Compounding TPN Admixtures: Then and Now*

Driscoll, David F

ABSTRACT. Compounding TPN admixtures has significantly developed since the first clinical reports by Dr. Dudrick and colleagues from the University of Pennsylvania approximately 35 years ago. Today, the responsibility for the compounding of sage parenteral nutrition admixtures for patients incapable of oral or enterai nutrition primarily rests with the pharmacy department. Although others may influence the desirable components to be contained therin, no one is more qualified to deal with the physicochemical issues and aseptic technique compounding requirements than a registered pharmacist. In fact, the United States Pharmacopeia (USP) , the official drug compendium in the US since 1906, has published Chapter 797 entitled “Pharmaceutical Compounding-Sterile Preparations”, enforceable by the FDA, and makes clear the role of the pharmacist in the compounding of safe parenteral admixtures. Ultimately, after careful pharmaceutical review of the final formulation, the composition of the final admixture for infusion will be determined based on the ability to safely compound the prescribed additives in the desired quantities of a specified volume of sterile fluid. There will always be instances, where, for example the patient’s needs cannot be safely met through the TPN admixture, primarily because of stability, compatibility and/or sterility issues. When this occurs, suitable alternative methods of delivering the additives in question must be sought so as not to compromise the safety issues of the final TPN infusion. Although there have been many advances in the development of nutritional additives, compounding devices, and containers, significant safety issues continue to arise necessitating further modification of paretneral nutrition protocols. ASPEN, through periodic reviews of tis published guidelines, such as the 1998 Safe Practices for Parenteral Nutrition Formulations, is in a key position to keep nutrition support clinicians abreast of the central issues affecting the safety of TPN therapy. (Journal of Parenteral and Enteral Nutrition 27:433-438, 2003)

The era when parenteral nutrition was developed was also a key period of interdisciplinary team-building. The complexity of the feeding modality required the varied training and skill-sets from several disciplines, and often gave the first serious exposure to the viewpoints of other health professionals. The largest teams, in major medical centers, generally were comprised of at least 1 physician (surgeon, gastroenterologist or internist), dietitian, nurse and pharmacist. The voluminous data management and tracking of laboratory results, common to this intensive practice, benefited from the skills of a data coordinator. Often a secretary was needed to transcribe and post team notes. Role delineation was sometimes difficult, since there was overlap in clinical points of interest, however, the generally-held opinion was that patients benefited from the attention of such diverse perspectives.

Compounding Total Parenteral Nutrition Admixtures: Then and Now, by David Driscoll, and the next paper in our series, The Impact of Nursing Practice on the History and Effectiveness of Total Parenteral Nutrition, by Peggi Guenter, Susan Curias, Lynne Murphy, and Marsha Orr, share a window into the contributions by pharmacists and nurses, respectively. Physicians were also very active in building team dynamics, gaining a foothold for team practice in the hospital structures, and often sharing their model of professional mentoring with other clinical team members. Dietitians were instrumental in bringing their knowledge base of nutritional requirements and intake to bear on this new mode of feeding. Many members of the early nutrition support teams view this period as a time of rich mutual professional development from which patients derived direct benefit and professionals gained immensely in the depth of their practice. Clearly, the improvements in the quality of care for patients receiving parenteral nutrition would not have evolved as they did without the input of many professionals from diverse points of view.

Charlene Compher, PhD, RD, FADA, CNSD

University of Pennsylvania School of Nursing Clinical Nutrition Support Service

Total parenteral nutrition (TPN) admixtures are clearly the most complex pharmaceutical dosage forms routinely compounded by pharmacists on a daily basis. The sheer number of individual chemical entities that compose these infusions approach 50 or more components. The range of interactions is vast, which makes the early efforts to bring this therapy into clinical practice by the pioneers in this field even more impressive. The issues of how much of each and in what form they may best be given so as not to induce harm have been reviewed in great detail at various times by Dr. Dudrick and his original colleagues (Drs. Jonathan Rhoads, Harry Vars, Douglas Wilmore, Stanley Serlick, Harry Flack and others) at the University of Pennsylvania. We got a retrospective glimpse of some of these issues at the American Society of Parenteral and Enterai Nutrition (A.S.P.E.N.) 25th Clinical Congress held in Chicago, IL, a couple of years ago. The early hurdles they faced were enormous, not the least of which was the provision of a safe and complete TPN admixture.

