A report published by the Kings Fund Report (1992) highlighted the issue of malnutrition both in the hospital and home setting. The findings led to the development of the British Association of Enteral and Parenteral Nutrition (BAPEN) and nutrition support teams throughout the UK. These multidisciplinary nutrition support teams comprise a doctor, nurse, pharmacist and dietitian. They function in a variety of ways, depending on the patient populations and resources. In general, they adopt either a consultative or an authoritative role in nutrition management. Many studies have shown their positive contribution to the total nutritional care of the patient through efficient and appropriate selection and monitoring of feed and route.

Components of a PN regimen

In addition to water, six main groups of nutrients need to be incorporated in a PN regimen (Table 7.2). The aim is to provide appropriate sources and amounts of all the equivalent building blocks in a single daily admixture.

Table 7.2 Oral and equivalent parenteral nutrition source

Oral diet	Parenteral nutrition source
Water	Water
Protein	L-amino acids mixture
Carbohydrate	Glucose
Fat with essential fatty acids	Lipid emulsions with essential fatty acids
Vitamins	Vitamins
Minerals	Trace elements
Electrolytes	Electrolytes

Water volume

Water is the principal component of the body and accounts for approximately 60% and 55% of total body weight in men and women, respectively. Usually, homeostasis maintains appropriate fluid levels and electrolyte balance, and thirst drives the healthy person to drink; however, some patients are not able physically to respond by drinking and so this homeostasis is ineffective. There is risk of over- or underhydration if the range of factors affecting fluid and electrolyte balance is not fully understood and monitored. In general, an adult patient will require 20–40 ml/kg/day fluid; however, Table 7.3 describes other factors that should be considered in tailoring input to needs.

Table 7.3 Factors affecting fluid requirements

Consider increasing fluid input	Consider reducing fluid input
Signs/symptoms of dehydration	Signs/symptoms of fluid overload
Fever: increased insensible losses from lungs in hyperventilation and from skin in sweating. Allow 10–15% extra water per 10°C above normal	High humidity: reduced rate of evaporation
Acute anabolic state: increased water required for increased cell generation	Blood transfusion: volume input
High environmental temperature or low humidity: increased rate of evaporation	Cardiac failure: may limit tolerated blood volume
	Drug therapy: assess volume and electrolyte content of infused drug
Abnormal GI loss (vomiting, wounds, ostomies, diarrhoea): consider both volume loss and electrolyte content
Burns or open wound(s): increased water evaporation
	Renal failure: fluid may accumulate so reduce input accordingly or provide artificial renal support
Blood loss: assess volume lost and whether replaced by transfusion, colloid, crystalloid

Amino acids

Twenty l-amino acids are required for protein synthesis and metabolism, and the majority of these can be synthesised endogenously. Eight are called ‘essential’ amino acids because they cannot be synthesised (isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine). A further group of ‘conditionally essential’ amino acids (arginine, choline, glutamine, taurine and S-adenosyl-l-methionine) are defined as the patient’s needs exceed synthesis in clinically stressed conditions. Also, due to the immature metabolic pathways of neonates, infants and children, some other amino acids are essential in the young patient, and these include histidine, proline, cysteine, tyrosine and taurine. Immature neonatal metabolism does not fully metabolise glycine, methionine, phenylalanine and threonine and so requirements are reduced.

To balance the patient’s amino acid requirements and the chemical characteristics of the amino acids (solubility, stability and compatibility), a range of commercially available licensed solutions has been formulated containing a range of amino acid profiles (Table 7.4). Aminoplasmal®, Aminoven, Synthamin® and Vamin® are designed for adult patients. The amino acid profiles of Primene® and Vaminolact® are specifically tailored to neonates, infants and children (reflecting the amino acid profile of maternal cord blood and breast milk, respectively).

Table 7.4 Examples of amino acid and consequential nitrogen content of licensed amino acid solutions available in the UK

Name	Nitrogen content (g/L)	Electrolytes present
Aminoplasmal® 5% E	8	Potassium, magnesium, sodium and dihydrogen phosphate
Aminoplasmal® 10%	16
Aminoven® 25	25.7
Glamin®	22.4
Hyperamine® 30	30	Sodium
Primene® 10%	15
Synthamin® 9	9.1	Potassium, magnesium, sodium and acid phosphate
Synthamin® 9 EF	9.1
Synthamin® 14	14	Potassium, magnesium, sodium and acid phosphate
Synthamin® 14 EF	14
Synthamin® 17	17	Potassium, magnesium, sodium and acid phosphate
Synthamin® 17 EF	17
Vamin® 9 Glucose	9.4	Potassium, magnesium, sodium and calcium
Vamin® 14	13.5	Potassium, magnesium, sodium and calcium
Vamin® 14EF	13.5
Vamin® 18EF	18
Vaminolact®	9.3

l-glutamine was initially excluded from formulations due to its low solubility and relatively poor stability in the aqueous environment; however, it is recognised that there is a clinical need for this amino acid in catabolic stress, and it is now available as an additive (Dipeptiven®) and as an amino acid solution containing a dipeptide form of glutamine (Glamin®) in which the peptide bond cleaves in the blood, releasing free l-glutamine. Research is also considering the rationale and merits of supplementing arginine, glutathione and ornithine α-ketoglutarate.

For adults, PN solutions are generally prescribed in terms of the amount of nitrogen they provide, rounding to the nearest gram; for example, 9, 11, 14 or 18 g nitrogen regimens may be prescribed. Assuming adequate energy is supplied, most adult patients achieve nitrogen balance with approximately 0.2 g nitrogen/kg/day, although care should be taken with overweight patients.

A 24-h urine collection can be used as an indicator of nitrogen loss, assuming all urine is collected and urea or volume output is not compromised by renal failure; however, a true nitrogen output determination requires measurement of nitrogen output from all body fluids, including urine, sweat, faeces, skin and wounds. Nitrogen balance studies can indicate the metabolic state of the patient (positive balance in net protein synthesis, negative balance in protein catabolism). Urinary urea constitutes approximately 80% of the urinary nitrogen. The universally accepted conversion factor for nitrogen to protein is 1 g nitrogen per 6.25 g of protein.

Amino acid solutions are hypertonic to blood and should not be administered alone into the peripheral circulation.

Energy

Many factors affect the energy requirement of individual patients and these include age, activity and illness (both severity and stage). Predictive formulae can be applied to estimate the energy requirement, for example, the Harris Benedict equation or the more commonly used Schofield equation, which is shown below in Table 7.5.

Table 7.5 Schofield equation

Age (years)	Male	Female
15–18	BMR = 17.6 × weight (kg) + 656	BMR = 13.3 × weight (kg) + 690
18–30	BMR = 15.0 × weight (kg) + 690	BMR = 14.8 × weight (kg) + 485
30–60	BMR = 11.4 × weight (kg) + 870	BMR = 8.1 × weight (kg) + 842
>60	BMR = 11.7 × weight (kg) + 585	BMR = 9.0 × weight (kg) + 656

BMR, basal metabolic rate.

