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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 LERNER B. A., U n i v e r s i t y of B r i t i s h Columbia A THESIS SUBMITTED 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 of Home Economics We accept t h i s t h e s i s as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA October, 1978. Sarah Ann Lerner, 1978 In presenting th is thes is in p a r t i a l fu l f i lment of the requirements f o r an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ib rary sha l l make i t f ree l y ava i lab le for reference and study. I fur ther agree that permission for extensive copying of t h i s t h e s i s for scho lar l y purposes may be granted by the Head of my Department or by h i s representat ives . It is understood that copying or p u b l i c a t i o n of th is thes is for f i n a n c i a l gain sha l l not be allowed without my wr i t ten permission. Department of \\Or\C (SCONJOMilS OF- HUMAiv i M UTEj - r i o/\) The Univers i ty of B r i t i s h Columbia 2075 W e s b r o o k P l a c e V a n c o u v e r , C a n a d a V6T 1W5 Date OCToBfcTg fe ,l°n& ABSTRACT The object of t h i s study was to assess the adequacy of the pr o t e i n s o l u t i o n given to premature inf a n t s r e c e i v i n g intravenous n u t r i t i o n . Plasma aminograms from premature i n f a n t s fed o r a l l y were determined and compared with aminograms from premature inf a n t s maintained on intravenous n u t r i t i o n . 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 , coupled with growth parameters, such as weight g a i n , body length, and head circumference were f u r t h e r used to evaluate n u t r i t i o n a l adequacy. Standardized plasma aminograms were obtained using c a p i l l a r y blood samples from a c o n t r o l group of 16 i n f a n t s ( g e s t a t i o n a l age 31-36 weeks, mean 33i weeks), fed SM^Q (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 of the day. The study group was comprised of 11 in f a n t s between 2^-30 weeks ge s t a t i o n (mean 28 weeks), fed intravenously, using a s y n t h e t i c c r y s t a l l i n e L-amino ac i d mixture (Vamin), running continuously. Blood samples from the study group were a l s o taken between the 7th-16th day of l i f e at the same time of the morning as the con t r o l group. Results showed that plasma samples from the study group had lower l e v e l s of threonine, asparagine, glutamic a c i d , l y s i n e , 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, 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 the c o n t r o l group. Plasma phenylalanine l e v e l s were 2-3 times higher in the study group than in the con t r o l group. i i i Plasma urea l e v e l s were lower in the intravenously fed group than in the o r a l l y fed group. It i s l i k e l y that both the low plasma urea and 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 use of the intravenously infused amino acids by i n f a n t s in the study group. It i s most probable that the infused amino acids are being used f o r p r o t e i n synthesis rather than f o r energy purposes. E f f i c i e n t use of infused amino acids i s f u r t h e r suggested by the actual growth in length, head circumference and weight gain noted in the intravenously fed i n f a n t s . Further studies are needed to e x p l a i n the higher plasma l e v e l s of phenylalanine seen in i n f a n t s intravenously infused with Vamin. R e l a t i v e l y low plasma l e v e l s of methionine and t y r o s i n e in the i n t r a -venously fed i n f a n t s seem to i n d i c a t e that an increase in t o t a l p r o t e i n intake may be b e n e f i c i a I. The t o t a l amount of phenylalanine in Vamin, in a d d i t i o n to r e l a t i o n s h i p to the other amino acids a l s o needs f u r t h e r study. "TABLE OF CONTENTS ABSTRACT TABLE OF CONTENTS LIST OF TABLES LIST OF FIGURES ACKNOWLEDGEMENTS CHAPTER I INTRODUCTION I I LITERATURE SURVEY A. P r o t e i n and Energy Requirements of the F u l l Term and Premature Infant B. Parenteral N u t r i t i o n 1. Hi story 2 . Parenteral n u t r i t i o n and premature i n f a n t s 3 . Types of amino a c i d mixtures a v a i l a b l e h. Method of a d m i n i s t r a t i o n C. Amino Acid Metabolism 1. Normal physiology 2. Infused amino a c i d mixtures 3 . Plasma aminograms D. P i t f a l l s in Studying Plasma Aminograms E. K i l o c a l o r i e : N i t r o g e n Ratio — 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 I I I MATERIALS AND METHODS A. The Control Group B. The Study Group C. Treatment and A n a l y s i s of Blood Samples D. Other Analyses E. Determination 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 A n a l y s i s IV RESULTS 46 V DISCUSSION 71 A. Control Values 71 B. Study Values 73 C. Comments on the Differences Between Control and Study Data lk D. Recommendations 80 REFERENCES CITED 81 APPENDICES A. L e t t e r of Introduction to P e d i a t r i c i a n s 3k B. Consent Form 95 C. Parenteral N u t r i t i o n Flow Chart 96 D. I n t r a u t e r i n e Growth Charts f o r Each Study Infant 99 V I LIST OF TABLES TABLE Page 1. Amino Acid Composition of SMA^Q and Breast M i l k 35 2. Study Protocol - Qu a n t i t i e s of Nutrients/Kg Body Weight/Day 36 3. Amino Acid Composition of Vamin 37 k. Sex, Gestational Age and B i r t h Weight of the Premature Infants in the Control Group kl 5. Head Circumference and Length at B i r t h of the Premature Infants in the Control Group 48 6. Sex, Gestational Age and B i r t h Weight of Premature Infants in the Study Group 49 7. Head Circumference and Length at B i r t h of Premature Infants in the Study Group 50 8. P r o t e i n Intake For The 3 Days P r i o r to the Drawing of the Blood Sample 53 9. Average Amino Acid Intake by the Control and Study Infants 5^ 10. I n d i v i d u a l Plasma Amino Acid Values f o r Control Group: Premature Infants Receiving Oral Feeds of SMA^Q 57 11. I n d i v i d u a l Plasma Amino Acid Values f o r the Study Group:Premature Infants Receiving Total Parenteral N u t r i t i o n 59 12. Mean Plasma Amino Acid Values f o r Control and Study Groups 61 13- Va1ine:Glycine Ratios f o r Infants Receiving Total Parenteral N u t r i t i o n 63 14. Linear Regression S t a t i s t i c s on Gestational Age and Plasma Amino Acid Concentrations, (Gestational Age 31-36 wks) 64 15- Linear Regression S t a t i s t i c s on Ges t a t i o n a l Age and Plasma Amino Acid Concentrations, (Gestational Age 24-31 wks) 65 16. Linear Regression and C o r r e l a t i o n C o e f f i c i e n t A n a l y s i s of Plasma Levels of Glutamine and Asparagine 66 S t a t i s t i c a l A n a l y s i s on Data Comparing Amino Acid Concentrations in C a p i l l a r y and Venous Samples Duration of Total Intravenous Feeding and Average K i l o c a l o r i e : N i t r o g e n Ratio A t t a i n e d Comparison of Plasma Amino Acids in Premature and Fu11 Term Infants v i i i L IST OF FIGURES FIGURE Page 1. Changes in D i s t r i b u t i o n in Major Body Components o f the F e t u s D u r i n g the L a s t T r i m e s t e r o f P regnancy 6 2. P a r e n t e r a l N u t r i t i o n U s i n g P e r i p h e r a l V e i n s 17 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 Samples in the Durrum D-500 Amino A c i d A n a l y z e r 43 k. W e i g h t , L e n g t h , and Head C i r c u m f e r e n c e Measurements a t B i r t h o f the C o n t r o l Group 51 5- W e i g h t , L e n g t h , and Head C i r c u m f e r e n c e Measurements a t B i r t h o f the Study Group 52 6. A Compar i son o f P lasma Amino A c i d C o n c e n t r a t i o n s o f the C o n t r o l and Study Groups 62 7- Growth Data f o r P a t i e n t 8 W h i l e 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 69 8. R e l a t i o n s h i p o f D a i l y i n t r a v e n o u s In take Wi th Weight Ga in 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 t h o u g h t f u l 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 the p r e p a r a t i o n o f t h i s t h e s i s . S p e c i a l thanks i s ex tended t o D r . M a r g a r e t Pendray who a r r a n g e d f o r the 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 i n d e b t e d 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 spec imen a n a l y s e s and f o r t a k i n g the t ime to t e a c h me how to i n t e r p r e t the 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 the moral s u p p o r t and e d i t o r i a l a s s i s t a n c e o f Dr . 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 the e n t h u s i a s t i c a s s i s t a n c e o f the 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 the I n t e n s i v e Care N u r s e r i e s o f the V a n c o u v e r Genera l and Grace 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 h e l p o f 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 i s ex tended to the t e c h n i c i a n s o f the B i o c h e m i c a l D i s e a s e s L a b o r a t o r y a t C h i l d r e n ' s H o s p i t a l . 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 the Vancouver 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 Caruk 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 in the p r e p a r a t i o n o f t h i s thes i s . CHAPTER 1 1 INTRODUCTION P a r e n t e r a l n u t r i t i o n i s a technique used to feed p a t i e n t s when the g a s t r o i n t e s t i n a l route is i m p o s s i b l e , inadequate or i l l a d v i s e d . Assessment of the adequacy of n u t r i t i o n g iven in t h i s manner i s d i f f i c u l t , e s p e c i a l l y in the case of i n f a n t s . Some i n f a n t s r e q u i r e int ravenous n u t r i t i o n immediately a f t e r b i r t h . As t h i s i s normal ly a per iod of very rap id growth i t i s important to assess the adequacy of the p r o t e i n in take in these i n f a n t s . Cerebral growth i s c r i t i c a l dur ing the p e r i n a t a l pe r iod and depends in par t on opt imal l e v e l s of c i r c u l a t i n g 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 homeostat ic mechanisms which c o n t r o l blood l e v e l s of plasma c o n s t i t u e n t s such as amino a c i d s . The 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 ve in 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 lutamate and a s p a r t a t e . This occurs d e s p i t e the f a c t that g lutamate and a s p a r t a t e may account fo r 20-30% of the c o n s t i t u e n t amino a c i d s in the ingested p r o t e i n . The gut a l s o p lays an a c t i v e r o l e in conver t ing ingested n i t r o g e n to a l a n i n e . 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 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 . The absence of t h i s aspect of homeostat ic c o n t r o l accentuates the need to monitor c a r e f u l l y plasma ami no ac i d l e v e l s . R e l a t i v e l y gross d i s tu rbances of plasma amino a c i d s are seen in inborn e r r o r s of metabol ism. Whether more modest a b n o r m a l i t i e s may cause problems i s not known. Plasma amino a c i d va lues have been shown to vary 2 w i t h both the q u a n t i t y and the q u a l i t y o f the p r o t e i n f e d as has been i l l u s t r a t e d in a d u l t s and c h i l d r e n . To e v a l u a t e the p lasma amino a c i d l e v e l s in i n f a n t s f e d i n t r a v e n o u s l y r e q u i r e s an a c c u r a t e knowledge o f the amino a c i d l e v e l s in a c o n t r o l g roup o f a d e q u a t e l y n o u r i s h e d i n f a n t s . The e s t a b l i s h m e n t o f a s t a n d a r d i z e d s e t o f p lasma amino a c i d v a l u e s f o r normal p r e m a t u r e i n f a n t s i s i m p o r t a n t f o r c o m p a r i s o n w i t h p remature 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 . A n o t h e r parameter o f n u t r i t i o n a l a d e q u a c y , commonly used f o r t h e s e r a p i d l y g rowing i n f a n t s , l i n k s p r o t e i n i n t a k e t o t o t a l : k i l o -c a l o r i e s consumed. T h i s i s 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 . When combined w i t h the p a r a m e t e r s o f growth (weight g a i n , body l e n g t h and head c i r c u m f e r e n c e ) the c l i n i c i a n can use t h i s r a t i o t o e s t i m a t e whether the d i e t a r y p r o t e i n i s b e i n g used e f f i c i e n t l y . D e t e r m i n i n g o p t i m a l l e v e l s o f p r o t e i n and k i l o c a l o r i e s in a d i e t i s i m p o s s i b l e due to many f a c t o r s a f f e c t i n g d i g e s t i o n , a b s o r p t i o n and u t i l i z a t i o n o f p r o t e i n . It s h o u l d be p o s s i b l e to d e t e r m i n e a range o f p r o t e i n i n t a k e f o r optimum g r o w t h . The p r i m a r y p u r p o s e o f t h i s s t u d y was to a s s e s s the adequacy o f the s y n t h e t i c amino a c i d m i x t u r e (Vamin) a d m i n i s t e r e d t o p r e m a t u r e 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 . A c c o m p l i s h m e n t o f t h i s r e q u i r e d : 1) e s t a b l i s h i n g a s e t o f s t a n d a r d normal aminogram v a l u e s f o r p r e m a t u r e i n f a n t s o r a l l y f e d , g e s t a t i o n a l age 31_38 weeks , 2) u s i n g t h i s s t a n d a r d t o e v a l u a t e the p lasma amino a c i d p a t t e r n s in p remature i n f a n t s o f the same g e s t a t i o n a l age 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 , and 3) e x a m i n i n g the r e l a t i o n s h i p between the r a t i o o f energy t o n i t r o g e n i n t a k e and the p a r a m e t e r s o f g r o w t h . 3 CHAPTER 11  LITERATURE SURVEY A . PROTEIN AND ENERGY REQUIREMENTS OF THE FULL TERM AND PREMATURE INFANT D u r i n g i n t r a u t e r i n e e x i s t e n c e a f e t u s i s s u p p l i e d w i t h a l l n u t r i t i o n a l r e q u i r e m e n t s by the m o t h e r . P r o p e r growth and deve lopment a r e dependent on the q u a n t i t y o f n u t r i e n t s r e a c h i n g the f e t u s a c r o s s the p l a c e n t a (1). A f t e r b i r t h the i n f a n t becomes t o t a l l y dependent on an o u t s i d e e n v i r o n m e n t where n u t r i t i o n a l d e f i c i e n c i e s and i m b a l a n c e s may r a p i d l y r e s u l t in growth d i s o r d e r s . A c c o r d i n g t o C a n a d i a n D i e t a r y S t a n d a r d s ( 2 ) , the recommended ; energy r e q u i r e m e n t f o r f u l l term i n f a n t s f rom b i r t h t o s i x months i s 117 k c a l / k g body w e i g h t . T h i s f i g u r e i s based on a b a s a l c a l o r i c r e q u i r e m e n t o f 55 k c a l / k g , a growth r e q u i r e m e n t o f 35 k c a l / k g and an a c t i v i t y a l l o w a n c e o f 10 t o 25 k c a l / k g body w e i g h t . Human m i l k p r o v i d e s 55, 38 and 1 p e r c e n t o f k i l o c a l o r i e s f rom f a t , c a r b o h y d r a t e , and p r o t e i n r e s p e c t i v e l y (3). The a v e r a g e f u l l term i n f a n t s h o u l d r e c e i v e 2.2 g p r o t e i n / k g body w e i g h t / d a y (2). Amino a c i d s a r e needed f o r the s y n t h e s i s o f body p r o t e i n s and o t h e r p h y s i o l o g i c a l l y i m p o r t a n t compounds. N ine o f t h e s e amino a c i d s c a n n o t be s y n t h e s i z e d in the body and a r e t h e r e f o r e termed e s s e n t i a l . These a r e : h i s t i d i n e , l y s i n e , l e u c i n e , i s o l e u c i n e , v a l i n e , m e t h i o n i n e , p h e n y l a l a n i n e , t h r e o n i n e , and t r y p t o p h a n (3,9,10,38). H i s t i d i n e was thought t o be e s s e n t i a l o n l y f o r the human i n f a n t (6,7,8, 12,15). It i s now b e l i e v e d t o be e s s e n t i a l f o r a d u l t s (4,5). These r e q u i r e m e n t s may not be the same f o r p r e m a t u r e i n f a n t s . U n t i l a few y e a r s ago p remature i n f a n t s were d e f i n e d as w e i g h i n g l e s s than 2500 grams (43). L i t t l e a t t e n t i o n was p a i d to the d u r a t i o n o f 4 i n t r a u t e r i n e l i f e . A premature i n f a n t i s now defined as an infant born before 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). Some i n f a n t s have survived a f t e r only 24 weeks ge s t a t i o n (44). Premature i n f a n t s often need more s o p h i s t i c a t e d forms of support than f u l l term i n f a n t s . Most i n f a n t s born prematurely have greater n u t r i t i o n a l needs than normal f u l l term i n f a n t s (11,13,14). Premature i n f a n t s f a l l i n to a category of 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 stores which are h e a v i l y taxed by e x c e p t i o n a l l y high metabolic demands (15,17). In Figure 1-, based on Widdowson's data (16), Heird and Winters (11) show the changes in body composition of the fetus during the l a s t t r i m e s t e r of pregnancy. I l l u s t r a t e d in t h i s f i g u r e i s the s u b s t a n t i a l increase in f a t and decrease in e x t r a c e l l u l a r water which takes place between 24 and 40 weeks of g e s t a t i o n . If a c h i l d i s born prematurely, weighing 1000 grams, only 1% of i t s body weight i s f a t and almost 8.5% i s p r o t e i n (21). If one assumes a v a i l a b i l i t y of a l l body f a t and p r o t e i n stores f o r c a l o r i c needs the t o t a l c a l o r i c reserve would be 430 kcal/kg body weight (15). Without n u t r i t i o n a l support, a small premature i n f a n t , r e c e i v i n g only water, w i l l s u r v i v e approximately four days (.1.5) • The basal metabolic requirement of the premature i n f a n t i s 50-60 kcal/kg body weight/24 hours (15,17). However, another 50-60 kcal/kg body weight/day must be added to account f o r cold s t r e s s , a c t i v i t y , growth (14,15,17,21). A d d i t i o n a l s t r e s s e s , such as sepsis or r e s p i r a t o r y d i s t r e s s w i l l 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 of l i f e , these i n f a n t s ' d a i l y c a l o r i c requirements reach 110-150 kcal/kg body weight (18). The p r o t e i n requirements f o r the premature infant have not yet been adequately defined. A great deal of controversy has clouded t h i s issue since Gordon ejt a_l_. , (24) found that premature i n f a n t s fed unmodified cow's milk mixtures showed excessive weight gains. These mixtures, however, a l s o contained more minerals than breast milk and several observers have suggested that the increased weight gain was due to f l u i d r e t e n t i o n (24 -28,29). It could be a n t i c i p a t e d that the q u a n t i t a t i v e p r o t e i n requirement of the premature infant would be greater than that of a f u l l term i n f a n t f o r a number of reasons. These include an impaired a b i l i t y to dige s t and absorb n u t r i e n t s , a rapid rate of growth, and a greater loss of amino acids in the urine as a r e s u l t of impaired renal tubular reabsorption (19). Although Snyderman and coworkers (19,20) found increased nitrogen r e t e n t i o n in i n f a n t s - f e d 9 grams pr o t e i n / k i l o g r a m body weight/day, a p p r e c i a t i o n of the s t r a i n that high s o l u t e loads impose on the immature kidney led her to recommend a more moderate p r o t e i n intake of 304 g/kg body weight/day. These recommendations are based on modified cow's milk formulas and on the assumption of an intake of 140 kcal/kg body weight/day. More r e c e n t l y , Raiha (23) f e e l s that since metabolic imbalances may be harmful to the developing 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 formulas (82:28 casein:1 acta 1bumin) should not be fed to premature i n f a n t s with metabolic immaturities. Raiha (23) and Gaull e_t aj_. , (55) f e e l that the p r o t e i n intake should be 2.25 g/kg body weight/day and that t h i s should be given in the form of breast milk or a 6 Fig. 1 Changes in Distribution in Major Body Components of the Fetus During the Last Trimester of Pregnancy 100 75 Fat (%) 50 25 Water Fat I Free I Wet I Weight 0 1000 l i t 1500 2000 2500 3000 Protein Other 3500 gms from Heird et a l , (11). 7 f o r m u l a w i t h a s i m i l a r p r o t e i n c o n t e n t ( 4 0 : 6 0 c a s e i n : 1 a c t a 1bumin ) . O t h e r r e s e a r c h e r s f e e l t h a t b r e a s t m i l k o r b r e a s t m i l k - s i m u l a t e d f o r m u l a may not p r o v i d e enough p r o t e i n t o s u p p o r t a d e q u a t e growth r a t e s in p r e m a t u r e i n f a n t s ( 3 0 , 3 1 ) . In a d d i t i o n t o the n i n e e s s e n t i a l amino a c i d s , c y s t i n e and t y r o s i n e a r e a l s o c o n s i d e r e d to be e s s e n t i a l f o r the p r e m a t u r e i n f a n t . C y s t a t h i o n a s e , one o f the key enzymes in the b i o s y n t h e t i c pathway o f c y s t i n e does not d e v e l o p d u r i n g f e t a l l i f e o r u n t i l l a t e r in p o s t n a t a l l i f e ( 1 9,33,3^,35,55,56). Low p lasma l e v e l s o f c y s t i n e and h i g h c o n c e n t r a t i o n s o f c y s t a t h i o n i n e in the u r i n e f u r t h e r s u p p o r t the c l a i m t h a t c y s t i n e cannot be s y n t h e s i z e d in a d e q u a t e amounts f rom d i e t a r y s o u r c e s ( 5 6 ) . Snyderman ( 1 9 ) and J u r g e n s and D o l i f (36) s u g g e s t e d t h a t t y r o s i n e i s an e s s e n t i a l amino a c i d f o r p remature i n f a n t s . They f e l t t h i s was due to an immature p h e n y l a l a n i n e h y d r o x y l a s e s y s t e m . More r e c e n t l y however , the enzyme sys tem has been found t o be a c t i v e in human f e t a l l i v e r f rom the e l e v e n t h week o f g e s t a t i o n ( 3 7 , 3 9 ) . Recent r e s e a r c h has i n d i c a t e d t h a t t a u r i n e may be e s s e n t i a l f o r the r a p i d l y d e v e l o p i n g human i n f a n t ( 4 1 1 , 4 2 ) . Sturman e_t a_j_. , ( 4 1 ) s u g g e s t t h a t i n f a n t s cannot s y n t h e s i z e a d e q u a t e amounts o f t a u r i n e f rom c y s t i n e and m e t h i o n i n e p r e c u r s o r s . The i n f a n t may then be e n t i r e l y dependent on d i e t to p r o v i d e s u f f i c i e n t t a u r i n e ( 4 1 , 5 6 ) . 