Parenteral Nutrition in Infants and Children

Journal of Pediatric Gastroenterology and Nutrition 36:587–607 © May 2003 Lippincott Williams & Wilkins, Inc., Philadelphia

Invited Review

Parenteral Nutrition in Infants and Children Robert J. Shulman and Sarah Phillips Department of Pediatrics, Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, Texas Children’s Hospital, Houston, Texas, U.S.A.

JPGN 36:587–607, 2003. Key Words: Parenteral nutrition— Intravenous—Feeding—Neonates—Energy—Protein—Amino

acids—Lipid emulsion. © 2003 Lippincott Williams & Wilkins, Inc.

INTRODUCTION

Our immediate reaction was to take offense, feel hurt, and shake our heads in disbelief that anyone could be so foolish as to think such things. However, as we thought about it, we realized that the question is pertinent and perceptive. Like the clinical pathways set out for common illnesses such as diarrhea and croup, the question is not so much how to follow the roadmap but rather, when not to follow it. Thus, our review will focus on two areas: 1) Common misconceptions surrounding the use of PN; and 2) When should “standard PN” (i.e., checking the weight and the box on the order sheet) not be used. These questions have lead us to review recent developments in PN (in the past 5–7 years). Whenever possible we will take an evidenced-based approach to the data. Unless specified, the studies we will discuss were carried out in pediatric patients. The risk of any review is that it is old hat to some and very new to others. We have done our best to strike a middle ground. Because it could be a subject unto itself, we will not review PN-associated cholestasis, although when pertinent, some comments will be made.

Parenteral nutrition (PN) came of age in 1964 with the demonstration that beagle puppies could be nourished successfully from 12 weeks of age to maturity by providing all nutrients intravenously (1). The first total parenteral nutrition of an infant with extreme short bowel syndrome followed in 1967 (1). Since them many lessons have been learned as a result of complications of PN. These have included nutrient deficiencies and excesses, infections, complications of inadequate or excessive energy and protein intake, liver disease, and toxicities from product contamination. Our patients have paid the price for these lessons, but fortunately improved survival has also resulted. These incidents have reinforced to us the physicians the axiom that “good judgment comes from experience . . . and experience comes from bad judgment.” (2). Along the way we have learned much about nutrition, infection, liver pathophysiology, and child development (e.g., yes, infants really can “unlearn” how to suck and swallow). Have we learned so much that administration of PN can now be placed on autopilot? The question posed to the authors when this review was solicited was whether the art and science of PN had reached the stage where administration could be treated as a routine clinical algorithm such as diarrhea or croup. Do we only need to check the weight, calculate the administration rate and check the box next to “Standard Child Solution” on the PN pharmacy order sheet? Is there really anything new in PN?

Energy Requirements, Energy Sources, and the Consequences of Overfeeding Estimating the appropriate energy intake is a fundamental step in prescribing PN. Although we have long acknowledged the risks of underfeeding our patients, more recently we have come to reevaluate energy requirements in particular clinical scenarios and to appreciate the problems associated with excessive energy intake.

Received November 25, 2002; accepted February 13, 2003. Address correspondence to Robert J. Shulman, 1100 Bates St., Houston, Texas 77030, U.S.A. (e-mail: [email protected]).

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R. J. SHULMAN AND S. PHILLIPS Energy Requirements