Alternatively, calorimetry techniques can be used; however, no single method is ideal or suits all scenarios. Often it is found that two methods result in different recommendations. The majority of adults can be appropriately maintained on 25–35 non-protein kcal/kg/day. There is debate over whether to include amino acids as a source of calories since it is simplistic to assume they are either all spared for protein synthesis or fed into the metabolic pathways (Krebs cycle) and contribute to the release of energy-rich molecules. In general, we refer to ‘non-protein energy’ and sufficient lipid and glucose energy is supplied to spare the amino acids. As a rough guide, the non-protein energy-to-nitrogen ratio is approximately 150:1, although an ideal ratio for all patients has not been absolutely defined. A lower ratio is considered for critically ill patients, while higher ratios are considered for less catabolic patients.

Dual energy

In general, energy should be sourced from a balanced combination of lipid and glucose; this is termed ‘dual energy’ and is more physiological than an exclusive glucose source. Typically, the fat-to-glucose ratio remains close to the 60:40–40:60 ranges.

Dual energy can minimise the risk of giving too much lipid or glucose since complications increase if the metabolic capacity of either is exceeded. A higher incidence of acute adverse effects is noted with faster infusion rates and higher total daily doses, especially in patients with existing metabolic stress. It is, therefore, essential that the administered dose complements the energy requirements and the infusion rate does not exceed the metabolic capacity.

While effectively maintaining nitrogen balance, lipid inclusion is seen to confer a number of advantages (Box 7.1). Some patients, notably long-term home patients, do not tolerate daily lipid infusions and need to be managed on an individual basis. Depending on the enteral intake and nutritional needs, lipids are prescribed for a proportion of the days. A trial with the newer generation lipid emulsions may be appropriate.

Glucose

Glucose is the recommended source of carbohydrate (1 g anhydrous glucose provides 4 kcal). Table 7.6 indicates the energy provision and tonicity for a range of concentrations. Glucose 5% is regarded as isotonic with blood. The higher concentrations cause phlebitis if administered directly to peripheral veins and should, therefore, be given by a central vein or in combination with compatible solutions to reduce the tonicity.

Table 7.6 Energy provision and tonicity of glucose solutions

Concentration (w/v)	Energy content (kcal/L)	Osmolarity (mOsmol/L)
5%	200	278
10%	400	555
20%	800	1110
50%	2000	2775
70%	2800	3885

The glucose infusion rate should generally be between 2 and 4 mg/kg/min. An infusion of 2 mg/kg/min (equating to approximately 200 g (800 kcal) per day for a 70 kg adult) represents the basal glucose requirement, whereas 4 mg/kg/day is regarded as the physiological optimal rate. Higher levels are tolerated by some patients especially those at home on PN, but monitoring of blood glucose is required at least initially. Care needs to be taken as glucose oxidation occurs, but there is an increased conversion to glycogen and fat. If excess glucose is infused and the glycogen storage capacity exceeded, the circulating glucose level rises, de novo lipogenesis occurs (production of fat from glucose) and there is an increased incidence of metabolic complications.

Lipid emulsions

Lipid emulsions are used as a source of energy and for the provision of the essential fatty acids, linoleic and alpha-linolenic acid. Supplying 10 kcal energy per gram of lipid, they are energy rich and can be infused directly into the peripheral veins since they are relatively isotonic with blood.

Typically, patients receive up to 2.5 g lipid/kg/day. For practical compounding reasons, and assuming clinical acceptance, this tends to be rounded to 100 g or 50 g. Details of lipid emulsions available within the UK can be found in Table 7.7.

Table 7.7 Examples of licensed lipid emulsions available in the UK

Lipid emulsion type	Details of products with kJ per litre
Soybean oil	Intralipid® 10% (4600), 20% (8400), 30% (12600)
Purified olive oil/soybean oil	ClinOleic® 20% (8360)
Medium chain triglycerides/soybean oil	Lipofundin® MCT/LCT 10% (4430), 20% (8000)
Purified structured triglycerides	Structolipid® 20% (8200)
Omega-3-acid triglycerides/soybean oil/medium chain triglycerides	Lipidem® (7900)
Highly refined fish oil	Omegaven® (4700)
Fish oil/olive oil/soybean oil/medium chain triglycerides	SMOFLipid® (8400)

Lipid emulsions are oil-in-water formulations. Figure 7.2 shows the structure of triglycerides (three fatty acids on a glycerol backbone) and a lipid globule, stabilised at the interface by phospholipids. Ionisation of the polar phosphate group of the phospholipid results in a net negative charge of the lipid globule and an electromechanically stable formulation. The lipid globule size distribution is similar to that of the naturally occurring chylomicrons (80–500 nm), as indicated in Fig. 7.3.

Fig. 7.2 Triglyceride structure and composition of lipid emulsion globule.

Fig. 7.3 Lipid globule size distribution curve of Ivelip® 20%.

The first-generation lipid emulsions have been in use since the 1970 s and utilise soybean oil as the source of long chain fatty acids. More recent research on lipid metabolic pathways and clinical outcomes has indicated that the fatty acid profile of soybean oil alone is not ideal. For example, it is now recognised that these lipid emulsions contain excess essential polyunsaturated fatty acids, resulting in a qualitative and quantitative compromise to the eicosanoid metabolites that have important roles in cell structure, haemodynamics, platelet function, inflammatory response and immune response.

The molecular structure of the fatty acids has an important impact on the patient’s oxidative stress. Two strategies have been applied to overcome this: a reduction in the polyunsaturated fatty acid content through an improved balance of fatty acids or the inclusion of medium chain fatty acids. This has resulted in the development of lipid emulsions that include olive oil (rich in monounsaturated oleic acid and antioxidant α-tocopherol with an appropriate level of essential polyunsaturated fatty acids), fish oil (rich in omega 3 fatty acids) and medium chain triglycerides or structured triglycerides (reduced long chain fatty acid content). Clinical application of these newer lipid emulsions depends upon good clinical studies within the relevant patient population. Such studies should evaluate the efficacy of energy provision and clinical tolerance and report improvements in the eicosanoid-dependent functions or oxidative stress.

Both egg and soybean phospholipids include a phosphate moiety. There is a debate as to whether this is bioavailable. Therefore, some manufacturers include the phosphate content in their stability calculations, while others do not.

The 20% lipid emulsions are favoured, especially in paediatrics, as they contain less phospholipid than the 10% emulsions in relation to triglyceride provision. If there is incomplete clearance of the infused phospholipids, lipoprotein X, an abnormal phospholipid-rich low-density lipoprotein, is generated and a raised blood cholesterol observed. The incidence of raised lipoprotein X levels is greater with the 10% emulsions as they present proportionally more phospholipid.

Lipid clearance monitoring is particularly important in patients who are at risk of impaired clearance, including those who are hyperlipidaemic, diabetic, septic, have impaired renal or hepatic function or are critically ill (Crook, 2000).

