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69 

Parenteral Nutrition for the


High-Risk Neonate
SCOTT C. DENNE

improved growth outcomes, Stephens et al. (2009) found an asso-


KEY POINTS
ciation between increased protein and energy intake in the first
• A high proportion of extremely low birth weight (ELBW) infants week of life and higher Bayley Mental Development Index scores
experience poor growth in the neonatal intensive care unit. Nutritional at 18 months’ corrected age. Parenteral nutrition solutions,
deficits that rapidly accumulate shortly after birth are a major factor in although still imperfect, have improved markedly from the early
these growth outcomes. days of use, and complications are less common. At present,
• Nutritional deficits can be minimized and growth outcomes improved
however, improved growth outcomes in preterm infants continue
by beginning parenteral nutrition soon after birth. Initial support should
include glucose at 4–7 mg/kg per min, amino acids at 2–3 g/kg per
to require a consistent effort at providing parenteral nutritional
day, and lipids at 2 g/kg per day. support, especially in early postnatal life. This means initiating
• Goals for full parenteral nutrition support in ELBW infants are parenteral nutrition within the first 24 hours, continuing until
90–100 kcal/kg per day (13–15 g/kg per day glucose, 3–4 g/kg per enteral nutrition supplies at least 75% of the total protein and
day lipid, 3.5–4.0 g/kg per day amino acids). energy requirements, and reinstituting parenteral nutrition
• There is increasing attention to fish oil–based lipid solutions, which quickly whenever enteral feeding is suspended.
appear to ameliorate parenteral nutrition–associated liver disease in
infants that require long-term intravenous nutrition. These products are
currently not commercially available in the United States. Randomized Components of Parenteral Nutrition
trials evaluating fish oil–based and other new parenteral nutrition
solutions in preterm infants are greatly needed. Protein
The initial goal of parenteral nutrition is to minimize losses and
preserve existing body stores; this is particularly important for
protein. Protein losses are significant in all neonates in the absence

E
ffective nutritional support of premature and critically ill of amino acid intake, and these losses are the highest in the most
infants is largely dependent on parenteral nutrition, espe- immature neonates. For example, 26-week-gestation infants lose
cially in early postnatal life. In practice, the supply of nutri- 1.5 g/kg per day of body protein; protein losses in term infants
ents to preterm neonates—especially extremely low birth weight are approximately half that rate (0.7 g/kg per day) (Denne et al.,
(ELBW) infants—is often inadequate, and these infants accumu- 1996). These high rates of loss in extremely premature infants
late major deficits in early postnatal life (Berry et al., 1997; result in substantial protein deficits. If extremely premature infants
Embleton et al., 2001; Olsen et al., 2002). A high proportion of are provided with no amino acid supply, they lose over 1.5% of
ELBW infants exhibit poor growth in the neonatal intensive care their body protein per day when they should be accumulating
unit (NICU), with those at the lowest gestational age and birth- protein at a rate of 2% per day. After only 3 days of no protein
weight at greatest risk (Clark et al., 2003; Fanaroff et al., 2007). intake, a 10% protein deficit results.
However, growing evidence indicates that early use of parenteral Fortunately, there is good evidence that early amino acid intake
nutrition may minimize protein losses and improve growth out- can compensate for high rates of protein loss and thus preserve
comes (Wilson et al., 1997; Thureen et al., 2003; Poindexter, body protein, even at low caloric intakes (Saini et al., 1989; Van
2005; Stephens et al., 2009). For example, Wilson et al. (1997), Lingen et al., 1992; Rivera et al., 1993; Kashyap and Heird, 1994).
in a randomized clinical trial in 125 sick very low birth weight Amino acid intakes of 1.1–2.3 g/kg per day at caloric intakes of
(VLBW) infants, demonstrated that early aggressive parenteral 30–50 kcal/kg per day change the protein balance from significantly
nutrition combined with early enteral feeding reduced growth negative to neutral or positive in sick VLBW infants (Saini et al.,
failure without an increased incidence of adverse clinical conse- 1989; Van Lingen et al., 1992; Rivera et al., 1993). In addition,
quences or metabolic derangements. Multiple observational Thureen et al. (1998) conducted a randomized trial of 1 g/kg per
studies have produced similar results (Poindexter, 2005; Valentine day versus 3 g/kg per day amino acid intake immediately after
et al., 2009; Cormack et al., 2013; Rigo and Senterre, 2013; birth in extremely premature infants. Despite a modest caloric
Bolisetty et al., 2014; Morgan et al., 2014). In addition to intake in both groups (approximately 50 kcal/kg per day), protein

