Biochemical stability during parenteral nutrition in children

Biochemical children J. W. L. PUNTIS,

S. K.

stability

during

parenteral

A. GREEN, D. E. SMITH,

tnstitute of Child He&h, Universiiy Hospital, Birmingham UK

of Birmingham

nutrition

in

I. W.

and Department

of Clinical

Chemistry

the Children’s

ABSTRACT-The aim of this study was to assess the frequency and importance of biochemical abnormality related to parenteral nutrition (PN) in a group of infants, and to devise an appropriate policy for routine biochemical surveillance. A standard monitoring protocol based on widely published guidelines was applied to 30 consecutive patients (age 3 days-3 years) referred to a children’s hospital nutritional care team for PN. No serious biochemical abnormalities were observed to arise simply as a consequence of PN. Electrolyte disturbance most commonly occurred before starting PN. Biochemical abnormality was most likely to be found in patients with abnormal fluid and electrolyte losses. Protocols for biochemical surveillance during PN err on the side of caution and often suggest frequent and comprehensive testing. In stable patients such as the surgical newborn, this is both expensive and unnecessary, and simpler monitoring regimes may be used with safety.

Introduction Clinicians providing parenteral nutrition for children may understandably feel anxious when confronted with the formidable list of published metabolic complications (I ). These concerns are still widely reflected in guidelines for routine biochemical monitoring, which generally advocate frequent measurement of a wide variety of analytes (2. 3, 4). Such an approach is not without disadvantages. however, as unnecessary blood taking is both unpleasant for the patient and expensive for the laboratory. In addition, patients may be exposed to the risks of anaemia (5) and sepsis (6). For these reasons we have reviewed current practices in relation to biochemical monitoring during PN in infants. This prospective study was performed in order to assess the frequency of biochemical abnormality attributable to parenteral feeding and which required a change in the parenteral prescription. A further aim was to produce more rational guidelines for patient monitoring. We have not assessed those techniques concerned with evaluating adequacy of nutritional support. such as nitrogen balance studies.

Patients Consecutive patients receiving PN for a minimum of one week were included in the study. 30 patients with

a median age of 2 weeks (range 3 days-3 y) and median weight 2.8 kg (range 1.8-12 kg) at the start of PN were studied for a median of two weeks (range 1 wk-10 wk). In all, data from 510 patient days of PN were examined. Patients were divided into those without abnormal fluid and electrolyte losses (stable group. n = 25). and those with abnormal fluid and electrolyte losses (unstable group. n = 5). The indications for parenteral feeding were congenital anomalies of the bowel requiring surgical correction and precluding enteral feeding (n = 14), bowel resection following necrotising enterocolitis (n = 9), and severe protracted diarrhoea which stopped when total parenteral feeding was instituted (n = 2).

Stable group.

Utzstable qoup. The indications for parenteral feeding in this group were protracted diarrhoea, continuing whilst receiving PN (n = 2). caustic oesophageal stricture and inability to swallow saliva (n = I ), duodenal atresia with dysmotility and persistent bile stained naso-gastric aspirates (n = 1) and multi-organ failure following curdio-pulmonary bypass surgery (n = 1).

Methods Nutr-itiorlul

srrperl?.sio~l

All patients had been referred for nutritional

support

154 BIOCHEMICAL STABILITY DURING PARENTERAL NUTRITION IN CHILDREN

Table 1 Parenteral nutrition regimens used in study patients Patient Group

Day of P.N.

Age

Fluid (ml)

Vamin Infant (ml)

I

3 4-5 6+ 4-5 6+ 5 6+ 6+ 6+ 6+

90 120 150 120 150 120 150 150 150 150 150 150 150 150 150 60 90

8 8 8 12 12 16 16 24 32 40 8 16 24 32 40 14* 28*

Neonates including Low birth Weight

1 1 2 2 3 3 4 5 6 1 2 3 4 5+ 1.2 3+

Infants >I month ~10 kg

IO-30 kg

Dextrose 5% (ml) 42 82 122 63 103 94 84 61 38 10 122 99 61 28 5 16 20

Dextrose 30% (ml) 30 20 10 35 25 40 30 45 50 65 IO 25 45 60 75 15 20

Intralipid 10% (ml) IO IO IO IO 10 20 70 20 3OS 35s IO IO 20 20 30 15 30

Additional Sodium (mmol) 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 1.5

