Amino acids are supplied in a variety of concentrations and sizes, both alone and in kits with dextrose 50% injection. For components, concentrations, and characteristics, see the labeling for the individual products.
Parenteral nutrition solutions composed of amino acids and high-concentration dextrose, which are strongly hypertonic, may be safely administered only through an indwelling intravenous catheter with the tip in the superior vena cava; they are used for severely depleted patients or those requiring long-term therapy.3267; 3268 For moderately depleted patients in whom the central venous route is not indicated, parenteral nutrition solutions with dextrose concentrations of 5 to 10%, which are substantially less hypertonic, may be administered peripherally.3267; 3268
It has been recommended that administration sets used to administer lipid emulsions be changed within 24 hours of initiating infusion because of the potential for bacterial and fungal contamination.2342
For non-lipid-containing (TPN, 2-in-1) parenteral nutrition, 0.22-µm filters, preferably endotoxin retaining, are recommended; for lipid-containing (TNA, 3-in-1, AIO) parenteral nutrition, 1.2-µm filters are recommended.2346; 3259
Solution containers should be visually inspected for cloudiness, haze, discoloration, precipitates, and bottle cracks and checked for the presence of vacuum before mixing and prior to administration. Only clear solutions should be administered. It is also recommended that the containers be protected from light until ready for use and from extremes of temperature such as freezing or over 40°C. Because of the risk of microbiological contamination, manufacturers recommend storing mixed parenteral nutrition solutions for as little time as possible after preparation. Administration of a single bottle should not exceed 24 hours.
A study of the original FreAmine showed that the mixed solution was stable at 4°C for 12 weeks. Increased temperature enhanced degradation. Decomposition due to the Maillard reaction is visible as a color change from the clear, light, pale yellow of the freshly prepared solution to yellow to red to dark brown. It was noted that the possibility of microbiological contamination limits the desirable storage time. It was recommended that solutions be stored under refrigeration and used as soon as possible after mixing.186
The previous study did not report on the stability of tryptophan because of variable and nonreproducible results.186 In another study, it was shown that the tryptophan content of the original FreAmine was reduced approximately 20% by the presence of the sodium bisulfite 0.1% antioxidant.187
An evaluation of amino acid 4.25% injection with dextrose 25% (prepared from FreAmine II 8.5%), without additional additives, stored at 4°C for 2 weeks showed little or no change in the concentrations of amino acids, including tryptophan, as well as pH. Particle counts were also normal over the period. When stored at 25°C, approximately 6% tryptophan loss occurred, but no other changes were observed.581
In contrast, parenteral nutrition solutions composed of amino acids solution with ethanol and vitamins (Aminofusin, Pfrimmer) along with dextrose and a variety of electrolytes exhibited a darkening of color on storage at 37, 25, and 5°C for 60 days. The rate of color change was less at the lowest temperature. A loss of ascorbic acid in the mixture was also demonstrated and was shown to be associated with the color changes. The rate of ascorbic acid decomposition was dependent on air space in the container and storage temperature. In addition, fine white crystals of calcium phosphate precipitated on day 12 at 25 and 37°C and on day 25 at 5°C.580
A photoreaction of the L-tryptophan in Nephramine essential amino acid injection was reported. The L-tryptophan in combination with bisulfite stabilizer, oxygen, and light yielded an indigo blue color. Although no toxicity was associated with the L-tryptophan degradation and blue color formation, it was recommended that Nephramine remain in its original carton until ready to be mixed with dextrose and that Nephramine mixtures be covered with amber, UV-light-resistant bags to retard the formation of the blue color. It was further noted that a slightly blue solution need not be changed for a colorless one, nor is it necessary to change a slightly blue filter for a white one.579 However, it has been emphasized that the clinical importance of this reaction is largely undetermined and may not be entirely benign.1055
The effects of photoirradiation on a FreAmine II-dextrose 10% parenteral nutrition solution containing 1 mL/500 mL of multivitamins (USV) were evaluated. During simulated continuous administration to an infant at 0.156 mL/min, the amino acids did not change when the bottle, infusion tubing, and collection bottle were shielded with foil. Only 20 cm of tubing in the incubator was exposed to light. However, if the flow was stopped, a marked reduction in methionine (40%), tryptophan (44%), and histidine (22%) occurred in the solution exposed to light for 24 hours. In a similar solution without vitamins, only the tryptophan concentration decreased. The difference was attributed to the presence of riboflavin, a photosensitizer. The authors recommended administering the multivitamin separately and shielding from light.833
The stability of amino acids in a parenteral nutrition solution composed of amino acids 3.5%, dextrose 25%, and electrolytes in polyvinyl chloride (PVC) bags was assessed at 4 and 25°C over 30 days. No significant decreases of the amino acids occurred in the refrigerated samples. However, the sample stored at room temperature showed significant losses of methionine (10.2%) and arginine (8.2%) in 30 days.1057
The long-term stability of the components of a parenteral nutrition solution composed of amino acids, dextrose, electrolytes, and trace metals in PVC bags was determined over a 6-month period of storage at 4°C. None of the amino acids decomposed more than 10% during the first 2 months. However, at 6 months, all of the amino acids except tyrosine, lysine, and histidine had degraded by more than 10%; some losses exceeded 25%. The dextrose, electrolytes, and trace elements remained constant for the 6-month period. Water loss through the PVC bag was only 0.2%. Visually the color remained unchanged.1058
The long-term stability of the components of 6 parenteral nutrition solutions containing variable amounts of amino acids, dextrose, electrolytes, trace elements, and vitamins, stored in PVC bags at 4 and 25°C, was evaluated. No significant changes to the amino acids, dextrose, electrolytes, or trace elements were noted during 28 days.1063
Peroxide Formation
Potentially toxic peroxide is generated in parenteral nutrition admixtures as a reaction between oxygen and various components catalyzed by riboflavin in the presence of light. This is particularly true in neonatal formulations.1650; 1653; 1947; 2306; 2309; 2316 Exposure of a neonatal parenteral nutrition admixture to ambient light resulted in the formation of peroxide concentrations up to 300 µM. Light protection from compounding through administration has been recommended as a more achievable approach to reduce the formation of peroxide than avoiding contact with oxygen.2316
Exposure of parenteral nutrition admixtures to light during phototherapy has been shown to generate substantially larger amounts of hydrogen peroxide.2310 In a study of the rate of hydrogen peroxide formation in a TrophAmine 1%-based parenteral nutrition admixture exposed to light, levels of peroxide increased linearly for about 8 hours and then reached a plateau at about 940 µM. A similar solution kept in the dark did not generate any detectable peroxide. A hydrogen peroxide concentration of as little as 25 µM has been shown to be lethal to 90% of human cells in culture. The authors speculated that additive hepatic oxidant injury over time might increase hepatic dysfunction as the duration of exposure to parenteral nutrition increases. The presence of sulfite antioxidants in the amino acids helps to reduce the formation of hydrogen peroxide, but the antioxidants are present in insufficient quantities to offer adequate protection. Shielding parenteral nutrition admixtures from light was recommended for neonatal administration.2309
The formation of toxic peroxides due to exposure of parenteral nutrition admixtures to light was reduced substantially by using colored administration sets. Both 2-in-1 and 3-in-1 parenteral nutrition admixtures exhibited little protection from peroxide formation when only the bag was shielded from light. Peroxide formation was 2 to 3 times higher using light-protected bags with clear tubing when compared to colored tubing. Shielding the parenteral nutrition bags from light and using black, yellow, or orange tubing would reduce peroxide loads down to about 100 µM.2306
Freezing Solutions
The acceptability of frozen storage of some parenteral nutrition solutions has been determined. Parenteral nutrition solutions composed of equal parts of Travasol 8.5% with electrolytes and dextrose 70% injection (final concentrations of amino acids and dextrose were 4.25 and 35%, respectively), in PVC containers were stored frozen at -20°C for 60 days. Both overnight room temperature thawing and 30-minute microwave thawing were utilized. The results indicated that, with either thawing technique, the amino acids, electrolytes, and dextrose were unchanged after 60 days of frozen storage and subsequent thawing.578
Plasticizer Leaching
A parenteral nutrition solution containing an amino acid solution, dextrose, and electrolytes in a PVC bag did not leach measurable quantities of diethylhexyl phthalate (DEHP) plasticizer during 21 days of storage at 4 and 25°C. However, addition of lipid emulsion 10 or 20% to the formula caused detectable leaching of DEHP from the PVC containers stored for 48 hours. Higher DEHP levels were found in the 25°C samples than in the 4°C samples. The authors recommended limiting the use of lipid-containing parenteral nutrition admixtures to 24 to 36 hours. Use of non-PVC containers and tubing is another option to eliminate the problem of plasticizer leaching.1430
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Multicomponent (3-in-1; TNA) Admixtures
Because of the potential benefits in terms of simplicity, efficiency, time, and cost savings, the concept of mixing amino acids, carbohydrates, electrolytes, lipid emulsion, and other nutritional components together in the same container has been explored. Within limits, the feasibility of preparing such 3-in-1 parenteral nutrition admixtures has been demonstrated as long as a careful examination of the emulsion mixtures for signs of instability is performed prior to administration.