1023
1024 PART XI I I  Nutrition

accretion was significantly greater in the higher amino acid intake amino acids is well tolerated by ELBW infants (Porcelli and Sisk,
group. In all these studies evaluating the effect of early amino acid 2002). For premature infants with birthweights over 1000 g,
intake in premature infants, no differences in ammonia concentra- estimated parenteral protein requirements are 3.0–3.5 g/kg per
tions or acid–base status were observed between infants who received day. Estimates for term infants are 2.5–3 g/kg per day. Parenteral
amino acids and those who did not (Saini et al., 1989; Van Lingen protein intake recommendations for premature infants are shown in
et al., 1992; Rivera et al., 1993; Paisley et al., 2000). In addition, Table 69.1.
these studies demonstrated no relationship between amino acid The composition of currently available amino acid solutions is
intake and blood urea nitrogen (BUN), although other studies shown in Table 69.2. These amino acid solutions were designed
reported modestly elevated BUN levels in neonates receiving higher to mimic plasma amino acid concentrations in healthy 30-day-old
amino acid intakes at 7 days of age (Clark et al., 2007; Blanco breastfed term infants (TrophAmine, B. Braun Medical Inc.) or
et al., 2008). The fact that BUN concentrations do not usually fetal or neonatal cord blood amino acid concentrations (Primene,
correlate with amino acid intake in early postnatal life suggests Baxter Corporation). No convincing information exists to support
these levels are related primarily to fluid status and that increased the superiority of one neonatal amino acid solution over another.
BUN levels should not be used as an indication of protein excess. Although the current neonatal amino acid solutions represent
These data indicate that providing parenteral amino acids at a rate a substantial advance over previous casein hydrolysates and early
of 2–3 g/kg per day as soon as possible after birth (within hours) crystalline amino acid mixtures, these solutions do not contain all
can preserve limited body protein stores in sick premature and the amino acids. Glutamine, an amino acid abundantly supplied
ELBW infants, even at low caloric intakes. by breast milk and potentially conditionally essential in premature
It is important to point out that even though parenteral amino infants, is not included in any available amino acid solution because
acid administration is beneficial at low caloric intakes, increasing of issues of stability. However, the National Institute of Child
caloric intake is likely to improve protein accretion. Older studies Health and Human Development Neonatal Research Network
in premature infants have suggested that increasing caloric intake conducted a multicenter randomized clinical trial of parenteral
from 50–80 kcal/kg per day can significantly improve protein glutamine supplementation and found that parenteral glutamine
balance (Pineault et al., 1988). Based on currently available data, supplementation did not decrease mortality or the incidence of
70–80 kcal/kg per day may be sufficient to maximize protein late-onset sepsis in ELBW infants (Poindexter et al., 2004). In
accretion. However, additional energy beyond this amount probably addition, glutamine had no effect on enteral feeding tolerance,
is necessary to produce appropriate fat accretion (see “Energy” incidence of necrotizing enterocolitis, or growth. Tyrosine has very
section later). limited solubility, so little is included in current amino acid solu-
The ultimate goal of parenteral amino acid administration is tions. TrophAmine contains a soluble derivative of tyrosine
to achieve the rate of fetal protein accretion. Based on a variety (N-acetyltyrosine), but this derivative appears to have poor bioavail-
of studies measuring protein losses and balance, 3.5–4.0 g/kg ability. A variety of studies in premature infants suggest that the
per day of amino acids is a reasonable estimate of parenteral tyrosine supply may not be optimal in current amino acid solutions
protein requirements in ELBW infants (Ziegler, 2007) (Table (Brunton et al., 2000). Cysteine is not included in most amino
69.1). Some evidence suggests that up to 4.0 g/kg per day of acid solutions because it is not stable for long periods. However,

TABLE
69.1  Suggested Daily Parenteral Intakes for Extremely Low and Very Low Birth Weight Infants

Component ELBW VLBW


(units/kg per day) Day 0a Transitionb Growing Day 0a Transitionb Growing
Energy (kcal) 40–50 70–80 90–100 40–50 60–70 90–100
Protein (g) 2.0–3.0 3.5 3.5–4.0 2.0–3.0 3.0–3.5 3.0–3.5
Glucose (g) 7–10 8–15 13–17 7–10 8–15 13–17
Fat (g) 2 2–3 3–4 2 2–3 3
Na (mEq) 0–1 2–4 3–7 0–1 2–4 3–5
Potassium (K) (mEq) 0 0–2 2–3 0 0–2 2–3
Chloride (mEq) 0–1 2–4 3–7 0–1 2–4 3–7
Calcium (mg) 20–60 60 60–80 20–60 60 60–80
Phosphorus (mg) 0 45–60 45–60 0 45–60 45–60
Magnesium (mg) 0 3.0–7.2 3.0–7.2 0 3.0–7.2 3.0–7.2

ELBW, Extremely low birth weight; VLBW, very low birth weight.
a
Recommended parenteral intakes on the first day of life.
b
Period of transition to physiologic and metabolic stability. For most premature neonates, this occurs between 2 and 7 days.
CHAPTER 69  Parenteral Nutrition for the High-Risk Neonate 1025

