions  When f a t  easily  agents.  f r o m more c o m p l e t e h y d r o l y s i s  positive  use o f  the  Canada.  toxic  successful  not  to  early  hydrolysates  term t o x i c  phospholipids  similar  available  acid  long  egg y o l k  sizes,  safe emulsifying  solutions  T h e s e were  infused  and p e r i p h e r a l  made  in  1966, when  that  beagle  and c o n t i n u e  distri-  Dudrick,  pups c o u l d to  research  grow  be  normally  10 when compared w i t h animals fed o r a l l y .  Further  r e s e a r c h with humans  showed that a p r o l o n g e d , s u s t a i n e d , and meaningful s t a t e of anabolism c o u l d be achieved with intravenous f e e d i n g In the p a s t ,  l i t t l e emphasis was p l a c e d on the need f o r  adequate v i t a m i n s and m i n e r a l s was b e l i e v e d to be o f secondary  in p a r e n t e r a l  important to the  body mass d u r i n g the time  n u t r i t i o n programs.  importance in the n u t r i t i o n a l  the o l d e r c h i l d or a d u l t p a t i e n t . extremely  (54).  However,  it  care of  is now r e a l i z e d to be  i n f a n t who may s i g n i f i c a n t l y it  It  i s maintained on t o t a l  increase  intravenous  its nutrition  (22). C e r t a i n v i t a m i n s and t r a c e elements play an a c t i v e r o l e metabolism (22).  in normal  Both v i t a m i n and t r a c e element s o l u t i o n s must be  a d m i n i s t e r e d to the p a t i e n t prolonged p e r i o d o f t i m e .  receiving total Further  parenteral  r e s e a r c h , however,  n u t r i t i o n over a is  e l u c i d a t e both the p r e c i s e r o l e s and requirements of a l l and m i n e r a l s so that recommended intakes f o r the  required the  intravenous  to  vitamins route can be  e s t a b l i shed.  2.  PARENTERAL NUTRITION AND PREMATURE Feeding o f the premature i n f a n t  problems f a c i n g him. reflexes,  relatively  poor gag r e f l e x e s  high c a l o r i c  requirement with small stomach c a p a c i t y ,  l e a d i n g to a s p i r a t i o n , an incompetent esophageal  When the premature i n f a n t ' s special  is c o m p l i c a t e d due to the many  Some o f these problems i n c l u d e poor suck and swallow  s p h i n c t e r , and a decreased a b i l i t y  feeding,  INFANTS  to absorb n u t r i e n t s c o n d i t i o n permits  techniques are used,  cardiac  (32).  gastrointestinal  such as gavage f e e d i n g  (43,44).  11  However,  nasojejunal  techniques  which  have a l s o  Parenteral infants  feeding  feeding  to provide  (45,46), a n d g a s t r o s t o m y  main groups  i s used  them w i t h  cularly  useful  intestinal chronic  infants infants  until  such  receiving  number o f p r e m a t u r e must  There  wall  suffering  to avoid  are s t i l l  metabolic disturbances,  in  peripheral  a l l , the problems growth  a premature  Infants  syndromes  nutrition  total  from  further  It  is  parti-  suffering  from  may r e q u i r e  c a n commence  parenteral  respiratory  tracts  A great  distress of  and/or to  (93).  complications  this  (93).  nutrition  and n u t r i e n t s  many p r o b l e m s a s s o c i a t e d w i t h  problems,  brain  method.  There a r e  syndrome .  regurgitation  (80,81,81,93)-  using  hand,  growth and  anomalies of the  (70,93,157)•  adequate c a l o r i e s  infants  this  immature g a s t r o i n t e s t i n a l  nutrition  of  from  t i m e as o r a l very  f o r proper  congenital  may r e q u i r e  be f e d i n t r a v e n o u s l y  and a s p i r a t i o n  who b e n e f i t  premature  a r e not p r a c t i c a l .  or undefined malabsorption  enterocolitis  them o f  feeding  born w i t h  prematures w i t h  necrotizing  i n t h e management o f  adequate n u t r i t i o n  or abdominal  diarrhea  small  assure  for  tract  kind of support Very  of  are  been u s e d .  d e v e l o p m e n t when m e t h o d s o f o r a l four  (47)  veins.  resulting  is  infant,  rapid  These  include  mineral  and a p e r i o d  of  fluid  deficiencies  from s e p s i s  in the f i r s t  parenteral and e l e c t r o l y t e a n d , most  (11,15,32,83,84).  few weeks  starvation  of  serious  On t h e o t h e r  l i f e , "even more s o  may i n t e r f e r e  with  this  (78,85,86,87).  process  Results adequate achieving  o f many s t u d i e s  calories positive  and n u t r i e n t s nitrogen  have  shown  that  parenteral  is capable of sustaining  balance  in small  premature  nutrition weight  infants  with  g a i n and  (11,80,  12  81,81,88,89,90,93)to  the  increased  In  rate  fact,  of  parenteral  survival  in  nutrition  the  has  contributed  low-birth-weight  premature  i n f a n t (90).  TYPES  3.  OF AMINO ACID MIXTURES  Although solutions  for  protein  associated with  still  widely  by  used  criteria  while result  of  protein  the  is  nutrition,  them.  ( 5 7 ) , b a s e d on  oral  hydrolytic  Long e t  not  ajk  to  (50)  as  partial  determined  retention.  peptides  ( 1 5 ) . The amino a c i d  a random r e s u l t  protein the  bearing  ingestion  no  of  of  levels  reflect  103,104).  Others  have  Since  in  significantly  parenteral  circulation,  and  care  infusate  should  resembles  the  the  that  of  fibrin  in  as  is  of  the  uncertain  in  solutions  terms of  of  the  hydrolysates  of  the  is  fibrin  pattern  seen  after  have d e m o n s t r a t e d  that  plasma  the  infused of  solution  hydrolysate  patterns  solutions  enter  amino a c i d  plasma aminogram o b t a i n e d  (64, solutions  (60,61).  directly  h o m e o s t a t i c mechanisms o f the  hydrolysis  hydrolysate  protein  are  judged  percent  utilization  plasma amino a c i d  that  fibrin  acid  solutions  administration  the  draw-  ( 5 8 ) . As a  which  serum amino a c i d  amino a c i d  taken  partial  hydrolysis  composition of  bypassing be  the  and  value  forty-five  inefficient found  valuable  hydrolysis  fate  Investigators  altered of  to  that  incomplete a c i d  shown  infusions  peripheral liver,  to  biological  amino a c i d  pattern  (58).  amino a c i d  result  due  resemblance to  a meal  thirty  be  c a s e i n and b e e f  undergoes  the m e t a b o l i c  nitrogen  simply  is  of  to  many p r o b l e m s  enzymatic  crystalline  This  are  high  Fibrin  procedure,  ,  as e f f e c t i v e  there  their  nutrition.  subjected  have p r o v e n  Hydrolysates  r e m a i n s as p e p t i d e s ,  (57,67). were  for  casein  hydrolysates  parenteral  backs  AVAILABLE  the  composition of  after  into  a balanced  gut the  meal.  the  13 Other s t u d i e s have found t h a t the f r e e amino a c i d  composition  of f i b r i n p r o t e i n h y d r o l y s a t e s o l u t i o n s vary from the l a b e l (59,60,61).  concentration  Apart from having v a r i a b l e amino a c i d c o m p o s i t i o n s ,  h y d r o l y s a t e s are c o m p l e t e l y  l a c k i n g i n some amino a c i d s .  protein  There i s no  c y s t i n e t o be found i n c a s e i n h y d r o l y s a t e s , so i f used f o r i n f a n t s , becomes e s s e n t i a l (60).  supplementation  u s e f u l n e s s , then,  P r o t e i n h y d r o l y s a t e s have l i m i t e d  i n the s p e c i a l i z e d areas o f p a r e n t e r a l n u t r i t i o n such  as the f e e d i n g o f premature i n f a n t s .  High c o n c e n t r a t i o n s o f g l u t a m i c a c i d  and g l y c i n e have been found in p r o t e i n h y d r o l y s a t e s .  G l y c i n e , infused  a t very high r a t e s , has been found t o produce t o x i c e f f e c t s (68,69). l e v e l s o f g l u t a m i c a c i d can produce "Chinese Restaurant  High  Syndrome",  p r e s e n t i n g symptoms o f nausea, v o m i t i n g , headaches and f l u s h i n g which a r e a m a n i f e s t a t i o n o f t r a n s i e n t a c e t y l c h o l i n o s i s (70,71,71)i n f a n t seems a b l e t o c o n t r o l adequately hydrolysate  However, t h e  the g l u t a m a t e l e v e l s d u r i n g p r o t e i n  i n f u s i o n (59,60).  Another c r i t i c i s m o f p r o t e i n h y d r o l y s a t e s o l u t i o n s i s t h e i r ammonia content may high  (62,63,64,65).  The h i g h  high  i n f u s i o n o f ammonia n i t r o g e n  exceed t h e i n f a n t ' s a b i l i t y t o make urea  (65).  l e v e l s o f blood ammonia may lead t o m e t a b o l i c  In the premature  infant,  a c i d o s i s , as t h e  i n f a n t i s not a b l e t o deal w i t h t h e i n c r e a s e d hydrogen ion l e v e l s which occur c o n c o m i t a n t l y Although  w i t h i n c r e a s e d urea c y c l e a c t i v i t y  more e x p e n s i v e  than p r o t e i n h y d r o l y s a t e , s y n t h e t i c  c r y s t a l l i n e L-amino a c i d m i x t u r e s  o f f e r many p o t e n t i a l b e n e f i t s  They p r o v i d e an enormous degree o f f l e x i b i l i t y the m e t a b o l i c  (61).  (58,59).  and may be t a i l o r e d t o meet  needs o f s p e c i f i c p h y s i o l o g i c a l s t a t e s  (58).  14  The lower  in  incidence of  infants  experience metabolic the  with  given these  acidosis.  a c i d o s i s was  excess  of  metabolic complications synthetic  that  the  metabolic precursors of  hydrogen  ion.  precursor  of  hydrogen  ions.  gap,  in  excess  could  the  the  production  the  addition  in  of  of  crystalline  unlike  protein  of  this  the  very  little  hormonal  of  11,76,77)deficiency {6k). of  The  newer  reasons  A possible of  arginine  exact  (11,64).  as  cause  contained  relation  to  charged by  the  amino  cation  (76,77).  amino a c i d s  releases  hydrogen  The  in  an  important  p r o b l e m was  ions.  role  corrected  amounts  that  would  occur  during  the  not  to  in with  result  This  was  an u n e x p e c t e d  amino a c i d m i x t u r e s  of  administration problem,  showed  aminograms  reflected  this  the  addition  been p r o p o s e d for with  to  explain  this  disorder  the  efficiency  is of  clarification.  not  continued  to  the  presence  finding.  arginine  this  further has  of  as,  contained  solutions  this  as a  ions  the  interferes  metabolic  a c t e d on b a l a n c e ,  reflected  an  (77).  Analysis  explanation  of  hydrogen  synthetic  with  of  of  solutions.  solutions  the  be  Initial  reports  positively  source  a l s o observed  mechanism needs  amino a c i d  consequence  have  in  then,  acidosis.  Plasma  in that  may h a v e p l a y e d  imbalance  ammonia.  arginine.  excess  aspartate  hydrolysates,  ion  presence of  pathway  hyperammonemia was c o r r e c t e d A variety  hydrogen  to  (75).  L-amino a c i d mixtures  charged  observed  amino a c i d  m i n u t e amounts o f of  the  glutamate or  amino a c i d o r  suggested  metabolizable anions,  Hyperammonemia was of  The  positively  activity  of  resulted  The m i x t u r e s ,  have c o n s t i t u t e d  Catabolism of Increased  of  (77)  synthetic  consumers  acids  however,  a 1.,  et  been f o u n d  L-amino a c i d mixtures  solutions, Heird  has  The  hydrochloride.  complex that the With be a  problem  the urea the  relative cycle availabil  serious  15 The  protein  amino a c i d s slightly  as a p a r t  different  (96,155)-  than  same p r o p o r t i o n s  other  proteins  amino a c i d s essential  of  range  should  in  parenteral  nutrition  premature  to  l-5 3-l  should  the  in  total  They  aminogram o f  value  40-50% of  essential  (11,74).  the  ratio  of  utilization  Aspartic  acid,  As provision  part of  expenditure and  the  glycine, of  the  intravenous  and s e r i n e  parenteral  sufficient (11).  vitamins  of  Other  must a l s o  When a l l  utilization  of  METHOD OF ADMINISTRATION  the  amino a c i d s  the  solutions  electrolytes  were  nutrition of  a reality  for  or essential  giving  an  3 (51»55)•  As  h a v e been f o u n d  to  preparation nitrogen  full  electrolytes, nutritive provided  pediatric  dextrose,  nitrogen,  vitamins,  a d m i n i s t e r e d by  inserting  a catheter  (51). (51)-  must be a caloric minerals,  requirements will  are  occur.  I966 D u d r i c k and c o w o r k e r s d e v e l o p e d a t e c h n i q u e o f  made p a r e n t e r a l  in  amino  t o meet t h e  be p r o v i d e d .  4.  Hypertonic  calories  non-  non-essential  program t h e r e  including  efficient  that  nutrition  to  nonspecific  nutrients,  met,  In  amino a c i d  provide  nonprotein  the  as  in  be p r e s e n t  infants,  close  used  proteins,  nitrogen  g l u t a m i c a c i d and p r o l i n e  increase  body  amino a c i d s ,  acids  Alanine,  as w e l l  total  i n c l u d e d among  feeds  solution  the  must be  are  mixture/kg  should  For  (74).  mentioned above a r g i n i n e (64,75)-  program  on o r a l  amino a c i d  contain  L-form  infants  crystalline  g amino a c i d  _  The o p t i m a l  biological  equal  amino a c i d  receiving  from  as found  high  infants  those for  nutrition  amino a c i d s  for  a total  (74,77,155)-  parenteral  essential the  of  Requirements  body w e i g h t / d a y total  requirements  patients minerals through  delivery (53)and an  external  16  or  internal  vena  jugular  cava.  region  of  logical  vein  c u t down a n d t h r e a d i n g  The h y p e r t o n i c rapid  blood  levels.  Thus  solutions,  flow  therefore,  the technical  difficulties  peripherally  a r e overcome.  to  interference  with  Shaw  the inspired  into  of  (156)  diluted  modified  percutaneously  rubber  scalp  needle  into  t h e long  saphenous o r b r a c h i a l  into  Infusion permits  the r i g h t of  c o m p l i c a t i o n s which hypertonic vein  solutions  (91,91)-  enable  early  Occasionally  mixtures  from c e n t r a l  such as s e p s i s  detection  the use o f a s i l a s t i c  mixed w i t h  a f a t emulsion  As c a n be s e e n  amino a c i d  nutrient  concurrently  throughout  a twenty-four  tubing  up t o t h e j u n c t i o n  twenty-four  through a  and then  of the scalp  alleviates  catheterization  before  period with  (91,92,157). vein  vein  when  monitoring feeding  according  Solutions  are administered  the a i d of a  Bottles  patients  intravenously  time-table  (79,93).  four-way  and i n t r a v e n o u s  n e e d l e a r e changed  to a structured  is  solutions are  the v e i n .  and I n t r a l i p i d  hour  (157)-  o r edema  amino a c i d  entering  of the  so as t o  in the p e r i p h e r a l  2,  many  with  and p e r f o r a t i o n  such as r e d n e s s  mixture,  pumps  This  every  hours.  Careful essential  He  a f a t emulsion  n o t be o b s c u r e d  in Figure  (Intralipid)  infusion  (79).  venous  catheter  dextrose,  and c o n s t a n t  containing  thrombosis,  of d i f f i c u l t i e s  (156).  