Micronutrients

Micronutrients have a key role in intermediary metabolism, as both co-factors and co-enzymes. For example, zinc is required by over 200 enzyme systems and affects many diverse body functions including acid–base balance, immune function and nucleic acid synthesis. It is evident, therefore, that the availability of micronutrients can affect enzyme activity and total metabolism. When disease increases the metabolism of the major substrates, the requirement for micronutrients is increased. Some of the micronutrients also play an essential role in the free radical scavenging system. These include the following:

• copper, zinc and manganese, in the form of superoxide dismutase, dispose of superoxide radicals

• selenium, in the form of glutathione peroxidase, removes hydroperoxyl compounds

• vitamin C is a strong reducing agent

• vitamins A, E and ß-carotene react directly with free radicals

By the time a patient starts PN, they may have already developed a deficiency of one or more essential nutrients. By the time a specific clinical deficiency is observed, for example, depigmentation of hair in copper deficiency or skin lesions in zinc deficiency, the patient will already have tried to compensate to maintain levels, compromised intracellular enzyme activity and antioxidant systems and expressed non-specific symptoms such as fatigue and impaired immune response. A summary of factors that affect micronutrient needs is presented in Box 7.2.

Measuring blood levels of vitamins and trace elements in acutely ill patients is of limited value. It is recommended that these are measured every 1–6 months depending on levels, and in patients at home on PN (NICE, 2006). Deficiency states are clinically significant but, with non-specific symptoms, they are often difficult to diagnose.

Micronutrient experts prefer to prevent a deficit developing and compromising the clinical state, rather than perform regular monitoring of blood results.

Micronutrients should be included daily from the start of the PN. The requirements are increased during critical illness and in chronically depleted patients. Patients with major burns and trauma or with artificial renal support can quickly become depleted. Their supplementation may influence the outcome of the disease. Even if the patient has reasonable levels and reserves initially, they can quickly become depleted if they are not supported by daily administration. Additional oral or enteral supplements may be considered if there is some intestinal absorption. However, copper deficiency can increase iron absorption and zinc intake can decrease copper absorption.

The micronutrients naturally fall into two groups: the trace elements and vitamins. Micronutrients should be added to all PN infusions under appropriate, controlled, environmental conditions prior to administration (NICE, 2006).

Trace elements

Trace elements are generally maintained at a relatively constant tissue concentration and are present to a level of less than 1 mg/kg body weight. They are essential; deficiency results in structural and physiological disorders which, if identified early enough, can be resolved by re-administration. Ten essential trace elements are known: iron, copper, zinc, fluorine, manganese, iodine, cobalt (or as hydroxycobolamin), selenium, molybdenum and chromium. Adult reference ranges for daily requirements of trace metals can be found in Table 7.8. Currently two preparations are commercially available for adults (Decan®, Additrace®) together with a single paediatric preparation (Peditrace®).

Table 7.8 Adult daily reference range for trace elements

Vitamins

There are two groups of vitamins: the water-soluble vitamins and the fat-soluble vitamins. Fat-soluble vitamins are stored in the body fat, whereas excess water-soluble vitamins are renally cleared; therefore, if there is inadequate provision, deficiency states for the water-soluble vitamins reveal themselves first. The adult reference range for daily requirements of vitamins can be found in Table 7.9. Commercially available preparations are Solivito® N (water soluble), Vitlipid® N Adult/Infant (fat soluble), Cernevit® (water and fat soluble).

Table 7.9 Adult daily reference ranges for vitamins

In an attempt to reduce the risk of osteoporosis, especially in home PN patients, there have been recent changes to recommended biochemical vitamin D levels (Holick, 2007). Patients on long-term PN should have vitamin D levels measured every 6 months. If low, this should be supplemented in order to help protect against osteoporosis which is a well recognised complication of home PN.

Electrolytes

Electrolytes are included to meet the patient’s needs. Typical daily parenteral requirements are

• sodium (1–1.5 mmol/kg)

• potassium (1–1.5 mmol/kg)

• calcium (0.1–0.15 mmol/kg)

• magnesium (0.1–0.2 mmol/kg)

• phosphate (0.5–0.7 mmol/kg).

Depending upon the stability of the patient’s clinical state, they are kept relatively constant or adjusted on a near daily basis, reflecting changes in blood biochemistry. Tables, for example, British National Formulary can be used to guide electrolyte replacement if there is excessive gastro-intestinal waste or high losses through burns. Hypophosphataemia should be corrected before starting parenteral or enteral nutrition to avoid the refeeding syndrome. Varying amounts of electrolytes are lost from the different gastro-intestinal secretions. Table 7.10 gives an indication of the content of various gastro-intestinal secretions. This should be taken into account when formulating PN for a patient who may have such losses.

Table 7.10 Electrolyte content of gastro-intestinal secretions

Administration of PN

Routes of administration

PN can be administered peripherally or centrally.

Peripheral route

Administration of PN via a peripheral venous catheter should be considered for patients who are likely to need short-term feeding (less than 14 days) and who have no other need for central venous access. Peripheral lines are less costly than central lines and they may be inserted at the bedside providing the patient has good venous access. Ultrasound machines may be used to aid placement. There is no need for a chest X-ray to confirm placement as the line does not reach the central circulation. Mid-lines should be considered which are usually about 20 cm long.

Care should be taken when formulating PN to be administered via a peripheral catheter with regard to the tonicity of the solution.

Some indications and contraindications to the use of the peripheral route are summarised in Box 7.3.

Peripheral administration is sometimes complicated or delayed by phlebitis, where an insult to the endothelial vessel wall causes inflammation, redness, pain and possible extravasation. Hot and cold compresses have been used to treat this. A 5 mg glyceryl trinitrate patch placed where the line tip is estimated to be may cause some local vasodilation which is believed to prevent thrombophlebitis (Khawaja and Williams, 1991). Peripheral tolerance can be influenced by a range of factors (Box 7.4).

Many consider that the tonicity of the infused solution or emulsion is a key factor defining peripheral infusion tolerance. The total number of osmotically active particles in the intracellular and extracellular fluids is essentially the same, approximately 290–310 mOsmol/L. When a lipid emulsion is included, infusions of approximately three times this osmolarity are generally well tolerated via the peripheral route and there are reports of success with higher levels. However, other factors should also be considered. Patient factors, such as vein fragility and blood flow, may mean that some infusion episodes are better tolerated than others. The osmolarity of a PN formulation can be estimated by applying the following equation:

where n indicates the component.

By considering the macronutrients included in the regimen, that is, the amino acids, glucose and lipid, an estimation of the osmolarity can be made. The value will be increased by electrolyte or micronutrient additions; however, since the peripheral tolerance is affected by so many factors, including tonicity, and because the limit is only an estimate, the effect of these additions is relatively low unless high levels of monovalent ions are included.

Central route

The central venous route is indicated when longer-term feeding is anticipated, high tonicity or large volume formulations are required, or the peripheral route is inaccessible. The rapid and turbulent blood flow in the central circulation and the constant movement of the heart ensure rapid mixing and reduce the risk of osmotically induced injury to the endothelium.

