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Stability issues in home parenteral nutrition
Clinical Nutrition (1998) 17(5): 199-203 © 1998 Harcourt Brace & Co. Ltd
REVIEW
Stability issues in home parenteral nutrition C. V. WORMLEIGHTON, T. B. CATLING Pharrnacia & Upjohn Ltd, Davy Avenue, Knowlhill, Milton Keynes, MK5 8PH, UK (Correspondence to: CVW) Abstract--Home parenteral nutrition (HPN) is a method of providing nutrients, fluid and electrolytes intravenously to patients with a malfunctioning gastrointestinal tract, at home. Parenteral nutrition (PN) formulations are checked carefully for stability by the hospital pharmacist before the bags are made. However, there are many differences between supplying PN regimens to in-patients on the ward and to patients at home. Transportation between the hospital and home may be prolonged if the patient lives a long w a y from the hospital and may not be straight-forward. A number of factors can adversely affect the stability of the PN, which in turn can cause complications such as line blockage; or even life-threatening events, such as pulmonary embolism. The hospital team caring for HPN patients needs to be aware of these stability issues if complications resulting from incompatibilities of the solutions in the bags or the infusion line are to be avoided. Key words: home parenteral nutrition; hospital pharmacy, stability; nutritional mixtures
trained to aseptically manage their feeding line and entry site, the patient/carer also needs to be able to make certain additions to PN bags, as the stability of the feed is often greatly reduced once micronutrient additions have been made (6, 7).
Introduction Home parenteral nutrition (HPN) is a method of providing nutrients, fluids and electrolytes intravenously to patients with a malfunctioning gastrointestinal tract, in the home environment (1). Parenteral nutrition (PN) was described as 'an artificial gastrointestinal tract' by Rhodes (2). Without the more recent technical and logistical developments, patients requiring long-term PN would ordinarily have had to stay in hospital. Now, many can be treated at home, although patients or their carets need to be very carefully assessed when being considered for HPN. This is due to the depth of understanding and the dexterity required to perform the often complex procedures necessary to maintain an uncomplicated feeding line (3). Once it has been decided that HPN is the optimal method of nourishing the nutritionally-compromised patient, a choice as to the type of venous access device must be made. This decision should involve all members of a multidisciplinary nutrition support team (typically a clinician, nurse, pharmacist and dietician (4); often with other relevant personnel) as well as the patient and carer (5). For long term use, silicone catheters have been generally regarded as the most suitable (1). However, with the more recent introduction of the subcutaneously implanted device, where daily accessing of the port with a needle is required, certain factors need to be taken into consideration. For instance, some patients and/or carers may feel unable to take on this task, so there must be resources within the local community service: such as a nurse with the necessary skills and knowledge required who is able to visit the patient, sometimes on a daily basis, to access the port. As well as being
HPN regimens PN regimens, in which the separate components of PN are mixed together in a single bag, have been successfully used in both hospital in-patients and patients treated at home for many years (8). HPN regimens may be 'All-in-One', in which an intravenous amino acid solution, glucose infusion, lipid emulsion, electrolyte solutions and (occasionally) micronutrient preparations are mixed together in a single bag. Alternatively, they may be lipid-free, where the lipid emulsion and fat-soluble vitamins are omitted from the bag. In practice, HPN patients often receive a combination of the two; having lipid-free bags some days and All-in-One bags on other days (9). This is determined by the physician and is dependent upon the nutritional requirements of the patient. The aim is to maintain body weight whilst encouraging an independent lifestyle. These bags are usually delivered without micronutrient additions, i.e. vitamins and trace elements, so that the solution remains stable for as long as possible. The patients or their carers are then taught to add the necessary vitamins and trace elements according to their individual needs. A single bag reduces the number of manipulations required to set up the infusion and therefore reduces the risk of contamination via administration (10). However, mixing the components (which can result in the combination of over 50 separate chemical entities) may result in compatibility problems if stability guidelines are not followed (11). In hospitals, PN bags are often compounded 199
200
STABILITY ISSUES IN HPN
on a daily basis and are supplied with micronutrient additions already made by the pharmacy; however, for HPN, bags are delivered on a weekly/fortnightly basis. If the patient/carer is unable to make additions, then reliable stability data needs to be readily available to ensure that the solutions remain safe to use for the whole period of time until another delivery of PN can be made. Supplying PN regimens to patients at home increases the risk of compatibility problems because the temperature of the PN bags may not be strictly controlled during transportation between the hospital and the home. Using a specialized homecare company can minimize this risk. HPN regimens should be compounded in a sterile production unit within the hospital pharmacy department under the supervision of a pharmacist - nurses or patients should not be allowed to compound PN regimens for a number of reasons. Sterility of the PN is essential and can only be assured by the use of a strict aseptic technique by suitably qualified and validated staff in a validated sterile room with appropriate sterile equipment (12, 13). The pharmacist is also responsible for assuring the physical and chemical stability of the PN regimens, in accordance with guidelines from the manufacturer of the PN products. These guidelines should address compatibility of the ingredients to be mixed, the correct mixing procedure, correct storage conditions and information regarding the maximum administration time and temperature (14, 15). The compounding pharmacist usually has a high degree of control in the in-patient setting, through being responsible for the compounding of the regimen and its storage until transfer to the ward. The ward pharmacist may then monitor the handling and administration of the filled bags on the ward. Bags will normally be compounded and used within 7 days. However, for the typical HPN patient, the PN regimen should have a longer expiry (e.g. 14 days), to fit in with delivery schedules and a less straight-forward route to the patient after compounding.