Once the clinical efficacy of TPN therapy was clearly demonstrated in 1968, the commercial production of an array of nutrients, containers, infusion sets, etc, would follow to assist in the preparation, composition, and delivery of these complex admixtures. Because of the instability of many of the additives that compose a TPN admixture, a complete, “ready-to-use” commercial product was (and still is) not available. Consequently, given the chemical complexity and the necessary compounding tasks to safely prepare these formulations, the responsibility was clearly and appropriately assigned to pharmacy departments around the country.

I would like to focus my comments on 3 general areas of special concern to all pharmacists in the compounding of TPN admixtures and to the patients they serve. Specifically, these include issues of aseptic technique, compatibility/stability, and safe nutrition support pharmacy practices.

Aseptic Technique: Early Events

In order to avoid contamination, during the manufacturing (intrinsically introduced), extemporaneous preparation, and the administration (extrinsically introduced) of sterile injections, aseptic technique is of paramount importance. By 1971, United States-based hospital pharmacy IV admixture programs were developing1 and suggesting procedures for the operations and monitoring of the compounding environment and final dosage forms.2 In the same year, as pharmacies were organizing to provide aseptic IV admixture services nationwide, a stunning report from the Centers for Disease Control and Prevention (CDC) revealed evidence of Enterobacter cloacae, or erwinia-based septicemias (n = 405 cases), in association with contamination of the inner cap assemblies of unopened 1-L IV solutions from 2 parenteral manufacturing plants in the United States.3 As well, evidence of infections associated with parenteral nutrition was mounting.4″7 The pressure was on because the nutritional content of the mixtures supported a variety of microorganisms and could easily be contaminated during preparation or administration. The continued existence and value of this emerging therapy was now under very close scrutiny. In 1973, however, a major breakthrough came from a CDC study that evaluated the differences in microbial growth potential between TPN solutions composed of conventional protein hydrolysates (referred to as “casein hydrolysate and dextrose,” or “CHD”) us those made from synthetic crystalline amino acids (referred to as “synthetic amino acids and dextrose,” or “SAAD”).8 Admixtures made from the new synthetic amino acids formulation failed to support the growth of bacteria and exhibited less rapid growth with fungal species when compared with TPNs made with protein hydrolysates. The CDC investigators recommended that “consideration should be given to using SAAD rather than CHD whenever possible” and concluded “[a]dequate infection control measures must be enforced during manufacture, in the pharmacy, and at the bedside if the risk of contamination is to be reduced.”8 Thus, the critical role of pharmacy in the safe provision of TPN therapy was officially recognized, as was the opportunity to reduce contamination of TPN admixtures by these new amino acid formulations. Furthermore, through the diligent efforts of the CDC, it appeared a better appreciation of the risks of contamination throughout the production of sterile products (“during manufacture”), and in the extemporaneous compounding of TPN admixtures (“in the pharmacy”), was gained in order to reduce the incidence of infectious complications. Soon, attention was focused on other infectious sources during TPN infusions (“at the bedside”), and special attention was placed on the care of the infusion catheters delivering parenteral nutrition.9

Although it appeared less likely that pharmacy departments were the main source of contamination of TPN formulations, largely because of the use of aseptic technique protocols and the inability of synthetic crystalline amino acids to support most common nosocomial pathogens, coupled with the hyperosmolar character (1500 to 2000 mOsm/L) and final acidic pH (5.8 to 6.4) of these concentrated infusions, other ways of admixture contamination continued to occur. These included touch contamination of sterile “tabs” or ports and tubing,10 use of nonpharmacy personnel compounding TPN,11 poor storage conditions,12 exposure to highly virulent organisms associated with deficiencies in cleaning and decontamination procedures within the compounding environment,13 and contamination from plastic tubing from automated compounding devices.14

Aseptic Technique: Present Issues

The separate administration of IV lipid emulsions (IVLEs) as syringes continues to be associated with significant morbidity and mortality in the very young.15″17 In all likelihood, this is a consequence of poor handling techniques (preparation, storage, or infusion) or excessive beyond-use date assignments or usage. For IVLEs, this is a particularly important issue when it is removed from its original container and transferred to an alternative delivery vehicle such as a syringe.18 Nevertheless, because of significant volume limitations, syringe-based delivery of IVLEs is a common nutrition support practice in neonatal and infant intensive care units and, for example, during the continuous administration of sedative drugs formulated in oil-in-water emulsions.

