24

Serial changes in selected serum constituentsin low birth weight infants on peripheralparenteral nutrition with different zincand copper supplements1-3Giiian Lockitch, FRCP(C), Margaret R Pendray, FRCP(C),William J Godolphin, PhD, and Gayle Quigley, RT

ABSTRACT One hundred and five infants of birth weight 2000 g or less who receivedperipherally administered parenteral nutrition for periods of three or more weeks� were randomlyassigned to groups receiving different amounts of zinc and copper supplement. The blood

concentrations of zinc, copper, retinol-binding protein, prealbumin, alkaline phosphatase andaspartate transaminase were followed weekly. Mean serum zinc, retinol-binding protein and

prealbumin declined significantlyover time while alkaline phosphatase rose. Only the groupreceiving the highest zinc supplement maintained a mean serum zinc concentration within the

normal range at seven weeks. No difference in the protein or enzyme concentrations was foundbetween the different zinc supplement groups. No difference was seen in serum copper orceruloplasmin between copper dose groups although one intravenous supplement was double thatof the other. Am J Clin Nut,’ 1985;42:24-30.

KEY WORDS Parenteral nutrition, zinc, copper, ceruloplasmin, retinol-binding protein,

prealbumin, alkaline phosphatase, aspartate aminotransferase, preterm infant

Introduction

The standard intravenous supplement pro-vided since the mid-seventies to infants onparenteral nutrition in our nursery was 40�g/kgJday zinc and 20 �tg/kgJday of copperin accordance with early recommendations(1). Suggestions that the zinc supplementshould be increased (2) prompted an initialevaluation of the effect of different zinc andcopper supplements on serum zinc and cop-per and several related serum proteins in thepreterm infants during the first two weeks ofparenteral nutrition (3).

To determine whether higher zinc andcopper supplements would benefit the lowbirth weight infant on longer term parenteralnutrition, we monitored the change in serumconcentration of zinc, copper, related proteinsand enzymes in newborn infants who receivedzinc and copper supplemented peripheralparenteral nutrition (PN) over a period ofseven weeks or longer. The results of a study

of acquired acrodermatitis in these infantshave been described elsewhere (4).

Methods

Low birth weight infants admitted to the neonatalIntensive Care Nursery (ICN) over an eighteen-monthperiod, who commenced PN during the first 10 days oflife, for a variety of clinical indications, were grouped bybirth weight (BW) into a weight group and then randomlyassigned within weight groups to one of seven supplementgroups (3). The first group received our standard supple-ment of 40 pg zinc and 20 pg copper per kg body weightper day. The remaining groups received either 100, 200,

‘From the Departments of Pathology and Pediatricsof Children’s Hospital, Vancouver General Hospital andUniversity of British Columbia.

2 by a grant from the British ColumbiaHealth Care Research Foundation.

3Address reprint requests to: Dr G Lockitch, Depart-ment of Pathology, Children’s Hospital, 4480 Oak St,Vancouver, BC, Canada, V6H 3V4.

Received October 12, 1984.Accepted for publication January 15, 1985.

The American Journal of Clinical Nutrition 42: JULY 1985, pp 24-30. Printed in USA© 1985 American Society for Clinical Nutrition

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PARENTERAL NUTRITION IN LOW BIRTH WEIGHT INFANTS

or 400 pg zinc and either 20 or 40 pg copper per kgbody weight per day. This supplement was added to acommercial intravenous mineral preparation, PediatricElectrolyte Solution (PES) (Pharmacia, Dorval, Quebec)and infused with the first twelve-hour infusion fluidseach day from mid-afternoon to early the followingmorning. This standard PN infusion provided 2.1 gprotein and 4 g Intralipid (Vitrum Co. Stockholm) perkg/day. Vitamin D, calcium, and phosphorus intakesdid not differ between the groups and remained constantthroughout the study.

Blood samples were collected between 0700 and 0930h on a specific day of the week for any one infant. Thesampling day was recorded as the actual number of daysafter birth. For the purpose of analysis the weeks werecalculated as follows: specimens obtained on samplingdays 0-4 were considered as week 1, days 5-10 = week2, days 11-17 = week 3, days 18-24 = week 4, days25-31 = week 5, days 32-38 = week 6, and days 39-45= week 7. The samples obtained in week I were collectedbefore PN was begun for each infant and comprise theinitial or baseline values.