8 B. PARENTERAL NUTRITION  1. HISTORY T o d a y , p a r e n t e r a l n u t r i t i o n i s the method by wh ich c a l o r i e s and n u t r i e n t s a r e g i v e n by v e i n . It i s w i d e l y used in the t r e a t m e n t o f c h i l d r e n and a d u l t s a l i k e . P a t i e n t s w i t h c h r o n i c bowel d i s o r d e r s , b u r n s , c o n g e n i t a l s u r g i c a l a b n o r m a l i t i e s o f the g u t , the v a r i o u s c o m p l i c a t i o n s a s s o c i a t e d w i t h p r e m a t u r i t y , u n d e r g o i n g t h e r a p y f o r n e o p l a s t i c d i s e a s e , o r r e c o v e r i n g f rom major s u r g i c a l o p e r a t i o n s may b e n e f i t f rom p a r e n t e r a l n u t r i t i o n . It i s a c h a l l e n g i n g a s p e c t o f human n u t r i t i o n w i t h a long and c o l o r f u l h i s t o r y . The f i r s t i n j e c t i o n o f a l i q u i d i n t o the b l o o d s t ream took p l a c e o v e r t h r e e hundred y e a r s a g o , as e x e c u t e d by Dr . Rober t B o y l e upon the s u g g e s t i o n o f S i r C h r i s t o p h e r Wren ( 4 8 ) . L a t e r , c h o l e r a e p i d e m i c s in the 1 8 20 ' s p r o v i d e d the f i r s t o p p o r t u n i t y f o r d o c t o r s t o p e r f o r m t r i a l i n j e c t i o n s o f s a l t s ( 4 9 ) . The s u c c e s s f u l r e s u l t s were d r a m a t i c but not a lways s u s t a i n e d ( 5 2 ) . C l a u d e B e r n a r d ' s s u c c e s s f u l i n j e c t i o n s o f egg w h i t e i n t o the v e i n s o f r a b b i t s were f o l l o w e d by many a t t e m p t s t o i n j e c t f o o d s i n t o both a n i m a l s and man ( 5 2 ) . P a r e n t e r a l n u t r i t i o n d u r i n g the f i r s t h a l f o f t h i s c e n t u r y has depended p r i m a r i l y on the use o f d e x t r o s e . The e x t e n s i v e use o f d e x t r o s e i s e a s i l y u n d e r s t o o d when one c o n s i d e r s the c e n t r a l r o l e o f g l u c o s e in m e t a b o l i s m and i t s n a t u r a l o c c u r r e n c e in the b l o o d ( 4 8 ) . Today some reg imes use g l u c o s e as t h e i r o n l y n o n - p r o t e i n c a l o r i e s o u r c e . Fat is u s e f u l because i t can s u p p l y a l a r g e amount o f energy in a s m a l l volume o f i s o t o n i c f l u i d . S u i t a b l e f a t e m u l s i o n s , however , were d i f f i c u l t to d e v e l o p due t o t e c h n i c a l p rob lems o f a t t a i n i n g o p t i m a l p a r t i c l e s i z e and f i n d i n g s a f e e m u l s i f y i n g a g e n t s . In the p a s t , p a t i e n t s s u f f e r e d f rom a c u t e and long term t o x i c r e a c t i o n s (50). A s a f e f a t e m u l s i o n , u s i n g egg y o l k p h o s p h o l i p i d s as e m u l s i f i e r s and h a v i n g s t a b l e p a r t i c l e s i z e s , s i m i l a r t o the s i z e o f n a t u r a l l y o c c u r r i n g c h y l o m i c r o n s , i s now a v a i l a b l e in C a n a d a . When f a t i s combined w i t h a c a r b o h y d r a t e , e n e r g y r e q u i r e m e n t s a r e e a s i l y s a t i s f i e d . As e a r l y as 1889 German s c i e n t i s t s made p r e p a r a t i o n s o f c a s e i n h y d r o l y s a t e s and i n j e c t e d them i n t r a v e n o u s l y i n t o a n i m a l s w i t h o u t p r o d u c i n g t o x i c s i d e e f f e c t s (52). C o m p l i c a t i o n s d e v e l o p e d when p r o d u c t s o b t a i n e d f rom more c o m p l e t e h y d r o l y s i s were u s e d . The f i r s t r e a l l y s u c c e s s f u l e x p e r i m e n t was r e p o r t e d in 1913 when a goat was m a i n t a i n e d in p o s i t i v e n i t r o g e n b a l a n c e f o r s i x t e e n days w h i l e r e c e i v i n g an i n t r a v e n o u s m i x t u r e o f g l u c o s e , s a l t s and an e n z y m a t i c h y d r o l y s a t e o f meat (52). It was not u n t i l w e l l a f t e r the F i r s t Wor ld War t h a t Elman i n i t i a t e d the use o f t h e s e p r o t e i n m i x t u r e s in t o t a l p a r e n t e r a l n u t r i t i o n (48). D u r i n g the e a r l y 19^0 's W r e t l i n d t r i e d t o d e v e l o p an i d e a l amino a c i d m i x t u r e (40) . It was not u n t i l 1 9 ^ t h a t he p r o d u c e d a r e a l l y s a t i s f a c t o r y amino a c i d p r e p a r a t i o n f o r i n t r a v e n o u s u s e . It was made by e n z y m a t i c h y d r o l y s i s o f c a s e i n f o l l o w e d by d i a l y s i s . As f a t s o l u t i o n s were not a v a i l a b l e in the U n i t e d S t a t e s , r e s e a r c h in p a r e n t e r a l n u t r i t i o n c e n t r e d around the use o f h y p e r t o n i c s o l u t i o n s o f beef f i b r i n h y d r o l y s a t e s and anhydrous g l u c o s e . These were i n f u s e d i n t o the s u p e r i o r vena cava where r a p i d d i l u t i o n and p e r i p h e r a l d i s t r i -b u t i o n o c c u r r e d . A major advancement was made in 1966, when D u d r i c k , e_t aj_. , (53) u s i n g t h i s t e c h n i q u e , showed t h a t b e a g l e pups c o u l d be m a i n t a i n e d o n ; t o t a l i n t r a v e n o u s n u t r i t i o n and c o n t i n u e t o grow n o r m a l l y 10 when compared with animals fed o r a l l y . Further research with humans showed that a prolonged, susta ined, and meaningful state of anabolism could be achieved with intravenous feeding (54). In the past , l i t t l e emphasis was placed on the need for adequate vitamins and minerals in parenteral nu t r i t i on programs. It was bel ieved to be of secondary importance in the nu t r i t i ona l care of the older ch i l d or adult pa t ien t . However, i t is now rea l i zed to be extremely important to the infant who may s i g n i f i c a n t l y increase i t s body mass during the time i t is maintained on tota l intravenous nu t r i t i on (22). Certa in vitamins and trace elements play an ac t i ve role in normal metabolism (22). Both vitamin and trace element so lut ions must be administered to the pat ient rece iv ing tota l parenteral nu t r i t i on over a prolonged period of time. Further research, however, is required to e luc ida te both the prec ise roles and requirements of a l l the vitamins and minerals so that recommended intakes for the intravenous route can be es tab l i shed. 2. PARENTERAL NUTRITION AND PREMATURE INFANTS Feeding of the premature infant is complicated due to the many problems fac ing him. Some of these problems include poor suck and swallow r e f l exes , r e l a t i v e l y high c a l o r i c requirement with small stomach capac i t y , poor gag ref lexes leading to a s p i r a t i o n , an incompetent esophageal cardiac sph inc te r , and a decreased a b i l i t y to absorb nutr ients (32). When the premature i n f an t ' s condi t ion permits gas t ro in tes t ina l feeding, spec ia l techniques are used, such as gavage feeding (43,44). 11 However , n a s o j e j u n a l f e e d i n g (45,46), and g a s t r o s t o m y (47) a r e t e c h n i q u e s wh ich have a l s o been u s e d . P a r e n t e r a l f e e d i n g i s used i n the management o f p r e m a t u r e i n f a n t s to p r o v i d e them w i t h a d e q u a t e n u t r i t i o n f o r p r o p e r growth and deve lopment when methods o f o r a l f e e d i n g a r e not p r a c t i c a l . T h e r e a r e f o u r main g roups o f i n f a n t s who b e n e f i t f rom t h i s m e t h o d . It i s p a r t i -c u l a r l y u s e f u l f o r i n f a n t s born w i t h c o n g e n i t a l a n o m a l i e s o f the i n t e s t i n a l t r a c t or abdominal w a l l (70,93,157)• I n f a n t s s u f f e r i n g f rom c h r o n i c d i a r r h e a o r u n d e f i n e d m a l a b s o r p t i o n syndromes may r e q u i r e t h i s k i n d o f s u p p o r t u n t i l such t ime as o r a l n u t r i t i o n can commence (93). Very s m a l l p rematures w i t h v e r y immature g a s t r o i n t e s t i n a l t r a c t s and/or n e c r o t i z i n g e n t e r o c o l i t i s may r e q u i r e 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 u r e them of r e c e i v i n g a d e q u a t e c a l o r i e s and n u t r i e n t s (93). A g r e a t number o f p r e m a t u r e i n f a n t s s u f f e r i n g f rom r e s p i r a t o r y d i s t r e s s syndrome . must be f e d i n t r a v e n o u s l y t o a v o i d f u r t h e r c o m p l i c a t i o n s o f r e g u r g i t a t i o n and a s p i r a t i o n (80,81,81,93)-There a r e s t i l l many p rob lems a s s o c i a t e d w i t h p a r e n t e r a l n u t r i t i o n u s i n g p e r i p h e r a l v e i n s . These i n c l u d e f l u i d and e l e c t r o l y t e p r o b l e m s , m e t a b o l i c d i s t u r b a n c e s , m i n e r a l d e f i c i e n c i e s a n d , most s e r i o u s o f a l l , the prob lems r e s u l t i n g f rom s e p s i s (11,15,32,83,84). On the o t h e r h a n d , b r a i n growth i s r a p i d in the f i r s t few weeks o f l i f e , "even more so in a p r e m a t u r e i n f a n t , and a p e r i o d of s t a r v a t i o n may i n t e r f e r e w i t h t h i s p r o c e s s (78,85,86,87). R e s u l t s o f many s t u d i e s have shown t h a t p a r e n t e r a l n u t r i t i o n w i t h a d e q u a t e c a l o r i e s and n u t r i e n t s i s c a p a b l e o f s u s t a i n i n g w e i g h t g a i n and a c h i e v i n g p o s i t i v e n i t r o g e n b a l a n c e in s m a l l p remature i n f a n t s (11,80, 12 81,81,88,89,90,93)- In f a c t , p a r e n t e r a l n u t r i t i o n has c o n t r i b u t e d t o the i n c r e a s e d r a t e o f s u r v i v a l in the l o w - b i r t h - w e i g h t p r e m a t u r e i n f a n t (90). 3. TYPES OF AMINO ACID MIXTURES AVAILABLE A l t h o u g h p r o t e i n h y d r o l y s a t e s have p r o v e n t o be v a l u a b l e s o l u t i o n s f o r p a r e n t e r a l n u t r i t i o n , t h e r e a r e many p rob lems and draw-backs a s s o c i a t e d w i t h them. H y d r o l y s a t e s o f c a s e i n and beef f i b r i n a r e s t i l l w i d e l y used (57), based on t h e i r h i g h b i o l o g i c a l v a l u e as judged by c r i t e r i a f o r o r a l n u t r i t i o n . F i b r i n undergoes p a r t i a l a c i d h y d r o l y s i s w h i l e c a s e i n i s s u b j e c t e d to p a r t i a l e n z y m a t i c h y d r o l y s i s (58). As a r e s u l t o f the h y d r o l y t i c p r o c e d u r e , t h i r t y to f o r t y - f i v e p e r c e n t o f the p r o t e i n remains as p e p t i d e s , the m e t a b o l i c f a t e o f wh ich i s u n c e r t a i n (57,67). Long e t ajk , (50) d e t e r m i n e d t h a t f i b r i n h y d r o l y s a t e s o l u t i o n s were not as e f f e c t i v e as 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 in terms o f n i t r o g e n r e t e n t i o n . T h i s i s due t o i n e f f i c i e n t u t i l i z a t i o n o f the p e p t i d e s (15). The amino a c i d p a t t e r n found in p r o t e i n h y d r o l y s a t e s i s s i m p l y a random r e s u l t o f i n c o m p l e t e a c i d h y d r o l y s i s o f the f i b r i n p r o t e i n b e a r i n g no r e s e m b l a n c e to the serum amino a c i d p a t t e r n seen a f t e r the i n g e s t i o n o f a meal (58). I n v e s t i g a t o r s have d e m o n s t r a t e d t h a t p lasma amino a c i d l e v e l s r e f l e c t the c o m p o s i t i o n o f the i n f u s e d s o l u t i o n (64, 103,104). O t h e r s have shown t h a t a d m i n i s t r a t i o n o f h y d r o l y s a t e s o l u t i o n s r e s u l t in s i g n i f i c a n t l y a l t e r e d p lasma amino a c i d p a t t e r n s (60,61). S i n c e p a r e n t e r a l i n f u s i o n s o f amino a c i d s o l u t i o n s e n t e r d i r e c t l y i n t o the p e r i p h e r a l c i r c u l a t i o n , b y p a s s i n g the h o m e o s t a t i c mechanisms o f the gut and l i v e r , c a r e s h o u l d be taken t h a t the amino a c i d c o m p o s i t i o n o f the i n f u s a t e r e s e m b l e s the plasma aminogram o b t a i n e d a f t e r a b a l a n c e d m e a l . 13 Other studies have found that 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 hydrolysate s o l u t i o n s vary from the label concentration (59,60,61). Apart from having v a r i a b l e amino a c i d compositions, p r o t e i n hydrolysates are completely lacking in some amino a c i d s . There i s no c y s t i n e to be found in casein hydrolysates, so i f used f o r i n f a n t s , supplementation becomes e s s e n t i a l (60). P r o t e i n hydrolysates have l i m i t e d u s efulness, then, in the s p e c i a l i z e d areas of parenteral n u t r i t i o n such as the feeding of premature i n f a n t s . High concentrations of glutamic a c i d and g l y c i n e have been found in p r o t e i n hydrolysates. G l y c i n e , infused at very high r a t e s , has been found to produce t o x i c e f f e c t s (68,69). High l e v e l s of glutamic a c i d can produce "Chinese Restaurant Syndrome", presenting symptoms of nausea, vomiting, headaches and f l u s h i n g which are a man i f e s t a t i o n of 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)- However, the inf a n t seems able to co n t r o l adequately the glutamate l e v e l s during p r o t e i n hydrolysate i n f u s i o n (59,60). Another c r i t i c i s m of p r o t e i n hydrolysate s o l u t i o n s i s t h e i r high ammonia content (62,63,64,65). The high i n f u s i o n of ammonia nitrogen may exceed the i n f a n t ' s a b i l i t y to make urea (65). In the premature i n f a n t , high l e v e l s of blood ammonia may lead to metabolic a c i d o s i s , as the inf a n t i s not able to deal with the increased hydrogen ion l e v e l s which occur concomitantly with increased urea c y c l e a c t i v i t y (61). Although more expensive than p r o t e i n hydrolysate, 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 mixtures o f f e r many p o t e n t i a l b e n e f i t s (58,59). They provide an enormous degree of f l e x i b i l i t y and may be t a i l o r e d to meet the metabolic needs of 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 i n c i d e n c e o f m e t a b o l i c c o m p l i c a t i o n s has been found to be lower in i n f a n t s g i v e n s y n t h e t i c L - a m i n o a c i d m i x t u r e s (75) . I n i t i a l e x p e r i e n c e w i t h t h e s e s o l u t i o n s , however , r e s u l t e d in r e p o r t s o f m e t a b o l i c a c i d o s i s . H e i r d e t a 1 . , (77) s u g g e s t e d t h a t the c a u s e o f the a c i d o s i s was t h a t t h e s y n t h e t i c L - a m i n o a c i d m i x t u r e s c o n t a i n e d an e x c e s s o f m e t a b o l i c p r e c u r s o r s o f hydrogen ion in r e l a t i o n to m e t a b o l i c consumers o f hydrogen i o n . The m i x t u r e s , t h e n , a c t e d on b a l a n c e , as a p r e c u r s o r o f hydrogen i o n s . The p r e s e n c e o f p o s i t i v e l y c h a r g e d amino a c i d s i n e x c e s s o f m e t a b o l i z a b l e a n i o n s , as r e f l e c t e d by the c a t i o n g a p , c o u l d have c o n s t i t u t e d the e x c e s s s o u r c e o f hydrogen ions (76 ,77) . C a t a b o l i s m o f the p o s i t i v e l y c h a r g e d amino a c i d s r e l e a s e s hydrogen i o n s . I n c r e a s e d a c t i v i t y o f t h i s pathway may have p l a y e d an i m p o r t a n t r o l e in the p r o d u c t i o n o f the o b s e r v e d a c i d o s i s . The p r o b l e m was c o r r e c t e d w i t h the a d d i t i o n o f g l u t a m a t e o r a s p a r t a t e in amounts t h a t would not r e s u l t in amino a c i d o r hormonal i m b a l a n c e (77) . Hyperammonemia was a l s o o b s e r v e d to o c c u r d u r i n g the a d m i n i s t r a t i o n o f 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 . T h i s was an u n e x p e c t e d p r o b l e m , a s , u n l i k e p r o t e i n h y d r o l y s a t e s , s y n t h e t i c amino a c i d m i x t u r e s c o n t a i n e d minute amounts o f ammonia. A n a l y s i s o f the s o l u t i o n s showed the p r e s e n c e o f v e r y l i t t l e a r g i n i n e . P lasma aminograms r e f l e c t e d t h i s f i n d i n g . The hyperammonemia was c o r r e c t e d w i t h the a d d i t i o n o f a r g i n i n e h y d r o c h l o r i d e . A v a r i e t y o f r e a s o n s have been p roposed t o e x p l a i n t h i s complex p rob lem 11 , 76 ,77) - A p o s s i b l e e x p l a n a t i o n f o r t h i s d i s o r d e r i s t h a t the r e l a t i v e d e f i c i e n c y o f a r g i n i n e i n t e r f e r e s w i t h the e f f i c i e n c y o f the u r e a c y c l e {6k). The e x a c t mechanism needs f u r t h e r c l a r i f i c a t i o n . Wi th the a v a i l a b i l o f newer amino a c i d s o l u t i o n s t h i s has not c o n t i n u e d to be a s e r i o u s c o n s e q u e n c e (11 , 6 4 ) . 15 The p r o t e i n r e q u i r e m e n t s f o r i n f a n t s r e c e i v i n g c r y s t a l l i n e amino a c i d s as a p a r t o f a t o t a l p a r e n t e r a l n u t r i t i o n program a r e s l i g h t l y d i f f e r e n t than t h o s e f o r p remature i n f a n t s on o r a l f e e d s (96,155)- Requ i rements range f rom l - 5 _ 3 - l g amino a c i d m i x t u r e / k g body we igh t/day (74,77,155)- The o p t i m a l amino a c i d s o l u t i o n used in t o t a l p a r e n t e r a l n u t r i t i o n s h o u l d c o n t a i n e s s e n t i a l as w e l l as n o n -e s s e n t i a l amino a c i d s in the L - f o r m ( 1 1 , 7 4 ) . They s h o u l d be p r e s e n t in the same p r o p o r t i o n s as found in the aminogram o f body p r o t e i n s , o r o t h e r p r o t e i n s o f h i g h b i o l o g i c a l v a l u e ( 7 4 ) . For i n f a n t s , the e s s e n t i a l amino a c i d s s h o u l d equa l 40-50% o f the t o t a l amino a c i d s , g i v i n g an e s s e n t i a l amino a c i d to t o t a l n i t r o g e n r a t i o o f c l o s e t o 3 (51»55)• As m e n t i o n e d above a r g i n i n e must be i n c l u d e d among the n o n - e s s e n t i a l amino a c i d s ( 6 4 , 7 5 ) - A l a n i n e , g l u t a m i c a c i d and p r o l i n e have been found t o i n c r e a s e u t i l i z a t i o n o f the i n t r a v e n o u s amino a c i d p r e p a r a t i o n ( 5 1 ) . A s p a r t i c a c i d , g l y c i n e , and s e r i n e p r o v i d e n o n s p e c i f i c n i t r o g e n ( 5 1 ) -As p a r t o f the p a r e n t e r a l n u t r i t i o n program t h e r e must be a p r o v i s i o n o f s u f f i c i e n t n o n p r o t e i n c a l o r i e s t o meet the f u l l c a l o r i c e x p e n d i t u r e ( 1 1 ) . O ther n u t r i e n t s , i n c l u d i n g e l e c t r o l y t e s , m i n e r a l s , and v i t a m i n s must a l s o be p r o v i d e d . When a l l n u t r i t i v e r e q u i r e m e n t s a r e m e t , e f f i c i e n t u t i l i z a t i o n o f the amino a c i d s p r o v i d e d w i l l o c c u r . 4. METHOD OF ADMINISTRATION In 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 d e l i v e r y t h a t made p a r e n t e r a l n u t r i t i o n a r e a l i t y f o r p e d i a t r i c p a t i e n t s ( 5 3 ) -H y p e r t o n i c s o l u t i o n s o f d e x t r o s e , n i t r o g e n , v i t a m i n s , m i n e r a l s and e l e c t r o l y t e s were a d m i n i s t e r e d by i n s e r t i n g a c a t h e t e r th rough an e x t e r n a l 16 o r i n t e r n a l j u g u l a r v e i n c u t down and t h r e a d i n g i t i n t o the s u p e r i o r vena c a v a . The h y p e r t o n i c s o l u t i o n s , t h e r e f o r e , a r e i n f u s e d i n t o a r e g i o n o f r a p i d b l o o d f l o w and a r e i n s t a n t a n e o u s l y d i l u t e d t o p h y s i o -l o g i c a l l e v e l s . Thus the t e c h n i c a l d i f f i c u l t i e s o f i n f u s i n g h y p e r t o n i c s o l u t i o n s p e r i p h e r a l l y a r e ove rcome. Shaw (156) m o d i f i e d t h i s t e c h n i q u e t o reduce i n t e r f e r e n c e w i t h the i n s p i r e d oxygen c o n c e n t r a t i o n . He i n t r o d u c e d a v e r y f i n e s i l i c o n e rubber c a t h e t e r p e r c u t a n e o u s l y t h r o u g h a s c a l p v e i n n e e d l e i n t o the long saphenous o r b r a c h i a l v e i n and then t h r e a d e d i t i n t o the r i g h t a t r i u m . I n f u s i o n o f i s o t o n i c n u t r i e n t m i x t u r e s c o n t a i n i n g a f a t e m u l s i o n p e r m i t s a d m i n i s t r a t i o n v i a p e r i p h e r a l v e i n s (79). T h i s a l l e v i a t e s many c o m p l i c a t i o n s wh ich a r i s e f rom c e n t r a l venous c a t h e t e r i z a t i o n w i t h h y p e r t o n i c s o l u t i o n s such as s e p s i s t h r o m b o s i s , and p e r f o r a t i o n o f the v e i n (91,91)- The t i p o f the n e e d l e must not be o b s c u r e d so as t o e n a b l e e a r l y d e t e c t i o n o f d i f f i c u l t i e s such as r e d n e s s o r edema (157)-O c c a s i o n a l l y the use o f a s i l a s t i c c a t h e t e r in the p e r i p h e r a l v e i n i s b e n e f i c i a l (156). As can be seen in F i g u r e 2, amino a c i d s o l u t i o n s a r e mixed w i t h a f a t e m u l s i o n ( I n t r a l i p i d ) b e f o r e e n t e r i n g the v e i n . S o l u t i o n s o f d e x t r o s e , amino a c i d n u t r i e n t m i x t u r e , and I n t r a l i p i d a r e a d m i n i s t e r e d c o n c u r r e n t l y t h r o u g h o u t a t w e n t y - f o u r hour p e r i o d w i t h the a i d o f a f o u r - w a y c o n n e c t o r and c o n s t a n t i n f u s i o n pumps (91,92,157). B o t t l e s and i n t r a v e n o u s t u b i n g up t o the j u n c t i o n o f the s c a l p v e i n n e e d l e a r e changed e v e r y t w e n t y - f o u r h o u r s . C a r e f u l m o n i t o r i n g a c c o r d i n g t o a s t r u c t u r e d t i m e - t a b l e i s e s s e n t i a l when f e e d i n g p a t i e n t s i n t r a v e n o u s l y (79,93). 