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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— acids—Lipid emulsion. © 2003 Lippincott Williams &
Intravenous—Feeding—Neonates—Energy—Protein—Amino Wilkins, Inc.

INTRODUCTION Our immediate reaction was to take offense, feel hurt,


and shake our heads in disbelief that anyone could be so
Parenteral nutrition (PN) came of age in 1964 with the foolish as to think such things. However, as we thought
demonstration that beagle puppies could be nourished about it, we realized that the question is pertinent and
successfully from 12 weeks of age to maturity by pro- perceptive. Like the clinical pathways set out for com-
viding all nutrients intravenously (1). The first total par- mon illnesses such as diarrhea and croup, the question is
enteral nutrition of an infant with extreme short bowel not so much how to follow the roadmap but rather, when
syndrome followed in 1967 (1). Since them many lessons not to follow it. Thus, our review will focus on two areas:
have been learned as a result of complications of PN. 1) Common misconceptions surrounding the use of PN;
These have included nutrient deficiencies and excesses, and 2) When should “standard PN” (i.e., checking the
infections, complications of inadequate or excessive en- weight and the box on the order sheet) not be used. These
ergy and protein intake, liver disease, and toxicities from questions have lead us to review recent developments in
product contamination. Our patients have paid the price PN (in the past 5–7 years). Whenever possible we will
for these lessons, but fortunately improved survival has take an evidenced-based approach to the data. Unless
also resulted. These incidents have reinforced to us the specified, the studies we will discuss were carried out in
physicians the axiom that “good judgment comes from pediatric patients. The risk of any review is that it is old
experience . . . and experience comes from bad judg- hat to some and very new to others. We have done our
ment.” (2). Along the way we have learned much about best to strike a middle ground. Because it could be a
nutrition, infection, liver pathophysiology, and child de- subject unto itself, we will not review PN-associated
velopment (e.g., yes, infants really can “unlearn” how to cholestasis, although when pertinent, some comments
suck and swallow). Have we learned so much that ad- will be made.
ministration 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
Energy Requirements, Energy Sources, and the
reached the stage where administration could be treated
as a routine clinical algorithm such as diarrhea or croup. Consequences of Overfeeding
Do we only need to check the weight, calculate the ad-
ministration rate and check the box next to “Standard Estimating the appropriate energy intake is a funda-
Child Solution” on the PN pharmacy order sheet? Is mental step in prescribing PN. Although we have long
there really anything new in PN? acknowledged the risks of underfeeding our patients,
more recently we have come to reevaluate energy re-
Received November 25, 2002; accepted February 13, 2003. quirements in particular clinical scenarios and to appre-
Address correspondence to Robert J. Shulman, 1100 Bates St., Hous- ciate the problems associated with excessive energy in-
ton, Texas 77030, U.S.A. (e-mail: rshulman@bcm.tmc.edu). take.

587
588 R. J. SHULMAN AND S. PHILLIPS

Energy Requirements mechanically ventilated critically ill children (N ⳱ 33; 6


± 5 years of age) whose mean length of stay in the
A few terms must be defined in order to discuss energy intensive care unit was approximately 2 weeks, measured
expenditure (3). Basal metabolic rate is the energy ex- energy expenditure was only about 8 kcal ⭈ kg−1 ⭈ d−1
penditure of a recumbent child or adult in a thermoneu- (17%) above expected based on more recent data (8,9).
tral environment after a 12- to 18-hour fast just when the Joosten et al. found even smaller increases in energy
individual has awakened but before daily activities have expenditure in a more heterogeneous group of 36 infants
commenced. Basal metabolic rate is a reflection of the and children in an intensive care unit (10). Finally, Turi
energy expenditure required for vital processes. Resting et al. measured energy expenditure in 21 patients in the
energy expenditure refers to the energy expenditure of a intensive care unit with systemic inflammatory response
person at rest in a thermoneutral environment. Basal syndrome or sepsis and compared their energy expendi-
metabolic rate and resting energy expenditure usually do tures to a group of hospitalized control children (11). No
not differ by more than 10% (3). Total energy expendi- differences were noted between the groups (11).
ture is the sum of requirements for basal metabolism, Taken together, these data support the idea that in
thermic effect of ingested food, thermoregulation, and most cases there is little need to provide post operative or
activity. In older children, activity accounts for a large critically ill infants and children with much more than
proportion of total energy expenditure. Thus, the total their resting energy expenditure, which in most cases
energy expenditure of a child who is hospitalized and will be an amount similar to their basal metabolic rate.
lying in bed is reduced. The information in Table 1 can be used to calculate basal
Historically, it has been thought that the surgical pa- metabolic rate in normal children (9). A recent report by
tient requires an energy intake proportional to the sever- Duro et al. used the Enhanced Metabolic Testing Activ-
ity of the illness. By definition, the energy intake would ity Chamber (EMTAC) to predict REE in 50 normal
be increased compared with that of a “non-stressed” pa- infants up to 7 months of age with a maximum weight of
tient. However, from a practical standpoint this concept 9 kg (12). Their data suggest that for this age group the
does not seem to be the case as the increased energy values of Shofield may be an underestimation (9,12).
expenditure is short-lived. For example, although new- However, part of this difference may be explained by the
borns have a 20% increase in resting energy expenditure fact that the values for Shofield are for BMR and those
after major surgery, this elevation returns to baseline of Duro et al. are for REE (9,12). The equations de-
within 12-24 hours (4). Infants who remain critically ill scribed by Duro et al. are:
and require PN also do not appear to require increased
energy intakes. Jaksic et al. measured energy expenditure REE (kcal/d) ⳱ [84.5 x Weight (kg)] – 117.33
in eight non-ventilated surgical neonates (gastroschisis, (R2 ⳱ 0.65, P < 0.01)
atresia, volvulus) on postoperative day 16 (± 12, SD) and
The prediction is improved somewhat by including
compared them with ten infants on extracorporeal life
length:
support studied at 7 ± 3 days of age (5). There were no
differences in energy expenditure between the groups REE (kcal/d) ⳱ [10.12 x Length (cm)]
(53 ± 5 vs. 55 ± 20 kcal ⭈ kg−1 ⭈ d−1) (5). This level of + [61.02 x Weight (kg)] – 605.08
energy expenditure is comparable to that of “non- (R2 ⳱ 0.7, P < 0.01)
stressed” infants (see below). The similarity in energy
expenditure was present despite the finding that IL-6 and It is evident in the study by Jaksic et al. that there may
C-reactive protein levels were significantly greater in the be significant interindividual variations in energy expen-
extracorporeal life support group reflecting an increased diture (5,7). This should not be surprising, as even
degree of illness, and ultimately, mortality (30% vs. 0) among normal newborns energy requirements do not fall
(5). This same group of investigators recently has shown within narrow margins (13). White et al. have shown that
that preterm infants (25 weeks gestation) behave simi- in pediatric intensive care unit patients that there is little
larly (6). within-day variation in energy expenditure but day-to-
Lloyd recently reviewed the data regarding energy re- day variation is as high as 21 ± 16% (mean ± SD) (14).
quirements in surgical newborns and children (7). The Ideally, energy expenditure should be measured in
evidence reveals that the increase in energy expenditure critically ill patients. However, it may not be practical
associated with surgery only lasts for 24 hours after the because of the expensive equipment and the expertise
procedure (7). Estimating energy expenditure during the required. At the very least, one should be flexible regard-
first 24 hours after surgery will overestimate the energy ing the “appropriate” energy intake and monitor the pa-
requirements for the entire postoperative period, poten- tient for weight gain (fluid vs. tissue) and evidence of
tially resulting in excess energy intake with its potential overfeeding (e.g., CO2 production; see below). Two re-
consequences (see below). cent studies may be of value in calculating resting energy
Energy requirements also have been examined in non- expenditure for surgical infants and intensive care pa-
operated children in the intensive care unit. In a group of tients.