connector  veins  T h e t i p o f t h e n e e d l e must  beneficial  of  nutrient  via peripheral  arise  vein  technique  atrium.  isotonic  administration  this  catheter  silicone  physiohypertonic  concentration.  fine  it  to  oxygen  a very  threaded  into a  infusing  introduced vein  the superior  are infused  and a r e i n s t a n t a n e o u s l y  solutions reduce  it  is  17  Fig 2  Electrolyte Solution  PARENTERAL NUTRITION USING PERIPHERAL VEINS  Amino Acid Nutrient Mixture  Intra lipid 10%  100 ml Burrette  18  C.  AMINO ACID  1.  NORMAL  PHYSIOLOGY  Free body.  to  amino a c i d s  Plasma  total  free  amino a c i d  in  release  of  from the the  from  the  into  in  the  and t h e  the  rate  vein  glutamic  is  the  The g u t  characterized  (98)  have  are  passed  ingested shown into  that  nitrogen after  acid.  amino a c i d  to  amino a c i d s  (99).  also  alanine  (10).  rich  are  protect This  the  they  the  of  are  The the  catabolized  in  the  the  the  from w i l d l y selective liver.  by  the  The  and an  fact  role  studies  response of  mechanism i s  amino a c i d s  constituent  23% o f  acid  homeostatic  alanine  despite  Animal  body  arising  metabolized  of  an a c t i v e  meal o n l y  of  a b s o r b e d amino  the  plays  acid  rate  considerable  occurs  in  proteins  The o u t f l o w  20-30%  circulation.  mechanism to  levels  for  This  them  changes  amino  a predominance of  The gut  a protein  the general  a buffering  essential  protein.  to which  exerts  the  pattern  the  endogenous  (129). by  has c a u s e d  emptying,  of  the  (9*0-  d e p e n d on  the  the  amount o f  amino a c i d  gastric  of  represent  pool  removal  amino a c i d s  and a s p a r t i c  ingested  They  extent  of  small  may n o t  plasma f r e e  digestion,  tract,  of  they  of  tissues  accessibility  amino a c i d  rate  and  relatively  complex.  during  levels  fluids  Their  and a s p a r t a t e may a c c o u n t  converting  provide  in  (97,100,102,128).  portal  glutamate  the  liver,  on b l o o d  absence of  plasma  and  free  are  protein,  amino a c i d s  a  though  place  proteins  the  blood  the  acids  of  take  all  (7^,9*0.  total  gastrointestinal  gut  control  that  in  constitute  pool  body's  to oral  composition  found  s a m p l e d , even  the  Changes response  are  amino a c i d s  be f r e q u e n t l y  occurring  by  METABOLISM  that  amino in Elwyn  amino a c i d s liver  is  to  fluctuating  as o n l y  some  of  branched-chain  19 amino a c i d s  (leucine,  circulation  (10,99,129).  degree  of  control  liver  exert  after  a protein  increase The  by  a great  After  are  deal  amino a c i d  continuously  the  after  released  unexpected  its to  to  form a l a n i n e  free  amino a c i d  control  of  since  where  is  is  of  AMINO ACID  When e i t h e r  protein  and g u t  upon  circumstances utilization  removal  for  of  to  the  the  the  a  gut  greater and  the  absorptive  period  also  source  the the  major fasted  to  alanine  The  is  in  comprises This  less  levels  in  third both  than  pyruvate  and  The  the  of  glutamine  alanine  is is  of  10%  in  the  state  the  explained  amino by  the  transaminated  t a k e n up by  major  (7^,129).  postabsorptive  movement  branched-chain  to  repletion  alanine  the  to g l u c o s e .  the  for  predominance of  subsequently  the  Insulin acts  muscle p r o t e i n  state  liver  (150).  is  by  rises.  in  the  liver  where  nitrogen  group  needed  amino a c i d s factor  of  absorptive  (129).  The  homeostatic and f a s t i n g  state.  MIXTURES  of  these  in  are In  muscle  intravenously  liver  Both  into  reconverted  administered the  (9*0 .  glucose-derived  supplied  pool  level  from muscle  plasma amino a c i d  INFUSED  2.  cycle  skeleton  into  subjected  control  from m u s c l e .  form a l a n i n e which  carbon  are  directly  incorporation  in muscle p r o t e i n  g1ucose-alanine muscle  and  a meal.  is  residues  tissues  homeostatic  amino a c i d s  amino a c i d s  acid  amino a c i d s  insulin  uptake  movement o f somewhat  of  pass  meal.  t h e meal  nitrogen  These  and v a l i n e )  extrahepatic  rich  branched-chain  muscle  isoleucine  hydrolysates the  amino a c i d s  and e n t e r  the  regulation  of  amino a c i d s  c a t a b o l i s m or  for  or  bypass  peripheral  L-amino  the m e t a b o l i c  circulation  plasma amino a c i d  for  body  crystalline  acids  alterations  directly.  concentrations  body  protein  synthesis  pools  such as  those  of  and  are  the  muscle.  Under depend rate  of  20  Equilibrium  i s c o n t r o l l e d by a d j u s t i n g  rate of t i s s u e synthesis.  the r a t e o f i n f l u x t o equal t h e  Excess amino a c i d s are d i v e r t e d t o energy  p r o d u c i n g pathways.  Anderson e_t a_l_. , (104)  a l s o found t h a t the r a t e o f  change o f amino a c i d  l e v e l s was a f f e c t e d by endogenous r e g u l a t i o n .  This  r e g u l a t i o n o c c u r s i n d e p e n d e n t l y f o r each amino a c i d . If e i t h e r the p r o t e i n h y d r o l y s a t e s are  infused  intravenously  o r s y n t h e t i c L-amino a c i d s  one would c e r t a i n l y expect t o see a v e r y  d i f f e r e n t plasma amino a c i d p a t t e r n  than t h a t o b t a i n e d  a f t e r f e e d i n g an  o r a l meal.  A l l o f the amino a c i d s , r a t h e r than a s e l e c t e d  plasma pool  (101).  i n terms o f m o d e l l i n g  the plasma amino  pattern. Currently  i t i s f e l t t h a t the  i d e a l amino a c i d m i x t u r e should mimic  the plasma amino a c i d p a t t e r n found in the p o s t - a b s o r p t i v e amino a c i d early  enter the  C r y s t a l l i n e amino a c i d s o l u t i o n s o f f e r a g r e a t e r  degree o f c o n t r o l than h y d r o l y s a t e s acid  few,  l e v e l s in the b l o o d , l a s t i n g over long p e r i o d s  i n l i f e may have s e r i o u s consequences (67,68).  (106), found t h a t c e r e b r a l uptake o f amino a c i d s arterial  concentration.  constitutes a c r i t i c a l  This  state.  Abnormal  and o c c u r r i n g  Settegren e t a l . ,  is proportional  to their  i s o f p a r t i c u l a r i n t e r e s t as i n f a n c y  period o f cerebral  growth (78,85,86,87).  I t i s now  known that e l e v a t i o n and imbalance o f some c i r c u l a t i n g amino a c i d s may have harmful e f f e c t s , p a r t i c u l a r l y on the d e v e l o p i n g c e n t r a l nervous system (107). C a r e f u l a t t e n t i o n , then, must be p a i d t o plasma amino a c i d l e v e l s i n o r d e r to p r o p e r l y  evaluate  what i s c o n s i d e r e d  a c i d s t o premature i n f a n t s (108).  t o be an o p t i m a l  s u p p l y o f amino  21  3.  PLASMA AMINOGRAMS The aminogram i s a measurement o f the r e l a t i v e amounts o f f r e e  amino a c i d s found i n the plasma.  S i n c e the plasma aminogram o f the  i n f a n t responds q u i c k l y t o any a l t e r a t i o n i n p r o t e i n  i n t a k e , i t may be  a s e n s i t i v e i n d i c a t o r o f the s t a t e o f p r o t e i n n u t r i t i o n (95,113)has  been w i d e l y  used f o r the e a r l y d e t e c t i o n of m a l n u t r i t i o n  Investigators  studying  (109).  plasma amino a c i d l e v e l s i n m a l n u t r i t i o n  proposed d i f f e r e n t amino a c i d r a t i o s t o e v a l u a t e p r o t e i n adequacy.  It  n u t r i t i o n s t a t u s and  These i n c l u d e Whitehead's r a t i o  (111,112) g l y c i n e / v a l i n e  q u o t i e n t s , g l y c i n e v a l u e s and the a 1 a n i n e / v a 1 i n e q u o t i e n t Whitehead's r a t i o was based on the s e p a r a t i o n  (110,151) •  of amino a c i d s by one-  d i m e n s i o n a l paper chromatography i n t o groups o f amino a c i d s t h a t were a m i x t u r e of s e v e r a l compounds. a c i d s " contained  The group i s o l a t e d as " e s s e n t i a l amino  the branched-chain amino a c i d s  isoleucine) plus methionine.  ( v a l i n e , l e u c i n e and  H i s " n o n - e s s e n t i a l " group  contained  g l y c i n e , s e r i n e , g l u t a m i n e and t a u r i n e .  The b a s i s f o r Whitehead's  r a t i o was t h a t d u r i n g  i n t a k e the branched-chain amino  restricted protein  a c i d s , p a r t i c u l a r l y v a l i n e , decreased, while g l y c i n e , a amino a c i d  increased.  A r r o y a v e (146) p r e f e r e n t i a l l y suggests the use o f  the v a l i n e / g l y c i n e q u o t i e n t .  I t i s the most s e n s i t i v e r a t i o as v a l i n e  d e c r e a s e s and g l y c i n e i n c r e a s e s undernutrition.  non-essential  i n the plasma very e a r l y i n p r o t e i n  I t t h e r e f o r e , has a h i g h e r d i s c r i m i n a t i n g power f o r  moderate p r o t e i n c a l o r i e m a l n u t r i t i o n .  22  D.  PITFALLS IN STUDYING PLASMA AMINOGRAMS There i s a g r e a t deal o f v a r i a b i l i t y  reported  i n the l i t e r a t u r e .  i n plasma amino a c i d  values  T h i s i s due t o the many f a c t o r s which  i n f l u e n c e plasma amino a c i d v a l u e s but which do not remain c o n s t a n t between s t u d i e s .  Some o f these f a c t o r s a r e : h a n d l i n g o f the sample p r i o r  t o and d u r i n g a n a l y s i s (147), age and sex o f the s u b j e c t , (131) whether the sample i s taken d u r i n g a f a s t i n g o r f e d s t a t e , and the d i e t consumed (95,1-02,103,105). There a r e many e r r o r s t h a t can o c c u r p r i o r t o and d u r i n g a n a l y s i s of the plasma samples (147).  Delay  i n d e p r o t e i n i z i n g the plasma  results  in l o s s o f c y s t e i n e and c y s t i n e by d i s u l f i d e b i n d i n g t o s u l f h y d r y l o f plasma p r o t e i n s .  Contamination  groups  o f the plasma w i t h l e u c o c y t e s and  p l a t e l e t s d u r i n g t h e p r e p a r a t i o n f o r a n a l y s i s can r e s u l t i n abnormal o f some amino a c i d s .  Soupart  (153) has shown t h a t the c o n c e n t r a t i o n o f  t a u r i n e and a s p a r t i c a c i d i s a p p r o x i m a t e l y and  l e u c o c y t e s than  cells.  levels  i n plasma.  500 times h i g h e r i n p l a t e l e t s  Glutamic a c i d  i s a l s o much h i g h e r i n these  Plasma must, t h e r e f o r e , be s e p a r a t e d from blood b e f o r e the  spontaneous r u p t u r e o f p l a t e l e t s o c c u r s .  A c c i d e n t a l hemolysis  o f red c e l l s  r e s u l t s i n i n c r e a s e d t a u r i n e , g l u t a m i c , and a s p a r t i c a c i d l e v e l s . levels are s i g n i f i c a n t l y  lowered.  Cystine  In a d d i t i o n , o r n i t h i n e c o n c e n t r a t i o n s  are doubled w h i l e a r g i n i n e l e v e l s a r e h a l v e d , p r o b a b l y , due t o the r e l e a s e of a r g i n a s e from the red c e l l s  i n t o the plasma.  i z i n g agent can a f f e c t r e s u l t s . t h i s procedure.  Partial  The c h o i c e o f d e p r o t e i n -  Many r e s e a r c h e r s used p i c r i c a c i d f o r  l o s s e s o f t r y p t o p h a n have been noted  the use o f t h i s agent (147)•  to occur with  Storage o f d e p r o t e i n i z e d plasma a t -20° C  23  over  long  periods  glutamine glutamic below  and  even  C will  that  when  high  temperatures.  certain plasma  amino a c i d  higher  rapidly  In  and g l y c i n e .  for ln  all  suggest  that is  adults  (ages  amino a c i d s (ages  6-18  for  isoleucine,  phenylalanine,  lysine,  combine the There  were  data  in  children  (136).  Concentrations during  amino a c i d s  day o l d  newborn  of  for  other of  e_t a_l_. , (135) infants.  plasma  the  a few  free  years)  relatively should  factors the  the  they  to a  variability  in  and  found  levels  of  found  Men had  threonine, significant including  tryptophan.  in  significant  amino a c i d s .  amino a c i d s ,  histidine  serine sex  methionine,  This  allowed  boys. correlations  between  plasma  two a m i n o a c i d s :  cystine  and  correlation studied  not  vary  amino a c i d  they  exception  amino a c i d s ,  They  carboxylic  at  these  (147)  literature.  threonine,  g r o w t h and d e c r e a s e d  no p o s i t i v e  to  temperatures  temperature  increasing  years)  and  of  and Hansen  operated  most o f  positive  and a d u l t s  periods  showed  Dickinson  from g i r l s  significant  and a g e  only  at  pyrolidone  All  18-77  with  i n mean v a l u e s  increased  the  values  be h y d r o l y z e d  Perry  column  eluted.  in  differences  them t o  the  studied  (131)  to  studies,  reported  children  to  Storage  columns a r e  b e t w e e n men and women f o r  values  thought  cyclized  analyzer  and S t a v e  lowered  from happening.  and between  values  and c h i l d r e n .  differences  this  is  in  conditions.  the g l u t a m i n e  degree w i t h i n  Armstrong adults  They  C until  35°  these  is  amino a c i d  results  Glutamine  under  glutamine  the  (3 m o n t h s )  prevent  acid  exceed  time  tryptophan.  acid,  -68°  suggest  of  with  plasma  observed  that  serine  throughout  levels  alanine and  asparagine  maturity.  Other  age.  amino a c i d newborns  levels  in  had h i g h e r  25  one^  values  of  2k  taurine,  threonine,  and o r n i t h i n e than  those  were  also  found  levels  stable  threonine, decreased.  serine, By  within  asparagine,  the end o f but  asparagine, elevated.  adult  glutamine,  on p l a s m a a m i n o a c i d other not  variables  pool.  glutamine,  the  a  level  fifth  ranges.  e_t aj_. ,  the  for  of  that  gestational  large  number o f  threonine,  study,  It  took  readily age,  and  in  showed a  times  serine  of  apparent.  and e x a c t  variables  the  lysine  the  week most v a l u e s  effect  after  taurine,  tyrosine  were  under  concentra-  and  and h i s t i d i n e , the  of  birth  while  three  Dickinson  Amino a c i d  alanine  week  but  a few d a y s  Increases  about  ornithine  were  acid,  46 i n f a n t s  glycine,  period  taurine  in  tyrosine  postnatal  (13*0 f e l t  later  to develop.  The e x c e p t i o n s  concentrations sex,  a  levels  second p o s t n a t a l  methionine,  such as  m e a s u r a b l e due t o  ami no a c i d  After  In  each amino a c i d .  remained at  control  Dickinson  the  Aspartic  t h e week a f t e r  found  life  and u r e a a l s o d r o p p e d ,  patterns  few d a y s w e r e  concentration. the  for  citrulline  day o f  35 weeks.  during  and  i m m e d i a t e newborn  range.  values.  