17 Fig 2 PARENTERAL NUTRITION USING PERIPHERAL VEINS Electrolyte Solution Amino Acid Nutrient Mixture Intra lipid 10% 100 ml Burrette 18 C. AMINO ACID METABOLISM  1. NORMAL PHYSIOLOGY F r e e amino a c i d s a r e found in a l l f l u i d s and t i s s u e s o f the body . P lasma amino a c i d s c o n s t i t u t e a r e l a t i v e l y s m a l l amount o f the t o t a l f r e e amino a c i d poo l (7^,9*0. T h e i r a c c e s s i b i l i t y has c a u s e d them t o be f r e q u e n t l y s a m p l e d , even though they may not r e p r e s e n t the changes o c c u r r i n g in the b o d y ' s t o t a l f r e e amino a c i d poo l (9*0-Changes t h a t t a k e p l a c e in p lasma f r e e amino a c i d p a t t e r n in r e s p o n s e t o o r a l p r o t e i n s a r e c o m p l e x . They depend on the amino a c i d c o m p o s i t i o n o f the p r o t e i n , the r a t e o f g a s t r i c e m p t y i n g , the r a t e o f r e l e a s e o f amino a c i d s d u r i n g d i g e s t i o n , the endogenous p r o t e i n s a r i s i n g f rom the g a s t r o i n t e s t i n a l t r a c t , the e x t e n t to wh ich they a r e m e t a b o l i z e d by the gut and l i v e r , and the r a t e o f removal o f the a b s o r b e d amino a c i d f rom the b l o o d (97,100,102,128). The gut e x e r t s c o n s i d e r a b l e h o m e o s t a t i c c o n t r o l on b l o o d l e v e l s o f amino a c i d s (129). The o u t f l o w o f amino a c i d s i n t o the p o r t a l v e i n i s c h a r a c t e r i z e d by a p redominance o f a l a n i n e and an a b s e n c e o f g l u t a m i c and a s p a r t i c a c i d . T h i s 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 a c c o u n t f o r 20-30% o f 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 . The gut 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 i n g e s t e d n i t r o g e n to a l a n i n e (10). An imal s t u d i e s by Elwyn (98) have shown t h a t a f t e r a p r o t e i n r i c h meal o n l y 23% of the amino a c i d s a r e passed i n t o the g e n e r a l c i r c u l a t i o n . The r e s p o n s e o f the l i v e r i s t o p r o v i d e a b u f f e r i n g mechanism to p r o t e c t the body f rom w i l d l y f l u c t u a t i n g p lasma amino a c i d l e v e l s (99). T h i s mechanism i s s e l e c t i v e as o n l y some o f the e s s e n t i a l amino a c i d s a r e c a t a b o l i z e d in the l i v e r . The b r a n c h e d - c h a i n 19 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 ) pass d i r e c t l y i n t o the c i r c u l a t i o n (10,99,129). These amino a c i d s a r e s u b j e c t e d to a g r e a t e r d e g r e e o f c o n t r o l by e x t r a h e p a t i c t i s s u e s (9*0 . Both the gut and the l i v e r e x e r t a g r e a t dea l o f h o m e o s t a t i c c o n t r o l in the a b s o r p t i v e p e r i o d a f t e r a p r o t e i n r i c h m e a l . A f t e r the meal the i n s u l i n l e v e l a l s o r i s e s . I n s u l i n a c t s t o i n c r e a s e amino a c i d u p t a k e and i n c o r p o r a t i o n i n t o m u s c l e p r o t e i n (7^,129). The b r a n c h e d - c h a i n amino a c i d s a r e the major s o u r c e f o r r e p l e t i o n o f m u s c l e n i t r o g e n a f t e r a m e a l . In the f a s t e d s t a t e a l a n i n e and g l u t a m i n e a r e c o n t i n u o u s l y r e l e a s e d f rom m u s c l e . The p redominance o f a l a n i n e in the movement o f amino a c i d s f rom m u s c l e t o l i v e r in the p o s t a b s o r p t i v e s t a t e i s somewhat u n e x p e c t e d s i n c e a l a n i n e c o m p r i s e s l e s s than 10% o f the amino a c i d r e s i d u e s in m u s c l e p r o t e i n (150). T h i s movement i s e x p l a i n e d by t h e g1u c o s e - a l a n i n e c y c l e where g l u c o s e - d e r i v e d p y r u v a t e i s t r a n s a m i n a t e d i n m u s c l e t o form a l a n i n e which i s s u b s e q u e n t l y t a k e n up by the l i v e r where i t s c a r b o n s k e l e t o n i s r e c o n v e r t e d to g l u c o s e . The n i t r o g e n g roup needed to fo rm a l a n i n e i s s u p p l i e d by the b r a n c h e d - c h a i n amino a c i d s (129). The f r e e amino a c i d poo l o f m u s c l e i s the t h i r d major f a c t o r o f h o m e o s t a t i c c o n t r o l o f p lasma amino a c i d l e v e l s in both the a b s o r p t i v e and f a s t i n g s t a t e . 2. INFUSED AMINO ACID MIXTURES When e i t h e r p r o t e i n h y d r o l y s a t e s o r c r y s t a l l i n e L - a m i n o a c i d s a r e a d m i n i s t e r e d i n t r a v e n o u s l y the amino a c i d s bypass the m e t a b o l i c a l t e r a t i o n s o f the l i v e r and gut and e n t e r the p e r i p h e r a l c i r c u l a t i o n d i r e c t l y . Under t h e s e c i r c u m s t a n c e s r e g u l a t i o n o f p lasma amino a c i d c o n c e n t r a t i o n s depend upon u t i l i z a t i o n o f amino a c i d s f o r body p r o t e i n s y n t h e s i s and the r a t e o f removal f o r c a t a b o l i s m or f o r body p o o l s such as t h o s e o f m u s c l e . 20 E q u i l i b r i u m i s c o n t r o l l e d by a d j u s t i n g the rate of i n f l u x to equal the rate of t i s s u e s y n t h e s i s . Excess amino acids are d i v e r t e d to energy producing pathways. Anderson e_t a_l_. , (104) a l s o found that the rate of change of amino ac 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 occurs independently f o r each amino a c i d . If e i t h e r the p r o t e i n hydrolysates or s y n t h e t i c L-amino acids are infused intravenously one would c e r t a i n l y expect to see a very d i f f e r e n t plasma amino a c i d pattern than that obtained a f t e r feeding an or a l meal. A l l of the amino a c i d s , rather than a selected few, enter the plasma pool (101). 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 greater degree of c o n t r o l than hydrolysates in terms of modelling the plasma amino aci d p a t t e r n . C u r r e n t l y i t is f e l t that the ideal amino a c i d mixture should mimic the plasma amino a c i d pattern found in the post-absorptive s t a t e . Abnormal amino a c i d l e v e l s in the blood, l a s t i n g over long periods and oc c u r r i n g e a r l y in l i f e may have serious consequences (67,68). Settegren et a l . , (106), found that cerebral uptake of amino acids i s p r o p o r t i o n a l to t h e i r a r t e r i a l c o n c e n t r a t i o n . This i s of p a r t i c u l a r i n t e r e s t as infancy c o n s t i t u t e s a c r i t i c a l period of cer e b r a l growth (78,85,86,87). It i s now known that e l e v a t i o n and imbalance of some c i r c u l a t i n g amino acids may have harmful e f f e c t s , p a r t i c u l a r l y on the developing c e n t r a l nervous system (107). Careful a t t e n t i o n , then, must be paid to plasma amino a c i d l e v e l s in order to properly evaluate what i s considered to be an optimal supply of amino acids to premature i n f a n t s (108). 21 3 . PLASMA AMINOGRAMS The aminogram is a measurement of the r e l a t i v e amounts of f r e e amino acids found in the plasma. Since the plasma aminogram of the in f a n t responds q u i c k l y to any a l t e r a t i o n in p r o t e i n intake, i t may be a s e n s i t i v e i n d i c a t o r of the s t a t e of p r o t e i n n u t r i t i o n (95,113)- It has been widely 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 (109). I n v e s t i g a t o r s studying plasma amino a c i d l e v e l s in m a l n u t r i t i o n proposed d i f f e r e n t amino acid r a t i o s to evaluate n u t r i t i o n status and p r o t e i n adequacy. These include 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 values and the a 1 anine/va1ine quotient (110,151) • Whitehead's r a t i o was based on the separation of amino acids by one-dimensional paper chromatography i n t o groups of amino acid s that were a mixture of several compounds. The group i s o l a t e d as " e s s e n t i a l amino a c i d s " contained the branched-chain amino acids ( v a l i n e , leucine and i s o l e u c i n e ) plus methionine. His " 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 , glutamine and t a u r i n e . The basis f o r Whitehead's r a t i o was that during r e s t r i c t e d p r o t e i n intake the 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 , decreased, while g l y c i n e , a non-essential amino a c i d increased. Arroyave (146) p r e f e r e n t i a l l y suggests the use of the v a l i n e / g l y c i n e q u o t i e n t . It 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 decreases and g l y c i n e increases in the plasma very e a r l y in p r o t e i n u n d e r n u t r i t i o n . It t h e r e f o r e , has a higher 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 great deal of v a r i a b i l i t y in plasma amino a c i d values reported in the l i t e r a t u r e . This i s due to the many f a c t o r s which influen c e plasma amino a c i d values but which do not remain constant between s t u d i e s . Some of these f a c t o r s are: handling of the sample p r i o r to and during a n a l y s i s (147), age and sex of the su b j e c t , (131) whether the sample i s taken during a f a s t i n g or fed s t a t e , and the d i e t consumed (95,1-02,103,105). There are many e r r o r s that can occur p r i o r to and during a n a l y s i s of the plasma samples (147). Delay in d e p r o t e i n i z i n g the plasma r e s u l t s in loss of 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 binding to s u l f h y d r y l groups of plasma p r o t e i n s . Contamination of the plasma with leucocytes and p l a t e l e t s during the preparation f o r a n a l y s i s can r e s u l t in abnormal l e v e l s of some amino a c i d s . Soupart (153) has shown that the concentration of tau r i n e and a s p a r t i c a c i d i s approximately 500 times higher in p l a t e l e t s and leucocytes than in plasma. Glutamic a c i d i s a l s o much higher in these c e l l s . Plasma must, t h e r e f o r e , be separated from blood before the spontaneous rupture of p l a t e l e t s occurs. A c c i d e n t a l hemolysis of red c e l l s r e s u l t s in increased t a u r i n e , glutamic, and a s p a r t i c a c i d l e v e l s . Cystine l e v e l s are s i g n i f i c a n t l y lowered. In a d d i t i o n , o r n i t h i n e concentrations are doubled while a r g i n i n e l e v e l s are halved, probably, due to the release of arginase from the red c e l l s i n t o the plasma. The choice of deprotein-i z i n g agent can a f f e c t r e s u l t s . Many researchers used p i c r i c a c i d f or t h i s procedure. P a r t i a l losses of tryptophan have been noted to occur with the use of t h i s agent (147)• Storage of dep r o t e i n i z e d plasma at -20° C 23 o v e r long p e r i o d s o f t ime (3 months) r e s u l t s in lowered v a l u e s o f g l u t a m i n e and t r y p t o p h a n . G l u t a m i n e i s thought to be h y d r o l y z e d t o g l u t a m i c a c i d , even under t h e s e c o n d i t i o n s . S t o r a g e a t t e m p e r a t u r e s below -68° C w i l l p r e v e n t t h i s f rom h a p p e n i n g . P e r r y and Hansen (147) s u g g e s t t h a t g l u t a m i n e i s r a p i d l y c y c l i z e d t o p y r o l i d o n e c a r b o x y l i c a c i d when the amino a c i d a n a l y z e r co lumns a r e o p e r a t e d a t r e l a t i v e l y h i g h t e m p e r a t u r e s . They s u g g e s t t h a t the column t e m p e r a t u r e s h o u l d not exceed 35° C u n t i l the g l u t a m i n e i s e l u t e d . A l l t h e s e f a c t o r s v a r y t o a c e r t a i n d e g r e e w i t h i n and between s t u d i e s , i n c r e a s i n g the v a r i a b i l i t y in p lasma amino a c i d v a l u e s r e p o r t e d in the l i t e r a t u r e . A r m s t r o n g and S t a v e (131) s t u d i e d p lasma f r e e amino a c i d l e v e l s in a d u l t s and c h i l d r e n . In a d u l t s (ages 18-77 y e a r s ) they found s i g n i f i c a n t d i f f e r e n c e s between men and women f o r most o f the amino a c i d s . Men had h i g h e r v a l u e s f o r a l l amino a c i d s w i t h the e x c e p t i o n o f t h r e o n i n e , s e r i n e and g l y c i n e . ln c h i l d r e n (ages 6-18 y e a r s ) they found s i g n i f i c a n t sex d i f f e r e n c e s in mean v a l u e s f o r o n l y a few amino a c i d s , i n c l u d i n g m e t h i o n i n e , i s o l e u c i n e , p h e n y l a l a n i n e , l y s i n e , h i s t i d i n e and t r y p t o p h a n . T h i s a l l o w e d them t o combine the d a t a f rom g i r l s and b o y s . T h e r e were s i g n i f i c a n t p o s i t i v e c o r r e l a t i o n s between plasma l e v e l s and age in c h i l d r e n and a d u l t s f o r two amino a c i d s : c y s t i n e and a l a n i n e (136). C o n c e n t r a t i o n s o f o t h e r amino a c i d s , t h r e o n i n e , s e r i n e and a s p a r a g i n e i n c r e a s e d d u r i n g p e r i o d s o f growth and d e c r e a s e d t h r o u g h o u t m a t u r i t y . O ther amino a c i d s showed no p o s i t i v e c o r r e l a t i o n w i t h a g e . D i c k i n s o n e_t a_l_. , (135) s t u d i e d p lasma amino a c i d l e v e l s in 25 one^ day o l d newborn i n f a n t s . They o b s e r v e d t h a t newborns had h i g h e r v a l u e s o f 2k t a u r i n e , t h r e o n i n e , g l u t a m i n e , g l y c i n e , t y r o s i n e , p h e n y l a l a n i n e and o r n i t h i n e and lower v a l u e s o f l e u c i n e , a r g i n i n e and c i t r u l l i n e than t h o s e found in a d u l t s . Changes w i t h i n the immediate newborn p e r i o d were a l s o s t u d i e d . They found t h a t by t h e t h i r d day of l i f e t a u r i n e and a l a n i n e had f a l l e n below the o r i g i n a l r a n g e . A s p a r t i c a c i d , t h r e o n i n e , g l y c i n e , p h e n y l a l a n i n e , l y s i n e , t r y p t o p h a n and u r e a a l s o d r o p p e d , but remained w i t h i n the range o f newborn v a l u e s . In a l a t e r s t u d y , D i c k i n s o n e_t a_l_. , (13*0 l ooked a t p lasma amino a c i d l e v e l s in 46 i n f a n t s o f under 2500 g w i t h a mean g e s t a t i o n a l age o f 35 weeks . It took a few days a f t e r b i r t h f o r s t a b l e p lasma amino a c i d p a t t e r n s t o d e v e l o p . Amino a c i d l e v e l s a p p e a r e d t o change r a p i d l y d u r i n g the week a f t e r b i r t h and the changes were c h a r a c t e r i s t i c f o r each amino a c i d . I n c r e a s e s in c o n c e n t r a -t i o n d u r i n g the f i r s t few days were found f o r t y r o s i n e w h i l e t a u r i n e , t h r e o n i n e , s e r i n e , a s p a r a g i n e , g l u t a m i n e , g l y c i n e , a l a n i n e and l y s i n e d e c r e a s e d . By the end o f the second p o s t n a t a l week t y r o s i n e showed a marked d e c r e a s e , but remained a t a l e v e l o f about t h r e e t i m e s the normal a d u l t c o n c e n t r a t i o n . A f t e r the f i f t h p o s t n a t a l week most v a l u e s were w i t h i n the a d u l t c o n t r o l r a n g e s . The e x c e p t i o n s were s e r i n e and a s p a r a g i n e , g l u t a m i n e , m e t h i o n i n e , o r n i t h i n e and h i s t i d i n e , wh ich remained e l e v a t e d . D i c k i n s o n e_t aj_. , (13*0 f e l t t h a t the e f f e c t o f p o s t n a t a l age on p lasma amino a c i d c o n c e n t r a t i o n s were r e a d i l y a p p a r e n t . The e f f e c t o f o t h e r v a r i a b l e s such as s e x , g e s t a t i o n a l a g e , and e x a c t b i r t h w e i g h t were not m e a s u r a b l e due t o the l a r g e number o f v a r i a b l e s wh ich i n f l u e n c e the ami no a c i d p o o l . 25 Data f rom most s t u d i e s use b l o o d f rom f a s t i n g s u b j e c t s . F a s t i n g b l o o d samples in i n f a n t s a r e u s u a l l y taken i m m e d i a t e l y p r i o r to a f e e d . Fo r i n f a n t s on f o u r - h o u r l y f e e d i n g a b l o o d sample i s taken f o u r hours a f t e r the l a s t f e e d . T h i s s a m p l i n g t ime emphas i zes the h o m e o s t a t i c c o n t r o l s wh ich o c c u r d u r i n g the f a s t i n g s t a t e . A n o t h e r f a c t o r wh ich a f f e c t s p lasma amino a c i d c o n c e n t r a t i o n i s the d i e t (42,95,113,127,138). Holmgren (137) s t u d i e d the e f f e c t o f low, normal and h i g h d i e t a r y p r o t e i n i n t a k e on p lasma amino a c i d c o n c e n t r a t i o n s in c h i l d r e n (age 7~13). He found t h a t no s i g n i f i c a n t d e c r e a s e in p lasma amino a c i d c o n c e n t r a t i o n was seen when p r o t e i n i n t a k e was changed f rom normal (1.9 9 p r o t e i n / k g body w e i g h t ) to low (0.2 g p r o t e i n / k g body w e i g h t ) . An i n c r e a s e in p r o t e i n i n t a k e o f 1.9 to 3-2 g/kg body w e i g h t r e s u l t e d in a s i g n i f i c a n t e l e v a t i o n in p lasma c o n c e n t r a t i o n s o f v a l i n e , l e u c i n e , i s o -l e u c i n e , t h r e o n i n e , s e r i n e , a s p a r a g i n e , g l u t a m i n e , p r o l i n e , c y s t i n e , t y r o s i n e and p h e n y l a l a n i n e . Snyderman e_t a_l_. , (95) s t u d i e d the i n f l u e n c e o f the l e v e l o f p r o t e i n i n t a k e on p lasma a c i d c o n c e n t r a t i o n s in newborn i n f a n t s . She no ted a l t e r a t i o n s in the p lasma aminograms as e a r l y as two days a f t e r r e d u c t i o n in p r o t e i n i n t a k e . These changes became more p ronounced as t h i s f e e d i n g p a t t e r n was p r o l o n g e d . G l y c i n e and s e r i n e l e v e l s were e l e v a t e d , w h i l e the b r a n c h e d - c h a i n 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 ) , l y s i n e and t y r o s i n e were d e p r e s s e d . They a l s o looked a t the e f f e c t s o f f e e d i n g amino a c i d m i x t u r e s as opposed to whole p r o t e i n . On the amino a c i d d i e t s lower a v e r a g e p lasma amino a c i d v a l u e s were seen f o r l e u c i n e , v a l i n e and i s o l e u c i n e , a l a n i n e , o r n i t h i n e , a s p a r a g i n e and c i t r u l l i n e ; h i g h e r v a l u e s were seen f o r t h r e o n i n e and s e r i n e . R igo and S e n t e r r e (42) s t u d i e d the e f f e c t o f human m i l k and humanized m i l k 26 f o r m u l a s on p r e m a t u r e i n f a n t s . They found t h a t i n f a n t s f e d b r e a s t m i l k had lower p lasma c o n c e n t r a t i o n s o f most amino a c i d s than i n f a n t s f e d humanized f o r m u l a s . As shown by o t h e r s (95) t h i s was r e l a t e d t o p r o t e i n i n t a k e . G a u l l e_t a_L , (56) s t u d i e d the e f f e c t s o f the q u a n t i t y o f m i l k p r o t e i n on p lasma s u l f u r amino a c i d s in p r e m a t u r e i n f a n t s . They found t h a t i n f a n t s f e d h i g h q u a n t i t i e s o f p r o t e i n had e l e v a t e d l e v e l s o f m e t h i o n i n e in t h e p lasma and i n c r e a s e d c y s t a t h i o n i n e in the u r i n e . They s u g g e s t t h a t the c a p a c i t y o f the human p remature i n f a n t to c o n v e r t m e t h i o n i n e to c y s t i n e i s l i m i t e d . T h i s l i m i t a t i o n i s a f u n c t i o n o f a b s e n t o r low c y s t a t h i o n a s e a c t i v i t y . In a l a t e r s t u d y R a s s i n et^ a_l_. , (138) l ooked a t the e f f e c t o f p r o t e i n q u a n t i t y on p lasma l e v e l s o f t y r o s i n e and p h e n y l a l a n i n e in p r e m a t u r e i n f a n t s . They f e l t t h a t i n c o m p l e t e b i o c h e m i c a l deve lopment o f the sys tem f o r the m e t a b o l i s m o f t h e s e a r o m a t i c amino a c i d s r e s u l t e d in a l i m i t e d a b i l i t y to m e t a b o l i z e i n c r e a s e d p r o t e i n l o a d s a d e q u a t e l y . The mean p lasma c o n c e n t r a t i o n s o f p h e n y l a l a n i n e and t y r o s i n e were c o n s i d e r -a b l y g r e a t e r in the i n f a n t s f e d f o r m u l a s c o n t a i n i n g k.5 g p r o t e i n / k g body w e i g h t / d a y than in the i n f a n t s f e d p o o l e d b r e a s t m i l k ( a p p r o x i m a t e l y 1.7 9 p r o t e i n / k g body w e i g h t / d a y ) . The hyperpheny1 a 1 a n i n e m i a and t y r o s i n e m i a t h a t o c c u r r e d may have been a r e s u l t of a d e l a y e d m a t u r a t i o n o f p - h y d r o x y p h e n y l p y r u v i c a c i d o x i d a s e . The mean c o n c e n t r a t i o n o f p lasma t y r o s i n e was f a r g r e a t e r than t h o s e o f p h e n y l a l a n i n e . T h i s i s c o m p a t i b l e w i t h the known p r e s e n c e o f p h e n y l a l a n i n e h y d r o x y l a s e in immature human 1i v e r . 