A range of single-, double-, triple- and quadruple-lumen central lines are available and one lumen must be dedicated for the intravenous nutrition. These lines require skilful insertion, usually into the jugular or subclavian vein, and confirmation of their position by X-ray. This relatively invasive and costly procedure is performed by trained medical staff. Tunnelling of the line to an appropriate exit site facilitates line care and may reduce the incidence of significant line sepsis. The femoral route is not favoured due to a higher incidence of sepsis. If cared for well, a tunnelled central line placed in a patient receiving home PN may last for many years.

Peripherally Inserted Central Catheters (PICCs)

PICCs are typically inserted into a peripheral vein, usually the cephalic or basilic in the upper arm, with the exit tip in the superior vena cava just above the right atrium. As the name suggests, they are used for the central administration of infusions. Single- and double-lumen versions are available; some also have a one-way valve to prevent backflow. Insertion is less invasive than for conventional central lines and can be undertaken by trained nurse practitioners at the bedside. A chest X-ray is necessary to confirm placement.

Infusion control

Standardised formulations

Depending on the type (size and specialty) of the hospital, a range of standard formulations are maintained and supported with prescribing guidelines. These may be compounded from scratch, compounded from ‘base-bags’ locally or by a licensed unit, or purchased as licensed ready-to-use presentations.

The range is specifically selected to meet the needs of the patients managed by the hospital and will typically include a low-tonicity regimen suitable for peripheral administration, a higher calorie and nitrogen regimen for central administration to catabolic patients and a high-tonicity regimen for fluid-restricted patients. Baseline electrolytes will generally be included, although the flexibility for reduced levels is usually offered.

Licensed ready-to-use products

A range of licensed ready-to-use preparations are available and should have micronutrients added prior to infusing. For convenience, baseline electrolyte levels are included in many formulations and meet the needs of most patients and additional electrolytes may be added up to the limits set by the manufacturer. Electrolyte-free options are also available. Some are licensed for use in paediatrics and/or for peripheral use. Manufacturers advise on stability and shelf-life for electrolyte and micronutrient additions. The range of ready-to-use products includes:

• triple chamber bags (OliClinomel®, Kabiven®, StructoKabiven® and Nutriflex® Lipid ranges): chambers separately pre-filled with lipid, amino acid and glucose and terminally sterilised, these are activated by applying external pressure so weak seal peels open, mixing the contents to form a 3-in-1 formulation.

• dual chamber bags (Clinimix® and Nutriflex® ranges): chambers separately pre-filled with amino acid and glucose and terminally sterilised, these are activated to form a 2-in-1 formulation. They provide the flexibility to allow staff to omit or add a compatible lipid.

The range of commercially available PN formulations is continually expanding. For hospital pharmacies who do not have compounding facilities, this offers an opportunity to ensure the correct formulation is given to meet individual patients needs. PN formulations are now available with micronutrients added and with extended shelf-lives when stored in a refrigerator.

Cyclic infusions

Cyclic PN is when the daily requirements are administered over a short period. A classic example is the stable home patient who administers their feed overnight, freeing themselves from the constraints of an infusion during the day. This enables them to have more physical freedom and improves their quality of life. Some patients, however, prefer to administer their PN during the day time. This is made possible by use of a small ambulatory pump and a back pack in which they may carry their PN.

Since cyclic feeding more closely simulates the human feeding pattern and is a closer match to normal hormonal and metabolic cycles, it also offers a range of metabolic and clinical advantages. Steatosis, fatty infiltration of the liver, is less common and may be corrected by employing cyclic feeding because the feed-free period facilitates lipolysis and fat mobilisation. Peripheral tolerance may be improved as the endothelia recover between infusion periods.

Initially, the patient should receive the PN infusion slowly over the full 24 h, as tolerated, the rate of infusion can be increased slowly to decrease the infusion time. This should be done over a series of days. During this period, the patient must be monitored closely for any signs of fluid, electrolyte or acid-base imbalance and hyper/hypoglycaemia. For example, on stopping the infusion, rebound hypoglycaemia may occur.

Pharmaceutical issues

Having identified the balance of nutrients required for a patient in a single day, it is necessary to formulate a physically and chemically stable aseptically prepared admixture. PN admixtures contain over 50 chemical entities and, as such, are extremely complex and have many chemical interactions taking place which could lead to instability in the final formulation. Professional advice or appropriate reference material should be sought and used before compounding and administering of PN takes place. Manufacturers and third party experts can advise on stability issues.

Physical stability

Physical instability takes a number of forms including precipitation of crystalline material and breakdown of the lipid emulsion.

Precipitation

Precipitation carries two key risks. First, the potential to infuse solid particles to the narrow pulmonary capillaries may result in fatal emboli. Second, the prescribed nutrients may not be infused to the patient. Clinically dangerous precipitates may not always be visible to the naked eye, especially if lipid emulsion is present. They may also develop over time, and an apparently ‘safe’ admixture may develop fatal precipitates when in use.

Precipitation of solid is epitomised by the formation of calcium phosphate; this is of special concern in neonatal admixtures where the requirements to prevent hypophosphataemic rickets and severe osteopenia may exceed the safe concentrations. Such concentrations are rarely seen in adult regimens. It is known that calcium and phosphate can form a number of different salt forms each with different solubility profiles, for example, Ca(H₂PO₄)₂ which is highly soluble in comparison to CaHPO₄ and Ca₃(PO₄)₂. Ca₃(PO₄)₂ precipitation occurs relatively immediate and has a white, fluffy amorphous appearance; however, CaHPO₄.2 H₂O precipitation is time mediated and has a more crystalline appearance.

Factors affecting calcium phosphate precipitation are shown in Table 7.11. Practical measures can be taken to minimise the risks; these include accurate calculation of the proposed formulation, comparison against professionally defined comprehensive matrices and thorough mixing. Solubility curves and algorithms should be used with extreme caution, even if they are quoted for a specific amino acid source, this is because they do not consider all the factors and do not consistently identify risk. Assuming the sodium content can be tolerated, use of an organic phosphate salt form may be beneficial due to the higher solubility of the sodium glycerophosphate salt form.

Table 7.11 Factors affecting calcium phosphate precipitation

Factor	Mechanism and effect
pH	Low pH supports solubility, whereas a higher pH supports precipitation. Depending on the amount and buffering capacity of the amino acids, this can be affected by different concentrations and sources of glucose solution and acetate salt forms.
Temperature	Higher temperatures associated with greater precipitation, increased availability of free calcium to interact and a shift to the more insoluble salt forms.
Amino acids	Buffer pH changes. Complex with calcium so less available to react with phosphate. Both the source of amino acid and the relative content are important.
Magnesium	Complex with phosphate forming soluble salts rather than less soluble calcium salts.
Calcium salt form	Calcium chloride dissociates more readily than calcium gluconate, releasing it to react with the phosphate.
Phosphate salt form	Monobasic salts, for example, dipotassium phosphate, dissociate more readily than dibasic salts, for example, potassium acid phosphate, releasing phosphate to react with the calcium. Organic salts, such as sodium glycerophosphate and glucose-1-phosphate, are more stable.
Mixing order	Optimum stability achieved by only permitting calcium and phosphate to come together in a large volume admixture. Agitate between additions to avoid pockets of concentration.