age o f  rapidly  the third  tryptophan  newborn  phenylalanine  arginine  the  plasma amino a c i d  change  first  marked d e c r e a s e , adult  range o f  characteristic the  by  the o r i g i n a l  plasma amino a c i d  appeared to  during  leucine,  that  a mean g e s t a t i o n a l  changes were tion  found  lysine,  (13*0 l o o k e d a t  for  of  tyrosine,  Changes w i t h i n  below  phenylalanine,  2500 g with birth  They  the  glycine,  values  in a d u l t s .  had f a l l e n  remained w i t h i n e_t a_l_. ,  lower  studied.  and a l a n i n e glycine,  and  glutamine,  normal were  and which  remained  postnatal  The e f f e c t  b i r t h weight  which  age  influence  of  were the  25 Data blood For  f r o m most  samples  infants  after  the  controls  in  in  This  which  occur  during  and  high  9 protein/kg  (1.9  increase  in  protein  was  elevation  in  threonine,  tyrosine  and p h e n y l a l a n i n e .  level  infants. days  as  were  this  protein.  On t h e  were  for  Rigo  feeding  effects  while  of  (42)  in  to to  low 3-2  was  and  g/kg  and  higher the  feed.  hours  concentration  is  the  low,  effect  of  proline,  p l a s m a a m i n o g r a m s as  prolonged.  tyrosine  lower  average  Glycine  depressed.  values  seen  effect  of  the  for  human m i l k  in  a  iso-  influence  in  newborn  early  and  as  two  serine  (leucine, They  also  to  plasma amino a c i d  alanine,  weight).  resulted  as opposed  isoleucine, were  body  became more  amino a c i d s  were  from  cystine,  studied  changes  plasma  leucine,  concentrations  These  in  changed  weight  valine,  of  concentrations  decrease  body  amino a c i d m i x t u r e s  diets  a  four  g protein/kg  (0.2  branched-chain  feeding  studied  the  to  homeostatic  i n t a k e was  glutamine,  intake.  the  valine  and c i t r u l l i n e ;  and S e n t e r r e  protein  on p l a s m a a c i d  pattern  lysine  amino a c i d  leucine,  1.9  studied  S n y d e r m a n e_t a_l_. , (95)  protein  and v a l i n e ) , the  asparagine  in  the  no s i g n i f i c a n t  asparagine,  intake  taken  on p l a s m a a m i n o a c i d  that  weight)  alterations  elevated,  looked at  seen  protein  reduction  pronounced  isoleucine  serine,  She n o t e d  after  levels  of  (137)  plasma c o n c e n t r a t i o n s  leucine,  the  intake  of  is  plasma amino a c i d  s e e n when  intake  sample  prior  Fasting  state.  Holmgren  body  subjects.  immediately  time emphasizes  affects  He f o u n d  concentration  taken  fasting  protein  7~13).  (age  significant  of  the  from f a s t i n g  a blood  sampling  which  dietary  blood  usually  (42,95,113,127,138).  amino a c i d  An  factor  use  feeding  feed.  children  normal  are  last  diet  normal  infants  on f o u r - h o u r l y  Another the  studies  whole values  ornithine, threonine  and  and h u m a n i z e d  serine. milk  26  formulas  on p r e m a t u r e  milk  lower  fed  had  infants.  protein  e_t a_L ,  methionine suggest  that  a  high  the the  to  quantities  p l a s m a and capacity  cystine  is  a  quantity  study  system f o r  limited  the  They  greater  in  the than  levels  felt  infants the  of  fed  than  was  infants  related  occurred  tyrosine  was  with  known  the  far  greater  in  infant  limitation  is  of  to  milk  They  levels the  found of  urine.  to  They  convert  a function  acid than  (138) l o o k e d a t  tyrosine  the  of  these aromatic  phenylalanine  loads  breast  resulted  adequately.  and t y r o s i n e k.5 g  in  development  amino a c i d s  containing  of  were  pooled  The  h y p e r p h e n y 1 a 1 a n i n e m i a and  been a r e s u l t  of  of  milk  (approximately  a delayed  maturation  T h e mean c o n c e n t r a t i o n phenylalanine.  phenylalanine  hydroxylase  This in  consider-  protein/kg  fed  oxidase. those  effect  and p h e n y l a l a n i n e  increased protein  may h a v e  presence of  had e l e v a t e d  incomplete biochemical  infants  tyrosinemia  p-hydroxyphenylpyruvic  infants.  cystathionine  formulas  body w e i g h t / d a y ) .  that  protein  of  that  1.7 9 p r o t e i n / k g  1i v e r .  breast  the q u a n t i t y  premature  This  to m e t a b o l i z e  in  in  of  human p r e m a t u r e  the metabolism of  ability  body w e i g h t / d a y  of  fed  activity.  The mean p l a s m a c o n c e n t r a t i o n s ably  (95) t h i s  effects  R a s s i n et^ a_l_. ,  on p l a s m a  infants.  of  limited.  In  later  the  increased  of  low c y s t a t h i o n a s e  premature  in  infants  most a m i n o a c i d s  by o t h e r s  amino a c i d s  or  protein  the  fed  in  methionine  of  shown  (56) s t u d i e d  on p l a s m a s u l f u r  infants  absent  As  of  that  intake. Gaull  that  found  plasma c o n c e n t r a t i o n s  humanized f o r m u l a s .  protein  They  is  of  plasma  compatible  immature human  27  Urea i s one o f the end p r o d u c t s of p r o t e i n c a t a b o l i s m . i n f a n t s i t s c o n c e n t r a t i o n in the blood protein  intake.  i n f a n t s fed cow's m i l k The  i s in p a r t a r e f l e c t i o n o f d i e t a r y  Davies and Saunders (139)  blood urea c o n c e n t r a t i o n s  In young  found s i g n i f i c a n t l y  i n i n f a n t s fed human b r e a s t m i l k than i n  formulas.  l a s t t h r e e s t u d i e s have p o i n t e d out t h a t abnormally  concentrations of methionine, of high p r o t e i n i n t a k e .  lower  p h e n y l a l a n i n e and  Increased blood urea  high  t y r o s i n e are a r e s u l t  l e v e l s a l s o suggest t h a t  amino a c i d s a r e used w a s t e f u l l y f o r energy purposes when p r o t e i n i s i n excess. The  type o f the amino a c i d m i x t u r e or p r o t e i n h y d r o l y s a t e i n f u s e d  i n t r a v e n o u s l y a l s o a f f e c t s the v a l u e s of the plasma aminogram. balanced  s o l u t i o n w i l l cause a r a p i d f a l l  o f the f i r s t l i m i t i n g amino a c i d  (107).  i n the plasma c o n c e n t r a t i o n Beef f i b r i n h y d r o l y s a t e c o n t a i n s  equal molar q u a n t i t i e s o f p h e n y l a l a n i n e and results  i n a plasma r a t i o o f 1:1  r e c e i v i n g such p r e p a r a t i o n s .  A poorly  t y r o s i n e (102).  f o r these amino  This  acids in infants  When compared w i t h a c a s e i n h y d r o l y s a t e  p r e p a r a t i o n the beef f i b r i n h y d r o l y s a t e has a lower a b s o l u t e amount of phenylalanine than  (102) hence the plasma l e v e l s of p h e n y l a l a n i n e are  in i n f a n t s i n f u s e d w i t h a c a s e i n h y d r o l y s a t e p r e p a r a t i o n .  l e v e l s o f g l y c i n e , c y s t i n e , a r g i n i n e and r e c e i v i n g beef f i b r i n h y d r o l y s a t e than hydrolysates  (102).  lower Plasma  t h r e o n i n e are h i g h e r i n i n f a n t s  in i n f a n t s infused with casein  T h i s supports o t h e r i n v e s t i g a t o r s ' c l a i m s t h a t plasma  aminograms a r e a f f e c t e d by the k i n d of amino a c i d m i x t u r e  infused  (64,  103,104). Intravenous mixtures  f e e d i n g w i t h s y n t h e t i c c r y s t a l l i n e L-amino a c i d  has been shown to a f f e c t plasma amino a c i d p a t t e r n s .  A well  28  designed  s o l u t i o n s h o u l d r e s u l t i n a plasma aminogram which c l o s e l y  resembles normal v a l u e s . and  D i f f e r e n c e s between aminograms o f o r a l l y  i n t r a v e n o u s l y f e d p a t i e n t s c o n t i n u e t o e x i s t but g e n e r a l t r e n d s i n  these d i f f e r e n c e s have not as y e t been e s t a b l i s h e d . (141)  looked a t the e f f e c t . o f an e x p e r i m e n t a l  L-amino a c i d m i x t u r e They found  Ghadimi and Abaci  synthetic crystalline  (not Vamin) on t h e plasma aminogram i n a d u l t s .  t h a t aminograms from p a t i e n t s r e c e i v i n g t o t a l  intravenous  n u t r i t i o n compared f a v o u r a b l y w i t h c o n t r o l v a l u e s from h e a l t h y a d u l t s . The o n l y s i g n i f i c a n t d i f f e r e n c e s lower  were h i g h e r l e v e l s o f methionine and  l e v e l s o f c y s t i n e i n the p a t i e n t s f e d i n t r a v e n o u s l y .  study plasma aminogram v a l u e s from c h i l d r e n  (ages  In the same  1 month-7 y e a r s ) ,  r e c e i v i n g the same amino a c i d m i x t u r e , f e l l w i t h i n the normal range f o r t h i s age group (141). be above normal.  The mean v a l u e o f g l y c i n e , however, was found t o  In another s t u d y , Ghadimi et_ aj_. , (140) examined plasma  amino a c i d s i n premature i n f a n t s o f l o w - b i r t h - w e i g h t , r e c e i v i n g intravenous n u t r i t i o n . c l o s e l y resembled  They found  total  t h a t plasma amino a c i d p a t t e r n s  cord v a l u e s , w i t h t h e e x c e p t i o n o f t h r e o n i n e and l y s i n e  l e v e l s which were much lower.  Shaw et_ aj_. , (154)  between the serum aminograms o f f u l l  term  s t u d i e d the d i f f e r e n c e s  i n f a n t s f e d b r e a s t m i l k and  i n f a n t s r e c e i v i n g p a r e n t e r a l n u t r i t i o n w i t h Vamin.  Although  no s e r i o u s  a b n o r m a l i t i e s were seen i n the aminograms o f the i n f a n t s i n f u s e d w i t h Vamin some d i f f e r e n c e s were noted.  Serum l e v e l s o f p h e n y l a l a n i n e , p r o l i n e ,  g l y c i n e , and s e r i n e were h i g h e r i n the i n t r a v e n o u s l y f e d i n f a n t s whereas low l e v e l s were found  f o r l y s i n e and l e u c i n e (154).  Plasma amino a c i d i n f u s i o n o f amino a c i d s .  l e v e l s a r e dependent on t h e r a t e o f i n t r a v e n o u s These l e v e l s i n c r e a s e w i t h f a s t e r i n f u s i o n r a t e s  29  (102,102,105).  I f the i n f u s i o n i s a d m i n i s t e r e d  hyperaminoacidemia  o r hyperammonemia may  a t too f a s t a r a t e , then  r e s u l t (102).  Dale et a 1.,  (105) found t h a t p r o l i n e , g l u t a m a t e , and the branched-chain amino a c i d s ( l e u c i n e , i s o l e u c i n e and v a l i n e ) w i t h the i n c r e a s i n g  increased  infusion rate.  tyrosine, histidine,  significantly  Other amino a c i d s , such as c y s t i n e ,  l y s i n e and a r g i n i n e , d i d not i n c r e a s e  i n f u s i o n r a t e of 350 mg n i t r o g e n / k g  E.  p r o g r e s s i v e l y and  up';to an  body weight/day.  KIL0CAL0RIE:NITROGEN RATIO -- A REFLECTION OF SATISFYING PROTEIN AND  ENERGY REQUIREMENTS I t has been noted t h a t the e x t e n t to which amino a c i d s a r e  u t i l i z e d f o r protein synthesis  is d i r e c t l y proportional  p r o t e i n c a l o r i e s u p p l y (114,121).  The  to the non-  r e l a t i o n s h i p between p r o t e i n  u t i l i z a t i o n and n o n - p r o t e i n c a l o r i e s i s a complex one, depending many v a r i a b l e s , such as the amount of a c t i v i t y u n d e r t a k e n , of i n f e c t i o n o r trauma and the n u t r i t i o n a l  on  stresses  s t a t u s of the p a t i e n t .  the s u r g i c a l p a t i e n t , Moore (158) suggested a k i 1 oca 1 o r i e : n i t r o g e n of 150:1.  Lee et_ a_l_. , (122) s t u d i e d  f o r the p a t i e n t w i t h r a t i o o f 200:1. care p a t i e n t s  renal f a i l u r e .  Peaston  For ratio  the adequacy of p a r e n t e r a l n u t r i t i o n He suggested a ki1 oca 1 o r i e : n i t r o g e n  (121) a l s o p r e f e r r e d  receiving total parenteral  this ratio for intensive  nutrition.  The  kilocalorie:  o  nitrogen Periods  r a t i o may  v a r y , depending on the s t a t e and needs of the p a t i e n t .  of r a p i d growth may  The r a t i o , t h e n , may  a l s o a f f e c t the k i l o c a l o r i e : n i t r o g e n r a t i o .  be d i f f e r e n t f o r premature  i n f a n t s than f o r a d u l t s .  Chen et^ aj_. , (114) found t h a t the u t i l i z a t i o n o f amino a c i d s reached a maximal l i m i t when 450 k c a l / g n i t r o g e n was p r o v i d e d .  Since  30  Rose e_t a j _ . , (124)  suggested t h a t d i f f e r e n t p r o t e i n sources  d i f f e r e n t q u a n t i t i e s of c a l o r i e s t o maintain reasonable  t o suspect  nitrogen balance,  i t may be  t h a t d i f f e r e n t amino a c i d s o l u t i o n s have d i f f e r e n t  c a l o r i e requirements f o r t h e i r o p t i m a l (114)  required  utilization  (114).  Chen e t a 1.,  used Sohamin as the n i t r o g e n source i n t h e i r study and found i t  r e q u i r e d 450 k i l o c a l o r i e s f o r the complete u t i l i z a t i o n o f one gram o f nitrogen.  Hendry e_t a_l_., (1 55)  compared Vamin and A m i n o f u s i n as n i t r o g e n  sources and found t h a t Vamin r e q u i r e d an average o f 245 k c a l / g w h i l e A m i n o f u s i n o n l y needed 217 k c a l / g n i t r o g e n .  nitrogen  They a l s o found  that  Vamin-fed i n f a n t s showed more e f f i c i e n t u t i l i z a t i o n o f t h e i r p r o t e i n s o u r c e i n terms o f n i t r o g e n b a l a n c e . r a t i o remains u n d e f i n e d . of 200 k c a l / g n i t r o g e n  F.  The o p t i m a l  k i 1 oca 1 o r i e : n i t r o g e n  Many regimes a d m i n i s t e r a s o l u t i o n w i t h a r a t i o (90,115) -  GROWTH PARAMETERS I n t r a u t e r i n e growth c h a r t s , based on data o b t a i n e d  neonatal  from a l a r g e  p o p u l a t i o n a r e used t o e v a l u a t e growth p o s t n a t a l l y (43,116,117).  Measurements o f w e i g h t g a i n , head c i r c u m f e r e n c e , r o u t i n e l y t o assess  and body l e n g t h are done  growth and development of t h e i n f a n t on t o t a l  parenteral  n u t r i t ion. Cashore e_t a_K , (125) u s i n g growth c h a r t s developed by Usher and McLean (126)  found t h a t i n f a n t s w e i g h i n g more than 1000  of 6.2% o f t h e i r b i r t h w e i g h t and regained days.  g l o s t an average  i t a f t e r an average o f e i g h t  A f t e r t h i s catch-up p e r i o d a w e i g h t g a i n o f 20 g/day was a c h i e v e d .  These i n f a n t s r e c e i v e d 90 k c a l / k g body weight/day i n t r a v e n o u s l y .  Other  s t u d i e s have shown a weight g a i n o f 24-40 g/day i n i n f a n t s o f d i f f e r e n t g e s t a t i o n a l ages (116,118).  H e i r d and W i n t e r s (159)  showed a w e i g h t g a i n  31  of  11.8  (125) half  g/kg/day  showed of  during  the the  that  first  requirements fluid  infants  infants  expected  Weight  body  in  of  This  "Catch-up"  of  than  growth  1000  rate  Cashore et  g gained only  for  26-29 weeks  a1 . ,  one  gestation  life.  not  the  best  in  measurement o f  (118,119,120).  