TABLE Composition of Commercial Parenteral Amino 70 kcal/kg per day; energy expenditure increases with energy intake
69.2  Acid Solutions and with advancing postnatal age (Bauer et al., 2003a, 2003b;
Torine et al., 2007; Weintraub et al., 2009). Energy expenditure
CONCENTRATION (MG/DL) also appears to be greater at lower birthweights (Weintraub et al.,
Aminosyn-PF TrophAmine Primene Premasol 2009). An intake of approximately 70 kcal/kg per day is a reasonable
Amino Acida (Hospira) (B. Braun) (Baxter)b (Baxter)b clinical goal to achieve neutral or slightly positive energy balance,
although because of glucose and lipid intolerance, this intake may
Histidine 312 480 380 480
not be achievable for a number of days after birth. Nevertheless,
Isoleucine 760 820 670 820 maximizing energy intake within the limits of glucose and lipid
tolerance can minimize accumulating energy deficits. It is also
Leucine 1200 1400 1000 1400
important to note that common clinical conditions such as sepsis
Lysine 677 820 1100 820 and chronic lung disease can significantly increase energy expen-
Methionine 180 340 240 340
diture, which can further exaggerate energy deficits (Bauer et al.,
2003c; Torine et al., 2007).
Phenylalanine 427 480 420 480 To support normal rates of growth, a positive energy balance
Threonine 512 420 370 420 of 20–25 kcal/kg per day must be achieved (Denne, 2001). This
requires 90–100 kcal/kg per day for preterm infants with birth-
Tryptophan 180 200 200 200 weights of less than 1000 g and 100–110 kcal/kg per day for
Valine 673 780 760 780 ELBW infants (Table 69.1). A parenteral intake of 80–90 kcal/kg
per day is most often sufficient for term infants. Most of the
Alanine 698 540 800 540 parenteral calories are best supplied by a balanced caloric intake
Arginine 1227 1200 840 1200 of lipid and glucose. Parenteral energy requirements are less than
those required for enteral nutrition because no energy is lost in
Proline 812 680 300 680 the stools. Recommendations for parenteral energy intake are shown
Serine 495 380 400 380 in Table 69.2.
Taurine 70 25 60 25
c
Glucose
Tyrosine 44 240 45 240c
Glucose is typically the first parenteral nutrient provided to the
Glycine 385 360 400 360
preterm infant, and glucose administration is initiated minutes
Cysteine – <16 189 <16 after birth to maintain glucose homeostasis and preserve endogenous
carbohydrate stores. Although the precise definitions of hypoglycemia
Glutamic acid 820 500 1000 500
and hyperglycemia remain a topic of debate, maintaining glucose
Aspartic acid 527 320 600 320 concentrations of above 40 mg/dL and below 150–200 mg/dL is
a
a reasonable clinical goal (Cornblath et al., 2000). Hypoglycemia
All amino acid mixtures shown are 10% solutions.
b
Primene available in Canada; Premasol available in the United States.
is easily avoided in preterm infants by maintaining a constant
c
Mixture of L-tyrosine and N-acetyltyrosine. intravenous (IV) glucose delivery, but hyperglycemia is more often
problematic, especially in ELBW infants shortly after birth.
Hyperglycemia is very common in this population in early postnatal
life, with up to three-quarters of ELBW infants having glucose
concentrations exceeding 150 mg/dL and a third of infants fre-
a cysteine hydrochloride supplement that can be added to the quently having glucose concentrations over 180 mg/dL (Blanco
parenteral nutrition solution just before delivery is commercially et al., 2006; Beardsall et al., 2008).
available. There is supporting evidence that when cysteine hydro- Glucose infusion rates of 4–7 mg/kg per minute (70–110 mL/
chloride supplements are added to parenteral nutrition, nitrogen kg per day of 10% dextrose in water [D10W]) are appropriate
retention is improved in premature infants (Soghier and Brion, starting points for most infants. These rates of glucose infusion
2006). The addition of cysteine hydrochloride also improves the approximate or slightly exceed the rate of endogenous glucose
solubility of calcium and phosphorus in parenteral nutrition solu- release from the liver in term and premature infants with birth-
tions and also may improve the status of the important antioxidant weights above 1000 g; therefore these rates of glucose infusion
glutathione. For these reasons, the addition of cysteine hydrochloride serve to preserve the limited carbohydrate stores in these infants.
(40 mg/g of amino acid, up to a maximum of 120 mg/kg) is recom- For ELBW infants, a rate of 8–10 mg/kg per minute is required
mended. Cysteine hydrochloride can result in metabolic acidosis, to match endogenous glucose production (Hertz et al., 1993).
but this possibility can be appropriately countered by the use of Unfortunately, many infants will not tolerate this rate of glucose
acetate in the parenteral nutrition solution as a buffer (Peters infusion for several days without developing hyperglycemia. Because
et al., 1997). ELBW infants can have fluid requirements in excess of 100 mL/
kg per day, beginning with 5% dextrose may be necessary to
maintain glucose infusion rates in the range of 4–7 mg/kg to
Energy achieve glucose homeostasis.
The initial goal of parenteral nutrition in early postnatal life is to A gradual increase in glucose intake over 2–7 days, up to
provide sufficient energy intake to at least match rates of energy 13–17 g/kg per day, is usually tolerated when the glucose is
expenditure, to preserve body energy stores. Measures of energy combined with amino acid intake. An infusion rate of 18 g/kg
expenditure in premature infants have ranged between 30 and per day is a reasonable maximum for IV glucose delivery, because
1026 PART XI I I  Nutrition

