Contents and properties of the parenteral nutrition mixture

A small part of this chapter is vaguely relevant for the CICM Fellowship Exam

It is remarkable how safe appears the infusion of incredibly random stuff into people's circulation, as evidence presented by homeless alcoholics who routinely inject beer, or resource-poor emergency physicians using coconut water to resuscitate their dehydrated patients. Along the same lines is the administration of intravenous food. TPN is a strange mixture of rather horrible corrosive chemicals which replace the normal nutritive output of the enteric circulation and the liver. Most centres use some sort of standard pre-mixed formula, to which various bits and pieces are added to reflect the electrolyte requirements of each individual patient. Remaining true to the solipsism of this website, I will only report on the local practice, as I have no experience of the broader Australian trends in TPN use.

Previous CICM exam questions about TPN have featured:

These have asked candidates to demonstrate how they would prescribe TPN (and, to some extent, the practical aspects to managing a TPN infusion). The range of issues explored in these questions has not dictated the content of this chapter. Rather, it is a self-indulgent exploration of strange biochemistry. For the time-poor exam candidate, the following brief list of TPN composition is sufficient for the purposes of answering the CICM TPN questions:

Practical guidelines for prescribing parenteral nutrition

  • Usually the bag is about 2L
  • Carbohydrate: fat ratio: 70:30.
  • Protein is also required: 1.5-2g/kg/day
    • Fat is supplied as 10% lipid emulsion, at  1.1 kcal/ml
    • Carbohydrate is supplied as 50% dextrose, at 3.4 kcal/g (1.7kcal/ml)
    • Protein is supplied as 10% amino acid solution, as 100g/L
  • Normal requirements are 25 kcal/kg/day
  • Thus, 17.5 kcal/kg/day is supplied by carbohydrate, and 7.5 kcal/kg/day is supplied by fat
  • Thus, a normal ICU patient (eg. the one from Question 7 from the first paper of 2015 ) getting 2000 kcal/day requires the following dose of TPN:
    • 1400 kcal/day of 50% dextrose (which makes about 824 ml)
    • 600 kcal/day of 10% lipid emulsion (which makes about 545ml)
    • 100 g/day of protein, which makes about 1000ml of 10% amino acid solution

That candidate, crazed with stress, will also benefit from the LITFL TPN page, which offers a brief and sane introduction to this fascinating topic. On the other hand, the candidate who is interested in neither brevity nor sanity is invited to explore the long rambling digression offered below, along with its references.  An ideal starting point would probably be the review article by Stawny et al (2013), which offers a pharmacologists' viewpoint on TPN contents. Unless otherwise specified, this article was the main source of information and inspiration for the discussion which follows. Another excellent resource were the 2014 ASPEN Clinical Guidelines on "Parenteral Nutrition Ordering, Order Review, Compounding, Labeling, and Dispensing."

A digression on the history of parenteral nutrition

"I injected wine and ale into the mass of blood of a living dog by vein in good quantities, until I made it drunk"

The boast above can be found in William Gibson's 1970 account of the scientific exploits of Sir Christopher Wren, a polymath scientist whose bulk of work was performed in the middle of the seventeenth century. No sooner than William Harvey's discovery of the circulation, people like Wren immediately started funnelling weird substances into it. Using hollowed-out goose quills, Wren and Boyle accessed the superficial veins in the hind limbs of dogs, injecting various substances into them. This was perhaps the first intravenous administration of parenteral opiates for recreational purposes, as the learned gentlemen observed the effects on some random puppy:

"...we had scarce untied the dog... before the opium began to disclose its Narcotick quality, and almost as soon as he was on his feet he began to nod with his head and falter and reel in his Pace, and presently after appeared so stupefied, that there were Wagers offered his life could not be saved..."

However the dog went on to make a complete recovery, gained weight  "so manifestly 'twas admired", and was then stolen from Boyle by some unknown person, which he greatly lamented. Of course, IV opium and wine cannot be even loosely described as parenteral nutrition, and represents a shameful tangent on this authors' part. The first "proper" attempt at parenteral nutrition is probably attributable to Krug, who in 1875 infused oil and protein extract subcutaneously into a patient with anorexia nervosa.