case reports in the literature regularly remind us of the significance of aseptic technique in the extemporaneous compounding of parenteral nutrition admixtures. Although more emphasis should be placed on receiving TPN compounding operations, A.S.P.E.N. has played a significant role in supporting and recognizing the Nutrition Support Clinical Certification Program administered by the American Pharmaceutical Association’s Board of Pharmaceutical Specialties. In addition, A.S.P.E.N. issued guidelines on safe practices for parenteral nutrition formulations in 1998.19 The United States Pharmacopeia20 and the American Society of Health-System Pharmacists (ASHP)21 have made significant contributions toward the standardization of methods for extemporaneous compounding of parenteral dosage forms, including TPN admixtures. In addition, the ASHP has also produced a guideline on the optimal use of automated TPN compounding devices (ACDs).22 In general, the use of ACDs by hospitals with at least 8 to 10 TPN bags compounded each day is generally viewed as cost-justified, leads to a reduced incidence of microbial contamination, and is a more accurate technique than that achieved using manual methods of TPN compounding.23 Nonetheless, we continue to see reports of flawed compounding or administration practices.24

Compatibility/Stability

The physicochemical compatibility and stability of TPN admixtures are affected by many factors, including the infusion container, administration sets, filters, and concentrations of “reactive” but essential additives. Clearly, the compounding processes greatly influence the relative significance of these issues with respect to the safety of the final TPN infusion. It is fundamentally recognized by nutrition support pharmacists that the mere act of opening the multiple commercial injectables that compose a final TPN admixture initiates degradation of the individual components, and that initiation, in many cases, accentuates multiple, potentially clinically significant, chemical interactions (eg, sorption, oxidation, coprecipitation, and coalescence) when combined in a single container. In recognition of this, it is the responsibility of all pharmacists, when assigning a beyond-use date to the final TPN admixture, to base it on the best available information that ensures these degradation reactions do not progress to a point where the infusion is clinically dangerous.25

Sorption, Oxidation, and Infusion Containers

The infusion containers and administration sets have undergone major transformations from the original glass bottles to various plastic alternatives. Although glass containers are generally viewed as less reactive than plastics, today they are generally not used for the delivery of TPN therapy. Plastic infusion bags have undergone several changes designed to make them less reactive with additives and more protective of the final admixture before use. Specifically, polyvinyl chloride (PVC) bags constructed with the plasticizer, di(2-ethylhexyl) phthalate (DEHP), have largely been replaced with bags made with ethylene vinyl acetate or other less reactive materials. DEHP, a carcinogen in laboratory animals, has been found to leach from the PVC containers under certain “lipophilic” conditions (eg, infusion of lipid emulsions and blood products) and has also been associated with facilitating the losses of certain vitamins26 and the destabilization of lipid emulsions.27 In addition, the DEHP-free infusion containers have evolved even further to include (1) dual-chamber bags that allow certain compartmentalized unstable TPN admixture components (eg, lipid emulsions) to be mixed just before use; (2) multichamber bags, to be mixed as above but that are designed to minimize the compounding tasks by use of standardized nutrient compositions; and (3) multilayered bags designed to protect labile components from certain degradation processes (eg, oxidation) that occur in the aforementioned plastic bags.

