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
INTRODUCTION
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 pro-
viding all nutrients intravenously (1). The first total par-
enteral 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 en-
ergy 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 judg-
ment.” (2). Along the way we have learned much about
nutrition, infection, liver pathophysiology, and child de-
velopment (e.g., yes, infants really can “unlearn” how to
suck and swallow). Have we learned so much that ad-
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
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 ad-
ministration rate and check the box next to “Standard
Child Solution” on the PN pharmacy order sheet? Is
there really anything new in PN?
Received November 25, 2002; accepted February 13, 2003.
Address correspondence to Robert J. Shulman, 1100 Bates St., Hous-
ton, Texas 77030, U.S.A. (e-mail: rshulman@bcm.tmc.edu).
587
acids—Lipid emulsion. © 2003 Lippincott Williams &
Wilkins, Inc.
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 com-
mon 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.
Energy Requirements, Energy Sources, and the
Consequences of Overfeeding
Estimating the appropriate energy intake is a funda-
mental step in prescribing PN. Although we have long
acknowledged the risks of underfeeding our patients,
more recently we have come to reevaluate energy re-
quirements in particular clinical scenarios and to appre-
ciate the problems associated with excessive energy in-
take.
588 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 ex-
penditure of a recumbent child or adult in a thermoneu-
tral 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 expendi-
ture 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 pa-
tient requires an energy intake proportional to the sever-
ity of the illness. By definition, the energy intake would
be increased compared with that of a “non-stressed” pa-
tient. 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 new-
borns 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 “non-
stressed” 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 simi-
larly (6).
Lloyd recently reviewed the data regarding energy re-
quirements 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, poten-
tially resulting in excess energy intake with its potential
consequences (see below).
Energy requirements also have been examined in non-
operated 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 expendi-
tures 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 Activ-
ity 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 de-
scribed 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 expen-
diture (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-to-
day 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 regard-
ing the “appropriate” energy intake and monitor the pa-
tient for weight gain (fluid vs. tissue) and evidence of
overfeeding (e.g., CO2 production; see below). Two re-
cent studies may be of value in calculating resting energy
expenditure for surgical infants and intensive care pa-
tients.
 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-
genesis and it has been shown that this method underes-
timates the contribution of glucose to CO2 when com-
pared with data obtained from indirect calorimetry (23).
Thus, the data in Table 2 probably do reflect the amount
of exogenous glucose required to prevent hypoglycemia
under most circumstances (23). Kalhan and Kiliç re-
viewed the evidence that this amount of exogenous glu-
cose also is sufficient to minimize nitrogen loss (23).
What about the maximum rate of glucose oxidation?
Lafeber et al. found a glucose oxidation rate of 6.6 ± 1.2
mg ⭈ kg−1 ⭈ min−1 (9.5 g ⭈ kg−1 ⭈ d−1) in appropriate for
gestational age preterm infants (birth weight: 1613 ± 151
g, gestational age: 31.1 ± 1.5 wk; mean ± SD)(26). The
rate was minimally greater than that found in small for
gestational age infants (26). In contrast, in term surgical
infants Jones et al. measured a maximal glucose oxida-
tion rate of 12.5 mg ⭈ kg−1 ⭈ min−1 (18 g ⭈ kg−1 ⭈ d−1)
(27). This rate is comparable to that of stable patients
both on long-term PN (N ⳱ 7, 30 ± 41 months of age)
or short-term PN (N ⳱ 36, 6 ± 4 months of age) (28,29).
Clinical status can modify glucose oxidative capacity
significantly. For example, Sheridan et al. noted that in
critically burned children the maximal rate of glucose
oxidation was 5 mg ⭈ kg−1 ⭈ min−1 (30).
Consequences of Overfeeding with Glucose
In critically ill individuals, glucose intakes above the
maximal glucose oxidation rate will result in the non-
oxidative production of fat, hence, are unlikely to en-
hance energy balance, or even reduce protein catabolism
(23). On the other hand, glucose intakes above the maxi-
mal oxidation rate promote fat deposition, which may be
a nutritional goal in specific clinical situations (e.g., pre-
term infants). We will use the term overfeeding to mean
providing calories in excess of the amount required for
normal weight gain.
A number of recent reviews have addressed issues
related to carbohydrate overfeeding in the intensive care
unit patient (31–35). Unfortunately, the relationship be-
tween carbohydrate feeding and impaired pulmonary
function (in the form of increased CO2 production) as
well as the development of fatty liver often is oversim-
plified.