infants  used  kcal/kg/day.  of  the  conjunction  It  the  may s i m p l y  adequacy of  with  nutritional  head  reflect  growth  is  circumference  head  is  valuable  gestational  g r o w t h may be s l o w head g r o w t h o c c u r s to  better  in  the  first  age and h e a l t h  initially between  in  the  nutritional  few weeks of  infants  third intake  and  the  of  postnatal  infant  (160,  who a r e  very  seventh  postnatal  and an  improved  ill.  state  of  (161).  reported  for  have  standard  shown  fetuses  that (127,  length  measurements p a r a l l e l e d  Dr.  Pendray,  M.  personal  values  communication).  SUMMARY  The of  is  on t h e  Some s t u d i e s  G.  less  A good e s t i m a t i o n  the  week c o r r e s p o n d i n g  health  of  100  length.  depending  161).  is  premature  changes.  Growth life,  weeks  alone  a c h i e v e d when w e i g h t and body  weighing  intrauterine  three  gain  receiving  the  literature  adequacy of  improved  quality  protein  premature  growth  critical  on o p t i m a l  levels  indicates  given  and a v a i l a b i l i t y  number o f is  reviewed  infants during  of  have  the  during of  need  parenteral  amino a c i d  benefitted  perinatal  circulating  the  for  nutrition.  solutions  from t h i s  period  amino a c i d s .  continual  an  assessment With  increased  technique.  and d e p e n d s  in  the  Cerebral  part  The p l a s m a a m i n o g r a m  32  is  a useful  way  standardized infants  evaluate  normal  receiving  evaluation been  to  of  achieved.  the  protein  nutrition.  plasma aminograms f o r  parenteral protein  nutrition,  nutrition  the  There  no  assessment of  therefore,  given  are  these  adequate premature  satisfactory  infants  has  not  yet  33  CHAPTER  MATERIALS  A.  AND METHODS  THE CONTROL GROUP  Approval the  III  Screening  for  this  section  Committee f o r  of  the  project  R e s e a r c h and O t h e r  Human S u b j e c t s :  Clinical.  Two n u r s e r i e s  patients  study:  Intensive  to  the  General  Hospital,  Letters  of  could  the  be  and/or  control  conception  at  sent  study,  the  author  consent.  but  had no o t h e r  on f e e d s o f  SMA^g.  or  scoring  at  in  an  infants  Grace  of  that  with  infant  and the  mother  and  their  approached  infants  in  the  the  seven at  determined  (152).  These  others  minimal j a u n d i c e . by  33~35  both  infants  Some r e q u i r e d  fed e i t h e r  the  B).  a g e was  incubator,  the  an  30-32 weeks;  methods  were  Hospital.  involved  physician  abnormalities.  had t r a n s i e n t  These  six  Gestational  prematurely  spells  the  Vancouver  informed  16 premature  age c a t e g o r i e s :  were m a i n t a i n e d  or  contributing  the  most  order  be  in  a copy  (See A p p e n d i x  c o n s i s t e d of  36-38 weeks.  with  physician  Either  Dubowitz  mild apneic  the  In  c o n c e r n e d had t o  and  i.e.,  A).  infant  group  at  pediatricians  both  dates  control,  study,  at  from  Involving  involved  Care Nursery  the  to  were  Studies  Care Nursery  (See A p p e n d i x  signed  gestational  and t h r e e  outlining  the  the  and o b t a i n e d  following  born  of  in  granted.  The  weeks  newborns.  father  Intensive  form were  included  permission parent  and t h e  introduction  informed consent care of  the  was o b t a i n e d  by were  thermal  suffered  from  All  were  maintained  bottle  or  by  gavage  feed i ng. SMA^Q composed o f  is  a h o m o g e n i z e d and s t e r i l i z e d  nonfat  cow's  milk,  formula  d e m i n e r a 1 i z e d whey,  for  infants.  lactose,  animal  It and  is  34  vegetable milk  it  fats,  is  relative  found  to  of  1isted  were  collected  infants  were  fed  time of  blood  full  (07:00)  B.  STUDY GROUP  in  These  between  infants  quantities  were  Care  and c a r e f u l  monitoring.  infants  were  shows  the q u a n t i t i e s  fluid  was a d m i n i s t e r e d  solution.  contains  all  to  and m i n e r a l s  for  blood  sample  7 1 & days -  it and milk  of  collection. age.  body w e i g h t / d a y ) at  I n f a n t s were  Nursery  support  acid  formula  selected with  gestation.  (the  and  SMA^Q and human b r e a s t  (150 ml/kg  sometime d u r i n g  2 4 - 2 8 weeks  Vamin,  type  least  fed  the  1-2  three  every hour  The of  days  three period  SMA^^, prior  hours  to  and  after  the  first  morning.  infants  These  the  breast  f o r m u l a c o m p r i s e s 6 0 % whey  the  from  of  were  to  carbohydrate  prior  taken  the  Intensive  respect  standardized  blood c o l l e c t i o n .  feed  in  c o m p o s i t i o n of  g p r o t e i n / 1 0 0 ml  s a m p l e s were  from the  component o f  were  Samples  the  similar  When c o m p a r e d t o  1.  in T a b l e  1.5  and m i n e r a l s .  protein,  The a m i n o a c i d s  Conditions  providing  fat,  The p r o t e i n  40% c a s e i n .  vitamins  be c l o s e l y  proportion  contains.  are  lecithin,  of  at  the  total  nutrients/kg providing  nitrogen  the e s s e n t i a l  the  the  infants  parenteral  nutrition.  a synthetic  composition  amino a c i d s  body  in  Table  2  150 ml  of  weight/day.  crystalline  the  Six  respiratory  supplied.  c a n be f o u n d  discussed  Hospital.  required  body w e i g h t / d a y  is  neonatologists  General  104 k i l o c a l o r i e s / k g  source)  The a m i n o a c i d  help of  Vancouver  Some o f  given  the  L-amino  in T a b l e  3-  literature  Vamin review.  'TABLE 1  AMINO A C I D  C O M P O S I T I O N OF SMA  20  SMA  ESSENTIAL AMINO A C I D S  amino  100 g  H i s t i d i ne : I s o l e i i c i ne L e u c i ne L y s i ne M e t h i on i ne P h e n y l a l a n i ne T h r e o n i ne Tryptophan Va 1 i ne C y s t i ne T y r o s i ne  BREAST  MILK  BREAST  2()  (g  AND  acid/  protein)  2.7 6.4 11.4 9-9 2.4 4.6 5.8 2.0 8.2 1 .9 4.5  (g  MILK  amino  100 g  2.5 6.3 11 . 7. 2. 4. 5. 2, 6.3 2.7 5.4  NON-ESSENTIAL AMINO A C I D S A l a n i ne Aspartic Glutamic G1 y c i n e P r o l i ne S e r i ne A r g i n i ne  Acid Acid  Manufactured  by W y e t h  4.6 10.6 22.5 2.0 9-2 5-4 3.7  4.1 13-6 26.9 0 9.3 8.1 6.0  118.0  125-3  Limited  acid/  protein)  36  TABLE 2:  STUDY PROTOCOL - QUANTITIES OF NUTRIENTS/KG BODY WEIGHT/DAY  Providing  150 ml /kg body weight/day  Fat  CHO  Protein  Kilocalories  44  40 ml  I n t r a 1 i pi d  30 ml  Vamin  3g  *10 ml  D 50 W  5g  20  *70 ml  D 10 W  7g  28  ^9  kg  15g  2. l g  2.1g  12  104  * D 50 W and D 10 W a r e 50% Dextrose water and 10% D e x t r o s e water respect i v e l y . ** I n t r a l i p i d c o n t a i n s g l y c e r o l i n a d d i t i o n t o soyabean o i l . The t o t a l k i l o c a l o r i e s i n c l u d e s these o b t a i n e d from g l y c e r o l . <ww'<  Does not i n c l u d e p r o t e i n c a l o r i e s .  TABLE 3:  AMINO  AMINO ACID COMPOSITION OF VAMIN *  ACID  I s o l e u c i ne Leuc ine Lys i ne Pheny1 a l a n i ne Tyros i ne Meth i on i ne C y s t e i ne-Cyst i ne Threon i ne Tryptophan V a l i ne A l a n i ne Arg i n i ne A s p a r a g i ne Aspartic Acid G1utam i c Ac i d G1utami ne Glycine Hi s t i d ine Orn i th i ne P r o l i ne Ser i ne  * VITRUM, STOCKHOLM, SWEDEN  GRAMS/100 ml  0.39 0.53 0.39 0.55 0.05 0.19 0.14 0.30 0.10 0.43 0.30 0.33  -  0.41 0.90  -  0.21 0.24  -  0.81 0.75  38  The amino a c i d c o m p o s i t i o n o f Vamin i s s i m i l a r t o t h a t o f egg protein  ( 5 1 ) , which  i s c o n s i d e r e d t o be a p r o t e i n o f h i g h b i o l o g i c a l  value.  F o r t y - f o u r p e r c e n t o f the amino a c i d s i n Vamin a r e e s s e n t i a l .  From a p e d i a t r i c p o i n t o f view, these q u a l i t i e s make Vamin a good choice f o r a parenteral protein All collected.  source.  t h e i n f a n t s were 7~16 days o l d when the blood samples were They had r e c e i v e d f u l l  q u a n t i t i e s of f a t , carbohydrate,  and p r o t e i n , as d e s c r i b e d i n the study p r o t o c o l , Table 2, f o r a t l e a s t t h r e e days b e f o r e the blood sample was taken.  No i n f u s i o n o f b l o o d o r  albumin was a d m i n i s t e r e d i n t h e 24-hour p e r i o d p r e v i o u s t o t h e time the blood was drawn.  Blood f o r a n a l y s i s was c o l l e c t e d , t o g e t h e r w i t h  o t h e r b l o o d f o r r o u t i n e m o n i t o r i n g , between 08:00-09:00 a.m.  C.  TREATMENT AND ANALYSIS OF BLOOD SAMPLES The  procedure o f treatment and a n a l y s i s o f b l o o d samples was the  same f o r both c o n t r o l and e x p e r i m e n t a l groups.  The blood was drawn by  a t e c h n i c i a n from the m i c r o c h e m i s t r y l a b o r a t o r y . o b t a i n e d from a heel  C a p i l l a r y blood was  prick.  In o r d e r t o m i n i m i z e enzymatic  changes, the samples had t o be  c o o l e d on i c e and d e p r o t e i n i z e d as r a p i d l y as p o s s i b l e .  Before deprotein-'  i z a t i o n the samples were c e n t r i f u g e d under r e f r i g e r a t e d c o n d i t i o n s a t 3000-4000 g f o r f i v e minutes.  The plasma was c a r e f u l l y removed so as t o  prevent a s p i r a t i o n o f the b u f f y c o a t . s u l f o s a l i c y l i c acid  I t was then d e p r o t e i n i z e d w i t h  (30 mg/ml plasma), shaken t o mix and c e n t r i f u g e d  a g a i n f o r f i v e minutes a t 3000 g.  The p r o t e i n - f r e e s u p e r n a t a n t was  39  f r o z e n a t -20 Laboratory  C and sent t o C h i l d r e n ' s H o s p i t a l B i o c h e m i c a l  f o r a n a l y s i s o f t h e amino a c i d c o n c e n t r a t i o n s .  samples were s t o r e d a t -20° C and a n a l y z e d  Disease  The  w i t h i n a month.  When  prepared f o r a n a l y s i s o f the amino a c i d c o n c e n t r a t i o n s , the samples were thawed and c e n t r i f u g e d a t 10,000 g i n a Beckman m i c r o f u g e . were spun u n t i l standard  They  they c l e a r e d , then were mixed w i t h an i n t e r n a l  o f gamma amino b u t y r i c a c i d (GABA) i n a r a t i o o f 1 p a r t  standard:** The  parts  supernatant.  analyses  were performed w i t h a D-500 Amino A c i d  manufactured by t h e Durrum Instrument  Analyzer  Corporation.  A n a l y s i s i s based on t h e theory o f ion-exchange chromatography (149).  The a p p l i c a t i o n o f s y n t h e t i c ion-exchange r e s i n s t o the chromato-  graphy o f amino a c i d s makes use o f t h e i r  ion-exchange p r o p e r t i e s i n  a d d i t i o n t o p a r t i t i o n and a b s o r p t i o n e f f e c t s .  Amino a c i d s found i n  p r o t e i n s show amphoteric p r o p e r t i e s which r e s u l t from the c a r b o x y l and amino groups a t t a c h e d  t o the ©C-carbon.  Additional a c i d i c or basic  groups i n t h e s i d e c h a i n modify the i o n i z a t i o n c h a r a c t e r i s t i c s , and the net charges o f a l l t h e amino a c i d s take p l a c e as a r e s u l t o f a l t e r i n g the pH o f the s o l u t i o n used f o r e l u t i o n o f t h e chromatogram.  This  c o n t r o l s the r e l a t i v e r a t e s o f amino a c i d m i g r a t i o n . S t r o n g l y a c i d i c c a t i o n exchange r e s i n s a r e used, i n t h i s case a Durrum Chemical DC-4A chromatographic r e s i n . 8-  jiim  I t has a bead d i a m e t e r o f  and i s a s u l f o n a t e d polymer w i t h 8% c r o s s l i n k .  2g o f r e s i n a r e packed i n a s t a i n l e s s s t e e l  column w i t h an i n s i d e  diameter o f 0.175 cm. and a l e n g t h o f 48 cm. (148). are s u f f i c i e n t l y small to penetrate  Approximately  Amino a c i d m o l e c u l e s  t h e network and become t e m p o r a r i l y  a s s o c i a t e d w i t h the n e g a t i v e l y charged groups on the r e s i n .  40  Amino a c i d s as  to  change  the  are  state  Substances  with  by  amino a c i d s  neutral  positively  acids  hydrocarbon  increasing of  the  from  of  charge  strongly  additional with  eluted  chain  side  for  branched  amino a c i d  chain  migration acid  for  down the  the  phosphoserine, hydroxy  sarcosine, cystine,  set  at  The  automatic  6.3  ml/hr)  Quantitation with  is  ninhydrin  serine,  acid,  apparatus the  by  and measurement The  the  concentrations.  areas Very  finely-divided  b a s e d on e l u t i o n  times  side  from  first.  increased  affinity  The o r d e r  of  asparagine,  histidine depends  glutamic  accuracy  eluate  under  the  various  amino a c i d  of  at  of  its  amino  then,  is  acid,  acid,  glutamine, valine,  phenylalanine,  its  pumps  (flow  calibration following  and  a  are of  peaks  formed  calibration  run.  plot.  and  represent  with  compounds  rate  reaction  two wave 1engths(590  amino a c i d  peaks  the  the  arginine.  Identification  as measured d u r i n g  the  citrulline,  a recorder  the  affinity  in  rate  aspartic  tyrosine, and  of  of  increases.  group  elution,  alanine,  amino  the  the  on c o n s t a n t - r a t e  means o f  resin.  in  the  order  resin  An h y d r o x y  urea,  have  in  larger,  the  so  followed  The  column  increases  leucine,  which  chain.  the  pH,  be e l u t e d ,  becomes  of  sharp  to  the  molecules.  amino a c i d s  chain  glycine,  continued  accomplished  nanometers).  sufficiently  phase.  lysine,  for  690  an  first  backbone o f  elute  to  increasing  amino a c i d  their  emerge  side  isoleucine,  ornithine,  in  by  phosphoethanolamine,  adipic  methionine,  are  considerable  due  threonine,  o<amino  tryptophan,  chains  the  basic  hydrocarbon  moving  taurine,  proline,  the  causes  column  aqueous  chains  As  the  the  group  resin  on  groups  then  charged  T h e more h i g h l y side  acidic  and  length.  amino a c i d  the  the  is  41  Using a t o t a l  of f i v e  lithium-citrate  buffers  in sequence, a  b u f f e r p r e s s u r e of 2400 p s i , a sample s i z e of 5 0 - 6 0 jul and three column temperatures, a complete a n a l y s i s of amino a c i d s may be accomplished in 5 i ~ 6 hours. C o n c e n t r a t i o n s of t a u r i n e ,  aspartic acid,  threonine,  serine,  glutamine, asparagine, p r o l i n e , g l y c i n e , alanine, v a l i n e ,  cystine,  methionine,  urea,  ornithine,  isoleucine, lysine,  leucine,  tyrosine,  phenylalanine,  h i s t i d i n e and a r g i n i n e were c a l c u l a t e d  by the amino a c i d a n a l y z e r . parenteral  C i t r u l l i n e values were so low f o r the  receiving  total  calculate  concentration values.  nutrition  were weighed and c o n c e n t r a t i o n s  T r a c i n g s were made from the sample to the sample.  f o r each sample were computed (see  below).  