Co-precipitation Reactions

One of the most lethal consequences of mishandling TPN admixtures is the formation of rigid, crystalline coprecipitates that may occur as a result of (1) poor compounding techniques (flawed admixture compounding sequences); (2) inadequate knowledge of admixture components (poor selection of electrolyte salts or reasonable admixture concentrations); or (3) assignment of excessively long beyond-use dates (inadequate or ill-informed documentation). Most notorious of these involves the precipitation of the insoluble product, dibasic calcium phosphate, generated by parenteral infusion containing soluble calcium and phosphate salts.28 In fact, this coprecipitate can be formed by either poor compounding techniques or inadequate knowledge of admixture components or patient conditions.29 Despite the well-publicized danger of this interaction, it continues to represent a potentially serious health risk. Often, given the complexity of the interaction between calcium and phosphate salts in TPN admixtures, compounding practices have been largely institution-specific and based on prior clinical experience. This form of compounding practice is seriously flawed, and previous successes can become lethal failures merely by changes in hospital contracts with the introduction of unfamiliar products.30 The fatal consequences associated with calcium phosphate precipitation, as outlined in the Food and Drug Administration (FDA) Safety Alert issued on April 18, 1994,28 and the subsequent publication of the circumstances surrounding these events in 199630 are instructive for all pharmacists involved in the provision of TPN therapy. Phosphate is a trivalent anion with 3 different acid dissociation constants (pKa’s), where pKal = 2.12 (the monobasic or “M” form); pKa2 = 7.21 (the dibasic or “D” form); and, pKa3 = 12.67 (the tribasic “T” form), producing monobasic calcium phosphate, dibasic calcium phosphate, and tribasic calcium phosphate salts (in decreasing aqueous solubility). The dibasic form was shown in postmortem examinations to be the culprit. Although tribasic calcium phosphate is even less soluble than the dibasic form, it requires a final pH of 11 or higher to be present in significant quantities, a condition that clearly falls outside the range of any TPN admixtures used in the clinical setting. Hence, the principal focus of any investigation of TPN precipitation suspected to be arising from the interaction of soluble calcium and phosphate salts should be on dibasic calcium phosphate (CaHPO^sub 4^).

By knowing the pKa of the dibasic form (7.21), one can easily substitute a given pH value and determine the amounts present at any time. Using the data from the 1996 report described above,30 one can calculate that the lethal admixtures (pH 6.68) had approximately 23% of the dibasic form present, equal to about 10 mg/dL of the elemental phosphorus prescribed, compared with the nonlethal admixtures (pH 5.86) with approximately one-tenth as much or approximately 4.3% present, equal to about 2 mg/dL of the elemental phosphorus prescribed. To illustrate the significance of this point, if we (wrongfully) assumed that all of the elemental calcium was completely dissociated from the gluconate ions and did not form any other possible soluble complexes with the other admixture components, yielding a concentration of 20 mg/dL, the calcium phosphate product for the lethal formulation (pH 6.68), would be 200, whereas for the nonlethal admixture (pH 5.86), it would be 40. This, of course, represents a fivefold difference in compatibility conditions and has potentially lethal consequences. Figure 1 depicts the amount of any form present over the entire pH range for all forms of ionized phosphate, with the approximate positions of the study formulations from 1996 shown in the plot of % ionized vs pH as “Dl” that represents the nonlethal formulations, and “D2” representing the lethal formulations containing dibasic calcium phosphate. Clearly, as pH rises, so too does the danger of calcium phosphate precipitation. Finally, it should be noted that parenteral nutrition admixtures intended for peripheral vein administration are less tolerant of calcium and phosphate salts than conventional TPN admixtures given by large central veins. Thus, as a general rule, the amounts of each salt routinely used in any TPN admixture should be no more than one half that used in parenteral nutrition admixtures per liter given by peripheral vein administration. However, such “rules” should be confirmed by actual compatibility data available from the individual parenteral nutrition manufacturers.

Alternative phosphate salts do exist outside the United States and should be mentioned here. A mono-basic calcium phosphate salt is available, which takes advantage of a 60-fold higher aqueous solubility (18 g/L), compared with its corresponding and dangerous dibasic calcium phosphate form (0.3 g/L). However, because the mono- and dibasic forms of calcium phosphate are pH-dependent, as shown in Figure 1, it makes little sense to consider this salt as an alternative to the present inorganic forms. The use of organic phosphate salts, such as sodium glycerophosphate, reduces the risk of precipitation, even in the presence of high final calcium concentrations, where substitution with inorganic phosphate salts precipitate.32 Injectable organic phosphate salts are presently not available in the US, but they should be developed for clinical use.

Finally, the inappropriate assignment of beyond-use dates for TPN, especially at room temperatures, may have potentially significant consequences with respect to coprecipitation reactions. This is especially true when vitamins are added for periods exceeding 24 hours, such as ascorbic acid, which can degrade to its terminal degradation product oxalic acid, which then can react with free calcium ions, forming the insoluble product calcium oxalate,33 or, for example, when vitamin A permeates the infusion container, causing clinically significant deficiencies.26 These examples point out the significance of assigning responsible beyonduse dates that are safe and reasonable.