When glucose is administered in excess of the amount
that can be directly oxidized for energy production and
glycogen production, the excess is directed to fat syn-
thesis (lipogenesis) (Fig. 1) (36,37). This conversion is
inefficient and probably accounts, in part, for the in-
crease in energy expenditure seen with high rates of glu-
cose infusion (Fig. 1) (20). This inefficiency can have
clinical consequences besides simply producing hyper-
glycemia.
Nose et al. studied energy expenditure and CO2 pro-
duction in 7 infants receiving long term PN (28). Three
J Pediatr Gastroenterol Nutr, Vol. 36, No. 5, May 2003
PN regimens were tested: 87:5:8 (glucose:fat:amino ac-
ids as percent of total energy), 60:32:8, and 34:58:8 Total
energy intake was comparable to the recommended daily
allowance. The increase in resting energy expenditure
(although reported as basal metabolic rate) induced by
the high glucose regimen was nearly 5 times greater than
that of the other two regimens (28). Bresson et al. also
noted increased energy expenditure in relationship to in-
creasing glucose intake, albeit to a lesser extent, amount-
ing to 16% of the energy value of infused glucose (29).
In the study by Nose et al. the respiratory quotient (RQ
⳱ CO2 production/O2 consumption) was significantly
greater on a high glucose regimen compared to lower
glucose regimens (28). The data suggest that in this
population of stable patients on long-term PN, glucose
intakes in excess of 10 mg ⭈ kg−1 ⭈ min−1 result in
conversion of glucose to fat (RQ >1) (28). As seen in
Figure 1, lipogenesis from glucose results in a large in-
crease CO2 production relative to O2 consumption (i.e.,
high RQ).
Talpers et al. (among others) examined the effect of
different glucose/fat ratios on CO2 production in adults
(19,38). In contrast to the studies of Nose et al (and other
investigators), they were unable to detect a change in
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-
portion of total energy provided by amino acids in Talp-
ers’ study (20% of total energy) than in Nose’s study (8%
of total energy) (28,38). Amino acids also can affect
ventilatory drive and the response to CO2. Increasing
amino acid intake (with energy intake constant) leads to
an increase in minute ventilation and more importantly,
an enhanced response to CO2 (i.e., minute ventilation
increases in a more responsive fashion to increasing lev-
els of CO2 (39,40). Thus, the higher percentage of amino
acids provided in the adult studies may have blunted the
differences in CO2 production at different glucose/fat
ratios.
Another factor with an impact on CO2 production is
total energy intake. There is a linear relationship between
energy intake and CO2 production and increased minute
ventilation (presuming glucose is providing a portion of
the energy) (38,40). Indeed, the patients reported to have
developed respiratory failure (i.e., CO2 retention and in-
creased minute ventilation) as a consequence of PN with
high concentrations of glucose were receiving excessive
energy intakes (see reference 35 for a review). Under
normal circumstances the increased CO2 production is
handled easily by increasing the respiratory rate and/or
depth. Problems potentially arise in patients with respi-
ratory compromise. The respiratory response to enteral
carbohydrate intake and enteral overfeeding mirrors
what is seen with PN (41).
In summary, the greater the proportion of glucose in
the PN energy mix, the larger the increase in CO2 pro-
duction and minute ventilation. Malnourished patients
 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-
ceptible. Normally nourished and metabolically normal
patients have an intermediate response (42). The greater
the total energy intake, the greater the effect.
In selected patient groups, giving glucose in amounts
above the maximal oxidative rate may be appropriate
(e.g., preterm infants who need to deposit fat). However,
the greater the amount of glucose, the greater the risk of
adverse consequences. Unfortunately, the absolute intake
at which the adverse consequences occur is poorly de-
fined.
Overfeeding of glucose also can affect liver function
although its contribution to the development of cholesta-
sis in humans is unclear. Burke et al. observed a rela-
tionship between glucose infusion rate and the develop-
ment of fatty infiltration of the liver in necropsies of
children who died of severe burns (43). In a study in 37
catabolic adults, Tulikoura et al. administered PN using
glucose and glucose and fat as energy sources (44).
There was a significant increase in hepatic steatosis in
the glucose group but none when glucose and fat were
used in combination (44). Steatosis was associated with
a rise in serum transaminases but no cholestasis was
noted (44). Studies in normal adult volunteers suggest
that high carbohydrate feeding leads to an increase in
total VLDL triglyceride secretion rate from de novo syn-
thesis primarily due to stimulation of the secretion of
preformed fatty acids (45). The results imply that the
liver derives all its energy from carbohydrate oxidation
as opposed to fatty acid oxidation such that fatty acids
taken up by the liver are channeled into VLDL triglyc-
erides (45). Hepatic steatosis results when export of the
VLDL triglycerides does not keep pace with production
(34,45).