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PARENTERAL NUTRITION IN INFANTS AND CHILDREN 589

TABLE 1. Equations for estimating basal metabolic exception is the preterm infant. PN is required after birth
rate (MJ/day)* because of the premature infant’s limited nutritional
Age
stores (21). A recent randomized controlled study com-
(years) Male Female pared preterm infants (27 weeks gestational age, N ⳱
125) receiving PN on the first day of life to those in
<3 0.249 wt − 0.127 0.244 wt − 0.130
<3 0.0007 wt + 6.349 L − 2.584 0.068 wt + 4.281 L − 1.730
whom it was started in the first few days of life and
3–10 0.095 wt + 2.110 0.085 wt + 2.033 advanced more slowly (22). Infants in the early PN group
10–18 0.074 wt + 2.754 0.056 wt + 2.898 had fewer infections during hospitalization and were
18–30 0.063 wt + 2.896 0.062 wt + 2.036 more likely to be above the 10th percentile for weight or
* Notes
height at the time of discharge (22).
1. To convert to kcal/day multiply by 239
2. Wt ⳱ weight in kilograms
3. L ⳱ Length in meters. Only predictions for children <3 years of
Energy Sources
age are improved by including length in the equation.
From (9). There is controversy around the choice of nutrients to
provide energy requirements via PN. There are glucose
advocates, lipid believers, and argument as to whether
Using indirect calorimetry and a number of covariates
protein (i.e., amino acids) should be counted as part of
in a group of surgical infants, Pierro et al. developed the
the total administered energy. At the expense of over-
formula shown below to calculate energy expenditure
simplification and wounding the true believers in each
(15,16).
camp (the authors are active participants in these contro-
Resting energy expenditure (kcal/d) ⳱ versies), we submit that a few basic principles can be
−74.436 +[34.661 x weight (kg)] agreed upon. 1) There is a minimum amount of glucose
+ [0.496 x heart rate (beats/min)] that must be provided in order to prevent hypoglycemia
+ [0.178 x age (days)] x [1.44] and a maximum that results in the production of exces-
sive CO2 and/or hepatic steatosis (see below); 2) There is
The prediction has an error of – 0.95 ± 3.65%; an R2 a minimum requirement (both dose and frequency) for
⳱ 0.85; and a P < 0.00001) intravenous fat emulsion to prevent essential fatty acid
White et al devised the following formula for estimat- deficiency but a maximum beyond which intravenous fat
ing energy expenditure in intensive care patients (17): may have deleterious effects; and 3) Amino acids must
be provided in adequate amounts to prevent hypoprotein-
Energy expenditure (kcal/day) ⳱ emia but there are adverse consequences of giving an
[(17 × age in months) + (48 × weight in kg) excess. Both the size and the age of the pediatric patient
+ (292 × body temperature in °C) – 9677] are important in determining the appropriate quantities of
x [0.239] (R2 ⳱ 0.867) glucose, fat and amino acids administered in PN.
Obese adolescents are an exception to the basal meta-
bolic rate calculations provided in Table 1. The basal Glucose
metabolic rate for obese children can be calculated as
follows (18): Estimates of glucose utilization by the brain are shown
in Table 2 (23). These estimates vary with age and, at
For Boys: BMR ⳱ first glance, reflect the minimum amount of glucose that
[16.6 x weight (kg)] + [77 x height (meters)] + 572 must be provided to prevent hypoglycemia (23). Some
investigators have argued that gluconeogenesis provides
For Girls: BMR ⳱ a significant amount of glucose (even in preterm infants)
[7.4 x weight (kg)] + [482 x height (m)] + 217 and suggest that not all the glucose shown in Table 2
The clinical significance of energy expenditure, par- need be provided exogenously (24,25). However, these
ticularly in the critically ill patient, also has an impact on
the timing of PN initiation. If very ill patients are going TABLE 2. Estimates of glucose consumption by the brain
to be “hypermetabolic”, available data suggest that it will
Utilization
be early in the disease process. PN administration itself
increases metabolic rate (19,20). The more malnourished Age (mg ⭈ kg −1
⭈ min )
−1
(g ⭈ kg−1 ⭈ d−1)
the patient, the greater the stimulatory effect of PN on Newborn 8.0 11.5
metabolic rate (20). Thus, administration of PN which 1 year 7.0 10.1
provides all nutritional requirements should be avoided 5 years 4.7 6.8
Adolescent 1.9 2.7
in the first couple of days of a patient’s critical illness, as Adult 1.0 1.4
it will further increase the metabolic rate and do little to
stem the protein catabolic response to the illness. An From (23).

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590 R. J. SHULMAN AND S. PHILLIPS

studies have used isotopic tracers to measure gluconeo- PN regimens were tested: 87:5:8 (glucose:fat:amino ac-
genesis and it has been shown that this method underes- ids as percent of total energy), 60:32:8, and 34:58:8 Total
timates the contribution of glucose to CO2 when com- energy intake was comparable to the recommended daily
pared with data obtained from indirect calorimetry (23). allowance. The increase in resting energy expenditure
Thus, the data in Table 2 probably do reflect the amount (although reported as basal metabolic rate) induced by
of exogenous glucose required to prevent hypoglycemia the high glucose regimen was nearly 5 times greater than
under most circumstances (23). Kalhan and Kiliç re- that of the other two regimens (28). Bresson et al. also
viewed the evidence that this amount of exogenous glu- noted increased energy expenditure in relationship to in-
cose also is sufficient to minimize nitrogen loss (23). creasing glucose intake, albeit to a lesser extent, amount-
What about the maximum rate of glucose oxidation? ing to 16% of the energy value of infused glucose (29).
Lafeber et al. found a glucose oxidation rate of 6.6 ± 1.2 In the study by Nose et al. the respiratory quotient (RQ
mg ⭈ kg−1 ⭈ min−1 (9.5 g ⭈ kg−1 ⭈ d−1) in appropriate for ⳱ CO2 production/O2 consumption) was significantly
gestational age preterm infants (birth weight: 1613 ± 151 greater on a high glucose regimen compared to lower
g, gestational age: 31.1 ± 1.5 wk; mean ± SD)(26). The glucose regimens (28). The data suggest that in this
rate was minimally greater than that found in small for population of stable patients on long-term PN, glucose
gestational age infants (26). In contrast, in term surgical intakes in excess of 10 mg ⭈ kg−1 ⭈ min−1 result in
infants Jones et al. measured a maximal glucose oxida- conversion of glucose to fat (RQ >1) (28). As seen in
tion rate of 12.5 mg ⭈ kg−1 ⭈ min−1 (18 g ⭈ kg−1 ⭈ d−1) Figure 1, lipogenesis from glucose results in a large in-
(27). This rate is comparable to that of stable patients crease CO2 production relative to O2 consumption (i.e.,
both on long-term PN (N ⳱ 7, 30 ± 41 months of age) high RQ).
or short-term PN (N ⳱ 36, 6 ± 4 months of age) (28,29). Talpers et al. (among others) examined the effect of
Clinical status can modify glucose oxidative capacity different glucose/fat ratios on CO2 production in adults
significantly. For example, Sheridan et al. noted that in (19,38). In contrast to the studies of Nose et al (and other
critically burned children the maximal rate of glucose investigators), they were unable to detect a change in
oxidation was 5 mg ⭈ kg−1 ⭈ min−1 (30). CO2 production as a consequence of alterations in the
glucose/fat ratios (19,38). It is possible that the discrep-
ancy between these studies is a result of the higher pro-
Consequences of Overfeeding with Glucose portion of total energy provided by amino acids in Talp-
ers’ study (20% of total energy) than in Nose’s study (8%
In critically ill individuals, glucose intakes above the of total energy) (28,38). Amino acids also can affect
maximal glucose oxidation rate will result in the non- ventilatory drive and the response to CO2. Increasing
oxidative production of fat, hence, are unlikely to en- amino acid intake (with energy intake constant) leads to
hance energy balance, or even reduce protein catabolism an increase in minute ventilation and more importantly,
(23). On the other hand, glucose intakes above the maxi- an enhanced response to CO2 (i.e., minute ventilation
mal oxidation rate promote fat deposition, which may be increases in a more responsive fashion to increasing lev-
a nutritional goal in specific clinical situations (e.g., pre- els of CO2 (39,40). Thus, the higher percentage of amino
term infants). We will use the term overfeeding to mean acids provided in the adult studies may have blunted the
providing calories in excess of the amount required for differences in CO2 production at different glucose/fat
normal weight gain. ratios.
A number of recent reviews have addressed issues Another factor with an impact on CO2 production is
related to carbohydrate overfeeding in the intensive care total energy intake. There is a linear relationship between
unit patient (31–35). Unfortunately, the relationship be- energy intake and CO2 production and increased minute
tween carbohydrate feeding and impaired pulmonary ventilation (presuming glucose is providing a portion of
function (in the form of increased CO2 production) as the energy) (38,40). Indeed, the patients reported to have
well as the development of fatty liver often is oversim- developed respiratory failure (i.e., CO2 retention and in-
plified. creased minute ventilation) as a consequence of PN with
When glucose is administered in excess of the amount high concentrations of glucose were receiving excessive
that can be directly oxidized for energy production and energy intakes (see reference 35 for a review). Under
glycogen production, the excess is directed to fat syn- normal circumstances the increased CO2 production is
thesis (lipogenesis) (Fig. 1) (36,37). This conversion is handled easily by increasing the respiratory rate and/or
inefficient and probably accounts, in part, for the in- depth. Problems potentially arise in patients with respi-
crease in energy expenditure seen with high rates of glu- ratory compromise. The respiratory response to enteral
cose infusion (Fig. 1) (20). This inefficiency can have carbohydrate intake and enteral overfeeding mirrors
clinical consequences besides simply producing hyper- what is seen with PN (41).
glycemia. In summary, the greater the proportion of glucose in
Nose et al. studied energy expenditure and CO2 pro- the PN energy mix, the larger the increase in CO2 pro-
duction in 7 infants receiving long term PN (28). Three duction and minute ventilation. Malnourished patients