27 Urea i s one of the end products of p r o t e i n catabolism. In young in f a n t s i t s concentration in the blood is in part a r e f l e c t i o n of d i e t a r y p r o t e i n intake. Davies and Saunders (139) found s i g n i f i c a n t l y lower blood urea concentrations in i n f a n t s fed human breast milk than in i n f a n t s fed cow's milk formulas. The l a s t three studies have pointed out that abnormally high concentrations of methionine, phenylalanine and t y r o s i n e are a r e s u l t of high p r o t e i n intake. Increased blood urea l e v e l s a l s o suggest that amino acids are 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 in excess. The type of the amino a c i d mixture or p r o t e i n hydrolysate infused intravenously a l s o a f f e c t s the values of the plasma aminogram. A poorly balanced s o l u t i o n w i l l cause a rapid f a l l in the plasma concentration of the f i r s t l i m i t i n g amino ac i d (107). Beef f i b r i n hydrolysate contains equal molar q u a n t i t i e s of phenylalanine and t y r o s i n e (102). This r e s u l t s in a plasma r a t i o of 1:1 f o r these amino acids in i n f a n t s r e c e i v i n g such preparations. When compared with a casein hydrolysate preparation the beef f i b r i n hydrolysate has a lower absolute amount of phenylalanine (102) hence the plasma l e v e l s of phenylalanine are lower than in i n f a n t s infused with a casein hydrolysate p r e p a r a t i o n . Plasma l e v e l s of g l y c i n e , c y s t i n e , a r g i n i n e and threonine are higher i n i n f a n t s r e c e i v i n g beef f i b r i n hydrolysate than in i n f a n t s infused with casein hydrolysates (102). This supports other i n v e s t i g a t o r s ' claims that plasma aminograms are a f f e c t e d by the kind of amino a c i d mixture infused (64, 103,104). Intravenous feeding with 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 mixtures has been shown to a f f e c t plasma amino a c i d p atterns. A w e l l 28 designed s o l u t i o n should r e s u l t in a plasma aminogram which c l o s e l y resembles normal values. Differences between aminograms of o r a l l y and intravenously fed p a t i e n t s continue to e x i s t but general trends in these d i f f e r e n c e s have not as yet been e s t a b l i s h e d . Ghadimi and Abaci (141) looked at the e f f e c t . o f an experimental s y n t h e t i c c r y s t a l l i n e L-amino acid mixture (not Vamin) on the plasma aminogram in a d u l t s . They found that 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 favourably with c o n t r o l values from healthy a d u l t s . The only s i g n i f i c a n t d i f f e r e n c e s were higher l e v e l s of methionine and lower l e v e l s of c y s t i n e in the p a t i e n t s fed intravenously. In the same study plasma aminogram values from c h i l d r e n (ages 1 month-7 y e a r s ) , r e c e i v i n g the same amino a c i d mixture, f e l l w i t h i n the normal range f o r t h i s age group (141). The mean value of g l y c i n e , however, was found to be above normal. In another study, Ghadimi et_ aj_. , (140) examined plasma amino acids in premature inf a n t s of low-birth-weight, r e c e i v i n g t o t a l intravenous n u t r i t i o n . They found that plasma amino ac i d patterns c l o s e l y resembled cord values, w i t h the exception of threonine and l y s i n e l e v e l s which were much lower. Shaw et_ aj_. , (154) studied the d i f f e r e n c e s between the serum aminograms of f u l l term i n f a n t s fed breast milk and inf a n t s r e c e i v i n g parenteral n u t r i t i o n with Vamin. Although no serious a b n o r m a l i t i e s were seen in the aminograms of the i n f a n t s infused with Vamin some d i f f e r e n c e s were noted. Serum l e v e l s of phenylalanine, p r o l i n e , g l y c i n e , and ser i n e were higher in the intravenously fed 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 leucine (154). Plasma amino ac i d l e v e l s are dependent on the rate of intravenous i n f u s i o n of amino a c i d s . These l e v e l s increase with f a s t e r i n f u s i o n rates 29 (102,102,105). If the i n f u s i o n is administered at too f a s t a r a t e , then hyperaminoacidemia or hyperammonemia may r e s u l t (102). Dale et a 1., (105) found that p r o l i n e , glutamate, and the branched-chain amino acids ( l e u c i n e , i s o l e u c i n e and v a l i n e ) increased p r o g r e s s i v e l y and s i g n i f i c a n t l y w i t h the increasing i n f u s i o n r a t e . Other amino a c i d s , such as c y s t i n e , t y r o s i n e , h i s t i d i n e , l y s i n e and a r g i n i n e , did not increase up';to an i n f u s i o n r a t e of 350 mg nitrogen/kg body weight/day. E. KIL0CAL0RIE:NITROGEN RATIO -- A REFLECTION OF SATISFYING PROTEIN  AND ENERGY REQUIREMENTS It has been noted that the extent to which amino acids are u t i l i z e d f o r p r o t e i n synthesis i s d i r e c t l y p r o p o r t i o n a l to the non-p r o t e i n c a l o r i e supply (114,121). The 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 non-protein c a l o r i e s i s a complex one, depending on many v a r i a b l e s , such as the amount of a c t i v i t y undertaken, s t r e s s e s of i n f e c t i o n or trauma and the n u t r i t i o n a l status of the p a t i e n t . For the s u r g i c a l p a t i e n t , Moore (158) suggested a ki1 oca 1 o r i e : n i t r o g e n r a t i o of 150:1. Lee et_ a_l_. , (122) studied the adequacy of parenteral n u t r i t i o n f o r the p a t i e n t with renal f a i l u r e . He suggested a ki1 oca 1 o r i e : n i t r o g e n r a t i o of 200:1. Peaston (121) a l s o p r e f e r r e d t h i s r a t i o f o r i n t e n s i v e care p a t i e n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n . The k i l o c a l o r i e : o nitrogen r a t i o may vary, depending on the s t a t e and needs of the p a t i e n t . Periods of rapid growth 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 . The r a t i o , then, may be d i f f e r e n t f o r premature i n f a n t s than for a d u l t s . Chen et^ aj_. , (114) found that the u t i l i z a t i o n of amino acids reached a maximal l i m i t when 450 kcal/g nitrogen was provided. Since 30 Rose e_t aj_., (124) suggested that d i f f e r e n t p r o t e i n sources required 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 to maintain nitrogen balance, i t may be reasonable to suspect that 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 optimal u t i l i z a t i o n (114). Chen et a 1., (114) used Sohamin as the nitrogen source in t h e i r study and found i t required 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 of one gram of nitro g e n . Hendry e_t a_l_., (1 55) compared Vamin and Aminofusin as nitrogen sources and found that Vamin required an average of 245 kcal/g nitrogen while Aminofusin only needed 217 kcal/g n i t r o g e n . 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 of t h e i r p r o t e i n source in terms of nitrogen balance. The optimal ki1 oca 1 o r i e : n i t r o g e n r a t i o remains undefined. Many regimes administer a s o l u t i o n w i t h a r a t i o of 200 kcal/g nitrogen (90,115) -F. GROWTH PARAMETERS I n t r a u t e r i n e growth c h a r t s , based on data obtained from a large neonatal population are used to evaluate growth p o s t n a t a l l y (43,116,117). Measurements of weight g a i n , head circumference, and body length are done r o u t i n e l y to assess growth and development of the in f a n t on t o t a l parenteral n u t r i t ion. Cashore e_t a_K , (125) using growth charts developed by Usher and McLean (126) found that i n f a n t s weighing more than 1000 g l o s t an average of 6.2% of t h e i r birthweight and regained i t a f t e r an average of eigh t days. A f t e r t h i s catch-up period a weight gain of 20 g/day was achieved. These i n f a n t s received 90 kcal/kg body weight/day intravenously. Other studies have shown a weight gain of 24-40 g/day in in f a n t s of d i f f e r e n t g e s t a t i o n a l ages (116,118). Heird and Winters (159) showed a weight gain 31 o f 11.8 g/kg/day in i n f a n t s r e c e i v i n g 100 k c a l / k g / d a y . C a s h o r e e t a 1 . , (125) showed t h a t i n f a n t s w e i g h i n g l e s s than 1000 g g a i n e d o n l y one h a l f o f the e x p e c t e d i n t r a u t e r i n e growth r a t e f o r 26-29 weeks g e s t a t i o n d u r i n g the f i r s t t h r e e weeks o f l i f e . Weight g a i n a l o n e i s not the b e s t measurement o f the n u t r i t i o n a l r e q u i r e m e n t s o f p r e m a t u r e i n f a n t s (118,119,120). I t may s i m p l y r e f l e c t body f l u i d c h a n g e s . A good e s t i m a t i o n o f the adequacy o f growth i s a c h i e v e d when we igh t i s used in c o n j u n c t i o n w i t h head c i r c u m f e r e n c e and body l e n g t h . Growth o f the head i s v a l u a b l e in the f i r s t few weeks o f p o s t n a t a l l i f e , depend ing on the g e s t a t i o n a l age and h e a l t h o f the i n f a n t (160, 161). T h i s growth may be s low i n i t i a l l y in i n f a n t s who a r e v e r y i l l . " C a t c h - u p " head growth o c c u r s between the t h i r d and s e v e n t h p o s t n a t a l week c o r r e s p o n d i n g to b e t t e r n u t r i t i o n a l i n t a k e and an improved s t a t e o f h e a l t h (161). Some s t u d i e s have shown t h a t l e n g t h measurements p a r a l l e l e d v a l u e s r e p o r t e d f o r s t a n d a r d f e t u s e s (127, D r . M. P e n d r a y , p e r s o n a l c o m m u n i c a t i o n ) . G . SUMMARY The l i t e r a t u r e rev iewed i n d i c a t e s the need f o r c o n t i n u a l a s s e s s m e n t o f the adequacy o f p r o t e i n g i v e n d u r i n g p a r e n t e r a l n u t r i t i o n . Wi th the improved q u a l i t y and a v a i l a b i l i t y o f amino a c i d s o l u t i o n s an i n c r e a s e d number o f p r e m a t u r e i n f a n t s have b e n e f i t t e d f rom t h i s t e c h n i q u e . C e r e b r a l growth i s c r i t i c a l d u r i n g 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 o f c i r c u l a t i n g amino a c i d s . The p lasma aminogram 32 i s a u s e f u l way to e v a l u a t e p r o t e i n n u t r i t i o n . T h e r e a r e no a d e q u a t e s t a n d a r d i z e d normal p lasma aminograms f o r the a s s e s s m e n t o f p remature 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 , t h e r e f o r e , s a t i s f a c t o r y e v a l u a t i o n o f the p r o t e i n n u t r i t i o n g i v e n t h e s e i n f a n t s has not ye t been a c h i e v e d . 33 CHAPTER I I I  MATERIALS AND METHODS A . THE CONTROL GROUP A p p r o v a l f o r t h i s s e c t i o n o f the p r o j e c t was o b t a i n e d f rom the S c r e e n i n g Committee f o r R e s e a r c h and Other S t u d i e s I n v o l v i n g Human S u b j e c t s : C l i n i c a l . Two n u r s e r i e s were i n v o l v e d in c o n t r i b u t i n g p a t i e n t s to the s t u d y : the I n t e n s i v e Care N u r s e r y a t the Vancouver Genera l H o s p i t a l , and the I n t e n s i v e Care N u r s e r y a t Grace H o s p i t a l . L e t t e r s o f i n t r o d u c t i o n o u t l i n i n g the s t u d y , w i t h a copy o f the in fo rmed c o n s e n t form were s e n t to p e d i a t r i c i a n s most i n v o l v e d w i t h the c a r e o f the newborns . (See A p p e n d i x A ) . In o r d e r t h a t an i n f a n t c o u l d be i n c l u d e d in the s t u d y , bo th the p h y s i c i a n and the mother and/or f a t h e r o f the i n f a n t c o n c e r n e d had t o be in fo rmed and t h e i r p e r m i s s i o n g r a n t e d . E i t h e r the a u t h o r or the p h y s i c i a n a p p r o a c h e d the p a r e n t and o b t a i n e d s i g n e d c o n s e n t . (See A p p e n d i x B ) . The c o n t r o l group c o n s i s t e d o f 16 p remature i n f a n t s in the f o l l o w i n g g e s t a t i o n a l age c a t e g o r i e s : s i x a t 3 0 - 3 2 weeks ; seven a t 33~35 weeks and t h r e e a t 3 6 - 3 8 weeks . G e s t a t i o n a l age was d e t e r m i n e d both by c o n c e p t i o n d a t e s and Dubowitz s c o r i n g methods ( 1 5 2 ) . These i n f a n t s were born p r e m a t u r e l y but had no o t h e r a b n o r m a l i t i e s . Some r e q u i r e d thermal c o n t r o l , i . e . , were m a i n t a i n e d in an i n c u b a t o r , o t h e r s s u f f e r e d from m i l d a p n e i c s p e l l s o r had t r a n s i e n t min imal j a u n d i c e . A l l were m a i n t a i n e d on f e e d s o f SMA^g. These i n f a n t s were f e d e i t h e r by b o t t l e o r by gavage f e e d i n g . SMA^Q i s a homogenized and s t e r i l i z e d f o r m u l a f o r i n f a n t s . It i s composed o f n o n f a t cow 's m i l k , d e m i n e r a1 i z e d whey, l a c t o s e , an imal and 34 v e g e t a b l e f a t s , l e c i t h i n , v i t a m i n s and m i n e r a l s . When compared t o b r e a s t m i l k i t i s found to be c l o s e l y s i m i l a r in r e s p e c t t o the t ype and r e l a t i v e p r o p o r t i o n o f f a t , p r o t e i n , c a r b o h y d r a t e and m i n e r a l s i t c o n t a i n s . The p r o t e i n component o f the f o r m u l a c o m p r i s e s 60% whey and 40% c a s e i n . The amino a c i d s c o m p o s i t i o n o f SMA^Q and human b r e a s t m i l k a r e 1 i s t e d in T a b l e 1. C o n d i t i o n s were s t a n d a r d i z e d p r i o r to b l o o d sample c o l l e c t i o n . Samples were c o l l e c t e d f rom i n f a n t s between 7 - 1 & days o f a g e . The i n f a n t s were f e d f u l l q u a n t i t i e s (150 ml/kg body we ight/day ) o f SMA^^, p r o v i d i n g 1.5 g p r o t e i n / 1 0 0 ml f o r m u l a f o r a t l e a s t t h r e e days p r i o r to the t ime o f b l o o d c o l l e c t i o n . I n f a n t s were f e d e v e r y t h r e e hours and b l o o d samples were taken sometime d u r i n g the 1-2 hour p e r i o d a f t e r the f i r s t f e e d ( 07 :00 ) i n the m o r n i n g . B. STUDY GROUP These i n f a n t s were s e l e c t e d w i t h the h e l p o f the n e o n a t o l o g i s t s f rom the I n t e n s i v e Care N u r s e r y a t the Vancouver Genera l H o s p i t a l . S i x were o f 2 4 - 2 8 weeks g e s t a t i o n . Some o f the i n f a n t s r e q u i r e d r e s p i r a t o r y s u p p o r t and c a r e f u l m o n i t o r i n g . These i n f a n t s were g i v e n 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 2 shows the q u a n t i t i e s o f n u t r i e n t s / k g body we ight/day s u p p l i e d . 150 ml o f f l u i d was a d m i n i s t e r e d p r o v i d i n g 104 k i l o c a l o r i e s / k g body w e i g h t / d a y . Vamin , ( the n i t r o g e n s o u r c e ) i s a 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 s o l u t i o n . The amino a c i d c o m p o s i t i o n can be found in T a b l e 3- Vamin c o n t a i n s a l l the e s s e n t i a l amino a c i d s d i s c u s s e d in the l i t e r a t u r e r e v i e w . ' T A B L E 1 AMINO A C I D C O M P O S I T I O N OF SMA 20 AND B R E A S T M I L K E S S E N T I A L AMINO A C I D S SMA2() (g a m i n o a c i d / 100 g p r o t e i n ) B R E A S T M I L K (g a m i n o a c i d / 100 g p r o t e i n ) H i s t i d i n e : I s o l e i i c i n e L e u c i n e L y s i n e M e t h i o n i n e P h e n y l a l a n i n e T h r e o n i n e T r y p t o p h a n V a 1 i n e C y s t i ne T y r o s i n e 2.7 6.4 11.4 9-9 2.4 4.6 5.8 2.0 8.2 1 .9 4.5 2.5 6.3 11 . 7. 2. 4. 5. 2, 6.3 2.7 5.4 N O N - E S S E N T I A L AMINO A C I D S A l a n i n e A s p a r t i c A c i d G l u t a m i c A c i d G1 y c i n e P r o l i n e S e r i n e A r g i n i n e 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 M a n u f a c t u r e d by W y e t h L i m i t e d 36 TABLE 2: STUDY PROTOCOL - QUANTITIES OF NUTRIENTS/KG BODY WEIGHT/DAY Pro v i d i n g 150 ml /kg body weight/day Fat CHO P r o t e i n K i l o c a l o r i e s 40 ml In t r a 1 i pi d 30 ml Vamin *10 ml D 50 W *70 ml D 10 W ^9 3g 5g 7g 2. lg 44 12 20 28 kg 15g 2.1g 104 * D 50 W and D 10 W are 50% Dextrose water and 10% Dextrose water respect i v e l y . ** I n t r a l i p i d contains g l y c e r o l in a d d i t i o n to soyabean o i l . The t o t a l k i l o c a l o r i e s includes these obtained from g l y c e r o l . <ww'< Does not include p r o t e i n c a l o r i e s . TABLE 3: AMINO ACID COMPOSITION OF VAMIN * AMINO ACID GRAMS/100 ml Iso l e u c i ne 0.39 Leuc ine 0.53 Lys i ne 0.39 Pheny1 alan i ne 0.55 Tyros i ne 0.05 Meth i on i ne 0.19 Cyste i ne-Cyst i ne 0.14 Threon i ne 0.30 Tryptophan 0.10 V a l i ne 0.43 Alan i ne 0.30 Arg i n i ne 0.33 Asparagi ne -A s p a r t i c Acid 0.41 G1utam i c Ac i d 0.90 G1utami ne -Glycine 0.21 Hi s t i d ine 0.24 Orn i th i ne -P r o l i ne 0.81 Ser i ne 0.75 * VITRUM, STOCKHOLM, SWEDEN 38 The amino a c i d composition of Vamin i s s i m i l a r to that of egg pro t e i n (51), which is considered to be a p r o t e i n of high b i o l o g i c a l value. Forty-four percent of the amino acids in Vamin are e s s e n t i a l . From a p e d i a t r i c point of view, these q u a l i t i e s make Vamin a good choice f o r a parenteral p r o t e i n source. A l l the in f a n t s were 7~16 days o l d when the blood samples were c o l l e c t e d . They had received 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 described in the study p r o t o c o l , Table 2, f o r at least three days before the blood sample was taken. No i n f u s i o n of blood or albumin was administered in the 24-hour period previous to the 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 , together with other blood f o r routine monitoring, between 08:00-09:00 a.m. C. TREATMENT AND ANALYSIS OF BLOOD SAMPLES The procedure of treatment and a n a l y s i s of blood samples was the same f o r both c o n t r o l and experimental groups. The blood was drawn by a t e c h n i c i a n from the microchemistry laboratory. C a p i l l a r y blood was obtained from a heel p r i c k . In order to minimize enzymatic changes, the samples had to be cooled on ice and de 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 at 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 to prevent a s p i r a t i o n of the buffy coat. It was then d e p r o t e i n i z e d with s u l f o s a l i c y l i c a c i d (30 mg/ml plasma), shaken to mix and c e n t r i f u g e d again f o r f i v e minutes at 3000 g. The p r o t e i n - f r e e supernatant was 39 frozen at -20 C and sent to Children's Hospital Biochemical Disease Laboratory f o r a n a l y s i s of the amino a c i d concentrations. The samples were stored at -20° C and analyzed w i t h i n a month. When prepared f o r a n a l y s i s of 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 cen t r i f u g e d at 10,000 g in a Beckman microfuge. They were spun u n t i l they c l e a r e d , then were mixed with an i n t e r n a l standard of gamma amino b u t y r i c a c i d (GABA) in a r a t i o of 1 part standard:** parts supernatant. The analyses were performed with a D-500 Amino Acid Analyzer manufactured by the Durrum Instrument Corporation. A n a l y s i s i s based on the theory of ion-exchange chromatography (149). The a p p l i c a t i o n of s y n t h e t i c ion-exchange r e s i n s to the chromato-graphy of amino acids makes use of t h e i r ion-exchange p r o p e r t i e s in a d d i t i o n to p a r t i t i o n and absorption e f f e c t s . Amino acids found in pro 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 carboxyl and amino groups attached to the ©C-carbon. A d d i t i o n a l a c i d i c or basic groups in the side chain 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 of a l l the amino acids take place as a r e s u l t of a l t e r i n g the pH of the s o l u t i o n used f o r e l u t i o n of the chromatogram. This c o n t r o l s the r e l a t i v e rates of amino a c i d m i g r a t i o n . Strongly a c i d i c c a t i o n exchange resins are used, in t h i s case a Durrum Chemical DC-4A chromatographic r e s i n . It has a bead diameter of 8 - jiim and is a sulfonated polymer with 8% c r o s s l i n k . Approximately 2g of r e s i n are packed in a s t a i n l e s s s t e e l column with an i n s i d e diameter of 0.175 cm. and a length of 48 cm. (148). Amino a c i d molecules are s u f f i c i e n t l y small to penetrate the network and become temporarily associated with the ne g a t i v e l y charged groups on the r e s i n . 