However, these 3-in-1 mixtures are very complex and inherently unstable. Emulsion stability is dependent on both zeta potential and van der Waals forces, influenced by the presence of dextrose.2029 The ultimate stability of each unique mixture depends on numerous complicated factors, making definitive stability predictions impossible. Injury and death have resulted from administration of unrecognized precipitates in 3-in-1 parenteral nutrition admixtures.1769; 1782; 1783 See the section on Calcium and Phosphate. In addition, the use of 3-in-1 admixtures is associated with a higher rate of catheter occlusion and reduced catheter life compared with giving the lipid emulsion separately from the parenteral nutrition solution.705; 1518; 2194
The use of a 5-µm inline filter for a 3-in-1 admixture (containing Travasol 8.5%, dextrose, Intralipid 10%, various electrolytes, vitamins, and trace elements) showed that fat, in the form of large globules or aggregates, comprised 99.4% of the filter contents. These authors recommend the use of an appropriate filter for preventing catheter occlusion with 3-in-1 admixtures.742
Using light microscopy, the presence of glass particles, talc, and plastic has been observed in administration line samples drawn from 20 adults receiving 3-in-1 parenteral nutrition admixtures and in 20 children receiving 2-in-1 admixtures with separate lipid emulsion infusions. Particles ranged from 3 to 5 µm to greater than 40 µm and were more consistently seen in the pediatric admixtures. The authors suggested the use of inline filters given that particulate contamination is present, has no therapeutic value, and can be harmful.2458
Combining an amino acids-glucose parenteral nutrition solution containing various electrolytes with lipid emulsion 20%, intravenous (Intralipid, Vitrum), resulted in a mixture which, although apparently stable for a limited time, ultimately exhibited a creaming phenomenon. Within 12 hours, a distinct 2-cm layer separated on the upper surface. Microscopic examination revealed aggregates believed to be clumps of fat droplets. Fewer and smaller aggregates were noted in the lower layer.560; 561
Amino acids were reported to have no adverse effect on the emulsion stability of Intralipid 10%. In addition, the amino acids appeared to prevent the adverse impact of dextrose and to slow the flocculation and coalescence resulting from mono- and divalent cations. However, significant coalescence did result after a longer time. Therefore, it was recommended that such cations not be mixed with lipid emulsion, intravenous.656
Three-in-one TNA admixtures prepared with Intralipid 20% and containing mono- and divalent ions as well as heparin sodium 5 units/mL were found to undergo changes consistent with instability including fat particle shape and diameter changes as well as creaming and layering. The changes were evident within 48 hours at room temperature but were delayed to between 1 and 2 months when refrigerated.58
Travenol stated that 1:1:1 mixtures of amino acids 5.5, 8.5, or 10% (Travenol), lipid emulsion 10 to 20% (Travenol), and dextrose 10 to 70% are physically stable but recommends administration within 24 hours. M.V.I.-12 3.3 mL/L and electrolytes may also be added to the admixtures up to the maximum amounts listed in Table 1.850
Table 1. Maximum Electrolyte Amounts for Travenol 3-in-1 Admixtures850
| Calcium | 8.3 mEq/L |
| Magnesium | 3.3 mEq/L |
| Sodium | 23.3 mEq/L |
| Potassium | 20.0 mEq/L |
| Chloride | 23.3 mEq/L |
| Phosphate | 20 mEq/L |
| Zinc | 3.33 mg/L |
| Copper | 1.33 mg/L |
| Manganese | 0.33 mg/L |
| Chromium | 13.33 mcg/L |
The stability of mixtures of 1 L of Intralipid 20%, 1.5 L of Vamin glucose (amino acids with dextrose 10%), and 0.5 L of dextrose 10% with various electrolytes and vitamins was evaluated. Initial emulsion particle size was around 1 µm. The mixture containing only monovalent cations was stable for at least 9 days at 4°C, with little change in particle size. The mixtures containing the divalent cations, such as calcium and magnesium, demonstrated much greater particle size increases, with mean diameters of around 3.3 to 3.5 µm after 9 days at 4°C. After 48 hours of storage, however, these increases were more modest, around 1.5 to 1.85 µm. After storage at 4°C for 48 hours followed by 24 hours at room temperature, few particles exceeded 5 µm. It was found that the effect of particle aggregation caused by electrolytes demonstrates a critical concentration before the effect begins. For calcium and magnesium chlorides, the critical concentrations were 2.4 and 2.6 mmol/L, respectively. Sodium and potassium chloride had critical concentrations of 110 and 150 mmol/L, respectively. The rate of particle aggregation increased linearly with increasing electrolyte concentration. The quantity of emulsion in the mixture had a relatively small influence on stability, but higher concentrations exhibited a somewhat greater coalescence.892
Instability of the emulsion systems is manifested by (1) flocculation of oil droplets to form aggregates, producing a cream-like layer on top; or (2) coalescence of oil droplets, leading to an increase in the average droplet size and eventually a separation of free oil. The lowering of pH and the adding of electrolytes can adversely affect the mechanical and electrical properties at the oil-water interface, eventually leading to flocculation and coalescence. Amino acids act as buffering agents and provide a protective effect on emulsion stability. Adding electrolytes, especially the divalent ions Mg++ and Ca++ in excess of 2.5 mmol/L, to simple lipid emulsions will cause flocculation. But in mixed parenteral nutrition solutions, the stability of the emulsion will be enhanced, depending on the quantity and nature of the amino acids present. The authors recommended a careful examination of emulsion mixtures for signs of instability prior to administration.849
Good stability was reported for an amino acid 4% (Travenol), dextrose 14%, and lipid emulsion 4% (Pharmacia) parenteral nutrition solution. The solution also contained electrolytes, vitamins, and heparin sodium 4000 units/L. The aqueous solution was prepared first, with the lipid emulsion added subsequently. This procedure allowed visual inspection of the aqueous phase and reduced the risk of emulsion breakdown by the divalent cations. Sample mixtures were stored at 18 to 25 and 3 to 8°C for up to 5 days. They were evaluated visually and with a Coulter counter for particle size measurements. Both room temperature and refrigerated mixtures were stable for 48 hours. A marked increase in particle size was noted in the room temperature sample after 72 hours, but refrigeration delayed the changes. The authors’ experience with over 1400 mixtures for administration to patients resulted in one emulsion creaming and another cracking, but the authors had no explanation for the failure of these particular emulsions.848
Six parenteral nutrition solutions having various concentrations of amino acids, dextrose, soybean oil emulsion (Kabi-Vitrum), electrolytes, and multivitamins were evaluated. All of the admixtures were stable for 1 week under refrigeration followed by 24 hours at room temperature, with no visible changes, changes in pH, or significant changes in particle size.1013 However, other researchers questioned this interpretation of the results.1014; 1015
The stability of 3-in-1 parenteral nutrition solutions prepared with 500 mL of Intralipid 20%, compared to Soyacal 20%, along with 500 or 1000 mL of FreAmine III 8.5% and 500 mL of dextrose 70% was reported. Also present were relatively large amounts of electrolytes and other additives. All mixtures were similarly stable for 28 days at 4°C followed by 5 days at 21 to 25°C, with little change in the emulsion. A slight white cream layer appeared after 5 days at 4°C but was easily redispersed with gentle agitation. The appearance of this cream layer did not statistically affect particle size distribution. The authors concluded that the emulsion mixture remained suitable for clinical use throughout the study period. The stability of other components was not evaluated.1019
The stability of 3-in-1 parenteral nutrition admixtures prepared with Liposyn II 10 and 20%, Aminosyn pH 6, and dextrose along with electrolytes, trace metals, and vitamins was reported. Thirty-one different combinations were evaluated. Samples were stored at: (1) 25°C for 1 day, (2) 5°C for 2 days followed by 30°C for 1 day, and (3) 5°C for 9 days followed by 25°C for 1 day. In all cases, there was no visual evidence of creaming, free oil droplets, and other signs of emulsion instability. Furthermore, little or no change in the particle size or zeta potential (electrostatic surface charge of lipid particles) was found, indicating emulsion stability. The dextrose and amino acids remained stable over the 10-day storage period. The greatest change of an amino acid occurred with tryptophan, which lost 6% in 10 days. Vitamin stability was not tested.1025
The stability of 4 parenteral nutrition admixtures, ranging from 1 L each of amino acids 5.5% (Travenol), dextrose 10%, and lipid emulsion 10% (Travenol) up to a “worst case” of 1 L each of amino acids 10% with electrolytes (Travenol), dextrose 70%, and lipid emulsion 10% (Travenol) was reported. The admixtures were stored for 48 hours at 5 to 9°C followed by 24 hours at room temperature. There were no visible signs of creaming, flocculation, and free oil. The mean emulsion particle size remained within acceptable limits for all admixtures, and there were no significant changes in glucose, soybean oil, and amino acid concentrations. The authors noted that 2 factors were predominant in determining the stability of such admixtures: electrolyte concentrations and pH.1065
Several parenteral nutrition solutions containing amino acids (Travenol), glucose, and lipid, with and without electrolytes and trace elements, produced no visible flocculation or any significant change in mean emulsion particle size during 24 hours at room temperature.1066
The compatibility of 10 parenteral nutrition admixtures, evaluated over 96 hours while stored at 20 to 25°C in both glass bottles and ethylene vinyl acetate bags was reported. A slight creaming occurred in all admixtures, but the cream layer was easily redispersed with gentle shaking. No fat globules were visually apparent. The mean drop size was larger in the cream layer, but no globules were larger than 5 µm. Analyses of the concentrations of amino acids, dextrose, and electrolytes showed no changes over the study period. The authors concluded that such parenteral nutrition admixtures could be safely prepared as long as the component concentrations are within the ranges found in Table 2.1067
Table 2. Range of Component Amounts for Compatibility Testing of 3-in-1 Admixtures1067
| Vamin glucose or Vamin N (amino acids 7%) | 1000 to 2000 mL |
| Dextrose 10 to 30% | 100 to 550 mL |
| Intralipid 10 or 20% | 500 to 1000 mL |
| Electrolyte (mmol/L) | |
| Sodium | 20 to 70 |
| Potassium | 20 to 55 |
| Calcium | 2.3 to 2.9 |
| Magnesium | 1.1 to 3.1 |
| Phosphorus | 0 to 9.2 |
| Chloride | 27 to 71 |
| Zinc | 0.005 to 0.03 |
The stability of 8 parenteral nutrition admixtures with various ratios of amino acids, carbohydrates, and fat was reported. FreAmine III 8.5%, dextrose 70%, and Soyacal 10 and 20% (mixed in ratios of 2:1:1, 1:1:1, 1:1:½, and 1:1:¼, where 1 = 500 mL) were evaluated. Additive concentrations were high to stress the admixtures and represent maximum doses likely to be encountered clinically. (See Table 3.)
Table 3. Range of Component Amounts for Compatibility Testing of 3-in-1 Admixtures1068
| Sodium acetate | 150 mEq |
| Sodium chloride | 210 mEq |
| Potassium acetate | 45 mEq |
| Potassium chloride | 90 mEq |
| Potassium phosphate | 15 mM |
| Calcium gluconate | 20 mEq |
| Magnesium sulfate | 36 mEq |
| Trace elements | present |
| Folic acid | 5 mg |
| M.V.I.-12 | 10 mL |
The admixtures were stored at 4°C for 14 days followed by 4 days at 22 to 25°C. After 24 hours, all admixtures developed a thin white cream layer, which readily redispersed on gentle agitation. No free oil droplets were observed. The mean particle diameter remained near the original size of the Soyacal throughout the study. Few particles were larger than 3 µm. Osmolality and pH also remained relatively unchanged.1068
Parenteral nutrition 3-in-1 admixtures with Aminosyn and Liposyn have been a problem. Standard admixtures were prepared using Aminosyn 7% 1000 mL, dextrose 50% 1000 mL, and Liposyn 10% 500 mL. Concentrated admixtures were prepared using Aminosyn 10% 500 mL, dextrose 70% 500 mL, and Liposyn 20% 500 mL. Vitamins and trace elements were added to the admixtures along with the following electrolytes (see Table 4).
Table 4. Electrolyte Amounts for Compatibility Testing of 3-in-1 Admixtures1069
| Electrolyte | Standard Admixture | Concentrated Admixture |
|---|---|---|
| Sodium | 125 mEq | 75 mEq |
| Potassium | 95 mEq | 74 mEq |
| Magnesium | 25 mEq | 25 mEq |
| Calcium | 28 mEq | 28 mEq |
| Phosphate | 37 mM | 36 mM |
| Chloride | 83 mEq | 50 mEq |
Samples of each admixture were: (1) stored at 4°C, (2) adjusted to pH 6.6 with sodium bicarbonate and stored at 4°C, or (3) adjusted to pH 6.6 and stored at room temperature. The compatibility was evaluated for 3 weeks.
