Parenteral Nutrition in the Management of Sick Low Birthweight Infants

Symposium on Respiratory Disorders in the Newborn

Parenteral Nutrition in the Management of Sick Low Birthweight Infants

J. C. L. Shaw, M.R.C.P.*

A period of malnutrition bordering on complete starvation occurs in pediatrics in three clinical circumstances: following surgical correction of severe gastrointestinal malformations, as a consequence of prolonged gastroenteritis when there are often secondary food intolerances, and in very low birthweight preterm infants, whose alimentary tract is so immature, that it is many weeks before it can equal the placenta as an organ of nutrition. As the high incidence of respiratory disorders in low birthweight infants frequently delays the introduction of adequate oral feeding, it is possible that in some cases the presence of undernutrition, in part, determines the fatal outcome of their illnesses. In this review I shall consider in some detail the nutritional requirements of very low birthweight infants using the intrauterine growth of the fetus as a standard of reference, and I shall then describe the application of modern techniques of total parenteral nutrition to these infants.

NUTRITIONAL CONSEQUENCES OF PREMATURE BIRTH From the moment of birth the low birthweight infant loses weight (Fig. 2) and goes into negative nitrogen balance. 4. 76 The provision of a 10 per cent glucose infusion at 100 ml. per kg. per day intravenously will limit negative nitrogen balance to about 200 mg. per kg. at 48 hours,4 but if the infant is suffering from respiratory distress syndrome the total nitrogen catabolism has been found to be as high as 497 mg. per kg. at 48 hours,76 equivalent to a loss of 3.0 gm. (3.5 per cent) of his body protein. In addition to this loss of nitrogen there may also be substantial losses of depot fat, liver glycogen stores,9l and trace elements.lOO.103 Heird and his associates 56 have calculated the approximate duration of survival in starvation and semistarvation to be expected in newborn infants of different weights on the basis of their caloric reserve. These data, compared with *Lecturer in Paediatrics, University College Hospital Medical School, London, England

Pediatric Clinics of North America- Vol. 20, No.2, May 1973

333

334

J. C. L. Table 1.

SHAW

Calculated Survival Time in Da ys 56 in Starvation and Semistarvation WATER ONLY

Small premature infant Large premature infant Full term infant Adult

10%

DEXTROSE':'

4 12 33

11 30

90

350

80

"75 ml. per kg. per day for infant; 3 liters per day for adult.

those from an adult, are summarized in Table 1. They show that a small premature infant is very close to death from starvation, and that, in contrast to the full-term infant or adult, the provision of 10 per cent dextrose at 75 ml. per kg. per day extends survival time by only 7 days. Great precision has not been claimed for these figures but they vividly illustrate the urgent need to introduce adequate nutrition in these infants. Intercurrent illness such as hyaline membrane disease, recurrent neonatal apnea, sepsis, and gastrointestinal disorders, by making the introduction of adequate oral feeding very much more difficult, exacerbate negative nitrogen balance and further prejudice the infant's chances of survival. Even if a sufficient oral food intake could be provided, the infant's capacity to absorb adequate amounts of nutrients such as fat,41. 90 calcium,90 and trace minerals loo , 103 is probably severely limited in the immediate postnatal period. Provided that the infant survives, the long term consequences of starvation may be serious. There is a growing body of evidence from animal studies that malnutrition early in development, when tissues are undergoing rapid cell division, results in a permanent reduction in brain size and cell number, a state of affairs that cannot be reversed by a period of liberal feeding later on. 24 , 26-28, 105-107, 113 Evidence that malnutrition has a similar effect in human infants is more difficult to obtain, but malnutrition has been shown to be associated with reduced brain weight and brain D.N_A_,114 and there is very suggestive evidence that early malnutrition may seriously affect intellectual development. 14 Since glial proliferation in the human brain is accelerating during the last trimester of pregnancy29 low birthweight pre term infants are likely to be particularly vulnerable to periods of malnutrition at this time. It is these cohsiderations that have directed pediatricians to apply techniques of parenteral feeding to the low birth weight infants in order to bridge the gap between placental and effective alimentary function.

INTRAUTERINE GROWTH AND THE NUTRITIONAL REQUIREMENTS OF LOW BIRTHWEIGHT INFANTS When designing a diet for low birth weight infants, a standard of nutrition should be aimed at, which results in growth that is quantitatively and qualitatively similar to that occurring in utero, and it is only from consideration of the rate of weight gain of the fetus, and the rate at which

PARENTERAL NUTRITION IN SICK

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elements accumulate in the fetal body in utero,'" that postnatal growth in these infants can be judged. Using this information, it is possible to make an estimate of the nutritional requirements of low birthweight infants, and to see how they can best be met using the currently available materials.

Weight Gain Figure 1 shows that weight gain in utero is exponential in character. 7(),71 From the calculated regression equation fitted to the mean weights between 24 and 36 weeks a rate constant can be obtained and used to calculate growth velocity, from which the intrauterine growth velocity curve in Figure 2 was constructed. In Figure 2 the growth velocities of two groups of infants of <1.5 kg. birthweight are compared with the intrauterine growth growth velocity curve, and it can be seen that few of these low birth weight infants ever equalled intrauterine rates of growth during the first 40 to 60 days of life. Furthermore, these measurements of daily rates of weight gain give only the sum of the increments of protein, fat, minerals, and water, and there is accumulating evidence that the composition of the daily weight gain in postnatal life is very different from that occurring in utero. 90 • 10K

':'Mathematical Methods. In order to obtain rate constants (k) describing the rate of increase of body weight, and the rage of increase of different substances in the fetal body in utero, regression lines, calculated by the method of least squares, were fitted to the means of two intrauterine growth curves 70 , 71 between 24 and 36 weeks, and to the data on the amounts of different substances in fetal bodiesHH.11l4 between 16 and 42 weeks gestation, using the equation In Y = InY" + kt. (t = gestational age in days, k =a rate constant, Y" is taken for convenience as the value of Y when t = O. The rates of weight gain, and rates of accumulation of substances at different periods of gestation (Table 2) are equal to k x Y1·)

BodyWeight Kilograms.

4,0

o Lubchenko et al[1963] • Kloosterman[1970] y=yo·ek t k=0·0144days-1

3·0

Yo= 70'5g

2·0

1·0

Gestat i on (weeks).

Figure 1. Comparison of the means of two intrauterine growth curves,'O.7! showing that growth is exponential between 24 and 36 weeks gestation.

336

J. C. L.

SHAW

GRAMS/DAY

+30

f

!

+20

+10

Surviving infants born at U.C.H. i n 1969.B.W.<1·5kg

§modalgest . 32wks

I

(range 30-34wks)tS.D

I

modal gest. 28wks

!

0

-10

(range 27-28wks):!:S.D.

- - - - intrauterine growth

velocity curve.

-20

-30 24

28

32

36

GESTATION (WEEKS)

Figure 2. Comparison of intrauterine growth velocity (calculated as described in mathematical methods) with the postnatal growth velocity in two groups of infants of birthweight less than 1.5 kg.

Nitrogen IIramll/foetus

100·r---------------------------~ o

o

k.O·OI86dByli' yo-0'34611 r.O·97 10

1~~

16

__~~~__~~~__~~~~ 24 32 40 Gestation(weeks)

Figure 3. Nitrogen content of fetal bodies at different periods of gestation. Nitrogen increases exponentially between 16 and 42 weeks' gestation.

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BIRTHWEIGHT INFANTS

Nitrogen mgfday

800

I

I

400

o~~__~~~~__~__~~__~

22

26

30

34

38

Gestation(weeks)

Figure 4. The rate of accumulation of nitrogen by the human fetus at different periods of gestation (calculated as described in mathematical methods).

