Incompatibilities of TPN & IV admixtures

1. Dr. Shahroz Siddiqui (Pharm.D , BCSCP)
Inpatient & Sterile area Pharmacist
ABDULLAH BIN OMRAN HOSPITAL, RAK
MINISTRY OF HEALTH & PREVENTION, UAE

2.  When one drug is mixed with others and produces an unsuitable product/s by some physicochemical
means that are no longer safe or effective for the patient.
 Stability generally refers to the loss or degradation of the admixed ingredients over time.
Compatibility relates to the physical and chemical interaction between ingredients.
 Like drug Sterility is important, drug Stability and Compatibility are also critically important in
the provision of safe and effective drug therapy.
 The TPN formulation is a complex mixture containing up to 40 different chemical components that
may cause problems with stability and compatibility. Serious harm and death have resulted from
improperly compounded parenteral feeding formulations.

3. Note : Like all side effects of drug are not necessarily adverse effects,
Similarly NOT all incompatibilities are dangerous, some are just normal.
 Color Change ( Imipenem-cilastatin or dobutamine may show some color change but NOT a sign of
incompatibility.)
 Hazy Appearance ( When ceftazidime is reconstituted, carbon dioxide gas is released and can cause
a hazy appearance.)
 Precipitations ( The precipitate that forms when paclitaxel is refrigerated dissolves again at room
temperature)
 Crystallization ( Mannitol crystalize at low temperature storage, so prior to administration re-
dissolve by warming the solution up to 37°C, followed by gentle agitation.)

5.  Light : Vitamin B complex, Linezolid and Acetylcysteine must be protected from light.
 Temperature : Cefazolin is stable at room temperature for 24 hours but under refrigeration for 9 days.
 Dilution : To maintain stability of Ferric carboxymaltose, do not dilute less than 2 mg iron/mL normal
saline.
 Concentration dependent : Meropenem higher concentrations tend to decompose faster in solution, it is
recommended to use 1 to 20 mg/mL final concentration.
 Buffer capacity/pH : Phenytoin precipitation caused by mixing with a solution that lowers its pH (e.g.
Dextrose 5%)
 Time : Infusing the TPN solution within 24 hours after preparation.
Albumin vial must be infused within 4 hours after opening

6. 1) Propofol and lidocaine incompatibility, resulting in layering and coalescence of propofol’s
vehicle
2) Phenytoin precipitation caused by mixing with a solution that lowers its pH (e.g. Dextrose 5%)

7.  1. Therapeutic Incompatibility (Aminoglycosides like gentamicin inactivated by high concentration
penicillin if infused at same time )
 2. Physical Incompatibility ( Propofol and lidocaine incompatibility, resulting in layering and
coalescence of propofol’s vehicle)
 3. Chemical Incompatibility (Amphotericin B dilution must be in Dextrose, never be performed with
a electrolyte solutions like sodium chloride solution or other chloride-containing solutions.)
Meropenem incompatible with Dextrose, diluted only with Normal Saline.
 4. Drug IV Container Incompatibilities : Paclitaxel solutions should preferably be stored in glass
bottles because plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC
infusion bags or sets.
Insulin and Diazepam adsorbs to Plastic/PVC used for intravenous (IV) tubing.

9.  Three factors for incompatibilities with parenteral nutrition
1: Precipitation of calcium and phosphate
2: Creaming/Cracking of the lipid emulsion
3: TPN & Drug Incompatibility (Addition/simultaneous application of drugs to/with the PN.)

10.  Ca & PO4 are common essential electrolytes in PN solutions. If mixed in too high concentration,
calcium and phosphorus may form an insoluble precipitate of calcium phosphate. causing a variety
of conditions, such as pulmonary emboli and respiratory distress, and in some cases even death.
 This concern is especially critical for pediatric and neonatal populations, where high concentrations
of calcium and inorganic phosphates are needed.
 This is especially problematic in Total nutrient admixture (TNA/ “3 in 1”) because
(a) the lipid emulsion clouds the solution, making it nearly impossible to visually detect a precipitate
and
(b) 1.2 micron TNA filters do not remove some calcium phosphate precipitates. (Unlike “2 in 1” TPN,
which is filtered by 0.22 micron filters)
 The smaller pore size filter does eliminate a greater amount of particulate matter, including some bacteria (Staphylococcus
epidermidis, Escherichia coli) than does the larger pore size; however, the 1.2-µm filter is adequate to remove precipitates (calcium-
phosphate) and particulate matter as well as large organisms, including C albicans.