Coalescence and IVLEs

IVLEs have had a significant history in TPN therapy. The early formulations, such as Lipomul I.V. (100% cottonseed oil; Upjohn Co., Kalamazoo, MI), was associated with significant clinical problems, including fat overload syndrome, and by 1965 was removed from the US market. Approximately 10 years later, Intralipid (100% soybean oil; Kabi-Vitrim, Stockholm, Sweden) was introduced and proved to be safe and efficacious. Other long-chain triglyceride (LCT) formulations followed, such as Liposyn (100% safflower oil; Abbott Laboratories, Abbott Park, IL). By 1984, LipofundinMCT (B. Braun, Melsungen, Germany), a 50:50 (by weight) physical mixture of medium-chain triglycerides (MCTs) and LCT were available in Europe. The past 5 to 7 years have seen the development of several other lipid emulsions, such as those containing olive oil or fish oil in combination with MCTs and/or soybean oil. In 1 case, the emulsion mixture has been structured, where the triglyceride backbone is comprised of both MCTs and LCTs, by transesterification of triglycerides to chemical mixtures. These newer emulsions may have pharmacologie and nutritional benefits.34

Parenteral lipid emulsions were originally intended as supplements to prevent essential fatty acid deficiency (EFAD). Thus, they were often given as weekly supplements to prevent EFAD in patients receiving TPN therapy. Use of IVLEs as a daily caloric source evolved according to the clinical experience of Solassol et al in 197435 and an important metabolic study conducted in 1975 by Jeejeebhoy et al,36 who demonstrated that lipids were equally nitrogen-sparing compared with glucose, after a brief period of metabolic adaptation in patients receiving parenteral nutrition. These were important events that helped spawn the clinical use of 3-in-1 or total nutrient admixtures during the 1980s in the United States37’38 so that by 1990, it was estimated that approximately 50% of all hospitals larger than 200 beds were using them.39 Total nutrient admixtures are formed when lipid emulsions are directly added to the final TPN formulation, converting the conventional nutritional “solution” to a nutritional “emulsion,” engendering additional, and unique, stability concerns.

All IVLEs are thermodynamically unstable and therefore have short shelf lives (ie, 24 months) compared with most other pharmaceutical dosage forms with expiration dates ranging from 36 to 60 months. Instability of IVLEs is manifested by the growth of submicron droplets (ie, 5 µm), a process known as coalescence. The consequences of coalescence can be expressed in a number of ways experimentally, such as volume- or number-weighting specific regions of the globule size distribution (GSD). For example, the percent of fat (PFAT) in the large-diameter tail of the distribution (>5 µm) is typically 5 µm grows to 0.4% or higher.27 By comparison, in terms of number-weighting globules in the large-diameter tail in the GSD (ie, >5 µm), stable IVLEs generally contain between 10^sup 3^ and 10^sup 4^ globules/mL, whereas unstable lipid emulsions contain 10^sup 5^ to 10^sup 6^/mL.41 No matter how the lipid droplet size data is portrayed, specific and identifiable growth detected in the largediameter tail of IVLEs signals destabilization of the emulsion, which heightens the danger of the infusion. The major concern for unstable IVLEs is the trapping of large-size globules in the capillaries of the lungs.42 Recent evidence in guinea pigs43 and rats44 has demonstrated tissue damage in association with the administration of unstable lipid emulsions compared with stable formulations. Finally, choosing the population threshold of 5 µm for in vitro and in vivo studies is reasonable for a number of pharmaceutical and physiologic reasons: (1) it represents a finite population in stable lipid emulsions; (2) it is the threshold region or “active zone” where significant changes in the GSD signals the onset of destabilization; (3) light-scattering issues are virtually eliminated, allaying concerns about the refractive index differences between the measured droplets or globules and the reference standards (polystyrene latex spheres) used to calibrate light obscuration instruments; and (4) it is a clinically relevant dimension with respect to the internal diameter of the pulmonary capillaries (range, 4 to 9 µm).