Rates of Accumulation of Different Substances by the Human Fetus in Utero Just as weight gain is exponential, so it seems are the rates of accumulation of different components of the fetal body in utero. Figure 3 gives, as an example, the results of analyses of fetal bodies for nitrogen at different periods of gestation68 , 104 plotted on a semi-log scale. The accumulation of this element is adequately described by a single exponential. Using the rate constant (k) from the regression equation the daily rate of accumulation of nitrogen in mg. per day can be calculated for different periods of gestation. The rates for nitrogen are given in Figure 4. Table 2. Calculated Daily Rates of Accumulation'~ of Various Substances by the Human Fetus at Different Periods of Gestation REGRESSION WEEKS OF GESTATION

24 Nitrogen Sodium Potassium Calcium Phosphorus Magnesium Iron Copper Zinc Fat Water

mg/day mg/day mg/day mg/day mg/day mg/day mg/day /Lg/day /Lg/day g/day g/day

26

28

30

32

PARAMETERS

34

36

159 207 269 349 452 587 761 15 18 28 23 33 43 53 15 19 24 31 39 50 64 59 79 105 140 186 248 330 36 47 82 108 142 188 62 1.9 2.4 3.1 3.9 5.0 6.4 8.1 0.8 1.1 1.4 1.9 2.5 3.3 4.3 39 52 67 88 116 151 199 169 208 256 316 389 480 591 0.25 0.43 0.75 1.32 2.31 4.0 7.1 7.6 9.7 12.3 15.7 20.0 25.6 32.6

'See Mechanical Methods

k days-l 0.0186 0.0151 0.0173 0.0203 0.0197 0.0171 0.0202 0.0193 0.0149 0.0399 0.0174

Yo 346.7 78.5 47.2 95.3 66.6 6.42 13.43 79.9 918 0.008 23.3

(mg) (mg) (mg) (mg) (mg) (mg) (mg) (",g) (/Lg) (g) (g)

338 Table 3.

Rates of Accumulation of Various Substances by the Human Fetus at Different Periods of Gestation (Expressed per kg. of Body Weight per Day) WEEKS OF GESTATION

Nitrogen Sodium Potassium Calcium Phosphorus Magnesium Iron Copper Zinc Fat Water

mg. mg. mg. mg. mg. mg. mg. /kg. /kg. gm. gm.

24

26

28

30

32

34

36

319 28 30 118 70 3.8 1.6 78 337 0.5 15.2

324 28 30 124

330 27 30 129 76 3.8 1.7 83 315 0.9 15.1

334 27 30 133 78 3.8 1.8 85 302 1.3 15.0

341 24 29 140 80 3.8 1.9 87 293 1.7 15.0

345 25 29 145 84 3.7 1.9 89 282 2.4 15.1

350 24 30 151 86 3.7 2.0 92 272 3.2 14.7

73

3.7 1.7 80 326 0.6 15.1

Similar calculations have been made for all the components of fetal bodies that have been measured 68 ,I04 and the results are assembled in Table 2, The values are given only up to 36 weeks because growth by weight ceases to be exponential toward term (Fig. 1), and the rates at which elements accumulate then are rather uncertain. The striking feature of this table is the unusually large amounts of nitrogen, calcium, iron, copper and zinc that accumulate each day in the fetus. Table 3 gives the values expressed per kilogram of body weight per day, and it is remarkable how constant many of these figures are when expressed this way. These values, though lacking the precision one would wish, nonetheless provide a valuable basis for arriving at the nutritional requirements of very low birth weight infants, and for designing intravenous solutions for them.

NUTRITIONAL REQUIREMENTS Calories The calorie requirement of growing preterm low birth weight infants has been estimated at 120 cal. per kg. per day,94 However, in solutions commonly used for parenteral feeding the principle source of calories is glucose, and when glucose is administered at such rates to very low birthweight infants, it has been found that they frequently develop hyperglycemia, and a dangerous osmotic diuresis (Table 11). For this reason we start intravenous feeding in low birth weight infants with a nutrient solution containing only 10 per cent dextrose at a volume of 65 ml. per kg. per day, gradually increasing to 150 ml. per kg. per day, providing a maximum of 0.63 gm. per kg. per hr. of glucose. The glucose concentration is then increased by steps to 20 per cent, while frequently measuring the blood and urine glucose concentrations. By this time the child will be receiving 1.25 gm. per kg. per hr, of glucose (Table 7). Similar tolerances for glucose have been reported by other authors.35, 79

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Fat Emulsions Though fat is probably not an important source of energy in utero, intravenous fat emulsions, which are isosmotic with plasma, provide an attractive adjunct to glucose as a calorie source in parenteral feeding. They are being increasingly used in Europe, but are not available at the present time in the United States for unrestricted clinical use. Since there are a few reports now of the use of Intralipid (made by Vitrum of Stockholm, Sweden) in low birth weight infants,:!:;' HH it will be worth considering it briefly. Intralipid consists of 100 to 200 gm. of soy bean oil emulsified in water with 12 gm. of egg lecithin and 25 gm. of glycerol per liter. It contains about 60 per cent essential fatty acid. The particles resemble chylomicrons and in the 20 per cent Intralipid they have a median diameter of 0.2 to 0.5 micron. Gustafson and his colleagues 50 have shown that Intralipid 20 per cent given as a single injection of up to 0.5 gm. per kg. of body weight is eliminated from the plasma of preterm low birth weight infants at a rate comparable to that of adults, but small-for-dates infants showed a slower rate of elimination of injected fat. Long-term infusions in animals and a large series of adult patients have shown this preparation to have very few acute or long-term side effects5l but there are no comparable studies in low birth weight infants. There is conflicting evidence on whether Intralipid interferes with blood coagulation mechanisms. l9 • 65 We have found a transient fall in blood fibrinogen levels following administration but no other effects were noticed. s5 This preparation is promising but still needs very careful evaluation before it can be used routinely in low birthweight infants. Nitrogen The usual allowance of amino acids in the parenteral nutrition of older infants is in the region of 4.0 gm. per kg. per day.56 We have never given more than 2.5 gm. per kg. per day and have found that low birthweight infants grow well on such an allowance (Figs. 5 and 8). It provides 650 mg. N2 per kg. per day, approximately twice that required for optimal growth (Table 3). When given with 15 or 20 per cent dextrose, the calorie:nitrogen ratio is probably satisfactory (Table 7),56 though much below that found in breast milk namely, 375 cal. per gm. N 2. The occurrence of high blood levels of amino acids 22 , 44 and hyperammonemia44 , 57. 62 in low birthweight infants given amino acid solutions parenterally has prompted several authors to recommend lower amino acid intakes for these patients. 56, 62 Amino Acids The essential amino acid requirements for premature infants are not known, but they are likely to be required in a proportion close to that found in a first class protein such as breast milk protein. Table 4 compares the amounts of essential amino acids provided by breast milk, and by 2.5 gm. of protein hydrolysate (Aminosol) with the allowances determined by Holt and Snyderman,59 and it is clear that the proportions are very similar. Since low birthweight infants will often ultimately tolerate

340 Table 4. Comparison of Amounts of Essential Amino Acids Contained in 2.5 gm. of Protein Hydrolysate (Aminosol) with the Daily Allowance in Human Breast Milk (Given at 150 ml. per kg. per day), and with the Requirements Determined by Holt and Snyderman 59 ESSENTIAL AMINO ACIDS

Isoleucine Leucine Lysine Phenylalanine Methionine Cystine-cysteine Threonine Tryptophan Valine Histidine Arginine

BREAST MILK41

AMINOSOL

HOL T AND SNYDERMAN 5!l

(mg. per kg. per 24 hr.) (mg. per kg. per 24 hr.) (mg. per kg. per 24 hr.) 129 241 118 96 34 43 93 33 139 35 77

123 233 176 118 62 26 77 27 156 57 78

102-119 76-150 88-103 '47- 90 33- 45 45- 87 15- 22 88-105 16- 34 ?

fluid intakes of up to 200 mI. per kg. per day it is possible to increase their intake of amino acids by one-third (see Table 7). This may be necessary since their protein requirements expressed per kg. per day are probably higher17 ,46 than those of a full-term infant.42 Since the observation of Sturman, Gaull, and Riiiha43 , 98 that fetal livers lack cystathionase it has seemed possible that cystine may be an essential amino acid and there is some preliminary evidence to show that this may be SO.96 Until this matter has been settled a provision of cystine should probably be made in all amino acid solutions used for low birthweight infants. HYDROLYSATES. Hydrolysates of fibrin and casein have both been widely used, and form the most usual source of amino acids for intravenous feeding. Inevitably, however, little influence can be exerted upon the amino acid composition, which is determined by the protein used. Furthermore there are wide discrepancies between the results of amino acid analyses provided by the manufacturers and those performed in other laboratories. 44, 56, 97 This suggests that either the product is very variable, or that there may be changes in composition occurring on storage. About two thirds of the amino acids are free, and one third are in the form of small peptides. Peptides have been shown to be taken up by the mucosal surface of the intestine, and are hydrolyzed to their component amino acids intracellularly.18 The fate of infused peptides, however, is not known for certain, but a proportion are almost certainly utilized. Autoclaving or storing hydrolysates in the presence of glucose results in a "browning reaction" which is associated with an increased loss of peptides in the urine. 13 Losses have been shown to be greater with pure casein hydrolysates than fibrin hydrolysates,ll and also when the glucose concentration is increased. 10 , 12 If the hydrolysate is mixed with glucose just prior to infusion, the observed peptiduria is not seen. 10 , 12 Protein hydrolysates have recently been reported to have a very high ammonium content,44, 45, 62 a matter that will be discussed below.