Over the course of the 20th century, the development of non-pyrogenic intravenous fluids had allowed short-term use of parenteral solutions consisting largely of dilute dextrose (5-10%) during the 1950s and 1960s.  The problem of supplying concentrated parenteral nutrients required central venous access, and was solved by Stanley Dudrick et al (1968) by means of subclavian catheterisation. This procedure was novel at the time, and it is described in great detail. Amazing artwork, unlike anything seen in the sterile modern medical journals, was produced by an A.B Digliotti, whose signature can be seen in the lower left of the image, but who is not referred to in the text, and whose contribution must have been viewed as irrelevant by Dudrick and his team. 

Subclavian cannulation for TPN, Dudrick et al (1969)

"The skin of the shoulder, chest and neckj is widely shaved, defatted with ether or acetone, prepared with 2% tincture of iodine or merthiolate, and draped into a sterile field. ... A 2-inch long #14 needle, attached to a 3ml syringe, is inserted through the weal and advanced beneath the inferior border of the clavicle with the needle point directed at a finger tip pressed firmly into the suprasternal notch (Fig 1A)"

This first attempt used a peristaltic pump to administer a carbohydrate-rich fat-poor solution with various electrolytes and vitamins compounded within. I offer Dudrick's own table, to commemorate this very first attempt at parenteral nutrition.

Dudrick et al (1969) - table of the nutritional composition of the first TPN mixture

Apart from the total absence of fatty acids, this mixture closely resembles the modern parenteral nutrition mixtures in its composition. Dudrick et al could not have used lipid. At this stage, Intralipid had already been developed (Schuberth and Wretlind, 1961) but was only being used in Europe, and was not available for American researchers until 1977 because the FDA had banned all parenteral oil emulsions following a series of adverse reactions to intravenous castor oil and cotton seed oil.

Macronutrient content of parenteral nutrition

There are lots of different local recipes for TPN. However, all mixtures must have a certain proportion of nutrients. Specifically, there must be a certain ratio between protein calories and non-protein calories: 1g of nitrogen per every 130-200 kcal. The ratio between carbohydrate and lipid calories must also be controlled, and may vary from 50:50 to 75:25. This is discussed later, far far below.

The weird TPN  mascot of the Westmead Intestinal Failure Service

In basic form, if the patient requires 2000 kcal/day of energy, 1400kcal of this energy should be supplied as dextrose, and 600 kcal/day as lipid. On top of this, about 100g per day of protein should be supplied as a mixture of amino acids.

The daily nutritional requirements of the critically ill patient are discussed in greater detail elsewhere. In brief, there are vague guidelines as to how much and of what macronutrient one requires, and these are derived largely from observations of populations which are (for many generations) depleted of one nutrient or another, for instance the Greenland Inuit who have survived perhaps since the Neolithic on diets composed entirely of protein and fat. Recommendations regarding the proportions of macronutrients are also derived from studies that have trialled parenteral nutrition mixtures particularly rich in one ingredient and poor in others. The details are discussed below; in brief, it appears pretty much anything goes (at least over a short period) but in the long term various nutritional deficiencies will surface if one major macronutrient group is omitted.

Carbohydrate supplied as 50% dextrose

The properties and contents of 50% dextrose have been discussed elsewhere. On its own, this is nasty stuff. With 500g of dextrose dissolved in every litre of water, 50% dextrose has an osmolality of 2780 mOsm/kg. The calorie content of dextrose is approximately 3.4 kcal/g, or 1.7 kcal/ml for 50% solution. For a comparison familiar to critical care staff, a can of Coke contains 0.43 kcal/ml. Thus, one may be able to survive for quite some time on this stuff, as it is very dense in calories and occupies little volume. For instance, a 70kg patient (with the daily requirement of 25 × 70 = 1750 calories) would require a little over 1030ml of 50% dextrose every day as TPN, if all of their non-protein nutritional needs were going to be supplied by dextrose.

In fact, for a long time dextrose was the only constituent of TPN solutions. Dudrick et al (1968) introduced this approach into practice on the basis of characteristically cruel animal experiments ("For 72 to 256 days 6 male beagle puppies were fed entirely by vein and compared with their littermates fed by mouth on a standard ration"). The solution used to feed them was glucose combined with fibrin hydrolysate and some vitamins and minerals. Good growth, positive nitrogen balance and normal activity was seen among the beagles, leading the authors to proceed immediately with human trials. "The parenteral solution, of 20% glucose, 5% fibrin hydrolysate, electrolytes, trace minerals and vitamins, was infused continuously... For 10 to 200 days 30 patients with chronic complicated gastrointestinal disease were supported exclusively by vein with 2400 to 4500 kcal per day. " Encouraging results were observed. Particularly, Dudrick et al gloated happily over the normal weight gain and development of a 1.8kg infant who was born with near-total bowel atresia.