Stability of HPN regimens Physical and chemical stability of All-in-One and lipid-free PN regimens are dependent upon several factors: concentrations of individual components, pH, temperature, forms of individual electrolyte solutions used, etc (11, 16). In particular, a high glucose concentration can destabilize the lipid emulsion in All-in-One regimens; a very low glucose concentration can lead to excessive 'creaming' (separation of aggregates of lipid globules from the mixture, which rise and form a layer of 'cream' on top of the regimen). Also, a high electrolyte content in the regimen, particularly of divalent cations (calcium and magnesium), can destabilize the lipid emulsion by neutralizing the negative repulsive charge (the zeta potential) on the surface of the lipid globules. In All-in-One and lipid-free regimens, high concentrations of calcium and phosphate (particularly at a higher pH) can cause insoluble calcium phosphates to precipitate out of solution (17-19). Some trace metal ions
can react with certain amino acids to form insoluble complexes (11). Vitamins may degrade so that the dose received by the patient is significantly lower than the dose prescribed (16). There are many publications on stability/instability of PN regimens and it is outside the scope of this paper to discuss this further (16, 20-22). It is essential that filled PN bags are stored at 2-8°C until required for use. They should normally be infused within 24h after removal from the refrigerator (23). Frozen bags containing lipid must not be used even after thawing (the lipid may be destabilized) (24). If bags have been kept above 8°C, instability of All-in-One or lipid-free regimens can result from acceleration of the reactions described.
Commercial homecare services A homecare company is often used for providing HPN. These companies can arrange for the compounding of PN bags, the delivery of bags plus ancillary items (e.g. disposable items, such as infusion sets), the loan of a dedicated refrigerator, pump, drip stand and other i.v. equipment, and stock checks in the home (25). The homecare company may be directly responsible for compounding the bags; or a hospital pharmacy may be used to compound the bags and the homecare company then dispenses them. In the latter case, the journey of a typical delivery of HPN regimens may be as follows. Twenty-four hours prior to the initial delivery a refrigerator of appropriate specification should be installed in the patient's home, so that the bags are stored at the correct temperature as soon as they are delivered. The bags are compounded in the hospital pharmacy and if necessary, stored in a refrigerator until transportation to the homecare company for checking and dispensing. They may be stored there overnight, prior to being transported to the patient's home and refrigerated until required for use. If strict procedures for handling and storage of the bags at every point in this process are not in place, then deviations in temperature may occur, which could adversely affect the stability of the regimens. For example, PN bags are ideally transported in a temperature-controlled vehicle or at least in a suitable coolbox with icepacks - validation of this system is required to ensure that the bags will remain at the correct temperature throughout their journey (Brierley E. Validation of packaging components used for transporting Kabi TPN bags. Portsmouth Hospitals NHS Trust, UK, 1993 - unpublished.) Bags should not be allowed to come into direct contact with the icepacks in order to avoid localized freezing. All refrigerators used for storing PN regimens in the home must be carefully monitored, and thermometers must be validated for accuracy. It is important that the driver who delivers the bags places them in the refrigerator straight away and any bags left over from the previous delivery are rotated to the top, once the expiry date has been checked. Any out of date bags must be destroyed or returned to the pharmacy so that the patient cannot use them. It is also important to keep a record of the temperature
CLINICAL NUTRITION
profile at various points within the refrigerator to maintain optimum storage conditions. Refrigerator temperatures are influenced by ambient air temperatures, the storage capacity and model of the refrigerator and how full it is (Minton A. Internal report, Welsh School of Pharmacy, UK, 1997 -unpublished). If the patients feel uncomfortable with the intrusion of a driver into their homes, then they must be adequately trained to perform these checks themselves, with regular compliance monitoring from the homecare company.