Visible signs of emulsion deterioration were evident by 96 hours in the standard admixture and by 48 hours in the concentrated admixture. Clear rings formed at the meniscus, becoming thicker, yellow, and oily over time. Free-floating oil was obvious in 3 weeks in the standard admixture and 1 week in the concentrated admixture. The samples adjusted to pH 6.6 developed visible deterioration later than the others. The authors indicated that pH may play a greater role than temperature in emulsion stability. However, precipitation (probably calcium phosphate and possibly carbonate) occurred in 36 hours in the pH 6.6 concentrated admixture but not the unadjusted (pH 5.5) samples. Mean particle counts increased for all samples over time but were greatest in the concentrated admixtures. The authors concluded that the concentrated admixtures were unsatisfactory for clinical use because of the early increase in particles and precipitation. Furthermore, they recommended that the standard admixtures be prepared immediately prior to use.1069
The physical stability of 10 parenteral nutrition admixtures with different amino acid sources was studied. The admixtures contained 500 mL each of dextrose 70%, lipid emulsion 20% (Alpha Therapeutic), and amino acids in various concentrations from each manufacturer. Also present were standard electrolytes, trace elements, and vitamins. The admixtures were stored for 14 days at 4°C, followed by 4 days at 22 to 25°C. Slight creaming was evident in all admixtures but redispersed easily with agitation. Emulsion particles were uniform in size, showing no tendency to aggregate. No cracked emulsions occurred.1217
The stability of parenteral nutrition solutions containing amino acids, dextrose, and lipid emulsion along with electrolytes, trace elements, and vitamins has been described. In one study the admixtures were stable for 24 hours at room temperature and for 8 days at 4°C. The visual appearance and particle size of the lipid emulsion showed little change over the observation periods.1218 In another study variable stability periods were found, depending on electrolyte concentrations. Stability ranged from 4 to 25 days at room temperature.1219
The effects of dilution, dextrose concentration, amino acids, and electrolytes on the physical stability of 3-in-1 parenteral nutrition admixtures prepared with Intralipid 10% or Travamulsion 10% was studied. Travamulsion was affected by dilution up to 1:14, exhibiting an increase in mean particle size, while Intralipid remained virtually unchanged for 24 hours at 25°C and for 72 hours at 4°C. At dextrose concentrations above 15%, fat droplets larger than 5 µm formed during storage for 24 hours at either 4°C or room temperature. The presence of amino acids increased the stability of the lipid emulsions in the presence of dextrose. Fat droplets larger than 5 µm formed at a total electrolyte concentration above approximately 240 mmol/L (monovalent cation equivalent) for Travamulsion 10% and 156 mmol/L for Intralipid 10% in 24 hours at room temperature, although creaming or breaking of the emulsion was not observed visually.1221
The stability of 43 parenteral nutrition admixtures composed of various ratios of amino acid products, dextrose 10 to 70%, and 4 lipid emulsions 10 and 20% with electrolytes, trace elements, and vitamins was studied. One group of admixtures included Travasol 5.5, 8.5, and 10%, FreAmine III 8.5 and 10%, Novamine 8.5 and 11.4%, Nephramine 5.4%, and RenAmine 6.5% with Liposyn II 10 and 20%. In another group, Aminosyn II 7, 8.5, and 10% was combined with Intralipid, Travamulsion, and Soyacal 10 and 20%. A third group consisted of Aminosyn II 7, 8.5, and 10% with electrolytes combined with the latter 3 lipid emulsions. The admixtures were stored for 24 hours at 25°C and for 9 days at 5°C followed by 24 hours at 25°C. A few admixtures containing FreAmine III and Novamine with Liposyn II developed faint yellow streaks after 10 days of storage. The streaks readily dispersed with gentle shaking, as did the creaming present in most admixtures. Other properties such as pH, zeta-potential, and osmolality underwent little change in all of the admixtures. Particle size increased fourfold in 1 admixture (Novamine 8.5%, dextrose 50%, and Liposyn II in a 1:1:1 ratio), which the authors noted signaled the onset of particle coalescence. Nevertheless, the authors concluded that all of the admixtures were stable for the storage conditions and time periods tested.1222
The stability of 24 parenteral nutrition admixtures composed of various ratios of Aminosyn II 7, 8.5, or 10%, dextrose, and Liposyn II 10 and 20% with electrolytes, trace elements, and vitamins was also studied. Four admixtures were stored for 24 hours at 25°C, 6 admixtures were stored for 2 days at 5°C followed by 1 day at 30°C, and 14 admixtures were stored for 9 days at 5°C followed by 1 day at 25°C. No visible instability was evident. Creaming was present in most admixtures but disappeared with gentle shaking. Other properties such as pH, zeta-potential, particle size, and potency of the amino acids and dextrose showed little or no change during storage.1223
The emulsion stability of 5 parenteral nutrition formulas (TNA #126 through #130 in Appendix) containing Liposyn II in concentrations ranging from 1.2 to 7.1% were reported. The parenteral nutrition solutions were prepared using simultaneous pumping of the components into empty containers (as with the Nutrimix compounder) and sequential pumping of the components (as with Automix compounders). The solutions were stored for 2 days at 5°C followed by 24 hours at 25°C. Similar results were obtained for both methods of preparation using visual assessment and oil globule size distribution.1426
The stability of 24 parenteral nutrition admixtures containing various concentrations of Aminosyn II, dextrose, and Liposyn II with a variety of electrolytes, trace elements, and multivitamins in dual-chamber, flexible, Nutrimix containers was studied as well. No instability was visible in the admixtures stored at 25°C for 24 hours or in those stored for 9 days at 5°C followed by 24 hours at 25°C. Creaming was observed, but neither particle coalescence nor free oil was noted. The pH, particle size distribution, and amino acid and dextrose concentrations remained acceptable during the observation period.1432
The physical stability of 10 parenteral nutrition formulas (TNA #149 through #158 in Appendix) containing TrophAmine and Intralipid 20%, Liposyn II 20%, and Nutrilipid 20% in varying concentrations with low and high electrolyte concentrations was studied. All test formulas were prepared with an automatic compounder and protected from light. TNA #149 through #156 were stored for 48 hours at 4°C followed by 24 hours at 21°C; TNA #157 and #158 were stored for 24 hours at 4°C followed by 24 hours at 21°C. Although some minor creaming occurred in all formulas, it was completely reversible with agitation. No other changes were visible, and particle size analysis indicated little variation during the study period. The addition of cysteine hydrochloride 1 g/25 g of amino acids, alone or with L-carnitine 16 mg/g fat, to TNA #157 and #158 did not adversely affect the physical stability of 3-in-1 admixtures within the study period.1620
The physical stability of five 3-in-1 parenteral nutrition admixtures (TNA #167 through #171 in Appendix) was evaluated by visual observation, pH and osmolality determinations, and particle size distribution analysis. All 5 admixtures were physically stable for 90 days at 4°C. However, some irreversible flocculation occurred in all combinations after 180 days.1651
The stability of several parenteral nutrition formulas (TNA #159 through #166 in Appendix) with and without iron dextran 2 mg/L was studied. All formulas were physically compatible both visually and microscopically for 48 hours at 4 and 25°C, and particle size distribution remained unchanged. The order of mixing and deliberate agitation had no effect on physical compatibility.1648
The influence of 6 factors on the stability of lipid emulsion in 45 different 3-in-1 parenteral nutrition mixtures was evaluated. The factors were amino acid concentration (2.5 to 7%); dextrose (5 to 20%); lipid emulsion, intravenous (2 to 5%); monovalent cations (0 to 150 mEq/L); divalent cations (4 to 20 mEq/L); and trivalent cations from iron dextran (0 to 10 mg elemental iron/L). Although many formulations were unstable, visual examination could identify instability in only 65% of the samples. Electronic evaluation of particle size identified the remaining unstable mixtures. Furthermore, only the concentration of trivalent ferric ions significantly and consistently affected the emulsion stability during the 30-hour test period. Of the parenteral nutrition mixtures containing iron dextran, 16% were unstable, exhibiting emulsion cracking. The authors suggested that iron dextran should not be incorporated into 3-in-1 mixtures.1814
The compatibility of 8 parenteral nutrition admixtures, 4 with and 4 without electrolytes, comparing Liposyn II and Intralipid (TNA #250 through #257 in Appendix) was reported. The 3-in-1 admixtures were evaluated over 2 to 9 days at 4°C and then 24 hours at 25°C in ethylene vinyl acetate (EVA) bags. No substantial changes were noted in the fat particle sizes and no visual changes of emulsion breakage were observed. All admixtures tested had particle sizes in the 2- to 40-µm range.2465
The stability of 3-in-1 parenteral nutrition admixtures prepared with Vamin 14 with electrolytes and containing either Lipofundin MCT/LCT 20% or Intralipid 20% was evaluated. The admixtures contained 66.7 mmol/L of monovalent and 6.7 mmol/L of divalent cations. Stability of the lipid emulsion was evaluated after 2, 7, and 21 days at 4°C in EVA bags followed by 24 hours of room temperature to simulate infusion. Microscopy, Coulter counter, photon correlation spectroscopy, and laser diffractometry techniques were used to determine stability. Droplet size by microscopy was noted to increase to 18 to 20 µm after 21 days in both of the admixtures with the Intralipid-containing admixture showing particles this large as early as day 2 and with Lipofundin MCT/LCT at day 7. The Coulter counter assessed particles greater than 2 µm to be approximately 1300 to 1500 with Lipofundin MCT/LCT and 37,000 in the Intralipid-containing admixtures immediately after their preparation. Heavy creaming with a thick firm layer was noted after 2 days with the Intralipid-containing admixture, making particle assessment difficult. The authors concluded that storage limitation of 2 days for the Intralipid-containing admixture and not more than 7 days for the Lipofundin-containing admixture appeared justified. They also noted that calcium and magnesium behaved identically in destabilizing lipid emulsion with greater concentrations of divalent cations.867
The drop size of 3-in-1 parenteral nutrition solutions in drip chambers is variable, being altered by the constituents of the mixture. In one study, multivitamins (Multibionta, E. Merck) caused the greatest reductions in drop size, up to 37%. This change may affect the rate of delivery if the flow is estimated from drops per minute.1016 Similarly, flow rates delivered by infusion controllers dependent on predictable drop size may be inaccurate. Flow rates up to 29% less than expected have been reported. Therefore, variable pressure volumetric pumps, which are independent of drop size, should be used rather than infusion controllers.1215
The physical instability of 3-in-1 total nutrient admixtures stored for 24 hours at room temperature was reported. The admixtures intended for use in neonates and infants were compounded with TrophAmine 2 to 3%, dextrose 18 to 24%, Liposyn II (Abbott) 2 to 3%, L-cysteine hydrochloride, and the following electrolytes in Table 5.