Lipid supplied as a fatty acid emulsion mixture

The necessity of dietary fat and the "essentiality" of essential fatty acids

As discussed above, it is probably possible to survive on intravenous carbohydrate alone for a prolonged period. However, this approach will not supply essential fatty acids, which the human body is unable to synthesise. These seem to consist of α-linolenic acid (an omega-3 fatty acid) and linoleic acid (an omega-6 fatty acid), which no mammal can synthesise de novo because of our shared inability to add double bonds to the ends of fatty acids beyond carbon 9 and 10. Additionally, docosahexaenoic acid may become "conditionally" essential in situations where linoleic acid is in dietary excess (the metabolic pathways favour production of docosapentaenoic acid instead) and in pregnancy.

The slow discovery of the importance of these essential fatty acids is detailed in an excellent article by Ralph Holman (1998). The "essentiality" of these molecules was first discussed by George and Mildred Burr in 1929. The husband and wife team experimented on a colony of rats, "kept in a spacious north room in which the upper half of the wall is glass". The rats died horribly. Detailed notes are offered by the authors: "Ovulating poorly. Much blood in urine. Tail black and dead for 3cm from tip." The lesions found at autopsy included an absence of body fat, scaling of the skin, and mottling of the kidneys.

In spite of these disturbing data, fat-free TPN was administered to humans in the 60s and 70s after Dudrick et al (1968) were apparently able to carry it out safely. However even as early as 1970 (Paulsrud et al)  from case reports and case series it was becoming clear that essential fatty acids contribute substantially to the health of humans.  The quoted study attributed a series of "severe dermal lesions" on an infant to a 4.5 month course of fat-free TPN. In adults, these lesions are "characterized by dryness and scaly appearance, initially confined to the folds but becoming subsequently generalized" (Riella et al, 1975). The skin symptoms are likely the consequence of linoleic acid deficiency: as a component of acylglycosylceramides, it contributes to the integrity of the skin water barrier. Other symptoms include poor platelet function and poor wound healing due to the loss of the derivatives of arachidonic acid.

In summary, terrible things will happen if lipid is completely omitted from nutrition. Specifically, of the total daily energy intake approximately 4% should be contributed by linoleic acid and 0.5% by α-linolenic acid  (the European Food Safety Authority statement, 2010). Additionally to this, 100-200mg of preformed docosahexaenoic acid may be added to compensate for oxidative losses, particularly in pregnancy. These values are not derived from some complex metabolic measurements or theories, but rather from the observed lowest mean estimated intakes seen to have no effect on health among a number of European countries. In these quantities, the essential fatty acid supply is enough to ensure that their occasional and inevitable use for energy does not preclude their "essential" use for synthesis of structural lipids, prostaglandins and leukotrienes.

The composition of commercially available lipid preparations

The composition of intravenous lipid emulsions therefore reflects the clinician's concern with supplying essential fatty acids. The commercially available intravenous fatty acid mixtures vary in their content of essential fats, and to illustrate this I have shamelessly robbed Stawny et al (2013). The following table is reproduced here with no permission whatsoever:

The oils mentioned above merit a more detailed discussion, not because it is an essential part of CICM fellowship exam preparation, but because it is an amusing distraction from the horror of it. 

Soybean oil and Intralipid

Soybean oil (the main constituent of Intralipid) was the first fatty acid mixture used in parenteral nutrition, after people began to appreciate the effects of essential fatty acid deficiency. It was known in experimental parenteral fat supplementation as early as the 1940s, but became introduced into clinical practice in the 1960s and 70s; Paul Schurr's article (1969) gives a good overview of the period literature on the subject. Soybean oil contains high concentrations of α-linolenic acid (7-10%) and linoleic acid (up to 50%).  Other components include oleic (23%) palmitic (10%) and stearic (4%) fatty acids.