Trace elements have also been associated with clinically significant precipitation; these include iron phosphate and copper sulphide (hydrogen sulphide from the minor degradation of cysteine/cystine). These very fine precipitate forms are less likely to cause occlusion of catheters or lung capillaries, but have been associated with significant clinical delivery losses when they are taken up by inline filtration devices.

Lipid destabilisation

The oil-in-water lipid emulsions are sensitive to destabilisation by a range of factors including the presence of positively charged ions, pH changes and changes in environmental temperature. The lipid globules may come together and coalesce to form larger globules and release free oil; this could occlude the lung microvasculature and cause respiratory and circulatory compromise and lead to death.

Positively charged ions destabilise the admixture by drawing the negatively charged lipid globules together, overwhelming the electromechanical repulsion of the charged phospholipids and increasing their tendency to join or coalesce. Divalent and trivalent ions have a more significant effect; therefore, there are tightly defined limits for the amount of Ca²⁺, Mg²⁺ and Fe³⁺ that can be added to a 3-in-1 admixture. Although the limits for the other polyvalent ions (such as zinc and selenium) are also controlled, because they are given in micromolar or nanomolar quantities, they are less of a problem. Low concentrations of amino acids and extremes of glucose concentration (high and low) also reduce the stability of the emulsion and increase the tendency for creaming and cracking of the lipid emulsion.

The naked eye can identify large-scale destabilisation, as shown in Table 7.12; however, the limitations of this method need to be recognised; clinically significant destabilisation might not be visible to the naked eye. In practice, stability laboratories use specialised technical equipment to determine defined criteria so as to establish the physical stability of a formulation. These tests include assessing changes in lipid globule size distribution with optical microscopes, and variety of particle size analysis instruments against the defined limits of pharmaceutical acceptance. A wide safety margin is applied.

Table 7.12 Lipid instability

	Description	Visual observation
Stable, normal emulsion	Lipid globules equally dispersed. Suitable for administration	Normal emulsion
Light creaming	Lipid globules rising to the top of the bag. Slight layering visible. Readily redisperses on inverting the bag. Suitable for administration	Light creaming
Heavy creaming, flocculation	Lipid globules coming together but not joining. Rising to the top of the bag. More obvious layering visible. Readily redisperses on inverting the bag. Acceptable for administration	Heavy creaming
Coalescence	Lipid globules come together, coalesce to form larger globules and rise to the surface. Larger globules join, releasing free oil. Irreversible destabilisation of the lipid emulsion. Not suitable for administration	Cracked. Oil layer viewed close up

Chemical stability

Chemical stability takes many forms, notably chemical degradation of the vitamins and amino acids.

Vitamin stability

Many vitamins readily undergo chemical degradation, and vitamin stability often defines the shelf-life of a given formulation.

Vitamin C (ascorbic acid), the least stable component, is generally regarded as the marker for vitamin degradation. Vitamin C oxidation is accelerated by heat, oxygen and certain trace elements, including copper. Other examples include vitamin A photolysis and vitamin E photo-oxidation. Measures that minimise oxygen presence, such as minimal aeration during compounding, evacuation of air at the end of compounding and use of multi-laminated oxygen barrier bags, and light protection of admixture containers and delivery sets are recommended.

Amino acid stability

The amino acid profile should be maintained for the shelf-life of the formulation and manufacturers perform assays to confirm this prior to issuing stability reports.

Maillard reaction

The Maillard reaction is a complex pathway of chemical reactions that starts with a condensation of the carbonyl group of the glucose and the amino group of the amino acid. At present, relatively little is known about the clinical effects of these Maillard reaction products; however, it is prudent to minimise their presence by protecting from light and avoiding high temperatures.

Microbial contamination

PN is a highly nutritious medium whose hypertonicity will partially limit microbial growth potential. Growth in the presence of lipid emulsion is greater. Pharmaceutical developments have enabled terminal sterilisation of many of the components, including the multi-chamber bag presentations; however, additional manipulations should only be performed using validated aseptic techniques in appropriate pharmaceutically clean environments by suitably trained staff. Nurses, patients and carers must be trained to apply aseptic methods when connecting and disconnecting infusions, for this reason, many centres have documented line care and PN protocols.

Shelf-life and temperature control

The manufacturer may be able to provide physical and chemical stability data to support a formulation for a shelf-life of up to 90 days at 2–8°C followed by 24 h at room temperature for infusion; this assumes that a strict aseptic technique is used during compounding. Units holding a manufacturing license covering aseptic compounding of PN are potentially able to assign this full shelf-life (if stability data is available), whilst unlicensed units are limited to a maximum shelf-life of 7 days.

PN must be stored and transported within the defined temperature limits and should not be exposed to temperature cycling (e.g. the formulations must not freeze); for this reason, a validated cold-chain must be employed especially when delivering formulations to home care patients. Pharmaceutical-grade fridges should be used and monitored to ensure appropriate air cycling and temperature maintenance. The temperature during the infusion period should be known with neonatal units and their patient incubators classically maintained at higher temperatures; therefore, formulations used for this environment must have been stability-validated at these temperatures.

Drug stability

The addition of drugs to PN admixtures, or Y-site co-administration, is actively discouraged unless the compatibility has been formally confirmed. Wherever possible, the PN should be administered through a dedicated line. Multilumen catheters can be used to infuse PN separately from other infusion(s); however, extreme competition for intravenous access may prompt consideration of drug and PN combinations. Many factors need to be considered: the physical and chemical stability of the PN, the physical and chemical stability of the drug, the bioavailability of the drug (especially when a lipid emulsion is present) and the effect of stopping and starting Y-site infusions on the actual administration rates. It is not possible to reliably extrapolate data from a specific PN composition, between brands of solutions and salt forms or between brands or doses of drugs. A range of studies has been performed and published; however, these should be used with caution.

In practice, drugs should only be infused with PN when all other possibilities have been exhausted. These may include gaining further intravenous access and changing the drug(s) to clinically acceptable non-intravenous alternatives. The relative risks of stopping and starting the PN infusion and repeatedly breaking the infusion circuit should be fully considered before sharing a line for separate infusions of PN and drug. In most cases, the risks outweigh the benefits; however, if this option is adopted, the line must be flushed before and after with an appropriate volume of solution known to be stable with both the PN and the drug. Strict aseptic technique should be adopted to minimise the risk of contaminating the line and infusions.

Filtration

All intravenous fluids pass through the delicate lung microvasculature with its capillary diameter of 8–12μm. The presence of particulate matter has been demonstrated to cause direct embolisation, direct damage to the endothelia, formation of granulomata and formation of foreign body giant cells, and to have a thrombogenic effect. In addition, the presence of microbial and fungal matter can cause a serious infection or inflammatory response.