A few terms must be defined in order to discuss energy expenditure (3). Basal metabolic rate is the energy expenditure of a recumbent child or adult in a thermoneutral environment after a 12- to 18-hour fast just when the individual has awakened but before daily activities have commenced. Basal metabolic rate is a reflection of the energy expenditure required for vital processes. Resting energy expenditure refers to the energy expenditure of a person at rest in a thermoneutral environment. Basal metabolic rate and resting energy expenditure usually do not differ by more than 10% (3). Total energy expenditure is the sum of requirements for basal metabolism, thermic effect of ingested food, thermoregulation, and activity. In older children, activity accounts for a large proportion of total energy expenditure. Thus, the total energy expenditure of a child who is hospitalized and lying in bed is reduced. Historically, it has been thought that the surgical patient requires an energy intake proportional to the severity of the illness. By definition, the energy intake would be increased compared with that of a “non-stressed” patient. However, from a practical standpoint this concept does not seem to be the case as the increased energy expenditure is short-lived. For example, although newborns have a 20% increase in resting energy expenditure after major surgery, this elevation returns to baseline within 12-24 hours (4). Infants who remain critically ill and require PN also do not appear to require increased energy intakes. Jaksic et al. measured energy expenditure in eight non-ventilated surgical neonates (gastroschisis, atresia, volvulus) on postoperative day 16 (± 12, SD) and compared them with ten infants on extracorporeal life support studied at 7 ± 3 days of age (5). There were no differences in energy expenditure between the groups (53 ± 5 vs. 55 ± 20 kcal ⭈ kg−1 ⭈ d−1) (5). This level of energy expenditure is comparable to that of “nonstressed” infants (see below). The similarity in energy expenditure was present despite the finding that IL-6 and C-reactive protein levels were significantly greater in the extracorporeal life support group reflecting an increased degree of illness, and ultimately, mortality (30% vs. 0) (5). This same group of investigators recently has shown that preterm infants (25 weeks gestation) behave similarly (6). Lloyd recently reviewed the data regarding energy requirements in surgical newborns and children (7). The evidence reveals that the increase in energy expenditure associated with surgery only lasts for 24 hours after the procedure (7). Estimating energy expenditure during the first 24 hours after surgery will overestimate the energy requirements for the entire postoperative period, potentially resulting in excess energy intake with its potential consequences (see below). Energy requirements also have been examined in nonoperated children in the intensive care unit. In a group of

J Pediatr Gastroenterol Nutr, Vol. 36, No. 5, May 2003

mechanically ventilated critically ill children (N ⳱ 33; 6 ± 5 years of age) whose mean length of stay in the intensive care unit was approximately 2 weeks, measured energy expenditure was only about 8 kcal ⭈ kg−1 ⭈ d−1 (17%) above expected based on more recent data (8,9). Joosten et al. found even smaller increases in energy expenditure in a more heterogeneous group of 36 infants and children in an intensive care unit (10). Finally, Turi et al. measured energy expenditure in 21 patients in the intensive care unit with systemic inflammatory response syndrome or sepsis and compared their energy expenditures to a group of hospitalized control children (11). No differences were noted between the groups (11). Taken together, these data support the idea that in most cases there is little need to provide post operative or critically ill infants and children with much more than their resting energy expenditure, which in most cases will be an amount similar to their basal metabolic rate. The information in Table 1 can be used to calculate basal metabolic rate in normal children (9). A recent report by Duro et al. used the Enhanced Metabolic Testing Activity Chamber (EMTAC) to predict REE in 50 normal infants up to 7 months of age with a maximum weight of 9 kg (12). Their data suggest that for this age group the values of Shofield may be an underestimation (9,12). However, part of this difference may be explained by the fact that the values for Shofield are for BMR and those of Duro et al. are for REE (9,12). The equations described by Duro et al. are: REE (kcal/d) ⳱ [84.5 x Weight (kg)] – 117.33 (R2 ⳱ 0.65, P < 0.01) The prediction is improved somewhat by including length: REE (kcal/d) ⳱ [10.12 x Length (cm)] + [61.02 x Weight (kg)] – 605.08 (R2 ⳱ 0.7, P < 0.01) It is evident in the study by Jaksic et al. that there may be significant interindividual variations in energy expenditure (5,7). This should not be surprising, as even among normal newborns energy requirements do not fall within narrow margins (13). White et al. have shown that in pediatric intensive care unit patients that there is little within-day variation in energy expenditure but day-today variation is as high as 21 ± 16% (mean ± SD) (14). Ideally, energy expenditure should be measured in critically ill patients. However, it may not be practical because of the expensive equipment and the expertise required. At the very least, one should be flexible regarding the “appropriate” energy intake and monitor the patient for weight gain (fluid vs. tissue) and evidence of overfeeding (e.g., CO2 production; see below). Two recent studies may be of value in calculating resting energy expenditure for surgical infants and intensive care patients.