Administration of HPN regimens Patients must be trained to ensure that their PN bags are correctly stored and handled at all times. A dedicated refrigerator of appropriate standard should be used for the bags and the patient will normally remove the bag required for infusion 2-3 h prior to connection to allow it to warm up to room temperature. This is done to avoid an unpleasant sensation caused by infusing a cold solution straight into a central venous catheter; and also to allow dissolved gases to come out of the solution. Warming the regimen up to room temperature prior to infusion will not adversely affect its stability provided it is infused immediately. Under no circumstances should the unused bag then be put back into the refrigerator with the intention of using it at a later date. Infusion temperature is important; it should be below 25°C, unless stability studies have been carried out to valiate the use of higher temperatures. Many patients will infuse their PN regimen on a cyclical basis overnight (26), so this should not be a problem. However, if patients are on PN during the day, they should be warned of the potential problems (e.g. sitting out in the sunshine on a hot day). HPN patients are generally encouraged to cover their feeds, as direct light can affect the stability (27). Trends have, up to now, indicated that the lipid protects the watersoluble vitamins from degradation and therefore there is no need to cover AIO bags, only those that are lipid-free. However, evidence now suggests that lipid peroxidation can result from the attack of free radicals and may '... have a special potential for causing human diseases...' (28, 29) Therefore, it is safer to cover all HPN bags, until further information can be given on the effects of this process. Management of the line varies from unit to unit. However, it has been universally acknowledged that patients on PN should have a dedicated feeding line, not only to reduce the risk of infection through frequent handling, but also to minimize the risk of incompatible solutions mixing in the catheter (30). This is largely avoided by using the correct protocol when flushing the line after each feed, the type of flush varying according to the preference of the clinician (31). However, research suggests that lines flushed or locked with heparin risk the flocculation of the lipid by the heparin if calcium is present (32-34). This will not only destabilize the solution, but will also reduce the life-span of the line, where narrowing may occur due to the built-up debris along the catheter (35, 36). This
201
phenomenon is not circumvented by infusing lipid separately via a Y-site (37). Therefore, it is suggested that contact between PN/lipid and heparin should be avoided by using sodium chloride alone, or before and after heparin locks, to flush lines. The use of a reliable infusion pump to administer the PN regimen at home is important; not only for the patient's peace of mind and the correct administration of the parenteral nutrition, but also because parenteral nutrition admixtures are generally only stable for 24 h at room temperature. If the pump malfunctions in the night and an engineer is unable to go to the patient's house to repair it until the morning, then the bag currently being infused will probably be wasted as the infusion will not be completed within 24 h.
Avoiding complications of HPN The infusion of free oil, excessively large lipid globules or insoluble matter in the form of precipitates into the patient could cause fatal pulmonary emboli, and must be avoided by ensuring that these do not occur during mixing, storage or infusion (38, 39). The use of an in-line filter (0.22 g for lipid-free regimens, or a special 1.2 g lipid filter for All-in-One regimens) may prevent precipitates or free oil in the bag from being infused into the patient; but such filters must not be used as a substitute for correct pharmaceutical formulation of stable PN regimens. The routine use of in-line filters is currently somewhat controversial; but based upon the available information (40, 41), it is the opinion of the authors that they should be used to prevent particulates from a variety of sources from being infused. In addition, the 0.22 g filter retains bacteria. Both types of filter should be changed every 24 h. The problem of 'gassing out' can be a nuisance for some patients. Air dissolves in the PN solution when it is refrigerated; when the bag warms up, the air bubbles come out of solution and can trigger the 'air in line' alarm on the infusion pump. The incidence of this is reduced by the use of multi-layered PN bags instead of standard ones: the standard empty PN bag is made of a single layer of ethylene vinyl acetate (EVA), which is quite permeable to air. Multilayered bags have several layers of EVA and other materials to make them less permeable to air (42). If air is excluded from the PN regimen in this way, 'gassing out' is unlikely to occur as air cannot pass through the bag to dissolve in the solution. The compounding process can affect the amount of air filled into the bag and the compounding pharmacist should ensure that this is minimized (43). If patients wish to holiday abroad, they need to be aware of the problems associated with this (44). A dedicated refrigerator must be available to them to store their bags in once they have arrived, and it is advisable that a thermometer is given to the patients prior to their holiday to check that their feeds are being stored at the correct temperature. Depending on the length of stay, it may be possible for the additions to be made to the bags prior to departure.
202 STABILITYISSUESIN HPN H o w e v e r , this can only be done safely if reliable and accurate stability data has b e e n given. For example, a P N f e e d with micronutrient additions m a y only be g i v e n a m a x i m u m 8 day shelf-life, so if a patient is planning a longer holiday this m i g h t not be an option. It m a y take less t i m e for the bags to w a r m up prior to infusion in a hotter climate, therefore patients should be e n c o u r a g e d to infuse i m m e d i a t e l y after m a k i n g additions and preferably overnight w h e n it will be cooler. T h e P N bags are taken to the airport in cool boxes and responsibility is handed o v e r to the patients. Therefore, it is v e r y important that the patients are educated thoroughly before going on holiday abroad. W i t h an increase in the n u m b e r o f c o m p a n i e s n o w providing a h o m e service and the variety of solutions available, H P N feeds are b e c o m i n g increasingly c o m p l e x . Care must be taken w h e n m i x i n g not only different solutions f r o m the s a m e manufacturer but also if substituting different brands o f similar solutions (11). The stability with one solution m a y not be the s a m e as with another, as all types of solution (e.g. lipid emulsions) are slightly different in their c o m position. C o m p o s i t i o n s v a r y as a result of differences in raw materials and m a n u f a c t u r i n g processes. Therefore, w h e n considering a change o f brand, n e w stability data m a y be required e v e n if the basic prescription has r e m a i n e d the same.
