Aluminium loading in children receiving long-term parenteral nutrition

CLINICAL 0 Lonlpnm

NUTRITION (1990) 9: 79-83 Group UK Ltd 1990

Aluminium Loading in Children Receiving Longterm Parenteral Nutrition M. Larchet*, P. Chaumontt,

M. Galliot$,

R. Bow-do&

0. Goulet* and C. Ricour*

*Service de reanimation Digestive et d’Assistance Nutritive et t Service de pharmacie, H&pita1 Necker-Enfants Malades, 149 rue de Sevres, 75743 Paris Cedex 15, France. SLaboratoire de Biochimie-Toxicologic, Hbpital Femand Widal, 200 rue Fbg Saint-Denis, 75475 Paris Cedex 10, France. (Reprint requests to C.R.)

Eight children on long-term, total parenteral nutrition (TPN) were found to have ABSTRACT elevated aluminium (Al) levels in plasma (5 1 f 11 pg 1/I), urine (223 f 78 pg 24 h) and bone. The load of Al in TPN solution was 232 f 89 ug/day, and, among the different parenteral solution components high Al concentrations were found in amino-acids, calcium gluconate, potassium lactate, and trace elements, representing respectively 40%, 30%, 15%, and 10% of the total Al intakes. The authors conclude that children receiving long-term TPN have excessive Al intakes and are exposed to Al toxicity. The prevention of Al contamination requires careful control of the TPN components.

INTRODUCTION

Nutrition

Since 1976 it has been shown that, in some pathological states, the body content of Al can be increased and lead to toxicity [ 1, 21. Uraemic children, treated orally with Al hydroxide, developed myoclonic encephalopathy, anaemia and osteomalacia resulting from an excessive Al loading and a lack of renal excretion [3]. In addition, patients on long-term TPN sometimes develop a hone disease characterised by bone pain,

Parenteral nutrition solutions (PNS) were prepared by the hospital pharmacy under aseptic conditions. Amino-acids (AA), dextrose, electrolytes, vitamins and trace elements were mixed in a container and the final solution sterilized by membrane filtration before filling the E.V.A. bags [7]. The patients took no enteral food (or less than 10% of the daily total energy intake), and Al content in the water they were given was lower than 1Oug I-‘. All of them were receiving cyclical home parenteral nutrition, during a 12 h period from 8p.m. to 8a.m. They attended a normal school. Daily parenteral intakes are reported in Table 1.

osteoporosis, or patchy osteomalacia and reduced bone apposition rate. Al accumulation has been postulated as an important factor in this multifactorial disease [4, 5,

61. This study was undertaken to assess the Al plasma and urine levels in 8 children on long-term TPN and to assess which parenteral solution components had been responsible for Al overload.

Table 1 Total parenteral nutrition intakes Components:

Per day:

Nitrogen* 377 f 102 mg kg-l Energy 265 f 52 kJ kg1 2.96f0.89mmol kg-l Sodium Potassium 3.45f 1.04mmol kg-’ Calcium 0.73f0.22mmolkg~’ Phosphorus 1.11f0.38mmolkg~L Magnesium 0.30f0.09mmol kg-’ Trace elements (Cu, Mn, Cr, F, Se, I, Fe, Zn) Vitamins (vitamin D: 1180 f 100 IU) Essential fatty acids in fat emulsion** (2 g kg ’ three times a week)

METHODS Patients

Eight children aged 1 to 16 years, receiving TPN for an average of 44 months (range 13 to 87 months), were studied. All of them were suffering from short-bowel syndrome. Four months before the study, patient 3 developed an osteopaenic bone disease characterized by severe bone pain, hypercalcaemia, hypercalciuria, tubulo-interstitial nephritis with nephrocalcinosis and renal insufficiency. After 6 months he recovered. The other children had normal renal function.