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PARENTERAL NUTRITION IN INFANTS AND CHILDREN 591

FIG. 1. Respiratory quotient (CO2 production / O2 consumption) and caloric yield from the oxidation of glucose, fat, amino acids, and the
conversion of glucose to fat. *Energy production values shown are theoretical. Actual energy produciton is less efficient. For conversion
of palmitate it is about 41% (980/2398) whereas glucose conversion to fat is only about 20% efficient. Adapted from Flatt JP: Energetics
of intermediary metabolism. In Assessment of Energy Metabolism in Health and Disease, p. 77 (ed.) JM Kinney, Report of the First Ross
Conference on Medical Research. Columbus, Ohio, Ross Laboratories, 1980.

are least and hypermetabolic individuals are most sus- used in combination (44). Steatosis was associated with
ceptible. Normally nourished and metabolically normal a rise in serum transaminases but no cholestasis was
patients have an intermediate response (42). The greater noted (44). Studies in normal adult volunteers suggest
the total energy intake, the greater the effect. that high carbohydrate feeding leads to an increase in
In selected patient groups, giving glucose in amounts total VLDL triglyceride secretion rate from de novo syn-
above the maximal oxidative rate may be appropriate thesis primarily due to stimulation of the secretion of
(e.g., preterm infants who need to deposit fat). However, preformed fatty acids (45). The results imply that the
the greater the amount of glucose, the greater the risk of liver derives all its energy from carbohydrate oxidation
adverse consequences. Unfortunately, the absolute intake as opposed to fatty acid oxidation such that fatty acids
at which the adverse consequences occur is poorly de- taken up by the liver are channeled into VLDL triglyc-
fined. erides (45). Hepatic steatosis results when export of the
Overfeeding of glucose also can affect liver function VLDL triglycerides does not keep pace with production
although its contribution to the development of cholesta- (34,45).
sis in humans is unclear. Burke et al. observed a rela- Another potential complication of overfeeding with
tionship between glucose infusion rate and the develop- glucose is an increase in infectious complications. PN
ment of fatty infiltration of the liver in necropsies of has been associated with an increased risk of infectious
children who died of severe burns (43). In a study in 37 complications compared with enteral feeding or no nu-
catabolic adults, Tulikoura et al. administered PN using tritional support in adult studies (46–49). Recent data
glucose and glucose and fat as energy sources (44). suggest that this finding may actually be explained by
There was a significant increase in hepatic steatosis in overfeeding with glucose (50). Hyperglycemia is a risk
the glucose group but none when glucose and fat were factor for infection (51,52). Recently, hyperglycemia

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592 R. J. SHULMAN AND S. PHILLIPS

was associated with an increased risk of infection in 1.5 g/kg (approximately 500 mL of 20% intravenous fat
children with burns (53). In a prospective randomized emulsion) twice a week in an adolescent, would be ad-
trial in adults there was no difference between groups equate for all such patients. In patients receiving no in-
receiving hypocaloric intravenous fluids and those re- travenous fat emulsion, some studies suggest that fatty
ceiving PN that did not overfeed the patients or induce acid deficiency develops faster when total energy intake
hyperglycemia (54). These intriguing results require fur- is low than it does when total energy intake is high
ther verification but may have great implications for pa- (66,67).
tient care. It often is suggested that intravenous fat emulsion be
administered over less than 24 hours (e.g., 20 hours) to
allow time for the fat to clear from the blood. In fact,
Clinical Implications
studies suggest that it is better to administer the daily
dose over 24 hours in patients who have difficulty tol-
Patients with respiratory compromise, particularly
erating the infusion. Preterm infants should receive the
CO2 retention (e.g., cystic fibrosis) are at risk for expe-
infusion over 24 hours to avoid hypertriglyceridemia.
riencing a worsening of their pulmonary status if glucose
For patients without hypertriglyceridemia or other evi-
provides a large proportion of their energy needs. The
dence of intolerance to intravenous fat emulsion, a less
risk increases as energy intake surpasses REE. Malnour-
than 24-hour infusion schedule may be tolerated well.
ished patients may not manifest this response until they
One of the major determinants of the rate of clearance of
begin to be nutritionally rehabilitated. A hypermetabolic
fat from the blood is the amount of intravenous fat emul-
patient will exhibit this reaction most quickly. Concerns
sion infused per unit time (68). The longer the infusion
about overfeeding have been addressed recently in a con-
time, the less likely the patient will develop hypertriglyc-
sensus statement on the care of the adult intensive care
eridemia (68,69). Intravenous fat emulsions with high
unit patient (55).
concentrations of phospholipids (i.e., 10% emulsions)
should be avoided as they carry a higher risk of produc-
Intravenous Fat Emulsion ing high serum levels of triglycerides, cholesterol, and
phospholipids than other emulsions (i.e., 20% and 30%
Unless otherwise noted, the term intravenous fat emul- emulsions) (70–72).
sion refers to the currently available (in the United A number of other factors decrease the rate of clear-
States) soy- or soy/safflower-based emulsions. A key ance of intravenous fat emulsions. The more malnour-
role for intravenous fat emulsion is the prevention of ished the patient, the slower the rate of clearance will be.
essential fatty acid deficiency. The usual preterm infant Slower clearance in malnourished patients is a result of
(< 2 kg birthweight) on PN without intravenous fat emul- lower levels of lipoprotein lipase. This enzyme, which is
sion or on enteral feedings begins to demonstrate bio- responsible for releasing fatty acids from the fat emul-
chemical evidence of essential fatty acid deficiency (in- sion, resides within the capillary system. The lower the
creased triene/tetraene ratio) within seven days of birth if capillary tissue mass (a situation found in preterm infants
not provided with adequate intravenous fat emulsion and malnourished patients), the slower the rate of intra-
(56). In the absence of intravenous fat emulsion, endog- venous fat emulsion clearance. Studies in adult volun-
enous adipose tissue and the liver are probably the source teers have shown that the muscle, splanchnic, myocardi-
of essential fatty acids (57). In order to prevent the mo- al, and subcutaneous fat capillary systems clear 47%,
bilization of fatty acids for energy, essential fatty acids 25%, 14%, and 13% of the total amount of lipid infused,
must be provided in amounts necessary to both replace respectively (73). Under normal circumstances the liver
deficits and supply ongoing needs for metabolism and clears less than 1% of infused lipid (73).
growth. In other words, essential fatty acid deficiencies Another factor that alters the tolerance to intravenous
are cumulative (58,59). Given that intravenous fat emul- fat emulsion is the concurrent administration of drugs.
sions contain approximately 50% essential fatty acids by Because of their lipolytic effect, steroids are the proto-
weight, about 0.5 g ⭈ kg−1 ⭈ d−1 of intravenous fat emul- type. Patients simultaneously receiving steroids and in-
sion is required to prevent essential fatty acid deficiency travenous fat emulsions are prone to hypertriglyceride-
in patients on total PN (56,60). However, there is con- mia (74). Additionally, a number of medications contain
troversy regarding this figure, particularly in adults (and lipid or are microsomal formulations. Drugs such as pro-
presumably adolescents) with some investigators sug- pofol and amphotericin B may contribute significant
gesting the recommendation is more than adequate (e.g., amounts of (fat) energy to the total daily intake and
1.5 g/kg twice weekly) and others stating it is too low which should be taken into account in nutritional calcu-
(61–64). There appears to be a fair amount of inter- lations.
individual variation in essential fatty acid requirements Patients who are metabolically stressed (i.e., sepsis,
based upon age, disease, and nutritional status (56,61,62, trauma) or who have organ dysfunction (e.g., liver and/or
65). Thus, one should not presume that giving the small- renal disease) also are likely to develop hypertriglyceri-
est recommended amount of essential fatty acid, such as demia during intravenous fat emulsion infusion. These