40 Amino a c i d s a r e e l u t e d f rom the r e s i n by i n c r e a s i n g the pH, so as to change the s t a t e o f the c h a r g e on the amino a c i d m o l e c u l e s . S u b s t a n c e s w i t h s t r o n g l y a c i d i c g roups a r e f i r s t t o be e l u t e d , f o l l o w e d by n e u t r a l amino a c i d s and then the b a s i c amino a c i d s wh ich have the a d d i t i o n a l p o s i t i v e l y c h a r g e d group in t h e i r s i d e c h a i n . The amino a c i d s w i t h h y d r o c a r b o n s i d e c h a i n s emerge f rom the column in o r d e r o f i n c r e a s i n g c h a i n l e n g t h . As the s i d e c h a i n becomes l a r g e r , the a f f i n i t y o f the amino a c i d f o r the h y d r o c a r b o n backbone o f the r e s i n i n c r e a s e s . The more h i g h l y b ranched c h a i n s e l u t e f i r s t . An hydroxy group in the amino a c i d s i d e c h a i n c a u s e s c o n s i d e r a b l e i n c r e a s e s in the r a t e o f i t s m i g r a t i o n down the column due t o an i n c r e a s e d a f f i n i t y o f the amino a c i d f o r the aqueous moving p h a s e . The o r d e r o f e l u t i o n , t h e n , i s p h o s p h o s e r i n e , t a u r i n e , p h o s p h o e t h a n o l a m i n e , u r e a , a s p a r t i c a c i d , hydroxy p r o l i n e , t h r e o n i n e , s e r 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 , g l u t a m i n e , s a r c o s i n e , o<amino a d i p i c a c i d , g l y c i n e , a l a n i n e , c i t r u l l i n e , v a l i n e , c y s t i n e , m e t h i o n i n e , i s o l e u c i n e , l e u c i n e , t y r o s i n e , p h e n y l a l a n i n e , t r y p t o p h a n , o r n i t h i n e , l y s i n e , h i s t i d i n e and a r g i n i n e . The a u t o m a t i c a p p a r a t u s depends on c o n s t a n t - r a t e pumps ( f l ow r a t e s e t a t 6.3 ml/hr ) f o r the c o n t i n u e d a c c u r a c y o f i t s c a l i b r a t i o n and p l o t . Q u a n t i t a t i o n i s a c c o m p l i s h e d by means o f a r e c o r d e r f o l l o w i n g a r e a c t i o n w i t h n i n h y d r i n and measurement o f the e l u a t e a t two wave 1engths(590 and 690 n a n o m e t e r s ) . The a r e a s under the v a r i o u s amino a c i d peaks r e p r e s e n t the c o n c e n t r a t i o n s . Ve ry s h a r p amino a c i d peaks a r e formed w i t h s u f f i c i e n t l y f i n e l y - d i v i d e d r e s i n . I d e n t i f i c a t i o n o f compounds i s based on e l u t i o n t imes as measured d u r i n g the c a l i b r a t i o n r u n . 41 Using a tota l of f i ve l i t h ium-c i t r a te buffers in sequence, a buffer pressure of 2400 p s i , a sample s i ze of 5 0 - 6 0 jul and three column temperatures, a complete ana lys is of amino acids may be accomplished in 5 i ~ 6 hours. Concentrations of taur ine , aspar t i c a c i d , threonine, s e r i ne , glutamine, asparagine, p r o l i n e , g l y c i ne , a l an ine , v a l i n e , c y s t i ne , methionine, i so l euc ine , leuc ine , t y ros ine , phenyla lanine, urea, o rn i t h i ne , l y s i ne , h i s t i d i n e and arg in ine were ca lcu la ted automat ica l ly by the amino acid ana lyzer . C i t r u l l i n e values were so low for the infants rece iv ing to ta l parenteral nu t r i t i on that an a l te rnate method was used to ca l cu la te concentrat ion va lues . Tracings were made from the sample chromatogram and from the standard run jus t previous to the sample. These were weighed and concentrat ions for each sample were computed (see sample c a l cu l a t i on below). Sample Ca l cu l a t i ons : For most amino acids in the stock s o l u t i o n , concentrat ion For c i t r u l l i n e in the stock s o l u t i o n , concentrat ion Af te r d i l u t i o n step 2.5/iM/ml 0.620 pM/m] Answer should be ca lcu la ted as: wt. of sample c i t r u l l i n e wt. of standard c i t r u l l i n e 2.5 /jM/ml 0.620 /jM/ml 0.1563 /JM/ml 0.1563 x 0.62 ;uM/ml 0.0388 /iM/ml 0.0388 ^M/ml = 0.0008 g 0.0020 g = 0.015 /JM/ml x 0.0388 uM/ml 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 to sample venous blood rather than c a p i l l a r y or a r t e r i a l blood in t h e i r determination of plasma amino a c i d concentrations. C a p i l l a r y blood was used in t h i s study. In order to compare the study data with the a v a i l a b l e l i t e r a t u r e values s t a t i s t i c a l 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 renal p a t i e n t s p r i o r to and a f t e r d i a l y s i s . This evaluated 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 c oncentrations. Blood ammonia l e v e l s were not a v a i l a b l e from the i n f a n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n . Glutamine l e v e l s , which could have been c o r r e l a t e d with 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 in scheduling samples f o r a n a l y s i s . Figure 3 shows the i n s t a b i l i t y of glutamine during storage of blood samples in the Durrum D-500 p r i o r to a n a l y s i s . Asparagine and glutamine values were used from various p a t i e n t s whose samples had been p r e v i o u s l y analyzed on the i n i t i a l run of the instrument. Va1ine:g1ycine r a t i o s were c a l c u l a t e d from aminograms of premature in f a n t s on t o t a l parenteral n u t r i t i o n to assess the i n f a n t s ' n u t r i t i v e s t a t u s . E. DETERMINATION OF THE KlLOCALORIE:NITROGEN RATIO The group of p a t i e n t s involved in t h i s part of the study were premature i n f a n t s maintained on t o t a l parenteral n u t r i t i o n . Data were obtained from the Parenteral N u t r i t i o n Flow C h a r t - F l u i d Balance and Fig. 3 STABIL ITY O F G L U T A M I N E A N D 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 IN T H E D U R R U M D 5 0 0 A M I N O A C I D A N A L Y Z E R 0) o > Glutamine 100 50 Asparagine 6 1 2 3 1 2 3 4 5 6 1 2 3 1 2 3 4 5 6 Run Number 15 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 25°C while awaiting analysis. kk N u t r i t i o n a l Intake. (See Appendix C). C a l c u l a t i o n s were done, using Wretlind's (51) conversion f a c t o r f o r Vamin of 7-5, to f i n d the amount of nitrogen in the p r o t e i n s o l u t i o n infused. Sample C a l c u l a t i o n : 2.1 protein/kg body weight/day = Q > 2 8 N i t r o g e n / k g b o d y w e i g n t / d a y / • P Total k i l o c a l o r i e s infused were then d i v i d e d by the grams of nitrogen and 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 _ , 7 1 0 . 2 8 Nitrogen/kg 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 b a s i s . F. GROWTH PARAMETERS Infants in the Intensive Care Nursery were weighed d a i l y using a Toledo balance sc a l e accurate to 10 g. Body length was measured from the crown of the head to the heel of the foot with the leg f u l l y extended. Head circumference was measured at the l a r g e s t o c c i p i t o f r o n t a l circum-ference. Head circumference and body length measurements were done every 10 days - 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 parenteral n u t r i t i o n . The data were p l o t t e d on i n t r a u t e r i n e growth charts developed by Lubchenco et aj_. , (116,117). Due to the 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 ) nature of the Intensive Care Nursery at the Vancouver General H o s p i t a l , when circumstances a l l o w , i n f a n t s are sent to other h o s p i t a l s . Consequently, i t was not p o s s i b l e to f o l l o w the growth of the i n f a n t s i n the study group. 45 G. STATISTICAL ANALYSIS Mean and s t a n d a r d d e v i a t i o n s were c a l c u l a t e d f rom the p lasma amino a c i d v a l u e s o b t a i n e d from the p remature i n f a n t s m a i n t a i n e d on o r a l f e e d s o f SMA^Q. Once c a l c u l a t e d , t h e s e d a t a p r o v i d e d the s t a n d a r d normal p lasma amino a c i d v a l u e s needed f o r f u r t h e r r e f e r e n c e . Means and s t a n d a r d d e v i a t i o n s were a l s o c a l c u l a t e d f o r the d a t a o b t a i n e d f rom t h e e x p e r i m e n t a l g r o u p . The d i f f e r e n c e between the two g r o u p s were c a l c u l a t e d u s i n g S t u d e n t ' s t - t e s t w i t h p ^ 0.05. L i n e a r r e g r e s s i o n a n a l y s i s was done on both s e t s o f d a t a t o see i f p lasma amino a c i d l e v e l s c o r r e l a t e d w i t h g e s t a t i o n a l a g e . C a p i l l a r y venous d i f f e r e n c e s were a n a l y z e d u s i n g the one sample t - t e s t . L i n e a r r e g r e s s i o n a n a l y s i s was done on 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 to see i f a r e l a t i o n s h i p e x i s t e d . 46 CHAPTER IV RESULTS Sex, g e s t a t i o n a l age, weight, length and head circumference 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 in Tables 4,5,6 and 7. Weight, length and head circumference at b i r t h are i l l u s t r a t e d g r a p h i c a l l y in Figures 4 and 5- The con t r o l group had a mean g e s t a t i o n a l age of 33i weeks. The mean value f o r body weight was 1940 g; body length 44 cm; and head circumference 31 cm, a l l of which f a l l on the 50th p e r c e n t i l e of the i n t r a u t e r i n e growth charts (116,117). This i n d i c a t e s that the c o n t r o l group i n f a n t s were a p p r o p r i a t e l y 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 of 28 weeks. Corresponding mean values f o r body weight 982 g; body length 36 cm; and head circumference 25 cm, were lower among the study group than in the c o n t r o l s and f a l l w i t h i n the 25 _50th 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 charts (116,117). Mean p r o t e i n intakes were c a l c u l a t e d f o r both the con t r o l and study groups f o r the three-day period p r i o r to the time the blood samples were taken. Table 8 shows that the average p r o t e i n intake f o r the co n t r o l group, 2 .6 g/kg body weight/day, was higher than that of the in f a n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n , 2.2 g/kg body weight/day. Average amino a c i d intakes f o r the two groups are compared in Table 9- The infa n t s fed intravenously received f a r less t y r o s i n e , 0.05 g/day, than did the con t r o l i n f a n t s , 0.20 g/day. They were infused greater q u a n t i t i e s of i s o l e u c i n e , phenylalanine, methionine, c y s t i n e , 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 per day than the inf a n t s fed SMA o n. T A B L E 4: S E X , G E S T A T I O N A L AGE AND B I R T H WEIGHT OF THE PREMATURE INFANTS IN THE CONTROL GROUP P A T I E N T NUMBER 5 EX G E S T A T I O N A L AGE (WKS) B J R T H WEIGHT (g ) I N T R A U T E R I N E WEIGHT * P E R C E N T I L E 1 M 36 2380 25 - 50th 2 F 36 2020 10 - 25th 3 M 32 1800 50 - 75th 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 10th 15 F 35 2115 25 - 50th 16 F 31 1960 90th MEAN 33-5 1940 50th L u b c h e n c o e t a l . , (116). TABLE 5: HEAD CIRCUMFERENCE AND LENGTH AT BIRTH OF THE PREMATURE INFANTS IN THE CONTROL GROUP PATIENT NUMBER BIRTH HEAD CIRCUMFERENCE (cm) INTRAUTERINE HEAD * CIRCUMFERENCE PERCENTILE B 1 RTH LENGTH (cm) 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 50th 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 50th 9. 30.2 75th 42 .5 50 - 75th 10 32.7 50th 45 50th 11 30.3 25 - 50th 46 75 - 90th 12 30 50th 43.5 50 - 75th 13 30 10 - 25th 43 10 - 25th 14 32 50th 42 10 - 25th 15 32 50th 46 50th 16 30 50th 42.5 50 - 75th MEAN 31 50th 44 50th * Lubchenco e t a l . , (117) TABLE 6: SEX, GESTATIONAL AGE AND BIRTH WEIGHT OF PREMATURE INFANTS IN THE STUDY GROUP PATIENT NUMBER SEX GESTATIONAL AGE (WKS) BIRTH WEIGHT (g) INTRAUTERINE WEIGHT * PERCENTILE 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 MEAN 28 982 25th Lubchenco e t a l . , (116) TABLE 7: HEAD CIRCUMFERENCE AND LENGTH AT BIRTH OF PREMATURE INFANTS IN THE STUDY GROUP PATIENT -BIRTH HEAD INTRAUTERINE HEAD * BIRTH INTRAUTERINE * NUMBER CIRCUMFERENCE CIRCUMFERENCE LENGTH LENGTH (cm) PERCENTILE (cm) 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 25th 38.5 10 - 25th MEAN 25 25th 36 25 - 50th " Lubchenco e t a l . , (117) 51 pFig. 4 Weight, Length and Head Circumference Measurements = at Birth of Control Group V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y I N T R A U T E R I N E GROWTH C H A R T 24 2S 28 27 28 29 30 31 32 33 34 35 38 37 36 38 40 41 4 2 4 3 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 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 40 4 WEEK Of GESTATION I 42 43 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 8 3 9 4 0 41 WEEK OF GESTATION ( F R O M 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 37: 403 . 19661 VANCOUVER GENERAL HOSPITAL INTENSIVE CARE NURSERY I N T R A U T E R I N E G R O W T H C H A R T 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 42 43 O 24 25 26 27 26 20 30 31 32 33 34 35 36 37 39 38 40 41 WEEK Of GESTATION 0 24 21 26 27 26 29 30 31 32 33 34 35 36 37 36 39 40 41 42 43 WEEK OF GESTATION ( F R O M 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: 403, 19661 53 TABLE 8: PROTEIN INTAKE FOR THE 3 DAYS PRIOR TO THE DRAWING OF THE BLOOD SAMPLE. CONTROL AVERAGE PROTEIN STUDY AVERAGE PROTEIN PATIENTS INTAKE PATIENTS INTAKE (g/kg body weight /day) . (g/kg body w e i g h t / d a y ) 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 TABLE 9: AVERAGE AMINO ACl;D INTAKE BY THE CONTROL AND STUDY INFANTS AMINO ACIDS CONTROL GROUP (SMA 2 ( )) STUDY GROUP (VAMIN) AVG. g AMINO ACID/DAY AVG. g AMINO ACID/DAY 1 s o l e u c i ne 0.29 0.42 Leuc i ne 0,51 0,57 L y s i ne 0.44 0.42 P h e n y l a l a n i n e 0,21 0,59 Tyros i ne 0.20 0.05 Meth i on i ne 0.11 0,20 Cys t i ne 0.08 0.15 Threon i ne 0.26 0.32 T r y p t o p h a n 0.09 0.11 Va1i ne 0.37 0.46 A l an i ne 0.21 0.32 A r g i n i n e 0.17 0.36 A s p a r a g i ne 0.48 0.44 G l u t a m i c A c i d 1 .01 0.96 G l y c i ne 0.09 0.22 H i s t i d i ne 0.12 0.26 P r o l i ne 0.41 0.86 S e r i ne 0.24 0.80 55 Plasma amino a c i d values f o r con t r o l and study groups can be found in Tables 10 and 11. Table 12 shows the comparison of the mean values of plasma amino a c i d concentrations f o r these two groups. In the study group, l e v e l s of threonine, asparagine, glutamic 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, l e u c i n e , o r n i t h i n e , l y s i n e , and a r g i n i n e were found to be s i g n i f i c a n t l y lower, whereas phenylalanine l e v e l s were s i g n i f i c a n t l y higher. Urea l e v e l s were a l s o lower in the study group than in 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 ac i d values of the con 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 of these two amino acids f o r the study group can be found in Table 13- The mean r a t i o value was 0.50 which i s s i g n i f i c a n t l y greater than the value associated with Kwashiorkor, 0.18 - 0.06. Tables 14 and 15 show the r e s u l t s of the l i n e a r regression a n a l y s i s done on the plasma amino a c i d concentrations and the i n f a n t s ' g e s t a t i o n a l age in both groups. No c o r r e l a t i o n was found to e x i s t between plasma amino a c i d concentration and g e s t a t i o n a l age. The r e s u l t s of the l i n e a r regression a n a l y s i s of glutamine and asparagine values are shown in Table 16. These r e s u l t s i n d i c a t e a p o s i t i v e c o r r e l a t i o n of r=0.80. Asparagine values can, t h e r e f o r e , be used as a crude e s t i m a t i o n of blood ammonia l e v e l s . The r e s u l t s of the s t a t i s t i c a l 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 concentrations are shown in Table 17- C a p i l l a r y and venous samples are comparable f o r a l l amino acids except t a u r i n e , asparagine, and v a l i n e . These three amino acids 56 a r e s i g n i f i c a n t l y h i g h e r in venous than in c a p i l l a r y s a m p l e s . C a p i l l a r y p lasma amino a c i d s c a n , t h e r e f o r e , be compared w i t h venous plasma amino a c i d s w i t h the e x c e p t i o n o f t a u r i n e , a s p a r a g i n e and v a l i n e . K i1 oca l o r i e : n i t r o g e n r a t i o s were c a l c u l a t e d d a i l y f o r the p r e m a t u r e 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 . T a b l e 18 shows the l e n g t h o f t ime each i n f a n t was 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 and the a v e r a g e k i1 oca 1 o r i e : n i t r o g a n , r a t i o a t t a i n e d . These i n f a n t s remained on the reg ime f o r an a v e r a g e o f 47 days (range=l2-94 days ) and r e c e i v e d mean k i1 oca l o r i e : n i t r o g e n r a t i o s o f 336 ( range= 297-403) P a t i e n t II was s t i l l b e i n g f e d i n t r a v e n o u s l y when t h i s s t u d y was c o n c l u d e d . Growth measurements were r e c o r d e d f o r i n f a n t s d u r i n g the t ime they r e c e i v e d t o t a l i n t r a v e n o u s n u t r i t i o n . These were g raphed on i n d i v i d u a l i n t r a u t e r i n e growth c h a r t s (see A p p e n d i x D ) . A l l i n f a n t s grew s t e a d i l y w i t h i n or p a r a l l e l i n g the p e r c e n t i l e s i n d i c a t e d on the g r a p h . F i g u r e 7 i l l u s t r a t e s t h i s g r o w t h . F i g u r e 8 f u r t h e r i l l u s t r a t e s the r e l a t i o n s h i p between n u t r i t i o n a l i n t a k e and w e i g h t g a i n . TABLE 10: INDIVIDUAL PLASMA AMINO ACID VALUES FOR CONTROL GROUP:PREMATURE INFANTS RECEIVING ORAL FEEDS OF S M A „ n ( juM/ml) PATIENT NUMBER AMINO ACIDS 1 2 3 4 5 6 7 8 Taur i ne 0. 061 0.072 0.044 0. ,111 0. 082 0.114 0.054 0.023 A s p a r t i c A c i d 0. .081 0.023 0.014 0. 026 0. 026 0.024 0.019 0.019 T h r e o n i ne 0. 248 0.294 0.288 0. 225 0. 325 0.352 0.417 0.493 S e r i ne 0. 193 0.213 0.172 0. ,225 0. 300 0.292 0.248 0.298 A s p a r a g i ne 0.063 0.073 0.058 - 0. 094 0.149 0.085 0.114 P r o1 i ne 0. 313 0.195 0.156 0. ,170 0. 259 0.380 0.305 0.297 G l u t a m i c A c i d 0. 060 0.092 0.045 0. ,080 0. 077 0.061 0.038 0.084 Ci t r u l1 i n e 0. ,022 0.033 0.041 0. 033 0. 026 0.047 0.026 0.038 G l y c i ne 0. 242 0.269 0.199 0. ,243 0. 351 0.519 0.257 0.338 A l a n i ne 0. 306 0.371 0.298 0. ,306 0. 393 0.825 0.395 0.689 Va1 i ne 0. ,114 0.191 0.101 0. 134 0. 221 0.202 0.184 0.236 C y s t i ne 0. ,026 0.050 0.028 0. .037 0.056 0.100 0.046 0.056 Meth ion i ne 0. 035 0.046 0.028 0.038 0. 047 0.095 0.063 0.059 1 s o l e u c i n e 0. ,030 0.048 0.020 0. ,022 0. 058 0.060 0.049 0.078 Leuc i ne 0. .079 0.125 0.057 0.089 0. 128 0.118 0.134 0.136 T y r o s i ne 0. ,149 0.067 0.085 0. .092 0. 114 0.116 0.140 0.080 Phenyl a l a n i ne 0. .039 0.041 0.021 0, .024 0. 045 0.091 0.041 0.084 Orn i th i ne 0. .067 0.137 0.080 0. .127 0. 123 0.110 0.120 0.117 Lys i ne 0. .097 0.172 0.123 0, . 1 5 T 0. 246 0.276 0.189 0.152 H i s t i d i ne 0. .095 0.109 0.061 0. .025 0. 086 0.071 .0.080 0.070 A r g i n i n e 0.063 0.098 0.097 0, .076 0. ,108 0.098 0.092 0.101 Urea 1 . .741 2.201 1 .212 2, .101 3. ,110 3-937 2.765 1 .209 cont i nued TABLE 10 (continued) PATIENT NUMBER AMINO ACIDS 9 10 11 12 -13 14 15 16 Tau r i ne 0 059 0.148 0.091 0 146 0 079 0.107 0 090 0.083 A s p a r t i c Acid 0 025 0.035 0.025 0 027 0 025 0.028 0 023 0.016 Threon i ne 0 391 0.432 0.477 0 288 0 328 0.399 0 442 0.290 Ser i ne 0 283 0.302 0.196 0 279 0.258 0.309 0 229 0.178 Asparagi ne 0. 069 O.O85 0.080 0 076 0 024 0.099 0 072 0.058 P r o l i n e 0 251 0.275 0.215 0 295 0 240 0.313 0 210 0.208 G1utami c Aci d 0 061 0.090 0.064 0 066 0 057 0.090 0 059 0.048 Ci tru1 1i ne 0 056 0.028 0.043 0 025 0 015 0.028 0 024 0.030 G l y c i ne 0 279 0.403 0.286 0 255 0 224 0.438 0 297 0.244 Alan i ne 0 242 0.387 0.280 0 388 0 336 0.518 0 371 0.295 Va1i ne 0 131 0.173 0.157 0 179 0 158 0.239 0 200 0.136 Cys t i ne 0.038 0.034 0.037 0 033 0 021 0.077 0 052 0.044 Meth i on i ne 0 039 0.041 0.040 0 065 0 053 0.085 0 070 0.049 1soleucine 0 041 0.051 0.046 0 072 0 052 0.092 0 064 0.040 Leuc i ne 0 099 0.099 0.089 0 138 0 106 0.155 0 027 0.078 Tyros i ne 0 125 0.108 0.086 0 088 0 097 0.100 0 181 0.147 Pheny1 a 1 an i ne 0 034 0.033 0.071 0 049 0 046 0.057 0 052 0.036 Orn i th i ne 0.098 0.165 0.106 0 115 0 099 0.146 0 128 0.094 Lys i ne 0 142 0.173 0.181 0 196 0 150 0.336 0 229 0.173 H i s t i d i ne 0 058 0.077 0.055 0.074 0 091 0.102 0 094 0.074 Arg i n i ne 0 108 0.115 0.106 0.078 0 045 0.167 0 092 0.103 Urea 1 949 1.066 1.473 2.698 1 275 3.633 2 205 1 .954 MEAN- S. O.O85-O 0.023^0 0.359T0 0.248^0 0.078-0 0.255T0 0.067-0 0.030-0 0.304-0 0.400-0 0.171-0 0.046-0 0.053-0 0.051-0 0.104-0 0.111-0 0.048^0 0.113-0 0.187-0 0.076-0 0.097TO 2.158-0 .034 .005 .077 .048 .028 .061 .017 .012 .086 .155 .042 .020 .019 .019 .034 .031 .020 .025 .060 .021 .026 .872 TABLE 11: INDIVIDUAL PLASMA AMINO ACID VALUES FOR THE STUDY GROUP:PREMATURE INFANTS RECEIVING TOTAL PARENTERAL NUTRITION ( juM/ml) PATIENT NUMBER AMINO ACIDS 1 2 3 4 5 6 7 Taur i ne 0. 076 0.031 0. 193 0. 