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The acid base properties of the amino acid source are likely to be very important. 9. 69 Examination of some protein hydrolysates has shown them to have a high titratable acidity (32.7 to 50.0 mEq. per L.), but because they have an anion gap, which would yield substantial amounts of base on metabolism, they are unlikely greatly to increase endogenous hydrogen ion production. 55 L-AMINO ACID MIXTURES. Mixtures of L-amino acids are attractive because of the precise control that can be exerted over their composition and because they do not undergo the "browning reaction." They have been shown to promote growth in low birth weight infants, but tend to produce metabolic acidosis. 9 The titratable acidity of some of these preparations is reported to be lower than that of the hydrolysates (10.2 to 11.4 mEq. per L.), but they have a net cation gap at pH 7.4 owing to the net positive charge on arginine and lysine. Under these circumstances there is an inevitable net yield of hydrogen ions on metabolism. This can be compensated by including acetate, glutamate, or aspartate. 55 An additional advantage of the L-amino acid mixtures is their substantially lower ammonium content. 62 Calcium and Phosphorus CALCIUM. Hypocalcemia is an almost constant finding in very low birth weight infants during the first 48 hours after birth, and presumably results from the interruption of the placental supply at a time when skeletal mineralization is accelerating. Inspection of Tables 2 and 3 shows that in utero there is a considerable amount of calcium being laid down in the skeleton each day, and the osteoporosis reported in low birthweight infants on long-term parenteral feeding 7 • 61, 62. 66 is possibly due in part to inadequate provision of calcium in the infusate. Since the incorporation of 1.0 gm. of calcium in the bone has been calculated to yield 20 mEq. of hydrogen ion,69 normal intrauterine skeletal mineralization will increase the endogenous hydrogen ion production by about 2 to 3 mEq. per kg. per day, a very significant part of an infant's net acid excretion. Because we have not yet established the safety of infusing such large amounts of calcium, we provide about a third of the requirement. This is usually, sufficient to prevent hypocalcemia, but more may be required on occasions. In these circumstances the blood calcium must be measured frequently as we have occasionally observed hypercalcemia. This may be prevented by adjusting the calcium:phosphorus ratio of the infusate. PHOSPHORUS. The inclusion of phosphate in the solution is probably essential, not only because it is an important intracellular anion, and necessary for normal skeletal mineralization, but also to provide sufficient urinary buffer. There have been reports of severe hypophosphatemia when phosphate-free solutions are used in itravenous feeding,93.101 and this has been shown to result in reduced concentration of erythrocyte A.T.P. and 2-3 D.P.G. levels, and shift of the hemoglobin dissociation curve to the left with a reduction in the p50. 101 Trace Elements Copper deficiencyl is the only trace metal deficiency so far described in infants maintained on long-term parenteral nutrition. 66 But consider-

342

J. C. L.

SHAW

ing the rate at which the elements iron, copper, and zinc accumulate in the fetus in utero, other deficiency states are likely to be described. Periodic transfusions of plasma have been advocated as a source of trace elements. Table 5 shows that the amount of trace elements in a transfusion of plasma at 20 mI. per kg. twice a week4o • 49 falls very short of the amounts of the elements accumulating in the fetus in utero. Bearing in mind the poor body stores of low birth weight infants,104 their rapid rate of growth, and the evidence that they may be in negative balance for these elements/oo • 103 it would seem reasonable to make a definite provision of them. These elements are essential components of metallo enzymes and are necessary for the normal functioning of metal-activated enzymes. 23 Animal work has shown that, for instance, zinc deficiency can seriously interfere with the growth of the fetal rat brain. 87 Essential Fatty Acids Essential fatty acids are rapidly incorporated into the lipids of the developing brain and in rats there is compelling evidence that deficiency can seriously impair brain growth. 78 Deficiency states have been observed in adults l5 and in infants,52 but only after prolonged periods on a low linoleic acid diet. Since very low birthweight infants have trivial fat stores (about 10 to 11 gm.) and a rapid rate of growth, it may be anticipated that they would be very likely to develop essential fatty acid deficiency when on a fat-free diet. Figure 5 shows the growth chart of a low birthweight infant maintained on total parenteral feeding for the first 39 days of life. During this time the infant had 6 blood transfusions totaling 180 mI. of whole blood and a small amount of breast milk orally. On day 34 she began to develop a severe exfoliative skin condition which was at its worst on day 38 (Fig. 6). Rapid recovery was seen when the volume of milk feeds was increased on day 39. The rash could have been the result of a number of deficiencies, but the resemblance to reported cases l5, 52 leads us to think that it was probably the result of essential fatty acid deficiency. We now make a point of providing a minimum allowance of essential fatty acids. Ethyllinoleate given orally is often well tolerated in the small amounts necessary. Otherwise Intralipid can be given intravenously, and in the small amounts required it is unlikely to be a hazard. Table 5. Comparison of Suggested I.V. Allowances of Some Trace Elements with the Daily Rate of Acculumation in Utero (mg. per kg. per day)

Iron Copper Zinc Manganese Cobalt Iodine

WILMORE ET AL.1l1

PLASMA AT 40 ML.

DAILY INCREMENTS

(1969)

PER KG. PER WK*

IN UTERO

0.020 0.022 0.040 0.040 0.014 0.015

0.008 0.006 0.007 0.0006 0.002 0.0004

1.6 -2.0 0.078-0.092 0.272-0.337 ? ? ?

*Calculated from values in Geigy Scientific Tables, 1970.30

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BIRTHWEIGHT INFANTS

Body Weight 1200

Gm .

•

1100

Oral.

Dlv. 1000

900

800

Kcals/day. 700 50

600

o

o

10

20

30

40

50

60

AGE IN DAYS Figure 5. Growth chart of a 765 gm. infant of about 25 weeks' gestation maintained on total parenteral nutrition from the fifth to the thirty-ninth day of life. Oral feeding was prevented by severe recurrent neonatal apnea.

Vitamins Mature infants fed synthetic diets have been shown to develop deficiency syndromes in 2 to 10 weeks when essential nutrients are omitted from the diet. n . 112 This can be prevented by a complete vitamin supplement such as Ketovite,':' Because there is no such complete preparation for intravenous injection we provide only the vitamins shown in Table 4. In practice the exact amounts of vitamins given are determined by the available preparations. When the infant can tolerate small amounts orally we give Ketovite liquid, 5 mI., and half a crushed Ketovite tablet down the feeding tube each day.

BACKGROUND TO PARENTERAL FEEDING OF LOW BIRTHWEIGHT INFANTS In 1966 Dudrick and his associates 33 demonstrated that Beagle puppies maintained on total parenteral feeding for periods of up to 175 days could be maintained in good health and grow normally when compared with matched controls. This was followed by a report in 1968 by Wilmore and Dudrick109 of growth and development in an infant maintained on total parenteral nutrition for 44 days. This report was the first instance in which growth had taken place under such circumstances in man, and "Paines and Byrne Ltd., Pabryn Laboratories, Greenford, England

J. c.

344

L.

SHAW

Figure 6. Photograph of infant described in Figure 5 taken on day 40, showing the severe exfoliative skin condition that developed between the thirty-fourth and thirty-ninth days of life.

since then the technique has been used successfully in surgical cases,61, 64, 111 cases of renal failure,llo infants with gastroenteritis,60,67 and in low birthweight infants6, 8, 31, 58 and there are a number of excellent review articles in the literature. 5 , 32, 38, 39, 54, 56, 94

INDICATIONS FOR PARENTERAL NUTRITION IN LOW BIRTHWEIGHT INFANTS Because of the inherent dangers of the technique, which vy-ill be discussed below, parenteral nutrition should for the present be used only in those infants whose survival is jeopardized through undernutrition. It is our practice to administer parenteral feeding to the following groups of infants: (1) surgical cases: intestinal resections, intestinal perforations, peritonitis; (2) severe respiratory distress syndrome; (3) severe recurrent neonatal apnea; (4) any very low birthweight infant « 1.0 kg.) who cannot tolerate oral feeding.