Additional Potassium (mmol) 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2 1.5

$ For Pre-term, reduce to 20 ml/kg only and make up volume with 5% Dextrose * Vamin Y Glucose Trace elements: Vitamins:

if weight I0 kg, add Addamel (Kabi Pharmacia) 0.2 ml/kg/day

Solivito (Kabi Pharmacia). Vitlipid (Kabi Pharmacia),

1 ml/kg/day 1 ml/kg/day

to the Nutritional Care Team in the Children’s Hospital, Birmingham (7). Two team members were responsible for feed prescribing and sample collection during the study. PN prescriptions were based on standard protocols widely used in the UK (Table 1) (2) but in order to meet the precise needs of individual patients, feed components, including fluid volume, could be adjusted independently of each other with the aid of a fully portable microcomputer as previously reported (8). This programme also allowed calculation of suitable replacement solutions for those patients with abnormal losses. These could be incorporated within the PN prescription, or run as a separate infusion. Vamin 9 (KabiPharmacia) was used as the nitrogen source for children over 10 kg, whilst Vamin Infant (KabiPharmacia) was used for those under 10 kg. The fat emulsion used was Intralipid 10% (KabiPharmacia). Biochemical

monitoring

Tests performed as part of biochemical monitoring were based on published (2. 3, 4) guidelines from a number of standard texts. Analyses of plasma aminoacids, triglycerides, free fatty-acids and ammonia were not included as these are rarely performed. The monitoring schedule was applied in a standard way to all patients, but for laboratory convenience tests were

done according to the day of the week (Table 2). This meant that only children starting PN on a Monday would have all week 1 investigations performed. Blood was sampled between 9 and 10 a.m. after the Intralipid infusion had been turned off for four hours. Laboratory analysis was performed using micromethods so that volumes of blood taken remained small. All changes made to the standard feed prescriptions in the light of the results of biochemical analysis were noted prospectively. Biochemicul

methods

Sodium and potassium were measured manually by flame photometry (9); calcium by cresolphthalein complexone calorimetry (Roche kit Cat No 0710288); magnesium by a modified atomic absorption spectroscopic method (10); phosphate by the acid molybdate reaction (Beckman kit Cat No 683357); alanine transaminase by BCL kit (Cat No 191345); alkaline phosphatase with p-nitrophenol phosphate substrate in diethanolamine buffer (BCL kit Cat No 123846); urea with urease and glutamate dehydrogenase (SKI kit Cat No 89317); and osmolality by freezing point depression (Roebling osmometer, obtained from Camlab). Creatinine was measured with JT Baker’s Jaffe modified kit (obtained from Diamed Diagnostics), which largely eliminates negative interference

Table 2 Studyprotocol parenteral mltrition

for biochemical

monitoring

during

Before starting PN Plasma N3. K. Ca. !vI$. PO-&. we3 biliruhin. ALT. AI-P. Zn. Cu. acid-baw. albumin. creatinine cholesterol. wleniwn red cell glutathions peroxldase owlol:lllt\ During PN Tuesday Wednesday Monda! venom capdlar! capillary Ya. K Na. K Na. K / wh I IIIII~~ urea LFT acid-bake CL PO4 M!!-1 albumin

Thursday capillary Na. K (wk I only)

Friday venous Na, K urea, albumin Ca. MS

cllole\terul

creatininr ovnolslit\ Week 3 Zn. Cu. Selenium.

red cell glutathione

peroxldase

by bilirubin; albumin by a modification of the bromocresol purple technique ( I Ii: and bilirubin by the method of Westwood (12). Cholesterol was measured using a BCL kit (Cat No 290319). All calorimetric methods were performed on a Cobas Bio centrifugal analyser. Plasma selenium was measured by fluorimetry and zinc and copper using atomic absorption spectroscopy. Glutathione peroxidase was measured at 37°C using t-butylhydroperoxide as substrate c 13I.

few days of feeding in three patients from the btable group who initially had low levels. until plasma sodium had become normal. One patient in this group with hypokalaemia pre-TPN needed extra potassium for three days. All five patients in the unstable group continued to need a variable amount of additional sodium throughout their parentrral feeding and foul required an increase in potassium intahe. In stable patients electrolyte concentrations tended to fall closrl to the reference mean with increasing time on PN.