Summary This paper has suggested reasons w h y accurate and reliable stability data should be obtained prior to g i v i n g a patient P N and the possible c o n s e q u e n c e s o f failing to consider stability once the bags h a v e left the hospital. Written stability data should be obtained f r o m the manufacturer. Products f r o m different manufacturers should not be mixed. Bags should not only be c o m p o u n d e d correctly using this data, but should also be correctly handled at e v e r y stage b e t w e e n leaving the hospital p h a r m a c y and administration to the patient. It is important that e v e r y o n e i n v o l v e d in the patient's care, including the patient, is aware of the potential p r o b l e m s and that the risks are m i n i m i z e d by ensuring that the bags are transported, stored, handled and administered correctly. A l t h o u g h v e r y little w o r k has been carried out to s h o w the effect of an unstable solution on the catheter itself and whether the l o n g e v i t y of a line is reduced for this reason (45), this and the other potentially life-threatening complications cannot be ignored.
Acknowledgement The authors would like to thank Dr M. I. Barnett and Dr A. G. Cosslett for their comments on the manuscript.
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Nutrition in Clinical Practice 1986:179-191 3. Dann A I. Central line sepsis in children with gastrointestinal disorders. Gastroenterology Nursing 1994; June: 259-263 4. McCrae J D, O'Shea R, Udine L M. Parenteral nutrition: hospital to home. J Am Diet Assoc 1993; 93(6): 664-670 5. Bloch A S, Brown P. Methods of nutritional support in the home. J Pain Symptom Manage 1990; October 5 (5): 297-306 6. Dahl G B, Jeppsson R I, Tengborn H J. Vitamin stability in a TPN mixture stored in an EVA plastic bag. Journal of Clinical and Hospital Pharmacy 1986; 11: 271-279 7. Allwood M C, Barnett M I. Micronutrient stability (letter). Pharmaceutical Journal 1996; 256 (March 23): 403 8. Cade A, Puntis J. Economics of home parenteral nutrition. Pharmacoeconomics 1997; 12(3): 327-338 9. Driscoll D F. Clinical issues regarding the use of total nutrient admixtures. Drug Intelligence and Clinical Pharmacy 1990; 24:296-303 10. Meguid M M. CIinical applications and cost-effectiveness of AIO. Nutrition 1989; 5(5) (Suppl): 5-6 11. Barnett M I, Cosslett A G, Duffield J R, Evans D A, Hall S B, Williams D R. Parenteral nutrition - pharmaceutical problems of compatibility and stability. Drug Saf 1990; 5 (Suppl 1): 101-106 12. Aseptic dispensing for NHS patients. A guidance document for pharmacists in the United Kingdom. London: Department of Health, 1994 13. American Society of Hospital Pharmacists. Technical assurance bulletin on quality assurance for pharmacy-prepared sterile products. American Journal of Hospital Pharmacy 1993; 50:2386-2398 14. Brown R, Quercia R A, Sigman R. Total nutrient admixture: A review. JPEN 1986; 10(6): 650-658 15. Pharmacia & Upjohn Nutrition. Complete admixtures for intravenous nutrition. Pharmacia & Upjohn Ltd, UK, 1997 16. Allwood M C. Compatibility and stability of TPN mixtures in big bags. Journal of Clinical and Hospital Pharmacy 1984; 9:181-198 17. Jimdnez Torres N V, Ronchera Oms C L. Calcium and phosphate in all-in-one mixtures. (Proc. 9th Annual Congress ESPEN, Barcelona, 1987). Clinical Progress in Nutrition Research 1988; 204-221 18. Cousins D H. Avoid TPN calcium phosphate risks. Hospital Pharmacy Practice 1994; September: 350-353 19. Knowles J B, Cusson G, Smith M, Sitrin M D. Pulmonary deposition of calcium phosphate crystals as a complication of home total parenteral nutrition. JPEN 1989; 13(2): 209-213 20. Jeppsson R I, Sj6berg B. Compatibility of parenteral nutrition solutions when mixed in a plastic bag. Clinical Nutrition 1984; 2:149-158 21. Driscoll D F, Bhargava H N, Li L, Zaim R H, Babayan V K, Bistrian B R. Physicochemical stability of total nutrient admixtures. Am J Health Syst Pharm 1995; 52:623-634 22. Manning R J, Washington C. Chemical stability of total parenteral nutrition mixtures. International Journal of Pharmacy 1992; 81:1-20 23. Letham A R, Jeraj H A, Terry A A. Survival of low-level microbial contamination in TPN regimens. British Journal of Pharmacy Practice 1988; September: 378-384 24. Thomas P. Studies on the pharmaceutical and clinical problems associated with the storage and administration of intravenous solutions. University of Wales PhD Thesis; section 3:91-134 25. Wood S (Ed), Shaffer J, Wheatley C. Home parenteral nutrition. Quality criteria for clinical services and the supply of nutrient fluids and equipment. British Association for Parenteral and Enteral Nutrition 1995 26. Matuchansky C, Messing B, Jeejeebhoy K N, Beau P, Beliah M, Allard J P. Cyclic parenteral nutrition. Lancet 1992; 340:588-592 27. Allwood M