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PARENTERAL NUTRITION IN INFANTS AND CHILDREN 593

patients have an outpouring of cortisol, catecholamines, polyunsaturated fatty acids in the emulsions to prosta-
and cytokines that promote the lipolysis of endogenous glandins, which then can cause vasoconstriction or va-
lipid stores (75–77). Liver and renal disease themselves sodilatation depending on the rate of infusion and the
are associated with hypertriglyceridemia. However, adult clinical state of the lungs (85,86,93). Peroxides are an-
(and presumably pediatric) patients with sepsis and liver other contaminant that can be found in the fat emulsion
disease can tolerate and utilize intravenous fat emulsions (94). Evidence suggests that they also promote increased
(78,79). Infants with ventricular septal defects or trans- prostaglandin levels (95).
position of the great vessels (i.e., cyanotic heart disease) Interpretation of the data linking intravenous fat emul-
do not have inordinate increases in serum triglycerides in sions and pulmonary dysfunction is complicated. The
response to intravenous fat emulsion (80). adverse effects appear to depend on the dose and rate of
Serum triglyceride levels should be measured four administration, presence of peroxides, and clinical state
hours after starting an intravenous fat infusion or four of the lungs (89,90,93–95). Are the effects clinically rel-
hours after any increase in infusion rate. It is at this time evant? In preterm infants the balance of data suggests
that hypertriglyceridemia is most likely to occur (81–83). that administration of intravenous fat emulsion at normal
Ideally the triglyceride level should be ⱕ100 mg/dL rates does not affect oxygenation (72). Studies to the
(84). However, this upper limit varies depending on the contrary have usually used inappropriately rapid rates of
method used to measure serum triglycerides. For ex- infusion (96–98). Because intravenous fat emulsion can
ample, some common methods of measuring triglycer- induce vasoconstriction that is not limited to the pulmo-
ides measure the free glycerol released from the triglyc- nary vasculature, observed decreases in transcutaneous
eride molecule (85). Given that intravenous fat emul- pO2 may be related to local declines in subcutaneous
sions contain free glycerol in addition to triglycerides, perfusion and not reflect systemic oxygenation (95,99).
the serum triglyceride level measured by evaluating The effects of intravenous fat emulsion on the develop-
glycerol will be an overestimation of the true serum tri- ment of chronic lung disease have been reviewed re-
glyceride level. A value of 150 mg/dL may correspond to cently (72). The balance of the data suggests no adverse
an actual triglyceride level of only 100 mg/dL (Buffone impact and possibly a beneficial effect (72,100). How-
and Shulman, unpublished data). Nephelometry should ever, much more work is needed in this area before we
not be used to monitor serum triglyceride levels as it is can be certain that there are no clinically significant ad-
unreliable (85,86). Heparin administration lowers serum verse effects.
triglyceride levels but does not affect the rate of fatty Even more confusing than the issue of pulmonary
acid oxidation (83,87,88). function is the controversy regarding the effect of intra-
Clinicians frequently ask what level of hypertriglyc- venous fat (101–105) emulsions on immune function.
eridemia is acceptable in a patient receiving PN. Given Some studies show a beneficial effect, some no effect,
the need to provide essential fatty acids to patients who and some an adverse effect. A complete discussion is
may have hypertriglyceridemia for prolonged periods beyond the scope of the present article and the reader is
(e.g., the critically ill patient), at what serum level do the referred to the supplied references. It should be pointed
triglycerides start having an adverse impact on the pa- out that reviews in this area sometimes give a prejudiced
tient? Unfortunately, to our knowledge, there are no data view in that only selected publications are quoted. Inter-
defining the level at which one should be concerned. pretation of publications often is blurred by the use of
Many investigators have studied the impact of intra- inappropriate doses (both in vivo and in vitro), differ-
venous fat emulsion on pulmonary function. Although an ences in patient groups or in vitro models (102). Similar
in depth review of this topic is beyond the scope of this to the situation in pulmonary function studies, many of
article, a few points can be touched upon and the reader the effects of intravenous fat emulsions on immune func-
is referred to two reviews (89,90). tion appear to be related to the generation of leukotrienes
After a fatty meal, the serum triglyceride of normal and other polyunsaturates from the emulsions. There also
adults may transiently approach 500 mg/dL (91). Even is evidence the long chain fats may alter cellular function
values above 1500 mg/dL do not appear to decrease the by changing membrane fluidity (104). Studies on pedi-
carbon monoxide diffusing capacity in healthy adults atric patients and tissues have not revealed evidence sug-
(91). This begs the question as to whether elevated tri- gesting an impairment of immune function by intrave-
glycerides cause some of the adverse oxygenation effects nous fat emulsions (106–113).
reported with intravenous fat emulsions that when severe Do intravenous fat emulsions promote infections?
is referred to as the “fat overload syndrome” (92). It was Data are limited. A study in adult and pediatric bone
first believed that the sometimes seen adverse effects of marrow transplant patients found no increase in the risk
intravenous fat emulsions on pulmonary function (e.g., of bacteremia or fungemia in patients receiving intrave-
decreased diffusion capacity, oxygenation, intrapulmo- nous fat emulsions (114). In contrast, a retrospective
nary shunting) were related to the serum triglyceride study of preterm infants identified intravenous fat emulsion
level (89,90,93). It appears more likely that these as potentially contributing to the development of coagulase-
changes, when seen, are due to the conversion of the negative staphylococcal infection (115). However,

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594 R. J. SHULMAN AND S. PHILLIPS

the lack of a temporal relationship between intravenous Amino Acids


lipid administration and infection weakens the conclu-
sions of this study (115). The lack of knowledge on this Use of amino acids in pediatric PN has recently been
important issue underscores the importance of monitor- reviewed and the reader is referred to these references for
ing and using intravenous fat emulsions judiciously. more details (121,122). Amino acid requirements vary
Newer intravenous fat emulsions not yet available in the from ⱖ 2.5 g ⭈ kg−1 ⭈ d−1 for preterm infants to 0.75 g ⭈
United States using olive oil or structured lipids may kg−1 ⭈ d−1 for adolescents (123,124). Similar to energy
obviate some of these immune-related concerns (116). requirements, amino acid requirements vary from indi-
The use of intravenous fat emulsions in patients with vidual to individual under normal circumstances. The
coagulation abnormalities requires comment. In rare immunodeficiency associated with malnutrition is to a
cases, intravenous fat emulsion has been associated with great extent related to protein malnutrition as opposed to
thrombocytopenia. However, prospective and retrospec- energy malnutrition. Consequently, amino acid require-
tive reports suggest that under normal circumstances ments should be attended to first in prescribing paren-
they do not induce thrombocytopenia (117,118). It teral nutrition. The intake of energy and amino acids in
should be kept in mind that essential fatty acid deficiency combination result in the greatest protein gain. Amino
itself is a cause of hematologic abnormalities (119). acid intake is the main determinant of protein gain (Fig-
ure 2). That is, there is a much larger gain in protein
accretion with increases in amino acid intake than with
increases in energy intake (Fig. 2).
Clinical Implications Since amino acids are generally not metabolized to
supply energy but to provide structural and visceral pro-
There is debate as to the appropriate amount of intra- teins and enzymes, some clinicians do not include them
venous fat emulsion required to prevent essential fatty in the total energy calculation. In practice, to include
acid deficiency. In infants (including preterms) who are them or not usually does not make much difference. For
most susceptible, at least 0.5 g ⭈ kg−1 ⭈ d−1 should be example, a term infant who weighs 4 kg requires about 8
used. In older children and adolescents the minimum g/d of amino acids, which is equivalent to 32 kcal (8 g x
dose is probably in the range of 1.5 g/kg (approximately 4 kcal/g). The total energy requirement is about 400
500 mL of 20% intravenous fat emulsion) twice a week. kcal/d (4 kg x 100 kcal/d). Thus, adding the calories from
For individuals on long term parenteral nutrition who protein changes the total energy calculation by less than
10%. Interindividual energy requirements easily can vary
either have little or no enteral intake of fat or who have
by this much. The bottom line is that both amino acids
severe fat malabsorption (e.g., severe short bowel) es-
and energy need to be titrated to the patient’s require-
sential fatty acid status should be assessed after a few
ments.
months of therapy. It has been suggested that measure-
Although serum prealbumin (transthyretin) and trans-
ment of n-6 and n-3 long chain polyunsaturated fatty ferrin are often used as short-term (1–2 day) measures of
acids is more reliable than the more commonly employed the response to amino acid intake, the blood urea nitro-
triene/tetraene ratio (57). gen (BUN) can be also be used in many cases. If renal
The American Gastroenterological Association Tech- function and hydration are normal, a low BUN (< 5)
nical Review on Parenteral Nutrition states that intrave- reflects inadequate amino acid intake and conversely, a
nous fat emulsion should not be administered to patients high BUN (> 20) suggests that the amino acid intake may
whose serum triglyceride levels exceed 400 mg/dL (21). be too great. For many patients a BUN between 10 and
No data are provided to support this statement but the 15 mg/dL is a good target and reflects an amino acid
authors agree that serum triglyceride levels ⱕ 400 are intake that is adequate for protein anabolism (Laine and
unlikely to cause clinically relevant problems. How the Shulman, unpublished).
duration hypertriglyceridemia might affect the complica- Although it has been stated in the literature that the
tion rate is unclear. In preterm infants pulmonary vascu- amino acid intake should be gradually increased over the
lar lipid deposition was more common in infants who first few days of PN administration, we know of no good
received intravenous fat emulsion and correlated with the scientific documentation for this view. For example, we
duration of lipid therapy although some infants who use intakes of 2.5 mg ⭈ kg−1 ⭈ d−1 even in 25-week
never received intravenous fat emulsion also demon- gestation infants without complications starting within a
strated lipid deposition (120). Liver or pancreatic dis- couple days after birth. A recent review of the literature
eases are not in themselves contraindications to the use on the use of early amino acid introduction found no
of intravenous fat emulsion. It is helpful to measure se- metabolic abnormalities (elevated BUN, serum pH, am-
rum triglyceride levels prior to starting intravenous fat monia, serum amniogram) associated with this practice
emulsion in patients who are likely to be hypertriglyc- even in preterm infants (123). Gradually increasing the
eridemic and when their clinical status deteriorates sig- amino acid concentration or volume only postpones the
nificantly. time at which the patient receives adequate intake.