TECHNIQUES The technique described here is the one used in the Neonatal Intensive Care Unit at University College Hospital, London, and is a modifica-

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tion of that of Wilmore and Dudrick. J09 It consists of the continuous infusion of a fat-free hyperosmolar solution of glucose, amino acids, minerals, and vitamins into the right atrium of the heart or into a large central vein. In order to insert the catheter rapidly, with minimal trauma and without interfering with the inspired oxygen concentration, we do not use the external jugular vein 109 or the facial vein l17 but introduce a very fine silicone rubber catheter percutaneously through a scalp vein needle into a superficial vein, and then thread it into the right atrium of the heart. Catheter Silas tic medical grade tubing':' 0.025 or 0.037 inch o.d. is used; the smaller tubing will pass through a 19 gauge thin wall scalp vein needle':":' and the larger tubing through a 16 gauge thin wall scalp vein needle. The tubing is cut into exact 20 inch lengths, and during preparation great care is taken to prevent chemical irritants coming in contact with the catheters, which are then double packed, and autoclaved. Technique of Insertion A scrupulous no-touch technique must be observed. In order to prevent glove powder from adhering to the catheter and later causing thrombophlebitis, the gloves are rinsed three times in distilled water. The best vein is decided upon by inspection. A scalp vein is preferred, but the long saphenous vein at the ankle, the median cubital vein, and veins on the dorsum of the hand have been used successfully. The skin is shaved and thoroughly cleansed with a providone-iodine preparation'~':":' and all the surrounding area is widely covered with towels. When the vein is easily visible, the skin is covered with Steridrapet (when the vein is difficult to see the Steridrape should cover the skin up to the point where the needle is to be inserted). The scalp vein needle, with the plastic tubing cut off, is introduced through the Steridrape a short way into the vein, and using fine forceps only, the catheter is threaded into the needle. Gripping the catheter close to the needle butt, it is advanced 1 to 2 mm. at a time, until it is thought to be in the right atrium. Occasionally the catheter will stick at the saphenous opening if the long saphenous vein is used, or at the shoulder if an arm vein is used. In these circumstances manipulation of the limb often makes it possible to negotiate the obstruction. The position is then checked with a paper tape measure autoclaved in the instrument pack for this purpose. Since, however, measurements are not sufficiently reliable, it is essential always to check the catheter position radiologically at the end of the procedure after opacifying with 1.0 ml. of a contrast medium such as Conray 280. t t The scalp vein needle is then withdrawn and discarded. The catheter is connected to the infusion set by inserting into it a 25 gauge scalp vein needle. The protective plastic tube from the scalp vein needle should be first threaded onto the catheter ':' Dow Corning Corporation, Medical Products Division, Midland, Michigan ':", Abbott Laboratories, Chicago, Illinois Betadine, Berk Pharmaceuticals Ltd., 8 Baker Street, London W.l., England t Medical Products Division 3 M Company, st. Paul, Minnesota itMay and Baker Co. Ltd., Dagenham, Essex, England

346

J. C. L. Table 6.

SHAW

Parenteral Infusion Fluids

Dextrose Electrolyte Solution Potassium Calcium (as gluconate) Magnesium Chloride Dextrose

15 mEq./L 30 mEq./L 8 mEq./L 23 mEq./L 150,250,350 gm./L.

Aminosol Glucose Solution Amino acids Sodium Potassium Dextrose

33 gm./L. 54 mEq./L 0.15 mEq./L 50 gm./L.

Phosphate Solutions: (5 m!. ampules)'" M K2 HP0 4 } • M Na2 HP0 4 2 mEq. of catIOn and 30 mg. phosphorus per m!. ':'Either salt can be used, depending on the plasma electrolyte results.

so that it can be slipped back over the needle to prevent it cutting the catheter. The wound is sealed with a dressing heavily impregnated with neomycin polymyxin bacitracin spray. The dressing is left undisturbed if the catheter is in a scalp vein and is only changed when absolutely necessary. The lower limb dressings usually require more frequent changing. Parenteral Infusion Fluid The parenteral infusion fluid is mixed at the bedside in a closed circuit system. This method is used for the following reasons. It is very important to have sufficient flexibility to be able to alter the glucose concentration of the infusate without altering the concentration of the other components. The pharmacy can manufacture their solutions in bulk, well in advance of requirements, and issue them after a full chemical assay and bacterial check. By mixing a strong glucose solution and amino sol just prior to administration some of the loss of peptides reported by Christenson and his colleagues 10 , 12 is likely to be prevented. Figure 7 illustrates the method of mixing. Five ml. of molar K2 HP0 4 is added by syringe to the 500 ml. bottle of Aminosol glucose and mixed. 50 ml. of dextrose electrolytes (Table 6) and 50 ml. of Aminosol glucose (containing 0.5 ml. of K2HP0 4) are mixed in the 100 ml. burette of the pediatric giving set." This solution is then driven by a peristaltic finger pump"':' through a 0.22 J1- pore diameter filter':":'~' and thence to the patient. The entire system up to and including the filter is discarded every 24 hours. The infusion bottles are sent for culture daily and aliquots of fluid taken just before and after the filter are also sent for culture daily. The nurses who change the system each day must be properly instructed in the method; they should scrub, be masked and gowned, and observe a strict aseptic technique. "AKCO 135, and AKC 2045, Baxter Laboratories Ltd., Thetford, Norfolk, England "':'IVAC 500, Tekmar Medical Ltd., Harrow-on-the-Hill, Middlesex, England ':'*"Millex Disposable Filter Unit. SLGS0250S-0.22 /Lm., Millipore Corporation, Redford, Massachusetts

PARENTERAL NUTRITION IN SICK

Table 7.

Low

347

BIRTHWEIGHT INFANTS

Parenteral Infusion Fluids

Composition of intravenous fluid made up of equal volumes of Aminosol glucose (Vitrum) and Dextrose Electrolyte solution + 5.0 mI. M K,HPO, per 100 ml. infusate, and daily intakes when administered at 150 ml. per kg. per day FINAL CONCENTRATION

DAILY INTAKE PER

RATE PER

IN INFUSATE

KILOGRAM BODY WEIGHT

KG.HR

Dextrose 15% 25% 35%

10% (106 cals/gN,) 15% (153 cals/gN,) 20% (200 cals/gN,)

15 G (68 cals) 22.5 G (98 cals) 30.0 G (128 cals)

0.63 g 0.93 g 1.25 g

Amino acids Sodium Potassium Calcium Phosphate Magnesium Chloride

1.7g% 27 mEq/L 17.5 mEq/L 15.0 mEq/L 10.0 mEq/L 4.0 mEq/L 31.5 mEq/L

2.5 g% (0.640 gN,) 4.0 mEq 2.6 mEq 2.25 mEq 1.5 mEq 0.6 mEq 4.5 mEq

Composition of the Fluid The composition of the solutions, and the approximate daily intakes of the nutrients are shown in Tables 6, 7 and 8. The dextrose electrolyte solution is made with a choice of three concentrations of glucose (Table 2), which when mixed with the Aminosol glucose, will give a final glucose concentration in the infusate of 10, 15, or 20 per cent. Very low birthweight infants are started on 10 per cent dextrose at a rate of 65 ml. per kg. per day. Any child maintained on total parenteral feeding for more than a few days is given vitamin supplements and essential fatty acid (Table 4). Daily and Weekly Routines Table 9 gives a list of daily routines that must be adhered to at all times. The blood investigations should be performed with discretion as it Table 8. Vitamins and Essential Fatty Acids Vitamins (given weekly in the infusate) Vitamin A 500-1000 IV Vitamin D 500 IV Vitamin K 0.25 mg 100 mg Vitamin C 8.0 mg Thiamine 12.8 mg Nicotinamide Ristoflavine 0.32 mg. Pyridoxine 4.0 mg. Cyanocobalamine 100/Lg Folic acid 0.5 mg Tocopherol 1.5 mg Essential Fatty Acid 300 mg/kg. day orally Ethyllinoleate 2.5 ml/kg. day i.v. or Intralipid 20%

348

J. C. L.

Table 9.

SHAW

Routines and Investigations for the Infant Receiving Parenteral Nutrition

DAILY

ONCE OR TWICE WEEKLY (or as indicated)

Weighing

Length and head circumference

Fluid Balance Input and Output chart Urine glucose (Clinitest) 4 hourly Plasma Chemistry Dextrostix 6-12 hourly

Bacteriology Change I. V. infusion set and filter daily

Urea and electrolytes Calcium and phosphorus pH, pCO" B.E. Transaminase levels Ammonia Glucose

Blood culture } If infection is C.S.F. exam. and culture d Urine culture suspecte

LV. Bottles ) Prefilter speci~en Send for culture daily Postfilter speCImen Filter membrane

Hematology

Hemoglobin and hematocrit W.B.C. and differential (if infection is suspected) Screening for blood coagulation defects

is easy to exsanguinate a very low birthweight infant. It is not our practice to give prophylactic antibiotics, but if an infection is suspected, after cultures have been taken (Table 5), antibiotics are given in full doses intravenously through a separate intravenous infusion. Under no circumstances must the intravenous feeding line be used for any purpose other thap the administration of nutrient solutions, because of the danger of introducing infection.