C. The influence of light on vitamin A degradation during administration. Clinical Nutrition 1982; 1:63-70 28. Mtihlebach S, Steger P. Lipid peroxidation and parenteral nutrition: significance in practice. European All-in-One society Newsletter 1997; September 18:2-6 29. Steger P J K, Mtihlebach S F. In vitro oxidation of IV lipid emulsions in different all-in-one admixture bags assessed by an iodometric assay and gas-liquid chromatography. Nutrition 1997; 13(2): 133-140 30. Murphy L M, Lipman T O. Central venous catheter care in parenteral nutrition: a review. JPEN 1987; 11(2): 190-201 31. Beecroft P C, Bossert E, Chung K et al. Intravenous lock patency in children: dilute saline vesus beparin. Journal of Pediatric Pharmacy Practice 1997; 2(4): 211-223 32. Johnson O L, Washington C, Davis S S, Schaupp K. Flocculation of fat emulsions in total parenteral feeding mixtures by heparin. Clinical Nutrition 1990; 9:29-30
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33. Raupp P, von Kries R, Schmidt E, Pfahl H-G, Giinther O. Incompatibility between fat emulsion and calcium plus heparin in parenteral nutrition of premature babies. Lancet 1988; March 26:700 34. Rattenbury J M, Taylor C J, Ganapathy S. Lipid deposition in parenteral infusion lines. Lancet 1988; March 26:701 35. Prasad G S, Ledger R, Puntis J W L, Ball P A. Occluding material present in central venous and haemodialysis catheters. British Association of Parenteral and Enteral Nutrition abstracts of multidisciplinary papers and poster communications (BAPEN Annual Meeting, December 1997), Poster No. PC26 36. Erdman S H, McElwee C L, Kramer J M, Zuppan C W, White J J, Grill B B. Central line occlusion with three-in-one nutrition admixtures administered at home. JPEN 1994; 18(2): 177-181 37. Barnett M I, Cosslett A G, Minton A. The interaction of heparin, calcium and lipid emulsion in simulated Y-site delivery of total parenteral nutrition (TPN) admixtures. European All-in-One Society Newsletter December 1996; 15:5-6 38. Lumpkin M M, Burlington D B (Food and Drug Administration). Safety alert: hazards of precipitation associated with parenteral nutrition. American Journal of Hospital Pharmacy 1994; 5'1:1427-1428
Submission date: 24 March 1998 Accepted: 28 April 1998
39. Hill S E, Heldman L S, Goo E D H, Whippo P E, Perkinson J C. Fatal microvascular pulmonary emboli from precipitation of a total nutrient admixture solution. JPEN 1996; 20(1): 81-87 40. Granger C A, Danial P P, Roe J A. The clinical consequences and management of particulate contamination in paediatric IV therapy. British Association of Critical Care Nurses Annual Conference, September 1994. (Abstract from Oral Presentation) 41. Lewis J S. Justification for use of 1.2 ~t end-line filters on total nutrient admixtures. Hospital Pharmacy 1993; 28(7): 656-658, 697 42. Jeppsson R. Impact of plastic material on admixture integrity. Nutrition 1989; September/October 5(5) (Suppl): 18-19 43. Ball P A, Barnett M I. The dissolved oxygen content of parenteral nutrition admixtures prepared by different methods. Pharmaceutical Science 1996; 2(7): 349-351 44. PINNT (Patients on Intravenous and Nasogastric Nutrition Therapy), UK. Holiday Guidelines for Patients on Parenteral or Enteral Nutrition Therapy 1997 45. Mughal M M. Complications of intravenous feeding catheters. Br J Surg 1989; 76:15-21
REVIEW
Stability issues in home parenteral nutrition C. V. WORMLEIGHTON, T. B. CATLING Pharrnacia & Upjohn Ltd, Davy Avenue, Knowlhill, Milton Keynes, MK5 8PH, UK (Correspondence to: CVW) Abstract--Home parenteral nutrition (HPN) is a method of providing nutrients, fluid and electrolytes intravenously to patients with a malfunctioning gastrointestinal tract, at home. Parenteral nutrition (PN) formulations are checked carefully for stability by the hospital pharmacist before the bags are made. However, there are many differences between supplying PN regimens to in-patients on the ward and to patients at home. Transportation between the hospital and home may be prolonged if the patient lives a long w a y from the hospital and may not be straight-forward. A number of factors can adversely affect the stability of the PN, which in turn can cause complications such as line blockage; or even life-threatening events, such as pulmonary embolism. The hospital team caring for HPN patients needs to be aware of these stability issues if complications resulting from incompatibilities of the solutions in the bags or the infusion line are to be avoided. Key words: home parenteral nutrition; hospital pharmacy, stability; nutritional mixtures
trained to aseptically manage their feeding line and entry site, the patient/carer also needs to be able to make certain additions to PN bags, as the stability of the feed is often greatly reduced once micronutrient additions have been made (6, 7).