Another potential complication of overfeeding with
glucose is an increase in infectious complications. PN
has been associated with an increased risk of infectious
complications compared with enteral feeding or no nu-
tritional support in adult studies (46–49). Recent data
suggest that this finding may actually be explained by
overfeeding with glucose (50). Hyperglycemia is a risk
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
children with burns (53). In a prospective randomized
trial in adults there was no difference between groups
receiving hypocaloric intravenous fluids and those re-
ceiving PN that did not overfeed the patients or induce
hyperglycemia (54). These intriguing results require fur-
ther verification but may have great implications for pa-
tient care.
Clinical Implications
Patients with respiratory compromise, particularly
CO2 retention (e.g., cystic fibrosis) are at risk for expe-
riencing a worsening of their pulmonary status if glucose
provides a large proportion of their energy needs. The
risk increases as energy intake surpasses REE. Malnour-
ished patients may not manifest this response until they
begin to be nutritionally rehabilitated. A hypermetabolic
patient will exhibit this reaction most quickly. Concerns
about overfeeding have been addressed recently in a con-
sensus statement on the care of the adult intensive care
unit patient (55).
Intravenous Fat Emulsion
Unless otherwise noted, the term intravenous fat emul-
sion refers to the currently available (in the United
States) soy- or soy/safflower-based emulsions. A key
role for intravenous fat emulsion is the prevention of
essential fatty acid deficiency. The usual preterm infant
(< 2 kg birthweight) on PN without intravenous fat emul-
sion or on enteral feedings begins to demonstrate bio-
chemical evidence of essential fatty acid deficiency (in-
creased triene/tetraene ratio) within seven days of birth if
not provided with adequate intravenous fat emulsion
(56). In the absence of intravenous fat emulsion, endog-
enous adipose tissue and the liver are probably the source
of essential fatty acids (57). In order to prevent the mo-
bilization of fatty acids for energy, essential fatty acids
must be provided in amounts necessary to both replace
deficits and supply ongoing needs for metabolism and
growth. In other words, essential fatty acid deficiencies
are cumulative (58,59). Given that intravenous fat emul-
sions contain approximately 50% essential fatty acids by
weight, about 0.5 g ⭈ kg−1 ⭈ d−1 of intravenous fat emul-
sion is required to prevent essential fatty acid deficiency
in patients on total PN (56,60). However, there is con-
troversy regarding this figure, particularly in adults (and
presumably adolescents) with some investigators sug-
gesting the recommendation is more than adequate (e.g.,
1.5 g/kg twice weekly) and others stating it is too low
(61–64). There appears to be a fair amount of inter-
individual variation in essential fatty acid requirements
based upon age, disease, and nutritional status (56,61,62,
65). Thus, one should not presume that giving the small-
est recommended amount of essential fatty acid, such as
J Pediatr Gastroenterol Nutr, Vol. 36, No. 5, May 2003
1.5 g/kg (approximately 500 mL of 20% intravenous fat
emulsion) twice a week in an adolescent, would be ad-
equate for all such patients. In patients receiving no in-
travenous fat emulsion, some studies suggest that fatty
acid deficiency develops faster when total energy intake
is low than it does when total energy intake is high
(66,67).
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,
studies suggest that it is better to administer the daily
dose over 24 hours in patients who have difficulty tol-
erating the infusion. Preterm infants should receive the
infusion over 24 hours to avoid hypertriglyceridemia.
For patients without hypertriglyceridemia or other evi-
dence of intolerance to intravenous fat emulsion, a less
than 24-hour infusion schedule may be tolerated well.
One of the major determinants of the rate of clearance of
fat from the blood is the amount of intravenous fat emul-
sion infused per unit time (68). The longer the infusion
time, the less likely the patient will develop hypertriglyc-
eridemia (68,69). Intravenous fat emulsions with high
concentrations of phospholipids (i.e., 10% emulsions)
should be avoided as they carry a higher risk of produc-
ing high serum levels of triglycerides, cholesterol, and
phospholipids than other emulsions (i.e., 20% and 30%
emulsions) (70–72).
A number of other factors decrease the rate of clear-
ance of intravenous fat emulsions. The more malnour-
ished the patient, the slower the rate of clearance will be.
Slower clearance in malnourished patients is a result of
lower levels of lipoprotein lipase. This enzyme, which is
responsible for releasing fatty acids from the fat emul-
sion, resides within the capillary system. The lower the
capillary tissue mass (a situation found in preterm infants
and malnourished patients), the slower the rate of intra-
venous fat emulsion clearance. Studies in adult volun-
teers have shown that the muscle, splanchnic, myocardi-
al, and subcutaneous fat capillary systems clear 47%,
25%, 14%, and 13% of the total amount of lipid infused,
respectively (73). Under normal circumstances the liver
clears less than 1% of infused lipid (73).