Precautions taken to minimise the particulate load of the compounded admixture must include:

• use of filter needles or straws (5μm) during compounding to catch larger particles such as cored rubber from bottles and glass shards from ampoules

• air particle levels kept within defined limits in aseptic rooms by the use of air filters and non-shedding clothing and wipes

• use of quality raw materials with minimal particulate presence, including empty bags and leads

• confirmation of physical and chemical stability of the formulation prior to aseptic compounding applying approved mixing order (stability for the required shelf-life time and conditions)

Guidelines have been published that endorse the use of filters, especially for patients requiring intensive or prolonged parenteral therapy, including home patients, the immunocompromised, neonates and children (Bethune et al., 2001). The filter should be placed as close to the patient as possible and validated for the PN to be used. For 2-in-1 formulations, 0.2μm filters may be used, for 3-in-1 formulations, validated 1.2μm filters may be used.

Light protection

It is widely recognised that exposure to light, notably phototherapy light and intense sunlight, may increase the degradation rate of certain constituents such as vitamins A and E. It is recommended that all regimens should be protected from light both during storage and during infusion, since

• the presence of a lipid emulsion does not totally protect against vitamin photodegradation

• the Maillard reaction is influenced by light exposure

• ongoing research suggests lipid peroxidation is accelerated by a range of factors, including exposure to certain wavelengths of light

• validated bag and delivery set covers should only be used

Nutritional assessment and monitoring

Initial assessment

Once screening has identified that a patient is in need of nutritional intervention, a more detailed assessment is performed; this will include an evaluation of nutritional requirements, the expected course of the underlying disease, consideration of the enteral route and, where appropriate, identification of access routes for PN. This will be supported by a clinical assessment that will include:

• clinical history

• dietary history

• physical examination

• anthropometry including muscle function tests

• biochemical, haematological and immunological review.

Monitoring

PN monitoring has a number of objectives. It should

• evaluate ongoing nutritional requirements, including fluid and electrolytes

• determine the effectiveness of the nutritional intervention

• facilitate early recognition of complications

• identify any deficiency, overload or toxicity to individual nutrients

• determine discrepancies between prescribed, delivered and received dose.

Regular monitoring contributes to the success of the PN and a monitoring protocol should be in place for each individual patient. Baseline data should be recorded so deviations can be recognised and interpreted. In the early stages, while the patient is in the acute stage of their illness and the nutritional requirements are being established, the frequency of monitoring will be greatest. Some tests may be defined by the underlying disease state, rather than by the presence of PN per se. As the patient’s status stabilises, the frequency of monitoring will reduce, although the range of parameters monitored is likely to increase. Examples of parameters monitored include the following:

• Clinical symptoms or presentation: may be specific, for example, thrombophlebitis, or non-specific, for example, confusion.

• Temperature, blood pressure and pulse: vigilance for the risk of sepsis.

• Fluid balance and weight: acute weight changes reflect fluid gain or loss and prompt review of the volume of the PN. Slow, progressive changes are more likely to reflect nutritional status.

• Nitrogen balance: an assessment of urine urea and insensible loss and their relation to nitrogen input. It is difficult to obtain accurate figures.

• Visceral proteins: albumin levels may indicate malnutrition but its long half-life limits sensitivity to detect acute changes in nutritional status. Other markers with a shorter half-life may be more useful, for example, transferrin.

• Haematology: platelet counts and clotting studies for thrombocytopenia.

• C-reactive protein: monitor the inflammatory process.

• Blood glucose: hyperglycaemia is a relatively frequent complication. Management includes either a reduction in the infused dose or lengthening of the infusion period. If these measures fail, insulin may be used. Hyperglycaemia may also indicate sepsis. Rebound hypoglycaemia can occur when an infusion is stopped. If this is a problem, the infusion should be tapered off during the last hour or two of the infusion. Some infusion pumps are programmed to do this automatically.

• Lipid tolerance: turbidity, cholesterol and triglyceride profiles required.

• Electrolyte profile: indicates appropriate provision or complicating clinical disorder. In the first few days, low potassium, magnesium and/or phosphate with or without clinical symptoms may reflect the refeeding syndrome (see below).

• Liver function tests: an abnormal liver profile may be observed and it is often difficult to identify a single cause. PN and other factors such as sepsis, drug therapy and underlying disease may all interplay. In adults, PN-induced abnormalities tend to be mild, reversible and self-limiting. In the early stages, fatty liver (steatosis) is seen. In longer-term patients, a cholestatic picture tends to present. Varying the type of lipid used and removing lipid from some formulations may be of benefit.

• Anthropometry: assesses longer-term status.

• Acid–base profile: indicative of respiratory or metabolic compromise and may require review of PN formulation.

• Vitamin and trace element screen: a range of single compounds or markers to consider tolerance and identify deficiencies, although of limited value as some tests are non-specific and inaccurate.

• Catheter entry site: vigilance for phlebitis, erythema, extravasation, infection, misplacement.

Complications

Complications of PN fall into two main categories: catheter- related and metabolic (Box 7.5). Overall, the incidence of such complications has reduced because of increased knowledge and skills together with more successful management (Maroulis and Kalfarentzos, 2000).

Line sepsis

This is a serious and potentially life-threatening condition. Monitoring protocols should ensure that signs of infection are identified early and a local decision pathway should be in place to guide efficient diagnosis and management. Management will depend upon the type of line and the source of infection. Alternative sources of sepsis should be considered. Initially, the PN is usually stopped.

Line occlusion

Line occlusion may be caused by a number of factors, including:

• fibrin sheath forming around the line, or a thrombosis blocking the tip

• internal blockage of lipid, blood clot or salt and drug precipitates

• line kinking

• particulate blockage of a protective line filter.

Management will depend on the cause of the occlusion; in general, the aim is to save the line and resume feeding with minimum risk for the patient. The use of locks and flushes with alteplase (for fibrin and thrombosis), ethanol (for lipid deposits) and dilute hydrochloric acid (for salt and drug precipitates) may be considered. In some cases, the lines may need to be replaced.

These complications can be minimised by having a dedicated line for PN, flushing the line well with sodium chloride 0.9% before and after use and a regular slow flush of ethanol 20% may be used to prevent lipid deposition.

Refeeding syndrome

Patients should be assessed as to their risk of developing refeeding syndrome (see Table 7.13). Refeeding syndrome can be defined as ‘the potentially fatal shifts in fluids and electrolytes that may occur in malnourished patients receiving nutrition’. Undernourished patients are catabolic and their major sources of energy are fat and muscle. As the PN infusion (which contains glucose) starts, this catabolic state is pushed to anabolic which in turn causes a surge of insulin. As the insulin levels increase, there is an intracellular shift of magnesium, potassium and phosphate, and acute hypomanganesaemia, hypokalaemia and hypophosphataemia result. This can cause cardiac and neurological dysfunction and may be fatal. PN should be gradually increased over a period of 2–7 days depending on the patient’s body mass index and risk of developing refeeding syndrome. Oral thiamine and vitamin B compound strong or full dose intravenous vitamin B preparation may be administered before PN is started and for the first few days of infusion.

