1848 
Michael Allwood
BPharm PhD
FRPharmSGB
Secretary
British Pharmaceutical Nutritional Group
Parenteral nutrition (PN) is a lifesaving treatment for patients unable to absorb any or sufficient nutrients from their gut to prevent starvation. It was first employed in the 1960s but only became an established treatment in the 1980s. In these early days, daily administration involved the preparation and setting up of up to six containers (separate infusions containing protein hydrolysates or amino acids, fat emulsion, high-concentration glucose solutions, and into which nurses on the ward would make additions of electrolytes, trace elements and vitamins). Infusion was performed through a peripherally or, less commonly, centrally-placed catheter. However, this approach was far from acceptable, resulting in poor nutritional control and, above all, unacceptable infusion line complications, including thrombophlebitis and sepsis. An infection rate of greater than 20% of such lines was common.
The innovative solution to these problems lay in the development of the “big bag” concept in which ideally all, or initially most, of the nutrients for each day’s requirements were combined into one three litre capacity sterile plastic bag. However, for this approach to be safe, it required the compounding of PN mixtures in an aseptic environment. It also required the research and knowledge necessary to ensure that mixtures remained stable and free from precipitates after compounding. The role of the pharmacist became central to the safe and effective application of PN in modern hospital practice, since they had the knowledge, skills and access to suitable aseptic facilities for such complex procedures.
Understanding the stability of PN mixtures
Early attempts to compound complete PN mixtures were constrained by two concerns. First, the realisation that mixing calcium and phosphate ions together could result in the precipitation of calcium phosphate salts, some of which are relatively insoluble in water. It was also recognised that the solubility of trace element additives might be compromised. Secondly, there was little if any information on the chemical stability of any of the ingredients after transfer from their original container into more dilute solutions, or of any possible chemical reactions between any of these ingredients. It was also considered that the fat emulsion would crack after dilution in any such complex chemical solution.
Initial studies focused on the physical and chemical stability of “two-in-one” mixtures (PN mixtures without the emulsion, which continued to be administered via a separate line). Research showed that mixtures containing amino acids, glucose, electrolytes and micronutrients were physically compatible, at least within certain identified limits, and that the amino acids were relatively stable after mixing. So big bags could be prepared and assigned limited shelf-lives – initially of up to three days – with some confidence. This was often increased as more knowledge and experience was gained.
Research through the 1980s resulted in two important developments. First, it became apparent that PN mixtures were actually quite stable chemically and longer shelf lives for compounded PN mixtures were possible. Secondly, that, in fact, fat emulsions were remarkably stable after inclusion in many PN mixtures, resulting in the realisation that most adult regimens could be compounded to include the fat emulsion in the big bag. So the all-in-one mixture became the norm, at least for adult PN.
One major issue that has always been recognised as a factor that tends to destabilise fat emulsions is the cation load – in particular the concentrations of divalent ions (ie, calcium and magnesium). Because neonates and small children have greater requirements for these elements, such PN mixtures cannot include the fat emulsion.
We have now reached the point in our knowledge and understanding of PN stability that most PN regimens can be safely compounded and assigned extended shelf-lives of weeks and even months. Factors that constrain the stability of PN mixtures are now well understood, enabling any requirement to be met. For example, the least stable component is ascorbic acid, which is oxidised by reaction with dissolved oxygen. This was the reason why complete mixtures could only be stored for a few days in the original big bags made from EVA or PVC, which are highly permeable to air. The introduction of a multi-layered big bag, which is essentially impermeable to gases, enabled the shelf-lives of such mixtures to be extended to several weeks without unacceptable loss of this and other vitamins.
The role of the pharmacist
When Nutrition Teams were becoming recognised in the 1980s as essential part for safe and effective delivery of clinical nutrition, the pharmacist was automatically included. Their key roles were:
- The operation and management of the compounding and delivery of PN in a form ready for administration.
- Advising on the pharmaceutical aspects of any prescription and on new developments and alternative nutritional products. This role has in many cases further developed to offer advice on clinical aspects of PN, such as commenting on complications, the use of standard as compared with individualised PN bags, cost benefit appraisals and, most recently, the prescribing function.
The British Pharmaceutical Nutritional Group
The British Pharmaceutical Nutritional Group (BPNG) was established in the late 1980s in response to the increasingly important role of the pharmacist and pharmacy department in clinical nutrition. It was started by a small number of hospital, academic pharmacists and colleagues from the pharmaceutical industry who were closely involved in a range of PN-related issues, including the clinical aspects (eg, nutritional parameters, prescribing and regimen design), technical issues (eg, compounding, design and operation of aseptic facilities, and quality assessment) and researching the stability and safety of PN mixtures. The BPNG was, and remains, a founder member of British Association of Parenteral and Enteral Nutrition. Its primary focus is to provide the following services to its members and others directly involved in the delivery of clinical nutrition:
- Educational activities, through meetings and other means, to provide basic and advanced training and sharing of experience and knowledge on all pharmaceutical aspects of clinical nutrition (including not only PN but issues associated with enteral nutrition (EN), which involve the pharmacists – for example, the administration of medication to recipients of EN).
- A resource of pharmaceutical expertise which can be offered via the BPNG’s website.
- Responding to official documents (eg, the recent National Institute for Clinical Excellence document on clinical nutrition).
- Providing a link between pharmacists and those pharmaceutical and technical companies with interests in any aspects of PN and pharmacy-managed aseptic operations.
- Encouraging research through the identification of problems and issues, providing limited funding, and opportunities to share the results of such research with colleagues.
- Providing expert advise and publishing best practice, research-based guidelines and position papers on key aspects of safe PN. Recent examples include the use of in-line filters and ensuring safe calcium phosphate additions. Future areas include catheter blockage, standard versus individualised bags and supplementary prescribing guidelines for PN.
The BPNG is therefore highly active in supporting the profession. It provides the focus for pharmacists, technicians and other professions with an interest in clinical nutrition concerned with the safe and effective preparation and delivery of PN, both in the secondary sector as well as for home patients.