Catheter Change Since the incidence of infected catheters increases with time 16, 81, 95 it is probably prudent to resite the catheter electively every 20 to 30 days.111 When the catheter is removed, a skin swab is taken and sent with the catheter for culture. EVALUATION OF RESULTS OF PARENTERAL NUTRITION While there are fairly numerous reports of the results of parenteral feeding in full term infants,3, 32, 38-40, 54, 64, 92 there have been only preliminary reports dealing specifically with low birthweight infants.6, 8, 31, 35, 58,

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Intravenous amino acids, glucose, and in some cases fat have been used to supplement oral feeding. n, 8. 3:;. 99 With the notable exception of surgical cases, the period of parenteral nutrition is fairly short seldom exceeding 40 days and frequently a period of 10 to 15 days has proved sufficient. The infants selected have generally been those less than 1.5 kg. who are undoubtedly the most difficult to feed and the most vulnerable to starvation. 79.88.99

Mortality and Quality of Survivors An effect upon mortality can only be formally demonstrated by a carefully controlled study and at present there is only one report of any reduction of mortality following the use of parenteral nutrition. sH Because the technique itself has an inherent mortality, most workers have confined its use to those groups of infants who are severely ill and whose survival is seriously jeopardized by their inability to tolerate or benefit from oral feeding. In these circumstances it is difficult to demonstrate unequivocally that they have benefitted from parenteral nutrition as the mortality will in any case be high. We have fed a total of 24 newborn infants intravenously. The mortality was 75 per cent for those less than 1.0 kg. birthweight and 50 per cent for those between 1.0 and 1.5 kg. birthweight. There were no deaths among 9 infants weighing over 1.5 kg. The immediate cause of death in each case was unrelated to the parenteral feeding, but in one case dehydration due to glycosuria and in two cases thrombi associated with the catheters may have been a contributory cause of death. The results so far reported are sufficiently good to make controlled trials mandatory, and the results are awaited with interest. The long term follow-up of survivors is an essential part of the program though it may be difficult to evaluate the contribution made by parenteral feeding to the improving prognosis of low birthweight infants. s3

Weight Gain Mean rates of weight gain of about 15 gm. per day have been reported in low birthweight infants on total parenteral nutrition. 3 t. 79 Whether these rates of weight gain are satisfactory or not depends on the gestation of the infant. Figures 5 and 8 give examples of two infants maintained on complete parenteral nutrition from birth. After an initial weight loss these infants gained weight at an average rate of 10.5 gm. per day and 13.5 gm. per day, respectively. Examination of Figure 2 shows that these rates of weight gain are comparable to those of orally fed infants in our nursery, but substantially below the rates occurring in utero. When parenteral feeding is used during the first 10 days of life the weight loss that occurs is much less than we usually observe with oral feeding. Analysis of our data for surviving infants of less than 1.5 kg. birthweight and fed intravenously, shows that the mean weight change during the first 10 days of life is +3 gm. per day ± 6.0 gm. S.D., whereas it was -6.8 gm. per day ± 8.5 S.D. for all the infants of birth weight less than 1.5 kg. surviving in this unit in 1969 before the introduction of parenteral feeding (see Fig. 2). The recent report of Willis and Usher,los however, serves to show that reliance solely upon body weight measurements can be very misleading.

350

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-100-

silastic catheter

- 50-

ffi0

0

•

[I]

25G

SHAW

Figure 7. Method used for mixing the infusate at the bedside using equal volumes of aminosol glucose and dextrose electrolyte.

scalp' neei:lle

vein

__

--- ill>=~1 .

filter

pump

Body Weight 1400 Gm.

1200

Figure 8. Growth chart of an infant weighing 1160 gm., of 27 weeks' gestation, who had severe hyaline membrane disease. She was maintained on parenteral nutrition from birth until she died at the age of 31 days from bronchopulmonary dysplasia.

1000

800

_Oral

c::::J Parenteral feeding

600

400

~-~ i

o

i

10

i

20

AGE IN DAYS

i

30

PARENTERAL NUTRITION IN SICK

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Nitrogen Balance Positive nitrogen balances ranging from 147 to 366 mg. per kg. per day have been reported by various authors.22, 31, 79 Since the errors in metabolic balances tend to over-estimate retentions,102 these figures mostly fall rather below the calculated intrauterine retentions derived from body analysis (Table 3). This does not necessarily mean that larger intakes of nitrogen are required. The optimal utilization of one dietary substance cannot occur when another substance is growth limiting, and it is therefore unlikely that the optimum values for nitrogen intake and retention will be determined until all dietary essentials are provided in the amounts required for normal growth. Amino acid imbalance or toxicity53 may be another important factor.

COMPLICATIONS Table 10 lists the complications that have been reported by various authors. Infection is the most commonly reported,')' 7, tH. 20. 2.;. :11. :32. :39. 48. ,;(;. 58. (;1. (;4. 74. 79. 84. H2, 111 and the most dangerous complication, which constitutes the principle deterrent to the use of parenteral feeding in low birth weight infants.:17· 36 The very high incidence of fungal septicemia is particularly alarming. 3 • 7. 20, :)1. 58. 79. 81l In some cases there has been a pre-existing focus of fungal sepsis 2 • 7 but in others it has been thought to track down the catheter or to be due to contamination of the infusate at some pOint. Candida has been shown to grow in casein hydrolysate solutions,H9 so great care must be exercised in the manufacture of the solutions, which should

Table 10.

Some Complications Occurring During Parenteral Feeding Reported in the Literature

Infection Septicemia Fungal (usually Candida albicans),' 7. 20. 31. 39. '". 58. 61. 86. 92.111 BacteriaF' ;19, 56, 61, 64, 84. 92, 111 Local skin infection" Nutritional deficiencies Copper deficiency"6 Essential fatty acid deficiency Osmotic diuresis 7 . :n. :15, 39. 48, 6t. 64, 79, 84. 92, 1J 1, 115 Hypophosphatemia9 :!.IOI Fatal hyperalimentation syndrome" Hyperaminoacidemia22 • 44 Hyperammonemia44, 57, 62 Metabolic acidosis 9 • 3 .> Hepatic necrosis" Hepatic cirrhosis and cholestasis 62 • '" Thrombosis of central veins'" 61. 79. 84 Hypocalcemia and bone disease 7 • 61. 62 Occlusion and displacement of catheter'" 79 Knotting of catheter in heart6 :! Metal connector in heart'

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Table 11. Summary of the Results of Bacteriologic Investigations in 24 Infants Maintained on Total Parenteral Nutrition

ORGANISM

NO. OF

CLINICALLY APPARENT

POSITIVE CULTURES

INFECTION

20

Staphylococcus albus Aspergillus fumigatus Streptococcus hemolyticus GP D Total

o o

2

23

FREQUENCY OF POSITIVE CULTURES BY SITE

Site Dextrose electrolytes Aminosol glucose Prefilter Filter membrane Post-filter Catheter Skin swab before removal of catheter

No. of cultures

No. of positive cultures

Percent of cultures positive

152 149 44 12 42 13

2 3 4 2 9 2

1,3% 2.0% 9.0% 17% 21% 15%

8

12%

be prepared in the pharmacy rather than on the ward. 7 • 47 • Neomycin polybactrin bacitracin ointment applied to the skin while reducing the incidence of pathogens 75 is associated with a significant increase in the incidence of positive cultures for fungi,77. 116 and for this reason a providone-iodine preparation is recommended. 21 Using the technique described in this paper, we have had only one case of septicemia, due to Staphylococcus albus. This child recovered rapidly when the catheter was removed and penicillin given. In this instance the organism was inadvertently introduced into the filter unit on the infant's side of the filter. Inspite of the low rate of clinically detectable infections (4.0 per cent) we have had a high incidence of positive cultures in samples taken from various sites when the equipment is changed each day, a complication reported by other workers.25 Since these positive cultures were mostly sporadic and only one of the infants was infected with the organism, it is presumed that these positive cultures are due mainly to contamination in sampling, but they provide a useful indication of contamination of the outside of the equipment. The results are summarized in Table 11. It can be seen that the number of positive cultures increases, the closer to the infant the sample is taken, and it is clear that the most heavily contaminated junction and the one most likely to be the point of entry of infection is the filter connection that is on the infant's side of the filter membrane. We are therefore making determined efforts to remove the filter and that connection from inside the incubator, to protect it from casual handling, and to use a no-touch technique for the daily change. In this way the risk of introducing infection at this point should be substantially reduced. It must be emphasized however that acceptable infection rates can only be