PARENTERAL NUTRITION IN INFANTS AND CHILDREN TABLE 1. Equations for estimating basal metabolic rate (MJ/day)* Age (years)

Male

0.4% of the total fat contains particles > 5 microns in size (162,163). What patients are candidates for PN admixtures? It may be more important to ask whether there are PN


mixtures that are inappropriate for certain patients. Because of the limitations in the amount of calcium and phosphorus that can be used in PN admixtures (even more severe than in non- admixture PN), their use may be inappropriate in young infants. One report has suggested that PN admixtures can be used in former preterm infants and newborns, however, in this study it was not clear that the PN admixtures had been validated as stable nor was there stability testing reported after the admixtures were prepared (169). Because the emulsion is opaque (as a result of fat emulsion) a precipitate may be invisible to the naked eye. The calcium and phosphorus requirements for neonates is 3–4 mEq ⭈ kg−1 ⭈ d−1 and 1–2 mmol ⭈ kg−1 ⭈ d−1, respectively (162). Based upon studies using a commonly employed pediatric amino acid solution (TrophAmine, B. Braun Medical, Inc., Melsungen, Germany) the PN admixture would provide inadequate amounts of these minerals (170). As an infant approached 4–6 months of age it is conceivable that their calcium and phosphorus needs could be met using a PN admixture (161,162,170). However, it must be stressed that this is dependent upon the amino acid, glucose, intravenous fat emulsion, calcium, and phosphorus products (as well as the other components) used as well as the mixing protocol. If a PN admixture is to be used in an infant less than a year of age, it should be done with particularly careful consideration regarding mineral requirements. PN admixtures only should be used in patients who are clinically stable. Changes in the formulation of PN admixtures are more costly than changes in traditional (two-in-one) PN because of the wastage of both the dextrose/amino acid and its components, and the intravenous fat emulsion. A number of questions remain about PN admixtures. These include the appropriate dosing of some vitamins, the true risks related to particulate matter and fat droplet size, and drug compatibilities. For example, there is less loss of fat-soluble vitamins such as vitamin A than in traditional (two-in-one) PN because the intravenous fat emulsion is protective (see below) (171). Some drugs are compatible with PN admixtures but not with traditional PN and visa versa (172).

PARENTERAL NUTRITION IN INFANTS AND CHILDREN TABLE 6. Adult and children (>11 years of age) parenteral multivitamin preparations Vitamin

Infuvite™* (Sabex)

M.V.I.-12™ (aaiPharma)

A (IU) D IU (␮g) E (IU) K (␮g) C (mg) Thiamin (mg) Riboflavin (mg) Niacin (mg) Pyridoxine (mg) Folate (␮g) B12 (␮g) Pantothenic Acid (mg) Biotin (␮g)

3300 IU 200 (5) 10 150 200 6 3.6 40 6 600 5 15 60

3300 200 (5) 10 — 200 3 3.6 40 4 400 5 15 60

* Conforms to the FDA amended formula for adult multivitamin preparations (165).

VITAMINS Guidelines for pediatric parenteral vitamin and mineral supplementation have been previously reviewed, albeit quite some time ago (173). Despite subsequent publications that have provided additional support for these recommendations, there has not been a recent significant evaluation or reformulation of parenteral vitamin products for premature infants, infants, or children (less than 11 years of age) (174,175). Recommendations from the 1998 National Advisory Group on Standards and Practice Guidelines emphasized the need for establishing optimal trace element and vitamin formulations for both adult and pediatric patients