Sample C a l c u l a t i o n s : For most amino a c i d s in the s t o c k s o l u t i o n , concentration  2.5 /jM/ml  For c i t r u l l i n e in the s t o c k s o l u t i o n , concentration  0.620 /jM/ml  A f t e r d i l u t i o n step 2.5/iM/ml  0.1563 /JM/ml  0.620 pM/m]  Answer should be c a l c u l a t e d wt. wt.  as:  of sample c i t r u l l i n e of standard c i t r u l l i n e  =  0.0008 g 0.0020 g  =  0.015 /JM/ml  x  infants  that an a l t e r n a t e method was used to  chromatogram and from the standard run j u s t p r e v i o u s  calculation  automatically  0.0388 uM/ml  0.1563 x 0.62 ;uM/ml  0.0388 /iM/ml  0.0388 ^M/ml  These sample  kl  D.  OTHER ANALYSES Many i n v e s t i g a t o r s have p r e f e r r e d t o sample venous blood r a t h e r  than c a p i l l a r y or a r t e r i a l amino a c i d c o n c e n t r a t i o n s .  blood i n t h e i r d e t e r m i n a t i o n o f plasma C a p i l l a r y blood was  used i n t h i s  study.  In o r d e r to compare the study data w i t h the a v a i l a b l e l i t e r a t u r e v a l u e s statistical  a n a l y s i s was  done on c a p i l l a r y and venous samples taken  from a group of r e n a l p a t i e n t s p r i o r t o and a f t e r d i a l y s i s .  This  e v a l u a t e d any d i f f e r e n c e between c a p i l l a r y and venous amino a c i d concentrations. Blood ammonia l e v e l s were not a v a i l a b l e from the receiving total parenteral n u t r i t i o n .  Glutamine  infants  l e v e l s , which c o u l d  have been c o r r e l a t e d w i t h blood ammonia (145), were a l s o not a v a i l a b l e due  to t e c h n i c a l d i f f i c u l t i e s  i n s c h e d u l i n g samples f o r a n a l y s i s .  F i g u r e 3 shows the i n s t a b i l i t y of g l u t a m i n e d u r i n g s t o r a g e o f blood samples i n the Durrum D-500 p r i o r t o a n a l y s i s .  Asparagine  and  glutamine  v a l u e s were used from v a r i o u s p a t i e n t s whose samples had been p r e v i o u s l y a n a l y z e d on the i n i t i a l Va1ine:g1ycine  run of the  instrument.  r a t i o s were c a l c u l a t e d from aminograms of premature  i n f a n t s on t o t a l p a r e n t e r a l n u t r i t i o n t o a s s e s s the i n f a n t s '  nutritive  status.  E.  DETERMINATION OF THE  KlLOCALORIE:NITROGEN RATIO  The group of p a t i e n t s i n v o l v e d i n t h i s p a r t of the study were premature i n f a n t s m a i n t a i n e d on t o t a l p a r e n t e r a l n u t r i t i o n .  Data were  o b t a i n e d from the P a r e n t e r a l N u t r i t i o n Flow C h a r t - F l u i d Balance  and  Fig. 3 STABILITY OF  BLOOD  OF  GLUTAMINE  SAMPLES  IN  THE  AND  ASPARAGINE  DURRUM  D500  DURING  AMINO  Glutamine  ACID  STORAGE ANALYZER  Asparagine 6  100  0)  o > 50  1  2  3  12  3  4  5  6  1 2  3  12  3  4  5  6  15  Run Number The ordinate is marked in % true value and the abscissa is marked in run number. Each  run takes 6 hours. The samples sit at a temperature of approximately 2 5 ° C  while awaiting analysis.  kk  Nutritional  Intake.  (See Appendix C ) .  C a l c u l a t i o n s were done, u s i n g W r e t l i n d ' s (51) c o n v e r s i o n f a c t o r f o r Vamin o f 7-5, t o f i n d t h e amount o f n i t r o g e n solution  i n the p r o t e i n  infused.  Sample C a l c u l a t i o n : 2.1 p r o t e i n / k g Total and  body weight/day /•P  =  >  2  8  k i l o c a l o r i e s i n f u s e d were then d i v i d e d  N  i  t  r  o  g  e  n  /  k  g  b  o  d  y  by the grams o f  w  e  i  g  n  t  /  d  a  y  nitrogen  a r a t i o value obtained. 104 k i l o c a l o r i e s / k g body weight/day 0 . 2 8 N i t r o g e n / k g body weight/day  These f i g u r e s were c a l c u l a t e d on a d a i l y  F.  Q  _  ,  7 1  basis.  GROWTH PARAMETERS Infants  i n the I n t e n s i v e  Care Nursery were weighed d a i l y  a Toledo b a l a n c e s c a l e a c c u r a t e t o 10 g. the crown o f the head t o the heel  using  Body l e n g t h was measured from  o f the f o o t w i t h  the leg f u l l y  extended.  Head c i r c u m f e r e n c e was measured a t the l a r g e s t o c c i p i t o f r o n t a l c i r c u m ference.  Head c i r c u m f e r e n c e and body length measurements were done  every 10 d a y s - 2 weeks on the i n f a n t s r e c e i v i n g t o t a l The data were p l o t t e d on i n t r a u t e r i n e growth c h a r t s Lubchenco e t aj_. , (116,117). nature of the Intensive  group.  nutrition.  developed by  Due t o t h e h i g h l y s p e c i a l i z e d ( t e r t i a r y )  Care Nursery a t the Vancouver General  when c i r c u m s t a n c e s a l l o w , i t was not p o s s i b l e  parenteral  i n f a n t s a r e sent t o o t h e r h o s p i t a l s .  Hospital, Consequently,  t o f o l l o w the growth o f the i n f a n t s i n t h e study  45  G.  STATISTICAL  ANALYSIS  Mean and s t a n d a r d amino a c i d oral  values  feeds of  normal  deviations  obtained  SMA^Q.  plasma amino a c i d v a l u e s  obtained  were  calculated  Linear see  if  using  regression  plasma amino a c i d Capillary  venous  were  group.  Student's  analysis levels  infants  further also  m a i n t a i n e d on  The d i f f e r e n c e t-test  with  correlated were  with  the  for  the  data  between  the  two  p ^ sets  0.05. of  gestational  analyzed  standard  reference.  calculated  was d o n e o n b o t h  differences  from the plasma  these data provided  needed f o r  deviations  from the e x p e r i m e n t a l  calculated  premature  Once c a l c u l a t e d ,  Means and s t a n d a r d  groups  from the  were  using  data  to  age.  the one sample  t-test.  values  Linear  regression  to  if  see  analysis  a relationship  was done on g l u t a m i n e  existed.  and  asparagine  46  CHAPTER IV RESULTS  Sex, g e s t a t i o n a l  age, w e i g h t ,  length and head c i r c u m f e r e n c e  at b i r t h f o r a l l i n f a n t s s t u d i e d , are presented 7.  Weight, l e n g t h and head c i r c u m f e r e n c e a t b i r t h a r e i l l u s t r a t e d  g r a p h i c a l l y i n Figures  4 and 5-  g e s t a t i o n a l age o f 33i weeks. 1940 g; body l e n g t h fall  i n Tables 4,5,6 and  The mean v a l u e f o r body weight was  44 cm; and head c i r c u m f e r e n c e 31 cm, a l l o f which  on the 50th p e r c e n t i l e  (116,117).  The c o n t r o l group had a mean  o f the i n t r a u t e r i n e growth  charts  T h i s i n d i c a t e s t h a t the c o n t r o l group i n f a n t s were  appropriately  grown f o r t h e i r g e s t a t i o n a l age. The study group had a  lower mean g e s t a t i o n a l  age o f 28 weeks.  body weight 982 g; body l e n g t h  Corresponding  mean v a l u e s f o r  36 cm; and head c i r c u m f e r e n c e 25 cm,  were lower among the study group than i n the c o n t r o l s and f a l l the 2 5 5 0 t h p e r c e n t i l e on the i n t r a u t e r i n e growth c h a r t s _  Mean p r o t e i n  p r i o r t o the time the blood samples  Table 8 shows t h a t t h e average p r o t e i n  c o n t r o l group, 2.6 g/kg body weight/day, infants receiving total parenteral Average amino a c i d Table 90.05  intakes  i n t a k e f o r the  was h i g h e r than t h a t o f the  n u t r i t i o n , 2.2 g/kg body  weight/day.  f o r the two groups a r e compared i n  The i n f a n t s f e d i n t r a v e n o u s l y  g/day, than d i d the c o n t r o l  greater  (116,117).  i n t a k e s were c a l c u l a t e d f o r both the c o n t r o l and  study groups f o r the three-day p e r i o d were taken.  within  received  f a r less  i n f a n t s , 0.20 g/day.  tyrosine,  They were  q u a n t i t i e s of i s o l e u c i n e , phenylalanine, methionine,  infused  cystine,  a r g i n i n e , g l y c i n e , h i s t i d i n e , p r o l i n e , and s e r i n e p e r day than the i n f a n t s f e d SMA . on  TABLE  4:  S E X , G E S T A T I O N A L A G E AND B I R T H W E I G H T  OF T H E P R E M A T U R E I N F A N T S  IN THE CONTROL GROUP  5 EX  PATIENT  GESTATIONAL  NUMBER  AGE  (WKS)  BJRTH  WEIGHT  (g)  INTRAUTERINE PERCENTILE  1  M  36  2380  25 - 50th  2  F  36  2020  10 - 25th  3  M  32  1800  50 -  4  M  32  2080  50 - 75th  5  F  36  2180  10 - 25th  6  F  35  1790  50th  7  F  32  1930  75th  8  M  34  1900  25 - 50th  9  M  31  1700  75th  10  F  34  2000  50th  11  M  33  1890  50 - 75th  12  M  31  1650  50th  13  M  33i  1980  10 - 25th  14  F  35  1670  15  F  35  2115  25 - 50th  16  F  31  1960  90th  33-5  1940  50th  MEAN  Lubchenco  et  a l . ,  (116).  75th  10th  WEIGHT  *  TABLE  5:  HEAD CIRCUMFERENCE AND LENGTH AT IN THE CONTROL GROUP  PATIENT NUMBER  BIRTH HEAD CIRCUMFERENCE (cm)  BIRTH OF THE  INTRAUTERINE HEAD * CIRCUMFERENCE PERCENTILE  PREMATURE  B 1 RTH LENGTH (cm)  INFANTS  INTRAUTERINE LENGTH PERCENTILE  1  33  50th  44  10 -  25th  2  29.8  10th  48  50 -  75th  3  29  25 - 50th  41  25 -  50th  4  31  50 - 75th  44  5  36  90th  48  75 -  90th  6  30  50th  41  25 -  50th  7  29.6  25 - 50th  43.2  25 -  50th  8  31  25 - 50th  45  9.  30.2  75th  42.5  10  32.7  50th  45  11  30.3  12  50th  50th 50 -  75th  50th  25 - 50th  46  75 -  90th  30  50th  43.5  50 -  75th  13  30  10 - 25th  43  10 -  25th  14  32  50th  42  10 -  25th  15  32  50th  46  16  30  50th  42.5  MEAN  31  *  Lubchenco  et  al.,  (117)  50th  44  50th 50 -  75th  50th  *  TABLE  6:  SEX,  GESTATIONAL AGE AND BIRTH WEIGHT OF PREMATURE  IN THE STUDY  INFANTS  GROUP  GESTATIONAL AGE (WKS)  BIRTH  WEIGHT  INTRAUTERINE PERCENTILE  PATIENT NUMBER  SEX  1  M  28  920  10 - 25th  2  F  29  1060  25th  3  M  27  800  10 - 25th  k  F  27  1190  75th  5  F  29  907  10th  6  F  29  920  10th  7  M  30  1200  25th  8  M  27  1100  50 - 75th  9  F  26  720  10 - 25th  10  F  2k  790  25 - 50th  11  F  31  1200  10 - 25th  28  982  25th  MEAN  Lubchenco  et  al.,  (116)  (g)  WEIGHT *  TABLE  7:  HEAD CIRCUMFERENCE IN THE  PATIENT  STUDY  -BIRTH HEAD  NUMBER  CIRCUMFERENCE (cm)  BIRTH OF PREMATURE  INFANTS  INTRAUTERINE HEAD * CIRCUMFERENCE PERCENTILE  BIRTH LENGTH (cm)  INTRAUTERINE * LENGTH PERCENTILE  1  25  25th  33.5  10 - 25th  2  26  25th  37  25 - 50th  3  21.4  10th  34  25 - 50th  4  26.7  50 - 75th  38  75th  5  23  10th  34  10th  6  24.5  10th  36  25th  7  24.5  10th  36.5  10 - 25th  8  26.5  50 - 75th  35-5  50 - 75th  9 10  -  11  27-7  25  MEAN  "  AND LENGTH AT  GROUP  Lubchenco  et  al.,  -  -  25th  38.5  10 - 25th  25th  36  25 - 50th  -  (117)  51  VANCOUVER GENERAL HOSPITAL INTENSIVE  CARE  INTRAUTERINE  NURSERY  GROWTH  CHART  p F i g . 4 Weight, Length and Head Circumference Measurements = at Birth of Control Group 24 2S 28 27 28 29 30 31 32 33 34 35 38 37 36 38 4 0 41 4 2 4 3  2 5 2 8 2 7 2 8 2 9 3 0 3 1 3 2 3 3 3 4 3 5 3 9 37 38 38 4 0 4 I 4 2 43 WEEK O f GESTATION  (FROM L U B C H E N C O , L . O . , E T A L .  P A E O I A T R I C S 3 7 : 4 0 3 . 19661  2 4 2 5 2 8 2 7 2 8 2 9 3 0 3 1 3 2 3 3 3 4 3 5 3 8 37 3 6 3 9 4 0 4 1 4 2 4 3  2 4 2 5 2 8 27 2 8 2 9 3 0 31 3 2 3 3 3 4 3 5 3 8 WEEK OF GESTATION  37 3 8 3 9 4 0 41  VANCOUVER GENERAL HOSPITAL INTENSIVE C A R E NURSERY  INTRAUTERINE  GROWTH  CHART  Fig. 5 Weight, Length and Head Circumference Measurements at Birth of Study Group 25 26 27 26 28 30 3 1 32 3 3 3 4 3 3 3 6 37 3 8 3 8 4 0 4  O 24 25 26 27 26 20 30 31 32 33 34 35 36 37 39 38 40 41 WEEK Of GESTATION  (FROM L U B C H E N C O . L . O . . E T A L .  PAEDIATRICS  37: 4 0 3 , 19661  0  24 21 26 27 26 29 30  31  4 2 43  32 33 34 35 36 37 36 39 40 41 42 43  WEEK OF GESTATION  53  TABLE  8:  CONTROL PATIENTS  PROTEIN INTAKE FOR THE 3 DAYS PRIOR TO THE DRAWING OF THE BLOOD SAMPLE.  AVERAGE  PROTEIN  INTAKE ( g / k g body  STUDY PATIENTS  weight/day).  AVERAGE  PROTEIN  INTAKE ( g / k g body  1  2.5  1  1.84  2  3.2  2  2.5  3  2.4  3  1.84  4  2.6  4  2.30  5  2.7  5  2.22  6  2.6  6  2.30  7  2.9  7  2.00  8  2.6  8  2.90  9  2.6  9  1.85  10  2.0  10  1.94  11  2.4  12  3.0  13  2.4  14  2.6  15  2.2  16  2.7  MEAN  2.6  2.2  weight/day)  TABLE 9:  AVERAGE AMINO ACl;D  AMINO ACIDS  1 s o l e u c i ne L e u c i ne L y s i ne Phenylalanine T y r o s i ne Meth i on i ne Cys t i ne T h r e o n i ne Tryptophan V a 1 i ne A l an i ne Arginine A s p a r a g i ne Glutamic Acid G l y c i ne H i s t i d i ne P r o l i ne S e r i ne  INTAKE BY THE CONTROL AND STUDY  CONTROL GROUP  (SMA  AVG. g AMINO  ACID/DAY  0.29 0,51  2()  )  INFANTS  STUDY GROUP AVG. g  (VAMIN)  AMINO  0.42  0,57  0.44  0.42  0,21 0.20 0.11 0.08  0,59  0.26  0.09 0.37 0.21 0.17  0.05  0,20 0.15 0.32 0.11 0.46  0.32 0.36  0.48  0.44  1 .01 0.09 0.12  0.96 0.22  0.41 0.24  0.26  0.86 0.80  ACID/DAY  55  Plasma amino a c i d v a l u e s f o r c o n t r o l and study groups can be found  i n Tables  10 and 11. T a b l e 12 shows the comparison  o f the  mean v a l u e s o f plasma amino a c i d c o n c e n t r a t i o n s f o r these two groups. In the study group, l e v e l s o f t h r e o n i n e , a s p a r a g i n e , g l u t a m i c a c i d , c i t r u l l i n e , a l a n i n e , c y s t i n e , methionine,  leucine, ornithine,  and a r g i n i n e were found t o be s i g n i f i c a n t l y l e v e l s were s i g n i f i c a n t l y h i g h e r .  lysine,  lower, whereas p h e n y l a l a n i n e  Urea l e v e l s were a l s o lower i n the  study group than i n the c o n t r o l group.  Figure 6 i l l u s t r a t e s the  plasma amino a c i d v a l u e s o f the c o n t r o l and study  groups.  V a l i n e : g l y c i n e r a t i o s c a l c u l a t e d on plasma l e v e l s o f these two amino a c i d s f o r the study group can be found r a t i o v a l u e was 0.50 which  i n Table 13-  The mean  i s s i g n i f i c a n t l y g r e a t e r than the v a l u e  a s s o c i a t e d w i t h K w a s h i o r k o r , 0.18 - 0.06. T a b l e s 14 and 15 show the r e s u l t s o f the l i n e a r r e g r e s s i o n a n a l y s i s done on the plasma amino a c i d c o n c e n t r a t i o n s and the i n f a n t s ' g e s t a t i o n a l age i n both groups.  No c o r r e l a t i o n was found t o e x i s t  between plasma amino a c i d c o n c e n t r a t i o n and g e s t a t i o n a l age. The  r e s u l t s o f the l i n e a r r e g r e s s i o n a n a l y s i s o f g l u t a m i n e and  a s p a r a g i n e v a l u e s a r e shown i n Table 16. p o s i t i v e c o r r e l a t i o n o f r=0.80.  These r e s u l t s i n d i c a t e a  A s p a r a g i n e v a l u e s c a n , t h e r e f o r e , be  used as a crude e s t i m a t i o n o f blood ammonia The  r e s u l t s of the s t a t i s t i c a l  levels.  a n a l y s i s done on the d i f f e r e n c e s  between c a p i l l a r y and venous amino a c i d c o n c e n t r a t i o n s a r e shown i n T a b l e 17-  C a p i l l a r y and venous samples a r e comparable f o r a l l amino  a c i d s except  t a u r i n e , a s p a r a g i n e , and v a l i n e .  