Nutrition Support Pharmacy Practice

Nutrition support pharmacy practice issues have been well described in the 1998 A.S.P.E.N. guideline entitled Safe Practices for Parenteral Nutrition Formulations.19 A.S.P.E.N. can take great pride in having established a comprehensive document on pharmacy practice and TPN admixtures that underwent rigorous multidisciplinary and multiorganizational review. From this document, for example, one can generate clinically reasonable ranges of nutritional intakes for both adult and pediatrie specific weights. This guideline should serve as a template for future review, revision, and publication by A.S.P.E.N. at least every 5 years, when and if significant changes in practice occur. For example, newer issues that have evolved since the publication of this document include the implications of the PDA’s Amendment of Regulations on Aluminum in Large and Small Volume Parenterals Used in Total Parenteral Nutrition, safe use and guidelines for the use of extemporaneously prepared lipid emulsion syringes, standardization of TPN compounding sequences, and minimum criteria for assigning validated beyond-use dates for all parenteral nutrition admixtures and dosage forms. By setting the minimally acceptable standards from the time the order is written and every process in between (dosing of nutrients, monitoring, compounding, labeling, quality assurance, storage, filtration) to its infusion, the current and future revisions of this document stand as a major accomplishment for A.S.P.E.N. in the provision of safe parenteral nutrition therapy for the patients we serve.

REFERENCES

1. Pulliam CC, Upton JH: Pharmacy coordinated intravenous admixture and administration service. Am J Hosp Pharm 28:92-101, 1971

2. Anon: Hospital pharmacies falling into line on contamination control. Contam Control 10:19-21, 1971

3. Centers for Disease Control and Prevention: Follow-up on septicemias associated with contaminated intravenous fluids. Morb Mortal WkIy Rep 20:91-92, 110, 1971

4. Ashcraft KW, Leape LL: Candida sepsis complicating parenteral feeding. JAMA 212:454-456, 1970

5. Boeckman CR, Krill CE: Bacterial and fungal infections complicating parenteral alimentation in infants and children. J Pediatr Surg 5:117-126, 1970

6. Curry CR, Quie PG: Fungal septicemia in patients receiving parenteral alimentation. N Engl J Med 285:1221-1225, 1971

7. Brennan MF, O’Connell RC, Rosol JA: The growth of Candida albicans in nutritive solutions given parenterally. Arch Surg 103:705-708, 1971

8. Goldmann DA, Martin WT, Worthington JW: Growth of bacteria and fungi in total parenteral nutrition solutions. Am J Surg 126:314-318, 1973

9. Alien JR: Prevention of infection in patients receiving total parenteral nutrition. Acta Chir Scand 507:405-418, 1981

10. Verschraegen G, Claeys G, Delanghe M, et al: Serotyping and phage typing to identify Enterobacter cloacae contaminating total parenteral nutrition. Eur J Clin Microbiol Infect Dis 7:306307, 1988

11. Moro ML, Maffei C, Manso E, et al: Nosocomial outbreak of systemic candidiasis associated with parenteral nutrition. Infect Control Hosp Epidemiol 11:27-35, 1990

12. Dugleux G, Le Coutour X, Hecquard C, et al: Septicemia caused by contaminated parenteral nutrition pouches: The refrigerator as an unusual cause. JPEN 15:474-475, 1991

13. Llop JM, Mangues I, Ferez JL, et al: Staphylococcus saprophyticus sepsis related to total parenteral nutrition admixtures contamination. JPEN 17:575-577, 1993

14. Two children die after receiving infected TPN solutions. Pharm J 8:3, 1994

15. Freeman J, Glodmann DA, Smith NE, et al: Association of intravenous lipid emulsion and coagulase-negative staphylococcal bacteremia in neonatal intensive care unit. N Engl J Med 323: 301-308, 1990

16. Shiro H, Muller E, Takeda S, et al: Potentiation of staphylococcal epidermidis catheter-related bacteremia by lipid infusions. J Infect Dis 171:220-224, 1995

17. Matlow AG, Kitai I, Kirpalani H, et al: A randomized trial of 72-versus 24-hour intravenous tubing set changes in newborns receiving lipid therapy. Infect Control Hosp Epidemiol 20:487-493, 1999

18. Sacks GS, Driscoll DF: Does lipid hang time make a difference? Time is of the essence. Nutr Clin Pract 17:284-290, 2002

19. National Advisory Group on Standards and Practice Guidelines for Parenteral Nutrition: Safe practices for parenteral nutrition formulations. JPEN 22: 49-66, 1998

20. Pharmaceutical compounding: Sterile preparations. Pharm Forum 29:940-965, 2003

21. ASHP guidelines on quality assurance for pharmacy-prepared sterile products. Am J Health Syst Pharm 57:1150-1169, 2000

22. Driscoll DF, Sanborn MD, Giampietro K: ASHP guidelines on the safe use of automated compounding devices for the preparation of parenteral nutrition admixtures. Am J Health Syst Pharm 57:1343-1348, 2000