Another factor that alters the tolerance to intravenous
fat emulsion is the concurrent administration of drugs.
Because of their lipolytic effect, steroids are the proto-
type. Patients simultaneously receiving steroids and in-
travenous fat emulsions are prone to hypertriglyceride-
mia (74). Additionally, a number of medications contain
lipid or are microsomal formulations. Drugs such as pro-
pofol and amphotericin B may contribute significant
amounts of (fat) energy to the total daily intake and
which should be taken into account in nutritional calcu-
lations.
Patients who are metabolically stressed (i.e., sepsis,
trauma) or who have organ dysfunction (e.g., liver and/or
renal disease) also are likely to develop hypertriglyceri-
demia during intravenous fat emulsion infusion. These
 PARENTERAL NUTRITION IN INFANTS AND CHILDREN
patients have an outpouring of cortisol, catecholamines,
and cytokines that promote the lipolysis of endogenous
lipid stores (75–77). Liver and renal disease themselves
are associated with hypertriglyceridemia. However, adult
(and presumably pediatric) patients with sepsis and liver
disease can tolerate and utilize intravenous fat emulsions
(78,79). Infants with ventricular septal defects or trans-
position of the great vessels (i.e., cyanotic heart disease)
do not have inordinate increases in serum triglycerides in
response to intravenous fat emulsion (80).
Serum triglyceride levels should be measured four
hours after starting an intravenous fat infusion or four
hours after any increase in infusion rate. It is at this time
that hypertriglyceridemia is most likely to occur (81–83).
Ideally the triglyceride level should be ⱕ100 mg/dL
(84). However, this upper limit varies depending on the
method used to measure serum triglycerides. For ex-
ample, some common methods of measuring triglycer-
ides measure the free glycerol released from the triglyc-
eride molecule (85). Given that intravenous fat emul-
sions contain free glycerol in addition to triglycerides,
the serum triglyceride level measured by evaluating
glycerol will be an overestimation of the true serum tri-
glyceride level. A value of 150 mg/dL may correspond to
an actual triglyceride level of only 100 mg/dL (Buffone
and Shulman, unpublished data). Nephelometry should
not be used to monitor serum triglyceride levels as it is
unreliable (85,86). Heparin administration lowers serum
triglyceride levels but does not affect the rate of fatty
acid oxidation (83,87,88).
Clinicians frequently ask what level of hypertriglyc-
eridemia is acceptable in a patient receiving PN. Given
the need to provide essential fatty acids to patients who
may have hypertriglyceridemia for prolonged periods
(e.g., the critically ill patient), at what serum level do the
triglycerides start having an adverse impact on the pa-
tient? Unfortunately, to our knowledge, there are no data
defining the level at which one should be concerned.
Many investigators have studied the impact of intra-
venous fat emulsion on pulmonary function. Although an
in depth review of this topic is beyond the scope of this
article, a few points can be touched upon and the reader
is referred to two reviews (89,90).
After a fatty meal, the serum triglyceride of normal
adults may transiently approach 500 mg/dL (91). Even
values above 1500 mg/dL do not appear to decrease the
carbon monoxide diffusing capacity in healthy adults
(91). This begs the question as to whether elevated tri-
glycerides cause some of the adverse oxygenation effects
reported with intravenous fat emulsions that when severe
is referred to as the “fat overload syndrome” (92). It was
first believed that the sometimes seen adverse effects of
intravenous fat emulsions on pulmonary function (e.g.,
decreased diffusion capacity, oxygenation, intrapulmo-
nary shunting) were related to the serum triglyceride
level (89,90,93). It appears more likely that these
changes, when seen, are due to the conversion of the
593
polyunsaturated fatty acids in the emulsions to prosta-
glandins, which then can cause vasoconstriction or va-
sodilatation depending on the rate of infusion and the
clinical state of the lungs (85,86,93). Peroxides are an-
other contaminant that can be found in the fat emulsion
(94). Evidence suggests that they also promote increased
prostaglandin levels (95).
Interpretation of the data linking intravenous fat emul-
sions and pulmonary dysfunction is complicated. The
adverse effects appear to depend on the dose and rate of
administration, presence of peroxides, and clinical state
of the lungs (89,90,93–95). Are the effects clinically rel-
evant? In preterm infants the balance of data suggests
that administration of intravenous fat emulsion at normal
rates does not affect oxygenation (72). Studies to the
contrary have usually used inappropriately rapid rates of
infusion (96–98). Because intravenous fat emulsion can
induce vasoconstriction that is not limited to the pulmo-
nary vasculature, observed decreases in transcutaneous
pO2 may be related to local declines in subcutaneous
perfusion and not reflect systemic oxygenation (95,99).