079 0.073 0.053 0.045 A s p a r t i c Acid 0. 015 0.012 0. 003 0. ,021 0.015 0.016 0.013 Threoni ne 0. 187 0.087 0. 261 0. 179 0.160 0.256 0.124 Ser i ne 0. 137 0.130 0. 346 0. ,129 0.225 0.241 0.232 Asparag i ne 0. 015 0.012 0. ,030 0. ,010 0.022 0.021 0.022 P r o l i ne 0. 156 0.165 0. 293 0. .179 0.293 0.269 0.259 Glutamic Acid 0. 025 0.021 0. ,050 0.043 0.038 0.043 0.024 Ci t r u l 1 i ne 0. 010 0.005 0. ,006 0. ,005 0.005 0.006 0.013 Gly c i ne 0. 217 0.207 0. 330 0. ,227 0.234 0.319 0.227 Al an i ne 0. 139 0.126 0. ,287 0. ,138 0.164 0.208 0.106 Va1i ne 0. 092 0.114 0. ,122 0. ,149 0.102 0.167 0.121 Cys t i ne 0. 017 0.024 0. 033 0. .027 0.016 0.028 0.029 Meth i on i ne 0. 012 0.014 0. ,020 0, .019 0.012 0.019 0.023 1 soleuc i ne 0. 036 0.032 0. ,028 0. .043 0.012 0.032 0.021 Leuc i ne 0. 040 0.041 0. ,041 0. .053 0.036 0.072 0.060 Tyros i ne 0. 062 0.031 0. ,056 0. .072 0.046 0.081 0.073 Pheny1 a 1 an i ne 0. 062 0.062 0. ,052 0. .062 0.117 0.106 0.094 Orni t h i ne 0. 015 0.167 0. ,027 0, .021 0.013 0.020 0.024 Lysine 0. 052 0.037 0. ,046 0. .044 0.030 0.051 0.122 H i s t id i ne 0. ,109 0.067 0, .071 0, .064 0.073 0.095 0.094 Arg i n i ne 0. ,017 0.023 0, .020 0, .019 0.008 0.015 0.027 Urea 0. 972 1 .381 1, .643 0.817 0.597 0.290 2.792 cont i nued TABLE 11 (continued): PATIENT NUMBER AMINO ACIDS 8 9 10 11 Taur i ne 0.064 0. .104 0.057 0.066 A s p a r t i c Acid 0.035 0. .028 0.020 0.032 Threon i ne 0.288 0. .162 0.208 0.423 Seri ne 0.372 0. .161 0.207 0.367 Asparag i ne 0.025 0.049 0.026 0.033 P r o l i ne 0.491 0. .201 0.227 0.441 G1utami c Aci d 0.053 0. .050 0.031 0.085 Ci t r u l 1 i ne 0.015 0. .026 0.003 0.014 Glycine 0.430 0. ,245 0.233 0.515 Al an i ne 0.258 0. ,185 0.146 0.394 Va1i ne 0.281 0. ,103 0.121 0.267 Cys t i ne 0.035 0. ,013 0.007 0.049 Meth i on i ne 0.027 0. ,006 0.010 0.034 1soleuc i ne 0.049 0. ,015 0.015 0.093 Leuc i ne 0.072 0. .033 0.044 0.111 Tyros i ne 0.129 0. ,042 0.207 0.231 Pheny1 a 1 an i ne 0.086 0. .039 0.104 0.111 Orn i t h i ne 0.032 0. ,024 0.010 0.040 Lys i ne 0.167 0. ,110 0.043 0.097 H i st i d i ne 0.065 0.083 O.O89 0.111 Arg i n i ne 0.030 0. ,013 0.006 0.038 Urea 2.202 2, .037 0.564 0.447 MEAN - S.D. 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 FOR CONTROL AND STUDY GROUPS ( juM/ml) AMINO ACID .CONTROL GROUP STUDY GROUP t,value ' + r. „ v]- n.. + r- I MEAN 1 S . D . MEAN 1 S . D . l T a u r i n e O.O85 - 0.043 0.076 - 0.043 0.501 A s p a r t i c A c i d 0 . 023^0.005 0.019 -0.009 1-50 T h r e o n i n e 0.359 - 0.077 0.212 - 0.092 4.500 S e r i n e 0.248 - 0.048 0.232 \ 0.093 0.62 A s p a r a g i n e O.O78 7 0.028 0.024 - 0.011 5-96 P r o l i n e 0,255 'J 0,061 0,270 - 0,109 -0.467 G l u t a m i c A c i d 0,067 - 0,017 0,042 \ 0.018 3-65 C i t r u l l i n e 0.030 - 0,012 0.010 - 0.007 4.90 G l y c i n e 0.304 - 0.086 0.289 ; 0.101 0.41 A l a n i n e 0.400 - 0,155 0,196 - 0.086 3,95 V a l i n e 0.172^0,042 0.144^0.056 1,47 C y s t i n e 0.046 - 0,020 0.025 7 0.012 3-10 M e t h i o n i n e 0.053 - 0,019 0,018 - 0.008 5-88 I s o l e u c i n e 0.051 \ 0.019 0,032 t 0..023 2.1 1 L e u c i n e 0.104 J 0,034 0.055 7 0,023 4,20 T y r o s i n e 0.111 - 0.031 0.094 - 0.067 0.91 P h e n y l a l a n i n e 0.048 - 0.020 0.081 J 0,027 -3-75 O r n i t h i n e 0.113 J 0.025 O.O36 - 0.044 5.89 L y s i n e 0.187 7 0,060 0,073 7 0.044 5-35 H i s t i d i n e 0.076 - 0.021 0.084 - 0.017 -0.97 A r g i n i n e 0.097 : 0.026 0.020 - 0.010 9-30 Urea 2.158 i 0.872 1.249 - 0.825 2.72 * S i g n i f i c a n c e o f d i f f e r e n c e by S t u d e n t ' s t t e s t a t p^-0.05 62 Fig. 6 A COMPARISON OF PLASMA AMINO ACID CONCENTRATIONS OF THE CONTROL AND STUDY GROUPS Plasma Cone. /Um/ml 0 .20 .40 .60 .80 1.0 Taurine Aspartic Acid Threonine Serine Asparagine Proline Glutamic Acid Citrulline Glycine Alanine Valine Cystine Methionine Isoleucine Leucine Tyrosine Phenylalanine Ornithine Lysine Histidine Arginine Urea TABLE 13: VALINE:GLYCINE RATIOS FOR INFANTS RECEIVING TOTAL PARENTERAL NUTRITION PATIENT VALINE:GLYCINE RATIO 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 TABLE 14: LINEAR REGRESSION STATISTICS ON GESTATIONAL AGE AND PLASMA AMINO ACID CONCENTRATIONS, (GESTATIONAL AGE 31-36 WKS) AMINO ACID CORRELATION SLOPE STD INTERCEPT STD COEFFICIENT ERROR ERROR Taur i ne - 0.030 - 0.001 0. ,005 0.104 0.165 A s p a r t i c Acid 0.163 0.000 0. ,001 0.008 0.025 Threon i ne 0.087 0.004 0. ,012 0.227 0.394 Ser i ne 0.414 0.008 0. ,005 - 0.028 0.155 Asparagine 0.457 0.008 0. ,004 - 0.200 0.142 P r o l i ne 0.294 0.010 0. ,008 - 0.066 0.280 Glutamic Acid 0.495 0.004 0. ,002 - 0.082 0.070 C i tru1 1i ne - 0.247 - 0.001 0. ,001 0.079 0.049 G lyc i ne 0.470 0.022 0. ,011 - 0.425 0.366 Alan i ne 0.383 0.032 0. ,021 - 0.673 0.692 Va1i ne 0.494 0.011 0. ,005 - 0.201 0.176 Cystine 0.421 0.005 0. ,003 - 0.106 0.088 Meth i on i ne 0.235 0.002 0. ,003 - 0.026 0.088 1 soleuc i ne 0.206 0.003 0. ,003 - 0.052 0.089 Leuc i ne 0.099 0.002 0. ,005 0.044 0.161 Tyros i ne 0.055 0.001 0. ,004 0.080 0.148 Phenylalanine 0.338 0.004 0. ,003 - 0.072 0.089 Orn i t h i ne 0.255 0.003 0. ,003 0.002 0.114 Lys i ne 0.342 0.011 0. ,008 - 0.183 0.272 Hi st i d i ne 0.625 0.007 0. ,002 - 0.157 0.078 Arg i ni ne 0.165 0.002 0. ,004 0.019 0.125 Urea 0.264 0.124 0. ,121 - 1.989 4.051 TABLE 15: LINEAR REGRESSION STATISTICS ON GESTATIONAL AGE AND PLASMA AMINO ACID CONCENTRATIONS (GESTATIONAL AGE 24-31 WKS) AMINO ACID CORRELATION SLOPE STD INTERCEPT STD COEFFICIENT ERROR ERROR Taur i ne - 0.294 - 0.006 ,0.007 0,256 0.195 A s p a r t i c Acid - 0.059 - 0.000 0.002 0.027 0.045 Threon i ne 0.280 0.000 0.000 0.192 0.036 Ser i ne 0.225 0.011 0,015 0.065 0.430 Asparag i ne - 0.209 - 0.001 0.002 0.056 0.050 P r o l i n e 0.264 0.015 0.018 - 0.135 0.496 Glutamic Acid 0.307 0.003 0.003 - 0.038 0.081 C i tru1 1i ne - 0.055 - 0.000 0.001 0.015 0.031 Glyc i ne 0.322 0.016 0.016 - 0.169 0.450 Alanine 0.263 0.012 0.014 - 0.128 0.396 Va 1 i ne 0.340 0.010 0.009 - 0.127 0.251 Cystine 0.644 0.004 0.002 0.082 0.043 Meth i on i ne 0.578 0.002 0.001 - 0.049 0.031 1soleuci ne 0.491 0.006 0.003 - 0.124 0.094 Leuc i ne 0.547 0.006 0.003 - 0.124 0.091 Tyros i ne - 0.059 - 0.002 0.011 0.150 0.318 Pheny1 a 1 an i ne 0.365 0.005 0.004 - 0.057 0.118 Orni t h i ne 0.269 0.006 0.007 - 0.133 0.202 Lys i ne 0.087 0.002 0.007 0.018 0.209 H i s t i di ne 0.348 0,003 0.003 - 0.001 0.076 Arg i n i ne 0.611 0.003 0.001 - 0.063 0.036 Urea - 0.034 - 0.014 0.139 1 .644 3.897 66 TABLE 16: LINEAR REGRESSION AND CORRELATION COEFFICIENT ANALYSIS OF PLASMA LEVELS OF GLUTAMINE AND ASPARAGINE * SAMPLE STATISTICS MEAN - S.D. Asparagine 0.099 0.080 Glutamine 0.749 - 0.807 CORRELATION COEFFICIENT r = 0.803 REGRESSION RESULTS Slope 8.061 Standard Error 0.742 Intercept - 0.048 Standard Error 0.094 Asparagine and glutamine values were chosen from p a t i e n t s not involved in t h i s study whose samples had been analyzed on the i n i t i a l run of the instrument. 67 T A B L E 1 7 : 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 CONCENTRATIONS IN C A P I L L A R Y AND VENOUS BLOOD S A M P L E S * AMINO A C I D N •T-STATI S T I C C O N F I D E N C E L I M I T S U P P E R LOWER T a u r i n e 7 - 4 . 0 1 0 . 9 0 0 . 5 7 ** A s p a r t i c A c i d 7 1 . 5 6 1 . 7 3 0 . 8 4 T h r e o n i n e 7 - 0 . 8 8 1 . 1 2 0 . 7 5 S e r i ne 7 1.28 1 . 3 9 0 . 8 8 A s p a r a g i n e 7 - 2 . 5 3 0 . 9 9 0 . 7 2 ** P r o l i n e 7 - 1.18 1 . 0 7 0 . 7 9 G l u t a m i c A c i d 6 - 1 . 3 0 1.17 0 . 4 8 C i t r u l 1 i n e 7 1 . 0 5 5 - 9 9 - 1 . 0 0 G 1 y c i n e 7 - 0 . 1 4 1 . 1 2 0 . 8 7 A l a n i n e 7 0 . 1 5 1 . 1 5 0 . 8 7 V a 1 i n e 7 - 2 . 5 0 0 . 9 9 0 .78 ** C y s t i n e 8 0 . 5 5 1 . 2 6 0 . 8 4 M e t h i o n i n e 8 - 0 . 8 4 1 . 1 5 0 . 6 8 1 s o l e u c i n e 8 - 1 . 9 0 1 . 0 3 0 . 6 9 L e u c i n e 8 - 1 . 3 0 1 . 1 0 0 . 6 6 T y r o s i n e 8 - 0 . 9 9 1 . 1 4 0 . 6 5 P h e n y l a 1 a n i n e 8 - 1 . 3 8 1 . 1 1 0 . 6 1 O r n i t h i n e 8 0 . 7 6 1 . 3 3 0 . 8 3 L y s i n e 8 1 . 0 6 1 . 0 6 0 . 7 4 H i s t i d i ne 8 1 . 0 7 1 . 0 7 0 . 8 6 A r g i n i n e 7 1 . 0 9 1 . 0 9 0 . 8 0 * V e n o u s a n d c a p i l l a r y b l o o d s a m p l e s w e r e t a k e n p r i o r t o a n d a f t e r d i a l y s i s f r o m a g r o u p o f r e n a l p a t i e n t s n o t i n v o l v e d i n t h i s s t u d y . * * S i g n i f i c a n c e o f d i f f e r e n c e b y o n e s a m p l e t - t e s t ( p ^ . 0 . 0 5 ) . 68 TABLE 18: DURATION OF TOTAL INTRAVENOUS FEEDING AND AVERAGE KlLOCALORIE:NITROGEN RATIO ATTAINED PATIENT NUMBER 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 V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y I N T R A U T E R I N E GROWTH C H A R T Patient 8 Fig. 7 Growth Data for Patient 8 while on Total Parenteral Nutrition 24 25 28 27 28 29 30 31 32 33 34 35 36 37 36 39 40 41 42 43 24 25 28 27 28 28 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 33343538 37 363940 414243 WEEK OF GESTATION 0 242528 27 262930 31 3233343536 37 363940 4142 43 WEEK OF GESTATION ( F R O M 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: 403, 1966) 70 Fig. 8 RELATIONSHIP OF DAILY INTRAVENOUS INTAKE WITH WEIGHT G A I N Birth Weight 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. /day 3.0 - i IV Protein(g/kg b.w./day) Time in Days 71 CHAPTER V  DISCUSSION A . CONTROL VALUES Plasma amino a c i d v a l u e s o b t a i n e d in t h i s s t u d y f rom premature i n f a n t s m a i n t a i n e d on o r a l f e e d s p r o v i d e d normal aminograms f o r i n f a n t s o f t h i s age g r o u p . To a s s u r e the v a l i d i t y o f t h e s e d a t a , the r e s u l t s were compared w i t h 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 , T a b l e 19-In compar ing our aminogram v a l u e s f o r p r e m a t u r e i n f a n t s w i t h P o h l a n d t ' s (130) d a t a f o r f u l l term i n f a n t s , we found t h a t l e v e l s o f t h r e o n i n e , s e r i n e , g l y c i n e , a l a n i n e , m e t h i o n i n e , and a r g i n i n e a r e h i g h e r in the p remature c o n t r o l i n f a n t . D i c k i n s o n e t aj_. , (13*0 a l s o found t h a t a l a n i n e and t h r e o n i n e c o n c e n t r a t i o n s were h i g h and remained h i g h f o r the " f i r s t few d a y s " o f l i f e and then d e c r e a s e d . It i s d i f f i c u l t t o compare t h e s e r e s u l t s w i t h the c u r r e n t s t u d y as the p o s t -n a t a l age a t wh ich t h e s e changes o c c u r r e d was not c l e a r l y i d e n t i f i e d by D i c k i n s o n e_t aj_. , (134). The t ime f a c t o r may e x p l a i n the e l e v a t e d v a l u e s f o r a l a n i n e and t h r e o n i n e o b s e r v e d in the p r e s e n t s t u d y . E l e v a t e d l e v e l s o f t y r o s i n e have been noted to o c c u r more o f t e n in p r e m a t u r e i n f a n t s , p resumab ly because o f d e l a y e d deve lopment o f key m e t a b o l i c enzymes , such as p - h y d r o x y pheny l p y r u v i c a c i d o x i d a s e , u n t i l l a t e in f e t a l l i f e (128). E l e v a t e d l e v e l s o f t y r o s i n e were not o b s e r v e d in the c u r r e n t s t u d y . P o l h a n d t ' s (130) d a t a showed h i g h e r c o n c e n t r a t i o n s o f t a u r i n e , v a l i n e and a s p a r a g i n e than o u r s , wh ich can be e x p l a i n e d by the d i f f e r e n c e s in c o n c e n t r a t i o n s o f t h e s e t h r e e amino 72 TABLE 19: COMPARISON OF PLASMA AMINO ACIDS IN PREMATURE AND FULL TERM INFANTS PREMATURE INFANTS FULL TERM INFANTS AMINO ACIDS CONTROLS PRZYREMBEL DICKINSON P0LHANDT ( juM/ml) et al.,(132) et al.,(135) (130) "C/iM/ml) "TjuM/ml) ( juM/ml) Taur i ne 0.085 0.072 0.145 0.096 A s p a r t i c Acid 0.023 0.018 0.016 -Threon i ne 0.359 0.256 0.224 0.134 Ser i ne 0.248 0.169 0.168 0.143 Asparagi ne 0.078 - - 0.087 P r o l i n e 0.255 0.190 0.192 0.283 Gl utami c Aci d 0.067 0.168 0.063 0.098 Ci t r u l 1 i n e 0.030 0.019 0.019 0.020 G1yc i ne 0.304 0.225 0.369 0.228 Alanine 0.400 0.313 0.323 0.387 Va1i ne 0.172 0.174 0.163 0.184 Cysti ne 0.046 0.071 0.000 0.062 Meth i on i ne 0.053 0.025 0.025 0.029 1 soleuc i ne 0.051 0.065 0.040 0.071 Leucine 0.104 0.114 0.078 0.160 Tyros i ne 0.111 O.O89 0.070 0.117 Pheny1 a 1 an i ne 0.048 0.050 0.076 0.063 Orn i th i ne 0.113 0.071 0.100 0.116 Lys i ne 0.187 0.113 0.191 0.210 H i s t i d i ne 0.076 0.057 0.081 0.085 Arg i n i ne 0.097 0.061 0.055 0.084 Cont r o l s : c a p i l l a r y samples; postnatal age 7_16 days; premature i n f a n t s ; SMA. PRZYREMBEL et_ aj_. , (132): venous sample; postnatal age 10 days; premature i n f a n t s ; SMA. DICKINS0N e_t aj_. , (135): venous sample; postnatal age 1 day; f u l l term i nfants. P0LHANDT (130): venous sample; postnatal age 7-5 days; f u l l term i n f a n t s ; breast milk. 73 acids between c a p i l l a r y and venous blood. Przyrembel e_t a_l_. , (132), studied plasma amino a c i d concentrations in premature i n f a n t s . Values from t h e i r study are from venous samples which were handled in a comparable manner to the procedure used in t h i s study. They used s i x t e e n premature i n f a n t s (eight boys and eight g i r l s ) of a median b i r t h weight of 1955 g ( g e s t a t i o n a l age not giv e n ) . Blood samples were taken on the tenth day a f t e r b i r t h j u s t before feeding. Their d i e t c o n s i s t e d of SMA and t h e i r median p r o t e i n intake was 2.5g/kg body weight/day. The plasma amino a c i d values in the co n t r o l group of the present study are compared with the r e s u l t s of these and other workers in Table 19 (130,132,135). On the basis of the f a c t o r s a f f e c t i n g plasma aminograms, the data of Przyrembel e_t aj_. , (132) compared favourably with our c o n t r o l values. On the whole, our values are s l i g h t l y higher 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 of the sampling time chosen. Despite the f a c t that v a r i a t i o n s in o v e r a l l procedures, poorly defined subjects and d i f f e r e n c e s in d i e t s fed make exact comparisons between published studies d i f f i c u l t , c o n t r o l values from the current study compare favourably with the few sets of 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 infants (42,132). B. STUDY VALUES It i s very d i f f i c u l t to compare the values found in r e l a t i v e l y healthy premature i n f a n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n with other values found in the l i t e r a t u r e f o r p a t i e n t s fed intravenously. There are too many unc 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 various 74 types of s o l u t i o n used, the age of the p a t i e n t and the s e v e r i t y of the i l l n e s s a l l markedly a f f e c t plasma amino ac i d p atterns. Compared to Ghadimi e_t a_l_. , ( l 4 l ) high g l y c i n e values were not observed in our study group. The low l e v e l s of threonine and l y s i n e observed by Ghadimi ejt a_l_. , (140) in t h e i r study of premature, low-birth-weight i n f a n t s were a l s o seen in the present study. Ghadimi et^ a_l_. , (140) did not i n t e r p r e t t h e i r values as being a r e s u l t of the e f f e c t of t o t a l parenteral n u t r i t i o n , but rather as a consequence of the standard values chosen f o r comparison which were obtained from cord blood. They f u r t h e r claimed that threonine and l y s i n e l e v e l s were higher in cord samples than in any other samples taken during infancy and childhood. C. COMMENTS ON THE DIFFERENCES BETWEEN CONTROL AND STUDY DATA The d i f f e r e n c e s in plasma amino a c i d concentrations between the con t r o l and study groups in t h i s i n v e s t i g a t i o n were not the same as those observed by Shaw et al_. , (154) in t h e i r study of o r a l l y and intravenously fed f u l l term i n f a n t s . The current study i n d i c a t e s that most of the mean plasma amino a c i d values in the intravenously fed i n f a n t s were lower than those in the in f a n t s fed SMA^Q- The exception was phenylalanine, which was higher in the i n f a n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n , Table 12. Shaw et a j_ ., (154) a l s o found higher serum l e v e l s of phenylalanine, p r o l i n e , g l y c i n e , and s e r i n e , in the in f a n t s infused with Vamin, whereas low values were found f o r l y s i n e and leucine. Elevated plasma l e v e l s of phenylalanine in in f a n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n were noted in both the present study and 75 that of Shaw e_t aj_. , (154). They were not, however, as high as the plasma l e v e l s of phenylalanine seen in p a t i e n t s with phenylketonuria (1.21 jjm/ml, Dr. L. I. Woolf, personal communication). Upon clos e examination of the d a i l y phenylalanine intake, i t was found in our study that i n f a n t s infused with Vamin were r e c e i v i n g 2-3 times more phenylalanine/day than i n f a n t s fed S M A 2 Q . Elevated plasma l e v e l s of phenylalanine in the intravenously fed in f a n t s may, then, be explained by high intakes of phenylalanine. Low plasma l e v e l s of leucine and l y s i n e in 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 parenteral n u t r i t i o n with Vamin were a l s o seen by Shaw e_t aj_. , (154). They e x p l a i n the low l e v e l s of leucine and l y s i n e as being the r e s u l t of low intakes of these s p e c i f i c amino a c i d s . Low plasma concentrations of leucine and l y s i n e were a l s o seen in the present study in i n f a n t s infused with Vamin. Table 9 shows, however, that the average intake of the two amino acids/day was the same f o r both o r a l l y and intravenously fed i n f a n t s . Low intake of leucine and l y s i n e may not be the sol e reason f o r low plasma amino a c i d l e v e l s . We were unable to adequately 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 explanation f or the lower l e v e l s of 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 in the intravenously fed in f a n t s i s a defect in t h e i r renal absorption mechanism. Such a defect would r e s u l t in an increased loss of these amino acids in the u r i n e . The occurrence of a defect is e n t i r e l y p o s s i b l e considering the severe degree of prematurity of some of these i n f a n t s . Generalized amino a c i d u r i a is known to occur in the newborn as a r e s u l t of lowered tubular reabsorption (142). Renal d e f e c t s , however, do not normally a f f e c t d i b a s i c amino 76 acids as l y s i n e or a r g i n i n e , although higher u r i n a r y e x c r e t i o n of o r n i t h i n e and 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 p r o t e i n intakes ( 1 3 2 ) . To 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 clearance studies should be done and amino a c i d losses measured. Unfortunately t h i s was not p o s s i b l e in the current study. Urea l e v e l s were a l s o found to be s i g n i f i c a n t l y lower in the i n f a n t s fed intravenously than in the i n f a n t s fed o r a l l y . Low urea l e v e l s can be a r e f l e c t i o n of diminished p r o t e i n intake o r , conceivably, a defect in the urea c y c l e . In the absence of an inborn e r r o r of metabolism, e i t h e r an i n s u f f i c i e n t amount of substrate f o r the urea c y c l e or delayed development of urea c y c l e enzymes may r e s u l t in what appears to be a d e f e c t i v e urea c y c l e . E i t h e r one of these would lead not only to lowered urea l e v e l s but a l s o to elevated blood ammonia 1 eve 1s. A r g i n i n e i s a major substrate source f o r the urea c y c l e . Low l e v e l s of a r g i n i n e in 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 ( 64 ) . Unlike the other 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 , Vamin contains adequate amounts of a r g i n i n e . Elevated ammonia l e v e l s are not l i k e l y to be explained by i n s u f f i c i e n t s u b s trate. R'aiha e_t a_l_. , (143) found that there was s u f f i c i e n t in v i t r o 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 . The i n f a n t s in t h i s study were a l l of g e s t a t i o n a l age 2k weeks or o l d e r , precluding the problem of urea c y c l e enzyme immaturity. Batshaw et^ a_l_. , (144) a l s o found no inverse 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 plasma ammonia l e v e l s or other l a b i l e nitrogen components, glutamine, glutamate, or a l a n i n e . Blood ammonia l e v e l s were not a v a i l a b l e from the i n f a n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n . Table 16 shows how asparagine 77 values could be used as crude i n d i c a t o r s of blood ammonia l e v e l s . As no increase in asparagine concentration in the i n f a n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n was observed, the assumption can be made, somewhat t e n t a t i v e l y , that there is no evidence f o r elevated ammonia l e v e l s in the intravenously fed premature i n f a n t s . A defect in any of the urea c y c l e enzymes would r e s u l t in an increase in one of the amino acids ( a r g i n i n e , o r n i t h i n e , or c i t r u l l i n e ) . Further evidence f o r the absence of a urea c y c l e defect l i e s in the f a c t that increased plasma l e v e l s of asparagine and the urea c y c l e amino acids were not observed. Low