Table 7.13 Risk factors for developing refeeding syndrome (NICE, 2006)

One or more of the following:	Two or more of the following:
BMI <16 kg/m²	BMI <18.5 kg/m²
Unintentional weight loss greater than 15% within the last 3–6 months	Unintentional weight loss greater than 10% within the last 3–6 months
Little or no nutritional intake for more than 10 days	Little or no nutritional intake for more than 5 days
Low levels of potassium, phosphate or magnesium prior to feeding	A history of alcohol abuse or drugs including insulin, chemotherapy, antacids or diuretics

Specific disease states

Liver

Although abnormal liver function tests associated with short-term PN are usually benign and transient, liver dysfunction in long-term PN patients is one of the most prevalent and severe complications. Its underlying pathophysiology, however, largely remains to be elucidated. The content of PN should be examined and care should be taken not to overfeed with glucose and/or lipid. Supplementation with taurine in the formulation has been reported to ameliorate PN associated cholestasis through promoted bile flow. Various lipid preparations are now available, including preparations containing fish oils which have been reported to be beneficial in reversing liver disease (De Meijer et al., 2009). Lipid emulsions containing a mix of medium and long chain triglycerides are also available and have an improved liver tolerability. Due to the complexity of liver function, the range of potential disorders and its role in metabolism, the use of PN in liver disease is not without problems. Consensus guidelines for the use of PN in liver disease have been published (Plauth et al., 2009). Nutritional intervention may be essential for recovery, although care must be exercised with amino acid input and the risk of encephalopathy, calorie input and metabolic capacity, and the reduced clearance of trace elements such as copper and manganese (Maroulis and Kalfarentzos, 2000). Low-sodium, low-volume feeds are indicated if there is ascites. Cyclic feeding appears useful, especially in steatosis.

Renal failure

Fluid and electrolyte balance demand close attention, and guidelines for nutrition in adult renal failure are available (Cano et al., 2009). A low volume and poor quality urine output may necessitate a concentrated PN formulation with a reduction in electrolyte content, particularly a reduction in potassium and phosphate. In the polyuric phase or the nephrotic syndrome, a higher volume formulation may be required. If there is fluid retention, ideal body weight should be used for calculating requirements rather than the actual body weight.

The metabolic stress of acute renal failure and the malnutrition of chronic renal failure may initially demand relatively high nutritional requirements; however, nitrogen restriction may be necessary to control uraemia in the absence of dialysis or filtration and to avoid uraemia-related impaired glucose tolerance, because of peripheral insulin resistance, and lipid clearance.

Micronutrient requirements may also change in renal disease. For example, renal clearance of zinc, selenium, fluoride and chromium is reduced and there is less renal 1α-hydroxylation of vitamin D.

Intradialytic PN (IDPN) may be administered at the same time as dialysis; however, this is not without complications. High blood sugars and fluid overload can be a problem and there is uncertainty as to how much of the PN is retained by the body and how much is removed by dialysis. Administration requires local guidelines and monitoring to be in place (Foulks, 1999; Lazarus, 1999).

Pancreatitis

Acute pancreatitis is a metabolic stress that requires high-level nutritional support and pancreatic rest to recover. Guidelines for nutrition in acute pancreatitis are available (Gianotti et al., 2009). While enteral nutrition stimulates the pancreas, PN does not appear to. Hyperglycaemia may occur and require exogenous insulin.

Sepsis and injury

Significant fluctuations in macronutrient metabolism are seen during sepsis and injury. There are two metabolic phases: the ‘ebb’ phase of 24–48 h and the following ‘flow’ phase. The initial hyperglycaemia, reflecting a reduced utilisation of glucose, is followed by a longer catabolic state with increased utilisation of lipid and amino acids. The effect of the different lipid emulsions on immune function is the subject of much research. It is important not to overfeed and also to consider the reduced glucose tolerance during the critical days. This is due to increased insulin resistance and incomplete glucose oxidation. Exogenous insulin may be required.

Respiratory

While underfeeding and malnutrition can compromise respiratory effort and muscle function, overfeeding can equally compromise respiratory function due to increased carbon dioxide and lipid effects on the circulation. While chronic respiratory disease may be linked with a long-standing malnutrition, the patient with acute disease will generally be hypermetabolic.

Cardiac failure

Cardiac failure and multiple drug therapy may limit the volume of PN that can be infused. Concentrated formulations are used and, as a consequence of the high tonicity, administered via the central route. Close electrolyte monitoring and adjustment is required. Cardiac drugs may affect electrolyte clearance. Although central lines may already be in use for other drugs or cardiac monitoring, it is essential to maintain a dedicated lumen or line for the feed.

Diabetes mellitus

Diabetic patients can generally be maintained with standard dual-energy regimens. It is important to use insulin to manage blood glucose rather than reduce the nutritional provision of the feed. Close glucose monitoring will guide exogenous insulin administration. This should be given as a separate infusion (sliding scale) or, if the patient is stable, in bolus doses. Insulin should not be included within the PN formulation due to stability problems and variable adsorption to the equipment. Y-site infusion with the PN should be avoided as changes in insulin rates will be delayed and changes in feed rates will result in significant fluctuations in insulin administration. Extra potassium and phosphate may be required due to the impact of the glucose and insulin. Long-term PN patients may need differing insulin regimes depending on the glucose load (aqueous/lipid) in the formulation. Although using oral antihypoglycaemic agents with PN may be considered, care should be taken as to the potentially erratic absorption and so varying blood glucose levels.

Cancer and palliative care

Nutritional support in cancer and palliative care is guided by the potential risks and benefits of the intervention, alongside the wishes of the patient and their carers. Further research is required to evaluate the effects of PN on length and quality of life.

Standard PN may be useful during prolonged periods of gastro-intestinal toxicity, as in bone marrow transplant patients. The use of PN is not thought to stimulate tumour growth (Nitenberg and Raynard, 2000).

Short bowel syndrome

The small intestine is defined as ‘short’ if it is less than 100 cm. Treatment options depend upon which part of the gut has been removed and the functional state of the remaining organ. The surface area for absorption of nutrition and reabsorption of fluid and electrolytes is significantly compromised. Fluid and electrolyte balance needs to be managed closely due to the high-volume losses. High-volume PN formulations with raised electrolyte content (notably sodium and magnesium) may be required. Vitamin and trace element provision is very important.

Long-term PN

Home care is well established in the UK, with some patients successfully supported for over 20 years. Total or supplemental PN may be appropriate. Trace elements, notably selenium, should be managed closely as requirements may be increased.

Most patients are extremely well informed about their underlying disease and their PN; many also benefit from support group PINNT (Patients on Intravenous and Nasogastric Nutrition Therapy) and LITRE (Looking into the Requirements for Equipment), a standing committee of BAPEN which looks at equipment issues.

There are an increasing number of patients at home on PN. Scotland and Wales now have designated networks to care for these patients. Many patients are trained to connect and disconnect their PN and to care for their central lines. Patients are encouraged to lead as active and normal life as possible. Foreign travel is now possible for patients on home PN, as are most other normal daily activities and sports (Staun et al., 2009).