The effects of intravenous fat emulsion on the develop-
ment of chronic lung disease have been reviewed re-
cently (72). The balance of the data suggests no adverse
impact and possibly a beneficial effect (72,100). How-
ever, much more work is needed in this area before we
can be certain that there are no clinically significant ad-
verse effects.
Even more confusing than the issue of pulmonary
function is the controversy regarding the effect of intra-
venous fat (101–105) emulsions on immune function.
Some studies show a beneficial effect, some no effect,
and some an adverse effect. A complete discussion is
beyond the scope of the present article and the reader is
referred to the supplied references. It should be pointed
out that reviews in this area sometimes give a prejudiced
view in that only selected publications are quoted. Inter-
pretation of publications often is blurred by the use of
inappropriate doses (both in vivo and in vitro), differ-
ences in patient groups or in vitro models (102). Similar
to the situation in pulmonary function studies, many of
the effects of intravenous fat emulsions on immune func-
tion appear to be related to the generation of leukotrienes
and other polyunsaturates from the emulsions. There also
is evidence the long chain fats may alter cellular function
by changing membrane fluidity (104). Studies on pedi-
atric patients and tissues have not revealed evidence sug-
gesting an impairment of immune function by intrave-
nous fat emulsions (106–113).
Do intravenous fat emulsions promote infections?
Data are limited. A study in adult and pediatric bone
marrow transplant patients found no increase in the risk
of bacteremia or fungemia in patients receiving intrave-
nous fat emulsions (114). In contrast, a retrospective
study of preterm infants identified intravenous fat emulsion
as potentially contributing to the development of coagulase-
negative staphylococcal infection (115). However,
J Pediatr Gastroenterol Nutr, Vol. 36, No. 5, May 2003
594
the lack of a temporal relationship between intravenous
lipid administration and infection weakens the conclu-
sions of this study (115). The lack of knowledge on this
important issue underscores the importance of monitor-
ing and using intravenous fat emulsions judiciously.
Newer intravenous fat emulsions not yet available in the
United States using olive oil or structured lipids may
obviate some of these immune-related concerns (116).
The use of intravenous fat emulsions in patients with
coagulation abnormalities requires comment. In rare
cases, intravenous fat emulsion has been associated with
thrombocytopenia. However, prospective and retrospec-
tive reports suggest that under normal circumstances
they do not induce thrombocytopenia (117,118). It
should be kept in mind that essential fatty acid deficiency
itself is a cause of hematologic abnormalities (119).
Clinical Implications
There is debate as to the appropriate amount of intra-
venous fat emulsion required to prevent essential fatty
acid deficiency. In infants (including preterms) who are
most susceptible, at least 0.5 g ⭈ kg−1 ⭈ d−1 should be
used. In older children and adolescents the minimum
dose is probably in the range of 1.5 g/kg (approximately
500 mL of 20% intravenous fat emulsion) twice a week.
For individuals on long term parenteral nutrition who
either have little or no enteral intake of fat or who have
severe fat malabsorption (e.g., severe short bowel) es-
sential fatty acid status should be assessed after a few
months of therapy. It has been suggested that measure-
ment of n-6 and n-3 long chain polyunsaturated fatty
acids is more reliable than the more commonly employed
triene/tetraene ratio (57).
The American Gastroenterological Association Tech-
nical Review on Parenteral Nutrition states that intrave-
nous fat emulsion should not be administered to patients
whose serum triglyceride levels exceed 400 mg/dL (21).
No data are provided to support this statement but the
authors agree that serum triglyceride levels ⱕ 400 are
unlikely to cause clinically relevant problems. How the
duration hypertriglyceridemia might affect the complica-
tion rate is unclear. In preterm infants pulmonary vascu-
lar lipid deposition was more common in infants who
received intravenous fat emulsion and correlated with the
duration of lipid therapy although some infants who
never received intravenous fat emulsion also demon-
strated lipid deposition (120). Liver or pancreatic dis-
eases are not in themselves contraindications to the use
of intravenous fat emulsion. It is helpful to measure se-
rum triglyceride levels prior to starting intravenous fat
emulsion in patients who are likely to be hypertriglyc-
eridemic and when their clinical status deteriorates sig-
nificantly.