This combination of ingredients is certain to defeat any sort of essential fatty acid deficiency; there's certainly plenty of them. However, that turns out to be something of a disadvantage. Even though the EFSA have decided not to recommend an upper limit to daily dietary  α-linolenic and linoleic acid intake (considering them essentially benign in any quantity) there seems to be a problem with them being infused parenterally. Specifically, they appear to impair the function of granulocytes and lymphocytes. For instance, Nordenström et al (1979) found a dose-related impairment of leukocyte chemotaxis and migration. Subsequent studies of infectious epidemiology among TPN-dependent patients found an increased risk of infection, particularly related to the central lines (Snydman et al, 1982). Lymphocyte function also appears to be affected: studies consistently report that soybean oil-based emulsions inhibit T cell activation, proliferation and and IL-2 production.

The modern prescribers of TPN tend to limit their reliance on soybean oil. The idea is to supply enough essential fatty acids to prevent deficiency while limiting the patients' exposure to excess linoleic acid by relying on other fatty acids for the bulk of the energy supply.

Olive oil and ClinOleic

Olive oil supplies the bulk of its energy as oleic acid, which supposedly helps to avoid the abovementioned immunomodulatory effects. The use of olive oil in parenteral nutrition is the subject of an excelent review by Sala-Vile et al (2007), written to discuss the rationale for introduction of ClinOleic into the market. This Baxter product contains 80% refined olive oil. According to propaganda, the advantages of olive oil in TPN include "cardioprotective" effects seen in traditional Mediterranean diets and antiinflammatory "ibuprofen-like" effects observed in vitro. These are likely contributed by the high α-tocopherol concentration in the culinary preparation (which probably has some sort of antioxidant effect, preventing lipid oxidation and atheroma formation) and the cyclooxygenase-inhibiting effect of oleocanthal. Both chemicals are unlikely to be present in substantial quantities in commercially available parenteral olive oil, as it is a carefully controlled product, refined in laboratories, and therefore unlikely to be offered to intensive care doctors with unregulated quantities of vitamin E in it.

Medium-chain triglycerides and Lipofundin

Medium-chain triglycerides are a source of fatty energy which are slightly less energy-dense than standard long chain triglycerides. Historic interest has initially revolved around their use in acute pancreatitis, as they are short enough not to require the intervention of lipase and may be safely pumped into the duodenum of a patient who cannot produce any lipase. Intravenous lipid emulsions were all mainly based on long-chain triglycerides until the 1980s, when  mixtures of medium and long-chain molecules became more available. The advantages of medium-chain triglycerides are numerous. Michael Adolph summarised these in the first paragraphs of his undated publication for ESPEN (linked here, reproduced below):

  • Better solubility
  • More readily hydrolyzed by tissue lipases
  • More quickly elimi­nated from the circulation and taken up by peripheral tissues.
  • Not stored as body fat but are oxidized more rapidly than long-chain triglycerides
  • They are ketogenic, and both medium-chain fatty acids and ketone bodies are carnitine-independent substrates.
  • "Compared directly with pure LCT emulsions, MCT/LCT emulsions are a more efficient fuel, put less strain on the liver, and have significantly less impact on the immune system and RES function"

The use of medium-chain triglyceride mixtures was found to have a positive effect on secondary non-patient centered outcomes (eg. Ball et al in 1990 found a better nitrogen balance and higher ketone levels with the medium-chain triglycerides, suggesting that they were a better source of energy and more likely to prevent protein catabolism).  The best review of (now slightly outdated) hard outcomes evidence can be found in the 2009 ESPEN guidelines. Overall, a cautious (Grade C) recommendation is made in favour of a mixture of long and medium chain triglycerides, on the basis of small poorly designed studies which confirmed the abovelisted advantages. The ASPEN position paper on the clinical role for alternative intravenous fat emulsions (Vanek et al, 2012) does not make any specific recommendations about medium-chain triglycerides.

Lecithin as an emulsifier

Lecithin is an egg-based phospholipid which is present in 0.6-1.8% concentration, and contributes little to the nutritional content of the lipid mixture, except by way of acting as a surfactant. Wherever parenteral emulsion of fat is required, one may bet lecithin is also present (it is a part of the propofol infusion, for example). In their discussion of parenteral microemulsions, Date and Nagarsenker (2008), the authors remark that "lecithins should always be first choice due to their excellent biocompatibility". It only works as a surfactant within the pH range of 7.0-8.0, and becomes hydrolysed into fatty acids outside this range, with the resulting instability of the microemulsion.