Asymptomatic hypocalcaemia was detected In four stable patients before the start of PN. and corrected with standard feeding without ad.justing the calciutn intake. One unstable patient with severe protracted diarrhoea needed additional calcium in hix feed. Plasma magnesium analysis showed remarkable stability with no abnormal magnesium concentrations being seen in stable patients whilst asymptomatic hypomagnesaemia was found in two unstable patients who were therefore given supplements.

Plasma phosphate was the single analyte which most commonly fell below reference ranges during PN. particularly in unstable patients. However. most abnormal results were only just below the lower reference interval and no patients were symptomatic. An increase in phosphate intake was prescribed only in one stable patient with evidence of bone disease of prematurity, and one unstable patient with protracted diarrhoea. Bilit-zrhitt.

Approval for the study was obtained from the research ethical committee of the Central Birmingham Health Authority. Informed consent was obtained from parents of each patient.

ulutzitle

tt.trt?arttlitlu.sr

Table 3 shows data for various analytes indicating how often measurements fell outside the laboratory reference range appropriate for the age of the child. together with the median and range of abnormal results.

Nearly all instances of hyperbilirubinaemia occurred in patients less than one week of age and in each case was predominantly unconjugated. Sis patients had their fat intake restricted at first because of jaundice. This was done according to our standard practice where fat intake is limited to 0.5 g/kg/day it bilirubin is loo-170 pmol/l. and no fat is given it’ bilirubin is above 170 pmol/l. No patients developed PN-associated cholestasis during the study and we recorded no instances of conjugated hyperbilirubinaemia. or raised alanine transaminase.

PlUSi?l~i elcc~ttY~lvtr.~

Alkalitw

Sodium and potassium concentrations were most commonly abnormal before PN (23% of measuremerits).. Supplementary sodium was given in the first

In some patients the plasma activity of this enzyme tended to rise within the reference range over the first few weeks of PN. and then to fall. but was not related

Results

phospittrttrsc~

30 (10%;8.5[7-291) 30 (0%) 25 (0%) 26 (15%:33[26-341) 22 (32%:10[7-121) 26 (4%;5.3) 30 (27%);273[264-3071) 30(27%;-5[-12--3.51)

I l-25 pmol/L

Zinc Copper Magnesium Selenium Glutathione peroxidasc Cholesterol Osmolality Base excess

3- I5 pmol/L >0.6 mmol/L 35-95 pgn 13-25 U/gHb c5.2 mmol/L 275-295 mosm/l\g f3.5

30 (23%;6.6[0.5-191) 25 (4%;289) 30 (13%:23[22-241)

1.OS.O mmol/L <:120 pmol/L >25 g/L

Urea Creatinine Albumin

30 (63%:83[21-3151) 30 (20%;114[61-2241) 29 (3%;1016)

30 (23%;13O[I 19-1481) 30(23%;3.1[1.1-3.41) 30 (7%;1.8[1.65-1.951) 29 (17%:0.8[0.55O.Y])

<20 pmol/L <60 IU/L 150600 w/L

132- 145 mmol/L 3.5-5.5 mmol/L 2.0-2.9 mmol/L 1.03.0 mmol/L

Bilirubin Alanine transaminase Alkaline phosphatase

Sodium Potassium Calcium Phosphate (11%;131[131-1471) (9%;3.3[3.2-6.4]) (2%; 1.74) (20%;0.66[0.&0.9])

Week I

0 0 39 (5%;0.57) 0 0 21 (5%5.7) 30 (13%;2701262-3.501) 2X (36%;-4-13.5--4.51)

2X (ll%;O.S~O.5~).6]) 21 (0%) 45 (27%;22( 17-241)

(10%:128[125-1311) (5%:5.6) (7%;1.98[1.72-1.981) (25%~0.55[0.420.8])

Week 2

0 0 35 10 0 15 28 19

(33%;5.6[5.4-6.5]) (11%;272[267-273 (26%;-51-I l-+6])

(6%0.3X) (90%:31[14-341)

19 (5%;0.5) 14 (0%) 39 (18%23[17-241) *

23 (17%;30[2165]) 17 (0%) 18 (6%;2243)

41 41 41 16

results: median [range] ).