J Pediatr Gastroenterol Nutr, Vol. 36, No. 5, May 2003
R. J. SHULMAN AND S. PHILLIPS
Amino Acids
Use of amino acids in pediatric PN has recently been
reviewed and the reader is referred to these references for
more details (121,122). Amino acid requirements vary
from ⱖ 2.5 g ⭈ kg−1 ⭈ d−1 for preterm infants to 0.75 g ⭈
kg−1 ⭈ d−1 for adolescents (123,124). Similar to energy
requirements, amino acid requirements vary from indi-
vidual to individual under normal circumstances. The
immunodeficiency associated with malnutrition is to a
great extent related to protein malnutrition as opposed to
energy malnutrition. Consequently, amino acid require-
ments should be attended to first in prescribing paren-
teral nutrition. The intake of energy and amino acids in
combination result in the greatest protein gain. Amino
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).
Since amino acids are generally not metabolized to
supply energy but to provide structural and visceral pro-
teins and enzymes, some clinicians do not include them
in the total energy calculation. In practice, to include
them or not usually does not make much difference. For
example, a term infant who weighs 4 kg requires about 8
g/d of amino acids, which is equivalent to 32 kcal (8 g x
4 kcal/g). The total energy requirement is about 400
kcal/d (4 kg x 100 kcal/d). Thus, adding the calories from
protein changes the total energy calculation by less than
10%. Interindividual energy requirements easily can vary
by this much. The bottom line is that both amino acids
and energy need to be titrated to the patient’s require-
ments.
Although serum prealbumin (transthyretin) and trans-
ferrin are often used as short-term (1–2 day) measures of
the response to amino acid intake, the blood urea nitro-
gen (BUN) can be also be used in many cases. If renal
function and hydration are normal, a low BUN (< 5)
reflects inadequate amino acid intake and conversely, a
high BUN (> 20) suggests that the amino acid intake may
be too great. For many patients a BUN between 10 and
15 mg/dL is a good target and reflects an amino acid
intake that is adequate for protein anabolism (Laine and
Shulman, unpublished).
Although it has been stated in the literature that the
amino acid intake should be gradually increased over the
first few days of PN administration, we know of no good
scientific documentation for this view. For example, we
use intakes of 2.5 mg ⭈ kg−1 ⭈ d−1 even in 25-week
gestation infants without complications starting within a
couple days after birth. A recent review of the literature
on the use of early amino acid introduction found no
metabolic abnormalities (elevated BUN, serum pH, am-
monia, serum amniogram) associated with this practice
even in preterm infants (123). Gradually increasing the
amino acid concentration or volume only postpones the
time at which the patient receives adequate intake.
 PARENTERAL NUTRITION IN INFANTS AND CHILDREN
Evidence suggests that amino acids contribute to the
development of PN-associated cholestasis (125,126).
Even enteral protein intake can decrease bile flow (127).
If amino acids are removed from the PN when the patient
develops cholestasis and no other source of protein is
provided, one then is faced with a patient who in addition
to having liver disease has hypoproteinemia or even
kwashiorkor. There are some data to support the idea that
provision of protein enterally while other nutrients (pri-
marily carbohydrate) are provided intravenously can re-
duce the risk of or lessen the severity of PN-associated
cholestasis (125). Protein is usually well digested and
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).
absorbed, even in patients with short bowel syndrome
(128). Consequently, this is an option for many patients
receiving PN. Of course, whenever possible other nutri-
ents should be provided enterally as well.
There are very limited data in pediatric patients re-
garding the use of specialized amino acid solutions for
specific conditions such as critical illness and liver or
renal failure. A crossover trial in children with end stage
liver disease suggested a benefit to a branched chain
supplemented enteral formulation in that the special for-
mula promoted more rapid nutritional rehabilitation
(129). Studies in adults with liver disease have been in-
J Pediatr Gastroenterol Nutr, Vol. 36, No. 5, May 2003
596 R. J. SHULMAN AND S. PHILLIPS
consistent. Most studies indicate that if used at all,
branched chain formulae should be reserved for patients
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
(132,133). Similarly, the nutritional benefit of parenteral
nutrition given during dialysis requires further study
(134,229). The two commercially available (in the
United States) pediatric amino acid solutions have con-
centrations of essential amino acids, including branched
chain amino acids, which are fairly close to those in the
specialized amino acids solutions.
Clinical Implications
Provision of amino acids should be a priority in cal-
culation of PN requirements. In situations where fluid
intake is significantly restricted, energy intake should be
sacrificed at the expense of maintaining a greater amino
acid intake, particularly when more than resting energy
expenditure can be provided. The PN concentration of
amino acids can be increased to 4%–8% (g/dL) depend-
ing on the amino acid brand used (concentration of the
stock amino acid solutions range from 10%–20%). The
BUN is a readily accessible and cheap method of titrat-
ing amino acid intake if renal function and hydration are
normal. Consideration of enteral (as much as possible)
rather than parenteral administration of protein should be
considered, particularly in patients at risk for cholestasis.