higher rates probably exceed the glucose oxidative capacity (Jones TABLE
et al., 1993; Chessex et al., 1995). Exceeding glucose oxidative 69.3  Composition of Parenteral Lipid Emulsions
capacity will drive extensive lipogenesis, an energy-expensive process.
Supplying appropriate amounts of glucose rarely requires glucose Intralipid 20% Liposyn II 20% Omegavena
solution concentrations in excess of 12.5%, unless infants are fluid Oil
restricted. Recommendations for glucose intake during parenteral
Soybean 20 10 –
nutrition are provided in Table 69.1.
Some ELBW infants have difficulty tolerating even moderate Safflower 10 –
rates of glucose delivery. This problem can usually be overcome
Fish – – 10
by a temporary reduction in the glucose infusion rate. The use of
insulin in this situation remains a controversial practice. Collins Fats (%)
et al. (1991), in a small randomized controlled trial, demonstrated Linoleic 50 65 0.1–0.7
increased weight gain in infants who received insulin infusions.
No differences in head circumference or length were observed α-Linolenic 9 4 <0.2
between these infants and controls, suggesting that insulin may have EPA – – 1.3–2.8
produced increases in fat mass but not in lean tissue. Poindexter
DHA – – 1.4–3.1
et al. (1998) evaluated the effect of insulin on protein metabolism
using a euglycemic hyperinsulinemic clamp. Insulin infusion Arachidonic acid – – 0.1–0.4
resulted in no improvement in protein balance and unexpectedly
Glycerol 2.3 2.5 2.5
produced significant lactic acidosis. An international randomized
clinical trial was conducted to determine whether early insulin Egg phospholipid 1.2 1.2 1.2
therapy would reduce hyperglycemia and improve outcomes in Phytosterols, mg/L 348 + 33 383 0
VLBW infants (Beardsall et al., 2008). The study demonstrated
no improvements in mortality, sepsis, growth, intracranial disease, DHA, Docosahexaenoic acid; EPA, eicosapentaenoic acid.
necrotizing enterocolitis, or chronic lung disease and was terminated a
Omegaven is not approved for use in the United States and is only available under experimental
early because of futility concerns. Although insulin reduced hyper- or compassionate use protocol. Omegaven is only available as a 10% solution (10 g lipid
per 100 mL).
glycemia, it also resulted in increased episodes of hypoglycemia.
Further, the mortality at 28 days was higher in the insulin group.
Another randomized controlled trial examined the effect of insulin
in hyperglycemic VLBW infants who were randomized to receive There is increasing attention on fish oil–based lipid solutions,
insulin either when glucose levels exceeded 150 mg/dL or when although none of these products are currently available in the
glucose levels exceeded 180 mg/dL (Alsweilier et al., 2012). The United States. A recent systematic review of fish oil–based emulsions
primary outcome of linear growth was significantly reduced in the concluded that these products are effective in reducing existing
more aggressive insulin use group, along with a two times greater parenteral nutrition–associated liver disease (PNALD) but do not
rate of hypoglycemia. At present, there is no evidence supporting seem to prevent PNALD in neonates (Park et al., 2015). Evaluating
a clinical benefit from routine insulin administration in VLBW fish oil–based and other new parenteral lipid solutions is an area
infants. Nevertheless, there are rare VLBW infants who remain of active interest and will require large randomized trials of pre-
hyperglycemic despite very low glucose infusion rates; these infants mature infants.
may require exogenous insulin, beginning at 0.05 unit/kg per hour IV lipid solutions contain lipid particles similar in size to
for a short period of time, to produce normoglycemia. endogenously produced chylomicrons. These particles are hydrolyzed
Meeting the goal of 13–17 g/kg per day of IV glucose will by lipoprotein lipase into free fatty acids. Lipoprotein lipase activity
result in a caloric intake of 45–60 kcal/kg per day, which is insuf- and triglyceride clearance are reduced in preterm infants of less
ficient by itself to meet total energy needs. IV lipids are necessary than 28 weeks’ gestation (Brans et al., 1990). Although heparin
to supply the rest of the nonprotein calories. A balanced glucose can release lipoprotein lipase from the endothelium into the circula-
and lipid approach to supplying nonprotein calories has a number tion, at present no evidence exists that this increases lipid utilization
of advantages: it better approximates the carbohydrate-to-fat ratio in preterm infants (Spear et al., 1988). In the absence of any
in enteral feedings, it may improve overall protein accretion, and information demonstrating clinical benefit of heparin administration,
it minimizes overall energy expenditure (Nose et al., 1987; Van the routine addition of heparin in lipid infusions is not
Aerde et al., 1989). recommended.
Linoleic and linolenic acids cannot be endogenously synthesized
and therefore are essential fatty acids for humans. Biochemical
Lipids evidence of essential fatty acid deficiency may be noted in preterm
IV lipids are made up of triglycerides, phospholipids from egg neonates within 72 hours of birth (Foote et al., 1991). Essential
yolk to emulsify, and glycerol, which is added to achieve isotonicity. fatty acid deficiency can be avoided if 0.5–1.0 g/kg per day of IV
IV lipid solutions commercially available in the United States are lipid is provided. Additional IV lipid beyond these amounts is
derived from soybean oil (Intralipid, Hospira, Inc.) or a combination necessary if the energy requirements of preterm infants are to be
of soybean oil and safflower oil (Liposyn II, Baxter Corporation); met in early postnatal life.
these solutions contain long-chain triglycerides. Differences in There is good evidence that early administration of IV lipid
lipid source result in a slightly different fatty acid profile; the to preterm infants is safe and well tolerated. Drenckpohl and
compositions of IV lipid solutions are shown in Table 69.3. All colleagues demonstrated that beginning 2 g/kg of lipid on day
available IV lipid products have a fatty acid profile substantially 1 significantly increased the energy intake of VLBW infants,
different from that of human milk. and hypertryglyeridemia occurred in only 15% of infants
CHAPTER 69  Parenteral Nutrition for the High-Risk Neonate 1027