Vamine glucoseR : Kabi-Vitrum Vintene”, Prim&en: Cemep-Syntbelabo ** Intralipid% Kabi-Vitrum l

79

80

ALUMINIUM LOADING IN CHILDREN RECEIVING LONG-TERM PARENTERAL NUTRITION

Table 2 Aluminium content in patient specimens and in final patenteral nutrition solutions

n

Weight (kg)

1 2 3 4 5 6 7 8

40 36 23 15 27 41 10 27

Mean f SD

Plasma (pg 1-l) (8 a.m.) (8 P.m.) 55 40 76 49 43 36 49 59 51f12

Urine (pg d-l)

61

259

37 80 48 55 47 51 34

224 216 81 229 373 160 245

53f13

Wet bone (CIBg- ‘) 1.6

44.5

223 f 78

TPN intake (d-l) (B) (pg kg-‘) 264 290 352 96 264 264 71 224

6.6 8.0 15.3 6.4 9.7 6.4 7.1 8.3

232 f 89

8.5f2.8

Normal Aluminium levels in use in our laboratory: Plasma (&15 years) <5 l.ig1-l; Urine (O-15 years) ~2 pg 1-Q Wet bone (adults) < 1 bg g-l.

Measurements Al concentrations were determined both in the individual components used and in the PNS bags given to the patients. Each sample was tested twice by inductively coupled plasma atomic emission sepectroscopy (ICPAES) with a minimum detection limit of 2 pg 1-r. Other measurements were carried out as described previously [8]; briefly these include: the trichloracetic acid deproteinization of plasma, the use of a 0.1 M caesium medium and a standardisation by spiking a plasma pool. Al protein reextraction was greater than 96% [8] and some high results were reassessed by atomic absorption spectrophotometry (AAS) [9]. The inter-assay precision was 696 at 2Opgl-’ and accuracy was checked with the Surrey University (U.K) external quality programme [8]. Al plasma levels in patients were measured by ICPAES at 8 p.m., before starting the TPN cycle, and at 8a.m. when TPN was withdrawn. The Al content was analysed in 24 h urine samples. For ethical reasons bone biopsies were performed only in patients 1 and 3, during general anaesthesia for another purpose. Al amount was measured by ICPAES in wet bone from an iliac biopsy. Special precautions were followed during sampling to avoid Al contamination through the needles, containers or the ambient air. RESULTS Al concentrations in plasma were grossly increased, in all patients and levels were very similar at 8 p.m and at the end of the cyclic TPN at 8 a.m. Al excretion in urine was 223 f 78 pg per day. This was nearly equal to the Al TPN intakes (232 f 89 pg per day). In one of the collected bone fragments (case 3) Al content was very high. This child also had the highest plasma Al level (8Opgll’f and moderate renal insuffi-

Table 3 Aluminium concentrations in PNS

Products

Number of batches

Aluminium concentrations @g/l) Mean of 2 samples by batches

I. Individual components of PNS 1. Amino-acids solutions

Vamine glucose* Vintenez Primen?

3 3 1

123 200 58

2. Glucose 509/03

1

5

3. Electrolytes Calcium gluconate 10%’ Calcium gluconate lOoi 4 Potassium lactate 12.8’$) Sodium chloride 20%’ Magnesium chloride lOo/03

2 1 2 1 1

1830 675 1890 950 1060 67 15

4. Trace elements N.P. Pediatric solution’ N.P. Pediatric solution 10%’ Zinc acetate3

1 2 1

9650 4700 <2

864

5. Sterile water3

2

<2

<2

6. Water used for the rinsing of: Fabrication containers E.V.A. bags5

1 1

<2 <2

II. Parenteral nutrition solutions n = 8 (mean & SD)

108 124 283 216

92.4& 17.1

I Kabi Vitrurn, zCernep Syntltilabo, 3Pharmacie Centrale AP Paris, 4Aguettant, 5Stedim.

ciency at the time of the study (creatinine clearance: 0.6 ml s-l/l .73 m’), recovering 3 months later (creatinine clearance: 1.4 ml s- 1/ 1.73 m’). Al concentration in the mixed solutions was 92f 17 pg 1-r (n = 8), and in the individual components the highest Al concentrations were found in the trace ele-

CLINICAL NUTRITION

ment, calcium gluconate, potassium lactate and AA solutions. The percentage of total aluminium contributed by each components was, AA 40%, calcium gluconate 30%, potassium lactate 15%, trace elements lo%, others 5%. Calcium gluconate, potassium lactate and AA solution represented more than 80% of total Al intake.