If not limited by intolerance (e.g., enteral carbohydrate in
a patient with short bowel syndrome) other nutrients
should be provided enterally as well.
CYCLIC PARENTERAL NUTRITION
The term cyclic PN refers to the administration of
intravenous fluids intermittently with regular breaks
from infusion. Cyclic PN offers the advantage of increas-
ing the mobility of the patient and family. Much has been
written regarding its other presumed advantages but
there are scant scientific data (135,136). One of the pro-
posed benefits is a lower risk for the development of liver
disease although reports have been anecdotal (137). Re-
cently, Hwang et al. carried out a prospective study in
adults on PN exhibiting various degrees of presumed
PN-associated liver disease (138). Patients who devel-
oped hyperbilirubinemia were randomized to either re-
main on continuous PN or were placed on cyclic PN.
Patients with initial serum bilirubin less than 20 mg/dL,
who remained on continuous PN, had a significant rise in
serum bilirubin compared with the cyclic PN groups
(138). There was no apparent advantage of cyclic PN in
patients with serum bilirubin greater than 20 mg/dL
(138). These results are intriguing and beg for similar
studies in pediatric patients. For information on PN-
J Pediatr Gastroenterol Nutr, Vol. 36, No. 5, May 2003
associated cholestasis the reader is referred to recent re-
views (139–141).
REFEEDING SYNDROME
Refeeding syndrome is a potentially lethal condition
characterized by severe electrolyte and fluid shifts asso-
ciated with metabolic abnormalities in malnourished
patients undergoing refeeding orally, enterally, or paren-
terally (139). Clinical features include fluid-balance ab-
normalities, abnormal glucose metabolism, hypophos-
phatemia, hypomagnesemia, hypokalemia, and some-
times thiamine deficiency (142).
Refeeding syndrome can occur with either parenteral
or enteral feeding. Because it is a preventable condition,
patients who are at risk should receive a PN prescription
from the outset that will decrease the likelihood of its
occurrence. A detailed review of the condition is beyond
the scope of this article but the reader is referred to
comprehensive reviews (142,143). The syndrome can be
prevented by adequate provision of phosphorus, and to a
lesser extent magnesium and potassium at the time the
patient begins to become anabolic. A common miscon-
ception is that additional phosphorus and potassium pro-
vided at the onset of PN will prevent the syndrome. This
is true only if adequate nutrition is being provided to the
patient so that they are actually regaining lost tissue mass
(i.e., muscle and viscera). If the amount of nutrition (en-
ergy) being provided is less than that required to main-
tain weight or promote catch-up weight gain, the syn-
drome will not develop. Consequently, the patient may
be at risk for hypophosphatemia and hypokalemia weeks
after the initiation of PN (or whenever nutrient intake
allows for catch-up weight gain).
Refeeding syndrome can be prevented by providing
additional phosphorus and potassium (usually as KxPOx)
at the time PN is started. The amount of additional phos-
phorus and potassium required depends on the degree of
malnutrition and the adequacy of total energy intake. A
general rule of thumb in the authors’ experience is that
twice the recommended daily allowance (RDA) of phos-
phorus is a reasonable starting point. Usually the risk for
clinically significant declines in these minerals lasts for
7–10 days. During this period, it is important to follow
serum phosphorus and potassium closely (e.g., every
other day or more often if serum levels are tenuous).
After this time, supplementation above the RDA can
gradually be reduced. Calcium and phosphorus should
not be given independently as administering one without
the other leads to renal wasting of the infused mineral
(144).
A rate-limiting factor in providing additional phospho-
rus is the risk of calcium/phosphorus precipitation. Table
3 provides guidelines for the maximal amounts of cal-
cium and phosphorus that can be administered in PN
(145–147). Note that the addition of cysteine (HCl) be-
 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).

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

598 R. J. SHULMAN AND S. PHILLIPS

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

From (159).

added to intravenous fat emulsion (160). Solutions may
be stable when refrigerated and become unstable at room
temperature. Another example, heparin stability, has
been a subject of great debate. Contradictions regarding
its risk of precipitating with calcium probably are re-
lated to differences in the studied heparin prepara-
tions and the other additives and their concentrations
in the admixtures (159). The reader is referred to com-
prehensive reviews regarding the factors related to PN
admixture stability as well as methodologies used to
test stability (159–163). In general, final concentra-
tions range from 2% to 5% for amino acids, 5% to 23%
for glucose, and 1.5% to 5% for intravenous fat emul-
sion (161).