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(162). In April 2000, the Food and Drug Administration amended the adult multivitamin formulation to bring it into accordance with the 1988 recommendations of the American Medical Association-FDA Public Workshop Committee (Table 6) (176). To date, the optimal parenteral vitamin and mineral requirements for children and neonates have not been determined and a parenteral multivitamin formulation specifically for preterm infants has not been developed. While there are several parenteral vitamin preparations available for older children (> 11 years) and adults (Table 6), few are available for neonates and children. InFuvite Pediatric™ (Sabex, Inc., Boucherville, Canada) and M.V.I. Pediatric™ (aaiPharma, Inc., Wilmington, NC) are approved for use in prematures, infants, and children < 11 years (Table 7). The adult formulations are not recommended for use in low birth weight infants less than 1500 grams because of concerns about the toxicity of the propylene glycol and polysorbate additives (177,178). Limitations in the availability of the pediatric products have made children vulnerable to shortages (179). Table 7 gives the doses of vitamins recommended for infants by the American Society of Clinical Nutrition Subcommittee on Pediatric Parenteral Nutrient Requirements (). This recommendation differs from the package inserts (180). Clearly, there are patients whose needs do not fit the current vitamin formulations. For example, preterm infants, children with liver or renal disease or short bowel syndrome, or who are severely malnourished require close attention to vitamin nutriture. Some adult parenteral vitamin products that are used for children >11 years of age may put younger patients on long term PN at risk for excessive vitamin intakes (see Table 6).

TABLE 7. Infant and child parenteral multivitamin requirements and commercial preparations*

Vitamin (amount/d)

Best estimate# preterm infant

Pediatric parenteral multivitamins# 2.5 kg–11 yrs 100% of the vial (5 ml) 700 80 400 7 200 1.2 1.4 17 1 140 1 5 20

* Infuvite Pediatric™/MVI-Pediatric™. # See reference (180). ** 500 ␮g ⳱ 1643 IU. ## 1 mg ⳱ 1 IU.


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R. J. SHULMAN AND S. PHILLIPS Vitamin K

One potential problem with the introduction of vitamin K into the new adult formulations is the possible interference with anticoagulants such as warfarin. Additionally, intravenous fat emulsions contain vitamin K in varying amounts (approximately 13–70 ␮g/dL) that can make titrating anticoagulant therapy even more problematic (181,182). Vitamin A A recent Cochrane review suggests that an increased vitamin A intake (via the intramuscular route) is beneficial in the preterm infant (183). Whether dosing of vitamin A in PN will provide a similar benefit is unclear. Dosing of vitamin A is complicated by its adherence to the bags and tubing and from photodegradation (184). Evidence suggests that when administered in the glucose/amino acid solution the current recommendation for vitamin A is too low (162,185,186). Loss of several lipid soluble (and water-soluble) vitamins occurs during their delivery in PN (187,188). Evidence suggests that using dark tubing and placing fatsoluble vitamins into the intravenous fat emulsion (see PN Admixtures, above) mitigates the losses of these vitamins (189–192,230). However, multivitamin manufacturers in the US do not recommend mixing vitamins in lipid emulsions (see package inserts). Obviously it is commonly done in the case of PN admixtures (see above). More research in this area is vital. Clinical Implications Our knowledge regarding the appropriateness of current vitamin preparations and intake levels is less than optimal. Prudence would suggest checking vitamin levels (especially vitamin A and possibly riboflavin) in patients on long term PN because of potential losses in the administration set, particularly when enteral intake and/or absorption is poor (191). Consideration also should be given to monitoring fat-soluble vitamin levels in patients whose vitamins are placed into the lipid emulsion. Carnitine The use of carnitine in PN for preterm infants recently has been the subject of a Cochrane Database review (193). Using weight gain as a primary outcome, there was no apparent effect of carnitine supplementation (193). However, the studies available did not assess the use of carnitine in long term PN, a situation that is more likely to result in carnitine deficiency. Tissue carnitine levels decline in infants receiving carnitine-free PN (194). An adult patient who received PN for over a year


has been described with symptomatic carnitine deficiency although the level of enteral intake was not described (195). It is possible that the effects of carnitine deficiency in patients on long term PN may be too subtle to be identified easily but are still metabolically relevant given the central role of carnitine in metabolism (196). Addition of carnitine does enhance intravenous fat emulsion oxidation although it has been argued that the increase may not be clinically relevant (193). In long term PN patients it may be reasonable to follow the suggestion that carnitine (as pure L-carnitine) be added at a dose of 2 to 5 mg ⭈ kg−1 ⭈ d−1 and that plasma and red blood cell concentrations be measured at baseline and at 4-month intervals until levels have stabilized, then yearly thereafter (196). Too high a carnitine dose may be detrimental (196).