Fish oil and  SMOFlipid

Fish oil in TPN is of interest because of the theoretical anti-inflammatory and antioxidant properties of the polyunsaturated series-3 fatty acids contained therein. These are molecules with a double bond (C=C) at the third carbon atom from the end, with intensivists specifically interested in eicosapentaenoic acid and docosahexaenoic acid.  To generalise "fish oil" is of course unfair, as each fish has its own brand of oil, with different concentrations of these fatty acids. An excellent review by Manzarenes et al (2013) scraped together all the evidence for this from 1980 to 2012, and found six trials worthy of metaanalysis (n=690). On close scrutiny, fish oil seemed to be beneficial. There was a statistically insignificant trend towards improved mortality. ICU length of stay was not affected, but the duration of mechanical ventilation was reduced slightly (the weighted mean difference in ventilation days was 1.4).  Among the fish-oiled patients, there was no improvement in the risk of infection. More recent data in support of fish oil can be Googled up if one wishes; for instance this 2015 dissertation by Hall et al found a significant improvement in mortality.  Another editorial by Manzanares et al (2015) again supports the benefits of fish oil, apparently without any sponsorship from Big Fish. Overall, authors seem to agree that some indefinite amount of fish oil is an appropriate addition to the PN lipid emulsion mixture.

Can't get enough of that wonderful SMOFAs a compromise between these known advantages and limitations, SMOFlipid was formulated as a reasonably balanced mixture of soybean oil, medium-chain triglycerides, olive oil and fish oil (6% - 6% - 5% - 3%, respectively). It is the emulsion of choice in the local unit, and it appears to be the only commercially available PN lipid emulsion with any amount of fish oil in it.  Its use is supported by recent data. For example, Dai et al (2016) found "nutritional advantages" in the use of SMOF and olive oil in terms of their effects on LFTs and the resulting serum concentrations of α-tocopherol, oleic acid, and the ω-3 PUFAs. An older analysis by Tian et al (2013) also attributed less toxicity to 20% SMOF formulae on the basis of lower hepatic enzyme levels. Inflammatory mediators such as IL-6 were also decreased in the SMOF group of ICU patients studied by Pan et al (2016). According to the Fresenius Kabi propaganda, their 20% SMOF cocktail was relatively free of adverse events in Phase I trials.

Caloric content of fatty acid emulsions

The usual 10% fatty acid emulsion has a calorie content of approximately 1.1 kcal/ml, which means the 70kg patient receiving 25 kcal/kg/day would require about 1590 ml/day of 10% fat emulsion. The lipid infusion also has the benefit of being isoosmolar with plasma. In contrast to 50% dextrose (which has nightmarish physicochemical properties) a lipid emulsion may be infused peripherally, and a patient fed exclusively with lipid may theoretically go on receiving their TPN via peripheral cannula, avoiding all the complications of central line insertion.

So, why not feed people with intravenous lipid alone?  Historically, whole populations -eg the Inuit, everybody's favourite model of carbohydrate-free existence - have persisted for generations on diets almost totally composed of fatty acids and protein. So, it is not completely inconceivable that a person may survive on a pure fat parenteral nutrition cocktail. Moreover, the fasted critically ill patient in any case derives nearly 100% of their energy needs by hydrolysing endogenous fat stores (ESICM working group, 2002)  However, there are limitations. The rate of lipid administration should match the rate of lipid elimination, with the liver being the rate-limiting metabolic organ. For each fatty emulsion this may be different. For instance, the manufacturer of SMOFlipid recommends a hourly rate no greater than 0.15g/kg/hr (or, 0.75ml/kg/hr of 20% SMOF). If this rate is exceeded, the patient risks becoming increasingly more and more hyperlipidaemic, with disastrous consequences (pancreatitis, fat overload syndrome, what have you).

Thus, if we decide that a 70kg patient requires 2000kcal/day of energy, and we decide to give all of it as lipid, we would be foced to infuse 1000ml of 20% SMOF (2kcal/ml), at a rate of about 42ml/hr. According to the maximum allowable rate above, a 70kg person can safely tolerate up to 52.5ml/hr (1260ml/day) of 20% lipid before fat overload becomes a problem. So, from a safety point of view, it could be possible to feed people purely with fat, provided their liver was able to process it. But would there be any metabolic sequelae to this?