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achieved by painstaking attention to detail, and a scrupulous aseptic technique. Thrombosis of major vessels due to damage to vasulcar endothelium from the hypertonic infusate has been reported (Table 10). We have had the opportunity of examining vessels with the catheter in situ at postmortem examination in those infants who died. In only two instances was there any thrombosis. In both these cases reliance had been placed upon measurement and too much catheter was inserted. The catheters coiled in the right atrium and in one case where the catheter touched the endothelium of the heart a small thrombus had formed. In the other case, the catheter re-entered the inferior vena cava where there was an extensive thrombus. Both these infants died of pulmonary insufficiency due to bronchopulmonary dysplasia, but the thrombi might easily have killed them. Where the catheters were properly positioned there was no visible damage to vascular endothelium nor any sign of any thrombus. These cases serve to emphasize the rule that the catheter position must always be checked radiologically. There has been one reported instance of these fine catheters forming a knot in the heart. Because the catheter was fine, the knot was small and no difficulty was encountered in removing it.6:1

METABOLIC COMPLICATIONS

H yperammonemia Following the demonstration of very high ammonia concentrations in protein hydrolysates ranging from 10,000 to 36,000 micrograms per .. 100 mI.,44, 45, 62 high blood ammonia concentrations have been reported in low birthweight infants during parenteral nutrition. 44 , 57, 62 Since these elevated levels occur during infusions of I-amino acids 57 which have a comparatively low ammonium concentration (600 to 700 micrograms per 100 mI.), as well as during infusions of protein hydrolysates; the quantity of the infused ammonium cannot be the only cause, and deficiency of urea cycle intermediates, has been postulated. 57 Heird et al,57 have shown that arginine Hel administered at 3.0 mM. per kg. per day abruptly reduced the blood ammonia concentration, and they further found that 0.5 to 1.0 mM. per kg. per day would prevent elevated blood ammonia levels in their patients. Johnson et aI., using smaller amounts of arginine, were unable to reduce the blood ammonia in their cases. Usually hyperammonemia is symptomless but in two cases 57 increasing lethargy leading to generalized grand mal fits occurred. Since high blood ammonia concentrations may damage the liver and the developing brain,62 periodic measurements must be made. We have not so far observed values more than 150 micrograms per 100 mI. on amino acid intakes of 2.5 gm. per kg. per day.

H yperaminoacidemia High blood amino acid levels have been reported in full term infants 44 and in low birth weight infants on parenteral feeding 44 - particularly methionine, lysine, threonine, glycine and serine. In some cases however blood values have been normal or low. 97 Since high blood levels may in-

J. C. L.

354

SHAW

jure the developing brain, it is probably reasonable to limit amino acid intake to about 2.5 gm. per kg. per day in these infants. We have not observed such high levels in our infants.73

H ypergl ycemia Because the poor glucose homeostasis of very low birth weight inmakes them liable to develop hyperglycemia and a dangerous osmotic diuresis, all urine passed must be tested for glucose, and periodic Dextrostix examinations should be performed. The administration of soluble insulin, 0.5 to 0.75 units, has been found to be effective in controlling serious hyperglycemia. 31 fants~6

CONCLUSIONS In this review I have outlined the case for using parenteral feeding in the case of sick, very low birth weight infants. With modern techniques it is possible to maintain low birthweight infants on total parenteral nutrition for quite long periods and for them to grow and develop during this time. Since however they are born with few body stores to subsidize their extremely rapid rate of growth it would seem reasonable in due course to aim to provide all known nutrients in adequate amounts. U sing the results of analyses of fetal bodies, I have calculated the rates at which elements accumulate in the fetus in utero. These values provide a useful reference standard for determining nutritional requirements of low birth weight infants and for evaluating the results of parenteral feeding. However, infusing substances at the rate they are accumulated in utero should be done prudently, and with frequent measurements, as such amounts may be harmful if over all growth rate is substantially less than that occurring in utero. The technique of parenteral feeding, though promising, has a definite mortality and morbidity which can only be kept at an acceptable level by obsessional attention to detaiJ.3l, 56 For this reason parenteral feeding is not yet ready for widespread use in the routine care of the low birthweight infant, and should only be used in those Units where the\"e are good facilities and abundant well trained staff. This point has recently been emphasized with some force. 37 In time, however, it seems likely that parenteral nutrition will earn itself a place in the routine management of the sick low birth weight infant.

REFERENCES 1. AI-Rashid, R. A., and Spangler, J.: Neonatal copper deficiency. New Eng. J. Med., 285:841, 1971. 2. Amris, C., Brockner, J., and Larsen, V.: Changes in the coagulability of the blood during the infusion of Intralipid. Acta. Chir. Scand. Supp!., 325:70,1964. 3. Ashcraft, K. W., and Leape, L. L.: Candida sepsis complicating parenteral feeding. J.A.M.A., 212:454,1970. 4. Auld, P. A. M., Bhangananda, P., and Mehta, S.: The influence of an early caloric intake with LV. glucose on catabolism of premature infants. Pediatrics, 37:592, 1966. 5. Babson, S. G.: Feeding the low birthweight infant. J. Pediat., 79:694, 1971.

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6. Benda, G. L M., and Babson, S. G.: Peripheral intravenous alimentation of the small premature infant. J. Pediat., 79:494, 1971. 7. Boeckman, C. R., and Krill, C. E., Jr.: Bacterial and fungal infections complicating parenteral alimentation in infants and children. J. Pediat. Surg., 5:117,197. 8. Bryan, H. M., Wei, P., Hamilton, R., et al.: Controlled study of LV. fibrin hydrolysate supplements in prematures less than 1.3 kg. Meeting of the Amer. Ped. Soc. Inc., & The So<;. for Ped. Res., April 1971. Abstract. In: Pediat. Res., 5:413, 1971. 9. Chan, J. C. M., Asch, M. J., Lin, S., et al.: Mechanism of acidosis complicating total intravenous alimentation with casein hydrolysate and synthetic amino acid infusions. Combined program and abstracts. Meeting of the Amer. Ped. Soc. Inc. and Soc. for Ped. Res., May 1972. In Pediat. Res., 6:137,1972. 10. Christensen, H. N., Wilber, P. B., Coyne, B. A.: Effects of simultaneous or previous infusion of sugars on the utilization of infused amino acids. Surg. Forum, 5:434, 1955. 11. Christensen, H. N., Lynch, E. L., Decker, D. G., et al.: A difference in utilization of the peptides of hydrolysates of fibrin and casein. J. Clin. Invest., 26:849,1947. 12. Christensen, H. N., Wilber, P. B., Coyne, B. A., et al.: Effects of simultaneous or prior infusion of sugars on the fate of infused protein hydrolysates. J. Clin. Invest., 34:86, 1955. 13. Christensen, H. N., and Lynch, E. L.: Peptidemia and hyperpeptiduria as a result of the intravenous administration of partially hydrolysed casein. J. BioI. Chern., 166:649, 1946. 14. Cobos, F.: Malnutrition and mental retardation: Conceptual issues. In :Lipids, Malnutrition and the Developing Brain. Ciba Foundation Symposium. New York, Assoc. Scientific Publishers, 1972, p. 227. 15. Collins, F. D., Sinclair, A. J., Royle, J. P., et al.: Linoleic acid deficiency in man. Proceedings of 2nd International Symposium on Atherosclerosis. Ed: R. J. Jones. New York, Springer-Verlag, 1970. 16. Collins, R. M., Braun, P. A., and Zinner, S. H.: Risk of local and systemic infection with polyethylene intravenous catheters. New Eng. J. Med., 279:340, 1968. 17. Cox, W. M., and Filer, L. J., Jr.: Protein intakes for low birthweight infants. J. Pediat., 74:1016,1969. 18. Crampton, R. F.: Nutritional and metabolic aspects of peptide transport. In: Peptide Transport in Bacteria and Mammalian Gut. Ciba Foundation Symposium. New York. Assoc. Scientific Publishers, 1972. p. 1. 19. Cronberg, S., and Nilsson, LM.: Coagulation studies after administration of a fat emulsion, Intralipid. Thromb. Diath. Hemorrh., 18:664, 1967. 20. Curry, C. R., and Quie, P. G.: Fungal septicemia in patients receiving parenteral hyperalimentation. New Eng. J. Med., 285:1221,1971. 21. Curry, C. R., and Quie, P. G.: Contamination of in use hyperalimentation solutions. New Eng. J. Med., 286:613, 1972. 22. Das, J. B., Filler, R. M., Rubin, V. G., et al.: Intravenous dextrose amino acid feeding: The metabolic response in the surgical neonate. J. Pediat. Surg., 5:127,1970. 23. Davies, L J. T.: The Clinical Significance of the Essential Biological Metals. London, Wm. Heineman Medical Books, Ltd., 1972. 24. Davison, A. N., and Dobbing, J.: The developing brain. In Davison, A. N., and Dobbing, J., eds.: Applied Neurochemistry. Oxford, Blackwell Scientific Publications, 1968. 25. Deeb, E. N., and Natsios, G. A.: Contamination of "in use" hyperalimentation solutions. New Eng. J. Med., 286:613, 1972. 26. Dobbing, J.: Undernutrition and the developing brain. The relevance of animal models to the human problem. Amer. J. Dis. Child., 120:411, 1970. 27. Dobbing, J.: Vulnerable periods in the developing brain. In Davison, A. N., and Dobbing, J., eds.; Applied Neurochemistry. Oxford, Blackwell Scientific Publications, 1968. 28. Dobbing, J.: Vulnerable periods of brain development. In Lipids, Malnutrition & the Developing Brain, Ciba Foundation Symposium. New York, Assoc. Scientific Publishers, 1972, p. 9. 29. Dobbing, J., and Sands, J.: The timing of neuroblast multiplication in developing human brain. Nature (Lond.). 226:639, 1970. 30. Documenta Geigy-Scientific Tables. Diem, K., ed., 1970. 31. Driscoll, J. M., Heird, W. C., Schullinger, J. N., et al.: Total intravenous alimentation in low birthweight infants: A preliminary report. J. Pediat., 81 :145, 1972. 32. Dudrick, S. J., Long, J. M., Steiger, E., et al.: Intravenous hyperalimentation. Med. Clin. N. Amer., 54:577, 1970. 33. Dudrick, S. J., Vars, H. M., Rawnsley, H. M., et al.: Totalintravenous feeding and growth in puppies. Fed. Proc., 25:481,1966. 34. Dudrick, S. J., Wilmore, D. W., and Vars, H. M.: Longterm total parenteral nutrition with growth, development and positive nitrogen balance. Surgery, 64:134,1968. 35. Duncan, J., and Usher, R.: Nutritional support of the under 1500 gram premature infant with intravenous fat, protein hydrolysate and glucose. Combined Program & Ab-