30 (40%:32[21-65]) 30 (10%;73[6Y-2081) 24 (0%)

46 47 46 25

analytes (%) abnormal

Day 0

during study of individual

Reference range

Table 3 Number of measurements

1)

17 (23%:8[6.5-IO]) I9 (5%17) 20 (0%) 7(71%:19[1021]) 15 (47%;9[&1 I]) 14 (43%:7.4[5.68.3]) 22 (9%;269) 9 (22%;4.5)

10 (10%;0.5) 10 (0%) 27 (22%;21[20-221)

14 (7%1;30[21-63]) 13 (8%;183) 12 (50%;927[629-16

26 (4%; 130) 23 (4%:2.8) 21 (0%) 12 (25%;0.7[0.5~.8])

Week 3

171)

5 (60%;8[628]) 5 (20%;23) 27 (4%: 0.42) 7 (X6%) 6 (67%;9.5[9-121) 8 (37%:7.0[5.8-X.01) 7X (13%:274[236-3341) 25 (28%;6[-10.5--51)

22 (5%:0.5) 10 (0%) 28 (6% 15)

15 (0%) 28 (0%) 8 (25%:945166X-15681)

28(11%:28[119-1291) 30 (13%;4.5[3.16.5]) 28 (0%) 12 (17%;0.6[0.5-0.7])

Week 4-6

8 9

P

2

t

;;i =i g

E fj g P z

2

to changes in bilirubin. Alkaline phosphatase was markedly increased in one patient with bone disease of prematurity.

Albumin levels were low in some patients before and during PN. Two patients with gastroschisis and three with NEC required albumin infusions when plasma concentrations fell below 33 g/l. The hypoalbuminaemia in these patients was probably related to protein 10~5 in serous effusions occurring during their initial illness.

metabolic acidosis after seven days of PN followed by a gradual return to normal. At no time was acidbase abnormality severe enough to cause symptoms or warrant a change in prescription. Urea

Plasma urea concentrations were sometimes below the lower limit of normal for age even in patients who were growing satisfactorily. No change in the prescription was made as a result.

Discussion

Zinc concentrations in plasma tended to fall during PN but results below the reference range were not seen before three weeks of PN. One unstable patient with protracted diarrhoea developed low plasma zinc and copper concentrations and therefore received supplements.

Several baseline selenium results fell below the lower limit of normal for neonates and levels tended to fall progressively as the duration of PN increased. Many baseline levels of red cell glutathione peroxidase were below the reference range (derived from studies on children) and in some patients showed a tendency to fall with time, although this trend was not as striking as in the case of selenium. One unstable patient with protracted diarrhoea required the addition of selenium to PN tluids.

There way a marked rise in plasma cholesterol concentrations during PN, even in the neonatal period, with concentrations exceeding 5.2 mmol/l in six (37%) patients parenterally fed for two weeks or more. reaching a maximum in one patient of 8.6 mmol/l.

The acid-base status of patients was assessed before and during PN using the calculated base excess. Prior to PN. 73% of patients in whom measurements were made (n = 30) had a base excess within our reference range of +/- 3.5 mmol/l. After one week of PN. 41% of patients assessed (n = 28) had a base excess within the normal range whilst 59% were acidotic. Taken overall there appeared to be an increase in cases of