Blood was collected weekly for serum zinc and copperanalysis by atomic absorption spectrophotometry withdeuterium background correction (Perkin-Elmer Model503, Norwalk, CT) with air acetylene flame for zinc andHGA-2000 graphite furnace for copper (5, 6). Retinol-binding protein (RBP), pre-albumin (PA), and cerulo-plasmin (CPL) were measured every second week byradial immunodiffusion, using plates from Behring Di-agnostic (Montreal) for RBP and PA and Hyland Diag-nostics (Deerfield, IL) for CPL

Alkaline phosphatase (ALP) is a zinc-dependent en-zyme which has been suggested as a functional markerfor zinc deficiency (7, 8). ALP increases gradually in theterm newborn during the first 3 mo of life (9). Cholestaticliver disease (10) and rickets (11) both of which may beassociated with elevated ALP may complicate long-termPN in the preterm infant. We monitored serum ALPover the 7-wk period to determine whether zinc supple-mentation would influence the change in values. Wealso monitored changes in serum aspartate aminotrans-ferase (AST) as an enzyme of hepatocellular origin tocompare with changes in ALP.

Precautions were taken to ensure that trace metalcontamination did not occur. Hemolyzed specimenswere not included in the study. Serum copper andceruloplasmin values from infants who had receivedplasma transfusions within 5 days prior to blood collectionwere excluded from the data analysis (12).

The evaluation of zinc, copper, and the proteins wasthe primary focus of the study. Since many of theseinfants were very low birth weight, blood sample sizewas a major restricting factor and data for other bloodchemistries such as the enzymes was obtained only whenthe tests were ordered by the neonatologists for routinemanagement of the infants. In order to evaluate thechanges that occur with medium- to long-term PN onlyresults from infants who received PN for a minimum ofthree weeks were included. Over the seven-week periodconsidered here, infants stopped PN or were dischargedto another hospital so that the study numbers declinefrom week one to week seven.

We attempted to obtain concurrent urine samples butcomplete and uncontaminated urine samples were difficult

to obtain consistently in these very tiny infants. We alsowished to contrast preterm infants who did not requirePN as a control group but this proved impossible sincethe few infants in this category were of significantlyhigher mean birth weight than the other infants and fewremained long enough in the ICN to provide suitablecontrol data (see Table I Non-PN group).

Data was analyzed using statistical programs for cor-relation, linear regression and analysis of variance betweengroups (13).

The research protocol was approved by the ScreeningCommittee for Research on Human Subjects of theUniversity of British Columbia.

Results

There were 105 infants of BW <2000 gentered into the study who required PN forat least three weeks.

Since we had shown earlier that initialserum zinc concentration is inversely pro-

-portional to BW (3) we examined the distri-bution of birth weight between the varioussupplement groups to ensure that the resultswere not biased by nonrandom BW distri-bution at onset and found no significantdifference at onset between the mean BW ofthe four zinc supplement groups and the twocopper supplement groups or the seven dif-ferent groups. We also calculated the meanBW each week for the whole group, zincgroups and copper groups during the sevenweeks of the study observing that no signifi-cant change occurred over the study period.

The mean serum concentrations for eachweek on PN over the study period is shownin the tables. In Table 1 the complete datafor the change in serum zinc concentrationby weight group, zinc supplement group, andcopper supplement group is given. Similartables are available for the other constituentsbut only the results for the whole study groupare presented in Tables 2 and 3.

There is a decline in mean (±SD) serumzinc concentration of 46 (±24) �g/dl overseven weeks for the group as a whole. Themagnitude of the drop in zinc level is greaterin the tiny baby (53 zg/dl in the infants< 1000 g versus 23 �g/dl in the infants of1501-2000 g) although for any specific weekthe difference between the weight groupsdoes not show statistical significance. Thedrop is greater in the lowest zinc supplementgroup than in the higher groups. The levelof copper supplement did not appear to affect

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20 �ig 40 �ig Non-PN group

Week n i(SD) n i(SD) n i(SD)

4 100(15) 0.59 100 114(29)0 - 0.93 89 108 (26)0 - 0.19 105 102 (26)0 - 0.31 82 93(26)0 - 0.01 63 81(26)0 - 0.01 51 70(19)0 - 0.83 28 68 (24)

<0.001

26 LOCKITCH ET AL

Significance of difference between groups by analysis of variance.