Paediatric PN

Nutritional requirements

Early nutritional intervention is required in paediatric patients due to their low reserve, especially in neonates. Where possible, premature neonates should commence feeding from day 1. In addition to requirements for the maintenance of body tissue, function and repair, it is also important to support growth and development, especially in the infant and adolescent.

Typical guidelines for average daily requirements of fluid, energy and nitrogen are shown in Table 7.14. The dual-energy approach is favoured in paediatrics. Approximately 30% of the non-protein calories are provided as lipid using a 20% emulsion. Most centres gradually increase the lipid provision from day 1 from 1 g/kg/day to 2 g/kg/day and then 3 g/kg/day, monitoring lipid clearance through the serum triglyceride level. This ensures the essential fatty acid requirements of premature neonates are met.

Formulation and stability issues

Many centres use standard PN formulations including the specific paediatric amino acid solutions (Primene® or Vaminolact®). Prescriptions and formulations are tailored to reflect clinical status, biochemistry and nutritional requirements.

Micronutrients are included daily. Paediatric licensed preparations are available and are included on a ml/kg basis up to a maximum total volume (Peditrace®, Solivito® N and Vitlipid® N Infant). Electrolytes are also monitored and included in all formulations on a mmol/kg basis. Acid–base balance should be considered. Potassium and sodium acetate salt forms are used in balance with the chloride salt forms in neonatal formulae to avoid excessive chloride input contributing to acidosis (acetate is metabolised to bicarbonate, an alkali). In the initial stages, neonates tend to hypernatraemia due to relatively poor renal clearance; this should be reflected in the standard formulae used.

Due to the balance of nutritional requirements, a relatively high glucose requirement with high calcium and phosphate provision, the neonatal and paediatric prescription may be supplied by a separate 2-in-1 bag of amino acids, glucose, trace elements and electrolytes and a lipid syringe with vitamins. These are generally given concurrently, joining at a Y-site. Older children can sometimes be managed with 3-in-1 formulations. A single infusion is particularly useful in the home care environment. Some ready-to-use formulations are licensed for use in paediatrics and include the Kabiven® and OliClinomel® range.

Improved stability profiles with the new lipid emulsions, and increasing stability data, may support 3-in-1 formulations that meet the nutritional requirements of younger children.

Concerns over the contamination of calcium gluconate with aluminium and the association between aluminium contamination of neonatal PN and impaired neurological development have favoured the use of calcium chloride over gluconate; however, chloride load should be considered if the former is used. If calcum gluconate is to be used it must be from plastic containers.

Heparin

Historically, low concentrations of heparin were included in 2-in-1 formulations in an attempt to improve fat clearance through enhanced triglyceride hydrolysis, prevent the formation of fibrin around the infusion line, reduce thrombosis and reduce thrombophlebitis during peripheral infusion; however, this is no longer recommended. It is recognised that when the 2-in-1 formulation comes into contact with the lipid phase, calcium-heparin bridges form between these lipid globules, destabilising the formulation. Also, there is limited evidence of clinical benefit of the heparin inclusion.

Route of administration

Peripheral administration is less common in neonates and children due to the risk of thrombophlebitis; however, it is useful when low-concentration, short-term PN is required and there is good peripheral access. The maximum glucose concentration for peripheral administration in paediatrics is generally regarded to be 12%. However, considering all the other factors that can affect the tonicity of a regimen and peripheral tolerance, it is clear that this is a relatively simplistic perspective. Many centres favour a limit of 10% with close clinical observation.

Central administration is via a PICC, a long-term tunnelled central line, a jugular or subclavian line. Femoral lines are a less preferred option owing to their location and, therefore, high risk of becoming infected.

Case study

Case 7.1

Mrs B, aged 47, was admitted for investigation of chronic diarrhoea and 6 kg weight loss over the past 3 months.

See Table 7.15.

Table 7.15 Clinical details for Case 7.1

Day	Clinical observation/event	PN changes
1	Admitted to gastroenterology ward from clinic for investigation of chronic diarrhoea and weight loss. Current weight 49 kg, height 1.65 m. Usual weight 55 kg, 1.65 m. Estimated current energy requirement 1500 kcal.
2	Contrast study revealed intestinal fistula between small bowel and transverse colon. Diarrhoea approx. 1.5 L/day.
3	Case discussed with surgeons. For PN for 2–3 weeks prior to surgery to improve nutritional status.	PN prescribed (considering both fluid and electrolytes from other therapies, and potassium loss from diarrhoea of approx. 30–70 mmol/L):
	Patient made ‘nil by mouth’. Central line inserted for PN use only.	Volume 2 L, nitrogen 9 g, carbohydrate 400 kcal, lipid 550 kcal, Na⁺ 230 mmol, K⁺ 80 mmol, Ca²⁺ 5 mmol, Mg²⁺ 11 mmol, phosphate 35 mmol and micronutrients added (daily).
4	Biochemistry results: Na⁺ 129 mmol/L (135–145 mmol/L), K⁺ 3.2 mmol/L (3.4–5.0 mmol/L), urea 6.9 mmol/L (3.1–7.9 mmol/L), Cr 86 μmol/L (75–1550 μmol/L), corr Ca²⁺ 2.3 mmol/L (2.12–2.60 mmol/L), Mg²⁺ 0.75 mmol/L (0.7–1.0 mmol/L), phosphate 0.85 mmol/L (0.80–1.44 mmol/L).	Regimen unchanged.
	Temperature/pulse/respiration normal, diarrhoea losses reduced to 800 mL/day.
5	Biochemistry results: Na⁺ 132 mmol/L, K⁺ 3.1 mmol/L, urea 4.3 mmol/L, Cr 85 μmol/L, corr Ca²⁺ 2.2 mmol/L, Mg²⁺ 0.50 mmol/L, phosphate 0.60 mmol/L	PN regimen unchanged. Additional 20 mmol Mg²⁺ prescribed in 500 mL of saline infused over 6 h.
6	Biochemistry results: Na⁺ 138 mmol/L, K⁺ 3.5 mmol/L, urea 3.0 mmol/L, Cr 86 μmol/L, corr Ca 2.2 mmol/L, Mg²⁺ 0.78 mmol/L, phosphate 0.9 mmol/L. Diarrhoea reduced to 500 mL/day.	PN regimen changed to: Volume 2 L, nitrogen 11 g, carbohydrate 800 kcal, lipid 800 kcal, Na⁺ 100 mmol, K⁺ 80 mmol, Ca²⁺ 5 mmol, Mg²⁺ 15 mmol, phosphate 40 mmol.
7	Biochemistry results: Na⁺ 139 mmol/L, K⁺ 4.1 mmol/L, urea 2.8 mmol/L, Cr 78 μmol/L, Mg²⁺ 0.95 mmol/L, phosphate 1.3 mmol/L.	K⁺ reduced to 60 mmol, Mg²⁺ reduced to 10 mmol, phosphate reduced to 30 mmol.