In a group comprising mainly neonatal surgical patients without abnormal fluid and electrolyte losses. fed intravenously for a median of two weeks. we found no instances of serious unexpected biochemical disturbance directly attributable to PN. Indeed, abnormal sodium, potassium and calcium concentrations usually became normal once PN (providing standard requirements for these micronutrients) was started. Trace elements such as magnesium. copper and zinc were remarkably stable. although the latter showed a tendency to fall with time: the fall in plasma selenium was more marked: at the time of the study we were not routinely adding selenium supplements to PN solutions. Measurement of the selenium dependent enzyme. glutathione peroxidase, showed little correlation with plasma selenium concentration and did not provide additional useful information. Since precise trace element requirements in the newborn remain uncertain. we feel a case can be made for routine plasma monitoring in infants on relatively long term PN. Mild acid-base abnormalities were common indicating that the ability of patients to metabolise the acid load provided by PN is variable. High plasma concentrations of unconjugated bilirubin at the start of PN may have implications fol administration of lipid emulsion ( 14). Although bilirubin, alanine transaminase and alkaline phosphatase concentrations are monitored to detect PN associated cholestasis we rarely see this complication. which is more likely to occur in very preterm infants ( 15) and can be prevented by early hypocaloric enteral feeding (16). One group of patients in whom biochemical disturbance must be carefully monitored are those with continuing abnormal fluid and electrolyte losses. such as those in our unstable group with diarrhoea or upper gastrointestinal obstruction. Homeostasis can be maintained by using a separate infusion of appropriate solution matching the electrolyte composition of the

158

BIOCHEMICAL

STABILITY

DURING

PARENTERAL

NLITRITION

abnormal losses. Clearly, standard guidelines for monitoring may not be appropriate for some groups of patients, including very low birthweight infants, those receiving chemotherapy, and when there is major organ failure. Many metabolic complications of parenteral nutrition have become less frequent over recent years. The high incidence of hyperammonaemia seen with hydrolysed protein preparations for example ( 17), was reduced with the advent of solutions incorporating synthetic crystalline L-amino-acids ( 18). Fructoseinduced lactic acidosis (19) is now avoided by using glucose as the carbohydrate source. The problem of aluminium accumulation associated with long term PN has also been much reduced (20). Further modification of crystalline amino-acid nitrogen sources has produced a reduction in amino-acid imbalance seen in plasma profiles from young infants on PN (21). The absence of taurine and selenium from PN solutions. however, has now been associated with clinical deficiency states in patients on long term feeding (22.23). The high plasma cholesterol concentrations seen in some of our patients are worrying but of uncertain significance. The use of Intralipid which is exclusively long chain triglyceride is known to be associated with higher plasma cholesterol concentrations than when a lipid emulsion containing 50% medium and 50% long chain triglyceride is used (24). Although many other complications related no PN have been reported. in our experience serious unexpected problems in stable patients are rare, and intensive biochemical monitoring as a routine is not required. The observations made in this study are particularly relevant to stable patients on neonatal surgical units. most of whom are fed for no more than a few weeks and who as a group represent a major consumer of PN (7). In practice there is often confusion about which biochemical monitoring investigations should be performed, and how often. Biochemical abnormalities which have implications for nutritional prescribing are most commonly found before starting PN or in those patients with persisting abnormal fluid and electrolyte losses, in whom frequent biochemical monitoring is mandatory for that very reason. In addition to the unnecessary measurement of analytes which are consistently within the normal range, we have often found other tests. in particular acid-base status and osmolality, frequently to be abnormal. but of little practical relevance in that they are not associated with symptoms and do not require alteration of prescription. Based on our findings we suggest more rational guidelines might be employed for monitoring stable patients receiving PN (Table 4). We estimate that the

IN CHILDREN

Table 4 Recommended protocol for routine biochemical monitoring of clinically stable infants receiving parenteral nutrition Pre-TPN Blood ~ Na. I<, hilirubin Each week of PN Blood: Na. K-twice weekly P04. bili - once weekly glucose (BM Stix) - daily first week or during increases in dextrose intake Additional tests after 2 weeks PN Blood: Ca. ALP, then each twn weeks Additional tests after 3 weeks PN Blood: Se. Zn. Cu - then each three week\

implementation of these guidelines will reduce unnecessary testing, with benefits to the patients and to the laboratory budget. We believe our guidelines would be appropriate for other units caring for stable newborn surgical patients and should also encourage centres caring for different categories of patients to examine their current monitoring practice.