urea l e v e l s may 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 p r o t e i n intake. The plasma aminogram has been used to a s c e r t a i n the adequacy of p r o t e i n intake (95)- C h a r a c t e r i s t i c plasma amino a c i d patterns develop as a r e s u l t of 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 while some of the non-e s s e n t i a l amino a c i d s , such as g l y c i n e , increase. Ghadimi (67) found that i n f a 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 with a p r o t e i n hydrolysate had plasma amino ac i d patterns resembling the aminogram of c h i l d r e n s u f f e r i n g from kwashiorkor. The plasma aminograms of i n f a n t s infused with Vamin, in t h i s study, were d i f f e r e n t than those found by Ghadimi (67). Plasma g l y c i n e concentrations were not elevated and the branched-chain amino acids as a group were not decreased. Va1ine:g1ycine r a t i o s , Table 13, were found to be s i g n i f i c a n t l y greater than the values associated w i t h kwashiorkor (146), (va1ine:g1ycine = 0.18 - 0.06). No c l i n i c a l evidence of m a l n u t r i t i o n was seen in terms of weight gain, head circumference and body length measurements. Weight gain 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) during s t a b i l i z e d periods of t o t a l parenteral n u t r i t i o n . Body length and head circumference 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 presented in the present study support the theory that adequate q u a n t i t i e s of p r o t e i n are being infused. The lack of elevated methionine and t y r o s i n e l e v e l s i n d i c a t e that an excess of p r o t e i n i s not being infused. In the absence of any evidence of problems in the urea c y c l e the most l i k e l y explanation f o r the lowered 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 l e v e l s i s one that r e l a t e s urea l e v e l s to p r o t e i n intake or to amino a c i d turnover. As discussed above, there is no evidence f o r a p r o t e i n intake that i s so low as to cause even mild biochemical or c l i n i c a l symptoms of p r o t e i n d e f i c i e n c y . It seems that there is hi g h l y e f f i c i e n t u t i l i z a t i o n of intravenously infused amino acids f o r synthesis of body p r o t e i n s . This is f u r t h e r s u b s t a n t i a t e d by the f a c t that amounts of t y r o s i n e and methionine s u b s t a n t i a l l y in excess of what i s required f o r p r o t e i n synthesis would cause e l e v a t i o n s of these s p e c i f i c amino acids in plasma because t h e i r key metabolic enzymes develop l a t e in f e t a l l i f e (20,33,34,93). Parahydroxy pyruvic a c i d oxidase, and cystathionase are known to be rate l i m i t i n g in premature i n f a n t s so that increased catabolism of p r o t e i n leads to e l e v a t i o n s of the substrates of these enzymes. Snyderman e_t aj_. , (95) showed increased plasma l e v e l s of methionine with high p r o t e i n intakes. Rassin e_t aj_. , (138) observed elevated t y r o s i n e l e v e l s in i n f a n t s 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 that there i s l i t t l e use of the carbon skeleton of most of the amino acids f o r energy purposes. This i s p o s s i b l e because much of the i n f a n t ' s c a l o r i c needs are met in 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 high as blood sugars in the i n f a n t s fed i n t r a -venously are u s u a l l y in a normoglycemic or higher range. I n s u l i n is one of the major hormones responsible f o r the uptake of amino acids by muscle. The data that point to the use of amino acids f o r p r o t e i n synthesis and not catabolism are: lowered l e v e l s of urea and most amino , a c i d s , and the absence of e l e v a t i o n s in t y r o s i n e and methionine. It appears, then, that intravenously fed i n f a n t s are e f f i c i e n t l y s y n t h e s i z i n g body p r o t e i n , or at the very l e a s t are not using t h e i r amino acids f o r energy purposes. The above theory can be f u r t h e r substantiated i f one looks at 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 supplied to the i n f a 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 . Hendry e_t a_l_. , (155) suggest that premature i n f a n t s infused with Vamin should receive an average ki1 oca 1 o r i e : n i t r o g e n r a t i o of 2k5- Their p a t i e n t s received a range of 204-534. The i n f a n t s in t h i s study were r e c e i v i n g an average of 336 ki1 oca 1 or i e s : 1 g nitrogen/day. The design of t h i s study d i d not a l l o w us to determine an optimal k i l o c a l o r i e : n i t r o g e n r a t i o . Only s i x i n f a n t s received t o t a l parenteral n u t r i t i o n f o r a s u f f i c i e n t length of time to adequately judge t h e i r growth. The ki1 oca 1 o r i e : n i t r o g e n r a t i o achieved seems to have been adequate f o r normal growth. One i n f a n t showed how growth rate was impaired 80 in the presence of severe i n f e c t i o n (Patient 6). Thus, n u t r i t i o n a l needs may vary f o r i n d i v i d u a l i n f a n t s . The mean and range values 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 during t h i s study (mean=336, range-207~402) compare favourably with those found by Hendry et a 1. , (155), (mean=245, range=2itO-53iO . The increased k i l o c a l o r i e : n i trogen r a t i o observed in the present 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 of amino acids observed in intravenously fed i n f a n t s . D. RECOMMENDATIONS Based on the r e l a t i v e l y elevated plasma concentration of phenylalanine found in the intravenously fed infants in t h i s study, i t i s recommended that the optimal amount of phenylalanine in Vamin should be e s t a b l i s h e d . Although the observed plasma concentrations of phenylalanine do not reach the dangerous l e v e l of 1.21 /jm/ml seen in p a t i e n t s w i t h phenylketonuria, r e l a t i v e l y elevated plasma l e v e l s of phenylalanine over long periods of time could p o t e n t i a l l y be harmful. R e l a t i v e l y low plasma l e v e l s of methionine and t y r o s i n e seen in the i n f a n t s r e c e i v i n g t o t a l parenteral n u t r i t i o n seem to i n d i c a t e that more p r o t e i n could be fed without c r e a t i n g an abnormal plasma amino a c i d p a t t e r n . Infants maintained on the n u t r i t i o n a l regime o u t l i n e d in Table 2 may w e l l b e n e f i t from an increase of p r o t e i n intake to approximately 3 g/kg body weight/day, as has been suggested by Hendry et_ a_l_. , (155), should be the subject of 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. P e d i a t r i c s . Boston: L i t t l e Brown & Co., 1969, p.165-2. Dietary Standard f o r Canada, Bureau of N u t r i t i o n a l Sciences, Health P r o t e c t i o n Branch, Department of National Health and Welfare, Ottawa, Information Canada, 1975-3. A l f i n - S l a t e r , R.B., and J e l l i f e , D.B. N u t r i t i o n a l requirements. P e d i a t r . C l i n . N o r t h Am. 24 : 3 , 1977. 4. Kopple, J.D., and Swendseid, M.E. Evidence that h i s t i d i n e i s an e s s e n t i a l amino a c i d in normal and c h r o n i c a l l y uremic man. J. C l i n . Invest. 55:881, 1975-5. Wixom, R.L., Anderson, H.L., Terry, B.E., and Sheng, Y.B. Total parenteral n u t r i t i o n w i t h s e l e c t i v e h i s t i d i n e d e p l e t i o n in man. 1. Responses in nitrogen metabolism and r e l a t e d areas. Am. J . C l i n . Nutr. 30:877, 1977. 6. Rose, W.C., Haines, W.J., Warner, D.T., and Johnson, J.G. The amino a c i d requirements of man. I I . The r o l e of threonine and h i s t i d i n e . J . B i o l . Chem. 188:49, 1951-7. H o l t , L.G., and Snyderman, S.E. The amino a c i d requirements of i n f a n t s . J . Am. Med. Assoc. 175:100, 1961. 8. Snyderman, S.W., Prose, D.H., and Ho l t , J.E. H i s t i d i n e , an e s s e n t i a l amino a c i d f o r the i n f a n t . AMAJ Dis. C h i l d . 98:459, 1959-9. Raiha, N.C.R. and Kekomaki, M. Developmental aspects of amino a c i d metabolism in the human. In: Total Parenteral N u t r i t i o n . Edited by H. Ghadimi. New York: John Wiley and Sons, 1975, p.199-10. W r e t l i n d , A. Amino a c i d s . In: Parenteral N u t r i t i o n in Acute Metabolic I l l n e s s . Edited by H. A. Lee. New York: Academic Press, 1974, p.53-11. Heird, W.C., and Winters, R.W. Total parenteral n u t r i t i o n : the s t a t e of the a r t . J . P e d i a t r . 86:2, 1975-12. Snyderman, S.W., Boyer, A., Roitman, E., Ho l t , L.E., and Prose, P.H. The h i s t i d i n e requirement of the i n f a n t . P e d i a t r i c s 31:786, 1963. 13- Avery, G.B. Growth f a i l u r e in s i c k prematures, In: Intensive Care of The Newborn. Edited by L. Stern, B. Fri i s - H a n s e n , and P. Kildeb e r g . New York: Masson, 1976, p.23-14. Fomon, S.J., Z i e g l e r , E.E., and O'Donnell, A.M. Infant feeding in health and disease. In: Infant N u t r i t i o n . Edited by B.J. Fomon. P h i l a d e l p h i a : W. B. Saunders, 1974, p.472. 82 15- Heird, W.C., D r i s c o l l , J.M., S c h u l l i n g e r , J.N., Grebin, B., and Winters, R.W. Intravenous a l i m e n t a t i o n in p e d i a t r i c p a t i e n t s . J , P e d i a t r . 80:352, 1972. 16. Widdowson, G. Changes in body proportions and composition during growth. In: S c i e n t i f i c Foundations of P e d i a t r i c s . Edited by J. A. Davis and J . Dobbing. London: Wm. Heinemann Medical Books Ltd . , 1974, p.153-17- Krauss, A.N., and Auld, P.A.M., Metabolic requirements of low-birth-weight i n f a n t s . J . P e d i a t r . 75:952, 1969. 18. Committee on N u t r i t i o n : N u t r i t i o n a l needs of low-birth-weight i n f a n t s . P e d i a t r i c s 60:519, 1977. 19. Snyderman, S.E., The p r o t e i n and amino a c i d requirements of the premature i n f a n t , In: Metabolic Processes in the Foetus and Newborn Infant. Edited by J . H. P. J o n x i s , H. K. A. V i s s e r , and J . A. T r o e l s t r a . Leidin:H. E. Stenfer Kroeses, N.J., 1971, p.128. 20. Snyderman, S.E., Boyer, A., Kogut, M.D., and H o l t , L.E. The p r o t e i n requirement of the premature i n f a n t . I. The e f f e c t of p r o t e i n intake on the r e t e n t i o n of nitrogen. J . P e d i a t r . 74:872, 1969-21. H e i r d , W.C., MacMillan, R.W., and Winters, R.W. Total parenteral n u t r i t i o n in the p e d i a t r i c p a t i e n t , In: Total Parenteral N u t r i t i o n . Edited by J . E. F i s c h e r . B o s t o n : L i t t l e , Brown & Co., 1976, p.253-22. Green, H.L. Trace elements and vitamins. In: Intravenous N u t r i t i o n in the High Risk Infant. Edited by R. W. Winters and E. G. Hasselmeyer. New York: John Wiley and Sons, 1975, p.273. 23. RSiha, N.C.R. P r o t e i n and the preterm i n f a n t . In: Intensive Care of The Newborn. Edited by L. Stern, B. Fr i i s - H a n s e n , P. Kilde b e r g . New York: Masson, 1976, p.35. 24. Gordon, H.H., Levine, S.Z., and McNamara, H. Feeding of premature i n f a n t s . Am. J . Dis. C h i l d . 73:442, 1947-25. Omans, W.B., Barness, L.A., Rose, C.S., and Gyorgy, P. Prolonged feeding studies in premature i n f a n t s . J . P e d i a t r . 59:951, 1961. 26. Crosse, V.M., Hickmans, E.M., Hawarth, B.E., and Aubrey, J . The value of human mil k compared with other feeds f o r premature i n f a n t s . Arch. Dis. C h i l d . 29:178, 1954. 27. Kagan, B.M., Hess, J.H., Lundeen, G., Shafer, K., Parker, J.B., S tiga1 1 , C. Feeding of premature i n f a n t s - a comparison of various m i l k s . P e d i a t r i c s 15=373, 1975-28. Kagan, B.M., F e l i x , N., Molander, C.W., Busser, J.B., and Kalman, D. Body water changes in r e l a t i o n to n u t r i t i o n of premature i n f a n t s . Ann. NY Acad. S c i . 110:830, 1963-83 29. Kagan, B.M., Staniacoya, V., F e l i x , N,S., Hodgman, J . , and Kalman, D. Body composition of premature i n f a n t s : R e l a t i o n to n u t r i t i o n . Am. J . C l i n . Nutr. 25:1153, 1972. 30. Cavies, D.P. Adequacy of expressed breast milk f o r e a r l y growth of preterm i n f a n t s . Arch. Dis. C h i l d . 52:296, 1977-31. Fomon, S.J., Z i e g l e r , E.E., and Vaquez, H.D. Human milk and the small premature i n f a n t . Am. J . Dis. C h i l d . 131:463, 1977-32. Avery, G.B., and F l e t c h e r , A.B. N u t r i t i o n . In: Neonatology. Edited by G. B. Avery. P h i l a d e l p h i a : J . B. L i p p i n c o t t Co., 1975, p.839. 33- P a s c a l , T.A, G i l l a m , B.M., and Gaul 1 , CG. Cystath i onase: immunochemical evidence of absence from human f e t a l l i v e r . P e d i a t r . Res. 6:773, 1972. 34. G a u l l , G., Sturman, J.A., and Raiha, N.C.R. Development of mammalian s u l f u r metabolism; absence of cystathionase in human f e t a l t i s s u e s . P e d i a t r . Res. 6:538, 1972. 35. Pohlandt, F. Cystine: a semi-essentia 1 amino a c i d in the newborn i n f a n t . Acta. Paed. Scand. 63:801, 1974. 36. Jurgens, S.P., and D o l i f , D. Experimental r e s u l t s of parenteral n u t r i t i o n w i t h amino a c i d s . In: Parenteral N u t r i t i o n . Edited by A. W. Wil k i n s o n . Edinburgh: C h u r c h i l l L i v i n g s t o n e , 1972, p.47. 37. Raiha, N.C.R. Phenylalanine hydroxylase in human l i v e r during development. P e d i a t r . Res. 7:1, 1973. 38. Snyderman, S.E., Norton, P.M., Fowler, D.I., and H o l t , L.E. The e s s e n t i a l amino ac i d requirements of i n f a n t s : l y s i n e . AMAJ Dis. C h i l d . 97:175, 1959-39- Jakubovic, A. Phenylalanine hydroxylating system in the human fetus at d i f f e r e n t developmental ages. Biochem. Biophys. Acta. 237:469, 1971. 40. A l l e n , P.C H i s t o r i c a l review. In: A C l i n i c a l Guide to Intravenous N u t r i t i o n . Edited by P. C. A l l e n and H. A. Lee. Oxford: Blackwell S c i e n t i f i c P u b l i c a t i o n s , 1969, P. 1. 41. Sturman, J.A., Rassin, D.K., and G a u l l , G.E. Taurine in developing rat b r a i n t r a n s f e r of (35$) t a u r i n e to pups v i a the milk. P e d i a t r . Res. 11:28, 1977-42. Rigo, J . , and Senterre, J . Is ta u r i n e e s s e n t i a l f o r neonates? B i o l . Neonate. 32:73, 1977-43. Korones, S.B. High-Risk Newborn Infants. S t . L o u i s : C. V. Mosby Co., 1972, p.65. 84 44. Usher, R.H. The s p e c i a l problems of the premature i n f a n t . In: Neonatology. Edited by G. B. Avery. P h i l a d e l p h i a : J . B. L i p p i n c o t t Co., 1974, p.157. 45- Rhea, J.W., and K i l b y , J.D. A nasojejunal tube f o r i n f a n t feeding. P e d i a t r i c s 46 :36, 1970. 46. Cheek, J.A., and Staub, G.F. Nasojejunal a l i m e n t a t i o n f o r premature and f u l l term newborn i n f a n t s . J . P e d i a t r . 82:955, 1973-47. Vengusamy, S., P i l d e s , R.S., Raffensperger, J.F., Levine, H.D., and Cornblath, M. C o n t r o l l e d study of feeding gastrostomy in low-birth-weight i n f a n t s . P e d i a t r i c s 43:815, 1969. 48. Lee, H.A. H i s t o r i c a l review of parenteral n u t r i t i o n . In: Parenteral N u t r i t i o n in Acute Metabolic I l l n e s s . Edited by H. A. Lee. London: Academic Press, 1974, p.3. 49. W i l k i n s o n , A.W. H i s t o r i c a l background of intravenous feeding. Nutr. Diet. 5:295, 1963. 50. W r e t l i n d , A. Fat emulsions. In: Parenteral N u t r i t i o n in Acute Metabolic I l l n e s s . Edited by H. A. Lee. London: Academic Press, 1974, p.77. 51. W r e t l i n d , A. Complete intravenous n u t r i t i o n : t h e o r e t i c a l and experimental background. Nutr. Metab. 14, Supp .1 , 1972. 52. Elman, R. Parenteral A l i m e n t a t i o n in Surgery. New York: Hoeber, 1945. 53- Dudrick, S.J., Vars, H.M., Rawnsley, H.M., and Rhoads, J.E. Total intravenous feeding and growth in puppies. Fed. Proc. 25:481, 1966. 54. Dudrick, S.J., Wilmore, D.W., Vars, H.M., and Rhoads, J.E. Can intravenous feedings as the s o l e means of n u t r i t i o n support growth in the c h i l d and restore weight loss in an adult? Ann. Surg. 169:974, 1969. 55. Gaul 1, G.E., Rassin, D.K., and Raiha, N.C.R. P r o t e i n intake of premature i n f a n t s ; a r e p l y . J . P e d i a t r . 90:507, 1977-56. G a u l l , G.E., Rassin, D.K., Raiha, N.C.R., and Heinon, K. M i l k p r o t e i n quantity and q u a l i t y in low-birth-weight i n f a n t s . I l l E f f e c t s on s u l f u r amino acids in plasma and u r i n e , J . P e d i a t r . 90:348, 1977. 57« Lorch, V., and Lay, S.A. Parenteral a l i m e n t a t i o n in the neonate. P e d i a t r . C l i n . North Am. 24 :547, 1977-58. Rosen, A.M. Types of s o l u t i o n s a v a i l a b l e . In: Total Parenteral N u t r i t i o n . Edited by J . E. F i s c h e r . Boston: L i t t l e Brown Co., 1976, p.15. 85 59. Long, C L . , Z i k r i a , B.A,, Kinney, J,M., and Geiger, J.W. Comparison of f i b r i n hydrolysates and 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 i n parenteral n u t r i t i o n . Am. J . C l i n . Nutr. 27:163, 1974. 60. Stegink, L.D., and Baker, G.L. Infusion of p r o t e i n hydrolysates in the new born i n f a n t : plasma amino aci d. concentrat i:on. J . P e d i a t r . 78:595, 1971. 61. Ghadimi, H., Abaci, F., Kumar, S., and Rathi , M. Biochemical aspects of intravenous a l i m e n t a t i o n . P e d i a t r i c s 48 :955, 1971. 62. Ghadimi, H., and Kumar, S. High ammonia content of p r o t e i n hydrolysate. Biochem. Med. 5:548, 1971. 63- Cockburn, F o r r e s t e r . Parenteral n u t r i t i o n in the newborn. B r i t i s h J . of Hosp. Med. 18:191, 1977-64. Dudrick, S.J., MacFadyen, B.V., VanBuren, C.T., Ruberg, R.L., and Maynard, A.T. Parenteral hyperalimentation, metabolic problems and s o l u t i o n s . Ann. Surg. 176:259, 1972. 65. Johnson, J.D., A l b r i t t o n , W.L., and Sunshine, P. Hyperammonemia accompanying parenteral n u t r i t i o n in newborn i n f a n t s . J . P e d i a t r . 81:154, 1972. 66. Higgs, S.C, Malan, A.F., and De V.Heise, H. A study of the plasma f r e e amino acids in infa n t s of low-birth-weight, w i t h a comparison of o r a l feeding with milk and t o t a l parenteral n u t r i t i o n . S. A f r . Med. J . 51 :6 , 1977-67- Ghadimi, H. Conventional amino a c i d s o l u t i o n s f o r parenteral use. In: Total Parenteral N u t r i t i o n . Edited by H. Ghadimi. New York: John Wiley and Sons, 1975, p.373. 68. Doolan, P.D., Harper, H.A., Hutchin, M.G., and Alpen, E.L. The renal tubular response to amino a c i d loading. J . C l i n . Invest. 35:888, 1956. 69. Harper, H.A., Naj a r i a n , J.S., and S i t e n , W. E f f e c t of intravenously administered amino acids on blood ammonia. Proc. Soc. Exper. B i o l . Med. 92:558, 1956. 70. Ghadimi, H., Kumar, S., and Abaci, F. Studies on monosodium glutamate i n g e s t i o n . I. Biochemical explanation of Chinese Restaurant Syndrome. Biochem. Med. 5:447, 1971-71. Olney, J.W., and Ho, O.L. Brain damage in inf a n t mice f o l l o w i n g o r a l intake of glutamate, aspartate or c y s t e i n e . Nature 227:609, 1970. 86 72. Olney, J.W., Ho, O.L., and Rhee, V. Brain damaging p o t e n t i a l of p r o t e i n hydrolysates, N. Engl. J . Med. 289:391, 1973. 73- Heird, W.C., Nicholson, J.F., D r i s c o l l , J.M., S c h u l l i n g e r , J.N., and Winters, R.W. Hyperammonemia r e s u l t i n g from intravenous a l i m e n t a t i o n using a mixture of s y n t h e t i c L-amino a c i d s : A pr e l i m i n a r y report. J . P e d i a t r . 81:162, 1972. 74. Harper, A.E. Amino a c i d requirements and plasma amino a c i d s . In: P r o t e i n N u t r i t i o n . Edited by H. Brown. S p r i n g i e l d : Charles C. Thomas, 1974, p.130. 75- A l v e a r , D.T., and Somers, L.A. Parenteral n u t r i t i o n in s e r i o u s l y i l l neonates, search f o r the ideal mixture. Am. J . Surg. 127:696, 1974. 76. Chan, J.C.M. The inf l u e n c e of s y n t h e t i c amino a c i d and casein hydrolysate on the endogenous production and uri n a r y e x c r e t i o n of a c i d in t o t a l intravenous a l i m e n t a t i o n . P e d i a t r . Res. 6:789, 1972. 77- Heird, W.C., D e l l , R.B., D r i s c o l l , J.M., Grebin.B., and Winters, R.W. Metabolic a c i d o s i s r e s u l t i n g from intravenous a l i m e n t a t i o n mixtures containing s y n t h e t i c amino a c i d s . N. Engl. J . Med. 287:943, 1972. 78. Bessman, S.P. Genetic f a i l u r e of f e t a l amino acids " J u s t i f i c a t i o n " , a common basis f o r many forms of metabolic n u t r i t i o n a l and "non s p e c i f i c " mental r e t a r d a t i o n . J . P e d i a t r . 81:834, 1972. 79- Borresen, H.C. C l i n i c a l a p p l i c a t i o n s in p e d i a t r i c surgery and p e d i a t r i c s . In: Parenteral N u t r i t i o n in Acute Metabolic I l l n e s s . Edited by H. A. Lee. London: Academic Press, 1974, p.221. 80. Peden, V.U., Karp e l , J.T. Total parenteral n u t r i t o n in premature i n f a n t s . J . P e d i a t r . 81:137, 1972. 81. Heird, W.C., D r i s c o l l , J.M., and Winters, R.W. Total intravenous n u t r i t i o n in p e d i a t r i c s . In: The Body F l u i d s in P e d i a t r i c s . Edited by R. W. Winter. Boston: L i t t l e Brown and Co., 1973, p.665. 82. P i l d e s , R.S., Ramamurthy, R.S., Cordero G.V., and Wong, P.W.K. Intravenous supplementation of L-amino acids and dextrose in low-birth-weight i n f a n t s . J . P e d i a t r . 