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PARENTERAL NUTRITION IN INFANTS AND CHILDREN 595

FIG. 2. Differential effect of amino acid and


energy intake on protein gain in preterm in-
fants. Expected protein gain in a preterm in-
fant related to amino acid and energy intake.
If amino acid intake is doubled from 1 g ⭈
kg−1 ⭈ d−1 to 2 g ⭈ kg−1 ⭈ d−1 and energy
intake is held constant at 60 kcal ⭈ kg−1 ⭈ d−1
(Top Panel) the corresponding increase in
protein gain is greater than if the energy in-
take is doubled from 60 kcal ⭈ kg−1 ⭈ d−1 to
120 kcal ⭈ kg−1 ⭈ d−1 and amino acid intake is
held constant at 1 g ⭈ kg−1 ⭈ d−1 (Middle
Panel). The greatest protein gain is achieved
with an increase in amino acid intake and
energy intake (Bottom Panel). Adapted from
(123).

Evidence suggests that amino acids contribute to the absorbed, even in patients with short bowel syndrome
development of PN-associated cholestasis (125,126). (128). Consequently, this is an option for many patients
Even enteral protein intake can decrease bile flow (127). receiving PN. Of course, whenever possible other nutri-
If amino acids are removed from the PN when the patient ents should be provided enterally as well.
develops cholestasis and no other source of protein is There are very limited data in pediatric patients re-
provided, one then is faced with a patient who in addition garding the use of specialized amino acid solutions for
to having liver disease has hypoproteinemia or even specific conditions such as critical illness and liver or
kwashiorkor. There are some data to support the idea that renal failure. A crossover trial in children with end stage
provision of protein enterally while other nutrients (pri- liver disease suggested a benefit to a branched chain
marily carbohydrate) are provided intravenously can re- supplemented enteral formulation in that the special for-
duce the risk of or lessen the severity of PN-associated mula promoted more rapid nutritional rehabilitation
cholestasis (125). Protein is usually well digested and (129). Studies in adults with liver disease have been in-

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596 R. J. SHULMAN AND S. PHILLIPS

consistent. Most studies indicate that if used at all, associated cholestasis the reader is referred to recent re-
branched chain formulae should be reserved for patients views (139–141).
who are malnourished and/or who are encephalopathic
(130,131). The benefit of specialized amino acid solu-
tions for patients with renal disease also is not clear REFEEDING SYNDROME
(132,133). Similarly, the nutritional benefit of parenteral
nutrition given during dialysis requires further study Refeeding syndrome is a potentially lethal condition
(134,229). The two commercially available (in the characterized by severe electrolyte and fluid shifts asso-
United States) pediatric amino acid solutions have con- ciated with metabolic abnormalities in malnourished
centrations of essential amino acids, including branched patients undergoing refeeding orally, enterally, or paren-
chain amino acids, which are fairly close to those in the terally (139). Clinical features include fluid-balance ab-
specialized amino acids solutions. normalities, abnormal glucose metabolism, hypophos-
phatemia, hypomagnesemia, hypokalemia, and some-
Clinical Implications times thiamine deficiency (142).
Refeeding syndrome can occur with either parenteral
or enteral feeding. Because it is a preventable condition,
Provision of amino acids should be a priority in cal- patients who are at risk should receive a PN prescription
culation of PN requirements. In situations where fluid from the outset that will decrease the likelihood of its
intake is significantly restricted, energy intake should be occurrence. A detailed review of the condition is beyond
sacrificed at the expense of maintaining a greater amino the scope of this article but the reader is referred to
acid intake, particularly when more than resting energy comprehensive reviews (142,143). The syndrome can be
expenditure can be provided. The PN concentration of prevented by adequate provision of phosphorus, and to a
amino acids can be increased to 4%–8% (g/dL) depend- lesser extent magnesium and potassium at the time the
ing on the amino acid brand used (concentration of the patient begins to become anabolic. A common miscon-
stock amino acid solutions range from 10%–20%). The ception is that additional phosphorus and potassium pro-
BUN is a readily accessible and cheap method of titrat- vided at the onset of PN will prevent the syndrome. This
ing amino acid intake if renal function and hydration are is true only if adequate nutrition is being provided to the
normal. Consideration of enteral (as much as possible) patient so that they are actually regaining lost tissue mass
rather than parenteral administration of protein should be (i.e., muscle and viscera). If the amount of nutrition (en-
considered, particularly in patients at risk for cholestasis. ergy) being provided is less than that required to main-
If not limited by intolerance (e.g., enteral carbohydrate in tain weight or promote catch-up weight gain, the syn-
a patient with short bowel syndrome) other nutrients drome will not develop. Consequently, the patient may
should be provided enterally as well. be at risk for hypophosphatemia and hypokalemia weeks
after the initiation of PN (or whenever nutrient intake
allows for catch-up weight gain).
CYCLIC PARENTERAL NUTRITION Refeeding syndrome can be prevented by providing
additional phosphorus and potassium (usually as KxPOx)
The term cyclic PN refers to the administration of at the time PN is started. The amount of additional phos-
intravenous fluids intermittently with regular breaks phorus and potassium required depends on the degree of
from infusion. Cyclic PN offers the advantage of increas- malnutrition and the adequacy of total energy intake. A
ing the mobility of the patient and family. Much has been general rule of thumb in the authors’ experience is that
written regarding its other presumed advantages but twice the recommended daily allowance (RDA) of phos-
there are scant scientific data (135,136). One of the pro- phorus is a reasonable starting point. Usually the risk for
posed benefits is a lower risk for the development of liver clinically significant declines in these minerals lasts for
disease although reports have been anecdotal (137). Re- 7–10 days. During this period, it is important to follow
cently, Hwang et al. carried out a prospective study in serum phosphorus and potassium closely (e.g., every
adults on PN exhibiting various degrees of presumed other day or more often if serum levels are tenuous).
PN-associated liver disease (138). Patients who devel- After this time, supplementation above the RDA can
oped hyperbilirubinemia were randomized to either re- gradually be reduced. Calcium and phosphorus should
main on continuous PN or were placed on cyclic PN. not be given independently as administering one without
Patients with initial serum bilirubin less than 20 mg/dL, the other leads to renal wasting of the infused mineral
who remained on continuous PN, had a significant rise in (144).
serum bilirubin compared with the cyclic PN groups A rate-limiting factor in providing additional phospho-
(138). There was no apparent advantage of cyclic PN in rus is the risk of calcium/phosphorus precipitation. Table
patients with serum bilirubin greater than 20 mg/dL 3 provides guidelines for the maximal amounts of cal-
(138). These results are intriguing and beg for similar cium and phosphorus that can be administered in PN
studies in pediatric patients. For information on PN- (145–147). Note that the addition of cysteine (HCl) be-