In order to see through the morass of information it is
best to follow a simple rule: after identifying a PN ad-
mixtures whose stability has been well documented, use
them exactly as described. Unlike standard PN solutions,
alterations of components, volumes, and/or concentra-
tions should not be made. A case in point is a recent
report of episodes of respiratory distress and death pos-
sibly related to changing from one commercial amino
acid brand to another despite (or it should be said, be-
cause of) not modifying any other aspect of the admix-
ture (164). A Food and Drug Administration (FDA) alert
was issued in 1994 regarding the hazards of precipitation
(165). It is recommended that information on the proper
preparation of a PN admixture be obtained directly from
the manufacturer(s) of the amino acids and intravenous
fat emulsion that are to be used. As a general rule, the
amino acids, glucose, and intravenous lipid are added in
fixed ratios by volume (e.g., 2:1:1, 1:1:1, 1:1:0.5, etc.)
(166). To reduce the risk of precipitates reaching the
patient an inline filter should be used. This should be a
1.2 micron air-eliminating filter (in contrast to the 0.22
micron air-eliminating filter recommended for nonlipid-
containing PN) (165). The importance of filtration re-
cently has been reviewed and revalidated (167,168). A
PN admixture is considered inappropriate for adminis-
tration if > 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. Be-
cause 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 sug-
gested 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 admix-
tures 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., Mel-
sungen, Germany) the PN admixture would provide in-
adequate 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, in-
travenous fat emulsion, calcium, and phosphorus prod-
ucts (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 re-
quirements.
PN admixtures only should be used in patients who are
clinically stable. Changes in the formulation of PN ad-
mixtures 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 intra-
venous 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).

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

 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.

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

600 R. J. SHULMAN AND S. PHILLIPS
Vitamin K
One potential problem with the introduction of vita-
min K into the new adult formulations is the possible
interference with anticoagulants such as warfarin. Addi-
tionally, intravenous fat emulsions contain vitamin K in
varying amounts (approximately 13–70 ␮g/dL) that can
make titrating anticoagulant therapy even more problem-
atic (181,182).
Vitamin A
A recent Cochrane review suggests that an increased
vitamin A intake (via the intramuscular route) is benefi-
cial in the preterm infant (183). Whether dosing of vita-
min 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) vita-
mins occurs during their delivery in PN (187,188). Evi-
dence suggests that using dark tubing and placing fat-
soluble vitamins into the intravenous fat emulsion (see
PN Admixtures, above) mitigates the losses of these vi-
tamins (189–192,230). However, multivitamin manufac-
turers 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 cur-
rent vitamin preparations and intake levels is less than
optimal. Prudence would suggest checking vitamin lev-
els (especially vitamin A and possibly riboflavin) in pa-
tients 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 emul-
sion.
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
J Pediatr Gastroenterol Nutr, Vol. 36, No. 5, May 2003
has been described with symptomatic carnitine defi-
ciency although the level of enteral intake was not de-
scribed (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 emul-
sion oxidation although it has been argued that the in-
crease 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 there-
after (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 malab-
sorption 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 em-
ployed in PN, the stability of iron dextran and its poten-
tial 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 prod-
ucts 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 (Ve-
nofer, 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 gen-
eral, including concerns regarding aluminum contamina-
tion 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, mul-
tivitamins) 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 ele-
ments 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 be-
cause of Se deficiency and our limited knowledge re-
garding adequacy of intake, it is prudent to check serum
Se levels in the short term (particularly in preterm in-
fants) 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 rec-
ommended 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 contami-
nation 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 glo-
merular 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 non-
intentional 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 appropri-
ately.
601
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
extrapyramidal system (206,207). Mn often contami-
nates PN solution components in amounts sufficient for
daily requirements (206,207,219). Manganese intoxica-
tion causes parkinsonian-like symptoms with muscular
weakness, stiffness, tremors, ataxia, abnormal gait, as-
thenia, and difficulty with speech (220). Psychological
changes have been reported including mental irritability,
headaches, nervousness, compulsive actions, and hallu-
cinations (220). Manganese accumulation can be de-
tected 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 re-
moved 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 se-
cretion (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 devel-
oped 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 chole-
stasis (225). Based on these and other data, it is sug-
gested 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
and that levels should be monitored in patients receiving
PN with Mn 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
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
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 hy-
pertriglyceridemia) than to PN per se, and essential fatty
acid requirements may not be as well defined as previ-
ously 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 re-
luctant 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 re-
sponsibility for improving PN safety and efficacy lies
with all concerned: industry, funding agencies, physi-
cians, 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 Agree-
ment 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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