82:945, 1973-83. F i l l e r , R.M. and Coran, A.G. Total parenteral n u t r i t i o n in i n f a n t s and c h i l d r e n : Central and peri p h e r a l approaches. Surg. C l i n . North Am. 56:395, 1976. 84. Winters, R.W. Total parenteral n u t r i t i o n in p e d i a t r i c s : the Borden Award Address. P e d i a t r i c s 56:17, 1975. 87 85. Dobbing, J . Und e r n u t r i t i o n and the developing b r a i n . Am. J . Dis. C h i l d . 120:411, 1970. 86. Winick, M. and Rosso, R. The e f f e c t of severe e a r l y m a l n u t r i t i o n on c e l l u l a r growth of human b r a i n . P e d i a t r . Res. 3:181 , 1969. 87. Winick, M. M a l n u t r i t i o n and bra i n development. J . P e d i a t r . 74:667, 1969. 88. Benda, G.I.M. and Babson, S.G. Peri p h e r a l intravenous a l i m e n t a t i o n of the small premature i n f a n t . J . P e d i a t r . 79=3, 1971. 89. D r i s c o l l , J.M., He i r d , W.C., S c h u l l i n g e r , J.N., Gongaware, R.D., and Winters, R.W. Total intravenous a l i m e n t a t i o n in l o w - b i r t h -weight i n f a n t s : a p r e l i m i n a r y report. J . P e d i a t r . 81:145, 1972. 90. Meng, H.C, Stahlman, M.T., Otten, A., Dolanski, E.A., C a l d w e l l , M.D., and O ' N e i l l , J.A. The use of c r y s t a l l i n e amino a c i d mixture f o r parenteral n u t r i t i o n in low-birth-weight i n f a n t s . P e d i a t r i c s 59:699, 1977. 91. G r o t t e , G., Jacobson, S., and W r e t l i n d , A. L i p i d emulsions and technique of peri p h e r a l a d m i n i s t r a t i o n in parenteral n u t r i t i o n . In: Total Parenteral N u t r i t i o n . Edited by J . E. F i s c h e r . Boston: L i t t l e Brown and Co., 1976, p.335-92. Coran, A.G. Total intravenous feeding of in f a n t s and c h i l d r e n without the use of a c e n t r a l venous c a t h e t e r . Ann. Surg. 179:445, 1974. 93- Pendray, M.R. Per i phera 1 ve i n If eed i ng in 44 i n f a n t s under 3i months of age. In: Proceedings of the I n t e r n a t i o n a l Congress of Parenteral N u t r i t i o n . Edited by C. Romieu, C. S o l a s s o l , H. Joyeux, and B. Astruc. M o n t p e l l i e r : U n i v e r s i t y of M o n t p e l l i e r , 1974, p.789-94. Munro, H.N. Free amino a c i d pools and t h e i r r o l e in r e g u l a t i o n . In: Mammalian P r o t e i n Metabolism. Edited by H. N. Munro. New York: Academic Press, 1970, V o l . IV, p.299. 95- Snyderman, S.E., H o l t , L.E., Norton, P.M., Roitman, E., and Phansalkar, S.V. The plasma aminogram, I. Influence of the l e v e l of p r o t e i n intake and a comparison of whole p r o t e i n and amino a c i d d i e t s . P e d i a t r . Res. 2:131, 1968. 96. F i l e r , L.J., Stegink, L.D., and Chandramouli, B. E f f e c t of d i e t on plasma aminograms of low-birth-weight i n f a n t s . Am. J . C l i n . Nutr. 30:1036, 1977-97- A d i b i , S.A. and Mercer, D.W, P r o t e i n d i g e s t i o n in human i n t e s t i n e as r e f l e c t e d in luminal, mucosal and plasma amino a c i d concentrations a f t e r meals. J . C l i n . Invest. 52:1586, 1973. 98. Elwyn, D. The r o l e of the l i v e r in r e g u l a t i o n of amino a c i d and p r o t e i n metabolism. In: Mammalian P r o t e i n Metabolism. Edited by H. N. Munro. New York: Academic Press, 1970, V o l . IV, p.523-88 99- Munro, H.N. Basic concepts in the use of amino acids and p r o t e i n hydrolysates f o r parenteral n u t r i t i o n . Drug I n t e l l i g e n c e S C l i n i c a l Pharmacy 6:216, 1972. 100. MacLean, W.C., Placko, R.P., and Graham, G.G. Post prandial plasma l y s i n e as an i n d i c a t o r of d i e t a r y l y s i n e adequacy in i n f a n t s . J . Nutr. 107:567, 1977-101. Elwyn, D.H. and Greenstein, A.J. A c r i t i q u e of parenteral a l i m e n t a t i o n with respect to amino a c i d metabolism. Am. J . Gast r o e n t e r o l . 58:242, 1972. 102. Stegink, L.D. Amino a c i d metabolism. In: Intravenous N u t r i t i o n in the High Risk Infant. Edited by R. W. Winters and E. G. Hasselmeyer. New York: John Wiley and Sons, 1975, p .181. 103- Stegink, L.D. and Baker, G.L. Infusion of p r o t e i n hydrolysates in the newborn i n f a n t : plasma amino a c i d concentrations. J . P e d i a t r . 78:595, 1971 . 104. Anderson, G.H., Bryan, H., Jeejeebhoy, K.N., and Corey, P. Dose response r e l a t i o n s h i p s between amino a c i d intake and blood l e v e l s in newborn i n f a n t s . Am. J . C l i n . Nutr. 30:1110, 1977-105. Dale, G., Pa n t e r - B r i c k , M., Wagget, J . , and Young, G. Plasma amino acid changes in the p o s t - s u r g i c a l newborn during intravenous n u t r i t i o n with a s y n t h e t i c amino a c i d s o l u t i o n . J . P e d i a t r ; Surg. 11:17, 1976. 106. Settegren, G., Lindblad, B.S., and Persson, B. Cerebral blood flow and exchange of oxygen, glucose, ketone bodies, l a c t a t e , pyruvate and amino acids in i n f a n t s . Acta. P e d i a t r . Scand. 65:343, 1976. 107- Harper, A.G. Amino a c i d t o x i c i t i e s and imbalances. In: Mammalian P r o t e i n Metabolism. Edited by H. N. Munro. New York: Academic Press, 1964, V o l . I I , p.87. 108. Lindblad, B.S., Sett e r g r e n , G., Feychting, H., and Persson, B. Total parenteral n u t r i t i o n in i n f a n t s . Acta. P e d i a t r . Scand. 66:409, 1977-109- H o l t , L.E., Snyderman, S.E., Norton, P.M., Roitman, E., and Finch, J . , The plasma aminogram in kwashiorkor. Lancet 11:1343, 1943-110. Lindblad, B.S. The plasma aminogram in "Small f o r dates" newborn i n f a n t s . In: Metabolic Processes in the Foetus and Newborn Infant. Edited by J . H. P. J o n x i s , H. K. A. V i s s e r , and J . A. T r o e l s t r a . Leiden: H. E. S t e n f e r t , N.V., 1971, p.111. 111. Whitehead, R.G. and Dean, R.F.A. Serum amino acids in kwashiorkor, I. R e l a t i o n s h i p to c l i n i c a l c o n d i t i o n . Am. J . C l i n . Nutr. 14:313, 1964. 89 112. Whitehead, R.G, and Dean, R.F.A. Serum amino acids in kwashiorkor, I I . An abbreviated method of esti m a t i o n and i t s a p p l i c a t i o n . Am. J . C l i n . Nutr. 14:320, 1964. 113. Snyderman, S.E., Ho l t , L.E., Norton, P.M., and Phansalkar, S.V. Pr o t e i n requirement of the premature i n f a n t , I I . Influence of p r o t e i n intake on fr e e amino a c i d content of plasma and red blood c e l l s . Am. J . C l i n . Nutr. 23:890, 1970. 114. Chen, W.J., Ohashi, E., and Kasai, M. Amino a c i d metabolism in parenteral n u t r i t i o n : with s p e c i a l reference to the c a l o r i c : n i t r o g e n r a t i o and the blood urea nitrogen l e v e l . Metabolism 23:1117* 1974. 115. O ' N e i l l , J.A., Meng, H.C., C a l d w e l l , M.C, Stahlman, M.T. Metabolic e v a l u a t i o n of s y n t h e t i c amino a c i d mixture f o r parenteral n u t r i t i o n in in f a n t s and c h i l d r e n . J . P e d i a t r . Surg. 11:979, 1976. 116. Lubchenco, L.O., Hansman, C , D r e s s i e r , M., and Boyd, E. I n t r a -u t e r i n e growth as estimated from l i v e b o r n birth-weight data at 24 to 42 weeks of g e s t a t i o n . P e d i a t r i c s 32:793, 1963-117. Lubchenco, L.O., Hansman, C , and Boyd, E. I n t r a u t e r i n e growth in length and head circumference as estimated from l i v e b i r t h s at g e t a t i o n a l ages from 26 to 42 weeks. P e d i a t r i c s 37:403, 1966. 118. Davidson, M., Levine, S.Z., Bauer, CH., and Dann, M. Feeding studies in low-birth-weight i n f a n t s . J , P e d i a t r . 79:695, 1967-119. Davidson, M. The feeding of prematurely born i n f a n t s - a c r i t i q u e of current s t u d i e s . J . P e d i a t r . 57:604, i960. 120. H o l t , L.E. The p r o t e i n requirement of i n f a n t s . J . P e d i a t r . 54:496, 1959-121. Peaston, M.J.T. Maintenance of metabolism during i n t e n s i v e p a t i e n t care. Postgrad. Med. J . 43:317, 1967-122. Lee, H.A., Sharpstone, P., and Ames, A.C Parenteral n u t r i t i o n in renal f a i l u r e . Postgrad. Med. J . 43:81, 1967-123. Johnston, I.D.A., Tweedle, D. , and Spivey, J . Intravenous feeding a f t e r s u r g i c a l operation. In: Parenteral N u t r i t i o n . Edited by A. W. Wilk i n s o n . Edinburgh: C h u r c h i l l L i v i n g s t o n , 1972, p.189. 124. Rose, W.C, Coon, M.J., and Lambert, G.F. The amino a c i d r e q u i r e -ment of man, VI. The r o l e of the c a l o r i c intake. J . B i o l . Chem. 210:331, 1954. 125. Cashore, W.J.., Sedaghatian, M.R., and Usher, R.H. N u t r i t i o n a l supplements with intravenously administered l i p i d , p r o t e i n hydro-l y s a t e , and glucose in small premature i n f a n t s . P e d i a t r i c s 56:8, 1975-126. Usher, R. and McLean, F. I n t r a u t e r i n e growth of l i v e b o r n Caucasian i n f a n t s at sea l e v e l . J . P e d i a t r . 74:901, 1969-90 127- Babson, S.G. Growth of low-birth-weight i n f a n t s . J . P e d i a t r . 77:11, 1970. 128. Berry, H.K. Plasma amino a c i d s . In: Newer Methods of N u t r i t i o n a l Biochemistry. Edited by A. A. Albanese. New York: Academic Press, 1970, p.79-129. F e l i g , P. Recent developments in body f u e l metabolism. In: This Year in Metabolism. Edited by N. F r e i n k e l . New York: Plenum Pub. , 1977, p.113-130. Pohlandt, F. Plasma amino a c i d concentrations in newborn i n f a n t s breast-fed ad l i b i t u m . J . P e d i a t r . 92:614, 1978. 131- Armstrong, M.D. and Stawe, U. A study of plasma f r e e amino a c i d l e v e l s I I . Normal values for c h i l d r e n and a d u l t s . Metabolism 22:561, 1973-132. Przyrembel, H., Leupold, D., Tosberg, P., and Bremer, H.J. Amino a c i d e x c r e t i o n of premature i n f a n t s r e c e i v i n g d i f f e r e n t amounts of p r o t e i n . C1in.Chim.Acta. 49:17, 1973-133- Graham, G.G. and Placko, R.P. Fasting plasma free amino acids of i n f a n t s on milk p r o t e i n d i e t s . John Hopkins Med. J. 126:19, 1970. 134. Dickinson, J.C., Rosenblum, H., and Hamilton, P.B. Ion exchange chromatography of the free amino acids in the plasma of in f a n t s under 2500 g at b i r t h . P e d i a t r i c s 45:606, 1969-135- Dickinson, J.C., Rosenblum, H., Hamilton, P.B. Ion exchange chromatography of the fr e e amino acids in the plasma of the newborn i n f a n t . P e d i a t r i c s 36:2, 1965-136. Armstrong, M.D. and Stawe, U. A study of plasma f r e e amino a c i d l e v e l s I I I . V a r i a t i o n s during growth and aging. Metabolism 22:571, 1973-137- Holmgren, G. E f f e c t of low, normal and high d i e t a r y p r o t e i n intake on ur i n a r y amino a c i d e x c r e t i o n and plasma aminogram in c h i l d r e n . Nutr. Metab. 16:223, 1974. 138. Rassin, D.K., G a u l l , G.E., Raiha, N.C.R., and Heinonen, K. Milk p r o t e i n quantity and q u a l i t y in low-birth-weight i n f a n t s . J . P e d i a t r . 90:356, 1977-139- Davies, D.P. and Saunders, R. Blood urea, normal values in e a r l y infancy r e l a t e d to feeding p r a c t i c e s . Arch. Dis. C h i l d . 48:563, 1973-140. Ghadimi, H., Iyer, L.B., and Desai, L. Total parenteral n u t r i t i o n f o r prevention of r e s p i r a t o r y d i s t r e s s syndrome. In: Total Parenteral N u t r i t i o n . Edited by H. Ghadimi. New York: John Wiley and Sons, 1975, p-543-91 141. Ghadimi, H., and Abaci, F. C l i n i c a l experience with GF s o l u t i o n s in c h i l d r e n and a d u l t s . In: Total Parenteral N u t r i t i o n . Edited by H. Ghadimi. New York: John Wiley and Sons, 1975, p.577. 142. Hollerman, C.E., Jose, P., and Calcagno, P.L. Renal diseases. In: Neonatology. Edited by G. B. Avery. P h i l a d e l p h i a : J.B. L i p p i n c o t t Co., 1975, p.487. 143- Raiha, N.C.R., and Suihkonen, J . Development of urea s y n t h e s i z i n g enzymes in human l i v e r . Acta. P e d i a t r . Scand. 57:121, 1968. 144. Batshaw, M.L. , and Brusilow, S.W. A symptomatic hyperammonemia in low-birth-weight i n f a n t s . P e d i a t r , Res. 12:221, 1978. 145. Perry, T.L., Hansen, S. and MacLean, J . Cerebrospinal f l u i d and plasma glutamine e l e v a t i o n by anticonvulsant drugs; a p o t e n t i a l d i a g n o s t i c and therapeutic trap. C l i n . Chim. Acta. 69:441, 1976. 146. Arroyave, G. Comparative s e n s i t i v i t y of s p e c i f i c amino a c i d r a t i o s versus " e s s e n t i a l to n o n e s s e n t i a l " amino a c i d r a t i o . Am. J . C l i n . Nutr. 23:703, 1970. 147. Perry, T.L. and Hansen, S. Technical p i t f a l l s leading to e r r o r s in the q u a n t i t a t i o n of plasma amino a c i d s . C l i n e . Chim. Acta. 25:53, 1969-148. Lee, P.L.Y. Single-column system f o r a c c e l e r a t e d amino a c i d a n a l y s i s of p h y s i o l o g i c a l f l u i d s using f i v e l i t h i u m b u f f e r s . Biochem. Med. 10:107, 1974. 149. Eastoe, J.E. Amino a c i d a n a l y s i s of g l y c o p r o t e i n s . In: Glycoproteins. Edited by A. Gottschalk. Amsterdam:E1sevier P u b l i s h i n g Co., 1966, p.112. 150. F e l i g , P., and Wahren, J . Pr o t e i n turnover and amino a c i d metabolism in the r e g u l a t i o n of g1uconeogenesis. Federation Proc. 33:1092, 1974. 151. Hendry, P.G., James, B.E., MacMahon, R.A. Nitrogen balance st u d i e s during o r a l and complete intravenous feeding of small premature i n f a n t s . Aust. P a e d i a t r . J . 14 :6 , 1978. 152. Dubowitz, L.M.S. and Dubowitz, V. (eds.) Gestational Age of the Newborn. London:Addison-Wes1ey P u b l i s h i n g Co., 1977-153. Soupart, P. Free amino a c i d pools of blood and ur i n e . In: Amino Acids. Edited by J.T.Holden. Amsterdam:E1sevier P u b l i s h i n g Co., I962, p.220. 154. Shaw, P.L.G., Kellerman, G.M., MacMahon, R.A., and James, B.E. Studies of amino a c i d metabolism in small premature i n f a n t s fed intravenously on Vamin-based s o l u t i o n s and o r a l l y on milk. Aust. Paediatr. J. 13:71, 1977-92 Hendry, P.G., James, B.E., and MacMahon, R.A. Nitrogen balance studies during o r a l and complete intravenous feeding of small premature i n f a n t s . Aust. Paediatr. J . 14 :6 , 1978. Shaw, J.C.L. Parenteral n u t r i t i o n in the management of s i c k low birthweight i n f a n t s . P e d i a t r . C l i n . North Amer. 29:333, 1973-Fraser, G.C., Simpson, W., Pendray, M., and Da i l e y , C. S u r g i c a l treatment of congenital defects in the abdominal w a l l . Am. Surg. 42:474, 1976. Moore, F.D. Metabolic Care of the Su 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. Heird, W.C. and Winters, R.W. Some metabolic aspects of t o t a l p arenteral n u t r i t i o n in s u r g i c a l neonates. In': Proceeding of the Int e r n a t i o n a l Congress of Parenteral N u t r i t i o n . Edited by, C. Romieu, C. S o l a s s o l , H. Joyeau and B. Astruc. M o n t p e l l i e r : U n i v e r s i t y of 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 of head growth in pre-term i n f a n t s . I. Normal rates of head growth. Dev. Med. Chi Id Neurol. 17:705, 1975-Sher, P.K., and Brown, S.B. A l o n g i t u d i n a l study of 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 hydrocephalus. Dev. Med. C h i l d Neurol. 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 babies are unable to t o l e r a t e milk feeding and must be fed intravenously. There are a few amino a c i d (protein) s o l u t i o n s a v a i l a b l e which help us to do t h i s . These are very valuable s o l u t i o n s but we are uncertain as to whether t h e i r composition could be improved. We want to review t h i s but do not know the amino aci d l e v e l s in the blood of normal premature babies. We need these values for comparison with i n f a n t s being fed amino acids intravenously to assess whether the amino a c i d mixture used could be improved. To do t h i s we need a small sample of blood from normal premature i n f a n t s r e c e i v i n g milk. In order to 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 the heel of an in f a n t and c o l l e c t s a small amount of blood two hours a f t e r one feed. This sample w i l l be analyzed by a s p e c i a l instrument in the laboratory to give us p r e c i s e l e v e l s f o r each amino a c i d in the blood. There are no problems associated with t h i s technique except that the baby requires a small p r i c k in the heel in order to c o l l e c t the blood. If anything, unusual is found the doctor and parents of the baby w i l l be informed. W i l l you agree to allow us to use your baby f o r e s t a b l i s h i n g normal values? You can refuse now or at any time in the f u t u r e . This w i l l not jeo p a r d i z e your i n f a n t ' s care. APPENDIX C: PARENTERAL NUTRITION FLOW CHART V A N C O U V E R G E N E R A L H O S P I T A L PARENTERAL NUTRITION FLOW CHART FLUID BALANCE AND NUTRITIONAL INTAKE DATE: WEIGHT: INTAKE Oral Intravenous - Amino Acid Mixture -Intralipid TOTAL OUTPUT Urine Stool TOTAL Calories f rom Amino Acid Mixture Calories from Intra!ipid Calories f rom 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 kilo-gmm p^ r 24 hours" Nitrogen Intake per 24 hours Nitrogen Excretion per 24 hours Nitrogen Balance LABORATORY INVESTIGATIONS DATE TIME Haemoglobin White Cell Count Differential Plat©let« Sodium Potassium Chloride Bicarbonate PH PC02 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 OF NUTRIENTS SOLUTION 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 APPENDIX D; INTRAUTERINE GROWTH CHARTS FOR EACH STUDY INFANT 99 V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y Patient 1 I N T R A U T E R I N E GROWTH C H A R T 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 40 41 4 2 4 3 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 43 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 WEEK OF GESTATION I 42 43 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 ( F R O M 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: 403, 19661 100 V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y I N T R A U T E R I N E G R O W T H C H A R T Patient 2 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 43 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 42 43 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 42 43 WEEK OF GESTATION 24 25 26 27 26 29 30 31 32 33 34 35 38 37 36 39 40 41 42 4 3 ' WEEK OF GESTATION ( F R O M 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: 403. 1 966> 101 V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y Patient 3 I N T R A U T E R I N E G R O W T H C H A R T ( F R O M 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: 403, 1966) 102 V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y Patient 4 I N T R A U T E R I N E GROWTH C H A R T 25 26 27 26 29 30 31 32 33 25 26 27 26 29 X 31 32 33343838 37 363940 41 24 25 26 27 26 29 30 31 32 33343538 37 3 6 3 9 4 0 4 WEEK OF GESTATION 242526 27 2 8 2 9 X 31 3233343538 37 363940 41 WEEK OF GESTATION ( F R O M 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: 403, 1966) 103 V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y I N T R A U T E R I N E G R O W T H C H A R T Patient 5 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 2 4 2 5 2 8 2 7 2 6 2 8 3 0 31 32 3 3 3 4 3 6 3 8 37 3 6 3 9 4 0 41 42 43 25 28 27 28 28 30 31 32 3 3 3 4 3 5 3 8 37 3 6 3 8 4 0 4 WEEK Of GESTATION 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 43 WEEK Of GESTATION ( F R O M 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: 403. 19661 104 V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y I N T R A U T E R I N E G R O W T H C H A R T Patient 6 24 25 28 27 26 29 30 31 32 33 34 35 36 37 36 39 40 41 42 43 2 4 2 5 2 8 2 7 2 6 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 43 0 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 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 8 3 9 4 0 4 1 4 2 43 WEEK OF GESTATION < F R O M 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 105 V A N C O U V E R G E N E R A L H O S P I T A L Patient 7 I N T E N S I V E C A R E N U R S E R Y I N T R A U T E R I N E G R O W T H C H A R T 25 26 27 26 29 30 31 32 33 2 5 2 6 2 7 2 6 2 8 3 0 3 1 3 2 3 3 3 4 3 5 3 6 37 3 6 3 9 4 0 4 1 4 2 4 3 0 2 4 2 5 2 6 2 7 2 6 2 8 3 0 3 1 3 2 3 3 3 4 3 5 3 6 3 7 3 6 3 8 4 0 4 WEEK OF GESTATION I 42 43 2 4 2 5 2 8 27 2 6 2 8 3 0 31 3 2 3 3 3 4 3 5 3 6 37 3 6 3 8 4 0 4 1 4 2 4 3 ' WEEK OF GESTATION ( F R O M 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 3 7 : 4 0 3 . 1966) V A N C O U V E R G E N E R A L H O S P I T A L I N T E N S I V E C A R E N U R S E R Y Patient 9 I N T R A U T E R I N E G R O W T H C H A R T 2528 27 2829 30 31 32 33 34 35 36 37 383040 414243 2 4 2 5 2 8 2 7 2 8 2 9 3 0 3132 33343538 37 363940 4142 43 24 25 28 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 WEEK OF GESTATION 242528 27 2 8 2 9 X 31 3 2 X 3 4 3 5 3 8 37 36 39 40 41 WEEK OF GESTATION ( F R O M 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 , 1966) 107 V A N C O U V E R G E N E R A L HOSPITAL I N T E N S I V E C A R E N U R S E R Y Patient 10 I N T R A U T E R I N E G R O W T H C H A R T 25 28 27 26 29 30 31 32 33 2627262930 3 1 3 2 3 3 3 4 3 6 3 6 37 363940 4142 43 2 4 2 5 2 6 2 7 2 8 2 9 3 0 3 1 3 2 3 3 3 4 3 5 3 6 3 7 3 6 3 9 4 0 414243 WEEK Of GESTATION 242528 27 262930 31 3233343536 37 363940 414243' WEEK Of GESTATION (FROM L U B C H E N C O , L.O., E T A L . PAEDIATRICS 37: 403, 1966) 

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