TABLE 1Change in a mean serum zinc concentration (pg/dl) with time by weight group, zinc group, copper group, non-PNgroup, and total group

Weight groups (g)

<1000 1001-1250 1251-1500 1501-2000

Week n i(5D) n i(SD) n i(SD) n i(SD) p’

1234567

p�

33334034283019

123(26)114 (29)104 (29)

90 (22)80 (24)70(19)65 (21)

<0.001

362836292314

9

116(31) 23107 (27) 19105 (24) 18101 (27) 14

87 (28) 874(16) 374 (29) 0

<0.001

106(23)105 (19)

90 (20)84 (24)75 (29)

-

-

<0.001

89

115440

87(21)90(13)

104 (24)82 (24)63 (18)64(18)

-

0.009

0.0050.080.160.080.310.420.38

40g&g

Zinc groups

100�sg 200ug 400Mg

Week n i(SD) n i(SD) n i(SD) n i(SD) p

1 16 112(30) 35 112(34) 31 117(27) 14 114(18) 0.852 17 105(21) 31 107(34) 26 104(18) 15 116(24) 0.513 22 97(24) 31 92(26) 36 106(23) 16 118(24) 0.0044 15 84(23) 27 94(29) 30 93(21) 10 102(27) 0.365 13 65 (26) 20 81(22) 20 84 (26) 10 95 (27) 0.046 9 52 (22) 17 69 (10) 16 74 (18) 9 81(16) 0.0037 3 - 9 54 (8) 9 70 (27) 7 90 (19) 0.006

p <0.001 <0.001 0.001 0.001

Copper groups

53 114(29) 43 116(32)2 55 108 (25) 34 107 (28)3 65 99(25) 40 106(27)4 46 90 (24) 36 96 (26)5 32 73 (25) 36 89 (25)6 27 64(20) 24 76(15)7 12 69(23) 16 67(27)

<0.001 0.001

* Significance of difference between groups by analysis of variance.

Total group

PS n i(SD)

serum zinc concentration although at 5 and groups with the higher zinc level in the higher6 wk the mean zinc concentration did differ copper dose group. By the seventh week thesignificantly between the two copper dose mean zinc levels in the 2 groups were equal.

TABLE 2Change in mean serum concentration over time for whole study group for copper, ALP and AST

Copperwk

Cu (pgjdl) ALP (lU/L)

n

AST (lUlL)

i(5D)n i(5D) n i(SD)

1 100 38 (18) 63 204 (68) 54 18 (9)2 89 40 (18) 77 272 (96) 79 16 (14)

3 100 39(17) 94 291(110) 96 17(17)

4 82 37(15) 71 364(139) 68 15(6)

5 63 37(15) 51 407(190) 50 17(16)

6 51 38(14) 38 530(240) 37 15(8)

7 28 40 (15) 25 602 (263) 26 17 (5)p5 NS 0.001 NS

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PARENTERAL NUTRI11ON IN LOW BIRTH WEIGHT INFANTS 27

TABLE 3Change in serum protein concentrations over time for whole study group

wk n

Ceruloplasinin(mg/dl)

i(SD)

Retinol binding protein(mgjdl)

Prealbumin(msJdl)

n i(SD) n i(SD)

1 94 11(6) 100 2.1 (0.7) 100 8.7 (3)2 27 10 (5) 27 2.0 (0.9) 28 9.5 (4)3 49 10 (4) 50 1.9 (0.9) 51 9.2 (4)4 36 10 (5) 33 1.7 (0.8) 37 8.3 (3)5 27 8 (4) 26 1.2 (0.5) 26 5.8 (3)6 25 10 (3) 23 1.2 (0.3) 26 5.6 (2)

p NS <0.001 <0.001

* Significance of difference between groups by analys is of variance.

Serum copper concentration at birth wasunrelated to BW (3). The initial mean serumcopper and CP concentration did not differsignificantly between weight groups, zinc orcopper dose groups. There was no significantchange in the mean serum copper concentra-tion for the group as a whole between weeks1 and 7 (Table 2) nor within each copperdose group, and the two copper groups donot differ significantly despite an intake inthe higher group that is double that of thelower group. There was no significant differ-ence in mean copper levels between zincdose groups. The CP levels similarly did notchange significantly over time, reflecting thefact that CP-bound copper represents themajor portion of serum copper. The corre-lation coefficient between concentrations ofCU and CP was r = 0.8.

Initial serum concentrations of CP, RBP,and PA were unrelated to BW. Neither wasthere any correlation with initial serum zincconcentration for either RBP (r = 0.09) orPA (r = 0.03). The initial copper and CPconcentrations showed a weak negative cor-relation with initial zinc concentration (r= -0.25 p <0.001 and r = -0.26 p <0.001respectively).