These t h r e e amino a c i d s  56  are  significantly  higher  plasma amino a c i d s amino a c i d s w i t h  can,  in  the  length  nutrition infants days)  infants of  the e x c e p t i o n  and  receiving  time each  the  of  total  in  capillary  be c o m p a r e d w i t h taurine,  ratios  infant  the a v e r a g e  r e m a i n e d on  than  therefore,  Ki1 oca l o r i e : n i t r o g e n premature  venous  were  II  was  venous  calculated daily  parenteral  total  ki1 oca 1 o r i e : n i t r o g a n , r a t i o  regime f o r  still  an a v e r a g e o f  being  fed  valine. for  nutrition.  was m a i n t a i n e d on  the  Table  18 shows  parenteral attained.  47 d a y s  ratios  Capillary  plasma  a s p a r a g i n e and  and r e c e i v e d mean k i 1 o c a l o r i e : n i t r o g e n  297-403) P a t i e n t  samples.  of  intravenously  These  (range=l2-94 (range=  336 when  this  study  was c o n c l u d e d . Growth they  received  individual  the  recorded  total  nutrition.  intravenous  intrauterine  grew s t e a d i l y graph.  measurements were  Figure  within  or  growth c h a r t s paralleling  7 illustrates  relationship  this  for  the  during  These were  (see Appendix percentiles  growth.  between n u t r i t i o n a l  infants  Figure  D).  the  g r a p h e d on All  infants  i n d i c a t e d on  8 further  i n t a k e and w e i g h t  time  gain.  the  illustrates  TABLE  10:  INDIVIDUAL PLASMA AMINO ACID VALUES FOR CONTROL GROUP:PREMATURE INFANTS  RECEIVING ORAL FEEDS OF S M A „  n  PATIENT AMINO  ACIDS  T a u r i ne A s p a r t i c Acid T h r e o n i ne S e r i ne A s p a r a g i ne P r o 1 i ne Glutamic Acid Ci t r u l 1 i n e G l y c i ne A l a n i ne V a 1 i ne C y s t i ne Meth i o n i ne 1soleucine L e u c i ne T y r o s i ne P h e n y l a l a n i ne Orn i t h i ne Lys i ne H i s t i d i ne Arginine Urea  1 0. 061 0..081 0. 248 0. 193 0.063 0. 313 0. 060 0.,022 0. 242 0. 306 0.,114 0.,026 0. 035 0.,030 0..079 0.,149 0..039 0..067 0..097 0..095 0.063 1 .741 .  2 0.072 0.023 0.294 0.213 0.073 0.195 0.092 0.033 0.269 0.371 0.191 0.050 0.046 0.048 0.125 0.067 0.041 0.137 0.172 0.109 0.098 2.201  3 0.044 0.014 0.288 0.172 0.058 0.156 0.045 0.041 0.199 0.298 0.101 0.028 0.028 0.020 0.057 0.085 0.021 0.080 0.123 0.061 0.097 1 .212  4  ( juM/ml)  NUMBER  5  0. 082 0. 026 0. 325 0. 300 0. 094 0.,170 0. 259 0. 077 0.,080 0. 026 0. 033 0.,243 0. 351 0. 393 0.,306 0. 134 0. 221 0.056 0..037 0. 047 0.038 0.,022 0. 058 0. 128 0.089 0..092 0. 114 0,.024 0. 045 0. 123 0..127 0,. 1 5 T 0. 246 0. 086 0..025 0.,108 0,.076 2,.101 3. ,110  0.,111 0. 026 0. 225 0.,225  6 0.114 0.024 0.352 0.292 0.149 0.380 0.061 0.047 0.519 0.825 0.202 0.100 0.095 0.060 0.118 0.116 0.091 0.110 0.276 0.071 0.098 3-937  7 0.054 0.019 0.417 0.248 0.085 0.305 0.038 0.026 0.257 0.395 0.184 0.046 0.063 0.049 0.134 0.140 0.041 0.120 0.189 .0.080 0.092 2.765 c o n t i nued  8  0.023 0.019 0.493 0.298 0.114 0.297 0.084 0.038 0.338 0.689 0.236 0.056 0.059 0.078 0.136 0.080 0.084 0.117 0.152 0.070 0.101 1 .209  TABLE 10 (continued) PATIENT NUMBER AMINO ACIDS  Tau r i ne Aspartic Acid Threon i ne Ser i ne Asparagi ne Proline G1utami c A c i d Ci t r u 1 1 i ne G l y c i ne A l a n i ne Va1i ne Cys t i ne Meth i on i ne 1soleucine Leuc i ne Tyros i ne Pheny1 a 1 an i ne Orn i t h i ne Lys i ne H i s t i d i ne Arg i n i ne Urea  9 0 059 0 025 0 391 0 283 0. 069 0 251 0 061 0 056 0 279 0 242 0 131 0.038 0 039 0 041 0 099 0 125 0 034 0.098 0 142 0 058 0 108 1 949  10  0.148 0.035 0.432 0.302 O.O85 0.275 0.090 0.028 0.403 0.387 0.173 0.034 0.041 0.051 0.099 0.108 0.033 0.165 0.173 0.077 0.115 1.066  11  0.091 0.025 0.477 0.196 0.080 0.215 0.064 0.043 0.286 0.280 0.157 0.037 0.040 0.046 0.089 0.086 0.071 0.106 0.181 0.055 0.106 1.473  12  -13  0 146 0 027 0 288 0 279 0 076 0 295 0 066 0 025 0 255 0 388 0 179 0 033 0 065 0 072 0 138 0 088 0 049 0 115 0 196 0.074 0.078 2.698  0 079 0 025 0 328 0.258 0 024 0 240 0 057 0 015 0 224 0 336 0 158 0 021 0 053 0 052 0 106 0 097 0 046 0 099 0 150 0 091 0 045 1 275  14  0.107 0.028 0.399 0.309 0.099 0.313 0.090 0.028 0.438 0.518 0.239 0.077 0.085 0.092 0.155 0.100 0.057 0.146 0.336 0.102 0.167 3.633  15 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2  090 023 442 229 072 210 059 024 297 371 200 052 070 064 027 181 052 128 229 094 092 205  16  0.083 0.016 0.290 0.178 0.058 0.208 0.048 0.030 0.244 0.295 0.136 0.044 0.049 0.040 0.078 0.147 0.036 0.094 0.173 0.074 0.103 1 .954  MEAN- S. O.O85-O .034 0.023^0 .005 0.359T0 .077 0.248^0 .048 0.078-0 .028 0.255T0 .061 0.067-0 .017 0.030-0 .012 0.304-0 .086 0.400-0 .155 0.171-0 .042 0.046-0 .020 0.053-0 .019 0.051-0 .019 0.104-0 .034 0.111-0 .031 0.048^0 .020 0.113-0 .025 0.187-0 .060 0.076-0 .021 0.097TO .026 2.158-0 .872  TABLE 11:  INDIVIDUAL PLASMA AMINO ACID VALUES FOR THE STUDY GROUP:PREMATURE INFANTS RECEIVING TOTAL PARENTERAL NUTRITION ( juM/ml)  PATIENT NUMBER AMINO  ACIDS  Taur i ne Aspartic Acid Threoni ne Ser i ne Asparag i ne P r o l i ne Glutamic A c i d Ci t r u l 1 i ne G l y c i ne Al an i ne Va1i ne Cys t i ne Meth i on i ne 1 s o l e u c i ne Leuc i ne Tyros i ne Pheny1 a 1 an i ne Orni t h i ne Lysine H i s t id i ne Arg i n i ne Urea  1  2  0. 076 0. 015 0. 187 0. 137 0. 015 0. 156 0. 025 0. 010 0. 217 0. 139 0. 092 0. 017 0. 012 0. 036 0. 040 0. 062 0. 062 0. 015 0. 052 0.,109 0.,017 0. 972  0.031 0.012 0.087 0.130 0.012 0.165 0.021 0.005 0.207 0.126 0.114 0.024 0.014 0.032 0.041 0.031 0.062 0.167 0.037 0.067 0.023 1 .381  3 0. 193 0. 003 0. 261 0. 346 0.,030 0. 293 0.,050 0.,006 0. 330 0.,287 0.,122 0. 033 0.,020 0.,028 0.,041 0.,056 0.,052 0.,027 0.,046 0,.071 0,.020 1,.643  4  0. 079 0.,021 0. 179 0.,129 0.,010 0..179 0.043 0.,005 0.,227 0.,138 0.,149 0..027 0,.019 0..043 0..053 0..072 0..062 0,.021 0..044 0,.064 0,.019 0.817  5  0.073 0.015 0.160 0.225 0.022 0.293 0.038 0.005 0.234 0.164 0.102 0.016 0.012 0.012 0.036 0.046 0.117 0.013 0.030 0.073 0.008 0.597  6  0.053 0.016 0.256 0.241 0.021 0.269 0.043 0.006 0.319 0.208 0.167 0.028 0.019 0.032 0.072 0.081 0.106 0.020 0.051 0.095 0.015 0.290 cont i nued  7 0.045 0.013 0.124 0.232 0.022 0.259 0.024 0.013 0.227 0.106 0.121 0.029 0.023 0.021 0.060 0.073 0.094 0.024 0.122 0.094 0.027 2.792  TABLE 11  (continued): PATIENT NUMBER  AMINO ACIDS Taur i ne Aspartic Acid Threon i ne S e r i ne Asparag i ne P r o l i ne G1utami c A c i d Ci t r u l 1 i ne Glycine Al an i ne Va1i ne Cys t i ne Meth i on i ne 1soleuc i ne Leuc i ne Tyros i ne Pheny1 a 1 an i ne Orn i t h i ne Lys i ne H i s t i d i ne Arg i n i ne Urea  8 0.064 0.035 0.288 0.372 0.025 0.491 0.053 0.015 0.430 0.258 0.281 0.035 0.027 0.049 0.072 0.129 0.086 0.032 0.167 0.065 0.030 2.202  9 0..104 0..028 0..162 0..161 0.049 0..201 0..050 0..026 0.,245 0.,185 0.,103 0.,013 0.,006 0.,015 0..033 0.,042 0..039 0.,024 0.,110 0.083 0.,013 2,.037  10  11  MEAN - S.D.  0.057 0.020 0.208 0.207 0.026 0.227 0.031 0.003 0.233 0.146 0.121 0.007 0.010 0.015 0.044 0.207 0.104 0.010 0.043 O.O89 0.006 0.564  0.066 0.032 0.423 0.367 0.033 0.441 0.085 0.014 0.515 0.394 0.267 0.049 0.034 0.093 0.111 0.231 0.111 0.040 0.097 0.111 0.038 0.447  0.076-0.043 0.019-0.009 0.212^0.092 0.232-0.093 0.024-0.011 0.270^0.109 0.042-0.018 0.010-0.007 0.289-0.101 0.196-0.086 0.144-0.056 0.025-0.012 0.018-0.008 0.032-0.023 0.05570.023 0.094-0.067 0.081-0.027 0.036^0.044 0.073-0.044 0.084-0.017 0.020-0.010 1 .249-0.825  TABLE  12:  MEAN PLASMA AMINO ACID VALUES  AMINO ACID  '  .CONTROL GROUP MEAN + Sr.. D „.  Taurine Acid  Threonine Serine Asparagine Proline Glutamic Acid Citrulline Glycine Alanine Valine Cystine Methionine Isoleucine Leucine Tyrosine Phenylalanine Ornithine Lysine Histidine Arginine Urea  Significance  AND STUDY GROUPS  STUDY GROUP MEAN v]-n.. + S r-. D .  1  Aspartic  *  FOR CONTROL  1  O.O85 - 0.043  0.076 - 0.043  0.023^0.005  0.019 - 0 . 0 0 9  0.359 - 0.077 0.248 - 0.048 O.O78 7 0.028 0,255 'J 0,061 0,067 - 0,017 0.030 - 0,012 0.304 - 0.086 0.400 - 0,155 0.172^0,042 0.046 - 0,020 0.053 - 0,019 0.051 \ 0.019 0.104 J 0,034 0.111 - 0.031 0.048 - 0.020 0.113 J 0.025 0.187 7 0,060 0.076 - 0.021 0.097 : 0.026 2.158 i 0.872  0.212 - 0.092 0.232 \ 0.093 0.024 - 0.011 0,270 - 0,109 0,042 \ 0.018 0.010 - 0.007 0.289 ; 0.101 0,196 - 0.086 0.144^0.056 0.025 7 0.012 0,018 - 0.008 0,032 t 0..023 0.055 7 0,023 0.094 - 0.067 0.081 J 0,027 O.O36 - 0.044 0,073 7 0.044 0.084 - 0.017 0.020 - 0.010 1.249 - 0.825  of difference  by S t u d e n t ' s  t  test  a t p^-0.05  ( juM/ml)  t,value  I l  0.501 1-50  4.500 0.62 5-96 -0.467 3-65 4.90 0.41 3,95 1,47 3-10 5-88 2.1 1 4,20 0.91 -3-75 5.89 5-35 -0.97 9-30 2.72  62  Fig. 6  A C O M P A R I S O N OF PLASMA A M I N O ACID  C O N C E N T R A T I O N S OF THE CONTROL A N D STUDY GROUPS Plasma Cone. /Um/ml 0 Taurine Aspartic Acid Threonine Serine Asparagine Proline Glutamic Acid Citrulline Glycine Alanine Valine Cystine Methionine Isoleucine Leucine Tyrosine Phenylalanine Ornithine Lysine Histidine Arginine  Urea  .20  .40  .60  .80  1.0  TABLE  V A L I N E : G L Y C I N E RATIOS FOR INFANTS TOTAL PARENTERAL NUTRITION  13:  PATIENT  VALINE:GLYCINE  1  0.42  2  0.55  3  0.37 0.66  5  0.43  6  0.52  7  0.53  8  0.54  9  0.42  10  0.52  MEAN  0.50  RECEIVING  RATIO  TABLE 14:  LINEAR REGRESSION STATISTICS ON GESTATIONAL AGE AND PLASMA AMINO ACID CONCENTRATIONS, (GESTATIONAL AGE 31-36 WKS)  AMINO ACID  Taur i ne Aspartic Acid Threon i ne Ser i ne Asparagine P r o l i ne Glutamic A c i d C i t r u 1 1 i ne G l y c i ne A l a n i ne Va1i ne Cystine Meth i on i ne 1 s o l e u c i ne Leuc i ne Tyros i ne Phenylalanine Orn i t h i ne Lys i ne Hi s t i d i ne Arg i ni ne Urea  CORRELATION COEFFICIENT - 0.030 0.163 0.087 0.414 0.457 0.294 0.495 - 0.247 0.470 0.383 0.494 0.421 0.235 0.206 0.099 0.055 0.338 0.255 0.342 0.625 0.165 0.264  SLOPE  - 0.001 0.000 0.004 0.008 0.008 0.010 0.004 - 0.001 0.022 0.032 0.011 0.005 0.002 0.003 0.002 0.001 0.004 0.003 0.011 0.007 0.002 0.124  STD ERROR 0.,005 0.,001 0.,012 0.,005 0.,004 0.,008 0.,002 0.,001 0.,011 0.,021 0.,005 0.,003 0.,003 0.,003 0.,005 0.,004 0.,003 0.,003 0.,008 0.,002 0.,004 0.,121  INTERCEPT  -  0.104 0.008 0.227 0.028 0.200 0.066 0.082 0.079 0.425 0.673 0.201 0.106 0.026 0.052 0.044 0.080 0.072 0.002 0.183 0.157 0.019 1.989  STD ERROR 0.165 0.025 0.394 0.155 0.142 0.280 0.070 0.049 0.366 0.692 0.176 0.088 0.088 0.089 0.161 0.148 0.089 0.114 0.272 0.078 0.125 4.051  TABLE 15:  LINEAR REGRESSION STATISTICS ON GESTATIONAL AGE AND PLASMA AMINO ACID CONCENTRATIONS (GESTATIONAL AGE 24-31 WKS)  AMINO ACID  Taur i ne Aspartic Acid Threon i ne Ser i ne Asparag i ne Proline Glutamic Acid C i tru11i ne G l y c i ne Alanine Va 1 i ne Cystine Meth i on i ne 1soleuci ne Leuc i ne Tyros i ne Pheny1 a 1 an i ne Orni t h i ne Lys i ne H i s t i di ne Arg i n i ne Urea  CORRELATION COEFFICIENT - 0.294 - 0.059 0.280 0.225 - 0.209 0.264 0.307 - 0.055 0.322 0.263 0.340 0.644 0.578 0.491 0.547 - 0.059 0.365 0.269 0.087 0.348 0.611 - 0.034  -  -  -  SLOPE  STD ERROR  0.006 0.000 0.000 0.011 0.001 0.015 0.003 0.000 0.016 0.012 0.010 0.004 0.002 0.006 0.006 0.002 0.005 0.006 0.002 0,003 0.003 0.014  ,0.007 0.002 0.000 0,015 0.002 0.018 0.003 0.001 0.016 0.014 0.009 0.002 0.001 0.003 0.003 0.011 0.004 0.007 0.007 0.003 0.001 0.139  -  INTERCEPT  STD ERROR  0,256 0.027 0.192 0.065 0.056 0.135 0.038 0.015 0.169 0.128 0.127 0.082 0.049 0.124 0.124 0.150 0.057 0.133 0.018 0.001 0.063 1 .644  0.195 0.045 0.036 0.430 0.050 0.496 0.081 0.031 0.450 0.396 0.251 0.043 0.031 0.094 0.091 0.318 0.118 0.202 0.209 0.076 0.036 3.897  66  TABLE 16:  LINEAR REGRESSION AND CORRELATION COEFFICIENT ANALYSIS OF PLASMA LEVELS OF GLUTAMINE AND ASPARAGINE *  SAMPLE STATISTICS MEAN - S.D.  Asparagine Glutamine CORRELATION COEFFICIENT  0.099 0.080 0.749 - 0.807 r = 0.803  REGRESSION RESULTS Slope Standard E r r o r Intercept Standard E r r o r  8.061 0.742 - 0.048 0.094  A s p a r a g i n e and g l u t a m i n e v a l u e s were chosen from p a t i e n t s not i n v o l v e d i n t h i s study whose samples had been a n a l y z e d on the i n i t i a l run o f the i n s t r u m e n t .  67  TABLE  17:  STATISTICAL  ANALYSIS  CONCENTRATIONS  AMINO  ACID  N  IN  ON  DATA C O M P A R I N G  CAPILLARY  •T-STATI S T I C  AND  VENOUS  AMINO  LIMITS  CONFIDENCE  LOWER  UPPER  T a u r i ne Aspartic Acid T h r e o n i ne  7 7 7  S e r i ne  7 7 7 6  A s p a r a g i ne P r o l i ne Glutamic Acid C i t r u l 1 i ne G1yc i ne Alanine V a 1 i ne  7 7 7 7 8  C y s t i ne M e t h i on i ne 1 s o l e u c i ne L e u c i ne T y r o s i ne P h e n y l a 1 an i ne Orn i t h i ne L y s i ne H i s t i d i ne A r g i n i ne  *  **  8 8 8 8 8 8 8 8  -  4.01 1.56 0.88  0.90  1.28  1 .39 0.99 1.07  1.18  of  0.72  1.17  -  5-99 1.12  -  0.55 0.84  1.15 0.99 1.26  0.87  -  0.15 2.50  1.90 1.30  -  0.99 1.38 0.76 1.06  1.15 1.03 1.10 1.14 1.11  0.68  -  1 .33 1.06  0.83 0.74 0.86 0.80  1.07 1.09  difference  by  -  0.87  0.78 0.84 0.69 0.66 0.65 0.61  1.07 1.09  one  sample  **  0.79 0.48 1 .00  1.30  7  **  0.75 0.88  1.05 0.14  Venous and c a p i l l a r y b l o o d samples were t a k e n a f t e r d i a l y s i s from a group of renal p a t i e n t s in t h i s study. Significance  0.57 0.84  1 .73 1 .12  2.53  ACID  BLOOD S A M P L E S  p r i o r to and not involved  t-test  (p^.0.05).  **  *  68  TABLE 18:  PATIENT NUMBER  DURATION OF TOTAL INTRAVENOUS FEEDING AND AVERAGE KlLOCALORIE:NITROGEN RATIO ATTAINED  DAYS ON TOTAL INTRAVENOUS FEEDING  AVERAGE Kl LOCALORIE: NITROGEN RATIO  1  20  332  2  16  334  3  52  338  4  12  309  5  54  332  6  13  402  7  39  337  8  Sk  327  9  Sk  297  10  76  354  MEAN  kl  336  RANGE  12-94  297-402  69  VANCOUVER GENERAL INTENSIVE  CARE  INTRAUTERINE  HOSPITAL  Patient 8  NURSERY  GROWTH  CHART  Fig. 7 Growth Data for Patient 8 while on Total Parenteral Nutrition 24 25 28 27 28 28 30 31 32 33 34 35 36 37 36 39 40 41 42 43  24 25 28 27 28 29 30 31 32 33 34 35 36 37 36 39 40 41 42 43  2 4 2 5 2 8 2 7 2 8 2 9 3 0 31 32 3 3 3 4 3 5 3 8 37 3 6 3 9 4 0 4 1 4 2 4 3 WEEK OF GESTATION  (FROM LUBCHENCO. L.O., E T A L .  0 2 4 2 5 2 8 27 2 6 2 9 3 0 31 3 2 3 3 3 4 3 5 3 6 37 3 6 3 9 4 0 4 1 4 2 43 WEEK OF GESTATION  P A E D I A T R I C S 3 7 : 4 0 3 , 1966)  70 Fig. 8  RELATIONSHIP O F DAILY I N T R A V E N O U S INTAKE WITH WEIGHT G A I N Birth W e i g h t 1.10 kg  Weight (kg)  Patient 8  2.9-1  T  r  T  IV Kcal: Nitrogen 500  - i  300  H  100  T  1  r  IV K c a l / k g b . w . / d a y  3.0  IV Protein(g/kg  b.w./day)  -i  Time in Days  71  CHAPTER V DISCUSSION  A.  CONTROL  VALUES  Plasma  amino a c i d  values  infants  m a i n t a i n e d on o r a l  of  age g r o u p .  this  were  In Pohlandt's  (130) d a t a  threonine,  serine,  in  found  that  high  for  the  the  difficult natal by  premature  "first  to  Dickinson for  Elevated  full  days"  these  of  The  infants,  presumably  metabolic  enzymes,  such  in  observed  time  fetal in  concentrations be e x p l a i n e d  (128).  life  the  by  current of  as  the  p-hydroxy Elevated  differences  in  that  not  the  phenyl levels  aj_. , high  is the  post-  identified the  elevated  study.  