DISCUSSION Al overload was first described in patients with chronic renal failure. Dialyzed [3] and non-dialyzed children [lo], who received large doses of Al in the form of phosphate binding gels, developed myoclonic encephalopathy, anaemia and osteomalacia [ll, 121. In neonatal uraemia an Al overload has been reported with the use of infant milk powder [13,14,15,16,17]. Since the kidney is efficient in eliminating most of the Al absorbed in the well subject, even in case of excessive loading, the Al body burden may not be excessively high. However Al accumulation has been reported in premature infants and children without renal failure during parenteral therapy [18,19]. In 1979, osteomalacia causing fractures was demonstrated by Ellis et al with parenteral administration of Al in animals [20]. Subsequently high Al loading in bone was reported by Klein et al [21] and de Vermejoul et al [6] during TPN. At the same time Al liver accumulation during TPN was demonstrated in children and premature infants [22] and Al associated hepatobiliary dysfunction was described in rats [23]. In this study, we also found an excessive Al loading during TPN. The toxicity resulting from parenterally administered Al is still to be estimated. Bone disease and microcytic anemia are common during long term TPN but it is difficult to relate them to Al intoxication [23]. In fact, TPN-related bone disease is multifactorial. Inappropriate intakes of calcium and phosphorus and excessive vitamin D load seem to be the most important factors in this disease [5, 61. Histologic study in this situation showed osteoporosis or an hyperkinetic state preceding osteoporosis. Bone biopsies in Al intoxication showed a different pattern of osteomalacia and osteopaenia [25, 26). In bone the presence of Al might impair the deposit of calcium [26]. Yet it has been shown that Al inhibits the activity of the renal enzyme 25-hydroxy vitamin D-hydroxylase in rats [27]. In addition, Al may accumulate in the parathyroid gland and, in vitro, can inhibit parathyroid hormone secretion [28]. It seems possible that small children, with rapidly maturing skeletal and nervous systems, may be susceptible to such toxicity [29].

C.N. --C

81

For these reasons it is necessary to prevent excessive Al contamination through parenterally administered fluids. Among the components, we found that AA solutions, potassium lactate and calcium gluconate were responsible for more than 80% of total Al contamination. Such high Al concentrations had previously been reported in casein hydrolysate, AA, phosphate salts, calcium gluconate and human albumin [16, 18,21,30, 31, 32, 331. The Al concentrations in AA solutions are lower than in calcium or trace elements solutions but, in our study, because of the high nitrogen needs in children, large volumes of AA solutions were required so that 40% of the Al intake came from AA. Like Sedman [ 181 and Koo [31] we found a great Al concentration variation in different batches of the assorted components. Al is a very widespread element and raw materials are often contaminated [32]. On the other hand glass bottles contain about 2% of Al oxide (A1203): Al transfer from glass bottles to solutions is possible and depends on contact time and pH [34]. The 1076 trace elements pediatric solution contained a high proportion of Al compared with its chemical concentration (1 mg trace element ml- ‘) but its pH is 1.5. Postaire et al demonstrated that Al concentration in plastic bags containing dialysis solutions increases with time and acidity [35]. In conclusion, children receiving TPN have significantly raised plasma and urinary Al concentrations. Several studies indicate that excessive bone, liver and perhaps brain Al accumulation may occur in some of these patients. The risk of Al intoxication appears to be greatest in children with reduced renal function and in premature infants. A number of substances commonly used in intravenous therapy including calcium, phosphorus, AA and trace elements may have high levels of Al contamination. It seems possible to reduce Al level in PNS by purifying raw materials and modifying glass composition. We suggest, for children with reduced renal function, premature infants and children on longterm TPN, the choice of parenteral components with a low Al concentration, so as to obtain no more than 15 ug 1-l of Al in the final PNS. This level of Al content is the norm accepted for the final aluminium concentration of the fluids used in haemodialysis and peritoneal dialysis [36]. We are conscious that the cost of removing Al from intravenous fluids will be high and that toxicity from Al infusion may have been occurring unrecognized for many years. However, before 1976, quantification of Al in biological samples was much more difficult and imprecise, and we think that such a prudent recommendation is necessary until a long-term prospective study, based on brain and bone Al levels and bone histomorphometry, has proved current TPN solutions harmless in children.