Acknowledgements We are grateful to Mr J. C. Corkery. Mr P. Gomall and Mr R. G. Buick for permission to study their patients. We would like to thank Dr S. Brown (Toxicology Laboratory. Dudley Road Hospital. Birmingham) for the selenium analyses, Professor A. Shenkin (Department of Chemical Pathology, Royal Liverpool Hospital) for red cell glutathione peroxidase measurements and Dr T. Delves (Southampton General Hospital) for zinc and copper analy\es. We would also lihe to thank the staff of the clinical chemistry department. Birmingham Children’s Hospital. We acknowledge the valuable secretarial assistance given b) Miss J. Patterson.

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7. PuntI\ J W L. Booth I W. The place of a nutritional care team in pacdiatric practtce. Intensive Therapy and Clinical Monttoring 1990: I I: 132-136 H. Ball P A, Candy DC A, Punti\ J W L, McNeish A S. Portable bedside microcomputer system for management of parenternl nutrttion in all age groups. Arch Dis Child 1985: 60: 41513’1 9 Cornmg 151 Flame Photometer Instruction Manual. Coming Ltd.. Halstead. lz\\ex 1977 IO. Pyhw J. Determination of calcium and magnesium in serum and wine b> atomic absorption spectrophotometry. Clinic Chim Acta I %X: 2.1:30%3I7 I I. Pinncll A E. Northam B E. New automated dye-binding method for wrum albumtn determination with bromocresol purple. Clin Chem 1978: 23: X0-86 12. Westuood A. Determination of total and direct bilirubin in plasma by mean\ of a bichromatic method on a centrifugal analyxzr. Ann Clin Biochem 1982: 19: 151-156 13. Beutlcr E. Blume K G. Kaplan J C, Lohr G W. Ramot B. Valentine W N. lntemalional committee for standardtsation in haematolog! : recommended method\ for red cell enzyme analysis. Brit J Haematol 1977: 35: 33 I-340 14. Andrew Cr. Ghan G. Schiff D. Lipid metabolism in the Intonate. II. The effect of Intralipid on bilirubin binding in \ itro Jnd in viva. J Pediatr 1976: 8X: 279-283 15. Pereirn G E. Sherman M S. DiGiacomo J. Ziegler M. Roth K. Jacotxwahi D. Hyperalimentation-induced cholestasis: mcreased incidence and severity in premature infants. Am J Dts Child 19X I : 13.5: 842-815

16. Dunn L, Hulman S. Weiner J. Kliegtnan R. Benefictal effect< of early hypocaloric enteral feeding on neonatal gastrointestinal function: preliminary report ot a randotnisrd trial. J Pediatr 1988; I 12: 611-9 17. Seashore J H. Metabolic complications of parenteral nutritiort in infants and children. Surg Clin North Am 19x0: 60: 123% I757 IX. Shohat M, Weilunshy E. Reisner S H. Plasma ammonia levels in preterm infants receiving parenteral nutrition \sith crystalline L-amino acids. JPEN 19%: 8: I 7% I X0 19. Saheb,jami H. Scalettar R. Effects of fructow int’ukn on lactate and uric acid metabolism. Lancet 1971: I: Zhh-369 20. Heyman M B. Klein G L. Wong A et al. .4lummum doe\ not accumulate in teenager\ and adult\ on prolonged parentcral nutrition containmg free amino actds. JPEN 1986: IO: X&t87 31. Puntis 3 W L. Ball PA. Preece M A. Gt-eer I\. Brown G A. Booth I W. Egg and hreast milk milk based nitrogen wurceh compared. Arch Dis Child 1989: 64: 1472.-1477 22. Gepgel H S. Amen1 M E. Heckenlively J R. Martin D A. Kipple J D. Nutritional requirement for taurine in pattent\ recetving long term parenteral nutrition. N En: .I hled I9S5: 312: 112-6 23. von Stockhausen H B. Selenium tn total parcnteral nutrition. Biological Trace Element Research 198X; 15: I.$-- lg.5 2-l. Lima L A M. Murphy J F. Stansbie D. Rowlandx~n P. Gra 0 P. Neonatal parenteral nutrition wtth a frit em&ion contammg mediutn chain triglyceride>. Acta Paediatr Stand I YXX: 77: 332-339