Wilmore et al (1973) who explored the effects of a lipid-rich PN in 12 hypercatabolic burns patients and 15 convalescent healing controls.Of these people, some received up to 5g/kg/day of fat (well in excess of the abovementioned safety margin) for up to 60 days, with no apparent ill effects. Not all of these patients received "total" parenteral nutrition, and being hypercatabolic the fat only supplied an average of 38% of their total energy needs (which were elevated to 150-250% of normal values, on average to 3770 kcal/day). For a more pure fat experience,  Anderson et al (1976) compared a dextrose-only TPN with a lipid-rich TPN (83% of which was Intralipid, and 17% dextrose) and found little difference in terms of nitrogen balance and clinical outcomes (healing of fistulae, weight gain etc). No adverse events were seen. More recently, Tappy et al (1998) performed a similar study in critically ill patients in a surgical ICU. Of the patients who received 85% of their energy needs as lipid, none had any major complications (whereas the 75% dextrose group had hyperglycaemia and a 15% increase in their CO2 production). In short, it appears that fat can supply all (or most) on your energy needs safely, at least for a period of time, and with a normal working liver.

Protein supplied as an amino acid solution

The formulation of intravenous protein has come a long way since 1913, when Henreiques and Anderson infused hydrolysed protein into a goat for 16 days. An excellent overview of the modern state of the art is available from Gundogan and Ziegler (2015), whose lucid and detailed article explores the subject to a satisfying depth. Table 1 from their article is reproduced below without any permission, but with the expectation that the authors will forgive copyright infringement in the service of medical education.

The scientific basis for the composition of parenteral amino acid supplements

In short, there is none. The composition of modern amino acid supplements is not based in any sound empirical research, but rather in expert opinion, animal studies, and metabolic theory. There are nine essential amino acids: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Approximately half of the PN mixture will be composed of these. The rest are "non-essential", i.e. may be synthesised from the others- they are alanine, arginine, glycine, proline, serine, and tyrosine. One finds the fact widely acknowledged, that both essential and non-essential amino acids must be supplemented, but apart from glutamine (as an "immunonutritient", or "pharmaconutritient" if you will) little attention has been paid to specific formulations in terms of randomised trials.

The local favourite is Aminoven 10%, not listed in the table above, but generally representative of the broad trends in "balanced" amino acid mixtures. The mixtures are called "balanced" because their concentration closely resembles that which might be found in the human bloodstream during normal health; no specific amino acid enjoys a specific emphasis.

The scientific basis for recommended dosage of amino acid

Generally, 1.5-2g/kg/day of protein is recommended by the various eminent societies. No more than 2g/kg/day of protein will be utilised; the rest is wasted  (ESPEN, 2009) - unless one is on dialysis or on ECMO, in which case excess protein should be given (as the CRRT circuit will wash out useful nutrients, and the ECMO circuit will adsorb them). Adequate non-protein energy must be supplied together with the amino acids, otherwise they will be incorporated into energy metabolism (and this is a waste of protein substrate).

Amino acid mixtures provide 17% less protein and energy than is expected from their mass, due to the hydration status of the amino acids. "The hydration status of free amino acids dilutes the protein substrate they provide by a fraction that depends on the molecular weight of each amino acid", because a molecule of water is released when a peptide bond is formed, with the consequence that the molecular weight of a peptide-bound amino acid is 18 mass units less than its formal molecular weight (Hoffer et al, 2011). Thus, 100g of free amino acids must provide less than 100g of protein substrate, when protein is constructed from the amino acids.

Physicochemical properties of TPN

Presentation of the mixture

This thing is a large opaque sack full of nutrient. The total volume is around 2270ml. The opaque sack is well protected from UV light (which degrades Vitamin A) and is made of a fairly inert plastic. It stays refrigerated until use, and must be discarded after 24 hours because of potential bacterial contamination. Many TPN mixtures present as unmixed bags of separated lipid mixture and aqueous mixture, combined at the last minute (or even in the vein) because of concerns regarding the stability of emulsion.

Stability of the lipid emulsion

The lipid component of the TPN mixture consists of tiny spherical micelles of oil suspended in water. The size of these particles is vaguely similar to the size of chylomicrons. They do not coalesce into one big oil droplet because there is a persistently negative charge on the outside of each micelle which repels the particles from one another. However, this helpful influence can be destabilised by the presence of excess cations in the aqueous phase of the mixture, particularly divalent and trivalent cations. The trivalent cation in iron dextran seems to be the worst offender (Driscoll et al, 1995)

The lipid emulsion mixtures typically have a CAN: Critical Aggregation Number, the maximal concentration of cations above which the aggregation of lipid particles may occur. This places a limit on how much cations one may prescribe. But what if the patient really needs a massive amount of daily calcium or magnesium? In order to overcome this CAN limit, some mixtures come as a "2 in 1" bag, which presents as separate lipid and aqueous compartments, and which is only mixed at the point of entering the vein.