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ALUMINIUM

LOADING

IN CHILDREN

RECEIVING

LONG-TERM

REFERENCES

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PARENTERAL

NUTRITION

WI Sedman A B, Klein G L, Merrit R J, Miller N L, Weber K 0, Gill W L, Anand H, Alfrey A C 1985 Evidence of aluminium loading in infants receiving intravenous therapy. New England Journal of Medicine 312: 13371343 I191 Koo W W, Kaplan L A, Bendon R, Succop P, Tsang R C, Horn J, Steichen J J 1986 Resnonse to ahuninium in parent&al nutrition during infancy. The Journal of Pediatrics 109: 877-883 WI Ellis H A, McCarthy J H, Herrington J 1979 Bone aluminium in haemodialysed patients and in rats injected with aluminium chloride: relationship to impaired bone mineralisation. Journal of Clinical Pathology 32: 832844 WI Klein G L, Alfrey A G, Miller N L, Sherrard D J, Hazlet T K, Ament M E, Cobum J W 1982 Altinium loading during total parenteral nutrition. American Journal of Clinical Nutrition 35: 1425-1429 PI Klein G L, Bergquist W E, Ament M E, Cobum J W, Miller N L, Alfrey A C 1984 Hepatic aluminium accumulation in children on total parenteral nutrition. Journal of Pediatric Gastroenterology and Nutrition 3: 740-743 ~31 Klein G L, Heyman M B, Lee T C, Miller N L, Marate G, Gourley W K, Alfrey A C 1988 Ahuniniumassociated hepatobiliary dysfunction in rats: relationships to dosage and duration of exposure. Pediatric Research 23: 275-278 [241 Lipkin E W, Ott S M, Klein G L, Chait A, Sheerrard D 1986 The role of aluminium in the bone disease associated with parenteral nutrition, American Journal of Clinical Nutrition 43: 704 [251 Lipkin E W, Ott S M, Klein G L 1987 Heterogeneity of bone histology in parenteral nutrition patients. American Journal of Clinical Nutrition 46: 673-680 I261 Parfitt A M 1988 The localixation of aluminium in bone: implications for the mechanism of fixation and for the pathogenesis of ahuninium-related bone disease. The International Journal of Artificial Organs 11: 79-90 (271 Smothers R L, Kawashima H, Cobum J W, Kurokawa K 1983 Effect of aluminhun administration of 25hydroxyvitamin D-l-@ hydroxylase in the rat kidney. Calcified Tissue International 35: 703 (abstract) PI Morrissey J, Rothstein M, Mayor G, Slatopolsky E 1983 Suppression of parathyroid hormone secretion by aluminium. Kidney International 23: 699-704 Lw Mitrovic D R, Stankovic A, Front P, Kuntz D 1987 La toxicite de l’aluminium pour les tissus est-elle due a la production de radicaux libres d’oxygene? La presse Medicale 16: 1702 r301 Messing B, Pfeiffer A, Gineston T, Chappuis P, Leflon P, Biusine A, Terrier J L 1986 Quel sont, en nutrition parenterale chez l’adulte, les solutes responsables de l’apport aluminique excessif? La Presse Medicale 15: 1425-1426 1311 Koo W W K, Kaplan LA, Horn J, Tsang R C, Steichen J J 1986 Aluminium in parenteral nutrition solution. Sources and possible alternatives. Journal of Parenteral and Enteral Nutrition 10: 591-595 1321 Fell G S, Shenkin A, Halls D 1 1986 Aluminium contamination of intravenous pharmaceutical, nutrients and blood products. Lancet 1: 380 r331 Milliner D S, Shinaberger J H, Shuman P, Coburn J W 1985 Inadvertent aluminium administration during plasma exchange due to aluminium contamination of albumin-replacement solutions. The New England Journal of Medicine 312: 165-167

CLINICAL NUTRITION

[34] Baylocq D, Bissery V, Pellerin F 1985 Contrble de la qualiti du verre: etude du relargage et d’interactions avec des solutions de midicaments. Sciences Techniques et Pratiques Pharmaceutiques 1: 670-674 [35] Postaire E, Petiot J, Prognon P, Perrin B, Hamon M 1984 Determination de la teneur en aluminium des matkiaux plastiques de conditionnement pour solutis

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d’tpuration extra-r&ale: ktude du transfert contenant contenu. Annales Pharmaceutiques Francaises 42: 113121 [36] Wills M R, Savory J 1989 Aluminium and chronic renal failure: sources, absorption, transport, and toxicity. Critical Reviews in Clinical Laboratory Sciences 27: 59107.

Submirsion date: 1 December 1988. Accepted after revision: 14 September 1989