Table 5. Incompatible Electrolyte Ranges in Neonatal 3-in-1 Admixtures2619
| Sodium | 20 to 50 mEq/L |
| Potassium | 13.3 to 40 mEq/L |
| Calcium chloride | 20 to 26.6 mEq/L |
| Magnesium | 3.4 to 5 mEq/L |
| Phosphates | 6.7 to 15 mmol/L |
The emulsion in the admixtures cracked and developed visible free oil within 24 hours after compounding. The incompatibility was considered to create a clinically significant risk of complications if administered. The authors determined that these 3-in-1 total nutrient admixtures containing these concentrations of electrolytes were unacceptable and should not be used.2619
Another evaluation of 3-in-1 total nutrient admixtures reported physical instabilities of several formulations evaluated over 7 days. The parenteral nutrition admixtures were prepared with dextrose 15% and Intralipos 4% (Fresenius Kabi) along with FreAmine 4.3%, NephrAmine 2.1%, TrophAmine 2.7%, Topanusol 5%, or HepatAmine 4%. Various electrolytes and other components were also present including sodium, potassium, calcium (salt form unspecified), magnesium, trace elements, vitamin K, and heparin. The admixtures were stored at 4°C and evaluated at 0, 3, and 7 days. After removal from refrigeration, the samples were subjected to additional exposure to room temperature and temperatures exceeding 28°C for 24 to 48 hours. Flocculation was found in the admixtures prepared with FreAmine and with TrophAmine after 24 hours storage at room temperature, and after 3 days under refrigeration followed by 24 hours at room temperature. All of the admixtures developed coalescence after 7 days under refrigeration followed by 24 hours at greater than 28°C.2621
The case of a 26-year-old female with Crohn’s disease and enterocutaneous fistulae receiving a 3-in-1 parenteral nutrition admixture composed of Travasol 3.6%, dextrose 13.6%, Intralipid 1.5%, sodium chloride 52.3 mEq/L, sodium acetate 27.4 mEq/L, potassium chloride 27.4 mEq/L, potassium acetate 13.7 mEq/L, magnesium sulfate 4.5 mEq/L, calcium gluconate 3.2 mEq/L, MVI-12, and trace elements but no inorganic phosphates was presented. The patient became febrile, short of breath, and developed a dry cough with diffuse crackles in both lungs. After failing to respond to conventional medical therapy, an open lung biopsy was performed and showed widespread vascular pulmonary thromboses from irregularly shaped crystals leading to the lung perfusion defects. High levels of calcium, potassium, and carbon were detected in the crystals. Subsequent repeat testing in vitro failed to find crystallization. The patient’s fever was postulated to contribute to the in vivo crystallization.2621
The physical stability of 5 highly concentrated 3-in-1 parenteral nutrition admixtures for fluid-restricted adults was evaluated. The admixtures were composed of Aminoplasmal (B. Braun) at concentrations over 7% as the amino acids source, dextrose concentrations of about 20%, and a 50:50 mixture of medium-chain triglycerides and long-chain triglycerides (Lipofundin MCT, B. Braun) at concentrations of about 2.5 to 2.7% as the lipid component with electrolytes and vitamins (TNA #269 through #273 in Appendix). The parenteral nutrition admixtures were prepared in EVA bags and stored at room temperature for 30 hours. Electronic evaluation of mean fat particle sizes and globule size distribution found little change over the 30-hour test period.2721
Considerations and Recommendations
When multicomponent, 3-in-1, parenteral nutrition admixtures are used, the following points should be considered:490; 703; 892; 893; 1025; 1064; 1070; 1214; 1406; 1951; 2029; 2030; 2215; 2282; 2308; 3251; 3252; 3253; 3254; 3255
Furthermore, a 1.2-µm filter should be used in the administration of lipid emulsion, intravenous, whether used alone or administered as a component of a TNA (3-in-1); filtration is necessary to remove large lipid particles, electrolyte precipitates, and other solid particulates and aggregates.1106; 1657; 1769; 2061; 2135; 2346; 3251; 3252; 3253; 3254; 3255; 3259; 3260
Blood Products
Amino acids injection should not be administered simultaneously with blood through the same infusion set because of possible pseudoagglutination.341
Calcium and Phosphate
UNRECOGNIZED CALCIUM PHOSPHATE PRECIPITATION IN A 3-IN-1 PARENTERAL NUTRITION MIXTURE RESULTED IN PATIENT DEATH.
The potential for the formation of a calcium phosphate precipitate in parenteral nutrition solutions is well studied and documented,1771; 1777 but the information is complex and difficult to apply to the clinical situation.1770; 1772; 1777 The incorporation of lipid emulsion in 3-in-1 parenteral nutrition solutions obscures any precipitate that may be present, which has led to substantial debate about the dangers associated with 3-in-1 parenteral nutrition mixtures and when or if the danger to the patient is warranted therapeutically.1770; 1771; 1772; 2031; 2032; 2033; 2034; 2035; 2036 Because such precipitation may be life threatening to patients,2037; 2291 FDA issued a Safety Alert containing the following recommendations:1769
Calcium Phosphate Precipitation Fatalities
Fatal cases of paroxysmal respiratory failure in 2 previously healthy women receiving peripheral vein parenteral nutrition were reported. The patients experienced sudden cardiopulmonary arrest consistent with pulmonary emboli. The authors used in vitro simulations and an animal model to conclude that unrecognized calcium phosphate precipitation in a 3-in-1 total nutrition admixture caused the fatalities. The precipitation resulted during compounding by introducing calcium and phosphate near to one another in the compounding sequence and prior to complete fluid addition. This resulted in a temporarily high concentration of the drugs and precipitation of calcium phosphate. Observation of the precipitate was obscured by the incorporation of 20% lipid emulsion, intravenous, into the nutrition mixture. No filter was used during infusion of the fatal nutrition admixtures.2037
In a follow-up retrospective review, 5 patients were identified who had respiratory distress associated with the infusion of the 3-in-1 admixtures at around the same time. Four of these 5 patients died, although the cause of death could be definitively determined for only 2.2291
Calcium and Phosphate Conditional Compatibility
Calcium salts are conditionally compatible with phosphate in parenteral nutrition solutions. The incompatibility is dependent on a solubility and concentration phenomenon and is not entirely predictable. Precipitation may occur during compounding or at some time after compounding is completed.
NOTE: Some amino acids solutions inherently contain calcium and phosphate, which must be considered in any projection of compatibility.
A study determined the maximum concentrations of calcium (as chloride and gluconate) and phosphate that can be maintained without precipitation in a parenteral nutrition solution consisting of FreAmine II 4.25% and dextrose 25% for 24 hours at 30°C. It was noted that the amino acids in parenteral nutrition solutions form soluble complexes with calcium and phosphate, reducing the available free calcium and phosphate that can form insoluble precipitates. The concentration of calcium available for precipitation is greater with the chloride salt compared to the gluconate salt, at least in part because of differences in dissociation characteristics. Consequently, a greater concentration of calcium gluconate than calcium chloride can be mixed with sodium phosphate.608
In addition to the concentrations of phosphate and calcium and the salt form of the calcium, the concentration of amino acids and the time and temperature of storage altered the formation of calcium phosphate in parenteral nutrition solutions. As the temperature was increased, the incidence of precipitate formation also increased. This finding was attributed, at least in part, to a greater degree of dissociation of the calcium and phosphate complexes and the decreased solubility of calcium phosphate. Therefore, a solution possibly may be stored at 4°C with no precipitation, but on warming to room temperature a precipitate will form over time.608
The compatibility of calcium and phosphate in several parenteral nutrition formulas for newborn infants was evaluated. Calcium gluconate 10% (Cutter) and potassium phosphate (Abbott) were used to achieve concentrations of 2.5 to 100 mEq/L of calcium and 2.5 to 100 mmol/L of phosphorus added. The parenteral nutrition solutions evaluated were as shown in Table 6. The results were reported as graphic depictions.
Table 6. Parenteral Nutrition Solutions Evaluated609
| Solution Number | ||||
|---|---|---|---|---|
| Component | #1 | #2 | #3 | #4 |
| FreAmine III | 4% | 2% | 1% | 1% |
| Dextrose | 25% | 20% | 10% | 10% |
| pH | 6.3 | 6.4 | 6.6 | 7.0a |
aAdjusted with sodium hydroxide.
The pH dependence of the phosphate-calcium precipitation has been noted. Dibasic calcium phosphate is very insoluble, while monobasic calcium phosphate is relatively soluble. At low pH, the soluble monobasic form predominates; but as the pH increases, more dibasic phosphate becomes available to bind with calcium and precipitate. Therefore, the lower the pH of the parenteral nutrition solution, the more calcium and phosphate can be solubilized. Once again, the effects of temperature were observed. As the temperature is increased, more calcium ion becomes available and more dibasic calcium phosphate is formed. Therefore, temperature increases will increase the amount of precipitate.609
Similar calcium and phosphate solubility curves were reported for neonatal parenteral nutrition solutions using TrophAmine (McGaw) 2, 1.5, and 0.8% as the sources of amino acids. The solutions also contained dextrose 10%, with cysteine and pH adjustment being used in some admixtures. Calcium and phosphate solubility followed the patterns reported previously.609 A slightly greater concentration of phosphate could be used in some mixtures, but this finding was not consistent.1024
Using a similar study design, 6 neonatal parenteral nutrition solutions based on Aminosyn-PF (Abbott) 2, 1.5, and 0.8%, with and without added cysteine hydrochloride and dextrose 10% were studied. Calcium concentrations ranged from 2.5 to 50 mEq/L, and phosphate concentrations ranged from 2.5 to 50 mmol/L. Solutions sat for 18 hours at 25°C and then were warmed to 37°C in a water bath to simulate the clinical situation of warming prior to infusion into a child. Solubility curves were markedly different than those for TrophAmine in the previous study.1024 Solubilities were reported to decrease by 15 mEq/L for calcium and 15 mmol/L for phosphate. The solutions remained clear during room temperature storage, but crystals often formed on warming to 37°C.1211
However, these data were questioned by Mikrut, who noted the similarities between the Aminosyn-PF and TrophAmine products and found little difference in calcium and phosphate solubilities in a preliminary report.1212 In the full report1213, parenteral nutrition solutions containing Aminosyn-PF or TrophAmine 1 or 2.5% with dextrose 10 or 25%, respectively, plus electrolytes and trace metals, with or without cysteine hydrochloride, were evaluated under the same conditions. Calcium concentrations ranged from 2.5 to 50 mEq/L, and phosphate concentrations ranged from 5 to 50 mmol/L. In contrast to the previous results1024, the solubility curves were very similar for the Aminosyn-PF and TrophAmine parenteral nutrition solutions but very different from those of the previous Aminosyn-PF study.1211 The authors again showed that the solubility of calcium and phosphate is greater in solutions containing higher concentrations of amino acids and dextrose.1213
Calcium and phosphate solubility curves for TrophAmine 1 and 2% with dextrose 10% and electrolytes, vitamins, heparin, and trace elements were reported. Calcium concentrations ranged from 10 to 60 mEq/L, and phosphorus concentrations ranged from 10 to 40 mmol/L. Calcium and phosphate solubilities were assessed by analysis of the calcium concentrations and followed patterns similar to those reported previously.608; 609 The higher percentage of amino acids (TrophAmine 2%) permitted a slightly greater solubility of calcium and phosphate, especially in the 10 to 50-mEq/L and 10 to 35-mmol/L ranges, respectively.1614
The maximal product of the amount of calcium (as gluconate) times phosphate (as potassium) that can be added to a parenteral nutrition solution, composed of amino acids 1% (Travenol) and dextrose 10%, for preterm infants was reported. Turbidity was observed on initial mixing when the solubility product was around 115 to 130 mmol2 or greater. After storage at 7°C for 20 hours, visible precipitates formed at solubility products of 130 mmol2 or greater. If the solution was administered through a barium-impregnated silicone rubber catheter, crystalline precipitates obstructed the catheters in 12 hours at a solubility product of 100 mmol2 and in 10 days at 79 mmol2, much lower than the in vitro results.1041
The solubility characteristics of calcium and phosphate in pediatric parenteral nutrition solutions composed of Aminosyn 0.5, 2, and 4% with dextrose 10 to 25% were reported. Also present were electrolytes and vitamins. Sodium phosphate was added sequentially in phosphorus concentrations from 10 to 30 mmol/L. Calcium gluconate was added last in amounts ranging from 1 to 10 g/L. The solutions were stored at 25°C for 30 hours and examined visually and microscopically for precipitation. The authors found that higher concentrations of Aminosyn increased the solubility of calcium and phosphate. Precipitation occurred at lower calcium and phosphate concentrations in the 0.5% solution compared to the 2 and 4% solutions. For example, at a phosphorus concentration of 30 mmol/L, precipitation occurred at calcium gluconate concentrations of about 1, 2, and 4 g/L in the 0.5, 2, and 4% Aminosyn mixtures, respectively. Similarly, at a calcium gluconate concentration of 8 g/L and above, precipitation occurred at phosphorus concentrations of about 13, 17, and 22 mmol/L in the 0.5, 2, and 4% solutions, respectively. The dextrose concentration did not appear to affect the calcium and phosphate solubility significantly.1042
The solubility of calcium and phosphorus in neonatal parenteral nutrition solutions composed of amino acids (Abbott) 1.25 and 2.5% with dextrose 5 and 10%, respectively, was evaluated. Also present were multivitamins and trace elements. The solutions contained calcium (as gluconate) in amounts ranging from 25 to 200 mg/100 mL. The phosphorus (as potassium phosphate) concentrations evaluated ranged from 25 to 150 mg/100 mL. If calcium gluconate was added first, cloudiness occurred immediately. If potassium phosphate was added first, substantial quantities could be added with no precipitate formation in 48 hours at 4°C (Table 7). However, if stored at 22°C, the solutions were stable for only 24 hours, and all contained precipitates after 48 hours.1210
Table 7. Maximum Calcium and Phosphorus Concentrations Physically Compatible for 48 Hours at 4°C1210
| Phosphorus (mg/100 mL) | ||
|---|---|---|
| Calcium (mg/100 mL) | Amino Acids 1.25% + Dextrose 5%a | Amino Acids 2.5% + Dextrose 10%a |
| 200b | 50 | 75 |
| 150 | 50 | 100 |
| 100 | 75 | 100 |
| 50 | 100 | 125 |
| 25 | 150b | 150b |
aPlus multivitamins and trace elements.bMaximum concentration tested.