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PARENTERAL NUTRITION IN INFANTS AND CHILDREN 597

TABLE 3. Maximal calcium and phosphorus concentrations teral Nutrition Packaging System, Fresenius Kabi,
in parenteral nutrition solutions Uppsala, Sweden). The bag and components can be
Without cysteine With cysteine#
stored up to 24 months with the seals between the cham-
bers intact. Seals are opened just before use. PN admix-
g/dL (%) Calcium Phosphorus Calcium Phosphorus tures find their greatest usefulness in older patients, par-
Amino acids mEq/L mmol/L mEq/L mmol/L
ticularly those on cyclic PN and those at home (see be-
1.0 50 12 50 23 low).
2 50 2 50 Because the admixture is a physical mix of naturally
1.5 50 11 50 18
5 50 12 50 incompatible substances (oil and water, calcium and
2.0 50 12 50 25 phosphorus), their utilization requires strict attention to
7 50 12 50 pharmaceutical guidelines for preparation, storage, and
2.5 50 22 50 38 use (156). Particulate matter (mobile, undissolved sub-
6 50 28 50
stances that are unintentionally present in products) re-
* Presumes the base amino acid solution has a pH of ⱕ5.5 sulting from inappropriate preparation or storage can be
Administration of intravenous fat emulsion into the same intrave- life threatening. For example, deaths have been reported
nous catheter may reduce solubility by 10%–20% (145, 146). Addition presumably as a result of precipitation of calcium and
of acetate without the addition of cysteine also may reduce solubility by
5–10% (147). # 40 mg/g of amino acids.
phosphorus in admixtures (157,158). Table 5 lists poten-
Note: This table is intended as a general guideline and is not to be tial areas of concern in the preparation and storage of PN
used in lieu of pharmacist verification of the compatibility of the PN admixtures.
solution. Modifications to the formulation and alterations in the method There have been multiple publications regarding how
and order of preparation may result in different calcium/phosphorus PN admixtures should be prepared and their stability.
solubilities.
Preparation of an admixture requires exquisite attention
to detail. The commercial product used, the sequence of
cause of its low pH enhances the solubility of the min- mixing, the type and concentration of additives, and stor-
erals. Computer software is available to assist in assuring age conditions are critical for maintaining lipid droplet
that calcium and phosphorus solubilities are not ex- size and distribution and preventing the development of
ceeded (148). In preterm infants and possibly other pa- particulate matter (159). For example, ideally all water-
tients prone to acidosis, the addition of cysteine may soluble additions should be mixed together whereas li-
require that the patient be supplemented with a source of pophilic additives (e.g., fat soluble vitamins) should be
base (e.g., acetate) (149). Calcium and phosphorus re- added to the intravenous fat emulsion (159). The last step
quirements for preterm infants have been fairly well de- should be mixing the intravenous fat emulsion (and its
lineated in contrast to older children (150,151). components) with the water-soluble components (159).
Undiluted hypertonic glucose solution should not be

PARENTERAL NUTRITION ADMIXTURES TABLE 4. Advantages and disadvantages of parenteral


nutrition admixtures
PN admixtures (also called Total Nutrient Admixtures
or TNA, Three-in-One solutions, or All-in-One solu- Advantages Disadvantages
tions) make use of the fact that under certain conditions Nursing time for administration Particulate matter is difficult to
the glucose/amino acid solution may be mixed with in- of PN is decreased see prohibiting visual
travenous fat emulsion and administered to the patient in inspection of solution
Rate of extrinsic touch Filtration must be performed
one bag. There are a number of potential advantages to contamination potentially with a larger filter (1.2
PN admixtures but also some drawbacks (Table 4; see reduced micron vs. 0.22 micron)
below) (152). Pharmacy preparation time
In addition to reducing cost, use of a PN admixture decreased
Admixtures support microbial Support the growth of
simplifies the patient’s life in that only a single infusion growth less than fat emulsion microorganisms better than
pump with less tubing and other accessories are needed alone glucose-amino acid solutions
(153). There also is evidence that it reduces the risk of A two pump system is Computer interfaced automated
bacterial growth in intravenous fat emulsion even after eliminated compounder expensive
24 hours (154). In a randomized trial in which adult Increased compliance of Emulsion instability can be
administering fat emulsion in disrupted with high
patients (N ⳱ 96) received either PN admixtures or tra- the home patient population concentrations of electrolytes
ditional (two-in-one) PN there was no difference in the or when base solution
rate of infection between the two groups (155). component amounts exceed
Recently, a bag has been developed that allows the compatibility limits
The cost of ‘Y’-site tubing and
solution to be made with the three components (amino additional supplies is saved
acids, glucose, fat) stored in separate compartments
separated by inner seals (Kabiven Multichamber Paren- From (152).

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598 R. J. SHULMAN AND S. PHILLIPS

TABLE 5. Three potential issues in the use of PN admixtures and contributing factors
Chemical precipitation Intravenous fat stability Vitamin stability
Calcium and phosphorus Low pH Thiamine reduction by
metabisulphite
Sulphur-containing amino acids Intravenous fat concentration Lack of exclusion of oxygen
and copper during compounding
Sulphur-containing amino acids Formation of peroxides Lack of use of
and calcium oxygen-impermeable
containers during storage
Ascorbic acid and selenium
Iron and phosphate
Order of Mixing

From (159).

added to intravenous fat emulsion (160). Solutions may mixtures that are inappropriate for certain patients. Be-
be stable when refrigerated and become unstable at room cause of the limitations in the amount of calcium and
temperature. Another example, heparin stability, has phosphorus that can be used in PN admixtures (even
been a subject of great debate. Contradictions regarding more severe than in non- admixture PN), their use may
its risk of precipitating with calcium probably are re- be inappropriate in young infants. One report has sug-
lated to differences in the studied heparin prepara- gested that PN admixtures can be used in former preterm
tions and the other additives and their concentrations infants and newborns, however, in this study it was not
in the admixtures (159). The reader is referred to com- clear that the PN admixtures had been validated as stable
prehensive reviews regarding the factors related to PN nor was there stability testing reported after the admix-
admixture stability as well as methodologies used to tures were prepared (169). Because the emulsion is
test stability (159–163). In general, final concentra- opaque (as a result of fat emulsion) a precipitate may be
tions range from 2% to 5% for amino acids, 5% to 23% invisible to the naked eye. The calcium and phosphorus
for glucose, and 1.5% to 5% for intravenous fat emul- requirements for neonates is 3–4 mEq ⭈ kg−1 ⭈ d−1 and
sion (161). 1–2 mmol ⭈ kg−1 ⭈ d−1, respectively (162). Based upon
In order to see through the morass of information it is studies using a commonly employed pediatric amino
best to follow a simple rule: after identifying a PN ad- acid solution (TrophAmine, B. Braun Medical, Inc., Mel-
mixtures whose stability has been well documented, use sungen, Germany) the PN admixture would provide in-
them exactly as described. Unlike standard PN solutions, adequate amounts of these minerals (170). As an infant
alterations of components, volumes, and/or concentra- approached 4–6 months of age it is conceivable that their
tions should not be made. A case in point is a recent calcium and phosphorus needs could be met using a PN
report of episodes of respiratory distress and death pos- admixture (161,162,170). However, it must be stressed
sibly related to changing from one commercial amino that this is dependent upon the amino acid, glucose, in-
acid brand to another despite (or it should be said, be- travenous fat emulsion, calcium, and phosphorus prod-
cause of) not modifying any other aspect of the admix- ucts (as well as the other components) used as well as the
ture (164). A Food and Drug Administration (FDA) alert mixing protocol. If a PN admixture is to be used in an
was issued in 1994 regarding the hazards of precipitation infant less than a year of age, it should be done with
(165). It is recommended that information on the proper particularly careful consideration regarding mineral re-
preparation of a PN admixture be obtained directly from quirements.
the manufacturer(s) of the amino acids and intravenous PN admixtures only should be used in patients who are
fat emulsion that are to be used. As a general rule, the clinically stable. Changes in the formulation of PN ad-
amino acids, glucose, and intravenous lipid are added in mixtures are more costly than changes in traditional
fixed ratios by volume (e.g., 2:1:1, 1:1:1, 1:1:0.5, etc.) (two-in-one) PN because of the wastage of both the
(166). To reduce the risk of precipitates reaching the dextrose/amino acid and its components, and the intra-
patient an inline filter should be used. This should be a venous fat emulsion.
1.2 micron air-eliminating filter (in contrast to the 0.22 A number of questions remain about PN admixtures.
micron air-eliminating filter recommended for nonlipid- These include the appropriate dosing of some vitamins,
containing PN) (165). The importance of filtration re- the true risks related to particulate matter and fat droplet
cently has been reviewed and revalidated (167,168). A size, and drug compatibilities. For example, there is less
PN admixture is considered inappropriate for adminis- loss of fat-soluble vitamins such as vitamin A than in
tration if > 0.4% of the total fat contains particles > 5 traditional (two-in-one) PN because the intravenous fat
microns in size (162,163). emulsion is protective (see below) (171). Some drugs are
What patients are candidates for PN admixtures? It compatible with PN admixtures but not with traditional
may be more important to ask whether there are PN PN and visa versa (172).

