Neonatal parenteral nutrition

The use of new lipid sources and early parenteral in the post-natal period may have an impact on long-term growth and health of neonates and premature infants

Venetia Simchowitz (née Horn) MRPharmS IPres MFRPSII PG Dip MSc
Senior Specialist Pharmacist – Clinical Nutrition & NICU, Great Ormond St Hospital for Children NHS Foundation Trust, London, UK

The use of new lipid sources and early parenteral in the post-natal period may have an impact on long-term growth and health of neonates and premature infants

Nutrition is one of the key factors for normal cell growth and development. For infants, and during early childhood, the therapeutic goal is to ensure that nutritional intake is sufficient to provide nutrients for maintenance of body tissues and balanced somatic growth. Malnutrition, particularly in the last trimester of pregnancy and first two years of life, will lead to stunting of growth and may be associated with neurodevelopmental outcomes such as intellectual impairment.

For the premature infant, there are limited body stores, immature body functions (gastrointestinal, renal, and metabolic), rapid tissue differentiation and organ development and therefore an increased nutrient requirement per kilogram body weight. The neonatal brain is sensitive to periods of malnutrition and metabolic insult during this period of rapid growth.

Energy and protein requirements need to be met to address ‘catch up’ growth, which is beneficial for neurodevelopment, but the consequences of nutritional programming or the ‘early origins of adult disease’ also need to be considered.

Parenteral nutrition
Parenteral nutrition (PN) should be initiated when normal metabolic and nutritional needs are not met by enteral feeding in patients with adequate intestinal function. Premature infants by nature of their prematurity and co-existing problems (necrotising enterocolitis, patent ductus arteriosus) will require nutritional support in the form of PN while enteral feeds are graded up or while recovering from gastrointestinal surgery. PN in a small infant who cannot tolerate feeds may be a matter of urgency due to the limited energy reserves. A preterm infant of 1kg, who has perhaps no more than 10g of storage fat, might survive for only four days if starved.¹

Fluid requirements
The requirement for fluid to body weight is much greater in very small children. Infants have a much larger body surface area relative to weight than older patients and lose more fluid through evaporation and dissipate much more heat per kilogram than their older counterparts, which accounts for the increased requirements. Fluid balance and hydration status can be monitored by regularly weighing the patient.

Energy requirements
Nutritional requirements differ according to age and are affected by the underlying disease and current nutritional status of the child. Energy requirements may be increased when the body is under catabolic stress, fever or sepsis or if there is failure to thrive. Suboptimal nutrition may be due to fluid restriction, lack of central access, and a build up of nutrition over several days. But in the critically ill child in the acute phase of illness, basal energy requirements will only need to met.¹ Catch-up growth may be achieved when more liberal volumes of fluid are available in the recovery phase.

Sufficient non-protein calories, as carbohydrate and fat, must be provided to meet basal metabolic energy demands and to ensure growth and development. An unbalanced substrate supply can lead to a high risk of physiological consequences (steatosis, hyperglycaemia, liver dysfunction).

Without adequate non-protein calories, the body uses protein for muscle, visceral protein, or protein from PN as a calorie source; conversely, excess calories with insufficient protein will be deposited as fat. For efficient protein anabolism, the energy to nitrogen ratio (kcals: 1g N ratio) should be less than 250 or 30–40kcals per gram of protein Minimum energy requirements in preterm infants will be met by providing 45–55kcals/kg/day (including protein) although 90–120kcals/kg/day will maximise protein accretion.¹

Protein requirements
Protein (nitrogen) is needed for growth and the formation of new tissues and the synthesis of plasma proteins, enzymes and blood cells. The protein required by the human body is manufactured from 20 different amino acids. Some of the amino acids become ‘conditionally essential’ in premature infants due to immaturity of the metabolic pathways and include cysteine, taurine, glutamine, tyrosine and histidine. Metabolic acidosis was common in the 1980s when casein-based adult solutions were used for premature infants who lack the ability to synthesise or metabolise some of these non-essential amino acids, such as phenylalanine, and tyrosine, which could lead to neurotoxicity.

The current solutions used in premature infants contain crystalline L-amino acids with a higher composition of branched chain amino acids (for example, isoleucine, leucine and valine) and a reduced amount of phenylalanine and tyrosine. The composition of the amino acid solutions are based on either breast milk or cord blood amino acid profiles. Branched chain amino acids produce greater rates of protein synthesis and accretion from amino acids.