Introduction Home parenteral nutrition (HPN) is a method of providing nutrients, fluids and electrolytes intravenously to patients with a malfunctioning gastrointestinal tract, in the home environment (1). Parenteral nutrition (PN) was described as 'an artificial gastrointestinal tract' by Rhodes (2). Without the more recent technical and logistical developments, patients requiring long-term PN would ordinarily have had to stay in hospital. Now, many can be treated at home, although patients or their carets need to be very carefully assessed when being considered for HPN. This is due to the depth of understanding and the dexterity required to perform the often complex procedures necessary to maintain an uncomplicated feeding line (3). Once it has been decided that HPN is the optimal method of nourishing the nutritionally-compromised patient, a choice as to the type of venous access device must be made. This decision should involve all members of a multidisciplinary nutrition support team (typically a clinician, nurse, pharmacist and dietician (4); often with other relevant personnel) as well as the patient and carer (5). For long term use, silicone catheters have been generally regarded as the most suitable (1). However, with the more recent introduction of the subcutaneously implanted device, where daily accessing of the port with a needle is required, certain factors need to be taken into consideration. For instance, some patients and/or carers may feel unable to take on this task, so there must be resources within the local community service: such as a nurse with the necessary skills and knowledge required who is able to visit the patient, sometimes on a daily basis, to access the port. As well as being
HPN regimens PN regimens, in which the separate components of PN are mixed together in a single bag, have been successfully used in both hospital in-patients and patients treated at home for many years (8). HPN regimens may be 'All-in-One', in which an intravenous amino acid solution, glucose infusion, lipid emulsion, electrolyte solutions and (occasionally) micronutrient preparations are mixed together in a single bag. Alternatively, they may be lipid-free, where the lipid emulsion and fat-soluble vitamins are omitted from the bag. In practice, HPN patients often receive a combination of the two; having lipid-free bags some days and All-in-One bags on other days (9). This is determined by the physician and is dependent upon the nutritional requirements of the patient. The aim is to maintain body weight whilst encouraging an independent lifestyle. These bags are usually delivered without micronutrient additions, i.e. vitamins and trace elements, so that the solution remains stable for as long as possible. The patients or their carers are then taught to add the necessary vitamins and trace elements according to their individual needs. A single bag reduces the number of manipulations required to set up the infusion and therefore reduces the risk of contamination via administration (10). However, mixing the components (which can result in the combination of over 50 separate chemical entities) may result in compatibility problems if stability guidelines are not followed (11). In hospitals, PN bags are often compounded 199
200
STABILITY ISSUES IN HPN
on a daily basis and are supplied with micronutrient additions already made by the pharmacy; however, for HPN, bags are delivered on a weekly/fortnightly basis. If the patient/carer is unable to make additions, then reliable stability data needs to be readily available to ensure that the solutions remain safe to use for the whole period of time until another delivery of PN can be made. Supplying PN regimens to patients at home increases the risk of compatibility problems because the temperature of the PN bags may not be strictly controlled during transportation between the hospital and the home. Using a specialized homecare company can minimize this risk. HPN regimens should be compounded in a sterile production unit within the hospital pharmacy department under the supervision of a pharmacist - nurses or patients should not be allowed to compound PN regimens for a number of reasons. Sterility of the PN is essential and can only be assured by the use of a strict aseptic technique by suitably qualified and validated staff in a validated sterile room with appropriate sterile equipment (12, 13). The pharmacist is also responsible for assuring the physical and chemical stability of the PN regimens, in accordance with guidelines from the manufacturer of the PN products. These guidelines should address compatibility of the ingredients to be mixed, the correct mixing procedure, correct storage conditions and information regarding the maximum administration time and temperature (14, 15). The compounding pharmacist usually has a high degree of control in the in-patient setting, through being responsible for the compounding of the regimen and its storage until transfer to the ward. The ward pharmacist may then monitor the handling and administration of the filled bags on the ward. Bags will normally be compounded and used within 7 days. However, for the typical HPN patient, the PN regimen should have a longer expiry (e.g. 14 days), to fit in with delivery schedules and a less straight-forward route to the patient after compounding.