were  of  in key  these  until  not  showed  than o u r s , of  remained  acid oxidase,  (130) d a t a  concentrations  of  are  more o f t e n  tyrosine  and a s p a r a g i n e  as  development  pyruvic of  It  clearly  present  with  (13*0 a l s o and  study  to o c c u r  results  levels  decreased.  delayed  Polhandt's  valine  were  infants  infants  may e x p l a i n  in  been n o t e d  because of  study.  taurine,  factor  the  and a r g i n i n e  current  was  observed  have  premature  late  the  changes o c c u r r e d  tyrosine  we f o u n d  then  premature  19-  Dickinson et  and  with  data,  premature  methionine,  life  a l a n i n e and t h r e o n i n e  levels  for  from  aminograms f o r  Table  concentrations  of  study  these  values,  infant.  results  (134).  of  infants,  alanine,  threonine  few  e_t aj_. ,  term  control  compare t h e s e  age a t which  values  for  and  literature  this  normal  validity  aminogram v a l u e s  glycine,  alanine  in  provided  the  available  comparing our  higher  feeds  To a s s u r e  compared w i t h  obtained  higher which  three  can amino  72  TABLE 19:  COMPARISON OF PLASMA AMINO ACIDS IN AND FULL TERM INFANTS  FULL TERM INFANTS  PREMATURE INFANTS  AMINO ACIDS  CONTROLS ( juM/ml)  Taur i ne Aspartic Acid Threon i ne Ser i ne A s p a r a g i ne Proline Gl utami c A c i d Ci t r u l 1 i n e G1yc i ne Alanine Va1i ne C y s t i ne Meth i on i ne 1 s o l e u c i ne Leucine Tyros i ne Pheny1 a 1 an i ne Orn i th i ne Lys i ne H i s t i d i ne Arg i n i ne Controls:  0.085 0.023 0.359 0.248 0.078 0.255 0.067 0.030 0.304 0.400 0.172 0.046 0.053 0.051 0.104 0.111 0.048 0.113 0.187 0.076 0.097  c a p i l l a r y samples; SMA.  PREMATURE  PRZYREMBEL et al.,(132)  DICKINSON e t al.,(135)  "C/iM/ml)  "TjuM/ml)  0.072 0.018 0.256 0.169  0.145 0.016 0.224 0.168  -  -  0.190 0.168 0.019 0.225 0.313 0.174 0.071 0.025 0.065 0.114  0.192 0.063 0.019 0.369 0.323 0.163 0.000 0.025 0.040 0.078 0.070 0.076 0.100 0.191 0.081 0.055  O.O89  0.050 0.071 0.113 0.057 0.061  P0LHANDT (130) ( juM/ml)  0.096 -  0.134 0.143 0.087 0.283 0.098 0.020 0.228 0.387 0.184 0.062 0.029 0.071 0.160 0.117 0.063 0.116 0.210 0.085 0.084  p o s t n a t a l age 7 16 days; premature _  infants;  PRZYREMBEL et_ aj_. , (132): venous sample; p o s t n a t a l age 10 days; premature i n f a n t s ; SMA. DICKINS0N e_t aj_. , (135): venous sample; p o s t n a t a l age 1 day; f u l l i nfants. P0LHANDT (130): venous sample; p o s t n a t a l age 7-5 days; f u l l i n f a n t s ; breast milk.  term  term  73 a c i d s between c a p i l l a r y and venous  blood.  Przyrembel e_t a_l_. , (132), s t u d i e d plasma amino a c i d in premature i n f a n t s .  concentrations  Values from t h e i r study a r e from venous samples  which were handled i n a comparable manner t o t h e procedure used i n t h i s study.  They used s i x t e e n premature i n f a n t s ( e i g h t boys and e i g h t  of a median b i r t h weight o f 1955 g ( g e s t a t i o n a l age not g i v e n ) . samples were taken on the t e n t h day a f t e r b i r t h j u s t b e f o r e  girls) Blood  feeding.  T h e i r d i e t c o n s i s t e d o f SMA and t h e i r median p r o t e i n i n t a k e was 2.5g/kg body weight/day. group o f the present  The plasma amino a c i d v a l u e s  i n the control  study a r e compared w i t h the r e s u l t s o f these and  o t h e r workers i n T a b l e 19 (130,132,135). On the b a s i s of the f a c t o r s a f f e c t i n g plasma aminograms, the data o f Przyrembel e_t aj_. , (132) compared f a v o u r a b l y w i t h our c o n t r o l values.  On the whole, our v a l u e s a r e s l i g h t l y h i g h e r  than t h e i r s , but  t h i s may be a r e f l e c t i o n o f the sampling time chosen. Despite  the f a c t t h a t v a r i a t i o n s i n o v e r a l l p r o c e d u r e s , p o o r l y  d e f i n e d s u b j e c t s and d i f f e r e n c e s i n d i e t s f e d make e x a c t between p u b l i s h e d  studies d i f f i c u l t ,  c o n t r o l values  comparisons  from the c u r r e n t  study compare f a v o u r a b l y w i t h the few s e t s o f l i t e r a t u r e  values  a v a i l a b l e f o r plasma aminograms from premature i n f a n t s (42,132).  B.  STUDY VALUES It  i s very d i f f i c u l t  t o compare the v a l u e s  h e a l t h y premature i n f a n t s r e c e i v i n g t o t a l other values  found i n r e l a t i v e l y  parenteral n u t r i t i o n with  found i n the l i t e r a t u r e f o r p a t i e n t s f e d i n t r a v e n o u s l y .  There a r e t o o many u n c o n t r o l l e d v a r i a b l e s between s t u d i e s .  The v a r i o u s  74  types o f s o l u t i o n used, t h e age o f t h e p a t i e n t and the s e v e r i t y o f the i l l n e s s a l l markedly a f f e c t plasma amino a c i d p a t t e r n s .  Compared  to Ghadimi e_t a_l_. , ( l 4 l ) high g l y c i n e v a l u e s were not observed study group.  i n our  The low l e v e l s o f t h r e o n i n e and l y s i n e observed by  Ghadimi ejt a_l_. , (140) i n t h e i r study o f premature, l o w - b i r t h - w e i g h t i n f a n t s were a l s o seen i n t h e p r e s e n t study.  Ghadimi et^ a_l_. , (140)  d i d not i n t e r p r e t t h e i r v a l u e s as being a r e s u l t o f t h e e f f e c t o f t o t a l p a r e n t e r a l n u t r i t i o n , but r a t h e r as a consequence o f the s t a n d a r d v a l u e s chosen f o r comparison which were o b t a i n e d from cord b l o o d .  They  f u r t h e r c l a i m e d t h a t t h r e o n i n e and l y s i n e l e v e l s were h i g h e r i n cord samples than  C.  i n any o t h e r samples taken d u r i n g i n f a n c y and c h i l d h o o d .  COMMENTS ON THE DIFFERENCES BETWEEN CONTROL AND STUDY DATA The d i f f e r e n c e s i n plasma amino a c i d c o n c e n t r a t i o n s between t h e  c o n t r o l and study groups i n t h i s i n v e s t i g a t i o n were not t h e same as those observed  by Shaw e t al_. , (154) i n t h e i r study o f o r a l l y and  intravenously fed f u l l  term  infants.  The c u r r e n t study i n d i c a t e s  t h a t most o f t h e mean plasma amino a c i d v a l u e s i n the i n t r a v e n o u s l y f e d i n f a n t s were lower than those  i n the i n f a n t s f e d SMA^Q-  e x c e p t i o n was p h e n y l a l a n i n e , which was h i g h e r i n the i n f a n t s t o t a l p a r e n t e r a l n u t r i t i o n , T a b l e 12.  Shaw  e t aj_.,  The receiving  (154) a l s o found  h i g h e r serum l e v e l s o f p h e n y l a l a n i n e , p r o l i n e , g l y c i n e , and s e r i n e , i n the i n f a n t s i n f u s e d w i t h Vamin, whereas low v a l u e s were found f o r l y s i n e and l e u c i n e . E l e v a t e d plasma l e v e l s o f p h e n y l a l a n i n e i n i n f a n t s t o t a l p a r e n t e r a l n u t r i t i o n were noted  receiving  i n both t h e p r e s e n t study and  75  t h a t o f Shaw e_t aj_. , (154).  They were n o t , however, as h i g h as t h e  plasma l e v e l s o f p h e n y l a l a n i n e (1.21 jjm/ml,  seen i n p a t i e n t s w i t h  Dr. L. I. Woolf, p e r s o n a l  e x a m i n a t i o n o f the d a i l y p h e n y l a l a n i n e study  communication).  phenylketonuria Upon c l o s e  i n t a k e , i t was found i n our  t h a t i n f a n t s i n f u s e d w i t h Vamin were r e c e i v i n g 2-3 times more  phenylalanine/day phenylalanine by high  than i n f a n t s f e d  SMA2Q.  E l e v a t e d plasma l e v e l s o f  i n the i n t r a v e n o u s l y f e d i n f a n t s may, then, be e x p l a i n e d  intakes of phenylalanine. Low plasma l e v e l s o f l e u c i n e and l y s i n e i n f u l l  term i n f a n t s  r e c e i v i n g t o t a l p a r e n t e r a l n u t r i t i o n w i t h Vamin were a l s o seen by Shaw e_t aj_. , (154). being  They e x p l a i n the low l e v e l s o f l e u c i n e and l y s i n e as  the r e s u l t o f low i n t a k e s o f these s p e c i f i c amino a c i d s .  plasma c o n c e n t r a t i o n s present  study  o f l e u c i n e and l y s i n e were a l s o seen i n the  i n i n f a n t s i n f u s e d w i t h Vamin.  T a b l e 9 shows, however,  t h a t the average i n t a k e o f the two amino a c i d s / d a y both o r a l l y and i n t r a v e n o u s l y f e d i n f a n t s . and  Low  was the same f o r  Low i n t a k e o f l e u c i n e  l y s i n e may not be the s o l e reason f o r low plasma amino a c i d  levels.  We were unable t o a d e q u a t e l y e x p l a i n t h i s f i n d i n g . One p o s s i b l e e x p l a n a t i o n ornithine,  and c i t r u l l i n e  f o r the lower l e v e l s o f a r g i n i n e ,  i n the i n t r a v e n o u s l y f e d i n f a n t s i s a d e f e c t  in t h e i r r e n a l a b s o r p t i o n mechanism. increased a defect  Such a d e f e c t would r e s u l t i n an  l o s s o f these amino a c i d s i n the u r i n e .  The o c c u r r e n c e o f  i s e n t i r e l y p o s s i b l e c o n s i d e r i n g the s e v e r e degree o f  prematurity  o f some o f these i n f a n t s .  Generalized  amino a c i d u r i a i s  known t o o c c u r i n the newborn as a r e s u l t o f lowered t u b u l a r (142).  Renal d e f e c t s , however, do not n o r m a l l y  reabsorption  a f f e c t d i b a s i c amino  76  a c i d s as  l y s i n e or a r g i n i n e , a l t h o u g h h i g h e r  o r n i t h i n e and intakes  c i t r u l l i n e occur in i n f a n t s r e c e i v i n g high To  (132).  clearance  urinary excretion  studies  Unfortunately  should be done and  t h i s was  not p o s s i b l e  amino a c i d l o s s e s measured. i n the c u r r e n t  intravenously  than i n the  study.  i n the urea c y c l e .  m e t a b o l i s m , e i t h e r an  protein  In the absence of an  1  E i t h e r one  urea  conceivably,  inborn e r r o r of  i n s u f f i c i e n t amount of s u b s t r a t e  appears t o be a d e f e c t i v e urea c y c l e .  Low  intake or,  c y c l e or delayed development of urea c y c l e enzymes may  not o n l y  lower i n the  i n f a n t s fed o r a l l y .  l e v e l s can be a r e f l e c t i o n of d i m i n i s h e d a defect  protein  i n v e s t i g a t e t h i s p o s s i b i l i t y f u r t h e r , renal  Urea l e v e l s were a l s o found t o be s i g n i f i c a n t l y i n f a n t s fed  of  f o r the urea r e s u l t i n what  of these would  to lowered urea l e v e l s but a l s o to e l e v a t e d  lead  blood ammonia  eve 1s. Arginine  i s a major s u b s t r a t e  l e v e l s of a r g i n i n e  s o u r c e f o r the urea c y c l e .  i n c r y s t a l l i n e amino a c i d s o l u t i o n s have been shown  to produce hyperammonemia ( 6 4 ) . a c i d s o l u t i o n s , Vamin c o n t a i n s ammonia l e v e l s are not  U n l i k e the o t h e r c r y s t a l l i n e amino adequate amounts of a r g i n i n e .  l i k e l y to be e x p l a i n e d  R'aiha e_t a_l_. , (143)  by  found t h a t t h e r e was  insufficient sufficient  a c t i v i t y of a l l urea c y c l e enzymes by 20 weeks g e s t a t i o n . i n t h i s study were a l l of g e s t a t i o n a l age  ammonia l e v e l s or o t h e r l a b i l e n i t r o g e n or a l a n i n e .  The  Batshaw et^ a_l_. ,  i n v e r s e c o r r e l a t i o n between g e s t a t i o n a l age  and  nutrition.  substrate.  infants precluding (144) plasma  components, g l u t a m i n e , g l u t a m a t e ,  Blood ammonia l e v e l s were not a v a i l a b l e from the  receiving total parenteral  Elevated  in v i t r o  2k weeks or o l d e r ,  the problem o f urea c y c l e enzyme i m m a t u r i t y . a l s o found no  Low  Table 16 shows how  infants  asparagine  77  v a l u e s c o u l d be used as crude i n d i c a t o r s of blood ammonia l e v e l s . no i n c r e a s e i n a s p a r a g i n e c o n c e n t r a t i o n i n the i n f a n t s  As  receiving  t o t a l p a r e n t e r a l n u t r i t i o n was o b s e r v e d , the assumption can be made, somewhat t e n t a t i v e l y , t h a t t h e r e i s no e v i d e n c e f o r e l e v a t e d ammonia l e v e l s i n the i n t r a v e n o u s l y f e d premature  infants.  A d e f e c t i n any of the urea c y c l e enzymes would  r e s u l t i n an  i n c r e a s e i n one o f the amino a c i d s ( a r g i n i n e , o r n i t h i n e , or  citrulline).  F u r t h e r e v i d e n c e f o r the absence of a urea c y c l e d e f e c t l i e s f a c t t h a t i n c r e a s e d plasma  i n the  l e v e l s of a s p a r a g i n e and the urea c y c l e  amino a c i d s were not observed. Low urea l e v e l s may intake. of  a l s o be a r e s u l t of i n s u f f i c i e n t  protein  The plasma aminogram has been used to a s c e r t a i n the adequacy  protein  i n t a k e (95)-  C h a r a c t e r i s t i c plasma amino a c i d p a t t e r n s  develop as a r e s u l t o f r e s t r i c t e d p r o t e i n d i e t s  (67,109).  Branched-chain  amino a c i d s , p a r t i c u l a r l y v a l i n e , decrease w h i l e some of the none s s e n t i a l amino a c i d s , such as g l y c i n e , i n c r e a s e . that infants receiving t o t a l  Ghadimi  (67) found  intravenous n u t r i t i o n w i t h a protein  h y d r o l y s a t e had plasma amino a c i d p a t t e r n s resembling the aminogram of c h i l d r e n s u f f e r i n g from k w a s h i o r k o r .  The plasma aminograms of  infants  i n f u s e d w i t h Vamin, i n t h i s s t u d y , were d i f f e r e n t than those found by Ghadimi  (67).  Plasma g l y c i n e c o n c e n t r a t i o n s were not e l e v a t e d and  b r a n c h e d - c h a i n amino a c i d s as a group were not d e c r e a s e d . r a t i o s , T a b l e 13,  Va1ine:g1ycine  were found t o be s i g n i f i c a n t l y g r e a t e r than the v a l u e s  associated w i t h kwashiorkor No c l i n i c a l  the  (146), ( v a 1 i n e : g 1 y c i n e = 0.18  e v i d e n c e of m a l n u t r i t i o n was  seen  - 0.06).  i n terms of weight  g a i n , head c i r c u m f e r e n c e and body l e n g t h measurements.  Weight g a i n was  78 steady and c o n s i s t e n t and p a r a l l e l e d Lubchenco p e r c e n t i l e s (116) d u r i n g s t a b i l i z e d periods of t o t a l parenteral  nutrition.  Body l e n g t h and  head c i r c u m f e r e n c e measurements a l s o f e l l w i t h i n the accepted p e r c e n t i l e s f o r i n t r a u t e r i n e growth  (117)-  The f i n d i n g s p r e s e n t e d i n the p r e s e n t study support the theory t h a t adequate q u a n t i t i e s of p r o t e i n a r e being  infused.  The l a c k o f  e l e v a t e d m e t h i o n i n e and t y r o s i n e l e v e l s i n d i c a t e t h a t an excess o f p r o t e i n i s not being  infused.  