11.  Order of mixing (avoiding mixing Ca and PO₄³⁻ in close sequence during preparation)
 Calcium salt used (using Ca Gluconate instead of Ca Chloride)
 Concentration of electrolytes Ca & PO₄³⁻ (keeping the Ca: PO₄³⁻ mEq ratio greater than 1:2.)
 Total mEq of Ca & PO₄³⁻ per liter of formulation (keeping the total amount of Ca & PO₄³⁻ less than 45 mEq/L.)
 Amino acid concentration ( final amino acid concentration at 2.5% or greater)
 Solubility product (keeping the calcium:phosphorus solubility product less than 150)
 pH of the formulation (final pH of 6.0 or lower). Adding cysteine to the amino acids reduce pH.
 Temperature (precipitation may be reduced by < 20°C )
 Time (Infusing the solution within 24-30 hours of preparation.).
 Total nutrient admixtures compounded with final concentrations of amino acid ≥4%, monohydrated dextrose ≥10%, and IVFE ≥2% are more likely to remain stable for
up to 30 hours at room temperature (25°C) or for 9 days refrigerated (5°C) followed by 24 hours at room temperature according to the A.S.P.E.N

19.  Stability and compatibility issues are especially important for 3-in-1 (total nutrient admixtures
TNA). Destabilization of the lipid component of a TNA formulation can occur under certain
conditions.
 Use of a TNA with evidence of aggregation, coalescence or cracking may be harmful to the patient,
because large triglyceride particles can potentially cause lipid emboli or pulmonary capillary
occlusion.
 If destabilization occurs during administration, it should be discontinued immediately.
 Mild creaming may be reversible with gentle agitation.

21. Stages of TNA destabilization
Creaming
accumulation of triglyceride particles at the top of the emulsion.
Aggregration
clumping of triglyceride particles within the emulsion.
Coalescense
fusion of small triglyceride particles into larger particles.
Cracking
separation of the oil and water components of the emulsion.

22. Order of mixing (Avoiding mixing dextrose and lipid directly). Add lipid last, after all other components
(except vitamins) are mixed.
Dextrose concentration (keeping the final dextrose concentration at 3.3% or greater.)
pH of the formulation (maintaining a final pH of 5.0 or above)
Amino acid concentration (keeping the final amino acid concentration at 2.5% or greater.)
Types of the electrolytes( avoiding trivalent cations ).
Trivalent (iron) > divalent (calcium, magnesium) > monovalent (sodium, potassium) cations may all
cause a decrease in the surface potential of the lipid droplets, resulting in aggregation and coalescence.
Concentration of the electrolytes (Compatibility and the solubility of Ca & PO₄³⁻ are less in TNA
formulations due to higher lipid pH around 8.0)
Divalent concentrations between 16 - 20 mEq/L requiring final concentrations of monohydrated dextrose
>10% and amino acids >4% to prevent lipid destabilization.

23.  The co-infusion of drugs and PN should be avoided.
 Drugs administered to patients receiving PN should be given through a separate IV
site or catheter lumen.
 If a separate site is not available, the drug may be given through a separate line
that has a Y-connection to the PN line as close to the patient as possible. The PN
should not be running and the common tubing must be adequately flushed before
and after drug administration
 No blood products are to be co-infused with PN.

24. 1. Always refer to compatibility references. ( e.g Micromedex IV Compatibilities)
2. verify correct diluent, IV fluid, drug, and final concentration before compounding
3. Order of mixing additives affects the compatibility
4. Minimize the number of drugs mixed together in an IV solution
5. Mix thoroughly when a drug is added to the preparation
6. Use freshly prepared solutions for compounding
7. Solutions should be administered promptly after mixing or within the defined stability & sterility
window.
8. Visually inspect final product after compounding for integrity, leaks, solution cloudiness,
particulates, color, and proper preparation
9. Ensure proper labeling of final IV product with beyond use date and time.(BUD according to
defined stability & sterility, whichever is less)

25. Multiple drugs may be administered simultaneously to a critically ill patient and determining the
compatibility of those agents is of great importance