Stability of HPN regimens Physical and chemical stability of All-in-One and lipid-free PN regimens are dependent upon several factors: concentrations of individual components, pH, temperature, forms of individual electrolyte solutions used, etc (11, 16). In particular, a high glucose concentration can destabilize the lipid emulsion in All-in-One regimens; a very low glucose concentration can lead to excessive 'creaming' (separation of aggregates of lipid globules from the mixture, which rise and form a layer of 'cream' on top of the regimen). Also, a high electrolyte content in the regimen, particularly of divalent cations (calcium and magnesium), can destabilize the lipid emulsion by neutralizing the negative repulsive charge (the zeta potential) on the surface of the lipid globules. In All-in-One and lipid-free regimens, high concentrations of calcium and phosphate (particularly at a higher pH) can cause insoluble calcium phosphates to precipitate out of solution (17-19). Some trace metal ions
can react with certain amino acids to form insoluble complexes (11). Vitamins may degrade so that the dose received by the patient is significantly lower than the dose prescribed (16). There are many publications on stability/instability of PN regimens and it is outside the scope of this paper to discuss this further (16, 20-22). It is essential that filled PN bags are stored at 2-8°C until required for use. They should normally be infused within 24h after removal from the refrigerator (23). Frozen bags containing lipid must not be used even after thawing (the lipid may be destabilized) (24). If bags have been kept above 8°C, instability of All-in-One or lipid-free regimens can result from acceleration of the reactions described.
Commercial homecare services A homecare company is often used for providing HPN. These companies can arrange for the compounding of PN bags, the delivery of bags plus ancillary items (e.g. disposable items, such as infusion sets), the loan of a dedicated refrigerator, pump, drip stand and other i.v. equipment, and stock checks in the home (25). The homecare company may be directly responsible for compounding the bags; or a hospital pharmacy may be used to compound the bags and the homecare company then dispenses them. In the latter case, the journey of a typical delivery of HPN regimens may be as follows. Twenty-four hours prior to the initial delivery a refrigerator of appropriate specification should be installed in the patient's home, so that the bags are stored at the correct temperature as soon as they are delivered. The bags are compounded in the hospital pharmacy and if necessary, stored in a refrigerator until transportation to the homecare company for checking and dispensing. They may be stored there overnight, prior to being transported to the patient's home and refrigerated until required for use. If strict procedures for handling and storage of the bags at every point in this process are not in place, then deviations in temperature may occur, which could adversely affect the stability of the regimens. For example, PN bags are ideally transported in a temperature-controlled vehicle or at least in a suitable coolbox with icepacks - validation of this system is required to ensure that the bags will remain at the correct temperature throughout their journey (Brierley E. Validation of packaging components used for transporting Kabi TPN bags. Portsmouth Hospitals NHS Trust, UK, 1993 - unpublished.) Bags should not be allowed to come into direct contact with the icepacks in order to avoid localized freezing. All refrigerators used for storing PN regimens in the home must be carefully monitored, and thermometers must be validated for accuracy. It is important that the driver who delivers the bags places them in the refrigerator straight away and any bags left over from the previous delivery are rotated to the top, once the expiry date has been checked. Any out of date bags must be destroyed or returned to the pharmacy so that the patient cannot use them. It is also important to keep a record of the temperature
CLINICAL NUTRITION
profile at various points within the refrigerator to maintain optimum storage conditions. Refrigerator temperatures are influenced by ambient air temperatures, the storage capacity and model of the refrigerator and how full it is (Minton A. Internal report, Welsh School of Pharmacy, UK, 1997 -unpublished). If the patients feel uncomfortable with the intrusion of a driver into their homes, then they must be adequately trained to perform these checks themselves, with regular compliance monitoring from the homecare company.
Administration of HPN regimens Patients must be trained to ensure that their PN bags are correctly stored and handled at all times. A dedicated refrigerator of appropriate standard should be used for the bags and the patient will normally remove the bag required for infusion 2-3 h prior to connection to allow it to warm up to room temperature. This is done to avoid an unpleasant sensation caused by infusing a cold solution straight into a central venous catheter; and also to allow dissolved gases to come out of the solution. Warming the regimen up to room temperature prior to infusion will not adversely affect its stability provided it is infused immediately. Under no circumstances should the unused bag then be put back into the refrigerator with the intention of using it at a later date. Infusion temperature is important; it should be below 25°C, unless stability studies have been carried out to valiate the use of higher temperatures. Many patients will infuse their PN regimen on a cyclical basis overnight (26), so this should not be a problem. However, if patients are on PN during the day, they should be warned of the potential problems (e.g. sitting out in the sunshine on a hot day). HPN patients are generally encouraged to cover their feeds, as direct light can affect the stability (27). Trends have, up to now, indicated that the lipid protects the watersoluble vitamins from degradation and therefore there is no need to cover AIO bags, only those that are lipid-free. However, evidence now suggests that lipid peroxidation can result from the attack of free radicals and may '... have a special potential for causing human diseases...' (28, 29) Therefore, it is safer to cover all HPN bags, until further information can be given on the effects of this process. Management of the line varies from unit to unit. However, it has been universally acknowledged that patients on PN should have a dedicated feeding line, not only to reduce the risk of infection through frequent handling, but also to minimize the risk of incompatible solutions mixing in the catheter (30). This is largely avoided by using the correct protocol when flushing the line after each feed, the type of flush varying according to the preference of the clinician (31). However, research suggests that lines flushed or locked with heparin risk the flocculation of the lipid by the heparin if calcium is present (32-34). This will not only destabilize the solution, but will also reduce the life-span of the line, where narrowing may occur due to the built-up debris along the catheter (35, 36). This
201
phenomenon is not circumvented by infusing lipid separately via a Y-site (37). Therefore, it is suggested that contact between PN/lipid and heparin should be avoided by using sodium chloride alone, or before and after heparin locks, to flush lines. The use of a reliable infusion pump to administer the PN regimen at home is important; not only for the patient's peace of mind and the correct administration of the parenteral nutrition, but also because parenteral nutrition admixtures are generally only stable for 24 h at room temperature. If the pump malfunctions in the night and an engineer is unable to go to the patient's house to repair it until the morning, then the bag currently being infused will probably be wasted as the infusion will not be completed within 24 h.