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PARENTERAL NUTRITION IN INFANTS AND CHILDREN 599

TABLE 6. Adult and children (>11 years of age) parenteral (162). In April 2000, the Food and Drug Administration
multivitamin preparations amended the adult multivitamin formulation to bring it
Infuvite™* M.V.I.-12™ into accordance with the 1988 recommendations of the
Vitamin (Sabex) (aaiPharma) American Medical Association-FDA Public Workshop
Committee (Table 6) (176). To date, the optimal paren-
A (IU) 3300 IU 3300
D IU (␮g) 200 (5) 200 (5) teral vitamin and mineral requirements for children and
E (IU) 10 10 neonates have not been determined and a parenteral mul-
K (␮g) 150 — tivitamin formulation specifically for preterm infants has
C (mg) 200 200 not been developed.
Thiamin (mg) 6 3
Riboflavin (mg) 3.6 3.6
While there are several parenteral vitamin prepara-
Niacin (mg) 40 40 tions available for older children (> 11 years) and adults
Pyridoxine (mg) 6 4 (Table 6), few are available for neonates and children.
Folate (␮g) 600 400 InFuvite Pediatric™ (Sabex, Inc., Boucherville, Canada)
B12 (␮g) 5 5 and M.V.I. Pediatric™ (aaiPharma, Inc., Wilmington,
Pantothenic Acid (mg) 15 15
Biotin (␮g) 60 60 NC) are approved for use in prematures, infants, and
children < 11 years (Table 7). The adult formulations are
* Conforms to the FDA amended formula for adult multivitamin not recommended for use in low birth weight infants less
preparations (165). 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
VITAMINS products have made children vulnerable to shortages
(179). Table 7 gives the doses of vitamins recommended
Guidelines for pediatric parenteral vitamin and min- for infants by the American Society of Clinical Nutrition
eral supplementation have been previously reviewed, al- Subcommittee on Pediatric Parenteral Nutrient Require-
beit quite some time ago (173). Despite subsequent pub- ments (). This recommendation differs from the package
lications that have provided additional support for these inserts (180).
recommendations, there has not been a recent significant Clearly, there are patients whose needs do not fit the
evaluation or reformulation of parenteral vitamin prod- current vitamin formulations. For example, preterm in-
ucts for premature infants, infants, or children (less than fants, children with liver or renal disease or short bowel
11 years of age) (174,175). syndrome, or who are severely malnourished require
Recommendations from the 1998 National Advisory close attention to vitamin nutriture. Some adult parenter-
Group on Standards and Practice Guidelines emphasized al vitamin products that are used for children >11 years
the need for establishing optimal trace element and vita- of age may put younger patients on long term PN at risk
min formulations for both adult and pediatric patients for excessive vitamin intakes (see Table 6).

TABLE 7. Infant and child parenteral multivitamin requirements and


commercial preparations*
Pediatric parenteral Pediatric parenteral
multivitamins# multivitamins*
Best estimate# <2.5 kg >2.5 kg–11 yrs
Vitamin (amount/d) preterm infant 40% of the vial (2 ml) 100% of the vial (5 ml)
A (␮g)** 500 280 700
C (mg) 25 32 80
D (IU) 160 160 400
E (mg)## 2.8 2.8 7
K (␮g) 80 80 200
Thiamin (mg) 0.35 0.48 1.2
Riboflavin (mg) 0.15 0.56 1.4
Niacin (mg) 6.8 6.8 17
Pyridoxine (mg) 0.18 0.40 1
Folate (␮g) 56 56 140
B12 (␮g) 0.3 0.4 1
Pantothenic Acid (mg) 2.0 2.0 5
Biotin (␮g) 6 8 20

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

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600 R. J. SHULMAN AND S. PHILLIPS

Vitamin K has been described with symptomatic carnitine defi-


ciency although the level of enteral intake was not de-
One potential problem with the introduction of vita- scribed (195). It is possible that the effects of carnitine
min K into the new adult formulations is the possible deficiency in patients on long term PN may be too subtle
interference with anticoagulants such as warfarin. Addi- to be identified easily but are still metabolically relevant
tionally, intravenous fat emulsions contain vitamin K in given the central role of carnitine in metabolism (196).
varying amounts (approximately 13–70 ␮g/dL) that can Addition of carnitine does enhance intravenous fat emul-
make titrating anticoagulant therapy even more problem- sion oxidation although it has been argued that the in-
atic (181,182). crease may not be clinically relevant (193). In long term
PN patients it may be reasonable to follow the suggestion
Vitamin A 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
A recent Cochrane review suggests that an increased concentrations be measured at baseline and at 4-month
vitamin A intake (via the intramuscular route) is benefi- intervals until levels have stabilized, then yearly there-
cial in the preterm infant (183). Whether dosing of vita- after (196). Too high a carnitine dose may be detrimental
min A in PN will provide a similar benefit is unclear. (196).
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 Iron
glucose/amino acid solution the current recommendation
for vitamin A is too low (162,185,186).
Loss of several lipid soluble (and water-soluble) vita- Parenteral nutrition patients at risk for iron deficiency
mins occurs during their delivery in PN (187,188). Evi- are premature infants, long-term PN patients with little or
dence suggests that using dark tubing and placing fat- no enteral intake, and patients with significant malab-
soluble vitamins into the intravenous fat emulsion (see sorption or fluid losses. Iron may be administered orally,
PN Admixtures, above) mitigates the losses of these vi- intramuscularly, or parenterally. Parenteral iron can be
tamins (189–192,230). However, multivitamin manufac- infused as an intermittent intravenous infusion or as a
turers in the US do not recommend mixing vitamins in diluted total dose infusion. Iron dextran has been used in
lipid emulsions (see package inserts). Obviously it is children (197–200). Despite its fairly widespread use,
commonly done in the case of PN admixtures (see total dose infusion is not approved by the Food and Drug
above). More research in this area is vital. Administration.
The use of iron dextran can be complicated by adverse
Clinical Implications reactions including a small but real risk of anaphylaxis.
A test dose is recommended prior to administration of
Our knowledge regarding the appropriateness of cur- the required amount (see package insert). Iron dextran in
rent vitamin preparations and intake levels is less than PN can be efficacious (201,202). Although often em-
optimal. Prudence would suggest checking vitamin lev- ployed in PN, the stability of iron dextran and its poten-
els (especially vitamin A and possibly riboflavin) in pa- tial interaction with other nutrients remain as concerns
tients on long term PN because of potential losses in the (202). Its use in PN admixtures should be undertaken
administration set, particularly when enteral intake with extreme caution if at all (163).
and/or absorption is poor (191). Consideration also Until recently, iron dextran was the only formulation
should be given to monitoring fat-soluble vitamin levels available for parenteral iron therapy. Two new iron prod-
in patients whose vitamins are placed into the lipid emul- ucts free of dextran have recently been approved for use
sion. in the United States. Sodium ferric gluconate complex in
sucrose (Ferrlecit, Watson, Inc., Morristown, NJ) has
Carnitine been used extensively in Europe and became available
for use in the United States in 1999. Iron sucrose (Ve-
The use of carnitine in PN for preterm infants recently nofer, Luitpold Pharmaceuticals, Inc., Shirley, NY) also
has been the subject of a Cochrane Database review previously available in Europe was introduced in late
(193). Using weight gain as a primary outcome, there 2000. These products appear to be safe and have fewer
was no apparent effect of carnitine supplementation side effects than those of iron dextran, although like iron
(193). However, the studies available did not assess the dextran, they can cause hypotension (203,204). While
use of carnitine in long term PN, a situation that is more the safety and efficacy of these products has not been
likely to result in carnitine deficiency. Tissue carnitine extensively studied nor are they approved by the FDA
levels decline in infants receiving carnitine-free PN for use in children, there is evidence that they are safe
(194). An adult patient who received PN for over a year and effective in children (205).