Iron Parenteral nutrition patients at risk for iron deficiency are premature infants, long-term PN patients with little or no enteral intake, and patients with significant malabsorption or fluid losses. Iron may be administered orally, intramuscularly, or parenterally. Parenteral iron can be infused as an intermittent intravenous infusion or as a diluted total dose infusion. Iron dextran has been used in children (197–200). Despite its fairly widespread use, total dose infusion is not approved by the Food and Drug Administration. The use of iron dextran can be complicated by adverse reactions including a small but real risk of anaphylaxis. A test dose is recommended prior to administration of the required amount (see package insert). Iron dextran in PN can be efficacious (201,202). Although often employed in PN, the stability of iron dextran and its potential interaction with other nutrients remain as concerns (202). Its use in PN admixtures should be undertaken with extreme caution if at all (163). Until recently, iron dextran was the only formulation available for parenteral iron therapy. Two new iron products free of dextran have recently been approved for use in the United States. Sodium ferric gluconate complex in sucrose (Ferrlecit, Watson, Inc., Morristown, NJ) has been used extensively in Europe and became available for use in the United States in 1999. Iron sucrose (Venofer, Luitpold Pharmaceuticals, Inc., Shirley, NY) also previously available in Europe was introduced in late 2000. These products appear to be safe and have fewer side effects than those of iron dextran, although like iron dextran, they can cause hypotension (203,204). While the safety and efficacy of these products has not been extensively studied nor are they approved by the FDA for use in children, there is evidence that they are safe and effective in children (205).

PARENTERAL NUTRITION IN INFANTS AND CHILDREN Trace Minerals Trace mineral requirements and metabolism in general, including concerns regarding aluminum contamination and toxicity, recently have been reviewed elsewhere (180,206–209). We briefly will touch on current issues regarding specific trace minerals in PN. First, it should be remembered that PN solutions usually contain some of the various trace minerals due to contamination of the components (e.g., amino acids, calcium gluconate, multivitamins) with trace metals (210). In one report Zn, Cu, Mn, and Se were found in greatest concentration but contamination will vary depending on the commercial products used to prepare the PN (210). Heat and storage time can modestly reduce the levels of some trace elements as well (210). The importance of Se as an antioxidant is well known. A recent report suggests that the recommended intake of Se for preterm infants (N ⳱ 29, gestational age 26 weeks) may not be adequate for all infants (211). In contrast, a study of children and adults on long term PN suggested Se status is well maintained even with low or no Se intake (212). However, in this study there was great variability in Se serum levels as well as glutathione peroxidase activity with some patients actually showing deficiency (212). Given the reports of heart failure because of Se deficiency and our limited knowledge regarding adequacy of intake, it is prudent to check serum Se levels in the short term (particularly in preterm infants) and serum Se levels and glutathione peroxidase activity in older infants and adolescents (207,211–213). Some studies have suggested that chromium toxicity may be a concern. Mouser et al. noted in infants and children (up to 12 years of age) on long term PN that serum Cr levels were elevated despite following the recommended intake (180,214). These data are consistent with other studies and imply that the addition of Cr to PN at recommended levels in combination with Cr contamination in the PN fluids raises serum Cr levels above that desired (210,215–217). Again, patients on long term PN should be closely observed. Whether the impaired glomerular filtration rate noted in children on long term PN is related to Cr excess requires further investigation (217). Zn has the widest range of functions of all the trace minerals and is particularly important in wound healing and immune function. Despite its intentional and nonintentional addition to PN, many patients are at risk for Zn deficiency because of the number of predisposing clinical situations (206,207). For example, patients with gastrointestinal losses due to diarrhea, ileostomies, or even nasogastric suction are at risk for Zn deficiency because of the high Zn content of gastrointestinal fluids (218). Serum Zn levels, although not entirely reliable, are easily obtained and Zn intake can be titrated appropriately.