356

36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67.

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stracts. The Amer. Pediat. Soc. Inc., & Soc. for Pediat. Res., May 1972. In Pediat. Res., 6:148,1972. Dweck, H. S., Siegal, A. M., and Cassady, G.: Glucose intolerance in infants of very low birthweight. Combined Program and Abstracts. The Amer. Pediat. Soc. Inc., & Soc. for Pediat. Res., May 1972. In Pediat. Res., 6:149,1972. Filer, L. J., Jr., Barness, L. A., Goldbloom, R B., et al.: Parenteral feeding-A note of caution. Pediatrics, 49:776, 1972. Filler, R M., Das, J. B., Rubin, V. G., et al.: Total intravenous nutrition in infants with a dextrose fibrin hydrolysate mixture. In Fox, C. L., and Nahas, G. G., eds.: Body Fluid Replacement in the Surgical Patient. New York, Grune and Stratton, 1970. Filler, R M., and Eraklis, A. J.: Care of the critically ill child: Intravenous alimentation. Pediatrics, 46:456, 1970. Filler, R M., Eraklis, A. J., Rubin, V. G., et al.: Longterm total parenteral nutrition in infants. New Eng. J. Med., 281 :589, 1969. Fomon, S. J.: Infant Nutrition. Philadelphia, W. B. Saunders Co., 1967. Fomon, S. J., and May, C. D.: Metabolic studies of normal full term infants fed pasteurized human milk. Pediatrics, 22:101, 1958. Gaull, G., Sturman, J. A., and Riiihii, N. C. R: Development of mammalian sulfur metabolism: Absence of cystathionase from foetal tissues. Pediat. Res., 6:538, 1972. Ghadimi, H., Abaci, F., Kumar, S., et al.: Biochemical aspects of intravenous alimentation. Pediatrics, 48:955, 1971. Ghadimi, H., and Kumar, S.: High ammonia content of protein hydrolysate. Biochem. Med., 5:548, 1971. Gordon, H. H., Levine, S. Z., Wheatly, M. A., et al.: Respiratory metabolism in infancy and childhood XX. The nitrogen metabolism in premature infants-comparative studies of human and cows milk. Amer. J. Dis. Child., 54:1030, 1937. Grant, J. A. N., Moir, E., and Fago, M.: Parenteral hyperalimentation. Amer. J. Nursing, 69:2392, 1969. Groff, D. B.: Complications of intravenous hyperalimentation in newborns and infants. J. Pediat, Surg., 4:460, 1969. Gruppo, R A., and Graham, G. G.: Total parenteral alimentation solution. Bull. Johns Hopkins Hosp., 127:352, 1970. Gustafson, A., Kjellmer, 1., Olegiird, R, et al.: Nutrition in low birth weight infants. 1. Intravenous injection of fat emulsion. Acta. Paed. Scand., 61 :149,1972. Hallberg, D., Holm, 1., Abel, A. L., et al.: Fat emulsions for complete intravenous nutrition. Post Grad. Med. J., 43:307, 1967. Hansen, A. E., Wiese, H. F., Boelsche, A. N., et al.: Role of linoleic acid in infant nutrition. Pediatrics, 31 :171,1963. Harper, A. E., Benevenga, N. J., and Wohlhueter, R M.: Effects of ingestion of disproportionate amounts of amino acids. Physiol. Rev., 50:428, 1970. Harries, J. T.: Intravenous feeding in infants. Arch. Dis. Childh., 46:855, 1971. Heird, W. C., Dell, R B., and Winters, R W.: Acid-base properties of "hyperalimentation" solutions. Combined Program & Abstracts. The Amer. Ped. Soc. Inc. & The Soc. for Ped. Res., May 1972. In Pediat. Res., 6:69, 1972. Heird, W. C., Driscoll, J. M., Jr., Schullinger, J. N., et al.: Intravenous alimentation in pediatric patients. J. Pediat., 80:351, 1972. Heird, W. C., Nicholson, J. F., Driscoll, J. M., Jr., et al.: Hyperammonemia resulting from intravenous alimentation using a mixture of synthetic L-amino acids: A preliminary report. J. Pediat., 81 :162,1972. Helmuth, W. V., Adam, P. A. J., and Sweet, A. Y.: The effects of protein hydrolysatemonosaccharide infusion on low birthweight infants. J. Pediat., 81 :129, 1972. Holt, L. E., Jr., and Snyderman, S. E.: The amino acid requirements of infants. J.A.M.A., 175:100,1961. Hyman, C. J., Reiter, J., Rodnan, J., et al.: Parenteral and oral alimentation in the treatment of the non-specific protracted diarrheal syndrome of infancy. J. Pediat., 78:17, 1971. Johnson, D. G.: Total intravenous nutrition in newborn surgical patients: A three year perspective. J. Pediat. Surg., 5:601, 1970. Johnson, J. D., Albritton, W. L., and Sunshine, P.: Hyperammonemia accompanying parenteral nutrition in newborn infants. J. Pediat., 81: 154, 1972. Jones, C., and McIntosh, N.: A new longterm catheter problem. 1973, In press. Kaplan, M. S., Mares, A., Quintana, P., et al.: High caloric glucose nitrogen infusions. Arch. Surg., 99:567, 1969. Kapp, J. P., Duck~t, F., and Hartman, G.: Platelet adhesiveness and serum lipids during and after Intralipid infusions. Nutrit. Metab., 13:92, 1971. Karpel, M. D., and Peden, M. D.: Copper deficiency in longterm parenteral nutrition. J. Pediat., 80:32, 1972. Keating, J. P., and Ternberg, J. L.: Amino acid hypertonic glucose treatment forintractable diarrhea in infants. Amer. J. Dis. Child., 122:226, 1971.