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PARENTERAL NUTRITION IN INFANTS AND CHILDREN 601

Trace Minerals Of great concern are the numerous observations re-


garding Mn retention. This essential trace mineral nor-
mally is excreted in bile and has a special affinity for the
Trace mineral requirements and metabolism in gen- extrapyramidal system (206,207). Mn often contami-
eral, including concerns regarding aluminum contamina- nates PN solution components in amounts sufficient for
tion and toxicity, recently have been reviewed elsewhere daily requirements (206,207,219). Manganese intoxica-
(180,206–209). We briefly will touch on current issues tion causes parkinsonian-like symptoms with muscular
regarding specific trace minerals in PN. First, it should weakness, stiffness, tremors, ataxia, abnormal gait, as-
be remembered that PN solutions usually contain some thenia, and difficulty with speech (220). Psychological
of the various trace minerals due to contamination of the changes have been reported including mental irritability,
components (e.g., amino acids, calcium gluconate, mul- headaches, nervousness, compulsive actions, and hallu-
tivitamins) with trace metals (210). In one report Zn, Cu, cinations (220). Manganese accumulation can be de-
Mn, and Se were found in greatest concentration but tected in the basal ganglia as symmetric, increased signal
contamination will vary depending on the commercial intensity on T-1 weighted magnetic resonance images
products used to prepare the PN (210). Heat and storage (220,221). These changes are reversible when Mn is re-
time can modestly reduce the levels of some trace ele- moved from the PN (222,223). Clinical symptoms are
ments as well (210). usually but not always reversible (224).
The importance of Se as an antioxidant is well known. It is not surprising that Mn accumulates in individuals
A recent report suggests that the recommended intake of with cholestatic liver disease given its hepatobiliary se-
Se for preterm infants (N ⳱ 29, gestational age 26 cretion (220). Of particular concern for pediatric patients
weeks) may not be adequate for all infants (211). In is the widely held suspicion that Mn accumulation in
contrast, a study of children and adults on long term PN patients on PN may cause cholestasis. A recent study
suggested Se status is well maintained even with low or randomized 244 children on PN to receive either 1.0
no Se intake (212). However, in this study there was (Group 1) or 0.0182 ␮mol ⭈ kg−1 ⭈ d−1 (Group 2) of Mn
great variability in Se serum levels as well as glutathione (224). When all patients were considered, those in Group
peroxidase activity with some patients actually showing 1 showed a trend towards higher peak manganese and
deficiency (212). Given the reports of heart failure be- direct bilirubin levels. The two groups did not differ in
cause of Se deficiency and our limited knowledge re- the occurrence of cholestasis but Group 1 patients
garding adequacy of intake, it is prudent to check serum showed a trend towards increased incidence and severity
Se levels in the short term (particularly in preterm in- of hyperbilirubinemia (225). Of the 160 children who
fants) and serum Se levels and glutathione peroxidase received >75% of their daily fluid intake from PN for
activity in older infants and adolescents (207,211–213). >14 days, peak whole blood manganese and peak serum
Some studies have suggested that chromium toxicity direct bilirubin concentrations were significantly higher
may be a concern. Mouser et al. noted in infants and in Group 1. Significantly more infants in Group 1 devel-
children (up to 12 years of age) on long term PN that oped a more severe degree of direct hyperbilirubinemia
serum Cr levels were elevated despite following the rec- (225). These data implicate Mn as a contributor to the
ommended intake (180,214). These data are consistent development and/or the severity of PN-associated chole-
with other studies and imply that the addition of Cr to PN stasis (225). Based on these and other data, it is sug-
at recommended levels in combination with Cr contami- gested that patients with any cholestasis (some would say
nation in the PN fluids raises serum Cr levels above that any liver disease) should not receive Mn in their PN
desired (210,215–217). Again, patients on long term PN (220,225,226). Others would go so far as to say that Mn
should be closely observed. Whether the impaired glo- should not be given to individuals on PN for <30 days
merular filtration rate noted in children on long term PN and that levels should be monitored in patients receiving
is related to Cr excess requires further investigation PN with Mn for >30 days (207,226).
(217). There is disagreement regarding the best measure of
Zn has the widest range of functions of all the trace Mn status (220). Whole blood Mn appears to correlate
minerals and is particularly important in wound healing (in adults) with MRI-documented Mn deposition (226).
and immune function. Despite its intentional and non- Most investigators use whole blood Mn, red blood cell
intentional addition to PN, many patients are at risk for Mn, or Mn superoxide dismutase as measures of tissue
Zn deficiency because of the number of predisposing deposition (220).
clinical situations (206,207). For example, patients with
gastrointestinal losses due to diarrhea, ileostomies, or
even nasogastric suction are at risk for Zn deficiency SUMMARY
because of the high Zn content of gastrointestinal fluids
(218). Serum Zn levels, although not entirely reliable, are Our knowledge regarding PN reflects the same pattern
easily obtained and Zn intake can be titrated appropri- we find in all of medicine: what we do is based part upon
ately. science and part upon best judgment. It turns out that

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


602 R. J. SHULMAN AND S. PHILLIPS

practices that seem clear (i.e., based on science), often cally ill surgical neonates have increased energy expenditure? J
turn out to be wrong or not so clear. We now realize that Pediatr Surg 2001;36:63–7.
6. Garza JJ, Shew SB, Keshen TH, Dzakovic A, Jahoor F, Jaksic T.
aggressive nutritional support carries risks. The risk of Energy expenditure in ill premature neonates. J Pediatr Surg
infection may be related more to hyperglycemia (or hy- 2002;37:289–93.
pertriglyceridemia) than to PN per se, and essential fatty 7. Lloyd DA. Energy requirements of surgical newborn infants re-
acid requirements may not be as well defined as previ- ceiving parenteral nutrition. Nutrition 1998;14:101–04.
8. Coss-Bu JA, Klish WJ, Walding D, Stein F, Smith EO, and Jef-
ously thought. When it seems as if knowledge is for ferson LS. Energy metabolism, nitrogen balance, and substrate
naught, the following quote comes to mind: “I reserve utilization in critically ill children 1-3. Am J Clin Nutr 2001;74:
the right to be smarter tomorrow than I am today” 664–69.
(227,228). 9. Schofield W. Predicting basal metabolic rate, new standards and
In a way, we are victims of our own success. PN can review of previous work. Hum Nutr Clin Nutr 1985;39C S1;5–41.
10. Koen FM, Joosten KFM, Verhoeven JJ, and Hazelzet JA. Energy
provide effective nutritional support but, as is evident Expenditure and Substrate Utilization in Mechanically Ventilated
from this review, there are large holes in our knowledge Children. Nutrition 1999;15:444–48.
and little likelihood of abundant future research to fill 11. Turi RA, Petros AJ, Eaton S, Fasoli L, Powis M, Basu R, Spitz L,
them. For the most part, these deficiencies in knowledge Pierro A. Energy metabolism of infants and children with sys-
are more problematic for pediatric patients than for temic inflammatory response syndrome and sepsis. Annals of Sur-
gery 2001; 233: 581–87.
adults. Unfortunately, because pediatric PN makes up 12. Duro D, Rising R, Cole C, Valois S, Cedillo M, Lifshitz F. New
such a small share of the market, manufacturers are re- equations for calculating the components of energy expenditure in
luctant to spend the resources to carry out the studies infants. J Pediatr 2002;140:534–9.
needed to define the child-specific impact of new lipid 13. http://www.nal.usda.gov/fnic/dga/rda.pdf
emulsions, reformulated vitamins, etc. Money spent on 14. White MS, Shepherd RW, McEniery JA. Energy expenditure
measurements in ventilated critically ill children: within- and
these questions would not be recouped quickly. The re- between-day variability. J Parenter Enteral Nutr 1999;23:300–4.
sponsibility for improving PN safety and efficacy lies 15. Pierro A, Jpnes MO, Hammond P, Donnell SC, Lloyd DA. A new
with all concerned: industry, funding agencies, physi- equation to predict the resting energy expenditure of surgical
cians, pharmacists, nurses, and nutritionists. infants. J Pediatr Surg 1994;29:1103–8.
16. Pierro A, Jones MO, Donnell SC. Total parenteral nutrition in
PN is still the life-saving, far-from-perfect therapy it surgical infants. Biochem Soc Trans 1998;26:131–6.
has been for over 40 years. Like all therapies it must be 17. White MS, Shepherd RW, McEniery JA. Energy expenditure in
used and monitored appropriately. Using it means more 100 ventilated, critically ill children: Improving the accuracy of
than just checking the patient’s weight, and monitoring predictive equations. Crit Care Med 2000; 28: 2307-2312.
now means more than checking the serum electrolytes. 18. Dietz WH, Bandini LG, Schoeller DA. Estimates of metabolic
rate in obese and nonobese adolescents. J Pediatr 1991;118:
Checking the box on the order sheet will never be 146–49.
enough. 19. Mondejar EF, Duro Lombardo M, Perez de la Cruz AJ, Merida
Morales A, Torres Ruiz JM, Ferron Orihuela JA. Variations in
Acknowledgments: The authors thank Dr. W.C. Heird for oxygen consumption and carbon dioxide production during par-
his very helpful comments. This study was supported by the enteral nutrition. Intensive Care Med 1982;8:169–72.
National Institute of Child Health and Human Development, 20. Elwyn DH, Askanazi J, Kinney JM, Gump FE. Kinetics of energy
Grant No. RO1 NR05337-01A2, the Daffy’s and Henriksen substrates. Acta Chir Scand Suppl 1981;507:209–19.
Foundations, and the USDA/ARS under Cooperative Agree- 21. Koretz RL, Lipman TO, Klein S. AGA Technical Review on
Parenteral Nutrition. Gastroenterology 2001;121:970–1001.
ment No. 58-6250-1-003. This work is a publication of the
22. Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge
USDA/ARS Children’s Nutrition Research Center, Department JA. Randomised controlled trial of an aggressive nutritional regi-
of Pediatrics, Baylor College of Medicine and Texas Children’s men in sick very low birthweight infants. Arch Dis Child Fetal
Hospital, Houston, TX. The contents of this publication do not Neonatal Ed 1997;77:F4–11.
necessarily reflect the views or policies of the USDA, nor does 23. Kalhan SC, Kilic I. Carbohydrate as nutrient in the infant and
mention of trade names, commercial products, or organizations child: range of acceptable intake. Europ J Clin Nutr 1999;53:
imply endorsement by the US Government. S94–S100.
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