Osmolality of parenteral nutrition solution

TPN mixture is usually quite hyperosmolar. It typically exceeds the osmolarity of blood by a factor of 6-10. The major contributors to the osmolality are the 50% dextrose and the amino acids; the dextrose by itself has an osmolality of 2780 mOsm/kg and it is added to a   10% w/v amino acid mixture (for instance Glamin has a theoretical osmolality of 1140 mOsm/kg). In contrast, the lipid mixture is usually isoosmolar and rather benign as a peripheral infusion. The osmolality of the aqueous phase of the mixture is unaffected by the lipid droplets, as the two stay well apart (in order to alter osmolality you actually have to dissolve in the water). The resulting mixture (with an osmolality anywhere from 1500 to 2000 mOsm/kg) is therefore well above the theoretical upper limit of vein-friendly osmolality. To exceed that upper limit means to court thrombophlebitis. Like any other hyperosmolar solution, TPN will denude the venous intima and render it prothrombotic.

What is the upper limit of peripheral PN osmolality? The ESPEN people recommend 850mosm/L and the ASPEN people recommend 900 mOsm/kg as the limit of safe osmolality.  This is not very high. Considering the total molar mass of necessary components (the daily requirements), this peripheral infusion limit would result in a rather dilute TPN solution, which would therefore require a large daily volume to be infused. It would therefore be insane to rely on peripheral PN for the entirety of one's nutritional needs. The ESPEN guidelines reflect this; they recommend the use of peripheral PN only as a supplement to inadequate enteric nutrition.

Interactions between TPN components

The TPN mixture is a complex two-phase drug; probably the most complex thing the pharmacy ever makes. Up to 50 components must co-exist in the same container, and they must all play nice together. Multiple interactions may occur between components and each other, the container, the outside environment (ambient light and temperature) and any other drugs being given to the patient. With even minor changes in ambient conditions the fragile peace between ingredients may be disturbed, resulting in hideous and frequently unpredictable reactions. These may range from relatively benign discolouration to some sort of accelerated precipitation state where the arse falls out of the aqueous phase and it suddenly separates into water and  insoluble crystals, while  the lipid emulsion droplets all coalesce into a thick oil slick.  The more clinically important of these reactions are discussed below.

Calcium phosphate precipitation

This is a sediment which forms when the calcium and phosphate ions added to the TPN exceed a certain level. For this reason, there is a limit to how much daily PO4 replacement one can prescribe for a TPN patient. Usually, the sedimentation reaction (in the aqueous phase) takes place when the combine concentration of calcium ions and phosphate ions exceeds 72 mmol/L. Obviously, the pH and temperature of the mixture play a role in this.

Vitamin inactivation

Water-soluble vitamins in the aqueous phase are susceptible to chemical and photo-degradation. Specifically, Vitamin A and B1 are degraded by photolysis, and are one of the main reasons the bags of TPN are not supposed to be exposed to light. Vitamin A may also adsorb onto the walls of the container, and Vitamin C may get oxidised. The consequence of these reactions is at best a vitamin-deficient nutrient mixture. At worst, the products of degradation are toxic or corrosive.

Instability of the stored mixture

Normal mixtures may remain stable in the refrigerator for up to 9 days, but the stability of the mixture at room temperature never exceeds 24-30 hours. In general, the mixture should never be exposed to a temperature in excess of 28° C for any duration of time,  and special attention should be paid to keeping air out of the container (Lee at al, 2001)

Monitoring TPN therapy

It would be reasonable to assume that something as complex as parenteral nutrition should be carefully observed during its initiation and maintenance. On a basic level:

  • Trace elements and fat-soluble vitamin levels at baseline
  • BSL every 6 hours on day 1, and then daily thereafter
  • CMP/EUC/LFTs watching for refeeding syndrome and hepatosteatosis (frequency depends on risk)
  • Serum cholesterol and triglycerides weekly at first, and then three-monthly
  • Regular fluid balance and weight measurements

Hartl et al (2009) have produced an excellent paper to list the complications of PN, including comments on when they happen and how to watch for them. One may divide these into categories by "early" and "late" but this does not do justice to the richness of the content. The author flatters himself by thinking that it would be better to separate them into functional domains, as follows:

  • Monitoring for refeeding syndrome:
    • Electrolytes (phosphate, potassium, magnesium)
    • ECG (arrhythmia)
    • Clinical features of heart failure
    • Volume status (watching for overload)
    • Glucose intolerance
  • Monitoring the adequacy of nutrition:
    • Baseline weight
    • Baseline trace element and fat-soluble vitamin levels
    • Weight and other anthropometry at regular intervals to watch for weight loss
    • Biochemistry (eg. albumin and pre-albumin)
  • Monitoring for metabolic complications:
    • Cholesterol and triglycerides weekly, and then three-monthly when well established on PN
    • BSL at least 6 hourly in the first days, and then daily until stable
    • LFTs daily, and then weekly 
    • Ultrasound of the gallbladder within 4-6 weeks to watch for cholestasis
    • Bone density tests (DEXA) over the timeframe of months

Supplemental parenteral nutrition

This was a substantive 60% part of Question 9 from the second paper of 2022, which asked about the rationale, timing, and "your evidence-based approach"Russell & Wischmeyer (2018) and the excellent narrative report by Berger et al (2022) treat this complex subject with the right level of detail, and were used to compile the approach below.

Rationale for supplemental PN

  • Malnutrition is a significant contributor to ICU morbidity and mortality, manifesting in terms of increased susceptibility to ICU-acquired weakness, pressure areas, poor wound healing, poor immune function, and many other problems
  • Many patients admitted to the ICU may already be malnourished at the time of admission
  • Early enteral nutrition is the recommended method of nutrition for the critically ill, but according to Cahill et al (2010), over the first twelve days in ICU on average only about 50-60% of the nutritional needs are met with enteral nutrition, and it takes almost two days on average to achieve.
  • From this, it follows that nutritional needs could (should?) be supplemented with parenteral nutrition to achieve the goal (100% of nutritional requirements fully met) earlier in the ICU stay

Definition of supplemental PN

  • "Parenteral nutrition added to EN when EN alone is insufficient" is how this tends to be defined in the literature; however specific dosing and timing are not consistent

Timing of supplemental PN

  • 2022 ASPEN guidelines recommend supplemental PN after 7-10 days, "if unable to
    meet 60% of energy and protein requirements by the enteral route alone",
    which remained unchanged from the 2016 guidelines.
  • 2017 ESPEN guidelines recommend supplemental PN after 7 days "if the energy and nutrient requirements cannot be met by oral and enteral intake alone (< 50% of caloric requirement)"
  • Furthemore, ESPEN do not recommend contemplating supplemental PN "if the expected time period of PN is < 4 days", which is perhaps inappropriately reliant on the intensivists' ability to predict the future
  • Clinical trials (eg. Gao et al, 2022) defined early supplemental PN as starting day 3 following surgery (these data were collected from abdominal surgery patients)

Evidence to support this practice

  • Systematic review and meta-analysis by Alsharif et al (2020) turned up only five studies, of which the largest was Heidegger et l (2013; n=320).
  • Mian take home message from the available trials was that supplemental PN was safe, in the sense that morbidity and mortality were unaffected, but also that it was pointless, in the sense that morbidity and mortality were unaffected.
  • More recently,  Gao et al, 2022, n=230 in China - early supplemental PN in major abdominal surgery patients was associated with a reduced risk of infection, but other outcomes were unchanged.

Counter-arguments to oppose the use of supplemental PN

  • Parenteral nutrition is associated with considerable expense and increased workload
  • Underfeeding patients to varying degrees has never been demonstrated to have much of a mortality disadvantage (eg. the PermiT trial by Arabi et al, 2015, or the EDEN trial by Rice et al, 2012)
  • The definition of supplemental PN is unclear (shall we supplement up to 100%, 80%, 60% of the expected nutritional intake), nor is the importance of specific components (for example, if a hypercatabolic state is your main concern, shall we just supplement protein, and not calories?)
  • The question of whether to supplement, and how much, relies on the assessment of nutritional requirements, which for the critically ill patient is challenging.

Own practice

  • The CICM exam candidate is suggested to adopt a non-controversial position here which obeys the ASPEN and ESPEN kabbalah while demonstrating some consultant-level individuality, eg. "in my practice, I will add PN to EN on day 7 of inadequate nutritional intake, or earlier in patients with pre-existing severe malnutrition, or those in whom EN is clearly and predictably unlikely to be established within this timeframe, such as those with severe ileus or GI tract injury"


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