The physical compatibility of calcium gluconate 10 to 40 mEq/L and potassium phosphates 10 to 40 mmol/L in 3 neonatal parenteral nutrition solutions (TPN #123 to #125 in Appendix), alone and with retrograde administration of aminophylline 7.5 mg diluted with 1.5 mL of sterile water for injection was reported. Contact of the alkaline aminophylline solution with the parenteral nutrition solutions resulted in the precipitation of calcium phosphate at much lower concentrations than were compatible in the parenteral nutrition solutions alone.1404
Additional calcium and phosphate solubility curves were reported for specialty parenteral nutrition solutions based on NephrAmine and also HepatAmine at concentrations of 0.8, 1.5, and 2% as the sources of amino acids. The solutions also contained dextrose 10%, with cysteine and pH adjustment to simulate addition of lipid emulsion used in some admixtures. Calcium and phosphate solubility followed the hyperbolic patterns previously reported.609 Temperature, time, and pH affected calcium and phosphate solubility, with pH having the greatest effect.2038
The maximum sodium phosphate concentrations were reported for given amounts of calcium gluconate that could be admixed in parenteral nutrition solutions containing TrophAmine in varying quantities (with cysteine hydrochloride 40 mg/g of amino acid) and dextrose 10%. The solutions also contained magnesium sulfate 4 mEq/L, potassium acetate 24 mEq/L, sodium chloride 32 mEq/L, pediatric multivitamins, and trace elements. The presence of cysteine hydrochloride reduces the solution pH and increases the amount of calcium and phosphate that can be incorporated before precipitation occurs. The results of this study cannot be safely extrapolated to TPN solutions with compositions other than the ones tested. The admixtures were compounded with the sodium phosphate added last after thorough mixing of all other components. The authors noted that this is not the preferred order of mixing (usually phosphate is added first and thoroughly mixed before adding calcium last); however, they believed this reversed order of mixing would provide a margin of error in cases in which the proper order is not followed. After compounding, the solutions were stored for 24 hours at 40°C. The maximum calcium and phosphate amounts that could be mixed in the various solutions were reported tabularly and are shown in Table 8.2039 However, these results are not entirely consistent with another study. See Table 9.
Table 8. Maximum Amount of Phosphate (as Sodium) (mmol/L) Not Resulting in Precipitation.2039 See CAUTION Below.a
| Amino Acid (as TrophAmine) plus Cysteine HCl 40 mg/g Amino Acid | |||||
|---|---|---|---|---|---|
| Calcium (as Gluconate) | 0% | 0.4% | 1% | 2% | 3% |
| 9.8 mEq/L | 0 | 27 | 42 | 60 | 66 |
| 14.7 mEq/L | 0 | 15 | 18 | 30 | 36 |
| 19.6 mEq/L | 0 | 6 | 15 | 27 | 30 |
| 29.4 mEq/L | 0 | 3 | 6 | 21 | 24 |
aCAUTION: The results cannot be safely extrapolated to solutions with formulas other than the ones tested. See text.
The temperature dependence of the calcium-phosphate precipitation has resulted in the occlusion of a subclavian catheter by a solution apparently free of precipitation. The parenteral nutrition solution consisted of FreAmine III 500 mL, dextrose 70% 500 mL, sodium chloride 50 mEq, sodium phosphate 40 mmol, potassium acetate 10 mEq, potassium phosphate 40 mmol, calcium gluconate 10 mEq, magnesium sulfate 10 mEq, and Shil’s trace metals solution 1 mL. Although there was no evidence of precipitation in the bottle, tubing and pump cassette, and filter (all at approximately 26°C) during administration, the occluded catheter and Vicra Loop Lock (next to the patient’s body at 37°C) had numerous crystals identified as calcium phosphate. In vitro, this parenteral nutrition solution had a precipitate in 12 hours at 37°C but was clear for 24 hours at 26°C.610
Similarly, a parenteral nutrition solution that was clear and free of particulates after 2 weeks under refrigeration developed a precipitate in 4 to 6 hours when stored at room temperature. When the solution was warmed in a 37°C water bath, precipitation occurred in 1 hour. Administration of the solution before the precipitate was noticed led to interstitial pneumonitis due to deposition of calcium phosphate crystals.1427
The maximum allowable concentrations of calcium and phosphate in a 3-in-1 parenteral nutrition mixture for children (TNA #192 in Appendix) were reported. Added calcium was varied from 1.5 to 150 mmol/L, and added phosphate was varied from 21 to 300 mmol/L. These mixtures were stable for 48 hours at 22 and 37°C as long as the pH was not greater than 5.7, the calcium concentration was below 16 mmol/L, the phosphate concentration was below 52 mmol/L, and the product of the calcium and phosphate concentrations was below 250 mmol2/L2.1773
Calcium phosphate precipitation phenomena was evaluated in a series of parenteral nutrition admixtures composed of dextrose 22%, amino acids (FreAmine III) 2.7%, and lipid emulsion (Abbott) 0, 1, and 3.2%. Incorporation of calcium gluconate 19 to 24 mEq/L and phosphate (as sodium) 22 to 28 mmol/L resulted in visible precipitation in the fat-free admixtures. New precipitate continued to form over 14 days, even after repeated filtrations of the solutions through 0.2-µm filters. The presence of the amino acids increased calcium and phosphate solubility, compared with simple aqueous solutions. However, the incorporation of the lipid emulsion did not result in a statistically significant increase in calcium and phosphate solubility. The authors noted that the kinetics of calcium phosphate precipitate formation do not appear to be entirely predictable; both transient and permanent precipitation can occur either during the compounding process or at some time afterward. Because calcium phosphate precipitation can be very dangerous clinically, the use of inline filters was recommended. The authors suggested that the filters should have a porosity appropriate to the parenteral nutrition admixture—1.2 µm for fat-containing and 0.2 or 0.45 µm for fat-free nutrition mixtures.2061
Laser particle analysis was used to evaluate the formation of calcium phosphate precipitation in pediatric TPN solutions containing TrophAmine in concentrations ranging from 0.5 to 3% with dextrose 10% and also containing L-cysteine hydrochloride 1 g/L. The solutions also contained in each liter sodium chloride 20 mEq, sodium acetate 20 mEq, magnesium sulfate 3 mEq, trace elements 3 mL, and heparin sodium 500 units. The presence of L-cysteine hydrochloride reduces the solution pH and increases the amount of calcium and phosphate that can be incorporated before precipitation occurs. The results of this study cannot be safely extrapolated to TPN solutions with compositions other than the ones tested. The maximum amount of phosphate that was incorporated without the appearance of a measurable increase in particulates in 24 hours at 37°C for each of the amino acids concentrations is shown in Table 9.2196 These results are not entirely consistent with previous results.2039 See above. The use of more sensitive electronic particle measurement for the formation of subvisible particulates in this study may contribute to the differences in the results.
Table 9. Maximum Amount of Phosphate (as Potassium) (mmol/L) Not Resulting in Precipitation.2196 See CAUTION Below.a
| Amino Acid (as TrophAmine) plus Cysteine HCl 1 g/L | ||||||
|---|---|---|---|---|---|---|
| Calcium (as Gluconate) (mEq/L) | 0.5% | 1% | 1.5% | 2% | 2.5% | 3% |
| 10 | 22 | 28 | 38 | 38 | 38 | 43 |
| 14 | 18 | 18 | 18 | 38 | 38 | 43 |
| 19 | 18 | 18 | 18 | 33 | 33 | 38 |
| 24 | 12 | 18 | 18 | 22 | 28 | 28 |
| 28 | 12 | 18 | 18 | 18 | 18 | 18 |
| 33 | 12 | 12 | 12 | 12 | 12 | 12 |
| 37 | 12 | 12 | 12 | 12 | 12 | 12 |
| 41 | 9 | 9 | 9 | 12 | 12 | 12 |
| 45 | 0 | 9 | 9 | 12 | 12 | 12 |
| 49 | 0 | 9 | 9 | 9 | 12 | 12 |
| 53 | 0 | 9 | 9 | 9 | 9 | 9 |
aCAUTION: The results cannot be safely extrapolated to solutions with formulas other than the ones tested. See text.