23. Driscoll DF: Delivery of nutritional therapy: Quality assurance of automated compounding devices. Nutrition 12:651-652, 1996

24. Reiter PD: Sterility of intravenous fat emulsion in plastic syringes. Am J Health Syst Pharm 59:1857-1859, 2002

25. Driscoll DF: Total nutrient admixtures: Theory and practice. Nutr Clin Pract 10:114-119, 1995

26. Howard L, Chu R, Fenian S, et al: Vitamin A deficiency from long-term parenteral nutrition. Ann Intern Med 93:576-577, 1980

27. Driscoll DF, Bhargava HN, Li L, Zaim, et al: The physicochemical stability of total nutrient admixtures. Am J Hosp Pharm 52:623-634, 1995

28. Food and Drug Administration: FDA safety alert: Hazards of precipitation associated with parenteral nutrition. Am J Hosp Pharm 51:1427-1428, 1994

29. Driscoll DF, Newton DW, Bistrian BR: Calcium phosphate precipitation from parenteral nutrition. Am J Hosp Pharm 51:2834-2836, 1994

30. Hill SE, Heldman LS, Goo EDH, et al: Fatal microvascular pulmonary emboli from precipitation of a total nutrient admixture. JPEN 20:81-87, 1996

31. Driscoll DF, Bacon MN, Provost PS, et al: Automated compounders for parenteral nutrition admixtures. JPEN 18:385-386, 1994

32. Driscoll DF, You YQ, Bacon MN, et al: Compatibility of inorganic vs. organic phosphate salts in TPN admixtures. JPEN 21:16, S3, 1997

33. Gupta VD: Stability of vitamins in total parenteral nutrition solutions. Am J Hosp Pharm 43:2132, 1986

34. Driscoll DF, Adolph M, Bistrian BR: Lipid emulsions in parenteral nutrition. IN Parenteral Nutrition, Rombeau JL, Rolandelli R (eds). 2001: W. B. Saunders Company, Philadelphia, PA, 2001, pp 35-59

35. Solassol C, Joyeaux H, Etco L, et al: New techniques for long-term intravenous feeding: An artificial gut in 75 patients. Ann Surg 179:519-522, 1974

36. Jeejeebhoy KN, Anderson GH, Nakhooda AF, et al: Metabolic studies in total parenteral nutrition in man. J Clin Invest 57:125-136, 1975

37. Driscoll DF, Baptista RJ, Bistrian BR, et al: Practical considerations regarding the use of total nutrient admixtures. Am J Hosp Pharm 43:416-419, 1986

38. Brown R, Quercia RA, Sigman A: Total nutrient admixture: A review. JPEN 10:650-658, 1986

39. Driscoll DF: Clinical issues regarding the use of total nutrient admixtures. Ann Pharmacother 24:296-303, 1990

40. Driscoll DF, Etzler F, Barber TA, et al: Physicocheniical assessments of parenteral lipid emulsions: Light obscuration vs. laser diffraction. Int J Pharm 219:21-37, 2001

41. Driscoll DF: The significance of particle-sizing measurements in the safe use of intravenous fat emulsions. J Disp Sei Tech 23:679-687, 2002

42. Globule size distribution in intravenous emulsions. Pharm Forum 24:6988-6994, 1998

43. Driscoll DF, Ling PR, Quist WC, et al: Tissue damage from unstable fat globules in the reticuloendothelial system (RES) organs of guinea pigs following a 24-hour all-in-one infusion [abstract]. Clin Nutr 21(Suppl 1):63, Abstract P-50, 2002

44. Driscoll DF, Ling PR, Quist WC, et al: Evidence of tissue damage from the infusion of unstable lipid emulsions [abstract]. JPEN 27:829, Abstract 060, 2003

David F. Driscoll, PhD

Senior Researcher, Department of Medicine, B.I. Deaconess Medical Center and Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts

Received for publication May 29, 2003.

Accepted for publication July 31, 2003.

*Presented in part at the History of Parenteral Nutrition (S06) Symposium, Nutrition Week, January 20, 2003.

Correspondence: David F. Driscoll, PhD, Baker Building, Suite 605, One Deaconess Road, Boston, MA 02215. Electronic mail may be sent to ddriscol@caregroup.harvard.edu.

Copyright American Society for Parenteral and Enteral Nutrition Nov/Dec 2003

Provided by ProQuest Information and Learning Company. All rights Reserved

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