Both for the copper groups and the groupas a whole, RBP and PA showed a steadyand significant decline between the first andseventh week (Table 2). Although the levelsdeclined in all the zinc groups, the dropcould not always be shown to reach statisticalsignificance. This may reflect in part thesmall numbers in the groups as well as thewide range of values as evidenced by therelatively large standard deviations.

The correlation between PA and RBP washigh as expected (r = 0.56 p <0.001) while

both showed a weak positive correlation withserum zinc over time (r = 0.34 p <0.001for RBP and r = 0.25 p <0.001 for PA).

The mean values of serum ALP and ASTmeasured within 1-4 days of birth werecompared with the reference values in ourlaboratory for term newborns. The mean± SD of ALP for the study (<2000 g) groupwas the same as that for term newborns ie207 ±71 lU/L. The mean ± SD of AST wasalso similar to that of our term newborns(41 ± 14 lU/L). The initial serum concentra-tion of ALP correlated with initial serumzinc concentration (r = 0.35 p =0.005) whileAST did not (r = 0.13 p = NS).

There was a steady increase in ALP overthe 6-week period for the group as a whole.Although within each dose group and eachweight group a significant increase in ALPwas seen with each succeeding week, meanALP values did not differ significantly be-tween the zinc dose groups, copper dosegroups or weight groups for any one week.Conversely the mean AST level did notchange over time in either the total group,weight groups, zinc or copper dose group.The mean values of ALP and AST for thegroup as a whole are given in Table 2.

Discussion

The drop in serum zinc noted in the first2-wk period of PN in the 40 �gfk�day zincsupplement group (3) continued with amarked decline in mean serum zinc over 6wk but whereas no change in mean zincconcentration was seen over 2 wk in thehighest supplement group, by 6 wk a dropin mean concentration of 33 �g/dl had oc-curred. However the mean value remained

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28 LOCKITCH El AL

within the normal range even at 7 wk, inthis group alone.

The significance of serum zinc concentra-tion as an indicator of initial and alteringbody zinc status in the newborn is unclear.The range of initial zinc levels in the infantsas a whole (mean ± 2 SD = 56-172 �sg/dl)shows a wider scatter than our adult normalrange of 80-120 �g/dl. When the weightgroups are considered independently therange in the 1000 g group (70-175 �sg/dl) ishigher than the adult range while the 150 1-2000 g group (45-130 �tg/d1) is lower. Otherstudies (14, 15) have also shown an inverserelationship of gestational age to initial serumzinc concentration without satisfactory ex-planation. Fetal zinc accretion has been cal-culated to increase from about 256 big/dayat 28 wk to almost 600 zg/day at 36 wk (16).The lower initial level in the term infant mayrelfect maternal inability to meet this in-creased demand or may simply reflect a moreefficient ability to clear zinc to body storesso that the intrauterine zinc requirement ofthe term infant needed to maintain a givenserum concentration exceeds that of the pre-term infant.

The subsequent decline in serum zinc re-sults in levels below the adult range in eventhe 400 �tg dose group. A study of growingpremature children fed standard infant for-mula showed that serum zinc decreased sig-nificantly over the first 6 wk in all the infants.No correlation was seen with growth rates,length or zinc intake but a highly significantcorrelation was seen with postconceptual age(17). The authors suggested a postmatura-tional change in gastrointestinal zinc absor-bance. However several studies of infants onparenteral nutrition have also shown a dropin serum zinc concentration with time (14,18, 19).

A distinct difference in the decline in serumzinc was seen with the different doses of ourintravenously supplemented groups where gutabsorption plays no role. Since in addition,serum zinc dropped in all our infants despiteintravenous supplementation it is apparentthat factors other than absorptive mechanismsmust be involved. An important factor isprobably increased urinary loss of zinc boundto low molecular weight amino acids asso-ciated with low albumin concentrations and

increased binding of zinc to amino acids inthe PN infusate.

A zinc-dependent system should provide amore suitable index for assessment of zincstatus than blood levels. We accordinglylooked at two zinc-related systems, ALP (7)and the RBP and PA system (20, 21).

The group mean initial serum ALP for theinfants in this study was the same as ourreference mean for healthy full term infants.These values are about twice as high as ouradult reference range and similar to literaturevalues for term newborns (9).