At birth, the supply of nutrients from the placenta rapidly ceases. The infant becomes dependent upon its own protein stores for protein catabolism. In extremely low birth weight infants who receive glucose alone, 1.2g/kg/day of protein or 1–2% of their endogenous body protein stores are lost per day therefore a catabolic state may be reached in the first few days’ post-natal life without an adequate supply of protein. This accounts for the negative nitrogen balance seen in premature infants upon discharge from the neonatal intensive care unit due to insufficient nutrition and protein intake.

Neonates have a high rate of whole body protein synthesis and the aim is to promote a positive nitrogen balance and optimise growth and development without causing metabolic acidosis from excess protein intake. A high intake is required to achieve physiological protein deposition and potentiates the anabolic effect of insulin. Intrauterine accretion rates have been used to estimate protein requirements in the neonate.

Aggressive and early introduction of amino acids with glucose on day one of life has been found to be safe in premature infants and will decrease protein catabolism and enhances net protein accretion. Recent studies, have demonstrated that premature infants who receive high amino acid intake approaching in utero accretion rates on day 1 of life achieve better short term growth at 36 weeks and less growth failure though there is little evidence to show long term growth or neurodevelopmental benefits.^1,2

Protein needs in infants and children who are malnourished or acutely stressed by infection or trauma can be increased, whereas patients who are in renal or liver failure require less protein, depending upon medical management.

Carbohydrates
In the last trimester of pregnancy, the foetus receives approximately 5mg/kg/min glucose or 7g/kg/day from the placenta.¹ Glucose is utilised by all cells in the body and serves as a metabolic fuel for the liver, gastrointestinal tract, muscle, heart and kidneys, and provides an energy source for the brain, erythrocytes and renal medulla. It should provide approximately 40–60% of the total non-protein calorie intake. Glucose intake should be adapted to age and clinical situation, for example, premature infants, critically ill patients. Premature infants have relatively high requirements due to the large body proportions of metabolically active organs. The majority of the basal glucose requirement is required to maintain adequate energy for the brain.

At birth, the placental supply of protein and glucose stops. Initially glucose is produced by glycogenolysis but due to limited glycogen stores, gluconeogenesis becomes the principal source of hepatic glucose production. The ability to convert glucose into glycogen starts when the foetus reaches the third trimester. Alternative energy substrates such as ketones are limited in infants at early gestational age due to low fat stores therefore a constant supply of glucose for energy is essential.

In preterm infants, glucose infusion should start with a minimum of 4mg/kg/min (5.8g/kg/day) to suppress hepatic glucose output.¹ It should be increased slowly (1–3g/kg/day increments) to prevent hyperglycaemia and glycosuria and allow an appropriate response of endogenous insulin. The inability to suppress glucose production or gluconeogenesis in extreme preterm infants may contribute to the risk of hyperglycaemia. Hyper- or hypoglycaemia in an individual previously stable on PN may indicate sepsis.

Recent studies have questioned the provision of high glucose loads to preterm infants less than 31 weeks of life as hyperglycaemia increases morbidity and mortality.³ Management of hyperglycaemia involves a reduction of glucose intake and/or administration of insulin when the blood sugar measurement is >10mmol/l. Care must be taken with insulin to avoid hypoglycaemia and brain hypoxia. The argument against prolonged severe restriction of parenteral glucose is that it may substantially reduce calorie intake and hence growth.

When the glucose intake exceeds oxidative capacity, glucose is converted into fat and deposited in the liver. Net lipogenesis occurs at glucose intakes of more than 18g/kg/day in infants (12.5mg/kg/min). The conversion of glucose to fat is an energy inefficient process, which leads to increased energy expenditure, increased oxygen consumption and increased carbon dioxide production. Excessive glucose intakes are thought to increase carbon dioxide production, which may have an effect on the weaning infants off artificial ventilation and contribute towards the development of liver impairment due to steatosis.

Lipid requirements
Lipid emulsions are an important component of a balanced PN regimen. They provide high energy needs without carbohydrate overload, improve the net nitrogen balance and prevent essential fatty acids deficiency. Lipids are incorporated into the structural components of cell and plasma membranes and are used for prostaglandin synthesis and platelet function. Lipid intake should usually cover 25–40% of non-protein calories in fully parenterally fed patients. Maximum fat oxidation occurs when lipids provide 40% of the non-protein PN calories in newborns and 50% in infants.