Calcium and phosphate compatibility was evaluated in a series of parenteral nutrition admixtures composed of Aminosyn II in concentrations ranging from 2% up to 5% (TPN #227 to #231 in Appendix). The solutions also contained dextrose ranging from 10% up to 25%. Also present were sodium chloride, potassium chloride, and magnesium sulfate in common amounts. Phosphates as the potassium salt and calcium as the acetate salt were added in variable quantities to determine the maximum amounts of calcium and phosphates that could be added to the representative TPN admixtures. The samples were evaluated at 23 and 37°C over 48 hours by visual inspection in ambient light and using a Tyndall beam and electronically measured for turbidity and microparticulates. The boundaries between the compatible and incompatible concentrations were presented graphically as hyperbolic curves.2265
The solubility of calcium acetate versus calcium gluconate with sodium phosphates was evaluated in pediatric parenteral nutrition solutions following storage for 30 hours at 25°C followed by 30 minutes at 37°C. Concentrations of Aminosyn PF studied varied from 1 to 3%, dextrose from 10 to 25%, calcium from 5 to 60 mEq/L, and phosphate from 1 to 60 mmol/L. L-cysteine hydrochloride at a dose of 40 mg/g of Aminosyn PF, magnesium 3.2 mEq/L, and pediatric trace elements-4 at 2.4 mL/L of pediatric parenteral nutrition solution were also added. Calcium acetate was found to be less soluble than calcium gluconate when prepared under these concentrations. The maximum concentrations of the calcium salts and sodium phosphates are shown in Table 10. Polarized light microscopy was used to identify the calcium acetate and sodium phosphate crystals adherent to the container walls because simple visual observation was not able to identify the precipitates. The authors recommended the use of calcium acetate to reduce the iatrogenic aluminum exposure often seen with calcium gluconate in the neonatal population receiving parenteral nutrition.2466 However, care must be taken to avoid inadvertent calcium phosphate precipitation at the lower concentrations found with calcium acetate if it is substituted for the gluconate salt to reduce aluminum exposure.
Table 10. Maximum Concentrations of Sodium Phosphates and Calcium as Acetate and as Gluconate Not Resulting in Precipitation2466
| Aminosyn PF (%) | Sodium Phosphates (mmol/L) | Calcium Acetate (mEq/L) | Calcium Gluconate (mEq/L) |
|---|---|---|---|
| 1 | 10 | 25 | 50 |
| 1 | 15 | 15 | 25 |
| 2 | 10 | 30 | 45 |
| 2 | 25 | 10 | 12.5 |
| 3 | 20 | 10 | 15 |
| 3 | 25 | 15 | 17.5 |
Calcium and phosphate compatibility was evaluated in a series of adult formula parenteral nutrition admixtures composed of FreAmine III, in concentrations ranging from 1 to 5% (TPN #258 through #262). The solutions also contained dextrose ranging from 15% up to 25%. Also present were sodium chloride, potassium chloride, and magnesium sulfate in common amounts. Cysteine hydrochloride was added in an amount of 25 mg/g of amino acids from FreAmine III to reduce the pH by about 0.5 pH unit and thereby increase the amount of calcium and phosphates that can be added to the TPN admixtures as has been done with pediatric parenteral nutrition admixtures. Phosphates as the potassium salts and calcium as the gluconate salt were added in variable quantities to determine the maximum amounts of calcium and phosphates that could be added to the test admixtures. The samples were evaluated at 23 and 37°C over 48 hours by visual inspection in ambient light and using a Tyndall beam and electronic measurement of turbidity and microparticulates. The addition of the cysteine hydrochloride resulted in an increase of calcium and phosphates solubility of about 30% by lowering the solution pH 0.5 pH unit. The boundaries between the compatible and incompatible concentrations were presented graphically as hyperbolic curves.2469
A 2-in-1 parenteral nutrition admixture with final concentrations of TrophAmine 0.5%, dextrose 5%, L-cysteine hydrochloride 40 mg/g of amino acids, calcium gluconate 60 mg/100 mL, and sodium phosphates 46.5 mg/mL was found to result in visible precipitation of calcium phosphate within 30 hours stored at 23 to 27°C. Despite the presence of the acidifying L-cysteine hydrochloride, precipitation occurred at clinically utilized amounts of calcium and phosphates.2622
The presence of magnesium in solutions may also influence the reaction between calcium and phosphate, including the nature and extent of precipitation.158; 159
The interaction of calcium and phosphate in parenteral nutrition solutions is a complex phenomenon. Various factors play a role in the solubility or precipitation of a given combination, including:608; 609; 1042; 1063; 1427; 2038; 2039; 2061
Enhanced precipitate formation would be expected from such factors as high concentrations of calcium and phosphate, increases in solution pH, decreased amino acid concentrations, increases in temperature, addition of calcium prior to the phosphate, lengthy standing times or slow infusion rates, and use of calcium as the chloride salt.854
Even if precipitation does not occur in the bottle, it has been reported that crystallization of calcium phosphate may occur in a Silastic infusion pump chamber or tubing if the rate of administration is slow, as for premature infants. Water vapor may be transmitted outward and be replaced by air rapidly enough to produce supersaturation.202 Several other cases of catheter occlusion also have been reported.610; 1427; 1428; 1429
Vitamins
As might be expected, vitamin stability has been found to be better during nighttime when compared to daytime because of the influence of photodecomposition.2307
A patient receiving 3000 international units of retinol daily in a parenteral nutrition solution, nevertheless, experienced 2 episodes of night blindness. The pharmacy prepared the parenteral nutrition solution in 1-L PVC bags in weekly batches and stored them at 4°C in the dark until use. A subsequent in vitro study showed losses of vitamin A of 23 and 77% in 3- and 14-day periods, respectively, under these conditions. About 30% of the lost vitamin A could be extracted from the PVC bag.1038
Losses of vitamin A from multivitamins (USV) in a neonatal parenteral nutrition solution was reported. The solution was prepared in colorless glass bottles and run through an administration set with a burette (Travenol). The total loss of vitamin A was 75% in 24 hours, with about 16% as decomposition in the glass bottle. The decomposition was not noticeable during the first 12 hours, but then vitamin A levels fell rather precipitously to about one-third of the initial amount. The balance of the loss, averaging about 59%, occurred during transit through the administration set. Removal of the inline filter and treatment of the set with albumin human had no effect on vitamin A delivery. The authors recommended a threefold to fourfold increase in the amount of vitamin A to compensate for the losses.1039
A parenteral nutrition solution in glass bottles exposed to sunlight was reported. Vitamin A decomposed rapidly, losing more than 50% in 3 hours. The decomposition could be slowed by covering the bottle with a light-resistant vinyl bag, resulting in about a 25% loss in 3 hours.1040
Vitamin E was stable in the parenteral nutrition solution in glass bottles exposed to sunlight, with no loss occurring during 6 hours of exposure.1040
It was reported that 40% retinol losses occurred in 2 hours and 60% in 5 hours from parenteral nutrition solutions pumped at 10 mL/hr through standard infusion sets at room temperature. The retinol concentration in the bottle remained constant while the retinol in the effluent decreased. Antioxidants had no effect. Much of the vitamin A was recoverable from hexane washings of the tubing.1050
The delivery of vitamins A, D, and E from a parenteral nutrition solution composed of amino acids 3% solution (Pharmacia) in dextrose 10% with electrolytes, trace elements, vitamin K, folate, and vitamin B12 was evaluated. To this solution was added 6 mL of multivitamin infusion (USV). The solution was prepared in PVC bags (Travenol), and administration was simulated through a fluid chamber (Buretrol) and infusion tubing with a 0.5-µm filter at 10 mL/hr. During the first 60 to 90 minutes, minimal delivery of the vitamins occurred. This was followed by a rise and plateau in the delivered vitamins, which were attributed to an increasing saturation of adsorptive binding sites in the tubing. Total amounts delivered over 24 hours were 31% for vitamin A, 68% for vitamin D, and 64% for vitamin E. Sorption of the vitamins was found in the PVC bag, fluid chamber, and tubing. Decomposition was not a factor.836
Vitamin A was found to rapidly and significantly decompose when exposed to daylight. The extent and rate of loss were dependent on the degree of exposure to daylight which, in turn, depended on various factors such as the direction of the radiation, time of day, and climatic conditions. Delivery of less than 10% of the expected amount was reported.1047 In controlled light experiments, the decomposition initially progressed exponentially. Subsequently, the rate of decomposition slowed. This result was attributed to a protective effect of the degradation products on the remaining vitamin A. The presence of amino acids provided greater protection. Compared to degradation rates in dextrose 5%, decomposition was reduced by up to 50% in some amino acid mixtures.1048
In a parenteral nutrition solution composed of amino acids, dextrose, electrolytes, trace elements, and multivitamins in PVC bags stored at 4 and 25°C, vitamin A rapidly deteriorated to 10% of the initial concentration in 8 hours at 25°C while exposed to light. The decomposition was slowed by light protection and refrigeration, with a loss of about 25% in 4 days. Folic acid concentration dropped 40% initially on admixture and then remained relatively constant for 28 days of storage. About 35% of the ascorbic acid was lost in 39 hours at 25°C with exposure to light. The loss was reduced to a negligible amount in 4 days by refrigeration and light protection. Thiamine content dropped by about 50% initially but then remained unchanged over 120 hours of storage.1063
A 50% loss of vitamin A from a bottle of parenteral nutrition solution prepared with multivitamin infusion (USV) after 5.5 hours of infusion was noted. The amount delivered through an Ivex-2 filter set was only 6.3% of the added amount. Similar quantities were found after 20 hours of infusion. A reduced light exposure and use of 3H-labeled vitamin A confirmed binding to the infusion bottles and tubing.704
Subsequently, solutions containing multivitamins (USV) spiked with 3H-labeled retinol were incubated in intravenous tubing protected from light and agitated to simulate flow for 5 hours. About half of the vitamin A was lost in 30 minutes, and 88 to 96% was lost in 5 hours. Spectrophotometric assays correlated closely with the radioisotope assays. Hexane rinses and radioactivity determinations on the tubing accounted for the decrease in radioactivity.1049
In another experiment, neonatal parenteral nutrition solutions containing multivitamins prepared in bags were delivered at 10 mL/hr through Buretrol sets (Travenol). The bags and sets were protected from light. Spectrophotometric and radioisotope assays showed that about 26% of the vitamin A was lost before the flow was started. At 10 mL/hr, about 67% was lost from the effluent. More rapid flow reduced the extent of loss. Analysis of clinical samples of parenteral nutrition solutions showed losses of 21 to 57% after 20 hours. Because losses after 5 hours were of the same magnitude, the authors concluded that the loss occurs fairly rapidly and is not due to gradual decomposition.1049
The quantity of retinol delivered from an M.V.I.-containing 2-in-1 parenteral nutrition solution and when M.V.I. was added to Intralipid 10% was evaluated during simulated administration through a PVC administration set. The parenteral nutrition solution was composed of amino acids 2.8%, dextrose 10%, and standard electrolytes; M.V.I. was added to yield a nominal retinol concentration of 455 mcg/150 mL. Retinol losses were about 80% of the admixed amount after being delivered through the PVC set. When M.V.I. was added to Intralipid 10% in a retinol concentration of 455 mcg/20 mL, retinol losses were reduced to about 10% of the admixed amount. The lipid emulsion provides retinol protection from sorption to the PVC administration set.2027