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68. Kelly, H. J., Sloan, R E., Hoffman, W., et al.: Accumulation of nitrogen and six minerals in the human foetus during gestation. Human BioI., 2:61, 1950. 69. Kildeberg, P., Engel, K., and Winters, R. W.: Balance of net acid in growing infants Endogenous and transintestinal aspects. Acta. Paed. Scand., 58:321, 1969. 70. Kloosterman, G. J.: On intrauterine growth. Int. J. Gynec. Obstet., 8:895, 1970. 7l. Lubchenko, L. 0., Hansman, C., Dressler, M., et al.: Intrauterine growth as estimated from liveborn birthweight data at 24 to 42 weeks of gestation. Pediatrics, 32:793, 1963. 72. Mann, T. B., Wilson, K. M., and Clayton, B. E.: A deficiency state arising in infants on synthetic foods. Arch. Dis. Childh., 40:364, 1965. 73. McAlpine, P., and Shaw, J. C. L.: Unpublished data. 74. Michener, W. M., and Law, D.: Parenteral nutrition: The age of the catheter. PEDIAT. CLIN. N. AMER., 17:373, 1970. 75. Moran, J. M., Atwood, R. P., and Rowe, M. I.: A clinical and bacteriologic study ofinfections associated with venous cut down. New Eng. J. Med., 272:554, 1965. 76. Nicolopoulos, D. A., and Smith, C. A.: Metabolic aspects of respiratory distress (hyaline membrane syndrome) in newborn infants. Pediatrics, 28:206, 1961. 77. Norden, C. W.: Application of antibiotic ointment to the site of venous catheterisation. J. Infect. Dis., 120:611, 1969. 78. Paoletti, R, and Galli, C.: Effects of essential fatty acid deficiency on the central nervous system in the growing rat. In Lipids, Malnutrition and the Developing Brain. Ciba Foundation Symposium. New York, Assoc. Scientific Publishers. 1972, p. 122. 79. Peden, V. H., and Karpel, J. T.: Total parenteral nutrition in premature infants. J. Pediat., 81 :137,1972. 80. Peden, V. H., Witzleben, C. L., and Skelton, M. A.: Total parenteral nutrition. J. Pediat., 78: 180, 1971. 8l. Peter, G., Lloyd-Still, J. D., and Lovejoy, F. H.: Local infection and bacteremia from scalp vein needles and polyethylene catheters in children. J. Pediat., 80:78, 1972. 82. Raffensperger, J. C., and Ramenofsky, M. I.: A fatal complication of hyperalimentation: A care report. Surgery, 68:393, 1970. 83. Rawlings, G., Reynolds, E. O. R., Stewart, A., et al.: Changing prognosis for infants of very low birthweight. Lancet, 1 :516, 1971. 84. Rea, W. J., Wyrick, W. J., McClelland, R N., et al.: Intravenous hyperosmolar alimentation. Arch. Surg., 100:393, 1970. 85. Rivers, R P. A., and Shaw, J. C. L.: Unpublished data. 86. Rodrigues, R J., Shinya, H., and Wolff, W. I.: Torulopsis glabrata fungaemia during prolonged intravenous alimentation therapy. New Eng. J. Med., 284:540, 1971. 87. Sandstead, H. H., Gillespie, D. D., and Brady, R N.: Zinc Deficiency: Effect on brain of the suckling rat. Pediat. Res., 6: 119, 1972. 88. Scott, K. E., Duncan, J., Belgaumkar, T. K., et al.: Role of intravenous nutrition in reduction of premature infant mortality. Clin. Res., 18:741, 1970. 89. Shadomy, S., and Shadomy, J. H.: Growth of candida in casein hydrolysate solutions. New Eng. J. Med., 286:612, 1972. 90. Shaw, J. C. L.: Unpublished data. 91. Shelley, H. J., and Neligan, G. A.: Neonatal hypoglycaemia. Brit. Med. Bull., 22:34, 1966. 92. Sherman, J. 0., Egan, T., and Macalalad, F. V.: Parenteral hyperalimentation: A useful surgical adjunct. Surg. Clin. N. Amer., 51 :37, 1971. 93. Silvis, S. E., and Paragas, P. V., Jr.: Fatal hyperalimentation syndrome. Animal studies. J. Lab. Clin. Med., 78:918, 1971. 94. Sinclair, J. C., Driscoll, J. M., Heird, W. C., et al.: Supportive management of the sick neonate. Pediat. Clin. N. Amer., 17:863, 1970. 95. Smits, H., and Freedman, L. R.: Prolonged venous catheterization as a cause of sepsis. New Eng. J. Med., 276:1229,1967. 96. Snyderman, S. E.: The protein and amino acid requirements of the premature infant. In Jonxis, J. H. D., Visser, H. K. A., and Troelstra, J. A.: Nutricia symposium. Metabolic processes in the foetus and the newborn infant. Leiden, Stenfert Kroese N.V. 97. Stegink, L. D., and Baker, G. L.: Infusions of protein hydrolysates in the newborn infant: Plasma amino acid concentrations. J. Pediat., 78:595, 1971. 98. Sturman, J. A., Gaull, J. G., and Ritihii, N. C. R: Absence of cystothionase in human foetal liver; is cysteine essential. Science, 169:74, 1970. 99. Subramanyam, R, Cordero, G. V., Wong, P. W. K., et al.: Intravenous supplementation of pure L-amino acids and dextrose in low birthweight infants. Combined Program & Abstracts. The Amer. Pediat. Soc. Inc., & The Soc. for Pediat. Res., May 1972. In Pediat. Res., 6:143,1972. 100. Tkacenko, S. K.: Postuplenie i vyredenie nekotoryh microiHementov u nedonosennyh detj. (Intake and excretion of some trace elements in premature infants). Pediatrija, 10: 10, 1970. 101. Travis, S. F., Sugerman, H. J., Ruberg, R. L., etal.: Alterations of red cell glycolytic inter-

358

102. 103. 104. 105. 106. 107. 108. 109. 110. Ill.

112. 113. 114. 115. 116. 117.

J. C. L.

SHAW

mediates and oxygen transport as a consequence of hypophosphataemia in patients receiving intravenous hyperalimentation. New Eng. J. Med., 285:763, 1971. Wallace, W. M.: Nitrogen content of the body and its relation to retention and loss of nitrogen. Fed. Proc., 18:1125, 1959. Widdowson, K M.: Trace elements in human development. In Barltrop, D., and Burland, W. L.: Mineral Metabolism in Paediatrics. London, Davis Co., 1969. Widdowson, K M., and Dickerson, J. W. T.: In Comar, C. L., and Bronner, F., eds.: Mineral Metabolism. New York, Academic Press, 1961, Vol. II, Pt. A. Widdowson, K M., and McCance, R. A.: Some effects of accelerating growth. 1. General somatic development. Proc. Roy. Soc. B., 152:188, 1960. Widdowson, K M., and Kennedy, G. C.: Rate of growth, mature weight and life span. Proc. Roy. Soc. B., 156:96, 1962. Widdowson, E. M., and McCance, R. A.: The effect of finite periods of undernutrition at different ages on the composition and subsequent development of the rat. Proc. Roy. Soc. B., 158:329, 1963. Willis, D. M., and Usher, R. H.: Postnatal growth and body water compartments of small premature infants. Combined Program & Abstracts. The Amer. Pediat. Soc. Inc., & The Soc. for Pediat. Res., May 1972. In Pediat. Res., 6:154,1972. Wilmore, D. W., and Dudrick, S. J.: Growth and development of an infant receiving all nutrients exclusively by vein. J.A.M.A., 203:860, 1968. Wilmore, W. D., and Dudrick, S. J.: Treatment of acute renal failure with intravenous essential L-amino acids. Arch. Surg., 99:669, 1969. Wilmore, D. W., Groff, D. B., Bishop, H. C., et al.: Total parenteral nutrition in infants with catastrophic gastrointestinal anomalies. J. Pediat. Surg., 4:181, 1969. Wilson, K. M., and Clayton, B. K: Importance of choline during growth with particular reference to synthetic diets in phenylketonuria. Arch. Dis. Childh., 37:565, 1962. Winick, M.: Cellular growth in intrauterine malnutrition. PEDIAT. CLIN. N. AMER., 17:69, 1970. Winick, M., and Rosso, P.: The effect of severe early malnutrition on cellular growth of the human brain. Pediat. Res., 3:181,1969. Wyrick, W. J., Jr., Rea, W. J., and McClelland, R. N.: Rare complications with intravenous hyperosmotic alimentation. J.A.M.A., 211 :1697,1970. Zinner, S. H., Denny Brown, B. C., Braun, P., et al.: Risk of infection with intravenous indwelling catheters: Effect of application of antibiotic ointment. J. Infect. Dis., 120:616, 1969. Zumbro, G. L., Mellin, M. J., and Nelson, T. G.: Catheter placement in infants needing total parenteral nutrition utilizing the common facial vein. Arch. Surg., 102:71, 1971.

Department of Paediatrics University College Hospital Medical School Gower Street London, WC1E 6 AU England