(Drenckpohl et al., 2008). A more recent study showed improved sodium concentrations and water balance. After the initial diuresis,
nitrogen balance when lipids were begun at 2g/kg on day 1 in 2–4 milliequivalent (mEq)/kg per day is usually sufficient to
VLBW infants (Vlaardingerbroek et al., 2013). A systematic maintain serum sodium in the normal range, but ELBW infants
review and metaanalysis of early versus late IV lipid use in pre- sometimes require higher sodium intakes to compensate for larger
mature infants showed no detrimental effects of early lipids on renal sodium losses. Chloride requirements follow the same time
either death, bronchopulmonary dysplasia, or sepsis (Vlaarding- course as for sodium requirements and are also usually 2–4 mEq/
erbroek et al., 2012). However, a beneficial effect from early kg per day. Once electrolytes are added to the parenteral nutrition
lipids on long-term growth could not be demonstrated. solution, chloride intake should not be less than 1 mEq/kg per
In view of the available data, beginning 2g/kg of IV lipid on day, and all chloride should not be omitted when sodium bicarbon-
day 1 in ELBW and VLBW infants is a recommended clinical ate or acetate is given to correct metabolic acidosis. Potassium
practice. This approach will support essential fatty acid needs and requirements are also low in the first few days of life, and potassium
minimize energy and protein deficits. should probably be omitted from parenteral solutions in ELBW
The rate of IV lipid infusion is important, and plasma lipid infants until renal function is clearly established. Potassium intake
clearance is improved when IV lipid is given as a continuous of 2–3 mEq/kg per day is usually adequate to maintain normal
infusion over 24 hours (Putet, 2000). Triglyceride concentrations serum potassium concentrations.
are most often used as an indication of lipid tolerance, and maintain- Parenteral nutrition solutions usually require the addition of
ing triglyceride concentrations below 150–200 mg/dL seems reason- anions, as either acetate or chloride. In general, excess anions should
able; however, there are no available outcome data supporting this be provided as acetate to prevent hyperchloremic metabolic acidosis.
practice. Recommendations for parenteral lipid intake are provided A randomized controlled clinical trial demonstrated that acetate
in Table 69.1. in parenteral nutrition solutions effectively ameliorates this metabolic
Numerous studies have documented the superiority of 20% acidosis (Phelps and Cochran, 1989).
over 10% lipid emulsions (Putet, 2000). Lipid clearance is improved Supplying calcium and phosphorus in parenteral nutrition
with the 20% solutions because they have half the amount of remains a significant clinical challenge because of limited solubility.
phospholipid emulsifier relative to the same amount of triglycerides. It is currently not possible to supply enough calcium and phosphorus
Phospholipids can combine with cholesterol to form lipoprotein to support adequate bone mineralization in preterm infants using
X, which ultimately interferes with the clearance of infused tri- the solutions available in the United States. In other countries,
glycerides. Consequently, the use of 10% lipid emulsions should organophosphate preparations are available (e.g., glycerophosphate),
be avoided. A 30% lipid solution has recently become available and calcium and phosphorus can be supplied in parenteral nutrition
and may confer even more advantages, although currently there solutions in amounts that approximate enteral intakes. Precipitation
are no comparative data. of calcium and phosphorus remains an issue in the United States,
IV lipid emulsions may undergo lipid peroxidation, with the however, and the solubility of calcium and phosphorus in parenteral
formation of organic free radicals, potentially initiating tissue injury. nutrition solutions depends on temperature, type and concentration
Light, especially phototherapy, may play some role in increasing lipid of amino acid, glucose concentration, pH, type of calcium salt,
peroxidation in IV lipid emulsions (Neuzil et al., 1995). However, sequence of addition of calcium and phosphorus to the solution,
multivitamin preparations included in the IV solutions are major the calcium-to-phosphorus ratio, and the presence of lipid. Adding
contributors to generation of peroxides, and lipid emulsions may cysteine to parenteral nutrition solutions lowers the pH, which
have only a minor additive effect (Lavoie et al., 1997). Some small improves calcium and phosphorus solubility. Intakes of 60–80 mg/
studies have suggested that light protection may reduce chronic kg per day of elemental calcium (1.5–2.0 mmol/kg per day) and
lung disease, but these results have not been consistent (Chessex 48–60 mg/kg per day of phosphorus (1.5–2.0 mmol/kg per day)
et al., 2007; Bassiouny et al., 2009; Sherlock and Chessex, 2009). have been recommended for premature infants receiving parenteral
On the basis of these findings, some clinicians protect IV lipid nutrition (Atkinson and Tsang, 2005). A calcium-to-phosphorus
solutions from light, although the importance or clinical efficacy ratio of 1.7 : 1 by weight (1.3 : 1 by molar ratio) may be optimal
of this practice remains in doubt. Only a large randomized clinical for bone mineralization, but it appears that neonates can tolerate
trial is likely to resolve this issue (Sherlock and Chessex, 2009). and adjust to molar ratios over the range of 0.8 to 1.5 (Atkinson
Carnitine facilitates transport of long chain fatty acids through and Tsang, 2005). In general, calcium and phosphorus should
the myocardial membrane and thereby plays an important role in be added to parenteral nutrition solutions in early postnatal life.
their oxidation. Premature infants receiving parenteral nutrition Magnesium is also a necessary nutrient and should be supplied
have low carnitine levels, but the clinical significance of this finding at 3.0–7.2 mg/kg per day. Calcium, phosphorus, and magnesium
remains uncertain. Metaanalysis of the studies evaluating carnitine serum concentrations should be frequently monitored.
supplementation in parenteral nutrition showed no evidence of Recommendations for trace elements in term and preterm infants
effect on ketogenesis, lipid utilization, or weight gain (Cairns and are primarily derived from the American Society for Clinical
Stalker, 2000). At present, insufficient information is available to Nutrition guidelines from 1988 (Greene et al., 1988), with some
support a recommendation for the routine supplementation of recent updates by the American Society of Parenteral and Enteral
carnitine for parenterally fed neonates. Nutrition (Vanek et al., 2012; Finch, 2015). There is reasonable
consensus that zinc and selenium should be included early in
Electrolytes, Minerals, Trace Elements, parenteral nutrition solutions (Finch, 2015). Other trace elements
are probably not needed until after the first 2 weeks of life. The
and Vitamins recommended intakes of trace elements for term and preterm
Sodium needs are low in the first few days of life because of the infants are shown in Table 69.4.
expected free water diuresis. For ELBW infants, addition of sodium Zinc and copper are available in the sulfate form and can be
to the parenteral nutrition solution may not be necessary until added separately to parenteral solutions. Several pediatric trace
about day 3 of life. It is, however, necessary to frequently measure metal solutions are available that contain zinc, copper, magnesium,
1028 PART XI I I  Nutrition

TABLE Recommended Parenteral Intake of Trace TABLE Recommended Parenteral Intake of Vitamins
69.4  Elements for Term and Preterm Infants 69.5  for Term and Preterm Infants
Term (µg/kg Preterm (µg/kg Term Preterm
Trace Element per day) per day) Vitamin (daily dose) (dose/kg per day)a
Chromiuma 0.20 0.05–0.30 Fat Soluble
Copper b
20 29 Vitamin A (IU) 2300 700–1500