Substantially higher amounts of retinol were found to be delivered using polyolefin administration set tubing when compared with PVC tubing during simulated neonatal intensive care administration. Retinol was added to a 2-in-1 parenteral nutrition solution (TPN #206) in concentrations of 25 and 50 international units/mL and run at 4 and 10 mL/hr through 3 meter lengths of polyolefin (MiniMed) and PVC (Baxter) intravenous extension set tubing protected from light and passed through a 37°C water bath. Delivered quantities of retinol varied from 19 to 74% through the PVC tubing and 47 to 87% through the polyolefin tubing. The authors noted that the loss of retinol to the PVC tubing appeared to be saturable. Even so, the use of polyolefin tubing increases the amount of retinol delivered during simulated neonatal administration.2028
Substantial loss of retinol all-trans palmitate and phytonadione from both TPN and TNA admixtures due to exposure to sunlight was reported. In 3 hours of exposure to sunlight, essentially total loss of retinol and 50% loss of phytonadione had occurred. The presence or absence of lipids did not affect stability. In contrast, tocopherol concentrations remained essentially unchanged by exposure to sunlight through 12 hours. The container material used to store the nutrition admixtures affected the concentration of the vitamins as well. Losses were greatest (10 to 25%) in PVC containers and were slightly better in EVA and glass containers.2049
The photodegradation of vitamins A and E in a 2-in-1 (Synthamin 9, dextrose 20%) admixture and a 3-in-1 (Synthamin 9, dextrose 20%, Intralipid 20%, electrolytes, vitamins, trace elements) admixture after exposure to 6 hours of indirect daylight was reported. The compounded admixtures were prepared in multilayer bags protected from light and stored at 5°C for a minimum of 5 days. The same admixtures were prepared in EVA bags 24 hours prior to use with vitamins added prior to study. Vitamin A decreased to 60 to 80% of the initial concentrations in 2 to 6 hours of exposure to indirect daylight. The type of bag had no influence on the photodegradation of vitamin A. Despite lipid emulsion, no significant light protection was noted with the 3-in-1 admixture. Vitamin E losses were 15% in 6 hours with multilayer bags of both admixtures; however, 100% loss was noted with EVA bags within 1 hour for the 2-in-1 admixture. The presence of the opaque lipid emulsion provided some protection; however, losses greater than 50% were noted by 6 hours in the EVA bags. The authors concluded that the use of multilayer bags prevents vitamin E losses during daylight exposure as compared to EVA bags but only light protection can minimize vitamin A losses.2459
The stability of retinol palmitate and tocopherols (d, ?, and a) in 3-in-1 admixtures of amino acids 4%, dextrose 10%, lipid emulsion 3% (Intralipid, Liposyn, and ClinOleic), various electrolytes, vitamins, and trace elements in EVA bags over 3 days at 4, 25, and 37°C was evaluated. Retinol palmitate was found to be unstable at room temperature with 33 and 50% degradation at 24 and 72 hours after compounding, respectively. Refrigeration of the admixture reduced the degradation to 29% at 72 hours. The tocopherols displayed varying stability over the temperature range with 16 to 25% degradation after 72 hours. The variation in the tocopherols was theorized to be from the free conversion between the oxidized and reduced forms over the temperatures tested.2460
The stability of vitamin E (alpha-tocopherol acetate from M.V.I.-1000 or Soluzyme) and selenium (from Selepen) in amino acids (Abbott) and dextrose in PVC bags was evaluated. Exposure to fluorescent light and room temperature (23°C) for 24 hours and simulated infusion at 50 mL/hr for 8 hours through a Medlon TPN administration set with a 0.22-µm filter did not affect the concentrations of vitamin E and selenium.1224
The stability of numerous vitamins in parenteral nutrition solutions composed of amino acids (Kabi-Vitrum), dextrose 30%, and lipid emulsion 20% (Kabi-Vitrum) in a 2:1:1 ratio with electrolytes, trace elements, and both fat- and water-soluble vitamins was reported. The admixtures were stored in darkness at 2 to 8°C for 96 hours with no significant loss of retinyl palmitate, alpha-tocopherol, thiamine mononitrate, sodium riboflavin-5'-phosphate, pyridoxine hydrochloride, nicotinamide, folic acid, biotin, sodium pantothenate, and cyanocobalamin. Sodium ascorbate and its biologically active degradation product, dehydroascorbic acid, totaled 59 and 42% of the nominal starting concentration at 24 and 96 hours, respectively. However, the actual initial concentration was only 66% of the nominal concentration.1225
When the admixture was subjected to simulated infusion over 24 hours at 20°C, either exposed to room light or light protected, or stored for 6 days in the dark under refrigeration and then subjected to the same simulated infusion, once again the retinyl palmitate, alpha-tocopherol, and sodium riboflavin-5'-phosphate did not undergo significant loss. However, sodium ascorbate and its degradation product, dehydroascorbic acid, had initial combined concentrations of 51 to 65% of the nominal initial concentration, with further declines during infusion. Light protection did not significantly alter the loss of total ascorbic acid.1225
The stability of several vitamins from M.V.I.-12 (Armour) admixed in parenteral nutrition solutions composed of different amino acid products, with or without Intralipid 10%, when stored in glass bottles and PVC bags at 25 and 5°C for 48 hours was reported. Riboflavin, folic acid, and vitamin E were stable in all samples. No vitamin A was lost in any formula in glass bottles, but samples in PVC containers lost as much as 35 and 60% at 5 and 25°C, respectively, in 48 hours. Thiamine hydrochloride was stable in the parenteral nutrition solutions prepared with amino acid products without sulfites. However, amino acid products containing sulfites (Travasol and FreAmine III) had a 25% thiamine loss in 12 hours and a 50% loss in 24 hours when the solutions were stored at 25°C; no loss occurred when the solutions were stored at 5°C. Ascorbic acid was lost from all samples stored at 25°C, with the greatest losses occurring in solutions stored in plastic bags. No losses occurred in any sample stored at 5°C.1431
In another study, the stability of vitamins A, E, C, riboflavin, thiamine, and folic acid following admixture (as M.V.I.-12) with 4 different amino acid products (Novamine, Neopham, FreAmine III, Travasol) with or without Intralipid when stored in glass bottles or PVC bags at 25°C for 48 hours was reported. They found that high-intensity phototherapy light did not affect folic acid, thiamine, or vitamin E; however, ascorbic acid and riboflavin losses were significant with all amino acid products tested. Furthermore, it was noted that vitamin A losses were reduced with the addition of Intralipid to the admixture. When bisulfite was added to the Neopham admixture, riboflavin, folic acid, and ascorbic acid were not affected; however, at a bisulfite concentration of 3 mEq/L, there was substantial losses of vitamin A and thiamine. The authors also noted that ascorbic acid losses were increased with a more alkaline pH and that bisulfite addition offered some protection presumably by bisulfite being preferentially oxidized. The authors concluded that intravenous multivitamins should be added to parenteral nutrition admixtures immediately prior to administration to reduce losses since commercially available amino acid products may contain bisulfites and have varying pH values.487
The stability of 5 B vitamins was studied over an 8-hour period in representative parenteral nutrition solutions exposed to fluorescent light, indirect sunlight, and direct sunlight. One 5-mL vial of multivitamin concentrate (Lyphomed) and 1 mg of folic acid (Lederle) were added to a liter of parenteral nutrition solution composed of amino acids 4.25%-dextrose 25% (Travenol) with standard electrolytes and trace elements. All 5 B vitamins tested were stable for 8 hours at room temperature when exposed to fluorescent light. In addition, folic acid and niacinamide were stable over 8 hours in direct or indirect sunlight. Exposure to indirect sunlight appeared to have little or no effect on thiamine hydrochloride and pyridoxine hydrochloride in 8 hours, but 47% of riboflavin-5'-phosphate was lost in that period. Direct sunlight caused a 26% loss of thiamine hydrochloride and an 86% loss of pyridoxine hydrochloride in 8 hours. Four-hour exposures of riboflavin-5'-phosphate to direct sunlight resulted in a 98% loss.842
The effects of photoirradiation on a FreAmine II-dextrose 10% parenteral nutrition solution containing 1 mL/500 mL of multivitamins (USV) were evaluated. During simulated continuous administration to an infant at 0.156 mL/min, no changes to the amino acids occurred when the bottle, infusion tubing, and collection bottle were shielded with foil. Only 20 cm of tubing in the incubator was exposed to light. However, if the flow was stopped, a marked reduction in methionine (40%), tryptophan (44%), and histidine (22%) occurred in the solution exposed to light for 24 hours. In a similar solution without vitamins, only the tryptophan concentration decreased. The difference was attributed to the presence of riboflavin, a photosensitizer. The authors recommended administering the multivitamins separately and shielding from light.833
In further work, the authors simulated more closely conditions occurring during phototherapy in neonatal intensive care units. Riboflavin 1 mg/100 mL was added to a solution of amino acids 2% (Abbott) with dextrose 10%. Infusion was simulated from glass bottles through PVC tubing with a Buretrol at a rate of 4 mL/hr. In addition to the fluorescent room lights, 8 daylight bulbs delivered phototherapy. After a simulated 24-hour infusion, riboflavin decreased to about 50% of its initial level. Also, a 7% reduction in total amino acids was noted, including individual losses of glycine (10%), leucine (14%), methionine (24%), proline (10%), serine (9%), tryptophan (35%), and tyrosine (16%). Although the authors did not believe that these losses of amino acids were nutritionally important, they were concerned about the possibility of toxicity from photo-oxidation products. In the same solution without riboflavin, the individual amino acids decreased only slightly.974
The extent and rapidity of ascorbic acid decomposition in parenteral nutrition solutions composed of amino acids, dextrose, electrolytes, multivitamins, and trace elements in 3-L PVC bags stored at 3 to 7°C was reported. About 30 to 40% was lost in 24 hours. The degradation then slowed as the oxygen supply was reduced to the diffusion through the bag. About a 55 to 65% loss occurred after 7 days of storage. The oxidation was catalyzed by metal ions, especially copper. In the absence of copper from the trace elements additive, less than 10% degradation of ascorbic acid occurred in 24 hours. The author estimated that 150 to 200 mg is degraded in 2 to 4 hours at ambient temperature in the presence of copper but that only 20 to 30 mg is broken down in 24 hours without copper. To minimize ascorbic acid loss, copper must be excluded. Alternatively, inclusion of excess ascorbic acid was suggested.1056
Extensive decomposition of ascorbic acid and folic acid was reported in a parenteral nutrition solution composed of amino acids 3.3%, dextrose 12.5%, electrolytes, trace elements, and M.V.I.-12 (USV) in PVC bags. Half-lives were 1.1, 2.9, and 8.9 hours for ascorbic acid and 2.7, 5.4, and 24 hours for folic acid stored at 24°C in daylight, 24°C protected from light, and 4°C protected from light, respectively. The decomposition was much greater than for solutions not containing catalyzing metal ions. Also, it was greater than for the vitamins singly because of interactions with the other vitamins present.1059