In the absence o f any e v i d e n c e o f  problems i n the urea c y c l e the most l i k e l y e x p l a n a t i o n urea, a r g i n i n e , o r n i t h i n e , and c i t r u l l i n e  f o r the lowered  l e v e l s i s one t h a t r e l a t e s  urea l e v e l s t o p r o t e i n i n t a k e o r t o amino a c i d t u r n o v e r . above, t h e r e  i s no e v i d e n c e f o r a p r o t e i n i n t a k e t h a t  cause even m i l d b i o c h e m i c a l It seems t h a t t h e r e  or c l i n i c a l  As  discussed  i s so low as t o  symptoms o f p r o t e i n d e f i c i e n c y .  i s highly e f f i c i e n t u t i l i z a t i o n of  i n f u s e d amino a c i d s f o r s y n t h e s i s of body p r o t e i n s .  intravenously  This  is further  substantiated  by the f a c t t h a t amounts o f t y r o s i n e and m e t h i o n i n e  substantially  i n excess o f what i s r e q u i r e d f o r p r o t e i n s y n t h e s i s would  cause e l e v a t i o n s o f these s p e c i f i c amino a c i d s key m e t a b o l i c  enzymes develop l a t e i n f e t a l  Parahydroxy p y r u v i c a c i d o x i d a s e , rate l i m i t i n g  i n plasma because t h e i r  life  (20,33,34,93).  and c y s t a t h i o n a s e  i n premature i n f a n t s so t h a t i n c r e a s e d  a r e known t o be catabolism of  p r o t e i n leads t o e l e v a t i o n s o f the s u b s t r a t e s o f these enzymes. Snyderman e_t aj_. , (95) showed i n c r e a s e d w i t h high p r o t e i n i n t a k e s .  Rassin  plasma l e v e l s o f m e t h i o n i n e  e_t aj_. , (138) observed  elevated  t y r o s i n e l e v e l s in infants r e c e i v i n g large q u a n t i t i e s of p r o t e i n .  79  It appears t h a t t h e r e  i s l i t t l e use of the carbon s k e l e t o n  most of the amino a c i d s f o r energy purposes. much of the  i n f a n t ' s c a l o r i c needs are met  This  of  i s p o s s i b l e because  i n the form of f a t or  carbohydrate. If i n s u l i n l e v e l s had  been measured they would l i k e l y have been  normal or r e l a t i v e l y h i g h as blood sugars in the i n f a n t s fed v e n o u s l y a r e u s u a l l y i n a normoglycemic o r h i g h e r one  range.  intra-  Insulin is  of the major hormones r e s p o n s i b l e f o r the uptake of amino a c i d s  by muscle.  The  s y n t h e s i s and a c i d s , and  data  t h a t p o i n t t o the use of amino a c i d s f o r p r o t e i n  not c a t a b o l i s m a r e : lowered l e v e l s of urea and most amino  the absence of e l e v a t i o n s i n t y r o s i n e and m e t h i o n i n e .  a p p e a r s , then, t h a t i n t r a v e n o u s l y fed body p r o t e i n , or at the v e r y  i n f a n t s are e f f i c i e n t l y  ,  It  synthesizing  l e a s t are not u s i n g t h e i r amino a c i d s f o r  energy purposes. The  above theory can be f u r t h e r s u b s t a n t i a t e d  the k i l o c a l o r i e : n i t r o g e n r a t i o s u p p l i e d to the intravenous  nutrition.  Hendry e_t a_l_. , (155)  i n f a n t s i n f u s e d w i t h Vamin should r a t i o of 2k5-  infants receiving total  r e c e i v e an average ki1 oca 1 o r i e : n i t r o g e n  T h e i r p a t i e n t s r e c e i v e d a range of 204-534.  kilocalorie:nitrogen ratio. nutrition for a sufficient The  infants nitrogen/day.  optimal  Only s i x i n f a n t s r e c e i v e d t o t a l  parenteral  l e n g t h of time to a d e q u a t e l y j u d g e t h e i r  ki1 oca 1 o r i e : n i t r o g e n r a t i o achieved  adequate f o r normal growth.  The  k i 1 oca 1 o r i e s : 1 g  d e s i g n of t h i s study d i d not a l l o w us to determine an  growth.  looks at  suggest t h a t premature  in t h i s study were r e c e i v i n g an average of 336 The  i f one  One  i n f a n t showed how  seems t o have been growth r a t e was  impaired  80  in t h e presence o f severe  infection  needs may vary f o r i n d i v i d u a l  (Patient 6).  infants.  Thus, n u t r i t i o n a l  The mean and range v a l u e s  f o r ki1 oca l o r i e : n i t r o g e n r a t i o s observed d u r i n g t h i s study  (mean=336,  range-207~402) compare f a v o u r a b l y w i t h those found by Hendry e t a 1. , (155),  (mean=245, range=2 tO-53 O . i  r a t i o observed  i n t h e present  i  The i n c r e a s e d k i l o c a l o r i e : n i trogen  study may have caused the seemingly  more e f f i c i e n t u t i l i z a t i o n o f amino a c i d s observed i n i n t r a v e n o u s l y fed  D.  infants.  RECOMMENDATIONS Based on the r e l a t i v e l y e l e v a t e d plasma c o n c e n t r a t i o n o f  phenylalanine it  found i n t h e i n t r a v e n o u s l y f e d i n f a n t s i n t h i s  i s recommended t h a t t h e o p t i m a l  should be e s t a b l i s h e d . phenylalanine  Although  amount o f p h e n y l a l a n i n e  study,  i n Vamin  t h e observed plasma c o n c e n t r a t i o n s o f  do not reach the dangerous l e v e l o f 1.21 /jm/ml seen  in p a t i e n t s w i t h p h e n y l k e t o n u r i a ,  r e l a t i v e l y e l e v a t e d plasma l e v e l s o f  p h e n y l a l a n i n e over long p e r i o d s o f time c o u l d p o t e n t i a l l y be h a r m f u l . Relatively  low plasma l e v e l s of m e t h i o n i n e and t y r o s i n e seen i n  the i n f a n t s r e c e i v i n g t o t a l p a r e n t e r a l n u t r i t i o n seem t o i n d i c a t e t h a t more p r o t e i n c o u l d be f e d w i t h o u t  c r e a t i n g an abnormal plasma amino  acid pattern.  on t h e n u t r i t i o n a l  I n f a n t s maintained  regime o u t l i n e d  i n T a b l e 2 may w e l l b e n e f i t from an i n c r e a s e o f p r o t e i n i n t a k e t o approximately  3 g/kg body w e i g h t / d a y , as has been suggested by Hendry  et_ a_l_. , (155), should be t h e s u b j e c t o f f u r t h e r study.  81  References C i t e d : 1.  Z i a i , M., Janeway, C.A., Cooke, R.E. L i t t l e Brown & Co., 1969, p.165-  2.  D i e t a r y Standard f o r Canada, Bureau o f N u t r i t i o n a l S c i e n c e s , H e a l t h P r o t e c t i o n Branch, Department o f N a t i o n a l H e a l t h and W e l f a r e , Ottawa, Information Canada, 1975-  3.  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P a r e n t e r a l n u t r i t i o n i n the management o f s i c k low b i r t h w e i g h t i n f a n t s . P e d i a t r . C l i n . North Amer. 29:333, 1973F r a s e r , G.C., Simpson, W., Pendray, M., and D a i l e y , C. treatment o f c o n g e n i t a l d e f e c t s i n the abdominal w a l l . 42:474, 1976.  Surgical Am. Surg.  Moore, F.D. M e t a b o l i c Care o f the S u r g i c a l P a t i e n t . P h i l a d e l p h i a Saunders, 1959. H e i r d , W.C. and W i n t e r s , R.W. Some m e t a b o l i c aspects of t o t a l p a r e n t e r a l n u t r i t i o n i n s u r g i c a l neonates. In': Proceeding o f the I n t e r n a t i o n a l Congress o f P a r e n t e r a l N u t r i t i o n . E d i t e d by, C. Romieu, C. S o l a s s o l , H. Joyeau and B. A s t r u c . M o n t p e l l i e r : U n i v e r s i t y o f M o n t p e l l i e r , 1974, p.741. Sher, P.K., and Brown, S.B. A l o n g i t u d i n a l study o f head growth i n pre-term i n f a n t s . I . Normal r a t e s o f head growth. Dev. Med. Chi Id N e u r o l . 17:705, 1975Sher, P.K., and Brown, S.B. A l o n g i t u d i n a l study o f head growth in pre-term i n f a n t s . I I . D i f f e r e n t i a t i o n between 'catch-up' head growth and e a r l y i n f a n t i l e h y d r o c e p h a l u s . Dev. Med. C h i l d N e u r o l . 17:711, 1975.  APPENDICES  95  APPENDIX B:  CONSENT FORM  CONSENT FORM  Dear Mrs. Your premature baby i s normal and has no unusual problems, however, some premature b a b i e s a r e unable t o t o l e r a t e m i l k f e e d i n g and must be f e d i n t r a v e n o u s l y . There a r e a few amino a c i d ( p r o t e i n ) s o l u t i o n s a v a i l a b l e which h e l p us t o do t h i s . These a r e very v a l u a b l e s o l u t i o n s but we a r e u n c e r t a i n as t o whether t h e i r c o m p o s i t i o n c o u l d be improved. We want t o review t h i s but do not know t h e amino a c i d l e v e l s i n the blood o f normal premature b a b i e s . We need these v a l u e s f o r comparison w i t h i n f a n t s being f e d amino a c i d s i n t r a v e n o u s l y to assess whether the amino a c i d m i x t u r e used c o u l d be improved. To do t h i s we need a s m a l l sample o f blood from normal premature i n f a n t s r e c e i v i n g m i l k . In o r d e r t o c o l l e c t the blood sample a t r a i n e d t e c h n i c i a n p r i c k s t h e heel o f an i n f a n t and c o l l e c t s a s m a l l amount o f blood two hours a f t e r one f e e d . T h i s sample w i l l be a n a l y z e d by a s p e c i a l instrument i n the l a b o r a t o r y t o g i v e us p r e c i s e l e v e l s f o r each amino a c i d i n t h e b l o o d . There a r e no problems a s s o c i a t e d w i t h t h i s t e c h n i q u e except t h a t the baby r e q u i r e s a s m a l l p r i c k i n the heel i n o r d e r t o c o l l e c t t h e b l o o d . I f anything, unusual i s found t h e d o c t o r and p a r e n t s o f t h e baby w i l l be informed. W i l l you agree t o a l l o w us t o use your baby f o r e s t a b l i s h i n g normal v a l u e s ? You can r e f u s e now o r a t any time i n the f u t u r e . T h i s w i l l not j e o p a r d i z e your i n f a n t ' s c a r e .  APPENDIX C:  VANCOUVER  PARENTERAL NUTRITION FLOW CHART  GENERAL  PARENTERAL FLOW  NUTRITION CHART  FLUID DATE: WEIGHT: INTAKE Oral Intravenous - Amino Acid Mixture Intralipid  TOTAL OUTPUT Urine Stool  TOTAL Calories f r o m Amino Acid Mixture Calories from Intra!ipid Calories f r o m Other Solutions Total IV Calories per 24 hours IV Calories per k i l o qram per 24 hours Oral Calorie Count Total IV Protein per 24 hours IV Protein per kilogmm p^r 24 hours" Nitrogen Intake per 24 hours Nitrogen Excretion per 24 hours Nitrogen Balance  HOSPITAL  BALANCE  AND N U T R I T I O N A L  INTAKE  LABORATORY INVESTIGATIONS  DATE TIME Haemoglobin White Cell Count Differential Plat©let«  Sodium Potassium Chloride Bicarbonate PH PC0  2  BUN Creatinine Blood Sugar Serum Magnesium Serum Calcium Serum Phosphorus Alkal ine Phosphatase SGOT  Bilirubin Serum Proteins Albumin Globul in Blood Ammonia Serum Osmolality Serum Milkness  98  COMPOSITION  DATE Intralipid 10% Heparin Type of Amino Acid Solution Amount of Amino Acid Solution 50% Dextrose Water 10% Dextrose Water 5% Dextrose Water Sodium Chloride Sodium Bicarbonate Potassium Chloride Potassium Acid Phosphate Calcium Gluconate Calcium Chloride Magnesium Sulphate  MV1  - 1000  Vitamin K Folic Acid Vitamin B^J  OF  NUTRIENTS  SOLUTION  99 APPENDIX D;  INTRAUTERINE GROWTH CHARTS FOR EACH STUDY INFANT  VANCOUVER GENERAL HOSPITAL INTENSIVE  CARE  INTRAUTERINE  Patient 1  NURSERY  GROWTH  CHART  Appendix D  3 4 2 5 2 8 27 2 6 2 9 3 0 31 32 33 34 3 5 3 8 37 36 38 4 0 41 4 2 4 3  24 25 2 8 2 7 2 6 2 9 3 0 3 1 3 2 3 3 3 4 3 5 3 8 37 3 6 3 9 4 0 4 I 42 43 WEEK OF GESTATION  (FROM L U B C H E N C O , L . O . , E T A L .  P A E D I A T R I C S 37: 4 0 3 , 19661  2 4 2 5 2 8 2 7 2 6 2 8 3 0 31 32 3 3 3 4 3 6 3 6 37 3 6 3 9 4 0 4 1 4 2 4 3  2 4 2 5 2 8 27 2 8 2 9 3 0 31 3 2 3 3 3 4 3 5 3 8 37 3 6 3 9 4 0 41 WEEK OF GESTATION  100  VANCOUVER GENERAL HOSPITAL INTENSIVE  INTRAUTERINE  CARE  Patient 2  NURSERY  GROWTH  CHART  2 4 2 5 2 8 27 2 6 2 9 3 0 31 32 3 3 3 4 3 5 3 6 37 3 8 3 9 4 0 4 1 42 4 3  25 26 27 28 29 30 31 32 3 3 3 4 3 5 3 6 37 3 6 3 9 4 0 4 1 WEEK OF GESTATION  (FROM L U B C H E N C O , L.O., ET A L .  42 4 3  P A E D I A T R I C S 37: 4 0 3 . 1 966>  2 4 2 5 2 6 2 7 2 6 2 8 X 31 32 3 3 3 4 3 6 3 8 37 3 6 3 8 4 0 41 4 2 43  24 25 26 27 26 29 30 31 32 33 34 35 38 37 36 39 40 41 42 4 3 ' WEEK OF GESTATION  101  VANCOUVER GENERAL HOSPITAL INTENSIVE  CARE  INTRAUTERINE  Patient 3  NURSERY  GROWTH  (FROM L U B C H E N C O , L.O., E T A L .  CHART  P A E D I A T R I C S 3 7 : 403,  1966)  102  VANCOUVER G E N E R A L HOSPITAL INTENSIVE  CARE  INTRAUTERINE  GROWTH  CHART  25 26 27 26 29 30 31 32 33  25 26 27 26 29 X 31 32 3 3 3 4 3 8 3 8 37 3 6 3 9 4 0 41  24 25 26 27 26 29 30 31 32 3 3 3 4 3 5 3 8 37 3 6 3 9 4 0 4 WEEK OF GESTATION  (FROM L U B C H E N C O , L . O . ,E T A L .  Patient 4  NURSERY  P A E D I A T R I C S 37: 4 0 3 , 1966)  2 4 2 5 2 6 27 2 8 2 9 X 31 3 2 3 3 3 4 3 5 3 8 37 3 6 3 9 4 0 41 WEEK OF GESTATION  103  VANCOUVER GENERAL HOSPITAL INTENSIVE  INTRAUTERINE  CARE  Patient 5  NURSERY  GROWTH  CHART  2 4 2 5 2 8 2 7 2 6 2 8 3 0 3 1 32 3 3 3 4 3 6 3 8 37 3 6 3 9 4 0 41 4 2 4 3  2 6 2 8 27 2 8 2 8 30 31 32 33 34 35 38 37 36 3 9 4 0 4 1 4 2 4 3  25 28 27 28 28 30 31 32 3 3 3 4 3 5 3 8 37 WEEK O f GESTATION  (FROM L U B C H E N C O . L . O . , E T A L .  3638404  P A E D I A T R I C S 37: 403. 19661  0  2 4 2 5 2 8 27 2 6 2 8 X 31 3 2 3 3 3 4 3 5 3 8 37 3 6 3 B 4 0 4I 42 4 3 WEEK Of GESTATION  104  VANCOUVER GENERAL INTENSIVE  INTRAUTERINE  CARE  HOSPITAL  NURSERY  GROWTH  CHART  24 25 28 27 26 29 30 31 32 33 34 35 36 37 36 39 4 0 41 42 4 3  0  Patient 6  2 4 2 5 2 8 2 7 2 8 2 9 3 0 3 1 3 2 3 3 3 4 3 5 3 8 37 3 6 3 9 4 0 41 42 43 WEEK OF GESTATION  < FROM L U B C H E N C O , L.O., ET A L .  P A E D I A T R I C S 3 7 : 4 0 3 . 19661  24252827262930  31 32 3 3 3 4 3 5 3 8  2 4 2 5 2 8 27 2 6 2 9 3 0 31 3 2 3 3 3 4 3 5 3 6 WEEK OF GESTATION  37 3 6 3 9 4 0 4 1 4 2 43  37 3 8 3 9 4 0 4 1 4 2 4 3  105  VANCOUVER  G E N E R A L  INTENSIVE  C A R E  INTRAUTERINE  HOSPITAL  Patient 7  N U R S E R Y  GROWTH  CHART  2 5 2 6 2 7 2 6 2 8 3 0  25 26 27 26 2 9 3 0 31 3 2 3 3  0  2 4 2 5 2 6 2 7 2 6 2 8 3 0  3132  3 3 3 4 3 5 3 6 3 7 3 6 3 8 4 0 4I 42  242528  43  W E E K O F GESTATION  (FROM  LUBCHENCO.  L.O.,  E T  AL.  PAEDIATRICS  27 2 6 2 8 3 0  3132 33343536  37 3 6 3 9 4 0  31  37 3 6 3 8 4 0  3233343536  WEEK OF GESTATION  37: 403.  1966)  4142  43  414243'  VANCOUVER INTENSIVE  GENERAL CARE  INTRAUTERINE  HOSPITAL  Patient 9  NURSERY  GROWTH  CHART  2528 27 2829 30 31 32 33 34 35 36 37 3 8 3 0 4 0 4 1 4 2 4 3  24 25 28 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 WEEK OF GESTATION  (FROM L U B C H E N C O ,  L.O., ET A L .  PAEDIATRICS  2 4 2 5 2 8 2 7 2 8 2 9 3 0 3 1 3 2 3 3 3 4 3 5 3 8 37 3 6 3 9 4 0 4 1 4 2 43  2 4 2 5 2 8 27 2 8 2 9 X 31 3 2 X 3 4 3 5 3 8 37 36 39 40 41 WEEK OF GESTATION  3 7 : 4 0 3 , 1966)  107  VANCOUVER GENERAL INTENSIVE  CARE  INTRAUTERINE  HOSPITAL  Patient 10  NURSERY  GROWTH  CHART  25 28 27 26 29 30 31 32 33  24252627282930 3 1 3 2 3 3 3 4 3 5 3 6 3 7 3 6 3 9 4 0 414243 WEEK Of GESTATION  (FROM L U B C H E N C O , L . O . , E T A L . PAEDIATRICS 37: 403, 1966)  2 6 2 7 2 6 2 9 3 0 3 1 3 2 3 3 3 4 3 6 3 6 37 3 6 3 9 4 0 4 1 4 2 43  2 4 2 5 2 8 27 2 6 2 9 3 0 31 3 2 3 3 3 4 3 5 3 6 37 3 6 3 9 4 0 4 1 4 2 4 3 ' WEEK Of GESTATION  

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