Ironc – – Vitamin D (IU) 400 40–160

Fluorided – – Vitamin E (IU) 7 2.8–3.5


b
Iodide 1 1 Vitamin K (µg) 200 10b

Manganeseb 1 1 Water Soluble


Vitamin B6 (µg) 1000 150–200
Molybdenum 0.25 0.25
Vitamin B12 (µg) 1 0.3
Seleniuma 2 1.5–4.5
Vitamin C (mg) 80 15–25
Zince 250 400
a
Biotin (µg) 20 5–8
Renal dysfunction can cause toxicity.
b
Impaired biliary excretion can cause toxicity. Folic acid (µg) 140 56
c
Iron not recommended unless on parenteral nutrition for longer than 2 months (estimated
daily intravenous requirement is 250–670 µg/kg for term infants and 100–200 µg/kg for Niacin (mg) 17 4.0–6.8
preterm infants).
d
Because of a lack of information on the compatibility of fluoride with TPN and on the contamina- Pantothenate (mg) 5 1–2
tion level of fluoride in TPN solutions, firm recommendations cannot be made; with long-term
Riboflavin (µg) 1400 150–200
TPN (longer than 3 months), a dosage of 500 µg/day may be important in preterm infants,
who already have a higher incidence of subsequent dental caries. 1200 200–350
e
Thiamin (µg)
The only trace element recommended on day 1 of parenteral nutrition. If the infant requires
TPN for longer than 3 months, the dosage must be reduced to 100 µg/kg/day. a
Maximum not to exceed dosage for term infant.
Data from Vanek VW, Boren P, Buchman A, et al. A.S.P.E.N. position paper: recommendations b
This does not include the 0.5 to 1 mg of vitamin K to be given at birth.
for changes in commercially available parenteral multivitamin and multi-trace element products.
Data from Vanek VW, Boren P, Buchman A, et al. A.S.P.E.N. position paper: recommendations
Nutr Clin Pract. 2012;27:440–491.
for changes in commercially available parenteral multivitamin and multi-trace element products.
Nutr Clin Pract. 2012;27:440–491.

and chromium in various proportions; these solutions are usually


provided at 0.2 mL/kg per day. When trace metal solutions are resolves after discontinuation of parenteral nutrition and initiation
used, additional zinc is usually needed to provide the recommended of enteral feedings. Some rare instances of irreversible liver failure
intake for preterm infants. In infants with cholestasis, copper and have been documented, but this seems to occur only after several
manganese should be discontinued, and chromium and selenium months of use.
should be used with caution and in smaller amounts in infants The etiology of PNALD cholestasis is unknown and most likely
with renal dysfunction. At present, parenteral iron is recommended multifactorial. The patients at greatest risk are critically ill premature
only when preterm infants are nourished exclusively by parenteral infants who are susceptible to multiple insults, such as hypoxia,
solutions for the first 2 months of life. hemodynamic instability, and sepsis. The most frequently identified
The recommended intakes of vitamins for term and preterm risk factors in parenteral nutrition–associated cholestasis are duration
infants on parenteral nutrition are shown in Table 69.5. Currently of parenteral nutrition, degree of immaturity, and delayed enteral
only two pediatric multivitamin preparations are available. These feeding (Steinbach et al., 2008). There is also evidence that being
preparations provide somewhat higher amounts of most of the B small for gestational age is also an independent risk factor for
vitamins relative to the recommendations. PNALD (Robinson and Ehrenkranz, 2008). A recent systematic
review estimated parenteral nutrition–associated cholestasis in
Complications of Parenteral Nutrition premature infants at 25%, but there is substantial variation across
studies (Lauriti et al., 2014).
Although a wide variety of complications associated with parenteral There is growing evidence implicating soybean-derived emulsions
nutrition were reported in the early days of use, most of these are in the pathogenesis of PNALD. Soybean-derived lipid solutions
now rare with current parenteral solutions. Many of the complica- contain phytosterols, high concentrations of the proinflammatory
tions (electrolyte and glucose imbalance) can be prevented or omega-6 polyunsaturated fatty acids (PUFAs), and low concentra-
corrected by manipulating the constituents of the infusate. The tions of antioxidants (i.e., alpha tocopheral). A variety of both animal
primary complications of parenteral nutrition as currently used and human studies have demonstrated that these components,
are cholestasis and those related to the infusion catheter. both alone and in combination, contribute to PNALD (Nandivada
Cholestatic jaundice as a result of hepatic dysfunction is a well- et al., 2013).
recognized complication of parenteral nutrition. The initial histologic There are now multiple studies, mostly observational, that
lesion is cholestasis, both intracellular and intracanalicular, followed demonstrate improvement in PNALD in infants using the fish
by portal inflammation and progression to bile duct proliferation oil–based product Omegaven (Gura et al., 2008; Diamond et al.,
after several weeks of parenteral nutrition. Cholestasis most often 2009; Puder et al., 2009; Park et al., 2015). Puder et al. (2009)
CHAPTER 69  Parenteral Nutrition for the High-Risk Neonate 1029