Avoiding complications of HPN The infusion of free oil, excessively large lipid globules or insoluble matter in the form of precipitates into the patient could cause fatal pulmonary emboli, and must be avoided by ensuring that these do not occur during mixing, storage or infusion (38, 39). The use of an in-line filter (0.22 g for lipid-free regimens, or a special 1.2 g lipid filter for All-in-One regimens) may prevent precipitates or free oil in the bag from being infused into the patient; but such filters must not be used as a substitute for correct pharmaceutical formulation of stable PN regimens. The routine use of in-line filters is currently somewhat controversial; but based upon the available information (40, 41), it is the opinion of the authors that they should be used to prevent particulates from a variety of sources from being infused. In addition, the 0.22 g filter retains bacteria. Both types of filter should be changed every 24 h. The problem of 'gassing out' can be a nuisance for some patients. Air dissolves in the PN solution when it is refrigerated; when the bag warms up, the air bubbles come out of solution and can trigger the 'air in line' alarm on the infusion pump. The incidence of this is reduced by the use of multi-layered PN bags instead of standard ones: the standard empty PN bag is made of a single layer of ethylene vinyl acetate (EVA), which is quite permeable to air. Multilayered bags have several layers of EVA and other materials to make them less permeable to air (42). If air is excluded from the PN regimen in this way, 'gassing out' is unlikely to occur as air cannot pass through the bag to dissolve in the solution. The compounding process can affect the amount of air filled into the bag and the compounding pharmacist should ensure that this is minimized (43). If patients wish to holiday abroad, they need to be aware of the problems associated with this (44). A dedicated refrigerator must be available to them to store their bags in once they have arrived, and it is advisable that a thermometer is given to the patients prior to their holiday to check that their feeds are being stored at the correct temperature. Depending on the length of stay, it may be possible for the additions to be made to the bags prior to departure.
202 STABILITYISSUESIN HPN H o w e v e r , this can only be done safely if reliable and accurate stability data has b e e n given. For example, a P N f e e d with micronutrient additions m a y only be g i v e n a m a x i m u m 8 day shelf-life, so if a patient is planning a longer holiday this m i g h t not be an option. It m a y take less t i m e for the bags to w a r m up prior to infusion in a hotter climate, therefore patients should be e n c o u r a g e d to infuse i m m e d i a t e l y after m a k i n g additions and preferably overnight w h e n it will be cooler. T h e P N bags are taken to the airport in cool boxes and responsibility is handed o v e r to the patients. Therefore, it is v e r y important that the patients are educated thoroughly before going on holiday abroad. W i t h an increase in the n u m b e r o f c o m p a n i e s n o w providing a h o m e service and the variety of solutions available, H P N feeds are b e c o m i n g increasingly c o m p l e x . Care must be taken w h e n m i x i n g not only different solutions f r o m the s a m e manufacturer but also if substituting different brands o f similar solutions (11). The stability with one solution m a y not be the s a m e as with another, as all types of solution (e.g. lipid emulsions) are slightly different in their c o m position. C o m p o s i t i o n s v a r y as a result of differences in raw materials and m a n u f a c t u r i n g processes. Therefore, w h e n considering a change o f brand, n e w stability data m a y be required e v e n if the basic prescription has r e m a i n e d the same.
Summary This paper has suggested reasons w h y accurate and reliable stability data should be obtained prior to g i v i n g a patient P N and the possible c o n s e q u e n c e s o f failing to consider stability once the bags h a v e left the hospital. Written stability data should be obtained f r o m the manufacturer. Products f r o m different manufacturers should not be mixed. Bags should not only be c o m p o u n d e d correctly using this data, but should also be correctly handled at e v e r y stage b e t w e e n leaving the hospital p h a r m a c y and administration to the patient. It is important that e v e r y o n e i n v o l v e d in the patient's care, including the patient, is aware of the potential p r o b l e m s and that the risks are m i n i m i z e d by ensuring that the bags are transported, stored, handled and administered correctly. A l t h o u g h v e r y little w o r k has been carried out to s h o w the effect of an unstable solution on the catheter itself and whether the l o n g e v i t y of a line is reduced for this reason (45), this and the other potentially life-threatening complications cannot be ignored.
Acknowledgement The authors would like to thank Dr M. I. Barnett and Dr A. G. Cosslett for their comments on the manuscript.
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Submission date: 24 March 1998 Accepted: 28 April 1998
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