ALP increases in normal infants duringthe first 3 mo of life (9). A steady increasein ALP was noted for our group of infantson PN. The 7-wk mean of 602 for the groupas a whole was 1.8 times higher than theupper reference limit (URL) (upper limit ofthe normal range) of 340 lU/L at one weekwhile the mean and URL at 7 wk was 3times higher than the corresponding valuesat 1 wk. A mild cholestatic jaundice (directbilirubin > 2 mg/dl) complicated PN inmany of the infants while in others there wasconcern that the rise in ALP was evidenceof possible metabolic bone disease due toinsufficient calcium, phosphate or vitaminD. However a similar increase in ALP was

also noted in infants in each birth weight,zinc and copper dose group who were clearlynot in either of the above categories.

When we compared the weekly groupmeans for ALP between the four zinc sup-plement groups, there was at no time asignificant difference. This confirms thatserum ALP is of poor value as an indicatorof zinc status in the newborn. Moreover it isapparent that to use ALP appropriately asan indicator of skeletal or hepatic dysfunctionin the preterm infant normal reference rangesshould probably be defined in terms of weeklychanges to distinguish elevations due to nor-mal bone growth from those due to hepaticor bone disease.

The second System which has been relatedto zinc status is RBP, the complex whichtransports retinol to the peripheral tissues(20). The role of zinc versus protein substratedeficiency in the determination of RBP con-centrations is controversial (20, 21). Theinitial values in our infants are far lower thanadult normal values (22, 23) but in agreement

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PARENTERAL NUTRITION IN LOW BIRTH WEIGHT INFANTS 29

with previously reported data in newborns(22). A definite decline in serial mean serumconcentrations of RBP and PA was seen inthis study. Initial values were not correlatedwith birth weight and no difference was seenbetween either BW or dose groups with time.A correlation with serum zinc was noted inthis study. However no difference could beshown between the zinc dose groups at anygiven time. It is possible therefore that thedecline reflects inadequacy of protein intakeon a daily protein administration of 2.1 g/kgrather than a zinc related effect.

No change in mean concentration of cop-per or ceruloplasmin was seen over the 7-wkperiod in either the weight groups, the copperor the zinc dose groups. Several studies ofserum copper status in orally fed newbornsand preterm infants have shown similar post-natal copper concentrations with a sponta-neous increase to a mean of around 60 �ig/dl occurring around four months of age (24-26). There was no significant difference shownbetween infants with or without additionaloral copper supplementation. The lack ofdifference between our two groups in whichone received an intravenous supplementdouble that of the other group confirms thatgastrointestinal absorption is of less signifi-cance than other factors such as trace metalutilization in ceruloplasmin synthesis by thesmall infant.

Our initial premise had been that preterminfants required higher levels of zinc supple-ment than the 40 jzg/kg/day suggested in theearly days of PN (1) and which had beenstandard practice in our ICN since that time.This was suggested by earlier balance studies(2) and tissue accretion studies (16) and laterin the AMA guidelines for parenteral tracemetal use (27) which also indicated a paucityof data on the very low birth-weight infant.We had further hypothesized that increasingthe zinc supplement from our standard levelshould prevent problems associated with sub-clinical or clinical zinc deficiency such as theacquired acrodermatitis syndrome, shortenthe length of time on PN and thereforeshorten the time period in an intensive careenvironment. This we were unable to show.

Our study of the acute dermatitis syndromeas an indicator of zinc deficiency (4) showedthat the clinically apparent dermatitis was

not always associated with concurrently notedhypozincemia. Conversely, many infants withvery low serum zinc concentrations did notshow any dermatitis. When we evaluated theincidence of dermatitis in infants on totalPN when dermatitis was diagnosed we wereunable to show a lower incidence in thehigher supplement groups.

We have shown that higher intravenoussupplements prevent a marked decrease inserum zinc concentration but do not affectserum copper concentrations in the preterminfant. Reports of trace metal concentrationsin various body fluids or tissues are appearingfrequently. However it is recognized thatthese values may often not reflect whole bodystatus and the clinical significance of changesin these constituents is often not easy toassess. In order to meaningfully determineoptimal supplementation levels a simple clin-ical endpoint is needed but is hard to select,reflecting the fact that a trace metal deficiencysuch as zinc deficiency may be only one ofmany causes of the complications which areseen in the extremely preterm infant. This iscompounded by the difficulty of managing awell controlled trial in this very fragile pop-ulation where blood sampling and handlingmust be kept to a minimum. U

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7. Prasad AS. Zinc in human nutrition. CRC Crit RevClin Lab Sci 1977;8:l-80.

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