performed an open-label trial of Omegaven in 42 infants with


short bowel syndrome with PNALD and compared them with a Use of Parenteral Nutrition in the Neonatal
similar cohort of short bowel syndrome infants who received only Intensive Care Unit: A Practical Approach
soy-based IV lipids. The group receiving Omegaven had lower
rates of mortality and liver transplantation and a higher rate of The preceding portion of this chapter has presented the scientific
cholestasis reversal. However, this therapy is currently only avail- basis for recommendations regarding provision of parenteral nutri-
able in the United States through research or compassionate use tion to neonates. The following paragraphs present a practical
protocols. Data from randomized clinical trials are needed before approach to the administration of parenteral nutrition, with a
recommending changes in clinical practice to include Omegaven particular emphasis on ELBW infants.
in the treatment of PNALD. Every clinician caring for ELBW infants must recognize the
Some infants with cholestasis will require continued paren- urgent need to initiate IV amino acids shortly after birth. As
teral nutrition. In these infants, the use of small-volume enteral mentioned previously, the ELBW infant loses 1.5% of total body
feedings in combination with parenteral nutrition may stabilize protein each day that amino acids are withheld. Consequently,
or improve hepatic function. The use of phenobarbital and urso- the goal of early parenteral nutrition should be to limit catabolism
deoxycholic acid has been shown to be beneficial in some studies and preserve endogenous protein stores. Numerous studies have
of older children and adults. However, a study in preterm infants clearly demonstrated both the safety and efficacy of early amino
demonstrated that tauroursodeoxycholic acid did not prevent the acids in accomplishing this goal, even at low caloric intakes.
development of parenteral nutrition–associated cholestasis and We recommend starting 3.0 g/kg per day of amino acids on
was ineffective in reducing cholestasis once it occurred (Heubi the first day after birth. This can be accomplished simply by adding
et al., 2002). At present, the routine use of ursodeoxycholic acid one of the crystalline amino acid solutions designed for use in
or phenobarbital in parenteral nutrition–associated cholestasis neonates (Aminosyn-PF, Hospira, Inc.; Primene, Baxter Corporation;
cannot be recommended. Premasol, Baxter Corporation; or TrophAmine, B. Braun Medical,
There is emerging information suggesting that lipid restriction Inc.) to glucose to use as the initial maintenance fluid in ELBW
may prevent or ameliorate PNALD; however, not all studies have infants. We recommend developing a neonatal amino acid stock
shown this effect (Calkins et al., 2014; Jakobsen et al., 2015). solution, made in advance in the pharmacy. The solution contains
Given the fundamental role of lipid in supporting caloric needs and amino acids in a 7.5% dextrose that, when delivered at 60 mL/
brain development, lipid restriction should not be routinely used kg per day, provides 3 g/kg per day of amino acids. Additional
for ELBW and VLBW infants. This strategy might be considered fluids with or without electrolytes and/or a higher concentration
for infants with long-term dependency on parenteral nutrition, of dextrose are “Y’d in,” with adjustments as needed for the
but additional studies are needed. individual infant’s fluid, dextrose, and electrolyte requirements,
Catheter-related complications remain an important problem eliminating the need to discard the bag of parenteral nutrition
associated with parenteral nutrition; the major complication fluid for such changes in status. It is important to note that this
is infection. Two of the most common bacterial pathogens are stock solution should not be increased beyond 60 mL/kg per day;
Staphylococcus epidermidis and Staphylococcus aureus. Fungal any alterations to total fluids must be made with ancillary fluids.
infections also occur, with Candida albicans and Malassezia furfur This mixture of glucose and amino acids can be given via a peripheral
being the most common agents. The incidence of sepsis during IV line, umbilical venous line, or percutaneous central venous
parenteral nutrition is higher at the lower gestational ages and catheter. Increased use of percutaneously placed central venous
also increases with the duration of parenteral nutrition. Paren- catheters has certainly facilitated early and widespread use of
teral nutrition–associated sepsis is likely to be a product of many parenteral nutrition in premature infants. In our nursery, strong
factors, not the least of which is that the most immature and consideration is given to percutaneous central venous line placement
critically ill patients are most likely to receive parenteral nutrition in ELBW infants early in their postnatal course.
for prolonged periods. In infants who have developed cholestasis To meet growth requirements, 3.5–4.0 g/kg per day of amino
while receiving parenteral nutrition, the rate of sepsis may be acids is required. It is important to point out that such amounts
increased. At present, avoiding parenteral nutrition–associated are merely estimates, and protein requirements to sustain optimal
infections is best accomplished by meticulous attention to sterile growth in ELBW infants might be even higher. Once administration
technique in catheter care, early initiation and advancement of amino acids is initiated, intake can be advanced to meet require-
of enteral nutrition, and prompt removal of the catheter when ments for growth over a relatively short period. We typically advance
adequate enteral nutrition is achieved. Prophylactic low-dose amino acid intake 3.5 g/kg per day by the second day of life.
vancomycin may diminish the incidence of parenteral nutrition– Given the available data, we also recommend the addition of cysteine
associated sepsis, but in view of concerns about toxicities and to the amino acid solution (40 mg/g of amino acids, to a maximum
the potential for antibiotic resistance, this approach cannot be of 120 mg). However, we delay adding cysteine until other elec-
recommended (Craft et al., 2004). trolytes are included in the parenteral nutrition solution so that
Complications specifically related to the catheter have also been acetate can be added to buffer the cysteine acid load.
reported. Broviac catheters are difficult to place and are associated Glucose should be supplied in a quantity sufficient to maintain
with thrombosis in neonates (Sadiq et al., 1987). In most NICUs, normal plasma glucose concentrations. As discussed previously,
Broviac catheters have largely been replaced by small-bore Silastic glucose production and utilization rates are highest in the most
catheters placed percutaneously. However, all central catheters, premature infants; their glucose needs are in the range of 6–8 mg/
including the small-bore variety, have produced life-threatening kg per minute, whereas the term infant’s needs are approximately
complications. Pericardial tamponade and significant pleural effu- 3–4 mg/kg per minute. Giving 10% dextrose at 100 mL/kg per
sions are known complications of the use of central catheters in day provides a glucose infusion rate of 7 mg/kg per minute. Starting
neonates (Hermansen and Hermansen, 2005). Although these are infants with birthweights less than 1000 g on 5% dextrose is likely
uncommon events, clinical awareness and early recognition of to be prudent if their total fluid requirements are greater than
these complications can prevent mortality. 120–150 mL/kg per day.
1030 PART XI I I  Nutrition