Traditional lipid emulsions contain a mixture of egg phospholipids, soybean oil and glycerol. The soybean oil provides essential linoleic (omega 6), alpha-linolenic acid (omega 3) and other long chain polyunsaturated fatty acids (LC-PUFA). Long chain fatty acids are essential to the newborn for brain and retina development and so should be introduced on day 1 of PN. Biochemical evidence of essential fatty acid deficiency may develop in one to two days in the premature infant, where there are limited fat stores, and a diet without lipid. The recommended minimum linoleic acid content for premature infants is 0.25g/kg/day and 0.1g/kg/day in term infants;¹ this requirement can be met using a traditional lipid emulsion in 0.5g/kg/day of a 20% solution. Omega 3 essential fatty acids (eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) are more important than omega 6 for brain development and complex neural function. They have positive effects on the immune system and are anti-inflammatory.

Small-for-gestational-age neonates and low-birth weight infants may have a limited ability to metabolise fat and should have their serum triglyceride concentrations monitored. Lipid clearance is maximised when the solution is infused over 24 hours as a continuous rather than an intermittent infusion¹. If plasma triglyceride concentrations during infusion exceed 250mg/dl or 2.82mmol/l, a reduction of lipid intake in newborns, premature and young infants should be considered.

There is no evidence to support routine lipid reduction in critically ill or infected patients and lipid may be the preferred energy source in sepsis. Lipid emulsions have been shown to inhibit bacterial clearance and depress platelet function. However, white cell function is normal when usual doses of fat are infused over a prolonged period of time. The monitoring of plasma triglyceride levels and dose adjustment in case of lipid intolerance are recommended in these patients.

Newer lipid emulsions have become available on the market and are licensed in paediatric patients. All contain LCT in varying proportions, which provide the essential fatty acids. These new lipid emulsions contain a combination of soybean oil and either olive oil, or medium chain triglycerides (LCT/MCT) or a combination of lipids (LCT/MCT/olive oil/fish oil) (Table 1).

Complications
Long-term complications of PN mainly relate to liver dysfunction especially with the sole use of traditional omega 6 lipid emulsions. The development of liver dysfunction is multifactorial but an excess of omega 6, increased intake of phytosterols, lack of enteral feeding and continuous PN over 24 hours are thought to contribute.^1,4 The rationale for the new lipid emulsions is the reduction in omega 6, phytosterols and the addition of antioxidant vitamin E and anti-inflammatory fish oils. The evidence is still limited, although there have been good results using either sole fish oil or combination fish oil in reversal of liver dysfunction. The complete lack of essential fatty acid (omega 6) content in the fish oil preparation would preclude use in premature infants.

Other complications include trace element and vitamin deficiencies especially for neonates post resection. Nutritional monitoring of these micronutrients should be undertaken on a monthly basis. Supplemental zinc, copper, selenium and fat-soluble vitamins may be added to the PN as required within stability of the formulation.^1,2

Other factors
Osmolarity
Other considerations that need to be taken into account when prescribing PN include the type of intravenous access, available volume and stability. If a patient is fluid-restricted with only a peripheral venous cannula, then full nutritional requirements will not be met. PN is considered to be peripheral if the glucose concentration of the formulation is <12.5% glucose but the protein and electrolyte content are equally important. If the PN has an osmolarity of >900mosmol/l,^2,5,6 then there is an increased risk of thrombophlebitis and extravasation and the formulation would only be suitable for infusion via a central venous line.

Non-clinical issues
The NHS has a reduced capacity for manufacturing, lack of appropriate facilities and skilled staff and lack of capital investment has led to the use of external suppliers or ‘outsourcing’. Aseptic manufacture is a complex and high-risk process where compounding errors and microbial contamination have led to patient harm and, in a few cases, death. The use of a standardised approach to PN in the context of short-term PN has been recommended by the Chief Pharmacists’ group^7,8 to improve risk management of the PN process.

The current debate in neonatal PN
Many preterm infants exhibit growth failure during their stay in the ICU due to inadequate nutrition. A deficit in calories leads to neurodevelopmental impairment due to poor brain growth. The ultimate goal therefore is not only to prevent growth failure but also to avoid inappropriate body composition with the associated adverse metabolic effects such as insulin resistance due to gain in adipose rather than lean tissue.^1,2

The first debate involves the two large-scale trials that have been published in the last few years with very different approaches to PN in neonates and, in particular, premature infants. The aim for both trials was to promote growth and, in particular, head circumference. The NEON trial³ of preterm infants of <31 weeks gestation proposed a peripheral PN with low calorie provision as an adjunct to rapid enteral feed progression. Patients either received a low or high protein intake. The results found poorer brain growth among the cohort with high protein PN. Conversely, the SCAMP trial⁹ in premature infants <29 weeks’ gestation used concentrated central PN with a more generous calorie provision and higher protein content based on previous trial data and found early brain growth that was still evident at 36 weeks’ corrected gestational age.