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Of great concern are the numerous observations regarding Mn retention. This essential trace mineral normally is excreted in bile and has a special affinity for the extrapyramidal system (206,207). Mn often contaminates PN solution components in amounts sufficient for daily requirements (206,207,219). Manganese intoxication causes parkinsonian-like symptoms with muscular weakness, stiffness, tremors, ataxia, abnormal gait, asthenia, and difficulty with speech (220). Psychological changes have been reported including mental irritability, headaches, nervousness, compulsive actions, and hallucinations (220). Manganese accumulation can be detected in the basal ganglia as symmetric, increased signal intensity on T-1 weighted magnetic resonance images (220,221). These changes are reversible when Mn is removed from the PN (222,223). Clinical symptoms are usually but not always reversible (224). It is not surprising that Mn accumulates in individuals with cholestatic liver disease given its hepatobiliary secretion (220). Of particular concern for pediatric patients is the widely held suspicion that Mn accumulation in patients on PN may cause cholestasis. A recent study randomized 244 children on PN to receive either 1.0 (Group 1) or 0.0182 ␮mol ⭈ kg−1 ⭈ d−1 (Group 2) of Mn (224). When all patients were considered, those in Group 1 showed a trend towards higher peak manganese and direct bilirubin levels. The two groups did not differ in the occurrence of cholestasis but Group 1 patients showed a trend towards increased incidence and severity of hyperbilirubinemia (225). Of the 160 children who received >75% of their daily fluid intake from PN for >14 days, peak whole blood manganese and peak serum direct bilirubin concentrations were significantly higher in Group 1. Significantly more infants in Group 1 developed a more severe degree of direct hyperbilirubinemia (225). These data implicate Mn as a contributor to the development and/or the severity of PN-associated cholestasis (225). Based on these and other data, it is suggested that patients with any cholestasis (some would say any liver disease) should not receive Mn in their PN (220,225,226). Others would go so far as to say that Mn should not be given to individuals on PN for 30 days (207,226). There is disagreement regarding the best measure of Mn status (220). Whole blood Mn appears to correlate (in adults) with MRI-documented Mn deposition (226). Most investigators use whole blood Mn, red blood cell Mn, or Mn superoxide dismutase as measures of tissue deposition (220). SUMMARY Our knowledge regarding PN reflects the same pattern we find in all of medicine: what we do is based part upon science and part upon best judgment. It turns out that


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practices that seem clear (i.e., based on science), often turn out to be wrong or not so clear. We now realize that aggressive nutritional support carries risks. The risk of infection may be related more to hyperglycemia (or hypertriglyceridemia) than to PN per se, and essential fatty acid requirements may not be as well defined as previously thought. When it seems as if knowledge is for naught, the following quote comes to mind: “I reserve the right to be smarter tomorrow than I am today” (227,228). In a way, we are victims of our own success. PN can provide effective nutritional support but, as is evident from this review, there are large holes in our knowledge and little likelihood of abundant future research to fill them. For the most part, these deficiencies in knowledge are more problematic for pediatric patients than for adults. Unfortunately, because pediatric PN makes up such a small share of the market, manufacturers are reluctant to spend the resources to carry out the studies needed to define the child-specific impact of new lipid emulsions, reformulated vitamins, etc. Money spent on these questions would not be recouped quickly. The responsibility for improving PN safety and efficacy lies with all concerned: industry, funding agencies, physicians, pharmacists, nurses, and nutritionists. PN is still the life-saving, far-from-perfect therapy it has been for over 40 years. Like all therapies it must be used and monitored appropriately. Using it means more than just checking the patient’s weight, and monitoring now means more than checking the serum electrolytes. Checking the box on the order sheet will never be enough. Acknowledgments: The authors thank Dr. W.C. Heird for his very helpful comments. This study was supported by the National Institute of Child Health and Human Development, Grant No. RO1 NR05337-01A2, the Daffy’s and Henriksen Foundations, and the USDA/ARS under Cooperative Agreement No. 58-6250-1-003. This work is a publication of the USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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