TABLE TABLE Suggested Monitoring During


69.6  Caloric Value of Parenteral Nutrition Solutions 69.7  Parenteral Nutrition
Kcal/kg % of Nonprotein Parameter Frequency
Compositiona per day Calories
Weight Daily
Example 1: Total Fluids at 110 mL/kg per day
Length and head circumference Weekly
10% dextrose 37 55
Serum glucose 1×/shift during week 1, then daily
3 g/kg per day lipid 30 45
Serum Na, K, Cl, BUN, Ca, P, Mg, 2–3×/week during week 1, then
3.5 g/kg per day amino acids 14 – hematocrit weekly
Total 81 – Alkaline phosphatase, ALT (SGPT), Weekly
GGT, fractionated bilirubin
Example 2: Total Fluids at 80 mL/kg per day
ALT, Alanine transaminase; BUN, blood urea nitrogen; GGT, gamma-glutamyl transferase;
12.5% dextrose 34 53
SGPT, serum glutamate-pyruvate transaminase.
3 g/kg per day lipid 30 47
3.5 g/kg per day amino acids 14 –
of enteral feeds cannot be overemphasized. Infants with intolerance
Total 78 –
of enteral feeds in whom nothing-by-mouth (NPO) status is
Example 3: Total Fluids at 140 mL/kg per day frequently necessary present an additional challenge. In such infants,
12.5% dextrose 60 67
it may be prudent to determine full-volume parenteral nutrition
needs as for NPO status and to then run the parenteral nutrition
3 g/kg per day lipid 30 33 solution at a lower rate if enteral feeds are administered. With this
3.5 g/kg per day amino acids 14 – approach, if a change to NPO status becomes necessary after
administration of the parenteral nutrition fluid has begun, the
Total 104 – volume can be safely increased without compromising caloric and
a
Dextrose: 3.4 kcal/g; protein: 4 kcal/g; lipid (20% emulsion): 10 kcal/g.
protein intake.

Acknowledgment
I would like to thank Dr. Brenda Poindexter who contributed to
Lipids should be started within the first 24 hours. We typically the previous version of this chapter.
start lipids at 2.0 g/kg per day and advance by 0.5–1.0 g/kg per
day to a usual maximum of 3 g/kg per day while monitoring and
maintaining serum triglycerides at less than 200 mg/dL. Given Suggested Readings
the numerous advantages over 10% solutions, 20% lipid emulsions Bauer J, Maier K, Hellstern G, Linderkamp O. Longitudinal evaluation
should always be used. To facilitate clearance and to avoid impair- of energy expenditure in preterm infants with birth weight less than
ment of oxygenation, lipids should be infused over a 24-hour 1000 g. Br J Nutr. 2003;89:533-537.
period. There is currently no evidence to support the use of cyclic Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Early insulin
infusion in the acute setting of the NICU. therapy in very-low-birth-weight infants. N Engl J Med. 2008;359:
Caloric goals during parenteral nutrition are lower than with 1873-1884.
enteral feeds. To achieve optimal protein retention, approximately Denne S. Protein and energy requirements in preterm infants. Semin
70–80 kcal/kg per day is a reasonable goal. To optimize growth, Neonatol. 2001;6:377-382.
somewhat higher caloric intakes may be necessary. The nonprotein Embleton ND, Morgan C, King C. Balancing risks and benefits of
balance between carbohydrate and lipid should be approximately parenteral nutrition for preterm infants: can we define the optimal
composition? Arch Dis Child Fetal Neonatal Ed. 2015;100:
60 : 40. These goals can usually be achieved using glucose solutions F72-F75.
with concentrations no greater than 12.5% (Table 69.6). Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity
There is a paucity of data related to monitoring laboratory tests and mortality for very low birthweight infants. Am J Obstet Gynecol.
during provision of parenteral nutrition. Suggested monitoring 2007;196(147).
for infants receiving parenteral nutrition is shown in Table 69.7. Morgan C, McGowan P, Herwtker S, Hart AE, Turner MA. Postnatal
Not all of these laboratory tests may be appropriate in ELBW head growth in preterm infants: a randomized controlled parenteral
infants because of constraints related to blood sampling. nutrition study. Pediatrics. 2014;133:e120-e128.
The use of parenteral nutrition should be accompanied by the Nandivada P, Carlson SJ, Chang MI, Cowan E, Gura KM, Puder M.
early initiation of enteral feeds (ideally on the first day). Parenteral Treatment of parenteral nutrition-associated liver disease: the role of
nutrition should be continued until enteral feedings are well lipid emulsions. Adv Nutr. 2013;4:711-717.
Stephens BE, Walden RV, Gargus RA, et al. First-week protein and
established and providing approximately 100–110 kcal/kg per day, energy intakes are associated with 18-month developmental out-
although availability of IV access may necessitate earlier termination comes in extremely low birth weight infants. Pediatrics. 2009;123:
of parenteral nutrition in some circumstances. As enteral feeds are 1337-1343.
advanced, the protein and lipid contents of the parenteral nutrition Thureen PJ, Melara D, Fennessey PV, Hay WW Jr. Effect of low versus
can be gradually decreased. In addition, careful and prompt attention high intravenous amino acid intake on very low birth weight infants
to reinstitution of parenteral nutrition during episodes of intolerance in the early neonatal period. Pediatr Res. 2003;53:24-32.
CHAPTER 69  Parenteral Nutrition for the High-Risk Neonate 1031

Uthaya S, Modi N. Practical preterm parenteral nutrition: systematic Vlaardingerbroek H, Veldhorst MAB, Spronk S, van den Akker CH, van
literature review and recommendations for practice. Earl Hum Dev. Goudoever JB. Parenteral lipid administration to very-low-birth-weight
2014;90:747-753. infants—early introduction of lipids and use of new lipid emulsions: a
Vanek VW, Boren P, Buchman A, et al. A.S.P.E.N. position paper: systematic review and meta-analysis. Am J Clin Nutr. 2012;96:255-268.
recommendations for changes in commercially available parenteral
multivitamin and multi-trace element products. Nutr Clin Pract. Complete references used in this text can be found online at www
2012;27:440-491. .expertconsult.com
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