The other topic of debate involves the multi-centre PEPaNic trial10 in critically ill children in intensive care. This was an unblinded trial of delayed PN (starting eight days post-admission) versus supplemental PN initiated on day 1 of admission to PICU. The main outcome was fewer new infections (p<0.001); in particular, airway and bloodstream infections (p<0.002) in the late group, and reduced stay in the PICU. The trial authors recommended delayed PN to all patient groups including neonates; but premature infants were excluded from the trial and only a small proportion of term neonates (15%) were enrolled. These patients were predominantly cardiac patients with the lowest weight specified in the paper of 4.5kg. There were no standard protocols for calorie provision or enteral feeding across the three centres although the authors state that this did not have any effect on the results. Of note, 75% of the late group were discharged from ICU by day 7 so did not receive any PN. This makes the data difficult to extrapolate to clinical practice.

It is worth noting that the evidence base for neonatal PN is sparse, with few randomised controlled trials, many of which are underpowered due to low patient numbers. Recommendations tend to be consensus driven.^1,2,11

The role of the pharmacist
Pharmacists are at the heart of the multi-disciplinary team caring for preterm and term infants. They provide advice for appropriate choices of drug therapy, drug adjustments for multi-organ failures, drug compatibilities and many now provide an extended role as independent prescribers for both PN and for medicines. They can also play an integral role in the development of national and international guidelines.

As one of two pharmacists invited to participate in the ESPEN/ESPGHAN 2005 guidelines for paediatric parenteral nutrition,¹ and the sole pharmacist for the update in 2015 (pending publication in 2017), I helped to provide practical advice on stability, suitability of the substrates, and provided input to the consensus of the complete guideline.

Conclusions
Appropriate nutrition in the premature infant is paramount for providing the substrates required at a time of rapid growth and development. The use of new lipid sources and early PN post-natally may have an impact on long-term growth and health.

Key points

Parenteral nutrition (PN) should only be initiated when normal metabolic and nutritional needs are not met by enteral feeding in patients with adequate intestinal function.
The neonatal brain is sensitive to periods of malnutrition and metabolic insult during this period of rapid growth.
Early introduction of amino acids with glucose on day one of life has been found to be safe in premature infants and will decrease protein catabolism and enhances net protein accretion.
Lipid emulsions are an important component of a balanced PN regimen.They provide high energy needs without carbohydrate overload, improve the net nitrogen balance and prevent essential fatty acids deficiency.
Aseptic manufacture is a complex and high- risk process that risks compounding errors and microbial contamination. The use of standardised PN in the short term is recommended by the Chief Pharmacists group.

References

Koletzko B et al; for the Parenteral Nutrition Guidelines Working Group. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Paediatr Gastroenterol Nutr 2005;41(Suppl 2):S1–87.
Worthington P et al. When is PN appropriate? JPEN J Parenter Enteral Nutr 2017;38:334–77.
Uthaya S et al. Nutritional evaluation and optimisation in neonates: a randomized, double-blind controlled trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition. Am J Clin Nutr 2016;103:1443–5.
Wales P et al. A.S.P.E.N clinical guidelines: Support of pediatric patients with intestinal failure at risk of parenteral nutrition associated liver disease. JPEN J Parenter Enteral Nutr 2014;38:538–57.
Boullata JI et al. ASPEN clinical guidelines: parenteral nutrition ordering, order review, compounding, labelling, and dispensing. JPEN J Parenter Enteral Nutr 2014;38:334–77.
Dugan S, Le J, Jew RK. Maximum tolerated osmolarity for peripheral administration of parenteral nutrition in pediatric patients. JPEN J Parenter Enteral Nutr 2014;38:847–51.
Mason DG et al. Parenteral nutrition for neonates and children: a mixed bag. Arch Dis Child 2011;96:209–10.
Paediatric Chief Pharmacist Group. Improving practice and reducing risk in the provision of parenteral nutrition for neonates and children. 2011. www.rpharms.com/support-pdfs/minimising-risk-pn-children-(6).pdf (accessed April 2017).
Morgan C et al. Postnatal head growth in preterm infants: A randomized controlled parenteral nutrition study. Pediatrics 2014;133:e120–128.
Fivez T et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med 2016;374(12):1111–22.
British Association of Perinatal Medicine. The provision of parenteral nutrition within neonatal services – A Framework for Practice. 2016. www.bapm.org/publications/documents/guidelines/Parenteral%20Nutrition%20April%202016.pdf (accessed April 2017).

Neonatal parenteral nutrition

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