The stability of ascorbic acid in parenteral nutrition solutions, with and without lipid emulsion, was studied. Both with and without lipid emulsion, the total vitamin C content (ascorbic acid plus dehydroascorbic acid) remained above 90% for 12 hours when the solutions were exposed to fluorescent light and for 24 hours when they were protected from light. When stored in a cool dark place, the solutions were stable for 7 days.1227
The stability of several vitamins from M.V.I.-12 (Armour) admixed in parenteral nutrition solutions composed of different amino acid products, with or without Intralipid 10%, when stored in glass bottles and PVC bags at 25 and 5°C for 48 hours was reported. Ascorbic acid was lost from all samples stored at 25°C, with the greatest losses occurring in solutions stored in plastic bags. No losses occurred in any sample stored at 5°C.1431
The stability of ascorbic acid and dehydroascorbic acid in a 3-in-1 admixture containing Vamin 14, dextrose 30%, Intralipid 20%, potassium phosphate, Cernevit, and trace elements in EVA bags over a temperature range of 2 to 22°C was examined. They observed an 89% loss of ascorbic acid and a 37% loss of dehydroascorbic acid over 7 days. The authors concluded that oxygen, trace elements, temperature, and an underfilled bag were the greatest determinants of ascorbic acid loss.2462
The long-term stability of ascorbic acid in 3-in-1 admixtures containing amino acids (Eloamin) 10%, dextrose 20%, dextrose 5%, lipid emulsion (Elolipid) 20%, calcium gluconate, M.V.C. 9 + 3, and trace elements mixed in EVA and multilayer (Ultrastab) bags at 5°C was compared. Ascorbic acid losses were greater than 75% in the first 24 hours and 100% after 48 to 72 hours in the EVA bags. In the multilayer bags, ascorbic acid showed a 20 and 40% loss over the first 24 hours with and without lipid emulsion, respectively. The initial rapid fall in ascorbic acid was presumably due to the initial oxygen content of the admixtures despite the use of the less oxygen-permeable multilayer bags. The authors noted the ascorbic acid concentration remained stable for up to 28 days in the multilayer bags after the initial fall and recommended adding additional ascorbic acid to compensate for the losses to facilitate extended shelf-life.2463
The influence of several factors on the rate of ascorbic acid oxidation in parenteral nutrition solutions was evaluted. Ascorbic acid is regarded as the least stable component in TPN admixtures. The type of amino acid used in the TPN was important. Some, such as FreAmine III and Vamin 14, contain antioxidant compounds (e.g., sodium metabisulfite or cysteine). Ascorbic acid stability was better in such solutions compared with those amino acid solutions having no antioxidant present. Furthermore, the pH of the solution may play a small role, with greater degradation as the pH rises from about 5 to about 7. Adding air to a compounded TPN container can also accelerate ascorbic acid decomposition. The most important factor was the type of plastic container used for the TPN. EVA containers (Mixieva, Miramed) allow more oxygen permeation, which results in substantial losses of ascorbic acid in relatively short time periods. In multilayer TPN bags (Ultrastab, Miramed) designed to reduce gas permeability, the rate of ascorbic acid degradation was greatly reduced. TPNs without antioxidants packaged in EVA bags were found to have an almost total loss of ascorbic acid activity occurring in 1 or 2 days at 5°C. In contrast, in TPNs containing FreAmine III or Vamin 14 packaged in the multilayer bags, most of the ascorbic acid content was retained for 28 days at 5°C. The authors concluded that TPNs made with antioxidant-containing amino acids and packaged in multilayer bags that reduce gas permeability can safely be given extended expiration dates and still retain most of the ascorbic acid activity.2163
The initial degradation product of ascorbic acid (dehydroascorbic acid) in a 2-in-1 admixture containing Synthamin 14, glucose 20%, and trace elements over a temperature range of 5 to 35°C was evaluated. The presence of trace elements, including copper, had no influence on the degradation of dehydroascorbic acid. At room temperature and 5°C, there was a greater than 50% loss of dehydroascorbic acid noted within 2 and 24 hours, respectively. The authors concluded this degradation was temperature dependent.2461
The degradation of vitamins A, B1, C, and E from Cernevit (Roche) multivitamins in NuTRIflex Lipid Plus (B. Braun) admixtures prepared in ethylene vinyl acetate (EVA) bags and in multilayer bags was evaluated. After storage for up to 72 hours at 4, 21, and 40°C, greater vitamin losses occurred in the EVA bags: vitamin A (retinyl palmitate) losses were 20%, thiamine hydrochloride losses were 25%, alpha-tocopherol losses were 20%, and ascorbic acid losses were approximately 80 to 100%. In the multilayer bags (presumably a better barrier to oxygen transfer), losses were less: vitamin A (retinyl palmitate) losses were 5%, thiamine hydrochloride losses were 10%, alpha-tocopherol losses were 0%, and ascorbic acid losses were approximately 25 to 70%.2618
Phytonadione stability in a TPN solution containing amino acids 2%, dextrose 12.5%, “standard” electrolytes, and multivitamins (M.V.I. Pediatric) was evaluated over 24 hours while exposed to light. Vitamin loss, about 7% in 4 hours and 27% in 24 hours, was attributed partly to the light sensitivity of phytonadione.1815
Trace Elements
Because of interactions, recommendations to separate the administration of vitamins and trace elements have been made.1056; 1060; 1061 Others have termed such recommendations premature based on differing reports895; 896 and the apparent absence of epidemic vitamin deficiency in parenteral nutrition patients.1062
The addition of trace elements to a 3-in-1 parenteral nutrition solution with electrolytes had no adverse effect on the particle size of the lipid emulsion after 8 days of storage at 4°C.1017
The stability of a 3-in-1 parenteral nutrition mixture (TNA #191 in Appendix) was compared with trace elements added as gluconate salts or chloride salts. TNA #191 with copper 0.24 mg/L, iron 0.5 mg/L, and zinc 2 mg/L in either salt form was physically stable for 7 days at 4 and 25°C.1787
Trace elements additives, especially those containing copper ions, have the potential to be incompatible in TPN solutions, resulting in precipitation. In a TPN admixture containing 5% Synthamin 17, 25% dextrose, 1 g of ascorbic acid injection, 14 mmol of calcium chloride, and trace elements solution (David Bull), storage at 20 to 25°C and 2 to 8°C, protected from light, resulted in the formation of a discolored solution in 3 to 7 days and an off-white to yellow precipitate in 8 to 12 days, respectively. Electron microscopy revealed the presence of numerous bipyramidal, 8-sided crystals in sizes from 3 to 30 µm. The authors proposed that the crystals were calcium oxalate. They suggested that the ascorbic acid decomposed to oxalic acid; the oxalic acid then interacted with calcium ions to form calcium oxalate. The authors did not verify their supposition. They noted that the crystals were conformationally different from calcium phosphate crystals and that no phosphate had been added to the admixture. In addition, mixing ascorbic acid injection 500 mg/5 mL with trace elements solution 5 mL results in the formation of a transparent gel that becomes an opaque flocculent precipitate after 5 minutes. The authors recommended adding trace elements well away from injections that can act as ligands and with thorough mixing after each addition. Introduction of air and prolonged storage should be avoided. Incorporating trace elements and ascorbic acid on alternate days was also suggested.2197
The chromium and zinc contamination of various components of parenteral nutrition solutions by atomic absorption spectrophotometry was evaluated. They analyzed FreAmine III, Aminosyn, TrophAmine, and dextrose 70% and found chromium concentrations were below the limit of detection but zinc ranged from 0.11 to 4.97 mg/L. Additionally, detectable chromium and zinc concentrations were seen with various lots of L-cysteine, potassium and sodium salts (chloride, acetate, and phosphate), calcium gluconate, and magnesium sulfate. The zinc contamination was thought to be a product of manufacturing procedures as it is present in many rubber stoppers and in the materials to produce glass. The authors suggested that the amount of contamination of chromium and zinc present in most pediatric parenteral nutrition solutions may exceed current recommendations, especially for infants less than 10 kg.2464
Heparin
Flocculation of lipid emulsion (Kabi-Vitrum) was reported during Y-site administration into a line used to infuse a parenteral nutrition admixture containing both calcium gluconate and heparin sodium. Subsequent evaluation indicated that the combination of calcium gluconate (0.46 and 1.8 mmol/125 mL) and heparin sodium (25 and 100 units/125 mL) in amino acids plus dextrose induced flocculation of the lipid emulsion within 2 to 4 minutes at concentrations that resulted in no visually apparent flocculation in 30 minutes with either agent alone.1214
Calcium chloride quantities of 1 and 20 mmol normally result in slow flocculation of lipid emulsion 20% over several hours. When heparin sodium 5 units/mL was added, the flocculation rate was accelerated greatly and a cream layer was observed visually in a few minutes. This effect was not observed when sodium ion was substituted for the divalent calcium.1406
Similar results were observed during simulated Y-site administration of heparin sodium into nine 3-in-1 nutrient admixtures having different compositions. Damage to the lipid emulsion component was found to occur immediately, with the possible formation of free oil over time.2215
The destabilization of lipid emulsion (Intralipid 20%) was also observed when administered simultaneously with a TPN admixture and heparin. The damage, detected by viscosity measurement, occurred immediately upon contact at the Y-site. The extent of the destabilization was dependent on the concentration of heparin and the presence of MVI Pediatric with its surfactant content. Additionally, phase separation was observed in 2 hours. The authors noted that TPN admixtures containing heparin should never be premixed with lipid emulsion as a 3-in-1 total nutrient admixture because of this emulsion destabilization. The authors indicated their belief that the damage could be minimized during Y-site co-administration as long as the heparin was kept at a sufficiently low concentration (no visible separation occurred at a heparin concentration of 0.5 unit/mL) and the length of tubing between the Y-site and the patient was minimized.2282
However, because the damage to emulsion integrity has been found to occur immediately upon mixing with heparin in the presence of the calcium ions in TPN admixtures1214; 2215; 2282 and no evaluation and documentation of the clinical safety of using such destabilized emulsions has been performed, use of such damaged emulsions is suspect.
Other Information
Titratable Acidity
The acidity of parenteral nutrition solutions can be a factor in the development of metabolic acidosis by a patient.577; 851 Titratable acidity is a measure of the hydrogen ion content that must be neutralized to raise the pH to a given endpoint and is often expressed as milliequivalents of titrant per liter of reactant. In a study577 of 5 amino acid injections and mixtures, the titratable acidities were determined for pH 7.4 by titrating with 0.1220 N sodium hydroxide and 7.54% (0.898 M) sodium bicarbonate. The results are noted in Table 11.
Table 11. Titratable Acidity of Several Amino Acids Products577
| Titratable Acidity | ||
|---|---|---|
| NaOH (mEq/L) | NaHCO3 (mEq/L) | |
| Aminosyn 7% | 37 | 314 |
| FreAmine II 8.5% | 16.8 | 176 |
| Travasol 8.5% | 34.7 | 354 |
| Travasol 8.5% with electrolytes | 45.2 | 420 |
Corresponding (although somewhat lower) values were also obtained for 1:1 mixtures with dextrose 50%. It was concluded that use of sodium bicarbonate to adjust to pH 7.4 was not usually feasible given the large volumes of fluid and increased sodium ion required. However, smaller amounts could be used for smaller pH adjustments.577
ReferencesFor a list of references cited in the text of this monograph, search the monograph titled References.